The Journal of Organic Chemistry
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3-Methyl-2-phenylbutan-2-ol (2b, Entry 2 in Table 3).9b
Colorless oil (82% yield). 1H NMR (400 MHz, CDCl3): δ 0.82 (d, J =
6.9 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 1.53 (s, 3H), 1.73 (s, 1H), 2.03
(septet, J = 6.9 Hz, 1H), 7.20−7.45 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 17.2, 17.4, 26.7, 38.6, 76.7, 125.3, 126.4, 127.9, 147.8.
2-Phenylbutan-2-ol (2c, Entry 3 in Table 3).18 Colorless oil
(95% yield). 1H NMR (400 MHz, CDCl3): δ 0.83 (t, J = 7.4 Hz, 3H),
1.58 (s, 3H), 1.77 (s, 1H), 1.87 (m, 2H), 7.24−7.47 (m, 5H). 13C
NMR (100 MHz, CDCl3): δ 8.3, 29.6, 36.7, 74.9, 124.9, 126.5, 128.1,
147.8.
1-Isopropyl-1,2,3,4-tetrahydro-1-naphthol (2n, Entry 9 in
Table 4).9b Colorless oil (65% yield). 1H NMR (400 MHz, CDCl3): δ
0.66 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H), 1.62−1.89 (m, 5H),
2.40 (septet, J = 6.9 Hz, 1H), 2.60−2.84 (m, 2H), 7.08 (d, J = 7.5 Hz,
1H), 7.14−7.26 (m, 2H), 7.52 (d, J = 7.5 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 16.3, 18.4, 19.1, 30.3, 30.9, 37.4, 74.4, 126.1, 126.4,
126.8, 128.9, 137.8, 141.6.
1-Isopropyl-1-cyclohexanol (2o, Entry 12 in Table 4).9b
Colorless oil (73% yield). 1H NMR (400 MHz, CDCl3): δ 0.90 (d, J =
6.9 Hz, 6H), 1.11 (s, 1H), 1.20−1.63 (m, 11H). 13C NMR (100 MHz,
CDCl3): δ 16.6, 21.9, 25.9, 34.1, 37.5, 73.1.
2-Phenylpent-4-en-2-ol (2d, Entry 4 in Table 3).19 Colorless
oil (99% yield). 1H NMR (400 MHz, CDCl3): δ 1.57 (s, 3H), 2.25 (s,
1H), 2.52 (dd, J = 8.2 Hz, 13.8 Hz, 1H), 2.70 (dd, J = 8.2 Hz, 13.8 Hz,
1H), 5.15 (m, 2H), 5.66 (m, 1H), 7.24−7.48 (m, 5H). 13C NMR (100
MHz, CDCl3): δ 29.9, 48.5, 73.7, 119.4, 124.8, 126.6, 128.2, 133.8,
147.7.
Synthesis of 4-(4-(Dimethylamino)-1-(4-fluorophenyl)-1-hy-
droxybutyl)-3-(hydroxymethyl)benzonitrile (7).
Method 1 (Entry 1 in Table 5). To 1 mL of THF solution
of a Schlenk tube equipped with a magnetic stirrer and charged with
5-cyanophthalide (6, 157 mg, 1.0 mmol), 4-fluorophenylmagnesium
bromide (1.5 mL, 1.5 mmol, 1.0 M in THF) was added dropwise over
30 min by a syringe at 0 °C. The reaction mixture was allowed to
warm to room temperature and stirred for 1 h and then cooled to
0 °C. The second freshly made Grignard reagent [3-(dimethylamino)-
propyl)magnesium chloride (1.5 mL, 1.5 mmol, 1.0 M in THF)] was
added dropwise over 30 min. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. Then, the reaction was
quenched by saturated aqueous NH4Cl (5 mL) and extracted with
CH2Cl2 (10 mL × 3). The combined extracts were washed by brine
(5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
afford the crude product as a colorless oil. Purification by silica gel
column chromatography (eluent: CH2Cl2/CH3OH, v/v = 40/1) and
recrystallization in heptane/isopropyl ether (v/v = 2/1) gave the pure
compound (7) as a white solid (67% yield, entry 1 in Table 5).
