2- malononitriles formation

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Pyridopyridazine 413 when treated with benzylidenemalononitrile in a mixture of DMF/ethanol (1 1) and a catalytic amount of triethylamine gives compound 414 as the only isolated product and formation of the corresponding regioisomer is not reported. The same starting compound treated with malononitrile and ethyl cyanoacetate under similar conditions provides products 415 and 220, respectively (Scheme 65) <2005HC089>. Similar reactivity of phthalahydrazide 416 to malononitrile and ethyl cyanoacetate was also described <1996PHA714>. 

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-... 

Closure of the triazole ring can be achieved either by oxidative formation of the N-N bond, or condensation of an fV-aminopyridone. The latter was formed by iV-amination of pyridines with mesitylhydroxylamine (MSH), or by forming the pyridine ring, starting from cyanoacetic hydrazide with malononitrile or 2-cyanoacrylates. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

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... 

Knoevenagel adduct 239 of oxohomophthalimide 240 with malononitrile 27a in reactions with CH-acids behaves ambiguously (82CPB1215). Reactions of 239 with acetylacetone, ethyl esters of acetoacetic and ben-zoylacetic acids, as well as methyl pyruvate led to the formation of the desired spiropyrans 241. However, benzoylacetone, dibenzoylmethane, cyanacetamide, and oxindole always gave the same 242. Authors explain this feature in terms of a retro-cleavage of adducts of Michael product 239... 

Reaction of the malononitrile-derived diazene 275 with active methylene compounds proceeds via addition to a cyano group followed by intramolecular hydrazide or thiohydrazide formation, pyridazin-3(2//)-ones and thio analogs 276 are respectively produced (Equation 70) <1999JCM8>. 

While ring annulation is not uncommon, the formation of a five-membered ring onto an existing pytazine is somewhat unique. Thus, 25 reacts with malononitrile and then with an amine to form the tricyclic product 26 (Equation 9) <2001MC152>. Thiophene and pyrrole analogs of 25 react similarly. Note that 26 is suitably substituted to add yet another ring. 

Aminomalononitrile (6), an HCN trimer, no doubt forms as an intermediate in the base-catalyzed formation of DAMN from HCN (Section II,C,1). However, its rate of formation is slower than its reaction with an additional 1 mol hydrogen cyanide. Aminomalononitrile has been synthesized from malononitrile and shown to give DAMN upon treatment with cyanide (730SC33 730SC344). 

The formation of a third ring by a PPA-catalyzed intramolecular cyclization of the malononitrile derivative (683) gives a single product (684), in contrast to the mixture obtained from a similar reaction on the thiochromanone (76JHC123). 

A variation involves the formation of the oxonitrile by self-condensation of the benzoyl-acetonitrile. The normal reaction with, for example, malononitrile then follows (79MI22401). 

In all instances, a necessary condition for successful formation of the pyran is the presence of an electron-withdrawing group at C-4 of the oxonitrile. For example, the ketone (148) derived from benzylideneacetophenone and malononitrile does not cyclize. 

Exercise 24-13 Propanedinitrile [malononitrile, CH2(CN)2] reacts with tetracyano-ethene in the presence of base to yield a compound of formula HC3(CN)5, which is a monobasic acid of strength similar to sulfuric acid. What is the structure of this compound and why is it such a strong acid Write a mechanism for the formation of the compound that is based in part on the Michael addition (Section 17-5B). 

Reaction of 220 (R = H) with malononitrile leads directly to formation of the cyanopyridonocoumarin, whereas with p-nitrophenyl-acetonitrile reaction stops at the pyronocoumarin stage. 

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