Grecian et al.
SCHEME 2
react in the presence of BF3‚OEt2. Although the expected ring-
expanded â-lactams 2 were consistently formed in 27-58%
yield, a significant amount of ethyl carbamate product of type
3 was also observed in every case (Table 1).
In an effort to increase the â-lactam yield, a variety of acids
such as TiCl4, SnCl4, BF3‚OEt2, TfOH, and TFA were surveyed.
Only BF3‚OEt2 was found to reproducibly provide the desired
products, although TFA also gave very low yields of â-lactam
and ethyl carbamate. The highest yields were obtained when
2.5 equiv of BF3‚OEt2 was used. Although the combined yield
of â-lactam and carbamates was good to excellent for the series
of alkyl azides examined (51-98% combined), we were unable
to obtain â-lactam products to the exclusion of carbamate
products, which in several cases were the major products.
In the case of â-lactam formation, typical azido-Schmidt
chemistry is at work: the azide attacks the ketone and the
ensuing azidohydrin collapses with the loss of nitrogen and
concomitant ring expansion to give â-lactams 2 (Scheme 3).9
The ethyl carbamates 3 could arise from an azidohydrin
intermediate that, instead of bond migration, undergoes ring-
opening to give a carbocation. This step is analogous to the
well-known cyclopropylcarbinyl cation homoallylic rearrange-
ment.11 Pirrung’s work in the study of ethylene biosynthesis
invokes a similar carbocation intermediate derived from 1-ami-
nocyclopropanecarboxylic acid, which fragments to produce
ethylene.12 Loss of ethylene provides an isocyanate that reacts
reaction of alkyl azides with cyclic ketones, which generally
leads to ring-expanded lactams in a process reminiscent of the
Schmidt reaction.9 Following Wasserman, we were initially
interested in reacting cyclopropanones with alkyl azides under
Lewis acidic conditions as a means of synthesizing N-substituted
â-lactams. In the course of this study, we discovered that the
Lewis acid promoted reactions of azides and cyclopropanones
provide a rich array of products that depend on the nature of
the cyclopropanone substitution. Previously, we disclosed that
the reactions of 2,2-dimethylcyclopropanone equivalents with
azides provide R-amino-R′-diazomethyl ketones.10 Herein, we
describe the results of a broader investigation on the reactions
of substituted cyclopropanones with alkyl azides. In so doing,
we describe several previously unknown reaction pathways that
result from both C1/C2 and C2/C3 bond rupture of the cyclo-
propanone reactant. The mechanisms of the various reactions
will also be discussed.
TABLE 1. Reactions of Cyclopropanone Acetal 1 with Azides
Results
Cyclopropanone Proper. As noted above, the present study
began as an attempt to make N-substituted â-lactams through
azide-mediated ring-expansion processes.9 To this end, a mixture
of cyclopropanone hemiketal and alkyl azide were allowed to
entry
R
product (yield, %)
a
b
c
d
e
f
C6H5CH2
n-C6H14
2a (45)
3a (13)
3b (40)
3c (60)
3d (35)
3e (43)
3f (34)
2b (58)
2c (36)
2d (27)
2e (38)
2f (45)
3-MeO(C6H4)CH2
4-MeO(C6H4)CH2
4-MeO2C(C6H4)CH2
4-Br(C6H4)CH2
(4) (a) McElvain, S. M.; Weyna, P. L. J. Am. Chem. Soc. 1959, 81,
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Glazer, E. J. Org. Chem. 1975, 40, 1505-1506.
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