Condensed isoquinolines. 37.* Heterocyclization using 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.     

Synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives via a TBAI-catalyzed radical cascade cyclization

We have developed a metal-free radical cascade reaction of N-substituted 2-aryl indoles with readily available sulfonyl hydrazides for the rapid construction of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives. With the TBAI–TBHP catalytic system, a broad series of structurally diverse indolo[2,1-a]isoquinolin-6(5H)-one derivatives were obtained in moderate to excellent yields. The reaction features mild reaction conditions, operationally easiness, scaled-up feasibility, and high functional-group-tolerance.     

Investigation of the one-pot synthesis of quinolin-2-(1H)-ones and the discovery of a variation of the three-component Ugi reaction

Rapid access to the quinolin-2-(1H)-one scaffold is afforded by a sequential 4 component Ugi–Knoevenagel condensation of an aminophenylketone, an aromatic aldehyde possessing electron donating moieties, cyanoacetic acid and an aliphatic isocyanide, in moderate to good yields (49–71%). Interestingly, when the reaction is performed using aromatic aldehydes bearing electron withdrawing moieties or isocyanides containing aromatic or ester units, a mixture of a quinolin-2-(1H)-one and an α-amino amide (Ugi three-component adduct) is afforded in varying ratios. Further when the reaction is performed utilizing a combination of an isocyanide-containing aromatic or carbonyl unit, and an aldehyde possessing an electron withdrawing functionality, the Ugi three-component adduct is exclusively afforded. In our hands this new variation of the Ugi 3CR proved to be efficient and robust affording analogues in good yields (51–70%).     

Condensed Isoquinolines. 18. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in the Michael Reaction

The reaction of benzimidazo[1,2-b]isoquinolin-11(5H)-one with activated olefins has been studied. The derivatives of 3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine formed are the result of an initial Michael reaction at C₍₆₎ followed by intramolecular heterocyclization.     

Synthesis of 7-(4-piperidyl)- [1,6]naphthyridin-5-one and 3-(4-piperidyl)isoqunolin-1-one

7-(4-Piperidyl)[1,6]napththiridin-5-one was synthesized on the basis of 2-methylnicotinic acid. 3-(4-Piperidyl)isoquinolin-1-one was synthesized from the diethylamide of o-toluic acid and Weinreb's amide of N-Boc-isonipecotic acid.     

A new and practical PIFA-promoted olefin amidohydroxylation: six- versus five-membered ring formation

A novel access to the isoindolinone and isoquinolin-2-one skeletons from adequately substituted aromatic precursors is described. The key intramolecular cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the corresponding vinyl or allyl substituted N-(p-methoxyphenyl)benzamide derivatives leading to the heterocyclic compounds through 5-exo-trig and 6-exo-trig processes, respectively.     

Microwave-assisted rapid and efficient synthesis of C-alkyl imidazoisoquinolinone derivatives

The synthesis of a set of 10-benzyl-2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one and 5-oxo-imidazo[1,2-b]isoquinolin-10-yl)-N-phenylacetamide derivatives was achieved by exposing the corresponding alkylating agent and imidazoisoquinolinone to microwave irradiation and traditional oil bath heating in the presence of K₂CO₃ and DMAP. The microwave technique as well as DMAP as base accelerated the alkylation reaction for 2-6 min giving 79-88% yields.     

Transition Metal-Catalyzed C−H Activation/Annulation Approaches to Isoindolo[2,1-b]isoquinolin-5(7H)-ones

The isoindolo[2,1-b]isoquinolin-5(7H)-one scaffold is widely present in lots of bioactive natural products. Diverse types of strategies have been developed to construct this scaffold. Recently, transition metal-catalyzed C−H activation/annulation is emerging as a powerful and straightforward method to construct diverse polyheterocycles with high atom- and step-economy. It also has been employed for the synthesis of the isoindolo[2,1-b]isoquinolin-5(7H)-one scaffold. This review provides an introduction to recent advances for the preparation of isoindolo[2,1-b]isoquinolin-5(7H)-ones by using transition metal-catalyzed C−H activation/annulation. It will help researchers to find hidden opportunities and accelerate the discovery of novel transformations based on C−H activation/annulation.     

