Convenient Synthesis of a Novel Flavonoid with Extended ππ-System : Active Agent for UVA Protection

Flavonoid derivative with extended cinnamic acid moiety was synthesized using Baker-Venkataraman reaction. The compound shows interesting UV absorption properties which make it a good UVA absorber. A bathochromic shift of 18 nm was observed when the size of cinnamic acid segment was increased by one styrylogous extension.


Introduction
Flavonoids play an important role in biological processes in plants and other biological species [1].Human diet contains trace amount of �avonoids which have been reported to exhibit a wide range of biological activities.ese biological properties include anti-in�ammatory [2], antibacterial, antitumor [3], antioxidant [4], antiviral [5], antiallergenic [6], and protein kinase C inhibitors [7].Besides, it is known that some �avonoids have antifeedant activity against some phytophagous and a subterranean termite (Coptotermes sp.) [8].Recently, �avonoids were recommended for the treatment of allergic and in�ammatory diseases [9].
In addition, �avonoids are known for their ability to act as UV-absorbers and radical quenching compounds [10,11].Because of this important property, �avonoids are exploited by plants to protect them from the sun UV radiation.is use could be utilized in the protection of human hair and skin from UV radiation.It is well known that exposure to UV radiation can damage skin and hair �bers [12,13].UVB radiation is the principal radiation responsible for inducing skin cancer and hair protein loss (causing dryness, reduced strength, rough surface texture, and decreased luster) [14].On the other hand, UVA radiation is responsible for premature photoaging of the skin and for color changes of hair [15].Structurally, �avonoids can be divided into two main segments: the cinnamic acid subchromophore and the benzoyl subchromophore (Figure 1).By altering the chromone substitution pattern, the UV absorption properties can be adjusted to individual needs.For example, a bathochromic shi was observed (from 294 nm to 330 nm) when the size of the cinnamic acid fragment was increased by introducing one vinylogous extension in the -system (Figure 2) [16].is means that �avone 1 would protect better against UVB and thus against hair protein loss, whilst 2-styryl-4H-chromen-4-one 2 would protect better against UVA radiation and hair color changes.
On the other hand, introducing an electron donating group such as hydroxyl group to the benzoyl subchromophore caused a hypsochromic shi from 294 nm to 265 nm (Figure 3) which means that 5-hydroxy�avone 3 would protect better against UVC [13].
Several methods have been applied for the synthesis of �avonoids for example, Allan-Robinson strategy, cyclization of chalcones, and via an intramolecular Wittig reaction [17,18].One of the most common methods used to prepare �avonoids involves acylation of o-hydroxyacetophenone with an aromatic acid chloride yielding an aryl ester.e ester is then rearranged by a base (the Baker-Venkataraman reaction) to a 1,3-diaryl-1,3-diketone [19].e later compound gives 2arylchromone (�avone) via acid-catalyzed cyclization.Here, we report the synthesis of a novel �avone derivative 4 in which the cinnamic acid fragment is increased by introducing a styryl extension in the -system and to study its UV absorption properties.F 2: UV absorption of �avone and 2-styryl-4H-chromen-4one.

Results and Discussion
Our strategy to make compound 4 started from the phosphonium salt 5 which was prepared by the reaction of 4-(bromomethyl)benzoic acid with triphenylphosphine in acetone (Scheme 1).We envisaged that the double bond between the two phenyl groups in the target compound 4 can be constructed via Wittig reaction between a suitable phosphorus ylide and benzaldehyde.So, the reaction of the salt 5 with benzaldehyde in H 2 O/CH 2 Cl 2 system in the presence of NaOH yielded the alkene as a mixture of Zand E-isomers which was isomerized to the E-isomer 6 by treatment of the product mixture with a trace of iodine.e conversion of 6 into the acid chloride 7 was afforded using thionyl chloride following literature procedures [20].e crude acid chloride 7 was subsequently reacted with 2hydroxyacetophenone in pyridine to give ester 8 in 50% yield.Next, we turned our attention to construct the heterocyclic ring in the desired �avonoid derivative 4 using Baker-Venkataraman rearrangement of ester 8. us, upon re�uxing a pyridine solution of 8 in the presence of KOH followed by treatment with H 2 SO 4 afforded successfully �avonoid derivative 4 in 63%.e UV absorption properties of compound 4 and �avone 1 were measured.A bathochromic shi was observed when the cinnamic acid fragment was extended by styryl group.e maximum absorption of �avonoid derivative 4 is at 312 nm (UVA) compared to 294 nm (UVB) for �avone 1.We believe that �avonoid derivative 4 is much better UVA absorber than �avonoid derivative 2 since it absorbs at a wide UVA range.

Experimental
e reagents and solvent were obtained from Aldrich and used without further puri�cation.UV-vis spectra were measured using a Shimadzu, Model UV-1650PC spectrophotometer and reported as  max in nm ().IR spectra were obtained with a Nicolet model Magna 560 spectrometer; absorption bands are recorded in wave number (cm −1 ).NMR spectra were recorded on a Bruker Avance 400 ( 1 H: 400 MHz, 13 C: 100.6 MHz).e chemical shis are in values (ppm) relative to the internal standard TMS and reported as chemical shi (multiplicity, coupling constant, and number of protons, assignment).Mass spectra were measured using HPLC-MS.

3.1.
Synthesis of E-4-Styrylbenzoic Acid 6. 4-Carboxybenzyltriphenylphosphonium bromide 5 (7.30g, 15.3 mmol) was suspended in dichloromethane (175 mL) in an Erlenmeyer �ask.75 mL of aqueous solution of sodium hydroxide (50 g) and benzaldehyde (2.0 mL) were added to the reaction mixture.e neck of the �ask was plugged with cotton wool and the yellow mixture stirred for 30 minutes.e organic layer was separated and the aqueous layer was extracted with (2 × 20 mL) dichloromethane.e combined organic layer was dried over MgSO 4 , �ltered, and concentrated under reduced pressure.Petroleum ether (50 mL) and few crystals of iodine were added to the residue and the mixture was re�uxed for 3 h.e reaction mixture was washed with 25% sodium metabisul�te and the organic layer was dried over MgSO 4 and concentrated under reduced pressure to give a white solid.e solid was recrystallised from ethanol to yield white needles (7.39 g, 0.033 mol, 75%).Mp 105.

Synthesis of Flavonoid Derivative 4.
To a solution of E-2-acetylphenyl 4-styrylbenzoate 8 (0.25 g, 0.73 mmol) in pyridine (0.85 mL) at 50 ∘ C was added potassium hydroxide (0.062 g, mmol) and the mixture was stirred for 15 min.Acetic acid solution (10%, 1.3 mL) was added to the cooled mixture and the solid intermediate was collected by �ltration (Figure 4).To a solution of the solid intermediate in acetic acid was added concentrated sulfuric acid (0.03 mL) and the mixture was re�uxed for 1 hour.e cooled mixture was poured into ice and the product was collected by suction �ltration and washed with water.e product was recrystallized from petroleum (0.13 g, 63%).IR (Nujol oil):  max (cm −1 ) = 1706, 1637, 1577, 1259;  max (nm) (log ) 252