Reactions Knoevenagel/Michael

3- amino[3- C]crotonates (route 1), which are readily obtained by treatment of the 

With formaldehyde or acetaldehyde as reaction component the corresponding 

4- unsubstituted or 4-methyl derivatives were obtained, which in the presence of sodium 

Reaction conditions la. NaN02, HOAc r.t., 5 h b. Zn, NaOAc, HOAc 95- 

Michael addition of ethyl [3- C]acetoacetate to ethyl crotonate followed by an intramolecular tandem enolate acylation opens an altemative approach to highly substituted labeled resorcinols (e.g., 3291 (see also Section 6.5.1). Aromatization of the initially formed ethyl 6-methyl-4-hydroxy-2-oxo[l- C]cyclohex-3-ene-l-carboxylate 13271 is readily 

---

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

M. N. Ehnson, A. S. Dorofeev, R. F. NasybuHin, S. K. Feducovich, G. I. Nikishin, ElectrochirtL Acta 2008, 53, 5033-5038. Electrocatalytic tandem Knoevenagel-Michael reaction of 3-methyl-2-pyrazolin-5-ones, aryl aldehydes and cyano-functionalized C-H acids facile and convenient multicomponent way to substituted 3-(5-hydroxy-3-methylpyrazol-4-yl)-3 - ary Ipropionitriles. 

In 2012, a chiral cinchona alkaloid-derived primary amine was associated by Wang et al. to a (R)-BINOL-derived phosphoric acid to induce a three-component domino Knoevenagel-Michael reaction between isatins, malononitrile, and acetone, providing the corresponding domino products in generally excellent yields and enantioselectivities, as shown in Scheme 2.13. A hypothetic cooperative catalysis can be envisaged to explain these excellent results. 

Scheme 2.13 Three-component domino Knoevenagel-Michael reaction catalysed by a combination of a chiral cinchona alkaloid-derived primary amine and a chiral phosphoric acid.

For Aldol and Related Reactions. The TMSI/(TMS)2NH combination can be used for the synthesis of polycyclic cyclobutane derivatives by tandem intramolecular Michael-aldol reaction. TMSI-induced diastereoselective synthesis of tetrahy-dropyranones by a tandem Knoevenagel-Michael reaction, has also been developed. More recently, the facile synthesis of a,a bis(substituted benzylidene)cycloalkanones has been reported, using TMSI (in situ generated) mediated cross-aldol condensations (eq 53). ... 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

Scheme 42.4 Three-component Knoevenagel/Michael reaction both steps are catalyzed by the amine 16 only the second enamine path is stereo-determining.

Figure 6.91 Use of alkyl C C]acetoacetates in a tandem Knoevenagel-Michael reaction sequence...

---