Alkyne Versus Ynamide Reactivity: Regioselective Radical Cyclization of Yne-Ynamides

Article abstract of DOI:10.1002/anie.201811947

Ynamides are typically more reactive than simple alkynes and olefins. However, a serendipitous observation revealed a rare case where the reactivity of simple alkynes exceeds that of ynamides. This led to the development of a unique sulfur-radical-triggered cyclization of yne-tethered ynamides, which involves attack of the alkyne by a thiyl radical followed by cyclization with the ynamide. A wide range of novel 4-thioaryl pyrroles that could tolerate common functional moieties and N-protecting groups were expediently constructed by this strategy. The current method contrasts with the typical cyclization of yne-ynamides, which involves the attack of the alkyne moiety by the ynamide core. Control experiments and DFT calculations supported the participation of the sulfur radical in the reaction and the regioselective cyclization. The synthetic potential of the substituted pyrroles is also discussed.

Full text of DOI:10.1002/anie.201811947

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Accepted Article
Title: Alkyne Reactivity Preferred over Ynamide: Regioselective
Radical Cyclization of Yne-Ynamides
Authors: Akhila Kumar Sahoo, Shubham Dutta, Rajendra K. Mallick,
Rangu Prasad, and Vincent Gandon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811947
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Alkyne Reactivity Preferred over Ynamide: Regioselective Radical
Cyclization of Yne-Ynamides
Shubham Dutta,† Rajendra K. Mallick,† Rangu Prasad,† Vincent Gandon‡¥* and Akhila K. Sahoo†*
Abstract: Ynamides are typically more reactive than simple alkynes
and olefins. However, a serendipitous observation revealed a rare
case where the reactivity of simple alkynes exceeds that of
ynamides. This led to the development of a unique sulfur radical-
triggered cyclization of yne-tethered-ynamides, which involves the
attack of a thiyl radical to the alkyne and then that of the ynamide. A
wide range of novel 4-thioaryl pyrroles that could tolerate common
functional moieties and N-protecting groups were expediently
constructed by this strategy. The current method opposes to the
typical cyclization of yne-ynamides, which involves the attack of the
ynamide core to the alkyne moiety. Control experiments and DFT
calculations supported the participation of the sulfur radical in the
reaction and the regioselective cyclization. The synthetic potential of
the substituted pyrroles is also discussed.
Ynamides, a distinct class of N-substituted alkynes, have been
used for various cyclization/cycloisomerization processes
towards the construction of structurally diverse complex N-
heterocyclic building blocks.[1] In this context, the transition-
metal-catalyzed, N-oxide and Brønsted/Lewis acid-triggered
cyclizations of yne-tethered-ynamides have shown great
potential. Importantly, all these transformations involve
nucleophilic attack of the ynamide motif (via oxo-metal
carbene[2]/ketene N,O-acetal) to the alkyne scaffold (Scheme
1a).[3,4] In contrast, synthetic techniques that are based on
reversing the usual reactivity of ynamides over alkynes have
been only rarely reported.[5] A worthwhile endeavor is to unravel
a radical-mediated cyclization[6] of yne-tethered-ynamides, with
the prediction of a preferred radical attack to the alkyne rather
than to the inherently polarized ynamide (path II over path I;
Scheme 1b), which, to the best of our knowledge, is
unprecedented. The radical-triggered 6-endo-/5-exo-cyclization
of the alkyne to the ynamide would result in the formation of 6-
or 5-membered N-heterocycles, respectively (path II, Scheme
1b). To overcome this challenge, we have developed a highly
regioselective thiyl-radical attack to an alkyne motif, followed by
regioselective 5-exo-dig intramolecular attack to the ynamide
moiety of yne-tethered-ynamides. This reaction yields novel
highly substituted 4-thioaryl-pyrroles (Scheme 1c). The reaction
has a broad scope and allows for the synthesis of unnatural
pyrrole derivatives (Scheme 1c).
