Cobalt-Bisoxazoline-Catalyzed Enantioselective Cross-Coupling of α-Bromo Esters with Alkenyl Grignard Reagents

Article abstract of DOI:10.1021/acs.orglett.0c01557

The first catalytic asymmetric Kumada cross-coupling of organic halides with alkenyl Grignard reagents has been developed. The reaction was promoted by the cobalt-bisoxazoline catalyst and afforded various α-alkyl-β,γ-unsaturated esters with excellent enantioselectivities and moderate to good yields (≤95% ee and ≤82% yields). The formal synthesis of the California red scale pheromone using this method was investigated, and radical clock experiments were performed.

Full text of DOI:10.1021/acs.orglett.0c01557

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Letter
Cobalt-Bisoxazoline-Catalyzed Enantioselective Cross-Coupling of
α‑Bromo Esters with Alkenyl Grignard Reagents
Yun Zhou, Lifeng Wang, Gucheng Yuan, Shikuo Liu, Xiao Sun, Chaonan Yuan, Yuxiong Yang,
Qinghua Bian, Min Wang, and Jiangchun Zhong*
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ABSTRACT: The first catalytic asymmetric Kumada cross-coupling of
organic halides with alkenyl Grignard reagents has been developed. The
reaction was promoted by the cobalt-bisoxazoline catalyst and afforded
various α-alkyl-β,γ-unsaturated esters with excellent enantioselectivities and
moderate to good yields (≤95% ee and ≤82% yields). The formal synthesis of
the California red scale pheromone using this method was investigated, and
radical clock experiments were performed.
California red scale pheromone via this coupling and
ransition metal-catalyzed cross-coupling reactions of
Torganic halides with alkenyl nucleophiles have emerged performed radical clock experiments.
We initially employed bisoxazoline ligand L1, previously the
as a powerful strategy for preparing alkene-containing
molecules, which are very important structural motifs in
medicines, pesticides, and natural products.1 Although some
significant progress has been achieved in alkenylation of
organic halides involving alkenyl Grignard reagents,2 alkenyl-
zinc halide or alkenylzirconium reagents,3 alkenylboranes or
boronic acids,4 and alkenyltin reagents,5 reports of catalytic
asymmetric vinylation of organic halides are rare. There are
only six examples: Hiyama cross-couplings of α-bromo esters,6
Negishi cross-coupling of α-bromoketones, α-bromonitriles,
and α-bromosulfonamides and -sulfones,7 and Suzuki−
Miyaura cross-couplings of 3-chlorocyclohex-1-ene.8 As for
catalytic asymmetric Kumada cross-coupling involving alkenyl
Grignard reagents, to the best of our knowledge, there is still
no successful approach.
Enantioriched α-alkyl-β,γ-unsaturated esters are versatile
intermediates of bioactive natural products, such as (+)-jas-
plakinolide9 and (−)-Vulcanolide.10 Due to the limited
number of methods for synthesizing these compounds,11
devising a more general and effective asymmetric strategy is
meaningful. Oshima, Yorimitsu, and Cahiez’s cross-coupling of
alkyl bromides with Grignard reagents showed that cobalt and
iron-catalyzed procedures were efficient, environmentally
friendly, and economical.12a−c In 2014, we have developed
the first cobalt-catalyzed asymmetric Kumada cross-coupling,
and various novel enantioriched α-arylalkanoic esters were
obtained via cobalt-bisoxazoline-catalyzed enantioselective
cross-coupling of α-bromo esters with aryl Grignard
reagents.12d Herein, we report the first catalytic asymmetric
Kumada cross-coupling of organic halides with alkenyl
Grignard reagents, which affords an efficient approach for
the enantioselective alkenylation of α-bromo esters. Further-
more, we have investigated the formal synthesis of the
best ligand for the asymmetric arylation of α-bromo esters,12d
in the enantioselective cross-coupling of racemic benzyl 2-
bromopropanoate (1a) with isobutenyl magnesium bromide
(2a). Fortunately, catalytic asymmetric alkenylation could be
achieved in 84% ee and 65% yield. To find a more efficient
ligand, a series of bisoxazoline ligands were screened (Scheme
1). Varying the groups on the backbone of the bisoxazoline
ligand from methyls (L1) to hydrogens (L2) and benzyl
groups (L4) led to a small decrease in yields and
enantioselectivities (56−60% yield, 80−84% ee), while the
replacement of the methyl groups with bulky isobutyl groups
(L3) caused a significant drop in the yield (40%) and
enantioselectivity (75%). On the basis of these results, we then
modified the backbone benzyl groups of L4. 2-Fluorobenzyl
bisoxazoline L7 and 2-methyl bisoxazoline L8 exhibited yields
and enantioselectivities similar to those of the parent
bisoxazoline L4, which indicated that the substitution at the
ortho position of the benzyl group had a minor impact on this
reaction. In contrast, the substitution at the para position
significantly influenced the enantioselectivity of the coupling.
