8-Iodo-4-methyl-2-oxo-2H-chromen-7-yl Benzenesulfonate

Abstract

We report a straightforward and efficient synthesis of 4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate (3a) and 8-iodo-4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate (3b) in good yields through an O-sulfonylation reaction of 7-hydroxy-2H-chromen-2-ones 1a and 1b with benzenesulfonyl chloride 2 mediated by triethylamine in dichloromethane at ambient temperature. The aryl sulfonyl esters were characterized using spectroscopic, spectrometric, and thermal analyses.

1. Introduction

The versatile properties of coumarins, whether synthetic or natural, have garnered growing interest among researchers in medicinal chemistry and drug design, owing to their broad spectrum of biological and pharmacological activities [1,2,3]. Structurally, coumarin consists of a benzene ring fused to an α-pyrone ring. Among its derivatives known for their intriguing anticancer properties are 7-hydroxycoumarins, with umbelliferone, a natural product, being a prominent member of this family [4,5]. However, there has been limited exploration into functionalizing 7-hydroxycoumarins in recent years [6]. We find this surprising given the high reactivity of the OH group at the C–7 position of coumarins, which is conducive to simple and efficient O-acylation [7], O-alkylation [8], and O-sulfonylation processes [9]. Notably, among these, the O-sulfonylation reaction has received minimal attention.

Therefore, we focused on synthesizing 4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonates 3a and 3b via an O-sulfonylation reaction between 7-hydroxy-4-methyl-2H-chromen-2-one 1a and 1b and benzenesulfonyl chloride 2 in the presence of a base (Scheme 1). Compound 3b has not been reported in the Reaxys database, whereas procedures for synthesizing compound 3a were reported in 1941 and 1958, using sodium ethoxide in ethanol and potassium carbonate in acetone, respectively [10,11]. In 1986, a patent described the synthesis of compound 3a in 81% yield, and its characterization was based solely on elemental analysis [12]. In 2008, compound 3a was synthesized employing an excess of pyridine as both the base and solvent, kept at 5–10 °C with stirring for 30 min, and subsequently analyzed by X-ray crystallography [13]. However, these reports did not include crucial information on spectroscopic, spectrometric, and thermal analyses. Therefore, we devised a novel procedure using a slight excess of triethylamine in dichloromethane at ambient temperature, with stirring for 1 h, resulting in the synthesis of aryl sulfonyl esters 3a and 3b in 77% and 82% yields, respectively (Scheme 1). Furthermore, our investigation offers valuable insights into their spectroscopic, spectrometric, and thermal properties. Remarkably, this research was conducted by three undergraduate students over 16 weeks, dedicating 3 h per week to laboratory work. This opportunity significantly enhanced their comprehension of structural analysis and synthesis techniques as part of two electives in the Chemistry Program at the Universidad Pedagógica y Tecnológica de Colombia.

2. Results and Discussion

Building on our previous investigations on the functionalization of hydroxy heterocyclic compounds [14,15], we have successfully synthesized 7-hydroxy-4-methyl-2H-chromen-2-one 1a in 72% yield using a previously reported Pechmann condensation protocol [16]. Subsequently, regioselective iodation at the C–8 position of compound 1a produced 7-hydroxy-8-iodo-4-methyl-2H-chromen-2-one 1b in 79% yield [17]. We then developed a straightforward and efficient protocol for synthesizing 4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate 3a by the O-sulfonylation of 7-hydroxy-4-methyl-2H-chromen-2-one 1a with benzenesulfonyl chloride 2 in the presence of triethylamine in dichloromethane at ambient temperature with stirring for 1 h (Scheme 1). After evaporating the dichloromethane under vacuum, the crude material was purified via column chromatography on silica gel using dichloromethane as the eluent to furnish compound 3a in 77% yield. We applied the same procedure to starting material 1b to afford 8-iodo-4-methyl-2-oxo-2H-chromen-7-yl benzenesulfonate 3b in 82% yield. Finally, the structural characterization of aryl sulfonyl esters 3 was carried out using FT-IR, UV–Vis, NMR, mass spectrometry, DSC, and TGA analyses (See Materials and Methods section).

