Asymmetric synthesis of aziridines by reduction of N-tert-butanesulfinyl α-chloro imines

Article abstract of DOI:10.1021/jo0624795

(Chemical Equation Presented) Reduction of (R_S)-N-tert- butanesulfinyl α-halo imines afforded chiral aziridines in good to excellent yields. Upon reduction of (R_S)-N-tert-butanesulfinyl α-halo imines with NaBH₄ in THF, in

Full text of DOI:10.1021/jo0624795

Asymmetric Synthesis of Aziridines by Reduction of
N-tert-Butanesulfinyl r-Chloro Imines
Bram Denolf, Erika Leemans, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000 Ghent, Belgium
Norbert.DeKimpe@UGent.be
ReceiVed December 4, 2006
Reduction of (RS)-N-tert-butanesulfinyl R-halo imines afforded chiral aziridines in good to excellent
yields. Upon reduction of (RS)-N-tert-butanesulfinyl R-halo imines with NaBH4 in THF, in the presence
of 10 equiv of MeOH, (RS,S)-â-halo sulfinamides were formed in excellent yield (up to 98%) with very
good stereoselectivity (>98:2). Simple treatment of the latter (RS,S)-â-halo-tert-butanesulfinamides with
KOH afforded the corresponding (RS,S)-N-(tert-butylsulfinyl)aziridines in quantitative yields. On the
contrary, its epimer, (RS,R)-N-(tert-butylsulfinyl)aziridine was synthesized by switchover of the reducing
agent from NaBH4 to LiBHEt3. (RS,R)-N-(tert-Butylsulfinyl)aziridines were synthesized in good yields
(up to 85%) and diastereoselectivity (up to 92:8) by reduction of (RS)-N-tert-butanesulfinyl R-halo imines
with LiBHEt3 in dry THF and subsequent treatment with KOH. All chiral aziridines were obtained as a
single diastereomer after recrystallization (overall yield up to 91%) or after flash chromatography.
Introduction
Activation of the imino function by a chiral N-sulfinyl group is
borne out in high yields and diastereoselectivities of the
aziridines synthesized. Diverse strategies, utilizing the Corey-
Chaykovsky-type reaction with sulfur or tellurium ylides,7 the
aza-Darzens-type addition with R-halo enolates,8 or allenylzinc
Aziridines are versatile synthetic intermediates for the
synthesis of a variety of attractive compounds via regio- and
stereoselective ring opening reaction with nucleophiles.1 In
recent years chiral aziridines have received an increasing amount
of attention since they are key substrates in the synthesis of a
number of useful alkaloids, amino acids, or â-lactam antibiotics
or are used as chiral auxiliaries and ligands.1,2 Noteworthy, while
the synthesis of aziridines has been well described, the stereo-
selective synthesis remains more limited.1,2 Main routes toward
chiral aziridines include an asymmetric aza-Darzens reaction,3
stereoselective nitrene addition to olefins,4 asymmetric additions
to azirines,5 or aza-Payne rearrangement of 2,3-epoxy amines.6
Also the chiral aziridine synthesis starting from N-sulfinyl imines
has proven to be a good alternative to known procedures.7-10
(3) (a) Sweeney, J. B.; Cantrill, A. A.; Drew, M. G. B.; McLaren, A.
B.; Thobhani, S. Tetrahedron 2006, 62, 3694. (b) Sweeney, J. B.; Cantrill,
A. A.; McLaren, A. B.; Thobhani, S. Tetrahedron 2006, 62, 3681. (c) Kim,
D. Y.; Suh, K. H.; Choi, J. S.; Mang, J. Y.; Chang, S. K. Synth. Commun.
2000, 30, 87. (d) Cantrill, A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M.
I.; Raphy, J.; Sweeney, J. B. J. Chem. Soc., Chem. Commun. 1996, 23,
2631.
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39, 194. (b) Ma, L.; Jiao, P.; Zhang, Q.; Xu, J. Tetrahedron: Asymmetry
2005, 16, 3718. (c) Atkinson, R. S.; Tughan, G. J. Chem. Soc., Perkin Trans.
1 1987, 2803.
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1996, 789. (b) Roth, P.; Somfai, P.; Andersson, P. G. Chem. Commun. 2002,
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Risberg, E.; Andreas, F. B.; Somfai, P. J. Chem. Soc., Chem. Commun.
2004, 2088. (e) Risberg, E.; Fischer, A.; Somfai, P. Tetrahedron 2005, 61,
8443.
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Org. Lett. 2005, 7, 3267. (b) Bouyacoub, A.; Volatron, F. Eur. J. Org.
Chem. 2002, 4143. (c) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun, H.;
Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem.
2002, 67, 8726. (e) Otaka, A.; Umeda, Y.; Oishi, S.; Ibuka, T.; Fujii, N.
Pept. Sci. 1999, 36, 195. (f) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145.
* To whom correspondence should be addressed: Phone: +32 92 64 59 51.
Fax: +32 92 64 62 43.
(1) (a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Sweeney, J. B. Chem.
Soc. ReV. 2002, 31, 247. (c) McCoull, W.; Davis, F. A. Synthesis 2000,
1347. (d) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599 and
references therein.
(2) (a) Halfen, J. A. Curr. Org. Chem. 2005, 9, 657. (b) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905. (c) Osborn, H. M. I.; Sweeney, J. B.
