A novel three-component butenolide synthesis.

Article abstract of DOI:10.1021/ol016328u

[reaction: see text]. 5-Acylamino butenolides can be assembled by a multicomponent reaction (MCR) of isocyanides, glyoxals, and acetophosphonic acid diethylesters, followed by a intramolecular Wittig-type reaction. The reaction can be performed either in one pot or with the isolation of the intermediate Passerini product. This versatile reaction offers three independent inputs displayed in the final product. Applications in combinatorial chemistry and natural product synthesis can be envisioned.

Full text of DOI:10.1021/ol016328u

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2875-2878
A Novel Three-Component Butenolide
Synthesis
Barbara Beck,† Marina Magnin-Lachaux,† 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 June 22, 2001
ABSTRACT
5-Acylamino butenolides can be assembled by a multicomponent reaction (MCR) of isocyanides, glyoxals, and acetophosphonic acid diethylesters,
followed by a intramolecular Wittig-type reaction. The reaction can be performed either in one pot or with the isolation of the intermediate
Passerini product. This versatile reaction offers three independent inputs displayed in the final product. Applications in combinatorial chemistry
and natural product synthesis can be envisioned.
Reactions are the tool kits for chemists to create new matter
with novel properties. They are the basis for today’s organic
chemistry art of assembling complex molecules with pre-
defined properties. Interestingly, novel reactions are hardly
discovered any more.1 However, in the field of multicom-
ponent reactions, novel reactions are described frequently.2
This can be attributed to the tremendous possibilities of
MCRs compared to traditional two-component chemistry.3
The utility of a new reaction can be defined as giving a target
molecule in optimal yields while using as few synthetic steps
as possible and giving as few side products as possible,
thereby using environmentally benign processes. The above
criteria are very much approached by the concept of
multicomponent reactions.4
The concept of divergence and convergence in organic
synthesis is very useful. Convergent synthesis pathways
generally show advantages over linear or divergent ap-
proaches with respect to speed, time, yield, and reproduc-
ibility. Among organic reactions, multicomponent reactions
are highly convergent.5 During a multicomponent reaction,
more than two starting materials are assembled to afford a
complex product. Up to seven-component reactions have
been described so far.6 Therefore, they constitute a superior
tool for diversity-oriented and complexity-generating syn-
thesis for drug discovery.7
† Morphochem AG.
‡ Universita¨t Mu¨nchen.
(1) Barton, D. H. R. Aldrichimica Acta 1990, 23, 3.
(2) Recent examples: (a) Semple, J. E.; Owens T. D.; Nguyen, K.; Levy,
O. E. Org. Lett. 2000, 2, 2769-2772. (b) Zhang, J.; Jacobson, A.; Rusche,
J. R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074-1076. (c) Armstrong, R.
W. J. Org. Chem. 1998, 63, 867-871. (d) Nair, L. G.; Fraser-Reid, B.;
Szardenings, A. K. Org. Lett. 2001, 3, 317. (e) Heck, S.; Do¨mling, A. Synlett
2000, 424. (f) Ballini, R.; Bosica, G.; Conforti, M. L.; Maggi, R.; Mazzacani,
A.; Righi, P.; Sartori, G. Tetrahedron Lett. 2001, 57, 1395. (g) Dumetsre,
P.; El Kaim, L.; Gregoire, A. Chem. Commun. 1999, 775. (h) Shaabani,
A.; Yavari, I.; Teimouri, M. B.; Bazigir, A. Tetrahedron 2001, 57, 1375.
(i) Scheffler, G.; Justus, M.; Vasella, A.; Wessel, H. P. Tetrahedron Lett.
1999, 40, 5845. (j). Petasis, N. A.; Patel, Z. D. Tetrahedron Lett., 2000,
41, 9607.
Butenolides, also named 2(5H)-furanones, are ubiquitious
chemical moieties found in many natural products. They are
(4) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
(5) Beck, B.; Hess, S.; Do¨mling, A. Biorg. Med. Chem. Lett. 2000, 10,
1701.
(3) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000,
6, 3321.
(6) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1993, 32, 563.
(7) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709.
10.1021/ol016328u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/04/2001

