Communications
DOI: 10.1002/anie.200906055
Transacylation
General and Chemoselective N-Transacylation of Secondary Amides
by Means of Perfluorinated Anhydrides**
Paola Rota,* Pietro Allevi, Raffaele Colombo, Maria L. Costa, and Mario Anastasia
Examples of direct N-transacylations of amides are very rare
and lacking in general applicability. For instance, earlier
attempts at N-transacylation were performed under harsh
conditions.[1] Other procedures required prolonged treatment
with an equimolar mixture of trifluoroacetic acid (TFA) and
trifluoroacetic anhydride (TFAA; 1008C, 48 h),[2,3] or even
running the reaction in TFAA followed by the addition of a
strong base, reported as necessary to abstract the hydrogen
atom in the alpha position to the eliminated acyl group.[4]
Finally, some acetanilides were treated with chloroacetyl
chloride under acid catalysis of zeolites or AlCl3 at 838C for
16 h,[5] or in refluxing pyridine containing dimethylaminopyr-
idine for 5 h.[6]
Thus, N-transacylations are usually accomplished by
hydrolysis of the acylamides and successive re-acylation of
the formed amines,[7] a procedure that does not allow the
simultaneous presence, in the amide molecule, of functional
groups labile to the basic or acidic conditions of the hydro-
lysis.[7d,8] Herein, we report the first direct, general, and
chemoselective procedure for the N-transacylation of secon-
dary acylamides to their perfluorinated analogues, in high
yields, with perfluorinated anhydrides. Remarkably, the
perfluorinated amide formed could then be directly converted
to a different amide by simple treatment with the desired acyl
chloride, followed by a very mild aqueous process of the
reaction mixture.
5 min, in CH3CN),[10] we did not obtain the expected
derivative 1b but the lactone 2b, which could be quantita-
tively transformed into lactone 2a by treatment of the
reaction mixture with methanol at room temperature.
Prompted by these initial results, we explored the scope of
this new reaction (Table 1). Because of the particular utility of
the reaction in carbohydrate chemistry,[7a] we started with
some sialic acid and amido sugar derivatives of interest in
organic synthesis and in biological studies.[11] In particular, we
were interested in testing molecules containing groups labile
to the commonly used conditions of amide hydrolysis and re-
acylation. In effect, our reaction conditions allowed the
successful N-transacylation of several compounds containing
a great variety of functional groups (often within the same
molecule), such as hydroxy groups, lactones, benzyloxycar-
bonyls (OCbz), methyl esters, acetates, tert-butyldimethylsilyl
(TBDMS) groups, and acyclic and cyclic acetals as their
2-methoxyethoxymethyl (MEM), methyl, and benzylidene
derivatives (Table 1, entries 1–18). Moreover, to test possible
anomerizations resulting from the perfluorinated acid liber-
ated in the reaction, we tested a- and b-glycosidic compounds
as well as a b-disaccharide. Finally, we selected carbohydrates
with an equatorial or an axial acetamido group, to test the
possible influence of the amide geometry.
The study was first performed with HFBAA,[10a] then the
reaction was repeated on some representative samples with
TFAA, which gave comparable results (Table 1, entries 3, 13,
14, and 17). In all cases, except for entry 7, the reaction
occurred in good yields, chemoselectively, and involving
exclusively the amido group independently of its equatorial or
axial geometry. Other functional groups present in the treated
compounds were conserved, with the exception of free
hydroxy, alcoholic, or acetalic groups, which, as expected,
were perfluoroacylated (mass spectrometry (MS) and NMR
evidence) under the reaction conditions employed. However,
they could be easily regenerated by simple, short treatment of
the crude reaction mixture with a solution of aqueous TFA in
THF.
Our work originated while studying sialic acid 1,7-lactone
1a.[9] Surprisingly, on reacting the lactone 1a with heptafluor-
obutyric anhydride (HFBAA) to volatilize it (1358C for
Only acyclic acetals appeared to be labile under the
reaction conditions, as observed for the MEM group (Table 1,
entry 7). Remarkably, analysis of the 1H NMR spectra of
compounds 4, 6, 8, 10, 12, 14, and 16 clearly showed in all cases
that the reaction does not modify the configuration of the
anomeric centers (see the Supporting Information). The
anomeric geometry for the sialic acid derivative 8a, which
lacks the anomeric proton, was established on the basis of the
values of the heteronuclear vicinal coupling constant (3JC1,H3ax
and 2JC2,H3ax).[12,13]
[*] Dr. P. Rota, Prof. Dr. P. Allevi, Dr. R. Colombo, Dr. M. L. Costa,
Prof. Dr. M. Anastasia
Department of Medical Chemistry, Biochemistry, and Biotechnology
University of Milan
via Saldini 50, 20133 Milano (Italy)
Fax: (+39)02-5031-6040
E-mail: paola.rota@unimi.it
[**] This work was financially supported by the Italian Ministero
dell’Universitꢀ e della Ricerca (MiUR).
To further study the general applicability of the reaction,
we tested it on other non-carbohydrate compounds, including
Supporting information for this article is available on the WWW
1850
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 1850 –1853