Ynoate-Initiated Selective C–N Esterification of Tertiary Amines under Transition-Metal and Oxidant-Free Conditions

Feixiang Sun; Huangdi Feng; Liliang Huang; Junhai Huang

doi:10.1055/a-1326-6973

Synlett, Table of Contents

Synlett 2021; 32(07): 713-717
DOI: 10.1055/a-1326-6973

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Ynoate-Initiated Selective C–N Esterification of Tertiary Amines under Transition-Metal and Oxidant-Free Conditions

Feixiang Sun

^aCollege of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China

,

Huangdi Feng∗

^aCollege of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China

^cShanghai Engineering Research Center of Textile Chemistry and Cleaner Production, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China

,

Liliang Huang

^aCollege of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China

,

Junhai Huang∗

^aCollege of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, P. R. of China

^bState Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, P. R. of China

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Abstract

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Abstract

An efficient and selective method for metal- and oxidant-free deaminated esterification of tertiary amines is presented. In this protocol, ynoates play a key role to activate the Csp³–N bond through a process of in situ generation of zwitterionic salts. The transformations show that Csp³–N bond in the zwitterionic species has a lower dissociation energy than Csp²–N bond, leading to break preferentially and be trapped by carboxylic acids to generate the corresponding products in moderate to good yield.

Key words

C–N activation - esterification - chemoselectivity - ynoate - amines

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References

References and Notes

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17 General Procedure for the Synthesis of Dibenzyl 2,6-Pyridine-dicarboxylate (4aa) A mixture of pyridine-2,6-dicarboxylic acid (2a, 83.5 mg, 0.5 mmol, 1.0 equiv) and ethyl propiolate (3a, 157 mg, 1.6 mmol, 3.2 equiv) was added a 10 mL tube along with a magnetic stir bar, and then 2 mL 1,4-dioxane was added. The tube was stirred and refluxed in oil bath at 80 °C. Subsequently, N,N-dimethylbenzylamine (1a, 202 mg, 1.5 mmol, 3 equiv) solved in 1 mL 1,4-dioxane was added to the tube slowly for 10 min. And the tube was stirred again and refluxed at 80 °C for 12 h. After the removal of the volatiles in vacuo, the crude residue was loaded on a silica gel (100–200 mesh) column and flashed with 20% ethyl acetate in petroleum ether to afford the desired product 4aa in 81% yield. Dibenzyl 2,6-Pyridine-dicarboxylate (4aa) White solid; 140 mg, 81% yield; mp 111–113 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.27 (d, J = 7.8 Hz, 2 H), 7.97 (t, J = 7.8 Hz, 1 H), 7.48 (m, J = 7.7 Hz, 4 H), 7.42–7.31 (m, 6 H), 5.45 (s, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 163.90, 148.01, 137.79, 134.97, 128.27, 127.88, 127.58, 67.26. Dibenzyl 2,6-Furan-dicarboxylate (4ab) White solid; 144 mg, 86% yield; mp 73–75 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.33 (m, 10 H), 7.20 (d, J = 4.1 Hz, 2 H), 5.36 (s, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 157.39, 146.36, 134.75, 128.30, 127.97, 118.22, 66.66. Dibenzyl 2,6-Thiophene-dicarboxylate (4ac) White solid; 101 mg, 57% yield; mp 56–58 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (s, 2 H), 7.46–7.33 (m, 10 H), 5.35 (s, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 161.38, 139.01, 135.35, 133.25, 128.60, 128.28, 67.30. HRMS (EI): m/z calcd for C₂₀H₁₆O₄S [M]⁺: 352.0764; found: 352.0765.

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