Molecules: Diazocarbonyl and Related Compounds in The Synthesis of Azoles

molecules
Review
Diazocarbonyl and Related Compounds in the Synthesis
of Azoles
Anton Budeev, Grigory Kantin, Dmitry Dar’in * and Mikhail Krasavin *
Institute of Chemistry, St. Petersburg State University, 198504 Peterhof, Russia; st079949@student.spbu.ru (A.B.);
g.kantin@spbu.ru (G.K.)
* Correspondence: d.dariin@spbu.ru (D.D.); m.krasavin@spbu.ru (M.K.); Tel.: +7-931-3617872 (M.K.);
Fax: +7-812-428-6939 (M.K.)
Abstract: Diazocarbonyl compounds have found numerous applications in many areas of chemistry.
Among the most developed fields of diazo chemistry is the preparation of azoles from diazo com-
pounds. This approach represents a useful alternative to more conventional methods of the synthesis
of azoles. A comprehensive review on the preparation of various azoles (oxazoles, thiazoles, imida-
zoles, pyrazoles, triazoles, and tetrazoles) from diazocarbonyl and related compounds is presented
for the first time along with discussion of advantages and disadvantages of «diazo» approaches
to azoles.
Keywords: diazocarbonyl compounds; azoles; atom economy

1. Introduction
Citation: Budeev, A.; Kantin, G.; Diazo compounds are incredibly useful reagents in synthetic organic chemistry due
Dar’in, D.; Krasavin, M. to their extremely versatile and unique reactivity [1–5]. These compounds are able to un-
Diazocarbonyl and Related dergo transformations with the loss of nitrogen (under catalytic, photochemical, or thermal
Compounds in the Synthesis of decomposition) or with its retention as a constituent part of a reaction product. Along with
Azoles. Molecules 2021, 26, 2530. diazoalkanes, EWG-substituted diazo compounds (diazo-carbonyl, -sulfonyl, -phosphonyl
https://doi.org/10.3390/ compounds, diazonitriles) are extensively used in organic synthesis. The latter stand out due
molecules26092530 to their higher stability, safety, and convenience in handling.
One of the highly demanded applications of diazocarbonyl compounds and other
Academic Editor: Lei Zhou
stabilized analogs is the construction of carbo- and heterocyclic systems. Recently, a range
of new methods have been developed for the synthesis of various heterocycles from diazo
Received: 7 April 2021
compounds, some of which are described in reviews [6–12]. Versatility and efficiency of
Accepted: 22 April 2021
diazo compounds are most clearly manifested in the synthesis of azoles—five-membered
Published: 26 April 2021
heterocycles containing a nitrogen atom and at least one other non-carbon atom of either
nitrogen, oxygen, or sulfur. Diazo reagents allow synthesis of azoles of many types with
Publisher’s Note: MDPI stays neutral
two, three, and four heteroatoms. These heterocycles have found broad application in many
with regard to jurisdictional claims in
published maps and institutional affil-
fields such as organic electronics, functional materials, explosives, dyes, fluorophores, and
iations.
especially medicine. According to the Drug Bank, there are over 300 FDA-approved drugs
containing azole moiety.
However, to our knowledge, there are only a few reviews on the synthesis of azoles
from diazocarbonyl compounds and these reviews are focused on one specific azole class,
namely 1,3-oxazoles [13], pyrazoles [14,15], and 1,2,3-thiadiazoles [16]. This review aims
Copyright: © 2021 by the authors.
to summarize all recent developments in this area covering all types of azoles available
Licensee MDPI, Basel, Switzerland.
from diazocarbonyl and related compounds (oxazoles, thiazoles, imidazoles, pyrazoles,
This article is an open access article
distributed under the terms and
triazoles, tetrazoles, with the exception of 1,2,3-thiadiazoles), as well as to consider earlier
conditions of the Creative Commons
useful methodologies not mentioned in other reviews.
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Molecules 2021, 26, 2530. https://doi.org/10.3390/molecules26092530 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, x FOR PEER REVIEW 2 of 74
Molecules 2021, 26, 2530 2 of 70
2.1. 1,3-Oxazoles
2. Azoles with Two Heteroatoms
1,3-Oxazole (in brief, oxazole) is a privileged motif for drug design. Oxazole deriva-
2.1. 1,3-Oxazoles
tives have shown a broad range of biological activities such as anti-inflammatory, anti-
1,3-Oxazole
bacterial, (in brief,
anticancer, oxazole)
antifungal, is a privileged
antiviral, motif for drug
antihyperglycemic, anddesign.
so on Oxazole deriva-
[17,18]. Numer-
tives have shown a broad range of biological activities such as anti-inflammatory,
ous oxazole medicinal agents are of natural origin. Oxazole alkaloids, including macro- antibac-
terial, anticancer,
lides, cyclic antifungal,
and acyclic antiviral,
peptides, antihyperglycemic,
siderophores, and so onare
and small molecules [17,18].
foundNumerous
in marine
oxazole medicinal agents are of natural origin. Oxazole alkaloids, including macrolides,
invertebrates, bacteria, fungi, and higher plants [19]. Therefore, a vast array of methods
cyclic and acyclic peptides, siderophores, and small molecules are found in marine inver-
for synthesis of 1,3-oxazoles have been developed to date [20].
tebrates, bacteria, fungi, and higher plants [19]. Therefore, a vast array of methods for
Among these methodologies, the following two strategies are rather commonly em-
synthesis of 1,3-oxazoles have been developed to date [20].
ployed: (i) synthesis of 1,3-oxazoles by formal [3+2] cycloaddition between metal carbenes
Among these methodologies, the following two strategies are rather commonly em-
derived from diazo carbonyl compounds and nitriles, and (ii) metal carbene insertion into
ployed: (i) synthesis of 1,3-oxazoles by formal [3+2] cycloaddition between metal carbenes
the N–H bond of amides with subsequent dehydrative cyclization. These routes have been
derived from diazo carbonyl compounds and nitriles, and (ii) metal carbene insertion into
comprehensively reviewed elsewhere [13,21]. In this section, we chose to present only
the N–H bond of amides with subsequent dehydrative cyclization. These routes have been
fairly recent examples of these strategies as well as a few rare approaches to 1,3-oxazoles.
comprehensively reviewed elsewhere [13,21]. In this section, we chose to present only
fairly recent examples of these strategies as well as a few rare approaches to 1,3-oxazoles.
2.1.1. Synthesis of 1,3-Oxazoles by Reaction of Diazocarbonyl Compounds and Nitriles
2.1.1.Since the pioneering
Synthesis work by
of 1,3-Oxazoles of Huisgen
Reaction on the formal [3+2]Compounds
of Diazocarbonyl cycloaddition andbetween
Nitrilesni-
trilesSince
and diazo
the pioneering work of Huisgen on the formal [3+2] cycloadditionemployed
carbonyls [22], this method has become the most frequently between
diazo strategy
nitriles and diazofor carbonyls
the synthesis[22],ofthis
1,3-oxazoles.
method has The main the
become disadvantage
most frequentlyof thisemployed
approach
is the strategy
diazo need to for
usethe
an synthesis
excess amount of the nitrile
of 1,3-oxazoles. The(often as a solvent). of
main disadvantage However, some
this approach
protocols
is the needhave been
to use andeveloped
excess amountthat allow
of thereducing the excess
nitrile (often of the nitrile
as a solvent). downsome
However, to 5-
fold.
protocols have been developed that allow reducing the excess of the nitrile down to 5-fold.
In 2016, the Park group developed an efficient method for the the synthesis
synthesis of highly
highly
substituted oxazoles
oxazoles 3 by gold-catalyzed cycloaddition reaction of α-diazo oxime ethers1
3 by gold-catalyzed cycloaddition reaction of α-diazo oxime ethers
1and nitriles
and 2 (Scheme
nitriles 2 (Scheme 1) [23]. The reaction
1) [23]. tolerated
The reaction a broad
tolerated a range
broadofrangesubstituents (includ-
of substituents
ing alkyl, aryl,
(including alkyl,heteroaryl, and vinyl)
aryl, heteroaryl, and afforded
and vinyl) good good
and afforded to excellent product
to excellent yields.
product The
yields.
formation
The of the
formation of oxazole ringring
the oxazole is believed to proceed
is believed via via
to proceed the the
formation
formation of zwitterionic
of zwitterionic in-
termediate 1A,
intermediate 1A,which
whichsubsequently
subsequentlyundergoes
undergoescyclization
cyclizationto to oxazole
oxazole 3. 3. Interestingly,
Interestingly, thethe
cyclization occurred
cyclization occurredviaviathe
theattack
attackofofthe
thecarbonyl
carbonyl group
group rather
rather thanthanthethe attack
attack of the
of the ox-
oxime
ether group on the nitrilium electrophilic center, presumably due to the
ime ether group on the nitrilium electrophilic center, presumably due to the Z-configura- Z-configuration of
the
tionC=N double
of the bond (Scheme
C=N double 1).
bond (Scheme 1).
Scheme 1. Gold-catalyzed oxazole synthesis from α-diazo

α-diazo oxime
oxime ethers
ethers and
and nitriles.
nitriles.
In
In the
the synthetic
synthetic exploration
exploration of
of 2-diazoacetyl-2H-azirines 5, which
2-diazoacetyl-2H-azirines 5, which areare available
available from
from
5-chloroisoxazoles
5-chloroisoxazoles 4, Khlebnikov and co-workers demonstrated the utility of 5 for the
4, Khlebnikov and co-workers demonstrated the utility of 5 for the
preparation
preparation of
of oxazoles
oxazoles [24]. Rhodium-catalyzed reaction
[24]. Rhodium-catalyzed reaction with
with nitriles
nitriles 66 afforded
afforded oxazoles
oxazoles
Molecules 2021, 26, 2530 3 of 70
7 with preservation of azirine functionality. On the other hand, NiCl2-catalyzed reaction

77 with
with preservation
preservation8of
acetylacetone
with in azirine
of azirine functionality.
acetonitrile providedOn
functionality. Onthe
theother
otherhand,
hand,NiCl
pyrrolyl-substituted 22-catalyzed
oxazoles
NiCl reaction
9 (Scheme
-catalyzed 2).
reaction
with
with acetylacetone
acetylacetone 88 in
inacetonitrile
acetonitrileprovided
providedpyrrolyl-substituted
pyrrolyl-substitutedoxazoles
oxazoles99(Scheme
(Scheme2).
2).
Scheme 2. Utilization of 2-diazoacetyl-2H-azirines for the synthesis of heterocycle-substituted oxa-

zoles.
Scheme 2. Utilization
Scheme 2. Utilizationofof2-diazoacetyl-2H-azirines
2-diazoacetyl-2H-azirinesforfor
thethe
synthesis of heterocycle-substituted
synthesis oxazoles.
of heterocycle-substituted oxa-
zoles.
An unusual
An unusualtris(pentafluorophenyl)borane
tris(pentafluorophenyl)boranecatalyst catalystwas
wasemployed
employed forfor
thethe reaction
reaction of
of nitriles
nitriles 10 and
An10unusual
and diazo diazo carbonyls 11 by Kumaraswamy
carbonyls 11 by Kumaraswamy
tris(pentafluorophenyl)borane and
and was
catalyst Gangadhar
Gangadhar
employed [25]. [25].
forThis This metal-
the metal-free
reaction of
free protocol
protocol
nitriles andwas
10was found found
diazo compatible
compatible
carbonyls by with
11with many many
Kumaraswamy functional
functional groups
andgroups including
including
Gangadhar alkyl,
alkyl,
[25]. This aryl,aryl,
metal-freeal-
alkyl(aryl)oxy,
kyl(aryl)oxy,
protocol wasand andallowed
found allowed usingaawith
using
compatible lower
lower (5-fold)
(5-fold)
many excessof
excess
functional ofgroups
thenitrile
the nitrile partners.
partners.
including A plausible
A
alkyl,plausible
aryl, al-
reaction
reaction mechanism
mechanism
kyl(aryl)oxy, implies
implies
and allowed initialaactivation
initial
using activation
lower ofofdiazocarbonyl
(5-fold) excess of thecompound
diazocarbonyl compound
nitrile partners.byby
1111 the catalyst
the cata-
A plausible
generating
lyst generatingalkenediazonium
alkenediazonium salt 3A,
salt which
3A, is
which attacked
is by
attacked nitrile
by 10
nitrile
reaction mechanism implies initial activation of diazocarbonyl compound 11 by the cata- with
10 extrusion
with of
extrusion Nof2
molecule
N to
2 molecule
lyst give
generating intermediate
to alkenediazonium 3B.
give intermediatesalt The latter
3B.3A, undergoes
Thewhich cyclization
latterisundergoes
attacked by to form
cyclization oxazole
to form
nitrile 10 with product
oxazole
extrusion of
N2(Scheme
12
product 3).to give3).intermediate 3B. The latter undergoes cyclization to form oxazole
12 (Scheme
molecule
product 12 (Scheme 3).
SchemeScheme
3. (C6 F5 )3.3 B-catalyzed
(C6F5)3B-catalyzed
oxazoleoxazole synthesis
synthesis fromcarbonyls
from diazo diazo carbonyls and nitriles.
and nitriles.
Scheme 3. (C6F5)3B-catalyzed oxazole synthesis from diazo carbonyls and nitriles.
Diazo homophthalimides
Diazo homophthalimides13 13were
werethe first
the heterocycles
first containing
heterocycles an α-diazocarbonyl
containing an α-diazocar-
moiety,
bonyl which
moiety,
Diazo were involved
which in a 13
were involved
homophthalimides [3+2]
incycloaddition
werea [3+2] with nitriles
cycloaddition
the first heterocycleswith to deliver
14nitriles
containing oxazole-fused
14an
to α-diazocar-
deliver ox-
adducts 15
azole-fused as reported
adducts 15by
as the Krasavin
reported by group
the [26].
Krasavin The reaction
group [26].displayed
The a generally
reaction
bonyl moiety, which were involved in a [3+2] cycloaddition with nitriles 14 to deliver high
displayed a
ox-
functional group tolerance giving low yields only in case of olefinic, benzylic,
azole-fused adducts 15 as reported by the Krasavin group [26]. The reaction displayed aand sterically
hindered nitriles. Diazo homophthalimides 13 are easily available via diazo transfer to the
corresponding homophthalimides (Scheme 4).
generally high functional group tolerance giving low yields only in case of olefinic, ben-
Molecules 2021, 26, 2530 generally
zylic, high functional
and sterically group
hindered tolerance
nitriles. Diazogiving low yields only
homophthalimides in case
13 are of available
easily olefinic,4 of
ben-
via
70
zylic, transfer
diazo and sterically
to the hindered nitriles.
corresponding Diazo homophthalimides
homophthalimides (Scheme 13
4).are easily available via
diazo transfer to the corresponding homophthalimides (Scheme 4).
Scheme 4. Synthesis of oxazolo[5,4-c]isoquinolin-5(4H)-ones from diazo homophthalimides and

Scheme4.4. Synthesis
nitriles.
Scheme Synthesisofofoxazolo[5,4-c]isoquinolin-5(4H)-ones
oxazolo[5,4-c]isoquinolin-5(4H)-ones from
from diazo
diazo homophthalimides
homophthalimides and
and nitriles.
nitriles.
Further exploring the synthesis of fused fused oxazoles
oxazoles from
from diazo
diazo containing
containing heterocycles,
heterocycles,
the sameFurther
samegroup exploring
groupreported the synthesis
reporteda a[3+2]
[3+2] of fused
cycloaddition
cycloaddition oxazoles from
reaction
reaction diazo containing
of diazobarbituric
of diazobarbituric acidheterocycles,
acid deriva-
derivatives
the(available
tives
16 same group
16 (available
fromreported a [3+2]
from barbituric
barbituric cycloaddition
acids acids
via via areaction
a novel of diazobarbituric
(SAFE)acid
novel sulfonyl-azide-free
sulfonyl-azide-free derivatives
(SAFE)
diazo diazo
transfer
16 (available
transfer
protocol [27])from
protocol with barbituric
[27]) acids
with nitriles
nitriles 17 17via a novel
[28].
[28]. sulfonyl-azide-free
Diversely
Diversely (SAFE) diazo transfer
substitutedoxazolo[5,4-d]pyrimidine-
substituted oxazolo[5,4-d]pyrimidine-
5,7(4H,6H)-diones
protocol [27]) with
5,7(4H,6H)-diones 18were
18 wereobtained
nitriles in generally
17 [28].
obtained inDiversely
generallymoderate to good
substituted
moderate yields.yields.
However, mono-
tooxazolo[5,4-d]pyrimidine-
good However,
N-substituted
5,7(4H,6H)-diones diazobarbituric
18 were acid
obtained failed
in to give
generally the desired
moderate product.
to good
mono-N-substituted diazobarbituric acid failed to give the desired product. Non-symmet- Non-symmetric
yields. However,
diazobarbituric
mono-N-substituted
ric diazobarbituric acidacid
gave
gavemixture
diazobarbituric of regioisomers.
mixture acid failed to Notably,
of regioisomers. giveNotably,the attempt
the desired of performing
the product.
attempt this
Non-symmet-
of performing
reaction with diazo
ric diazobarbituric
this reaction with diazoMeldrum’s
acid gave acid
mixture
Meldrum’s 19 led to the formation
of regioisomers.
acid of oxazolo[4,5-e][1,3]oxazinone
Notably, the
19 led to the formation attempt of performing
of oxazolo[4,5-e][1,3]oxa-
20 viareaction
this
zinone acyl
20 keteneacylintermediate
viawith diazo
ketene 5B, which
Meldrum’s
intermediate was
acid5B, involved
19 led
whichto the
wasintinvolved
[4+2] cycloaddition
formation ofint with another
oxazolo[4,5-e][1,3]oxa-
[4+2] cycloaddition
molecule
zinone
with 20ofvia
another acetonitrile
acyl ketene
molecule of(Scheme 5). (Scheme
intermediate
acetonitrile 5B, which
5). was involved int [4+2] cycloaddition
with another molecule of acetonitrile (Scheme 5).
Scheme 5. Synthesis of oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-diones 18

Scheme 5. 18 from diazobarbituric acids 16
16 and nitriles
nitriles 17.
17.
Scheme 5. Synthesis of oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-diones 18 from diazobarbituric acids 16 and nitriles 17.
Alicyclic diazocarbonyl
Alicyclic diazocarbonyl compounds
compounds have have also
also been
been employed
employed in oxazole
oxazole synthesis.
synthesis.
Thus,Alicyclic
in 2018, Fandiazocarbonyl
and co-workers compounds have
described thealso been employed
synthesis in oxazole synthesis.
6,7-dihydrobenzo[d]oxazol-
of 6,7-dihydrobenzo[d]oxazol-
Thus, in 2018,
4(5H)-ones 23by
23 Fan
by and co-workers
reacting
reacting cyclic diazo
cyclic described
diketones
diazo diketonesthe
21 synthesis
with
21 with of 22
nitriles 6,7-dihydrobenzo[d]oxazol-
nitriles[29]. The best
22 [29]. The yields were
best yields
4(5H)-ones
obtained
were with
obtained 23 non-substituted
by reacting
with cyclicdiazo
non-substituted diazo diketones
substrates.
diazo 21 with
Analogously
substrates. nitriles 22 to
to the
Analogously [29].
theThe
example best yields
discussed
example dis-
were
above, obtained
diazo with
Meldrum’s non-substituted
acid did not diazo
provide substrates.
the desiredAnalogously
oxazole.
cussed above, diazo Meldrum’s acid did not provide the desired oxazole. From the mech- Fromto the
the example dis-
mechanistic
standpoint,
anistic the
cussedstandpoint, reaction
above, diazo likely
theMeldrum’s proceeds via
acid did
reaction likely the attack
not provide
proceeds of
via thethethe nitrile
desired
attack of the on the
oxazole. rhodium
nitrile onFrom carbene,
the the mech-
rhodium
generated
carbene, from diazo
anistic standpoint,
generated the species,
from diazofollowing
reaction likely steps similar
proceeds
species, following the to
via steps the above-mentioned
attack of the
similar to nitrile on theexamples
the above-mentionedrhodium
(Scheme
carbene, 6).
examples generated
(Scheme 6).from diazo species, following steps similar to the above-mentioned
examples (Scheme 6).
Molecules 2021,26,
Molecules 2021, 26,2530
x FOR PEER REVIEW 55 of
of 70
74
Scheme 6. Synthesis of 6,7-dihydrobenzo[d]oxazol-4(5H)-ones 23 from alicyclic diazo diketones

and nitriles.
Scheme
Scheme 6. Synthesis
6. Synthesisofof6,7-dihydrobenzo[d]oxazol-4(5H)-ones
6,7-dihydrobenzo[d]oxazol-4(5H)-ones 23alicyclic
23 from from alicyclic diazo diketones
diazo diketones and nitriles.
and nitriles.
The reaction
The reactionbetween
betweenpolybrominated
polybrominatedo-quinone
o-quinonediazides
diazides2525 (available
(available viavia diazoti-
diazotiza-
zation
tion of of aminophenols
aminophenols 24) 24)
and and nitriles
nitriles 26 26 leading
leading to to benzoxazoles
benzoxazoles 27 27
was was described
described
The reaction between polybrominated o-quinone diazides 25 (available via diazoti- in 2017in
2017
by by
Vasin Vasin
and and co-workers
co-workers [30]. [30].
The The reaction
reaction proceeded
proceeded on on conventional
conventional heating,
heating,
zation of aminophenols 24) and nitriles 26 leading to benzoxazoles 27 was described in albeit
albeit in
in modest
modest
2017 yields
by yields
Vasin (Scheme
(Scheme
and 7). 7). [30]. The reaction proceeded on conventional heating, albeit
co-workers
in modest yields (Scheme 7).
Scheme 7.
Scheme 7. Synthesis
Synthesis of
of polybrominated
polybrominatedbenzoxazoles
benzoxazoles27
27from
fromo-quinone
o-quinonediazides
diazides2525and
andnitriles
nitriles26.
26.
Scheme 7. Synthesis of polybrominated benzoxazoles 27 from o-quinone diazides 25 and nitriles
26. The nitrile cycloaddition strategy has been used for preparation of a number of oxazole-
containing biologically
The nitrile active compounds
cycloaddition strategy has such
beenasused
cyclin-dependent
for preparation kinase
of a2number
inhibitors
of [31],
oxa-
peroxisome proliferator-activated
zole-containing biologically activereceptor
compounds
δ agonists
such [32],
as and atypical
cyclin-dependent antipsychotics
The nitrile cycloaddition strategy has been used for preparation of a number of oxa-kinase 2 [33].
inhibi-
tors [31], peroxisome
zole-containing proliferator-activated
biologically active compounds receptor
such δasagonists [32], and atypical
cyclin-dependent kinase 2antipsy-
inhibi-
2.1.2.
choticsSynthesis
[33]. of 1,3-Oxazoles by Reaction of Diazocarbonyl Compounds with Amides
tors [31], peroxisome proliferator-activated receptor δ agonists [32], and atypical antipsy-
The[33].
chotics currently well-known approach to oxazoles 31 from amides 28 and diazo com-
pounds 29 was of
2.1.2. Synthesis first described by
1,3-Oxazoles by Moody
Reactionand co-workers in 1996
of Diazocarbonyl (Schemewith
Compounds 8) [34,35].
AmidesIt
was developed
2.1.2.The
Synthesis as an alternative
of 1,3-Oxazoles
currently well-known by to the cycloaddition
Reaction
approach toofoxazolesof nitriles,
Diazocarbonyl which
31 fromCompounds gave
amides 28 and unsatisfactory
with Amides
diazo com-
results
pounds when
29 wasapplied
first to N-protected
described by Moodyα-aminonitriles
and derived
co-workers in by (Scheme
1996 dehydration
8) of α-amino
[34,35]. It was
The currently well-known approach to oxazoles 31 from amides 28 and diazo com-
acid amides.asThe
developed an new approach
alternative to involves
the Rh carbene
cycloaddition of NH-insertion
nitriles, which into
gavetheunsatisfactory
amide molecule re-
pounds 29 was first described by Moody and co-workers in 1996 (Scheme 8) [34,35]. It was
followed by
sults whenas cyclodehydration
applied via
to N-protected the so-called Wipf
α-aminonitriles protocol,
derivedwhichi.e., using
by dehydrationa mixture of Ph
of α-amino 3 P,
developed an alternative to the cycloaddition of nitriles, gave unsatisfactory re-
I2 and Et3 N (Scheme 8).
sults when applied to N-protected α-aminonitriles derived by dehydration of α-amino
acid
acid amides.
amides. TheThe new
new approach
approach involves
involves Rh
Rh carbene
carbene NH-insertion
NH-insertion into
into the
the amide
amide mole-
Molecules 2021, 26, 2530 6mole-
of 70
cule
cule followed by cyclodehydration via the so-called Wipf protocol, i.e., using aa mixture
followed by cyclodehydration via the so-called Wipf protocol, i.e., using mixture of
of
Ph
Ph33P,
P, II22 and
and Et
Et33N
N (Scheme
(Scheme 8).
8).
Scheme 8.
Scheme 8.
Scheme Moody’s
8. Moody’s approach
Moody’s approach for
approach for the
for the synthesis
the synthesis of
synthesis of oxazoles
of oxazoles from
oxazolesfrom amides
fromamides and
amidesand diazo
anddiazo compounds.
diazocompounds.
compounds.
Notably, several
Notably, several methodologies
several methodologieshave
methodologies havebeen
have beendeveloped
been developed
developed that
that
that allow
allow
allow the synthesis
thethe synthesis
synthesis of
of ox-
of
ox-
azoles
oxazoles regioisomeric
regioisomeric to tothetheones
onesobtained
obtained by
by the
the Moody
Moody approach.
approach.
azoles regioisomeric to the ones obtained by the Moody approach. The key step in these The
The key
key step in these
these
alternative
alternative methods
methods is
methods isthe
is theformation
the formationof
formation ofaaacarbonyl
of carbonylylide
carbonyl ylide
ylide via
via
via amide
amide
amide oxygen
oxygen
oxygen atom
atom
atom attack on
attack
attack on
metal
on carbene
metal carbene rather than
rather an
than NH-insertion
an NH-insertion as the
as first
the step
first of
stepthe
metal carbene rather than an NH-insertion as the first step of the synthetic sequence (vide of synthetic
the syntheticsequence (vide
sequence
infra). Another
infra).infra).
(vide Another attractive
Another feature
attractive
attractive feature contrasting
feature these
these protocols
contrasting
contrasting to
to the
these protocols
protocols the Moody oxazole
to the Moody
Moody synthe-
oxazoleoxazole
synthe-
sis is that
synthesis the
is oxazole
that the ring
oxazole is constructed
ring is in
constructed
sis is that the oxazole ring is constructed in one step. one step.
in one step.
Cu(OTf)222-catalyzed
Cu(OTf) -catalyzed synthesis
-catalyzed synthesis of
synthesis of 2,4-substituted
of 2,4-substituted oxazoles
2,4-substituted oxazoles 34
oxazoles 34 from
from terminal
terminal diazocar-
diazocar-
bonyl 32 amides 33 was developed
bonyl compounds 32 and amides 33 was developed by the Subba Reddygroup
compounds and developed by
by the
the Subba
Subba Reddy
Reddy group [36].
group[36]. This
[36].This
This
method works well for both
both aliphatic
aliphatic and
and aromatic
aromatic substrates
substrates
method works well for both aliphatic and aromatic substrates providing good product providing
providing good
good product
product
yields. Thereaction
yields. The
The reactionwas
reaction wasunsuccessful
was unsuccessfulonly
unsuccessful onlywhen
only when
when both
both
both substrates
substrates
substrates were
were
were aliphatic.
aliphatic.
aliphatic. TheThe
The fol-
fol-
following
lowing mechanism was invoked. Initially, copper carbene intermediate is formed on on
lowing mechanism
mechanism was was invoked.
invoked. Initially,
Initially, copper
copper carbene
carbene intermediate
intermediate is is formed
formed on in-
in-
interaction
teraction of of3232with
withthetheCu-catalyst.
Cu-catalyst.RatherRatherunexpectedly,
unexpectedly, the the subsequent
subsequent attack of the the
teraction of 32 with the Cu-catalyst. Rather unexpectedly, the subsequent attack of the
amide on the Cu-carbene occurs through the carbonyl group, giving corresponding ylide
amide on the Cu-carbene occurs through the carbonyl group, group, giving
giving corresponding
corresponding ylide ylide
in preference to the attack attack by
by the
the nitrogen
nitrogen atom,
atom, which
which would
would result
result in
in an
an NH-insertion
NH-insertion
in preference to the attack by the nitrogen atom, which would result in an NH-insertion
product.
product. Subsequent protodemetallation and cyclodehydration gives thethe observed oxazole
product. Subsequent
Subsequent protodemetallation
protodemetallation and and cyclodehydration
cyclodehydration gives gives the observed
observed oxa-oxa-
34
zole(Scheme
34 9).
(Scheme 9).
zole 34 (Scheme 9).
Scheme
Scheme 9.
9. Cu-catalyzed
Cu-catalyzed synthesis
synthesis of
of oxazoles
oxazoles from
from terminal diazo
terminaldiazo carbonyls
diazocarbonyls and
carbonylsand amides.
andamides.
amides.
In 2018, Chen and co-workers reported the involvement of diazo dicarbonyl com-
In 2018, Chen and co-workers reported the involvement of diazo dicarbonyl com-
pounds 35 in a similar reaction under Rh(I) catalysis, which afforded fully substituted
pounds 35 in in aa similar
similar reaction
reaction under
under Rh(I)
Rh(I) catalysis,
catalysis, which
which afforded
afforded fully
fully substituted
substituted
oxazoles 37 [37]. In this case, however, the yields were significantly lower for aliphatic
oxazoles 37 [37]. In this case, however, the the yields
yields were
were significantly
significantly lower
lower forfor aliphatic
aliphatic
substrates
substrates in comparisontotothe the previous example. From the mechanistic perspective,
substrates inin comparison
comparison to the previous
previous example.
example. From
From the
the mechanistic
mechanistic perspective,
perspective, rho-
rho-
rhodium(I)
dium(I) carbene complex 10A likely reacted with the carbonyl oxygen atom of amide
dium(I) carbene
carbene complex
complex 10A
10A likely
likely reacted
reacted with
with the
the carbonyl
carbonyl oxygen
oxygen atom
atom ofof amide
amide 36a
36a
36a
to to form
form intermediate
intermediate 10B, 10B,
whichwhich underwent
underwent metal metal protonation
protonation (with (with regeneration
regeneration of the
to form intermediate 10B, which underwent metal protonation (with regeneration of the
of the catalyst) to afford β-ketoester 10C. The latter entered the cyclization/dehydration
sequence, thus producing trisubstituted oxazole 37a. Preliminary mechanistic studies
revealed that the attack on Rh(I) carbenes was likely the rate-determining step (Scheme 10).
Molecules 2021, 26, 2530 catalyst) to afford β-ketoester 10C. The latter entered the cyclization/dehydration 7 of se-
70
quence, thus producing trisubstituted oxazole 37a. Preliminary mechanistic studies re-
vealed that the attack on Rh(I) carbenes was likely the rate-determining step (Scheme 10).
Scheme 10. Rh(I)-catalyzed

