Azepines tautomerism

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). 

Azepine, 5-bromo- 1-ethoxycarbonyl-X-ray crystallography, 7, 520 1 //-Azepine, 5-cyano-4,5-dihydro-rearrangement, 7, 512 1 //-Azepine, 3-cyclopropyl-2-diethylamino-synthesis, 7, 536 1//-azepine, 2,6-dicyano-ring contractions, 7, 506 1//-Azepine, 2,3-dihydro-synthesis, 7, 42 1 //-Azepine, 2,5-dihydro-valence tautomerism, 7, 506 1 //-Azepine, 2,7-dihydro-rearrangement, 7, 507 1//-Azepine, 4,5-dihydro-... 

B. Compounds with Potentially Tautomeric Groups 1. Azepines... 

Four tautomeric forms I -4 can be drawn for azacycloheptatriene and of these four tautomers only 1 ff-azepine ( ) is formally a fully conjugated system however, the chemistry of all four tautomers is covered in this section together with the three isomeric, fully conjugated, cyclopentazepines 5-7, in which nitrogen is located in the seven-membered ring, and their indeno analogs. 

There arc no methods for the preparation of azepines by ring transformation of other seven-membered systems however, interconversion between the four tautomeric azepines, either by [1,5]-H sigmatropic shifts or under base catalysis, is common and almost always results in formation of a 3//-azepine. Such transformations are dealt with in Section 3.1.1.5.7. 

A similar sequence of reactions on l,2-dihydroindeno[l,2-tautomeric mixture of the oxo 11a and hydroxy 12a forms.57 Prolonged treatment of the tetrahydro compound 10 with NBS in refluxing dibro-momethane results in bromination of the indene ring and formation of the 10-bromo derivative... 

Thermal equilibration between isolable, unsymmetrically substituted 3//-azepines has been noted on a few occasions,28-31 and for such systems it has been suggested31 that the [1,5]-H shifts observed in the tautomerism of the azepines always proceed in the direction of theC —N double bond rather than in the direction of the N —C double bond. 

Unlike the parent system, 5-methyl-5//-dibenz[c,e]azepine (1, R1 = Me R2 = H) on treatment with lithium diisopropyl amide fails to yield the tautomeric phenanthridine-imine (see Section 3.2.1.5.4.2.), but forms the 5-carbanion, which on quenching with deuterium oxide furnishes 5-methyl-[5-2H,]-5//-dibenz[e,e]azepine (l).83 5,7-Diphenyl-5//-dibenz[r,e]azepine (1. R1 = R2 = Ph) behaves similarly. In contrast, however, 5,7-dimethyl-5//-dibcnz[c,e]azepine (1, R1 = R2 = Me) yields theazaallyl anion 3, which on addition of deuterium oxide deuterates regiospecifically at the 7-methyl group to give derivative 4. 

Likewise, amine functions on the azepine ring at an unsaturated carbon center behave as enamines and undergo hydrolysis under both acid and alkaline conditions to the benzazepinones.15,64 8084 However, hydrolysis of dimethyl l-acetyl-5-piperidino-l//-l-benz-azepine-3,4-dicarboxylate(18) yields not the benzazepinone but the tautomeric 5-hydroxy derivative 19.13 Presumably, the enol form is stabilized by intramolecular hydrogen bonding. 

Tautomerism of benz- and dibenzazepines is much less common than with monocyclic azepines since, as pointed out in the introduction, with most of these bi- and tricyclic systems the number of tautomers in which the carbocyclic ring retains its benzenoid character is severely restricted. Rare examples in the benzazepine series are the thermal isomcrizations of butyl l-aryl-5//-2-benzazepine-5-carboxylates 1 (X = H, Cl, F) to their 3//-tautomers 2,7S and of 3-ethoxy-1-phenyl-5//-2-benzazepines 3 (R = Me, Bn) to the 1//-tautomers 4.240... 

Fully unsaturated monocyclic 1,4-diazepines have been reported only recently. Representatives of the three tautomeric systems 1H-, 2H-, and 6//-l,4-diazepines are known, but 5//-l,4-di-azepines have not been described. 

