Intramolecular amination, Buchwald-Hartwig coupling reactions

Recently, Buchwald and Hartwig have developed the palladium-catalyzed coupling reaction of aryl halides with amines (Scheme 165), and they have extended this reaction to the intramolecular version to give a variety of the aza-heterocyclic compounds 547 (Scheme 166).231 This methodology has provided a wide variety of alkaloids, such as indoles,232 inda-zoles,233 benzimidazoles,234 benazepines,235 phena-zines,236 carbapenems,237 the mitomycin ring system,238 a-carbolines,239 and polyheterocycles.240 Pharmacologically active natural products, such as (—)-asperlicin (550) (Scheme 167),241 dehydrobufotenine (553) (Scheme 168),242 and makaluvamine C... 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

The Buchwald-Hartwig amination (see Chapter 13) can be combined with an intramolecular carbopalladation. In particular, an allene as in 142 can serve as a suitable initiator (Scheme 8.33) [336]. Depending on the reaction conditions, either the C-N or the C-C coupling proceeds first... 

Indole is one of the most important heterocyclic scaffolds for drug discovery. Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329, 330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331, 332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334, 335] (Scheme 15.104). Alternatively, o-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198, 200, 336-340]. These approaches have been thoroughly reviewed [10]. 

In 2002, the expansion of the Buchwald-Hartwig amination reaction to alkenyl halide electrophiles was reported. This has proven to be a useful method for the construction of enamines or imines that are difficult to prepare using traditional condensation reactions [127]. For example, Voskoboynikov and coworkers [128] demonstrated that azoles could be stereoselectively coupled with either E- or Z-p-bromostyrene to generate enamines using a catalyst composed of Pd(dba)2 and P(t-Bu)3 (Eq. 15). In the same year, Mori and Kozawa reported Pd(OAc)2/DPE-Phos catalyzed intramolecular iV-aUcenylation reactions that afforded bicycUc p-lactams (Eq. 16) [129]. 

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