2-Methoxy-3//-azepines

Interestingly, treatment of bicyclic imidate 5 (R = OMe) with lithium diisopropylamide at — 78 C, followed by addition of iodomethane and quenching into ammonium chloride solution, gives 2-methoxy-3-methyl-37/-azepine. In the absence of iodomethane, 2-methoxy-3i/-azepine (6, R = OMe) is produced. Rearrangement of the lithiated bicycle to a lithiated 2-methoxy-3//-azepine, followed by regioselective trapping by the electrophile, is the most likely mechanistic rationale. 

The thermolysis of aryl azides in alcoholic solution has been used to prepare 2-alkoxy-37f-azepines. Thermolysis of 3-azidophenyl methyl ketone in methanol in a sealed ampule furnishes a mixture of the 6-acetyl- (36a) and 4-acetyl-2-methoxy-3//-azepine (37a) in superior yields to those obtained in the corresponding photolytic reaction.78 Other 3-substituted azides behave similarly, with a preference for the 6-substituted isomers 36, as is observed for azide photolyses in amine solutions. 

Likewise, thermolysis of 4-azidophenyl methyl ketone in methanol yields 5-acetyl-2-methoxy-3//-azepine (60%), compared to only an 8% yield from the photolytic reaction.78 119 The thermolysis of phenyl azide in refluxing cyclohexanol yields no 3H-azepine, only diphenyl-diazene (10%) and aniline (30%).74 In contrast, thermolysis of methyl 2-azidobenzoate in cyclohexanol furnishes a mixture of methyl 2-(cyclohexyloxy)-3//-azepine-3-carboxylate (20 % bp 127°C/0.1 Torr) and methyl 2-aminobenzoate (60%). Thermolysis of the azido ester in methanol under nitrogen in an autoclave at 150 C yields a 7 10 mixture (by 1HNMR spectroscopy) of the amino ester and methyl 2-methoxy-3//-azepine-3-carboxylate, which proved to be difficult to separate, and much tar.74 The acidic medium179 is probably responsible for the failure of methyl 2-azidoberjzoate to yield a 3//-azepine when thermolyzed in 3-methoxyphenol aniline (40%) is the major product.74... 

Early efforts to effect the photoinduced ring expansion of aryl azides to 3H-azepines in the presence of other nucleophiles met with only limited success. For example, irradiation of phenyl azide in hydrogen sulfide-diethyl ether, or in methanol, gave 17/-azepine-2(3//)-thione35 (5% mp 106—107 " O and 2-methoxy-3//-azepine (11 %),2 3 respectively. Later workers194 failed to reproduce this latter result, but found that in strongly basic media (3 M potassium hydroxide in methanol/dioxane) and in the presence of 18-crown-6, 17/-azepin-2(3//)-one was produced in 48% yield. In the absence of the crown ether the yield of azepinone falls to 35%. 

Cyanophenyl azide is of interest in that on photolysis in methanol/tetrahydrofuran solution, an unseparated 1 1 mixture (by HNMR spectroscopy) of 2-methoxy-3//-azepine-3-carbonitrile and -7-carbonitrile (44%) is formed.197-282 Likewise, irradiation of 2-azidophenyl methyl ketone in methanol furnishes a mixture of 3-acetyl-2-methoxy- (11 %) and 7-acetyl-2-methoxy-3//-azcpine (3%) along with 3-methyl-2,l-benzisoxazole (18%).78... 

An extension of these ring expansions involves the photolysis of bis(2-azidobenzoyl)ethyl-ene glycol (88) in methanol/tetrahydrofuran whereupon 1,2-ethanediyl bis(2-methoxy-3//-azepine-3-carboxylate) (89) is formed.198... 

Practicable yields of 5-substituted 2-methoxy-3//-azepines 94 can be obtained by photolysis of aryl azides 56 bearing an electron-withdrawing group para to the azide function, although irradiation times tend to be longer and, in general, yields lower than with the corresponding 2-substituted azides.197... 

Alkoxy-3//-azepines 98 by Deoxygenation of Nitroarenes in Alcohol Solution Typical Procedures 79 Method A 2-Methoxy-3//-azepine (98, R = Me) ... 

A -Phenyl-3//-azepin-2-amine (3), obtained in 25% yield by heating 2-methoxy-3//-azepine with aniline at 120 C for four hours,81 in refluxing ethanolic sodium benzenethiolate undergoes displacement of aniline and forms 2-(phenylsulfanyl)-3//-azepine (4).116... 

