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Org. Synth. 2002, 78, 239
DOI: 10.15227/orgsyn.078.0239
TRIBUTYLSTANNANE (Bu3SnH)-CATALYZED BARTON-McCOMBIE DEOXYGENATION OF ALCOHOLS: 3-DEOXY-1,2:5,6-BIS-O-(1-METHYLETHYLIDENE)-α-D-RIBO-HEXOFURANOSE
[ α-D-ribo-Hexofuranose, 3-deoxy-1,2:5,6-bis-O-(1-methylethylidene)- ]
Submitted by Jordi Tormo and Gregory C. Fu1 .
Checked by Jan W. Thuring and Andrew B. Holmes.
1. Procedure
A. 1,2:5,6-Bis-O-(1-methylethylidene)-O-phenyl carbonothioate-α-D-glucofuranose (1). All glassware is oven-dried. A 250-mL, two-necked, round-bottomed flask is fitted with a magnetic stirring bar and an argon inlet. Under a gentle flow of argon, the flask is charged with 100 mL of anhydrous dichloromethane (CH2Cl2) (Note 1) and 12.6 g (48.2 mmol) of 1,2:5,6-di-O-isopropylidene-D-glucose (Note 2). The flask is immersed in an ice bath, stirring is started, and 7.34 mL (53.1 mmol) of phenyl chlorothionoformate (Note 3) and 4.63 mL (57.9 mmol) of pyridine (Note 4) are added by syringe. After 30 min, the ice bath is removed, and the resulting mixture is stirred at room temperature for 14 hr. Then, in order to destroy the excess phenyl chlorothionoformate , 5 mL of anhydrous methanol (MeOH) (Note 5) is added via syringe, and the mixture is stirred at room temperature for 15 min. The resulting solution is washed with 100 mL of aqueous hydrochloric acid (HCl) (1 N) and 100 mL of brine, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The crude product (20.5 g; yellow oil) is triturated by the addition of hexane (50 mL), scratched with a spatula and stirred for 30 min at 0°C. The cream-colored solid is collected by filtration of the cold suspension and washed with a minimal amount (5-10 mL) of hexane to give 15.2 g of 1. Recrystallization from hexane (50 mL) affords the product as white crystals (13.9 g; 74%). The mother liquors are combined and evaporated to dryness to give a residue that is recrystallized from hexane (10 mL) to give a second crop of 1 (1.50 g; 8%) (Notes 6, 7 and 8).
B. 3-Deoxy-1,2:5,6-bis-O-(1-methylethylidene)-α-D-ribo-hexofuranose (2). All glassware is oven-dried. A 250-mL, two-necked, round-bottomed flask is fitted with a magnetic stirring bar and a reflux condenser with an argon inlet. Under a gentle flow of argon , the flask is charged with 15 mL of anhydrous benzene (Note 9) and 13.0 g (32.7 mmol) of 1 . To this mixture are added via cannula a solution of 0.620 mL (1.21 mmol) of bis(tributyltin) oxide [(Bu3Sn)2O] (Note 10), 0.800 g (4.90 mmol) of 2,2'-azobis(isobutyronitrile) (AIBN) (Note 11), 9.81 g (164 mmol) of poly(methylhydrosiloxane) (PMHS) (Note 12), and 16.4 mL (180 mmol) of 1-butanol (Note 13) in 20 mL of anhydrous benzene . The resulting mixture is heated at reflux for 3 hr, after which time a solution of 0.620 mL (1.21 mmol) of (Bu3Sn)2O and 0.800 g (4.90 mmol) of AIBN in 9 mL of anhydrous benzene is added via cannula. The reaction mixture is heated at reflux for an additional 3 hr. The solution is allowed to cool to room temperature, and then transferred to a 1-L, one-necked, round-bottomed flask. Benzene and excess 1-butanol are removed under water pump vacuum, and the resulting residue is redissolved in 100 mL of THF (Note 14) . To this solution is added SLOWLY (Note 15) 400 mL of aqueous sodium hydroxide (NaOH) (2 N). The resulting mixture is stirred at room temperature for 15 hr. The layers are separated, and the aqueous layer is extracted twice with 100 mL of diethyl ether . The combined organic layers are washed with 100 mL of aqueous HCl (1 N) and 100 mL of brine, dried over anhydrous Na2SO4 , filtered, and concentrated under reduced pressure. The resulting residue is purified by chromatography (Note 16) to give 6.2-6.4 g (76-80%) of 2 as a pale-yellow oil (Notes 17 and 18).
2. Notes
1. Laboratory grade dichloromethane was first distilled and then was further purified and dried by distillation from calcium hydride . The submitters used solvent supplied by EM Science.
