Nitrogen bridgehead compounds. Part 55 Synthesis of substituted 7,8-dihydro-5H,13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones

Fischer indolization of 6-arylhydrazono-6,7,8,9-tetahydro-11H-pyrido[2,1-b]quinazolin-11-ones 1 afforded substituted 7,8-dihydro-5H,13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones 3-12 in high yields.     

2-Oxobenzo[h]chromene: a novel entry for the synthesis of functionalized angular polycyclic azaarenes

An efficient and short synthesis of (5,6-dihydrobenzo[h]pyrido[2,1-b]quinazolin-2-ylidene)acetonitriles, (5,6-dihydrobenzo[h]pyrazino[2,1-b]quinazolin-2-ylidene)acetonitriles and (5,6-dihydrobenzimidazo[1,2-b]benzo[f]isoquinolin-7-yl)acetonitriles in good yields is delineated through base catalyzed ring transformation of 4-(piperidin-1-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 2-amino-pyridine, 2-aminopyrazine and (imidazo-2-yl)acetonitrile.     

Nitrogen bridgehead compounds. Part 72 Straightforward synthesis of 1,2,3,4-tetrahydrorutaecarpine and derivatives

In polyphosphoric acid, the Fischer indolization of 6-arylhydrazono-1,2,3,4,6,7,8,9-octahydro-11H-pyrido-[2,1-b]quinazolin-11-ones, obtained from 1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazolin-11-ones by three pathways, afforded substituted 1,2,3,4,7,8-hexahydro-5H-13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones in high yields. The structures of the 6-substituted octahydropyridoquinazolinones and hexahydroindo-lopyridoquinazolinones were characterized by uv, ¹H and ¹³C nmr data.     

Indoloquinazoline Alkaloids from Araliopsis tabouensis

Three new indoloquinazolidine‐type alkaloids, 8,13‐dihydro‐2‐methoxyindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 1 ), 8,13‐dihydro‐2‐methoxy‐13‐methylindolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolin‐5(7H)‐one ( 2 ), and 5,8,13,14‐tetrahydro‐2‐methoxy‐14‐methyl‐5‐oxo‐7H‐indolo[2′,3′: 3,4]pyrido[2,1‐b]quinazolim‐6‐iun chloride ( 3 ) were isolated from Araliopsis tabouensis, together with three known compounds. The structures of the new compounds were determined primarily from 1D‐ and 2D‐NMR analysis. The antimalarial activities of compounds 1 – 5 were evaluated against Plasmodium falciparum D6 and W2 clones. The IC₅₀ values in antimalarial bioassay for compounds 2 – 5 varied from 1.8 to 4.7 μg/ml.     

Synthesis of palladium–biscarbene complexes derived from 1,1′-methylenebis(1,2,4-triazole) functionalized in the methylene bridge

Palladium–biscarbene complexes derived from N,N′-bis(1,2,4-triazol-1-yl)methane, which bear an alkyl chain functionalized with a hydroxyl group, have been synthesized ([Pd(L1)Br₂] (6) and [Pd(L1)I₂] (7) [L1 = 1,1′-(3-hydroxypropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)]). Each product is obtained as a non-equimolecular mixture of two conformers. The hydroxyl group has been replaced by bromide and methanesulphonate and ( [Pd(L2)Br₂] [L2 = 1,1′-(3-bromopropylidene)bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (9)) and ([Pd(L3)Br₂] [L3 = 1,1′-(3-methanesulphonyloxypropylidene)-bis(4-butyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene)] (10)) were obtained, respectively, as mixtures of conformers. All compounds consist of a six-membered metallacyclic structure in a boat conformation. Major conformers present the functionalized chain in the axial position, while in minor conformers it is located in the equatorial position.     

Alkylation of pyrimido[5′,4′:5,6]pyrido[3,2-b]indol-4-one derivatives

Alkylation of 11-benzyl-3,11-dihydro-4H-pyrimido[5′,4′:5,6]pyrido[3,2-b]indol-4-one with methyl iodide and methyl bromoacetate in DMF gave 3-alkylpyrimidopyridoindolones as the corresponding salts. The reaction in acetone in the presence of K₂CO₃ yielded 3,6-disubstitution products. Alkylation with DMF dimethyl acetal gave a mixture of the 3- and 6-alkylpyrimidopyridoindol-4-one bases. The structure of 4-oxo-4,6-dihydro-3H-pyrimido-[5′,4′:5,6]pyrido[3,2-b]indol-11-ium chloride (3b) was proved by X-ray diffraction analysis.     

