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Modification of the quinolizine backbone of the alkaloid lupinine was carried out by introducing substituted 1,2,3-triazole. When NaN3 acts upon the product of the reaction of lupinine with methanesulfonyl chloride, lupinyl azide is formed which in the reaction with terminal alkynes in the presence of aqueous CuSO4 and sodium ascorbate forms the corresponding (1S,9aR)-1-[(1,2,3-triazol-1-yl)-methyl]octahydro-1H-quinolizines with various substituents at the C-4 position of the triazole ring. The structures of lupinine methanesulfonate and 1-[(1,2,3-triazol-1-yl)methyl]octahydroquinolizines were confirmed by X-ray structural analysis. 1-[(1,2,3-Triazol-1-yl)methyl]octahydroquinolizines containing a hydroxymethyl or 2-hydroxypropan-2-yl substituent at the C-4 position of the triazole ring exhibit pronounced analgesic activity.

A novel protocol for the synthesis of quinolizines (3) and quinolizinium salts (4) from chromone-3-carboxaldehydes 1 with ethyl 2-(pyridine-2-yl)acetate derivatives 2via an unprecedented cascade reaction in water was constructed. As a result, functionalized quinolizines (3) bearing a chromone skeleton were prepared by simple reflux of the mixture of chromone-3-carboxaldehydes with ethyl 2-(pyridine-2-yl)acetate derivatives in water. Quinolizinium salts (4) were also prepared in water under acidic conditions. The formation of quinolizinium salts was accompanied by the formation of two bonds and the cleavage of one bond in a single step. This protocol can be used in the synthesis of a wide variety of quinolizines and quinolizinium salts, and is suitable for combinatorial and parallel syntheses of quinolizine derivatives natural-like products. This approach has several advantages such as the use of an environmentally friendly solvent, simple and practical operation (with filtration and washing without column chromatography separation), excellent yields (83–96%), and formation of a product with potential biological activity.

2-Pyridone is characterized by a very wide range of reactivity of a different nature, ranging from electrophilic aromatic substitution, CH–metal-mediated reactions, and NH/OH functionalization of both possible lactam/lactim tautomers, through cycloaddition, to nucleophilic addition and transformation of the tautomeric C=O/C–OH moiety. The high availability of 2-pyridones and the possibility of their far-reaching functionalization additionally increased their values. Therefore, they are very useful building blocks for the synthesis of structurally diverse piperidine and pyridine compounds, including naturally occurring 2-pyridones. This review reports on the use of simple 2-pyridones in the synthesis of alkaloids and alkaloids-inspired compounds based on the piperidine or pyridine framework.1 Introduction2 Structure, Availability, and Reactivity of 2-Pyridones3 Monocyclic Piperidine Alkaloids from 2-Pyridones4 Polycyclic Alkaloids, Their Derivatives, and Alkaloid-Inspired Compounds from 2-Pyridones4.1 New Ring Formation Involving C/N Atoms of the 2-Pyridone Ring4.1.1 Indolizine-Fused 2-Pyridones: Camptothecins and Related Compounds4.1.2 Other Indolizines from 2-Pyridones4.1.3 Compounds Bearing the Quinolizine Ring System4.2 New Ring Formation Involving C/C Atoms of the 2-Pyridone Ring4.2.1 C-2/C-3 Ring Fusion4.2.2 C-3/C-4 Ring Fusion4.2.3 C-4/C-5 Ring Fusion4.2.4 C-5/C-6 Ring Fusion4.2.5 C-2/C-4 Ring Bridge4.2.6 C-2/C-6 Ring Bridge4.2.7 C-3/C-5 Ring Bridge4.2.8 C-3/C-6 Ring Bridge4.2.9 C-4/C-6 Ring Bridge5 Conclusion

