Organic Syntheses, CV 7, 139
DEOXYGENATION OF SECONDARY ALCOHOLS: 3-DEOXY-1,2:5,6-DI-O-ISOPROPYLIDENE-α-d-ribo-HEXOFURANOSE
Submitted by S. Iacono and James R. Rasmussen
1.
Checked by Peter J. Card and Bruce E. Smart.
1. Procedure
A.
1,2:5,6-Di-O-isopropylidene-3-O-(S-methyldithiocarbonate)-α-D-glucofuranose. A
1-L, three-necked, round-bottomed flask equipped with a
magnetic stirring bar,
nitrogen-inlet adapter,
pressure-equalizing addition funnel, and stopper is charged with
26.0 g (0.10 mol) of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose,
25 mg of imidazole (Note
1), and
400 mL of anhydrous tetrahydrofuran (Note
2). The reaction vessel is flushed with
nitrogen and a nitrogen atmosphere is maintained during the ensuing steps. Over a 5-min period,
7.2 g (0.150 mol) of a 50% sodium hydride dispersion (Note
3) is added. Vigorous gas evolution is observed. After the reaction mixture is stirred for 20 min,
22.8 g (0.30 mol) of carbon disulfide is added all at once. Stirring is continued for 30 min, after which time
25.3 g (0.177 mol) of iodomethane is added in a single portion. The reaction mixture is stirred for another 15 min, and
5.0 mL of glacial acetic acid is added dropwise to destroy excess
sodium hydride. The solution is filtered (Note
4) and the filtrate is concentrated on a
rotary evaporator. The semisolid residue is extracted with three
100-mL portions of ether, and the combined
ether extracts are washed with two
100-mL portions of saturated sodium bicarbonate solution and two 100-mL portions of water. The ethereal solution is dried over anhydrous
magnesium sulfate, the drying agent is removed by filtration, and the solvent is removed by rotary evaporation. The product is dried further at 0.05 mm overnight. The resulting orange syrup is distilled (Kugelrohr) to give
32.2–33.0 g (
92–94%) of product, bp
153–160°C (0.5–1.0 mm) (Note
5).
B.
3-Deoxy-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranose. A dry, 1-L, round-bottomed flask is equipped with a magnetic stirring bar and a
reflux condenser to which a nitrogen inlet is attached. The apparatus is charged with
500 mL of anhydrous toluene (Note
6),
24.7 g (0.085 mol) of tributyltin hydride (Note
7) and
19.25 g (0.055 mol) of 1,2:5,6-di-O-isopropylidene-3-O-(S-methyldithiocarbonate)-α-D-glucofuranose. The reaction mixture is heated at reflux under a nitrogen atmosphere until TLC analysis indicates the disappearance of starting materials (4–7 hr) (Note
8). During this time the reaction solution changes from deep yellow to nearly colorless. The
toluene is removed on a rotary evaporator to yield a thick, oily residue that is partitioned between
250-mL portions of petroleum ether and
acetonitrile. The
acetonitrile layer is separated and washed with three
100-mL portions of petroleum ether and is then concentrated on a rotary evaporator. The residual yellow oil is taken up in hexane-ethyl acetate (10 : 1) and filtered through a
pad of silica gel (Note
9). The filtrate is concentrated and the residual oil is distilled to give
10.0 g (
75%) of product as a colorless syrup, bp
72–73°C (0.2 mm);
nD25 1.4474 (Note
10).
2. Notes
3.
Sodium hydride, a 50% dispersion in mineral oil, was purchased from Alfa Products, Morton Thiokol, Inc. It is not necessary to remove the mineral oil before conducting the reaction.
5. The submitters report pure product with bp
135–136°C (0.07 mm). The material obtained by the checkers is pure by NMR analysis. It shows
1H NMR (CDCl
3) δ: 1.35 (s, 6 H), 1.42 (s, 3 H), 1.55 (s, 3 H), 2.60 (s, 3 H), 3.90–4.40 (m, 4 H), 4.68 (d, 1 H), 5.85–6.0 (m, 2 H).
6.
Reagent-grade toluene was dried by distilling the toluene–water azeotrope and then cooling the remaining liquid under an atmosphere of nitrogen.
8. An E.
Merck Silica Gel 60 F-254 0.25-mm plate was used for the TLC analysis.
9. Silica Woelm TSC, obtained from Woelm Pharma, was used.
10. The product is pure by NMR and TLC analyses and shows
1H NMR (CDCl
3) δ: 1.27 (s, 3 H), 1.31 (s, 3 H), 1.38 (s, 3 H), 1.46 (s, 3 H), 1.60–1.90 (m, 1 H), 2.05–2.30 (dd, 1 H), 3.65–4.25 (m, 4 H), 4.71 (t, 1 H), 5.77 (d, 1 H).
3. Discussion
This procedure illustrates a simple, general method for the deoxygenation of secondary hydroxyl groups. It is particularly useful for reducing hindered alcohols. The method was first described by Barton and McCombie,
3 who have reviewed a number of other examples.
4
The
tributyltin hydride reduction usually proceeds without complications. The most common byproduct is starting alcohol, which is postulated to be derived from a mixed
thioacetal.
3 Use of the
phenyl thionocarbonate ester has been reported to minimize this side reaction in cases where it is a problem.
6
3-Deoxy-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranose has been prepared by a variety of other methods, the most widely used of which is the
Raney nickel reduction of the
3-S-[(methylthio)carbonyl]-3-thioglucofuranose derivative.
8
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