Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence

A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-S_NAr reaction sequence, affords 50–86% yields when R¹ is n-alkyl but ≤30% yields when R¹ is α-branched.     

An efficient, greener, and solvent-free one-pot multicomponent synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones

Herein, we report an efficient, greener, and solvent-free novel method for the synthesis of 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones in a one-pot sequence using methyl anthranilate or 2-aminothiophene-3-carboxylate with N,N′-dimethyl formamide dimethyl acetal and various anilines. The driving force for this reaction is the removal of N,N′-dimethylamine by various anilines resulting in 3-substituted quinazolin-4(3H)ones and thienopyrimidin-4(3H)ones.     

2-Cyanopyridazin-3(2H)-ones: effective and chemoselective electrophilic cyanating agents

2-Cyanopyridazin-3(2H)-ones are novel, effective, selective and electrophilic cyanating agents. A variety of amino, thiol and carbon nucleophiles are chemoselectively N-, S- or C-cyanated in excellent yield using 2-cyanopyridanzin-3(2H)-ones in water or tetrahydrofuran.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

Efficient N-arylation of pyridazin-3(2H)-ones

A variety of substituted pyridazin-3(2H)-ones are directly N-arylated in good yield using lead tetraacetate/zinc chloride in benzene or in substituted benzenes including chloro- and bromobenzene.     

Base promoted facile route to functionalized benzo[b][1,8]naphthyridin-2-(1H)-ones from N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides

A facile synthesis of 4-amino-N-benzylbenzo[b][1,8]naphthyridin-2(1H)-ones 3 is described from N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides 2 with t-BuOK in excellent yields in mild conditions. These reactions proceeded at room temperature under aerobic atmosphere in very short period. The cyclization reactions were also extended with N-alkyl amino acetamide analogues affording the products in good yields.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

A new approach to the synthesis of 4-(N-aryl)carbamoylmethyl-4,5-dihydropyridazin-3(2H)-ones

Reaction of N-aryl substituted maleimides with aliphatic ketazines leads to the formation of 4,5-dihydropyridazin-3(2H)-ones in moderate yields. The reaction proceeds through 1,4-addition of an azine to the maleimide double bond, as confirmed by separation of the corresponding adducts in some cases, which are then converted into 4,5-dihydropyridazin-3(2H)-ones. In addition, the solid-state synthesis of 4,5-dihydropyridazin-3(2H)-ones is demonstrated for the first time.     

Investigation towards an efficient synthesis of benzo[g]isoquinoline-1,5,10(2H)-triones

As part of our research on 2-aza analogues of pentalongin, the active principle of Pentas longiflora Oliv., the first synthesis of 2,3-disubstituted benzo[g]isoquinoline-1,5,10(2H)-triones via 3,4-disubstituted 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones as the key intermediates is reported. The latter compounds have been prepared by treating 2-methoxycarbonyl-1,4-naphthoquinone with N-substituted enaminoesters under acidic conditions. These reagents are easily accessible from readily available 1,4-dihydroxy-2-naphthoic acid, β-ketoesters and primary amines. Finally, a short synthesis of substituted benzo[g]isoquinoline-1,5,10(2H)-triones is achieved by an oxidative addition of N-substituted enaminoesters onto methyl 1,4-dihydroxynaphthalene-2-carboxylate.     

Synthesis of 1H-pyrrolo[3,2-c]quinoline derivatives via palladium-catalyzed heteroannulation of 2-aryl-3-iodo-4-(phenylamino)quinolines and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinolines

Palladium(0)/copper iodide catalyzed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinolines with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single-step operation. Conversely, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo PdCl₂(PPh₃)₂/CuI catalyzed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines.     

Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.     

Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2-vinyl-1H-pyrroles

The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to 2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied. Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole derivative.     

