Copper-Catalysed Alkoxylation of Aryl Bromides
Ethyl 4-Ethoxybenzoate (2i): Colourless oil (conversion/selectivity:
1-Isobutoxy-3-methoxybenzene (5n): Colourless oil (conversion/
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100/100%), 0.51 g (88%). 1H NMR (400 MHz, CDCl3): δ = 7.98 selectivity: 98/100%), 0.51 g (94%). H NMR (400 MHz, CDCl3):
(d, J = 8.8 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 2 H), 4.34 (q, J = 7.2 Hz,
δ = 7.17 (t, J = 8.4 Hz, 1 H), 6.50 (dt, J = 8.4, J = 2.4 Hz, 2 H),
2 H), 4.08 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.37 (t, 6.47 (t, J = 2.4 Hz, 1 H), 3.79 (s, 3 H), 3.70 (d, J = 6.8 Hz, 2 H),
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.4,
162.7, 131.5 (2 C), 122.7, 113.9 (2 C), 63.6, 60.6, 14.7, 14.4 ppm.
HRMS (ESI): calcd. for C11H15O3 [M + H]+ 195.1021; found
195.1025.
2.13–2.03 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.9, 160.6, 129.8, 106.7, 106.1, 100.9,
74.4, 55.2, 28.3, 19.3 (2 C) ppm. HRMS (ESI): calcd. for C11H17O2
[M + H]+ 181.1229; found 181.1224.
2-Ethoxythiophene (2j): Colourless oil (conversion/selectivity: 100/
100%), 0.34 g (89%). H NMR (400 MHz, CDCl3): δ = 6.71 (dd,
4-Methoxy-2-methyl-1-(pentyloxy)benzene (6m): Yellow oil (conver-
sion/selectivity: 92/98%), 0.55 g (88%). 1H NMR (400 MHz,
CDCl3): δ = 6.75–6.73 (m, 2 H), 6.66 (dd, J = 8.8, J = 3.2 Hz, 1
H), 3.90 (t, J = 6.8 Hz, 2 H), 3.76 (s, 3 H), 2.22 (s, 3 H), 1.78 (quint,
J = 6.8 Hz, 2 H), 1.49–1.34 (m, 4 H), 0.93 (t, J = 6.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3, 151.6, 128.2, 116.9,
112.3, 110.8, 68.8, 55.6, 29.3, 28.4, 22.5, 16.4, 14.1 ppm. HRMS
(EI): calcd. for C13H20O2 [M]+ 208.1463; found 208.1464.
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J = 5.6, J = 3.6 Hz, 1 H), 6.54 (dd, J = 5.6, J = 1.2 Hz, 1 H), 6.21
(dd, J = 3.6, J = 1.2 Hz, 1 H), 4.10 (q, J = 6.8 Hz, 2 H), 1.42 (t, J
= 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.6,
124.7, 111.8, 104.7, 69.5, 14.8 ppm. HRMS (EI): calcd. for C6H8OS
[M]+ 128.0296; found 128.0297.
2-Propoxythiophene (3j): Colourless oil (conversion/selectivity: 100/
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100%), 0.39 g (92%). H NMR (400 MHz, CDCl3): δ = 6.71 (dd,
4-Ethyl-2-(pentyloxy)phenol (6o): Yellow oil (conversion/selectivity:
95/100%), 0.57 g (91%). 1H NMR (400 MHz, CDCl3): δ = 6.84 (d,
J = 8.4 Hz, 1 H), 6.69 (s, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 5.50 (br.
s, 1 H), 4.03 (t, J = 6.8 Hz, 2 H), 2.57 (q, J = 7.2 Hz, 2 H), 1.82
(quint, J = 6.8 Hz, 2 H), 1.48–1.36 (m, 4 H), 1.21 (t, J = 6.8 Hz, 3
H), 0.94 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.8, 143.7, 136.2, 120.1, 114.1, 111.4, 68.8, 29.0, 28.6, 28.2,
22.5, 16.0, 14.0 ppm. HRMS (EI): calcd. for C13H20O2 [M]+
208.1463; found 208.1462.
