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Synlett 2012(4): 559-564  
DOI: 10.1055/s-0031-1290355
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Synthesis of 5-Arylbenzo[c]xanthones from Photoinduced Electrocyclisation and Oxidation of (E)-3-Styrylflavones

Djenisa H. A. Rochaa, Diana C. G. A. Pinto*a, Artur M. S. Silva*a, Tamás Patonayb, José A. S. Cavaleiroa
a Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt; e-Mail: diana@ua.pt;
b Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary

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Publication History

Received 17 November 2011
Publication Date:
13 February 2012 (online)

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Abstract

A new synthetic route to 5-arylbenzo[c]xanthones is ­established. This was accomplished by use the Heck reaction of 3-bromoflavones with styrene derivatives, leading to (E)-3-styrylflavones with total diastereoselectivity. This transformation was greatly improved under microwave irradiation. The one-pot, photoinduced electrocyclisation of (E)-3-styrylflavones and further in situ oxidation of the cycloadduct leads to 5-arylbenzo[c]xan­thones.

Key words

microwave irradiation - Heck reaction - photocyclisation - oxidation

The xanthone ring system is a structural motif present in natural products and prevalent in higher plant families such as Guttiferae and Gentianaceae. [¹] Both natural and synthetic derivatives are often endowed with interesting pharmacological properties, such as anti-inflammatory, [²] antitumour [³] and antioxidant activity. [4] To the best of our knowledge, benzo[c]xanthones and 3-styrylflavones are not found in natural sources and their syntheses are scarce. [5] On the other hand, related compounds, such as benzo[a] and benzo[b]xanthones exhibit appealing pharmacological properties. For instance, antibacterial and fungicidal activities, [6] α-glucosidase inhibition [7] and cytotoxicity against L1210 cells [8] have been described.

Following our research interests in the synthesis of 3-styrylchromone [9] and benzoxanthone derivatives, [5d] [¹0] along with the fact that new synthetic routes towards these compounds are of significance in both synthetic and medicinal chemistry, a program aimed at the synthesis of (E)-3-styrylflavones 4a-g and their photoinduced electrocyclisation and oxidation into 5-arylbenzo[c]xanthones 5a-h was set up (Scheme  [¹] ). One important transformation in this synthetic route is the Heck reaction of 3-bromoflavones 2a-f with styrene derivatives 3a and 3b. The Heck reaction is widely used in synthetic chemistry as it is one of the most noteworthy methodologies for carbon-carbon bond formation, [¹¹] however, it has rarely been used in the field of oxygen heterocycles. [9b] [¹²] Photoinduced reactions have played important roles in building diverse organic frameworks that are otherwise difficult to make. [¹³] In our case, the photoinduced electrocyclisation of (E)-3-styrylflavones 4a-g plays a key role in the new synthetic procedure.

Initially, we studied the synthesis of 3-bromoflavones 2a-f by treating 3-aryl-1-(2-hydroxyphenyl)propan-1,3-­diones 1a-f with phenyltrimethylammonium tribromide (PTT), [¹²] in a one-pot method in which bromination and cyclisation occurred leading to the formation of 3-bromochromones in moderate yields. [¹4] However, in this work, the expected bromo-derivatives were obtained in only modest yields, with the highest being obtained with 3-bromo-4-methylflavone [¹5] (2b; 45%) and the lowest with 3-bromo-3,4-dimethoxyflavone (2f; 32%). Since our results were not satisfactory, mostly because the corresponding non-brominated flavones were obtained as by-products, we investigated other methodologies. The direct bromination of flavones using pyridinium bromide perbromide [¹6] or N-bromosuccinimide, [¹7] and also microwave irradiation, [¹8] were attempted, but in all cases the results were unsatisfactory, with the desired 3-bromo-flavones being obtained in poor yields (up to 20%). [¹9]

Scheme 1

These results, together with the fact that the first method involves fewer reaction steps and can be applied to derivatives bearing either electron-donating or electron-withdrawing groups, meant that the initial approach was used to obtain 3-bromoflavones 2a-f. The most important features in the NMR spectra of 3-bromoflavones 2a-f are: (i) the resonances of the deshielded aromatic protons H-5 and H-7 at δ = 8.29-8.31 and 7.72-7.78 ppm, due to the mesomeric (both protons) and anisotropic (H-5) deshielding effect of the carbonyl group; (ii) the absence of the typical H-3 signal of flavones, which generally appears as a singlet at δ = 6-7 ppm; and (iii) the resonances of C-3 and C-4 carbon atoms appearing at, respectively, δ = 108.6-110.8 and 172.6-173.3 ppm.

The next step in our strategy was the Heck reaction [9b] [¹²] [²0] of 3-bromoflavones 2a-f with styrene 3a. A study to find the optimal reaction conditions (palladium catalysts, solvent, reaction time and heating conditions) was carried out (Table  [¹] ). Attempts were made to take advantage of the beneficial effects of microwave (MW) irradiation in synthesis, [²¹] and using the Jeffery reaction conditions, [²²] since they are reported to improve the yields of the Heck reaction; however, (E)-3-styrylflavone 4a was only obtained in poor yields (Table  [¹] , entries 1-4). Lowering the MW irradiation power allowed 4a to be obtained in good yields (Table  [¹] , entry 5). Changing the palladium source did not improve our results (Table  [¹] , entries 6 and 7), nor did using classical heating conditions (Table  [¹] , entry 8). In the latter case, the reaction time was clearly too long (3 h) compared with the reaction time under MW irradiation (10 min).

