Reaction with malononitrile nitriles

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

Fluorinated esters may also act as electrophiles in reactions with nonfluori-nated ketones [28] (equation 23) or malononitrile [29] (equation 24). Unfortunately, the yields of p-diketones may be modest, but those of p-keto nitriles are excellent (Table 9)... 

The cycloadduct 420 formed from the reaction between 1,3,4-thiadiazines and acrylate derivatives spontaneously loses N2 to give 2,4,5-trisubstituted 477-thiopyrans 421. The products from the reaction of the 4-nitrile derivatives with malononitrile and ethyl cyanoacetate cyclize on treatment with base to give 177-2-benzothiopyrans (Scheme 128) <2006AP608>. 

Like / -keto esters, /3-keto nitriles react smoothly with hydrazine the latter give aminopyrazoles.78,310-321 Under the same conditions cyanoacetic ester and its derivatives give aminopyrazolones.322-325 The reaction of malononitrile is more complex, giving 1-substituted 3-cyanomethyl-4-cyano-5-aminopyrazole and products formed by further condensation.328... 

The reaction of mesityl oxide with malononitrile gave 5-amino-7-(pyrrolidin-l-yl)-2,4,4-trimethyl-1,4-dihydro-l,6-naphthyridine-8-carbonitrile. The non-linear optical studies of this pyridinenitrile derivative showed a high value while that of nicotino-nitrile was low (2003T3761). 

Treatment of the 5-arylidene derivatives of l,3-diphenyl-2-thiohydantoin with malononitrile affords tetrahydropyrano(2,3-d)imidazoles (110), while 3-phenyl- or unsubstituted 2-thiohydantoins originate pyrrolo(l,2-c)imidazoles (111). These products are also obtained in a Michael-type reaction of 2-thiohydantoins with activated nitriles.282... 

A large number of papers from Russian laboratories dealing with the synthesis of 2,2-dichloro-1,3,22 -diazaphosphinines by reaction of malononitrile, derivatives of malononitrile, and other monosubstituted nitriles with PCI5 were published between 1966 and 1980. A brief overview of this work is given in Figure 5. 

Condensation of the pyrrolidine enamine of V-[4-(/-butyloxycarbonylphe-nyl)]piperidone and (chloromethylene)malononitrile followed by reaction with ammonia in methanol at room temperature afforded the amino nitrile (IV.234) in 72% overall yield [148]. Cleavage of the t-butyl ester was accomplished readily with HCl in nitromethane, and the resulting acid ((IV.235), 77% yield) was coupled to di-t-butyl L-glutamate with the aid of diphenyl... 

A,A-Disubstituted 4-amino-1,1-dicyanobuta-1,3-dienes were obtained from ylidene-malononitriles by reactions with triethyl orthoformate and amines232. Furfurylidenemalono-nitriles have been subjected to various reactions to form different open-chain derivatives, which are useful intermediates. So 157 was reacted with ketene thioacetal 158 to yield furylhexadienonitriles 15923. ... 

The COj species in the HT interlayer could be exchanged with OH ions by calcination at 723 K and hydration at room temperature. A spinel phase of Mg-Al mixed oxide obtained after the calcination transforms into the original layered structure during the hydration. This reconstruction is known as the memory effect of HT materials. The reconstructed HT catalyzed the Knoevenagel condensation of various aldehydes with nitriles in the presence of water [119]. The reconstracted HT also showed an aqueous Michael reaction of nitriles with a,p-unsaturated compounds. The layered double-hydroxide-supported diisopropylamine catalyzed the Knoevenagel condensation of aromatic carbonyl compounds with malononitrile or ethyl cyanoacetate [120]. This solid base could be recycled at least four times, and exhibited activity for aldol, Henry, Michael, transesterification, and epoxidation of alkenes. 

Aldehydo nitriles are readily available and can be used to prepare 4-amino-6-unsubstituted pyrimidines carrying one or more substituents in any of the other positions. Equivalents of the formyl group are also often used, for example, a 3-ethoxy-, 3-amino-, or 3-haloacrylonitrile. Most syntheses with /3-keto nitriles are carried out with equivalents thereof Such equivalents are /3-substituted /3-alkoxy-, /3-amino-, or /3-haloacrylonitriles. /3 -Ester nitrile reactions are also well established. Malononitriles and substituted malononitriles react readily with thiourea and N-substituted thioureas in refluxing ethanolic sodium ethoxide to form pyrimidine-4,6-diamines. An example is the reaction of N2-malononitrile 680 with N2-thiourea 681 to give N4- 4,6-diamino-2-(l//)-pyrimidinethione 682 which was then used in the synthesis of Ns-labeled adenine derivatives <2001JOC5463>. 

In the presence of morpholine and malononitrile, the initial reaction of cyclohex-3-enal with cyanothioacetamide is followed by a condensation with the dinitrile. Cyclization follows through attack of the thiol on a nitrile function and a penta-substituted 477-thiopyran is formed (Scheme 126) <1998RJ0557, 2005RJC1537>. 

A one-pot synthesis of 3,5-disubstituted 7-hydroxy-3//-l,2,3-triazolo[4,5-d]pyrimidines (130) has been carried out by using benzyl azide, cyano-acetamide, ethyl or methyl esters of the appropriate carboxylic acid, and sodium ethoxide as catalyst. The reaction proceeds via a 5-amino-l-benzyltriazole-4-carboxamide intermediate (85JHC1607). 7-Amino-3H-l,2,3-triazolo[4,5-d]pyrimidines 133 (R2 = H) were prepared starting from benzyl azide, malononitrile, and an aliphatic or aromatic nitrile, or by reaction of 130 with phosphorus oxychloride followed by amination. Compound 132 was formed in most reactions from two molecules of the 5-amino-4-cyano-l-benzyltriazole intermediate by an intermolecular nucleophilic at-... 

Another field of research is concerned with the one-pot synthesis of this system from readily available starting materials. In Scheme 12, reaction of phenyl azide and malononitrile in the presence of sodium ethoxide leads, via the intermediate triazole (139), to the self-condensation product (140), itself a triazolopyrimidine. In the presence of other nitriles the preferred formation of the more useful compounds (141) occurs in low to moderate yields with small amounts of dimer <87JHC997>. Direct synthesis of the 5,7-dione derivatives (143) (60-90%) is achieved by the reaction of the readily available aminopyrimidinedione (142) with an azide iminium salt in dichloromethane at moderately high dilution <87JHC1493>. 

Apart from the addition reaction to electrophilic olefins, the / -carbon atom of 1,1-enediamines can also substitute a,/ -unsaturated compounds carrying a leaving group. Schafer and Gewald129 have shown that 141 and 142 react with 143 to give product 144 in moderate to good yields (equation 54). Ketene dithioacetals derived from an alkyl cyanoacetate and malononitrile behave similarly to 143130. When imine 145 is employed, the reaction results in the formation of 146 (equation 55)129. Apparently displacement of ethoxy group and cyclocondensation by attack on the nitrile moiety are the key steps in the reaction. 

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