Syntheses of 2-Substituted Indoles and Fused Indoles by Photostimulated Reactions of o-Iodoanilines with Carbanions by the SRN1 Mechanism Silvia M. Barolo, Andre´s E. Lukach, and Roberto A. Rossi* INFIQC, Departamento de Quı´mica Orga´ nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´ rdoba, Ciudad Universitaria, 5000 Co´ rdoba, Argentina
[email protected] Received November 6, 2002
2-Substituted indoles (5a,b and 7) and fused indoles (9a-c, 11a,b, and 12) have been obtained by the SRN1 mechanism from photostimulated reactions of o-iodoaniline (1) and 1-halo-2-naphthalen2-ylamines (3a,b) with enolate ions of acyclic (acetophenone (6), 2- (4a) and 4-acetylpyridine (4b)) and cyclic ketones (1- (8a) and 2-indanone (10a), 1- (8b) and 2-tetralone (10b) and 1-benzosuberone (8c)) in DMSO and liquid ammonia as solvents. The carbanions derived from 4a,b, 8a, and 10b are novel nucleophiles that form new C-C bonds by the SRN1 mechanism. Introduction Indoles are probably the most widely distributed heterocyclic compounds in nature. The indole ring belongs to an important class of compounds due to their pharmacological activity.1-3 There are several reported procedures to obtain indoles. The most used method is the Fischer synthesis, which involves the reaction of N-arylhydrazones in acid media or in the presence of ZnCl2.4 Most often, the indole is obtained directly form the ketone and phenylhydrazine without isolation of the intermediate. Recently, the synthesis of N-arylhydrazones has been improved by using palladium catalysis.5 Another approach utilized in acidic media is the Bischler synthesis, which has been modified in the last years by Moody.6 Indoles can be obtained from o-alkynylanilines by palladium-catalyzed cyclization under acid7 or basic conditions8 or from o-alkenylbenzonitriles by radical cyclization.9 Another procedure is the preparation of indoles from o-haloanilines by the palladium cross(1) Saxton, J. E. In The Chemistry of Heterocyclic Compounds; John Wiley and Sons: New York, 1994; Vol. 25, Part IV. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 7, 1045. Gribble, G. W. In Second Supplements to the 2nd Edition of Rodd’S Chemistry of Carbon Compounds, Vol. IV - Heterocyclic Compounds; Sainsbury, M., Ed.; Elsevier Science Publications: Amsterdam, 1997; Part B, pp 69-164. Bosch, J.; Bonjoch, J.; Amat, M. The Alkaloids 1996, 48, 75-189. (2) For a description of the biological activity of indoles, see: Sunberg, R. J. Indoles; Academic Press: London, 1996; and references therein. (3) For recent developments in indole ring synthesis and applications, see: Gribble, G. W. J. Chem. Soc., Perkin. Trans. 1 2000, 7, 1045. (4) For reviews on the Fisher indole synthesis, see: Robinson, B. In The Fisher Indole Synthesis; John Wiley and Sons: New York, 1982. Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607. (5) Wasag, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 62, 6464. (6) Moody, C. J.; Swann, E. Synlett 1998, 135. (7) Cachi, S.; Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289. (8) (a) Kondo, Y.; Sakamoto, H. Heterocycles 1989, 29, 1013. (b) Kondo, Y.; Kojima, S.; Sakamoto, H. J. Org. Chem. 1997, 62, 6507.
coupling reaction followed by Rh-catalyzed hydroformylation of the Heck adducts.10 Recently, a method for indole synthesis using a palladium-catalyzed annulation between o-iodoaniline and ketones has been described.11 The development of a new method for the regioselective synthesis of functionalized indoles through the benzyne mechanism has also been reported.12 The SRN1 mechanism is an important route to achieve the formation of a new C-C bond by the reaction of aromatic substrates with carbanions.13 Good yields of substitution are usually obtained in the reactions of aliphatic and aromatic ketones enolate ions. These anions react with aromatic halides under photostimulation in liquid ammonia or in DMSO as solvents. The SRN1 mechanism is a chain process. The initiation step (eq 1) is an electron transfer (ET) from the nucleophile to the substrate to afford a radical anion. In some of these systems the ET step is spontaneous but in others light is required to catalyze the reaction. Electrons (from dissolution of alkali metals in liquid ammonia, or from a cathode) and inorganic salts (Fe2+, SmI2) can initiate the reaction as well. The propagation steps consist of the fragmentation of the radical anion to afford a radical and the nucleofugal group (eq 2) and coupling of the radical (9) Fukuyama, T.; Chen, X.; Peng, G. A. J. Am. Chem. Soc. 1994, 116, 3127. (10) Dong, Y.; Busacca, C. A. J. Org. Chem. 1997, 62, 6464. (11) Chen, C. Y.; Larsen, R. D. Org. Synth. 2000, 78, 36. (12) Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chem. Eur. J. 2002, 8, 2034. (13) For reviews, see: (a) Rossi, R. A.; de Rossi, R. H. In Aromatic Substitution by the SRN1 Mechanism; Monograph 178; American Chemical Society: Washington, DC, 1983. (b) Norris, R. K. Comprehensive Organic Synthesis; Trost, B. M., Ed. 1991, 4, 451. (c) Rossi, R. A.; Pierini A. B.; Pen˜e´n˜ory, A. B. In The Chemistry of Functional Groups; Patai S., Rappoport, Z., Ed.; Wiley: Chichester, 1995; Supplement D2, Chapter 24, pp 1395-1485. (d) Rossi, R. A.; Pierini, A. B.; Santiago, A. N. In Aromatic Substitution by the SRN1 Reaction; Paquette, L. A., Bittman, R., Eds.; Organic Reactions Vol. 54; Wiley & Sons: 1999; pp 1-271. (e) Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B. Chem. Rev. 2003, 103, 71-167.
