A novel entry toward 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines by ring transformation of 2-(thiocyanomethyl)aziridines

Article abstract of DOI:10.1021/jo048486f

(Chemical Equation Presented). A new, efficient, and straightforward synthesis of 3-arylmethyl-4-chloromethyl-2-imino-1,3-thiazolidines and 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines has been developed by ring transformation of 1-arylme

Full text of DOI:10.1021/jo048486f

A Novel Entry toward 2-Imino-1,3-thiazolidines and
2-Imino-1,3-thiazolines by Ring Transformation of
2-(Thiocyanomethyl)aziridines
Matthias D’hooghe, Alex Waterinckx, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@UGent.be
Received August 30, 2004
A new, efficient, and straightforward synthesis of 3-arylmethyl-4-chloromethyl-2-imino-1,3-
thiazolidines and 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines has been developed
by ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines upon treatment with a
catalytic amount of titanium(IV) chloride in dichloromethane. The latter 2-(thiocyanomethyl)-
aziridines were prepared in high yields from 1-arylmethyl-2-(bromomethyl)aziridines by reaction
with potassium thiocyanate in DMF. The 2-imino-1,3-thiazolidines and 2-(N-acylimino)-1,3-
thiazolidines thus obtained can be easily interconverted, either by treatment with an acid chloride
and a base in ether toward 2-(N-acylimino)thiazolidines or by treatment with potassium carbonate
in methanol toward N-deprotected 2-iminothiazolidines. Dehydrohalogenation of 2-(N-acylimino)-
3-arylmethyl-4-chloromethyl-1,3-thiazolidines by means of potassium tert-butoxide in DMSO
afforded 2-(N-acylimino)-4-methyl-2,3-dihydro-1,3-thiazolines in good yields.
Introduction
ties.3 The unsaturated 2-imino-1,3-thiazolines in their
turn have also drawn the attention of the pharmaceutical
chemistry, featuring important biological activities such
as antimicrobial, anti-inflammatory, antihistaminic, an-
tihypertensive, hypnotic, and anticonvulsant activity, and
very recently for their applicability for the identification
of human cells with positive myeloperoxidase reactivity.4
Furthermore, thiazolines have interesting applications
in agriculture as acaricides, insecticides, and plant
growth regulators.5
The enhanced prevalence of infectious diseases and the
rapid emergence of multi-drug-resistant strains has
become a major concern in medicine worldwide, and this
evolution has imposed a significant threat upon public
health. Therefore, the development of new potential
drugs to counteract the advancing resistance is one of
the key issues and challenges for medicinal chemistry
and related disciplines nowadays. In view of the fact that
heterocyclic compounds in general and thiazolidines and
thiazolines in particular exhibit a wide variety of biologi-
cal activities, the search for new strategies toward the
latter entities is of significant importance. An impressive
list of physiological activities illustrates the relevance of
2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines as
target compounds in organic synthesis. 2-Imino-1,3-
thiazolidines are known and appreciated for their anti-
inflammatory, anodyne, and anti-Alzheimer activity.1
Some thiazolidines are also used in agriculture as
pesticides, such as the insecticide thiacloprid,2 and others
against γ-radiation as a result of their protective proper-
(1) (a) Takagi, M.; Ishimitsu, K.; Nishibe, T. PCT Int. Appl. WO
0172723 A1, 2001; Chem. Abstr. 2001, 135, 288773. (b) Latli, B.;
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303904. (c) Tomizawa, M.; Cowan, A.; Casida, J. E. Toxicol. Appl.
Pharmacol. 2001, 177, 77.
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10.1021/jo048486f CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/10/2004
J. Org. Chem. 2005, 70, 227-232
227

D’hooghe et al.
SCHEME 1
In the literature, several strategies for the synthesis
of thiazolidines and thiazolines are known. A general
approach toward 2-imino-1,3-thiazolidines involves the
intramolecular cyclization of N-(2-hydroxyethyl)thiourea
derivatives in acetic medium or, alternatively, in the
presence of triphenylphosphine and diethyl azodicar-
boxylate.6 2-Imino-1,3-thiazolidines have also been pre-
pared from aziridines upon treatment with thiocyanuric
acid,7 from 2-vinylaziridines in reaction with phenyl-
isothiocyanate,8 and from 1-(phenylthiocarbamoyl)aziri-
dines upon treatment with sodium iodide or acid cataly-
sis,9 although the latter transformation gave rise to
2-amino-4,5-dihydro-1,3-thiazoles rather than the iso-
meric 2-iminothiazolidines. The first reports on the
synthesis of 2-imino-1,3-thiazolines were published more
than a century ago and comprise condensation reactions
of R-haloketones with thiourea, in neutral or basic
medium, or with ammonium thiocyanate.10 The conden-
sation reaction of R-haloketones with thiourea under
acidic conditions gave rise to 2-iminothiazolines in ad-
dition to variable amounts of aminothiazoles as side-
products. The problem of isomerism emerged when it was
observed that methylation of the products obtained from
condensation of R-haloketones with thiourea or with
ammonium thiocyanate resulted in 2-imino-3-methyl-
thiazolines.10a,11 NMR studies a few decades ago con-
firmed that the initially reported condensation products
were in fact 2-amino-4,5-dihydrothiazoles rather than the
tautomeric 2-iminothiazolines.12 At present, the best
entries to 2-imino-1,3-thiazolines involve, first, alkylation
of 2-aminothiazoles obtained from the condensation of
R-haloketones with thiourea,11 second, the condensation
of R-haloketones with N-benzoyl N-substituted thio-
ureas,13 and third, the reaction of R-bromoketimines with
potassium thiocyanate.14 Less general approaches involve
the reaction of ketones with N-alkyl rhodanamines or bis-
benzyl formamidine disulfide15 or the reaction of R-chlo-
roketones with thiosemicarbazide in acid medium.16
In this report, a new, efficient, and straightforward
synthesis of both 2-imino-1,3-thiazolidines and 2-imino-
1,3-thiazolines is reported, starting from 1-arylmethyl-
2-(bromomethyl)aziridines via ring transformation of
1-arylmethyl-2-(thiocyanomethyl)aziridines in high over-
all yields and without the formation of undesired side
products.