The Heck/Jeffery reaction conditions were extended to the reaction of 3-bromoflavones 2b-f with styrene 3a, [²³] and the corresponding (E)-3-styrylflavone derivatives 4b-f were obtained in moderate to good yields (46%). The reaction of 3-bromoflavone (2a) with 3,4-dimethoxystyrene (3b) also yielded the expected (E)-3-styrylflavone 4g [²4] in good yield (63%).

Table 1 Synthesis of (E)-3-Styrylflavone 4a
Entry Reagents Solvent Heating Time (min) Yield 4a (%)a
1 Pd(OAc)2, K2CO3, KCl, TBAB, DABCO NMP 400 W (MW) 15 35
2 Pd(OAc)2, K2CO3, TBAB DMF 400 W (MW) 10 40
3 Pd(OAc)2, K2CO3, NBu4HSO4 DMF 400 W (MW) 10  -
4 Pd(OAc)2, K2CO3, TBAB NMP 400 W (MW) 10 25
5 Pd(OAc)2, K2CO3, TBAB DMF 300 W (MW) 10 72
6 PdCl2(PPh3)2, K2CO3, TBAB DMF 300 W (MW) 10 40
7 Pd(Ph3)4, K2CO3, TBAB DMF 300 W (MW) 10 37
8 Pd(OAc)2, K2CO3, TBAB DMF 150 ˚C  1-3 h 45
a Maximum yield obtained.

The main features in the ¹H NMR spectra of (E)-3-styryl-flavones are the resonances of H-α and H-β, which appear as two doublets at δ = 6.72-6.88 and 7.95-8.04 ppm, respectively. The coupling constant for these protons (J ˜17 Hz) indicates a trans configuration for this vinylic system. The higher frequency values of H-β resonances are due to the anisotropic deshielding effect of the carbonyl group. The depicted 3-styryl group conformation was also confirmed by NOESY experiments in which NOE correlations between H-α and H-2′,6′ were observed. The ¹³C NMR spectroscopic assignments were possible due to HSQC and HMBC experiments, and the most noticeable carbon resonances appeared at δ = 177.1-177.6 ppm (C-4), and at δ = 118.3-120.4 and 133.9-136.3 ppm, due to the vinylic C-α and C-β, respectively.

Following our interest in thermal electrocyclisations, [¹²] [²5] (E)-3-styrylflavones 4a-g were heated at reflux in 1,2,4-trichlorobenzene, however, all attempts to cyclise the compounds failed, even when iodine [²6] was used as catalyst or microwave radiation as heating source (Table  [²] , entries 1-4). Knowing that photoinduced electrocyclisations can be a successful methodology, [5c] a chloroform solution of (E)-3-styrylflavone 4a was irradiated with a halogen white-light projector; under these conditions, the desired 5-phenyl-7H-benzo[c]xanthen-7-one (5a) [²7] was obtained, albeit in poor yield (Table  [²] , entry 5). Some starting material 4a was recovered (50%) and the by-product, 5-phenyl-5H-benzo[c]xanthen-7(6H)-one (6a) [²8] was also obtained (8%; Scheme  [²] ). The most important features in the ¹H NMR spectrum of 6a are the double doublets at δ = 3.24, 3.33 and 4.32 ppm, assigned respectively to the resonances of H-6 cis , H-6 trans , and H-5. In the ¹³C NMR spectrum, the aliphatic resonances of C-6 and C-5 at δ = 27.2 and 43.1 ppm, respectively, and the carbonyl carbon at δ = 177.2 ppm should be highlighted. The most noticeable signal from the ¹H NMR spectrum of benzo[c]xanthen-7-one (5a) is the singlet at δ = 8.24 ppm assigned to H-6, which resonates at high frequency values due to the carbonyl anisotropic deshielding effect.

Since the previous procedures in the synthesis of benzo[c]xanthen-7-one 5a did not give satisfactory results, an attempt using daylight in the presence or absence of iodine was carried out, but, once again, the desired product was obtained in only poor yield (Table  [²] , entries 6 and 7). These results, together with the fact that the use of a mercury lamp seems to be a good method for a photocyclization process to give a dihydrobenzo[c]xanthone, [5a] led us to use a high pressure mercury UV lamp. This procedure led us to develop a new synthetic route for 5-phenyl-7H-benzo[c]xanthen-7-one (5a) [²9] (Table  [²] , entry 8). We then successfully extended this method to the other derivatives, except for 3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one (5e), which was obtained in low yield. [²9] This low yield can be explained by the formation of 6-hydroxy-3-nitro-­5-phenyl-7H-benzo[c]xanthen-7-one [³0] (7e; 54%, Scheme  [²] ). The ¹H NMR spectrum of 7e shows, in addition to the benzo[c]xanthone protons, a singlet at δ = 12.71 ppm due to a hydroxyl group proton involved in a hydrogen bond with a carbonyl group. This data, the disappearance of the typical H-6 singlet of 5-aryl-benzo[c]xanthone 5a, and the HMBC connectivities unequivocally prove the structure of 7e (Scheme  [²] ).

Scheme 2 Structures of 5-phenyl-5H-benzo[c]xanthen-7(6H)-one (6a), 6-hydroxy-3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one (7e) and formation of 3,4-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5f) and 2,3-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5g)

Table 2 Synthesis of 5-Arylbenzo[c]xanthone 5a
Entry Conditionsa Heating Time (d) Yield 6a (%)b Yield 5a (%)
1 TCB 230 ˚C  3  -  -
2 TCB, I2 230 ˚C  3  -  -
3 TCB, I2 230 ˚C  7  -  -
4 TCB, I2 400 W 45 min  -  -
5 CHCl3 500 Wc  7  8 15b
6 CHCl3 r.t.  7 15 14b
7 TCB, I2 r.t.  5 10 17b
8 TCB, I2, hυ 400 W    - 70d
a TCB = 1,2,4-trichlorobenzene.
b Maximum yield obtained.
c Halogen white light projector;
d Average yield.

