Cobalt-Catalyzed Enantioselective Negishi Cross-Coupling of Racemic α-Bromo Esters with Arylzincs

Article abstract of DOI:10.1002/chem.201705463

The first cobalt-catalyzed enantioselective Negishi cross-coupling reaction, and the first arylation of α-halo esters with arylzinc halides, are disclosed. Employing a cobalt-bisoxazoline catalyst, various α-arylalkanoic esters were synthesized in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield). A diverse range of functional groups, including ether, halide, thioether, silyl, amine, ester, acetal, amide, olefin and heteroaromatics is tolerated by this method. This method was suitable for gram-scale reactions, enabling the synthesis of (R)-xanthorrhizol with high enantiopurity. Radical clock experiments support the intermediacy of radicals.

Full text of DOI:10.1002/chem.201705463

A Journal of
Accepted Article
Title: Cobalt-Catalyzed Enantioselective Negishi Cross-Coupling of
Racemic α-Bromo Esters with Arylzincs
Authors: Feipeng Liu, Jiangchun Zhong, Yun Zhou, Zidong Gao,
Patrick J Walsh, Xueyang Wang, Sijie Ma, Shicong Hou,
Shangzhong Liu, Minan Wang, Min Wang, and Qinghua Bian
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To be cited as: Chem. Eur. J. 10.1002/chem.201705463
Link to VoR: http://dx.doi.org/10.1002/chem.201705463
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10.1002/chem.201705463
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Cobalt-Catalyzed Enantioselective Negishi Cross-Coupling of
Racemic α-Bromo Esters with Arylzincs
Feipeng Liu,[a] Jiangchun Zhong,[a] Yun Zhou,[a] Zidong Gao,[a] Patrick J. Walsh,[b] Xueyang Wang,[a]
Sijie Ma,[a] Shicong Hou,[a] Shangzhong Liu,[a] Minan Wang,[a] Min Wang,[a] Qinghua Bian*[a]
Abstract: The first cobalt-catalyzed enantioselective Negishi cross-
coupling reaction, and the first arylation of -halo esters with arylzinc
halides, are disclosed. Employing a cobalt-bisoxazoline catalyst,
various α-arylalkanoic esters were synthesized in excellent
enantioselectivities and yields (up to 97% ee and 98% yield). A
diverse range of functional groups, including ether, halide, thioether,
silyl, amine, ester, acetal, amide, olefin and heteroaromatics is
tolerated by this method. This method was suitable for gram-scale
reactions, enabling the synthesis of (R)-xanthorrhizol with high
enantiopurity. Radical clock experiments support the intermediacy of
radicals.
(bisoxazoline)Co complexes.[3o] To devise a more functional
group tolerant synthesis of α-arylalkanoic acids, which are an
important class of nonsteroidal anti-inflammatory drugs
(NSAIDs),[8] we herein report the first cobalt-catalyzed
asymmetric Negishi cross-coupling to generate α-arylalkanoic
acids derivatives [Scheme 1, Eq. (3)]. This reaction enables the
previously unrealized coupling of α-halo esters with arylzinc
halides. We demonstrate this coupling’s utility and scalability in
the synthesis of (R)-xanthorrhizol and provide preliminary
mechanistic investigations.
Fu's Nickel catalyzed enantioselective Negishi coupling
R
R'
R
R'
L*Ni cat.
