Acyl tosylates ketones

This method accommodates aryl aldehydes with both electron-deficient and electron-rich aryl substitutents. Acetaldehyde is also a competent couphng partner, providing the corresponding amido ketone in 62% yield. Acyl substitution of the tosyl amide varies to include hydrogen, methyl, tert-butoxy, and phenyl producing the desired a-amido ketones in moderate to high yields. Expansion of this methodology to synthesize di- and tri-substituted imidazoles was reported by Murry and co-workers (Scheme 7) [54]. 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

Ionic routes to allylic 4 and benzylic 6 alcohols include reduction of the ketones 3 and 5 as these are easily made by aldol reactions and Friedel-Crafts acylation. The alcohols can be converted into electrophiles by tosylation or conversion into bromides. 

Although nitriles lack an acyl group, they are considered acid derivatives because they hydrolyze to carboxylic acids. Nitriles are frequently made from carboxylic acids (with the same number of carbons) by conversion to primary amides followed by dehydration. They are also made from primary alkyl halides and tosylates (adding one carbon) by nucleophilic substitution with cyanide ion. Aryl cyanides can be made by the Sandmeyer reaction of an aryldiazonium salt with cuprous cyanide. a-Hydroxynitriles (cyanohydrins) are made by the reaction of ketones and aldehydes with HCN. 

The synthesis can be extended to the preparation of ketones in six distinct ways. " These include quenching 180 with a second alkyl halide (R X) rather than acetic acid omitting PPhs with first RX and then adding the second, R X treatment with RX in the presence of CO, followed by treatment with R X treatment with an acyl halide followed by treatment with an alkyl hahde or an epoxide, gives an a,p-unsaturated ketone. The final variations involve reaction of alkyl halides or tosylates with Na2Fe(CO)4 in the presence of ethylene to give alkyl ethyl ketones when 1,4-dihalides are used, five-mem-... 

In the benzoin condensation, one molecule of aldehyde serves as an electrophile. If a carbanion is generated from protected cyanohydrins, a-aminonitriles or dithioacetals, it can react with electrophiles such as alkyl halides, strongly activated aryl halides or alkyl tosylates to form ketones. Amongst other electrophiles which are attacked by the above carbanions are heterocyclic A -oxides, carbonyl compounds, a,p-unsaturated carbonyl compounds, a,3-unsaturated nitriles, acyl halides, Mannich bases, epoxides and chlorotiimethyl derivatives of silicon, germanium and tin. 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

Another potential approach towards 1 was reported by Seido et al. utilizing an asymmetric reduction of the ketone (57 Scheme 15) as the key step. Acylation of the lithium enolate of methyl phenylacetate with the imidazolide, obtained by treatment of the acid 56 with A, V -carbonyldiimidazole, gave the ketoester 57 in 66.4% yield. Asymmetric reduction of 57 with [RuI(/7-cymene)(5)-binap]I, tin chloride, and cam-phor-lO-sulfonic acid in methanol at 80 °C afforded the alcohol 58 as a mixture of syn and anti forms in 87.4% yield. The ratio of syn to anti isomers was 76.3 23.7 and the enantiomeric purity of each form was 95.6% ee and 97.8% ee, respectively. Tosylation of 58 with p-toluenesulfonyl chloride and pyridine in the presence of catalytic amounts of DMAP yielded a diastereomeric mixture of tosylate 59 in 61.8% yield. Deprotection of the /V-Cbz group in 59 by hydrogenation over 5% Pd-C followed by cyclization of the resulting amino tosylate 60 with potassium carbonate in methanol furnished methylphenidate as a mixture of erythro and threo isomers in a 7 3 ratio and 77.5% yield. 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

Under similar conditions 7-methoxy-l-acyl-l, 2,3,7-tetrahydrodiazepin-4-one (28), the corresponding 1-tosyl compound, and the bicyclic ketones (29) also yield the quaternary salts (26).4M9... 

The thus established stereocenter served in the following steps. Conversion of 50 to 51 was achieved by acyl chloride formation followed by Friedel-Crafts reaction with ethylene and A1C13. Addition of the lithium enolate of t-butylacetate occurred from the less-hindered face of the cyclic ketone to give, after reduction and tosylation, adduct 52. Tosylate displacement with amine 53, esterification with methoxyacetylchloride, and addition of HC1 gave mibefradil 54. 

Di-t-butyl chromate and its pyridine adduct are suitable for large-scale oxidations of alcohols to ketones, thus cyclododecanol was converted into cyclododecanone (97 Alcohols are easily separated from non-hydroxylic compounds via their calcium chloride complexes. This method was used to separate cyclododecanone and cyclododecanol and is suitable for the separation of large quantities of material." All-cis-cyclododecane-l,5,9-triol was converted into the all-cis-tri-amine by tosylation, azide substitution, and reduction, and the amine acylated with 2,3-dimethoxybenzoyl chloride to give the tri-amide, an analogue of enterochelin. ... 

P-Enamino ketones or esters 30, readily accessible from 1,3-diketones or P-ketoesters, are susceptible to diazo transfer (Regitz reaction [499]) with mesyl or tosyl azide in basic medium at room temperature and subsequent cyclization to give 4-acyl-(or 4-carbalkoxy-) 1,5-substituted 1,2,3-triazoles 32 [500] ... 

Organozirconocene Chlorides. Acyl zirconocene chlorides function as efficient donors of acyl anions and can react with allylic or propargylic halides (X=Cl, Br, I, OTs) under Cul catalysis. In these reactions, acyl copper species (RCOCu), generated by the transfer of acyl group fromZr to Cu, were speculated to be the reactive species. These Cul-catalyzed reactions of acyl zirconocene chloride are cort5)lementary to the palladium-catalyzed reactions and enable the formation of -y-unsaturated ketones, which suffer ready isomerization under the palladium-catalyzed conditions (eq 23). On the other hand, carbonylative cross-coupling of F-o -selanylvinylzirconiums with alkynyUodonium tosylates can be performed in THF in the presence of 3 mol% of Cul and atmospheric pressure of carbon monoxide in a palladium-free system. 

The acid 2.8 is used to provide the acid chloride which gives a route to dimethylene linked-compounds by Friedel-Crafts acylation and reduction of the product ketone [34] and the alcohol 2.7 is used for the methyl-eneoxy-linked systems [36] by a direct DEAD reaction to a phenol [37] or by conversion into an alkyl halide or tosylate and reaction with a phenolate anion. 

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