Chloromethyl thioethers

In an extension of the procedure, thiols react with gem-dihaloalkanes (Table 4.4) to produce thioacetals [ 10,20-23] and the reaction can be employed in the Corey-Seebach synthesis of aldehydes and ketones (see ref. 24 and references cited therein), gem-Dichlorocyclopiopanes having an electron-withdrawing group at the 2-position react with thiols to produce the thioacetals [25]. In the corresponding reaction of the thiols with biomochloromethane exclusive nucleophilic substitution of the bromo group by the thiolate anion occurs to yield the chloromethyl thioethers [13, 14] (Table 4.5). 

The thiol (25 mmol) is added with stirring to KOH (1.94 g, 30 mmol) in CH2BrCl (150 ml). Upon addition of TEBA-Br (0.3 g, l. I mmol), the reaction becomes exothermic and the mixture is stirred at room temperature for 2 h and then filtered. Excess CH2BrCl is removed under reduced pressure and the residue is extracted with Et20 (75 ml). The dried (MgS04) ethereal solution is diluted with n-C6H14 (50 ml) and evaporated to yield the chloromethyl thioether. 

Methylene compounds from mercaptans via chloromethyl thioethers and sulfones... 

Zn, (CH30)2CH2, BrCH2C02Et, 80-82% yield. Formation of the meth-oxymethyl thioether with dimethoxymethane avoids the use of the carcinogen chloromethyl methyl ether. The reaction forms an intermediate zinc thiolate, which then forms the monothioacetal. 

Bis(2-diisopropylaminoethyl) Disulfide Bis(2-diisopropylaminoethyl) Sulfide Bis(2-fluoroethyl) 2-Chloroethylamine Bis(2-fluoroethyl)methylamine Bis(2-hydroxyethyl) Sulfide Bis(2-hydroxyethyl) Thioether Bis(2-hydroxyethyl)amine Bis(2-hydroxyethyl)methylamine Bis(2-propenyl) Sulfide Bis(bromomethyl) Ether Bis(chloromethyl) Ether Bis(cyclohexyl)carbodiimide Bis(ethenyl)sulfone Bis(trichloromethyl) Carbonate Bis(/3-bromoethyl) Sulfide Bis(/3-chloroethyl)ethylamine Bis(/3-Chloroethyl)methylamine Bis(/3-chloroethylthio)ethane Bis(/3-mercaptoethyl) Sulfide... 

Methylthiomethyl has been used as the protecting group in the total synthesis of neoechinulin A (80TL2817). Cyclo(L-Ala-Gly) was treated with sodium hydride in DMF and N-alkylated with chloromethyl methyl thioether at room temperature, to give the bis(methylthiomethyl) derivative. After further chemical transformations, deprotection was achieved by treatment with methyl iodide in the presence of NaHC03 at 40°C for 3 days, followed by heating in dioxane at 100°C for 1 h. 

Phase transfer reaction of the conjugate base of the JV,iV,iV -trialkylsulphamides (345) in the presence of benzyl triethylammonium chloride with chloromethyl ethyl ether or chloromethyl alkylthioethers yields the N,iV-dialkyl-iV -alkyl-iV -ether and thioether sulphamides (341)365 (equation 117). 

The reactions of lithiophosphide reagents with alkyl halides or sulphonate esters have continued to find wide application in the synthesis of new phosphines. A series of phosphino-ethers, e.g., (22), has been prepared from the reactions of chloromethyl-substituted ethers with lithium diphenylphosphide. " A one-step synthesis of macrocyclic phosphino-ethers and -thioethers (23) is afforded by the reactions of dilithio-organophosphides with bis(j8-chloroethyl)-ethers and -thioethers derived from ethane-1,2-diol and ethane-1,2-dithiol, respectively. " A new family of water soluble phosphonio-phosphine ligands (24) has been prepared by the reaction of a,o)-dihaloalkanes with one mole of lithium diphenylphosphide, followed by quatemisation of the intermediate w-haloalkylphosphine with trimethylphosphine. The new ligand system (25) has been prepared by the reaction of chloromethylbenzene-chromium tricarbonyl with... 

Bis(alkene) derivatives of crown thioethers may also be prepared [2-1-2] reaction of 1,4,7-trithiaheptane with 3-chloro-2-chloromethyl-l-propene in the presence of B(OPr)3/Al(OPr), gave 9,19-dimethylene-20S6 in 67% yield <93AG(E)436>. 

While each of these strategies addressed the sourcing of CMCS, they did not overcome the isolation of 2—a key requirement for either process change. An early introduction of the prodrug would obviate the need to isolate 2 and potentially provide an alternative that could be easier to isolate. Thus, 15 was alkylated with (chloromethyl)(4-chlorophenyl)sulfide (26) prior to coupling of the piperazine (Scheme 7). Thioaminal 29 proved stable to direct amidation, " furnishing 27 in good yield. Conversely, the stability of the related acetate was insufficient for it to be installed prior to the introduction of the piperazine— thus, the thioether route was selected. 

Vinylbenzyl chloride (VBC Dow Chemical) represents a functional monomer with electrophilic sites which can be post-reacted after polymerization with nucleophiles such as amines, thiols, thioethers and thiourea [28]. The chloromethyl group may also be reacted before polymerization to form a new monomer, which can itself then be polymerized. VBC is typically copolymerized with monomers such as butadiene, styrene, acrylic or methacrylic acid, acrylonitrile, acrylamide and a variety of acrylate and methacrylate monomers [29] or it can be homopoly-merized to form functionalized particles [30]. Typical properties of vinylbenzyl chloride monomers include a homopolymer Tg of 82 °C, a boiling point of 229 °C (at 1 atm), a water solubility of 0.073 g dm , and Q and e values of 1.06 and —0.45, respectively. 

---