3.4- Disubstituted indoles synthesis

The pseudoisourea paUadium(ll) complex described by Mandapati and coworkers (Scheme 5) has been used by the same group in a solid-phase version. (2013JOM162, 2014JOM31). The polystyrene-supported pseudoisourea paUadium(II) complex was used for 2,3-disubstituted indole synthesis by reaction between the iodoanihne and diphenylacetylene. Among the studied bases and solvents, K2CO3 and DMF gave the best results. 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately substituted pyrazolidine has been noted (67HC(22)l), but the most interesting ring fission of pyrazolidines involves the N(l)—N(2) bond of 1-phenylpyrazolidines (421). If, instead of phenylhydrazone, compound (421) is used in the Fischer indole synthesis, N- aminopropylin-doles are formed (73T4045). Scheme 39 shows the reaction with cyclohexanone. 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

Again, using a Pd-catalyzed amidation as the first step, Edmondson and coworkers [162] developed a synthesis of 2,3-disubstituted indoles 6/1-340 by reaction of 6/1-337 and 6/1-338 with catalytic amounts of Pd2(dba)3 and the ligand 6/1-341. On order to achieve good results, a second charge of Pd had to be added after 12 h. In the first step the enaminone 6/1-339 is formed, which then cydizes in a Heck-... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

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. 

Takano et al. reported an efficient synthesis of the carbazole framework using the annulation of a 2,3-disubstituted indole (512,513). This method involves the condensation of 2-benzyltryptamine (530) with ethoxymethylene acetoacetate (531) to give the enamine 532, which, on treatment with acetic anhydride/acetic acid (3 2),... 

The reactive indolo-2,3-quinodimethanes are generated in situ generally from N-protected 2,3-disubstituted indoles (514,515). Generation of reactive indolo-2,3-quinodimethanes was achieved by fluoride-induced, 1,4-elimination of silylated indolyl ammonium salts, and was applied in the synthesis of substituted tetrahydrocarbazoles (516). Subsequently, the iodide-induced 1,4-elimination of ]V-benzoyl-2,3-bis(bromomethyl)indole (534) methodology was developed for the synthesis of reactive indolo-2,3-quinodimethanes and was applied for the first time in the synthesis of substituted carbazoles (e.g., 536) (517) (Scheme 5.14). 

A large number of carbazole syntheses have involved the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles, which are 2,3-disubstituted indoles. These, in turn, are usually prepared by the Fischer indole synthesis or the Bischler synthesis. This section will not deal with the preparation of the tetrahydrocarbazole, because... 

Fisher indole synthesis.1 2,3-Disubstituted indoles are formed in 70-90% yield when a ketone phenylhydrazone is treated in benzene with PC13 at 25°. The same indoles are formed when the ketone and phenylhydrazine are treated with PC13. PC15 is less satisfactory than PC13. The method is not applicable to aldehydes. 

An impressive procedure for 2-stannylindole is depicted in Scheme 53 [219]. Since the product is prone to proto-destannylation, in situ generated indolyltin reagent is directly used for the cross-coupling reaction. Thus the overall schemes provides a direct synthesis of 2,3-disubstituted indoles from 2-alkenylphenyl-isonitrile [51,220,221]. 

A huge number of additives have been tested, highlighting not only the necessity for a proton source but also the influence of the conjugated base and its coordinating ability. For example, aqueous HPFe allows high yield synthesis contrary to aqueous FI Cl, and the mechanism accounting for the influence of the additive has still to be elucidated. Nonetheless, this methodology has found application for the synthesis of quinolines [94] and 2,3-disubstituted indoles (Scheme 8.33) [96]. 

Scheme 8.33 Synthesis of quinolines and 2,3-disubstituted indoles via hydroamination.

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