The appearance of this 6-hydroxyl group can be envisaged from the reaction mechanism (Scheme  [³] ). After electrocyclisation and rearomatisation of I, the intermediate 6 can be directly oxidised to compounds 5; this is the main pathway for derivatives having electron-donating R substituents (e.g., 4b). In the case of strong electron-withdrawing groups (R = NO2; 4e), the loss of the acidic methylenic H-6 proton generates diene II, which may react with singlet oxygen leading to the formation of cycloadduct III (Scheme  [³] ). The latter can rearrange to hydroperoxide IV, which can dehydrate, as reported by others authors in similar circumstances, [³¹] to give a ketone that undergoes a keto-enol tautomerism to afford a completely aromatised 3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one (7e). To confirm this idea, reactions of 4b and 4e were repeated in the presence of methylene blue, which is a known singlet oxygen sensitiser. [³¹] Under these conditions, 4e was only transformed into 5e and the yield of xanthone 7e improved to 86%, confirming the involvement of singlet oxygen in the unexpected formation of 7e.

Photoinduced electrocyclisation and oxidation processes of (E)-3,4-dimethoxy-3-styrylflavone (4f) yielded two isomers, 3,4-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5f) and 2,3-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5g), with the latter being formed as the major product. The free rotation of the (E)-3,4-dimethoxy-3-styrylflavone B ring allowed two possible sites for electrocyclisation, C-2′ or C-6′. Probably due to some steric hindrance between the 3′-OMe group and the styryl group, the cyclisation at C-6′ is favourable (Scheme  [²] ). Unequivocal proof for the proposed structures was mainly based on the ¹H and ¹³C NMR spectra. The ¹H NMR spectrum of compound 5f [³²] shows, in addition to the phenyl-xanthone moiety protons, two doublets at δ = 7.49 and 8.60 ppm (J = 9.2 Hz), due to the resonance of H-2 and H-1, respectively. In the case of 5g, [³³] the ¹H NMR spectrum shows, in addition to the phenylxanthone moiety protons, two singlets at δ = 7.34 and 8.01 ppm, due to the resonance of protons H-4 and H-1, respectively. The higher frequency values of the H-1 resonances in both cases can be attributed to the through-space deshielding effect of the heterocyclic oxygen atom.

Scheme 3

In conclusion, a successful methodology for the synthesis of (E)-3-styrylflavones using microwave irradiation to perform the Heck reaction of 3-bromoflavones with styrene has been developed. The beneficial effects of microwave irradiation were a reduction in reaction time (from more than 1 h to 10 min or less), and an improvement in product yield (from 45 to 73%). Photoinduced electro­cyclisation and oxidation processes undergone by (E)-3-styrylflavones with a high-pressure mercury lamp led to a new synthetic route to 5-arylbenzo[c]xanthones in moderate yields.

Acknowledgment

Thanks are due to the University of Aveiro, Fundação para a Ciência e a Tecnologia (FCT) and FEDER for funding the Organic ­Chemistry Research Unit (project PEst-C/QUI/UI0062/2011) and the grants to D.H.A.R. (BI/UI51/4889/2010 and SFRH/BD/68991/2010). We are also grateful to the Portuguese National NMR Network (RNRMN) supported with funds from FCT.

14

Optimised procedure for the synthesis of 3-bromo-flavones 2a-f: Phenyltrimethylammonium tribromide (0.94 g, 2.45 mmol) was added to an anhydrous THF (30 mL) solution of the appropriate 3-aryl-1-(2-hydroxyphenyl)-propan-1,3-dione 1a-f (1.63 mmol). The reaction mixture was stirred at room temperature for 24-48 h. After that period, the reaction mixture was poured into a mixture of ice (10 g) and water (30 mL), stirred for 30 min, and extracted with chloroform (3 × 20 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness. The obtained residue was purified by TLC (CH2Cl2-light petroleum, 9:1). After solvent evaporation, the obtained residue was recrystallised from ethanol giving 3-bromoflavones 2a-f [2a: 196 mg (40%); 2b: 226 mg (44%); 2c: 343 mg (45%); 2d: 230 mg (42%); 2e: 237 mg (42%); 2f: 188 mg (32%)]

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3-Bromo-4-methylflavone(2b): Yellow solid; mp 146-148 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 2.47 (s, 3 H, 4′-CH3), 7.34 (d, J = 8.2 Hz, 2 H, H-3′,5′), 7.44 (br dd, J = 7.1, 8.3 Hz, 1 H, H-6), 7.51 (br d, J = 8.3 Hz, 1 H, H-8), 7.72 (ddd, J = 1.7, 7.1, 8.1 Hz, 1 H, H-7), 7.78 (d, J = 8.2 Hz, 2 H, H-2′,6′), 8.31 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl3): δ = 21.6 (4′-CH3), 108.9 (C-3), 117.8 (C-8), 121.8 (C-10), 125.6 (C-6), 126.5 (C-5), 129.0 (C-3′,5′), 129.3 (C-2′,6′), 133.7 (C-1′), 134.1 (C-7), 141.7 (C-4′), 155.6 (C-9), 162.1 (C-2), 173.2 (C-4). MS (ESI+): m/z (%) = 315 (100) ([M + H]+, 79Br), 317 (90) ([M + H]+, 8¹Br), 337 (87) ([M + Na]+, 79Br), 339 (83) ([M + Na]+, 8¹Br). Anal. Calcd for C16H11O2Br (315.16): C, 60.98; H, 3.52. Found: C, 60.88; H, 3.52

