Quinoline-malononitrile

The presence of a cyano group seems to be important[649]. The reaction has been successfully applied to halides of pyridine, quinoline, isoquinoline, and oxazoles[650]. An interesting application is the synthesis of tetracyanoquino-dimethane (789) by the reaction of / -diiodobenzene with malononitrile[65l]. 

Reaction of malononitrile and quinazolinone 429 in the presence of three drops of NEts yielded pyrido[2,l-Z)]quinazolinone 430 (97MI7). 9,11-Dioxo-5,9-dihydro-l l//-pyrido[2,l-Z)]quinoline-8-carboxylates 432 were prepared in the reaction of anthranilonitrile and 2-piperidones 431 in boiling EtOH in the presence of AcOH (00JCS(P1)3686, 00PS133). 

The same zwitterions can give pyrid-2-ones (798) when treated with dimethyl acety-lenedicarboxylate (71AG(E)925). Quaternary pyrimidinium salts are attacked by the anions from diethyl malonate or malononitrile to produce pyrid-2-ones (799) or 2-aminopyridines (800) respectively (74RCT233). Quinazoline Af-oxide (801) reacts with ketones on heating to give quinolines the reaction is assumed to be initiated by attack at C-4, with subsequent... 

Methoxy-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxamide (228) was prepared by cyclization of A -(4-methoxy-2-quinolyl)aminomethylene-malononitrile (227) in polyphosphoric acid at 110-130°C for 4.5 h (79MIP2). 

Sodio malononitrile, prepared from malononitrile with 57% sodium hydride in dimethylacetamide, and l-(3-chloropropyl)isatoic anhydride (398) at room temperature for 30 min, then at 120°C for 18 h, gave 6-oxo-l,2,3,4-tetrahydro-6//-pyrimido [1,2-a quinoline-5 -nitrile (399) (76JOC825). 

For the cyclocondensation of 5-bromo-2-(cis-2,6-dimethylmorpholin-4-yl)benzaldehyde with malononitrile in DMSO at 23 °C for 1 h, at 130 °C for 20 h furnished l,2,4,4a,5,6-hexahydro[1,4Joxazino[4,3-a]quinoline-5,5-dinitrile 168 in 54% yield (09JA3991). Similar cyclocondenzation of dideut-erated 428 provided a 3 1 mixture of spiro derivatives 429 and 430, which were separated by using preparative HPLC. 

Tu and co-workers [112] have elaborated a simple and efficient microwave-assisted one-pot three-component synthesis of polysubstituted quinoline-3-carbo-nitriles 65 in excellent yields. An aldehyde, malononitrile and an enaminone were reacted in acidic medium using microwave irradiation. When the reaction was performed at high temperature, compound 65 was observed as the main product (Scheme 49). 

A number of unusually fused heterocyclic compounds have been reported by Tu and co-workers [118]. The three-component domino reaction of an aldehyde, an enaminone 72 and malononitrile resulted in the formation of polysubstituted imi-dazo[l,2-a]quinazolines 73 and pyrimido[l,2-a]quinolines 74. (Scheme 56) When enaminone 75 was reacted using the same reaction conditions, this resulted in the formation of quinolino[l,2-a]quinazolines 76 in good yields. In this one-pot reaction, up to five new bonds were formed accompanied by the generation of the lactam group. Interestingly, the volume of ethylene glycol used seems to influence the yield of the product (Scheme 57). 

Aminonaphtho[l,2-b]pyrans are converted into 5,6-dihydrobenzo[h]quinolines under basic conditions through a Dimroth rearrangement. The oxygen heterocycle is formed by a Michael addition of malononitrile to a 2-arylidene-l-tetralone and the whole sequence provides an... 

The addition of water (see Section II,B) and other nucleophiles across the 3,4-double bond of quinazoline is well established. More recently other nucleophiles, such as dimedone, have given isolable 3,4-adducts. ° Similarly, malononitrile and other compounds with active methylene groups added across the 3,4-double bond of quinazoline, but in this case the reaction proceeded further with ring opening and formation of 2-amino-3-cyano-quinoline. The dimedone adduct was also made to react further in the presence of alkali to form the acridone 38. ... 

Dichloromaleimide is converted at or below ambient temperature to a thieno-pyrrole by malononitrile-methoxide, and then hydrogen sulphide [3378]. Several dithienothiophenes are synthesized by oxidative cyclization of the lith-iated intermediates, but when the latter are unstable, the dibromosulphides may be treated with butyllithium and copper(II) chloride [2287]. The chlorodibromo-quinoline (81.2) is efficiently converted into the fused thiophene when heated with thiourea in a protic solvent [2873]. 

