Ring expansion of 11H-benzo[b]fluorene-11-methanols and related compounds leading to 17,18-diphenyldibenzo[a,o]pentaphene and related polycyclic aromatic hydrocarbons with extended conjugation and novel architectures

Condensation between 7-(1,1-dimethylethyl)-13-phenyl-8H-indeno[2,1-b]phenanthrene and paraformaldehyde produced the corresponding 9-fluorenylmethanol derivative, which on treatment with P₂O₅ to promote a Wagner-Meerwein rearrangement for ring expansion furnished 14-phenyldibenzo[a,j]anthracene in 88% yield. Similarly, 17,18-diphenyldibenzo[a,o]pentaphene possessing a helical twist and bearing two phenyl substituents at the most sterically congested C17 and C18 positions and other related compounds were likewise synthesized. Subsequent intramolecular arylation reactions involving the phenyl substituents produced polycyclic aromatic hydrocarbons with novel architectures.     

Design and synthesis of boron containing 2,4-disubstituted-phthalazin-1(2H)-one and 3,7-disubstituted-2H-benzo[b][1,4] oxazine derivatives as potential HGF-mimetic agents

We synthesized boron containing 2-(4-methoxybenzyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioaborolan-2-yl)phenyl) phthalazin-1(2H)-one 3 and 7-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-benzo[b][1,4] oxazine 8. The reaction of compound 2 with B₂pin₂ using potassium acetate as the base and Pd(PPh₃)₂Cl₂ as the catalyst, produced the corresponding boron-containing derivative 3 as a white solid in 65% yield. Alternatively, we have synthesized compound 8 as a yellow solid in 59% yield using the Miyaura borylation reaction. The potassium trifluoro(4-(-methyl-2H-benzo[b][1,4]oxazine-3-yl)phenylborate 9 was then obtained after treatment of 8 with aqueous solution of KF₂H in methanol as white solid product in 60% yield. The biological activities of the synthetic compounds are currently being evaluated.     

Reductive opening of 1H,3H-benzo[de]isochromene: synthesis of 1,8-difunctionalised naphthalenes

The lithiation of 1H,3H-benzo[de]isochromene (6) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 5% molar) in THF at −50 °C gives dianionic intermediate 7, which by reaction with different electrophiles {H₂O, D₂O, ^tBuCHO, PhCHO, Me₂CO, (CH₃CH₂)₂CO, [CH₃(CH₂)₄]₂CO, (CH₂)₅CO, (CH₂)₇CO, (−)-menthone} at the same temperature followed by hydrolysis leads to functionalised alcohols 8. If after addition of a carbonyl compound as the first electrophile [^tBuCHO, (CH₂)₅CO, (−)-menthone], the resulting dialcoholate 9 is allowed to react at 0 °C, a second lithiation takes place to give intermediate 10 which by reaction with a second electrophile [H₂O, ^tBuCHO, (CH₂)₅CO, CO₂], yields, after hydrolysis, 1,8-difunctionalised naphthalenes 11. Cyclization under acidic conditions of diols 8e-i gives oxygen-containing eight-membered heterocycles, which are homologous to the starting material 6.     

Reductive electrochemical formation of 6H-dibenzo[b,d]pyran-6-one and 2-benzopyran-1(1H)-one

In the present Letter several carbolactones (oxidative products) are obtained under aprotic cathodic conditions in the preparative scaled electrolysis of 1,2-quinones in a divided electrochemical cell and in the presence of oxygen. When 9,10-phenanthrenequinone is reduced 6H-dibenzo[b,d]pyran-6-one and [1,1′-biphenyl]-2,2′-dicarboxylic acid are obtained as major products. In the reduction of 1,2-naphthoquinone, 2-benzopyran-1(1H)-one, and 2-(2-carboxyethenyl)-benzoic acid were formed as main products. The proposed mechanism to explain the formation of these and other products, that involves an electron-transfer reaction to the oxygen in air, is now discussed.     

Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, pK_a, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.     

Preparation of substituted 1,2,3,4-tetrahydroquinoxalines and 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepines from catalytic CpIr hydrogen transfer N-heterocyclization of anilino alcohols

The [Cp^∗IrCl₂]₂/K₂CO₃ catalyzed hydrogen transfer N-heterocyclization on a series of anilino alcohols has been investigated. The catalyst (20% loading) converts anilino alcohols to 1,2,3,4-tetrahydroquinoxalines and 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepines in 30-84% isolated yield.     

