Highly Substituted Pyrrolidinones and Pyridones by 4-CR/2-CR Sequence

Article abstract of DOI:10.1021/ol035787n

(Equation presented) By combining a Ugi four-component reaction of isocyanides, phosphonoacetic acids, primary amines, and glyoxals or alternatively 3-keto aldehydes with a subsequent Wittig ring-closing reaction (using the Horner/Wadsworth/Emmons variant (HWE)), highly substituted 5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid amides and 6-oxo-1,2,3,6- tetrahydro-pyridine-2-carboxylic acid amides can be assembled, respectively. The corresponding tandem of a Passerini reaction on 3-keto aldehydes and subsequent Wittig ring closure does not afford the expected six-membered 6-oxo-3,6-dihydro-2H-pyran-2-carboxylic acid amides but instead leads to the formation of 4-oxo-pent-2-enoic acid amides via an elimination route.

Full text of DOI:10.1021/ol035787n

ORGANIC
LETTERS
2004
Vol. 6, No. 1
39-42
Highly Substituted Pyrrolidinones and
Pyridones by 4-CR/2-CR Sequence
,†
Barbara Beck,† Anne Picard,† Eberhardt Herdtweck,‡ and Alexander Do1mling*
Morphochem AG, Gmunderstr. 37-37a, 81379 Mu¨nchen, Germany,
and Anorganisch Chemisches Institut der Technischen UniVersita¨t Mu¨nchen,
Lichtenbergstr. 4, 85747 Garching, Germany
alexander.doemling@morphochem.de
Received September 16, 2003
ABSTRACT
By combining a Ugi four-component reaction of isocyanides, phosphonoacetic acids, primary amines, and glyoxals or alternatively 3-keto
aldehydes with a subsequent Wittig ring-closing reaction (using the Horner/Wadsworth/Emmons variant (HWE)), highly substituted 5-oxo-2,5-
dihydro-1H-pyrrole-2-carboxylic acid amides and 6-oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid amides can be assembled, respectively.
The corresponding tandem of a Passerini reaction on 3-keto aldehydes and subsequent Wittig ring closure does not afford the expected
six-membered 6-oxo-3,6-dihydro-2H-pyran-2-carboxylic acid amides but instead leads to the formation of 4-oxo-pent-2-enoic acid amides via
an elimination route.
Heterocycles are among the most important structural classes
of chemical substances and are particularly well-represented
among natural products and pharmaceuticals. It is estimated
that far more then 50% of the published chemical literature
concerns heterocyclic structures. One striking structural
feature inherent to heterocycles, which continues to be
exploited to great advantage by the drug industry, lies in
their ability to manifest substituents around a core scaffold
in a defined three-dimensional representation, thereby al-
lowing for far less degrees of conformational freedom than
the corresponding conceivable acyclic structures. In addition,
as a result of the presence of heteroatoms such as O, N, and
S, heterocycles often exhibit altered absorption, distribution,
metabolism, and excretion properties.
initial MCR. Of particular relevance to heterocycle synthesis
is the planned possibility that such functional groups can
then be utilized in a secondary reaction to enable ring closure
through various methodologies.
Theoretically, the combinations of the functional groups
of the classical Ugi reaction utilizing bifunctional educts
allow the construction of six topologically different cyclic
scaffolds (Scheme 1). Thus, for example, one can distinguish
between intramolecular variations wherein two functional
Scheme 1. Intramolecular Isocyanide-Based MCRs, via
Bifunctional Starting Materials
An especially effective and fruitful way to synthesize
heterocycles is by isocyanide-based MCR.1 This strategy
relies mostly on the classical Passerini and Ugi reactions.
All isocyanide-based MCRs are highly compatible with a
range of ancillary functional groups not taking part in the
† Morphochem AG.
‡ Anorganisch Chemisches Institut.
(1) For comprehensive reviews, see: Maccarchini, S.; Torroba, P. Org.
Prep. Proc. Intl. 1993, 25, 141. Do¨mling, A.; Ugi, I. Angew. Chem., Intl.
Ed. 2000, 39, 3168.
10.1021/ol035787n CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

Table 1. Some Produced Substituted 5-Oxo-2,5-dihydro-1H-pyrrole-2-carboxylic Acid Amides and
6-Oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic Acid Amidesb
a Mixture of diastereomers. b Total yields over both steps are given.
40
Org. Lett., Vol. 6, No. 1, 2004

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
41

almost all reactions, the expected cyclized product arising
from the HWE reaction was not obtained. Thus, we argued
that under the basic reaction conditions an elimination
reaction leading toward the highly conjugated 4-keto acrylic
acid amides must be occurring. This hypothesis was proven
by X-ray structure analysis of two crystalline products, 3
and 4 (Scheme 4).
Scheme 4
In conclusion, we report here the first convergent assembly
of five- and six-membered 5-oxo-2,5-dihydro-1H-pyrrole-
2-carboxylic acid amides and 6-oxo-1,2,3,6-tetrahydro-
pyridine-2-carboxylic acid amides, respectively. The unop-
timized overall yields for the two reaction steps are mostly
below 50%. From the standpoint of array synthesis, the
strategy described here has high potential utility. The needed
starting materials are broadly commercially available or are
easily synthesized.4 The chemistry is easily adaptable to a
96-well plate synthesis format. In our hands, the quality of
the products resulting from a filtration procedure through a
96-well filtration plate is mostly very high (>90% purity
by NMR). As an added advantage, in many cases the
products crystallize straight out of ethyl acetate.
Acknowledgment. This work is dedicated to Kris Venkat
on the occasion of his 57th birthday.
Supporting Information Available: General procedure
for the reactions and H and 13C NMR, X-ray, and HPLC
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
In analogy to the above-described MCR/HWE strategy
leading to the synthesis of pyridones, we were interested in
further investigating the feasibility of formation of the
corresponding oxo-counterparts, namely, 6-oxo-3,6-dihydro-
2H-pyran-2-carboxylic acid amides (Scheme 4). Surprisingly,
even though the Passerini intermediate could be detected in
OL035787N
(4) A versatile source of isocyanides: www.priaton.de
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Org. Lett., Vol. 6, No. 1, 2004