Chloroacetaldehyde, condensation with

When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz s method (222), 2-substituted thiazoles are obtained (4, 10,"22, 175). 

The N,N-disubstituted thioureas (135) condensed with a-halocarbonyl compounds give 2-disubstituted aminothiazoies (136) but in lower yields (30 to 70%) (Scheme 65 and Table 11-20) (518). For example, N,N-dialkylthioureas condensed with chloroacetaldehyde or dibromoether lead to Ar,At-dialkyl-2-aminothiazoles in 136, Ri=R2 = methyl (342, 404, 436, 637), ethyl (343, 436), n-propyl (518), n-butyl (518), ally] (518), and benzyl (26, 29). When chloroacetone and dichloroacetone are the carbonyl reactants the corresponding 4-methyl (518) and 4-chloromethyl derivatives (572) were obtained. 

When 3-mercaptocyclohexanone condenses with dichloroacet-aldehyde or chloroacetaldehyde in the presence of a catalytic quantity of acid (e.g., p-toluenesulfonic acid), simultaneous cyclization occurs to give 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one (see Section VI, B, 4) and 2,4,5,6,7,7a-hexahydrobenzo[6]thiophen-4-one (see Section... 

Thieno[2,3- >][l]benzothiophens (293), including the parent compound, were prepared from substituted 2-benzo[Z>]thiophenthiols, obtained from the corresponding lithium derivative followed by condensation with chloroacetaldehyde diethylacetal, chloroacetone, or 3-chlorobutan-2-one, and finally cyclization with hot polyphosphoric acid. For the synthesis of thieno[3,2-6][l]benzothiophens (294), the necessary thiol was... 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

Other aldehydes which have been used in the reaction are pro-panal, butanal, glycolaldehyde, 3-hydroxybutanal, and a number of phenylacetaldehydeand benzaldehyde derivatives. Whereas condensation of tryptophan with acetaldehyde takes place even at room temperature and pH 6.7, the reactions with chloral, chloroacetaldehyde, and crotonaldehyde fail entirely. 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

One of the earliest diazo components of this type to be introduced was 2-amino-5-nitrothiazole (4.81), prepared by condensation of thiourea with chloroacetaldehyde and nitration of the resultant 2-aminothiazole (Scheme 4.32). This component yields bright dischargeable blues, such as Cl Disperse Blue 82 (4.82), which have outstanding build-up, very high extinction coefficients and good fastness to burnt gas fumes. Use of diazo component 4.81 with coupling component 4.83 yields a greenish blue dye. 

Some of the simple condensations of a-ketoesters with a-halogenoketones suffer from the disadvantage that mixtures of furans may result. Nakanishi used this reaction in condensing chloroacetaldehyde with ethyl acetoacetate in the presence of pyridine to give the known 2-methyl-3-furoate in 55% yield during the synthesis of an insecticide (70MI31200). 

Condensations of erythritol with benzaldehyde,78,78 o-, wi-andp-chloro-benzaldehyde,18 p-methylbenzaldehyde,18 p-methoxybenzaldehyde,18 o-, m- and p-nitrobenzaldehyde,18,87 3-nitro-4-chlorobenzaldehyde,18 acetaldehyde,74 chloroacetaldehyde,74 acetone,1718 formaldehyde,78 and val-eraldehyde76 have been reported, but in no case has the structure of the product been determined. The physical constants of these acetals and ketals are recorded in Table VII. The photo-sensitivity of o-nitrobenzyl-idene-erythritols has been discussed on page 149. 

Thiazole itself can be obtained by condensing chloroacetaldehyde and thioformamide (Scheme 159). The reaction is explosive and proceeds in low yield because of the instability of the thioformamide under acid conditions. Higher thioamides are more stable and react under milder conditions with chloroacetaldehyde, affording 2-substituted thiazoles in moderate yields. It is possible, and often preferable, to prepare the thioamide in situ in dioxane solution by the action of phosphorus pentasulfide on the corresponding amide and in the presence of solid MgC03 (Scheme 160). With arylthioamides, except for some nitrothiobenzamides, yields are usually higher and the cyclization is carried out over several hours in boiling absolute alcohol. Chloroacetaldehyde can be replaced in these reaction by derivatives such as 1,2-dichloro- or dibromo-ethyl methyl or ethyl ether, 1,2-dichloro- or dibromo-ethyl acetate, 2-chloro- or dibromo-ethyl acetate, and 2-chloro or bromo-diethyl-acetal. 

In both processes the aqueous crude aldehyde is concentrated and byproducts are removed in a two-step distillation. Both processes give 94% yields of aldehyde, along with small amounts of 2-chloroethanol, ethyl chloride, acetic acid, chloroacetaldehydes and acetaldehyde condensation products. The Wack-er-Hoechst process currently accounts for 85% of the worldwide production capacity for acetaldehyde. 

More recently, Tada and co-workers reported the total synthesis of patulin (348) in 1994 (Scheme 7.1) (507). Starting with the condensation of acetonedicarboxylic acid dimethyl ester (353) and chloroacetaldehyde to form an appropriately 2,3-disubstituted furan 354, this was further reduced and selectively oxidized at the aromatic carbinol to deliver 3-furaldehyde 355. Dean-Stark condensation of this species in the presence of methanol gave the methyloxy furanopyran 356. Oxidative ring-opening to a carboxylate intermediate and subsequent methylation with diazomethane provided ester 357, which was lactonized and finally demethylated to deliver the natural product 348 in 7% yield over a total of eight consecutive steps. 

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