Synthesis of chiral cis-1,2,3-trisubstituted aziridines

Article abstract of DOI:10.1016/S0040-4020(00)00627-X

Chiral cis-1,2,3-trisubstituted aziridines were conveniently synthesized from (1R,2S)-(-)- or (1S,2R)-(+)-norephedrine via the corresponding chiral N-(arylidene)-β-chloroamines. The enantiomeric purity of the chiral aziridines (e.e. >98%) was established by NMR spectroscopy utilizing (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00627-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7299–7304
Synthesis of Chiral cis-1,2,3-Trisubstituted Aziridines
*
Tuyen Nguyen Van and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 7 April 2000; revised 23 June 2000; accepted 6 July 2000
Abstract—Chiral cis-1,2,3-trisubstituted aziridines were conveniently synthesized from (1R,2S)-(Ϫ)- or (1S,2R)-(ϩ)-norephedrine via the
corresponding chiral N-(arylidene)-b-chloroamines. The enantiomeric purity of the chiral aziridines (e.e. Ͼ98%) was established by NMR
spectroscopy utilizing (S)-(ϩ)-1-(9-anthryl)-2,2,2-trifluoroethanol. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
The ability of aziridines to undergo highly regio and stereo-
selective ring opening reactions gives them great value in
organic synthesis.1 In addition, it has been shown that a
number of naturally occurring and synthetic aziridines
have potent biological activity. For this reason, aziridines
have been frequently target compounds in synthetic organic
chemistry.
As shown in Scheme 1, (1R,2S)-(Ϫ)-norephedrine 1 was
chlorinated with PCl5 in dry chloroform under reflux to
give (1S,2S)-(ϩ)-1-chloro-1-phenyl-2-propylamine hydro-
chloride 2 in 81% yield.9 (1S,2S)-(ϩ)-1-Chloro-1-phenyl-
2-propylamine hydrochloride 2 was then treated with
different 4-substituted benzaldehydes in dichloromethane
in the presence of triethylamine and magnesium sulfate to
afford (1S,2S)-(ϩ)-N-(arylidene)-1-chloro-1-phenyl-2-propyl-
amines 3a–d in 88–97% yield.
Classical methods for the synthesis of chiral aziridines are
the ring closure of chiral amino alcohols1 and the ring open-
ing of chiral epoxides with azide1,2 and subsequent ring
closure.
The reaction of the chiral N-(b-chloroalkyl)aldimines 3a–d
with excess sodium borohydride in methanol under reflux
gave rise to a series of (2S,3R)-(Ϫ)-1-benzyl-2-methyl-3-
phenylaziridines 4a–d in 96–99% yield. The reaction
products are formed by nucleophilic addition of hydride
across the imino bond and subsequent intramolecular
nucleophilic substitution, which occurs by a Walden
inversion (Scheme 1).9 The reaction products were
attributed the cis-configuration, based on the reaction
mechanism and clearly confirmed by the coupling constant
of the vicinal hydrogens H-2 and H-3 of the aziridines 4 of
6.4–7.2 Hz.10
Racemic 1,2,3-trisubstituted aziridines have been
previously synthesized by the Wenker procedure, involving
ring closure of b-aminoalcohols3–5 or b-chloroamines6 or
by reductive ring closure of a,a-dichloroketimines.7
Another synthesis of racemic 1,2,3-trisubstituted aziridines
was achieved by N-alkylation of N-unsubstituted aziridines
under phase transfer catalytic conditions, but this method
has limited generality.8
We report here a convenient synthesis of chiral 1,2,3-tri-
substituted aziridines 4 and 9 from (1R,2S)-(Ϫ)-nore-
phedrine 1 and (1S,2R)-(ϩ)-norephedrine 11 via the
corresponding N-(arylidene)-b-chloroamines. In addition,
we report on an NMR method, employing (S)-(ϩ)-1-(9-an-
thryl)-2,2,2-trifluoroethanol (Pirkle alcohol) as the chiral
solvating agent, for the rapid and convenient determination
of the enantiomeric composition of chiral 1,2,3-trisubsti-
tuted aziridines.
In order to establish the enantiomeric purity of the aziridines
4, an NMR technique employing a chiral solvating agent
(CSA) 5 was utilized. Chiral aryltrifluoromethyl carbinols
are known to be most useful in NMR analyses, which induce
a spectral nonequivalence in lactones, amines and alcohols,
probably due to the fact that both the hydroxyl and carbinyl
hydrogens of 5 are capable of giving bonding interactions
with basic sites.10–13
It was found that (S)-(ϩ)-1-(9-anthryl)-2,2,2-trifluoro-
ethanol 5 has the ability to induce a spectral nonequivalence
in the racemic mixture of cis-aziridines 4a and 9a in
deuterated chloroform. In the present case of aziridines,
Keywords: chiral aziridines; N-(arylidene)-b-chloroamines; e.e. determina-
tion; NMR.
