2-Hydroxyethyl Phenyl Sulfone

[20611-21-6]  · C8H10O3S  · (MW 186.2)

(protection of carboxylic acids;1 preparation of a chloroformate reagent for protecting alcohols and amines;2 protection of phosphates and phosphonates;3 preparation of a phosphitylation reagent for nucleotide synthesis;4 2-ethanol carbanion equivalent;5 preparation of a triflate reagent for amine quaternization6)

Alternate Name: 2-(phenylsulfonyl)ethanol.

Physical Data: bp 177 °C/2 mmHg.

Solubility: soluble in organic solvents.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: NMR, HPLC.

Purification: distillation.

Handling, Storage, and Precautions: irritant, handle with gloves in a fume hood.

Protection of Carboxylic Acids

2-Hydroxyethyl phenyl sulfone (1) is a useful reagent for the protection of carboxylic acids.1 Thus, treatment of the protected muramic acid derivative (2) with 1 and DCC afforded the 2-(phenylsulfonyl)ethyl ester (3) in excellent yield (1).1a

In another example, the unsaturated acid 4 was protected in the same manner to afford ester 5 (2).1b,c

The 2-(phenylsulfonyl)ethyl ester is stable to acidic conditions [tetrahydropyranyl (THP), tert-butoxycarbonyl (BOC), and ethoxyethyl (EE) groups can be selectively removed], and to oxidation (peroxide) but can be readily removed by treatment with DBU. Note that in both examples cited above, the 2-(phenylsulfonyl)ethyl ester was cleaved without causing epimerization of the acid. The closely related reagent, 2-(p-toluenesulfonyl)ethanol, has also been used as a carboxylic acid protecting group.1d,e The two reagents work equally well for this purpose and both are commercially available.

Preparation of a Chloroformate Reagent (6) for the Protection of Alcohols and Amines

Reaction of 1 with phosgene affords the chloroformate (6) (3),2a a useful reagent for the protection of alcohols2a,b and amines.2c,d

Chloroformate (6) reacts with alcohols in pyridine at room temperature to afford carbonates 7.2a The 2-phenylsulfonylethoxycarbonyl (PSEC) group is stable to the conditions required to cleave tetrahydropyranyl (THP) ethers, 2-trimethylsilylethoxy carbonates (TEOC), and levulinate and benzoate esters.2a,b The alcohol can be regenerated when desired by treatment with triethylamine in pyridine (4).

Reagent 6 has also been used to protect amines, generating carbamates which are readily cleaved under mild basic conditions.2c,d In one case, the carbamate resulting from reaction of 6 with daunomycin was proposed as a potential prodrug for daunomycin.2d As mentioned above for carboxylic acid protection, similar chemistry has been reported using 2-(p-toluenesulfonyl)ethanol instead of 1.

Protection of Phosphates and Phosphonates

2-Hydroxyethyl phenyl sulfone (1) has been used to differentially protect phosphate esters for nucleotide synthesis.3a,b Thus, reaction of the diphosphate (8) with 1 and 1-(mesitylene-2-sulfonyl)-3-nitro-1,2, 4-triazole (MSNT) in pyridine afforded the differentially protected phosphate 9 in very good yield (5).3a The 2-phenylsulfonylethyl phosphate can be cleaved under mild conditions by treatment with triethylamine.

Alcohol 1 has also been used to protect a phosphonic acid (10) as part of a synthesis of cyclic nucleotides (6).3c

Preparation of a Phosphitylation Reagent (12) for Nucleotide Synthesis

The phosphitylation reagent (12), useful for nucleotide synthesis, is readily prepared by reaction of 1 with phosphorus trichloride in acetonitrile (7).4a,b

Reagent 12 is an easily handled solid which is stable for at least one year when stored in a freezer.4b

Use as a 2-Ethanol Carbanion Equivalent

Treatment of 1 with more than 2 equiv of butyllithium followed by treatment of the resulting dianion with 1 equiv of an electrophile and removal (either reductively or by elimination) of the phenylsulfonyl group results in a net addition of a 2-ethanol carbanion to the electrophile.5 Thus, reaction of 1 with 2.2 equiv of butyllithium followed by quenching of the dianion with benzyl chloride afforded intermediate 13 in very good yield (8).5a Desulfurization of 13 with Raney nickel afforded 3-phenylpropanol (14) in good yield.

