HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 8, 2010, pp. 1871-1879
Received, 20th May, 2010, Accepted, 21st June, 2010, Published online, 21st June, 2010.
DOI: 10.3987/COM-10-S(E)36

■ Efficient Synthesis of Biflavones Having A Ring-A Ring of Two Flavone Units Using Suzuki Cross-Coupling Reactions

Yoshihito Kohari, Yukio Hoshino, Haruo Matsuyama, and Hiroto Nakano*

College of Environmental Technology, Muroran Institute of Technology, 27-1 Mizumoto, Muroran, Hokkaido 050-8585, Japan

Abstract

Biflavones having a A ring-A ring of two flavone units were easily prepared by using Suzuki cross-coupling reaction of borylated flavones with bromoflavones or flavone-5-triflate in good to excellent yields.

INTRODUCTION
Flavonoids belong to a important class of natural compounds and occur naturally in fruits, vegetables, nuts, seeds, flowers, and barks.1 Natural flavonoids are known to exhibit a wide range of biological activity such as antioxidant, anti-inflammatory, antiviral etc.,2 and are increasingly being used as dietary supplement. Many other related compounds have been classified in this group, and new ones continue to be isolated and identified from various plants.

Biflavonoids form a subclass of flavonoids, of which they are dimers. Unlike the other flavonoids, the biflavones are distributed in only a limited area in plants. Their major presence is in the gymnosperms. Most biflavonoids are derived from carbon-carbon linking of two similar flavone units, but mixed dimers such as flavone-flavanone and flavanone-chalcone are also known. Furthermore, some biflavonoids such as cupressflavone, succedaneaflavanone and agathisflavone, which are composed of two flavone units linking at each A ring, have been identified in plants (Figure 1). Some attempts have been made at constructing a biflavone framework.3 With regard to the biflavone units, however, there has been to our knowledge no attempt to prepare unsymmetric biflavones with a flavone-flavone unit linked at each A ring. Thus, our research has focused on the synthesis of biflavones having various patterns of linkage in the A ring based on Suzuki cross-coupling using a borylated compound. We describe in this paper the details of a new and efficient synthetic method utilizing Suzuki coupling for biflavones having an A ring-A ring linkage.

RESULTS AND DISCUSSION
We first examined the reactions of 6-, 7-, and 8-bromoflavone (1a-c)4 with bis(pinacolato)diboron (pin2B2) in the presence of palladium catalysts to afford borylated compound 2a using a precursor for the the synthesis of biflavones (Scheme 1).

The borylation reaction using pin2B2 was carried out in the presence of Pd catalysts and KOAc in DMSO at 80 °C under a nitrogen atmosphere.5 First, the effect of palladium catalyst were examined. The results

are summarized in Table 1. It can be seen that the Pd-catalysts used were effective in the borylation reactions, except in the case of Pd(OAc)2 or Pd(PPh3)4 (runs 1 and 7). The reaction using Pd(OAc)2 as a catalyst progressed slowly under the conditions employed to afford 2a in poor yield (27%, run 1), likely due to the lack of a factor to reduce Pd(II) to Pd(0) (run 1). Pd(PPh3)4 was also relatively ineffective (run 7), and the yield was moderate (62%), probably due to the formation of phenyl-boronate derived from the coupling with a phosphine-bounded phenyl group.6 In contrast, a small amount of 6,6’’-biflavone 3aa was formed as a by-product (13％, run 9: 15%, run 8) in the reactions using Pd(dba)2 or Pd2(dba)3.

Next, the effects of a base in this borylation reaction were examined. In general, it has been well known that Pd-catalyzed boron-containing cross-coupling reactions are strongly accelerated by suitable base.5 Thus, the reaction were carried out using several bases with the best catalysts PdCl2(PPh3)2 or PdCl2(PPh3)2-2PPh3 (Table 2).
The bases such as KOAc or NaOAc afforded 2a in almost quantitative yields (runs 3, 4 and 6). In contrast, a mixture of dimers 3aa and 2a was obtained by using stronger bases such as K2CO3 or Na2CO3 (runs 1, 2 and 5). Although the reason for this difference is not clear, a strong base might promote the further reaction of the prepared 2a with 1a to afford biflavone 3aa. The borylation reactions of 7- and 8-bromoflavones 1b,c were also attempted with pin2B2 under the optimized conditions (PdCl2(PPh3)2+2PPh3, KOAc system). As a result, the reactions using 1b or 1c afforded the desired borylated compounds 2b,c in moderate to good yields (2b: 82%, 2c: 68%).
We next tried the Suzuki cross-coupling of bromoflavones 1a-c with borylated compounds 2a-c, respectively, to obtain biflavones 3 (Table 3). The reactions of 2a-c with 1a-c carried out under the employed conditions (2M-Na2CO3, in benzene, reflux, for 16 h)7 using Pd(PPh3)4 as a catalyst gave 3 in a wide range of yields. Although the coupling reaction is usually carried out using a slightly excess of boron compound, we utilized an excess of 1 to prevent the homocoupling of 2a.