Iridium(I) N-heterocyclic carbene complexes of formula Ir(κ2O,O’-BHetA)(IPr)(η2-coe) [BHetA=bis-heteroatomic acidato, acetylacetonate or acetate; IPr=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-carbene; coe=cyclooctene] have been prepared by treating Ir(κ2O,O’-BHetA)(η2-coe)2 complexes with IPr. These complexes react with 2-vinylpyridine to afford the hydrido-iridium(III)-alkenyl cyclometalated derivatives IrH(κ2O,O’-BHetA)(κ2N,C-C7H6N)(IPr) through the iridium(I) intermediate Ir(κ2O,O’-BHetA)(IPr)(η2-C7H7N). The cyclometalated IrH(κ2O,O’-acac)(κ2N,C–C7H6N)(IPr) complex efficiently catalyzes the hydroalkenylation of aromatic and aliphatic terminal alkynes and enynes with 2-vinylpyridine to afford 2-(4R-butadienyl)pyridines with Z,E configuration as the major reaction products (yield up to 89 %). In addition, unprecedented (Z)-2-butadienyl-5R-pyridine derivatives have been obtained as minor reaction products (yield up to 21 %) from the elusive 1Z,3gem-butadienyl hydroalkenylation products. These compounds undergo a thermal 6π-electrocyclization to afford bicyclic 4H-quinolizine derivatives that, under catalytic reaction conditions, tautomerize to 6H-quinolizine to afford the (Z)-2-(butadienyl)-5R-pyridine by a retro-electrocyclization reaction., Financial support from the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER) under Project PID2019-103965GB-I00, and the Departamento de Ciencia, Universidad y Sociedad del Conocimiento del Gobierno de Aragón (group E42_20R) is gratefully acknowledged. I.G. thanks the Humboldt Foundation for a research fellowship.

Here we report the 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with nitriles to produce highly fused imidazole derivatives, that is, tribenzo[b,g,ij]imidazo[2,1,5-de]quinolizine. The advantages of this transformation are the broad substrate scope and the good functional group compatibility. The subsequent palladium-catalyzed intramolecular cyclization provides an efficient approach to further π-extended imidazoles, that is, 14b1,15-diazadibenzo[fg,ij]cyclopenta[rst]pentaphene.

Indolo[2,3-a]quinolizidine 1 (Scheme 1) has an interesting history. First synthesized by Keufer1 in 1950, this tetracyclic amine was subsequently prepared by several others,2–7 only later to be dis...

An efficient synthesis of 6-oxo-1,2,3,4,5,7,12,12b-octahydroindolo[2,3-α]quinolizine from 2-acetylpyridine and phenylhydrazine is described. This derivative of the natural alkaloid desbromoarborescidine A is an important entry point to the sarpagine-vobasine family of plant alkaloids.

An activatable BODIPY probe for in vitro detection and fluorescence cell imaging of free Mg2+ without interference from Ca2+ is described. Fluorescence amplification of the probe is observed upon detection of physiological concentrations of Mg2+ due to reduced rotation of the fluorophore and effective chelation by a quinolizine-based core.

A method for preparation of thermodynamic (4R,11bS)-benzo[a]quinolizine-2-one derivatives in good enantio- and diastereoselectivity by a one-pot oxidative formal aza-Diels−Alder reaction of 1,2,3,4-tetrahydroisoquinolines and α,β-unsaturated ketones is described. The reaction proceeds via tandem Ru-catalyzed amine dehydrogenation using TBHP as the oxidant and a chiral thiourea-catalyzed formal aza-[4+2] cycloaddition, providing a step-economical strategy for synthesis of valuable heterocyclic products.

Phosphodiesterase 5A enzyme has been the upcoming and promising target in hypertension management. In this research, reported 270 bioactive natural products having antihypertensive potential were selected and docked against PDE5A using vLife MDS 4.6 software. Based on docking score, π-stacking, H-bond and ionic interactions with PDE5A, 82 tricyclic compounds were selected for further study. Protein residue Gln817A was associated in H-boding, Leu804A in ionic interaction whereas Val782A and Phe820A were associated in π-stacking interaction with ligand. In silico docking studies resulted in discovery of oxygen containing naphthofuran and nitrogen and oxygen containing pyrano quinolizine tricyclic lead scaffolds as novel PDE5A inhibitors. Additionally, developed pharmacophore model suggested that one centre of hydrogen bond acceptor, one aromatic centre and two aliphatic centres are minimum pharmacophoric features required in the molecule so as to show sildenafil like activity. The identified lead scaffolds would provide novel platform for drug discovery of bioactive natural products.

A Cu(OAc)2-catalyzed domino tricyclization between naphthalene-1,8-diamine and 2-(phenylethynyl)benzaldehyde is described, enabling aerobic oxidative dehydrogenation coupling to access heptacyclic quinolizino[3,4,5,6-kla]perimidines. In this reaction, the formation of three new rings and four new bonds was achieved in a functional-group-compatible fashion, allowing a facile method toward fused aza-heterocycles containing both quinolizine and perimidine moieties.

