Advances in the Synthesis of Methylated Products through Indirect Approaches

Abstract

Methylation is a well‐known structural modification in organic and medicinal chemistry. In addition to using conventional methylation reagents for direct methylation, indirect methylation approaches have been also successfully applied, particularly to tackle the isolation difficulty among the methylated product, the unreacted starting material, and the dimethylated by‐product due to the structural similarities between them. This review summarizes recent advances in the synthesis of methylated products through indirect approaches – transforming functionalized intermediates into the methylated products. The indirect methodologies surveyed in this review are useful for chemists to select appropriate methylation strategies, particularly for the challenging synthesis of methylated products at a large scale in drug discovery. Abbreviations: AIBN: azobisisobutyronitrile; Cbz: carbobenzyloxy; DBU: 1,8‐diazabicyclo[5.4.0]undec‐7‐ene; DIBAL: diisobutylaluminium hydride; FA: formic acid; Fmoc: fluorenylmethyloxycarbonyl; KOTMS: potassium trimethylsilanolate; LAH: lithium aluminium hydride; LiHBEt3: lithium triethylborohydride; PC: photocatalyst; PMHS: polymethylhydrosiloxane; PSMS: zinc bis(phenylsulfonylmethanesulfinate); SAM: S‐adenosylmethionine; SET: single electron transfer; TBAF: tetra‐n‐butylammonium fluoride; TBS: tert‐butyldimethylsilyl; TEA: trimethylamine; TFA: trifluoroacetic acid; TMS: trimethylsilyl; Ts: 4‐toluenesulfonyl.

Towards better syntheses of partially methylated carbohydrates?

“…22 Therefore, the C-H methylation of bioactive molecule is still the subject of important efforts. 23 While C-H and N-H 24 methylation have been reviewed recently, including discussions about methylation reagents 25,26 and indirect approaches, 27 the specific case of carbohydrate methylation has been the subject of less attention.…”

Aromatic C–H Methylation and Other Functionalizations via the Rh(III)-Catalyzed Migratory Insertion of Bis(phenylsulfonyl)carbene and Subsequent Transformations

“…The introduction of a methyl group usually generates profound effects on the pharmacokinetic, pharmacodynamic, and metabolic properties of drugs. In the last two decades, great efforts have been exerted to develop efficient methylation methods for arenes . The direct methylation strategy was developed for some substrates using various nucleophilic or electrophilic methylation agents .…”

C(sp 3 )–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

“…Methylation of benzylic C-H bonds leading to 7 and 12 was favored over reaction with the acidic O-H/N-H bonds, in contrast to the outcome expected from other metal-catalyzed methylation reactions (8). The compatibility of aryl boronates and aryl bromides with the reaction conditions (8,9,10,11) is especially useful in elaborating lead compounds in medicinal chemistry. A silyl-protected alcohol (9) was unaffected by the methylation reaction.…”

“…1A) due to changes in lipophilicity, three-dimensional shape, or conformational flexibility (4,5). The introduction of methyl groups into molecules is often nontrivial, requiring de novo chemical synthesis using a methylated starting material (6,7), and numerous efforts have been initiated to develop synthetic methods for methylation of bioactive molecules (8)(9)(10)(11)(12). Methods for direct methylation of C-H bonds would be particularly valuable because they would provide efficient access to structures that might not otherwise be available for biological testing (3,8,13,14).…”

“…The compatibility of aryl boronates and aryl bromides with the reaction conditions (8,9,10,11) is especially useful in elaborating lead compounds in medicinal chemistry. A silyl-protected alcohol (9) was unaffected by the methylation reaction. Minisci-type addition of the methyl radical to heteroarenes did not compete with C(sp 3 )-H methylation of pyridine-containing substrates (6 and 9), despite the mildly acidic conditions (14,34).…”