Haloacetic acid derivatives

To synthesize the monoxacetam stmctures (Fig. 6), alkylation of A/-protected 1-hydroxyazetidinones (46) with the appropriate haloacetic acid derivatives provided (47). Alternatively, (47) could be prepared from the acycHc hydroxamate ester (48). Deprotection of (47) furnished the zwitterionic intermediate (49) [90849-16-4] CgH2QN204, which subsequendy underwent acylation using the C-3 aminothiazole oxime side chain to afford SQ 82,291 (45) also known as oximonam (37). 

In 1962 Gompper, Kutter, and Topfl prepared substituted thieno-thiophenes (1) from dithiocarboxylate s ts. With haloacetic acid derivatives these give ketenemercaptals (104), which are easily converted by base into 3-amino- and 3-hydroxythiophenes (105). Further cyclization of 105 results in substituted thienotMophenes 106, which may also be obtained directly by heating the dithiocarboxylates with haloacetic acid derivatives in alcoholic sodium alkoxide (Scheme 7). 

For Sn2 reactions the effect of electron-withdrawing groups is less easy to predict than for SnI reactions. a-Halo ketones, a-halo nitriles, or haloacetic acid derivatives undergo bimolecular substitutions at much higher rates than unfunctionalized alkyl halides (Scheme 4.42). 

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)]. 

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>. 

Similar methodology has been applied in the syntheses of 2-amino-3-hydroxycarboxylic acids in high diastereomeric and enantiomeric purity. Two separate pathways give either the antt- or. WM-products. The first strategy relies on haloacetate precursors derived either from (S )-valine 17"- oi or from norephedrine 18102, which are converted into the boron enolates103 and subsequently reacted with aldehydes to deliver. ym-adducts99 102. The diastereomeric ratio, defined as the ratio of the desired diastereomer/the sum of all others, is 50 1 for the former and about 95 5 for the latter adducts. 

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... 

Illustrative examples of the acylation of support-bound amines with carbodiimides as coupling agents are listed in Table 13.3. Difficulties are usually encountered in the acylation of a-alkylamino acid derivatives (which are significantly less nucleophilic than simple secondary amines Entries 3 and 4) and Al-alkyl (Entries 5 and 6) or iV-aryl anilines. Acylations with haloacetic or related acids containing a leaving group prone to nucleophilic displacement should not be performed with the aid of HOBt and bases because O-alkylation of HOBt by the product occurs readily. 

Haloacetic acids are derivatives of acetic acid in which one or more hydrogen atoms on the alpha carbon are replaced by halogens (fluorine, chlorine, bromine or iodine) (Figure 12.1). The haloacetic acid most commonly used in peels is trichloroacetic acid, and we will therefore look at the chlorine derivatives of acetic acid. 

The reaction of derivatives of acetic acid (or its salts) with the Vilsmeier reagent is widely used to prepare malonaldehydes or their derivatives. The simple haloacetic acids 137 (or their salts) give fluoro- " or chloromalonaldehyde derivatives " " or chloro- or bromotriformylmethane derivatives (Eq. 115). ... 

Low-level chlorination of 0.5-1.5 mg/1, resulting in a chlorine residual of 0.1 -0.2 mg/1, is used to reduce the degree of biofouling. In sea-water, chlorine oxidizes bromide, present at about 65 mg/1, to bromine, which also contributes to the generation of halogenated by-products [176]. The by-products include hypobromous acid, hypobromite, chloramines, bromamines, trihalomethanes, haloacetonitriles,haloacetic acids, and small amounts of halophenols. However, some haloforms and bromophenols as well as other organobromine compounds are also produced naturally in coastal waters [ 181,182]. Empirical equations for the disappearance of chlorine/bromine derived oxidants from brackish water have been published [183]. 

Jia, M. Wu, W.W. Yost, M.G. Chadik, P.A. Stacpoole, P.W. Henderson, G.N. Simultaneous determination of trace levels of nine haloacetic acids in biological samples as their pentafluorobenzyl derivatives by gas chromatogra-phy/tandem mass spectrometry in electron capture negative ion chemical ionization mode. Anal. Chem. 2003, 75, 4065 080. 

Derivatization processes The derivatization carried out before or during the extraction can increase the technique sensibility and selectivity. Different derivatization techniques are discussed in Refs. [46,164]. However, it should be used only when necessary, since SPME becomes more complex. Formaldehyde exposed to a previously doped fiber with the derivatizing agent o-(2,3,4,5,6-pentafluorobenzyljhydroxylamine is converted to the oxime derivative [176]. Haloacetic acids, which are disinfection by-products, have been successfully derivatized to ethyl/methyl esters [177,178]. 

Other Alkyl and Aryl Ethers. - The preparation of selectively 0-alkylated saccharides, including benzyl, allyl, triphenylmethyl, and arylalkyl ethers has been reviewed. Analogues of lipids A and X incorporating 3-O-alkyl (rather than acyl) linkages have been described, and some carbohydrate monoalcohol derivatives have been alkylated with haloacetic acid ester derivatives. ° 3-C -Carboxymethyl D-glucose and D-fhictose compounds have been coupled via the carboxylic acid group to L-lysine in a search for acrosin inhibitors."... 

Since the vast majority of the substrates employed in diastereoselective syntheses are attached via a carboxyl function to the respective auxihary, this chapter deals with the diastereoselective a-fiinctionalization of chiral carboximides and esters, as well as with the homologation and aldolization alternatives of chiral glycinates, glycolates and haloacetates. Also discussed is the use of chiral a,/3-unsaturated representatives in the synthesis of e.p. linear /3- and a,/3-substituted carboxyhc acid derivatives and cyclic analogs (Diels-Alder reactions). Other methods, in which substrates are coupled, for example, via a carbonyl function in order to facilitate the diastereoselective a-aUcylation of aldehydes or... 

Chiral haloacetates of the Evans and Oppolzer type are highly potent and versatile synthons for the preparation of a broad variety of e.p. intermediates. The boron enolates of Evans haloacetates and the titanium enolates of Oppolzer s derivatives undergo aldol additions with aliphatic and aromatic aldehydes to provide syn 2-halo-3-hydroxy carboxylic acid derivatives with excellent diastereoselectivities, generally exceeding syn/anti ratios >50 1 . In the Oppolzer series, only with acetaldehyde (diasteromeric ratio... 

As already pointed out, the chief advantage of using derivatives of haloacetates as modification reagents is that the carboxymethyl derivatives of most of the nucleophilic amino acids have been described. The chromatographic behavior of the carboxymethylated derivatives of lysine, cysteine and histidine have been described in ch. 2. O-Carboxymethyl tyrosine appears as a single peak in the long column... 

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