A convenient synthesis of activated enantiomerically pure 2- ethynylaziridines

Article abstract of DOI:10.1016/S0957-4166(98)00406-6

2,3-cis- and 2,3-trans-N-Arylsulfonyl-2-ethynylaziridines with high enantiomeric purity have been synthesized. N-Protected amino aldehydes synthesized from natural α-amino acids were successively treated with Ph₃P=C(Br)CO₂Me, DIBAL, MsCl-Et₃N, NaH in DMSO, and tert-BuOK in THF to yield 2-ethynylaziridines in good to high yields.

Full text of DOI:10.1016/S0957-4166(98)00406-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3929–3933
A convenient synthesis of activated enantiomerically pure
2-ethynylaziridines
Hiroaki Ohno, Ayako Toda, Nobutaka Fujii and Toshiro Ibuka ∗
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 22 September 1998; accepted 7 October 1998
Abstract
2,3-cis- and 2,3-trans-N-Arylsulfonyl-2-ethynylaziridines with high enantiomeric purity have been synthe-
sized. N-Protected amino aldehydes synthesized from natural α-amino acids were successively treated with
Ph3P_C(Br)CO2Me, DIBAL, MsCl–Et3N, NaH in DMSO, and tert-BuOK in THF to yield 2-ethynylaziridines
in good to high yields. © 1998 Elsevier Science Ltd. All rights reserved.
Aziridines, the smallest of the azacycles, are known to undergo reaction with a wide variety of
nucleophiles, and various methods for new bond formation via aziridine ring-opening have been de-
veloped utilizing this chemistry.1,2 Although the synthesis and reaction of alkenylaziridines and their
derivatives have attracted considerable interest over the past decade,3 relatively little is known about the
chiral alkynylaziridines. The alkynylaziridines contain synthetically exploitable and versatile ethynyl and
aziridinyl moieties and hence should be amenable to a variety of important synthetic transformations.
Recently, Dai and co-workers have reported an interesting synthesis of alkynylaziridines.4 The reported
synthesis of aziridines bearing an alkynyl group either provides racemic material or necessitates the use of
D-(+)-camphor-derived sulfonium salts providing alkynylaziridines with moderate enantiomeric purity.
In connection with a general programme directed towards the synthesis and reaction of chiral amino
allenes, we required a reliable procedure for the synthesis of alkynylaziridines with high enantiomeric
purity. It is generally accepted that ee or de values in excess of 90% are necessary. In this context,
construction of chiral molecules using natural α-amino acids has assumed increasing importance.5 In this
communication, we report a new synthetic route to activated chiral ethynylaziridines from commercially
available S-α-amino acids.
The requisite starting materials, mesylates of amino allylic alcohols 9–12, for our initial study were
prepared in a straightforward manner as depicted in Scheme 1. α-Bromo-α,β-unsaturated esters 1–4,
synthesized from the corresponding chiral amino aldehydes by treatment with Ph3P_C(Br)CO2Me,6
were successively treated with DIBAL and methanesulfonyl chloride–Et3N or pyridine to yield the allylic
mesylates 9–12 in good to excellent overall yields.
∗
Corresponding author. E-mail: tibuka@pharm.kyoto-u.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00406-6

