Enantioselective nickel-catalyzed reductive coupling of alkynes and imines

Article abstract of DOI:10.1021/ja104505t

The nickel-catalyzed reductive coupling of alkynes and imines with Et ₂Zn as a reductant by using electron-rich phosphine ligands has been developed, affording various allylic amines with high yields and excellent chemoselectivities. Chiral induction was also achieved in this reductive coupling reaction when a nickel catalyst containing a chiral spiro phosphine ligand was used.

Full text of DOI:10.1021/ja104505t

Published on Web 07/28/2010
Enantioselective Nickel-Catalyzed Reductive Coupling of Alkynes and Imines
Chang-Yue Zhou, Shou-Fei Zhu, Li-Xin Wang, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received February 5, 2010; E-mail: qlzhou@nankai.edu.cn
reducing agent. Fortuitously, the N-tosyl protected imine 2a
underwent the three-component coupling reaction smoothly in the
presence of 10 mol % nickel catalyst formed in situ from Ni(acac)2
and PPh3. The expected reductive coupling product 3a was isolated
along with the alkylative coupling product 4a and the direct Et2Zn
addition byproduct 5a in a ratio of 3/4/5 ) 2:1:1 (Table 1, entry
1). Other organometallic reagents such as Et3B, Et3Al, and HSiEt3
Abstract: The nickel-catalyzed reductive coupling of alkynes and
imines with Et2Zn as a reductant by using electron-rich phosphine
ligands has been developed, affording various allylic amines with
high yields and excellent chemoselectivities. Chiral induction was
also achieved in this reductive coupling reaction when a nickel
catalyst containing a chiral spiro phosphine ligand was used.
were ineffective in this reaction. Replacement of the tosyl group
with another protecting group such as phenyl, methyl, or P(O)Ph2
The nickel-catalyzed multicomponent coupling reaction repre-
sents one of the most efficient protocols for carbon-carbon bond
formations and has drawn increasing attention.1 Initiated by
Montgomery in 1997, nickel-catalyzed three-component coupling
reactions between alkynes, carbonyl compounds, and organo-
metallics have been developed for the preparation of allylic
alcohols.2 However, the nickel-catalyzed coupling reaction of
alkynes with imines are difficult to perform because imines are
weaker electrophiles than aldehydes and, furthermore, the allylic
amine products may deactivate or decompose the nickel catalyst.
The first breakthrough in the nickel-catalyzed coupling reaction of
alkynes with imines was made by Jamison and co-workers.3 They
achieved the alkylative coupling (AC) of disubstituted alkynes,
N-alkyl imines, and organoboron reagents to produce allylic amines
with a tetrasubstituted olefin moiety with good to excellent yields,
high regioselectivities, and moderate to high enantioselectivities.
However, the reductive coupling (RC) of alkynes with imines,
which produces allylic amines with a trisubstituted olefin moiety,
is simply a side reaction in Jamison’s system. To date, the nickel-
catalyzed RC of alkynes with imines has not been achieved.4 In
2005, Krische reported rhodium-catalyzed diastereoselective cou-
plings of 1,3-enynes and 1,3-diynes with ethyl N-sulfinyliminoac-
etates employing H2 as a reductant.5 Recently, highly enantiose-
lective iridium-catalyzed reductive coupling of dialkyl-substituted
alkynes with N-sulfonyl-imines and rhodium-catalyzed couplings
of acetylene and imines have also been developed by the same
group.6 Here we report the nickel-catalyzed reductive coupling
reaction of aryl-substituted alkynes, imines, and Et2Zn, providing
allylic amines in high yields (up to 96%) and excellent chemose-
lectivities (RC/AC up to 42:1). We also accomplished an asym-
metric version of this reaction by using chiral spiro phosphine
ligands, and high enantioselectivities (up to 94% ee) were achieved
(Scheme 1).
was also unsuccessful for increasing the yield and chemoselectivity
of the reaction. Both monodentate and bidentate phosphorus ligands
can promote the coupling reaction; however, only the less-hindered
and electron-rich ligand n-Bu3P yielded the reductive coupling
product in good yield (66%) and excellent chemoselectivity (3/4/5
) 23:1:3) (entry 4). When the catalyst precursor Ni(COD)2 was
used the yield increased to 86% (entry 6). Under the optimal
conditions, the catalyst loading was reduced to 5 mol % and the
ratio of the alkyne, imine, and Et2Zn was lowered to 2:1:1 (entry
8). Imines with other sulfonyl protecting groups were also suitable
substrates (entries 9 and 10). Because the N,N-dimethylsulfamoyl
protecting group is easy to remove,7 we chose imine 2c for further
investigation.
Table 1. Nickel-Catalyzed Three-Component Reductive Coupling
a
of 1-Phenyl-1-propyne, Imine, and ZnEt2
a Reaction conditions: [Ni]/ligand/1a/2/Et2Zn ) 0.04/0.044/1.6/0.4/
0.96 (mmol), in 2 mL of solvent at room temperature. b Determined by
1H NMR. c Determined by 1H NMR (see Supporting Information for
details). d 1,2-Di(diphenylphosphino)ethane. e 1a/2/Et2Zn ) 2:1:1. f 5
mol % catalyst was used.
Scheme 1
The reductive coupling reaction was applicable to a broad range
of substrates. Benzaldehyde-derived imines with different substitu-
ent patterns underwent reductive coupling with 1-phenyl-1-propyne
(1a) under the optimal reaction conditions to produce various allylic
amines with good to excellent yields (69-96%) and high to
excellent chemoselectivities (3/4 ranged from 15:1 to 42:1) (Table
We initially conducted the nickel-catalyzed reductive coupling
of 1-phenyl-1-propyne (1a) with imines by using Et2Zn as a
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10.1021/ja104505t  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10955–10957 10955

