377-Azepines

Azepines. - Formation. The thermal and photolytic decomposition of aryl azides provides important routes to azepines via inter- and intra-molecular reactions of the derived nitrene with aromatic rings. New work has been reported on several aspects of this chemistry. 

In the first study on the decomposition of phenyl azide in the presence of electrophilic reagents it has been shown that both thermal and photochemical reactions lead to the azepinone (2) and to disubstituted arenes such as (4). The azepinone is thought to be formed by the addition of acetic acid to the didehydroazepine intermediate (1) and subsequent acetolysis, and the disubstituted arenes are formed from the nitrenium ion (3). 

The didehydroazepine (1) or benzazirine intermediates that are generated by the photolysis of phenyl azide have also been intercepted by the naked anions that are produced from various potassium salts when they are used in the presence of crown ethers Potassium acetate and hydroxide both gave the azepinone (2) while potassium halides gave only the o-halo-anilines. 

In the intermolecular reaction of the nitrene that is derived from tosyl azide with benzene, little of the A -tosylazepine (5) is obtained at normal pressures, but the yield is markedly increased when the reaction takes place under a high pressure of nitrogen for example, to 48% at ca 90 atm.In a similar reaction with dimethyl terephthalate, it is suggested that the reaction involves an initial [1,3] cycloaddition of the azide to the aromatic ring to give (6), rather than a nitrene reaction. 

The vinylaziridine (8) reacts with various alkynes and alkenes to give, respectively, the dihydro- and tetrahydro-azepines (7) and (9). These reactions  

Among azepines and their benzo derivatives, antiaromatic IH-azepine 14a is known as a very unstable (even at -78°C in CDCI3 solution) red oil which in the presence of acid or base rearranges to the marginally 

Prinzbach and Limbach have studied the valence isomerism between N-substituted azepines 14b and benzeneimines 14c (76CB3505) although 14b is much more stable (actually it is the only form detected by NMR), the compound could react, depending on R, as 14c with diazomethane. Later, Prinzbach et al. reported the study of the equilibrium 14b (90% )/14c (10%) in the case of R = p-tosyl [the compound has the following C-substituents 3,6-dichloro-4,5-di(methoxycarbonyl)] in the solid state (X-ray) only 14b is present [86CB616], 

Of the four dibenzazepines, 5//-dibenz[h,d]azepine (19), 5//-dibenz [h,e]azepine (20), 5//-dibenz[h,/]azepine (21), and 6//-dibenz[c,e]azepine (22), only 21 is known as such (74CRV101 84JHC197), while 22 exists as the nonaromatic 5//-tautomer (81LA240). 

Monocyclic Azepines.—Formation. Two new valence isomers of azepine have been prepared by photochemical routes. Photolysis of the triazoline (1) gave (2), which thermally isomerized to AT-phenylazepine when R was phenyl, but which gives a fused oxazoline if R is COaEt.  

The 3-azaquadricyclane (4) was prepared by photoisomerizing (3) it was thermally quite unstable (ti/2 at 70 °C was ca. 2 min), and on heating in benzene it was converted into N-tosylazepine rather than reverting to (3).  

The reactive l-thiacyclohept-4-yne (5) adds pyridine iV-oxide at room temperature to give (6), said to be the first 2ff-azepine at 145 °C the azepine ring contracts to become a (2-pyridyl) substituent.  

The first indeno[l,2- i]azepine (7), shown by n.m.r. to have a fully conjugated 147T-system, has been synthesized via the successive bromination-dehydro-bromination of (8). The same group has developed two routes to (9), as a possible precursor for the same system via dehydrogenation.  

AT-Ray analysis has shown that the aromatic azatropolone ring (11 R = COaEt) is, surprisingly, not planar, and it has chirality. A general route to a range of these interesting compounds is provided by the base-induced ringopening of (10) followed by dehydrogenation.  

Perhaps the most common drugs based on 7-membered rings are the benzodiazepines. Different benzodiazepines have been used for the treatment of seizures, insomnia, depression, or anxiety. Examples of benzodiazepines include alprazolam (XANAX, Pfizer, Inc.), chlordiazepoxide (LIBRIUM, Hoffman-LaRoche, Inc.), diazepam (VALIUM, Roche Laboratories), and lorazepam (ATIVAN, Biovail Pharmaceuticals, Inc.). 

Olanzapine is a psychotropic agent that belongs to the thienoben-zodiazepine class. Olanzapine (ZYPREXA Eli Lilly and Company) is approved by the U.S. Food and Drug Administration (FDA) for treating the symptoms of schizophrenia and acute mixed, manic episodes, or maintenance treatment of bipolar disorder. Quetiapine 

Oxcarbazepine (TRILEPTAL, Novartis Pharmaceuticals Corporation) is used for the treatment of partial seizures in people with epilepsy. 

Varenicline (used as the tartrate salt as CHANTIX, Pfizer Inc.) is a smoking cessation dmg containing a benzazepine ring structure. 

Azelastine (hydrochloride salt is ASTELIN, Meda Pharmaceuticals Inc.) is an antihistamine that is used as a nasal spray and provides reMef for seasonal allergies. 

Pyrido[l,2-fl]azepine core is common to a group of alkaloids extracts from Stemona plants (Stemonaceae). Stemona together Pentastemona, Croomia, and Stichoneuron are four genera of Stemonaceae. The roots of three species, Stemona tuberosa, Stemona japonica, and Stemona sessifolia, have been used for centuries in traditional Chinese medicine for a variety of purposes such as treatment of cough, bronchitis, tuberculosis, pertussis, and as antiparasitic agents [1-5], 

More than 130 alkaloids from various species of the genus Stemona are known in the literature, and different classification are also reported [6], Structurally, the alkaloids are characterized by a pyrrolo[l,2-a]azepine nucleus usually linked with two carbon chains mostly forming terminal lactone rings. 