Scheme 10. Rh(I)-catalyzed synthesis
synthesis of oxazoles of diazo
from oxazoles from diazo
dicarbonyl dicarbonyl
compounds andcompounds
amides. and amides.
Thus,
Thus,by byusing
usingeither
eitherofofthese
thesemethods
methodsofofthe
theMoody
Moody protocol, both
protocol, oxazole
both oxazoleregioiso-
regioi-
mers can be accessed starting from the same set of substrates. The reasons
somers can be accessed starting from the same set of substrates. The reasons for for such a switch
such a
in regiospecificity
switch are not entirely
in regiospecificity clear. Presumably,
are not entirely it can beitexplained
clear. Presumably, by the change
can be explained by the
in electrophilicity of the intermediate metal carbene either upon changing metal,
change in electrophilicity of the intermediate metal carbene either upon changing metal, upon
changing ligands, or both [38].
upon changing ligands, or both [38].
2.1.3. Other Approaches to the Synthesis of 1,3-Oxazoles
2.1.3. Other Approaches to the Synthesis of 1,3-Oxazoles
The reaction of α-ketooximes 38 with terminal α-diazo carbonyl compounds 39 af-
The reaction of α-ketooximes 38 with terminal α-diazo carbonyl compounds 39 af-
forded polysubstituted oxazoles 40 in moderate to good yields as reported in 2018 by
forded polysubstituted oxazoles 40 in moderate to good yields as reported in 2018 by
Swamy and co-workers [39]. The reaction tolerates many substituents, including alkyl,
Swamy and co-workers [39]. The reaction tolerates many substituents, including alkyl,
(hetero)aryl, as well as ester, ketone, and nitrile functional groups. The following reac-
(hetero)aryl, as well as ester, ketone, and nitrile functional groups. The following reaction
tion mechanism was proposed by the authors. The reaction is believed to be initiated by
mechanism was proposed by the authors. The reaction is believed to be initiated by the
the interaction between copper carbene 11A and ketooxime 38a, which leads to aziridine
interaction between
11B. The latter copperan
undergoes carbene 11A and ketooxime
intramolecular 38a, which
rearrangement leads
to form to aziridine 11C.
intermediate 11B.
The latter undergoes an intramolecular rearrangement to
Subsequent dehydration of 11C leads to oxazole 40a (Scheme 11). form intermediate 11C. Subse-
quentIndehydration
2015, Trujilloofand
11Cco-workers
leads to oxazole 40a (Scheme
synthesized a series11).
of novel 4-(benzylthio)oxazoles
44 by reacting acyl isothiocyanates 41 with trimethylsilyl diazomethane (TMSCHN2 ) 42
with subsequent treatment of the oxazole thiones 43 with BnBr-DBU [40]. Isolated in
moderate yields, compounds 44 were then converted to oxazole sulfonyl chlorides 45 in
treatment with N-chlorosuccinimide (NCS). BnS-derivatives 44 were formed along with
thiadiazoles 46, which is explained by two possible reaction pathways. In path A, initially
formed intermediate 12A underwent cyclization via the attack of the carbonyl group on
the carbon atom adjacent to N2 + , while in path B, intermediate 12A undergoes cyclization
via the attack of the thiocarbonyl group on the N2 + moiety (Scheme 12).
Molecules 2021, 26, 2530 8 of 70
Scheme 11. Cu(OAc)2-catalyzed synthesis of oxazoles from α-ketooximes and diazo carbonyl compounds.
In 2015, Trujillo and co-workers synthesized a series of novel 4-(benzylthio)oxazoles

44 by reacting acyl isothiocyanates 41 with trimethylsilyl diazomethane (TMSCHN2) 42
with subsequent treatment of the oxazole thiones 43 with BnBr-DBU [40]. Isolated in mod-
erate yields, compounds 44 were then converted to oxazole sulfonyl chlorides 45 in treat-
ment with N-chlorosuccinimide (NCS). BnS-derivatives 44 were formed along with thia-
diazoles 46, which is explained by two possible reaction pathways. In path A, initially
the carbon atom adjacent to N2+, while in path B, intermediate 12A undergoes cyclization
Scheme 11. Cu(OAc)via the attack
22-catalyzed
-catalyzed of the of
synthesis
synthesis thiocarbonyl group
oxazoles from on the Nand
α-ketooximes
α-ketooximes 2+ moiety (Schemecompounds.
diazo carbonyl 12).
In 2015, Trujillo and co-workers synthesized a series of novel 4-(benzylthio)oxazoles

44 by reacting acyl isothiocyanates 41 with trimethylsilyl diazomethane (TMSCHN2) 42
with subsequent treatment of the oxazole thiones 43 with BnBr-DBU [40]. Isolated in mod-
erate yields, compounds 44 were then converted to oxazole sulfonyl chlorides 45 in treat-
ment with N-chlorosuccinimide (NCS). BnS-derivatives 44 were formed along with thia-
diazoles 46, which is explained by two possible reaction pathways. In path A, initially
the carbon atom adjacent to N2+, while in path B, intermediate 12A undergoes cyclization
via the attack of the thiocarbonyl group on the N2+ moiety (Scheme 12).
Scheme 12. Synthesis

Scheme 12. Synthesis of
of sulfur
sulfur derivatives
derivatives of
of oxazoles
oxazoles from
fromacyl
acylisothiocyanates
isothiocyanatesand
andTMSCHN
TMSCHN22..
2.1.4.
2.1.4. Total
Total Synthesis
Synthesisof of1,3-oxazole
1,3-oxazoleContaining
ContainingNatural
NaturalProducts
Products
Both
Both nitrile cycloaddition (Scheme 13, path A) and amideNH-insertion/cyclization
nitrile cycloaddition (Scheme 13, path A) and amide NH-insertion/cyclization
(Scheme 13, path B) diazo strategies have found application in total synthesis of oxazole-
containing natural products. The former strategy works best with simple alkyl and aryl
nitriles 49 or in those cases when 5-unsubstituted oxazole is the target. For fully decorated
oxazoles, the latter strategy is often preferred. The choice of a particular synthetic approach
can also be dictated by the availability of the requisite nitrile 49 or amide 48. However, both
routes are complementary and can be considered interchangeable as was shown by Moody
and co-workers
Scheme [34].ofHence,
12. Synthesis this subsection
sulfur derivatives deals with
of oxazoles from selected works by the
acyl isothiocyanates andMoody group
TMSCHN 2.
that have not yet been reviewed.
2.1.4. Total Synthesis of 1,3-oxazole Containing Natural Products
Both nitrile cycloaddition (Scheme 13, path A) and amide NH-insertion/cyclization
nitriles 49 or in those cases when 5-unsubstituted oxazole is the target. For fully decorated
oxazoles,
nitriles 49the latter
or in thosestrategy is often
cases when preferred. The
5-unsubstituted choice
oxazole of atarget.
is the particular synthetic
For fully ap-
decorated
proach
oxazoles,canthe
alsolatter
be dictated
strategybyisthe availability
often of the
preferred. Therequisite
choice ofnitrile 49 or amide
a particular 48. How-
synthetic ap-
ever,
proach both
can routes
also be are complementary
dictated and can
by the availability be requisite
of the considered interchangeable
nitrile 49 or amide 48.asHow-
was
shown by Moody
ever, both routes and
are co-workers
complementary[34]. Hence,
and canthisbesubsection
considered deals with selected as
interchangeable works
was
Molecules 2021, 26, 2530 9 of 70
by the Moody
shown by Moodygroupandthat have not yet
co-workers [34].been reviewed.
Hence, this subsection deals with selected works
by the Moody group that have not yet been reviewed.
Scheme 13. Two complementary strategies for the synthesis of oxazoles from diazocarbonyl com-
pounds.
Scheme 13.
Scheme 13. Two
Twocomplementary
complementary strategies
strategies forfor
thethe synthesis
synthesis of oxazoles
of oxazoles fromfrom diazocarbonyl
diazocarbonyl com-
compounds.
pounds.
Total synthesis
Total synthesisofofsiphonazole
siphonazole anan
58,58, unusual
unusualmetabolite from
metabolite Herpetosiphon
from species
Herpetosiphon [41],
species
involves the
[41], involves construction
the construction
Total synthesis of the oxazole
of the 58,
of siphonazole intermediate
oxazole containing
intermediate
an unusual a bulky
containing
metabolite styrene substituent
a bulky styrene
from Herpetosiphon sub-
species
(55)
[41],via
stituent an NH-insertion
(55)
involves via
thean reaction
NH-insertion
construction of TBS-protected
reaction
of the oxazole 3-hydroxy-4-methoxycinnamamide
ofintermediate
TBS-protected 3-hydroxy-4-methoxycinna-
containing 52
a bulky styrene sub-
and
mamidemethyl
stituent (55)2-diazo-3-oxobutanoate
52 and
via methyl 53 followed
2-diazo-3-oxobutanoate
an NH-insertion reaction by
53 the Wipf cyclodehydration.
followed
of TBS-protected The other
by the Wipf cyclodehydra-
3-hydroxy-4-methoxycinna-
oxazole
tion.
mamideTheportion
other
52 ofmethyl
andoxazole the siphonazole
portion molecule
of the (57) was
siphonazole
2-diazo-3-oxobutanoate obtained
53molecule
followed by was
(57)
by a [3+2]
the cycloaddition
obtained
Wipf of
by a [3+2]
cyclodehydra-
53 with iodoacetonitrile
cycloaddition of 53 with 56. From oxazoles
iodoacetonitrile 56.55 and
From 57, the
oxazolesnatural
55 and product
57, the
tion. The other oxazole portion of the siphonazole molecule (57) was obtained by a [3+2] was assembled
natural product
in
was three steps (Scheme
assembled
cycloaddition ofin53three
with14).
steps (Scheme 14).56. From oxazoles 55 and 57, the natural product
iodoacetonitrile
was assembled in three steps (Scheme 14).
Scheme 14. Preparation of oxazole building block for the total synthesis of siphonazole.
siphonazole.
Scheme 14. Preparation of oxazole building block for the total synthesis of siphonazole.
A more
A more complex
complex target
targetpolyazole
polyazolepeptide
peptideantibiotic
antibioticgoadsporin
goadsporin was
6868 synthesized
was in
synthesized
2017 [42].
in 2017 It consists
[42]. Itcomplex
A more of four
consiststarget oxazole
of four and two
oxazole and
polyazole thiazole rings,
two antibiotic
peptide linked
thiazole rings, through
linked 68
goadsporin a number
through of amino
a number
was synthesized
acid residues.
in 2017 [42]. It5-Substituted
consists of fouroxazoles 60,and
oxazole 64 were
62, two synthesized
thiazole from the
rings, linked corresponding
through a number
amino acids amides 59, 61, 63 using NH-insertion/cyclization strategy, whilst 5-unsubstituted
oxazole 67 was synthesized by [3+2] cycloaddition strategy from L-serine-derived nitrile 65
and ethyl 2-diazo-3-oxopropanoate 66 (Scheme 15).
of amino acid residues. 5-Substituted oxazoles 60, 62, 64 were synthesized from the corre-
ofsponding amino
amino acid acids5-Substituted
residues. amides 59, 61, 63 using
oxazoles 60,NH-insertion/cyclization strategy,
62, 64 were synthesized from whilst 5-
the corre-
unsubstituted oxazole 67 was synthesized by [3+2] cycloaddition strategy from
sponding amino acids amides 59, 61, 63 using NH-insertion/cyclization strategy, whilst L-serine-
5-
Molecules 2021, 26, 2530 10 of 70
derived nitrile
unsubstituted 65 and67ethyl
oxazole was 2-diazo-3-oxopropanoate 66 (Scheme
synthesized by [3+2] cycloaddition 15). from L-serine-
strategy
derived nitrile 65 and ethyl 2-diazo-3-oxopropanoate 66 (Scheme 15).
Scheme 15. Preparation of oxazole building blocks for the total synthesis of goadsporin.
Scheme 15.15.Preparation
Scheme Preparationofofoxazole
oxazolebuilding
building blocks for the
blocks for thetotal
totalsynthesis
synthesisofofgoadsporin.
goadsporin.
Similarly,with
Similarly, with agoal goal
of of synthesizing cyclic dodecapeptides wewakazole 69 and
Similarly, with aa goal synthesizing
synthesizing cyclic
cyclicdodecapeptides
dodecapeptideswewakazole
wewakazole andand
69 69
wewakazole
wewakazoleBBB 7070 [43], 2,4-disubstituted
2,4-disubstituted oxazolesand
oxazoles 73 and 76 were accessed via the nitrile
wewakazole 70 [43],
[43], 2,4-disubstituted oxazoles73 73 and7676were
wereaccessed
accessedviavia
thethe
nitrile
nitrile
cycloaddition strategy
cycloadditionstrategy
cycloaddition strategywhilewhile 2,4,5-trisubstituted
while 2,4,5-trisubstituted oxazoles
2,4,5-trisubstituted oxazoles
oxazoles60, 60, 78,
78,and
60,78, and 80
were
and8080 were
prepared
were prepared
preparedby by by
theNH-insertion/cyclization
the NH-insertion/cyclization
NH-insertion/cyclization strategy.
strategy.
strategy. Nitriles
Nitriles
Nitriles 72 72 and
72and
and 75 were
75were
75 were obtained
obtained
obtained byby by dehydration
dehydration
dehydration of of of
amino acid
amino acidamides
amides and
7171 respectively
74,74,
and (Scheme
respectively 16). 16).
(Scheme
amino acid amides 71 and 74, respectively (Scheme 16).
Scheme 16. Preparation of oxazole building blocks for the total synthesis of wewakazole and wewakazole B.
Scheme16.
Scheme Preparation of
16.Preparation of oxazole
oxazolebuilding
buildingblocks forfor
blocks thethe
totaltotal
synthesis of wewakazole
synthesis and wewakazole
of wewakazole B.
and wewakazole B.
Molecules 2021,
Molecules 2021, 26,
26, 2530
x FOR PEER REVIEW 11
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of 70
2.2.
2.2. 1,2-Oxazoles
1,2-Oxazoles (Isoxazoles)
(Isoxazoles)
1,2-Oxazole
1,2-Oxazole ringring plays
plays an
an important role in
important role in organic
organic synthesis.
synthesis. This
This heterocycle serves
heterocycle serves
as a masked equivalent of a 1,3-dicarbonyl compound, which can be
as a masked equivalent of a 1,3-dicarbonyl compound, which can be useful in total synthesisuseful in total syn-
thesis of natural compounds [44]. Moreover, other heterocycles are available
of natural compounds [44]. Moreover, other heterocycles are available from isoxazoles, such from isoxa-
zoles, such as 1,3-oxazoles,
as 1,3-oxazoles, azirines [45],azirines [45],and
pyridines, pyridines,
pyrrolesand[46].pyrroles
Biological[46]. Biological
profile profile of
of isoxazoles is
isoxazoles is somewhat
somewhat similar similar to[47].
to 1,3-oxazoles 1,3-oxazoles [47].toClassic
Classic routes routes
isoxazoles to isoxazoles
include include
condensation of
condensation
hydroxylamine of with
hydroxylamine
1,3-dicarbonylwithcompounds
1,3-dicarbonyl andcompounds
1,3-dipolarand 1,3-dipolarof
cycloaddition cycload-
nitrile
dition of nitrile oxides to alkynes, although many other methods have
oxides to alkynes, although many other methods have been developed [46,48]. As for diazo been developed
[46,48]. As for diazo
methodologies for themethodologies for the synthesis
synthesis of isoxazoles, of isoxazoles,
information remainsinformation
scarce. Only remains
a few
scarce.
reports Only
can bea few
found reports
in thecan be found
literature in the literature to date.
to date.
Duffy and
andco-workers
co-workersdescribed
describedthe thepreparation
preparation of of unusual
unusual 4H-imidazo[4,5-c]isoxa-
4H-imidazo[4,5-c]isoxazole
zole 84 from
84 from diazodiazo
compoundcompound 83 which,
83 which, in turn,inwas
turn, was obtained
obtained via the coupling
via the coupling of acid
of acid chloride
chloride 81 with
81 with ethyl ethyl diazoacetate
diazoacetate 82 [49].
82 [49]. On On heating,
heating, 83 underwent
83 underwent the Wolff therearrangement
Wolff rearrange- to
ment to give17B,
give ketene ketene 17B,cyclized
which which cyclized
to formtozwitterionic
form zwitterionic intermediate
intermediate 17C.latter
17C. The The latter
elim-
inated a COa2 CO
eliminated molecule, thereby
2 molecule, producing
thereby producingortho-nitroso carbene
ortho-nitroso intermediate
carbene intermediate
17D.17D.The
electrocyclization
The electrocyclizationthat followed afforded
that followed imidazoisoxazole
afforded imidazoisoxazole 84 (Scheme 17). 17).
84 (Scheme
Scheme 17. Synthesis of 4H-imidazo[4,5-c]isoxazole from nitroimidazolyl diazo ketoester

ketoester 83.
In a 2018 work by the Wan group,group, diazo

diazo esters 85 were
were used
used for
for in
in situ
situ preparation
preparation
of nitrile oxides, which
which underwent
underwent highly
highly regioselective
regioselective [3+2]
[3+2] cycloaddition
cycloaddition with enols enols
generated from β-ketoesters 86 [50]. The reaction tolerated a broad range of
86 [50]. of substituents
substituents
in the
in the aromatic
aromatic ring
ring and
and furnished
furnished 3,4,5-substituted
3,4,5-substituted isoxazoles
isoxazoles 87 87 in
in moderate
moderate to to good
good
yields.
yields. Based on preliminary studies, authors proposed the following mechanism for
Based on preliminary studies, authors proposed the following mechanism for the
the
reaction (shown
reaction (shownfor for(Het)Ar
(Het)Ar= =Ph).
Ph).Presumably,
Presumably, copper carbene
copper 18A18A
carbene generated fromfrom
generated 85 was85
attacked
was by tert-butyl
attacked nitrite
by tert-butyl to form
nitrite intermediate
to form The The
18B.18B.
intermediate latter decomposed
latter decomposed to nitrile
to ni-
oxideoxide
trile which,
18C, 18C, in turn,
which, underwent
in turn, underwenta [3+2] cycloaddition
a [3+2] with with
cycloaddition magnesium
magnesiumenolate 18D
enolate
to produce intermediate 18E. Isoxazole 87 was likely produced via the
18D to produce intermediate 18E. Isoxazole 87 was likely produced via the dehydration dehydration of
hydroxyisoxazoline 18E (Scheme
of hydroxyisoxazoline 18E (Scheme 18). 18).
Molecules 2021,26,
Molecules2021, 26,2530
12 of70
74
Scheme 18. Synthesis of isoxazoles from β-ketoesters 86 and diazo acetates 85.
Scheme18.
Scheme 18.Synthesis
Synthesisof
ofisoxazoles
isoxazolesfrom
fromβ-ketoesters
β-ketoesters86
86and
anddiazo
diazoacetates
acetates85.
85.
Alkynes
Alkynes 89 can
can also be be effective replacements
replacements for β-ketoesters
β-ketoesters in this this reaction as as
Alkynes 89 89 can alsoalso beeffective
effective replacementsfor for β-ketoesters in in thisreaction
reaction as
demonstrated
demonstrated by Wang and co-workers [51]. The reaction proceeded in a highly regiose-
demonstratedby byWang
Wangand andco-workers
co-workers [51]. The
[51]. The reaction
reaction proceeded
proceeded in ainhighly regioselec-
a highly regiose-
lective
tive manner
manner evenevenwithwith internal
internal alkynes
alkynes (isoxazoles
(isoxazoles 90a),90a),
albeitalbeit in lower
in lower yield.
yield. The The
authorsau-
lective manner even with internal alkynes (isoxazoles 90a), albeit in lower yield. The au-
thors proposed
proposed the
the followingfollowing radical
radicalradical
mechanismmechanism for
for the for the
reaction.reaction. Nitroso
NitrosoNitroso radical
radical radical
generatedgener-
by
thors proposed the following mechanism the reaction. gener-
ated by homolytic
homolytic cleavage cleavage
of of tert-butyl
tert-butyl nitrite nitrite
along along
with with tert-butoxy
tert-butoxy radical radical
is thought is thought
to react
ated by homolytic cleavage of tert-butyl nitrite along with tert-butoxy radical is thought
to react
with with
Cu(I) Cu(I) carbene
carbene intermediate 19A to give organocopper intermediate 19B. Het-
to react with Cu(I) intermediate 19A to give
carbene intermediate 19Aorganocopper
to give organocopperintermediate 19B. Heterolytic
intermediate 19B. Het-
erolytic
bond bond cleavage
cleavage of 19B of 19B
with with elimination
elimination of copper(0) of followed
copper(0)by followed
deprotonationby deprotonation
could give
erolytic bond cleavage of 19B with elimination of copper(0) followed by deprotonation
could
nitrile give nitrile oxide 19D, which could then undergo a [3+2] cycloaddition to alkyne 89
could oxide 19D, which
give nitrile couldwhich
oxide 19D, then undergo
could then a [3+2]
undergocycloaddition to alkyne 89 to
a [3+2] cycloaddition to alkyne
produce 89
to produce
desired desired
isoxazole isoxazole 90.
In the course In the
ofthe course
thecourse of
reaction, the reaction, Cu(0) is oxidized to Cu(I)
by thetotBuO
to produce desired 90.isoxazole 90. In of Cu(0) is oxidized
the reaction, Cu(0)toisCu(I)oxidized Cu(I)
by the tBuO
radical, whichradical,
completeswhichthecompletes the catalytic
catalytic cycle. cycle. Alternatively,
Alternatively, deprotonationdeprotonation
of intermediate of
by the tBuO radical, which completes the catalytic cycle. Alternatively, deprotonation of
intermediate
19B could occur19Bwith
could occur withheterolytic
subsequent subsequent heterolytic
C-Cu C-Cu bond
bond cleavage to givecleavage to give
the nitrile the
oxide
intermediate 19B could occur with subsequent heterolytic C-Cu bond cleavage to give the
nitrile oxide intermediate
intermediate 19D with the19D same with the sameevents
subsequent subsequent(Schemeevents
19). (Scheme 19).
nitrile oxide intermediate 19D with the same subsequent events (Scheme 19).
SchemeScheme 19. Synthesis

19. Synthesis of isoxazoles
of isoxazoles from alkynes
from alkynes and diazocarbonyl
and diazocarbonyl compounds.
compounds.
Scheme 19. Synthesis of isoxazoles from alkynes and diazocarbonyl compounds.
Molecules 2021, 26, 2530 13 of 70
2.3. 1,3-Thiazoles
2.3. 1,3-Thiazoles
1,3-Thiazole-based materials are now extensively studied for application in organic
1,3-Thiazole-based
electronics due to their materials are now extensively
suitable electronic, studied
optical, and spatialfor application
properties. in organic
1,3-Thiazoles
electronics due to their suitable electronic, optical, and spatial properties. 1,3-Thiazoles
have been employed for the preparation of organic field-effect transistors (OFETs), or-
have been employed for the preparation of organic field-effect transistors (OFETs), organic
ganic photovoltaic cells (OPVs), and organic light-emitting diodes (OLEDs) [52]. Moreo-
photovoltaic cells (OPVs), and organic light-emitting diodes (OLEDs) [52]. Moreover, the
ver, the thiazole ring has been utilized in the design of medicinal agents for the treatment
thiazole ring has been utilized in the design of medicinal agents for the treatment of viral
of viral and bacterial infections, diabetes, Alzheimer’s disease, neglected protozoan dis-
and bacterial infections, diabetes, Alzheimer’s disease, neglected protozoan diseases, and
eases, and more [53]. Standard approaches to the synthesis of 1,3-thiazoles, such as thio-
more [53]. Standard approaches to the synthesis of 1,3-thiazoles, such as thionation of α-
nation of α-acylaminoketones (the Gabriel synthesis) and condensation of α-halocarbonyl
acylaminoketones (the Gabriel synthesis) and condensation of α-halocarbonyl compounds
compounds with thioamides (the Hantzsch synthesis) are frequently employed [54,55].
with thioamides (the Hantzsch synthesis) are frequently employed [54,55].
The diazo approaches to thiazoles discussed in this subsection of the review are
The diazo approaches to thiazoles discussed in this subsection of the review are
somewhat similar to these classic methods: (i) reaction of α-diazocarbonyl compounds
somewhat similar to these classic methods: (i) reaction of α-diazocarbonyl compounds
(acting as the α-halocarbonyl compounds equivalent) with thioamides or thioureas; (ii) α-
(acting as the α-halocarbonyl compounds equivalent) with thioamides or thioureas; (ii)
carbonyl carbene
α-carbonyl carbeneNH
NHinsertion
insertioninto
intothioamides
thioamides or
or thiourea with subsequent
thiourea with subsequent thionation;
thionation;
and (iii) less conventional reactions.
and (iii) less conventional reactions.
2.3.1. Synthesis
2.3.1. Synthesis of
of 1,3-Thiazoles
1,3-Thiazolesfrom
fromDiazocarbonyl
DiazocarbonylCompounds
Compoundsand
andThioamides
Thioamides or
Thioureas
or Thioureas
In
In1995,
1995,Kim
Kimand andco-workers
co-workers developed
developed a method
a methodfor the
for synthesis of 2,4-disubstituted
the synthesis of 2,4-disubsti-
thiazoles 93 by BF
tuted thiazoles ·OEt
93 3by BF23-promoted reaction
∙OEt2-promoted of ethyl
reaction diazopyruvate
of ethyl 91 with
diazopyruvate thioamides
91 with thioam-
92 [56,57].
ides The best
92 [56,57]. The yields werewere
best yields obtained with with
obtained aromatic thioamides,
aromatic whilewhile
thioamides, for aliphatic and
for aliphatic
heteroaromatic
and heteroaromaticthioamides, lowerlower
thioamides, product yield were
product yield obtained. The following
were obtained. mechanism
The following mech-
was proposed
anism as plausible:
was proposed The initially
as plausible: formed boron
The initially formed enolate
boron20A could
enolate be attacked
20A could be byat-
thioamide 92 to produce thiocarbonyl ylide 20B. The thiazole product
tacked by thioamide 92 to produce thiocarbonyl ylide 20B. The thiazole product (93)(93) could arise as
could
the result
arise of result
as the the cyclodehydration of the intermediate
of the cyclodehydration 20B (Scheme
of the intermediate 20).
20B (Scheme 20).
Scheme
Scheme20. BF33·.OEt22-promoted
20.BF -promoted synthesis
synthesis of
of thiazoles
thiazoles from
from ethyl diazopyruvate and thioamides.
Later,
Later,the
thesame
samegroup
groupdemonstrated
demonstrated thethe
applicability
applicabilityof this procedure
of this to bisthioamides,
procedure to bisthioam-
namely benzene-1,3-bis(carbothioamide)
ides, namely benzene-1,3-bis(carbothioamide) 94 [58]. Thus,Thus,
94 [58]. bisthiazolylbenzene 95 was
bisthiazolylbenzene ob-
95 was
tained in 83%
obtained yield.
in 83% In In
yield. this case,
this thethe
case, use
useofof
MgSO
MgSO 4 or molecular sieves as desiccants was
4 or molecular sieves as desiccants was
essential
essentialtotoavoid
avoidthe
theformation
formationofofby-products.
by-products. Compound
Compound was
95 95 used
was forfor
used preparation of
preparation
unusual thiazole-containing crown ethers 98 (Scheme
of unusual thiazole-containing crown ethers 98 (Scheme 21). 21).
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Scheme 21.
Synthesis of
of bisthiazolylbenzene
bisthiazolylbenzene 95
95 and
and thiazole-containing
thiazole-containing crown
crown ethers
ethers 98.
98.
Scheme 21. Synthesis of bisthiazolylbenzene 95 and thiazole-containing crown ethers 98.
In 1990,
In
In 1990, Capuano
1990, Capuano and
Capuano and co-workers
and co-workers observed
co-workers observed the
observed the formation
the formation of
formation of 2,4,5-substituted
of 2,4,5-substituted thia-
2,4,5-substituted thia-
zoles
zoles
zoles 101101 upon
101 upon thermolysis
upon thermolysis
thermolysis or or irradiation
or irradiation
irradiation of of 2-diazo-1,3-diketones
of 2-diazo-1,3-diketones
2-diazo-1,3-diketones 99 in 99 in the
in the presence
the presence
presence of of
of
thioamides
thioamides
thioamides100 100 [59].
100[59]. Under
[59].Under thermolysis
Underthermolysis conditions,
thermolysisconditions,
conditions, thiazoles
thiazoles
thiazoles 101 were
were
101101 were formed
formed
formed as a mix-
as aasmixture
a mix-
ture with
with
ture with 4H-1,3-oxazin-4-ones
4H-1,3-oxazin-4-ones
4H-1,3-oxazin-4-ones 102 (with
102 (with
102 (with aa predominance
predominance
a predominance of theoflatter),
of the latter),
the latter),
while while on irradia-
irradia-
on irradiation,
while on
tion, thiazoles
tion, thiazoles
thiazoles were
were the
were theproducts.
only
the only products.
only products. Unfortunately,
Unfortunately, the yields
the yields
Unfortunately, the yields weremodest
were only
were only modest
only modest incases.
in bothin both
both
cases.
The The
reaction reaction presumably
presumably proceededproceeded
via via ketocarbene
ketocarbene 22A, 22A,
which which
cases. The reaction presumably proceeded via ketocarbene 22A, which can react with thi-can can
react react
with with thi-
thiourea
ourea
to to
produce produce intermediate
intermediate 22B. 22B. Subsequent
Subsequent cyclodehydration
cyclodehydration can
ourea to produce intermediate 22B. Subsequent cyclodehydration can afford thiazole 101. can
afford afford thiazole
thiazole 101. 101.
Al-
Alternatively,
ternatively,
Alternatively, 22A can
cancan
22A22A undergo
undergo
undergo the
the Wolff Wolff rearrangement
rearrangement
the Wolff rearrangement with
with with the
the formationformation
the formation of α-oxo-
of α-oxoketene
of α-oxo-
ketene intermediate
intermediate
intermediate
ketene 22C,could
22C, which
22C, which
which could
becould be attacked
attacked
be attacked
by the NHby by the NH
moiety
the NH moiety
of moiety
thioamide of thioamide
of thioamide
100 to give100 100 to
inter-
to
give
mediate intermediate
22D. The 22D.
latter The
could latter
cyclizecould
with cyclize
the with
loss of HtheS loss
and of H
afford
give intermediate 22D. The latter could cyclize with the loss of H2S and afford 4H-1,3-
2 2S and afford
4H-1,3-oxazin-4-one4H-1,3-
oxazin-4-one
102 (Scheme 22).
oxazin-4-one 102 (Scheme
102 (Scheme 22).
22).
Scheme22.
Scheme
Scheme 22. Thermally
22. Thermallyoror
Thermally orphotochemically
photochemically
photochemically promoted
promoted reactions
reactions
promoted of 2-diazo-1,3-diketones
2-diazo-1,3-diketones
of 2-diazo-1,3-diketones
reactions of with thio-
thio-
with thioamides.
with
amides.
amides.
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The Villalgordo group employed Cu(I) bromide for this reaction to selectively pre-
The Villalgordo group employed Cu(I) bromide for this reaction to selectively prepare
pare thiazoles 105 in good yields [60]. Further extending the scope of this methodology,
thiazoles 105 in good yields [60]. Further extending the scope of this methodology, func-
functionalized 2-aminobenzothioamide 106 was used to obtain thiazoles 107, albeit in
tionalized 2-aminobenzothioamide 106 was used to obtain thiazoles 107, albeit in lower
lower yields.
yields. The useThe use of aromatic
of aromatic thioamides
thioamides proved
proved to be crucialtofor
bethis
crucial for since
reaction this reaction
aliphatic since
aliphatic
ones failedones failed
to give the to give products.
desired the desired
Theproducts.
tentative The tentative
mechanism mechanism
involves involves
the reaction of the
reaction
copper carbene 23A (generated from α-diazo-β-ketoester 103 on action of CuBr) with theCuBr)
of copper carbene 23A (generated from α-diazo-β-ketoester 103 on action of
with the thioamide
thioamide 104 to give 104 to give an intermediate
an intermediate 23B whose cyclodehydration
23B whose cyclodehydration produced thiazoleproduced
105
thiazole 23).
(Scheme 105 (Scheme 23).
Scheme 23.Copper(I)-mediated
Scheme 23. Copper(I)-mediatedsynthesis of thiazoles
synthesis from α-diazo-β-ketoesters
of thiazoles and aromatic
from α-diazo-β-ketoesters andthioamides.
aromatic
thioamides.
Rhodium catalysis was also successfully employed in the synthesis of thiazoles. In
2010, Rhodium
the Moodycatalysis
group reported the reaction
was also of diversely
successfully substituted
employed in the 1-diazopropan-2-ones
synthesis of thiazoles. In
108 with aromatic thioamides 109 catalyzed by rhodium perfluorobutyramide (Rh2 (pfm)4 ),
2010, the Moody group reported the reaction of diversely substituted 1-diazopropan-2-
which afforded fully substituted thiazoles 110 in generally good yields (Scheme 24) [38].
ones 108 with aromatic thioamides 109 catalyzed by rhodium perfluorobutyramide
The mechanism is similar to that shown in Scheme 23. Other Rh(I) catalysts, namely by
(Rh 2(pfm)4), which afforded fully substituted thiazoles 110 in generally good yields
[Rh(COD)Cl] 2 , were also found suitable for promoting this reaction [37].
(Scheme 24) [38]. The mechanism is similar to that shown in Scheme 23. Other Rh(I) cata-
lysts, namely by [Rh(COD)Cl]2, were also found suitable for promoting this reaction [37].
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74
Scheme 24.
Scheme 24.
Scheme Rh
Rh222(pfm)
24. Rh (pfm)444-catalyzed
-catalyzed synthesis
-catalyzed of thiazoles
synthesis of thiazoles from
thiazoles from 1-diazopropan-2-ones
from1-diazopropan-2-ones 108
1-diazopropan-2-ones108 and
108and aro-
andaromatic
aro-
matic thioamides
matic thioamides 109.
thioamides 109. 109.
Trifluoromethyl-substituted
Trifluoromethyl-substituted
Trifluoromethyl-substitutedthiazoles thiazoles 113 and
113and
thiazoles113 115 were
115were
and115 synthesized
weresynthesized
synthesizedby by Obijalska
byObijalska and
Obijalskaand
and
co-workers
co-workers
co-workers via via the
via the
theBFBF ∙OEt
BF33·∙OEt
3 -promoted condensation
OEt22-promoted condensation of
2 of 3-diazo-1,1,1-trifluoropropan-2-
of 3-diazo-1,1,1-trifluoropropan-2-
3-diazo-1,1,1-trifluoropropan-2-
one
one 111
111and
one 111 and thiourea
andthiourea
thiourea 112112
112or or benzothioamides
benzothioamides
or benzothioamides 114 114 (Scheme
(Scheme
114 25)
25) [61].
(Scheme [61].
25) The The
The reaction
[61].reaction pro-
proceeded
reaction pro-
ceeded
smoothly smoothly
with with
thiourea, thiourea,
but when but when
thioamides thioamides
were used, were used,
dehydration
ceeded smoothly with thiourea, but when thioamides were used, dehydration under dehydration
under under
MsCl/Et 3N
MsCl/Et ◦ C under
MsCl/Et3N conditions was additionally needed. To overcome this drawback, heating at
conditions3Nwasconditions was
additionally additionally
needed. To needed.
overcome To overcome
this drawback, this drawback,
heating at 150 heating at
150
the °C
°C under
under the
150 microwave microwave
irradiation
the microwave wasirradiation was
alternatively
irradiation was alternatively
performed, which
alternatively performed,
also gavewhich
performed, also
slightly
which gave
higher
also gave
slightly
yields ofhigher
slightly yields
the desired
higher yields of
of the
the desired
2-arylthiazoles
desired115. 2-arylthiazoles
As in some of
2-arylthiazoles 115.
theAs
115. As in
in some
previous of
of the
the previous
someexamples, exam-
the aliphatic
previous exam-
ples,
ples, the aliphatic thioamides failed to give any thiazole products. 2-Aminothiazole 113
the
thioamides aliphatic
failed thioamides
to give any failed
thiazole to give any
products. thiazole products.
2-Aminothiazole 2-Aminothiazole
113 was also furtherly
113
was also
derivatized furtherly
to obtainderivatized
CF -analogsto obtain
of CF 3-analogs of immunomodulatory
immunomodulatory drug candidate
was also furtherly derivatized to obtain CF3-analogs of immunomodulatory drug candi-
3 drug
Fanetizole candi-
(117)
and
dateanti-inflammatory
date Fanetizole
Fanetizole (117)
(117) and
anddrug Lotifazole (119) (Scheme
anti-inflammatory
anti-inflammatory drug 25).
drug Lotifazole
Lotifazole (119)
(119) (Scheme
(Scheme 25).25).
Scheme
Scheme 25.
25. Synthesis of
Synthesis of trifluoromethylated
of trifluoromethylated thiazoles
trifluoromethylated thiazoles and
thiazoles and their
and their further
their furtherderivatization.
further derivatization.
derivatization.
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The Narsaiah group reported another example of the coupling of diazo compounds
The Narsaiah
The Narsaiahgroup
groupreported
reported another
another example
example of the
of the coupling
coupling of diazo
of diazo compounds
compounds 120
120 with thiourea 112 under Cu(OTf)2 catalysis [62]. This protocol worked well for a vari-
with thiourea
120 with 112 under
thiourea Cu(OTf)
112 under 2 catalysis
Cu(OTf) [62]. [62].
2 catalysis This This
protocol worked
protocol well for
worked a variety
well of
for a vari-
ety of aliphatic, donor- and acceptor-substituted aromatic, and benzylic diazoketones, af-
aliphatic, donor- donor-
ety of aliphatic, and acceptor-substituted aromatic,
and acceptor-substituted and benzylic
aromatic, diazoketones,
and benzylic affordingaf-
diazoketones, 2-
fording 2-aminothiazoles 121 in excellent yields. A catalyst-free version of this reaction
aminothiazoles 121 in excellent yields. A catalyst-free version of this reaction using
fording 2-aminothiazoles 121 in excellent yields. A catalyst-free version of this reaction PEG-400
using PEG-400 as a solvent was also reported (Scheme 26) [63].
as a solvent
using wasas
PEG-400 also reported
a solvent (Scheme
was 26) [63].(Scheme 26) [63].
also reported
Scheme 26. Cu(OTf)2-catalyzed synthesis of 2-aminothiazoles from diazo ketones and thiourea.
Scheme 26.
Scheme 26. Cu(OTf)22-catalyzed synthesis of 2-aminothiazoles from diazo ketones and thiourea.
thiourea.
2.3.2. Synthesis
2.3.2. of 1,3-Thiazoles
1,3-Thiazoles Through thethe Reaction ofof Diazocarbonyl Compounds
Compounds and
2.3.2. Synthesis
Synthesis ofof 1,3-Thiazoles Through
Through the Reaction
Reaction of Diazocarbonyl
Diazocarbonyl Compoundsand and
followed by
Amides followed by Cyclization
Cyclization
Amides followed by Cyclization
In 2004,
2004, the
theMoody
Moodygroup
groupdemonstrated
demonstrated thethe
generality of their
generality approach
of their approachtowards
towards1,3-
In 2004, the Moody group demonstrated the generality of their approach towards 1,3-
oxazoles via NH-insertion/cyclodehydration
1,3-oxazoles via NH-insertion/cyclodehydration cascade (section
cascade 2.1.2., Scheme
(Section 8) for synthe-
2.1.2, Scheme 8) for
oxazoles via NH-insertion/cyclodehydration cascade (section 2.1.2., Scheme 8) for synthe-
sis of other
synthesis of1,3-azoles, such assuch
other 1,3-azoles, thiazole and imidazole
as thiazole (section
and imidazole 2.4.1., Scheme
(Section 35) [64].
2.4.1, Scheme 35)Thus,
[64].
sis of other 1,3-azoles, such as thiazole and imidazole (section 2.4.1., Scheme 35) [64]. Thus,
fully substituted
Thus, thiazoles
fully substituted 125 were
thiazoles 125obtained in varying
were obtained yields via
in varying the treatment
yields of α-(ac-
via the treatment
fully substituted thiazoles 125 were obtained in varying yields via the treatment of α-(ac-
of
ylamino)ketones 124 with124
α-(acylamino)ketones with Lawesson’s
Lawesson’s reagent reagent in refluxing
in refluxing THF. The THF. The approach
approach demon-
ylamino)ketones 124 with Lawesson’s reagent in refluxing THF. The approach demon-
demonstrated high functional
strated high functional group group tolerance
tolerance in the in the amide
amide moiety,moiety, also working
also working well even
well even with
strated high functional group tolerance in the amide moiety, also working well even with
with aliphatic
aliphatic amidesamides (Scheme
(Scheme 27). 27).
aliphatic amides (Scheme 27).
Scheme 27. Synthesis of fully

