Three-component synthesis of polysubstituted 6-azaindolines and its tricyclic derivatives

Article abstract of DOI:10.1021/ol0477881

(Chemical Equation Presented) By simply heating a toluene solution of isocyanoacetamide (3), amine (4), and aldehyde (5), a clean three-component reaction occurred to provide the pyrrolidinone-fused azaindoline (2). In this multicomponent reaction, the is

Full text of DOI:10.1021/ol0477881

ORGANIC
LETTERS
2005
Vol. 7, No. 2
239-242
Three-Component Synthesis of
Polysubstituted 6-Azaindolines and Its
Tricyclic Derivatives
Aude Fayol and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
Received October 28, 2004
ABSTRACT
By simply heating a toluene solution of isocyanoacetamide (3), amine (4), and aldehyde (5), a clean three-component reaction occurred to
provide the pyrrolidinone-fused azaindoline (2). In this multicomponent reaction, the isocyanoacetamide (3) reacted four times in a highly
ordered manner creating three heterocylic rings with the concurrent formation of five chemical bonds and a minimal loss of molecular weight.
Heating is the only external energy required to promote this powerful complexity-generating MCR.
The synthesis of functionalized indoles and indolines has
been of interest to organic chemists for many years due to
the presence of these structural units in a variety of bio-
logically active natural products1 and medicinally relevant
compounds.2 Numerous elegant methods have continuously
been developed to reach this important bicyclic skeleton over
the years.3 Incorporation of an additional basic nitrogen atom
into the indole derivatives are known to not only enlarge
the SAR studies of parent compounds but also induce a
different physical4 and pharmacological profile.5 Therefore,
azaindoles and azaindolines are attractive scaffolds in medic-
inal chemistry6 and various synthetic methods, including
ionic,7 radical,8 and transition-metal-catalyzed processes,9
photocyclization,10 and cycloaddition,11 have been developed.
A recent zirconcene-mediated coupling of silicon-tethered
diyne and nitrile developed by Xi and co-workers is note-
worthy since the bicyclic ring system of 5-azaindole is con-
structed in a single step from the linear starting materials.12
In continuation of our research program aimed at the
development of multicomponent synthesis of polyhetero-
cycles,13 we report herein a three-component synthesis of
(5) Selected examples: (a) Devillers, I.; Pevet, I.; Jacobelli, H.; Durand,
C.; Fasquelle, V.; Puaud, J.; Gaudillie`re, B.; Idrissi, M.; Moreau, F.;
Wrigglesworth, R. Bioorg. Med. Chem. Lett. 2004, 14, 3303-3306. (b)
Doisy, X.; Dekhane, M.; Le Hyaric, M.; Rousseau, J. F.; Singh, S. K.; Tan,
S.; Guilleminot, V.; Schoemaker, H.; Sevrin, M.; George, P. Potier, P.;
Dodd, R. H. Bioorg. Med. Chem. 1999, 7, 921-932. (c) Coburn, C.; Vacca,
J. P. (Merck & Co.). WO 2000064449, 2000; Chem. Abstr. 2000, 133,
321893. (d) Chambers, M. S.; Matassa, V. G.; Giulio, V. (Merck Sharp
and Dohme). GB 2295615, 1996; Chem. Abstr. 1996, 125, 167798. (e)
Mathews, C. J. (Zeneca). WO 9514019, 1995; Chem. Abstr. 1995, 123,
340083. (f) Takahashi, T.; Horigome, M.; Momose, K.; Nagai, S.; Oshida,
N.; Sugita, M.; Katsuyama, K.; Suzuki, C.; Nakamaru, K. (Nisshin Flour
Milling). JP 06247967, 1994; Chem. Abstr. 1995, 122, 105862. (g) Huth,
A.; Schmiechen, R.; Schumann, I.; Scheinder, H.; Turski, L.; Stephens, D.
N.; Schering, A.-G. DE 4227791, 1993; Chem. Abstr. 1993, 118, 254914.
(6) (a) Willette, R. E. Monoazaindoles: The Pyrrolopyridines. In AdV.
In Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J., Eds.; Academic
Press: New York, 1968; Vol. 9, pp 27-105. (b) Varlamov, A. V.; Borisova,
T. N.; Voskressensky, L. G. Synthesis 2002, 155-168.
(1) For recent reviews of the indole-containing natural products, see:
(a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278-311. (b)
Lounasmaa, M.; Hanhinen, P. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 2001; Vol. 55, pp 1-90. (c) Takayama, H.;
Sakai, S.-I. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San
Diego, 1998; Vol. 50, pp 415-452.
(2) (a) Glennon, R. A. J. Med. Chem. 1987, 30, 1-12. (b) Hugel, H.
M.; Kennaway, D. J. Org. Prep. Proc. Int. 1995, 27, 1-31.
(3) For a recent review, see: (a) Gribble, G. W. J. Chem. Soc., Pekin
Trans. 1 2000, 1045-1075. (b) Alvarez, M.; Salas, M. Heterocycles 1991,
32, 1391-1429.
(4) (a) Catala´n, J. J. Am. Chem. Soc. 2001, 123, 11940-11944. (b) Adler,
T. K.; Albert, A. J. Med. Chem. 1963, 6, 480-483.
10.1021/ol0477881 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/17/2004

