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Synlett 2009(14): 2242-2244  
DOI: 10.1055/s-0029-1217722
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Unexpected Variations in Sites of Lithiation of N-(2-Methoxybenzyl)-pivalamide

Keith Smith*, Gamal A. El-Hiti, Amany S. Hegazy
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
Fax: +44(2920)870600; e-Mail: smithk13@cardiff.ac.uk;
Further Information

Publication History

Received 21 May 2009
Publication Date:
03 August 2009 (online)

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Abstract

Directed lithiation of N-(2-methoxybenzyl)pivalamide with two mole equivalents of t-BuLi in anhydrous THF at -78 ˚C followed by reactions with various electrophiles gave ring substitution, but ortho to the methoxy group rather than ortho to the pivaloylaminomethyl group, which was unexpected in view of earlier results reported with n-BuLi.

Key words

N-(2-methoxybenzyl)pivalamide - directed lithiation - synthesis - dilithium intermediate - electrophile

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8

Analytical Data for Compound 2: Mp 170-171 ˚C (lit. [6] 168-169 ˚C). ¹H NMR (500 MHz, DMSO-d 6): δ = 7.43 (t, J = 6 Hz, exch., 1 H, NH), 7.34 (app. t, J = 8 Hz, 1 H, H-5), 7.27 (dd, J = 2, 8 Hz, 1 H, H-6), 7.19 (br d, J = 8 Hz, 1 H, H-4), 4.47 (d, J = 6 Hz, 2 H, CH2), 3.82 (s, 3 H, OCH3), 1.05 [s, 9 H, C(CH3)3] ppm. ¹³C NMR (125 MHz, DMSO-d 6): δ = 177.5 (s, C=O), 169.7 (s, CO2H), 158.4 (s, C-3), 134.3 (s, C-2), 128.7 (d, C-5), 126.7 (s, C-1), 121.6 (d, C-6), 114.6 (d, C-4), 56.5 (q, OCH3), 38.4 [s, C(CH3)3], 35.7 (t, CH2), 27.8 [q, C(CH3)3] ppm. MS (ES+): m/z (%) = 553 (34) [2 M + Na]+, 531 (42) [2 M + H]+, 329 (32) [M + MeCNNa]+, 304 (3) [M + K]+, 266 (100) [MH]+. HRMS (ES+): m/z calcd for C14H20NO4 [MH]+: 266.1392; found: 266.1392. FT-IR: νmax = 3401, 2965, 1698, 1611, 1539, 1467, 1385, 1219
cm-¹.

9

Analytical Data for Compound 4: Mp 156-157 ˚C. ¹H NMR (500 MHz, DMSO-d 6): δ = 8.03 (t, J = 6 Hz, exch., 1 H, NH), 7.57 (dd, J = 2, 8 Hz, 1 H, H-6), 7.32 (dd, J = 2, 8 Hz, 1 H, H-4), 7.16 (app. t, J = 8 Hz, 1 H, H-5), 4.32 (d, J = 6 Hz, 2 H, CH2), 3.79 (s, 3 H, OCH3), 1.15 [s, 9 H, C(CH3)3] ppm. ¹³C NMR (500 MHz, DMSO-d 6): δ = 178.1 (s, C=O), 167.8 (s, CO2H), 157.1 (s, C-2), 134.6 (s, C-3), 131.5 (d,
C-4), 129.6 (d, C-6), 126.1 (s, C-1), 123.9 (d, C-5), 62.1 (q, OCH3), 38.6 [s, C(CH3)3], 37.3 (t, CH2), 27.9 [q, C(CH3)3] ppm. MS (ES+): m/z (%) = 569 (12) [2 M + K]+, 553 (100) [2 M + Na]+, 548 (32) [2 M + NH4]+, 329 (25) [M + MeCNNa]+, 304 (27) [M + K]+, 288 (70) [M + Na]+, 266 (71) [MH]+. HRMS (ES+): m/z calcd for C14H20NO4 [MH]+: 266.1392; found: 266.1386. FT-IR: νmax = 3377, 2972, 1698, 1610, 1540, 1427, 1368, 1247 cm-¹.