C O M M U N I C A T I O N S
Table 2. Nickel-Catalyzed Reductive Coupling of Alkynes with
2). The studies for accurate mechanism are undergoing in this
laboratory and will be reported in due course.
Iminesa
yield of
3 (%)
alkyne: R1, R2
imine: R4
product
3/4
Scheme 2
entry
1
2
3
4
5
6
7
8
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Me (1a)
Ph, Et (1b)
Ph, Ph (1c)
Et, Et (1d)
Ph (2c)
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3bc
3cc
3dc
28:1
15:1
22:1
30:1
27:1
30:1
25:1
27:1
29:1
30:1
42:1
37:1
26:1
25:1
22:1
6:1
87
74
74
85
91
88
69
84
83
96
80
85
82
87
51
50
59
70
81
56
o-MeOC6H4 (2d)
o-MeC6H4 (2e)
o-ClC6H4 (2f)
m-MeC6H4 (2g)
m-ClC6H4 (2h)
p-MeOC6H4 (2i)
p-MeC6H4 (2j)
p-FC6H4 (2k)
p-ClC6H4 (2l)
p-CF3C6H4 (2m)
3,4-Cl2C6H3 (2n)
1-naphthyl (2o)
2-naphthyl (2p)
n-Pr (2q)b
In summary, highly efficient nickel-catalyzed reductive coupling
of alkynes and imines with Et2Zn as a reductant has been realized.
The asymmetric version of this reaction was also achieved in high
enantioselectivity by using a chiral spiro phosphine ligand. The
nickel catalyst developed in this study favors the aromatic alkynes
and provides a complement to Krische’s iridium catalyst which
prefers aliphatic alkynes.
9
10
11
12
13
14
15
16
17
18
19
20c
i-Pr (2r)b
c-C6H11 (2s)b
Ph (2c)
16:1
19:1
18:1
14:1
Table 3. Nickel-Catalyzed Asymmetric Reductive Coupling of
Alkynes with Iminesa
Ph (2c)
Ph (2c)
entry alkyne: R1, R2
imine: R4
Ph, Me (1a) Ph (2c)
Ph, Me (1a) o-MeOC6H4 (2d) 3ad
product 3/4 yield of 3 (%) ee of 3(%)
b
b
1
2
3
4
5
6
7
8
9
3ac
9:1
7:1
74(64)
63
87(96)
94
a Unless otherwise noted, reaction conditions were the same as those in
Table 1, entry 10. All reactions complete within 2 h. b Protecting group is
Ts. c [Ni]/n-Bu3P/1d/2c/ Et2Zn ) 0.02/0.04/0.48/0.4/0.96 (mmol), 80 °C.
Ph, Me (1a) o-MeC6H4 (2e)
Ph, Me (1a) o-ClC6H4 (2f)
Ph, Me (1a) m-MeC6H4 (2g)
Ph, Me (1a) m-ClC6H4 (2h)
Ph, Me (1a) p-MeOC6H4 (2i) 3ai
Ph, Me (1a) p-MeC6H4 (2j)
Ph, Me (1a) p-FC6H4 (2k)
3ae
3af
3ag
16:1
11:1
12:1
71
80
77(66)
75
82
76
86(98)
85
b
b
3ah 11:1
2, entries 1-12). The imines with 1-naphthyl (2o) and 2-naphthyl
(2p) substituents exhibited properties that were similar to those of
imine 2c in the reductive coupling reaction (entries 13 and 14).
The imines derived from aliphatic aldehydes (2q-2s) were less
reactive under the standard reaction conditions, affording the
reductive coupling products in only moderate yields (entries
15-17). In addition to 1-phenyl-1-propyne (1a), all other tested
alkynes were suitable substrates for the reaction, although the
aliphatic alkyne afforded a lower yield (entries 18-20).
14:1
13:1
9:1
7:1
6:1
9:1
4:1
8:1
6:1
6:1
9:1
7:1
1:1
68
71
72
78(61)
67
69
62
80
65
51
81
62
41(41)
89
86
86
85(96)
84
87
88
87
11
9
88
86
67(84)
3aj
3ak
3al
b
b
10 Ph, Me (1a) p-ClC6H4 (2l)
11 Ph, Me (1a) p-CF3C6H4 (2m) 3am
12 Ph, Me (1a) 3,4-Cl2C6H3 (2n) 3an
13 Ph, Me (1a) 1-naphthyl (2o)
14 Ph, Me (1a) 2-naphthyl (2p)