6-azaindoline (1) and its tricyclic derivative (2) from a readily
accessible linear precursor.14 Key to the present approach is
the design and use of a densely functionalized isocyanoac-
etamide15 whose functional groups, isonitrile, amide, double
bond, and ester, participated in the reaction sequentially and
in a highly ordered manner to provide 1 and 2 in good yield
(Figure 1).
Scheme 1. Synthesis of Isocyanoacetamides 3a and 3b
tenoate (7)16 in the presence of EDC in dichloromethane gave
the amide 8a, which was dehydrated (POCl3, Et3N, CH2Cl2)
to give the desired isonitrile 3a in 58% overall yield.
Compound 3b containing an electronically neutral double
bond was prepared similarly from N-formyl-phenyglycine
and 5-benzylamino-1-pentene.
Figure 1. 6-Azaindoline and its tricyclic derivative: structure and
synthesis strategy.
Using isocyanoacetamide 3a, morpholine 4a, and heptanal
5a as test substrates (Scheme 2), we performed a survey of
The previously unknown R-substituted R-isocyanoaceta-
mide (3a) is synthesized as shown in Scheme 1. Coupling
of N-formyl phenylalanine (6) with 5-benzylamino-2-pen-
Scheme 2. Three-Component Synthesis of 6-Azaindoline
(7) (a) Frydman, B.; Buldain, G.; Repetto, J. C. J. Org. Chem. 1973, 38,
1824-1831. (b) Dodd, R. H.; Doisy, X.; Potier, P. Heterocycles 1989, 28,
1101-1113. (c) Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992,
29, 359-367. (d) Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993,
49, 8139-8146. (e) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877-882. (f) Rousseau, J.
F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731-2737. (g) Beller, M.; Breindl,
C.; Riermeier, T. H.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int.
Ed. Engl. 1998, 37, 3389-3391. (h) Rodriguez, A. L.; Koradin, C.; Dohle,
W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488-2490. (i) Kuzmich,
D.; Mulrooney, C. Synthesis 2003, 1671-1678.
(8) Recent examples, see: (a) Leroi, C.; Bertin, D.; Dufils, P.-E.; Gigmes,
D.; Marque, S.; Tordo, P.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A.
Org. Lett. 2003, 5, 4943-4945. (b) Viswanathan, R.; Prabhakaran, E. N.;
Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163-168. (c)
Moutrille, C.; Zard, S. Z. Tetrahedron Lett. 2004, 45, 4631-4634. For an
excellent application in natural product synthesis, see: (d) Yokoshima, S.;
Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 2137-2138.
reaction conditions; the results are summarized in Table 1.
When the reaction was carried out in MeOH at room
temperature, oxazole 9a was isolated in 88% yield (entry
1).17 However, when the toluene solution was heated to
reflux, the desired 6-azaindoline 1a was isolated in 61% yield
(entry 2). Addition of ammonium chloride18 and camphor-
sulfonic acid19 did not improve the product yield (entries 6
(9) (a) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355-
5358. (b) Zakrzewski, P.; Gowan, M.; Trimble, L. A.; Lau, C. K. Synthesis
1999, 1893-1902. (c) Penoni, A.; Nicholas, K. M. J. Chem. Soc., Chem.
Commun. 2002, 484-485. For recent related reviews, see: (d) Battistuzzi,
G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671-2681. (e)
Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198. (f) Zeni,
G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309.
(10) Campos, P. J.; An˜o´n, E.; Carmen Malo, M.; Rodr´ıguez, M. A.
Tetrahedron 1999, 55, 14079-14088.
(11) (a) Li, J. H.; Snyder, J. K. J. Org. Chem. 1993, 58, 516-519. (b)
Rashatasakhon, P.; Padwa, A. Org. Lett. 2003, 5, 189-191.
(14) Palladium-catalyzed three-component synthesis of indoline has been
reported; see: Grigg, R.; Mariani, M.; Sridharan, V. Tetrahedron Lett. 2001,
42, 8677-8680.
(15) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25, 141-
208.
(12) Sun, X.; Wang, C.; Li, Z.; Zhang, S.; Xi, Z. J. Am. Chem. Soc.
2004, 126, 7172-7173.
(13) For recent reviews on the subject, see: (a) Weber, L. Curr. Med.
Chem. 2002, 9, 2085-2093. (b) Do¨mling, A. Curr. Opin. Chem. Biol. 2002,
6, 306-313. (c) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80.
(d) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471-1499. (e) Balme,
G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101-4111. (f)
Jacobi von Wangelin, A.; Neumann, H.; Go¨rdes, D.; Klaus, S. Stru¨bing,
D.; Beller, M. Chem. Eur. J. 2003, 9, 4286-4294. (g) Murakami, M. Angew.
Chem., Int. Ed. 2003, 42, 718-720. (h) Zhu, J. Eur. J. Org. Chem. 2003,
1133-1144.
(16) Hirai, Y.; Terada, T.; Hagiwara, A.; Yamasaki, T. Chem. Pham.
Bull. 1988, 36, 1343-1350.
(17) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.; Zhu, J. Org. Lett.
2001, 3, 877-880. (b) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am.
Chem. Soc. 2002, 124, 2560-2567.
(18) (a) Fayol, A.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 3633-
3635. (b) Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115-118.
240
Org. Lett., Vol. 7, No. 2, 2005

