Substituted 2,3,4,5-tetrahydro-1H-3-benzazepine and 2,3,4,5-tetrahydro-1H-naphth[1,2-d] azepine derivatives

The multi-step synthetic procedures to prepare a number of 2,3,4,5-tetrahydro-1H-benzazepine derivatives 1 through a series of intermediates are described. The condensation of arylaldehydes 2 with 2-nitropropanes 3 gave nitroalcohols 4 which were reduced to alcohol amines 5 . The condensation of 5 with arylacetaldehydes 6 gave imino derivatives 7 which on reduction with borohydride gave secondary amines 8 . By employing different methods, alcohol amines 5 were condensed with arylacetic acids 9 to give amides 10 which were then reduced to amines 8 . On treatment with mineral acids, amines 8 were cyclized to the target compounds 1 . Biological activities of 1 are also briefly discussed.     

Aromatie-substituted derivatives of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine. Syntheses via chloromethylation

Chloromethylation of N-acetyl-2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine ( 4 ) proceeded, depending on reaction conditions, at the 6- or 6,9- positions. Subsequent transformation of these intermediates provided a series of mono and bis aromatic-substituted derivatives of the parent benzazepine 3 .     

The synthesis of some 7- and 7,8-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines

The nitration of 2,3,4,5-tetrahydro-1H-3-benzazepine and its 3-methyl and 3-acetyl derivatives yields the corresponding 7-nitro derivatives which can be further transformed by classical procedures. The preparation of the ether cleavage products of the known 2,3,4,5-tetrahydro-7,8-dimethoxy-1H-3-benzazepine is also reported.     

Ring-opening reactions of halogenated N-aryl-1,2,3,4-tetrahydroisoquinoline and 2,3,4,5-tetrahydro-1H-2-benzazepine derivatives

Compounds 4a-4d, 4f and 10 were prepared and their ring-opening reactions with N-bromosuccinimide (NBS) investigated. Compounds 4a and 4b gave a mixture of products which did not contain any significant quantity of the corresponding aldehydes 5a and 5b whereas compounds 4c, 4d and 4f gave exclusively the aldehydes 5c, 5d and 5f respectively. Compound 10 similarly gave the aldehyde 11 when treated with NBS.     

A novel synthesis of aromatic methoxy and methylenedioxy substituted 2,3,4,5-tetrahydro-1H-3-benzazepines

A new synthesis of aromatic methoxy and methylenedioxy substituted 2,3,4,5-tetrahydro-1H-3-benzazepines is described. Suitably substituted phenethylamines and their α-methyl homologs in the form of their N-acetyl derivatives are chloromethylated, the resulting benzyl chlorides are reacted with cyanide and hydrolysis of the latter yields 2-(2-aminoethyl)phenylacetic acid derivatives. Thermal cyclization yields the corresponding lactams. Hydride reduction of these lactams furnishes the substituted 2,3,4,5-tetrahydro-1H-3-benzazepines which may be methylated on nitrogen by formaldehyde and hydrogen. By this sequence a number of previously unde-scribed compounds have been prepared.     

Synthesis of 3-alkyl-8-substituted- and 4-hydroxy-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazepines

Based on the Schmidt reaction and an iodolactone ring expansion reaction, two different synthetic routes to substituted 2,3,4,5-tetrahydro-1H-2-benzazepines were developed. The Schmidt reaction on 2,3-dihydro-2H-1-naphthalenone ( 1 ) gave 3 , the product resulting from the alkyl group migration, as the major product instead of the tetrazole 2. This prompted the investigation of the Schmidt reaction on aromatic ketones 8 and 12. The product 9 due to alkyl group migration was the major product of the Schmidt reaction on 2-methyl-3,4-dihydro-2H-1-naphthalenone ( 8 ). The β-keto diester 12 gave a mixture of decarb-oxylated lactams after the Schmidt reaction. In this case, the lactam 13 resulting from the migration of the aromatic ring dominated over the other lactam 14. When lactam 14 was subjected to nitration, a single regioisomer was produced and transformed to the bromo alcohol 19. The other approach was based on the single pot ring expansion of the iodolactone 22 to the lactam 23 in the presence of methanolic ammonia. The iodolactone 22 was readily prepared from 2-allylbenzoic acid.     

