Me3Ga-mediated addition of acetylenes to α-keto esters: A new method for the synthesis of α-hydroxy esters

Article abstract of DOI:10.1055/s-0030-1261173

Trimethylgallium reagent was found to promote the addition of acetylenes to various α-keto esters. This reaction was efficiently carried out in anhydrous hexane at room temperature under mild conditions, and the corresponding α-hydroxy esters were obtained in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261173

LETTER
2039
Me3Ga-Mediated Addition of Acetylenes to a-Keto Esters: A New Method for
the Synthesis of a-Hydroxy Esters
N
a
ew
M
ethod for th
o
e
S
ynthesis
n
of
a
-Hydrox
g
Esters lai Jiang,a Aijun Lin,a Hao Peng,a Yuhua Zhu,a Yi Pan,a Chengjian Zhu,*a,b Yixiang Cheng*a
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, P. R. of China
Fax +86(25)83594886; E-mail: cjzhu@nju.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
b
Received 24 April 2011
was reported by Huang in the synthesis of ketones from
acyl chlorides with the formation of lithium tetraorgan-
ogallates.8 To the best of our knowledge, there was no ex-
ample which applied organogallium reagents to the
addition of acetylenes to a-keto esters. Over the course of
our continuing studies on organogallium reagents,9 we
herein wish to report the novel synthesis of a-hydroxy es-
ters by the alkynylation of a-keto esters in the presence of
trimethylgallium.
Abstract: Trimethylgallium reagent was found to promote the ad-
dition of acetylenes to various a-keto esters. This reaction was effi-
ciently carried out in anhydrous hexane at room temperature under
mild conditions, and the corresponding a-hydroxy esters were ob-
tained in good to excellent yields.
Key words: trimethylgallium, alkynylation, a-keto ester, a-hy-
droxy ester, acetylene
The addition of organometallic reagents to a-keto esters
provides a straightforward synthetic way to a-hydroxy es-
ters containing quaternary centers. This kind of com-
pounds are useful intermediates in the synthesis of natural
products and biologically active molecules, and many are
bioactive themselves.1 The alkylation of a-keto esters
with organozinc reagents2 and Grignard reagents3 afford-
ed an easy route to such compounds. However, the alky-
nylation methods have been scarcely studied.4 Jiang
reported the alkynylation of a-keto esters catalyzed by
Zn(OTf)2 and amine4a and Cozzi reported the alkynylation
by using ZnMe2 with moderate yield.4b Although a few
significant results have been achieved in this area, the im-
portance of these compounds in academic research and in-
dustrial applications provides the constant driving force
for the development of this reaction.
Initially, the alkynylation of methyl benzoylformate (1)
with 4-methoxyphenylacetylene (2) was selected as the
model reaction with Me3Ga as a promoter at room temper-
ature for five hours. In order to obtain the optimized reac-
tion conditions, several different solvents were screened
to carry out the reaction. The results are summarized in
Table 1. In toluene, 1,2-dichloroethane, and dichlo-
romethane, the product was obtained in moderate yields
(Table 1, entries 1–3). However, no product was observed
when the reaction took place in THF. To our delight, the
yield was improved to 92% (Table 1, entry 5) when the
hexane was used as the media for the reaction. Further de-
creasing the amount of Me3Ga to 1.0 or 0.5 equivalent had
a negative impact on the yield (Table 1, entries 6 and 7).
With above optimized conditions in hand (Table 1, entry
5), a variety of a-keto esters were screened to evaluate the
scope of this reaction.10 The reaction was conducted in 1
mL hexane with 1.5 equivalents Me3Ga and 1.5 equiva-
lents acetylene. We were pleased to find that all a-keto
esters were quickly converted to the corresponding a-hy-
droxy esters in good to excellent yields. From the results
listed in Table 2, the ester group in the a-keto esters im-
posed a limit effect on the yield (Table 2, entries 1–4).
The best result was obtained with the isopropyl ester
(Table 2, entry 3). The electronic nature of the substitu-
ents on the a-keto esters had a slight influence on the yield
of the products. In general, a-keto esters with electron-
withdrawing substituents were more reactive; they needed
less time to complete the reaction than those with elec-
tron-donating substituents. A variety of acetylenes could
undergo the addition to the substrate (methyl benzoylfor-
mate). All acetylenes with electron-donating or electron-
withdrawing substituents gave good results, showing that
the electronic properties of the acetylenes had a negligible
effect on the yield (Table 2, entries 1, 14, and 15). It
should be noted that the heterocyclic aromatic and aliphat-
Recently, organogallium reagents have attracted consid-
erable attention in synthetic organic chemistry. Most of
the studies on the utilization of organogallium reagents
are based on the Lewis acidity of gallium. Maruoka5a and
Utimoto5b reported that trimethylgallium could be used as
a catalyst in the reaction of alkynyllithium with epoxides.
Our group presented the first example of enantioselective
isocyanosilylation of meso-epoxides using TMSCN to
form b-isocyanohydrins catalyzed by chiral organogalli-
um and organoindium complexes with moderate to excel-
lent enantioselectivities.6 Very recently, Yamaguchi
reported that trialkylgalliums could serve as a base to gen-
erate enolates from ketones, the resulting gallium enolates
underwent facile C-benzoylation,7a aldol reaction7a and a-
ethynylation reaction7b of ketones. The first example of
the utilization of trialkylgallium as an alkylation reagent
SYNLETT 2011, No. 14, pp 2039–2042
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x
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x
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Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261173; Art ID: W09811ST
© Georg Thieme Verlag Stuttgart · New York

