A-Halocarboxylic acid

Oxoselenazolines with a 2-(disubstituted amino) group are obtained by the action of a-halocarboxylic acid or rather their esters on N-disubstituted selenoureas (Scheme 63, Table X-14) (27. 67. 68). 

Comrie et al. (68) have thus prepared several compounds of this type by condensation of various selenoureas with a-halocarboxylic acids and have assigned them the imino structure (Table X-15a). 

The a-sulfinyl carbanion attacks a-halocarboxylic acid esters at the carboxylic carbon atom, not at the a-carbon atom, and the corresponding ketones are obtained slereoselectively in high yield62. 

Even with a-halocarboxylic acid esters 466 the attack of a-sulphinyl carbanion 467 takes place at the carbonyl carbon atom and not at the a-carbon atom and the corresponding a-halo-a-sulphinyl ketones 468 are obtained in high yields539-540 (equation 279). 

As deduced from the DNA sequence of the gene, AMDase contains four cysteine residues. Since a-halocarboxylic acids are generally active alkylating agents there is a possibility that a-bromophenylacetic acid reacts with several cysteine residues of the enzyme. Therefore, we tried to clarify how many cysteine residues react with this inhibitor. It is well established that when p-chloromercuri-benzoate (PCMB) binds to a cysteine residue, the absorbance at 255 nm increases due to the formation of an aryl-Hg-S bond. Thus it is possible to estimate the number of free S-H residues of the enzyme by titration with PCMB solution (Fig. 6). When the native enzyme had reacted with PCMB, the absorbance at 255 nm increased by 0.025. On the other hand, when PCMB solution was added to the enzyme solution after the enzyme was incubated with a-bromophenyl-... 

Carboxylic acids having an a-hydrogen are halogenated at the a-position on treatment with chlorine or bromine in the presence of small amount of red phosphorus to give a-halocarboxylic acids. The reaction is known as Hell-Volhard-Zelinsky reaction. 

The reaction of a -halocarboxylic acids with sodium nitrite has been used to synthesize ni-tromethane, nitroethane and nitropropane, although the reaction fails for higher nitroalkanes. " A number of other reactions have been reported which use nitrite anion as a nucleophile, including (1) reaction of alkyl halides with potassium nitrite in the presence of 18-crown-6, (2) reaction of alkyl halides with nitrite anion bound to amberlite resins, (3) synthesis of 2-nitroethanol from the acid-catalyzed ring opening of ethylene oxide with sodium nitrite, and (4) reaction of primary alkyl chlorides with sodium nitrite in the presence of sodium iodide. ... 

Normally, an equilibrium is formed, so that the ester serving as acyl source has to be employed in excess. The separation of the optically active esters, e.g., (S )-2 and (S)-4 from the unreacled alcohols (R)-l and (R)-3 may be effected by distillation or chromatography. Resolution of a-halocarboxylic acids can be achieved with lipase in butanol60. 

The first synthesis1121 of A -foi-BocHN-alky]) amino acid building units used nucleophilic substitution of a-halocarboxylic acids or their esters 30 (Scheme 18) with mono-Boc-sub-stituted diamines 29. The nucleophilic substitution product 31 was reacted with Fmoc-OSu to give the orthogonally protected building unit 32. 

This approach gave fair yields of Gly-based building units (R2=H). A similar approach was used 122 to prepare a variety of monomers (Scheme 18) used in the synthesis of Leu-enkephalin peptoids. In the case of substituted a-halocarboxylic acids or esters bearing R2 side chains the yields were lowered because of racemization and p-elimination resulting in the undesired a, 3-dehydrocarboxylic acids in addition to the desired chiral building unit. Another problem was polyalkylation. 

The stereoselective synthesis of /(-branched a-halocarboxylic acids containing two newly formed chiral centres (155) has been accomplished by a reaction consisting of 1,4-addition of dialkylaluminium chlorides to a,/(-unsaturated A -acyloxazolidinones (154) followed by quenching the intermediate aluminium enolate with /V-halosuccini-mides. The most efficient stereo-control was achieved with oxazolidines derived from glucosamine (154). Although /(-branched aliphatic a-halo carboxylic acids were synthesized stereo selectively, the highest stereoselectivity was observed for (3-aryl substrates.112... 

In variants of the above processes, the bifunctional reactivity of 4-(dialkylamino-methylene)pyrazolin-5-thiones (155) (Scheme 25) and oxazolin-5-thiones (157) (Equation (45)) with a-halocarboxylic acids (or esters) was exploited for the synthesis of thieno[2,3-c]pyrazoles (156)... 

Salts of a-halocarboxylic acids react similarly with sodium nitrite to yield salts of a-nitro acids (method 490). 

Table 7 Enzymatic Resolution of a-Halocarboxylic Acids (equation 35)...

Comrie et al. prepared a number of 2,4-dioxoselenazolidine 2-alkyl-idenehydrazones (71) by the reaction of a-halocarboxylic acids with ketone and aldehyde selenosemicarbazones (70), [Eq. (18)], and Tsurkan et have recently made other derivatives of 71 by a similar method. 

Reaction with organoboranes.1 Brown has extended the reaction of ethyl bromo-acetate with trialkylboranes to ethyl dibromoacetate. If one equivalent of potassium r-butoxide is used, an a-halocarboxylic acid is obtained dialkylation is achieved by use of two equivalents of the base. Since the first reaction occurs readily at 0°, whereas the second requires a higher temperature (50°), two different alkyl groups... 

Thiourea reacts with a-halocarbonyl compounds to produce 2-aminothiazoles. 2-Amino-4-hydroxythiazoles 6 are formed with a-halocarboxylic acids ... 

The dianions of a-halocarboxylic acids give epoxy acids (called glycidic acids) on reaction with aldehydes and ketones. 

In 2010, Rovis and co-workers reported a related reaction providing a-halocarboxylic acids from o,a-dihaloaldehydes or a-fluoroenals in good yields and excellent enantioselectivity (up to 95% yield and 96% ee). Buffered, biphasie aqueous conditions were employed to overeome the problem of epimerization and achieve high seleetivity (Seheme 7.86). 

It has been claimed that a-chloroester carbanions and Grignard reagents derived from /-butyl esters of a-halocarboxylic acids are pyramidal and hard. They tend to attack the enone carbonyl. On the other hand, carbanions of a-chlorophenylacetates are planar, delocalized, and soft, and they behave as Michael donors (50). 

---