Method 2 (Entry 2 in Table 5). To 1 mL of THF solution of a
Schlenk tube equipped with a magnetic stirrer and charged with
tetrabutylammonium chloride (278 mg, 1.0 mmol), 5-cyanophthalide
(6, 157 mg, 1.0 mmol), and DGDE (0.21 mL, 201 mg, 1.5 mmol),
4-fluorophenylmagnesium bromide (1.5 mL, 1.5 mmol, 1.0 M in THF)
was added dropwise over 30 min by a syringe at 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred for 1 h
and then cooled to 0 °C. The second freshly made Grignard reagent
(3-(dimethylamino)propyl)magnesium chloride (1.5 mL, 1.5 mmol,
1.0 M in THF) was added dropwise over 30 min. The reaction mixture
was allowed to warm to room temperature and stirred for 2 h. Then,
the reaction was quenched by saturated aqueous NH4Cl (5 mL) and
extracted with CH2Cl2 (10 mL × 3). The combined extracts were
washed by brine (5 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to afford the crude product as a colorless oil. Purification by
silica gel column chromatography (eluent: CH2Cl2/CH3OH, v/v =
40/1) and recrystallization in heptane/isopropyl ether (v/v = 2/1)
gave the pure compound (7) as a white solid (90% yield, entry 2 in
Table 5).
Method 3 (Entry 4 in Table 5). To 1 mL of THF solution of a
Schlenk tube equipped with a magnetic stirrer and charged with
Dowex-1-chloride resin (300 mg), 5-cyanophthalide (6, 157 mg, 1.0
mmol), and diethylene glycol dimethyl ether (0.21 mL, 201 mg, 1.5
mmol), 4-fluorophenylmagnesium bromide (1.5 mL, 1.5 mmol, 1.0 M
in THF) was added dropwise over 30 min by a syringe at 0 °C. The
reaction mixture was allowed to warm to room temperature and stirred
for 1 h and then cooled to 0 °C. The second freshly made Grignard
reagent (3-(dimethylamino)propyl)magnesium chloride (1.5 mL, 1.5
mmol, 1.0 M in THF) was added dropwise over 30 min. The reaction
mixture was allowed to warm to room temperature and stirred for 2 h.
Then, the reaction was quenched by saturated aqueous NH4Cl (5 mL)
and extracted with CH2Cl2 (10 mL × 3). The combined extracts were
washed by brine (5 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to afford the crude product as a colorless oil. Purification by
silica gel column chromatography (eluent: CH2Cl2/CH3OH, v/v =
40/1) and recrystallization in heptane/isopropyl ether (v/v = 2/1)
gave the pure compound (7) as a white solid (83% yield, entry 4 in
Table 5).
1,1-Diphenylethanol (2e, Entry 5 in Table 3).9b White solid
1
(94% yield). H NMR (400 MHz, CDCl3): δ 1.96 (s, 3H), 2.25 (s,
1H), 7.25 (m, 2H), 7.32 (t, J = 7.19 Hz, 4H), 7.42 (m, 4H). 13C NMR
(100 MHz, CDCl3): δ 30.9, 76.2, 125.8, 127.0, 128.2, 148.0.
1-(4-Fluorophenyl)-1-phenylethanol (2f, Entry 6 in Table 3)20.
White solid (90% yield). 1H NMR (400 MHz, CDCl3): δ 1.95 (s, 3H),
2.67 (s, 1H), 7.02 (t, J = 8.7 Hz, 2H), 7.30−7.45 (m, 7H). 13C NMR
(100 MHz, CDCl3): δ 30.8, 75.8, 114.7 (d, J = 21.1 Hz), 125.7, 127.0,
127.5 (d, J = 8.0 Hz), 128.1, 143.7 (d, J = 3.2 Hz), 147.7, 160.4, 162.8.
19F NMR (376 MHz, CDCl3): δ −115.96.
3-Methyl-2-(4-methoxyphenyl)butan-2-ol (2g, Entry 1 in
Table 4).21 Colorless oil (82% yield). 1H NMR (400 MHz,
CDCl3): δ 0.82 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H), 1.50
(s, 3H), 1.69 (br, 1H), 1.98 (septet, J = 6.9 Hz, 1H), 3.80 (s, 3H),
6.84−6.89 (m, 2H), 7.30−7.36 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 17.2, 17.4, 26.4, 38.7, 55.2, 76.5, 113.1, 126.4, 139.9, 158.0.
