Thiophenols, alkylation preparation

The second cycloaddition substrate took to form of 91 (Scheme 1.9b), incorporating a vinyl sulfone dipolarophile. Beginning with cyano ketone 84, which was readily prepared from 1,5-dicyanopentane via a previously reported three-step sequence [45], condensation with thiophenol produced vinyl sulfide 85 in 84 % yield. Vinyl sulfide 85 underwent bromination in acetonitrile to afford bromo-vinyl sulfide 86 (86 %), which was then treated with isopropylmagnesium chloride [46] to effect metal-halogen exchange affording an intermediate vinyl magnesium bromide species. Subsequent alkylation with Mel in the presence of catalytic CuCN provided the alkylated vinyl sulfide 87 in 93 % yield. The nitrile within vinyl... 

Peptides typically are prepared for this ligation process using a-alkyl thioesters, because they are simple to make at the time of peptide synthesis. However, due to the relatively slow reaction kinetics of alkyl thioesters, most native chemical ligation processes have been catalyzed through the use of thiol compound additives, such as benzyl mercaptan or thiophenol (Dawson et al., 1997). These compounds react with the initial a-alkyl thioester to form another intermediate, an aryl thioester, which is more reactive toward the N-terminal cysteine on the other peptide to be coupled. A study... 

An attractive feature of this route is that the macrobicyclic intermediate 40a can be readily N-alkylated without affecting the masked thiolate functions (209). Thus, reductive methylation of 40a with formaldehyde and formic acid under Eschweiler-Clarke conditions, followed by deprotection of 40b with Na/NH3 provides the otherwise inaccessible N6S2 ligand H2L19 in nearly quantitative yield (Scheme 1). Several other aza-thioethers 40c-p and their corresponding thiophenolate ligands were prepared by this route (see Fig. 30 and Table I) and some of them will be discussed further in later sections (210-215). 

The equivalence of sulfur and oxygen in this ring system carries over to NSAIDs as well. Preparation of the sulfur analogue of isoxepac (6-4) starts with the alkylation of thiophenol (27-1) with benzyl chloride (26-1). Cyclization of the intermediate thioether (27-2) then affords the homothioxanthone (27-3). The carboxyl side chain is then extended by means of the Amdt-Eistert homologation reaction. The acid is thus hrst converted to its acid chloride by means of thionyl chloride. Reaction with excess diazomethane leads to the diazoketone (27-4). Treatment of that intermediate with silver benzoate and triethylamine leads the ketone to rearrange to an acetic acid. There is thus obtained tiopinac (27-5) [28]. 

Formation of a symmetrical sulphide (a) (e.g. dipropyl sulphide, Expt 5.204), is conveniently effected by boiling an alkyl halide (the source of carbocations) with sodium sulphide in ethanolic solution. Mixed sulphides (b) are prepared by alkylation of a thiolate salt (a mercaptide) with an alkyl halide (cf. Williamson s ether synthesis, Section 5.6.2, p. 583). In the case of an alkyl aryl sulphide (R-S Ar) where the aromatic ring contains activating nitro groups (see Section 6.5.3, p. 900), the aryl halide is used with the alkyl thiolate salt. The alternative alkylation of a substituted thiophenol is described in Section 8.3.4, p. 1160. The former procedure is illustrated by the preparation of isobutyl 2,4-dinitrophenyl sulphide (Expt 5.205) from l-chloro-2,4-dinitrobenzene and 2-methylpropane-1-thiol. 

Reaction of Resin-Bound Iron Complex (54) with Alkyl Mercaptans, Thiophenols, and Phenols (Fig. 9)31. Sodium thiolates are prepared analogously to the alkoxides from thiol and sodium hydride, except that dry DMF is used as a solvent. The substitution on the polymer-bound arene (54) is performed at 70° in DMF within 16 h. The resin is filtered and washed with DMF (2 x 50 ml), MeOH (2 x 50 ml), H20 (2 x 50 ml), MeOH (2 x 50 ml), and CH2CI2 (3 x 50 ml) and then dried in vacuo at 40° to yield a red resin. 

The Leuckart Thiophenol Reaction allows the preparation of thiophenols and corresponding thioethers from anilines or their corresponding diazonium salts. The first step is the reaction of an aryl diazonium salt with a potassium alkyl xanthate to give an aryl xanthate, which affords an aryl mercaptan upon basic hydrolysis or an aryl thioether upon warming. 

