6074 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
25.4, 25.7, 29.0, 44.1, 49.8, 105.5, 174.5. Anal. Calcd for
of a clear oil: 1H NMR δ 1.05 (t, J ) 7, 3H), 2.42 (q, J ) 7, 2H),
2.73 (m, 2H), 2.93 (m, 2H), 7.15-7.35 (m, 5H); 13C NMR δ 7.7,
22.7, 30.6, 31.9, 35.9, 126.7, 128.4, 129.3, 134.3, 208.0.
C
11H20O3: C, 66.0; H, 10.1. Found: C, 65.9; H, 9.9.
2-Tetr a h yd r op yr a n yl Cycloh exa n eca r boxyla te (4). The
above procedure employing 2,3-dihydropyran (21.0 mmol) was
modified by stirring the reaction for 4 h at -25 °C and then
following the same isolation to yield 4.34 g (100%) of 4 as a
colorless oil: 1H NMR δ 1.11-1.98 (m, 16H), 2.30 (m, 1H), 3.63
(m, 1H), 3.85 (m, 1H), 5.91 (s, 1H); 13C NMR δ 18.6, 25.1, 25.5,
28.8, 28.9, 29.1, 43.3, 63.0, 92.0, 174.4. Anal. Calcd for
4-Meth yl-1-p h en yl-3-p en ta n on e (9b).37 The above proce-
dure was employed using THF as solvent and isopropyl-
magnesium bromide to yield 202 mg (82%) of a clear oil: 1H
NMR δ 1.07 (d, J ) 7, 3H), 2.57 (sept, J ) 7, 2H), 2.76 (m, 2H),
2.89 (m, 2H), 7.13-7.32 (m, 5H); 13C NMR δ 18.0, 29.8, 40.9,
41.9, 125.9, 128.2, 128.3, 141.2, 213.5.
C
12H20O3: C, 67.9; H, 9.2. Found: C, 67.8; H, 9.5.
4,4-Dim et h yl-1-p h en yl-3-p en t a n on e (9c).38 The above
procedure was employed using tert-butylmagnesium bromide
into yield 91 mg (50%) of a clear oil: 1H NMR δ 1.05 (s, 9H),
2.75 (m, 2H), 2.82 (m, 2H), 7.08-7.33 (m, 5H); 13C NMR δ 26.2,
30.0, 38.3, 43.9, 125.8, 128.19, 128.22, 141.4, 214.5.
1,3-Dip h en yl-1-p r op a n on e (9f).39 The above procedure was
employed using phenylmagnesium bromide to yield 497 mg
(70%) of a clear oil: 1H NMR δ 3.05 (m, 2H), 3.28 (m, 2H), 7.11-
7.56 (m, 8H), 7.93 (d, J ) 8, 2H); 13C NMR δ 30.0, 40.3, 125.9,
126.6, 127.8, 129.0, 128.2, 128.3, 128.4, 132.9, 199.0.
2-Tetr a h yd r ofu r a n yl Cycloh exa n eca r boxyla te (5). The
above procedure employing 2,3-dihydrofuran (21.0 mmol) was
modified by stirring the reaction for 2 h at -25 °C and then
following the same isolation to yield 4.01 g (100%) of 5 as a
colorless oil: 1H NMR δ 1.10-2.08 (m, 14H), 2.20 (m, 1H), 3.86
(m, 1H), 3.99 (m, 1H), 6.24 (s, 1H); 13C NMR δ 22.8, 25.3, 25.7,
28.8, 32.0, 43.2, 68.6, 98.5, 175.2. Anal. Calcd for C11H18O3:
C, 66.6; H, 9.2. Found: C, 66.5; H, 9.3.
