Azepines and Diazepines

Contrary to the stable azepines and diazepines, benzo[ 7]benzofuro[2,3-/][l,4]-oxazepine 272 undergoes ring cleavage under reductive conditions in the acetic acid/acetic anhydride to afford open chain acetoxy amine 273 (Scheme 58, Section 3.2.2 (2001JHC383)). 

This approach has now been applied to the preparation of many naturally occurring and pharmacologically active compounds. In addition, two papers have been published > in which the photolysis reactions of quinolyl and isoquinolyl azides are discussed. Azepine and diazepine derivatives (200) and (201) may be obtained, and guidelines have been proposed to allow one to predict... 

The X-ray crystal structure of the 1 -tosyl-1H-1,2-diazepine (10) shows a boat conformation with N(l) at the prow (Figure 1) (72T581). Double bonds are clearly localized at N(2)—C(3) 1.255 A, C(4)—C(5) 1.326 A, and C(6)—C(7) 1.333 A, and the imine bond is isolated, whereas bond delocalization is present in the butadiene-like part C(4)—C(5)—C(6)—C(7). In contrast, when the diazepine is complexed with Fe(CO)3, for example (11), the iron atom is bound to the butadiene moiety C(4) to C(7), as also occurs in the lf/-azepine and l-methoxycarbonyl-l//-azepine complexes the N(l) atom adopts a planar sp2 configuration and the seven-membered ring consists of the two planar parts bent along the C(4)... C(7) line by 140° (70AG(E)958). 

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). 

Since decomplexing is usually possible, many applications await realization, for background see (78JHC1057, 81ACR348, 71JA1123). The chemistry of azepines (CHEC 5.16.3.8.1 and 5.16.3.8.2) and diazepines (CHEC 5.18.2) (78JHC1057, 81ACR348) provides examples. 

The thermal and photochemical [4 + 2] cycloadditions of o-quinones with olefinic and acetylenic dienophiles have been extensively re viewed and include their 4ir heterodiene Diels-Alder reactions with olefins, " vinyl ethers,enamines, selected dienes, " diphenyl Iketenimines, ketenes, fulvenes, " and selected heterocycles including furan, " - benzofuran, - - indoles, azepines, and 1,2-diazepines. The tetrahalo-substituted o-quinones, tetrachloro- and tetrabromo-o-quinone, generally participate in heterodiene [4 + 2] cy-cloadditions at an increased rate over the unsubstituted systems and generally provide higher overall yields of the Diels-Alder products." With simple olefins, the dienophile geometry is maintained in the course of the thermal [4 + 2] cycloadditions [Eq. (52)J, ... 

By analogy with azepines and 1,2-diazepines <8iH(i5)i569>, the fully unsaturated 1,4-diazepines with their 8ti electron system should not be aromatic but should behave as cyclic polyenes and, hke cycloheptatriene should have a chair or boat conformation. If the ring system were able to become planar, one would expect the fully unsaturated 1,4-diazepines to be anti-aromatic. Additional evidence for the nonaromatic nature of the 1,4-diazepines is provided by the NMR spectra, where the ring protons are found in the typical range for alkenic protons, i.e. 5 5.0-7.0. 

As in the case of the piperidine derivatives, azepine drugs in complex with protein were searched for in the PDB using the MSD server. Since the number of hits was very low no resolution criteria was used for this search that yielded one each in azepin and benzothiazepine and five in fused-diazepine (Table 6). 

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]. 

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. 

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). 

It is likely that initially the open-chain adducts 353 and 354 are formed by the addition of an amino group either to the carbonyl function or to the triple bond, whereupon these intermediates close up to the azepines 355 and their bis-imine tautomers 356. In the H NMR spectra, the methylene protons of 356 are at 2.85-2.97 ppm, whereas the methyl protons are fixed at 2.20-2.27 ppm. The IR spectra show absorption bands corresponding to the aromatic ring (1600 cm ) and to the diazepine cycle C=N double bonds (1580 cm ). However, there are no bands of... 

Triphenyl-47/-l,2-diazepine is transformed into a mixture of 2,4,6-triphenylpyridine and the rearranged diazepines 3,5,6-triphenyl-4//-l,2-diazepine (28) and 3,5,6-triphenyl-l H-, 2-di-azepine (29) on prolonged heating.111... 

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. 

Irradiation of the caged oxadiazabicyclo[2.23]nonadiene derivative 24 (X = CH) brings about its rearrangement to the isomeric system 25 and the formation of the 1-ethoxycatbonyl-l//-azepine (26) <99H(51)141>. The latter is also the product of irradiation 25, but the authors interpret their kinetic results to suggest that the azepine is not derived solely from 25, but is also formed directly from 24. Similar studies with 24 (X = N) give 1-ethoxycarbonyl-l// l,2-diazepine (Scheme 4). 

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