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(b) Vittoria, D. M.; Mazzoni, O.; Piscopo, E.; Caligmano, A.; Bolognese,
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Abstr. 1989, 110, 192810. (b) Hoelzel, H.; Creuzburg, D.; Stohr, P.;
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Williahm, B.; Rabinovitz, J. Helv. Chim. Acta 1967, 50, 331. (c) Kim,
T. H.; Cha, M.-H. Tetrahedron Lett. 1999, 40, 3125.
Results and Discussion
1-Arylmethyl-2-(bromomethyl)aziridines 4 are readily
available substrates, suitable for diverse applications in
organic synthesis, prepared in a three-step procedure
starting from the appropriate aldehydes 1 (Scheme 1).17
Condensation of benzaldehydes 1 with 1.05 equiv of
allylamine in dichloromethane in the presence of mag-
nesium sulfate afforded the corresponding N-allylimines
2 in excellent yields (95-99%), which were distilled and
subsequently brominated by bromine in dichloromethane
to give N-(arylmethylidene)-2,3-dibromopropylamines 3
in a quantitative yield. The latter dibromoimines 3 were
used as such because of their instability and hence
treated with 2 equiv of sodium borohydride in methanol
under reflux for 2 h, furnishing 1-arylmethyl-2-(bromo-
methyl)aziridines 4 in high yields via reduction of the
(7) (a) Gabrie¨l, S.; Colman, J. Chem. Ber. 1914, 47, 1866. (b)
Mousseron, M.; Winternitz, F.; Dennilauer, R. Bull. Soc. Chim. Fr.
1956, 1228. (c) Wohl, R. A.; Headley, D. H. J. Org. Chem. 1972, 37,
4401.
(8) Butler, D. C.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65,
5887.
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V. Khim. Geterotsikl. Soedin. 1967, 1036; Chem. Abstr. 1968, 69, 52055.
(b) Jurasek, A.; Safar, P.; Zvak, V. Chem. Pap. 1988, 41, 693; Chem.
Abstr. 1988, 109, 37772.
(14) (a) De Kimpe, N.; Boelens, M.; Declercq, J.-P. Tetrahedron 1993,
49, 3411. (b) De Kimpe, N.; De Cock, W.; Keppens, M.; De Smaele, D.;
Me´sza´ros, A. J. Heterocycl. Chem. 1996, 33, 1179.
(15) (a) Schmitz, E.; Striegler, H. J. Prakt. Chem. 1970, 312, 359.
(b) Bhattacharya, A. K. J. Indian Chem. Soc. 1967, 44, 57.
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(b) Beyer, H.; La¨ssig, W.; Bulka, E.; Behrens, D. Chem. Ber. 1954, 87,
1392. (c) Beyer, H.; Wolter, G. Chem. Ber. 1956, 89, 1652.
(17) (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem.
Commun. 1994, 1221. (b) De Kimpe, N.; De Smaele, D.; Szakonyi, Z.
J. Org. Chem. 1997, 62, 2448. (c) Abbaspour Tehrani, K.; Nguyen Van,
T.; Karikomi, M.; Rottiers, M.; De Kimpe, N. Tetrahedron 2002, 58,
7145.
(9) (a) Campbell, M. M.; Craig, R. C. J. Chem. Soc., Perkin Trans.
1 1979, 766. (b) Iwakura, Y.; Nabeya, A.; Nishiguchi, T. J. Org. Chem.
1967, 32, 2362. (c) Nishiguchi, T., Tochio, H.; Nabeya, A.; Iwakura, Y.
J. Am. Chem. Soc. 1969, 99, 5835. (d) Vingiello, F. A.; Rorer, M. P.;
Ogliaruso, M. A. Chem. Commun. 1971, 329. (e) Nabeya, A.; Shigemoto,
T.; Iwakura, Y. J. Org. Chem. 1975, 40, 3536.
(10) (a) Hantzsch, A.; Weber, J. H. Ber. 1887, 20, 3118. (b) Trau-
mann, V. Liebigs Ann. Chem. 1888, 31.
(11) (a) Wilson, W.; Woodger, R. J. J. Chem. Soc. 1955, 2943. (b)
Birkinshaw, T. N.; Harkin, S. A.; Kaye, P. T.; Meakins, G. D.; Smith,
A. K. J. Chem. Soc., Perkin Trans. 1 1982, 939. (c) Bramley, S. E.;
Dupplin, V.; Goberdhan, D. G.; Meakins, G. D. J. Chem. Soc., Perkin
Trans. 1 1987, 639. (d) Krasovskii, V. A.; Burmistrov, S. I. Khim.
