Synthesis and reactivity of 3-(2-chloroalkyl)-2,2-dihaloaziridines

Article abstract of DOI:10.1016/j.tet.2008.05.121

3-(2-Chloroalkyl)-2,2-dihaloaziridines were synthesized via cycloaddition of dihalocarbenes to the C{double bond, long}N double bond of β-chloroimines. Under the action of Lewis acids or HCl, N-C³ bond cleavage occurred, giving rise to N-substi

Full text of DOI:10.1016/j.tet.2008.05.121

Tetrahedron 64 (2008) 7524–7530
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Synthesis and reactivity of 3-(2-chloroalkyl)-2,2-dihaloaziridines
,
b,
*
Ekaterina Yu. Shinkevich a, Kourosch Abbaspour Tehrani a , Alexander F. Khlebnikov
,
*
Mikhail S. Novikov b
a Faculty of Sciences, Department of Applied Biological Sciences and Engineering, Laboratory of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
b Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Petrodvorets, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(2-Chloroalkyl)-2,2-dihaloaziridines were synthesized via cycloaddition of dihalocarbenes to the C]N
double bond of b
-chloroimines. Under the action of Lewis acids or HCl, N–C3 bond cleavage occurred,
Received 24 April 2008
Received in revised form 23 May 2008
Accepted 29 May 2008
giving rise to N-substituted 2,4-dichloro-3,3-dimethylbutanamides, which were further converted to 3-
chloropyrrolidin-2-ones under alkaline conditions. When 2,2-dichloro-3-(2-chloro-1,1-dimethylethyl)-1-
phenylaziridine was reacted with sodium methoxide, aziridine ring opening with N–C2 bond cleavage
took place, leading to methyl 4-chloro-3,3-dimethyl-2-(phenylamino)butanoate.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 3 June 2008
Keywords:
Dihalocarbenes
Aziridines
Selective ring opening
Cyclizations
1. Introduction
2. Results and discussion
The development of new efficient syntheses of halogenated
nitrogen heterocycles and their precursors from reactive iminium
ylides is a rather persisting problem in organic chemistry.1–5 There
are many methods available for the synthesis of halo substituted
aziridines.6 C-Alkyl substituted 2,2-dihaloaziridines have been very
poorly investigated. So far, 1,3-di(tert-butyl)-2,2-dichloroaziridine7
and 3-(tert-butyl)-2,2-dichloro-1-isopropylaziridine8 are the only
known alkyl substituted gem-dichloroaziridines. The most
common method for the synthesis of 2,2-dihaloaziridines is the
dihalocarbene–imine addition. Azomethine ylides generated from
C-alkyl aldimines and halogenated carbenes, however, have been
It was found that the reactions of b
-chloroimines 116 and diha-
locarbenes generated by alkaline hydrolysis of chloroform (or
dichlorofluoromethane) or thermocatalytic decomposition of so-
dium trichloroacetate in the presence of benzyltriethylammonium
chloride (TEBA), leads to gem-dihaloaziridines 2a–f in moderate to
good yields (Scheme 1, Table 1).
R
R
H
Cl
X
N
N
(:CClX)
Cl
Cl
i (X = Cl)
ii ( X = F)
only rarely reported.1 On the other hand,
b-chloroimines have been
2a-f (44-80%)
b-chloroimines. Reagents and conditions:
1a-e
iii (X = Cl, R = COOMe)
used with success in the synthesis of various classes of organic
Scheme 1. Reactions of dihalocarbenes with
compounds.9–15 Therefore, it was supposed that a synthetic se-
(i) method A1: CHCl3, 10 equiv KOH, 0.2 equiv TEBA, 5–13 h, 18–23 ꢀC; (ii) method A2:
CHCl2F, CH2Cl2, 10 equiv KOH, 0.2 equiv TEBA, 1.5 h, 8–11 ꢀC; (iii) method B: 10 equiv
CCl3CO2Na, CHCl3, 0.2 equiv TEBA, 3 h, reflux.
quence involving cycloaddition of dihalocarbenes to
b-chloro-
imines to give functionalized gem-dihaloaziridines followed by
aziridine isomerization and subsequent transformations would be
a potentially simple route to various acyclic and heterocyclic
nitrogen-containing compounds.
Dihaloaziridines 2a–f decompose very easily on silica. The use of
silica gel for their isolation was possible only for N-phenyl
substituted aziridines 2a and 2f. For preparative purification of
these compounds it was better to use Al2O3 (2a and 2f), while the
purification of compounds 2b–e was best performed by chroma-
tography on Florisil. Aziridines 2b and 2c were isolated as a mixture
with the corresponding amides 5b and 5c.
The present report describes our examination of reactions of
b-chloroimines with dichloro- and chlorofluorocarbenes and
a preliminary reactivity study of the obtained aziridines.
Attempts to prepare aziridine 2e under the conditions of
method A1 all failed. Probably the imine 1e and aziridine 2e are too
strong CH acids and therefore they may be deprotonated by the
* Corresponding authors. Tel.: þ32 (0) 26293292; fax: þ32 (0) 26293304.
E-mailaddresses:kourosch.abbaspour.tehrani@vub.ac.be(K.A. Tehrani), alexander.
khlebnikov@pobox.spbu.ru (A.F. Khlebnikov).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.121

E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
7525
Table 1
Cl
R
Cl
Synthesis of 3-(2-chloroalkyl)-2,2-dihaloaziridines 2a–f
i
N
N
Cl
Yielda (%)
R
2
R
X
Method
Cl Cl
Cl
2a
2b
2c
2d
2e
2f
Ph
i-Pr
c-Hex
Bn
CH2CO2Me
Ph
Cl
Cl
Cl
Cl
Cl
F
A1
A1
A1
A1
B
60
49b
44b
47
4
2a-f
H2O
(workup or
chromatography)
58
A2
80c
a
b
c
After column chromatography.
Mixture with corresponding compound 5 (5%).
Mixture of diastereoisomers.
Cl
R
N
H
N
ii
R
Cl
O
O
Cl
excess potassium hydroxide applied for the generation of dichloro-
carbene. On the other hand, dichlorocarbene generated by neutral
method B reacts with imine 1e to afford the target aziridine 2e.
Chlorofluoroaziridine 2f was obtained as a 15:1 (trans- and cis-
HF) mixture of diastereoisomers (calculated from 1H NMR spectra
of the crude reaction mixture). The stereochemical identification of
the two isomers was based on the H,F-coupling constants in 1H
NMR spectra. For the trans-isomer a vicinal H,F-coupling of 4 Hz
was found, the cis-isomer showed a coupling constant of 8 Hz.