Scheme 1. a) Known cyclization protocols of ynamides, b) Radical-triggered
cyclization and hypothesis, c) Current work. [Ts = SO2p-Tolyl]
ynamide 1a with 3-methylbenzenethiol (2a) and a radical initiator.
The results are detailed in Table 1. When the reaction was
performed in the presence of AIBN (1.5 equiv) in CH3CN for 24 h
at 70 °C, the desired product 5 was isolated in 40% yield along
with the alkyne hydrothiolation compound 3 (15%), and the
ynamide hydration product 4 (30%) (entry 1). This result
encouraged us to screen other radical initiators. The oxidant
K2S2O8 (1.0 equiv) or N-hydroxyphthalimide (20 mol %) proved
more efficient, affording 5 in 48% and 61% yield respectively, yet
along with substantial amount of 3 (entries 2 and 3). In air and in
the absence of initiator, 5 (30%) was also produced (entry 4).
However, the reaction in DMF selectively provided 3 (entry 5),
justifying the attack of the thiyl-radical to the propargyl alkyne
moiety over the ynamide motif (DFT studies corroborate this
observation, vide infra). The yield of 5 (78%) was enhanced
when the reaction was conducted in dichloromethane (DCM)
(entry 6). On the other hand, the reaction at 50 °C was less
efficient (entry 7). The use of 1,2-dichloroethane (DCE), acetone,
or toluene as solvent, or even neat conditions, also resulted in
The study started by examining the reaction of yne-tethered
[†]
Shubham Dutta, Rajendra. K. Mallick, Rangu. Prasad and Prof. Dr.
Akhila K. Sahoo, School of Chemistry, University of Hyderabad
Hyderabad (India)
E-mail: akhilchemistry12@gmail.com
Homepage: http://chemistry.uohyd.ac.in/~aks/index.htm
Vincent Gandon,
- -
Vincent Gandon, Laboratoire de Chimie Moléculaire (LCM), CNRS
UMR 9168, Ecole Polytechnique, Université Paris-Saclay, route de
Saclay, 91128 Palaiseau cedex (France)
[‡]
[¥]
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10.1002/anie.201811947
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lower yields of 5 (entries 811). Only a trace of 5 was detected
when the reaction was performed under inert atmosphere (entry
12). Use of phenyl disulfide radical source also did not provide
the desired product (entry 13).
OMe (1c), o-OMe (1d), o-Ph (1e), and o,m-diMe (1f)] with 2-
methyl thiophenol (2g) delivered 22 (79%), 23 (72%), 24 (71%),
and 25 (87%), respectively. The desired pyrrole derivatives
2629 (6291%) were readily isolated from the cyclization of 2g
with yne-ynamides having electron-withdrawing aryl groups at
the propargyl terminus [p-COMe (1g), m-NO2 (1h), p-F (1i), and
m-F (1j)]. Besides, yne-ynamides having 2-Br/unprotected 2-NH2
bearing aryls (1k/1l) reacted well with 2g, providing 30 (90%)
and 31 (51%), respectively. Thus, electronic and steric effects of
the aryl moiety at the propargyl terminus of the yne-ynamides
did not affect the reaction outcome. Moreover, electron-
withdrawing (possibly radical inhibitors) halo/ester/nitro, and
(possibly catalyst inhibitors) amino/hydroxyl groups never
obstructed the reaction progress and productivity. Ynamides
having alkyl moieties at the alkyne terminus resulted in complex
mixtures; presumably due to the less stability of the vinyl radical
generated in situ upon attack of thiyl radical to the alkyne.
Owing to the inherent N-lone pair polarization of the ynamide,
the electron distribution could possibly affect the reaction
outcome. To examine this, we used yne-ynamides having
substituents with various steric and electronic properties at the
ynamide terminus in the radical-triggered cyclization (Figure 1c).
