Preparation of new N6, 9‐disubstituted 2‐phenyl‐adenines and corresponding 8‐azaadenines.: A feasibility study for application to solid‐phase Synthesis. I

A suitably substituted pyrimidine 1 was converted to a number of title compounds. Nucleophilic substitu tion involving the chlorine atoms in 1 by treatment with phenylmethanethiol yielded 2 or 3 , depending on the reaction temperature. Treatment of 3 with an amine afforded 6‐phenylmethanesulfanyl‐N⁴‐substituted‐2‐phenyl‐pyrimidine‐4,5‐diamines 4–7 . These pyrimidines were converted into 2‐phenylpurines 8–11 and 2‐phenyl‐8‐azapurines 12–14 , by treatment with triethyl orthoformate in the presence of hydrochloric acid (or acetic anhydride), or with potassium nitrite and acetic acid respectively. The thioether function on C(6) was then converted into a sulfonyl group by oxidation with m‐chloroperoxybenzoic acid affording purines 15–18 and their 8‐azaanalogs 19–21 ; these compounds, as crude products, were treated with an amine to yield the corresponding adenines 22–25 or 8‐azaadenines 26–31. All reactions were performed under conditions com patible with the possible use of a thiomethyl resin in place of phenylmethanethiol to bind the pyrimidine ring of 1 to a solid phase.     

Conformational flipping of the N(6) substituent in diprotonated N6‐(N‐glycylcarbonyl)adenines: The role of N(6)H in purine‐ring‐protonated ureido adenines

Conformational transitions of the N(6) substituent, in hypermodified nucleic acid base N⁶‐(N‐glycylcarbonyl)adenine, gc⁶Ade, on diprotonation of the adenine ring at any two of N(1), N(3), and N(7) sites, are studied using the quantum chemical perturbative configuration interaction with localized orbitals (PCILO) method. The N(6) substituent retains the usual “distal” orientation (α=0°) in (N(1),N(3)) diprotonated gc⁶Ade, but the “proximal” orientation (α=180°) is preferred instead, for (N(3),N(7)) and (N(7),N(1)) diprotonated gc⁶Ade. The proximal orientation may alter the reading frame during translation. Intramolecular N(6)HO(13b) hydrogen bonding is the key common feature, present in the preferred structure, for each of these variously diprotonated gc⁶Ade. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 78: 398–405, 2000     

New C(2)‐substituted 8‐alkylsulfanyl‐9‐phenylmethyl‐hypoxanthines III

Title compounds were obtained starting from the key imidazole intermediate, 5‐amino‐1‐phenyl‐methyl‐2‐mercapto‐1H‐imidazole‐4‐carboxylic acid amide 5 , readily derived from the base catalyzed rearrangement of a thiazole, 5‐amino‐2‐phenylmethylaminothiazole‐4‐carboxylic acid amide 4 . Alkylation of the thiol function on 5 with phenylmethyl and allylic chlorides gave compounds 6 and 7 respectively. Cyclization of 6 with a variety of esters afforded 8‐phenylmethylthiohypoxanthines, 8–11 . Similarly, 7 was cyclized to 8‐allylthiohypoxanthines, 20–21 . Compound 5 was also cyclized, but formed 8‐mercaptohypox‐anthines, 22–24 . Alkylation of 8‐mercaptohypoxanthines afforded 8‐alkylthiohypoxanthines, 8, 9,25 and 26 (see Scheme 2). Chlorination of 9–11 afforded 16–18 ; adenine 19 was derived from 16 . Oxidation of hypox‐anthines 8–11 with m‐chloroperbenzoic acid gave the corresponding 8‐phenylmethylsulfonyl derivatives 12 ‐ 15 . These derivatives proved resistant to nucleophilic displacement reactions with primary amines.     

Synthesis and catalytic properties of 1‐alkyl‐2‐imidazolineruthenium(II) complexes

New [RuCl₂(imidazoline)(arene)] complexes have been prepared. The complexes were characterized by conventional spectroscopic methods and elemental analyses. Upon reaction with 1,1‐diphenylprop‐2‐ynol they generate catalyst precursors that can perform the cycloisomerization of diallyltosylamide into N‐tosyl‐α‐methylenepyrrolidine. Copyright © 2004 John Wiley & Sons, Ltd.     

A Study on the Intramolecular Mitsunobu Reaction of N6‐(ω‐Hydroxyalkyl)adenines

The cyclization of N ⁶‐(ω‐hydroxyalkyl)adenines with a N⁶H‐group leads to N⁶,N1 ring closure regardless of the method of the cyclization that was used. Five‐membered to eight‐membered rings were obtained using NBS/PPh₃; however, under Mitsunobu conditions, the eight‐membered fused purine was not formed. Surprisingly, the cyclization of N ⁶‐methyl‐N ⁶‐(4‐hydroxybutyl)adenine only leads to N⁶,N7 ring closure using both methods.     

