Schmidt rearrangement forming

Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21. An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p-liydroxyacetophenone. ... 

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). 

A practical example of this reaction is given in Table 23-6 together with examples of related reactions known as the Curtins and Schmidt rearrangements. The latter two probably also involve rearrangement of an acyl nitrene, this time formed by decomposition of an acyl azide ... 

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... 

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... 

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. 

In the second reported synthesis IS) (Scheme 3) racemic A-benzoyl-meroquinene (42 R = H) was obtained from hexahydroisoquinolone 34. The cis vinyl and acetic acid side chains were formed by a sequence of reactions including stereoselective hydrogenation, Schmidt rearrangement, and pyrolytic JV-nitrosolactam fragmentation. 

Schmidt rearrangement. With pyridinium tosylate as a catalyst, gewj-azido silyl ethers are formed from silyl enol ethers. The products undergo photoinduced rearrangement to give amides or lactams. 

Scheme 4.2 Syntheses of homoerythrina alkaloids by domino alkylation/Michael addition. 6b with iodide 7 gave spiro compound 8b in 48% yield, which could be subsequently increased to 80% by using cesium t-butoxide as a base in t-BuOH/THF (tetrahydro-furan) solvent [5]. The ketoesters 8a,b were found to be useful precursors for Homoerythrina alkaloids such as 10. Thus, ( )-3-demethoxy-l,2-dihydrocomosidine 10b was obtained in good yield in four steps form ketoesters 8b, involving a Schmidt rearrangement as the final step (Scheme 4.2) [6].

Azides are utilized for various C-C cleavage reactions [45]. For example, the alkylarene 78 v ras converted to the aniline 81 upon treatment with n-nonyl azide and an iron catalyst under oxidative reaction conditions (Scheme 7.30). Oxidation of the arene 78 generates the benzyhc cation 79, which reacts with the azide. Subsequent Schmidt rearrangement generates the iminium cation 80, which hydrolyzes to form the aniline 81. This method was applicable to degradation of low molecular weight polystyrenes to arylamines [45c]. 

The addition of hydrazoic acid onto non-activated olefins is a difficult reaction that has been observed only in rare cases. The main problem was the prevention of subsequent decomposition of the azide formed via nitrogen release or Schmidt rearrangement due to harsh reaction conditions that are typically employed. 

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)... 

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). 

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. 

Reactions which insert an O or NH group next to a carbonyl can be used to form heterocycles (Scheme 23). The Schmidt reaction or the Beckmann rearrangement can accomplish this for nitrogen, the Baeyer-Villiger oxidation does it for oxygen. For example, cyclohexanone is converted in this way into 2-azepinone and into 2-oxepinone cycloheptanone yields the corresponding eight-membered heterocycles. 

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. 

This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement, in that an electropositive nitrogen is formed that initiates an alkyl migration. 

The participation of nitrilium salts has also been postulated42 in the Schmidt reaction and in some Beckmann rearrangements when concentrated sulfuric acid is employed. Hill43 has demonstrated recently that some Beckmann rearrangements carried out in a concentrated sulfuric acid medium are Ritter-type reactions in which the nitrile formed in situ from the oxime combines with a carbonium ion to yield a nitrilium salt, which, when diluted with water, leads to the N-alkylamide. 

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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