A Convenient Synthesis of 3,3-Dichloroazetidines, a New Class of Azetidines

Article abstract of DOI:10.1021/jo970342w

A short synthesis of appropriately substituted 3,3-dichloroazetidines, a virtually unknown class of azetidines, is described. The reaction of 3,3-dichloro-1-azaallylic carbanions, generated from N-(1-aryl-2,2-dichloroethylidene)amines, with aromatic aldehydes produced α,α-dichloro-α-hydroxy imines that, upon treatment with mesyl chloride, were converted into the corresponding β-(mesyloxy) imines. Reaction of these α,α-dichloro-α-(mesyloxy) ketimines with potassium cyanide or sodium borohydride in methanol furnished a variety of 2-cyano- and 2-methoxy-3,3-dichloroazetidines in a stereoselective manner. Reduction of β-(mesyloxy) imines with sodium cyanoborohydride followed by cyclization with potassium carbonate in DMSO yielded 3,3-dichloroazetidines as well.

Full text of DOI:10.1021/jo970342w

6
J . Org. Chem. 1998, 63, 6-11
Articles
A Con ven ien t Syn th esis of 3,3-Dich lor oa zetid in es, a New Cla ss of
Azetid in es
Wim Aelterman and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, University of
Gent, Coupure Links 653, B-9000 Gent, Belgium
J ean-Paul Declercq
Laboratoire de Chimie Physique et de Cristallographie, Universite´ Catholique de Louvain,
1, Place Louis Pasteur, B-1348 Louvain-la-Neuve, Belgium
Received February 24, 1997 (Revised Manuscript Received August 27, 1997X)
A short synthesis of appropriately substituted 3,3-dichloroazetidines, a virtually unknown class of
azetidines, is described. The reaction of 3,3-dichloro-1-azaallylic carbanions, generated from N-(1-
aryl-2,2-dichloroethylidene)amines, with aromatic aldehydes produced R,R-dichloro-â-hydroxy imines
that, upon treatment with mesyl chloride, were converted into the corresponding â-(mesyloxy)
imines. Reaction of these R,R-dichloro-â-(mesyloxy) ketimines with potassium cyanide or sodium
borohydride in methanol furnished a variety of 2-cyano- and 2-methoxy-3,3-dichloroazetidines in a
stereoselective manner. Reduction of â-(mesyloxy) imines with sodium cyanoborohydride followed
by cyclization with potassium carbonate in DMSO yielded 3,3-dichloroazetidines as well.
Sch em e 1
In tr od u ction
Azetidines are an important class of azaheterocyclic
compounds with remarkable biological activities, which
make it an interesting synthetic topic.1-4 3,3-Dichloro-
azetidines 1 constitute a nearly unknown class of four-
membered heterocycles. The isolation of only two 3,3-
dichloroazetidines has been reported in the literature. A
first example was obtained as a byproduct during the
synthesis of R-amino acids.5 The other example con-
cerned the reduction of a strained 3,3-dichloro-1-azetine
in 37% yield.6
Several general procedures exist for the preparation
of azetidines.1-4 Previously, we have reported a method
for the synthesis of azetidines that is based on the
reaction of â-chloro imines with nucleophiles, such as
hydride and cyanide,7-11 or bases (leading to 2-methyl-
eneazetidines).12 In this paper, a novel approach based
on the reaction of â-(mesyloxy) imines 2 with nucleophiles
was used to synthesize 3,3-dichloroazetidines 1 (Scheme
1). To our knowledge, only one cyclization of a â-(tosyl-
oxy) aldimine leading to an azetidine in very low yield
(20%) has been described.13 â-(Mesyloxy) imines 2 can
be obtained by reaction of the corresponding â-hydroxy
imines 3 with mesyl chloride. Here, we describe a new
type of directed aldol condensation of 3,3-dichloro-1-
azaallylic anions 4 with aldehydes, giving access to R,R-
dichloro-â-hydroxy ketimines 3. This aldol-type conden-
sation holds a pivotal position in the construction of 3,3-
dichloroazetidines 1 from 1-azaallylic anions 4 and
aldehydes 5 (Scheme 1).
* To whom correspondence should be addressed. TEL: 32 9 264 59
51; FAX: 32 9 264 62 43; E-mail: norbert.dekimpe@rug.ac.be
X Abstract published in Advance ACS Abstracts, October 15, 1997.
(1) Cromwell, N. H.; Phillips, B. Chem. Rev. (Washington, D.C.)
1979, 79, 331-358.
(2) Moore, J . A.; Ayers, R. S. In Chemistry of Heterocyclic Compounds
-Small Ring Heterocycles; Hassner, A., Ed.; Wiley: New York, 1983;
Part 2, pp 1-217.
(3) Davies, D. E.; Starr, R. C. In Comprehensive Heterocyclic
Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7, Part 5,
pp 237-284.
(4) De Kimpe, N. In Comprehensive Heterocyclic Chemistry II;
Padwa, A., Ed.; Elsevier: Oxford, 1996; Vol. 1, Chapter 1.21. 3- and
4-membered rings, with all fused systems containing 3- and 4-mem-
bered rings.
(9) Sulmon, P.; De Kimpe, N.; Schamp, N. J . Org. Chem. 1989, 54,
2587-2590.
(5) Kashima, C.; Aoki, Y.; Omote, Y. J . Chem. Soc., Perkin Trans. 1
1975, 2511-2513.
(10) Sulmon, P.; De Kimpe, N.; Schamp, N. Tetrahedron 1989, 45,
2937-2955.
(6) Harnisch, J .; Szeimies, G. Chem. Ber. 1979, 112, 3914-3933.
(7) Sulmon, P.; De Kimpe, N.; Schamp, N. J . Chem. Soc., Chem.
Commun. 1985, 715-716.
(11) De Kimpe, N.; Stevens, C. Synthesis 1993, 89-91.
(12) Sulmon, P.; De Kimpe, N.; Schamp, N. J . Org. Chem. 1988,
53, 4462-4465.
(8) Sulmon, P.; De Kimpe, N.; Schamp, N. Tetrahedron 1988, 44,
3653-3670.