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10.1021/jo0624795 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/31/2007
J. Org. Chem. 2007, 72, 3211-3217
3211

Denolf et al.
SCHEME 1. Asymmetric Aziridine Synthesis from
N-Sulfinyl Imines
SCHEME 2. Aziridine Synthesis from N-tert-Butanesulfinyl
r-Chloro Aldimine 5a
reactions9 with nonfunctionalized N-sulfinyl imines are described
to afford chiral aziridines. As a result, the nucleophile is
incorporated as part of the backbone of the ring (Scheme 1,
pathway 1).
Via an alternative strategy, the stereoselective aziridine
synthesis has already been described by us, starting from
N-sulfinyl R-halo aldimines 4 (Scheme 1, pathway 2).10 Given
the interest in and synthetic potential of R-halo imines11 in
combination with the enhanced reactivity of N-sulfinyl imines
reported by Davis12 and Ellman,13 a more profound research of
N-sulfinyl R-halo ketimines is highly desirable. The simple
synthesis of N-sulfinyl R-halo imines 4 and the subsequent
cyclization after an addition reaction, toward aziridines 2, make
the R-halo imino moiety an interesting building block. Needless
to say, the chemistry of such imines might differ substantially
from that of nonfunctionalized N-sulfinyl imines by virtue of
other possible reactions, e.g., substitution, dehydrohalogenation,
enhanced reactivity, etc.
Upon Grignard addition (EtMgBr, PhMgCl, vinyl-MgBr) to
N-tert-butanesulfinyl R-chloro aldimine 5a, N-(tert-butylsul-
finyl)aziridines 7 have been synthesized in good to excellent
yield with high stereoselectivity (Scheme 2),10 though it has to
be reported that the steric bulk of both the substrate and Grignard
reagent, in combination with its electronic properties, had its
limitations. For example, N-sulfinyl R-chloro aldimine 5a was
reduced to â-chloro sulfinamide 9 at -78 °C in CH2Cl2 if 1.1
equiv of i-PrMgCl was added at -97 °C.10 The addition of
PhMgCl to N-tert-butanesulfinyl R-chloro aldimine 5a in CH2-
Cl2 afforded 2-phenylaziridine 7b only when performed at well-
controlled reaction conditions to avoid competitive side reactions
(Scheme 2).
Therefore, it was considered that the steric hindrance could
be anticipated by reduction of N-tert-butanesulfinyl R-halo
ketimines followed by ring closure of the resulting â-halo
sulfinamide intermediates in a complementary, simple, and
straightforward strategy. For many synthetic targets a ketone
precursor is readily accessible. The hydride addition to non-
functionalized N-sulfinyl imines has been described to proceed
in high yields and with excellent diastereofacial control in some
cases.14 At the start of our research a thoroughly elaborated study
of hydride addition across N-sulfinyl imines seemed to be
lacking in the literature, yet very recently a profound study of
hydride reduction of nonfunctionalized N-sulfinyl imines toward
chiral secondary amines has been reported,15 but the reduction
of functionalized N-sulfinyl imines and N-sulfinyl R-halo imines
specifically, allowing further elaboration after reaction, was not
incorporated. This study will fill this gap by the development
of a synthetic method for chiral aziridines from N-tert-
butanesulfinyl R-halo ketimines.
(7) (a) Ferna`ndez, I.; Valdivia, V.; Gori, B.; Alcudia, F.; Alvarez, E.;
Khiar, N. Org. Lett. 2005, 7, 1307. (b) Morton, D.; Pearson, D.; Field, R.
A.; Stockman, R. A. Org. Lett. 2004, 6, 2377. (c) Yang, Y.-F.; Zhang,
M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2002, 67, 8097. (c) Garc´ıa
Ruano, J. L.; Ferna´ndez, I.; Hamdouchi, C. Tetrahedron Lett. 1995, 36,
295. (d) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E. Tetrahedron:
Asymmetry 1995, 6, 1511.
(8) (a) Zheng, J.-C.; Liao, W.-W.; Sun, X.-X.; Sun, X.-L.; Tang, Y.;
Dai, L. X.; Deng, J. G. Org. Lett. 2005, 7, 5789. (b) Ferreira, F.; Audouin,
M.; Chemla, F. Chem.sEur. J. 2005, 11, 5269. (c) Chemla, F.; Ferreira, F.
Synlett 2004, 983.
(9) (a) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J.
Org. Chem. 2003, 68, 2410. (b) Davis, F. A.; Deng, J.; Zhang, Y.;
Haltiwanger, R. C. Tetrahedron 2002, 58, 7135. (c) Volonterio, A.; Bravo,
P.; Pesenti, C.; Zanda, M. Tetrahedron Lett. 2001, 42, 3985. (d) Kim, D.
Y.; Suh, K. H.; Choi, J. S.; Mang, J. Y.; Chang, S. K. Synth. Commun.
2000, 30, 87. (e) Davis, F. A.; McCoull, W.; Titus, D. D. Org. Lett. 1999,
1, 1053.
Results and Discussion
New N-tert-butanesulfinyl R-halo imines (RS)-5 and -12 were
prepared by condensation of R-halo ketones (1-1.1 equiv) or
R-chloro aldehydes (1.05 equiv) with (RS)-tert-butanesulfin-
amide in the presence of 2 equiv of Ti(OEt)4 in 82-92% yield
(the reaction conditions and yields are reported in the Supporting
Information).
