A. Gopi Krishna Reddy et al. / Tetrahedron Letters 53 (2012) 5635–5640
5639
product 3am in inferior yield (33%). This may be due to the forma-
tion of an undesired condensed by-product 6 in higher yield
(Table 1).
In summary, we have developed an efficient one-pot C–O and
C–C bond formation via an intermolecular oxy-Michael addition
and subsequent intermolecular Heck reaction for the synthesis of
functionalized cinnamates. An initial oxy-Michael addition step
with less sterically hindered alkyl acrylates (ethyl or methyl acry-
lates) leads to the formation of condensed ester as a by-product
along with the desired oxy-Michael addition product. Gratifyingly,
the reaction with Michael acceptor tert-butyl acrylate gave solely
the oxy-Michael addition product. Therefore, the overall yield of
products was improved. Most importantly, the present method
was further divergently extended to the successful synthesis of
various isochromenes via a sequential one-pot O-allylation and
subsequent intramolecular Heck cyclization.
After achieving the cinnamate derivatives 3aa–am, to check the
generality of the method we attempted the reaction with different
Michael acceptors. Similar results were observed with methyl
acrylate, and products 3bd and 3bg were obtained in inferior yields
(Table 2). This can be ascribed to the sterically less hindered nature
of the methoxy group of the acrylate that may further facilitate the
formation of the undesired by-product 6 (Table 1). Also, a further
drop in yield (25%) was observed in the case of acrylonitrile as Mi-
chael acceptor (Table 2). This is possibly due to the interference of
the electron deficient cyano group with the hydroxy functionality.
The above accomplishment of cinnamate derivatives 3aa–am,
3bd, 3bg, and 3cf, in moderate yields, encourages us to improve
the yields further. We also realized that by inhibiting cross conden-
sation of the Michael acceptor, we could avoid the formation of
undesired by-product 6 (Table 1). This may be due to the sterically
less hindered nature of the ethoxy (or methoxy) group of Michael
acceptor that allowed the formation of cross condensed undesired
ester by-product 6. We anticipate that the use of a bulky alkoxy
acrylate such as tert-butyl acrylate might preclude the formation
of an undesired condensed by-product 6, and this consequently
improves the yield of product 3. Therefore, ortho-bromobenzyl
alcohols 1a–m possessing electron deficient as well as electron rich
aromatic substituents, were treated with tert-butyl acrylate as Mi-
chael acceptor, using optimized conditions. As expected, a dra-
matic improvement in the yield was observed, and 3da–3dm
were isolated as sole products in good to excellent yields (Table 2).
After achieving the cinnamate derivatives 3aa–dm, we checked
the generality and applicability of the present method divergently
for a one-pot O-allylation and subsequent intramolecular Heck-
cyclization to afford 4-methylene-3,4-dihydro-1H-isochromenes.
Pd-catalyzed intramolecular Heck cyclization is an efficient meth-
od to achieve heterocyclic structures.20 This method has been suc-
cessfully employed to the synthesis of many natural products as
well.21 Usually, such systems have been achieved only by a step-
wise O-allylation and intramolecular Heck cyclization strategy.22
To the best of our knowledge there are no reports on such cyclic
ethers based on a one-pot process. Our optimized conditions em-
ployed for 3aa–dm were found to be unproductive (Table 3, entries
1 to 4). It was observed from TLC that there was no conversion to
allylation product using base Cs2CO3 and therefore a strong base
was used to promote the O-allylation. Alcohol 1 was treated with
allyl bromide in the presence of base NaH, in DMF. The formation
of a less polar spot was observed on TLC and it was then subjected
to in situ Heck cyclization by loading Pd-catalyst at 80 °C for 24 h.
On increasing the reaction time to 24 h, a mixture of cyclic ethers
in 85% yield was obtained. The exo-cyclized ether 9ag was formed
as the major product along with the minor endo-isomer 9bg with
respect to the double bond. Both the isomers were separated by
column chromatography (Table 3, entry 6). It is noteworthy that
the use of quaternary ammonium salts was found to be crucial
for Heck cyclization [in the present case we have used triethylben-
zylammonium chloride (TEBAC)].22e Since, we established that
prolonged reaction time in the presence of Pd-catalyst can favor
isomerization of the exo-olefin to the thermodynamically more sta-
ble endo-olefin; we decided to decrease the reaction time of Heck
cyclization to control the formation of exo-olefin. However, the
conversion of intermediate 8g was incomplete, even after 12 h (Ta-
ble 3, entry 5).
Acknowledgments
Financial support by the Council of Scientific and Industrial Re-
search [(CSIR), 02(0018)/11/EMR-II] and the Department of Science
and Technology [(DST), CHE/2010-11/006/DST/GSN] New Delhi is
gratefully acknowledged. We thank Dr. P.C. Ravi Kumar for his
valuable suggestions. A.G.K. and J.K. thank CSIR, New Delhi, for
the award of research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
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Gopi Krishna Reddy