J = 5.6, J = 3.6 Hz, 1 H), 6.53 (dd, J = 5.6, J = 1.2 Hz, 1 H), 6.20
(dd, J = 3.6, J = 1.2 Hz, 1 H), 3.99 (t, J = 7.2 Hz, 2 H), 1.81 (sext, J
= 7.2 Hz, 2 H), 1.03 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.8, 124.7, 111.7, 104.5, 75.4, 22.6, 10.4 ppm.
HRMS (EI): calcd. for C7H10OS [M]+ 142.0452; found 142.0454.
1-Butoxy-4-ethoxybenzene (4k): Yellowish oil (conversion/selectiv-
ity: 99/100%), 0.56 g (96%). 1H NMR (400 MHz, CDCl3): δ = 6.82
(s, 4 H), 3.98 (q, J = 6.8 Hz, 2 H), 3.91 (t, J = 6.4 Hz, 2 H), 1.74
(quint, J = 6.4 Hz, 2 H), 1.48 (sext, J = 7.2 Hz, 2 H), 1.39 (t, J =
6.8 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.3, 153.0, 115.4 (4 C), 68.3, 64.0, 31.5, 19.3, 15.0,
13.9 ppm. HRMS (EI): calcd. for C12H18O2 [M]+ 194.1307; found
194.1309.
1,3-Methyl-5-(pentyloxy)benzene (6p): Yellowish oil (conversion/
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selectivity: 92/100%), 0.52 g (90%). H NMR (400 MHz, CDCl3):
δ = 6.59 (s, 1 H), 6.54 (s, 2 H), 3.92 (t, J = 6.8 Hz, 2 H), 2.29 (s, 6
H), 1.77 (quint, J = 6.8 Hz, 2 H), 1.47–1.35 (m, 4 H), 0.93 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.2, 131.4
(2 C), 126.6, 111.1 (2 C), 68.2, 29.1, 28.4, 22.5, 20.4 (2 C),
14.1 ppm. HRMS (EI): calcd. for C13H20O [M]+ 192.1514; found
192.1516.
2-Butoxy-4,6-dimethylphenol (4l): Yellow oil (conversion/selectivity:
100/100%), 0.55 g (95%). 1H NMR (500 MHz, CDCl3): δ = 6.55
(s, 1 H), 6.53 (s, 1 H), 5.57 (br. s, 1 H), 4.01 (t, J = 6.5 Hz, 2 H),
2.25 (s, 3 H), 2.22 (s, 3 H), 1.79 (quint, J = 6.5 Hz, 2 H), 1.49 (sext,
J = 7.5 Hz, 2 H), 0.99 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 145.4, 141.6, 128.4, 126.4, 23.3, 110.0, 68.6,
31.4, 21.0, 19.3, 15.4, 13.8 ppm. HRMS (ESI): calcd. for C12H19O2
[M + H]+ 195.1385; found 195.1390.
1-Isopropoxy-4-methylbenzene (7a): Colourless oil (conversion/
selectivity: 100%/67%), 0.28 g (63%). 1H NMR (400 MHz,
CDCl3): δ = 7.10 (d, J = 7.6 Hz, 2 H), 6.83 (d, J = 7.6 Hz, 2 H),
4.53 (heptet, d, J = 5.2 Hz, 1 H), 2.31 (s, 3 H), 1.35 (d, J = 5.2 Hz,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7, 129.9 (2 C),
129.8, 115.9 (2 C), 70.0, 22.1 (2 C), 20.5 ppm. HRMS (EI): calcd.
for C10H14O [M]+ 150.1045; found 150.1044.
