Chiral 4-Hydroxy-, 4-Halogeno [2.2]paracyclophanes
J . Org. Chem., Vol. 62, No. 11, 1997 3747
temperature was allowed to rise to 10-15 °C, and stirring was
continued for another 30 min. The resulting precipitate was
filtered, washed first with cold water, and then with diethyl
ether, and finally dried under vacuum to obtain 1.4 g of (R)-4
H), 6.30 (m, 2 H), 3.80-2.75 (m, 7 H), 2.60 (ddd, J ) 13, 10.1,
-
1
5.6, 1 H); IR 3027-2943, 1632, 1425, 1108 cm ; MS m/ z (rel
+
intensity) 252 (M , 43), 148 (13), 147 (20), 120 (16), 104 (100),
91 (19), 51 (7). Anal. Calcd for C17
Found: C, 80.72; H, 6.27.
16 2
H O : C, 80.93; H, 6.39.
which was used without purification.
-
(
BF
R)-(-)-4-Acetoxy[2.2]p a r a cyclop h a n e, (R)-5. (R)-4 (A
4
(R)-(+)-4-F lu or o[2.2]p a r a cyclop h a n e, (R)-7. A solution
-
-
-
4
)
) (0.3 g, 0.9 mmol) was added to a mixture of AcOH
O (2.4 mL) at 0 °C. After a rapid evolution
of (R)-4 (A ) BF ) (0.3 g, 0.9 mmol) in xylene (50 mL) was
(
1.8 mL) and Ac
2
gently heated to 40-45 °C until nitrogen no longer evolved.
After standing at room temperature for 12 h, the solvent was
evaporated at reduced pressure and the residue was purified
by chromatography on silica gel (9:1 petroleum ether/diethyl
ether as the eluent). Recrystallization of the product from
of nitrogen, the mixture was kept for 2 h at room temperature,
then diluted with cold water (10 mL), and extracted with
CHCl
3
(3 × 5 mL). The usual workup and purification of the
crude product by chromatography on silica gel (eluent 9:1
1
5
petroleum ether/ethyl acetate) gave (R)-5 (0.12 g, 45%): mp
ethanol gave (R)-7 (0.11 g, 54%): mp 234-236 °C; [lit. mp
20 1
1
4
1
22-123 °C (from hexane) [lit. mp 132.5-134 °C (racemic
233-234 °C (racemic mixture)] [R]
D
) +33.7 (c ) 1.11); H-
2
0
1
mixture)]; [R]
7
D
) -41.2 (c ) 1.02); H-NMR δ 6.88 (dd, J )
NMR δ 7.00-6.88 (m, 1 H), 6.55-6.35 (m, 5 H), 5.90 (dd, J )
11.2, 1.6, 1 H), 3.5-2.6 (m, 8 H); MS m/ z (rel intensity) 226
.8, 1.9, 1 H), 6.50-6.38 (m, 5 H), 5.98 (s, 1 H), 3.2-2.6 (m, 8
+
H), 2,31 (s, 3 H); IR 3020-2870, 1750, 1603, 1375, 1230, 1022,
(M , 13), 122 (19), 104 (100), 78 (14), 51 (6). Anal. Calcd for
-
1
+
9
2
14, 721 cm ; MS m/ z (rel intensity) 266 (M , 14), 224 (14),
16
C H15F: C, 84.92; H, 6.68. Found: C, 85.19; H, 6.76.
-
09 (4), 120 (100), 104 (59), 91 (28), 51 (9), 43 (64). Anal. Calcd
(R)-(-)-4-Br om o[2.2]p a r a cyclop h a n e, (R)-3. (R)-4 (A
-
for C18
H
18
O
2
: C, 81.17; H, 6.81. Found: C, 80.88; H, 6.96.
) BF
4
) (0.3 g, 0.9 mmol) was added to a solution of CuBr‚-
(
R)-(+)-4-Hydr oxy[2.2]par acycloph an e, (R)-1. (R)-5 (0.30
SMe (0.6 g, 2.9 mmol) in 48% aqueous HBr (4 mL) at 0 °C.
2
g, 1.1 mmol) was added to a methanolic solution of KOH (0.5
M, 5 mL) and the mixture stirred for 30 min at room
temperature. Water (50 mL) was added; the product was
extracted with diethyl ether (3 × 25 mL) and worked up as
After the nitrogen evolution ceased, the mixture was kept for
another 30 min at 0 °C and then for 2 h at room temperature.
Water (50 mL) was added, and the mixture was extracted with
CHCl
3
(3 × 25 mL). After the usual workup, chromatography
1
4
above to give (R)-1 (0.23 g, 91%): mp 232-234 °C [lit. mp
on silica gel (petroleum ether as the eluent) gave pure (R)-3
2
23-228 °C (racemic mixture)]; [R]20
D
) +8.4 (c ) 1.22); H-
1
(0.15 g, 58%): mp 157-158 °C from CH
2
Cl
2
[lit. mp 136-
1
12
138 °C (racemic mixture)]; [R]20
) -144.7 (c ) 1.02); H-NMR
NMR δ 6.98 (dd, J ) 7.8, 1.9, 1 H), 6.54 (dd, J ) 7.8, 1.9, 1 H),
D
6
1
3
.50-6.35 (m, 3 H), 6.25 (dd, J ) 7.7, 1.6, 1 H), 5.51 (d, J )
δ 7.16 (dd, J ) 7.8, 1.8, 1 H), 6.6-6.4 (m, 6 H), 3.53-2.73 (m,
8 H); MS m/ z (rel intensity) 288 (15), 126 (15), 184 (10), 182
.6, 1 H), 4.49 (br s, 1 H), 3.40, 2.55 (m, 8 H); IR 3604, 3320,
-
1
030, 2943, 1422, 1219, 750 cm ; MS m/ z (rel intensity) 224
(10), 104 (100), 51 (5). Anal. Calcd for C16
H, 5.26. Found: C, 67.08; H, 4.97.
