The assignment of the 1H-NMR and 13C-NMR spectra of 5H-dibenz[b,f]azepine and 10,11-dihydro-5H-dibenz[b,f]azepine

The total assignments of the ¹H-nmr and ¹³C-nmr spectra of 5H-dibenz[b,f]azepine [1] and 10,11-dihydro-5H-dibenz[b,f]azepine ( 2 ) have been made based on comparison with the corresponding 4,6-dideuterated derivatives 3 , and 4 . These compounds were prepared via repeated lithiations and subsequent deuterations of 1 and 2 .     

Synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines; key synthons in syntheses of pharmaceutically active compounds

Substituted 10,11-dihydro-5H-dibenz[b,f]azepines are key synthons in the syntheses of a number of pharmaceutically active compounds such as imipramine, chlorimipramine, and desimipramine analogues. A facile synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines is described, starting out from com mercially available 2-bromotoluenes or 2-nitrotoluenes. Initial α-bromination with N-bromosuccinimide and subsequent reaction with triethylphosphite afforded the corresponding benzyl phosphonic ester deriva tives. After reaction with benzaldehyde derivatives, the expected Horner-Emmons reaction products were obtained. Hydrogenation gave the amino derivatives which were transformed into the corresponding formamides. Under Goldberg conditions [1], the final ring closing step was performed to give the substituted 10,11-dihydro-5H-dibenz[b,f]azepines in 46–75% yield.     

Reaction of 5-acetyl-10,11-didehydro-5H-dibenz[b,f]azepine with pyrrole,N-methylpyrrole,imidazole and N-methylimidazole: Cycloaddition versus michael addition

Reaction of 5-acetyl-10-bromo-5H-dibenz[b, f]azepine 1 with potassium t-butoxide results in the reactive intermediate 5-acetyl-10,11-didehydro-5H-dibenz[b, f]azepine ( 2 ). The intermediate 2 reacts with N-methylpyrrole to give a mixture of the Michael addition adduct 10-(2-N-methylpyrrolyl)-5H-dibenz[b, f]azepine ( 9 ) and the Diels-Alder/retro Diels Alder adduct 8H-(N-methylpyrrolo[3,4-d]dibenz[b, f]azepine ( 8a ). Reaction of 2 with pyrrole gives a mixture of two Michael addition adducts 10-(1-pyrrolyl)-5H-dibenz[b, f]azepine ( 16 ) and 10-(2-pyrrolyl)-5H-dibenz[b, f]azepine ( 18 ). Reaction of 2 with imidazole results in the Michael addition adduct 10-(1-imidazolyl)-5H-dibenz[b, f]azepine ( 21 ).     

Metallations of 5 H-dibenz [b,f] azepine and 10,11-dihydro-5H-dibenz [b,f] azepine. Synthesis of 4-substituted derivatives

The synthesis of 4-substituted 5 H-dibenz [b, f] azepines and 10, 11-dihydro-5 H-dibenz [b, f] azepine resulting from the reaction of the corresponding 4, 5-dilithio derivatives and different N, N-dimethylamides is reported. The total assignment of the pmr spectra of the prepared formyl derivatives based on decoupling experiments is also described.     

Reaction of 5H-dibenz[b,f]azepine with t-butyl hypochlorite: An aromatic nitrenium ion intermediate?

The reaction of 5H-dibenz[b,f]azepine with t-butyl hypochlorite and this same reaction in the presence of silver(I) were studied in an attempt to generate dibenz[b,f]azatropylium, an aromatic nitrenium ion. Analysis of the product mixture from this reaction mitigate against formation of this ion. An alternate mechanism is presented.     

Synthesis of trans-10,11-Dihydro-10,11-dihydroxy-5H-dibenz[b,f]azepine-5-carboxamide,a Major Metabolite of Carbamazepine

The stereoselectivity of the reduction of 5-carbamoyl-10,11-dihydro-11-oxo-5H-dibenz[b,f]azepine-10-yl acetate ( 6 ), prepared in two steps from 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide ( 4 ), has been studied. Among the reagents used, diisobutylaluminum hydride (DIBAH) was found to give the highest trans/cis diol ratio. This allowed the preparation of the important trans-diol metabolite 3 of carbamazepine ( 1 ).     

