ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Amide Formation in One Pot from
Carboxylic Acids and Amines via
Carboxyl and Sulfinyl Mixed Anhydrides
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Bartosz K. Zambron, Srinivas R. Dubbaka, Dean Markovic, Elena Moreno-Clavijo, and
Pierre Vogel*
Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Federal Institute of
Technology (EPFL), CH 1015 Lausanne, Switzerland
Received April 17, 2013
ABSTRACT
An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically
hindered 2-methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method
for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and
liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method.
Amide formation from carboxylic acids and amines is a
fundamental reaction in organic, polymer, and medicinal
chemistry for which a lot of research is still pursued.1 The
main challenge is to find smooth reaction conditions that
require neither heating nor strong bases or acids in order to
avoid R-epimerization of the resulting carboxamides and
require no excess of reagents. A classical method for acyl
group transfers onto free amines is the use of carboxylic
mixed anhydrides,2 including acyloxyborates and boronates3
and sulfonyl carboxylates.4 Acyclic mixed anhydrides of
sulfinic and carboxylic acids (sulfinyl carboxylates)
are unstable compounds that have not yet been isolated,5
and their reactions with amines have not yet been re-
ported. However, cyclic sulfinyl carboxylates such as 1,2-
oxathiolane-5-ones6 have been reported to add alcohols
and amines preferentially onto their carbonyl moiety
generating the corresponding carboxylic esters and car-
boxamides, respectively.7 Amides can be obtained directly
from carboxylic acids using thionyl chloride in di-
methylacetamide in the absence of base.8 Recently, Cossy
and co-workers reported XtalFluor-E to be an excellent
coupling reagent for the amidification of carboxylic acids,
which in some cases generate mixtures containing the
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10.1021/ol401053y
XXXX American Chemical Society