On the basis of purely chemical aspects, an alternative classification into five [7], seven [8], or eight [9] groups was suggested, where the name of the structurally simplest derivative was used for group denomination. The different types can be 

Biosynthesis of Heterocycles From Isolation to Gene Cluster, First Edition. Patrizia Diana and Girolamo Cirrincione. 

SEVEN-, EIGHT-MEMBERED AND LARGER HETEROCYCLIC RINGS 

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However, the relative stabilities of azepine conformers are highly dependent on the nature of the ring substituents, and some substantial inversion energy barriers have been noted, e.g. dimethyl 2,7-dimethyl-3//-azepine-4,6-dicarboxylate [57.3 kJ - mol-coalescence temperature (Tc) 25 5°C],76 isochalciporone (26)(49.4kJ mol-1 Tc 2 + 1 C),40 and 2,4,6,7-tetraphenyl-3/7-azepine (68.1 kJ mol-1 Tt 80°C).37 Ring-inversion activation energies of similar magnitudes have been determined for 4//-azepines.83 85... 

The alicyclic analogs 4 with hydrogen bromide in diethyl ether at room temperature behave similarly to yield the 4,5-fused 7-bromo-3/7-azepin-2-amines 5 as their hydrobromide salts. Yields are high except for the cyclooctane derivative (n = 4). Once again, the free bases are liberated by treatment with sodium hydrogen carbonate. 

A comparison of the photolysis of 2-azidophenyl methyl ketone and 3-methyl-2,1-benzisoxazole in piperidine reveals that whereas the former gives a mixture of isomeric 3//-azepines the latter furnishes 3-acetyl-2-piperidino-3/7-azepine (4) in almost quantitative yield.124... 

The ring contraction of 3//-azepines is also promoted by acylating agents,54 35 and by arenesulfonyl halides.34 For example, in refluxing acetic anhydride A,-phenyl-3//-azepin-2-amine yields 2-acetamidodiphenylamine (22% mp 121-122°C),34 whereas A,A,-diethyl-3/7-azepin-2-amine (30) with 4-nitrobenzoyl chloride in pyridine yields the benzanilide 31.35... 

The rearrangement of 3-acetyl-2-piperidino-3/f-azepine to 3-acetyl-2-piperidinopyridine in the injection port during GC analysis of the 3/7-azepine has been noted.124... 

In contrast to its reaction with methyllithium, jV,Af-diethyl-5-phcnyl-3//-azepin-2-amine (1) with butylithium undergoes 4,5-addition to give 4-butyl-A, V-diethyl-5-phenyl-4,5-dihydro-3/7-azepin-2-amine (2)38. 

Of particular interest is the syn-l,6-imino-8,13-methano[14]annulene (59) which represents the first authenticated example of a stable 1H-azepine with a free NH group (80AG(E)1015). The annulene with aluminum oxide undergoes a remarkable isomerization to the anti isomer (61). Investigation shows that the isomerization is not a thermal reaction but involves alumina-catalyzed proto tropic shifts via the 3/7-azepine tautomer (60). This system is unique in that it is the first example of a 3H -> 1H azepine tautomerism, and is a consequence of the high degree of strain in the anti-Bredt 3iT-azepine (60). 

Molecular models reveal that the five-membered ring constrains the azepine nucleus in a near planar conformation with the result that the oxazoloazepine (232 n = 1), unlike most other Af-acyl-1//-azepines, is unstable and dimerizes spontaneously in a highly selective [6+4] manner (see Section 5.16.3.2.3). In contrast, the oxazinoazepine (232 n= 2) formed in 26% yield by FVP of phenethyl azidoformate is less strained and is stable as the monomer (8ICC 1087). Likewise, the benzoxazinoazepine (233), derived from biphenyl-2-yl azidoformate, is thermally quite stable, but in acid rearranges to 2-(o-hydroxyphenyl)-3/7-azepine (81CC241). 

Photolysis of PhN3 in an argon matrix gives l-aza-l,2,4,6-cycIoheptatetraene (232) (79RTC334) in aniline the photoproduct is the 3/7-azepine (233) (8lAHC(28)23i). 

Photolysis of PI1N3 in aniline gives 3/7-azepine <1981AHC(28)231>. For related preparation of azepines from indazole derivatives, see Section 3.4.3.2.4. 

Anomalous isomerizations have been noted during the photolytic and thermal rearrangements of 3-acyl-2-methoxy-3jF3T-azepines (2 R = acyl, R = OMe) and 3-acyl-3/7-azepin-2-ones (69T5217). Irradiation in methanol solution produces mixtures of 3-azabicyclo[4.1.0]hepta-2,4-dienes (28 R = acyl and H, R = OMe, R = H) (or -4-ene-2-ones) and 3-phenacylpyridines (or pyridones), albeit in poor yields. Detailed, but tentative, arguments involving azanorcaradiene and/or diradical intermediates are presented to explain the formation of these unusual products. 

Not unexpectedly the 5a,9a-dihydro-l-benzazepine (64) on heating isomerizes to the conjugated 2,3-dihydro isomer (78JOC315). Likewise, NMR spectra reveal that after 24 hours at 25 °C, 30% of the unconjugated bis-(trifluoromethyl)dihydroazepine (65) (see Section 5.16.4.2.1(ii)) is converted via prototropic shift to the conjugated 2,3-dihydro-3/7-azepine (67JA605). 

The rearrangement of 17/-azepines into 3/7-azepines (see above) corresponds to a 1,5-sigmatropic hydrogen shift. If the 37/-azepine is part of strained system, e.g. in 6, rearrangement giving a 17/-azepine is also possible [12] ... 

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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