Ketones, reaction with thiols

Reaction of the pyridine-2-thiol (109) with ketones and with triethyl orthoformate has led to A(5-acetals (112) and 1,3,4-thiadiazoles (110) which on methylation and subsequent ring opening gave two new pyridine derivatives (113) and (111) <96JPR516>. 

Butane-2,3-diol undergoes a reaction with ketones to form a ketal derivative as shown in Figure 50.12. The absolute configurations of acyclic ketones, cyclopentanones, and cyclohexanones with a preference for the chair conformation can be assigned based on an examination of the NMR spectra of the ketal derivatives. Butane-2,3-thiol can be used in the same manner and gives larger enantio meric discrimination, but it is not commercially available. 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

In an extension of the procedure, thiols react with gem-dihaloalkanes (Table 4.4) to produce thioacetals [ 10,20-23] and the reaction can be employed in the Corey-Seebach synthesis of aldehydes and ketones (see ref. 24 and references cited therein), gem-Dichlorocyclopiopanes having an electron-withdrawing group at the 2-position react with thiols to produce the thioacetals [25]. In the corresponding reaction of the thiols with biomochloromethane exclusive nucleophilic substitution of the bromo group by the thiolate anion occurs to yield the chloromethyl thioethers [13, 14] (Table 4.5). 

Dithioketals, especially the cyclic dithiolanes and dithianes, are also useful carbonyl-protecting groups. These can be formed from the corresponding dithiols by Lewis acid-catalyzed reactions. The catalysts that are used include BF3, Mg(03SCF3)2, Zn(03SCF3)2, and LaCl3.100 S-Trimethylsilyl ethers of thiols and dithiols also react with ketones to form dithioketals.101... 

The compound in which the 3-keto group is reduced to a hydrocarbon interestingly still acts as an orally active progestin. The preparation of this compound starts with the hydrolysis of dihydrobenzene (13-2) to afford 19-nortestosterone (15-1). Reaction with ethane-1,2-thiol in the presence of catalytic acid leads to the cyclic thioacetal (15-2). Treatment of this intermediate with Raney nickel in the presence of alcohol leads to the reduced desulfurized derivative (15-3). The alcohol at 17 is then oxidized by any of several methods, such as chromic acid in acetone (Jones reagent), and the resulting ketone (15-4) treated with hthium acetylide. There is thus obtained the progestin lynestrol (15-5) [18]. 

Reactions of 4,7-phenanthroline-5,6-dione have been the subject of considerable study. It is reduced to 5,6-dihydroxy-4,7-phenanthroline by Raney nickel hydrogenation226,249 or by aromatic thiols in benzene,262 and oxidized by permanganate to 3,3 -bipyridyl-2,2 -dicarboxylic acid.263 It forms bishemiketals with alcohols226 and diepoxides with diazomethane.226 The diepoxides by reaction with hydrochloric acid form diols of type 57, R = Cl, which on oxidation with lead tetraacetate give 3,3 -bipyridyl diketones of type 58, R = Cl. Methyl ketones of type 58, R = H, are also obtained by lead(IV) acetate oxidation of the diol 57, R = H, obtained by lithium aluminum hydride reduction of 57, R = Cl. With phenyldiazomethane and diphenyldiazomethane the dione forms 1,3-dioxole derivatives,264,265 which readily hydrolyze back to the dione with concomitant formation of benzaldehyde and benzophenone, respectively. 

Substituted, 2,3-disubstituted, and 2,3-annulated thiophenes can be prepared by reactions of ketone enolates with carbonodithioic acid O-ethyl 5-(2-oxoethyl)ester. Hydrolysis of the resulting aldols, intramolecular addition of thiol group to the carbonyl group, and elimination of two molecules of water lead to the thiophenes (116) (Scheme 38) (92HCA907). 

The Vilsmeier-Haack reaction of ketones forms chlorovinyl aldehydes, which can add thiols readily. The reaction with a-tetralone gave the chlorovinyl aldehyde (230), and reaction with ethyl thioglycolate in ethanolic ethoxide solution formed the dihydro derivative (231), easily dehydrogenated to naphtho[l,2-6]thiophene-2-carboxylate (73JCS(P1)2956). 

Thioacetals and -ketals. A1C13 is an effective catalyst for the condensation of aldehydes and ketones with thiols or dithiols. The reaction of thiols with carbonyl groups with an a-proton results in low yields but the reaction with dithiols proceeds in high yield.8... 

Thioacetals. Aldehydes, ketones, or acetals, both cyclic and acyclic, can be converted into thioacetals by reaction with a thiol or dithiol and MgBr2 (2.1 equiv.) in ether at 25°. The difference in reactivity between acetals and ketones permits selective conversion of acetals into thioacetals without acetalization of a ketone. 

Dithianes, thioacetals and -ketals, enol thiol ethers. This clay is a useful catalyst for reactions of ketones with thiols. The condensations are usually conducted in refluxing toluene with a Dean-Stark trap for water.1... 

Both ketones and aldehydes, as well as acylsilanes can be employed as carbonyl substrates in the new p-lactone synthesis (Table). Reactions involving ketones are most conveniently carried out by adding the neat carbonyl compound to the thiol ester enolate solution. Under these conditions aliphatic aldehydes react to form substantial quantities of 2 1 adducts however, formation of these side products can be suppressed simply by slowly adding the aldehyde component as a precooled (-78°C) solution to the reaction mixture. Wide variation is also possible in the thiol ester component, although a few limitations of the method have been noted. For example, a,p-unsaturated ketones such as methyl vinyl ketone and cyclohexenone fail to yield p-lactones, and attempts to generate p-lactones with severe steric crowding have also met with limited success.3... 

Not surprisingly, thiol ester enolates combine with ketones (and many aldehydes) to form predominantly the less sterically crowded p-lactone diastereomers, in some cases with excellent stereoselectivity. However, the stereochemical course of reactions involving aldehydes has proved to be rather complicated, and further studies are required to clarify the factors that control the stereochemical outcome of these reactions. 

Acetylenic ketones. Reaction of thiol esters with trimethylsilylalkynes catalyzed by AgBF 4 in CH,CI, provides acetylenic ketones in moderate to high yield (equation I). 

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