Highly enantioselective zinc/amino alcohol-catalyzed alkynylation of aldehydes

Article abstract of DOI:10.1002/chem.200900070

A highly enantioselective and practical alkynylation of aldehydes catalyzed by a cyclopropane-based amino alcohol zinc catalytic system was reported. The results show that in the absence of dimethoxypolyethylene glycol (DiMPEG), 10 mol% of amino alcohol l

Full text of DOI:10.1002/chem.200900070

COMMUNICATION
DOI: 10.1002/chem.200900070
Highly Enantioselective Zinc/Amino Alcohol-Catalyzed Alkynylation of
Aldehydes
Jiang-Chun Zhong,[a] Shi-Cong Hou,[a] Qing-Hua Bian,[a] Min-Min Yin,[a] Ri-Song Na,[a]
Bing Zheng,[a] Zhi-Yuan Li,[a] Shang-Zhong Liu,*[b] and Min Wang*[a]
Enantioselective addition of terminal alkynes to carbonyl
compounds is an area of intense research aimed at, for ex-
ample, producing optically active propargylic alcohols,
which are important and versatile building blocks for many
natural products, pharmaceuticals, etc.[1] Recently, a number
of catalytic protocols[2] have achieved significant progress in
the asymmetric addition of terminal alkynes to aldehydes,
amino alcohol ligand 1 exhibited a high asymmetric induc-
tion capability in the asymmetric addition of alkylzinc or
phenylzinc to aldehydes.[8] These studies prompted us to in-
vestigate the enantioselective
performance of cyclopropane-
based amino alcohol in the al-
kynylzinc addition to aldehydes.
Initially, in the presence of
10 mol% of 1, the asymmetric
addition of alkynylzinc to ben-
but only N-methylephedrine-Zn
A
amide alcohol–Ti[5] are practicable as catalytic systems.
However, these catalytic systems also hold obvious draw-
backs like high catalyst loading and the need for additional
zaldehyde afforded the corre-
reagents such as Ti
G
sponding propargylic alcohol in
tioselective and practical alkynylation of aldehydes cata-
lyzed by a cyclopropane-based amino alcohol zinc catalytic
system which does not require any additional titanium alk-
oxide.
heptane at 08C in 43% yield with 85% ee (Table 1,
entry 1); however, half of the benzaldehyde was not con-
verted. As a possible reason for the poor yield was the low
Chiral amino alcohols are one of the most widely em-
ployed types of ligands for asymmetric catalysis, and zinc
amino alcohol complexes have been shown to exhibit excel-
lent enantioselectivity in the alkylzinc addition to alde-
hydes,[6] but not, as yet, in the similar alkynylzinc addition to
aldehydes.[7] Chiral cyclopropane-based amino alcohols pos-
sess an advantageous combination of structural rigidity, low
molecular weight on a well-defined and highly variable plat-
form, and unusual bond angle. Earlier we found that the
Table 1. Enantioselective addition of phenylacetylene to benzaldehyde.[a]
Entry Ligand 1 [mol%]
Solvent
T
t
Yield[b] ee[c]
[8C] [h] [%]
[%]
1
2
3
4
5
6
7
10%
10%
heptane
toluene
toluene
0
0
0
36
36
48
43
91
99
97
90
45
43
85
84
94
92
95
96
96
10%+10% DiMPEG
10%+10% DiMPEGt toluene
10%+10% DiMPEG
10%+10% DiMPEG
10%+10% DiMPEG
20 48
À10 48
À20 65
À20 94
toluene
toluene
toluene
[a] Dr. J.-C. Zhong, Dr. S.-C. Hou, Dr. Q.-H. Bian, Dr. M.-M. Yin,
R.-S. Na, B. Zheng, Z.-Y. Li, Prof. M. Wang
Department of Applied Chemistry
China Agricultural University
[a] Reaction conditions: 2.6 mmol phenylacetylene, 2.4 mmol Me2Zn.
[b] Yield of isolated product. [c] Determined by HPLC on Chiralcel OD.
Beijing 100193 (China)
Fax : (+86)10-62815939
E-mail: wangmincau@yahoo.com.cn
solubility of the catalytic complex in the reaction solution,
subsequently toluene was used instead of heptane and the
reaction yield increased to 91%, whilst retaining the good
ee of 84% (Table 1, entry 2). Dahmen and Wang and co-
workers reported that the use of DiMPEG [dimethoxypoly-
(ethylene glycol), MW 2000] markedly improved the enantio-
selectivity in the addition of alkynes to aldehydes.[7d,i] In our
[b] Prof. S.-Z. Liu
Department of Applied Chemistry
China Agricultural University
Beijing 100193 (China)
Fax : (+86)10-62731070
E-mail: shangzho@cau.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900070.
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3069

