Ammonium chloride-promoted four-component synthesis of pyrrolo[3,4-b] pyridin-5-one

Article abstract of DOI:10.1021/ja017563a

A novel multicomponent synthesis of 5-aminooxazole starting from simple and readily available inputs is described. Thus, simply heating a methanol solution of an aldehyde 3, an amine 4, and an α-isocyanoacetamide 5 provided the 5-aminooxazole (1) in good

Full text of DOI:10.1021/ja017563a

Published on Web 02/16/2002
Ammonium Chloride-Promoted Four-Component Synthesis of
Pyrrolo[3,4-b]pyridin-5-one
Pierre Janvier,† Xiaowen Sun,† Hugues Bienayme´,‡ and Jieping Zhu*,†
Contribution from the Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette, France, and Chrysalon, 11 AVenue A. Einstein,
69100 Villeurbanne, France
Received November 18, 2001
Abstract: A novel multicomponent synthesis of 5-aminooxazole starting from simple and readily available
inputs is described. Thus, simply heating a methanol solution of an aldehyde 3, an amine 4, and an
R-isocyanoacetamide 5 provided the 5-aminooxazole (1) in good to excellent yield. The reaction of 1 with
R,â-unsaturated acyl chloride 13 lead to the formation of pyrrolo[3,4-b]pyridin-5-one (2) in a single operation.
A triple domino sequence, acylation/IMDA/retro-Michael cycloreversion, is involved in this new scaffold-
generating reaction. After the observation that ammonium chloride can significantly accelerate the oxazole
formation in toluene, a one-pot four-component synthesis of 2 is developed.
Introduction
of the high-throughput synthesis has gradually been transformed
into a quality and strategy game such that synthetic libraries
Small polyfunctionalized heterocyclic compounds play im-
portant roles in the drug discovery process1 and in isolation and
structural identification of biological macromolecules.2,3 Indeed,
analysis of drugs in late development or on the market shows
that 68% of them are heterocycles. With the progress achieved
in the field of functional genomics and proteomics,4 more
information about the structures and functions of biologically
active macromolecules is becoming available. To match such a
formidable advance in biological research, the identification and
optimization of new small molecular chemical substances that
can specifically interact with therapeutical targets is of utmost
importance5 and constitute actually the bottleneck in medicinal
chemistry.6 It is therefore not surprising that researches in the
field of combinatorial synthesis of heterocycles and natural
product analogues have received special attention.7
were more and more oriented from oligomeric compounds to
nonoligomeric heterocyclic structures.10 Within this context, we
initiated a research program aimed at the development of highly
efficient synthesis of heterocyclic and macrocyclic compounds
by combined use of multicomponent reaction (MCR)11 and
domino processes.12 The guiding principle is to devise a novel
(8) For general reviews, see: (a) Thompson, L. A.; Ellman, J. A. Chem. ReV.
1996, 96, 555-560. (b) Balkenhohl, F.; Von dem Bussche-Hu¨nnefeld, C.;
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H. J. J. Am. Chem. Soc. 2000, 122, 9939-9953. (f) Nicolaou, K. C.;
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Q.; Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954-9967.
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Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 9968-9976. (h)
Wipf, P.; Reeves, J. T.; Balachandran, R.; Giuliano, K. A.; Hamel, E.;
Day, B. W. J. Am. Chem. Soc. 2000, 122, 9391-9395. (i) Sheehan, S. M.;
Lalic, G.; Chen, J. S.;. Shair, M. D Angew. Chem., Int. Ed. 2000, 39, 2714-
2715. (j) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-
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Combinatorial chemistry is now firmly integrated in the drug
discovery enterprise, for both lead identification and lead
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were considered to be library size.9 However, the number game
† Institut de Chimie des Substances Naturelles.
‡ Chrysalon.
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2000, 37, 669-674.
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Engl. 1998, 37, 688-749. (b) Hung, D. T.; Jamison, T. F.; Schreiber, S.
