Subscribe to RSS
DOI: 10.1055/s-0029-1219935
One-Pot Conversion of Aromatic Bromides and Aromatics into Aromatic Nitriles
Publication History
Publication Date:
10 May 2010 (online)
![](https://www.thieme-connect.de/media/synlett/201010/lookinside/thumbnails/10.1055-s-0029-1219935-1.jpg)
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
- 1
Fabiani ME. Drug News Perspect 1999, 12: 207 -
2a
Friedrick K.Wallensfels K. The Chemistry of the Cyano GroupRappoport Z. Wiley-Interscience; New York: 1970. -
2b
North M. Comprehensive Organic Functional Group TransformationKatritzky 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: Thieme; 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: Thieme; Stuttgart: 2004. p.403-425 - 3
Comprehensive
Organic Transformations
Larock RC. VCH Publishers; New York: 1989. p.976-993 -
4a
Sandmeyer T. Chem. Ber. 1884, 17: 1633 -
4b
Sandmeyer T. Chem. 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 -
5k
Yan G.Kuang C.Zhang Y.Wang J. Org. Lett. 2010, 12: 1052 -
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. Chem. Ber. 1967, 100: 2719 -
7b
Lohaus G. Org. Synth. 1970, 50: 52 - For reviews, see:
-
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 2007, 407 -
9i
Iida S.Togo H. Synlett 2008, 1639 -
9j
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 - 11
Ushijima S.Togo H. Synlett 2010, 1067 - 13
Hughes TV.Cava MP. J. Org. Chem. 1999, 64: 313 - 14
Singh MK.Lakshman MK. J. Org. Chem. 2009, 74: 3079
References and Notes
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.