The reactions of borylated flavone 2a with bromoflavones 1a-c gave the corresponding biflavones (3a, 3ab, and 3ac) in 68%, 67% and 4% yields, respectively (entries 1-3). In addition, the combinations of 2b with 1b,c, respectively, afforded the corresponding biflavones 3bb or 3bc. It is clear from these results that the formation of unsymmetric biflavone is difficult to achieve. This difficulty might be due to the highly steric factors in the structures of unsymmetric flavones 3ac and 3bc. The cross-coupling reaction of 2c with 1c was also carried out to prepare the unsymmetric biflavones 8,8”-biflavone 3cc. However, the formation of this sterically bulkier 3cc was almost not observed (entry 2). We examined the cross-coupling reactions of 2a-c with flavone-5-triflate 1d under the above-mentioned conditions (Table 4). Triflate 1d was easily prepared from the reaction of 5-hydroxyflavone with Tf2NPh 4 under microwave conditions according to the procedure by Fitzmaurice et al (Scheme 2).8

As a result, the corresponding unsymmetric biflavones 3ad, 3bd and 3cd were obtained in fairly good yields in every case (entries 1-3).

In conclusion, we have developed an efficient synthesis for obtaining unsymmetric and symmetric bisflavone by the Suzuki cross-coupling of borylated flavones 2a-c with bromoflavones 1a-c or flavone-5-triflate 1d in good to excellent yields. Further studies to examine the scope and limitations of our new synthetic methodology for the synthesis of flavonoids are now in progress.

EXPERIMENTAL
Unless otherwise stated, all chemicals and reagents were commercially available grades and were used without further purification. All reactions were performed under a nitrogen atmosphere and monitored by thin-layer chromatography (TLC) using silica gel 60 F254 on aluminium pre-coated plates (0.25 mm). Column chromatography was performed on silica gel (Wakogel C-200). 1H NMR and 13C NMR spectra were recorded at 270 MHz and 67.8 MHz on a JEOL JNM-EX 270 FT NMR SYSTEM in CDCl3 using tetramethylsilane as an internal standard.

General procedure for the preparation of borylated flavones (2a-c). The mixture of bis(pinacolato)diboron (0.55 mmol), PdCl2(PPh3)2 (3 mol%), PPh3 (6 mol%), 1 (0.5 mmol), KOAc (1.5 mmol) which was dried by oven for 1 h, and DMSO (3 mL), were stirred for 6 h at 80 °C under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the products were extracted with CHCl3. The organic layer was washed with water and brine, followed by dried over anhydrous MgSO4 and filtered. After the filtrate was concentrated, Kugelrohr distillation in vacuo gave flavone boronates (2).

6-Pinacolatoborylflavone (2a). Colorless needles; mp 158-160 °C; 1H NMR (CDCl3, 270MHz, ppm) δ 1.37 (12H, s), 6.84 (1H, s), 7.52-7.55 (3H, m), 7.56 (1H, d, J=8. 4 Hz), 7.91-7.95 (2H, m), 8.10 (1H, dd, J=8.4, 1.6 Hz), 8.74 (1H, d, J=1.6 Hz); 13C NMR(CDCl3, 65MHz, ppm): δ 24.9, 84.2, 107.9, 117.4, 123.2, 126.3, 129.1, 131.6, 131.7, 133.3, 139.6, 158.2, 163.2, 178.4.9

7-Pinacolatoborylflavone (2b). Colorless needles; mp 172-173 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 1.35 (12H, s), 6.81 (1H, s), 7.47-7.50 (3H, m), 7.78 (1H, d, J=7.6 Hz), 7.85-7.92 (2H, m), 8.01 (1H, s), 8.18 (1H, d, J=7.8 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 24.8, 84.5, 107.5, 124.5, 124.6, 125.5, 126.2, 129.0, 130.6, 131.6, 131.6, 155.6, 163.3, 178.5.

