Checked by Michelle A. Laci and Robert K. Boeckman, Jr..
1. Procedure
C.
3-[(1S)-1,2-Dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine. A 2-L, three-necked, round-bottomed flask is equipped with a
mechanical stirrer, a
thermometer, and a rubber septum. The flask is charged with
dihydroquinidine 9-O-(9'-phenanthryl) ether (Note 1) and (Note 11), [0.75 g, (1.5 mmol, 1 mol%, 0.0057 M in the organic phase)],
148.2 g (0.45 mol) of potassium ferricyanide (Note
1),
62.2 g (0.45 mol) of potassium carbonate (Note
1),
264 mL of tert-butyl alcohol (tert-BuOH) (Note
1), and 264 mL of distilled water. Mechanical stirring is initiated,
0.11 g (0.3 mmol, 0.2 mol%) of potassium osmate (VI) dihydrate, which generates a 0.0011 M solution of OsO
4 in the organic phase (Note
1), is added, and the mixture is stirred at room temperature for 0.5 hr, resulting in an orange suspension. The flask is immersed in a 0°C cooling bath, and the mixture stirred for 1 hr (Note
12). Over a period of 24 hr at 0°C,
26.25 g (0.16 mol) of 3-vinyl-1,5-dihydro-3H-2,4-benzodioxepine is added dropwise via syringe (Note
13), and the reaction mixture is stirred an additional 24 hr at 0°C (Note
14). After the required time period has elapsed,
30.25 g (0.24 mol) of solid sodium sulfite (Na2SO3) is added in portions, the reaction mixture is stirred for an additional 1 hr at room temperature, poured into a
3-L beaker, and allowed to stand for another 1 hr at room temperature (Note
1). After the organic phase is decanted, the aqueous phase is diluted with 300 mL of water to dissolve the salts, and poured into a 2-L separatory funnel using
90 mL of dichloromethane (CH2Cl2) to rinse the flask and beaker. The aqueous phase is extracted three times with
150 mL of CH2Cl2. The organic extracts are combined with the decanted organic phase, dried over
Na2SO4, filtered, and concentrated, under reduced pressure, to afford
33.1 g (
104%) of crude product, as a pale yellow liquid (Note
15) that crystallizes rapidly. The ee of the crude
3-[(1S)-1,2-dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine is determined by HPLC analysis of the derived bis-Mosher ester to be 84% (Note
16).
A
2-L Erlenmeyer flask is charged with
33.1 g of the crude protected diol which is dissolved in
600 mL of hot ethyl acetate (EtOAc), and the solution is allowed to stand at room temperature for 3 hr and at 0°C to −5°C for 24 hr (Note
17). The resulting white precipitate is collected by suction filtration through a
10-cm Büchner funnel (Note
18), and the mother liquor is concentrated under reduced pressure to afford
21.15 g of a pale yellow liquid that slowly crystallizes (Note
19). The residual liquid is placed in a
500-mL Erlenmeyer flask, dissolved in
150 mL of hot toluene (Note
20), and allowed to stand for 24 hr at 0°C to −5°C. The slightly yellow precipitate is collected by suction filtration through a 10-cm Büchner funnel and dried under reduced pressure to give
16.0–17.4 g (
50–55%) of
3-[(1S)-1,2-dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine, mp
73–75°C,
[α]D23 −12.4° (CHCl
3,
c 2.62) (Note
21). The ee of the product is determined by HPLC analysis of the derived bis-Mosher ester to be 97% (Note
16).
The mother liquor is then concentrated to afford
2.4 g of a brown yellow liquid (Note
22). Flash chromatography of this material on
30 g of SiO2 with elution by
EtOAc then by EtOAc:MeOH (5:1 v/v) affords
0.63 g (
2%) of
3-[(1S)-1,2-dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine and
0.69 g (
92% recovery) of
dihydroquinidine 9-O-(9'-phenanthryl) ether.
2. Notes
1. This reagent was purchased from Aldrich Chemical Company, Inc., and used without further purification.
2.
Anhydrous ether was purchased from J. T. Baker Chemical Company and used as received.
3.
Tetrahydrofuran was purchased from J. T. Baker Chemical Company and dried and deoxygenated prior to use by distillation from
sodium-benzophenone ketyl under
argon.
4. During the initial stages of the addition of water, care must be exercised to control the vigorous exothermic reaction by use of efficient cooling and agitation along with careful regulation of the rate of addition. This procedure must be conducted in an efficient fume hood since a considerable volume of
hydrogen gas is produced that must be vented.
