Highly Efficient Synthesis of Chalcones from Poly Carbonyl Aromatic Compounds Using BF₃–Et₂O via a Regioselective Condensation Reaction

Abstract

A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substituted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF₃–Et₂O as a reagent is described.

Chalcones are considered as the precursors of flavonoids/isoflavonoids and are abundant in edible plants. Flavonoids represent an outstanding class of naturally occurring compounds.¹⁾ Chalcones are open chain flavonoids in which two aromatic rings are separated by a three carbon α,β-unsaturated carbonyl system, i.e. 1,3-diphenyl-2-propen-1-one derivative. The equilibrium between the open chain chalcone form and the cyclic flavanone isomer is the key step for the origin of the skeletal modifications of the biosynthetic pathway. Chalcones are known for diverse biological activities, among which anti-inflammatory,²⁾ antimalarial,³⁾ antitubercular,⁴⁾ nitric oxide regulation modulatory,⁵⁾ cardiovascular,⁶⁾ anticancer⁷⁾ and antileishmanial activities⁸⁾ have been reported in the past decade.

The structure–activity relationship (SAR) study of chalcones revealed that the presence of hydroxyl, allyl and prenyl groups in its skeleton commonly enhances its biological activities.^9,10) The reported synthetic chalcones I–IV (Fig. 1) exhibit various biological activities.^11–14) Many methods are available for the synthesis of chalcones. Among those, base catalyzed Claisen–Schmidt reaction is the most widely used, in which ketone condenses with an aldehyde in the presence of aq. NaOH,¹⁵⁾ KOH,^16,17) Ba(OH)₂,¹⁸⁾ hydrotalcites,¹⁹⁾ lithium hexamethyldisilazide (LiHDMS)²⁰⁾ and calcined NaNO₃/natural phosphates.²¹⁾ Beside base catalyzed methods, some acid catalyzed methodologies have also been reported for the synthesis of chalcones which includes the use of AlCl₃,²²⁾ dry Zn(bpy)(OAc)₂,²³⁾ TiCl₄,²⁴⁾ Cp₂ZrH₂/NiCl₂,²⁵⁾ Zeolites¹⁹⁾ and RuCl₃.²⁶⁾

Fig. 1. Biologically Active Synthetic Chalcones

Recently, BF₃–Et₂O has been utilized as a condensing agent in the synthesis of chalcones,²⁷⁾ stilbenes,²⁸⁾ regioselective deacetylation regioselective cyclization of prenylated chalcones²⁹⁾ and in the synthesis of chromano-chalcones via regioselective cyclization of prenylated chalcones.³⁰⁾ However, the use BF₃–Et₂O has not been yet explored for the synthesis of carbonyl chalcones with free aldehyde group on benzene ring.

Results and Discussion

In the present study, chalcones were prepared by using the key starting material, i.e. 5-acetyl-2-hydroxybenzaldehyde (1). Salicylaldehyde was acetylated with AC₂O in the presence of AlCl₃ in dichloromethane (DCM) solvent³¹⁾ to afford 5-acetyl-2-hydroxybenzaldehyde (1). Another starting material, i.e., 4-hydroxy-5-methylisothalaldehyde (2) was prepared via the Duff formylation reaction of commercially available O-cresol in the presence of hexamethylenetetramine (HMTA) and trifluoroacetic acid (TFA) at 120°C.³²⁾ In the previous reports on the synthesis of chalcones, we observed that, acetyl group adjacent to the hydroxyl group might be forming a complex with BF₃–Et₂O to prevent the condensation reaction²⁷⁾ (Fig. 2). Therefore, an attempt was made to investigate the above described property of BF₃–Et₂O to perform the regioselective Claisen–Schmidt condensation reaction of 1 and 2.