As compared to the hydride reduction of nonfunctionalized
N-sulfinyl imines, the incorporation of a vicinal chlorine atom
next to the imino bond was expected to influence the reaction
rate of the reduction reaction by hydride. Complete reduction
of N-tert-butanesulfinyl R-chloro imine (RS)-5a was achieved
with 2 equiv of NaBH4 with stirring for 12 h in THF at room
temperature (Table 1, entry 1). To further elaborate these
(10) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2006, 8, 3129.
(11) (a) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. ReV. 2004,
104, 2353. (b) Concellon, J. M.; Riego, E.; Rivero, I. A.; Ochoa, A. J.
Org. Chem. 2004, 69, 6244. (c) Stevens, C.; De Kimpe, N. Org. Prep.
Proced. Int. 1990, 22, 589. (d) Giubellina, N.; Aelterman, W.; De Kimpe,
N. Pure Appl. Chem. 2003, 75, 1433. (e) Sulmon, P.; De Kimpe, N.;
Schamp, N. Tetrahedron 1989, 45, 3907. (f) De Kimpe, N.; De Smaele, D.
Tetrahedron Lett. 1994, 35, 8023. (g) De Kimpe, N.; Verhe´, R. In The
chemistry of R-haloketones, R-haloaldehydes and R-haloimines; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1988.
(12) (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555. (b) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003 and references therein.
(14) Borg, G.; Cohan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709.
(15) Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul,
M. F. J. Org. Chem. 2006, 71, 6859.
(13) (a) Cohan, D. A.; Lui, G.; Ellman, J. A. Tetrahedron 1999, 55,
8883. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (c) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39.
3212 J. Org. Chem., Vol. 72, No. 9, 2007

Asymmetric Synthesis of Aziridines
TABLE 1. Reduction of N-Sulfinyl r-Chloro Imines (RS)-5a,b in
THF Using Various Metal Hydrides
TABLE 2. Ring Closure of Chiral â-Chloro Sulfinamides 10a and
13a by Treatment with Base
amt,
temp,
time,
h
yield,a
%
reducing
agent
amt,
equiv
conversion of
entry sulfinamide base equiv
°C
solvent
entry
R1
(RS)-5,a %
(RS)-10:(RS)-11
1
2
3
4
5
13a
13a
10a
13a
13a
BuLi 1.1 -78 (rt) 1 (1) THF
60
73
70
87
99b
1
2
3
4
5
6
7
8
8
NaBH4
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
2
2
2
2
2
2
2
2
1.1
1.1
1.1
1.1
1.1
1.1
100
100
49
1:0
1:0
1:0
1:0
4:1
4.5:1
1:0
1:0
1:2
1:2
1:4
1:3
1:1
1:1
NaH
Et3N
KOH
KOH
1.1 -78 (rt) 1 (1) THF
3
3
3
∆
∆
∆
16
8
16
MeCN
THF/H2O (1:1)
THF/H2O (1:1)
NaCNBH3
LiBH4
34
100b
100b
100
100
100b
100b
100b
100b
100b
100b
a Conversion determined by NMR analysis of the reaction mixture.
b Determined by a mass balance of the reaction mixture.
9-BBN
LiBHEt3
LiAlH4
tiopure aziridines in the literature (vide infra). As reported in
Table S2 in the Supporting Information, changing the time, the
solvent, and the amount of NaBH4 added did result in a
substantial improvement of the â-chloro sulfinamide (RS,S)-13a
formed. Shortening of the reaction from 12 to 1 h changed
neither the yield nor the stereoselectivity of the reaction.
Enhanced diastereoselectivities were observed at reduced tem-
perature, but with substantial prolongation of the reaction time.
Surprisingly, the reaction rate was improved without loss of
diastereoselectivity by addition of small amounts of MeOH. The
reaction at -78 °C was finished within 1 h, yielding 98%
sulfinamide (RS,S)-13a in 98:2 diastereoselectivity. It turned out
that MeOH increased the reaction rate to a high extent without
affecting the diastereoselectivity of the reaction performed.
Notably, if the solvent was changed to MeOH, the solvent
interaction on the reactive intermediate was borne out in the
low diastereoselectivity obtained.
Notably, enantiopure â-halo sulfinamide (RS,S)-13a formed
was not ring closed toward the corresponding aziridine (RS,S)-
14a under the conditions used (2 equiv of NaBH4 in the presence
of 2 equiv of MeOH at -78 °C for 1 h in THF). Moreover, if
the reaction temperature of the reduction of ketimine (RS)-12a
was allowed to increase to room temperature, after 1 h of
reaction at -78 °C, no aziridine was formed. Further stirring
at reflux temperature was insufficient to ring close the â-halo
sulfinamide (RS,S)-13a quantitatively toward the corresponding
N-(tert-butylsulfinyl)aziridine (RS,S)-14a. Strong bases, such as
BuLi or NaH, afforded aziridine 14a in a rather costly procedure
(cooling and drying conditions were needed). Addition of 1.1
equiv of BuLi at -78 °C and subsequent stirring for 1 h at
room temperature provided N-(tert-butylsulfinyl)aziridine 14a
in 60% conversion on the basis of the 1H NMR spectrum (Table
2, entry 1). Better results were obtained if NaH was used as a
base under the latter conditions (Table 2, entry 2). Heating
â-chloro sulfinamide 10a for 16 h in boiling MeCN, in the
presence of 3 equiv of Et3N, afforded 70% of the corresponding
aziridine 11a (Table 2, entry 3). Beneficial results were obtained
if â-chloro sulfinamide 13a was stirred for 8 h with 3 equiv of
KOH in H2O/THF (1:1 ratio).
