Heck reaction nucleophilic substrates

This transformation can also be achieved using malonates and P-keto ester nucleophiles. Tietze and Raschke have used a silane-terminated Heck reaction, in which the substrate (10.151) loses the silyl group to give the cyclised product (10.152). Incorporation of a nitrogen atom at the requisite position in the side chain allows the enantioselective synthesis of tetrahydroisoquinolines and benzazepines using this methodology. ... 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

Jia and coworkers [71] reported a very nice palladium-catalyzed domino reaction involving a C-H activation process (Scheme 12.47). The regioselectivity of the attack of the nucleophile at the intermediately formed palladacyle 121 is solely controlled by the reaction conditions using the same substrate. In the Pd-catalyzed transformation of 120 in DMF in the absence of water, the aryl-substituted product 122 was obtained in 47-95% yield, and, in the presence of water, the alkyl-substituted product 123 in 60-95% yield. However, it should be noted that the reaction temperature has also some influence. The paUadacycle intermediate 121 was successfully trapped by cyanation, Heck reaction, secondary C-H activation, and Suzuki coupling. 

Diazonium salts react with various nucleophiles in water (Eq. 11.62).106 In acidic aqueous solution, p-pheny I e ncbis di azo ni um ion reacts with alcohols more rapidly than it does with water.107 In the presence of nucelophiles such as halides, the substitution products are obtained. Furthermore, diazonium salts of aromatic compounds are excellent substrates for palladium-catalyzed coupling reactions such as the Heck-type reactions in water. 

In Scheme 62 are shown recently developed cyclization reactions of iV-nucleophiles on olefmic electrophiles to give piperidines. In an iodolactamization method, chiral 154 gave 155 in 90% yield and 97% de. <04JOC7906>. A tandem Heck-allylic substitution reaction served to convert 156 to 157 with modest diastereoselectivity. A proposed intermediate is the ally lie palladium species 158 <04T9687>. An amidomercuration reaction of similar olefinic substrates to give 2,6-dialkylpiperidines has been reported <040L3067>. 

Another tandem possibility is to use oxidative addition to generate the palladium(II) species that initiates cyclization (Scheme 6.44). The result is formation of both a C-C bond and a bond between an alkene carbon and a heteroatom. The C-C bond is formed by reductive elimination that generates a palladium(O) species. This is then returned to the palladium(II) state by oxidative addition, hence no added oxidant is required. The reaction has often been used in an intramolecular fashion to ensure regioselectivity. If the nucleophilic attack is slow, a by-product may occur, which is the Heck product arising from alkene insertion. Alkynes may also be used as substrates. 

---