Transition-Metal-Free Easy Access to 2-(2-Oxo-2-arylethyl)-4H-chromen-4-ones from 2-Hydroxyacetophenone

Abstract

A stepwise synthetic strategy has been devised to access 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones from 2-hydroxyacetophenone, offering a structurally oxidized analogue of 2-(2-phenylethyl)chromones (PECs). The key substrate, 2-(methylthio)-4H-chromen-4-one, is readily synthesized in two steps from a protected 2-hydroxyacetophenone. Under mild reaction conditions (25 °C) in DMSO/KOH, 2-(methylthio)-4H-chromen-4-one undergoes nucleophilic substitution with various arylmethyl ketones to furnish 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones in moderate to good yields. The transformation exhibits broad substrate scope and excellent functional group tolerance. Notably, the resulting 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones can serve as valuable intermediates for the development of medicinally and materially relevant functionalized molecules, highlighting the synthetic and applicative significance of this methodology.

Among various heterocyclic compounds, chromone analogues are ubiquitous and possess diverse biological profiles including anti-inflammatory, antiallergic, and antimicrobial activity.[1] In light of the pharmaceutical significance of these compounds, it has been a subject of interest among chemists to synthesize molecules bearing this chromone moiety.[2] Chromones in nature exist in various forms, the most common ones are flavones and isoflavones.[3a] These are of interest among chemists as they have shown a broad range of biological activities, which include antioxidant,[3b] anti-inflammatory[3c] and antiviral effects.[3d] Besides, a less discussed and relatively new class of naturally occurring chromones are the 2-(2-phenylethyl)chromones (PECs),[4] which have begun to receive growing attention. 2-(2-Phenylethyl)chromones have a rare phenylethyl substituent at the C-2 position. This compound and its derivatives are naturally found in the species of plants called Aquilaria sinensis, Gyrinops salicifolia, and Aquilaria malaccensis Lam. These compounds can be identified by the smell of burning woods.[5] [6] The chemists are enthusiastic about studying them because of their unique structural characteristics and various biological activities such as antidiabetic, anticancer, antioxidant, antibacterial, and anti-inflammatory.[7] 2-(2-Phenylethyl)chromones also have been found to exhibit diverse pharmacological activities including tyrosinase inhibitory, neuroprotective, phosphodiesterase inhibitory, and acetylcholinesterase inhibitory activities, etc.[8] (Figure [1]). Besides, the hydroxy derivatives of phenylethyl chromones also show antitumor and neuroprotective activities.[9]

As far as its synthetic route is concerned, PECs can be accessed by simple reduction of 2-styrylchromones[10] in one step, as well as multistep routes often harness classical approaches such as Claisen condensation,[9] aldol condensation,[11] esterification, and cyclization approach[12a] [b] (Scheme [1]) and Baker–Venkataraman rearrangement.[12c] While synthetic routes of PECs are still well discussed in the literature, so far there are hardly any reports present on the synthesis of the oxidized form of PECs, i.e., the introduction of the 2-oxo-arylethyl group at the C-2 position of chromones resulting in the formation of 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones. Angel et al. reported the formation of these compounds by treating benzoyl acetone with an excess of lithium diisopropylamide (LDA) and condensing with lithiated methyl salicylates[13] (Scheme [1]). Since 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones also act as unsymmetrical derivatives like deoxybenzoin and deoxyanisoin, it can be used as a suitable precursor for further utilization to get new synthetic derivatives.

The carbonyl group of these compounds can also be reduced to afford PECs easily. Considering this synthetic utility, we planned to synthesize this class of compound efficiently. Herein, we present a convenient route to synthesize a new analogue of PEC, i.e. 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones, by a simple base-mediated aromatic nucleophilic substitution reaction of 2-(methylthio)-4H-chromen-4-ones with various arylmethyl ketones. For this synthesis, the precursor molecule 2-(methylthio)-4H-chromen-4-one has been chosen, as it leverages a nucleophilic attack at its C-2 position without the ring opening of chromone.[14]

To obtain the precursor molecule firstly, i.e. 2-(methylthio)-4H-chromen-4-one (4), a three-step procedure was followed where all these steps are well optimized and documented by Pratap et al.[14] The first step comprises of protection of 2-hydroxyacetophenone by refluxing it with benzyl bromide in acetone. Consequently, 1-(2-benzyloxy)-phenyl)ethan-1-one (2) was obtained in 95% yield. In the second step, 2 undergoes ketene dithioacetal formation by stirring a mixture of 2, carbon disulfide, and methyl iodide at 0–5 °C in THF under basic conditions to render 1-[2-(benzyloxy)phenyl]-3,3-bis(methylthio)prop-2-ene-1-one (3) in 97% yield. The third step involves an intramolecular cyclization of 3 in the presence of iodine in DCE at 80 °C to form 2-(methylthio)-4H-chromen-4-one (4) in 95% yield. Compound 4 can be considered as a cyclized ketene dithioacetal, hence it was envisioned that it can be subjected to aromatic nucleophilic substitution at the C-2 position with various arylmethyl ketones to produce 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones 5. Since arylmethyl ketones are highly enolizable due to the presence of an α-hydrogen, which on abstraction leads to a stable enolate formation. Thus, a suitable base can be used to abstract the α-hydrogen to generate a nucleophile for an aromatic nucleophilic substitution at 2-(methylthio)-4H-chromen-4-one (4). A stepwise approach has been established starting from 2-hydroxyacetophenone, to access 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones 5 (Scheme [2]).

