Copper-Catalyzed Asymmetric Coupling of Allenyl Radicals with Terminal Alkynes to Access Tetrasubstituted Allenes

Article abstract of DOI:10.1002/anie.202013022

In contrast to the wealth of asymmetric transformations for generating central chirality from alkyl radicals, the enantiocontrol over the allenyl radicals for forging axial chirality represents an uncharted domain. The challenge arises from the unique elongated linear configuration of the allenyl radicals that necessitates the stereo-differentiation of remote motifs away from the radical reaction site. We herein describe a copper-catalyzed asymmetric radical 1,4-carboalkynylation of 1,3-enynes via the coupling of allenyl radicals with terminal alkynes, providing diverse synthetically challenging tetrasubstituted chiral allenes. A chiral N,N,P-ligand is crucial for both the reaction initiation and the enantiocontrol over the highly reactive allenyl radicals. The reaction features a broad substrate scope, covering a variety of (hetero)aryl and alkyl alkynes and 1,3-enynes as well as radical precursors with excellent functional group tolerance.

Full text of DOI:10.1002/anie.202013022

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Copper-Catalyzed Asymmetric Coupling of Allenyl Radicals with
Terminal Alkynes to Access Tetrasubstituted Allenes
Authors: Xiao-Yang Dong, Tian-Ya Zhan, Sheng-Peng Jiang, Xiao-
Dong Liu, Liu Ye, Zhong-Liang Li, Qiang-Shuai Gu, and Xin-
Yuan Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013022
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10.1002/anie.202013022
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Copper-Catalyzed Asymmetric Coupling of Allenyl Radicals with
Terminal Alkynes to Access Tetrasubstituted Allenes
Xiao-Yang Dong+, Tian-Ya Zhan+, Sheng-Peng Jiang, Xiao-Dong Liu, Liu Ye, Zhong-Liang Li, Qiang-
Shuai Gu, and Xin-Yuan Liu*
Dedicated to the 70th anniversary of the Shanghai Institute of Organic Chemistry
[*]
X.-Y. Dong,[+] T.-Y. Zhan,[+] Dr. S.-P. Jiang, Dr. X.-D. Liu, Prof. Dr. X.-Y. Liu
Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis
Southern University of Science and Technology, Shenzhen 518055 (China)
E-mail: liuxy3@sustech.edu.cn
Dr. L. Ye, Dr. Z.-L. Li, Dr. Q.-S. Gu
Academy for Advanced Interdisciplinary Studies and Department of Chemistry
Southern University of Science and Technology, Shenzhen 518055 (China)
These authors contribute equally to this work.
[+]
Supporting information for this article can be found under: https://doi.org/10.1002/anie.2020XXXX.
Abstract: In contrast to the wealth of asymmetric transformations for
generating central chirality from alkyl radicals, the enantiocontrol
over the allenyl radicals for forging axial chirality represents an
uncharted domain. The challenge arises from the unique elongated
linear configuration of the allenyl radicals that necessitates the
stereo-differentiation of remote motifs away from the radical reaction
site. We herein describe a copper-catalyzed asymmetric radical 1,4-
carboalkynylation of 1,3-enynes via the coupling of allenyl radicals
with terminal alkynes, providing diverse synthetically challenging
tetrasubstituted chiral allenes. A chiral N,N,P-ligand is crucial for
both the reaction initiation and the enantiocontrol over the highly
reactive allenyl radicals. The reaction features a broad substrate
scope, covering a variety of (hetero)aryl and alkyl alkynes and 1,3-
enynes as well as radical precursors with excellent functional group
tolerance.
catalysts to achieve the enantiocontrol over allenyl radical
species for the expedient assembly of diverse tetrasubstituted
chiral allenes is still highly desirable.
In the past decades, tremendous progress has been made
in the development of asymmetric catalysis to realize
enantioselective
radical
reactions
for
synthesis
of
enantioenriched molecules.[1,2] Among innovative approaches,
chiral first-row transition metal catalysis represents an appealing
strategy for generating central chirality from mostly sp2-
hybridized planar alkyl radical species (Scheme 1A, left).[2] In
contrast, the sp-hybridized allenyl radicals feature a linear
geometry with two flanking substituents far away from the radical
reaction sites,[3] thus rendering the enantiocontrol over such
radicals to forge axial chirality difficult and significantly
unexplored (Scheme 1A, right).[4,5] On the other hand, axially
chiral allenes not only are important structural motifs in natural
products, bioactive molecules, and functional materials, but also
serve as versatile synthons, ligands, and catalysts in organic
synthesis.[6] In this context, although many elegant strategies
have been described for the synthesis of chiral di- and
trisubstituted allenes,[7] only a limited number of approaches
have been reported for the synthesis of tetrasubstituted chiral
allenes based on metal catalysis[8] and organocatalysis.[9]
Moreover, most of these methodologies rely on substrates with
particular polar functional groups and/or kinetic resolution
processes, which arguably impedes their wide applications in
organic synthesis.[8,9] Therefore, the development of robust
Scheme 1. Motivation and design of enantioselective alkynylation of allenyl
radicals to access tetrasubstituted chiral allenes.
