Synthesis of paramagnetic and diamagnetic flavones and flavanones

Paramagnetic and diamagnetic flavone and flavanone derivatives modified on the C or B rings were synthesized by condensation, Sonogashira reaction, lithiation, and the Baker-Venkataraman procedure.


Introduction
Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin.Recently, much attention has been paid to different flavonoid derivatives as antioxidants, and dietary intake of these natural compounds has a significant effect on preventing a variety of diseases.][4] It is well known that nitroxides exhibit SOD mimicry properties, 5 and their precursors are good protectors against ionizing radiation and H 2 O 2 caused stress. 6From our laboratory we reported the synthesis of compounds 4-7, substituting the B ring of flavonoid structures with five-and six-membered nitroxides and their precursors. 7,8We thought this offered a chance of improving the antioxidant properties of flavones and flavanones by combining them with nitroxides or their precursors.In the present paper we report the synthesis of paramagnetic flavonoid derivatives bearing paramagnetic rings on their original B or C rings in order to diminish alterations in their structure.

Results and Discussion
We used a paramagnetic benzaldehyde 8 9 to synthesize paramagnetic flavone derivatives.This aldehyde was condensed with 2-hydroxyacetophenone in EtOH, in the presence of sodium hydroxide, and the paramagnetic chalcone 9 was cyclised in 50 % acetic acid, in the presence of a catalytic amount of HCl, to yield the paramagnetic flavanone derivative 10a.The latter was converted to a hydroxylamine compound by ascorbic acid and transformed to the diamagnetic Oacetate 10 10d for NMR spectroscopic identification.For the synthesis of the paramagnetic flavone derivatives a paramagnetic acid chloride was required.Thus, oxidation of aldehyde 8 with Ag 2 O in a basic aqueous medium 11 gave 11, a paramagnetic benzoic acid, which was converted to the acid chloride by treatment with thionyl chloride in benzene. 12The moisture sensitive acid chloride was not isolated in pure form, but used immediately in the next reactions.Acylation of 2,6-dihydroxyacetophenone with this acid chloride, in a one-pot procedure, in the presence of K 2 CO 3 , gave a mixture of the 5-hydroxy-flavone derivative 12a and biradical 13a. 8,13or spectroscopic identification, these products were converted to diamagnetic derivatives 12d and 13d and, for biological study, to hydroxylamines 12b and 13b, by refluxing in ethanol saturated by HCl gas, 6 or to diamine 13c, by reduction with Fe/AcOH. 14The IR and NMR spectra suggested the 3-acyl structure instead of the 5-O-acyl derivative, as well as the findings that treatment of 13a with NaOH did not gave compound 12a as a possible hydrolysis product.
To study the effect of the absence of OH groups on the A ring, a paramagnetic flavone also was synthesized.Acylation of 2-hydroxyacetophenone with paramagnetic benzoyl chloride afforded the keto ester 14 in 74 % yield which in turn underwent a Baker-Venkataraman rearrangement in pyridine in the presence of KOH. 15 This latter compound was cyclised to the paramagnetic flavone 16a by acid catalysis (Figure 2).Conjugation of a pyrroline nitroxide ring to the C ring of a flavone also was considered.Thus, condensation of 2-hydroxychalcone 17 with aldehyde 18 16 , in the presence of base, gave the paramagnetic flavanone derivative 19a as a 1:2 mixture of the Z and E isomers (determined by 1 H NMR from the ratio of peaks at 5.40 ppm and 5.34 ppm). 17,18Lithiation of flavone 20 with LDA in THF gave the 3-lithio derivative, 19 which, upon treatment with paramagnetic aldehyde 18, gave alcohol 21.The latter was oxidized to the 1,3diketone 22 by MnO 2 in CHCl 3 .Sonogashira reaction of 3-iodo-4'-methoxyflavone 23 20 with the paramagnetic acetylene compound 24, 21 in the presence of L-prolinol, CuI and a palladium catalyst, gave a flavone derivative 25 22 where attachment to the pyrroline ring was from the 3 position of the C ring via an ethynyl spacer (Figure 3).
In conclusion, classical synthetic methodologies could be used for the synthesis of paramagnetic flavone and flavanone derivatives containing nitroxides on the B and C rings.The antioxidant activity of the new compounds is under study.

Experimental Section
General Procedures.Melting points were determined with a Boetius micro melting point apparatus and are uncorrected.Elemental analyses (C, H, N, S) were performed on a Fisons EA 1110 CHNS elemental analyser.The IR (Specord 75) spectra were in each case consistent with the assigned structure.Mass spectra were recorded on a VG TRIO-2 instrument in the EI mode.NMR spectra were recorded with Varian Unity Inova 400 WB spectrometer; chemical shifts were referenced to TMS.ESR spectra were taken on Miniscope MS 200 in 10 -4 M CHCl 3 solution and all monoradicals gave triplet line a N = 14.0-14.4G, and biradical 13a gave quintet line a N1 = 14.0 G, a N2 = 7.3 G. Flash column chromatography was performed on Merck Kieselgel 60 (0.040-0.063 mm).Qualitative TLC was carried out on commercially prepared plates (20 x 20 x 0.02 cm) coated with Merck Kieselgel GF 254 .Compound 17 was purchased from Fluka, all reagents and compound 20 were purchased from Aldrich, compounds 8, 9 18, 16 23, 20 24 21 were prepared according to published procedures.(0.05 eq.), L-prolinol (4.0 eq.), CuI (0.1 eq), DMF/H 2 O, rt. 1 h, then 24 (3 eq.), 12 h, 15 %.