Domino reactions in the synthesis of benzothieno[2,3-c]pyridines. New one-pot method of preparing 2-([1]benzothieno-[2,3-c]pyridin-1-yl)benzoic acids and 8,13b-dihydro[1]benzothieno[2',3':3,4]pyrido-[2,1-a]isoindol-5(7?H)-ones

A series of previously unknown 2-([1]benzothieno[2,3-c]pyridin-1-yl)benzoic acids and 8,13b-dihydro-[1]benzothieno[2',3':3,4]pyrido[2,1-a]isoindol-5(7 H)-ones has been synthesized using domino reactions, taking place at the cyclization of 2-[3-oxo-4-(phenylsulfanyl)butyl]-1,3-isoindolinediones in polyphosphoric acid.     

anti-Tuberculosis natural products: synthesis and biological evaluation of pyridoacridine alkaloids related to ascididemin

There is an urgent need for novel therapeutics possessing new modes of action to treat tuberculosis (TB) infections. In this study we report on the synthesis and biological evaluation of a series of pyrido[2,3,4-kl]acridin-6-one alkaloids related to the anti-TB (MIC 0.35 μM) but cytotoxic (IC₅₀ <0.14 μM) marine natural product ascididemin (1). The most interesting compounds identified were 21 and 24, which were found to inhibit the growth of Mycobacterium tuberculosis (Mtb) H₃₇Rv with MIC 2.0 μM, but with negligible cytotoxicity towards Vero and P388 cells (IC₅₀>25 μM). Another analogue (10) was evaluated against a range of singly-drug-resistant strains of Mtb and was found to exhibit no cross-resistance. These results suggest that the pyrido[2,3,4-kl]acridin-6-one skeleton may provide a useful scaffold for future studies directed towards possible anti-TB drugs.     

Five-membered 2,3-dioxoheterocycles: LVIII. Reaction of methyl 1-Aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrol-2-carboxylates with substituted 1-methyl-3,4-dihydroisoquinolines. New approach to the synthesis of steroid 13-azaanalogs

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with substituted 1-methyl-3,4-dihydroisoquinolines with the formation of substituted 3-oxo-2,3,5,6-tetra-hydropyrrolo[2,1-a]-isoquinoline-2-spiro-2′-(1-aryl-3-aroyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrroles). A new approach was developed to the synthesis of 13-azagonanes, substituted benzo[f]pyrrolo[2,1-a]isoquinoline-9-spiro-2′-pyrroles.     

Multicomponent access to novel dihydroimidazo[1′,5′:1,2]pyrido[3,4-b]indol-2-ium salts and indoles by means of Ugi/Bischler–Napieralski/heterocyclization two step strategy

A simple, efficient and general two step procedure, through a sequential Ugi reaction followed by a Bischler–Napieralski/heterocyclization tandem closure, to give novel 6,11-dihydro-5H-imidazo[1′,5′:1,2]pyrido[3,4-b]indol-2-ium salt derivatives, is described. By changing the amine and the acid components with ammonium formate, the same procedure affords 6,11-dihydro-5H-imidazo[1′,5′:1,2]pyrido[3,4-b]indole derivatives.     

Action of 1,2-diamines and o-aminophenols on 1-alkyl-3-carboxyindole-2-acetic acid anhydrides. Preparation of new ring systems

1-Alkyl-3-carboxyindole-2-acetic acid anhydrides (I) react with ethylenediamine and with o-phenylenediamine to give directly 10-alkylimidazo[3,2:1′,2′]pyrido[4,5-b]indol-5(1H)-ones (II) and 5,6-dihydro-5-alkyl-13H-indolo[2′,3′:4,5]pyrido[1,2-a]benzimidazol-13-one (V), respectively. However, anhydrides I react with o-aminophenol and with o-aminothiophenol to give carboxyindole-acetanilide derivatives IX, which can be cyclised to indolo[2′,3′:4,5]pyrido[2,1-b]benzoxazolone and indolo[2′,3′:4,5]pyrido[2,1-b]benzthiazolone (XI). Some derivatives of II and V were prepared to help in elucidating the structures.     

Simple and practical method for selective acylation of primary hydroxy group catalyzed by N-methyl-2-phenylimidazole (Ph-NMI) or 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT)

N-Methyl-2-phenylimidazole (Ph-NMI) and 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT) catalyzed selective acylation of primary alcohols using acid anhydrides. The Ph-NMI- or Ph-IBT-catalyzed reaction using (PhCO)₂O as an acylating agent could particularly acylate the primary hydroxy group of 1,n-diols (n ⩾ 3) with a high, synthetically useful selectivity.     

