Metal-Free One-Pot Conversion of Electron-Rich Aromatics into Aromatic Nitriles

Abstract

Various electron-rich aromatics could be smoothly converted into the corresponding aromatic nitriles in good to moderate yields by treatment of electron-rich aromatics with POCl₃ and DMF, followed by treatment with molecular iodine in aqueous ammonia. The present reaction is a novel metal-free one-pot method for the preparation of aromatic nitriles from electron-rich aromatics.

Key words

aromatics - aromatic N,N-dimethyliminium salt - aromatic nitrile - Vilsmeier-Haack reaction - molecular iodine - aqueous ammonia

References and Notes

• 1 Fabiani ME. Drug News Perspect.  1999,  12:  207 
• 2a Friedrick K. Wallensfels K. The Chemistry of the Cyano Group   Rappoport Z. Wiley Interscience; New York: 1970. 
• 2b North M. Comprehensive Organic Functional Group Transformation   Katritzky AR. Meth-Cohn O. Rees CW. Pergamon; Oxford: 1995. 
• 2c Murahashi S.-I. Synthesis from Nitriles with Retention of the Cyano Group, In Science of Synthesis   Vol. 19:  Georg Thieme Verlag; Stuttgart: 2004.  p.345-402  
• 2d Collier SJ. Langer P. Application of Nitriles as Reagents for Organic Synthesis with Loss of the Nitrile Functionality, In Science of Synthesis   Vol. 19:  Georg Thieme Verlag; Stuttgart: 2004.  p.403-425  
• 3 Comprehensive Organic Transformations   Larock RC. Wiley-VCH; Weinheim: 1989.  p.976-993  
• 4 Sandmeyer T. Ber.  1884,  17:  2650 
• 5a Sharman WM. Van Lier JE. in Porphyrin Handbook   Vol. 15:  Kadish E. Smith KM. Guilard R. Academic Press; New York: 2003.  p.1 
• 5b Weissman SA. Zewge D. Chen C. J. Org. Chem.  2005,  70:  1508 
• 5c Littke A. Soumeillant M. Kaltenbach RF. Cherney RJ. Tarby CM. Kiau S. Org. Lett.  2007,  9:  1711 
• 5d Martin MT. Liu B. Cooley BE. Eaddy JF. Tetrahedron Lett.  2007,  48:  2555 
• 5e Nandurkar NS. Bhanage BM. Tetrahedron  2008,  64:  3655 
• 5f Iqbal Z. Lyubimtsev A. Hanack M. Synlett  2008,  2287 
• 5g Chen G. Weng J. Zheng Z. Zhu X. Cai Y. Cai J. Wan Y. Eur. J. Org. Chem.  2008,  3524 
• 5h Schareina T. Zapf A. Cotte A. Müller N. Beller M. Synthesis  2008,  3351 
• 5i Buono FG. Chidambaram R. Mueller RH. Waltermire RE. Org. Lett.  2008,  10:  5325 
• 5j Chattopadhyay K. Dey R. Ranu BC. Tetrahedron Lett.  2009,  50:  3164 
• 6a Chen X. Hao X.-S. Goodhue CE. Yu J.-Q. J. Am. Chem. Soc.  2006,  128:  6790 
• 6b Jia X. Yang D. Zhang S. Cheng J. Org. Lett.  2009,  11:  4716 
• 7a Gerhard L. Ber.  1967,  100:  2719 
• 7b Gerhard L. Org. Synth.  1970,  50:  52 
• Reviews:
• 8a Togo H. Iida S. Synlett  2006,  2159 
• 8b Togo H. J. Synth. Org. Chem.  2008,  66:  652 
• 9a Mori N. Togo H. Synlett  2004,  880 
• 9b Mori N. Togo H. Synlett  2005,  1456 
• 9c Mori N. Togo H. Tetrahedron  2005,  61:  5915 
• 9d Ishihara M. Togo H. Synlett  2006,  227 
• 9e Iida S. Togo H. Synlett  2006,  2633 
• 9f Ishihara M. Togo H. Tetrahedron  2007,  63:  1474 
• 9g Iida S. Togo H. Tetrahedron  2007,  63:  8274 
• 9h Iida S. Togo H. Synlett  2008,  1639 
• 9i Iida S. Ohmura R. Togo H. Tetrahedron  2009,  65:  6257 
• 10a Misono A. Osa T. Koda S. Bull. Chem. Soc. Jpn.  1966,  39:  854 
• 10b Talukdar S. Hsu J. Chou T. Fang J. Tetrahedron Lett.  2001,  42:  1103 
• 12 Nakao Y. J. Am. Chem. Soc.  2006,  128:  8146 
• 13 Fuson RC. J. Org. Chem.  1948,  13:  484 

