Synthesis of 2,4‐diaminothieno‐ and pyrrolo[2,3‐d]pyrimidine‐6‐carboxylic acid derivatives

A series of new 2,4‐diaminothieno[2,3‐d]‐ and 2,4‐diaminopyrrolo[2,3‐d]pyrimidine derivatives were synthesised. Reaction of 2‐amino‐4,6‐dichloropyrimidine‐5‐carbaldehyde ( 1 ) with ethyl mercaptoacetate, methyl N‐methylglycinate or ethyl glycinate afforded ethyl (2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)thioacetate ( 2a ), methyl N‐(2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)‐N‐methylglycinate ( 2b ) and ethyl N‐(2‐amino‐4‐chloro‐5‐formylpyrimidin‐6‐yl)glycinate ( 2c ), respectively. Compounds 2a,b by treatment with bases cyclised to the corresponding 2‐amino‐4‐chlorothieno‐ and pyrrolo[2,3‐d]pyrimidine‐6‐carboxylates ( 3a,b ). Heating 2,4‐diamino‐6‐chloropyrimidine‐5‐carbaldehyde ( 5 ) with ethyl mercaptoacetate or methyl N‐methylglycinate gave 2,4‐diaminothieno[2,3‐d]‐ and 2,4‐diaminopyrrolo[2,3‐d]‐pyrimidine‐6‐carboxylates ( 6a,b ), whereas compound 5 with ethyl glycinate under the same reaction conditions afforded ethyl N‐(2,4‐diamino‐5‐formylpyrimidin‐6‐yl)glycinate ( 7 ). Treatment of 2,4‐diaminothieno[2,3‐d]pyrimidine‐6‐carboxylic acid ( 8a ) with 4‐methoxy‐, 3,4,5‐trimethoxyanilines or ethyl N‐(4‐aminobenzoyl)‐L‐glutamate in the presence of dicyclohexylcarbodiimide and 1‐hydroxybenzotriazole furnished the corresponding N‐arylamides 9‐11.     

Synthesis of 2‐imino‐7‐methyl‐2,3‐dihydroimidazo[1,2‐a]‐pyrimidin‐5(1H)‐ones and their reactions with nucleophiles

[2‐Alkylthio‐6‐methyl‐4‐oxopyrimidin‐3(4H)‐yl]acetonitriles ( 3‐5 ) treated with sodium methoxide in methanol followed by ammonium chloride were cyclized to 2‐imino‐7‐methyl‐2,3‐dihydroimidazo[1,2‐a]‐pyrimidin‐5(1H)‐ones ( 6‐8 ). Under acid or base‐catalyzed hydrolysis they were converted to 7‐methyl‐imidazo[1,2‐a]pyrimidine‐2,5‐[1H,3H]‐diones ( 9‐11 ), whereas in the reaction with butyl‐ or benzylamine the corresponding 7‐methyl‐2‐(substitutedamino)imidazo[1,2‐a]pyrimidin‐5(3H)‐ones ( 13‐18 ) were produced. The latter were found to exist in two tautomeric forms in CDCl₃ solution.     

Synthetic studies connected with the preparation of h+/k+‐ATPase inhibitors rabeprazole and lansoprazole

Synthesis of lansoprazole and rabeprazole using common intermediates is devised. The common intermediates, 2‐[(4‐nitro‐3‐methylpyridin‐2‐yl)methanesulfanyl]‐1H‐benzoimidazole and 2‐[(4‐chloro‐3‐methyl‐pyridin‐2‐yl)methanesulfanyl]‐1H‐benzoimidazole, were prepared in several ways.     

Synthesis of 5‐Hydroxy‐2‐(naphth‐2‐yl)chromone derivatives

The Diels‐Alder reaction of 5‐hydroxy‐2‐styrylchromones with ortho‐benzoquinodimethane, generated “in situ” by thermal extrusion of sulfur dioxide from 1,3‐dihydrobenzo[c]thiophene 2,2‐dioxide, leads to 2‐(3‐aryl‐1,2,3,4‐tetrahydronaphth‐2‐yl)‐5‐hydroxychromones. These cycloadducts were dehydrogenated with DDQ, using classical thermal reflux conditions and microwave irradiation, affording the corresponding 2‐(3‐arylnaphth‐2‐yl)‐5‐hydroxychromones in high yields (48‐96%).     

