chemoselectivity shift for 1,2-diarylalkenes upon treatment
with alkyllithiums from carbolithiation to deprotonation
would be required.
Scheme 1. Directed Lithiation Methods (DG ) Directing
Group)
As it is known that in general the carbolithiation of cis-
1,2-disubstituted alkenes is less effective than the trans
isomers, we speculated that conditions could be identified
that would favor vinyl deprotonation over carbolithiation.
Using cis-stilbene Z-1 as a test substrate, we screened a series
of organolithiums in conjunction with amine additives (Table
1). In each case the conversion, product yield, and stereo-
Table 1. Direct Lithiation of Z-Stilbene; Stereoselective
Synthesis of R-Phenyl-cis-cinnamic Acida
ylethene (stilbene) E-1 to produce a vinyl lithium E-2 has
not, to the best of our knowledge, been previously reported
(eq 3). This can be attributed to the known propensity of
alkenes, including trans-stilbene 1, to readily undergo
carbolithiation reactions to generate the benzylic lithiated
species 3 (eq 3).5 In fact, despite the obvious synthetic
potential of this transformation, the direct vinyl deprotonation
of substituted stilbenes is very rare, with one recent example
of note being the deprotonation of an ortho-O-carbamoyl-
substituted stilbene.6
Previously reported methods for the generation of 1-lithio-
1,2-diphenylethene E-2 have utilized the monoprotonation
of 1,2-dilithio-1,2-diphenylethene (prepared by the reduction
of diphenylacetylene with metallic lithium).7 Alternatively,
a lithium-mercury exchange of stilbene 4 at low temperature
in THF has provided a route to E-2 (Scheme 2).8 It was
entry
RLi
equiv
temp (°C)
additive
yield (%)b
1
2
3
4
5
6
7
8
s-Bu
s-Bu
s-Bu
n-Bu
t-Bu
LDA
LTMP
LTMP
2
1
2
2
2
2
2
1
-25
-25
-25
-25
-25
-25
-25
0
PMDTA
PMDTA
none
PMDTA
PMDTA
none
76
36
66
15
55
0
none
none
17
30
a Only the Z-isomer was observed by 1H NMR in each example. b Isolated
purified yield (average of 2 runs).
selectivity was determined by reacting the lithiated inter-
mediate with CO2, with the crude reaction products analyzed
by NMR. Encouragingly, it was found that using 2 equiv of
s-BuLi as base and N,N,N′,N′′,N′′-pentamethyldiethylenetri-
amine9 (PMDTA) as additive, in THF at -25 °C for 2 h,
followed by addition of solid CO2, a single stereoisomer of
R-phenyl-cis-cinnamic acid Z-5 was formed in an excellent
76% isolated yield (Table 1, entry 1). This route compares
very favorably with the base-catalyzed Perkin condensation
of phenylacetic anhydride and benzaldehyde or the transition-
metal-catalyzed carboxylation of diphenylacetylene, which
both predominately yield the opposite isomer R-phenyl-trans-
cinnamic acid E-5.10 It was found that the use of 1 equiv of
s-BuLi with PMDTA or 2 equiv in the absence of the
PMDTA additive both gave rise to a lowering of the isolated
yield (entries 2 and 3). Both n-BuLi and t-BuLi also gave
inferior yields when compared to s-BuLi as a result of
inefficient deprotonation for n-BuLi and the generation of
carbolithiation products for t-BuLi (entries 4 and 5). Ex-
amination of LDA as base revealed no product formation,
but the stronger lithium tetramethyl piperidide (LTMP) gave
an isolated yield of 17% (entries 6 and 7).
Scheme 2. Lithium-Mercury Exchange Route to E-2a
a X ) Hg-stilbene.
shown that in these strongly coordinating solvent conditions
the initially formed Z-2 rapidly isomerized to generate,
almost exclusively, the more thermodynamically stable E-2.
Despite the synthetic potential of E-2 for further reaction
with electrophiles, a principal drawback to the general
utilization of this approach would be the requirement to
synthesize the substituted stilbene from which the lithium-
mercury exchange could be effected. Yet, if a direct lithiation
method was available, this would open up the synthetic scope
of E-2 and other substituted analogues. To achieve this, a
(5) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J. F.; Normant, J. F.
Chem. Eur. J. 1999, 5, 2055.
(6) Reed, M. A.; Chang, M. T.; Snieckus, V. Org. Lett. 2004, 6, 2297.
(7) Maercker, A.; Kemmer, M.; Wang, H. C.; Dong, D.-H.; Szwarc, M.
Angew. Chem., Int. Ed. 1998, 37, 2137 and references therein.
(8) Curtin, D. Y.; Koehl, W. J., Jr. J. Am. Chem. Soc. 1962, 84, 1967.
(9) For the influence of PMDTA on organolithiums, see: Bauer, W.;
Winchester, W. R.; von Rague´ Schleyer, P. Organometallics 1987, 6, 2371.
(10) (a) Zimmerman, H. E.; Ahramjian, L. J. Am. Chem. Soc. 1959, 81,
2086. (b) Aoki, M.; Kaneko, M.; Izumi, S.; Ukai, K.; Iwasawa, N. Chem.
Commun. 2004, 2568 and references therein.
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Org. Lett., Vol. 9, No. 8, 2007