Chalcones malononitrile

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... 

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). 

This reaction involves 1 equiv of chalcone and pyrrolidine and two molecules of malononitrile. The structure of compound 112 was unambiguously established only with help of X-ray analysis [119]. 

A reinvestigation of the recently described efficient synthesis of substituted 1,6-naphthyridines was carried out. It was found that the reaction of chalcones with malononitrile catalyzed by pyrrolidine afforded a mixture of four products thermal or microwave heating was used. The previously claimed 1,6-naphthyridine formation was an exception (2002SC2903). 

Dithiins are produced by the reactions of geminal dithiols with enones such as chalcone and benzylidene acetophenone (Equation (54)) <62JOC4488, 66BSF1920>. Treatment of geminal dithiols with malononitrile also gives rise to 1,3-dithiins (Equation (55)) <62JPR2ll>. 

This approach has also been applied to the use of malonates as C-H acidic carbon pro-nucleophiles, observing that the reaction performed excellently with a wide range of different chalcones and (3-aryl substituted 2-butenones (Scheme 4.28). Moreover, other 1,3-dicarbonyl compounds and related derivatives such as malononitriles, (3-ketoesters, 2,4-pentanedione and ethyl nitroacetate have also been tested with success in the reaction using chalcone as Michael acceptor. In an independent work, the use of cyanoacetates was also surveyed with good results, although in this case mixtures of diastereoisomers were typically obtained. In all these cases, the stereochemical outcome of the reaction was consistent with the model proposed by Soos. 

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

Extension of substrate scope in Michael-type reactions was demonstrated in the diatyl prolinol Ij catalysed conjugate addition of malononitrile to t/ fl/is-chalcones (Scheme 7.8). ... 

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... 

The enantioselective Michael addition of malononitrile CH2(CN)2 to trans-chalcones R CH=CHCOR catalysed by diarylprolinols (151), has been studied in detail. Both experimental and computational results are consistent with a bifunctional non-covalent activation of the reactants (152). The latter mechanism correctly predicts formation of the (R)-configured products (<75% eef- but is in conflict with the generally accepted iminium mechanism. Furthermore, (151) is likely to form the corresponding oxazolidine derivative as an intermediate, which has not been taken into account. 

Scheme 19.25 Asymmetric Michael additions of malononitrile to chalcones catalysed by Al-quinine complex.

Recently, other research groups have developed the addition of 1,3 dicarbonyl or related compounds to enones. For example, Lattanzi reported the addition of malononitriles to enones catalyzed by cinchona alkaloids with good yields and enantioselectivities [84], Jaszay reported the addition of diethylcyanomethyl phos-phonate to enones using thiourea catalysts with moderate yields and enantioselectivities [85], and Wang reported the Michael addition of ketones to chalcones using pyrroUdine-derived catalysts with good yields and excellent enantioselectivities [86]. 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

---