Initially, we attempted an aromatic nucleophilic substitution by reacting acetophenone and 4 in DMSO using KOH as the base (Table [1], entry 1). The reaction was stirred at room temperature and consequently, we isolated 75% of 2-(2-oxo-2-arylethyl)-4H-chromen-4-one. To obtain the best reaction conditions we embarked on optimizing the reaction conditions by screening various solvents. Surprisingly, when the reaction was set in DMF, it produced only 40% of 5 (Table [1], entry 2), while the reaction in ethanol did not proceed (Table [1], entry 3). Switching over to solvents such as THF and acetonitrile to carry out this nucleophilic substitution also failed to yield the desired product (Table [1], entries 4 and 5). DMSO was found to be the best solvent for this reaction. Subsequently, we proceeded to screen different bases, hence we replaced KOH with NaOH (Table [1], entry 6), keeping the other reaction conditions identical. This change in base provided a significant reduction in yield to 50% for 5. Furthermore, experiments were also performed in the presence of K₂CO₃, Cs₂CO₃, and NEt₃, but these also failed to obtain a good yield of the desired product (Table [1], entries 7–9). Thus, we found that KOH was the better choice for base in this reaction to the decent yield of 5. Furthermore, the effect of temperature was also studied by performing reactions at different temperatures such as 40 °C, 60 °C, and 80 °C.

Table 1 Optimization of Reaction Conditions^a

Entry	Base	Solvent	Temp (°C)	Yield of 5a (%)c
1	KOH	DMSO	25	75
2	KOH	DMF	25	40
3b	KOH	ethanol	25	–
4b	KOH	THF	25	–
5b	KOH	MeCN	25	–
6	NaOH	DMSO	25	50
7	K2CO3	DMSO	25	30
8	Cs2CO3	DMSO	25	48
9	NEt3	DMSO	25	25
10	KOH	DMSO	40	70
11	KOH	DMSO	60	65
12	KOH	DMSO	80	58

^a Reactions were carried out by stirring 2-(methylthio)-4H-chromen-4-one 4 (0.2 mmol), acetophenone (0.2 mmol), and base (0.3 mmol) in solvent (5.0 mL).

^b Starting material was recovered.

^c Yield of isolated product.

At 40 °C, we obtained 70% of product 5 in 3 h (Table [1], entry 10), but when the temperature was increased to 60 °C, the reaction was completed in less than 3 h (Table [1], entry 11) but the yield of 5 was dropped to 65%. When the reaction was carried out at 80 °C, a significant reduction of yield was observed, and the desired product was obtained in 58% yield (Table [1], entry 12). This observation indicates that the reaction works well at 25 °C to afford the desired product 5 in high yield.

After optimization of the reaction conditions, we expanded the scope of this reaction by synthesizing various derivatives of 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones 5 using the reaction of 2-thiomethylated chromone 4 and arylmethyl ketones in DMSO containing KOH at 25 °C. The reaction took 3 h to complete. Based on the type of functional groups present in the aryl group, it has been observed that the presence of a methyl group has significantly enhanced the product yield of 5b and 5c, while if a bulky group such as the phenyl group is substituted at the para position (5d), the yield dropped significantly to 47%. Electron-releasing groups, such as the methoxy group, have reduced the product yield in 5e and 5f. Out of halogen-substituted products, chloro-substituted products have shown a good yield (5h,i). Bromo derivatives showed a pattern in terms of their yield, i.e., o-bromo substitution yielded 59% of the product 5k, while m-bromo substitution improved the yield to 76% (5l) and p-substituted product came out to be 82% (5j). Possibly, the inductive effect of the electronegative bromo group is reducing the yield as it moves from the para to the ortho position. However, the fluoro derivative 5g provides a product yield of 75%. Naphthyl-group-substituted products 5m and 5n showed good yields of 76% and 80%, respectively. Cyclic ketones such as 1-tetralone, when substituted at the C-2 position of chromone, gave an excellent yield of 96% for 5p, while with 2-tetralone (5o) 35% product was obtained. This drastic decrease in yield is attributed to the steric hindrance of the ring. The presence of heterocycles, such as furan in the substrate, gave 94% of the product 5q, while the thiophene-substituted product 5r came out to be 74% (Scheme [3]).

The mechanistic pathway for the synthesis of 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones 5 involved a nucleophilic substitution reaction at the C-2 position of 2-(methylthio)-4H-chromen-4-one (4.) The reaction proceeds via proton abstraction from arylmethyl ketone under basic conditions to generate a carbanion A. The overall generation of carbanion/enolates in the reaction proceeds due to the difference in the dissociation constants of the base and acetophenone in DMSO solvent. In situ generated A in turn attacks at the C-2 position of chromone 4 via 1,4-Michael addition to form an adduct or intermediate B. The intermediate enolate B on reversal of negative charge provides the elimination of potassium methanethiolate to produce 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones 5 (Scheme [4]). The complete conversion involves addition followed by elimination reaction.

In summary, we have developed a convenient stepwise methodology to construct a series of 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones in moderate to good yields by the aromatic nucleophilic substitution reaction of arylmethyl ketones with 2-(methylthio)-4H-chromen-4-one under basic conditions in DMSO.[15] This facile metal-free approach operates at 25 °C, demonstrates wide scope and good functional group tolerance, as various enolizable aromatic ketones having diverse functional groups participated to produce the corresponding 2-(2-oxo-2-arylethyl)-4H-chromen-4-ones in moderate to good yields.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank the University of Delhi for providing the instrumentation facility.