The values of Jvic-HF are in accordance with literature data of
trans-chlorofluoroaziridines (3.5 Hz,17 4.5 Hz18), cis- and trans-
monofluoroaziridines (2.5 and 5.5 Hz,19 2.5 and 6.1 Hz20). Similar
stereoselectivity was observed for synthesis of 1,3-diphenyl-
2,2-chlorofluoroaziridine,17,18 chlorofluoroazirino[2,1-e][1,6]benz-
oxazocines (thiazocines),3 2-fluoro-2-phenylaziridines,21 and
1,3-diaryl-2-fluoroaziridines19 by carbene approaches. Opposite
stereoselectivity was only observed for synthesis of 1-alkyl-3-
phenyl-2-fluoroaziridines.20
Attempts to synthesize the N-tert-butyl-substituted dichloro-
aziridine 2g, using both methods of dichlorocarbene generation,
were unsuccessful. Instead, a small amount of 3 was isolated when
using method B (Scheme 2). The formation of 3,3-dichloroazetidin-
2-ones as side products from the reaction of imines with sodium
trichloroacetate is known.1,22–26 It is proposed, that the azetidin-2-
one is formed without participation of dichlorocarbene, via reaction
of the imine with trichloroacetyl chloride arising from thermolysis
of sodium trichloroacetate.27 Imines are known to react with tri-
chloroacetyl chloride in the presence of triphenylphosphine28 and
with dichloroacetylchloride29 to give dichloroazetidinones.
5a-e
6a R = Ph (76%)
6b R = i-Pr (77%)
6c R = c-Hex (72%)
6d R = Bn (67%)
Scheme 3. Ring opening of 2,2-dichloroaziridines under acidic conditions and syn-
thesis of 3-chloro-4,4-dimethylpyrrolidin-2-ones. Reagents and conditions: (i) 0.2–
2.5 equiv ZnCl2$1.5H2O, 1–4 h, 0 ꢀC to rt; (ii) 0.1 equiv TEBA, 10 equiv NaOH, H2O,
CH2Cl2, o.n., rt.
Table 2
Synthesis of 2,4-dichloro-3,3-dimethylbutanamides 5a–e
4
R
Reagent
Conditions
Yielda (%)
4a
4b
4b
4c
4c
4c
4d
4e
Ph
i-Pr
i-Pr
c-Hex
c-Hex
c-Hex
Bn
ZnCl2
HClaq
ZnCl2
HClaq
ZnCl2
HClg
rt, 1 h
rt, o.n.
rt, o.n.
rt, o.n.
0–5 ꢀC, 2.5 h
rt, 1 h
0–5 ꢀC, 2.5 h
rt, o.n.
73
24
48
18
38
18
59
33
ZnCl2
ZnCl2
CH2CO2Me
a
After column chromatography.
The stability of aziridines 2 and yields of compounds 5 strongly
depend on the nitrogen substituent. In order to optimize the re-
action conditions the type and amount of Lewis and protic acid
(SbF3, ZnCl2, BF3$Et2O, TiCl4, HClaq, HClg), the temperature and
solvent were varied. The best results were obtained when a cata-
lytic amount of ZnCl2 in CH2Cl2 was used.
Cl
10 equiv CCl3CO2Na, CHCl3
0.2 equiv TEBA
N
Cl
Cl
N
N
(method A1)
X
Cl
Cl
Cl
H
O
3 h, reflux
Cl
3 (18%)
2g
1g
Scheme 2. Formation of 3,3-dichloroazetidin-2-one.
To extend the synthetic potential of the obtained functionalized
gem-dihaloaziridines, we investigated their reaction with nucleo-
philes. It is known that for aziridines derived from acyclic imines
rupture of the C–N bond opposite to the dichloromethylene group
most often occurs.6,25 In azirino-fused heterocycles, however, ring
opening can occur through cleavage of any C–N bond.2,3,30
The reaction of compound 2a with an excess of BF3$Et2O in
CH2Cl2 at room temperature gave a complex mixture in which the
fluorinated analogue of compound 5a (2-fluoro-4-chloro-3,3-di-
methyl-N-phenylbutanamide) can be detected in addition to
compound 5a (Scheme 4). This reaction is one more example of ring
opening of aziridines using BF3$Et2O as a fluorine source.33
Atfirst, westudied thereaction ofcompounds 2 in thepresence of
Lewis acids and HCl (Scheme 3, Table 2). It is proposed that com-
plexation of theLewisacidwiththenitrogen atom(or protonation by
HCl), followed by the N–C3 bond cleavage, led to the corresponding
imidoyl halides4, whichareeasilyhydrolyzedtodichlorosubstituted
amides 5.25 The formation of imidoyl halides by aziridine ring
openinghasbeenpreviouslyshownforthermalisomerizationof 3,3-
dihalo-1,2-diphenylaziridines6,31,32 and Lewis acid-catalyzed ring
expansion of dichloroazirinobenzoxazine (benzothiazine).2
Treatment of aziridine 2c with aqueous HCl in Et2O in a biphase
system or hydrogen chloride gas in CH3CN gave compound 5c in
18% yield. Chlorofluoroaziridine 2f was stable in the presence of
ZnCl2 in CH2Cl2. When 2,2-dichloroaziridine 2a was reacted in the
presence of TiCl4, the product of ring opening and subsequent hy-
drolysis (compound 5a) was detected on TLC as the only product.
The compounds 5 can be cyclized to 3-chloropyrrolidine-2-ones
6 under mild reaction conditions in the presence of sodium
hydroxide and TEBA in CH2Cl2 in good yields (Scheme 3).

7526
E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
F
3. Conclusion
NHPh
Cl
In conclusion, the reaction of dihalocarbenes with
b-chloro-
O
imines has proven to be an efficient and short method for the
synthesis of a new elusive class of 3-(2-chloroalkyl)-2,2-dihalo-
aziridines. The latter compounds can easily be transformed to
2,4-dichlorobutanamides, 4-chloro-2-aminobutanoate, and 3-
chloropyrrolidin-2-ones by selective C–N bond cleavage, and sub-
sequent cyclization reactions.
5a-F
i
Ph
Cl
N
+
1 : 1
Cl
Cl Cl
NHPh
2a
Cl
O
5a
4. Experimental
4.1. General
Scheme 4. Ring opening of 2,2-dichloroaziridine. Reagents and conditions: (i) 4 equiv
BF3$Et2O, CH2Cl2, o.n., rt.