Synthesis, properties, and oxidizing function of 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates

Uracil-annulated heteroazulenes, 6-substituted 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrole-8(7H),10(9H)-dionylium tetrafluoroborates 7a,b·BF₄⁻, which are the isoelectronic compounds of 5-dezazaflavin, were synthesized. X-Ray crystal analysis and MO calculations were carried out to clarify the structural characteristics of 7a,b·BF₄⁻. The stability of cations 7a,b is expressed by the pK_R+ values which were determined spectrophotometrically to be 10.9 and 11.2, respectively. The electrochemical reduction of 7a,b exhibited high reduction potentials at −0.84 and −0.87 (V vs Ag/AgNO₃) upon cyclic voltammetry (CV). A good linear correlation between the pK_R+ values and reduction potentials (E1_red) of 7a,b·BF₄⁻ and reference compounds 4·BF₄⁻ and 5·BF₄⁻ was obtained. In a search of the reactivity, reactions of 7a,b·BF₄⁻ with some nucleophiles, hydride and diethylamine, were carried out to clarify that the introduction of nucleophiles to give regio-isomers is dependent on the nucleophile. The photo-induced oxidation reactions of 7a,b·BF₄⁻ toward some alcohols under aerobic conditions were carried out to give the corresponding carbonyl compounds in more than 100% yield [based on compounds 7a,b·BF₄⁻], suggesting the oxidizing function of 7a,b·BF₄⁻ toward alcohols in the autorecycling process.     

A convenient synthesis of chiral amino acid derived 3,4-dihydro-2H-benzo[b][1,4]thiazines and antibiotic levofloxacin

A series of 3,4-dihydro-2H-benzo[b][1,4]thiazine derivatives 8a-g were synthesized via- a copper-catalyzed intramolecular N-aryl amination reaction on substituted 2-(2-bromophenylthio)-ethanamines which were synthesized by the nucleophilic substitution reaction of 2-bromobenzenethiol with Boc-protected amino alcohol derivatives. This strategy provides a short and an efficient entry to (S)-3-methyl-1,4-benzoxazine 12, an advanced synthetic intermediate for the synthesis of levofloxacin.     

Novel synthesis and properties of 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]thiophen-8(7H),10(9H)-dionylium tetrafluoroborate: autorecycling oxidation of some alcohols under photo-irradiation

Three-step reactions starting from 2-chlorotropone with dimethylthiobarbituric acid afforded 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]thiophen-8(7H),10(9H)-dionylium tetrafluoroborate 5·BF₄⁻, which is the isoelectronic compound of the 5-ethyl-3-methyllumiflavinium ion. The X-ray crystal analysis and MO calculation were carried out to clarify the structural characteristics of 5·BF₄⁻. The stability of cation 5 is expressed by the pK_R+ value, which was determined spectrophotometrically as 5.1. The electrochemical reduction of 5 exhibited low reduction potential at −0.53 (V vs Ag/AgNO₃), upon cyclic voltammetry (CV). In a search for the reactivity, reactions of 5·BF₄⁻ with some nucleophiles, hydride, diethylamine, thiols, and methanol, were carried out, which revealed that the introduction of nucleophiles to give regio-isomers is dependent on the nucleophile. The photo-induced oxidation reactions of 5·BF₄⁻ toward some alcohols under aerobic conditions were carried out to give the corresponding carbonyl compounds in more than 100% yield [based on compound 5·BF₄⁻], suggesting the oxidizing function of 5·BF₄⁻ toward alcohols in the autorecycling process. The UV-vis and fluorescence spectra of 5 were studied to suggest the electron transfer from alcohols to the excited 5.     

Synthesis of 2,5-dihydrobenzo[b]oxepines and 5,6-dihydro-2H-benzo[b]oxocines based on a ‘[3+3] cyclization-olefin-metathesis’ strategy

Functionalized 2,5-dihydrobenzo[b]oxepines and 5,6-dihydro-2H-benzo[b]oxocines were prepared based on a ‘[3+3] cyclization-olefin-metathesis’ strategy.     

A one-pot synthesis of 2,3-dihydro-1H-pyrrolo[3,2-c]quinolines

A one-pot synthesis of the 2,3-dihydro-1H-pyrrolo[3,2-c]quinoline core from substituted 2-iodoanilines and 2,3-dihydro-1H-pyrrole was achieved using 10 mol % Pd(PPh₃)₄, and K₂CO₃ in 1,4-dioxane at 170 °C for 1 h in a microwave oven. This reaction can be carried out on a gram scale. The proposed mechanism involves a Heck-coupling reaction followed by intra-molecular Schiff base formation and double bond migration.     

Formation of pyridin-4(1H)-one versus 1H-azepin-4(7H)-one by treatment of 4-tert-butyldimethylsilyloxy-2-amino-1-aza-bicyclo[4.1.0]hept-3-enes with tetrabutylammonium fluoride

Cycloadducts 3 and 4 were treated with tetrabutylammonium fluoride and rapidly suffer cleavage on the three-membered ring to form either pyridin-4(1H)-one or 1H-azepin-4(7H)-one. When R¹ is an oxycarbonyl or a 2-pyridyl group and R² is a negative charge-stabilizing group (cases 3a,b and 4f) the C-C bond cleaves forming products 5. However, when R²=H (case 3c) the ring expands to seven members. When R¹ is an acyl group the pyridin-4(1H)-one formation includes an unexpected shift of the carbonyl group.     

