A facile route to 2-substituted N-Boc pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(00)01763-9

Dipole stabilized carbanion 2 cyclizes to afford the key intermediate 2-benzotriazolyl-N-Boc-pyrrolidine 3, which undergoes nucleophilic displacement of the benzotriazolyl group to afford various 2-substituted-N-Boc-pyrrolidines in good yields. (C) 2000 P

Full text of DOI:10.1016/S0040-4039(00)01763-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9691–9693
†
A facile route to 2-substituted N-Boc pyrrolidines
Alan R. Katritzky,* Zhushou Luo and Yunfeng Fang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville,
FL 32611-7200, USA
Received 6 October 2000
Abstract
Dipole stabilized carbanion 2 cyclizes to afford the key intermediate 2-benzotriazolyl-N-Boc-pyrrolidine
3, which undergoes nucleophilic displacement of the benzotriazolyl group to afford various 2-substituted-
N-Boc-pyrrolidines in good yields. © 2000 Published by Elsevier Science Ltd.
Keywords: pyrrolidine; dipole stabilization; intramolecular cyclization.
1
a–h
Numerous pyrrolidines are of biological importance
and the development of versatile
1
a–h,2a–g
methods for their preparation has shown much recent activity.
2
-Substituted-N-Boc-pyrrolidines have been prepared by two general methods: (i) by direct
3a–c
electrophilic substitution at the 2-position of the N-Boc-pyrrolidine ring
and (ii) by
intramolecular cyclization of arylmethyl- or allyl-(3-chloropropyl)-N-Boc-amines by treatment
4
a,b
with s-BuLi or n-BuLi.
We now report a third approach by nucleophilic displacement of the
benzotriazole moiety from N-Boc-pyrrolidine 3 (which is easily available from N-Boc-N-(3-
halopropyl)-(benzotriazol-1-ylmethyl)amine 1, Scheme 1): a single previous example related to
the present approach utilizes 2-methoxy-N-Boc-pyrrolidine prepared by electromethoxylation of
5
N-Boc protected pyrrolidine.
Starting material 1 was prepared in two steps in 40% overall yield. Protection of 3-chloro-
propylamine hydrochloride with (Boc) O in the presence of Et N gave N-Boc-3-chloropropyl-
2
3
6
amine, which reacted further (without purification) with benzotriazole and paraformaldehyde in
the presence of p-TsOH in refluxing toluene with azeotropic removal of water to give
N-Boc-N-(benzotriazol-1-ylmethyl)-3-chloropropylamine (1). The reaction conditions were opti-
mized for the cyclization of compound 1 to compound 3: the best solvent was toluene; others
gave a complex reaction mixture (such as THF) or low yields (16% in Et O). The best base was
2
n-BuLi which (1.5 equiv.) was preferred to s-BuLi and t-BuLi for the cyclization. Compound 3
was thus formed via intramolecular cyclization in 55% yield.
*
Corresponding author. Tel: (352) 392-0554; fax: (352) 392-9199; e-mail: katritzky@chem.ufl.edu
Dedicated to Harry Wasserman, long-time colleague and friend.
†
0
040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01763-9

9692
Scheme 1.
Treatment of the benzotriazole derivative 3 with organozinc reagents gave compounds 4 in
good to excellent yields (Scheme 1). Arylzinc reagents and an alkynylzinc reagent all afforded
the corresponding desired products. However, when allyltrimethylsilane or vinyloxytrimethylsi-
lane were used as nucleophiles to carry out this reaction, no desired products were obtained.
In conclusion,
a
general method using N-Boc-N-(3-halopropyl)(benzotriazol-1-yl-
methyl)amine as the starting material is proposed for the preparation of 2-substituted-N-Boc-
pyrrolidines in good to excellent yields. In the cyclization step, the benzotriazole moiety assists
the dipole stabilization in the formation of a carbanion intermediate to make the lithiation
regiospecific.
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