Halo-acids, preparation from

Af-Ethyl-A-(3-halo-2-methylphenyl)aminomethylenemalonates (106, R = Et, R1 = Me, R2 = Hlg, R3 = H) were heated in polyphosphoric acid, prepared from phosphoric acid and phosphorus pentoxide, at 140°C for 40 min. The reaction mixture was then poured into water, and the product was hydrolyzed with 10% aqueous sodium hydroxide to give quinoline-3-carboxylic acids (696, R = Et, R1 = Me,R2 = Hlg) in 68-70% yields (80GEP3007006). 

Although hydrolysis of acyl halides and anhydrides is infrequently used in the preparation of acids, several important examples are noted. The acyl chlorides, ArjC = CHCOCl, from the action of oxalyl chloride on di-arylethylenes are hydrolyzed to yS,yS-diarylacrylic acids by stirring with ice-cold sodium carbonate solution. a-Halo acids prepared by the Hell-Volhard-Zelinsky reaction are obtained from the a-halo acid halide by stirring with cold water (method 67). 

Syntheses of adenine and guanine from uric acid illustrate well the selective transformations to which the halo-purines, prepared from a precursor oxy-purine, can be put. 

Nucleophilic substitution by ammonia on a halo acids (Section 19 16) The a halo acids obtained by halogenation of car boxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reac tive substrates in nucleophilic substitu tion processes A standard method for the preparation of a ammo acids is dis placement of halide from a halo acids by nucleophilic substitution using excess aqueous ammonia... 

Although alcohols are oxidized by tetra-n-butylammonium persulphate when the reaction is conducted in dichloromethane, tetrahydropyranyl ethers have been produced (>90%) when attempts to oxidize the alcohol are conducted in tetrahydro-pyran (see Chapter 10) [ 19], Tetrahydrofuranyl ethers have been prepared by an analogous method [20,21 ]. Base-mediated elimination of halo acids from P-halo alcohols under phase-transfer catalysed conditions produce oxiranes in high yield (70-85%). The reaction has particular use in the synthesis of epihalohydrins from p,y-dihalo alcohols [22],... 

One of the more important uses of thioureas has been in the preparation of 2-imino-4-thiazolidinones, first reported by Meyer135 and Andreasch,136 138 via reaction with a-halo acids or esters. This reaction has been covered by Brown139 in a review on 4-thiazolidinones which appeared in 19(51, and, therefore, will not be discussed in detail here. The corresponding reaction between a-halo acids or esters and scleno-ureas to produce 2-iminoselenazolidin-4-ones is also known and has been reviewed.77-78 Akerblom140 has attempted to clear up some of the confusion in the literature on whether 3-alkyl-2-iminothiazolidin-4-ones (63) or 2-alkylamino-2-thiazolin-4-ones (64) are formed from 1-alkyl-thioureas and chloroacetic acid. She found that the reaction in water... 

Usually, 3- and 4-substituted thianes are prepared from the 3- and 4-oxothians by the common techniques applicable to alicyclic chemistry. Reduction affords alcohols which may be etherified or halogenated, while oximation and reduction produces the amino derivatives, which are also accessible via the halo compounds. 2-Alkoxy and 2-alkylthio compounds are made by acid catalyzed addition of alcohols and thiols to 3,4-dihydro-2H-thiopyran (75MI22502) in a reaction analogous to the use of dihydropyran for protection of alcohols as THP ethers. 

Many of the types of reactions that are useful for the preparation of amino acids have been discussed previously in connection with separate syntheses of carboxylic acids (Chapter 18) and amino compounds (Chapter 23). Examples include the SN2 displacement of halogen from a-halo acids by ammonia,... 

Azine approach. Oxazolo[3,2-a]pyridinium salts (210) were first obtained from the cyclodehydration reaction of l-phenacyl-2(lii)-pyridinone in sulfuric acid (67JHC66). These salts can also be prepared from 2-halo-l-phenacylpyridinium derivatives (211) by treatment with a base which causes ylide formation and hence cyclization by intramolecular substitution (69JOC2129, 76CB3646). It is recommended that a bulky tertiary amine is used as base in order to avoid opening of the ring or substitution of the 2-halo substituent in the starting material (211). Isoquinoline and quinoline analogues have also been prepared by these methods. 

COOH — —CHO. This conversion can be effected in one flask by treatment of the carboxylic acid with N,N dimethylchloromethyleniminium chloride (prepared from DMF and oxalyl chloride) and pyridine to form a betaine, which is then reduced to the aldehyde by the hydride in the presence of a catalytic amount of Cul at — 78° The reaction is applicable to aliphatic and aromatic acids, and can tolerate halo, cyano, ester, and even carbonyl groups. Yields are usually —65-80%. 

Aryl ortho thioesters, which can be readily prepared from the corresponding acid chlorides or methyl esters, react with A-halo compounds, such as 1,3-dibromo-5,5-dimethylhydantoin (DBH) or A-bromosuccinimide, and hydrogen fluoridc/pyridine to give aromatic trifluoromethyl compounds,i.e. formation of... 

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