Variations in Site of Lithiation of N-[2-(4-Methoxyphenyl)ethyl]pivalamide – Use in Ring Substitution

Abstract

Lithiation of N-[2-(4-methoxyphenyl)ethyl]pivalamide at –20 to 0 °C with three equivalents of n-BuLi in anhydrous THF, followed by reactions with various electrophiles, gives high yields of products involving ring substitution ortho to the pivaloylaminoethyl group, which was unexpected in view of earlier results reported with t-BuLi.

Key words

N-[2-(4-methoxyphenyl)ethyl]pivalamide - directed lithiation - synthesis - electrophile - dilithium intermediate

• References and Notes

• 1 Permanent address: G. A. El-Hiti, Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt.

See, for example:
• 2a Clayden J. Organolithiums: Selectivity for Synthesis. Pergamon; Oxford: 2002
• 2b Schlosser M. Organometallics in Synthesis . 2nd ed. Wiley; Chichester: 2002: 1-352
• 2c Capriati V, Florio S, Salomone A. Top. Stereochem. 2010; 26: 135
• 2d Coldham I, Sheikh NS. Top. Stereochem. 2010; 26: 253

See, for example:
• 3a Beak P, Snieckus V. Acc. Chem. Res. 1982; 15: 306
• 3b Nájera C, Sansano JM, Yus M. Tetrahedron 2003; 59: 9255
• 3c Whisler MC, MacNeil S, Snieckus V, Beak P. Angew. Chem. Int. Ed. 2004; 43: 2206
• 3d Chadwick ST, Ramirez A, Gupta L, Collum DB. J. Am. Chem. Soc. 2007; 129: 2259
• 3e Dyke AM, Gill DM, Harvey JN, Hester AJ, Lloyd-Jones GC, Muñoz MP, Shepperson IR. Angew. Chem. Int. Ed. 2008; 47: 5067
• 3f Coldham I, Raimbault S, Chovatia PT, Patel JJ, Leonori D, Sheikh NS, Whittaker DT. E. Chem. Commun. 2008; 4174
• 3g Coldham I, Leonori D, Beng TK, Gawley RE. Chem. Commun. 2009; 5239
• 3h Coldham I, Raimbault S, Whittaker DT. E, Chovatia PT, Leonori D, Patel JJ, Sheikh NS. Chem. Eur. J. 2010; 16: 4082
• 3i Robinson SP, Sheikh NS, Baxter Carl A, Coldham I. Tetrahedron Lett. 2010; 51: 3642
• 3j Guerrand HD. S, Adams H, Coldham I. Org. Biomol. Chem. 2011; 9: 7921
• 3k Thompson MJ, Louth JC, Little SM, Jackson MP, Boursereau Y, Chen B, Coldham I. ChemMedChem 2012; 7: 578
• 3l Sheikh NS, Leonori D, Barker G, Firth JD, Campos KR, Meijer AJ. H. M, O’Brien P, Coldham I. J. Am. Chem. Soc. 2012; 134: 5300

See, for example:
• 4a Beak P, Zajdel WJ, Reitz DB. Chem. Rev. 1984; 84: 471
• 4b Snieckus V. Chem. Rev. 1990; 90: 879
• 4c El-Hiti GA. Heterocycles 2000; 53: 1839
• 4d Turck A, Plé N, Mongin F, Quéguiner G. Tetrahedron 2001; 57: 4489
• 4e Anctil EJ.-G, Snieckus V. J. Organomet. Chem. 2002; 653: 150
• 4f Smith K, El-Hiti GA. Curr. Org. Synth. 2004; 1: 253
• 4g Chinchilla R, Nájera C, Yus M. Chem. Rev. 2004; 104: 2667
• 4h Schlosser M. Angew. Chem. Int. Ed. 2005; 44: 376
• 4i Foubelo F, Yus M. Curr. Org. Chem. 2005; 9: 459
• 4j Rathman TL, Bailey WF. Org. Process Res. Dev. 2009; 13: 144
• 4k Houlden CE, Lloyd-Jones GC, Booker-Milburn KI. Org. Lett. 2010; 12: 3090
• 4l Page A, Clayden J. Beilstein J. Org. Chem. 2011; 7: 1327
• 4m El-Hiti GA, Hegazy AS, Alotaibi MH, Ajarim MD. ARKIVOC 2012; (vii): 35

Examples for substituted benzenes:
• 5a Clayden J, Turner H, Pickworth M, Adler T. Org. Lett. 2005; 7: 3147
• 5b Clayden J, Dufour J. Tetrahedron Lett. 2006; 47: 6945
• 5c Burgos PO, Fernández I, Iglesias MJ, García-Granda S, Ortiz FL. Org. Lett. 2008; 10: 537
• 5d Castanet A.-S, Tilly D, Véron J.-B, Samanta SS, De A, Ganguly T, Mortier J. Tetrahedron 2008; 64: 3331
• 5e Michon C, Murai M, Nakatsu M, Uenishi J, Uemura M. Tetrahedron 2009; 65: 752
• 5f Tilly D, Fu J.-M, Zhao B.-P, Alessi M, Catanet A.-S, Snieckus V, Mortier J. Org. Lett. 2010; 12: 68
• 5g Slocum DW, Wang S, White CB, Whitley PE. Tetrahedron 2010; 66: 4939
• 5h Cho I, Meimetis L, Belding L, Katz MJ, Dudding T, Britton R. Beilstein J. Org. Chem. 2011; 7: 1315
• 5i Schmid M, Waldner B, Schnürch M, Mihovilovic MD, Stanetty P. Tetrahedron 2011; 67: 2895
• 5j Volz N, Clayden J. Angew. Chem. Int. Ed. 2011; 50: 12148

