Simple preparation of 7-alkylamino-2-methylquinoline-5,8-diones: regiochemistry in nucleophilic substitution reactions of the 6- or 7-bromo-2-methylquinoline-5,8-dione with amines

7-Alkylamino-2-methylquinoline-5,8-diones (7) were prepared from 6-bromo-2-methylquinoline-5,8-dione (2) not from 7-bromo-2-methylquinoline-5,8-dione (1). The chemistry of the transformation of 6-bromo-2-methylquinoline-5,8-dione (2) and various alkylamines, such as piperidine, 2-methylaziridine, benzylamine, n-butylamine, cyclohexylamine, t-butylamine, and ammonia, to 7-alkylamino compounds 7 as well as the transformation of 7-bromo compound 1 and the alkylamines to 6-alkylamino-2-methylquinoline-5,8-diones 11 was studied. The efficient and simple synthetic routes of the key intermediates, 6- and 7-bromo-2-methylquinoline-5,8-diones (2 and 1), from 5,8-dihydroxy-2-methylquinoline (15) and 5,7-dibromo-8-hydroxy-2-methylquinoline (9), respectively, were developed. We also proposed the mechanism for the unusual regioselectivity on the nucleophilic amination of 6- and 7-bromo-2-methylquinoline-5,8-diones (2 and 1).     

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.     

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.     

A practical route for synthesizing a PET ligand containing [F]fluorobenzene using reaction of diphenyliodonium salt with [F]F

The aim of this study was to develop a practical route for preparing a fluorine-18 ([¹⁸F]) labelled ligand ([¹⁸F]1) containing [¹⁸F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [¹⁸F]F⁻. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [¹⁸F]DAA1106 ([¹⁸F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared.     

Preparation of the novel fluorine-18-labeled VIP analog for PET imaging studies using two different synthesis methods

Vasoactive intestinal peptide (VIP) receptors are expressed on various tumor cells in much higher density than somatostatin receptors, which provides the basis for radiolabeling VIP as tumor diagnostic agent. However, fast proteolytic degradation of VIP in vivo limits its clinical application. With the aim to develop and evaluate new ligands for depicting the VIP receptors with positron emission tomography (PET), the structure modified [R^8,15,21, L¹⁷]-VIP analog was radiolabeled with ¹⁸F using two different methods. With the first method, N-4-[¹⁸F]fluorobenzoyl-[R^8,15,21, L¹⁷]-VIP ([¹⁸F]FB-[R^8,15,21, L¹⁷]-VIP 7) was produced in a decay-corrected radiochemical yield (RCY) of 33.6 ± 3%, a specific radioactivity of 255 GBq/μmol (n = 5) within 100 min in four steps. Similarly, N-4-[¹⁸F](fluoromethyl)-benzoyl-[R^8,15,21, L¹⁷]-VIP ([¹⁸F]FMB-[R^8,15,21, L¹⁷]-VIP 8) was synthesized in a RCY of 34.85 ± 5%, a specific radioactivity of 180 GBq/μmol (n = 5) within 60 min in only one step. The two products 7 and 8 were both shown good stability in HSA. Moreover, the low bone uptakes of 7 and 8 in vivo of mice showed good defluorination stability.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

Improved syntheses of precursors for PET radioligands [F]XTRA and [F]AZAN

Improved syntheses of 7-methyl-2-exo-[3′-(2-bromopyridin-3-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptanes (3) and 7-methyl-2-exo-[3’-(6-bromopyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptanes (4), precursors for PET radioligands [¹⁸F]XTRA (1) and [¹⁸F]AZAN (2), involving a key Stille coupling step followed by deprotection of Boc group and N-methylation are described. The new synthetic procedures provided the title compounds in more than 40% overall yields.     

Reactions promoted by [hydroxy(tosyloxy)iodo]benzene in pyrazino[1,2-b]isoquinolines

The hypervalent iodine reagent PhI(OH)OTs (HTIB) promoted oxidative demethylation of 1,4-hydroquinone methyl ethers to give quinones in a quantitative conversion. The efficacy of this reaction, that has been applied to simple arene compounds and to heterocyclic systems, such as 2-isopropoxycarbonyl-7,10-dimethoxy-pyrazino[1,2-b]isoquinoline-4-ones and 1,4-diones to get the corresponding 7,10-quinones (compounds 6-8), is similar to those promoted by CAN and does not require the presence of water. Instead of oxidative demethylation, HTIB promoted in 1-methoxy-pyrazino[1,2-b]isoquinoline-4-ones complex multi-step processes to give compounds 9 or 10.     

Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.     

A new synthetic procedure to spiro[cyclohexane-1,3′-indoline]-2′,4-diones

A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefsky's diene 2. Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. Using a ‘one pot reaction’, starting from 1 and 2, compounds 7 were obtained in satisfactory overall yield.     

A unique peroxide formation based on the Mn(III)-catalyzed aerobic oxidation

The autoxidation of a mixture of 1,1-diarylsubstituted alkenes 4 and 4-hydroxy-1H-quinolin-2-ones 5 in the presence of a catalytic amount of manganese(III) acetate dihydrate in air gave 3,3-bis(2-hydroperoxyethyl)-1H-quinoline-2,4-diones 6 in 31-91% yields together with [4.4.3]propellane-type cyclic peroxides 7 (10-34%). A similar aerobic oxidation of 3-substituted quinolinones 8 yielded cyclic peroxide derivatives 9 and/or 3-hydroperoxyethylated quinolinediones 10 depending on the substituent. The structures of the bis(hydroperoxide) 6 (R¹=Me, Ar=4-ClC₆H₄) and the [4.4.3]propellane 7 (R¹=Me, Ar=Ph) have been corroborated by X-ray crystallography.     

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.     

Synthetic studies of benzo[b]pyrrolo[4,3,2-de][1,10]phenanthroline

6,11-Dihydrobenzo[b]pyrrolo[4,3,2-de][1,10]phenanthroline-5,8-dione (6), which possesses a unique heterocyclic ring system similar to that in plakinidines A-D (1-4), was synthesized from 2-acetyl-3′-nitrodiphenylamine (16) in nine steps.     

Synthesis and biological evaluation of 1-(4-(4-(4-[18F]fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one as dopamine D4 receptor ligand

A potential dopamine D₄ receptor ligand, 1-(4-(4-(4-fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one (4) was synthesized through a four-step process and its affinity and selectivity for dopamine D₂-like receptors was determined through in vitro receptor binding assay. [¹⁸F]4 was prepared using a one-pot two-step method with total radiochemical yield 21.2 % (decay-corrected). The molar radioactivity was around 135 GBq/μmol and the radiochemical purity was greater than 95.5 %. The partition coefficient (Log P) of [¹⁸F]4 was determined to be 2.10 ± 0.30 through octanol experiment. The in vivo biodistribution and the competitive distribution of [¹⁸F]4 in rat exposed that the tracer passes through blood–brain-barrier (BBB) and may specifically bind to D₄ receptor. Metabolite analysis revealed that there was no metabolism of [¹⁸F]4 in brain. Conclusively, these preliminary results demonstrated that [¹⁸F]4 shows promises as a radioligand for the in vivo study of dopamine D₄ receptor.     

An efficient new route towards biologically active isocryptolepine and γ-carboline derivatives using an intramolecular thermal electrocyclization strategy

An efficient and short route is established for biologically active 11H-indolo[3,2-c]quinoline 1, naturally occurring antiplasmodial isocryptolepine 2 and 5-methyl-11H-indolo[3,2-c]quinoline-5-inium iodide 3 using intramolecular thermal electrocyclization strategy.     

Polymerization of methyl methacrylate in the presence of iron(II) complex with tetradentate nitrogen ligands under conditions of atom transfer radical polymerization

Four tetradentate nitrogen ligands, viz. dichloro{[N,N^′-diphenyl-N,N^′-di(quinoline-2-methyl)]-1,2-ethylene diamine} (1), {[N,N^′-dioctyl-N,N^′-di(quinoline-2-methyl)]-1,2-ethylene diamine} (2), {[N,N^′-dibenzyl-N,N^′-di(quinoline-2-methyl)]-1,2-ethylene diamine} (3), and (1R,2R)-(−)-N,N^′-di(quinoline-2-methyl) di-iminocyclohexane (4), were investigated as novel complexing ligands in iron-mediated atom transfer radical polymerization (ATRP) of methyl methacrylate where ethyl-2-bromoisobutyrate was the initiator in o-xylene at 90 °C. With ligands 1 and 2 the experimental molecular weights increased gradually with monomer conversion. High to moderate conversions (87%, 43%) were obtained in relatively short times (90 min for 1 and 30 min for 2), which indicates an efficient catalyst system, but after these times a dramatic increase in viscosity of the polymerization medium led to loss of control. It is noteworthy that polymerization proceeded in a controlled manner with ligand 1, which has two rather bulky substituents on the N-atom. Such bulky ligands did not work for a copper-based system, where they led to excessive terminations or other side reactions. When the bulkiness of the substituents was significantly increased, as in ligand 3, a decrease in polymerization rate and loss of control occurred. Ligand 4 was less efficient than the other ligands, probably because the ethylene bridge was replaced by cyclohexane bridge.     