fully substituted
substituted thiazoles
thiazolesvia
viarhodium
rhodiumcarbene
carbeneNH-insertion
NH-insertioninto
intoamide
amide
Scheme 27. Synthesis of fully substituted thiazoles via rhodium carbene NH-insertion into amide
with
with subsequent thionation.
with subsequent
subsequent thionation.
thionation.
approachhas
This approach hasfound
foundapplication
applicationininthe
thetotal
total synthesis
synthesis of of natural
natural products.
products. OneOne
of
This approach has found application in the total synthesis of natural products. One
of the
the six six thiazoles
thiazoles (127)
(127) required
required forconstruction
for the the construction of thiopeptide
of thiopeptide antibiotic
antibiotic amythi-
amythiamicin
of the six thiazoles (127) required for the construction of thiopeptide antibiotic amythi-
D (128) D
amicin was prepared
(128) using this
was prepared methodology
using from aspartic
this methodology acid amide
from aspartic acidderivative 126 and
amide derivative
amicin D (128) was prepared using this methodology from aspartic acid amide derivative
methyl
126 and2-diazo-3-oxobutanoate 53 (Scheme
methyl 2-diazo-3-oxobutanoate 28) [65,66].
53 (Scheme 28)This route
[65,66]. wasroute
This also was
involved in
also in-
126 and methyl 2-diazo-3-oxobutanoate 53 (Scheme 28) [65,66]. This route was also in-
total
volved synthesis
in totalofsynthesis
other thiazole-containing antibiotics, such
of other thiazole-containing as GE2270A
antibiotics, suchand GE2270T [67].
as GE2270A and
volved in total synthesis of other thiazole-containing antibiotics, such as GE2270A and
GE2270T [67].
GE2270T
2.3.3. Other[67].
Approaches to 1,3-Thiazoles Starting from Diazo Compounds
An interesting procedure for the chemoselective synthesis of 2,4,5-substituted thia-
zoles from diazo carbonyls 129 and α-(N-hydroxy/aryl)imino-β-oxodithioesters 130/132
was reported in 2017 by Srivastava and co-workers [68]. The [Cu(CH3 CN)4 ]PF6 -catalyzed
reaction gives access to both 5-mercaptothiazoles 131 and 5-mercapto-2,3-dihydrothiazoles
133 in good to excellent yields. Mechanistically, the initially formed Cu-carbene 29A was
chemoselectively attacked by thiocarbonyl sulfur of α-imino-β-oxodithioester 130/132 to
give thiocarbonyl ylide 29C, which, in turn, reacted with diazocarbonyl compound 129
to afford intermediate 29D, thereby regenerating copper carbene species 29A. Interme-
diate 29D underwent intramolecular cyclization producing 2,3-dihydrothiazole 133. If
N-hydroxy-substrate 130 was used, 133 was converted to aromatic thiazole 131 with a loss
of water molecule on moderate heating (Scheme 29).
BnO2C
Rh2(Oct)4 (2.5 mol%) N N
BocHN CO2Me
NH2 Me N S
BocHN DCM, reflux S O
O 74%
Me HN S Me
HN
126 127 H
N Me
Me N O
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128
amythiamicin D
S
Scheme 28. Preparation of thiazole 127 from amino acid amide and diazo compound in the total synthesis of amythiamicin
CO2Me
D. N
O
O O N N
CO2Me Approaches to 1,3-Thiazoles Starting from Diazo Compounds
2.3.3. Other
Me
S
N
An
interesting MeHN NH
2 BnO2Cprocedure for the chemoselective synthesisN of 2,4,5-substituted thia-
BnO2C 53 S S
zoles from diazo carbonyls 129 and α-(N-hydroxy/aryl)imino-β-oxodithioesters
N 130/132
Rh2(Oct)4 (2.5 mol%) N
BocHN
was reported in 2017 by Srivastava CO2Me andMe
co-workers [68]. The [Cu(CH3CN)4]PF6-catalyzed
NH2 N S
BocHN DCM, reflux O
reaction
74%
gives access toS both 5-mercaptothiazoles 131 and 5-mercapto-2,3-dihydrothia-
O Meyields. Mechanistically, Me Cu-carbene 29A
zoles 133 in good to excellent HN S the initially formed
HN
126 127 H
was chemoselectively attacked by thiocarbonyl sulfur of α-imino-β-oxodithioester
N Me 130/132
Me N O
to give thiocarbonyl ylide 29C, which, in turn, reacted Me
with diazocarbonyl compound 129
O
to afford intermediate 29D, thereby regenerating copper carbene species 29A. Intermedi-
128
ate 29D underwent intramolecular cyclization producing 2,3-dihydrothiazole
amythiamicin D 133. If N-
hydroxy-substrate 130 was used, 133 was converted to aromatic thiazole 131 with a loss
Scheme
Scheme 28. Preparation
28. Preparation of thiazole
of thiazole 127127 from
from amino
amino acidamide
acid amideand
anddiazo
diazocompound
compound inin the
the total
totalsynthesis
synthesisofofamythiamicin
amythiamicin D.
D.
2.3.3. Other Approaches to 1,3-Thiazoles Starting from Diazo Compounds

An interesting procedure for the chemoselective synthesis of 2,4,5-substituted thia-
zoles from diazo carbonyls 129 and α-(N-hydroxy/aryl)imino-β-oxodithioesters 130/132
was reported in 2017 by Srivastava and co-workers [68]. The [Cu(CH3CN)4]PF6-catalyzed
reaction gives access to both 5-mercaptothiazoles 131 and 5-mercapto-2,3-dihydrothia-
zoles 133 in good to excellent yields. Mechanistically, the initially formed Cu-carbene 29A
was chemoselectively attacked by thiocarbonyl sulfur of α-imino-β-oxodithioester 130/132
to give thiocarbonyl ylide 29C, which, in turn, reacted with diazocarbonyl compound 129
to afford intermediate 29D, thereby regenerating copper carbene species 29A. Intermedi-
ate 29D underwent intramolecular cyclization producing 2,3-dihydrothiazole 133. If N-
hydroxy-substrate 130 was used, 133 was converted to aromatic thiazole 131 with a loss
Scheme
Scheme 29. [Cu(CH
29. [Cu(CH 3CN)
3 CN) 4]PF
4 ]PF 6-catalyzed
6 -catalyzed synthesisofof5-mercaptothiazoles
synthesis 5-mercaptothiazoles and
and 5-mercapto-2,3-dihydrothiazoles
5-mercapto-2,3-dihydrothiazoles from
fromdi-
diazo
azo carbonyl
carbonyl compounds
compounds and α-(N-hydroxy/aryl)imino-β-oxodithioesters.
and α-(N-hydroxy/aryl)imino-β-oxodithioesters.
2.4.Imidazoles
2.4. Imidazoles
Imidazolederivatives
Imidazole derivatives are
are widely
widelyused
usedininmedicinal
medicinal chemistry.
chemistry.Agents
Agentsbased on im-
based on im-
idazole moiety possess anticancer, antifungal, antibacterial, antiviral, anti-inflammatory,
idazole moiety possess anticancer, antifungal, antibacterial, antiviral, anti-inflammatory,
and other biological activities [69]. Another area of application of imidazoles is in organic
light-emitting diodes (OLEDs) and semiconductors [70]. To date, many methods have been
developed for the synthesis of imidazoles, including the classical Debus-Radziszewski imida-
zole synthesis and reaction of α-halo carbonyl compounds with amidines [71,72]. However,
syntheses based on diazocarbonyl compounds have not yet become widespread.
There are two main approaches to the preparation of imidazoles using diazocarbonyl
compounds: Metal catalyzed insertion into the NH bond of ureas followed by cyclization
Scheme 29. [Cu(CH3CN)with
4]PF6-catalyzed
formationsynthesis of 5-mercaptothiazoles
of 2-imidazolones (which canandbe
5-mercapto-2,3-dihydrothiazoles fromimidazoles),
easily converted to substituted di-
azo carbonyl compoundsand
and α-(N-hydroxy/aryl)imino-β-oxodithioesters.
NH-insertion into amides followed by cyclization in the presence of amine or an
ammonia source. In addition, there are also some more exotic syntheses making use of
2.4. Imidazoles
isocyanides, imines, and nitriles.
Imidazole derivatives are widely used in medicinal chemistry. Agents based on im-
idazole moietyof
2.4.1. Synthesis possess anticancer,
Imidazoles antifungal,
by Reaction antibacterial, antiviral,
of Diazocarbonyl Compoundsanti-inflammatory,
with Amides
and Ureas
In 2003, the Janda group reported the one-pot procedure for the synthesis of 2-
imidazolones 137 by rhodium(II)-catalyzed NH-insertion involving α-diazo-β-ketoesters
oles), and NH-insertion into amides followed by cyclization in the presence of amine or
an ammonia source. In addition, there are also some more exotic syntheses making use of
isocyanides, imines, and nitriles.
Molecules 2021, 26, 2530 2.4.1. Synthesis of Imidazoles by Reaction of Diazocarbonyl Compounds with Amides 19 of 70
and Ureas
In 2003, the Janda group reported the one-pot procedure for the synthesis of 2-imid-
azolones 137 by rhodium(II)-catalyzed NH-insertion involving α-diazo-β-ketoesters 134
134 and primary ureas 135 followed by TFA-mediated cyclodehydration of insertion prod-
and primary ureas 135 followed by TFA-mediated cyclodehydration of insertion products
ucts 136 (Scheme
136 (Scheme 30) The
30) [73]. [73].reaction
The reaction resulted
resulted in goodinyields
good yields
with a with a full chemoselectivity.
full chemoselectivity.
Encouraged by the successful results obtained by performing
Encouraged by the successful results obtained by performing these syntheses these syntheses
in so- in
solution, the authors investigated this strategy on solid phase using hydroxypentyl-JandaJel
lution, the authors investigated this strategy on solid phase using hydroxypentyl-JandaJel
polymer-bound α-diazo-β-ketoesters 138
polymer-bound α-diazo-β-ketoesters 138(Scheme
(Scheme31).31).Imidazolones
Imidazolones were
140140 thenthen
were cleaved
from thefrom
cleaved resinthe
either
resinby transesterification
either to givetoesters
by transesterification 141 or141
give esters by orthebyamidation reaction
the amidation
to give more
reaction to givediversely substituted
more diversely amides
substituted 142 in
amides 142fair yields
in fair andand
yields high
highpurity.
purity.The
Theonly
limitation was was
only limitation the unallowable
the unallowableuse use
of diazo substrates
of diazo substrates bearing long
bearing longalkyl R1Rsubstituents.
alkyl 1 substit-
In these
uents. Incases, the yield
these cases, the was
yieldpoor, or theorproduct
was poor, could
the product not be
could notisolated.
be isolated.
Scheme 30.
30. Two-step
Two-step2-imidazolone
2-imidazolonesynthesis
synthesisfrom α-diazo-β-ketoesters
from andand
α-diazo-β-ketoesters primary ureas.
primary ureas.
Scheme 31. 2-Imidazolone

Scheme 2-Imidazolonesynthesis
synthesisfrom
fromα-diazo-β-ketoesters andand
α-diazo-β-ketoesters primary ureas
primary on solid
ureas phase.
on solid phase.
In a continuation of this topic, a work on the expansion of the range of suitable diazo
carbonyls and further functionalization of imidazolones by the same authors was pub-
lished in 2004 (Scheme 32) [74]. α-Diazo-β-ketophosphonates, α-diazo-1,3-diketones, α-
diazo-β-ketoamides, diazomalonic ester, ethyl diazoacetate, amd ethyl 2-diazo-2-(dieth-
Molecules 2021, 26, 2530 20 of 70
In a continuation of this topic, a work on the expansion of the range of suitable diazo
carbonyls and further functionalization of imidazolones by the same authors was published
in 2004 (Scheme 32) [74]. α-Diazo-β-ketophosphonates, α-diazo-1,3-diketones, α-diazo-β-
ketoamides, diazomalonic ester, ethyl diazoacetate, amd ethyl 2-diazo-2-(diethoxyphosphoryl)
acetate have been successfully involved in the reaction. It should be noted that some of
the intermediates 144 could be isolated. The resulting imidazolones 145 could be alkylated
Molecules 2021, 26, x FOR PEER REVIEW
both in solution (Scheme 33a) and on solid phase (Scheme 33b). In the second21
Molecules 2021, 26, x FOR PEER REVIEW 21
of 74
case,
of 74both
transesterification and amidation can be used to cleave the product from the polymer resin.
Scheme 32.
Scheme Synthesis
Synthesisof
of2-imidazolones
2-imidazolonesfrom various
from diazo
various carbonyls
diazo andand
carbonyls primary ureas.
primary ureas.
Scheme 32.
32. Synthesis of 2-imidazolones from various diazo carbonyls and primary ureas.
Scheme 33. Derivatization of 2-imidazolones in solution- and solid-phase.

Scheme 33. Derivatization
Scheme Derivatizationofof2-imidazolones
2-imidazolones inin
solution- and
solution- solid-phase.
and solid-phase.
The
The above
above method
method hashas found
found application
application in
in medicinal
medicinal chemistry
chemistry [75,76].
[75,76]. In
In 2015,
2015,
Gong
Gong and co-workers obtained a number of imidazolones 152, which were then used
and co-workers obtained a number of imidazolones 152, which were then used in
in
the
the synthesis
synthesis of
of aa series
series of
of potential
potential c-Met
c-Met kinase
kinase inhibitors
inhibitors 153
153 (Scheme
(Scheme 34)
34) [75].
[75].
Molecules 2021, 26, 2530 21 of 70
Another aspect of this work was the conversion of imidazolones 145 to 2-bromoimi-
dazoles 148 by the treatment with POBr3 in refluxing benzene or toluene. Compounds 148
can be further derivatized via the Suzuki cross-coupling reaction (Scheme 33c).
Thus, in this series of works, the authors have shown the applicability of this approach
for the synthesis of libraries of various imidazolone and imidazole derivatives, also in an
array mode.
The above method has found application in medicinal chemistry [75,76]. In 2015,
Molecules
Molecules 2021,
2021, 26,
26, xx FOR
FOR PEER
PEER REVIEW
REVIEW 22
22 of 74
of in
74
Gong and co-workers obtained a number of imidazolones 152, which were then used
the synthesis of a series of potential c-Met kinase inhibitors 153 (Scheme 34) [75].
Scheme
Scheme 34.34. Diazo
Diazoapproach
Diazo approachfor
approach forthe
for thepreparation
the preparation
preparationof 2-imidazolones
ofof
2-imidazolones 152
152
2-imidazolones in
152in the synthesis
thethe
in synthesis of
of c-Met
synthesis c-Met
of c-Met
kinase inhibitors
kinaseinhibitors
kinase 153.
inhibitors153.
153.
In
In 2004,
2004, the
the aforementioned
aforementionedMoody’s strategy
Moody’sstrategy for
strategyfor
forthe synthesis
thesynthesis
synthesisof 1,3-oxazoles
of1,3-oxazoles based
1,3-oxazolesbased
based
on
on the NH-insertion
theNH-insertion
NH-insertion of rhodium
ofrhodium carbene
rhodiumcarbene intermediates
carbeneintermediates generated
intermediatesgenerated
generatedfromfrom α-diazocarbonyl
fromα-diazocarbonyl
α-diazocarbonyl
compounds
compounds into into primary
primary amides
amides (Section
(section 2.1.2,
2.1.2.,Scheme
(section 2.1.2., Scheme8)
Scheme 8)was
8) wasextended
was extendedto
extended tothe
to thesynthesis
the synthesis
synthesis
of
of 1,3-thiazoles
1,3-thiazoles (Section
(section 2.3.2,
2.3.2.,Scheme
(section 2.3.2., Scheme27)
Scheme 27)and
27) andimidazoles
and imidazoles[64].
imidazoles [64].Thus,
[64]. Thus,imidazoles
Thus, imidazoles156
imidazoles 156were
156 were
were
obtained
obtainedby bytreatment
treatmentofofintermediate
intermediate155
intermediate 155with
155 withaaprimary
with primaryamine
primary amineor
amine orammonium
or ammoniumacetate
ammonium acetatein
acetate in
in
the presence of acetic acid under reflux
reflux conditions
conditions (Scheme
(Scheme
the presence of acetic acid under reflux conditions (Scheme 35). 35).
35).
Scheme 35. Two-step

Scheme35. Two-stepimidazole
Two-step imidazolesynthesis
imidazole synthesisfrom
synthesis from α-diazo-β-ketoestersand
α-diazo-β-ketoesters
fromα-diazo-β-ketoesters andprimary
and primaryamides.
primary amides.
amides.
2.4.2.
2.4.2. Other
Other Syntheses
Syntheses of of Imidazoles
Imidazoles from
from Diazo
Diazo Compounds
Compounds
In
In 2017,
2017, Zhao
Zhao and and co-workers
co-workers devised
devised an
an effective
effective copper-catalyzed
copper-catalyzed cascade
cascade cycliza-
cycliza-
tion
tion reaction
reaction ofof isocyanides
isocyanides 157
157 with
with α-diazocarbonyls
α-diazocarbonyls 158158 [77].
[77]. This
This protocol
protocol furnishes
furnishes
imidazolines
imidazolines 159
159 (Scheme
(Scheme 36,
36, a)
a) and
and biimidazoles
biimidazoles 160
160 (Scheme
(Scheme 36b)
36b) in
in good
good yields
yields under
under
Molecules 2021, 26, 2530 Biimidazoles 160 were obtained when tosyl methyl isocyanide (TosMIC) 157b22was of 70used
as the isocyanide component.
A plausible reaction mechanism is presented in Scheme 37. Initially, the copper iso-
cyanide complex 161 is formed in which the acidity of the α-H atom is significantly en-
2.4.2. Other Syntheses of Imidazoles from Diazo Compounds
hanced compared to the non-complexed 157. Subsequently, nucleophilic attack of 161
In 2017, Zhao and co-workers devised an effective copper-catalyzed cascade cycliza-
onto the terminal nitrogen atom of α-diazocarbonyl compound 158 occurs under basic
tion reaction of isocyanides 157 with α-diazocarbonyls 158 [77]. This protocol furnishes
conditions to give intermediate 37A. Intermediate 37B, (generated by the formal [3+2] cy-
imidazolines 159 (Scheme 36, a) and biimidazoles 160 (Scheme 36b) in good yields under
cloaddition
very reaction Imidazolines
mild conditions. of 37A with complex
159 were 161) thenas
obtained undergoes
a mixture intramolecular
of diastereomerscyclization
using
ethyl isocyanoacetate 157a. Stereochemistry of the product depends onfrom
to give the bicyclic intermediate 37C. Imidazoline 159 is formed the Rintermediate
2 substituent: 37C
via ring-opening
Bulky hydroxyalkylfollowed by HCN elimination
R2 substituents and protonation.
gave the mixture When TosMIC
with predominance of the was
trans-used,
imidazoline 159 suffered base-mediated elimination of sulfinic acid to produce
isomer whereas aryl substituents afforded the product mixture with predominance of the the inter-
mediate 37E,
cis-isomer. Onlywhich then
in the caseunderwent a formal
of the ethoxy group [3+2] cycloaddition
was the trans-isomerwith the third
obtained equivalent
exclusively.
of complex 161.
Biimidazoles 160 The
werefollowing elimination
obtained when of sulfinic
tosyl methyl acid from
isocyanide the intermediate
(TosMIC) 157b was used 37F
asgave
the
the isocyanide
biimidazolecomponent.
160.
Scheme36.
Scheme 36.CuI-catalyzed
CuI-catalyzedsynthesis
synthesis
of of imidazolines
imidazolines 147147
andand biimidazoles
biimidazoles 148 from
148 from diazodiazo carbon-
carbonyls
yls and isocyanides.
and isocyanides.
A plausible reaction mechanism is presented in Scheme 37. Initially, the copper iso-
cyanide complex 161 is formed in which the acidity of the α-H atom is significantly enhanced
compared to the non-complexed 157. Subsequently, nucleophilic attack of 161 onto the
terminal nitrogen atom of α-diazocarbonyl compound 158 occurs under basic conditions
to give intermediate 37A. Intermediate 37B, (generated by the formal [3+2] cycloaddition
reaction of 37A with complex 161) then undergoes intramolecular cyclization to give the bi-
cyclic intermediate 37C. Imidazoline 159 is formed from intermediate 37C via ring-opening
followed by HCN elimination and protonation. When TosMIC was used, imidazoline 159
suffered base-mediated elimination of sulfinic acid to produce the intermediate 37E, which
then underwent a formal [3+2] cycloaddition with the third equivalent of complex 161. The
following elimination of sulfinic acid from the intermediate 37F gave the biimidazole 160.
Molecules 2021, 26, 2530 23 of 70
Scheme 37. Mechanism of CuI-catalyzed synthesis of imidazolines 159 and biimidazoles 160 from diazo carbonyls and
isocyanides.
Scheme 37. Mechanism
Scheme MechanismofofCuI-catalyzed
CuI-catalyzedsynthesis of of
synthesis imidazolines 159159
imidazolines andand
biimidazoles 160 160
biimidazoles from diazo
from carbonyls
diazo and
carbonyls
isocyanides.
and isocyanides.
In 2016, the reaction of α-diazo oxime ethers 162 (available from β-ketoester via one-
pot oxime formation
In 2016,
2016, the with of
thereaction
reaction subsequent
α-diazooxime
ofα-diazo diazoethers
oxime transfer
ethers162 reaction
162(available [78])
(availablefromwith
from nitriles 163
β-ketoester
β-ketoester viain pres-
one-pot
via one-
ence
oximeof copper
formation
pot oxime triflate
withwith
formation (Cu(OTf)
subsequent 2
subsequent) catalyst
diazo was
transfer
diazo described
reaction
transfer by Kuruba
[78])[78])
reaction and
withwith co-workers
nitriles 163 in
nitriles in [79].
163presence
pres-
The
of
ence developed
copper triflate
of copper procedure
(Cu(OTf)
triflate 2 )provided
(Cu(OTf) catalyst fully
was
2) catalyst
decorated
described
was N-methoxyimidazoles
by Kuruba
described and co-workers
by Kuruba and co-workers 164
[79].and
The
[79].
worked
developedwell with a
procedure broad range
provided of
fully nitriles,
decorated both aliphatic and
N-methoxyimidazoles
The developed procedure provided fully decorated N-methoxyimidazoles 164 and aromatic.
164 Mechanistically,
and worked well
two
withpossible
worked wellreaction
a broad range
with aof pathways
nitriles,
broad range were
both proposed.
of aliphatic
nitriles, and
bothInaliphatic
both cases,
aromatic. thearomatic.
reaction Mechanistically,
Mechanistically,
and begins
twowith the
possible
formation
two possible reaction pathways were proposed. In both cases, the reaction begins withat-
reaction of metal
pathways carbene
were 38A
proposed. fromIn diazo
both compound
cases, the 162.
reaction In Path
begins 1,
withcarbene
the 38A
formationis of
the
tacked
metal by nitrile
carbene
formation 163
38A from
of metal to form
carbenediazo adduct
38Acompound 38B,
from diazo which affords ylide
In Path 1, carbene
162.compound 38C after
38A 1,
162. In Path the release
is attacked
carbene 38A of the
by nitrile
is at-
catalyst.
163
tacked Ylide
to form
by 38C163
adduct
nitrile then
38B, undergoes
which
to form adduct cyclization
affords
38B, ylide
which giving
38C after
affordsimidazole
the release
ylide 38C164.
ofPath
afterthe 2 release
leads toof
thecatalyst. the
Ylide
the
formation
38C then of azirine
undergoes 38D with
cyclization subsequent
giving ring
imidazole expansion.
164. However,
Path 2
catalyst. Ylide 38C then undergoes cyclization giving imidazole 164. Path 2 leads to theleads no
to azirine
the interme-
formation of
diates
azirinehave
38D been
with detected
subsequent or isolated,
ring so
expansion.it was concluded
However, no that
azirine
formation of azirine 38D with subsequent ring expansion. However, no azirine interme- path 1 was
intermediatesfavored
have over
been
path 2 (Scheme
detected
diates have been38).detected
or isolated, so it was concluded
or isolated, sothat
it waspath 1 was favored
concluded over 1path
that path was2favored
(Schemeover 38).
path 2 (Scheme 38).
Scheme 38. Copper-mediated synthesis of N-methoxyimidazoles from α-diazo oxime ethers and nitriles. .
Scheme 38. Copper-mediated synthesis of N-methoxyimidazoles from α-diazo oxime ethers and nitriles.
Scheme 38. Copper-mediated synthesis of N-methoxyimidazoles from α-diazo oxime ethers and nitriles.
methods for the synthesis of polyarylated imidazolium salts would be a timely undertak
ing. To achieve this goal, the Liu group developed a gold-catalyzed [2+2+1] annulation
reaction involving two equivalents of imine 165 and one equivalent of aryl diazoacetoni
trile 166 [83]. Introducing electron-rich aryl substituents in the imine component resulted
Molecules 2021, 26, 2530 in higher yields of imidazolium salts 167 compared to the imines bearing24electron-defi of 70
cient substituents. The same effects were observed from the substituents in the diazo ni
trile aryl ring. Moreover, these imidazolium salts can be further modified by the So
nogashira reaction
Imidazolium saltstoare
afford polyalkynyl-substituted
currently being intensively studied derivatives 168metal
as electrolytes, (Scheme 39).
ligands,
Based on
ionic liquids, andDFT-calculations, the However,
liquid crystals [80–82]. followingonly mechanism washave
a few studies proposed. Imine cis-16
been devoted
to the synthesis
attacks of polyarylated
gold carbene imidazolium
40A to produce salts. Thus,
iminium development
intermediate 40B of new methods
which for attacked
is, in turn,
the synthesis of polyarylated imidazolium salts would be a timely undertaking.
by another imine molecule to give intermediate 40C (or its conformer 40C’). The latter can To achieve
this goal, the Liu group developed a gold-catalyzed [2+2+1] annulation reaction involving
evolve along two possible pathways. Path a involves the formation of imidazolidine 40D
two equivalents of imine 165 and one equivalent of aryl diazoacetonitrile 166 [83]. Intro-
However, this path is unlikely to occur according to DFT-calculations. In path b, 40C
ducing electron-rich aryl substituents in the imine component resulted in higher yields of
loses HCN to
imidazolium form
salts 167acompared
stable gold carbene
to the imines40E, which
bearing then undergoes
electron-deficient 6π-electrocyclization
substituents. The
in disrotatory mode. 40F is affected by a neighboring cation to release
same effects were observed from the substituents in the diazo nitrile aryl ring. Moreover, LAu+. Zwitterion
40G is
these subsequently
imidazolium oxidized
salts to desired
can be further compound
modified by the 167. It is worth
Sonogashira mentioning
reaction to affordthat in thi
case, aryl diazoacetonitriles
polyalkynyl-substituted can serve
derivatives as arylmethine
168 (Scheme 39). fragment source (Scheme 40).
Scheme39.
Scheme 39.Gold-catalyzed
Gold-catalyzed [2+2+1]
[2+2+1] annulation
annulation reactionreaction for synthesis
for synthesis of polyarylated
of polyarylated imidazolium
imidazolium salts.
salts.
Based on DFT-calculations, the following mechanism was proposed. Imine cis-165
attacks gold carbene 40A to produce iminium intermediate 40B which is, in turn, attacked
by another imine molecule to give intermediate 40C (or its conformer 40C’). The latter can
evolve along two possible pathways. Path a involves the formation of imidazolidine 40D.
However, this path is unlikely to occur according to DFT-calculations. In path b, 40C’ loses
HCN to form a stable gold carbene 40E, which then undergoes 6π-electrocyclization in
disrotatory mode. 40F is affected by a neighboring cation to release LAu+ . Zwitterion 40G
is subsequently oxidized to desired compound 167. It is worth mentioning that in this case,
aryl diazoacetonitriles can serve as arylmethine fragment source (Scheme 40).
Molecules
Molecules 2021,
2021, 26,x 2530
26, FOR PEER REVIEW 25
26ofof7074
Ph Ph
Ph LAu
Ph Ph N H
N N H N
Ph Ph
cis-165 Ph
trans-165
Ph CN
a 40D
Ph Ph Ph
Ph H LAu Ph Ph
N Ph Ph N
Ph Ph N
H Ph b H
N a N Ph N Ph
cis-165 AuL N Ph b
LAu NC Ph
LAu CN
Ph CN CN Ph AuL
Ph
40A 40B-cis 40C-cis 40C'-cis
- HCN
Ph Ph Ph Ph
Ph Ph Ph Ph 6
N
N N disrotatory N
N Ph Ph N Ph
Ph Ph N Ph N Ph
Ph
H H Ph
Ph H2 LAu
H Ph LAu Ph AuL
167
40G 40F 40E-cis
Scheme 40.
40. Mechanism
Mechanism of gold-catalyzed
gold-catalyzed [2+2+1] annulation.
Scheme
Scheme 40. Mechanism of gold-catalyzed[2+2+1]
[2+2+1] annulation.
annulation.
2.4.3. Fused
2.4.3.Fused Imidazoles
FusedImidazoles from
Imidazoles from Diazo
from Diazo Compounds
Diazo Compounds
2.4.3. Compounds
The
Themostmost common
most common fused
fused imidazole
imidazole derivative being synthesized from diazo com-
The common fused imidazole derivative
derivative being
being synthesized
synthesizedfrom fromdiazo
diazocom-com-
pounds
pounds is
is imidazo[1,2-a]pyridine.
imidazo[1,2-a]pyridine. The
The classic approach
classic approach to this
to heterocyclic
this ring
heterocyclic is theiscon-
ring the
pounds is imidazo[1,2-a]pyridine. The classic approach to this heterocyclic ring is the con-
densation
condensation of 2-aminopyridines
of 2-aminopyridines and and
α-haloketones
α-haloketones or their
or synthetic
their equivalents
synthetic equivalents[84]. [84].
The
densation of 2-aminopyridines and α-haloketones or their synthetic equivalents [84]. The
imidazo[1,2-a]pyridine-based
The imidazo[1,2-a]pyridine-based drugsdrugs
have found application
have found in therapy
application of musculoskele-
in therapy of muscu-
imidazo[1,2-a]pyridine-based drugs have found application in therapy of musculoskele-
tal, gastrointestinal,
loskeletal, CNS disorders,
gastrointestinal, cardiovascular,
CNS disorders, and infectious
cardiovascular, diseases [85].
and infectious Little[85].
diseases in-
tal, gastrointestinal, CNS disorders, cardiovascular, and infectious diseases [85]. Little in-
formation is available
Little information on the synthesis
is available of other
on the synthesis offused
other imidazole systems
fused imidazole from diazo
systems com-
from diazo
formation
pounds. is available on the synthesis of other fused imidazole systems from diazo com-
compounds.
pounds. The first example of coupling of α-diazoketones
α-diazoketones 169 with 2-aminopyridines 170 was
The
reported
reported infirst
in2007example
2007byby of
Yadav
Yadav coupling
andand of α-diazoketones
co-workers
co-workers [86].[86]. The169
The Cu(OTf) with
Cu(OTf) 2-aminopyridines
2-catalyzed reaction 170pro-
was
2 -catalyzed reaction proceeded
reported
ceeded in 2007 by
regioselectively
regioselectively Yadav and
and afforded
and afforded co-workers [86]. The
imidazo[1,2-a]pyridines
imidazo[1,2-a]pyridines Cu(OTf) 2-catalyzed reaction pro-
171 inyields.
171 in high high yields. Both ar-
Both aromatic
ceeded
omatic regioselectively
and aliphatic
and aliphatic and afforded
diazo ketones
diazo ketones imidazo[1,2-a]pyridines
ere suitable
ere partners partners
suitable for this reaction 171 (Scheme
for this in high yields.
reaction 41). Both
Later,
(Scheme inar-
41).
omatic
Later, and
2014, this
in 2014,aliphatic
method thiswas diazo
method ketones
employed
was ere suitable
towards
employed the partners
synthesis
towards for this
of glucagon-like
the synthesis reaction (Scheme
peptide-1
of glucagon-like receptor
peptide- 41).
Later, in 2014,
1agonists
receptor [87]. this method
agonists [87]. was employed towards the synthesis of glucagon-like peptide-
1 receptor agonists [87].
Scheme 41. Synthesis of imidazo[1,2-a]pyridines from α-diazoketones

