2//-Azepine

The azepine system occurs in four tautomeric forms, the 1//-, 2H-, 3H- and 4//-azepines 1-4 [10]. The IH- and 3//-systems are the most important. 

Very few l//-azepines are known. The parent compound l//-azepine 1 is an unstable red oil even at -78°C, and rearranges to the more stable 3//-azepine 3 in the presence of acid or base. Electron-attracting V-substituents increase the stability of the l//-azepines. In l-(/7-bromophenylsulfonyl)-l//-azepine (Fig. 7.1) the seven-membered ring is boat shaped with alternating Csp2-Csp2 single and double bonds. 

The protons of the li/-azepine system appear in the vinyl region of the NMR spectrum. The parent compound has 5.22 (H-2/H-7), 4.69 (H-3/H-6) and 5.57 (H-4/H-5) (CCI4). Hence, lif-azepines are not 8 r-antiaromatic planar molecules, either as solids or in solution, but are atropic nonplanar cyclopolyenes. 

377-Azepines with substituents in the 2-position are conformationally mobile and display ring inversion between two boat structures (5a and 5b). The inversion barrier can be ascertained by temperature-dependent NMR spectroscopy and was found to be AG = 42.7 kJ mol for 2-anilino-3//-azepine [11]. 

Azepines display the chemical behaviour of polyenes as shown by pericyclic reactions such as cycloadditions and dimerizations, and also by cheletropic and sigmatropic rearrangements. 

The stable tbiepin 5 is obtained from interaction of the thiinium salt 2 and lithiodia-zoacetic ester via C-4 addition to 3 and ring enlargement of the corresponding carbene intermediate 4 [12]  

Thiepins are converted by valence isomerism into thiirans (6), which on desulfurization (cf p. 27) and ring contraction yield arenes, for example  

Dibenzo[b,f]thiepin (8) is obtained by POCI3-promoted intramolecular Friedel-Crafts acylation of [2-(phenylsulfanyl)phenyl]acetic acid (7) with concomitant chlorination (7 — 8)  

lTDihydrodibenzo[b,f]thiepins of type 9 are used as pharmaceuticals because of their marked CN S-stimulating, antidepressive, and anti-inflammatory effects. 

The azepine system occurs in four tautomeric forms, the 1H-, 2H-,3H-, and 4H-azepines I I 

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The PdCli-catalyzed instantaneous rearrangement of A -carbethoxy-S-azabi-cyclo[5.1.0]oct-3-ene (60) takes place at room temperature to give A -car-bethoxy-8-azabicyclo[3.2.1]oct-2-ene (61)[50], The azepine 62 undergoes a smooth skeletal rearrangement to give 63, and the diazepine 64 is converted into the open-chain product[51]. Beckmann fission of the oxime 65 of ketones and aldehydes to give the nitrile 66 is induced by a Pd(0) complex and oxygen [52,53]. 

A radically different course is followed when the reaction of 2-alkyl-substituted thiazoles is periormed in methanol or acetonitrile (335), 2 1 adducts containing seven-membered azepine rings (91) are being formed in which two of the original activated hydrogen atoms have altered positions (Scheme 55). A similar azepine adduct (92) was obtained by... 

Solvent has an important influence on the course of this cycloaddition, and in the reaction of 2,5-dimethylthiazole with DMAD in DMF the product analogous to (415) was obtained. However, in DMSO or acetonitrile a thiazolo[3,2-a]azepine was formed in addition to this product, whereas with THF, dichloromethane or nitromethane, only the thiazoloazepine was isolated. 

Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused systems that would be difficult to synthesize in other ways. H- 1,2-Diazepines (538) undergo electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also undergo similar valence bond isomerizations. 

The reaction of nitrones with allenes produced three main products an azepine, a pyrrolidinone and an isoxazolidine (Scheme 155) (79JOC4213). The intramolecular cycloaddition of nitrones (529) produced different products depending on the length of n (Scheme 156) (78H(10)257). 

Saturated large rings may form nitrogen radicals by H abstraction from N, or abstraction may occur in the a- or /3-positions in nonnitrogen systems. Oxepane gives the radical in the 2-position, with subsequent cleavage and reclosure of the intermediate carbenoid to cyclohexanol (Section 5.17.2.1.5). In unsaturated large systems a variety of reactions, unexceptional in their nature, are found. Some azepines can be brominated by A -bromosuc-cinimide others decompose under similar conditions (Section 5.16.3.7). 