The initial alkylation product can be subjected to a second alkylation to afford a more highly substituted product. For example, alkylation of 13 with allyl bromide provides the di-substituted analog 15 (9).5c These bis-alkylated products have been elaborated further to furanones5b and furans.5c

Preparation of a Triflate Reagent (16) for Nitrogen Quaternization

Reaction of 1 with triflic anhydride in pyridine affords the triflate (16) in excellent yield (86%).6 Triflate (16) reacted with oxazole (17) to afford the quaternized oxazole (18) (10). Subsequently, 18 was reduced with sodium borohydride to afford a dihydro-oxazole with a phenylsulfonylethyl substituent on the tertiary nitrogen. Thus, 16 was used to activate the oxazole ring to chemistry which generated a protected secondary amine.

1. (a) Hitchcock, S. A.; Eid, C. N.; Aikins, J. A.; Zia-Ebrahimi, M.; Blaszczak, L. C., J. Am. Chem. Soc. 1998, 120, 1916. (b) Dommerholt, F. J.; Thijs, L.; Zwanenburg, B., Tetrahedron Lett. 1991, 32, 1495. (c) Dommerholt, F. J.; Thijs, L.; Zwanenburg, B., Tetrahedron Lett. 1991, 32, 1499. (d) Roush, W. R.; Blizzard, T. A., J. Org. Chem. 1984, 49, 4332. (e) Colvin, E. W.; Purcell, T. A.; Raphael, R. A., J. Chem. Soc. Chem. Comm. 1972, 1031.
2. (a) Balgobin, N.; Josehpson, S.; Chattopadhyaya, J. B., Tetrahedron Lett. 1981, 22, 3667. (b) Josephson, S.; Balgobin, N.; Chattopadhyaya, J., Tetrahedron Lett. 1981, 22, 4537. (c) Nyilas, A.; Foldesi, A.; Chattopadhyaya, J., Nucleosides Nucleotides 1988, 7, 787. (d) Maligres, P. E.; Nicolaou, K. C.; Wrasidlo, W., Bioorg. Med. Chem. Lett. 1993, 3, 1051.
3. (a) Zhou, X.; Remaud, G.; Chattopadhyaya, J., Tetrahedron 1988, 44, 6471. (b) Sund, C.; Foldesi, A.; Yamakage, S.; Agback, P.; Chattopadhyaya, J., Tetrahedron 1991, 47, 6305. (c) Zeng, F.; Jones, R. A., Nucleosides Nucleotides 1996, 15, 1679.
4. (a) Balgobin, N.; Chattopadhyaya, J., Acta. Chem. Scand. Ser. B. 1985, 39, 883. (b) Claesen, C. A. A.; Segers, R. P. A. M.; Tesser, G. I., Rec. Trav. Chim. Pays. Bas. 1985, 104, 119.
5. (a) Julia, M.; Uguen, D.; Callipolitis, A., Bull. Soc. Chim. Fr. 1976, 519. (b) Tanaka, K.; Ootake, K.; Imai, K.; Tanaka, N.; Aritsune, K. Chem. Lett. 1983, 633. (c) Jung, J. H.; Lee, J. W.; Oh, D. Y., Tetrahedron Lett. 1995, 36, 923.
6. Vedejs, E.; Piotrowski, D. W.; Tucci, F. C., J. Org. Chem. 2000, 65, 5498.

T. A. Blizzard

Merck Research Laboratories, Rahway, New Jersey, USA

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