4- Chlorophenyl sulfide

The submitters followed the course of the reaction by HPLC, monitoring for the disappearance of 4-chlorophenyl trifluoromethanesulfonate. HPLC conditions were as follows 0.46 x 7.5 cm Eclipse-XDB column, gradient elution (10 80 85 15 acetonitrile/10 mM pH 6.3 phosphate buffer over 8.5 min, flow rate = 1,5 mLVmin, detection = 210 nm). Rj (4-chlorophenyl trifluoromethanesulfonate) = 6.25 min, Rj (n-butyl 4-chlorophenyl sulfide) = 7.10 min. 

Distillation is required to remove the primary side-product, di-n-butyl disulfide. Purification by silica gel chromatography gave inferior results because of similar retention times of the two compounds. The initial distillate fractions are turbid, indicating the presence of di-n-butyl disulfide. The absence of turbidity in the higher boiling fractbn indicates distillate that is predominantly the desired n-butyl 4-chlorophenyl sulfide, containing only small amounts of n-butyl disulfide. 

However, conditions foracaricidal action are aalso satisfied by those derivatives in which the two phenyl groups are linked directly or through the insertion of a methylene group by a bivalent sulfur atom. 2,4,4 5-TetrachIorodiphenyl sulfide (tetrasul, 20), 4-chlorobenzyl-4-chlorophenyl sulfide (chlorbenside, 21) and the... 

Thus, we focused on identifying a compound which contained only one active electrophile and a second latent electrophile, which would require orthogonal activation to couple to the phosphoryl moiety. We identified two potential options capable of this type of reactivity (Scheme 6) (1) alkylation with chloromethyl acetate, which occurred with high selectively for the N1 position, followed by treatment with B-bromocatechol borane to provide bromide 25 and (2) alkylation with (chloromethyl)(4-chlorophenyl)sulfide (26) to produce a mixture of 27 and 28. Activation of sulfur with chlorine resulted in conversion of 27 to chloromethyl intermediate 22. Both 22 and 25 readily converted to 21 upon treatment with 18. 

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. 

The reversibility of sulfenyl chloride addition allows exchange with another alkene, leading to elimination from the initial adduct. The rates of the exchange reactions vary considerably, and when an excess of an olefin that undergoes slow elimination is present with an adduct that eliminates rapidly near-quantitative exchange may occur. An appropriate exchange pair was found to be 2-chlorocyclooctyl 4-chlorophenyl sulfide (elimination half-life = 1.3 hr) and cyclopentene (elimination half-life = 400 hr) [Eq. (38)]. 

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