3-Chloropyrrolidinones and their derivatives have been reported as
medicinal fungicides34 and herbicides.35–39 However, only a few
preparative routes are known from the literature. The most com-
Melting points were determined on a Bu¨chi melting point ap-
paratus B-540; uncorrected values are given. GC–MS analyses were
performed using an Interscience, GC 8000 series gas chromato-
graph with an ECÔ-5 column (length: 30 m, internal diameter:
mon method is the radical cyclization of
a-halogenated N-allyl-
acetamides.40–44
0.32 mm, film thickness: 0.25 mm). Products are injected in a split
The reaction of aziridine 2a with sodium methoxide in methanol
was also investigated. Unexpectedly, it was found that the ring
opening in that case occurs by the rupture of the N–C2 bond
(Scheme 5). The selection between the structures 8 and 10 in favor
of the latter was based on NMR and IR spectroscopies. In the 1H
NMR spectrum of compounds 5a–e the characteristic NH signal is
observed at 6.15–8.00 ppm, in contrast to 4.11 ppm for compound
10. In the 13C NMR spectrum of compounds 5a–e the peak C]O is
located at 165–167 ppm, in contrast to 173.5 ppm for compound 10.
The bands of carbonyl stretching vibrations in IR spectra of these
compounds are also different. For compounds 5a–e it is 1650–
1660 cmꢁ1, but for compound 10 it is 1730 cmꢁ1. Moreover, the
spectra of the proposed structure 10 is in good agreement with data
published for N-isopropyl and N-benzyl analogues prepared from
4-chloro-3,3-dimethylbutan-2-one in 6 steps.45
injector (250 ꢀC); the inert carrier gas is helium. The mass spec-
trometer is a Fisons Instruments MD 800 using electron impact
(70 eV) as ionization method. HRMS was measured with
a VGQuattro II mass spectrometer (positive ion mode). 1H NMR
spectra were recorded on a Bruker Avance DRX 250 spectrometer
at 250 MHz, Bruker Avance II 500 spectrometer at 500 MHz,
Bruker DPX 300 spectrometer at 300 MHz with internal standard
TMS. 13C NMR spectra were recorded on a Bruker Avance DRX 250
spectrometer at 63 MHz, Bruker Avance II 500 spectrometer at
125 MHz, Bruker DPX 300 spectrometer at 75 MHz with internal
standard CDCl3 (
d
¼77). 19F NMR spectra were recorded on a Bruker
Avance DRX 250 spectrometer at 235 MHz. 13C NMR assignments
were made using DEPT spectra. Infrared spectra were recorded
with an Avatar 370 FT-IR apparatus (Thermo Nicolet) using the
attenuated total reflection technology. Column chromatography
It should be mentioned that the N–C2 bond cleavage in diha-
loaziridines derived from acyclic imines takes place rather rarely.
Mixture of products of ring opening in both directions have been
observed in the reaction of bromination of 1,3-diaryl-2,2-
dichloroaziridines.46
was performed using Merck silica (diameter 40–63 mm), basic
aluminum oxide and Florisil. TLC-analysis was performed on glass
backed plates (Merck) coated with 0.2 mm silica 60F254. All sol-
vents were purified according to standard procedures. Chloroform
was washed with water to remove ethanol and dried by distilla-
tion over P2O5. Imines 1 were prepared according published pro-
So, this reaction may present a short and simple route to func-
cedures.16 Microanalyses were performed on
(Eurovector).
a
EuroEA3000
tionalized a-amino esters, which can be converted to potentially
physiological active small ring
a
-amino acids45,47 and azahetero-
cycles.47
4.2. Synthesis of aziridines 2a–d; typical procedure
(method A1)
Ph
Cl
Cl
N
Cl
Pellets of KOH (10 equiv) were added to a solution of imine 1
and TEBA (0.2 equiv) in CHCl3 under vigorous stirring, keeping the
temperature of the mixture at 21–23 ꢀC (water bath). The mixture
was stirred at this temperature for several hours until an aliquot
from the reaction mixture showed no IR absorption due to C]N
(1663–1668 cmꢁ1). Then the reaction mixture was filtered through
the layer of anhydrous Na2SO4. The solvent was evaporated under
reduced pressure and the residue was worked up in different ways,
depending on the structure to give compounds 2 as pale-yellow
oils. The purity of these compounds was satisfactory to be used in
the following step. Correct elemental analyses of the dihaloazir-
idines 2 could not be obtained because of the presence of the cor-
responding amides 5.
2a
i (a)
Ph
OMe
N
HN
OMe
Cl
Cl
Ph
Cl
OMe
Cl
7
9
i (b)
Ph
MeO
HN
H
N
OMe
Cl
Cl
Ph
4.2.1. 2,2-Dichloro-3-(2-chloro-1,1-dimethylethyl)-1-
phenylaziridine (2a)
O
O
8
This compound was obtained from imine 1a (1.50 g, 7.7 mmol)
in CHCl3 (60 mL) during 6 h. The residue was chromatographed on
basic Al2O3 (petroleum ether/Et2O) to give compound 2a (1.27 g,
60%). IR (ATR): 1491, 1599, 2969 cmꢁ1. 1H NMR (250 MHz, CDCl3):
10
Scheme 5. Reaction of 2,2-dichloroaziridine 2a with sodium methoxide in methanol.
Reagents and conditions: (i) (a) 2.2 equiv NaOMe, MeOH (0.2 M), 3 h, rt; (b) CH3CN, aq
HCl (2 M), 15 min, rt, 82%.

E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
7527
d
1.28 and 1.30 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.70 (1H, s, CH), 3.59 and 3.71
4.3. Synthesis of compounds 2e and 3; typical procedure
(method B)
(2ꢂ1H, 2ꢂd, J¼11.1 Hz, CH2Cl), 6.99–7.03 (2H, m, Ph), 7.11–7.17 (1H,
m, Ph), 7.31–7.38 (2H, m, Ph). 13C NMR (63 MHz, CDCl3):
d 22.2
(CH3), 23.4 (CH3), 37.0 (C(CH3)2), 53.6 (CH2), 57.5 (CH), 73.8 (CCl2),
119.8 (CHPh), 124.4 (CHPh), 129.0 (CHPh), 145.2 (CPh). MS (EI, 70 eV):
m/z (%)¼281 (8) [Mþ4], 279 (23) [Mþ2], 277 (24) [M], 246 (22), 245
(16), 244 (28), 243 (53), 242 (39) [MꢁCl], 230 (12), 228 (21)
[MꢁCH2Cl], 208 (23), 207 (12), 206 (40), 194 (14), 192 (32), 189 (29),
187 (35),170 (34), 158 (38),152 (42), 138 (45),104 (100), 77 (97). MS
(ESI): m/z (%)¼287 (11) [MꢁClþCH3CNþ4], 286 (11)
[MꢁClþCH3CNþ3], 285 (64) [MꢁClþCH3CNþ2], 284 (19)
[MꢁClþCH3CNþ1], 283 (100) [MꢁClþCH3CN], 196 (30).
