A-Haloacetates

Potential applications of vitamin Bi2 in electrocatalytic degradation of dibromide and a-haloacetic acid pollutants has been demonstrated in aqueous buffers303,304 and in surfactant-stabilized emulsions.305 Electroreductive dehalogenations in water and microemulsions were also efficiently catalyzed by a vitamin Bi2 derivative grafted onto a polylysine-coated electrode.306... 

The relative reactivity of a-haloacetates toward protein functionalities is sulfhydryl > imid azolyl > thioether > amine. Among halo derivatives the relative reactivity is I > Br > Cl > F, with fluorine being almost unreactive. The a-haloacetamides have the same trend of relative... 

Thus, iodoacetamide has the highest reactivity toward cysteine sulfhydryl residues and may be directed specifically for —SH blocking. If iodoacetamide is present in limiting quantities (relative to the number of sulfhydryl groups present) and at slightly alkaline pH, cysteine modification will be the exclusive reaction. For additional information on a-haloacetate reactivities and a protocol for blocking, see Section 4.2 (this chapter). 

The products from the N-alkylation of (anilinomethylene)malonodinitriles with a-haloacetic esters and a-haloketones spontaneously cyclize to produce pyrroles (Scheme 5.3) [21]. When the A -acylated product of the reaction of the dinitrile with ethyl chloroformate is treated with an arylamine, 5-cyanopyrimidones are obtained [21]. 

The electroreductive dehalogenation of a-haloacetic acids has been achieved with cobalamin [387]. The hydrophobic vitamin B12 Co complex immobilized on a glassy carbon electrode (252) may catalyze the electrochemical carbon-skeleton rearrangements of... 

Alkylation of enamines may lead to the formation of N-alkylated product, which on heating is converted to C-alkyl compound (This rearrangement is common with allylic halide, alkyl halide or a-haloacetic ester. 

Iminothiazolidin-4-ones have also been prepared by the reaction between thiourea and iV-chloroacetylanilines157-159 or a-haloacet-amides.160,161 In addition, these heterocycles are produced by treatment of thiourea with a-trichloromethylbenzyl alcohol162 and from thio-pseudoureas and thioglycolic acid.163... 

On the basis of these results, a mechanism (Scheme 8.10) involving the intermediacy of a silver-carbene 54 was proposed in which the insertion product arises from the formation of the halonium ylide 55, followed by a 1,2 shift (55 —> 26, or 51 or 52). Alternatively, if the substrate and thus the halonium ylide 56 contain a (3-hydrogen, this could be removed by an intramolecular deprotonation with concomitant loss of halide resulting in formation of the olefin 57 and the a-haloacetate 53. At this stage, no independent evidence has been obtained to support this pathway thus this mechanism is purely speculative (see text below). Indeed, although the pathway has been depicted as involving metal-free intermediates, it is quite likely that this is not the case, but this awaits independent experimental verification. 

Reactions of 5-oxo-4,5-dihydrooxazoles with O-nucleophiles 93UK55. Syntheses of oxazolones from L-tryptophan and a-haloacetic anhydrides, and their reactions 92BSB643. 

Rusling, J.F., Miaw, C.L. and Couture, E.C. (1990) Electrocatalytic dehalogenation of a-haloacetic acids by vitamin B12. Inorg. Chem. 29, 2025-2027. 

The simplest synthesis of pseudothiohydantoins (8) is by condensation of thiourea (6) with substituted a-chloroacetates (7)3 5 [Eq. (1)]. Synthons6 of 7, epoxyacids,7 a-chloroacetic anhydrides,8 and dialkyl acetylenedi-carboxylate,9 have been successfully substituted for 7. Symmetrical diaryl-thioureas (9), conveniently synthesized from the corresponding arylamine and carbon disulfide, react with a-haloacetic acid derivatives to give a single thiazolidinone 108,10,11 [Eq. (2)]. 

An alternative approach to information about tautomeric equilibria with these compounds is via ultraviolet data. Ultraviolet data for substituted 2U9.U3,181.182 312.126.132.179-182 have been reported. In the condensation of thiourea and a-haloacetic acids, the main absorption maximum at 241-249 nm is preserved due to the polar structures of pseudothiohy-dantoins.181 Generally, in the UV spectra of substituted 2 and 3, the amide bond is weak.181... 