2-Tetr ah ydr ofu r an yl 3-P h en ylpr opion ate (8). To a stirred
solution32 of 3-phenylpropionic acid (200 mmol) and 2,3-dihy-
drofuran (210 mmol) in dichloromethane (200 mL) at -40 °C
was added a solution of methanesulfonic acid (195 µL, 10% v/v
in CH2Cl2, 0.15 mol %, 0.30 mmol). The stirred reaction mixture
was warmed over 30 min to 0 °C, stirred for 4 h, and then
recooled to -40 °C. A solution of dry 1,2-ethylenediamine33 (800
µL, 10% v/v in CH2Cl2, 0.60 mol %, 1.2 mmol) was added, and
the reaction mixture was warmed to 10 °C and placed in a
separatory funnel containing dichloromethane (450 mL). The
dichloromethane solution was washed with chilled bicarbonate
solution (2 × 200 mL, 1/1/1 H2O/brine/saturated NaHCO3, 5 °C)
and brine (2 × 100 mL), dried (Na2SO4), evaporated in vacuo
(40 °C bath), and chased by dilution and evaporation with
hexanes (2 × 60 mL) to yield 8 as a clear oil (43.54 g, 99%
yield): 1H NMR δ 1.85-2.07 (m, 4H), 2.62 (t, J ) 7, 2H), 2.95
(t, J ) 7, 2H), 3.93 (m, 1H), 4.02 (m, 1H), 6.30 (d, J ) 4, 1H),
7.20 (m, 3H), 7.29 (m, 2H); 13C NMR δ 22.7, 30.6, 31.9, 35.9,
68.7, 98.8, 126.0, 128.0, 128.2, 140.2, 172.0. Anal. Calcd for
1-P h en yl-4-h ep tyn -3-on e (9g). The above procedure was
employed using 1-hexynylmagnesium bromide to yield 198 mg
(75%) of a clear oil: 1H NMR δ 0.91 (t, J ) 7, 3H), 1.35-1.62
(m, 4H), 2.35 (t, 2H), 2.86 (m, 2H), 2.95 (m, 2H), 7.15-7.35 (m,
5H); 13C NMR δ 13.5, 18.6, 21.9, 29.7, 46.9, 80.8, 94.8, 126.1,
128.2, 128.4, 140.2, 187.0; HRMS calcd for C15H18O (M+)
214.1357, found 214.1358.
Sin gle F la sk Acyla tion Rea ction . Gen er a l P r oced u r e.
To a stirred solution32 of the carboxylic acid (10.0 mmol) in
dichloromethane (40 mL) at -20 °C under nitrogen was added
2,3-dihydrofuran (10.5 mmol) and then a solution of methane-
sulfonic acid (1.0% v/v in CH2Cl2, 0.20 mol %, 0.020 mmol). The
stirred reaction mixture was warmed to 0 °C over 4 h and then
recooled to -20 °C. The organomagnesium reagent (in ether or
THF, 1-3 M, 10.0 mmol) was added dropwise over 5 min to yield
a clear colored solution. After 30 min at -20 °C, the reaction
mixture was very slowly warmed to 18 °C over 18 h, then
recooled to 0 °C. Quenching and isolation as described in the
above reaction with Grignard reagents yielded the pure ketone.
1-P h en yl-2-bu ta n on e (12a ).40 The above procedure was
employed using phenylacetic acid and ethylmagnesium bromide
to yield 1.36 g (90%) of a clear oil: 1H NMR δ 1.07 (t, J ) 7,
3H), 2.52 (q, J ) 7, 2H), 3.73 (s, 2H), 7.23-7.46 (m, 5H); 13C
NMR δ 7.8, 35.2, 49.8, 126.8, 128.6, 129.3, 134.4, 208.8.
C
13H16O3: C, 70.9; H, 7.3. Found: C, 70.9; H, 7.4.
2-Tetr a h yd r ofu r a n yl Cin n a m a te. The above procedure
was used to yield 15.3 g (100%) of the cinnamate as a white
solid: mp 73-75 °C (Et2O); 1H NMR δ 1.89-2.10 (m, 4H), 3.96
(m, 1H), 4.1 (m, 1H), 6.4 (d, J ) 16, 1H), 6.43 (m, 1H), 7.38 (m,
3H), 7.51 (m, 2H), 7.68 (d J ) 16, 1H); 13C NMR δ 23.0, 32.3,
69.0, 99.2, 118.2, 128.0, 128.8, 130.2, 134.3, 145.0, 166.0. Anal.
Calcd for C13H14O3: C, 71.5; H, 6.5. Found: C, 71.6; H, 6.6.
