molecules
Review
Friedel-Crafts-Type Acylation and Amidation Reactions in
Strong Brønsted Acid: Taming Superelectrophiles †
Akinari Sumita and Tomohiko Ohwada *
Citation: Sumita, A.; Ohwada, T.
Friedel-Crafts-Type Acylation and
Amidation Reactions in Strong
Brønsted Acid: Taming
Superelectrophiles. Molecules 2022,
27, 5984. https://doi.org/10.3390/
molecules27185984
Academic Editor: Prasad V. Bharatam
Received: 13 August 2022
Accepted: 8 September 2022
Published: 14 September 2022
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Attribution (CC BY) license (https://
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4.0/).
Molecules 2022, 27, 5984. https://doi.org/10.3390/molecules27185984
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
* Correspondence: ohwada@mol.f.u-tokyo.ac.jp
† This paper is dedicated to Koop Lammertsma in appreciation of his great contribution to phosphorus chemistry
and also his guidance of T.O.
Abstract: In this review, we discuss Friedel-Crafts-type aromatic amidation and acylation reactions,
not exhaustively, but mainly based on our research results. The electrophilic species involved
are isocyanate cation and acylium cation, respectively, and both have a common + C=O structure,
which can be generated from carboxylic acid functionalities in a strong Brønsted acid. Carbamates
substituted with methyl salicylate can be easily ionized to the isocyanate cation upon (di)protonation
of the salicylate. Carboxylic acids can be used directly as a source of acylium cations. However,
aminocarboxylic acids are inert in acidic media because two positively charged sites, ammonium
and acylium cation, will be generated, resulting in energetically unfavorable charge-charge repulsion.
Nevertheless, the aromatic acylation of aminocarboxylic acids can be achieved by using tailored
phosphoric acid esters as Lewis bases to abrogate the charge-charge repulsion. Both examples tame
the superelectrophilic character.
Keywords: superelectrophile; isocyanate cation; acylium cation; amidation; acylation; aminocarboxylic
acid; phosphoric acid esters; charge-charge repulsion
1. Introduction: Acylium Ions
The Friedel-Crafts reactions are reactions of cationic carbon electrophilic species with
an aromatic compound, enabling carbon substituents to be introduced onto the aromatic
ring. [1] Indeed, the aromatic acylation reaction [2] is one of the most useful reactions in
organic synthesis, particularly in medicinal chemistry, because many medicines contain
an aromatic system that participates in hydrophobic interactions. In aromatic acylation,
the cationic electrophilic species that reacts with the aromatic compound is an acylium ion.
This is usually generated from carboxylic acid derivatives such as carboxylic anhydride
and acid chloride under strongly acidic conditions, such as in the presence of aluminum
trichloride and sulfuric acid. The structures of some acylium ions have been determined by
means of NMR spectroscopy [3,4] and X-ray crystallography [5,6].
Effenberger et al. examined the reactivity of isolated and purified acylium ion salts
with alkylbenzenes to give 3 (Scheme 1) [7]. They showed that the acylium ion salt (2)
is in equilibrium with the trifluoromethanesulfonate form (1) in the reaction solvent (1,2-
dichloroethane) (Scheme 1). When the electron density of the carboxylic acid is high
(1, R = MeO, Scheme 1) the equilibrium is biased towards the acylium ion (2) and the
electrophilicity is lower. On the other hand, when the electron density of the carboxylic acid
is low (1, R = NO2 , Scheme 1), the contribution of the acylium ion (2) in the equilibrium is
small, but the electrophilicity is greater.
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Scheme 1. Aromatic acylation reaction using triflate salt (2) as a substrate.

Scheme 1. Aromatic acylation reaction using triflate salt (2) as a substrate.
Scheme
SchemeAnother
1. 1.
Aromaticrecent
Aromatic study [8]
acylation
acylation concluded
reaction
reaction that
usingtriflate
using acylium
triflate
saltsalt ion
(2) (2)
as salts
aassubstrate.are the active species in the
a substrate.
aromatic
Another acylation
recentreaction,
study [8] even though
concluded theacylium
that acylium ionion precursor
salts (a complex
are the active speciesofinacidthe
chloride Another
Another
aromatic and recent
Lewis
recentreaction,
acylation study
acid) is [8]
study [8]even concluded
observed
concluded as the
thoughthatthat
mainacylium
the acyliumcomponent
acylium ion ion salts
ion salts in are
the
precursor the active
solvent.
are the (a active species
complex species in
of acid in the
the aromatic acylation reaction, even though the acylium
ions is ion
chloride
aromatic Nevertheless,
and Lewis
acylation the
acid)electrophilicity
reaction,is observed
even asofthe
though acylium
main
the component
acylium ionprecursor
not high
in theand
precursor (a complex
thus
solvent.(athey
complexof acid
react effi-
of acid
chloride
ciently onlyand Lewis acid) is observed as the main component in the solvent.
chloride and with
Nevertheless,Lewis electron-rich
the
acid) benzenes,
electrophilicity
is observed as but
of acylium
the not
main with
ions non-activated
is not high
component inand
thearomatic
thus they
solvent. compounds
react effi-
such Nevertheless,
as benzene and the electrophilicity
halobenzenes. of acylium
Therefore, in ions
order is not
to high
improve andthethus they react effi-of
electrophilicity
ciently only with electron-rich
Nevertheless, benzenes,ofbut
the electrophilicity not with
acylium ions non-activated
is not higharomatic aromatic
and thus compounds
they react effi-
ciently only with electron-rich benzenes, but not with non-activated compounds
acylium
such
ciently as ions,
benzene research
and has been
halobenzenes. focused on
Therefore,superacids,
in order [9]
to which
improve havethe higher acidity
electrophilicity thanof
such only with electron-rich
as benzene and halobenzenes. benzenes, but not
Therefore, with to
in order non-activated aromatic compounds
improve the electrophilicity of
100% sulfuric
acylium ions, acid.
research has been focused on superacids, [9] which have higher acidity than
such as benzene
acylium and halobenzenes.
ions, research has been focused Therefore, in order
on superacids, to improve
[9] which the electrophilicity
have higher acidity than of
100% Itsulfuric
is well acid.
known that the reactivity of acylium ions increases with increasing acidity
acylium ions, research
100% sulfuric acid. has been focused on superacids, [9] which have higher acidity than
of theItreaction solution. thatOhwada and Shudo et al.ions
alsoincreases
reportedwith a relationship between
100% It isiswell
sulfuric known
wellacid.
known that the
the reactivity
reactivity of acylium
of acylium ions increases with increasing
increasing acidity
acidity
the
of acidity
the
of It reaction
theisreaction of the reaction
solution.
solution. medium
Ohwada andand the
Shudo efficiency
et al. also of the
reported aromatic
a acylation
relationship reaction
between
well known thatOhwada and Shudo
the reactivity et al. also
of acylium ions reported
increases a relationship
with increasingbetween acidity
(Scheme
the
theacidity
acidity2) [10].
ofofthe Inreaction
the the reaction
reaction mediumof an and
isolated
and acylium
efficiencyion
the efficiency
the ofthe
of salt (4)
thearomaticwith benzene,
aromatic acylation
acylation they found
reaction
reaction
ofthat
thethereaction solution. Ohwada and Shudo et al. also reported a relationship between
(Schemeyield
(Scheme of In
2)2)[10].
[10]. the
Inthe target
the aromatic
reaction
reaction of anketone
of isolated(5)
isolated was low
acylium
acylium ion
ion insaltTFA
salt (4)(acidity
(4) function
withbenzene,
with benzene, they
they = 2.7),
−Hfound
0 found
the
butacidity of the reaction medium and the efficiency of the aromatic acylation reaction
thatincreased
that the
theyield
yieldof as thetarget
ofthe
the acidity
target of the reaction
aromatic
aromatic ketone(5)
ketone medium
(5) waslow
was lowwas
ininTFAincreased
TFA (Scheme
(acidity
(acidity 2).
function
function −H−H 0 =0 = 2.7),
2.7),
(Scheme
but 2)
increased [10]. In
as
but increased as the acidity the
the reaction
acidity of of
the an isolated
reaction acylium
medium was ion salt
increased
reaction medium was increased (Scheme 2). (4) with
(Scheme benzene,
2). they found
that the yield of the target aromatic ketone (5) was low in TFA (acidity function −H0 = 2.7),
but increased as the acidity of the reaction medium was increased (Scheme 2).

Scheme 2. Acidity dependence of the aromatic acylation reaction of 4.

Scheme
Scheme2.2.Acidity
Aciditydependence
dependence of
of the aromatic acylation
the aromatic acylationreaction
reactionofof4.4.
The acylium dication has been proposed to play a role in the high efficiency of this
reaction
The(Scheme
The acylium3).
acylium That is,
dication
dication hasthe
has monocation
been proposed (4) isplay
toto converted
play a role in to
the ahigh
dication (6) orof
efficiency protosolv-
this re-
Scheme 2. Acidity dependence of been proposed
the aromatic acylation a role
reaction in
of the
4. high efficiency of this
ated form
action
reaction (7) by3).
(Scheme
(Scheme further
3).That
That protonation
is, thethe
is, or hydrogen
monocation (4) (4)
monocation bonding,
is converted to athereby
is converted dication
to increasing
(6) or(6)
a dication its electro-
protosolvated
or protosolv-
formform
ated (7) by
philicity. further
(7) by protonation
further or hydrogen
protonation or bonding,
hydrogen therebythereby
bonding, increasing its electrophilicity.
increasing its electro-
The acylium dication has been proposed to play a role in the high efficiency of this
philicity.
reaction (Scheme 3). That is, the monocation (4) is converted to a dication (6) or protosolv-
ated form (7) by further protonation or hydrogen bonding, thereby increasing its electro-
philicity.

Scheme
Scheme3.3. Reactive species
Reactive species (6 (6 orin7)the
or 7) inaromatic
the aromatic acylation
acylation reaction
reaction under veryunder very
strongly strongly
acidic acidic
conditions.
conditions.
Scheme 3. Reactive species (6 or 7) in the aromatic acylation reaction under very strongly acidic
Such multivalent cations with enhanced electrophilicity have been called superelec-
conditions.
trophiles, and various cations
Such multivalent kinds ofwith
superelectrophile species have been
enhanced electrophilicity havereported [11,12].
been called superelec-
Thus,
trophiles,
Such in
and the aromatic
various
multivalent kindsacylation
cationsof reaction, higher
superelectrophile
with enhanced acidity
species
electrophilicity of
have the
been
have reaction medium
reported
been [11,12].
called gen-
superelec-
Scheme 3. Reactive species (6 or 7) in the aromatic acylation reaction under very strongly acidic
erally accelerates
Thus,and
in the the reaction.
aromatic However,
acylation there are
reaction, higher still some
acidity cases
ofbeen in which
the reaction the desired
trophiles,
conditions. various kinds of superelectrophile species have reportedmedium
[11,12]. gen-
acylation
erallyThus, does
acceleratesnot proceed
the reaction.even when
However, the acidity
there is increased.
are still Two
someofcases examples
in which theare dis-
desired
in the aromatic acylation reaction, higher acidity the reaction medium gen-
cussed
acylation below.
does not proceed even when the acidity is increased. Two examples are dis-
erally accelerates the reaction. However, there are still some cases in which
Such multivalent cations with enhanced electrophilicity have been called superelec- the desired
cussed below.
acylation and
doesvarious
not proceed
trophiles, kinds even when the acidityspecies
of superelectrophile is increased. Two reported
have been examples[11,12].
are dis-
cussed below.
Thus, in the aromatic acylation reaction, higher acidity of the reaction medium gen-
erally accelerates the reaction. However, there are still some cases in which the desired
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Molecules 2022, 27, 5984 3 of 27

