A novel multicomponent synthesis of polysubstituted 5-aminooxazole and its new scaffold-generating reaction to pyrrolo[3,4-b]pyridine

Article abstract of DOI:10.1021/ol007055q

matrix presented A novel three-component synthesis of 5-amino oxazole (1) is reported. Its subsequent reaction with α,β-unsaturated acyl chloride leads to polysubstituted pyrrolopyridine (2). A triple domino process, acylation/IMDA/retro-Michael cycloreve

Full text of DOI:10.1021/ol007055q

ORGANIC
LETTERS
2001
Vol. 3, No. 6
877-880
A Novel Multicomponent Synthesis of
Polysubstituted 5-Aminooxazole and Its
New Scaffold-Generating Reaction to
Pyrrolo[3,4-b]pyridine
Xiaowen Sun,† Pierre Janvier,† Gang Zhao,† Hugues Bienayme´,‡ and
,†
Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France, and
Rhoˆne-Poulenc Industrialisation, 24 AV. Jean-Jaures, F-69153 De´cines Cedex, France
zhu@icsn.cnrs-gif.fr
Received December 23, 2000
ABSTRACT
A novel three-component synthesis of 5-amino oxazole (1) is reported. Its subsequent reaction with r,â-unsaturated acyl chloride leads to
polysubstituted pyrrolopyridine (2). A triple domino process, acylation/IMDA/retro-Michael cycloreversion, was involved in the latter process.
The methodology allows the quick preparation, from simple and readily available inputs, of highly functionalized title compounds not easily
accessed by other methods.
Complexity-generating/diversity-oriented high throughput
synthesis of druglike compounds and libraries thereof has
been a recent focus in the arsenal of combinatorial synthe-
sis.1,2 Being capable of combining three or more reactants
together in a single ordered event, multicomponent reaction
(MCR) exemplified by the Ugi 4CR offers great possibility
for molecular diversity per step and is becoming a corner-
stone of combinatorial syntheses.3 Clearly, a proper union
of a MCR with other reactions in a sequential or a domino
process will further expand its potential.4,5 As part of our
research program directed at synthesizing druglike hetero-
cycles, we were interested in the development of a novel
multicomponent synthesis of polysubstituted 5-aminooxazole
(1) and its subsequent use as a chemical platform to generate
new scaffolds such as polysubstituted pyrrolo[3,4-b]pyridine
(2). While compound 1 is known to be a useful template in
designing bioactive peptides,6 the generic structure of 2 can
(4) Recent examples: (a) Kobayashi, S.; Nagayama, S. J. Am. Chem.
Soc. 1996, 118, 8977-8978. (b) Fokas, D.; Ryan, W. J.; Casebier, D. S.;
Coffen, D. G. Tetrahedron Lett. 1998, 39, 2235-2238. (c) Wang, H.;
Ganesan, A. Org. Lett. 1999, 1, 1647-1649. (d) Bienayme, H.; Bouzid, K.
Tetrahedron Lett. 1999, 40, 2735-2738. (e) Paulvannan, K. Tetrahedron
Lett. 1999, 40, 1851-1854. (f) Paulvannan, K.; Jacobs, J. W. Tetrahedron
1999, 55, 7433-7440. (g) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett.
2000, 2, 709-712. (h) Hulme, C.; Ma, L.; Cherrier, M.-P.; Romano, J. J.;
Morton, G.; Duquenne, C.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett.
2000, 41, 1883-1887.
(5) For reviews on the domino sequence, see: (a) Tietze, L. F.; Modi,
A. Med. Res. ReV. 2000, 20, 304-322. (b) Tietze, L. F.; Haunert, F. In
Stimulating Concepts in Chemistry; Shibasaki, M., Stoddart, J. F., Vo¨gtle,
F., Eds.; Wiley: New York, 2000; pp 39-64. (c) Tietze, L. F. Chem. ReV.
1996, 96, 115-136. (d) Filippini, M. H.; Rodriguez, J. Chem. ReV. 1999,
99, 27-76. (e) Bunce, R. A. Tetrahedron 1995, 51, 13103-13160.
† Institut de Chimie des Substances Naturelles.
‡ Rhoˆne-Poulenc Industrialisation.
(1) Schreiber, S. L. Science 2000, 287, 1964-1969.
(2) (a) Marx, M. A.; Grillot, A.-L.; Louer, C. T.; Beaver, K. A.; Bartlett,
P. A. J. Am. Chem. Soc. 1997, 119, 6153-6167. (b) Nicolaou, K. C.; Zhong,
Y. L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622-625; 625-628.
(c) Sheehan, S. M.; Lalic, G.; Chen, J. S.;. Shair, M. D. Angew. Chem., Int.
Ed. 2000, 39, 2714-2715.
(3) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(b) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647-
658. (c) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem.
1999, 6, 255-270. (d) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
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10.1021/ol007055q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/28/2001