5. Since the solids have a tendency to occlude significant amounts of the diol, efficient washing of the solids is essential to obtain good yields. Warm solvent can be employed to assist in removal of the product.
6.
1,2-Benzenedimethanol (lit.
3 mp
63–65°C) has the following spectral characteristics:
1H NMR (300 MHz, CDCl
3) δ: 3.97 (s, 2 H), 4.61 (s, 4 H), 7.30 (s, 4 H);
13C NMR (75 MHz, CDCl
3) δ: 63.8, 128.5, 129.6, 139.3; IR (CHCl
3) cm
−1: 3279, 2890, 1454, 1214, 1182, 1110, 1036, 1005, 758.
7. A freshly opened bottle of
reagent grade 1,2-dimethoxyethane (Aldrich Chemical Company, Inc.) was used without further purification.
9. Slightly impure forerun, 6–9 g, was separated from the main fraction. After the distillation was stopped, approximately 6–9 g of residue remained.
10. The spectroscopic data and elemental analysis of the product are as follows:
1H NMR (300 MHz, CDCl
3) δ: 4.91 (q, 4 H, J = 14.2), 5.33–5.38 (m, 2 H), 5.53 (dt, 1 H, J = 17.4, 1.4), 5.90–5.99 (m, 1 H), 7.10–7.25 (m, 4 H);
13C NMR (75 MHz, CDCl
3) δ: 70.0, 104.2, 118.4, 127.0, 127.2, 134.7, 138.8; IR (neat) cm
−1: 3068, 3024, 2950, 2860, 1769, 1725, 1497, 1445, 1412, 1376, 1353, 1291, 1268, 1221, 1210, 1150, 1123, 1094, 1046, 1032, 944, 932, 749; m/z Calcd. for Cs
+-C
11H
12O
2: 308.9892; Found 308.9892; Anal. Calcd for C
11H
12O
2: C, 74.98; H, 6.86; O, 18.16. Found: C, 75.12; H, 6.84; O, 18.26.
12. Upon cooling, the mixture becomes a viscous suspension, and vigorous stirring is required. At temperatures below −5°C, the reaction mixture starts to freeze, thereby precluding efficient mixing.
13. Neat
3-vinyl-1,5-dihydro-3H-2,4-benzodioxepine was added by syringe drive (Syringe Infusion Pump 22, Harvard Apparatus, South Natick, MA) using a gas-tight syringe. If the material has crystallized, it is liquified by gentle warming (

30°C) and
2 mL of t-BuOH-H2O is added before placing the material in the syringe. The tip of the syringe needle is 15 cm above the reaction surface to prevent freezing of the liquid which occurs around 5°C. Careful temperature control is required to prevent the mixture from freezing during the slow addition. Without slow addition, the ee of the product drops to 67%. The ee also deteriorates if the mixture is allowed to freeze during addition, permitting unreacted olefin to accumulate prior to warming enough to achieve efficient stirring.
14. Reaction progress was monitored by TLC on
silica gel (
5:1 EtOAc:MeOH v/v). As the reaction neared completion, the color of the reaction mixture turned yellow.
15. The oil contained 5–10%
t-BuOH by weight.
3-[(1R)-1,2-Dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine was produced with 84% ee when
dihydroquinine-9-O-(9'-phenanthryl) ether (Aldrich, Cat. No. 38197-7: Hydroquinine 9-phenanthryl ether) (Note
1) was used instead of
dihydroquinidine 9-O-(9'-phenanthryl) ether.
5
16. The ee was determined by HPLC analysis (Chemcosorb 3Si, Chemco, Japan) of the corresponding bis-Mosher
6 ester eluted with
5% EtOAc in hexane (2 mL/min, (R)-diol: t
R = 14.8 min, (S)-diol: t
R = 18.2 min). The checkers employed a
25 × 10-mm Prep Nova-Pak HR Silica Column (particle size 6 mm, 60 Å) with UV detection at 220 nm and elution by
10% diethyl ether/hexane at 12 mL per min flow rate (R-diol: t
R = 12.6 min and S-diol: t
R = 15.1 min).
17.
Ethyl acetate is preferable to aromatic hydrocarbon solvents such as
benzene or
toluene because of the high solubility of the diol in
EtOAc; this results in higher recovery of the enantomerically enriched diol from the mother liquor.