Nuclear magnetic resonance spectra of psychotherapeutic agents. III.. Stereochemistry of 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones

The stereochemistry of some 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones was determined by proton magnetic resonance using the paramagnetic shift reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium [Eu(fod)₃] two of these compounds, clobazam and triflubazam, are clinically used as psychotherapeutic agents. Several model structures, with intermediate stereochemistry in the range of the possible limit situations of benzocycloheptene, -cycloheptadiene or -cycloheptatriene type, are considered; LIS (3) are computer simulated on the basis of proton geometric parameters. It was found that at room temperature, these derivatives exist in only one pseudo-boat cycloheptadiene-like conformation, showing the 5-phenyl group directed pseudo-axially. This conformational preference is interpreted in terms of a balance between the steric requirements of the bulky substituent and electronic repulsion in the ring π-system.     

Azabicyclo chemistry II. Synthesis of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepines. B-norbenzomorphans

The syntheses of the B-norbenzomorphans, 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepine (1a) and its N-methyl derivative (Ib) were accomplished. Phenylsuccinic anhydride (III) was cyclized to 3-carboxy-1-indanone (IVa), which was converted by the Arndt-Eistert method to the homologous methyl indanone-3-acetate (V). One experiment in the synthesis of V led to the by-products 3-carboxamido-1-indanone (IVd) and 3-(N-methylcarboxamido)-1-indanone (IVe), identified by physical and chemical means. Methyl 1-aminoindan-3-acetate (VII) was prepared by catalytic reduction of methyl indanone-3-acetate oxime (VI). Hydrolysis of VII afforded 1-aminoindan-3-acetic acid (VIII), which was cyclized with dicyclohexylcarbodiimide to 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (IX). Reduction (lithium aluminum hydride) of IX gave amine Ia which was then methylated to Ib. The mass spectral fragmentation patterns of IX and Ia are discussed.     

Preparation of 1,5-methano-2,3,4,5- tetrahydro-1H-3-benzazepine via Pd-catalyzed cyclization

[reaction: see text] A new approach to prepare 1,5-methano-2,3,4,5-tetrahydro-1H-3-benzanepine (1) is discussed. This strategy utilized a tandem Michael addition and Pd-catalyzed cyclization to afford cyanobenzofulvene acetal 13. This indene intermediate (13) was subjected to hydrogenolysis to provide an amino ester (12) and was cyclized with base to afford lactam 5. The lactam (5) was reduced with borane to afford the desired benzazepine (1).     

A 13C-NMR assignment study of a series of 2,3,4,5-tetrahydro-1-methyl-1H-1,5-benzodiazepine-2,4-diones

The natural abundance ¹³C-nmr spectra of a series of 2,3,4,5-tetrahydro-1-methyl-1H-1,5-benzodiazepine-2,4-diones have been recorded: two of these compounds, clobazam and triflubazam, are clinically used as psychotherapeutic agents. The assignments of the various resonances have been made by chemical shift arguments, by the analysis of the fine splittings caused by one bond and long range couplings, and also by comparison with model compounds.     

A new procedure for regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046) and its 3-methyl analogue as inhibitors of phenylethanolamine N-methyltransferase (PNMT)

A regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046, 10 ) and its 3-methyl analogue 26 from 6,7-dichloro-3-hydroxyphthalide ( 16 ) is described. The key step involved 1,4-hydride addition to the α,β-unsaturated nitrile 17 to give the saturated nitrile 18 using sodium borohydride in 2-propanol. In the preparation of LY134046 10 , the COOH group in 18 was first esterified and then the nitrile function was selectively reduced with borane to yield the aminoester 20 . The aminoester 20 was then cyclized to the azepinone 21 which on reduction with borane provided LY134046 10 in an overall yield of 22%. The route is adaptable to the preparation of hitherto unknown 3-substituted-2-benzazepines as demonstrated by the preparation of the 3-methyl analogue 26 . In this case the nitrile 18 was reacted with an excess methylmagnesium iodide to give the ketoacid 22 . Esterification of 22 followed by reductive amination with sodium cyanoborohydride and ammonium acetate provided the aminoester 24 , which was then converted to the target benzazepine 26 as described earlier for the title compound. The reaction conditions and the reagents used throughout the sequence are fairly mild and many functional groups may be tolerated. The only limitation to this procedure is the availability of the corresponding hydroxyphthalide. A variation in the choice of reagent in the Grignard reaction of 18 should provide an access to a variety of 3-substituted-2-benzazepines.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H-[1]-benzopyrano[3,2-b]pyridine, 4,5-Dihydro-4,5-dioxo-1H-[1]-benzopyrano[2,3–6]pyridine and 1,5-Dihydro-1,5-dioxo-4H-[1]-benzopyrano[3,4-b]pyridine derivatives from aminobenzopyrones

3-Aminochromone and 3-aminocoumarin were condensed with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate to give intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-lH-[1]-benzopyrano[3,2-b]pyridinecarboxylates and 1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano-[3,4-b]pyridinecarboxylates. 2-Aminochromone was converted to 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano-[2,3-b]pyridinecarboxylate via an intermediate condensation product with diethyl ethoxymethylenemalonate. These esters were hydrolyzed to the corresponding carboxylic acids (21, 30, 36, 50, and 60). Attempts to prepare 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano[4,3-b]pyridinecarboxylates from 4-aminocoumarin were unsuccessful.     

DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3, 6-dihydropyrimidin-1[2H]-yl)-N-(4-(1, 3-dioxo-1H-benzo [de]isoquinolin-2[3H]-yl) aryl) acetamides as antimicrobial agents

We report herein DABCO mediated one pot synthesis of 2-(3-benzyl-2, 6-dioxo-3,6-dihydropyrimidin-1[2H]-yl)-N-(4-(1,3-dioxo-1H-benzo[de]isoquinolin-2[3H]-yl) aryl) acetamides ( 4a-j ). The silent features of this new one pot synthesis include the shorter reaction time, high yields, simple workup, and simultaneous formation of N-Amide and N-benzyl bonds in the one pot. The newly synthesized compounds ( 4a-j ) were characterized by different spectral techniques such as IR, ¹H-NMR, ¹³C-NMR, HRMS. All the synthesized compounds were evaluated for their anti-bacterial and anti-fungal activities. The anti-bacterial activities results reveal that the compounds 4a , 4g , 4i , and 4j are most active against S. aureus. In the case of B. subtilis the compounds 4a , 4i , and 4j are found to be most active. The compounds 4c , 4e , 4i , and 4j are most active against E. coli. In the case of P. aeruginosa 4a , 4i & 4j are found to be more active. On the other hand, the anti-fungal activity result shows that the compounds 4d , 4f , 4i , and 4j are more active against A. niger. The compounds 4a , 4d , 4i , and 4j are found to be more active against C. albicans.     

3-Aryl-5-[(aryloxy)methyl]-3-[(1H-1,2,4-triazol-1-yl)methyl]-2-methylisoxazolidine derivatives. Synthesis and antifungal activity

The synthesis and antifungal activity of a novel series of 3-aryl-5-[(aryloxy)methyl]-3-[(1H-1,2,4-triazol-1-yl)-methyl]-2-methylisoxazolidines are described. The in vitro activity was evaluated in solid agar cultures against a variety of dermatophytes and yeast fungi, while in vivo activity was measured in an immune-compromised mouse model of systemic candidiasis. The activity of the title series was compared to that of ketoconazole and one derivative, the cis-3-(4-chlorophenyl)-5-(4-chlorophenyloxy)methyl analogue 5f was found to possess a similar potency in the in vivo assay. Structure-activity relationship correlations are also discussed.     

Electron impact mass spectrometry of 3-hydroxy-3,4,5,6-tetrahydro-2H-[1]benzoxocines. A comparison with the behaviour of isomeric 2-hydroxymethyl-2,3,4,5-tetrahydro-[1]-benzoxepines and 1,2-epoxy-5-(2-hydroxyphenyl)pentane

The mass spectrometric behavior of 3-methyl-3-hydroxybenzoxocines has been studied in detail by means of linked scans and mass analyzed ion kinetic energy spectrometry. The structure of the molecular ion and the fragmentation processes are strictly related to the structure of the neutral moieties. The possible isomerization of 3-hydroxy-10-methoxy-3-methyl-3,4,5,6-tetrahydro-2H-[1]benzoxocine to 2-methyl-2-[3-(3′-methoxy-2′-hydroxy)phenyl]pentyloxirane and to 2-hydroxymethyl-9-methoxy-2-methyl-2,3,4,5-tetrahydro[1]benzoxepine is investigated.     

Extraction of hydrochloric and nitric acid with 1-{[2-(2,4-Dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]-methyl)-1H-1,2,4-triazole and (RS)-1-(4-Chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-yl-methyl)-pentan-3-ol

Extraction of hydrochloric and nitric acid with 1-{[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]-methyl}-1H-1,2,4-triazole (propiconazole) and hydrochloric acid with (RS)-1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-yl-methyl)-pentan-3-ol (tebuconazole) was studied. It is established that extraction of acids proceeds with the formation of monosolvates as an exothermic process. Effective extraction constants of acids are evaluated. By means of the IR and ¹H NMR spectroscopy it was shown that the protonaccepting center of tebuconazole is N⁴ atom of the triazole ring.     

