Carboxylic acids a-halo

One of the oldest methods for the synthesis of ammo acids dates back to the nineteenth century and is simply a nucleophilic substitution m which ammonia reacts with an a halo carboxylic acid... 

The cyclization of a-halo carboxylic acid ureides can be complicated with products from different modes of cyclization. For example, bromination of 70 at low pH affords the 2-amino-4(5//)-oxazolone 71 in excellent yield, whereas bromination at pH 5-6 generates a mixture of hydantoins 72 and 73 in poor yield (Scheme 6.19)." Japanese workers" reported that cyclization of a-bromoisovaleryl-urea with 28% aqueous ammonia yields 2-amino-5-isopropyl-4(5H)-oxazolone 74, not 75 or 76. The structure of 74 was established spectroscopically and confirmed by hydrolysis to 77 (Scheme 6.20). 

The halogen of an a-halo aldehyde or an a-halo ketone is exceptionally unreactive in SN1-displacement reactions, but is exceptionally reactive in Sn2 displacements, compared with the halogen of alkyl halides having comparable potential steric effects. Similar behavior is observed with a-halo carboxylic acids and is discussed further in Chapter 18. 

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... 

Stereoselective enolate bromination as an approach to a-halo carboxylic acids and a-aminoketones.32 a-Haloketones are useful synthetic intermediates,33 and may be derived from enolates by treatment with sources of electrophilic halide. This methodology has been applied by others34,35 as a stereoselective approach to chiral a-aminoacids. 

In addition, OPEN is an efficient chiral solvating agent for determination of the enantiomeric excess in the H NMR analysis of various chiral mono- and dicarboxylic acids including a-arylpropanoic and a-halo carboxylic acids. The chemical-shift non-equivalence (S A) in certain diastereomeric complexes is greater than 0.05 ppm. A DPEN/Pd(II) complex can be used for determination of enantiomeric excess of the non-protected chiral amino acids by H and C NMR analysis. For example, Pd[(S,S)-dpen](D20)2 and racemic alanine with a base forms the square-planar complex (eq 14). The 5 A of H-NMR resonance in the diastereomeric complexes in D2O is 0.056 ppm, while this complex hardly dissolves in D2O. 

Amino acids can be prepared from a-halo carboxylic acids [RCH(X)COOH] by reaction with excess NH3. Why is excess NH3 needed for this reaction ... 

The most direct way to synthesize an a-amino acid is by 8 2 reaction of an a-halo carboxylic acid with a large excess of NH3. 

Although the alkylation of ammonia with simple alkyl halides does not generally afford high yields of 1° amines (Section 25.7A), this reaction using a-halo carboxylic acids does form the desired amino acids in good yields. In this case, the amino group in the product is both less basic and more sterically crowded than other 1° amines, so that a single alkylation occurs and the desired amino acid is obtained. 

Rueck-Braun, K, Stamm, A, Engel, S, Kunz, H, (i-branched a-halo carboxylic acid derivatives via stereoselective 1,4-addition of dialkylaluminum chlorides to a,p-unsaturated A-acyloxazolidinones, J. Org. Chem., 62, 967-975, 1997. 

The Kunz group further demonstrated the asymmetric s)uithesis of )3-alkylated a-halogenated (Cl or Br) carboxylic acid derivatives. Eor this purpose, the Al-functionalized D-galactosamine-derived oxazolidinone 52 was treated with dialkylaluminum chloride, which was followed by addition of NXS (X = Cl, Br) to trap the intermediary enolate. Consequently, a variety of j8-branched a-halo carboxylic acid derivatives were obtained with good diastereoselectivities [63]. 

On the other hand, resolution of racemic a-halo carboxylic acids (93) with butanol can be effected with lipase (Table 7 and equation 35). Applications of enzyme-catalyzed acyl transfer reactions, among many others, are the synthesis of the pheromone (5)-sulcatol (95 equation 36) and of (/ )-glycidylbu-... 

With a-halo carboxylic acids and formation ol thiazolidin-4-one-2-... 

Dithiocarbamic acids and a-halo carboxylic acids (scheme IJ... 

Thiazolidin-4-one-2-thiones (CLXXXVIII), compounds which possess strong bacteridical and fungicidal properties, can be very simply prepared by reacting an a-halo carboxylic acid or its ester with dithiocarbamic acids (CLXXXVI) [35, 42, 170, 205, 285, 396). The N-alkyl-S-a-(carboxyalkyl) dithiocarbamic acid or ester (CLXXXVII) is first formed and the cychzation carried on by refluxing with strong acids (method A). 

Method A Dithiocarbamic acid and a-halo carboxylic acid (ester). B Amines and bis-(carboxymethyl) trithiocarbonate. 

Brown and co-workers (43) have recently shown, by means of spectroscopic evidence, that dithiocarbazates and a-halo carboxylic acid practically always jdeld 3-amino thiazolidin-4-one-2-thiones. They compared... 

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