Powdered sodium trichloroacetate (10 equiv) was added in
small portions with stirring to a mixture of the imine 1 and TEBA
(0.2 equiv) in refluxing CHCl3. Then the mixture was filtered and
the solvent was evaporated under reduced pressure and the residue
was worked up in different ways.
4.3.1. Methyl 2-(2,2-dichloro-3-(2-chloro-1,1-
dimethylethyl)aziridin-1-yl)acetate (2e)
This compound was obtained from imine 1e (1.44 g, 7.5 mmol)
in CHCl3 (80 mL) over 3 h. The residue was extracted by ether
(3ꢂ50 mL) to give crude product (1.78 g, 86%). Pure product was
obtained by chromatography on Florisil (1.2 g, 58%). IR (ATR): 1585,
4.2.2. 2,2-Dichloro-3-(2-chloro-1,1-dimethylethyl)-1-
isopropylaziridine (2b)
This compound was obtained from imine 1b (2.00 g, 12.4 mmol)
in CHCl3 (100 mL) during 7 h. The residue was unstable on silica gel
and on basic Al2O3. Two ways of purification were used. Extraction
by hexane (3ꢂ50 mL) led to a crude mixture (2.77 g) containing
compounds 2b (yield 87%) and 4b (yield 5%) in ratio of 18:1 (cal-
culated from 1H NMR). Chromatography on Florisil (hexane/Et2O)
furnished a mixture (1.63 g) containing compounds 2b (yield 49%)
and 4b (yield 5%) in ratio of 9:1. IR (ATR): 1468, 2875, 2972 cmꢁ1. 1H
1754 (C]O), 2953 cmꢁ1. 1H NMR (250 MHz, CDCl3):
d 1.16 and 1.23
(2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.10 (1H, s, CH), 3.49 and 3.71 (2ꢂ1H, 2ꢂd,
J¼16.7 Hz, CH2Cl), 3.57 (2H, s, CH2), 3.81 (3H, s, OCH3). 13C NMR
(63 MHz, CDCl3): d 22.2 (CH3), 22.3 (CH3), 36.8 (C(CH3)2), 52.2 (CH),
54.3 (CH2), 54.9 (CH2), 58.7 (OCH3), 76.1 (CCl2), 169.2 (C]O). MS
(ESI): m/z (%)¼281 (7) [MꢁClþCH3CNþ2], 279 (10) [MꢁClþCH3CN],
278 (6) [MþHþþ4], 276 (19) [MþHþþ2], 274 (18) [MþHþ], 194 (32)
[MþHþþ2ꢁCCl2], 192 (100) [MþHþꢁCCl2].
NMR (500 MHz, CDCl3):
d
1.13 and 1.14 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 1.15
and 1.31 (2ꢂ3H, 2ꢂd, J¼6.5 Hz, CH(CH3)2), 1.99 (1H, s, CH), 2.51 (1H,
4.3.2. 1-tert-Butyl-3,3-dichloro-4-(2-chloro-1,1-
dimethylethyl)azetidin-2-one (3)
septet, J¼6.2 Hz, CH(CH3)2), 3.44 and 3.60 (2ꢂ1H, 2ꢂd, J¼10.9 Hz,
CH2Cl). 13C NMR (125 MHz, CDCl3):
d
21.8 (CH3), 21.9 (CH3), 22.3
This compound was obtained from imine 1g (0.50 g, 2.85 mmol)
in CHCl3 (40 mL) over 1.5 h. The residue was chromatographed on
silica gel (hexane/Et2O) to give compound 3, as a pale-yellow oil
(CH3), 23.6 (CH3), 36.2 (C(CH3)2), 53.5 (CH2Cl), 55.2 (CH(CH3)2), 57.2
(CH), 76.9 (CCl2). MS (EI, 70 eV), MS (ESI): no molecular ion was
observed.
(0.145 g, 18%). IR (ATR): 1776 (C]O) cmꢁ1 1H NMR (250 MHz,
.
CDCl3):
d
1.29 and 1.34 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 1.46 (9H, s, C(CH3)3),
4.2.3. 2,2-Dichloro-3-(2-chloro-1,1-dimethylethyl)-1-
cyclohexylaziridine (2c)
3.56 and 3.84 (2ꢂ1H, 2ꢂd, J¼11.4 Hz, CH2Cl), 4.30 (1H, s, CH). 13
C
NMR (63 MHz, CDCl3): d 21.4 (CH3), 23.3 (CH3), 29.0 (C(CH3)3), 38.3
This compound was obtained from imine 1c (1.30 g, 6.45 mmol)
in CHCl3 (70 mL) during 13 h (after 7 h the additional 3 equiv of
KOH were added). The residue was unstable on silica and on basic
Al2O3. Two ways of purification were used. Extraction by hexane
(3ꢂ50 mL) led to a crude mixture (1.6 g) containing compounds 2c
(yield 78%) and 4c (yield 9%) in ratio of 8:1 (calculated from 1H
NMR). Chromatography on Florisil (hexane/Et2O) furnished a mix-
ture (0.89 g) containing compounds 2c (yield 44%) and 4c (yield 5%)
in ratio of 8:1. IR (ATR): 1450, 2856, 2932 cmꢁ1. 1H NMR (500 MHz,
(C(CH3)2), 53.5 (CH2), 56.4 (C(CH3)3), 81.2 (CCl2), 162.5 (C]O). MS
(ESI): m/z (%)¼331 (4) [MþCH3CNþ4], 329 (12) [MþCH3CNþ2], 327
(13) [MþCH3CN], 290 (34) [MþHþþ4], 288 (100) [MþHþþ2], 286
(97) [MþHþ], 234 (4) [MþHþþ4ꢁ(CH3)2C]CH2], 232 (16)
[MþHþþ2ꢁ(CH3)2C]CH2], 234 (18) [MþHþꢁ(CH3)2C]CH2].
HRMS (ESI): m/z calcd for C11H18Cl3NOþH: 286.0527; found:
286.0532.