Geterotsikl. Soedin. 1969, 56; Chem. Abstr. 1969, 70, 115051.
(12) Weitzberg, M.; Aizensthat, Z.; Blum, J. J. Heterocycl. Chem.
1984, 21, 1597.
228 J. Org. Chem., Vol. 70, No. 1, 2005

2-Imino-1,3-thiazolidines and -thiazolines
SCHEME 2
SCHEME 3
imino bond and intramolecular nucleophilic substitution
(Scheme 1). The various nucleophilic interactions with
the constrained heterocyclic ring and with the haloge-
nated carbon atom of aziridines 4, combined with the
nucleophilicity of the aziridine nitrogen lone pair, allow
useful (intramolecular) reactions for the construction of
a variety of heterocyclic compounds. Despite the inherent
synthetic potential of 1-arylmethyl-2-(bromomethyl)aziri-
dines 4, the reactivity of these substrates has hardly been
investigated in the literature up to now.
N-Activated aziridines, such as 1-arenesulfonylaziri-
dines, are prone to undergo ring opening reactions upon
treatment with nucleophiles, resulting in a variety of
acyclic amines depending on the choice of the nucleo-
phile.18 Analogously, 1-arenesulfonyl-2-(bromomethyl)-
aziridines suffer ring opening upon treatment with a
nucleophile followed by intramolecular displacement of
bromine, instead of direct nucleophilic substitution.19
1-Alkylaziridines, however, are much less susceptible to
ring opening as a result of the absence of an electron-
withdrawing group at nitrogen, and treatment of 1-alkyl-
2-(bromomethyl)aziridines with one or more equivalents
of a nucleophile affords the corresponding 2-substituted
aziridines through a direct nucleophilic substitution at
the bromomethyl unit.20
Treatment of 1-arylmethyl-2-(bromomethyl)aziridines
4 with 2 equiv of the ambident nucleophile potassium
thiocyanate furnished 1-arylmethyl-2-(thiocyanomethyl)-
aziridines 5 in excellent yields (90-96%) after heating
for 20 h at 70 °C in DMF (Scheme 2). When the reaction
time was reduced to 10 or 15 h, small amounts of starting
material were still present. These 2-(thiocyanomethyl)-
aziridines 5 constitute a new and interesting class of
substrates for the synthesis of heterocyclic compounds
via intramolecular cyclization reactions due to the pres-
ence of an electrophilic center in δ-position of the nu-
cleophilic nitrogen atom. Indeed, addition of a catalytic
amount of the Lewis acid titanium(IV) chloride to a
solution of 2-(thiocyanomethyl)aziridines 5 in dichlo-
romethane afforded 3-arylmethyl-4-chloromethyl-2-imino-
1,3-thiazolidines 6 as single reaction products in high
yields (84-89%) after stirring for 2 h at room tempera-
ture. When a diluted aqueous hydrogen chloride solution
(2 N) was used instead of TiCl4, the isolated yield
amounted only 60%. Prolonged reaction times did not
result in improved yields. This reaction probably proceeds
through the formation of a bicyclic aziridinium salt 8
resulting from a nucleophilic attack of the lone pair of
nitrogen onto the electrophilic carbon atom of the thio-
cyano group, which is activated by the Lewis acid.
Subsequently, this aziridinium intermediate 8 undergoes
ring opening by chloride, furnishing a heterocyclic moiety
(Scheme 3). Although two possible pathways might occur,
only the route leading to a five-membered ring 6 appears
favorable (route a), since no traces of 2-imino-1,3-thiaz-
ines 9 were detected (route b). The structural identity of
the isolated compounds 6 was confirmed by detailed
spectroscopic analysis and by comparison of the NMR
data with literature references for analogous com-
pounds.14 It is noteworthy that the very sticky reaction
mixture, obtained after treatment of aziridines 5 with
TiCl4 and stirring for 2 h at room temperature, had to
(18) (a) Yus, M. Pure Appl. Chem. 2003, 75, 1453. (b) Stamm, H. J.
Prakt. Chem. 1999, 341, 319.
(19) (a) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62, 2671.
(b) Sweeney, J. B.; Cantrill, A. A. Tetrahedron 2003, 59, 3677. (c)
D’hooghe, M.; Kerkaert, I.; Rottiers, M.; De Kimpe, N. Tetrahedron
2004, 60, 3637.
(20) D’hooghe, M.; De Kimpe, N. Synlett 2004, 2, 271.
J. Org. Chem, Vol. 70, No. 1, 2005 229

D’hooghe et al.
TABLE 1. Synthesis of 2-(N-Acylimino)-3-arylmethyl-4-
SCHEME 4
chloromethyl-1,3-thiazolidines 7 from Aziridines 5
aziridines 5 R1
R2
R3
R
thiazolidines 7 yield (%)
5a
5b
5c
5d
5e
5a
5b
5e
5b
5c
5d
5e
H
H
H
Me
7a
7b
7c
7d
7e
7f
7g
7h
7i
95
96
94
95
96
92
91
88
87
84
91
88
H
H
MeO Me
H
MeO
H
H
H
H
H
Me
Me
Me
Ph
Br
Cl
H
H
H
H
Cl
H
H
Br
Cl
H
MeO Ph
H Ph
MeO EtO
H
H
H
H
H
MeO
H
EtO
MeO
MeO
7j
7k
7l
H
thiazolidine 7a was isolated in 56% yield, supporting the
assumption that TiCl4 delivers the nucleophilic chloride.