Transition-metal-catalyzed enantioselective cross-coupling
reactions between alkyl electrophiles and organometallic
nucleophiles, such as organozinc,[1] organoboron,[2] Grignard[3]
and organosilane reagents,[4] have emerged as powerful tools
for the construction of tertiary and quaternary stereogenic
centers. Among these reactions, the Negishi cross-coupling of
organozinc reagents exhibits exceptional functional group
tolerance. As a result, significant progress has been made in
broadening the scope of this powerful reaction, including the use
of sp3 hybridized electrophiles.[5] In the realm of enantioselective
Negishi reactions, remarkable progress has been made by Fu
and co-workers using enantioenriched nickel catalysts and
racemic sp3 hybridized electrophiles [Scheme 1, Eq. (1)].[1] In a
complementary approach, enantiospecific Negishi reactions
have been introduced by Jarvo and coworkers, as illustrated in
the conversion of enantioenriched alkyl esters and ethers with
preservation of enantiopurity [Scheme 1, Eq. (2)].[6]
(1)
+
R"ZnX
R"
enantioenriched
X
racemic
R" = aryl, alkyl
R = alkyl, aryl, amide
alkynyl, carbonyl etal
R' = alkyl
Jarvo's Nickel catalyzed enantiospecific Negishi coupling
Ar
achiral Ni
catalyst
Ar
n
+
n
(2)
FG
ZnMe2
FG
LG
enantioenriched
FG = alkene, alkyne, amine
alcohol, ester, and acetal
Me
enantioenriched
This work: Cobalt catalyzed enantioseletive Negishi coupling
Br Ar
CoI2, L*
RO
RO
(3)
+
ArZnBr
Alkyl
Alkyl
O
O
up to 97% ee, 98% yield
racemic
Scheme 1. Transition-metal-catalyzed enantioselective and enantiospececific
Negishi cross-coupling reactions.
The inexpensive and environmentally benign nature of cobalt
has led to the development of cobalt-catalyzed Negishi cross-
coupling reactions as valuable alternatives to the use of noble
metal catalysts.[7] Despite the spectacular success of cobalt
catalyzed cross-coupling reactions between alkyl halides and
arylzinc reagents by Knochel and co-workers,[7e,f] no cobalt-
catalyzed enantioselective Negishi cross-coupling reactions
have been reported. We recently reported the first
enantioselective Kumada cross-coupling reaction catalyzed by
We initially surveyed chiral ligands in the enantioselective
cross-coupling of racemic benzyl α-bromopropanoate 1a with
phenylzinc bromide 2a (Table 1). The phenyl, isopropyl and
isobutyl substituted bisoxazoline ligands L1–L3 exhibited poor
enantioselectivities (31–61%). In contrast, the benzyl-substituted
bisoxazoline ligand (L4) exhibited high yield (93%) and
enantioselectivity (90%). To search for a more efficient catalyst
for this stereoconvergent cross-coupling, the methyl groups on
the ligand backbone were replaced with hydrogens (L5), isobutyl
[a]
F.Liu, Prof. J. Zhong, Y. Zhou, Z. Gao, X. Wang, S. Ma, Prof. S.
Hou, Prof. S. Liu, Prof. M. A. Wang, Prof. M. Wang, Prof. Q. Bian
Department of Applied Chemistry
(L6)
and
benzyl
(L7)
groups.
Unfortunately,
the
enantioselectivities did not exceed those of the parent L4. We
next modified the backbone benzyl groups of L7. Our
bisoxazoline ligands (L8–L14) bearing either electron-donating
or electron-withdrawing groups were more effective (84–92%
ee) than the parent L7, and 4-fluorobenzyl bisoxazoline L9
exhibited excellent yield (94%) and enantioselectivity (92%). The
effect of other reaction parameters was elaborated in Tables S1
and S2 (see Supporting Information). The optimized reaction
conditions involved 1.0 equiv of benzyl α-bromopropanoate and
China Agricultural University
2 West Yuanmingyuan Road, Beijing 100193 (China)
E-mail: bianqinghua@cau.edu.cn
[b]
Prof. P. Walsh
Department of Chemistry
University of Pennsylvania
231 South 34th Street, Philadelphia, Pennsylvania 19104–6323
(USA)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201705463
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o
2.0 equiv of phenylzinc bromide at –25 C in THF, catalyzed by
10 mol% CoI2 and 12 mol% bisoxazoline L9 (entry 11, Table S1
in Supporting Information). Based on comparison with reported
specific rotations, the absolute configuration of the cross-
coupling product 3a was (S).[3o,9]
with 89% ee and 84% yield. Likewise, use of ester bearing
heterocycle 2-(5-methyl)furyl led to cross-coupling in 90% ee
and 89% yield of 5h.