(13) Nerdel, F.; Weyerstahl, P.; Zabel, K. Chem. Ber. 1969, 102,
1606-1609.
S0022-3263(97)00342-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Convenient Synthesis of 3,3-Dichloroazetidines
J . Org. Chem., Vol. 63, No. 1, 1998
7
Sch em e 2
Sch em e 3
Ta ble 1. Syn th esis of r,r-Dich lor o-â-h yd r oxy Im in es 7,
â-(Mesyloxy)-r,r-d ich lor o Im in es 8, a n d N-Alk yl-N-
[1,3-d ia r yl-2,2-d ich lor o-3-(m esyloxy)p r op yl]a m in es 12
cleavage of the initially formed â-hydroxy imine 7.17
Surprisingly, when the condensation was performed with
aliphatic aldehydes, such as 2-ethylbutanal, instead of
aromatic aldehydes 9, a mixture of cis- and trans-2-
chloro-2-imidoyloxiranes 10 was obtained via a Darzens-
type reaction (Scheme 3). A novel Darzens-type conden-
sation of R-monochlorinated ketimines with carbonyl
compounds producing R,â-epoxy ketimines has already
been reported by us.18 It has also been described that
the anion of 2-(dichloromethyl)-4,4-dimethyl-2-oxazoline
reacts with carbonyl compounds to give 2,2-dichloro-3-
hydroxy- or 2-chloro-2,3-epoxy-2-oxazolines depending on
the reaction conditions.19 Upon distillation of the R-chloro-
R,â-epoxy imine 10, a thermal rearrangement20 with
formation of R-imino ketone 11 took place (Scheme 3).
entry
R1
R2
R3
reaction time (h) product (yield, %)
1
2
3
4
5
6
7
8
9
i-Pr
Et
i-Pr
i-Pr
Et
i-Pr
i-Pr
Et
H
Cl
H
H
Cl
H
H
Cl
H
H
H
Me
H
H
Me
H
H
1a
7a (60)b
7b (77)b
7c (68)b
8a (77)d
8b (81)d
8c (90)d
12a (88)f
12b (77)f
12c (71)f
2.5a
2a
15c
17c
20c
24e
48e
48e
i-Pr
Me
a
The deprotonations were performed with 1.2 equiv of LDA in
THF at 0 °C during 45 min; 10 min before the addition of the
aldehyde 9 the reaction mixture was cooled to -15 °C. All reactions
were run with 1 equiv of aldehyde 9 in THF; the reaction mixture
was allowed to warm from -15 to 0 °C during the condensation.
Yield after recrystallization. c 10% w/v solutions of compound 7
b
in pyridine were treated with 1.5 equiv of MsCl at room temper-
ature. Yields after workup and washing with pentane/ether 4:1;
In the next step (Scheme 2), â-(mesyloxy) ketimines 8
were prepared by treatment of the corresponding â-hy-
droxy imines 7 with mesyl chloride in pyridine (Table
1). When dichloromethane was used as solvent and the
imines 7 were reacted at room temperature with mesyl
chloride in the presence of 1-5 equiv of pyridine or
triethylamine, the starting materials 7 were completely
recovered. At higher temperatures conversions into
unidentified reaction products occurred.
d
purity >99% (1H NMR). e Solutions of imines 8 in methanol were
treated with 2-3 equiv of sodium cyanoborohydride and 1-1.2
equiv of acetic acid at room temperature. f Yields after washing
the crude amines 12 with pentane/ether (9/1); purity >99% (1H-
NMR); diastereomeric ratio anti/syn > 99/1 (1H- and 13C-NMR).
Resu lts a n d Discu ssion
Aromatic aldehydes 9 were reacted with the lithium
azaenolates derived from R,R-dichloro ketimines 6, pre-
pared by condensation of R,R-dichloro ketones with
primary amines in the presence of titanium(IV) chloride14
and subsequent deprotonation with lithium diisopropyl-
amide, to give R,R-dichloro-â-hydroxy ketimines 7 in 60-
77% yield after recrystallization (Scheme 2). The relative
stability of the intermediate 3(,3-di-)chloro-1-azaallylic
anions has already been proved by their reaction with
other electrophiles.15,16 The new type of directed-aldol
condensation was performed by adding the aldehydes 9
to solutions of the heteroallylic anions derived from
imines 6 in THF at -15 °C and quenching with water at
0 °C after a reaction time of 1-2.5 h (Table 1). When
the reaction mixture was allowed to warm to room
temperature, up to 30% of the starting ketimine 6 and
aldehyde 9 were observed in the reaction mixture. This
can be explained as originating from a retro-aldol-type
Next, the â-(mesyloxy) ketimines 8 were converted into
3,3-dichloroazetidines 13 either by a nucleophile-induced
one-step cyclization or in a two-step sequence consisting
of a reduction followed by a ring closure under basic
conditions (Scheme 4).
In the first approach, the R,R-dichloro-â-(mesyloxy)
imines 8 were smoothly reduced in good yields (70-88%)
by acid-catalyzed reaction with sodium cyanoborohydride
in methanol in the presence of acetic acid (1-1.2 equiv)
1
at room temperature (Table 1). As evidenced by H and
13C NMR spectroscopy, only one pair of diastereomers of
the γ-(mesyloxy)amines 12 was obtained after recrystal-
lization. There was no proof that, before purification, the
other diastereomeric pair was present in the reaction
mixture (vide infra).
(17) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N. Tetrahedron
Lett. 1985, 26, 2709-2712.
(18) Sulmon, P.; De Kimpe, N.; Schamp, N. J . Org. Chem. 1988,
53, 4457-4462.
(14) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Moe¨ns, L.; Schamp, N.
Synthesis 1982, 43-46.
(19) Combret, J . C.; Meghni, A.; Postaire, D.; Tekin, J . Tetrahedron
Lett. 1991, 32, 87-90.
(15) De Kimpe, N.; Sulmon, P.; Schamp, N. Angew. Chem., Int. Ed.
Engl. 1985, 24, 881-882.
(20) (a) Kline, S. A.; Solomon, J . J .; Van Duuren, B. L. J . Org. Chem.
1978, 43, 3596-3600. (b) Katritzky, A. R.; Xie, L.; Serduyck, L. J . Org.
