Organic Letters
Letter
substituents at each of the possible positions on the azole
aldehydes. Deactivated azole aldehydes, for example those
containing halogen and ester functionalities, showed a modest
decline in yield. Aldehydes with substituents at the α-position
(e.g., 1b,h,l) showed a moderate decrease in cyclization rate,
potentially due to the A1,3 strain present between the C-3 and
C-5 substituents in the cyclized products.
With no cyclization occurring at −78 °C, we hypothesized
that the dianion of alkene 2a formed at low temperatures could
react with electrophiles regioselectively at the allylic position.
The resulting alkylated monoanions would then cyclize in situ
upon warming. This method would allow for selective
installation of C6 substituents in the indolizine products. A
set of electrophiles were chosen, and the results are summarized
in Table 2. Selective addition of alkyl-, allyl-, propargyl-,
heteroaromatic compounds. Isosteres and nitrogen-rich homo-
logues of indole present geometrically definable hydrogen bond
donors and acceptors that greatly expand the usefulness of this
privileged nucleus in medicinal chemistry. The substituents and
substitution patterns readily achievable by this approach enrich
and complement those available by current methods.15
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed synthetic procedures and characterization data can be
found in the Supporting Information. This material is available
AUTHOR INFORMATION
Corresponding Author
■
Table 2. Tandem, One-Pot Alkylation/Cyclization Sequence
to 5,6,7-Trisubstituted Indolizines 4a−e
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National
Institutes of Health Research Grant ES001670. We also thank
Dr. I. P. Mortimer (Johns Hopkins University, Department of
Chemistry) for mass spectral analysis.
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