4918 J . Org. Chem., Vol. 61, No. 15, 1996
Azzena et al.
was added dropwise to a well stirred suspension of the
appropriate Grignard reagent (from 4 g, 165 mmol, of Mg and
150 mmol of CH3I or C6H5Br) in 50 mL of Et2O under N2. The
mixture was stirred at rt for 12 h and then chilled to 0 °C.
Saturated aqueous NH4Cl was added dropwise until a white
precipitate formed. The mixture was filtered, the precipitate
washed with Et2O (3 × 20 mL), the organic phase washed with
saturated NH4Cl and dried (Na2SO4), and the solvent evapo-
rated. The crude product was suspended in 60 mL of 50% H3-
PO4 and the mixture stirred at reflux temperature under N2
for 4 h. The mixture was chilled to rt and extracted with Et2O
(3 × 20 mL). The collected organic fractions were washed with
H2O (50 mL) and saturated NaHCO3 (50 mL), and dried (Na2-
SO4). Evaporation of the solvent and vacuum distillation
afforded the pure products, which were characterized as
follows.
Gen er a l P r oced u r e for th e Red u ctive Electr op h ilic
Su bstitu tion of Com p ou n d s 1. The appropriate substrate
was reduced according to the general procedure reported above
in the presence of a catalytic amount of naphthalene, and the
reaction mixture was chilled to the temperature reported in
Table 3. The appropriate amount of electrophile dissolved in
THF (5 mL) was slowly added, and the mixture was stirred
for the reported time. Crude products were purified and
characterized as follows.
[2-(Hyd r oxym eth yl)p h en yl]eth a n e (4d a ). Purified by
flash chromatography (AcOEt/hexane ) 3:7); bp 150 °C/20
1
mmHg (lit.29 bp 229 °C/760 mmHg); H NMR δ 1.24 (t, J )
7.5 Hz, 3H), 1.59 (br s, 1H), 2.72 (q, J ) 7.5 Hz, 2H), 4.73 (s,
2H), 7.17-7.31 (m, 3H), 7.37 (d, J ) 7.5 Hz, 1H); 13C NMR δ
15.34, 25.16, 63.12, 126.03, 128.02, 128.07, 128.59, 138.02,
142.22; IR 3612, 3458 cm-1
.
1,1-Dip h en ylp h th a la n (1c). Isolated in 91% yield by
recrystallization from EtOH, mp 95-97 °C; 1H NMR δ 5.18
(s, 2H), 7.20-7.37 (m, 14H); 13C NMR δ 71.45, 93.01, 121.07,
123.84, 127.21, 127.33, 127.64, 127.96, 139.57, 144.10, 144.61;
1H and 13C NMR in perfect agreement with the literature.24
P r ep a r a tion of 1-Su bstitu ted P h th a la n s 1d a n d 1e. A
solution of 1a (2 g, 16.5 mmol) in 30 mL of THF was chilled to
-40 °C under dry N2. To this mixture, 14 mL (1.1 equiv) of a
1.3 M solution of sec-BuLi in cyclohexane was added dropwise,
and the mixture was stirred for 2 h, before adding to it 1.2
equiv of the appropriate alkyl halide dissolved in 2 mL of THF.
After 1 h stirring, the reaction was quenched by slow dropwise
addition of H2O (10 mL) (caution!), the cold bath removed, and
the resulting mixture extracted with Et2O (3 × 30 mL). The
organic fractions were collected, washed with H2O (30 mL),
and dried (CaCl2), and the solvent was evaporated. Crude
products were purified by fractional distillation and were
characterized as follows.
