K. L. McPhail et al. / Tetrahedron 56 (2000) 9391±9396
9395
and the combined ether layers washed with 10% KOH
(3£30 mL), water (30 mL), dried and concentrated to give
15 as a colorless oil (2.08 g, 53%). If only two equivalents
of thymol were used a 2:1 mixture of 15 and 2,5 dibromo-p-
cymene (16) was obtained. The bromination of 19 (7.76 g,
51.7 mmol) also proceeded smoothly by this method.
Repeated Si gel chromatography (hexane) proved more
effective than steam distillation for the isolation of
4-bromo-m-cymene as a colorless oil (1.48 g, 54%) from
the reaction mixture.
(171 mg) eluted with 8:2 hexane±EtOAc was subjected to
NPHPLC (8:2 hexane±EtOAc) to give [2-isopropyl-5-
methylphenyl](furan-3-yl)methanol (20, 145 mg, 49%) as
a colorless oil. The regioisomers of 20, [2-isopropyl-4-
methylphenyl](furan-3-yl)methanol (21) and [5-isopropyl-
2-methylphenyl](furan-3-yl)methanol (25) were similarly
prepared, and in comparable yields (64 and 30% respec-
tively), from 18 and 23 respectively
[2-Isopropyl-5-methylphenyl](furan-3-yl)methanol (20).
1
IR nmax 3351, 2964, 1501, 1158, 1026, 874, 600 cm21; H
3-Bromo-p-cymene (15). IR nmax 2960, 2927,1501, 1463,
1379, 1051, 816 cm21; 1H NMR (CDCl3, 400 MHz) d 1.24
(6H, d, J7 Hz, H3-9, H3-10), 2.30 (3H, s, H3-7), 3.34 (1H,
sept, J7 Hz, H-8), 7.09 (1H, d, J8 Hz, H-6), 7.17 (1H, d,
J8 Hz, H-5), 7.38 (1H, s, H-2) ppm; 13C NMR (CDCl3,
100 MHz) d 20.5 (q, C-7), 22.9 (q, C-9), 22.9 (q, C-10), 32.4
(d, C-8), 124.0 (s, C-3), 126.3 (d, C-5), 128.4 (d, C-6), 133.2
(d, C-2), 137.1 (s, C-1), 144.2 (s, C-4) ppm; EIMS (70eV)
m/z (rel. int.) 214 (33), 212 (32), 199 (91), 197 (87), 118
(100), 117 (51); HRFABMS obsd. 213.027795 (M11),
C10H1479Br requires 213.027887.
NMR (CDCl3, 400 MHz) d 1.13 (3H, d, J7 Hz, H3-14),
1.22 (3H, d, J7 Hz, H3-13), 2.08 (1H, d, J4 Hz, OH),
2.32 (3H, s, H3-15), 3.19 (1H, sept, J7 Hz, H-12), 6.06
(1H, d, J4 Hz, H-7), 6.33 (1H, d, J1 Hz, H-11), 7.11
(1H, d, J8 Hz, H-6), 7.20 (1H, d, J8 Hz, H-5), 7.21
(1H, s, H-9), 7.31 (1H, s, H-2), 7.36 (1H, t, J2 Hz,
H-10) ppm; 13C NMR (CDCl3, 100 MHz) d 20.9 (q,
C-15), 23.8 (q, C-14), 24.2 (q, C-13), 27.9 (d, C-13), 65.8
(d, C-7), 109.7 (d, C-11), 125.4 (d, C-5), 126.8 (d, C-2),
128.7 (d, C-6), 129.2 (s, C-8), 135.3 (s, C-1), 139.4 (s,
C-3), 139.8 (d, C-9), 142.9 (s, C-4), 143.2 (d, C-10) ppm;
EIMS (70 eV) m/z (rel. int.) 230 (16), 212 (21), 197 (93),
187 (28), 183 (57), 179 (22), 169 (60), 162 (100), 143 (31),
128 (27), 91 (20); HRFABMS obsd. 231.138574 (M11),
C15H19O2 requires 231.138505.
2,5-Dibromo-p-cymene (16). IR nmax 2964, 1471, 1383,
1
1360, 1070, 1046, 880 cm21; H NMR (CDCl3, 400 MHz)
d 1.21 (6H, d, J7 Hz, H3-9, H3-10), 2.32 (3H, s, H3-7),
3.26 (1H, sept, J7 Hz, H-8), 7.38 (1H, s, H-3), 7.39 (1H, s,
H-6) ppm; 13C NMR (CDCl3, 100 MHz) d 22.1 (q, C-7),
22.7 (q, C-9), 22.7 (q, C-10), 32.6 (d, C-8), 122.6 (d, C-5),
124.1 (d, C-2), 130.3 (d, C-6), 134.4 (d, C-6), 137.0 (s, C-1),
146.7 (s, C-4) ppm; EIMS (70 eV) m/z (rel. int.) 290 (18),
279 (46), 277 (100), 275 (49), 198 (36), 196 (34);
HRFABMS obsd. 289.930921, C10H1279Br2 requires
289.930573.
[2-Isopropyl-4-methylphenyl](furan-3-yl)methanol (21).