Table 2. Enantioselective Negishi cross-coupling reactions of racemic α-
bromo propionic esters with phenylzinc bromide.[a]
O
O
10 mol % CoI2
12 mol % L9
Table 1. Ligands screening for the enantioselective Negishi cross-coupling
PhZnBr
+
RO
RO
reaction.[a]
THF, _ 25 o
C
Br
Ph
1
2a
3
O
O
10 mol % CoI2
O
O
3l: (R = H): 90%, 90% ee
3m: (R = 3-F): 94%, 90% ee
3n: (R = 4-Cl): 90%, 90% ee
3o: (R = 4-Me): 92%, 92% ee
12 mol % Ligand
R
BnO
PhZnBr
+
BnO
THF, _ 25 o
C
RO
O
Br
N
Ph
N
2a
Ph
1
3
Ph
3a: (R = Bn): 94%, 92% ee
3b: (R = Me): 88%, 89% ee
O
O
L1: (R = i-Bu): 74%, 31% ee
L2: (R = Ph): 85%, 61% ee
L3: (R = i-Pr): 76%, 48% ee
L4: (R = Bn): 93%, 90% ee
O
O
O
O
N
3c: (R = Et): 92%, 90% ee
3d: (R = i-Bu): 92%, 91% ee
3e: (R = cyclohexylmethyl): 92%, 91% ee
3f: (R = cyclopentyl): 91%, 91% ee
3g: (R = cyclohexyl): 91%, 90% ee
N
Bn
Bn
R
L5: 61%, 53% ee
Ph
R
R
R
R
Bu Bui
i
L7: (R = H): 78%, 82 % ee
L8: (R = t-Bu): 92%, 90% ee
L9: (R = F): 94, 92% ee
L10: (R = CF3): 87%, 84% ee
L11: (R = Br): 95%, 90% ee
3p: (R = 4-F): 93%, 90% ee
3q: (R = 4-CF3): 85%, 89% ee
O
O
3h: (R = i-Pr): 94%, 91% ee
N
N
O
O
3r: (R = 4-Br): 89%, 89% ee
3s: (R = 4-Me): 95%, 92% ee
3i: (R = t-Bu): 95%, 91% ee
3j: (R = 2-bromoethyl): 88%, 92% ee
Bn
Bn
N
N
L6: 87%, 81% ee
3t: (R = 4-t-Bu): 92%, 94% ee
3u: (R = 4-OMe): 96%, 94% ee
3k: (R = isopentenyl: 87%, 91% ee
3v: (R = 2-naphthlenylmethyl): 84%, 91% ee
Bn
Bn
F
F
F
F
F
F
[a] All reactions were run for 24 h, and conducted on 0.5 mmol scale. 2.0
Equiv of PhZnBr was used. Isolated yields after chromatographic purification.
Ee were determined by chiral HPLC.
F
F
O
O
O
O
O
O
N
N
N
N
N
N
Bn
Bn
Bn
Bn
Bn
Bn
Table 3. Enantioselective Negishi cross-coupling reactions of racemic α-
L14: 90%, 87% ee
L12: 93%, 90% ee
L13: 94%, 86% ee
bromo esters with phenylzinc bromide.[a]
O
O
10 mol % CoI2
[a] All reactions were run for 24 h, and conducted on 0.5 mmol scale. 2.0
Equiv of PhZnBr was used. Isolated yields after chromatographic purification.
Ee were determined by chiral HPLC.
