Regioselective Heteroannelation in 4-Cyanomethyl-3,5-pyridinedicarbonitriles. Synthesis of 6-Alkoxy-3-dialkylamino-1,8-diamino-2,7-naphthyridine-4-carbonitriles

 The title naphthyridines were found to be the sole products obtained after treatment of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles with alkoxides. The starting pyridine derivatives were prepared by amination of the readily available 2-amino-6-chloro-4-cyanomethyl-3,5-pyridinedicarbonitrile in quantitative yields.     

Synthesis of pyrrolo[2,3-c]2,7-naphthyridine derivatives by cascade heterocyclization reaction of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles

Alkylation of the title pyridinedicarbonitriles with N-substituted chloroacetamides was found to give 5,6-diamino-8-dialkylamino-2,3-dihydro-2-oxo-1H-pyrrolo[2,3-c]2,7-naphthyridine-9-carbonitriles. The structure of obtained compounds was unambiguously confirmed by X-ray crystallographic study. The heterocyclization reaction proceeded regioselectively involving 3-CN group of the starting pyridines without participation of 5-CN. The reasons of the selectivity were discussed. An interaction of prepared naphthyridine derivatives with acetic acid anhydride and cyclohexanone yielded 2-dialkylamino-6,8,9,10-tetrahydro-5-methyl-9-oxopyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-4,5,6,8,9,10-hexahydro-9-oxospiro{pyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles, respectively. All fused 2,7-naphthyridines obtained were derivatives of novel heterocyclic systems.     

An Easy Synthesis of Pyranopyrimidines

Summary.  The one-pot reaction of valerolactone with nitriles in the presence of triflic anhydride affords 2,4-disubstituted pyrano[2,3-d]pyrimidines. Subsequent addition of methyl thiocyanate leads to 2,4-bis(methylthio)pyranopyrimidines which can easily be converted into the corresponding methylsulfonyl derivatives. The reaction of these derivatives with different nucleophiles produces a variety of substituted pyranopyrimidines.     

Regioselective hydrodehalogenation of 3,5-dihaloisothiazole-4-carbonitriles: synthesis of 3-haloisothiazole-4-carbonitriles

3,5-Dibromoisothiazole-4-carbonitrile 1 treated with Zn or In dust (5 equiv) and HCO₂H undergoes regioselective hydrodebromination to give 3-bromoisothiazole-4-carbonitrile 3 in 70-74% yield. Similarly, 5-bromo and iodo 3-chloroisothiazole-4-carbonitriles 8 and 9 give 3-chloroisothiazole-4-carbonitrile 4 in 77 and 85% yields, respectively. Also hydrodeamination of 5-amino-3-chloroisothiazole-4-carbonitrile 7 using isoamyl nitrite gives the latter in 95% yield. The dibromoisothiazole 1 reacts with Zn dust in either DCO₂D or HCO₂D to give 3-bromo-5-deuterioisothiazole-4-carbonitrile 10 in 71 and 58% yields, respectively. The 3-bromoisothiazole 3 reacts with cyclic dialkylamines to give the corresponding 2-(dialkylaminomethylene)-malononitriles and not the expected 3-dialkylaminoisothiazole-4-carbonitriles. Finally, the 3-bromoisothiazole 3 is readily converted into both 3-bromoisothiazole-4-carboxamide 19 and the carboxylic acid 20. All products are fully characterized.     

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines as potential protein kinase inhibitors

Abstract  A short and efficient sequence for the synthesis of a series of 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines was developed. 1-Phenyl-2-(6-pyrimidinyl)-ethanones, obtained via Weinreb’s methodology, were used in a Hantzsch thiazole cyclization reaction, followed by introduction of the aniline moieties via nucleophilic substitution. Graphical abstract        

On the reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine with several amines in different experimental conditions: monosubstitution,disubstitution, and a new unexpected rearrangement

The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivatives of 5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted derivatives 2 were obtained, which under harsher conditions was transformed into the diamino derivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4. The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for the rearrangement is tentatively suggested.     

