Synthesis of 4-aminomethyl-tetrahydrofuran-2-carboxylates with 2,4-cis and 2,4-trans relationships

Templated tetrahydrofuran-based γ-azido esters were prepared with the C-2 and C-4 functionalities in cis and trans relative configurations. This was achieved by ring contraction of the suitably protected 2-O-triflates of pentono-1,5-lactones (d-ribose and l-arabinose) with subsequent introduction of the azide via the 4-O-triflate. Access to a corresponding β-azido ester was achieved in good yield. Little elimination product was observed by introduction of the azide via the 3-O-triflate. These azido esters are scaffolds, which may be predisposed to adopt secondary structural motifs, for example, for use as peptidomimetics; they may also be utilised for the preparation of stereodiverse compound libraries.     

Reaction of 3-aminoquinoline-2,4-diones with nitrourea. Synthetic route to novel 3-ureidoquinoline-2,4-diones and imidazo[4,5-c]quinoline-2,4-diones

1-Unsubstituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with 1-substituted and 1,1-disubstituted ureas in boiling acetic acid to give 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones. In contrast, the reaction of these amines with nitrourea in dioxane affords novel 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones or 9b-hydroxy-3a-alkyl/aryl-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones, which can smoothly be dehydrated to 3a-alkyl/aryl-3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. All three types of products can be converted to 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones by refluxing in acetic acid.     

Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones using the Vilsmeier reaction

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives.     

Synthesis of N,N-dimethyl-2,4-dinitro-5-fluorobenzylamine and its reactions with amino acids and peptides

A practical synthesis is described for N,N-dimethyl-2,4-dinitro-5-fluorobenzylamine (DMDNFB) and its -d₆ analog as an alternative Sanger's reagent (DNFB), for purposes of amino acid derivatization detectable by positive mode electrospray ionization mass spectrometry. DMDNFB is comparable to DNFB in its efficiency to derivatize amino acids and peptides. Various DMDNP (d₀/d₆) derivatives of (modified) lysine were synthesized to evaluate the potential use of isotope-edited LC-ESI-MS as a tool for structural definition of the posttranslational modification of protein-based lysines.     

Regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by radical cyclization

5-Hydroxy uracils or 4-hydroxy[1]benzopyran-2-ones were refluxed with 2-bromobenzyl bromides in acetone in the presence of anhydrous potassium carbonate to afford a number of 5-(2′-bromobenzyloxy) pyrimidine-2,4-dione (80-92%) or 4-(2′-bromobenzyloxy) benzopyran-7-ones (70-82%) respectively. These were then refluxed with tri-n-butyltin chloride and sodium cyanoborohydride in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) for 3-4 h to give 1H,3H,6H [2]benzopyrano[4,3-d]pyrimidine-2,4-diones (75-85%) or 12H-benzopyrano[3,2-c][1]benzopyran-5-ones (70-85%) respectively.     

The first entry to pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones

Wittig olefination of 3-aminoquinoline-2,4(1H,3H)-diones 1 with ethyl (triphenylphosphoranylidene)acetate (Ph₃PCHCO₂Et) afforded (E)-3-amino-4-ethoxycarbonylmethylene-1,2,3,4-tetrahydro-2-quinolones (E)-2 and pyrrolo[2,3-c]quinoline-2,4(3aH,5H)-diones 3. An alternative approach for the synthesis of 3 via 3-bromoacetamidoquinoline-2,4(1H,3H)-diones 7, their corresponding triphenylphosphonium salts 8, and ylides A that undergo intramolecular Wittig reaction, was investigated. Under the applied reaction conditions, the phosphonium salts 8 and ylides A are so unstable that they partly decompose to 3-acetamidoquinoline-2,4(1H,3H)-diones 9 during the synthesis of 3.     

Rearrangement of furo[2,3-c]quinoline-2,4(3aH,5H)-diones to furo[3,4-c]quinoline-3,4(1H,5H)-diones

Thermally assisted base-catalyzed rearrangement of furo[2,3-c]quinoline-2,4(3aH,5H)-diones 1 to the corresponding furo[3,4-c]quinoline-3,4(1H,5H)-diones 2 is reported, and a mechanism of the transformation is proposed.     

Indole-substituted 2,4-diamino-5,8-dihydropyrido[2,3-d]pyrimidines from one-pot process and evaluation of their ability to bind dopamine receptors

A series of novel 7-indole substituted 2,4-diamino-5,8-dihydropyrido[2,3-d]pyrimidine analogous to the 2,4-diaminopteridine core were synthesized by the three-component one-pot cyclocondensation between 2,4,6-triaminopyrimidine, 3-(2-cyanoacetyl)indole and aromatic aldehydes. The reactions, which exhibited good performance, proceeded in EtOH using indium (III) chloride as catalyst under microwave irradiation, in short reaction times. On the basis of certain structural similarity of these compounds with known ligands of the D2 dopamine receptors (D2DR), the study of these compounds as possible ligands of dopamine D2 and D1 receptors was carried out. Three of them showed moderate affinity to D2-DR since the Ki D1/D2 ratio reached values of 40, 65 and 31 for compounds 4c, 4k and 4j, respectively. Finally, molecular modeling studies revealed stronger molecular interactions of such derivatives with the D2DR than with D1DR, what agrees with the experimental data, and gives an additional support to the observed selectivity to the D2DR.     

Unprecedented reactivity of 3-amino-1H,3H-quinoline-2,4-diones with urea: an efficient synthesis of 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones

Substituted 3-amino-1H,3H-quinoline-2,4-diones react with urea in acetic acid to give novel 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones in high yields. The same compounds were obtained, albeit with small yields, from 3-chloro-1H,3H-quinoline-2,4-diones and urea. In the proposed reaction mechanism, a molecular rearrangement of the primarily formed mono-substituted urea takes place. The prepared 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones were characterized by their ¹H, ¹³C, ¹⁵N NMR and IR spectra and atmospheric pressure chemical ionisation mass spectra.     