Unusual structures derived from N‐acridin‐9‐yl methyl N′‐acridin‐9‐yl thiourea based on the propensity of N‐10 to retain H

N‐Acridin‐9‐yl methyl N′‐acridin‐9‐yl thiourea spontaneously spiro cyclises via nucleophilic attack of the methylene carbon onto the C‐9 of the other acridine moiety. The thiourea, upon reaction with bromoacetonitrile, provided a spiro fused‐bicyclic product displaying unusual dynamic behavior.     

The synthesis and fluorescence of novel N‐substituted‐1,8‐naphthylimides

The synthesis and characterisation of a series of novel 4‐acylamino and 4‐alkylamino‐N‐1,8‐naphthalimides is described. The UV‐visible absorption and emission properties of the compounds are reported. Significant solvent effects are noted for 4‐n‐butyl‐9‐n‐butyl‐1,8‐naphthylimide. The incorporation of acetyl and chloroacetyl groups into the 4‐substituent markedly increases the fluorescence quantum yield compared with 4‐alkylamino substituemnts.     

Aromatization and ring cyclization: A reasonable understanding on the ring cyclization mechanism of 3‐amino‐6‐hydrazino‐1,2,4‐triazin‐5(2H)‐one reacted with one‐carbon fragment reagents or nitrous acid

The cyclization mechanism for the title compound ( 2 ) reacting with one‐carbon fragment reagents or nitrous acid to afford heterobicyclic compounds 6‐amino‐3‐substituted‐1,2,4‐triazolo[3,4‐f][1,2,4]triazin‐8(7H)‐ones ( 3a～d ) or 6‐amino‐1,2,3,4‐tetrazolo[5,1‐f][1,2,4]triazin‐8(7H)‐one ( 4 ), respectively, is explored in this paper. When 3‐amino‐2‐benzyl‐6‐hydrazino‐1,2,4‐triazin‐5(2H)‐one ( 10 ), the N‐2 benzylated derivative of 2 , is treated under the same conditions, ring cyclization does not occur; instead, 3‐amino‐2‐benzyl‐6‐substituted‐1,2,4‐triazin‐5(2H)‐ones ( 11,12,14 ) and 2‐N‐(2‐amino‐1‐benzyl‐4‐oxo‐1,2,4‐triazin‐5‐yl)semicarbazide ( 13 ) are formed. Alternatively, when 3‐amino‐6‐hydrazino‐2‐[(2‐hydroxyethoxy)methyl]‐1,2,4‐triazin‐5(2H)‐one ( 16 ), a compound bearing the 2‐[(2‐hydroxyethoxy)methyl] side‐chain at N‐2 of 2 by an N? C? O bond, reacts with glacial acetic acid or nitrous acid, the side‐chain is cleaved through acidolysis to affford the ring‐closed compound 6‐amino‐3‐methyl‐1,2,4‐triazolo[3,4‐f][1,2,4]triazin‐8(7H)‐one ( 3b ) or compound 4 , respectively. From these results, we suggest a cyclization mechanism that the ring cyclization is dependent on the aromatization of the 1,2,4‐triazine ring, which influence the reactivity and reaction behavior of the π‐deficient 1,2,4‐triazine.     

