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Alkynogenic fragmentation
a,b
Jingyue Yang, Tung T. Hoangc and Gregory B. Dudley *d
Fragmentation reactions in synthetic organic chemistry involve substrates breaking into three or more
pieces (fragments), adding degrees of unsaturation into two or more parts. Most examples of fragmenta-
tion reactions generate alkenes from saturated substrates. Those fragmentation reactions that generate

Received 19th February 2019,
Accepted 8th May 2019
DOI: 10.1039/c9qo00266a
rsc.li/frontiers-organic
alkynes are typically discussed as an extension of alkene-generating fragmentation reactions, perhaps due
to some clear mechanistic parallels. However, alkyne-generating (alkynogenic) fragmentation reactions
require distinct strategic and tactical considerations, and observations from the broader class of fragmen-
tation examples do not immediately translate. Whereas establishing proper orbital alignment through sub-
strate conformational control is a primary consideration for promoting alkene-generating fragmentations,
orbital alignment is generally pre-ordained by unsaturation in the alkynogenic fragmentation substrate,
and overcoming the enthalpic barriers associated with breaking strong bonds to sp2-hybridized carbon
atoms is key. Elevated temperature and judicious selection of nucleofuge (terminal leaving group) is often
required, but the pay-off can be high-value alkynes for chemical synthesis that are not readily available
directly from acetylene. This review covers historic and more recent contributions to a specific class of
reactions referred to as alkynogenic fragmentations.

a
Hebei Key Laboratory of Applied Chemistry, School of Environmental and Chemical
Engineering, Yanshan University, Qinhuangdao 066004, China
b
State Key Laboratory of Metastable Materials Science and Technology,
Yanshan University, Qinhuangdao 066004, China
c
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306-4390, USA
d
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown,
WV, 26506, USA. E-mail: gregory.dudley@mail.wvu.edu
1. Introduction
The alkyne is a metastable functional group in organic chem-
istry. Alkynes are kinetically stable to a wide range of con-
ditions that affect polar functional groups, like alcohols,
amines, carbonyls, organometallic species, etc. However,
addition reactions of alkynes tend to be exothermic as a conse-
quence of leveraging π-bonds for the production of σ-bonds. In
this regard, alkynes possess high thermodynamic potential
energy. The combination of thermodynamic potential and

Jingyue Yang received her Ph.D. Tung T. Hoang was born in Ha

degree with Prof. G. Dudley from Long, a small yet beautiful city
the Florida State University in known for the Ha Long Bay with
2011. She continued her career thousands of islets and its sun-
as a post-doctoral research shine beach in northeast
fellow with Prof. S. Martin at Vietnam. He earned a B.A.
UT-Austin and as a senior degree in chemistry at Vietnam
research associate with National University in 2006, and
Prof. X. Sun at UTSW Medical PhD degree in organic chemistry
Center, Dallas, TX. At the end of from Florida State University in
2017, she started her indepen- 2015, where he worked in the
dent career as a professor at labs of Prof Dudley on fragmen-
Jingyue Yang Yanshan University, Hebei, Tung T. Hoang tation chemistry. He was a reci-
China. Her current research pient of the Vietnam Education
activities focus on the design, synthesis and study of bioactive Foundation Fellowship in 2009.
molecules as well as organic methodology development.

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kinetic stability is attractive for many applications in synthesis

and catalysis.1 Alkynes tend to be inert to many common reac-
tion conditions, but react exothermically in the presence of an
appropriate catalyst. Harvesting the potential energy stored in
the triple bonds can drive innovation in organic synthesis and
methodology.2
The attractive reactivity features of alkynes are balanced
against the limited methods for their preparation.3
Traditionally, there are two main approaches: the first one is
de novo synthesis of the triple bond via elimination reactions,
and the other is serial substitution of acetylene (C2H2).
De novo alkyne synthesis can be energy-intensive. It typically
requires a strong driving force and/or high temperature to
overcome enthalpic barriers and introduce the characteristic
thermodynamic potential energy of the alkyne π-system.
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Acetylene itself arises industrially as a waste by-product of

