Dendritic polyallyl and polyferrocenyl bipyridine ligands: Synthesis, MALDI-TOF characterization and ruthenium(II) complexation studies

A series of 6- and 18-armed dendritic polyallyl- and polyferrocenyl-containing bipyridine ligands were synthesized through the coupling reaction of 4,4′-bis(bromomethyl)-2,2′-bipyridine with AB₃ and AB₉ dendrons. All these bipyridine ligands were successfully characterized using standard physico-chemical techniques as well as MALDI-TOF mass spectrometric analysis. The complexation studies of these ligands toward RuCl₂(bpy)₂ indicated that, in contrast to the bulky 18-ferrocenyl bipyridine ligand 7, the 6-allyl 4 and the 18-allyl 5 bipyridine ligands react with Ru(bpy)₂Cl₂ to give the corresponding ruthenium(II) complexes 9 and 10. In the case of ligand 7, the steric bulk of the two nonaferrocenyl wedges at the 4,4′-position of the bipyridine moiety prevents the conversion of the transoid structure of the ligand to the cisiod structure needed for chelation to the metal. Thus, the 18-ferrocenyl ruthenium(II) dendrimer was not obtained. Metallodendrimers 9 and 10 have been characterized by a combination of analytical methods, especially MALDI-TOF mass spectrometric techniques. The hydrogenation of the 6-allyl ruthenium(II) dendrimer 9 in the presence of Pd/C catalyst gave the expected n-propyl complex 11. This reaction constitutes a new way for the direct synthesis of alkyl bipyridine metallodendrimers. The coordination of the alkene dendritic bipyridine ligand to the metal before the catalytic hydrogenation is absolutely necessary, because of their poisoning effect for the catalyst.     

Synthesis of a tetraoxy-bis-nortaxadiene, en route to taxol, using a cascade radical cyclisation sequence

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu₃SnH-AIBN did not lead to the oxy-substituted taxadiene 37 expected from a tandem radical macrocyclisation-radical transannulation sequence; instead, a mixture of unidentified products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu₃SnH-AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36, underwent a tandem radical macrocyclisation-transannulation sequence, when treated with Bu₃SnH-AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an intramolecular oxy-Michael reaction.     

Regioselective reductive opening of substituted phthalans: synthetic applications

The reductive opening of substituted phthalans 6, 11, 12, 20, 21 and 28 with lithium and a catalytic amount of DTBB leads to the formation of corresponding functionalised organolithium intermediates 8, 15, 16, 23, 25 and 29+30 in a regioselective manner. The further reaction of these dianions with different electrophiles, mainly carbonyl compounds, gives the expected functionalised benzylic alcohols 9, 17, 18, 24, 26 and 31+32. The observed stereochemistry can be easily explained taking into account the values of the electron densities deduced by semiempirical PM3 calculations.     

Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines

A facile and expeditious synthetic approach for the synthesis of α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals 1 with cyclic and acyclic secondary amines 2.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.     

Effect of ancillary ligands on the properties of heteroleptic green iridium dendrimers functionalized with carbazole dendrons

A series of heteroleptic green iridium dendrimers functionalized with carbazole dendrons, such as G2(pic) and G2(acac), have been synthesized, in which picolinic acid and acetylacetone are used as the ancillary ligands, respectively. Compared with the corresponding homoleptic iridium dendrimer G2 (8%), these heteroleptic ones can be prepared under mild conditions with total yields as high as 55-67%. Both the dendrimer G2(pic) and G2(acac) display bright green emissions with photoluminescence quantum yields higher than 0.80 in toluene solution. As a result, a maximum external quantum efficiency of 7.1% (21.0 cd/A) for G2(pic) and 7.7% (25.8 cd/A) for G2(acac) has been realized based on non-doped device configuration. The state-of-art performance indicates that the heteroleptic dendrimers can be promising candidates used for non-doped electrophosphorescent devices, especially when the ease of synthesis in a large scale is considered.     

