The Schmidt Reaction

8) For reviews of the Schmidt reaction, see ref. [80], with respect to bicyclic ketones, see ref. [81]. 

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]. 

A variation of the Schmidt type reaction is the rearrangement of an azidocyc-loalkane, which is formed from the addition of hydrazoic acid to an cycloalkene. This reaction was used in the synthesis of muscopyridine (II/U4), a base isolated from the perfume gland of the musk deer [85]. In this context the reaction of II/115 as a model compound under the conditions of the Schmidt reaction gave a mixture of two compounds which after dehydrogenation yielded 11/116 and 11/117. The mechanism can be explained in terms of the migration of different bonds in the precursor. 

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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. 

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). 

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)... 

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 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. 

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... 

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. 

The Schmidt reaction of ketones works best with aliphatic and alicyclic ketones alkyl aryl ketones and diaryl ketones are considerably less reactive. The reaction is only seldom applied to aldehydes as starting materials. The hydrazoic acid used as reagent is usually prepared in situ by treatment of sodium azide with sulfuric acid. Hydrazoic acid is highly toxic, and can detonate upon contact with hot laboratory equipment. 

With alkyl aryl ketones, it is the aryl group that generally migrates to the nitrogen, except when the alkyl group is bulky. The reaction has been applied to a few aldehydes, but rarely. With aldehydes the product is usually the nitrile (16-21). Even with ketones, conversion to the nitrile is often a side reaction, especially with the type of ketone that gives 17-31. A useful variation of the Schmidt reaction treats a cyclic ketone with an alkyl azide (RN3) in the presence of TiCU, generating a... 

In the first step of the mechanism, the OH group is converted by the reagent to a better leaving group (e.g., proton acids convert it to OHj). After that, the mecha-nism follows a course analogous to that for the Schmidt reaction of ketones (18-16) from the formation of 71 on ... 

Carboxylic acids and esters can also be converted to amines with loss of the carbonyl group by reaction with hydrazoic acid, HN3, which is known as the Schmidt reaction,278 The mechanism is related to that of the Curtius reaction. An azido intermediate is generated by addition of hydrazoic acid to the carbonyl group. The migrating group retains its stereochemical configuration. 

Both inter- and intramolecular variants of the Schmidt reaction in which an alkyl azide effects overall insertion have been observed. 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

The Curtius and Schmidt reactions both involve N2 as the leaving group from the azide intermediate (67), and here again the migration of R occurs in a concerted process. The azide may be obtained either by nitrosation of an acid hydrazide (65)—Curtius reaction—or by the reaction of hydrazoic acid, HN3, on a carboxylic acid (66)—the Schmidt reaction. 

The Schmidt reaction of ketones with hydrazoic acid is believed to be a similar rearrangement, again with concerted trans migration and elimination of nitrogen. 

When the two groups of the ketone are para-substituted phenyls, the product of the Schmidt reaction is usually a nearly equimolecular mixture of the two isomeric amides.806 This result, obtained instead of a preferential migration of the more electron-releasing group, is consistent with a mechanism in which the formation of the intermediate rather than its rearrangement is rate determining. 

The rate of the Schmidt reaction of para-substituted benzoic acids is governed by the electron-releasing character of the substituent, the value of the Hammett p parameter being the same as that needed to correlate product ratios in the related reaction of 1,1-diarylethylenes.807 The latter reaction is believed to go by a similar mechanism. 

The Schmidt reaction is also applied to a variety of 1-tetralones, yielding (51). The use of sodium azide in acetic acid and sulphuric acid [7, 12, 13, 30, 34, 36, 37, 72, 73, 84] is preferable to the procedure in the earlier stage, in which hydrazoic acid, sulphuric acid and chloroform are employed [115]. Other acidic reagents such as polyphosphoric acid [116, 117], sulphuric acid [116, 118], methasulphonic acid [119] and trichloroacetic acid [116] are used in some cases. Variation of substituents affects the course of the rearrangement 6-methoxytetralones are rather liable to afford the isomeric 2-benzazepine-l-ones in preference to the desired (51) [ 7, 116, 118]. The Schmidt reaction is also conveniently applied to various 1,4-naphthoquinones and yields a wide range of 2,5-dihydro-l-benzazepin-2,5-diones [85, 120-122]. 

This is the first example of a direct coupling of a diazo compound in a / position of the thiophene nucleus. The Beckmann rearrangement with the ketoxime of 2-thienylketone was found to give poor yields of the aceto-2-thiopheneamide. Furthermore, the Schmidt reaction using hydrazoic and sulphuric acids was investigated and did give rise to aceto-2-thiopheneamide but probably as an eutectic with the isomeric 2-thenoylmethylamide. 

The reactions of methyl ether 84a with hydroxylamine give under acid or neutral conditions, predominantly, isomeric isoxazolotropones 90 and 91, respectively, in addition to their oximes (Section IV,A,8,b) and other products (Scheme 22 82JHC525). 3-Acetyltropolones and analogs (e.g., 88, 96) behave similarly (82JHC525 87JHC779). The Schmidt reaction of halogen-substituted 3-acetyltropolones 92 affords oxazolotropones 93 (87JHC779). 

Thienobenzazocine 179 is formed regioselectively in 65-93% yield when the rearrangement is carried out in PPA or PPA in xylene. The use of H2SO4 or PCI5 gives a mixture of regioisomers 179 180 in ratios from 90 10 to 60 40. The Schmidt reaction forms only thienobenzazocine 179 in 25-65% yield from benzo[4,3]-cyclohepta[l,2- 7]thiophen-4-one 181 (Scheme 50). 

Krow and colleagues investigated the migratory preferences of the Schmidt and Beckmann rearrangements in norcamphors. Two isomeric lactams are usually formed in the Schmidt reaction but one lactam is obtained almost exclusively in a Beckmann reaction (equation 178). 

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