Overcoming peri- and ortho-selectivity in C–H methylation of 1-naphthaldehydes by a tunable transient ligand strategy

Abstract

Methyl groups widely exist in bioactive molecules and site-specific methylation becomes a valuable strategy for their structural functionalization. Aiming to introduce this smallest alkyl handle, a high regioselective peri- and...

Synthesis of Naphthalene Natural Products Dehydrocacalohastine and Musizin

“…In our previous work, nordehydrocacalohastine have been obtained in shorten steps and higher yields with the assistance of peri-meathylation of 1-naphthaldehyde. [10] Compared with nordehydrocacalohastine 1, an extra methyl is placed at C4 position of dehydrocacalohastine 2. Retrosynthetic analysis indicated that the methyl group would be introduced by the reduction of formyl group after the peri-methylation (Scheme 1a).…”

“…Although dehydrocacalohastine 2 showed anti‐inflammatory [4d] and neuroprotective [4f] activities, there was no report about their preparation by chemical methods, which may be attributed to the difficulty in installing multiple methyl groups at diffrent sites accurately. In our previous work, nordehydrocacalohastine have been obtained in shorten steps and higher yields with the assistance of peri ‐meathylation of 1‐naphthaldehyde [10] . Compared with nordehydrocacalohastine 1 , an extra methyl is placed at C4 position of dehydrocacalohastine 2 .…”

“…According to the previous route, [10] naphthaldehyde 16 was constructed by two steps in 46% yield from the starting material 12 . The hydroxyl group was then protected by reacting with benzyl bromide in CH 3 CN, due of its incompatibility in peri ‐methylation.…”

“…[9] It is recognized that natural methylated naphthalene molecules would be garnered via direct CÀ H functionalizations of naphthalene material rather than awkward beginning from benzene ring. Enabled by tunable catalysts and ligands, our group has recently developed a regioselective periand ortho-CÀ H methylation of 1-naphthaldehydes, [10] which may confer an accessibility to these methylated naphthalene molecules and further pharmaceutical and biological research.…”

Theoretical Study for Evaluating and Discovering Organic Hydride Compounds as Potential Novel Methylation Reagents

“…The introduction of the methyl group to drug molecules is helpful to improve their binding affinity, biological availability, and metabolic stability (called “magic methyl effect”), which greatly changes the pharmacological properties of bioactive molecules. − Methylation plays an important role in the modification of drug molecules, DNA, as well as proteins. − According to different reaction mechanisms, the methylation agents are divided into three classes, i.e., electrophilic methylation reagents, nucleophilic methylation reagents, and free radical methylation reagents . At present, great progress has been made in the methylation reaction. − Many chemists have made outstanding contributions in this field, and a large number of new methyl reagents − and new methylation reactions have been developed, − especially electrocatalytic, , visible-light-induced, or transition-metal-catalyzed − methylation, in recent years. In 2021, Dixon and co-workers published an important review about C–H methylation in chemical synthesis, which covered the various methylation reagents and diverse strategies employed to realize the selective installation of the C–Me bond in extensive chemical structures .…”