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.

Key words

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

References and Notes

• 1a Clayden J. Organolithiums: Selectivity for Synthesis   Vol. 23:  Tetrahedron Organic Chemistry Series, Pergamon; Oxford: 2002. 
• 1b Schlosser M. Organometallics in Synthesis   2nd ed.:  Wiley; Chichester: 2002. 
• See, for example:
• 2a Gschwend HW. Hamdan A. J. Org. Chem.  1975,  40:  2008 
• 2b Fitt JJ. Gschwend HW. J. Org. Chem.  1976,  41:  4029 
• 2c Fuhrer W. Gschwend HW. J. Org. Chem.  1979,  44:  1133 
• 2d Beak P. Snieckus V. Acc. Chem. Res.  1982,  15:  306 
• 2e Nájera C. Sansano JM. Yus M. Tetrahedron  2003,  59:  9255 
• 2f Schlosser M. Angew. Chem. Int. Ed.  2005,  44:  376 
• 2g Chadwick ST. Ramirez A. Gupta L. Collum DB. J. Am. Chem. Soc.  2007,  129:  2259 
• See, for example:
• 3a Beak P. Zajdel WJ. Reitz DB. Chem. Rev.  1984,  84:  471 
• 3b Snieckus V. Chem. Rev.  1990,  90:  879 
• 3c El-Hiti GA. Heterocycles  2000,  53:  1839 
• 3d Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4059 
• 3e Turck A. Plé N. Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4489 
• 3f Anctil EJ.-G. Snieckus V. J. Organomet. Chem.  2002,  653:  150 
• 3g Smith K. El-Hiti GA. Curr. Org. Synth.  2004,  1:  253 
• 3h Chinchilla R. Nájera C. Yus M. Chem. Rev.  2004,  104:  2667 
• 3i Foubelo F. Yus M. Curr. Org. Chem.  2005,  9:  459 
• 3j Rathman TL. Bailey WF. Org. Process Res. Dev.  2009,  13:  141 
• Recent examples for substituted benzenes:
• 4a Clayden J. Turner H. Pickworth M. Adler T. Org. Lett.  2005,  7:  3147 
• 4b Chodakowski J. Kliś T. Serwatowski J. Tetrahedron Lett.  2005,  46:  1963 
• 4c Clayden J. Dufour J. Tetrahedron Lett.  2006,  47:  6945 
• 4d Burgos PO. Fernández I. Iglesias MJ. García-Granda S. Ortiz FL. Org. Lett.  2008,  10:  537 
• 4e Wilkinson JA. Raiber E.-A. Ducki S. Tetrahedron  2008,  64:  6329 
• 4f Porcs-Makkay M. Komáromi A. Lukács G. Simig G. Tetrahedron  2008,  64:  1029 
• 4g Castanet A.-S. Tilly D. Véron J.-B. Samanta SS. Ganguly T. Mortier J. Tetrahedron  2008,  64:  3331 
• 4h Michon C. Murai M. Nakatsu M. Uenishi J. Uemura M. Tetrahedron  2009,  65:  752 
• Recent examples for substituted heterocycles:
• 5a Philipova I. Dobrikov G. Krumova K. Kaneti J. J. Heterocycl. Chem.  2006,  43:  1057 
• 5b Robert N. Bonneau A.-L. Hoarau C. Marsais F. Org. Lett.  2006,  8:  6071 
• 5c Aliyenne AO. Khiari JE. Kraïem J. Kacem Y. Hassine BB. Tetrahedron Lett.  2006,  47:  6405 
• 5d Comoy C. Banaszak E. Fort Y. Tetrahedron  2006,  62:  6036 
• 5e Luisi R. Capriati V. Florio S. Musio B. Org. Lett.  2007,  9:  1263 
• 5f Clayden J. Hennecke U. Org. Lett.  2008,  10:  3567 
• 5g McLaughlin M. Marcantonio K. Chen C. Davies IW. J. Org. Chem.  2008,  73:  4309 
• 5h Capriati V. Florio S. Luisi R. Mazzanti A. Musio B. J. Org. Chem.  2008,  73:  3197 
• 5i Affortunato F. Florio S. Luisi R. Musio B. J. Org. Chem.  2008,  73:  9214 
• 6 Simig G. Schlosser M. Tetrahedron Lett.  1988,  29:  4277 
• See, for example:
• 7a Smith K. El-Hiti GA. Abdo MA. Abdel-Megeed MF. J. Chem. Soc., Perkin Trans. 1  1995,  1029 
• 7b Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  647 
• 7c Smith K. El-Hiti GA. Abdel-Megeed MF. Abdo MA. J. Org. Chem.  1996,  61:  656 
• 7d Smith K. El-Hiti GA. Pritchard GJ. Hamilton A. J. Chem. Soc., Perkin Trans. 1  1999,  2299 
• 7e Smith K. El-Hiti GA. Shukla AP. J. Chem. Soc., Perkin Trans. 1  1999,  2305 
• 7f Smith K. El-Hiti GA. Hawes AC. Synthesis  2003,  2047 
• 7g Smith K. El-Hiti GA. Mahgoub SA. Synthesis  2003,  2345 
• 7h El-Hiti GA. Synthesis  2003,  2799 
• 7i Smith K. El-Hiti GA. Abdel-Megeed MF. Synthesis  2004,  2121 
• 7j El-Hiti GA. Synthesis  2004,  363 
• 7k Smith K. El-Hiti GA. Hegazy AS. Synthesis  2005,  2951 
• 7l Smith K. Barratt ML. J. Org. Chem.  2007,  72:  1031 

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.