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L. El Kaim et al.
LETTER
(5) (a) Weber, W. P.; Gokel, G. W.; Ugi, I. K. Angew. Chem.,
Int. Ed. Engl. 1972, 11, 530. (b) Gokel, G. W.; Widera,
R. P.; Weber, W. P. Org Synth., Coll. Vol. VI 1988, 232.
(6) (a) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239. (b) Ugi, I.;
Fetzer, U.; Eholzer, U.; Knupper, H.; Offermann, K. Angew.
Chem., Int. Ed. Engl. 1965, 4, 472; Angew. Chem. 1965, 77,
492. (c) Ugi, I.; Meyr, R.; Lipinski, M.; Bodensheim, F.;
Rosendahl, F. Org. Synth., Coll. Vol. V 1973, 300.
(7) (a) O’Neil, I. A. In Comprehensive Organic Functional
Group Transformations, Vol 3; Katrizky, A. R.; Meth-Cohn,
D.; Rees, C. W., Eds.; Pergamon: Oxford, 1995, 693–726.
(b) Hoffman, P.; Gokel, G.; Marquading, D.; Ugi, I. In
Isonitrile Chemistry; Ugi, I., Ed.; Academic Press: New
York, 1971, 9. (c) Periasamy, M. P.; Walborsky, H. M. Org.
Prep. Proced. Int. 1979, 11, 293; and references cited
therein.
To the best of our knowledge, it is the first time that an
isocyanide can be synthesized and used without further
purification in a four-component process.22 The opera-
tional simplicity of the present protocol, combined with
the extreme foul odor of several isocyanides, which prob-
ably deterred many groups from working with them,
makes the method potentially attractive. We are still
exploring the scope of this process to develop further iso-
cyanide-based multicomponent reaction (IMCR) chemis-
try without intermediate purification of isocyanides.
Typical Procedure for the Product of Table 2, Entry 6
To a 3 M solution of bromide derivative (1.0 mmol, 1.0 equiv) in
MeCN were added AgCN (134 mg, 1.0 mmol, 1.0 equiv), KCN (65
mg, 1.0 mmol, 1.0 equiv), and Et3NBnCl (46 mg, 0.20 mmol, 20
mol%). The mixture was then stirred at 80 °C in a sealed vial over-
night. After completion of the formation of the isocyanide (checked
(8) Mukaiyama, T.; Nambu, H.; Okamoto, M. J. Org. Chem.
1962, 27, 3651.
(9) Makaiyama, T.; Masutani, K.; Minowa, T. Chem. Lett. 2005,
34, 1124.
1
(10) (a) Schröder, R.; Schöllkopf, U.; Blume, E.; Hoppe, I.
Justus Liebigs Ann. Chem. 1975, 533. (b) Whitney, S. E.;
Rickborn, B. J. Org. Chem. 1991, 56, 3058. (c) Pirrung,
M. C. J. Am. Chem. Soc. 2006, 128, 11772.
(11) (a) Gassman, P. G.; Guggenheim, T. L. J. Am. Chem. Soc.
1982, 104, 5849. (b) Imi, K.; Yanagihara, N.; Utimoto, K.
J. Org. Chem. 1987, 52, 1013. (c) Onaka, M.; Ohta, A.;
Sugita, K.; Izumi, Y. Appl. Catal., A 1995, 125, 203.
(12) (a) Gautier, A. Justus Liebigs Ann. Chem. 1867, 142, 289.
(b) Gautier, A. Ann. Chim. (Paris) 1869, 17, 103.
(c) Gautier, A. Ann. Chim. (Paris) 1869, 17, 203.
(13) Jackson, H. L.; McKusick, B. C. Org. Synth., Coll. Vol. IV
1963, 438.
(14) Heldt, W. Z. J. Org. Chem. 1961, 26, 2604.
(15) (a) Davis, T. L.; Yelland, W. E. J. Am. Chem. Soc. 1937, 59,
1998. (b) Carretero, J. C.; Garcia Ruano, J. L. Tetrahedron
Lett. 1985, 26, 3381. (c) Kitano, Y.; Manoda, T.; Miura, T.;
Chiba, K.; Tada, M. Synthesis 2006, 405.
(16) (a) Kitano, Y.; Chiba, K.; Tada, M. Tetrahedron Lett. 1998,
39, 1911. (b) Kitano, Y.; Nogata, Y.; Matsumara, K.;
Yoshimura, E.; Chiba, K.; Tada, M.; Sakaguchi, I.
