1.2.3- Trisubstituted indole

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

The Larock indole synthesis was adapted to the solid phase both for the synthesis of 1,2,3-trisubstituted indole-5-carboxamides [396] and, as illustrated, for the "traceless" synthesis of 2,3-disubstituted indoles 308 [397], As seen earlier, the trimethylsilyl group is fastened to C-2 with complete regioselectivity. The TMS group is cleaved under the resin cleavage conditions. The original Larock conditions were not particularly successful. 

In a simple extension of this indole work, Collini and Ellingboe27 introduced an extra element of diversity by using a method originally exemplified in solution.28 This allowed for the synthesis of trisubstituted indoles. The method, shown in Scheme 6, involves the Sonogashira palla-dium/copper co-catalyzed step to introduce the initial alkyne diversity. After conversion of the aniline group to the trifluoroacetamide, a second palla-... 

Zhang, H.-C. Brumfield, K. K. Maryanoff, B. E. Synthesis of Trisubstituted Indoles on the Solid Phase via Palladium-Mediated Heteroannulation of Internal Alkynes, Tetrahedron Lett. 1997, 38, 2439-2442. 

Koerber-Ple, K. Massiot, G. Synthesis of an unusual 2,3,4-trisubstituted indole derivative found in the antibiotic nosiheptide. Synlett 1994, 759-760. 

F. 1,2,3-Trisubstituted Indoles with Substituents in the Benzenoid Ring. 305... 

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid incorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted indole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteine (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used in the United States only as a polyantimicrobial veterinary ointment (Panalog, Squibb), but thiazole antibiotics have, in the past, been used as feed additives in various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and /-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3-trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>. 

Yamada K, Yamada F, Shiraishi T, Tomioka S, Somei M (2009) Nucleophilic substitution reaction in indole chemistry l-methoxy-6-nitroindole-3-carbaldehyde as a versatile building block for 2,3,6-trisubstitute indoles. Heterocycles 77 971-982... 

Carboxamides, carbamates, and halogens have served as DMGs for lithiation in the benzenoid portion of the indole ring. In an extension of the C4-lithiation chemistry, Iwao transformed 4-aminogramine 120n into carbamate 121, which then tmderwent selective lithiation at C5 (Table 24) [341]. Treatment of 121 with three equivalents of t-butyllithium followed by various electrophiles gave 3,4,5-(trisubstituted)indoles 123 via dianion 122. This chemistry was also investigated... 

The trisubstituted indole nucleosides 16 (X = Cl, Br) have been made as... 

Pd-mediated heteroannulation of alkynes with resin-bound o-iodoaniHnes 16 gives trisubstituted indoles with good yields. Zhang and coworkers have used Rink amide AM resin as solid support and the iodoanihne was linked by formation of an amide bond (1997TL2439 Scheme 7). After the heteroannulation reaction, cleavage with trifluoroacetic acid gave the indoloamide functionalized compounds 17. 

A small library of 2,3,5-trisubstituted indoles was obtained by Schultz and coworkers starting from a solid-supported 3-bromo-2-iodoaniline on commercially available PS-TsCl resin (polystyrene sulfonyl chloride Argonaut Technologies). A successive Larock heteroannulation, followed by electrophilic substitution on indole position three and final Suzuki or Sonogashira cross-coupling reactions, gave excellent results for the preparation of an important number of indole derivatives 19 and 20 (Scheme 9 20010L3827). 

Methoxyindole-3-carbaldehyde (10a) undergoes nucleophilic substitution reactions in sharp contrast with indole-3-carbaldehyde that does not react with nucleophiles under forcing reaction conditions. The most reactive reactant among the thus-far obtained l-hydroxy and 1-methoxy derivatives is l-methoxy-6-nitroindole-3-carbaldehyde (10b) as shown in Fig. 2. So, the nudeophihc substitution reactions of 10b in DMF are examined for the synthesis of new 2,3,6-trisubstituted indoles. The representative results are shown in Scheme 14 [13]. 

Cycloisomerization of o-alkynylanUines 114 into multisubstituted N-protected as well as NH-indoles 115 in the presence of various Cu(II) catalysts was extensively investigated by Hiroya et al. (Scheme 9.44) [200, 201). The authors, demonstrated that, in addition to Cu-catalysts, Ti(IV) and Zn(II) salts could also trigger this cyclization to some extent. Further, it was shown that Cu(OTf)2 catalyst displayed good activities in the case of primary aniline derivatives, whereas Cu(OAc)2 was better suited for secondary aniline derivatives. In both cases, moderate to excellent yields of up-to-trisubstituted indoles 115, bearing a variety of labile functional groups, can be synthesized using this procedure. A cascade cydization-intramolecular C3-alkyl-ation leading to C2-C3 fused indoles was also demonstrated. 

Recently, Fagnou reported a very interesting, atom-economical route to the 1,2,3-trisubstituted indole derivatives 273 via the Rh(II)-catalyzed oxidative coupling-indolization reaction (Scheme 9.95) [251]. Accordingly, simple acetanilides 271, upon a directed C-H activation with the Rh(II)-catalyst [252] followed by a subsequent carborhodation-indolization sequence of alkyne 272, gave N-acylated indoles 273. Both electron-rich and electron-deficient acetanilides 271, possessing different functionalities were perfectly tolerated under these reaction conditions. In the case of unsymmetrical alkyl-alkyl-substituted acetylenes, a mixture of indole products... 

Che has reported the tandem hydroamination/hydroarylation of aromatic amines wirh terminal alkynes to form dihydroquinolines in which 1 equiv of aniline combines with 2 equiv of alkyne [23]. For example, reaction of 3-methoxyanilme with pheny-lacetylene (5 equiv) and a catalytic 1 1 mixture of the gold(I) N-heterocydic carbene complex (IPr)AuCl (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgOTf at 150 °C under microwave irradiation led to isolation of dihydroquinoline 21 in 82 % yield (Eq. (11.15)). Alternatively, reaction of o-acetylaniline with pheny-lacetylene catalyzed by a mixture of (IPr)AuCl and AgOTf at 150 °C led to isolation of the quinoline derivative 22 in 93% yield via incorporation of a single equivalent of alkyne (Eq. (11.16)). Arcadi has reported the gold(IlI)-catalyzed hydroamination/ hydroarylation of 2-alkynylanilines with a,p-enones to form C3-alkyl indoles [24]. As an example of this transformation, treatment of 2-(phenylethynyl)aniline with 4-phenyl-3-buten-2-one and a catalytic amount of sodium tetrachloroaurate dihydrate in ethanol at 30°C formed 1,2,3-trisubstituted indole 23 in 88% yield (Eq. (11.17)). 

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