Chloromethyl with thiols

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). 

Halomethyl ketones and acids are known to react with thiols and imidazoles. TPCK reacts far more rapidly with chymotrypsin than it does with normal histidine-containing peptides because of its high reactivity as an affinity label. This can be seen in Table 9.2 for an analogous chloromethyl ketone. In addition to this important diagnostic feature, the irreversible inhibition of chymotrypsin by TPCK has four other characteristic features 1,4... 

Chloromethyl ketones also react with thiol proteases, and could therefore be useful collagenase inhibitors.82... 

Another entry into the anti ulcer sweepstakes is etinfidine (50). It is synthesized by displacement of halide from 4-chloromethyl-5-methylimidazole (4 ) with substituted thiol The latter is itself made from thiourea analogue by an addition-elimination reaction with cysteamine 52. °... 

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. 

Methoxyphenylene diamine 12 was treated with potassium ethylxanthate to afford benzimidazole-thiol 13. The coupling of thiol 13 and chloromethyl-pyridine 11 was then... 

Inhibitors of Thiol and Carboxyl Proteases. Thiol proteases are inactivated by peptide chloromethyl ketones (30) and other alkylating agents. Peptide diazomethyl ketones are much more selective reagents since they do not react with serine proteases as do chloromethyl ketones. Diazoketones have been applied to papain and cathepsin B (48) thus far and it appears that they should be applicable to most thiol proteases. Specificity should be obtainable by changing the peptide sequence of the inhibitor to match that of the enzyme being studied. 

A useful route toward heteronines is an application of 1,3-dielectrophiles when they react with O- and S-nucleophiles. The chiral (R)-l,l -bi-2-naphthol 152 was reacted with 3-chloro-2-(chloromethyl)prop-l-ene to afford dioxonine 153 (Scheme 28, Section 14.10.6.1) <1998JA5943, 1997TA2921>. A novel procedure for the preparation of cyclic polythioethers by the reaction of dithioiminium salt with 1,3-dihalopropane using phase-transfer catalyst has been reported (Equation 28) <2003PS1295>. This approach avoided the use of thiols, which are not only hard to handle, but also prone to oxidation. 

Thiols may be converted into alkenes with one extra carbon atom by successive chloromethylation, oxidation at sulfur, and Ramberg-BScklund rearrangement. If the original thiol is prepared by free radical addition of H2S to an alkene, the sequence constitutes a one-carbon homologation of alkenes. Although these transformations were at one time important applications of the Ramberg-Backlund reaction, they have hardly been used in recent years. 

Alternatively, we prefer to prepare polymers containing the thiol functionally (15,25) by reacting chloromethylated resin with thiourea (25). The reaction of y-CI Cl with thiourea gives a supported isothiouromium chloride. The latter solid is reacted with hydroxyl groups to produce a thiol-containing polymer. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Formaldehyde benzyl ethyl dithioacetal Chloromethyl ethyl sulfide (11 g) and a-toluene-thiol (12.4 g) react very vigorously, with evolution of hydrogen chloride, and control by cooling is necessary. After being kept overnight, the mixture is fractionated in a vacuum, affording the dithioacetal, b.p. 165°/19 mm, in 60% yield. 

Oxiranes can also be cleaved by mercaptanes, this yielding -hydroxy sulfides. This reaction has been carried out386 with oxirane, 7-oxabicyclo[4.2.1]heptane, and epichlorohydrin [(chloromethyl)oxirane] and, as sulfur components, ethane-, 1-propane-, benzene-, and a>toluene-thiol in the presence of a little active charcoal as catalyst. 

The additions of thiols and sulphenyl chlorides to alkenylphosphonic derivatives to yield (2-alkylthioethyl)phosphonic compounds are reactions which have already been noted" Dialkyl (alkylthiomethyl)phosphonates yield a-chloro derivatives when treated with ncs in CCl/° the resultant dialkyl (l-alkylthio-l-chloromethyl)phosphonates undergo Friedel-Crafts arylation with benzene, alkylbenzenes or other activated aromatics in the presence of SnCl4 or TiCl/ yields are said to be good. 

Reactions of the Y-chloromethyl carbamoyl chlorides 343 and 346 with benzimidazole-2-thiol 344 or 3a,4,5,6,7,7a-hexahydro-l//-benzimidazole-2-thiol 347 for preparation of fused thiadiazines 345 and 348 have been reported. 

Similarly, 3-substituted 1,2,4-triazole-5-thiols 349 react with A -chloromethyl carbamoyl chlorides 346 to afford 5,6-dihydro-7-thia-l,3,3a,5-tetraaza-inden-4-ones 351. The N-1 and N-2 positions of r-triazoles are more nucleophilic than the N-4 position. The nucleophilic thiol group of 349 attacks the chloromethyl group of A -chloromethyl carbamoyl chloride 346 in preference to the carbamoyl chloride moiety. After the initial attack, the carbamoyl group reacts with N-1 of the triazole to afford the corresponding 5,6-dihydro-7-thia-l,3,3a,5-tetraaza-inden-4-one 351 (Scheme 71) <2000M953>. 

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. 

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