Suzuki reaction 5- -1 //-indole

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. 

A paper concerned with the synthesis of pyridazino[3,4-fe]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work <06T121>. 

An alternative method of producing indole-containing compounds involves a bis-Suzuki reaction of 2,3-dihaloindoles 114 with 2 equiv of boronic acids 115 with 10 mol % Pd(OAc)2 [75]. The paper describes the difference in electronic effects of the boronic acids. Electron-rich boronic acids give better yields (85-95%) whilst the electron-deficient boronic acids give poorer yields (44-55%). Scheme 28 shows the general synthesis of these compounds. 

Similarly, while exploring a route toward the synthesis of strychnine, Bodwell and Li reported hydroboration of i f-[2-(l-allyl-17/-indol-3-yl)ethyl]-6-iodopyridazin-3-amine 184 followed by intramolecular Suzuki reaction (Scheme 45) <2002AGE3261>. 

A versatile and convenient method for the synthesis of substituted benzo[o]carbazoles and pyrido[2,3-a]carbazoles has recently been developed [59]. Treatment of 2-(o-tolyl)- or 2-(3-methyl-2-pyridyl)-substituted indole-3-carbaldehydes (obtained by Suzuki reaction) with potassium tert-butoxide in DMF at 70-80 °C under irradiation by a 400 W high-pressure mercury lamp afforded benzo[a] carbazoles and pyrido] 2,3-o] carbazoles, respectively, in good yields (Eq. (30)). 

Several other groups have reported the synthesis and Suzuki reactions of an N-methylindolyl-3-carboxamido-2-boronic acid for the synthesis of benzo[a]carbazoles [128], an iV-Boc-5-sulfonamidoindolyl-2-boronic acid for the synthesis of novel KDR kinase inhibitors [129], indolyl-4-boronic acid in a new synthesis of lysergic acid [130], and 5-, 6-, and 7-indolylboronic acids for the synthesis of aryl-substituted indoles [131]. Carbazole-2,7-bis (boronates) have been employed to construct diindolocaibazoles [132]. 

Bis-indole alkaloids, such as 208, possess interesting scaffolds with biological activity. A general route to these compounds that allowed for various heteroaromatic rings to be used as the linker for the indole moieties was desired and the Suzuki reaction of 206 with 207 appeared to be the most direct method for their assembly [74]. 

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... 

A detailed study of the Suzuki reaction of benzene-ring substituted bromoindoles was published <04JOC6812>. The highest yields were obtained with indole substrates containing a tosyl nitrogen protecting group. Palladium-catalyzed carbonylation reactions of unprotected bromoindoles allowed for the synthesis of indolecarboxamides. For example, treatment of 5-... 

Solid phase bromination of indole-2-carboxylic acids linked to Merrifield resin by pyridinium bromide perbromide gives 3-bromo derivatives that were subsequently coupled via Suzuki reactions [58]. 

Remarkably, one year later Leadbeater described that biaryls can be synthesized via a Suzuki-type coupling under transition-metal free conditions [51, 52]. The reaction conditions were almost identical to those reported for the ligand-free process, with the difference being that a larger amoimt of Na2C03 and arylboronic acid were used. Only one successful example of a heteroaryl haUde substrate is shown namely, the coupling of 2-bromopyridine with phenylboronic acid (Scheme 32). 3-Bromothiophene did not couple under the same reaction conditions. Unfortimately, attempts to use heteroarylboronic acids such as 3-pyridinylboronic acid, 3-thienylboronic acid, and lH-indol-5-ylboronic acid on 4-bromoacetophenone completely failed. 

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). 

Cossy and coworkers described a precise combination of a Heck and a Suzuki-Miyama reaction using ynamides and boronic acids to give indole and 7-azaindole derivatives [46]. Thus, reaction of 6/1-73 with 6/1-74 using Pd(OAc)2 as catalyst led to 6/1-75 in 68% yield (Scheme 6/1.18). 

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. 

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. 

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... 

Palladium-catalyzed reactions of arylboronic acids have been utilized to craft precursors for constructing indole rings. Suzuki found that tris(2-ethoxyethenyl)borane (149) and catechol-derived boranes 150 readily couple with o-iodoanilines to yield 151, which easily cyclize to indoles 152 with acid [158]. Kumar and co-workers used this method to prepare 5-(4-pyridinyl)-7-azaindoles from 6-amino-5-iodo-2-methyl-3,4 -bipyridyl [159], A similar scheme with catechol-vinyl sulfide boranes also leads to indoles [160]. A Suzuki protocol has been employed by Sun and co-workers to synthesize a series of 6-aryloxindoles [161]. 

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],... 

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