Chem. 1996, 61, 7564-7570.
(16) De Kimpe, N.; Coppens, W.; Welch, J .; De Corte, B. Synthesis
1990, 675-677.

8
J . Org. Chem., Vol. 63, No. 1, 1998
Aelterman et al.
Sch em e 4
Sch em e 5
Ta ble 2. Syn th esis of cis-3,3-Dich lor oa zetid in es 13
reaction
condns
azetidine 13
entry
R1
R2
R3
methoda
(yield, %)b
1
2
3
4
5
6
7
8
9
i-Pr
Et
i-Pr
i-Pr
Et
i-Pr
i-Pr
Et
H
Cl
H
H
Cl
H
H
Cl
H
H
H
Me
H
H
Me
H
H
A
A
A
B
B
B
C
C
C
90 °C, 48 h
85 °C, 48 h
85 °C, 48 h
∆, 6 h
13a (63)
13b (60)c
13c (78)
13d (54)
13e (57)
13f (84)
13g (66)
13h (91)d
13i (88)
via two plausible pathways as presented in Scheme 5.
The first possibility concerns a 1,2-dehydrochlorination
of 12b leading to the â-chloro enamine 14, which isomer-
izes into R-chloro ketimine 16 (path A). Alternatively,
an intramolecular nucleophilic substitution can give rise
to the 2-chloroaziridine 15, which thermally rearranges
to the same intermediate 16 (path B). Under the basic
conditions, two 1,2-elimination reactions finally lead to
the formation of the alkyne 18 (Scheme 5). Both mecha-
nistic pathways are plausible, but the route via the
aziridine 15 (path B) better answers the question why
the side reaction is only observed starting from a steri-
cally less hindered N-ethyl derivative 12b.
In a second approach, the synthesis of 2,4-diaryl-3,3-
dichloroazetidines 13 from â-(mesyloxy) imines 8 was
accomplished conveniently in one step by a nucleophile-
induced ring closure (Scheme 4). Treatment of â-(mesyl-
oxy)-R,R-dichloro imines 8 with potassium cyanide and
sodium borohydride in methanol under reflux furnished
2-cyano- and 2-methoxyazetidines 13d -f and 13g-i,
respectively, which were obtained in pure form after
recrystallization or flash chromatography (Table 2).
2-Cyanoazetidines have been reported scarcely in the
literature.7,8,22 Some 2-cyanoazetidines could be con-
verted into useful medicinal products, such as appetite
depressants and products that can control obesity.23 Also,
R-alkoxy azetidines have rarely been reported in the
literature until now and they are only accessible in very
special cases.10,12,13,24 Although the rapid conversion of
R-methoxy azetidines into â-(alkylamino) carbonyl com-
pounds has been reported by us,9,10 the 2,4-diaryl-3,3-
dichloro-2-methoxyazetidines 13g-i are rather stable
under the reaction conditions mentioned in Table 2. The
stabilizing character of the two chloro atoms at the
∆, 20 h
∆, 6 h
∆, 30 h
∆, 30 h
i-Pr
Me
∆, 20 h
a
Method A: amines 12 were reacted with 3 equiv of K2CO3 in
DMSO at 85-90 °C. Method B: imines 8 were treated with 2 equiv
of KCN in methanol under reflux. Method C: imines 8 were
treated with 2 equiv of NaBH4 in methanol under reflux. Yields
after purification by recrystallization (pentane/ether) or flash
chromatography (hexane/ethyl acetate) (see the Experimental
Section). c The imine 13 was isolated as a byproduct in 22% yield
b
d
(Scheme 5). Crude product (purity >95%).
In the next stage, cyclization of the 3-(mesyloxy)
amines 12 with potassium carbonate in DMSO at 85-
90 °C afforded 2,4-diaryl-3,3-dichloroazetidines 13a -c
(Table 2). After purification by recrystallization or flash
chromatography, these azetidines (one stereoisomer)
were obtained as crystalline products in yields ranging
from 60 to 78% (Table 1). No long-range couplings were
observed between the protons at C-2 and C-4 of the
azetidines 13. The relative stereochemistry at C-2 and
C-4 of the azetidines 13a -c was undoubtedly assigned
by X-ray crystallographic analysis,21 showing that com-
pound 13c had the cis stereochemistry. The fact that
only cis-2,4-diarylazetidines were obtained also implies
that in the previous step anti-(RR,SS)-3-(mesyloxy)
amines 12 were formed exclusively.
Only N-ethylamine 12b did not cyclize without side
reactions when treated with potassium carbonate in
DMSO at 85 °C. Functionalized azetidine 13b was the
major product in the reaction mixture, but it was
contaminated with the imidoyl-substituted alkyne 18,
which was isolated in 22% yield after flash chromatog-
raphy. It seemed likely that the reaction occurred via
an intermediate R-chloro imine 16, which can be formed
(22) For previous syntheses of 2-cyanoazetidines see: (a) Masuda,
T.; Chinone, A.; Ohta, M. Bull. Chem. Soc. J pn. 1970, 43, 3281-3282.
(b) Chen, T.-Y.; Hung, M.-H.; Chen, P.-T.; Ohta, M. Bull. Chem. Soc.
J pn. 1972, 45, 1179-1183. (c) Guillemin, J . C.; Denis, J . M.; Lablanche-
Combier, A. J . Am. Chem. Soc. 1981, 103, 468-469. (d) Shiozaki, M.;
Maruyama, H.; Ishida, N. Heterocycles 1984, 22, 1725-1726; Chem.
Abstr. 1984, 101, 191455p. (e) Shono, T.; Matsumura, Y.; Uchida, K.;
Nakatani, F. Bull. Chem. Soc. J pn. 1988, 61, 3029-3031.
(23) Gold, E. H.; Solomon, D. M. Ger. Offen. 2,548,053 (Cl. C07D205/
04), 6 May 1976, US Appl. 519,396, 30 Oct 1974; Chem. Abstr. 1976,
85, 46359g.
(21) An ORTEP diagram is included in the Supporting Information.