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Rocha D. H. A., Pinto D. C. G. A., Silva A. M. S., Patonay T., Cavaleiro J. A. S.; unpublished results

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Optimised procedure for the synthesis of 3-styryl-flavones 4a-g: A mixture of the appropriate 3-bromo-flavone 2a-f (0.296 mmol), anhydrous K2CO3 (123 mg, 0.888 mmol), tetrabutylammonium bromide (TBAB; 238 mg, 0.740 mmol), palladium acetate (9.97 mg, 0.044 mmol) and styrene 3a (0.170 mL, 1.48 mmol) in DMF (6 mL), was poured into a two-necked flask equipped with a magnetic stirring bar, fibre-optic temperature control, and reflux condenser and placed under a nitrogen atmosphere. The mixture was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at constant power of 300 W from 5-10 min. After that period, the reaction mixture was poured into a mixture of ice (1 g) and water (10 mL) and extracted with diethyl ether (3 × 10 mL). The organic layer was evaporated to dryness and the obtained residue was taken in ethyl acetate (10 mL) and washed with water (2 × 10 mL). The organic layer was dried with anhydrous sodium sulfate, evaporated and purified by column chromatography (CHCl3-acetone, 9.6:0.4). After solvent evaporation, the obtained residue was recrystallised from ethanol to give 3-styrylflavones 4a-g [4a: 67 mg (70%); 4b: 68 mg (68%); 4c: 73 mg (70%); 4d: 66 mg (62%); 4e: 55 mg (50%); 4f: 51 mg (45%)]. The reaction of 3-bromoflavone 2a (0.296 mmol) with styrene 3b (1.48 mmol), under the same reaction conditions, yielded 3-(3,4-dimethoxystyryl)flavone 4g (72 mg, 63%)

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( E )-3-(3,4-Dimethoxystyryl)flavone (4g): Yellow solid; mp 158-160 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 3.86 (s, 3 H, 4′′-OCH3), 3.88 (s, 3 H, 3′′-OCH3), 6.72 (d, J = 16.2 Hz, 1 H, H-α), 6.82 (d, J = 8.1 Hz, 1 H, H-5′′), 6.93 (d, J = 1.6 Hz, 1 H, H-2′′), 6.95 (d, J = 9.2 Hz, 1 H, H-6′′), 7.44 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-6), 7.51 (dd, J = 1.7, 8.3 Hz, 1 H, H-8), 7.53-7.58 (m, 3 H, H-3′,4′,5′), 7.69 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-7), 7.76-7.79 (m, 2 H, H-2′,6′), 7.95 (d, J = 16.2 Hz, 1 H, H-β), 8.33 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl3): δ = 55.8 (4′′-OCH3), 55.9 (3′′-OCH3), 109.3 (C-2′′), 111.2 (C-5′′), 117.8 (C-3), 117.9 (C-8), 118.3 (C-α), 119.3 (C-6′′), 123.5 (C-10), 125.1 (C-6), 126.3 (C-5), 128.4 (C-3′,5′), 129.9 (C-2′,6′), 130.6 (C-4′), 131.3 (C-1′′), 133.3 (C-1′), 133.4 (C-7), 134.1 (C-β), 148.8 (C-3′′), 148.9 (C-4′′), 155.4 (C-9), 162.5 (C-2), 177.6 (C-4). MS (ESI+): m/z (%) = 385 (100) [M + H]+, 407 (20) [M + Na]+. Anal. Calcd for C25H20O4 (384.42): C, 78.11; H, 5.24. Found: C, 78.15; H, 5.31

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5-Phenyl-7 H -benzo[ c ]xanthen-7-one (5a): Mp 197-198 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 7.47 (br dd, J = 7.0, 8.0 Hz, 1 H, H-9), 7.47-7.50 (m, 1 H, H-4′), 7.52-7.54 (m, 4 H, H-2′,3′,5′,6′), 7.67 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-3), 7.74 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-2), 7.75 (br d, J = 8.0 Hz, 1 H, H-11), 7.81 (ddd, J = 1.3, 7.0, 8.0 Hz, 1 H, H-10), 8.02 (dd, J = 1.5, 8.0 Hz, 1 H, H-4), 8.24 (s, 1 H, H-6), 8.44 (dd, J = 1.3, 8.0 Hz, 1 H, H-8), 8.81 (dd, J = 1.5, 8.0 Hz, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 117.1 (C-6a), 118.1 (C-11), 121.9 (C-6), 122.5 (C-7a), 123.1 (C-1), 124.4 (C-12b), 124.5 (C-9), 126.6 (C-2), 126.7 (C-4), 126.8 (C-8), 127.6 (C-4′), 128.4 (C-2′,6′), 129.6 (C-3), 130.1 (C-3′,5′), 132.1 (C-10), 133.7 (C-4a), 134.4 (C-5), 136.6 (C-1′), 155.8 (C-12a), 168.4 (C-11a), 177.2 (C-7). MS (ESI+): m/z (%) = 323 (100) [M + H]+, 345 (22) [M + Na]+. MS (EI+): m/z calcd for C23H14O2: 322.0994; found: 322.0995

