Copper-Catalyzed Enantioselective Sonogashira Type Coupling of Alkynes with α-Bromoamides

Article abstract of DOI:10.1002/anie.202000860

An asymmetric copper-catalyzed Sonogashira type coupling between alkynes and α-bromoamides has been developed. This method represents a facile approach to synthetically useful β, γ-alkynyl amides from two readily available starting materials in a highly enantioselective manner. A Bisoxazoline diphenylanaline (BOPA) serves as the effective chiral ligand. Preliminary mechanistic studies support the formation of alkyl radical species.

Full text of DOI:10.1002/anie.202000860

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Copper-Catalyzed Enantioselective Sonogashira Type Coupling
of Alkynes with α-Bromoamides
Authors: Xueling Mo, Bin Chen, and Guozhu Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000860
Link to VoR: https://doi.org/10.1002/anie.202000860

Angewandte Chemie International Edition
10.1002/anie.202000860
COMMUNICATION
Copper-Catalyzed Enantioselective Sonogashira Type Coupling
of Alkynes with α-Bromoamides
Xueling Mo, Bin Chen, Guozhu Zhang*
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry
Abstract: An asymmetric copper-catalyzed Sonogashira type
coupling between alkynes and α-bromoamides has been developed.
This method represents a facile approach to synthetically useful β, γ-
alkynyl amides from two readily available starting materials in a
coupling of α-bromoamide to construct quaternary carbons, in
which alkynylated copper is a key intermediate.[ Li’s group
recently reported light-mediated couplings with terminal alkynes
and α-carbonyl halides (eq. 2).[ Despite all those elegant
progress, as far as we know, the asymmetric Sonogashira type
coupling of terminal alkynes with α-carbonyl halides has been
met with limited success. Liu recently reported an elegant
13]
14]
highly enantioselective manner.
BOPA) serves as the effective chiral ligand. Preliminary mechanistic
studies support the formation of alkyl radical species.
A bisoxazoline diphenylanaline
(
3
copper-catalyzed stereoconvergent Sonogashira C(sp )–C(sp)
cross-coupling of a broad range of terminal alkynes and racemic
alkyl halides enabled by a chiral cinchona alkaloid-based P,N-
ligand.[ In their scope studies, they reported one example of α-
bromoamide as substrate, a good yield and ee was obtained (eq.
3). Given the significance of α-alkynylcarbonyl functionality,
alternative chiral catalyst system that can directly employ the
commercially available compounds, such as alkynes and α-halo
15]
Transition-metal-catalyzed
cross-coupling
reactions
between alkyl electrophiles and prefunctionalized nucleophiles,
such as organozinc, organoboron, Grignard and organosilane
reagents, with a nonsymmetrical ligands have been one of the
most powerful tools for the synthesis of enantioenriched
products. [ Among these reactions, coupling of α-halocarbonyl
and carbonyl-like compounds (such as nitriles, sulfonates,
phosphates, amides and so forth) is noteworthy because the
resulting α-functionalized carbonyl compounds are versatile
building blocks in organic synthesis.[ Although significant
progresses have been made on the α-functionalization of
1]
carbonyl compounds, leading to enantioenriched
alkynylcarbonyls is still highly desired.
α-
We herein report the copper-catalyzed asymmetric
Sonogashira cross-coupling to generate β, γ-alkynyl amides (eq.
4). This reaction enables the enantioselective coupling of α-halo
amides with unfunctionalized terminal alkynes. We demonstrate
this coupling’s utilities as many manipulations can be applied to
the alkyne functionalities. Preliminary mechanistic investigations
suggest the formation of alkyl radical species.
2]
3
[3]
2 [4]
carbonyl groups with both C(sp )
and C(sp )
coupling
partners, relatively limited reports are available for the C(sp)
ones, presumably due to the facile side reactions occurring on
alkynes.[ Given the fact that internal alkynes are important
5]
[
6]
motifs in natural and bioactive molecules as well as functional
materials,[ the methodology development of introduction of the
C≡C moiety has been attracting continuous attention from the
7]
[
8]
synthetic community.
