ORGANIC
LETTERS
2012
Vol. 14, No. 20
5266–5269
Synthesis of Oxindolyl Pyrazolines
and 3‑Amino Oxindole Building Blocks
via a Nitrile Imine [3 þ 2] Cycloaddition
Strategy
Anand Singh, Amanda L. Loomer, and Gregory P. Roth*
Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road,
Orlando, Florida 32827, United States
Received September 1, 2012
ABSTRACT
The [3 þ 2] dipolar cycloaddition reaction of nitrile imines with 3-alkylidene oxindoles is described. The pyrazoline spiroadducts were obtained in
high yields and with excellent regio- and diastereoselectivities. These spirocyclic intermediates have been elaborated to synthetically versatile
3-amino oxindole building blocks such as β-amino nitrile, 1,3-diamine, and pyrrolo[2,3-b]indoline derivatives.
Substituted oxindole-based scaffolds represent a large
family of compounds that have been the subject of syn-
thetic interest owing to their medicinal promise and overall
versatility as natural product building blocks.1 Our labora-
tory has been involved in the synthesis of oxindole-based
spirocyclic molecules generated via a [3 þ 2] cycloaddition
reaction using nitrile oxide dipoles.2,3 Herein, we present
results from our ongoing method development program
highlighting the first reported cycloaddition of nitrile
imines with 3-alkylidene-oxindole dienophiles. We were
interested in exploring the isosteric equivalency of nitrile
oxides to nitrile imines as an opportunity to establish
efficient synthesis of novel pyrazolines and studying their
synthetic applications. The prevalence of the pyrazoline
scaffold in bioactive molecules has also sparked interest.4
Our objective was to demonstrate the efficient synthesis of
novel oxindole-based spirocyclic derivatives with subse-
quent elaborationto3,3-amino-disubstitutedoxindoleand
pyrrolo[2,3-b]indoline-based scaffolds.
Having established a convenient, practical, and scalable
cycloaddition toward 3-hydroxy-disubstituted oxindoles
using nitrile oxides,2 we next explored the application of
nitrile imines as the dipole component of the cycloaddition
reaction.5 We envisioned a conceptually distinct synthesis
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Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
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10.1021/ol302425h
Published on Web 10/10/2012
2012 American Chemical Society