Selective copper-promoted cross-coupling of aromatic amines with alkyl boronic acids

Article abstract of DOI:10.1055/s-0030-1258523

A simple copper-promoted N-monoalkylation of anilines that utilizes alkyl boronic acids as the alkylating partner is presented. The reaction is carried out in refluxing dioxane, and it allows a number of structurally and electronically diverse anilines to be functionalized in a single step. A broad study was carried out to demonstrate the utility of this new methodology for the preparation of phenethylanilines.

Full text of DOI:10.1055/s-0030-1258523

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0030-1258523
© Georg Thieme Verlag KG Stuttgart · New York 2010
Thieme

Supporting Information
Selective Copper-Promoted Cross-Coupling of Aromatic Amines
with Alkyl Boronic Acids
Marta Larrosa, César Guerrero, Ramón Rodríguez and Jacobo Cruces*
GalChimia, S.L. R&D Department, Cebreiro s/n 15823 O Pino. A Coruña. SPAIN.
Fax: +34 981 814 507.
E-mail: jacobo.cruces@galchimia.com.
Copper-Promoted Cross-Coupling of Anilines with Alkyl Boronic Acids; General Procedure
Cu(OAc)2 (1.3-4 mmol) was added to a solution of aniline (1 mmol) and pyridine (3-4 mmol) in
dioxane (5 mL), and the mixture was refluxed for 15 min. Boronic acid (1.3-4 mmol) was added, and
the reaction mixture was allowed to react at reflux until no unreacted aniline was detected or for a
maximum time of 10 h. It was allowed to reach r.t., poured into H2O (25 mL) and extracted with
EtOAc (40 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated.
The crude residue was flash chromatographed on SiO2 using EtOAc-hexanes as eluent.
N-butyl-N-(4-tert-butylphenyl)amine (Table 1, entry 2, R = tBu)
Yield: 83%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 3.10 (t, J =
6.7 Hz, 2H), 1.55-1.62 (m, 2H), 1.38-1.49 (m, 2H), 1.28 (s, 9H), 0.96 (t, J = 7.1 Hz, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.2, 139.7, 125.9, 112.3, 43.8, 33.8, 33.7, 31.5, 20.3, 13.9.
(ESI+) = 206.7 (M+1).
N-(4-tert-butylphenyl)-N-isobutylamine (Table 1, entry 3, R = tBu)
Yield: 57%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 2.93 (d, J =
6.6 Hz, 2H), 1.81-1.94 (m, 1H), 1.29 (s, 9H), 0.99 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.2, 139.6, 125.9, 112.3, 52.0, 33.8, 31.5, 28.0, 24.5.
(ESI+) = 205.9 (M+1).
N-(4-tert-butylphenyl)-N-(3-methylbutyl)amine (Table 1, entry 4, R = tBu)
Yield: 82%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.21 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 3.11 (t, J =
7.4 Hz, 2H), 1.65-1.78 (m, 1H), 1.51 (c, J = 7.4 Hz, 2H), 1.28 (s, 9H), 0.95 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.2, 139.7, 125.9, 112.4, 42.3, 38.6, 33.7, 31.5, 25.9, 22.6.
(ESI+) = 219.9 (M+1).
N-(4-tert-butylphenyl)-N-(2-cyclohexylethyl)amine (Table 1, entry 5, R = tBu)
Yield: 72%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 3.11 (t, J =
7.1 Hz, 2H), 1.71 (m, 6H), 1.49 (m, 3H), 1.35 (m, 2H), 1.28 (s, 11H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.2, 139.7, 125.9, 112.3, 41.7, 37.2, 35.4, 33.7, 33.3, 31.5,
26.5, 26.2.
(ESI+) = 260.0 (M+1).