Alkyl
Alkyl
O
12 mol % L9
+
RO
PhZnBr
RO
THF, _ 25 o
C
Ph
Br
5
2a
4
O
5a: (R = Et): 95%, 95% ee
5d: (R = i-Pr): 83%, 32% ee
R
Under the optimized conditions, the coupling reaction
between racemic α-bromo propionic esters bearing a variety of
ester O–R groups and phenylzinc bromide were examined
(Table 2). The reaction proved remarkably tolerant of the size
and nature of the O–R group. Thus, α-bromo propionic esters
with O–R substituents methyl (3b), ethyl (3c), iso-butyl (3d), and
cyclohexylmethyl (3e) to more hindered cyclopentyl (3f),
cyclohexyl (3g), iso-propyl (3h), and even bulky tert-butyl (3i)
reliably exhibited excellent enantioselectivities (89–92%) and
high yields (88–95%). Likewise, α-bromo propionic esters with
functional groups, including alkyl bromide (3j), olefin (3k), phenyl
(3l), benzyl (3a), and naphthalenylmethyl (3v), were very good
substrates for this stereoconvergent arylation (90–92% ee, 84–
94% yield). The nature of the substituent on the O–Ar group had
little impact on the product enantioselectivity (90–94% ee, 3m–
3u), and the best results (94% ee, 96% yield, 3u) were obtained
with 4-methoxybenzyl 2-bromopropanoate (1u).
5b: (R = n-Bu): 94%, 95% ee 5e: (R = Bn): 93%, 92% ee
Ph
5f: (R = 2-bromoethyl):
MeO
5c: (R = i-Bu): 92%, 92% ee
84%, 89% ee
O
O
O
O
O
O
O
O
O
Ph
MeO
Ph
Ph
5h: 89%, 90% ee
5g: 83%, 90% ee
5i: 91%, 91% ee
O
O
O
O
O
O
OTBDPS BnO
OBn
BnO
Ph
5k: 90%, 92% ee
NEt2
Ph
Ph
5l: 92%, 92% ee
5j: 88%, 85% ee
[a] All reactions were run for 24 h, and conducted on 0.5 mmol scale. 2.0
Equiv of PhZnBr was used. Isolated yields after chromatographic purification.
Ee were determined by chiral HPLC.
In addition to phenylzinc bromide, a wide array of arylzinc
reagents successfully participated in this stereoconvergent
coupling (Table 4). In general, electron-neutral and donating
groups on the aryl ring (3-Me, 4-Me, 4-OMe, 4-iso-Bu, 4-Ph, 4-
SiMe3, 4-SMe, 4-NMe2, 6-OMe) or electron-with drawing
substituents (3-OMe, 3-OMe-4-Me, 3-F, 4-F, 4-CF3, 3-Cl, 4-Cl,
4-CO2Et, 3,4-F2, 3,5-F2, 3-Cl-4-F) on the aryl zinc uniformly
We next explored the use of different alkyl groups attached
to the α-carbon of the bromo ester substrates (Table 3). When
the α-alkyl was primary (Et, n-Bu, i-Bu), 92–95% ee and 92–95%
yield were obtained (5a–5c). However, in the case of the bulky
iso-propyl group, the cross-coupling product 5d was generated
in only 32% ee. Gratifyingly, α-bromo esters bearing
functionalized alkyl groups, such as benzyl (5e), allyl (5g), acetal
(5i), silyloxy (5j), ester (5k) and amide (5l), exhibited high
enantioselectivities (85–92%) and 83–93% yield. The -bromo
ester containing a primary alkyl bromide underwent coupling
with excellent chemoselectivity for the α-position, leading to 5f
afforded
the
cross-coupling
products
with
excellent
enantioselectivities (86–97%) and high yields (85–98%, 6b–6t,
6v). Notably, α-aryl propionic esters 6g and 6v could be
transformed into two well known nonsteroidal anti-inflammatory
drugs (NSAIDs), (S)-ibuprofen and (S)-naproxen, with high
enantiomeric
purity
via
simple
deprotection
and
recrystallization.[3p,10] Our stereoconvergent arylation was
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Br
compatible with other functional groups, including acetal (6y)
and heteroaromatics (6w, 6x, 6z, and 6za). Furthermore,
halogenated arylzinc reagents coupled smoothly with α-bromo
ester 1u indicating that this enantioselective coupling occurred
with high chemoselectivity at the sp3 C−Br bond. It is noteworthy
that our method tolerated hindered substrates, and some ortho-
substituted arylzinc reagents reacted smoothly with excellent
enantioselectivities (87–88% ee) and yields (88–94%, 6zb–6ze).