The authors have deposited atomic coordinates for these structures
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

Convenient Synthesis of 3,3-Dichloroazetidines
J . Org. Chem., Vol. 63, No. 1, 1998
9
Sch em e 6
Sch em e 7
3-position and the steric influence imposed by the aryl
groups contribute to the fact that compounds 13g-i are
stable 2-methoxyazetidines.
The nucleophilic attack of cyanide and methoxide
across the imino function and following cyclization into
four-membered azaheterocyclic rings 13d -i was found
to be highly stereoselective. X-ray crystallographic analy-
sis revealed that the relative position of the two aryl
groups at C2 and C4 of the azetidines 13d -i was cis, as
exemplified by azetidine 13f.21
Sch em e 8
The reaction of 2-methoxyazetidine 13g with lithium
aluminum hydride in ether afforded 3-chloroazetidine 19
by nucleophilic substitution of the methoxy group by
hydride via an azetinium intermediate (neighboring
group participation of the adjacent amino group)12 and
subsequent conversion of the geminal dichloro derivative
to the monochlorinated azetidine 19 via a single electron-
transfer reaction25 (Scheme 6). Some other minor com-
ponents (probably ring-opening products), although clearly
present in the reaction mixture (1H NMR), could not be
isolated in pure form. The spectroscopic data indicated
that 3-chloroazetidine 19 is a symmetrical molecule.
Only one chemical shift value is observed for the protons
at C-2 and C-4. Also taking into account that a NOE
effect between the vicinal protons at C-2, C-3, and C-4
was observed, the configuration of 3-chloroazetidine 19
can be depicted as cis-3-chloro-cis-2,4-diphenylazetidine
(Scheme 6).
Although the Cram steric model for 1,3-induction has
been widely recognized,26 we suggest that the observed
stereoselectivity (8 f 12 f 13a -c and 8 f 13d -i) is
best rationalized by a steric model proposed by Evans,27
based on a study by J acques and co-workers28 (Scheme
7). In this model, (a) staggered rather than eclipsed
transition structures 20 are preferred, having an anti
orientation between Câ and the forming bond,29 and (b)
the dominant destabilizing interactions are between the
imidoyl carbon substituent (R) and the â-aryl substitu-
ents (Scheme 7).
stable product formed in a subsequent equilibration.
Indeed, one might propose that in a first step a nonste-
reospecific addition occurs, providing a mixture of 1,3-
syn- and 1,3-anti-adducts 21, which lead to cis- and trans-
2,4-diarylazetidines 22 after ring closure (Scheme 8).
Subsequent equilibration via the azetinium intermediate
23 and attack of the nucleophile at the opposite side of
the 4-aryl substituent also gives cis-2,4-diarylazetidines
13d -i exclusively. Evidently, this is only applicable to
the synthesis of 2-cyano- and 2-methoxyazetidines 13d -i
where the reacting nucleophile is also a leaving group.
In conclusion, the reaction of 3,3-dichloro-1-azaallylic
carbanions with aromatic aldehydes and subsequent
mesylation leads to R,R-dichloro-â-(mesyloxy) ketimines
that were converted into rare classes of azetidines,
including 3,3-dichloroazetidines and 2-methoxyazetidines,
in a highly stereoselective way.
Of course, this rule applies only to reactions that are
kinetically controlled, i.e., where the product isolated is
that formed in a rate-controlled process, not the more
(24) For previous syntheses of 2-methoxyazetidines see: (a) Zeifman,
Y. V.; Gambaryan, N. P.; Simonyan, L. A.; Minasyan, R. B.; Knunyants,
I. L. Zh. Obshch. Khim. 1967, 37, 2476-2486; Chem. Abstr. 1968, 69,
2919e. (b) Mitzlaff, M.; Warning, K.; J ensen, H. Ger. Offen. 2,539,777
(Cl. C07D211/40), 17 Mar 1977, Appl. 06 Sep. 1975; Chem. Abstr. 1977,
87, 5820y. (c) Mitzlaff, M.; Warning, K.; J ensen, H. Liebigs Ann. Chem.
1978, 1713-1733. (d) Cabral, J .; Laszlo, P.; Montaufier, M. T.
Tetrahedron Lett. 1988, 29, 547-550.
(25) Ashby, E. C.; Deshpande, A. K. J . Org. Chem. 1994, 59, 3798-
3805.
(26) Leitereg, T. J .; Cram, D. J . J . Am. Chem. Soc. 1968, 90, 4011-
4026.
(27) Evans, D. A.; Dart, M. J .; Duffy, J . L. Tetrahedron Lett. 1994,
35, 8541-8544.
Exp er im en ta l Section
(28) Brienne, M.-J .; Ouannes, C.; J acques, J . Bull. Soc. Chim. Fr.
1968, 1036-1047.
1H and 13C NMR spectra were recorded at 270 and 68 MHz.
The type of carbon and hydrogen atom was determined via
DEPT and 13C-1H and 1H-1H COSY techniques. Mass
spectra were performed at 70 eV. Ether and THF were freshly
(29) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T.; Eisenstein, O. Nouv. J . Chim. 1977, 1, 61-
70.

10 J . Org. Chem., Vol. 63, No. 1, 1998
Aelterman et al.
distilled from sodium wire and sodium benzophenone ketyl,
respectively. Melting points are uncorrected.
was purified by recrystallization (pentane/ether 4/1) to afford
3.12 g (77%) of pure white needles.
N-[2,2-Dich lor o-3-(m esyloxy)-1,3-d ip h en yl-1-p r op yli-
d en e]isop r op yla m in e (8a ): mp 115 °C; 1H NMR (CDCl3) δ
1.09 and 1.16 (2 × 3H, 2 × d, J ) 6.27 Hz, Me2CH), 2.76 (3H,
s, MeSO2), 3.31 (1H, septet, J ) 6.27 Hz, CHMe2), 6.83 (1H, s,
CHO), 7.00-7.20, 7.34-7.47, and 7.68-7.76 (10H, m, 2 ×
C6H5); 13C NMR (CDCl3) δ 23.0 and 23.1 (Me2CH), 39.9
(MeSO2), 54.2 (CHMe2), 85.0 (CHO), 89.4 (CCl2), 127.8, 127.9,
128.1, 128.8, 129.8, and 130.6 (Co, Cm, and Cp), 133.3 and 133.9
(Cq), 163.1 (CdN); IR (KBr) 1636 cm-1 (CdN); MS m/z no M+,
378/380 (M+ - Cl; 5), 172 (5), 146 (55), 107 (6), 104 (100), 77
(10), 43 (9). Anal. Calcd for C19H21Cl2NO3S: C, 55.07; H, 5.11;
N, 3.38. Found: C, 55.19; H, 5.01; N, 3.44.