2040
H. Jiang et al.
LETTER
Table 1 Optimization of Reaction Conditionsa
O
O
HO
OMe
Me3Gab
OMe
OMe
+
solvent, r.t., 5 h
O
1
2
2 (equiv)
1.5
3
OMe
Entry
Me3Ga (equiv)
Solvent
toluene
DCE
Yield (%)c
1
2
3
4
5
6
7
1.5
1.5
1.5
1.5
1.5
1.0
0.5
74
1.5
68.5
60
1.5
CH2Cl2
THF
1.5
n.r.
92
1.5
hexane
hexane
hexane
1.5
60
1.5
48
a All the reactions were carried out on 0.1 mmol scale of a-keto ester 1 with acetylene (2, 1.5 equiv) and Me3Ga (1.5 equiv) in hexane (1.0 mL)
for indicated time. See ref. 10 for experimental details.
b 1.0 M in toluene.
c Isolated yields.
ic a-keto esters were also good substrates for this reaction trimethylgallium as a promoter. The present method is ap-
(Table 2, entries 7 and 16). We also investigated the reac- plicable to various aromatic and aliphatic a-keto esters.
tion of aliphatic substituted acetylenes such as 1-heptyne This reaction did not require other Lewis acid and Lewis
and trimethylsilylacetylene with several a-keto esters un- base as catalyst. The corresponding a-hydroxy esters were
der the optimized conditions. Unfortunately, no products obtained in high yields under the mild reaction conditions.
were detected even at higher temperature (60 °C). This Further work is under way in our group to achieve the cat-
behavior could result from the low reactivity of alkyl acet- alytic asymmetric version of this reaction and other appli-
ylenes, which is consistent with Dahmen’s report.11
cation of organogallium reagent.
Although the mechanism of Me3Ga-mediated alkynyla-
tion of a-keto esters has not yet been clarified, a plausible
reaction mechanism was proposed in Scheme 1. The first
step involved the formation of alkynylgallium12 species 4,
in situ generated from acetylenes and trimethylgallium.
This intermediate further attacked the carbonyl of a-keto
esters to form the gallium alcoxide 5. Finally, hydrolysis
of gallium alcoxide 5 with saturated NH4Cl solution fur-
nished the corresponding a-hydroxy esters 3.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We gratefully acknowledge the National Natural Science Foundati-
on of China (20832001, 20972065, 21074054) and the National Ba-
sic Research Program of China (2007CB925103, 2010CB923303)
for their financial support.
In conclusion, we have developed the efficient and facile
addition of acetylenes to a-keto esters, which firstly using
References and Notes
Me3Ga
Ar
Ar
GaMe2
OR2
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Scheme 1 Proposed reaction course
Synlett 2011, No. 14, 2039–2042 © Thieme Stuttgart · New York

LETTER
New Method for the Synthesis of a-Hydroxy Esters
2041
Table 2 The Reaction of Different a-Keto Esters with Acetylenes under Optimized Conditionsa
O
O
HO
R1
OR2
Me3Ga, r.t.
hexane–tolueneb
OR2
Ar
+
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O
1
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3
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R1
R2
Ar
Product
3a
Time (h)
Yield (%)c
Ph
Me
Et
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
3.5
3.5
4
92
89
95
90
89
86
92
92
91
88
95
96
94
87
92
90
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Ph
3b
3c
3
Ph
i-Pr
Bn
Me
Me
Me
Et
4
Ph
3d
3e
6
5
4-FC6H4
5
6
2-thiophene
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-FC6H4
3,4-Me2C6H4
4-MeOC6H4
4-BrC6H4
Ph
3f
7
7
3g
8
8
3h
3i
3.5
5
9
Et
10
11
12
13
14
15
16
Et
3j
4
Et
3k
3l
5
Et
6
Et
3m
3n
3o
5
Me
Me
Et
6
Ph
4-FC6H4
10
5
Me
4-MeOC6H4
3p
a All the reactions were carried out on 0.1 mmol scale of a-keto esters with acetylenes (1.5 equiv) and Me3Ga (1.5 equiv) in hexane (1.0 mL)
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Synlett 2011, No. 14, 2039–2042 © Thieme Stuttgart · New York

2042
H. Jiang et al.
LETTER
gave the crude product, which was further purified by
preparative TLC (PE–EtOAc = 10:1) to give corresponding
a-hydroxy esters.
phenylacetylene (20 mg, 0.15 mmol) were dissolved in
anhyd hexane (1 mL) and stirred for 1 h at r.t. under an
nitrogen atmosphere. Then the mixture was cooled to 0 °C
and methyl benzoylformate (0.1 mmol) was added, and
stirred at r.t. for indicated time in Table 2, then sat. NH4Cl (1
mL) was added to quench the reaction. The aqueous layer
was separated and further extracted with EtOAc, the organic
layers were combined and dried. Evaporation of the solvent
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Synlett 2011, No. 14, 2039–2042 © Thieme Stuttgart · New York

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