LETTER
Three-Component Reaction to N-Acyloxyethylamino Acid Amides
2283
H
(6) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron
1997, 53, 14381.
(7) (a) Bleikolm, A.; Griengl, H. Tetrahedron Lett. 1975, 2565.
H
N
N
O
N
tBu
O
OH
H
N
a or b
O
O
nHex
(b) Bleikolm, A.; Griengl, H. Liebigs Ann. Chem. 1976,
nHex
O
O
1783. (c) Bleikolm, A.; Griengl, H. Liebigs Ann. Chem.
1976, 1791.
nHex
5d
6
Ph
(
8) Giovenzana, G. B.; Tron, G. C.; Di Paola, S.; Menegotto, I.
G.; Pirali, T. Angew. Chem. Int. Ed. 2006, 45, 1099.
9) Bergmann, E. D. Chem. Rev. 1953, 53, 309.
Scheme 5 Reagents and conditions: a) p-TsOH (0.1 equiv),
PhCO H (1 equiv), t-BuNC (1 equiv), MeCN, reflux, 13% (5d), 25%
(
2
(
(
10) Oxazolidine Preparation (Method A); General
Procedure. A solution of the amino alcohol (20 mmol) and
aldehyde (20 mmol) in EtOH (20 mL) was stirred at r.t. for
90 min. The solvent was removed under reduced pressure;
EtOH (3 × 10 mL) was added, then removed under reduced
pressure repeatedly. The product was then dried under high
vacuum to give the oxazolidine as a colourless oil.
11) Oxazolidine Preparation (Method B); General
Procedure. A trace of iodine was added to a solution of
amino alcohol (174 mmol) and aldehyde (174 mmol) in
anhyd benzene (125 mL). The reaction mixture was heated
under Dean–Stark water-removal conditions for 90 min.
After removal of the solvent under reduced pressure the
residue was distilled under reduced pressure to give the
oxazolidine as a colourless oil.
(
6); b) p-TsOH (1 equiv), t-BuNC (1 equiv), MeCN, reflux 36% (6).
In summary, a novel multicomponent reaction between an
oxazolidine, an isocyanide, and a carboxylic acid has been
developed which provides ethanolamine derivatives in
good yield and readily allows the variation of functional
groups at five different sites within the product. The N-
acyloxyethylamino acid derivatives 5 provide a comple-
mentary product structure to those which are produced by
the well established Ugi and Passerini reactions and we
therefore anticipate that the reaction will be of value for
compound library synthesis. Further work is underway on
the extension of this and other related multicomponent re-
actions.
(
12) Multicomponent Reaction; Typical Procedure. 2-Hexyl-
3-methyloxazolidine (1b, 343 mg, 2 mmol), benzoic acid
(244 mg, 2 mmol), p-TsOH (38 mg, 0.2 mmol) and tert-butyl
isocyanide (166 mg, 2 mmol) were added to MeCN (5 mL)
and refluxed under an atmosphere of nitrogen for 21 h.
Excess solvent was removed under reduced pressure and the
crude product was purified by column chromatography (PE–
EtOAc, 4:1) to yield 2-[(tert-butylcarbamoylheptyl)methyl-
amino]ethyl benzoate (5d, 599 mg, 80%) as a colourless oil.
Rf 0.34 (hexanes–EtOAc, 2:1). IR: 3365 br (NH), 3026,
Acknowledgment
The provision of a studentship (to R.W.) by the EPSRC and Astra-
Zeneca is gratefully acknowledged.
References and Notes
2
948, 2926, 2856 (CH), 1724, 1674 (C=O), 1506 (NH)
(
1) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew.
Chem. 1959, 71, 386. (b) Ugi, I. Angew. Chem., Int. Ed.
Engl. 1962, 1, 8.
–
1 1
cm . H NMR (CDCl , 300 MHz): d = 0.74 (3 H, t, J = 6.9
3
Hz, Me), 1.16 (9 H, s, t-Bu), 1.17–1.41 (6 H, m, 3 × CH ),
2
1.44–1.59 (2 H, m, CH ), 1.62–1.77 (2 H, m, CH ), 2.23 (3
2
2
(
2) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
H, s, NMe), 2.77–2.87 (3 H, m, CH N, CHN), 4.32–4.47 (2
H, m, CH O), 6.62 (1 H, br s, NH), 7.40 (2 H, t, J = 7.8 Hz,
m-ArH), 7.53 (1 H, t, J = 7.8 Hz, p-ArH), 8.00 (2 H, d, J =
2
(
b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181.
2
(
3) (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187. (b) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51. (c) Zhu, J. P. Eur.
J. Org. Chem. 2003, 1133. (d) Hulme, C.; Nixey, T. Curr.
Opin. Drug Discov. Devel. 2003, 6, 921. (e) Domling, A.
Chem. Rev. 2006, 106, 17.
1
3
7
2
1
.8 Hz, o-ArH). C NMR (75 MHz, CDCl ): d = 14.0, 22.5,
3
7.2, 27.4, 28.6, 29.5, 31.6, 38.3, 50.2, 53.7, 62.7, 68.9,
28.3, 129.5, 130.0, 133.0, 166.4, 172.2. MS (FAB): m/z
+
(%) = 378 (18), 377 (74, M + H ), 375 (5), 277 (18), 276
(
(
4) (a) Normant, J. F.; Germon, C.; Alexakis, A. Bull. Soc.
Chim. Fr. 1984, 377. (b) Senkus, M. J. Am. Chem. Soc.
(
100), 154 (8). HRMS (FAB): m/z calcd for C H N O [M
2
2
37
2
3
+
+
H] : 377.28042; found: 377.28061.
1945, 67, 1515. (c) Maryanoff, B. E.; Nortey, S. O.;
(
13) Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.;
Gardocki, J. F. J. Med. Chem. 1984, 27, 1067.
5) (a) Bergmann, E. D.; Lavie, D.; Pinchas, S. J. Am. Chem.
Soc. 1951, 73, 5664. (b) Tararov, V. I.; Kadyrov, R.;
Riermeier, T. H.; Börner, A. Synlett 2002, 375.
Koh, H. Y.; Kim, Y. Org. Lett. 2001, 3, 4149.
Synlett 2006, No. 14, 2281–2283 © Thieme Stuttgart · New York