LETTER
Efficient Syntheses of Cyclopropylacetylene
1949
Cl
Keeping convenience and practicality in mind, a two step
process was carried out without purification of intermedi-
ates under the preferred conditions which were explored
O
i
Cl
CH2
PCl5, Pr2NEt
Cl
+
PhCH3, 40 °C, 0.6 h
then reflux, 2 h
CH3
CH3
2
5 (32%)
3
(12%)
4
in our laboratories (Scheme 4). Presumably because a
t
KO Bu
nonpolar solvent can help to suppress ring opening and
enyne synthesis (vide supra), toluene was more efficient
when compared with other polar solvents including
dichloromethane, etheral solvents, etc. Due to its relative-
ly high boiling point, the distillation directly from the re-
action was anticipated to be facile, delivering the desired
acetylene 1 in the distillate.
+
t
PhCH3, BuOH
1
reflux, 2 h
7
(11% from 2)
(1% from 2)
Scheme 2
fort to avert these problems, it was found that steam distil-
lation directly from the reaction mixture offered a quick
and facile purification, delivering a toluene solution con-
taining 5 and 3 in a 44% combined yield. Subsequently,
the distilled mixture was subjected to elimination, leading
to the production of acetylene 1 along with enyne 7. Be-
cause of the failure to separate the two products, alterna-
tive conditions were sought to effect dehydrochlorination
selectively without concomitant formation of enyne 7.
O
1. PCl , PhCH , -10 °C, 3 h
5
3
CH3 2. KOtBu, PhCH , 40 °C, 4 h
2
3
1
4
3%
Scheme 4
At a low temperature, ketone 2 was smoothly converted to
dichloride 3, and the crude reaction mixture was treated
with excess base to minimize the formation of ring open-
ing product 4. The toluene solution of the crude dichloride
was subjected to elimination without further purification
at low temperature. Although efficient stirring was inhib-
ited by the formation of a brown gel, the reaction went to
completion upon standing over 4 hours. Cyclopropylacet-
ylene 1 was produced from cyclopropyl methyl ketone 2
in 43% yield after distillation and washing the distillate
with water.4
Cl
t
t
Cl
KO Bu, BuOH
+
CH3
PhCH3
then distillation
,
40 °C
1
7
3
(4
:
1)
Scheme 3
To investigate the source of enyne 7, we then focused on
the dehydrochlorination reaction of dichloride 3 (Scheme
Although the isolation yield of the target molecule is mod-
erate, this methodology is an improvement over the
known methods in terms of yield and reproducibility. Fur-
thermore, these conditions were pragmatic and conve-
nient, producing the desired acetylene 1 free from known
side products. Moreover, this two step sequence simpli-
fies the purification process, which was one of the most
difficult shortcomings to overcome. As a consequence,
this synthetic protocol is believed to be cost effective and
facile on an industrial scale, offering an alternative route
for the synthesis of cyclopropylacetylene.
3
), which was obtained cleanly from the chlorination in
4
absence of base. It was found that double elimination of
dichloride 3 resulted in a mixture of 1 and 7, implying that
7
was generated from 3 but not 5 through a different
mechanistic pathway. More importantly, at higher reac-
tion temperatures, more enyne 7 was observed, suggesting
an enhancement of a side reaction via a higher energy spe-
cies such as the internal olefin 6 (Figure 3). Therefore, it
was hypothesized that the formation of terminal olefin 5,
and subsequently 1, was kinetically favored. This prompt-
ed us to employ use of a hindered base in a nonpolar me-
dia at a low temperature for optimum results. This
approach was implemented successfully to prevent the References and Notes
production of enyne 7, as delineated in the Scheme 4.
(
1) Efavirenz (DMP-266) was recently developed at Merck
Research Laboratories. (a) Thompson, A.; Corley, E. G.;
Huntington, M. F.; Grabowski, E. J. J.; Remenar, J. F.;
Collum, D. B. J. Am. Chem. Soc. 1998, 120, 2028. (b) Young,
S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W.
C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.;
Carrol, S. S.; Pettibone, D. J.; O’Brien, J. A.; Ball, R. G.;
Balani, S. K.; Lin, J. H.; Chen, I-W; Schleif, W. A.; Sardana,
V. V.; Long, W. J., Byrnes, V. W.; Emini, E. A. Antimicrob.
Agents Chemother. 1995, 39, 2602. (c) Thompson, A. S.;
Corley, E. G.; Huntington, M. F.; Grabowski, E. J. J.
Tetrahedron Lett. 1995, 36, 8937.
Cl
1
kinetic
C
H
H
Cl
5
Cl
CH3
3
high
temp.
Cl
7
CH3
(
2) (a) Schoberth, W.; Hanack, M. Synthesis 1972, 703. (b)
Hanack, M.; Bässler, T. J. Am. Chem. Soc. 1969, 91, 2117. (c)
Hudson, C. E.; Bauld, N. L. J. Am. Chem. Soc. 1972, 94, 1158.
H
6
Figure 3
(
d) Salaün, J. J. Org. Chem. 1976, 41, 1237. (e) Dolgii, I. E.;
Synlett 1999, No. 12, 1948–1950 ISSN 0936-5214 © Thieme Stuttgart · New York