Malononitrile, arylation

Catalytic benzylation of 10 was performed under solid-liquid phase-transfer conditions to yield benzylidenemalononitrile Alkylidenemalononitriles can undergo reduction to yield the corresponding saturated malononitriles ". Aryl malononitriles 125 have been obtained from 10 and halobenzenes " or from aroyl chlorides in three steps. Surprisingly, the aliphatic malononitrile derivative 126 has been obtained when 2-indolone was reacted with 43. The same reaction was also observed for two other cyclic carbonyl compounds... 

Synthesis of pinojaden A convergent synthetic route leads to the pyrazolidine-dione NO A 407854, which is esterihed in the last step with pivaloyl chloride. Pinoxaden is prepared effectively in a total of 5 (longest linear sequence) + 3 (oxadiazepane synthesis), total 8 steps. Key reachons are an efficient malononitrile arylation via cross-coupling [12] to access a sterically hindered aryl malononitrile and the unprecedented condensation of its malonamide derivative with [l,4,5]oxa-diazepane [8], This sequence fits feasibility criteria for a technical application. 

Keywords Ninhydrin, malononitrile, aryl isothiocyanates, primary aliphatic amines, ethanol, triethylamine, room temperature, one-pot multicomponent synthesis, thio-Michael and Knoevenagel reactions, sulfur-nitrogen heterocycles, oxathiaaza[3.3.3]-propellanes, che-moselectivity, regioselectivity... 

Ninhydrin (1 1 mmol) Malononitrile Aryl isothiocyanate Amine... 

Arylation or alkenylation of soft carbon nucleophiles such as malonate is carried out by using a copper catalyst, but it is not a smooth reaction. The reaction of malononitrile, cyanoacetate, and phenylsulfonylacetonitrile with aryl iodide is possible by using a Pd catalyst to give the coupling products. 

The first reaction can be conducted using various derivatives of methylenemalonic ester, such as malononitriles 7, malonamides 8, P-keto-esters 9 or Meldrum s acid 10. Substitutions of the aryl ring (including fused rings) and within the aryl ring are well tolerated for this reaction. 

Cycloaddition of 2-styryl-4/7-3,l-benzoxazines and malononitrile gave 1 -amino-3-aryl-2-cyano-1 //,6//-pyrido[l, 2-n][3, l]benzoxazin-4-ones (99ZN(B)923). These tricyclic derivatives were also prepared in the reaction of 2-methyl-4//-3,l-benzoxazin-4-one and arylidenemalononitrile in AcOH in the presence of NaOAc. 

The nucleophilic attack on the bridging carbon results in two different reactivities. Usually ring opening occurs. Malononitrile under hydrolytic solid-liquid phase-transfer conditions attacks the methiodides 26 at the fusion carbon atom, thereby inducing ring opening and the formation of 4-(Ar-aryl-3 -methylisothioureido)-5-(dicyanomethylcnc)-l-... 

Scheme 6.70 Mechanistic proposal for the 12-catalyzed asymmetric Michael addition of malononitrile to (J-aryl and alkyl substituted N-acyl pyrrolidinones (cyclic imide) (A) and to a,P-unsaturated N-aryl substituted 2-methoxybenzamides such as N-cinnamoyl-2-methoxybenzamide (acyclic imide) (B).

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>. 

A clean twofold Heck coupling of unsubstituted butadiene 46 (R = H) in the 1- and 4-positions has not been reported. However, the initial carbopalladation product from 46 (R = H) and an in situ formed arylpalladium halide, the cr-allylpalladium halide 47 equilibrating with the corresponding 7r-allylpalladium halide, can efficiently be trapped with the anion formed by arylation of malononitrile or cyanoacetate to give 48, a product of reductive 1,4-arylation-alkylation of 1,3-butadiene 46 (R = H)." /3-Hydride elimination from the intermediate 47 (R H) can be accomplished when the reaction is carried out in the presence of silver acetate or thallium acetate, leading to the... 

Arylation of malononitriles 5-17 Addition of nitriles to unsaturated nitriles (Michael)... 

The most popular preparations of pyrimido[4, 5 ]pyrimidi nes are based on cyanoethylene or cyanomethylene derivatives. In many of these preparations the appropriate acid chloride (R1 = alkyl, aryl) is reacted with malononitrile to give an enol (250), which is readily alkylated to the enol ether (251). This can be condensed with guanidine or a variety of amidines (R2 = H, alkyl, aryl) to yield the key intermediate 4-amino-5-cyanopyrimidines (252) (81S955). Reaction with a second mole of guanidine or amidine is a convenient preparation of a variety of pyrimido[4,5 ]pyrimidines. Under the appropriate conditions the final ring system can be obtained from the enol ether in one step (68JMC568). 

Other nucleophiles than amines which have been employed in the reaction are malononitrile and cyanoacetic ester anions. Both of these anions undergo a preliminary reaction with the aryl halide to form the C-aryl derivatives before they attack the ir-allylpalladium intermediate, so that diarylated products are formed (equation 31).86 Phenylmalononitrile anion reacts with iodobenzene and butadiene to give the same product in 70% yield. 

Although arylation or alkenylation of active methylene compounds can be carried out using a Cu catalyst, the reaction is sluggish. However, the arylation of malononitrile (390) or cyanoacetate proceeds smoothly in the presence of a base and Pd catalysts [189], Tetracyanoquinodimethane (392) is prepared by the coupling of / -diiodoben-zene with malononitrile (390) to give 391, followed by oxidation [190], Presence of the cyano group seems to be essential for intermolecular reactions. However, the intramolecular arylation of malonates, / -keto esters and /i-diketones proceeds smoothly [191]. The bromoxazole 393 reacts with phenylsulphonylacetonitrile (394)... 

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