8-Pinacolatoborylflavone (2c). Colorless needles; mp 178-179 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 1.38 (12H, s), 6.82 (1H, s), 7.35(1H, dd, J=7.7, 7.3 Hz), 7.43-7.46 (3H, m), 8.07 (1H, dd, J=7.3, 1.9 Hz), 8.15-8.18 (2H, m), 8.27 (1H, dd, J=7.7, 1.9 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 25.1, 84.1, 106.5, 123.6, 124.7, 126.7, 128.7, 129.0, 131.5, 133.8, 141.6, 160.0, 163.3, 178.9.

General procedure for the preparation of biflavone (3). The mixture of borylated flavone (2) (0.55 mmol), tetrakis(triphenylphosphine)palladium as a catalyst (3 mol%), bromoflavone or flavone-5-triflate (1) (0.5 mmol), 2M Na2CO3 (1 mL), and benzene (3 mL) were stirred for 16 h at reflux temperture under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, the products were extracted with CHCl3. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and filtered. After the filtrate was concentrated, biflavones (3) were isolated by silicagel column chromatoglaphy.

6,6”-Biflavone (3aa). Colorless needles; mp 312-313 °C (lit.,10 312-313 °C); 1H NMR (CDCl3, 270 MHz, ppm): δ 6.89 (2H, s) 7.55-7.58 (6H, m), 7.72 (2H, d, J=8.9 Hz), 7.96-7.99 (4H, m), 8.09 (2H, dd, J=8.9, 2.4 Hz), 8.53 (2H, d, J=2.4 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.7, 119.0, 123.7, 124.2, 126.4, 129.1, 132.0, 131.8, 132.7, 136.5, 156.0, 163.6, 178.3; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

6,7”-Biflavone (3ab). Colorless needles; mp 236-238 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.88 (1H, s), 6.90 (1H, s), 7.52-7.59 (6H, m), 7.74(1H, d, J=8.8 Hz), 7.76 (1H, dd, J=8.1, 1.5 Hz), 7.93 (1H, d, J=1.5 Hz), 7.96-8.00 (4H, m), 8.06 (1H, dd, J=8.8, 2.3 Hz), 8.33 (1H, d, J=8.1 Hz), 8.58 (1H, d, J=2.3 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.8, 107.8, 116.4, 119.2, 123.1, 124.2, 124.4, 126.3, 126.4, 126.6, 129.2, 131.6, 131.7, 131.9, 132.5, 136.2, 144.9, 156.4, 156.7, 163.7, 178.2; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

6,8”-Biflavone (3ac). Colorless needles; mp 292-293 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.91 (1H, s), 6.93 (1H, s), 7.41-7.62 (6H, m), 7.54 (1H, dd, J =7.9, 7.4 Hz), 7.75 (1H, d, J=8.6 Hz), 7.75-7.81 (2H, m), 7.83 (1H, dd, J=7.4, 1.8 Hz), 7.96-8.03 (2H, m), 8.04 (1H, dd, J=5.8, 3.0 Hz), 8.31 (1H, dd, J=7.9, 1.7 Hz), 8.59 (1H, d, J=2.0 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.4, 107.8, 118.3, 124.1, 124.6, 125.4, 125.8, 126.4, 126.8, 129.2, 130.1, 131.6, 131.7, 131.8, 133.4, 134.9, 135.1, 153.1, 156.0, 163.5, 163.7, 178.1, 178.4; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1199.

7,7”-Biflavone (3bb). Colorless needles; mp 356-358 °C (lit.,10 346 °C); 1H NMR (CDCl3, 270 MHz, ppm): δ 6.90 (2H, s), 7.52-7.61 (6H, m), 7.77 (2H, dd, J=8.3, 1.7 Hz), 7.92 (2H, d, J=1.5 Hz), 7.95-8.01 (4H, m), 8.37 (2H, d, J=8.3 Hz) ; 13C NMR(CDCl3, 68 MHz, ppm): δ 107.9, 116.9, 123.7, 124.4, 126.4, 126.4, 129.2, 131.6, 131.8, 144.7, 156.6, 163.8, 178.0; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