28

5-Phenyl-5 H -benzo[ c ]xanthen-7(6 H )-one (6a): ¹H NMR (300.13 MHz, CDCl3): δ = 3.24 (dd, J = 9.0, 16.5 Hz, 1 H, H-6cis), 3.33 (dd, J = 7.3, 16.5 Hz, 1 H, H-6trans), 4.32 (dd, J = 7.3, 9.0 Hz, 1 H, H-5), 7.06 (dd, J = 7.6 Hz, 1 H, H-2), 7.18-7.23 (m, 2 H, H- 3′,5′), 7.23-7.26 (m, 1 H, H-4), 7.27-7.32 (m, 2 H, H-2′,6′), 7.38- 7.49 (m, 3 H, H-9,3,4′), 7.59 (dd, J = 1.4, 8.3 Hz, 1 H, H-11), 7.69 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.09 (dd, J = 1.8, 7.6 Hz, 1 H, H-1), 8.24 (dd, J = 1.4, 8.3 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl3): δ = 27.2 (C-6), 43.1 (C-5), 115.4 (C-6a), 117.9 (C-11), 123.6 (C-7a), 124.0 (C-1), 125.9 (C-8), 126.8 (C-4), 127.3 (C-4′), 128.2 (C-3′,5′), 128.47 (C-12b), 128.5 (C-2′,6′), 128.7 (C-2), 131.4 (C-3), 133.3 (C-10), 141.7 (C-1′), 142.7 (C-4a), 155.6 (C-11a), 157.4 (C-12a), 177.2 (C-7). MS (EI+): m/z calcd for C23H16O2: 324.1150; found: 324.1147

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Optimised procedure for the synthesis of 5-phenyl-7 H -benzo[ c ]xanthen-7-ones 5a-h: A mixture of the appropriate 3-styrylflavone 4a-g (0.15 mmol) and a catalytic amount of I2 (10% mol) in 1,2,4-trichlorobenzene (20 mL), was poured into a three-necked flask equipped with a magnetic stirring bar, reflux condenser and a high-pressure mercury UV lamp with 400 W power. The mixture was then irradiated from 2 to 6 days. After that period, the reaction mixture was poured into a silica gel column and eluted with light petroleum to remove the excess of iodine and 1,2,4-trichlorobenzene. Upon changing the eluent to ethyl acetate-light petroleum (1:9 or 3:7), 5-phenyl-7H-benzo[c]xanthen-7-ones were obtained, which were recrystallised from ethanol 5a-h [5a: 50 mg (70%); 5b: 22 mg (45%); 5c: 50 mg (73%); 5d: 35 mg (74%); 5e: 15 mg (30%); 5f: 11 mg (20%); 5g: 23 mg (40%); 5h: 35 mg (60%)]

30

Physical data of 6-hydroxy-3-nitro-5-phenyl-7 H -benzo[ c ]xanthen-7-one (7e): ¹H NMR (300.13 MHz, CDCl3): δ = 7.46 (br d, J = 8.4 Hz, 2 H, H-3′,5′), 7.52-7.56 (m, 1 H, H-4′), 7.53-7.59 (m, 1 H, H-9), 7.56-7.62 (m, 2 H, H-2′,6′), 7.79 (br d, J = 8.3 Hz, 1 H, H-11), 7.93 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.20 (dd, J = 2.2, 9.2 Hz, 1 H, H-2), 8.41 (dd, J = 1.4, 8.3 Hz, 1 H, H-8), 8.51 (d, J = 2.2 Hz, 1 H, H-4), 8.77 (d, J = 9.2 Hz, 1 H, H-1), 12.71 (s, 1 H, 6-OH). ¹³C NMR (75.47 MHz, CDCl3): δ = 109.5 (C-6a), 116.9 (C-2), 118.2 (C-11), 119.5 (C-5), 120.3 (C-12b), 121.3 (C-7a), 121.4 (C-4), 125.0 (C-1), 125.5 (C-9), 126.2 (C-8), 128.3 (C-4′), 128.9 (C-2′,6′), 131.0 (C-3′,5′), 133.3 (C-1′), 136.1 (C-10), 136.6 (C-4a), 148.7 (C-3), 153.0 (C-12a), 154.3 (C-6), 155.7 (C-11a), 182.0 (C-7) ppm. MS (EI+): m/z calcd for C23H13O5N 383.0794; found: 383.0791

32

Physical data of 3,4-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5f): ¹H NMR (300.13 MHz, CDCl3): δ = 3.18 (s, 3 H, 4-OCH3), 4.03 (s, 3 H, 3-OCH3), 7.34-7.46 (m, 6 H, H-9,2′,3′,4′,5′,6′), 7.49 (d, J = 9.2 Hz, 1 H, H-2), 7.72 (d, J = 8.3 Hz, 1 H, H-11), 7.79 (ddd, J = 1.5, 7.0, 8.3 Hz, 1 H, H-10), 8.04 (s, 1 H, H-6), 8.41 (dd, J = 1.5, 8.3 Hz, 1 H, H-8), 8.60 (d, J = 9.2 Hz, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 56.4 (4-OCH3), 60.6 (3-OCH3), 110.1 (C-6a), 114.0 (C-2), 118.0 (C-11), 120.1 (C-1), 122.6 (C-7a), 124.4 (C-9), 124.8 (C-6), 126.3 (C-4′), 126.6 (C-8), 126.9 (C-2′,6′), 129.2 (C-3′,5′), 130.4 (C-4a), 130.8 (C-5), 134.2 (C-10), 141.4 (C-12a), 144.6 (C-4), 155.1 (C-3), 156.7 (C-11a), 178.9 (C-7). MS (EI+): m/z calcd for C25H18O4: 382.1205; found: 382.1207

