Scheme 2. Two-Step Sequence toward Substituted
5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic Acid Amides
Figure 1.
groups participating in a MCR are both present in the same
molecule versus cases wherein a molecule bears one
functional group necessary for the MCR plus a second
functional group for a ring-forming reaction. Of these
intramolecular possibilities, four have been already real-
ized: cyclic amides, e.g., cyclic hexapeptides A, five- to nine-
membered (benzo-)-lactams B, â-lactams and γ-lactames D,
and cyclic Schiff bases F, whereas amino isocyanide and
keto isocyanide derived C and E, respectively, are still to
be explored.2
We also proceeded to demonstrate that isocyanides,
primary amines, â-keto aldehydes, and phosphono acetic
acids react smoothly at ambient temperature in methanol to
afford the corresponding Ugi products and, analogous to the
strategy described above, to provide the six-membered
substituted 6-oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid amides under HWE conditions (Scheme 3).
Recently we communicated that glyoxals, phosphono
acetic acids, and isocyanides can be utilized to assemble
5-aminoacetylbutenolides in a very versatile and efficient
manner by a combination of Passerini and HWE reactions.3
Herein we want to introduce two more heterocyclic chemo-
types, which can be assembled utilizing a Ugi/HWE tandem
strategy.
Scheme 3. Two-Step Sequence toward Substituted
6-Oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic Acid Amides
We observed that isocyanides, primary amines, glyoxals,
and phospono acetic acids react smoothly under ambient
conditions in methanol to provide the corresponding Ugi
products. The subsequent HWE reaction, when performed
in THF at 0 °C utilizing LiCl and triethylamine as base,
results in the formation of the corresponding 5-oxo-2,5-
dihydro-1H-pyrrole-2-carboxylic acid amides (Scheme 2).
Some representative examples are shown in Table 1. During
the course of a preliminary investigation of the scope and
limitations of this strategy we realized that the use of
substituted phosphono acetic acids considerably reduced the
yields of the Ugi reaction.
Representative examples of this reaction scheme are shown
in Table 1. The identity of the products has been proven by
spectroscopic means and in one case, 2, by X-ray structure
analysis (Figure 2). Again the reaction is versatile in the
starting materials, comprising both aliphatic and aromatic
compounds. As with the pyrrolidinones, we noticed that
substituted phosphono acetic acids under the present reaction
conditions reacted poorly.
All of the compounds were obviously obtained as racemic
mixtures. An X-ray structure analysis of an intermediate Ugi
product 1 not surprisingly reveals the R-keto aminoacyl
moiety to be present in the enol form (Figure 1).
(2) Isocyano carboxylic acids as educts, e.g.: (a) Gockel, G.; Lu¨dke,
Ugi, I. In Isonitrile Chemistry; Ugi, I. Ed.; Academic Press: New York,
1971; p 159. Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R. Synthesis
1994, 672. Formyl(keto)carboxylic acids as educts, e.g.: (b) Gross, H.;
Gloede, J.; Keitel, I.; Kunath, D. J. Prakt. Chem. 1968, 37, 192. Harriman,
G. C. B. Tetrahedron Lett. 1997, 38, 5591. â-Amino acids and peptides as
educts, e.g.: (c) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810. Failli,
A.; Immer, H.; Go¨tz, M. Can. J. Chem. 1979, 57, 3257. Cyclic Schiff bases,
e.g.: (d) Do¨mling, A.; Ugi, I. Angew. Chem., Intl. Ed. Engl. 1993, 32, 563.
Do¨mling, A.; Ugi, I. Herdtweck, E. Acta Chem. Scand. 1998 52, 107.
Unprotected isocyano amines with a primary or secondary amine are mostly
unstable, but see, e.g., p-isocyano aniline: (f) New, R. G. A.; Sutton, L. S.
J. Chem. Soc. 1932, 1415. Kim, M.; Euler, W. B.; Rosen, W. J. Org. Chem.
1997, 62, 3766. Protected isocyano amines are known and very useful
compounds, e.g., in PNA synthesis: (g) Do¨mling, A. Nucleosides Nucle-
otides 1998, 17, 1667.
Figure 2.
(3) Beck, B.; Magnin-Lachaux, M.; Herdtweck E.; Do¨mling, A. Org.
Lett. 2001, 3, 2875.
Org. Lett., Vol. 6, No. 1, 2004
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