Fig. 2. Possible Mechanism for the Formation of Desired Chalcones Using BF₃–Et₂O

Initially, we attempted the reaction of 5-acetyl-2-hydroxybenzaldehyde 1 with benzaldehyde 3a in 1,4-dioxane using 2 eq of BF₃–Et₂O (Chart 1). The reaction proceeded smoothly at ambient temperature to afford the desired chalcone 4a in 81% yield. The scope of the reaction was explored with different aromatic aldehydes such as 3-methoxybenzaldehyde, 4-isopropylbenzaldehyde, 4-methoxybenzaldehyde, 3-methoxy-4-benzyloxybenzaldehyde, 4-fluorobenzaldehyde, 3-phenoxybenzaldehyde, 4-methylbenzaldehyde and 3,4,5-trimethoxybenzaldehyde (entries 2, 4–10, Table 1). All the above aldehydes reacted well with acetophenone 1 affording its desired chalcones 4b and d–j, respectively in good yields. Heteroaromatic aldehydes such as thiophene-2-carboxaldehyde also participated well in this reaction to give respective product 4c (entry 3, Table 1).

Chart 1

Table 1. Synthesis of Aldehyde Chalcones (4a–j) Using BF₃–Et₂O

Entry	Ketone	Aldehyde	Chalcone	Yield (%)a)	mp (°C)
1				81	145
2				79	161
3				73	130
4				68	226
5				85	158
6				70	161
7				41	193
8				67	139
9				78	205
10				71	205

a) Isolated yield. b) All products were characterized by ¹H-NMR, ¹³C-NMR and MS data.

Next, we studied the reaction of 4-hydroxy-5-methylisothalaldehyde 2 with acetophenone 5a under similar reaction conditions (Chart 2). In that case, the corresponding chalcone 6a was obtained as a sole product in 82% yield. The scope of the above reaction was examined with respect to various others acetophenones and the results are summarized in Table 2. Several other acetophenones like 3-methoxyacetophenone, 3,4-dimethoxyacetophenone, 3-bromoacetophenone, 2,4-dichloroacetophenone, 4-methoxyacetophenone, 4-fluoroacetophenone and thiophene-2-carboxaldehyde reacted smoothly with 2 affording their respective chalcones 6b–h in good yields (entries 2–8, Table 2).

Chart 2

Table 2. Synthesis of Aldehyde Chalcones (6a–h) Using BF₃–Et₂O

Entry	Acetophenone	–Ar group	Chalcone	Yield (%)a)	mp (°C)
1				82	134
2				81	163
3				71	201
4				77	173
5				76	212
6				86	160
7				69	205
8				71	174

a) Isolated yield. b) All products were characterized by ¹H-NMR, ¹³C-NMR and MS data.

In case of low yielding reactions, the starting materials were recovered through column chromatography and we did not observe the formation of their regioisomers. All the products were characterized by NMR, Mass and IR spectroscopy. Beside BF₃–Et₂O, the effect of various other Lewis acids such as AlCl₃, ZnCl₂, SnCl₄ and TiCl₄ was studied for this transformation. In all those cases, formation of desired chalcone was not regioselective; indeed those Lewis acids gave mixture of cross condensation and self condensation products in variable ratios along with unreacted staring materials which could not be separable on column chromatography.

Conclusion

We have reported a simple protocol for the synthesis of carbonyl chalcones with free aldehyde group on benzene ring via Claisen–Schmidt condensation using BF₃–Et₂O. This method has several advantages such as regioselectivity, high yields and simple procedure. Free aldehyde group in products can be used in further modifications to generate a large number of hybrid molecules of biological importance.

Experimental

All the reagents and solvents were of reagent grade and used without purification unless specified otherwise. Technical grade ethyl acetate and hexane were used for column chromatography and were distilled prior its use. 1,4-Dioxane was purchased from Aldrich Chemicals Co. Column chromatography was carried out using silica gel (60–120, 100–200 mesh) packed in glass columns. All the reactions were performed under an atmosphere of nitrogen in oven dried glassware. Fourier transform (FT)-IR spectra were recorded as KBr discs or neat. The ¹H- and ¹³C-NMR spectra were recorded in CDCl₃ and DMSO-d₆ using 300, 400 and 500 MHz spectrometers. Mass spectra were recorded on Micro mass VG-7070H for electron ionization (EI) and VG Autospec M for FAB-MS.

