Organic &
Biomolecular Chemistry
COMMUNICATION
Chemoselective N-deacetylation under mild
conditions†
Cite this: Org. Biomol. Chem., 2014,
12, 261
Prakash R. Sultane, Trimbak B. Mete and Ramakrishna G. Bhat*
Received 29th September 2013,
Accepted 28th October 2013
DOI: 10.1039/c3ob41971a
A mild and efficient chemoselective N-deacetylation using the under harsh conditions may lead to racemization in certain
Schwartz reagent at room temperature in rapid time is described. cases. Nevertheless, efforts have been made in recent times to
The mild and neutral conditions enable orthogonal N-deacetyl- overcome this limitation. Some of the available protocols
ation in the presence of some of the common protecting groups utilize moisture sensitive and corrosive reagents such as oxalyl
(viz. Boc, Fmoc, Cbz, Ts). The deprotection conditions did not chloride,6 and a triphenyl phosphite complex7 under basic
induce any epimerization at the chiral amino centre.
conditions at lower temperatures. Recently an elegant method
has been described by employing transamidation using an
ammonium salt.8 However, this protocol demands the sacrifice
of a stoichiometric equivalent of another amine for the trans-
amidation. While searching through the literature, we learnt
that the Schwartz reagent has been elegantly and effectively
employed for the conversion of carboxamides to imines, and
also for the conversion of amides to aldehydes.9 However to
the best of our knowledge, the Schwartz reagent has not been
exploited for a straight forward N-deacetylation protocol. Also
there are not many standard protocols for N-deacetylation
under mild conditions. Based on this consideration it would
be valuable to develop a method for N-deacetylation under
mild conditions that can tolerate a variety of functional
groups. We envisioned that the Schwartz reagent can be
utilized for N-deacetylation and the protocol would particularly
be very useful for laboratory scale reactions.
Herein, we wish to report a convenient selective N-deacety-
lation protocol using the Schwartz reagent at room tempera-
ture in a very short time (2–5 min). Moreover, we demonstrate
the selective (orthogonal) deprotection by carrying out compe-
tition experiments. The methodology proved to be very
efficient for aromatic, heteroaromatic and aliphatic amides
and also no epimerization was observed during the N-deacety-
lation of chiral acetamides.
Organic compounds with amine functionality are widespread
in many natural products, bioactive compounds and pharma-
ceuticals.1 However, due to their remarkable nucleophilicity
quite often amines are protected to carry out a series of
organic transformations. Though protecting group free syn-
thesis is highly desirable and demanding,2 in many instances
the protection of amines is unavoidable, thus making the reac-
tion reliable for obtaining the target compound efficiently
without any side reactions.
The acetyl moiety is one of the widely employed protecting
group for amines in organic synthesis and also it is one of the
most common protecting groups used by nature in natural
product synthesis.1,3 Acetylated amines (acetamides) have a
remarkably reduced nucleophilic character in comparison to
amines. Acetylated amines have been explored for the catalytic
asymmetric hydrogenations of enamides.4 Acetylated amines
such as acetamides have been successfully utilized as directing
groups in C–H activation.5 In spite of the wide utility of acetyl
protection for amines in organic synthesis, acetyl deprotection
(N-deacetylation) is practically limited to the traditional harsh
deprotecting conditions. As the amide bond is robust, N-deacetyl-
ation usually requires the use of a strong base or acid at a
high temperature.3 These deprotective conditions limit the
scope of acetylated amines along with the variety of functional
groups which are sensitive to acid and base. N-deacetylation
In order to demonstrate the utility of the Schwartz reagent
we began our study with the synthesis of various N-acetamides
(1a–1t) starting from the corresponding amines with varying
electronic and steric properties (Table 1). In our initial exper-
iment, compound 1a was treated with the Schwartz reagent in
anhydrous THF at room temperature. The turbid reaction
mixture changed into a clear solution in a very short time
(3 min). The completion of the reaction was monitored by TLC
and the reaction was quenched by the addition of water and
Mendeleev Block, Department of Chemistry, Indian Institute of Science Education &
Research (IISER), Pune, 411008 Maharashtra, India. E-mail: rgb@iiserpune.ac.in;
Fax: +91-(20)-25899790; Tel: +91-20-25908092
†Electronic supplementary information (ESI) available: Experimental procedure,
characterization data and copies of 1H-NMR for compounds 1a–1t, 3, 4, 5, 6, 7,
8, 11. 1H and 13C-NMR spectra for the compounds 2a–2t, 9, 10, 12. See DOI:
10.1039/c3ob41971a
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 261–264 | 261