When the aminomethylene 270 (R1 = R2 = H or Me), obtained from reaction of 1 with triethoxymethane in the presence of amine, was reacted with malononitrile, it gave the quinolines 271-273 (74M1283 03JHC689) and with cyanoacetamide 274 gave quinolines 272 (R = Ar) (04T8633) (Scheme 50). 

Condensation of endione 328 with aminal 329 in acetonitrile gave the imidazo[l,2-fl]quinoline 330 via the formation of a C-C bond intermediate. Alternatively, 330 was prepared in a one-pot reaction by refluxing 1 with 329 and benzaldehyde in acetonitrile (99JCS(P1)2087). When the enamine 31 (R = CH2CC>2Et), obtained from reaction of 1 and ethyl glycinate, was reacted with 2-(3-nitrobenzylidene)malononitrile, it gave 330 (R = CN, Y, X = O) via the formation of 2-aminoquinoline 331 that spontaneously cyclized to 330 (01ARK73) (Scheme 62). 

Pyrimido[4,5-fr]quinolines 344 were obtained from 2-amino-3-cyanoqui-noline 280 (R = Ar1) upon reaction with benzoyl isothiocyanate (96IJC(B)608) (Scheme 67). Reaction of enamine 31 (R = o-CNC6H4) with benzylidene malononitrile in the presence of DBU gave the pyrimidoquinoline 345 via the respective quinoline 280 (01ARK73). A series of pyrimidoquinolines were prepared by cyclization of the... 

Cyclization of 2,6-diarylidenecyclohexanone 323 with malononitrile in the presence of sodium hydroxide in methanol was carried out under MWI for 5-10 min to give quinoline derivatives 324 in 91-98% yields (Scheme 65). The reaction required 3h under classical heating to afford 324 in 70-85% yields (01MI3). 

Arylation of active methylene compounds has been carried out using Cu salts as promoters under severe conditions [2], Recently it was discovered that the reaction can be carried out much more smoothly using Pd catalysts. The first Pd-catalyzed intermolecular arylation of cyanoacetate and malononitrile with aryl iodides was carried out by Takahashi using PPhs as a ligand, and was applied to a simple synthesis of tetracyanoquinodimethane (2) by the reaction of p-diiodobenzene with malononitrile [3], The intramolecular arylation of malonates and -diketones with aryl iodides proceeds smoothly. Presence of a cyano group seemed to be important [4,5], The arylation has been successfully extended to halides of heterocycles, such as pyridine, quinoline and isoquinoline. The reaction of bromoxazole 3 with sulfone 4 is an example [6]. 

Sadjadi et al. reported a nano-CuO-catalyzed one-pot three-component synthesis of imidazo[l,2-fl]quinolines and quinolino[l,2-a]quinazolines in water (Scheme 4.57) (Ahmadi et al., 2011). Using aromatic aldehyde, malononitrile, and enaminones as the substrates, the corresponding tricyclic and tetracyclic products, which might be of biological and medicinal importance, were assembled in good to excellent yields within 1.5 h. The isolation of the catalyst is simple, and it can be reused in several runs without loss of catalytic activity. 

A range of secondary A-alkylanilines undergo oxidative olefination with 2-alkyl-quinoline, 4-methylquinoline, 1-methylisoquinoline, 2-methylquinoxaline, 2-methyl-quinazoline, 2-methylbenzo[fiG-thiazole, acetophenone, and malononitrile in DMF to form structurally diverse polysubstituted alkenes in moderate to excellent yields with excellent E Z >99 1 selectivity with the use of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone as the oxidant. Mechanistically, the oxidative olefination reaction proceeds through amine oxidation followed by imine olefination." ii... 

C2 Ha aBrNOa 9 2-p-Bromophenyl-4a,5,5a,6,7,8,9,9a,10,10a-decahydro-5a-methyl-10a-morpholino-4H-naphtho[2,3-b]pyran, 40B, 336 C211H3fiNeO, N,N -Bis-(2-cyanoethyl)-l, 10-diaza-4,7,13,16-tetraoxa-cyclo-octadecane malononitrile complex, 45B, 417 C25H20CINO13, 6,7-Bis(methoxycarbonyloxy)-l,2,3,4-tetrahydro-iso-quinoline-[1,2-c]-oxazol-2-one-[3,4-b]-1-chloro-3-methoxycarbonyl-oxy-6,7-methylenedioxyindane, 45B, 418 C2 5H21 Cl2NO, 3-(3,5-Dichloro-2,4,6-trimethylphenyl)-4-diphenylmeth-ylene-2-isoxazoline, 42B, 283... 

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