9
10
11
12
13
DIBAL-H
a Determined by TLC and by 1H NMR. b Partial ring closure and
subsequent N-sulfinyl deprotection occurred.
reductions in detail, the reaction conditions were systematically
changed. Therefore, addition of a series of reducing agents, such
as NaBH4, LiBH4, 9-BBN, NaCNBH3, LiBHEt3, LiAlH4, and
DIBAL-H, across N-tert-butanesulfinyl R-chloro aldimines 5a,b
was monitored with stirring in THF for 12 h at room temperature
(Table 1). Reduction of N-tert-butanesulfinyl R-chloro imines
(RS)-5a,b with 2 equiv of NaBH4 or 9-BBN yielded â-chloro
sulfinamides (RS)-10a,b quantitatively with little or no formation
of the ring-closed product, i.e., aziridines 11a,b (<2%), while
the reduction of N-tert-butanesulfinyl R-chloro imines (RS)-5a,b
with LiBH4, LiBHEt3, DIBAL-H, and LiAlH4 afforded mixtures
of â-chloro sulfinamides (RS)-10a,b and N-(tert-butylsulfinyl)-
aziridines 11a,b in a complex reaction mixture. Deprotection
of the N-sulfinyl group by the HCl liberated during the ring
closing step was a common observed side reaction complicating
the spectrum of the reaction mixture. Full conversion of N-tert-
butanesulfinyl R-chloro imines (RS)-5 toward â-chloro sulfin-
amides (RS)-10a,b was observed if an excess of reducing agent
was used in all cases except one. If NaCNBH3 (2 equiv) was
used, N-tert-butanesulfinyl R-chloro imines (RS)-5a,b were
recovered in 51% and 66% yield, respectively, on the basis of
1H NMR (Table 1, entries 3 and 4). Consequently, the reduction
of N-tert-butanesulfinyl R-halo imines (RS)-12 was tested for
all reducing agents, apart from NaCNBH3.
N-tert-Butanesulfinyl R-chloro aldimines (RS)-5 were reduced
in excellent yield to afford the corresponding â-chloro tert-
butanesulfinamides (RS)-10. In contrast, if N-tert-butanesulfinyl
R-halo ketimines 12 were reduced toward â-halo tert-butane-
sulfinamides 13 or N-(tert-butylsulfinyl)aziridines 14, a stereo-
genic center was formed, so two diastereomers could be formed.
In a first attempt, reduction of N-tert-butanesulfinyl R-chloro
ketimine (RS)-12a was tried with NaBH4 (2 equiv) in dry THF
at room temperature for 12 h, affording â-chloro sulfinamide
(RS,S)-13a in 99% yield but in disappointing stereoselectivity
(58:42 dr). The major diastereomer of the â-chloro sulfinamide
15a formed after reduction of R-halo ketimine 12a with NaBH4
was assigned as (RS,S)-13a by evaluation with known enan-
Experimentally, it was shown that N-(2-chloro-1,2-dimeth-
ylpropyl)sulfinamide 13a could also be quantitatively converted
toward the corresponding N-(tert-butylsulfinyl)aziridine 14a by
being stirred overnight (16 h) in boiling THF/H2O (1:1 ratio)
in the presence of 3 equiv of KOH (Table 2). Importantly, only
one diastereomer of N-(tert-butylsulfinyl)-2,2,3-trimethylaziri-
J. Org. Chem, Vol. 72, No. 9, 2007 3213

Denolf et al.
SCHEME 3. Reversal of Stereofacial Attack in the
Reduction of N-Sulfinyl r-Chloro Imine (RS)-12a with
NaBH4 vs LiBHEt3
chiral â-halo sulfinamides (RS,S)-13 in greater than 90% yield
with excellent stereoselectivity (>95:5 dr) within 1 h at -78
°C in THF after addition of 2 equiv of NaBH4 and 10 equiv of
MeOH. Therefore, an attempt was made to purify the â-halo
sulfinamides (RS,S)-13c-e by flash chromatography and after-
ward, upon treatment with base, to further ring close sulfin-
amides (RS,S)-13c-e to the corresponding aziridines (RS,S)-
14c-e. However, it turned out that â-halo sulfinamides (RS,S)-
13c-e could only be purified by flash chromatography with
major loss of product on the column (solvent mixture petroleum
ether-ethyl acetate, 85:15). Partial ring closure and/or N-sulfinyl
deprotection were the two major side reactions on the column.
1
Since both diastereomers were partially overlapping in the H
NMR spectra, and different rotamers were further complicating
the spectrum, the diastereomeric ratio could not be accurately
established for â-halo sulfinamides (RS,S)-13c-e. Therefore, the
latter sulfinamides (RS,S)-13c-e were further ring closed to
N-(tert-butylsulfinyl)-2-arylaziridines (RS,S)-14c-e to obtain the
1
diastereomeric ratio by H NMR analysis. The diastereomeric
ratio of the N-(tert-butylsulfinyl)aziridines (RS,S)-14c-e ob-
tained after separate treatment with base turned out to be greater
than 90:10. Thus, both aliphatic and aromatic â-halo sulfin-
amides (RS,S)-13 were synthesized in high yield (>90%) and
stereoselectivity (>90:10 dr) by treatment of N-tert-butane-
sulfinyl R-halo imines (RS)-12 with 2 equiv of NaBH4 for 1 h
at -78 °C in THF, with little MeOH as cosolvent. Noteworthy,
if N-(tert-butylsulfinyl)-2-phenylaziridine (RS,S)-14c was stirred
for 4 more days in refluxing H2O/THF (1:1 ratio), in the
presence of 3 equiv of KOH, no epimerization was observed
after workup as judged by 1H NMR spectroscopy. All N-(tert-
butylsulfinyl)aziridines 14 were synthesized quantitatively from
â-halo sulfinamides 13 by reflux overnight (16 h) in THF/H2O
(1:1 ratio) in the presence of 3 equiv of KOH.