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9
2560 VOL. 124, NO. 11, 2002 J. AM. CHEM. SOC.
10.1021/ja017563a CCC: $22.00 © 2002 American Chemical Society

Synthesis of Pyrrolo[2,3-b]pyridin-5-one
A R T I C L E S
Scheme 1
Figure 1.
multicomponent synthesis of a heterocycle13 that is appropriately
functionalized, allowing it to be engaged in the subsequent
domino process. In an ideal case, the heterocycle obtained by
MCR should be polyfunctionalized in such a way that different
domino processes can be envisaged leading to completely
different but biologically relevant cyclic scaffolds.14 At the
current stage of development in this field, although the sequence
of MCR/postfunctionalization has been elegantly developed,15
the multicomponent synthesis of heterocycles that is susceptible
for further scaffold diversification and amplification is rare.16
In this paper, we describe a novel three-component synthesis
of 5-aminooxazole (1) and its subsequent one-pot triple domino
transformation to pyrrolopyridine 2 (Figure 1).17 A serendipitous
discovery that ammonium chloride can promote the Ugi-type
condensation in toluene allowed us to develop subsequently a
one-pot four-component synthesis of pyrrolopyridine.
domimetics.19 Recently, polyfunctionalized oxazoles20 and ox-
azole-containing macrocycles21 have also been designed and
used for multidirectional elaboration of combinatorial libraries
and for selective molecular recognition of smaller molecular
targets. 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.22,23 Conse-
quently, an expeditious construction of oxazole via multicom-
ponent reaction was sought. The sequence of event that we
envisaged is shown in Scheme 1. Thus, condensation of an
aldehyde 3 and an amine 4 should give the imine 6, which would
react with isonitrile 5 to produce the nitrilium intermediate 7.
This latter intermediate, after tautomerization would cyclized
to produce the desired oxazole 1. While the proposed sequence
seemed logical, two uncertainties persisted. First, it has been
reported that the reaction between imine and isonitrile occurred
only in the presence of acid catalysis.24 In Ugi 4CR, the role of
carboxylic acid is not only to trap the nitrilium intermediate
Results and Discussion
Three-Component Synthesis of 5-Aminooxazole. Synthesis
of oxazole has attracted a renewed interest due to its presence
in a number of bioactive marine natural products18 and its
application in the design of conformationally restricted pepti-
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Abbenante, G.; Fairlie, D. P. J. Am. Chem. Soc. 2001, 123, 333-334.
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J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2561

A R T I C L E S
Janvier et al.
Scheme 2
but also to activate the imine toward nucleophilic attack via
salt formation. However, aminooxazole is very unstable under
acidic consitions.25 Second, both the divalent isonitrile carbon
and the R- methylene carbon are nucleophilic in nature; hence,
their relative reactivity needed to be carefully controlled if one
wanted to favor one particular reaction manifold. The rich
chemistry of R-isocyanoacetate and TOSMIC developed by
Scho¨llkopf26 and Van Leusen,27 respectively, is based on the
nucleophilicity of the R-methylene carbon.28
Matsumoto and co-workers reported in 1978 that simply
heating a solution of 4-chlorobenzaldehyde (9), methyl R-iso-
cyanoacetate (10), and piperidine (11) in MeOH led to the
formation of amidine 12 in ∼50% yield (Scheme 2).29 The
reaction is suggested to be initiated by the Knoevenagel
condensation followed by a formal R-addition of the secondary
amine onto the isocyano group. It is thus evident that the relative
nucleophilicity of the R-methylene carbon and that of the
divalent isonitrile carbon needed to be counterbalanced in order
to orient the three-component reaction toward the direction we
expected.
Toward this end, we thought to use the R-isocyanoacetamide
instead of the R-isocyanoacetate for the following reasons. First,
The pKa(RCH) of an amide is 2-4 units higher than that of an
ester. Consequently, the R-methylene proton of amide should
be less easily deprotonated. The fact that the amide function is
less electron-withdrawing than the ester function should also
render the isonitrile carbon slightly more nucleophilic. Second,
the higher Lewis basicity of amide oxygen than the ester
counterpart should kinetically favor the ring-forming process.
Since oxazole formation is nonreversible, the increased reaction
rate of this step should provide the overall driving force to the
desired sequence. Experimentally, it was found that simply
heating a methanol solution of heptaldehyde (3a), 2-(3′,4′-
dimethoxy)phenethylamine (4a), and an isocyanoacetamide 5a
led to the formation of 5-aminooxazole (1a, R1 ) nC6H13,
Figure 2.