Klumpp
Klumpp et et al.
al. reported
reported the the reactivity
reactivity of of cinnamic
cinnamic acid acid (8)(8) in
in very
very strong
strong acids
acids
(Scheme
(Scheme 4) [13].
Klumpp They
4) [13]. et found
al. found
They that
reported
thattheif the aromatic
reactivity
if the aromatic moiety
of moiety
cinnamic of cinnamic
ofacid acid
(8) in acid
cinnamic (8)
very(8) has
strong an
has an electron
acids
electron
density
(Scheme higher
4) than
[13]. that
They of halobenzene,
found that if thethe aromatic
aromatic acylation
moiety of reaction
cinnamic
density higher than that of halobenzene, the aromatic acylation reaction does not proceed does
acid (8) not
has proceed
an
to electron
give the density
aromatic higher
ketonethan that
(10), of
buthalobenzene,
benzene the
reacts aromatic
at the acylation
to give the aromatic ketone (10), but benzene reacts at the β-position of the olefin and the
β-position reaction
of the does
olefin not
and the
proceedsaturated
resultant to give thecarboxylic
aromatic ketoneacid (10), but benzene
undergoes an reacts at the β-position
intramolecular aromatic ofacylation
the olefin reac-
resultant saturated carboxylic acid undergoes an intramolecular aromatic acylation reac-
tionandto the resultant saturated carboxylic acid undergoes an intramolecular aromatic acylation the
to give
givetothe
tionreaction the cyclized
cyclized product
product (9). (9). This
This is
is because
because the the acylium
acylium ion ion is
give the cyclized product (9). This is because the acylium ion is conjugated to
is conjugated
conjugated to to the
styrene
styrene moiety,
moiety, so that
so that the cationic
the the
cationic carbon
carbon is switched from the carbonyl carbon (C ) to
carbonisisswitched fromthethecarbonyl
carbonyl carbon (CC=O
) ) to
C=O
the styrene moiety, so that cationic switched from carbon (CC=O
the benzyl
thetobenzyl (β-)carbon
(β-)carbon
the benzyl (C), as
(C), as
(β-)carbon in 12 (Scheme
(C),inas12in(Scheme
12 (Scheme5) [14].
5) [14]. Therefore,
Therefore,
5) [14]. the desired
the the
Therefore, desired
desired aromatic
aromatic
aromaticketone
ketone
formation
formation does
ketone formation not
does notdoes proceed
proceed because
because
not proceed the aromatic
the aromatic
because the aromaticring reacts
ringring
reacts with
with
reacts the benzyl
thethe
with benzyl carbon
carbon atom
benzylcarbon atom
first.
first.
atom first.

Scheme 4.
4. Aromatic
Scheme
Scheme 4. Aromaticacylation
Aromatic acylation reaction
acylation reaction using
reaction using cinnamic
usingcinnamic
cinnamic acid
acid (8)(8)
acid as aas
(8) aa substrate.
assubstrate.
substrate.

Scheme
Scheme 5.
5. Cinnamic
Scheme 5. Cinnamicacid
Cinnamic acidcation.
acid cation.
cation.

Anotherexample
Another
Another example isis
example isaminocarboxylic
aminocarboxylic
aminocarboxylic acid.acid.
Olah Olah
acid. et al. examined
Olah et
et al. the structure
al. examined
examined theofstructure
the amino
structure of
of
aminoacidsacids
in very
in strong
very acids, acids,
strong and they
andfound
they that
found an that
amino an acid
amino(13)acid
with(13)
a sufficiently
with a long
sufficiently
amino acids in very strong acids, and they found that an amino acid (13) with a sufficiently
long carbon
carbon chain between the amino and carboxyl groups could could
form a dication (14), that is, that
long carbon chain
chain between
between the the amino
amino andand carboxyl
carboxyl groups
groups could form form aa dication
protonation of the amino nitrogen atom and ionization to the acylium ion both occurred
dication (14),
(14), that
is,
is, protonation
protonation of
of the
the amino
amino nitrogen
nitrogen atom
atom and
and ionization
ionization to
to the
the acylium
acylium ion
ion both
both occurred
occurred
(Scheme 6a) [15]. On the other hand, when an α-amino acid (15) such as valine was used,
(Scheme
(Scheme 6a) [15].
6a) was
a dication
On
On the
[15].formed, other
the but
other hand,
hand, when
protonationwhen an
tookan
α-amino
α-amino
place
acid
at the acid
amino
(15)
(15) such
suchand
group
as valine
as the
valine was
was used,
carboxyl used,
aa dication
dication
group, and was formed,
wasionization
formed, to but
but protonation
protonation
afford took
took
the acylium place
ionplace at the
at the
(17) did amino
not amino
occur due group
group and
and the carboxyl
the
to charge-chargecarboxyl
group, and
and ionization
repulsion
group, (Scheme 6b)to
ionization afford
afford the
to[16–20]. While
the acylium ion
ion (17)
protonation
acylium did
of the
(17) not
not occur
didamino nitrogen
occur due to
to charge-charge
dueatom and the
charge-charge
repulsion
carbonyl(Scheme
repulsion oxygen 6b)
(Scheme atom
6b) [16–20]. While
can occur,
[16–20]. protonation
ionization
While to form
protonation of
of the
the amino
the acyliumnitrogen
amino ion (17) atom
nitrogen and
and the
in superacid
atom the car-
car-
bonyldepends strongly on the energy requirement for C–O bond cleavage
bonyl oxygen atom can occur, ionization to form the acylium ion (17) in superacid de-
oxygen atom can occur, ionization to form the acylium ion during
(17) acylium
in ion
superacid de-
pendsformation, due to theenergy
repulsion between thefor positivebond
charges (Schemeduring 6b). Therefore, the
pends strongly
strongly on on the
the energy requirement
requirement for C–O C–O bond cleavage
cleavage during acylium acylium ionion for-
for-
aromatic acylation
mation, reaction of aminocarboxylic acids has been little studied so far.
mation, due due to to the
the repulsion
repulsion between
between thethe positive
positive charges
charges (Scheme
(Scheme 6b). 6b). Therefore,
Therefore, thethe
Aromatic ketones, the products of aromatic acylation reactions, are components of var-
aromatic
aromatic acylation
acylation reaction
reaction of of aminocarboxylic
aminocarboxylic acids acids has
has been
been little
little studied
studied so so far.
far.
ious bioactive substances and pharmaceuticals, and are also useful as synthetic intermedi-
ates [21]. Therefore, if we can overcome the problem of charge-charge repulsion and control
the reaction, we can expect to achieve concise syntheses of a variety of useful compounds.
ules 2022, 27, x FOR PEER REVIEW 4
Molecules 2022, 27, 5984 4 of 27

SchemeScheme 6. Acylium
6. Acylium ionion formationfrom
formation from amino
aminoacids. Distance
acids. dependency:
Distance (a) ionization
dependency: of the
(a) ionization of th
carboxylic acid 13 to acylium ion 14; (b) ionization of the carboxylic acid 15 to acylium
carboxylic acid 13 to acylium ion 14; (b) ionization of the carboxylic acid 15 to acylium ion 17 ion 17 is
prohibited. Only 16 is formed.
prohibited. Only 16 is formed.
Here, we review our efforts to solve these problems, focusing especially on activation
Aromatic
of the ketones,
carboxylic the products
acid functionality. of aromatic
We discuss aromaticacylation
amidation andreactions, are componen
acylation reactions.
The electrophilic
various bioactive substances species involved are isocyanate cation and acylium cation, respectively,
and pharmaceuticals, and are also useful as synthetic i
and both have a common + C=O structure, which can be generated from carboxylic acid
mediates [21]. Therefore,
functionalities in a strongifBrønsted
we canacid.overcome thesubstituted
Carbamates problemwith of charge-charge repulsion
methyl salicylate can
controlbethe reaction,
easily ionized towe thecan expectcation
isocyanate to achieve concise syntheses
upon (di)protonation of a variety
of the salicylate. of useful
Carboxylic
pounds.acids can be used directly as a source of acylium cations. However, aminocarboxylic acids
are inert in acidic media because two positively charged sites, ammonium and acylium
Here, we review our efforts to solve these problems, focusing especially on activ
cation, will be generated, resulting in energetically unfavorable charge-charge repulsion.
of theThe
carboxylic
activation ofacid functionality.
the leaving We methyl
group by using discuss aromatic
salicylate amidation
was not valid to theand acylation
aromatic
tions. acylation
The electrophilic species
of aminocarboxylic involved
acids. are isocyanate
Nevertheless, cation and
the aromatic acylation acylium cation, re
of aminocarboxylic
acids can be achieved by using tailored phosphoric
tively, and both have a common C=O structure, which can be generated
+ acid esters as Lewis bases to abrogate
from carbo
the charge-charge repulsion. Both examples tame the superelectrophilic character.
acid functionalities in a strong Brønsted acid. Carbamates substituted with methyl sa
late can be easily
2. Aromatic ionized to the isocyanate cation upon (di)protonation of the salicy
Amidation
2.1. Utility of
Carboxylic acids can beMethyl Salicylate as a Leaving
used directly asGroup in Generation
a source of Electrophiles
of acylium cations. However, amin
boxylic acids are inert in acidic media because two positivelytocharged
In the aromatic acylation reaction, carboxylic acids are converted acid chlorides
sites,or ammon
anhydrides, and then the acyl group is introduced into aromatic compounds via acylium
and acylium cation,
ion formation underwill
acidicbe generated,
conditions. resulting
However, in energetically
acid chlorides unfavorable
and acid anhydrides have ch
chargelimited
repulsion.
chemicalThe activation
stability. of the
In contrast, Olahleaving groupchemically
et al. employed by using methyl
stable methyl salicylate
esters wa
in the aromatic acylation reaction [22]. In their method, methyl esters
valid to the aromatic acylation of aminocarboxylic acids. Nevertheless, the aromatic are activated under
strongly acidic conditions to produce acylium ions. This is a practical approach from the
ation of aminocarboxylic acids can be achieved by using tailored phosphoric acid e
viewpoint of synthetic chemistry. However, because it requires heating in strong acid,
as Lewis
whichbases to abrogate
may result the charge-charge
in the decomposition repulsion.
of other functional groups,Both
thereexamples
is still a needtame
for the su
electrophilic character. of the methodology.
further improvement
Salicylic acid has long been known as a good leaving group [23]. Olah et al. focused
on the intramolecular hydrogen bond formation of salicylic acid and examined protonation
2. Aromatic Amidation
of the phenolic oxygen atom (as in 18, Scheme 7). They found that acetylsalicylic acid was
2.1. Utility of Methyl
diprotonated Salicylate
to give as a19
the dication at −40 ◦Group
Leaving in Generation
C (Scheme of Electrophiles
7) [24]. However on warming to
◦
0 C, the dication 19 was transformed to monocation 20 and acyl cation 21 (Scheme 7). This
In the aromatic
suggests acylation
that salicylic acid can reaction, carboxylichydrogen
form an intramolecular acids are converted
bond toaacid
and serve as goodchlorid
anhydrides, and then
leaving group to formthetheacyl group
acylium is This
ion 21. introduced into aromatic
aromatic acylation compounds
reaction has the potential via acy
to be a versatile synthetic method.
ion formation under acidic conditions. However, acid chlorides and acid anhydrides
limited chemical stability. In contrast, Olah et al. employed chemically stable methy
ters in the aromatic acylation reaction [22]. In their method, methyl esters are activ
under strongly acidic conditions to produce acylium ions. This is a practical appr
from the viewpoint of synthetic chemistry. However, because it requires heating in st
acid, which may result in the decomposition of other functional groups, there is s
need for further improvement of the methodology.
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Scheme 7. Ionization of acetylsalicylic acid in magic acid.