* Corresponding author. Tel.: ϩ32-9-264-59-51; fax: ϩ32-9-264-62-43;
e-mail: norbert.dekimpe@rug.ac.be
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00627-X

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T. Nguyen Van, N. De Kimpe / Tetrahedron 56 (2000) 7299–7304
Scheme 1.
tetrachloride, followed by imination of a-chloroketone 7
with benzylamine in benzene in the presence of titanium-
(IV) chloride. Sodium borohydride reduction of a-chloro-
ketimine 8 in methanol under reflux afforded a mixture of
the racemic cis-aziridine (composed of 4a and 9a) (17%)
and the racemic trans-aziridine 10 (64%).14
The 1:1 mixture of the enantiomers 4a and 9a showed a
Figure 1.
good separation in many of the corresponding signals for
1
the two components in the H NMR spectrum (270 MHz;
the interaction of 5 induced a nonequivalence in the
magnetic environment, probably by the bonding interaction
between the hydroxyl and the carbinyl hydrogens of CSA 5
with the aziridine nitrogen atom and the aromatic ring of the
aziridine, respectively. In addition, p-stacking of the
aromatic nucleus of 5 with the N-benzyl group will also
play a role (see Fig. 1).
CDCl3) on addition of 30 mol% of the chiral aryltrifluoro-
methylcarbinol 5. In these spectra, two well-resolved
signals for each methyl group at C-2 and two different
signals for the proton at C-4 of the two enantiomers were
observed, allowing discrimination of the cis-aziridine
enantiomers.
Application of the same protocol with the chiral (S)-aryltri-
fluoromethylcarbinol 5 to the (Ϫ)-cis-aziridine 4a, obtained
according to the procedure outlined in Scheme 1, showed no
signals resulting from the enantiomer 9a. To ascertain that
The racemic 1-benzyl-2-methyl-3-phenylaziridine (com-
posed of 4a and 9a) was synthesized by a-chlorination of
1-phenyl-2-propanone 6 with sulfuryl chloride in carbon
Scheme 2.

T. Nguyen Van, N. De Kimpe / Tetrahedron 56 (2000) 7299–7304
7301
Scheme 3.
1
this aziridine 4a is enantiomerically pure, the H NMR
spectrum of the mixture of compound 4a, the racemic
mixture of cis-aziridines 4a and 9a and the chiral solvating
agent 5 (molar ratio 1:1:0.3) was recorded. In this case, there
is a clear visible separation of the signals of both the
enantiomers in a 3:1 ratio. These experiments established
unambiguously that cis-aziridine 4a was optically pure (e.e.
Ͼ98%) within the limits of the NMR technique.
Experimental
Melting points were determined on a Buchi 535 apparatus.
1H NMR spectra (270 MHz) and 13C NMR (67 MHz) were
recorded with a Jeol JNM-EX 270 NMR spectrometer. IR
spectra were measured with a Perkin Elmer model 983 spec-
trophotometer. Mass spectra were recorded with a Varian-
MAT 112 mass spectrometer (70 eV). Optical rotations
were determined with a AA-10 automatic polarimeter.
Similar NMR experiments on the determination of the
enantiomeric excess were also carried out with the chiral
aziridines 4b–d. It was confirmed as well that these
aziridine 4b–d were enantiomerically pure (e.e. Ͼ98%)
(Scheme 2).
(1S,2S)-(ϩ)-1-Chloro-1-phenyl-2-propylamine hydro-
chloride 2 and (1R,2R)-(Ϫ)-1-chloro-1-phenyl-2-propyl-
amine hydrochloride 12.9 To a solution of 1.0 g
(6.6 mmol) of (1R,2S)-(Ϫ)-norephedrine 1 or (1S,2R)-(Ϫ)-
norephedrine 11 in 20 ml of dry chloroform was added
8.6 mmol of PCl5. The mixture was stirred and refluxed
for 1 h, after which the reaction mixture was kept at room
temperature for 2 h. The excess of PCl5 was decomposed
cautiously with 5 ml of methanol. Finally, the solvent was
removed in vacuo and the reaction mixture was stirred with
30 ml of dry diethyl ether. The white crystalline hydrochlo-
ride was separated by filtration. The crude product was
recrystallized from a mixture of methanol and ether (1/5)
to give the pure compound 2 or 12, respectively.
The opposite enantiomers of the former aziridines 9a,b were
synthesized from (1S,2R)-(ϩ)-norephedrine 11 in good
yield (Scheme 3). After conversion of (1S,2R)-(ϩ)-nor-
ephedrine 11 into (1R,2R)-(Ϫ)-1-chloro-1-phenyl-2-propyl-
amine hydrochloride 12, the latter was reacted with
benzaldehyde or 4-chlorobenzaldehyde in dichloromethane
in the presence of triethylamine and magnesium sulfate to
afford the chiral imines 13a,b in 89–98% yield. Reduction
of these N-(b-chloroaryl)imines 13a,b with sodium boro-
hydride in methanol under reflux gave (2R,3S)-1-benzyl-2-
methyl-3-phenylaziridines 9a,b in 92–97% yield. Also in
this case, the enantiomeric purity of aziridines 9a and 9b
was determined by the above NMR technique utilizing the
chiral solvating agent 5. By this way it was shown that also
(ϩ)-cis-aziridines 9a and 9b were enantiomerically pure
(e.e. Ͼ98%).
