Journal of the American Chemical Society
Article
yne-ynamide derivatives 9 (Figure 1, part C). Ynamides (N-
alkynyl amides) were targeted as TACs in this work, as they
can be readily accessed with a variety of substitutions on the
nitrogen atom,20 are easy to handle and manipulate, and
exhibit enhanced stability as compared to their parent
ynamines.21 It is interesting to note that despite the popular
use of ynamides in organic synthesis, their reactivity has been
limited, almost exclusively, to the functionalization of their C−
C alkynyl portion22 without any direct participation of the
nitrogen atom in the formation of new nitrogen−carbon
bonds.23 The synthetic interest of this new (3+2) cyclo-
addition was further highlighted by the possibility to derivatize
the pyrrole products in various heterobicyclic compounds
relevant to medicinal chemistry. A combined experimental and
density functional theory (DFT) mechanistic study was also
performed to gain insight into the nature of the cycloaddition
reaction.
of sulfonyl groups to migrate from sulfonylammonium
intermediates.24
Heating a solution of 9a in toluene at 80 °C for 15h led to
its slow conversion (42%) mostly into degradation products25
(entry 1). We could, however, detect in the crude reaction
mixture the formation of a new compound in very low
amounts (13% NMR yield). This compound was isolated as a
solid and its structure pleasingly assigned after 1H NMR
analyses as the targeted bicyclic pyrrole 10a. Single-crystal X-
ray diffraction analysis of 10a confirmed the connection
around the pyrrole core and the migration of the tosyl group
from the N atom of the ynamide moiety in the substrate to its
α carbon in the product (see Table 1). While the yield was
low, the formation of 10a validated our approach and the
possibility to use ynamides as TACs in cycloaddition
processes. By raising the temperature to 130 °C (oil bath)26
9a was fully consumed after 2 h of reaction and an improved
yield of 72% was obtained (entry 2). Running the reaction
under argon had almost no influence on the course of the
reaction (entry 3). Hypothesizing that the loss of material may
be due to deleterious uncontrolled radical processes consum-
ing the diyne substrate,27 additives known to stop radical chain
degradation processes were examined.28 As seen in entries 4−
7, the addition of 2,6-di-tert-butyl-4-methylphenol (BHT), a
phenolic radical scavenger, proved to be quite beneficial, and
an almost quantitative yield of pyrrole 10a (96%) could be
obtained when 1 equiv of the additive was used. Another
radical scavenger, γ-terpinene, was slightly beneficial, but not as
effective (entry 8). The conditions described in entry 6,
employing 0.5 equiv of BHT, were deemed sufficient and were
therefore used to evaluate the scope of the transformation. It is
interesting to note that the reaction was very selective toward
the migration of the tosyl group and that no alternative (4+2)
dehydro Diels−Alder cycloadduct29 derived from 9a could be
observed.
RESULTS AND DISCUSSION
■
Validation of the Approach, Reaction Optimization,
and Scope. We started our investigation with diyne 9a, which
was chosen as a model substrate to validate our reactivity
proposal. This diyne was conveniently accessed by Cu-
catalyzed coupling between bromoalkyne 11 and sulfonamide
12 (Table 1). The initial choice of the tosyl group on the
ynamide moiety was based on the well-documented coupling
of sulfonamides under Cu catalysis20a−c and the known ability
Table 1. Optimization of the Reaction Conditions
A variety of strategies were employed in the synthesis of the
yne-ynamide substrates in order to vary the substitution
pattern on the ynamide, the alkyne moiety, and the nature of
details).30 As seen from the results compiled in Tables 2 and 3,
the reaction exhibits good functional group compatibility, and
a variety of bicyclic cycloadducts could be obtained from yne-
ynamides 9a−ak. As for the nature of the alkyne terminus
(Table 2, part A), the reaction proceeded rapidly and cleanly
for all screened aryl derivatives 9a−h. An array of electron-
donating (EDG) and electron-withdrawing groups (EWG)
were well tolerated on the aromatic moiety, leading to the
desired pyrroles in yields ranging from 79% to 97% after only 1
h of reaction at 130 °C. Heteroaromatic substituents were also
shown to be compatible, as attested by the conversion of
thiophene and pyridine derivatives 9i−j into pyrroles 10i−j
with respective 82% and 90% yields. Pleasingly, a C-sp2-
hybridized alkenyl substituent was also tolerated and cyclo-
hexenyl derivative 10k could be formed in 83% yield after 2 h
of reaction. The use of a conjugated 1,3-diyne unit was,
however, detrimental to the yield of the reaction. In the case of
substrate 9l, the major product obtained was 10l, with a
modest yield of 33%, and byproducts derived from a potential
(4+2) hexadehydro Diels−Alder reaction, if present, were only
minor.31 While the reaction of alkyl-substituted derivative 9m
and terminal alkyne 9n proceeded very slowly and with low
yields (15−20%), that of trimethylsilyl (TMS)-substituted
alkyne 9o was comparatively very efficient (80%), yet slow.
T
n
time
(h)
conversion
c
c
entry (°C)
additive
(equiv)
(%)
yield (%)
d
1
2
3
4
5
6
7
8
80
130
130
15
2
2
2
2
2
2
2
42
13
72
69
79
86
90
100
100
100
100
100
100
100
e
130 BHT
130 BHT
130 BHT
130 BHT
130 γ-terpinene
0.1
0.25
0.5
1
f
96 (90)
1
77
a
Reaction conditions: CuSO4·5H2O (10 mol %), 1,10-phenanthroline
(20 mol %), K3PO4 (2 equiv), toluene, 80 °C, 48%; see SI for more
b
details. Unless otherwise noted, reactions were performed with 0.05
mmol of 9a in screw-cap NMR tubes in toluene-d8 (0.1 M) under air
c
1
and monitored by H NMR spectroscopy. Conversions and yields
were determined by 1H NMR spectroscopy using mesitylene as
d
internal standard. In a sealed vial in toluene (0.1 M). Conversion
and yield were determined by analysis of the crude reaction mixture
using mesitylene as a standard. NMR tube was purged with argon.
Isolated yield.
e
f
9603
J. Am. Chem. Soc. 2021, 143, 9601−9611