We have now developed a significantly simplified two-
step synthesis of alkoxyvinylcyclopropanes that is based on
relatively inexpensive reagents and can be conducted safely
on a multigram scale. The procedure is illustrated for the
preparation of 1-(2-methyoxyethoxy)-1-vinylcyclopropane
(9). The selection of the methoxyethyl group is based on
cost and volatility considerations. This ether is less volatile
and therefore easier to use than the corresponding methyl
and ethyl ethers, and 2-methoxyethanol is relatively inex-
pensive. In an optimized procedure 1,3-butadiene (6) was
monobrominated using N-bromosuccinimide6 with con-
comitant incorporation of an equivalent of the solvent,
2-methoxyethanol, to produce bromo ether intermediate 7.
In situ dehydrohalogenation was accomplished by portion-
wise addition of 2.2 equiv of KOH7 to give 8 in 44-57%
isolated yield.8 Modified Simmons-Smith conditions were
used to effect selective cyclopropanation of the more electron
rich double bond of 8 in 53% yield.9 These reactions have
been regularly conducted in our laboratories on a multigram
scale (Scheme 2). This modified synthesis allows access to
readily purified by vacuum distillation and are sufficiently
nonvolatile to minimize evaporative losses during weighing
and handling.
With the availability of the new five-carbon reagent 9,
the next issue to be addressed was its performance relative
to reagent 5 in [5 + 2] cycloadditions. The comparison of
reagents 5 and 9 in the [5 + 2] cycloaddition is presented in
Table 1.5 Vinylcyclopropane 9 clearly functions as a
Table 1. Comparison of [5 + 2] Cycloadditions of 5 and 9
Scheme 2
competent substrate for these cycloadditions, giving in these
unoptimized procedures comparable cycloadduct yields at
somewhat longer reaction times.
In an effort to determine whether the reaction rates with
9 could be increased, changes in the reaction conditions were
explored. Toward this end, the use of 1,2-dichloroethane
instead of dichloromethane was found to be beneficial and
a temperature increase from 40 to 80 °C was tolerated
without decomposition of the catalyst or reagents. The
combined changes proved to be of significant benefit: the
cycloaddition of 9 with methyl propargyl ether (1.3 equiv)
in the presence of only 0.5 mol % of [Rh(CO)2Cl]2 in DCE
at 80 °C was complete within 15 min and provided upon
hydrolysis of the resulting enol ether cycloadduct (1% HCl/
MeOH) cycloheptenone 14 in 92% isolated yield (Table 2,
entry 5). Compared to our preVious results, this represents
9 in 30% overall yield at less than one-tenth the cost per
mole of generating 5 and without the use of highly reactive
metals.10 In addition, methoxyethyl ethers 8 and 9 can be
(2) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995,
117, 4720-4721. Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J.
A. J. Am. Chem. Soc. 1998, 120, 1940-1941. Wender, P. A.; Husfeld, C.
O.; Langkopf, E.; Love, J. A. Pleuss, N. Tetrahedron 1998, 54, 7203-
7220. Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998, 120,
10976-10977. Wender, P. A.; Sperandio, D. J. Org. Chem. 1998, 63, 4164-
4165. Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J.
A. J. Am. Chem. Soc. 1999, 121, 5348-5349. Wender, P. A.; Fuji, M.;
Husfeld, C. O.; Love, J. A. Org. Lett 1999, 1, 137-139. Wender, P. A.;
Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H. J.
Am. Chem. Soc. 1999, 121, 10442-10443. For recent studies from other
laboratories see: Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett. 1998,
39, 2075-2078. Binger, P. Wedemann, P. Kozhushkov, S. I. de Meijere,
A. Eur. J. Org. Chem. 1998, 113-119. Trost, B. M.; Toste, F. D.; Shen,
H. J. Am. Chem. Soc. 2000, 122, 2379-2380.
(8) In a representative procedure, N-bromosuccinimide (100 g, 0.56 mol)
and 2-methoxyethanol (560 mL) are added to a two-neck round-bottom
flask under a nitrogen atmosphere. The suspension is cooled to -78 °C at
which point condensed 1,3-butadiene (60 mL, 0.75 mol) is added. The
reaction is allowed to warm to rt with vigorous stirring. After 16 h to the
now clear and colorless solution is added portionwise KOH (85%, 82 g,
1.24 mol) (see safety note, ref 7). The mixture turns a deep red color and
reaches 90 °C due to the exothermic nature of the reaction. Upon cooling
to rt, the reaction is diluted with 400 mL of water. The product is extracted
using pentane (4 × 250 mL). The combined pentane extract is washed with
brine, dried (MgSO4), filtered, and condensed by rotoary evaporation.
Distillation of the product (10 torr, 60 °C) affords diene 7 in 44-57% yield
as a colorless oil.
(3) Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A. Org. Lett. 1999,
1, 137-139.
(4) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998, 120,
10976-10977.
(5) Preparation of 5 by analogy to the methods in the following: Salau¨n,
J.; Marguerite, J. Org. Synth. 1985, 63, 147-153. Wasserman, H. H.; Hearn,
M. J.; Cochoy, R. E. J. Org. Chem. 1980, 45, 2874-2880.
(6) Overman, L. E.; Kakimoto, M.; Okazaki, M. E.; Meier, P. G. J. Am.
Chem. Soc. 1983, 105, 6622-6629. Original work using N-bromosulfon-
amides: Petrov J. Gen. Chem. U.S.S.R. 1938, 8, 208-212.
(7) Caution. It is important to add the KOH slowly due to the exothermic
nature of the reaction causing excess 1,3-butadiene to rapidly boil out of
solution at approximately 40 °C.
(9) Friedrich, E. C.; Lewis, E. J. J. Org. Chem. 1990, 55, 2491-2494.
(10) On the basis of the price of reagents purchased from Aldrich in
1999, 9 cost $211.88/mol ($1.49/g) and 5 cost $2785.25/mol ($14.04/g).
1610
Org. Lett., Vol. 2, No. 11, 2000