[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.
Handling, Storage, and Precautions: irritant, handle with gloves in a fume hood.
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 (
In another example, the unsaturated acid 4 was protected in the same manner to afford ester 5 (
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.
Reaction of 1 with phosgene affords the chloroformate (6) (
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 (
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.
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 (
Alcohol 1 has also been used to protect a phosphonic acid (10) as part of a synthesis of cyclic nucleotides (
The phosphitylation reagent (12), useful for nucleotide synthesis, is readily prepared by reaction of 1 with phosphorus trichloride in acetonitrile (
Reagent 12 is an easily handled solid which is stable for at least one year when stored in a freezer.4b
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 (
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 (
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) (
Merck Research Laboratories, Rahway, New Jersey, USA