Tetrahedron Letters
Intermolecular Schmidt reaction of alkyl azides with acyl silanes
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Chun-Jiao Yu, Rui Li , Peiming Gu
School of Chemistry & Chemical Engineering, Ningxia Engineering and Research Center for Natural Medicines, Ningxia University, Yinchuan 750021, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first intermolecular Schmidt reaction of alkyl azides with acyl silanes has been designed and realized,
producing a range of amides with absolute site selectivity in good to excellent yields. The mechanism of
the conversion has been proposed, and the reaction exhibits scope of substrates.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 22 May 2016
Revised 24 June 2016
Accepted 27 June 2016
Available online 28 June 2016
Keywords:
Schmidt reaction
Acyl silanes
Alkyl azides
Amides
Rearrangement
The classic Schmidt rearrangement involves the acid-promoted
reaction of hydrazoic acid (HN3) and electrophiles.1 A variety of
electrophiles including aldehydes, ketones, carbenium ions from
alkenes or alcohols, and acylium ions from carboxylic acids, are
used for the conversion, producing several different types of
N-containing products. Soon after, replacement of HN3 with the
more weakly nucleophilic alkyl azides has become a hot research
topic with the Schmidt reaction. The alkyl azides have proven to
be very successful for the intramolecular Schmidt reaction, while
the intermolecular reaction is comparatively less efficient. In the
early stage, the electrophiles for the Schmidt reaction of alkyl
azides were mainly restricted to aldehydes, ketones, and carbe-
nium ions. Investigation on new electrophiles for this reaction
should be academically desirable and interesting. Toste and co-
workers had reported the Au(I)-catalyzed intramolecular Schmidt
reactions of acetylenic azides.2 Very recently, our group had
demonstrated that the acyl chlorides were suitable for the
intramolecular Schmidt reaction of alkyl azides.3 Herein, we
reported the extension of electrophiles to acyl silanes for the inter-
molecular Schmidt reaction of alkyl azides, efficiently affording
amides with absolute site selectivity.
selective.5 Generally, the analogy intermolecular insertion of alkyl
azides with ketones with less efficiency was observed, and the
reaction was very sensitive to substrates.6 Further, the conceptu-
ally intermolecular Schmidt reaction could be highly efficient
when the alkyl azide was replaced by an azido alkanol4b,7 or an
azido alkylamine,8 where the intermolecular reaction was in fact
changed to an intramolecular one before the Schmidt rearrange-
ment. It should be noted that the amidation of aldehydes with
azides was recently developed through the strong base promoted
process9 or the transition metal catalyzed conversion,10 however
the conversion suffered from very severe substrate limitation.
For the Schmidt reaction of alkyl azides with aldehydes, the ini-
tial nucleophilic attack of an alkyl azide onto an aldehyde would
generate a diazonium cation intermediate (Scheme 2, R1 = H). Then
elimination of proton with the synchronous loss of nitrogen gas
would afford an amide as the product. The cleavage of C–Si bond
might be easier than that of C–H bond under the acidic conditions.
Therefore, if a silyl group was attached to the carbonyl unit, then
the intermolecular Schmidt reaction could be more efficient
(Scheme 2, R1 = silyl group). For this envision to be successful,
the following three key points should be concerned: (1) could
the azide attack proceed effectively when the electronic effect
and steric effect of the carbonyl group were obviously changed
by introducing a silyl group? (2) Would the decomposition of the
acyl silane to an aldehyde occur before the Schmidt reaction? (3)
Could the migration of the R group or a silyl group (R1 = Si) to
the nitrogen atom take place when the acyl silane was employed?
With the above considerations, the acyl siliane 1a and n-heptyl
azide 2a were selected as the model substrates for this investiga-
tion. A series of Lewis acids and Brunsted acids were examined
Generally, the intermolecular Schmidt reaction of alkyl azides
suffers from poor yields (Scheme 1). Aldehydes, very reactive car-
bonyl compounds, had been examined with the alkyl azides under
protic acid conditions, and the best yield was only 25%.4 Lewis
acids had been used to enhance the efficiency of the conversion,
but the yield was still moderate and the reaction was poorly site
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0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.