One‐pot synthesis of N2‐aminoprotected 6‐substituted and cycloalka[d] 4‐trifluoromethyl‐2‐acetylaminopyrimidines

The one‐pot synthesis of a novel series of amino‐protected 6‐alkyl‐, 6‐aryl‐, 6‐heteroaryl‐ and 5,6‐fused‐cycloalkane 4‐trifluoromethyl‐2‐acetylaminopyrimidines, where alkyl = Me; aryl = Ph, 4‐CH₃Ph, 4‐FPh, 4‐ClPh, 4‐BrPh, 4‐OCH₃Ph, 4‐NO₂Ph, 4,4′‐biphenyl, 1‐naphthyl; heteroaryl = 2‐thienyl, 2‐furyl and cycloalkyl = c‐C₆H₄, c‐C₇H₅ from the reaction of substituted 4‐methoxy‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 1‐acetylguanidine in acetonitrile or propan‐2‐ol as solvent, is reported. The acetylamino group of 2‐acetylaminopyrimidines was hydrolyzed under three different conditions to afford the corresponding free 2‐aminopyrimidines.     

Quinolone analogues 2. A facile synthesis of novel 3‐substituted 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalines

The reaction of the 2‐(1‐alkylhydrazino)‐6‐chloroquinoxaline 4‐oxides 1a,b with diethyl acetone‐dicarboxylate or 1,3‐cyclohexanedione gave ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐1,5‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylates 5a,b or 6‐alkyl‐10‐chloro‐1‐oxo‐1,2,3,4,6,12‐hexahydroquinoxalino[2,3‐c]cinnolines 7a,b , respectively. Oxidation of compounds 5a,b with nitrous acid afforded the ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐4‐carboxylates 9a,b , whose reaction with base provided the ethyl 2‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)acetates 6a,b , respectively. On the other hand, oxidation of compounds 7a,b with N‐bromosuccinimide/water furnished the 4‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)butyric acids 8a,b , respectively. The reaction of compound 8a with hydroxylamine gave 4‐(7‐chloro‐4‐hydroxyimino‐1‐methyl‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)‐butyric acid 12 .     

Synthesis of New N‐alkyl‐5‐formyl‐2‐methylpyrrole Derivatives from Glucosamine

Glucosamine hydrochloride 1 was treated with 1,3‐dicarbonyl compounds to obtain 2‐methyl‐5‐(1,2,3,4‐tetrahydroxy‐butyl) pyrrole 2a and 2b , respectively. Under the role of NaIO₄, 2a and 2b were successfully transformed into the related 5‐formal pyrrole derivative 3a and 3b , respectively. Compounds 4a – 4d and 5a – 5e were obtained by reacting 3a and 3b with chlorinated hydrocarbons by alkylation reactions, respectively. The structures of all new products were confirmed by IR, NMR, and HRMS spectra.     

Substituent effects in the ring‐chain tautomerism of 4‐alkyl‐2‐aryl substituted oxazolidines and tetrahydro‐1,3‐oxazines

The condensation products of 2‐aminoethanol or 3‐aminopropanol (bearing an alkyl substituent on the carbon adjacent to the nitrogen) with substituted benzaldehydes proved to exist in CDCl₃ at 300 K as threecomponent tautomeric mixtures of the diastereomeric five‐ or six‐membered 1,3‐O,N‐heterocyclic ring forms and the corresponding imines. For each equilibrium, the electronic effects of the 2‐aryl substituents were characterized by the Hammett equation. The steric effects of the alkyl groups could be described by Hansch‐type equations for the equilibria involving oxazolidine ring forms. While the alkyl substituents did not cause any significant effect on the ring cis‐chain and the ring trans‐chain equilibria for tetrahydro‐1,3‐oxazines, increasing bulk of the 4‐alkyl group increased the stability of the cyclic tautomers for the analogous oxazolidines.     

Synthesis and complete NMR characterization of 4‐alkyl‐2‐(6‐substituted‐1,3‐benzoxazol‐2‐yl)benzenols

This paper describes the complete assignment of all carbons and hydrogens of several newly synthesized 6‐substituted 2‐(2‐hydroxyaryl)benzoxazoles from 2,2′‐dihydroxydiaryl Schiff bases by the use of two‐dimensional NMR techniques. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthese de C-nucleosides. VII β-D-ribofuranosyl-2 et -8 adenines

Benzyl (O-benzoyl-5-D-ribofuranosyl)thioformimidate IV reacts with aminomalodinitrile or with 5-amino-4-cyanoimidazole to yield the two C-nucleoside analogues III and II of adenosine. The β-configuration is determined with NMR and CD spectra.     

