6- thiomethyl substituted

Phenylthio)carbene,18 a heteroatom-substituted carbene, reacts similarly with a variety of alkoxides to give a-thiomethyl-substituted alcohols 14 (Scheme 8... 

In the presence of a catalytic amount of CuBr, thiomethyl-substituted-l,3,4-aza-triene 472 underwent cydization to afford tetrasubstituted pyrroles 473 [215],... 

Animal metabolism is similar for the chloro- and thiomethyl-substituted triazines, with both undergoing conjugations with glutathione (Bakke et al, 1972). Prometon (methoxy substituted) is not readily conjugated, but all of the triazine herbicides show side-chain dealkylation of the amino groups. 

The 1,3-dipolar cycloaddition of diazomethane to bicyclic 2,/S-unsaturated /-lactams produces pyrazolidines which are transformed photolytically into cyclopropane derivatives80. The overall yields arc moderate to good while the diastereomeric ratio is at least 95 5. Reaction of the thiomethyl-substituted lactam with 2-diazopropane provides the corresponding geminal dimethyl-substituted cyclopropane with a d.r. of 95 5. These cyclopropane derivatives have been used for the synthesis of optically active cyclopropanecarboxylates and ethenylcyclopropanes80. 

The through space interaction between a sulfide ng orbital and a distant ethylenic n orbital has been briefly mentioned in the case of 14 (Fig. 16). In this paragraph we consider the much stronger conjugative interaction in the case of thioalkyl substituted tt systems. PE spectroscopic investigation of mono-, di-, and tetra-thiomethyl substituted ethylenes suggests an effective Pcs parameter for the n interaction between the linked S3p and C2p atomic orbitals of —1.6 eV This value is consistent with the PE data for thioanisole ° and a- and j8-thiomethyl-naphthalene ... 

Denny and co-workers used a two-step sequence to prepzire 4-thiomethyl substituted quinazolines as versatile intermediates for the synthesis diversely substituted quinazolines. Treatment of 6-methyl-6//-pyrrolo[2,3-g]-quinazoline with Lawesson s reagent, followed by methylation using methyl iodide under basic conditions, gave the corresponding quinazoline in 32% yield over two steps. 

Denny and co-workers used their 4-thiomethyl substituted quinazolines to generate 4-amino substituted quinazolines as potential antitumor therapeutics. Treatment of 6-methyl-4-(methylthio)-6//-pyrrolo[2,3-g]quinazoline with 4-bromoaniline under thermal conditions gave the desired 4-substituted quinazoline in 85% yield. 

F. Costanzo, D. ToneUi, G. Scahnani, J. Cornil, Theoretical investigation of the electronic and optical properties of oligothiophenes upon methyl, thiol and thiomethyl substitutions. Polymer, 47, 6692-6697 (2006). 

All the examples discussed so far have been of ethyl enolates because simple methyl enolates give very poor diastereofacial selection. This problem can be avoided by the use of thiomethyl-substituted enolates. Raney nickel removes the sulphur to give the desired unsubstituted aldol (73). 

A series of substituted coumestans 87 were synthesized by Liu, Wang, and coworkers through the formal [3 + 2] cycloaddition of quinone monoketals 85 and the thiomethyl-substituted coumarin 86 (Scheme 39) [138]. The reaction, catalyzed by tin tetrachloride, involves an allylic substitution/intramolecular cyclization/thiol elimination sequence. 

For a viable commercial process, the selection of materials and the choice of synthetic route is governed primarily by cost, not by overall yield. The selection of starting material is dictated usually by the desked C-3 substituent. For cephalosporins containing 3-acetoxymethyl or 3-(substituted)methyl such as 3-thiomethyl and 3-aminomethyl derived moieties, the most dkect synthetic route is from cephalosporin C, whereas pencillin V or G is the preferred starting material for the synthesis of the C-3 methyl cephalosporins. The three chemical transformations (2), (5), and 6) can potentially be carried out in a variety of ways, the precise sequence being determined by a balance of competing factors such as cost and optimization of yield (87). 

The early chemistry leading to these derivatives was originally carried out via the 6a-(methylthio) derivative (17) which was prepared by way of a Schiff s base (39). The 6a-thiomethyl group could then be displaced by various nucleophiles giving rise to 6a-methoxy or other 6a-substituted penicillins. A stereo-specific one-step introduction of a methoxy group at C-6 in penicillins provided a simple entry to 6a-methoxy penicillins (40) in yields ranging from 50—62%. 

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

The 5-methoxy seems less critical its replacement by methylthio or ethylthio groups, especially in 3,4,5-substituted compounds, has recently been explored by Jacob and Shulgin (116). Activity in this series is not reduced. Recently, the authors (117) prepared the 2- and 5-thio isosteres of DOM and DOET. With a 2-thiomethyl, activity was retained but was attenuated to about 1/20 to 1/25 of the oxygen isosteres. The 5-thiomethyl isomers possessed two to four times the activity of the thiomethyls at the 2-position. When both the 2- and 5-methoxys were replaced by thiomethyl groups, activity was essentially abolished. 

