Angewandte
Chemie
DOI: 10.1002/anie.201202354
Protecting Groups
Microwave-Assisted Deacylation of Unactivated Amides Using
Ammonium-Salt-Accelerated Transamidation**
Yuhei Shimizu, Hiroyuki Morimoto, Ming Zhang, and Takashi Ohshima*
Amines are ubiquitous organic molecules in natural products
and pharmaceuticals[1] and efficient synthesis of amines is an
important topic in synthetic organic chemistry. Recent efforts
to streamline organic synthesis favors the use of unprotected
molecules in synthetic protocols,[2] but amine protection is still
a reliable way to obtain satisfactory yields of the desired
products and unprotected amines are often too reactive to
avoid undesired reactions such as oxidation of amines.
Acyl groups are one of the most useful amine protecting
groups because of their ability to reduce the nucleophilicity of
amines and to prevent undesired side reactions.[3] Such
acylated amines (amides) are well utilized in asymmetric
hydrogenation of enamides[4] and kinetic resolutions,[5] and
the acyl group is often essential for obtaining optically active
amines with excellent enantioselectivity. Acylated amines
amounts of moisture-sensitive reagents (oxalyl chloride and
triphenyl phosphite chlorine complex) are required to
activate the amides, and the reaction must be performed
under anhydrous conditions.[7] Enzymatic methods, in which
neutral reaction conditions can be used, are another option,
but the high substrate specificity is limiting.[8]
Transamidation is the process of transferring an acyl
group from one amine to another (Scheme 1, bottom).[9] This
process can be considered amide deacylation to give depro-
tected amines. Because amines are more nucleophilic than
water, transamidation could potentially be performed under
less harsh reaction conditions than hydrolysis, and thus may
be a good alternative for the deprotection of acylated amines.
Despite its high potential to cleave amide bonds with the aid
of amine nucleophiles, transamidation is thought to be
difficult to apply for the deacylation of amides because:
1) traditional transamidation often requires a high temper-
ature because robust amide bonds are cleaved in the
processes, 2) transamidation is an equilibrium process which
provides a mixture of the starting material and product thus
requiring appropriate reaction conditions, and 3) separation
of the liberated amines from the reaction mixture, including
the starting amine, is difficult due to the similar chemical
properties of the amines. Although recent efforts addressed
some of these problems, the resulting transamidations were
mostly limited to the reactions of either primary amides, to
give secondary or tertiary amides with the concomitant
liberation of ammonia, or an intramolecular variant, with
the release of ring strains.[10] Among them, Gellman, Stahl,
and co-workers reported aluminum or zirconium amide
catalyzed intermolecular transamidations of secondary and
tertiary amides, and some even proceeded at ambient
temperature.[11] Most of the reactions using metal amide
catalysts, however, provide equilibrium mixtures of starting
materials and products. In addition, the metal amide com-
plexes are highly basic and sensitive to acidic functionalities,
which limits their substrate scope. Thus, practical application
of transamidation for the deacylation of amides to amines
requires further development. Herein, we report microwave-
assisted transamidation for deacylation of unactivated amides
to produce a variety of amines using readily available
ammonium salts with ethylenediamine.
À
were recently used in C H activation reactions, in which acyl
groups served as an efficient directing group.[6] Although the
synthesis and application of acylated amines has attracted
much attention, removal of the acyl groups from the amines,
that is, amide bond cleavage, has generally not been explored
in detail. Amide bonds are chemically robust because of the
delocalization of the electrons across the amide, and thus
classical hydrolysis of amides generally requires harsh reac-
tion conditions, that is, strong acids or bases at high temper-
ature (Scheme 1, top).[3] Such harsh reaction conditions limit
Scheme 1. Deacylation of amides to amines.
the synthetic potential of acylated amines in terms of the
compatibility of their functional groups. Methods to remove
acyl groups from amides below room temperature have been
developed to overcome this limitation, but stoichiometric
[*] Y. Shimizu, Dr. H. Morimoto, M. Zhang, Prof. Dr. T. Ohshima
Graduate School of Pharmaceutical Sciences, Kyushu University
Maidashi Higashi-ku, Fukuoka, 812-8582 (Japan)
We began our investigation of deacylation reactions on
the basis of our recent findings in platinum-catalyzed direct
amination of allylic alcohols.[12] Under reaction conditions for
the direct allylation of amines, transamidation of
N,N-dimethylformamide (DMF) with alkylamine proceeded
to produce dimethylamine as a side product. Thus, we next
evaluated the effective reaction conditions for transamida-
tion. Using N-acetylbenzylamine (1a) and pentylamine (2a)
E-mail: ohshima@phar.kyushu-u.ac.jp
[**] This work was supported by the Grant-in-Aid for Scientific Research
(B) and Scientific Research on Innovative Areas from MEXT, the A-
STEP and CREST from JST, and the Uehara Memorial Foundation.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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