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• 15 1-[2-(Benzyloxy)phenyl]-3,3-bis(methylthio)prop-2-ene-1-one (3); General Procedure To a stirred solution containing NaH (20 mmol) in THF (20 ml) placed in ice cold water was added dropwise a solution of protected 2-hydroxy acetophenone (5 mmol). The addition continued for 15 min, and then the reaction mixture was stirred for another 15 min. Subsequently, a solution of carbon disulfide (6.5 mmol) in 5.0 mL of THF was added dropwise over 15 min at a constant temperature of less than 5 °C, and the reaction mixture was again kept stirred for 15 min. A solution containing methyl iodide (11 mmol) in 5.0 mL of THF was added to the reaction mixture in 15 min. The temperature of the resultant reaction mixture was maintained at 0–5 °C, and stirring was continued for 18 h at room temperature. Completion of the reaction was monitored by TLC. After completion, THF was removed under vacuum, followed by the addition of ice-cold water and stirred well. The formed solid was filtered and washed with water (2 × 25 mL). The compound was recrystallized for purification using hexane and ethyl acetate as solvent. 2-(Methylthio)-4H-chromen-4-one (4) To a 10 mL Schlenk tube, 0.5 mmol of 3, 2 mL of DCE (0.25 mmol), and iodine were added, and the reaction was closed well and stirred for 3 h at 80 °C. After completion, the reaction was quenched with 3% Na₂S₂O₃ (5 mL), diluted with brine (10 mL), and extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and crude product was purified through silica gel column chromatography using 10% EtOAc/hexane to afford the desired chromone. 2-(2-Oxo-2-arylethyl)-4H-chromen-4-ones 5a–r; General Procedure A solution containing 0.5 mmol of 4, 0.75 mmol of arylmethyl ketone, 0.5 mmol of KOH in DMSO (2 mL) was stirred at 25 °C for 3 h. After the completion of reaction, which was indicated by TLC, the reaction mixture was poured onto ice-cold water and then neutralized by using 10% HCl solution. The resultant solution was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified through silica gel column chromatography using 15–30% EtOAc/hexane as eluent. 2-(2-Oxo-2-phenylethyl)-4H-chromen-4-one (5a) Yield 75% (100 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 145 °C. IR (KBr): 1714, 1681.9, 1593.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.29 (s, 2 H), 6.31 (s,1 H), 7.36–7.41 (m, 2 H), 7.51 (t, 2 H), 7.63 (t, 2 H), 8.01 (d, 2 H), 8.18 (d, 2 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91, 117.85, 123.65, 125.18, 125.70, 128.37, 128.92, 133.64, 134.03, 135.85, 156.62, 162.19, 177.92, 192.86. HRMS (ESI): m/z calcd for C₁₇H₁₃O₃: 265.0859 [M + H]⁺; found: 265.0859. 2-[2-Oxo-2-(p-tolyl)ethyl]-4H-chromen-4-one (5b) Yield 93% (130 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 70 °C. IR (KBr): 1639.4, 1681.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.42 (s, 3 H), 4.25 (s, 2 H), 6.29 (s,1 H), 7.29 (d, 2 H), 7.35–7.40 (m, 2 H), 7.62 (t, 1 H), 7.90 (d, 2 H), 8.16 (dd, 1 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 21.68, 44.08, 112.80, 117.93, 123.57, 125.11, 125.60, 128.55, 129.57, 133.25, 133.60, 145.06, 156.48, 162.61, 177.95, 192.50. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1021. 2-(1-Oxo-1-phenylpropan-2-yl)-4H-chromen-4-one (5c) Yield 93% (130 mg); R_f = 0.25 (20% ethyl acetate–hexane); yellow liquid. IR (KBr) 1638, 1680.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 1.64 (d, J = 7.0 Hz, 3 H), 4.69 (q, J = 7.1 Hz, 1 H), 6.34 (s, 1 H), 7.40–7.36 (m, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.64–7.56 (m, 2 H), 8.01 (d, J = 7.3 Hz, 2 H), 8.15 (d, J = 7.8 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 15.37, 46.73, 110.53, 117.93, 123.65, 125.25, 125.68, 128.41, 128.61, 128.89, 130.11, 133.71, 133.75, 135.57, 156.27, 167.48, 178.09, 196.14 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1019. 2-[2-(1,1′-Biphenyl)-4-yl]-2-oxoethyl)-4H-chromen-4-one (5d) Yield 47% (80 mg); R_f = 0.25 (30% ethyl acetate–hexane); yellow solid; mp 181 °C. IR (KBr): 1602.8, 1654.