Trinuclear copper(I) complex of 1,3-bis(2-pyridinylmethyl)imidazolylidene as a carbene-transfer reagent for the preparation of catalytically active nickel(II) and palladium(II) complexes

Reactions of 1,3-bis(pyridin-2-ylmethyl)-1H-imidazol-3-ium hexafluorophosphate, ([HL1](PF₆), L1 = 1,3-bis(pyridin-2-ylmethyl)imidazolylidene) and 1,3-bis(pyridin-2-ylmethyl)-1H-benzimidazol-3-ium hexafluorophosphate ([HL2](PF₆), L2 = 1,3-bis(pyridin-2-ylmethyl)benzoimidazolylidene) with cuprous oxide in acetonitrile readily yielded trinuclear complexes [Cu₃(L1)₃(PF₆)₃] (1) and [Cu₃(L2)₃(PF₆)₃] (2). Treatment of 1 with Ni(PPh₃)₂Cl₂ and Pd(cod)Cl₂ gave [Ni(L1)Cl](PF₆) (3) and [Pd(L1)Cl](PF₆) (4), respectively, due to transmetalation. [Ni(L1)₂](PF₆)₂ (5) was obtained from the reaction of [Cu₃(L1)₃(PF₆)₃] and Raney nickel in acetonitrile. All these complexes have been fully characterized. Both 1 and 2 consist of a triangular Cu₃ core with each Cu–Cu bond capped by an imidazolylidene group. Each imidazolylidene acts as a bridging ligand in a μ₂ mode and is bonded equally to two Cu(I) ions. The pincer nickel and palladium complexes are square-planar and contain a tridentate NCN ligand. Complexes 3 and 4 are efficient catalyst precursors for Kumada–Corriu and Suzuki–Miyaura coupling reactions of aryl halides with organometallic reagents.     

2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant

Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidine privileged scaffold as EGFR^C797S inhibitors. One of the most potent compound 6i potently suppressed EGFR^{L858R/T790M/C797S} kinase with an IC₅₀ value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} mutants with IC₅₀ values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.     

New thioether–dithiolate complexes of Cp1Ir and some reactivity features

The reaction of [Cp1IrCl₂]₂ (Cp* = η⁵ ? C₅Me₅) with the tridentate 3-thiapentane-1,5-dithiolate ligand, S(CH₂CH₂S^?)₂ (tpdt), led to the formation of [Cp1Ir(η³ ? tpdt)] (1) in 81% isolated yield. Subsequent reactions of 1 with [Cp1IrCl₂]₂ in 2:1 and 1:1 molar equiv ratios resulted in the formation of [Cp1Ir(μ ? η²:η³ ? tpdt)Cp1IrCl][PF₆] (2) and [Cp1Irμ ? η²:η³ ? tpdt)Cp1IrCl][Cp1IrCl₃] (3) in 86 and 79% yields, respectively, based on 1, whereas the reactions of 1 with [(COD)IrCl]₂ (COD = 1,5-cyclooctadiene) in 2:1 and 1:1 molar equiv ratios resulted in the formation of the homo-bimetallic derivatives Cp1Ir(μ ? η¹:η³ ? tpdt)(COD)IrCl (4) (92% yield) and [Cp1Ir(μ ? η²:η³ ? tpdt)(COD)Ir] [(COD)IrCl₂] (5) (82% yield). Reactions between 1 and [(COD)RhCl]₂, yielded the hetero-bimetallic derivatives Cp1Ir(μ ? η¹:η³ ? tpdt)(COD)RhCl (6) and [Cp1Ir(μ ? η²:η³ ? tpdt)(COD)Rh][(COD)RhCl₂] (7), in 92 and 93% yields, respectively. The reaction of 1 with methyl iodide gave mono-methylated derivative [Cp1Ir(η³-C₄H₈S₃Me)]I (8) (93% yield). All these compounds have been comprehensively characterized.     

New thioether–dithiolate complexes of Cp1Ir and some reactivity features

The reaction of [Cp1IrCl₂]₂ (Cp* = η⁵ − C₅Me₅) with the tridentate 3-thiapentane-1,5-dithiolate ligand, S(CH₂CH₂S⁻)₂ (tpdt), led to the formation of [Cp1Ir(η³ − tpdt)] (1) in 81% isolated yield. Subsequent reactions of 1 with [Cp1IrCl₂]₂ in 2:1 and 1:1 molar equiv ratios resulted in the formation of [Cp1Ir(μ − η²:η³ − tpdt)Cp1IrCl][PF₆] (2) and [Cp1Irμ − η²:η³ − tpdt)Cp1IrCl][Cp1IrCl₃] (3) in 86 and 79% yields, respectively, based on 1, whereas the reactions of 1 with [(COD)IrCl]₂ (COD = 1,5-cyclooctadiene) in 2:1 and 1:1 molar equiv ratios resulted in the formation of the homo-bimetallic derivatives Cp1Ir(μ − η¹:η³ − tpdt)(COD)IrCl (4) (92% yield) and [Cp1Ir(μ − η²:η³ − tpdt)(COD)Ir] [(COD)IrCl₂] (5) (82% yield). Reactions between 1 and [(COD)RhCl]₂, yielded the hetero-bimetallic derivatives Cp1Ir(μ − η¹:η³ − tpdt)(COD)RhCl (6) and [Cp1Ir(μ − η²:η³ − tpdt)(COD)Rh][(COD)RhCl₂] (7), in 92 and 93% yields, respectively. The reaction of 1 with methyl iodide gave mono-methylated derivative [Cp1Ir(η³-C₄H₈S₃Me)]I (8) (93% yield). All these compounds have been comprehensively characterized.     