2.2. Aromatic
Scheme Amidation
7. Ionization Reaction Using
of acetylsalicylic acidMethyl Salicylate
in magic acid. as a Leaving Group
Scheme 7. Ionization of acetylsalicylic acid in magic acid.
Our group has reported a method for generating isocyanate cations by using methyl
2.2. Aromatic Amidation Reaction Using Methyl Salicylate as a Leaving Group
salicylate
2.2. Aromaticas aAmidation
leaving group (Scheme
Reaction Using 8) [25,26].
Methyl The carbamate
Salicylate functional
as a Leaving Group group consist-
ing ofOurOur group
isocyanate has reported
andreported a method
methyl asalicylate for generating
is chemically isocyanate cations by usingreactive,
methyl but
group has method for generatingstable [27] and
isocyanate poorly
cations
salicylate as a leaving group (Scheme 8) [25,26]. The carbamate functional group consisting
by using methyl
under strongly
salicylate acidic conditions,
as a leaving group the isocyanate
(Scheme 8) [25,26]. cation
The (23 or 27)
carbamate is quicklygroup
functional generated at
consist-
of isocyanate and methyl salicylate is chemically stable [27] and poorly reactive, but under
room oftemperature
ingstrongly
isocyanate by methyl
and the cleavage of methyl salicylate (Scheme 8) [28–30]. The formed
acidic conditions, thesalicylate
isocyanate iscation
chemically
(23 or stable [27] and
27) is quickly poorly at
generated reactive,
room but
isocyanate
under
temperaturecation reacts
stronglybyacidic intramolecularly
conditions,
the cleavage with
thesalicylate
of methyl isocyanate the aromatic
cation
(Scheme 8) (23 moiety
or 27)
[28–30]. to afford
Theisformed
quickly the aromatic
generated
isocyanate at
lactam
cation24 [31,32].
reacts Furthermore,
intramolecularly when
with 25
the and 26
aromatic react intermolecularly,
moiety to afford
room temperature by the cleavage of methyl salicylate (Scheme 8) [28–30]. The formed the the aromatic
aromatic lactamamide
(28)
24can becation
[31,32].
isocyanate generated
reactsthrough
Furthermore, when 25theandisocyanate
intramolecularly 26 react intermediate
withintermolecularly,
the aromatic moiety (27)aromatic
the via a similar
to affordamide process
(28)
the aromatic
(Scheme
can be
lactam 248).
generated through the isocyanate
[31,32]. Furthermore, when 25intermediate
and 26 react(27) via a similar process
intermolecularly, (Scheme 8).
the aromatic amide
(28) can be generated through the isocyanate intermediate (27) via a similar process
(Scheme 8).

Scheme 8. Formation
Scheme 8. Formation of isocyanate
of isocyanate cation
cationand
andapplication
applicationtotoaromatic
aromatic amide
amide synthesis.
synthesis. (a)
(a) Intra-
In-
molecular cyclization
tramolecular of isocyanate
cyclization cation
of isocyanate (23)(23)
cation to give lactam
to give lactam(24).
(24).(b)
(b)Intermolecular
Intermolecular aromatic
aromatic
amidation of of
amidation isocyanate
isocyanatecation
cation(27)
(27) to giveopen-chain
to give open-chain amide
amide (28).
(28).
Scheme 8. Formation of isocyanate cation and application to aromatic amide synthesis. (a) Intra-
molecular cyclization
However, of isocyanate
theefficiency
efficiency cation
of the
the (23) towas
reaction give lactam (24). (b) Intermolecular aromatic
However,
amidation of the
isocyanate cation of
(27) to reaction
give wasdrastically
open-chain drastically
amide
reduced
(28). reducedfor chemical species
for chemical species
with a cationic charge in the vicinity. This suggests that the reaction between carbamate and
with a cationic charge in the vicinity. This suggests that the reaction between carbamate
the aromatic compound does not proceed via the Aac 2 mechanism, in which the aromatic
and the aromatic
However, thecompound
efficiency doesthenot proceed viadrastically
the Aac2 mechanism, forin which the aro-
ring reacts with the carbamateoffunctionalreaction
group wasand generates areduced
tetrahedral chemical
intermediate, species
matic
withbutaring
ratherreacts
cationic with
via charge
the Aac 1the carbamate
inmechanism,
the vicinity.infunctional
This suggests
which group and
that
the electrophilicthegenerates
reaction
species a tetrahedral
between
(isocyanate inter-
carbamate
cation)
mediate,
andproduced but
the aromaticrather via
by thecompound the A ac
eliminationdoes1 mechanism,
not proceed
of methyl in which
via from
salicylate the
the Atheelectrophilic
ac2 carbamate
mechanism, species
in which
reacts (isocyanate
with the the aro-
cation) produced
aromatic ring. Inbythethe
caseelimination
of dicarbamate of methyl
(29), one salicylate
methyl from
salicylate
matic ring reacts with the carbamate functional group and generates a tetrahedral inter-the carbamate
was not cleaved,reacts
and with
the aromatic
the mono-amidering. In
(31)the
was case of
formed dicarbamate
in 32% yield, (29), one
probably methyl
because salicylate
the
mediate, but rather via the Aac1 mechanism, in which the electrophilic species (isocyanate cleavage was
of not cleaved,
salicylate
and from the intermediate
the produced
cation) mono-amide (31)
by the to
wasform
32eliminationthe acylium
formed ofinmethyl
32% cation
yield, was slow
33probably
salicylate from(Scheme
because 9).
theThis
the carbamate isreacts
cleavagelikelyofwith
sa-
due to
licylate charge-charge
from the repulsion32
intermediate between
to form the protonated
the acylium amide
cation and
33 the forming
was slow isocyanate
(Scheme 9). This
the aromatic ring. In the case of dicarbamate (29), one methyl salicylate was not cleaved,
is cationdue
likely 33 [26].
to charge-charge
and the mono-amide (31) was repulsion
formed inbetween32% yield, theprobably
protonated amidethe
because and the forming
cleavage of sa-
isocyanate cation 33 [26].
licylate from the intermediate 32 to form the acylium cation 33 was slow (Scheme 9). This
is likely due to charge-charge repulsion between the protonated amide and the forming
isocyanate cation 33 [26].
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x FOR
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66ofof of 26

Scheme 9. Inhibition of isocyanate cation (33) formation due to charge-charge repulsion.

Scheme
Scheme 9. 9.
Inhibition
Inhibitionofofisocyanate cation(33)
isocyanate cation (33)formation
formation duedue to charge-charge
to charge-charge repulsion.
repulsion.
Thus, we next synthesized carbamate (35) (Scheme 10), whose cleavage ability was
improvedThus,
Thus, bywe
we nextsynthesized
next synthesized
introducing carbamate
carbamate(35)
electron-withdrawing (35)(Scheme
o,(Scheme 10),10),
p-bis(methyl whosewhose cleavage ability
cleavage
salicylate). We was
ability
found thatwas
improved
improved
the reaction by introducing
by introducing
with an aromatic electron-withdrawing
electron-withdrawing o, p-bis(methyl
compound (36) in o,a p-bis(methyl salicylate).
strong acid gave We
salicylate). found
diamideWe that
37 found
in 66%that
the reaction with an aromatic compound (36) in a strong acid gave diamide 37 in 66%
yield
the (Scheme
reaction 10) an
with [26].aromatic
These experimental
compoundresults (36) insuggest
a strongthatacid
it is gave
possible to control
diamide the66%
37 in
yield (Scheme 10) [26]. These experimental results suggest that it is possible to control the
reactivity
yield of carbamates by regulating their cleavage capacity.
(Scheme 10) [26]. These experimental results suggest that it is possible to control the
reactivity of carbamates by regulating their cleavage capacity.
reactivity of carbamates by regulating their cleavage capacity.

Scheme
Scheme10.
10.Synthesis
Synthesisof
ofaromatic
aromatic diamides (37) using
diamides (37) usingelectron-withdrawing
electron-withdrawinggroups.
groups.

Scheme
2.3. 10. Synthesis
2.3.Aromatic
Aromatic of aromatic
Acylation
Acylation Reaction diamides
Reaction Using Methyl
Using (37) Salicylate
Methyl using electron-withdrawing
Salicylate asasaaLeaving Groupgroups.
LeavingGroup
IfIfthe
thegood
goodcleavage
cleavage ability
ability of
of methyl
methyl salicylate
salicylateisisapplicable
applicabletotoesters,
esters,the
theformation
formation
2.3.ofAromatic
acylium Acylation
ions can Reaction
be expectedUsing Methyl
(Scheme Salicylate
11). as a we
Therefore, Leaving Groupthe phenolic
acetylated
of acylium ions can be expected (Scheme 11). Therefore, we acetylated the phenolic hy-
hydroxyl groupcleavage
of methylability
salicylate. Indeed, salicylate
the ester 38isreacted rapidly towith
If the
droxyl groupgood of methyl salicylate.ofIndeed,
methyl the applicable
ester 38 reacted rapidly withthe
esters, the aromatic
the formation
aromatic
compound
ofcompound
acylium ions in a strong
can be acid to
expected afford the
(Scheme desired
11). aromatic
Therefore, ketone
we (39) in
acetylated83% yield
the at 0 ◦ C hy-
phenolic
in a strong acid to afford the desired aromatic ketone (39) in 83% yield at 0 °C
(Scheme 11) [33]. The rate of elimination of methyl salicylate from the ester 38 is greater
droxyl
(Scheme group of methyl
11) [33]. The rate salicylate. Indeed,
of elimination of the
methylester 38 reacted
salicylate from rapidly
the esterwith 38 the aromatic
is greater
than that from the corresponding carbamate (40). At 0 ◦ C, the carbamate (40) was stable
compound
than that in a strong
from the acid to
corresponding afford the
carbamate desired
(40). aromatic
At 0 °C, ketone
the (39)
carbamate in 83%
(40) yield
was at 0 °C
stable
for at least 90 min at 0 ◦ C and the starting carbamate was recovered in 89% yield, while at
(Scheme
for
20at◦ C, 11)90
least
the [33].
minThe at 0 rate
corresponding of elimination
°C and
amide the41starting
was formed of methyl
carbamate
in 85%was salicylate
yield from
recovered
after 60 in the
min 89% ester
(Schemeyield, 38while
11). is greater
This at
20result
than °C,
that the corresponding
from the amide
corresponding 41 was formed
carbamate in 85%
(40). Atyield
0 after
°C, the 60 min
carbamate
indicates that the chemoselectivity of this reaction can be kinetically controlled by (Scheme (40) 11).
was This
stable
result
for indicates
at least
adjusting 90themin that
at 0the
°Cchemoselectivity
temperature. and the startingofcarbamate
Mechanistically this reaction
charge-charge wascan be kinetically
recovered
repulsion ofinthe89% controlled
yield, while
intermediate by at
20adjusting
dications the
°C, the corresponding
B and temperature.
D was weakenedMechanistically
amide 41bywas formed
separationcharge-charge
inthe
of 85% repulsion
yield
cationic after
centers of the(Scheme
60(Scheme
min intermediate
11). 11). This
dications
result B andthat
indicates D was theweakened by separation
chemoselectivity of this ofreaction
the cationic
cancenters (Schemecontrolled
be kinetically 11). by
2.4. Difference in Cleavage Ability
adjusting the temperature. Mechanistically charge-charge repulsion of the intermediate
2.4. Difference in Cleavage
TheB difference Ability
in weakened
the reactivity
dications and D was by of carbamates
separation of and esters having
the cationic centers methyl
(Schemesalicylate
11).
as a leaving group (Scheme 11) can be explained on the basis of the DFT calculations
The difference in the reactivity of carbamates and esters having methyl salicylate as a
(Scheme 12). We believe the real active cationic species are dictations B and D in which the
2.4. Difference
leaving groupin(Scheme
Cleavage11) Ability
can be explained on the basis of the DFT calculations (Scheme
two cationic centers are separated and distal, but in these calculations, the equilibrating
12). We believe the real active cationic(Scheme
species are dictations B and D in which the two
Themonocations
difference Ainand were calculated
theCreactivity of carbamates11). and esters having methyl salicylate as a
cationic centers are separated and distal, but in these calculations, the equilibrating mon-
leaving
ocations group
A and(Scheme 11) can be(Scheme
C were calculated explained 11).on the basis of the DFT calculations (Scheme
12). We believe the real active cationic species are dictations B and D in which the two
cationic centers are separated and distal, but in these calculations, the equilibrating mon-
ocations A and C were calculated (Scheme 11).
Molecules 2022,
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Molecules 2022, 27, x FOR PEER REVIEW 7 of 26