N-(4-tert-butylphenyl)-N-(2-phenylethyl)lamine (Table 2, entry 1)
Yield: 83%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.19-7.35 (m, 7H), 6.57 (d, J = 8.8 Hz, 2H), 3.39 (t, J = 7.1 Hz,
2H), 2.91 (t, J = 7.1 Hz, 2H), 1.28 (s, 9H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.6, 140.1, 139.3, 128.7, 128.5, 126.3, 125.9, 112.6, 45.2,
35.5, 33.8, 31.5.
(ESI+) = 246.1 (M+1).
N-(4-tert-butylphenyl)-N-isopropylamine (Table 1, entry 7, R = tBu)
Yield: 22%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 3.60 (c, J =
6.3 Hz, 1H), 1.28 (s, 9H), 1.21 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.1, 139.7, 126.0, 112.8, 44.3, 33.8, 31.5, 23.1.
(ESI+) = 192.4 (M+1).
N-(4-tert-butylphenyl)-N-cyclohexylamine (Table 1, entry 8, R = tBu)
Yield: 62%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 3.22 (m, 1H),
2.05 (m, 2H), 1.60-1.79 (m, 3H), 1.17-1.40 (m, 14H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.0, 139.5, 125.9, 112.7, 51.8, 33.7, 33.6, 31.5, 25.9, 25.0.
(ESI+) = 232.1 (M+1).
N-butyl-N-(4-methoxyphenyl)amine (Table 1, entry 2, R = OMe)
Yield: 91%.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.78 (d, J = 9.0 Hz, 2H), 5.59 (d, J = 9.0 Hz, 2H), 3.75 (s, 3H),
3.07 (t, J = 6.9 Hz, 2H), 1.60 (m, 2H), 1.44 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.8, 142.7, 114.8, 113.9, 55.7, 44.6, 31.7, 20.2, 13.8.
(ESI+) = 180.4 (M+1).
N-isobutyl-N-(4-methoxyphenyl)amine (Table 1, entry 3, R = OMe)
Yield: 90%.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.78 (d, J = 8.8 Hz, 2H), 5.59 (d, J = 8.8 Hz, 2H), 3.74 (s, 3H),
2.88 (d, J = 6.9 Hz, 2H), 1.80-1.95 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.7, 124.2, 114.8, 113.8, 55.7, 52.7, 27.9, 20.4.
(ESI+) = 180.3 (M+1).
N-(4-methoxyphenyl)-N-(3-methylbutyl)amine (Table 1, entry 4, R = OMe)
Yield: 89%.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.78 (d, J = 9.0 Hz, 2H), 6.58 (d, J = 9.0 Hz, 2H), 3.75 (s, 3H),
3.07 (t, J = 7.5 Hz, 2H), 1.70 (m, 1H), 1.50 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.8, 142.8, 114.8, 113.9, 55.7, 43.1, 38.6, 25.9, 22.6.
(ESI+) = 194.1 (M+1).
N-(2-cyclohexylethyl)-N-(4-methoxyphenyl)amine (Table 1, entry 5, R = OMe)
Yield: 69%.

1H NMR (CDCl3, 250 MHz) δ ppm: 6.79 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H),
3.08 (t, J = 7.4 Hz, 2H), 1.72 (m, 6H), 1.49 (m, 2H), 1.23 (m, 3H), 0.96 (m, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.8, 142.8, 114.8, 113.9, 55.7, 42.5, 37.2, 35.5, 33.3, 26.5,
26.2.
(ESI+) = 243.3 (M+1).
N-(2-phenylethyl)-N-(4-methoxyphenyl)amine (Table 2, entry 5)
Yield: 94%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.15-7.30 (m, 5H), 6.72 (d, J = 9.0 Hz, 2H), 6.53 (d, J = 9.0 Hz,
2H), 3.69 (s, 3H), 3.30 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 152.0, 142.1, 139.3, 128.7, 128.4, 126.2, 114.8, 114.2, 55.6,
45.9, 35.4.
(ESI+) = 228.0 (M+1).
N-isopropyl-N-(4-methoxyphenyl)amine (Table 1, entry 7, R = OMe)
Yield: 39%.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.77 (d, J = 9.1 Hz, 2H), 6.58 (d, J = 9.1 Hz, 2H), 3.75 (s, 3H),
3.54 (m, 1H), 1.19(d, J = 6.3 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.9, 141.7, 114.9, 114.8, 55.7, 45.2, 23.0.
(ESI+) = 243.3 (M+1).
N-cyclohexyl-N-(4-methoxyphenyl)amine (Table 1, entry 8, R = OMe)
Yield: 63%.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.58 (d, J = 9.0 Hz, 2H), 6.41 (d, J = 9.0 Hz, 2H), 3.57 (s, 3H),
2.99 (m, 1H), 1.89 (m, 2H), 1.43-1.62 (m, 2H), 0.88-1.25 (m, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.7, 141.5, 114.8, 114.7, 55.7, 52.7, 33.5, 25.9, 25.0.
(ESI+) = 206.4 (M+1).
N-butyl-N-(4-chlorophenyl)amine (Table 1, entry 2, R = Cl)
Yield: 82%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.10 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 3.07 (t, J =
6.9 Hz, 2H), 1.58 (m, 2H), 1.41 (m, 2H), 0.95 (t, J = 7.1 Hz, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 147.0, 128.9, 121.4, 113.6, 43.7, 31.5, 20.2, 13.8.
(ESI+) = 180.4 (M+1).
N-isobutyl-N-(4-chlorophenyl)amine (Table 1, entry 3, R = Cl)
Yield: 49%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.11 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 8.9 Hz, 2H), 2.88 (d, J =
6.6 Hz, 2H), 1.87 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 147.1, 129.0, 121.4, 113.6, 55.8, 27.9, 20.4.
(ESI+) = 184.2 (M+1).
N-(4-chlorophenyl)-N-(3-methylbutyl)amine (Table 1, entry 4, R = Cl)
Yield: 74%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.10 (d, J = 9.0 Hz, 2H), 6.51 (d, J = 9.0 Hz, 2H), 3.08 (t, J =
7.7 Hz, 2H), 1.70 (m, 1H), 1.50 (c, J = 7.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H).

