replacement of environmentally unacceptable CH2Cl2 with
PhMe in both bis O-triflation [(R)-8 f (R)-9] and N-
deallylation [(R)-12 f (R)-1]; (2) replacement of easy-to-
ignite Et2O with safer tert-BuOMe in Kumada’s cross-
coupling [(R)-9 f (R)-10] without affecting the stereochemical
integrity of (R)-10; (3) no application of cryogenic conditions
to the bis O-triflation [(R)-8 f (R)-9]; (4) no resort to column
chromatography throughout the overall processes; (5) simple
isolation of the final product, (R)-1, as its hydrogen oxalate
salt, (R)-13. With all these improvements in combination,
enantiomerically pure (R)-13 was now obtained in 41%
overall yield from (R)-1,1′-bi-2-naphthol 8 in five steps.
in MTBE (7.0 mL) such that gentle reflux was maintained
throughout the addition. The mixture was allowed to cool
to 30 °C where MTBE (5.0 mL) and NiCl2(dppp) (250 mg,
0.46 mmol) were added in sequence. A solution of crude
(R)-9 (5.00 g, 9.08 mmol) in MTBE (20 mL) was added
dropwise, and the mixture was stirred and heated under reflux
(at 55 °C) for 30 min. Consumption of (R)-9 was confirmed
by TLC [AcOEt/n-hexane (1:4); Rf 0.46 for (R)-9, 0.79 for
(R)-10]. The mixture was allowed to cool to room temper-
ature (20-25 °C). PhMe (30 mL) was added, and the mixture
was poured into ice-chilled water (50 mL). To the mixture
was added 35% aqueous HCl (5.0 mL). The layers were
separated, and the organic layer was washed with H2O (30
mL × 2) and saturated aqueous NaCl solution (30 mL ×
1). The organic solution was dried (MgSO4) and concentrated
in vacuo [40-50 °C (bath temperature), 50-60 mmHg]. The
solid residue (2.60 g) was mounted on a short pad of silica
gel (Merck Kieselgel 60, 7.8 g). Elution with AcOEt/n-
hexane (1:4; 200 mL) gave (R)-10 (2.46 g, 96.1%) as white
crystals: 99.6% ee [HPLC: column, Chiralpak OD (Daicel;
4.6 mmφ × 250 mm), 25 °C; eluent, n-hexane/i-PrOH (99.8:
0.2), 0.5 mL/min; detection, UV at 240 nm; injected was 1
µL of a solution of the crystals (1.0 mg) in MTBE (1.0 mL);
tR 9.5 min for (S)-10 (0.2%), 12.3 min for (R)-10 (99.8%)].
Experimental Section
Melting points were measured on an Electrothermal
1
1A8104 melting point apparatus and are uncorrected. H
NMR spectra were recorded at 400 MHz on a Varian
UNITY-400 spectrometer with tetramethylsilane as an
internal standard. FT-IR spectra were recorded on a Nicolet
Avatar 360 FT-IR spectrometer. Mass spectra were recorded
on a Hitachi M-8000 mass spectrometer (ESI). Elemental
analyses were performed on an Elementar vario EL analyzer.
Optical rotations were measured on a Horiba SEPA-200
polarimeter. Thin-layer chromatography (TLC) was per-
formed on Merck Kieselgel 60 plates (0.25 mm thick, art
1.057 14).
Mp 77-79 °C; [R]20D -42.6° (c 0.20, CHCl3) {lit.:15b [R]20
D
-35.6° (c 1.0, CHCl3) for (R)-10 of 94% ee}; IR νmax(KBr)
1
3045, 2910, 1503, 1421, 1219, 815, 744 cm-1; H NMR δ
(R)-1,1′-Bi-2-naphthol Bis(trifluoromethanesulfonate)
9. Under an atmosphere of nitrogen, trifluoromethanesulfonic
anhydride (49.3 g, 174 mmol) was added dropwise to a
stirred and ice-cooled solution of (R)-1,1′-bi-2-naphthol 8
(Kankyo Kagaku Center Co., Ltd.; 99.8% ee; 20.0 g, 69
mmol) and pyridine (22.1 g, 279 mmol) in PhMe (140 mL)
over 40 min at 2-9 °C (internal temperature). After addition
was complete, the cooling bath was removed and the mixture
was stirred at room temperature (20-25 °C) for 3 h.
