Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.     

Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one via palladium-catalyzed intramolecular arylation

The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.     

Synthesis of 4b,5,10a,11-tetrahydroindeno[1,2-b]quinolin-10-ones from Baylis-Hillman adducts

We developed an efficient synthetic method for indenoquinoline skeletons from Baylis-Hillman adducts. 4b,5,10a,11-Tetrahydroindeno[1,2-b]quinolin-10-ones and 7H-indeno[2,1-c]quinolines were prepared from Baylis-Hillman adducts in polyphosphoric acid.     

Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction

Representatives of the 3H-imidazo[4,5-c]quinolin-4(5H)-ones have shown interesting biological activity. We have found 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-one as a potent dipeptidyl peptidase 4 inhibitor. However effective synthesis of this nucleus with various substituents at the 6-9-positions has not been reported. We report herein the development of a novel and efficient synthesis of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Our optimization of the reaction conditions revealed that the most important factors for this reaction are use of silver carbonate as a base and high reaction temperature.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.     

Application of N,3-diaryl-3-oxo-propanethioamide in synthesis: an efficient and mild domino approach to highly substituted fused chromenones

A convenient and rapid synthesis of hitherto unknown 3-aroyl-4-aryl-2-phenylamino-4H-benzo[g]chromene-5,10-diones in high yield from β-aroyl-thioacetanilide, aromatic aldehyde, and 2-hydroxy-1,4-naphthoquinone via InCl₃ catalyzed one-pot three-component tandem Knoevenagel condensation–Michael addition–intramolecular cyclization–elimination reaction sequence is disclosed for the first time. This domino protocol has been used to obtain highly substituted pyrano[3,2-c]chromen-5(4H)-ones and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-ones from N,3-diaryl-3-oxo-propanethioamide, aromatic aldehyde, and 4-hydroxycoumarine or dimedone under mild reaction conditions. A plausible reaction mechanism is proposed. The 4H-pyrano[3,2-c]chromen-5-one and 7,7-dimethyl-7,8-dihydro-4H-chromen-5(6H)-one derivatives possessing 3-(2-chlorobenzoyl)-2-phenylamino-substituents further cyclized under basic conditions to yield penta-cyclic 7,13-diaryl-5,14-dioxa-13-aza-benzo[a]naphthacen-6,8(7H,13H)-dione and tetra-cyclic 6,12-diaryl-3,3-dimethyl-3,4-dihydro-2H-chromeno[2,3-b]quinolin-1,11(6H,12H)-dione, respectively.     

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.     

Synthesis of furo[2,3-b]pyridin-4(7H)-ones and related quinolinone via Brønsted acid-promoted cyclisation of alkynes

N-Alkyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo acid-promoted 5-endo-heteroannulation to furopyridinium intermediates that are dealkylated in situ to provide the corresponding furo[2,3-b]pyridin-4(7H)-ones. The same strategy applies to the formation of furo[2,3-b]quinolin-4(9H)-ones. In the case of Me₃Si-substituted alkynes, hydration of the triple bond was observed.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

One-pot synthesis of 2-substituted furo[3,2-c]quinolines via tandem coupling-cyclization under Pd/C-copper catalysis

Pd/C-Cu catalyzed coupling reactions of 3-iodo-1H-quinolin-4-ones with a variety of terminal alkynes afforded furo[3,2-c]quinolines regioselectively in good to excellent yields. 3-Alkynyl quinolones were isolated under the same reaction conditions when the nitrogen of 3-iodo-1H-quinolin-4-one was substituted with an alkyl group.     

Skeletal Wagner-Meerwein rearrangement of perhydro-3a,6;4,5-diepoxyisoindoles

An investigation of a skeletal Wagner-Meerwein rearrangement of variously substituted or quinoline-annulated 3a,6;4,5-diepoxyisoindol-1-ones is reported. Optimum reaction conditions (Ac₂O, BF₃·OEt₂, rt) were discovered for the formation of the target 4,6-epoxycyclopenta[c]pyridines in 40-80% yields. It was shown that the direction of the sigmatropic rearrangement of 3a,6;4,5-diepoxyisoindol-1-ones depended dramatically on the carboxyl group position (exo-/endo-) in the oxabicyclo[2.2.1]heptane moiety. The spatial structure of previously unknown 7,9-epoxycyclopenta[4,5]pyrido[1,2-a]quinolines derived from Wagner-Meerwein rearrangement of 2,11b-epoxyoxireno[6,7]isoindolo[2,1-a]quinolines was established based on the X-ray analysis data. The skeletal rearrangement proceeded regio- and stereospecifically in all the cases examined due to the absence of the epimerization of the carbon atoms adjacent to the carbocation centres.     