General Experimental Procedure for the Synthesis of Aldehyde Chalcones (4a–j)

To a stirred solution of 5-acetyl-2-hydroxybenzaldehyde 1 (100 mg, 0.61 mmol) and benzaldehyde 3 (0.61 mmol) in dry 1,4 dioxane (5 mL) was added gradually BF₃–Et₂O (1.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×25 mL) to decompose the BF₃–Et₂O complex. After extraction, the organic phase was dried over anhydrous Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane–ethyl acetate as a mobile phase to afford desired chalcones 4a–j in good yields, which were light yellow solids.

5-Cinnamoyl-2-hydroxybenzaldehyde (4a)

Yield 81%, light yellow solid, mp 145°C; IR ν_max: 2923, 2845, 1654, 1598, 1444, 1213, 1160, 1038, 848 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 11.41 (s, 1H), 10.02 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.24 (dd, J=2.2, 9.0 Hz, 1H), 7.83 (d, J=15.8, 1H), 7.68–7.60 (m, 2H), 7.50 (d, J=15.1 Hz, 1H), 7.45–7.38 (m, 3H), 7.09 (d, J=9.0 Hz, 1H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.3, 187.1, 164.8, 145.0, 136.7, 134.9, 134.4, 130.6, 130.2, 129.5, 128.8, 128.3, 120.5, 117.9; electrospray ionization (ESI)-MS: m/z=253 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(3-methoxyphenyl)acryloyl)benzaldehyde (4b)

Yield 79%, light yellow solid, mp 161°C; ¹H-NMR (400 MHz, CDCl₃) δ: 11.39 (s, 1H), 10.00 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.21 (dd, J=2.3, 8.5 Hz, 1H), 7.76 (d, J=15.5 Hz, 1H), 7.45 (d, J=15.5 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.21 (d, J=7.01, 1H), 7.11 (s, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.92 (dd, J=2.3, 8.5 Hz, 1H), 3.85 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.2, 164.9, 159.8, 145.0, 136.8, 135.9, 135.0, 130.3, 129.9, 121.0, 120.9, 120.0, 118.0, 116.2, 113.5, 55.3; ESI-MS: m/z=283 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(thiophen-2-yl)acryloyl)benzaldehyde (4c)

Yield 73%, light yellow solid, mp 130°C; ¹H-NMR (400 MHz, CDCl₃) δ: 11.40 (s, 1H), 10.02 (s, 1H), 8.30 (d, J=2.6 Hz, 1H), 8.21 (dd, J=2.6, 8.9 Hz, 1H), 7.96 (d, J=15.1 Hz, 1H), 7.42 (d, J=5.3 Hz, 1H), 7.37 (d, J=3.5 Hz, 1H), 7.29 (d, J=15.1 Hz, 1H), 7.10 (d, J=5.3 Hz, 1H), 7.07 (d, J=5.3 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.4, 186.6, 165.0, 140.1, 137.5, 136.7, 134.9, 132.4, 130.3, 129.0,128.4, 120.0, 119.3, 118.9; ESI-MS: m/z=259 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(4-isopropylphenyl)acryloyl)benzaldehyde (4d)

Yield 68%, light yellow solid, mp 226°C; ¹H-NMR (500 MHz, CDCl₃) δ: 11.38 (s, 1H), 10.01 (s, 1H), 8.30 (d, J=2.0 Hz, 1H), 8.22 (dd, J=2.0, 9.0 Hz, 1H), 7.80 (d, J=16.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.44 (d, J=16.0 Hz, 1H), 7.25 (d, J=8.0, 2H), 7.07 (d, J=8.0 Hz, 1H), 2.99–2.90 (m, 1H), 1.28 (d, J=7.0, 6H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.3, 164.8, 152.1, 145.2, 136.7, 134.9, 132.1, 130.5, 128.5, 127.0, 119.9, 119.7, 117.9, 34.0, 23.6; ESI-MS: m/z=259 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(4-methoxyphenyl)acryloyl)benzaldehyde (4e)

