Indoles coupling with isoquinoline

The medicinal importance of 2-aryltryptamines led Chu and co-workers to develop an efficient route to these compounds (130) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 128 with arylboronic acids 129 [137]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 128. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70-100%). 2-Phenyl-5-(and 7-)azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [19]. 

It was also reported that the use of quinoxaline A-oxide gives rise to coupling in even a higher yield than the parent indole-pyridine coupling reaction (Scheme 8) [26], The coupling reactions with isoquinoline, phthalazine, and pyrimidine A-oxides proved to proceed smoothly, and their regioselective outcomes were found to be consistent with the parent coupling reaction. 

Like simple aryl halides, furyl halides take part in Suzuki couplings as electrophiles [41, 42]. Young and Martin coupled 2-bromofuran with 5-indolylboronic acid to prepare 5-substituted indole 37 [43]. Terashima s group cross-coupled 3-bromofuran with diethyl-(4-isoquinolyl)borane 38 to make 4-substituted isoquinoline 39 [44]. Similarly, 2- and 3-substituted isoquinolines were also synthesized in the same fashion [45]. 

The biochemical importance of secologanin is indicated by the fact that the coupling reaction with tryptamine and dopamine is the first step in the biosynthesis of about 2500 indole, isoquinoline and related alkaloids [2, 7], the most typical of which are shown in Fig. (2). 

A combination of a Mizoroki-Heck reaction and a C—N coupling on solid phase was reported by Yamazaki et al. [105] in the synthesis of indole carboxylate 197 employing immobilized A-acetyldehydroalanine (194) and a bifunctionalized arene 195. In these transformations, 196 is the intermediate. The best results were obtained with o-dibromoarenes such as 195b and 195d using the Pd2(dba)3/P-r-Bu3/Cy2NMe catalytic system developed by Littke and Fu [106]. The protocol was also extended to the synthesis of isoquinolines [107] (Scheme 8.50). 

Transition-metal-mediated C—X bond formation by intramolecular reactions with alkynes is a powerful strategy for the construction of heteroarene rings such as pyridines, pyrroles, and furans. Because of the wide availability of Sonogashira coupling of various haloarenes with terminal alkynes, these transformations provide efficient routes to synthesize fused heteroarenes, including isoquinolines, indoles, and benzofurans. In this chapter the construction of aromatic rings by transition-metal-catalyzed or transition-metal-mediated intramolecular C—X bond formation between C—X or X—H and alkynes is described. As shown in Scheme 19.1, Section... 

In 2011, Li etal. described a Rh(III)-catalyzed coupling of JV-aryl and Al-alkyl ben-zamidines with internal alkynes that afforded less accessible 1-aminoisoquinolines 55 [30]. In the presence of ort/zo-substituted benzamidines, the reaction occurred by dual oxidative cyclization and furnished indole-isoquinoline 56. This unusual result occurred in the presence of an ortho steric effect after the formation of the isoquinoline moiety. The steric repulsion between the ortho substituent and AT-phenyl ring forced these two groups apart (Eq. (5.54)). 

---