1H-Azepin

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

Chemical Name 6-[((Hexahvdro-1H-azepin-1-vl)methvlene]amino] -3,3-dimethvl-7-oxo4-thia-1 azabicvclo(3.2.0] heptane-2-carboxylic acid... 

The intermolecular process is employed almost exclusively for the preparation of 1H-azepines and in most cases involves addition of a singlet nitrene133 to the arene to give, initially, an unstable 7-azabicyclo[4.1.0]hepta-2,4-diene (benzaziridine) intermediate, e. g. 1, which undergoes an electrocyclic ring opening to the l//-azepine, e. g. 2. 

Subsequently it was found140 that ethyl 2-alkyl-1//-azepine-1-carboxylates can be isolated from a mixture of isomeric 1//-azepines by stirring the mixture with potassium hydroxide in ethanol at room temperature. Apparently, this method, which is limited to 2-alkylated azepines, depends on the slower rate of hydrolysis (and subsequent decomposition of the resulting 1H-azepine-l-carboxylic acid) of the sterically hindered 1-(ethoxycarbonyl) group. Although the yields of l//-azepines are poor (4-7%, vide supra), the method provides access to otherwise difficult to obtain, isomerically pure 2-alkyl-1//-azepines. Under the basic hydrolysis conditions aryl 2-alkyl-l//-azepine-1-carboxylates undergo transesterification to the l-(ethoxycarbonyl) derivatives. 

In contrast to the acyl- and sulfonylnitrenes described in this section, arylnitrenes produced thermally or photolytically from aryl azides, including those bearing strongly electron-withdrawing substituents (e.g., CN, N02, CF3), fail to promote ring expansion of arenes to 1H-azepines, although intermolecular substitution of electron-rich substrates, e.g. mesitylene and A.TV-dimethylaniline, have been noted.167... 

Tricarbonylchromium,221 -molybdenum,221 -tungsten,221 and-ruthenium222 complexes of 1H-azepine-l-carboxylatcs have been prepared by treating the azepines with tris(acetonitrile)tricar-bonylchromium(O), tricarbonyldiglymemolybdenum(O), tris(acetonitrile)tricarbonyltung-sten(O), and dodecacarbonylruthcnium(O), respectively. 

Tricarbonyl[t/M-(ethoxycarbonyl)-l//-azepine]iron(0) (30) with the 2-oxyallyl cation derived from 2,4-dibromo-2,4-dimethylpentan-3-one and nonacarbonyldiiron(O) yields a mixture of adducts which, after oxidative decomplexation with tetrachloro-l,2-benzoquinone (o-chloranil), affords the tetrahydrofuro[2,3-A)azcpine derivative 33 and the 3-substituted 1H-azepine-l-carboxylate 34.227... 

Unlike unsubstituted and 3,4-disubstituted 1H-azepine-1 -carboxylates, which dimerize on heating, methyl 2-methyl-l//-azepine-l-carboxylate remains unchanged at 130 C, but on heating to 200°C ring contracts to Ar-(methoxycarbonyl)-2-methylaniline (64% mp 60°C).115 Similarly, the 4,5-dimethyl- and 3,6-dimethyl-l//-azepine-1-carboxylates, in which [6 + 4] dimerization is sterically retarded by the methyl groups, give only the A-arylurethanes. Methyl 2,7-dimethyl-1//-azepine-1-carboxylate is particularly stable and remains unchanged even after 24 hours at 200 C. 

H-Azepines 1 undergo a temperature-dependent dimerization process. At low temperatures a kinetically controlled, thermally allowed [6 + 4] 7t-cycloaddition takes place to give the un-symmetrical e.w-adducts, e.g. 2.231-248-249 At higher temperatures (100-200°C) the symmetrical, thermodynamically favored [6 + 6] rc-adducts, e.g. 3, are produced. These [6 + 6] adducts probably arise by a radical process, since a concerted [6 + 6] tt-cycloaddition is forbidden on orbital symmetry grounds, as is a thermal [l,3]-sigmatropic C2 —CIO shift of the unsym-metrical [6 + 4] 7t-dimer. 

Attempts to isomerize the 2-methylene-3/f- azepine (45 R1 = H, R2 = PhCO) to the AT-benzoyl- 1H-azepine under acid- or base-catalyzed conditions failed. Irradiation of the 3//-azepine resulted only in a photo-Fries type rearrangement of the benzoyl group to give aminoketone (45 R1 = PhCO, R2 = H) (74JOC3076). 

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). 

A-Ethoxycarbony 1-1H-azepine is converted rapidly (5 min) and quantitatively into ethyl N -phenylcarbamate by boron trifluoride (81JCS(P1)447). The dichloroborane (15 R1 = H, R2 = BCl2) results from the action of boron trichloride on 10,11-dihydro-5//-dibenz[f>,/]azepine (74IC2783). 

Surprisingly, there are only a few reports concerning the action of carbenes on azepines. A-ethoxycarbonyl-1//- azepine and dichlorocarbene, generated by the action of 50% potassium hydroxide on chloroform, furnish the trans -trishomoazepine (136 R1 = R2 = Cl) in 35% yield. Under similar conditions the 2,3- and 4,5-homoazepines yield the trans homoazepines (136 R1 = Cl, R2 = H and R1 = H, R2 = C1 respectively). From a careful study of the addition of dichlorocarbene, generated by thermal decomposition of (dichloromethyl)phenylmercury, it is concluded that carbene addition to the 1H-azepine takes place sequentially in the order C-4—C-5, C-2—C-3 and C-6—C-7 (74JOC455). 