Yield 85%, light yellow solid, mp 158°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.38 (s, 1H), 10.01 (s, 1H), 8.30 (d, J=2.2 Hz, 1H), 8.22 (dd, J=2.2, 9.0 Hz, 1H), 7.79 (d, J=15.8 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.37 (d, J=15.1 Hz, 1H), 7.07 (d, J=8.3, 1H), 6.91 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.2, 164.8, 161.7, 145.0, 136.7, 134.8, 130.6, 130.2, 127.3, 118.2, 117.9, 114.3, 120.0, 55.3; ESI-MS: m/z=283 [M+Na]⁺.

(E)-5-(3-(4-(Benzyloxy)-3-methoxyphenyl)acryloyl)-2-hydroxybenzaldehyde (4f)

Yield 70%, light yellow solid, mp 161°C; ¹H-NMR (500 MHz, CDCl₃) δ: 11.41 (s, 1H), 10.00 (s, 1H), 8.31 (s, 1H), 8.23 (d, J=8.6, Hz, 1H), 7.79 (d, J=15.3 Hz, 1H), 7.44 (d, J=7.6 Hz, 2H), 7.41–7.30 (m, 4H), 7.18 (s, 2H), 7.09 (d, J=8.6 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 5.21 (s, 2H), 3.96 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.2, 164.8, 150.7, 149.7, 145.2, 136.2, 136.3, 134.9, 130.6, 128.5, 128.0, 127.9, 127.1, 122.9, 122.0, 118.7, 117.9, 113.4, 110.8, 70.8, 56.0; ESI-MS: m/z=389 [M+Na]⁺.

(E)-5-(3-(4-Fluorophenyl)acryloyl)-2-hydroxybenzaldehyde (4g)

Yield 41%, light yellow solid, mp 193°C; ¹H-NMR (400 MHz, CDCl₃) δ: 11.46 (s, 1H), 10.02 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.25 (dd, J=2.2, 8.8 Hz, 1H), 7.84 (d, J=15.5 Hz, 1H), 7.69–7.64 (m, 2H), 7.47 (d, J=15.56 Hz, 1H), 7.17–7.10 (m, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 190.1, 184.9, 162.8, 140.7, 134.3, 129.6, 129.5, 129.1, 129.0, 127.6, 119.9, 115.9, 114.1, 113.9; ESI-MS: m/z=293 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(3-phenoxyphenyl)acryloyl)benzaldehyde (4h)

Yield 67%, light yellow solid, mp 139°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.40 (s, 1H), 10.00 (s, 1H), 8.30 (d, J=1.5 Hz, 1H), 8.21 (dd, J=2.2, 9.0 Hz, 1H), 7.77 (d, J=15.1 Hz, 1H), 7.45 (d, J=15.1 Hz, 1H), 7.39–7.37 (m, 5H), 7.15–6.95 (m, 5H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.3, 187.0, 164.9, 157.7, 156.6, 144.2, 136.7, 136.4, 135.0, 130.2, 129.8, 123.6, 123.5, 121.3, 120.8, 119.9, 118.9, 118.0; ESI-MS: m/z=345 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-p-tolylacryloyl)benzaldehyde (4i)

Yield 78%, light yellow solid, mp 205°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.40 (s, 1H), 10.01 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 8.23 (dd, J=2.2, 9.0 Hz, 1H), 7.82 (d, J=15.1 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.47 (d, J=15.8 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 2.41 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.3, 164.9, 145.3, 141.3, 136.8, 134.9, 131.8, 130.6, 129.7, 128.5, 120.0 119.7, 118.0, 21.5; ESI-MS: m/z=267 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(3,4,5-trimethoxyphenyl)acryloyl)benzaldehyde (4j)

