One-Pot Conversion of Aromatic
Bromides and Aromatics into Aromatic Nitriles

Sousuke Ushijima; Hideo Togo

doi:10.1055/s-0029-1219935

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Synlett 2010(10): 1562-1566
DOI: 10.1055/s-0029-1219935

LETTER

One-Pot Conversion of Aromatic Bromides and Aromatics into Aromatic Nitriles

Sousuke Ushijima, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Fax: +81(43)2902792; e-Mail: togo@faculty.chiba-u.jp;

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Publication History

Received 15 March 2010
Publication Date:
10 May 2010 (online)

Abstract
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Abstract

Various aromatic bromides and iodides were smoothly converted into the corresponding aromatic nitriles in good to moderate yields by the treatment with butyllithium and subsequently DMF, followed by treatment with molecular iodine in aqueous ammonia. The same treatment of typical aromatics and heteroaromatics with butyllithium and subsequently DMF, followed by treatment with molecular iodine in aqueous ammonia also provided the corresponding aromatic nitriles in good yields. The present reactions are novel one-pot methods for the preparation of aromatic nitriles from aromatic bromides and aromatics, respectively, through the formation of aryllithiums and their DMF adducts.

Key words

aromatics - butyllithium - aryllithium - aromatic nitrile - molecular iodine - aqueous ammonia - aromatic bromide - aromatics

References and Notes

1 Fabiani ME. Drug News Perspect 1999, 12: 207

Google Scholar
2a Friedrick K. Wallensfels K. The Chemistry of the Cyano Group Rappoport Z. Wiley-Interscience; New York: 1970.

Google Scholar
2b North M. Comprehensive Organic Functional Group Transformation Katritzky AR. Meth-Cohn O. Rees CW. Pergamon; Oxford: 1995.

Google Scholar
2c Murahashi S.-I. Synthesis from Nitriles with Retention of the Cyano Group, In Science of Synthesis Vol. 19: Thieme; Stuttgart: 2004. p.345-402

Google Scholar
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: Thieme; Stuttgart: 2004. p.403-425

Google Scholar
3 Comprehensive Organic Transformations Larock RC. VCH Publishers; New York: 1989. p.976-993

Google Scholar
4a Sandmeyer T. Chem. Ber. 1884, 17: 1633

Google Scholar
4b Sandmeyer T. Chem. Ber. 1884, 17: 2650

Google Scholar
5a Sharman WM. Van Lier JE. In Porphyrin Handbook Vol. 15: Kadish E. Smith KM. Guilard R. Academic Press; New York: 2003. p.1

Google Scholar
5b Weissman SA. Zewge D. Chen C. J. Org. Chem. 2005, 70: 1508

Google Scholar
5c Littke A. Soumeillant M. Kaltenbach RF. Cherney RJ. Tarby CM. Kiau S. Org. Lett. 2007, 9: 1711

Google Scholar
5d Martin MT. Liu B. Cooley BE. Eaddy JF. Tetrahedron Lett. 2007, 48: 2555

Google Scholar
5e Nandurkar NS. Bhanage BM. Tetrahedron 2008, 64: 3655

Google Scholar
5f Iqbal Z. Lyubimtsev A. Hanack M. Synlett 2008, 2287

Google Scholar
5g Chen G. Weng J. Zheng Z. Zhu X. Cai Y. Cai J. Wan Y. Eur. J. Org. Chem. 2008, 3524

Google Scholar
5h Schareina T. Zapf A. Cotte A. Müller N. Beller M. Synthesis 2008, 3351

Google Scholar
5i Buono FG. Chidambaram R. Mueller RH. Waltermire RE. Org. Lett. 2008, 10: 5325

Google Scholar
5j Chattopadhyay K. Dey R. Ranu BC. Tetrahedron Lett. 2009, 50: 3164

Google Scholar
5k Yan G. Kuang C. Zhang Y. Wang J. Org. Lett. 2010, 12: 1052

Google Scholar
6a Chen X. Hao X.-S. Goodhue CE. Yu J.-Q. J. Am. Chem. Soc. 2006, 128: 6790

