Azepines acylation

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-allyloxytetrahydro-Claisen rearrangement, 7, 508 3H-Azepine, 2-amino-acylation, 7, 511 effect of acidification, 7, 510 nucleophilic displacement reactions, 7, 514 synthesis, 7, 533, 535 3H-Azepine, 2-amino-7-bromo-synthesis, 7, 529 3H-Azepine, 2-anilino-ring inversion, 7, 495-499 structure, 7, 533... 

H-Azepin-2-one, 3-acetyl-synthesis, 7, 542-543 3/f-Azepin-2-one, 7-acetyl-synthesis, 7, 542-543 3H-Azepin-2-one, 3-acyl-rearrangements, 7, 505 3/f-Azepin-2-one, 3-acyl-2-alkoxy-formation, 7, 542-543 3H-Azepin-2-one, 1-alkyl-rearrangements, 7, 505 3/f-Azepin-2-one, N-alkyl-synthesis, 7, 511 Azepinones... 

Dibenz[6,/]azepine, 5-acetyl-lO-cyano-reduction, 7, 517 Dibenz[6,/]azepine, 1-acyl UV spectra, 7, 501-502 Dibenz[6,/]azepine, N-acyl-10,11-dihydro-NMR, 7, 499... 

H-Dibenz[6,/]azepine, 10,11-dihydro-acylation, 7, 511 alkylation, 7, 511 amination, 7, 512 lithiation, 7, 528 PE spectrum, 7, 502 pharmacological properties, 7, 546 reactions... 

Dibenz[6, ejazepines conformation, 7, 499 11H-Dibenz[6, ejazepines oxidation, 7, 525 reduction, 7, 517 synthesis, 7, 532, 533 Dibenz[6,/]azepines N-acyl derivatives UV spectra conformation, 7, 499 mass spectrum, 7, 501 nitroxide... 

Compilations of UV data for 1-acyl- and 1-sulfonyl-l//-azepines are available.61 These systems display three major absorptions at 210-215, 240-247 and 285-330 nm. The weak, long wavelength band, which is thought to be due to interaction of the nitrogen lone pair with the triene system, often extends into the visible region and is responsible for the orange-yellow color of many 1-substituted 1//-azepines. 2,7-Disubstituted 1/7-azepines, in which the azepine ring is in the boat conformation, are colorless.61... 

Apparently, the 1H NMR spectra of 1 //-azepines are invariant over substantial temperature ranges.61 However, temperature dependence has been noted69 in the 13CNMR spectra of some 1 -acyl-1 //-azepines, and is attributed to hindered rotation about the N-CO bond rather than to ring-inversion phenomena AG free enthalpies of activation for hindered rotation of 62-66 kJ moP1 have been calculated. E/Z-rotamcr ratios for l-aroyl-l//-azepines have been assessed and show a slight preference for the -rotamer 22 however, an X-ray structural analysis of l-(4-bromobenzoyl)-2-methyl-3.5,7-triphenyl-l//-azepine demonstrates that in the crystal state it is exclusively in the E configuration.22... 

Mass spectral data on l-(arylsulfonyl)-l//-azepines have been amassed,73 and the fragmentation patterns of several 1-acyl-1//-azepines elucidated.61 For the latter systems, the base peaks correspond to the azatropylium cation (m/z 92). Loss of hydrogen cyanide to yield the cyclo-pentadienyl cation (m/z 65) has also been noted. 

In contrast to the A-sulfonyl derivatives, Ar-acylcyclohexadienamines 5, on treatment with p-toluenesulfonic acid in toluene at 20 C, yield 3 a,7a-dihydrobenzoxazoles 6 rather than 1-substituted 1//-azepines.21 However, the dihydrobenzoxazoles 6 are thermally unstable and on heating at 180X rearrange smoothly to the 1-acyl-l//-azepines 7 in high yields. 