dine (14a) could be observed in 1H NMR and/or HPLC. Thus,
no epimerization reaction occurred.
The reducing agent was also altered from NaBH4 to LiBH4,
9-BBN, LiBHEt3, LiAlH4, and DIBAL-H to examine the
generality of the reduction reaction. Reduction of N-tert-
butanesulfinyl R-chloro ketimine (RS)-12a with 1.1 equiv of
LiAlH4 or DIBAL-H in dry THF at -78 °C afforded the
resulting sulfinamide (RS,S)-13a in combination with the N-(tert-
butylsulfinyl)aziridine (RS,S)-14a in less than 1 h in good yield
(90-95%) but with disappointing selectivity (56:44 to 63:37
dr). Better results were obtained if ketimine (RS)-12a was
reduced with 2 equiv of 9-BBN or LiBH4 in THF at -78 °C
for 1 h (88-93%, 70:30 to 81:19 dr). Reaction of ketimine (RS)-
12a with 2 equiv of LiBH4 in THF with additional MeOH did
improve the outcome slightly but still was not competitive in
comparison with the NaBH4 reduction. Better results were
obtained if LiBHEt3 was used as a reducing agent. It was
gratifying to observe that reduction of ketimine (RS)-12a with
1.1 equiv of LiBHEt3 in dry THF at -78 °C afforded â-chloro
sulfinamide (RS,R)-13a together with aziridine (RS,R)-14a (∼9:1
mixture) after 1 h in 87% yield with 78:22 dr (Scheme 3). Most
important, the stereoselectivity of the reaction was altered as
compared to that of the reduction with NaBH4 (Scheme 3).
However, it has to be reported that the intermediate â-halo
sulfinamide (RS,R)-13a could not be synthesized without partial
ring closure toward N-(tert-butylsulfinyl)aziridine (RS,R)-14a.
Aziridine (RS,R)-14a was formed almost quantitatively (98%
yield) after separate treatment of â-halo sulfinamide (RS,R)-
13a with 3 equiv of KOH in boiling THF/H2O (1:1) for 16 h.
Recrystallization from Et2O afforded N-(tert-butylsulfinyl)-
aziridine (RS,R)-14a as a single diastereomer in 61% overall
yield. Thus, N-(tert-butylsulfinyl)aziridines (RS,R)-14a and
(RS,S)-14a were synthesized separately in high yield and with
excellent stereoselectivity, depending on the reducing reagent
used (Scheme 3).
Aziridines (RS,R)-14 were synthesized via a two-step proce-
dure starting from the corresponding ketimines (RS)-12. Reduc-
tion of the latter N-tert-butanesulfinyl R-halo ketimines (RS)-
12 with LiBHEt3 in THF for 1 h at -78 °C, followed by
treatment with 3 equiv of KOH in boiling THF/H2O (1:1 ratio)
for 16 h, afforded aziridines (RS,R)-14 in good yield (76-85%)
with high diastereoselectivity (78:22 to 92:8 dr). Recrystalli-
zation from Et2O of the N-(tert-butylsulfinyl)aziridines (RS,R)-
14 formed resulted in the isolation of the enantiopure N-(tert-
butylsulfinyl)aziridines (RS,R)-14 in 86-96% yield (Table 3).
Apparently, simultaneously with our research Coyler et al.
have been investigating the reduction of nonfunctionalized
N-sulfinyl imines.15 The reduction of N-tert-butanesulfinyl
ketimines with 3 equiv of NaBH4 proceeded in high yield with
good diastereomeric excess in wet THF (with 2% water). It has
been described that the temperature was allowed to increase
from -50 °C to room temperature over 3 h.15 These results are
in accordance with our findings, but it seems that the vicinal
halogen atom activates the imino bond. If N-tert-butanesulfinyl
R-chloro imine (RS)-12a was reduced by means of 2 equiv of
NaBH4 in THF with 10 equiv of MeOH at -50 °C, a reduced
diastereomeric excess, compared to that of the reduction at -78
°C, was observed. Also, the reduction of N-tert-butanesulfinyl
R-chloro imine (RS)-12a was terminated within 40 min at -78
°C, whereas the reduction of N-(1,2,2-trimethylethylidene)-tert-
butanesulfinamide has been reported to be completed only after
3 h at higher temperature. Noteworthy, whereas aziridine (RS,S)-
14a, obtained after the reduction of N-tert-butanesulfinyl
The hydride reduction was tested for its generality. Therefore,
N-tert-butanesulfinyl R-chloro imines (RS)-5 and -12 were
treated with NaBH4 and LiBHEt3 under the conditions as
optimized before (vide supra). These results are listed in Table
3.
