A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

Synthesis and X-ray crystal structure of pyrrolo[1,2-a]benzimidazoles

Reaction of nitrilimines 1 with 2-cyanomethylbenzimidazole 2 gave the 3-arylazo-2-methylpyrrolo[1,2-a]benzimidazole 4a rather than the reported 2-arylazo-3-methylpyrrolo[1,2-a]benzimidazole 3a. The correct structure of the product was determined using X-ray crystal structure analysis. The similar reaction of nitrilimines with 2-aminobenzimidazole 5 gave the acyclic nucleophilic addition product 6.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

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.     

Dioxamethylene intramolecular bridging of p-tert-butylcalix[8]arene

The first examples of dioxamethylene bridged calix[8]arenes 2-6 have been obtained by Cs₂CO₃-promoted direct O-alkylation of p-tert-butylcalix[8]arene with BrCH₂Cl. Assignment of the 1,2-, 1,2:3,4-, 1,2:3,4:6,7-, 1,4:2,3:5,6:7,8-, and 1,2:3,4:5,6:7,8-bridging pattern of 2-6, respectively, was mainly based on chemical shift of OH groups and chemical correlations. Dynamic ¹H NMR studies and MM3 calculations indicated that in these compounds the dioxocine subunit adopts a boat-chair conformation.     

A simple approach for the regioselective synthesis of imidazo[1,2-a]pyrimidiones and pyrimido[1,2-a]pyrimidinones

Several imidazo and pyrimido[1,2-a]pyrimidinones of type 1 and 2 were synthesized through intramolecular cyclization of pyrimidines 9 or pyrimidinones 10 bearing a variety of β and γ-aminoalcohols at the 2-position. Ring closure of the pyrimidinones of type 10 under Mitsunobu conditions lead to mixtures of both bicyclic regioisomers 1 and 2. Treatment of pyrimidines of type 9 with H₂SO₄ provided an efficient and operationally simple one-pot hydrolysis-cyclization procedure for obtaining imidazo and pyrimido[1,2-a]pyrimidinones 1 in good yields as the sole regioisomeric bicyclic product.     

Synthesis and structures of dialkyl zirconium complexes with an [OSSO]-type bis(phenolate) ligand bearing a trans-1,2-cyclooctanediylbis(thio) unit

Dimethyl and bis[(trimethylsilyl)methyl] zirconium complexes ([OSSO]ZrR₂) [4, R = Me; 5, R = CH₂SiMe₃] having [OSSO]-type bis(phenolato) ligand 1 based on the trans-1,2-cyclooctanediylbis(thio) core have been synthesized by the reactions of the corresponding dichloro zirconium complex 3 with 2 equiv. of MeMgBr and Me₃SiCH₂MgCl, respectively, in Et₂O/toluene at −78 °C. The molecular structures of these complexes 3-5 were characterized by NMR spectroscopy, elemental analyses, and X-ray crystallography. ¹H and ¹³C NMR data of complexes 3-5 exhibited that they took the C₂-symmetry in solution in the NMR time scale. In the crystal structures of 3-5, each zirconium center lies at the center of a distorted octahedral coordination sphere with cis sulfur atoms and trans oxygen atoms, which adopts a cis-α [(Λ^∗,S^∗,S^∗)] configuration.     

Synthesis and self-assembly of novel calix[4]arenocrowns: formation of calix[4]areno[2]catenanes

A series of novel calix[4]arenocrowns 1a-c were efficiently synthesized by a one-pot reaction of calix[4]monohydroquinone diacetate 5 with ditosylate 6 and its analogues in the presence of sodium hydroxide. It was found that the calix[4]arenocrowns could form stable pseudorotaxane-type complexes 2a-c with paraquat, and further self-assemble into calix[4]areno[2]catenanes 3a-c with dicationic salt 8 and p-bis(bromomethyl)benzene.     

A convenient synthesis of linear pyridinoimidazo[1,2-a]pyridine and pyrroloimidazo[1,2-a]pyridine cores

Two new imidazo[1,2-a]pyridine derivatives, pyridinoimidazo[1,2-a]pyridine (10) and pyrroloimidazo[1,2-a]pyridine (16), were synthesised from 2-amino-4-methyl-5-nitropyridine (1) by linear cyclisation, making use of dimethylformamide dimethylacetal (DMFDMA) as an agent of vinylamine functionalisation. This report describes first the formation of pyridine and pyrroloimidazopyridine from (1), and then the formation of pyridine-fused and pyrrolo-fused pyridine by the Friedländer method and reductive cyclisation followed by treatment of the resulting adduct with chloroacetaldehyde.     

Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.     

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.     

Diacenaphtho[1,2-c:1,2-e]-1,2-dithiin: synthesis, structure and reactivity

Diacenaphtho[1,2-c:1^′,2^′-e]-1,2-dithiin 2 was synthesized in 23% yield by the reaction of acenaphthylene with elemental sulfur at 120 °C. This reaction also afforded either diacenaphtho[1,2-b:1^′,2^′-d]thiophene 1 or diacenaphtho[1,2-b:1^′,2^′-e]-dihydro[e]-1,4-dithiin 3 depending on the reaction time. Compound 2 was desulfurized and converted to 1 under UV-vis irradiation in a benzene solution. Reaction of 2 with Pt(COD)₂ yielded the complex Pt(COD)(C₂₄H₁₂S₂) 4 (COD=1,5-cyclooctadiene) by insertion of a Pt(COD) group into the S-S bond of 2. When heated, 4 was desulfurized and converted to 1 by elimination of a (COD)PtS grouping. Compounds 1-4 were characterized crystallographically.     

Regioselective double intramolecular bridging of p-tert-butylcalix[7]arene

The first examples of doubly bridged calix[7]arenes 2a-h have been obtained by base-promoted O-alkylation of p-tert-butylcalix[7]arene 1 or 1,4-tetramethylene-bridged calix[7]arene 3a with a variety of bis-electrophiles including BrCH₂Cl, oligoethylene glycol ditosylates, and 1,2-bis(bromomethyl)benzene. In the presence of Cs₂CO₃ as the base, in acetone, the syn-1,4:2,3-bis-bridged regioisomer was obtained in yields up to 76%. Assignment of bridging pattern was based on chemical shift of OH groups in conjunction with chemical correlations with known compounds. Stereochemical and conformational features were investigated with the aid of 2D and Dynamic NMR studies and MM3 calculations.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

Azobenzene-bridged calix[8]arenes

An azobenzene bridge was introduced into the lower (or smaller) rim of p-tert-butylcalix[8]arene (1) and 1,5-calix[8]crown-3 (2) to form 1,4-singly bridged (3) and 1,5:3,7-doubly bridged (4) calix[8]arene derivatives, respectively. Trans and cis isomers of conformationally rigid 4 were isolated. The quantum yields of the trans-cis photoisomerisation reactions have been measured.     

Synthesis of dihydrobenzoimidazo[2,1-a]isoquinolines

A one-pot protocol toward several substituted 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines 1 starting with 2-allylbenzaldehydes 2 was described. The process was carried out the one-pot condensation/hydroamination reaction of substituted 2-allylbenzaldehydes 2 with 1,2-diaminobenzenes 3 in refluxing toluene in good yields. Skeleton 2 was prepared via one-pot ortho-metalative PhBCl₂-mediated double alkylation of hydroxybenzaldehyde 4 with LDA in moderate yields.     

[1,2]-Wittig rearrangement from chloromethyl ethers

The reaction of different chloromethyl ethers 1 with an excess of lithium powder and a catalytic amount of 4,4′-di-tert-butylbiphenyl (2.5 mol %) in THF at 0 °C leads to the corresponding α-lithiomethyl ether intermediates, through a chlorine-lithium exchange, which spontaneously undergo a clean [1,2]-Wittig rearrangement affording the expected homobenzylic alcohols 2. This is the first version of this rearrangement starting from easily available chloromethyl ethers.     

Intramolecular rearrangement of 1,3-bistriflate ester of thiacalix[4]arene to 1,2-counterpart: an efficient di-O-protection method for the stereoselective synthesis of anti-1,2-diethers

A net anti-selective dialkylation of the proximal hydroxy groups of thiacalix[4]arene 2 is achieved for the first time via the initial protection of the two proximal hydroxy groups of compound 2 with Tf moieties by intramolecular rearrangement of easily preparable 1,3-bistriflate ester 3 to 1,2-counterpart 4, followed by anti-selective dialkylation of the remaining hydroxy groups with alkyl halides or under the Mitsunobu conditions and subsequent removal of the Tf moieties.     

An efficient and facile synthesis of substituted cinnoline and benzo[h]cinnoline derivatives

New substituted 3-amino-5,7,8-trihalo-6-hydroxycinnoline-4-carbonitriles 7 and 8 and the 3-amino-5-chloro-6-hydroxy-benzo[h]cinnoline-4-carbonitrile 9 were synthesized in two-steps starting from tetrahalo-1,4-benzoquinones or dichloro-1,4-naphthoquinones, malononitrile and hydrazine.