O
BrZn
O
LiAlH4
THF, _ 78oC
O
O
2f
OMe
MeO
10 mol % CoI2
95%, 92% ee
OMe
rac-1u
12 mol % L9
THF, _ 25 o
C
OMe
(S)-6f, 1.43 g
5 mmol, 1.37 g
91%, 92% ee
HO
Br
H2C CHMgBr
(1) CuI, THF, 0 o
CBr4, PPh3
C
CH2Cl2, rt
87%
(2) 9-BBN,THF, rt
then H2O2, NaOH
75%, 2 steps, 92% ee
OMe
OMe
Table 4. Enantioselective Negishi cross-coupling reactions of racemic α-
bromo ester with arylzinc bromide.[a]
(S)-7
(S)-8
Dess-Martin
reagent
THF, n-BuLi
MeO
MeO
OH
O
O
MeO
O
_ 15 oC to rt
(H3C)2C
84%
O
10 mol % CoI2
12 mol % L9
CH2Cl2, rt
94%, 92% ee
O
PPh3
(R)-10
Ar
(R)-9
Br
+ ArZnBr
MeO
THF, _ 25 o
C
MeO
2
6
1u
Et2NCH2CH2SH
O
HO
6b: (R = 3-Me): 92%, 91% ee
6c: (R = 4-Me): 95%, 94% ee
6d: (R = 3-MeO): 92%, 92% ee
NaH, DMF, reflux
89%, 92% ee
O
(R)-xanthorrhizol
(R)-11
MeO
6e: (R = 4-MeO): 94%, 94% ee
6f: (R = 3-MeO, 4-Me): 94%, 92% ee
R
6r: (R = 4-SMe): 85%, 92% ee
6s: (R = NMe2): 86%, 92% ee
6g: (R = 4-i-Bu): 90%, 93% ee
6h: (R = 3-F): 94%, 92% ee
6i: (R = 4-F): 97%, 95% ee
6j: (R = 3,4-F2): 98%, 97% ee
6k: (R = 3,5-F2): 92%, 86% ee[b]
6l: (R = 4-CF3): 88%, 94% ee
Scheme 2. Enantioselective synthesis of (R)-xanthorrhizol.
6t: (R = 4-COOEt): 85%, 93% ee[b]
To gain insight into the mechanism of this cobalt-catalyzed
reaction, radical probes 12 and 14 with phenylzinc bromide 2a
were examined (Scheme 3). The ring-opened product 13 was
formed in 88% yield from α-bromo cyclopropyl ester 12. In
addition, the cyclized cross-coupling product 15 was obtained as
a racemic mixture of diastereomers (78% yield, trans:cis =
56:44) from α-bromo ester 14 that bears pendant olefin. These
results indicate that this cobalt-catalyzed cross-coupling process
likely involves a radical pathway similar to cobalt-catalyzed
cross-coupling reactions of alkyl halides.[19]
6u: (R = 2-naphthlenyl): 91%, 89% ee
6v: (R = 6'-MeO-2-naphthyl): 83%, 89% ee
6z: (R = 4-pyrrolyl): 89%, 93% ee
6za: (R = 4-thienyl): 83%, 92% ee
6m: (R = 3-Cl-4-F): 97%, 95% ee
6n: (R = 3-Cl): 92%, 92% ee
6o: (R = 4-Cl): 95%, 94% ee
6p: (R = 4-Ph): 92%, 92% ee
6q: (R = 4-SiMe3): 92%, 92% ee
6zb: (R = 2-Me): 93%, 87% ee[c]
6zc: (R = 2,4-Me2): 90%, 87% ee[c]
6zd: (R = 2-OMel): 94%, 88% ee[c]
6ze: (R = 1-naphthyl): 88%, 87% ee[c]
O
O
O
O
O
O
MeO
MeO
MeO
N
O
O
20 mol % CoI2
24 mol % L9
6y: 91%, 94% ee
6x: 74%, 89% ee
6w: 72%, 87% ee
O
O
O
+
PhZnBr
O
THF, _ 25 o
C
[a] All reactions were run for 24 h, and conducted on 0.5 mmol scale. 2.0
Equiv of ArZnBr was used. Isolated yields after chromatographic purification.