α-diazoketones and
and 2-aminopyridines.
2-aminopyridines.
Scheme 41. Synthesis of imidazo[1,2-a]pyridines from α-diazoketones and 2-aminopyridines.
In 2013, the Gevorgyan group in their work on three-component coupling reaction reaction of
2-aminopyridines 172, aldehydes 173, and diazo compounds 174, demonstrated
demonstrated
In 2013, the Gevorgyan group in their work on three-component coupling reaction that the
theof
product of this reaction
reaction 175
175 can
can be
be transformed
transformed to
to imidazo[1,2-a]pyridine
imidazo[1,2-a]pyridine
2-aminopyridines 172, aldehydes 173, and diazo compounds 174, demonstrated that the 176
176 [88].
[88]. The
The
reactionof
product proceeds
this via intermediate
reaction 175 can be177 (formed
(formed via
transformed viato aaimidazo[1,2-a]pyridine
AgBF
AgBF44-catalyzed 1,2-hydride shift)
176 [88]. The
followed by I+ -mediated cyclization, tautomerization, and elimination of HI (Scheme 42).
followed by I + -mediated cyclization, tautomerization, and elimination of HI
reaction proceeds via intermediate 177 (formed via a AgBF4-catalyzed 1,2-hydride shift) (Scheme 42).
followed by I+-mediated cyclization, tautomerization, and elimination of HI (Scheme 42).
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2021, 26,
26, 2530
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x FOR 26, x
PEER FOR PEER REVIEW
REVIEW 26 of
27 of 70
74 27 of
Scheme 42. Scheme 42.ofSynthesis

Synthesis of imidazo[1,2-a]pyridines
imidazo[1,2-a]pyridines 176 from 2-diazo-3-(pyridin-2-ylamino)propanoate.
2-diazo-3-(pyridin-2-ylamino)propanoate.
176 from 2-diazo-3-(pyridin-2-ylamino)propanoate.
An interesting
An interesting example
example of
An interesting using aa of
ofexample
using banana ash
usingash
banana extractash
a banana
extract andextract
and dimethylsulfoxide (WEB-
and dimethylsulfoxide
dimethylsulfoxide (WEB- (WE
DMSO) as
DMSO) asDMSO)
solvent as
solvent cum
cum reagent
solvent cum
reagent system
reagent
system forsystem
for three-step one-pot synthesis
for three-step
three-step one-pot synthesis
one-pot of of imidazo[1,2-
synthesis of imidazo[1
imidazo[1,2-
a]pyridinesa]pyridines
a]pyridines 180was
180 wasreported
180 was
reportedbybyDutta andand
reported
Dutta co-authors
by Dutta in 2019
and
co-authors [89]. Initially,
co-authors
in 2019 in 2019
[89]. a WEB-DMSO-
[89].aInitially,
Initially, WEB- a WE
promoted
DMSO-promotedaldol condensation
DMSO-promoted of ethyl diazoacetate
aldol condensation
aldol condensation 82 and aldehyde
of ethyl diazoacetate
of ethyl diazoacetate 178 occurred
82 and178
82 and aldehyde to
aldehyde give
occurred178 occurr
diazo alcohol
to give diazo 181,
to give which
diazo
alcohol was converted
alcohol
181, which181, to
waswhich 182
was converted
β-ketoester
converted by a
to β-ketoester Pd-catalyzed
to β-ketoester 1,2-H shift. Treat-
182 by a Pd-catalyzed
182 by a Pd-catalyzed 1,2- 1
ment
H of Treatment
shift. 182Hwith
shift.NBS andwith
Treatment
of 182 aminopyridine
ofNBS
182 and 179 on theaminopyridine
withaminopyridine
NBS and third
179step
onafforded
the 179 on
third the corresponding
the
step third stepthe
afforded afforded t
correspondingcorresponding (Scheme 43).180 (Scheme
180imidazo[1,2-a]pyridine
imidazo[1,2-a]pyridine 18043).
(Scheme 43).
Scheme
Scheme 43. WEB-DMSO
43. Scheme
WEB-DMSO promoted
43. WEB-DMSO
promoted synthesis
promoted
synthesis of imidazo[1,2-a]pyridines.
ofsynthesis of imidazo[1,2-a]pyridines.
imidazo[1,2-a]pyridines.
A work
A work bybyAthe Lee
work
the Leebygroup shows
the Lee
group shows that
group imidazopyridines
thatshows can
can bebe synthesized
that imidazopyridines
imidazopyridines not
not only
can be synthesized
synthesized only not on
from aminopyridines, but
from aminopyridines,
from aminopyridines, also directly
but also
but also directly from pyridines
directly
from 183
from 183
pyridines by a
pyridines formal aza-[3+2]
183 byaza-[3+2]
by a formal cycload-
a formalcycload-
aza-[3+2] cycloa
dition reaction
dition dition
reaction with
with α-diazooxime
reaction ethers
ethers 184
with α-diazooxime
α-diazooxime under
under copper
184 ethers 184 catalysis
under
copper copperconditions
catalysis [90].
[90]. The
catalysis conditions
conditions The [90]. T
reaction works well for a broad range of substituents and also allows for preparation of
reaction works well
reaction for
works a broad
well range
for a of
broad substituents
range of and also
substituents allows
and for
also preparation
allows for preparation
of
other N-heterocyclic compounds
other N-heterocyclic such as imidazopyridazines,
compounds imidazopyrimidines,
such as imidazopyridazines, and
imidazopyrimidines, an
other N-heterocyclic compounds such as imidazopyridazines, imidazopyrimidines, and
imidazopyrazines 187 (Scheme
imidazopyrazines 44).
18744). A proposed
(Scheme reaction
44). A reactionmechanism
proposed begins
reaction mechanism with conversion
begins with conve
imidazopyrazines 187 (Scheme A proposed mechanism begins with conver-
of α-diazooxime
sion of ether 184 to Cu-carbene
α-diazooxime ether 184 to 45A, which is attacked
Cu-carbene byisthe pyridine
by nitro-
sion of α-diazooxime ether 184 to Cu-carbene 45A, which45A, which
is attacked byattacked
the pyridinetheni-
pyridine n
gen atom to formatom
trogen zwitterionic intermediateintermediate
to form zwitterionic 45B. Then, 45B undergoes cyclizationcyclization
with
trogen atom to form zwitterionic intermediate 45B. Then,45B. 45B Then, 45B undergoes
undergoes cyclization with wi
regeneration of copper catalyst to give 45C, which, after elimination of alcohol, affords
regeneration of copper catalyst to give 45C, which, after elimination
regeneration of copper catalyst to give 45C, which, after elimination of alcohol, affords of alcohol, affor
imidazo[1,2-a]pyridine 185 (Scheme 45).
imidazo[1,2-a]pyridine 185 (Scheme 18545).
(Scheme 45).
Molecules2021,
Molecules 26, x2530
2021, 26, FOR PEER REVIEW 27 of28
70 of 74
Scheme44.
Scheme
Scheme 44.Synthesis
44. Synthesisofof
Synthesis ofimidazo[1,2-a]pyridines
imidazo[1,2-a]pyridines
imidazo[1,2-a]pyridines from
from
from α-diazooxime
α-diazooxime
α-diazooxime ethers
ethers and
andand
ethers pyridines.
pyridines.
pyridines.
Scheme
Scheme 45. Mechanism of formal aza-[3+2] cycloaddition of α-diazooxime ethers and pyridines.
Scheme 45.
45. Mechanism
Mechanism of
offormal
formalaza-[3+2]
aza-[3+2]cycloaddition
cycloadditionofofα-diazooxime
α-diazooximeethers
ethersand
andpyridines.
pyridines.
AA rare
rare example of
example of another
anotherfused
fusedimidazole
imidazoleheterocycle
heterocycleprepared
preparedfromfromthethediazo
diazo
sub-
substrate was presented in the work by Ueda and co-workers [91]. Theophyllines 191 sub-
A rare example of another fused imidazole heterocycle prepared from the diazo
strate was presented
strateobtained
was presented in the
in the work by
work by192 Ueda
Ueda and
and co-workers [91]. Theophyllines 191 were
were along with cyanamides from theco-workers [91].acid
diazobarbituric Theophyllines
derivative 189 191
bywere
obtained along with cyanamides 192 from the diazobarbituric acid derivative 189 byby
treat-
treatment with amine 190 in the presence of Rh2 (OAc)4 . The imino diazo compound 189treat-
obtained along with cyanamides 192 from the diazobarbituric acid derivative 189
ment
ment with amine
with amine 190 in the presence of Rh 2(OAc)4. The imino diazo compound 189 was
was synthesized by190 in the of
oxidation presence of Rh2(OAc)4. The
7,8-diaminotheophyline 188imino diazo compound
with Pb(OAc) 4 (Scheme 189
46). was
synthesized by oxidation of 7,8-diaminotheophyline 188 with Pb(OAc)4 (Scheme 46). Un-
synthesized bythe
Unfortunately, oxidation
method is ofcharacterized
7,8-diaminotheophyline 188 with Pb(OAc)4 (Scheme 46). Un-
by low selectivity.
fortunately, the method is characterized by low selectivity.
fortunately, the method is characterized by low selectivity.
Molecules 2021, 26, 2530 28 of 70

Scheme 46. Synthesis of theophyllines from diazobarbituric acid derivative and amines.
Scheme
2.5. 46. Synthesis
Pyrazoles (1H, 3Hofand
theophyllines from diazobarbituric
diazobarbituric acid
4H) and Indazoles acid derivative
derivative and
and amines.
amines.
2.5. Pyrazole (1H,

Pyrazoles and 3H
indazole
and are common units in a number of synthetic products, such as
2.5. Pyrazoles (1H, 3H and 4H)
4H) and
and Indazoles
Indazoles
tartrazine (food coloring agent), dipyrone (antipyretic and analgesic agent), sildenafil
Pyrazole and indazole
indazole are common units
units in
in aa number of
of synthetic products, such as
(drugPyrazole
used forand the treatment are commondisfunction),
of erectile number
rimonabant synthetic products,
(drug used such
to treat as
obe-
tartrazine
tartrazine (food coloring
(food(selective agent),
coloring COX-2 dipyrone
agent), inhibitors(antipyretic
dipyrone (antipyretic and analgesic agent),
and analgesic sildenafil (drug
agent), sildenafil
sity), celecoxib and non-steroidal anti-inflammatory drug,
used
(drugfor thefor
used treatment of erectile
the(insecticide),
treatment disfunction),
ofpazopanib
erectile rimonabant
disfunction), rimonabant(drug(drug
usedusedto treat obesity),
to treat obe-
NSAID), fipronil (tyrosine kinase inhibitor), and benzydamide
celecoxib
sity), (selective
celecoxib COX-2
(selective inhibitors
COX-2 and non-steroidal
inhibitors and anti-inflammatory
non-steroidal drug,
anti-inflammatory NSAID),
drug,
(locally acting NSAID). Other biological activities of pyrazole- and indazole-containing
fipronil
NSAID),(insecticide),
fipronil pazopanib
(insecticide), (tyrosine (tyrosine
pazopanib kinase inhibitor),
kinase and benzydamide
inhibitor), (locally
and benzydamide
compounds include antimicrobial, antihyperglycemic, pesticidal, leishmanicidal, an-
acting NSAID).
(locally acting Other
NSAID). biological activities
Other biological of pyrazole- and indazole-containing
activities of pyrazole- compounds
tichagasic, anti-HIV, anti-depressant, and antiarrhythmic [92–95].and
Amongindazole-containing
methods for the
include antimicrobial, antihyperglycemic, pesticidal, leishmanicidal, antichagasic, anti-
compounds
synthesis include antimicrobial,
of pyrazoles diazo strategiesantihyperglycemic,
are widely pesticidal, leishmanicidal, an-
HIV, anti-depressant, and antiarrhythmic [92–95].used. One
Among commonly
methods forknown approach
the synthesis of
tichagasic,
is anti-HIV,
the 1,3-dipolar anti-depressant,
cycloaddition betweenand antiarrhythmic
diazo compounds [92–95]. Among methods for the
pyrazoles diazo strategies are widely used. One commonlyand alkynes,
known or alkenes
approach is thewith
1,3-
synthesis
the leaving ofgroup
pyrazoles diazo
[96,97], strategies
including are widely used. [14,15].
One commonly known isapproach
dipolar cycloaddition between diazodeacylative
compoundsvariant
and alkynes, orAnother
alkenesroute
with the an intra-
leaving
is the
molecular 1,3-dipolar cycloaddition
cyclization of vinyldiazo between diazo
compounds compounds
[98]. Moreover, and toalkynes,
date, a or alkenes
number of with
other
group [96,97], including deacylative variant [14,15]. Another route is an intramolecular
the leaving
methods group [96,97],
involving including deacylative
diazo compounds
compounds been variant
have Moreover, [14,15]. Another route is an intra-
developed.
cyclization of vinyldiazo [98]. to date, a number of other methods
molecular cyclization of vinyldiazo compounds [98]. Moreover, to date, a number of other
involving diazo compounds have been developed.
methods
2.5.1. involving diazo compounds have been developed.
1H-Pyrazoles
2.5.1. 1H-Pyrazoles
2.5.1. 1H-Pyrazoles
Synthesis
Synthesis of
of 1H-Pyrazoles
1H-Pyrazoles by by 1,5-Electrocyclization of Vinyldiazo
1,5-Electrocyclization of Vinyldiazo Compounds
Compounds
AA mechanism
mechanism of of this
this transformation
transformationisisdepicted
depictedininScheme
Scheme47.
47.ItItinvolves
involves1,5-electrocy-
1,5-electro-
Synthesis of 1H-Pyrazoles by 1,5-Electrocyclization of Vinyldiazo Compounds
cyclization
clization ofofthe
thevinyldiazo
vinyldiazocompound
compound193 193with
withsubsequent
subsequent tautomerization
tautomerization to to yield
yield 1H-
1H-
A mechanism
pyrazole 195 [99]. of this transformation is depicted in Scheme 47. It involves 1,5-electro-
cyclization of the vinyldiazo compound 193 with subsequent tautomerization to yield 1H-
pyrazole 195 [99].
Scheme
Scheme 47.
47. The
The mechanism
mechanism of
of intramolecular
intramolecular cyclization
cyclization of
of vinyldiazo
vinyldiazo compounds.
compounds.
Scheme 47. The

Inmechanism
In of intramolecular
the works by the Nikolaev
the cyclization
Nikolaevgroup, of vinyldiazo
group,ititwas
was shownthat
shown compounds.
that configuration
configuration ofof double
double bond
bond in
vinyldiazo
in vinyldiazocompounds
compoundssignificantly affectsaffects
significantly their reactivity in this reaction
their reactivity (Scheme (Scheme
in this reaction 48) [100,101].
48)
In thetrans-Vinyl
trans-Vinyl
[100,101]. works by the Nikolaev
diazo compounds
diazo 196 group, itunderwent
readily196
compounds was shown
readily that configuration
electrocyclization
underwent of double
under bond
moderate
electrocyclization under
in vinyldiazo(80
temperature ◦ C), whilesignificantly
compounds affects their
their cis-counterparts 198reactivity
produced in pyrazoles
this reaction
199(Scheme 48)
only at ele-
[100,101].
vated trans-Vinyl
temperatures (updiazo ◦ C) or decomposed
to 120compounds 196 readily
withunderwent
formation electrocyclization under
of furans 200. Moreover,
Molecules 2021, 26, 2530 29 of 70
moderate temperature (80 °C), while their cis-counterparts 198 produced pyrazoles 199
moderate temperature (80 °C), while their cis-counterparts 198 produced pyrazoles 199
only at elevated temperatures (up to 120 °C) or decomposed with formation of furans 200.
only at elevated temperatures (up to 120 °C) or decomposed with formation of furans 200.
Moreover,
the authorsthe authors demonstrated
demonstrated that fluoroalkyl-substituted
that fluoroalkyl-substituted vinyldiazo
vinyldiazo carbonyls trans
carbonyls
201 (both
Moreover, the authors demonstrated that fluoroalkyl-substituted vinyldiazo carbonyls
201 cis) failed
and(both trans to
andgive
cis)any pyrazole
failed to giveproducts, furnishing
any pyrazole onlyfurnishing
products, carbene-derived products
only carbene-de-
201 (both trans and cis) failed to give any pyrazole products, furnishing only carbene-de-
on heating.
rived products Interestingly,
on heating.the Interestingly, enol-202
diazo enol the diazoformed in situ can
enol enol-202 also in
formed undergo
situ canthis
also
rived products on
transformation, heating.
affording Interestingly, the 203.
4-hydroxypyrazole diazo enol enol-202 formed in situ can also
undergo this transformation, affording 4-hydroxypyrazole 203.
undergo this transformation, affording 4-hydroxypyrazole 203.
Scheme
Scheme
Scheme 48.
48. Effectofof
Effect
48. Effect ofdouble
doublebond
double bondconfiguration
bond configurationand
configuration andfluoroalkyl
fluoroalkylsubstituent
fluoroalkyl substituenton
on1,5-electrocyclization
1,5-electrocyclization reaction.
1,5-electrocyclizationreaction.
reaction.
AnAn attempt
attemptto
Anattempt toprepare
to preparecarbapenem
prepare carbapenem
carbapenem precursor
precursor
precursor by by
206206
206 treatment
by treatment of diazo
treatment of carbonyls
ofdiazo
diazo 204
carbonyls
carbonyls
with
204 DBU
204with
withDBU and
DBUand andβ-lactam 205 unexpectedly
β-lactam 205
β-lactam 205 unexpectedly led
unexpectedly ledto the
led to formation
to the of
the formation
formationofhydroxypyrazoles
ofhydroxypyrazoles207
hydroxypyrazoles
(Scheme
207(Scheme
207 49) 49)
(Scheme [102]. From
49)[102].
[102]. the the
From
From mechanism
the mechanism
mechanism standpoint, the 1,5-electrocyclization
standpoint,
standpoint, the
the 1,5-electrocyclizationof enolate
1,5-electrocyclization ofofeno-
eno-
50A
late likely
50A gave
likely pyrazolium
gave anion
pyrazolium 50C,
anion which
50C, reacted
which with
reacted imine
with 50D,
imine
late 50A likely gave pyrazolium anion 50C, which reacted with imine 50D, which was, which
50D, was,
which in turn,
was, inin
formed
turn, by DBU-promoted
formed by DBU-promotedelimination of acetic
elimination of acid from
acetic acid from 205 (Scheme
β-lactam
β-lactam 205 50). The
(Scheme 50).
turn, formed by DBU-promoted elimination of acetic acid from β-lactam 205 (Scheme 50).
direct regiospecific
Thedirect
direct synthesis
regiospecific of N-arylpyrazoles
synthesis by theby
of N-arylpyrazoles
N-arylpyrazoles co-catalyzed reaction of vinyl diazo
The regiospecific synthesis of by the
the co-catalyzed
co-catalyzedreaction
reactionofofvinyl
vinyl
carbonyls and
diazocarbonyls aryl
carbonylsand diazonium
andaryl salts
aryldiazonium has
diazonium salts also been
salts has
has alsoreported [103].
diazo also been
been reported
reported[103].
[103].
Scheme 49. Formation ofScheme

N-substituted hydroxypyrazoles
49. Formation from enolizable
of N-substituted diazo carbonyls
hydroxypyrazoles from and β-lactam
enolizable derivatives.
diazo carbonyls and
Scheme 49. Formation of N-substituted hydroxypyrazoles from enolizable diazo carbonyls and β-lactam derivatives.
β-lactam derivatives.
Molecules 2021, 26, 2530 30 of 70
Scheme 50.
50. Mechanism
Mechanismof of formation
offormation
formationof N-substituted hydroxypyrazoles
N-substituted from enolizable diazo
Scheme
Scheme 50. Mechanism of of
N-substituted hydroxypyrazoles
hydroxypyrazoles fromfrom enolizable
enolizable diazodiazo car-
carbonyls
bonyls and
andand β-lactam derivatives.
derivatives.
carbonyls β-lactam
β-lactam derivatives.
Thesynthesis
The
The synthesisof
synthesis of mono-,
ofmono-, di-,
mono-,di-, and
di-,and
andtri-substituted
tri-substituted
tri-substituted pyrazoles
pyrazoles
pyrazoles 209209
209 from
from vinyldiazo
from vinyldiazo
vinyldiazo com-com-
com-
pounds
pounds 208
208 was
was recently
recently reported
reported by
by Dikermann
Dikermann and
andco-workers
co-workers
pounds 208 was recently reported by Dikermann and co-workers (Scheme 51) [104]. The (Scheme
(Scheme51) [104].
51) TheThe
[104].
reactionproceeds
reaction proceedssmoothly
smoothlyon onheating
on heatingin
heating intrifluoromethylbenzene
in trifluoromethylbenzene affording
trifluoromethylbenzeneaffording desired
affordingdesired prod-
desiredprod-
products
ucts
in in yields
yields
ucts in yields
of upofoftoup
up
94%.to 94%.
to 94%. The synthesis
The The synthesis
synthesis of 5-arylsubstituted
5-arylsubstituted
of 5-arylsubstituted
of pyrazoles
pyrazoles
pyrazoles by
byby the
thethe one-pot
one-pot
one-potdiazo
diazo transfer-cyclization
transfer-cyclization
diazo transfer-cyclization approach approach
has also
approach has also
has been been reported
reported
also been [105].
[105].[105].
reported Separate
Separate examples
examples
Separate examples of
of cycliza-
of
cyclization
tion of
of vinyldiazo
cyclization vinyldiazo
compounds
of vinyldiazo compounds
compounds to pyrazoles
to pyrazoles are presented
are presented
to pyrazoles in a number
in ainnumber
are presented a number of
of of works
works
works by
bybyother
otherauthors
authors
other authors [106–111].
[106–111].
[106–111].
Scheme 51. Synthesis of diversely substituted pyrazoles from vinyl diazo compounds.
Scheme 51.
Synthesisofofdiversely
diverselysubstituted pyrazoles
substituted from
pyrazoles vinyl
from diazo
vinyl compounds.
diazo compounds.
AA cascade
cascade electrocyclization-Michael
electrocyclization-Michael addition
addition process
process for
for the
the synthesis
synthesis of of py-
py-
A cascade electrocyclization-Michael addition process for the synthesis of pyrano[3,2-
rano[3,2-c]pyrazol-7(1H)-ones
rano[3,2-c]pyrazol-7(1H)-ones 211 from 2-diazo-3,5-dioxo-6-ynoates
2112-diazo-3,5-dioxo-6-ynoates
from 2-diazo-3,5-dioxo-6-ynoates (ynones)
(ynones) 210
210 was was de-
de-
c]pyrazol-7(1H)-ones 211 from (ynones) 210 was developed
veloped
veloped by Deng and co-workers [112]. The reaction tolerates a broad range of substitu-
by Dengby andDeng and co-workers
co-workers [112]. The[112]. The reaction
reaction tolerates
tolerates a broada range
broad of range of substitu-
substituents giving
entsgiving
ents givinggenerally
generallyexcellent
excellentyields
yieldsof
ofannulated
annulatedpyrazoles.
pyrazoles.Apparently,
Apparently,the thereaction
reactionbe- be-
generally excellent yields of annulated pyrazoles. Apparently, the reaction begins with
ginswith
gins withthetheformation
formationof ofenolate
enolate52A,
52A,which
whichundergoes
undergoesaa6-π6-πelectrocyclic
electrocyclicringring closure
the formation of enolate 52A, which undergoes a 6-π electrocyclic ring closure closure
to produce
to
to produce
produce 3H-pyrazole
3H-pyrazole intermediate
intermediate 52B.
52B. The
The following
following Michael
Michael addition
addition of
of enolateox-
enolate ox-
3H-pyrazole
ygen to triple
intermediate
bond provides
52B. The following
carbanion 52C.
Michael addition
Subsequent
of enolate
protonation and
oxygen
[1,5]-H
toaf-
shift
triple
ygen to
bond triple bond
provides provides
carbanion 52C.carbanion 52C.protonation
Subsequent Subsequent andprotonation
[1,5]-H and [1,5]-H
shift affords shift
the af-
desired
fordsthe
fords thedesired
desiredproduct
product211211(Scheme
(Scheme52).
52).
product 211 (Scheme 52).
Electrocyclization of vinyl diazo compounds 212 can trigger subsequent rearrange-
ments, such as the Cope rearrangement and 1,3-sigmatropic shift as was discovered by
Babinski and co-workers [113,114]. The initially formed 3H-pyrazole 53A (although it can
undergo the van Alphen-Hüttel rearrangement to become aromatic) in this case undergoes
Molecules 2021, 26, 2530 31 of 70
proton shift to give intermediate 53B. The latter has two pathways to transform itself to
aromatic pyrazole. In path I, a rare [3,3]-aromatic Cope rearrangement can occur, followed
by re-aromatization to afford pyrazole 213. In path II, intermediate 53B can suffer a 1,3-
alkyl shift to give pyrazole 214 (Scheme 53) [114]. Path II presents a radical reaction, so it
can be facilitated by addition of radical initiator (such as AIBN), whereas path I is favored
in presence of radical inhibitor (such as BHT). Although the scope of this tunable reaction
is limited to benzyls with electron-withdrawing groups in positions 2 and 4, it gives32 access
of 74
to two types of fully substituted pyrazoles 213 and 214.
O
O O O H
Et3N (1 eq.) N
N
R2
EtOH or DCE R1 O
R1 N2 50 °C
74–97% O
R2
210 211
R1 = Alk, (Het)Ar
R2 = Ph, OEt
O O
O O O first N
Et3N N cyclization N
R2 R1 N R1
O O
R1 N2 R2
Et3NH O
O R2
210 52A 52B
O O O
H H
second N N
N
cyclization Et3NH H[1,5]
N N N
R1 O R1 O R1 O
R2 Et3N R2 R2
O O O
52C 52D 211