Condensed Isoquinolines. 16. Enamine Properties of Benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one in Terms of Its Acylation Reactions

A study has shown that the acylation of benzo[4,5]imidazol[1,2-b]isoquinolin-11(5H)-one occurs at N₍₅₎ or at C₍₆₎ depending on the nature of the acylating reagent and the reaction conditions. It was found that principally C-acylation takes place in the absence of base. The reaction with -halo-substituted carboxylic acid chlorides leads to the formation of C-acylated products which are converted to derivatives of the novel heterocyclic system 7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione in the presence of base.     

A One‐Pot O‐Phosphinative Passerini/Pudovik Reaction: Efficient Synthesis of Highly Functionalized α‐(Phosphinyloxy)amide Derivatives

A one‐pot O‐phosphinative Passerini/Pudovik reaction has been developed, based on reacting aldehydes, isocyanides, and phosphinic acids followed by the addition of second aldehydes to form the corresponding α‐(phosphinyloxy)amide derivatives. This is the first reported instance of a Passerini‐type, isocyanide‐based multicomponent reaction using a phosphinic acid instead of a carboxylic acid. The nucleophilicity of the phosphinate group allows a subsequent catalytic Pudovik‐type reaction, affording the highly functionalized α‐(phosphinyloxy)amide derivative in high yield. A wide range of aldehydes and isocyanides are applicable to this reaction.     

Isoquinolone derivatives via a furan recyclization reaction

A new approach to the synthesis of isoquinolone derivatives has been developed. It is based on the protolytic recyclization of amides of 2-carboxybenzylfurans. It was shown that the reaction proceeds via formation of allylic alcohols of isoquinolone series, which under acidic conditions undergo isomerization into the corresponding ketones. A new condensed heterocyclic system of furo[2′,3′:3,4]cyclohepta[1,2-c]isoquinolin-8(6H)-one has been synthesized.     

Isocyanide-based multicomponent reactions: synthesis of 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives

A new isocyanide-based multicomponent reaction between an aromatic aldehyde, malononitrile, an isocyanide, and acetic acid efficiently provides 3,3-dicyano-N-alkyl-2-arylpropanamide derivatives in excellent yields in ethanol at 70 °C. This reaction led to the construction of two carbon-carbon bonds and one amide group in a single synthetic step.     

Condensed Isoquinolines. 17. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in Alkylation Reactions

The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N₍₅₎ or C₍₆₎ depending on the type of alkylating agent and the reaction conditions. It was shown that C₍₆₎ alkylation is effected in reactions with reactive alkyl halides. A repeat alkylation occurs preferentially at the same position. Interaction with o-xylylidene dibromide leads to spiro[benzimidazo[1,2-b]-isoquinolin-6,2'-indan]-11-one and 1,6-dihydro-11H-6a,11b-diazobenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one, which are derivatives of new heterocyclic systems.     

2-Methyl-s-triazolo[1,5-b]isoquinolin-5(10H)-one

Acetamidrazone hydrochloride reacts with homophthalic anhydride to give 3-o-carboxybenzyl-5-methyl-1,2,4-triazole 1, which can be cyclised to 2-methyl-s-triazolo[1,5-b] isoquinolin-5(10H)-one 2. Reduction with lithium aluminium hydride gives 5,10-dihydro-2-methyl-s-triazolo [1,5-b] isoquinoline, while condensation with aromatic aldehydes gives 10-arylmethylene derivatives. Coupling with arenediazonium salts gives the 10-arylhydrazones of 5,10-dihydro-2-methyl-s-triazolo [1,5-b] isoquinoline-5,10-diones, while condensation with p-nitrosodimethylaniline gives the 10-imino derivative. Alkylation of 2 produces the corresponding 10,10-dialkyl derivatives.     

A facile reaction involving zwitterionic intermediates for the synthesis of 5-hydroxy-2H-pyrrol-2-one derivatives

The reaction of cyclohexyl isocyanide with various aldehydes and 1,3-dicarbonyl compounds catalyzed by piperidine is described. The protocol offers facile and efficient synthesis of 5-hydroxy-2H-pyrrol-2-one derivatives from readily available starting materials in high yields.     