ethylene production,4 so deriving higher alkynes and other
fine chemicals from acetylene should be viewed favorably from
a resource management standpoint. However, serial substi-
tution of acetylene is not universally applicable for the syn-
thesis of higher alkynes. Some fine chemical alkynes are pro-
duced by isomerization of other alkynes. The alkyne zipper
reaction (Scheme 1, eqn (a)),5 in which internal alkynes iso-
merize into terminal alkynes under strongly basic conditions,
is one way to prepare higher value alkynes from more readily
available alkyne sources. TMS-diazomethane6 (Scheme 1,
eqn (b)), the Seyferth–Gilbert7 (Scheme 1, eqn (c)) and Ohira–
Bestmann8 reagents (Scheme 1, eqn (d)), and the Corey–Fuchs
protocol9 (Scheme 1, eqn (e)) are known to homologate alde-
hydes using one-carbon synthons into terminal alkynes. The
introduction of alkyne metathesis10 (Scheme 1, eqn (f ))
opened a new strategy for the preparation of value-added
alkynes from other alkynes. We regard those alkynes that are
(a) useful in fine chemical synthesis and (b) not readily avail-
able from acetylene or other simple starting materials as
“high-value alkynes”. De novo generation of high-value alkynes
by fragmentation reactions is the focus of ongoing research
efforts in our group and the focus of this review.
Gregory B. Dudley is the Eberly
Family Distinguished Professor
of Chemistry and Chair of the
C. Eugene Bennett Department
of Chemistry at West Virginia
University in Morgantown, WV.
The current mission of his
research program is to impact
the drug discovery and develop-
ment process by contributing
fundamental knowledge in
organic chemistry, including new
Gregory B. Dudley strategies, tactics, and research
tools for best practices in organic
synthesis.
Scheme 1 Select methods for alkyne synthesis other than simple elim-
ination or serial substitution of acetulene.
Fragmentation reactions may be mechanistically related to
elimination reactions, but they are better conceptualized stra-
tegically among C–C bond cleavage reactions for design and
development of efficient chemical synthesis. Synthetic che-
mists justifiably tend to focus on C–C bond forming reactions,
but judicious use of C–C bond cleavage reactions11,12 on
readily available starting materials can provide significant stra-
tegic advantages13 in chemical synthesis. Alkynogenic (alkyne-
generating) fragmentation reactions have received increasing
attention in recent years, in part driven by the increasing inter-
est in catalytic reactions of alkynes. Here we emphasize the
use of fragmentation reaction for preparation of alkynes,
including brief discussion on historical development, mechan-
istic analysis and useful tactical operations.
We use Grob’s definition14,15 of fragmentation reactions as
a reference in our discussion. Grob defined fragmentation
reactions in organic synthesis as heterolytic bond-cleavage
reactions in which a molecule breaks into three or more frag-
ments (Scheme 2, eqn (a)). The three major components are:
an electrofuge (a, b), a middle part (c, d), and a nucleofuge (X).
The nucleofuge is essentially the same as a leaving group in
substitution and elimination reactions, but in this context the
leaving group designation is insufficient because the fragmen-
tation reaction involves at least two leaving groups: the middle
part is leaving from the electrofuge and the nucleofuge is
leaving from the middle part.16 A key feature of these fragmen-