A facile multi-component process for the synthesis of perfluoroalkylated quinolizine derivatives was achieved using various arylidenemalononitriles, pyridine, and methyl perfluoroalk-2-ynoates as starting materials. Moderate yields were obtained under mild condition. The structures of perfluoroalkylated quinolizine derivatives were characterized by means of 1H NMR, 13C NMR, 19F NMR, IR, LRMS and HRMS. Furthermore, the reaction mechanism was proposed.

Ent-homocyclopiamine B (1), a new prenylated indole alkaloid bearing an alicyclic nitro group along with 2-methylbutane-1,2,4-triol (2) were isolated from an endophytic fungus Penicillium concentricum of the liverwort Trichocolea tomentella (Trichocoleaceae). The structure of 1 was elucidated through extensive spectroscopic analyses and comparison with data reported for a structurally related nitro-bearing Penicillium metabolite, clopiamine C (3), which contain an indolizidine ring instead of the quinolizine ring in 1. The new compound, ent-homocyclopiamine B, exhibited slight growth inhibition against Gram-positive bacteria. Based on the reported biosynthesis of related compounds and the isolation of the mevalonic acid derived compound 2-methyl-1,2,4-butanetriol (2), we proposed that ent-homocylopiamine B (1) was biosynthesized from lysine and prenyl group-producing mevalonic pathway.

The cascade oxidative annulation reactions of aryl imidazoles with two molecules of alkynes via multiple C-H activation proceed efficiently in the presence of [Cp*RhCl2]2 and Cu(OAc)2·H2O to give substituted benzo[ij]imidazo[2,1,5-de]quinolizine-based polyheteroaromatic compounds. This method is compatible with various functional groups, which are very useful for further synthetic transformations.

A facile synthetic method for the construction of 2-substituted-4-oxo-4H-quinolizine-based core structure has been successfully developed. The synthesis made use of a one-pot Stobbe condensation followed by cyclization starting from the commercially available 2-pyridinecarbaldehyde. The structure of the formed 4-oxo-4H-quinolizine-2-carboxylate was fully confirmed by mass spectra, 1H NMR and 13C NMR, correlation spectrography, heteronuclear multiple bond correlation, and heteronuclear single quantum coherence (HSQC) spectra. The ethyl carboxylate moiety was then further functionalized via direct aminolysis by a range of amines to afford the corresponding 4-oxo-4H-quinolizine-2-carboxamides 4a–i in moderate to good yields.

Pyridines were found to be a convenient nucleophile in the copper(I)-catalyzed synthesis of N-tosyl-4-iminoquinolizines from 2-pyridyl compounds. Intramolecular cyclization of an in situ generated ketenimine and a tethered pyridine, followed by a base-promoted oxidation, affords the desired products in moderate to good yields under mild reaction conditions.

The stereoselective synthesis of (−)-protoemetinol has been accomplished through nine steps from a known homoallylic amine. The key steps of the synthesis involve the efficient preparation of an aza-Claisen rearrangement (ACR) precursor using cross metathesis and amide enolate-induced ACR followed by acid-catalyzed transannulation for the elaboration of the benzo[α]quinolizine skeleton and three stereogenic centers. This unique synthetic route envisages a unified and versatile strategy for the synthesis of 2,3-disubstituted benzo[α]quinolizidine.

Novel, one-pot, three-component reactions of the zwitterions generated in situ from pyridine and acetylenic esters with alkoxymethylenemalononitriles via 1,4-dipolar cycloadditions are described. The reactions afforded dialkyl 1,1-dicyano-2-alkoxy-1,9a-dihydro-2H-quinolizine-3,4-dicarboxylate derivatives in good to high yields without using any catalyst or activation. Structural, electronic, energetic, and mechanistic details of the reaction are also revealed by density functional theory (DFT) calculations, which strongly support the exclusive formation of the observed products.

The three-component reactions of 4-dimethylamino- or 4-methoxypyridine with acetylenedicarboxylates and arylidene cyanoacetates showed very interesting molecular diversity. The polysubstituted 1,8,9,9a-tetrahydro-4H-1,4-ethanoquinolizines, 2H-pyran-2,3-dicarboxylates, and buta-1,3-diene-1,2,4-tricarboxylates derivatives can be formed in high yields and with good diastereoselectivity depending on the substrates and reaction conditions.

International audience; Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C₂ position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.