The additions of alkyl or aryl silyl chlorides to 1 -ethoxycarbonyl- 1H-azepine in HMPA solution in the presence of magnesium proceed via anion radicals to yield trans adducts... 

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). 

The ring expansion of arenes by electron-deficient singlet nitrenes is by far the most versatile synthetic route to 1H -azepines. The first l//-azepines were prepared independently in 1963 by Hafner, and by Lwowski, and their coworkers. They found that ethoxycarbonyl-nitrene (Scheme 26, path a R=C02Et), generated by photolysis of ethyl azidoformate, adds to benzene to give initially the unstable azanorcaradiene (227), electrocyclic ring... 

Two other azepine syntheses involving the interconversion of valence isomers are worthy of note, namely the isomerization of the novel 7-azatetracycloheptane (261), prepared from benzvalene as indicated in Scheme 34, to l-phenyl-l//-azepine (79TL1553) and the rearrangement of the syn isomer of the 2-azatricycloheptane (70 H in place of D), which at 120 °C yields 1 -ethoxycarbonyl-2,3-dihydro- 1H-azepine by a [ 2 +v4t] concerted process. As expected, the anti isomer, for which a concerted process would require a geometrically unfavoured [ 2, + w4a] process, rearranges only at 350 °C, and then by a non-concerted polar reaction (73JA7320). 

Synthesis (Cavalla and White (Wyeth), 1969 1969 Bradley 1980 Kleemann et al. 1999) By condensation of 2-(m-methoxyphenyl)butyronitrile with ethyl 4-iodobutyrate by means of NaNH2 in liquid NH3 to give ethyl 5-cyano-5-(m-methoxyphenyl)heptanoate, which is cyclized by hydrogenation with H2 over Raney Ni in cyclohexane to yield 6-ethyl-6-(m-methoxyphenyl)hexahydro-2H-azepin-2-one this ketone is reduced with LiAIH4 in THF to 3-ethyl-3-(m-methoxyphenyl)hexahydro-IH-azepine, which in turn, is reductively methylated with HCHO, H2 and Pd/C in ethanol to give 1-methyl-3-ethyl-3-(m-methoxyphenyl)-hexahydro-1H-azepine, and finally demethylated by refluxing with 80% HBr to yield a racemic mixture of the final product. 

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 XH 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 lH-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... 

N-Unsubstituted 1H-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(ii)). This rearrangement is particularly apparent with 2-amino- and 2-alkoxy derivatives since stabilization of the 3//-azepine is then possible by amidine and imidate type resonance. For the CH2-containing tautomers the order of stability appears to be 3H > 4H > 2H, a fact attested to by the facile thermal and base-catalyzed rearrangements of 4H- azepines to the 3H-tautomers (72CB982) and the rarity and inherent instability of 2//-azepines. The latter are well established as intermediates in the formation of 3H- azepines (74JOC3070) but have been characterized only as their benzologues. 

Early work (B-69MI51600) on N-substituted- 1H-azepines revealed that they undergo photoinduced ring contraction to bicyclic valence tautomers as indicated in Scheme 1. Subsequently, it has been found that 3H- and AH- azepines enter into analogous ring contractions, as do some of their oxo and benzo derivatives. These transformations, which parallel those undergone by cycloheptatriene, are often thermally reversible and occur by an orbital symmetry-controlled disrotatory electrocyclic process. 

Recently, a new reactivity index has been proposed (80H(14)1717> which predicts accurately the site selectivity of photocyclization of substituted cycloheptatrienes to their bicyclic valence tautomers. Unfortunately, application of the method to substituted 1H-azepines is far less successful. For example, for 2-methyl-1 -methoxycarbonyl-lH-azepine (37 R = 2-Me) AGrs values for C-2—C-5 and C-4—C-7 cyclization are calculated as 0.093 and 0.040 kJ mol-1, respectively, i.e. predicting the 1-methyl isomer (39) as the major product. Experimentally, however, the reverse is true, the yields being 93.5% for 3-methyl (38 R = Me) and 6.5% for 1-methyl (39 R = Me). The corresponding photoinduced valence isomerizations of 1-benzazepines to 3,4-benz-2-azabicyclo[3.2.0]hepta-3,6-dienes (38a) have been recorded (80JOC462). These isomerizations have also been achieved thermally in the presence of silver ion (80TL3403). 

H-Azepines bearing /V-alkyl substituents are unstable in acid solution and yield resinous products. In contrast, N- acyl, N-p- tosyl and N -ethoxycarbonyl derivatives undergo rapid aromatization to N-arylurethanes (69JOC2879,73CB3824). The ring contraction is much slower with 2-substituted N-acyl-liT-azepines, a feature made use of in the separation of 1H-azepine mixtures (71JHC729). 

Ethoxycarbonyl-l/f-azepine forms normal [4+2]7r adducts with 4-phenyl-l,2,4-triazo-line-3,5-dione and with diethyl azodicarboxylate (81H(15)1569, 77JCS(P1)1824), but unlike cycloheptatriene, which yields a [6 + 2]7r adduct, it gives no cycloadduct with AT-ethoxycar-bonylmethyleneimine (CH2=NC02Et) <81JCS(P1)447). The critical solvent dependence of the addition of DMAD to 1H-azepines has been referred to in Section 5.16.3.4 only in hot carbon tetrachloride is the [4+2]7r cycloadduct obtained (80TL1145). 

Dipolar cycloadditions to azepines are confined to diazomethane and diphenyl-nitrilimine. The former reagent, depending on the nature of the substituents on the 1H-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 5H-dibenz[i,/]azepine (B-67MI51600). 

H-AZEPINE-1-CARBOTHIOIC ACID HEXAHYDRO- 3-ETHYL ESTER 2212-67-1... 

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