Syn th esis of 3-(Mesyloxy) Am in es 12. The synthesis of
N-isopropyl-N-(2,2-dichloro-3-(mesyloxy)-1,3-diphenylpropyl)-
amine (12a ) is representative (Table 1). To a solution of R,R-
dichloro-â-(mesyloxy) imine 8a (1.24 g, 3 mmol) in methanol
(15 mL) was added NaCNBH3 (0.47 g, 7.5 mmol), followed by
acetic acid (0.22 g, 3.6 mmol). The mixture was stirred for 24
h at room temperature, poured into a 0.5 N NaOH solution
(50 mL), and extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were dried (MgSO4) and evaporated
in vacuo to yield 1.21 g (97%) of crude 12a , which was washed
with 20 mL of a solution of pentane/ether (9/1) to give 1.10 g
(88%) of pure white solid.
Syn th esis of â-Hyd r oxy Im in es 7. The synthesis of
N-(2,2-dichloro-3-hydroxy-1,3-diphenyl-1-propylidene)iso-
propylamine (7a ) is representative (Table 1). To an ice- cooled
solution of diisopropylamine (3.51 g, 34.70 mmol) in THF (35
mL) was added under an N2 atmosphere n-BuLi (12.83 mL
2.5 M in hexane, 32.07 mmol) followed after 10 min by a
solution of N-(2,2-dichloro-1-phenyl-1-ethylidene)isopropy-
lamine (6a )16 (6.15 g, 26.70 mmol) in THF (25 mL). After 35
min of stirring at 0 °C, the reaction mixture was cooled to -15
°C and stirred additionally for 10 min at -15 °C. Then, a
solution of freshly distilled benzaldehyde (2.83 g, 26.70 mmol)
in THF (15 mL) was added dropwise. The mixture was
gradually warmed to 0 °C during 1 h and then poured into an
ice-cooled 0.5 N NaOH solution (150 mL) and extracted with
ether (3 × 100 mL), and the combined organic extracts were
dried with K2CO3. Evaporation of the solvent in vacuo yielded
8.04 g (90%) of crude 7a , which was purified by recrystalliza-
tion (pentane/ether 1/1) to afford 5.39 g (60%) of the pure
substance.
N -(2,2-Dich lor o-3-h yd r oxy-1,3-d ip h e n yl-1-p r op yli-
d en e)isop r op yla m in e (7a ): mp 112-113 °C; 1H NMR
(CDCl3) δ 1.12 and 1.13 (2 × 3H, 2 × d, J ) 6.1 Hz, Me2CH),
3.29 (1H, septet, J ) 6.1 Hz, CHMe2), 5.61 (1H, br s, CHOH),
6.12 (1H, br s, CHOH), 7.25-7.43 and 7.63-7.69 (10H, m, 2
× C6H5); 13C NMR (CDCl3) δ 23.1 and 23.2 (Me2), 53.1
(CHMe2), 79.5 (CHOH), 89.7 (CCl2), 127.3, 127.9, 128.4, 129.0,
and 130.0 (Co, Cm and Cp), 132.6 and 136.8 (Cq), 167.9 (CdN);
IR (KBr) 3120-3470 (OH), 1635 cm-1 (CdN); MS m/z no M+,
300/302 (M+ - Cl; 9), 194/196 (21), 146 (23), 106 (28), 105 (46),
104 (100), 77 (44). Anal. Calcd for C18H19Cl2NO: C, 64.32; H,
5.70; N, 4.17. Found: C, 64.41; H, 5.59; N, 4.29.
N -I s o p r o p y l-N -[2,2-d ic h lo r o -3-(m e s y lo x y )-1,3-d i-
p h en ylp r op yl]a m in e (12a ): mp 129 °C; 1H NMR (CDCl3) δ
0.98 and 1.10 (2 × 3H, 2 × d, J ) 6.27 Hz, Me2CH), 1.70-1.90
(1H, br s, NH), 2.60 (3H, s, MeSO2), 2.69 (1H, septet, J ) 6.27
Hz, CHMe2), 4.54 (1H, s, Cl2CCHN), 6.65 (1H, s, CHO), 7.28-
7.49 and 7.66-7.74 (10H, m, 10 × CHd); 13C NMR (CDCl3) δ
22.0 and 24.5 (Me2CH), 40.1 (MeSO2), 46.5 (CHMe2), 66.0
(Cl2CCHN), 83.5 (CHO), 95.1 (CCl2), 127.8, 128.0, 128.1, 129.9,
and 130.6 (Co, Cm, and Cp), 133.1 and 137.6 (Cq); IR (KBr) 3320
N-[2-Ch lor o-2,3-ep oxy-4-eth yl-1-p h en yl-1-h exylid en e]-
isop r op yla m in e (10). The same procedure as described for
the preparation of the â-hydroxy imines 7 provided 10 in 86%
yield (cis/trans : 1/1): 1H NMR (CDCl3) δ 0.92-1.29 (2 × 12H,
m, NCHMe2 and MeCH2), 1.35-1.82 (2 × 5H, m, CH(CH2Me)2),
2.88 and 3.11 (2 × 1H, 2 × d, J ) 8.58 Hz, CHO), 3.47 (1H,
septet, J ) 6.27 Hz, CHMe2), 4.37 (1H, septet, J ) 5.94 Hz,
(NH, weak), 1354, 1170 cm-1; MS m/z no M+; 319/321 (M+
-
OSO2Me; 7), 172 (13), 148 (20), 147 (59), 132 (100), 105 (15),
104 (20), 43 (18). Anal. Calcd for C19H23Cl2NO3S: C, 54.81;
H, 5.57; N, 3.36. Found: C, 54.98; H, 5.42; N, 3.44.