(1S,2S)-(ϩ)-1-Chloro-1-phenyl-2-propylamine hydro-
chloride 2. Compound 2 was obtained from (1R,2S)-(Ϫ)-
norephedrine 1 as white crystals in 81% yield. mp 178–
179ЊC (MeOH); [a]D22ˆϩ81 (cˆ0.5; MeOH) [Lit9 mp
1
167ЊC, Lit15 mp 198–203ЊC; [a]ˆϩ76 (cˆ6; EtOH)]. H
NMR (D2O): 1.21 (3H, d, Jˆ6.7 Hz, CH3), 3.96–4.04 (1H,
m, H-2), 5.13 (1H, d, Jˆ9.7 Hz, H-1), 7.47–7.56 (5H, m,
C6H5); 13C NMR: 16.9 (CH3), 54.4 (C-2), 65.1 (C-1), 128.6
(C-30 and C-50), 130.3 (C-20 and C-60), 130.7 (C-40), 137.8
(C-10); IR (KBr): 3440 (NHϩ3 ), 1599, 1575, 1492, 1450,
In conclusion, the chiral 1,2,3-trisubstituted aziridines (Ϫ)-
4a–d and (ϩ)-9a–b were synthesized conveniently in high
yield and high enantiomeric excess (Ͼ98%) from (1R,2S)-
(Ϫ)-norephedrine 1 and (1S,2R)-(ϩ)-norephedrine 11 via
the corresponding N-(arylidene)-b-chloroamines.
1194, 1146, 1005, 712 cmϪ1
.
(1R,2R)-(Ϫ)-1-Chloro-1-phenyl-2-propylamine hydro-
chloride 12. Compound 12 was obtained from (1S,2R)-
(ϩ)-norephedrine 11 as white crystals in 78% yield. Mp
168–170ЊC (MeOH); [a]2D2ˆϪ91 (cˆ0.93; MeOH). 1H
Pirkle alcohol 5 was used as the chiral solvating agent for
the rapid and convenient determination of the enantiomeric
composition of 1,2,3-trisubstituted aziridines.

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T. Nguyen Van, N. De Kimpe / Tetrahedron 56 (2000) 7299–7304
NMR (D2O): 1.21 (3H, d, Jˆ6.7 Hz, CH3), 3.96–4.04 (1H,
m, H-2), 5.13 (1H, d, Jˆ9.7 Hz, H-1), 7.48–7.56 (5H, m,
C6H5); 13C NMR: 16.9 (CH3), 54.4 (C-2), 65.1 (C-1), 128.7
(C-30 and C-50), 130.3 (C-20 and C-60), 130.7 (C-40), 137.8
(C-10); IR (KBr): 3430 (NHϩ3 ), 1599, 1575, 1494, 1450,
(3H, d, Jˆ6.6 Hz, CH3), 3.73–3.77 (1H, m, H-2), 3.85
(3H, s, OCH3), 4.94 (1H, d, Jˆ8.4 Hz, H-1), 6.94 (2H, d,
Jˆ8.4 Hz, vCH, A2B2 system), 7.30–7.40 (5H, m, vCH),
7.73 (2H, d, Jˆ8.4 Hz, vCH, A2B2 system), 8.28 (1H, s,
CHvN); 13C NMR (CDCl3): 20.2 (CH3), 55.2 (OCH3), 68.1
(C-2), 72.2 (C-1), 113.9 (2× vCH), 127.9 (2× vCH), 128.3
(vCH), 128.4 (2× vCH), 128.9 (vCquat), 129.8 (2×
vCH), 139.5 (vCquat), 160.7 (CvN), 161.8 (vCquat);
IR (KBr): 1639 (CvN), 1604, 1574, 1449, 1250, 1168,
1029, 831, 819, 706 cmϪ1; MS m/z: no Mϩ, 252 (1,
MϩϪCl), 163 (16), 162 (100, MeCHvNϩvCH–
C6H4OCH3), 135 (19). Anal. C17H18ClNO, calcd C
70.95%, H 6.30%, N 4.87%; Found C 70.86%, H 6.15%,
N 5.09%.
1390, 1244, 1195, 1147, 1030, 1006, 987, 837, 698 cmϪ1
.
(1S,2S)-(ϩ)-(E)-N-(Benzylidene)-1-chloro-1-phenyl-2-pro-
pylamine 3 and 13. A solution of 333 mg (1.624 mmol) of
1-chloro-1-phenyl-2-propylamine hydrochloride 2 or 12,
188 mg (1.78 mmol) of benzaldehyde, 179 mg (1.78
mmol) of triethylamine and 303 mg (2.528 mmol) of
MgSO4 in 15 ml of dichloromethane was refluxed for 1 h.
The reaction mixture was filtered and then evaporated in
vacuo. The reaction product was dissolved in 10 ml of dry
diethyl ether and filtered, then washed with NaHCO3 (5N),
water and dried (K2CO3). The filtered solution was evapo-
rated in vacuo to afford the crude product.
