J . Org. Chem. 1999, 64, 6989-6992
6989
2-Ch lor o-1,3-d im eth ylim id a zolin iu m Ch lor id e. 2. Its Ap p lica tion to
th e Con str u ction of Heter ocycles th r ou gh Deh yd r a tion Rea ction s
Toshio Isobe
Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd., 6-11-24 Tsudanuma,
Narashino, Chiba 275-0016, J apan
Tsutomu Ishikawa*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, J apan
Received February 3, 1999
2-Chloro-1,3-dimethylimidazolinium chloride (DMC) (1) can act as a powerful dehydrating equivalent
to DCC (2) under nearly neutral conditions. Its application to the construction of heterocycles
through dehydration reactions is described.
Ch a r t 1
In tr od u ction
In the preceding paper in this issue1 we showed that
2-chloro-1,3-dimethylimidazolinium chloride (DMC) (1)
was a good dehydrating agent and that 1 could be
superior to dicyclohexylcarbodiimide (DCC) (2) (Chart 1).
In this paper we describe the additional capability of 1
to construct heterocycles based on dehydration reactions.
Ta ble 1. Effectivity of DMC An a logu es on P r ep a r a tion
of a Syd n on e fr om a n N-Nitr oso-N-p h en ylglycin e
Resu lts a n d Disscu sion
Syd n on e Syn th esis. It is well-known that sydnones
are easily synthesized by the cyclodehydration of N-
substituted N-nitroso-R-amino acids.2 Thus, we at first
compared the versatility of DMC (1) to that of related
reagents3 such as the bromo equivalent in the prepara-
tion of 1,2,3-oxadiazole (sydnone) from N-nitroso-N-
phenylglycine. Treatment of the N-nitroso derivative with
either 1 or its analogues under standard conditions1 led
to the expected cyclodehydration (Table 14). The sydnone
was prepared in an excellent yield, when either 1 (run 1
in Table 1) or its hexafluorophosphate derivative (run 2
in Table 1) was used. On the other hand, use of the bromo
analogues resulted in moderate yields (runs 3 and 4 in
Table 1). The unsatisfactory yields obtained in the latter
cases could be due to the instability of the bromo
equivalent of 1. Therefore, we decided to use DMC (1) in
the following heterocycle constructions.
a
Nonoptimized, isolated yield.
F ou r -Mem ber ed Rin gs: Azetid in -2-on e Con str u c-
tion . There are numerous modifications for the prepara-
tion of azetidin-2-ones by interaction of acid halides with
imines in the presence of bases,5 and a wide variety of
â-lactams are available by these reactions. We attempted
their preparation from carboxylic acids using DMC (1).
Carboxylic acids were treated with imines in the presence
of 1 and triethylamine to afford expected â-lactams in
good yields (Table 26). It is known that the stereochem-
istries of the products are dependent upon the substit-
uents present on the carboxylic acids used. In our case a
similar tendency was observed.7
(1) Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6984.
(2) Clapp, L. B. In Comprephensive Heterocyclic Chemistry; Katritz-
ky, A., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984, Vol. 6, pp
376-378.
(3) 2-Chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP)
was prepared by treatment of an aqueous solution of DMC (1) with
ammonium hexafluorophosphate (NH4PF6). It was obtained as non-
hygroscopic colorless prisms, mp 231 °C dec [see Okamura, H.;
Kawamoto, H.; Shiraishi, H. Eur. Patent EP 162308, 1985; Chem.
Abstr. 1986, 104, 159540. Kiso, Y.; Fujiwara, Y.; Kimura, T.; Nishitani,
A.; Akaji, K. Int. J . Peptide Protein Res. 1992, 40, 308]. CIP is now
commercially available from Fluka (¥17500/5 g in J apan: this corre-
sponds to $145.8/5 g, based on the exchange rate of ¥120/$ of J apanese
yen to U.S. dollars). Other DMC analogues were similarly synthesized
from the corresponding reactants and/or reagents according to the
preparation method of 1 (see the Supporting Information).
(4) Reference to the product in Table 1 is as follows. Thoman, C. J .;
Voaden, D. J . Organic Syntheses; Wiley: New York, 1973; Collect. Vol.
V, p 962.
(5) Davies, D. E.; Storr, R. C. In Comprephensive Heterocyclic
Chemistry; Katritzky, A., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 7, pp 247-267.
(6) References to the products in Table 2 are as follows. (a) Runs 1,
3, and 5: Georg, G. I.; Mashava, P. M.; Guan, X. Tetrahedron Lett.
1991, 32, 581. (b) Run 2: Isobe, T. J pn. Kokai Tokkyo Koho J P 07
330721, 1995; Chem. Abstr. 1996, 124, 289241. (c) Run 4: Arrieta, A.;
Aizpurua, J . M.; Palomo, C. Tetrahedron Lett. 1984, 25, 3365.
10.1021/jo9909756 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/24/1999