4-Fluorobenzyl bisoxazoline L5 and 4-trifluorobenzyl bisoxazo-
line L6 bearing electron-withdrawing groups decreased
enantioselectivities to 68−70%, while 4-isobutylbenzyl bisox-
azoline L9 containing electron-donating group gave the best
result (65% yield, 86% ee), a slight increase compared with
Received: May 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01557
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Scheme 1. Ligand Screening in the Enantioselective
Kumada Cross-Coupling of Isobutenyl Magnesium
Bromide
Table 1. Enantioselective Kumada Alkenylations of Racemic
α-Bromo Propionic Esters
a
a
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
60
62
70
70
75
76
77
73
65
61
63
59
73
69
58
50
75
66
79
69
91
90
85
91
90
83
85
72
85
85
86
76
81
87
90
86
74
90
90
93
81
PMB
i-Bu
i-Pr
t-Bu
cyclopentyl
cyclohexyl
cyclohexylmethyl
2-bromoethyl
isopentenyl
Ph
3-F-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
3j
3k
3l
a
4-Cl-C6H4
4-Me-C6H4
3m
3n
3o
3p
3q
3r
3s
3t
All reactions were performed for 5 h, and 4.0 equiv of 2a was used.
Isolated yields after chromatographic purification. Values of ee were
determined by chiral HPLC.
4-F-C6H4CH2
4-CF3-C6H4CH2
4−Br-C6H4CH2
4-Me-C6H4CH2
4-tert-Bu-C6H4CH2
2-naphthenylmethyl
2-naphthyl
those of the parent bisoxazoline L4. However, 3,5-dimethyl
bisoxazoline L10 and 3.5-diisobutyl bisoxazoline L11 furnished
only 45−70% ee coupling product. The influence of other
reaction parameters is depicted in Tables S1 and S2, and the
absolute configuration of the cross-coupling product 3a was
confirmed as S.11b
3u
a
All reactions were performed for 5 h, and 4.0 equiv of 2a was used.
Isolated yields after chromatographic purification. Values of ee were
b
c
A series of racemic α-bromo propionic esters could be
coupled with isobutenyl magnesium bromide (2a) in the
presence of CoCl2 and bisoxazoline ligand L9 (Table 1). All α-
bromo propionic esters derived from aliphatic alcohols except
cyclohexylmethanol (entry 8) exhibited good enantioselectiv-
ities (83−91%, entries 3−10). Likewise, esters derived from
phenols (entries 11, 13, and 14), naphthol (entry 21), and
benzyl alcohols (entries 1, 2, 15, 16, 18, and 19) afforded the
alkenylation products with high enantioselectivities (81−90%).
However, 3-fluorophenyl ester (3l) and 4-bromobenzyl ester
(3q) gave only moderate enantioselectivity (74−76%, entries
12 and 17). It should be noted that 2-naphthenylmethyl ester
was the best substrate and the coupling product 3t was
obtained with 93% ee in 79% yield (entry 20).
determined by chiral HPLC.