Thus, electron-rich [p-Me (1m), o-Ph (1n), and m,p-diMe (1o)],
electron-poor [p-COMe (1p), m-CN (1q)], and halo-containing [p-
F (1r), o-I (1s)] aryl moieties at the ynamide termini of 1
underwent cyclizations with 2g to yield the corresponding 4-
thioaryl substituted pyrroles [3238 (7492%)]. Once again, the
reaction proved successful irrespective of the electronic/steric
effects of the functional groups at the periphery of the ynamide
scaffold. Despite repeated attempts, the reaction of yne-
ynamides having alkyl substituents at the ynamide terminus with
2g failed to deliver the desired product 49a. Only the
hydrothiolation product was observed in such case. We
hypothesized that the alkyl moiety inhibited the cyclization of the
putative vinyl radical generated in situ upon the addition of the
thiyl radical to the alkyne.
Next, the reaction of yne-ynamides (1ty) with diverse
substitutions (arenes bearing electron-withdrawing/electron-
donating groups) at both the propargyl and ynamide terminus
with 2a/2g in the presence of N-hydroxyphthalimide successfully
dispensed 39 (86%), 40 (82%), 41 (77%), and 42 (85%) (Figure
1d). Similarly, thienyl substituted pyrrole derivatives 43 (78%)
and 44 (73%) were synthesized. Yne-ynamides 1z and 1aa with
different N-protecting groups [N-SO2Ph / N-Ms (mesyl)] took part
in this thiyl radical-mediated cyclization and delivered the
corresponding N-SO2Ph (45), N-Ms (46) derived pyrroles in
appreciable yields.
Finally, the utility of this thiyl radical-triggered cyclization of yne-
ynamides was demonstrated in the synthesis of tetra-
substituted pyrrole derivatives (Figure 1d). This can be realized
from yne-ynamides having alkyl substituents at the propargyl
sp3-carbon. Gratifyingly, the desired 2-Me substituted pyrrole
scaffolds 47/48 were constructed from the cyclization of 1ab/1ac
with 2g under the established conditions. Moreover, the reaction
of 2g with 1ad (having an alkyl moiety at the ynamide terminus
and 2-Me substitution in the propargyl side) produced 49, albeit
in a moderate 47% yield.
Table 1. Optimization of thiyl-radical triggered cyclization of yne-
ynamides[a]
Entry
1
Initiator
(mol%)
150
100
20
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Yield (3/4/5) %
(15/30/40)
(41//48)
(31//61)
(/40/30)
(75//10)
(/10/78)
(/10/40)
(/25/63)
(40//50)
(/25/40)
(/25/64)
(//trace)
(05//00)
AIBN
2
K2S2O8
3
X
Air
X
4
--
5
20
6
X
20
CH2Cl2
7
X
20
CH2Cl2, 50 °C
ClCH2CH2Cl
acetone
toluene
neat
8
X
20
9
X
20
10
11
12 b
13c
X
20
X
20
--
--
CH2Cl2
X
20
CH2Cl2
[a]Reaction condition: yne-ynamide 1 (0.3 mmol), thiophenol 2a (0.75 mmol),
initiator (0.060.45 mmol), solvent (0.5 mL) at 70 °C for 36 h. [b]Under inert
atmosphere without X. [c]Phenyl disulfide (Ph2S2) (0.75 mmol) instead of 2a.
(Ts = SO2p-Tol).
To probe the synthetic generality, reactions between various
yne-ynamides (displaying substituents at the alkyne/ynamide
terminus and N-PG) and thiol derivatives were carried out under
the established conditions corresponding to Table 1, entry 6.