As our continuous efforts in copper-catalyzed asymmetric
radical reactions,[2e,2f,10] we have demonstrated that
a
copper/chiral N,N,P-ligand catalyst is robust for the
enantiocontrol over sp2-hybridized alkyl radicals to construct
chiral C(sp3)−C(sp) bonds with terminal alkynes (Scheme 1B).[11]
We speculated that such a strategy might also be suitable for
the enantiocontrol over the sp-hybridized allenyl radicals to
construct tetrasubstituted chiral allenes. Given the easy
availability of alkyl halides and terminal alkynes, along with the
ubiquity of 1,3-enynes,[5] we targeted the development of an
asymmetric radical 1,4-difunctionalization of 1,3-enynes with
alkyl halides as the radical precursors and terminal alkynes as
1
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the nucleophiles (Scheme 1C). However, several challenges
have to be solved: (1) the aforementioned unexplored
enantiocontrol over the highly reactive allenyl radicals; (2) the
identification of a suitable ligand to initiate the reaction; (3) the
inhibition of easily occurring side reactions, such as the Glaser
homocoupling of terminal alkynes,[12] the cross-coupling of alkyl
halides with terminal alkynes,[11a] and 1,2-carboalkynylation of
alkynes.[13] Herein, we describe the development of a copper-
With the optimal reaction conditions established, the
substrate scope of alkynes was then investigated. As shown in
Table 1, a number of aryl alkynes were applicable to the reaction,
providing the chiral allenes 4−20 in 64−99% yields with 91−93%
ee. A myriad of electron-donating or -withdrawing substituents,
such as methoxyl (6−8), halo (10−13), trifluoromethyl (14), formyl
(15), methoxylcarbonyl (16), nitro (17), and pinacolborato (18),
at para, meta, or ortho positions of the phenyl rings were
tolerated under the standard conditions. The aryl alkynes with a
naphthalene ring (19) and a ferrocene ring (20) were also
amenable to the 1,4-carboalkynylation reaction. More
importantly, heteroaryl alkynes containing heterocycles
commonly existing in therapeutics—such as pyridine, thiophene
and benzo[b]furan—were suitable for the reaction to afford the
desired products 21−23 with 85−93% ee. Notably, many alkyl
alkynes with aliphatic chains or a series of functionalities, such
as chloride, carbazole, imide, sulfonimide, nitrile, acetal, free
alcohol as well as silicon, underwent the reaction smoothly to
deliver 24−35 in good to excellent yields with excellent ee.
catalyzed
three-component
asymmetric
radical
1,4-
carboalkynylation of 1,3-enynes, providing straightforward
access to diverse tetrasubstituted chiral allenes.
We initiated our investigation by searching for a suitable
ligand for the 1,4-carboalkynylation of 2-phenyl-1,3-enyne 1a
with alkyne 3a and ethyl α-bromoisobutyrate 2a. A screening of
bidentate ligands (L1−L4) with CuTc as the catalyst indicated
very low reaction efficiency, presumably due to the insufficient
reducing capability of the copper complex (Scheme 2 and Table
S1, entries 1−5). Thus, we next examined the more electron-rich
N,N,P-tridentate ligand L5 and found that the reaction provided
product 4 in 61% yield, along with side products 4' and 4''
(Scheme 2 and Table S1, entry 6).[14] We then evaluated a
series of chiral cinchona alkaloid-derived N,N,P-ligands (L6−10)
with diverse substituents at different positions of the P-phenyl
rings and found that L10 with an isopropyl group on the ortho
position proved to be the best (Scheme 2 and Table S1, entries
7−11). The ratios of starting materials also affected the ratio
between the desired product and side products and the reaction
of 1a, 2a, and 3a in a molar ratio of 1.5:1.2:1.0 gave the sole
product 4 with excellent enantioselectivity (Table S1, entry 12).