Synthesis of 2,5-dihydrobenzo[b]oxepins and 5,6-dihydro-2H-benzo[b]oxocines based on [3+3] cyclizations of 1,3-bis(silyl enol ethers)

Functionalized 2,5-dihydrobenzo[b]oxepins and 5,6-dihydro-2H-benzo[b]oxocines were prepared based on a ‘[3+3] cyclization-olefin-metathesis’ strategy.     

Synthese et etude de 5H-pyrido[4,3-b]-benzo[f]indoloquinones-6,11 apparentees aux ellipticines et aux anthracyclines

1-Chloro-5-methyl-5H-pyrido[4,3-b]benzo[f]indole-6,11-quinones, variously substituted on ring D, have been synthesised from 4-chloro-3-formyl-1-methylpyrrolo[3,2-c]pyridine and lithiated N,N-diethylbenzamides. These, with amines, formed the corresponding 1-alkylamino derivatives. In some cases the substitution was accompanied by the formation of polysubstituted by-products. It was found that the méthoxy groups of 7- and 10-methoxy-5-methyl-5H-pyrido[4,3-b]benz[f]indole-6,11-quinones are themselves substituted by amines; this accounts for the complexity of the reaction products formed on substitution of some chloro-intermediates mono- or poly-methoxylated on ring D.     

Highly efficient and regioselective allylic amination of allylic alcohols catalyzed by [Mo3PdS4] cluster

A highly efficient and regioselective allylation reaction of amines with allylic alcohols under mild conditions catalyzed by the cubane-type sulfido cluster [(Cp∗Mo)₃S₄Pd(dba)][PF₆] with H₃BO₃ as an additive has been developed. A variety of amines and allylic alcohols are investigated, and in the case of allylic alcohols bearing substituents at either α- or γ-position only linear allylic amination products are obtained.     

Pd/C mediated synthesis of 2-substituted benzo[b]furans/nitrobenzo[b]furans in water

An efficient synthesis of 2-alkyl/aryl substituted benzo[b]furans/nitrobenzo[b]furans in water has been accomplished via Pd/C catalyzed reaction of o-iodophenols with terminal alkynes in the presence of PPh₃, CuI and prolinol. This method can tolerate a variety of functional groups present in the alkynes as well as base labile nitro group in the o-iodophenols. The protocol does not require the use of a phase transfer catalyst or water-soluble phosphine ligands and is free from the use of any organic co-solvent.     

A new course of the Perkin cyclization of 2-(2-formyl-6-methoxyphenoxy)alkanoic acids. Synthesis of 2-alkyl-7-methoxy-5-nitrobenzo[b]furans

2-Alkyl-7-methoxy-5-nitrobenzo[b]furan, 2-alkyl-9-methoxy-7-nitro-3-oxo-2,3-dihydro-5H-benzo[e][1,4]-dioxepin-5-yl acetate and 2-alkyl-5-hydroxy-9-methoxy-7-nitro-5H-benzo[e][1,4]-dioxepin-3-one were formed as a result of the cyclization of 2-(2-formyl-6-methoxy-4-nitrophenoxy)alkanoic acids under classical Perkin reaction conditions. The products were characterized by spectroscopic methods and the mechanism of the cyclization is discussed.     

Structures and conformations of 1-aryl-1,4-dihydro-3(2H)-isoquinolinones

The X-ray crystal structures of series of 1-aryl-1,4-dihydro-3(2H)-isoquinolinones (1-7) have been determined. Lactame heterocyclic ring possesses more or less deformed boat conformation in all examined structures. The aryl substituent adopts the equatorial position in the structures 1-3 and the axial one in 5-7. In the structure of 4, due to extremely flattened heterocyclic ring, aryl substituent location can be named as bisectional. In all solved structures the molecules are joined into the dimers via two N-H?O hydrogen bonds. At the same time, ¹H NMR studies in DMSO-d₆ solutions were accomplished and profound analysis of ²J, ³J, and ⁵J coupling constants have shown that in isoquinolinone system the heterocyclic ring adopts the boat conformation in all investigated compounds. The stereochemical orientations of the phenyl ring at C1 do not depend on the nature of the substituent but, exclusively, on the mode of substitution. However, three forms of undulated laktam heterocyclic ring conformation in respect of 1-aryl substituent positions were confirmed by calculation (conformational analysis).     

Stereoselective synthesis of morphine fragments trans- and cis-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolines

A stereoselective synthesis of the ACNO partial structures of morphine has been developed. Palladium-catalyzed cyclization of carbamate 2 provided the tetracyclic (ACNO) 3-ethoxycarbonyl-9-methoxy-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (14); while treatment of 5-(2-bromo-6-methoxyphenoxy)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (8) under the same reaction condition gave 8a-(2-hydroxy-3-methoxyphenyl)-1,2,3,4,6,7,8,8a-octahydroisoquinoline (11) via an unusual Claisen rearrangement. 9-Methoxy-3-methyl-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (7) was successfully transformed to trans-octahydroisoquinoline 3 and cis-octahydroisoquinoline 4 via catalytical hydrogenation over PtO₂ and chemical reduction with acidic NaBH₄, respectively.     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.