Indole cross-coupling reactions

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>. 

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. 

Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719-721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from CIS- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from... 

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... 

One of the most frequently studied transition metal catalyzed transformations of azoles and indole is their participation in cross-coupling reactions. Due to the abundance of examples in this field we only present some representative examples of the different reaction classes. In this chapter reactions where a halogenated azole is used to introduce the five membered ring onto the palladium in the oxidative addition and processes,... 

Akita, Y. Itagaki, Y. Takizawa, S. Ohta, A. Cross-coupling reactions of chloropyrazines with 1-substituted indoles. Chem. Pharm. Bull. 1989, 37, 1477-1480. 

A general and convenient route to 2-substituted benzofurans or indoles is based on intramolecular annulation of 2-alkynylphenols or 2-alkynylanilines (Scheme 23), which are in turn readily available via alkynylaryl cross-coupling reactions. In a representative example, base-induced cyclization of the precursors 37 with concomitant elimination of the TMS-moiety affords the indoles 38 in good yields (Scheme 24) <1997JOC6507>. 

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. 

As a further synthetic application, 3-lithioindole 1 was converted to 1 -(tert-butyldimethylsilyl)-3-indolylzlnc chloride, which has been successfully employed in the heteroarylation of the indole 3-position by a palladium(0)-catalyzed cross-coupling reaction.8... 

A mild and general cross-coupling reaction of 2-indolylsilanols has been developed <2004OL3649>. The experimental variables that lead to successful coupling are (1) the use of Bu ONa as the activator, (2) the use of copper)l) iodide in stoichiometric quantities, and (3) the use of Pd2(dba)3-CHCl3 as the catalyst. Under these conditions (l-BOC-indol-2-yl)(dimethyl)silanol 622 reacts with a variety of aromatic iodides to afford the coupling products 623 in good yield (70-84%) (Equation 147). 

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