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H. Ohno et al. / Tetrahedron: Asymmetry 9 (1998) 3929–3933
Scheme 1. Abbreviations: Ts=4-methylbenzenesulfonyl; Mts=2,4,6-trimethylbenzenesulfonyl; Mtr=4-methoxy-2,3,6-trimethyl-
benzenesulfonyl. Reagents: i. DIBAL in toluene–CHCl3; ii. MsCl–pyridine or Et3N
Although conversion of the allylic mesylates such as 9 to ethynylaziridines 13 and 14 (Scheme 2) can
be carried out in one pot by treating with tert-BuOK in DMSO, the yields of aziridines are considerably
lower than those obtained from the two-step procedure described below.
Scheme 2.
Based on our previous synthetic studies of alkenylaziridines from the corresponding allylic mesylates,7
we anticipated that 3-alkyl-2-(1-bromovinyl)aziridines such as 15–18 could easily be prepared from
the corresponding allylic mesylates 9–12 (Scheme 3). However, this was not to be the case. After
considerable experimentation, we found that improved yields in the aziridine ring-forming reaction could
be obtained by the use of sodium hydride in DMSO or mixed solvents containing DMSO. As illustrated
in Table 1, except for entry 2, bromoaziridines 15, 17 and 18 were obtained from the corresponding
allylic mesylates 9, 11 and 12 in both acceptable yields and high diastereoselectivities. Typically, the
treatment of 9 with sodium hydride (1.2 equiv.) in DMSO at 30°C gave a mixture of bromoaziridine 15
and its 2,3-cis-isomer. Analysis by HPLC or 1H NMR indicated a 97:3 ratio of diastereomers in favor of
2,3-trans-isomer 15 (Table 1, entry 1). Reaction in other solvents (e.g., THF and DMF) or in the absence
of DMSO gave the expected products by slow reactions that often failed to proceed to completion.
Scheme 3.
Although 2,3-trans-bromoaziridines 16 and 17 could be separated, albeit with difficulty, from the
corresponding 2,3-cis-isomers, other mixtures of the 2,3-trans- and 2,3-cis-isomers listed in Table 1
(entries 1 and 4) were inseparable by flash chromatographic techniques on various silica flash chromato-
graphic columns. The predominant formation of 2,3-trans-bromoaziridines 15–18 could be rationalized
by considering the 1,3-allylic strain of two aza-anionic intermediates A and B (Fig. 1). If the reaction
conformers are as depicted in A and B, the higher diastereoselectivity is readily understood. Examination

H. Ohno et al. / Tetrahedron: Asymmetry 9 (1998) 3929–3933
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Table 1
Aziridination reactions of bromo allylic mesylates 9–12 by treatment with sodium hydridea
of the nonbonded interactions in the conformers A and B reveals that in conformer A a substantial
nonbonded interaction does exist to destabilize this conformer. Thus, an aziridine ring-forming reaction
would proceed preferentially from the more abundant conformer B.
Figure 1.
Next, dehydrobromination reaction of the bromoaziridines 15–18 was investigated. Exposure of pure
bromoaziridine 17 to tert-BuOK in THF unexpectedly gave a separable 65:35 mixture of 2,3-trans-
and 2,3-cis-ethynylaziridines 20 and 23 in 80% combined yield. Consequently, without separating the
mixtures of bromoaziridines, all the 2,3-trans- and cis-mixtures (2,3-trans:2,3-cis=95–97:5–3) were
dehydrobrominated to yield the corresponding ethynylaziridines (2,3-trans:2,3-cis=63–77:35–23) in
good to excellent yields. The results are listed in Table 2.8 It should be clearly noted that, among various
reaction conditions, only tert-BuOK in THF gave satisfactory results.
Interestingly, the reaction condition (tert-BuOK in THF) used for the dehydrobromination reaction did
not cause any epimerization at the C-2 position of alkynylaziridine 13. No sign of epimerization at the
C-2 position of 13 was detected by 1H NMR and HPLC after treatment with tert-BuOK (−78–0°C for 1
h).
Table 2
Synthesis of ethynylaziridines from 2-(1-bromovinyl)aziridinesa

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H. Ohno et al. / Tetrahedron: Asymmetry 9 (1998) 3929–3933
Although the details of the dehydrobromination reactions have still not been elucidated, we are
working under the assumption that both paths A and B are involved as depicted in Scheme 4. If the
bromoaziridine 15 reacts with tert-BuOK only by path A, it will produce the 2,3-trans-ethynylaziridine
13 and if it proceeds only by path B, it will generate either only 2,3-trans-13 or 2,3-cis-14 or a mixture
of both via an allenic intermediate A. The treatment of 13 with tert-BuOK in THF containing 5 equiv. of
tert-BuOD gave a mixture of 2,3-trans- and 2,3-cis-alkynylaziridines as expected. Although no evidence
was obtained of the incorporation of deuterium in the C-2 position of 2,3-trans-alkynylaziridine, it
was found that ca. 10% of deuterium was incorporated at the C-2 position of 2,3-cis-ethynylaziridine.
Taking together the above results, we propose the reaction of bromoaziridine 15 would proceed via two
competitive paths A and B to yield 2,3-trans- and 2,3-cis-ethynylaziridines (13 and 14).
Scheme 4.
In summary, chiral 2,3-trans- and 2,3-cis-2-ethynylaziridines with high enantiomeric purity have been
synthesized. Work on synthetic transformations of ethynylaziridines thus obtained is in progress and will
be reported in due course.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture of Japan.
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