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A Mild Heteroatom (O-, N-, and S-) Methylation Protocol Using Trimethyl Phosphate (TMP)-Ca(OH)2 Combination

Yu Tang*, Biao Yu*

*Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, Email:,

Y. Tang, B. Yu, Synthesis, 2022, 54, 2373-2390.

DOI: 10.1055/a-1731-3852

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The combination of trimethyl phosphate (TMP) and Ca(OH)2 enables a mild and efficient heteroatom methylation in DMF, water, or under neat conditions, at 80 C or at room temperature. A series of O-, N-, and S-nucleophiles, including phenols, sulfonamides, N-heterocycles, such as 9H-carbazole, indole derivatives, and 1,8-naphthalimide, and aryl/alkyl thiols, are suitable substrates.

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Key Words

trimethyl phosphate, calcium hydroxide, aryl ethers, sulfonamides, sulfides, heteroatom methylation, aqueous S-methylation, N-sulfonamide methylation

ID: J66-Y2022