The merit of this approach concerns the possibility to
interconvert 3-arylmethyl-4-chloromethyl-2-imino-1,3-
thiazolidines 6 into 2-(N-acylimino)-3-arylmethyl-4-chlo-
romethyl-1,3-thiazolidines 7 and vice versa. Treatment
of 3-arylmethyl-4-chloromethyl-2-imino-1,3-thiazolidines
6 with 1.2 equiv of an acid chloride, e.g., acetyl chloride
or benzoyl chloride, in ether in the presence of 1.2 equiv
of Et3N afforded 2-(N-acylimino)-3-arylmethyl-4-chloro-
methyl-1,3-thiazolidines 7 after stirring for 2 h at room
temperature (Scheme 2). In this way, the presence of an
imino group (instead of a carbonyl group) in thiazolidines
6 was demonstrated unambiguously. The opposite con-
version of 2-(N-acylimino)-3-arylmethyl-4-chloromethyl-
1,3-thiazolidines 7 into 3-arylmethyl-4-chloromethyl-2-
imino-1,3-thiazolidines 6 comprises more synthetic
relevance. Treatment of 2-(N-acylimino)-1,3-thiazolidines
7 with 10 equiv of potassium carbonate in methanol
afforded 2-imino-1,3-thiazolidines 6 in 70% yield after
reflux for 1 h (Scheme 2). In this way, the mostly
crystalline and highly stable 2-(N-acylimino)-1,3-thiazo-
lidines 7 can be prepared very easily and efficiently and
converted into 2-imino-1,3-thiazolidines 6 in a simple
manner whenever the latter heterocycles are desired. The
presence of a chloromethyl moiety in thiazolidines 6 and
7 offers perspectives for the prospective synthesis of a
large variety of 4-substituted 2-imino-1,3-thiazolidines,
since the halogenated carbon atom might undergo sub-
stitution reactions by different types of nucleophiles.
An extra assignation for the molecular structure of
2-(N-acylimino)-1,3-thiazolidines 7 resulted from the
dehydrochlorination toward 2-(N-acylimino)-1,3-thiazo-
lines 10 (Scheme 4). Treatment of thiazolidines 7 with
1.02 equiv of sodium hydride in DMSO (dimsyl-Na)
furnished the corresponding thiazolines 10 after heating
for 1-3 h at 50-70 °C, although the reaction mixtures
thus obtained contained some undesired side products
in minor quantities. An excellent alternative for sodium
hydride appeared to be the combination of 1.02 equiv of
potassium tert-butoxide in DMSO, affording the pure
2-(N-acylimino)-4-methyl-2,3-dihydro-1,3-thiazolines 10
as single reaction products in high crude yields (95%).
Purification of thiazolines 10 by means of column chro-
matography in order to obtain analytically pure samples
proceeded in good yields (61-69%) (Scheme 4). It should
be remarked that the exocyclic double bond formed upon
dehydrochlorination moved from its initial position to-
ward the endocyclic position, probably as a result of the
aromatic stability of the resulting unsaturated hetero-
cycles.
be neutralized using a saturated sodium bicarbonate
solution until pH 7 upon stirring for 15 min, after which
the sticky paste became clear. Without this neutralization
step no thiazolidines or other products could be isolated
from the reaction mixtures. Attempts to purify 2-imino-
1,3-thiazolidines 6 using column chromatography in order
to obtain analytically pure samples failed, as these oily
compounds decomposed during the attempted purifica-
tion. Decomposition of thiazolidines 6 was also observed
upon prolonged preservation, even at low temperatures
(-20 °C).
When the same reaction was carried out in the pres-
ence of 2.5 equiv of an acid chloride, applying the original
reaction conditions (i.e., 0.4 equiv of TiCl4, 2 h at room
temperature), the starting 2-(thiocyanomethyl)aziridines
5 were converted into 2-(N-acylimino)-3-arylmethyl-4-
chloromethyl-1,3-thiazolidines 7 in high yields (84-96%)
(Scheme 2, Table 1). Different acid chlorides were evalu-
ated, such as acetyl chloride and benzoyl chloride, as well
as methyl and ethyl chloroformate. All derivatives were
isolated in high yields (Table 1). Thiazolidines 7 appeared
to be highly stable upon purification by means of column
chromatography and upon preservation for a long time,
without any loss of purity. These features illustrate why
thiazolidines 7 are very suitable target compounds in
organic synthesis, especially when large amounts are
needed. It should be noted that TiCl4 has to be added to
a solution of the starting aziridines 5 in CH2Cl2 before
the acid chloride, and not the other way around, to obtain
2-(N-acylimino)-1,3-thiazolidines 7 in the highest purity.
A neutralization step using a saturated sodium bicarbon-
ate solution was necessary, otherwise no thiazolidines
were isolated from the reaction mixtures. Reduction of
the amount of acid chloride (1.2 instead of 2.5 equiv)
resulted in the recovery of some starting material (15%).
