Schmidt reaction with acids

The reaction sequence - including subsequent reaction with water which leads to amines - is named the Curtius Reaction. This reaction is similar to the Schmidt Reaction with acids, differing in that the acyl azide in the present case is prepared from the acyl halide and an azide salt. 

Insight has been gained into the mechanism of the Schmidt reaction with acids by the observation that the transformation proceeds most easily with those hindered acids which, in sulfuric acid solution, give rise... 

In addition to the present method,2 1-amino-1-methylcyclo-hexane has been synthesized by the following procedures Ritter reaction, e.g., with 1-methylcyclohexanol (76%, 67%)3i 4 or 1-methylcyclohexene (35%,) 4 5 Hofmann reaction with 1-methyl-cyclohexanecarboxamide (80% as hydrochloride) 6 reduction of 1-methyl-l-nitrocyclohexane (63%) 6 Schmidt reaction with 1-methylcyclohexanecarboxylic acid (42%).6... 

The synthesis of TATB (14) from the reaction of 2,3,4,5,6-pentanitroaniline (31) with ammonia has been reported. " In one route, 2,3,4,5,6-pentanitroaniline (31) is synthesized from the nitration of 3,5-dinitroaniline (30) " the latter is obtained from the selective reduction of TNB ° or via a Schmidt reaction with 3,5-dinitrobenzoic acid. Another route to 2,3,4,5,6-pentanitroaniline (31) involves the selective reduction of TNT (1) with hydrogen sulfide in ammonia followed by nitration of the resulting 4-amino-2,6-dinitrotoluene (46), during which the methyl group is lost by oxidation-decarboxylation. 

Schmidt reactions with sodium azide and strong acids, if they occur through tetrahedral reaction intermediates, lead primarily to nitrogen insertion adjacent to methylene rather than methine groups. There are no really satisfactory reasons for preferential methylene migration in this case [81]. 

The Schmidt reaction with the dienone 11/102 (Scheme 11/15) yields the 1,4-thiazepine, 11/103. Treatment of its dihydroderivate, II/104, gives exclusively the enlargement product 11/105, in which the methylene group migrated [82]. A similar reaction can be observed if the synthetic ergot alkaloid precursors of type 11/106 are treated with in situ generated hydrazoic acid. Again no trace of the isomeric lactam can be observed [83]. 

Many attempts have been made to carry out the Schmidt reaction with alkyl or aryl azides in place of hydrazoic acid in the presence or absence of catalysing acids and either in the cold or on heating. Most have been fruitless although a few apparently valid claims are recorded. One is that treatment of acetophenone with methyl azide led to a trace of acetanilide and since the reagent was strictly free of hydrazoic acid and was not hydrolysed or otherwise split under the reaction conditions some demetliylation must have occurred at... 

Koldobskii, G. I., Ostrovskii, V. A., Gidaspov, B. V. Schmidt reaction with aldehydes and carboxylic acids. Russ. Chem. Rev. 1978,47, 1084-1094. 

This does not react as a diazo-compound unless a mineral acid is added to the solution. Bamberger called it an isodiazo -compound, which isomerises to a diazo-compound. By the action of hot concentrated potassium hydroxide solution on Griess s diazobenzene potassium (see p. 771), Schraube and Schmidt obtained an isomeric compound giving the diazo-reaction with acid. Von Pechmann and L. Frobenius found that the silver salt of /)-nitrodiazo-benzene with methyl iodide does not give a nitrosamine but the methyl ether CeH4(N02)-N N-0CH3, so that the nitrosamine formula appeared to represent a tautomeric form of diazobenzene. 

Ketones generally fail to react with alkyl azides under standard Schmidt conditions. However, when these reactions are conducted in the presence of Lewis acid instead of the protic conditions used in the standard Schmidt reactions, the intermolecular Schmidt reactions can be carried out in moderate to good yields. Titanium(IV) chloride (> 1.0 equiv) in dichloromethane is the best reagent for effecting this type of reactions. The best substrates include the sterically unhindered ketones, especially cyclohexanones. This transformation is sensitive to steric effects, and even the a-substituted ketones may lead to poor yields and require long reaction time. The intermolecular Schmidt reaction with alkyl azides is still limited to a small range of cyclic ketones. For example, cyclopentanones do not react well with alkyl azides. 

The lack of regioselectivity, the limitation that tertiary or benzylic alcohols must be used as precursors to Schmidt reactions with carbocations, and the harsh Lewis acidic... 

There are many examples for the application of Schmidt reaction with aldehydes in the synthesis of nitriles. For example, the reaction using vanilhn to prepare vanillonitrile and vanillic acid was carried out by Schuerch [35]. Vanillin was employed in one hundred grams scale, and the corresponding nitrile was obtained in approximately 70 % yield (Scheme 4.2). 

The reactions of HN3 with cyclic alcohols to yield mixtures of ketones, amines, and products with an enlarged ring are catalyzed by H2SO4 [1]. Tertiary alcohols are converted to azides in the presence of acid [12] or TiCU [13]. Aldehydes and ketones with HN3 undergo a Schmidt-type reaction by liberating N2 and inserting NH In the presence of H or Lewis acids [14]. Ketones yield secondary amides and, in the case of cyclic ketones, lactames. Aldehydes are converted to nitriles or N-formylamines. Tetrazole derivatives result with excess HN3 [1, 15]. However, a-azido ethers are obtained from aldehydes and HN3 in the presence of alcohols by catalysis of TiC [16]. Carboxylic acids and anhydrides form amines, N2, and CO2 in Schmidt reactions with HN3. Intermediates are carbamic acids which form by insertion of NH into the R-COOH bond [1, 14]. High yields result for acids of arenes [17]. 

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 ... 

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. 

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). 

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 ... 

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-... 

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. 

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