Me3Ga-mediated alkynylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2007.12.086

The trimethylgallium reagent was found to promote the addition of phenylacetylene to various aromatic and aliphatic aldehydes. This reaction was efficiently carried out in anhydrous CH₂Cl₂ at room temperature under mild conditions an

Full text of DOI:10.1016/j.tetlet.2007.12.086

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1370–1372
Me3Ga-mediated alkynylation of aldehydes
Xuefeng Jia a, Hongwei Yang a, Ling Fang a, Chengjian Zhu a,b,
*
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received 20 September 2007; revised 16 December 2007; accepted 18 December 2007
Available online 23 December 2007
Abstract
The trimethylgallium reagent was found to promote the addition of phenylacetylene to various aromatic and aliphatic aldehydes. This
reaction was efficiently carried out in anhydrous CH2Cl2 at room temperature under mild conditions and the corresponding propargylic
alcohols were obtained in good to excellent yields up to 98%.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Trimethylgallium; Alkynylation; Propargylic alcohol; Benzaldehyde
The alkynylation of carbonyl compounds is one of the
most useful carbon carbon bond-forming reactions.1 The
corresponding propargylic alcohols are important and ver-
satile building blocks for many biologically active com-
pounds and natural products such as adociacetylene B,2a
longimicin D,2b leukotriene B4,2c and steroids,2d and have
gained considerable significance in recent years. The nucle-
ophilic addition of alkynylmetals containing Ce,3 B,4 V5
and Al6 to carbonyl compounds represents a type of useful
methods for producing these compounds. However, these
methods are not straightforward, because most of these
alkynylmetals must be generated by the transmetalation
of Li, Na, or Mg acetylides,7 and low temperature condi-
tion is required to stabilize the metal acetylides. On the
other hand, the combined use of a Lewis acid, such as
Sn(OTf)2,8 GaI3,9 Zn(OTf)2,10a ZnCl2,10b and InBr3,11 with
a Lewis base, such as an amine, provides a practical
method for the preparation of propargylic alcohols in
stoichiometric or catalytic amounts. Apart from the
methods mentioned above, stoichiometric amounts of
dialkylzinc reagents are also widely used for synthesis of
propargylic alcohols with or without Lewis acid.12
Although many significant results have been achieved in
this area, the importance of these compounds in academic
research and industrial applications provides the constant
driving force for the development of this reaction.
Recently, organogallium reagents have attracted consid-
erable attention in synthetic organic chemistry. However,
the synthetic potential of organogallium compounds has
scarcely been explored because of their very low reactivity
toward most organic electrophiles. Most of the studies on
the utilization of organogallium are based on the Lewis
acidity of gallium. Maruoka et al.13a and Utimoto
et al.13b 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 organogallium and
organoindium complexes with moderate to excellent
enantioselectivities.14 Very recently, Yamaguchi et al.
reported that trialkylgalliums could serve as a base to gen-
erate enolates from ketones, the resulting gallium enolates
underwent facile C-benzoylation,15a an aldol reaction15a
and a-ethynylation reaction15b of ketones. The first exam-
ple of the utilization of trialkylgallium as an alkylation
reagent was reported by Huang et al. in the synthesis of
ketones from acyl chlorides with the formation of lithium
tetraorganogallates.16 To the best of our knowledge, there
*
Corresponding author. Tel.: +86 25 83594886; fax: +86 25 83317761.
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.086