The infrared spectra confirmed the O-sulfonylation of 7-hydroxy-4-methyl-2H-chromen-2-ones 1a and 1b, as evidenced by the disappearance of the O–H stretching vibrations at 3124 and 3150 cm⁻¹, respectively (Figures S5 and S6). The C=O/C–S stretching vibrations of aryl sulfonate esters 3a and 3b were observed at 1734/762 cm⁻¹ and 1728/758 cm⁻¹, respectively. In addition, the asymmetric/symmetric SO₂ stretching vibrations of compounds 3a and 3b were assigned at 1365/1192 cm⁻¹ and 1382/1175 cm⁻¹, respectively. The C–I stretching vibration of compound 3b was assigned at 535 cm⁻¹.

The UV–Vis spectra of 7-hydroxy-4-methyl-2H-chromen-2-ones 1 and aryl sulfonate esters 3 were measured in methanol at a concentration of 15 μM within the range of 200 to 400 nm (Figures S9 and S10). The chemical transformation of the –OH into the –OSO₂Ph group altered the UV–Vis spectra. Specifically, compounds 3a and 3b showed the appearance of bands at 272 nm (ε = 17,250 L·mol⁻¹·cm⁻¹) and 283 nm (ε = 20,147 L·mol⁻¹·cm⁻¹), respectively, attributed to π → π* transitions within the phenyl ring and the sulfonate ester group. When comparing compounds 3a/3b, we observed a slight hypsochromic shift in the bands at 272/283 nm and 311/318 nm, which can be attributed to an increased band gap caused by the electron-withdrawing effect of the iodine atom.

Table 1. NMR assignments and correlations of compound 3a.

Number	δH (Mult, J in Hz)	δC (ppm)	COSY	HMBC
Me	2.39 (s)	18.1	--	H–3 (3J)
2	--	159.2	--	H–3 (2J)
3	6.41 (s)	114.5	--	Me (3J)
4	--	152.6	--	Me (2J)
4a	--	118.9	--	H–5 (2J) Me (3J) H–3 (3J) H–6 (3J) H–8 (3J)
5	7.78 (d, J = 8.4)	127.1	H–6 (3J)	--
6	7.06 (dd, J = 8.6, 2.2)	118.1	H–5 (3J)	H–8 (3J)
7	--	150.6	--	H–6 (2J) H–8 (2J) H–5 (3J)
8	7.12 (d, J = 2.4)	110.3	--	H–6 (3J)
8a	--	153.3	--	H–8 (2J) H–5 (3J)
i	--	133.9	--	Hm (3J)
o	7.92 (dd, J = 8.4, 1.2)	128.3	Hm (3J)	Hm (2J) Hp (3J)
m	7.69 (dd, J = 8.0, 8.0)	130.0	Ho (3J) Hp (3J)	Ho (2J)
p	7.85 (tt, J = 7.4, 1.2)	135.4	Hm (3J)	Ho (3J)

and

Table 2. NMR assignments and correlations of compound 3b.

Number	δH (Mult, J in Hz)	δC (ppm)	COSY	HMBC
Me	2.42 (s)	18.2	--	H–3 (3J)
2	--	159.2	--	H–3 (2J)
3	6.45 (s)	114.8	--	Me (3J)
4	--	152.7	--	Me (2J)
4a	--	119.1	--	Me (3J) H–3 (3J) H–6 (3J)
5	7.84 (d, J = 8.8)	126.8	H–6 (3J)	--
6	7.16 (d, J = 8.8)	117.9	H–5 (3J)	--
7	--	152.0	--	H–6 (2J) H–5 (3J)
8	--	84.0	--	H–6 (3J)
8a	--	153.8	--	H–5 (3J)
i	--	134.7	--	Hm (3J)
o	7.95 (d, J = 7.6)	128.4	Hm (3J)	Hm (2J) Hp (3J)
m	7.71 (dd, J = 7.8, 7.8)	130.1	Ho (3J) Hp (3J)	--
p	7.88 (t, J = 7.4)	135.6	Hm (3J)	Ho (3J)