NMR study of O and N,O‐substituted 8‐quinolinol derivatives

The ¹H and ¹³C NMR spectral study of several biologically active derivatives of 8‐quinolinol have been made through extensive NMR studies including homodecoupling and 2D‐NMR experiments such as COSY‐45°, NOESY, and HeteroCOSY. Electron donating resonance and electron withdrawing inductive effect of several groups showed marked changes in chemical shifts of nuclei at the seventh positions of O‐substituted quinolinols (2–15). Although in N‐alkyl, 8‐alkoxyquinolinium halides (16–21), ring A rightly showed low frequency chemical shift values. Copyright © 2013 John Wiley & Sons, Ltd.     

[(1,4,8,11‐Tetraazacyclotetradeca‐1,4,8,11‐tetrayl)tetraacetamide‐κ6N1,N4,N8,N11,O1,O8]copper(II) sulfate 4.5‐hydrate

The crystal structure of the title copper(II) complex, [Cu(C₁₈H₃₆N₈O₄)]SO₄·4.5H₂O, formed with the tetra­amide cyclam derivative 2‐(4,8,11‐triscarbamoyl­methyl‐1,4,8,11‐tetra­aza­cyclo­tetradec‐1‐yl)­acet­amide (TETAM), is described. The macrocycle lies on an inversion centre occupied by the hexacoordinated Cu atom. The four macrocyclic tertiary amines form the equatorial plane of an axially Jahn–Teller elongated octahedron. Two O atoms belonging to two diagonally opposite amide groups occupy the apical positions, giving rise to a trans‐III stereochemistry, while both the remaining pendant side arms extend outwards from the macrocyclic cavity and are engaged in hydrogen bonds with sulfate anions and co‐crystallized water mol­ecules.     

Four cytotoxic N4‐substituted thiosemicarbazones derived from 2‐hydroxynaphthalene‐1‐carboxaldehyde

The X‐ray crystal structures are reported of four novel and potentially O,N,S‐tridentate donor ligands that demonstrate antitumour activity. These ligands are 1‐[(4‐methyl­thio­semicarbazono)methyl]‐2‐naphthol, C₁₃H₁₃N₃OS, (III), 1‐[(4‐ethylthio­semicarbazono)­methyl]‐2‐naphthol, C₁₄H₁₅N₃OS, (IV), 1‐[(4‐phenyl­thio­semicarbazono)­methyl]‐2‐naphthol, C₁₈H₁₅N₃OS, (V), and 1‐[(4,4‐di­methyl­thio­semicarbazono)­methyl]‐2‐naphthol di­methyl sulfoxide solvate, C₁₄H₁₅N₃OS·C₂H₆OS, (VI). These chelators are N4‐substituted thio­semicarbazones, each based on the same parent aldehyde, namely 2‐­zhydroxynaphthalene‐1‐carboxaldehyde isonicotinoylhydrazone. Conformational variations within this series are discussed in relation to the optimum conformation for metal‐ion binding.     

Synthesis and Some Reactions of 2‐Acyl‐2‐alkyl‐1,3‐dithiolane 1,1‐Dioxides

The selective formation of optically active 2‐acyl‐2‐alkyl‐1,3‐dithiolane 1,1‐dioxides from the corresponding 2‐acyl‐2‐alkyl‐1,3‐dithiolane 1‐oxides, by reaction with OsO₄ and NMO in acetone, is reported. These compounds underwent stereoselective reactions at the carbonyl group of the acyl group with organometallic reagents. These reactions were completely regioselective, and no attack at either of the S‐atoms was observed, unlike similar reactions with the corresponding sulfoxides. The nature of the metal atom had a direct effect upon the configuration of the product alcohols.     

A facile synthesis of 1‐alkyl‐5‐arylalkoxy‐6‐methoxy‐3,4‐dihydroisoquinolines

1‐Alkyl‐5‐arylalkoxy‐6‐methoxy‐3,4‐dihydroisoquinolines were synthesized by the alkylation of 1‐alkyl‐5‐hydroxy‐6‐methoxy‐3,4‐dihydroisoquinolines with arylalkyl halide in the presence of potassium carbonate. 1‐Alkyl‐5‐hydroxy‐6‐methoxy‐3,4‐dihydroisoquinolines as key precursor prepared from o‐vaniline via 6 steps.     

Convenient preparations of 2‐alkyl‐5‐oxopyrrolidine‐3‐carboxylic acids

Reduction of the Michael addition products of anions of nitro compounds to dimethyl maleate led to the spontaneous formation of the respective 2‐alkyl‐5‐oxopyrrolidine‐3‐carboxylic acid methyl esters. Conventional hydrolysis of the later gave the desired compounds.