Yield 71%, light yellow solid, mp 146°C; ¹H-NMR (500 MHz, CDCl₃) δ: 11.38 (s, 1H), 10.02 (s, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.21 (dd, J=2.9, 8.8 Hz, 1H), 7.71 (d, J=15.8 Hz, 1H), 7.33 (d, J=14.8 Hz, 1H), 7.08 (d, J=9.8 Hz, 1H), 6.82 (s, 2H), 3.91 (s, 6H), 3.87 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 187.3, 164.9, 153.4, 145.4, 136.8, 135.0, 130.4, 130.0, 129.6, 120.0, 118.0 105.7, 60.9, 56.1; ESI-MS: m/z=343 [M+Na]⁺.

General Experimental Procedure for the Synthesis of Aldehyde Chalcones (6a–h)

To a stirred solution of 4-hydroxy-5-methylisophthalaldehyde 2 (0.61 mmol) and acetophenone 5 (0.61 mmol) in dry 1,4 dioxane (5 mL) was added gradually BF₃–Et₂O (1.22 mmol) at room temperature. The reaction mixture was stirred at room temperature (r.t.) for 24 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×25 mL) to decompose the BF₃–Et₂O complex. After extraction, the organic phase was dried over anhydrous Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using hexane–ethyl acetate as a mobile phase to afford desired chalcones 6a–h in good to moderate yields, which were light yellow solids.

(E)-2-Hydroxy-3-methyl-5-(3-oxo-3-phenylprop-1-enyl)benzaldehyde (6a)

Yield 82%, light yellow solid, mp 134°C; IR (neat) ν_max 2925, 2874, 1658, 1589, 1208, 1160, 984, 815 cm⁻¹; ¹H-NMR (300 MHz, CDCl₃) δ: 11.53 (s, 1H), 9.93 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.76 (d, J=15.1 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.53 (s, 1H), 7.51 (s,1H), 7.46 (d, J=15.8 Hz, 2H), 2.32 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 190.0, 161.8, 143.1, 138.1, 136.4, 132.7, 132.3, 128.6, 128.4, 128.0, 126.5, 120.6, 119.9, 15.1; ESI-MS: m/z=267 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(3-methoxyphenyl)-3-oxoprop-1-enyl)-3-methylbenzaldehyde (6b)

Yield 81%, light yellow solid, mp 163°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.54 (s, 1H), δ 9.94 (s, 1H), 7.77 (d, J=15.8, 1H), 7.73 (s, 1H), 7.67 (d, J=1.5 Hz, 1H) 7.62 (d, J=7.5 Hz, 1H), 7.56 (t, J=1.5, 1H), 7.48–7.39 (m, 2H), 7.14 (dd, J=3.0, 8.3 Hz, 1H), 3.90 (s, 3H), 2.33 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 196.4, 189.7, 161.8, 159.8, 143.1, 139.5, 136.6, 132.4, 129.5, 128.0, 126.5, 120.9, 120.6, 119.9, 119.1, 112.9, 55.4, 15.1; ESI-MS: m/z=297 [M+Na]⁺.

(E)-5-(3-(3,4-Dimethoxyphenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-methylbenzaldehyde (6c)

Yield 71%, light yellow solid, mp 201°C; ¹H-NMR (300 MHz, CDCl₃,) δ: 11.52 (s, 1H), 9.94 (s, 1H), 7.77 (d, J=15.8 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J=2.2, 8.3 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H) 7.49 (d, J=15.1 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H) 3.98 (s, 6H), 2.34 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.4, 188.1, 161.6, 153.3, 149.2, 142.2, 136.3, 132.2, 131.2, 127.9, 126.7, 122.9, 120.2, 119.9, 110.7, 109.9, 29.6, 15.1; ESI-MS: m/z=327 [M+Na]⁺.