15 Ph, Me (1a)
16 Ph, Me (1a)
17 Ph, Et (1b) Ph (2c)
18 Ph, Ph (1c) Ph (2c)
19 Et, Et (1d) Ph (2c)
3ao
3ap
3aq
3as
3bc
3cc
3dc
c
n-Pr (2q)
c
c-C6H11 (2s)
The asymmetric version of the nickel-catalyzed reductive
coupling was then studied. After systematic evaluation of various
chiral ligands,8 we found that the spiro phosphine 7f was the most
efficient ligand in terms of yield (74%), chemoselectivity (3/4 )
9:1), and enantioselectivity (87% ee) (Table 3, entry 1). When
Ni(COD)2/(R)-7f was used as a catalyst, all the tested imines derived
from aromatic aldehydes underwent the coupling reaction smoothly
to produce the corresponding allylic amines with good yields and
high to excellent selectivities. Except for o-methoxyphenyl imine
2d and o-chlorophenyl imine 2f, which interestingly afforded the
highest (94% ee) and lowest (76% ee) enantioselectivities, respec-
tively, the other imines derived from aromatic aldehydes gave
almost the same level of enantioselectivity (82-89% ee) (entries
1, 3, 5-14). The coupling of o-methylphenyl imine 2e gave the
highest chemoselectivity (3/4 ) 16:1) (entry 3), whereas 1-naphthyl
imine 2o gave the lowest chemoselectivity (3/4 ) 4:1) (entry 13).
In contrast, imines derived from aliphatic aldehydes give lower
enantioselectivities (entries 15 and 16). Changing the R2 group of
the alkyne had almost no influence on the reactivity and enanti-
oselectivity of the reaction (entries 17 and 18). Dialkyl substituted
hex-3-yne can also proceed in the coupling reaction but afforded a
1:1 mixture of products 3 and 4 (entry 19). Most of the reductive
coupling products were solids and were easily purified by recrys-
tallization (entries 1, 5, and 10). Furthermore, the N,N-dimethyl-
sulfamoyl group of products was easily removed by means of the
published procedure.7,8 The absolute configuration of 3ac was
determined to be S by chemical correlation.8
d
d
a Reaction conditions: Ni(COD)2/(R)-7f/1/2/ZnEt2 ) 0.0075/0.009/0.3/
0.15/0.36 (mmol) in 0.75 mL of DME at rt. All reactions complete
within
3
h. b Data in parentheses are those after recrystallization.
c Protecting group is Ts. d Data in parentheses are for alkylative product
4dc.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China, the National Basic Research
Program of China (973 Program, 2006CB806106, 2010CB833300),
the Ministry of Health (2009ZX09501-017) and the “111” project
(B06005) of the Ministry of Education of China.
Supporting Information Available: Detailed experimental proce-
dures, the synthetic methods and analytic data for new ligands, and
the analytic data and ee values for products. This material is available
free of charge via the Internet at http://pubs.acs.org.
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hydrogen was most likely from the ethyl group of Et2Zn (Scheme
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C O M M U N I C A T I O N S
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