present the assignment of all proton and carbon signals for aryl sulfonate esters 3a and 3b, respectively. The ¹H NMR analysis of 3a confirmed the presence of the coumarin ring by identifying a singlet at 6.41 ppm corresponding to the H–3 proton, a doublet of doublets at 7.06 ppm (J = 8.6, 2.2 Hz) assigned to the H-6 proton, and two doublets at 7.12 ppm (J = 2.4 Hz) and 7.78 ppm (d, J = 8.4 Hz) corresponding to the H–8 and H–5 protons, respectively. In contrast, the ¹H NMR analysis of 3b did not show the ABX system due to an iodine atom at the eighth position of the coumarin ring. The absence of the OH proton indicates the successful O-sulfonylation process. At the same time, the introduction of the –OSO₂Ph substituent in compound 3a was confirmed by a triplet of triplets at 7.85 ppm (J = 7.4, 1.2 Hz) and two doublets of doublets at 7.69 ppm (J = 8.0, 8.0 Hz) and 7.92 ppm (J = 8.4, 1.2 Hz).

Similarly, compound 3b exhibited a triplet at 7.88 ppm (J = 7.4 Hz), a doublet of doublets at 7.71 ppm (J = 7.8, 7.8 Hz), and a doublet at 7.95 ppm (J = 7.6 Hz). The ¹³C-NMR and DEPT-135 analysis of aryl sulfonate ester 3a revealed one methyl carbon (18.1 ppm), seven aromatic methines (110.3, 114.5, 118.1, 127.1, 128.3, 130.0, and 135.4 ppm), and six quaternary aromatic carbons (118.9, 133.9, 150.6, 152.6, 153.3, and 159.2 ppm). Similarly, the ¹³C-NMR and DEPT-135 analysis of 3b displayed one methyl carbon, six aromatic methines, and seven quaternary aromatic carbons. The presence of the iodine atom in the coumarin ring of 3b caused higher shielding of the C–8 carbon (Cq, 84.0 ppm) compared to the C–8 carbon in the iodine-free coumarin 3a (CH, 110.3 ppm). The analysis of 2D NMR spectra, including HSQC, HMBC, and COSY, allowed for an unambiguous structural assignment.

Principio del formulario The exact masses of the pseudo-molecular ions ([M + H]⁺) and their corresponding elemental formulas, C₁₆H₁₃O₅S⁺ and C₁₆H₁₂IO₅S⁺, were confirmed through high-resolution mass spectrometry, affording mass errors of 2.84 and 0.22 ppm, respectively (Figures S3 and S4).

Aryl sulfonate esters 3a and 3b underwent separate TGA and DSC analyses, as shown in Figures S26 and S27, respectively. The thermal analysis was conducted under a nitrogen atmosphere, spanning temperatures from 25 to 400 °C, maintaining a constant gas flow of 25 mL min⁻¹ and a heating rate of 10 °C min⁻¹. The TGA thermograms of compounds 3a and 3b indicate high thermal stability, as evidenced by the temperature ranges of 274 to 329 °C and 282 to 328 °C, respectively. In addition, the DSC thermograms show endothermic peaks at 115 and 200 °C for compounds 3a and 3b, respectively, suggesting that the melting process involves moderate heat absorption of 89.8 and 78.0 J g⁻¹. Conversely, the exothermic peaks at 350 and 308 °C, accompanied by substantial heat emissions of 173.5 and 147.5 J g⁻¹, likely indicate structural transformations within compounds 3a and 3b, respectively.

