Schmidt reactions with carbonyl compounds

Schmidt Reaction.54 Closely related to the Curtins reaction in its mechanism is the Schmidt reaction, whereby carbonyl compounds react with hydrazoic acid in acid solution to give rearranged products. Amines, amides, nitriles, and tetrazoles are the most common substances obtained from the reaction. 

The most important group of Schmidt reactions are those carried out with carbonyl compounds. Aromatic and aliphatic acids and ketones form amines and amides respectively (reactions 17 and 18), but aldehydes and a few ketones give mainly cyanides together sometimes with very poor yields of formyl derivatives of amines, RNHCHO. 

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

The reaction of carbonyl compounds with hydrazoic add was first reported by Karl Friedrich Schmidt in 1923 in a study of the decomposition of hydrazoic add by sulfuric add. He observed that benzene had an accelerating effect on the decomposition > and that the products obtained differed according to the temperature at which the reaction was carried out at room temperature hydrazine sulfate was the main product, but at a temperature of 60-70° anihne sulfate was formed in high... 

The Schmidt reaction with a carbonyl compound can be carried out in essentially three different ways ... 

Schmidt Reactions of Alkyl Azides with Carbonyl Compounds... 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

In the course of the structure elucidation of the natural occurring spermidine alkaloides such as inandeninone 11/108, (Scheme 11/15) the Schmidt reaction played an important role. The alkaloid is a nearly 1 1 mixture of two isomers, isolated from Oncinotis inandensis Wood et Evans. To make sure that the compounds differed only in the location of the carbonyl group at positions C(12) and C(13), the mixture was treated with sodium azide, sulfuric acid, and chloroform. The product consisted of a mixture of four ring enlarged dilactams (one of them, compound 11/109, is shown) with nearly equal ratios [84],... 

If there are two carbonyl compounds present, then a cross condensation might occur, but usually it is of little synthetic value as there are four possible products. However, if one of the carbonyl compounds lacks an a-hydrogen, then the reaction might prove useful, because this compound cannot form the enol intermediate. An example is the Claisen-Schmidt condensation involving an aromatic aldehyde, e.g. benzaldehyde, with a simple aldehyde or ketone,... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. To be useful as a method for synthesis there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Reaction with Cyclic Enones. Conjugate addition of azide ion to cyclic enones in water using sodium azide in the presence of Lewis base resulted in the formation of 8-azido carbonyl compounds (eq 55). The Schmidt reaction of benzopyranones with sodium azide led to pyrano[3,2-b]azepines in reasonable yields (eq 56). 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and aUcenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, nitriles, amides or imines. 

Many functional groups besides the carbonyl group react with hydrazoic acid to give tetrazoles. In most of these reactions no catalyst is required. The tetrazoles thus obtained frequently are formed by rearrangement of intermediate azides. Since it may be desired to apply the Schmidt reaction to a molecule containing other functional groups or to a mixture of compounds, a few of the reactions leading to the formation of tetrazoles will be discussed briefly. 

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