13C NMR (CDCl3, 62.9 MHz) δ ppm: 147.0, 128.9, 121.4, 113.6, 42.2, 38.3, 25.9, 22.5.
(ESI+) = 198.2 (M+1).
N-(4-chlorophenyl)-N-(2-cyclohexylethyl)amine (Table 1, entry 5, R = Cl)
Yield: 68%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.11 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, 2H), 3.08 (t, J =
7.4 Hz, 2H), 1.45-1.73 (m, 8H), 1.24 (m, 3H), 0.94 (m, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 147.0, 128.9, 121.4, 113.6, 41.7, 36.9, 35.4, 33.3, 26.5, 26.2.
(ESI+) = 238.1 (M+1).
N-(4-chlorophenyl)-N-(2-phenylethyl)amine (Table 2, entry 9)
Yield: 63%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20-7.33 (m, 5H), 7.11 (d, J = 9.0 Hz, 2H), 6.53 (d, J = 9.0 Hz,
2H), 3.37 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.5, 139.0, 129.0, 128.7, 128.6, 126.5, 121.9, 114.0, 45.0,
35.2.
(ESI+) = 232.2 (M+1).
N-(4-chlorophenyl)-N-isopropylamine (Table 1, entry 7, R = Cl)
Yield: 22%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.10 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 3.57 (m, 1H),
1.19 (d, J = 6.6 Hz, 6H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.0, 129.0, 121.3, 114.2, 44.3, 22.8.
(ESI+) = 205.0 (M+1).
N-(4-chlorophenyl)-N-cyclohexylamine (Table 1, entry 8, R = Cl)
Yield: 27%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.09 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 3.18 (m, 1H),
2.04 (m, 2H), 1.11-1.80 (m, 8H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.9, 129.0, 121.1, 114.1, 51.8, 33.3, 25.8, 24.9.
(ESI+) = 210.2 (M+1).
N-(3-methylphenyl)-N-(2-phenylethyl)amine (Table 2, entry 3)
Yield: 65%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.11-7.35 (m, 6H), 7.01 (m, 1H), 6.66 (m, 2H), 3.43 (t, J = 6.9
Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.02 (s, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.8, 139.3, 130.0, 128.7, 128.6, 127.1, 126.4, 122.0, 116.9,
109.7, 44.9, 35.3, 17.2.
(ESI+) = 212.2 (M+1).
N-(2-methylphenyl)-N-(2-phenylethyl)amine (Table 2, entry 4)
Yield: 63%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.21-7.35 (m, 5H), 7.00 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.5 Hz,
2H), 3.38 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.24 (s, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 145.6, 139.4, 139.0, 129.7, 128.7, 128.6, 126.6, 126.4, 126.3,
113.1, 45.3, 35.4, 20.3.
(ESI+) = 212.2 (M+1).