Colorless needles (mp 39±418C); IR nmax 3351, 2964,
1
1501, 1158, 1026, 875, 774, 600 cm21; H NMR (CDCl3,
400 MHz) d 1.13 (3H, d, J7 Hz, H3-14), 1.22 (3H, d, J
7 Hz, H3-13), 1.97 (1H, d, J4 Hz, OH), 2.34 (3H, s,
H3-15), 3.21 (1H, sept, J7 Hz, H-12), 6.05 (1H, d, J
4 Hz, H-7), 6.31 (1H, s, H-11), 7.02 (1H, d, J8 Hz, H-5),
7.10 (1H, s, H- 2), 7.21 (1H, s, H-9), 7.36 (1H, d, J8 Hz),
7.36 (1H, d, J2 Hz, H-10) ppm; 13C NMR (CDCl3,
100 MHz) d 21.3 (q, C-15), 23.9 (q, C-14), 24.2 (q,
C-13), 28.2 (d, C-12), 65.9 (d, C-7), 109.5 (d, C-11),
126.3 (d, C-2), 126.4 (d, C-6), 126.8 (d, C-5), 129.2 (s,
C-8), 136.6 (s, C-4), 137.7 (s, C-1), 140.0 (d, C-9), 143.3
(d, C-10), 145.9 (s, C-3) ppm; EIMS (70 eV) m/z (rel.
int.) 230 (24), 212 (14), 201 (29), 197 (79), 187 (47),
183 (56), 169(59), 162 (100), 143 (40), 128 (32), 91 (23);
HRFABMS obsd. 231.138458 (M11), C15H19O2 requires
231.138505.
4-Bromo-m-cymene (18). IR nmax 2961, 2929, 1502, 1463,
1382, 815 cm21; 1H NMR (CDCl3, 400 MHz) d 1.25 (6H, d,
J7 Hz, H3-9, H3-10), 2.31 (3H, s, H3-7), 3.35 (1H, sept,
J7 Hz, H-8), 6.86 (1H, dd, J2, 8 Hz, H-6), 7.09 (1H, d,
J1 Hz, H-2), 7.40 (1H, d, J8 Hz, H-5) ppm; 13C NMR
(CDCl3, 100 MHz) d 21.1 (q, C-7), 22.8 (q, C-9), 22.8 (q,
C-10), 32.7 (d, C-8), 120.9 (s, C-4), 127.4 (d, C-2), 128.1 (d,
C-6); 132.4 (d, C-5), 137.3 (s, C-1), 146.9 (s, C-3); EIMS
(70eV) m/z (rel. int.) 215 (82), 213 (85), 134 (100), 119 (8),
105 (7), 91 (8) HRFABMS obsd. 213.027802 (M11),
C10H1479Br requires 213.027887.
[5-Isopropyl-2-methylphenyl](furan-3-yl)methanol (25).
Biaryl coupling of compounds 15, 18 and 23 with 3-fural-
dehyde. The following procedure is representative. A solu-
tion of 3-bromo-p-cymene (15, 300 mg, 1.41 mmol) and
TMEDA (386 mL, 2.56 mmol) in dry THF (3 mL) was
cooled to 2788C and n-BuLi (1.6 M in hexane, 800 mL,
1.28 mmol) added slowly over several minutes. The reac-
tion mixture was stirred (1 h) and a solution of 3-furalde-
hyde (111 mL, 1.28 mmol) in dry THF (1 mL) added
dropwise. The reaction mixture was stirred (4.5 h) and
allowed to warm up gradually to room temperature before
quenching with water. The removal of THF under reduced
pressure from the reaction mixture was followed by the
addition of brine. The aqueous solution was extracted with
CH2Cl2 (4£20 mL), the organic layers combined, dried and
concentrated to yield a crude product mixture which was
chromatographed over Si gel (EtOAc±hexane). The fraction
Amorphous white solid; IR n
3351, 2960, 1501, 1459,
max
1158, 1025, 874, 728 cm21; 1H NMR (CDCl3, 400 MHz) d
1.23 (6H, d, J7 Hz, H3-13, H3-14), 2.01 (1H, d, J4 Hz,
OH); 2.25 (3H, s, H3-15), 2.89 (1H, sept, J7 Hz, H-12),
5.94 (1H, d, J4 Hz, H-7), 6.34 (1H, s, H-11), 7.07 (2H, s,
H-3, H-5), 7.21 (1H, s, H-9), 7.36 (1H, s, H-10), 7.40 (1H, s,
H-6) ppm; 13C NMR (CDCl3, 100 MHz) d 18.6 (q, C-15),
24.0 (q, C-13), 24.1 (q, C-14), 33.9 (d, C-12), 66.5 (d, C-7),
109.5 (d, C-11), 123.9 (d, C-6), 125.5 (d, C-5), 128.2 (s,
C-8), 130.5 (d, C-3), 132.2 (s, C-1), 140.1 (d, C-9), 140.7 (s,
C-2), 143.4 (d, C-10), 146.9 (s, C-4) ppm; EIMS (70 eV)
m/z (rel. int.) 212 (42), 197 (58), 183 (11), 169 (21), 162
(100), 147 (24), 128 (8), 95 (15); HRFABMS obsd.
231.138511 (M11), C15H19O2 requires 231.138505.
Dehydroxylation of compounds 20, 21 and 25. The