33

Physical data of 2,3-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5g): ¹H NMR (300.13 MHz, CDCl3): δ = 3.88 (s, 3 H, 3-OCH3), 4.18 (s, 3 H, 2-OCH3), 7.34 (s, 1 H, H-4), 7.45 (br dd, J = 7.0, 8.2 Hz, 1 H, H-9), 7.46-7.49 (m, 1 H, H-4′), 7.50-7.58 (m, 4 H, H-2′,3′,5′,6′), 7.75 (dd, J = 1.7, 8.2 Hz, 1 H, H-11), 7.79 (ddd, J = 1.7, 7.0, 8.2 Hz, 1 H, H-10), 8.01 (s, 1 H, H-1), 8.13 (s, 1 H, H-6), 8.45 (dd, J = 1.7, 8.2 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl3): δ = 55.9 (3-OCH3), 56.2 (2-OCH3), 102.0 (C-4), 105.9 (C-1), 116.4 (C-6a), 118.0 (C-11), 119.2 (C-12b), 120.7 (C-6), 122.4 (C-1′), 124.2 (C-9), 126.5 (C-7a), 126.7 (C-8), 127.6 (C-4′), 128.5 (C-2′,6′), 129.9 (C-3′,5′), 131.4 (C-4a), 134.1 (C-5), 135.3 (C-10), 139.9 (C-12a), 149.8 (C-2), 151.9 (C-3), 155.8 (C-11a), 176.9 (C-7). MS (EI+): m/z calcd for C25H18O4: 382.1205; found: 382.1207

14

Optimised procedure for the synthesis of 3-bromo-flavones 2a-f: Phenyltrimethylammonium tribromide (0.94 g, 2.45 mmol) was added to an anhydrous THF (30 mL) solution of the appropriate 3-aryl-1-(2-hydroxyphenyl)-propan-1,3-dione 1a-f (1.63 mmol). The reaction mixture was stirred at room temperature for 24-48 h. After that period, the reaction mixture was poured into a mixture of ice (10 g) and water (30 mL), stirred for 30 min, and extracted with chloroform (3 × 20 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness. The obtained residue was purified by TLC (CH2Cl2-light petroleum, 9:1). After solvent evaporation, the obtained residue was recrystallised from ethanol giving 3-bromoflavones 2a-f [2a: 196 mg (40%); 2b: 226 mg (44%); 2c: 343 mg (45%); 2d: 230 mg (42%); 2e: 237 mg (42%); 2f: 188 mg (32%)]

15

3-Bromo-4-methylflavone(2b): Yellow solid; mp 146-148 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 2.47 (s, 3 H, 4′-CH3), 7.34 (d, J = 8.2 Hz, 2 H, H-3′,5′), 7.44 (br dd, J = 7.1, 8.3 Hz, 1 H, H-6), 7.51 (br d, J = 8.3 Hz, 1 H, H-8), 7.72 (ddd, J = 1.7, 7.1, 8.1 Hz, 1 H, H-7), 7.78 (d, J = 8.2 Hz, 2 H, H-2′,6′), 8.31 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl3): δ = 21.6 (4′-CH3), 108.9 (C-3), 117.8 (C-8), 121.8 (C-10), 125.6 (C-6), 126.5 (C-5), 129.0 (C-3′,5′), 129.3 (C-2′,6′), 133.7 (C-1′), 134.1 (C-7), 141.7 (C-4′), 155.6 (C-9), 162.1 (C-2), 173.2 (C-4). MS (ESI+): m/z (%) = 315 (100) ([M + H]+, 79Br), 317 (90) ([M + H]+, 8¹Br), 337 (87) ([M + Na]+, 79Br), 339 (83) ([M + Na]+, 8¹Br). Anal. Calcd for C16H11O2Br (315.16): C, 60.98; H, 3.52. Found: C, 60.88; H, 3.52

19

Rocha D. H. A., Pinto D. C. G. A., Silva A. M. S., Patonay T., Cavaleiro J. A. S.; unpublished results

23

Optimised procedure for the synthesis of 3-styryl-flavones 4a-g: A mixture of the appropriate 3-bromo-flavone 2a-f (0.296 mmol), anhydrous K2CO3 (123 mg, 0.888 mmol), tetrabutylammonium bromide (TBAB; 238 mg, 0.740 mmol), palladium acetate (9.97 mg, 0.044 mmol) and styrene 3a (0.170 mL, 1.48 mmol) in DMF (6 mL), was poured into a two-necked flask equipped with a magnetic stirring bar, fibre-optic temperature control, and reflux condenser and placed under a nitrogen atmosphere. The mixture was then irradiated in an Ethos SYNTH microwave (Milestone Inc.) at constant power of 300 W from 5-10 min. After that period, the reaction mixture was poured into a mixture of ice (1 g) and water (10 mL) and extracted with diethyl ether (3 × 10 mL). The organic layer was evaporated to dryness and the obtained residue was taken in ethyl acetate (10 mL) and washed with water (2 × 10 mL). The organic layer was dried with anhydrous sodium sulfate, evaporated and purified by column chromatography (CHCl3-acetone, 9.6:0.4). After solvent evaporation, the obtained residue was recrystallised from ethanol to give 3-styrylflavones 4a-g [4a: 67 mg (70%); 4b: 68 mg (68%); 4c: 73 mg (70%); 4d: 66 mg (62%); 4e: 55 mg (50%); 4f: 51 mg (45%)]. The reaction of 3-bromoflavone 2a (0.296 mmol) with styrene 3b (1.48 mmol), under the same reaction conditions, yielded 3-(3,4-dimethoxystyryl)flavone 4g (72 mg, 63%)

