Organic Syntheses Procedure

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Org. Synth. 1987, 65, 243

DOI: 10.15227/orgsyn.065.0243

6-BROMO-6-DEOXY HEXOSE DERIVATIVES BY RING OPENING OF BENZYLIDENE ACETALS WITH N-BROMOSUCCINIMIDE: METHYL 4-O-BENZOYL-6-BROMO-6-DEOXY-α-D-GLUCOPYRANOSIDE

[Glucopyranoside, methyl 6-bromo-6-deoxy-, 4-benzoate, α-D-]

Submitted by S. Hanessian¹

Checked by Janice Cammack and James D. White.

1. Procedure

To a suspension containing 20.5 g (72.61 mmol) of methyl 4,6-O-benzylidene-α-D-glucopyranoside (Note 1) in 1 L of carbon tetrachloride and 60 mL of 1,1,2,2-tetrachloroethane (Note 2) are added 15 g (84.27 mmol) of N-bromosuccinimide and 8 g (31.13 mmol) of barium carbonate (Note 3). The resulting suspension is heated at the reflux temperature of the mixture with mechanical stirring for a 2.5-hr period and filtered while hot. During the initial period of heating, a reddish orange color develops but fades before termination of the reaction. The yellowish gummy residue in the flask is washed with two 100-mL portions of hot carbon tetrachloride and the filtrate and washings are evaporated under reduced pressure to give a pale-yellow oil that is dissolved in 500 mL of ether. The solution is washed with three 60-mL portions of water, then dried over anhydrous sodium sulfate. Evaporation affords a pale-yellow oil that crystallizes (Note 4) on trituration with cold ether to yield 12.1 g of white crystals, mp 120–123°C. A second crop of 1.72 g is obtained from the mother liquors (Note 5). Recrystallization of 1 g of product by dissolution in a minimum volume of acetone and addition of ether, then pentane gives 0.9 g of white crystals, mp 131–132°C; [α]_D + 118° (CHCl₃, c 1).

2. Notes

1. The preparation of methyl 4,6-O-benzylidene-α-D-glucopyranoside follows essentially the procedure reported.² A mixture of 60 g (0.31 mol) of methyl α-D-glucopyranoside, 45 g of freshly fused and powdered zinc chloride, and 150 mL of benzaldehyde ("practical" grade) is stirred at room temperature for a period of 48 hr. The resulting pale-yellow, cloudy reaction mixture is poured slowly, with stirring, into 1.25 L of cold water, stirred for an additional 10 min, and refrigerated overnight. Hexane (75 mL) is added and the resulting mixture is stirred for 0.5 hr to aid in removing excess benzaldehyde. The product is separated on a Büchner funnel, washed twice with 100 mL of cold water, and dried under vacuum at room temperature overnight. Recrystallization from chloroform–ether affords 55 g (63% yield) of analytically pure material, mp 164–165°C.

2. Carbon tetrachloride (spectral grade) was passed through a thick layer of Woelm alumina (neutral). 1,1,2,2-Tetrachloroethane was used as a cosolvent to aid in the dissolution of the starting sugar derivative. In other instances carbon tetrachloride was the solvent.

3. Barium carbonate can be replaced by calcium carbonate in some cases; see Chretien, F.; Khaldi, M.; Chapleur, Y. Syn. Commun., 1990, 20, 1589.

4. Crystallization did not occur if traces of tetrachloroethane were present. The checkers found it necessary to evaporate at ~0.05 mm in a warm water bath for ca. 2 hr to remove residual solvent.

5. Evaporation of the mother liquors and flash-column chromatography (350 mL of silica gel; column height 28 cm; eluant 70% ethyl acetate–hexanes, fraction size, 30 mL), given additional (1.87 g) product that was eluted with fractions 25–36; total yield 15.69 g, (Silica gel, Kieselgel 60; E. Merck AG, Darmstadt, Germany.)

