Alkylation of nonstabilized aziridinylmagnesiums catalyzed by Cu(I) iodide: A new synthesis of amines, including optically active form, bearing a quaternary chiral center

Article abstract of DOI:10.1016/S0040-4039(00)01085-6

A high-yield alkylation of aziridinylmagnesiums, which were generated from sulfinylaziridines with EtMgBr by sulfoxide-magnesium exchange, with primary alkyl halides in the presence of Cu(I) iodide as a catalyst, was realized. The alkylated aziridines were converted in quantitative yield to amines bearing a quaternary chiral center by hydrogenation with Pd(OH)₂. A synthesis of the optically active amines, bearing a quaternary chiral center, was realized, starting from optically active (R)-chloromethyl p-tolyl sulfoxide, in good overall yield by the presented method. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01085-6

Tetrahedron Letters 41 (2000) 6495±6499
Alkylation of nonstabilized aziridinylmagnesiums catalyzed
by Cu(I) iodide: a new synthesis of amines, including
optically active form, bearing a quaternary chiral center
Tsuyoshi Satoh,* Rie Matsue, Toshinari Fujii and Satoshi Morikawa
Department of Chemistry, Faculty of Sciences, Science University of Tokyo, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Received 24 May 2000; revised 19 June 2000; accepted 23 June 2000
Abstract
A high-yield alkylation of aziridinylmagnesiums, which were generated from sul®nylaziridines with
EtMgBr by sulfoxide±magnesium exchange, with primary alkyl halides in the presence of Cu(I) iodide as a
catalyst, was realized. The alkylated aziridines were converted in quantitative yield to amines bearing a
quaternary chiral center by hydrogenation with Pd(OH)2. A synthesis of the optically active amines,
bearing a quaternary chiral center, was realized, starting from optically active (R)-chloromethyl p-tolyl
sulfoxide, in good overall yield by the presented method. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aziridinyl anion; aziridinylmagnesium; quaternary chiral center; optically active amine.
Asymmetric synthesis of compounds having a quaternary chiral center has been a formidable
but quite interesting challenge in synthetic organic chemistry.1 In the chemistry of amines,
optically active amines bearing a chiral quaternary center, including quaternary a- and b-amino
acids,2 are important as biologically active compounds, pharmaceuticals, catalysts, etc. However,
few methods have so far reported the construction of these optically active amines bearing a
chiral quaternary center.3
In our previous papers, we reported a new method for the generation of nonstabilized
aziridinyl anions 34 by the sulfoxide±metal exchange reaction5 of sul®nylaziridines 2, which were
synthesized from 1-chloroalkyl p-tolyl sulfoxides 1 with imines.6 In continuation of our study for
the generation of nonstabilized aziridinyl anions and their application to the development of new
synthetic methods, herein we report a new method for the synthesis of amines bearing a
quaternary chiral center 5 from sul®nylaziridine 2. The key step of this method is the generation
of the aziridinylmagnesium 3 and alkylation of 3 with alkyl halides, using Cu(I) iodide as a
* Corresponding author. Fax: +81 3 3235 2214; e-mail: tsatoh@ch.kagu.sut.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01085-6

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catalyst. We also report a new chiral synthesis of optically pure amines having a quaternary chiral
center 5 starting from (R)-chloromethyl p-tolyl sulfoxide (1, R1=H) (Scheme 1).
Scheme 1.
First, sul®nylaziridine 66b was treated with 3.5 equiv. of EtMgBr at ^78ꢀC and the temperature
of the reaction mixture was allowed to warm to room temperature to give the aziridinyl-
magnesium 7 in quantitative yield. The carbanion 7 was found to be stable at room temperature
for several hours. It was also found that the reactivity of 7 was quite low. For example, 7 reacted
only with acetaldehyde but neither ketones nor iodomethane reacted with 7.6b
We further investigated the alkylation of 7 with iodoalkanes in the presence of metal catalysts
and ®nally found that copper(I) iodide worked excellently.7 For instance, aziridinylmagnesium 7
was treated with 3.5 equiv. of iodoethane and 10 mol% of Cu(I) iodide in THF at room
temperature for 30 min to give the ethylated aziridine 8 in 86% yield, as a single isomer (Scheme 2).
The stereochemistry of product 8 was investigated with the 1H NMR NOESY spectrum. As the
NOE between the hydrogen on the aziridine ring and the methyl group of the ethyl substituent
was observed, the structure of 8 was unambiguously determined to be E. From this result, it was
found that the stereochemistry of the carbon bearing the sul®nyl group of 6 was retained
throughout the whole sequence.
Scheme 2.
Representative results for the alkylation of the aziridinylmagnesiums with alkyl halides are
summarized in Table 1. As shown in the table, both the aziridinylmagnesiums having a methyl
and decyl group gave quite good results with primary alkyl iodides (entries 1±3 and 8±10). Allyl
bromide and benzyl bromide show much higher reactivity than other primary alkyl iodides in this
reaction (entries 4, 5, 11, and 12). However, secondary alkyl iodide (2-iodopropane) and aryl
iodide (iodobenzene) did not react at all (entries 6 and 13). Although the TBDMS ether of
2-iodoethanol reacted less vigorously, it gave the desired product in moderate yield (entry 14). In

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Table 1
Generation of aziridinylmagnesiums and alkylation with alkyl halides
an attempt to synthesize b-amino acids, the aziridinylmagnesium was reacted with iodoacetonitrile
and ethyl iodoacetate (entries 7 and 15); however, the reaction gave either a complex mixture or
desul®nylated aziridine.
We then investigated the regioselective cleavage of the produced aziridines by hydrogenation
with a palladium catalyst to a€ord the amines bearing a quaternary chiral center. Usually, the
hydrogenative cleavage of aziridines is conducted with Pd(OH)2.8 We also used Pd(OH)2 as the
catalyst for cleavage of the C N bond, and the results are summarized in Table 2.
As shown in Table 2, the regioselective cleavage of the aziridines is quite e€ective, to a€ord the
desired amines bearing a quaternary chiral center. However, the reaction required 100 to 300

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Table 2
Hydrogenation of alkylated aziridines to the amines bearing a quaternary chiral center
wt% of the Pd(OH)2. When this reduction was conducted with less Pd(OH)2, a considerable
amount of the starting material remained. It is noted that the product in entry 5 is a g,g-di-
substituted g-amino alcohol.
Finally, we applied the presented procedure to an asymmetric synthesis of amines bearing a
quaternary chiral center, starting from the chiral sulfoxide 96b (see Scheme 3). Optically active
sul®nylaziridine 11 (over 98% ee)6b was treated with 3.5 equiv. of EtMgBr, followed by 3-meth-
26
D
oxybenzyl bromide in the presence of 10 mol% of Cu(I) iodide, to give the optically active 12 (‰ꢀŠ
^87.45ꢀ (c 0.27, acetone), 98% ee)9 as a colorless oil in 98% yield. The catalytic hydrogenation of
12 with Pd(OH)2 (200 wt%) in a mixture of MeOH:EtOH (2:1) as above, a€orded the optically
25
D
active amine bearing a quaternary chiral center (S)-(^)-13 (‰ꢀŠ ^2.2ꢀ (c 0.1, acetone)) as a
colorless oil with over 97% ee9 in quantitative yield.
Scheme 3. Asymmetric synthesis of the optically active amine (S)-13 starting from (R)-chloromethyl p-tolyl sulfoxide 9

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Acknowledgements
This work was supported by a Grant-in-Aid for Scienti®c Research No. 11640545 from the
Ministry of Education, Science, Sports, and Culture, Japan, which is gratefully acknowledged.
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