In 2003, Fu et al. pioneered a method of coupling terminal
alkynes with unactivated primary bromides and iodides by using
catalytic amounts of both palladium and copper salts combined
with N-heterocyclic carbene ligands.[9] It inspired chemists to
explore other metal/ligand systems to couple more challenging
secondary alkyl halides, and α-carbonyl halides as well. Lei
group and others reported the coupling of alkynylmetallic
species (alkynylstannanes and alkynyltrifluoroborates) with α-
halo carbonyl compounds through the Pd-catalyzed Stille and
Suzuki reactions (Scheme 1, eq. 1).[10] Oshima and others
realized the reaction of gallium or indium acetylides with α-halo
carbonyl compounds through
fragmentation process. Fu, Wang and others showed that the
a tandem radical addition-
[
11]
Cu could catalyze the reaction between alkynes and
a
carbenoid intermediate.[
12]
diazocarbonyl compounds via
Nishikata group developed a Cu-catalyzed Sonogashira type
Scheme 1. The synthesis of α-alkynyl carbonyl compounds
[
[
*]
X. Mo, B. Chen, Prof. Dr. G. Zhang
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Center for Excellence in Molecular
Synthesis, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.
China
Adopted the conditions from our previous study on
[16]
enantioselective arylalkynylation of alkenes, our investigations
began with reaction of commercially available racemic N-benzyl-
2-bromo-N-phenylpropionamide and ethynylbenzene to make β,
E-mail: guozhuzhang@sioc.ac.cn
γ-alkynyl amide c1 using a variety of chiral ligands in the
presence of copper salt and base (Table 1, entries 1-8). We
tested a variety of Cbzbox with different substituents (L1–L3).
However, no better results in terms of ee were obtained (Table 1,
entries 1–3). Surprisingly, we were pleased to find that the
reaction using CuI as catalyst, iPr-BOPA L4 as ligand and
**]
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202000860
COMMUNICATION
o
K
3
PO
4
as base provided the desired product c1 with 76% ee, in
mesitylpropanamide and 2.0 equiv of ethynylbenzene at -10 C
in CH
[
17]
80% yield (Table 1, entry 4).
3
CN, catalyzed by 10 mol% CuI and 10 mol% iPr-BOPA L4
(
Table 1, entry 11).
Table 1. Optimization of the reaction conditions.
Under the optimized conditions, the coupling reactions
between racemic α-bromoamide with various alkynes were
examined (Table 2). Firstly, a range of substituted aryl alkynes
were evaluated to identify the generality of the method with
respect to this substrate. In this regard, α-alkynylation
proceeded smoothly with N,N-dimethylamino-, methoxy-, alkyl-,
and halogen-substituted arylalkynes (products c5-c13). In
addition to aromatic alkynes, a number of alkyl-substituted
alkynes (products c14, c15) and cycloalkyl- (products c16, c17)
proved to be good substrates for the coupling reaction. Silyl
subsituted alkynes (c18, c19) were also tolerated, and the
corresponding products were obtained in good yields with
excellent
enantioselectivities.
Notably,
3-ethynylestrone
containing carbonyl group and four continuous chiral centers
resulted in the desired product in 70% yield and > 20:1 dr by this
method (c20).
entry[a]
R ，R
1
2
catalyst
ligand
ee%
yield%[b]
Table 2. Scope studies with alkynes. [a][b]
1
2
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Ph (b1)
Bn, Mes (b2)
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L7
L8
L4
L4
L4
13
13
3
67 (c1)
86 (c1)
55 (c1)
80 (c1)
60 (c1)
0
3
4
76
40
-
5
6
7
-
0
8
-
0
9[c]
87
89
94
76 (c1)
45 (c1)
84 (c2)
1
1
1
1
1
0[d]
1[c]
2[c]
3[c]
4[c]
Bn, 4-FC
Bn, Bn (b4)
Ph(CH , H (b5)
6
H
4
(b3)
CuI
CuI
CuI
L4
L4
L4
83
41
0
80 (c3)
70 (c4)
0
2 3
)
[
a] The reaction conditions were α-halo amides (0.1 mmol), alkyne (0.2
mmol), Cu(I) (10 mol%), ligand (10 mol%), base (0.2 mmol), in CH
3
CN(1.0 mL)
at 25 C for 24 h unless noted otherwise. [b] The yields were measured by 1
o
H
[a] Unless noted otherwise, reactions were performed in CH CN ( 0.1 M) at -
3
NMR analysis using 1,3,5-trimethoxybenzene as internal standard. The ee
10
o
C; [b] Yields of isolated products are given. The ee values were
values were determined by HPLC analysis on a chiral stationary phase. [c]
determined by HPLC analysis on a chiral stationary phase. [c] Reactions at rt.