3-Methyl-2-(4-(trifluoromethyl)phenyl)butan-2-ol (2h, Entry
2 in Table 4).9e Colorless oil (89% yield). H NMR (400 MHz,
1
CDCl3): δ 0.77 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H), 1.53 (s,
3H), 1.75 (br, 1H), 2.02 (septet, J = 6.9 Hz, 1H), 7.53 (d, J = 8.4 Hz,
2H), 7.58 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 16.9,
17.3, 27.1, 38.5, 77.3, 123.0, 124.8 (q, J = 271.0 Hz), 125.7, 128.8
(q, J = 32.4 Hz), 151.8. 19F NMR (376 MHz, CDCl3): δ −62.38.
3-Methyl-2-(2-naphthalenyl)-2-butanol (2i, Entry 3 in Table 4).9b
Colorless oil (80% yield). 1H NMR (400 MHz, CDCl3): δ 0.92 (d, J =
6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H), 1.68 (s, 3H), 2.09 (s, 1H),
2.21 (septet, J = 6.9 Hz, 1H), 7.51−7.62 (m, 3H), 7.86−7.92 (m, 3H),
7.98 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 17.3, 17.6, 26.8,
38.5, 77.0, 123.8, 124.2, 125.7, 126.0, 127.5, 127.6, 128.3, 132.3, 133.2,
145.5.
3-Methyl-2-(1-naphthalenyl)-2-butanol (2j, Entry 4 in Table 4).9b
Colorless oil (75% yield). 1H NMR (400 MHz, CDCl3): δ 0.85 (d, J =
6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H), 1.78 (s, 3H), 2.12 (s, 1H), 2.88
(septet, J = 6.9 Hz, 1H), 7.44−7.56 (m, 4H), 7.80−7.93 (m, 2H), 8.87
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 17.2, 18.3, 25.2, 36.3, 79.0,
124.4, 124.7, 125.1, 127.3, 128.4, 129.3, 131.0, 135.1, 143.3.
2-Methyl-3-phenyl-3-pentanol (2k, Entry 5 in Table 4).9b
Colorless oil (92% yield). 1H NMR (400 MHz, CDCl3): δ 0.70 (t, J =
7.3 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.59 (s,
1H), 1.89 (q, J = 6.9 Hz, 2H), 2.05 (septet, J = 6.9 Hz, 1H), 7.18−7.40
(m, 5H). 13C NMR (100 MHz, CDCl3): δ 7.9, 16.6, 17.5, 32.0, 37.5,
79.3, 125.9, 126.1, 127.7, 145.0.
2-Methyl-3-phenyl-3-heptanol (2l, Entry 6 in Table 4).22
Colorless oil (85% yield). 1H NMR (400 MHz, CDCl3): δ 0.72 (d, J =
6.8 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H), 0.95 (m, 4H), 1.25 (m, 3H),
1.61 (d, J = 11.8 Hz, 1H), 1.85 (m, 2H), 2.04 (septet, J = 6.9 Hz, 1H),
7.20−7.38 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 14.0, 16.6, 17.4,
23.2, 25.8, 37.8, 39.4, 79.0, 125.8, 126.1, 127.7, 145.5.
2-Methyl-1,1-diphenyl-1-propanol (2m, Entry 7 in Table 4).9b
Colorless oil (69% yield). 1H NMR (400 MHz, CDCl3): δ 0.93 (d, J =
6.9 Hz, 6H), 2.10 (s, 1H), 2.93 (septet, J = 6.9 Hz, 1H), 7.18−7.55 (m,
10H). 13C NMR (100 MHz, CDCl3): δ 17.1, 35.0, 80.4, 125.7, 126.3,
128.0, 146.7.
4-(4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-
3-(hydroxymethyl)benzonitrile (7, Table 5).23,24 White solid, mp
G
dx.doi.org/10.1021/jo3004277 | J. Org. Chem. XXXX, XXX, XXX−XXX