R2 ) 2-(3′,4′-dimethoxy)phenethyl, R3 ) Bn, X ) morpholinyl;
Scheme 1) in good yield.30 Neither imidazoline nor amidine
resulting from the competitive aldol- (Knoevenagel) and
Mannich-type condensation was observed.31 The desired se-
quence dominated over the Pictet-Spengler condensation since
no tetrahydroisoquinoline was isolable.32 Apparently, the in-
termolecular reaction between isonitrile and the imine interme-
diate was faster than the intramolecular trapping of the imine
by a properly positioned electron-rich aromatic ring under these
conditions. From 6 aldehydes, 12 amines, and 3 isonitriles
(Figure 2), some representative oxazoles synthesized are listed
in Figure 3. The condensation can be performed with ap-
proximately equimolar quantities of three components, simplify-
ing the purification step. Under these mild conditions, ring-
chain tautomerization of isonitrile to 2-unsubstituted oxazole
via a nitrilium intermediate was not observed.33 With secondary
amine as input, higher than 90% yield of pure oxazole was
obtained (1g, 1h). As expected for an Ugi-type reaction, racemic
(24) (a) Deyrup, J. A.; Vestling, M. M.; Hagan, W. V.; Yun, H. Y. Tetrahedron
1969, 25, 1467-1478. (b) Deyrup, J. A.; Killion, K. K. J. Heterocycl. Chem.
1972, 1045-1048.
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(26) For reviews, see: (a) Scho¨llkopf, U. Angew. Chem. Int. Ed. Engl. 1997,
16, 3339-348. (b) Marcaccini, S. Org. Prep. Proceed. Int. 1993, 25, 141-
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(27) Van Leusen, A. M.; Van Leusen, In Encyclopedia of Reagents for Organic
Synthesis, Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, pp 4973-
4979.
(28) For recent selected examples, see: (a) Barton, D. H. R.; Zard, S. Z. J.
Chem. Soc. Chem. Commun. 1985, 1098-1099. (b) Kulkarni, B. A.;
Ganesan, A. Tetrahedron Lett. 1999, 40, 5633-5636. (c) Sisko, J. Kassick,
A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem.
2000, 65, 1516-1524 and references therein.
(29) Suzuki, M.; Nunami, K.-I.; Moriya, T.; Matsumoto, K.; Yoneda, N. J. Org.
Chem. 1978, 26, 4933-4935.
(30) Alternative syntheses of 5-amino oxazole: (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) M. Sekiya, J. Suzuki, Chem. Pharm.
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(31) The same reaction using the corresponding methyl R-isocyano ester as input
led to a complex reaction mixture from which oxazole could be isolated in
less than 20% yield. P. Cristau, unpublished results.
(32) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797-1842.
9
2562 J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002

Synthesis of Pyrrolo[2,3-b]pyridin-5-one
A R T I C L E S
synthesis of vitamine B6 (pyridoxine) was developed by Merck
chemists in the 1960s.40 By analogy, we thought to exploit
similar chemistry to develop a one-pot domino process to access
the pyrrolopyridine 2. Interestingly enough, studies on the
cycloaddition of the 5-amino derivative were relatively rare in
contrast to its 5-alkoxy counterpart. Kondrat’eva et al. showed
that the intermolecular reaction of 5-aminooxazole with dieno-
phile was quite sensitive to the reaction conditions and various
pathways involving [2 + 4], [2 + 3], and even [2 + 2]
cycloaddition could occur.41,42 To channel these different
reactivities into a productive process, we set out to examine
the previously unexplored intramolecular cycloaddition of
5-aminooxazole.43 The presence of the secondary amine in
compounds 1 provided an ideal handle for realization of this
endeavor. Eventually, stirring a solution of oxazole 1a and acid
chloride 13a (R5 ) COOEt) in toluene at 0 °C for 30 min
followed by heating to reflux provided the pyrrolopyridine 2a
in 65% yield (Scheme 3). Toluene was the solvent of choice as
the same reaction performed in other solvents such as THF,
MeCN, and benzene produced only a low yield of the desired
pyrrolopyridine. Other acyl chlorides, such as p-nitrocinnamic
acid chloride (13b; R5 ) 4-NO2-C6H5) and p-methoxycinnamic
acid chloride (13c; R5 ) 4-MeO-C6H5) can also be used as
dienophile leading to pyrrolopyridines with a biaryl unit (Figure
4). The presence of an ester and a nitro function is particularly
interesting since it provided an extra diversity point. One of
such an example is shown in Scheme 3. Thus, stirring a solution
of pyrrolopyridine 2a and 2-(3′,4′-dimethoxy)phenethylamine
(4a) in dichloromethane in the presence of 2-hydroxypyridine
(14) provided the amide 15 in over 95% yield.44 In the absence
Figure 3.
(36) (a) Sattler, H.-J.; Schunack, W. Chem. Ber. 1975, 108, 1003-1009. (b)
Goto, T.; Saito, M.; Sato, R. Bull. Chem. Soc. Jpn. 1987, 60, 4178-4180.