(1S,2S)-(ϩ)-(E)-1-Chloro-N-(4-methylbenzylidene)-1-
phenyl-2-propylamine 3d. The synthesis of compound 3d
was carried out according to the general procedure to afford
the crude product. This product was crystallized from
hexane to give white crystals in 92% yield. Mp 104–
(1S,2S)-(ϩ)-(E)-N-(Benzylidene)-1-chloro-1-phenyl-2-pro-
pylamine 3a. This compound was synthesized from
(1S,2S)-1-chloro-1-phenyl-2-propylamine hydrochloride 2,
as described above, to give compound 3a in 88% yield. The
crude product was recrystallized from hexane. Mp 85–87ЊC
(hexane); [a]2D2ˆϩ225 (cˆ0.32; MeOH). 1H NMR
(CDCl3): 1.08 (3H, d, Jˆ6.6 Hz, CH3), 3.74–3.80 (1H, m,
H-2), 4.95 (1H, d, Jˆ8.5 Hz, H-1), 7.30–7.42 (8 H, m,
vCH), 7.77–7.80 (2H, m, vCH), 8.34 (1H, s, CHvN);
13C NMR (CDCl3): 20.2 (CH3), 67.9 (C-2), 72.3 (C-1),
127.9 (2× vCH), 128.3 (2× vCH), 128.5 (4× vCH),
129.5 (vCquat), 130.7 (vCquat), 135.9 (vCH), 139.4
(vCH), 161.4 (CvN); IR (KBr): 1643 (CvN), 1445,
1366, 1121, 1069, 970, 757, 718 cmϪ1; MS m/z: no Mϩ,
133 (11), 132 (100, MeCHvNϩvCH–C6H5). Anal.
C16H16ClN, Calcd C 74.55%, H 6.26%, N 5.43%; Found
C 74.72%, H 6.35%, N 5.29%.
1
105ЊC (hexane); [a]2D0ˆϩ252 (cˆ0.75; MeOH); H NMR
(CDCl3): 1.09 (3H, d, Jˆ6.2 Hz, CH3), 2.40 (3H, s, Ar–
CH3), 3.73–3.79 (1H, m, H-2), 4.95 (1H, d, Jˆ8.6 Hz,
H-1), 7.23 (2H, d, Jˆ7.8 Hz, vCH, A2B2 system), 7.31–
7.39 (5H, m, vCH), 7.68 (2H, d, Jˆ7.8 Hz, vCH, A2B2
system), 8.32 (1H, s, CHvN); 13C NMR (CDCl3): 20.2
(CH3), 21.4 (Ar–CH3), 68.0 (C-2), 72.3 (C-1), 127.9 (2×
vCH), 128.3 (3× vCH), 129.5 (2× vCH), 129.2 (2×
vCH), 133.4 (vCquat), 139.5 (vCquat), 140.9 (vCquat),
161.3 (CvN); IR (KBr): 1639 (CvN), 1607, 1449, 1381,
1106, 975, 838, 818, 778, 723, 698 cmϪ1; MS m/z: no Mϩ,
236 (1, MϩϪCl), 146 (22, MeCHvNϩvCH–C6H4Me),
132 (100). Anal. C17H18ClN, calcd C 75.13%, H 6.68%, N
5.15%; Found C 75.24%, H 6.80%, N 5.01%.
(1R,2R)-(ϩ)-(E)-N-(Benzylidene)-1-chloro-1-phenyl-2-
propylamine 13a. The synthesis of compound 13a was
carried out according to the general procedure to afford
the crude product. This product was crystallized from
hexane to give white crystals in 98% yield. Mp 79–81ЊC
(hexane); [a]2D2ˆϪ246 (cˆ0.86; MeOH); 1H NMR
(CDCl3): 1.08 (3H, d, Jˆ6.6 Hz, CH3), 3.74–3.80 (1H, m,
H-2), 4.96 (1H, d, Jˆ8.5 Hz, H-1), 7.30–7.42 (8 H, m,
vCH), 7.77–7.80 (2H, m, vCH), 8.33 (1H, s, CHvN);
13C NMR (CDCl3): 20.2 (CH3), 67.9 (C-2), 72.4 (C-1),
128.0 (2× vCH), 128.4 (2× vCH), 128.5 (2× vCH),
128.6 (2× vCH), 129.6 (vCquat), 130.8 (vCquat),
136.0 (vCH), 139.5 (vCH), 161.5 (CvN); IR (KBr):
(1S,2S)-(ϩ)-(E)-1-Chloro-N-(4-chlorobenzylidene)-1-
phenyl-2-propylamine 3b. The synthesis of compound 3b
(97% yield) was carried out according to the general pro-
cedure given above. The crude product was crystallized
from hexane to give white crystals. Mp 88–90ЊC (hexane);
1
[a]2D0ˆϩ189.8 (cˆ0.59; MeOH). H NMR (CDCl3): 1.07
(3H, d, Jˆ6.7 Hz, CH3), 3.72–3.77 (1H, m, H-2), 4.93 (1H,
d, Jˆ8.6 Hz, H-1), 7.29 (2H, d, Jˆ8.0 Hz, vCH, A2B2
system), 7.30–7.43 (5H, m, vCH), 7.68 (2H, d,
Jˆ8.0 Hz, vCH, A2B2 system), 8.26 (1H, s, CHvN); 13C
NMR (CDCl3): 20.2 (CH3), 67.8 (C-2), 72.3 (C-1), 127.2
(2× vCH), 128.5 (vCH), 128.5 (2× vCH), 128.7 (2×
vCH), 129.5 (2× vCH), 134.4 (vCquat), 136.7
(vCquat), 139.2 (vCquat), 160.0 (CvN); IR (KBr):
1640 (CvN), 1590, 1485, 1380, 837, 826, 723 cmϪ1; MS
m/z: no Mϩ, 256/258 (1, MϩϪCl), 166/168 (100,
MeCHvNϩvCH–C6H4Cl). Anal. C16H15Cl2N, calcd C
65.77%, H 5.17%, N 4.79%; Found C 65.61%, H 5.30%,
N 4.66%.
