The Schmidt rearrangement

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 methyl group at C-16 hinders addition to the double bond and the reaction then proceeds normally and in good yield to the 16-methyl-17-acetyl-amino steroid, which gives the 16j9-methyl-17-ketone on hydrolysis. 

While 17a-hydroxy-20-keto steroids do not react, those without the 17-hydroxyl group give good yields of 17/ -acetylamino steroids, and the presence of a 16a- or 16j8-methyl group does not interfere. 

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  

17j5-Aminoandrost-5-en-3j5-oI Cone sulfuric acid (0.5 ml, 1.84 M) is added, dropwise over 40 min, to a solution of 2 g of pregnenolone acetate in 4 ml of chloroform containing 14 ml of a 1 M solution of hydrazoic acid. Stirring is continued for another 30 min at room temperature after the evo- 

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Conversion of pregnanes to androstanes via the Schmidt Rearrangement 17/3-aminoandrost-5-en-3/3-ol, 145 Cyclobutanol formation by ketone irradiations... 

In addition to the Beckmann reaction, the Schmidt rearrangement is used to generate M-alkylated lactams, too. Alkyl azides 231 react with the cyclic ketones (and aldehydes) in the presence of proton or Lewis acids. On running the inter-molecular reactions, in most cases symmetric ketals 230 have been converted... 

Benzodiazocines 429 were prepared to be tested as calcium-sensitizing agents (equation 181). A mixture of isomeric lactams was obtained when the Schmidt rearrangement was applied to 427, but only one product 428 was produced using the Beckmann reaction. 

The synthesis of lactams has attracted considerable attention in recent years. This is presumably because they represent versatile synthetic intermediates that are present h many biologically important molecules. Despite the wide range of methodologies that have been examined for the synthesis of lactams, the Beckmann and Schmidt rearrangements still remain by far the most convenient and general methods. The strongly acidic conditions required for the Schmidt rearrangement often lead to undesired byproducts. This is a major limitation particularly with acid-labile substrates. 

In the Schmidt rearrangement of carboxylic acids the formation of the adduct is apparently usually not rate-determining. The evidence for this comes from studies of the comparative rate of nitrogen evolution from HN3 in the presence and in the absence of carboxylic acids When m- or />-nitrobenzoic acid is added to HN3 in H2S04, the rate of nitrogen evolution decreases. Thus HN3 must be rapidly converted to an adduct from which loss of nitrogen is slower than from HN3 itself. Moreover, the adduct, to be formed at all, must be formed more rapidly than N2 is lost from HN3.165... 

The intramolecularity of the migration step in the Schmidt rearrangements has been convincingly demonstrated by showing the retention of chirality of the migrating group.166... 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

Nitrilium ions are generally indicated as discrete intermediates in the Beckmann rearrangement of oximes (equation 37, Y = OH2) and in the Schmidt rearrangement (equation 37, Y = N2) of ketones and aldehydes with hydrogen azide. The first stage of these reactions has been defined as an ionization by rearrangement process through a transition state of type 183 (Smith, 1963). 

C-ring contracted 4,5-epoxymorphinans (252) have been reported(379) during studies on the photolysis of codeinone analogs.<220,221) A 7-membered C-ring lactam (2a, Chap. 4) was isolated as a product of the Schmidt rearrangement of dihydrocodeinone.<380) In neither report were biological data presented. 

The rearrangement has a mechanism similar to those of the Hofmann rearrangement of amides, the Lossen rearrangement of acylhydroxamic esters, the Schmidt rearrangement of carbonyl compounds and the Wolff rearrangement of diazoketones. Evidence concerning the mechanism of one can often be applied to the others, and the whole family has been reviewed briefly . Sometimes the distinction is made that the conversion of an acyl azide into an isocyanate or urethane is the Curtius rearrangement whereas the overall sequence is the Curtius reaction, but usually the former name is used for both processes. 

The Schmidt rearrangement of optically active a,a-bisalkylated 3-keto esters (161) regioselectively proceeds to give N-acyl a-alkylated a-amino acid esters (162) with retention of configuration and little or no racemization." Acid hydrolysis of (162), followed by treatment with propylene oxide, affords a-alkylated a-amino acids (163) in high yield and optical purity (equation 48). 

In the Schmidt rearrangement, the treatment of a carboxylic acid with hydrogen azide (hydrazoic acid) also gives the amine, via the isocyanate, when catalysed by an acid, such as sulphuric acid. The first step is the same as the AAC1 mechanism to form the acylium cation, and so is favoured by hindered substrates. The protonated azide undergoes the rearrangement reaction. Illustrate this mechanism as well. 

Fluorenone oxime was recovered unchanged after being heated with PPA at 120°, but at 180° it was rearranged in almost quantitative yield (Conley )- Conley found PPA to be a superior solvent-catalyst for the Schmidt rearrangement. He added sodium azide in portions to a mixture of a diaryl, aryl-alkyl, symmetrical or unsymmetrical ketones with 15-20 parts of PPA at a temperature in the range 25-75° until evolution of nitrogen ceased, and obtained amides in yields mainly of 80-90%. Doorenbos and Wu studied the conversion of cholestanone and... 

Several similar rearrangements, e g the Schmidt rearrangement, can be used analogously, to Introduce the amino function)... 

The electronic effect of a variety of substituents in the aromatic ring in the position para to the carbonyl group of 1-tetralones on the direction of the Schmidt rearrangement has been studied by Uyeo and coworkers143 144a 0 with the use of sulfuric, and trichloroacetic acid, and... 

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