Copper-Catalyzed Cross-Coupling of Secondary α-Haloamides with Terminal Alkynes: Access to Diverse 2,3-Allenamides

Article abstract of DOI:10.1002/adsc.201701556

A copper-catalyzed C(sp)?C(sp³) cross-coupling of terminal alkynes with readily available secondary α-haloamides for the efficient synthesis of 2,3-allenamides is realized. The methodology is characterized by its wide substrate scope, which makes it an important complement to traditional methods for synthesizing allenes. A mechanism involving an alkynylcopper species is proposed. (Figure presented.).

Full text of DOI:10.1002/adsc.201701556

Title: Copper-catalyzed cross-coupling of secondary α-haloamides with
terminal alkynes: access to diverse 2,3-allenamides
Authors: Yunhe Lv, Weiya Pu, Xueli Zhu, Tiantian Zhao, and Feifei Lin
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10.1002/adsc.201701556
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-catalyzed cross-coupling of secondary α-haloamides
with terminal alkynes: access to diverse 2,3-allenamides
Yunhe Lv,a,b* Weiya Pu,a Xueli Zhu,a Tiantian Zhao,a and Feifei Lina
a
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 455000, P. R. China.
E-mail: luyh086@nenu.edu.cn; lvyunhe0217@163.com
Henan Province Key Laboratory of New Opto-Electronic Functional Materials, Anyang 455000, P. R. China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: A copper-catalyzed C(sp)-C(sp3) cross-coupling
of terminal alkynes with readily available secondary α-
haloamides for the efficient synthesis of 2,3-allenamides is
realized. The methodology is characterized by its wide
substrate scope, which makes it an important complement to
traditional methods for synthesizing allenes. A mechanism
involving an alkynylcopper species is proposed.
Keywords: alkynes; copper; cross-coupling; α-haloamides;
trisubstituted allenes
Allenes are a useful class of synthetic intermediates
because of their orthogonal cumulative π-systems,
which result in extraordinary reactivities.[1] They are
also key structural units in natural products,
pharmaceuticals, and molecular materials.[2] Many
significant methodologies for the synthesis of allenes
have been developed in recent decades.[3] However, an
allene synthesis based on a coupling reaction,
Scheme 1. Allene synthesis by direct coupling of two
especially the coupling of trisubstituted 2,3-
allenamides,[4] which are extremely useful precursors
in the synthesis of iminolactones, γ-hydroxy-γ-lactams,
and 1,3-oxazine-2,4-diones, is relatively less
developed. There are only a few reports of such
reactions in the literature. These methods include
C(sp)-C(sp2) and C(sp)-C(sp) cross-coupling reactions
(Scheme 1). For C(sp)-C(sp2) couplings, Barrett and
co-workers reported the interaction of Grubbs catalyst
ruthenium carbene with monosubstituted allenes to
generate 1,3-disubstituted allenes or polyallenes
(Scheme 1a1).[5] In this field, alkynes are frequently
used as starting materials, and an enormous amount of
effort has been devoted to the enhancement of this
method over the past few decades. Bertrand and co-
workers have also developed an efficient gold (I)
complex-catalyzed cross-coupling reaction of
enamines with terminal alkynes for the synthesis of
allene derivatives in good yields (Scheme 1a2).[6]
Crabbé homologation, namely, the CuBr-mediated
cross-coupling of 1-alkynes and
fragments.
formaldehyde in the presence of diisopropylamine has
been established as a powerful tool for the synthesis of
terminal allenes.[7] However, it should be noted that the
reaction only works with formaldehyde; no allenes
were formed when other aldehydes were used.
Recently, Ma and co-workers reported a ZnI2-
mediated protocol for the one-pot synthesis of 1,3-
disubstituted allenes from terminal alkynes, normal
aldehydes, and morpholine, which was a significant
improvement in the synthesis of allenes.[8] Later, Ma
and coworkers also reported the cross-coupling of
ketones with terminal alkynes utilizing CdI2 as a
mediator or CuI as a catalyst (Scheme 1a3).[9] Wang,
Feng, Fox, Ley and Sun independently reported cross-
coupling reactions of N-tosylhydrazones or diazo
compounds with terminal alkynes (Scheme 1a4).[10]
Recently, the formation of allenes via other coupling
reactions, such as those using propargylic alcohols, has
also been extensively explored. [Cp*RhCl2]2-
1
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10.1002/adsc.201701556
Advanced Synthesis & Catalysis
catalyzed SN2’-type couplings between arenes and
propargylic alcohols were demonstrated by Ma and co-
workers.[11] For C(sp)-C(sp) couplings, a silver-
catalyzed cross-coupling of propargylic alcohols with
isocyanides was described by Bi and co-workers
(Scheme 1b).[12] Although significant advancements
have been made in C–C cross-couplings of terminal
alkynes with both C(sp2)[5-11] and C(sp)[12] coupling
partners for the synthesis of allenes, few reports are
available using C(sp3) coupling partners, presumably
due to the formation of diynes or ethynylation products
under traditional Sonogashira coupling conditions.[13]
Consequently, the development of C(sp)-C(sp3) cross-
couplings of terminal alkynes with readily available
starting materials, such as alkyl halides, is in high
demand.
direct synthesis of trisubstituted allenes by a C(sp)-
C(sp3) cross-coupling of terminal alkynes with
secondary α-haloamides.