H15Br: C, 66.91;
+
(M , 31), 120 (100), 104 (43), 91 (26), 51 (5). Anal. Calcd for
C
16
H
16O: C, 85.68; H, 7.19. Found: C, 85.74; H, 7.28.
(R)-(-)-4-Iod o[2.2]p a r a cyclop h a n e, (R)-9. (R)-2 (0.2 g,
(
R)-(+)-5-F or m yl-4-h yd r oxy[2.2]p a r a cyclop h a n e, (R)-
0.9 mmol) was added to a stirred solution of 96% H SO (0.1
2
4
6
. To a solution of the sodium salt of (R)-1, prepared by the
reaction of (R)-1 (11.2 g, 50 mmol) with NaH (55 mmol) in a
:1 mixture (400 mL) of anhydrous diethyl ether/DMF (26 mL),
mL) in water (12 mL). The mixture was purged with nitrogen
and then heated to 85 °C under nitrogen bubbling, while
stirring, until a clear solution resulted. After 25 min, the
solution was cooled to -1 to -3 °C and an aqueous solution of
NaNO2 (0.12 g, 1.7 mmol in 2.5 mL of water) was added
dropwise. The temperature was kept between -5 and -3 °C,
and stirring was continued for another 30 min. A solution of
9
was added chloromethyl methyl ether (5.6 mL, 74 mmol) under
nitrogen while stirring. After 30 min water (100 mL) was
added; the organic phase was separated and worked up as
above. Chromatography of the resulting oil on silica gel
(eluent 9:1 petroleum ether/diethyl ether) allowed us to recover
KI (0.5 g, 3.0 mmol) in H O (2 mL) was added between -1
2
crystalline MOM-protected (R)-1 (12.8 g, 95%). The latter (12
g, 45 mmol) was dissolved in diethyl ether (200 mL) containing
TMEDA (85 mmol), and n-butyllithium (43 mL, 1.6 M in
hexane, 69 mmol) was added at 0 °C under nitrogen while
stirring. The mixture was allowed to react for 1.5 h at 0 °C,
DMF (6.4 mL, 83 mmol) was added, and the reaction was
allowed to proceed for 1 h at room temperature; 5% aq HCl
and -3 °C, and the mixture was allowed to react for 30 min
at 0 °C and then for 2 h at room temperature. After extraction
with CHCl3 (3 × 25 mL), the collected organic phases were
washed first with 10% aq NaHSO and then with brine. The
3
usual workup gave a crude product which was purified by
chromatography on silica gel (petroleum ether as the eluent)
1
6
to isolate pure (R)-9 (0.16 g, 53%): mp 179-181 °C (from CH -
2
1
2
20
(
150 mL) was added, the organic phase was separated and
Cl ) [lit. mp 146.5-148.5 °C (racemic mixture)]; [R]
)
2
D
1
washed with water, and the solvent was evaporated. The
resulting crude oil was dissolved in a 1:1 THF/2-propanol
mixture (100 mL), concd aq HCl (10 mL) was added, and the
clear solution was kept at room temperature for 10 h. After
-186.6 (c ) 0.57); H-NMR δ 7.24 (dd, J ) 7.8, 1.8, 1 H), 6.82
(d, J ) 1.7, 1 H), 6.60-6.38 (m, 5 H), 3.45-2.85 (m, 8 H); MS
+
m/ z (rel intensity) 230 (M - CH C H CH ), 104 (100), 77 (18),
2
6
4
2
51 (6). Anal. Calcd for C H I: C, 57.50; H, 4.52. Found:
1
6
15
neutralization with 5% aq NaHCO
with CH Cl
3
, the mixture was extracted
C, 57.31; H, 4.66.
2
2
(3 × 50 mL) and the solvent was evaporated at
reduced pressure. Chromatography of the crude product on
silica gel (eluent 9:1 petroleum ether/diethyl ether) gave pure
Ack n ow led gm en t. Thanks are due to Ministero
della Pubblica Istruzione (MPI) and Italian National
Reseach Council (CNR) for financial support.
(
R)-6 (5.0 g, 40%): mp 200-203 °C (from hexane-ethanol);
2
0
7
25
[
)
R]
D
) +587 (c ) 0.51 benzene) (lit. mp 201-204 °C; [R]
D
1
+591); H-NMR δ 11.95 (s, 1 H), 9.79 (s, 1 H), 6.92 (dd, J )
J O962142A
7
.8, 1.8, 1 H), 6.64 (d, J ) 7.7, 2 H), 6.41 (dd, J ) 7.9, 1.8, 1
(
15) Takemura, T.; Mori, N. Chem. Lett. 1978, 857.
(
14) Norcross, B. E.; Becker, D.; Cukier, R. I.; Schultz, R. M. J . Org.
(16) Compound 9 was previously prepared, in only a 15% yield, by
metalation of 3 with n-butyllithium and successive reaction with I .
2
1
2
Chem. 1967, 32, 220.