H-azepine

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... 

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

IH-Azepine, 1-methoxy carbonyl-cycloaddition reactions, 7, 522 with nitrosobenzene, 7, 520 tricarbonyliron complex acylation, 7, 512-513 conformation, 7, 494 tricarbonylruthenium complex cycloaddition reactions, 7, 520 1 H-Azepine, l-methoxycarbonyl-6,7-dihydro-synthesis, 7, 507... 

H-Azepine, 2-methyl-1-methoxycarbonyl-rearrangement, 7, 504 1 //-Azepine, 3-methyl-1 -methoxycarbonyl-cycloaddition reactions, 7, 520 IH-Azepine, 1-phenyl-synthesis, 7, 542 1 H-Azepine, N-phthalimido-formation, 7, 508 IH-Azepine, N-sulfonyl-UV spectra, 7, 501 1 H-Azepine, tetrahydromethylene-synthesis, 7, 540 IH-Azepine, N-p-tosyl-protonation, 7, 509 synthesis, 7, 537 3H-Azepine, 3-acyl-2-alkoxy-synthesis, 7, 542-543 3H-Azepine, 3-acyl-2-methoxy-rearrangements, 7, 505 3H-Azepine, 2-alkoxy-hydrolysis, 7, 510... 

H-Azepine, 2-(o-hydroxyphenyl)-synthesis, 7, 538 3 H-Azepine, methyl- H NMR, 7, 495 3H-Azepine, 3-methylring inversion barrier, 7, 14 3 H-Azepine, 2-methylene-isomerization, 7, 505 3H-Azepine, 7-(N-phthalimido) synthesis, 7, 538 4H-Azepine, 4,5-dihydro-cyclization, 7, 524... 

H-Azepine, 2,6,7-tri(methoxycarbonyl)-ring inversion, 7, 499 Azepine-1-carboxylic acid tricarbonylruthenium complexes, 7, 523 1 H-Azepine-2,3-dicarboxylic acid, 4,7-dihydro-6-phenyl-diethyl ester synthesis, 7, 539-540 1 H-Azepine-3,6-dicarboxylic acid... 

Schmidt reaction of ketones, 7, 530 from thienylnitrenes, 4, 820 tautomers, 7, 492 thermal reactions, 7, 503 transition metal complexes reactivity, 7, 28 tungsten complexes, 7, 523 UV spectra, 7, 501 X-ray analysis, 7, 494 1 H-Azepines conformation, 7, 492 cycloaddition reactions, 7, 520, 522 dimerization, 7, 508 H NMR, 7, 495 isomerization, 7, 519 metal complexes, 7, 512 photoaddition reactions with oxygen, 7, 523 protonation, 7, 509 ring contractions, 7, 506 sigmatropic rearrangements, 7, 506 stability, 7, 492 N-substituted mass spectra, 7, 501 rearrangements, 7, 504 synthesis, 7, 536-537... 

H -Azepin-2-one, 4-allyloxytetrahydro-Claisen rearrangement, 7, 508 1 H-Azepin-2-one, hexahydro-conformation analysis, 7, 499 mass spectra, 7, 501... 

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). 

Chemical Name a -Cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-1 H-azepin-1 -yDethyl ester... 

The nitrile may then be hydrolyzed to cyclohexyl-(3-thienyl)acetic acid which is reacted with 1-(2-chloroethyl)-hexahydro-1 H-azepine to give cetiedil. It Is commonly used as the citrate. 

Chemical Name N-[2-[4-[ [ [[(hexahydro-1 H-azepin-1-yl)amino] carbonyl] amino] sulfonyl] phenyl] ethyl] -B-methyl-S-isoxazolecarboxamide... 

Chemicel Name 3-Ethyl-3-(m-hydroxyphenyl)-1-methylhexahydro-1 H-azepine Common Name —... 

That product was then heated under reflux with 50% hydrobromic acid for 1.5 hours. The reaction mixture was evaporated to dryness and reevaporated with three portions of propan-2-ol. The oil obtained was dissolved in propan-2-oi and diluted with ether. 3-Ethyl-3-(m-hydroxyphenyl)hexahydro-1 H-azepine was obtained. That material in turn was reductively methylated by hydrogenation in the presence of formaldehyde in absolute ethanol solution to give 3-ethyl-3-(m-methoxyphenyl)-1 -methylhexahydro-1 H-azepine. 

Chemical Name 6-(((Hexahydro-1 H-azepin-1-yOmethylene] amino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0l heptane-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester... 

Careful chromatographic and detailed HNMR spectroscopic analysis of the products from the thermolyses of ethyl azidoformate in o-, m- and p-xylene revealed in all cases a mixture of 1 //-azepines.80 In o-xylene, only two of the four possible isomers were separated and characterized, namely, ethyl 4,5-dimethy 1-1 //-azepine-1 -carboxylate (9 %) and ethyl 3,4-dimethyl-l H-azepine-1-carboxylate (7 %). w-Xylene yielded a 2 3 mixture of ethyl 3,5-dimethyl-l//-azepine-1-carboxylate and ethyl 2,4-dimethyl-l//-azepine-l-carboxylate. The 2,4-dimethyl isomer (20 %) can be isolated from the mixture by removal of the 3,5-dimethyl isomer as its Diels-Alder cycloadduct with ethenetetracarbonitrile. p-Xylene gave a mixture of the two possible isomeric azepines which were partially separated by column chromatography. A pure sample of ethyl 2,5-dimethyl-1//-azepine-1-carboxylate (26%) was obtained from the mixture by selective decomposition of the 3,6-dimethyl isomer with refluxing alcoholic potassium hydroxide. 