Pyrrolo[2,l-4 [l,5]benzothiazocine 563a was prepared by alkylation of thiophenol 602 with a-bromophenylacetic acid 603 that furnished the carboxylic acid 604 (73% yield) which, by an intramolecular cyclization in presence of PCl5, yielded 563a (41% yield) (Scheme 121) <1997EJM241>. 

Thiophene sulfonium salts have also been used for alkylation of phenols, thiophenols, and other nucleophiles (Equation 70) <2001T2871>. Ylides generated from THT and alkyl or allyl halides are known to react with aldehydes to form oxiranes. However, a modified procedure has been developed in which only a catalytic amount of THT is used for the preparation of vinyloxiranes from allyl bromides and aldehydes. In most of the cases, a m-/ra r-mixture of vinyloxiranes was obtained. Optically pure C2-symmetric /ra r-2,5-dimethyltetrahydrothiophene has also been used for the asymmetric version of this reaction, but the enantioselectivity was poor (25% ee) (Equation 71) <2003CC2074>. 

Good yields were always obtained for the final hydrolysis step. Moreover, the silyl group had a remarkable effect in reducing the thiophenol smell. More recently, longer alkyl chains instead of TMS have been used in the preparation of other odourless thiols [59]. 

This reaction is analogous to similar methods for the preparation of ethers (methods 113 and 116), Both simple and mixed sulfides may be made from aliphatic mercaptans or thiophenols. The sodium mercaptides are formed from the mercaptans and aqueous or alcoholic solutions of sodium hydroxide or alcoholic sodium ethoxide. Alkylation is effected by halides, alkyl sulfates, or esters of sulfonic acids. The over-all yields of sulfides are usually above 70%. r-Butyl mercaptan is alkylated directly by /-butyl alcohol in strong sulfuric acid to give /-butyl sulfide in 87% yield. ... 

These reactions are convenient methods for incorporating a sulfur-containing group onto an aromatic ring. With Ar S, diazosulfides Ar—N=N—S—Ar are intermediates/° which can in some cases be isolated. ° Thiophenols can be made as shown above, but more often the diazonium ion is treated with EtO-CSS or 82, which give the expected products, and these are easily convertible to thiophenols. Aryldiazonium salts are prepared by the reaction of an aniline derivative with an alkyl nitrite (RONO), and when formed in the presence of dimethyl disulfide (MeS-SMe), the product is the thioether, Ar-S-Me. ° Aryl triflates have been converted to the aryl thiol using NaST(P5) and a palladium catalyst, followed by treatment with tetrabutylammonium fluoride ° (see also, 14-22). 

Alternatives to the acylation-type reaction are even more important in the thioxo- and dithio-carbox-ylic ester series 4 >5,24-29 dithiocarboxylate salts are most conveniently obtained from a variety of precursors and can be not only alkylated but also arylated by arenediazonium hydrogen sulfates (equation 3). An advantage of the latter method is that no thiophenols are needed, which are necessary, but sometimes not easily obtained, educts in most other S-aryl thiocarboxylate preparations (c/. Chapter 1.5). 

Cholesteric PEIs may also be obtained by extension with chiral spacers - a methyl substituent placed on the alkyl chain of the aforementioned thiophenol on the 3 carbon [20]. Photo-reactive cholesteric PEIs with this type of structure have subsequently been reported by the same author [23] formed from the condensation of 1,4-phenylene di-acrylic acid and N-(4-carboxyphenyl) trimellitimide with a chiral spacer prepared from (S)-3-bromo-2-methylpropanol and 4-mercaptophenol. The resulting polymer had enantriotropic cholesteric melt with grandjean texture upon slight shearing (6). 

A method of preparing alkanethiols and thiophenols by means of thio-carboxylic acids consists of converting, preferably, thioacetic or thiobenzoic acid by an alkyl (or aryl) halide into an 5-alkyl (or 5-aryl) thiocarboxylate and hydrolysing this by acid or alkali this method, and that described in the following paragraphs, have the advantage that the thiols can be obtained free from sulfide.268... 

Phenol and (thiophenol)FeCp complexes were prepared by substitution for Cl by OH- and SH- nucleophiles. Alcohols are initially converted to alkoxides using a base such as KOt-Bu or NaH and then give smooth substitution [63,64]. Both aryl and alkyl thiols react smoothly using K2CO3 as a base [65]. Substitution with selenium nucleophiles is also known [66]. Primary and secondary amines are sufficiently reactive without added base if used in excess, although a base (e.g., Et3N, pyridine or K2CO3) can be used to drive the reaction [67-69]. Mild reaction conditions allow arylation of amino acids with (PhF)FeCp (Eq. 17) [69]. The process is of limited value, however, since decomplexation of the arene led to decomposition. 

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