Irradiation of 3-benzoyl-2-methoxy-3//-azepine (32) in methanol gives rise to a mixture of the 3-azabicyclo[4.1.0]hepta-2,4-diene 33 (detected by HNMR spectroscopy, but not isolated), 2-methoxy-3-phenacylpyridine(34), and a trace of 2-phenylfuro[2,3-A]pyridine (35), this last product being an artefact derived from the phenacylpyridine 34.246... 

Anomalous isomerizations have been noted during the photolytic and thermal rearrangements of 3-acyl-2-methoxy-3//-azepines (2 R -acyl, R2 = OMe) and 3-acyl-3H- azepin-2-ones (69T5217). Irradiation in methanol solution produces mixtures of 3-azabicyclo[4.1.0]hepta-2,4-dienes (28 R1==acyl and H, R2 = OMe, R3 = 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. 

Photochemically induced nitrogen-oxygen bond cleavage is also thought to be the initial step in the conversion of 6-chloro-3-phenyl-anthranil (84) into 3-benzoyl-5-chloro-2-methoxy-3 -azepine (85) in methanol.67 Analogous transformations are reported in 3-methyl-and 6-chloroanthranil.67... 

The azepinium anions from 2-methoxy-3//-azepine <90JHC107> and 2-dimethylamino-5-phenyl-3/f-azepine <84RTC225> react with electrophiles to give a number of 3-alkyl-, 3-thioalkyl-, and 3-acyl-3/f-azepines. Further alkylation studies reveal that C, is the next position of attack <85RTC166>. Under similar conditions, the anion from ethyl 2-dimethylamino-5-phenyl-3//-azepine-3-car-boxylate undergoes rearrangement with methyl iodide to give the azanorcaradiene, ethyl 2-diethylamino-7-methyl-3,4-dihydro-3,4-methano-4-phenylpyridine-7-carboxylate (36) (Equation (4)) <87H(26)685>. 

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-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... 

Pyridazinium salts, 1-methoxy-reaction with pyridazines, 3, 23 Pyridazino[4,5-6]azepines synthesis, 7, 522 Pyridazino[4,5-d]azepines synthesis, 7, 522 Pyridazinofuroxans synthesis, 6, 425 Pyridazinoheteronins synthesis, 7, 729 Pyridazino[2,3-a]indole synthesis, 4, 297... 

H-Pyrido[3,2-c]azepine, 7-methoxy-nucleophilic displacement reactions, 7, 514 Pyridoazepines synthesis, 7, 535, 540 Pyridoazepinones synthesis, 7, 531 Py rido[2,1-a]benzazepin-6-one physiological properties, 7, 546 Py rido[ 1,2-a]benzimidazoles reactions, 6, 1041... 

Recently, a one-pot conversion of 2-methoxy-2,3-dihydro-3,6-alkanooxepins to imidazoazepine derivatives by treatment with glycine methyl ester was reported. In the heptano series a symmetrical azepine triester was isolated as a byproduct.206... 

Although theseazepin-2-onesexhibitdeshieldedprotonresonances(<5 = 7.8 8.2), with an ortho coupling for the 5,6-unsubstituted derivative of J5 6 = 10 Hz, an X-ray structural analysis of ethyl 7-(4-bromophenyl)-3-methoxy-2-oxo-6-phenyl-27/-azepine-4-carboxylate reveals a non-planar azepine ring 48 53 3,5-Dihaloazepin-4-ones have been detected recently in the photolysis of 4-azido-2,6-dihalophenols at 12-14 K.286... 

Dehydrogenation is a rarely used method for the production of fully unsaturated azepines, and there are no examples of its use for the formation of simple monocyclic systems, although 3-hydroxy- and 3-methoxy-2//-azepin-2-ones can be obtained by dehydrogenation of the corresponding l,5-dihydro-2//-azepin-2-ones with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in benzene in a sealed tube at 100 48-51-52-67... 

Dimethyl 4-ethoxy-2,7-dimethyl-4,5-dihydro-l 7/-azepine-3,6-dicarboxylate (1) with sodium ethoxide in refluxing diethyl ether, or on standing at room temperature in carbon tetrachloride solution, readily loses ethanol to yield dimethyl 2,7-dimethyl-4//-azepine-3,6-dicar-boxylate (2).29 The 4-methoxy derivative is also unstable and on warming at 100 C under reduced pressure loses methanol to yield the same product (44%).120... 

Pyrolysis of dimethyl 4-methoxy-2,5,7-trimethyl-4,5-dihydro-l//-azepine-3,6-dicarboxylate (6a), or the corresponding 4-succinimido derivative 6b, at 160-180°C in a sublimation tube containing glass beads furnishes the 4//-azepine 7.121... 