Three-component condensation of lower aliphatic aldehydes (C1-C3) with arylamines and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]-quinolines. Ozonization of their N-trifluoroacetyl derivatives afforded the corresponding ozonides. Cyclocondensation of 4-fluoroaniline with formaldehyde and cyclopentadiene gave earlier unknown 2-fluoro-3b,6,6a,7,9,9a,10,12a-octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential multicomponent reaction between tryptamine, α,β-unsaturated aldehydes, and β-dicarbonyl compounds affords highly substituted indolo[2,3-a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C-C and two C-N bonds by a domino process comprising initial β-enaminone formation, followed by individual Michael addition, 6-exo-trig cyclization, iminium formation, and Pictet-Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H-2 and H-12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5-bromotryptamine, 3,4-dimethoxyphenylethylamine) prevents the Pictet-Spengler final step and leads to N-indolylethyl or N-phenylethyl-1,4-dihydropyridines, which are cyclized to the corresponding indolo[2,3-a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3-a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers.

Starting from Boc-protected tryptamine and (S)-tetrahydro-5-oxo-2-furancarboxylic acid, facile enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine have been accomplished via a common intermediate (S)-indolo[2,3-a]quinolizine. Synthesis of enantiomerically pure (S)-acetoxyglutarimide, stereoselective reductive intramolecular cyclization, hydroxyl group-assisted in situ N-Boc-deprotection, selective deoxygenation of the xanthate ester, and lactam hydrolysis followed by an appropriate exchange of nitrogen regioselectivity in intramolecular cyclization were the decisive steps.

An expedited method was developed for the enantioselective synthesis of dodecahydrobenz[a]indolo[3,2-h]quinolizine containing five contiguous stereogenic centers with high enantioselectivities (99% ee). The methodology comprises a domino organocatalytic double Michael reaction and Pictet-Spengler-lactamization reaction. The structures and absolute configurations of the appropriate products were confirmed by X-ray analysis.

A facile multi-component process for the synthesis of perfluoroalkylated quinolizine derivatives was achieved using various arylidenemalononitriles, pyridine, and methyl perfluoroalk-2-ynoates as starting materials. Moderate yields were obtained under mild condition. The structures of perfluoroalkylated quinolizine derivatives were characterized by means of 1H NMR, 13C NMR, 19F NMR, IR, LRMS and HRMS. Furthermore, the reaction mechanism was proposed.

The aminobenzo[a]quinolizines were investigated as a novel class of DPP-IV inhibitors. The stereochemistry of this class plays an important role in the bioactivity. In this study, the mechanisms of how different configuration of three chiral centers of this class influences the binding affinity were investigated by molecular dynamics simulations, free energy decomposition analysis. The S configuration for chiral center 3* is decisive for isomers to maintain high bioactivity; the chirality effect of chiral center 2* on the binding affinity is largely dependent, while the S configuration for chiral center 2* is preferable to R configuration for the bioactivity gain; the effect of chiral center 11b* on the binding affinity is insignificant. The chirality specificity for three chiral centers is responsible for distinction of two van der Waals contacts with Tyr547 and Phe357, and of H-bonding interactions with Arg125 and Glu206. Particularly, the Arg125 to act as a bridge in the H-bonding network contributes to stable H-bonding interactions of isomer in DPP-IV active site.

The three-component reactions (TCRs) involving quinoline or isoquinoline, dialkyl acetylenedicarboxylate and β-trifluoroacetyl vinyl ethyl ether were investigated. The reaction proceeded smoothly under ambient temperature in DMSO to give the 4-trifluoroacetyl substituted benzo[c]quinolizine derivatives in moderate yields. However, under the same reaction condition, isoquinoline afforded the 2-trifluoromethyl substituted 1-oxa-(11H)-benzo[a]dihydroquinolizine or 4-trifluoroacetyl substituted benzo[a]dihydroquinolizine products. The possible reaction pathways were proposed.

Ionic liquids were found to be a suitable reaction medium for 1,4-dipolar cycloaddition reactions of an isoquinoline, an activated alkyne, and a 4-oxo-4H-1-benzopyran-3-carboxaldehyde at room temperature to afford [1]benzopyrano-pyrido-isoquinoline (=9aH,15H-benzo[a][1]benzopyrano[2,3-h]quinolizine) derivatives selectively in good yields. The ionic liquid can be recovered and recycled in further runs without loss of activity.

