J . Org. Chem. 2000, 65, 1889-1891
1889
aldehydes to terminal alkynes through a three-step
reaction sequence: addition of dihalomethyllithium to
aldehydes, sulfonation of the adducts, and then elimina-
tion of chloride and tosylate followed by elimination of
HX to generate the desired alkynes.2 Although this is a
good method for the synthesis of alkynes from aldehydes,
it is still necessary to handle a thermolabile and moisture-
sensitive species, dihalomethyllithium, at low tempera-
ture (-78 to -50 °C) for good yields. To better meet our
project needs, we have developed a better preparation of
1 and a general reaction sequence for the conversion of
aldehydes to terminal alkynes. In this report, we disclose
a new methodology for the synthesis of terminal alkynes.
This process has three steps: (1) addition of trichloro-
methyl anion generated in situ from trichloroacetic acid
to aldehydes 2 to form trichloro alcohols 3; (2) transfor-
mation of 3 into trichlorosulfonates 4; and finally, (3)
sequential elimination of chloride, tosylate, and HCl
followed by metalation of the remaining chloride and
protonation to generate the desired alkynes, 5 (Scheme
1).
This procedure works well for our target: cyclopropyl-
acetylene 1. We have applied this procedure for the
synthesis of cyclopropylacetylene in 300-400 g scale in
approximately 80% overall yield. Furthermore, this reac-
tion sequence provides a simple, reliable, and economical
general methodology for the conversion of aldehydes to
terminal alkynes with excellent yields (Table 1).
Trichlorocarbinols are useful synthons in organic syn-
thesis,9 which can be obtained by the reaction of chloro-
form and strong base in the presence of an aldehyde.10
Recently, the Corey group developed a superior method
for the preparation of trichlorocarbinols which we found
fits well into our reaction sequence.11 In the presence of
aldehydes, trichloromethyl anion was generated by de-
carboxylation at room temperature when trichloroacetic
acid was mixed with sodium trichloroacetate in DMF,
which in turn added to aldehydes 2 to form the desired
trichloromethyl carbinols 3. The release of carbon dioxide
of this reaction was observed during the first 5-10 min
after the addition of sodium trichloroacetate in one
portion; however, it took 1.5-2.0 h for the completion of
the decarboxylation. The yields of the preparation of
trichlorocarbinols are summarized in Table 1.
A P r a ctica l P r ep a r a tion of Ter m in a l
Alk yn es fr om Ald eh yd es
Zhe Wang,* Silvio Campagna, Kaihong Yang,†
Guoyou Xu, Michael E. Pierce,
J oseph. M. Fortunak, and Pat. N. Confalone
DuPont Pharmaceuticals Company,
Research & Development, Chambers Works,
Deepwater, New J ersey 08023
Received October 21, 1999
As a part of the project for the development of an
economical and efficient synthesis of Efavirenz (Sustiva,
DMP 266), a marketed nonnucleoside reverse tran-
scriptase inhibitor of the HIV-1 virus developed by our
company for the treatment of AIDS,1 we have searched
for new methodologies for the synthesis of cyclopropyl-
acetylene 1 (CPA). As discussed previously,2 we antici-
pated that the most efficient synthesis of 1 would occur
from cyclopropylcarboxaldehyde via a one carbon homolo-
gation.
Alkynes are useful and versatile intermediates in
organic synthesis.3 The utility of the acetylenic functional
group in organic chemistry has been well documented.4
The most frequently used methods for the conversion of
aldehydes to terminal alkynes include the reactions of
Corey-Fuchs,5 Wittig/Horner-Emmons,6 and Gilbert-
Seyferth7 and its modifications.8 However, the need for
phosphorus reagents limits the usefulness of these ap-
plications due to toxicity, exothermicity, and voluminous
waste streams, particularly for large scale preparations.
As an extension of our preparation of 1, we have
developed an alternative approach for the conversion of
* Corresponding author. Telephone: (856) 540 4898; fax: (856) 540
4803; email: zhe.wang@dupontpharma.com.
† Current address: Department of Chemistry, The University of
Tennessee, Knoxville, TN 37996.
(1) (a) Pierce, M. E.; Parsons, R. L.; Radesca, L. A.; Lo, Y. S.;
Silverman, S.; Moore, J . R.; Islam, Q.; Choudhury, A.; Fortunak, J .
M.; Nguyen, D.; Luo, C.; Morgan, S. J .; Davis, W. P.; Confalone, P. N.;
Chen, C.; Tillyer, R. D.; Frey, L.; Tan, L.; Xu, F.; Zhao, D.; Thompson,
A. S.; Corley, E. G.; Grabowski, E. J . J .; Reamer, R.; Reider, P. J . J .
Org. Chem. 1998, 63, 8536. (b) Corley, E. G.; Thompson, A. S.;
Huntington, M. Org. Synth., submitted for publication. (c) Schoberth,
W.; Hanack, M. Synthesis 1972, 703. (d) Liang, S.; Price, T. W.; Nolen,
D. B.; Attride, D. C. US Patent 5,502,257, 1996; Chem. Abstr. 1996,
125, 10231. (e) Torihara, M.; Minagawa, Y. J apan Patent Application
H08-233884, 1996.
(2) Wang, Z.; Yin, J .; Campagna, S.; Pesti, J . A.; Fortunak, J . M. J .
Org. Chem. 1999, 64, 6918.
(3) Patai, S. Ed. The Chemistry of Carbon-Carbon Triple Bond;
Wiley: New York, 1978.
(4) Stang, P. J .; Diederich, F., Ed. Modern Acetylene Chemistry;
VCH: New York, 1995.
(5) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(6) (a) Corey, E. J .; Achiwa, K.; Katzenellenbogen, J . A. J . Am. Chem.
Soc. 1969, 91, 4318. (b) Horner, L.; Hoffmann, H.; Wippel, H. G. Chem.
Ber. 1958, 61. (c) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klaher, G.
Chem. Ber. 1959, 2499. (d) Wadsworth, W. S., J r.; Emmons, W. D. J .
Am. Chem. Soc. 1961, 83, 1733. (e) Villieras, J .; Perriot, P.; Normant,
J . F. Synthesis 1975, 458.
(7) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1982, 47, 1837.
(8) Muller, S.; Liepold, B.; Roth, G. J .; Bestman, H. J . Synlett 1996,
521.
The trichlorocarbinols 3 were efficiently transformed
into their corresponding acetate or methanesulfonate
esters by treatment with acetyl chloride or methane-
sulfonyl chloride, respectively, in the presence of triethyl-
amine. However, some of these compounds were low-
melting solids, inconvenient for large-scale purification.
Instead, we turned our attention to synthesize trichlo-
rocarbinol p-toluenesulfonates 4. The conventional meth-
ods12 (p-toluenesulfonyl chloride, triethylamine or pyri-
dine) for the synthesis of tosylates 4 produced poor
results, probably due to the steric hindrance arising from
three chlorine atoms adjacent to the hydroxide in the
molecules 3. It is possible to convert cyclopropyl trichlo-
(9) Corey, E. J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906.
(10) Gallina, C.; Giordano, C. Synthesis 1989, 466.
(11) Corey, E. J .; Link, J . O.; Shao, Y. Tetrahedron Lett. 1992, 3435.
(12) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183.
10.1021/jo9916582 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000