1-Methylimidazole-Catalyzed Regioselective Synthesis of Highly Substituted Benzenes

Abstract

A novel 1-methylimidazole-catalyzed synthesis of 4-amino-3,5-dicyano-6-arylphthalates is described. A one-pot, three-component reaction between arylidenemalononitriles, dialkyl ­acetylenedicarboxylates, and malononitrile gave highly substituted benzenes in good to excellent yields.

Key words

multicomponent reactions - regioselective synthesis - ring closure - 4-amino-3,5-dicyano-6-arylphthalates - 1-methylimidazole - catalysis

References and Notes

• 1a Modern Arene Chemistry   Astruc D. Wiley-VCH; Weinheim: 2002. 
• 1b Xi C. Chen C. Lin J. Hong X. Org. Lett.  2005,  7:  347 
• 2 Taylor R. Electrophilic Aromatic Substitution   Wiley; New York: 1990. 
• 3 Zoltewicz JA. Top. Curr. Chem.  1975,  59:  33 
• 4 Dyker G. Angew. Chem. Int. Ed.  1999,  38:  1698 
• 5 Lin WW. Baron O. Knochel P. Org. Lett.  2006,  8:  5673 ; and references therein
• 6a Dötz KH. Tomuschat P. Chem. Soc. Rev.  1999,  28:  187 
• 6b Wang H. Huang J. Wulff WD. Rheingold AL. J. Am. Chem. Soc.  2003,  125:  8980 
• 6c Vorogushin AV. Wulff WD. Hansen H.-J. J. Am. Chem. Soc.  2002,  124:  6512 
• 7a Danheiser RL. Brisbois RG. Kowalczyk JJ. Miller RF. J. Am. Chem. Soc.  1990,  112:  3093 
• 7b Danheiser RL. Gee SK. J. Org. Chem.  1984,  49:  1672 
• 8a Takahashi T. Xi Z. Yamazaki A. Liu Y. Nakajima K. Kotora M. J. Am. Chem. Soc.  1998,  120:  1672 
• 8b Takahashi T. Tsai F.-Y. Li Y. Nakajima K. Kotora M. J. Am. Chem. Soc.  1999,  121:  11093 
• 9 Takahashi T. Ishikawa M. Huo S. J. Am. Chem. Soc.  2002,  124:  388 
• 10a Saito S. Yamamoto Y. Chem. Rev.  2000,  100:  2901 
• 10b Boñaga LVR. Zhang H.-C. Moretto AF. Ye H. Gauthier DA. Li J. Leo GC. Maryanoff BE. J. Am. Chem. Soc.  2005,  127:  3473 
• 10c Volhardt KPC. Angew. Chem., Int. Ed. Engl.  1984,  23:  539 
• 10d Takeuchi R. Nakaya Y. Org. Lett.  2003,  5:  3659 
• 10e Kotha S. Brahmachary E. Lahiri K. Eur. J. Org. Chem.  2005,  4741 
• 10f Sugihara T. Wakabayashi A. Nagai Y. Takao H. Imagawa H. Nishizawa M. Chem. Commun.  2002,  576 
• 11a Asao N. Nogami T. Lee S. Yamamoto Y. J. Am. Chem. Soc.  2003,  125:  10921 
• 11b Asao N. Aikawa H. Yamamoto Y. J. Am. Chem. Soc.  2004,  126:  7458 
• 12a Langer P. Bose G. Angew. Chem. Int. Ed.  2003,  42:  4033 
• 12b Katritzky AR. Li J. Xie L. Tetrahedron  1999,  55:  8263 
• 13a Serra S. Fuganti C. Moro A. J. Org. Chem.  2001,  66:  7883 
• 13b Turnbull P. Moore HW. J. Org. Chem.  1995,  60:  644 
• 14a Sato S. Isobe H. Tanaka T. Ushijima T. Nakamura E. Tetrahedron  2005,  61:  11449 
• 14b Isobe H. Sato S. Tanaka T. Tokuyama H. Nakamura E. Org. Lett.  2004,  6:  3569 
• 15 Bi X. Dong D. Liu Q. Pan W. Zhao L. Li B. J. Am. Chem. Soc.  2005,  127:  4578 
• 16 Barun O. Nandi S. Panda K. Ila H. Junjappa H. J. Org. Chem.  2002,  67:  5398 
• 17 Ballini R. Barboni L. Fiorini D. Giarlo G. Palmieri A. Chem. Commun.  2005,  2633 
• 18 Lee MJ. Lee KY. Park DY. Kim JN. Tetrahedron  2006,  62:  3128 
• 19a Smith AB. Kozmin SA. Adams CM. Paone DV. J. Am. Chem. Soc.  2000,  122:  4984 
• 19b Dudley GB. Takaki KS. Cha DD. Danheiser RL. Org. Lett.  2000,  2:  3407 
• 20a Adib M. Sheibani E. Abbasi A. Bijanzadeh HR. Tetrahedron Lett.  2007,  48:  1179 
• 20b Adib M. Sheibani E. Mostofi M. Ghanbary K. Bijanzadeh HR. Tetrahedron  2006,  62:  3435 
• 20c Adib M. Mahdavi M. Mahmoodi N. Pirelahi H. Bijanzadeh HR. Synlett  2006,  1765 
• 20d Adib M. Ghanbary K. Mostofi M. Bijanzadeh HR. Tetrahedron  2005,  61:  2645 
• 20e Adib M. Mollahosseini M. Yavari H. Sayahi MH. Bijanzadeh HR. Synlett  2004,  1086 
• 23 Nair V. Devi BR. Vidya N. Menon RS. Abhilash N. Rath NP. Tetrahedron Lett.  2004,  45:  3203 

