5-Alkylation thioacetates, synthesis

SYNTHESIS OF THIOLS, THIOETHERS, THIOACETALS AND S-ALKYL THIOCARBOXYLIC ESTERS... 

A superior and relatively versatile procedure for the synthesis of unsymmetrical dialkyl thioethers, which avoids the unattractive direct use of thiols, utilizes the stable l-alkylthioethaniminium halides, which are readily obtained from thioacet-amidc [32] (Scheme 4.4). The reaction has also been used for the synthesis of alkyl aryl thioethers from activated aryl halides [33], but it cannot be used for the synthesis of cyclic thioethers, as polymeric sulphides are formed from a,co-dihaloalkanes. A similar sequence to that which leads to the thioethers has been used for the synthesis of S-alkyl thioesters [34] (see 4.1.26). 

Thiol esters RC(0)SR are stronger acylating agents than simple alkyl esters, and have been prepared on solid phase mainly as synthetic intermediates. The preparation of thiol esters as intermediates for the synthesis of support-bound thiols is discussed in Section 8.1. Further examples of the preparation of thiol esters on insoluble supports include the aldol addition of ketene thioacetals to polystyrene-bound aldehydes... 

Michael additions. Gerlach and Kiinzler report that the lithium enolate of S-t-butyl thioacetate undergoes 1,4-addition to cyclopentenone. They have extended this Michael reaction to a synthesis of methyl jasmonate (5), based on the similar conjugate addition of the trimethylsilyl enolate 1 promoted by tetra-n-butylam-monium fluoride. The adduct 2 was alkylated by l-bromo-2-pentyne in the presence of tetra-n-butylammonium fluoride to give 3 in rather low yield. Remaining steps to 5 were methanolysis and partial hydrogenation of the triple bond. 

Thietanones also have been obtained by treatment of aliphatic ketones with an a-methylene group with thionyl chloride, usually in the presence of a base as shown for the synthesis of 359. A 3-thietanone was suggested as a possible structure for the product obtained by the acid-catalyzed hydrolysis of the bis-thioglycolic thioacetal of substituted benzaldehydes, but an elemental analysis was the only evidence. Treatment of l-diazo-3-phenylthio-2-propanone with acid gives the -phenyl salt of 3-thietanone (Section VII.1.). Similar 5-alkyl salts may be intermediates, but they readily decompose either by loss of the 5-alkyl group or... 

Synthesis of 3-Acetylthio-2-alkyl Alkanals. Piperidine (100 pL) was added to alkenals 5a-f (34 mmol) under nitrogen at 10 °C in separated cylinders of die Quest 205 apparatus. Thioacetic acid (3.68 mL, S1.6 mmol) was dien added d op-wise at 10 °C. Thereafter, the reaction mixture was stirred for another 18 h at room temperature. The mixture was diluted widi Et20 (10 mL), washed first with HCl (10 mL, 1 N) and then twice with a saturated NaHCOa solution (10 mL). The organic phases were dried over Na2S04. All these steps were carried out at the same time in the Quest 205. Then, the solvent was evaporated for each sample. The GC purity of the crude products was 50-90%, depending on the starting alkenal. In each case, a mixture of the two diastereomers was obtained. The detailed analytical description of the 3-acelylthio-2-alky-alkanals 6a-f has been reported elsewhere (//). 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

A synthesis of 4-alkyl-2-methoxy-1-phenylthio-1,3-butadienes by a simple -elimination of thiophenol from a thioacetal is not possible owing to skeletal rearrangement that is fostered by stabilization of a cyclopropylcarbinyl carbocation intermediate by the alkyl substituent (eq 51). Interconversion of an initial a-phenylthio carbocation to a more stable a-methoxy carbocation intermediate leads to the generation of a 4-alkyl-l-methoxy-2-phenylthio- 1,3-butadiene instead. 

The method has been extended to a general synthesis of a-alkylidene- and a-alkyl-ketones. The same group describes the reaction of allylic and benzylic halides with silyl enol ethers in the presence of catalytic quantities of zinc(ii) bromide. Other workers also report the use of secondary benzylic halides, allylic halides, and diethyl thioacetals as alkylating agents in the presence of Lewis acids. t-Alkyl halides also alkylate these systems with titanium(iv) chloride as catalyst. ... 

A new method of synthesis of substituted cyclohex-1-enyl alkyl sulphides involves the reaction of the appropriate cyclohexanone with a thioacetal or thiol in the presence of aluminium chloride.Aldehydes and ketones give symmetrical dialkyl disulphides on treatment with hydrogen sulphide in the presence of pyridine and triethylamine. ... 

The intramolecular carbonyl olefination of esters bearing a thioacetal moiety is also applicable to the synthesis of cyclic vinyl ethers. The formation of simple monocyclic vinyl ethers by the treatment of co,(B-bis(phenylthio)alkyl alkanoates with 44 is rather complicated owing to the concomitant formation of oligomers... 

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