Ar = 2,4,6-trimethyl phenyl; PMB = p-Methoxbenzyl.
o
Reactions were performed in CH
performed in CH
3
CN ( 0.1 M) at -10 C. [d] Reactions were
o
3
CN ( 0.1 M) at -20 C.
According to the condition studies, disubsituted α-
bromoamide with a sterically demanding aryl group (2,4,6-
trimethyl phenyl in this case) are critical for good stereocontrol.
Thus, fixing of the aryl substitution, the substituent on the
nitrogen of the amide can be an electron-rich or an electron-poor
benzyl groups (c21 to c26), or it can be an alkyl group (c27 and
c28). Based on single crystal X-Ray analysis of c24, the
absolute configuration of the cross-coupling product was (S).
Thiophene and naphylnene could be tolerated as well (c29 and
c30). We next explored the use of different alkyl groups attached
to the α-carbon of the bromo amide substrates. When the α-alkyl
was Et or nBu, 72–75% yields with the ee up to 99% were
obtained (c31 and c32). However, the current catalytic process
was unsatisfactory with other α-bromocarbonyl compounds.
Reactions of ɑ-bromo ester and ketone didn’t provide the
L5 and L6 exhibited lower enantioselectivities (entries 5 and
). Further examination of chiral ligands revealed that Pybox L7
6
and privileged box L8 were not effective for current reaction
o
(
entries 7 and 8). Lowering the reaction temperature to -10 C
further improved the ee to 90% with no compromise in product
yield (entry 9). Further adjustment of the reaction parameters
2
showed that the steric demand of R plays an important role in
improving the efficiency of the cross-coupling process. The
o
reaction of b2 with a mesitylene subsititution at -10 C provide
c2 in 84% yield and 94% ee (entry 11). Dialkyl tertiary amide
and secondary amide are less efficient substrates for this
reaction (entries 13 and 14). The tuning of other parameters
such as changing the solvent to something other than
3 4
acetonitrile, using other bases in place of K PO and other Cu-
desired products, homocoupling products dominated with small
catalysts instead of CuI was elaborated in Tables S1 to S5 (see
the Supporting Information). The optimized reaction conditions
was thus determined to be 1.0 equiv of N-benzyl-2-bromo-N-
[18]
amount of allenyl derivative.
Reaction of ɑ-bromo nitrile
provide the vinyl bromide as the major product which is derived
from atom transfer radical addition pathway.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202000860
COMMUNICATION
Table 3. Scope studies with α-carbonyl compounds. [a][b]
Scheme 2. Mechanistic investigation.
[
13], [15]
Based on the literature
and these findings, we
proposed a reaction mechanism (Fig. 1). The Cu(I)X undergoes
ligand exchange with L in the presence of base leading to
tridentate complex Cu(I)L.[
19]
[21]
A subsequent interaction with
-
+
RC≡CH in the presence of K
3
4
PO yields [LCu(I)(C≡CR)] K (A),
which could reduce the α-bromoamide to provide a copper(II)
species LCu(II)(C≡CR) with a simultaneous formation of an alkyl
radical (B). The cyclic voltammogram of LCu(I) C≡CPh show a
reversible wave at -2.58V versus the saturated calomel
electrode (SCE) corresponding to the Cu (I)/Cu (II) redox
[
a] All reactions were performed in CH
3
CN (0.1 M) at -10 oC. [b] Yields of
isolated products are given. The ee values were determined by HPLC analysis
on a chiral stationary phase. [c] Reactions were at rt.
couple.[
22a,
22b]
)Br) have
Those results
2 3
The alkyl bromides (MeO CCH(CH
reduction potential E1/2 = -0.68V versus SCE.[
22c]
Control experiments were conducted to probe the possible
mechanism of this copper catalysed coupling reaction (Scheme
2
suggest that the SET process form copper acetylide to α-
). The reaction of CuX and ethynylbenzene in the presence of a
bromoamide may be viable, an halogen atom abstraction is also
[
19a]
[23] [24]
[13]
base readily give copper acetylide A1.
A1 did not react with
possible.
Two possible pathways might be as follows: In
b2 in the absence of BOPA ligand or base, suggesting both
factors are crucial for the coupling reaction taking place
path a, the alkyl radical reacts with copper(II), delivering a
copper(III) complex (C), which undergoes reductive elimination
to generate the product, with regeneration of the catalyst.
