tives for this coupling, and complete reaction takes place in
THF under the indicated conditions either at room temper-
ature for several hours or at reflux for several minutes.
Overall yields for the sequence involving ring expansion
annulation, sulfonylation with PhNTf2, and Suzuki cross-
coupling range from 56% to 60%.
of the triflate derivative of 27 with methyl acrylate furnished
the expected cinnamic ester, which was saponified and
elaborated to 29 by employing our standard protocol. The
conversion of phenol 27 to the â′-bromo-R-diazo ketone 29
can be carried out without purification of any intermediates
and proceeds in 51% overall yield. Surprisingly, ring
expansion-annulation of 29 did not take place in good yield
under our previous conditions but proceeded smoothly when
diethyl ether was employed in place of dichloromethane as
the reaction solvent. Suzuki coupling with triethylborane
followed by sulfonylation with SO3/pyridine then furnished
KT1-32 with spectroscopic characteristics in full accord with
those previously reported for this compound.
In summary, we have developed a ring expansion-
annulation strategy that begins with readily available benzene
derivatives and provides access to a variety of azulenes
substituted on both the five- and seven-membered rings. The
utility of the 1-hydroxyazulene annulation products is
enhanced by the ability of their triflate derivatives to
participate in Suzuki coupling reactions, as illustrated with
the application of this methodology in an efficient synthesis
of the antiulcer drug egualen sodium. Further studies on the
synthesis of substituted and functionalized azulenes are in
progress and will be reported in due course.
The ability of this ring expansion-annulation strategy to
streamline the preparation of substituted azulenes is il-
lustrated by its application in the synthesis of the antiulcer
drug egualen sodium (KT1-32).20 As outlined in Scheme 3,
Scheme 3a,b
Acknowledgment. We thank the National Institutes of
Health (GM 28273), Kotobuki Seiyaku Co., Ltd., Pharmacia,
and Merck Research Laboratories for generous financial
support.
a Key: (a) 1.25 equiv Tf2O, 1.4 equiv DMAP, CH2Cl2, -20 °C
f rt, 2 h. (b) 5.0 equiv methyl acrylate, 0.1 equiv Pd(OAc)2, 0.1
equiv dppp, DMSO, 120 °C, 16 h. (c) 7.5 equiv LiOH-H2O, MeOH,
0 °C, 72 h. (d) HBr/SiO2, CH2Cl2, rt, 20 h. (e) 1.4 equiv (COCl)2,
benzene, 65 °C, 15 h; then 4.0 equiv CH2N2, Et2O, 0 °C f rt, 1 h;
51% overall from 27. (f) 0.01 equiv Rh2(OCOt-Bu)4, Et2O, rt, 45
min, then add 1.0 equiv PhNTf2, 3.0 equiv DMAP, rt, 5 min. (g)
1.4 equiv Et3B, 0.05 equiv Pd(OAc)2, 0.075 equiv (o-biphenyl)PCy2,
3.0 equiv KF, THF, reflux, 10-20 min, 25-42% overall from 29.
(h) SO3/pyridine, benzene, 80 °C, 6 h; then NaOH, 90%; see ref
Supporting Information Available: Representative ex-
perimental procedures for key reactions and characterization
data for all azulene products. This material is available free
OL0156897
(18) Reviews: (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b)
Miyaura, N. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S.,
Ed.; JAI: London, 1998; Vol. 6, pp 187-243. (c) Suzuki, A. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; pp 49-97. (d) Stanforth, S. P. Tetrahedron
1998, 54, 263. (e) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(19) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550. See also: (c) Littke, A. F.; Dai, C.; Fu, G. F.
J. Am. Chem. Soc. 2000, 122, 4020. (d) Zhang, C.; Huang, J.; Trudell, M.
L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804.
(20) (a) Yanagisawa, T.; Wakabayashi, S.; Tomiyama, T.; Yasunami,
M.; Takase, K. Chem. Pharm. Bull. 1988, 36, 641. See also: (b)
Yanagisawa, T.; Kosakai, K.; Tomiyama, T.; Yasunami, M.; Takase, K.
Chem. Pharm. Bull. 1990, 38, 3355. (c) Yanagisawa, T.; Kosakai, K.; Izawa,
C.; Tomiyama, T.; Yasunami, M. Chem. Pharm. Bull. 1991, 39, 2429. (d)
Mochizuki, S.; Matsumoto, M.; Wakabayashi, S.; Kosakai, K.; Tomiyama,
A.; Kishimoto, S. J. Gastroenterol. 1996, 31, 785.
b
20a. Isolated yields of products purified by chromatography on
1
silica gel. IR, H NMR, and 13C NMR data were fully consistent
with the assigned structures.
this synthesis delivers KT1-32 (32) in eight steps beginning
with commercially available m-isopropylphenol, a consider-
able improvement over the prior route. Thus, Heck coupling
(17) Formed in 91% yield as estimated by 1H NMR analysis. This
compound is stable to storage in solution (e.g., diethyl ether or dichloro-
methane) at 0 °C but decomposes upon concentration.
1084
Org. Lett., Vol. 3, No. 7, 2001