X. Jia et al. / Tetrahedron Letters 49 (2008) 1370–1372
1371
Table 2
are few examples which apply organogallium reagent to the
Alkynylation of aldehydes with phenylacetylene mediated by Me3Gaa
addition of phenylacetylene to aldehydes. Over the course
of our continuing studies on organogallium reagents,17
we herein wish to report the novel synthesis of propargylic
alcohols by the alkynylation of aldehydes in the presence of
trimethylgallium.
OH
Me3Ga
O
Ph
R
R
H
CH2Cl2, rt
Ph
1
3
2
Entry Aldehyde
Product Time (h) Yieldb (%)
Initially, the commercially available 1 M solution of
Me3Ga in toluene was mixed with phenylacetylene
(1.2 equiv each) in anhydrous CH2Cl2 at room temperature
and an hour later benzaldehyde (1 equiv) was added, 1,3-
diphenylprop-2-yn-1-ol was isolated in 40% yield after
reacting for 24 h (entry 1).18 When the amount of phenyl-
acetylene (2 equiv) and trimethylgallium (2.2 equiv) was
increased, the yield of the product was promoted to 65%
(entry 2). To obtain the optimized reaction conditions,
we changed the amount and ratio of phenylacetylene and
trimethylgallium reagent, then carried out the reaction
using several different solvents. The results are summarized
in Table 1. Consequently, we found that the yield of the
product was improved to 95% when the mixture of phenyl-
acetylene (2.5 equiv) and Me3Ga (3 equiv) was used (entry
5). Methane dichloride was the best solvent among all the
ones examined. In contrast, in the cases of 1,2-dichloro-
ethane and toluene, the yields decreased sharply (entries 7
and 8). When THF and hexane were used, no alkynylation
product was observed (entries 9 and 10).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a
Benzaldehyde
3a
3b
3c
3d
3e
24
8
8
8
8
95
91
94
98
90
86
88
85
84
84
79
88
88
75
72
74
84
67
4-Nitrobenzaldehyde
3-Nitrobenzaldehyde
2-Nitrobenzaldehyde
3-Bromobenzaldehyde
2-Fluoromethylbenzaldehyde 3f
24
18
24
24
18
36
24
24
24
24
24
24
36
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehye
o-Tolualdehyde
m-Tolualdehyde
2-Furaldehyde
Thiophene-2-carboxaldehyde 3m
2-Naphthaldehyde
Butyraldehyde
Isobutyraldehyde
Isovaleraldehyde
Cinnamaldehyde
3g
3h
3i
3j
3k
3l
3n
3o
3p
3q
3s
All reactions were performed on 0.5 mmol scale of substrates for
indicated time, detail experiments see Ref. 18.
b
Isolated yields.
With above optimized conditions in hand, a variety of
aromatic and aliphatic aldehydes were screened to evaluate
the scope of this reaction. We were pleased to find that all
substrates were smoothly converted to the corresponding
propargylic alcohols in good to excellent yields. The results
are listed in Table 2. The reactivity of different aromatic
aldehydes was influenced by the nature and position of
the substituents on the aromatic ring. The benzaldehyde
derivatives having an electron-withdrawing substituent
were highly reactive and gave the products in excellent
yields (entries 2–8). Changing the substituent from nitro
to trifluoromethyl, halogens groups, the yields of the prod-
ucts had a slight decrease. It was surprising that the addi-
tion of phenylacetylene to the sterically more hindered
carbonyl group in 2-nitro- and 2-chlorobenzaldehyde pro-
ceeded easier than 4-substituted congeners. Especially 2-
nitrobenzaldehyde gave the product in nearly quantitative
yield (entry 4). This behavior could be explained by a
strong inductive effect from 2-substituents. When the
aromatic aldehydes containing electron-donating group
(–Me, –OMe) were used, the yields of the products
decreased slightly (entries 9–11). In the case of m-tolualde-
hyde, reaction time was prolonged to obtain a satisfactory
yield (entry 10). It should be noted that the heterocyclic
aromatic aldehydes and 2-naphthaldehyde were also good
substrates for this reaction (entries 12–14). More impor-
tantly, our method was also suitable to both linear and
branched aliphatic aldehydes (entries 15–17), for example,
the alkynylation of isovaleraldehyde proceeded with 84%
yield (entry 17). For the a,b-unsaturated cinnamaldehyde,
good result was also observed when reaction time was
increased to 36 h (entry 18).
Table 1
Optimization of reaction conditionsa
O
OH
Me3Ga
H
Ph
Ph
Solvent, rt, 24 h
Entry
Phenylacetylene
(equiv)
Me3Ga
(equiv)
Solvent
Yieldb
(%)
1
2
3
4
5
6
7
8
9
1.2
2
2
2
2.5
3
2.5
2.5
2.5
2.5
1.2
2.2
2.5
3
3
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClC2H4Cl
Toluene
THF
40
65
84
90
95
86
64
54
We also checked the reaction of aliphatic-substituted
acetylene such as 1-heptyne with several aldehydes under
optimized conditions. Unfortunately, no products were
detected. This behavior could result from the low reactivity
of alkyl acetylene. Du et al. have also reported that alkyl-
substituted acetylene did not work in their conditions.12e
According to Dahmen’s report, less acidic acetylene
required a higher deprotonation temperature.12j We then
NDc
NDc
10
a
Hexane
All reactions were carried out in anhydrous solvent at room temper-
ature for 24 h.
b
Isolated yields based on the benzaldehyde.
ND = not detected.
c