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Scheme 2 Grob’s definition of fragmentation reactions and the alkyno-
genic fragmentations in this review.
tation reactions is that they add degrees of unsaturation to two
or more of the fragments. In the alkynogenic fragmentation of
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this review, formation of the alkyne functional group
(Scheme 2, eqn (b)) is the specific focus.
Alkynogenic fragmentations warrant a focused discussion
apart from other fragmentation reactions because – despite
obvious mechanistic parallels – the energetic considerations
with respect to entropy and enthalpy of activation are often
orthogonal. Fragmentation reactions in a broader context have
been the subject of several recent reviews,16,17 but the reviews
focus almost entirely on fragmentation reactions that produce
alkenes. One of the central challenges in these more common
alkene-generating fragmentation processes is entropy of acti-
vation: how best to achieve the proper anti-periplanar orbital
alignment to allow fragmentation across a saturated middle
part. Alkynogenic fragmentations, in contrast, benefit from an
unsaturated middle part in which the optimal orbital align-
ment is pre-ordained. On the other hand, the enthalpic costs
are significantly greater. Observations and insights from the
larger body of alkene-producing fragmentation methodologies
do not necessarily translate to alkynogenic fragmentations.
2. Fragmentation of vinyl diazoniums
from epoxy-hydrazones:
Eschenmoser–Tanabe methodology
The first alkynogenic fragmentation reaction to make a broad
impact on strategic approaches in chemical synthesis was the
Eschenmoser–Tanabe fragmentation of cyclic epoxy hydrazones.
Since the independent publications of this methodology by two
groups in 1967,18,19 the Eschenmoser–Tanabe fragmentation reac-
tion has been serving as a powerful method that often emerges as
a top choice when synthetic chemists want to make alkynes.
Starting from readily available cyclic enones, the reaction
sequence progresses via a series of epoxidation, hydrazone for-
mation and rearrangement of epoxy sulfonylhydrazones to vinyl-
diazenes, which ultimately undergo fragmentation (Scheme 3).
The fragmentation event in the Eschenmoser–Tanabe
process represents an extended variant of the classic Grob-type
fragmentation, in that there are two middle parts: the alkyne
and molecular nitrogen (N2). Keys to this process include: (1)
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Scheme 3 Generic plan and mechanism of Eschenmoser–Tanabe
fragmentation.
relief of epoxide ring strain to drive rearrangement of the epox-
yhydrazone to the vinyldiazene, and (2) the release of mole-
cular nitrogen (along with a sulfinate) to drive the C–C bond
cleavage events central to fragmentations.
The sequence of epoxidation and hydrazine formation can
be reversed, depending on which way is more convenient for
different substrates. The epoxyhydrazines are usually formed
and used either in one pot or without purifications. A recent
study has shown that they are stable enough to be purified and
utilized for other synthetic applications.20 Upon rearrange-
ment, fragmentation of vinyldiazenes 4 was driven by the
release of molecular nitrogen, cleaving the original cycle and
leading to either linear alkynones via ring opening fragmenta-
tions (Scheme 3) or cyclic alkynones via ring expansions21
(Scheme 4). The ring expansion pathway allows for access to
medium-ring cyclic alkynones, which are difficult to prepare
because of the linear geometry of alkynes.
Following original reports by Eschenmoser and Tanabe, the
scope of the reaction has been significantly broadened. Fehr
and Ohloff (co-author with Eschenmoser on the seminal publi-
cation) pointed out that in the cases in which the epoxy
ketones could not be formed, the unsaturated hydrazones were
treated with N-bromosuccinimide to give the desired alky-
nones directly.22 Other derivatives of epoxy ketones are useful
in this fragmentation reaction, including oximes,23 aminoaziri-
dines,24 2,4-dinitrobenzenesulfonyl hydrazones,25 1,3,4-ozadia-
zolines and diazirines.26 Selected applications of the
Eschenmoser–Tanabe fragmentation in synthesis are chosen
and presented here to demonstrate important features of this
reaction. Some of the variants address the general difficulties
associated with producing alkyne-tethered aldehydes by this
process, as opposed to the more typical formation of alkyne-
tethered ketones. Aldehydes are generally more labile than
ketones, and especially enolizable aldehydes may be prone to
oligomerization under the acidic or basic reaction conditions
used to promote rearrangement and fragmentation. Variants
such as using dinitrobenzenesulfonyl hydrazones enable frag-
mentation to occur under milder conditions, increasing the
Scheme 4 Eschenmoser–Tanabe fragmentation producing cyclic
alkynones.
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probability that aldehyde decomposition pathways can be
effectively suppressed. Nonetheless, formation of alkyne-teth-
ered aldehydes remains a challenging proposition using the
Eschenmoser–Tanabe strategy.
One of the classic applications of the Eschenmoser–Tanabe
fragmentation and related tactics is in the controlled degra-
dation of steroids27 and steroid-like ring systems.28 For
example, Batzold and Robinson exploited the Eschenmoser–
Tanabe fragmentation to cleave the fusion bond between the A
and B rings en-route to seco-steroids including constrained
medium-ring cycloalkynes29 (Scheme 5).
Trost used the Eschenmoser–Tanabe reaction to prepare
substrates for 1,6-enyne metathesis chemistry.30 This example
highlighted the utility of the Eschenmoser–Tanabe reaction for
the preparation of a non-enolizable alkynyl aldehyde, which
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was immediately forwarded to a Wittig olefination in the next
steps to form 1,6-enynes (Scheme 6). These 1,6-enynes are ver-
satile intermediates for a number of transformations such as
Pauson–Khand reactions, enyne cyclizations, enyne meta-
thesis, etc. to various cyclic and polycyclic structures.
Another application of the Eschenmoser–Tanabe fragmen-
tation was featured in the total synthesis of Galbulimina alka-
