Buchwald-Hartwig coupling cyclization

The palladium-catalyzed intramolecular C-H arylation of aromatic C-H bonds with haloarenes (Ar-H/Ar-X coupling, where X is halogen) is effective for the synthesis of carbazole alkaloids with amine linkers, as reported by Bedford and coworkers in 2006 (Scheme 16.16a) [34]. Buchwald-Hartwig coupling of an aryl bromide and an aniline derivative generated aryl chloride 91 in situ, which was easily cyclized under palladium catalysis to give clausine P in 80% yield. They also... 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

The Buchwald-Hartwig palladium-catalyzed aryl-amino coupling reaction was applied to the synthesis of functionalized A-phenyl-2-quinolinones <03TL4207>. This was especially powerful because known methods of cyclization preclude anilines with electron-withdrawing groups para, or any ortho substituents, for steric reasons. 

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. 

Scheme 45 Synthesis of carbazoles 32 by Buchwald-Hartwig amination and subsequent cyclization by intramolecular Heck-type coupling of the intermediate diarylamines 197...

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

The Buchwald-Hartwig reaction ( 5.1) can be combined with an intramolecular cyclization i.e., carbopalladation). In particular, an allene can serve as suitable starter molecules see the Experimental Procedure below. "" Depending on the reaction conditions, either the C-N or the C-C coupling proceeds first. 

Although one of the more recent additions to the armamentarium of these palladium-catalysed reactions, the Buchwald-Hartwig cross-coupling of amines with aiyl halides already has found applications in macrocycle synthesis. In the first example, Iqbal et al used this coupling as the cyclization step in the synthesis of constrained tri- or tetra-peptidomimetics with a biaiyl linker (Scheme 11.13 illustrates a tripeptidomimetic (112)). Fair to moderate yields were obtained for products containing 16- to 22-membered rings. 

The first high yielding one-pot tandem Hartwig-Buchwald-Heck cyclization was reported and applied to the synthesis of 2,3-disubstituted indoles [201]. Commercially available enone 123 was coupled with 1,2-dibromobenzene to provide A -arylcncaminonc 124 which subsequently cyclized to indole derivative 125 [201]. This reaction was widely applicable to a variety of electron rich, electron poor and neutral aromatic bromides and chlorides as well as heterocyclic halides. Excellent yields were obtained regardless of the substitution pattern on the aromatic halide. 

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