During the investigation of the copper-catalyzed
aminodifluoroalkylation and oxyalkylation of alkenes
and alkynes, we observed that using ethynylbenzene
(1a) and 2-bromo-N-(4-bromophenyl)propanamide
(2a) as the substrates afforded 2,3-allenamides 3a
under similar reaction conditions (Table 1, entry 1),
while
the
corresponding
oxyalkylation
or
aminoalkylation product was not detected. Due to the
importance of developing a C(sp)−C(sp3) cross-
coupling that is significantly complementary to the
current methods for synthesizing allenes, we decided
to optimize this coupling reaction. A range of solvents
was first screened, and the results showed that acetone
is a highly effective solvent, affording product 3a in
73% yield (Table 1, entries 2-5). To our delight, 3a
was obtained in 91% yield when the reaction was
performed at 120 °C (Table 1, entry 6). The reaction in
the absence of ligand gave the desired product in 38%
yield (Table 1, entry 7). Other ligands such as bipy,
PPh3 and dppe were not as effective as Phen (Table 1,
entries 8-10). Further control experiments
demonstrated that CuI and K2CO3 were both important
(entries 11 and 12). Other bases such as Cs2CO3,
NaHCO3 and Et3N were examined, but the reactions
gave product 3a in lower yields (entries 13-15). In
addition, CuCl and CuBr were also effective catalysts
for this transformation, affording product 3a in 78%
and 83% yields, respectively (Table 1, entries 16 and
17).
Table 1. Optimization of the Reaction Conditions.[a]
Entry Metal Ligand Additive Solvent
T
Yield
(°C) (%)[b]
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
none
CuI
CuI
CuI
CuI
CuCl
CuBr
Phen
Phen
Phen
Ph3P
Phen
Phen
none
bipy
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
CH3CN 100
39
32
THF
100
100
100
3
CH2Cl2
DMSO
20
4
trace
73
5
acetone 100
acetone 120
acetone 120
acetone 120
acetone 120
acetone 120
acetone 120
acetone 120
acetone 120
6
91
7
38
8
43
9
PPh3
dppe
Phen
Phen
Phen
Phen
Phen
Phen
Phen
40
Table 2. Reactions of alkynes 1 with 2a.[a]
10
11
12
13
14
15
16
17
42
0
trace
68
Cs2CO3
NaHCO3 acetone 120
20
Et3N
acetone 120
acetone 120
acetone 120
15
K2CO3
K2CO3
78
83
[a] Reactions were carried out with 1a (0.24 mmol), 2a (0.2
mmol), metal (10 mol %), ligand (10 mol %) and additive
(2.0 equiv) in 3.0 mL of solvent at the indicated
temperature for 1.0 h unless noted otherwise.
[b] Yield of the isolated product. Phen = 1,10-phenanthroline,
bipy=2,2'-bipyridine,
dppe
=
1,2-
bis(diphenylphosphino)ethane.
Recently, we reported the copper-catalyzed
aminodifluoroalkylation of alkenes and alkynes with
α-bromodifluoroacetamides.[14a,b] We also developed a
Cu-catalyzed intermolecular oxyalkylation of styrenes
with readily available α-bromoacetamides under
air.[14c] These reactions are proposed to follow a similar
pathway that involves the copper-catalyzed generation
of a difluoroalkyl and a tertiary-alkyl radical. Herein,
we further report the Cu-catalyzed cross-coupling of
terminal alkynes with secondary α-haloamides, which
leads to the formation of 2,3-allenamides (Scheme 1c).
It should be noted that this reaction represents the first
[a] Reactions were carried out with 1 (0.24 mmol), 2a (0.2
mmol), CuI (10 mol %), Phen (10 mol %) and K2CO3 (2.0
equiv) in acetone (3.0 mL) 120 °C, 1.0 h. Yield of the
isolated product.
We then evaluated the generality of the reaction
using various alkynes under the optimized reaction
2
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10.1002/adsc.201701556
Advanced Synthesis & Catalysis
conditions (Table 1, entry 6). As described in Table 2,
ethynylbenzenes with both electron-donating and
electron-withdrawing groups all worked well with 2a,
and they afforded desired coupling products 3b-3p in
60–96% yields. Halo-substituted ethynylbenzenes
(1b-d, 1i, 1j, 1o, and 1p) were tolerated under these
coupling conditions, and these substituents allow for
further functionalization through subsequent cross-
couplings. Heteroaromatic alkynes such as 3-
ethynylthiophene (1q) was also effective and provided
3q in 83% yield. Remarkably, the reaction also worked
well with alkyl alkynes(3r and 3s).
product 3a in 56% yield. However, 2-bromo-1-(4-
bromophenyl)propan-1-one (2p) and ethyl 2-
bromopropanoate (2q) were not tolerated as substrates,
and desired products 4p and 4q were not observed.