1-Butoxy-4-methoxy-2-methylbenzene (4m): Yellow oil (conversion/
selectivity: 98%/98%), 0.53 g (92%). 1H NMR (400 MHz, CDCl3):
δ = 6.75 (d, J = 9.2 Hz, 1 H), 6.74 (s, 1 H), 6.67 (d, J = 9.2 Hz, 1
H), 3.92 (t, J = 6.4 Hz, 2 H), 3.76 (s, 3 H), 2.23 (s, 3 H), 1.77 (quint,
J = 6.4 Hz, 2 H), 1.62 (sext, J = 7.6 Hz, 2 H), 0.99 (t, J = 7.6 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.7, 140.5, 136.3,
128.9, 126.7, 115.1, 67.0, 62.9, 28.0, 21.0, 15.9, 13.3 ppm. HRMS
(ESI): calcd. for C12H19O2 [M + H]+ 195.1385; found 195.1395.
1-Isopropoxy-3-methoxybenzene (7n): Colourless oil (conversion/
selectivity: 100%/65%), 0.31 g (62%). 1H NMR (400 MHz,
CDCl3): δ = 7.18 (t, J = 8.0 Hz, 1 H), 6.50 (d, J = 8.0 Hz, 2 H),
6.47 (s, 1 H), 6.53 (heptet, d, J = 6.0 Hz, 1 H), 3.79 (s, 3 H), 1.35
(d, J = 6.0 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.9,
159.2, 129.8, 107.9, 106.1, 102.3, 69.8, 55.2, 22.1 (2 C) ppm. HRMS
(EI): calcd. for C10H14O2 [M]+ 166.0994; found 166.0995.
1-Chloro-4-isobutoxybenzene (5g): Colourless oil (conversion/selec-
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tivity: 97%/97%), 0.50 g (91%). H NMR (400 MHz, CDCl3): δ =
General Procedure for the Dialkoxylation: (Table 4): A Teflon®-
lined sealed tube (25 mL) was loaded with a solution of RONa in
ROH [freshly prepared from metallic Na (0.18 g, 8.0 mmol) and
ROH (8 mL)], LiCl (0.17 g, 4.0 mmol), aryl bromide (2.0 mmol),
CuBr (0.09 g, 0.6 mmol), and HCOOR (4.0 mmol). The mixture
was stirred in the sealed tube for 15 min, and then it was heated at
110 °C for 7 h. After the reaction was complete, the mixture was
stirred open to the air for 0.5 h at room temperature, and then it
7.22 (d, J = 8.8 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 3.68 (d, J =
6.8 Hz, 2 H), 2.12–2.02 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 157.9, 132.8, 130.2, 129.2, 125.2,
115.8, 74.7, 28.3, 19.2 (2 C) ppm. HRMS (EI): calcd. for
C10H13ClO [M]+ 184.0655; found 184.0657.
1-Chloro-3-isobutoxybenzene (5h): Colourless oil (conversion/selec-
1
tivity: 93%/98%), 0.49 g (89%). H NMR (400 MHz, CDCl3): δ =
7.18 (t, J = 8.4 Hz, 1 H), 6.91 (s, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), was concentrated in vacuo to recover the ROH solvent and give a
6.78 (dd, J = 8.4, J = 2.4 Hz, 1 H), 3.70 (d, J = 6.8 Hz, 2 H), 2.12– residue. MTBE (10 mL) and dilute hydrochloric acid (1.0 m; 10 mL)
2.03 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz,
were added to the residue. The organic phase was separated, and
CDCl3): δ = 160.0, 134.8, 130.1, 120.6, 114.9, 113.1, 74.6, 28.2, 19.2 the aqueous phase was extracted with MTBE (3ϫ 10 mL). The
(2 C) ppm. HRMS (EI): calcd. for C10H13ClO [M]+ 184.0655; combined organic layers were dried with anhydrous MgSO4, and
found 184.0657.
then concentrated in vacuo. The crude product, which was evalu-
Eur. J. Org. Chem. 2015, 4744–4755
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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