A practical one-pot procedure for the synthesis of pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidinones by a tandem aza-Wittig/heterocumulene-mediated annulation strategy

A simple one-pot and efficient method is described for the synthesis of pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidinone derivatives 6 via a tandem aza-Wittig/heterocumulene-mediated annulation process. The iminophosphorane 3 reacted with aryl isocyanates, followed by heterocyclization on addition of secondary amines to give the corresponding guanidine intermediates 5, which were cyclized in the presence of a catalytic amount of potassium carbonate to tricyclic compounds 6. Similarly, iminophosphorane 3 reacts with phenols, thiophenol, or ROH to give 2-aryl(alkyl)oxy(thio)pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidinone derivatives 7 in good yields. The corresponding carbodiimide 4c and guanidine-type intermediate compounds 5 could be isolated and characterized, thus confirming the suggested reaction pathway. However, two isomeric pyrazinothienopyrimidinones 8 and 9 may be produced in the reaction of iminophosphorane 3 with aromatic isocyanates and subsequent reaction with primary amines in the presence of a catalytic amount of potassium carbonate. The effects of the nucleophiles and isocyanates on the regioselectivity of the cyclization have been investigated.     

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodifluoromethyl ketones 2 in good yields. The reaction of 1a with electrophilic reagent ICl yielded α-iodoenone 4. The substitution reaction of the cyclic enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate yields.     

An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea with alkyl and aryl amines under mild conditions

An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea 5 with alkyl and aryl amines under mild conditions has been developed. In the presence of NaH as a base, trifluoroacetic anhydride (TFAA) reacted with 5 providing intermediate 6, which then reacted with amines giving thioureas 7 in excellent yields. This reaction conditions tolerated other functional groups such as amide, ester, enol ether and hydroxyl groups.     

Efficient synthesis of various acycloalkenyl derivatives of pyrimidine using cross-metathesis and Pd(0) methodologies

Novel acyclonucleosides (9a-d, 10a-d, 18a,b and 19a,b) have been prepared using Pd(0) and cross-metathesis methodologies. The allylic N-alkylation under Tsuji-Trost conditions was used to introduce the nucleobase, while the Suzuki-Miyaura reaction afforded C-5 substituted uracil analogues. The cross-metathesis performed with a ruthenium catalyst was used to provide new acycloalkenyl nucleosides. The antiviral activities of all final compounds have been evaluated.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Chemoenzymatic enantiodivergent total syntheses of (+)- and (−)-codeine

Whole-cell fermentation of β-bromoethylbenzene with the recombinant strain Escherichia coli JM109 (pDTG601) that over-expresses toluene dioxygenase provided the corresponding cis-dihydrodiol 19, which served as a starting material for both enantiomers of codeine. The key intermediate for the synthesis of (+)-codeine was diol 25b, whose Mitsunobu coupling with bromoisovanillin was followed by an intramolecular Heck cyclization to aldehyde 35b. Elaboration of this material to vinyl bromide 27b allowed for the second Heck cyclization 36b. Adjustment of the C-6 stereogenic center and hydroamination completed the synthesis of ent-codeine in 14 steps from β-bromoethylbenzene. Diol 33b was converted via Mitsunobu reaction to epoxide 29, whose allylic opening with bromoisovanillin provided ether 54, the enantiomer of 35b. The synthesis of (−)-codeine was completed via two Heck cyclizations and a hydroamination protocol, in an analogous manner as that of ent-codeine. In addition, both enantiomers of epoxide 29, convenient precursors for the coupling with bromoisovanillin, were prepared from diol 33b by Mitsunobu reactions and cyclizations of the trans-diol moiety. Spectral and experimental data are provided for all compounds.     

Synthesis of new biologically active isothiazolo[4,5-b]carbazole-type tetracyclic derivatives via an indole-2,3-quinodimethane approach

A number of isothiazolo[4,5-b]carbazole derivatives were prepared via a Diels–Alder approach involving thermally induced indole-2,3-quinodimethane intermediates. Preliminary biological tests revealed a GSK-3β kinase inhibitor (29) and some free NH group containing compounds (17d, 19c, 29) displayed selective human carbonic anhydrase I inhibitory activities.     

