Synlett 2018; 29(03): 322-325
DOI: 10.1055/s-0036-1591494
letter
© Georg Thieme Verlag Stuttgart · New York

Selective N-Monoalkylation of Amide Derivatives with Trialkyl Phosphates

Shota Asai
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan   Email: sajiki@gifu-pu.ac.jp   Email: sawama@gifu-pu.ac.jp
,
Kazuho Ban
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan   Email: sajiki@gifu-pu.ac.jp   Email: sawama@gifu-pu.ac.jp
,
Yasunari Monguchi
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan   Email: sajiki@gifu-pu.ac.jp   Email: sawama@gifu-pu.ac.jp
,
Hironao Sajiki*
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan   Email: sajiki@gifu-pu.ac.jp   Email: sawama@gifu-pu.ac.jp
,
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan   Email: sajiki@gifu-pu.ac.jp   Email: sawama@gifu-pu.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 22 August 2017

Accepted after revision: 25 September 2017

Publication Date:
23 October 2017 (eFirst)

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.

Supporting Information

 
  • 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).