Four tautomeric forms, designated as 1H-, 2H-, 3H- and 4//-azepine may be drawn for azacycloheptatriene. IH- Azepine (1 R = H) is known as a very unstable (even at -78 °C in CDC13 solution) red oil which in the presence of acid or base rearranges to the marginally more stable colorless 3//-azepine (2 R1 = R2 = H) (80AG(E)1016). 

N-Unsubstituted 1//-azepines are rare since, like the parent system, they tautomerize readily to the 3H-isomers in whose preparation they are often considered as transient intermediates (see Section 5.16.4.1.2(h)). This rearrangement is particularly apparent with 2-amino- and 2-alkoxy derivatives since stabilization of the 37/-azepine is then possible by amidine and imidate type resonance. For the CH2-containing tautomers the order of stability appears to be 3H > AH > 2H, a fact attested to by the facile thermal and base-catalyzed rearrangements of AH- azepines to the 3H-tautomers (72CB982) and the rarity and inherent instability of 2H-azepines. The latter are well established as intermediates in the formation of 3H- azepines (74JOC3070) but have been characterized only as their benzologues. 

Valence tautomerization to the bicyclic azetine (47 R1 = OEt, R2 = Me) has been observed in the photosensitized (PlfcCO or PhCOMe) ring contraction of the otherwise photostable 2-ethoxy-4,5-dihydro-3.H-azepine (46 R4 = OEt, R2 = Me) (71JOC1934). In contrast, sensitized photolysis of the dimethylamino derivative (46 R1 = NMe2, R2 = H) gave only polymers. Unsensitized photolysis in pyrex yields several cyclic products, all of which are attributable to the intermediacy of an unstable 7-azabicyclo[3.2.0]hepta-3,6-diene (47 R1 = NMe2, R2 = H) (73CC327). 

The four tautomeric monocyclic azepines are formally interchangeable by a series of 1,5-H shifts. Often, e.g. the parent 1//-azepine (80AG(E)1016), this isomerization is acid-and base-catalyzed. Many examples however, are known to occur under thermal non-catalytic conditions, and the accepted order of stability of azepines (i.e. 3H>4H >2H > 1H) is based on such observations. For example, the 4//-azepine (57) on heating for a few minutes at 190 °C undergoes consecutive 1,5-H shifts to give ultimately the 3H -azepine (58) (72CB982). The facile interconversion of 2H-azepines to 3H -azepines is similarly explained (76JOC543). 

The facility of 1H-azepines to form transition metal carbonyl complexes was realized soon after they were first synthesized. Variable temperature HNMR studies on the tricarbonyliron complex formed either by photolysis of 1-ethoxycarbonyl-l//-azepine with tricarbonyliron in THF, or by heating the azepine with nonacarbonyldiiron in hexane, demonstrated that it undergoes rapid reversible valence tautomerism and that there is considerable restricted rotation about the N—CO bond (B-69MI51600). The molecular geometry of the complex has been determined by X-ray analysis (see Section 5.16.2.2). 

Valence tautomerism of azepines and azabicyclo[3.2.0]heptadienes has been discussed in Section 5.16.3.2.1. In most cases the process is reversible and the azepine can be regenerated by gentle thermolysis of the bicycle. Sano and coworkers have capitalized on this thermal lability of azabicycloheptadienes to synthesize several azatropone and azatropolone derivatives (see Section 5.16.3.1.2), by ring expanding the 2,3-dioxopyrrole [2 + 2] cycloadducts, e.g. (251), as illustrated in Scheme 31 (81H(16)363). 

Annular tautomerism between one or more NH-forms and various CH forms of 1,2-diazepines is possible with the favored species dependent upon the nature and position of substituents (69ACS3125, 70T739). Interestingly, unlike monocyclic azepines and tautomeric 1,2-diazepines, 5H- 1,2-diazepines (47) exist preferentially in their bicyclic diazanorcaradiene form (48) (72JA2770). 

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

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