was also tolerated, providing 14 in 70% yield after reaction
with 2 equiv of n-BuLi. The reaction of bromide 154a,c took
a slightly different course. In this case, lithium-halogen
exchange with n-BuLi (1 equiv) occurred faster than addition
at sulfur.4d,7 After trapping the resultant lithiate with MeI,
however, n-BuLi (2 equiv) cleanly added at sulfur to yield
16 in 84% yield.
The addition of Grignard reagents to 5 was also examined.
Adding i-PrMgCl (2 equiv) to a THF solution of 5 produced
the isopropyl adduct 22 in 54% isolated yield (Scheme 7).
Scheme 7
The availability of 2-thioalkyl- or 2-thioarylimidazoles
with alternate substitution patterns was also explored using
this new protocol. For instance, trapping intermediates such
as 7 with an electrophile should give rise to 1,2,4-trisubsti-
tuted imidazoles.8 Thus, addition of n-BuLi (2 equiv) to 5
produced intermediate 17, which was trapped with benzyl
bromide to give 18 in 77% isolated yield (Scheme 5). The
Scheme 5
However, switching to allylmagnesium chloride and ben-
zylmagnesium chloride (2 equiv) gave 23 and 24, respec-
tively, in which the Grignard added to C-2 of the imidazole
nucleus and ejected the ethanethiol moiety.11,12 Unfortunately,
we found no reaction conditions which could induce other
alkyl or aryl Grignard reagents to add to 5, regardless of the
choice of solvent, reaction temperature, magnesium coun-
terion, or choice of catalyst.13
Returning to our original goal, we attempted to access the
C-5 lithiated intermediateby treating 5 with lithium amide
bases (Scheme 8). Adding LDA to a THF solution of 5,
regiochemistry of the alkylation was confirmed after Raney
nickel desulfurization of 18 gave a compound with NMR
spectra identical to those for imidazole 19, which was
prepared independently.9
Scheme 8
In addition to imidazole substrates, the reactivity of the
corresponding benzimidazole substrates with organolithium
reagents was also examined in this study (Scheme 6).
however, gave a mixture of 8f and 25 in a 1:1 mixture,
presumably from deprotonation adjacent to either sulfur or
nitrogen followed by â-elimination. Using a less hindered
base such as lithium pyrrolidide, however, produced the
N-vinyl compound 25 as the sole product.
Scheme 6
In summary, we have observed that imidazo[2,1-b]-
thiazolines react with organolithium reagents at sulfur to
deliver 2-thioalkyl- and 2-thioarylimidazoles in high yield.
This process constitutes a versatile and expedient synthesis
of polysubstituted imidazoles prepared ultimately from
Addition of either PhLi or s-BuLi (2 equiv) at 0 °C to 20,
itself readily prepared from 2-benzimidazolethiol,10 produced
21a (72%) and 21b (75%), respectively.
(9) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen,
M. A. J. Org. Chem. 2000, 65, 1516.
(6) Typical procedure: A solution of 5 (0.29 g, 1.44 mmol) in THF was
cooled to -78 °C and MeLi (1.5 M, 1.9 mL, 2.88 mmol) was added. After
1 h, the mixture was diluted with H2O and EtOAc and the organic layer
was concentrated to dryness. After silica gel chromatography, the product
(10) Suri, O. P.; Khajuria, R. K.; Saxena, D. B.; Rawat, N. S.; Atal, C.
K. J. Heterocycl. Chem. 1983, 20, 813.
(11) We are unaware of other examples of nucleophilic displacement of
2-thioalkyl or 2-thioaryl groups of imidazoles. Jones, however, has reported
a similar process with 2-phenylthio-2-imidazolines. See: Jones, R. C. F.;
Nichols, J. R. Tetrahedron Lett. 1990, 31, 1767.
(12) For a similar process with 2-thioalkylbenzothiazoles, see: Katritzky,
A. R.; Kuzmierkiewcz, W.; Aurrecoechea, J. M. J. Org. Chem. 1987, 52,
844.
(13) Pridgen, L. N.; Killmer, L. B. J. Org. Chem. 1981, 46, 5402. Pridgen,
L. N. Synthesis 1984, 1047.
1
8e was obtained as a white solid (0.19 g, 70%): mp ) 133-134 °C; H
NMR (300 MHz, CDCl3) δ 11.23 (1H, s), 7.67 (2H, d, J ) 7.7 Hz), 7.33
(3H, m), 7.22 (1H, m), 2.54 (3H, s); 13C NMR (75 MHz, CDCl3) δ 142.4,
139.6, 132.3, 128.7, 127.1, 124.8, 118.0, 17.2; MS (ESP) 191 (M + 1).
(7) Pridgen, L. N.; Shilcrat, S.; Lantos, I.; McGuire, M. Private
communication.
(8) Dodson, R. M. J. Am. Chem. Soc. 1950, 72, 1478.
Org. Lett., Vol. 2, No. 18, 2000
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