Examples for substituted heterocycles:
• 6a Robert N, Bonneau A.-L, Hoarau C, Marsais F. Org. Lett. 2006; 8: 6071
• 6b Comoy C, Banaszak E, Fort Y. Tetrahedron 2006; 62: 6036
• 6c Luisi R, Capriati V, Florio S, Musio B. Org. Lett. 2007; 9: 1263
• 6d Clayden J, Hennecke U. Org. Lett. 2008; 10: 3567
• 6e McLaughlin M, Marcantonio K, Chen C, Davies IW. J. Org. Chem. 2008; 73: 4309
• 6f Capriati V, Florio S, Luisi R, Mazzanti A, Musio B. J. Org. Chem. 2008; 73: 3197
• 6g Affortunato F, Florio S, Luisi R, Musio B. J. Org. Chem. 2008; 73: 9214
• 6h Musio B, Clarkson GJ, Shipman M, Florio S, Luisi R. Org. Lett. 2009; 11: 325
• 6i Clayton J, Clayden J. Tetrahedron Lett. 2011; 52: 2436
• 6j Ibrahim N, Chevot F, Legraverend M. Tetrahedron Lett. 2011; 52: 305

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
• 8a Smith K, El-Hiti GA, Hegazy AS. Synlett 2009; 2242
• 8b Smith K, El-Hiti GA, Hegazy AS, Fekri A, Kariuki BM. ARKIVOC 2009; (xiv): 266
• 9a Smith K, El-Hiti GA, Hegazy AS. Chem. Commun. 2010; 46: 2790
• 9b Smith K, El-Hiti GA, Hegazy AS, Fekri A. Heterocycles 2010; 80: 941
• 9c Smith K, El-Hiti GA, Hegazy AS. Synthesis 2010; 1371
• 9d Smith K, El-Hiti GA, Hegazy AS, Kariuki B. Beilstein J. Org. Chem. 2011; 7: 1219
• 10 Simig G, Schlosser M. Tetrahedron Lett. 1988; 29: 4277
• 11 Smith K, El-Hiti GA, Alshammari MB. Synthesis 2012; 44: 2013
• 12 Simig G, Schlosser M. Tetrahedron Lett. 1991; 32: 1963
• 13 Assignments of signals are based on integration values, coupling patterns, and expected chemical shifts and have not been rigorously confirmed. Signals with similar characteristics might be interchanged.
• 14 Analytical Data for 7 White solid (0.32 g, 92%); mp 179–181 °C. FTIR: ν_max = 3321, 2958, 1627, 1575, 1292, 1243 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.35–7.26 (m, 11 H, OH and 2 C₆H₅), 7.16 (d, J = 8.3 Hz, 1 H, H-6 of 4-MeOC₆H₃), 6.79 (dd, J = 2.8, 8.3 Hz, 1 H, H-5 of 4-MeOC₆H₃), 6.24 (d, J = 2.8 Hz, 1 H, H-3 of 4-MeOC₆H₃), 6.15 (br, exch., 1 H, NH), 3.63 (s, 3 H, OCH₃), 3.37 (app q, J = 7 Hz, 2 H, CH₂ NH), 2.60 (t, J = 7.2 Hz, 2 H, CH₂), 1.11 [s, 9 H, C(CH₃)₃] ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 178.8 (s, C=O), 156.9 (s, C-4 of 4-MeOC₆H₃), 147.1 (s, C-1 of 2 C₆H₅), 146.6 (s, C-2 of 4-MeOC₆H₃), 132.8 (d, C-6 of 4-MeOC₆H₃), 130.7 (s, C-1 of 4-MeOC₆H₃), 127.9 (d, C-3/C-5 of 2 C₆H₅), 127.7 (d, C-2/C-6 of 2 C₆H₅), 127.2 (d, C-4 of 2 C₆H₅), 117.1 (d, C-3 of 4-MeOC₆H₃), 111.9 (d, C-5 of 4-MeOC₆H₃), 83.0 (s, COH), 55.0 (q, OCH₃), 41.1 (t, CH₂NH), 38.4 [s, C(CH₃)₃], 32.5 (t, ArCH₂), 27.5 [q, C(CH₃)₃] ppm. MS (EI): m/z (%) = 399 (77) [M – H₂O]⁺, 298 (99), 285 (90), 261 (33), 239 (10), 222 (26), 209 (31), 193 (73), 165 (53), 152 (13), 105 (48), 83 (100). HRMS (EI): m/z calcd for C₂₇H₂₉NO₂ [M – H₂O]⁺: 399.2198; found: 399.2187.