3. Discussion

Halogeno sugar derivatives are versatile intermediates for the preparation of aminodeoxy, deoxy, thio, and related analogs.³ These transformations are easily achieved in the case of primary halides, which in turn can be prepared by a variety of methods. A number of 6-deoxy and 6-amino-6-deoxy hexoses are components of antibiotics and related natural products.⁴^,⁵ Benzylidene acetals of the 1,3-dioxane or 1,3-dioxolane type undergo a ring-opening reaction in the presence of N-bromosuccinimide to give the corresponding O-benzoylated bromohydrins.⁶ This transformation has been known for a number of years in the carbohydrate series (Hanessian–Hullar reaction),⁷ and has been used extensively in synthetic work. In the case of 4,6-O-benzylidene acetals, the products are the 6-bromo-6-deoxy-4-benzoates. Internal acetals of the 1,3-dioxolane type often undergo ring opening to give the two possible regioisomeric bromo benzoates. The reaction is compatible with a variety of functional and protecting groups (ester, ether, amide, halide, epoxide, etc.). It is also applicable to substrates containing free hydroxyl groups such as the example given above. A unique feature, which arises as a consequence of the nature of the ring opening, is seen in the case of methyl 4,6-O-benzylidene-α-D-galactopyranoside and its derivatives. In this series the benzoate group is found at the C-4 position which has an axial orientation. Hence one achieves halogenation at the primary position as well as an indirect benzoylation of an axial hydroxyl group in the parent sugar. Other applications have been found in amino sugars and nucleosides. Table I illustrates a selection of such ring-opening reactions. The reaction has also been applied with disaccharide acetals.⁶^,⁸

TABLE I
REACTION OF O-BENZYLIDENE ACETALS WITH N-BROMOSUCCINIMIDE
Starting Acetal	Product(s)	Reference


		⁵
		⁵
		⁵
		⁵
		⁵
		⁵
		⁹
		¹⁰
		¹¹
		⁵
		¹²

Acknowledgments

The authors thanks Mrs. Ani Glamyan for valuable technical assistance.

¹³

References and Notes

Department of Chemistry, University of Montreal. C.P. 6210, Succursal, A., Montreal (Que.), Canada H3C 3V1.
Richtmyer, N. K. Methods Carbohydr. Chem. 1962, 1, 107.
See for example, "International Review of Science, Organic Chemistry Series One and Two, Vol. 7, Carbohydrates," Aspinall, G. O., Ed., Butterworths: London, 1973; 1976.
See for example, Umezawa, S. In "International Review of Science, Organic Chemistry Series Two, Vol. 7, Carbohydrates," Aspinall, G. O., Ed., Butterworths: London, 1976; p. 149.
Hanessian, S.; Haskell, T. H. In "The Carbohydrates: Chemistry and Biochemistry," 2nd ed.; Pigman, W.; Horton, D.; Eds.; Academic Press: New York, 1970; Vol. IIA, p. 139.
See for example, Hanessian, S. Carbohydr. Res. 1966, 2, 86; Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035, 1045, 1053; Hanessian, S. Methods Carbohyd. Chem. 1972, 6, 183.
See for example, Guthrie, R. D.; Ferrier, R. J.; How, M. J.; Somers, P. J. In "Carbohydrate Chemistry," Specialist Periodical Report, The Chemical Society, 1968; Vol. 2, p. 3; Failla, D. L.; Hullar, T. L.; Siskin, S. B. J. Chem Soc., Chem. Commun. 1966, 716; Hullar, T. L.; Siskin, S. B. J. Org. Chem. 1970, 35, 225.
Thiem, J.; Horst, K. Tetrahedron Lett. 1978, 4999.
Chiba, T.; Maga, M.; Tejima, S. Chem. Pharm. Bull. 1975, 23, 1283.
Baer, H. H.; Georges, F. F. Z. Can. J. Chem. 1977, 55, 1348.
Cheung, T.-M.; Horton, D.; Sorenson, R. J.; Weckerle, W. Carbohydr. Res. 1978, 63, 77.
Florent, J.-C.; Monneret, C.; Khuong-Huu, Q. Carbohydr. Res. 1977, 55, 301.
Ponpipom, M. M.; Hanessian, S. Can. J. Chem. 1972, 50, 246, 253.

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

silica gel

Glucopyranoside, methyl 6-bromo-6-deoxy-, 4-benzoate, α-D-

hexanes

ethyl acetate (141-78-6)

ether (60-29-7)

chloroform (67-66-3)

sodium sulfate (7757-82-6)

carbon tetrachloride (56-23-5)

benzaldehyde (100-52-7)

calcium carbonate (471-34-1)

acetone (67-64-1)

zinc chloride (7646-85-7)

barium carbonate (513-77-9)

Pentane (109-66-0)

tetrachloroethane (630-20-6)

N-bromosuccinimide (128-08-5)

hexane (110-54-3)

1,1,2,2-tetrachloroethane (79-34-5)

Methyl 4-O-benzoyl-6-bromo-6-deoxy-α-D-glucopyranoside (10368-81-7)

Methyl 4,6-O-benzylidene-α-D-glucopyranoside (3162-96-7)

methyl α-D-glucopyranoside (97-30-3)

methyl 4,6-O-benzylidene-α-D-galactopyranoside

Notes

References/EndNotes

Article Compounds

Authors