Journal of the American Chemical Society
Communication
was well tolerated. Sterically demanding secondary bromides
(36) also gave the product in good yield.
Table 1. Reaction Development
Our initial attempts to couple secondary α-bromo amides
were unsuccessful. Under the reaction conditions used for
coupling α-bromo esters, product 47 was formed in only 47%
yield. The primary side reactions were the reductions of both
the α-bromo amide and the alkyne. Eventually, we found that
by subtly changing the reaction conditions, we could obtain
product 47 in 86% yield.
a
entry
change from standard conditions
yield (%)
1
2
3
none
81
0
11
chloro ester instead of bromo ester
iodo ester instead of bromo ester
4
5
6
SIPrCuCl instead of IPrCuCl
IMesCuCl instead of IPrCuCl
(R)-DTBM-Segphos/Cu(OAc)2 instead of IPrCuCl
72
1
<5
7
8
9
Ph2MeSiH instead of PMHS
Me(OEt)2SiH instead of PMHS
(MeOSiH)4 instead of PMHS
3
0
46
To achieve these results, we lowered the solvent ratio of
benzene/THF from 9:1 to 7:3, adjusted the stoichiometry of
the reactants, and increased the reaction time to 24 h.
These modified conditions could be applied to the coupling
of a variety of secondary α-bromo amides. These included
amide derivatives of numerous biologically important amines,
such as piperazine (34), pyrrolidine (32), indolone (33), and
morpholine (31). This adaptation could also be used to couple
cyclic tertiary α-bromo amides. Tertiary α-bromo-β-lactams
(35) as well as secondary α-bromo-β-lactams (40) were found
to provide the desired products in useful yields. Acyclic tertiary
amides or esters failed to provide any product.
10
11
12
13
LiOt-Bu instead of NaOt-Bu
NaOi-Pr instead of NaOt-Bu
NaOSiMe3 instead of NaOt-Bu
KOt-Bu instead of NaOt-Bu
37
22
74
0
14
15
16
17
benzene instead of benzene/THF (9:1)
benzene/THF (1:1) instead of benzene/THF (9:1)
toluene instead of benzene/THF (9:1)
THF instead of benzene/THF (9:1)
58
66
52
27
We also noted a few limitations of the present hydro-
alkylation reaction. Aryl acetylenes (41) and disubstituted
internal alkynes (42) did not participate in the hydroalkylation
reaction. Similarly, α-bromo ketones (43), α-bromo nitriles
(45), aryl substituted α-bromo esters (44), and primary α-halo
carbonyls were not viable substrates. Finally, protic functional
groups, such as hydroxyl groups and unprotected amines, and
reducible functional groups, like aldehydes and ketones, were
not tolerated.
18
ethyl ester instead of pinacolyl ester
61
a
Determined by GC using standard. Z stands for pinacolyl.
The key feature of the mechanism proposed in Scheme 3 is
the cross coupling of the alkenyl copper intermediate with the
α-bromo carbonyl. Although stoichiometric experiments
shown in Scheme 4b established the feasibility of this
elementary step, the exact mechanism of this process was
unclear. While we initially postulated a pathway initiated by
SET, a two-electron oxidative addition/reductive elimination
sequence is also plausible.
Support for a SET pathway came from radical trap
experiments (Scheme 5). Our previous work has shown that
the electrophilic functionalization of the alkenyl copper
intermediate is not affected by the addition of TEMPO.20
On the other hand, the SET pathway is expected to show
sensitivity to TEMPO.43,46,47 We observed that as little as 20
mol % of TEMPO impacts the catalytic reaction and 1.5 equiv
of TEMPO completely prevents the formation of the alkene
product (Scheme 5). Stochiometric experiment with alkenyl
copper revealed that TEMPO inhibits the cross-coupling step
of the reaction, producing TEMPO adduct 48 as the major
product of the reaction (63% yield).
lower solubility. The highest yields of the desired product were
obtained using a 9:1 benzene/THF solvent mix. Other ratios
of these solvents and other aryl/etherial solvent mixtures
resulted in depressed yields (see the Supporting Information,
Table S6) Benzene or toluene alone provided less of the
desired product and a significant amount of the reduced
alkyne.
Using the standard conditions from Table 1, we found that a
wide range of E-alkenes could be synthesized (Table 2) with E-
We also found that the reaction is compatible with many
functional groups and can be accomplished in the presence of
esters (11), epoxides (10), nitriles (17), alkyl chlorides (13),
aryl bromides (24) and fluorides (9), acetals (20), and amides
(22). Sterically demanding alkynes such as 15 and 25 also
performed well under the reaction conditions. The reaction
also tolerates several nitrogen-containing heteroarenes, such as
halo pyridines (12, 26), indoles (21), quinoxalines (16),
phenoxazines (19), and phenothiazines (14).
We also explored the reaction with different secondary α-
bromo esters. In general, esters of sterically bulky alcohols
afforded the desired product in good yield, presumably because
of the increased stability of these esters under catalytic
conditions. The presence of heteroatomic substituents, such as
bromide (37) or thioether (38), at the γ position of the ester
The results of these experiments allow us to exclude the
alkylation mechanism involving two electron processes.
Distinguishing between different SET mechanisms is much
harder. Extensive mechanistic investigations of similar
processes involved in ATRP suggest ISET as the most likely
SET mechanism for the reaction of alkenyl copper with an α-
7905
J. Am. Chem. Soc. 2021, 143, 7903−7908