Watanabe indole synthesis

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

In addition to the above diverse and imaginative variations on the original Watanabe reaction conditions. Table 2 

HOCHgCHgOH, RUCI3 SnCl2 2H20, toluene 120 °C dppe 

What began as almost a curiosity, the Watanabe indolization has developed into a remarkably useful and general indole synthesis from o-nitrotoluene substrates. 

Hendry, N.S. Nixon, B.S. Roughley, et al (2004) The synthesis of carbon-14 labelled indoles, in Synthesis and Applications of Isotopically Labelled Compounds, vol. 8 (eds D.C. Dean, C.N. Filer, and KE. McCarthy), John Wiley Sons, Ltd, New York, pp. 25-28. 

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Table 1 New Catalytic Systems Based on the Watanabe Indole Synthesis... 

Matsumoto, M., and Watanabe, N., Synthesis of 4-(cyanomethylidene)- and 4-(ethoxycarbonylmeth-ylidcnc)-4,5,6,7-lclrahydroindolcs and their dehydrogenation to 4-(cyanomethyl)- and 4-(ethoxycar-bonylmethyl)indoles. Heterocycles, 24, 2611, 1986. 

Although Zamyshlyaeva and her colleagues in 1970 described a low yield of indole (6%-7%) by the catalytic cyclization of A-(p-hydroxyethyl)aniline with ThO and Al Oj at 300-380 °C [6, 7], it was Watanabe who elevated this reaction to a bona fide indole synthesis (Scheme 2, equations 1-4) [3, 5], Indoles are also obtained from 2-nitrophenethyl alcohols using this ruthenium catalyst (equation 4). A mechanism proposed by Watanabe involves hydroxyl coordinating to the Ru center, oxidation to the corresponding aldehyde (loss of H ), and cyclodehydration to indole [5]. For a detailed mechanistic discussion see Watanabe et al [1]. 

Scheme 2 Applications of the Watanabe-Cenini-Soderberg Indole Synthesis...

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

The2-aminophenethyl alcohols resulting from condensation of orr/ici-nitrotoliienes are good precursors for preparation of indoles. Watanabe and co workers have developed ruthenium-catalyzed dehydrogenadveiV-heterocyclizadon for synthesis of indoles and other hereto cycles from 2-aminophenethyl alcohols or 2-nitrophenylethyl alcohols fEq. 10.52. The oxidadve cycli-zadon of 2-aminophenethyl alcohols are also catalyzed by Pd-based catalysts. ... 

Several investigators have developed the reductive cyclization of o-nitrostyrenes into an efficient synthesis of indoles. Thus, research by the groups of Watanabe [458, 459], Sbderberg [460, 461], and Cenini [462, 463] have established this reductive Pd-catalyzed AMieteroannulation reaction as a viable route to simple indoles and fused indoles (372) as shown below. Ohta... 

Katayama, S., Watanabe, T., Yamauchi, M. Convenient synthesis of 3H-indoles (indolenines) by reaction of 1 H-indoles with Corey-Kim reagent. Chem. Pharm. Bull. 1992, 40, 2836-2838. 

Matsumoto, M., Watanabe, N., and Ishida, Y, A facile synthesis of 4-(cyanomethyl)indoles and 4-(ethoxycarbonylmethyl)indoles from 5-halo-4-oxo-4,5,6,7-tetrahydroindolcs, Heterocycles, 24, 3157, 1986. 

Murakami, Y, Tani, M., Ariyasu, T., Nishiyama, C., Watanabe, T., and Yokoyama, Y, The Friedel-Crafts acylation of ethyl pyrrole-2-carboxylate. Scope, limitations, and apphcation to synthesis of 7-substituted indoles, Hetemcycles, 27, 1855, 1988. 

Following their discovery of the ruthenium-catalyzed A -alkylation of anilines with alcohols to give secondary and tertiary amines (Scheme 1, equation 1) [1], Watanabe and his colleagues adapted their chemistry to a synthesis of indoles as shown in equations 2 and 3 12-5], The reaction of Af-methylaniline with propylene glycol under typical conditions affords 1,2-dimethylindole and 1,3-dimethylin-dole in a 1 1 ratio (50% yield), whereas aniline plus styrene glycol gives only 2-phenyUndole (43% yield) [4], The best yield was 89% for the preparation of 5-chloro-2,3-dimeth-ylindole (equation 2). 

Palladium-Catalyzed Indole Ring Synthesis Watanabe-Cenini-Soderberg... 

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