Condensation promoters, Knoevenagel reaction

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... 

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. 

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. 

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. 

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. 

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... 

In 1885, Arthur Hantzsch showed that the condensation of ethylacetoacetate, benzaldehyde and ammonia provided the symmetrical dihydropyridine 6. 1,5-Diketone 7 was also isolated from the reaction mixture and it was shown that it could be converted to 6 by treatment by resubjecting it to ethanolic ammonia. Subsequent experiments showed that if a primary amine such as methyl, ethyl or allyl amine was used, 7 was isolated as the sole product. Hantzsch showed that the amine was an essiential part of the condensation, as no reaction occurred between ethylacetoacetate and benzaldehde in the absence of amine, but even a catalytic amount of amine was an effective promoter of this condensation. Hantzsch s synthesis of 7 was probably the first reported instance of what was to become known as the Knoevenagel condensation. 

Activation of C=X Bonds. The mild Lewis acid character of ZnCl2 is frequently exploited to promote the addition of various nucleophiles to carbon-heteroatom double bonds. The well-established Knoevenagel condensation and related reactions have been effectively catalyzed by ZnC (eq 26). " The addition of enol ethers and ketene acetals to aldehydes and ketones has been noted (eq 27), though ZnCl2 has been used less widely in these aldol-type condensations than other Lewis acids, including TiCU,... 

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... 

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). 

Aldol reactions. The Knoevenagel condensation between aromatic aldehydes and cyanoacetic acid or ethyl ester or malononitrile in the solid state can be promoted by LiBr as a catalyst (13 examples, 25- ... 

The classical Pechmann approach for synthesis of coumarins via the microwave-promoted reaction [75] has been extended to a solvent-free system in which salicyl-aldehydes undergo Knoevenagel condensation with a variety of ethyl acetate derivatives in the presence of piperidine to afford coumarins (Scheme 8.23) [76]. 

Heteroatom conjugate addition reactions are promoted by superbases. Draper et al. described the synthesis of the estrogen antagonist Sch 57050 (179) [53]. Knoevenagel condensation reaction with ketone 176 and aldehyde 177 in the presence of piperidine... 

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