CDCl3):
d
1.14 and 1.16 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 1.25–1.48 (5H, m,
4.4. Synthesis of 2-chloro-3-(2-chloro-1,1-dimethylethyl)-2-
fluoro-1-phenylaziridine (2f) (method A2)
CH2cHex), 1.57–1.70 (3H, m, CH2cHex), 1.75–1.85 (2H, m, CH2cHex),
2.01 (1H, s, CH), 2.24–2.29 (1H, m, CHcHex), 3.46 and 3.62 (2ꢂ1H,
2ꢂd, J¼10.9 Hz, CH2Cl). 13C NMR (125 MHz, CDCl3):
d
22.3 (2ꢂCH3),
Dichlorofluoromethane was bubbled through a vigorously stir-
red mixture of imine 1a (1.5 g, 7.7 mmol), powdered KOH (4.30 g,
76.8 mmol), and TEBA (0.35 g, 1.5 mmol) in CH2Cl2 (60 mL) at 8–
11 ꢀC for 1.5 h. The reaction mixture was filtered and the solvent
was evaporated under reduced pressure. The residue was chro-
matographed on basic Al2O3 (petroleum ether/EtOAc) to give
23.6, 24.1, 25.7, 31.5, 32.0 (CH2cHex), 36.2 (C(CH3)2), 53.6 (CH2Cl),
56.8 (CH), 61.9 (CH), 76.8 (CCl2). MS (ESI): m/z (%)¼291 (5)
[MꢁClþCH3CNþ2], 289 (9) [MꢁClþCH3CN], 288 (8) [MþHþþ4],
286 (23) [MþHþþ2], 284 (22) [MþHþ], 204 (54) [MþHþþ2ꢁCCl2],
202 (100) [MþHþꢁCCl2].
compound 2f, as
a mixture of diastereoisomers trans-HF
4.2.4. 2,2-Dichloro-3-(2-chloro-1,1-dimethylethyl)-1-
benzylaziridine (2d)
(JHF¼4 Hz)/cis-HF (JHF¼8 Hz) ca. 15:1 (1.60 g, 80%) [ratio calculated
from 1H NMR spectra of the crude reaction mixture]. IR (ATR): 1491,
This compound was obtained from imine 1d (1.30 g, 6.2 mmol)
in CHCl3 (90 mL) during 5 h. The residue was extracted by hexane
(3ꢂ50 mL) to give crude product (1.23 g, 68%). Analytically pure
product was obtained by chromatography on Florisil (hexane/Et2O)
(0.84 g, 47%). IR (ATR): 1454, 1497, 2932 cmꢁ1. 1H NMR (500 MHz,
1595, 2977 cmꢁ1. 1H NMR (250 MHz, CDCl3):
d
1.21 and 1.24 (2ꢂ3H,
2ꢂs, 2ꢂCH3) [major isomer], 1.26 and 1.30 (2ꢂs, 2ꢂCH3) [minor
isomer], 2.68 (1H, d, JHF¼4 Hz, CH) [major isomer], 2.84 (d,
JHF¼8 Hz, CH) [minor isomer], 3.51–3.68 (m, CH2Cl) [minor isomer],
3.59 (2H, d, JHF¼3 Hz, CH2Cl) [major isomer], 6.98–7.01 (2H, m, Ph),
7.11–7.17 (1H, m, Ph), 7.31–7.38 (2H, m, Ph). 13C NMR (63 MHz,
CDCl3):
d
0.94 and 1.09 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.06 (1H, s, CH), 3.15
and 3.39 (2ꢂ1H, 2ꢂd, J¼10.9 Hz, CH2Cl), 3.68 and 4.18 (2ꢂ1H, 2ꢂd,
CDCl3) [major isomer]:
d
22.6 (d, J¼2 Hz, CH3), 23.4 (d, J¼3 Hz, CH3),
J¼13.3 Hz, CH2Ph), 7.30–7.40 (5H, m, Ph). 13C NMR (125 MHz,
36.9 (d, J¼6 Hz, C(CH3)2), 53.8 (d, J¼2 Hz, CH2Cl), 56.9 (d, J¼14 Hz,
CDCl3):
d 22.1 (CH3), 22.6 (CH3), 36.6 (C(CH3)2), 54.0 (CH2Cl), 57.8
CH), 96.7 (d, J¼296 Hz, CFCl), 119.8 (d, J¼3 Hz, CHPh), 124.4 (CHPh),
(CH), 57.9 (CH2Ph), 77.5 (CCl2), 127.7 (CHPh), 2ꢂ128.6 (CHPh), 137.0
(CPh). MS (ESI): m/z (%)¼296 (22) [MþHþþ4], 294 (97) [MþHþþ2],
292 (100) [MþHþ].
129.0 (CHPh), 145.1 (CPh). 19F NMR (235 MHz, CDCl3):
d
ꢁ101.0
[major isomer], ꢁ102.7 [minor isomer]. MS (EI, 70 eV), MS (ESI): no
molecular ion was observed.

7528
E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
4.5. Synthesis of amides 5a–e
CDCl3):
d
22.2 (CH3), 22.4 (CH3), 24.6 (2ꢂCH2cHex), 25.4, 32.6, 32.8
(CH2cHex), 40.1 (C(CH3)2), 48.7 (CHcHex), 53.4 (CH2Cl), 65.9 (CHCl),
165.9 (C]O). MS (ESI): m/z (%)¼270 (10) [MþHþþ4], 268 (71)
[MþHþþ2], 266 (100) [MþHþ]; Anal. Calcd for C12H21Cl2NO: C,
54.14; H, 7.95; N, 5.26. Found: C, 54.23; H, 7.92; N, 5.27.
4.5.1. 2,4-Dichloro-3,3-dimethyl-N-phenylbutanamide (5a)
A mixture of ZnCl2$1.5H2O (0.30 g, 1.8 mmol), aziridine 2a
(0.205 g, 0.74 mmol), and CH2Cl2 (7 mL) was stirred at room tem-
perature for 1 h. Then ZnCl2 was filtered off, the solvent was
evaporated and the residue was chromatographed on silica gel
(hexane/Et2O). Yield 0.14 g (73%), colorless crystals, mp 111–112 ꢀC
4.5.4. 2,4-Dichloro-3,3-dimethyl-N-benzylbutanamide (5d)
A mixture of ZnCl2$1.5H2O (0.075 g, 0.46 mmol), aziridine 2d
(0.68 g, 2.3 mmol), and CH2Cl2 (30 mL) was stirred at 0 ꢀC (ice bath)
during 4 h. Then the mixture was poured into water, extracted with
CH2Cl2 (3ꢂ30 mL) and the combined extracts were dried (Na2SO4).