1640 (CvN), 1449, 1371, 1088, 1013, 825, 723 cmϪ1
MS m/z: no Mϩ, 222 (1, MϩϪCl), 133 (10), 132 (100,
MeCHvNϩvCH–C6H5). Anal. C16H16ClN, calcd
;
C
74.55%, H 6.26%, N 5.43%; Found C 74.41%, H 6.34%,
N 5.35%.
(1R,2R)-(ϩ)-(E)-1-Chloro-N-(4-chlorobenzylidene)-1-
phenyl-2-propylamine 13b. The synthesis of compound
13b was carried out according to the general procedure to
afford the crude product. This product was crystallized from
hexane to give white crystals in 89% yield. Mp 96–98ЊC
(hexane); [a]2D2ˆϪ250 (cˆ0.54; MeOH); 1H NMR
(CDCl3): 1.07 (3H, d, Jˆ6.7 Hz, CH3), 3.72–3.77 (1H, m,
H-2), 4.93 (1H, d, Jˆ8.6 Hz, H-1), 7.29 (2H, d, Jˆ8.0 Hz,
vCH, A2B2 system), 7.30–7.43 (5H, m, vCH), 7.69 (2H,
(1S,2S)-(ϩ)-(E)-1-Chloro-N-(4-methoxybenzylidene)-1-
phenyl-2-propylamine 3c. The synthesis of compound 3c
was carried out according to the general procedure to afford
the crude product, which was crystallized from hexane to
give white crystals in 91% yield. Mp 78–80ЊC (hexane);
1
[a]2D0ˆϩ236 (cˆ1.31; MeOH); H NMR (CDCl3): 1.08

T. Nguyen Van, N. De Kimpe / Tetrahedron 56 (2000) 7299–7304
7303
d, Jˆ8.0 Hz, vCH, A2B2 system), 8.27 (1H, s, CHvN); 13
C
overl.); 13C NMR (CDCl3): 12.8 (CH3), 41.6 (C-2), 46.1
(C-3), 55.0 (OCH3), 63.8 (C-4), 113.6 (2× vCH), 126.3
(vCH), 127.7 (2× vCH), 127.8 (2× vCH), 128.8 (2×
vCH), 131.5 (vCquat), 137.5 (vCquat), 158.5 (vCquat);
IR (NaCl): 1608, 1508, 1245, 1035, 739 cmϪ1; MS m/z: 253
(Mϩ, 1), 133 (11), 132 (100), 121 (19), 105 (27), 86 (19), 84
(31), 49 (63). Anal. C17H19NO, calcd C 80.60%, H 7.56%, N
5.53%; Found C 80.69%, H 7.50%, N 5.39%.
NMR (CDCl3): 20.2 (CH3), 67.9 (C-2), 72.3 (C-1), 127.2
(2× vCH), 128.4 (vCH), 128.5 (2× vCH), 128.8 (2×
vCH), 129.5 (2× vCH), 134.4 (vCquat), 136.7
(vCquat), 139.3 (vCquat), 160.10 (CvN); IR (KBr):
1640 (CvN), 1590, 1482, 1379, 1088, 1013, 974, 825,
723, 725 cmϪ1; MS m/z: 291/293/295 (Mϩ, 1), 261 (3),
221 (7), 168 (26), 166 (100). Anal. C16H15Cl2N, calcd C
65.77%, H 5.17%, N 4.79%; Found C 65.87%, H 5.30%,
N 4.63%.
(2S,3R)-(Ϫ)-2-Methyl-1-(4-methylbenzyl)-3-phenylaziri-
dine 4d. The synthesis of aziridine 4d was carried out
according to the general procedure to give the pure aziridine
Chiral 1,2,3-trisubstituted aziridines 4 and 9. To a solu-
tion of 330 mg (1.28 mmol) of benzaldimine 3 or 13 in
20 ml of absolute methanol was added 145 mg
(3.85 mmol) of sodium borohydride. The reaction mixture
was refluxed for 1 h, then MeOH was evaporated in vacuo.
The residue was treated with water, then extracted with
CH2Cl2. The combined extracts were washed with water,
dried (K2CO3) and evaporated in vacuo to give the crude
product, which was purified by flash chromatography on
silica gel column with ethyl acetate/hexane (10/90) to afford
the pure aziridines 4 and 9.
