New entry into β-lactams via reaction of dimethoxycarbene with isocyanates

Article abstract of DOI:10.1021/ol061101q

Highly substituted β-lactams have been isolated as the major product of the reaction of dimethoxycarbene with selected isocyanates. This reaction offers the potential for rapid access into a variety of highly functionalized species.

Full text of DOI:10.1021/ol061101q

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3121-3123
New Entry into
of Dimethoxycarbene with Isocyanates
â-Lactams via Reaction
James H. Rigby,* Jean-Christophe Brouet, Patrick J. Burke, Stephanie Rohach,
Shyama Sidique, and Mary Jane Heeg
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jhr@chem.wayne.edu
Received May 4, 2006
ABSTRACT
Highly substituted
â-lactams have been isolated as the major product of the reaction of dimethoxycarbene with selected isocyanates. This
reaction offers the potential for rapid access into a variety of highly functionalized species.
Nucleophilic carbenes have a characteristic reactivity profile
that differs markedly from other classes of carbenes.1 The
nucleophilic character of these reactive intermediates stems
from π-donation of heteroatom substituents flanking the
divalent carbene center.2 These species were traditionally
difficult to generate but have become much more accessible
with the advent of oxadiazoline precursors such as 1 and 2
(Scheme 1), which are reasonably stable and decompose
under controlled thermolysis conditions.3
Hydantoin or indolone species have been previously
reported as the primary products obtained from the reaction
of nucleophilic carbenes with isocyanates. The specific
pathway followed by these transformations depends on
factors such as the type of carbene employed and the
substitution pattern of the isocyanate. A typical example of
this reactivity diversity is illustrated by the reaction of phenyl
isocyanate with dimethoxycarbene,4 which leads to a hy-
dantoin, or bis(propylthio)carbene,5 which affords the cor-
responding indolone (Scheme 1).
Disclosed herein is the production of yet a third species,
a â-lactam, in moderate to good yields when dimethoxy-
oxadiazoline is decomposed in the presence of select
isocyanates by virtue of a simple change in reaction
conditions. Specifically, simply replacing toluene or xylene
with chlorobenzene as solvent afforded a â-lactam as the
principal product instead of the expected hydantoin.
With this advance, one can control whether a hydantoin
or a â-lactam is produced preferentially (Scheme 2). This
development has further expanded the utility of nucleophilic
carbenes in heterocyclic synthesis.
Scheme 1. Reported Products of Nucleophilic Carbenes and
Phenyl Isocyanate
(2) (a) Couture, P.; Warkentin, J. Can. J. Chem. 1997, 75, 1281. (b)
Arduengo, A. J., III; Goerlich, J. R.; Marshall, W. J. J. Am. Chem. Soc.
1995, 117, 11027. (c) Ge, C. J.; Jefferson, E. A.; Moss, R. A. Tetrahedron
Lett. 1993, 34, 7549.
(3) (a) El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J.
J. Am. Chem. Soc. 1992, 114, 8751. (b) Rigby, J. H.; Danca, M. D.
Tetrahedron Lett. 1999, 40, 6891.
(4) (a) Hoffmann, R. W.; Steinbach, K.; Dittrich, B. Chem. Ber. 1973,
106, 2174. (b) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1971.
(5) Rigby, J. H.; Danca, M. D. Tetrahedron Lett. 1999, 40, 6891.
(1) (a) Zhou, H.; Mloston, G.; Warkentin, J. Org. Lett. 2005, 7, 487. (b)
Spino, C.; Rezaei, H.; Dupont-Gaudet, K.; Belanger, F. J. Am. Chem. Soc.
2004, 126, 9926. (c) Nair, V.; Bindu, S.; Sreekumar, V.; Chiaroni, A. Org.
Lett. 2002, 4, 2821. (d) Rigby, J. H.; Wang, Z. Org. Lett. 2002, 4, 4289.
(e) Dawid, M.; Mloston, G.; Warkentin, J. Org. Lett. 2001, 3, 2455.
10.1021/ol061101q CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/15/2006