(c) Hitchings, G. J.; Vernon, J. M. J. Chem. Soc.. Chem. Commun. 1988,
623-624. (d) Hitchings, G. J.; Vernon, J. M. J. Chem. Soc. PT1 1990,
1757-1763. (e) Goto, T.; Utsunomiya, S.; Aiba, H.; Hayasaka, H.; Endo,
M.; Watanabe, R.; Ishizaki, T.; Sato, R.; Saito, M. Bull. Chem. Soc. Jpn.
1991, 64, 1901-1910. (f) Anzini, M.; Cappelli, A.; Vomero, S.; Cagnotto,
A.; Skorupska, M. J. Heterocycl. Chem. 1992, 29, 1111-1115. (g) Kuno,
A.; Sakai, H.; Sugiyama, Y.; Takasugi, H. Chem. Pharm. Bull. 1993, 41,
156-162.
(37) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1972, 11, 1031-1032. (b)
Campbell, J. B.; Firor, J. W. J. Org. Chem. 1995, 60, 5243-5249.
(38) Bhandari, A.; Li, B.; Gallop, M. A. Synthesis 1999, 1951-1960.
(39) For a review, see: (a) Karpeiskii, M. Ya, Florent’ev, V. L. Russ. Chem.
ReV. 1969, 38, 540-546. For general reviews on oxazole chemistry, see:
(b) Hassner, A.; Fischer, B. Heterocycles 1993, 35, 1441-1465. (c) Turchi,
I. J.; Dewar, M. J. S. Chem. ReV. 1975, 75, 389-437. (d) Lakhan, R.;
Ternai, B. In AdVances in Heterocyclic Chemistry; Katritzky, A. R., Boulton,
A. J., Eds.; Academic Press: New York, 1974; Vol. 17, 99-211. (e) Boger,
D. L. Chem. ReV. 1986, 86, 781-793. (f) Lipshutz, B. H. Chem. ReV. 1986,
86, 795-819.
(40) (a) Harris, E. E.; Firestone, R. A.; Pfister, K., III; Boettcher, R. R.; Cross,
F. J.; Currie, R. B.; Monaco, M.; Peterson, E. R.; Reuter, W. J. Org. Chem.
1962, 27, 2705-2706. (b) Firestone, R. A.; Harris, E. E.; Reuter, W.
Tetrahedron 1967, 23, 943-955.
(41) (a) Kondrat’eva, G. Y.; Aitzhanova, M. A.; Bogdanov, V. S. IzV. Akad.
Nauk. SSSR. Ser. Khim. 1976, 2146-2147; Chem. Abstr. 1977, 86, 121223j.
(b) Kondrat’eva, G. Y.; Aitzhanova, M. A.; Bogdanov, V. S.; 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.; Aitzhanova, M. A.
IzV. Akad. Nauk. SSSR. Ser. Khim. 1980, 1017-1029; Chem. Abstr. 1980,
93, 185242s.
oxazoles were obtained when enantiomerically pure isonitriles
5 (R ) Bn, phenyl) were used as inputs. On the other hand,
using proline methyl ester as amine input, a moderate asym-
metric induction was observed leading to two separable dia-
stereomers in a ratio of 2.5/1 (1h). To the best of our knowledge,
this procedure consists of the first multicomponent synthesis
of 2,4,5-trisubstituted oxazole.34
From 5-Aminooxazole to Pyrrolo[3,4-b]pyridin-5-one by
a Triple Domino Process. The 6,7-dihydro-5H-pyrrolo[3,4-b]-
pyridin-5-one (2), a cyclic analogue of nicotinamide and an aza
nalogue of isoindolinones, has been used as pharmacophore by
many research laboratories,35 which has led to the development
of number of new synthetic routes.36-38 Except for Bhandari
and Gallop’s elegant multistep solid-phase synthesis,38 most of
the syntheses started from the azaphthalimide and hence are
limited in scope as they were not amenable for diversity
incorporation on the heterocyclic ring.
It has been known for half a century thanks to the seminal
contribution of Kondrat’eva39 that the aza-diene system of
5-alkoxyoxazole reacts readily with the activated dienophile to
give a [2 + 4] cycloadduct. Based on this reaction, a landmark
(42) (a) McEwen, W. E.; Grossi, A. V.; MacDonald, R. J.; Stamegna, A. P. J.
Org. Chem. 1980, 45, 1301-1308. (b) Shimada, S. J. Heterocycl. Chem.
1987, 24, 1237-1241.
