InCl3 catalyzed reactions of ethyl diazoacetate with aldimines: A highly diastereoselective synthesis of cis-aziridine carboxylates

Article abstract of DOI:10.1016/S0040-4039(00)01042-X

InCl₃ catalyzed reactions of ethyl diazoacetate with aldimines give aziridine carboxylates under mild conditions, low catalyst loading and with high cis-selectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01042-X

Tetrahedron Letters 41 (2000) 6245±6248
InCl catalyzed reactions of ethyl diazoacetate with
3
aldimines: a highly diastereoselective synthesis of
cis-aziridine carboxylates
Saumitra Sengupta* and Somnath Mondal
Department of Chemistry, Jadavpur University, Calcutta 700 032, India
Received 3 May 2000; accepted 20 June 2000
Abstract
InCl catalyzed reactions of ethyl diazoacetate with aldimines give aziridine carboxylates under mild
3
conditions, low catalyst loading and with high cis-selectivity. # 2000 Elsevier Science Ltd. All rights
reserved.
3
Keywords: InCl ; diazoacetate; imines; aziridines.
Aziridines are useful building blocks for the synthesis of many biologically active compounds
1
such as amino alcohols, unnatural amino acids and nitrogenous heterocycles. In view of this,
stereoselective synthesis of aziridines continues to attract the attention of synthetic chemists.
In 1995, a conceptually new synthesis of aziridines via catalyzed carbene-transfer reactions of
2
a-diazoacetates with imines, appeared in the literature. Although copper(II) salts were seminally
used as catalysts for these reactions, the yields and/or diastereoselectivities of aziridine formation
2
were somewhat unsatisfactory. Subsequent improvements have been reported using MeReO
3
3
and Rh±clay catalysts which produced aziridine carboxylates with high trans-selectivity. In a
related development, recently, it has been shown that reactions of a-diazoacetates and imines can
.
also be catalyzed by Lewis acids (BF Et O, Zn(OTf) , lanthanide tri¯ates) to produce aziridine
3
2
2
4
carboxylates, albeit in moderate yields. Interestingly, a high degree of cis-selectivity has been
observed in some of these Lewis acid catalyzed reactions.4 Although in its infancy, this Lewis
acid catalyzed aziridine synthesis, by virtue of its operational simplicity, mild reaction conditions
and the prospect of asymmetric indiction4 via the use of chirally modi®ed Lewis acids, holds
more promise than the metal-catalyzed route described above and hence, if properly developed,
can lead to broader synthetic rami®cations.
a,d
c,f
*
Corresponding author. Fax: 91 33 4734266.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01042-X

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InCl has recently emerged as a versatile Lewis acid catalyst for a variety of organic reactions.5
3
.
We have reported that InCl is an excellent catalyst (vis-a-vis BF Et O or Rh (OAc) ) for a
3
3
2
2
4
6
number of reactions of a-diazocarbonyl compounds, which led us to investigate the ecacy of
this Lewis acid in carbene-transfer reactions of a-diazoacetates with aldimines. Results of this
study, which has indeed given rise to a highly diastereoselective synthesis of cis-aziridine
carboxylates, are described here.
Model studies were carried out with the imine 1a and ethyl diazoacetate (2) which revealed that
InCl catalyzed aziridine formation is quite sensitive to the reaction solvent, catalyst loading and
3
the time of the reaction (Scheme 1, Table 1). Thus, the reaction of 1a with 2, when carried out
with 10% InCl in CH Cl for 12 h at rt, produced only 23% of the aziridine 3a together with
3
2
2
1
6% of the enamines 4a and 5a and other unidenti®ed side products (entry 1). However, only the
1
cis-isomer of 3a was formed in this reaction, as evident from the H NMR spectrum of the crude
product mixture which showed a large coupling constant (J=6.9 Hz) for the aziridine ring
protons at ꢀ 3.20 and 3.59 (ring protons of trans-3a appear at ꢀ 3.20 and 3.80 with a smaller
coupling constant, J=2±3 Hz).3
,4a,c
Scheme 1.
Table 1
3
InCl catalyzed reactions of 1a and 2 (Scheme 1)