The results are outlined in Figure 1. To start with, the aryl thiol
derivatives 2ah [having m-Me (2a), m-OMe (2b), p-Me (2c), p-
iPr (2d), p-tBu (2e), p-OMe (2f), o-Me (2g) and o-OMe (2h)
substituents] were reacted with 1a. The respective 2-benzyl-4-
(thioaryl)-3-phenyl-1-tosyl-1H-pyrrole 512 were successfully
produced in 7284% yield (Figure 1a). Thiophenol (2i) reacted
well with 1a to afford 13 (88%). The halogenated aryl thiols [2j
(p-Cl), 2k (p-Br), 2l (o-Br), 2m (m-F) did not affect the radical-
triggered cyclization, as shown by the efficient formation of 14
(68%), 15 (80%), 16 (58%), and 17 (56%), respectively. Pyrroles
18 (66%) and 19 (80%) were obtained from the reaction of 1a
with sterically hindered -naphthylthiol (2n) and 2,6-dimethyl
thiophenol (2o). The unprotected OH group containing
thiophenol (2p) reacted well to provide the desired product 20
(65%). On the other hand, the aliphatic ethanethiol did not react,
presumably due to the poor stability of the alkyl thiyl radical.
The thiyl radical-triggered cyclization of yne-ynamides having
substitution at the alkyne terminus was next probed (Figure 1b).
Thus, the cyclization of 1b [having p-Me-aryl motif at the
propargyl terminus] with 2a under the optimized conditions led to
21 in excellent yield (92%). Likewise, reaction of yne-ynamides
possessing electron-rich aryl motifs at the propargyl terminus [p-
To gain some insights into the reaction mechanism, the reaction
between 1a and p-chlorobenzenethiol (2j) in the presence of N-
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Figure 1. Scope of thiyl radical triggered cyclization of yne-ynamides (synthesis of 4-thioaryl-pyrroles). [Ts = SO2p-Tolyl]
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Figure 2. Computed Free Energy Profile [G343, kcal/mol; R = SO2Ph]
of the yne-ynamide scaffold are available for the attack of the
thiyl radical,[13] which would eventually result in eight different
products on the basis of specific exo/endo-mode of cyclization.
All these possibilities have been investigated and are presented
in the Supporting Information (Schemes S2, S4, Table S3). Only
radical additions via 5-exo-dig cyclizations, which turn out to be
the best computational options, are discussed here. The values
are G343 in kcal/mol obtained at the UB3LYP[14]/6-
311++G(d,p)[15] level including solvent correction for CH2Cl2
(PCM method[16]) (Figure 2). The B3LYP functional remains
widely used in the computational study of radicals.[17] Starting
from system A comprising a model yne-ynamide and the
benzothiyl radical, two pathways can provide pyrroles. The
radical can attack the internal propargyl alkyne carbon to give
B,[18] which then undergoes a 5-exo-dig cyclization to yield C.[19]
The first step is endergonic by 9.2 kcal/mol, and the second one
is exergonic by 17.0 kcal/mol. The corresponding transition
states have free energies of 16.9 and 17.5 kcal/mol.[20] Radical C
is then likely to abstract a hydrogen atom from thiophenol to give
D. The latter should then easily tautomerize to the aromatic 4-
thioaryl-pyrrole E, which displays the experimentally observed
regiochemistry. If the benzothiyl radical attacks the internal
Scheme 2. Control Experiments and Synthetic Applications. [DMF = N,N-
dimethylformamide, m-CPBA
=
meta-chloroperbenzoic acid, TFAA
=
trifluoroacetic anhydride]
hydroxyphthalimide and the radical scavenger TEMPO under
the standard reaction conditions was performed. The respective
bis(4-chlorophenyl)disulfane 50 was exclusively produced,
leaving 1a untouched (Scheme 2a). On the other hand, the
same reaction in DMF at 70 ºC produced the hydroathiolation
product 51 (82%). Thus, the attack of the thiyl radical across the
alkyne initiates the reaction (DFT studies support this
observation, see the SI; Scheme S2 and Table S2). The
robustness of the catalytic system has been tested in the gram
scale synthesis of 11 (1.1 g, 72%) from 1a (1.15 g, 2.2 mmol)
and 2g (6.6 mmol) (Scheme 2b).
