Acid chlorides Curtius reaction

Strategy Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative—either an amide (Hofmann) or an acid chloride (Curtius)—into a primary amine with loss of one carbon, RCOY — RNH. Both reactions begin with the same carboxylic acid, which can be identified by replacing the -NH2 group of the amine product by a -COOH group. In the present instance, o-methylphenylacetic acid is needed. 

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

Curtius rearrangement (Section 24.6) The conversion of an acid chloride into an amine by reaction with azide ion, followed by heating with water. 

Significantly, trimethylsilyl azide is an excellent substitute for hydrazoic acid in many reactions-such as curtius rearrangement of acid chlorides to isocyanates which proceeds with Me3SiN3 in one pot process and in higher yields. 

The reaction of Curtius, which is especially to be preferred in the case of the higher members on account of the favourable solubilities of the intermediate products, involves as its first stage the preparation of the hydrazide from an ester (or acid chloride). The hydrazide is then converted, usually very readily, by the action of nitrous acid into the azide. In many cases it is more convenient to prepare the azide by treating an acid chloride with sodium azide previously activated with hydrazine hydrate.1 Azides easily undergo thermal decomposition, the two azo nitrogen atoms being eliminated as elementary nitrogen. In this way, however, the same radicle is formed as was invoked above to explain the Hofmann reaction ... 

Phenylcyclopentylamine has also been prepared from 1-phenylcyclopentanecarboxylic acid by means of the Hofmann degradation of the intermediate amide4 6 and from the intermediate carboxylic acid chloride by the Curtius reaction.6 In the method described, using the mixed carboxylic-carbonic anhydride,7 improved yields of the amine are obtained. 

Curtius rearrangement of the heteroaroyl azides, obtained from the reaction of the carboxylic acid chlorides with sodium azide, provides a route to the amino-pyrroles and -indoles (e.g. B-70MI30504, B-77MI30506, 78CPB1054), which, because of the ease of synthesis of the carboxylic acids, is frequently preferable to reduction of the nitro compounds. 

According to T. Curtius, feme chloride is reduced by hydrazine to ferrous chloride a reaction investigated by E. Miiller and G. Wegdin, and F. Schrader. E. J. Cuy found that in the reaction between hydrazine and a ferric salt in acid soln., one mol of hydrazine requires between one and two eq. of ferric salt for oxidation. The limiting reaction may be expressed as follows N2H 5-)-Fe" =NH 4+JN2+H +Fe". A. W. Browne and F. F. Shetterly showed that ferric oxide and hydrazine in aq. soln, yield ammonia, but no hydrazoic acid, while nickel sesquioxide and cobalt sesquioxide yield ammonia and traces of hydrazoic acid. H. Franzen and 0. von Mayer made complex cobalt salts—e.g. CoC12(N2H4)2, etc.—with hydrazine in place of ammonia. T. Curtius found that platinum is precipitated when a soln. of hydrazine is added to a neutral soln. of platinum... 

Overall, then, the Curtius rearrangement converts an acid chloride to an amine with loss of a car- tk>n atom—very useful. Also useful is the related Hofmann rearrangement, which turns an amide ito an amine with loss of a carbon atom. This time we start with a primary amide and make a trene by treatment with base and bromine. Notice how close this nitrene-forming reaction is to the tarbene-forming reactions we talked about on p. 1072. The nitrene rearranges just as in the Curtius reaction, giving an isocyanate that can be hydrolysed to the amine. 

Diphenylphosphoryl azide (DPPA) 58 was first introduced as a reagent for peptide synthesis by Yamada in 197233 and has been widely used since it gives good yields and very little racemization. It may also be used to bring about a modified Curtius reaction in which a carboxylic acid, R CC H and an alcohol, R2OH, react in the presence of triethylamine to afford the carbamate R1 NHCO2R2.33 In Protocol 15, the use of DPPA to form a macrocyclic lactam 61 is illustrated. The 82% yield of the product using this method should be compared with the value of 24% for reaction of the bis(acid chloride) of 59 with the diamine 60. 

In both of these reactions, the product amine is formed from a carboxylic acid derivative precursor that has one more carbon than the amine. In the Hofmann rearrangement, the precursor is an amide, which is treated with Br2, NaOH and H2O. In the Curtius rearrangement, the precursor is an acid chloride, which is treated with NaN3, then with H2O and heat. 

Modified Curtius rearrangement. Acyl azides, preferably prepared in situ under phase-transfer conditions by reaction of acid chlorides and NaN, are converted to tri-fluoroacetamides by reaction with CF,COOH in refluxing CH CI, solution. These products are cleaved to primary amines under mild conditions (equation I). ... 

The acid chloride of phenothiazine-1-carboxylic acid has been prejDared by treating the acid with the calculated amount of PCI5 in benzene, thus avoiding ring chlorination -(see Section V, A, 1, d). Another way to prevent ring chlorination in this reaction is first to acylate at position 10. ° Some amides have been prepared from phenothiazine carboxylic acid chlorides - ° and Curtius degradations performed. ... 

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