Google Scholar
6b Jia X. Yang D. Zhang S. Cheng J. Org. Lett. 2009, 11: 4716

Google Scholar
7a Gerhard L. Chem. Ber. 1967, 100: 2719

Google Scholar
7b Lohaus G. Org. Synth. 1970, 50: 52

Google Scholar
For reviews, see:
8a Togo H. Iida S. Synlett 2006, 2159

Google Scholar
8b Togo H. J. Synth. Org. Chem. 2008, 66: 652

Google Scholar
9a Mori N. Togo H. Synlett 2004, 880

Google Scholar
9b Mori N. Togo H. Synlett 2005, 1456

Google Scholar
9c Mori N. Togo H. Tetrahedron 2005, 61: 5915

Google Scholar
9d Ishihara M. Togo H. Synlett 2006, 227

Google Scholar
9e Iida S. Togo H. Synlett 2006, 2633

Google Scholar
9f Ishihara M. Togo H. Tetrahedron 2007, 63: 1474

Google Scholar
9g Iida S. Togo H. Tetrahedron 2007, 63: 8274

Google Scholar
9h Iida S. Togo H. Synlett 2007, 407

Google Scholar
9i Iida S. Togo H. Synlett 2008, 1639

Google Scholar
9j Iida S. Ohmura R. Togo H. Tetrahedron 2009, 65: 6257

Google Scholar
10a Misono A. Osa T. Koda S. Bull. Chem. Soc. Jpn. 1966, 39: 854

Google Scholar
10b Talukdar S. Hsu J. Chou T. Fang J. Tetrahedron Lett. 2001, 42: 1103

Google Scholar
11 Ushijima S. Togo H. Synlett 2010, 1067

Article in Thieme Connect Google Scholar
13 Hughes TV. Cava MP. J. Org. Chem. 1999, 64: 313

Crossref Google Scholar
14 Singh MK. Lakshman MK. J. Org. Chem. 2009, 74: 3079

Crossref Google Scholar

12

Typical Experimental Procedure for the Conversion of Aromatic Bromides into Aromatic Nitriles
Butyllithium (1.67 M solution in hexane, 3.3 mL, 5.5 mmol) was added dropwise to a solution of 4-bromotoluene (855 mg, 5 mmol) in THF (5 mL) at -70 ˚C. After 30 min, the resulting mixture was warmed and stirred for 5 min at 0 ˚C. Then, DMF (0.43 mL, 5.5 mmol) was added to the mixture, and the obtained mixture was stirred at 0 ˚C. After 1 h at the same temperature, aq NH₃ (10 mL, 150 mmol) and I₂ (1396 mg, 5.5 mmol) were added, and the obtained mixture was stirred for 2 h at r.t. The reaction mixture was quenched with sat. aq Na₂SO₃ (15 mL) and was extracted with Et₂O (3 × 20 mL). The organic layer was washed with brine and dried over Na₂SO₄ to provide 4-methylbenzonitrile in 80% yield. If necessary, the product was purified by a short column chromatography on silica gel (hexane-EtOAc = 9:1) to give pure 4-methylbenzonitrile as a colorless solid.
Most aromatic nitriles mentioned in this work are commer-cially available and were identified by comparison with the authentic samples.
4-Methylbenzonitrile
Mp 26-28 ˚C (commercial, mp 26-28 ˚C). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.41 (s, 3 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.52 (d, J = 8.1 Hz, 2 H).
3-Methylbenzonitrile Oil (commercial). IR: 2229 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.38 (s, 3 H), 7.32-7.47 (m, 4 H).
2-Methylbenzonitrile
Oil (commercial). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.54 (s, 3 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H).
2,4-Dimethylbenzonitrile
Mp 23-24 ˚C (commercial, mp 23-25 ˚C). IR: 2221 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.36 (s, 3 H), 2.47 (s, 3 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.10 (s, 1 H) 7.43 (d, J = 8.0 Hz, 1 H).
3,4-Dimethylbenzonitrile
Mp 63-64 ˚C (commercial, mp 64-67 ˚C). IR: 2224 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.29 (s, 3 H), 2.32 (s, 3 H), 7.21 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.41 (s, 1 H).
2,5-Dimethylbenzonitrile
Oil (commercial). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.33 (s, 3 H), 2.48 (s, 3 H), 7.18 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 7.9 Hz, 1 H), 7.36 (s, 1 H).

