Malononitriles heterocyclic

Heterocyclic malononitriles. 2-Pyridylmalononitriles have been prepared from pyridinium iodides 3-pyridylmalononitriles were obtained by reacting 3-halopyridines with malononitrile anion. Other heterocyclic malononitriles like pyrazinemalononitrile and 2-thiazolemalononitrile have been prepared by direct ring-closure reactions from aliphatic precursors. 

Recyclization reactions of heterocycles with participation of malononitrile and its derivatives 99UK45. 

Amino-5-hydrazinopyrazole dihydrochloride 300 is a good source for the synthesis of this type of heterocyclic compound [78JCS(P1)885] and it was prepared by reaction of malononitrile with two equivalents of hydrazine. Reaction of 300 with ethyl pyruvate afforded 301. Unstable hydra-zone 302 formed when 300 was boiled with diacetyl rapidly cyclized to 303. Reaction of 300 with benzil gave 304 directly, which gave an acetyl derivative and resisted reductive deamination. On the other hand, a polymer was isolated from the reaction of 300 with glyoxal (Scheme 65). 

The fused heterocyclic compounds 276 containing furazan fragment were prepared by reaction of the annelated 2,3-dichloropyrazines with malononitrile, followed by treatment with RH <2001MC152>. 

Subsequent studies on thioamide pyrans with application of the competitive reactions method contribute to our understanding of the mechanisms of heterocyclizations with cyanothioacetamide 114 (89ZOR1331). 2,6-Diaminothiopyrans 115, on heating in benzene, open their thiopyran ring reversibly forming intermediate 116, which can eliminate cyanothioacetamide 114 or malononitrile 27a with formation of UNs 30 or 117, respectively. The direction of the subsequent reaction with... 

These heterocycles (240) are the first representatives of meso-ionic compounds to be S3mthesized in which the raocyclic subsfituent f. Table I) is a stabilized carbanionoid group [-C(CN)C02Me or -CfChOi]-Their synthesis d involves the reaction between (i) JV-aminoamidines (23 ) and bis(methylthio)acrylonitriles (241), (ii) iV-thioacylhydrazines (232), and 3-alkylamino-3-methylthioacrylonitriles (242), and (iii) 1,2,4-triazolium iodides (234, R = Me, X = I) and malononitrile. 

The salts (294) with malononitrile and triethylamine in boiling acetonitrile yield the new class of meso-ionic heterocycles in which the exocyclic carbanionoid residue is a biscyanomethylene group. The diphenyl derivative (296, R = R = Ph) has a dipole moment of 9.54 D in benzene solution. ... 

Ring synthesis from non-heterocycles by closure y to the heteroatom are reported. Sulfonium ylides (135) with active methylene compounds such as malononitrile give a C-phenacyl product (136) however, when reacted with /3-diketones and /3-ketonic esters they produce furans quantitatively (74CL101). In these cases O-phenacylation takes place followed by cyclization to give the 3-hydroxydihydrofuran (137), which is dehydrated to the furan (138) (Scheme 30). These furans differ from those formed by the reaction of the diketone or ketonic esters with phenacyl halides. The latter reaction takes place by C-phenacylation, yielding the isomeric furans (139). 

Only a few exchange reactions of substituents directly bound to the heterocyclic ring have been reported. Gompper has studied the nucleophilic substitution of bromo- and chloro-l,2,3-triazines and observed replacement of bromine or chlorine with sodium ethoxide, sodium ethanethiolate and amines. In most cases yields are quantitative. With the trihalo compound, first the 4-mono- then the 4,6-di-substituted derivative is obtained (79CB1529). Reaction of 5-chloro-2-methyl-4,6-bis(dimethylamino)-l,2,3-triazinium iodide (61) with malononitrile affords compound (62). Compounds of the general structure (63) are hydrolyzed to l,2,3-triazin-5(2//)-ones (64) (79CB1535). 

Health and Safety Factors. Malononiirilc is usually available as a solidified melt in plastic-lined drums. Remclting has to he done carefully because spontaneous decomposition can occur at elevated temperatures, particularly above lOO C. in the presence of impurities such as alkalies, ammonium, and zinc sails. Occupational exposure to malononitrile mainly occurs by inhalation of vapors and absorption through the skin. Malononitrile has a recommended workplace exposure limn of 8 mg/m Uses. Malononitrile is extensively used in the life sciences industry The most important products ate vitamin B (thiamine) and bensulfuron-melhyl. a sulfonyl urea herbicide. Most other product uses fall under the. V-containing heterocycles. 

Most of the publications on the reactions of malonic acid derivatives are devoted to the reaction of a,(3-unsaturated carbonyls with malononitrile 107. In this book we do not describe the results of all known publications but only the most characteristic or interesting ones in our opinion. The reactions of unsaturated ketones with malononitrile are usually carried out in methanol or ethanol in the presence of ammonium acetate [102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117]. Treatment of malononitrile 107 with chalcone 5 [115] and its heterocyclic analogue 109 [104] yielded 3-cyanopyri-dines 108 and 110 (Scheme 3.33). 

In several cases the application of other basic catalysts is described, but such reactions often are followed by numerous side reactions or proceed in another direction. For example, in the reaction of malononitrile 107 with dimethylami-nochalcone 111 in the presence of pyrrolidine as the catalyst, instead of the expected cyanopyridines being formed the heterocycle 5-amino-7-(pyrrolidin-l-yl)-l,6-naphthyridine-8-carbonitrile 112 [118] is produced (Scheme 3.34). 

Examples of nitrogen-containing heterocycle syntheses based on condensation reactions continue to be forthcoming. Examples include a tandem oxidation-annulation of propargyl alcohols in a one-pot synthesis of pyridines (Equation 148) <2003SL1443>, trifluoromethyl-substituted pyridines (Scheme 94) <2003S1531>, and standard malononitrile additions to a,/3-unsaturated ketones <1995JCM392>. 

Multicomponent one-pot reactions continue to be the focus of heterocyclic synthesis when multi-bonds are formed. Malononitrile condenses with 3-pyridinecarbaldehyde and a ketone to form a substituted bipyridine (Equation 179) <1995JCM146>. In another condensation, with aniline being the ultimate source of the tetrahydroquinoline nitrogen atom, iodine is used as a catalyst in a reaction that was optimized for yield and diastereoselectivity (Equation 180) <2005SL2357>. 

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). 

In addition to isocyanide-based MCRs, a wealth of highly functionalized heterocycles can be obtained from 1,3-dicarbonyl, cyanomalonate and malononitrile based MCRs [19]. These easily accessible starting materials participate in a variety of multi-component reactions and have found numerous applications in drug discovery. 

Carboranyl acid halides can be very easy prepared. We have studied the acylation of malononitrile and acetoacetic ester by methylcarboranyl carboxylic acid chloride (15). The reaction with malononitrile leads to the compound 17a, which exists also as a enol form, similar to compound 13. Compound 17a can be methylated to give compound 17b, a novel synthon for the preparation of wide range of heterocyclic compounds (Scheme 7). 

Compounds of the type 171 can generally be easily dehydrated and many reactions of isatins lead directly to isatylidene derivatives. Use of active methylene compounds such as malononitrile and cyano-acetate gave compounds of the type 184. Various 4-thiazolidones have been condensed with isatin, generally under acidic conditions, to give 185. " Similar type compounds (186) have been obtained from thianaphthenes and isatin using acetic acid. " These compounds (186) have been used as dyes. Other heterocyclic ketones... 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

---