Prolonged reaction times did not result in improved
yields, and heating the mixture to 40 °C resulted in
complex reaction mixtures. It is noteworthy that the
omission of TiCl4 in these reactions gave rise to rather
complex reaction mixtures in which the desired 2-imino-
thiazolidines 7 were present for approximately 50%,
besides a set of undesired side products. The introduction
of a chloro atom into the newly formed heterocycles 7
might originate from two different sources, namely,
titanium(IV) chloride on one hand and the acid chloride
on the other hand. When the acid chloride was replaced
by, e.g., acetic anhydride, in the presence of 0.4 equiv of
TiCl4, 2-acetylimino-4-chloromethyl-3-phenylmethyl-1,3-
230 J. Org. Chem., Vol. 70, No. 1, 2005

2-Imino-1,3-thiazolidines and -thiazolines
SCHEME 5
purified by distillation (bp 77 °C/0.1 mmHg). The spectroscopic
When the same dehydrochlorination procedure was
applied using 2-imino-1,3-thiazolidines 6 instead of 2-(N-
acylimino)-1,3-thiazolidines 7, i.e. KOtBu or NaH in
DMSO and heating at 55 °C for 1 h, no thiazolines 11
were isolated (Scheme 5). Depending on the amount of
base used, either no reaction occurred when 1 equiv of
base was added or a complex reaction mixture was
obtained when 2 equiv of base was added. These results
confirm the unstable nature of 3-arylmethyl-4-chloro-
methyl-2-imino-1,3-thiazolidines 6 and might give an
indication of the probably low stability of the target
2-imino-1,3-thiazolines 11. A similar drawback was
encountered when attempts were made to prepare 2-im-
ino-1,3-thiazolines 11 starting from 2-(N-acylimino)-1,3-
thiazolines 10 upon treatment with 10 equiv of potassium
carbonate in methanol and reflux for 1 h (Scheme 5). In
analogy with the conversion of 2-(N-acylimino)-3-aryl-
methyl-4-chloromethyl-1,3-thiazolidines 7 into 3-aryl-
methyl-4-chloromethyl-2-imino-1,3-thiazolidines 6 (Scheme
2), no thiazolines 11 were formed.
data of compounds 2a and 2b have been described elsewhere.17c
N-[(3-Methoxyphenyl)methylidene]-2-propenyl-
1
amine 2c. Colorless oil, 95% yield. Bp 75 °C/0.1 mmHg. H
NMR (270 MHz, CDCl3): δ 3.84 (3H, s); 4.24-4.27 (2H, m);
5.13-5.27 (2H, m); 5.99-6.14 (1H, m); 6.95-6.99 and 7.18-
7.45 (1H and 3H, 2 × m); 8.25 (1H, s). 13C NMR (68 MHz,
CDCl3): δ 55.2, 63.4, 111.5, 116.0, 117.5, 121.5, 129.5, 135.9,
137.6, 159.8, 161.8. IR (NaCl, cm-1): νCdN ) 1649; νmax ) 3076,
2958, 2836, 1583, 1262, 919, 786, 690. MS (70 eV) m/z (%) 175
(M+, 95), 174 (83), 160 (16), 144 (17), 136 (100), 107 (37), 77
(46), 68 (17), 65 (18), 51 (15), 41 (27). Anal. Calcd for C11H13-
NO: C 75.40; H 7.48; N 7.99. Found: C 75.22; H 7.31; N 8.13.
Synthesis of N-(Arylmethylidene)-2,3-dibromoopyl-
amines 3. As a representative example, the synthesis of N-[(2-
chlorophenyl)methylidene]-2,3-dibromopropylamine 3e is de-
scribed here. To a stirred, ice-cooled solution of N-[(2-chloro-
phenyl)methylidene]-N-(2-propenyl)amine 2e (17.84 g, 100
mmol) in dry dichloromethane (150 mL) was added slowely a
solution of bromine (16.31 g, 102 mmol, 1.02 equiv) in
dichloromethane (50 mL) during 30 min, followed by stirring
for 30 min at room temperature. Removal of the solvent in
vacuo afforded N-[(2-chlorophenyl)methylidene]-2,3-dibro-
mopropylamine 3e (33.77 g, 100 mmol, 100%), which was used
as such in the next step because of its lability.
Conclusions
A novel type of ring expansion toward 3-arylmethyl-
4-chloromethyl-2-imino-1,3-thiazolidines and 2-(N-acylim-
ino)-3-arylmethyl-4-chloromethyl-1,3-thiazolidines has
been developed by treatment of 1-arylmethyl-2-(thiocya-
nomethyl)aziridines with a catalytic amount of titanium-
(IV) chloride in dichloromethane. The latter substrates
were prepared from 1-arylmethyl-2-(bromomethyl)aziri-
dines and potassium thiocyanate in DMF in high yields,
demonstrating the synthetic versatility of these con-
strained heterocycles. The flexibility of this approach
involves the possibility to interconvert the highly stable
2-(N-acylimino)-3-arylmethyl-4-chloromethyl-1,3-thiazo-
lidines into less stable 3-arylmethyl-4-chloromethyl-2-
imino-1,3-thiazolidines and vice versa, either by treat-
ment with an acid chloride and a base in ether or by
treatment with potassium carbonate in methanol. De-
hydrohalogenation of 2-(N-acylimino)-3-arylmethyl-4-
chloromethyl-1,3-thiazolidines by means of potassium
tert-butoxide in DMSO afforded 2-(N-acylimino)-4-meth-
yl-2,3-dihydro-1,3-thiazolines in good yields.
