CO,11 aryl chlorothionoformate,12 and supported sulfonyl
chlorides under microwave irradiation.13 Unfortunately,
most of these methods have limited utility and ap-
plicability due to the extreme toxicity and cumbersome
handling, and high costs in the availability of the
reagents. Sometimes the reagents employed require
tedious preparation procedures or workup, and purifica-
tion of the reaction product can be problematic due to
the reactivity of the isonitriles.
Microwave-Assisted Synthesis of
Isonitriles: A General Simple Methodology
Andrea Porcheddu,* Giampaolo Giacomelli, and
Margherita Salaris
Dipartimento di Chimica, Universita` degli Studi di Sassari,
via Vienna 2, 07100 Sassari
Taking into account our interest in the application of
Ugi reaction for the synthesis of new building blocks for
combinatorial chemistry, we investigated the possibility
to synthesize isonitriles using a very cheap reagent, such
as 2,4,6-trichloro[1,3,5]triazine (cyanuric chloride, TCT),14
as dehydration agent of formamides.15 The reaction was
checked using a CH2Cl2 solution of TCT (1 equiv) and
the formamide, which was charged with pyridine (2
equiv), and the mixture was refluxed on a water bath.
Under these conditions the characteristic isonitrile odor
was evident but the reaction occurred generally with
modest yields.
Automated and focused microwave flash heating was
recently proven to improve the preparative efficiency and
to dramatically reduce reaction times for several different
types of organic transformations.16 Moreover, recent
advances in the microwave instrumentation have made
this technique more accessible and the results more
reproducible. “Although the basis of these practical
benefits remains speculative,17 the preparative advan-
tages are obvious and have motivated a large and
continuing survey of nearly all classes of thermal reac-
tions for improvement upon microwave heating.
Received November 23, 2004
A facile conversion of formamides to isonitriles under very
mild conditions and microwave irradiation is described. This
simple and efficient method has been applied for the
synthesis of both aliphatic and aromatic isonitriles in high
yields.
Multicomponent reactions have become an important
component of the combinatorial chemist’s library, as a
great number of compounds can be produced in a rapid
parallel synthetic program.1 Thus, the Passerini2 and
Ugi3 reactions, for example, have become well-established
procedures in library synthesis.
One of the most important and recurring reagents of
these reactions, although very limited in accessibility, is
the isonitrile. Isonitriles are versatile intermediates, with
a extraordinary functional group, owing to their unusual
reactivity, acting as both nucleophiles and electrophiles
in the course of the reaction. Many natural isonitriles
are known to have a strong antibiotic, fungicidal, or
antineoplastic effect. Isonitriles are also used as versatile
building blocks for the synthesis of heterocyclic systems.4
Recently a series of terpene isonitriles have been reported
to show significant antimalarial activity in vitro.5
There are several methods reported for isonitrile
synthesis, by dehydration of formamides with various
reagents,6 using chlorodimethylformiminium chloride,7
phosphoryl chloride,8 phosgene9 or diphosgene,10 DAB-
In light of the improvements, microwave-assisted
organic synthesis has bestowed upon similar thermal
(6) Obrecht, R.; Hermann, R.; Ugi, I. Synthesis 1985, 400.
(7) Walborsky, H. M.; Niznik, G. E. J. Org. Chem. 1972, 37, 187.
(8) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239.
(9) Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K.
Angew. Chem., Int. Ed. Engl. 1965, 4, 472.
(10) Skorna, G.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1977, 16, 259.
(11) Barton, D. H. R.; Bowles, T:, Husinec, S.; Forbes, J. E.; Llobera,
A.; Porter, A. E. A.; Zard, S. Z. Tetrahedron Lett. 1988, 29, 3343.
(12) Bose, D. S.; Goud, P. R. Tetrahedron Lett. 1999, 40, 747.
(13) Launay, D.; Booth, S.; Clemens, I.; Merritt, A.; Bradley, M.
Tetrahedron Lett. 2002, 43, 7201. Crosignani, S.; Launay, D.; Linclau,
B.; Bradley, M. Mol. Diversity 2003, 7, 203.
(14) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett. 1999,
40, 4395. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org.
Chem. 1999, 64, 8962. Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei,
M. Synlett 2000, 275. De Luca, L.; Giacomelli, G.; Taddei, M. J. Org.
Chem. 2001, 66, 2534. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org.
Lett. 2001, 3, 1519. De Luca, L.; Giacomelli, G.; Porcheddu, A. Org.
Lett. 2002, 4, 553. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org.
Chem. 2002, 67, 5152. De Luca, L.; Giacomelli, G.; Porcheddu, A. J.
Org. Chem. 2002, 67, 6272.
(15) Cyanuric chloride in acetone was previously used as dehydrat-
ing agent of formamides only for the preparation of three simple
aliphatic isonitriles: Wittmann, R. Angew. Chem. 1961, 73, 219.
Contrary to the data reported by Wittmann for aliphatic isonitriles,
this procedure does not give any result when performed on aromatic
formamides and requires additional purification steps.
(16) Recent reviews: C. O. Kappe, Angew. Chem., Int. Ed. 2004,
43, 6250. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetra-
hedron 2001, 57, 9225. Larhed, M.; Hallberg, A. Drug Discovery Today
2001, 6, 406-416. Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin,
A. R. J. Comb. Chem. 2002, 4, 95.
(17) Garbacia, S.; Desai, B.; Lavastre, O.; Kappe, O. J. Org. Chem.
2003, 68, 9136. Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863.
Strauss, C. R. Angew. Chem., Int. Ed. 2002, 41, 3589.
(1) Recent reviews: Armstrong, R. W.; Combs, A. P.; Tempest, P.
A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. Do¨mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. Do¨mling, A. Curr.
Opin. Chem. Biol. 2002, 6, 306.
(2) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. Passerini, M.;
Ragni, G. Gazz. Chim. Ital. 1931, 61, 964. Andreana, P. R.; Liu, C. C.;
Schreiber, S. L. Org. Lett. 2004, 6, 4231.
(3) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386. Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72, 267.
Ugi, I.; Betz, W.; Fetzer, U.; Offermann, K. Chem. Ber. 1961, 94, 2814.
(4) Kobayashi, K.; Nakahashi, R.; Takanohashi, A.; Kitamura, T.;
Morikawa, O.; Konishi, H. Chem. Lett. 2002, 624. Tsunenishi, Y.;
Ishida, H.; Itoh, K.; Ohno, M. Synlett 2000, 1318. Moderhack, D.;
Daoud, A.; Ernst, L.; Jones, P. G. J. Prakt. Chem. 2000, 342, 707.
(5) Singh, C.; Srivastav, N. C.; Puri, S. K. Bioorg. Med. Chem. Lett.
2002, 12, 2277. Schwartz, O.; Brun, R.; Bats, J. W.; Schamalz, H.-G.
Tetrahedron Lett. 2002, 43, 1009.
10.1021/jo047924f CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/05/2005
J. Org. Chem. 2005, 70, 2361-2363
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