First reactions of dialkoxycarbenium tetrafluoroborates with pyrroles, 5H-dibenz[b,f]azepines,and electron-rich arenes

Pyrrole ( 2a ) and 2,5-dimethylpyrrole ( 2b ) react with the dialkoxycarbenium tetrafluoroborates 1a-1c under kinetic control to yield the corresponding acylpyrrole derivatives. 5H-Dibenz[b,f]azepine ( 9a ) and the 10,11-dihydro derivative 9b react only with the most electrophilic of the series of electrophiles tested, namely, diethoxycarbenium tetrafluoroborate ( 1a ), to furnish the corresponding formyl derivatives. Similarly, in arene chemistry, the highly electron-rich N,N-dimethylaniline ( 13a ) and 1,3,5-trimethoxybenzene ( 13b ) are formylated by reaction with 1a .     

SYNTHESIS,REACTIVITY AND CONFORMATION OF 10,11-DIHYDRODIBENZO-[b,f]PHOSPHEPIN AND DIBENZO[b,f]PHOSPHEPIN DERIVATIVES. PHOSPHORUS ANALOGUES OF IMINOBIBENZYL ANTIDEPRESSANTS

Abstract

Derivatives of the novel dibenzo[b,f]phosphepin system are prepared from 10,11-dihydro-5-phenyl-5H-bibenzo[b,f]phosphepin 5-oxide (2). New members in the 10,11-dihydro-5H-dibenzo[b,f]phosphepin series, including phosphorus analogues (7, 10) of the andidepressant drug imipramine (30), are also reported. Products of nucleophilic substitution at tetrahedral phosphorus in 2 appear to be determined by the relative apicophilicity of the nucleophile. Conformational analysis based on ¹H NMR data suggests folded (“butterfly”) conformation for the tricyclic compounds. The twisted boat conformation of the central ring in the 10,11-dihydro compounds bears a pseudo-equatorial P[dbnd]O oxygen or a P[dbnd]S sulfur, in solution. Symmetric AA‘BB’ spin systems are found in 4,5 and 7, and their solution conformations appear to be similar to those of analogous 10,11-dihydrodibenzo[b,f]azepine derivatives. The interaction of some compounds with NMR shift reagents and their mass spectral fragmentations are discussed.     

Preparation of 8H-Furo[3,4-d]dibenz[b,f]azepine. A Novel Heterocyclic Ring system

The synthesis of 8H-furo[3,4-d]dibenz[b,f]azepine 8 from 5H-dibenz[b,f]azepine 1a is described. The preparation of 8 represents the synthesis of a new heterocyclic system.     

Hydrolysis of ureas. Kinetics and mechanism of the basic hydrolysis of indole-1-carboxamides and (5H-dibenz[b,f]azepine)-5-carboxamide

The hydroxide ion catalyzed hydrolysis of indole-1-carboxamide and indole-1-(N,N-dimethyl)carboxamide has been studied in water at 60.0° and [OH⁻] concentration between 0.3--2.4N. The rate constants of formation of the tetrahedral intermediate are strongly increased by N-substitution with a heteroaromatic ring in comparison with simple amides. Carbamazepine, (5H-dibenz[b,f]azepine)-5-carboxamide, a potent anticonvulsant drug, is particularly stable under these conditions.     

Novel polycyclic heterocycles. IX. Dibenz[b,f] [1,4]oxazocin-11 (12H)one, 6,11-dihydro-12H-dibenz[b,f] [1,4]oxazocine,and their derivatives

Dibenz[b,f][1,4]oxazocin-11 (12H)one, 14 , was synthesized by the dicyclohexylcarbodiimide induced cyclization of α-(o-aminophenoxy)-o-toluic acid ( 13 ). Reduction of 14 by lithium aluminum hydride gave 6,11-dihydro-12H-dibenz[b,f][1,4]oxazocine ( 16 ). Both 14 and 16 were converted to a series of 12-alkylated and -acylated derivatives. The pmr spectra of some of these compounds are discussed.     

