6486
J . Org. Chem. 1996, 61, 6486-6487
Sch em e 1
Con ver sion of P r im a r y Am id es to Nitr iles
by Ald eh yd e-Ca ta lyzed Wa ter Tr a n sfer
Marie-Pierre Heck,† Alain Wagner,‡ and
Charles Mioskowski*,†,‡
Ta ble 1
CEA, CE-Saclay, Service des Mole´cules Marque´es, Baˆt 547,
De´partement de Biologie Cellulaire et Mole´culaire,
F-91191 Gif Sur Yvette, France, and Universite´ Louis
Pasteur, Laboratoire de Synthe`se Bio-Organique associe´ au
CNRS, Faculte´ de Pharmacie, 74 route du Rhin BP 24,
F-67401 Illkirch, France
entry
RCHO
RCO2H
isolated yield (%)
1
2
3
4
C7CHO
C7CHO
C7CHO
HCOH
HCO2H
87
0
0
CH3CO2H
CF3CO2H
HCO2H
85
Received J une 17, 1996 (Revised Manuscript Received August 1,
1996)
Sch em e 2
The synthetic importance of the dehydration of primary
alkyl- or arylamides to their corresponding nitriles has
been thoroughly documented in the literature. As early
as 19451 this reaction has been reviewed, and since that
time alternate conditions and dehydration reagents
providing higher yields have been introduced.2 Many of
these reported sequences, however, require the use of
strong acids and bases or involve difficult procedures.
Phosphorus pentoxide3 is the most common dehydrating
agent for this reaction, but many others including
phosphorus oxychloride4 or thionyl chloride5 are usually
employed.
these methods are generally limited to only arylamides
and the reagents employed require special preparation.11
In our efforts toward the total synthesis of natural
products and glycosidase inhibitors,12 we explored the
conversion of carboxamides to nitriles. The dehydration
reaction of 3-phenylpropanamide, which proceeds in
refluxing acetonitrile with formic acid, was interestingly
catalyzed by an aldehyde (Scheme 1).
In contrast to the previously reported methods,3-10 no
strong dehydration or sophisticated reagent is needed
and the reaction can be easily carried out on large scales.
Mechanistically, the trans amidation of an alkyl- or
arylamide to its corresponding nitrile requires the trans-
fer of water from the amide to acetonitrile. Experimen-
tally, this transfer could be quantified upon replacement
of acetonitrile with benzonitrile, which in addition to the
desired nitrile produced 1 equiv of benzamide.
More recently, dehydrating and alkylating reagents
have been disclosed, permitting the reaction to proceed
at lower temperature6 and under neutral,7 mild condi-
tions8,9 or in liquid triphasic systems.10 Unfortunately,
* To whom correspondence should be addressed. Phone:
(33)88676863. Fax: (33)88678891. E-mail: mioskow@aspirine.u-stras-
bg.fr.
† CEA.
To understand this dehydration reaction and to inves-
tigate the role of the required acid and aldehyde, we
varied the experimental conditions. The results are
summarized in Table 1.
‡ Universite Louis Pasteur.
(1) (a) Kent, R. E.; McElvain, S. M. Org. Synth. 1945, 25, 61. (b)
Mowry, D. T. Chem. Rev. 1948, 42, 189.
(2) (a) Patai, S. In The Chemistry of Functional Groups: Amides;
Zabicky, J ., Ed.; J ohn Wiley and Sons: New York, 1970. (b) Larock,
R. C. Comprehensive Organic Transformations; VCH Publishers, Inc.:
New York, 1989.
(3) (a) Humber, L. G.; Davis, M. A. Can. J . Chem. 1966, 44, 2113.
(b) Reisner, D. B.; Horning, E. C. Organic Syntheses; Wiley: New York,
1963; Collect. Vol IV, p 144.