Phosphane-free Pd0-catalyzed intramolecular aromatic amination was studied. o-Halophenethylamines and 3-(o-halophenyl)propylamines were found to be transformed into indolines and quinolines in a catalytic system based on Pd(OAc)2 and Cu(OAc)2 in the presence of K2CO3. Application of the method to substrates containing isoquinoline rings – the 1-(o-bromobenzyl)-3,4-dihydroisoquinolines 6, the 1-(o-bromobenzyl)-1,2,3,4-tetrahydroisoquinolines 7, and the 1-(o-bromophenethyl)isoquinolines 9 – provided the indolo[2,1-a]isoquinoline and dibenzo[a,f]quinolizine ring systems 8 and 10. Extension of the method to β-carbolines (compounds 11, 12, and 17) produced the benz[f]indolo[2,3-a]indolizine-13-ones 15 and the benz[f]indolo[2,3-a]quinolizine 18. The benzo[f]pyrido[3,4-a]indolizine and indolo[f]pyrido[3,4-a]indolizin-12-one ring systems 27 and 31 were built in a similar manner. It was also found that under an atmosphere of CO the same catalytic system produced the corresponding benzolactams, the isoquino[2,1-a][2,7]naphthyridine 34 and the indolo[2,3-a]pyrido[g]quinolizin-8-one 36 [(±)-dihydronauclefine] in good yields.

This review summarizes recent medicinal chemistry investigations in vitro and in vivo in search for new phenothiazines of promising biological activities. New phenothiazine derivatives (over 50 main structures) contain dialkylaminoalkyl, cycloaminoalkyl and aminoalkyl substituents and their acyl and sulfonyl derivatives, and other substituents with varied the monocyclic (pyrazole, thiazole, oxadiazole, thiadiazole, tetrazole) and bicyclic (quinolizine, pyrazolopyrimidine, thiazolopyridine, azabicyclononane and spiro[chromanpyrimidine] heterocycles linked directly or via the alkyl chain with the thiazine nitrogen atom or with the benzene ring. The modifications of the tricyclic ring system with the bicyclic homoaromatic ring (naphthalene) and monocyclic and bicyclic azine rings (pyridine, pyrimidine, pyrazine and quinoline) led to compounds of significant biological activities. Recently obtained phenothiazines exhibit promising antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antimalarial, antifilarial, trypanocidal, anticonvulsant, analgesic, immunosuppressive and multidrug resistance reversal properties. These activities were the results of the actions of phenothiazines on biological systems via the interaction of the pharmacophoric substituent (in some cases of strict length), via the interaction of the multicyclic ring system (π-π interaction, intercalation in DNA) and via the lipophilic character allowing the penetration through the biological membranes. The activities were examined by using various biological systems such as cell lines, bacteria, viruses, parasites, laboratory mice, rats and rabbits, and monolayer and bilayer membranes. Some mechanisms of the actions are discussed. This review shows current tendency in the phenothiazine synthesis (without synthetic routes) and reveals the phenothiazine core to be very potent pharmacophoric moiety which can be a rich source of new compounds having desirable biological activities.

Room temperature ionic liquids are rapidly emerging as a new class of media that are ideally suited for various applications including carrying out chemical reactions. In the present article, we report the photophysics of a β-carboline analogue, namely, 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine (AODIQ), in three room temperature ionic liquids (RTILs), 1-butyl-3-methylimidazolium methyl sulfate ([BMIM][MeSO(4)]), 1-butyl-3-methylimidazolium octyl sulfate ([BMIM][C(8)SO(4)]) and 1-ethyl-3-methylimidazolium methyl sulfate ([EMIM][MeSO(4)]). Out of these, [BMIM][C(8)SO(4)] is a typical RTIL that forms micellar aggregates above a critical micellar concentration (CMC). Steady state absorption, steady state and time resolved fluorescence techniques are used to probe the properties of these systems. The investigation reveals that the photophysics of AODIQ is modified significantly in the micelle-forming RTIL as compared to that in the other two. A comparative study with the fluorophore in [BMIM][C(8)SO(4)] and a conventional anionic surfactant of a similar hydrophobic chain length from the sodium-n-alkyl sulfate series, viz., sodium octyl sulfate (S(8)S), reveals that the fluorophore experiences a more constrained environment in the RTIL micelle as compared to the conventional anionic micelle.