Further evaluation of different copper salts, solvents, and
catalyst loadings led to the discovery of the optimal conditions
as follows: the reaction in the presence of 10 mol% CuTc and
L10 with 4.0 equivalents of Cs2CO3 in Et2O at room temperature
for 24 h provided 4 in 98% yield and 92% ee (Table S1, entry
20). An experiment with the L11, which is the pseudoenantiomer
of L10, gave the enantiomer ent-4 in 88% yield with 88% ee.
Table 1. Substrate scope of alkynes.[a]
Ph
CuTc (10 mol%)
O
1a
L10 (10 mol%)
+
Cs2CO3 (4.0 equiv.)
OEt
H
OEt
R
Br
Et2O, rt
Ph
R
O
2a
4–35
3
aryl and heteroaryl alkynes
MeO
OMe
NC
MeO
4
5
6
7
8
94%, 92% ee
93%, 93% ee[b] 99%, 93% ee[b] 89%, 93 % ee[b] 79%, 91% ee[b]
F
Me
Br
F
F
9
10
11
12
13
93%, 93% ee[b] 88%, 93 % ee
83%, 92% ee
72%, 92% ee
82%, 93 % ee
Bpin
O2N
MeO2C
F3C
OHC
17
18
15
16
14
98%, 91% ee
83%, 91% ee
92%, 92% ee
93%, 93% ee
98%, 91% ee
Fe
S
MeO
N
O
23
19
20
21
22
98%, 93% ee
64%, 93% ee 62%, 93% ee 32%, 85% ee
82%, 91% ee
alkyl alkynes
Cy
Me
Cl
26, 55%, 93% ee[c]
25, 61%, 93% ee[c]
27, 77%, 93% ee[c]
24, 70%, 94% ee[c]
O
SO2Ph
CN
Ph
N
N
N
PhO2S
Ph
O
28, 97%, 92% ee[d] 29, 85%, 93% ee[d]
30, 44%, 91% ee[d]
[d]
31, 88%, 92% ee
EtO
TIPS
TMS
HO
OEt
35, 79%, 94% ee[c]
33, 44%, 93% ee[c]
34, 89%, 94% ee[c]
[d]
32, 97%, 92% ee
[a] Reaction conditions: 1a (0.30 mmol), 2a (0.24 mmol), 3 (0.20 mmol), CuTc
(10 mol%), L10 (10 mol%), and Cs2CO3 (4.0 equiv.) in Et2O (4.0 mL) at room
temperature for 24 h under argon; the yields are isolated and the ee values
were determined by HPLC. [b] Cs2CO3 (6.0 equiv.). [c] CuTc (15 mol%), PPh3
(45 mol%). [d] CuTc (15 mol%).
Scheme 2. The effect of different ligands for model reaction.
2
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We then switched our attention to the scope of substituted
1,3-enynes (Table 2). Many 1,3-enynes with 2-phenyl rings
bearing functional groups, such as (bis)methoxy, bromo,
trifluoromethyl, nitrile, and alkyne, at different positions and even
a naphthalene ring were well compatible with the mild reaction
conditions, delivering tetrasubstituted chiral allenes 36−43 with
88−98% ee. The 1,3-enynes containing medicinally relevant
heterocycles, such as pyridine (44), thiophene (45), pyrimidine
(46), and thiazole (47), were viable substrates to give the
desired products with good to excellent ee. With respect to the
4-substituents, the 1,3-enynes having benzyl or purely aliphatic
functional groups provided 48−53 in excellent yields with
80−96% ee. Notably, many functionalities, such as alkene,
chloride, free alcohol, ester, amide as well as imide, at different
distances away from the allenyl radicals were well tolerated to
generate the chiral allenes 54−59 with up 91% ee. The absolute
configurations of 58 have been determined by chiroptical
methods (See Supporting Information for details) and other
products were assigned by analogy thereafter.
carbonyl compounds.[15] Furthermore, with bromide 2d as the
radical precursor, the reaction proceeded smoothly to yield 62 in
88% yield with 91% ee. Importantly, alkyl chlorides 2e−2h were
also viable radical precursors to generate diversely
functionalized chiral allenes 63−66 with excellent ee. Notably,
the Togni’s reagent 2i was also a suitable radical precursor to
provide 56 and 57 with
trifluoromethyl moiety.[16]
a
pharmaceutically important
Table 3. Substrate scope of radical precursors.[a]
Table 2. Substrate scope of 1,3-enynes.[a]
[a] Reaction conditions: 1a (0.30 mmol), 2 (0.24 mmol), 3 (0.20 mmol), CuTc
(10 mol%), L10 (10 mol%), and Cs2CO3 (4.0 equiv.) in Et2O (4.0 mL) at room
temperature for 24 h under argon; the yields are isolated and the ee values
were determined by HPLC. [b] CuTc (15 mol%).
