Schmidt reactions

Reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid 

The reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid in the presence of a strong acid is known as the Schmidt reaction A common application is the conversion of a carboxylic acid 1 into an amine 2 with concomitant chain degradation by one carbon atom. The reaction of hydrazoic acid with a ketone 3 does not lead to chain degradation, but rather to formation of an amide 4 by formal insertion of an NH-group. 

When applied to a cycloketone, the Schmidt reaction leads to formation of a ring-expanded lactam—e.g. 14 15  

In recent years the applicability of the Schmidt reaction for the synthesis of more complex molecules—especially the variant employing alkyl azides—has been further investigated. Cycloketones bearing an azidoalkyl side-chain at the a-carbon center have been shown to undergo, upon treatment with trifluoroacetic 

Intermolecular Schmidt reactions of alkyl azides and hydroxyalkyl azides with cycloketones in the presence of a Lewis acid, lead to formation of iV-alkyl lactams and A-hydroxyalkyl lactams respectively in good yield. The synthesis of chiral lactams by an asymmetric Schmidt reaction has also been reported.  

The Schmidt reaction comprises all reactions of carbonyl compounds with hydrogen azide in the presence of a strong mineral acid.137 

The reaction of carboxylic acids with hydrogen azide, as follows  

As described by von Braun,138 2-methyl-3-phenylpropionic acid (5.5 g) is dissolved in concentrated sulfuric acid (8 ml) and treated, dropwise at 40°, with a 10% chloroform solution of hydrogen azide (1.3 moles). When evolution of nitrogen ceases, the mixture is poured on ice, the chloroform is distilled off, and the amine is carried over in steam. Neutralizing the distillate with hydrochloric acid and evaporation give pure oc-methylphenethyl-amine hydrochloride (4 g, 73%), m.p. 146°. 

The reaction of ketones with hydrogen azide is formally the insertion of an NH group between the carbonyl-carbon and a neighboring carbon atom, thus  

A symmetrical ketone gives in this way the same amide as it does by way of the oxime and a Beckmann rearrangement. 

In a one-pot process which has been described as an intramolecular Schmidt reaction it has been shown that treatment of ketals or enol ethers of 1,5-azidoketones with Lewis or protic acids followed by sodium iodide in acetone results in formation of lactams in 68-95% yield. 

Give a mechanism for this reaction, a representative example of which is shown. 

Conversion of ketones to amides using HN3 (hydrazoic acid). 

Schmidt, K. F. Z Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (1887—1971) collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. 

Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 351. Mphahlele, M. J. J. Chem. Soc., Perkin Trans. 1 1999, 3477. 

R° = H, alkyl or aryl Lewis acid TiCL, TFA, CH3SO3H acid catalyst H2SO4, PPA, CI3CCO2H/H2SO4, TFA, TFAA 

Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 351. 

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Claisen-Schmidt reaction. Aromatic aldehydes condense with aliphatic or mixed alkyl-aryl ketones in the presence of aqueous alkali to form ap-unsaturated ketones ... 

The above are examples of the Claisen - Schmidt reaction. The formation of p-nitrostyrenes by reaction of nitroalkanes with aromatic aldehydes in the presence of aqueous alkali may be included under the Claisen- hmidt condensation ... 

By catalytic reduction of a p-unsaturated ketones, prepared from aldehydes by the Claisen - Schmidt reaction (see under Aromatic Aldehydes), for example ... 

The conversion of a carboxylic acid into an amine by treatment with hydrazoic acid in concentrated sulphuric acid is known as the Schmidt reaction or rearrangement ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Pinacol-pinacolone rearrangement Prileschajew epoxidation reaction Reformataky reaction Reimer-Tiemanii reaction Rosenmund reduction Sandmeyer reaction Schiemaim reaction Schmidt reaction or rearrangement Schotten-Baumann reaction Skraup reaction Sommelet reaction. ... 

The intermediates in making amines are isocyanates (0==C==N) just like the Hofmann Rearrangement. The isocyanates are decomposed with water, just like the Hofmann. In fact, there is a lot of similarity between the Hofmann and the Schmidt reactions. Before I detail the synthesis steps, I should note that if you wish to generate the Hydrazoic Acid in the flask by adding Sodium Azide, you might need a powder addition funnel. This bit of equipment is quite pricey and it s likely you won t have one, so the first part of the synthesis details how to make the Hydrazoic Acid separately. 