24

( E )-3-(3,4-Dimethoxystyryl)flavone (4g): Yellow solid; mp 158-160 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 3.86 (s, 3 H, 4′′-OCH3), 3.88 (s, 3 H, 3′′-OCH3), 6.72 (d, J = 16.2 Hz, 1 H, H-α), 6.82 (d, J = 8.1 Hz, 1 H, H-5′′), 6.93 (d, J = 1.6 Hz, 1 H, H-2′′), 6.95 (d, J = 9.2 Hz, 1 H, H-6′′), 7.44 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-6), 7.51 (dd, J = 1.7, 8.3 Hz, 1 H, H-8), 7.53-7.58 (m, 3 H, H-3′,4′,5′), 7.69 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-7), 7.76-7.79 (m, 2 H, H-2′,6′), 7.95 (d, J = 16.2 Hz, 1 H, H-β), 8.33 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). ¹³C NMR (75.47 MHz, CDCl3): δ = 55.8 (4′′-OCH3), 55.9 (3′′-OCH3), 109.3 (C-2′′), 111.2 (C-5′′), 117.8 (C-3), 117.9 (C-8), 118.3 (C-α), 119.3 (C-6′′), 123.5 (C-10), 125.1 (C-6), 126.3 (C-5), 128.4 (C-3′,5′), 129.9 (C-2′,6′), 130.6 (C-4′), 131.3 (C-1′′), 133.3 (C-1′), 133.4 (C-7), 134.1 (C-β), 148.8 (C-3′′), 148.9 (C-4′′), 155.4 (C-9), 162.5 (C-2), 177.6 (C-4). MS (ESI+): m/z (%) = 385 (100) [M + H]+, 407 (20) [M + Na]+. Anal. Calcd for C25H20O4 (384.42): C, 78.11; H, 5.24. Found: C, 78.15; H, 5.31

27

5-Phenyl-7 H -benzo[ c ]xanthen-7-one (5a): Mp 197-198 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 7.47 (br dd, J = 7.0, 8.0 Hz, 1 H, H-9), 7.47-7.50 (m, 1 H, H-4′), 7.52-7.54 (m, 4 H, H-2′,3′,5′,6′), 7.67 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-3), 7.74 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-2), 7.75 (br d, J = 8.0 Hz, 1 H, H-11), 7.81 (ddd, J = 1.3, 7.0, 8.0 Hz, 1 H, H-10), 8.02 (dd, J = 1.5, 8.0 Hz, 1 H, H-4), 8.24 (s, 1 H, H-6), 8.44 (dd, J = 1.3, 8.0 Hz, 1 H, H-8), 8.81 (dd, J = 1.5, 8.0 Hz, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 117.1 (C-6a), 118.1 (C-11), 121.9 (C-6), 122.5 (C-7a), 123.1 (C-1), 124.4 (C-12b), 124.5 (C-9), 126.6 (C-2), 126.7 (C-4), 126.8 (C-8), 127.6 (C-4′), 128.4 (C-2′,6′), 129.6 (C-3), 130.1 (C-3′,5′), 132.1 (C-10), 133.7 (C-4a), 134.4 (C-5), 136.6 (C-1′), 155.8 (C-12a), 168.4 (C-11a), 177.2 (C-7). MS (ESI+): m/z (%) = 323 (100) [M + H]+, 345 (22) [M + Na]+. MS (EI+): m/z calcd for C23H14O2: 322.0994; found: 322.0995

28

5-Phenyl-5 H -benzo[ c ]xanthen-7(6 H )-one (6a): ¹H NMR (300.13 MHz, CDCl3): δ = 3.24 (dd, J = 9.0, 16.5 Hz, 1 H, H-6cis), 3.33 (dd, J = 7.3, 16.5 Hz, 1 H, H-6trans), 4.32 (dd, J = 7.3, 9.0 Hz, 1 H, H-5), 7.06 (dd, J = 7.6 Hz, 1 H, H-2), 7.18-7.23 (m, 2 H, H- 3′,5′), 7.23-7.26 (m, 1 H, H-4), 7.27-7.32 (m, 2 H, H-2′,6′), 7.38- 7.49 (m, 3 H, H-9,3,4′), 7.59 (dd, J = 1.4, 8.3 Hz, 1 H, H-11), 7.69 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.09 (dd, J = 1.8, 7.6 Hz, 1 H, H-1), 8.24 (dd, J = 1.4, 8.3 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl3): δ = 27.2 (C-6), 43.1 (C-5), 115.4 (C-6a), 117.9 (C-11), 123.6 (C-7a), 124.0 (C-1), 125.9 (C-8), 126.8 (C-4), 127.3 (C-4′), 128.2 (C-3′,5′), 128.47 (C-12b), 128.5 (C-2′,6′), 128.7 (C-2), 131.4 (C-3), 133.3 (C-10), 141.7 (C-1′), 142.7 (C-4a), 155.6 (C-11a), 157.4 (C-12a), 177.2 (C-7). MS (EI+): m/z calcd for C23H16O2: 324.1150; found: 324.1147