Scheme
Scheme11. 11.Aromatic
Aromaticacylation
acylationand
andamidation
amidationreactions.
reactions.Possible electrophilic
Possible electrophilicspecies
speciescan
canbebegen-
Scheme 11. Aromatic acylation and amidation reactions. Possible electrophilic species can be gen-
erated by
generated the elimination of methyl salicylate from ester and carbamate compounds throughthe the
erated by bythethe elimination
elimination of of methyl
methyl salicylate
salicylate from
from ester
ester and
and carbamatecompounds
carbamate compoundsthrough
throughthe
intermediates
intermediates (A–D). Charge-charge repulsion was weakened by tuning hydrogen bonding in the
intermediates (A–D).
(A–D). Charge-charge repulsionwas
Charge-charge repulsion wasweakened
weakenedby bytuning
tuninghydrogen
hydrogenbonding
bondingininthe
the
dications
dications (B,D).
dications (B,D).
(B,D).

Scheme 12.
Scheme 12. Energy
Energy plots
plots of
of methyl
methyl salicylate
salicylate cleavage
cleavage from
fromester
ester(38)
(38)and
andcarbamate
carbamate(40).
(40).
Scheme 12. Energy plots of methyl salicylate cleavage from ester (38) and carbamate (40).
The formation of acylium ion (43) from the protonated ester (42) requires cleavage of
the The
C–Oformation
bond between the carbonyl
of acylium carbon
ion (43) fromand the phenolicester
the protonated hydroxyl group of cleavage
(42) requires methyl of
the C–O bond between the carbonyl carbon and the phenolic hydroxyl group of methyl
 Molecules 2022, 27, 5984 8 of 27

The formation of acylium ion (43) from the protonated ester (42) requires cleavage of
the C–O bond between the carbonyl carbon and the phenolic hydroxyl group of methyl
salicylate through the TS (44). In this case, the intramolecular hydrogen bond of methyl
salicylate reduces the activation energy required for C–O bond cleavage, resulting in
rapid acylium ion formation (∆G‡ 298K = 13.1 [kcal/mol], ∆H‡ = 13.7 [kcal/mol]). On
the other hand, the carbamate (45) forms Y-type conjugation [27] around the carbonyl
carbon atom, which increases the activation energy of C–O bond cleavage between the
carbonyl carbon and the phenolic hydroxyl group of methyl salicylate through the TS
(47) (∆G‡ 298K = 16.1 [kcal/mol], ∆H‡ = 17.1 [kcal/mol]). Therefore, isocyanate cation (46)
formation from the carbamate (40) is slower than acylium ion formation from the ester [33].
The DFT calculations also showed that in strong acids, carbamate is most stable in an
8-membered ring structure (40) with intramolecular hydrogen bonding between the methyl
ester group carbonyl oxygen atom of methyl salicylate and the carbamate. However, in the
case of the ester, the structure with intramolecular hydrogen bonding between the phenolic
oxygen atom and the methyl ester carbonyl oxygen atom of methyl salicylate (42) appears
to be more stable than the 8-membered ring structure (38). Therefore, in the case of the ester
group, the acylium ion is rapidly formed from the intramolecular hydrogen-bonded state,
but in the case of the carbamate group, the total activation energy is increased because it
takes extra energy to convert the 8-membered ring state to the structure 45.

2.5. Tandem Reactions

The cleavage capacity was found to affect the rate of generation of the electrophilic
species (isocyanate cation and acylium cation). The reaction of the electrophilic species
with aromatic compounds proceeds rapidly, suggesting that the electrophilic reaction can
be controlled by varying the rate of generation of the electrophilic species, i.e., by differ-
ences in cleavage capacity. This idea can be extended to the tandem reactions (Scheme 13)
of indole [34], indene [35,36], dihydroindene [37], indanone [38], fluorene [39–41], car-
bazole [42–44], diphenylmethane-triphenylmethane [45,46], naphthoquinone [47–51], and
Molecules 2022, 27, x FOR PEER REVIEW 9 of 26
so on. While the focus is on skeleton formation [52], the ability to link sub-skeletons in this
reaction is attractive.

Scheme
Scheme13.
13.Tandem
Tandem reaction
reaction using sequentiallygenerated
using sequentially generatedelectrophile
electrophile species
species inin a one-pot
a one-pot reaction.
reaction.

When theofester
2.6. Limitations (48) andReaction
the Present carbamate (49), containing o-methyl salicylate as a leaving
System
group react in a strong acid at 0 ◦ C, o-methyl salicylate is selectively removed from the ester
In the reaction using o-methyl salicylate as the leaving group, aromatic ketone (55) is
rapidly synthesized from the active ester (54), even at low temperature (Scheme 14).
Molecules 2022, 27, 5984 9 of 27

group and reacts with the aromatic ring present in the carbamate (49) in an intermolecular
reaction to give the aromatic ketone (50) (Scheme 13). Subsequently, another carbamate
(51) bearing an aromatic ring is added to the reaction solution, and when the temperature
is raised to room temperature (20 ◦ C), o-methyl salicylate is cleaved from the carbamate
(50) and reacts intermolecularly with the aromatic part B of the carbamate (51) to give
an aromatic amide (52) (Scheme 13). After a sufficient reaction time (15 hr), isocyanate
cation is also formed from the carbamate (52) incorporating p-methyl salicylate to give an
aromatic amide via intramolecular cyclization (53) (Scheme 13). These three electrophilic
reactions can be conducted sequentially in one pot by adjusting the leaving group, reaction
temperature Scheme 13. Tandem
and reaction timereaction
[33]. using sequentially generated electrophile species in a one-pot rea

2.6. Limitations
2.6. Limitations of the PresentofReaction
the Present Reaction System
System
In the
In the reaction reaction
using using
o-methyl o-methyl
salicylate as salicylate
the leaving asgroup,
the leaving group,
aromatic aromatic
ketone (55) is ketone (
rapidly synthesized from the active
rapidly synthesized fromester
the (54),
activeeven at (54),
ester low temperature
even at low (Scheme 14). (Scheme 14)
temperature

Scheme 14. Scheme

Aromatic14. Aromatic
acylation acylation
reaction usingreaction
methyl using methyl
salicylate salicylate
as a leaving as a leaving group.
group.

However, when methyl

However, salicylate
when methylis salicylate
used as a leaving group,
is used as the efficiency
a leaving of cleav-
group, the efficiency of c
age from anthranilic acid, which has an amino group in the ortho position, is
age from anthranilic acid, which has an amino group in the ortho position, not high is not
(Scheme 14). Even when the ester (56), a condensation product of anthranilic acid with
(Scheme 14). Even when the ester (56), a condensation product of anthranilic acid w
o-methyl salicylate, was reacted with benzene in TfOH, the desired aromatic ketone (57)
methyl salicylate, was reacted with benzene in TfOH, the desired aromatic keton
was not formed, and only the starting material was recovered (Scheme 14). The reason for
was not formed, and only the starting material was recovered (Scheme 14). The reaso
this is thought to be inhibition of acylium ion formation by the protonated amino nitrogen
this is thought to be inhibition of acylium ion formation by the protonated amino nit
atom, that is charge-charge repulsion [16].
atom, that is charge-charge repulsion [16].
3. Aromatic Acylation Reaction with Phosphoric Acid Esters and Strong Bronsted Acid
3. Aromatic Acylation Reaction with Phosphoric Acid Esters and Strong Bronsted
3.1. Phosphoric Acid Esters
Acid
Phosphoric acid esters have high oxygen affinity and are commonly utilized by en-
zymes such 3.1.
as Phosphoric
glutamine Acid Esters [52–55] and aminoacyl-tRNA synthetase [56–59] to
synthetase
Phosphoric
activate carboxylic acids in acid
livingesters have high
organisms. Acyloxygen affinity
phosphates and are
[60–66] cancommonly
react with autilized b
zymes such asare
variety of nucleophiles, glutamine synthetase
highly reactive with [52–55] andacids,
carboxylic aminoacyl-tRNA
and can mediatesynthetase
effi- [56–
cient functional group conversion reactions, as exemplified by synthetic reagents such as
polyphosphate [67], Eaton reagents [68,69], DPPA reagents [70], and BOP reagents [71].
Therefore, by utilizing phosphoric acid esters with high oxygen affinity, aromatic
acylation reactions with various carboxylic acids can be expected, even where the reactivity
is reduced due to charge-charge repulsion. However, phosphoric acid esters themselves
are chemically stable [72–74] and require electrophilic activation.
Salicylic acid or methyl salicylate has been used for electrophilic activation of phos-
phoric acid esters (Scheme 15), and Bender et al. attributed the high hydrolysis re-
action rate of salicylic acid-linked phosphoric acid monoesters (54) to the presence of
 is reduced due to charge-charge repulsion. However, phosphoric acid esters themselves
are chemically stable [72–74] and require electrophilic activation.
Salicylic acid or methyl salicylate has been used for electrophilic activation of phos-
phoric acid esters (Scheme 15), and Bender et al. attributed the high hydrolysis reaction
Molecules 2022, 27, 5984 rate of salicylic acid-linked phosphoric acid monoesters (54) to the presence10ofofthe 27 intra-
molecular hydrogen bond between the carboxyl and phenolic hydroxyl groups (Scheme
15a) [75]. Brown et al. also reported that the reaction of phosphoric acid diesters (57) with
the intramolecular
methyl salicylate-bound hydrogen bond between
methanol the carboxyl
under strongly and phenolic
acidic conditions hydroxyl groupsrapidly
proceeded
(Scheme 15a) [75]. Brown et al. also reported that the reaction of phosphoric
(Scheme 15b) [76]. They attributed the high reaction rate to the coordination of the yttrium acid diesters
(57) with methyl salicylate-bound methanol under strongly acidic conditions proceeded
cation to methyl salicylate and the non-bridged oxygen atom of the phosphoric acid ester
rapidly (Scheme 15b) [76]. They attributed the high reaction rate to the coordination of the
(58),yttrium
whichcation
enhanced thesalicylate
to methyl cleavageand capacity of methyl
the non-bridged salicylate
oxygen atom of(Scheme 15b). As de-
the phosphoric
scribed above,
acid ester salicylic
(58), acid andthe
which enhanced methyl salicylate
cleavage capacityare electrophilically
of methyl salicylate (Schemeactive15b).
chemical
As spe-
ciesdescribed
that enhance the cleavage capacity by forming noncovalent bonds
above, salicylic acid and methyl salicylate are electrophilically active chemicalto protons and cat-
species
ionic thatmaking
species, enhance the
the cleavage
phosphoric capacity
acidby forming
ester noncovalent
electrophilic. bonds
Kirby ettoal.protons and
also reported the
cationic species, making the phosphoric acid ester electrophilic. Kirby et
high reactivity of a phosphoric acid diester (61) with two salicylic acids attached, propos- al. also reported
the high reactivity of a phosphoric acid diester (61) with two salicylic acids attached,
ing intramolecular nucleophilic reaction of the carbonyl oxygen atom of salicylic acid,
proposing intramolecular nucleophilic reaction of the carbonyl oxygen atom of salicylic
which
acid,iswhich
not ais leaving group,
not a leaving group,to tophosphorus (Scheme15c)
phosphorus (Scheme 15c)
[77].[77].
The The intermediate
intermediate (62) (62)
formed
formed bybythe
theintramolecular nucleophilic
intramolecular nucleophilic reaction
reaction accelerates
accelerates the of
the cleavage cleavage of salicylic
salicylic acid.
acid. Thus, salicylic acid and methyl salicylate not only serve as good
Thus, salicylic acid and methyl salicylate not only serve as good leaving groups, but may leaving groups, but
mayalso enhance
also enhance the the
cleavage capacity
cleavage of other
capacity ofester linkers
other ester[78,79].
linkers [78,79].