Scheme 52.
52. Cascade electrocyclization-Michael
Cascade addition
electrocyclization-Michael process
addition for synthesis
process 33 of 74
of pyrano[3,2-c]py-
for synthesis of pyrano[3,2-
razol-7(1H)-ones 211 from
c]pyrazol-7(1H)-ones 2-diazo-3,5-dioxo-6-ynoates
211 from (ynones)
2-diazo-3,5-dioxo-6-ynoates 210. 210.
(ynones)
Electrocyclization of vinyl diazo compounds 212 can trigger subsequent rearrange-

ments, such as the Cope rearrangement and 1,3-sigmatropic shift as was discovered by
Babinski and co-workers [113,114]. The initially formed 3H-pyrazole 53A (although it can
undergo the van Alphen-Hüttel rearrangement to become aromatic) in this case under-
goes proton shift to give intermediate 53B. The latter has two pathways to transform itself
to aromatic pyrazole. In path I, a rare [3,3]-aromatic Cope rearrangement can occur, fol-
lowed by re-aromatization to afford pyrazole 213. In path II, intermediate 53B can suffer
a 1,3-alkyl shift to give pyrazole 214 (Scheme 53) [114]. Path II presents a radical reaction,
so it can be facilitated by addition of radical initiator (such as AIBN), whereas path I is
favored in presence of radical inhibitor (such as BHT). Although the scope of this tunable
reaction is limited to benzyls with electron-withdrawing groups in positions 2 and 4, it
gives access to two types of fully substituted pyrazoles 213 and 214.
Scheme 53. Vinyl diazoScheme 53. Vinyl

compound diazo compound
electrocyclic ring closureelectrocyclic
triggers tworing closuresigmatropic
alternative triggers tworearrangements.
alternative sigmatropic
rearrangements.
Miscellaneous Methods for Pyrazole Ring Construction from Vinyl Diazo Compounds
In 2013, the Doyle group devised a regiospecific one-pot, two-step method for the
Molecules 2021, 26, 2530 32 of 70
Scheme 53. Vinyl diazo compound electrocyclic ring closure triggers two alternative sigmatropic
rearrangements.
Miscellaneous Methods for Pyrazole Ring Construction from

from Vinyl
Vinyl Diazo
Diazo Compounds
Compounds
In 2013,
2013, the
theDoyle
Doylegroup
groupdevised
devised a regiospecific
a regiospecific one-pot,
one-pot, two-step
two-step method
method forsyn-
for the the
synthesis of pyrazoles
thesis of pyrazoles 217the
217 via viarhodium-catalyzed
the rhodium-catalyzed vinylogous
vinylogous addition
addition of donor-ac-
of donor-acceptor
ceptor hydrazones
hydrazones 216 to
216 to enol enolacetates
diazo diazo acetates 215 followed
215 followed by Lewis byacid
Lewis acid catalyzed
catalyzed cy-
cyclization
(Scheme
clization 54) [115].54)
(Scheme Numerous substituents
[115]. Numerous were tolerated,
substituents although
were tolerated, in the case
although of sub-
in the case
stituents
of other than
substituents otherhydrogen in the in
than hydrogen vinylogous position
the vinylogous (R1 ), the
position (R1),yields were were
the yields lower.lower.
Scheme 54. Synthesis of pyrazoles from enol diazo acetates and donor-acceptor hydrazones.
hydrazones.
An unprecedented chemo- and regioselective gold-catalyzed cross-coupling

cross-coupling of
of vinyl
diazo compounds 218/221 and
218/221 and arylaryl diazo acetates 219/222 was described by Xu
219/222 was described by Xu and and co-
workers [116].
[116]. The ligand-controlled reaction gave pyrazoles
pyrazoles 220 and 223 in a position-
220 and
switchable mode.
switchable mode.IfIf[IPrAuNTf
[IPrAuNTf 2 ]2]was
wasused
usedasas
thethe
catalyst, thethe
catalyst, products were
products pyrazoles
were 220
pyrazoles
with the N-substituent adjacent to the aryl (or ethyl) group, while with [(ArO)3 PAuCl] as
the catalyst, the regioselectivity was reversed and the products were pyrazoles 223. For the
first mode of the reaction, the presence of an ortho-substituent in the aryl moiety of aryl
diazo acetates 219 was essential, whereas the second mode tolerated substituents in all
positions of the phenyl ring of 222 (Scheme 55).
Another example of gold-catalyzed reaction of vinyl diazo compounds for the syn-
thesis of pyrazole derivatives was described in 2019 by Raj and Liu [117]. The procedure
involving [5+4]-annulation between 2-alkynyl-1-carbonylbenzenes 224 and vinyl diazo
ketones 225 afforded 4,5-dihydro-benzo[g]indazoles 226 in generally good yields and
with high diastereoselectivity. These initial products can be further converted to aromatic
pyrazoles 227 and 228/228’. The possible reaction mechanism likely involves the gold-
catalyzed formation of benzopyrilium cation 56B followed by its [5+4]-cycloaddition with
vinyldiazo ketone 225 to yield intermediate 56C. The latter can be hydrolyzed to give inter-
mediate 56E, which then undergoes a disrotatory 6π-electrocyclization with subsequent
diastereoselective protonation leading to the observed pyrazoline 226 (Scheme 56).
DCM, r. t.
CO2Me 35–81% CO2Me
220 with the N-substituent adjacent to the aryl (or ethyl) R2
group, while with [(ArO)3PAu
as218
the catalyst, the 219 regioselectivity was reversed and 220 the products were pyrazoles 223.
BArthe first mode of the reaction, the presenceR1 of
F = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate = Ar,an ortho-substituent
Et; R 2 = Me, Hal in the aryl moiety
Molecules 2021, 26, 2530
aryl diazo acetates 219 was essential, whereas Ar the second mode tolerated33substituents
of 70
all positions of the phenyl N

ring of 222 (Scheme 55).
2
[(ArO)3PAuCl]/NaBArF N
Ar N2 N CO2R1
3 H
+ CO2R MeO2C
DCM, r. t.
CO2Me 41–85% CO2Me
42
RR N2
Ar = 2,4-tBu2C62H
[IPrAuNTf ]/NaBAr
3 N
R1 N2
F
N R1
R2
+ CO2Me H
221 222 DCM, r. t. 223
CO2Me R3 = Me, Et, tBu, Bn; R4 = Me,CO
35–81% 2Me
Hal, OMe
2
R by cross-coupling of vinyl
Scheme 55. Gold-catalyzed position-switchable synthesis of pyrazoles
218 219 220
diazo compounds with aryl diazo acetates.
BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate R1 = Ar, Et; R2 = Me, Hal
Another example of gold-catalyzed reaction of vinyl Ar diazo compounds for the syn-
thesis of pyrazole derivatives N2
was described in 2019 by Raj and Liu [117]. The procedure
[(ArO)3PAuCl]/NaBArF N 1
involving
Ar [5+4]-annulation
N2 between 2-alkynyl-1-carbonylbenzenes N CO2R224 and vinyl diazo
+ CO2R3 H
ketones 225 afforded 4,5-dihydro-benzo[g]indazoles
DCM, r. t. 226 in generally good yields and with
CO2Me
high diastereoselectivity. 41–85% can be further CO
These initial products 2Me
converted to aromatic py-
R4 Ar = 2,4-tBu2C6H3
razoles 227 and 228/228’. The possible reaction mechanism R 2 likely involves the gold-cata-
221
lyzed formation 222
of benzopyrilium cation 56B followed by its223 [5+4]-cycloaddition with vi-
R3 = Me, Et, tBu, Bn; R4 = Me, Hal, OMe
nyldiazo ketone 225 to yield intermediate 56C. The latter can be hydrolyzed to give inter-
mediate
Scheme
Scheme 56E,
55. which then undergoes
55.Gold-catalyzed
Gold-catalyzed a disrotatory
position-switchable synthesis
position-switchable 6π-electrocyclization
of pyrazoles
synthesis with subsequent
by cross-coupling
of pyrazoles of vinyl of viny
by cross-coupling
diastereoselective
diazo
diazocompounds
compounds protonation
with arylaryl
with diazo leading
acetates.
diazo to the observed pyrazoline 226 (Scheme 56).
acetates.
Another example of gold-catalyzed reaction of vinyl diazo compounds for the s

thesis of pyrazole derivatives was described in 2019 by Raj and Liu [117]. The proced
involving [5+4]-annulation between 2-alkynyl-1-carbonylbenzenes 224 and vinyl di
ketones 225 afforded 4,5-dihydro-benzo[g]indazoles 226 in generally good yields and w
high diastereoselectivity. These initial products can be further converted to aromatic
razoles 227 and 228/228’. The possible reaction mechanism likely involves the gold-ca
lyzed formation of benzopyrilium cation 56B followed by its [5+4]-cycloaddition with
nyldiazo ketone 225 to yield intermediate 56C. The latter can be hydrolyzed to give in
mediate 56E, which then undergoes a disrotatory 6π-electrocyclization with subsequ
diastereoselective protonation leading to the observed pyrazoline 226 (Scheme 56).

Scheme ofof4,5-dihydro-benzo[g]indazoles
56. Synthesis by gold-catalyzed
4,5-dihydro-benzo[g]indazoles by gold-catalyzed [5+4]-annulation
[5+4]-annulation between 2-alkynyl-1-carbon-
between 2-alkynyl-1-carbonylbenzenes
ylbenzenes and vinyldiazo
and vinyldiazo ketones. ketones.
Synthesis of 1H-Pyrazoles from Diazo Compounds and Alkynes

In this section, only selected examples are considered that have not been reviewed
previously.
In the classic 1,3-dipolar cycloaddition of diazo compound 229 to alkyne 230, 3H-pyrazole
231 is initially formed and, in some cases, can be isolated (Section 2.5.2). However, it usually
undergoes a prototropic shift or the van Alphen–Hüttel [118,119] rearrangement to produce
1H-pyrazole 232 (Scheme 57) [120].
Scheme 56. Synthesis of 4,5-dihydro-benzo[g]indazoles by gold-catalyzed [5+4]-annulation between 2-alkynyl-1-carbon-

ylbenzenes and vinyldiazo ketones.
Synthesis
In thisofsection,
1H-Pyrazoles from Diazo
only selected Compounds
examples and Alkynes
are considered that have not been reviewed
In this
previously. section, only selected examples are considered that have not been reviewed
previously.
In the classic 1,3-dipolar cycloaddition of diazo compound 229 to alkyne 230, 3H-
In the
pyrazole 231classic 1,3-dipolar
is initially formedcycloaddition
and, in some of diazo
cases, cancompound
be isolated229 to alkyne
(Section 230,
2.5.2). 3H-
How-
Molecules 2021, 26, 2530 34 of 70
pyrazole
ever, 231 is undergoes
it usually initially formed and, in some
a prototropic shift cases,
or thecanvanbeAlphen–Hüttel
isolated (Section 2.5.2). How-
[118,119] rear-
ever, it usually
rangement undergoes
to produce a prototropic
1H-pyrazole shift or57)the
232 (Scheme van Alphen–Hüttel [118,119] rear-
[120].
rangement to produce 1H-pyrazole 232 (Scheme 57) [120].
Scheme
Scheme57.
57.Synthesis
Synthesisof
of1H-pyrazoles
1H-pyrazolesfrom
fromdiazo
diazocompounds
compoundsand
andalkynes.
alkynes.
Scheme 57. Synthesis of 1H-pyrazoles from diazo compounds and alkynes.
In2015,
In 2015,Sultanova
Sultanovaandandco-authors
co-authors reported
reported an an efficient
efficient synthesis
synthesis of 7-oxo-4,5,6,7-
of 7-oxo-4,5,6,7-tet-
tetrahydropyrazolo[1,5-c]pyrimidines
In 2015, Sultanova and co-authors
rahydropyrazolo[1,5-c]pyrimidines 234 234 by reaction
reported of 3-diazopyrrolidones
an efficient
by reaction withwith
233 233
synthesis of 7-oxo-4,5,6,7-tet-
of 3-diazopyrrolidones di-
dimethyl
methyl acetylenedicarboxylate
rahydropyrazolo[1,5-c]pyrimidines
acetylenedicarboxylate (DMAD)
(DMAD)234 [121].[121].
by reaction The reaction is believed
of 3-diazopyrrolidones
The reaction is believed to through
233
to proceed proceed
with di-
through
methyl
the the formation
formation of a spirocyclic
acetylenedicarboxylate
of a spirocyclic (DMAD)3H-pyrazole
3H-pyrazole [121]. intermediate
The reaction
intermediate 58Aisvia believed via
58Ato
1,3-dipolar 1,3-dipolar
proceed cy-
through
cycloaddition
cloaddition
the formation with
of asubsequent
spirocyclic ring expansion
3H-pyrazole via the
intermediatevan58AAlphen–Hüttel
via 1,3-dipolar
with subsequent ring expansion via the van Alphen–Hüttel rearrangement (Scheme 58). rearrangement
cycloaddition
(Scheme 58).
with subsequent ring expansion via the van Alphen–Hüttel rearrangement (Scheme 58).
Scheme 58. Synthesis of 7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidines 234 from 3-di-

Scheme 58.
58. Synthesis
Synthesis
azopyrrolidones
Scheme ofof7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidines
and DMAD. 7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidines 2343-diazopyrrolidones
234 from from 3-di-
azopyrrolidones
and DMAD. and DMAD.
An interesting rearrangement of aryl propargyl α-aryl diazo acetates 235 to 1,5-dihy-
An interesting
interestingrearrangement
dro-4H-pyrazol-4-ones 236 and 237of
rearrangement ofaryl
was propargyl
aryl
reported by α-aryl
propargyl diazo
theα-aryl
Doyle acetates
diazo
group 235 to
acetates
in 2016 2351,5-dihy-
[122]. to The
1,5-
dro-4H-pyrazol-4-ones
dihydro-4H-pyrazol-4-ones 236 and
236 237
and was
237 reported
was by
reported the
by Doyle
the group
Doyle
gold-catalyzed 1,3-acyloxy rearrangement of 235 likely gives allene species 59A, which in
group2016
in [122].
2016 The
[122].
gold-catalyzed
The
may gold-catalyzed1,3-acyloxywithrearrangement
1,3-acyloxy
exist in equilibrium rearrangement
235. Intermediate of of
235235
59A likely
likelygives
undergoes allene
allenespecies
species 59A,
givesrearrangement which
which
to produce
may exist in equilibrium
dihydropyrazolone with 235.
236 directly in Intermediate 59A undergoes
a concerted fashion or stepwiserearrangement
rearrangement produce
to produce
through intermediate
dihydropyrazolone
59D. Under the reaction directly in aacompound
236 conditions, concerted
concerted 236fashion
is in or
fashion or stepwise
stepwise through
equilibrium with 237,intermediate
through intermediate
via 1,3-acyl
59D. UnderAtthe
migration. reaction
room conditions,
conditions,
temperature, thecompound
ratio of 236236
compound to is
236 is
237in is
equilibrium
equilibrium with
generally about 3:1. via
with 237,
237, It is1,3-acyl
via 1,3-acyl
worth
migration. At room temperature, the ratio of 236 to 237
237 is
is generally
generally
mentioning that these dihydropyrazolones can act as acyl transfer reagent, and when about
about 3:1.
3:1. It is
is worth
worth
re-
mentioning that
that these
these dihydropyrazolones
dihydropyrazolones can
can act
act
acted with amine, afforded 4-hydroxypyrazoles 238 (Scheme 59). asas acyl
acyl transfer
transfer reagent,
reagent, and andwhen whenre-
reacted with amine, afforded 4-hydroxypyrazoles
acted with amine, afforded 4-hydroxypyrazoles 238 (Scheme 59). 238 (Scheme 59).
A rare example of synthesis of 4H-pyrazoles was reported in 2018 by Zhang and co-
workers (Scheme 60) [123]. An intramolecular 1,3-dipolar cycloaddition of alkyne-tethered
α-cyano diazoamides 239 with subsequent 1,5-carbonyl migration provided spiro-4H-
pyrazole-oxindoles 240 in good to excellent yields (Scheme 60, path a). The reaction worked
well even with terminal alkyne. α-Methyl diazoamide 239a also gave the corresponding
4H-pyrazole 240a, albeit in diminished yield. In addition, α-sulfonyl diazo compounds 241
were employed in the reaction but in this case, the product was 1H-pyrazole 242 resulting
from 1,5-sulfonyl migration to the N-atom in the 3H-pyrazole intermediate 60A (Scheme 60,
path b).
Molecules 2021, 26, 2530 35 of 70

Scheme
Scheme59.59.
Rearrangement of diazo
Rearrangement esters esters
of diazo 235 to 1,5-dihydro-4H-pyrazol-4-ones 236-237.
235 to 1,5-dihydro-4H-pyrazol-4-ones 236-237.
A rare example of synthesis of 4H-pyrazoles was reported in 2018 by Zhang and co-
workers (Scheme 60) [123]. An intramolecular 1,3-dipolar cycloaddition of alkyne-teth-
ered α-cyano diazoamides 239 with subsequent 1,5-carbonyl migration provided spiro-
4H-pyrazole-oxindoles 240 in good to excellent yields (Scheme 60, path a). The reaction
worked well even with terminal alkyne. α-Methyl diazoamide 239a also gave the corre-
sponding 4H-pyrazole 240a, albeit in diminished yield. In addition, α-sulfonyl diazo com-
pounds 241 were employed in the reaction but in this case, the product was 1H-pyrazole
242 resulting from 1,5-sulfonyl migration to the N-atom in the 3H-pyrazole intermediate
60A (Scheme 60, path b).
SchemeScheme 60. Synthesis

60. Synthesis of spiro-4H-pyrazoles
of spiro-4H-pyrazoles 240240and
andfused
fused 1H-pyrazoles
1H-pyrazoles 242242
from alkyne-tethered
from diazo amides.
alkyne-tethered diazo amides.
A continuous-flow synthesis of fluoroalkyl-substituted diazomethanes 244 from the

corresponding amines 243 and their application in [3+2]-cycloaddition reactions with var-
ious alkynes and alkenes was described by Mertens and co-workers (Scheme 61) [124].
The method proved to be efficient for the preparation of fluoroalkyl-substituted 1H-pyra-
Molecules 2021, 26, 2530 36 of 70
Scheme 60. Synthesis of spiro-4H-pyrazoles 240 and fused 1H-pyrazoles 242 from alkyne-tethered diazo amides.
A
A continuous-flow synthesisofoffluoroalkyl-substituted
continuous-flow synthesis fluoroalkyl-substituted diazomethanes
diazomethanes 244 244
fromfrom
the the
corresponding
corresponding amines 243 and their application in [3+2]-cycloaddition reactions with var-vari-
amines 243 and their application in [3+2]-cycloaddition reactions with
ous
iousalkynes
alkynesandandalkenes
alkeneswaswasdescribed
describedbybyMertens
Mertensand andco-workers
co-workers(Scheme
(Scheme 61)61)[124].
[124]. The
method proved to be efficient for the preparation of fluoroalkyl-substituted
The method proved to be efficient for the preparation of fluoroalkyl-substituted 1H-pyra- 1H-pyrazoles
zolespyrazolines
248, 249, and
248, pyrazolines 249,3H-pyrazoles 250 with
and 3H-pyrazoles 250 absolute regioselectivity
with absolute in generally
regioselectivity in gener-good
to excellent
ally good toyields. Anyields.
excellent approach for the preparation
An approach of mono-, of
for the preparation bis-, and tris(trifluoromethyl)-
mono-, bis-, and tris(tri-
substituted pyrazoles from
fluoromethyl)-substituted ethyl 2-diazo-3,3,3-trifluoropropanoate
pyrazoles has also been
from ethyl 2-diazo-3,3,3-trifluoropropanoate hasreported
also
by
beenthereported
Reissig by
group [125]. group [125].
the Reissig

Scheme 61. Continuous-flow
Scheme Continuous-flowsynthesis
synthesisofoffluoroalkyl-substituted diazomethanes
fluoroalkyl-substituted for for
diazomethanes 38 of 74 of
preparation
preparation
of 1H-pyrazoles,
1H-pyrazoles, pyrazolines,and
pyrazolines, and3H-pyrazoles.
3H-pyrazoles.
2.5.2. 3H-Pyrazoles
2.5.2. 3H-Pyrazoles
Relativelystable
Relatively stable3H-pyrazoles,
3H-pyrazoles, containing
containing twotwo substituents
substituents in position
in position 3, com-
3, are are com-
monly
monly prepared from disubstituted diazo compounds. Although, they are still prone to to
prepared from disubstituted diazo compounds. Although, they are still prone
rearrange
rearrange totomore
morestable
stableproducts
productsvia,via,
forfor instance,
instance, thethe
vanvan Alphen–Hüttel
Alphen–Hüttel rearrangement
rearrangement
or denitrogenative transformations
or denitrogenative transformations [126]. [126].
In 2007,
In 2007, Strakova
Strakova andand co-workers
co-workers reported
reported the
the synthesis
synthesis of
ofspiro-3H-pyrazoles
spiro-3H-pyrazoles adducts
ad-
252
ductsand
252254 by254
and [3+2]
by cycloaddition of DMAD
[3+2] cycloaddition to diazo
of DMAD compounds
to diazo 251 and
compounds andrespectively
251253, 253, re-
(Scheme
spectively62) [127]. 62)
(Scheme The[127].
reaction proceeded
The reaction smoothly
proceeded at room
smoothly temperature;
at room however,
temperature; how- the
reaction
ever, the took fourtook
reaction days to go
four to to
days completion.
go to completion.
Scheme 62.
Synthesisofofspiro-3H-pyrazole
spiro-3H-pyrazoleadducts
adducts252
252and 254
and from
254 diazo
from compounds
diazo and
compounds and DMAD.
DMAD.
A regio- and stereoselective synthesis of spiro-3H-pyrazole-penicillanates 257 was

achieved by Santos and co-workers [128]. Benzhydryl esters provided better yields than
their benzyl counterparts. The observed stereoselectivity likely resulted from the alkyne
Molecules 2021, 26, 2530 37 of 70
Scheme 62. Synthesis of spiro-3H-pyrazole adducts 252 and 254 from diazo compounds and
DMAD.
A
A regio-
regio- and
and stereoselective
stereoselective synthesis
synthesis of
of spiro-3H-pyrazole-penicillanates
spiro-3H-pyrazole-penicillanates 257 257 was
was
achieved
achieved byby Santos
Santos and
and co-workers
co-workers [128].
[128]. Benzhydryl
Benzhydryl esters
esters provided
provided better
better yields
yields than
than
their
their benzyl
benzyl counterparts.
counterparts. The observed
observed stereoselectivity
stereoselectivity likely
likely resulted
resulted from
from the
the alkyne
alkyne
256 approaching diazo β-lactam 255 from the less sterically hindered α-side (Scheme63).
256 approaching diazo β-lactam 255 from the less sterically hindered α-side (Scheme 63).
Scheme 63. Regio-

Scheme Regio-and
andstereoselective
stereoselectivesynthesis
synthesisofof
spiro-3H-pyrazole-penicillanates 257257
spiro-3H-pyrazole-penicillanates from 6- 6-
from
diazopenicillanates 255 and alkynes 256.
diazopenicillanates 255 and alkynes 256.
In 2015,
In 2015, Shelke
Shelke andand Suryavanshi
Suryavanshi described a method for the synthesis synthesis of 3,3 0 -spiro-
3,3’-spiro-
phosphonylpyrazole-oxindoles 260
phosphonylpyrazole-oxindoles 260 from
from methylidene
methylidene indolinones
indolinones 258 and the Bestmann-
Ohira
Ohira reagent (BOR) 259 (Scheme 64a) [129]. The regioselective reaction
reagent (BOR) 259 (Scheme 64a) [129]. The regioselective reaction tolerated
tolerated aa broad
broad
range substituentsand
range of substituents andafforded
affordedgood
goodyields
yields of of
thethe desired
desired products.
products. Moreover,
Moreover, a
a one-
one-pot procedure
pot procedure withwith generation
generation of indolinones
of indolinones situinbysitu
258 in258 the by the Wittig
Wittig reactionreaction of
of readily
readily available
available isatinsisatins
261 and and phosphonium
261 phosphonium ylides
ylides 262262waswas developed(Scheme
developed (Scheme 64b). The The
mechanism
mechanismof ofthe
thereaction
reactionlikely involves
likely involvesthethe
deacylation
deacylation of BOR
of BOR259a by the
259a by methoxide
the methoxide ion
with subsequent 1,3-dipolar cycloaddition of the diazo-phosphonate anion
ion with subsequent 1,3-dipolar cycloaddition of the diazo-phosphonate anion (arising (arising from
to methylidene
64A)64A)
from indolinone
to methylidene 258a to258a
indolinone formto intermediate 64B. Subsequent
form intermediate protonation
64B. Subsequent of
proto-
64B and proton transfer produces intermediate 64D, which is oxidized by
nation of 64B and proton transfer produces intermediate 64D, which is oxidized by air to air to afford the
final compound
afford 260a.
the final compound 260a.
Scheme
Scheme64.
64.Synthesis 3,30 -spiro-phosphonylpyrazole-oxindoles 260
Synthesisofof3,3’-spiro-phosphonylpyrazole-oxindoles 260 by
by deacylative
deacylative1,3-dipolar
1,3-dipolarcycloaddition
cycloadditionofofBOR
BORtoto
methylidene
methylideneindolinones.
indolinones.
Inaastudy
In studydevoted
devotedto tothe
theexploration
exploration ofof fluorescence
fluorescence turn-on
turn-oncycloadditions
cycloadditionsofofdiben-
diben-
zocyclooctyne derivative 263 with various 1,3-dipoles, including di- and mono-substituted
zocyclooctyne derivative 263 with various 1,3-dipoles, including di- and mono-substi-
diazodiazo
tuted compounds 264 and
compounds andFriscourt
264266, and co-authors
266, Friscourt prepared
and co-authors 3H-pyrazole
prepared and 1H-
3H-pyrazole and
pyrazole cycloadducts 265 and 267 [130]. The reaction is believed to be strain-promoted,
1H-pyrazole cycloadducts 265 and 267 [130]. The reaction is believed to be strain-pro-
which resulted
moted, in a shortinreaction
which resulted a shorttime (2 h),time
reaction even (2
at h),
room temperature.
even 3H-Pyrazole adducts
at room temperature. 3H-Pyra-
zole adducts 265 showed low quantum yields of the fluorescence whereas 1H-pyrazole
adducts 267 exhibited a 160-fold fluorescence enhancement over the starting compound
263 (Scheme 65).
methylidene indolinones.
In a study devoted to the exploration of fluorescence turn-on cycloadditions of diben-

zocyclooctyne derivative 263 with various 1,3-dipoles, including di- and mono-substi-
Molecules 2021, 26, 2530 tuted diazo compounds 264 and 266, Friscourt and co-authors prepared 3H-pyrazole
38 of 70 and
1H-pyrazole cycloadducts 265 and 267 [130]. The reaction is believed to be strain-pro-
moted, which resulted in a short reaction time (2 h), even at room temperature. 3H-Pyra-
zole adducts 265 showed low quantum yields of the fluorescence whereas 1H-pyrazole
265 showed low267
adducts quantum yields
exhibited of the fluorescence enhancement
a 160-fold whereas 1H-pyrazole
over the adducts
starting 267
compound
exhibited a 160-fold
263 (Schemefluorescence
65). enhancement over the starting compound 263 (Scheme 65).

Scheme 65. Strain-promoted
Scheme 65.cycloaddition reaction
Strain-promoted of dibenzocyclooctyne
cycloaddition derivative 263 and
reaction of dibenzocyclooctyne diazo compounds
derivative for the
263 and diazo
synthesis of 3H- and 1H-pyrazoles.
compounds for the synthesis of 3H- and 1H-pyrazoles.
An An unusual
unusual three-step
three-step approach
approach to 5-substituted
to 5-substituted spiro-3H-pyrazoles
spiro-3H-pyrazoles waswas reported
reported in in
20082008 by Khidre
by the the Khidre
group group
[131].[131].
DiazoDiazo indan-1,3-dione
indan-1,3-dione 268 reacted
268 reacted with triphenyl(vi-
with triphenyl(vinyl)
phosphonium bromidebromide
nyl)phosphonium 269 to give
269 pyrazoline 270, which
to give pyrazoline 270,was then
which wasconverted to phospho-
then converted to phos-
nium ylide 271
phonium upon
ylide 271treatment with EtONa.
upon treatment with Reaction of 271 with
EtONa. Reaction benzaldehyde
of 271 afforded af-
with benzaldehyde
spiro-3H-pyrazole derivative 272.
forded spiro-3H-pyrazole On the 272.
derivative otherOnhand,
thethe involvement
other hand, theofinvolvement
triphenyl(prop-
of tri-
1-en-1-yl)phosphonium bromide (273) into the reaction allowed for the direct
phenyl(prop-1-en-1-yl)phosphonium bromide (273) into the reaction allowed for the synthesis of di-
5-methyl-spiro-3H-pyrazole 274 (Scheme 66).
rect synthesis of 5-methyl-spiro-3H-pyrazole 274 (Scheme 66).
Scheme 66. Synthesis ofScheme 66. Synthesis

spiro-3H-pyrazoles 272ofand
spiro-3H-pyrazoles 272 and 274 from
274 from diazo indan-1,3-dione diazo indan-1,3-dione and triph-
and triphenyl(alkenyl)phosphonium
bromides. enyl(alkenyl)phosphonium bromides.
2.5.3. Indazoles
A vast majority of methods for the preparation of indazoles from diazo compounds
make use of a 1,3-dipolar cycloaddition reaction with an aryne species generated in situ.
Among aryne precursors, o-silylaryl triflates are the most commonly used.
Molecules 2021, 26, 2530 39 of 70
Scheme 66. Synthesis of spiro-3H-pyrazoles 272 and 274 from diazo indan-1,3-dione and triphenyl(alkenyl)phosphonium
bromides.
2.5.3. Indazoles
2.5.3. Indazoles
A vast majority
A vast majority of
of methods
methods for
for the
the preparation
preparation of
of indazoles
indazoles from
from diazo
diazo compounds
compounds
make use of a 1,3-dipolar cycloaddition reaction with an aryne species generated in
make use of a 1,3-dipolar cycloaddition reaction with an aryne species generated in situ.
situ.
Among aryne precursors, o-silylaryl triflates are the most commonly
Among aryne precursors, o-silylaryl triflates are the most commonly used. used.
1H-Indazoles
When a terminal diazo compound reacts with aryne, 3H-indazole is initially formed.
Subsequently, it can
can undergo
undergoaaprototropic
prototropicisomerization
isomerizationtoto give 1H-indazole.
give 1H-indazole. In 2007, Jin
In 2007,
andand
Jin Yamamoto
Yamamoto described a method
described for the
a method for synthesis of 1H-indazoles
the synthesis 277 and
of 1H-indazoles 277 278
andby such
278 by
an approach
such [132].[132].
an approach Using 1.2 equivalents
Using of the
1.2 equivalents diazo
of the reagent
diazo 276276
reagent andandKF/18-crown-6
KF/18-crown-6 in
in
THFTHF system
system provided
provided N-unsubstituted
N-unsubstituted indazoles
indazoles 277277 while
while using
using 0.5 0.5 equivalents
equivalents of
of the
the diazo
diazo reagent
reagent 276 with
276 with CsF CsF in acetonitrile
in acetonitrile led toled to N-arylated
N-arylated products
products 278. As278.for As for
asym-
asymmetrical silylaryl triflates, the complete regioselectivity was achieved only
metrical silylaryl triflates, the complete regioselectivity was achieved only in the case ofin the case
of methoxy-substituted
methoxy-substituted oneone (7-methoxyisomer
(7-methoxy isomer277a wasformed
277awas formed exclusively)
exclusively) whereas in in
other cases, a 1:1 mixture of regioisomers
regioisomers waswas obtained
obtained (Scheme
(Scheme 67).
67).
Molecules 2021, 26, x FOR PEER REVIEW 41 of 74 and

