momethyl)pyrrolo[2,3-b]pyridine and TosMIC under
phase-transfer conditions7 (Scheme 1). The mechanism
proposed for this new heterocyclization involves initial
nucleophilic substitution of TosMIC followed by intramo-
lecular transfer of the methoxycarbonyl protecting group.
Subsequent attack of the pyrrole nitrogen on the isocya-
nide group would lead to cyclization, and 1,2-elimination
of p-toluenesulfinic acid would afford the azolopyrimidine
derivative.
The ease with which TosMIC reagents react with
different bromomethylazoles presents new opportunities
for expanding TosMIC chemistry for the synthesis of
azines, a use that remains almost unexplored.8 Described
herein are the results of a study that has culminated in
the development of a process for the efficient synthesis
of substituted azolopyrimidines under phase-transfer
catalysis conditions using bromomethyl azoles and dif-
ferent TosMIC derivatives.
Heterocyclizations with Tosylmethyl
Isocyanide Derivatives. A New Approach to
Substituted Azolopyrimidines
Alejandro Baeza, Javier Mendiola, Carolina Burgos,*
Julio Alvarez-Builla, and Juan J. Vaquero*
Departamento de Quı´mica Orga´nica, Universidad de Alcala´,
28871 Alcala´ de Henares, Madrid, Spain
Received January 5, 2005
The heterocyclization reaction leading to the pyrimi-
dine nucleus shown in Scheme 1 allowed efficient access
to different azolopyrimidines, including the tricyclic core
of variolins. However, this approach suffers from the
drawback associated with the ease of deprotection of the
azole under the phase-transfer conditions used, which
leads in some cases to low or moderate yields of the
azolopyrimidine system.9 On the other hand, phase-
transfer conditions are necessary for successful hetero-
cyclization since we proved that under different homo-
geneous conditions, TosMIC suffers a competitive double
alkylation with the formation of unstable products 12
(Scheme 2).
An efficient synthesis of substituted azolopyrimidines such
as pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines, pyrimido[1,6-
a]indoles, benzo[4,5]imidazo-[1,2-c]pyrimidines, an imidazo-
[1,2-c]pyrimidine, and pyrazolo[1,5-c]pyrimidines is de-
scribed. The method involves the reaction of N-protected
bromomethylazoles and tosylmethyl isocyanide (TosMIC)
derivatives in nonanhydrous media. The study of the reac-
tion conditions shows that the method is only successful
under phase-transfer conditions (CH2Cl2/30% aq NaOH)
using benzyltriethylammonium chloride as a catalyst.
Since the introduction of tosylmethyl isocyanide
(TosMIC) by van Leusen,1 this class of reagent has been
extensively used in azole chemistry,2 mainly in reactions
with activated carbon-carbon double bonds (pyrrole
synthesis)3 and carbon-heteroatom double bonds (ox-
azole4 and imidazole5 synthesis).
In the course of our studies on the total synthesis of
variolin B6 and some analogues, we reported a new
synthesis of pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine, which
is the heterocyclic core of the variolin family of marine
alkaloids. The synthesis is based on an unprecedented
reaction between a methyl carbamate-protected 2-(bro-
We envisaged that the use of TosMIC derivatives10
would avoid the formation of these undesired products
resulting from consecutive alkylation, thus facilitating
the isolation of the monoalkylated compound 14 (Scheme
3). Compound 14 could then be transformed into the
substituted azolopyrimidine by deprotection of the azole
and subsequent cyclization. Initial studies using 1a and
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* To whom correspondence should be addressed. Fax: 34-91-
8854660.
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10.1021/jo050029r CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/13/2005
J. Org. Chem. 2005, 70, 4879-4882
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