1
4d in 96% yield. [a]2D0ˆϪ89 (cˆ1.27; MeOH); H NMR
(CDCl3): 0.95 (3H, d, Jˆ5.7 Hz, CH3), 1.88–1.93 (1H, m,
H-2), 2.32 (3H, s, Ar–CH3), 2.65 (1H, d, Jˆ6.5 Hz, H-3),
3.51 (1H, d, Jˆ13.8 Hz, H-4), 3.75 (1H, d, Jˆ13.8 Hz, H-
4), 7.22–7.32 (9H, m, vCH); 13C NMR (CDCl3): 12.8
(CH3), 21.0 (Ar–CH3), 41.7 (C-2), 46.1 (C-3), 64.2 (C-4),
126.3 (vCH), 127.7 (3× vCH), 127.8 (3× vCH), 128.9
(2× vCH), 136.3 (2× vCquat), 137.5 (vCquat); IR
(NaCl): 1601, 1448, 1346, 1117, 795 cmϪ1; MS m/z: 237
(Mϩ, 2), 133 (10), 132 (100). Anal. C17H19N, calcd C
86.03%, H 8.07%, N 5.90%; Found C 86.19%, H 8.15%,
N 5.78%.
(2S,3R)-(Ϫ)-1-Benzyl-2-methyl-3-phenylaziridine 4a. The
synthesis of aziridine 4a was carried out according to the
general procedure to give the pure aziridine 4a in 99% yield.
(2R,3S)-(ϩ)-1-Benzyl-2-methyl-3-phenylaziridine 9a. The
synthesis of aziridine 9a was carried out according to the
general procedure to give the pure aziridine 9a in 97% yield.
[a]2D2ˆϩ116 (cˆ1.2; MeOH); 1H NMR (CDCl3): 0.95 (3H,
d, Jˆ5.7 Hz, CH3), 1.80–1.85 (1H, m, H-2), 2.59 (1H, d,
Jˆ6.9 Hz, H-3), 3.50 (1H, d, Jˆ13.8 Hz, H-4), 3.69 (1H, d,
Jˆ13.8 Hz, H-4), 7.15–7.37 (10H, m, vCH); 13C NMR
(CDCl3): 12.8 (CH3), 41.7 (C-2), 46.2 (C-3), 64.4 (C-4),
126.4 (vCH), 127.7 (vCH), 127.6 (2× vCH), 127.8 (4×
vCH), 128.2 (2× vCH), 137.4 (vCquat), 139.4
(vCquat); IR (NaCl): 1601, 1492, 1449, 1348, 1027, 733,
698 cmϪ1; MS m/z: 223 (Mϩ, 2), 133 (12), 132 (100), 99
(23), 91 (17).
1
[a]2D2ˆϪ60 (cˆ0.9; MeOH); H NMR (CDCl3): 0.95 (3H,
d, Jˆ5.7 Hz, CH3), 1.80–1.85 (1H, m, H-2), 2.59 (1H, d,
Jˆ6.9 Hz, H-3), 3.50 (1H, d, Jˆ13.8 Hz, H-4), 3.70 (1H, d,
Jˆ13.8 Hz, H-4), 7.15–7.37 (10H, m, vCH); 13C NMR
(CDCl3): 12.8 (CH3), 41.8 (C-2), 46.3 (C-3), 64.5 (C-4),
126.4 (vCH), 126.7 (vCH), 127.7 (2× vCH), 127.8 (4×
vCH), 128.3 (2× vCH), 137.5 (vCquat), 139.4
(vCquat); IR (NaCl): 1599, 1491, 1374, 1119, 732,
698 cmϪ1; MS m/z: 223 (Mϩ, 2), 222 (1), 133 (10), 132
(100). Anal. C16H17N, calcd C 86.05%, H 7.67%, N
6.27%; Found C 85.94%, H 7.80%, N 6.23%.
(2S,3R)-(Ϫ)-1-(4-Chlorobenzyl)-2-methyl-3-phenylaziri-
dine 4b. The synthesis of aziridine 4b was carried out
according to the general procedure to give the pure aziridine
(2R,3S)-(ϩ)-1-(4-Chlorobenzyl)-2-methyl-3-phenylaziri-
dine 9b. The synthesis of aziridine 9b was carried out
according to the general procedure to give the pure aziridine
9b in 92% yield. [a]D22ˆϩ92.8 (cˆ0.98; MeOH); 1H NMR
(CDCl3): 0.94 (3H, d, Jˆ5.7 Hz, CH3), 1.84–1.89 (1H, m,
H-2), 2.61 (1H, d, Jˆ6.5 Hz, H-3), 3.47 (1H, d, Jˆ14.0 Hz,
H-4), 3.69 (1H, d, Jˆ14.0 Hz, H-4), 7.23–7.35 (10H, m,
vCH); 13C NMR (CDCl3): 12.8 (CH3), 41.9 (C-2), 46.4
(C-3), 63.8 (C-4), 126.5 (vCH), 127.8 (2× vCH), 127.9
(2× vCH), 128.4 (2× vCH), 129.1 (2× vCH), 132.5
(vCquat), 137.2 (vCquat), 137.9 (vCquat); IR (NaCl):
1601, 1487, 1404, 1088, 1014, 813, 738, 700 cmϪ1; MS
m/z: 257/259 (Mϩ, 1), 179 (1), 164 (1), 133 (9), 132 (100).