Cyclopenta[a]quinolizine, a novel tricyclic pseudoazulene, was prepared by reaction of cyclopentadienyllithium with oxazolo[3,2-a]pyridinium or substituted pyridinium salts. Structural analysis (X-ray analysis, NMR and UV spectroscopy) and DFT calculations confirm its highly dipolar nature (due to delocalization of the negative charge around the five-membered ring) combined with partial localization of bonds in both six-membered rings.

We report a highly diastereoselective approach for the synthesis of a functionalized dodecahydrobenz[a]indolo[3,2-h]quinolizine ring system that is present as the heterocyclic core of the manadomanzamine alkaloids. We have achieved complete control over the relative and absolute stereochemistries at the three contiguous stereocentres at ring positions 1, 10 and 24 in only two linear synthetic steps. The introduction of useful functionality to the heterocyclic skeleton is significant as this may allow for future derivatization, and application of this route in an asymmetric synthesis of the manadomanzamine natural products.

In the synthesis of 4H-quinolizine derivatives involving the use of a sulfonyl ketene dithioacetal, we found a novel reaction in which the remaining methylsulfanyl group was replaced with a proton after the ring-closure reaction in the quinolizine skeleton under mild conditions, without the use of any metallic reagent. The reaction of 3,3-bis(methylsulfanyl)-2-phenylsulfonylacrylonitriles (1a,b) with 2-pyridylacetonitrile (2a) in the presence of potassium carbonate as a base in DMSO afforded 4-imino-2-methylsulfanyl-3-phenylsulfonyl-4H-quinolizine-1-carbonitriles (3a,b). The methylsulfanyl group at the 2-position of 3a,b was readily removed under methanol reflux conditions to afford 4-imino-3-phenylsulfonyl-4H-quinolizine-1-carbonitriles (4a,b) in good yields. Alkyl 3-phenylsulfonyl-4H-quinolizine-1-carboxylates (4c-f) were directly synthesized from sulfonyl ketene dithioacetal (1a,b) with alkyl 2-pyridylacetates (2b,c) and involved desulfanylation by simple hydrolysis. In addition, the fluorescent properties of these compounds were investigated., European Journal of Organic Chemistry, 2009(33), pp.5847-5853; 2009

In the present work the rotational dynamics of a polarity sensitive biologically active β-carboline derivative, 3-acetyl-4-oxo-6,7-dihydro-12H indolo-[2,3-a] quinolizine (AODIQ), have been discussed in three native cyclodextrin environments using ultrafast time-resolved fluorescence technique. AODIQ exhibited bi-exponential anisotropy decay in the cyclodextrin environments. The rotational motion of the probe was interpreted on the basis of two independent motion; local (internal motion of the guest within the aggregate) and global (overall rotational tumbling of the complexes). It is found that the cyclodextrin environment causes significant retardation of rotational motion of the probe. Experimental results reveal that relative host–guest size determines the character of the intermolecular host–guest dynamics.

Polycyclic quinolizine derivatives, quinolizino[3,2-α]quinolizines (4a-c), were synthesized in moderate yields by a one-pot method using ketene dithioacetal, methyl bis(methylsulfanyl)methylene-cyanoacetate (2), alkyl 2-pyridylacetates (1a, b), and 2-pyridylacetonitrile (1c). Compounds 4a, b exhibited red fluorescence (Em max: 576 nm) in solid state., HETEROCYCLES, 78(5), pp.1271-1279; 2009

The cyclization via the mechanism of “tert-amino effect” of 2-(4-R-piperidino)benzaldehydes with cyclic active methylene components (Meldrum’s acid, 1,3-cyclohexanedione, and N,N-disubstituted barbituric acids) proceeded stereoselectively giving spiro-joined 2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizines with axially oriented hydrogen atoms in the positions 3 and 4a of the benzo[c]quinolizine ring.

A highly efficient total synthesis of (+/-)-yohimbenone and a formal synthesis of (+/-)-emetine is described. The key element of the synthesis consists of a conjugate addition-dipolar cycloaddition of 2,3-bis(phenylsulfonyl)-1,3-butadiene with an appropriate oxime. The resulting cycloadducts are cleaved reductively to provide azapolycyclic scaffolds with strategically placed functionality for further manipulation to the target compounds.