Aldimines (RS)-5a,b were reduced with NaBH4 in excellent
yields (>95%) to afford the corresponding â-chloro sulfinamide
(RS)-10, but crucially, all ketimines (RS)-12 were reduced toward
3214 J. Org. Chem., Vol. 72, No. 9, 2007

Asymmetric Synthesis of Aziridines
TABLE 3. Reduction of N-Sulfinyl r-Chloro Imines (RS)-5 and -12 Using NaBH4 vs LiBHEt3
entry
substrate
reagent
product
(RS)-10a
(RS)-10b
(RS,S)-13a
(RS,R)-13a/14a
(RS,S)-13b
(RS,R)-13b/14b
(RS,S)-13c
(RS,R)-13c/14c
(RS,S)-13d
(RS,R)-13d/14d
(RS,S)-13e
ratio 13:14a
yield,b,c
%
drd
1
2
3
d
4
5
6
7
8
(RS)-5a
(RS)-5b
NaBH4
NaBH4
NaBH4
LiBHEt3
NaBH4
LiBHEt3
NaBH4
LiBHEt3
NaBH4
LiBHEt3
NaBH4
LiBHEt3
99 (95)
97 (95)
98 (88)
87 (61)
92 (92)
80 (57)
95 (90)
81 (62)
94 (89)
85 (66)
98 (91)
83 (71)
(RS)-12a
(RS)-12a
(RS)-12b
(RS)-12b
(RS)-12c
(RS)-12c
(RS)-12d
(RS)-12d
(RS)-12e
(RS)-12e
1:0
9:1
1:0
18:1
1:0
5.5:1
1:0
4:1
1:0
2.5:1
98:2
78:22
99:1
80:20
>98:2e
87:13e
>98:2e
89:11e
>98:2e
92:8e
9
10
11
(RS,R)-13e/14e
a Determined by NMR analysis of the isolated product. b Determined by a mass balance of the isolated product. c In parentheses is given the yield (%)
determined by a mass balance of the isolated N-sulfinylaziridine (RS,R)-14 after ring closure and subsequent recrystallization from Et2O. d Determined by
NMR analysis of the isolated product. e Determined by NMR analysis of the corresponding aziridine after ring closure.
SCHEME 4. Reversal of Stereofacial Attack in the Reduction of N-Sulfinyl Imines (RS)-12c and -15a with Hydrides
R-chloro ketimine (RS)-12a with NaBH4 in THF with 10 equiv
of MeOH as cosolvent, is synthesized in better yield and
stereoselectivity as compared to the aziridine (RS,R)-14a,
synthesized by reaction of ketimines (RS)-12a with LiBHEt3,
an inverse reactivity trend is reported by Coyler et al. for
nonfunctionalized N-tert-butanesulfinyl imines (Scheme 4).15 It
has been reported that the reduction of the latter imines, such
as (RS)-N-(1-phenylethylidene)-tert-butanesulfinamide [(RS)-
15a] in wet THF (2% H2O) afforded (RS,R)-N-(1-phenylethyl)-
tert-butanesulfinamide [(RS,R)-16a] in 80% yield with 74%
diastereoselectivity. The opposite C-epimer (RS,S)-16a was
obtained in 82% yield with 84% diastereoselectivity after
reduction of imine (RS)-15a with L-Selectride in dry THF. (RS)-
N-(2-Chloro-1-phenylethylidene)-tert-butanesulfinamide [(RS)-
12c], the R-chloro analogue of the latter imine (RS)-15a, was
reduced with NaBH4 under the optimized conditions as men-
tioned before, yielding 95% (RS,S)-N-(2-chloro-1-phenylethyl)-
tert-butanesulfinamide [(RS,S)-13c] with an excellent diastere-
omeric ratio (>98:2). However, reduction of N-tert-butanesulfinyl
R-chloro imine 12c with superhydride never yielded aziridine
(RS,R)-15c after ring closure, in greater than 87:13 diastereo-
meric ratio. It appears that the vicinal chloro atom has a
contribution in both the reactivity and stereoselectivity of the
reaction.
The chiral N-(tert-butylsulfinyl)aziridines (RS,S)-14 and (RS,R)-
14 could be deprotected by simple treatment with a saturated
solution of dry HCl in dioxane. Stirring of 5 mmol of aziridine
14 with 5 mL of saturated 1,4-dioxane‚HCl for 15 min at room
temperature in dry diethyl ether afforded the aziridinium chloride
salts 17 in high yield (90-95%) and purity (90-95%) (Scheme
5).
The stereochemistry of aziridines 14 was checked by com-
parison of the optical rotation of N-(tert-butylsulfinyl)aziridine
14c ([R]D20 +310 vs +298 reported) and its spectroscopical data
with literature values.16 Hence, it was found that N-sulfin-
ylaziridines (RS,S)-14 were synthesized via reduction of N-tert-
butanesulfinyl R-halo ketimine 12 with NaBH4, while N-
J. Org. Chem, Vol. 72, No. 9, 2007 3215

Denolf et al.
diastereofacial control via reduction of N-sulfinyl R-halo imines.
Depending on the reagent used both C-epimers of N-(tert-
butylsulfinyl)aziridines were formed. For one epimer the
intermediate â-halo N-sulfinamide could be isolated. Further
treatment with base afforded chiral N-(tert-butylsulfinyl)-
aziridines in quantitative yields. The latter compounds could
be further deprotected toward the corresponding aziridinium
salts.