loid GB 13 by Mander.31 In this example, the epoxidation of
cyclic unsaturated ketone substrate 14 did not proceed. This
substrate required a detour to reduction of the ketone to its
corresponding alcohol, epoxidation and then oxidation back to
the epoxy ketone (Scheme 7).
Fukuyama used the Eschenmoser–Tanabe fragmentation in
the early stage of the total synthesis of (−)mersicarpine32
(Scheme 8). Semicarbazone 17 was oxidized by lead tetraace-
tate to form a 1,3,4-oxadiazoline intermediate (not shown),
which fragmented to give the desired alkynyl aldehyde 18. It
Scheme 5 Robinson’s controlled degradation of steroids.
Scheme 6 Trost’s synthesis of 1,6-enynes by Eschenmoser–Tanabe
fragmentation.
Scheme 7 Eschenmoser–Tanabe fragmentation in the total synthesis of galbulimima alkaloid GB 13.
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Scheme 8 Eschenmoser–Tanabe fragmentation in total synthesis of
(−)-mersicarpine.
was noted that the tosyl or nosylhydrazide version of 17 did
not fragment under the original conditions and harsher
conditions led to extensive decomposition of the substrates.
Chen and coworkers harnessed a particularly efficient
Eschenmoser–Tanabe fragmentation sequence in the context
of the total synthesis of echinopines A and B.33 A tricyclic
hydrocarbon framework 19, prepared in part by intramolecular
Diels–Alder cycloaddition, was first oxidized to the requisite
enones, then subjected to the standard sequence of base
mediated epoxidation followed by acidic hydrazone formation
and ultimately acid-promoted fragmentation to produce the
desired bicyclic ketoalkyne (Scheme 9). Although oxidation to
the requisite cyclic enone proceeded with moderate efficiency,
the fragmentation sequence itself proved very effective at
opening this unusual ring system.
More recently Ding and cowokers employed the
Eschenmoser–Tanabe fragmentation at the beginning of the
total synthesis of pharicin A, pharicinin B, 7-O-acetylpseurata
C and pseurata C34 (Scheme 10). Ketone 22 was converted to
its enone form via IBX oxidation, then to epoxide 23 by H2O2,
which underwent Eschenmoser fragmentation to provide the
acetylene aldehyde 24. Aldehyde 24 provided divergent entry
into the four target compounds.
One common attractive feature of these alkynogenic frag-
mentation reactions is that stereochemistry that had been
established in cyclic systems is reliably maintained through
the ring-opening event. The ability to leverage cyclic stereo-
control in the preparation of tethered alkynyl ketones is
quite powerful. If one can access the appropriate cyclic
enone, then Eschenmoser–Tanabe alkynogenic fragmenta-
tion provides the opportunity to access value-added alkynyl
ketones.
Scheme 9 Eschenmoser–Tanabe fragmentation in syntheses of echi-
nopines A and B.
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Scheme 10 Eschenmoser–Tanabe fragmentation in total synthesis of
pharicin A, pharicin B, 7-O-acetyipseurata C and pseurata C.
3. Fragmentation of vinyl diazoniums
from hydroxyalkyl diazo compounds:
Brewer methodology
Brewer and coworkers also take advantage of formation of
molecular nitrogen as a driving force for the fragmentation of
a family of cyclic γ-silyloxy-β-hydroxy-α-diazocarbonyls.35 The
treatment of substrate 25 with Lewis acids promoted the elim-
ination of a hydroxide group at the β position to the carbonyl,
generating vinyl diazonium 26 (Scheme 11). This diazonium
intermediate is reminiscent of the sulfonylated vinyl diazene
in the mechanism of the Eschenmoser–Tanabe described
above (Scheme 3). Other similarities between the
Eschenmoser–Tanabe reaction and the Brewer reaction are
their starting material substrates are all cyclic compounds,
they are capable of preparing medium-ring alkynes via ring
expansion fragmentation,36 and they both can produce alkynyl
aldehydes37 (27, R5 = H). An important distinction here is the
strategic use of a cyclic α-alkoxy (or silyloxy) ketones as the
initiating structural features, as opposed to the cyclic enones
of the Eschenmoser–Tanabe process.
Important stereoelectronic effects in this fragmentation
reaction were investigated38 (Scheme 12, 28 → 31). The reactive
conformations for an effective fragmentation are those in
which the plane of the diazo and ester groups aligns perpen-
Scheme 11 Generic plan and mechanism of the Brewer fragmentation.
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Scheme 12 Stereoelectronic effects in Brewer fragmentation.
Scheme 13 Parallel reactions in mechanistic studies of Brewer
fragmentation.
dicular to the hydroxyl leaving group. These conformations
(29, 30) have a parallel alignment of the p-orbital at the α
carbon position with the anti-bonding of the breaking σ C–O
bond, hence maximizing the interactions between them.
Two pairs of isomeric substrates give distinct outcomes
when subjected to the fragmentation conditions (Scheme 13).
Generally, the isomer (32) that has the bulky OTBS group on
the same side (cis) with the carbon that bears both the diazo
group and ester group would give low yield relative to the trans
isomer (34).
Brewer and coworkers applied this methodology in the syn-
thesis of demissidine39 and (±)-cycloclavine.40 In Brewer’s syn-
thesis of demissidine, Brewer used his fragmentation reaction
strategically to break down the steroid D ring of epi-androster-
one (36) into requisite functional groups (37) for the construc-
tion of demissidine. Demissidine was successfully made from
epi-androsterone in 12% overall yield via a longest linear
sequence of 12 steps (Scheme 14a). Brewer has also incorpor-
ated a similar strategy in an approach to cycloclavine, as out-
lined in Scheme 14b. The fragmentation reaction gave alde-
hyde tethered ynoate 39, which is set for intramolecular azo-
methine ylide 1,3-dipolar cycloaddition to give 2,5-dihydropyr-
role 40 in a polycyclic framework.41 The 2,5-dihydropyrrole
product (40) generated by this methodology has a key double
bond in place for the installation of a cyclopropane ring of the
natural product.
4. Fragmentation of vinyl triflates
from vinylogous acyl triflates: Dudley
methodology
We have found that upon nucleophilic attack, vinylogous acyl
triflates can undergo fragmentation reactions in a parallel
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nucleophiles (cf. 46 to 41, Scheme 15). The methodology was

