Transmetal-Catalyzed Enantioselective Cross-Coupling Reaction of Racemic Secondary Benzylic Bromides with Organoaluminum Reagents

Article abstract of DOI:10.1021/acs.orglett.6b02933

The transmetal-catalyzed enantioselective cross-coupling reaction of secondary benzylic electrophiles with organoaluminum reagents has been developed. The reaction of secondary benzylic electrophiles with alkynylaluminum reagents provides a mild way for the chiral propargyl compounds bearing aromatic group in high yields with good enantioselectivities using NiBr₂·diglyme and (R)-iPr-Pybox as the catalytic system. The reaction of secondary benzylic electrophiles with alkenylaluminum reagents affords the corresponding chiral aryl alkenes in moderate yields with excellent stereoselectivities using commercially available PdCl₂ and (R)-BINAP as the catalytic system.

Full text of DOI:10.1021/acs.orglett.6b02933

Letter
pubs.acs.org/OrgLett
Transmetal-Catalyzed Enantioselective Cross-Coupling Reaction of
Racemic Secondary Benzylic Bromides with Organoaluminum
Reagents
Hong Fang,‡ Zhiyong Yang,‡ Lijun Zhang, Wei Wang, Yimei Li, Xiaolong Xu, and Shuangliu Zhou*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, P. R. China
S
* Supporting Information
ABSTRACT: The transmetal-catalyzed enantioselective
cross-coupling reaction of secondary benzylic electrophiles
with organoaluminum reagents has been developed. The
reaction of secondary benzylic electrophiles with alkynylalu-
minum reagents provides a mild way for the chiral propargyl
compounds bearing aromatic group in high yields with good
enantioselectivities using NiBr2·diglyme and (R)-iPr-Pybox as
the catalytic system. The reaction of secondary benzylic
electrophiles with alkenylaluminum reagents affords the
corresponding chiral aryl alkenes in moderate yields with excellent stereoselectivities using commercially available PdCl2 and
(R)-BINAP as the catalytic system.
n the past decade, palladium- and nickel-catalyzed cross-
coupling reactions of secondary alkyl electrophiles bearing β-
reaction of secondary benzylic bromides with alkenyl- or
alkynylaluminum reagents.
The asymmetric cross-coupling reaction of α-methyl benzyl
bromide 1a with alkynyldiethylaluminum 2a was used as the
template reaction to screen different chiral ligands (Figure 1),
I
hydrogens have benefitted from significant progress,1 namely,
the groundbreaking studies on Negishi reactions of primary
alkyl bromides and iodides with a range of organozinc reagents
catalyzed by the nickel complexes.2 Recently, Fu and co-
workers have further championed an array of transmetal-
catalyzed asymmetric cross-coupling reaction3 of various
secondary alkyl electrophiles with organozincs,4 -borons,5
-silicons,6 and aryl Grignard reagents.7 Compared with the
asymmetric cross-coupling reactions of aryl nucleophiles, fewer
examples of the asymmetric cross-coupling reactions of alkenyl
and alkynyl nucleophiles were reported. For alkenyl nucleo-
philes, Fu and co-workers reported a sole nickel-catalyzed
enantioselective cross-coupling reaction of racemic α-bromo-
ketones with alkenylsilanes and alkenylzirconium reagents.6,8
For alkynyl nucleophiles, only one example of the asymmetric
alkynylation of alkyl electrophiles through the cross-coupling
reaction of alkynyl indiums with racemic benzyl bromides was
reported.9 Alkynes and alkenes are extremely versatile func-
tional groups; therefore, the development of the asymmetric
cross-coupling reactions of alkenyl and alkynyl nucleophiles is
attractive.
Figure 1. Different chiral ligands.
and the results are summarized in Table 1. First, chiral
bidentate phosphine L1 or phosphoramidite ligands L2−L4 gave
disappointing results with trace product formation (Table 1,
entries 1−4). The reaction employing NiBr2·diglyme with the
(diphenylphosphino)phenyl substituted chiral oxazoline L5−L6
afforded the coupling product 3a in moderate yields with low
enantioselectivities (Table 1, entries 5−6). Next, we examined
the chiral bis(oxazoline) ligand L7 (Table 1, entry 7) and Pybox
L8−L12 (Table 1, entries 8−12) for the asymmetric cross-
coupling reactions. Results are consistent with the asymmetric
Organoaluminum nucleophiles have been widely applied in
asymmetric addition to carbonyl compounds10 and cross-
coupling reactions,11 due to the high reactivity and Lewis
acidity of the aluminum center. Recently, cross-coupling
reactions of aluminum acetylide with benzylic bromides
catalyzed by NiCl2(PPh3)2 have also been reported.12 However,
the organoaluminum nucleophiles for asymmetric cross-
coupling reactions remains to be disclosed. Herein, we will
report the first example of enantioselective cross-coupling
Received: September 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02933
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Organic Letters
Letter
Table 1. Optimization for Nickel-Catalyzed Cross-Coupling
Scheme 1. Substrate Scope for Nickel-Catalyzed Cross-
Coupling Reaction of Benzylic Bromides with
Alkynyldiethylaluminum Reagents
Reaction of α-Methyl Benzylbromide 1a with
a
a,b
Alkynyldiethylaluminum 2a
b
c
entry
ligand (mol %)
solvent
yield (%)
ee (%)
1
L1 (12)
L2 (12)
L3 (12)
L4 (12)
L5 (12)
L6 (12)
L7 (12)
L8 (12)
L9 (12)
L10 (12)
L11 (12)
L12 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (12)
L10 (10)
L10 (15)
L10 (12)
L10 (12)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
trace
trace
trace
trace
61
2
3
4
5
8
6
34
rac
24
14
18
50
30
15
7
73
8
80
9
82
10
11
12
85
85
63
d
13
trace
52
e
14
rac
10
f
15
70
16
17
18
19
20
21
22
23
n-hexane
trace
11
CH2Cl2
2
Et2O
8
DME
trace
83
DMA
75
82
76
82
81
76
THF/DMA (1:1)
THF/DMA (1:1)
THF/DMA (1:1)
THF/DMA (1:1)
THF/DMA (1:1)
89
84
88
g
24
89
h
25
80
a
Conditions: 1a (0.5 mmol), 2a (0.75 mmol), solvent (10.0 mL).