be considered as a cyclic analogue of nicotinamide (3, Figure
1). Indeed, pyrrolopyridine 2 has attracted increased attention
implementation of such a novel synthetic sequence was the
purpose of the present communication.
The synthesis of oxazole has attracted renewed interest
as a result of its presence in a number of bioactive marine
natural products.14 However, none of the existing methods
could satisfy our general goal aimed at using oxazole as a
scaffold-generating template in a diversity-oriented synthetic
program. Consequently, an expeditious construction of
oxazole via a multicomponent reaction was sought. After
some experimentation, it was found that simply heating a
methanol solution of an aldehyde (4), an amine (5), and an
isocyanoacetamide (6) led to the formation of 5-amino
oxazole (1) in good yield.15 From three aldehyde inputs, eight
amine inputs, and two isonitrile inputs, some representative
oxazoles were synthesized (Figure 2.)16 The condensation
was performed with approximately equimolar quantities of
the three components, thus simplifying the purification step.
Under these mild conditions, ring-chain tautomerization of
isonitrile 6 to 2-unsubstituted oxazole via a nitrilium
intermediate was not observed,17 nor was the Pictet-Spengler
reaction even when (3,4-dimethoxy)phenethylamine 5a con-
taining a properly positioned electron-rich aromatic ring was
employed.18 With a secondary amine as input, a yield of pure
oxazole greater than 90% was obtained (1g and 1h). As
expected for the Ugi-type reaction, racemic oxazoles were
obtained when enantiomerically pure isonitriles 6 (R ) Bn
or phenyl) were used as inputs. On the other hand, when
proline methyl ester was used as the amine input, a moderate
asymmetric induction was observed that led to two separable
diastereomers in a ratio of 2.5/1 (1h). To the best of our
knowledge, this procedure represents the first multicompo-
nent synthesis of 2,4,5-trisubstituted oxazole.19
Figure 1.
as biologically active compounds such as central nervous
system agents,7 as herbicides8 and as antidiabetic agents.9
With a few notable exceptions,10 most of the reported
syntheses are based on the functionalization of azaphthal-
imide and thus are limited in scope.11
The reaction sequence we envisaged is highlighted in
Scheme 1. A three-component reaction of an aldehyde (4),
Scheme 1
In contrast to 5-alkoxyoxazole,20 studies on the cyclo-
addition of the 5-amino derivative are relatively rare.21,22
Kondrat’eva et al. have shown that the intermolecular
reaction of the latter with dienophile was quite sensitive to
the reaction conditions leading to [2 + 4], [2 + 3], and even
an amine (5), and a suitably functionalized isocyanoaceta-
mide (6) was sought to provide a key 5-aminooxazole (1),
which could then be used as a branching point to produce
diverse bioactive chemotypes.12 One possible new scaffold-
generating reaction was illustrated by its reaction with R,â-
unsaturated carboxylic acid chloride 7 to afford the pyrrol-
opyridine after a directed fragmentation.13 A successful
(13) For the concept of “from libraries to libraries”, see: Ostresh, J. M.;
Husar, G. M.; Blondelle, S. E.; Do¨rner, B.; Weber, P. A.; Houghten, R. A.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11138-11142.
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A. Tetrahedron Lett. 2000, 41, 4239-4242. (b) Nishida, A.; Fuwa, M.;
Naruto, S.; Sugano, Y.; Saito, H.; Nakagawa, M. Tetrahedron Lett. 2000,
41, 4791-4794. (c) Lee, J. C.; Song, I.-G. Tetrahedron Lett. 2000, 41,
5891-5894. (d) Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469-471.
(e) Lautens, M.; Roy, A. Org. Lett. 2000, 2, 555-557. (f) Phillips, A. J.;
Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165-
1168.
(6) (a) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Dettori, G. Eur. J.
Org. Chem. 2000, 3217-3222. (b) Von Geldern, T. W.; Kester, J. A.; Bal,
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Chem. 1996, 39, 957-967; 968-981.
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1988; Chem. Abstr. 1988, 109, 170430b.
(15) For syntheses of 5-amino oxazole, see: (a) Ferris, J. P.; Orgel, L.
E. J. Am. Chem. Soc. 1966, 88, 3829-3831. (b) Martin, A. R.; Ketcham,
R. J. Org. Chem. 1966, 31, 3612-3615. (c) Sekiya, M.; Suzuki, J. Chem.
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Heterocycl. Chem. 1980, 17, 711-715. (f) Freeman, F.; Kim, D. S. H. L.
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Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X.; Sun, J. Tetrahedron 1998, 54, 12445-
12456.
(16) The purity of the raw material was not measured carefully for the
individual reaction. From the 1H NMR spectra of the crude reaction mixture,
the purity of 1g and 1h exceeded 75%.
(17) Chupp, J. P.; Leschinsky, K. L. J. Heterocycl. Chem. 1980, 705-
709.
(9) Hitzel, V.; Geisen, K.; Werner, R.; Guenter, R. Ger. Offen. 2948522,
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878
Org. Lett., Vol. 3, No. 6, 2001

