A-Bromo acid chlorides

The HVZ reaction is limited to the formation of a-bromo compounds and is, in truth, sometimes awkward to carry out. The reagents, bromine and phosphorus, are noxious reaction times are often long, and reaction conditions are harsh. For these reasons, methods have evolved to extend and replace the classic HVZ process. For example, David Harpp (b. 1937) and his colleagues at McGill University use the reaction of acid chlorides and iV-bromosuccinimide (NBS, p. 613), in the presence of a catalytic amount of HBr, to form a-bromo acid chlorides conveniently and in excellent yields (Fig. 19.44). 

Bromobenzaldehyde, 100 Bromobenzene, 97 a-Bromo- -butyric acid, 62 a-Bromo- -butyryl chloride, 62 Butadiene, 93... 

In fact, even in such a low acidic medium, fluoride is not reactive enough to compete with strong nucleophiles and, for example, a-chloro or a-bromo acids can be obtained by halodediazoniation of a-amino acids with sodium nitrite/potassium chloride (or bromide) in 48% hydrogen fluoride/pyridine mixture.311... 

The Curtius rearrangement provides a route to carbamates of a-amino sulfonamides (Scheme 25). 108 Reaction of the ethyl ester of an a-bromo acid 52 with Na2S03 yielded the sodium salt of the corresponding sulfonic acid 53. Treatment of 53 with PQ5 afforded the sulfonyl chloride 54 which on reaction with an amine gave the sulfonamide 55. The latter... 

Ester chlorides of dicarboxylic acids, ROOC(CH2) COCl, which contain both an ester and an acid chloride group in the one molecule, thus give only poor yields of a crude a-bromo ester chloride ROOC(CH2) 1CHBrCOCl, unless a special procedure is used (bromination in SOCl2, see page 179) for, when... 

Monohalo ketones may be prepared by starting from pure diazo ketones an ethereal or benzene solution or suspension of a carboxylic acid chloride (1 mole) is added during 1-2 h to a stirred solution of diazomethane (3 moles) at 0-5°, reaction is allowed to proceed at 20-25°, the solvent is removed in a vacuum, and the product is recrystallized 1169 -chloro ketones may be formed as by-products during preparation of the diazo ketone, particularly if an insufficient excess of diazomethane is used hydrogen halide is often added directly to the ethereal solution of acid chloride and diazomethane 1170,1171 if then, for example, HBr is used, the resulting a>bromo ketone will contain... 

According to von Braun,125 Curtius degradation of a>bromo carboxylic acids provides a practical synthesis of aldehydes or ketones containing one fewer carbon atoms. The reaction from the a>bromo carbonyl chloride runs through the following steps ... 

VI-Halo acyl chlorides (3,35). a-Bromo acyl chlorides can be prepared In about 70-80% yield by reaetion of acyl chlorides, prepared in situ by reac-llon of carboxylic acids with thionyl chloride, which can also be employed as solvent for the bromination reaction. NBS is considerably more efficient than liromine in this reaction. Use of NCS under similar conditions gives a-chloro acyl chlorides in comparable yields. Benzyhc protons are not replaced by either leiigcnt. a-Iodo acyl chlorides can be obtained in 70-80% yield by iodination of acyl chlorides with molecular iodine in this case thionyl chloride must be iiNi d as solvent rather than CCI4 and a higher temperature (140°) is required. 

A related synthesis produces indolones by a different Friedel-Crafts route. The Stolle synthesis reacts with a secondary aryl amine such as diphenylamine with an a-chloro acid chloride or an a-bromo acid bromide to give an a-bromoamide (such as 315) or an a-chloroamide. An early version of the reaction used oxalyl chloride, but a more typical example is the reaction of 2-bromopropanoyl bromide with 314 to give 315. Friedel-Crafts cyclization (with AICI3) led to the indolone 316.1 ... 

Hydroxy-acids.—Optically active a-hydroxy-acids can be obtained from a/ -unsaturated acid chlorides by condensation with 5-proline followed by bromo-lactonization, debromination, and hydrolysis (Scheme 5). Optical yields are as high as 90%. a-Keto-acids can be reduced to a-hydroxy-acids by reaction with trialkyl phosphites followed by alkaline hydrolysis of the intermediate phos-phonate. Yields are said to be higher than those obtained by other methods using selective reduction (NaBH4 Raney nickel). 

An alternative method for a-halogenation has been developed by D. N. Harpp (McGill University). Acyl chlorides, formed in situ by the reaction of the carboxylic acid with SOCI2, are treated with the appropriate A -halosuccinimide and a trace of HX to produce a-chloro and a-bromo acyl chlorides. 

Formation of polypeptides by treatment of an a-chloro or a-bromo acyl chloride with an amino acid ester, hydrolysis to the acid and conversion to a new acid chloride which is again condensed with a second amino acid ester, and so on. The terminal chloride is finally converted to an amino group with ammonia ... 

Phosphorus trichloride converts the carboxylic acid to the corresponding acyl chloride, which has a less stabilized carbonyl group (see Section 19.2) and, therefore, a greater enol content. Bromination of this enol takes place, followed by a process that gives the a-bromo acid plus another molecule of the acyl chloride, which then undergoes enolization, bromination, and so on. 

Hydroxy-acids.—A full report has been published on the preparation of chiral a-hydroxy-acids in optical yields of up to 98% from a, -unsaturated acid chlorides by sequential N-acylation of an optically pure a-amino-acid, bromo-lactonization, dehydrobromination, and hydrolysis " (2, 23). Enolates of /-menthyl mandelate can be alkylated in ca. 50% yield with typical enantiomeric excesses of less than 40%, An elegant use of the prophos ligands in rhodium(i)-catalysed asymmetric hydrogenation (see 3,322) is in the preparation of all twelve isomers of chiral methyl chiral lactic acid the method is illustrated for one isomer in Scheme 5. The other isomers are obtained by changing the order of introduction of H, D, and T and the chirality (i.e. R or S) of the prophos ligand. 

Tetronic Acids.—a-Alkoxytetronic acids (and ultimately a,a -dihydroxy-ketones) can be obtained from a-hydroxy-acids by condensation with a-bromo-alkanoyl chlorides to give lactides which undergo base-induced ring contraction (Scheme 19). °"... 

Ethylcarbethoxyketene. A solution of 26 g. (0.1 mole) of the bromo acid chloride in 200 cc. of absolute ether is added to 15 g. (0.23 mole) of zinc shavings at such a rate that the ether refluxes gently. After the addition is complete the reaction mixture is refluxed briefly and 600 cc. of petroleum ether is added in order to precipitate the zinc chloride. 

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