b
c
Isolated yield. The enantiomeric excess was determined by HPLC
d
e
analysis. Employing 10 mol % CuCl2. Employing 10 mol % PdCl2.
f
g
h
Employing 10 mol % NiCl2·diglyme. 1.8 equiv of 2a was used. 1.2
a
Conditions: 1 (0.5 mmol), 2 (0.75 mmol), DMA/THF (10.0 mL).
The absolute configuration of 3a was assigned by comparison of the
equiv of 2a was used.
b
specific rotation value in ref 9, and those of other products were
assigned by analogy.
cross-coupling reactions of secondary benzyl bromides and
trialkynylindium reagents,9 and the best catalytic system was
NiBr2·diglyme and (R)-iPr-Pybox to afford the product 3a in
85% yield with 50% ee (Table 1, entry 10). The use of other
metal catalysts did not improve the yield and enantioselectivity
(Table 1, entries 13−15). When the reaction was performed by
using NiBr2·diglyme and (R)-iPr-Pybox in a 1:1 mixed solvent
of DMA/THF (DMA = dimethylacetamide), the yield of the
coupling product rose up to 89% with good enantioselectivity
of 82% ee (Table 1, entry 21). Further optimization of the
loadings of chiral ligand L10 and the equivalents of 2a did not
improve the enantioselectivity (Table 1, entries 22−25).
With the optimized reaction conditions established, we
extended the reaction to various alkynyldiethylaluminum
reagents and various benzyl bromide (Scheme 1). The catalytic
system works well to various alkynyldiethylaluminum reagents
bearing either electron-donating or electron-withdrawing
substituents. Reaction of α-methylbenzyl bromide 1a with
alkynyldiethylaluminum reagents gives the corresponding
coupling products 3a−3i in high yields with good enantiose-
lectivities (86−94% yield, 74−84% ee). Furthermore, the
reaction of other benzylic substrates with phenylethynyl
aluminum reagents was examined, results showed the
corresponding coupling products 3j−3m in high yields with
good enantioselectivities. Notably, the substrate containing a
methoxy group was well-tolerated in the reaction to give the
product 3k. However, the benzylic bromide bearing an amide
group was not a suitable substrate. Reaction with α-ethylbenzyl
bromide also gave the corresponding coupling products 3n and
3o in high yields with good enantioselectivities. It was
noteworthy that the reaction of alkynyldiethylaluminum
reagents bearing pyridyl group could also work well to afford
the chiral propargyl compounds 3p−3u in good yields with
good to high enantioselectivities of up to 93% ee.
Unfortunately, aliphatic hexyn-1-yl or trimethylsilylethynyl
aluminum reagents were not tolerated in the reaction.
In order to further develop the organoaluminum nucleo-
philes for asymmetric cross-coupling reaction, we further tested
the cross-coupling reaction of α-methyl benzyl bromide 1a with
alkenylaluminum reagent 4a using NiBr2·diglyme and (R)-iPr-
Pybox as the catalytic system. Unfortunately, under the same
conditions the secondary benzyl electrophiles were not able to
efficiently cross-couple with alkenylaluminum reagent. Re-
cently, Pd-catalyzed stereospecific allyl−aryl coupling reactions
B
DOI: 10.1021/acs.orglett.6b02933
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Organic Letters
Letter
of enantioenriched allylic electrophiles with arylboronic acids
afforded structurally diverse alkenes in good yields with perfect
retention of ee, indicating Pd-catalyzed controllable stereo-
specific cross-coupling reactions.13 So, we tested the cross-
coupling reaction of the secondary benzyl electrophiles with
alkenylaluminum reagents employing a palladium catalyst.
