We believed that either the Suzuki5 or Stille6 coupling
procedures would provide the desired biaryl pyridine system.
For instance, coupling of 3-pyridyldiethylborane and 2-bromo-
6-methoxypyridine 3 has been reported by Terashima in 77%
yield.7 A related tin-mediated process was reported by
Dehmlow in 81% yield.8 We made few attempts to mirror
either of these two processes as formation of the required
organolithium (or magnesium) reagent from bromonicotinic
ester 7 or the corresponding protected alcohol was problem-
atic. The modified Suzuki approach, depicted in Scheme 1,
The cesium fluoride conditions were designed for sub-
strates that are sensitive to base. The yield of 8a was
enhanced by 20% relative to the reaction without cesium
fluoride. The role this salt plays in our reaction is not clear,
although disproportionation of the preformed ate complex
with substitution of methoxy by fluoride seems unlikely.12
Formation of the ate complex from B(OMe)2F also afforded
a satisfactory substrate for Suzuki coupling (6), but yields
dropped without added cesium fluoride. Alternatively, rate
enhancement may be due to the presence of cesium ion.13
An equally promising Stille coupling removed the need
for highly nucleophilic organometallics (Scheme 2). Methyl
Scheme 1. Suzuki Coupling
Scheme 2. Stille Coupling
5-bromonicotinate 7 was incompatible with organolithium
reagents, limiting the role of 7 to an acceptor in the Suzuki
process (above). Formation of the organostannane 9 was
readily accomplished through palladium-mediated reaction
of 7 and hexabutylditin to afford 9 in 44-50% yield. The
Stille coupling with bromide 3 provided the desired biaryl
8a in 50% yield, demonstrating that either partner can serve
as the donor.14
We then considered whether generation of the heteroaryl
stannane 9 could be conducted “in situ” followed by
heteroaryl coupling as a “one-pot” process. The prospects
for this reaction were initially viewed as weak as we
suspected coproduction of two undesired homodimeric
heterobiaryl species. In the event (Scheme 3), the halides 3
and 7 were combined in degassed DMF followed by
hexabutylditin and palladium catalyst. The reaction mixture
was rapidly heated to 130 °C, and within 45 min palladium
metal was deposited. The reaction was judged to be complete
by TLC. Remarkably, the desired methoxybipyridinyl ester
effected the desired coupling after conditions for handling
the organoboranes were devised. Formation of organolithium
4 through halogen-metal exchange of 3 in ether at -40 °C
was followed by addition of one of several boronic esters or
alkyl boranes. Unfortunately, isolation of the requisite
pyridine-2-borane adducts was always problematic.9 For
instance, reaction of 4 with triethylborane, followed by
treatment with iodine, afforded low yields (20-30%) of the
desired 6-methoxypyridyl-2-diethylborane. This alkylborane,
once isolated, was a good substrate for Suzuki coupling. An
80% yield of purified 8a was obtained after palladium-
mediated reaction with methyl 5-bromonicotinate 7. At-
tempted formation and isolation of a boronic acid from
reaction of 4 with triisopropoxyborane was similarly prob-
lematic. Fortunately, it proved unnecessary to isolate the
boronic acid. “In situ” treatment, by the method of Keay, of
4 with trimethylborate formed the presumed boron “ate”
complex 5.10 Without isolation, the Suzuki coupling of 5 and
7 proceeded in moderate yield in the presence of palladium-
(0) and 2 equiv of cesium fluoride under the conditions of
Wright et al.11
(11) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095-6097.
(12) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M.
R. J. Org. Chem. 1995, 60, 3020-3027. Littke, A. F.; Dai, C.; Fu, G. C.
J. Am. Chem. Soc. 2000, 122, 4020-4028. No other salts were studied.
(13) Katz, H. E. J. Org. Chem. 1987, 52, 3932-3934. Zhang, H.; Kwong,
F. Y.; Tian, Y.; Chan, K. S. J. Org. Chem. 1998, 63, 6886-6890. Bei, X.;
Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen, J. L. J. Org.
Chem. 1999, 64, 6797-6803.
(5) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(6) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(7) Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984, 936-938.
(8) Dehmlow, E. V.; Sleegers, A. Liebigs Ann. Chem. 1992, 953-959.
(9) See, however: Thompson, W. J.; Jones, J. H.; Lyle, P. A.; Thies, J.
E. J. Org. Chem. 1988, 53, 2052-2055.
(10) Cristofoli, W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5881-
5884. Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1994, 59, 6501-6503.
Andersen, N. G.; Maddaford, S. W. P.; Keay, B. A. J. Org. Chem. 1996,
61, 9556-9559.
(14) We have thus far been unable to use the conditions of Miyaura to
directly prepare the “boron pinacolate” via a related palladium-catalyzed
process. Ishiyama, T.; Myrata, M.; Miyaura, N. Tetrahedron Lett. 1997,
38, 3447. We have confirmed that the stannane derived from 2 methoxy-
6-bromopyridine is also an excellent substrate for Stille coupling, affording
8a in 40% yield.
4202
Org. Lett., Vol. 2, No. 26, 2000