Consumption of (R)-8 was confirmed by TLC [AcOEt/n-
hexane (1:4); Rf 0.16 for (R)-8, 0.46 for (R)-9]. PhMe (100
mL), H2O (100 mL), and 35% aqueous HCl (30 mL) were
added in sequence at room temperature (20-25 °C). The
layers were separated, and the PhMe layer was washed with
H2O (100 mL × 2) and saturated aqueous NaCl solution
(100 mL × 1). The PhMe solution was dried (MgSO4) and
concentrated in vacuo [40-50 °C (bath temperature), 50-
60 mmHg] to give crude (R)-9 (36.4 g, quantitative) as an
(CDCl3) 7.89 (2H, d, J ) 8.4 Hz), 7.87 (2H, d, J ) 8.4 Hz),
7.50 (2H, d, J ) 8.4 Hz), 7.39 (2H, ddd, J ) 1.2 Hz, 6.8
Hz, 8.4 Hz), 7.20 (2H, ddd, J ) 1.2 Hz, 6.8 Hz, 8.4 Hz),
7.04 (2H, dd, J ) 1.2 Hz, 8.4 Hz), 2.03 (6H, s).
(R)-2,2′-Bis(bromomethyl)-1,1′-binaphthyl 11. To a
suspension of (R)-10 (24.4 g, 86.4 mmol) in cyclohexane
(170 mL) was added N-bromosuccinimide (NBS, 33.8 g, 190
mmol) followed by 2,2′-azobisisobutyronitrile (AIBN, 0.70
g, 4.26 mmol) at room temperature (20-25 °C). The mixture
was stirred and heated at reflux for 2 h, during which the
progress of the reaction was monitored by TLC [AcOEt/n-
hexane (1:10); Rf 0.60 for (R)-10, 0.49 for (R)-11]. On
consumption of (R)-10, the mixture was allowed to cool to
room temperature (20-25 °C), and AcOEt (56 mL) was
added with stirring. The mixture was poured into H2O (350
mL). The biphasic mixture was stirred for not longer than
an hour by which solids had ceased to precipitate. Crystalline
solids were collected by filtration and air-dried overnight
(8-12 h) to give (R)-11 (20.6 g, 54.3%): mp 178-181 °C
(lit.:18 171-174 °C); [R]20D +160.5° (c 0.11, benzene) [lit.:
18 [R]20D +148° (c 1.7 benzene)]; IR νmax (KBr) 3045, 1507,
off-white solid: mp 64-74 °C (lit.:17 mp 82-85 °C); [R]20
D
-151° (c 0.29, CHCl3) {lit.:17 [R]23D -146.0° (c 1, CHCl3)};
IR νmax (KBr) 1507, 1421, 1215, 1136, 961, 938, 830 cm-1;
1H NMR δ (CDCl3) 8.14 (2H, d, J ) 8.8 Hz), 8.01 (2H, d,
J ) 8.0 Hz), 7.62 (2H, d, J ) 8.0 Hz), 7.59 (2H, ddd, J )
1.2 Hz, 6.8 Hz, 8.4 Hz), 7.41 (2H, ddd, J ) 1.2 Hz, 6.8 Hz,
8.4 Hz), 7.27-7.24 (2H, m). This was employed in the next
step without further purification.
(R)-2,2′-Dimethyl-1,1′-binaphthyl 10. Under an atmo-
sphere of nitrogen, a solution of MeI (3.90 g, 27.5 mmol) in
tert-butyl methyl ether (MTBE, 4.0 mL) was added dropwise
to a stirred suspension of Mg turnings (660 mg, 27.1 mmol)
1
1432, 1211, 826, 759 cm-1; H NMR δ (CDCl3) 8.02 (2H,
d, J ) 8.8 Hz), 7.93 (2H, d, J ) 8.0 Hz), 7.75 (2H, d, J )
8.4 Hz), 7.49 (2H, ddd, J ) 1.2 Hz, 6.8 Hz, 8.0 Hz), 7.27
(2H, ddd, J ) 1.2 Hz, 6.8 Hz, 8.0 Hz), 7.07 (2H, dd, J )
0.8 Hz, 8.8 Hz), 4.26 (4H, s).
(R)-3,5-Dihydro-4-(2-propenyl)dinaphth[2,1-c:1′2′-e]-
azepine 12. Under an atmosphere of nitrogen, allylamine
(2.20 g, 38.5 mmol) was added to a stirred solution of (R)-
(17) The mp and [R]D values of (R)-9 recorded in the Aldrich catalog are cited
(18) Harris, J. M.; McDonald, R.; Vederas, J. C. J. Chem. Soc., Perkin Trans. 1
1996, 2669-2674.
as authentic ones.
Vol. 7, No. 5, 2003 / Organic Process Research & Development
•
647