Scheme 67. Synthesis of N-unsubstituted and N-arylated indazoles from o-silylaryl triflates
diazo compounds.
Scheme 67. Synthesis of N-unsubstituted and N-arylated indazoles from o-silylaryl triflates and diazo compounds.
When an
When aninternal
internaldiazo
diazocompound
compound reacted
reacted with
with a benzyne
a benzyne intermediate,
intermediate, 3H-indazole
3H-indazole
intermediate 68Aisisformed.
intermediate 68A formed.ForFordiazodicarbonyl
diazodicarbonyl compounds
compounds 279,279, intermediate
intermediate was was
68A68A
prone to
to undergo
undergoacyl acylmigration
migrationtotogive
give 1H-indazoles
1H-indazoles 281281 as was
as was shown
shown by the
by the Larock
Larock
group [133]. On
group [133]. Onthetheother
otherhand,
hand,benzyl-substituted
benzyl-substituted diazo
diazo ester
ester andand
282 282 diazo
diazo diphenyl-
diphenyl-
methane gavesTable
284gave
methane 284 stable 3H-indazoles
3H-indazoles283 and285
283and 285 exclusively
exclusively (Scheme
(Scheme 68).68).
Schemeof
Scheme 68. Synthesis Synthesis
68.1H- of 1H- and
and 3H-indazoles 3H-indazoles
from from
internal diazo internal diazo
compounds compounds and benzynes.
and benzynes.
An efficient protocol for the synthesis of N-substituted indazoles from the Bestmann–
Ohira reagent (BOR) analogs 286, silylaryl triflates 287, and Michael acceptors 288 was
developed by Phatake and co-workers [134]. A role of fluoride anion in this reaction was
Molecules 2021, 26, 2530 40 of 70
Scheme 68. Synthesis of 1H- and 3H-indazoles from internal diazo compounds and benzynes.
An efficient
An efficientprotocol
protocolfor
forthe
thesynthesis
synthesisofofN-substituted
N-substitutedindazoles
indazoles from
from thethe Bestmann–
Bestmann–
Ohira
Ohira reagent (BOR) analogs 286, silylaryl triflates 287, and Michael acceptors 288288
reagent (BOR) analogs 286, silylaryl triflates 287, and Michael acceptors was
was
developed by Phatake and co-workers [134]. A role of fluoride anion in this
developed by Phatake and co-workers [134]. A role of fluoride anion in this reaction was reaction was
not
not only in the
only in the generation
generationofofthe
thearyne
aryneintermediate,
intermediate,but butalso
also
inin the
the dephosphonylation
dephosphonylation of of
BOR. The
The cascade
cascade[3+2]
[3+2] cycloaddition
cycloadditionofofthe
theacyl
acyldiazomethane
diazomethane anion
anion to to aryne
aryne following
following
the aza-Michael additionprocess
aza-Michael addition processfurnished
furnished1,3-substituted
1,3-substituted indazoles
indazoles 289289
in in generally
generally high
high
yields under
under very
verymild
mildreaction
reactionconditions
conditions(Scheme
(Scheme 69).
69).
O
R1
O O CsF
TMS (6 eq.)
P OMe + R2 + R2 N
R1 Z
OMe MeCN N
N2 OTf Z
25 °C, 4 h
286 287 288 31–85% 289
R1 = Me, iPr, Cyclopropyl, (Het)Ar, OEt; R2 = H, Dioxol; Z = CO2Et, CN
Scheme 69. SynthesisScheme 69. Synthesis

of 1,3-substituted of 1,3-substituted
1H-indazoles 2891H-indazoles 289 from BOR,
from BOR, Michael Michael
acceptors andacceptors and
silylaryl silylaryl triflates.
triflates.
In
In 2016,
2016,Ikawa
Ikawaandandco-workers demonstrated
co-workers demonstratedthat that
2,4-bis(trimethylsilyl)-1,3-bis(trifluo-
2,4-bis(trimethylsilyl)-1,3-bis(tri-
romethanesulfonyloxy)benzene 290 could act as a 1,4-benzdiyne
fluoromethanesulfonyloxy)benzene 290 could act as a 1,4-benzdiyne equivalent [135]. More-
equivalent [135].
over,
Molecules 2021, 26, x FOR PEER REVIEW aryne “triple bonds” could be generated in a sequential manner. Using this methodol-
42 ofthis
74
Moreover,
Molecules 2021, 26, x FOR PEER REVIEW aryne “triple bonds” could be generated in a sequential manner. Using
ogy, an exotic indazole derivative 293 was prepared in a two-step procedure with 42 of 74
good
methodology, an exotic indazole derivative 293 was prepared in a two-step procedure
overall yield (Scheme 70).
with good overall yield (Scheme 70).
Scheme 70. Synthesis of tricyclic indazole from 1,4-benzdiyne equivalent, ethyl diazoacetate, and 1,1-dimethoxyethene.
Scheme70.
Scheme Synthesisofoftricyclic
70.Synthesis tricyclicindazole
indazolefrom
from 1,4-benzdiyne
1,4-benzdiyne equivalent,
equivalent, ethyl
ethyldiazoacetate,
diazoacetate,and
and1,1-dimethoxyethene.
1,1-dimethoxyethene.
A tunable approach for the synthesis of1H-1H- and3H-indazoles

3H-indazoles wasreported
reported by Chen
AAtunable
tunableapproach
approach for
for the
the synthesis
synthesis of
of 1H-and
and 3H-indazoleswas was reportedbybyChen
Chen
and
and co-authors
co-authors [136].
[136]. The
The product
product distribution
distribution depended
depended on on
the the structure
structure of the of the phos-
phosphoryl
and co-authors [136]. The product distribution depended on the structure of the phos-
phoryl group
group in in α-substituted-α-diazophosphonates
α-substituted-α-diazophosphonates 294. Bulky294. Bulky diisopropyl
diisopropyl phosponates phosponates
provided
phoryl group in α-substituted-α-diazophosphonates 294. Bulky diisopropyl phosponates
provided stable 3H-indazoles
stable 3H-indazoles 296,less
296, whereas whereas lesshindered
sterically stericallydimethyl
hinderedphosphonates
dimethyl phospho-
gave
provided stable 3H-indazoles 296, whereas less sterically hindered dimethyl phospho-
nates gave 1H-indazoles
1H-indazoles 297 (Scheme 297 (Scheme 71).
71).
nates gave 1H-indazoles 297 (Scheme 71).
Scheme
Scheme71.
71.Phosphoryl
Phosphorylgroup-controlled
group-controlled synthesis
synthesis of 1H- and
and 3H-indazoles
3H-indazolesfrom
fromdiazo
diazophosphonates
phosphonatesand
and arynes.
arynes.
Scheme 71. Phosphoryl group-controlled synthesis of 1H- and 3H-indazoles from diazo phosphonates and arynes.
The ‘hexadehydro Diels-Alder’ (HDDA) reaction was employed in the synthesis of

indazoles. In 2017, the Hoye group—in their work devoted to investigation of photochem-
indazoles. In 2017, the Hoye group—in their work devoted to investigation of photochem-
ical variation of this reaction—demonstrated that a highly functionalized 1H- and 3H-in-
ical variation of this reaction—demonstrated that a highly functionalized 1H- and 3H-in-
dazoles 300 and 301 can be constructed from a tetraalkyne derivative 298 and correspond-
dazoles 300 and 301 can be constructed from a tetraalkyne derivative 298 and correspond-
ing diazo compounds (Scheme 72a) [137]. While developing this methodology further,
ing diazo compounds (Scheme 72a) [137]. While developing this methodology further,
Molecules 2021, 26, 2530 41 of 70

indazoles. In 2017, the Hoye group—in their work devoted to investigation of photo-
chemical variation of this reaction—demonstrated that a highly functionalized 1H- and
3H-indazoles 300 and 301 can be constructed from a tetraalkyne derivative 298 and cor-
responding diazo compounds (Scheme 72a) [137]. While developing this methodology
further, this group showed that an efficient domino HDDA reaction of polyalkynes (such
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74
as 302) could be used for the synthesis of diverse polyaromatic systems, including indazole
303 (Scheme 72b) [138].
Scheme72.
Scheme
Scheme 72.(a)
72. a) Photochemical
a) Photochemical and
and (b)
b) thermal
b) thermal domino
thermaldomino HDDA
dominoHDDA for
HDDAfor the
forthe synthesis
thesynthesis of
synthesisof indazoles.
ofindazoles.
indazoles.
Other aryne
Other aryne
Other precursors,
aryne precursors, including
precursors, including heteroaromatic ones,
including heteroaromatic ones, have
have also
also been
been reported
reported to-
to-
date
date [139–145].
[139–145]. The
The aryne
aryne cycloaddition
cycloaddition approach
approach also
alsofound
found its application
its in
application
date [139–145]. The aryne cycloaddition approach also found its application in the synthe- the
in synthesis
the synthe-
of
sisbiologically
sis of biologically
of biologicallyactive indazoles
active
active indazoles
indazoles [146].[146].
[146].
As for
Asfor
As other
forother methodologies
othermethodologies
methodologiesnot not involving
notinvolving arynes,
involvingarynes, Muruganantham
arynes,Muruganantham
Murugananthamand and Namboothiri
andNamboothiri
Namboothiri
reported
reported aa reaction
reported reaction of BOR 259a
of BOR
BOR 259awith
259a withnitroalkenes,
with nitroalkenes,including
nitroalkenes, includingnitroethylene
including nitroethylenemoiety
nitroethylene moietyas
moiety asasaa
a part
part of of aromatic
aromatic or or heteroaromatic
heteroaromatic ring ring (such
(such as as
304) 304)
[147].[147].
The The
processprocess consisting
consisting
part of aromatic or heteroaromatic ring (such as 304) [147]. The process consisting of [3+2] of [3+2]
of [3+2] cycloaddition
cycloaddition
cycloaddition followedfollowed
followed by HNO2by
by HNO HNO2 elimination
elimination
2 elimination provides
provides benzo-
provides benzo- or orbenzo- or pyrido-fused
pyrido-fused
pyrido-fused phospho-
phospho-
nylindazoles 305 in moderate yields (Scheme 73). Unfortunately, the reaction failedreaction
phosphonylindazoles
nylindazoles 305 in 305
moderate in moderate
yields yields
(Scheme (Scheme
73). 73).
Unfortunately, Unfortunately,
the reaction the
failed togive
to give
failed to
any indazole
any give any
indazole products indazole
products with products
with simple with simple
simple nitrobenzene nitrobenzene
nitrobenzene derivatives.
derivatives. derivatives.
Scheme 73.
Scheme
73. Synthesis of
Synthesis of fused
of fused phosphonylindazoles
fused phosphonylindazoles from
phosphonylindazoles from nitroarenes
from nitroarenesand
nitroarenes andBOR.
and BOR.
BOR.
AA 1,3-dipolar
1,3-dipolar cycloaddition
cycloaddition reaction
reaction of
of naphthoquinones
naphthoquinones 306 306 and
and diazo
diazo compounds
compounds
307 was
307 was used
used for
for the
the synthesis
synthesis of
of naphthohydroquinone-derived
naphthohydroquinone-derived indazoles
indazoles 308
308 in
in aa work
work
by Tandon
by Tandon and
and co-workers
co-workers [148].
[148]. Biological
Biological evaluation
evaluation of of obtained
obtained compounds
compounds showed
showed
that 308a
that 308a exhibited
exhibited antifungal
antifungal and
and antibacterial
antibacterial activities.
activities. The
The drawback
drawback ofof this
this approach
approach
is that indazoles 308 were obtained as a mixture with (1,4)-naphthoquinono-[3,2-c]-1H-
is that indazoles 308 were obtained as a mixture with (1,4)-naphthoquinono-[3,2-c]-1H-
Molecules 2021, 26, 2530 42 of 70
A 1,3-dipolar cycloaddition reaction of naphthoquinones 306 and diazo compounds

307 was used for the synthesis of naphthohydroquinone-derived indazoles 308 in a work by
Tandon and co-workers [148]. Biological evaluation of obtained compounds showed that
308a exhibited antifungal and antibacterial activities. The drawback of this approach is that
Molecules
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44 of
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74
indazoles 308 were obtained as a mixture with (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles
309 (Scheme 74).
Scheme
Scheme 74. A
74.of
Scheme 74. A 1,3-dipolar cycloaddition 1,3-dipolar
1,3-dipolar cycloaddition
Anaphthoquinones and diazoof
cycloaddition naphthoquinones
ofcompounds
naphthoquinones and
and diazo
diazo
for the synthesis of compounds
compounds for
for the
the synthe-
synthe-
naphthohydroquinone-
sis
sis of
of naphthohydroquinone-derived
naphthohydroquinone-derived indazoles
indazoles and
and (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles.
(1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles.
derived indazoles and (1,4)-naphthoquinono-[3,2-c]-1H-pyrazoles.
3H-Indazoles
3H-Indazoles and and 2H-Indazoles
2H-Indazoles
When
When a 5-,6- or7-membered
When a
a 5-,6-
5-,6- or
or 7-memberedcyclic
7-membered cyclicdiazocarbonyl
cyclic diazocarbonyl
compound
compound 310 reacted
310310
reacted with
with
reacted an
an ar-
with ar-
an
yne
yne
aryneintermediate
intermediate
intermediate 75A,
75A, the
75A,the migration
themigration of a carbonyl
migrationofofaacarbonyl moiety
carbonylmoiety
moietyofof initially
of initially formed
initially formed spiro-3H-
formed spiro-3H-
spiro-3H-
indazole 311
311 isis
indazole 311 restricted
restrictedtoto
isrestricted 1,2-rearrangement
to1,2-rearrangement
1,2-rearrangement since
since
since 1,3-migration
1,3-migration
1,3-migration is
is impossible
impossible
is impossible in this
in case.
in this this
case.
Such Such
case. Such aa rearrangement
rearrangement
a rearrangement typically
gives gives
typically
typically gives 2H-indazole
2H-indazole
2H-indazole 312
312 (Scheme
(Scheme
312 (Scheme 75)
75) [149].
75) [149]. [149]. Although
Although
Although these
these
these spiro-3H-indazoles
spiro-3H-indazoles
spiro-3H-indazoles 311 can311
311becan
can be
be quite
quite stable,stable,
quite some some
stable, some methods
have have
methods
methods been been
have been reported
reported
reported for
for
for their
their conversion
conversion
their to
to 2H-indazoles
to 2H-indazoles
conversion 2H-indazoles312. 312.
312.
Scheme 75. The

Scheme 75. The general
general pathway
pathway for
for the
the formation
formation of
of 2H-indazoles
2H-indazoles by
by the
the reaction
reaction of
of cyclic
cyclic diazocarbonyl
cyclic diazocarbonyl compounds
diazocarbonyl compounds
with arynes.
In 2017, the
In 2017,
2017, the Zhai
the Zhai group
Zhai group devised
group devised aaa protocol
devised protocol for
protocol for the preparation of
the preparation
preparation of stable
of stable spiro-3H-
stable spiro-3H-
spiro-3H-
indazoles
indazoles
indazoles by by
by thethe cycloaddition
the cycloaddition
cycloaddition of of 3-diazoindolin-2-ones
of 3-diazoindolin-2-ones
3-diazoindolin-2-ones 313 313
313 to to arynes
to arynes generated
arynes generated
generated from from
from si-
si-
silylaryl
lylaryl triflates
lylaryl triflates
triflates 314 314 [150].
314 [150].
[150]. The The reaction
The reaction tolerated
reaction tolerated electron-withdrawing
tolerated electron-withdrawing
electron-withdrawing and and electron-
and electron-donat-
electron-donat-
donating
ing
ing groups
groups groups
in
in both
both inindolinone
both indolinone
indolinone and and silylaryl
and silylaryl
silylaryl triflatetriflate
triflate moieties
moieties
moieties providing
providing
providing spiro[indazole-
spiro[indazole-3,3′-
spiro[indazole-3,3′-
0 0
3,3 -indolin]-2 -ones in to
good to excellent
indolin]-2′-ones
indolin]-2′-ones 315 in315
315 in good
good to excellent
excellent yields. yields.
yields. Under Under conditions,
Under thermal
thermal thermal conditions,
conditions, these these
these products
products
products underwent
underwent rearrangement rearrangement
to produce tofused
produce fused 2H-indazoles
2H-indazoles 316 (Scheme (Scheme
31676). The 76). The
syntheses
underwent rearrangement to produce fused 2H-indazoles 316 (Scheme 76). The syntheses
syntheses of
of various other spiro-3H-indazoles from 3-diazoindolin-2-one derivatives have
of various
various other
other spiro-3H-indazoles
spiro-3H-indazoles from from 3-diazoindolin-2-one
3-diazoindolin-2-one derivatives
derivatives have
have also
also been
been
also been
reported reported in other works [151,152].
reported in in other
other works
works [151,152].
[151,152].
Molecules 2021,26,
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74
Scheme 76. Synthesis Scheme 76. Synthesis 315

of spiro-3H-indazoles of spiro-3H-indazoles 315 and their thermal
and their thermal rearrangement rearrangement
into fused 2H-indazoles into
316. fused 2H-
Scheme 76. Synthesis of spiro-3H-indazoles
indazoles 316. 315 and their thermal rearrangement into fused 2H-indazoles 316.
This methodology was further extended to carbocyclic diazo compounds 317 [153].
This
In this methodology
methodology
case, was
was further
the rearrangement further extended
extended to
into 2H-indazolesto carbocyclic
carbocyclic diazo
diazo
319 could be compounds
compounds
carried 317
out not only [153].
[153].
317under
In this case, the rearrangement into 2H-indazoles 319 could be carried out
thermal but also under acidic conditions, even with weakly acidic SiO2 (Scheme 77). The not only under
thermal
reaction but also well
worked under acidic
with conditions,
conditions,
6-membered even with
evendiazo
cyclic weakly
weakly acidic
withcompounds,acidic SiO
butSiO (Scheme
in22the case of77). The
7-mem-
reaction
bered ones,worked
worked wellwith
purewell with6-membered
3H-indazole 6-membered becyclic
could not cyclic diazo
diazo
obtained. compounds,
compounds,
Fortunately, but but
in the
performingincase
the case
of
the of 7-
7-mem-
two-step
membered
bered ones, ones,
pure pure 3H-indazole
3H-indazole could could
not be not be
obtained. obtained. Fortunately,
Fortunately, performing
reaction in a one-pot fashion allowed to prepare 2H-indazole fused with the seven-mem- performing
the the
two-step
two-step
reaction inreaction
a one-potin a one-pot
fashion fashion
allowed to allowed
prepare to prepare
2H-indazole 2H-indazole
fused with
bered ring in a moderate yield. Noteworthily, the five-membered cyclic diazo compound fused
the with
seven-mem- the
seven-membered
bered
failed ring in aany
to give ring
moderate in ayield.
indazole moderate yield. Noteworthily,
Noteworthily,
products. the five-membered
the five-membered cyclic diazocyclic diazo
compound
compound failed to give any
failed to give any indazole products.indazole products.
Scheme 77. Synthesis of spiro-3H-indazoles and fused 2H-indazoles from cyclic diazo ketones.
Schemeof77.spiro-3H-indazoles and fused 2H-indazoles
Synthesis of spiro-3H-indazoles and fused from cyclic diazo
2H-indazoles ketones.
from cyclic diazo ketones.
Molecules 2021,26,
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74
In
In 2012, Wang
Wang and and Liu
Liufound
foundthat
thatcationic
cationicAg(I)
Ag(I) species
species cancan dramatically
dramatically affect
affect the
the chemoselectivity
chemoselectivity of reaction
of the the reaction of terminal
of terminal diazodiazo carbonyls
carbonyls 320an
320 with with an excess
excess of arynesof
arynes [154].inThus,
[154]. Thus, in the presence
the presence of AgOTf, of2-aryl-2H-indazoles
AgOTf, 2-aryl-2H-indazoles 322. This
322. This result is inresult is in
contrast to
contrast to 1-aryl-1H-indazoles 278 which were obtained by Jin and Yamamoto
1-aryl-1H-indazoles 278 which were obtained by Jin and Yamamoto in absence of any cat- in absence
of any(vide
alyst catalyst (vide
supra, supra, 67).
Scheme Scheme
The 67). The authors
authors postulated postulated the following
the following mechanism mechanism
for this
for this reaction.
reaction. Intermediate
Intermediate 78A generated
78A generated by initialbycycloaddition
initial cycloaddition is deprotonated
is deprotonated by
by fluoride
fluoride
to give atocarbonyl-stabilized
give a carbonyl-stabilized anion
anion 78B, 78B,is,which
which is, in
in turn, turn, trapped
trapped by Ag(I)by Ag(I)tocation
cation form
to form (1H-indazol-1-yl)silver
(1H-indazol-1-yl)silver 78C. The78C. The reaction
reaction of intermediate
of intermediate 78C with78C with benzyne
benzyne is likely isto
likely to produce the distinct arylation product 78D. Subsequent elimination
produce the distinct arylation product 78D. Subsequent elimination of silver with tautom- of silver with
tautomerization
erization furnishes furnishes
the finalthe final 2H-indazole
2H-indazole product product 322a (Scheme
322a (Scheme 78). 78).
Scheme 78. Ag(I)-promoted synthesis

Scheme 78. of 2-aryl-2H-indazoles
Ag(I)-promoted from terminal diazo
synthesis of 2-aryl-2H-indazoles from carbonyls andcarbonyls
terminal diazo benzynes.and benzynes.
Not
Notonly
only«aryne»
«aryne»approaches
approaches have been
have beenemployed
employed for for
the the
synthesis of 2H-indazoles.
synthesis In a
of 2H-indazoles.
study by the Lee
In a study group,
by the Lee2H-indazoles were prepared
group, 2H-indazoles werefrom 2-iodoazoarenes/2-iodoaryltriazenes
prepared from 2-iodoazoarenes/2-io-
323 and α-acetyldiazoacetate
doaryltriazenes 151 by a one-pot 151
323 and α-acetyldiazoacetate tandem
by a palladium-catalyzed deacylative
one-pot tandem palladium-cata-
cross-coupling/denitrogenative cyclization processcyclization
lyzed deacylative cross-coupling/denitrogenative [155]. The process
method[155].
was applicable
The methodto
awas
broad range of
applicable to substituents
a broad rangeinofthe aryl moiety
substituents inofthe323 and
aryl afforded
moiety 2-substituted
of 323 2H-
and afforded 2-
indazoles 324 in generally good yields (Scheme 79). Moreover, this protocol provided
substituted 2H-indazoles 324 in generally good yields (Scheme 79). Moreover, this proto- entry
into indazolesentry
col provided withinto
different substituents
indazoles in the substituents
with different two aryl rings, which
in the two is notrings,
aryl achievable
which
when using «aryne» methodologies.
is not achievable when using «aryne» methodologies.
Molecules 2021,26,
Molecules 2021, 26,2530
47 of 70
74
Scheme 79. Pd-catalyzed tandem deacylative cross-coupling/denitrogenative cyclization reaction for the synthesis of 2H-
indazoles.
Scheme 79. Pd-catalyzed tandemAzoxy compounds

deacylative can be used for the cyclization
cross-coupling/denitrogenative synthesis reaction
of 2H-indazoles, as was
for the synthesis of shown
2H- by
indazoles. Scheme
Scheme 79. Pd-catalyzed tandem 79. Pd-catalyzed
deacylative tandem deacylative cross-coupling/denitrogenative
cross-coupling/denitrogenative cyclization reaction for the cyclization
synthesis of reaction
2H-
the You group [156]. The Rh(III)-catalyzed C-H-alkylation/intramolecular decarboxyla
indazoles. for the synthesis of 2H-indazoles.
tive cyclization reaction of diazo esters 325 and aryldiazene oxides 326 provided 3-acyl
Azoxy compounds
2H-indazoles 327 in a highlycan be used for the manner
regioselective synthesis(Scheme
of 2H-indazoles,
80). as
As inasthewas showncase
previous by
Azoxy
Azoxy compounds
compounds can
can bebe used
used for
for the
the synthesis
synthesis of
of 2H-indazoles,
2H-indazoles, as was
was shown
shown by
by
the
both
the
You group
symmetrical [156].
and The Rh(III)-catalyzed
non-symmetrical C-H-alkylation/intramolecular
diaryldiazene oxides weredecarboxylative
found decarboxyla-
suitable for the
the You
You group
group[156].
[156]. The
TheRh(III)-catalyzed
Rh(III)-catalyzed C-H-alkylation/intramolecular
C-H-alkylation/intramolecular decarboxyla-
tive cyclization
reaction. reaction
Inreaction
addition, theof diazo
protocol esters
325isand 325
also and aryldiazene
compatible with oxides 326 provided
2-alkyl-1-aryldiazene 3-acyl-
cyclization
tive cyclization of diazo
reaction esters
of diazo esters 325 aryldiazene
and oxides
aryldiazene 326
oxides provided
326 provided 3-acyl- oxides
3-acyl-2H-
2H-indazoles
indazoles 327 in327 in a highly regioselective manner (Scheme 80). As in the previous case,
giving 327a in
highly
N-alkyl-2H-indazoles
2H-indazoles regioselective
a highly manner
in acceptable
regioselective (Scheme
yields.
manner 80). As
(Scheme 80).inAs
theinprevious case, both
the previous case,
both symmetrical
symmetrical andnon-symmetrical
non-symmetrical
and non-symmetrical
both symmetrical and diaryldiazene
diaryldiazene oxides were
diaryldiazene oxides
found
oxides were
foundfound
weresuitable for thesuitable
suitable for thefor the
reaction.
reaction.
reaction. In addition, the protocol is also compatible with 2-alkyl-1-aryldiazene oxidesoxides
In In
addition, addition,
the protocol the
is protocol
also is
compatible also
with compatible with
2-alkyl-1-aryldiazene 2-alkyl-1-aryldiazene
oxides giving N-alkyl-
2H-indazoles
giving in acceptable yields.
N-alkyl-2H-indazoles
giving N-alkyl-2H-indazoles in in acceptable
acceptable yields.
yields.
Scheme 80. Rh(III)-catalyzed C-H-alkylation/intramolecular decarboxylative cyclization reaction for synthesis of 2H-in-
dazoles.
Scheme 80. Rh(III)-catalyzed C-H-alkylation/intramolecular decarboxylative cyclization reaction for synthesis of 2H-in-
Scheme Scheme
dazoles.80. Rh(III)-catalyzed 80. Rh(III)-catalyzed C-H-alkylation/intramolecular
C-H-alkylation/intramolecular decarboxylative
decarboxylative cyclization reaction cyclization reaction
for synthesis for
of 2H-in-
3. Azoles
synthesis of
with Three Heteroatoms
2H-indazoles.
dazoles.
3.1. 1,2,3-Thiadiazoles
3. Azoles
Azoles with Three
Three Heteroatoms
Heteroatoms
3. with
3. Azoles with Three
A general approach
1,2,3-Thiadiazoles Heteroatoms
to the synthesis of 1,2,3-thiadiazoles from diazo compounds is
3.1.
based on the reaction
A general
generalapproach of
approachtoto diazocarbonyl ofcompound 328 with a thionation reagent.is The ini
A thethe synthesis
synthesis 1,2,3-thiadiazoles
of 1,2,3-thiadiazoles fromfrom
diazodiazo compounds
compounds is based
tially
based
on formed
on
theAreaction
generalofdiazothiocarbonyl
the reaction of diazocarbonyl
approach
diazocarbonylto the compound
compound
synthesis
compound 329
a328 iswith
usually
of 1,2,3-thiadiazoles
328 with thionation unstable
a reagent.
thionation and compounds
Thereagent.
from diazo
initially undergoes
The ini-
formed 1,5
is
electrocyclization
tially formed
diazothiocarbonyl
based to form
diazothiocarbonyl
compound
on the reaction 1,2,3-thiadiazole
329 iscompound
usually compound
of diazocarbonyl unstable330 (Scheme
329 is and
usually
328 81).
unstable
undergoes
with This topic has
and undergoes
a 1,5-electrocyclization
thionation been
reagent. 1,5- recently
toThe ini-
reviewed
form
tially by Shafran
electrocyclization
1,2,3-thiadiazole
formed 330and
to form co-authors
(Scheme
diazothiocarbonyl 81). This[16],
1,2,3-thiadiazole
compound 330therefore
topic (Scheme
has
329been weThis
81). chose
recently
is usually nothas
topic
reviewed
unstable cover
bybeen
and itrecently
Shafran in and
the presen
undergoes 1,5-
reviewed
review.
co-authors by Shafran
[16], and
therefore weco-authors
chose not [16],
cover therefore
it in the we
presentchose not
review. cover
electrocyclization to form 1,2,3-thiadiazole 330 (Scheme 81). This topic has been recentlyit in the present
review.
reviewed by Shafran and co-authors [16], therefore we chose not cover it in the present
review.
Scheme
Scheme 81.General
Scheme 81.
81. General«diazo» approach
«diazo» to
to 1,2,3-thiadiazoles.
approach
approach to 1,2,3-thiadiazoles.
1,2,3-thiadiazoles.
3.2. 1,2,3-Triazoles
Scheme 81. General «diazo» approach to 1,2,3-thiadiazoles.
Molecules 2021, 26, 2530 46 of 70
Since the revolutionary discovery of Copper-Azide-Alkyne Cycloaddition (CuAAC)
by Meldal the
Since revolutionary
[157] and Fokin and discovery
Sharpless of Copper-Azide-Alkyne
[158], this reaction has Cycloaddition
become the most (CuAAC)
widely
by Meldal [157] and Fokin and Sharpless [158], this reaction has become
used method for the preparation of 1,2,3-triazoles. Due to the great versatility and the most widely
sim-
used
plicitymethod
of this for the preparation
approach, of 1,2,3-triazoles.
it found application in many Due to the
fields of great versatility
chemical science,and
suchsim-
as
plicity of this approach, it found application in many fields of chemical
bioorthogonal reactions [159], design of functional coatings [160], preparation of organic science, such
as bioorthogonal
dyes reactions
and fluorophores [161],[159],
etc. Itdesign of functional
has also become a handycoatings
tool[160], preparation
in medicinal of or-
chemistry
ganic dyes and fluorophores [161], etc. It has also become a handy tool
and drug design for the preparation of triazole-containing bioactive molecules possessing in medicinal
chemistry and drug design for the preparation of triazole-containing bioactive molecules
anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial, anti-leish-
possessing anticancer, antimicrobial, anti-tubercular, antiviral, antidiabetic, antimalarial,
manial, and neuroprotective activities [162].
anti-leishmanial, and neuroprotective activities [162].
Standard CuAAC is suitable for terminal alkynes and allows the synthesis of 1,4-
Standard CuAAC is suitable for terminal alkynes and allows the synthesis of 1,4-
disubstituted 1,2,3-triazoles, but the regioselectivity can be reversed by using a ruthenium
disubstituted 1,2,3-triazoles, but the regioselectivity can be reversed by using a ruthenium
catalyst for synthesis of 1,5-disubstituted triazoles. Additionally, RuAAC also works well
catalyst for synthesis of 1,5-disubstituted triazoles. Additionally, RuAAC also works well
with internal alkynes providing fully substituted triazoles, although in this case, regiose-
with internal alkynes providing fully substituted triazoles, although in this case, regioselec-
lectivity cannot always be reliably controlled [163]. In contrast with this method, a number
tivity cannot always be reliably controlled [163]. In contrast with this method, a number of
of azide-free methodologies for regiospecific synthesis of variously substituted 1,2,3-tria-
azide-free methodologies for regiospecific synthesis of variously substituted 1,2,3-triazoles
zoles have been developed [164,165], including the «diazo» approach, specifically, the
have been developed [164,165], including the «diazo» approach, specifically, the Wolff cyclo-
Wolff cyclocondensation.
condensation. Moreover, for Moreover,
the latterfor the latter
reaction, reaction,
common common
Lewis Lewis
acids are usedacids
and are used
often no
and often no transition metal
transition metal catalyst is needed. catalyst is needed.
3.2.1. 1,2,3-Triazoles
3.2.1. via Cyclization
1,2,3-Triazoles via Cyclization of
of Imino
Imino Diazo
Diazo Compounds
Compounds
The Wolff
The Wolff cyclocondensation
cyclocondensation is is aa reaction
reaction ofof diazocarbonyl
compound with with amine
amine
leading to 1,2,3-triazoles [166]. The mechanism of this reaction is depicted
The mechanism of this reaction is depicted in in Scheme 82.
The condensation of amine 332 with diazo compound 331 carbonyl group, usually occur-
intermediate 333, which
ring under acidic catalysis, gives diazo imine intermediate which isis in
in equilibrium
equilibrium
with 1,2,3-triazole
with 1,2,3-triazole 334.
334. When the R group in the the imine
imine moiety
moiety isis not
not electron-withdrawing,
electron-withdrawing,
equilibriumisiscompletely
this equilibrium completely shifted
shifted towards
towards triazole.
triazole. The The disadvantages
disadvantages of thisofapproach
this ap-
proach
in in comparison
comparison with CuAAC
with CuAAC includeinclude its questionable
its questionable bioorthogonality
bioorthogonality andharsh
and often often
harsh reaction
reaction conditions.
conditions.
Scheme 82. Mechanism of Wolff