Reactions of methyl 2‐(benzyloxycarbonyl)amino‐3‐dimethylaminopropenoate and related compounds with hydrazines. Regiospecific synthesis of 1‐substituted‐4‐amino‐substituted‐1H‐pyrazol‐5‐(2H)‐ones

In this paper the regiospecific transformations of methyl 2‐(benzyloxycarbonyl)amino‐3‐dimethylaminopropenoate ( 1 ) with hydrazine, alkyl‐, aryl‐ and heteroaryl‐substituted hydrazines via the corresponding hydrazones 12‐16 into pyrazoles 17‐25 are described. Heteroaryl‐substitued hydrazones 13‐16 afforded by oxidation with bromine or lead tetraacetate the corresponding substituted (1,2,4‐triazolo[4,3‐b]pyridazin‐3‐yl)glycinates 27‐30 . Alkyl 2‐(2,2‐disubstituted‐1‐ethenyl)amino‐3‐dimethylaminopropenoates 31‐33 gave with hydrazines alkyl 2‐[2,2‐(disubstituted)ethenyl]amino‐3‐heteroarylhydrazonopropanoates 40‐48 and 2‐alkyl 2,3‐bis((hetero)arylhydrazono)propanoates 51‐55 .     

The Regio‐ and Stereoselective Synthesis of trans‐2,3‐Dihydropyridine N‐oxides and Piperidines

Reactivity N? Own : Pyridine N‐oxides can be used for the complete regio‐ and stereoselective synthesis of trans‐substituted piperidines. The sequential addition of Grignard reagents and aldehydes or ketones to pyridine N‐oxides yields a complete regio‐ and stereoselective trans 2,3‐addition reaction in high yields, and the substituted 2,3‐dihydropyridine N‐oxide can be reduced to form 2,3‐trans‐substituted piperidines (see scheme).

     

Design,synthesis and biological evaluation of novel 6,7,8,9‐tetrahydro‐2‐(2‐aryloxypyrimidin‐4‐yl)‐2H‐[1,2,4]triazolo[4,3‐a]azepin‐3(5H)‐ones

A series of novel 6,7,8,9‐tetrahydro‐2‐(2‐aryloxypyrimidin‐4‐yl)‐2H‐[1,2,4]triazolo[4,3‐a]azepin‐3(5H)‐ones were designed and efficiently synthesized. Their structures were determined by IR, ¹³C and ¹H NMR, mass spectroscopy, and elemental analysis. These compounds were screened for herbicidal activities against rape and barnyard grass. Compounds 5a‐5f and 5m exhibited moderate herbicidal activity against rape. In addition, the synthesis of the intermediate 1‐(azepan‐2‐ylidene)‐2‐(2‐chloropyrimidin‐4‐yl)‐hydrazine ( 3 ) was studied and the reason for the low yield in the initial procedure is discussed as well.     

Synthesis and reactions of n‐methyl‐4‐(methylthio)thieno[2,3‐d]‐pyrimidinium salts

Two methods for the preparation of N‐methyl‐4‐(methylthio)thieno[2,3‐d]pyrimidinium salts 6a,b and 13a,b are described. Treatment of 6a,b and/or 13a,b with active methylene compounds such as malononitrile and ethyl cyanoacetate in the presence of sodium methoxide caused nucleophilic addition followed by elimination of methanethiol, giving the corresponding N‐methyl‐4‐ylidenethieno[2,3‐d]‐pyrimidines 7a,b, 8a,b, 14a,b and 15a,b .     

Nitropyridyl isocyanates in 1,3‐dipolar cycloaddition reactions

The reactivity of 3‐nitro‐4‐pyridyl isocyanate ( 7 ) and 5‐nitropyridin‐2‐yl isocyanate ( 9 ) in 1,3‐dipolar cycloaddition reactions with azides and pyridine N‐oxides has been investigated. 1,3‐Dipolar cycloaddition to trimethylsilylazide (TMSA) afforded the respective tetrazolinones, 1‐(3‐nitropyridin‐4‐yl)‐1H‐tetrazol‐5(4H)one ( 8 , 50 %) and 1‐(5‐nitropyridin‐2‐yl)‐1H‐tetrazol‐5(4H)one ( 11 , 64 %). Respectively, 1,3‐dipolar cycloaddition of nitropyridyl isocyanates 7 and 9 to 3,5‐dimethylpyridine N‐oxide ( 14 ), 3‐methylpyridine N‐oxide ( 21 ) and pyridine N‐oxide ( 22 ) gave the substituted amines, 3,5‐dimethyl‐N‐(3‐nitropyridin‐4‐yl)pyridin‐2‐amine ( 17 ), 3,5‐dimethyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 20 ), N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 24 ), 5‐methyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 23 ) and 3‐methyl‐N‐(5‐nitropyridin‐2‐yl)pyridin‐2‐amine ( 25 ) in 65 ‐ 80 % yield, obtained by cycloaddition, rearrangement and decarboxylation. The results demonstrate that the nitropyridyl isocyanates ( 7,9 ) readily undergo 1,3‐dipolar cyloaddition reactions similar to phenyl isocyanates.     