Alternatively, in path b, the alkyl radical could undergo direct out-
of-cage bond formation with the copper(II) species to provide the
same result.
(
3 4
Scheme 2, eq. 5). In the presence of K PO (1.0 equiv) with
ligand (1.0 equiv), c2 was generated in 67% yield and 95% ee.
This result suggests that A1 is likely the key intermediate in this
reaction. We also added TEMPO to these reaction mixtures, 10
mol% of TEMPO was enough to shut down the reaction (eq. 6).
Reaction of b18 provide the cyclized product d1 in cis selectivity
(
eq. 7), a typical reactivity and stereoselectivity that have been
reported for the cyclization of the derived secondary alkyl
radical.[ Those results implied that free-radical species may be
generated during the reaction, which is in sharp contrast to the
20]
1
,10-phen and copper catalyzed alkynylation of tertiary α-
[
13][18]
bromoamide.
Consistent with our hypothesis that an
enantioconvergent process is involved, the choice of either
S,S)-L4 or (R,R)-L4 as the chiral ligand leads to the formation
(
of opposite enantiomers of the desired product with the
stereochemical outcome determined entirely by the configuration
of the ligand (eq. 8). Enantiomericaly pure ent-b2 reacted well,
analysis of the remaining bromide revealed a significant erosion
of the enantiopurity, suggesting a fast racemization of an alkyl
bromide (eq. 9). To gain more insight into the mechanism, we
monitored the ee of the product as a function of the ee of the
ligand (see the Supporting Information). The near linear
relationship may indicate only one chiral ligand is involved in the
enantiodetermining step.
Figure 1. Proposed reaction mechanism.
β, γ-alkynyl amides are a particularly interesting class as the
two functional groups have widely orthogonal reactivity, making
them highly versatile intermediates in complex molecule
synthesis. To illustrate the synthetic utility of the β, γ-alkynyl
amide products, several derivatization reactions of product were
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202000860
COMMUNICATION
pursued. As shown in Scheme 3 (eq. 10), the desilylation[25] by
Buchwald, J. Am. Chem. Soc. 2000, 122, 1360; i) D. A. Culkin, J. F. Hartwig,
Acc. Chem. Res. 2003, 36, 234.
2 6
catalytic H SiF occurred smoothly to give free terminal alkyne
e1 with maintenance of enantiopurity. Treatment of c2 with
catalytic TBD led to a strained bridged polycyclic lactam f1, [26]
however, in racemic form (eq. 11). The 1,4-diketone g1 could be
readily obtained by acidic hydration (eq. 12).[27]
[5] Alkylative Sonogashira primary-alkylation: a) M. Eckhardt, G. C.Fu, J. Am. Chem.
Soc. 2003, 125, 13642; b) O.Vechorkin, D. Barmaz, V. Prous, X. Hu, J. Am.
Chem. Soc. 2009, 131, 12078; c) P. M. Pꢀrez García, P. Ren, R. Scopelliti, X. Hu,
ACS Catal. 2015, 5, 1164; d) F.-X. Luo, X. Xu, D. Wang, Z.-C. Cao, Y.-F.
Zhang, Z.-J. Shi, Org. Lett. 2016, 18, 2040; e) L. Jin, W. Hao, J. Xu, N. Sun, B.
Hu, Z. Shen, W. Mo, X. Hu, Chem. Commun. 2017, 53, 4124; Secondary-
alkylation: f) G. Altenhoff, S. Würtz, F. Glorius，Tetrahedron Lett. 2006, 47,
2
925; g) J. Yi, X. Lu， Y.-Y. Sun, B. Xiao, L. Liu, Angew. Chem. Int. Ed. 2013,
2, 12409; Angew. Chem. 2013, 125, 12635.
5
[
6] a) Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; Wiley: New
York, 1994; b) J. Liu, J. W. Y. Lam, B. Z. Tang, Chem. Rev. 2009, 109, 5799; c)
H. K. Bisoyi, S. Kumar, Chem. Soc. Rev. 2010, 39, 264.
[
7] a) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
Germany, 1995; (b) M. C. Willis, Chem. Rev. 2010, 110, 725; (c) P. Siemsen, R.
C. Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39, 2632; Angew.
Chem. 2000, 112, 2740.
