5- -17/-indole, Suzuki coupling reaction

Another Suzuki coupling reaction was described by Zhang et al., to produce arylindoles 116a and b, using solid-phase synthesis [76]. The synthesis was achieved by palladium-mediated coupling/intramolecular indole cycli-zation of resin-bound 2-trimethylsilylindole 117, Scheme 29. 

Scheme 53. The Suzuki coupling reaction in indole alkaloid synthesis...

Indole-5-boronic add has also been used successfully in Suzuki coupling <92H(34)1395). Organothallium derivatives have also been used in Suzuki coupling reactions. The 4-substituted thallation intermediate from indole-3-carboxaldehyde can be coupled with both aryl and vinyl-boronic acids (Equation (122)) <86CPB397i>. 

AT-acetyltryptamines could be obtained via microwave-assisted transition-metal-catalyzed reactions on resin bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide. While acceptable reaction conditions for the application of microwave irradiation have been identified for Stille heteroaryla-tion reactions, the related Suzuki protocol on the same substrate gave poor results, since at a constant power of 60 W, no full conversion (50-60%) of resin-bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide could be obtained even when two consecutive cross-coupling reaction cycles (involving complete removal of reagents and by-products by washing off the resin) were used (Scheme 36). Also under conventional heating at 110 °C, and otherwise identical conditions, the Suzuki reactions proved to be difficult since two cross-coupling reaction cycles of 24 h had to be used to achieve full conversion. 

Another example of a one-pot indole synthesis, which proceeds through a Heck carbonylation and a Suzuki coupling, is shown below. The reaction conditions are similar to the previous example however microwave heating is employed [174] (Scheme 6.54). 

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. 

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... 

Abell utilized a Suzuki cross-coupling reaction on resin 153. Subsequent acid treatment effected cyclization to indole 154, which was readily cleaved with amines and alcohols to form potential libraries of amides and esters, respectively [162],... 

Doi and Mori made excellent use of dihydroindole triflate 189 in Pd-catalyzed cross-coupling reactions. This compound was discussed earlier in the Suzuki section, and it also undergoes Stille couplings as illustrated below [140]. A final dehydrogenation completes the sequence to indoles. 

The bromo derivative of A -mcthylsuccinimide did also undergo Suzuki coupling when treated with naphthylboronic acid in the presence of palladium acetate, triphenylphosphine and potassium carbonate (6.3.). The coupled product was deprotected under the reaction conditions and an indole derivative was isolated in good yield, which was successfully converted into the hexacyclic naphthopyrrolo[3,4-c]carbazole structure. Using the analogous trimethylstannyl-naphthalene derivative and optimised Stille coupling conditions the desired product was isolated only in 56% yield.5... 

C-Arylation of indoles can be accomplished by means of palladium-catalyzed coupling reactions, such as the Suzuki coupling (Entry 7, Table 15.7) or Stille coupling with resin-bound 2-bromoindoles [88] or 5-bromoindoles [75]. 2-Iodoindoles have been prepared on polystyrene by iododesilylation of 2-silylindoles with NIS (Entry 8, Table 15.7), and these can be C-arylated with arylboronic acids [73]. 

Several other examples of the utility of Pd-mediated reactions in synthesis of aryl and vinyl derivatives of pyrrole and indole were reported. Schmidt and coworkers examined arylation of 1-vinylpyrroles under Heck conditions. Reaction took place at the A-vinyl group. While the parent compound gave a mixture of -and -arylation, 2,3-dialkyl-1-vinylpyrroles preferred -substitution. <95RCB767> Grieb and Ketcha used Suzuki coupling conditions to prepare several 1-... 

Finally, ortho- 2,2-dibromovinyl)-aniline or -acetanilide can successfully be applied in a sequential cyclizing amination-cross coupling reaction with diethyl phosphonate to furnish the indolyl phosphonic ester 136 or the N-acetyl 2-aryl indole 137 as recently shown by Bisseret and coworkers [ 105] (Scheme 50). This sequence can be also performed with corresponding phenol derivatives furnishing benzofurans. For the N-acetyl 2-aryl indole 137 it can be shown that the Suzuki coupling occurs prior to the intramolecular animation as a consequence of the gradual difference in reactivity between trans-and czs-carbon-bromine bonds. 

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for l-methyl-2-bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1-methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively. 

A direct approach for selective construction of properly substituted bis(indole) pyrazine 100, the skeleton of a marine alkaloid dragmacidin D, has been reported. The Suzuki and the Stille cross-coupling reactions are key steps involved for regioselective introduction of two indole units [6]. 

Early examples of the total synthesis of naturally occurring indole alkaloids employing the Suzuki reaction include ellipticine (10) as repotted by Miller et al. [34], The aryl bromide, 6-amino-7-bromo-5,8-dimethylisoquinoline (45) was derived from 2,5-dimethylanilinc in nine steps. The Suzuki coupling of 45 with phenylboronic acid was carried out using catalytic tetrakis(triphenylphosphine)palladium in benzene and with Na,CO, serving as the base to furnish... 

I-Chloro-p-carboline (50) was prepared from tryptamine in three steps. It served as a common intermediate for palladium-catalyzed cross-coupling reactions that offered easy access to three natural indole alkaloids [36]. The Suzuki reaction of SO with S-formylfuranyl-2-boronic acid (51) formed the C-C bond between the pyridine and the furan rings. Reduction of the resulting adduct with NaBH, yielded perlolyrine (52, Scheme 10). In the same manner, the Suzuki reaction... 

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