Scheme 15. 15.

Scheme P–OP–Obond cleavage
bond using
cleavage usingsalicylic
salicylicacid
acid(or
(ormethyl
methylsalicylate).
salicylate). P–O
P–O bond cleavage driven
bond cleavage
by (a) intramolecular
driven hydrogen-bonding
by (a) intramolecular hydrogen-bonding(b) intramolecular
(b) intramolecularmetal
metal chelation
chelation (c)(c) intramolecular nu-
intramolecular
cleophilic attackattack
nucleophilic withwith
assistance of of
assistance hydrogen
hydrogenbond formation.
bond formation.

These results suggest that by using salicylic esters, which are chemically stable and
easy to synthesize, as phosphate linkers, various electrophilic activation pathways can be
generated in the phosphoric acid ester. This enables the reaction with the carboxylic acid to
proceed rapidly to afford the acylium ion, followed by aromatic acylation.
 (TfOH) in the presence of phosphoric acid triester (67), a triester of o-methyl salicylate, at
room temperature for 20 min gave the desired aromatic ketone (68) in a yield of 92%
(Scheme 16, Table 1, Entry 1) [80]. In a control experiment in the absence of 67, the desired
aromatic ketone (68) was not obtained after reaction for 20 min. When the reaction time
was extended to 24 h, the aromatic ketone (68) was produced even in the absence of 67,
Molecules 2022, 27, 5984 11 of 27
but in only 48% yield (Table 1, Entries 2 and 3). Thus, it was suggested that phosphoric
acid triester (67) promotes the reaction of benzoic acid (65) with benzene, and can be re-
garded as an organocatalyst. When a much weaker acid, trifluoroacetic acid (TFA) was
3.2. Aromatic Acylation of Aminocarboxylic Acids
used, the desired aromatic ketone (68) was not formed, but ester 70 was produced (Table
1, EntryThe4).reaction
Thus, theof benzoic
aromaticacid (65) withreaction
acylation benzene in trifluoromethanesulfonic
requires a strong acid. acid (TfOH)
in the presence of phosphoric acid triester (67), a triester of o-methyl salicylate, at room
Anthranilic acid (66), which bears an amino group at the ortho position, is also avail-
temperature for 20 min gave the desired aromatic ketone (68) in a yield of 92% (Scheme 16,
able as a substrate. While anthranilic acid (66) in TfOH produced the ketone 69 in less than
Table 1, Entry 1) [80]. In a control experiment in the absence of 67, the desired aromatic
7%ketone
yield (68)
evenwasafter
not 24 hr (Scheme
obtained 16, Table
after reaction 1, min.
for 20 Entries
When 6 and 7), the reaction
the reaction time wasproceeded
extended in
88%to yield in the
24 h, the presence
aromatic of 67
ketone (Table
(68) 1, Entry 5)
was produced [80].inWhen
even the acidity
the absence of 67, was lowered
but in only 48% (acid-
ityyield
function
(TableH01,= Entries
−11.8) by mixing
2 and 3). TfOH
Thus, it with
wasthe weaker that
suggested acid phosphoric
TFA, the yieldacid of aromatic
triester
ketone (69) decreased
(67) promotes to 10 of
the reaction % benzoic
and an acid
ester(65)
(71)with
wasbenzene,
formed and
in 38%
can yield through
be regarded as the
an re-
organocatalyst.
action of methyl When a much
salicylate withweaker acid, trifluoroacetic
anthranilic acid (Table acid (TFA)8).
1, Entry was used,the
When theacidity
desired was
aromatic
further ketone(trifluoroacetic
reduced (68) was not formed,
acid; Hbut
0 =ester wasaromatic
−2.7),70the produced (Table (69)
ketone 1, Entry
was4).
notThus,
formed
the aromatic acylation reaction
and 67 was recovered in 99% yield. requires a strong acid.

O H Conditions O H O H
HO
(see Table 1) + O
+ 67 COOMe
(1 mmol) (3 mmol) (1 mmol) 68 70
65 Acid (2 mL)
O NH2 Conditions O NH2 O NH2
HO (see Table 1) + O
+ 67 COOMe
(1 mmol) (3 mmol) (1 mmol) 69 71
66 Acid (2 mL)

O COOMe
O
P
O O
COOMe
MeOOC
Phosphate Ester 67

Scheme
Scheme 16.16. Aromaticacylation
Aromatic acylation reactions
reactions of 65and
of65 and6666with
withthethe
aidaid
of phosphoric acidacid
of phosphoric triester 67. 67.
triester

Table 1. Aromatic acylation with the aid of phosphoric acid triester 67.

Entry Carboxylic Acid Phosphate Ester Acid Temp. Time Yield of 68 or 69 Yield of 70 or 71
1 H (65) 67 TfOH 20 ◦C 20 min 92% (68) <1% (70)
2 H (65) – TfOH 20 ◦C 20 min <1% (68) <1% (70)
3 H (65) – TfOH 20 ◦C 24 h 48% (68) <1% (70)
4 H (65) 67 TFA 20 ◦C 48 h <1% (68) 81% (70)
5 NH2 (66) 67 TfOH 20 ◦C 20 min 88% (69) <1% (71)
6 NH2 (66) – TfOH 20 ◦C 24 h <7% (69) <1% (71)
7 NH2 (66) – TfOH 20 ◦C 20 min <1% (69) <1% (71)
8 NH2 (66) 67 TfOH + TFA a 20 ◦C 20 min 10% (69) 38% (71)
9 NH2 (66) 67 TFA 20 ◦C 20 min <1% (69) <1% (71)
a TfOH/TFA= 53/47 (w/w).
 5 NH2 (66) 67 TfOH 20 °C 20 m
6 NH2 (66) – TfOH 20 °C 24 h
7 NH2 (66) – TfOH 20 °C 20 m
Molecules 2022, 27, 5984 12 of 27
TfOH +
8 NH2 (66) 67 20 °C 20 m
TFA a
Anthranilic acid (66), which bears an amino group at the ortho position, is also
available9as a substrate.
NH2While(66)anthranilic67acid (66) in TfOH
TFAproduced20
the °C
ketone 69 20 m
in less than 7% yield even after 24 hr (Scheme 16, Table 1, Entries 6 and 7), the reaction
a TfOH/TFA= 53/47 (w/w).
proceeded in 88% yield in the presence of 67 (Table 1, Entry 5) [80]. When the acidity was
lowered (acidity function H0 = −11.8) by mixing TfOH with the weaker acid TFA, the
yield of aromatic ketone (69) decreased to 10 % and an ester (71) was formed in 38% yield
These reactions are noteworthy, because the acylium catio
through the reaction of methyl salicylate with anthranilic acid (Table 1, Entry 8). When the
anthranilic
acidity was furtheracid,
reducedas shown in
(trifluoroacetic Scheme
acid; H0 = −2.7),16. The aromatic
the aromatic amine
ketone (69) was
not formed and 67 was recovered in 99% yield.
nated
Thesein the acid
reactions media, because
are noteworthy, and the subsequent
the acylium ionization
cation is difficult of the ca
to form from
to the acylium
anthranilic acid, as showncation
in Scheme is 16.
blocked due
The aromatic to ischarge-charge
amine repulsion
basic enough to be pronated
in the acid media, and the subsequent ionization of the carboxylic acid functionality to the
the promoting
acylium cation is blockedeffect
due to of phosphoric
charge-charge acid
repulsion triester
(Scheme 67 plays
17) [16–20]. Thus, thea key
promoting effect of phosphoric acid triester 67 plays a key role.

Scheme 17. Charge–charge repulsion in the case of anthranilic acid.

Scheme 17. Charge–charge repulsion in the case of anthranilic acid.
3.3. Characterization of Phosphoric Acid Esters of Methyl Salicylate
The reactivities of various phosphoric acid esters were examined (Scheme 18) [80]. A
3.3. Characterization
combination of Phosphoric
of o-methyl salicylate (72) and methylAcid Esters of Methyl
4-hydroxybenzoate (73) changedSalicylate
the
promoting activity in the aromatic acylation reaction of benzoic acid (65) with benzene in
The reactivities of various phosphoric acid esters were exa
TfOH to give the ketone 68. As the amount of para-isomer (73) moieties increased in the
combination
phosphoric of ino-methyl
acid triesters the order 67 → salicylate
74 → 75 → 76, (72) and methyl
the chemical yield of the4-hydroxy
ketone
(68) decreased; that is, the promoting effect decreased (Scheme 18). The tri-p-isomers 68
promoting
showed no promotingactivity
effect onin
thethe aromatic
aromatic acylation. acylation reaction of benzoi
TfOH The yield of aromatic
to give the ketone
ketone (68) was
68.greatly
As the increased
amount when the
ofphosphoric
para-isomeracid (73
ester contained two (74) or three (67) methyl salicylate linkers rather than a single methyl
phosphoric
salicylate acid
(75). In other triesters
words, the orthoin the
ester order
group 67salicylate,
of methyl → 74 → 75is→
which 76, the ch
a potent
leaving group, functions to promote P–O bond formation with an external carboxylic acid,
(68) decreased; that is, the promoting effect decreased (Schem
65, leading to ester exchange (Scheme 19).
showed no promoting effect on the aromatic acylation.
 Molecules2022,
Molecules 27,x5984
2022,27, FOR PEER REVIEW of2726
13 of

Scheme 18. Promoting effect of various phosphoric acid triester compounds containing o-methyl
salicylate (72) or methyl 4-hydroxyl benzoate (73) moieties. Comparison of yields of product (68).