Synthesis of new calix[4]arenes containing nucleoside bases

A family of novel calix[4]arene derivatives containing nucleoside bases were designed and synthesized. Coupling reaction between para mono- or bis-amino calix[4]arenes 5, 6 or 7 and thymin-1-ylacetic acid in the presence of DCC afforded mono- or bis-thymine-substituted calix[4]arenes 8, 9 or 10 in over 70% yield. Owing to the low solubility of adenine-N⁹-ylacetic acid in DMF and DMSO and the weak nucleophilicity of aminocalix[4]arene derivatives, alternatively, the substitution reaction of bromoacetylated aminocalix[4]arenes derivatives 11, 12, 13 with adenine in the presence of sodium hydride was carried out to synthesize mono- or bis-adenine-substituted calix[4]arenes. Two kinds of isomers 15 and 16 or 17 and 18 were obtained due to the non-regiospecific alkylation of adenine, and their structures have been confirmed by ¹³C NMR and ¹H NMR spectra.     

Facile radiosynthesis of <Superscript>18</Superscript>F-labeled β-glutamic acid as a new PET tracer for imaging lung cancer

In this paper, N-(2-[¹⁸F]fluoropropionyl)-β-glutamic acid 8 ([¹⁸F]FP-β-Glu), a new N-substituted ¹⁸F-labeled amino acid tracer, was synthesized from the precursor 4 (diethyl 3-(2-bromopropanamido)pentanedioate) via a two-step reaction on the modified FDG synthesizer. The radiochemical yield was 20 ± 5% (n = 10, decay-corrected) from [¹⁸F]fluoride within 40 min, the radiochemical purity was 98%. Moreover, microPET studies showed that [¹⁸F]FP-β-Glu 8 exhibited rapid tumor uptake and good tumor-to-lung ratio in SPC-A-1 tumor-bearing mice. A high accumulation of radioactivity was found in the kidneys and bladder, which suggested that the tracer was mainly eliminated through the urinary system.     

Novel tricarbonyl rhenium complexes of 5,8-quinolinedione derivatives - Synthesis, spectroscopic characterisation, X-ray structure and DFT calculations

The molecular structure of 7-acetamido-2-methyl-quinoline-5,8-dione has been determined and the reactivity of 7-acetamido-2-methyl-quinoline-5,8-dione (1) and 6-acetamido-2-methyl-quinoline-5,8-dione (2) towards Re(CO)₅Cl has been examined. Two novel tricarbonyl rhenium complexes, fac-[Re(CO)₃(7-acetamido-2-methyl-quinoline-5,8-dione)Cl]·CHCl₃ (3·CHCl₃) and fac-[Re(CO)₃(6-acetamido-2-methyl-quinoline-5,8-dione)Cl]₂·CHCl₃ (4·CHCl₃), have been synthesized and characterized spectroscopically and structurally. The electronic spectrum of 3 was investigated at the TDDFT level employing B3LYP functional in combination with LANL2DZ.     

Synthesis of heterocyclic propellanes using Mn(III)-based oxidative cyclization

The manganese(III)-based oxidative cyclization of 1,1-diarylethenes 1 with 3-(2-oxoethyl)piperidine-2,4-diones 2 was carried out in acetic acid at reflux temperature to selectively produce azadioxa[4.3.3]propellanes 3 in high yields. A similar cyclization with the 2-(2-oxoethyl)cycloalkane-1,3-diones 7 and 2-(3-oxopropyl)cycloalkane-1,3-diones 10 also gave the corresponding dioxapropellanes 8 and 11 in moderate to good yields.