typical products of a polyketide biochemical synthesis
pathway. Examples are the cardiotonic digitoxines 1 from
Digitaliz sp.8 and the antifungal (-)-incrustoporine9 2 (Figure
1). Rofecoxib 3 is a recently launched NSAID with a
procedure, furnished the butenolides in good to acceptable
yield.13 The overall transformation can be run with isolation
of the intermediate Passerini product or in a one-pot
procedure. The reaction proceeds under mild conditions and
is compatible with a wide range of functional groups. The
products belong to the class of 3,4-disubstituted 5-aminoacyl-
2(5H)-furanones. A X-ray structure of a typical example 4
is shown in Figure 2.14
Figure 1. Examples of pharmaceutically relevant butenolides.
butenolide core structure and is efficacious in treating
rheumatoid arthritis.10 There are many ways to synthesize
the butenolide moiety, but no one-pot multicomponent
approach has been published to the best of our knowlegde.11
In this Letter we report a new MCR of isocyanides,
arylglyoxals, and R-substituted diethylcarboxylicmethane-
phosphonates producing butenolides. The total transformation
is a combination of the Passerini three-component reaction
followed by a intramolecular Wittig-type reaction (Scheme
1). In the first step, the Passerini three-component reaction
Scheme 1
Figure 2. Above: X-ray structure of one molecule of 4A. Below:
A stereoview of a unit cell. Two crystallographic independent
molecules A and A′ are in the asymmetric unit. They are connected
by weak hydrogen bonds building a chain A...A′...A running parallel
to the b-axis of the unit cell.
of diethylcarboxylicmethanephosphonates, isocyanides, and
arylglyoxals takes place in good yield.12
Typically, the yield was nearly quantitative, and in many
cases the reaction product precipitates during the reaction.
The cyclization of this Passerini intermediate, using a
Horner-Wadsworth-Emmons modification of the Wittig
reaction with LiBr and Et3N in THF according to the Rathke
Three substituents in the products can be varied indepen-
dently of each other (Table 1). Each type of starting material
is easily accessible from its corresponding precursor. A
variety of R-substituted diethylcarboxylicmethanephos-
(8) Review: Repke, K. R. H.; Megges, R.; Weiland, J.; Scho¨n, R. Angew.
Chem., Int. Ed. Engl. 1995, 34, 282.
(9) Zapf, S.; Anke, T.; Sterner, O. Acta Chem. Scand. 1995, 49, 233.
(10) Scott, L. I.; Lamb, H. M. Drugs 1999, 3, 499.
(11) For a review on butenolide synthesis, see: (a) Rao, Y. S. Chem.
ReV. 1976, 76, 625. The reaction of R-acidic acetic acids (cyan acetic acid,
arensulfonylacetic acids, 2-nitrophenylacetic acid) with glyoxals and iso-
cyanides followed by Dieckmann-type condensations resulting in 5-ami-
noacyl-2(5H)-furanones has been reported: (b) Bossio, R.; Marcaccini, S.;
Pepino, R.; Torroba, T. Synthesis 1993, 783. (c) Bossio, R.; Marcaccini,
S.; Pepino, R. Liebigs Ann. Chem. 1994, 5, 527. (d) Marcaccini, S.; Pepino,
R.; Marcos, C. F.; Polo, C.; Torroba, T. J. Heterocyl. Chem. 2000, 37,
1501.
(13) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(14) X-ray single-crystal structure determination of 4 (crystallized from
acetic acid ethylester). Crystal data: C21H21NO3, Mr ) 335.39, orthorhombic,
space group Pbc21 (nonstandard Pca21; No. 29), a ) 9.9119(3), b )
19.0265(7), c ) 19.2249(5) Å, V ) 3625.6(2) Å3, Z ) 8, Fcalcd ) 1.229 g
cm-3, F(000) ) 1424, µ(Cu KR) ) 0.659 mm-1, T ) 293 K. Data
collection: Nonius CAD4 diffractometer, λ(Cu KR) ) 1.54180 Å, colorless
crystal 0.15 × 0.25 × 0.28 mm-3, unit cell parameters by least-squares for
25 reflections with 80.0° < 2θ < 89.5°. Structure solution and refinement:
direct methods (SHELXS-86a), full-matrix least-squares on F2 (SHELXL-
97b). (a) Sheldrick G. M. SHELXS-86, University of Go¨ttingen: Germany,
1997. (b) Sheldrick G. M. SHELXL-97, University of Go¨ttingen: Germany,
1997.
(12) Passerini, M. Gazz. Chim. Ital. 1924, 54, 529.
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Org. Lett., Vol. 3, No. 18, 2001