The reaction was very sensitive to the acid employed,
with optimal yields being recognized when formic acid
was used (entry 1, Table 1). As seen in entries 2 and 3
(Table 1), both acetic and trifluoroacetic acid were
ineffective. The choice of the aldehyde, however, appears
less critical (entry 4, Table 1). We noted that various
aldehydes could be used and selected paraformaldehyde
because of its ease of removal. The amount of aldehyde
used did effect the reaction, and our studies show it to
act in a catalytic fashion. For example, using 0.2 equiv
of octanal (versus 3 equiv) resulted in a decrease in yield
of the corresponding nitrile from 87% to 60%. The
catalytic role of the aldehyde was further verified by the
transformation of 10-oxodecanamide to its corresponding
nitrile (80%) in the absence of any added aldehyde
(Scheme 2). Here, the internal aldehyde moiety serves
as the catalyst. In the absence of either the acid or
aldehyde components, no products were isolated.
Furthermore, we observed that replacement of aceto-
nitrile by benzonitrile leads to similar results, and in this
case 1 equiv of benzamide is recovered at the end.
In a typical experiment amide was solubilized in aceto-
nitrile and an excess of formic acid and paraformaldehyde
(4) (a) Reid, W. B., J r.; Hunter, J . H. J . Am. Chem. Soc. 1948, 70,
3515. (b) Friedrich, K.; Gallmeier, H. J . Tetrahedron Lett. 1981, 22,
2971. (c) Yamada, S.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1976,
1, 57. (d) Yates, P.; Bichan, D. J . Can. J . Chem. 1975 53, 2045.
(5) (a) McElvain, S. M.; Stevens, C. L. J . Am. Chem. Soc. 1947, 69,
2663. (b) Neuman, M. S.; Arkell, A.; Fuknaga, T. J . Am. Chem. Soc.
1960, 82, 2498. (c) Cram, D. J .; Haberfield, P. J . Am. Chem. Soc. 1961,
83, 2363. (d) Rickborn, B.; J ensen, F. R. J . Org. Chem. 1962, 27, 4608.
(e) Krynitsky, J . A.; Carhart, H. W. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, p 436. (f) Baldwin, J . E.; Carter, C. G. J .
Org. Chem. 1983, 48, 3912. (g) Ressler, C.; Nagarajan, G. R.; Kirisawa,
M.; Kashelikar, D. V. J . Org. Chem. 1971, 36, 3960. (h) Ressler, C.;
Kashelikar, D. V. J . Am. Chem. Soc. 1966, 88, 2025.
(6) (a) Sznaidman, M. L.; Crasto, C.; Hecht, S. M. Tetrahedron Lett.
1993, 34, 1581. (b) Rigo, B.; Lespagnol, C.; Pauly, M. J . Heterocycl.
Chem. 1986, 23, 183. (c) Rigo, B.; Lespagnol, C.; Pauly, M. Tetrahedron
Lett. 1986, 27, 347. (d) Campagna, F.; Carroti, A.; Casini, G. Tetra-
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Soc. 1955, 77, 1701. (b) Pesson, M. Bull. Soc. Chim. Fr. 1965, 2262.
(c) Yamamoto, E.; Sugasawa, S. Tetrahedron Lett. 1970, 4383. (d)
Snatzke, G.; Klein, H. Chem. Ber. 1972, 105, 244. (e) Ficken, G. E.;
France, H.; Linstead, R. P. J . Chem. Soc. 1954, 3731.
(8) (a) Bagar, T. M.; Riley, C. M. Synth. Commun. 1980, 10, 479.
(b) Saednya, A. Synthesis 1985, 184. (c) Mai, K., Patil, G. Tetrahedron
Lett. 1986, 27, 2203. (d) Lehnert, W. Tetrahedron Lett. 1971, 1501.
(9) (a) Saraie, T.; Ishiguro, T.; Kawashima, K.; Morita, K. Tetrahe-
dron Lett. 1973, 2121. (b) Denis, W. E. J . Org. Chem. 1970, 35, 3253.
(c) Olah, G. A.; Narang, S. C.; Fung, A. P.; Gupta, B. C. G. Synthesis
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(12) Heck, M. P.; Monthiller S.; Mioskowski, C. Unpublished results.
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