Silylmethyl-substituted aziridine and azetidine as masked 1,3- and 1,4-dipoles for formal [3 + 2] and [4 + 2] cycloaddition reactions

Article abstract of DOI:10.1021/ja055664t

2-tert-Butyldiphenylsilylmethyl-substituted aziridine and the corresponding azetidine reacted efficiently with nitriles and carbonyl substrates to generate imidazoline, oxazolidine, and tetrahydropyrimidine products. The azetidine rearranged efficiently t

Full text of DOI:10.1021/ja055664t

Published on Web 11/03/2005
Silylmethyl-Substituted Aziridine and Azetidine as Masked 1,3- and
1,4-Dipoles for Formal [3 + 2] and [4 + 2] Cycloaddition Reactions
Veejendra K. Yadav* and Vardhineedi Sriramurthy
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received August 18, 2005; E-mail: vijendra@iitk.ac.in
Scheme 1
Small polyfunctional heterocycles play an important role in the
drug discovery process.1 Aziridine is a versatile building block for
the syntheses of many nitrogen-containing biologically active
molecules. It reacts with various nucleophiles, and its ability to
undergo regioselective ring-opening contributes largely to its high
synthetic value.2,3 The cycloaddition reaction of aziridine with
Table 1. Formal [3 + 2] Additions of Aziridines 1a-b with Nitrilesa
dipolarophiles, in particular, is a useful method for the syntheses
of nitrogen-containing five- and six-ring molecules.4 We report
herein on the generation of 1,3- and 1,4-dipoles from aziridine and
azetidine, respectively, wherein the negative charge is stabilized
on the nitrogen by a sulfone function and the positive charge is
stabilized on a carbon by tert-butyldiphenylsilylmethyl substituent
through the â-effect of silicon5,6 (Scheme 1), and their applications
for formal [3 + 2] and [4 + 2] cycloadditions with nitrile and
carbonyl substrates to generate five- and six-ring heterocycles in a
single step. The cycloaddition chemistry of aziridine has thus far
been limited to the stabilization of the above cation by an aryl
substituent that has limited further usage. Since tert-butyldiphen-
ylsilylmethyl is latent to CH2OH function,7 the present methodology
widens the scope of the aziridine chemistry enormously.
The reaction outlined in Scheme 1 entails initial nucleophilic
attack of nitrile or cabonyl function at the positive end of the dipole
1′. The subsequent intramolecular nucleophilic capture of the
nitrilium or oxonium ion by the negatively charged nitrogen results
in the formation of 2-imidazolines or oxazolidines, respectively.
2-Imidazolines are useful intermediates for the syntheses of
molecules with pharmacological activities, such as anticancer, anti-
inflammatory, and antidiabetic.8 The reactions with nitriles, leading
to 2-imidazolines, are collected in Table 1. BF3‚Et2O offered the
best results among the several Lewis acids attempted to promote
the reaction. Both aromatic and aliphatic nitriles reacted with 1a
to furnish the products 2-8 in excellent yields (entries 1-7).
TBDPS-protected 3-hydroxy propionitrile reacted without event
while retaining the protecting group (entry 6). The reaction is
stereospecific. The cis-1b reacted with acetonitrile to form the cis
product exclusively (entry 8), and the trans-1b gave mainly the
trans product at low temperature. However, the trans-1b exhibited
increased tendency with increased temperature for the formation
of the cis product (entry 9). The cis and trans relationships of the
TBDPSCH2 and CH3 substituents in the adducts were ascertained
by nOe measurements.
We ascertained next the efficacy of the above aziridine-derived
1,3-dipole for reaction with carbonyl species to construct oxazo-
lidines. BF3‚Et2O was discovered again to be the most effective
Lewis acid as several other Lewis acids were found to be either
much less effective or not effective at all. The reactions proceeded
smoothly to generate the desired products in excellent yields (Table
2). Both aromatic and aliphatic carbonyl compounds reacted with
1a to furnish the products 11-15 (entries 1-5). The reaction is
stereospecific. The cis-1b reacted with propanal to form predomi-
nantly the cis product 16 (entry 6), and the trans-1b gave mainly
a Unless noted otherwise, all the reactions were carried out in CH2Cl2
for 5 min using 1 equiv each of the nitrile and BF3‚Et2O at 25 °C. b Isolated
yields. c Reaction was conducted at -78 °C.
the trans product (entry 7) at low temperature. However, trans-1b
exhibited increased tendency with increasing temperature for the
formation of the cis product. Thus, three stereocenters had been
generated in the product with high control by taking advantage of
aziridine’s methyl substituent. The relative stereochemistries of the
substituents in the adducts were ascertained by nOe measurements.
We have extended the above chemistry to the silylmethyl-
substituted azetidine 19 to generate the 1,4-dipole 19′ and then
employed the same for [4 + 2] cycloaddition (Scheme 2). The
cycloaddition of azetidine with dipolarophiles constitutes a powerful
protocol for the formation of nitrogen-containing six-ring hetero-
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10.1021/ja055664t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. [3 + 2] Cycloadditions of 1a-b with Carbonyl
Scheme 3
Substratesa
The TBDPS function in 11 was transformed into a hydroxy group
under basic conditions following a literature protocol7 in 60%
isolated yield with the sulfonamide function fully intact.
In summary, 2-tert-butyldiphenylsilylmethyl-substituted aziri-
dines and the corresponding azetidine reacted efficiently with nitriles
and carbonyl substrates to form imidazoline, oxazolidine, and
tetrahydropyrimidine products. The azetidine rearranged to the
pyrrolidine skeleton efficiently under BF3‚Et2O conditions. These
protocols will find application in synthesis, in general, and in drug
design, in particular. The development of the enantioselective
versions of these ring-forming methodologies and their applications
to the syntheses of selected drug candidates are currently being
explored.
Acknowledgment. Authors thank CSIR, Government of India,
for financial support. This work is dedicated to Professor Mugio
Nishizawa on the occasion of his 60th birthday.
Supporting Information Available: Experimental details and
characterization data (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
a Unless noted otherwise, all the reactions were carried out in CH2Cl2
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Scheme 2
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a All the reactions were carried out in CH2Cl2 for 1 h using 1 equiv
each of the nitrile substrate and BF3‚Et2O at 25 °C. b Isolated yield.
cycles.9 The azetidine 19 reacted smoothly with several nitriles
under BF3‚Et2O conditions at 25 °C to generate the tetrahydropy-
rimidine derivatives 20-22. The results are collected in Table 3.
Tetrahydropyrimidines are reported to exhibit a wide range of
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(Scheme 3). The pyrrolidine derivatives are ubiquitous among
natural products as they are materials of much pharmacological
interest.11
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