Rea ction of THF Ester s w ith Gr ign a r d Rea gen ts. Gen -
er a l P r oced u r e. To a stirred solution of the THF ester (10.0
mmol) in dichloromethane (30 mL) at -20 °C under nitrogen
was added dropwise over 5 min the organomagnesium reagent
(in Et2O or THF, 1-3 M, 10.0 mmol) to yield a clear lightly
colored solution. After 30 min at -20 °C, the reaction mixture
was slowly warmed to 18 °C over 18 h and then recooled to 0 °C
during dropwise addition with stirring into 1.0 M H3PO4 (14 mL)
at 0 °C.34 The mixture was warmed to 20 °C, diluted with water
(10 mL), and added to a separatory funnel using dichloro-
methane (50 mL). The organic layer was separated, and the
aqueous phase was extracted (CH2Cl2, 3 × 10 mL). The
combined organic phases were shaken with 0.25 M H3PO4 (12
mL) for 5 min, separated,35 washed with aqueous NaHCO3 (3 ×
20 mL, 1/1, H2O/saturated NaHCO3) and brine (25 mL), and then
dried (Na2SO4) and evaporated (up to 40 °C). Dilution and
evaporation with hexanes (2 × 60 mL) yielded the crude ketone
as an oil. Chromatography on silica gel using pentane/Et2O,
when necessary, provided the pure ketone.
1-P h en yl-4-m eth yl-3-p en ta n on e (9b). The above proce-
dure was employed using 3-phenylpropionic acid and isopro-
pylmagnesium bromide to yield 2.7 g (86%) of a clear oil whose
physical properties were the same as above.
1-P h en yl-3-m eth yl-2-bu ta n on e (12b).41 The above proce-
dure was employed using phenylacetic acid and isopropyl-
magnesium bromide to yield 1.31 g (81%) of a clear oil: 1H NMR
δ 1.11 (d, J ) 7, 6H), 2.75 (sept, J ) 7, 1H), 3.76 (s, 2H), 7.16-
7.42 (m, 5H); 13C NMR δ 18.2, 40.0, 47.6, 126.7, 128.4, 129.3,
134.3, 215.4.
Isobu tyr op h en on e (12c).42 The above procedure was em-
ployed using benzoic acid and isopropylmagnesium bromide to
yield 1.27 g (86%) of 12a as a clear oil.
3,4-Dim eth oxyp h en yl Isop r op yl Keton e (12d ).43 The
above procedure was employed using 3,4-dimethoxybenzoic acid
and isopropylmagnesium bromide to yield 1.92 g (72%) of a clear
oil: 1H NMR δ 1.24 (d, J ) 7, 6H), 3.56 (sept, J ) 7, 1H), 3.96
(s, 3H), 3.97 (s, 3H), 6.91 (d, J ) 8, 1H), 7.57 (d, J ) 2, 1H), 7.62
(dd, J ) 8, 2, 1H); 13C NMR δ 19.4, 34.7, 55.87, 55.94, 109.9,
110.5, 122.5, 129.2, 149.0, 152.9, 203.0.
1-P h en yl-3-p en ta n on e (9a ).36 The above procedure was
employed using ethylmagnesium bromide to yield 289 mg (88%)
(32) When the carboxylic acid was not completely soluble at -40 or
-20 °C, addition of the methanesulfonic acid to the suspension
catalyzed a slow clarification to form a solution of the more soluble
THF ester.
J O9607471
(33) Dry amine quenches (dilute ammonia, triethylamine, or 1,2-
ethylenediamine in CH2Cl2) at low temperature gave better results
than an aqueous alkaline quench (NaHCO3).
(34) Quenching by bolus addition of the quench into the vigorously
stirred reaction mixture gave similar results. The ketone 9g was
quenched with pH 7, 0.1 M phosphate buffer.
(35) If the THF ester is still present (TLC), the CH2Cl2 solution is
stirred with methanesulfonic acid and methanol (e.g., 5 µL and 1 mL,
respectively), at 20 °C until hydrolyzed (1 h).
(37) J acquier, R.; Mousseron, M.; Boyer, S. Bull. Soc. Chim. Fr.
1956, 1653.
(38) Berliner, E.; Berliner, F. J . Am. Chem. Soc. 1950, 72, 222.
(39) Russell, G. A.; Mikol, J . G. J . Am. Chem. Soc. 1966, 88, 5498.
(40) Castelli, F.; Canonne, P. Bull. Soc. Chim. Fr. 1974, 317.
(41) Bordwell, F. G.; Almy, J . J . Org. Chem. 1973, 38, 575.
(42) Inukai, T.; Yoshizawa, R. J . Org. Chem. 1967, 32, 404.
(43) Horton, W. J .; Paul, E. G. J . Am. Chem. Soc. 1957, 79, 2264.
(36) Schultz, E. M.; Bicking, J . B. J . Am. Chem. Soc. 1953, 75, 1128.