Aryl halides, repetitive coupling

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

Repetitive coupling of acetylenes with aryl halides is an effective way to directly build hyperbranched architecture in a stepwise manner. This type of polycoupling is often catalyzed by palladium complexes in the presence of amines and has been widely used for the preparation of well-defined oligomers, linear polymers, and perfectly branched dendrimers [19,20]. 

Heck in one of his first papers already demonstrated the feasibility of applying the palladium-catalyzed crosscoupling of aryl and alkenyl halides with alkenes repetitively on appropriate oligofunctional substrates. For example, twofold coupling of 1,4-diiodobenzene with styrene furnished 1,4-distyrylbenzene in 67% yield (Scheme 1). Since then, a large number of ortho-, meta-, and / r< -dihaloarenes and -heteroarenes have been subjected to twofold Heck reactions with various alkenes (Schemes 2-4). 

---