Azaquadricyclanes2,formed by photolysis of the Diels-Alder [4 + 2]cycloadductsl of 1-acyl-or 1-sulfonylpyrroles with dimethyl acetylenedicarboxylate at room temperature, undergo isomerization in high yield to l//-azepine-4,5-dicarboxylates 3 (cf. Houben-Weyl, Vol.4/5b, p 1094).122,128 129 However, the azepines are difficult to purify since they dimerize, even at low temperatures (20-40°C). 

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... 

There is evidence from a detailed study of the photolyses of 2-alkyl-substituted aryl azides 40 in diethylamine that A3,7V-diethyl-1 //-azepin-2-amines are formed as oxygen-sensitive, meta-stablc intermediates that can give rise to a variety of byproducts, including 5-acyl- A%V-diethyl-pyridin-2-amines and 6-alkyl-7-(diethylamino)-2//-azepin-2-ones 11 however, formation of these oxidation products can be avoided by refluxing the photolysate mixture with methanol prior to exposure to oxygen, in which case practicable yields of the /V,/V-diethyl-3W-azepin-2-amines 41 result. 

In acid solution 1-acyl-1//-azepines and alkyl l//-azepine-l-carboxylates undergo rapid aromatization to A-arylcarbamates,115,139,142 whereas 1/Z-azepine-l-carbonitrile suffers quantitative rearrangement and hydrolysis to phenylurea.163 Rearrangement of ethyl l//-azepine-l-carboxylate to ethyl A-phenylcarbamate is also rapid (5 min) and quantitative with boron trifluoride-diethyl ether complex in benzene.245... 

The ring contraction of 3//-azepines is also promoted by acylating agents,54 35 and by arenesulfonyl halides.34 For example, in refluxing acetic anhydride A,-phenyl-3//-azepin-2-amine yields 2-acetamidodiphenylamine (22% mp 121-122°C),34 whereas A,A,-diethyl-3/7-azepin-2-amine (30) with 4-nitrobenzoyl chloride in pyridine yields the benzanilide 31.35... 

Thermolysis of the 3-acyl-3/f-azepine 32 in Decalin at 250°C also gives the phenacylpyridine but in much reduced yield (6%). In a similar manner, 4-chloro-yV,/V-diethyl-3-phenacylpyridin-2-amine (53 % bp 160 C/0.18 Torr) is produced by the photolysis or thermolysis of 3-benzoyl-5-chloro-Ar,Ar-diethyl-3/f-azepin-2-amine.246 However, if the 3ff-azepine bears a secondary amine residue at the 2-position, e.g. 36, then photolysis or thermolysis yields a pyrrolo[2,3-/>]pyridine by intramolecular cyclization of the 3-phenacylpyridin-2-amine intermediate. 

The [l,3]oxazino[3,4- ]azepinone 42, isolated as a byproduct (8%) during the preparation of 2//-azepine from the 1-carboxylate 40, is believed to arise by a [2 + 4] cycloaddition of 2-methylpropene (formed in situ) with the l-acyl-2/7-azepinium ion 40 via intermediate 41.290... 

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-... 

The mass spectra of l-acyl-l//-l-benzazepines have been recorded.23 The mass spectrum of 3-mesyl-3/7-3-benzazepine shows an intense base peak at m/e = 142duetothebcnzazepinylium ion and a peak (51 %) at m/e — 115 (-HCN) which is attributed to the indenium cation.26 Fragmentation patterns for 1H- and 5/7-2-benzazepines40 and for 5//-dibenz[c,e]azepine5 are available. The electron-impact induced fragmentation pattern of 5//-dibenz[6,/]azepine displays an intense molecular ion as the base peak, and a moderately intense (M + 1) peak.5 ... 

