Organic Letters
Letter
bromoacetophenone presumably via the alkylative pathway,
while the less basic/nucleophilic aminopyridine substrates
provide little or no conversion. In fact, of the imidazo[1,2-
a]pyridines 5a−s prepared, none represent previously known
compounds when the precursor 2-aminopyridine 4 has a
calculated pKa of less than 4. In the course of the reaction
condition optimization studies, we observed that basic additives
inhibited the annulation reaction (Table 2, entries 2 and 3). A
question therefore arises: do the more basic substrates that do
not undergo the annulation reaction fail because of inadequate
reactivity or because they actively inhibit condensation to the
imine. To address this question, the cyclization of 4,6-
dichloropyridine 4a was conducted in the presence of 2-
aminopyridine (5r). In this experiment, no cyclization of 4,6-
dichloropyridine 4a to imidazo[1,2-a]pyridine 5a was observed.
This result suggests that the more basic substrates do indeed
inhibit the condensation step, presumably through sequestration
of the scandium catalyst and explains why pKa correlates with
relative reactivity. As a practical matter, 2-aminopyridine
substrates which demonstrate high relative reaction rates (+++
and ++) should proceed well under reflux conditions (82 °C).
The two distinct reaction pathways, the alkylative pathway and
the imine pathway (Scheme 2), represent a continuum of
reactivity rather than a strict dichotomy. The operable pKa range
of <6 for the imine pathway overlaps significantly with the pKa
range observed for the alkylative pathway of >4 (Figure 2). Both
A new procedure for the preparation of the imidazo[1,2-
a]pyridine ring system from 2-aminopyridine substrates has been
presented. The new cyclization reaction relies upon the reaction
proceeding via an imine intermediate rather than a pyridinium
through the use of a dimethyl ketal precursor. Importantly, the
scope of electron-deficient, non-nucleophilic 2-aminopyridine
substrates is complementary to the well-known classic reaction of
nucleophilic 2-aminopyridines with α-halo ketones. This new
annulation procedure expands the range of potential substrates
that can undergo conversion to imidazo[1,2-a]pyridine and the
related imidazo[1,2-b]pyridazine, imidazo[1,2-c]pyrimidine,
imidazo[1,2-a]pyrazine, and imidazo[1,2-a]pyrimidine and
thus provides a valuable addition to the heterocycle preparation
literature.
ASSOCIATED CONTENT
* Supporting Information
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S
The Supporting Information is available free of charge on the
Procedures, characterization data, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Nick Meanwell (Bristol-Myers Squibb) and John Kadow
(Bristol-Myers Squibb) are acknowledged for reading the
manuscript and providing helpful comments and suggestions.
Prasanna Siva (Bristol-Myers Squibb) is acknowledged for
helpful discussions regarding molecular calculations.
Figure 2. Operable pKa ranges for the alkylative pathway and the imine
pathway.
REFERENCES
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mechanistic pathways, however, reflect the innate propensity of
the acetophenone substrate to undergo either imine formation
via a ketal precursor or undergo alkylation via a halo ketone
precursor. Ethyl bromopyruvate (10) presents an interesting
substrate wherein the halo ketone component is capable of both
modes of reactivity since it presents both a reactive alkyl halide
and an electrophilic carbonyl and thus should have a broad
substrate scope. In our hands, the unoptimized reaction of ethyl
bromopyruvate (10) with either dichloropyridine 4a or
unsubstituted pyridine 4s under conditions very similar to the
general protocol delivers the imidazo[1,2-a]pyridine 11a (60%)
and 11s (46%), respectively (Scheme 6). This result confirms the
reactivity of ethyl bromopyruvate (10) with both classes of
substrates, electron-deficient and -rich pyridines, consistent with
accessing both reaction pathways. The key feature of this new
annulation reaction is the enablement of the imine pathway
through the use of the ketal as the substrate.
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(8) The use of the term pKa in this context refers to the pKa of
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Scheme 6
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