A-Chloroacids

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). 

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... 

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... 

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 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 ... 

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. 

The alkene (39), produced by Wittig reaction, gave exclusively 0-anomers (40) on cyclization and hydrolysis. The a-chloroacid was... 

It was reported that hydroxy acid can also be produced by the hydrolysis of a-chloroacid ... 

The WGS reaction can be used as a source of PdH species for various reductions including the hydrogenation of the double bond and hydrogenolysis of the hydroxyUc group in a-hydroxyacids or chlorine atom in a-chloroketones (Scheme 86) or a-chloroacids.f ... 

When a,P-unsaturated esters of type (139) underwent reaction with Grignard reagents R MgBr under Cu catalysis, the major adducts had the stereochemistry indicated in (140), a result that was attributed to a k-stacking interaction of the benzene ring and enoate helping to rix the conformation of (139).H0 Trimethylsilyl ketene acetals (141) reacted stereoselectively with NCS to give products (142), and hence (5)-a-chloroacids.lii... 

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). 

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. 

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 ... 

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... 

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. 

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. 

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. 

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. 

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

Better yields are recorded from oo-chloroacids because of the electrophilic assistance by the generated lithium chloride, while bromides, iodides, or tosylate give poor results. 2 vVhen applied to a dipeptide precursor (Fig. 13), experiments using the sonochemically in situ generated LDA exhibit a higher stereoselectivity than with a conventionally prepared reagent. 

Providing excess solid sodium chloride assures that any formation of chloroacidic species, for example, due to electrode reaction, is quickly neutralized by the sodium chloride, and thus the solution is buffered. The solution is considered buffered from the acidic side in this case, because the buffer prevents the formation of excess acid (see Reference 80 for a review of these concepts). This work and additional studies on the use of other species for buffering (such as HCl,LiCl and MgiQ ) are discussed later, but it is noted here... 

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