21

Preparation of Dimethyl 4-Amino-3,5-dicyano-6-phenylphthalate (3a) - General Procedure
To a solution of benzylidenemalononitrile (0.308 g, 2 mmol) and 1-methylimidazole (0.033 g, 0.4 mmol) in anhydrous CH₂Cl₂ (4 mL) was added dropwise a solution of dimethyl acetylenedicarboxylate (0.284 g, 2 mmol) in anhydrous CH₂Cl₂ (2 mL) at -10 °C over 5 min, and was stirred at 25 °C for 25 min. Then, a solution of malononitrile (0.132 g, 2 mmol) in anhydrous CH₂Cl₂ (1 mL) was added to the reaction mixture and was stirred at 25 °C for 2 h (progress of the reaction followed by TLC monitoring). Afterwards, the solvent was removed and the residue was purified with column chromatography [n-hexane-EtOAc (4:1) as eluent]. The product 3a was obtained as colorless crystals; yield 0.64 g (95%). IR (KBr): 3435, 3340 and 3245 (NH), 2190 (CN), 1732 (C=O) cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.50 and 3.99 (2 × s, 6 H, 2 × OCH₃), 5.61 (br s, 2 H, NH₂), 7.29-7.32 (m, 2 H, 2 × CH), 7.46-7.49 (m, 3 H, 3 × CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 53.20 and 54.26 (2 × OCH₃), 95.89 and 101.15 (2 × CN), 114.28, 114.67, and 124.40 (3 × C), 128.64, 129.24, and 130.41 (3 × CH), 135.95, 139.24, 150.65, and 152.80 (4 × C), 164.89 and 166.26 (2 × C=O). MS: m/z (%) = 335 (40) [M⁺], 304(84), 272 (20), 245 (12), 217 (35), 189 (42), 163 (32), 77 (40), 59 (100), 57 (36), 39 (36). Anal. Calcd (%) for C₁₈H₁₃N₃O₄ (335.32): C, 64.48; H, 3.91; N, 12.53. Found: C, 64.4; H, 4.0; N, 12.4.
Compound 3c: colorless crystals; yield 0.62 g (85%). IR (KBr): 3430, 3340, and 3245 (NH), 2190 (CN), 1732 (C=O) cm^-1. ¹H NMR (300.1 MHz, CDCl₃): δ = 3.55, 3.86, and 3.99 (3 × s, 9 H, 3 × OCH₃), 5.58 (br s, 2 H, NH₂), 6.99 (d, J = 8.8 Hz, 2 H, 2 × CH), 7.26 (d, J = 8.8 Hz, 2 H, 2 × CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 52.70, 53.65, and 55.31 (3 × OCH₃), 94.84 and 100.98 (2 × CN), 113.81 (C), 114.15 (CH), 114.37, 124.05, and 127.33 (3 × C), 129.62 (CH), 138.20, 149.81, and 152.23 (3 × C), 160.76 (C-O), 164.30 and 165.96 (2 × C=O). MS: m/z (%) = 365 (61) [M⁺], 334 (39), 302 (32), 274 (19), 246 (21), 204 (52), 177 (21), 101 (86), 86 (99), 58 (100). Anal. Calcd (%) for C₁₉H₁₅N₃O₅ (365.35): C, 62.46; H, 4.14; N, 11.50. Found: C, 62.4; H, 4.3; N, 11.4.

Compound 3h: colorless crystals; yield 0.75 g (95%). IR (KBr): 3450, 3350, and 3200 (NH), 2190 (CN), 1722 (C=O) cm^-1. ¹H NMR (300.1 MHz, CDCl₃): δ = 0.96 and 1.40 (2 × t, J = 7.1 Hz, 6 H, 2 × OCH₂CH ₃), 3.98 and 4.45 (2 × q, J = 7.1 Hz, 4 H, 2 × OCH ₂CH₃), 5.71 (br s, 2 H, NH₂), 7.25 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.45 (d, J = 8.5 Hz, 2 H, 2 × CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.39 and 13.72 (2 OCH₂ CH₃), 61.98 and 63.37 (2 × OCH₂CH₃), 95.46 and 99.97 (2 × CN), 113.54, 113.96, and 123.35 (3 × C), 128.87 and 129.53 (2 × CH), 133.92, 136.00, 139.37, 148.72, and 152.29 (5 × C), 163.84 and 164.94 (2 × C=O). MS: m/z (%) = 399 (16) [M⁺ + 2], 397 (36) [M⁺], 352 (18), 324 (98), 252 (42), 217 (39), 189 (52), 163 (10), 97 (12), 83 (19), 69 (41), 57 (58), 43 (100). Anal. Calcd (%) for C₂₀H₁₆ClN₃O₄ (397.82): C, 60.38; H, 4.05; N, 10.56. Found: C, 60.4; H, 4.2; N, 10.4.

22

Selected X-ray Crystallographic Data for Compound 3a
C₁₈H₁₃N₃O₄, M = 335.31, triclinic, space group P1, final R indices [I > 2σ(I)], R1 = 0.0396, wR2 = 0.1208, R indices (all data) R1 = 0.0512, wR2 = 0.1248, a = 7.8994(6) Å, b = 9.8692(7) Å, c = 11.7832(10) Å, α = 108.772(7)°, β = 96.067(7)°, γ = 102.822(7)°, V = 832.32(11)ų, T = 290(2) K, Z = 2, reflections collected/unique: 12943/3994 (R _int = 0.0421), number of observations [>2σ(I)] 3015, parameters: 255. CCDC 638396 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.