N-[(4-Methoxyphenyl)methylidene]-2,3-dibromopro-
pylamine 3b. Yellow oil, 100% yield. 1H NMR (270 MHz,
CDCl3): δ 3.83 (3H, s); 3.87 (2H, d, J ) 6.3 Hz); 4.05 and 4.14
(2H, 2×d×d, J ) 13.2, 5.9, 4.3 Hz); 4.48-4.57 (1H, m); 6.94
and 7.77 (2×2H, 2×d, J ) 8.9 Hz); 8.26 (1H, s). 13C NMR (68
MHz, CDCl3): δ 34.2, 51.2, 55.4, 63.7, 114.2, 127.9, 130.5,
163.6, 164.6. IR (NaCl, cm-1): νCdN ) 1605; νmax ) 3006, 2960,
2936, 2839, 1512, 1255, 909, 832, 733. MS (70 eV): m/z (%)
333/5/7 (M+, 10), 254/6 (34), 194 (17), 148 (100), 121 (72), 91
(36), 77 (13). Decomposes partially or completely upon puri-
fication.
Synthesis of 1-Arylmethyl-2-(bromomethyl)aziridines
4. As a representative example, the synthesis of 1-(2-chlo-
rophenyl)methyl-2-(bromomethyl)aziridine 4e is described
here. To a stirred, ice-cooled solution of N-[(2-chlorophenyl)-
methylidene]-2,3-dibromopropylamine 3e (33.77 g, 100 mmol)
in methanol (300 mL) was added sodium borohydride (7.60 g,
200 mmol, 2 equiv) in small portions, followed by a reflux
period of 1 h. The reaction mixture was poured into water (100
mL), extracted with dichloromethane (3×50 mL), and dried
(MgSO4). Filtration of the drying agent and removal of the
solvent yielded 1-(2-chlorophenyl)methyl-2-(bromomethyl)-
aziridine 4e (24.21 g, 95 mmol, 95%). The spectroscopic data
of aziridines 4a and 4b have been described elsewhere.17c
2-(Bromomethyl)-1-[(3-methoxyphenyl)methyl]aziri-
dine 4c. Light-yellow oil, 81% yield. 1H NMR (270 MHz,
CDCl3): δ 1.64 (1H, d, J ) 5.9 Hz); 1.82 (1H, d, J ) 3.3 Hz);
1.91-1.98 (1H, m); 3.31 and 3.35 (2H, 2 × d × d, J ) 10.2,
6.9, 6.3 Hz); 3.40 and 3.54 (2H, 2 × d, J ) 13.4 Hz); 3.82 (3H,
s); 6.80-6.93 and 7.22-7.28 (3H and 1H, 2 × m). 13C NMR
(68 MHz, CDCl3): δ 35.2, 35.5, 40.2, 55.1, 64.0, 112.7, 113.5,
120.3, 129.3, 140.0, 159.6. IR (NaCl, cm-1): νmax ) 2938, 2834,
1601, 1585, 1489, 1265, 1154, 1048, 780, 693. MS (70 eV): m/z
(%) 255/7 (M+, 9), 176 (26), 122 (11), 121 (100), 91 (14). Anal.
Calcd for C11H14BrNO: C 51.58; H 5.51; N 5.47. Found: C
51.46; H 5.43; N 5.68.
Experimental Part
Synthesis of N-Arylmethylidene-N-(2-propenyl)amines
2. As a representative example, the synthesis of N-[(2-
chlorophenyl)methylidene]-N-(2-propenyl)amine 2e is de-
scribed here. To a stirred solution of 2-chlorobenzaldehyde 1e
(14.05 g, 100 mmol) and anhydrous MgSO4 (18.05 g, 150 mmol,
1.5 equiv) in dry dichloromethane (100 mL) was added
allylamine (6.03 g, 105 mmol, 1.05 equiv) at room temperature,
and the resulting mixture was stirred for 1 h under reflux.
Filtration of the cooled reaction mixture and removal of the
solvent in vacuo afforded N-[(2-chlorophenyl)methylidene]-N-
(2-propenyl)amine 2e (17.66 g, 99 mmol, 99%), which was
J. Org. Chem, Vol. 70, No. 1, 2005 231

D’hooghe et al.
Synthesis of 1-Arylmethyl-2-(thiocyanomethyl)aziri-
dines 5. As a representative example, the synthesis of 1-(2-
chlorophenyl)methyl-2-(thiocyanomethyl)aziridine 5e is de-
scribed here. To a solution of 2-(bromomethyl)-1-[(2-chloro-
phenyl)methyl]aziridine 4e (5.21 g, 20 mmol) in dimethylform-
amide (55 mL) was added potassium thiocyanate (1.94 g, 40
mmol, 2 equiv) at room temperature, and the resulting mixture
was stirred for 20 h at 70 °C. The cooled reaction mixture was
poured in brine (100 mL) and extracted with ethyl acetate
(3×50 mL). The combined organic extracts were washed with
brine (50 mL) and dried with MgSO4. Filtration of the drying
agent and evaporation of the solvent afforded 1-(2-chlorophen-
yl)methyl-2-(thiocyanomethyl)aziridine 5e (4.49 g, 18.8 mmol,
94%), wich was purified by means of column chromatography
(SiO2) (petrol ether/EtOAc/Et3N 40/9/1, Rf 0.36).