Wolff cyclocondensation.
cyclocondensation.
In
In aa study
study devoted
devotedtotothe
thesynthesis
synthesisofof potential
potential anti-tubercular
anti-tubercular agents,
agents, Costa
Costa andandco-
co-workers employed a reaction of diazo malonaldehyde 335 with aniline
workers employed a reaction of diazo malonaldehyde 335 with aniline hydrochlorides hydrochlorides
336 conducted
336 conducted in inwater
wateratatroom
roomtemperature
temperature toto
afford 1,2,3-triazoles
afford with
1,2,3-triazoles a 1,4-substitution
with a 1,4-substitu-
pattern 337 (Scheme 83) [167]. It should be noted that amine hydrochlorides
tion pattern 337 (Scheme 83) [167]. It should be noted that amine hydrochlorides themselves
them-
provide an acidic medium, which facilitates the generation of intermediate
selves provide an acidic medium, which facilitates the generation of intermediate imine species.
imine
Such 1-aryl-1,2,3-triazole-4-carbaldehydes
species. 337 can be further
Such 1-aryl-1,2,3-triazole-4-carbaldehydes 337 can converted into difluoromethyl-
be further converted into
substituted triazoles 338 in excellent
difluoromethyl-substituted triazoles yields
338 in simply onyields
excellent treatment
simplywith
ondiethylaminosulfur
treatment with di-
trifluoride (DAST).trifluoride (DAST).
ethylaminosulfur
In contrast to diazo aldehydes, the reaction of amines with α-diazoketones usually
requires the use of elevated temperature and the addition of Lewis acids in stoichiometric
amounts [168]. α-Diazo-β-oxosulfones 339 can also be involved in this reaction, as was
shown by the Krasavin group [169]. Heating at 80 ◦ C in chlorobenzene in the presence of 1.5
equivalents of TiCl4 turned out to be the best conditions for this transformation, although
the desired 4-sulfonyl-1,2,3-triazoles 341 were obtained in moderate yields (Scheme 84).
Molecules 2021, 26, 2530 47 of 70
Scheme 83. Synthesis of 1,2,3-triazoles from diazo malonaldehyde and aniline hydrochlorides.

shown by the Krasavin group [169]. Heating at 80 °C in chlorobenzene in the presence of
1.5 equivalents of TiCl4 turned out to be the best conditions for this transformation, alt-
hough the desired 4-sulfonyl-1,2,3-triazoles 341 were obtained in moderate yields
Scheme 83. Synthesis of 1,2,3-triazoles from diazo malonaldehyde and aniline hydrochlorides.
Scheme 84).Synthesis of 1,2,3-triazoles from diazo malonaldehyde and aniline hydrochlorides.
(Scheme83.
shown by the Krasavin group [169]. Heating at 80 °C in chlorobenzene in the presence of
1.5 equivalents of TiCl4 turned out to be the best conditions for this transformation, alt-
hough the desired 4-sulfonyl-1,2,3-triazoles 341 were obtained in moderate yields
(Scheme 84).
Scheme 84.
Scheme 84.The
TheWolff
Wolffcyclocondensation
cyclocondensationbetween α-diazo-β-oxosulfones
between and anilines.
α-diazo-β-oxosulfones and anilines.
An effectofofintramolecular
An interesting effect intramolecularhydrogen
hydrogenbonding
bonding activation
activation of carbonyl
of carbonyl group in
group in α-diazo-β-oxoamides
α-diazo-β-oxoamides 342 was in
342 was described described
2012 by in 2012and
Wang by co-workers
Wang and (Scheme
co-workers85) [170].
(Scheme
This 85)
effect [170]. This
allowed effect
the use allowed the
of catalytic use of(20
amounts catalytic
mol.%)amounts
of Lewis(20 mol.%)
acid, of Lewis
affording diversely
acid, affording diversely substituted triazole-4-carboxamides 344 in good
substituted triazole-4-carboxamides 344 in good yields (Scheme 85a). The method works yields (Scheme
85a). with
well The method works well
both aliphatic andwith both aliphatic
aromatic and
amines, as aromatic
well amines,such
as diamines as well as diamines
as 345 (Scheme 85b),
such as
substituted345 (Scheme
hydrazine, 85b), substituted
hydroxylamine, hydrazine,
and evenhydroxylamine,
ammonium and
acetateeven ammonium
(Scheme 85c). In the
Scheme 84. The Wolff cyclocondensation between α-diazo-β-oxosulfones and anilines.
acetatecase,
latter (Scheme 85c). In the latter case, 1H-triazole-5-carboxamides
1H-triazole-5-carboxamides 347 were obtained. This 347 were obtained.
methodology 50 ofwas
74 later
This methodology was later used for the preparation of some triazole-containing poly-
used An for interesting
the preparation
effect of
ofsome triazole-containing
intramolecular hydrogen polymers [171].
bonding activation of carbonyl
mers [171].
group in α-diazo-β-oxoamides 342 was described in 2012 by Wang and co-workers
(Scheme 85) [170]. This effect allowed the use of catalytic amounts (20 mol.%) of Lewis
acid, affording diversely substituted triazole-4-carboxamides 344 in good yields (Scheme
85a). The method works well with both aliphatic and aromatic amines, as well as diamines
such as 345 (Scheme 85b), substituted hydrazine, hydroxylamine, and even ammonium
acetate (Scheme 85c). In the latter case, 1H-triazole-5-carboxamides 347 were obtained.
This methodology was later used for the preparation of some triazole-containing poly-
mers [171].
Scheme 85.
Scheme 85.FeCl
FeCl2-catalyzed Wolff
2 -catalyzed cyclocondensation
Wolff of amines
cyclocondensation and α-diazo-β-oxoamides.
of amines and α-diazo-β-oxoamides.
Even poorly nucleophilic amines, such as aminofuroxans 348, can be employed for
this reaction, as was shown by Fershtat and co-authors [172]. The use of 20 mol.% of boron
trifluoride etherate at room temperature proved to be the optimal conditions for this sub-
strate, although the desired triazoles 350 were obtained in low to moderate yields. It is
Molecules 2021, 26, 2530 48 of 70
Scheme 85. FeCl2-catalyzed Wolff cyclocondensation of amines and α-diazo-β-oxoamides.
Even poorly nucleophilic

Even poorly nucleophilic amines,
amines, such
such as aminofuroxans 348,
as aminofuroxans can be
348, can be employed
employed for
for
this reaction, as was shown by Fershtat and co-authors [172]. The use of 20
this reaction, as was shown by Fershtat and co-authors [172]. The use of 20 mol.% of mol.% of boron
trifluoride etherate
boron trifluoride at room
etherate at temperature
room temperatureproved to be to
proved thebeoptimal conditions
the optimal for this
conditions forsub-
this
strate, although
substrate, the the
although desired
desired triazoles 350350
triazoles were obtained
were obtainedin in
low to to
low moderate
moderate yields. It It
yields. is
worth
is worthmentioning
mentioning that
thatininthis
thiscase,
case,α-diazodiketones
α-diazodiketonesgave
gavebetter
better yields
yields than
than α-diazo-β-
α-diazo-β-
ketoesters (Scheme 86).
ketoesters (Scheme 86).
Scheme 86. Synthesis of (1,2,3-triazol-1-yl)furoxans from aminofuroxans

aminofuroxans and
and diazo
diazo dicarbonyls.
dicarbonyls.

An intramolecular
An intramolecularvariant
variantof
ofthis
thisreaction
reactionusually
usuallyrequires
requiresmilder
milderconditions
conditions andandoften
51 ofof-
74
no use
ten of aofLewis
no use a Lewisacid catalyst.
acid InIn
catalyst. 2019,
2019,Santiago
Santiagoand
andBurtoloso
Burtolosoreported
reportedthethe synthesis
synthesis
of fused
of fusedbicyclic
bicyclic1,2,3-triazoles
1,2,3-triazoles355
355 from
from γ-N-protected
γ-N-protected amino
amino diazo
diazo ketones
ketones 354 [173].
354 [173]. The
The starting diazo compounds were prepared in four steps from
starting diazo compounds were prepared in four steps from γ-nitro esters 351.351.
γ-nitro esters TheThecy-
aqueous
cyclization solution
step wasof potassium
performedby carbonate.
bygently The yieldsthe
gentlyrefluxing
refluxing ondiazo
the final step 354
ketones wereingood to excel-
aa methanolic
clization step was performed the diazo ketones 354 in methanolic
lent,
aqueousthe only diminished
solution yieldcarbonate.
of potassium was observed with α-methyl-α-diazoketone
The yields on the final step were good 354a (Scheme
to excellent,
87).
the only diminished yield was observed with α-methyl-α-diazoketone 354a (Scheme 87).
Scheme 87. Intramolecular Wolff cyclocondensation

cyclocondensation with γ-N-protected amino
with γ-N-protected amino diazo
diazo ketones.
ketones.
Combining the
Combining the halo,
halo, keto,
keto, and
and diazo
diazo functions
functions in
in α-diazo-β-keto-γ-haloesters 356 has
α-diazo-β-keto-γ-haloesters 356 has
a potential for constructing fused triazole systems. This potential was realized in a recent
a potential for constructing fused triazole systems. This potential was realized in a recent
work by Krasavin and co-workers who reacted these diazo compounds with aminothiols
357 (Scheme 88) [174]. Initially, halogen is substituted by a more nucleophilic thiol group
so that the subsequent imine formation becomes an intramolecular reaction and requires
rather mild conditions to proceed. Both aliphatic and aromatic aminothiols worked well,
Molecules 2021, 26, 2530 49 of 70
work by Krasavin and co-workers who reacted these diazo compounds with aminothiols
357 (Scheme 88) [174]. Initially, halogen is substituted by a more nucleophilic thiol group
so that the subsequent imine formation becomes an intramolecular reaction and requires
rather mild conditions to proceed. Both aliphatic and aromatic aminothiols worked well,
providing 6,7-dihydrotriazolothiazines 358 in good to excellent yields. Attempts to perform
this reaction with thiosemicarbazides 359 only resulted in the formation of substitution
product, which, however, underwent rapid cyclization into triazole 360 in pure acetic acid
(Scheme 88).
Scheme 88.
Scheme 88. Synthesis of fused triazole
triazole systems
systems from
from α-diazo-β-keto-γ-haloesters
α-diazo-β-keto-γ-haloesters and aminothiols.
aminothiols.
The reaction
The reaction of diazo
of diazo ketone
ketone 151 with
151 with substituted
substituted hydrazines
hydrazines 361 occurs
361 occurs underunder
mildmild
con-
conditions and acetic acid as acidic promoter is usually sufficient for formation
ditions and acetic acid as acidic promoter is usually sufficient for formation of hydrazone of hydra-
zone intermediates
intermediates 89A [175].
89A [175]. Jordão
Jordão and co-workers
and co-workers usedused
this this approach
approach in their
in their workwork on
on the
the synthesis and antiviral testing of N-amino-1,2,3-triazoles 362 and their hydrazides
synthesis and antiviral testing of N-amino-1,2,3-triazoles 362 and their hydrazides 363 363
against
against the
the Cantagalo
Cantagalovirus
virus(Scheme
(Scheme89) 89)[176].
[176].TheThebest
bestyield
yieldwas
wasachieved
achievedwith unsubsti-
with unsub-
tuted phenylhydrazine.
stituted phenylhydrazine. The
Theyield
yielddecreased
decreasedasaselectron-withdrawing
electron-withdrawingsubstituents
substituentswere
were
introduced. These triazoles were further modified in order to obtain potential
introduced. These triazoles were further modified in order to obtain potential anti-HSV-1 anti-HSV-
1[177]
[177]and
andanti-candidiasis
anti-candidiasis[178]
[178]agents.
agents.
The steps sequence in a «diazo» approach to 1,2,3-triazoles can be reversed so that
imine is formed first and then undergoes a diazo transfer reaction. In 2016, the Emmanuvel
group developed a one-pot procedure for the synthesis of N-aminotriazoles 365 from β-
ketocarbonyl compounds 364 and tert-butyl carbazate [179]. The reaction also worked well
with 2,4-dinitrophenylhydrazine 366. However, when phenylhydrazine was involved into
this process, pyrazolone 368 formation was observed instead of the desired 1,2,3-triazole
(Scheme 90). In other work by this group, authors were able to isolate the intermediate
diazo hydrazones using different diazo transfer conditions [180]. A deacylative variation
of diazo transfer on enaminones for the synthesis of 1,5-disubstituted triazoles have also
been reported to date [181].
intermediates 89A [175]. Jordão and co-workers used this approach in their work on the
synthesis and antiviral testing of N-amino-1,2,3-triazoles 362 and their hydrazides 363
against the Cantagalo virus (Scheme 89) [176]. The best yield was achieved with unsub-
stituted phenylhydrazine. The yield decreased as electron-withdrawing substituents were
Molecules 2021, 26, 2530 50 of 70
introduced. These triazoles were further modified in order to obtain potential anti-HSV-1
[177] and anti-candidiasis [178] agents.
The steps sequence in a «diazo» approach to 1,2,3-triazoles can be reversed so that

imine is formed first and then undergoes a diazo transfer reaction. In 2016, the Emmanu-
vel group developed a one-pot procedure for the synthesis of N-aminotriazoles 365 from
β-ketocarbonyl compounds 364 and tert-butyl carbazate [179]. The reaction also worked
well with 2,4-dinitrophenylhydrazine 366. However, when phenylhydrazine was in-
volved into this process, pyrazolone 368 formation was observed instead of the desired
1,2,3-triazole (Scheme 90). In other work by this group, authors were able to isolate the
intermediate diazo hydrazones using different diazo transfer conditions [180]. A deacyl-
ative variation of diazo transfer on enaminones for the synthesis of 1,5-disubstituted tria-
Scheme 89.Scheme
Synthesis
zoles 89. of
have N-(arylamino)triazoles
Synthesis
also beenofreported from
to date diazo
N-(arylamino)triazoles
[181]. ketones
from and arylhydrazines.
diazo ketones and arylhydrazines.
Scheme 90. Synthesis of N-aminotriazoles by imine formation

Scheme 90. formation with
with subsequent
subsequent diazo
diazo transfer.
transfer.
5-Aminotriazoles 370 can

5-Aminotriazoles 370 can be
be obtained
obtained by
by performing
performing diazo
diazo transfer
transfer on
on amidine
amidine hy-
hy-
drochlorides
drochlorides 369 as was demonstrated by Dankova and co-authors [182]. The reaction
369 as was demonstrated by Dankova and co-authors [182]. The reaction
proceeded
proceeded regioselectively
regioselectivelywith
withasymmetric
asymmetricamidines,
amidines,except
exceptfor 369b when
for369b when aa 3:1
3:1 mixture
mixture
of isomeric triazoles 370b and 370b’ was obtained (Scheme 91).
of isomeric triazoles 370b and 370b’ was obtained (Scheme 91).
Molecules 2021, 26,
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74
Scheme 91. Synthesis of 5-aminotriazoles by diazo transfer on α-acyl acetamidine hydrochlorides.

α-acyl acetamidine
Scheme 91. Synthesis of 5-aminotriazoles by diazo transfer on α-acyl acetamidine hydrochlorides.
hydrochlorides.
α-Diazoamides are
areknown
knownto undergo cyclization under basic conditions to give salts
α-Diazoamides
α-Diazoamides are known totoundergo
undergo cyclization
cyclization under
under basic
basic conditions
conditions to give
to give salts
of 5-hydroxy-1,2,3-triazoles
salts of [183].
5-hydroxy-1,2,3-triazoles In 1984,
[183]. In Murrey-Rust
1984, Murrey-Rustand coworkers
and developed
coworkers developeda sim-a
of 5-hydroxy-1,2,3-triazoles [183]. In 1984, Murrey-Rust and coworkers developed a sim-
ple method
simple for for
method the the
preparation
preparationof 5-hydroxytriazole
of 5-hydroxytriazole ammonium
ammonium salts 373373
salts byby
treatment
treatment of
ple method for the preparation of 5-hydroxytriazole ammonium salts 373 by treatment of
dimethyl
of dimethyl diazomalonate
diazomalonate 371371
with an excess
with an excessnuber of amines
nuber 372—neat
of amines or in or
372—neat toluene solu-
in toluene
dimethyl diazomalonate 371 with an excess nuber of amines 372—neat or in toluene solu-
tion. (Scheme
solution. 92) [184].
(Scheme The The
92) [184]. role of amine in this reaction is both as aas
nucleophile for the
tion. (Scheme 92) [184]. The role role of amine
of amine in this
in this reaction
reaction is both
is both a nucleophile
as a nucleophile for for
the
formation
the formationof diazo amide
of diazo amideandand
as a base forforthe subsequent cyclization. The limitation of
formation of diazo amide and as aasbase
a base
for thethe subsequent
subsequent cyclization.
cyclization. TheThe limitation
limitation of
this approach
of this approachis that aromatic
is that aromaticamines fail fail
amines to react, which
to react, is consistent
which withwith
is consistent reduced
reduced nu-
this approach is that aromatic amines fail to react, which is consistent with reduced nu-
cleophilicity
nucleophilicity (and basicity)
(and of the
basicity) amino
of the aminogroupgroupin aromatic amines.
in aromatic ThisThis
amines. methodology
methodology has
cleophilicity (and basicity) of the amino group in aromatic amines. This methodology has
been used recently for the preparation of 5-hydroxytriazole derivatives
has been used recently for the preparation of 5-hydroxytriazole derivatives acting as a acting as a poten-
been used recently for the preparation of 5-hydroxytriazole derivatives acting as a poten-
tial carboxylic
potential acid bioisosters
carboxylic [185,186].
acid bioisosters Hydroxytriazole
[185,186]. salts can
Hydroxytriazole becan
salts acidified to afford
be acidified to
tial carboxylic acid bioisosters [185,186]. Hydroxytriazole salts can be acidified to afford
free
afford5-hydroxytriazoles 374, but
free 5-hydroxytriazoles 374,these compounds
but these compounds are often unstable
are often and undergo
unstable and undergo ring
free 5-hydroxytriazoles 374, but these compounds are often unstable and undergo ring
ring opening
opening to form
to form parent
parent diazo
diazo amide
amide species[187].
species [187].Some
Somemechanistic
mechanistic investigations
investigations of
opening to form parent diazo amide species [187]. Some mechanistic investigations of
these equilibrium processes have been reported reported elsewhere
elsewhere [188,189].
[188,189].
these equilibrium processes have been reported elsewhere [188,189].
Scheme 92. Synthesis of 5-hydroxytriazoles from dimethyl diazomalonate and

and amines.
amines.
Scheme 92. Synthesis of 5-hydroxytriazoles from dimethyl diazomalonate and amines.
The information on
The information on synthesis
synthesis of N-hydroxytriazoles from
of N-hydroxytriazoles from diazo
diazo compounds
compounds is is scarce.
scarce.
The information on synthesis of N-hydroxytriazoles from diazo compounds is scarce.
In aa report
In report by
by Jiang
Jiang and
and co-workers
co-workers devoted
devoted toto the
the synthesis
synthesis of some N-hydroxytriazoles
of some N-hydroxytriazoles
In a their
and report by Jiang as
evaluation and co-workers
peptide devoted
coupling to the
reagents, synthesis of some N-hydroxytriazoles
1-hydroxy-5-methyltriazole-4-carboxylate
and their evaluation as peptide coupling reagents, 1-hydroxy-5-methyltriazole-4-carbox-
andwastheirprepared
evaluation as peptide
by the Wolff coupling reagents, 1-hydroxy-5-methyltriazole-4-carbox-
375
ylate 375 was prepared by thecondensation of α-diazo-β-ketobutanoate
Wolff condensation 151 with hydroxy-
of α-diazo-β-ketobutanoate 151 with
ylate
lamine 375 was
[190]. prepared
This by
procedure,the Wolff
however, condensation
did not work of α-diazo-β-ketobutanoate
well for the synthesis 151 with
of 5-unsubstituted
hydroxylamine [190]. This procedure, however, did not work well for the synthesis of 5-
hydroxylamine [190].
1-hydroxytriazole 379, This
so anprocedure,
alternativehowever,
route haddid not
to be work well
devised. fordiazoacetate
Ethyl the synthesis82 of
was5-
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74
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unsubstituted 1-hydroxytriazole
unsubstituted 1-hydroxytriazole 379, 379, so
so an
an alternative
alternative route
route had
had to
to be
be devised.
devised. Ethyl
Ethyl di-
di-
azoacetate
coupled
azoacetatewith82 was coupled
82 Vilsmeier
was coupled with
reagent Vilsmeier
with376 reagent
and the reagent
Vilsmeier 376
product 376 and the
was the
377 and product
treated 377
with 377
product was treated
hydroxylamine.
was treated
withcyclization
The
with hydroxylamine.
of diazo
hydroxylamine. The
The cyclization
oxime 378 thus
cyclization ofobtained
of diazo oxime
diazo oxime 378 thus
thus
was carried
378 obtained
out either by
obtained was carrieditout
refluxing
was carried out
in
either
benzeneby orrefluxing
by it
storing in
itsbenzene
solution or
in by storing
chloroform its
at solution
room in chloroform
temperature for 2 at room
days.
either by refluxing it in benzene or by storing its solution in chloroform at room tempera- Thetempera-
overall
ture for
yield
ture for 22 days.
of thedays. The
target overall yield
yield of
N-hydroxytriazole
The overall of the
the target N-hydroxytriazole
was fair
379target (Scheme 93).
N-hydroxytriazole 379 was
379 was fair
fair (Scheme
(Scheme 93).
93).
Scheme 93.
Synthesis of
of N-hydroxytriazoles.
N-hydroxytriazoles.
Several approaches
Several
Several approachesto
approaches tothe
to thesynthesis
the synthesisofof
synthesis ofintermediate
intermediate
intermediate diazo
diazo
diazo imines
imines
imines have
have been
been
have reported
reported
been to
reported
to date.
date. ForFor example,
example, Regitz
Regitz and and Schoder
Schoder reported
reported the the synthesis
synthesis of of triazoles
triazoles 382 in382 in
which
to date. For example, Regitz and Schoder reported the synthesis of triazoles 382 in which which
diazo
diazo imine
imine
diazo imine intermediate
intermediate
intermediate 94A was 94A was prepared
prepared
prepared
94A was by iminomethylation
iminomethylation
by iminomethylation
by of terminal
of terminal
of terminal diazo com-
diazo compounds
diazo com-
pounds
380 with 380 with formamidine
formamidine 381 381
under under
reflux in reflux in acetonitrile
acetonitrile (Scheme (Scheme
94) [191].
pounds 380 with formamidine 381 under reflux in acetonitrile (Scheme 94) [191]. 94) [191].
Scheme 94.
Scheme
Scheme 94. Iminomethylation
94. Iminomethylation of terminal diazo
of terminal
terminal diazo compounds
diazo compounds for
compounds for the
for the synthesis
the synthesis of
synthesis of 1,2,3-triazoles.
of 1,2,3-triazoles.
1,2,3-triazoles.
5-Halo-substituted
5-Halo-substitutedtriazoles
5-Halo-substituted triazoles
triazoles384 can
384
384 be be
can
can prepared
be prepared
prepared from from
from 383 by
α-diazo-β-ketonitriles
α-diazo-β-ketonitriles
α-diazo-β-ketonitriles treat-
383
383 by
by
ment of the
treatment of
treatment latter
of the with
the latter HHal,
latter with as
with HHal,was
HHal, asdescribed
as was in a
was describedwork
described in by the
in aa workMokrushin
work byby the group
the Mokrushin [192].
Mokrushin group The
group
reaction
[192]. is believed
The reaction to
is proceed
believed via
to diazoimidoyl
proceed via chloride intermediate
diazoimidoyl chloride 95A. The presence
intermediate 95A.ofThe
an
[192]. The reaction is believed to proceed via diazoimidoyl chloride intermediate 95A. The
acyl group
presence of at
of anthe
an acyl
acyl group
group at
α-position of diazo
at the nitrile
the α-positionproved
α-position of to
of diazo be crucial
diazo nitrile for this
nitrile proved
proved to reaction
to be (Scheme
be crucial
crucial for 95).
for this
this
presence
reaction (Scheme
α-Phosphonyl 95). α-Phosphonyl
α-diazoacetonitriles wasα-diazoacetonitriles
also shown to undergo was this
alsotransformation.
shown to undergo this
reaction (Scheme 95). α-Phosphonyl α-diazoacetonitriles was also shown to undergo this
transformation.
transformation.
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74
Scheme 95.
Synthesis of
of 5-halo-1,2,3-triazoles
5-halo-1,2,3-triazoles from
from α-acyl
α-acyl α-diazoacetonitriles.
α-acyl α-diazoacetonitriles.
α-diazoacetonitriles.
1,2,3-Triazoles via
3.2.2. via Formal
via Formal Cycloaddition
Formal Cycloadditionto
Cycloaddition toMultiple
to MultipleCN
Multiple CNbonds
CN bonds
bonds
This
This section describes
This section describesmethods
describes methodsthat
methods thatdo
that donot
do notrely
not rely
rely onon
on the
thethe formation
formation
formation of diazo
of diazo
of diazo imine
imine
imine in-
in-
intermediates.
termediates. In
termediates. In
In 2010,2010,
2010, Chen Chen
Chen and and co-workers
and co-workers
co-workers reported reported
reported aa methoda method
method forfor the for the construction
the construction
construction ofof fully
fully
of fully
substitutedsubstituted
triazoles triazoles
387 by a by a DBU-mediated
DBU-mediated reaction reaction
of diazo of diazo
substituted triazoles 387 by a DBU-mediated reaction of diazo compounds 385 with385
387 compounds compounds
385 with N-
N-
with
PMP N-PMP
aryl aryl
imines imines
386 386
(Scheme (Scheme
96) 96)
[193]. [193].
The The
best best
yields yields
were were
obtainedobtained
PMP aryl imines 386 (Scheme 96) [193]. The best yields were obtained with EWG-substi- with with EWG-
EWG-substi-
substituted
tuted aryl aryl imines,
aryl imines,
imines, diminishing
diminishing thein
in the theof
case case of halogen
halogen or EDG-substituted
or EDG-substituted
EDG-substituted ones. ones.
tuted diminishing in case of halogen or ones.
Scheme 96.
Scheme
Scheme 96. DBU-mediated
96. DBU-mediated reaction
reaction of
of diazo
diazo compounds
compounds with
with aryl
aryl imines
imines for
for the
the synthesis
synthesis of
of fully
fully
substituted 1,2,3-triazoles.
substituted 1,2,3-triazoles.
Thisreaction
This
This reactioncan
reaction can
can be
bebe performed
performed
performed inthree-component
in ain aa three-component
three-component fashion
fashion using
usingusing
fashion aldehyde aldehyde 388,
388, amine
aldehyde 388,
amine
389, and 389,
BOR and BOR
(390) as (390)
the as
diazo the diazo
component component
as was as
shown was by
amine 389, and BOR (390) as the diazo component as was shown by the Mohanan group shown
the by
Mohanan the Mohanan
group group
[194]. The
method
[194]. The
[194]. Theallows
method
method theallows
diastereoselective
allows the synthesis synthesis
the diastereoselective
diastereoselective of either triazolines
synthesis of either
of 391 or triazoles
either triazolines
triazolines 391 or
391 392,
or tria-
tria-
depending
zoles 392, on the
depending natureon of the
the amine
nature and
of thethe aldehyde
amine and used.
the
zoles 392, depending on the nature of the amine and the aldehyde used. The tentative The
aldehyde tentative
used. mechanism
The tentativeis
as follows.
mechanism is
mechanism BOR
is as (390),
as follows.upon
follows. BOR deacylation,
BOR (390),
(390), upon reacted
upon deacylation, with imine
deacylation, reacted 97B
reacted with to give
with imine the
imine 97B intermediate
97B to
to give
give the
the
97C. Subsequent
intermediate
intermediate 97C.5-endo-dig
97C. Subsequent
Subsequent cyclization
5-endo-digand
5-endo-dig proton transfer
cyclization
cyclization and proton
and furnished
proton transferthe
transfer triazoline
furnished
furnished the391.
the tri-
tri-
When
azoline the aldehyde
391. When and
the the
aldehydeamine andare
the both
aminearomatic,
are both391 can
aromatic,
azoline 391. When the aldehyde and the amine are both aromatic, 391 can undergo a spon-undergo
391 cana spontaneous
undergo a air
spon-
oxidation
taneous air
taneous airtooxidation
form triazole
oxidation to form
to form (Scheme
392triazole
triazole 392
392 97). Interestingly,
(Scheme
(Scheme in contrastin
97). Interestingly,
97). Interestingly, inwith the previous
contrast
contrast with the
with the
example,
previous aldehydes
example, bearing
aldehydes EWG-substituents
bearing in
EWG-substituents the aryl
in
previous example, aldehydes bearing EWG-substituents in the aryl moiety failed to de-moiety
the aryl failed
moiety to deliver
failed to the
de-
product.
liver the An analogous
the product.
product. protocolprotocol
An analogous
analogous for the for preparation of triazole-4-sulfones
the preparation
preparation have been
of triazole-4-sulfones
triazole-4-sulfones have
liver An protocol for the of have
reported by
been reported this
reported by group
by this [195].
this group
group [195].
[195].
been
Li and co-workers used CuBr2 oxidation of secondary amines, namely N-arylglycine
derivatives 393, for the in situ generation of imines [196]. Their reaction with diazo
compounds 394 afforded fully decorated triazoles 395 in moderate to high yields. Mecha-
nistically, the reaction proceeds through iminium salt 98A, which upon cycloaddition with
diazo compound 394 forms intermediate 98B. Subsequent oxidation, probably by copper
ions, produces the triazole product 395 (Scheme 98).
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Scheme 97. Three-component synthesis of triazole-4-phosphonates.

derivatives 393, for the in situ generation of imines [196]. Their reaction with diazo com-
pounds 394 afforded fully decorated triazoles 395 in moderate to high yields. Mechanisti-
cally, the reaction proceeds through iminium salt 98A, which upon cycloaddition with
ions, produces
Scheme
Scheme 97. the triazolesynthesis
97. Three-component
Three-component product of
synthesis395 (Scheme 98).
oftriazole-4-phosphonates.
triazole-4-phosphonates.

derivatives 393, for the in situ generation of imines [196]. Their reaction with diazo com-
pounds 394 afforded fully decorated triazoles 395 in moderate to high yields. Mechanisti-
cally, the reaction proceeds through iminium salt 98A, which upon cycloaddition with
ions, produces the triazole product 395 (Scheme 98).
Scheme 98. CuBr

Scheme 98. CuBr22-promoted
-promoted synthesis
synthesisof
oftriazoles fromN-arylglycine
triazolesfrom N-arylglycinederivatives
derivativesand diazocarbonyl
and diazocar-
bonyl compounds.
compounds.
Silver-catalyzed
Silver-catalyzed [3+2]
[3+2] cycloaddition
cycloaddition of of diazo
diazo compounds
compounds 396 396 to
to isocyanides 397 was
isocyanides 397 was
reported
reported by Wang and co-workers [197]. The reaction proceeded smoothly to give 1,4-
by Wang and co-workers [197]. The reaction proceeded smoothly to give 1,4-
disubstituted
disubstituted triazoles 398 with
triazoles 398 with complete
complete regioselectivity
regioselectivity(Scheme
(Scheme99).99). This
This protocol
protocol is is
compatible
compatiblewithwithboth
bothEWG-
EWG- and EDG-substituted
and EDG-substituted arylaryl
isocyanides. However,
isocyanides. whenwhen
However, aliphatic
ali-
isocyanides were used,
phatic isocyanides were theused,
yieldsthe
were decreased.
yields As for the As
were decreased. diazo
forcompounds, trifluorodi-
the diazo compounds,
azoethane, diazo esters,
trifluorodiazoethane, andesters,
diazo trimethylsilyl diazomethane
and trimethylsilyl can be used,
diazomethane canalthough
be used, the latter
although
Scheme
provides 98.the
CuBr 2-promoted synthesis of triazoles from N-arylglycine derivatives and diazocar-
desired triazoles only in moderate yields.
the latter provides the desired triazoles only in moderate yields.
bonyl compounds.
Silver-catalyzed [3+2] cycloaddition
1,2,4-Triazoles possess of diazo
the biological profile thatcompounds
is somewhat396 to isocyanides
similar 397 was
to that displayed
reported by WangMoreover,
by 1,2,3-triazoles. and co-workers [197].
medicinal Thecontaining
agents reaction proceeded smoothly
1,2,4-triazole to give
moiety exhibit nu-1,4-
disubstituted triazoles
merous biological 398 with
activities suchcomplete regioselectivity
as antifungal, antiparasitic,(Scheme 99).antidepressant,
anxiolytic, This protocol is
compatible with etc.
anticonvulsant, both[198].
EWG-Besides,
and EDG-substituted aryl isocyanides.
1,2,4-triazole derivatives are used However,
as ligand inwhen
coor-ali-
phatic isocyanides
dination chemistrywere
[199]used,
and asthea building
yields were decreased.
blocks As for the diazo
for the construction compounds,
of coordination
polymers and metal organic
trifluorodiazoethane, frameworks
diazo esters, [200]. Classical
and trimethylsilyl methods for the
diazomethane cansynthesis
be used,ofalthough
1,2,4-
triazoles include condensation of substituted hydrazines
the latter provides the desired triazoles only in moderate yields. with imides, reaction of amides
with hydrazides, and coupling of amidrazones with acyl chlorides, although many other
Molecules 2021, 26, 2530 55 of 70
Scheme 99. Ag-catalyzed [3+2]-cycloaddition of diazo compounds to isocyanides affording 1,
disubstituted triazoles.

