Malononitrile, Michael addition

As shown above, it was not so easy to optimize the Michael addition reactions of l-crotonoyl-3,5-dimethylpyrazole in the presence of the l ,J -DBFOX/ Ph-Ni(C104)2 3H20 catalyst because a simple tendency of influence to enantio-selectivity is lacking. Therefore, we changed the acceptor to 3-crotonoyl-2-oxazolidi-none in the reactions of malononitrile in dichloromethane in the presence of the nickel(II) aqua complex (10 mol%) (Scheme 7.49). For the Michael additions using the oxazolidinone acceptor, dichloromethane was better solvent than THF and the enantioselectivities were rather independent upon the reaction temperatures and Lewis base catalysts. Chemical yields were also satisfactory. 

Finally we have performed the Michael addition reactions of malononitrile and 3-(2-alkenoyl)-2-oxazolidinones in dichloromethane in the presence of the R,R-DBF0X/Ph-Ni(C104)2-31 20 and TMP (10 mol% each). Enantioselectivities were a little lower than 90% ee for acceptors having a variety of / -substituents. The best selectivity was 94% ee in the reaction of t-butyl-substituted acceptor (Scheme 7.50). 

Reactions of a,(3-unsaturated acylzirconocene chlorides with stable carbon nucleophiles (sodium salts of dimethyl malonate and malononitrile) at 0°C in THF afford the Michael addition products in good yields (Scheme 5.38). Direct treatment of the reaction mixture with allyl bromide in the presence of a catalytic amount of Cul -2LiCl (10 mol%) in THF at 0 °C gives the allylic ketone in a one-pot reaction. This sequential transformation implies the electronic nature of a,P-unsaturated acylzirconocene chloride to be of type E as shown in Scheme 5.37. 

Electron-poor alkenes are suitable starting points for Michael additions. For example, the arylidene malononitrile 363 adds quantitatively to solid dimedone (255) upon milling at 80 °C followed by heating of the yellow powder to 100 °C. The initial Michael adduct 364 is not isolated, as it cyclizes in the solid state to give the pyrone 365 with 100% yield [107] (Scheme 58). The potentials for waste-free solid-state chemistry are manifold indeed and deserve further exploration. 

Scheme 6.69 Products obtained from the 12-catalyzed asymmetric Michael addition of malononitrile, nitromethane, and methyl a-cyanoacetate to N-cinnamoylbenzamide derivatives (acylic imides) and 12-catalyzed derivatization of the Michael adduct.

The addition of nitromethane (56% yield/168h 87% ee) or methyl a-cyanoacetate (94% yield/52h 82% ee) as alternative CH-acidic methylene compounds required increased reaction temperatures (60 to 80 °C) to furnish the adducts 7 and 8. As exemplarily depicted in Scheme 6.69 for benzylic alcohol thiourea 12 catalyzes the transformation of the obtained malononitrile Michael products to the respective carboxyhc acid derivatives (89% yield/88h). This method of derivatization also described for methanol (87% yield/24h rt), benzyl amine (77% yield/3h rt), and N,0-dimethylhydroxyamine (75% yield/20h 60°C) as nucleophiles was reported to be feasible as a one-pot strategy without isolation of the initially formed Michael adduct [222]. 

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).

Highly substituted [l,6]naphthyridines have been prepared by the Michael addition and subsequent Thorpe-Ziegler cyclization of a series of chalcones with malononitrile in the presence of pyrrolidine, over extended periods of heating <1999SC3881>. Attempts to reduce the reaction times using microwave irradiation gave mixtures of products... 

The cyclization of 5-oxonitriles offers an attractive route to 2-amino-4//-pyrans (Scheme 18) (78JHC57). The starting materials, a-benzoylcinnamonitriles, are available from benzoyl-acetonitrile and an aromatic aldehyde. Michael addition of ethyl cyanoacetate or malononitrile to the benzoylcinnamonitrile affords the oxonitrile and is followed by cyclization to the imine. The reaction proceeds at room temperature in the presence of either piperidine or sodium ethoxide. 

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). 

Various unsaturated compounds, such as CO2, isocyanates and aldehydes, undergo Pd-catalysed cycloaddition with vinyl epoxides. Reaction of CO2 with 127 affords cyclic carbonates 128 with retention of the configuration at C(3), offering a method of cis hydroxylation of epoxides [66], and has been used for the synthesis of the side-chain unsaturated (—)-exo-brevicomin (129) [67], The tetrahydrofuran 131 was prepared by [3+2] cycloaddition of activated alkenes such as benzylidene malononitrile (130) with vinyl epoxide via Michael addition and allylation [68],... 