Table 1. Three-Component Synthesis of Azaindoline 1a, a
Survey of Conditionsa
entry
solvent
additive
yielde [%]
1
2
3
4
5
6
7
8
MeOHb
toluene
o-xyle`ne
DMSOc
toluene
toluene
toluene
toluene
(88f)
61
50
21
LiBr
21(41f)
63
NH4Cl
SiO2
CSAd
(63f)
60
a Concentration ) 0.1 M; additive ) 1.0 equiv; room temperature for 1
h followed by reflux for 15 h. b Room temperature, 2 h. c T ) 110 °C.
d Performed with 0.5 equiv of CSA. e Isolated yield. f Yield of oxazole 9a;
CSA ) camphorsulfonic acid; LiBr ) lithium bromide; NH4Cl )
ammonium chloride.
and 8), while the presence of lithium bromide20 and silica
gel has a detrimental effect on the reaction outcome (en-
tries 5 and 7). The reaction performed in the polar solvent
DMSO at 110 °C did produce 1a, but with much reduced
yield (entry 4).
Using a primary amine (C4H9NH2, 4d) as an input, a
tricyclic compound 2a was obtained in 54% yield under
optimum conditions (toluene, c 0.1 M, room temperature for
1 h and then reflux for 15 h). The reaction appears to be
general, and tricyclic compounds 2a-e were obtained in
good yields from all the primary amines used, including
aniline (Figure 3).
Figure 3. Three-component synthesis of 6-azaindolines and its
tricyclic derivatives. In the cases of 1h and 1i, o-xylene was used
as the solvent (room temperature, 1 h, then reflux, 15 h).
2 is depicted in Scheme 3. A three-component reaction
between amine, aldehyde, and isocyanide is expected to pro-
vide the oxazole 9 via an imininum (10) and then a nitrilium
(11) intermediate according to our previous results.17 The
isolation of oxazole 9a supported this hypothesis. We stress
that under these conditions, Michael addition between amine
and the enoate moiety of isocyanoacetamide (3a) did not
occur that could otherwise interrupt the entire reaction
sequence. The condensation between amine and aldehyde is
apparently a much faster process or thermodynamically more
favorable over the undesired Michael addition in this circum-
stance. Interception of the resultant oxazole by the tethered
Figure 2. Amine and aldehyde inputs used for three-component
reaction.
(19) Janvier, P.; Bienayme´, H.; Zhu, J. Angew. Chem., Int. Ed. 2002,
41, 4291-4294.
(20) Gonza´lez-Zamora, E.; Fayol, A.; Bois-Choussy, M.; Chiaroni, A.;
Zhu, J. J. Chem. Soc., Chem. Commun. 2001, 1684-1685.
A possible reaction sequence that accounts for the forma-
tion of 6-azaindoline 1 and its pyrrolidinone-fused derivative
Org. Lett., Vol. 7, No. 2, 2005
241

