The Knoevenagel reaction is defined by the condensation of an aldehyde or ketone with a carbon nucleophile produced by the deprotonation of a methylene species whose acidity is dramatically increased by bonds to strongly electron withdrawing groups. Previously, our group developed an effective one-pot method for the preparation of 4H-chromenes using sodium borohydride reduction of the cyclized intermediates formed by the Knoevenagel condensation of malononitrile with salicylaldehydes in aqueous ethanol. In this study we outline the extension of these strategies to include 2’-hydoxyphenylketones as the starting material. Many of these compounds are also unique and were prepared by Friedel-Crafts acylation of phenols with acyl chlorides and/or Fries Rearrangement of the corresponding phenyl ester. The objective of this project has been to expand the application of the methods optimized in our lab for the simple and efficient formation of carbon-carbon bonds via the selective reduction of the alkylidene portion of the Knoevenagel reaction products. These methods have allowed for the production of several important classes of natural product-like compounds. Specifically, in this investigation, we have adapted these methods to the production of various 4-alkyl and 4-aryl substituted 3-amino-2-cyano-4H-chromenes. These types of molecules exhibit diverse pharmacological activity and have been shown to be potentially useful for the treatment of various diseases. A subset of the synthesized compounds will be submitted to Eli Lilly through their PD2 program. Further variation of substrates included the reaction of salicylaldehydes with ethyl cyanoacetate or cyanoacetamide which provided products unreported in the literature. Reactions with cyanoacetates gave the expected 3-carboethoxy(ester) functionalized 4H-chromene compounds. Products from cyanoacetamide were found to occur in open rather than cyclized forms. / Introduction and background literature -- Synthesis of 2'-hydroxyphenylketones -- Synthesis of 2-amino-3-cyano-4H-chromenes -- One pot method applied to salicylaldehydes with ethylcyanoacetate or cyanoacetamide. / Department of Chemistry

A powerful new one-pot method has been developed for the reductive alkylation of malononitrile with aromatic aldehydes. This new procedure has vastly improved the yield and efficiency and increased the scope for the aromatic aldehydes. Incorporating water as the catalyst in ethanol for the condensation step allows stoichiometric amounts of malononitrile and aldehyde to be employed. After dilution and cooling the reduction step takes place quickly and efficiently with sodium borohydride to give monosubstituted malononitriles.The product from the reductive alkylation of malononitrile with 2-quinolinecarboxaldehyde quickly rearranges to a novel indolizine on silica gel or with heat, while alkylation of the monosubstituted derivative provides an unsymmetrically disubstituted malononitrile.We have also investigated this improved one-pot reductive alkylation using various 2-hydroxybenzaldehydes where intramolecular cyclization occurs following the condensation step and various 2-amino-3-cyano-4H-chromenes are formed. / Department of Chemistry

Isoxazoles and isoxazolines have been shown in the literature to be an important scaffold for pharmaceuticals and insecticides, as well as a source of synthetic versatility important to many syntheses. As a substitute for other aromatic rings, isoxazoles are known to change the efficacy of a given compound. Isoxazolines can be used as a precursor to many other functional moieties that may be effected during earlier synthetic steps. There are many routes to the heterocyclic moiety, allowing for their insertion in a wide range of molecules. Our group has previously reported a condensation of arylaldehydes with hydroxylamine to first make an aryloxime which can, after generating the nitrile oxide, then cyclize with an alkene or alkyne in situ and create the isoxazoline or isoxazole, respectively. The Knoevenagel Condensation reaction is identified as the addition of an activated methylene complex, malononitrile or cyanoacetamide, with a carbonyl followed by dehydration.. Our group has previously reported a facile, one-pot reductive alkylation of benzyl malononitriles. These compounds have been noted as having many insecticidal uses, as well as being potent pharmacophores. The scope of this project is to further explore and optimize the condensation of aryl aldehydes and methylene complexes. The condensed and reduced methylene complex will then be alkylated to join the heterocyclic moiety to reach the final disubstituted methylene product. A second approach will also be explored in which the monosubstituted malononitrile will first be alkylated with allyl or propargyl bromide, which can then undergo a 1,3-dipolar cycloaddition with a nitrile oxide. The library of compounds generated will be sent to collaborators to test the biological activity of the molecules. / Introduction and background literature -- Reactions of methylene complexes -- Synthesis of disubstituted methylene complexes. / Department of Chemistry