(33) Ring-chain tautomization of R-isocyanoacetate to oxazole is well known;
see: (a) Chupp, J. P.; Leschinsky, K. L. J. Heterocycl. Chem. 1980, 705-
709. (b) Maeda, I.; Togo, K.; Yoshida, R. Bull. Chem. Soc. Jpn. 1971, 44,
1407-1410.
(34) For a two-step synthesis via a key 3C Passerini reaction, see: Bossio, R.;
Marcaccini, S.; Pepino, R. Liebigs Ann. Chem. 1991, 1107-1108.
(35) (a) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer, T.; Bruni,
G.; Romeo, M. R.; Basile, A. S. J. Med. Chem. 1996, 39, 4275-4284. (b)
Duerr, D.; Brunner, H. G.; Szczepanski, H. U.S. Patent US4721522, 1988;
Chem. Abstr. 1988, 109, 170430b. (c) Hitzel, V.; Geisen, K.; Werner, R.;
Guenter, R. Ger. Offen. 2948522, 1981; Chem. Abstr. 1981, 95, 150632h.
(43) 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. Heterocycles
1994, 39, 767-778. (f) Vedejs, E.; Piotrowski, D. W.; Tuci, F. C. J. Org.
Chem. 2000, 65, 5498-5505. (g) Padaw, A.; Dimitroff, M.; Liu, B. Org.
Lett. 2000, 2, 3233-3235. (h) Paquette, L. A.; Efrenov, I. J. Am. Chem.
Soc. 2001, 123, 4492-4501.
(44) Rony, P. R. J. Am. Chem. Soc. 1969, 91, 6090-6096.
9
J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2563

A R T I C L E S
Janvier et al.
Scheme 3
Figure 4.
Table 1. Three-Component Synthesis of Oxazole in Toluene, a
Salt Effect
entry
additiveb
temp (°C)/time (h)
yield (%)a
of bifunctional catalyst 14, no transamidation occurred under
such mild conditions.
1
2
3
4
5
6
7
8
9
10
11
12
10
none
none
none
BF3‚Et2O
LiBr
Et3N‚HCl
pyridine‚HCl
2,6-lutidine.HCl
NH4Cl
rt/4
24
68
32
ndc
49
71
69
69
73
34
36
67
69
rt/96
60/4
60/4
60/4
60/4
60/4
60/4
60/4
60/4
60/4
60/4
60/4
Ammonium Chloride-Promoted Three-Component Reac-
tion in Toluene and a Four-Component Synthesis of Pyr-
rolopyridine. Having developed a two-step synthesis of pyr-
rolopyridine using 5-aminooxazole as the chemical platform, a
one-pot four-component reaction to the same pyrrolopyridine
was next sought. To be able to combine two steps in a single
operation, an appropriate choice of solvent is crucial. Since
N-acylation was involved in the conversion of aminooxazole 1
to pyrrolopyridine 2, the protic solvent that was the solvent of
choice for the three-component synthesis of oxazole is better
avoided. On the other hand, toluene has been found to be a
good solvent for the triple domino process. We therefore thought
to examine conditions that could allow us to perform the three-
component synthesis of oxazole in the same solvent. Experi-
mentally, it was observed that three-component reaction of
heptaldehyde (3a), n-butylamine (4g), and isocyanoacetamide
(5a) proceeded very slowly in toluene and long reaction time
was required to obtain a reasonable conversion (Table 1, entries
1-3). To accelerate the oxazole formation, we surmised that
either a Bro¨nstedt acid or a Lewis acid would be required.
Toward this end, a number of reaction conditions varying
additives were examined and the results are summarized in
Table 1.
BuMe3NCl
Bu4NI
CSAd
Bu4NI/CSAe
a Unless specified, 1.5 equiv of additive was used. b Isolated yield of
pure 5-aminooxazole. c Intractable tars. d Additive, 0.1 equiv. e A total of
1.5 equiv of Bu4NI together with 0.1 equiv of CSA.
promoters, the best being ammonium chloride (entry 9). Thus,
simply heating the amine 4g, the aldehyde 3a, and the isonitrile
5a in toluene in the presence of 1.5 equiv of ammonium
chloride, the desired oxazole 1m was isolated in 73% yield.