The solvent was evaporated and the residue was chromatographed
on silica (petroleum ether/EtOAc). Yield 0.375 g (59%),ꢁ1mp 110.7–
(Et2O–pentane). IR (ATR): 1664 (C]O), 3300 (NH) cmꢁ1
.
1H NMR
(500 MHz, CDCl3):
d
1.25 and 1.28 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.59 and
3.70 (2ꢂ1H, 2ꢂd, J¼11.1 Hz, CH2Cl), 4.58 (1H, s, CHCl), 7.15–7.19 (1H,
m, Ph), 7.34–7.38 (2H, m, Ph), 7.52–7.54 (2H, m, Ph), 8.00 (1H, br s,
NH). 13C NMR (63 MHz, CDCl3):
d 22.2 (CH3), 22.5 (CH3), 40.5
(C(CH3)2), 53.2 (CH2), 66.1 (CHCl), 120.2 (CHPh), 125.2 (CHPh), 129.1
(CHPh), 136.7 (CPh), 165.2 (C]O). MS (ESI): m/z (%)¼264 (10)
[MþHþþ4], 262 (72) [MþHþþ2], 260 (100) [MþHþ], 226 (4)
[MꢁClþ2], 224 (12) [MꢁCl]. Anal. Calcd for C12H15Cl2NO: C, 55.40;
H, 5.81; N, 5.38. Found: C, 55.27; H, 5.81; N, 5.54.
111.3 ꢀC (Et2O). IR (ATR): 1648 (C]O), 3279 (NH) cm 1H NMR
.
(250 MHz, CDCl3):
d
1.19 and 1.21 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 3.55 and
3.67 (2ꢂ1H, 2ꢂd, J¼11.0 Hz, CH2Cl), 4.48 (1H, s, CHCl), 4.51 (2H, d,
J¼1.5 Hz, CH2Ph), 6.66 (1H, br s, NH), 7.29–7.40 (5H, m, Ph). 13C NMR
(63 MHz, CDCl3):
d 22.2 (CH3), 22.6 (CH3), 40.3 (C(CH3)2), 44.0
(CH2Ph), 53.4 (CH2Cl), 65.8 (CHCl), 127.77 (CHPh), 127.79 (CHPh),
128.8 (CHPh), 137.5 (CPh), 167.1 (C]O). MS (ESI): m/z (%)¼278 (10)
[MþHþþ4], 276 (70) [MþHþþ2], 274 (100) [MþHþ]. Anal. Calcd for
4.5.2. 2,4-Dichloro-3,3-dimethyl-N-isopropylbutanamide (5b)
Method A. A mixture of concentrated HCl (2 mL), crude aziridine
2b (0.5 g), and Et2O (5 mL) was stirred overnight at room temper-
ature. Then, the mixture was poured into a saturated Na2CO3 so-
lution, extracted with Et2O (3ꢂ30 mL) and the combined extracts
were dried (Na2SO4). The solvent was evaporated and the residue
was chromatographed on Al2O3 (hexane/Et2O). Yield: 0.13 g (24%,
calculated taking into account the amide already present in the
starting aziridine).
C13H17Cl2NO: C, 56.95; H, 6.25; N, 5.11. Found: C, 56.72; H, 6.29; N,
5.11.
4.5.5. Methyl 2-(2,4-dichloro-3,3-dimethylbutanamido)-
acetate (5e)
Method B. Compound 5e was prepared from aziridine 2e (0.56 g,
2.0 mmol, filtered through Florisil) at room temperature overnight.
After workup, the residue was chromatographed on silica gel (pe-
troleum ether/EtOAc) to give colorless crystals (0.17 g, 33%), mp 69–
70 ꢀC (Et2O–petroleum ether). IR (ATR): 1660 (C]O), 1755 (C]O),
Method B. A mixture of ZnCl2$1.5H2O (0.06 g, 0.37 mmol), azir-
idine 2b (0.51 g, filtered through Florisil), and CH2Cl2 (30 mL) was
stirred at room temperature overnight. Then ZnCl2 was filtered, the
solvent was evaporated and the residue was chromatographed on
Al2O3 (hexane/Et2O). Yield: 0.25 g (48%, calculated taking into ac-
count the amide already present in the starting aziridine), colorless
crystals, mp 76–77 ꢀC (hexane). IR (ATR): 1650 (C]O), 3284
3366 (NH) cmꢁ1. 1H NMR (500 MHz, CDCl3):
d
1.23 (6H, s, 2ꢂCH3),
3.57 and 3.68 (2ꢂ1H, 2ꢂd, J¼11 Hz, CH2Cl), 3.80 (3H, s, OCH3), 4.04
and 4.15 (2ꢂ1H, 2ꢂdd, J¼18.2 Hz, J¼5.3 Hz, CH2CO2CH3), 4.52 (1H,
s, CHCl), 6.82 (1H, br s, NH). 13C NMR (125 MHz, CDCl3):
d 22.1 (CH3),
(NH) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.17–1.22 (12H, m, 4ꢂCH3),
22.4 (CH3), 40.3 (C(CH3)2), 41.4 (CH2CO2CH3), 52.4 (OCH3), 53.2
(CH2Cl), 65.4 (CHCl), 167.1 (C]O), 169.7 (C]O). MS (ESI): m/z
(%)¼260 (10) [MþHþþ4], 258 (77) [MþHþþ2], 256 (100) [MþHþ].
HRMS (ESI): m/z calcd for C9H15Cl2NO3þH: 256.0502; found:
256.0507.
3.54 and 3.66 (2ꢂ1H, 2ꢂd, J¼11.3 Hz, CH2Cl), 4.05 (1H, octet,
J¼6.9 Hz, CH(CH3)2), 4.40 (1H, s, CHCl), 6.15 (1H, br s, NH). 13C NMR
(75 MHz, CDCl3):
d 22.2 (CH3), 22.3 (CH3), 22.4 (CH3), 22.5 (CH3),
40.1 (C(CH3)2), 42.0 (CH(CH3)2), 53.4 (CH2Cl), 65.8 (CHCl), 166.0
(C]O). MS (ESI): m/z (%)¼230 (35) [MþHþþ4], 228 (63)
[MþHþþ2], 226 (100) [MþHþ]. Anal. Calcd for C9H17Cl2NO: C,
47.80; H, 7.58; N, 6.19. Found: C, 47.69; H, 7.54; N, 6.28.