Thiochromenone-Annelated Heterocycles: Regioselective Synthesis of Furo[3,2-b]-thiochromen-9-ones

Summary.  A number of hitherto unreported furo[3,2-b]thiochromenone derivatives were regioselectively synthesized in good yields starting from 3-allyloxy-thiochromenones. Received September 18, 2000. Accepted (revised) November 15, 2000     

Regioselective Heterocyclization of 3-(Cyclohex-2′-enyl)-4-hydroxy-6-methylpyran-2-one

Summary.  Regioselective heterocyclization of 3-(cyclohex-2′-enyl)-4-hydroxy-6-methyl pyran-2-one with various reagents afforded different heterocycles. With N-iodosuccinimide in acetonitrile at 0–5°C it gave 6-methyl-9′-iodo-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one, with C₅H₅NHBr₃ or C₆H₁₂N₄HBr₃ in CHCl₃ at 0–5°C it furnished 6-methyl-9′-bromo-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one. Cold concentrated H₂SO₄ lead to 6-methyl-2′-oxabicyclo[3.3.1]nonano[3,2-c]pyran-2-one, whereas PdCl₂(PhCN)₂ in C₆H₆ at 80°C afforded 9-methyl benzofuro[3,2-c]pyran-2-one. Corresponding author. E-mail: kcm@klyuniv.ernet.in Received December 27, 2001. Accepted (revised) March 1, 2002     

Synthesis of 6-Alkoxy- and 1,6-Dialkoxy-4-amino-1-aryl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles

Russian Journal of Organic Chemistry - Base-catalyzed reaction of 3-aroyl-6-halopyridine-3,5-dicarbonitriles with alcohols involved successive regioselective pyrrole ring fusion at the pyridine [c]...     

Synthesis and Photochemistry of Novel 3,5-Diacetyl-1,4-dihydropyridines. II [1]

Summary. In continuation of previous work some novel 3,5-diacetyl-1,4-dihydropyridine derivatives were synthesized and their photochemical behavior was studied under oxygen and argon atmosphere. Oxidation of the dihydropyridine ring and formation of pyridine derivatives was the result of the reaction. The presence of oxygen affects not only on the rate of oxidation, but also the formation of some unidentified by-products was observed on irradiation under this atmosphere.     

Synthesis and antibacterial activity of new 5-substituted 1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

The 5-hydroxymethyl and the 5-formyl-1-cyclopropyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared via a 5-trimethylsilyl group and were tested in vitro as potential antibacterials.     

Synthesis of 2,3-Dihydrothiopyran-4-ones from 3-Oxo-1-pentene-4-ynes

Summary. 3-Oxo-1-pentene-4-ynes were converted with sodium sulfide or hydrogensulfide to give 2,6-disubstituted 2,3-dihydrothiopyran-4-one derivatives. The starting materials were prepared in two steps from terminal alkynes and α,β-unsaturated aldehydes.     

Application of Organolithium in Organic Synthesis: A Simple and Convenient Procedure for the Synthesis of More Complex 6-Substituted 3H-Quinazolin-4-ones

Summary. 6-Methyl-3H-quinazolin-4-one reacted with alkyllithium reagents at –78°C in THF to give 2-alkyl-1,2-dihydro-6-methyl-3H-quinazolin-4-ones in high yields. However, no reaction took place when LDA was used as the lithium reagent. 6-Bromo-3H-quinazolin-4-one reacted with excessive butyllithium to give 2-butyl-1,2-dihydro-3H-quinazolin-4-ones in very good yields. However, the lithiation of 6-bromo-3H-quinazolin-4-one was achieved by the use of a combination of methyllithium (1.1 equivalents) and tert-butyllithium (2.2 equivalents) at –78°C in THF. The dilithio reagent thus obtained reacted with a variety of electrophiles (H₂O, iodoethane, benzaldehyde, anisaldehyde, cyclohexanone, 2-hexanone, benzophenone, phenyl isothiocyanate, TITD) to give the corresponding 6-substituted 3H-quinazolin-4-ones in excellent yields. Reaction of the dilithio reagent with 1,3-dibromopropane gave 6,6-(propanediyl)bis(3H-quinazolin-4-one).Present address: Centre for Clean Chemistry, Department of Chemistry, University of Wales Swansea, Swansea SA2 8PP, UK     

Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity

A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiproliferative activities to establish structure–activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional thermal method. This was followed by chlorination for compounds 13a–e and subsequent nucleophilic substitution of the chlorine group by ethylenediamine at C₂ position of the pyridine ring. The antiproliferative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all compounds, 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity on the three cancer cell lines with IC₅₀ values of 4.1–13.4 μM.     