Several points deserve further comments. First, the hydrochlo-
ride salts of tertiary amines (triethylamine, entry 6), as well as
those of pyridine and 2,6-lutidine, are capable of accelerating
the reaction (entries 7 and 8), and so did a catalytic amount of
camphorsulfonic acid (CSA, 0.1 equiv). However, addition of
an excess of protic acid is detrimental due to the decomposition
of 5-aminooxazole. Second, increasing the ionic strength of the
reaction medium seems not to be responsible for the rate-
accelerating effect of ammonium salt since only a negligible
effect was observed when trimethylbenzylammonium chloride
or tetrabutylammonium iodide (Bu4NI) was used as the promotor
(entries 10 and 11).47 On the other hand, a combined use of
Bu4NI (1.5 equiv) and CSA (0.1 equiv) restored the efficiency
While a strong Lewis acid led to the formation of intractable
tars due most probably to the instability of the 5-aminooxazole,45
a weak Lewis acid such as LiBr was found to be able to promote
the 3CR, leading to oxazole in 49% yield (entry 5).46 On the
other hand, the weak Bro¨nstedt acids proved to be far better
(45) For Lewis acid-catalyzed reaction of isocyanide, see: (a) Mu¨ller Von, E.
Zeeh, B. Liebigs Ann. 1966, 696, 72-80. (b) Ito, Y.; Kato, H.; Saegusa,
T. J. Org. Chem. 1982, 47, 741-743. (c) Kobayashi, K.; Irisawa, S.;
Matoba, T.; Matsumoto, T.; Yoneda, K.; Morikawa, O.; Konishi, H. Bull.
Chem. Soc. Jpn. 2001, 74, 1109-1114.
(46) For a LiBr-promoted three-component synthesis of tetracyclic tetrahy-
droisoqunoline, see: Gonzalez-Zamora, E.; Fayol, A.; Bois-Choussy, M.;
Chiaroni, A.; Zhu, J. J. Chem. Soc., Chem. Commun. 2001, 1684-1685.
(47) McFarland, J. M. J. Org. Chem. 1963, 28, 2179-2181.
9
2564 J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002

Synthesis of Pyrrolo[2,3-b]pyridin-5-one
A R T I C L E S
Figure 5.
observed with protic additives. Therefore, we assume that the
role of ammonium chloride was to provide a proton source that
is able to form an hydrogen bond with the imine intermediate,
favoring subsequently the nucleophilic attack of isonitrile. It is
worthy noting that ammonium chloride, a potential donor of
NH3, did not participate in this reaction under these mild
conditions.48 Some representative oxazoles synthesized using
ammonium chloride as promoter in toluene are listed in Figure
5. Interestingly, the present conditions allowed us to use
aromatic aldehydes as input to give compounds 1j and 1k in
good yield.
If a hydrochloride salt of amine was used as input, neutraliza-
tion in situ with triethylamine in toluene followed by addition
of aldehyde and isonitrile led to the corresponding 5-aminoox-
azole 1f in 75% yield. Apparently, the stoichiometric amount
of Et3N‚HCl generated in situ is enough to promote this
multicomponent reaction.
Figure 6.
Scheme 4
With these conditions in hand, the development of a one-pot
four-component synthesis of pyrrolopyridine was straightfor-
ward. Thus, a solution of an aldehyde, an amine, and an isonitrile
(60 °C) in the presence of 1.5 equiv of ammonium chloride
was stirred at room temperature. Once oxazole formation was
deemed complete by TLC analysis, an appropriate R,â-
unsaturated acyl chloride and triethylamine was added at 0 °C.
Heating to reflux produced pyrrolopyridine in good yield. Some
representative structures synthesized by this novel procedure
were listed in Figure 6. Both aromatic and aliphatic aldehydes
participate well in this reaction. Amino ester took part in this
reaction, effectively leading to the functionalized pyrrolopyridine
as a separable mixture of two diastereomers. The conditions
are sufficiently mild so that no epimerization was observed. It
is nevertheless appropriate to point out that 4-nitrobenzaldehyde
did not participate in the reaction sequence, nor did the methyl
valinate. The former may be the result of electronic effect while
the latter may be due to the severe steric congestion around the
nitrogen atom. The yield is generally higher than the two-step
procedure, which signifies that oxazole formation is in fact a
much cleaner reaction than the isolated yield may indicate.
Partial degradation of the oxazole during the column chroma-
tography purification (SiO2) may account for the phenomenon.
Discussion
shown in Scheme 4. Thus, acylation of the secondary amine of
oxazole 1 gave the amide 16, which underwent intramolecular
Diels-Alder reaction affording the bridged tricycle intermediate
17. 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,
reaction between oxazole 1a and N-phenylmaleimide did not
For the conversion of 5-aminooxazole to pyrrolopyridine, a
possible reaction scenario involving a triple domino process is
(48) For NH4Cl as a doner of NH3, see: (a) Matier, W. L.; Owens, D. A.; Comer,
W. T.; Deitchman, D.; Ferguson, H. C.; Seidehamel, R. J.; Young, J. R. J.
Med. Chem. 1973, 16, 901-908. (b) Larsen, S. D.; Grieco, P. A. J. Am.