1-[2-(Hydr oxym eth yl)ph en yl]-1-ph en ylpen tan e (5i). Pu-
rified by flash chromatography (AcOEt/hexane ) 3:7); bp 190
°C/1 mmHg; 1H NMR δ 0.86 (t, J ) 6.9 Hz, 3H), 1.30-1.45
(m, 4H), 1.57 (br s, 1H), 2.02 (q, J ) 7.8 Hz, 2H), 4.25 (t, J )
7.5 Hz, 1H), 4.66 (dd, J ) 12.9 Hz, J ) 5.1 Hz, 1H), 4.72 (dd,
J ) 12.9 Hz, J ) 6.3 Hz, 1H), 7.12-7.37 (m, 8H), 7.40-7.45
(m, 1H); 13C NMR δ 13.97, 22.75, 30.22, 36.18, 45.87, 63.19,
126.01, 126.29, 127.15, 127.97, 127.99, 128.38, 128.54, 138.49,
142.79, 145.06; IR 3611 cm-1. Anal. Calcd for C18H22O: C,
84.98; H, 8.73. Found: C, 84.87; H, 8.91.
Gen er a l P r oced u r e for th e Syn th esis of Su bstitu ted
Isoch r om a n -3-on es 6. The appropriate substrate was re-
duced according to the general procedure reported above in
the presence of a catalytic amount of naphthalene, and the
reaction mixture was stirred for the reported time. Gaseous
CO2 was bubbled for 5 min into the reaction mixture chilled
to -40 °C. The reaction mixture was quenched by slow
dropwise addition of H2O (10 mL, caution!), acidified with
concd HCl, and worked up as reported above. Crude products
were purified and characterized as follows.
1-Meth ylp h th a la n (1d ). Bp 80 °C/20 mmHg (lit.6 94-95
°C/25 mmHg); 1H NMR δ 1.50 (d, J ) 6.3, 3H), 4.98-5.08 (m,
1H), 5.13 (dd, J ) 12.3, J ) 2.4, 1H), 5.26-5.38 (m, 1H), 7.10-
7.30 (m, 4H).
Isoch r om a n -3-on e (6a ). Purified by flash chromatography
(AcOEt/hexane ) 1:1); mp 80-81 °C (CH3OH/H2O) (lit.38 mp
82-83 °C, benzene) 1H NMR δ 3.72 (s, 2H), 5.32 (s, 2H), 7.18-
Gen er a l P r oced u r e for th e Red u ctive Clea va ge of
Com p ou n d s 1. Li metal (42 mg atom, 0.96 g of a 30% wt.
dispersion in mineral oil, 5 equiv)26 was placed under Ar in a
two-necked flask equipped with reflux condenser and magnetic
stirrer, washed with THF (3 × 10 mL), and suspended in 30
mL of THF. In some cases, 30 mg (0.2 mmol) of naphthalene
were added to the suspension of the metal, and the mixture
was stirred until a dark green color appeared. The mixture
was chilled to the temperature reported in Table 1 or 2, and a
solution of the appropriate substrate (8 mmol) in 5 mL of THF
was added. After stirring for the reported time, the reaction
was quenched by slow dropwise addition of H2O (10 mL,
caution!), and the resulting mixture was extracted with Et2O
(3 × 30 mL). The organic phase was dried (Na2SO4) and the
solvent evaporated. D2O-quenching was performed as de-
scribed in ref 14. Crude products were characterized as
follows.
7.39 (m, 4H); IR (KBr) 1745 cm-1
.
Gen er a l P r oced u r e for th e Syn th esis of 3-Su bstitu ted -
Isoch r om a n s 7. The substrate (1 mmol) was dissolved in a
minimum amount of THF and the solution added under N2 to
30 mL of a vigorously stirred 50% aqueous solution of H3PO4.
The mixture was stirred at reflux temperature overnight. After
cooling to rt, the mixture was extracted with Et2O (3 × 10 mL),
and the organic phase was washed with saturated NaHCO3
(20 mL), H2O (20 mL), and dried (CaCl2). The solvent was
evaporated, and the crude products were purified and char-
acterized as follows.
3-P h en ylisoch r om a n (7a ). Purified by recrystallization,
mp 74-75 °C (EtOH) (lit.37 76-77 °C, EtOH); 1H NMR δ 2.96
(dd, J ) 16.3 Hz, J ) 3.6 Hz, 1H), 3.08 (dd, J ) 16.3 Hz, J )
10.8 Hz, 1H), 4.72 (dd, J ) 10.8 Hz, J ) 3.6 Hz, 1H), 5.00 (s,
2H), 6.98-7.52 (m, 9H); 13C NMR δ 36.08, 68.70, 76.84, 124.19,
125.87, 126.17, 126.46, 127.67, 128.46, 128.77, 133.48, 134.51,
142.11.