The participation of a single double bond of a heterocycle is found in additions of small and large rings azirines (Section 5.04.3.3) and thietes (Section 5.14.3.11) furnish examples. Azepines and nonaromatic heteronins react in this mode, especially with electron deficient dienes (Scheme 16 Section 5.16.3.8.1). 

Diene moieties, reactive in [2 + 4] additions, can be formed from benzazetines by ring opening to azaxylylenes (Section 5.09.4.2.3). 3,4-Bis(trifluoromethyl)-l,2-dithietene is in equilibrium with hexafluorobutane-2,3-dithione, which adds alkenes to form 2,3-bis-(trifluoromethyl)-l,4-dithiins (Scheme 17 Section 5.15.2.4.6). Systems with more than two conjugated double bonds can react by [6ir + 2ir] processes, which in azepines can compete with the [47t + 27t] reaction (Scheme 18 Section 5.16.3.8.1). Oxepins prefer to react as 47t components, through their oxanorcaradiene isomer, in which the 47r-system is nearly planar (Section 5.17.2.2.5). Thiepins behave similarly (Section 5.17.2.4.4). Nonaromatic heteronins also react in orbital symmetry-controlled [4 + 2] and [8 + 2] cycloadditions (Scheme 19 Section 5.20.3.2.2). 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

H-Azepine derivatives form a diene complex with tricarbonyliron, leaving uncomplexed the third of the double bonds. If the 3-position is substituted, two different such complexes are possible, and are in equilibrium, as seen in the NMR spectrum. An ester group in the 1-position of the complex can be removed by hydrolysis, to give an NH compound which, in contrast to the free 1/f-azepine, is stable. The 1-position can then be derivatized in the manner usual for amines (Scheme 22). The same tricarbonyliron complex can, by virtue of the uncomplexed 2,3-double bond, serve as the dienophile with 1,2,4,5-tetrazines. The uncomplexed N-ethoxycarbonylazepine also adds the tetrazine, but to the 5,6-double... 

Tricarbonyliron complexes of 1,2-diazepines do not show the rapid isomerization found in their azepine counterparts (Scheme 22) the iron forms a diene complex with the C=C double bonds in the 4- and 6-positions. The chemistry of the 1,2-diazepine complexes is similar to that of the azepine complexes (Section 5.18.2.1) (81ACR348). 

Physical Data Index 4H-Azepine-2-carboxylic acid... 

H-Azepin-2-amine, 1,1 -diethyl-3-methyl- HNMR, 7, 495 (72JA513)... 

Azepine-1-carboxylic acid, methyl ester, tricarbonyliron complex X-ray, 7, 494 <70JCS(B)1783) 4//-Azepine-2-carboxylic acid, 6,7-diphenyl-, methyl ester... 

H-Azepine-3-carboxylic acid, 2-methoxy-, methyl ester... 

C NMR, 7, 498 (79TH51600) 2H-Azepine-4-carboxylic acid, 7-(4-bromophenyl)-3-methoxy-2-oxo-6-phenyl-X-ray, 7, 494 <79H(12)1423> 3H-A2epine-4-carboxylic acid, 6-acetyl-2-ethoxy-3-oxo-7-phenyl-, ethyl ester H NMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2,6-diethoxy-3-oxo-7-phenyl-, ethyl ester H NMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2-ethoxy-3-oxo-6,7-diphenyl-, ethyl ester HNMR, 7, 503 <81H(16)363) 3H-Azepine-4-carboxylic acid, 2-ethoxy-3-oxo-7-phenyl-, ethyl ester... 

IH-Azepine 1-oxide, 1-methyl- C NMR, 7, 498 <770MR<9)333) 2H-Azepine-2-selenone, hexahydro-l-methyl- C NMR, 7, 498 <79AJC567> 3H-Azepine-2,3,5,7-tetracarboxylic acid, 4,6-diphenyl-, tetramethyl ester X-ray, 7, 494 <72CB982) 3H-Azepine-2,4,6,7-tetracarboxylic acid, 3,5-diphenyl-, tetramethyl ester X-ray, 7, 494 <72CB982>... 

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