Highly diastereoselective aziridination of α,β-unsaturated amides using diaziridine

Article abstract of DOI:10.1246/cl.2001.984

Racemic 3-cyclohexyl-1-methyldiaziridine was found to react with α,β-unsaturated amides in basic conditions, giving N-unprotected trans-aziridines, while 3,3-pentamethylenediaziridine had been reported to afford cis-aziridines in high diastereoselectivity

Full text of DOI:10.1246/cl.2001.984

984
Chemistry Letters 2001
Highly Diastereoselective Aziridination of α,β-Unsaturated Amides Using Diaziridine
Hiroyuki Ishihara, Yoshio N. Ito,* and Tsutomu Katsuki*
Department of Chemistry, Faculty of Sciences, Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581
(Received July 27, 2001; CL-010713)
Racemic 3-cyclohexyl-1-methyldiaziridine was found to
react with α,β-unsaturated amides in basic conditions, giving
N-unprotected trans-aziridines, while 3,3-pentamethylenedi-
aziridine had been reported to afford cis-aziridines in high
diastereoselectivity. The trans-selectivity was partially depend-
ent on the stereochemistry of the substrate. The stereo-
chemistries of these reactions were reasonably explained by the
conformational analysis of the intermediary enolates.
Three-membered ring compounds undergo various ring-
opening reactions due to their high strain energies. We recently
reported a non-stereospecific cis-aziridination of α,β-unsaturat-
ed amides by treatment with a lithiated diaziridine derivative
which was produced in situ from 3,3-pentamethylenediaziridine
(1) and butyllithium at low temperature (Figure 1, upper
scheme).1 The reaction was considered to proceed in a stepwise
manner, (i) 1,4-addition of N-lithiodiaziridine and (ii) the ring
closure of the resulting enolate, as similar to the epoxidation of
enones by hydrogen peroxide in basic conditions. Although
N–N bond is less reactive than O–O bond, the strain energy of
diaziridine enables the N–N bond fission by nucleophilic attack
of the enolate to give aziridine.
cyclization to aziridine (see Figure 2). Conformer B1 leading
to trans-aziridine, has no severe strain when R5=H and becomes
the most preferred. Accordingly, diaziridine 2 was prepared
from cyclohexanecarbaldehyde and employed for the azridina-
tion of cinnamide 3 (Table 1, entries 1–4).3 The reaction
afforded trans-isomer as the major diastereomer in a ratio of
2.5:1 as expected (entry 1). Lowering the reaction temperature
enhanced the selectivity to 5.6:1 (entry 2). Employment of less
polar solvent further increased the selectivity and trans-isomer
was exclusively obtained when toluene was used as the solvent
(entry 4).4 On the other hand, opposite tendency was observed
for the aziridination of cis-cinnamide 11 (entries 14–16). The
ratio of trans- and cis-aziridines varied from 3:1 to 1:3 merely
by switching the solvent from THF to toluene. The use of
toluene may increase the diastereoselectivity in the first 1,4-
addition and/or stabilize the chelating structure in conformers
A2 and B1 where the electrophilicity of the coordinating nitro-
gen is expected to increase. Accordingly, the stereochemistry
of the substrate was better retained during the reaction in less-
polar solvent. Thus, the aziridination of other trans-α,β-unsat-
urated amides (4–10) in toluene was examined. As expected,
high trans-selectivity was observed for all the reactions, irre-
spective of the nature of the β-substituents, though the reactions
of 8, 9 and 10 bearing a β-alkyl substituent was slow (entries
9–13).5
The high cis-selectivity was explained by conformational
consideration of the enolate intermediates. Reversible 1,4-addi-
tion of N-lithiodiaziridine gives two diastereomeric enolates
(Figure 2, A and B).1 For the subsequent ring-closure, antiperi-
planar N–N–C–C conformation is required. Thus, the enolate
moiety can adopt two conformational orientations, giving four
conformers (A1, A2, B1, B2). Among the conformers, A2 is
considered to be the most preferred when R4 =/ H.2
The above mechanistic consideration for the cis-selectivity
further suggested that trans-selectivity would be realized by an
appropriate modification of the diaziridine. It may be the case
that 3-mono-substituted diaziridine 2 is used in place of 3,3-di-
substituted one. Because, the cis-trans selectivity is largely
dependent on the steric repulsion of R4 or R5 group with the β-
substituent (R1) and enolate moiety in transition state for the
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
985
a high diastereoselective manner and subsequent cyclization
complies with stereoelectronic requirement.
As shown here, not only cis-selective but also trans-selec-
tive aziridination of α,β-unsaturated amides was achieved by
using reasonably designed diaziridine derivatives. The stereo-
chemistry of the reaction was well predicted by conformation
analysis of the transition state model. Further extension to
asymmetric aziridination is in investigation in our laboratory.
Dedicated to Prof. Hideki Sakurai on the occasion of his
70th birthday.
References and Notes
1
K. Hori, H. Sugihara, Y. N. Ito, and T. Katsuki,
Tetrahedron Lett., 40, 5207 (1999).
2
After we published the original paper (Reference 1) on cis-
selective aziridination, we found that chemical yields of
cis-aziridines were remarkably improved by optimizing
reaction temperature. The results should be published else-
where.
3
4
Diaziridine 2 was prepared from cyclohexanecarbaldehyde,
methylamine, and chloramine according to the reported
method. E. Schmitz, Chem. Ber., 95, 688 (1962).
Typical experiment is as follows (Table 1, entry 4). A solu-
tion of butyllithium in hexane (1.56 mol dm−3, 0.256 mL,
0.40 mmol) was added to a solution of 2 (56.1 mg, 0.40
mmol) in toluene (4 mL) at −78 °C and the mixture was
stirred for 30 min. A toluene solution of 3 (40.3 mg, 0.20
mmol) was added to the mixture at the same temperature.
After stirring for 4 h at −78 °C, the mixture was diluted
with water and CH2Cl2. Extraction and column chromatog-
raphy on basic silica gel (Fuji Silysia Chemical Ltd., NH-
DM1020, hexane–AcOEt 4:1–3:7) afforded the correspon-
ding trans-aziridine as colorless crystals (32.0 mg, 74%).
The stereochemistry of the aziridine obtained from 10 was
confirmed to be 2,3-trans by measuring NOESY. The
tarns-isomer showed NOE between 2- and 3-methyl
groups.
5
With the generality of the trans-selective aziridination, its
asymmetric version was next examined by employing optically
active diaziridine 12.6 As shown in Scheme 1, the reaction pro-
ceeded smoothly to give highly optically active aziridine amide
in high yield.7 This result showed good agreement with the
above mentioned reaction mechanism. Namely, the first 1,4-
addition of diaziridine to α,β-unsaturated amides takes place in
The other 2,3-disubstituted aziridine products were
assigned to be trans based on the coupling constants of
hydrogens at C2 and C3 of the aziridines.
Diaziridine 12 was prepared by the method employed for
the preparation of 2 (Reference 3). The relative stereo-
chemistry of 12 was not asgined though 12 was single
diastereomer.
The stereochemistry of the product was determined by the
following chemical correlation. Tosylation with tosyl
chloride and triethylamine and the subsequent hydrogenol-
ysis with hydrogen and palladium on carbon afforded N-
(N-tosylphenylalanyl)pyrrolidine, which showed identical
NMR spectra and retention time in HPLC analysis using
chiral stationary phase column with the compound pre-
pared from (S)-phenylalanine.
6
7