methodologies have been developed [201]. However, there are only few reports on the
synthesis of 1,2,4-triazoles using diazo compounds.
1,2,4-Triazoles possess the biological profile that is somewhat similar to that
played by 1,2,3-triazoles. Moreover, medicinal agents containing 1,2,4-triazole moiet
hibit numerous biological activities such as antifungal, antiparasitic, anxiolytic, an
pressant, anticonvulsant, etc. [198]. Besides, 1,2,4-triazole derivatives are used as lig
in coordination chemistry [199] and as a building blocks for the construction of coord
tion polymers and metal organic frameworks [200]. Classical methods for the synthes
1,2,4-triazoles include condensation of substituted hydrazines with imides, reactio
amides with hydrazides, and coupling of amidrazones with acyl chlorides, altho
many other methodologies have been developed [201]. However, there are only few
Scheme 99.
Scheme 99. Ag-catalyzed [3+2]-cycloaddition of
Ag-catalyzed [3+2]-cycloaddition of diazo
diazo compounds
compoundsto toisocyanides
isocyanidesaffording
affording1,4-
1,4-
ports on the
disubstituted
synthesis of 1,2,4-triazoles using diazo compounds.
triazoles.
disubstituted triazoles.
A protocol for the synthesis of 1,2,4-triazole-3-carboxylates 401 from imines 399
A
diazo protocol
ketones
3.3. 1,2,4-Triazolesfor400
the synthesis
was devised of 1,2,4-triazole-3-carboxylates
by Zhao and co-wrokers from imines
401 [202]. 399 and involv
The reaction
diazo ketones
nucleophilic 400 was devised
attack of anion by Zhao and co-wrokers [202]. The reaction involved a with D
1,2,4-Triazoles
nucleophilic attack ofpossess the 100A,
anion 100A,
generated
biological
generated uponprofile upon
that isdeprotonation
deprotonationsomewhat of imine
of iminesimilar
399 with
399
toDBU,
that dis-
onto abyterminal diazo Moreover,
nitrogen ofmedicinal
400 followed by proton transfer and tautomerizatio
onto a terminal diazo nitrogen of 400 followed by proton transfer and tautomerization to ex-
played 1,2,3-triazoles. agents containing 1,2,4-triazole moiety
give
hibit
give the
the hydrazone
numerous
hydrazone
intermediate
biological activities
intermediate
100D.asSubsequent
100D. such
Subsequentantifungal,
cyclization
cyclization
antiparasitic,and airfurnishes
oxidation
anxiolytic,
and air oxidation
furn
antide-
the
the final
pressant,
final triazole
triazole product
anticonvulsant,
product 401 401 (Scheme
etc.(Scheme
[198]. Besides, 100). Interestingly,
1,2,4-triazole
100). Interestingly, only onlyα-diazoketones
derivatives
terminal terminal
are used asα-diazoket
ligand
inproduced
coordination 1,2,4-triazoles,
chemistry whereas
[199] and as diazo
a esters
building gave
blocks tetrahydro-1,2,4-triazines.
for the
produced 1,2,4-triazoles, whereas diazo esters gave tetrahydro-1,2,4-triazines. construction of coordina-
tion polymers and metal organic frameworks [200]. Classical methods for the synthesis of
1,2,4-triazoles include condensation of substituted hydrazines with imides, reaction of
amides with hydrazides, and coupling of amidrazones with acyl chlorides, although
many other methodologies have been developed [201]. However, there are only few re-
ports on the synthesis of 1,2,4-triazoles using diazo compounds.
A protocol for the synthesis of 1,2,4-triazole-3-carboxylates 401 from imines 399 and
diazo ketones 400 was devised by Zhao and co-wrokers [202]. The reaction involved a
nucleophilic attack of anion 100A, generated upon deprotonation of imine 399 with DBU,
onto a terminal diazo nitrogen of 400 followed by proton transfer and tautomerization to
give the hydrazone intermediate 100D. Subsequent cyclization and air oxidation furnishes
the final triazole product 401 (Scheme 100). Interestingly, only terminal α-diazoketones
produced 1,2,4-triazoles, whereas diazo esters gave tetrahydro-1,2,4-triazines.
Scheme
Scheme 100. DBU-promoted 100. DBU-promoted
reaction reaction
of glycine imines of diazo
with glycineketones
imines with diazo
for the ketones for
synthesis the synthesis of
of 1,2,4-triazole-3-carbox-
ylates. 1,2,4-triazole-3-carboxylates.
In 2018, the Chen group described a base-mediated reaction of diazo oxindoles 402
with oxazol-5-(4H)-ones 403 affording 3-(1H-1,2,4-triazol-1-yl)indolin-2-ones 404 in rea-
sonable yields (Scheme 101) [203]. The best results were obtained with electron-donating
R1 groups on the phenyl ring of 402. As for the oxazolones 403, electron-poor aryl rings
as the R3 substituents provided the desired product in higher yields in comparison with
Scheme 100. DBU-promoted reaction of glycine imines with diazo ketones for the synthesis of 1,2,4-triazole-3-carbox-
In 2018, the Chen group described a base-mediated reaction of diazo oxindoles 402
with oxazol-5-(4H)-ones 403 affording 3-(1H-1,2,4-triazol-1-yl)indolin-2-ones 404 in rea-
Molecules 2021, 26, 2530 sonable yields (Scheme 101) [203]. The best results were obtained with electron-donating 56 of 70
R1 groups on the phenyl ring of 402. As for the oxazolones 403, electron-poor aryl rings as
the R3 substituents provided the desired product in higher yields in comparison with elec-
tron-rich ones.
electron-rich Noteworthily,
ones. Noteworthily, when
when4-unsubstituted
4-unsubstitutedoxazolone
oxazolone 403 (R44 =
403 (R = H) was used,
H) was used, the
the reaction failed to give any triazole product. Attempts to perform the reaction withdiazo
reaction failed to give any triazole product. Attempts to perform the reaction with
dicarbonyl
diazo compounds
dicarbonyl and aand
compounds vinyl diazodiazo
a vinyl compound
compounddid did
not not
work as well.
work TheThe
as well. mecha-
nism of the of
mechanism reaction is presumably
the reaction similar
is presumably to the
similar previous
to the example.
previous example.
Scheme 101.Synthesis
Scheme101. Synthesisofof3-(1H-1,2,4-triazol-1-yl)indolin-2-ones
3-(1H-1,2,4-triazol-1-yl)indolin-2-onesfrom diazo
from oxindoles
diazo and oxazol-5-
oxindoles and oxazol-
(4H)-ones.
5-(4H)-ones.
Radical
Radicalreactions
reactionsofofdiazo
diazocompounds
compounds have also
have alsobeen employed
been employed for the
for assembly of of
the assembly
hydrazones with subsequent cyclization to 1,2,4-triazoles. Chan and co-workers developed
hydrazones with subsequent cyclization to 1,2,4-triazoles. Chan and co-workers devel-
a photoredox decarboxylative C(sp3 )−N coupling of N-hydroxyphthalimide (NHPI) esters
oped a photoredox decarboxylative C(sp3)−N coupling of N-hydroxyphthalimide (NHPI)
with α-diazoacetates 406 for the synthesis of hydrazones [204]. When N-acetyl amino acids
esters with α-diazoacetates 406 for the synthesis of hydrazones [204]. When N-acetyl
derived NHPI esters 405 were used, the initially formed hydrazones 102A underwent
amino acids
cyclization to derived NHPI esters
give 1,2,4-triazoles 407405 wereyields.
in good used, Mechanistically,
the initially formed hydrazones
the reaction begins102A
underwent cyclization to give 1,2,4-triazoles 407 in good yields. Mechanistically,
with photoexcitation of Rose bengal (RB) with 585 nm yellow LED irradiation. An excited the reac-
tion begins
state with
RB* reacts photoexcitation
with Hantzsch esterof Rose
408 bengal (RB) with
by single-electron 585 (SET)
transfer nm yellow
processLED irradiation.
to generate
An excited state RB* reacts with •−
Hantzsch ester 408 by single-electron
the Rose bengal radical anion (RB ), which reduces the NHPI ester 405 to form radical transfer (SET) pro-
cess to102B.
anion generate the Rose
Subsequent C–Cbengal
bondradical anion (RB
fragmentation gives),alkyl
•− which reduces
radical •
R , the NHPI
which ester
reacts 405 to
with
form
the radicaldiazo
terminal anionnitrogen
102B. Subsequent C–C bond
of 406 to produce fragmentation
intermediate gives alkyl
102C. Following radical R•,
hydrogen
atom
whichtransfer (HAT)the
reacts with from the cationic
terminal diazoradical,
nitrogenHantzsch
of 406 to ester 102D provides
produce hydrazone
intermediate 102C. Fol-
102A. Finally, 102A undergoes cyclization to afford the desired 1,2,4-triazole
lowing hydrogen atom transfer (HAT) from the cationic radical, Hantzsch ester 102D product 407 pro-
(Scheme 102).
vides hydrazone 102A. Finally, 102A undergoes cyclization to afford the desired 1,2,4-
A three-component
triazole product 407 (Schemeprotocol for the preparation of 1,2,4-triazoles 413 from aryl diazo-
102).
nium salts 410, diazo esters 411, and nitriles 412 was developed by the Wan group [205].
EDG-substituted aryl diazonium salts performed better than EWG-substituted ones. Based
on preliminary mechanistic studies and DFT-calculations, the authors suggest the following
mechanism for the reaction. Nitrile 412 most likely attacks copper carbene 103A to form
intermediate 103B, which then undergoes a highly regioselective [3+2] cycloaddition to
diazonium salt 410 to afford cyclic intermediate 103C. The latter suffers base-mediated
isomerization to deliver the desired 1,2,4-triazole 413 (Scheme 103).
Diazo azoles, namely diazo pyrazoles 414 and diazo imidazoles 417, were employed
for the synthesis of N-azolyl-1,2,4-triazoles 416 and 418 in a study reported by Sadchikova
and co-workers [206]. The reaction of 414 and 417 with ethyl isocyanoacetate 415 proceeded
smoothly to afford the desired products in good to excellent yields (Scheme 104). Interest-
ingly, when a primary or secondary amide moiety was present in the diazo heterocyclic
substrate, the reaction gave azolotriazinones instead of triazoles.
Molecules 2021, 26, 2530 57 of 70
Molecules 2021, 26, x FOR PEER REVIEW 3 )3− 61 of 74

Scheme Scheme 102. Photoredox
102. Photoredox decarboxylative
decarboxylative C(sp
C(sp )−N coupling ofofN-hydroxyphthalimide
N coupling N-hydroxyphthalimide(NHPI) estersesters
(NHPI) with α-diazoacetates
with α-diazoacetates
for the synthesis of 1,2,4-triazoles.
for the synthesis of 1,2,4-triazoles.
A three-component protocol for the preparation of 1,2,4-triazoles 413 from aryl dia-
zonium salts 410, diazo esters 411, and nitriles 412 was developed by the Wan group [205].
EDG-substituted aryl diazonium salts performed better than EWG-substituted ones.
Based on preliminary mechanistic studies and DFT-calculations, the authors suggest the
following mechanism for the reaction. Nitrile 412 most likely attacks copper carbene 103A
to form intermediate 103B, which then undergoes a highly regioselective [3+2] cycloaddi-
tion to diazonium salt 410 to afford cyclic intermediate 103C. The latter suffers base-me-
diated isomerization to deliver the desired 1,2,4-triazole 413 (Scheme 103).
Scheme 103. Three-component synthesis

Scheme 103. of 1,2,4-triazoles synthesis
Three-component from diazoof
esters, aryl diazonium
1,2,4-triazoles salts
from and esters,
diazo nitriles. aryl diazonium salts
and nitriles.
and co-workers [206]. The reaction of 414 and 417 with ethyl isocyanoacetate 415 pro-
ceeded smoothly to afford the desired products in good to excellent yields (Scheme 104).
Interestingly, when a primary or secondary amide moiety was present in the diazo heter-
and co-workers [206]. The reaction of 414 and 417 with ethyl isocyanoacetate 415 pro-
ceeded smoothly to afford the desired products in good to excellent yields (Scheme 104).
Molecules 2021, 26, 2530 58 of 70
Interestingly, when a primary or secondary amide moiety was present in the diazo heter-
ocyclic substrate, the reaction gave azolotriazinones instead of triazoles.

Scheme of 1,2,4-triazoles
104. Synthesis from diazo
of 1,2,4-triazoles azoles
from and
diazo ethyland
azoles isocyanoacetate.
ethyl isocyanoacetate.
4. Azoles with
4. Azoles with Four
Four Heteroatoms
Heteroatoms
Tetrazoles
Tetrazoles
Tetrazole derivatives are known to be high-energy compounds. They have found
Tetrazole derivatives are known to be high-energy compounds. They have found ap-
application in explosives, propellants, and pyrotechnics. In these fields, tetrazoles are used
plication in explosives, propellants, and pyrotechnics. In these fields, tetrazoles are used
either as individual compounds [207] or as complexes with metals, which are called energetic
metal-organic frameworks (EMOFs) [208]. Several tetrazoles have been prepared which
outperform classic high performance explosives, such as RDX [207]. As for medicinal
chemistry, 5-substituted tetrazoles are commonly considered as carboxylic acids bioisosteres
whereas 1,5-disubstituted ones are used as amide surrogates. Moreover, tetrazoles possess
remarkable metabolic stability. According to the Drug Bank, there are more than 40 drugs
that exhibit antimicrobial, anticancer [209], antiallergic, hypertensive, nootropic, and other
biological activities [210]. The general approach for the synthesis of 1-unsubstituted and
1,5-disubstituted tetrazoles is the reaction of nitriles or imidoyl derivatives with inorganic
or organic azides, respectively [210,211]. In contrast to these methodologies, the synthesis
of tetrazoles using diazo compounds provides access to an alternative regioisomer, namely,
2,5-disubstituted tetrazole, with high regioselectivity.
In 1982, Aoyama and Shioiri reported a reaction of a 2-fold excess of lithium trimethylsi-
lyl diazomethane 419 with methyl esters 420, which afforded 2-substituted-5-TMS-tetrazoles
421 in generally good yields [212]. The authors propose the following mechanism for the
reaction. Lithium derivative 419 initially attacks the ester carbonyl carbon of 420 producing
intermediate 105A. Either the 1,3-dipolar cycloaddition of 105A to 419 or the nucleophilic
attack at the terminal diazo nitrogen of 105A with a second molecule of 419, followed by
cyclization, leads to the formation of intermediate 105B. The latter is hydrolyzed during
the aqueous work-up to give the desired tetrazole products 421. Similar «dimerization» of
α-diazophosphonates has also been reported (Scheme 105) [213].
In recent years, an alternative «diazo» approach for the preparation of tetrazoles, which
is based on the reaction of terminal diazo compounds with aryl diazonium salts, has been ex-
tensively studied. In 2015, the Ma group for the first time described a silver acetate-catalyzed
[3+2]-cycloaddition of diversely substituted aryl diazonium tetrafluoroborates 422 and 2,2,2-
trifluorodiazoethane 423 for the synthesis of 2-aryl-5-trifluoromethyltetrazoles 424 [214]. The
reaction tolerated a wide range of electron-donating and electron-withdrawing substituents
in the aryl ring. Some heterocyclic diazonium salts were also found to be compatible
with this protocol. Moreover, the reaction could be performed in a one-pot diazotiza-
tion/cycloaddition sequence starting from anilines 425. In this case, electron-deficient
substrates showed better yields in comparison with electron-rich ones (Scheme 106).
tetrazoles 421 in generally good yields [212]. The authors propose the following mecha-
nism for the reaction. Lithium derivative 419 initially attacks the ester carbonyl carbon of
420 producing intermediate 105A. Either the 1,3-dipolar cycloaddition of 105A to 419 or
the nucleophilic attack at the terminal diazo nitrogen of 105A with a second molecule of
Molecules 2021, 26, 2530
419, followed by cyclization, leads to the formation of intermediate 105B. The latter 59
is of
hy-70
drolyzed during the aqueous work-up to give the desired tetrazole products 421. Similar
«dimerization» of α-diazophosphonates has also been reported (Scheme 105) [213].

Scheme 105.
Scheme 105. Synthesis of 2,5-disubstituted tetrazoles from lithium trimethylsilyl diazomethane and
and methyl
methyl esters.
esters.
In recent years, an alternative «diazo» approach for the preparation of tetrazoles,

which is based on the reaction of terminal diazo compounds with aryl diazonium salts,
has been extensively studied. In 2015, the Ma group for the first time described a silver
acetate-catalyzed [3+2]-cycloaddition of diversely substituted aryl diazonium tetra-
fluoroborates 422 and 2,2,2-trifluorodiazoethane 423 for the synthesis of 2-aryl-5-trifluo-
romethyltetrazoles 424 [214]. The reaction tolerated a wide range of electron-donating and
electron-withdrawing substituents in the aryl ring. Some heterocyclic diazonium salts
were also found to be compatible with this protocol. Moreover, the reaction could be per-
formed in a one-pot diazotization/cycloaddition sequence starting from anilines 425. In
this case, electron-deficient substrates showed better yields in comparison with electron-
rich ones (Scheme 106).
Scheme 106. AgOAc-catalyzed [3+2]-cycloaddition

[3+2]-cycloaddition ofof 2,2,2-trifluorodiazoethane
2,2,2-trifluorodiazoethane to
to aryl
aryl diazonium
diazonium
tetrafluoroborates for the synthesis of 2,5-disubstituted tetrazoles.
Further developing
developingthe theabove
abovemethodology,
methodology, the same
the same group
groupdemonstrated
demonstrated its utility for
its utility
the synthesis of CF -functionalized tetrazoles. ((2-Diazo-1,1-difluoroethyl)sulfonyl)benzene
for the synthesis2 of CF2-functionalized tetrazoles. ((2-Diazo-1,1-difluoroethyl)sul-
426 was used as
fonyl)benzene 426a was
diazo reagent
used to afford
as a diazo the desired
reagent to affordtetrazoles
the desired in good to
427tetrazoles 427excellent
in good
yields
to [215].yields
excellent As in the previous
[215]. example,
As in the previous theexample,
reaction can also be performed
the reaction can also beinperformed
a one-pot
fashion.
in More
a one-pot importantly,
fashion. the obtained
More importantly, the tetrazoles 427 can be
obtained tetrazoles 427easily
can beconverted to the
easily converted
medicinally
to relevantrelevant
the medicinally CHF2 -substituted tetrazoles
CHF2-substituted 428 either
tetrazoles by either
428 treatment with tBuOK
by treatment or
with
by reduction with LiAlH (Scheme 107).
tBuOK or by reduction with LiAlH4 (Scheme 107).
4
In a 2016 study by Patouret and Kamenecka, trimethylsilyl diazomethane 42 was
involved into this reaction in the presence of CsF to obtain 5-unsubstituted 2-aryltetrazoles
429 [216]. In this case, CF3 CO2 Ag was found to be the silver source of choice. The use
of a stoichiometric amount of silver salt (1.2 eq.) and low temperature (−78 ◦ C) proved
to be crucial for a successful reaction. When the reaction was carried out in the absence
of CsF, 5-TMS-substituted tetrazole 430 could be isolated. The latter can be used for the
preparation of 5-bromotetrazole 431, which has the potential for further modifications via
cross-coupling reactions (Scheme 108).
Further developing the above methodology, the same group demonstrated its utility
for the synthesis of CF2-functionalized tetrazoles. ((2-Diazo-1,1-difluoroethyl)sul-
fonyl)benzene 426 was used as a diazo reagent to afford the desired tetrazoles 427 in good
to excellent yields [215]. As in the previous example, the reaction can also be performed
Molecules 2021, 26, 2530 in a one-pot fashion. More importantly, the obtained tetrazoles 427 can be easily converted
60 of 70
to the medicinally relevant CHF2-substituted tetrazoles 428 either by treatment with
tBuOK or by reduction with LiAlH4 (Scheme 107).
5-TMS-substituted tetrazole 430 could be isolated. The latter can be used for the prepara-
tion of 5-bromotetrazole 431, which has the potential for further modifications via cross-
coupling
Scheme
Scheme reactions
107.
107. (Scheme
Synthesis
Synthesis of
of CF 108).
CF22-substituted tetrazoles.
In a 2016 study by Patouret and Kamenecka, trimethylsilyl diazomethane 42 was in-

volved into this reaction in the presence of CsF to obtain 5-unsubstituted 2-aryltetrazoles
429 [216]. In this case, CF3CO2Ag was found to be the silver source of choice. The use of a
stoichiometric amount of silver salt (1.2 eq.) and low temperature (‒78 °C) proved to be
crucial for a successful reaction. When the reaction was carried out in the absence of CsF,
Scheme 108.
Synthesis of
of C-unsubstituted
C-unsubstituted and
and 5-bromo-substituted
5-bromo-substituted2-aryltetrazoles.
2-aryltetrazoles.
α-Diazoketonesalong
α-Diazoketones alongwith α-diazoamides(433)
withα-diazoamides (433)were
werefirst
firstemployed
employedfor forthis
thisreaction
reaction
by
by Krasavin and co-workers to obtain 2-aryl-5-acyltetrazoles 434 in moderate to good
Krasavin and co-workers to obtain 2-aryl-5-acyltetrazoles 434 in moderate to good
yields
yields (Scheme
(Scheme 109)
109) [217].
[217]. In
In this
this case,
case, silver
silver nitrate
nitrate as
as aa catalyst
catalyst showed
showed thethe best
best results.
results.
As
As aa diazonium
diazonium reagent,
reagent, aryl
aryl diazonium
diazonium tosylates 432 were
tosylates 432 were used
used as
as they
they are
aremore
morestable
stable
and convenient to handle compared to the respective tetrafluoroborates.
and convenient to handle compared to the respective tetrafluoroborates. The reaction The reaction
was
was found to be not particularly sensitive to substituent effects in the diazonium
found to be not particularly sensitive to substituent effects in the diazonium moiety. As moiety.
As
forfor
thethe diazo
diazo portion,aromatic
portion, aromaticand andheteroaromatic
heteroaromaticdiazo diazo ketones
ketones performed
performed better
better in
in
comparison
comparison with aliphatic diazo ketone and diazo amides. Recently, α-diazoesters [218]
with aliphatic diazo ketone and diazo amides. Recently, α-diazoesters [218]
and
and the
theSeyferth–Gilbert
Seyferth–Gilbert reagent
reagent [219] have
[219] havebeenbeen
involved in this
involved inreaction by the by
this reaction Mathegroup.
Ma
group.
As a diazonium reagent, aryl diazonium tosylates 432 were used as they are more stable
and convenient to handle compared to the respective tetrafluoroborates. The reaction was
found to be not particularly sensitive to substituent effects in the diazonium moiety. As
for the diazo portion, aromatic and heteroaromatic diazo ketones performed better in
Molecules 2021, 26, 2530
comparison with aliphatic diazo ketone and diazo amides. Recently, α-diazoesters61[218]
of 70
and the Seyferth–Gilbert reagent [219] have been involved in this reaction by the Ma
group.
Scheme 109.
Scheme 109. Silver nitrate-catalyzed [3+2]-cycloaddition of diazo ketones and diazo amides to aryl
diazonium tosylates
diazonium tosylates for
for the
the synthesis
synthesis of
of 2-aryl-5-acyltetrazoles.
2-aryl-5-acyltetrazoles.
Krasavin group, it was demonstrated that (hetero)aryl-, alkyl-

In a 2020 work by the Krasavin
sulfonyl, and aminosulfonyl diazomethanes 435 are also applicable for this reaction [220].
Thus,
Thus, the rare 2-aryltetrazol-5-yl
2-aryltetrazol-5-ylsulfones
sulfonesand andpreviously
previouslynot notdescribed
describedininthe
the literature
literature 2-
2-aryltetrazol-5-yl sulfonamides
aryltetrazol-5-yl sulfonamides 436436werewere prepared
prepared in in generally
generally goodgood yields.
yields. However,
However, di-
diminished
minished yieldsyields
werewere observed
observed withwitharyl aryl diazonium
diazonium tosylates
tosylates 432 bearing
432 bearing electron-
electron-donat-
donating or ortho-substituents. The following plausible mechanism
ing or ortho-substituents. The following plausible mechanism was suggested (which was suggested (which
can
can be presumably extended also to the examples discussed above).
be presumably extended also to the examples discussed above). Diazo substrate 435 wasDiazo substrate 435
was deprotonated
deprotonated by theby base
the base
and andbound bound
by theby Ag
thecation
Ag cation to give
to give intermediate
intermediate 110A.110A.
The
The
latterlatter coordinated
coordinated withwith diazonium
diazonium salt insalt in a way
a way that unambiguously
that unambiguously determines
determines the
the regi-
ochemistry of the
regiochemistry final
of the product,
final product,i.e.,i.e.,
providing
providingintermediate
intermediate110C. Subsequent
110C. Subsequent silver-as-
silver-
sisted cycloaddition
assisted cycloadditionwithwiththe
theliberation
liberationofofthe thecatalyst
catalyst delivers
delivers the desired tetrazole
tetrazole 436436
(Scheme 110).
(Scheme 110).

Scheme 110. Synthesis of
of 2-aryltetrazol-5-yl
2-aryltetrazol-5-yl sulfones
sulfones and
and 2-aryltetrazol-5-yl
2-aryltetrazol-5-yl sulfonamides.
sulfonamides.
5. Conclusions
5. Conclusions
As we have demonstrated in this review, diazocarbonyl and related compounds provide
As we have demonstrated in this review, diazocarbonyl and related compounds pro-
rapid and efficient access to a wide range of various azoles. Among the most thoroughly
vide rapid and efficient access to a wide range of various azoles. Among the most thor-
studied are approaches to 1,3-oxazoles, pyrazoles, and 1,2,3-triazoles. Some of these have
oughly studied are approaches to 1,3-oxazoles, pyrazoles, and 1,2,3-triazoles. Some of
even become common synthetic methodologies in the organic chemist’s toolbox. On the
these have even become common synthetic methodologies in the organic chemist’s
other hand, the synthesis of 1,3-thiazoles, imidazoles, 1,2,3-thiadiazoles, and 1,2,4-triazoles
toolbox. On the other hand, the synthesis of 1,3-thiazoles, imidazoles, 1,2,3-thiadiazoles,
is less developed. To date, information on the synthesis of isoxazoles from diazocarbonyl
and 1,2,4-triazoles is less developed. To date, information on the synthesis of isoxazoles
compounds has been limited to only a few reports. Most recently, great progress has been
from diazocarbonyl compounds has been limited to only a few reports. Most recently,
achieved in the synthesis of tetrazoles from various diazo compounds. However, it is obvious
great progress has been achieved in the synthesis of tetrazoles from various diazo com-
that the synthetic potential of diazo compounds in this area is far from its full disclosure.
pounds. However, it is obvious that the synthetic potential of diazo compounds in this
In addition, despite the extensive research, some mechanistic details are still not clear and
area is
need far from
further its full disclosure.
investigation. The mainInadvantage
addition, of
despite theapproaches
«diazo» extensive research, some
to azoles is theirmech-
high,
anistic details are still not clear and need further investigation. The main advantage
often absolute regioselectivity. The utility of these methods is emphasized by numerous of
«diazo» approaches to azoles is their high, often absolute regioselectivity. The utility of
these methods is emphasized by numerous examples of the use of diazo compounds at
key steps of the total synthesis of azole-containing natural products. Given the easy avail-
ability of diazo substrates, the described methodologies represent a valuable alternative
to more conventional methods.
Molecules 2021, 26, 2530 62 of 70
examples of the use of diazo compounds at key steps of the total synthesis of azole-containing
natural products. Given the easy availability of diazo substrates, the described methodologies
represent a valuable alternative to more conventional methods.
Author Contributions: Conceptualization, A.B., D.D. and M.K.; literature search, A.B. and D.D.;
figure drawing, A.B.; writing—original draft preparation, A.B.; writing—review and editing, D.D.,
G.K. and M.K. All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by the Russian Science Foundation (project grant 20-13-00024).
Conflicts of Interest: The authors declare no conflict of interest.
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Molecules: Diazocarbonyl and Related Compounds in The Synthesis of Azoles

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Molecules: Diazocarbonyl and Related Compounds in The Synthesis of Azoles

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molecules

Keywords: diazocarbonyl compounds; azoles; atom economy

Molecules 2021, 26, 2530. https://doi.org/10.3390/molecules26092530 https://www.mdpi.com/journal/molecules

Scheme 1. Gold-catalyzed oxazole synthesis from α-diazo

7 with preservation of azirine functionality. On the other hand, NiCl2-catalyzed reaction

Scheme 2. Utilization of 2-diazoacetyl-2H-azirines for the synthesis of heterocycle-substituted oxa-

Scheme 4. Synthesis of oxazolo[5,4-c]isoquinolin-5(4H)-ones from diazo homophthalimides and

Scheme 5. Synthesis of oxazolo[5,4-d]pyrimidine-5,7(4H,6H)-diones 18

Scheme 6. Synthesis of 6,7-dihydrobenzo[d]oxazol-4(5H)-ones 23 from alicyclic diazo diketones

Scheme 10. Rh(I)-catalyzed

In 2015, Trujillo and co-workers synthesized a series of novel 4-(benzylthio)oxazoles

In 2015, Trujillo and co-workers synthesized a series of novel 4-(benzylthio)oxazoles

Scheme 12. Synthesis

Scheme 17. Synthesis of 4H-imidazo[4,5-c]isoxazole from nitroimidazolyl diazo ketoester

In a 2018 work by the Wan group,group, diazo

SchemeScheme 19. Synthesis

Scheme 27. Synthesis of fully

2.3.3. Other Approaches to 1,3-Thiazoles Starting from Diazo Compounds

Molecules 2021, 26, x FOR PEER REVIEW 20 of 74

Scheme 31. 2-Imidazolone

Scheme 33. Derivatization of 2-imidazolones in solution- and solid-phase.

Scheme 35. Two-step

Scheme 41. Synthesis of imidazo[1,2-a]pyridines from α-diazoketones

Scheme 42. Scheme 42.ofSynthesis

Molecules 2021, 26, 2530 28 of 70

2.5. Pyrazole (1H,

Scheme 47. The

Scheme 49. Formation ofScheme

to two types of fully substituted pyrazoles 213 and 214.

Molecules 2021, 26, x FOR PEER REVIEW

Electrocyclization of vinyl diazo compounds 212 can trigger subsequent rearrange-

Scheme 53. Vinyl diazoScheme 53. Vinyl

Miscellaneous Methods for Pyrazole Ring Construction from

An unprecedented chemo- and regioselective gold-catalyzed cross-coupling

all positions of the phenyl N

Another example of gold-catalyzed reaction of vinyl diazo compounds for the s

Scheme 56. Synthesis

Synthesis of 1H-Pyrazoles from Diazo Compounds and Alkynes

Scheme 56. Synthesis of 4,5-dihydro-benzo[g]indazoles by gold-catalyzed [5+4]-annulation between 2-alkynyl-1-carbon-

Scheme 58. Synthesis of 7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidines 234 from 3-di-

Molecules 2021, 26, x FOR PEER REVIEW 37 of 74

SchemeScheme 60. Synthesis

A continuous-flow synthesis of fluoroalkyl-substituted diazomethanes 244 from the

Molecules 2021, 26, x FOR PEER REVIEW

A regio- and stereoselective synthesis of spiro-3H-pyrazole-penicillanates 257 was

Scheme 63. Regio-

In a study devoted to the exploration of fluorescence turn-on cycloadditions of diben-

Molecules 2021, 26, x FOR PEER REVIEW 40 of 74

Scheme 66. Synthesis ofScheme 66. Synthesis

Molecules 2021, 26, x FOR PEER REVIEW 41 of 74 and

R1 = Me, iPr, Cyclopropyl, (Het)Ar, OEt; R2 = H, Dioxol; Z = CO2Et, CN

Scheme 69. SynthesisScheme 69. Synthesis

A tunable approach for the synthesis of1H-1H- and3H-indazoles

The ‘hexadehydro Diels-Alder’ (HDDA) reaction was employed in the synthesis of

The ‘hexadehydro Diels-Alder’ (HDDA) reaction was employed in the synthesis of

A 1,3-dipolar cycloaddition reaction of naphthoquinones 306 and diazo compounds

Scheme 75. The

Scheme 76. Synthesis Scheme 76. Synthesis 315

Scheme 78. Ag(I)-promoted synthesis

Scheme 79. Pd-catalyzed tandemAzoxy compounds

Scheme 82. Mechanism of Wolff

In contrast to diazo aldehydes, the reaction of amines with α-diazoketones usually

Scheme 85. FeCl2-catalyzed Wolff cyclocondensation of amines and α-diazo-β-oxoamides.