The direct arylation of 1,3,5-triazin-2,4(1H,3H)-dione

Direct introduction of non-activated arenes to 1,3,5-triazin-2,4(1H,3H)-dione in the presence of AlCl₃ is described.     

Synthesis of (3RS,3aSR,8aSR)-3-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one via the aza-Cope-Mannich rearrangement

A convenient and scalable method for the preparation of (3RS,3aSR,8aSR)-phenyloctahydrocyclohepta[b]pyrrol-4(1H)-one based on the aza-Cope-Mannich rearrangement is described. This approach allows us to synthesize the target compound in nine steps in a high overall yield (42%) with complete stereocontrol and up to 100 g scale.     

Synthesis of pyrido and pyrazinodithienodipyrimidine-4,8(3H,9H)-dione derivatives by the aza-Wittig methodology

A one-pot synthesis of the hitherto unreported pyrido[5″,6″:4,5;3″2″:4′,5′]dithieno[3,2-d:3′,2′-d′]dipyrimidine-4,8(3H,9H)-dione 6a-o and pyrazino[5″,6″:4,5;3″2″:4′,5′]dithieno[3,2-d:3′,2′-d′]dipyrimidine-4,8(3H,9H)-dione 6p-y pentaheterocyclic systems, based on the tandem aza-Wittig heterocumulene-mediated annulation strategy is described.     

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.     

Di(1H,1H,2H,2H-perfluorooctyl)-dibenzo-18-crown-6: A “light fluorous” recyclable phase transfer catalyst

A series of dibenzo-18-crown-6 lariat ethers containing two C₇H₁₅ (11), (CH₂)₂C₆F₁₃ (14), (CH₂)₂C₈F₁₇ (15), NHC₇H₁₅ (18) and NHCH₂C₆F₁₃ (19) sidearms were prepared and the single crystal X-ray structure of cis-4,4′-di(1H,1H,2H,2H-perfluorodecyl)-dibenzo-18-crown-6 (15a) is reported. The “light fluorous” dibenzo-18-crown-6 ether (14) has emerged as a stable and robust PTC catalyst, which can be recycled efficiently by fluorous solid-phase extraction, and gives better PTC catalytic activity compared to the parent, non-fluorinated PTC catalyst, dibenzo-18-crown-6, and the alkylated derivative (11) in aliphatic and aromatic nucleophilic substitutions.     

Convenient synthesis and unusual reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes

The reaction of 4-oxo-4H-chromen-3-carbaldehydes with coumarin-4-acetic acids under the Perkin conditions follows an interesting pathway that involves aldol reaction and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton. In contrast to chromone-3-carbaldehydes, the same reaction with chromone-2-carbaldehydes yielded only the aldol condensation product. The reaction was performed under thermal and microwave conditions. The reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes in water, alcohol and acetic acid was described.     

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes: a simple and efficient one-pot approach to the substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′(1′H,3H,3′H)-pentone framework

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes in the presence of bromine leads to the selective and efficient formation of substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′-(1′H,3H,3′H)-pentones in 70-88% yields via a complex cascade process. Spirobarbiturates containing the furo[2,3-d]pyrimidine framework are a class of compounds with interesting pharmacological and physiological activity.     

A study of the physico-chemical properties of 1,3,5-trihydroxy-1,3,5-triazin-2,4,6[1H,3H,5H]-trione

Acetyl (Ia) and pivaloyl (Ib) triesters of the 1N,3N,5N-trihydroxy-1,3,5-triazin-2,4,6[1H,3H,5H]-trione (I) were synthesised. The spectrophotometric and potentiometric investigation of I revealed a weak acidic properties of triprotonic acid (pK_a1=5.23, pK_a2=6.32, and pK_a3=7.93). The MS and TGA analyses of I indicated on hydroxyisocyanate as possible degradation product. The chelating ability of I with Fe(III)-ion was preliminary explored. IR measurements of aqueous solutions of I in the presence of Fe(III) ion showed the possible chelating ability of all hydroxamic moieties. The chemical structures and properties of investigated compounds were derived from the results of IR, ¹H and ¹³C NMR, UV and MS spectrometric data, as well as thermogravimetric and potentiometric analysis.     

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.     