Rea ction of Am in es 7a -c w ith P ota ssiu m Ca r bon a te.
Syn th esis of 3,3-Dich lor oa zetid in es 13a-c. The synthesis
of 3,3-dichloro-1-isopropyl-2,4-diphenylazetidine (13a ) is rep-
resentative (Table 2). To a solution of â,â-dichloro-γ-(mesy-
loxy) amine 12a (0.62 g, 1.5 mmol) in DMSO (10 mL) was
added potassium carbonate (0.62 g, 4.5 mmol). The mixture
was stirred for 48 h at 90 °C, poured into H2O (30 mL), and
extracted with CH2Cl2 (4 × 15 mL). The combined organic
extracts were dried (MgSO4) and evaporated to give crude 3,3-
dichloroazetidine 13a as a solid material, which was purified
by recrystallization (pentane/ether 4/1) to afford 0.30 g (63%)
of pure crystals.
CHMe2), 7.16-7.47 and 7.85-7.89 (2 × 5H, 2 × m, C6H5); 13
C
NMR (CDCl3) δ 10.5, 11.0, and 11.1 (MeCH2), 23.1 and 23.4
(CHMe2), 21.7, 23.6 and 24.8 (CH2CH3), 40.2 (CHCH2), 52.3
and 52.5 (CHMe2), 65.4 and 67.0 (CHO), 75.5 and 83.4 (CCl),
127.6, 127.6, 128.2, 128.4, 128.9 and 129.9 (CHd), 134.2 and
136.0 (Cq), 157.9 and 162.5 (CdN); IR (NaCl) 1630-1640 cm-1
(CdN); MS m/z 293/5 (M+; 0.5), 146 (42), 104 (100), 77 (27),
51 (13), 43 (20). Anal. Calcd for C17H24ClNO: C, 69.49; H,
8.23; N, 4.77. Found: C, 69.57; H, 8.20; N, 4.66.
N -[3-Ch lor o-4-e t h yl-2-oxo-1-h e xylid e n e ]isop r op yl-
a m in e (11). This compound was formed during distillation
of the epoxide 10: bp 89-94 °C/0.015 mmHg; 1H NMR (CDCl3)
δ 0.89 and 0.99 (2 × 3H, 2 × t, J ) 7.4 Hz, 2 × MeCH2), 1.15
and 1.17 (2 × 3H, 2 × d, J ) 6.1 Hz, Me2CH), 1.35-1.65 (4H,
m, 2 × CH2CH3), 1.99-2.10 (1H, m, CHCHCl), 3.69 (1H,
septet, J ) 6.1 Hz, CHMe2), 5.92 (1H, d, J ) 5.28 Hz, CHCl),
7.03-7.15 and 7.30-7.46 (5H, m, C6H5); 13C NMR (CDCl3) δ
11.3 and 11.4 (MeCH2), 21.9 and 23.2 (2 × CH2), 23.4 and 23.5
(Me2CH), 44.0 (CHCHCl), 53.6 (CHMe2), 62.2 (CHCl), 127.5,
128.3, and 129.1 (CHd), 132.7 (Cq), 163.1 (CdN), 195.6 (CdO);
IR (NaCl) 1712 (CdO), 1626 cm-1 (CdN); MS m/z no M+; 258
(M+ - Cl, 1), 163 (6), 146 (33), 104 (100), 77 (31), 51 (14), 43
(18). Anal. Calcd for C17H24ClNO: C, 69.49; H, 8.23; N, 4.77.
Found: C, 69.51; H, 8.14; N, 4.69.
Syn th esis of â-(Mesyloxy) Im in es 8. The synthesis of
N-(2,2-dichloro-3-(mesyloxy)-1,3-diphenyl-1-propylidene)iso-
propylamine (8a ) is representative (Table 1). To a solution of
R,R-dichloro-â-hydroxy imine 7a (3.31 g, 9.85 mmol) in pyridine
(30 mL) was added dropwise at room temperature mesyl
chloride (1.69 g, 14.77 mmol). After 5 h of stirring at room
temperature, the reaction mixture was poured into an ice-
cooled 0.5 N NaOH solution (100 mL) and extracted with CH2-
Cl2 (3 × 75 mL). The organic layer was dried (MgSO4) and
evaporated in vacuo to give 8a as a crude solid product, which
3,3-Dich lor o-1-isop r op yl-2,4-d ip h en yla zetid in e (13a ):
1
mp 90-91 °C; H NMR (CDCl3) δ 0.85 (6H, d, J ) 6.27 Hz,
Me2), 2.84 (1H, septet, J ) 6.27 Hz, CHMe2), 4.73 (2H, s,
NCHCCl2), 7.33-7.45 (6H, m, Cm, and Cp), 7.61 (4H, dd, J )
7.92, 1.65 Hz, Co); 13C NMR (CDCl3) δ 21.6 (Me2), 59.2
(CHMe2), 80.8 (CCl2CHN), 85.2 (CCl2), 128.0, 128.3, and 128.5
(Co, Cm, and Cp), 137.6 (Cq); IR (KBr) 2965, 1452, 1330, 1025;
MS m/z 319/321/323 (M+; 5), 172 (11), 148 (12), 147 (58), 146
(17), 132 (100), 105 (15), 104 (19). Anal. Calcd for C18H19
-
Cl2N: C, 67.50; H, 5.98; N, 4.37. Found: C, 67.59; H, 6.09; N,
4.30.
3,3-Dich lor o-2-(4-ch lor op h en yl)-1-eth yl-4-p h en yla zeti-
d in e (13b). Purification by flash chromatography hexane/
ethyl acetate 98/2 (Rf ) 0.46): 1H NMR (CDCl3) δ 0.90 (3H, t,
J ) 7.26 Hz, Me), 2.75 and 2.77 (2 × 1H, 2 × q, J ) 7.26 Hz,
CH2), 4.60 and 4.64 (2 × 1H, 2 × s, CHN), 7.36-7.61 (9H, m,
Co, Cm, and Cp); 13C NMR (CDCl3) δ 13.7 (Me), 51.4 (CH2), 80.7
and 81.3 (CHN), 85.3 (CCl2), 128.0, 128.2, 128.4, 128.7, and
129.5 (Co, Cm, and Cp), 134.5, 134.8, and 136.0 (Cq); IR (NaCl)
1488, 1180, 1086, 1011, 696 cm-1; MS m/z 339/341/343 (M+;
9), 304/306 (38), 208 (34), 206 (35), 174 (67), 172 (100), 152
(71), 133 (72), 132 (95), 118 (87). Anal. Calcd for C17H16
-
Cl3N: C, 59.93; H, 4.73; N, 4.11. Found: C, 60.09; H, 4.61; N,
4.03.

