Halocarboxylic acid esters

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). 

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. 

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). 

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. 

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)... 

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). 

When esters with other functional groups are to be identified one should not forget that some other reactions could also take place for example, when j -ketoesters are hydrolyzed they are further cleaved (decarboxylation), esters of halocarboxylic acids give hydroxy acids, etc. 

The reaction of dihydropyrimidine-2(lH)-thione (propylenethiourea) 1 with a-halocarboxylic acids gives only the bicyclic thiazolo[3,2-a]pyrimidine. The most convenient procedme for the synthesis of 3,4-dihydropyrimidine-2(l//)-thiones (known as the Biginelli reaction) is based on one-pot three-component condensation of aldehydes with P-keto esters and thiomea. Thiazolopyrimidine derivatives (3, Scheme 1) were obtained by a simple one-pot condensation reaction of 1 and 2-bromopropionic acid (2, R3 = H, bromoacetic acid (2, R3 = H, CH3) imder microwave irradiation and conventional conditions [12, 13]. 

Diacids.—Succinic acid derivatives can be obtained in good yields by coupling lithium a-lithiocarboxylates (or ester enolates) with lithium a-halocarboxylates, or a-halo-esters/ Carboxylic acid dianions also react with isocyanates and iso thiocyanates to give malonamic acids (13 X = O) and 3-thiomalonamic acids (13 X = S), respectively/ A route to c/5-cyclobutane-l,2-dicarboxylic acids (16), which could be of some generality, consists of photocyclization of acryl-imides (14) to maleimides (15) and hydrolysis/ Yields of (15), as judged by n.m.r. spectra, are between 45 and 82%. 

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