A short and efficient synthesis for a series of 1,6-diaryl- 3,4-diarylaminohexa-2,4-diene-1,6-diones was developed. Based on the acylation-prototropism sequence during the reaction of vari- ous aryl methyl ketones with bis-imidoyl chlorides, the products were isolated in good yields. Substituted acetophenones, acetyl- thiophene, 3-acetylpyridine, and acetylferrocene can be integrated into this reaction as ketone component. Similarly, a-tetralone can be transformed with bis-electrophiles into the corresponding bis- enaminones. Treatment of 2-acetylpyridine with N,N¢-bis(4- tolyl)ethanebis(imidoyl) dichloride yielded not only the expected bis-enaminone, but also a new quinolizine derivative which was structurally characterized by single crystal X-ray analysis. Analo- gously, pinacolone and cyclopropyl methyl ketone can readily be converted into bis-enaminones. Monoimidoyl chlorides showed the same reactivity, providing derivatives in high yields.

New fluorescent compounds 1,11-dihydro-11-imino-1-oxo-3-phenylpyrano[4,3-b]quinolizines were synthesized in good yields by the reaction of 6-aryl-3-cyano-4-methylsulfanyl-2H-pyrones and 4-methylsulfanyl-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-carbonitrile with 2-pyridylacetates. These fused quinolizine derivatives exhibited fluorescence in solid and solution states.

A three-step synthesis of (±)-harmacine is described from the readily available 4,4-diethoxybutan-1-amine via an acid-mediated acyl iminium ion cyclisation. The synthesis of the homologous (±)1,2,3,4,6,7,12,12b-octahydroindole[2,3-a]quinolizine from 5,5-diethoxypentan-1-amine is also described. Although similar, the two systems required very different cyclisation conditions.

In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.

The synthesis of 2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4′-pyrazol]-5′-ones has been achieved by the reaction of 2-piperidinobenzaldehydes with 2-aryl-5-methyl-2,4-dihydropyrazol-3-one via the “tert-amino effect” mechanism.

Synthesis of some novel classes of quinolizine-, indolizine- and pyrido-1,4-oxazine-fused quinoline derivatives via a three-component reaction under solvent-free conditions by exploring the 'tertiary amine effect' reaction strategy.

Total synthesis of the two series of new pentacycilc cycloalk[g]indolo[2,3-a]quinolizine alkaloids (modified sempervirine possessing the wide range of activity), has been elaborated in five steps from 5-acetyl-3-methylthio-1,2,4-triazine (obtained from the simple acyclic materials). In the two key steps: inverse electron demand Diels–Alder reaction of precursor with cyclic enamines and the following Fischer indolization of 3-acetyl-1-methylthiocycloalka[c]pyridines, the AB–DE synthons, has been obtained. The final stages: desulfuration, and formation of the C-ring via the Gribble method have led to the expected zwitterionic alkaloids. Model syntheses of the indolopyridocoline and its methoxy analogue from 2-acetylpyridine have been performed for investigation of the microwave-induced Fischer synthesis of sensitive indoles and for obtaining compounds for comparative study of spectroscopic data.

A new procedure has been developed for the synthesis of fused nitrogen-containing heterocycles having a bridgehead nitrogen atom via condensation of cyclic Schiff bases with β-keto esters.

We present a facile and highly stereoselective approach to the indolo[2,3-a]quinolizine ring system from a readily available, non-racemic chiral template. We demonstrate the potential for application of this methodology to natural product synthesis through conversion of the template to some representative indole alkaloids with high enantiomeric purity in both enantiomeric series. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

4-Hetaryl and 4-tosyl-1,2,3,3a,4,5-hexahydropyrrolo[l,2-a]quinoline-4-carbonitriles were prepared in two steps by the condensation of 2-(l-pyrrolidinyl)benzaldehydes with substituted acetonitriles XCH 2 CN (X = hetaryl, tosyl), followed by the thermal cyclization of the corresponding arylidene derivatives. Similarly, starting from 2-(l-piperidinyl)benzaldehydes 5-hetaryl and 5-tosyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[l,2-a]qumoline-5-carbonitriles were obtained. For the hetaryl-substituted derivatives the cyclization step was found to be assisted by protons. In addition 4,5,5a,6,7,8-hexahydro-1H-pyrazolo[3,4-e]indolizine and l,4,5,5a,6,7,8,9-octahydro-pyrazolo[4,3-c]quinolizine derivatives were prepared by the same method starting from 5-(1-pyrrolidinyl)-and 5-(1-piperidinyl)-3-methyl-l-phenylpyrazole-4-carbaldehydes. The relative configuration between the bridgehead hydrogen and the cyano group was assigned as trans on the basis of x-ray crystallographic data.