aliphatic and aromatic aldehydes having different steric and
electronic properties were tolerated, and aliphatic amines as
well as anilines participated in this reaction. Importantly, the
electronically neutral double bond of isonitrile 3b acted as
a dienophile efficiently leading to the formation of 1h and
1i, although higher temperature (xylene, reflux) was neces-
sary to accelerate the cycloaddition process. On the other
hand, when aminopentynoate (4c) was used as an amine
input, two potential Diels-Alder reactions could occur
leading to two different heterocycles. However, only azain-
doline 1g was isolated in this case.
Scheme 3. Three-Component Synthesis of 1 and 2: A
Mechanistic Working Hypothesis
The N-benzyl function of azaindoline 1 and 2 is readily
removed. Thus, treatment of 1a under standard hydrogenoly-
sis conditions [H2, 1 atm, Pd(OH)2, EtOH) provided the
Na-unsubstituted azaindoline 13 (Figure 3) in 83% yield. The
presence of the ester and amine functions in 13 provided
handles for additional structural diversification.
In summary, by the proper design of the reaction partners,
we have developed a novel, very convenient, and conceptu-
ally simple multicomponent synthesis of polysubstituted
6-azaindoline 1 and its tricyclic derivative 2. Initiated by
the nucleophilic addition of the isonitrile carbon to the
iminium species, four functional groups of isocyanoacet-
amide 3a participated in the bond-forming process at different
stages, and heating is the only external energy required to
promote this powerful MCR that generates five chemical
bonds in a one-pot fashion. We emphasize also that only
two molecules of water were lost on the way to azaindoline
1, making it both ecologically benign and atom-economic.22,23
dienophile via an intramolecular Diels-Alder (D-A) cy-
cloaddition21 should then afford the oxa-bridged intermediate,
which would undergo nitrogen-assisted fragmentation leading
to azaindoline (1). When primary amine was used as an input,
a further intramolecular transamidation (R6 ) COOMe) took
place to afford the tricyclic compound (2). The intermediate
12 was not isolable, indicating that the fragmentation is an
easy process in this case. This final irreversible step might
provide the driving force to the overall process.
The scope of this novel multicomponent reaction is ex-
amined with various inputs, including two isocyano acet-
amides (Scheme 1), seven representative amines, and six
aldehydes (Figure 2). As is indicated in Figure 3, this MCR
was quite versatile and 6-azaindolines (1a-i) as well as its
tricyclic derivatives (2a-e) having different substitution
patterns were readily synthesized in good yield. Both
Acknowledgment. Financial support from CNRS and a
doctoral fellowship from the “Ministe`re de l’Enseignement
Supe´rieur et de la Recherche” to A.F. are gratefully
acknowledged.
Supporting Information Available: Experimental details
and physical data for compounds 1a-i, 2a-e, 3a, 3b, 8a,
8b, 9a, and 13. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0477881
(22) Trost, B. M. Science 1991, 254, 1471-1477.
(23) For a discussion of an ideal synthesis, see: Wender, P. A.; Handy,
S.; Wright, D. L. Chem. Ind. 1997, 765-769.
(21) Recent example, see: Ohba, M.; Natsutani, I.; Sakuma, T. Tetra-
hedron Lett. 2004, 45, 6471-6474 and references therein.
242
Org. Lett., Vol. 7, No. 2, 2005