Fused pyrimidine systems: XIII. Synthesis and some transformations of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines

2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]-pyrimidin-4-one results in a linear pyrido[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazin-6-one. The iodocyclization of the same substrates affords the corresponding 9-(iodomethyl)(iodomethylidene)pyrido[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-5-ones and 3-iodopyrido[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure. 9-(Iodomethyl)-8,9-dihydro-5H-pyrido[4,3-e][1,3]thiazolo[3,2-a]pyrimidin-5-one treated with sodium azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper compounds provided pyrido [4,3-e][1,3]thiazolo[3,2-a]pyrimidinylmethyltriazoles.     

One-pot synthesis of quinazolin-4(3H)-ones and fused quinazolinones by a palladium-catalyzed domino process

An efficient one-pot synthesis of quinazolin-4(3H)-ones, benzoimidazo[2,1-b]quinazolin-12(6H)-ones and imidazo[2,1-b]quinazolin-5(1H)-ones via a palladium-catalyzed domino process has been developed. The Pd-catalyzed reactions of 2-azidobenzamides 1 with isocyanides 2 produced quinazolin-4(3H)-ones 4 at room temperature by a domino Pd-catalyzed cross-coupling/carbodiimide-mediated cyclization. However, as 2-azido-N-(2-bromophenyl)benzamides 1 were used under heating condition in the presence of Cs₂CO₃, the benzoimidazo[2,1-b]quinazolin-12(6H)-ones 5 were directly obtained by twice Pd-catalyzed domino cyclization. A domino reogioselective 5-exo-dig intramolecular cyclization reaction of alkynyl-containing azides 6 with isocyanides 2 generated imidazo[2,1-b]quinazolin-5(1H)-ones 9 in 74–93% yields in the presence of catalyst Pd(PPh₃)₄ and K₂CO₃.     

Six-coordinate uranium complexes featuring a bidentate anilide ligand

The synthesis of a new bidentate anilide ligand and four uranium amide complexes utilizing the ligand are reported. The secondary aniline HN[R]Ar_MeL (R = C(CD₃)₂CH₃, Ar_MeL = 2-NMe₂-5-MeC₆H₃) is prepared by condensation of H₂NAr_MeL and acetone-d₆ followed by alkylation of the resulting imine with MeLi. The ligand precursors (Et₂O)Li(N[R]Ar_MeL) and K(N[R]Ar_MeL) are prepared through deprotonation of HN[R]Ar_MeL with n-BuLi and KH, respectively. Treatment of UI₃(THF)₄ with (Et₂O)Li(N[R]Ar_MeL) (2 equiv) provides the uranium(III) -ate complex Li[I₂U(N[R]Ar_MeL)₂] (Li[1]), while treatment of UI₃ with three equiv. of K(N[R]Ar_MeL) provides the neutral uranium(III) complex U(N[R]Ar_MeL)₃ (2). Both uranium(III) complexes are susceptible to 1e oxidation, as is demonstrated by the syntheses of the uranium(IV) derivatives I₂U(N[R]Ar_MeL)₂ (1) and [U(N[R]Ar_MeL)₃][OTf] ([2][OTf]; OTf = CF₃SO₃). The spectroscopic and X-ray structural characterization of all four uranium complexes is described. The structures of 2 and [2][OTf] exhibit a large degree of steric pressure about the uranium center, effectively preventing the [2]⁺ ion from achieving a seven-coordinate structure.     

Synthesis of 12-aryl-1-oxo-1,2,3,4,5,12-hexahydroindolo-[2,1-b]quinazoline-6-carbonitriles by recyclization of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles

A general and convenient method for the synthesis of 12-aryl-1-oxo-1,2,3,4,5,12-hexahydroindolo[2,1-b]quinazoline-6-carbonitriles was proposed. The method is based on the recyclization of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles. The structure of 12-(3-methoxyphenyl)-8-methyl-1-oxo-1,2,3,4,5,12-hexahydroindolo[2,1-b]quinazoline-6-carbonitrile was studied by X-ray diffraction analysis.