10.1021/jo026672k CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/04/2003
J. Org. Chem. 2003, 68, 2807-2811
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with the nucleophile to afford a radical anion (eq 3), which by ET to the substrate (eq 4) forms the intermediate necessary to continue the propagation cycle. Overall, eqs 2-4 depict a nucleophilic substitution (eq 5) in which radicals and radical anions are intermediates.
One of the most widely studied approaches to ring closure reactions is the SRN1 substitution of aromatic compounds that have an appropriate substituent ortho to the leaving group.14 An important example of substitution followed by spontaneous ring closure in the reaction media is the synthesis of indoles by the photostimulated reaction of o-iodoaniline (1) with carbanions derived from aliphatic ketones in liquid ammonia to give 2-substituted indoles 2 (eq 6).15,16
Unsubstituted and substituted o-bromo- and o-chloroanilines are adequate substrates for obtaining indoles with functionalities such as Me, Ph, or MeO groups in 50-90% yield.17 Under electrochemical initiation, the reactions of 1 with the enolate ions of acetone, isopropyl methyl ketone, and acetaldehyde afford the respective indoles in 7593% yields.18 The syntheses of benzo[e]- and benzo[g]indoles have been performed by reaction of 2-amino-1-bromo- and 1-amino-2-bromonaphthalene with the anion of pinacolone, respectively.19 The reactions of 1 with the enolate anions of aromatic ketones (viz. acetophenone, 2-naphthyl-methyl ketone, 2-acetyl-N-methylpyrrole, and 2-acetylthiophene) furnish the corresponding 2-substituted indoles 2 in good yields in DMSO as solvent.20 Depending on the ketone enolate ion involved, the reactions can occur under light or Fe2+ initiation. (14) Rossi, R. A.; Baumgartner, M. T. Synthesis of Heterocycles by the SRN1 Mechanism. In Targets in Heterocyclic Systems: Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Soc. Chimica Italiana: Italy, 1999; Vol. 3, pp 215-243. (15) Beugelmans, R.; Roussi, G. J. Chem. Soc., Chem. Commun. 1979, 950. (16) Beugelmans, R.; Roussi, G. Tetrahedron 1981, 37, 393. (17) Bard, R. R.; Bunnett, J. F. J. Org. Chem. 1980, 45, 1546. (18) Boujlet, K.; Simonet, J., Roussi, G.; Beugelmans, R. Tetrahedron Lett. 1982, 23, 173. (19) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132, 729. (20) Baumgartner, M. T.; Nazareno, M. A.; Murguı´a, M. C.; Pierini, A. B.; Rossi, R. A. Synthesis 1999, 2053.
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TABLE 1. Reactions of 1 with Ketone Enolate Ionsa expt
nucleophile
conditions
X- b (%)
1 2 3 4 5 6 7e 8f 9g 10g 11 12 13 14 15 16 17 18 19 20 21 22 23j 24k 25l
4a 4a 4a 4b 4b 4b 6 6 8a 8a 8a 8b 8b 8b 8b 8c 8c 10a 10a 10b 10b 10b 8b 8b 8b
DMSO, dark, 3 h DMSO, hν, 3 h DMSO, hν, 3 hc DMSO, dark, 3 h DMSO, hν, 3 h DMSO, hν, 3 hc DMSO, hν, 3 h DMSO, hν, 3 h DMSO, dark, 3 h DMSO, hν, 3 h NH3, hν, 2 h DMSO, dark, 3 h DMSO, hν, 3 h DMSO, hν, 3 hc NH3, hν, 2 h DMSO, hν, 3 h NH3, hν, 2 h DMSO, hν, 3 h NH3, hν, 2 h DMSO, hν, 3 h DMSO, hν, 3 hi NH3, hν, 2 h DMSO, hν, 3 h DMSO, hν, 3 h DMSO, hν, 3 h