Unexpected behavior of 6H,13H-5:12,7:14-dimethanedibenzo[d,i][1,3,6,8]tetraazecine (DMDBTA) toward phenols

A new 20-membered octaazamacrocyclic compound named 1:4,6:9,11:14,16:19-tetramethylentetrabenzo[b,g,l,q][1,4,6,9,11,14,16,19]octaazaeicocine (TTBOE) (9) has been prepared by means of in situ one-pot synthesis between the aminal 6H,13H-5:12,7:14-dimethanedibenzo[d,i][1,3,6,8]tetraazecine (DMDBTA) (3) and electron-deficient phenols. Otherwise, electron-rich phenols such as 4-chloro-3,5-dimethylphenol or 2-naphthol produce an ortho-regioselective aminomethylation resulting in 2-(1H-benzimidazol-1-ylmethyl)-4-chloro-3,5-dimethylphenol (7) and 1-(1H-benzimidazol-1-ylmethyl)-2-naphthol (8) in a Mannich type reaction in a basic medium. Moreover, obtainment of 1,1′-methylenbis(1H-benzimidazole) (15) from TTBOE is discussed.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls by palladium-catalyzed Ullmann reaction

A novel palladium-catalyzed Ullmann protocol is described for the synthesis of 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls. In the presence of Pd(OAc)₂ and KOAc, intramolecular or intermolecular Ullmann coupling of aryl halides proceeds efficiently under ligand-free and aerobic conditions to afford the corresponding 6,7-dihydro-5H-dibenzo[c,e]azepines and biaryls in moderate to excellent yields.     

6,8-Dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione: new heterocyclizations based on SN-methodology. Unexpected formation of the first iso-π-electronic analogue of the still unknown dibenzo[a,o]pycene

N₍₂₎-Oxide and 3-amino derivatives of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione have been shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines or imidazoles. Both conversions based on S_N^H-strategy represent a new approach to imidazoline-(imidazole-)ring annulation. Heterocyclic analogues of the still unknown dibenzo[a,o]pycene were obtained as a by-products of the above transformations upon using of cyclohexylamine.     

N-Functionalised polyfluoropyridazin-3(2H)-one derivatives

Pyridazin-3(2H)-one systems have very useful biological properties and have found many applications within the pharmaceutical and agrochemical industries but, in general, synthesis of polysubstituted analogues can be very difficult to achieve. An approach to the syntheses of polyfunctional pyridazinone systems involving sequential nucleophilic substitution reactions of N-aryl and N-THP protected 4,5,6-trifluoropyridazin-3(2H)-ones as the core scaffolds is described.     

Unprecedented N(H)-bridged tetraaza[1.1.1.1]m,p,m,p-cyclophanes

The first uncatalyzed preparation of tetraaza[1.1.1.1]m,p,m,p-cyclophanes (symmetrical and unsymmetrical) gave access to previously unknown N(H)-bridged derivatives that could be further substituted. NMR studies and theoretical calculations show that these macrocycles adopt an 1,3-alternated conformation.     

Flash vacuum pyrolysis of 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2-vinyl-1H-pyrroles

The flash vacuum pyrolysis of new 1,1-dimethyl- and 1-methyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides gave penta-substituted 2-vinyl-1H-pyrroles via sigmatropic [1,8]-H shift of the corresponding azafulvenium methide intermediates. In some cases these 1H-pyrroles underwent rearrangement to 2-allyl-1H-pyrroles. Di-substituted 2-vinylpyrroles have also been prepared and their reactivity studied. Under FVP N-benzyl-pyrrol-2-ylpropenoates were converted into 3H-pyrrolizin-3-ones. On the other hand, microwave-assisted reaction of 1-benzyl-2-vinyl-1H-pyrrole gave a 4,5,6,7-tetrahydro-1H-indole derivative.     

A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.     

Water mediated catalyst-free efficient domino synthesis of 9-(quinolin-2(1H)-one)-xanthene-1,8(5H,9H)-diones using parallel synthesizer

A facile and efficient method for the preparation of 3,4,6,7-tetrahydro-9-(1,2-dihydro-2-oxoquinolin-3-yl)-2H-xanthene-1,8(5H,9H)-diones from substituted 2-chloro-3-formylquinoline and 1,3-cyclohexanedione or dimedone in water at 90 °C using parallel synthesizer is reported. The present methodology offers a tandem-cascade methodology, high yield, and operational simplicity.