Mechanistic aspects of oxidation of N-substituted 5H-dibenz[c,e]azepines by aldehyde oxidase

5H-Dibenz[c,e]azepine ( 2 ) and its N-ethyl and N-(2-ethoxyethyl) analogues 3 and 4 were prepared and evaluated as substrates for aldehyde oxidase. Quaternization of 2 with ethyl iodide furnished 3 , while 4 was prepared by lithium aluminum hydride reduction of N-(2-ethoxy)ethyldiphenimide followed by mercuric acetate oxidation of the resultant amine 6 . The rates of oxidation of 2 and 3 were similar, suggesting a lack of selectivity by the enzyme for the respective imine and iminium functional groups in these compounds. The rate of oxidation of 3 decreased with increasing pH while the extent of “hydration” of this substrate increased over a similar pH range, signifying a preference by the enzyme for 3 over its carbinolamine equilibrium partner. Experiments with deuterium labelled analogues of 2 and 3 indicated that azomethine hydrogen loss from these substrates during enzymatic oxidation was not rate determining. Thus 5H-dibenz[c,e]azepine-5,5,7-d₃ ( 7 ), prepared by lithium aluminum deuteride reduction of diphenimide ( 5 ), and its N-ethyl analogue 8 , had respective enzymatic oxidation rates which did not differ from those of their non-deuterated counterparts.     

A convenient synthesis of 9H-dibenz[c,f]imidazo[1,2-a]azepin-9-ones

A convenient three step synthesis of 9H-dibenz[c,f]imidazo[1,2-a]azepin-9-ones from readily available 2-phenylimidazoline and a methyl benzoate is described.     

The first examples of the 11H-[2]benzazepino[1,2-a]dibenz[b,f]azocine ring system

The ring closure of 2-[(11,12-dihydro-6-oxodibenz[b,f]azocin-5-yl)methyl]benzoic acid in polyphosphoric acid to 16,17-dihydro-11H-[2]benzazepino[1,2-a] dibenz[b,f]azocine-4-(9H)-11-dione is reported. Degradation studies supporting this structural assignment for the annelation product are described.     

An anomalous reaction of 10-chloro-5H-benzoxazolo[3,2-a]quinolin-5-one with sodium diethyl malonate to form 9-chloro-8-ethoxy-12-hydroxy-5H-dibenz[c,f]quinolizin-5-one

Treatment of 10-chloro-5H-benzoxazole[3,2-a]quinolin-5-one (I) with an excess of sodium diethyl malonate at 190° for 3 hours in hexamethylphosphoramide gave, in 38% yield, 9-chloro-8-ethoxy-12-hydroxy-5H-dibenz[c,f]quinolizin-5-one (IV) which, on heating with acetic anhydride, afforded monoacetylated product, V. A possible reaction mechanism for the novel ring expansion reaction is suggested.     

Synthesis of 2,4‐diaminopyrido[2,3‐d]pyrimidines and 2,4‐diamino‐quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]‐cycloheptene substituents at the 6‐position as inhibitors of dihydrofolate reductases from pneumocystis carinii,toxoplasma gondii,and mycobacterium avium

The synthesis of four previously undescribed 2,4‐diaminopyrido[2,3‐d]pyrimidines ( 3,4 ) and 2,4‐diaminoquinazolines ( 5,6 ) with a bulky tricyclic aromatic group at the 6‐position is described. Condensation of dibenz[b,f]azepine with 2,4‐diamino‐6‐bromomethylpyrido[2,3‐d]pyrimidine ( 8 ) and 2,4‐diamino‐6‐bromomethylquinazoline ( 17 ) in the presence of sodium hydride afforded N‐[(2,4‐diaminopyrido[2,3‐d]‐pyrimidin‐6‐yl)methyl]dibenz[b,f]azepine ( 3 ) and N‐[(2,4‐diaminoquinazolin‐6‐yl)methyl]dibenz[b,f]‐azepine ( 4 ), respectively. Condensation of 5‐chlorodibenzo[a,d]cycloheptene ( 19 ) and 5‐chloro‐10,11‐dihydrodibenzo[a,d]cycloheptene ( 20 ) with 2,4,6‐triaminoquinazoline ( 13 ) afforded 5‐[(2,4‐diamino‐quinazolin‐6‐yl)amino]‐5H‐dibenzo[a,d]cycloheptene ( 5 ) and the corresponding 10,11‐dihydro derivative ( 6 ), respectively. The bromides 8 and 17 , as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three‐step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3–6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC₅₀ values in the 0.03–0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was<10‐fold, whereas the recently reported lead compound in this series, N‐[(2,4‐diaminopteridin‐6‐yl)methyl]dibenz[b,f]azepine ( 1 ) has > 100‐fold selectivity for the T. gondii and M. avium enzyme and 21‐fold selectivity for the P carinii enzyme.     