An elegant extension of these intramolecular acylnitrene-induced ring expansions has been used for the synthesis of cyclopent[h]azepines.2 2-Haloindan-l-yl azidoformates 14 (X = Cl, Br), when subjected to pyrolysis at 300 °C in a hot tube packed with calcium oxide and copper turnings, produce cyclopent[6]azepine (15), as a dark turquoise oil, in excellent yield. Lesser yields (30 and 50%, respectively) of the 4-bromo and 3-methoxy derivatives can be similarly obtained. 

Similarly, photolysis of l-(2-azidophenyl)-l/f-pyrazole in acetonitrile in the presence of dipropylamine affords AfN-dipropyl-7-(lF/-pyrazol-l-yl)-3//-azepin-2-amine in low yield (4%).192 Surprisingly, however, photolysis of the corresponding 1-(2-azidophenyl)-3,5-dimethyl-l//-pyrazole (84) in cyclohexane in the presence of the base yields 85 which, on the basis of H NMR spectroscopic evidence, has been formulated as a rare example of a stable 2 H-azepine. 

An interesting annelation reaction of allene-derived 13-dipoles with 3-(IV-aryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel iV-aryl-2,3-dihydro-4-ethoxycarbonylchromano[2,3-h]azepin-6-one system 39 (for example, R = Me, R1 = Cl) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023>... 

This reaction can be generally applied with equal success to other 2,6-dialkylphenols,4 many of which are commercially available. Although the procedure cannot be extended to phenol or o-monosubstituted phenols (aminophenols result6), it represents a facile synthetic method for obtaining a ring system heretofore relatively unavailable. The dihydroazepinones in turn are excellent starting materials for the preparation of other novel heterocyclic systems such as 2,3-dihydro-1 H-azepines,6 2-sub-stituted-3H-azepines,7 and derivatives of 2-azabicydo[3.2.0]hept-6-ene.8... 

A species with the same fragmentation pattern as 14c was also detected by GC-MS, but attempts to isolate this compound failed. It is attributed to the 1 H-azepine analogue of 14c which is formed initially and isomerizes to 14c. The data in the table is the sum of the IH- and 37/-azepine yields, ///-azepines related to 13c were not observed by GC-MS. 

Paquette and coworkers (69JOC2866) have demonstrated that H-azepines can be forced into adopting the benzeneimine structure by bridging the 2,7-positions with a trimethylene chain (25). The length of the methylene chain is, however, critical and the tetramethylene derivative (26) exists solely as the bridged azepine. A suggestion that benzeneimines may be involved as intermediates in the formation of 3H-azepines from 2//-azirines and cyclopentadienones (Section 5.16.4.2.1(i)) has been discounted (74JOC3070). 

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). 

Ring contractions of yet a different kind are observed with H- azepines of type (54), which on heating yield 6-substituted fulvenes as illustrated in Scheme 3 for the dicyano-1//-azepine (7lJCS(C)l237). Analogous reactions occur with 3//-3-benzazepines. 

Ethoxycarbonyl-l//-azepine forms normal [4+2]7t adducts with 4-phenyl-1,2,4-triazo-line-3,5-dione and with diethyl azodicarboxylate (81H(15)1569, 77JCS(Pl)l824), but unlike cycloheptatriene, which yields a [6 + 2]ir adduct, it gives no cycloadduct with N-ethoxycar-bonylmethyleneimine (CH2=NC02Et) (8iJCS(Pl)447>. The critical solvent dependence of the addition of DMAD to H-azepines has been referred to in Section 5.16.3.4 only in hot carbon tetrachloride is the [4+2]7t cycloadduct obtained (sotlims). 

Dipolar cycloadditions to azepines are confined to diazomethane and diphenyl-nitrilimine. The former reagent, depending on the nature of the substituents on the H-azepine, either adds at the 4,5-bond to yield pyrazolines (160) or traps the benzeneimine tautomer of the azepine as the bis-pyrazoline (Section 5.16.2.4) (76CB3505). A pyrazoline is also the product from the addition of diphenylnitrilimine to 5//-dibenz[i,/]azepine (B-67MI51600). 

H-Azepines are more rare than 1H- or 2>H-azepines and only a few synthetic approaches have been developed. Of these the two main methods involve the ring expansion of six-membered heterocycles. Early studies revealed that highly substituted 4//-azepines (269) result from the base-catalyzed ring expansion of 4-(chloromethyl)-l,4-dihydro-pyridines (267 Scheme 37). The reaction was found to be temperature and solvent sensitive, and azepines (268)-(270) have been isolated and characterized. However, later studies (68JCS(C)1675> on cyano derivatives (267 E = CN) show the reaction to be even more... 

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