Sulfides, alkylating agents

The most frequentiy used halo alkylating agents are aldehydes and hydrogen haUdes, haloalkyl ethers, haloalkyl sulfides, acetals and hydrogen haUdes, di- and polyhaloalkanes, haloalkenes, haloalcohols, haloalkyl sulfates, haloalkyl -tosylates, and miscellaneous further haloalkyl esters. Haloalkylations include halomethylation, haloethylation, and miscellaneous higher haloalkylations. Under specific conditions, bis- and polyhaloalkylation can also be achieved. 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

Sulfonium ions are themselves useful alkylating agents because a nucleophile can attack one of the groups bonded to the positively charged sulfur, displacing a neutral sulfide as leaving group. We saw an example in Section l 1.6... 

Among the most biologically reactive alkylating agents are the nitrogen and sulfur "mustards" such as bis-(2-chloroethyl)sulfide. These toxic bifunctional compounds cause lethal crosslinking of DNA chains... 

Another method is the use of esters as alkylating agents in triflic acid172 [Eq. (4.44)]. This method has been used to synthesize. S -methylated phenylene sulfide oligomers (methyl triflate, triflic acid, 25°C, 10 h) and to solubilize poly(phenylenesulfide) by transforming it to poly(arylenesulfonium) salts 62 (methyl triflate, methyl or ethyl formate, triflic acid, 110°C, lOh). In a similar way, alkylation of thianthrene to yield the corresponding sulfonium salts (63) has been achieved using alkyl formates.173... 

This reaction is an equilibrium and it may be necessary in making sulfonium salts from less reactive sulfides (sterically hindered ones for example) to use more powerful alkylating agents with non-nucleophilic counterions, for example, Me30+ BF4, trimethyloxonium fluoroborate (also known as Meerwein s salt). The sulfur atom captures a methyl group from 0+, but the reverse does not happen and the BF4 anion is not a nucleophile. 

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

Dialkyl sulfides can react with alkyl halides to form trialkylsulfonium salts, which are also good alkylating agents. 

Meier, H.L., Johnson, J.B. (1992). The determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2 -dichlorodiethyl sulfide (sulfur mustard, HD). Toxicol. Appl. Pharmacol. 113 234-9. 

The generation of sulfonium yhdes relies mostly on three strategies (Scheme 78). The classic variant uses sulfide alkylation to the sulfonium salts 316 which can be deprotonated to dehver the desired yhdes 317 [180,181]. A related method involves silane 320 as the alkylating agent to allow for regioselective ylide generation via fluoride ion induced desilylation [182]. Finally, the action of carbenes 319 or metal-bound carbenoids offers a direct means for ylide generation [183,184]. 

Recent work by Voss and coworkers has shown that tertiary thioamides, thioesters and dithio-esters can all be reduced electrochemically to the aldehyde level in the presence of alkylating agents. The process is summarized in equation (9). The cleanest and most efficient of the reactions appears to be that of the thioamides (68 X = NR 2), using anhydrous acetonitrile as solvent and simple alkyl bromides (e.g. EtBr, Bu Br) as alkylating agents. Although the method was only demonstrated for (68 R = Ph and (9-CIC6H4), the yield of a-amino sulfides was 95% in both cases. 

The reaction between thiols and alkyl bromides in benzene in the presence of DBU led to sulfides in high yield (80S952). When dichloromethane or bromochloromethane was used as alkylating agent, formaldehyde dithio-acetals or chloromethylsulfides were obtained in good yields. 

The reduction of sulfonyl chlorides may lead to sulfinates [265-267], thiosulfonates [267], disulfides, and mercaptans depending on the conditions in the presence of alkylating agents [266], sulfones or sulfides are among the products. 

The pentasulfido complex reacts with tertiary phosphines to give dimers [Ti(MeCp)2]2Sj, (x = 4 and 6). The pentasulfido complex also gives heterocycles of the type Ti(MeCp)2S4CR2 when treated with ammonium sulfide in the presence of certain alkylating agents. In fact, the Me2CS4 chelate is a minor side product in the synthesis of Ti(MeCp)2Sj. The compound Ti(MeCp)2S5 reacts with electrophilic acetylenes to give dithiolenes... 

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