Chem. Soc. 1985, 107, 1768-1769.
9
J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2565

A R T I C L E S
Janvier et al.
time, we assume that steric effect is not responsible for such an
“anomaly” since 17c readily fragmented by a retro-Michael
process to give the pyrrolopyridine 2i.
Conclusion
In summary, we reported a novel multicomponent reaction
leading to polysubstituted 5-aminooxazole starting from simple
and readily available inputs. Its subsequent new scaffold-
generating reaction involving a triple domino sequence, acyla-
tion/IMDA/retro-Michael cycloreversion, led to polyfunction-
alized pyrrolopyridine in a single operation. Key to the sequence
design is the use of R-isocyanoacetamide instead of the
R-isocyanoacetate that completely suppressed the alternative
reaction pathway initiated by the R-methylene carbon nucleo-
philicity. The observation that ammonium chloride can acceler-
ate the oxazole formation in toluene permitted us to develop
subsequently a one-pot four-component synthesis of pyrrolo-
pyridine. The observed beneficial effect of ammonium chloride
may be a general phenomenon and should find application in
designing novel multicomponent reactions based on the isonitrile
chemistry.51 The reaction sequence developed herein is espe-
cially suitable for combinatorial synthesis since the skeleton of
both 5-aminooxazole and pyrrolopyridine can be decorated by
different substituents. Further work based on the pairwise use
of MCR/Domino process is in progress and will be reported in
due course.52
Figure 7.
give the corresponding cycloadduct. This result supported the
idea that acylation preceded cycloaddition.49 (2) When the
reaction was carried out in CH2Cl2 at room temperature, we
were able to isolate the intermediate 17a (R1 ) n-C6H13, R2 )
2-(3′,4′-dimethoxy)phenethyl, R3 ) Bn, R5 ) COOEt; Figure
7) The coupling constant between Ha and Hb (JHa-Hb ) 4.1 Hz)
indicated a gauche relationship (dihedral angle of 40°c 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
17. In this intermediate, the proton Hb is properly aligned with
the Cc-O bond, facilitating the difficult 5-endo-trig reversal.
The morpholine 19 generated was in situ acylated leading to
amide 20.50 Thus, for conformational reasons, this retro-Michael
cycloreversion dominated over the alternative fragmentation
assisted by the lone pair electrons on the morpholine nitrogen,
an otherwise “normal process”. It is worth noting that alternative
reaction pathways of 5-aminooxazoles such as [2 + 3] cycload-
dition were not observed under these reaction conditions.
The residue R3 exerted influence on both the stability of oxa-
bridged tricyclic compound 17 and the fragmentation pathway.
Thus, compound 17b bearing a phenyl substituent is stable and
did not fragment to the pyrrolopyridine under standard reaction
conditions (toluene, Et3N, 110 °C). Under acidic conditions, 17b
was either recovered from the reaction mixture (AcOH, room
temperature to 80 °C) or completely decomposed to an
intractable mixture (AcOH, refluxing in toluene and TFA, CH2-
Cl2, room temperature). Only by refluxing a toluene solution
of 17b in the presence of DBU did the fragmentation occur to
provide pyrrolopyridine 21 in 65% yield. It is interesting to note
that, in this case, the fragmentation was assisted by the lone
pair of nitrogen leading to 21 with a morpholinyl substituent.
While no clear-cut explanation can be offered at the present
Experimental Section
Three-Component Synthesis of 5-Aminooxazole (1) (Procedure
A, in Methanol). A solution of amine (0.20 mmol, 1.3 equiv) and
aldehyde (0.18 mmol, 1.2 equiv) in dry methanol (1 mL) was stirred
at room temperature for 30 min. Isocyanide (0.15 mmol) was then
added. The reaction mixture was stirred at 60 °C, and the reaction course
was followed by TLC. After the disappearance of isonitrile (typically
4 h), the reaction mixture was cooled to room temperature and the
solvent was evaporated. The crude reaction mixture was purified by
flash chromatography (silica gel, eluent: AcOEt/Hept or CH2Cl2/
MeOH) to give the corresponding oxazole.