The yield of aromatic ketone (68) was greatly increased when the phosphoric acid
ester contained two (74) or three (67) methyl salicylate linkers rather than a single methyl
salicylate (75). In other words, the ortho ester group of methyl salicylate, which is a potent
leaving 18.
Scheme
Scheme group,
18. functions
Promoting
Promoting to of
effect
effect promote
of variousP–O
various bond formation
phosphoric
phosphoric with
acidtriester
acid triester an external
compounds
compounds carboxylic
containing
containing acid,
o-methyl
o-methyl
salicylate
65, leading
salicylate (72) or
(72)to methyl
orester 4-hydroxyl
exchange
methyl benzoate
(Scheme
4-hydroxyl (73)moieties.
19).(73)
benzoate moieties.Comparison
Comparisonofofyields
yieldsofofproduct
product(68).
(68).

The yield of aromatic ketone (68) was greatly increased when the phosphoric acid
ester contained two (74) or three (67) methyl salicylate linkers rather than a single methyl
salicylate (75). In other words, the ortho ester group of methyl salicylate, which is a potent
leaving group, functions to promote P–O bond formation with an external carboxylic acid,
65, leading to ester exchange (Scheme 19).

Scheme 19.
Scheme 19. Ester
Ester exchange
exchange of
of 67
67 as
as the
the key
key initial
initial step
step in
in the
the reaction.
reaction.

3.4. Structure of
3.4. Structure of Phosphoric
Phosphoric Acid
Acid Ester
Ester in
in Strong
Strong Acid
Acid
A strong acid is needed for the reaction
A strong acid is needed for the reaction to proceed to proceed (Table
(Table 1,1, Entries
Entries 11 and
and 4).
4). There-
There-
fore,
fore, we investigated the structure of the phosphoric acid ester (67) under strongly acidic
we investigated the structure of the phosphoric acid ester (67) under strongly acidic
conditions
conditions [80].
[80].
The 1 H NMR spectrum of 67 in trifluoromethanesulfonic acid showed a peak at low
Scheme The19.1HEster
NMR exchange
spectrumof 67ofas67
theinkey initial step in the reaction.acid showed a peak at low
trifluoromethanesulfonic
field
field (about 15 ppm), that was assigned to
(about 15 ppm), that was assigned to aa proton
proton forming
forming anan intramolecular
intramolecular hydrogen
hydrogen
bond
3.4.
bond between
Structure the
betweenofthe phenolic
Phosphoric oxygen
phenolicAcid
oxygen atom
Esteratom of
in Strongone methyl salicylate and
methyl
of oneAcid salicylate and the carbonyl oxygen
the carbonyl oxygen
atom of the ortho ester group [25]. On the other hand, the NMR signal of the proton
A strong acid is needed for the reaction to proceed (Table 1, Entries 1 and 4). There-
bound to the phosphate non-bridged oxygen atom is difficult to observe due to fast proton
fore, we investigated the structure of the phosphoric acid ester (67) under strongly acidic
exchange with the solvent (CF3 SO3 –H) [25].
conditions [80].31 P NMR spectrum, the peak of 67 was observed at about −19 ppm in CDCl
In the 3
The 1H NMR spectrum of 67 in trifluoromethanesulfonic acid showed a peak at low
and in TFA, whereas in TfOH the signal shifted significantly toward high field at about
field (about 15 ppm), that was assigned to a proton forming an intramolecular hydrogen
bond between the phenolic oxygen atom of one methyl salicylate and the carbonyl oxygen

Molecules 2022, 27, 5984
SchemeScheme
In the P NMR spectrum, the peak of 67 was observed at about −19 ppm in CDC
and in TFA, whereas in TfOH the signal shifted significantly toward high field at abo
−78 ppm. Olah et al. [81] reported that a significant change in 31P NMR peak values
usually not observed upon protonation of phosphoric acid esters at unbridged oxyge
atoms. In addition, the 31P NMR peak values of the positional isomers 74 (−19 ppm) an
14 of 27
75 (−19 ppm) in CDCl3 are similar to those in TfOH (74: −21 ppm, 75: −24 ppm). Thus, w
consider that the significant shift in the 31P NMR peak values of 67 in TfOH is attributab
−78 ppm. Olah et al.(Scheme
[81] reported 31
to a structural change 20). that a significant change in P NMR peak values is
usually not observed upon protonation of phosphoric acid esters at unbridged oxygen
Possible structures of the phosphoric acid triester (67) include tetrahedral (78), trig
atoms. In addition, the 31 P NMR peak values of the positional isomers 74 (−19 ppm) and
nal bipyramidal
75 (−19 ppm) in (79),
CDCland octahedral (80) forms (Scheme 20). The variety of structures
3 are similar to those in TfOH (74: −21 ppm, 75: −24 ppm). Thus, we
due to the different
consider possible shift
that the significant interactions of thepeak
in the 31 P NMR carbonyl oxygen
values of atom(s)
67 in TfOH of the ortho est
is attributable
to a structural change (Scheme
group with the phosphorus atom [82,83]. 20).
20. Possible structures
20. Possible of diprotonated
structures of diprotonatedphosphoric acid
phosphoric acid triester.
triester.
Possible structures of the phosphoric acid triester (67) include tetrahedral (78), trigonal
The 31P NMR chemical shifts were calculated for the diprotonated form, which is pr
bipyramidal (79), and octahedral (80) forms (Scheme 20). The variety of structures is due to
tonated at the non-bridged
the different oxygen
possible interactions ofatom and inoxygen
the carbonyl one methyl
atom(s)salicylate,
of the orthoof each
ester of the stru
group
tureswith
shown in Scheme 20. The
the phosphorus atom [82,83]. calculated 31P chemical shift of the trigonal bipyramid
31 P NMR chemical shifts were calculated for the diprotonated
structureThe(79) was closest to the experimental value (31P NMR = −78 form,ppm).
which Therefore,
is proto- the
nated at the non-bridged oxygen atom and in one methyl salicylate, of each
are two possible reaction pathways31leading to P–O bonding of carboxylic acid 65 (Schemof the structures
shown in Scheme 20. The calculated P chemical shift of the trigonal bipyramidal structure
21): path a involves dissociation of methyl salicylate first from dication 79, followed b
(79) was closest to the experimental value (31 P NMR = −78 ppm). Therefore, there are
addition of the carboxylic
two possible acid (65),
reaction pathways while
leading path
to P–O b involves
bonding addition
of carboxylic of(Scheme
acid 65 the carboxylic
21): ac
(65) to dication 79, followed by dissociation of methyl salicylate. Experimentally,
path a involves dissociation of methyl salicylate first from dication 79, followed by addition the pre
enceofand
the intermediacy
carboxylic acid of 77while
(65), werepath
confirmed
b involves(see the following
addition section),
of the carboxylic acidbut
(65)distinguis
to
dication 79, followed by dissociation of methyl salicylate. Experimentally,
ing the two pathways is not easy. The DFT calculations suggest that path b is marginal the presence
and intermediacy of 77 were confirmed (see the following section), but distinguishing the
more favorable than path a.
two pathways is not easy. The DFT calculations suggest that path b is marginally more
favorable than path a.
3.5. Experimental Evidence for the P–O Bond Formation of Carboxylic Acid
In order to detect the intermediate 77, kinetic analysis using 31 P NMR was carried
out during the reaction of phosphoric acid triester (67) and benzoic acid (65). Scheme 22
shows the 31 P NMR spectral changes of a mixture of 67 and 65 in TfOH, obtained at
2-min intervals. Note that 85% H3 PO4 is used as a standard. In the presence of benzoic
acid (65), a new peak appears at around −6 ppm along with a decrease in the peak of 67
(31 P NMR = −78 ppm). This new peak was assigned to acyl phosphate (77) formed by the
reaction of 67 and benzoic acid (65) (Scheme 22).
lecules 2022, 27, x FOR PEER REVIEW 15 of
Molecules 2022, 27, 5984 15 of 27

Scheme 21. Two possible pathways leading to P–O bond formation of carboxylic acid.

3.5. Experimental Evidence for the P–O Bond Formation of Carboxylic Acid
In order to detect the intermediate 77, kinetic analysis using 31P NMR was carried
out during the reaction of phosphoric acid triester (67) and benzoic acid (65). Scheme 22
shows the 31P NMR spectral changes of a mixture of 67 and 65 in TfOH, obtained at 2-min
intervals. Note that 85% H3PO4 is used as a standard. In the presence of benzoic acid (65),
a new peak appears at around −6 ppm along with a decrease in the peak of 67 (31P NMR =
−78 ppm). This new peak was assigned to acyl phosphate (77) formed by the reaction of
Scheme
67 21. benzoic
and
Scheme Two possible
21. Two pathways
acid (65)
possible leading
(Schemeleading
pathways to P–O
22). to P–O bondbond formation
formation of carboxylic
of carboxylic acid. acid.

Phosphoric acid triester

3.5. Experimental 67 + for
Evidence PhCOOH
the P–O (1 eq.)Formation
Bond in TfOH of Carboxylic Acid
85% H3PO4 aq.
In order to detect the intermediate 77, kinetic analysis using 31P NMR was carr
out during the reaction of phosphoric acid triester (67) and benzoic acid (65). Scheme
shows the 31P NMR spectral changes of a mixture of 67 and 65 in TfOH, obtained at 2-m
intervals. Note that 85% H3PO4 is used as a standard. In the presence of benzoic acid (6
a new peak appears at around −6 ppm along with a decrease in the peak of2067min(31P NM

−78 ppm). This new peak was assigned to acyl phosphate (77) formed by the reaction
e
67 and benzoic acid (65) (Scheme 22). 0 min tim
0 −5 −10 −15 −20 −25 −30 −35 −40 −45 −50 −55 −60 −65 −70 −75 ppm
O
MeOOCPhosphoric acid
COOMe triester
HO 67 + PhCOOH (1 Oeq.)
O in TfOH O
O P O MeOOC Ph-H
85% H3PO4 aq. C TfOH O P O 3.0 eq. Ph
o O o O
+ 0 °C, 20 min o O
o 20 °C, 20 min
MeOOC o
MeOOC
67 1.0 eq. 65 1.0 eq. 77 68: 63%
ESI-MS [M+Na+]: 493.0668, (calcd.; 493.0659)
calcd. 31P NMR : -6 ppm (H3PO4 = 0 ppm)
20 m
Scheme 22. Tracking
Scheme 22. the reaction
Tracking the reaction of
of phosphoric
phosphoric acid
acid triester
triester (67)
(67) with
with carboxylic
carboxylic acid
acid (65).
(65).