1,2,3,6,7,11b-Hexahydro-4H-pyrimido[2,1-a]isoquinoline-2-ones

The reaction of 1-methyl-3,4-dihydroisoquinolinium salts with acrylamide forms 2-(2-carbamoylethyl)-1-methyl-3,4-dihydroisoquinolinium salts, which are cyclized by the action of bases to form 11b-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrimido[2,1-a]isoquinolin-2-one. Treatment of this compound with iodomethane yields 5, 11b-dimethyl-2-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrimido[2,1-a]isoquinolinium iodide. The 11b-methylpyrimido[2,1-a]isoquinolin-2-one enters into condensation with aromatic aldehydes, forming the corresponding styryl compounds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 499–502, April, 1993.     

Green synthesis of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives catalyzed by heteropoly acid supported montmorillonite K-10 clay

Herein, synthesis of a series of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives directly by one-pot multi-component reaction of 1,3-dicarbonyl compounds (1,3-indanedione/1,3-cyclohexanedione), 2-aminoantharacene/2-naphthylamine and various substituted aldehydes under solvent-free conditions using heteropoly-11-molybdo-1-vanadophosphoric acid supported on montmorillonite K-10 clay catalyst (10% PVMoK-10) is reported. The successful formation of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives was confirmed by various spectroscopic techniques. This study offers a green approach for the synthesis of novel quinolinone derivatives.     

Studies on the reductively triggered release of heterocyclic and steroid drugs from 5-nitrothien-2-ylmethyl prodrugs

Hypoxia (inadequate concentrations of dioxygen in tissues) is present in several disease states, including cancer and rheumatoid arthritis. Prodrug systems, which after bioreduction, selectively release active drugs in these tissues may be important in therapy. The 5-nitrothien-2-ylmethyl ester of aspirin was synthesised by treatment of 5-nitrothiophene-2-methanol with 2-acetoxybenzoyl chloride, whereas that of prednisolone hemisuccinate was prepared by reaction of prednisolone with 5-nitrothien-2-ylmethyl pentafluorophenyl butanedioate. In chemical model systems, both of these ester-linked potential prodrugs suffered hydrolysis, rather than reductively triggered release of the corresponding drug. 1-(5-Nitrothien-2-ylmethoxy)isoquinolines released the corresponding isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) rapidly upon reduction of the nitro group with sodium borohydride/palladium, showing that these may be useful as reductively triggered prodrugs. In approaches to N-linked potential prodrugs, isoquinolin-1-one and nifedipine (a 1,4-dihydropyridine Ca²⁺ channel antagonist) were alkylated at nitrogen by 2-chloromethylthiophene but the corresponding 5-nitrothien-2-ylmethyl derivatives were synthetically inaccessible.     

Comparative Studies on Two 1,8-Naphthalimide Derivatives with Experimental and Theoretical Methods

Two 1,8-naphthalimide derivatives of 7H-benzimidazo[2,1,-a]benz[de] isoquino- lin-7-one（1） and 4-bromo-7H-benzimidazo[2,1,-a]benz[de]isoquinolin-7-one（2） have been synthesized and characterized by elemental analysis, IR, 1H NMR, UV-Vis and fluorescence spectra. For the two compounds, density functional theory（DFT） calculations of the structures and natural population atomic charge analysis have been performed at the B3LYP/6-311G＊＊ level of theory. Based on Onsager reaction filed model and by using TD-DFT method at the B3LYP/6-311G＊＊ level, electron spectra of 1 and 2 with solvent effect in CHCl3 solvent have been predicted, which are in agreement with the experimental ones. Comparative studies on 1 and 2 indicate that introducing an electron-withdrawing group of Br into the 4-position of naphthalene ring in 2 does not significantly make the molecular geometry of 2 different from that of 1, but evidently changes the atomic charge redistribution, moves the positive-negative charges center and then changes the dipole moment in 2. Additionally, for compound 2, the existence of Br atom has also influenced the peak intensity and peak locations in both electron and fluorescence spectra.     

Synthesis of 6-Membered-Ring Fused Thiazine-Dicarboxylates and Thiazole-Pyrimidines via One-Pot Three-Component Reactions

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76–85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70–91%.