1-Phenylmethyl-2-(thiocyanomethyl)aziridine 5a. Col-
orless oil, 93% yield. 1H NMR (270 MHz, CDCl3): δ 1.68 (1H,
d, J ) 6.3 Hz); 1.89 (1H, d, J ) 3.3 Hz); 1.91-1.99 (1H, m);
2.85 and 3.09 (2H, 2 × d × d, J ) 13.1, 7.1, 4.9 Hz); 3.46 and
3.54 (2H, 2 × d, J ) 13.0 Hz); 7.25-7.38 (5H, m). 13C NMR
(68 MHz, CDCl3): δ 34.4, 37.2, 37.3, 63.8, 111.9, 127.1, 128.0,
128.2, 138.0. IR (NaCl, cm-1): νSCN ) 2154; νmax ) 3061, 3029,
2983, 2930, 2833, 1605, 1495, 1453, 1357, 1249, 738, 699. MS
(70 eV): m/z (%) 204 (M+, 2), 146 (20), 91 (100), 65 (10). Anal.
Calcd for C11H12N2S: C 64.67; H 5.92; N 13.71. Found: C
64.83; H 6.14; N 13.59.
Synthesis of 3-Arylmethyl-4-chloromethyl-2-imino-1,3-
thiazolidines 6. As a representative example, the synthesis
of 4-chloromethyl-3-(2-chlorophenyl)methyl-2-imino-1,3-thia-
zolidine 6e is described here. To a stirred, ice-cooled solution
of 1-(2-chlorophenyl)methyl-2-(thiocyanomethyl)aziridine 5e
(1.19 g, 5 mmol) in dry dichloromethane (25 mL) was added
dropwise titanium(IV) chloride (0.22 mL, 2 mmol, 0.4 equiv),
and the resulting mixture was stirred for 2 h at room
temperature. Afterward, the suspension was neutralized (pH
7) using a saturated solution of sodium bicarbonate, and the
sticky paste was stirred for 15 min until the precipitate
disappeared. Subsequently, the reaction mixture was filtered
over Celite, the filter cake was washed with dichloromethane
(3 × 20 mL), and the filtrate was extracted with dichlo-
romethane (3 × 25 mL). The combined organic extracts were
washed with brine (3 × 50 mL) and dried (MgSO4). Filtration
of the drying agent and removal of the solvent in vacuo
afforded 4-chloromethyl-3-(2-chlorophenyl)methyl-2-imino-1,3-
thiazolidine 6e (1.18 g, 4.3 mmol, 86%, purity > 95% based
on NMR).
4-Chloromethyl-3-phenylmethyl-2-imino-1,3-thiazoli-
dine 6a. Yellow oil, 87% yield. Purity > 95% (NMR). 1H NMR
(270 MHz, CDCl3): δ 3.22 (1H, d × d, J ) 11.2, 3.0 Hz); 3.36
(1H, d × d × d, J ) 11.2, 6.8, 1.0 Hz); 3.50 (1H, d × d × d,
J ) 11.1, 3.5, 1.0 Hz); 3.62 (1H, d × d, J ) 11.1, 8.9 Hz); 3.85-
3.92 (1H, m); 4.20 and 5.08 (2H, 2 × d, J ) 15.5 Hz); 7.28-
7.38 (5H, m); NH not detected. 13C NMR (68 MHz, CDCl3): δ
30.1, 41.9, 47.3, 62.0, 127.9, 128.7, 137.0, 163.0. IR (NaCl,
cm-1): νNH ) 3327; νCdN ) 1602; νmax ) 3092, 2952, 1494, 963,
735, 699. MS (70 eV): m/z (%) 241/3 (M+ + 1, 100), 91 (5).
Decomposes partially or completely upon purification.
(3 × 20 mL), and the filtrate was extracted with dichlo-
romethane (3 × 25 mL). The combined organic extracts were
washed with brine (3 × 50 mL) and dried (MgSO4). Filtration
of the drying agent and removal of the solvent in vacuo
afforded 2-acetylimino-4-chloromethyl-3-(2-chlorophenyl)methyl-
1,3-thiazolidine 7e (1.52 g, 4.8 mmol, 96%), which was purified
by means of column chromatography (SiO2) (petrol ether/
EtOAc 4/1, Rf 0.10).
Procedure B. To a stirred solution of 4-chloromethyl-3-(2-
chlorophenyl)methyl-2-imino-1,3-thiazolidine 6e (1.38 g, 5.0
mmol) and triethylamine (0.52 g, 5.1 mmol, 1.02 equiv) in dry
dichloromethane (50 mL) was added acetyl chloride (0.40 g,
5.1 mmol, 1.02 equiv) at room temperature, followed by a
stirring period of 2 h at room temperature. Afterward, the
suspension was neutralized (pH 7) using a saturated solution
of sodium bicarbonate, and the organic phase was washed with
brine (3 × 40 mL). Drying (MgSO4), filtration of the drying
agent, and removal of the solvent in vacuo afforded 2-acetyl-
imino-4-chloromethyl-3-(2-chlorophenyl)methyl-1,3-thiazoli-
dine 7e (1.48 g, 4.65 mmol, 93%), which was purified by means
of column chromatography (SiO2) (petrol ether/EtOAc 4/1, Rf
0.10).