(E)-5-(3-(3-Bromophenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-methylbenzaldehyde (6d)

Yield 77%, light yellow solid, mp 173°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.56 (s, 1H), 9.95 (s, 1H), 8.15 (s, 1H), 7.95 (d, J=7.74 Hz, 1H), 7.79 (d, J=15.6 Hz,1H), 7.75–7.66 (m, 3H), 7.44–7.35 (m, 2H), 2.34 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.3, 188.5, 162.0, 143.9, 139.9, 136.4, 135.6, 132.6, 131.3, 130.2, 128.1, 126.9, 126.2, 122.9, 119.9, 119.8, 15.1; ESI-MS: m/z=345 [M+Na]⁺.

(E)-5-(3-(2,4-Dichlorophenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-methylbenzaldehyde (6e)

Yield 76%, light yellow solid, mp 212°C; ¹H-NMR (300 MHz, CDCl₃) δ: 11.53 (s, 1H), 9.90 (s, 1H), 7.63 (s, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.41 (s, 1H), 7.38–7.35 (m, 2H), 7.00 (d, J=15.8 Hz, 1H), 2.31 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.3, 192.1, 162.2, 144.7, 144.1, 136.5, 132.6, 131.7, 130.7, 130.3, 130.1, 129.6, 128.2, 127.3, 125.8, 124.4, 15.1; ESI-MS: m/z=335 [M+Na]⁺.

(E)-2-Hydroxy-5-(3-(4-methoxyphenyl)-3-oxoprop-1-enyl)-3-methylbenzaldehyde (6f)

Yield 86%, light yellow solid, mp 160°C; ¹H-NMR (500 MHz, CDCl₃) δ: 11.51 (s, 1H), 9.94 (s, 1H), 8.05 (d, J=8.8 Hz, 2H), 7.76 (d, J=15.5 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J=2.1, 1H), 7.47 (d, J=15.5 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 3.90 (s, 3H), 2.33, (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 196.4, 188.1, 163.4, 161.6, 142.2, 136.3, 132.3, 130.9, 130.6, 127.8, 126.6, 120.2, 119.8, 113.7, 55.4, 15.0; ESI-MS: m/z=297 [M+Na]⁺.

(E)-5-(3-(4-Fluorophenyl)-3-oxoprop-1-enyl)-2-hydroxy-3-methylbenzaldehyde (6g)

Yield 69%, light yellow solid, mp 205°C; ¹H-NMR (500 MHz, CDCl₃) δ: 11.54 (s, 1H), 9.94 (s, 1H), 8.10–8.05 (m, 2H), 7.78 (d, J=15.5 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.43 (d, J=15.5 Hz, 1H), 7.19 (t, J=8.5, 8 Hz, 2H), 2.30 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.4, 188.3, 164.3, 161.9, 143.3, 136.3, 132.4, 131.0, 130.9, 128.1, 126.4, 120.0, 115.8, 115.6, 15.1; ESI-MS: m/z=285 [M+Na]⁺.

(E)-2-Hydroxy-3-methyl-5-(3-oxo-3-(thiophen-2-yl)prop-1-enyl)benzaldehyde (6h)

Yield 71%, light yellow solid, mp 174°C; ¹H-NMR (400 MHz, CDCl₃) δ: 11.54 (s, 1H), 9.95 (s, 1H), 7.89 (dd, J=1.1, 3.7 Hz, 1H), 7.81 (d, J=15.5 Hz, 1H), 7.73 (br s, 1H), 7.70 (dd, J=1.1, 4.8 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.34 (d, J=15.52 Hz, 1H), 7.20 (dd, J=3.7, 4.8 Hz, 1H), 2.34 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.4, 181.6, 161.8, 145.4, 142.3, 136.4, 133.8, 132.4, 131.6, 128.2, 128.0, 126.3, 120.1, 119.9, 15.1; ESI-MS: m/z=273 [M+H]⁺.

Acknowledgment

The author J. S. R. thanks to UGC, New Delhi, India for providing UGC-JRF and SRF fellowships and also gratefully thank to Dr. J. S. Yadav, Natural Products Chemistry division for his constant support.

Conflict of Interest

The authors declare no conflict of interest.

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