Figure 2. Isolated yield of analytically pure compound.
[2 + 2] cycloadducts. To channel these different reactivities
into a productive process, we set out to examine the
previously unexplored intramolecular cycloaddition of 5-
aminooxazole.23 The presence of the secondary amine in
compounds 1 provided an ideal handle for realization of this
endeavor. Heating a solution of oxazole 1a and acid chloride
(20) Reviews: (a) Hassner, A.; Fischer, B. Heterocycles 1993, 35, 1441-
1465. (b) Turchi, I. J.; Dewar, M. J. S. Chem. ReV. 1975, 75, 389-437. (c)
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Chizhov, O. S. IzV. Akad. Nauk. SSSR Ser. Khim. 1979, 1313-1322; Chem.
Abstr 1979, 91, 140753b. (c) Bogdanov, V. S.; Kondrat’eva, G. Y.;
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(23) For related examples, see: (a) Levin, J. L.; Weinreb, S. M. J. Org.
Chem. 1984, 49, 4325-4332. (b) Jung, M. E.; Street, L. J. J. Am. Chem.
Soc. 1984, 106, 8327-8329. (c) Subramanyam, C.; Noguchi, M.; Weinreb,
S. M. J. Org. Chem. 1989, 54, 5580-5585. (d) Levin, J. I. Tetrahedron
Lett. 1989, 30, 2355-2358. (e) Jung, M. E.; Dansereau, S. M. K.
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Liu, B. Org. Lett. 2000, 2, 3233-3235 and references therein.
Figure 3. Isolated yield of analytically pure compound.
7a (R5 ) COOEt) in toluene at reflux temperature led to
the formation of pyrrolopyridine 2a in 65% yield (Figure
3). Toluene was the solvent of choice as the same reaction
performed in other solvents such as THF, MeCN, and
benzene produced only low yields of the desired pyrrolo-
pyridine. Other acyl chlorides, such as p-nitro cinnamic acid
chloride 7b (R5 ) 4-NO2-C6H5) and p-methoxy cinnamic
acid chloride 7c (R5 ) 4-OMe-C6H5) can also be used as
dienophiles.
Org. Lett., Vol. 3, No. 6, 2001
879

temperature, we were able to isolate the intermediate 10 (R1
) n-C6H13, R2 ) 2-(3,4-dimethoxyphenyl) ethyl, R3 ) Bn).
The coupling constant between Ha and Hb (JHa-Hb ) 4.1 Hz)
indicated a gauche relationship (dihedral angle of 40° or so)
between these two protons. For the inherent ring strain
imposed by the connecting bridge, only the lactam-exo-ester
endo mode of cycloaddition was possible, leading to observed
compound 10. In this intermediate, the proton Hb is properly
aligned with the Cc-O bond, which facilitates the difficult
5-endo-trig reversal leading to 11 and morpholine 12, the
latter being isolated as its corresponding amide 13.25 Thus
for conformational reasons, this retro-Michael cycloreversion
dominated over the alternative fragmentation assisted by the
lone pair electron on the morpholine nitrogen (compound 8,
Scheme 1), an otherwise normal process.20-22
Scheme 2
In conclusion, we report a novel multicomponent synthesis
of polysubstituted 5-aminooxazole starting from simple and
readily available inputs. Its subsequent reaction with R,â-
unsaturated acyl chloride led to polyfunctionalized pyrrolo-
pyridine. The latter one-pot reaction involves a triple domino
sequence: acylation/IMDA/retro-Michael cycloreversion.
The chemistry described is especially suitable for combina-
torial synthesis since the oxazole and the bicyclic skeleton
of pyrrolopyridine can be “decorated” by different substit-
uents at will. The methodology developed should be easily
adapted to solid-phase synthesis as well as automation.
A possible reaction scenario is shown in Scheme 2. Thus,
acylation of secondary amine of oxazole 1 gave the amide
9, which underwent intramolecular Diels-Alder reaction
affording the bridged tricyclic intermediate (10). Base-
catalyzed retro-Michael cycloreversion then furnished the
pyrrolopyridine. The following facts are in accord with this
reaction sequence: (1) In sharp contrast to Kondrat’eva’s
reports,20 reaction between oxazole 1a and N-phenylmale-
imide did not give the corresponding cycloadduct, probably
because of the steric hindrance of oxazole 1a. This result
supports the idea that acylation preceded cycloaddition.24 (2)
When the reaction was carried out in CH2Cl2 at room
Acknowledgment. Financial support from Rhoˆne-Pou-
lenc Industralisation (X.W.S. and G.Z.), Rhodia (P.J.) ,and
CNRS is gratefully acknowledged. This paper is dedicated
with deep respect to Dr. R. Beugelmans
Supporting Information Available: Physical data for
compounds 1a-h, 2a-h, and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL007055Q
(24) Cyclic olefins are generally more reactive as dienophiles than their
acyclic counterparts in a given Diels-Alder reaction; see: (a) Vaughan,
W. R.; Anderson, K. S. J. Org. Chem. 1956, 21, 673-683. (b) Cookson,
R. C.; Gilani, S. S. H.; Stevens, I. D. R. Tetrahedron Lett. 1962, 615-618.
(25) Keay, B. A.; Rajapaksy, D.; Rodrigo, R. Can. J. Chem. 1984, 62,
1093-1098.
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