Halocarboxylic acids

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). 

McGrath JE, CG Harfoot (1997) Reductive dehalogenation of halocarboxylic acids by the phototrophic genera Rhodospirillum and Rhodopseudomonas. Appl Environ Microbiol 63 333-335. 

Another useful oxidative reaction in aqueous medium is the cleavage of cyclic ketones by hydrogen peroxide in the presence of Fe(II) salts (Eq. 8.25). The reaction proceeds through an a-hydroxy hydroperoxide, leading to a variety of products.50 The presence of Fe(II) salts decomposes the intermediate, generating a radical. In the presence of halide ions, the radical leads to synthetically useful halocarboxylic acids.51... 

Intramolecular alkylation of the amides of co-halocarboxylic acids, under phase-transfer catalysed conditions, provides an excellent route to lactams. The procedure... 

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. 

In our synthesis (57) of the arsonomethyl analogue of AMP, we developed a method (Fig. 12) for converting an alcohol, R—CH2—OH, into the arsonomethyl analogue, R—CH2—CH2—As03H2, of its phosphate, R—CH2— —P03H2. In this pathway the Meyer reaction is used on a 2-halocarboxylic acid, so that the reactant will be soluble in aqueous... 

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 scope of the chemistry outlined in Figure 16.21 can be further expanded by including other acids susceptible to irreversible reaction with a primary amine. These can be other halocarboxylic acids, such as (chloromethyl)benzoic acids, or acrylic acid, which reacts with amines to yield N-substituted (1-alanines. N-Substituted oligo((5-ala-nines) have been successfully prepared by sequentially acylating support-bound amines with acrylic acid and then performing a Michael addition with primary amines [239]. 

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... 

Novel approach for optically pure alcohol from racemic compounds is the use of dehalogenases.24 For example, L-2-halo acid dehalogenase Pseudomonas putida was used for the synthesis of D-3-chlorolactic acid from racemic 2,3-dichloropropionic acid (Figure 23(a)).24ad The enzyme catalyzed hydrolytic release of halogen from 2-halocarboxylic acids and produces 2-hydroxy acids with inversion of the configuration. L-2-Halo acid dehalogenase acted on the L-isomer of 2-halo acids and produces D-2-hydroxy acid with an excellent enantioselectivity. 

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)... 

Oxetanes are commonly obtained by intramolecular ether synthesis from a suitably functionalized alcohol. Leaving groups employed include halides, tosylates, and others. The base can range from an alkoxide to a non-nucleophilic amine . The classical, straightforward approach to 2-oxetanones (-lactones) is by the lacto-nization of the salts of -halocarboxylic acids and similar precursors . Thietanes and -thio-lactones are obtained analogously . 

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

Nonracemic phenylserine derivatives can be prepared by the addition of ammonia to a,/ -di-halocarboxylic acid esters via aziridines59. Treatment of (li )-menthyl 2,3-dibromo-3-phenyl-propanoate (7) with methanolic ammonia proceeds stereoselectively to give a readily separable mixture of the diastereomeric and thermodynamically more stable (17 )-menthyl a s-3-phenyl-2-aziridinecarboxylates (8A and 8B) as crystalline solids59. 

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

Many workers have employed j3-halocarboxylic acids (142) to prepare tetrahydro-l,3-thiazines (143) from thioureas. The halogen atom (X)... 

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