Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Annulated 1,2,3,4-tetrahydro-β-carbolines by intramolecular Mannich-type amino- and amidoalkylations of N(9)-(ω-nitroalkyl)-3,4-dihydro-β-carbolines

2-[1-(ω-Nitroalkyl)-1H-indol-3-yl]ethylformamides 11 were transformed to the corresponding 9-(ω-nitroalkyl)-4,9-dihydro-3H-β-carbolines 5 and through a diastereoselective intramolecular aminoalkylation to the annulated tetrahydro-β-carbolines 13, in high yields. Intramolecular N-acyliminium cyclisation of compounds 5 afforded the tetracyclic diazacycloalkano[jk]fluorenes in two diastereoisomeric forms 18 and 19 with moderate selectivity. Conjugate addition reactions performed on compounds 18 and 19 led to pentacyclic indolo[3,2,1-de]pyrido[3,2,1-jk]naphthyridinone 26a or diazabenzo[a]naphtho[2,1,8-cde]azulenone 26b.     

Application of intramolecular cycloaddition/retro cycloaddition reactions for the synthesis of unsymmetrical 2,2′-bipyridine and 2-benzofuropyrazin-2-ylpyridine analogues

1,2,4-Triazines bearing cycloalkeno[c]pyridine substituents at the 5-position, 2a-d, prepared by an intermolecular Diels-Alder reaction of bi-5,5-triazines with cyclic enamines, were provided with an alkynyloxy or a 2-cyanophenoxy group at the 3-position of the triazinyl unit. A subsequent intramolecular Diels-Alder reaction of the former, followed by loss of N₂ leads to two new classes of 2,2′-bipyridine analogues containing different heterocyclic units, namely cycloalkeno[c]pyridine and 2,3-dihydrofuro- or 2,3-dihydropyrano[2,3-b]pyridine 8a-h; the intramolecular reaction of the 2-cyanophenoxy compound gives benzo[4,5]furo[2,3-b]pyrazine 10a-c.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

From N,N-diphenyl-N-naphtho[2,1-b]thieno[2,3-b:3′,2′-d]dithiophene-5-yl-amine to propeller-shaped N,N,N-tri(naphtho[2,1-b]thieno[2,3-b:3′,2′-d]dithiophene-5-yl)-amine: syntheses and structures

Three unique propeller-shaped helicenyl amines compounds: N,N-diphenyl-N-naphtho[2,1-b]thieno[2,3-b:3′,2′-d]dithiophene-5-yl-amine (1), N-phenyl-N,N-di(naphtho[2,1-b]thieno[2,3-b:3′,2′-d]dithiophene-5-yl)amine (2), and N,N,N-tri(naphtho[2,1-b]thieno[2,3-b:3′,2′-d]dithiophene-5-yl)amine (3) were efficiently synthesized by Wittig reaction and oxidative photocyclization. The crystal structures of 1, 2 and molecular configuration optimization (DFT-B3LYP/6-31+G(d)) of 3 reveal that the steric hindrance from the moiety of trithia[5]helicene effectively forces the nitrogen atom and the three bonded carbon atoms to coplanar and the interplanar angles of the facing terminal thiophene ring and benzene ring becoming larger when the helical arm increased from 1 to 3. Electrochemical properties and UV–vis absorption behaviors of 1, 2, 3 were primarily determined by the moiety of trithia[5]helicene.     

Pyrrolo-dC and pyrrolo-C: fluorescent analogs of cytidine and 2-deoxycytidine for the study of oligonucleotides

Pyrrolo-dC (1a, 6-methyl-3-(2-deoxy-β-d-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one) and its cyanoethyl phosphoramidite 2a were synthesized. The latter was incorporated into oligodeoxyribonucleotides by standard automated synthesis techniques, where pyrrolo-dC was found to serve as a fluorescent analog of deoxycytidine. The cyanoethylphosphoramidite (2b) of pyrrolo-C (2a, 6-methyl-3-(β-d-ribofuranosyl)-3H-pyrrolo[2,3-d]pyrimidin-2-one) was also synthesized and may find use for the site-specific incorporation of a fluorescent cytidine analog into oligoribonucleotides.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).     