Ludwig Claisen was a Ger man chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth His name is associated with three reac tions The Claisen-Schmidt reaction was presented in Section 18 10 the Claisen condensation is discussed in this section and the C/a/sen rearrangement will be intro duced in Section 24 13... 

Alkylphenols undergo a carboxylation reaction known as the Kolbe Schmidt reaction. In the following example, the phenolate anion of /)-nonylphenol (15) reacts with carbon dioxide under pressure. Neutralization generates a sahcyhc acid (16) (10). 

Unlike saUcyhc acid, > -hydroxyben2oic acid does not undergo the Friedel-Crafts reaction. It can be converted in 80% yield to y -aminophenol by the Schmidt reaction, which involves treating the acid with hydra2oic acid in trichloroethylene in the presence of sulfuric acid at 40°C (47). 

Schmidt reaction of ketones, 7, 530 from thienylnitrenes, 4, 820 tautomers, 7, 492 thermal reactions, 7, 503 transition metal complexes reactivity, 7, 28 tungsten complexes, 7, 523 UV spectra, 7, 501 X-ray analysis, 7, 494 1 H-Azepines conformation, 7, 492 cycloaddition reactions, 7, 520, 522 dimerization, 7, 508 H NMR, 7, 495 isomerization, 7, 519 metal complexes, 7, 512 photoaddition reactions with oxygen, 7, 523 protonation, 7, 509 ring contractions, 7, 506 sigmatropic rearrangements, 7, 506 stability, 7, 492 N-substituted mass spectra, 7, 501 rearrangements, 7, 504 synthesis, 7, 536-537... 

Schmidt reaction is the reaction between carbonyl compounds and hydrazoic acid in the presence of e.g. concentrated sulphuric acid... 

Although the Schmidt reaction is formally analogous to the Beckmann rearrangement, it is less versatile in the 20-keto steroid series since only 1,4-addition to the double bond has been observed with the important A -derivatives. 

A potential advantage of the Schmidt reaction is illustrated by the conversion of progesterone to the 17j5-acetylamino derivative, without affecting the A-ring. A 35 % yield is obtained when 1 mole of sodium azide in polyphos-phoric acid is used. With excess azide the A-ring is transformed into an a,jS-unsaturated lactam ... 

In the Schmidt reaction of fluonnated dicarboxyhc acids, the appropnate amides can be obtained in fairly good yield [48] Complications arise from possible cychzation if the fluorine atom is in the 8 position relative to the newly formed amino group [/] Fluonnated aromatic ethers, upon heating in dimethylformamide, undergo Smiles rearrangement to give diarylamines [49, 50] (equation 11)... 

Claisen-Schmidt reaction (Section 18.10) A mixed aldol condensation in which an aromatic aldehyde reacts with an enolizable aldehyde or ketone. 

Only one of the two acetyl groups of diacetylfuroxans underwent a Schmidt reaction. A mixture of acetylamino- (127) and aminofuroxans 128 was obtained (95MC56) (Scheme 75). Under similar conditions 3-acetyl-4-nitrofuroxan afforded a mixture of tetrazole 129 and A-methylamide 130, albeit in low yield. 

Among other reactions proceeding with the retention of the heterocyclic nucleus may be noted the synthesis of amino acids of the isoxazole series from isoxazole-5-aldehydes/ the successful extension of the Schmidt reaction to 3-acylisoxazoles, and the synthesis of various polycyclic heterocycles, e.g. 101 102, involving the isoxa-... 

Schmidt reaction of indanones 803 by treatment with HN3-BF3 etherate gave 4,5-dihydro[5,l-a]tetrazoloquinoline 804 (92IJC(B)610)) (Scheme 142). 

A different situation is found in the case of crossed aldol reactions, which are also called Claisen-Schmidt reactions. Here the problem arises, that generally a mixture of products might be obtained. 

The cationic species 4 thus formed reacts with water to give the iminol 5, which tautomerizes to a more stable amide tautomer, the N-substituted carboxylic amide 2. Those steps correspond to the formation of amides by the Schmidt reaction. A side reaction can give rise to the formation of nitriles. 

By application of the Schmidt reaction, the conversion of a carboxylic acid into an amine that has one carbon atom less than the carboxylic acid, can be achieved in one step. This may be of advantage when compared to the Curtius reaction or the Hofmann rearrangement, however the reaction conditions are more drastic. With long-chain, aliphatic carboxylic acids yields are generally good, while with aryl derivatives yields are often low. 

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