Thiophenes are also readily available by treatment of 3-halocinnamonitriles with a-haloacetic acid derivatives in the presence of sodium sulfide and a base. In a stepwise route, the precursor 4 was converted to the intermediate 5, which was finally subjected to base induced cyclization giving the thiophene 6 <07SC1133>. Related annulation methodology has been used for construction of a series of 3-amino-5-arylthiophene-2-carbonitriles <07S1027>, and thieno[3,2-Z>]pyridine-5(477)-ones <07S2153>. 

The most versatile method, for the preparation of this ring system is the condensation of an a-halocarbonyl compound with a 3-amino-l,2,4-triazine. For example, treatment of 3-amino-5,6-dimethyI-l,2,4-triazine (565) with phenacyl bromide (512) produced only (566) (65JHC287). In addition to a-hdoketones, a-haloaldehydes (72JHC1157, 55MI41000), a-haloacetals (80MI41000) and a-haloesters (79CHE1255) have been used. The direction of condensation is always as shown for the preparation of (566). 

TABLE U-12, 2-AMINOTHIAZOLES FROM THIOUREA AND a-HALOACET-ALDEHYDE AND DERIVATIVES... 

General chemical structure of a haloacetic acid, a indicates the alpha carbon atom. X, Y and Z represent hydrogen (H) or a halogen (F, Cl, Br or I) - at least one of these must be a halogen. 

Substituted haloacetates (R and R 7 = H) are exceptions to the rule that branched-chain halides are unreactive in the Michaelis-Arbuzov reaction. A large variety of easily available a-chloro or bromo esters "- react with trialkyi phosphites at 160-190°C to produce a-substituted phosphonoacetic esters in fair to excellent yields (31-96% , Scheme 8.7, Table 8.2). Because secondary a-haloacetates are stable compounds that may be either easily prepared on laboratory scale or may be obtained commercially, the Michaelis-Arbuzov rearrangement appears as a reaction of special importance. 

Several innovations have significantly extended the scope and synthetic utility of the classical Michaelis-Becker phosphonoacetate preparation. Eor example, the coupling of the Michaelis-Becker and Homer-Wadsworth-Emmons reactions for the synthesis of a-substituted acrylic acids represents a useful modification. According to Scheme 8.10, Michaelis-Becker alkylation of a dialkyl phosphite with a haloacetic acid in the presence of 3 eq of a base (one to neutralize the carboxyl group, one to form the phosphite conjugate base, and one to deprotonate the initially formed alkylation product) leads to the phosphoryl-stabilized anion directly. Treatment of the anion... 

Indoxyls are normally prepared from anthranilic acids via alkylation with a haloacetic acid followed by a cyclising condensation with loss of carbon dioxide. " Indoxyl itself is best prepared by Friedel-Crafts type ring closure of iV-phenylglycine activated with triphenylphosphine oxide/triflic anhydride in the presence of triethylamine at room temperature. " ... 

While successful couplings with a-haloacetals are rare (elimination of HBr and/or alcohol usually is the main reaction), satisfactory yields of alkylation products have been obtained from the reactions of 2-furyllithium and of 2-thienyllithium with BrCH2CH(OEt)2 in THF [43]. This haloacetal is less reactive than simple primary alkyl bromides. Addition of HMPT, in order to give higher rates of conversion, had an adverse effect due to promotion of the elimination reaction [9]. With phenyl-lithium, which is more strongly basic than the heteroaryllithiums, elimination predominated, even in the absence of HMPT [9]. 

In 1951-1953 Rabindran and Tilak51,52 introduced a new dibenzo-thiophene synthesis and extended it to tetracyclic and pentacyclic systems. This method involves a two-step process of condensing a thioarenol with an a-halo ketone or a-haloacetal to form an a-(arylthio) ketone or a-(arylthio)-acetal intermediate, which is subsequently cyclized intramolecularly. The three principal variations introduced by Tilak and co-workers are presented in Schemes 3, 5, and 6 and were summarized in I960.528... 

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