Benzylic thiols reduction

The pyridazine dioxide derivative (108) was made by intramolecular nitroso compound dimerization as shown (Scheme 23). 1,2-Oxathiin 2,2-dioxides are obtained by the addition of sulfuric acid to a,(3-unsaturated ketones, e.g. (109) — (110) (66HC(21-2)774). 1,2-Dithiins are synthesized from conjugated diynes using benzyl thiol reductive debenzylation of intermediate (111) by sodium in liquid ammonia at - 70°C gives, after aerial oxidation, the 1,2-dithiin (112) (67AG(E)698). 

A thio-substituted, quaternary ammonium salt can be synthesized by the Michael addition of an alkyl thiol to acrylamide in the presence of benzyl trimethyl ammonium hydroxide as a catalyst [793-795]. The reaction leads to the crystallization of the adducts in essentially quantitative yield. Reduction of the amides by lithium aluminum hydride in tetrahydrofuran solution produces the desired amines, which are converted to desired halide by reaction of the methyl iodide with the amines. The inhibitor is useful in controlling corrosion such as that caused by CO2 and H2S. 

The asymmetric reduction of the benzoxathiin is very appealing because of its simplicity (Scheme 5.3). It was envisioned that intermediate 16 could be prepared from thiol-phenol 7 and bro moke tone 17. Scheme 5.8 summarized the synthesis for 16. The l,3-benzoxathiol-2-one 35 was prepared from 1,4-benzoquinone and thiourea following a literature procedure with minor modifications. Benzylation of 35 with benzyl bromide in the presence of KI gave benzyl ether 36 as a crystalline solid. It was observed that the benzylation gave better results when the reaction was run under anaerobic conditions. Hydrolysis of thiocarbonate 36 gave free thiophenol 7 which was used directly in the next reaction. 

Williams and Rastetter also accomplished an elegant synthesis of ( )-hyalodendrin (83) in 1980 [39]. Beginning with the sarcosine anhydride-derived enolic aldehyde 78, silyl protection of the enal enabled alkylation of the glycine center with benzyl bromide and thiolation using LDA and monoclinic sulfur a la Schmidt. After protection of the thiol with methylsulfenyl chloride and deprotection of the silyl ether, the enol was sulfenylated with triphenylmethyl chlorodisulfide to afford bis(disulfide) 82 as a 2 1 mixture of diastereomers favoring the anti isomer. Reduction of the disulfides with sodium borohydride and oxidation with KI3 in pyridine afforded ( )-hyalodendrin (83) in 29 % yield (Scheme 9.4). 

Reductive Thiolation. Treatment of aldehydes with triethylsilane, thiols, and boron trifluoride monohydrate 217 yields sulfides in a one-flask process. For example, this method gives a 97% yield of benzyl isopropyl sulfide from benzaldehyde and 2-propanethiol (Eq. 204).365... 

An intriguing use of a quaternary ammonium salt in a two-phase reaction is to be found with the regeneration of 1 -benzyl-1,4-dihydronicotinamide by sodium dithionite in a biomimetic reduction of thiones to thiols [12], The use of sodium dithionite in the presence of sodium carbonate for the 1,4-reduction of the pyri-dinium salts to 1,4-dihydropyridines is well established but, as both the dithionite and the pyridinium salts are soluble in water and the dihydropyridine and the thione are insoluble in the aqueous phase and totally soluble in the organic phase, it is difficult to identify the role of the quaternary ammonium salt in the reduction cycle. It is clear, however, that in the presence of benzyltriethylammonium chloride, the pyridine system is involved in as many as ten reduction cycles during the complete conversion of the thione into the thiol. In the absence of the catalyst, the thione is recovered quantitatively from the reaction mixture. As yet, the procedure does not appear to have any synthetic utility. 

The at complex from DIB AH and butyllithium is a selective reducing agent.16 It is used tor the 1,2-reduction of acyclic and cyclic enones. Esters and lactones are reduced at room temperature to alcohols, and at -78 C to alcohols and aldehydes. Acid chlorides are rapidly reduced with excess reagent at -78 C to alcohols, but a mixture of alcohols, aldehydes, and acid chlorides results from use of an equimolar amount of reagent at -78 C. Acid anhydrides are reduced at -78 C to alcohols and carboxylic acids. Carboxylic acids and both primary and secondary amides are inert at room temperature, whereas tertiary amides (as in the present case) are reduced between 0 C and room temperature to aldehydes. The at complex rapidly reduces primary alkyl, benzylic, and allylic bromides, while tertiary alkyl and aryl halides are inert. Epoxides are reduced exclusively to the more highly substituted alcohols. Disulfides lead to thiols, but both sulfoxides and sulfones are inert. Moreover, this at complex from DIBAH and butyllithium is able to reduce ketones selectively in the presence of esters. 