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.32 (s, 2 H), 6.34 (s, 1 H), 7.36–7.40 (m, 3 H), 7.84 (t, 2 H), 7.63 (d, 3 H), 7.72 (d, 2 H), 8.09 (d, 2 H),8.17–8.20 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.17, 112.85, 117.92, 123.57, 125.16, 125.62, 127.22, 127.45, 128.46, 129.04, 133.64, 134.35, 139.37, 146.63, 156.48, 162.44, 178.16, 192.29. HRMS (ESI): m/z calcd for C₂₃H₁₇O₃: 341.1172 [M + H]⁺; found: 341.1180. 2-[2-(4-Methoxyphenyl)-2-oxoethyl]-4H-chromen-4-one (5e) Yield 68% (100 mg); R_f = 0.24 (40% ethyl acetate–hexane); yellow solid; mp 119 °C. IR (KBr): 1643, 1681 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 3.87 (s, 3 H), 4.23 (s, 2 H), 6.29 (s, 1 H), 6.95 (d, 2 H), 7.34–7.39 ( m, 2 H), 7.61 (t, 1 H), 7.98 (d, 2 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.89, 55.52, 112.71, 114.02, 117.92, 123.42, 125.10, 125.57, 128.72, 130.60, 133.59, 156.47, 162.81, 164.12, 177.98, 191.35. HRMS (ESI): m/z calcd for C₁₈H₁₅O₄: 295.0965 [M + H]⁺; found: 295.0973. 2-[2-Oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (5f) Yield 65% (115 mg); R_f = 0.25 (50% ethyl acetate–hexane); white solid; mp 157 °C. IR (KBr): 1126.4, 1647.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = ¹H NMR (400 MHz, CDCl₃): δ = 3.93 (s, 10 H), 4.27 (s, 2 H), 6.32 (s, 1 H), 7.26 (s, 3 H), 7.39 (s, 2 H), 7.64 (s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.80, 56.04, 61.10, 106.06, 112.58, 117.87, 123.59, 125.26, 125.68, 130.79, 133.73, 143.44, 153.07, 156.50,162.61, 177.98, 191.60. HRMS (ESI): m/z calcd for C₂₀H₁₉O₆: 355.1176 [M + H]⁺; found: 355.1170. 2-[2-(4-Fluorophenyl)-2-oxoethyl)-4H-chromen-4-one (5g) Yield 75% (105 mg); R_f = 0.25 (22% ethyl acetate–hexane); white solid; mp 114 °C. IR (KBr): 1681, 1593 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.17 (t, 2 H), 7.37 (d, 2 H), 7.63 (t, 1 H), 8.04 (dd, 2 H), 8.16 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.32, 112.88, 115.92, 116.22, 117.89, 123.59, 125.20, 125.65, 128.79, 131.12, 131.21, 132.22, 133.67, 156.55, 162.07, 164.84, 167.46, 177.84, 191.29. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃F: 283.0765 [M + H]⁺; found: 283.0772. 2-[2-(4-Chlorophenyl)-2-oxoethyl)-4H-chromen-4-one (5h) Yield 70% (100 mg); R_f = 0.28 (15% ethyl acetate–hexane); white solid; mp 109 °C. IR (KBr): 1688.2, 1590 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.30 (s, 1 H), 7.38 (m, 2 H), 7.48 (d, 2 H), 7.63 (t, 1 H), 7.95 (d, 2 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.39, 112.93, 117.91, 123.60, 125.26, 125.70, 129.27, 129.83, 133.72, 134.07, 140.63, 156.63, 161.86, 177.70, 191.71. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Cl: 299.0469 [M + H]⁺; found: 299.0475. 2-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-4H-chromen-4-one (5i) Yield 96% (160 mg); R_f = 0.29 (40% ethyl acetate–hexane); yellow solid; mp 161 °C. IR (KBr): 1317.3, 1614 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.31 (s, 2 H), 6.29 (s, 1 H), 7.34–7.40 (m, 3 H), 7.47 (d, 1 H), 7.57 (d, 1 H), 7.64 (dt, 1 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.74, 112.97, 117.88, 123.57, 125.29, 125.71, 127.68, 130.76, 132.47, 133.99, 135.60, 138.55, 156.42, 161.15, 177.73, 194.21. HRMS (ESI): m/z calcd for C₁₇H₁₁O₃Cl₂: 333.0080 [M + H]⁺; found: 333.0086. 2-[2-(4-Bromophenyl)-2-oxoethyl-4H-chromen-4-one (5j) Yield 82% (140 mg); R_f = 0.26 (20% ethyl acetate–hexane); white solid; mp 148 °C. IR (KBr): 1651, 1687.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.25 (s, 2 H), 6.30(s, 1 H), 7.37–7.40 (m, 2 H), 7.61–7.66 (m, 3 H), 7.88 (d, 2 H), 8.17 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.11, 112.94, 117.90, 123.59, 125.26, 125.70, 129.41, 129.89, 132.28, 133.73, 134.44, 156.48, 161.91, 177.87, 191.93. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9969. 2-[2-(2-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5k) Yield 59% (100 mg); R_f = 0.12 (30% ethyl acetate–hexane); pale yellow solid; mp 107 °C. IR (KBr): 1666, 1698 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.22 (s, 2 H), 6.25 (s, 1 H), 7.33–7.24 (m, 4 H), 7.44 (dd, J = 7.6, 1.8 Hz, 1 H), 7.58–7.55 (m, 2 H), 8.08 (dd, J = 7.9, 1.5 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.20, 112.74, 117.80, 118.78, 123.36, 125.07, 125.40, 127.52, 128.80, 132.36, 133.60, 133.81, 139.68, 156.24, 161.32, 177.39, 196.34. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9966. 