To demonstrate the synthetic value of our method,
this novel transformation has also been attempted in
late-stage cross-couplings of biologically active
compounds for drug discovery and development. As
shown in eqn (1), ethynyl estradiol, which is the first
orally active progestin,[15] smoothly underwent cross-
coupling to yield desired products 5 and 5’ in 78%
yield. This compound may be interesting to medicinal
chemists. In addition, the cross-coupling reaction of 1a
on a gram scale (4 mmol) afford 3a in 77% yield (eqn
(2)).
Table 3. Reactions of ethynylbenzene 1a with secondary α-
haloamides 2.[a]
Some mechanistic experiments have been
conducted to probe the mechanism of this reaction.
When radical scavengers such as 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.)
and 2,6-di-tert-butyl-4-methylphenol (BHT, 2.0 equiv.)
were added to the cross-coupling reaction of 1a under
the optimized conditions, product 3a was isolated in
85% and 82% yields, respectively (eqn (3)). These
results indicate that a radical pathway may not be
involved in this transformation. This was further
confirmed by a radical clock experiment with
ethynylcyclopropane as the substrate. The reaction of
ethynylcyclopropane (1t) with 2a under the standard
reaction conditions produced cross-coupling product
3t in 82% yield, and the corresponding ring-opened
product was not detected (eqn (4)).[16]
[a] Reactions were carried out with 1a (0.24 mmol), 2 (0.2
mmol), CuI (10 mol %), Phen (10 mol %) and K2CO3 (2.0
equiv) in acetone (3.0 mL), 120 °C, 1.0 h. Yield of the
isolated product.
Further evaluation of the generality of the reaction
by varying the 2-bromopropanamide demonstrated the
robustness of the current C(sp)-C(sp3) cross-coupling
protocol, and the results are shown in Table 3. 2-
Bromopropanamides bearing F, Cl, Br, cyano, methyl,
tert-butyl, and methoxy substituents at the ortho, meta,
and para positions of the aromatic ring could be
converted to desired products 4b-4m in good to
excellent yields. Starting from 2-bromo-N-(4-
bromophenyl)butanamide (2n), 4n was obtained in 96%
yield. Remarkably, alkyl 2-bromopropanamide 2o was
tolerated in the cross-coupling reaction. In addition, α-
chloropropanamides such as N-(4-bromophenyl)-2-
chloropropanamide also provided desired coupling
Based on the above experimental results and related
reports in this field, a possible mechanism was
proposed (Scheme 2). Alkynylcopper species A,[13a,17]
3
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10.1002/adsc.201701556
Advanced Synthesis & Catalysis
EtOAc (3.0 mL×3), the combined organic phases were dried
over anhydrous Na2SO4 and the solvent was evaporated
under vacuum. The residue was purified by column
chromatography to give the corresponding products (3a,
59.1 mg, 91%).
readily generated from ethynylbenzene and CuI in the
presence of K2CO3 and Phen, reacted with 2b to form
intermediate B by oxidative addition. Subsequently, a
C(sp)−C(sp3) bond-forming reductive elimination
occurred from intermediate B and lead to intermediate
C,[13b] which underwent facile rearrangement to afford
the allene product in the presence of K2CO3.[10b,h]
Although intermediate C was not detected, we carried
out a labeling study using D2O as an additive in
acetone-d6 (eqn (5)). This resulted in 94% deuterium
incorporation into allene 3a-d1, which provides
evidence for species C as an intermediate.
Acknowledgements
We gratefully acknowledge the Science & Technology Foundation
of Henan Province, the Foundation of Henan Educational
Committee (18A150001), the Program for Innovative Research
Team of Science and Technology in the University of Henan
Province (18IRTSTHN004), the Henan province key laboratory of
new opto-electronic functional materials and AYNU-KP-A04 for
financial support.
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Typical procedure for the cross-coupling of secondary α-
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a
solution
of
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2-bromo-N-(4-
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0.24 mmol), Phen (3.6 mg, 0.02 mmol), CuI (3.8 mg, 0.02
mmol), and K2CO3 (55.3 mg, 0.4 mmol) under air in a
screw-cap test tube. The reaction mixture was stirred at
120 °C for 1.0 h. After the reaction was finished, the
reaction mixture was cooled to room temperature and
quenched with water. The mixture was extracted with
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COMMUNICATION
Copper-catalyzed cross-coupling of secondary α-
haloamides with terminal alkynes: access to diverse
2,3-allenamides
Adv. Synth. Catal. 2018, 360, xx – xx
Yunhe Lv,* Weiya Pu, Xueli Zhu, Tiantian Zhao,
and Feifei Lin
6
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