Heterocyclic Chalcone Derivatives

The aforementioned section described the synthesis of a wide range of biologically important heterocyclic derivatives of combretastatin. The next part of this chapter will focus on the synthesis of heterocyclic chalcone derivatives. 

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

The synthesis of biologically important heterocyclic stilbene and chalcone derivatives of combretastatins has been discussed. Combretastatins have been shown to be inhibitors of tubulin polymerization. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. It is the author s opinion that a great number of the compounds contained within this review are worthy of further investigation as potential tubulin binders. 

Very pale yellow-colored chalcones derive from fhe preceding sfrucfures when fhe heterocycle opens and have a ketone function in 2 or 4, C2 being the most probable. Furthermore, these molecules may exist in two isomer forms, cis and trans. 

A -Alkylated thiazolium salts are often used to introduce complexity into the thiazole heterocycle. The synthesis of imidazothiazole-chalcone derivatives as anti-cancer and apoptosis inducing agents by Kamal et al. at the Indian Institute of Chemical Technology illustrates this point. Here, a new class of imidaza[2,l-6]thiazole chalcone derivatives were synthesized from the corresponding imidazol[2,l-6]thiazole aldehydes, which in turn... 

ZnEt2 to chalcone with mercaptocam-phan-2-ol-derived hgand 96-7 A, 0-heterocycle ligands 120 (+)-5-e/7i-nojirimycin-5-lactam, synthesis of 338, 340 Noyori, Ryoji 2... 

Fig-1 General structure of a stilbene heterocyclic derivative (A), and two chalcone heterocyclic derivatives (B and C). (Dashed circles represent the location of the herocydic ring)... 

There are considerably fewer examples of heterocyclic chalcone analogs of combretastatin than in the heterocyclic stilbene derivative category. Of these,... 

Shi, Y.-Q., Fukai, T., and Nomura, T., Structure of sanggenon O, a Diels-Alder type adduct derived from a chalcone and a dehydroprenylated sanggenon-type flavanone from Morus cathayana, Heterocycles, 54, 639, 2001. 

In contrast to the reaction products of the 1,3-dipolar cycloaddition to linear enones (chalcones and their derivatives), spiro- 1-pyrazolines 25-28 are stable heterocycles. Their isomerization into spiro-2-pyrazolines 29-31 can be carried out under acidic conditions at room temperature for 24 h in the case of the cis isomers, and for more than 1 month in the case of trans isomers [30, 41, 42, 43]. 

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). 

During the past few years, heterocyclic 1,2-diamines such as derivatives of pyrazole [50, 51], imidazole [52], tetrazole [53], pyridine [54, 55] and pyrimidine [56,57,58,59] were intensively studied as components of the condensation with a, (3-unsaturated ketones. In particular, reliable data were presented in [50,51,60] on the formation of dihydrodiazepine systems 45 and 46 in the reaction of 5-methyl-2-phenyl-277-pyrazol-3,4-diamine 42 with chalcones 43 and diarylideneacetones 44 (Scheme 4.13). 

Inexpensive di-, tri-, and tetramethoxyanthraquinones can be selectively dealkylated to hydroxymethoxyanthraquinones by the formation of difluoroboron chelates with BF3-OEt2 in benzene and subsequent hydrolysis with methanol. These un-symmetrically functionalized anthraquinone derivatives are useful intermediates for the synthesis of adriamycin, an antitumor agent. 2,4,6-Tiimethoxytoluene reacts with cinnamic acid and BF3-OEt2, with selective demethylation, to form a boron heterocycle which can be hydrolyzed to the chalcone aurentiacin (eq 34). 2 ... 

NHC-Catalyzed MCRs in Heterocyclic Chemistry In 2001, Muller and coworkers developed an elegant example where chalcones could be transformed in a one-pot sequence to the corresponding pyrrole derivatives [55], stating the potential of NHC-catalyzed umpolung strategies in heterocyclic chemistry. Scheidt and coworkers... 

Chalcones are not flavan derivatives since they lack the characteristic central heterocycle. They are converted spontaneously into true flavan derivatives, the flavanones, the reacjtion occurring particularly readily in acidic medium. They play a central role in the biosynthesis of the flavan derivatives. Chalcone glycosides oceur in relatively high quantities in the flowers of several of the Compositae and Leguminosae, which, as a result. 

Modifications of the Heterocycle (Fig, 770). In the next step the open chain structure is closed to form ring A. We obtain the kind of substance which we recognize, namely, a chalcone. Isotope experiments, especially those of Grisebach, have removed all doubt that such chalcones are the parent substances of all flavan derivatives. The chalcones are converted to flavones and all of the subsequent reaction sequences up to the anthocyanidins consist only of appropriate modifications of the central ring system. We should realize that the elucidation of the biosynthesis of the anthocyanins implies at the same time an understanding of the biosynthesis of all flavan derivatives. This is because the individual flavan derivatives are either precursors of the anthocyanins or they can be derived from such precursors. 

---