2-Acetylimino-4-chloromethyl-3-phenylmethyl-1,3-thia-
zolidine 7a. Yellow oil, 95% yield. 1H NMR (270 MHz,
CDCl3): δ 2.24 (3H, s); 3.20-3.22 (2H, m); 3.49 and 3.61 (2H,
2 × d × d, J ) 11.6, 8.3, 3.3 Hz); 3.92-3.95 (1H, m); 4.33 and
5.46 (2H, 2 × d, J ) 15.2 Hz); 7.25-7.40 (5H, m). 13C NMR
(68 MHz, CDCl3): δ 27.4, 30.2, 41.6, 49.2, 59.8, 127.9, 129.0,
128.1, 135.9, 170.6, 182.7. IR (NaCl, cm-1): νCdN and νCdO
)
1635; νmax ) 3064, 3030, 2940, 1513, 1401, 1249, 910, 733, 701.
MS (70 eV): m/z (%) 282/4 (M+ + 1, 31), 239/41 (8), 206 (33),
191 (5), 164 (8), 136 (5), 104 (19), 103 (38), 91 (100), 65 (12),
61 (13). Anal. Calcd for C13H15ClN2OS: C 55.21; H 5.35; N
9.91. Found: C 55.06; H 5.53; N 9.84.
Synthesis of 2-(N-Acetylimino)-4-methyl-2,3-dihydro-
1,3-thiazoles 10. As a representative example, the synthesis
of 2-acetylimino-3-(2-chlorophenyl)methyl-4-methyl-2,3-dihy-
dro-1,3-thiazole 10e is described here. A mixture of 2-acetyl-
imino-4-chloromethyl-3-(2-chlorophenyl)methyl-1,3-thiazoli-
dine 7e (0.32 g, 1 mmol) and potassium tert-butoxide (0.11 g,
1.02 mmol, 1.02 equiv) in DMSO (15 mL) was heated for 1 h
at 55 °C. The cooled reaction mixture was poured into brine
(20 mL) and extracted with diethyl ether (3 × 30 mL). The
combined organic extracts were washed with brine (3 × 50
mL) and dried (MgSO4). Filtration of the drying agent and
removal of the solvent in vacuo afforded 2-acetylimino-3-(2-
chlorophenyl)methyl-4-methyl-2,3-dihydro-1,3-thiazole 10e (0.19
g, 0.67 mmol, 67%), which was purified by means of column
chromatography (SiO2) (petrol ether/EtOAc 7/3, Rf 0.17).
2-Acetylimino-3-phenylmethyl-4-methyl-2,3-dihydro-
1,3-thiazole 10a. Colorless crystals, 69% yield. Mp 119.5 °C.
1
Rf 0.15 (petrol ether/EtOAc 7/3). H NMR (270 MHz, CDCl3):
δ 2.17 (3H, d, J ) 1.1 Hz); 2.26 (3H, s); 5.44 (2H, s); 6.23 (1H,
d, J ) 1.1 Hz); 6.71-6.73, 6.80-6.83 and 7.21-7.27 (2H, 1H
and 1H, 3×m). 13C NMR (68 MHz, CDCl3): δ 14.2, 27.0, 49.0,
104.2, 126.7, 127.8, 128.8, 134.0, 135.9, 168.9, 180.5. IR (KBr,
cm-1): νCdN and νCdO ) 1586; νmax ) 2924, 2854, 1476, 1367,
1281, 950, 840, 729, 694. MS (70 eV): m/z (%) 247 (M+ + 1,
100), 205 (14), 91 (13). Anal. Calcd for C13H14N2OS: C 63.39;
H 5.73; N 11.37. Found: C 63.54; H 5.91; N 11.49.
Synthesis of 2-(N-Acylimino)-3-arylmethyl-4-chloro-
methyl-1,3-thiazolidines 7. As a representative example, the
synthesis of 2-acetylimino-4-chloromethyl-3-(2-chlorophenyl)-
methyl-1,3-thiazolidine 7e is described here.
Acknowledgment. The authors are indebted to the
“Fund for Scientific Research-Flanders (Belgium)”
(F.W.O.-Vlaanderen) and Ghent University (GOA project)
for financial support.
Procedure A. To a stirred, ice-cooled solution of 1-(2-
chlorophenyl)methyl-2-(thiocyanomethyl)aziridine 5e (1.19 g,
5 mmol) in dry dichloromethane (25 mL) was added dropwise
titanium(IV) chloride (0.22 mL, 2 mmol, 0.4 equiv). After 5
min, acetyl chloride (0.98 g, 12.5 mmol, 2.5 equiv) was added
dropwise at 0 °C, after which the mixture was stirred for 2 h
at room temperature. Afterward, the suspension was neutral-
ized (pH 7) using a saturated solution of sodium bicarbonate,
and the sticky paste was stirred for 15 min until the precipitate
disappeared. Subsequently, the reaction mixture was filtered
over Celite, the filter cake was washed with dichloromethane
Supporting Information Available: General information
and all spectroscopic data of compounds 2d,e, 3d,e, 4d,e, 5b-
e, 6b-e, 7b-l, and 10c-e. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO048486F
232 J. Org. Chem., Vol. 70, No. 1, 2005