3. Conclusions

In summary, we developed a novel protocol for synthesizing aryl sulfonyl esters 3a and 3b with good yields under mild-reaction conditions. Our protocol offers several advantages, including reduced reaction time, operational simplicity, and the use of a slight excess of triethylamine, which can be easily removed under reduced pressure, eliminating the need for an additional extraction process. Additionally, we conducted an extensive characterization of the aryl sulfonyl esters using spectroscopic, spectrometric, and thermal analyses.

4. Materials and Methods

4.1. General Information

The progression of reactions was monitored using Thin Layer Chromatography employing a UV lamp with wavelengths of 254 or 365 nm. Flash column chromatography was performed using silica gel 60 (mesh 230–400) (Alfa Aesar, Tewksbury, MA, USA). An ATR accessory-equipped PerkinElmer FT-IR spectrometer (PerkinElmer, Inc., Waltham, MA, USA) was employed to acquire infrared spectra at room temperature. UV–Vis spectra were obtained from a methanol solution (1.5 × 10⁻⁵ M) using a UV–Vis Evolution 201 spectrophotometer (Thermo Fischer Scientific Inc., Madison, WI, USA). The Bruker Advance 400 spectrophotometer (Bruker BioSpin GmbH, Rheinstetten, Germany) was utilized for acquiring NMR spectra in DMSO-d₆. Chemical shifts are reported in ppm (δ), and coupling constants are expressed in Hz (J). The ¹H and ¹³C NMR spectra were calibrated using the residual non-deuterated signal (δ = 2.50 ppm) and the deuterated solvent signal (δ = 39.52 ppm), respectively. High-resolution mass spectrometry (HRMS) was conducted using a Q-TOF 6520 spectrometer (Agilent Technologies Inc., Santa Clara, CA, USA) with electrospray ionization (ESI, 4000 V). Measurements for both differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were independently performed utilizing the STA7200 thermogravimetry/differential thermal analyzer (Hitachi America Ltd., Santa Clara, CA, USA).

4.2. Synthesis of 7-Hydroxy-4-methyl-2H-chromen-2-one (1a)

Concentrated H₂SO₄ (5.5 mL, 30.0 mmol) was placed under magnetic stirring in an ice bath to maintain the temperature at approximately 0 °C. Meanwhile, a separate solution containing resorcinol (1101 mg, 10.0 mmol) in methyl acetoacetate (1.08 mL, 10.0 mmol) was prepared. This solution was then slowly added drop by drop to the concentrated H₂SO₄ while ensuring the temperature remained at approximately 0 °C and continuous stirring. After completing the addition, stirring continued for 30 min at room temperature. Subsequently, the mixture was poured over crushed ice (approximately 50 g) to afford a solid product. The solid product was dissolved by adding an aqueous solution of NaOH (25.0 mL, 1.0 M), followed by the addition of an HCl solution (6.0 M) drop by drop until the pH reached 2.0. The precipitate was filtered, washed with distilled water (5.0 mL), and purified by recrystallization using ethanol (10.0 mL). Subsequently, the precipitate was filtered, washed with cold ethanol (5.0 mL), and dried to yield compound 1a as a brown solid (1268 mg, 72%). M.p. 186–187 °C (Lit. 187–189 °C) [3]. FTIR–ATR: ν = 3124 (ν O–H), 3011, 2886, 2805, 1673 (ν C=O), (1591 and 1571, ν C=C), 1391, 1272, (1237 and 1212, ν C–O–C), 1067 (ν C–O–C), 981, 844, 745, 693, 641, 583 cm⁻¹. UV–Vis (Methanol, 15 μM) λ_max (ε, L·mol⁻¹·cm⁻¹): 202 (47,449, π → π*), 216 (16,417, π → π*), 322 (14,559, π → π* and n → π*) nm. ¹H NMR (400 MHz, DMSO-d₆) δ = 2.35 (s, 3H), 6.11 (s, 1H), 6.70 (d, J = 1.2 Hz, 1H), 6.79 (dd, J = 8.8, 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.4 Hz, 1H), 10.52 (br s, 1H, OH) ppm. ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 18.1 (CH₃), 102.2 (CH), 110.3 (CH), 112.0 (Cq), 112.9 (CH), 126.6 (CH), 153.5 (Cq), 154.8 (Cq), 160.3 (Cq), 161.2 (Cq) ppm. HRMS (ESI+): calcd for C₁₀H₉O₃⁺, 177.0546 [M + H]⁺; found, 177.0543. These NMR data match previously reported data [3].