ethylene and phenyl isocyanate. Subsequently, hydantoin
products were principally observed in the reaction between
phenyl isocyanate and various dimethoxycarbene precursors.9
On the basis of the Hoffmann report, it was initially
assumed that this new reaction was taking place through a
[2+2] cycloaddition of the isocyanate and the 1,2,3,4-
tetramethoxyethylene that was rapidly formed by initial
dimerization of dimethoxycarbene (pathway B, Scheme 3).
Scheme 2. Solvent Effects on Carbene Additions to Aryl
Isocyanates
â-Lactams are the key substructural unit in one of the most
important classes of antibiotics.6 As resistant bacteria con-
tinue to emerge, the synthesis and development of new
â-lactam derivatives could provide new clinical candidates
for the treatment of these strains. The current methodology
produces highly substituted â-lactam derivatives that could
be useful in this regard.
Scheme 3. Mechanistic Possibilities for â-Lactam Formation
Table 1. Summary of Examples of â-Lactam Productsa,b
To test this notion, control experiments were performed
with the purified dimer of dimethoxycarbene. These control
experiments led to some interesting results. The â-lactam
product was isolated in small yields (less than 10%) when
the reaction mixture was refluxed for several hours at
concentrations greater than 0.5 M (pathway B, Scheme 3).
However, none of the product was isolated when the reaction
was performed with a purified carbene dimer at concentra-
tions consistent with those under which the â-lactam product
was observed. This led to the conclusion that under these
conditions the â-lactam formation likely took place in a
stepwise fashion (pathway A, Scheme 3), exclusive of the
dimer. Indeed, the proposed mechanism is not without
precedent as dimethoxycarbene (generated at 50 °C) has been
recently reported to react with electrophilic alkenes, via a
a All reactions were performed at 0.01 M in refluxing chlorobenzene.
b Acyl azides rearrange in situ to form isocyanates. c The product structure
was confirmed by X-ray diffraction studies in this case. d A small yield
(6%) of an ortho ester product was also isolated. A product similar to this
was reported in 2004 and is believed to follow a similar mechanism.7
The results of these studies are summarized in Table 1.
The best yields were obtained at 0.01 M concentration. When
the reaction was performed at higher concentrations, the
yields of the â-lactam decreased and the yields of the
hydantoin product increased.
A 1964 publication by Hoffmann8 reported that a â-lactam
product was isolated in the reaction of 1,2,3,4-tetramethoxy-
(7) Dawid, M.; Reid, D. L.; Warkentin, J.; Mloston, G. J. Phys. Org.
Chem. 2005, 18, 86
(8) Hoffmann, R. W.; Hauser, H. Tetrahedron Lett. 1964, 197.
(9) (a) Hoffmann, R. W.; Steinbach, K.; Dittrich, B. Chem. Ber. 1973,
106, 2174. (b) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1971, 10,
529. (c) Lemal, D. M.; Gosselink, E. P.; McGregor, S. D. J. Am. Chem.
Soc. 1966, 88, 582.
(6) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. ReV. 2005, 105,
395.
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Org. Lett., Vol. 8, No. 14, 2006

zwitterionic intermediate, to provide functionalized cyclobu-
tane products.1a
°C, ꢀ ) 2.38),10 no â-lactam was isolated. When the reaction
was performed in ethylbenzene (bp 136 °C, ꢀ ) 2.41),10
a
The initial investigations that led to the observation of
â-lactam products employed chlorobenzene as solvent. It is
noteworthy that by simply changing the solvent one can
access either a â-lactam or a hydantoin as the major product.
For example, in the case of entry 4 (Table 1), when the
solvent was changed from chlorobenzene to toluene, the
product distribution changed from 65% â-lactam/14% hy-
dantoin to 27% â-lactam/50% hydantoin. Furthermore, by
increasing the reaction concentration in toluene from 0.01
to 0.04 M, we observed 80% hydantoin accompanied by 15%
â-lactam. It is not completely understood why changing the
solvent from toluene to chlorobenzene resulted in such a
dramatic change in the course of the reaction. It is assumed
that the more polar nature and the high boiling point of
chlorobenzene are likely playing a role.
solvent that approximates the boiling point of chlorobenzene
and the polarity of toluene, a complex reaction mixture was
obtained from which â-lactam was isolated in 33% yield.
This result can be contrasted with the 68% yield of â-lactam
when the reaction was performed in chlorobenzene. Further
investigations into the mechanism of this reaction that are
currently underway could lead to a better understanding of
the effect that solvent has on this reaction.
In summary, a new reaction pathway has been observed
between dimethoxycarbene and isocyanates, leading to the
rapid formation of highly substituted â-lactam products in
moderate to good yields.
Acknowledgment. The authors wish to thank the Na-
tional Science Foundation for their generous support of this
research.
To evaluate these possibilities, the reaction depicted in
entry 2 (Table 1) was performed in toluene, chlorobenzene,
and ethylbenzene. When the solvent was changed from
chlorobenzene (bp 132 °C, ꢀ ) 5.62)10 to toluene (bp 111
Supporting Information Available: General experimen-
tal procedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org
(10) Gordan, A. J.; Ford, R. A. The Chemists Companion: A Handbook
of Practical Data, Techiques, and References; John Wiley & Sons: New
York, 1972.
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