Table 1. Representative Examples of Butenolides Synthesized by the New 3-CR; Total Yields over Both Steps Are Given
a de ) 82%. b de ) 54% as determined by 1H NMR. c de could not be determined by 1H NMR. The relative stereochemistry could not be determined by
1H NMR.
phonates have been synthesized using the Arbuzov reaction
of halides with triethyl phosphite followed by treatment with
BuLi and carboxylation (Scheme 2).15 Although many
general methods toward isocyanides are known, the most
versatile access to isocyanides starts from primary amines
via formylation and dehydration.16 Many different syntheses
(15) Coutrot, P.; Ghribi, A. Synthesis 1986, 661.
Org. Lett., Vol. 3, No. 18, 2001
2877

intramolecular Wittig-type ring closure. The reaction is
highly versatile. The one-pot MCR protocol has several
distinct advantages over sequential multistep procedures.
These include superior atom economy,18 simplified workup
procedures, greater efficiency, and superior overall yields.19
Currently, we are investigating solid-phase procedures of the
above-described three-component butenolide synthesis.
Scheme 2
Supporting Information Available: General procedures
for the two-step synthesis as well as the one-pot synthesis,
1H and 13C NMR spectra of several butenolides and a
Passerini intermediate, and the data for the X-ray structure
analysis of 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
have been described toward glyoxals. For example, aryl-
glyoxals can be made by oxidation of the corresponding
acetophenones.17
In conclusion, we are reporting a new MCR, yielding
butenolides, by a sequence of a Passerini reaction and an
OL016328U
(16) Formamide dehydration: (a) Ugi, I.; Meyr, R. Angew. Chem. 1958,
70, 702. (b) Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239. Hoffmann’s
carbylamine method: (c) Weber, W. P.; Gokel, G. W.; Ugi, I. Angew.
Chem., Int. Ed. Engl. 1972, 11, 520. Meyer’s method (AgCN): (d) Meyer,
E. J. Prakt. Chem. 1866, 147. (e) Boullanger, P.; Descotes, G. Tetrahedron
Lett. 1976, 38, 4327. Gassman’s merhod (epoxides, TMS-CN): (f)
Gassman, P. G.; Guggenheim, T. L. J. Am. Chem. Soc. 1982, 104, 5849.
Appels method (PPh3, CCl4, NEt3): (g) Appel, R.; Kleistu¨ck, R.; Ziehn,
K. D. Angew. Chem., Int. Ed. Engl. 1971, 10, 132.
(17) (a) SeO2, dioxan/water: Edlin, C. D.; Faulkner, S.; Parker, D.;
Wilkinsom, M. P. J. Chem. Soc., Chem. Commun. 1996, 1249. (b) Aqueous
Cu(OAc)2: Evans, W. E.; Carr, C. J.; Krantz, J. C. J. Am. Chem. Soc. 1938,
60, 1628. (c) dmso, HBr: Ushami, K.; Isobe, M. Tetrahedron 1996, 37,
12061.
(18) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(19) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
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Org. Lett., Vol. 3, No. 18, 2001