2
Tetrahedron
Triethylamine was found
1
0,14,19,23
constants than trans-isomers.
Careful examination of the reactions of different substrates
provides further support for the proposed mechanism and hints to
an alternative mechanism for reactions with a strong electron-
donating group (EDG) present. As shown in Table 1, reactions
with strong electron-donating groups are less stereoselective. In
these cases, the initial bromonium ion opens up to a stabilized
benzylic carbocation intermediate 8 which is subject to rotation
before being captured intramolecularly by the ester oxygen to the
β-lactone 2f as a mixture of both diastereomers (Scheme 3).
Decarboxylation with DBU thus gives both the cis-isomer 3f and
the trans-isomer 9f. Furthermore, when a substrate was used
carrying a strong electron-donating group ( i.e., 2-and 4-
methoxy) on the aryl group, and ether was employed as solvent,
the bromination reaction produced a mixture of lactones 2 as well
as both cis- and trans-β-bromostyrenes.
to be a much less effective base, as expected, requiring elevated
temperatures and resulting in lower yields.
The mechanism of the sequence of reactions was also shown in
Scheme 2. DBU deprotonates the α-proton to give 5, which
displaces the C–O bond with concomitant C=C formation leading
to the carboxylate 6 in an E1cb-like mechanism. Compound 6
then decarboxylates to form the corresponding Z-vinyl carbanion
(
structure not shown), which is protonated to produce (Z)-β-
bromostyrenes 1. The fact that only the Z isomer is formed
indicates that the decarboxylation of β-lactone 2 is not a thermal
nor concerted process (only the E-isomer would be expected
from such a pathway). Instead, after the deprotonation of the
acidic α-proton, the resulting enolate stereospecifically
undergoes a well-known “forbidden” β-elimination by a E1cB
mechanism to give the Z-alkene as concluded by the detailed
In support of this mechanism is the fact that bromine additions
2
4
study of lactone enolates like 5 by Mulzer et al. An enthalphy
of –18 kcal/mol was reported for the isomerization of β-lactone
2 2
to styrenes in CH Cl change from near nonstereoselective for the
most reactive styrene (p-methoxy) to antistereospecific for the
26
least reactive one (3,5-(CF ) ).
3 2
24
enolates of the type 5 to the more stable Z carboxylates like 6.
The study concluded that enolates of the type 5 represent
equivalents of vinyl anions of the type 7 with fixed
2
4
stereochemistry (Figure 1). The carboxylate intermediate 6
decarboxylates with ease in the present case because the resulting
-bromovinyl carbanion is stabilized by the bromine. Therefore,
1
our mechanism rationalizes both the formation of the β-lactone
intermediate and the observed Z stereochemistry of the product
and is entirely consistent with the findings of Mulzer et al.
24
(
Scheme 2).
Scheme 3. Mechanism for the nonstereoselective formation of
styrene bromides from 1f.
Figure 1. Enolate 5 as an equivalent of vinyl anion 7
These reactions work well for various substituting groups on
the aromatic moiety as shown in Table 1. Although lactone 3 was
stable and readily isolated, it can be used in the second reaction
without purification. The methylene chloride solvent and excess
bromine were stripped off in vacuo to leave the crude lactone
3
. Conclusions.
In summary, cinnamic acids are converted to β-lactones upon
bromination, which are subsequently transformed to cis-β-
bromostyrenes in a stereospecific manner. The β-lactone
intermediates can be readily isolated and identified except when
strong electron-donating groups are present on the aromatic ring.
However, isolation and purification of the lactone intermediates
is not necessary. The tandem substitutive bromination-
decarboxylation sequence presented herein thus provides an
efficient and stereospecific method for the conversion of
cinnamic acids to cis-β-bromostyrenes.
2 2
product behind which was treated with DBU in CH Cl . The
product can be isolated by simple extraction of the reaction
residue with hexanes or column chromatography if necessary.
25
Table 1. Conversion of cinnamic acids to β-bromostyrenes
Acknowledgments
Entries
Y
Combined Yield %
isolated)
This investigation was partly supported by the National
Institutes of Health, United States [Grant No. SC1 GM095419
(
(
W.W.) and Grant No. SC1 GM082340 (I.E.)]. The NMR facility
was funded by the National Science Foundation, United States
DUE-9451624 and DBI 0521342). K.G.T. and G.T.K. were
a
b
c
d
e
f
g
h
i
H
99
70
72
75
92
70
75
75
4-methyl
4-fluoro
4-chloro
4-bromo
4-methoxy
2-methoxy
4-nitro
(
supported by Departmental Summer Research Fellowships. We
thank ACS Project SEED student Qiying Huang for technical
assistance.
a
b
References and Notes
2-nitro
65
b
a
5:1 mixture of cis- to trans- isomers; 1:1 mixture of cis- to
trans- isomers.
1. Davis FA, Lal GS, Wei, J. Tetrahedron Lett. 1988; 29: 4269-4272.
2
.
Molander GA, Gormisky PE, Sandrock DL J. Org. Chem. 2008; 73:
052–2057.
2
Tang, Khanh G.