Convenient Synthesis of 3,3-Dichloroazetidines
J . Org. Chem., Vol. 63, No. 1, 1998 11
N-[1-(4-Ch lor op h en yl)-3-p h en yl-2-p r op yn -1-ylid en e]-
eth yla m in e (18). This compound was formed as a byproduct
during the synthesis of (13b). Flash chromatography with
hexane/ethyl acetate 98/2 (Rf ) 0.24) afforded it as an oil: 1H
NMR (CDCl3) δ 1.38 (3H, t, J ) 7.4 Hz, Me), 3.94 (2H, q, J )
7.4 Hz, CH2), 7.35-7.46 and 7.58-7.63 (7H, m, Co, Cm, Cp),
8.02 (2H, d, J ) 8.58 Hz, 2 × CHd); 13C NMR (CDCl3) δ 15.6
(Me), 51.0 (CH2), 81.0 and 98.2 (CtC), 128.5, 128.6, 128.8,
129.8, and 132.2 (Co, Cm, and Cp), 121.4, 136.1, and 136.4 (Cq),
149.3 (CdN); IR (NaCl) 2196 cm-1 (CtC); MS m/z 267/269 (M+;
100), 266/268 (60), 191 (64), 139 (69), 128 (46), 125 (55), 115
(81). Anal. Calcd for C17H14ClN: C, 76.26; H, 5.27; N, 5.23.
Found: C, 76.13; H, 5.39; N, 5.39.
Rea ction of Im in es 8a -c w ith P ota ssiu m Cya n id e.
Syn th esis of 2-Cya n oa zetid in es 13d -f. The synthesis of
3,3-dichloro-2-cyano-1-isopropyl-2,4-diphenylazetidine (13d ) is
representative (Table 2). Potassium cyanide (0.39 g, 6 mmol)
was added to a solution of â-(mesyloxy) imine (8a ) (1.24 g, 3
mmol) in methanol (15 mL). The mixture was then refluxed
for 6 h after which it was cooled to room temperature, poured
into water (50 mL), and extracted with CH2Cl2 (3 × 30 mL).
The combined organic extracts were dried (MgSO4) and
evaporated to give crude 13d , which was purified by flash
chromatography (hexane/ethyl acetate 97/3; Rf ) 0.38) to afford
0.56 g (54%) of pure azetidine 13d .
3,3-Dich lor o-2-cya n o-1-isop r op yl-2,4-d ip h en yla zet i-
d in e (13d ): 1H NMR (CDCl3) δ 0.89 and 0.94 (2 × 3H, 2 × d,
J ) 6.27 Hz, Me2CH), 3.25 (1H, septet, J ) 6.27 Hz, CHMe2),
4.90 (1H, s, CCl2CHN), 7.38-7.60 and 7.80-7.88 (10H, m, 2
× C6H5); 13C NMR (CDCl3) δ 21.8 and 22.3 (Me2CH), 56.1
(CHMe2), 79.9 (CCtN), 80.2 (CCl2CHN), 85.7 (CCl2), 115.6
(CN), 127.8, 128.2, 128.3, 128.5, 129.3, and 130.1 (Co, Cm, and
Cp), 134.8 and 135.9 (Cq); IR (NaCl) 1451, 1390, 1237, 1188
cm-1; MS m/z 344/346/348 (M+; 6), 311 (10), 172 (100), 147
(40), 132 (56), 104 (29). Anal. Calcd for C19H18Cl2N2: C, 66.09;
H, 5.25; N, 8.11. Found: C, 66.16; H, 5.36; N, 8.01.
3,3-Dich lor o-2-(4-ch lor op h e n yl)-2-cya n o-1-e t h yl-4-
p h en yla zetid in e (13e). Purification by flash chromatogra-
phy hexane/ethyl acetate 98/2 (Rf ) 0.26): 1H NMR (CDCl3) δ
0.98 (3H, t, J ) 7.2 Hz, Me), 2.93 and 2.93 (2 × 1H, 2 × q, J
) 7.2 Hz, CH2), 4.86 (1H, s, NCH), 7.39-7.56 (7H, m, Co, Cm,
and Cp), 7.73 (2H, d, J ) 8.58 Hz, 2 × CHd); 13C NMR (CDCl3)
δ 13.8 (Me), 47.4 (CH2), 79.8 (CCtN), 80.4 (NCH), 86.1 (CCl2),
114.9 (CtN), 128.1, 128.4, 128.8, 128.9, and 129.5 (Co, Cm, Cp),
132.2, 133.9, and 136.4 (Cq); IR (NaCl) 2250 (CtN, weak),
1488, 760, and 698 cm-1; MS m/z 364/366/368 (M+; 1), 176 (19),
and Cp), 136.7 and 137.4 (Cq); IR (KBr) 1250, 1190, 1101, 870
cm-1; MS m/z 318 (M+ - OMe; 1), 177 (51), 176 (77), 162 (100)
105 (44), 104 (40), 77 (22). Anal. Calcd for C19H21Cl2NO: C,
65.15; H, 6.04; N, 4.00. Found: C, 65.24; H, 6.01; N, 4.12.