N-(3-methoxyphenyl)-N-(2-phenylethyl)amine (Table 2, entry 6)
Yield: 83%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20-7.36 (m, 5H), 7.08 (t, J = 8.0 Hz, 1H), 6.16-6.29 (m, 3H),
3.77 (s, 3H), 3.39 ppm (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 160.8, 149.3, 139.2, 129.9, 128.7, 128.5, 126.3, 106.4, 101.5,
98.8, 55.0, 44.9, 35.4.
(ESI+) = 228.1 (M+1).
N-(2-methoxyphenyl)-N-(2-phenylethyl)amine (Table 2, entry 7)
Yield: 69%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.22-7.35 (m, 5H), 6.88 (m, 1H), 6.64-6.78 (m, 3H), 3.81 (s,
3H), 3.41 (t, J = 7.4 Hz, 2H), 2.95 (t, J = 7.4 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.8, 139.4, 137.9, 128.7, 128.4, 126.2, 121.2, 116.4, 109.8,
109.4, 55.3, 45.0, 35.6.
(ESI+) = 228.1 (M+1).
N-(3-chlorophenyl)-N-(2-phenylethyl)amine (Table 2, entry 8)
Yield: 95%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20-7.33 (m, 5H), 7.06 (t, J = 7.8 Hz, 1H), 6.66 (m, 1H), 6.58
(m, 1H), 6.46 (m, 1H), 3.38 (t, J = 6.9 Hz, 2H); 2.91 ppm (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 149.0, 138.9, 134.9, 130.1, 128.7, 128.6, 126.5, 117.1, 112.4,
111.1, 44.6, 35.2.
(ESI+) = 232.3 (M+1).
N-(3-bromophenyl)-N-(2-phenylethyl)amine (Table 2, entry 10)
Yield: 68%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20-7.36 (m, 5H), 6.98-7.06 (m, 1H), 6.79 (m, 1H), 6.80 (m,
1H), 6.50 (m, 1H), 3.37 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 149.2, 138.8, 130.4, 128.7, 128.6, 126.5, 123.2, 120.0, 115.3,
115.6, 44.6, 35.2.
(ESI+) = 278.2 (M+1).
N-[4-(methylthio)phenyl]-N-(2-phenylethyl)amine (Table 2, entry 11)
Yield: 85%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.20-7.36 (m, 7H), 6.55 (d, J = 8.5 Hz, 2H), 3.39 (t, J = 6.9 Hz,
2H), 2.90 (t, J = 6.9 Hz, 2H), 2.41 (s, 3H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 146.7, 139.0, 131.4, 128.7, 128.5, 126.4, 121.1, 113.5, 44.9,
35.3, 19.0.
(ESI+) = 244.3 (M+1).
4-[(2-phenylethyl)amino]benzonitrile (Table 2, entry 12)
Yield: 61%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.42 (d, J = 8.9 Hz, 2H), 7.19-7.33 (m, 5H), 6.54 (d, J = 8.9 Hz,
2H), 3.44 (c, J = 6.6 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 151.0, 138.4, 133.6, 128.7, 128.6, 126.6, 120.4, 112.2, 98.5,
44.1, 35.0.

(ESI+) = 223.3 (M+1).
Methyl 2-[(2-phenylethyl)amino]benzoate (Table 2, entry 13)
Yield: 64%.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.90 (t, J = 8.0 Hz, 1H), 7.24-7.40 (m, 7H), 6.9 (t, J = 8.0 Hz,
1H), 3.84 (s, 3H), 3.47 (c, J = 6.6 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 166.8, 150.8, 139.2, 134.5, 131.6, 128.7, 128.5, 126.4, 114.5,
111.0, 109.9, 51.3, 44.4, 35.5.
(ESI+) = 256.3 (M+1).
N-(2-phenylethyl)pyridin-2-amine (Table 2, entry 14)
Yield: 26%.
1H NMR (CDCl3, 250 MHz) δ ppm: 8.09 (m, 1H), 7.22-7.44 (m, 6H), 6.57 (t, J = 6.6 Hz, 1H), 6.36
(d, J = 8.5 Hz, 1H), 3.55 (c, J = 6.9 Hz, 2H), 2.92 (t, J = 6.9 Hz, 2H).
13C NMR (CDCl3, 62.9 MHz) δ ppm: 157.6, 145.3, 138.8, 128.7, 128.5, 127.9, 126.4, 112.2, 106.8,
43.6, 35.4.
(ESI+) = 199.2 (M+1).