PdCl2 and different ligands were first examined for cross-
coupling reaction of alkenylaluminum reagents (Table 2, entries
Scheme 2. Substrate Scope for Palladium-Catalyzed Cross-
Coupling Reaction of Benzylic Bromides with
Alkenylaluminum Reagents
a,b
Table 2. Optimization for Palladium-Catalyzed Cross-
Coupling Reaction of α-Methyl Benzyl Bromide 1a with
a
Alkenylaluminum Reagent 4a
b
c
entry ligand
solvent
temp (°C) time (h) yield (%)
ee (%)
1
L1
L2
L4
L8
L12
L1
L1
L1
L1
L1
L1
THF
rt
6
80
60
20
25
2
THF
rt
6
92
3
THF
rt
6
90
4
THF
rt
6
trace
trace
78
5
THF
rt
6
a
Conditions: 1 (0.5 mmol), 4 (0.75 mmol) at −35 °C for 48 h in THF
6
THF
0
12
48
48
48
48
48
61
88
79
b
(10.0 mL). The absolute configuration of 5a was assigned by
7
THF
−35
−35
−35
−35
−35
58
comparison of the specific rotation value in ref 13f, and those of other
products were assigned by analogy.
8
toluene
n-hexane
THF
50
9
trace
55
d
e
10
11
8
Pd(0) species, two tentative pathways have been proposed to
rationalize the stereoconvergence of such cross-couplings:9 the
adduct might undergo nucleophilic exchange with Ni(0) or
Pd(0) species in the system or a rearrangement via planar
benzylic metal species to form the most reactive or stable
diastereoisomeric metal complex with the chiral ligand.
THF
50
71
a
Conditions: 1a (0.5 mmol), 4a (0.75 mmol), solvent (10.0 mL).
b
c
Isolated yield. The enantiomeric excess was determined by HPLC
d
e
analysis. Employing 10 mol % Pd(η3-C5H3)2Cl2. Employing 10 mol
% Pd(CH3CN)2Cl2.
In summary, we described the transmetal-catalyzed enantio-
selective cross-coupling reaction of secondary benzyl electro-
philes with organoaluminum reagents. The reaction of
secondary benzylic electrophiles with alkynylaluminum re-
agents provides the chiral internal alkynes bearing (hetero)-
aromatic groups in high yields with good enantioselectivities
using NiBr2·diglyme and (R)-iPr-Pybox as the catalytic system.
It was noteworthy that the cross-coupling of secondary benzyl
electrophiles with alkenylaluminum reagents affords the
corresponding chiral aryl alkenes in moderate yields with
excellent stereoselectivities of up to 99% ee employing the
commercially available PdCl2 and (R)-BINAP.
1−5), and results showed that PdCl2 and (R)-BINAP was the
appropriate catalytic system to afford the product 5a in 80 yield
with 60% ee (Table 2, entry 1). Decreasing reaction
temperature to −35 °C improved the results to give 5a in
58% yield with 88% ee (Table 2, entry 7). Further optimization
of the different palladium catalyst, we did not obtain the desired
product in the satisfactory yield or enantioselectivity (Table 2,
entries 10 and 11).
With the optimized reaction conditions established, we
extended the reaction to various alkenylaluminum reagents and
benzyl bromides (Scheme 2). As illustrated in Table 4, the
catalytic system works well to various alkenylaluminum
reagents bearing either electron-donating or electron-with-
drawing substituents to afford the corresponding coupling
products 5a−5g in moderate yields with excellent enantiose-
lectivities except for 4-chlorophenylethynyl aluminum to afford
product 5e in 81% ee. The cross-coupling reaction of α-methyl
benzyl bromide 1a with 3-thienyl vinylaluminum afforded the
corresponding product 5h in 98% ee; however, reaction with 2-
pyridylethenylaluminum afforded the racemic product 5i,
probably due to coordination of heteroatom. Further, the
cross-coupling reaction of different benzyl bromides also
provided the corresponding products 5j−5k in moderate yields
with good to excellent enantioselectivities. An aliphatic 1-
hexenyldiisobutylaluminum reagent is not suitable for the
reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02933.
Experimental and characterization data for all com-
pounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slzhou@ahnu.edu.cn.
ORCID
Based on previous relevant studies on Ni- and Pd-catalyzed
cross-couplings of benzylic halides with other organometallic
reagents,14 after formation of the M−C bond via oxidative
addition of benzylic bromide to in situ generated Ni(0) or
Shuangliu Zhou: 0000-0002-0103-294X
Author Contributions
‡H.F. and Z.Y. contributed equally.
C
DOI: 10.1021/acs.orglett.6b02933
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Groll, K.; Blumke, T. D.; Unsinn, A.; Haas, D.; Knochel, P. Angew.
Notes
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Chem., Int. Ed. 2012, 51, 11157. (e) Chen, X.; Zhou, L.; Li, Y.; Xie, T.;
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Li, Y.; Zhang, L.; Fang, H.; Wang, W.; Zhu, X.; Wang, S. J. Org. Chem.
2015, 80, 6323.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the financial support from the National
Natural Science Foundation of China (21172003, 21372009),
Special and Excellent Research Fund of Anhui Normal
University for this work.
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DOI: 10.1021/acs.orglett.6b02933
Org. Lett. XXXX, XXX, XXX−XXX