Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals

Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.     

Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

Synthesis of enantiopure furo[2,3-b]pyrroles

A simple method for the preparation of enantiopure furo[2,3-b]pyrroles, a rare class of concave bicyclic nitrogen and oxygen heterocycle, in promising yield has been developed. The 3-substituted pyrrolidinediones prepared from (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (Garcinia acid) have been cyclized diastereo as well as enantioselectively to furo[2,3-b]pyrroles. The cyclization follows Baldwin’s rule.     

Synthesis and conformational analysis of new naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives

A new highly functionalized aminonaphthol derivative, 1-(amino(2-aminophenyl)methyl)-2-naphthol (4), was synthesized by the reaction of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl carbamate or benzyl carbamate, followed by reduction and/or removal of the protecting group. The aminonaphthol derivative thus obtained was converted in ring-closure reactions with formaldehyde, benzaldehyde and/or phosgene to the corresponding naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives. The conformational analysis of some derivatives by NMR spectroscopy and accompanying molecular modelling are also reported.     

An unexpected synthesis of 7-azidofurazano[3,4-b]tetrazolopyrazine

In the course of our program focused on the preparation of high-nitrogen content heterocyclic compounds, we wish to report an original synthesis of the tricyclic 7-azidofurazano[3,4-b]tetrazolopyrazine via an unprecedented reaction between 2,6-dimethoxy-3,5-dinitropyrazine and hydrazine hydrate. This compound was identified by an X-ray diffraction analysis. Further studies of its structure by ¹⁵N and ¹³C NMR spectroscopy were carried out in different solvents. This allowed us to observe a noteworthy equilibrium involving three forms resulting from the reversible opening of a tetrazole ring.     

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.     

Conformational analysis of bridgehead-substituted bicyclo[m.m.m]alkanes and bicyclo[8.8.n]alkanes

Conformational analyses of bicyclo[m.m.m]alkanes where m=1-10 and of bicyclo[8.8.n]alkanes where n=1-7 bearing methyl groups on the bridgeheads were carried out using a Monte Carlo search strategy. In the bicyclo[m.m.m]alkane series, greater variability was observed for the inter-bridgehead distance for larger values of m. This suggests that properly substituted bicyclo[8.8.8]hexacosanes or larger ring systems might serve as molecular springs.     

Synthesis, characterization, and conformational analysis of new perfunctionalized calix[9]arenes

The synthesis of a series of six new per-substituted p-tert-butylcalix[9]arenes derivatives has been achieved. Functions such as ester, nitrile, or carbonate have been grafted on the phenolic oxygens of calix[9]arene: p-tert-butylcalix[9]arene nona-ethyl acetate, p-tert-butylcalix[9]arene nona-carboxylic acid, p-tert-butylcalix[9]arene nona-cyanopropyloxy, p-tert-butylcalix[9]arene nona-tert-butoxycarbonyle, p-tert-butylcalix[9]arene nona-acetyl, and p-tert-butylcalix[9]arene nona-trifluoroacetyl have been obtained in good yields (from 48% to 78%) and fully characterized. The X-ray structures of p-tert-butylcalix[9]arene nona-tert-butoxycarbonyl and p-tert-butylcalix[9]arene nona-ethyl acetate have been determined. A dynamic NMR study has revealed the high conformational mobility of such structures, even at low temperature.     

Synthesis and X-ray structures of new cycloalka[e]pyrano[2,3-b]pyridine derivatives: novel tacrine analogues

A new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) analogues consisting of a cycloalka[e]pyrano[2,3-b]pyridine linked to a quinolyl ring has been synthesized. These compounds were prepared from the appropriately substituted pyran derivative via a Friedländer reaction with selected cycloalkanones in high yields. Single crystal X-ray structures are reported for four compounds.     

Synthesis and conformational analysis of glycomimetic analogs of thiochitobiose

The synthesis of six analogs of N,N′-diacetylchitobiose is reported, including a novel transglycosylation reaction for the preparation of S-aryl thioglycosides. The conformations of the compounds were studied by a combination of NMR spectroscopy and molecular modeling, using force field calculations. In the case of the S-aryl thioglycosides with exclusively S-glycosidic linkages, dihedral angles of the disaccharidic S-glycosidic bonds, Φ′ and Ψ′ and of the S-arylglycoside bonds, Φ and Ψ, were found to be similar, whereas they were different in mixed glycosides and in a thiazoline derivative. An adequate correlation between the calculated H,H-distances of the local minima and the measured NOE contacts was achieved by applying population-weighted averages over participating conformers based on weighted relative energies.     