1
4b in 96% yield. [a]2D0ˆϪ76 (cˆ0.54; MeOH); H NMR
(CDCl3): 0.94 (3H, d, Jˆ5.7 Hz, CH3), 1.84–1.89 (1H, m,
H-2), 2.61 (1H, d, Jˆ6.5 Hz, H-3), 3.47 (1H, d, Jˆ14.0 Hz,
H-4), 3.69 (1H, d, Jˆ14.0 Hz, H-4), 7.23–7.35 (9H, m,
vCH); 13C NMR (CDCl3), 12.7 (CH3), 41.8 (C-2); 46.3
(C3), 63.6 (C-4); 126.5 (vCH), 126.7 (2× vCH), 127.8
(2× vCH), 128.3 (2× vCH), 128.9 (2× vCH), 132.4
(vCquat), 137.2 (vCquat), 137.9 (vCquat); IR (NaCl):
1601, 1486, 1347, 1121, 733, 699 cmϪ1; MS m/z: 257/259
(Mϩ, 1), 133 (10), 132 (100). Anal. C16H16ClN, calcd C
74.55%, H 6.26%, N 5.43%; Found C 74.63%, H 6.14%,
N 5.37%.
1-Chloro-1-phenyl-2-propanone 7. To solution of 10.0 g
(7.46 mmol) of ketone 6 in 20 ml of carbon tetrachloride
was added 11.0 g (8.2 mmol) of sulfuryl chloride over a
period of 1 h at 0ЊC, after which the reaction mixture was
refluxed for 24 h. Then, the reaction mixture was poured in
the same amount of cold water, and was extracted with
dichloromethane. The extracts were washed with saturated
NaHCO3 solution and dried (MgSO4). The solvent was
removed in vacuo to give a residue, which was distilled to
give 10.68 g of pure a-chloroketone 7 in 85% yield; b.p.
(2S,3R)-(Ϫ)-2-Methyl-1-(4-methoxybenzyl)-3-phenyla-
ziridine 4c. The synthesis of aziridine 4c was carried out
according to the general procedure to give the pure aziridine
1
4c in 97% yield. [a]2D0ˆϪ91 (cˆ0.99; MeOH); H NMR
(CDCl3): 0.94 (3H, d, Jˆ5.7 Hz, CH3), 1.87–1.91 (1H, m,
H-2), 2.63 (1H, d, Jˆ6.7 Hz, H-3), 3.45 (1H, d, Jˆ13.5 Hz,
H-4), 3.72 (1H, d, Jˆ13.5 Hz, H-4), 3.75 (3H, s, OCH3),
6.84 (2H, d, Jˆ8.9 Hz, vCH, A2B2 system), 7.20–7.28
(5H, m, C6H5), 7.3 (2 H, d, Jˆ8.9 Hz, vCH, A2B2 system,

7304
T. Nguyen Van, N. De Kimpe / Tetrahedron 56 (2000) 7299–7304
120–121ЊC/12 mmHg; 1H NMR (CDCl3): 2.2 (3H, s, CH3),
5.39 (1H, s, H-1), 7.25–7.43 (5H, m, vCH); 13C NMR
(CDCl3): 25.6 (CH3), 66.4 (C-1), 127.7 (2× vCH), 128.9
(2× vCH), 129.0 (vCH), 134.9 (vCquat), 199.7 (CvO);
IR (NaCl): 1719 (CvO), 1597, 774, 697 cmϪ1; MS m/z:
168/170 (Mϩ, 6), 132 (8), 125 (23), 89 (11), 43 (100).
Jˆ5.6 Hz, CH3), 1.18–2.30 (1H, m, H-2), 2.30 (1H, d,
Jˆ3.2 Hz, H-3), 3.78 (1H, d, Jˆ14.5 Hz, H-4), 3.89 (1H,
d, Jˆ14.5 Hz, H-4), 7.21–7.44 (10 H, m, vCH); 13C NMR
(CDCl3): 11.5 (CH3), 42.9 (C-2), 48.5 (C-3), 55.4 (C-4),
126.0 (2× vCH), 126.6 (2× vCH), 126.6 (vCH), 127.6
(2× vCH), 128.2 (3× vCH), 130.2 (vCH), 140.1
(vCquat), 140.7 (vCquat); IR (NaCl): 1600, 1492, 1449,
1090, 730, 697 cmϪ1; MS m/z: 223 (Mϩ, 2), 133 (10), 132
(100), 105 (28), 99 (23).