2-[2-(3-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5l) Yield 76% (130 mg); R_f = 0.26 (30% ethyl acetate–hexane); pale yellow solid; mp 115 °C. IR (KBr): 1645, 1695 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.36–7.41 (m, 3 H), 7.63 (dt, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.13 (t, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.14, 112.96, 117.74, 123.23, 123.54, 125.24, 125.65, 126.91, 130.47, 131.43, 133.73, 136.83, 137.36, 156.45, 161.75, 177.86, 191.61. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9979. 2-[2-Napthalen-1-yl)-2-oxoethyl]-4H-chromen-4-one (5m) Yield 76% (120 mg); R_f = 0.12 (20% ethyl acetate–hexane); bright yellow; mp 118 °C. IR (KBr): 1670, 1643 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.37 (s, 2 H), 6.34 (s, 1 H), 7.30–7.46 (2 H), 7.62–7.50 (m, 4 H), 7.87 (d, J = 7.7 Hz, 1 H), 8.02 (t, J = 8.2 Hz, 2 H), 8.17 (dd, J = 8.0, 1.5 Hz, 1 H), 8.74 (d, J = 8.7 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 46.94, 76.68, 77.00, 77.32, 112.81, 117.87, 123.51, 124.19, 125.11, 125.56, 126.72, 128.52, 128.79, 130.20, 133.61, 133.92, 134.02, 156.41, 162.50, 177.92, 196.07. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1023. 2-[2-(Napthalen-2-yl)-2-oxoethyl]-4H-chromen-4-one (5n) Yield 80% (125 mg); R_f = 0.20 (40% ethyl acetate–hexane); white solid; mp 110 °C. IR (KBr): 1681.9, 1645.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.42 (s, 2 H), 6.36 (s, 1 H), 7.35–7.41 (m, 2 H), 7.56–7.65 (m, 3 H), 7.88–7.94 (m, 2 H), 7.98 (d, 1 H), 8.05 (dd, 1 H), 8.18 (dd, 1 H), 8.53 (s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91,117.92, 123.64, 125.16, 125.64, 127.11, 127.82, 129.87, 129.05, 129.62, 130.52, 132.34, 133.64, 135.85, 156.51, 162.47, 177.96, 192.83. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1019. 2-(2-Oxo-1,2,3,4-tetrahydronapthalen-1-yl)-4H-chromen-4-one (5o) Yield 36% (50 mg); R_f = 0.25 (30% ethyl acetate–hexane); orange solid; mp 138 °C. IR (KBr): 1618, 1722.2 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.68–2.76 (m, 1 H), 2.81–2.88 (m, 1 H), 3.08–3.15 (m, 1 H), 3.26–3.34 (m, 1 H), 4.67 (s, 1 H), 6.16 (s, 1 H), 7.15 (d, 1 H), 7.24–7.28 (m, 1 H), 7.31 (s, 1 H), 7.32 (s,1 H), 7.38 (t, 2 H), 7.63 (t, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.82, 37.78, 58.57, 112.53, 118.09, 123.51, 125.32, 125.65, 127.53, 128.30, 128.47, 128.90, 132.24, 133.80, 136.51, 156.22, 164.57, 178.23, 205.22. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1019. 2-(1-Oxo-1,2,3,4-tetrahydronapthalen-2-yl)-4H-chromen-4-one (5p) Yield 96% (140 mg); R_f = 0.25 (36% ethyl acetate–hexane); yellow solid; mp 131 °C. IR (KBr): 1617.3, 1722 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.49 (td, J = 8.9, 4.4 Hz, 1 H), 2.67–2.57 (m, 1 H), 3.17–3.12 (m, 2 H), 3.79 (dd, J = 11.8, 4.5 Hz, 1 H), 6.26 (s, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.56–7.52 (m, 1 H), 7.65–7.61 (m, 1 H), 8.08 (d, J = 7.0 Hz, 1 H), 8.18 (d, J = 9.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.61, 28.49, 53.20, 111.74, 117.84, 123.81, 125.00, 125.66, 127.09, 127.89, 128.87, 131.82, 133.57, 134.12, 143.49, 156.52, 166.05, 177.95, 193.73. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1025. 2-[2-(Furan-2-yl)-2-oxoethyl]-4H-chromen-4-one (5q) Yield 94% (120 mg); R_f = 0.20 (30% ethyl acetate–hexane); white solid; 99 °C. IR (KBr): 1433, 1637, 1678 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.14 (s, 2 H), 6.32 (s, 1 H), 6.59 (dd, 1 H), 7.32–7.41 (m, 2 H), 7.61 (dd,1 H), 7.63 (m, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.97, 112.90, 117.96, 118.55, 123.59, 125.18, 125.63, 133.68, 147.24, 151.74, 156.47, 161.67, 177.62, 181.73. HRMS (ESI): m/z calcd for C₁₅H₁₁O₄: 255.0652 [M + H]⁺; found: 255.0659. 2-[2-Oxo-2-(thiophen-2-yl)]-4H-chromen-4-one (5r) Yield 74% (100 mg); R_f = 0.22 (28% ethyl acetate–hexane); brown solid; mp137 °C. IR (KBr): 1631, 1660.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.20 (s, 2 H), 6.32 (s, 1 H), 7.17 (t, 1 H), 7.34–7.40 (m, 2 H), 7.62 (t, 1 H), 7.72 (dd, 1 H), 7.82 (dd, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 45.03, 112.76, 117.92, 123.53, 125.18, 125.70, 128.44, 132.98, 133.68, 135.25, 142.78, 156.26, 161.97, 177.87, 185.44. HRMS (ESI): m/z calcd for C₁₅H₁₁O₃S: 271.0423 [M + H]⁺; found: 271.0433.