Synthesis and spectral data of new 1,2‐bis‐(2‐hetaryl‐4‐oxothiazolidin‐3‐yl)ethanes and 1,4‐bis‐(2‐hetaryl‐4‐oxothiazolidin‐3‐yl)butanes

New αω‐bis‐(2‐hetaryl‐4‐oxothiazolidin‐3‐yl)alkanes were prepared via a common two step procedure using N,N‐bis‐hetarylidenamines condensation with α‐mercaptoacetic acid. The used bis‐aldimines were obtained from reaction between ethylenediamine or putrescine and benzaldehyde or the isomeric pyridinecarboxyaldehydes. The bis‐(2‐phenyl‐4‐oxothiazolidin‐3‐yl)alkanes were prepared by one‐pot three component reaction of diamine, aldehyde and α‐mercaptoacetic acid under very mild conditions.     

Stepwise Strategy to Cyclometallated PtII Complexes with N‐Heterocyclic Carbene Ligands: A Luminescence Study on New β‐Diketonate Complexes

The imidazolium salt 3‐methyl‐1‐(naphthalen‐2‐yl)‐1H‐imidazolium iodide ( 2 ) has been treated with silver(I) oxide and [{Pt(μ‐Cl)(η³‐2‐Me‐C₃H₄)}₂] (η³‐2‐Me‐C₃H₄=η³‐2‐methylallyl) to give the intermediate N‐heterocyclic carbene complex [PtCl(η³‐2‐Me‐C₃H₄)(H$\widehat{CC}$ *‐κC*)] ( 3 ) (H$\widehat{CC}$ *‐κC*=3‐methyl‐1‐(naphthalen‐2‐yl)‐1H‐imidazol‐2‐ylidene). Compound 3 undergoes regiospecific cyclometallation at the naphthyl ring of the NHC ligand to give the five‐membered platinacycle compound [{Pt(μ‐Cl)($\widehat{CC}$ *)}₂] ( 4 ). Chlorine abstraction from 4 with β‐diketonate Tl derivatives rendered the corresponding neutral compounds [Pt($\widehat{CC}$ *)(L‐O,O′)] {L=acac (HL=acetylacetone) 5 , phacac (HL=1,3‐diphenyl‐1,3‐propanedione) 6 , hfacac (HL=hexafluoroacetylacetone) 7 }. All of the compounds ( 3 – 7 ) were fully characterized by standard spectroscopic and analytical methods. X‐ray diffraction studies were performed on 5 – 7 , revealing short Pt?Pt and π–π interactions in the solid‐state structure. The influence of the R‐substituents of the β‐diketonate ligand on the photophysical properties and the use of the most efficient emitter, 5 , as phosphor converter has also been studied.     

An efficient synthesis of benzo[b][1,8]naphthyridine‐3‐carboxylic methyl esters

Methyl‐3‐(2‐chloroquinolin‐3‐yl)acrylates 5a‐i on reaction with methyl amine in acetonitrile yielded methyl‐3‐[2‐(methylamino)quinolin‐3‐yl]acrylates 6a‐i . When, these were followed by the reaction with the Vilsmeier reagent, they afforded methyl benzo[b][1,8]naphthyridin‐3‐carboxylate 7a‐i in good yields.     