3,3-Dich lor o-2-(4-ch lor op h en yl)-1-et h yl-2-m et h oxy-4-
p h en yla zetid in e (13h ). This azetidine was obtained as an
oil (purity 95%) and could not be purified by recrystallization
or chromatography: 1H NMR (CDCl3) δ 1.01 (3H, t, J ) 7.3
Hz, MeCH2), 2.89 and 3.09 (2H, AB × q, J ) 12.3, 7.3 Hz, CH2),
3.42 (3H, s, OMe), 4.95 (1H, s, NCH), 7.31-7.60 (9H, m, C6H5
and C6H4), 13C NMR (CDCl3) δ 14.3 (MeCH2), 43.2 (CH2), 56.3
(OMe), 78.7 (NCH), 88.8 (CCl2), 102.1 (NCOMe), 127.7, 128.1,
128.3, 128.4, and 129.2 (Co, Cm and Cp), 134.5, 134.6, and 135.9
(Cq); IR (KBr) 1090, 1045, 698 cm-1; MS m/z 369/371/373 (M+;
11), 196 (75), 182 (36), 172 (42), 139 (49), 57 (44), 43 (100).
Anal. Calcd for C18H18Cl3NO: C, 58.32; H, 4.89; N, 3.78.
Found C, 58.19; H, 4.99; N, 3.61.
Syn th esis of 3-Ch lor oa zetid in e (19). To an ice-cooled
solution of 3,3-dichloroazetidine (13c) (0.35 g, 1 mmol) in
diethyl ether (5 mL) was added LiAlH4 (0.08 g, 2 mmol). The
mixture was stirred at room temperature for 8 h, poured into
ice-cooled water (30 mL), and extracted with diethyl ether (3
× 20 mL). The combined organic extracts were dried (MgSO4)
and evaporated in vacuo. The residual oil was purified by flash
chromatography to yield 0.08 g (28%) of pure 3-chloroazetidine
19 as white needles (hexane/ethyl acetate 96/4; Rf ) 0.42): mp
101 °C; 1H NMR (CDCl3) δ 0.80 (6H, d, J ) 6.3 Hz, Me2), 2.70
(1H, septet, J ) 6.3 Hz, CHMe2), 4.52 (2H, d, J ) 6.7 Hz,
CHNCH), 4.88 (1H, t, J ) 6.7 Hz, CHCl), 7.25-7.42 and 7.50-
7.59 (10H, m, 2 × C6H5); 13C NMR (CDCl3) δ 21.5 (Me2), 58.5
(CHCl), 58.8 (CHMe2), 68.7 (CHNCH), 127.6, 127.7, 128.6 (Co,
Cm, and Cp), 139.3 (Cq); IR (KBr) 1457, 763 cm-1; MS m/z 285/
287 (M+; 3), 250(14), 147 (19), 132 (100), 104 (13), 77 (9). Anal.
Calcd for C18H20ClN: C, 75.64; H, 7.05; N, 4.90. Found: C,
75.73; H, 6.98; N, 4.98.
X-r a y Cr ysta llogr a p h ic An a lysis of 13c.21 Pure crystals
were obtained by recrystallization from pentane/ether (4/1).
The principal crystallographic parameters of compound 13c
are as follows:21 M ) 334.27; monoclinic; space group P21/C;
a ) 5.925(2) Å, b ) 16.225(8) Å, c ) 18.739(10) A; R ) 90°, â
) 94.95(4)°, γ ) 90°; V ) 1795(2) A3; Z ) 4; Dc ) 1.237 g/cm3;
Mo KR; λ ) 1.541 78 A, µ ) 3.204 mm-1; F(000) ) 704. The
structure was refined to a final R ) 0.0782, Rw ) 0.2368 for
3225 reflections, I > 2σ(I).
X-r a y Cr ysta llogr a p h ic An a lysis of 13f.21 Pure crystals
were obtained by recrystallization from pentane/ether (4/1).
The principal crystallographic parameters of compound 13f
are as follows:21 M ) 359.28; monoclinic; space group P21/n;
a ) 10.897(7) Å, b ) 14.379(3) Å, c ) 12.105(11) A; R ) 90°, â
) 92.40(6)°, γ ) 90°; V ) 1895(2) A3; Z ) 4; Dc ) 1.259 g/cm3;
Mo KR; λ ) 0.710 69 A, µ ) 0.346 mm-1; F(000) ) 752. The
structure was refined to a final R ) 0.0460, Rw ) 0.1273 for
3730 reflections, I > 2σ(I).
172 (100), 132 (41), 118 (32), 84 (35). Anal. Calcd for C18H15
-
Cl3N2: C, 59.12; H, 4.13; N, 7.66. Found: C, 59.19; H, 4.02;
N, 7.69.
Rea ction of Im in es 8a -c w ith Sod iu m Bor oh yd r id e.
Syn th esis of 2-Meth oxya zetid in es 13g-i. The synthesis
of 3,3-dichloro-1-isopropyl-2-methoxy-2,4-diphenylazetidine (13g)
is representative (Table 2). To a solution of â-(mesyloxy) imine
(8a ) (0.82 g, 2 mmol) in methanol (10 mL) was added sodium
borohydride (0.15 g, 4 mmol). After 30 h of reflux, the mixture
was poured into water (50 mL) and extracted with CH2Cl2 (3
× 30 mL). The combined organic extracts were dried (MgSO4)
and evaporated to give crude 13g as a solid material, which
was purified by recrystallization (pentane/ether 4/1) to afford
0.46 g (66%) of pure product.
3,3-Dich lor o-1-isop r op yl-2-m eth oxy-2,4-d ip h en yla zeti-
d in e (13g): mp 89 °C; 1H NMR (CDCl3) δ 1.01 and 1.15 (2 ×
3H, 2 × d, J ) 6.4 Hz, Me2CH), 3.49 (1H, septet, J ) 6.4 Hz,
CHMe2), 3.50 (3H, s, OMe), 5.16 (1H, s, CHCCl2), 7.26-7.70
(10H, m, 2 × C6H5); 13C NMR (CDCl3) δ 20.9 and 24.4 (Me2-
CH), 48.2 (CHMe2), 56.5 (OMe), 76.4 (CHCCl2), 89.5 (CCl2),
103.7 (NCOMe), 127.7, 128.0, 128.4, 128.5, and 128.8 (Co, Cm,
Ack n ow led gm en t. We are indebted to the Fund for
Scientific Research-Flanders (Belgium) and the I.W.T.
for financial support.
Su p p or tin g In for m a tion Ava ila ble: An ORTEP presen-
tation for 13c and 13f. Detailed 1H NMR, 13C NMR, IR, and
MS data for all compounds 7, 8, 10-13, 17, and 19 (13 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
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