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247
Encouraged by this high cis-selectivity, we then looked for conditions that would improve the
ꢀ
yield of aziridine formation. Lowering the reaction temperature (^10 C) or changing the solvent
to THF, however, gave low conversions (entry 2). In MeOH at rt (entry 3), the yield of 3a
dropped even further and the proportions of enamines (4a and 5a) increased together with the
formation of a new side product 6 (14%). The latter was perhaps formed via InCl mediated ring-
3
opening of 3a with MeOH, which led us to believe that InCl , while catalyzing the formation of
3
the aziridine 3a, was also instrumental in its decomposition through activation of the aziridine
nitrogen. To minimize this, the reaction of 1a and 2 was re-examined in CH Cl with a lower
catalyst loading (2% InCl ) and a shorter reaction time (2 h) which indeed led to a much
2
2
3
improved yield of 3a (56%), again, exclusively as the cis-isomer (entry 5). Reactions carried out
with 2% InCl in petroleum ether, on the other hand, gave 3a in high yield (83%) but as a 78/22
3
mixture of cis/trans isomers (entry 6). Similar loss of diastereoselectivity, albeit with higher
chemical yields, has also been reported by others in their Lewis acid catalyzed aziridine formation
in hydrocarbon solvents.4 However, as has been reported with other Lewis acid catalysts,
under no circumstances could we completely suppress the formation of the enamine side products
c,d
4
(4a, 5a) in this reaction.
For preparatory purposes, a number of N-arylidene anilines 1a±d were reacted with 2 in presence
of 2% InCl in CH Cl at rt for 1±3 h (entry 5, Table 1) which produced the corresponding
3
2
2
aziridines 3a±d together with the corresponding enamine by-products. The latter could be easily
7
removed by silica-gel chromatography to give the pure aziridines 3a±d in 45±65% yields (Scheme 2).
The isolated yields of these aziridines were always found to be somewhat lower than their NMR
yields due to some unavoidable decomposition during silica-gel chromatography, but are,
4
nevertheless, comparable to those obtained with other Lewis acid catalysts. Most signi®cantly,
all the aziridines were produced either exclusively as the cis-isomer (3a±c) or with a high cis/trans
4
a
4d
.
ratio (3d). It may be noted that only lanthanide tri¯ates and BF Et O have, until now, shown
3
2
such high degrees of cis-selectivity in these reactions. In this work, imines derived from electron
de®cient or weakly electron rich aldehydes gave the best results, whereas those derived from
strongly electron rich aldehydes, e.g. p-anisaldehyde, gave complex product mixtures having large
amounts of the enamine side products. In another limitation, aldimines prepared from electron
rich anilines, e.g. p-anisidine, when reacted with 2 in presence of 2% InCl led to gradual
3
darkening of the reaction mixture with no aziridine formation. Similar electronic e€ects have also
been previously observed with other Lewis acids.4
d
Scheme 2.
In summary, InCl catalyzed reactions of ethyl diazoacetate with aldimines provide a highly
3
diastereoselective synthetic route to cis-aziridine carboxylates under mild and operationally sim-
ple conditions (low catalyst loading, short reaction times). Improvements in the yields as well as

6
248
synthesis of enantiopure aziridines via use of chiral auxiliaries in these reactions are currently
under investigation.
Acknowledgements
DST (SP/S1/G-14/97) and UGC (senior research fellowship to S.M.) are warmly thanked for
nancial support.
®
References
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(
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. The aziridines 3a±d were characterized by matching their spectral (IR, NMR) data with those reported in the
5
6
7
literature (Ref. 4). Typical procedure: cis-Ethyl 1,3-diphenylaziridine-2-carboxylate (3a): InCl
mmol) was added to a mixture of N-benzylidene aniline 1a (0.11 g, 0.7 mmol) and ethyl diazoacetate 2 (0.07 g,
.7 mmol) in CH Cl (7 ml) and the mixture stirred at room temperature for 2 h. The solvent was then removed in
3
(0.003 g, 0.014
0
2
2
vacuo and the residue puri®ed by preparative thin layer chromatography on silica-gel (15% EtOAc in petroleum
ether) to give 3a (0.092 g, 56%) as a waxy solid; IR (KBr): 1750, 1600, 1540, 1370, 1190 cm ; H NMR (300 MHz,
^1 1
CDCl ): ꢀ 0.99 (t, 3H, J=7.2 Hz), 3.20 (d, 1H, J=6.9 Hz), 3.59 (d, 1H, J=6.9 Hz), 3.90±4.11 (m, AB, 2H), 7.06
3
(
d, 2H, J=8.7 Hz), 7.20±7.38 (m, 6H), 7.51 (d, 2H, J=6.8 Hz).