The structure
structureofof7777was
wasconfirmed
confirmed bybyhigh-resolution
high-resolution mass spectroscopy.
mass Further-e
Furthermore,
spectroscopy.
after structural
more, optimization
after structural by thebyDFT
optimization the method,
DFT method, the NMR
the NMRchemical 0 min
shift
chemical value
shift value
im
of tthe
of
0 −5 monoprotonated
−10the −15 −20 −25 acyl
monoprotonated phosphate
−30 acyl −40 77
−35 phosphate−45was calculated
77−50
was−55 to be
calculated
−60 −6be
to
−65 ppm. This supports
−6 ppm.
−70 −75 This the view
ppm supports the
O that the
view new
that thepeak
newatpeak
around −6 ppm
at around −6isppm
due to acyl to
is due phosphate (77) formed
acyl phosphate (77) by the reaction
formed by the
eOOC COOMe of benzoic acid (65) and phosphoric acid O
triester O
(67). O
O P O HO
reaction of benzoic acid (65) and phosphoric acid triester (67).
Ph-H
ordertotocheck
checkthetheMeOOC
involvement of path a (Scheme 20),also
we tried
also to
tried to iden-
In order
C dicationic TfOH involvement of O
path P
a (Scheme
O
20), we identify the
3.0 eq.As the31peak of Ph
o O o tify the
dicationic Ospecies 81 species
(Scheme (Scheme
81 21) 21) in aofsolution
in a solution of 67Asinthe
67 in TfOH. TfOH.
peak of 67 ( P NMR
+ (31 Pppm)
=67−78 =0 −°C,
NMRdecreased 20(Scheme
78 ppm)mindecreased onew peak
20), a(Scheme
O
20),emerged
a new peak emerged
at around atppm
−19 around −19 ppm
(Scheme 22).
20 °C, 20 min
MeOOC o (Scheme 22). This peak was identified as a new phosphate o cationic species [84] (81), which
is formed from 67 by the removal of MeOOC
one methyl salicylate 72. When the 31 P NMR chemi-
67 1.0 eq. cal65shift1.0 eq. was calculated for the DFT-optimized
value 77 phosphorus cation species (81),68: the63%
ESI-MS + 493.0668, (calcd.; 493.0659)
predicted value was − 19 ppm,[M+Na
in good ]: agreement with the experimental value. Further-
31P NMR : -6 ppm (H PO = 0 ppm)
more, treatment of thecalcd. reaction solution with an excess 3 amount
4 of methanol under basic
conditions at −78 ◦ C yielded equal amounts of methyl salicylate (72) and phosphoric acid
Scheme 22. Tracking the reaction of phosphoric acid triester (67) with carboxylic acid (65).

The structure of 77 was confirmed by high-resolution mass spectroscopy. Furth

more, after structural optimization by the DFT method, the NMR chemical shift value
 This peak was identified as a new phosphate cationic species [84] (81), which is formed
from 67 by the removal of one methyl salicylate 72. When the 31P NMR chemical shift
value was calculated for the DFT-optimized phosphorus cation species (81), the predicted
value was −19 ppm, in good agreement with the experimental value. Furthermore, treat-
Molecules 2022, 27, 5984 16 of 27
ment of the reaction solution with an excess amount of methanol under basic conditions
at −78 °C yielded equal amounts of methyl salicylate (72) and phosphoric acid methyl ester
(82) in 46% yield (Scheme 23). Compound 82 is formed by the addition of methanol to the
methyl ester (82) in 46% yield (Scheme 23). Compound 82 is formed by the addition of
cation 81. These experimental results indicate that the phosphoric acid triester (67) releases
methanol to the cation 81. These experimental results indicate that the phosphoric acid
one methyl
triester (67)salicylate in TfOH
releases one methyl through 79 and
salicylate is converted
in TfOH through to 79the
andcationic species
is converted to (81),
the in
which the phosphorus atom is stabilized by the carbonyl oxygen atom
cationic species (81), in which the phosphorus atom is stabilized by the carbonyl oxygenof the ortho ester
group
atom of
of the
the neighboring methyl
ortho ester group salicylate
of the (Scheme
neighboring methyl23). The results
salicylate suggest
(Scheme 23). that the phos-
The results
phorus
suggestcation 81phosphorus
that the is rather stable,
cationbut
81 isreacts
ratherwith anbut
stable, excess
reactsofwith
methanol to of
an excess give the phos-
methanol
phoric
to giveacid triester (82).acid
the phosphoric This latter(82).
triester process
This is similar
latter to path
process a (Scheme
is similar to path 21), in which
a (Scheme 21),the
in which
cation the cation
81 reacts thereacts
with 81 with the
carboxylic acidcarboxylic
(65). Thisacid (65). This
indicates thatindicates
path a isthat path a is
experimentally
experimentally plausible.
plausible.

Phosphoric acid triester 67 in TfOH

85% H3PO4 aq.

22 min

e
tim
0 min

0 −5 −10 −15 −20 −25 −30 −35 −40 −45 −50 −55 −60 −65 −70 −75 ppm

O H
MeOOC COOMe O
O P O
TfOH
o O o MeO O P O
o 20 °C, 20 min O O OMe
MeOOC
67 81
(1.0 equiv.) 31P NMR: -19 ppm (85% H3PO4aq. = 0 ppm)
31P (calcd: 31P NMR: -19 ppm (H3PO4 = 0 ppm))
NMR: -78 ppm (solution:TfOH)
(85% H3PO4aq. = 0 ppm)
Na2CO3, MeOH
O -78 °C, 1 h
MeOOC
O P OMe COOMe
O HO
+
MeOOC
82 (46% yield) 72 (1.02 equiv.)

Scheme
Scheme23.
23.Monitoring
Monitoringthe
the formation of81
formation of 81from
from6767ininTfOH.
TfOH.

3.6.Reactivity
3.6. ReactivityofofAcyl
AcylPhosphate
Phosphate
Tounderstand
To understand thethe high
high reactivity
reactivityofofacyl
acylphosphate
phosphateitself, wewe
itself, synthesized
synthesizedacyl phos-
acyl phos-
phates (83 and 85) using phenol without any substituent on the aromatic ring as a phosphate
phates (83 and 85) using phenol without any substituent on the aromatic ring as a phos-
linker [85] and examined the reaction with benzene in a strong acid (Scheme 24). [80] The
phate linker [85] and examined the reaction with benzene in a strong acid (Scheme 24).
desired aromatic ketone (68) was obtained in 82% yield (Scheme 24). This experimental
[80] The desired aromatic ketone (68) was obtained in 82% yield (Scheme 24). This exper-
result is similar to that obtained with the phosphoric acid triester (67), suggesting that
imental result is similar
acyl phosphates to that(83)
themselves obtained withreactivity
have high the phosphoric acidquickly
and react triesterwith
(67),aromatic
suggesting
that acyl phosphates
compounds themselves
under strongly (83)
acidic have hightoreactivity
conditions and react
form aromatic quickly
ketones. withsimilar
Under aromatic
compounds under strongly acidic conditions to form aromatic ketones. Under
reaction conditions, the acyl phosphate (85) containing an anthranilic acid moiety reacted similar
with benzene in TfOH, but the chemical yield of the ketone (69) was only moderate (40%
yield). This is in sharp contrast to the results for the putative intermediate 77 (63% yield,
Scheme 22) and the phosphoric acid triester 67 (92% yield, Scheme 18).
 Molecules 2022, 27, x FOR PEER REVIEW 17 of 26

reaction conditions, the acyl phosphate (85) containing an anthranilic acid moiety reacted
Molecules 2022, 27, 5984 with benzene in TfOH, but the chemical yield of the ketone (69) was only moderate (40% 17 of 27
yield). This is in sharp contrast to the results for the putative intermediate 77 (63% yield,
Scheme 22) and the phosphoric acid triester 67 (92% yield, Scheme 18).

Scheme 24. Reactivity of acyl phosphates in strong acids.

Scheme 24. Reactivity of acyl phosphates in strong acids.
3.7. Computed
3.7. Computed Reaction
ReactionProfile of Acyl
Profile Phosphate
of Acyl Containing
Phosphate an Anthranilic
Containing Acid Moiety
an Anthranilic Acid Moiety
The reason for the high reactivity of acyl phosphates is probably their high cleavage
The reason for the high reactivity of acyl phosphates is probably their high cleavage
capacity, in spite of charge-charge repulsion in the resultant cation in the case of acyl phos-
capacity, in spite of charge-charge repulsion in the resultant cation in the case of acyl
phates of anthranilic acid (Scheme 17).
phosphates of anthranilic acid (Scheme 17).
The reaction profiles of carboxylic acid (66), ester (86) using methyl salicylate as the
leaving Thegroup
reaction profiles
[86], and of carboxylic
acyl phosphate acid
(87) to form (66),
the ester (86) acylium
respective using methyl
ion weresalicylate
ex- as
the leaving group [86], and acyl phosphate (87) to form the respective
amined by means of DFT calculations (Scheme 25). In the case of anthranilic acid, dipro- acylium ion were
examined
tonation can byoccur
means of DFT
at both calculations
amino (Scheme
nitrogen and carbonyl25).oxygen.
In the case of anthranilic
However, dehydrationacid, dipro-
tonation
Molecules 2022, 27, x FOR
does canREVIEW
notPEER
occur occur at both
to generate theamino
acyliumnitrogen
cation due and carbonyl oxygen.
to charge-charge However,
repulsion (Schemedehydration
17). 18 of 26
does One not occur
of thetopossible
generatestarting
the acylium cation
structures is due to charge-charge
intramolecularly repulsion (Scheme
hydrogen-bonded 66 17).
(Scheme 25). Another candidate is an ester of methyl salicylate (86), in which an intramo-
lecular hydrogen bond can be formed within methyl salicylate. InTS-C this case, a counter an-
MeO
ion was placed in the vicinity of the proton in order to avoid charge-charge repulsion in
the product acylium cation. We compared the reaction profiles of O66 and 86 with that of
H
O
the acyl phosphate 87. The activation energy was low in Hthe N Hcase
O of acyl phosphate 87,
P
TS-B
probably due to stabilization byClthe Hhydrogen-bonding network,Oin
C O
particular in TS-C
O
H H
structure (Scheme 25) [80]. N O H O OMe
C
The high reactivity of acyl phosphates, and
O
thus the high cleavage capacity of phos-
phate diesters, canTS-A be explained in termsH of O
resonance
OMe
effects within the phosphate
diesters.
H H
H H O
N
C O

H H H
O
H
33.4 N
O
(33.6) C
26.7
TS-A (25.7) 88
25.0 88
Cl
∆H (kcal/mol) (24.6)
25.0 H H
N
H
O
∆G298K (kcal/mol) TS-B (23.7) C H
O
15.8 89 89 O OMe
(17.7) 16.3
TS-C (15.5)

0 0 0 90 OMe

(0) (0) (0) MeO H

O
H
66 86 87 N H O
O O
C P
Cl H O O
H H H H O
H H H H N HO O
N O N O P
O O 90 H
O OMe
O O O
O OMe
H O OMe H
66 86 87
Scheme 25. Comparison of the reactivity of carboxylic acid (66), ester (86), and acyl phosphate
Scheme 25. Comparison of the reactivity of carboxylic acid (66), ester (86), and acyl phosphate (87).
(87).

3.8. Substrate Generality

The generality of substrate carboxylic acids was next examined (Scheme 26) [80]. In
this reaction, the desired aromatic ketone can be rapidly synthesized from various carbox-
ylic acids. In particular, carboxylic acids bearing a basic amine group can serve as sub-
Molecules 2022, 27, 5984 18 of 27

One of the possible starting structures is intramolecularly hydrogen-bonded 66 (Scheme 25).

Another candidate is an ester of methyl salicylate (86), in which an intramolecular hydrogen
bond can be formed within methyl salicylate. In this case, a counter anion was placed in
the vicinity of the proton in order to avoid charge-charge repulsion in the product acylium
cation. We compared the reaction profiles of 66 and 86 with that of the acyl phosphate 87.
The activation energy was low in the case of acyl phosphate 87, probably due to stabilization
by the hydrogen-bonding network, in particular in TS-C structure (Scheme 25) [80].
The high reactivity of acyl phosphates, and thus the high cleavage capacity of phos-
phate diesters, can be explained in terms of resonance effects within the phosphate diesters.