then extended to other classes of nucleophiles44 to synthesize
a variety of functional group-rich intermediates. Both carbon
and nitrogen based nucleophiles work well, forming alkynes
tethered to ketones or amides respectively. Stabilized carba-
nion nucleophiles can also be added to the carbonyl of the
vinylogous acyl triflates to form alkyne-tethered 1,3-dicarbo-
nyls, most importantly to form alkyne-tethered Horner–
Wadsworth–Emmons phosphonates.45 Fragmentation of dihy-
dropyrone triflates and dihydropyridone triflates, respectively,
yield homopropargyl alcohols46 and homopropargyl amines47
stereospecifically. While strong hydride sources such as super-
hydride could be used to trigger fragmentation, milder
hydride reagents such as DIBAL reduce the carbonyl in vinylo-
gous acyl triflates into their alcohol analogs 47 both con-
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veniently and effectively. These vinylogous hemiacetal triflates

undergo fragmentation reactions upon the deprotonation of
the alcohol. Due to the strong basic conditions used in this
Scheme 14 (a) Brewer fragmentation in synthesis of demissidine. (b)
fragmentation methodology, aldehyde tethered alkynes can
Brewer fragmentation in synthesis of cycloclavine.
only be formed in situ and trapped immediately for the next
transformations.48,49 Studies on the isolation of the aldehyde
alkynes are under investigation.
fashion to the Eschenmoser–Tanabe fragmentation. The
It is important to note that in the mechanism of the frag-
rationale here is that while the classic Eschenmoser–Tanabe
mentation of dihydropyrones to give homopropargyl alcohols,
fragmentation and the Brewer fragmentation use the gaseous
the cleavage of the C–O bond in the tetrahedral intermediate
and stable properties of molecular nitrogen as the driving
formed by nucleophilic addition to dihydropyrone triflate 52,
force to the reactions, our design uses triflate as a powerful
occurs before the fragmentation that forms the triple bond
leaving group (nucleofuge). Vinyl triflates are important inter-
(Scheme 16). In other words, this reaction features an open
mediates in organic synthesis, especially with the recent
chain alkynogenic fragmentation.
advance in metal catalyzed cross-coupling of the triflate group.
The fragmentation reaction works well in common solvents
There are several convenient ways to form these vinylogous
such as tetrahydrofuran or toluene. The expensive triflate
acyl triflates, usually from 1,3-dicarbonyl compounds.
leaving group could be substituted by the cheaper nonaflate if
The vinylogous acyl triflates have multiple reactive centers,
necessary.50 In an attempt to understand the mechanism of
including: the carbonyl, the conjungated double bond, and
this reaction, we used calculations to estimate the energy
the triflate group. Reactivities of these centers can be exploited
levels of several proposed transition states. The counter cation
individually or by any combination amongst them. The
seems to play an important role in the fragmentation event, at
general chemistry of vinylogous acyl triflates was recently
least in non-coordinating solvents. The cation can act as an
reviewed.42
ion bridge to facilitate the departure of the leaving group/
In our seminal publication,43 we investigated tandem
nucleofuge as the contact ion pair (e.g., lithium
nucleophilic addition/fragmentation reactions of cyclic vinylo-
trifluoromethanesulfonate).
gous acyl triflates 46, generally initiated with aryllithium
This methodology has been applied in total syntheses of
natural products and important synthetic targets. For example,
moth pheromone 60 is available by reduction of keto alkyne
59, which itself has been prepared by Eschenmoser–Tanabe
fragmentation in the Kocienski lab51 and, more concisely, by
the tandem addition/fragmentation of vinylogous acyl triflate
6147 (Scheme 17).

