Wang et al.
reaction during the past decades. Recently, we have proposed
a model that successfully explains and predicts the relative
stereoselectivity in the Staudinger reaction on the basis of a
kinetic analysis of the cis/trans ratio of reaction products.8
In the Staudinger reaction, ketenes are generated in situ
mainly via three ways: (1) the elimination of acyl chlorides or
related derivatives in the presence of a base,6a,b,9 (2) the
photolysis of metal-carbene complexes,6k,10 and (3) the Wolff
rearrangement of R-diazocarbonyl compounds under thermal,
photo, or microwave irradiation conditions.8,11 Thus, reaction
conditions,5 such as temperature,8 solvent,7e,12a base,12b the
chloride anion,6c,6k,7e and the metal6k,7f may affect the stereo-
chemical outcomes. Moreover, Arrieta et al.7e pointed out that
the different stereoselectivites of the Staudinger reaction
depended on the methods used in the generation of the active
species on the basis of their computational investigations and
predicted that when the ketene was formed before the cycload-
dition, the â-lactam product was predominantly cis, while when
the imine reacted directly with the acyl chloride, the subsequent
intramolecular SN2 displacement determined the final trans
selectivity. Thus, the addition order of reagents could also
obviously affect the stereochemical outcomes in the Staudinger
reaction between acyl chlorides and imines. To understand the
influence of the reaction conditions on the stereoselectivity
better, a comprehensive comparison of the “origin” ketene-
imine reaction13 and the “modified” ketene-imine reaction,
especially the most widely used Staudinger reaction between
acyl chlorides and imines, is required. Fortunately, we have
found a clean ketene-imine reaction system,8 which provides
an efficient and sensitive platform to study the influence of the
reaction conditions on the stereoselectivity. Herein, we present
our experimental results and hope to provide a deeper under-
standing of the stereoselectivity in the Staudinger reaction,
especially the Staudinger reaction involving acyl chlorides and
imines.
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368 and references therein.
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Results and Discussion
Influence of Solvents on the Stereoselectivity in the
Staudinger Reaction. The Staudinger reaction is a stepwise
reaction involving the nucleophilic attack of an imine to a ketene
giving rise to a zwitterionic intermediate and a subsequent ring
closure of the zwitterionic intermediate producing the â-lactam
product.5 When the direct ring closure of the zwitterionic
intermediate is fast enough, the final â-lactam product is cis,
while when the direct ring closure is not so fast, the isomer-
ization of the imine moiety in the zwitterionic intermediate
occurs to form a sterically more favorable intermediate, which
produces the final trans-â-lactam product. The relative (cis/trans)
stereoselectivity is generated as a result of the competition
between the direct ring closure and the isomerization of the
imine moiety in the zwitterionic intermediate.8 The competition
is mainly controlled by the electronic effect of the substituents
of ketenes and imines and the steric hindrance of the N-
substituent of imines.8 However, solvents possibly affect the
stability and half-life of the zwitterionic intermediate, resulting
in the change of the stereoselectivity. Arrieta et al. concluded
previously that the polarity of the solvent enhanced the
diastereomeric excess of the Staudinger reaction according to
their computational results.7e
In our previous work, the reaction of S-phenyl 2-diazo-
ethanethioate (1) with a series of N-isopropyl imines 2a-f in
toluene at 80 °C was well studied.8 This clean reaction is a
quite efficient and sensitive to the stereoselectivity, which could
produce â-lactam products from predominately trans to mainly
cis isomers depending on the electronic effect of the imine
substituents. To investigate the influence of solvents on the
stereoselectivity, we conducted these reactions at 80 °C in
different solvents (Table 1, entries 1-7). It is notable that the
cis/trans14 ratios of products correlate well with the Hammett
constants15 (σ) (Table 1, entries 1-7, and Figure 1). Moreover,
it is found that increasing the polarity of the solvent does not
enhance the stereoselectivity. For instance, the stereoselectivities
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