Schmidt reactions azides

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. 

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 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 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... 

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. 

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine... 

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused l-azabicyclo[m.n.O]alkanes, the perhydrobenzo[/]pyrrolo[l,2-a] azepine 29 was prepared in 72% yield . 

Alkyl azides have been involved in the synthesis of indolizidinone derivatives in several ways. One example (Scheme 7) is the intramolecular Schmidt reaction between alkyl azides and ketones which can be used to transform azidoketone 24 into the corresponding indolizidinones 26 through intermediate 25 <2001JOC886> or with epoxides to obtain the indolizidine 27 <2004JOC3093>. 

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]. 

Of equal importance to the Beckmann rearrangement for the preparation of azepines and azepinones is the Schmidt reaction of ketones. Again, however, with unsymmetrically substituted cyclohexanones or with bicyclic ketones such as a-tetralone, two azepines are possible, a -Substituted cyclohexanones invariably yield the product of attack by azide ion at the least hindered side of the protonated ketone as exemplified in Scheme 19 (B-67MI51600). 

Anomalous ring expansions occur with 2-alkoxynaphtho-l,4-quinones, e.g. (202 R] = Me, R2 = H), in that attack by azide ion takes place at the more hindered carbonyl function (i.e. C-l) to give the l//-l-benzazepine-2,5-dione (203 R OH, R2 = R3 = H). In contrast, the 6-methoxy derivatives (202 R1 = alkyl R2 = MeO) suffer attack at the 4-carbonyl group to yield benzazepinedione (203 R1 = H, R2 = OMe, R3 = OH) (74CJC610). These results have led the authors to conclude that electronic as well as steric factors are important in the Schmidt reaction in determining the direction of ring expansion. 

An extensive review of the chemistry of aliphatic and aromatic azides is given by Boyer and Canter [167] and Gray [168]. Organic azides are subject to various reactions such as the Bergmann degradation and the synthesis of peptides, the well known Curtius rearrangement, the Darapsky synthesis of a-aminoacids [169], for synthesis of triazoles [170], tetrazoles ( Schmidt reaction ) [169] and [171] etc. These reactions lie beyond the scope of the present book. 

Amides lactams. Dimethyl thioketals of cyclic or acyclic ketones react with iodine azide to form an a-azido sulfide in 75-95% yield. The product rearranges to an amide or a lactam in high yield in the presence of trifluoroacctic acid. This sequence is an attractive alternative to the Beckmann rearrangement or Schmidt reaction. 

The Schmidt reaction of cyclic ketones with hydrazoic acid affords convenient access to ring-expanded N-unsub-stituted lactams but extension of this process to alkyl azides to provide Aralkyl lactams is capricious in nature. A protocol... 

A closely related reaction of general applicability is the Curtius rearrangement222 of acyl azides. The rearranging species in the Schmidt reaction (see p. 898) is in fact also a protonated acyl azide these azides are readily prepared by the action of nitrous acid on acyl hydrazides which are themselves formed from esters and hydrazine (Section 9.6.17, p. 1269). On heating in aprotic solvents the acyl azides decompose to yield the corresponding isocyanates in good yield. 

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. 

Consideration of the mechanism has to account for the fact, that hydrazoic acid and dinitrogen is liberated during the course of the reaction. The similarity to the Schmidt reaction is obvious, and it should be mentioned that quinisatine (2,3,4-trioxo-tetrahydroquinoline) reacts with sodium azide and sulfuric acid at 0 °C in moderate yield to give 14 [96TH000],... 

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