Double amination, Buchwald-Hartwig

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

Suzuki-Miyaura Coupling Followed by Double Buchwald-Hartwig Amination (Pd[0]/Pd[0])... 

A-Substituted carbazoles 192 are available by double Buchwald-Hartwig amination of 2,2 -dihalobiaryl compounds or biaryl bistriflates 204 with primary amines 205 in the presence of catalytic amounts of palladium(O) (Scheme 48) [203-205]. 

Chida et al. used this strategy for the total synthesis of murrastifoline A [204, 205]) and ( )-murrayazoline [( )-206] [206]. In addition to the double Buchwald-Hartwig amination generating the carbazole framework, two further palladium(0)-catalyzed couplings have been applied to construct the hexacyclic skeleton of ( )-murrayazoline [( )-206], an 0-arylation and a Suzuki-Miyaura coupling. Retrosynthetic analysis of ( )-murrayazoline [( )-206] led to 2-bromo-phenylboronic acid, the arylamine 211, and the monoprotected cyclohexane-1,4-dione 212 as precursors (Scheme 49). 

Dibromobiphenyl 210 and the amine 209 were prepared in five and ten steps, respectively. The double Buchwald-Hartwig coupling of 209 and 210 using 0.2 equiv. of tris(dibenzylideneacetone)dipalladium, 0.6 equiv. of 2-dicyclohexyl-phosphino-2, 4, 6 -triisopropylbiphenyl (X-Phos), and 3 equiv. of sodium ferf-but-oxide in toluene at 130°C in a sealed tube afforded the carbazole 213 in 59% yield (Scheme 50) [206]. Subsequent treatment with scandium(III) triflate resulted in removal of the MOM group, cleavage of the ketal, and subsequent Friedel-Crafts-... 

Several tandem reaction sequences have been developed for indole synthesis featuring a Buchwald-Hartwig aryl amination as one component. For instance, a tandem double JV-arylation of substrate 5 leads to indoles 6 through a cascade of C-N bond forming reactions. A range of structurally and electronically diverse amines can be used successfully in this transformation. 

Metal-catalyzed N-arylation of amines with haloarenes (Buchwald-Hartwig coupling) has been developed since the 1990s and provided more efficient access to carbazoles. Nozaki et al. reported the palladium-catalyzed double N-arylation of primary amines with 2,2 -dihalobiphenyls [8], A variety of dihalobiphenyls 10 and anilines 11 with electron-donating or electron-withdrawing substituent(s) are applicable to give multisubstituted carbazoles 12 in moderate to high yields (Scheme 23.4). 

Aniline and N-methylaniUne derivatives are the most reliable substrates for the Hartwig-Buchwald coupling, and they experience a high level of functional group tolerance. Similar to the coupling of primary amines, the double arylation of aniline can be a competing side reaction. A slight excess of the amine relative to the aryl component usually diminishes this side reaction. 

The Heck cyclization proceeds via methylene indolenines (83) (isolable in the presence of Ag salts) and migration of their exocyclic double bond to the internal enamine position under the reaction conditions. A variety of 3-methylindoles (84) is accessible directly from 2-bromoiodobenzenes by a Pd-catalyzed aryl amination (Hartwig-Buchwald reaction)/Heck cyclization cascade [172]. 

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