Cross-coupling reactions for indoles

Metal-catalyzed cross-coupling reactions have emerged as an important advancement in organic chemistry during the last few decades. Meanwhile, due to indole s importance in medicinal chemistry and many other fields, metal-catalyzed cross-coimling reactions have been extensively applied in the field of indole synthesis.  

The oxidative coupling/cyclization reaction is the intramolecular or inter-molecular union of two arenes with formal loss of H2 promoted by a Pd(II) species, typically Pd(OAc)2. Thanks to the entropy benefit, intramolecular oxidative coupling, also known as oxidative cyclization, is much more facile than the inter-molecular oxidative coupling. Hill described the oxidative coupling Pd(OAc)2-mediated oxidative cyclization of bisindolylmaleimides to give indolo[2,3- 3f]pyrrolo[3,4-c]carbazoles, which is the core ring system in numerous natural products, many of which have potent protein kinase activity. 

Since direct alkylation of a 2-lithioindole failed, a Negishi protocol was utilized to synthesize a 2-benzylindole, an intermediate for the novel CNS agent. 

Negishi methodology can also be used to achieve the 3-acylation of indoles. Thus, a series of 3-acylindoles was prepared from 1,2-substituted indole. The 1,2-substituted indole could also be iodinated cleanly at C-3 with 7V-iodosuccinimide. 

An asymmetric synthesis of prolino-homotryptophane was accomplished via amino-zinc-ene-enolate cyclization followed by transmetalation of the cyclic zinc intermediate with indolyliodide. The use of palladium catalyst derived from [t-Bu3PH] BF4 was required to avoid the undesired P-hydride elimination. The resulting proline chimeras are useful tools for medicinal chemistry and/or biological applications. 

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Metal-Catalyzed Cross-Coupling Reactions for Indoles... 

In Chap. 6, a companion to the preceding chapter, Li and Gribble document Metal-Catalyzed Cross-Coupling Reactions for Indoles , which covers palladium, copper, rhodium, iron, and nickel cross-couplings of indole - a suite of reactions that has assumed great importance in indole synthesis and chemistry. 

Li. J. J. Chapter 6. Metal-catalyzed Cross-coupling Reactions for Indoles, in Indoles, Gribble, G. W., Ed. Springer Helderberg, Germany, 2010, pp. 193-234. 

The halogen-substituted indoles are key intermediates for some biologically active compound synthesis via Suzuki-Miyaura cross-coupling reactions. Furthermore, indoles also could be obtained from a, -ynones and primary amines directly by a sequential process and a wide variety of indole derivatives could be synthesized easily [44] (Scheme 8.18). 

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 concise method for the synthesis of the 5-substituted azepino[3,4-b]indol-l-ones 37 (eg. R = Bn, R1 = Ph) has been described, based on the Pd-mediated cross coupling reactions of azepino[3,4-b]indol-5-yl trifluoromethanesulfonates eg. 36. These latter compounds were accessed in turn from the corresponding azepino[3,4-i>]indole-l,5-dione <00T4491>. 

The formation of seven membered heterocycles and larger rings through cross-coupling reactions is quite rare (except for some macrocyclic natural products). An example of such a process is presented in 5.1. The intramolecular Stille-coupling of the tributylstannyl-indole and vinyl bromide moieties led to the formation of a seven membered ring in good yield.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. 

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]. 

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