Tetrahedron 2005, 61, 9969.
via H NMR analysis), the aldehyde (1.0 mmol, 1.0 equiv), the
amine (1.0 mmol, 1.0 equiv), and the nitrophenol (1.0 mmol, 1.0
equiv) were added to the mixture, which was then stirred at 80 °C
for 3 d. After checking the completion of the reaction via TLC, the
reaction was quenched with the addition of a 1 M NaOH soln, and
diluted with CH2Cl2. The aqueous phase was washed several times
with CH2Cl2, the organic phases were then collected, dried over an-
hyd MgSO4, and concentrated in vacuo. Finally, a flash column
chromatography on SiO2 afforded the desired product as a yellow
solid (42%); mp 131–132 °C. 1H NMR (400 MHz, CDCl3): d = 8.00
(d, J = 9.3 Hz, 2 H), 7.32–7.27 (m, 3 H), 7.21 (d, J = 7.1 Hz, 2 H),
6.71 (d, J = 9.3 Hz, 2 H), 6.54 (br s, 1 H), 5.83 (ddt, J = 17.2, 10.3,
5.3 Hz, 1 H), 5.24 (d, J = 10.3 Hz, 1 H), 5.21 (d, J = 17.2 Hz, 1 H),
4.45–4.40 (m, 3 H), 4.10 (dd, J = 17.4, 5.1 Hz, 1 H), 4.01 (dd,
J = 17.4, 5.1 Hz, 1 H), 2.10 (ddd, J = 14.1, 7.3, 5.8 Hz, 1 H), 1.79–
1.59 (m, 2 H), 0.96 (d, J = 6.3 Hz, 3 H), 0.93 (d, J = 6.3 Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 171.1, 153.3, 138.6, 138.2,
133.4, 129.1, 128.2, 128.0, 126.4, 118.7, 112.8, 62.2, 51.0, 44.2,
38.5, 25.6, 23.2, 22.7. IR (thin film): 2958, 1655, 1593, 1505, 1306,
1264, 1204, 1171, 1114 cm–1. HRMS: m/z calcd 381.2052; found:
381.2057.
(17) (a) Grigg, R.; Lansdell, M. I.; Thornton-Pett, M.
Tetrahedron 1999, 55, 2025. (b) Bon, R. S.; van Vliet, B.;
Sprenkels, N. E.; Schmitz, R. F.; de Kanter, F. J. J.; Stevens,
C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.; Orru,
R. V. A. J. Org. Chem. 2005, 70, 3542.
Acknowledgment
A.S. thanks the Délégation Générale de l’Armement for a fel-
lowship. Financial support was provided by the ENSTA.
(18) (a) Songstad, J.; Stangeland, L. J.; Austad, T. Acta Chem.
Scand. 1970, 24, 355. (b) Engemyr, L. B.; Martinsen, A.;
Songstad, J. Acta Chem. Scand., Ser. A 1974, 28, 255.
(19) Even if these conditions seemed promising, iron salts were
abandoned because we failed to perform the one-pot
multicomponent couplings with them.
(20) (a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem. Int. Ed.
2005, 117, 7961. (b) El Kaim, L.; Gizolme, M.; Grimaud,
L.; Oble, J. J. Org. Chem. 2007, 72, 4169. (c) Barthelon,
A.; El Kaïm, L.; Gizolme, M.; Grimaud, L. Eur. J. Org.
Chem. 2008, 35, 5974.
(21) Dai, W.-M.; Li, H. Tetrahedron 2007, 63, 12866.
(22) Though a previous one-pot isocyanide synthesis–Ugi
reaction sequence has been reported, the starting material
was already a benzyl isocyanide which was alkylated under
basic treatment: Tempest, P. A.; Brown, S. D.; Armstrong,
R. W. Angew. Chem., Int. Ed. Engl. 1996, 35, 640; Angew.
Chem. 1996, 108, 689.
References and Notes
(1) Lieke, W. Justus Liebigs Ann. Chem. 1859, 112, 316.
(2) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
(b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 180. (c) For a
recent review on Passerini reaction, see: Banfi, L.; Riva, R.
Org. React. 2005, 65, 1.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I.; Steinbrückner, C. Angew.
Chem. 1960, 72, 267. For recent reviews, see: (c) Dömling,
A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(d) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321. (e) Ugi, I.; Werner, B.; Dömling, A.
Molecules 2003, 8, 53. (f) Dömling, A. Curr. Opin. Chem.
Biol. 2002, 6, 306. (g) Multicomponent reactions; Zhu, J.;
Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005.
(h) Dömling, A. Chem. Rev. 2006, 106, 17.
(4) Hoffmann, A. W. Ann. Chem. Pharm. 1867, 144, 114.
Synlett 2009, No. 9, 1401–1404 © Thieme Stuttgart · New York