ORGANIC
LETTERS
2
005
Vol. 7, No. 23
237-5239
Mild and Reversible Dehydration of
5
Primary Amides with PdCl in Aqueous
2
Acetonitrile
Sonia I. Maffioli,* Ettore Marzorati, and Alessandra Marazzi
Vicuron Pharmaceuticals, Via R. Lepetit 34, Gerenzano (VA), Italy
smaffioli@Vicuron.it
Received September 1, 2005
ABSTRACT
2
A new, mild, and reversible method to convert primary amides to nitriles in good yields using PdCl in aqueous acetonitrile is described.
1
According to literature, phosphorus pentoxide, titanium
organic solvents under mild conditions. It was found that
by using PdCl in water/acetonitrile as solvent mixture,
primary amides dehydrated in good yields after a few hours
at room temperature (Scheme 1).
2
3
tetrachloride, thionyl chloride, and trifluoroacetic anhy-
dride are some reagents used to prepare nitriles through
primary amide dehydration. In addition, more recently,
methods using other reagents to perform the dehydration
under milder conditions, such as PyBOP, EDCI, and
2
4
5
6
7
cyanuric chloride, have been reported. All of these methods
Scheme 1
are characterized by a common requirement, that is, the
reaction must be performed under anhydrous conditions, in
which the use of moisture-sensitive reagents is allowed and
the formation of dehydrated product is favored.
Transition metal complexes have been reported in the
literature as useful catalysts for different organic reactions.
Although palladium(II) complexes have been known to be
used in the hydrolysis of nitriles to primary amides, the
reverse reaction of dehydration has never been described.
To better characterize this new process and its reaction
parameters, further experiments were conducted.
Catalyst. A stoichiometric amount of PdCl was first
2
tested. Successive experiments (see Table 1) showed that a
catalytic process could be accomplished with 0.1 equiv of
8
In this article, we report the use of PdCl
2
to convert
PdCl
that an amount of PdCl
lead to good conversion in an acceptable time frame (see
Table 1, entries 3 and 4). In addition, we found that PdCl
could be replaced with PdCl (MeCN) or Pd(OAc) with
similar results. However, when employing Pd(OAc) instead
of PdCl , although conversion and reaction speed were
similar, the reaction solutions showed different pH. PdCl
generated reaction solutions with pH in the range 2.8-3.5,
whereas Pd(OAc) generated solutions with pH in the range
4.7-5. This was a useful finding, which indicated that Pd-
OAc) would be preferred for substrates particularly sensi-
tive to an acidic environment.
2
per mole of substrate. However, it was also noticed
primary amides into the corresponding nitriles in aqueous
2
as low as 0.005 equiv could also
(
1) Reisner, D. B.; Coring, E. G. Organic Syntheses; Wiley: New York,
1
963; Collect. Vol. IV, p 144.
2
(
2) Lehnert, W. Tetrahedron Lett. 1971, 12, 1501.
(3) Krynitsy, J. A.; Carhart, H. W. Organic Syntheses; Wiley: New York,
2
2
2
1
963; Collect. Vol. IV, p 436.
4) Campagna, F.; Carroti, A.; Casini, G. Tetrahedron Lett. 1977, 18,
813.
5) PyBOP: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflu-
orophosphate. Bose, D. S.; Narsaiah, A. V. Synthesis 2001, 373.
6) EDCI: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Bose, D.
S.; Sunder, K. S. Synth. Commun. 1999, 4235.
2
(
2
1
(
2
(
2
(
7) Maetz, P.; Rodriguez, M. Tetrahedron Lett. 1997, 38, 4221.
(8) (a) Paraskevas, S. Synthesis 1974, 574. (b) McKenzie, C. J.; Robson,
(
2
R. J. J. Chem. Soc., Chem. Commun. 1988, 112. (c) Villain, G.; Kalck, P.;
Gaset, A. Tetrahedron Lett. 1980, 21, 2901.
1
0.1021/ol052100l CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/15/2005