Synthesis of 2,3,4,6,7,8-Hexahydro-5H-1-benzopyran-5-ones and 3-(6-Oxo-1-cyclohexenyl)alkanoic Acids by Reduction of 4,6,7,8-Tetrahydro-2H-1-benzopyran-2,5(3H)-diones

Comparative results on the reduction of 4,6,7,8-tetrahydro-7,7-dimethyl-2H-1-benzopyran-2,5(3H)-diones 1 are reported. Hydride reduction (LiAlH₄ in Et₂O or NaBH₄ in i-PrOH) affords 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones 5 in 30-60% isolated yield. Photochemical reduction of 1b and 1d (direct irradiation at λ = 300 or 254 nm in i-PrOH, or sensitized irradiation in acetone/i-PrOH or benzene/i-PrOH) gives 3-(6-oxo-1-cyclohexenyl)alkanoic acids 6 in 50–80%, while 1c affords the isomeric 3-(4,4-dimethyl-6-oxo-1-cyclohexenyl)-4-methyl-4-pentenoic acid ( 9 ) in 73% isolated yield. Electrochemical reduction (Hg, CH₃CN, Bu₄N⁺ClO, ?2.6 V vs. Ag/Ag⁺) requires more than 4 Farad/mol for the consumption of 1 without any major product being detected.     

Esters of 4-(3-Dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrolyl)phenylacetic acids

Reaction of equivalent amounts of alkyl 4-aminophenylacetates with maleic anhydride gave rise to the corresponding alkyl 4-N-maleimidophenylacetates which with diethylamine, piperidine, and morpholine afforded esters of 4-(3-dialkylamino-2,5-dioxo-2,3,4,5-tetrahydro-1H-pyrrolyl)phenylacetic acids as stereoisomer mixtures.     

Synthesis and structure of 4-[(4-Nitro-1,2,5-oxadiazol-3-yl)-NNO-azoxyl]-1, 2,5-oxadiazol-3-amine

The synthesis of the energetic compound 4-[(4-nitro-1,2,5-oxadiazol-3-yl)-NNO-azoxyl]-1,2,5-oxadiazol-3-amine (3) was achieved in two steps from diaminofurazan (1). Compound 3 was characterized by X-ray diffraction. From the X-ray structure a bifurcated intramolecular H bond between O(2)-H(2)-N(4) was observed. In addition, intramolecular H bonding was observed between H(1) and N(7) of an adjacent molecule. One molecule of ethanol and one-half molecule of water per molecule of3 was observed in the crystal lattice. However, no H bonding was observed between the solvent molecules and3 in the crystal lattice. Despite the presence of solvent in the crystal lattice,3 was found to have a high crystal density (d=1.856 g/cm³).     

Synthesis, 1H- and 13C-NMR spectra,crystal structure and ring openings of 1-methyl-6,9-epoxy-9-aryl-5,6,9,10-tetrahydro-1H-imidazo [3,2-e] [2H-1,5] oxazocinium methanesulfonate

The methanesulfonic acid catalyzed reaction of 1-(4-chloro- and 2,4-dichlorophenyl)-2-(1-methyl-2-imida-zolyl)ethanones 1a and 1b with glycerol produced cis- and trans-{2-haloaryl-2-[(1-methyl-2-imidazolyl)methyl]-4-hydroxymethyl}-1,3-dioxolanes 2a and 2b with a 2:1 cis/trans ratio. Besides these five-membered ketals, the reaction of 1a with glycerol afforded a small amount of trans-{2-(4-chlorophenyl)-2-[(1-methyl-2-imidazolyl)methyl]-5-hydroxy}-1,3-dioxane ( 3a , 7%). The reaction of methanesulfonyl chloride with cis-1 formed the corresponding methanesulfonates, cis- 4 , which rapidly cyclized to the title compounds 5 . Base-catalyzed ring opening of 5 furnished 1-methyl-5,6-dihydro-6-hydroxymethyl-8-(4-chloro- and 2,4-dichlorophenyl)-1H-imidazo[3,2-d][1,4]oxazepinium methanesulfonates 7 . Acid-catalyzed hydrolyses of 5 or 7 provided 1-methyl-2-[(4-chloro- and 2,4-dichloro)phenacyl]-3-[(2,3-dihydroxy)-1-propyl]imidazolium salts 12 . Structure proofs were based on extensive ¹H and ¹³C chemical shifts and coupling constants and structures of 3a and 5a were confirmed by single crystal X-ray crystallography.