Schmidt reactions, sodium azide

SCHMIDT DEGRADATION Sodium azide. SILYLATION Trimethylsilyldiethylamine. SIMMONS-SMITH REAGENT, which see. SOMMELET REACTION Hexamethylenetetramine. 

Similarly l,2,3-benzotriazin-4(3//)-one (13, R = H) or its 3-aryl derivatives (R = Ar) decompose in refluxing acetic acid containing sodium azide or sodium iodide to afford 2-azido- and 2-iodobenzamides 14 (X = N3, I), respectively, in high yields.340 Schmidt reaction (sodium acid, 40% sulfuric acid, 1,2-dichloroethane, 40-50°C) of 13 (R = H) afforded 2-azidobenz-amide (X = N3 R = H 49%).341... 

Unsaturated acids are converted to amines most satisfactorily by the Curtius reaction (sodium azide method). The Hofmann reaction is applicable with certainty only to a,/3-olefinic acid amides, since the olefin group in another position is likely to be halogenated by the reagent. The Schmidt reaction is applicable to all olefinic acids, although there is a possible danger of sulfonation at the site of unsaturation. 

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 ... 

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. 

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 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]. 

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],... 

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]. 

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],... 

Another fascinating intramolecular process involves the spirocyclic epoxide 103, which carries a pendant azide group. Under the influence of ethylaluminum chloride, this substrate undergoes Lewis acid assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species 105 upon addition of sodium borohydride. This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <03OL583>. 

Chloro-3-methoxycarbonyl-5,6-diphenylpyrazine refluxed with sodium methoxide gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (371) and the attempted Schmidt reaction of 2,5-dimethoxycarbonylpyrazine, in concentrated sulfuric acid with trichloroacetic acid at 60° with subsequent addition of sodium azide, gave 2,5-dicarboxypyrazine (1176). 2-Methoxy-3-methoxycarbonyl-5,6-diphenylpyrazine, when refluxed with cuprous chloride in dry dimethylformamide, gave 2-carboxy-3-methoxy-5,6-diphenylpyrazine (10%) 2-hydroxy-3-methoxycarbonyl-5,6-diphenyl-pyrazine similarly treated gave 5-hydroxy-2,3-diphenylpyrazine (30%) (837). 

Phthalein type dyes have been prepared from 2,3-dicarboxypyrazine by heating with phenols or aromatic amines and zinc chloride. For example, compound (25) was obtained with resorcinol (1353). Efforts to prepare 2,6-diaminopyrazine through a Curtius-Schmidt reaction on 2-acetamido-6-carboxypyrazine (with sodium azide, sulfuric acid, and trichloroacetic acid) proved unsuccessful (434). The preparation of bicyclic heterocyles from 2-amino-3-carboxypyrazines has been described in Section VIII. 1D(6). 

Treatment of phthalic acid (145) with sodium azide under acidic conditions has been reported" to give various products anthranilic acid (147) and a trace of o-phenylenediamine (148) in concentrated sulfuric acid and anthranilazide (149) and benzimidazol-2-one (150) in 90% sulfuric acid. Analogously, phthalic anhydride (146) gives the following products anthranilic acid (147), benzimidazol-2-one (150) and some 3,l-benzoxazine-2,4(l//)-dione (isatoic anhydride) (151) in sulfuric acid and benzimidazol-2-one (150) in acetic acid. A recent report" has revealed that Ae Schmidt reaction of phthalic acid (145) in 90-98% sulfuric acid gives anthranilic acid (147) and anthranilazide (149) (major products) by a process thought to involve 3,l-benzoxazine-2,4(l//)-dione (151) as an intermediate. Benzimidazol-2-one (150) is produced in this reaction by a secondary process from anthranilazide (149). Photolysis of (149) also produces (150). 

The usual procedures for use of PPA in the Schmidt reaction call for a temperature in the range 60-100° or even higher. Stockel and HalP report that improved yields can be obtained at room temperature (excess sodium azide is used). However, the yield depends upon the substituents present. Thus p-nitrobenzoic acid gives p-nitroaniline in only 50% yield, whereas p-methoxyaniline is obtained from p-methoxybenzoic acid in 80% yield. 