FIGURE 1. Proposed transition states for the reduction of ketimine
(RS)-12.
Experimental Section
SCHEME 5. N-Sulfinyl Deprotection of Aziridines 14 in
(RS)-(-)-N-(2-Chloro-2-methylpropyl)-tert-butanesulfin-
amide [(RS)-10a]. Imine (RS)-5a (2.10 g, 10 mmol) was dissolved
in THF (20 mL). To the stirred solution was then added NaBH4
(0.76 g, 20 mmol) at room temperature, after which stirring was
continued for 12 h before quenching with NH4Cl (5 mL), aqueous
KHCO3 (20 mL), and EtOAc (20 mL). The aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated to furnish (RS)-
10a as a colorless oil (2.10 g, 99%). Pure â-chloro N-sulfinamide
10a was obtained after recrystallization from Et2O. Mp 88.6 ( 0.2
°C. [R]D -11 (c 0.05, MeOH). IR (NaCl, cm-1): νmax 1057, 1369,
1457, 2973, 3210. MS: m/z (M + H) 212.2/214.2 (100). 1H NMR
(300 MHz, CDCl3): δ 1.27 (9H, s), 1.58 (3H, s), 1.61 (3H, s),
3.17 (1H, dd, J ) 13.5 Hz, 8.9 Hz), 3.45 (1H, dd, J ) 13.5 Hz, 5.2
Hz), 3.73 (1H, dd (br), J ) 8.9 Hz, 5.2 Hz). 13C NMR (75 MHz,
CDCl3): δ 22.7, 29.6, 30.4, 56.4, 57.9, 70.0. Anal. Calcd for C8H18-
ClNOS: C, 45.38; H, 8.57; N, 6.61. Found: C, 45.58; H, 8.50; N,
6.72.
1,4-Dioxane Hydrochloride/Diethyl Ether
(RS,S)-N-(2-Chloro-1,2-dimethylpropyl)-tert-butanesulfin-
amide [(RS,S)-13a]. Imine (RS)-12a (2.24 g, 10 mmol) was
dissolved in THF (45 mL) and cooled to -78 °C. To the stirred
solution were then added MeOH (4.6 mL, 100 mmol) and NaBH4
(0.76 g, 20 mmol). Then the reaction was stirred for 1 h at -78 °C
before quenching with NH4Cl (5 mL), saturated aqueous KHCO3
(20 mL), and EtOAc (20 mL). The aqueous layer was extracted
with EtOAc (2 × 20 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated to furnish pure â-chloro
N-sulfinamide 13a (2.20 g, 89%) as white crystals after recrystal-
lization from Et2O. Mp: 54.4 ( 0.2 °C. [R]D -44 (c 0.7, MeOH).
IR (KBr, cm-1): νmax 1054, 1364, 1459, 2980, 3247. MS: m/z (M+
+ H) 226.2/228.2 (100). 1H NMR (300 MHz, CDCl3): δ 1.25 (9H,
s), 1.27 (3H, d, J ) 6.6 Hz), 1.55 and 1.68 (2 × 3H, 2 × s), 3.48
(1H, dq, J ) 4.4 Hz, 6.6 Hz), 3.96 (1H, d (br), J ) 5.0 Hz). 13C
NMR (75 MHz, CDCl3): δ 16.7, 22.7, 27.8, 30.6, 55.9, 59.9, 74.6.
Anal. Calcd for C9H20ClNOS: C, 47.88; H, 8.93; N, 6.20. Found:
C, 47.71; H, 8.86; N, 6.35.
(RS,S)-N-(tert-Butylsulfinyl)-2,2,3-trimethylaziridine [(RS,S)-
14a]. â-Chloro sulfinamide 13a (2.26 g, 10 mmol) was dissolved
in a 1:1 mixture of H2O/THF (45 mL), and KOH (1.68 g, 30 mmol)
was added. The stirred mixture was warmed to reflux temperature.
When the reaction was complete (16 h), the reaction mixture was
cooled to 0 °C. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated. Aziridine
14a (1.55 g, 88%) was obtained as pure colorless crystals after
recrystallization from Et2O. Mp: 54.0 ( 0.2 °C. [R]D -88 (c 0.7,
MeOH). IR (KBr, cm-1): νmax 1081, 1361, 1457, 2928, 2961.
MS: m/z (M+ + H) 190.1 (100). 1H NMR (300 MHz, CDCl3): δ
1.21 (3H, d, J ) 5.8 Hz), 1.24 (9H, s), 1.26 (3H, s), 1.58 (3H, s),
2.32 (1H, q, J ) 5.8 Hz). 13C NMR (75 MHz, CDCl3): δ 13.5,
21.5, 21.6, 22.3, 44.8, 46.2, 55.7. Anal. Calcd for C9H19NOS: C,
57.10; H, 10.12; N, 7.40. Found: C, 57.26; H, 10.27; N, 7.53.
(RS,R)-N-(tert-Butylsulfinyl)-2,2,3-trimethylaziridine [(RS,R)-
14a]. Imine (RS)-12a (1.12 g, 5 mmol) was dissolved in THF (22
mL) and the solution cooled to -78 °C. To the stirred solution
was then added LiBHEt3 dropwise (1 M in THF, 5.5 mL). Then
the reaction was stirred for 1 h at -78 °C before quenching with
sulfinylaziridines (RS,R)-14 were formed via the reduction with
superhydride (LiBHEt3).