To provide insights into the reaction mechanism, we
conducted control experiments. When the radical scavenger
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was added, the
reaction was completely inhibited, implying a possible radical
pathway (Scheme S1 in Supporting Information). To probe the
reaction intermediates, we carried out the radical clock
experiment with substrate 69. The reaction furnished the ring-
opening product 70 in 32% yield, indicating the involvement of a
propargyl radical, the resonance form of an allenyl radical, in this
process (Scheme 3A). In addition, the reaction of copper
phenylacetylide in the presence of L10 proceeded as well to
afford 5 in 40% yield with 93% ee, suggesting the possible
intermediacy of copper acetylide (Scheme 3B). Based on the
above observations and our previous reports,[11] we proposed a
possible mechanism (Scheme 3C). Under basic conditions, CuI,
L10, and alkyne reacted to afford the complex I, which next
reduced 2, simultaneously generating the CuII complex II and an
alkyl radical (⋅R4). The addition of this alkyl radical to the alkene
moiety of 1,3-enyne 1 provided the propargyl radical III and its
resonance structure trisubstituted allenyl radical IV. Afterwards,
the allenyl radical IV reacted with the CuII complex II to give rise
[a] Reaction conditions: 1 (0.30 mmol), 2a (0.24 mmol), 3a (0.20 mmol), CuTc
(10 mol%), L10 (10 mol%), and Cs2CO3 (4.0 equiv.) in Et2O (4.0 mL) at room
temperature for 24 h under argon; the yields are isolated and the ee value was
determined by HPLC.
These results encouraged us to investigate the scope of
radical precursors (Table 3). The commercially available tert-
butyl α-bromoisobutyrate 2b was applicable to this
transformation, furnishing 60 in 81% yield with 93% ee.
Importantly, the Weinreb amide-type bromide 2c was also
suitable for the reaction to provide 61 in 91% yield with 89% ee,
of which the amide group could be easily transformed to other
3
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Scheme 3. Mechanistic studies and proposal.
In summary, we have described a copper-catalyzed three-
component asymmetric radical 1,4-carboalkynylation of 1,3-
enynes, providing an efficient tool for the construction of diverse
tetrasubstituted chiral allenes from easily available starting
materials. The key to the success is the strategic utilization of a
cinchona alkaloid-derived N,N,P-ligand to enhance the reducing
capability of copper catalyst for reaction initiation and further
achieve the enantiocontrol over the structurally unique allenyl
radical. A wide range of (hetero)aryl and alkyl alkynes and 1,3-
enynes as well as various readily available radical precursors
are easily accommodated in this reaction. Further extension of
the asymmetric coupling of allenyl radicals to other nucleophiles
and detailed mechanistic studies are ongoing in our laboratory.
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Financial support from the National Natural Science Foundation
of China (Nos. 21722203, and 21831002), Guangdong
Provincial Key Laboratory of Catalysis (No. 2020B121201002),
Guangdong Innovative Program (No. 2019BT02Y335), and
SUSTech Special Fund for the Construction of High-Level
Universities (No. G02216303) are acknowledged. The authors
appreciate the assistance of SUSTech Core Research Facilities.
[9]
Conflict of interest
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G.-X. Xu, Z.-L. Li, L. Ye, X. Zhang, G.-J. Cheng, X.-Y. Liu, Chem 2020,
6, 1692.
The authors declare no conflict of interest.
Keywords: allenes • asymmetric radical reactions • copper •
1,4-enynes • alkyl bromides
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S.-P. Jiang, X.-Y. Liu, Nat. Chem. 2019, 11, 1158; b) Z.-H. Zhang, X.-Y.
4
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5
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Entry for the Table of Contents
Enantiocontrol over allenyl radical: A copper-catalyzed asymmetric radical 1,4-carboalkynylation of 1,3-enynes is realized,
providing diverse tetrasubstituted chiral allenes. The utilization of copper/chiral N,N,P-ligand is crucial for the enantiocontrol over the
allenyl radicals, which is difficult due to their elongated linear configuration that necessitates the stereo-differentiation of remote
motifs away from the reaction site.
6
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