N-(1-Chloro-1-phenyl-2-propylidene)benzylamine 8. To
a solution of 500 mg (2.97 mmol) of a-chloroketone 7 and
963 mg (9.0 mmol) of benzylamine in 20 ml of dry benzene
was added dropwise a solution of 336 mg of TiCl4
(1.78 mmol) in 10 ml of pentane at 0ЊC over a period of
15 min. The solution was stirred for 45 min at this tempera-
ture, then the mixture was poured in cold water. The
reaction product was extracted with ether, the combined
extracts were washed with NaHCO3 (5N), water and dried
(K2CO3) then evaporated under vacuum to give 590 mg of
Measurement of the enantiomeric excess of aziridines 4
and 9. The measurement of the enantiomeric excess of
aziridines 4a–d and 9a–b was performed by NMR utilizing
the solvating agent 5 in CDCl3. It was shown that aziridines
4a–b and 9a–b were enantiomeric pure (e.e. Ͼ98%). For
this purpose, 0.03 mmol of aziridine 4 or 9 was dissolved in
0.5 ml of CDCl3. To this solution was added 2.73 mg
1
1
a-chloroketimine 8 in 78% yield (purity Ͼ95%). H NMR
(0.0099 mmol) of Pirkle alcohol 5. The H NMR spectrum
(CDCl3): 1.89 (3H, s, CH3), 4.5 (2H, d, Jˆ3.2 Hz, CH2–Ar),
5.68 (1H, s, H-1), 7.36 (8H, m, vCH), 7.52 (2H, dd,
Jˆ8.1 Hz and Jˆ2.1 Hz, vCH); 13C NMR (CDCl3): 13.4
(CH3), 55.1 (CH2–Ar), 68.5 (CH–Cl), 126.6 (vCH), 127.0
(2× vCH), 127.5 (2× vCH), 128.1 (vCH); 128.3 (2×
vCH), 128.4 (2× vCH), 136.9 (vCquat), 139.4
(vCquat), 167.5 (CvN); IR (NaCl): 1654 (CvN), 1489,
1449, 733, 696 cmϪ1; MS m/z: 257/259 (Mϩ, 1), 168 (8),
125 (23), 91 (33), 43 (100).
of this mixture was run in order to determine the e.e. A
similar analysis was performed on racemic mixture 4a and
9a.
References
1. Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619.
2. Sinou, D.; Emziane, M. Tetrahedron Lett. 1986, 27, 4423–
4426.
(^)-cis-1-Benzyl-2-methyl-3-phenylaziridine. To a solu-
tion of 257 mg (1 mmol) of compound 8 in 10 ml of
methanol was added 113 mg (3 mmol) of sodium boro-
hydride. The mixture was refluxed for 1 h, then MeOH
was removed by evaporation in vacuo. The product was
treated with cold water, then extracted with CH2Cl2, the
combined extracts were washed with water, dried (K2CO3)
and the solvent was evaporated in vacuo to give 210 mg of a
mixture of cis- and trans-aziridines (4a, 9a) and (10). The
product was isolated by flash chromatography on a silica gel
column with the solvent system hexane/ethyl acetate (1/9)
to give 40 mg of (^)-cis-aziridine (17%) and 150 mg of
(^)-trans-aziridine (64%).
3. Wenker, H. J. Am. Chem. Soc. 1935, 57, 2328.
4. Bottini, A. T.; Vanetten, R. L.; Davidson, A. J. J. Am. Chem.
Soc. 1965, 87, 755–757.
5. Ghirardelli, A.; Lucas, H. J. J. Am. Chem. Soc. 1957, 79, 734–
741.
6. Hennion, J. F.; Butler, P. E. J. Org. Chem. 1962, 27, 2088–
2090.
7. De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. J. Org.
Chem. 1980, 45, 5319–5325.
8. Maurette, M. T.; Lopez, A.; Martino, R.; Lattes, A. C.R. Acad.
Sci. Paris C 1976, 282, 599–602.
9. Galindo, A.; Orea, L. F.; Gnecco, D.; Enriquez, R. G.; Toscano,
R. A.; Reynolds, W. F. Tetrahedron: Asymmetry 1997, 8 (17),
2877–2879.
10. Brois, S. J.; Beardsley, G. P. Tetrahedron Lett. 1966, 5113–
5119.
11. Pirkle, W. H.; Hauske, W. R. J. Org. Chem. 1976, 41 (5), 801–
805.
1
(^)-cis-Aziridine 4a (9a). H NMR (CDCl3): 0.94 (3H, d,
Jˆ5.7 Hz, CH3), 1.80–1.85 (1H, m, H-2), 2.59 (1H, d,
Jˆ6.8 Hz, H-3), 3.50 (1H, d, Jˆ13.8 Hz, H-4), 3.70 (1H,
d, Jˆ13.8 Hz, H-4), 7.15–7.37 (10H, m, vCH); 13C NMR
(CDCl3): 12.9 (CH3), 41.9 (C-2), 46.3 (C-3), 64.6 (C-4),
126.4 (vCH), 126.8 (vCH), 127.8 (2× vCH), 127.8 (2×
vCH), 127.9 (2× vCH), 128.3 (2× vCH), 137.5
(vCquat), 139.4 (vCquat); IR (NaCl): 1601, 1492, 1449,
1348, 1027, 733, 698 cmϪ1; MS m/z: 223 (Mϩ, 2), 72 (10),
71 (100), 41 (20).
12. Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem.
1976, 42 (2), 384–387.
13. Pirkle, W. H.; Rinaldi, P. L. J. Org. Chem. 1977, 42 (20),
3217–3219.
14. For a leading reference on the formation of aziridines from
a-haloimines, see De Kimpe, N.; Moens, L. Tetrahedron 1990, 46
(8), 2965–2974.
1
(^)-trans-Aziridine 10. H NMR (CDCl3): 1.40 (3H, d,
15. Hassner, A.; Burke, S. S. Tetrahedron 1974, 30, 2613–2621.