4.6. Reaction of aziridine 2a with BF3$Et2O
BF3$Et2O (0.42 g, 2.960 mmol) was added dropwise to a stirred
solution of compound 2a (0.21 g, 0.8 mmol) in CH2Cl2 (7 mL) and
the mixture was kept overnight at room temperature. The solvent
was removed in vacuo and a complex mixture in which compounds
5a and 5a–F (1:1) could be detected in 1H NMR was obtained. The
residue was purified by column chromatography on silica (hexane–
Et2O). A mixture (30 mg) containing compounds 5a and 5a–F in
a ratio of 1:2 was only isolated in addition to the mixture of two
unknown compounds (140 mg). In the NMR spectra of the mixture
following signals could be attributed to 4-chloro-2-fluoro-3,3-di-
methyl-N-phenylbutanamide (5a–F). 1H NMR (250 MHz, CDCl3):
4.5.3. 2,4-Dichloro-3,3-dimethyl-N-cyclohexylbutanamide (5c)
Method A. Compound 5c (0.125 g, 18%, calculated taking into
account the amide already present in the starting aziridine) was
obtained from crude aziridine 2c (0.5 g) at room temperature
overnight.
Method B. Compound 5c (0.21 g, 38%, calculated taking into ac-
count the amide already present in the starting aziridine) was
obtained from aziridine 2c (0.5 g, filtered through Florisil) at 0 ꢀC
(ice bath) during 2.5 h.
Method C. Hydrogen chloride gas was bubbled through a solu-
tion of aziridine 2c (0.285 g, filtered through Florisil) in Et2O
(20 mL) during 1 h. Then the mixture was poured into water,
extracted with Et2O and the combined extracts were dried
(Na2SO4). The solvent was evaporated and the residue was chro-
matographed on Al2O3 (hexane/Et2O). Yield: 0.07 g (18%, calculated
taking into account the amide already present in the starting
aziridine), colorless crystals, mp 118–119 ꢀC (hexane). IR (ATR):
d
1.18 and 1.22 (2ꢂ3H, 2ꢂd, J¼1.4 Hz, 2ꢂCH3), 3.62 (2H, d, J¼1.8 Hz,
CH2Cl), 4.98 (1H, d, J¼47.9 Hz, CHF), 7.13–7.19 (1H, m, Ph), 7.32–7.38
(2H, m, Ph), 7.51–7.57 (2H, m, Ph), 7.98 (1H, br s, NH). 13C NMR
(63 MHz, CDCl3):
d
21.05 (d, J3¼7 Hz, CH3), 21.06 (d, J3¼7 Hz, CH3),
39.9 (d, J2¼18 Hz, C(CH3)2), 51.8 (d, J3¼7 Hz, CH2), 93.9 (d,
J1¼193 Hz, CHF), 120.2 (CHPh), 125.2 (CHPh), 129.1 (CHPh), 136.7
(CPh), 166.2 (d, J2¼19 Hz, C]O).
1647 (C]O), 3273 (NH) cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 1.12–
1.20 (4H, m, CH2cHex), 1.17 and 1.19 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 1.32–1.40
(2H, m, CH2cHex), 1.60–1.70 and 1.89–1.93 (2ꢂ2H, 2ꢂm, CH2cHex),
3.52 and 3.65 (2ꢂ1H, 2ꢂd, J¼10.9 Hz, CH2Cl), 3.70–3.85 (1H, m,
CHcHex), 4.40 (1H, s, CHCl), 6.24 (1H, br s, NH). 13C NMR (75 MHz,
4.7. Synthesis of compounds 6a–d; typical procedure
A mixture of compound 5 (0.1 g), TEBA (0.01 g, 0.04 mmol),
NaOH (0.17 g, 4.3 mmol), H2O (0.3 mL), and CH2Cl2 (7 mL) was

E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
7529
vigorously stirred overnight at room temperature. Then water
(5 mL) was added, the organic phase was separated and dried over
MgSO4. The solvent was evaporated under reduced pressure. The
residue was chromatographed on silica gel to give compound 6.
CH2Cl), 3.70 (3H, s, OCH3), 4.11 (1H, br s, NH), 4.21 (1H, s,
CHCO2CH3), 6.72–6.81 (3H, m, Ph), 7.15–7.22 (2H, m, Ph). 13C NMR
(63 MHz, CDCl3):
d 21.2 (CH3), 22.9 (CH3), 39.2 (C(CH3)2), 51.9
(OCH3), 53.2 (CH2Cl), 61.6 (CHCl), 114.7 (CHPh), 119.2 (CHPh), 129.4
(CHPh), 147.3 (CPh), 173.5 (C]O). MS (ESI): m/z (%)¼258 (31)
[MþHþþ2], 256 (100) [MþHþ], 220 (49) [MꢁHCl], 198 (20)
[MꢁCO2CH3þ2], 196 (58) [MꢁCO2CH3]. HRMS (ESI): m/z calcd for
4.7.1. 3-Chloro-4,4-dimethyl-1-phenylpyrrolidin-2-one (6a)
Yield: 65 mg (76%), colorless crystals, mp 65.8–66.4 ꢀC (Et2O–
hexane). Spectroscopic data (1H NMR) were in accordance with
C13H18ClNO2þH: 256.1093; found: 256.1104.
literature data.40 IR (ATR): 1707 (C]O) cmꢁ1 13C NMR (125 MHz,
.
CDCl3):
d 22.2 (CH3), 25.2 (CH3), 38.2 (C(CH3)2), 58.6 (CHCl), 67.0
Acknowledgements
(CH2N), 119.9 (CHPh), 125.1 (CHPh), 129.0 (CHPh), 139.0 (CPh), 168.7
(C]O). MS (ESI): m/z (%)¼226 (31) [MþHþþ2], 225 (12)
[MþHþþ1], 224 (100) [MþHþ].
We gratefully acknowledge the Government of Flanders ‘Bi-
lateral Scientific Cooperation’ program and the Russian Foundation
for Basic Research (project nos. 05-03-34811, 08-03-00112a) for
support of this research.
4.7.2. 3-Chloro-4,4-dimethyl-1-isopropylpyrrolidin-2-one (6b)
Yield: 65 mg (77%), colorless crystals, mp 40–41 ꢀC (pentane). IR
(ATR): 1691 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.08 and 1.10
Supplementary data
(2ꢂ3H, 2ꢂd, J¼3.1 Hz, 2ꢂCH3), 1.12 and 1.16 (2ꢂ3H, 2ꢂs, 2ꢂCH3),
2.96 and 3.11 (2ꢂ1H, 2ꢂd, J¼9.8 Hz, CH2N), 4.00 (1H, s, CHCl), 4.33
Copies of 1H NMR and 13C NMR spectra for compounds 2, 3, 5, 6
and 10 are included in Supplementary data. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.05.121.
