Bromocarboxylic acid

Thiazoles may be obtained starting from the imidazolicte of a-bromocarboxylic acids and thiobenzamide, as shown by the following example. 

Samarium enolates 60 can be easily prepared by reduction of ct-bromocarboxylic acid esters with SmT. These enolates mediated well-defined synthesis of star-shaped block co-polymers 61 (Scheme 21 ).32 32l Sml3 also mediated the formation of samarium enolates. Phenacyl thiocyanate 6233 and cr-haloketone 6434 are converted to samarium(lll) enolate intermediates 63 and 65, respectively, which undergo addition to benzaldehyde derivatives affording the corresponding oy i-unsaturatcd ketones as shown in Schemes 22 and 23. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

McKillop and Ford synthesized a range of primary and secondary alkyl nitrates in excellent yields by treating alkyl bromides with mercury (I) nitrate in 1,2-dimethoxyethane at reflux (Equation 3.9). This method has been used to synthesize substituted nitrate esters from both a-bromocarboxylic acid and a-bromoketone substrates. Unlike metathesis with silver salts, which are widely known to promote SnI reactions, this method is not useful for the synthesis of nitrate esters from tertiary alkyl halides. 

Hydrohalogenation of racemic 4-rerr-butylcyclohexylideneacetic acid yields the tram-jg-ehloro-and / -bromocarboxylic acids 1 as single diastereomers which, on dehydrohalogenation with chiral lithium amides, yields 4 tcrt-butylcyclohexylideneacetic acid 2 b in high yield with modest to good enantioselectivity (Table 8)6,15,83b. 

Macrocyclic derivatives are of considerable importance in biological areas and as complexing agents, particularly for metals. Macrocyclic examples are given in MACROLIDES FROM CYCLIZATION OF w-BROMOCARBOXYLIC ACIDS 11-HYDROXYUNDECANOIC LACTONE and MACROCYCLIC POLY AMINES 1,4,7,10,13,16-HEX AAZ ACYCLOOCT ADE-... 

Chloroacetic acid is readily converted into glycine by treatment with concentrated aqueous ammonia solution, but in general an a-bromocarboxylic acid is preferred. This can usually be prepared in good yield by a Hell-Volhard-Zelinsky bromination (Section 5.14.1, p. 720) of the corresponding carboxylic acid if the carboxylic acid is not readily available it can usually be obtained by the synthesis and bromination of the appropriate alkylmalonic, acid (see Expt 5.166). 

Two variants of the Hell-Volhard-Zelinsky brominations are commonly conducted. According to the first procedure, carboxylic acids A are reacted with one equivalent of bromine and a catalytic amount of phosphorus tribromide to form oc-bromocarboxylic acids (Formula B... 

Fig. 12.7. Bromination of carboxylic acids in the presence of catalytic amounts of phosphorus tribromide ("Hell-Volhard-Zelinsky reaction I") the reaction product is an a-bromocarboxylic acid.

The mechanism in Figure 12.7 implies that the stoichiometric use of phosphorus tribromide in the second variant of the Hell-Volhard-Zelinsky bromination leads to the selective formation of the a-bromocarboxylic acid bromide (Formula B in Figure 12.8). Often these compounds are hydrolyzed to give the bromocarboxylic acids C. More importantly, a-bromocarboxylic acid bromides B can also undergo alcoholysis and in this way provide access to a-brominated esters D. 

Fig. 12.8. Bromination of carboxylic acids in the presence of stoichiometric amounts of phosphorus tribromide ("Hell-Volhard-Zelinsky reaction II"). The actual reaction product is an a-bromocarboxylic acid bromide (B), which often undergoes further in situ reaction to afford an a-bromocarboxylic acid (C) or an a-bromocarboxylic acid ester (D).

Several reaction were examined the dehydrobromination of bromoalkanes, the esterification of benzoic acid with 1-bromobutane and the macrolactonisation of [Pg.138]

Bold and Balu escu (13) found the monomeric copper(II) a-bromostearate CuA2(HA)2 in the extraction of Cu(II) with a-bromostearic acid in benzene. The bromine in the a-position was said to prevent sterically the formation of dimeric copper(II) species, a-Bromocarboxylic acid, being stronger than the nonsubstituted hom-ologues, is anticipated to form a less stable copper carboxylate dimer. 