Scheme 15 Versatility of vinylogous acyl triflates and vinylogous hemi- Scheme 16 Mechanism of the fragmentation of dihydropyrone triflate
acetal triflates. showing an open chain alkynogenic fragmentation pathway.

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Scheme 17 Syntheses of moth pheromone by Kocienski (a) and
Dudley (b).
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Scheme 18 Fragmentation reaction generated Horner–Wadsworth–
Emmons reagent in synthesis of palmerolide A.
Scheme 19 Synthesis of medium sized cycloalkynes.
The phosphonate tethered alkyne products generated by
our fragmentation reaction served as the Horner–Wadsworth–
Emmons moiety in synthesis of palmerolide A,52 a marine
cytotoxic macrolide from Antarctica (Scheme 18).
Similar to the Eschenmoser–Tanabe and Brewer fragmenta-
tions, both of which can produce medium-ring cycloalkyne
ketones via ring expansion, Dudley’s methodology can also be
used in the preparations of cyclic alkynes at various ring sizes
by incorporating the nucleophile at the C-2 position of the tri-
flates53 (Scheme 19). Because of their high potential energies,
cyclic alkynes of smaller ring sizes (eight and nine carbon-mem-
bered rings) react spontaneously with azides in non-catalyzed
cycloadditions, therefore attracting attention as bioorthogonal
click reagents. The cyclic keto-alkynes prepared by
Eschenmoser–Tanabe and/or Dudley fragmentation methods
possess unique stereoelectronic properties because of the trans-
annular interaction between the carbonyl and the alkyne.54
5. Miscellaneous alkynogenic
fragmentations
Isolated early examples of what we would now call alkynogenic
fragmentations foreshadowed the work of Eschenmoser,
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Scheme 20 Bodendorf’s tandem hydroxide addition/decarboxylative
fragmentation of β-chloroacroleins for the preparation of alkynes.
Tanabe, Brewer, ours, and others. In a 1963 report,55
Bodendorf used high temperature to assist a fragmentation
reaction of β-chloroacroleins initiated by the addition of
hydroxide anion to the carbonyl of substrates, then decarboxy-
lations (Scheme 20). Soon after Bodendorf’s report, Grob used
CO2 extrusion as a driving force to enable the decarboxylative
fragmentation of β-bromocinamic acid in basic conditions.56
Like molecular nitrogen, formation of carbon dioxide can be
quite powerful for overcoming the enthalpic barriers to alkyne
production. Interestingly, the Z-isomer exclusively gave frag-
mentation product while the E-isomer gave acetophenone as a
by-product alongside with the fragmented product, phenyl-
acetylene (Scheme 21).
These results showed two important features of this reac-
tion. First, the fragmentation of the E-isomer is slow enough
for the hydrolysis of its vinyl bromide to compete, perhaps due
to conformational deviation from co-planarity to avoid
A-strain. Second, this example demonstrates that a syn-copla-
nar arrangement of atoms involved in the fragmentation
pathway is viable. Indeed, co-planarity of the orbitals involved
in the reaction seems to be more important than access to
anti-geometry. As long as the coplanarity requirement can be
achieved, there is good probability for the commonly underes-
timated syn-fragmentations to happen.57
Fleming later reported the decarboxylative fragmentations
of vinyl triflates58 which were prepared from β-ketoesters
(Scheme 22). In many cases, the triflation step gives a mixture
of E/Z isomers. Presumably, the Z-isomers are reacting via a
syn-fragmentation mechanism, although in situ isomerization
to the E-isomers cannot be ruled out.
Scheme 21 Grob’s decarboxylative fragmentation of both (Z) and (E)
β-bromocinamic acids.
Scheme 22 Synthesis of alkynes by decarboxylative fragmentation of
enol triflates.
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Also starting from β-ketoesters, Zard developed a con-