(1H, septet, J¼6.5 Hz, CH(CH3)2). 13C NMR (75 MHz, CDCl3):
d 19.1
(CH3), 19.4 (CH3), 21.9 (CH3), 25.2 (CH3), 38.3 (C(CH3)2), 42.7
(CH(CH3)2), 52.0 (CH2N), 66.5 (CHCl), 168.8 (C]O). MS (ESI): m/z
(%)¼192 (34) [MþHþþ2], 190 (100) [MþHþ]. HRMS (ESI): m/z calcd
for C9H16ClNOþH: 190.0993; found: 190.0999. Anal. Calcd for
C9H16ClNO: C, 56.99; H, 8.50; N, 7.38. Found: C, 57.01; H, 8.36; N,
7.25.
References and notes
1. Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ. Chem. Rev. 2005, 74, 171.
2. Shinkevich, E. Yu.; Novikov, M. S.; Khlebnikov, A. F. Synthesis 2007, 225.
3. Khlebnikov, A. F.; Novikov, M. S.; Shinkevich, E. Yu.; Vidovich, D. Org. Biomol.
Chem. 2005, 3, 4040.
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Chem. 2003, 39, 559; Translated from Zh. Org. Khim. 2003, 39, 595.
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4.7.3. 3-Chloro-4,4-dimethyl-1-cyclohexylpyrrolidin-2-one (6c)
Yield: 62 mg (72%), colorless crystals, mp 47.5–48.5 ꢀC (hexane).
IR (ATR): 1683 (C]O) cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.13 and
1.17 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 1.22–1.40 and 1.60–1.80 (2ꢂ5H, 2ꢂm,
CH2cHex), 2.99 and 3.14 (2ꢂ1H, 2ꢂd, J¼9.4 Hz, CH2N), 3.85–3.98 (1H,
m, CHcHex), 4.02 (1H, s, CHCl). 13C NMR (75 MHz, CDCl3):
d 22.0
8. Makosza, M.; Kacprowicz, A. Roczniki Chem. 1974, 48, 2129.
(CH3), 25.10, 25.13, 25.22 (CH2cHex), 25.25 (CH3), 29.6, 29.9
(CH2cHex), 38.4 (C(CH3)2), 50.7 (CHcHex), 53.2 (CH2N), 66.5 (CHCl),
168.9 (C]O). MS (ESI): m/z (%)¼232 (37) [MþHþþ2], 230 (100)
[MþHþ]. Anal. Calcd for C12H20ClNO: C, 62.73; H, 8.77; N, 6.10.
Found: C, 62.94; H, 8.70; N, 6.17.
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14. Sulmon, P.; De Kimpe, N.; Schamp, N.; Declercq, J.-P. J. Org. Chem. 1989, 54, 2587.
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1988, 44, 3653.
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192.
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Translated from Zh. Org. Khim. 1977, 13, 1857.
19. Konev, A. S.; Novikov, M. S.; Khlebnikov, A. F. Tetrahedron Lett. 2005, 46, 8337.
20. Van Hende, E.; Verniest, G.; Surmont, R.; De Kimpe, N. Org. Lett. 2007, 9, 2935.
21. Kusei, E. Yu.; Novikov, M. S.; Khlebnikov, A. F. Russ. J. Gen. Chem. 2005, 75, 1643;
Translated from Zh. Obshch. Khim. 2005, 75, 1720.
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707; Translated from Zh. Org. Khim. 1999, 35, 732.
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637; Translated from Zh. Org. Khim. 1996, 32, 715.
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from Zh. Org. Khim. 1992, 28, 482.
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Chem. 1999, 35, 91; Translated from Zh. Org. Khim. 1999, 35, 98.
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4.7.4. 3-Chloro-4,4-dimethyl-1-benzylpyrrolidin-2-one (6d)
The reaction mixture was vigorously stirred at reflux for 5 h.
Yield: 60 mg (67%), pale-yellow oil. IR (ATR): 1697 (C]O) cmꢁ1. 1H
NMR (250 MHz, CDCl3):
d
1.11 and 1.15 (2ꢂ3H, 2ꢂs, 2ꢂCH3), 2.92
and 3.08 (2ꢂ1H, 2ꢂd, J¼9.7 Hz, CH2N), 4.10 (1H, s, CHCl), 4.42 and
4.54 (2ꢂ1H, 2ꢂd, J¼14.6 Hz, CH2Ph), 7.20–7.40 (5H, m, Ph). 13C NMR
(63 MHz, CDCl3):
d 22.1 (CH3), 25.4 (CH3), 38.3 (C(CH3)2), 47.0
(CH2Ph), 56.7 (CH2N), 66.0 (CHCl), 127.8 (CHPh), 128.2 (CHPh), 128.7
(CHPh), 135.6 (CPh), 169.8 (C]O). MS (ESI): m/z (%)¼240 (33)
[MþHþþ2], 238 (100) [MþHþ]. HRMS (ESI): m/z calcd for
C
13H16ClNOþH: 238.0993; found: 238.0999.
4.8. Synthesis of methyl 4-chloro-3,3-dimethyl-2-
(phenylamino)butanoate (10)
To a solution of sodium methoxide in methanol (0.4 M, 10 mL)
was added dropwise at stirring a solution of aziridine 2a (0.5 g,
1.8 mmol) in methanol (10 mL). The mixture was stirred at room
temperature during 3 h. Then, methanol was evaporated and ace-
tonitrile (5 mL) and aqueous 2 M HCl (1 mL) were added to the
residue. The mixture was stirred at room temperature during
15 min. Then, the mixture was poured into water, extracted with
Et2O and the combined extracts were dried (Na2SO4). The solvent
was evaporated and the residue was chromatographed on silica gel
(hexane/Et2O) to give a pale-yellow oil. Yield: 0.38 g (82%). IR
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(ATR): 1601, 1730 (C]O), 3386 (NH) cmꢁ1 1H NMR (250 MHz,
CDCl3):
d
1.11 (6H, s, 2ꢂCH3), 3.41 and 3.73 (2ꢂ1H, 2ꢂd, J¼10.9 Hz,

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E.Yu. Shinkevich et al. / Tetrahedron 64 (2008) 7524–7530
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´
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