Flash-vacuum pyrolysis of 3-alkyl-or 3-aryl-2-azabicyclo[3.2.0]hepta-2,6-dienes 5a-c, prepared by the action of a Grignard reagent (RMgX) on the 3-methoxy derivative 5 (R = OMe), furnishes mixtures of the 2- and 7-substituted 3//-azepines 6 and 7, respectively.113... 

Likewise, //-(4-methoxy-l-methyl-2,4,6-triphenylcyclohexa-2,5-dienyl)-p-toluenesulfon-amide (6), in the presence of p-toluenesulfonic acid, suffers ring expansion with loss of methanol to yield the l//-azepine 7.21... 

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. 

The yield of 3//-azepine appears to be influenced by substituents on the azide ring although no in-depth study has been reported. 4-Halophenyl azides, in most cases, give rise to complex mixtures of products.177 4-Tolyl azide, on thermolysis in aniline, yields 5-methyl-iV-phenyl-3//-azepin-2-amine (18% mp 157-158°C), whereas the thermolyses of 4-methoxy-, 4-methyl-, 4-chloro-, and 4-nitrophenyl azides in a range of arylamines (4-chloro-, 4-methoxy-, and pen-tafluoroaniline) yield only azo compounds and uncharacterized tarry products.178... 

Poor yields of azepines are formed with 6-carboxy, 6-chloro, and 3,5-dichloro groups, and methyl 2-azido-5-nitrobenzoate fails to undergo ring expansion.74 Surprisingly, the azido-fluorobenzoates, which undergo successful ring expansion in diethylamine solution, fail to yield 2-methoxy-37/-azepines on photolysis in methanol.188... 

With cyanide ion in aqueous ethanol azepinedicarboxylate 3 forms the corresponding racemic 4,5-dihydro-l//-azepine-4-carbonitrile (85%),121,241 whereas with dimethyl 2,5,7-trimethyl-4//-azepinc-3,6-dicarboxylate (6) diastereospecific addition occurs to give racemic lrans-5-me thy 1-4.5-di hydro-1-//-azepine-4-carbonitrile 7 together with a small amount of the trans 4S-methoxy-5 / -methyl compound 8.121... 

Similar problems arise with the four isomeric dibenzazepines 4-7. since only 5//-dibenz-[6,d]azepine (4) and 5//-dibenz[/>,./]azepine (7) can be drawn as fully benzenoid ring structures. Even so, 5//-dibenz[/ ,t/]azepines are rare and are known only as the 7-oxo derivatives.4 In contrast, 5//-dibenz[6,e azepine (5) and 6//-dibenz[r,t>]azepine (6) exist only as the 11//- 5a and 5H- 6a isomers, respectively. In fact, there is no chemical or spectrosopic evidence for the isomerization of 5//-dibenz[e,e]azepine,5 or its 6-oxide,6 to the 6//-dibenz[r, e]azcpinc isomer (6). In addition, an X-ray crystal structure of 7-methoxy-5//-dibenz[e,e]azepine supports unequivocally the benzenoid rather than the quinonoid form.7 9//-Tribenz[6,d /]azepine (8) has only recently been prepared.8... 

An X-ray crystal structure of 7-methoxy-5//-dibenz[c,c]azepine reveals that the seven-mem-bered ring is in the boat conformation.7 Likewise, X-ray structural determinations of 2-morpho-lino-5H-d benz.[A/]azepi ne,7 and 5//-dibenz[/>, /]azepi ne.1 " 11 and its 5-acyl derivatives,12 in-... 

X-ray analysis of 2-methoxy-4-hydroxy-5//-l-benzazepin-5-one (a benzazatropolone), prepared by methylation of the corresponding 4-hydroxy-l-benzazepin-2,5-dione with Meerwein s reagent, demonstrates the presence of a planar seven-membered ring but, in contrast to tropolone, little 71-electron delocalization.17 Likewise, ll//-dibenz[f>,e]azepin-ll-ones display no significant aromatic character.18 In contrast, 7-chloro-8//-thieno[3,2-c]azepin-8-one (12) has azepine ring hydrogen resonances at 8.7 and 9.02 ppm that indicate a substantial contribution from the polar zwitterionic mesomer 13.19... 