Synthesis of novel 2,3-substituted-2,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-diones

Novel 2,3-substituted-2,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-diones were successfully synthesized with moderate to good yields using a new synthetic approach. The structures of the regio-isomers in this series were determined by single crystal X-ray analysis and NMR spectra.     

Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

Efficient synthesis of novel pyrido[3,2-d]pyrimidine-2,4-diones

A series of pyrido[3,2-d]pyrimidine-2,4-diones 5a-g have been synthesized through conversion of 2,3-pyridinedicarboxylic anhydride 1 into half-ester 2, subsequent Curtius rearrangement and further reaction with amino acids.     

Doubly carbon-branched pentoses: synthesis of both enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose using only acetonide protection

An acetonide is the only protecting group used in the synthesis of both the enantiomers of 2,4-di-C-methyl arabinose and 2-deoxy-2,4-di-C-methyl arabinose via the enantiomeric 3-C-methyl-l-erythronolactone [from 2-C-methyl-d-ribono-lactone or d-ribose] and 3-C-methyl-d-erythronolactone [from d-tagatose or l-ribose]. NMR studies on unprotected C-methyl arabinoses show that methyl branching significantly affects the ratios of pyranose and furanose forms present in aqueous solution.     

First straightforward synthesis of 2,4-disubstituted benz[g]isoquinoline-3,5,10(2H)-triones, 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones

Structural modifications to the benz[g]isoquinoline skeleton of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were envisaged in order to make future SAR studies possible for this type of bioactive compounds. Several N-substituted benz[g]isoquinoline-3,5,10(2H)-triones were converted to novel 2,4-substituted benz[g]isoquinoline-3,5,10(2H)-triones, new tetracyclic 1,2,3,5-substituted naphtho[3,2,1-de]isoquinoline-4,7-diones, and 6-substituted benzo[h]pyrido[3,4,5-kl]-1,2,3,4-tetrahydroacridine-5,8-diones. All the synthesized target compounds represent new heterocyclic systems, which were previously undescribed in the literature.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Highly efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4-dione derivatives catalyzed by iodine

A new and efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4-dione derivatives through the reaction of 6-aminouracils and N,N′-bis(arylmethylidene) arylmethane in the presence of molecular iodine as a readily available and feasible catalyst.     

Boron-mediated aldol reactions of ethyl α-(N,N)-dibenzylamino ketones: control of enolisation geometry and aldehyde π-facial selectivity

The boron-mediated aldol reactions of a range of chiral α-(N,N)-dibenzylamino ketones with aldehydes can be controlled to provide stereodefined adducts. Complementary induction can be achieved with ^cHex₂BCl/Me₂NEt leading to preferential formation of the 1,2-anti-2,4-syn adducts, while Bu₂BOTf/ⁱPr₂NEt provides 1,2-syn-2,4-anti adducts.     

Studies on enzymatic oxidation of 3′,4′-dihydroxy-l-phenylalanine to dopachrome using kinetic isotope effect methods

We report the studies on the mechanism of oxidation of 3′,4′-dihydroxy-l-phenylalanine (l-DOPA) to neurotoxic dopachrome catalyzed by enzyme horseradish peroxidase (EC 1.11.1.7) using the kinetic (KIE), and solvent (SIE), isotope effect methods. For kinetic studies two specifically deuterated isotopomers: [2′,5′,6′-²H₃]-l -DOPA was synthesized by the acid catalyzed isotopic exchange between native l-DOPA and heavy water, and [5′-²H]-l-DOPA was synthesized in two step reaction. The first step involved acid catalyzed isotopic exchange between l-tyrosine and deuterated water and resulting product [3′,5′-²H₂]-l-tyrosine was hydroxylated by enzyme tyrosinase (EC 1.14.18.1). The values of deuterium KIEs and SIE’s in the enzymatic oxidation of l-DOPA and its isotopomers are determined using non-competitive spectrophotometric method. The measured values were: KIE on V _max (1.1 and 2.2) and KIE on V _max/K _M (1.7 and 3.2) for [2′,5′,6′-²H₃]-l-DOPA and [5′-²H]-l-DOPA, respectively, while the corresponding values of SIE were: SIE on V _max (2.1, 2.4, and 2.1) and SIE on V _max/K _M (1.3. 1.6, and 1.1) for l-DOPA, [2′,5′,6′-²H₃]-l-DOPA, and [5′-²H]-l-DOPA, respectively. The size of KIE and SIE, typical for secondary isotope effects indicate that both the solvent and presence of deuterium at the 2′-, 5′, and 6′-positions of l-DOPA has the little impact on the enzymatic oxidation of this compound.     

Synthesis of pyrrolo[2,3-d]pyrimidine-2,4-diones by sunlight photolysis of N-(5-vinyluracil-6-yl)sulfilimines

Uracil derivatives having a vinyl group at the C-5 position and a sulfilimine moiety at the C-6 position were prepared and cyclized to 1,3,6-trisubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones by sunlight photolysis in good yields.     

Synthesis and aromatic nucleophilic N-N, N-S and N-O exchange reactions of N,N-dimethyl-2-trifluoroacetyl-1-naphthylamine

We succeeded in the synthesis of N,N-dimethyl-2-trifluoroacetyl-1-naphthylamine (10) by the regioselective deacylation of N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine with trifluoroacetic acid and water. The aromatic nucleophilic substitutions of 10 with various amines, thiols and alcohols proceeded cleanly to give the corresponding N-N, N-S and N-O exchanged products in moderate to excellent yields.