Nickel-catalyzed enantioselective alkylative coupling of alkynes and aldehydes: Synthesis of chiral allylic alcohols with tetrasubstituted olefins

Article abstract of DOI:10.1021/ja805296k

A highly efficient nickel-catalyzed asymmetric alkylative coupling of alkynes, aldehydes, and dimethylzinc has been realized by using bulky spirobiindane phosphoramidite ligands, affording allylic alcohols with a tetrasubstituted olefin functionality in high yields, high regioselectivities, and excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja805296k

Published on Web 10/04/2008
Nickel-Catalyzed Enantioselective Alkylative Coupling of Alkynes and
Aldehydes: Synthesis of Chiral Allylic Alcohols with Tetrasubstituted Olefins
Yun Yang, Shou-Fei Zhu, Chang-Yue Zhou, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received July 9, 2008; E-mail: qlzhou@nankai.edu.cn
Table 1. Ni-Catalyzed Asymmetric Alkylative Coupling of
Transition metal-catalyzed asymmetric carbon-carbon bond
1-Phenyl-1-propyne and Benzaldehyde: Optimization of
formation is the essence of organic synthesis. Nickel-catalyzed
Conditionsa
coupling reactions of alkynes and carbonyl compounds1 provide a
direct access to stereochemically defined allylic alcohols, valuable
intermediates in organic synthesis that commonly occur as building
blocks in natural products.2 The nickel-catalyzed asymmetric
reductive coupling between alkynes and aldehydes or ketones in
the presence of reducing reagents such as organometallics or silanes
(Scheme 1, eq 1) has been well developed by Jamison and by other
Scheme 1
entry
ligand
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1c
1c
1c
1c
1c
1c
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
10
38
87
84
63
61
71
84
80
88
70
71
12
28
94
90
84
91
92
90
85
95
90
88
Et2O
groups.3 Chiral allylic alcohols with a di- or trisubstituted olefin
have been prepared in good to excellent enantioselectivities. Besides
the reductive coupling reactions, the nickel-catalyzed alkylative
coupling reaction of alkynes with aldehydes developed by Mont-
gomery and co-workers is another important coupling reaction.4
The alkylative coupling reaction includes a transfer of an alkyl group
instead of a hydrogen atom from organometallic reagents to the
alkyne (Scheme 1, eq 2), and is therefore a more atom-efficient
process compared to its reductive counterpart and commonly
produces allylic alcohols with a tetrasubstituted olefin. Because the
chiral allylic alcohols with a tetrasubstituted olefin are useful
building blocks for bioactive compounds5 and because they are
difficult to synthesize by other methods, the nickel-catalyzed
asymmetric alkylative coupling of alkyne and aldehydes holds great
potential in organic synthesis. However, the asymmetric version
of this important transformation is, to our best knowledge, still
unexplored.6 In this Communication, we report the first highly
enantioselective alkylative coupling of alkynes and aldehydes
catalyzed by nickel complexes of chiral spiro phosphoramidite
ligands, which provides a convenient approach to the preparation
of chiral allylic alcohols bearing a tetrasubstituted olefin.
We initially examined the alkylative coupling of 1-phenyl-1-
propyne (1.0 equiv), benzaldehyde (2.0 equiv) and dimethylzinc
(3.0 equiv) in the presence of nickel catalysts prepared in situ from
Ni(COD)2 and chiral spiro phosphoramidite ligands in 1:1.2 molar
ratio. With the ligand (R)-SIPHOS, both yield and enantioselectivity
of the reaction were low (Table 1, entry 1). To improve the activity
and enantioselectivity of the catalyst, a variety of chiral spiro
phosphoramidite ligands (1) with different substituents at the 6,6′-
positions of the spirobiindane backbone and the N-atom were
examined. Introduction of phenyl groups on the 6,6′-positions of
9
CH2Cl2
toluene
toluene
toluene
10
11d
12e
a Reaction conditions: Ni(COD)2/Ligand/ZnMe2/2a/3a ) 0.015/0.018/
0.45/0.15/0.30 (mmol), toluene, 25 °C for 20 h. b Isolated yield.
Regioselectivity (4a/4a′) was >95% in all cases. c Determined by HPLC
using a Chiralcel OD column. d With 5 mol % catalyst. e With 1 mol %
catalyst.
the spirobiindane backbone of ligand (1c) significantly increased
the yield (87%) and the enantioselectivity (94% ee) (entry 3). The
amine moiety of the phosphoramidite ligand was also important in
the alkylative coupling reaction. Replacement of the Me2N group
in the ligand 1c by either a Et2N group (1e) or a morpholine (1f)
diminished both yield and enantioselectivity of the reaction (entries
5 and 6). Other monodentate chiral phosphorus ligands including
Monophos and Mop with a binaphthyl backbone gave either low
yield or low enantioselectivity (see Supporting Information). The
reactions with bidentate ligands such as BINAP, SDP, and Phox
provided a racemic product, indicating that only monodentate
ligands induce enantioselectivity in the Ni-catalyzed alkylative
coupling reactions.7 Toluene was the most suitable solvent for high
yield as well as for enantioselectivity (entry 10). Efforts to optimize