The origin of the reversal of diastereofacial attack upon
changing the reducing agent from NaBH4 to a lithiated hydride
species was explained very recently by Coyler et al. via a cyclic
transition state (TTS) in the former case (NaBH4) and an open
transition state for the latter reduction (LiBHEt3).15 Due to the
incorporation of one extra functional group, slightly more
complex transition states are proposed in the present paper for
the reduction of N-sulfinyl R-halo ketimines. Hence, if the
sulfinyl oxygen atom participates in the delivery of the hydride
(NaBH4 reduction, Figure 1, TTS 1), the chloro atom is
considered to complex also with the reducing agent, inducing
a flip of the haloalkyl substituent in the Zimmerman-Traxler
TTS from the equatorial toward the axial position. An identical
switchover of stereoselectivity has already been observed for
R-functionalized substituents, next to the imino function.10a,17
More reactive reagents, such as LiBHEt3, react too fast with
N-tert-butanesulfinyl ketimines (RS)-12 to allow the haloalkyl
substituent to flip toward an axial position (Figure 1, TTS 2).
An open transition state, with the halogen atom in an R-position
of the imino function, is not considered. Starting from the
Cram-Chelate model na Re-face attack is favored. Thus, this
would be a secondary possible intermediate in the reaction of
NaBH4 with ketimine (RS)-12 (Figure 1, TTS 3).
In conclusion, it has been demonstrated that enantiopure
aziridines are formed in high yields with excellent, predictable
(16) (a) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Synlett
2003, 13, 1985. (b) Garc´ıa Ruano J. L.; Ferna´ndez, I.; del Prado Catalina,
M.; Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407.
(17) (a) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock, M.
G. Tetrahedron Lett. 2004, 45, 6641. (b) Davis, F. A.; McCoull, W. J.
Org. Chem. 1999, 64, 3396. (c) Fujisawa, T.; Kooriyama, Y.; Shimizu, M.
Tetrahedron Lett. 1996, 37, 3881.
3216 J. Org. Chem., Vol. 72, No. 9, 2007

Asymmetric Synthesis of Aziridines
NH4Cl (5 mL), saturated aqueous KHCO3 (20 mL), and EtOAc
(20 mL). The aqueous layer was extracted with EtOAc (2 × 20
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated to furnish a colorless oil which was dissolved in
a 1:1 mixture of H2O/THF (22 mL) to which KOH (0.84 g, 15
mmol) was added. The stirred mixture was warmed to reflux
temperature. When the reaction was complete (16 h), the reaction
mixture was cooled to 0 °C. The organic layer was separated, and
the aqueous layer was extracted with Et2O (3 × 10 mL). The
combined organic layers were dried (MgSO4), filtered, and con-
centrated. Aziridine (RS,R)-14a (0.53 g, 61%) was obtained as pure
colorless crystals after recrystallization from Et2O. Mp: 60.6 (
0.3 °C. [R]D -115 (c 1.3, MeOH). IR (KBr, cm-1): νmax 1080,
1363, 1457, 2929, 2960. MS: m/z (M+ + H) 190.1 (100), 134.1
freshly prepared saturated dioxane hydrochloride. The mixture was
allowed to stir for 15 min at room temperature before the solution
was concentrated in vacuo (10 mL). The crystals were filtered and
washed with Et2O (5 mL) before drying in vacuo. Recrystallization
from Et2O afforded analytically pure white crystals (91%). Mp:
203.0 ( 0.1 °C. [R]D -46 (c 0.8, MeOH). IR (KBr, cm-1): νmax
1491, 1510, 1605, 1998, 2957. MS: m/z (M+ + H) 190.2/192.3/
1
194.2 (100). H NMR (300 MHz, CD3OD): δ 3.52 (1H, d, J )
5.8 Hz), 3.52 (1H, d, J ) 8.5 Hz), 5.27 (1H, dd, J ) 8.5, 5.8 Hz),
7.45 and 7.51 (2 × 2H, 2 × d, J ) 8.8 Hz). 13C NMR (75 MHz,
CD3OD): δ 47.2, 59.6, 130.1, 130.3, 136.5, 137.4.
Acknowledgment. Funding by a Ph.D. grant of the Institute
for the Promotion of Innovation through Science and Technol-
ogy in Flanders (IWT-Vlaanderen, Belgium) is gratefully
acknowledged.
1
(65). H NMR (300 MHz, CDCl3): δ 1.19 (3H, s), 1.20 (9H, s),
1.21 (3H, d, J ) 5.8 Hz), 1.40 (3H, s), 2.54 (1H, q, J ) 5.8 Hz).
13C NMR (75 MHz, CDCl3): δ 13.5, 20.6, 20.9, 22.6, 36.4, 42.9,
55.9. Anal. Calcd for C9H19NOS: C, 57.10; H, 10.12; N, 7.40.
Found: C, 57.31; H, 10.19; N, 7.52.
(S)-2-(4-Chlorophenyl)aziridinium Chloride [(S)-17b]. N-(tert-
Butylsulfinyl)aziridine (RS,S)-14d (1.29 g, 5 mmol) was dissolved
in dry diethyl ether (20 mL) before the flask was placed in a water
bath. To the stirred solution was then added dropwise 5 mL of
Supporting Information Available: Reaction optimization of
the reduction of (RS)-12a with NaBH4 and the experimental details
and characterization data of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0624795
J. Org. Chem, Vol. 72, No. 9, 2007 3217