Table 2. Enantioselective Kumada Alkenylations of Racemic
a
α-Bromo Esters
The scope of the substituents attached to the α-carbon of
the bromo ester was next explored (Table 2). Excellent
enantioselectivities and moderate to good yields were obtained
(86−90% ee, 62−82% yield, entries 1−5) when the
substituents were primary alkyl groups (Et, n-Bu, and i-Bu).
Unfortunately, secondary substituents (i-Pr and cyclohexyl)
gave poor results (32% ee, 28−46% yield, entries 6 and 7) due
to their steric hindrance. α-Bromo ester bearing functionalized
substituents, such as 2-bromoethyl (5h), allyl (5i), ester (5j),
silyloxy (5k), and benzyl (5l), were tolerated with this
coupling (66−88% ee, 52−65% yield, entries 8−12). However,
the ester bearing 2-(5-methyl)furyl (5m) led to only 33% ee
coupling product (entry 13).
To extend these enantioselective Kumada alkenylations with
respect to the nucleophiles, we applied the same conditions to
the cross-coupling of racemic benzyl 2-bromopropanoate (1a)
with isopropenyl magnesium bromide (2c). However, desired
alkenylation product 6c was not obtained. Previous refer-
ences2d,13 demonstrated that HMTA could promote the
a
All reactions were performed for 5 h, and 4.0 equiv of 2a was used.
Isolated yields after chromatographic purification. Values of ee were
b
c
determined by chiral HPLC.
TMEDA-Fe-catalyzed cross-coupling of Grignard reagents.
Fortunately, the promising result (44% yield, 53% ee) was
B
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observed when we used HMTA as the additive. The other
bisoxazoline ligands (L12−L18) were then surveyed (Scheme
2). Introduction of an ethanediyl (L12) and cyclopentane
Table 3. Asymmetric Kumada Alkenylations of Racemic α-
Bromo Esters with Alkenyl Grignard Reagents
a
Scheme 2. Ligand Screening in the Enantioselective
Kumada Cross-Coupling of Isopropenyl Magnesium
a
Bromide
a
All reactions were performed for 24 h, and 4.0 equiv of 2 was used.
b
c
Isolated yields after chromatographic purification. Values of ee were
d
determined by chiral HPLC. 2 was a commercial mixtures of (Z)-
and (E)-alkenyl magnesium bromide.
a
To demonstrate the utility of this enantioselective Kumada
alkenylation, the formal synthesis of the California red scale
pheromone, isolated from female Aonidiella aurantii (Mas-
kell),14 was investigated (Scheme 3). Our synthesis started
All reactions were performed for 12 h, and 4.0 equiv of 2c was used.
Isolated yields after chromatographic purification. Values of ee were
determined by chiral HPLC. The reaction was conducted for 24 h;
80 mol % LiI, 40 mol % CoCl2, and 48 mol % L14 were used.
b
(L13) backbone resulted in a small increase in enantiose-
lectivity, while biphenyl bisoxazoline L14 afforded the
alkenylation product with 72% ee. Varying the substitutions
on oxazoline from benzyl to phenyl (L15), isobutyl (L16),
isopropyl (L17), and ethyl (L18) significantly decreased the
product ee. To optimize the reaction conditions, we tried LiI as
the additive, which could improve the enantioselective
alkenylation by stabilizing the cobalt ate complex.12b,e,f We
were pleased to obtain an excellent result (57% yield, 90% ee),
and the details about the optimizing reaction conditions are
elaborated in Tables S3 and S4.