In accord with experimental observations, SCFMO calculations indicate that an /V-acyl function should deactivate 5f/-dibenz[/>,/]azepine towards electrophilic substitution at the carbocyclic rings, and that substitution should occur preferentially at the CIO position.32 The calculated dipole moment (0.98 D) for 5f/-dibenz[A,/]azepine compares favorably with the measured value (0.96 D), and is expected for a nonplanar ring system.58... 

The pharmacologically active and commercially important 5//-dibenz[/>,/]azepines 40 are available by base-catalyzed dehydrobromination of their 5-acyl- 10-bromo-l 0.11-dihydro derivatives 38,118 followed by hydrolysis of the isolable tV-acyl compounds 39 29.119-121... 

Friedel-Crafts acylation of 5-acyl-56/-dibenz[6,/]azepines, e.g. 3, affords the 5,10-diacyl derivatives, e.g. 4.32 Curiously, 5-methyl-5//-dibenz[6,/]azepine is unreactive towards electrophilic acylation and only trace amounts of a product, identified tentatively as 2,8-diacetyl-5// dibenz[6,/]azepin-10-one, have been isolated. 

On heating with sodium borohydride in glacial acetic acid. 5//-dibenz[/t,/ azepine (5) undergoes sequential acylation and reduction to yield 5-ethyl-5/7-dibcnz[A,/ ]azepine (8, R = Et).192 Similarly, reduction in trifluoroacetic acid produces the trifluoroethyl derivative 8 (R = CF3CH2 61% mp 69-70 C).193... 

A-Acylations of 57/-dibenz[b,/]azepine (5) can be carried out under standard conditions,69 124 142,196 197 as exemplified below. There is some evidence to suggest that acetylation under acidic conditions is accompanied by ring contraction to yield acridones.32... 

Treatment of 5//-dibenz[6,/]azepine (5, R1 = H) with an excess of butyllithium furnishes the 4,5-dilithio derivative 6, which with an equivalent of an A. A-dimethylcarboxamide undergoes regiospecific acylation at C4.206 In a similar manner, 5-acyl-5f/-dibenz[6,/]azepines, e.g. 5 (R1 = Ac), with butyllithium and carbon dioxide form dibenz[6,/]azepine-4-carboxylic acids, e.g. 7 (R1 = Ac R2 = OH).207... 

Acyl-lO.l l-epoxy-5//-dibenz[6,/]azepines 11 are obtained in moderate yields by oxidation of 5-acyl-5//-dibenz[A,/]azepines 10 with 3-chloroperoxybenzoic acid124 197,219 (see also Section 3.2.2.2.2.). As expected, peracid oxidation of 10-(alkylsulfanyl)-5//-dibenz[A,/]azepincs occurs at sulfur rather than at the CIO —Cl 1 double bond.213... 

Acetyl-5//-dibenz[/>,/]azepine-10-car bon itrile (17, R = CN) when treated with sodium borohydride undergoes reduction (73 % yield) at the CIO - Cl 1 double bond without reduction of the acetyl or cyano groups.212 However, hydroboration of 5-acetyl-5//-dibenz[/y/]azepine (17, R = H) with diborane in tetrahydrofuran under standard conditions is accompanied by reduction of the acyl function to yield 5-ethyi-10,l l-dihydrodibenz[6,/]azepin-10-ol (18).72... 

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

In 1995, and regrettably missed in last year s review, Klotgen and Wiirthwein described the formation of the 4,5-dihydroazepine derivatives 2 by lithium induced cyclisation of the triene 1, followed by acylation <95TL7065>. This work has now been extended to the preparation of a number of l-acyl-2,3-dihydroazepines 4 from 3 <96T14801>. The formation of the intermediate anion and its subsequent cyclisation was followed by NMR spectroscopy and the stereochemistry of the final product elucidated by x-ray spectroscopy. The synthesis of optically active 2//-azepines 6 from amino acids has been described <96T10883>. The key step is the cyclisation of the amino acid derived alkene 5 with TFA. These azepines isomerise to the thermodynamically more stable 3//-azepines 7 in solution. 

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