Ee were determined by chiral HPLC. [b] 5.0 Equiv of ArZnBr was used. [c]
Ligand L4 and 3.0 equiv of ArZnBr were used.
O
Ph
Br
88%
2a
12
13
20 mol % CoI2
24 mol % L9
O
+
PhZnBr
THF, _ 25 o
C
O
Br
14
O
Ph
78%
O
To demonstrate the scalability and utility of our method, (R)-
xanthorrhizol was prepared (Scheme 2). (R)-Xanthorrhizol is a
sesquiterpene isolated from Curcuma xanthorrhiza Roxb.
Rhizome,[11] and has anti-inflammatory, antioxidant, and
antiestrogenic properties.[12] The synthesis started from coupling
of racemic 4-methoxybenzyl 2-bromopropanoate (1u, 5 mmol,
2a
15 (racemic)
trans/cis = 56:44
Scheme 3. Cobalt-catalyzed reaction of radical probes 12 and 14 with PhZnBr.
In conclusion, we have developed the first cobalt-catalyzed
enantioselective Negishi cross-coupling reaction and the first
arylation of -halo esters with arylzinc halides. A diverse range
of functionalized arylzinc reagents were successfully coupled
with various α-bromo esters to afford enantioenriched α-
arylalkanoic esters with high enantioselectivities and yields
under mild conditions. In particular, ortho-substituted arylzinc
reagents, which had not previously been successfully employed
in asymmetric cross-coupling reactions with α-bromo
esters,[3o,3p,4a] were excellent substrates. This stereoconvergent
arylation could be readily conducted on gram-scale, as
demonstrated in the enantioselective synthesis of (R)-
xanthorrhizol. We expect that this cobalt-catalyzed asymmetric
Negishi cross-coupling reaction will find further applications in
medicinal chemistry.
1.37 g) to generate the arylated product (S)-6f (1.43 g, 91%
[4a]
yield, 92% ee). Subsequent reduction with LiAlH4
and
bromination with carbon tetrabromide[13] afforded primary
bromide (S)-8. After coupling with vinylmagnesium bromide,[14]
hydroboration with 9-BBN and oxidation with basic H2O2
furnished primary alcohol (R)-9 (92% ee, 75% yield over 2
steps).[15] Finally, Dess-Martin oxidation[16] and Wittig olefination
with iso-propyltriphenylphosphonium iodide,[17] followed by
cleavage of the methyl ether with 2-diethylaminoethanethiol and
NaH gave (R)-xanthorrhizol with 92% ee.[18]
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2008, 130, 3302-3303; b) F. Glorius, Angew. Chem. 2008, 120, 8474-
8476; F. Glorius, Angew. Chem., Int. Ed. 2008, 47, 8347-8349; c) H.
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Acknowledgements
We thank for the National Key Technology Research and
Development Program of China (No. 2015BAK45B01 and
2017YFD0201404) for the financial support. PJW thanks the
NSF (CHE-1464744).
Keywords: cobalt • Negishi cross-coupling• α-bromo ester •
arylzinc • asymmetric catalysis
[1]
For recent leading references of enantioselective Negishi cross-
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The first cobalt-catalyzed
Feipeng Liu, Jiangchun Zhong, Yun
enantioselective Negishi cross-
coupling reaction and the first
examples of arylation of -halo esters
with arylzinc halide, have been
developed. Employing a cobalt-
bisoxazoline catalyst, various α-
arylalkanoic esters (64 examples)
were synthesized in excellent
enantioselectivity and yield (up to 97%
ee and 98 % yield) from racemic α-
bromo esters and arylzincs.
Zhou, Zidong Gao, Patrick J. Walsh,
Xueyang Wang, Sijie Ma, Shicong Hou,
Shangzhong Liu, Minan Wang, Min
Wang, Qinghua Bian*
Page No. – Page No.
Cobalt-Catalyzed Enantioselective
Negishi Cross-Coupling of Racemic
α-Bromo Esters with Arylzincs
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