venient method59,60 for preparing alkynes via oxidative ring
opening of the N-nitroso isoxazolinones and then decarboxyla-
tive syn-fragmentation with the generation of gaseous CO2 and
N2O (Scheme 23).
Coke61 and Kuwajima62 studied the ring opening fragmen-
tations of cyclic vinyl chlorides and vinyl selenones, respect-
ively. Scheme 24 shows the Kuwajima fragmentation of endo-
cyclic vinyl selenone (83) as well as that of exo-cyclic vinyl sele-
nones (86, 89). These individual studies focus on substrates
Scheme 23 Zard’s strategy for synthesis of alkynes.
that are very similar to the Eschenmoser–Tanabe reaction and
the Dudley reaction, except for the differences in the leaving
groups (nucleofuges).
More recently Tian and Gui63 reported a general transform-
ation from furans to alkynes through a sequential Diels–Alder
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reaction followed by the fragmentation of endoperoxide 93

(Scheme 25). The fragmentation could go through either a
radical pathway (via 94) or ionic pathway (via 95) to provide
alkyne 96, which was hydrolysed to yield the alkynoic acid 97.
The method was then utilized in the synthesis of a steroid
natural product, aglatomin B. The standard reaction
condition converted furan 99 to alkyne 100 in 70% yield,
which was converted to the natural product in two steps
(Scheme 26).

Scheme 24 Kuwajima fragmentation of endo- and exo-cyclic vinyl

selenones.

Scheme 27 Generation of arynes by (a) oxidative degradation of

anthranilic acid; (b) degradation of 2-(trimethylsilyl)phenyl trifuoro-
methansulfonate; (c) ring-opening of the fomal [2 + 2] cycloadducts of
3-triflyloxyarynes; (d) carbon–carbon bond cleavage of benzocyclobu-
Scheme 25 Gui fragmentation of furans. tenols by organolithium reagents.

Scheme 26 Fragmentation from furans to alkynes in the synthesis of the proposed structure of aglatomin B.

This journal is © the Partner Organisations 2019 Org. Chem. Front., 2019, 6, 2560–2569 | 2567

Review
Finally, generation of benzyne by oxidative degradation of
anthranilic acid,64 degradation of 2-(trimethylsilyl)phenyl tri-
fuoromethansulfonate,65 ring-opening of the formal [2 + 2]
cycloadducts of 3-triflyloxyarynes66 and carbon–carbon bond
cleavage of benzocyclobutenols by organolithium reagents,67
etc. can be classified as an alkynogenic fragmentation as well
(Scheme 27), although they are perhaps not commonly
regarded as such. These types of syn-fragmentations are
among the common and important methods for generating
reactive arynes,68 pyridynes69 and related intermediates.70
6. Concluding remarks
In conclusion, alkynogenic fragmentation chemistry has a
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long history and plays a vital role in alkyne synthesis, particu-
larly for those alkynes that are not readily available by (serial)
substitution of acetylene. Different strategies and tactics have
been developed to overcome the enthalpic penalties associated
with forming the metastable alkyne functional group. When it
comes to fragmentation reactions, entropic gains coupled with
release of stable gases (N2, CO2, N2O, etc.) and/or other power-
ful nucleofuges (e.g., lithium triflate) enable a range of alkyno-
genic fragmentations for producing high-value alkynes.
Preparative alkyne chemistry continues to be an important
area of synthetic methodology, driven by and enabling broader
development in alkyne chemistry.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Jingyue Yang thanks the Yanshan University High-end Talents
Project for support of this research: BL18014. Gregory
B. Dudley thanks the National Science Foundation for support
of this research: CHE-1300722 and CHE-1834949.
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