Moody indole synthesis

M. Inman and C.J. Moody, Indole Synthesis - Something Old, Something New, Chem. ScL, 2013, 4, 29-41. An excellent review that focuses on a monosubstituted arene starting point by a leading practitioner of indole chemistry and synthesis (Moody). D.F. Taber and P.K. Tirunahari, Indole Synthesis A Review and Proposed Classification, Tetrahedron, 2011, 67, 7195-7210. 

In a cycloaddition reminiscent of the Moody indole synthesis (Chapter 54), Ko5evar and Kranjc effected the high-pressure Diels-Alder cycloaddition of 2/7-pyran-2-ones with (Z)-l-methoxy-l-en-3-yne to afford indoles after acid-cycUzation (Scheme 10, equation 1) [39]. In some cases the 2,2-dimethoxyethyl intermediates were formed, but these were transformed to indoles under the same acidic conditions. An intramolecular [4+2] cycloaddition between ynamides and conjugated enynes to indolines and indoles was featured by Danheiser and Dunetz (equation 2)... 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Some other modifications of the Bischler indole synthesis have been developed. One such modification is that of Moody and coworkers, who employed rhodium to effect N-H insertion of an a-diazo-p-ketoester to an aniline (Scheme 5, equations 1 and 2) [58-60]. The so-formed arylamino P-ketoester 16 was smoothly converted to indole 17 with the ion-exchange resin Amberlyst 15 or in somewhat lower yield with boron trifluoride etherate [59]. These workers extended the method to the synthesis of A-unsubstituted indoles using the novel A-protecting groups, A-(2-ethoxycarbonylethyl)... 

Scheme 5 Moody and Yu Variations of the Bischler Indole Synthesis...

Scheme 2 Moody Carbazole Synthesis from Pyrano[3,4-b]indol-3-ones...

Nakaura and Ukita devised a simple indole synthesis from the Rh-catalyzed condensation of a-diazophospho-nates and o-acylanilines (Scheme 6, equation 1) [58]. Moody and colleagues combined diethyl diazomalonate and Af-alkylanilines in a Rh-catalyzed synthesis of indox-ylic acid esters (equation 2) [59], This chemistry represents a simple synthesis of these rare indoxyl-2-carboxylates. 

In 1981, Nordlander demonstrated that acetals 22 can be used as reactants in the Bischler-Mdhlau indole synthesis, providing 2,3-unsubstituted indoles in good yield. Subsequent modification was made by Sundberg in 1984. From 1998 to 2002, Moody and co-workers developed a modified Bischler indole synthesis by using rhodium(II) acetate to catalyze the reaction of N-methylanilines with a-diazo-P-ketoesters via an N-H insertion reaction of a rhodium carbenoid. The resulting a-(A -arylamino)ketones cyclize to give indoles upon treatment with BF3 or an acidic ion exchange resin. ... 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Murakami et al. reported (575) a total synthesis of murrayaquinone A (107) by oxidation of l-hydroxy-3-methylcarbazole (23) with Fremy s salt, as previously described by Martin and Moody (632). The hydroxycarbazole 23 required for this synthesis was obtained via the Fischer indolization of the O-methanesulfonyl phenylhydrazone 614 (575) (see Scheme 5.38). The oxidation of l-hydroxy-3-methylcarbazole (23) with Fremy s salt afforded murrayaquinone A (107) as the major product, along with a 5% yield of isomeric carbazole-l,2-quinone 876 (575) (Scheme 5.108). 

Moody and Rahimtoola reported a short synthesis of staurosporinone (293) without the use of protecting groups at the indole or the lactam nitrogen (761,762). This route involves an intramolecular Diels-Alder reaction of the pyrano[4,3- 7]indol-3-one 1325 and a subsequent cyclization by nitrene insertion. The pyrano[4,3-l7]indol-3-one 1325 was obtained in four steps from ethyl indol-2-yl... 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

Cycloaddition reactions continue to find application in the synthesis of natural products and related substances containing indole and carbazole rings. Moody has published a summary of syntheses of carbazole alkaloids in which cycloadditions of pyrano[3,4-b]indol-3-ones figure prominently. <94SL681>... 

Comber ME, Moody CJ (1992) 2-ChlOTo-l-methoxymethylindole-3-carboxaldehyde introduction of nucleophiles into the indole 2-position and an approach to the unusual TrpHis fragmtait of moroidin. Synthesis 731—733... 

Moody CJ, Noitrai CL (1997) Synthesis of 1, 2-fused indoles by radical cyclisation. J Chem Soc Perkin Trans 1 17 2639-2644... 

Jones GB, Moody CJ (1989) Structurally modified antitumor agents. Part 1. Synthesis of cyclopropapyrrolo[l,2-a]indoles related to mitosenes by intramolecular cycloaddition. J Chem Soc Perkin Trans 1 2449-2454... 

The synthesis of l,2-cyclopropapyrrolo[l,2-a]indoles devised by Moody and Jones [54] was based on 1,3-dipolar addition of a diazo group to an alkene (Scheme 24). In this synthesis, indole-2-carboxaldehyde 169 was alkylated with allyl bromide in the presence of sodium hydride and then condensed with tosylhydrazine to give 170. The sodium salt of 170 underwent [3 + 2] cycloaddition, affording 171, when it was heated in benzene. Further heating in refluxing... 

The first example of an indole-2,3-quinodimethane (IQM) undergoing a Diels-Alder cycloaddition to furnish a carbazole was reported by Plieninger and coworkers in 1964 [9], Thus, indole-3-acetic acid was readily converted to pyrano[3,4-fe]indol-3-ones upon treatment with carboxylic acid anhydrides (Scheme 1, equation 1). These stable synthetic equivalents of IQMs undergo Diels-Alder reactions with electron-deficient dienophiles (A-phenytma-leimide,maleicanhydride,dimethylacetylenedicarboxylate) (equation 2). Plieninger s discovery notwithstanding, it was Moody and coworkers who parlayed this chemistry into a powerful carbazole synthesis (equations 3,4) [10-18],... 

Moody, C.J., and P. Shah Diels-Alder Reactivity of Pyrano [3,4-6] Indol-3-ones Part 4, Synthesis of Alkaloids Carbazomycin A, B, and Hyellazole. J.C.S. Parkin Trans 1, 2463 (1989). 

Moody, C.J. and Shah, P. (1989h) Diels-Alder reactivity of pyrano[3,4-b]indol-3-ones. Part 4. Synthesis of the carbazole alkaloids carbazomycin A and B and hyellazole. J. Chem. Soc. Perkin Trans. I, 2463-2471. 

Bagley, M.C., Hind, S.L., and Moody C.J. (2000) Studies towards the synthesis of diazonamide A. Synthesis of the indole bis-oxazole fragment. Tetrahedron Lett., 41, 6897-6900. 

Sperry, J. and Moody, C.J. (2010) Diazonamide studies. A direct synthesis of the indole bis-oxazole fragment from tri- and tetra-peptides using biomimetic oxidative cydizations. Tetrahedron, 66, 6483-6495. 

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