18. The white precipitate was dried under reduced pressure to afford
8.7–11.1 g (
28–35%) of
3-[(1S)-1,2-dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine (55–60% ee).
19. The ee of this crude mixture before recrystallization was 97%.
20. Aromatic hydrocarbon solvents such as
toluene or
benzene are preferable to several other solvents such as
EtOAc or
ethanol because of efficient recovery of the diol and better separation of the diol from the ligand.
21. The melting point of the racemic diol was
110–113°C. The spectral data and elemental analysis of the diol are as follows:
1H NMR (300 MHz, CDCl
3) δ: 2.13 (t, 1 H, J = 6.4), 2.57 (d, 1 H, J = 4.2), 3.73 (m, 1 H), 3.80 (dd, 2 H, J = 6.4, 4.2), 4.93–5.01 (m, 5 H), 7.20–7 30 (m, 4 H);
13C NMR (75 MHz, CDCl
3) δ: 62.42, 72.17, 72.86, 73.23, 108.20, 127.73, 127.79, 138.89, 138.93; IR (CHCl
3) cm
−1: 3575, 3018, 2966, 2892, 2855, 1456, 1446, 1375, 1294, 1265, 1138, 1103, 1083, 1048; m/z Calcd. for Na
+-C
11H
14O
4: 233.0790; Found 233.0970; Anal. Calcd for C
11H
14O
4: C, 62.85; H, 6.71; Found: C, 62.78; H, 6.57.
22. The oil contained 10–30%
toluene by weight.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
brine
SiO2
3-[(1S)-1,2-Dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine
potassium osmate
dihydroquinidine 9-O-(9'-phenanthryl) ether
ethyl acetate (EtOAc)
sodium-benzophenone ketyl
dihydroquinidine-9-O-(4'-methyl-2'-quinolyl) ether
t-BuOH-H2O
t-BuOH
3-[(1R)-1,2-Dihydroxyethyl)]-1,5-dihydro-3H-2,4-benzodioxepine
dihydroquinine-9-O-(9'-phenanthryl) ether
2,3-O-isopropylidene-, 2,3-O-cyclohexylidene-, or 2,3-di-O-acylated glyceraldehyde
ethanol (64-17-5)
potassium carbonate (584-08-7)
Benzene (71-43-2)
ethyl acetate,
EtOAc (141-78-6)
MeOH (67-56-1)
ether,
diethyl ether (60-29-7)
hydrogen (1333-74-0)
sodium sulfite (7757-83-7)
sodium hydroxide (1310-73-2)
Acrolein (107-02-8)
sodium bicarbonate (144-55-8)
sodium sulfate,
Na2SO4 (7757-82-6)
toluene (108-88-3)
dichloromethane,
CH2Cl2 (75-09-2)
Acrolein acetal
potassium ferricyanide (13746-66-2)
glyceraldehyde (56-82-6)
Tetrahydrofuran (109-99-9)
lithium aluminum hydride (16853-85-3)
hexane (110-54-3)
diethyl phthalate (84-66-2)
tert-butyl alcohol (75-65-0)
1,2-dimethoxyethane (110-71-4)
argon (7440-37-1)
osmium
trimethyl orthoformate (149-73-5)
glycidol (556-52-5)
p-toluenesulfonic acid monohydrate (6192-52-5)
3-[(1S)-1,2-Dihydroxyethyl]-1,5-dihydro-3H-2,4-benzodioxepine,
1,2-Ethanediol, 1-(1,5-dihydro-2,4-benzodioxepin-3-yl)-, (S)- (142235-22-1)
1,2-Benzenedimethanol (612-14-6)
3-Vinyl-1,5-dihydro-3H-2,4-benzodioxepine (142169-23-1)
3-Methoxy-1,5-dihydro-3H-2,4-benzodioxepine (67461-24-9)
dihydroquinidine 4-chlorobenzoate,
Hydroquinidine 4-chlorobenzoate
Hydroquinine 9-phenanthryl ether
3-(1,2-dihydroxyethyl)-1,5-dihydro-3H,2,4-benzodioxepine,
3-(1,2-dihydroxyethyl)-1,5-dihydro-3H-2,4-benzodioxepine
phenanthryl ether
Hydroquinidine 9-phenanthryl ether
Hydroquinidine 4-methyl-2-quinolyl ether
potassium osmate (VI) dihydrate (19718-36-3)
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