[
8] B. M. Trost and C.-J. Li, Modern Alkynes Chemistry: Catalytic and Atom-
Economic Transformations, ed, B. M. Trost and C.-J. Li, Wiley-VCH, Weinheim,
014, p. 424.
[9] M. Eckhardt, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 13642.
2
Scheme 3. Synthetic utilities of β, γ-alkynyl amide
[
10] a) W. Shi, C. Liu, Z. Yu, A. Lei, Chem. Commun. 2007, 2342; b) J. Y. Kang, B. T.
Connell, J. Org. Chem. 2011, 76, 6856; c) G. A. Molander, K. M. Traister, Org.
Lett. 2013, 15, 5052.
In conclusion, a general and highly effective, Cu-catalyzed
enantioselective alkynylation of α-bromo amide have been
achieved. This reaction can be applied to a variety of amides
and a broad range of terminal alkynes. An unusual mono-anionic
NNN pincer ligand (BOPA) accounts for the high efficiency and
stereoselectivity. Owing to the ready availability of starting
material, mild reaction conditions, the significance of resulting
functionalities, and high enantioselectivity, the application of this
novel strategy established here in synthetic and medicinal
chemistry is positively expected.
[11] a) S.-i. Usugi, H. Yorimitsu, H. Shinokubo, K. Oshima, Bull. Chem. Soc. Jpn.
2002, 75, 2687; b) K. Takami, S.-i. Usugi, H. Yorimitsu, K. Oshima, Synthesis
2005, 824; c) T. Hirashita, A. Hayashi, M. Tsuji, J. Tanaka, S. Araki,
Tetrahedron 2008, 64, 2642.
[12] a) A. Suárez, G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 3580; Angew. Chem.
2004, 116, 3664; b) G. Liu, G. Xu, J. Li, D. Ding, J. Sun, Org. Biomol. Chem.
2014, 12, 1387; c) M. L. Hossain, F. Ye, Y. Zhang, J. Wang, Tetrahedron 2014,
70, 6957; d) M. L. Hossain, F. Ye, Y. Zhang, J. Wang, J. Org. Chem. 2013, 78,
1
236; e) L. Zhou, J. Ma, Y. Zhang, J. Wang, Tetrahedron Lett. 2011, 52, 5484.
[
13] Y. Yamane, N. Miwa, T. Nishikata, ACS Catal. 2017, 7, 6872.
14] a) W. Liu, L. Li, C.-J. Li, Nat. Commun. 2015, 6, 6526; b) W. Liu, Z. Chen, L. Li,
H. Wang, C.-J. Li, Chem. Eur. J. 2016, 22, 5888.
[
-
Acknowledgements
[15] X.-Y. Dong, Y.-F. Zhang, C.-L. Ma, Q.-S. Gu, F.-L. Wang, Z.-L. Li, S.-P. Jiang,
We are grateful to NSFC-21772218, 21421091, XDB20000000,
the “Thousand Plan” Youth program, State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, and the Chinese Academy of Sciences.
X.-Y. Liu, Nat. Chem. 2019, 11, 1158.
[16] G. Lei, H. Zhang, B. Chen, M. Xu, G. Zhang, Chem. Sci. 2020, 11, 1023.
[17] a) H. A. McManus, P. J. Guiry, J. Org. Chem. 2002, 67, 8566; b) H. A. McManus,
P. G. Cozzi, P. J. Guiry, Adv. Synth. Catal. 2006, 348, 551; c) G. C. Hargaden, H.
A. McManus, P. G. Cozzi, P. J. Guiry, Org. Biomol. Chem. 2007, 5, 763.
[
18] Y. Lv, W. Pu, X. Zhu, T. Zhao, F. Lin, Adv. Synth. Catal. 2018, 360, 1397–1401
19] (a) K. Jouvin, J. Heimburger, G. Evano, Chem. Sci. 2012, 3, 756. (b) F. Monnier,
F. Turtaut, L. Duroure, M. Taillefer, Org. Lett. 2008, 10, 3203.
20] J. Lusztyuk, B. Maillard, S. Deycard, D. A. Lindsay, K. U. Ingold, J. Org. Chem.
1987, 52, 3509.
Keywords: Copper-catalysed • Sonogashira reaction
[
•Enantioselective • α-Bromoamide • Terminal alkyne
[
[
1] Alan H. Cherney, Nathaniel T. Kadunce, and Sarah E. Reisman Chem. Rev. 2015,
15, 9587−9652 and references therein.