Derivation of saddle shaped cyclooctatetrathiophene: increasing conjugation and fabricating pentamer

With cyclooctatetrathiophene (COTh) as building block, two α,α,α,α-tetraaryl COThs, COThP and COThTh have been efficiently synthesized. Phenyl and thienyl were employed as end-capping groups to introduce to COTh and increase its conjugation. For enlarging the special ‘saddle’ shaped structure, a pentamer of COTh was synthesized via Negishi reaction and CuCl₂-promoted oxidative coupling reaction. The pentamer (COThF) is a new type of dendrimer with COTh as dendron, which presents an artistic configuration possessing a large saddle shape. All compounds were fully characterized by ¹H NMR, ¹³C NMR, HRMS and IR. The crystal structures of COThP and COThTh were confirmed by X-ray analysis. The molecular configuration of COThF was optimized by theoretical calculations. Their UV–vis properties, electrochemical behaviours and thermo-gravimetric analysis of COThP, COThTh and COThF were also described.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Application of the aza-Wittig reaction to the synthesis of pyrazinothienotriazolopyrimidinones: a new tetracyclic ring system

A simple one-pot and efficient method is described for the synthesis of pyrazinothienopyrimidines 6 by domino processes involving aza-Wittig/intermolecular nucleophilic addition/intramolecular cyclization. A tandem aza-Wittig reaction of phosphazenes 7, derived from 6, with heterocumulenes (isocyanates, carbon disulfide or carbon dioxide) generates the pyrazinothienotriazolopyrimidinones 9, 11 and 12, respectively. Pyrazino[2′,3′:4,5]thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-4(3H)-ones 15 and bis(pyrazinothienotriazolopyrimidinones) 17 were synthesized by the intermolecular aza-Wittig reaction of phosphazenes 7 with acyl chlorides or α,ω-dichlorides followed by heterocyclization via imidoyl chloride intermediate 16. Further S-alkylation of 11 and reaction of 6 with phosgeniminium chloride produce 2-alkylthio- and 2-N,N-dimethylaminopyrazinothienotriazolopyrimidinones 13 and 19, respectively.     

Cyanuric and thiocyanuric esters as carriers of boron-containing fragments and their fragmentation in mass spectrometry

Tripropargylic esters 2 and 10 of cyanuric and thiocyanuric acids were synthesized. Interaction of these compounds with disubstituted amines gives monoaminoderivatives of dipropargyloxy-s-triazine 4 and 11. Diaminosubstituted propargyloxy-s-triazine 6 was prepared from the corresponding diaminochloroderivative 5. First examples of boron-containing s-triazines 7, 8, 12, 13 were prepared by reaction of propargyl esters 4, 6, 10, 11 with decaborane. New rearrangements of the molecular ions of the 2-aminoderivatives of 4,6-dipropargyloxy-1,3,5-triazine in mass spectrometry were found.     

Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration-demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet-Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.     

Unexpected regiospecific reactivity of a substituted phthalic anhydride

Regioselective nucleophilic addition at C1 of anhydride 7 by a range of nucleophiles occurs to produce amide, ester and thioester derivatives 8-15 (60-99%). The increased electrophilic reactivity of the C1 carbonyl group of anhydride 7 is supported by a competition experiment with phthalic anhydride. Unexpected formation of lactams 18 and 19 from amides 12 and 13 was shown to proceed via the lactamols 16 and 17 and could be controlled by the reaction conditions. The solid-state structure of 19 is reported.     

Ring transformation of chromone-3-carboxamide

4-Hydroxycoumarin-3-carboxaldehyde (5) was obtained from chromone-3-carboxaldehyde (1) via chromone-3-carboxamide (2) and 3-aminomethylene-2H-chroman-2,4-dione (3). 3-Alkylaminomethylenechroman-2,4-diones (7,8) were obtained from the reaction of primary aliphatic amines with chromone-3-carboxamide (2). Treatment of chromone-3-carboxamide with sodium methoxide gives 3-(2-hydroxybenzoyl)-2H-chromeno[2,3-b]pyridine-2,5(1H)-dione (9).