case, the addition of 10 mol% of DiMPEG led to a dramatic
increase in the ee from 84% to 94% (Table 1, entries 2 and
3). This was the first time that such a high ee value was ob-
tained in the alkynylation of benzaldehyde using an amino
alcohol–zinc complex as catalyst system. Encouraged by this
exciting result, we further optimized the reaction conditions
as follows. Increasing the reaction temperature from 08C to
208C led to a decrease in the optical purity of the propargyl-
ic alcohols to 92% ee (Table 1, entry 4), whereas decreasing
the reaction temperature from 08C to À208C led to a slight
increase to 96% ee but this was accompanied by a decrease
in the yield of the reaction product to 45% (Table 1,
entry 6). Prolonging the reaction time to 94 h did not lead to
a distinct change in yield (Table 1, entry 7).
studies[9] have been reported to date that utilize the direct
asymmetric addition of an alkylpropiolate to aldehydes
rather than the traditional approach that involves the addi-
tion of propargyllithium and aldehyde, followed by oxida-
tion, and asymmetric reduction.[10] We attempted to use 1
with zinc to achieve the challenging asymmetric addition re-
action of methyl propiolate to benzaldehyde. Unfortunately,
when the optimized procedure used for the asymmetric ad-
dition of phenylacetylene to aldehydes was applied to the
reaction of methyl propiolate to benzaldehyde, the desired
reaction did not occur. However, in the absence of
DiMPEG, 10 mol% of 1 catalyzed the above reaction at
208C to give the highly optically active g-hydroxy-a,b-acety-
lenic esters in 87% yield and 88% ee. Decreasing the reac-
tion temperature to À108C led to an increase in the ee value
to 93%, but the yield decreased to 33%. Subsequently, by
increasing the catalyst loading to 20 mol%, the reaction
yield at 08C was improved to 66%, while the ee value re-
mained high at 92%. A series of aromatic aldehydes were
tested under these conditions; in all cases, 1 exhibited excel-
lent enantioselectivity (90–92% ee), and the results are sum-
marized in Table 3.
Under the optimized reaction conditions of entry 5 in
Table 1, 1 was used to catalyze the enantioselective addition
of phenylacetylene to a variety of aldehydes. As the results
summarized in Table 2 show, excellent enantioselectivity
Table 2. Enantioselective addition of alkynylzinc to aldehydes catalyzed
by 1.[a]
Table 3. Enantioselective addition of methyl propiolate to aldehydes.[a]
Entry
R
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
o-FC6H4
p-FC6H4
90
91
96
85
90
84
88
86
85
95
95
90
90
80
92
95
92
95
94
94
92
95
93
95
95
93
93
93
94
91
94
92
79
88
Entry
R
Ligand 1
[mol%]
T
[8C]
t
Yield[b]
[%]
ee[c]
[%]
G
[h]
p-BrC6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
o-CH3OC6H4
m-CH3OC6H4
p-CH3OC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
1-naphthyl
2-naphthyl
cyclohexyl
isopropyl
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
10
10
10
20
20
20
20
20
20
20
20
20
20
20
0
24
48
48
24
24
24
24
24
24
24
24
24
24
87
49
33
66
85
63
56
68
65
73
76
85
75
88
87
93
92
92
90
91
91
91
92
93
93
90
À10
0
9
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
m-CH3OC6H4
p-CH3OC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
1-naphthyl
0
0
0
0
0
0
0
0
10
11
12
13
14
15
16
17
9
10
11
12
13
0
[a] Reaction conditions: 2.6 mmol phenylacetylene, 2.4 mmol Me2Zn.
[b] Yield of isolated product. [c] Determined by HPLC on Chiralcel OD.
[a] Reaction conditions: 3.2 mmol Methyl propiolate, 3.0 mmol Me2Zn,
1 mmol aldehyde, toluene. [b] Yield of isolated product. [c] Determined
by HPLC on Chiralcel OD and AD.
(91–95% ee) was achieved for the reaction of phenylacety-
lene with aromatic aldehydes containing electron-donating
or electron-withdrawing substituents at the ortho-, meta-, or
para-positions, and good enantioselectivity (79%, 88%) was
also afforded in the reaction of phenylacetylene with ali-
phatic aldehydes (Table 2, entries 16 and 17). These results
showed that 1 is one of most efficient ligands for the asym-
metric addition of phenylacetylene to aldehydes.
To expand the scope of this reaction, we also examined
methyl propiolate as a nucleophile, with the aim to produce
optically active g-hydroxy-a,b-acetylenic esters, which are a
class of more versatile building blocks containing multifunc-
tional groups. With respect to its preparation, only a few of
In conclusion, we have demonstrated that the cyclopro-
pane-based amino alcohol–zinc complex is a highly enantio-
selective catalyst for the alkynylation of aldehydes under
mild reaction conditions, which alleviates the need for a tita-
nium alkoxide additive. Furthermore, this catalytic system
exhibited excellent enantioselectivity in the challenging
asymmetric reaction of methyl propiolate with aldehydes.
To the best of our knowledge, ligand 1 with zinc is the most
effective system reported to date for the asymmetric addi-
tion of alkynylzinc to aromatic aldehydes. Based on the re-
sults we have obtained, the optically active cyclopropane de-
rivative with its special structural configuration is a good po-
3070
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Chem. Eur. J. 2009, 15, 3069 – 3071

Highly Enantioselective Alkynylation of Aldehydes
COMMUNICATION
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Experimental Section
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General procedure for the asymmetric addition of phenylacetylene to al-
dehydes: Phenylacetylene (0.26 mL, 2.4 mmol, 2.4 equiv) was added to a
solution of Me2Zn (2 mL, 1.2m in toluene, 2.4 mmol, 2.4 equiv) in dry tol-
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(48 h), the mixture was treated with saturated NH4Cl solution and ex-
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iPrOH in hexanes if not stated otherwise).
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aldehydes: Methyl propiolate (0.29 mL, 3.2 mmol, 3.2 equiv) was added
to a solution of Me2Zn (2.5 mL, 1.2m in toluene, 3 mmol, 3.0 equiv) in
dry toluene (3.5 mL) at room temperature under an atmosphere of
argon, and stirred for 90 min. Then the solution was transferred by sy-
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was determined by HPLC (Chiralcel OD, 10% iPrOH in hexanes if not
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Acknowledgements
We are grateful to the National Natural Sciences Foundation of China
(No. 20742004 and No. 20572129) for financial support.
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Keywords: alkynylation
catalysis · zinc
· amino alcohols · asymmetric
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Received: January 12, 2009
Published online: February 13, 2009
Chem. Eur. J. 2009, 15, 3069 – 3071
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3071