Reaction of alpha-oxoketene-N,S-arylaminoacetals with Vilsmeier reagents: an efficient route to highly functionalized quinolines and their benzo/hetero-fused analogues

A simple, highly efficient, and regioselective synthesis of functionalized quinolines through Vilsmeier cyclization of a variety of alpha-oxoketene-N,S-anilinoacetals has been reported. The cyclization is found to be facile with N,S-acetals bearing strongly activating groups on aniline, whereas yields of quinolines are moderate in other cases. The reaction could also be extended for the synthesis of substituted tricyclic benzo[h]quinoline, pyrido[2,3-h]quinoline, 4,7-diphenylphenanthroline, and tetracyclic quino[8,7-h]quinoline by performing a Vilsmeier reaction on N,S-acetals derived from 1-naphthylamine, m-phenylenediamine, o-phenylenediamine, and 1,5-diaminonaphthalene, respectively. A few of the newly synthesized quinolines are subjected to further transformation to afford 2-unsubstituted (Raney-Ni/Ethanol), quinoline-5,8-quinone (NBS/H(2)SO(4)), or 2-alkyl/aryl aminoquinolines through sequential m-CPBA oxidation to the corresponding (2-methylsulfonyl)quinoline followed by replacement with appropriate amines. Similarly, cycloannulation of a few 2-methylthio-3-benzoylquinolines with hydrazine hydrate under microwave irradiation afforded the corresponding substituted and fused pyrazolo[3,4-b]quinolines in excellent yields, whereas TBTH/AIBN-mediated cyclization of the corresponding 3-(2-bromobenzoyl)-2-methylthioquinolines yielded the corresponding benzothiopyrano-fused quinolines through radical translocation.     

Synthesis of 5-iodopyrrolo[1,2-a]quinolines and indolo[1,2-a]quinolines via iodine-mediated electrophilic and regioselective 6-endo-dig ring closure

The endo-cyclic ring closure of 1-(2-(substituted ethynyl)phenyl)-1H-pyrroles 3a-t and 1-(2-(substituted ethynyl)phenyl)-H-indole 4a-o mediated by Lewis acid (I(2)) under mild conditions afforded substituted 5-iodopyrrolo[1,2-a]quinolines 5a-t and 5-iodoindolo[1,2-a]quinolines 6a-o in good to excellent yields. The reaction shows selective C-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized product. Iodo derivatives of pyrrolo- and indoloquinolines allow functional group diversification on the quinoline nucleus, which proves to be highly advantageous for structural and biological activity assessments.     

Synthesis and spectral data of quinoline products obtained by reaction of N‐(4‐pyridinyliden)anilines and N‐benzylidenaniline with 2,2‐dimethoxypropane (kametani reaction)

A study on interaction between N‐(4‐pyridinyliden)anilines 1‐4 and 2,2‐dimethoxypropane under Kametani reaction conditions was realized. According to the GC‐MS analysis of crude reaction, besides the needed 4‐methyl‐2‐(4‐pyridinyl)quinolines 5‐8 , three collateral products: secondary amines 9‐12 , 4‐(2‐methylprop‐1‐enyl)quinolines 13‐16 and 4‐(2‐methoxy‐2‐methylpropyl)quinolines 17‐20 were formed. Unexpected quinolines 13‐16 as well the desired quinolines 5‐8 were isolated and fully characterized. In contrast, a condensation of N‐benzylidenaniline 21 with 2,2‐dimethoxypropane afforded a set of different quinoline products.     

Synthesis of functionalized quinolines and benzo[c][2,7]naphthyridines based on a photo-Fries rearrangement

An efficient one-pot method for the synthesis of functionalized quinolines and tetrahydronaphthyridines has been developed. The photo-Fries rearrangement of p-substituted anilides afforded differently substituted o-amino ketones that reacted in situ with acetylenic Michael acceptors such as dimethyl acetylenedicarboxylate (DMAD) to give 6,4-disubstituted quinoline 2,3-dicarboxylates. Starting from anilides derived from β-alanine, a naphthyridine nucleus can also be assembled.     

