[40900-03-6]  · C14H10LiNO2S  · 2-Lithio-N-phenylsulfonylindole  · (MW 263.26)

(nucleophilic organolithium reagent useful for addition to ketones, aldehydes, esters, lactones, acid chlorides, anhydrides, nitriles, methyl iodide, halogen sources, and sulfur dioxide; employed in the synthesis of 2-substituted indoles and alkaloids)

Preparative Methods: by deprotonation of N-phenylsulfonylindole1 with t-Butyllithium in ether (-12 °C to room temperature),1 by treatment of N-phenylsulfonylindole with n-Butyllithium in THF (-70 °C),2 and by deprotonation of N-phenylsulfonylindole with Lithium Diisopropylamide in THF (-70 to 5 °C) (eq 1).3

Handling, Storage, and Precautions: the reagent is generated in situ, under anhydrous conditions, in an inert atmosphere, and used shortly after preparation. The stability in storage is unknown. Precautions for preparation and use are as for other reactive organolithium reagents.

Synthesis of 2-Substituted Indoles.

Heteroaromatic compounds such as Furan and thiophene are readily metalated at an a-position and the resulting organometallic reagents can be captured by a variety of electrophiles.4a N-Unsubstituted indoles and pyrroles suffer removal of the acidic N-H, affording ambident nucleophiles4a which give rise to mixtures of C- and N-substituted products upon reaction with electrophiles.4b 1-Methylindole can be lithiated at the 2-position to provide 1,2-disubstituted indoles after capture by an electrophile.5 Difficulties associated with N-dealkylation restrict this method to the preparation of 1,2-disubstituted indoles.1 Substitution at the 1-position of the indole moiety with a readily removable group provides access to 2-substituted indoles. N-Phenylsulfonylindole is readily deprotonated (eq 1) to give 2-lithio-N-phenylsulfonylindole (1) which reacts with electrophiles (eq 2) such as aldehydes,1 ketones,1 acid chlorides,1 Carbon Dioxide,1 anhydrides,1,6 arylsulfonyl chloride,7 Cyanogen Bromide,7 Iodine,7 and Sulfur Dioxide2 to give N-phenylsulfonyl substituted indolyl-2-carbinols (from aldehydes, ketones), 2-ketones (from acid chlorides, anhydrides), 2-carboxylic acid (from carbon dioxide), 2-sulfones (from arylsulfonyl chlorides), 2-bromide (from cyanogen bromide), 2-iodide (from iodine), and 2-sulfonic acid salt (from sulfur dioxide) in reasonable yields (25-85%). 2-Lithio-N-phenylsulfonylindole (1) appears to react poorly with alkyl halides. The reaction of (1) with ethyl benzoate gives 2-indolyl phenyl ketone (26%), a product of in situ phenylsulfonyl cleavage.1 Similarly, the reaction of (1) with benzonitrile also yields 2-indolyl phenyl ketone (30%).1 Cleavage of the N-phenylsulfonyl group to generate the target 2-substituted indole is readily accomplished with 2N Sodium Hydroxide in methanol (reflux, eq 3)1 or Potassium Carbonate in methanol/water (3:1) at reflux (eq 4).6

Alkaloid Synthesis.

Indole alkaloids such as ellipticine (eq 5)6 and the genotoxic amine TrpP-1 (eq 6)8 have been prepared from 2-lithio-N-phenylsulfonylindole (1).

Related Reagents.

A number of indole N-protecting groups have been reported to afford variants of 2-lithio-N-phenylsulfonylindole which lead to the preparation of 2-substituted products amenable to further synthetic transformation. Table 1 shows a number of removable nitrogen blocking groups in the indole and pyrrole series. In the indole series, (2a-g)1-3,9a-i readily provide N-deprotected 2-substituted indoles. Indolyllithium reagents (2g)1 and (2h)1 are less well explored. In the pyrrole series, (3a)9a and (3g)10g,h are problematic due to competitive desulfonylation (3a) and silicon migration (3g). Pyrrolyllithiums (3b),9a,10a (3c),9d,10b-d (3d),10e and (3e)9h provide satisfactory yields of 2-substituted pyrroles, although (3b)9a has been reported to be thermally labile and (3c)9d,10b-d requires carefully controlled deprotection conditions. Pyrrolyllithium (3f) has not been widely examined.10f

1. Sundberg, R. J.; Russel, H. F. JOC 1973, 38, 3324.
2. Graham, S. L.; Hoffman, J. M.; Gautheron, P.; Michelson, S. R.; Scholz, T. H.; Schwam, H.; Shepard, K. L.; Smith, A. M.; Smith, R. L.; Sondey, J. M.; Sugrue, M. F. JMC 1990, 33, 749.
3. (a) Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S. JOC 1981, 46, 2979. (b) Saulnier, M. G.; Gribble, G. W. JOC 1982, 47, 757.
4. (a) Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon: Oxford, 1985; p 261. (b) Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon: Oxford, 1985; p 245.
5. Shirley, D. A.; Roussel, P. A. JACS 1953, 75, 375.
6. (a) Saulnier, M. G.; Gribble, G. W. JOC 1982, 47, 2810. (b) Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D. M. JOC 1992, 57, 5891.
7. Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.; Gribble, G. W. JOC 1989, 54, 4350.
8. Hibino, S.; Sugino, E.; Kuwada, T.; Ogura, N.; Sato, K.; Choshi, T. JOC 1992, 57, 5917.
9. (a) Hasan, I.; Marinelli, E. R.; Lin, L-C. C.; Fowler, F. W.; Levy, A. B. JOC 1981, 46, 157. (b) Cheng, A. C.; Shulgin, A. T.; Castagnoli, N., Jr. JOC 1982, 47, 5258. (c) Kline, T. JHC 1985, 22, 505. (d) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D. CC 1983, 630. (e) Katritzky, A. R.; Akutagawawa, K. TL 1985, 26, 5935. (f) Bergman, J.; Venemalm, L. TL 1987, 28, 3741. (g) Bergman, J.; Venemalm, L. TL 1988, 29, 2993. (h) Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V. S 1991, 1079. (i) Katritzky, A. R.; Lue, P.; Chen, Y-X. JOC 1990, 55, 3688.
10. (a) Martina, S.; Enkelmann, V.; Wegner, G.; Schlüter, A-D. S 1991, 613. (b) Muchowski, J. M.; Solas, D. R. JOC 1984, 49, 203. (c) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D.; Williams, D. J. JOC 1984, 49, 3503. (d) Edwards, M. P.; Doherty, A. M.; Ley, S. V.; Organ, H. M. T 1986, 42, 3723. (e) Katritzky, A. R.; Akutagawawa, K. OPP 1988, 20, 585. (f) Martinez, G. R.; Grieco, P. A.; Srinivasan, C. V. JOC 1981, 46, 3760. (g) Chadwick, D. J.; Hodgson, S. T. JCS(P1) 1982, 1833. (h) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. JOC, 1990, 55, 6317.

Mark A. Collins & Steven P. Tanis

The Upjohn Company, Kalamazoo, MI, USA

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