Five closely related 4‐chloro‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepines: similar molecular structures but different supramolecular assemblies

Dibenz[b,f]azepine (DBA) is a privileged 6‐7‐6 tricyclic ring system of importance in both organic and medicinal chemistry. Benzo[b]pyrimido[5,4‐f]azepines (BPAs), which also contain a privileged 6‐7‐6 ring system, are less well investigated, probably because of a lack of straightforward and versatile methods for their synthesis. A simple and versatile synthetic approach to BPAs based on intramolecular Friedel–Crafts alkylation has been developed. A group of closely‐related benzo[b]pyrimido[5,4‐f]azepine derivatives, namely (6RS)‐4‐chloro‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₄H₁₄ClN₃, (I), (6RS)‐4‐chloro‐8‐hydroxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₄H₁₄ClN₃O, (II), (6RS)‐4‐<!?tlsb=‐0.14pt>chloro‐8‐methoxy‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₁₅H₁₆ClN₃O, (III), and (6RS)‐4‐chloro‐8‐methoxy‐6,11‐dimethyl‐2‐phenyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₂₁H₂₀ClN₃O, (IV), has been prepared and their structures compared with the recently published structure [Acosta‐Quintero et al. (2015). Eur. J. Org. Chem. pp. 5360–5369] of (6RS)‐4‐chloro‐2,6,8,11‐tetramethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, (V). All five compounds crystallize as racemic mixtures and they have very similar molecular conformations, with the azepine ring adopting a boat‐type conformation in each case, although the orientation of the methoxy substituent in each of (III) and (IV) is different. The supramolecular assemblies in (II) and (IV) depend upon hydrogen bonds of the O—H...N and C—H...π(arene) types, respectively, those in (I) and (V) depend upon π–π stacking interactions involving pairs of pyrimidine rings, and that in (III) depends upon a π–π stacking interaction involving pairs of phenyl rings. Short C—Cl...π(pyrimidine) contacts are present in (I), (II) and (IV) but not in (III) or (V).     

Acetylenchemie 11. Mitt.: Synthese und Kristallstruktur des 11-Isopropyliden-1a,10b-dihydro-1H-1,6-methanodibenzo[b,f]cyclopropa[d]azepins

Summary The synthesis of 11-isopropyliden-1a,10b-dihydro-1H-1,6-methano-dibenzo[b,f]cyclopropa[d]azepine by phase-transfer catalysed reaction of 5H-dibenzo[b, f]azepine with 2-chloro-2-methyl-3-butyne is described. The structure is confirmed by X-ray diffraction.

     

Synthesis of 2-methylcarbamazepine,a new internal standard for chromatographic assays of carbamazepine (tegretol®)

The synthesis of 2-methyl-5H-dibenz[b,f]azepine-5-carboxamide (2-methylcarbamazepine, 2-MCBZ, 8), a promising internal standard for chromatographic assays of the antiepileptic agent carbamazepine (CBZ, 1), is described. N-(p-Tolyl)anthranilic acid (2) was utilized as a starting material for the synthesis of a key compound, 2,9-dimethylacridine (4), which was converted in two steps to 2-methyl-9-hydroxymethylacridan (6). The acridan 6, in the presence of poly-phosphoric acid, was ring-expanded to form 2-methyl-5H-dibenz[b,f]azepine (7), this latter compound being converted by conventional reactions to its 5-carbamyl derivative, 2-MCBZ (8).     

Conformational studies of 5-acetyl-10-cyano-10,11-dihydro-5H-dibenz[b,f]azepine

5 - Acetyl - 10 - cyano - 10,11 - dihydro - 5H - dibenz[b,f]azepine, 3, has been synthesized and its conformations in solution have been studied by variable temperature NMR. At ?55° in CDCl₃ solution, 3 shows the signals due to four different conformational isomers. At 55°, signals due to only two conformers can be seen. The ABX pattern of each of the four conformers was analyzed using double resonance experiments and the LAOCN3 computer program. The relative abundances of the isomers in the mixtures were estimated by computer additions of different proportions of the spectra calculated for the separate isomers. These spectral observations are discussed in detail and interpreted in terms of slow inversion of the seven-membered ring by torsion of the 4a55a bonds and restricted twisting of the C10C11 ethylene bridge.