The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Micelles catalyzed one pot regio- and chemoselective synthesis of benzo[a]phenazines and naphtho[2,3-d]imidazoles ‘in H2O’

An efficient, novel, and concise one pot regio- and chemoselective synthesis of benzo[a]phenazines (4) and naphtho[2,3-d]imidazoles (8) has been accomplished in excellent yields by nucleophilic substitution reaction of 2,3-dichloro-1,4-naphthoquinone (1) with o-phenylenediamine (2) and benzamidines (7) respectively ‘in H₂O’ using base and micelles (SDS) as catalyst. Analog reaction of 2,3-dichloro-1,4-naphthoquinone (1) with 2-aminobenzenethiol (9) under identical conditions led to formation of a mixture of benzo[b]phenothiazine (10), benzo[a]phenothiazine (11), and benzo[a]-1,4-benzothiazino-3,2-phenothiazine (12) in 17%, 23%, and 57% yields, respectively.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-tetrahydropyrano[2,3-b]indole derivatives

The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole 20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, respectively, was performed starting from the racemic spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. The enantiopure spiro oxo-azepinoindolinone (+)-10, obtained from (±)-7 by the way of an asymmetric ring enlargement, and the amino acid (+)-14, obtained by the hydrolysis of 10, were prepared as key intermediates for the synthesis of enantiopure compounds (−)-19 and (−)-20. Since the amino acid 14 is the common intermediate for the chemoselective preparation of derivatives 19 and 20, experimental and computational studies were performed in order to selectively obtain these compounds and to provide a mechanistic rationalization for their formation.     

Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal

A series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d]pyrimidines 9a-q were obtained by the three-component reaction between 6-aminopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected cyclization process was established by NMR and X-ray diffraction measurements.     

Chemistry of cyclopropenones: synthesis of new pyrrolo[2,1-b]-1,3,4-oxadiazoles

2,3-Diphenylcyclopropenone (1) reacts with ylidene-N-phenylhydrazine-carbothioamides 2a-e to form the pyrrolo[2,1-b]-1,3,4-oxadiazoles 5a-e.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Synthesis of enantiomerically pure Sb-chirogenic organoantimony compounds and their crystal structures

Sb-chirogenic organoantimony compounds (±)-5a-c bearing heteroatom moieties such as 4,4-dimethyl-2-oxazolinyl, methoxymethyl, and diphenylphosphanyl substituents on the o-position of an aryl group have been prepared by nucleophilic displacement of the ethynyl moiety on (1-naphthyl)(phenylethynyl)(p-tolyl)stibane (3) with aryllithium reagents (2a-c). The optical resolution of the racemic (±)-5a,b was attained via separation of a diastereomeric mixture of their palladium complexes (S)-7 formed from the reactions of (±)-5a,b with di-μ-chlorobis[(S)-dimethyl(1-ethyl-α-naphthyl)aminato-C²,N]dipalladium(II) (6). The enantiomerically pure Sb-chirogenic stibanes isolated here were optically stable, and no racemization on the chiral antimony center was observed even when they were allowed to stand at room temperature for over 72 h in chloroform. The structure of 5a,b including the absolute configuration was determined by single crystal X-ray analyses of (+)-5aB and antimony-palladium complex (7bB), respectively. The analyses also revealed the presence of intramolecular interaction between the antimony and sp²-nitrogen atoms in the molecule Sb(S)-(+)-5aB.     

Microwave-assisted manganese(III) acetate based oxidative cyclizations of alkenes with β-ketosulfones

The microwave-assisted synthesis of 5-(4-nitrophenyl)-2-phenyl-4-(phenylsulfonyl)-2,3-dihydrofuran (5a) was performed via manganese(III) acetate based oxidative cyclization of 1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone (3a) with vinylbenzene (4a). This new protocol was applied to four sulfone derivatives (3a-d), using vinylbenzene (4a) and diphenylethene (4b), affording a series of 2,3-dihydrofurans (5a-d, 6a-d) in moderate to good yields (26-55%). Similar methodology, applied on allylbenzene (4c), surprisingly, led to dehydronaphthalene derivatives (7a-d) in moderate yields. The unexpected mechanism and the role of allylbenzene (4c) are herein discussed.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.