Synthesis of Pyrimidine-Annelated Heterocycles: Regioselective Heterocyclization of 5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil [1]

Summary.  5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil undergoes regioselective heterocyclization to afford fused tricyclic heterocycles upon treatment with bromine and m-CPBA. However, the same substrate furnished bridged tricyclic heterocycles when treated with N-iodosuccinimide and conc. H₂SO₄ and a mixture of bridged tricyclic heterocycles and fused tricyclic heterocycles when treated with hexamine hydrotribromide or pyridine hydrotribromide. Corresponding author. E-mail: kcm@klyuniv.ernet.in Received September 27, 2001. Accepted (revised) December 3, 2001     

3-烷氧基-6-（4-甲氧羰基苯基）哒嗪的合成及介晶性研究

3，6-二氯哒嗪和醇在相转移催化剂(C_4H_9)_4NBr和浓碱作用下，合成3-氯- 6-烷氧基哒嗪，在三苯基膦钯的催化下，用3-氯-6-烷氧基哒嗪与对甲氧羰基苯基 硼酸偶联，并以较好产率合成了八种中心桥连基为哒嗪环，含有苯环、酯基、不同 长度烷氧基的哒嗪衍生物，并通过差示扫描量热法（DSC）对其介晶性进行了表征 ，同时发现其中七种都具有介晶性。研究表明，末端链长度对相变温度和清亮点温 度均有影响。     

1-(Cyanoacetyl)-3,5-dimethylpyrazole as Active Methylene Compound in Hantzsch-type Pyridine Synthesis: A Convenient and Highly Effective Approach to 3,5-Dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates

Summary. Reaction of 1-(cyanoacetyl)-3,5-dimethylpyrazole with (E)-2-cyano-3-(het)arylprop-2-enethioamides was used for the synthesis of N-methylmorpholinium 3,5-dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates for the first time. The latter were also obtained in a multicomponent one-pot mode via the condensation of cyanothioacetamide with corresponding aldehydes and above 1-cyanoacetylpyrazole in the presence of N-methylmorpholine under mild conditions. Thiolates 1 exist as a pair of cis/trans-diastereomers in different ratios (from 3:4 to 2:1). Last author was Deceased on February 26, 2007     

The Reaction of Cyclic Nitroenamines with Isocyanates. Synthesis of 1,6-Polymethylene-6-nitromethyl-1,3,5-triazine-2,4-dione Derivatives

Summary. The reactions of cyclic nitroenamines with isocyanates were investigated. It was found that two different products could be obtained: in inert media -carbamoyl products were observed and when a strong base was used 1,6-polymethylene-6-nitromethyl-1,3,5-triazine-2,4-dione derivatives were isolated.     

An Efficient and Practical Method for the Synthesis of 1-(2,6-Difluorobenzoyl)-3-(2-alkyl-3-oxopyridazin-4-yl)ureas as Potential Chitin Synthesis Inhibitors

Summary. A mild and efficient method for the synthesis of 4-amino-3(2H)-pyridazinones from their corresponding 4,5-dichloropyridazinones under microwave-assisted conditions is described. A series of novel chitin synthesis inhibitors, benzoylphenylureas containing the 3(2H)-pyridazinone, were synthesized. The biological activity of these target compounds was evaluated.     

Synthesis of Pyrimidine Annelated Heterocycles [1]. Regioselective Heterocyclization of 6-Cyclopent-2-enyl-5-hydroxy-1,3-dimethyl-pyrimidine-2,4( 1H, 3H)-dione and 5-Cyclopent-2-enyl-6-hydroxy-1,3-dimethylpyrimidine-2,4( 1H, 3H)-dione

Summary. Two hitherto unreported pyrimidine annelated heterocycles were synthesized from 6-cyclopent-2-enyl-5-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and 5-cyclopent-2-enyl-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione by reaction with pyridine hydrotribromide or hexamethylenetetramine hydrotribromide. The first one was also obtained by reaction with concentrated sulfuric acid.Received October 28, 2002; accepted October 30, 2002 Published online June 2, 2003