1
[21] Q.-H. Deng, H. Wadepohl, L. H. Gade, J. Am. Chem. Soc. 2012, 134, 2946.
[22] a) V. W.-W.Yam, K. Kam-Wing Lo,K.Man-Chung Wong, J. Organomet. Chem.
1999, 578, 3. b) A. Sagadevan, A. Ragupathi, and K. C. Hwang, Angew. Chem.
Int. Ed. 2015, 54, 13896; Angew. Chem. 2015, 127, 14102. c) A. A. Isse, C. Y.
Lin, M. L. Coote, A. Gennaro, J. Phys. Chem. B 2011, 115, 678.
[23] a) X. Chen, X. Liu, J. T. Mohr, J. Am. Chem. Soc. 2016, 138, 6364; b)T. Xu, X.
Hu, Angew. Chem., Int. Ed. 2015, 54, 1307. 1323. Angew. Chem. 2015, 127,
1323.
[
2] a) B. M. Stoltz, N. B. Bennett, D. C. Duquette, A. F. G. Goldberg, Y. Liu, M. B.
Loewinger, C. M. Reeves, in Comprehensive Organic Synthesis II, 2nd ed. (Ed.:
P. Knochel), Elsevier, Amsterdam, 2014, pp.1; b) R. Fern.ndez de La Pradilla, A.
Viso, in Comprehensive Organic Synthesis II, 2nd ed. (Ed.: P. Knochel), Elsevier,
Amsterdam, 2014, pp. 157.
[
3] a) C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594; b) D. A. Evans, M. D.
Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104, 1737; c) A. G. Myers, B. H.
Yang, H. Chen, L. McKinstry, D. J. Kopecky, J. L. Gleason, J. Am. Chem. Soc.
[24] a) H. Yin, R. J. Carroll, J. M. Anna, E. J. Schelter, J. Am. Chem. Soc. 2015, 137,
9234−9237; b) J. D. Nguyen, E. M. D'Amato, J. M. R. Narayanam, C. R. J.
Stephenson, Nat. Chem. 2012, 4, 854
1
997, 119, 6496.
[4] a) P. M. Lundin, J. Esquivias, G. C. Fu, Angew. Chem. Int. Ed. 2009, 48, 154;
Angew. Chem. 2009, 121, 160; b) S. Lou, G. C. Fu, J. Am. Chem. Soc. 2010, 132,
[25] D. Lasꢁnyi, G. L. Tolnai, Org. Lett. 2019, 21, 10057.
1
264; c) S. Lou, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 5010; d) P. M. Lundin,
[26] J. K. Lam, H. V. Pham, K. N. Houk, C. D. Vanderwal, J. Am. Chem. Soc. 2013,
135, 17585.
G. C. Fu, J. Am. Chem. Soc. 2010, 132, 11027; e) J. Choi, P. Martín-Gago, G. C.
Fu, J. Am. Chem. Soc. 2014, 136, 12161; f) C. Liu, S. Tang, D. Liu, J. Yuan, L.
Zheng, L. Meng, A. Lei, Angew. Chem. Int. Ed. 2012, 51, 3638; Angew. Chem.
[27] M. Wang, H. Zhang, J. Liu, X. Wu, C. Zhu, Angew.Chem.Int. Ed. 2019, 58,
17646. Angew.Chem. 2019, 131, 17810.
2
012, 124, 3698; g) T. Nishikata, Y. Noda, R. Fujimoto, T. Sakashita, J. Am.
Chem. Soc. 2013, 135, 16372; h) J. M. Fox, X. Huang, A. Chieffi, S. L.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202000860
COMMUNICATION
Layout 2:
COMMUNICATION
Xueling Mo, Bin Chen and Guozhu
Zhang*
Page No. – Page No.
Copper-Catalyzed Enantioselective
Sonogashira Type Coupling of
Alkynes with α-Bromoamides
An asymmetric copper-catalyzed Sonogashira type coupling between alkynes and
α-bromo amide compounds has been developed. This method represents a facile
approach to synthetically useful β,γ-alkynyl amides from two readily available
starting materials in
a
highly enantioselective manner.
A
bisoxazoline
diphenylanaline(BOPA) serve as the effective chiral ligand. Preliminary mechanistic
investigations suggest the formation of alkyl radical species.
This article is protected by copyright. All rights reserved.