7,8”-Biflavone (3bc). Colorless needles; mp 293-294 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.94 (2H, s), 7.44-7.60 (5H, m), 7.57 (1H, dd, J=7.5, 7.9 Hz), 7.76-7.80 (2H, m), 7.78 (1H, dd, J=8.3 1.5 Hz), 7.84 (1H, dd, J=7.9, 1.7 Hz), 7.91 (1H, d, J=1.5 Hz), 7.95-7.99 (2H, m), 8.36 (1H, dd, J=7.9, 1.7 Hz), 8.40 (1H, d, J=8.3 Hz); 13C NMR(CDCl3, 68 MHz, ppm:) δ 107.4, 107.9, 119.1, 123.4, 124.6, 125.4, 125.7, 126.2, 126.3, 126.5, 126.9, 129.2, 129.2, 129.9, 131.4, 131.6, 131.9, 134.8, 142.1, 153.0, 156.3, 163.4, 163.7, 178.2; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

8,8”-Biflavone (3cc). Colorless needles; mp 289-290 °C (lit.,10 290-291 °C); 1H NMR (CDCl3, 270 MHz, ppm:) δ 6.85 (2H, s), 7.24-7.30 (4H, m), 7.35-7.41 (6H, m), 7.62 (2H, dd, J=7.9, 7.3 Hz), 7.86 (2H, dd, J=7.3, 1.8 Hz), 8.42 (2H, dd, J=7.9, 1.8 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.1, 124.2, 125.1, 125.7, 126.3, 126.4, 129.0, 131.0, 131.6, 135.6, 135.4, 163.2, 178.3; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

5,6”-Biflavone (3ad). Colorless needles; mp 235-238 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.69 (1H, s), 6.86 (1H, s), 7.28 (1H, dd, J=7.09, 1.49 Hz), 7.50-7.55 (6H, m), 7.58 (1H, d, J=8.6 Hz), 7.63 (1H, dd, J=8.4, 1.5 Hz), 7.70 (1H, dd, J=8.4, 7.1 Hz), 7.72 (1H, dd, J=8.6, 2.1 Hz), 7.91-7.97 (4H, m), 8.19 (1H, d, J=2.1 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.7, 108.6, 116.7, 118.4, 121.1, 123.3, 124.6, 126.1, 126.2, 128.6, 129.0, 131.4, 131.5, 131.5, 131.9, 132.6, 135.6, 138.5, 141.1, 155.6, 157.4, 162.0, 163.3, 178.1, 178.4; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1205.

5,7”-Biflavone (3bd). Colorless needles; mp 271-273 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.71 (1H, s), 6.85 (1H, s), 7.25 (1H, dd, J=6.9, 1.6 Hz), 7.38 (1H, dd, J=8.1, 1.5 Hz), 7.49-7.55 (6H, m), 7.56 (1H, d, J=1.5 Hz), 7.67 (1H, dd, J=8.4, 1.7 Hz), 7.73 (1H, dd, J=8.4, 6.9 Hz), 7.90-7.95 (4H, m), 8.24 (1H, d, J=1.5 Hz); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.8, 108.7, 117.8, 118.8, 121.3, 122.7, 124.6, 126.2, 126.3, 126.5, 128.0, 129.0, 129.1, 131.4, 131.4, 131.7, 132.0, 132.7, 141.0, 147.5, 155.7, 157.3, 162.3, 163.4, 177.9, 178.4; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

5,8”-Biflavone (3cd). Colorless needles; mp 208-209 °C; 1H NMR (CDCl3, 270 MHz, ppm): δ 6.61 (1H, s), 6.80 (1H, s), 7.20-7.35 (3H, m), 7.33 (1H, dd, J=6.68, 1.90 Hz), 7.42-7.58 (5H, m), 7.48 (1H, dd, J=7.9, 7.3 Hz), 7.61 (1H, dd, J=7.3, 1.7 Hz), 7.75 (1H, dd, J=8.5, 1.9 Hz), 7.80 (1H, dd, J=8.5, 6.7 Hz), 7.89-7.93 (2H, m); 13C NMR(CDCl3, 68 MHz, ppm): δ 107.3, 108.5, 119.0, 122.3, 123.4, 124.6, 124.9, 125.9, 126.2, 128.5, 128.8, 129.1, 131.2, 131.3, 131.7, 131.8, 131.9, 133.0, 133.2, 136.3, 153.9, 157.0, 162.3, 162.7, 177.9, 178.7; HRMS (EI): calcd for C30H18O4: 442.1205; found: 442.1207.

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