A facile synthesis of the novel thiazolo[3,2-a]pyrimidine derivatives

2-Bromomethyl- and 2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones are prepared via the reaction of 3-allyl-2-thiouracil derivatives with bromine or iodine chloride, respectively. The 6-bromo and 6-nitro derivatives are synthesized by an electrophilic substitution at C-6 of the thiazolopyrimidine system. As a result, novel 2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one derivatives are obtained. Hydrogen halide elimination from the 2-halomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones is also reported.     

Synthesis and reactions of 2-[3-(trifluoromethyl)phenyl]furo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyridine

(E)-3-{5-[3-(Trifluoromethyl)phenyl]furan-2-yl}propenoic acid (I) was prepared from 5-[3-(tri-fluoromethyl)phenyl]furan-2-carbaldehyde under the Doebner’s conditions. The obtained acid was converted to the corresponding azide II, which was cyclized by heating in diphenyl ether to 2-[3-(trifluoromethyl)phenyl]-4,5-dihydrofuro[3,2-c]pyridin-4-one (III). This compound was aromatized with phosphorus oxychloride to chloroderivative IV which was reduced with H₂NNH₂-Pd/C to the title compound V. 2-[3-(Trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-oxide (VI) was synthesized by reaction of V with 3-chloroperoxybenzoic acid in dichloromethane. On treatment of VI with benzoyl chloride and potassium cyanide (Reissert-Henze reaction), corresponding 2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridine-1-carbonitrile (VII) resulted. 5-Amino-2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-ium-4-methylbenzene sulfonate (VIII) was prepared by direct N-amination of the title compound V with 1-[(aminooxy)sulfonyl]-4-methylbenzene in dichloromethane. Then, VIII was transformed to a non-isolated zwitterionic N-imid IX which afforded the corresponding furo[3,2-c]pyrazolo[1,5-a]pyridine carboxylic acid esters X, XI by 1,3-dipolar cycloaddition reactions with dimethyl but-2-ynedionate (DBD) or ethyl propiolate. The structures of all compounds were confirmed by their IR and NMR spectra. Presented at the 1st International Conference “Applied Natural Sciences” on the occasion of 10th anniversary of the University of St. Cyril and Methodius, Trnava, 7–9 November 2007.     

Reaction of 2-alkylthio-6-amino-pyrimidin-4(3H)-ones with ethyl bromopyruvate. Synthesis of furo-[2,3-<Emphasis Type="Italic">d</Emphasis>]-pyrimidine and furo[3,2-<Emphasis Type="Italic">e</Emphasis>]imidazo-[1,2-<Emphasis Type="Italic">c</Emphasis>]pyrimidine carboxylates

Reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones with ethyl bromopyruvate to give ethyl 2-alkyl-thio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates has been shown to proceed under neutral or acidic conditions. The obtained furo[2,3-d]pyrimidines underwent further cyclocondensation reaction with ethyl bromopyruvate to afford diethyl 5-alkylthiofuro[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxy-lates. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 440–443, March, 2009.     

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.     

Preparation of a set of 4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-ones as potential Hsp90 ligands

A synthetic route for the preparation of 4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-ones characterized by a decorated benzyl moiety at different positions of the five-membered ring has been developed, and some compounds have been tested as Hsp90 ligands. One of them displayed IC₅₀ = 50 μM representing an interesting starting point for further investigations.     

Synthesis and Reactions of 4-Oxiranylmethylfuro[3,2-b]pyrroles and Their Benzo Derivatives

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1-c][1,4]oxazin-8-ones 4a-e.     

Preparation of 2,4,5-trisubstituted pyrazolo[4,3-c]quinolin-3-ones

The preparation of pyrazolo[4,3-c]quinolinones is reported starting from 2-substituted-5-(2-fluorophenyl)-3-oxo-2,4-dihydro-3H-pyrazol-3-ones. A one-pot protocol, in which condensation with an orthoamide followed by substitution with a primary amine and subsequent S_NAr-cyclization to provide rapid access to 4- and 5-substituted pyrazolo[4,3-c]quinolinones was developed.     

Unexpected nitrilimine cycloaddition of thiazolo[3,2-a]pyrimidine derivatives

1,3-Dipolar cycloaddition of 2-arylidene-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-3(5H)-ones to diphenylnitrilimine (generated in situ by triethylamine dehydrohalogenation of the N′-phenylbenzohydrazonoyl chloride) proceeded regio- and site-selectively affording a mixture of two unexpected isomer products at reflux temperature. The cycloaddition/ring-opening/rearrangement/substitution, mechanism of the reaction was also discussed.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).