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

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.

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

References and Notes

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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: ν_max = 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: ν_max = 3377, 2972, 1698, 1610, 1540, 1427, 1368, 1247 cm^-¹.