Triphosgene, an efficient acid activator for the Staudinger reaction

Article abstract of DOI:10.1016/S0040-4039(99)02074-2

An efficient one-step synthesis of β-lactams by the reaction of imines with acids in the presence of triphosgene and triethylamine has been described.

Full text of DOI:10.1016/S0040-4039(99)02074-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 417–419
Triphosgene, an efficient acid activator for the Staudinger
reaction
D. Krishnaswamy, B. M. Bhawal and A. R. A. S. Deshmukh ∗
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India
Received 30 September 1999; accepted 2 November 1999
Abstract
An efficient one-step synthesis of β-lactams by the reaction of imines with acids in the presence of triphosgene
and triethylamine has been described. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: triphosgene; Staudinger reaction; azetidinones; ketenes; imines.
During the last decade, triphosgene [bis(trichloromethyl)carbonate] has become a versatile synthetic
auxiliary for the synthesis of some important classes of organic compounds.1 This white crystalline
compound has proven to be safe and advantageous over its gaseous congener, phosgene. As a part of
our on-going program on the synthesis and development of methodologies for β-lactam synthesis, we
herein report, for the first time, the efficient use of triphosgene as an acid activator in the construction of
β-lactams via ketene–imine cycloaddition reactions (Staudinger reaction).
Among the several methods for the synthesis of β-lactams, the cycloaddition of ketenes with imines for
the construction of β-lactam rings has found wide acceptance.2 This is mainly because of its simplicity,
predictability of stereochemical outcome and the proven utility of this method for the synthesis of a large
number of monocyclic, bicyclic, tricyclic, and spirocyclic β-lactams.3 The ketenes are usually generated
from acid halides (preformed or generated in situ) in the presence of tertiary amines. Alternatively,
acid activating reagents2 like chloroformates,4 trifluoroacetic anhydride,5 p-TsCl,6 phosphorous derived
reagents,7 the Mukaiyama reagent,8 cyanuric chloride,9 etc. have been used.
Triphosgene is known to react with acids to produce acid chlorides or anhydrides.10 We have
successfully employed this reagent for one-step cycloaddition reactions of acids and imines to give β-
lactams.11 This reaction was found to be very clean and gave excellent yields of β-lactams (Scheme 1).
Moreover, this reagent was shown to be better than other acid activators in terms of yield and simplicity
of the work-up procedure.
In most of the cases, pure products were isolated by filtration of the reaction mixture through a short
silica gel column. Several β-lactams were synthesized in very good yields using this reagent (Table 1). In
∗
Corresponding author. Tel: +91-20-5893153; fax: +91-20-5893153; e-mail: arasd@dalton.ncl.res.in (A. R. A. S. Deshmukh)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02074-2
tetl 16002

418
Scheme 1.
all the cases the cycloaddition reaction was found to be stereoselective and only cis-β-lactam formation
was observed. This method can also be applied for the synthesis of β-lactams derived from Dane salt (see
entry 10) and acids which are sensitive to mineral acids or thionyl chloride (see entry 9).
Table 1
Synthesis of β-lactams (3a–j) from acids (1) and imines (2)
Acknowledgements
One of the authors (D.K.) thanks CSIR, New Delhi, for financial support.
References
1. Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic, V. Synthesis 1996, 553.
2. Georg, G. I.; Ravikumar, V. In The Organic Chemistry of β-lactams; Georg, G. I., Ed.; VCH: New York, 1993; p 295 and
references cited therein.
3. (a) Manhas, M. S.; Amin, S. G.; Bose, A. K. Heterocycles 1976, 5, 669. (b) Caroll, R. D.; Reed, L. L. Tetrahedron Lett.
1975, 3435. (c) Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277.
4. Bose, A. K.; Manhas, M. S.; Amin, S. G.; Kapur, J. C.; Kreder, J.; Mukkavilli, L.; Ram, B.; Vencent, J. E. Tetrahedron Lett.
1979, 2771.

419
5. Bose, A. K.; Kapur, J. C.; Sharma, S. D.; Manhas, M. S. Tetrahedron Lett. 1973, 2319.
6. Miyake, M.; Tokutake, N.; Kirisawa, M. Synthesis 1983, 833.
7. (a) Cossio, F. P.; Lecea, B.; Palomo, C. J. Chem. Soc., Chem. Commun. 1987, 1743. (b) Arrita, A.; Lecea, B.; Cossio, F. P.;
Palomo, C. J. Org. Chem. 1988, 53, 3784. (c) Manhas, M. S.; Lal, B.; Amin, S. G.; Bose, A. K. Synth. Commun. 1976, 6,
435. (d) Shridar, D. R.; Ram, B.; Narayana, V. L. Synthesis 1982, 63. (e) Cossio, F. P.; Ganboa, I.; Garcia, J. M.; Lecea, B.;
Palomo, C. Tetrahedron Lett. 1987, 28, 1945.
8. George, G. I.; Mashava, P. M.; Guan, X. Tetrahedron Lett. 1991, 32, 581.
9. Manhas, M. S.; Bose, A. K.; Khajavi, M. S. Synthesis 1981, 209
10. (a) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894. (b) Kotz, R.; Roestemadji, J.; Mobashry, S. J. Org.
Chem. 1994, 59, 2913.
11. Typical procedure: To a solution of acid 1 (1.5 mmol), imine (1 mmol) and triethylamine (6 mmol) in dry CH2Cl2 (10 ml), a
solution of triphosgene (1 mmol) in dry CH2Cl2 (5 ml) was added at −40°C over a period of 20 min and the mixture allowed
to warm up to room temperature and stirred for 12 h. The reaction mixture was washed successively with water (20 ml), satd
NaHCO3 (20 ml) and brine (10 ml). The organic layer was dried (Na2SO4), filtered through short column of silica gel and
the solvent was removed to give the crude product, which was purified either by crystallization or column chromatography
to give the β-lactams (3a–j) in 65 to 95% yields.
12. Ahluwalia, V. K.; Mallika, N.; Singh, R.; Mehta, V. D. J. Indian Chem. Soc. 1989, 66, 200.