2. 1,2:5,6-Di-O-isopropylidene-D-glucose (diacetone-D-glucose; Aldrich Chemical Company, Inc., 98%) was used without purification.
3. Phenyl chlorothionoformate (Aldrich Chemical Company, Inc., 99%) was used without purification.
4. Pyridine (Aldrich Chemical Company, Inc.) was purified by distillation from calcium hydride .
5. Methanol was used as supplied by Merck & Company, Inc. or Mallinckrodt Inc.
6. Both crops were pure as judged by elemental analysis. The combined yield ranged from 15.4-17.3 g (82-90%). The checkers found the recrystallization procedure to be more convenient (albeit in slightly lower yield) than isolation by chromatography. The residue can alternatively be purified by flash column chromatography with 30 g of silica (Merck 9385 Kieselgel 60, 230-400 ASTM) per g of residue, eluting with a gradient of 0 → 50% EtOAc/hexane to afford 18.0 g (94%; the checkers obtained 91% on half scale) of 1 as a colorless solid, mp 108-110°C (Notes 7 and 8).
7. TLC analyses (Rf = 0.47, in EtOAc/hexane 7:3; the submitters observed Rf = 0.49 in EtOAc/hexane 4:1) were performed on 0.25-mm Merck 60 F254 silica gel plates (the submitters used 0.25-mm silica gel 60 plates supplied by EM Reagents) that were stained with a solution of phosphomolybdic acid in 95% ethanol .
8. Compound 1 ([α]D 18 −44.9° (CHCl3, c 0.6), lit.2 [α]D 18 −43° (CHCl3)) has the following spectral data: 1H NMR (250 MHz, CDCl3) δ: 1.35 (s, 3 H), 1.38 (s, 3 H), 1.45 (s, 3 H), 1.56 (s, 3 H), 4.04-4.15 (m, 2 H), 4.31 (m, 2 H), 4.78 (d, 1 H, J = 4), 5.65 (d, 1 H, J = 2), 5.97 (d, 1 H, J = 4), 7.12 (d, 2 H, J = 8), 7.31 (t, 1 H, J = 8), 7.44 (t, 2 H, J = 7) ; 13C NMR (62.5 MHz, CDCl3) δ: 25.7, 26.7, 27.1, 27.3, 67.5, 72.7, 80.1, 83.3, 85.5, 105.4, 109.9, 112.9, 122.1, 127.2, 130.0, 153.7, 194.1 ; IR (KBr pellet) cm−1: 2987, 1164, 1082, 948, 917 . HRMS (FAB) m/z Calcd for C19H24O7S: 396.1243. Found: 396.1243 . Anal. Calcd for C19H24O7S: C, 57.6; H, 6.1. Found: C, 57.5; H, 6.1.
9. Benzene (Aldrich Chemical Company, Inc. or EM Science) was purified by distillation from sodium benzophenone ketyl . CAUTION: Benzene is harmful as a vapor and by skin absorption, and it should always be handled in a well-ventilated hood. Chronic exposure may cause fatal blood disease.
10. (Bu3Sn)2O (Aldrich Chemical Company, Inc. or Gelest) was distilled [bp 140-142°C (0.1 mm)] before its use.
11. 2,2'-Azobis(isobutyronitrile) (98%; Aldrich Chemical Company, Inc.) was used without purification.
12. Poly(methylhydrosiloxane) (Fluka Chemical, Corp.) was degassed overnight under full vacuum at 25°C (≈0.1 mm) prior to use.
13. Anhydrous 1-butanol (99.8%; Aldrich Chemical Company, Inc.) was used without purification.
14. Tetrahydrofuran (Merck or EM Science) was used without purification.
15. The addition of base should be slow, as the aqueous NaOH (2 N) cleaves the siloxanes and ionizes the phenol that is generated in the reaction. The reaction is vigorous.
16. Flash column chromatography is performed with 30 g of silica (Merck 9385 Kieselgel 60, 230-400 ASTM) per gram of residue, eluting with a gradient of 0 → 50% EtOAc/hexane .
17. TLC analyses (Rf = 0.32, in hexane:EtOAc 7:3; the submitters observed Rf = 0.33 in hexane :EtOAc 4:1) were performed on 0.25-mm Merck 60 F254 silica gel plates (the submitters used 0.25-mm silica gel 60 plates supplied by EM Reagents) that were stained with a solution of phosphomolybdic acid in 95% ethanol .