4.3. Synthesis of 7-Hydroxy-8-iodo-4-methyl-2H-chromen-2-one (1b)

7-Hydroxy-4-methyl-2H-chromen-2-one 1a (440 mg, 2.50 mmol) was dissolved in 2.0 mL of aqueous ammonium hydroxide (5.3 M). A solution of iodine (634 mg, 2.50 mmol) in 20.0 mL of aqueous potassium iodide (0.32 M) was then added dropwise. The reaction mixture was stirred at room temperature for 2 h. Then, aqueous hydrochloric acid (2.9 M) was added dropwise until the pH reached 2.0. The resulting precipitate was filtered, washed with distilled water (5.0 mL), and purified by recrystallization from ethanol (10.0 mL). Subsequently, the precipitate was filtered again, washed with cold ethanol (5.0 mL), and dried to yield compound 1b as a yellow solid (596 mg, 79%). M.p. 231–233 °C (Lit. 234–236 °C) [17]. FTIR–ATR: ν = 3150 (ν O–H), 3011, 2886, 2805, 1682 (ν C=O), 1598 (ν C=C), 1381, 1308, (1247 and 1226, ν C–O–C), (1079 and 1045, ν C–O–C), 1004, 908, 851, 809, 756, 702, 600, 538 (ν C–I) cm⁻¹. UV–Vis (Methanol, 15 μM) λ_max (ε, L·mol⁻¹·cm⁻¹): 204 (59,237, π → π*), 265 (9543, π → π*), 322 (20,711, π → π* and n → π*) nm. ¹H NMR (400 MHz, DMSO-d₆) δ = 2.37 (s, 3H), 6.18 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 11.36 (br s, 1H, OH) ppm. ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 18.2 (CH₃), 74.6 (Cq), 110.7 (CH), 111.6 (CH), 112.8 (Cq), 126.4 (CH), 153.6 (Cq), 154.3 (Cq), 160.0 (Cq), 161.0 (Cq) ppm. HRMS (ESI+): calcd for C₁₀H₈IO₃⁺, 302.9513 [M + H]⁺; found, 302.9508. These NMR data match previously reported data [17].

