Chloroacids

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

In much the same vein, the basic ester 7 can be obtained by reaction of the same chloroacid with morpholine derivative 6. Reaction with aniline 4 affords mornif1umate (8). 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

An essentially similar approach has been used for the synthesizing thieno[2,3-c]pyrazoles. Thus, 307 reacted with a-chloroacids (R = H, Me) to give the corresponding thieno[2,3-c]pyrazoles (309), via 308 (71ZOR1253). 

Chlorobutanoic acid is dehydrohalogenated to 2-butenoic acid and HCl is added. H adds to give a /3-carbocation which bonds to Cl to form the /3-chloroacid. 

The title compounds (568) were prepared by reaction of anthranilic acids with y-chloroacid chlorides, followed by cyclization with hydroxylamine (77AF766). The title compounds exhibited antiinflammatory, analgesic and antipyretic activities (77AF766). 

Acylation of ethoxymagnesio derivatives of 1,3-dicarbonyl compounds with a-chloroacid chlorides produces 4-carbonyl substituted 3(2//)-furanones (72JCS(P1)1225). Potassium phenylacetate reacts with a-bromoaldehydes in the presence of 18-crown-6 ether to give 2(5//)-furanones (311) (Scheme 81) (75JOC3139). Dihydrofuranones such as (312) have... 

Amino fatty acids can he treated wilh a mixture of nitric oxide and chlorine to produce the corresponding chloroacid. Mono- and dichlorosuccinic acids are examples of chlorinated dicarboxylic acids. 

Room-temperature chloroaluminate melts exhibit adjustable Lewis acidity, defined by the chloride ion concentration or chloroacidity [6]. Acidic melts result when a molar excess of aluminum chloride is combined with the organic chloride salt (>50 mol% A1C13), and basic melts are obtained when an excess of the salt is mixed with A1C13 (<50 mol% A1C13). The chloroacidity of these melts is well described by the following equilibrium reaction ... 

Besides Equation 17.11, additional equilibria govern the chloroacidity of the AlCl3-NaCl melt ... 

Many a-chloroacids are available commercially (chloro-acetic, propanoic, etc.) and chloroacetyl chloride 41 is made on a very large scale industrially.8 The a-chloro amide 40, needed to make some analeptic tetrazoles, is best disconnected as an amide as 41 is cheap.9... 

You may be surprised to know that the chloroacid 65 can be made from available pivalic acid 63 by photochemical chlorination. This is again a radical reaction, chlorine radicals abstracting one of the nine hydrogens from the /-butyl group as there are no others. Though the chloride in 65 is rather unreactive, it combines well with sulfide anions and the acyloin goes in good yield without any silicon.14... 

TABLE 23. Kinetic parameters and comparative rates for chloroester and chloroacid pyrolysis at 400 °C... 

Melton et al. [452] found that the electrochemical properties of buffered melts remained identical to those of neutral melts. The buffered melts maintained their neutrality, as well as the electrochemical window, even if changes were induced in the chloroacidity by the addition or electrogeneration of a Lewis acid or base. 

Heating the diazonium salt below in the presence of methyl acrylate gives a reasonable yield of a chloroacid. Why is this unlikely to be nucleophilic aromatic substitution by the S l mechanism (Chapter 23) Suggest an alternative mechanism that explains the regioselectivity. 

The structure XXII for rhynehophylline has been confirmed, and the relative stereochemistry at C-15 and C-20 has been elucidated, by a total synthesis (80) of (+) JV-methylrhynchophyllane (XXVI) (Marion s N-methylisorhynchophyllane), which had been prepared earlier by methyl-ation of (iso)rhynchophyllane with sodium methoxide and methyl iodide (28). The lactone (XXVII) of threo-3,4-diethyl-5-hydroxyvaleric acid was converted by reaction with phosphorus pentachloride into the corresponding S-chloroacid chloride (XXVIII), which on treatment with methylaniline gave the anilide XXIX. Reduction of XXIX with lithium aluminum hydride gave the aldehyde XXX, which slowly reacted with... 

In discussing the permanent polarization of single bonds we cannot help wondering how far along a carbon chain this factor exerts its influence. From an examination of the ionization constants of the aliphatic chloroacids we see (Table 2) that two methylene groups interposed between the carboxyl group and the carbon to which the chlorine atom is attached almost destroy the effect of the permanent polarization of the carbon-chlorine bond upon the carboxyl group. 

One of these was synthesized by the Friedel-Crafts acylation of o)-chloroacid chloride(26) (0.1 mole) and AICI3 (0.15 mole) with Bio-beads SXl, SX2, SX12 and SM2 (0.1 mole) in 200 ml of nitrobenzene for 2 hours at 5 C. The resin was washed with acetic acid, 61 HCl dioxane (1 1), H20-dioxane (1 1), dioxane, CH2CI2 and MeOH. The resin was dried under vacuo at 45°C and treated with the sodium derivative of imidazole in DMF. 

The only chiral intermediate is the chloroacid 116 which Zeneca manufacture as a racemic compound. They use the enzyme chloropropionic acid dehalogenase to destroy the unwanted isomer by conversion to lactic acid. It is easy to separate these two compounds as they are not even isomers. 

The same reaction works well with chloride as nucleophile to give 14 and, after reduction of the acid group and cyclisation of the alcohol 15, the epoxide 16. Such epoxides, made from many of the amino acids, now count as members of the new chiral pool. The diazonium salt 11 and the chloroacid 14 are susceptible to racemisation by enolisation and it is only after two distillations that the epoxide 16 has 97% ee. There are very detailed Organic Syntheses procedures for both these steps.6... 

T) ivalolactone (a,a-dimethyl-/ -propiolactone) is a colorless liquid that - can be prepared from pivalic acid via chlorination and subsequent ring closure of the sodium salt of the chloroacid. 

The question remains now how to synthesize the two starting materials (the salts). Sodium (a-chloroacetate) can be made by treating the corresponding a-chloroacid in the presence of sodium hydroxide and this in turn is made by treating acetic acid with chlorine and the chlorinating agent PCI 3. These conditions are specific for chlorination of the alpha carbon of a carboxylic acid. Outlining this sequence ... 

Amino acids can be prepared from chloroacids by heating them in a sealed tube with an ethanolic solution of ammonia. 

Derivatized starches are obtained by reaction with a-chloroacids, epoxy derivatives or anhydrides in alkaline conditions. In general, they have lower gelatinization temperature, better film-forming properties and tend to give softer gels. Typical products used in oil drilling fluids, adhesives and paper applications are carboxymethylated starches, hydroxypropylated starches, cationized starches and acetylated starches. 

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