Solvent-free synthesis of quinoline derivatives via the Friedländer reaction using 1,3-disulfonic acid imidazolium hydrogen sulfate as an efficient and recyclable ionic liquid catalyst

A convenient, highly versatile and eco-friendly protocol for the synthesis of quinoline derivatives via the Friedländer reaction is presented. The method is based on the use of 1,3-disulfonic acid imidazolium hydrogen sulfate (DSIMHS) as an efficient and reusable ionic liquid catalyst. A variety of ketones afforded the substituted quinolines in excellent yields during relatively short reaction times under solvent-free conditions; the catalyst could be easily recovered and reused for several times without any appreciable loss of activity.     

O. ISOTHIOCYANATO CINNAMALDEHYDE - A USEFUL INTERMEDIATE FOR HETEROCYCLIC SYNTHESES

Abstract

Reaction of isothiocyanato cinnamaldehyde - (1), a scission product from quinoline and thiophosgene, with diethyl sodiomalonate gives 3-formylquinoline-2-thione (2). This compound has been used as an intermediate in the synthesis of thieno [2,3-b]quinolines, isothiazolo [5,4-b]quinoline and some 2,3-substituted quinolines. A review will be given of other di- and tri-cycles which may be obtained from the aldehyde (1) and thione (2).     

Synthese von Furo [2,3-b]chinolinen

A new route to furo[2,3-b]quinolines has been developed based on the use of N-arylaconamides as starting materials. These anilides when heated with polyphosphoric acid, readily underwent intramolecular cyclization to furnish the respective 1,2-dihydro-2-oxo-quinoline-3-acetic acids which were then transformed into the corresponding dihydrofuro[2,3-b]quinolines by literature procedures. Sequential treatment of the dihydro compound withNBS andDBU afforded the corresponding furo[2,3-b]quinoline. The NMR spectra of the furoquinolines are discussed.

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Mitt.: siehe Lit.     

Reactions of 4-Methoxy-3-quinolinyl and 1,4-Dihydro-4-oxo-3-quino-linyl Sulfides Aiming at the Synthesis of 4-Chloro-3-Quinolinyl Sulfides

The preparation of 1,4-dihydro-4-oxo-3′-alkylthio-3,4′-diquinolinyl sulfides 3 or 1,4-dihydro-4-oxo-3-(alkylthio)quinolines 4 by acid catalysed hydrolysis of 4-methoxy-3′-alkylthio-3,4′-diquinolinyl sulfides 1 or 4-methoxy-3-(alkylthio)-quinolines 2 is described. The reactions of 4-methoxy-3′-alkylthio-3,4′-diquinolinyl sulfides 1 or 1,4-dihydro-4-oxo-3′-alkylthio-3,4′-diquinolinyl sulfides 3 with phosphoryl chloride in DMF afforded 4-chloro-3′-alkylthio-3,4′-diquinolinyl sulfides 5 . Treatment of the title compounds 1 or 3 with boiling phosphoryl chloride systems:leads to 4-chloro-3-(alkylthio)quinolines 6 and thioquinanthrene but those of alkoxy- or oxo-quinolines 2 or 4 lead to 4-chloro-3-(alkylthio)quinolines 6 . The reactions of N-methyl-4(1H)-quinolinones 3n and 4n with phosphoryl chloride directed to 4-chloro-3-(alkylthio)quinolines 6 were studied as well.     

Iodine-catalyzed stepwise [4+2] cycloaddition of phenothiazine- and ferrocene-containing Schiff bases with DHP promoted by microwave irradiation

On simultaneous effect of iodine-catalysis and microwave irradiation Schiff bases deactivated by electron-donating C-phenothiazinyl- and ferrocenyl-substituents, respectively, underwent formal inverse electron demand aza-Diels-Alder (DA) cycloaddition with 3,4-dihydro-2H-pyrane (DHP) employed as donor component. Depending on the substitution pattern of the N-phenyl group the reactions of phenothiazine-containing imines afforded 2H-pyrano[3,2-c]quinolines or 3-(3-hydroxypropyl)quinolines. Irrespective of the electronic properties of the N-phenyl substituent the less reactive ferrocene-based imines were directly converted into quinoline products. The intermediate iodoiminium ions were analysed by B3LYP/DGZVP calculations suggesting stepwise mode for the cycloaddition process. In one case the regioselectivity of the second step of cycloaddition was also interpreted by DFT analysis of the alternative rotamers of the primarily formed DHP adduct.     