Ammonium Chloride-Promoted Three-Component Synthesis of
5-Aminooxazole (1) (Procedure B, in Toluene). A solution of amine
(0.20 mmol, 1.3 equiv) and aldehyde (0.18 mmol, 1.2 equiv) in dry
toluene (1 mL) was stirred at room temperature for 30 min. Isocyanide
(0.15 mmol) and ammonium chloride (1.5 equiv.) were added,
successively. The reaction mixture is stirred at 60 °C and followed by
TLC (typically 4 h). After the disappearance of isonitrile, the reaction
mixture was cooled to room temperature, diluted with aqueous sodium
bicarbonate, and extracted with ethyl acetate. The combined organic
phase was washed with brine, dried (Na2SO4), and evaporated under
reduced pressure. The crude reaction mixture was purified by flash
chromatography (silica gel, eluent: AcOEt/Hept or CH2Cl2/MeOH) to
give the corresponding oxazole.
Three-Component Synthesis of 5-Aminooxazole (1) (Procedure
C, in Toluene) Using the Hydrochloride Salt of the Amine as Input.
A solution of the hydrochloride salt of amine (0.20 mmol, 1.3 equiv),
Et3N (0.23 mmol, 1.5 equiv), and aldehyde (0.18 mmol, 1.2 equiv) in
dry toluene (1 mL) was stirred at room temperature for 30 min.
Isocyanide (0.15 mmol) was then introduced, and stirring was continued
at 60 °C After the disappearance of isonitrile, the reaction mixture was
cooled to room temperature, diluted with aqueous sodium bicarbonate,
and extracted with ethyl acetate. The combined organic extracts were
(49) 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.
(50) Keay, B. A.; Rajapaksy, D.; Rodrigo, R. Can. J. Chem. 1984, 62, 1093-
1098.
(51) Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079-4082.
(52) See, for example: Zhao, G.; Sun, X.; Bienayme´, H. Zhu., J. J. Am. Chem.
Soc. 2001, 123, 6700-6701.
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2566 J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002

Synthesis of Pyrrolo[2,3-b]pyridin-5-one
A R T I C L E S
washed with brine, dried (Na2SO4), and evaporated under reduced
pressure. The crude reaction mixture was purified by flash chroma-
tography (silica gel, eluent: AcOEt/Hept or CH2Cl2/MeOH) to give
the corresponding oxazole.
Et3N (0.75 mmol, 5 equiv) was added followed by acid chloride (0.22
mmol, 2.2 equiv) in small portions. Stirring was continued at room
temperature for 30 min and at 110° for 12 h. After cooling the mixture
to room temperature, the reaction mixture was diluted with water and
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (Na2SO4), and evaporated under reduced pressure.
The crude reaction mixture was purified by flash chromatography (silica
gel, eluent: AcOEt/Hept or CH2Cl2/MeOH) to give the corresponding
pyrrolopyridine.
From 5-Aminooxazole (1) to Pyrrolo[3,4-b]pyridin-5-one (2). To
a solution of oxazole (0.10 mmol) and Et3N (0.50 mmol, 5 equiv) in
dry toluene (2 mL) cooled at 0 °C, acid chloride (0.22 mmol, 2.2 equiv)
was added in small portions. After being stirred at room temperature
for 30 min, the reaction mixture was heated to reflux for 12 h. The
reaction mixture, cooled to room temperature was diluted with water
and extracted with EtOAc. The combined organic extracts were washed
with brine, dried (Na2SO4), and evaporated under reduced pressure.
The crude reaction mixture was purified by flash chromatography (silica
gel, eluent: AcOEt/Hept or CH2Cl2/MeOH) to give the corresponding
pyrrolopyridine.
Acknowledgment. Financial support from Rhodia (P.J.),
Rhoˆne-Poulenc Industralisation (X.S.), and CNRS is gratefully
acknowledged. This paper is dedicated with deep respect to
Professor H. -P. Husson.
Four-Component Synthesis of Pyrrolo[3,4-b]pyridin-5-one (2).
To a solution of amine (0.20 mmol, 1,3 equiv) in dry toluene (1 mL)
was added aldehyde (0.18 mmol, 1.2 equiv). After being stirred at room
temperature was for 30 min, isocyanide (0.15 mmol), and ammonium
chloride (0,23 mmol, 1.5 equiv) were added, successively. The reaction
mixture is stirred at 60 °C until the disappearance of isonitrile. The
reaction mixture was cooled to 0 °C and diluted with toluene (1 mL).
Supporting Information Available: Spectroscopic and ana-
lytical data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org. See any current
masthead page for ordering information and Web access
instructions.
JA017563A
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J. AM. CHEM. SOC. VOL. 124, NO. 11, 2002 2567