Direct Etherification of Alkyl Halides by Sodium Hydride in the Presence of N,N-Dimethylformamide

Abstract

A novel synthetic method for the preparation of various alkyl ethers is described. The reaction between alkyl halides and sodium hydride in the presence of N,N-dimethylformamide afforded the corresponding symmetrical and unsymmetrical ethers in high yields. A reaction mechanism for etherification is also proposed.

Key words

etherification - dimethylformamide - sodium hydride - symmetrical and unsymmetrical ethers - alkyl halides

References and Notes

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1

These authors contributed equally to this work.

16

Compound 3a: ¹H NMR (300 MHz, CDCl₃): δ = 4.67 (s, 4 H), 7.40-7.51 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 72.45, 127.95, 128.09, 128.73, 138.66. ¹H NMR and ¹³C NMR spectra were identical to an authentic sample.
Compound 3b: ¹H NMR (300 MHz, CDCl₃): δ = 1.71 (br, 1 H), 4.74 (s, 2 H), 7.30-7.43 (m, 5 H). ¹H NMR spectrum was identical to that of an authentic sample.
Compound 4a: ¹H NMR (300 MHz, CDCl₃): δ = 4.27 (dd, J = 6.0, 1.2 Hz, 4 H), 6.39 (dt, J = 15.6, 6.0 Hz, 2 H), 6.70 (d, J = 15.6 Hz, 2 H), 7.30-7.49 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 70.99, 126.30, 126.75, 127.93, 128.80, 132.83, 136.99. ¹H NMR and ¹³C NMR spectra were consistent with literature values.^19a
Compound 5a: ¹H NMR (300 MHz, CDCl₃): δ = 1.03 (t, J = 7.5 Hz, 6 H), 2.04-2.14 (m, 4 H), 3.93 (dd, J = 6.3, 1.2 Hz, 4 H), 5.56-5.64 (m, 2 H), 5.72-5.81 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.53, 25.51, 71.00, 125.57, 136.48.
Compound 6a: ¹H NMR (300 MHz, CDCl₃): δ = 1.66-1.79 (m, 8 H), 2.69 (t, J = 7.5 Hz, 4 H), 3.47 (t, J = 6.3 Hz, 4 H), 7.22-7.36 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 28.33, 29.67, 35.99, 70.98, 125.91, 128.51, 128.67, 142.76.
Compound 6b: ¹H NMR (300 MHz, CDCl₃): δ = 1.34 (br, 1 H), 1.63-1.79 (m, 4 H), 2.70 (t, J = 7.5 Hz, 2 H), 3.71 (t, J = 6.3 Hz, 2 H), 7.22-7.36 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.77, 32.58, 35.87, 63.07, 125.99, 128.54, 128.64, 142.55. ¹H NMR and ¹³C NMR spectra were identical to an authentic sample.
Compound 7a: ¹H NMR (300 MHz, CDCl₃): δ = 1.45 (d, J = 6.6 Hz, 6 H), 1.53 (d, J = 6.6 Hz, 6 H), 4.32 (q, J = 6.6 Hz, 2 H), 4.60 (d, J = 6.6 Hz, 2 H), 7.21-7.42 (m, 20 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.23, 24.93, 74.67, 74.89, 126.47, 126.56, 127.37, 127.61, 128.47, 128.69, 144.42, 144.50. Products 7a were 1:1 mixture of dl enantiomers and meso compounds, as illustrated in the literature.^19b
Compound 7b: ¹H NMR (300 MHz, CDCl₃): δ = 1.54 (d, J = 6.6 Hz, 3 H), 2.09 (br, 1 H), 4.93 (q, J = 6.6 Hz, 1 H), 7.31-7.41 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 25.38, 70.65, 125.62, 127.71, 128.74, 146.06. ¹H NMR and ¹³C NMR spectra were identical to an authentic sample.
Compound 7c: ¹H NMR (500 MHz, CDCl₃): δ = 5.30 (d, J = 11.0 Hz, 1 H), 5.81 (d, J = 17.5 Hz, 1 H), 6.78 (dd, J = 17.5, 11.0 Hz, 1 H), 7.31-7.49 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 114.04, 126.48, 128.06, 128.78, 137.17, 137.87. ¹H NMR and ¹³C NMR spectra were identical to an authentic sample.

18

DMF-¹⁸O was prepared from chloromethylenedimethyl-ammonium chloride and H₂O-¹⁸O (ca. 10 atom%) according to the literature.¹⁷ Mass spectrometric comparison of the parent ion peak ratios (74 and 76) to that of DMF-¹⁶O indicated that an enrichment of approx. 7.4% of ¹⁸O was present. The mass spectra of dibenzyl ether prepared from DMF-¹⁶O and DMF-¹⁸O was compared at m/e 221:223 [M + Na] and indicated that an enrichment of approx. 6.4% of ¹⁸O was present.