Synthesis and some transformations of new 9-furylnaphtho[2,3-b]furan derivatives

The synthesis of a number of naphtho[2,3-b]furan derivatives, containing a furyl substituent in position 9 by intramolecular cyclization of 2-carboxy and 2-formylbis(5-alkylfur-2-yl)methanes is described. The reactivity of the title compounds in formylation, acetylation, nitration, and oxidation reactions has been investigated. It was shown that nitration of 2-methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan-4-yl acetate leads to oxidative furan ring opening rather than to electrophilic substitution.     

Synthesis, NMR characterization and ion binding properties of 1,3-bridged p-tert-butyldihomooxacalix[4]crown-6 bearing pyridyl pendant groups

1,3-Di(2-pyridylmethoxy)-p-tert-butyldihomooxacalix[4]arene-crown-6 (2) was synthesized for the first time. 2 was isolated in a cone conformation in solution at room temperature, as established by NMR spectroscopy (¹H, ¹³C and NOESY). Complete assignment of both proton and carbon NMR spectra was achieved by a combination of COSY, HSQC and HMBC experiments. The binding properties of ligand 2 towards alkali, alkaline earth, transition and heavy metal cations have been assessed by phase transfer and proton NMR titration experiments. The results are compared to those obtained with other dihomooxacalix[4]arene-crowns-6 and closely-related calix[4]arene-crown derivatives. 2 shows a preference for the soft heavy metal cations (except for Cd²⁺), with a very strong affinity for Ag⁺. Some transition metal cations are also well extracted. 2 forms 1:1 complexes with K⁺, Ca²⁺ and Ag⁺, and ¹H NMR titrations indicate that they should be encapsulated into the cavity defined by the crown ether unit and by the two pyridyl pendant arms. A 1:2 (ML₂) complex is formed with Zn²⁺ and two species, probably 1:1 and 1:2 complexes, are obtained with Pb²⁺.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Optically transparent and thermally stable nonlinear optic chromophores featuring a thieno[2,3-b]thiophene donor

A thieno[2,3-b]thiophene core has been utilized as a π-donor component to design two series of push-pull thienothiophenes by introducing various acceptor groups either via olefinic or aza-spacers. The molecules show a UV-visible cut-off wavelength below the second harmonic generation (SHG) at λ/2 of 532 nm, thereby conforming to the nonlinearity-transparency trade-off. Second order molecular nonlinearity, β measured by Hyper-Rayleigh scattering technique was found in the range of 9.58-47.66×10⁻³⁰ esu, while the Kurtz powder technique produced signals of the order of 0.43-1.02 U. Thermal decomposition temperatures measured by differential scanning calorimetry revealed decomposition temperatures≥275 °C, indicating high thermal stability.     

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.     

Synthesis of new thieno[3,2-b]pyridine derivatives by palladium-catalyzed couplings and intramolecular cyclizations

Two methyl 3-aminothieno[3,2-b]pyridine-2-carboxylates were prepared from 3-fluoro or 3-nitropicolinonitriles and methyl thioglycolate in DMF/KOH(aq). From the unsubstituted precursor in the pyridine ring, di(hetero)arylamines were obtained by C-N Buchwald-Hartwig coupling with bromonitrobenzenes and with 2-bromopyridine. In the latter case a tetracyclic compound was formed by intramolecular cyclization. Using a brominated derivative in the pyridine ring as a coupling component, it was possible to synthesize C-C (Suzuki and Sonogashira) and C-N (Buchwald-Hartwig) coupling products and a tetracyclic compound obtained by bifunctionalization of the thienopyridine system.     

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.     

First construction of 12H-thiochromeno[2,3-b]quinolines and 5H-benzo[7,8]thiocino-[2,3-b]quinolines via intramolecular Friedel-Crafts reaction of Morita-Baylis-Hillman adducts

An acid-promoted intramolecular Friedel-Crafts reaction of the Morita-Baylis-Hillman adducts 3 derived from 2-arylthioquinolin-3-carbaldehydes 2 was investigated. Interestingly, promoted by sulfuric acid, the substrates with electron-donating groups on the aromatic ring gave six-membered fused-ring 12H-thiochromeno[2,3-b]quinolines 4 with good yields, while those with electron-withdrawing groups afforded eight-membered fused-ring 5H-benzo[7,8]thiocino[2,3-b]quinolines 5 in moderate yields. Using triflic acid instead of sulfuric acid, only products 4 could be obtained under the similar condition.     

Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations

The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one via palladium-mediated oxidative cyclisation of benzo[b]thien-2-oyl indole derivatives is also reported.