In a one-pot three-component reaction, aromatic aldehydes, malononitrile and 1,3-dicarbonyl compounds react to form 2-amino-5-carboxy-4-aryl-47/-pyran-3-carbonitriles 87. The reaction proceeds by an initial Knoevenagel condensation of malononitrile with the aromatic aldehyde to afford the 2-benzylidenemalononitrile intermediate 88. Michael addition of the activated methylene group forms the 1,5-dicarbonyl equivalent 89, which upon ring closure affords 477-pyrans (Scheme 29) <2004SL871, 1999H(51)1101 >. 

Michael addition of the anion from malononitrile to the conjugated system (246) results in the pyranopyrazole (247) (74AP444). For (246 R = Ph) adducts form with vinyl ethers at 70-80 °C. With extra activation (246 R = PhCO or MeCO) the adducts form at room temperature. The reaction is regiospecific but gives a mixture of cis (248 ca. 80%) and trans (249 ca. 20%) isomers (Scheme 77) (80JPR711). 

Ni(II)(OAc)2bpy and Co(II)(OAc)2bpy catalyze the Michael addition of nitro-methane, malononitrile, and aniline to a,j8-unsaturated ketones, methyl acrylate, and acrylonitrile in DMF under neutral conditions [116]. FeCls 6H2O is a highly efficient catalyst of Michael reaction of 1,3-dicarbonyl compounds with a,/3-unsaturated ketones under mild and neutral conditions (Sch. 24) [117]. There is literature precedent for this reaction with dual catalysis Ni(II) immobilized on a clay support and FeCl3 to activate the enone [118]. The mechanism proposed for the single-center catalysis involves coordination of the enone to a diketonato complex [119]. The chemo-... 

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 first step of this process involves the Knoevenagel condensation of an aldehyde with malononitrile to form the corresponding Knoevenagel product (5). The second molecule of malononitrile then undergoes Michael addition to 5 followed by simultaneous thiolate addition to C N of the adduct and cyclization to dihydropyridine (6) which on aromatization and oxidation (air) under the reaction conditions leads to pyridine. 

Itoh, K. and Kanemasa, S. (2002) Enantioselective Michael additions of nitromethane by a catal3ftic double activation method using chiral Lewis acid and chiral atitine catalysts. Journal of the American Chemical Society, 124, 13394—13395 Itoh, K., Oderaotoshi, Y. and Kanemasa, S. (2003) Enantioselective Michael addition reactions of malononitrile catalysed by chiral Lewis acid and achiral antine catalysts. Tetrahedron Asymmetry, 14, 635 39. 

The tosylate 191 was synthesized from the malononitrile 194 obtained in modest yield by potassium fluoride catalyzed Michael addition of malononitrile to 3,6, trimethyl-2-cyclohexenone. A series of unexceptional steps led from 194 to 191 obtained in overall yield of 26%. 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

Interestingly, the addition of malononitriles to chalcones has been successfully carried out using natural quinine 84a as catalyst (Scheme 4.31). This contrasts with the poor performance of the same catalyst in the Michael addition of malonates to nitroalkenes (see Scheme 4.24), which was explained in terms of the difficulty in forming the intermediate in which both reagents, the... 

Scheme 4.31 Enantioselective Michael addition of malononitrile and cyanosulfones to enones.

Scheme 4.43 Enantioselective Michael addition of malononitrile, methyl cyanoace-tate and nitromethane to M-enoylimides.

Scheme 7.8 Enantioselective Michael addition of malononitrile to trans-chalcones catalysed by prolinol Ij.

The tandem Michael addition-cyclization reaaions of ( )-2-(2-nitrovi-nyl)phenols with malononitrile using a chiral thiophosphonodiamide as catalyst deliver 2-amino-3-cyano-4H-chromenes in high yields (14T181). Other derivatives are obtained from a two-step reaction of benzaldehydes... 

A couple of benzo[/]coumarins arise from the reaction of ( )-3-(2-hydroxynaphthalen-l-yl)propenoic acids with primary amines in DMF (14H(89)1503). Some iminocoumarin-fused benzo[(]coumarins were obtained by a three-step sequence involving condensation of salicylalde-hydes with malononitrile in ethanol to afford various 3-cyanoiminocouma-rins, subsequent Michael addition reaction with 2-naphthol and finally heterocyclization with formic acid in a mixture of methanol and toluene (14SC2870). 

Alternatively, the catalytic activity of chiral bifunctional annnonium bromide 147 has resnlted more general than for catalyst 124b. Under low loading conditions (3 mol%), catalyst 147 is able to promote the Michael addition of malonates (especially ethyl malonates) and malononitrile to chalcone derivatives in a highly enanti-oselective manner as depicted in Scheme 2.87 [233]. The authors have also shown... 

---