Cyclization of 1-benzyl-1,2-dihydro-2-(substituted methylene)quinolines to pyrrolo[1,2-a]quinoline derivatives

1-Alkyl-2-alkylthioquinolinium salts were prepared from 1-alkyl-2(1H)-quinolones via 1-alkyl-2(1H)-thioquinolones in two steps. Under mild conditions, the reaction of 1-alkyl-2-alkylthioquinolinium iodides with active methylene compounds in the presence of sodium hydride afforded 1-alkyl-1,2-dihydro-2-(substituted methylene)quinolines in good yields. The cyclization of 1-benzylquinolines using acetic anhydride produced the corresponding pyrrolo[1,2-a]quinoline derivatives.     

InCl3‐Driven Regioselective Synthesis of Functionalized/Annulated Quinolines: Scope and Limitations

The efficient, regioselective synthesis of functionalized/annulated quinolines was achieved by the coupling of 2‐aminoaryl ketones with alkynes/active methylenes/α‐oxoketene dithioacetals promoted by InCl₃ in refluxing acetonitrile as well as under solvent‐free conditions in excellent yields. This transformation presumably proceeded through the hydroamination–hydroarylation of alkynes, and the Friedländer annulation of active methylene compounds and α‐oxoketene dithioacetals with 2‐aminoarylketones. In addition, simple reductive and oxidative cyclization of 2‐nitrobenzaldehyde and 2‐aminobenzylalcohol, respectively, afforded substituted quinolines. Systematic optimization of the reaction parameters allowed us to identify two‐component coupling (2CC) conditions that were tolerant of a wide range of functional groups, thereby providing densely functionalized/annulated quinolines. This approach tolerates the synthesis of various bioactive quinoline frameworks from the same 2‐aminoarylketones under mild conditions, thus making this strategy highly useful in diversity‐oriented synthesis (DOS). The scope and limitations of the alkyne‐, activated methylene‐, and α‐oxoketene dithioacetal components on the reaction were also investigated.     

Synthesis and Reactions of the Novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde

The novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde ( 2 ) was efficiently synthesized from Vilsmeier–Haack formylation of 3‐(1‐ethy1‐4‐hydroxy‐2‐oxo‐(1H)‐quinolin‐3‐yl)‐3‐oxopropanoic acid ( 1 ). The aldehyde 2 was allowed to react with some nitrogen nucleophiles producing a variety of hydrazones 3 – 7 . Reaction of aldehyde 2 with hydrazine hydrate and hydroxylamine hydrochloride afforded pyrazole and isoxazole annulated pyrano[3,2‐c]quinoline‐2,5(6H)‐dione, respectively. The reactivity of aldehyde 2 was examined toward some active methylene nitrile, namely, malononitrile, ethyl cyanoacetate, and cyanoacetamide leading to 2‐iminopyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines 10 – 12 , respectively. Also, some novel pyrazolo[4″,3″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 13 , 14 ) and thiazolo[5″,4″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 15 , 16 ) were synthesized. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

Synthesis of derivatives of 7-iodo-4-aminoquinolines

7-Iodo- and 7,8-diiodo-4-(3-dimethylaminopropylamino)quinolines and 7-iodo-4-(3) dipropyl-aminopropylamlno)- and 7-iodo-4-(3-diallylaminopropylamino)quinoline were obtained by the reaction of 7-iodo- and 7,8-diodo-4-chloroquinolines with the corresponding diamines. The catalytic hydrogenation of 7-iodo-4-(3-diallylaminopropylamino)quinoline at normal pressure leads to 7-iodo-4-(3-dipropylaminopropylamino)quinoline.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 972–975, July, 1980.     

Selective conversion of diallylanilines and arylimines to quinolines

A variety of diallylanilines are shown to undergo cobalt-carbonyl catalyzed rearrangement to quinolines. Diallylanilines are also used as allyl transfer reagents to convert benzaldimines into quinolines. Substitution in the 2- and 3-positions of the quinoline is featured in all transformations.     