3.8. Substrate Generality

The generality of substrate carboxylic acids was next examined (Scheme 26) [80].
In this reaction, the desired aromatic ketone can be rapidly synthesized from various
Molecules 2022, 27, x FOR PEER REVIEW
carboxylic acids. In particular, carboxylic acids bearing a basic amine group can serve 19 of 26
as substrates (Scheme 26). The reaction proceeds efficiently for amino acids having an
unprotected aromatic or aliphatic amino groups (91–100 and 102). Other carboxylic acids
such as conjugated construction methods
carboxylic for the
acids (101, 2,3-benzodiazepine
103–104) skeleton havefunctionalized
and other electrophilic been reported recently,
new methods remain of interest.
benzenic acid derivatives (106–109) also reacted well (Scheme 26).

Scheme
Scheme 26. Substrate 26. Substrate
generality generality
of ketone of ketone
formation withformation with yield).
67 (isolation 67 (isolation yield).
Molecules 2022, 27, 5984 19 of 27

3.9. Application to 2,3-Benzodiazepine Skeleton Construction

A concise synthesis of the 2,3-benzodiazepine skeleton can be achieved by using the
aromatic acylation reaction with phosphoric acid triester (67).
The 2,3-benzodiazepine skeleton (Scheme 27) is an important scaffold in medicinal
chemistry, especially for drugs related to the central nervous system (CNS), because of its
pharmacological activity towards AMPA receptors [87]. There have been reports of side
effects such as drug-dependence [88], but this is a more serious problem with the struc-
turally isomeric 1,4-benzodiazepine derivatives [89]. Therefore, although some efficient
construction methods for the 2,3-benzodiazepine skeleton have been reported recently, new
Scheme 26. Substrate
methods generality
remain of interest. of ketone formation with 67 (isolation yield).

Scheme 27. Typical

Scheme 2,3-benzodiazepine
27. Typical derivatives
2,3-benzodiazepine derivatives for medicinal
for medicinal use. use.

Recently reported methods for the construction of the 2,3-benzodiazepine skeleton are
Recently reported methods for the construction of the 2,3-benzodiazepine skelet
illustrated in Scheme 28. Chan et al. constructed the skeleton by employing the Wacker
are illustrated
reaction to in Scheme
produce 28. Chan
a diketone et al. constructed
followed by cyclization the
withskeleton
hydrazineby employing
(Scheme the Wack
28a) [90].
Zhu et al. applied the C–H activation reaction of an aromatic hydrazone compound with
rhodium (III) to form the 2,3-benzodiazepine skeleton (Scheme 28b) [91]. Okuma et al.
used a benzyne precursor and 1,3-diketone to form a diketone, which was cyclized with
hydrazine (Scheme 28c) [92].
Further, the acylation reaction directly produces diketones or their derivatives, ben-
zopyrylium salts, from aromatic rings with a ketone group at the β-position, and this is ex-
pected to provide a concise synthetic route from commercial reagents (Scheme 28d) [93,94].
However, synthetic methods using the aromatic acylation reaction generally produce ben-
zopyrylium salts quickly, and the synthesis of the 2,3-benzodiazepine skeleton is largely
dependent on the reaction of the benzopyrylium salt with hydrazine. In particular, the reac-
tion of benzopyrylium salts with hydrazine having an aliphatic alkyl chain attached to the
C1 carbon precedes the nucleophilic reaction at the C1 carbon to give the benzoisoquinolium
salt (Scheme 29) [95]. The conversion of benzoisoquinolium salts to 2,3-benzodiazepine
skeletons involves ring-opening reactions of the heterocyclic quinolium skeleton [96], which
is generally inefficient.
 reaction to produce a diketone followed by cyclization with hydrazine (Scheme 28a) [90].
Zhu et al. applied the C–H activation reaction of an aromatic hydrazone compound with
rhodium (III) to form the 2,3-benzodiazepine skeleton (Scheme 28b) [91]. Okuma et al.
Molecules 2022, 27, 5984 used a benzyne precursor and 1,3-diketone to form a diketone, which was cyclized
20 of 27 with
hydrazine (Scheme 28c) [92].

Scheme 28. Typical syntheses of the 2,3-benzodiazepine skeleton. (a) Waker oxidation method,
Wang et al., 2017 [90]; (b) C–H activation method, Okuma et al., 2015 [91]; (c) Benzyne method,
Nikolyukin et al., 1990 [92]; (d) Pyrylium ion method, Bogza et al., 1995 [93].

Further, the acylation reaction directly produces diketones or their derivatives, ben-
zopyrylium salts, from aromatic rings with a ketone group at the β-position, and this is
expected to provide a concise synthetic route from commercial reagents (Scheme 28d)
[93,94]. However, synthetic methods using the aromatic acylation reaction generally pro-
duce benzopyrylium salts quickly, and the synthesis of the 2,3-benzodiazepine skeleton
is largely dependent on the reaction of the benzopyrylium salt with hydrazine. In partic-
ular, the reaction of benzopyrylium salts with hydrazine having an aliphatic alkyl chain
attached to the C1 carbon precedes the nucleophilic reaction at the C1 carbon to give the
Scheme
Scheme28.28.Typical
Typicalsyntheses
benzoisoquinolium salt (Scheme
syntheses of the
of the 2,3-benzodiazepine
29) [95]. The conversion
2,3-benzodiazepine skeleton.
skeleton. (a) Waker
of benzoisoquinolium
(a) Waker oxidation
oxidation salts tomethod,
method,
2,3-benzodiazepine
Wang
Wanget al., 2017
et al., 2017[90];[90];skeletons
(b)
(b) C–H involves method,
activation
C–H activation ring-opening
method, reactions
Okuma
Okuma et 2015
et al., of 2015
al., the heterocyclic
[91]; [91];
(c) quino-method,
(c) Benzyne
Benzyne method,
lium skeleton
Nikolyukin
Nikolyukin et et [96],
al.,al.,1990 which
1990[92]; is
[92]; (d) generally
Pyryliumion
(d) Pyrylium inefficient.
ion method,
method, Bogza
Bogza et al.,et1995
al., [93].
1995 [93].

Further, the acylation reaction directly produces diketones or their derivatives, ben-
zopyrylium salts, from aromatic rings with a ketone group at the β-position, and this is
expected to provide a concise synthetic route from commercial reagents (Scheme 28d)
[93,94]. However, synthetic methods using the aromatic acylation reaction generally pro-
duce benzopyrylium salts quickly, and the synthesis of the 2,3-benzodiazepine skeleton
Scheme
Scheme 29.
29. Synthesis
Synthesis of
of 2,3-benzodiazepine
2,3-benzodiazepine skeleton via aromatic
skeleton via aromatic acylation
acylation reaction.
reaction.
is largely dependent on the reaction of the benzopyrylium salt with hydrazine. In partic-
ular, theThereaction ofacylation
aromatic benzopyrylium salts with
reaction proceeds hydrazine
quickly having an aliphatic
at room temperature alkyl chain
in the presence
attached to the C1
of phosphoric carbon
acid triesterprecedes
(67), so inthe
thisnucleophilic reaction
case, the acylation at the C1
is expected carbon
to be to give the
complete
before the benzopyrylium salt is formed (see Scheme 29) [97].
benzoisoquinolium salt (Scheme 29) [95]. The conversion of benzoisoquinolium salts to
When we triedskeletons
2,3-benzodiazepine to synthesize diketone
involves (112) from anreactions
ring-opening aromatic compound (110) and quino-
of the heterocyclic
4-aminobenzoic acid (111) using 67 in TfOH, we found that the diketone (112) gradually
lium skeleton [96], which is generally inefficient.
decomposed during purification (Scheme 30, method (1)). The reason for this is thought to
be that the diketone (112) and pyrylium ion (113) are in equilibrium, and both compounds
are unstable [98]. Therefore, we examined the synthesis of nerizopam (114) by reacting
the crude product of the aromatic acylation reaction with hydrazine in ethanol solution
after aqueous work-up, and obtained the desired compound (114) in moderate yield (48%)
(Scheme 30, method (2)). Then, since the diketone (112) and pyrylium ion (113) seemed
to gradually decompose during work-up, we developed a method in which hydrazine is
added to the aromatic acylation reaction vessel together with base (Scheme 30, method (3)).
Scheme 29. Synthesis of 2,3-benzodiazepine skeleton via aromatic acylation reaction.
 reacting the crude product of the aromatic acylation reaction with hydrazine in ethan
solution after aqueous work-up, and obtained the desired compound (114) in modera
yield (48%) (Scheme 30, method (2)). Then, since the diketone (112) and pyrylium ion (11
seemed to gradually decompose during work-up, we developed a method in which h
Molecules 2022, 27, 5984 drazine is added to the aromatic acylation reaction vessel together with base
21 of(Scheme
27

method (3)).

Scheme 30. Optimization

Scheme 30. Optimizationof
of the synthesis
the synthesis of nerizopam
of nerizopam (114)
(114) by byaromatic
rapid rapid acylation
aromaticreaction
acylation
in react
in the presence of phosphoric acid triester (67).
the presence of phosphoric acid triester (67).

Method 3 (Scheme 30) gave nerizopam 114 in 73% yield. Next, the scope and lim-
Method
itations of3this
(Scheme
method30)
for gave nerizopam
synthesizing 114 in 73% yield.
2,3-benzodiazepine Next,
derivatives theexamined
were scope and limi
tions (Scheme
of this31).method for synthesizing 2,3-benzodiazepine derivatives were examin
(Scheme 31).
Molecules 2022, 27,
Molecules x FOR
2022, PEER REVIEW
27, 5984 22 of 22
27 of 26

Scheme 31.31.
Scheme Generality
GeneralityofofSynthesis
Synthesis of 2,3-Benzodiazepines
of 2,3-Benzodiazepines (115)
(115) using
using 67. 67.

4. Summary
The isocyanate cation and the acylium cation can be generated by the elimination of
methyl salicylate from the corresponding carbamate and ester compounds (Scheme 11).
Charge-charge repulsion was weakened in the dication intermediates (B and D) by tuning
hydrogen bonding (Scheme 11). If the reaction sites are multiple, charge-charge repulsion
Molecules 2022, 27, 5984 23 of 27

4. Summary
The isocyanate cation and the acylium cation can be generated by the elimination of
methyl salicylate from the corresponding carbamate and ester compounds (Scheme 11).
Charge-charge repulsion was weakened in the dication intermediates (B and D) by tuning
hydrogen bonding (Scheme 11). If the reaction sites are multiple, charge-charge repulsion
determined the reaction order, which enabled the tandem reactions (Scheme 13). On the
other hand, the acylium cation is difficult to generate from anthranilic acid in a strong acid,
as shown in Scheme 14, because the aromatic amine nitrogen atom is sufficiently basic to be
protonated in acidic media. Thus, subsequent ionization of the carboxylic acid functionality
to the acylium cation is blocked due to charge-charge repulsion, even though the leaving
group ability was increased by using o-methyl salicylates (Schemes 14 and 17) [16–20].
However, phosphoric acid triester 67 works as a Lewis base to neutralize the cationic
character, enabling these reactions to be conducted efficiently. Both examples of aromatic
amidation and acylation, discussed here indicated taming superelectrophilicity is crucial to
activate electrophilicity and to reduce destabilization due to charge-charge repulsion at the
same time.

Author Contributions: Conceptualization, A.S. and T.O.; methodology, A.S. and T.O.; writing—
original draft preparation, A.S.; writing—review and editing, T.O. All authors have read and agreed
to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The computation was performed using Research Center for Computational
Science, Okazaki, Japan.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds (115) are available from the authors.

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