An efficient HCCP-mediated direct amination of quinazolin-4(3H)-ones

An efficient direct amination of quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, DIPEA, and N-contained nucleophiles in acetonitrile could be able to form the corresponding 4-aminoquinazoline derivatives. Under the optimal reaction conditions, the amination products were achieved in good yields.     

Superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids: synthesis of quinolin-2(1H)-one derivatives

The superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids by Bronsted superacids (CF₃SO₃H, HSO₃F) or strong Lewis acids AlX₃ (X=Cl, Br) results in the formation of 4-aryl quinolin-2(1H)-ones in quantitative yields. The vinyl triflates or vinyl chlorides may be formed as additional reaction products. The investigated amides in reactions with benzene give 4,4-diaryl 3,4-dihydroquinolin-2-(1H)-ones under the superelectrophilic activation. 4-Aryl quinolin-2(1H)-ones in POCl₃ are converted into 4-aryl 2-chloroquinolines. 4-Fluorophenyl-4-phenyl 3,4-dihydroquinolin-2-(1H)-one give N-formylation products in a yield of 79% under the Vilsmeier–Haack reaction conditions.     

Design and synthesis of 2(1H)-pyrazinones as inhibitors of protein kinases

Kinase enzymes play a key role in the development and progression of cancer. Inhibitors of deregulated kinases are effective small molecule anticancer drugs. The 2(1H)-pyrazinone heterocycle is a previously unexploited motif that can fulfil the structural requirements for ATP-competitive inhibition of kinases. Rapid solution-phase syntheses of novel 3,5- and 3,6-disubstituted-2(1H)-pyrazinones were developed through selective, sequential substitution of 2,5-dihalo-3-benzyloxypyrazine and 3,5-dihalo-2(1H)-pyrazinone intermediates. Palladium-catalysed cross-couplings and S_NAr reactions were used to introduce substituents chosen on the basis of the calculated physicochemical properties of the target pyrazinones. Representative compounds demonstrated good solubility, kinase inhibitory activity and antiproliferative activity in human tumour cells, confirming the suitability of this chemical class as a kinase-focused library.     

Chemoselective synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives from 3-phenacylideneoxindoles and substituted tosylmethyl isocyanide (TosMIC)

A simple and convenient synthetic approach to access of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives by the reaction of (Z)-3-(2-oxo-2-ethylidene)indolin-2-one derivatives 1 with functionalized TosMICs under basic conditions has been reported. The desired products were obtained in good to excellent yields (82–94%). The easy accessibility of the starting materials, simple and mild reaction conditions, short reaction time, and good to excellent chemical yields make this methodology highly efficient.     

An efficient catalytic method for the synthesis of 2,7-dialkyl-2,3a,5a,7,8a,10a-hexaazaperhydropyrenes

An efficient method for the synthesis of 2,7-dialkyl-2,3a,5a,7,8a,10a-hexaazaperhydropyrenes in high yields (up to 95%) via the intermolecular cyclization of 1,4,5,8-tetraazadecalin with N,N-bis(methoxymethyl)-N-alkylamines in the presence of SmCl₃·6H₂O as the catalyst has been developed.     

A new approach to fluorinated 4(3H)-quinazolinones

A new approach for the synthesis of fluorinated 1H-quinazolin-4-ones and 4-substituted quinazolines has been developed. 6-Fluoro-1H-quinazolin-4-ones were obtained by intramolecular cyclization of fluorine-containing S-ethyl N-benzoylisothioureas. Nucleophilic substitution reactions at positions 2 and 7, as well as alkylation at 1-position of quinazolinones were investigated. In addition, the synthesis of fluorine-containing 4-aminoquinazolines was carried out.     

Synthesis of zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives

Zwitterionic 4-hydroxy-2(1H)-quinolinone derivatives were synthesized through a unique reaction of 4-hydroxy-2(1H)-quinolinone with p-benzoquinone and N-heterocyclic aromatics. The zwitterions possessed astropisomeric nature. A possible mechanism of the reaction was presented.