A variant of this procedure is provided by the preparation of S-benzyl-l-cysteine (Expt 5.206). The required thiolate salt is prepared by the reductive cleavage with sodium in liquid ammonia of the disulphide linkage in the amino acid, (S)-cystine, and is alkylated in situ with benzyl chloride. The preparation of this S-benzyl derivative constitutes a method of protection of the thiol grouping in cysteine. 

With R = benzyl and in the absence of 02, the major product (73%) is the de-carbonylation product [reaction (209) possible formed to a large extent within the solvent cage], and the dimer of the allylic radical [reaction (207)] is formed only in small amounts. Addition of a thiol increases the yield of Thd [reaction (208)]. If an evaluation of the data reported for the reduction of the allylic OH-adduct to 1,3-cylohexadiene by a thiol (Pan et al. 1988), estimated at 104 dm3 mor1 s"1, is a good guide the rate constant for reaction (208) should be similar. This would revise an assumed rate constant of 106 dm3 mol-1 s-1 and the conclusions as to the repairability of allylic Thy in DNA radicals by cellular thiols (Anderson et al. 2000). 

With sulfides as intermediates, alkenes can be used as precursors to organolithiums with regioselectivity in the formation of 56 determined by whether a radical11 or polar73 thiol addition is employed. Easy lithiation of phenyl benzyl sulfide 57 makes substituted benzyllithiums such as 58 readily available.73 Reductive C-S cleavage is probably the best way of making benzylic organolithiums. 

In a study of the reducing action of various thiols at 0.1 M concentration in aqueous solutions of alcohols (Maclaren, 1962), benzyl mercaptan was found to be the most effective. Maximum reduction exceeding 90 % was obtained in 20 % propanol solution, and under these conditions the wool remained intact. If 5 M Nal was incorporated in the solution approximately 65 % of the protein was extracted in 48 hr at 20°C under essentially neutral conditions (Maclaren, unpublished observations, 1962). This protein could be alkylated with iodoacetate and fractioned into low-sulfur and high-sulfur fractions using the methods of Gillespie. 

Certain benzylic alcohols, ethers, acetals and thiols, which are normally resistant to reduction by LAH, can be reduced to the hydrocarbon when the substrate is activated with a Lewis acid. AICI3 has been most widely used in this role. Various acetals can also be reduced to ethers using the same reagent (equation 44). A related procedure has been used to convert aldehydes into sulfides (equation 45). ... 

A number of other groups can be used for the protection of thiols benzyl thioethers of amino acids and peptides have been cleaved electrochemically at a platinum cathode in liquid ammonia [121], at mercury in MeOH-TMACl [122], and in DMF [123,124], and the trityl group has been used to protect cysteine cysteine was recovered in 90% yield after reduction in DMF [124]. The 4-pyridylmethyl [125,126] and diphenyl-4-pyridylmethyl groups can be cleaved in acid solution [124] at a mercury cathode. 

General problems, as compared to the formation of 0-glycosides, are the incompatibility between catalytic hydrogenolysis and sulfur functions, which complicates the use of benzyl ethers as protecting groups, although Birch reduction might be an alternative, and the easy formation of disulfides from thiols, irrespective of if they are used as donors or acceptors. 

Reductive opening of 2-phenyltetrahydrothiophene (30) takes place by treatment with lithium in the presence of a catalytic amount of DTBB at low temperature to give the benzylic dianion (31) in a similar way as for thietane (22) (e.g., see Section II.B). The reaction with electrophiles followed by hydrolysis gives functionalized thiols (32). The treatment of the sulfanyl alcohol obtained by addition of acetone as electrophile with 85% phosphoric acid leads to the expected tetrahydrothiopyran (33) (Scheme 10) (97T5563). 

The addition of other sulfur nucleophiles was reported by Jacobsen to be catalyzed by the same Cr(salen) complex 1 initially reported for the ARO with TMSNj. Benzyl mercaptan afforded the ring-opened hydroxy sulfides in excellent yield and 59-70% ee [17]. The moderate levels of enantioselectivity were improved by use of the dithiol 5, which afforded mixtures of bishydroxy sulfides in which the ee of the chiral product 6 was substantially enriched (Scheme 5). The sulfide products could be easily elaborated into the free thiols by reductive de-benzylation, providing access to the jl-silyloxy thiol 8 in optically pure form. 

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