Corresponding Authors

Publication History

Received: 28 February 2025

Accepted after revision: 07 April 2025

Accepted Manuscript online:
07 April 2025

Article published online:
20 May 2025

© 2025. Thieme. All rights reserved

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• 15 1-[2-(Benzyloxy)phenyl]-3,3-bis(methylthio)prop-2-ene-1-one (3); General Procedure To a stirred solution containing NaH (20 mmol) in THF (20 ml) placed in ice cold water was added dropwise a solution of protected 2-hydroxy acetophenone (5 mmol). The addition continued for 15 min, and then the reaction mixture was stirred for another 15 min. Subsequently, a solution of carbon disulfide (6.5 mmol) in 5.0 mL of THF was added dropwise over 15 min at a constant temperature of less than 5 °C, and the reaction mixture was again kept stirred for 15 min. A solution containing methyl iodide (11 mmol) in 5.0 mL of THF was added to the reaction mixture in 15 min. The temperature of the resultant reaction mixture was maintained at 0–5 °C, and stirring was continued for 18 h at room temperature. Completion of the reaction was monitored by TLC. After completion, THF was removed under vacuum, followed by the addition of ice-cold water and stirred well. The formed solid was filtered and washed with water (2 × 25 mL). The compound was recrystallized for purification using hexane and ethyl acetate as solvent. 2-(Methylthio)-4H-chromen-4-one (4) To a 10 mL Schlenk tube, 0.5 mmol of 3, 2 mL of DCE (0.25 mmol), and iodine were added, and the reaction was closed well and stirred for 3 h at 80 °C. After completion, the reaction was quenched with 3% Na₂S₂O₃ (5 mL), diluted with brine (10 mL), and extracted with DCM (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and crude product was purified through silica gel column chromatography using 10% EtOAc/hexane to afford the desired chromone. 2-(2-Oxo-2-arylethyl)-4H-chromen-4-ones 5a–r; General Procedure A solution containing 0.5 mmol of 4, 0.75 mmol of arylmethyl ketone, 0.5 mmol of KOH in DMSO (2 mL) was stirred at 25 °C for 3 h. After the completion of reaction, which was indicated by TLC, the reaction mixture was poured onto ice-cold water and then neutralized by using 10% HCl solution. The resultant solution was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and purified through silica gel column chromatography using 15–30% EtOAc/hexane as eluent. 2-(2-Oxo-2-phenylethyl)-4H-chromen-4-one (5a) Yield 75% (100 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 145 °C. IR (KBr): 1714, 1681.9, 1593.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.29 (s, 2 H), 6.31 (s,1 H), 7.36–7.41 (m, 2 H), 7.51 (t, 2 H), 7.63 (t, 2 H), 8.01 (d, 2 H), 8.18 (d, 2 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91, 117.85, 123.65, 125.18, 125.70, 128.37, 128.92, 133.64, 134.03, 135.85, 156.62, 162.19, 177.92, 192.86. HRMS (ESI): m/z calcd for C₁₇H₁₃O₃: 265.0859 [M + H]⁺; found: 265.0859. 2-[2-Oxo-2-(p-tolyl)ethyl]-4H-chromen-4-one (5b) Yield 93% (130 mg); R_f = 0.25 (30% ethyl acetate–hexane); white solid; mp 70 °C. IR (KBr): 1639.4, 1681.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.42 (s, 3 H), 4.25 (s, 2 H), 6.29 (s,1 H), 7.29 (d, 2 H), 7.35–7.40 (m, 2 H), 7.62 (t, 1 H), 7.90 (d, 2 H), 8.16 (dd, 1 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 21.68, 44.08, 112.80, 117.93, 123.57, 125.11, 125.60, 128.55, 129.57, 133.25, 133.60, 145.06, 156.48, 162.61, 177.95, 192.50. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1021. 2-(1-Oxo-1-phenylpropan-2-yl)-4H-chromen-4-one (5c) Yield 93% (130 mg); R_f = 0.25 (20% ethyl acetate–hexane); yellow liquid. IR (KBr) 1638, 1680.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 1.64 (d, J = 7.0 Hz, 3 H), 4.69 (q, J = 7.1 Hz, 1 H), 6.34 (s, 1 H), 7.40–7.36 (m, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.64–7.56 (m, 2 H), 8.01 (d, J = 7.3 Hz, 2 H), 8.15 (d, J = 7.8 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 15.37, 46.73, 110.53, 117.93, 123.65, 125.25, 125.68, 128.41, 128.61, 128.89, 130.11, 133.71, 133.75, 135.57, 156.27, 167.48, 178.09, 196.14 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₁₅O₃: 279.1016 [M + H]⁺; found: 279.1019. 