Azepinone

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

Because authors have approached similar topics from different viewpoints, index entries to those topics may appear under several headings. Thus a reader interested in, for example, the synthesis of acetyl-3Tf-azepin-2-ones should refer both to general entries (e.g. Azepinones, Azepin-2-ones, 3JT-Azepin-2-ones) and to specific entries (e.g. 3JT-Azepin-2-one, 3-acetyl- 3f7-Azepin-2-one, 7-acetyl-). 

H-Azepin-2-one, 3-acetyl-synthesis, 7, 542-543 3/f-Azepin-2-one, 7-acetyl-synthesis, 7, 542-543 3H-Azepin-2-one, 3-acyl-rearrangements, 7, 505 3/f-Azepin-2-one, 3-acyl-2-alkoxy-formation, 7, 542-543 3H-Azepin-2-one, 1-alkyl-rearrangements, 7, 505 3/f-Azepin-2-one, N-alkyl-synthesis, 7, 511 Azepinones... 

Dibenzazepin-2-one, 5-aminomethyl-transannular nucleophilic attack, 7, 25 Dibenzazepin-2-ones tautomerism, 7, 503 Dibenz[6,dJazepinones phenanthridinones from, 2, 507 synthesis, 7, 530 Dibenz[6,d]azepinones, hydrosynthesis, 7, 536 Dibenz[6,eJazepinones synthesis, 7, 529, 530 5H-Dibenz[c,eJazepin-7-ones synthesis, 7, 529... 

Only brief reference is made in this section to azepinones as there is scant evidence for the existence of their azepinol tautomers. 1 //-Azepin-3(2//)-ones, e.g. 12, exist exclusively as the nonconjugated, nonplanar 3-oxo forms in a wide range of solvent systems.43 44 All attempts to generate the enolates have failed. Likewise, l//-azepin-2(3//)-ones, for which lactim and enol tautomers are possible, prefer the amide form 13.45... 

Early efforts to effect the photoinduced ring expansion of aryl azides to 3H-azepines in the presence of other nucleophiles met with only limited success. For example, irradiation of phenyl azide in hydrogen sulfide-diethyl ether, or in methanol, gave 17/-azepine-2(3//)-thione35 (5% mp 106—107 " O and 2-methoxy-3//-azepine (11 %),2 3 respectively. Later workers194 failed to reproduce this latter result, but found that in strongly basic media (3 M potassium hydroxide in methanol/dioxane) and in the presence of 18-crown-6, 17/-azepin-2(3//)-one was produced in 48% yield. In the absence of the crown ether the yield of azepinone falls to 35%. 

The oxazolo[3,4-a]azepinones 4, in which 5 7 ring fusion imparts considerable planarity and hence antiaromatic character on the ring system, undergo spontaneous dimerization.153 The mode of dimerization appears to depend on the nature and position of substituents. The unsubstituted system and the 9-chloro derivative 4 (R1 = Cl R2 = H) produce the exo.anti-dimers, e.g. 5, upon spray-vacuum pyrolysis at 300 C, whereas the 7-/ert-butyl, 7-bromo, 7-methyl, and 7,9-dichloro (4, R1 = R2 = Cl) compounds yield the exo,syn-dimcrs, e.g. 6. 

The [l,3]oxazino[3,4- ]azepinone 42, isolated as a byproduct (8%) during the preparation of 2//-azepine from the 1-carboxylate 40, is believed to arise by a [2 + 4] cycloaddition of 2-methylpropene (formed in situ) with the l-acyl-2/7-azepinium ion 40 via intermediate 41.290... 

Hydroxydeethoxylation of the 2>H- -benzazepine 3 in refluxing methanolic potassium hydroxide (Method A) is accompanied by selective hydrolysis and loss of the 3-carboxylate group.20 Hydrolysis in concentrated hydrochloric acid, however, is rapid and yields only the bcnz-azepinone 4 (Method B). 

Reduction of the 5A/-2-benzazepin-5-one 5, prepared by base-catalyzed (triethylamine) dehydrobromination of4-bromo-8-chloro-l-(2-chlorophenyl)-3//-2-benzazepin-5(4//)-one, with lithium aluminum hydride at — 78 C yields a mixture of the 5//-azepin-5-ol 6 and the dihydrobenz-azepinone 7.78 Attempts to prepare the 5-bromo derivative from the alcohol 6 failed. 

A further variant of Method B is the conversion of the readily available aryl(2-methyl-aminoaryl)methanols 16 into the chloroacelyl derivatives 17, followed by oxidation to Ihe benzophenones 18 with chromium(VI) oxide. The products are transformed into benzodi-azepinones by treatment with sodium iodide and ammonium carbonate (Method D). Selected... 

A solution of KN03 (0.48 g, 4.8 mmol) in coned H2S04 (3 mL) was added dropwise to the benzodi-azepinone (4 mmol) in coned H2S04 (5 mL). The resulting solution was stirred for 4h at 20°C and then poured on ice. The mixture was neutralized with dil aq NH3 and the resulting precipitate was collected, washed with H,0 and dissolved in CH2CL. The filtered solution was dried (MgS04) and evaporated and the residue was recrystallized. 

The use of cycloadditions for synthesizing medium-sized ring lactams is more or less restricted to the generation of seven-membered rings. The simplest method to generate azepinones seems to be the [6-1-1] reaction of a 1,6-dicar-boxylic acid chloride 148/152 and a phosphinimine 149, the in situ formed chloro enamine 150 underwent a Chapman rearrangement to give a cyclic imide 151/153 (Scheme 28)] [36]. 

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

Finally, an acid catalyzed rearrangement of an o-(2-arylphenyl)-hydroxyl-amine followed by a ring enlargement to yield some unsaturated 7-aryl-azepinones should be mentioned (not shown). Until now, scope and limitations of that process are not known [52]. 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

In the rearrangement of divinylaziridines 289, the participation of a boat-like transition state 290 explained the stereochemical outcome of the reactions to give the azepinones 291 in 73 to 85% yield. The divinylaziridines 289 were synthesized via ex-chiral pool sequences starting from optically active a-amino acids. Table 16, Eq. (26) [55]. 

In the case of the related starting material 95, bearing a chlorovinyl fragment in the side chain, the expected azepinone 96 was accompanied by a new rearranged quinolizine derivative 97 that was generated from allylic transposition of the side chain to C-12b, as shown in Scheme 8 <1996TL5701>. 

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