11

Typical Experimental Procedure: To a flask containing 1,3,5-trimethoxybenzene (1009.1 mg, 6 mmol) were added POCl₃ (1011.9 mg, 6.6 mmol) and DMF (1754.1 mg, 24 mmol) at 0 ˚C. After being stirred for 3 h at 40 ˚C, I₂ (3045.7 mg, 12 mmol) and aq ammonia (12 mL, 28-30%) were added to the reaction mixture. The obtained mixture was stirred for 3 h at r.t. After the reaction, the mixture was poured into aq sat. Na₂SO₃ solution and extracted with CHCl₃ (3 × 20 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated to provide almost pure 2,4,5-trimethoxybenzonitrile (1156.1 mg) in 99% yield. If it was necessary, it was recrystallized from a mixture of hexane and EtOAc (1:1).
Most aromatic nitriles mentioned in this work are commercially available and were identified by comparison with the authentic samples.
2,4-Dimethoxybenzonitrile: mp 93-94 ˚C (commercial, mp 93-94 ˚C). IR: 2219 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 3.90 (s, 3 H), 6.46 (s, 1 H), 6.51 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H).
2,4,6-Trimethoxybenzonitrile: mp 139-140 ˚C (commercial, mp 143-145 ˚C). IR: 2212 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 3.89 (s, 6 H), 6.07 (s, 2 H).
2,3,4-Trimethoxybenzonitrile: mp 55-56 ˚C (commercial, mp 56-57 ˚C). IR: 2226 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.87 (s, 3 H), 3.92 (s, 3 H), 4.06 (s, 3 H), 6.70 (d, J = 8.7 Hz, 1 H), 7.29 (d, J = 8.7 Hz, 1 H).
3-Cyanoindole: mp 177-179 ˚C (commercial, mp 179-182 ˚C). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.28-7.36 (m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.73 (s, 1 H), 7.78 (d, J = 7.3 Hz, 1 H), 8.91 (s, 1 H).
N -Methyl-3-cyanolindole: mp 60-61 ˚C (lit. ^¹² mp 60.5-61.5 ˚C). IR: 2219 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.75 (s, 3 H), 7.25 (t, J = 6.4 Hz, 1 H), 7.28-7.35 (m, 2 H), 7.44 (s, 1 H), 7.68 (d, J = 7.9 Hz, 1 H).
4-Methoxy-1-cyanonaphthalene: mp 100-102 ˚C (commercial, mp 100-102 ˚C). IR: 2213 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.07 (s, 3 H), 6.84 (d, J = 8.2 Hz, 1 H), 7.59 (t, J = 8.2 Hz, 1 H), 7.69 (t, J = 8.2 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.32 (d, J = 8.2 Hz, 1 H).
2-Methoxy-1-cyanonaphthalene: mp 96-97 ˚C (lit.^¹³ mp 95-96 ˚C). IR: 2211 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.08 (s, 3 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H).
4,8-Dimethoxy-1-cyanonaphthalene: mp 126-129 ˚C. IR: 2211 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.05 (s, 6 H), 6.85 (d, J = 8.2 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 1 H), 7.89 (d, J = 7.7 Hz, 1 H). HRMS (ESI): m/z calcd for C₁₃H₁₁O₂N: 213.0784; found: 21.0780.
4-Cyano- N , N -dimethylaniline: mp 74-75 ˚C (commercial, mp 75 ˚C). IR: 2210 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.04 (s, 6 H), 6.64 (d, J = 9.1 Hz, 2 H), 7.47 (d, J = 9.1 Hz, 2 H).
9-Cyanoanthracene: mp 173-175 ˚C (commercial, mp 173-177 ˚C). IR: 2212 cm^-¹. ^¹H NMR (500 MHz, CDCl₃):
δ = 7.59 (t, J = 8.5 Hz, 2 H), 7.73 (t, J = 8.5 Hz, 2 H), 8.09 (d, J = 8.5 Hz, 2 H), 8.43 (d, J = 8.5 Hz, 2 H), 8.69 (s, 1 H).
2-Cyano- N -benzylpyrrole: oil. IR: 2215 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.19 (s, 2 H), 6.19 (dd, J = 2.9, 2.7 Hz, 1 H), 6.80-6.86 (m, 2 H), 7.18 (d, J = 7.4 Hz, 2 H), 7.31-7.38 (m, 3 H). HRMS (FAB): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂: 183.0922; found: 183.0927.
3-Cyano- N -benzylpyrrole: oil. IR: 2224 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 5.06 (s, 2 H), 6.44 (d, J = 1.7 Hz,
1 H), 6.65 (s, 1 H), 7.11-7.17 (m, 3 H), 7.33-7.41 (m, 3 H). HRMS (FAB): m/z [M + H]⁺ calcd for C₁₂H₁₁N₂: 183.0922; found: 183.0927.
2-Cyanothiophene: oil. IR: 2222 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.14 (dd, J = 5.2, 3.7 Hz, 1 H), 7.62 (d, J = 5.2 Hz, 1 H), 7.64 (d, J = 3.7 Hz, 1 H).
5-Decyl-2-cyanothiophene: oil. IR: 2218 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.23-1.38 (m, 14 H), 1.67 (quint, J = 7.5 Hz, 2 H), 2.83 (t, J = 7.5 Hz, 2 H), 6.78 (d, J = 3.6 Hz, 1 H), 7.43 (d, J = 3.6 Hz, 1 H). HRMS (FAB): m/z [M + H]⁺ calcd for C₁₅H₂₄NS: 250.1629; found: 250.1636.
5-Decyl-2-cyanofuran: oil. IR: 2229 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.21-1.38 (m, 14 H), 1.65 (quint, J = 7.1 Hz, 2 H), 2.66 (t, J = 7.1 Hz, 2 H), 6.11 (d, J = 3.4 Hz, 1 H), 6.99 (d, J = 3.4 Hz, 1 H). HRMS (FAB): m/z [M + H]⁺ calcd for C₁₅H₂₄NO: 234.1858; found: 234.1861.
3-Cyanobenzofuran: mp 90-91 ˚C (commercial, mp 93 ˚C). IR: 2211 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.35 (t, J = 7.5 Hz, 1 H), 7.44 (s, 1 H), 7.48-7.56 (m, 2 H), 7.67 (d, J = 9.1 Hz, 1 H).