Heck reaction aniline derivatives

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

In an example illustrating an approach to tryptamines, the aniline derivative 98, which is available by a Heck reaction involving the corresponding o-iodoaniline, was subjected to rhodium-catalyzed hydroformylation leading to the target indole 99 via the intermediate 100 (Equation 26) <1997JOC6464>. 

Related to the Heck reaction is the Larock annulation of internal alkynes, which is a general route to heterocyclic and carbocyclic systems. Especially attractive is the construction of the pharmaceutically important indole ring system via palladium-catalyzed coupling of 2-iodo-aniline and the corresponding V-methyl, acetyl, and tosyl derivatives with a wide variety of internal alkynes. The catalytic process appears to involve arylpalladium formation, regioselective addition to the carbon-carbon triple bond, and subsequent intramolecular palladium displacement.- ... 

Three reviews have detailed progress in the formation of biaryl systems using metal-catalysed substitutions of carbon—hydrogen bonds. The preferential arylation at the para-position of phenol and aniline derivatives with diaryl iodonium salts has been achieved using copper catalysis. Under similar reaction conditions, a-arylacetamides are selectively arylated at the meta-position. A mechanistic study, including DFT calculations, suggests that the meta-selectivity in the copper-catalysed arylation of anilides derives from a Heck-like four-membered transition state involving a Cu(III)-phenyl species (47). 

Mori-Ban reaction refers to a synthesis of indole derivatives by an intramolecular Heck reaction of o-halo-aniline with pendant olefin catalyzed by a low-valent metal complex Pd and Ni. The preferred ortho-haXogcn is bromine or iodine (chlorine has very low reactivity under this case). More often, the o-iodo-iV-allylaniline is more reactive than corresponding o-bromo-and o-chloro-substrate. Also, it has been found that the catalyst can be deactivated under the reaction. Therefore, a periodic provision of fresh catalyst normally gives higher overall yields than that using the same total amount of catalyst with one addition. In the past three decades, the Mori-Ban reaction has been improved and applied to variety of organic synthesis. 

In 2015, Liu and coworkers reported the formal synthesis of tipifarnib, a farne-syltransferase inhibitor, by using a palladium-catalyzed C-H alkenylation as a key step (Scheme 16.35) [71]. Aniline derivative 160 reacted with AC2O to form an acetanilide intermediate, followed by ort/zo-palladation under the influence of a palladium catalyst to produce compound 162. Oxidative Heck reaction with 161 and cyclization/deacetylation then occurred to afford quinolinone 163 in 95% yield in one pot. This quinolinone was then converted to tipifarnib by the reported procedure [72]. 

Indole and isoquinolone nuclei are prominent structural units frequently found in numerous natural products and pharmaceutically active compounds. Thus, the search for new methodologies to obtain these scaffolds with different substitution patterns is a current major objective in organic synthesis. Similar to benzofuran synthesis, Aluraez et al. observed that the palladium-catalyzed cascade intramolecular alkyne aminopaUadation/intermolecular Heck-type coupling reaction under oxidative conditions is an efficient methodology for the synthesis of indole 217 and isoquinolone 219 derivatives, starting from readily available aniline 216 or benzamide 218 substrates and functional alkenes [77] (Scheme 6.60). 

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