The reactivity of 11 was further explored through the m-CPBA
assisted oxidation of the S-atom to the corresponding sulfoxide
52 (70%), and the direct synthesis of sulfoximine 53 (63%)
(Scheme 2b).[7] The reaction of sulfoxide 52 with phenyl
acetylene in presence of Ph3PAuCl (7.5 mol%) and AgSbF6 (15
mol%) provided the alkylation product 54.[8] The cross-
dehydrogenative-coupling of 52 led to the unusual [6,7]-fused
thiepino-pyrrole 55 in 85% yield.[9] Exposing 52 to p-tBu-phenol
in presence of TFAA delivered the arylation product 56 via
Pummerer-type transformation.[10]
ynamide carbon, vinyl radical
H would be formed. Its
transformation into the 5-membered ring radical I, which displays
an unobserved 2-thio regioselectivity, was then modeled through
a 5-exo-dig cyclization. Both inter- and intramolecular radical
additions leading to I are more difficult to achieve than those
providing C. Indeed, the corresponding transition states have
free energies of 20.2 and 20.6 kcal/mol. The preference for TSAB
over TSAH can be rationalized on the basis of electronic and
steric effects (see the SI). Despite our effort, we could not find
an energetically reasonable pathway for the selective formation
of 3 over 5 in DMF (see the SI).[21] In spite of a good match
between our method and the known calculated BDE of
To validate a radical cyclization pathway and rationalize the
selective formation of 4-thioaryl-pyrroles, DFT computations
were carried out using the Gaussian 09 software package (see
the SI for details).[11,12] In principle, four sites of the two yne units
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10.1002/anie.201811947
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thiophenol (see the SI),[22, 23] the computed mechanism remains
to be validated.
Soc. 2017, 139, 10104. (m) R. N. straker, Q. Peng, A. Mekareeya, R.S.
Paton, E. A. Anderson, Nat. communications. 2016, 7, 10109.
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[4]
[5]
[6]
In summary, a metal-free regioselective radical cyclization of
arylthiols with yne-tethered ynamides to fully substituted 4-
thioaryl-pyrroles has been developed. The transformation
involves an attack of a thiyl radical to the alkyne motif, followed
by the cyclization with the ynamide core. The preferred reactivity
of an alkyne over an ynamide, although previously observed,
remains a rare case. The transformation is general, exhibiting a
broad substrate scope and high functional group tolerance (the
free NH2, OH groups and the common radical trap electron-
withdrawing groups did not affect the reaction outcome). Control
experiments suggest the involvement of radical intermediates.
Preliminary DFT calculations support the reaction pathway
involving the alkyne moiety as the most reactive part of the yne-
ynamide. Implementation of this method for the synthesis of
complex molecules of biological significance and detailed
mechanistic studies are currently underway. We believe these
findings would open new avenues for discovering novel methods
in yne/allene/olefin tethered ynamides.
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This research was supported by the CEFIPRA (grant no.: 5505-
2). We thank University of Hyderabad (UoH; UPE-CAS and
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India, for fellowship. VG thanks CNRS, UPS, Ecole
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[14] See the Supporting Information [ref. 9].
Keywords: • • alkyne reactivity preferred
• -exo- g z • -thioaryl-pyrrole
[15] See the Supporting Information [ref. 10].
[16] See the Supporting Information [ref. 11a].
[17] See the Supporting information [ref. 11].
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CCDC 1871002 contains the supplementary crystallographic data for
compound 14.
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10.1002/anie.201811947
Angewandte Chemie International Edition
COMMUNICATION
Shubham Dutta, Rajendra K. Mallick, Rangu
Prasad, Vincent Gandon, and Akhila K. Sahoo
Alkyne Reactivity Preferred over Ynamide:
Regioselective Radical Cyclization of Yne-
Ynamides
Discussed herein is an unprecedented radical cyclization of arylthiols with alkyne-tethered ynamides to highly-substituted 4-arylthio-
pyrroles. The transformation involves an unusual attack of a thiyl radical to the alkyne motif followed by the cyclization with the
ynamide core, showcasing the reactivity of an alkyne preferred over an ynamide. Density functional theory (DFT) studies support the
proposed mechanism.
This article is protected by copyright. All rights reserved.