Detailed IR and UV spectroscopic data on 5//-dibenzfc,c]azepine5 and its 7-methoxy- and 7-methylsulfanyl derivatives7 have been reported. IR, UV and HNMR spectroscopic data for 2-amino-3//-l-benzazepin-3-one, 2-amino-l//-3-benzazepin-l-one, and 6-amino-7H-dibenz[7>,(/]azepin-7-one have been gathered,27 and confirm their oxo amidinc structures. Spec-trophotometrically determined pATa values of 4.46 and 5.20 (in water at 21 C) have been obtained for 1 l//-dibenz[(>,e]azepine and its 6-methyl derivative, respectively.28... 

Acetyl-lO,11-dibromo-5//-dibenz[7>,/]azepine (49), formed by addition of bromine to 5-acetyl-5/7-dibenz[7>,/]azepine, undergoes dehydrobromination to the 5-acetyldibenz[7>,/]-azepinc 50a on treatment with ethanolic potassium hydroxide.121-132 In contrast, on heating the dibromo compound under reflux with sodium methoxide in methanol, amide hydrolysis and methoxy denomination occur to give the 10-methoxy derivative 50b.132,1 33 Dehydrobromination of the dibromo compound 49, without hydrolysis or replacement of bromine, can be accomplished in hot dibutylamine.118... 

Later studies demonstrated that the yields of A-alkyl-5L/-pyrido[2,3-c]azepin-9-amines 7 from 8-azidoquinoline 6 are enhanced by the presence of a 6-methoxy group107 108 and that ring expansion is now possible in secondary aliphatic amine solution. In each case, however, significant yields of quinolinediamines 8 are also produced. 

However, under the same conditions, 6-azidoquinazoline (32) yields the acid-sensitive 5.7-dimethoxy-8,9-dihydro-5//-pyrimido[5,4-c]azcpine (34 16%) by a 1,4-addition of methanol to the initially formed 7-methoxy-9//-pyrimido[5,4-c]azepine (33).153... 

An elegant extension of these ring expansions involving diazidonaphthalenes has been reported. Early results on the photolysis of 1,8-diazidonaphthalene (14) indicated the formation of benz[t d]indazole (17).176 However, it has since been found that photolysis of the diazide in sodium methoxide-methanol/dioxane solution for a short period (20 -40 min) yields, in addition to the benz[c,d]indazole (17, 40%), a mixture of 9-azido-l-methoxy-5//-2-benzazepine (15 15-20%) and l,10-dimethoxy-5,5a-dihydroazepino[3,4-c]azepine (16 10-15%).117... 

Methoxy-5//-pyrido[2,3-c]azepin-9(8//)-one (4) on chlorodehydroxylation with phosphoryl chloride in A,A, -dimethylaniline yields a mixture (20 %) of the chlorc)-6-methoxypyrido[2,3-c -azepines5and6.192 An unseparablemixture (3 7) of 5H- and 7ff-pyrido[2,3-c]azcpine-9-thione 7 and 8 is obtained on treating the pyridoazepinone 4 with phosphorus pentasulfide in warm pyridine. 

In contrast, chlorodehydroxylation of the isomeric 9-methoxy-5//-pyrido[3,2-r]azepin-7(6//)-one (9) furnishes, in poor yield, a mixture of the unstable 7-chloro-9-methoxy-5//-pyrido[3,2-c]azcpine (10) and, unexpectedly, the dichloro derivative 11.192... 

Arylation of the azepine ring has been carried out by treating either 9-chloro-6-methoxy-5/7-pyrido[2,3-c]azepine (50, X = Cl) as a mixture with the isomeric 9-chIoro-6-methoxy-7A/-py-rido[2,3-c]azepine (see Section 3.2.1.5.5.1.). or, better, the 6,9-dimethoxy derivative (50, X = OMe) with phenyllithium.152 In the former case, a mixture (20%) of the 9-phenyl-5//-and 9-phenyl-7//-pyrido[2,3-c]azepine is formed. 

In contrast to the 3-methoxy derivative (see Section 3.2.2.5.3.), the 3-isopropoxy-l//-2-benz-azepine 1 on treatment with sodium propan-2-olate undergoes dehydrobromination to the propenyl derivative 2.80... 

Treatment of a mixture of 6-methoxy-9-chloro-7//- and 6-methoxy-9-chloro-5//-pyrido[2,3-c]-azepine (20) (see Section 3.2.1.5.5.1) with 1-acylhydrazines yields 3-substituted 5//-pyrido[2,3-c][l,2,4]triazolo[4,3-a]azepines, e.g. 21.191 Likewise, with sodium azide in dimethyl sulfoxide, the tetrazolo[4,5- ]azepine 22 is formed in good yield. 

Methoxy-6//-l,4-diazepine reacts with acyl chlorides in pyridine to afford 1 -acyl-1 //-l,4-di-azepines 7.187... 

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