R2, R3 Denote the substitution pattern at the phenol (phenoxyl) pendent arm the ortho position is indicated first, then the para position Bu = ferf-butyl, Met = methoxy, Me = methyl, SMe = thiomethyl. 

Example I The Gas Phase Structure and the Ionization Pattern of Pi(thiomethyl) Acetylene H2CS-CSC-SCH3. Unstable substituted acetylenes can be generated in the gas phase by thermal... 

Instead of bromobenzophenone (see Scheme 5.1), 4-bromobenzonitrile may also be used as a substrate (Pinson and Saveant 1978). The latter two compounds carry not only bromine, but also other electrochemically active groups, that is, C=0 or C N. These groups do not inhibit the substitution. Along with the thiophenyl, the thiomethyl or thio-tert-butyl groups can be introduced as substituting fragments. The yields of the substitution products are high (from 60 to 95%), and one electron is consumed for every 20-30 molecules of substrate. The reactions proceed at an ambient temperature and do not take place when a potential difference is not set up. 

Oxidation of a thiomethyl group in indolo azepines to a sulfoxide and a sulfone has been reported (2004AP486). Thione 415 with a variety of hydrazides 416 under thermal conditions (n-butanol, reflux) gives fused triazoles 417 in moderate to good yields as the products of a substitution/cyclization sequence (Scheme 87, Section 5.2.1.3 (1993LA1141)). 

The mass spectra of a number of A-substituted isomeric derivatives based on the 3-thiomethyl-5-aminotriazole structure have been correlated with the type of cleavage of the substituent <83JCR(S)126>. 

The dimethyl thioiminoearbonate derivative (115), whieh ean be prepared from the eorresponding aminotriazole <90JHC1689>, undergoes nueleophilie addition with amines and displaeement of a thiomethyl group <92CCC134>. A similar reaetion oceurs with the 1-substituted derivative (116) <92JHC1677>. 

The chloromethylpyrimido[5,4-( ]-l,2,4-triazine 86 is an extremely versatile starting material (see Section 10.20.7.2, Equation 12) and was synthesized from the commercially available thiol 151 as shown in Scheme 25. Thus, 6 -methylation of compound 151 gave the sulfide 152, which was nitrosated to allow access to the nitroso-thiomethyl derivative 153. Nucleophilic substitution of the thiomethyl group by hydrazine gave the cyclization precursor 154, which underwent cyclization with chloroacetaldehyde diethyl acetal under acidic conditions to give the chloro-methylpyrimido[5,4-( ]-l,2,4-triazine 86 after workup with aqueous ammonia <2003BML2895>. 

Tumelty, D. Schwarz, M. K. Needels, M. C. Solid-Phase Synthesis of Substituted l-Phenyl-2-aminomethyl-benzimidazoles and l-Phenyl-2-thiomethyl-benzimidazoles, Tetrahedron Lett. 1998, 39,1461. 

As shown in Scheme 27, 6-lithio-2//-thiopyran (517) further underwent thiomethylation and sulfurization accompanied by 3-propynylation to aiford 6-substituted 2//-pyrans 522377a and 523.428 The latter was thermally converted to bicyclic 2//-pyran system 524428 by the general procedure mentioned in Section III,F. 

Thieno[3,2-c]pyridin-4-one (277) has been prepared by thermal cyclization of 2-thienyl-vinyl isocyanate (Scheme 73) (70BSB301). The derived chloro compound (278) can either be reduced by zinc-acetic acid to (260) or be readily converted into other derivatives by nucleophilic substitution of the halogen. The formation of 4-thiomethyl-6,7-dihydro-thieno[3,2-c]pyridine (280) by cyclization of the isothiocyanate (279) has also been reported (equation 23) (73GEP2318399). 

More recently, 3,3-dimethyl-1 -trimethylsilylcyclopropene was metallated using lithium diisopropylamide (LDA) in THF261. Methylation, silylation and thiomethylation of the lithiocyclopropene intermediate afforded the corresponding 2-substituted cyclopropenes (equation 191). 

The capture of 4,6-dichloro-2-(methylthio)pyrimidine (8) was performed in DMF with diisopropylethylamine (DIPEA, Huenig s base) as a base and tetrabutylammonium bromide as a catalyst at 90°. The substitution of the remaining chlorine atom on the polymer-bound scaffold requires harsher conditions. Thus the immobilized 6-chlorothiomethylpyrimidine (9) could be substituted with aliphatic amines in neat amine at 140°. The coupling with anilines could be afforded consistently only by using KO Bu as base and [18]crown-6. Also, the use of Pd catalysts gave positive results, but failures were observed occasionally. Finally, the substitution of the thiomethyl group in resin-bound 2-(methylthio)pyrimidine-4,6-diamines... 

---