other reaction parameters including the nickel precursors and
reaction temperatures, however, had no positive effects (data not
shown). The reaction was also performed with a reducing catalyst
loading of 5 mol % or even as low as 1 mol %, although the yield
and enantioselectivity were slightly lower (entries 11 and 12).
Once the optimal conditions were established, the scope of
substrates was explored. The alkylative couplings of 1-phenyl-1-
propyne with benzaldehyde and its derivatives were smoothly
9
14052 J. AM. CHEM. SOC. 2008, 130, 14052–14053
10.1021/ja805296k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ni-Catalyzed Asymmetric Alkylative Couplings of Alkynes
Scheme 2
with Aldehydesa
entry
R1
R2
R3
yield of 4 (%)
4/4′
ee (%)
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
88 (4a)
92 (4b)
95 (4c)
94 (4d)
89 (4e)
89 (4f)
70 (4g)
82 (4h)
88 (4i)
90 (4j)
92 (4k)
92 (4l)
92 (4m)
91 (4n)
>95/5
>95/5
>95/5
93/7
>95/5
85/15 95
>95/5
>95/5
>95/5
95 (R)
95
94
93
96
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
m-MeOC6H4
p-MeC6H4
p-MeOC6H4
p-FC6H4
p-CF3C6H4
2-naphthyl
2-thiophene
n-butyl
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
aldehyde from its Si face, leading to the formation of allylic alcohols
with R configuration, which is consistent with our experiment
results.
86
92
88
98
99
98
98
99
9
10
11
12
13
14
In summary, we have developed a nickel-catalyzed highly
enantioselective alkylative coupling reaction between alkynes and
aldehydes in the presence of Me2Zn by using 6,6′-disubstituted spiro
phosphoramidite ligands. The asymmetric alkylative coupling
reaction provides an efficient approach to varieties of chiral allylic
alcohols with tetrasubstituted olefin functionality in high yields,
high regioselectivities, and enantioselectivities.
n-Pr n-Pr
Ph
Ph
Ph
Ph
Et
6/1
6/1
n-Bu p-FC6H4
a Reaction conditions were the same as those in Table 1, entry 10.
For analysis of products see Supporting Information.
accomplished to provide the corresponding allylic alcohols contain-
ing tetrasubstituted olefins in good yields and excellent enantiose-
lectivities (Table 2, entries 2-6). The nature and the position of
the substituent on the phenyl ring of benzaldehydes have little
influence on the reaction with the exception of the CF3 group at
the para position, which resulted in a slightly lower regioselectivity
(4/4′) (entry 6). In addition to benzaldehyde and its derivatives,
naphthaldehyde, thiophene-2-carbaldehyde, as well as aliphatic
n-butylaldehyde can also be coupled with 1-phenyl-1-propyne to
produce the corresponding allylic alcohols in good enantioselec-
tivities (entries 7-9). To extend the scope of the reaction, various
disubstituted alkynes were investigated in the coupling reactions
with p-fluorobenzaldehyde and the desired allylic alcohols with the
tetrasubstituted olefin functionality were obtained in high yields
and excellent enantioselectivities (98-99% ee, entries 10-14).
However, lower regioselectivities (4/4′ ) 6:1) were obtained in
the reactions with 1-phenyl-1-butyne and 1-phenyl-1-hexyne (entries
13 and 14). The decreased regioselectivity may be attributed to
the fact that as the difference between the sizes of the two
substituents of the alkyne became smaller, distinguishing the two
ends of the alkyne became more difficult. Different dialkylzinc
reagents were investigated in the alkylative coupling of 1-phenyl-
1-propyne and benzaldehyde. When Et2Zn, which contained ꢀ-H
atoms, was used, a mixture of the reductive coupling product (33%,
57% ee) and the alkylative coupling product (50%, 71% ee) was
obtained, while Ph2Zn gave no reaction under the standard reaction
conditions.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grants 20532010, 20721062), the Major Basic
Research Development Program (Grant 2006CB806106), and the
“111” project (B06005) for financial support.
Supporting Information Available: Experimental procedures, the
characterizations and the analysis of ee values of products. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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A reaction model was proposed for rationalizing the steric
determination based on the absolute configuration of the alkylative
coupling products and the literature work.8 Two transition states
(TS) of enantioselectivity-determined step were proposed (Scheme
2). In the model TS-1, there is an obvious repulsion between the
two phenyl groups, one at the 6,6′-position of ligand and the other
located on the aldehyde. Conversely, no repulsion occurs in the
model TS-2 since the phenyl group of the aldehyde is oriented away
from the phenyl group on the 6,6′-position of the ligand. According
to the model TS-2, the nickel-activated alkyne approaches the
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Chem. Soc. 2005, 127, 54.
(7) See Supporting Information and refs 3a, b, j, and 3l.
(8) Ogoshi, S.; Arai, T.; Ohashi, M.; Kunosawa, H. Chem. Commun. 2008, 1347.
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J. AM. CHEM. SOC. VOL. 130, NO. 43, 2008 14053