Selective N-Monoalkylation of Amide Derivatives with Trialkyl Phosphates

Abstract

A highly selective and easily handled monoalkylation of primary amide derivatives by using trialkyl phosphates as alkylating reagents in cyclopentyl methyl ether (CPME) was developed. Various monoalkylated amide derivatives were efficiently synthesized by changing the alkyl moiety (e.g., methyl, ethyl, butyl, or benzyl) of the trialkyl phosphate. These phosphate reagents are relatively stable and easily available, and CPME is a useful solvent in process chemistry.

Key words

alkylation - monoalkylation - amides - trialkyl phosphates - cyclopentyl methyl ether

• References and Notes


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• 11 N-Methylbenzamide (2a) Colorless solid; yield: 24.6 mg (79%); mp 80 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.51–7.49 (m, 1 H), 7.44 (t, J = 7.0 Hz, 2 H), 6.11 (br s, 1 H), 3.03 (d, J = 4.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.4, 134.7, 131.4, 128.6, 127.0, 27.0. The ¹H NMR and ¹³C NMR spectra were identical to those reported (see Ref. 5).

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• 14 N-Monoalkyl Amides 2; General Procedure NaOH (14.4 mg, 0.36 mmol, 1.8 equiv) or a 2.65 M solution of n-BuLi in hexane (0.14 mL, 0.37 mmol, 1.8 equiv) and the appropriate trialkyl phosphate (0.60 mmol, 3.0 equiv) were added sequentially to a solution of the appropriate amide derivative 1 (0.20 mmol, 1.0 equiv) in CPME (1.0 mL), and the mixture was stirred at 115 °C under argon for 24 h. The reaction was then quenched with brine (2 mL) and the mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated in vacuo to give a residue that was purified by column chromatography (silica gel).
• 15 4-Methoxy-N-methylbenzamide (2b) Colorless solid; yield: 30.7 mg (66%); mp 116–118 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.73 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 6.03 (br s, 1 H), 3.85 (s, 3 H), 3.01 (d, J = 5.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 162.1, 128.7, 127.0, 113.8, 55.5, 26.9. The ¹H NMR and ¹³C NMR spectra were identical to those reported (see Ref. 5).
• 16 Trimethyl, triethyl, and tributyl phosphates are commercially available. Tribenzyl phosphate was synthesized (see Supplementary Information).