3- Substituted 4,5-disubstituted acetic anhydride

Microwave-assisted procedures have also been developed for the condensation of substituted amidines and ureas with malonic acid derivatives <2005TL5727, 2007AJC120>. For example, reaction of substituted ureas 668 with malonic acid 667 in the presence of acetic anhydride gave 1,3-disubstituted barbituric acids 669, while similar condensation with cyanoacetic acid 670 gave 6-aminouracil derivatives 671 <2005TL5727>. 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

Ferrocene reacts with acetyl chloride and aluminum chloride to afford the acylated product (287) (Scheme 84). The Friedel-Crafts acylation of (284) is about 3.3 x 10 times faster than that of benzene. Use of these conditions it is difficult to avoid the formation of a disubstituted product unless only a stoichiometric amount of AlCft is used. Thus, while the acyl substituent present in (287) is somewhat deactivating, the relative rate of acylation of (287) is still rapid (1.9 x 10 faster than benzene). Formation of the diacylated product may be avoided by use of acetic anhydride and BF3-Et20. Electrophilic substitution of (284) under Vilsmeyer formylation, Maimich aminomethylation, or acetoxymercuration conditions gives (288), (289), and (290/291), respectively, in good yields. Racemic amine (289) (also available in two steps from (287)) is readily resolved, providing the classic entry to enantiomerically pure ferrocene derivatives that possess central chirality and/or planar chirality. Friedel Crafts alkylation of (284) proceeds with the formation of a mixture of mono- and polyalkyl-substituted ferrocenes. The reaction of (284) with other... 

Isothiouronium chlorides (317) undergo condensation reactions with formamidinium chloride (318a) or substituted formamide acetals (318b), and with acyl chlorides (319a) or anhydrides (319b) furnishing 2,5-disubstituted or 2,4,5-trisubstituted thiazoles in moderated yields (Scheme 79) <85S414>. 

When hydantoins are treated with acetic anhydride, sodium hypochlorite, or nitiric acid, substitution takes place at the N-l position, followed by the formation of a 1,3-disubstituted hydantoin.1 Intramolecular processes yield only the amide cyclized products (102).255,256... 

Electrophilic attack by aldehydes can also take place at positions 3 and 4 in suitably substituted thiophenes. Thus, 2,5-bis(trimethylsilyloxy)thiophene reacts with aromatic aldehydes in the presence of the Lewis acid trimethylsilyl trifluoromethanesulfonate (0.1-1.0%) to form 3,4-disubstituted thiosuccinic anhydrides (88) in quantitative yield. With aliphatic aldehydes, the yields are lower, the catalyst being ZnBry, the products so obtained have been hydrolyzed in the presence of lead acetate to form the lactones (89) in 30-40% yields. 2,5-Bis(trimethylsilyloxy)thiophene also reacts with orthoesters in the presence of trimethylsilyl triflate to form (90) <87C152,92LA615>. 

Of the esters, starch phosphate is produced by reaction with phosphorus oxychloride, polyphosphates, or metaphosphates a cross-bonded product results. Total degree of substitution is determined by measuring the phosphorus content, and the mono- to disubstitution ratio can be calculated by potentio-metric titration. Allowance is made for the natural phosphorus content of the starch. Treatment of starch with acetic anhydride produces starch acetate, which has improved paste stability over native starch. The acetyl group is very labile, and hydrolyses readily under mild alkaline conditions. When a known amount of alkali is used, the excess can be titrated and the ester function measured. This is not specific, however, and a method based on an enzymatic measurement of the acetate has been developed in an ISO work group. The modified starch is hydrolyzed under acidic conditions, which releases acetic acid and permits filtration of the resulting solution. Acetic acid is then measured by a commercially available enzyme test kit. Both bound and free acetyl groups can be measured, and the method is applicable... 

Starch adipate, a cross-bonded starch for food use, is made by reaction with adipic anhydride, which is formed from adipic acid in the presence of excess acetic anhydride. It is also a labile ester, and after hydrolysis with alkali, followed by acidification, is extracted with ethyl acetate and silylated. Gas chromatographic analysis is performed on a capillary column of fused silica coated with dimethyl siloxane, film thickness 5 pm. Pimelic acid is the internal standard. The method cannot differentiate between mono- and disubstitution. Alkyl succinate substitution can be determined using the same procedure as for adipate. 

Starting from 3,4-disubstituted maleic anhydride, Klopfleisch and coworkers synthesized the bilirubin oxidation end-product BOX A and isomers in four or six steps (20130L4608). Within this synthesis they transformed 5-alkylidene-furan-2-ones to the corresponding substituted 3-pyrrolin-2-ones using ammonium acetate and glacial acetic acid. Seidel and coworkers employed a similar approach to BOX B analogs (2014TL6526). 

Examples of well-established 1,3,4-thiadiazole syntheses have been extended to the production and study of their selenium analogues." 1,4-Disubstituted selenosemicarbazides (191 R = Aik, Ar, or Ac) are readily accessible in good yield by the addition of isoselenocyanate esters (including benzoyl isoselenocyanate) to acylhydrazines." Their cyclization in acidic media affords the stable crystalline 1,3,4-selenadiazoles (192 R = Aik, Ar, or Ac) " the members of the aroylamino-series are stable to alkalis, but are hydrolysable by acids to the parent amines (192 R = H) these are convertible into conventional derivatives, as expected." Bis-selenoureas of type (194) are similarly accessible, but usually cyclize spontaneously to the substituted 2,5-dianilino-1,3,4-selenadiazoles (195). The action of acetic anhydride on (194) yields diacetyl derivatives of (195)... 

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