Scheme 3. Formal Synthesis of the California Red Scale
Pheromone
With the optimized conditions in hand, other alkenyl
Grignard reagents were examined (Table 3). Vinyl magnesium
bromide, as well as isopropenyl magnesium bromide, could be
coupled with racemic α-bromo esters in high enantioselectiv-
ities and moderate yields (86−91% ee, 44−52% yield, entries
1−4 and 8). It was noteworthy that the commercial mixtures of
(Z)- and (E)-alkenyl Grignard reagents could afford the (E)-
coupling product with 92−95% ee, while lower enantiose-
lectivities for (Z)-isomers were given (entries 5−7).
Taken together, these results show that the scope of this
bisoxazoline-cobalt-catalyzed cross-coupling was broad. Thirty-
four different α-bromo esters could be employed, while vinyl
Grignard reagent, α- or β-monosubstituted, α,β-disubstituted,
and β,β-disubstituted alkenylmagnesium were all suitable
nucleophiles. However, there are some limitations associated
with this new cross-coupling. Under the optimized conditions
in Table 1, alkenylation products were detected by GC-MS in
only 4%, 7%, and 2% when (1-bromoethyl)benzene, 2-bromo-
1-phenylpropan-1-one, and 2-bromobutane, respectively, were
used.
from the enantioselective cross-coupling of racemic α-bromo
ester 4n with isopropenyl magnesium bromide (2c) to afford
alkenylation product 6h with 90% ee and 52% yield.
15
Subsequent reduction with LiAlH4
and Dess-Martin
oxidation16 generated chiral dienoic aldehyde 8. The one-
carbon elongation was then achieved via the Wittig reaction
with methoxymethyltriphenylphosphonium chloride and the
hydrolysis with p-toluenesulfonic acid,17 and the key
intermediate 9 was obtained in an 80% yield over two steps.
The target California red scale pheromone could be prepared
C
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by Wittig alkenylation and acetylation according to the method
described in the literature.14,18
To gain insight into the mechanism of this cobalt-
bisoxazoline-catalyzed cross-coupling, radical clock experi-
ments were performed (Scheme 4). The ring-opened product
Lifeng Wang − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Gucheng Yuan − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Shikuo Liu − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Xiao Sun − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Chaonan Yuan − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Yuxiong Yang − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Qinghua Bian − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Min Wang − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
Scheme 4. Cobalt-Catalyzed Reaction of Radical Probes 10
and 12 with Isobutenyl Magnesium Bromide
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01557
Notes
The authors declare no competing financial interest.
11 was obtained in 51% yield when α-bromocyclopropyl ester
10 was reacted with isobutenyl magnesium bromide (2a).
However, another radical probe 12, an α-bromo ester bearing a
pendant olefin, afforded the mixtures of the cyclized cross-
coupling product 13 and direct cross-coupling product 14 in
53% yield (85:15 13:14), which was similar to the nickel-
catalyzed enantioselective Negishi reaction of α-bromosulfo-
namide.7c These results suggest that this Kumada enantiose-
lective alkenylation mainly occurs via a radical intermediate
consistent with other cobalt-catalyzed cross-coupling of alkyl
halides.12,19
In conclusion, we have developed the first catalytic
asymmetric Kumada cross-coupling of organic halides with
alkenyl Grignard reagents. Various alkenyl Grignard reagents
were coupled with 34 different α-bromo esters to afford highly
enantioenriched α-alkyl-β,γ-unsaturated esters. Furthermore,
this enantioselective Kumada alkenylation could be applied to
the formal synthesis of the California red scale pheromone, and
preliminary mechanistic investigations support the intermedi-
acy of radicals.
ACKNOWLEDGMENTS
■
The authors thank the National Key Technology Research and
Development Program of China (2017YFD0201404) for
financial support.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01557.
Experimental procedures, optimization, characterization
1
data, H and 13C NMR spectra, and HPLC chromato-
grams of the products. (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jiangchun Zhong − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China;
orcid.org/0000-0002-6594-979X; Email: zhong@
cau.edu.cn
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Authors
Yun Zhou − Department of Applied Chemistry, China
Agricultural University, Beijing 100193, P. R. China
D
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