29

Optimised procedure for the synthesis of 5-phenyl-7 H -benzo[ c ]xanthen-7-ones 5a-h: A mixture of the appropriate 3-styrylflavone 4a-g (0.15 mmol) and a catalytic amount of I2 (10% mol) in 1,2,4-trichlorobenzene (20 mL), was poured into a three-necked flask equipped with a magnetic stirring bar, reflux condenser and a high-pressure mercury UV lamp with 400 W power. The mixture was then irradiated from 2 to 6 days. After that period, the reaction mixture was poured into a silica gel column and eluted with light petroleum to remove the excess of iodine and 1,2,4-trichlorobenzene. Upon changing the eluent to ethyl acetate-light petroleum (1:9 or 3:7), 5-phenyl-7H-benzo[c]xanthen-7-ones were obtained, which were recrystallised from ethanol 5a-h [5a: 50 mg (70%); 5b: 22 mg (45%); 5c: 50 mg (73%); 5d: 35 mg (74%); 5e: 15 mg (30%); 5f: 11 mg (20%); 5g: 23 mg (40%); 5h: 35 mg (60%)]

30

Physical data of 6-hydroxy-3-nitro-5-phenyl-7 H -benzo[ c ]xanthen-7-one (7e): ¹H NMR (300.13 MHz, CDCl3): δ = 7.46 (br d, J = 8.4 Hz, 2 H, H-3′,5′), 7.52-7.56 (m, 1 H, H-4′), 7.53-7.59 (m, 1 H, H-9), 7.56-7.62 (m, 2 H, H-2′,6′), 7.79 (br d, J = 8.3 Hz, 1 H, H-11), 7.93 (ddd, J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.20 (dd, J = 2.2, 9.2 Hz, 1 H, H-2), 8.41 (dd, J = 1.4, 8.3 Hz, 1 H, H-8), 8.51 (d, J = 2.2 Hz, 1 H, H-4), 8.77 (d, J = 9.2 Hz, 1 H, H-1), 12.71 (s, 1 H, 6-OH). ¹³C NMR (75.47 MHz, CDCl3): δ = 109.5 (C-6a), 116.9 (C-2), 118.2 (C-11), 119.5 (C-5), 120.3 (C-12b), 121.3 (C-7a), 121.4 (C-4), 125.0 (C-1), 125.5 (C-9), 126.2 (C-8), 128.3 (C-4′), 128.9 (C-2′,6′), 131.0 (C-3′,5′), 133.3 (C-1′), 136.1 (C-10), 136.6 (C-4a), 148.7 (C-3), 153.0 (C-12a), 154.3 (C-6), 155.7 (C-11a), 182.0 (C-7) ppm. MS (EI+): m/z calcd for C23H13O5N 383.0794; found: 383.0791

32

Physical data of 3,4-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5f): ¹H NMR (300.13 MHz, CDCl3): δ = 3.18 (s, 3 H, 4-OCH3), 4.03 (s, 3 H, 3-OCH3), 7.34-7.46 (m, 6 H, H-9,2′,3′,4′,5′,6′), 7.49 (d, J = 9.2 Hz, 1 H, H-2), 7.72 (d, J = 8.3 Hz, 1 H, H-11), 7.79 (ddd, J = 1.5, 7.0, 8.3 Hz, 1 H, H-10), 8.04 (s, 1 H, H-6), 8.41 (dd, J = 1.5, 8.3 Hz, 1 H, H-8), 8.60 (d, J = 9.2 Hz, 1 H, H-1). ¹³C NMR (75.47 MHz, CDCl3): δ = 56.4 (4-OCH3), 60.6 (3-OCH3), 110.1 (C-6a), 114.0 (C-2), 118.0 (C-11), 120.1 (C-1), 122.6 (C-7a), 124.4 (C-9), 124.8 (C-6), 126.3 (C-4′), 126.6 (C-8), 126.9 (C-2′,6′), 129.2 (C-3′,5′), 130.4 (C-4a), 130.8 (C-5), 134.2 (C-10), 141.4 (C-12a), 144.6 (C-4), 155.1 (C-3), 156.7 (C-11a), 178.9 (C-7). MS (EI+): m/z calcd for C25H18O4: 382.1205; found: 382.1207

33

Physical data of 2,3-dimethoxy-5-phenyl-7 H -benzo[ c ]xanthen-7-one (5g): ¹H NMR (300.13 MHz, CDCl3): δ = 3.88 (s, 3 H, 3-OCH3), 4.18 (s, 3 H, 2-OCH3), 7.34 (s, 1 H, H-4), 7.45 (br dd, J = 7.0, 8.2 Hz, 1 H, H-9), 7.46-7.49 (m, 1 H, H-4′), 7.50-7.58 (m, 4 H, H-2′,3′,5′,6′), 7.75 (dd, J = 1.7, 8.2 Hz, 1 H, H-11), 7.79 (ddd, J = 1.7, 7.0, 8.2 Hz, 1 H, H-10), 8.01 (s, 1 H, H-1), 8.13 (s, 1 H, H-6), 8.45 (dd, J = 1.7, 8.2 Hz, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl3): δ = 55.9 (3-OCH3), 56.2 (2-OCH3), 102.0 (C-4), 105.9 (C-1), 116.4 (C-6a), 118.0 (C-11), 119.2 (C-12b), 120.7 (C-6), 122.4 (C-1′), 124.2 (C-9), 126.5 (C-7a), 126.7 (C-8), 127.6 (C-4′), 128.5 (C-2′,6′), 129.9 (C-3′,5′), 131.4 (C-4a), 134.1 (C-5), 135.3 (C-10), 139.9 (C-12a), 149.8 (C-2), 151.9 (C-3), 155.8 (C-11a), 176.9 (C-7). MS (EI+): m/z calcd for C25H18O4: 382.1205; found: 382.1207

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Scheme 1

Scheme 2 Structures of 5-phenyl-5H-benzo[c]xanthen-7(6H)-one (6a), 6-hydroxy-3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one (7e) and formation of 3,4-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5f) and 2,3-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one (5g)

Scheme 3