18. Compound 2 ([α]D 20 −8.1° (CHCl3, c 2.4), lit.3 [α]D 18 −8.5° (CHCl3, c 1.5)) has the following spectral data: 1H NMR (250 MHz, CDCl3) δ: 1.32 (s, 3 H), 1.36 (s, 3 H), 1.43 (s, 3 H), 1.51 (s, 3 H), 1.77 (m, 1 H), 2.19 (dd, 1 H, J = 4, 14), 3.82 (m, 1 H), 4.12 (m, 3 H), 4.75 (t, 1 H, J = 4), 5.81 (d, 1 H, J = 4) ; 13C NMR (62.5 MHz, CDCl3) δ: 25.5, 26.5, 26.8, 27.1, 35.6, 67.6, 77.2, 79.0, 80.8, 106.0, 110.0, 111.7 ; IR (neat) cm−1: 1064, 957, 941 . HRMS (FAB) m/z Calcd for C12H20O5: 244.1311. Found: 244.1312 . Anal. Calcd for C12H20O5: C, 59.0; H, 8.2. Found: C, 59.0; H, 8.3.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The Barton-McCombie protocol for the deoxygenation of alcohols 4,5 is an extremely useful method that has found widespread application in synthetic organic chemistry.6 This radical-mediated process typically employs 1.5-3 equiv of Bu3SnH7 as the reducing agent. Because some tributyltin-containing compounds are toxic,8 and product isolation from large quantities of organotin residues can be difficult,9 the development of alternative reducing agents to Bu3SnH has been an active area of investigation. Indeed, it has been established that silicon hydrides10 and dialkyl phosphites11 can serve as substitutes for Bu3SnH in many instances. Despite these facts, Bu3SnH continues to be the reagent most commonly used for effecting this reduction.12
Given this, the development of a reaction variant in which Bu3SnH is employed as a catalyst, while a non-toxic second metal hydride serves as the stoichiometric reductant, has significant practical advantages. The procedure reported here uses 15 mol% Bu3SnH [generated in situ from (Bu3Sn)2O13] in conjunction with poly(methylhydrosiloxane) (PMHS) 14,15 (for the proposed catalytic cycle, see the figure below).16
Additional applications of this method to the deoxygenation of secondary alcohols are provided in the Table.
Table
References and Notes
  1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
  2. Shasha, B. S.; Doane, W. M; Russell, C. R.; Rist, C. E. Carbohyd. Res. 1968, 6, 34-42.
  3. Sano, H.; Takeda, T.; Migita, T. Synthesis 1988, 402-403.
  4. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574-1585.
  5. The use of phenyl thionocarbonate esters was pioneered by Robins: (a) Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc. 1981, 103, 932-933; (b) Robins, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc. 1983, 105, 4059-4065.
  6. (a) Hartwig, W. Tetrahedron 1983, 39, 2609-2645; (b) McCombie, S. W. In "Comprehensive Organic Synthesis"; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 8, Chapter 4.2; (c) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413-1432; (d) Pereyre, M.; Quintard, J.-P.; Rahm, A. "Tin in Organic Synthesis"; Butterworths: Boston, 1987; Chapter 5.
  7. For reviews of the chemistry of Bu3SnH, see: (a) Neumann, W. P. Synthesis 1987, 665-683; (b) RajanBabu, T. V. In "Encyclopedia of Reagents for Organic Synthesis"; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, pp. 5016-5023.
  8. (a) De Mora, S. J. "Tributyltin: Case Study of an Environmental Contaminant"; Cambridge University Press: Cambridge, UK, 1996; (b) Boyer, I. J. Toxicology 1989, 55, 253-298.
  9. For a succinct discussion, see: Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200-7201.
  10. For an overview of the use of silanes as reducing agents in the Barton-McCombie deoxygenation, see: Chatgilialoglu, C.; Ferreri, C. Res. Chem. Intermed. 1993, 19, 755-775.
  11. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. J. Org. Chem. 1993, 58, 6838-6842.
  12. This statement is based on a search of the Beilstein Crossfire database.
  13. Prices from Aldrich Chemical Company, Inc., per mole of tin are as follows: (Bu3Sn)2O: $38; Bu3SnH: $250. Unlike Bu3SnH, (Bu3Sn)2O is not sensitive to light, O2, or adventitious impurities.
  14. Prices from Aldrich Chemical Company, Inc., per mole of hydride are as follows: PMHS: $6; Bu3SnH: $250.
  15. D50 of PMHS: 80 g/kg: Klyaschitskaya, A. L.; Krasovskii, G. N.; Fridlyand, S. A. Gig. Sanit. 1970, 35, 28-31; Chem. Abs. 1970, 72, 124864r.
  16. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949-6950. The Bu3SnH-catalyzed deoxygenation of dithiocarbonates requires more vigorous reaction conditions.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Tributylstannane :
Stannane, tributyl- (8,9); (688-73-3)