2-[2-(1,1′-Biphenyl)-4-yl]-2-oxoethyl)-4H-chromen-4-one (5d) Yield 47% (80 mg); R_f = 0.25 (30% ethyl acetate–hexane); yellow solid; mp 181 °C. IR (KBr): 1602.8, 1654.9 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.32 (s, 2 H), 6.34 (s, 1 H), 7.36–7.40 (m, 3 H), 7.84 (t, 2 H), 7.63 (d, 3 H), 7.72 (d, 2 H), 8.09 (d, 2 H),8.17–8.20 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.17, 112.85, 117.92, 123.57, 125.16, 125.62, 127.22, 127.45, 128.46, 129.04, 133.64, 134.35, 139.37, 146.63, 156.48, 162.44, 178.16, 192.29. HRMS (ESI): m/z calcd for C₂₃H₁₇O₃: 341.1172 [M + H]⁺; found: 341.1180. 2-[2-(4-Methoxyphenyl)-2-oxoethyl]-4H-chromen-4-one (5e) Yield 68% (100 mg); R_f = 0.24 (40% ethyl acetate–hexane); yellow solid; mp 119 °C. IR (KBr): 1643, 1681 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 3.87 (s, 3 H), 4.23 (s, 2 H), 6.29 (s, 1 H), 6.95 (d, 2 H), 7.34–7.39 ( m, 2 H), 7.61 (t, 1 H), 7.98 (d, 2 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.89, 55.52, 112.71, 114.02, 117.92, 123.42, 125.10, 125.57, 128.72, 130.60, 133.59, 156.47, 162.81, 164.12, 177.98, 191.35. HRMS (ESI): m/z calcd for C₁₈H₁₅O₄: 295.0965 [M + H]⁺; found: 295.0973. 2-[2-Oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (5f) Yield 65% (115 mg); R_f = 0.25 (50% ethyl acetate–hexane); white solid; mp 157 °C. IR (KBr): 1126.4, 1647.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = ¹H NMR (400 MHz, CDCl₃): δ = 3.93 (s, 10 H), 4.27 (s, 2 H), 6.32 (s, 1 H), 7.26 (s, 3 H), 7.39 (s, 2 H), 7.64 (s, 1 H), 8.18 (d, J = 8.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.80, 56.04, 61.10, 106.06, 112.58, 117.87, 123.59, 125.26, 125.68, 130.79, 133.73, 143.44, 153.07, 156.50,162.61, 177.98, 191.60. HRMS (ESI): m/z calcd for C₂₀H₁₉O₆: 355.1176 [M + H]⁺; found: 355.1170. 2-[2-(4-Fluorophenyl)-2-oxoethyl)-4H-chromen-4-one (5g) Yield 75% (105 mg); R_f = 0.25 (22% ethyl acetate–hexane); white solid; mp 114 °C. IR (KBr): 1681, 1593 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.17 (t, 2 H), 7.37 (d, 2 H), 7.63 (t, 1 H), 8.04 (dd, 2 H), 8.16 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.32, 112.88, 115.92, 116.22, 117.89, 123.59, 125.20, 125.65, 128.79, 131.12, 131.21, 132.22, 133.67, 156.55, 162.07, 164.84, 167.46, 177.84, 191.29. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃F: 283.0765 [M + H]⁺; found: 283.0772. 2-[2-(4-Chlorophenyl)-2-oxoethyl)-4H-chromen-4-one (5h) Yield 70% (100 mg); R_f = 0.28 (15% ethyl acetate–hexane); white solid; mp 109 °C. IR (KBr): 1688.2, 1590 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.30 (s, 1 H), 7.38 (m, 2 H), 7.48 (d, 2 H), 7.63 (t, 1 H), 7.95 (d, 2 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.39, 112.93, 117.91, 123.60, 125.26, 125.70, 129.27, 129.83, 133.72, 134.07, 140.63, 156.63, 161.86, 177.70, 191.71. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Cl: 299.0469 [M + H]⁺; found: 299.0475. 2-[2-(2,4-Dichlorophenyl)-2-oxoethyl]-4H-chromen-4-one (5i) Yield 96% (160 mg); R_f = 0.29 (40% ethyl acetate–hexane); yellow solid; mp 161 °C. IR (KBr): 1317.3, 1614 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.31 (s, 2 H), 6.29 (s, 1 H), 7.34–7.40 (m, 3 H), 7.47 (d, 1 H), 7.57 (d, 1 H), 7.64 (dt, 1 H), 8.17 (d, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.74, 112.97, 117.88, 123.57, 125.29, 125.71, 127.68, 130.76, 132.47, 133.99, 135.60, 138.55, 156.42, 161.15, 177.73, 194.21. HRMS (ESI): m/z calcd for C₁₇H₁₁O₃Cl₂: 333.0080 [M + H]⁺; found: 333.0086. 2-[2-(4-Bromophenyl)-2-oxoethyl-4H-chromen-4-one (5j) Yield 82% (140 mg); R_f = 0.26 (20% ethyl acetate–hexane); white solid; mp 148 °C. IR (KBr): 1651, 1687.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.25 (s, 2 H), 6.30(s, 1 H), 7.37–7.40 (m, 2 H), 7.61–7.66 (m, 3 H), 7.88 (d, 2 H), 8.17 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.11, 112.94, 117.90, 123.59, 125.26, 125.70, 129.41, 129.89, 132.28, 133.73, 134.44, 156.48, 161.91, 177.87, 191.93. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9969. 2-[2-(2-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5k) Yield 59% (100 mg); R_f = 0.12 (30% ethyl acetate–hexane); pale yellow solid; mp 107 °C. IR (KBr): 1666, 1698 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.22 (s, 2 H), 6.25 (s, 1 H), 7.33–7.24 (m, 4 H), 7.44 (dd, J = 7.6, 1.8 Hz, 1 H), 7.58–7.55 (m, 2 H), 8.08 (dd, J = 7.9, 1.5 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 47.20, 112.74, 117.80, 118.78, 123.36, 125.07, 125.40, 127.52, 128.80, 132.36, 133.60, 133.81, 139.68, 156.24, 161.32, 177.39, 196.34. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9966. 