An efficient domino Pd-catalyzed transformation of simple ortho-bromobenzyl tertiary alcohols to chromenes is presented. Their formation is believed to proceed via the formation of a five-membered palladacycle, which, in turn, involves in an intermolecular homocoupling with the second ortho-bromobenzyltertiary alcohol to yield the homo-biaryl bond followed by intramolecular C-O bond formation. Interestingly, when there is an allylic substituent on the benzylic carbon atom, a chemoselective switch was observed, which preferred intramolecular Heck coupling and gave indenols. Further, it has been confirmed that the tertiary alcohol functionality is indispensible to give the coupled products, whereas the use of primary/secondary benzylic alcohols furnished the simple carbonyl products via a possible reductive debromination followed by oxidation due to the availability of β-hydrogen(s).

An efficient Pd-catalyzed domino reaction of α,α-dialkyl-(2-bromoaryl)methanols to 6,6-dialkyl-6H-benzo[c]chromenes is presented. Their formation can be explained via a five membered Pd(II)-cycle that efficiently involves a domino homocoupling with the second molecule, β-carbon cleavage, and finally intramolecular Buchwald-Hartwig cyclization. This domino process effectively involves breaking of five σ-bonds (2C-Br, 2O-H, and a C-C) and formation of two new σ-bonds (C-C and C-O). This mechanistic pathway is unprecedented and further illustrates the power of transition metal catalysis.

A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics.

The outcomeo fr ing-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previousw ork on Successive Ring Expansion (SuRE) methods, detailse fforts to betterd efine the scope andl imitations of these reactions on lactam and b-ketoester ring systems with respecttoring size and additional functionality. The synthetic resultsp rovide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using ad ensity functional theory(DFT) approach. Calculating the relative Gibbs free energies of the three isomeric speciest hat are formed reversibly duringr ing expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational resultsa re expected to support the design of new lactam-a nd b-ketoester-based ring-expansion reactions. Scheme1.Side-chain insertion ring-expansion reactionsand Successive Ring Expansion (SuRE).

An efficient domino [Pd]-catalysis for the synthesis of isobenzofuran-1(3H)-ones is presented. The strategy shows broad substrate scope and is amenable to o-bromobenzyl tertiary/secondary/primary alcohols. Significantly, the method was applied to the synthesis of antiplatelet drug n-butyl phthalide and cytotoxic agonist 3a-[4'-methoxylbenzyl]-5,7-dimethoxyphthalide.