3-Deoxy-1,2:5,6-bis-O-(methylethylidene)-α-D-ribo-hexofuranose:
D-ribo-Hexofuranose, 3-deoxy-1,2:5,6-bis-O-isopropylidene, α- (8);
α-D-ribo-Hexofuranose, 3-deoxy-1,2:5,6-bis-O-(1-methylethylidene)- (9); (4613-62-1)

1,2:5,6-Bis-O-(1-methylethylidene)-, O-phenyl carbonothioate-α-D-glucofuranose:
Glucofuranose, 1,2:5,6-di-O-isopropylidene, O-phenyl thiocarbonate, α-D- (8);
α-D-Glucofuranose, 1,2:5,6-bis-O-(1-methylethylidene)-, O-phenyl thiocarbonate (9); (19189-62-9)

1,2:5,6-Di-O-isopropylidene-D-glucose:
Glucofuranose 1,2:5,6-di-O-isopropylidene-α-D- (8);
α-D-Glucofuranose, 1,2:5,6-bis-O-(1-methylethylidene)- (9); (582-52-5)

Phenyl chlorothionoformate:
Formic acid, chlorothio-, O-phenyl ester (8);
Carbonochloridothioic acid, O-phenyl ester (9); (1005-56-7)

Pyridine (8,9); (110-86-1)

Benzene: CANCER SUSPECT AGENT (8,9); (71-43-2)

Bis(tributyltin) oxide:
Distannoxane, hexabutyl- (8,9); (56-35-9)

Azobisisobutyronitrile:
Propionitrile, 2,2'-azobis[2-methyl- (8);
Propanenitrile, 2,2'-azobis[2-methyl- (9); (78-67-1)

Poly(methylhydrosiloxane): PMHS:
Poly[oxy(methylsilylene)] (8,9); (9004-73-3)

1-Butanol:
Butyl alcohol (8);
1-Butanol (9); (71-36-3)

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