4.4. Synthesis of 4-Methyl-2-oxo-2H-chromen-7-yl Benzenesulfonate (3a)

A mixture of 7-hydroxy-4-methyl-2H-chromen-2-one 1a (100 mg, 0.57 mmol), benzenesulfonyl chloride 2 (87 µL, 0.68 mmol), and triethylamine (95 µL, 0.68 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 1 h. Subsequently, the solvent was removed under vacuum pressure, and the solid was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to yield compound 3a as a colorless solid (139 mg, 77%). M.p. 113–114 °C (Lit. 104–105 °C and 107–108 °C) [10,11]. FTIR–ATR: ν = 3106, 3078, 2882, 2812, 1734 (ν C=O), (1627 and 1609, ν C=C), 1492, 1447, 1365 (ν_a SO₂), 1259 (ν C–O–C), 1192 (ν_s SO₂), 1175, 1150, 1118, 1089, 1065 (ν C–O–C), 978, 887, 862, 837, 762 (ν C–S), 687, 631, 582, 567, 529 cm⁻¹. UV–Vis (Methanol, 15 μM) λ_max (ε, L·mol⁻¹·cm⁻¹): 202 (56,732, π → π*), 211 (42,543, π → π*), 272 (17,250, π → π*), 311 (12,822, π → π* and n → π*) nm. ¹H NMR (400 MHz, DMSO-d₆) δ = 2.39 (s, 3H, CH₃), 6.41 (s, 1H, H–3), 7.06 (dd, J = 8.6, 2.2 Hz, 1H, H–6), 7.12 (d, J = 2.4 Hz, 1H, H–8), 7.69 (dd, J = 8.0, 8.0 Hz, 2H, Hm), 7.78 (d, J = 8.4 Hz, 1H, H–5), 7.85 (tt, J = 7.4, 1.2 Hz, 1H, Hp), 7.92 (dd, J = 8.4, 1.2 Hz, 2H, Ho) ppm. ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 18.1 (CH₃), 110.3 (CH, C–8), 114.5 (CH, C–3), 118.1 (CH, C–6), 118.9 (Cq, C–4a), 127.1 (CH, C–5), 128.3 (2CH, Co), 130.0 (2CH, Cm), 133.9 (Cq, Ci), 135.4 (CH, Cp), 150.6 (Cq, C–7), 152.6 (Cq, C–4), 153.3 (Cq, C–8a), 159.2 (Cq, C–2) ppm. HRMS (ESI+): calcd for C₁₆H₁₃O₅S⁺, 317.0478 [M + H]⁺; found, 317.0487.

4.5. Synthesis of 8-Iodo-4-methyl-2-oxo-2H-chromen-7-yl Benzenesulfonate (3b)

A mixture of 7-hydroxy-8-iodo-4-methyl-2H-chromen-2-one 1b (172 mg, 0.57 mmol), benzenesulfonyl chloride 2 (87 µL, 0.68 mmol), and triethylamine (95 µL, 0.68 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 1 h. Subsequently, the solvent was removed under vacuum pressure, and the solid was purified by flash column chromatography on silica gel using dichloromethane as the mobile phase to yield compound 3b as a colorless solid (207 mg, 82%). FTIR–ATR: ν = 3069, 2982, 1728 (ν C=O), (1621 and 1589, ν C=C), 1447, 1382 (ν_a SO₂), 1261 (ν C–O–C), 1175 (ν_s SO₂), 1079 (ν C–O–C), 1026, 1003, 862, 820, 758 (ν C–S), 734, 683, 627, 576, 535 (ν C–I) cm⁻¹. UV–Vis (Methanol, 15 μM) λ_max (ε, L·mol⁻¹·cm⁻¹): 202 (61,895, π → π*), 283 (20,147, π → π*), 318 (9637, π → π* and n → π*) nm. ¹H NMR (400 MHz, DMSO-d₆) δ = 2.42 (s, 3H, CH₃), 6.45 (s, 1H, H–3), 7.16 (d, J = 8.8 Hz, 1H, H–6), 7.71 (dd, J = 7.8, 7.8 Hz, 2H, Hm), 7.84 (d, J = 8.8 Hz, 1H, H–5), 7.88 (t, J = 7.4 Hz, 1H, Hp), 7.95 (d, J = 7.6 Hz, 2H, Ho) ppm. ¹³C{¹H} NMR (101 MHz, DMSO-d₆): δ = 18.2 (CH₃), 84.0 (Cq, C–8), 114.8 (CH, C–3), 117.9 (CH, C–6), 119.1 (Cq, C–4a), 126.8 (CH, C–5), 128.4 (2CH, Co), 130.1 (2CH, Cm), 134.7 (Cq, Ci), 135.6 (CH, Cp), 152.0 (Cq, C–7), 152.7 (Cq, C–4), 153.8 (Cq, C–8a), 159.2 (Cq, C–2) ppm. HRMS (ESI+): calcd for C₁₆H₁₂IO₅S⁺, 442.9445 [M + H]⁺; found, 442.9446.