Cleavage of lactones and carbonates. Lactones and carbonates react with bromotrimethylsilane to afford trimethylsilyl ethers (equation II), respectively acyclic, aliphatic esters do not react with bromotrimethylsilane. lodotrimethylsilane reacts in an analogous fashion with lactones, but in reaction with ethylene carbonate the main product is 1,2-diiodoethane (equation III). The >-bromocarboxylate derivatives are converted into acid chlorides by reaction with SOCL (equation I). 

Polycarbobetaines derived from aromatic or heteroaromatic systems are listed in Scheme 3. The vinylimidazolium betaines 13 and 14 were prepared by alkylation of 1-vinyhmidazole with the corresponding bromocarboxylic acid, and aqueous solution polymerization using an azo initiator [29]. Polymers 13b, 15, 16, and 17b were made by the addition of acryUc or propiolic acid to poly(4-vinylpyridine) and poly(N-vinylimidazole). Kinetic measurements revealed a mechanism consisting of two reactions first, addition of two molecules of acid to the polymer second, the formation of an equilibrium between the adduct and the betaine structure [30,31]. 

Diorgano tellurium compounds have been reacted with methyl iodide (Vol. IX, p 1076), ethyl iodide ethyl iodoacetate, cyclohexyl iodide , methyl bromide, allyl bromide , benzyl bromide , bromoacetone , bromomethyl phenyl ketone , a-bromocarboxylic acids , a-bromocarboxylic acid esters , methyl chloride, and benzyl chloride . 

Dialkyl, diaryl, unsymmetrical dialkyl, alkyl aryl, and unsymmetrical diaryl telluriums served as the tellurium-containing starting materials (Vol. IX, p. 1075). The reactions with methyl iodide and low molecular mass organic bromides proceed at 20° in organic solvents such as chloroform and methanol or in mixtures of the neat reagents.With aryl telluriums several days are required for completion of the reaction. Diaryl telluriums with ortho-substituents react only with difficulty. Bis[2,4,6-trimethylpheny 1] tellurium did not combine with methyl iodide. The reactions with ethyl iodide and a-bromocarboxylic acids are accelerated by gentle heating. 

The intra- and intermolecular reactions of co-bromocarboxylic acids in the presence of PDBUs in toluene afforded mainly macrolides with small amounts of linear oligomers (85MI9). 

A number of syntheses of (V-hydroxy-a-amino acids and derivatives thereof have been reported. a-Bromocarboxylic acids or their r-butyl esters can be treated with hydroxylamine or 0-alkylated hydroxylamines to give the corresponding hydroxylamine derivatives. yV-Benzyloxy-t-alanine has been obtained by reaction of (/ )-a-bromopropionic acid with O-benzylhydroxylamine. But due to bromide exchange the optical yield was low. Anchimeric assistance of a suitable attached thio group can bring... 

This may be illustrated by the reaction of a-bromocarboxylic acids, which undergo substitution of the bromine atom by hydroxide anions with retention of configuration when the concentration of the hydroxide anions is low. Suggest what is the mechanism for the substitution reaction at low and high concentrations of hydroxide anions. 

Hell-Volhard-Zelinskii reaction The reaction in which a carboxylic acid is treated with Br2 and PBr3 (often formed in situ from red phosphorus and bromine) to give the a-bromocarboxylic acid bromide. 

Franchimont reaction. Carboxylic acid dimerization to 1,2-dicarboxylic acids by treating a-bromocarboxylic acids with potassium cyanide followed by hydrolysis and decarboxylation. 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

Scheme 16.1 Solid-phase synthesis of isoxazolidines according to the split-and-combine method, (a) Distribution of the resin into two equal portions, coupling of bromocarboxylic acids with N,N -diisopropyl-carbodiimide (D1C), combination of the resin, substitution with hydroxylamine. (b) Distribution of the resin into three equal portions, condensation with three different aromatic aldehydes to the corresponding nitrones, combination of the resin, (c) Distribution of the resin into three equal portions, cyclo-addition with three different dipolarophiles to isoxazolidines, combination of the resin.

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