Reaction of quinolines fluorinated at the benzene ring with nitrogen-centered nucleophiles

A primary functionalization of quinolines polyfluorinated at the benzene ring (5,7-difluoro-, 5,7,8-trifluoro-, 5,6,8-trifluoro-, 8-chloro-5,7-difluoro-, 5,6,7,8-tetrafluoro-, and 5,7,8-trifluoro-6-(trifluoromethyl)quinolines) by the reaction with nitrogen-centered nucleophiles (aqueous and liquid ammonia, hydrazine hydrate, piperidine) has been studied. If the molecule of fluorinated quinoline contains three or four halogen atoms, their combined orientation effect outweighs the influence of the heterocycle N atom. It was found that the orientation of substitution in the reactions of 5,6,8-trifluoro- and 5,7,8-trifluoro-6-(trifluoromethyl)quinolines with piperidine depends on temperature, because the enthalpy control of the ratio of the rates of competing reactions changes to the entropy control. Nineteen new quinoline derivatives containing F atoms and amino or modified amino groups in the benzene ring have been obtained.     

Synthesis of highly substituted dihydropyrrolophenanthridine derivatives by tandem reaction

The efficient cross-coupling of bromo(iso)quinoline to 1,6-diynes with the Pd-catalyzed system was established. Using unactivated simple diynes with bromo(iso)quinoline in the presence of palladium catalytic system afforded different kinds of rare 7,11-diphenyl-9,10-dihydro-8H-pyrrolo[3,4-j]phenanthridine derivatives through regioselective C–H functionalization in one step. Different diynes (a–p) and different bromo(iso)quinolines were shown to be very active in the reaction. Thus, the generality of this process makes the reaction highly valuable in view of the synthetic and medicinal importance of these pyrrolo[3,4-j]phenanthridine derivatives.     

The synthesis of monomethoxy[1]benzothieno[2,3-c]quinolines

A series of monomethoxy[1]benzothieno[2,3-c]quinolines 24-28 were prepared by photocylization of the appropriate 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamides 9–13 to [1]benzothieno[2,3-c]quinolin-6(5H)-ones 14-18 followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 19-23 then dechlorination resulting in the title compounds except for 25 which was achieved by direct reduction of 15 . Reaction of 24-28 with methyl iodide provided the corresponding N-methyl quaternary salts 29-33 . Also, conversion of 4-meth-oxy[1]benzothieno[2,3-c]quinolin-6(5H)-one 16 to 4-methoxy-6-methylthio[1]benzothieno[2,3-c]quinoline 35 and 4,6-dimethoxy[1]benzothieno[2,3-c]quinoline 36 is described.     

Quinolines spiro annulated at heterocyclic fragment: Synthesis and properties

Chemical information of the quinolines spiro annulated at heterocyclic fragment with cycloalkanes or heterocycles is reviewed. Synthetic approaches to three possible spiro‐2(1H)‐, spiro‐3(4H)‐ and spiro4(1H)quinoline core derivatives are analysed. Their syntheses are divided into three groups: a) chemical transformations of the substituted quinoline ring, b) construction of spiro structure from the alicyclic precursors, mainly, amine derivatives or imines preformed from cyclic ketones; c) rearrangements of more complex heterocycles leading to the spiro quinolines. Special attention is paid to spiro quinolines that display pharmacological properties. Synthetic routes to the discorhabdin alkaloids are also briefly discussed on in this review.     

I2-catalyzed base-free cyclization of 3-homoallylquinoline-2-thiones: facile synthesis of tetracyclic,furothiopyrano[2,3-b]quinolines

I₂-catalyzed base-free reactions of 3-homoallylquinoline-2-thiones have been described for the synthesis of tetracyclic quinolines, tetrahydrofuro [2′,4′:4,6]thiopyrano[2,3-b]quinolines in excellent yields. Similarly, I₂-catalyzed reactions could proceed to tricyclic quinolines from hydroxyl group protected 3-homoallylquinoline-2-thiones. However, deprotection of group in tricyclic quinoline with HI again transformed into tetracyclic quinoline. The sulfonium salt intermediate has been proposed to explain these reactions.     

New synthetic approach to epoxyisoindolo[2,1-a]quinolines based on cycloaddition reactions of 2-furyl-substituted tetrahydroquinolines with maleic anhydride and acryloyl chloride

A procedure was developed for the synthesis of hydrogenated furyl-substituted furo[3,2-c]quinolines, pyrano[3,2-c]quinolines, and 4-ethoxy-and 4-(2-oxopyrrolidin-1-yl)quinolines. The reactions of these compounds with acryloyl chloride and maleic anhydride produce epoxyisoindolo[2,1-a]quinoline derivatives through successive acylation at the quinoline nitrogen atom and intramolecular exo-[4+2]-cycloaddition at the furan moiety. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1023–1038, May, 2007.