(2-Meth ylp h en yl)m eth a n ol (2). Bp 120 °C/20 mmHg (lit.7
115 °C/20 mmHg); 1H NMR (300 MHz, CDCl3) δ 1.64 (br s,
1H), 2.36 (s, 3H), 4.69 (s, 2H), 7.10-7.30 (m, 3H), 7.30-7.40
Gen er a l P r oced u r e for th e Syn th esis of Dih yd r oiso-
cou m a r in s 9. The substrate (1 mmol) was added to a solution
of KMnO4 (320 mg, 2 mmol) dissolved in 30 mL of H2O and
(m, 1H); IR 3613, 3367 cm-1
.
1,2-Bis[2-(h yd r oxym eth yl)p h en yl]eth a n e (3). Mp 151-
152 °C (acetone); 1H NMR δ 2.05 (br s, 1H), 3.02 (s, 4H), 4.64
(s, 4H), 7.15-7.40 (m, 8H); 13C NMR (DMSO-d6) δ 33.38 (t),
60.87 (t), 125.80 (d), 126.93 (d), 127.53 (d), 128.95 (d), 139.35
(28) Letsinger, R. L.; J amison, J . D.; Hussey, A. S. J . Org. Chem.
1961, 26, 97.
(29) Mayer, F.; English, F. A. Liebigs Ann. Chem. 1918, 417, 60.
(30) Picard, S. T.; Smith, H. E. J . Am. Chem. Soc. 1990, 112, 5741.
(31) Nakai, H.; Konno, M.; Kosuge, S.; Sakuyama, S.; Toda, M.; Arai,
Y.; Obata, T.; Katsube, N.; Miyamoto, T.; Okegawa, T.; Kawasaki, A.
J . Med. Chem. 1988, 31, 84.
(32) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473.
(33) Heinze, A.; Lauterbach, G.; Pritzkow, W.; Schmidt-Renner, W.;
Voerckel, V.; Zewegsuren N. J . Prakt. Chem. 1987, 329, 439.
(34) Davies, A. G.; White, A. M. J . Chem. Soc. 1952, 3300.
(35) Rigaudy, J .; Maumy, M. Bull. Soc. Chim. Fr. 1972, 3936.
(36) Hatanaka, A.; Kajiwara, T.; Ohno, M. Agr. Biol. Chem., 1967,
31, 969.
(s), 139.78 (s); IR (KBr) 3333, 3244 cm-1
. Anal. Calcd for
C16H18O2: C, 79.29; H,7.51. Found: C, 79.11; H, 7.38.
[2-(Hyd r oxym eth yl)p h en yl]p h en ylm eth a n e (4b). Bp
155 °C/1 mmHg (lit.27 bp 147-148 °C/1 mmHg); 1H NMR δ
1.80 (br s, 1H), 4.04 (s, 2H), 4.58 (s, 2H), 7.07-7.30 (m, 8H),
7.33-7.40 (m, 1H); IR 3612, 3459 cm-1
.
(24) Nishio, T. J . Chem. Soc., Perkin Trans. 1 1993, 1113.
(25) Rieche, A.; Schulz, M. Liebigs Ann. Chem. 1962, 653, 32.
(26) Li metal tends to accumulate in the upper layer of commercially
available dispersions; drawing a sample without homogenizing the
dispersion with a spatula can lead to stoichiometric errors.
(27) Bordwell, F. G.; Cutshall, T. W. J . Org. Chem. 1964, 29, 2019.
(37) Vaulx, R. L.; J ones, F. N.; Hauser, C. R. J . Org. Chem. 1964,
29, 1387.
(38) Spangler, R. J .; Kim, J . H. Synthesis 1973, 107.