1372
X. Jia et al. / Tetrahedron Letters 49 (2008) 1370–1372
Tanaka, T. Eur. J. Org. Chem. 2006, 1422; (c) Treilhou, M.; Fauve,
Me3Ga
´
A.; Pougny, J.-R.; Prome, J.-C.; Veschambref, H. J. Org. Chem. 1992,
Ph
H
Ph
GaMe2
57, 3203; (d) Sierra, M. A.; Torres, M. R. J. Org. Chem. 2007, 72,
4213.
3. Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25,
4233.
4
CH4
RCHO
4. Brown, H. C.; Molander, G. A.; Singh, S. M.; Racherla, U. S. J. Org.
Chem. 1985, 50, 1577.
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A. R. J. Org. Chem. 1999, 64, 488; (b) Ahn, J. H.; Joung, M. J.; Yoon,
N. M. J. Org. Chem. 1995, 60, 6173.
OH
R
Ph
3
Scheme 1. Proposed reaction course.
7. Hurdlik, P. F.; Hurdlik, A. M. In The Chemistry of the Carbon–
Carbon Triple Bond; Patai, S., Ed.; John Wiley and Sons: New York,
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carried out the reaction of 1-heptyne with aldehydes med-
iated by Me3Ga at higher temperature (60 °C), and the
products were not obtained. This demonstrated that ali-
phatic terminal alkynes could not be applied to our reac-
tion systems.
9. Han, Y.; Huang, Y.-Z. Tetrahedron Lett. 1995, 36, 7277.
ꢀ
Although the mechanism of Me3Ga-mediated alkynyl-
ation of aldehydes has not yet been clarified, we presume
that the first step involves the formation of alkynylgallium
species 4, in situ generated from phenylacetylene and trim-
ethylgallium, which is most likely as the reactive intermedi-
ate, and this intermediate further attack carbonyl of
aldehydes to produce the corresponding propargylic alco-
hols 3 in the following step (Scheme 1).
In conclusion, we have described the efficient and facile
addition of phenylacetylene to aldehydes using trimethyl-
gallium as a promoter. The present method is complemen-
tary to the previously reported methods, and applicable to
various aromatic and aliphatic aldehydes. This reaction did
not require other Lewis acid catalyst and the use of Lewis
base. The corresponding propargylic alcohols were
obtained in high yields under the mild reaction conditions.
Further work is underway in our group to achieve the
catalytic asymmetric version of this reaction and other
application of organogallium reagent.
10. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
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Acknowledgments
15. (a) Nishimura, Y.; Miyake, Y.; Amemiya, R.; Yamaguchi, M. Org.
Lett. 2006, 8, 5077; (b) Nishimura, Y.; Amemiya, R.; Yamaguchi, M.
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We gratefully acknowledge the National Natural Sci-
ence Foundation of China (20472028, 20332050 and
20672053) and the National Basic Research Program of
China (2007CB925103) for their financial support. The
Program for New Century Excellent Talents in the Univer-
sity of China (NCET-06-0425) is also acknowledged.
17. Dai, Z. Y.; Zhu, C. J.; Yang, M. H.; Zheng, Y. F.; Pan, Y.
Tetrahedron: Asymmetry 2005, 16, 605.
18. General procedure for alkynylation of various aldehyde: In a 20 mL
Schlenk reaction tube, commercially available 1 M solution of Me3Ga
(1.5 mL, 1.5 mmol, 1 M in toluene) was mixed with phenylacetylene
(0.125 mL, 1.25 mmol) in anhydrous CH2Cl2 (3 mL) at room
temperature under an argon atmosphere. The solution was stirred
for an hour followed by the addition of aldehyde (0.5 mmol). After
the resulting mixture was stirred at this temperature for indicated time
in Table 2, water (4 mL) was added to quench the reaction. The
aqueous layer was separated and further extracted with dichloro-
methane; the organic layers were combined and dried. Evaporation of
the solvent gave the crude product, which was further purified by
preparative TLC (petroleum ether–ethyl acetate = 5:1) to give corres-
ponding propargylic alcohols.
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