A general and versatile synthesis of 3‐phenylthio β‐lactams as lead molecules for 3‐methyl‐2‐azetidinones

Ketene‐imine cycloaddition using phosphorus oxychloride and benzenesulfonyl chloride under the described reaction conditions yielded trans 3‐phenylthio 2‐azetidinones in good yields. Desulfurization using Raney nickel and alkylation finally afforded trans 3‐methyl‐2‐azetidinones in a stereoselective manner.     

Studies with enamines and azaenamines: Synthesis and reactivity of 3‐dimethylamino‐2‐[(3‐indolyl) carbonyl]propenonitrile

2‐Oxo‐3‐(indol‐3‐yl)propanonitrile 2 condensed with dimethylformamide dimethylacetal to yield the enaminonitrile 3 . The latter reacted with 4‐chloroaniline to yield the 4‐chlorophenylaminoacrylonitrile 5 . Reaction of 3 with hydrazine hydrate led to formation of pyrazole‐4‐carbonitrile 6 . Compound 3 reacted with ethyl acetoacetate in refluxing acetic acid and in presence of ammonium acetate to yield the indolylpyridine 10 . Enamine 3 reacted with 5(1H)‐aminotriazole 13 and 3(5)‐aminopyrazole 17 to yield the pyrimidine derivatives 15 and 19 , respectively.     

Preparation of 2‐(1H‐pyrazol‐5‐yl)benzenesulfonamides from polylithiated C(α),N‐carbo‐tert‐butoxyhydrazones and methyl 2‐(aminosulfonyl)benzoate

Select C(α), N‐carbo‐tert‐butoxyhydrazones were dilithiated with excess lithium diisopropylamide followed by condensation with methyl 2‐(aminosulfonyl)benzoate, acid cyclization, hydrolysis, and decarboxylation to afford new 2‐(1H‐pyrazol‐5‐yl)benzenesulfonamides, [NH‐pyrazolyl‐ortho‐benzene‐sulfonamides].     

Synthesis and biological activity of 3‐[(6‐chloropyridin‐3‐yl)methyl]‐6‐substituted‐6,7‐dihydro‐3H‐1,2,3‐triazolo[4,5‐d]‐pyrimidin‐7‐imines

A series of 3‐[(6‐chloropyridin‐3‐yl)methyl]‐6‐substituted‐6,7‐dihydro‐3H‐1,2,3‐triazolo[4,5‐d]pyrimidin‐7‐imines were designed and synthesized via a multi‐step sequence using 2‐chloro‐5‐(chloromethyl)‐pyridine as the starting material. Various primary aliphatic amines, hydrazine and hydrazide reacted with 3 to obtain the cyclization products 4 . Their structures were confirmed by ¹H NMR and elemental analyses, some of them were also confirmed by IR, ¹³C NMR, MS and single crystal X‐ray diffraction. The preliminary bioassay indicated that some of the target compounds 4 displayed moderate to weak fungicidal activity and insecticidal activity.     

Synthesis of benzo[c][1,8]phenanthrolin‐6‐one through cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐benzamide derivatives

In the course of our search for compounds with potential antitumor properties we have undertaken the synthesis of benzo[c][1,8]phenanthroline derivatives. Our project required the preparation of 8,9‐dimethoxy benzo[c][1,8]phenanthrolin‐6‐ones. This was first attempted by the lithiumdiisopropylamide cyclization of N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide. The reaction led to 40% of the unexpected internal Diels‐Alder adduct 3,4‐dimethoxy‐6H‐pyrido[2,3‐i]6,8a‐ethenoindolo[cd]isoquinoline‐2(1H)‐one, which arose from a benzyne intermediate. In a second and more successful approach, the internal biaryl palladium diacetate‐assisted coupling reaction of properly N‐protected N‐(isoquinol‐5‐yl)‐2‐bromo‐4,5‐dimethoxybenzamide was studied. The optimisation of the protecting group necessary for this procedure led to a 64% yield of the target compound starting from N,N‐(isoquinol‐5‐yl)‐bis‐(2‐bromo‐4,5‐dimethoxybenzamide).