Sulfinamides, hydrolysis

The utility of methanesulfinyl chloride lies in its great chemical reactivity. Through its ready hydrolysis, it serves as a convenient source of methanesulfinic acid. It reacts at low temperature with aromatic amines to form sulfinamides, and with alcohols to form sulfinate esters. When it is hydrolyzed in the presence of an equimolar quantity of sulfenyl chloride, a thiol-sulfonate ester is produced. 

Scheme 5.24 Subtilisin-Carlsberg-catalyzed hydrolysis of sulfinamides.

The 2-alkenyl sulfinamides appeared to be slightly unstable. They could, however, be quickly converted into anilines by base-catalyzed hydrolysis in good yields (Scheme 52) <91JOC5059 91T8855>. This general route to 2-alkenyl anilines is regioselective, but not stereoselective. 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

Ab initio calculations have been earned out on the gas-phase acid-catalysed hydrolysis reactions of sulfinamide (319) using the 3-21G sets.290 The first step in the acid-catalysed hydrolysis of A-methylmethanesulfinamide (319 R1 = R2 = Me) is O-protonation and this form is then transformed by addition of water to the sulfiirane intermediate (320). Intramolecular proton transfer from 0 to N follows and then slow N—S bond cleavage to give products.290 Studies with (319 R1 = Me, R2 =aryl) also... 

In 1995 Pyne and Dong95 found that the ally lie sulfoximine 165 underwent a facile and completely regioselective and efficient rearrangement to the allylic sulfinamide 166 in the presence of tetrakis(triphenylphosphine)palladium(0) ((PPh3)4Pd) catalyst (5 mol%) at room temperature. Mild base hydrolysis of the reaction mixture (10% aqueous sodium hydroxide/methanol, 1 10, room temperature, 2 h) gave pure sulfonamide 167 after purification by column chromatography (silica gel) in 90% overall yield. 

The reaction of Grignard reagents with sulfimines is the method of choice for preparing sulfinamides [7-9] mild hydrolysis conditions are necessary for maximum yields [7]. 

When the allylic sulfinamides are hydrolyzed under special conditions (classical methods like alkali-or acid-catalyzed hydrolysis did not work properly) the obtained allylic sulfinic acids are unstable and will fragment smoothly again with allylic rearrangement into terminal alkenes. 

The administration of TNT to laboratory animals leads to the excretion of 4-NHOH-DNT, 2-NH2-DNT, and 4-NH2-DNT in the urine [59], and to the formation of covalent adducts with microsomal liver and kidney proteins, hemoglobin, and other blood proteins [60], The acid hydrolysis of adducts yielded mainly 2-NH2-DNT (2-ADNT) and 4-NH2-DNT (4-ADNT). Incubation of rat liver microsomes with TNT and NADPH under aerobic conditions resulted in the formation of NH2-DNTs and the transient metabolite 4-NHOH-DNT [57], The formation of covalent protein adducts with TNT metabolites was enhanced by the presence of 02 and decreased by GSH. This is consistent with the scheme of the TNT adduct formation with the central role of the nitroso metabolite (NO-DNT) reaction with protein or nonprotein thiols (RSH Equation 9.11) [57], The acid hydrolysis of the sulfinamide adduct (RS(0)-NH-DNT) formed after the rearrangement of the semimercaptal (RS-N(OH)-DNT Equation 9.12) will yield NH2-DNT. The mixture of NHOH-DNTs inhibits bacterial glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase more efficiently than TNT [61]. This was attributed to the covalent modification of protein -SH groups. 

The cycloadducts of sulfur diimides exhibit hydrolytic behavior very similar to that of dihydrothiazine oxides (Scheme 1-XI). Alkaline hydrolysis of a dihydrothiazine imine affords an intermediate sulfinamide which, on treatment with aqueous acid, yields a homoallylic amine, presumably via a retro-ene process. A homoallylic amine is formed directly from a cycloadduct on acidic hydrolysis. ... 

The products arc useful for preparation of optically active /3-amino acids. Thus addition of the enolatc (LDA) of methyl acetate to (—)-(Rs)-2 affords sulfinamides 3. separated by flash chromatography. Pure (3S)-3 is converted by hydrolysis into the (S)-... 

Scheme 1034. The synthesis of (l/ )-l-phenylpropylamine hydrochloride. Beginning with tert-butyl disnlfide, oxidation with hydrogen peroxide in the presence of VO(acac>2 and (5 )-2-(A -3,5-di-f-butylsaIicylidene)amino-3,3-dimethyl-l-butanol prodnces the chiral sulfinate (5 )-f-butyl-f-butanethiosulfinate. Then, addition of the sulfinate in THF (oxocyclopentane, THF) to a suspension of lithium amide (L1NH2) in Uquid ammonia (NHs )) generates K)-t-butanesulfinamide. The optically active sulfinamide reacts with propanal to form the corresponding sulfinimine. Reaction of the latter with phenylmagnesium bromide (CtllsMgBr) in ether yields A -(l-phenylpropyl)-f-butanesulhnamide and hydrolysis in methanolic HCI generates the corresponding (IR)-l-phenylpropylamine hydrochloride. The cartoon drawing of the presumed cyclic transition state is used to account for the stereochemical outcome. But see Hose, D. R. I Mahon, M. E Molloy, K. C. Raynham, T Wills, M. /. Chem. Soc. Perkin Trans. 7,1996, 7, 691.

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