2-[2-(3-Bromophenyl)-2-oxoethyl]-4H-chromen-4-one (5l) Yield 76% (130 mg); R_f = 0.26 (30% ethyl acetate–hexane); pale yellow solid; mp 115 °C. IR (KBr): 1645, 1695 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.26 (s, 2 H), 6.29 (s, 1 H), 7.36–7.41 (m, 3 H), 7.63 (dt, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.13 (t, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.14, 112.96, 117.74, 123.23, 123.54, 125.24, 125.65, 126.91, 130.47, 131.43, 133.73, 136.83, 137.36, 156.45, 161.75, 177.86, 191.61. HRMS (ESI): m/z calcd for C₁₇H₁₂O₃Br: 342.9964 [M + H]⁺; found: 342.9979. 2-[2-Napthalen-1-yl)-2-oxoethyl]-4H-chromen-4-one (5m) Yield 76% (120 mg); R_f = 0.12 (20% ethyl acetate–hexane); bright yellow; mp 118 °C. IR (KBr): 1670, 1643 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.37 (s, 2 H), 6.34 (s, 1 H), 7.30–7.46 (2 H), 7.62–7.50 (m, 4 H), 7.87 (d, J = 7.7 Hz, 1 H), 8.02 (t, J = 8.2 Hz, 2 H), 8.17 (dd, J = 8.0, 1.5 Hz, 1 H), 8.74 (d, J = 8.7 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 46.94, 76.68, 77.00, 77.32, 112.81, 117.87, 123.51, 124.19, 125.11, 125.56, 126.72, 128.52, 128.79, 130.20, 133.61, 133.92, 134.02, 156.41, 162.50, 177.92, 196.07. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1023. 2-[2-(Napthalen-2-yl)-2-oxoethyl]-4H-chromen-4-one (5n) Yield 80% (125 mg); R_f = 0.20 (40% ethyl acetate–hexane); white solid; mp 110 °C. IR (KBr): 1681.9, 1645.2 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.42 (s, 2 H), 6.36 (s, 1 H), 7.35–7.41 (m, 2 H), 7.56–7.65 (m, 3 H), 7.88–7.94 (m, 2 H), 7.98 (d, 1 H), 8.05 (dd, 1 H), 8.18 (dd, 1 H), 8.53 (s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 44.19, 112.91,117.92, 123.64, 125.16, 125.64, 127.11, 127.82, 129.87, 129.05, 129.62, 130.52, 132.34, 133.64, 135.85, 156.51, 162.47, 177.96, 192.83. HRMS (ESI): m/z calcd for C₂₁H₁₅O₃: 315.1016 [M + H]⁺; found: 315.1019. 2-(2-Oxo-1,2,3,4-tetrahydronapthalen-1-yl)-4H-chromen-4-one (5o) Yield 36% (50 mg); R_f = 0.25 (30% ethyl acetate–hexane); orange solid; mp 138 °C. IR (KBr): 1618, 1722.2 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.68–2.76 (m, 1 H), 2.81–2.88 (m, 1 H), 3.08–3.15 (m, 1 H), 3.26–3.34 (m, 1 H), 4.67 (s, 1 H), 6.16 (s, 1 H), 7.15 (d, 1 H), 7.24–7.28 (m, 1 H), 7.31 (s, 1 H), 7.32 (s,1 H), 7.38 (t, 2 H), 7.63 (t, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.82, 37.78, 58.57, 112.53, 118.09, 123.51, 125.32, 125.65, 127.53, 128.30, 128.47, 128.90, 132.24, 133.80, 136.51, 156.22, 164.57, 178.23, 205.22. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1019. 2-(1-Oxo-1,2,3,4-tetrahydronapthalen-2-yl)-4H-chromen-4-one (5p) Yield 96% (140 mg); R_f = 0.25 (36% ethyl acetate–hexane); yellow solid; mp 131 °C. IR (KBr): 1617.3, 1722 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 2.49 (td, J = 8.9, 4.4 Hz, 1 H), 2.67–2.57 (m, 1 H), 3.17–3.12 (m, 2 H), 3.79 (dd, J = 11.8, 4.5 Hz, 1 H), 6.26 (s, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.40–7.34 (m, 3 H), 7.56–7.52 (m, 1 H), 7.65–7.61 (m, 1 H), 8.08 (d, J = 7.0 Hz, 1 H), 8.18 (d, J = 9.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 27.61, 28.49, 53.20, 111.74, 117.84, 123.81, 125.00, 125.66, 127.09, 127.89, 128.87, 131.82, 133.57, 134.12, 143.49, 156.52, 166.05, 177.95, 193.73. HRMS (ESI): m/z calcd for C₁₉H₁₅O₃: 291.1016 [M + H]⁺; found: 291.1025. 2-[2-(Furan-2-yl)-2-oxoethyl]-4H-chromen-4-one (5q) Yield 94% (120 mg); R_f = 0.20 (30% ethyl acetate–hexane); white solid; 99 °C. IR (KBr): 1433, 1637, 1678 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.14 (s, 2 H), 6.32 (s, 1 H), 6.59 (dd, 1 H), 7.32–7.41 (m, 2 H), 7.61 (dd,1 H), 7.63 (m, 1 H), 8.16 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 43.97, 112.90, 117.96, 118.55, 123.59, 125.18, 125.63, 133.68, 147.24, 151.74, 156.47, 161.67, 177.62, 181.73. HRMS (ESI): m/z calcd for C₁₅H₁₁O₄: 255.0652 [M + H]⁺; found: 255.0659. 2-[2-Oxo-2-(thiophen-2-yl)]-4H-chromen-4-one (5r) Yield 74% (100 mg); R_f = 0.22 (28% ethyl acetate–hexane); brown solid; mp137 °C. IR (KBr): 1631, 1660.7 cm^–1. ¹H NMR (400 MHz CDCl₃): δ = 4.20 (s, 2 H), 6.32 (s, 1 H), 7.17 (t, 1 H), 7.34–7.40 (m, 2 H), 7.62 (t, 1 H), 7.72 (dd, 1 H), 7.82 (dd, 1 H), 8.15 (dd, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 45.03, 112.76, 117.92, 123.53, 125.18, 125.70, 128.44, 132.98, 133.68, 135.25, 142.78, 156.26, 161.97, 177.87, 185.44. HRMS (ESI): m/z calcd for C₁₅H₁₁O₃S: 271.0423 [M + H]⁺; found: 271.0433.

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