2,4,6-Trimethylbenzonitrile
Mp 50-51 ˚C (lit.⁹ⁱ mp 54-55 ˚C). IR: 2218 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.32 (s, 3 H), 2.47 (s, 6 H), 6.92 (s, 2 H).
4-Methoxybenzonitrile
Mp 54-55 ˚C (commercial, mp 57-59 ˚C). IR: 2216 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.59 (d, J = 8.9 Hz, 2 H).
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).
4-( N , N -Dimethyamino)benzonitrile
Mp 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).
1-Naphthonitrile
Mp 35-36 ˚C (commercial, mp 36-38 ˚C). IR: 2219 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.49 (t, J = 7.9 Hz, 1 H), 7.59 (t, J = 8.2 Hz, 1 H), 7.67 (t, J = 8.2 Hz, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H).
2-Naphthonitrile
Mp 68-70 ˚C (commercial, mp 66-70 ˚C). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.58-7.68 (m, 3 H), 7.88-7.93 (m, 3 H), 8.24 (s, 1 H).
4-Cyanobiphenyl
Mp 85-88 ˚C (commercial, mp 85-87 ˚C). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.44 (t, J = 7.3 Hz, 1 H), 7.49 (t, J = 7.3 Hz, 2 H), 7.59 (d, J = 7.3 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 2 H).
2-Cyanopyridine
Mp 24-25 ˚C (commercial, mp 24-27 ˚C). IR: 2236 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.56 (dd, J = 7.8, 4.6 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.88 (t, J = 7.8 Hz, 1 H), 8.74 (d, J = 4.6 Hz, 1 H).
Typical Experimental Procedure for the Conversion of Aromatics into Aromatic Nitriles
Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol) was added dropwise into a solution of 1,3-dimethoxyben-zene (552 mg, 4 mmol) in THF (5 mL) at 0 ˚C, and the mixture was stirred for 2 h at the same temperature. Then, DMF (0.34 mL, 4.4 mmol) was added to the mixture, and the obtained mixture was stirred at 0 ˚C. After 2 h at the same temperature, aq NH₃ (8 mL, 120 mmol) and I₂ (1117 mg, 4.4 mmol) were added and stirred for 2 h at r.t. The reaction mixture was quenched with sat. aq Na₂SO₃ (15 mL) and was extracted with Et₂O (3 × 20 mL). The organic layer was washed with brine and dried over Na₂SO₄ to provide 2,6-dimethoxybenzonitrile in 91% yield. If necessary, the product was purified by a short column chromatography on silica gel (hexane-EtOAc = 3:1) to give pure 2,6-dimeth-oxybenzonitrile as a colorless solid.
2,6-Dimethoxybenzonitrile
Mp 117-119 ˚C (commercial, mp 119-123 ˚C). IR: 2220 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.90 (s, 6 H), 6.56 (d, J = 8.5 Hz, 2 H), 7.44 (t, J = 8.5 Hz, 1 H).
2-Methoxybenzonitrile
Oil (commercial). IR: 2230 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.91 (s, 3 H), 7.02-6.97 (m, 2 H), 7.59-7.52 (m, 2 H).
2,5-Dimethoxybenzonitrile
Mp 79-82 ˚C (commercial, mp 81-85 ˚C). IR: 2224 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.78 (s, 3 H), 3.89 (s, 3 H), 6.91 (d, J = 9.0 Hz, 1 H), 7.05-7.11 (m, 2 H).
2,3-Dimethoxybenzonitrile
Mp 41-42 ˚C (commercial, mp 43-46 ˚C). IR: 2228 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.89 (s, 3 H), 4.03 (s, 3 H), 7.07-7.16 (m, 3 H).
2-Cyano- N -methylindole
Mp 70-75 ˚C. IR: 2223 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.91 (s, 3 H), 7.16 (s, 1 H), 7.21 (t, J = 6.8, 1 H), 7.34-7.44 (m, 2 H), 7.66 (d, J = 8.2 Hz, 1 H).
N -Tosylindole-2-carbonitrile
Mp 160-161 ˚C (lit.^¹³ mp 160-162 ˚C). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.37 (s, 3 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H) 7.36 (s, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 2 H), 8.21 (d, J = 8.4 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).
Benzofuran-2-carbonitrile
Oil (lit.^¹4). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.36 (t, J = 7.5 Hz, 1 H), 7.46 (s, 1 H), 7.49-7.58 (m, 2 H), 7.68 (d, J = 7.9 Hz, 1 H).
Benzothiophene-2-carbonitrile
Oil (commercial, mp 24-28 ˚C). IR: 2217 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.43 (t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.77-7.85 (m, 3 H).
5-Decylfuran-2-carbonitrile
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 calcd for C₁₅H₂₄NO [M + H]⁺: 234.1858; found: 234.1861.