Alkynylation of carbonyl compounds with terminal acetylenes promoted by ZnCl2 and Et3N: Simple, mild and efficient preparation of propargylic alcohols

Article abstract of DOI:10.1016/S0040-4039(02)01986-X

A mild and efficient addition of terminal acetylenes to carbonyl compounds in the presence of ZnCl₂ and Et₃N gives propargylic alcohols in good to high yields.

Full text of DOI:10.1016/S0040-4039(02)01986-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8323–8325
Alkynylation of carbonyl compounds with terminal acetylenes
promoted by ZnCl2 and Et3N: simple, mild and efficient
preparation of propargylic alcohols
Biao Jiang* and Yu-Gui Si
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, PR China
Received 26 July 2002; revised 2 September 2002; accepted 13 September 2002
Abstract—A mild and efficient addition of terminal acetylenes to carbonyl compounds in the presence of ZnCl2 and Et3N gives
propargylic alcohols in good to high yields. © 2002 Elsevier Science Ltd. All rights reserved.
Propargylic alcohols are often key intermediates in the
synthesis of many natural products such as
prostaglandins, steroids, carotenoids etc.1 The most
common method to obtain propargylic alcohols is the
addition of alkynylmetals to aldehydes and ketones.
However, the high reactivity and strong basicity of
many alkynylmetals including alkynyl-Li, Na, K and
Mg, also cause undesired side reactions.2 Several
improved procedures including addition of alkynyl-B,3
Al,4 Ce5 and V6 prepared from the transmetallation of
alkali or alkali earth metal derivatives to carbonyl
compounds have been reported. However, these meth-
ods are not straightforward. The addition of the metal
acetylide generated in situ to carbonyl compounds is a
good choice for this purpose. Recently, considerable
progress has been developed in the alkynylation of
aldehydes using a Lewis acid in combination with a
marized in Table 1. We found that ZnCl2 efficiently
promoted the alkynylation reaction of benzaldehyde 1a
with phenylacetylene 2a as did Zn(OTf)2. It is worth
noting that the inexpensive ZnCl2 gave almost the same
yield as Zn(OTf)2 (Scheme 1).
In subsequent studies, we used ZnCl2 to promote the
alkynylation reaction of various carbonyl compounds.
Thus, a mixture of terminal alkyne (1.1 mmol), anhy-
drous ZnCl2 (1.5 mmol) and Et3N (1.5 mmol) in tolu-
ene was stirred at 35°C for 1 h, then a carbonyl
Table 1. Reaction of phenylacetylene with benzaldehyde in
the presence of zinc salts and Et3Na
Entry
Zinc salts
Yieldb
base. For example, SnCl4,7 GaI3,8 Sn(OTf)2 and
9
1
2
3
4
Zn(OTf)2
ZnCl2
ZnCO3
92
91
15
0
Zn(OTf)210 were all reported to promote the addition of
alkynes to aldehydes successfully. In contrast, a few
successes have been achieved in the nucleophilic alkynyl-
ation of ketones with zinc alkynide complexes.11
Despite a number of Lewis acid and Lewis base systems
having been developed for the alkynylation of alde-
hydes, no attention was paid to the inexpensive ZnCl2
as a promoter. In this communication, we disclose the
alkynylation of aldehydes and ketones simply promoted
by ZnCl2 in the presence of Et3N, furnishing propar-
gylic alcohols in moderate to high yields.
Zn3(PO4)2
a Carried out with 1.0 molar equiv. of benzaldehyde, 1.1 molar equiv.
of phenylacetylene , 1.5 molar equiv. of the zinc(II) salt, 1.5 molar
equiv. of Et3N in toluene at 35°C for 10 h.
b Isolated yields.
A preliminary screening of commercially available zinc
salts as promoters for the alkynylation reaction is sum-
* Corresponding author.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01986-X

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B. Jiang, Y.-G. Si / Tetrahedron Letters 43 (2002) 8323–8325
Table 2. The alkynylation of carbonyl compound 1 via
ZnCl2 and Et3Na
Scheme 2.
low yield (10%) of an addition product was obtained.
This may be due to enolization of the aryl ketone in the
presence of the base, so that the alkynylation reaction
was inhibited. Using trifluoroacetylbenzene to avoid the
enolization led to the corresponding trifluoromethyl-
ated propargylic alcohol in good yield (entry 12). When
the phenylacetylene was changed to alkyl acetylenes,
such as cyclopropylacetylene or hindered t-butyl-
acetylene, propargylic alcohols were isolated in good
yields (entries 13 and 14). In particular, 4-chloro-2-tri-
fluoroacetylaniline underwent the addition reaction
with cyclopropylacetylene to furnish the corresponding
trifluoromethylated propargylic alcohol in 70% yield
(entry 15), which is a cost-effective process for the
preparation of a new class of potent non-nucleoside
reverse transcriptase inhibitors (Scheme 2).12,13
In conclusion, we have described an extensive study of
addition reactions to aldehydes and ketones by terminal
acetylenes utilizing inexpensive ZnCl2 as the promoter.
This simple and cost-effective process is attractive for
the chemical industry.
Acknowledgements
This work was financially supported by the Shanghai
Municipal Committee of Science and Technology,
Shanghai Overseas Scholarship and the National Natu-
ral Science Foundation of China.
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