Promoters Knoevenagel reaction

Ionic liquids are also alternative reaction media considered as green, mostly because of their lack of vapor pressure and the possibility of reuse [68, 69]. Base-catalyzed Knoevenagel reactions have been described in these media [70-73]. The development of task specific ionic liquids in which the solvent and promoter are coupled is a real breakthrough in the field and some of them have been used in the Knoevenagel condensation [74—81]. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

Knoevenagel reactions. Alkylidenemalonic esters are prepared from the dibromomalonic esters and carbonyl compounds with promotion by BUjSb in THF (6 examples, 70-95%). 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

The ability of L-Pro to promote the Knoevenagel reaction has been harnessed in domino reaction sequences for the preparation of important target products. Several bicyclic and polycyclic systems have been obtained by these means. As an example, coumarines were prepared by the one-pot condensation reaction of o-hydroxybenzaldehydes with active methylene compounds (Scheme 2.8). In a related procedure, flavanones were synthesised from aromatic (3-ketoesters and aldehydes (Scheme 2.8). The domino sequence comprises in this case, a proline-catalysed Knoevenagel condensation and an intramolecular Michael addition. 

The first exanple is the use of chloranil in C—H oxidation of sulfides, leading to the in situ formation of the electrophilic thionium ion, which was trapped by 1,3-dicarbonyl conpounds in a Knoevenagel reaction. The products obtained were a-acyl-p-sulfurated carbonyl conpounds 192. This transformation and the authors proposed activation mechanism are shown in Scheme 20.37. Elimination of the sulfur-containing moiety promoted by chloranil afforded the usual Knoevenagel products 189. 

Hu Y, Wei P, Huang H, Le ZG, Chen ZC (2005) Organic reactions in ionic liquids ionic liquids ethylammonium nitrate promoted knoevenagel condensation of aromatic aldehydes with active methylene compounds. Synth Commun 23(35) 2955-2960... 

Palmisano et al. [103] worked with ultrasound at 60 W power and 19.6 kHz, for 1.5 h, to get a wide range of (het)-3-arylmethyl-4-hydroxycoumarins (134) through a tandem Michael Knoevenagel-reductive reaction (Scheme 34). The efficient ultrasoxmd method promoted the reaction in the absence of organic solvents, with temperature control at 30-40 °C in an open vessel, without the need of an excess of Hantzsch 1,4-dihydropyridine. These compoxmds have biological properties such as anticoagulant, photosensitizing, and antineoplastic. 

A few years after Knoevenagel proposed his mechanism for the reaction that came to bear his name, Hann and Lapworth showed that primary or secondary amines were not required for the transformation to take place, as Knoevenagel had claimed, but that tertiary amines could indeed promote the reaction between menthylacetoacetate 15 and aldehydes (although they were less efficient)." The use of a tertiary amine obviously precludes the possibility of an aminal or imine intermediate, therefore Hann and Lapworth proposed direct reaction between the enolized dicarbonyl compound and the aldehyde (Hann-Lapworth mechanism). This mechanism would proceed similarly to that proposed by Knoevenagel, but without aminal formation, and proceeding through a P-hydroxy dicarbonyl compound such as 18, rather than a P-amino dicarbonyl compound (e.g., 13). 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

These examples of Knoevenagel condensations illustrated that reaction times could be reduced from 1-2 days to 30-60 min by employing parallel microwave-promoted synthesis in open vessels, without affecting the purity of the resin-bound products. 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

PS-BEMP was able to promote the first step (the alkylation process) in higher yield but failed in the Knoevenagel condensation (very long reaction times, 48-72 h, were needed) the best results were obtained by employing the supported TBD catalysts. No significant differences between SiO2-TBD and PS-TBD were observed, probably because the latter catalyst can swell sufficiently in THF. Consequently, the less expensive PS-TBD was employed for the preparation of a library of substituted aza-heterocycles Table 3.7 gives some examples. 

---