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 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 ).     

Mass spectral fragmentation patterns of heterocycles. IX . Investigation of fundamental processes in 5H-dibenz[b,f]azepines and dihydro-5H-dibenz[b,f]azepines

Electron impact induced fragmentation patterns of 5H-dibenz[b,f]azepine ( 1a ), 10,11-dihydro-5H-dibenz-[b,f]azepine ( 2a ) and some 5-substituted derivatives were investigated using metastable ion studies, exact mass measurements and deuterated analogues. Studies employing 4,6-dideuterio derivatives indicate that the formations of ions of m/e 191, 180, 167, 166 and 152 are associated with a variety of skeletal reorganization processes accompanied by hydrogen (or deuterium) transfers involving peri (4- or 6-) hydrogen (or deuterium) atoms. The methyl radical expelled in the formation of the M-15 ion in the spectrum of 2a is derived from the benzylic carbon(s). A similar process is, in part, responsible for the expulsion of a methyl radical from the molecular ion of 5-methyl-10,1 1-dihydro-5H-dibenz[b,f]azepine ( 2c ) based on the fragmentation of the trideuteriomethyl derivative ( 2d ). Side chain α-cleavage processes dominate the spectra of (5H-dibenz[b,f]azepine-5-yl)acetaldehyde diethylacetal and its 10,11-dihydro analogue. Hydrogen atom transfer processes involving benzylic hydrogen atoms occur in the fragmentation of the 10,11-dihydro-5H-dibenz[b,f]azepines 2a, 2c and 2e .     

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.     

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.     

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.     

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.     

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 ).     

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.     

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.     

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 .     

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.     

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-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).     

Synthesis of 1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine

The synthesis of 7,8‐dihydro‐5(6H)‐quinolinone ( 3 ) from commercially available 3‐amino‐2‐cyclohexen‐1‐one ( 1 ) and 3‐(dimethylamino)acrolein ( 4 ) in 23% yield avoids the preparation of propynal ( 2 ). Conversion of 5‐(4‐methylphenylsulfonyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]azepine ( 12 ) to 6‐(4‐methylphenylsulfonyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 24 ) is described. Removal of the N‐(4‐methylphenylsulfonyl) group with 40% sulfuric acid in acetic acid gave the tricyclic azepine 26. Application of a similar series of reactions to 5‐(4‐nitrobenzoyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]‐azepine ( 13 ) afforded 6‐(4‐nitrobenzoyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 25 ).     

A concise,efficient and versatile synthesis of amino‐substituted benzo[b]pyrimido[5,4‐f]azepines: synthesis and spectroscopic characterization,together with the molecular and supramolecular structures of three products and one intermediate

A concise, efficient and versatile synthesis of amino‐substituted benzo[b]pyrimido[5,4‐f]azepines is described: starting from a 5‐allyl‐4,6‐dichloropyrimidine, the synthesis involves base‐catalysed aminolysis followed by intramolecular Friedel–Crafts cyclization. Four new amino‐substituted benzo[b]pyrimido[5,4‐f]azepines are reported, and all the products and reaction intermediates have been fully characterized by IR, ¹H and ¹³C NMR spectroscopy and mass spectrometry, and the molecular and supramolecular structures of three products and one intermediate have been determined. In each of N,2,6,11‐tetramethyl‐N‐phenyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepin‐4‐amine, C₂₂H₂₄N₅, (III), 4‐(1H‐benzo[d]imidazol‐1‐yl)‐6,11‐dimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, which crystallizes as a 0.374‐hydrate, C₂₁H₁₉N₅·0.374H₂O, (VIIIa), and 6,7,9,11‐tetramethyl‐4‐(5‐methyl‐1H‐benzo[d]imidazol‐1‐yl)‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, C₂₄H₂₅N₅, (VIIIc), the azepine ring adopts a boat conformation, but with a different configuration at the stereogenic centre in (VIIIc), as compared with (III) and (VIIIa). In the intermediate 5‐allyl‐6‐(1H‐benzo[d]imidazol‐1‐yl)‐N‐methyl‐N‐(4‐methylphenyl)pyrimidin‐4‐amine, C₂₂N₂₁N₅, (VIIb), the immediate precursor of 4‐(1H‐benzo[d]imidazol‐1‐yl)‐6,8,11‐trimethyl‐6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepine, (VIIIb), the allyl group is disordered over two sets of atomic sites having occupancies of 0.688 (5) and 0.312 (5). The molecules of (III) are linked into chains by a C—H…π(pyrimidine) hydrogen bond, and those of (VIIb) are linked into complex sheets by three hydrogen bonds, one of the C—H…N type and two of C—H…π(arene) type. The molecules of the organic component in (VIIIa) are linked into a chain of rings by two C—H…π(arene) hydrogen bonds, and these chains are linked into sheets by the water components; a single weak C—H…N hydrogen bond links molecules of (VIIIc) into centrosymmetric R₂²(10) dimers. Comparisons are made with some related compounds.     

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.     

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.     

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).     

Heterocyclic systems. VIII. synthesis of 1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a]azepine derivatives

The synthesis of the unknown title Compounds is described. The preparation involves intramolecular acylation of 3-[1-phenyl-5-(1-pyrryl)pyrazol-4-yl]propanoic acid 9 to the tricyclic ketone 10 , which was then transformed into 1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a]azepine 12 and its dihydro derivative 13 by reductive procedures.