regioisomers, the 8-chloro-10-bromo and the 8-bromo-10-
chloro azaketones. Thus, we turned our attention to an
anionic “Friedel-Crafts” acylation by preactivating the 11-
position with an iodo group.
with s-BuLi followed by alkylation with 2-bromobenzyl-
bromide gave the alkylated acid. The acid group was then
converted to the corresponding amide 4 via an acid chloride.
The other three examples in Table 1 were prepared starting
with 3-methylpyridinic amides. Both n-BuLi and LDA
worked well for the lateral lithiation of 3-methylpyridinic
amides.9 However, LDA is necessary for the lithiation of
5-bromo-3-methylpyridinic amide 8 because of the presence
of the bromo group. In addition, a binary solvent system of
methyl tert-butyl ether and THF was found to work best for
entry 4 in order to minimize the de-iodonation side reaction.
Since only tertiary amides are suitable for the anion-induced
acylation, the secondary amides derived from 5 and 8 were
further converted in good yields to their corresponding
tertiary amides 6, 7, and 2b, using NaH and MeI. Direct
lithiation/alkylation of tertiary amides afforded the same
products but in much lower yields.
Intramolecular anionic Friedel-Crafts equivalent reactions
were first reported by Snieckus’s group for the formation of
tricyclic ketones.7 The reported acylations are generally
initiated by an amide-induced remote lithiation followed by
an intramolecular addition of the newly formed anion to the
amide group. This type of reaction cannot be applied directly
to our synthesis as there are two nondiscriminative lithiation
sites on the aromatic moiety in compound 2a. Thus, it is
necessary to regioselectively activate the 11-position. We
postulated that a selective iodo-lithium or iodo-magnesium
exchange of the 11-iodo substituent in 2b followed by an
intramolecular cyclization would afford the desired tricyclic
ketone 1. This assumption was supported by three very recent
publications in which halogen-lithium and halogen-
magnesium exchange-induced cyclizations are reported.5 All
these reported examples produced good yields for five- and
six-membered heterocycles but poor yields for seven-
membered rings. Furthermore, those substrates do not contain
any other halogen groups that could compete with the desired
iodo-metal exchange. Therefore, there are two key questions
for our proposed reaction. (1) Can we achieve a selective
activation of the iodo group at the hindered 11-positon? (2)
Can we accomplish an effective subsequent cyclization to
form the seven-membered ketones?
The desired 2-iodo-3-bromo-5-chlorobenzyl bromide, 9,
was prepared in excellent overall yield by following the
procedure in Scheme 1. Thus, bromination of 2-amino-5-
Scheme 1. Preparation of Benzyl Bromide 9
First, we studied this type of acylation with simpler
substrates. These substrates were prepared via a lateral
lithiation followed by alkylation with an appropriate elec-
trophile. Some of the alkylated products prepared are
summarized in Table 1. Lateral lithiation of o-toluic acid8
chlorobenzoic acid followed by diazotization and iodide
displacement afforded 2-iodo-3-bromo acid 10 in 87% yield.
Reduction of the acid group with (MeO)3B and BH3-Me2S10
gave the alcohol 11 in 98% yield. 11 was converted to the
Table 1. Lateral Lithiation-Alkylation
(3) (a) Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.;
Mallams, A. K.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu,
Y.; Wong, J.; Vibulbhan, B.; Pinto, P.; Deskus, J.; Alvarez, C. S.; del
Rosario, J.; Connolly, M.; Wang, J.; Desai, J.; Rossman, R. R.; Bishop, W.
R.; Patton, R.; Wang L.; Kirschmeier, P.; Bryant, M. S.; Nomeir, A. A.;
Lin, C. C.; Liu, M.; McPhail, A.; Doll, R. J.; Girijavallabhan, V.; Ganguly,
A. K. J. Med. Chem. 1998. 41, 4890. (b) Njoroge, F. G.; Vibulbhan, B.;
Wong, J. K.; White, S. K.; Wong, S.; Carruthers, N. I.; Kaminski, J. J.;
Doll, R.; Girijavallabhan, V.; Ganguly, A. K. Org. Lett. 1999, 1, 1371.
(4) Wu, G.; Wong, Y.; Poirier, M. Org. Lett. 1999, 1, 745.
(5) (a) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett.
2001, 42, 4841. (b) Kondo, Y.; Asai, M.; Miura, T.; Uchiyama, M.;
Sakamoto, T. Org. Lett. 2001, 3, 13. (c) Inoue, A.; Kitagawa, K.; Shinokubo,
H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
(6) Part of the contents in this Letter are covered by our U.S. patent:
5,998,620, 1999.
(7) (a) Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508. (b)
Familoni O. B.; Ionica, I.; Bower, J. F.; Snieckus, V. Synlett 1997, 1081.
(c) MacNeil, S. L.; Gray, M.; Briggs, L. E.; L, J. J.; Snieckus, V. Synlett
1998, 419.
(8) Creger, P. L. J. Am. Chem. Soc. 1970, 92, 1396.
(9) (a) Clark, R. D.; Jahangir. J. Org. Chem. 1987, 52, 5378. (b)
Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A.
J. Org. Chem. 1989, 54, 2242.
(10) Lane, C. F.; Myatt, H. L.; Daniels, J.; Hopps, H. B. J. Org. Chem.
1974, 39, 3052.
3796
Org. Lett., Vol. 3, No. 23, 2001