Lithiopyridine with cyclobutanone gives the alcohol ( 57 ). This when treated with azoic acid and sulphuric acid undergoes the. Schmidt reaction to afford the azide ( 58 ) which rearranges to myosmine ( 59 ). Reduction with sodium cyanoboro-hydride yields ( )-nornicotine and thence by N-methylation ( )-nicotine. Replacement of cyclobutanone by cyclopentanone allows the formation in turn of ( )-noranabastine and ( )-anabastine. 

Schmidt reaction. By the Schmidt reaction cyclobutanecarboxylic acid (Aldrich Chem. Co.) can be converted into cyclobutylamine in one step in high yield.12 On addition of powdered sodium azide to a stirred mixture of chloroform, cyclobutanecarboxylic acid, and concentrated sulfuric acid and heating at 50° for 1.5 hrs., the... 

Schmidt reaction Hydrazoic acid. Sodium azide. 

Reaction with adamantanone. Japanese chemists1 treated adamantanone (1) with sodium azide in methanesulfonic acid with the expectation of achieving the Schmidt reaction. However, the unexpected 4-methylsulfonoxyadamantanone was obtained in 90% yield. Alkaline hydrolysis cleaves (2) to A2-bicyclo[3.3.1]-mmcnc-7-carboxylic acid (3) in 85% yield by a quasi-Favorsky reaction. Adaman-lanc itself does not undergo this unusual substitution reaction. 

Neighbouring acetyl and hydroxy groups are annulated when the compound is treated with sodium azide in a Schmidt reaction which is followed by cyclization. 

An interesting new approach to monoterpene pyridine alkaloids has been described recently by Vidari and co-workers (206), based on the ability of a Schmidt reaction to desymmetrize bicyclo[3.3.0]octane-3,7-dione (249). This was achieved through reaction with sodium azide and boron trifluoride in CH2CI2 H20 (1 1) at 25°C for 3 h, which gave the lactam 250 in 25% yield. This could be increased to 50% yield by reacting 249 with sodium azide and cone. HC1. Ketalization followed by N-methylation with a phase transfer catalyst gave the lactam 251. Monomethylation of 251 afforded... 

The reaction of naphthoquinones with sodium azide and acetic acid was reported148 to give only aminonaphthoquinones. Folkers and coworkers149 were able to carry out the normal Schmidt rearrangement with 1,4-naphthoquinones using concentrated sulfuric acid 130 (R1 = H R2 = Me) gave a lactam claimed to be 131 (R1 = H R2 = Me). However,... 

Many tetrazoles are biologically active. 1,5-Pentamethylenetetrazole 10 (pentetrazol, Cardiazol) is the most widely known of such compounds. It is a CNS-active cardiac and respiratory stimulant and narcotic antagonist and is injected in cases of barbiturate poisoning. It is prepared via hexano-6-lactam by addition of sodium azide and sulfuric acid to cyclohexanone (Schmidt reaction) ... 

In continuation of his work on azides, Schmidt and his co-workers have now isolated compounds of the type OP(OMe) (N3)3 and OP(NMe2)n(N3)3 , where n = 1 or 2, from reactions between the corresponding chlorides and sodium azide in acetonitrile. Similar reactions in pyridine at room temperature gave the stable azides R2P(X)N3, where R = Me or Et and X = O or S. ... 

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). 

The Schmidt rearrangement of a six-membered benzo-fused ketone with sodium azide yielded benzazepinone derivatives en route to the synthesis ofa library of tubulin-polymerization inhibitors (14JME1390).The reaction of N-nitrosoaniUnes 16 with 2-vinyloxirane 17, catalyzed by rhodium (111), followed by Raney-nickel-catalyzed hydrogenation led to a series of benzazepane derivatives 18 via a reductive amination of a proposed aldehyde intermediate (140L1200). 

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