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Article

Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications

by
Mei Sun
1,2,†,
Chong-Yang Zeng
1,†,
Lu-Lu Bu
1,
Mai Xu
1,
Kai Chen
1,
Jia-Lin Liu
1,
Tao Zhang
1,
Jia-You Dai
1,
Jia-Xin Hong
3,* and
Ming-Wu Ding
2,*
1
School of Chemistry and Materials Engineering, Huainan Normal University, Huainan 232038, China
2
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University, Wuhan 430079, China
3
College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(11), 2449; https://doi.org/10.3390/molecules29112449
Submission received: 5 April 2024 / Revised: 1 May 2024 / Accepted: 14 May 2024 / Published: 23 May 2024
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

:
A novel metal-free synthesis of 3-substituted isocoumarins through a sequential O-acylation/Wittig reaction has been established. The readily accessible (2-carboxybenzyl)-triphenylphosphonium bromide and diverse chlorides produced various 1H-isochromen-1-one in the presence of triethylamine, employing sequential O-acylation and an intramolecular Wittig reaction of acid anhydride. Reactions using these facile conditions have exhibited high functional group tolerance and excellent yields (up to 90%). Moreover, the fluorescence properties of isocoumarin derivatives were evaluated at the theoretical and experimental levels to determine their potential application in fluorescent materials. These derivatives have good photoluminescence in THF with a large Stokes shift and an absolute fluorescence quantum yield of up to 14%.

Graphical Abstract

1. Introduction

Isocoumarins, especially 3-substituted isocoumarins, constitute an important class of heterocyclic scaffolds owing to their diverse biological activities, including antibacterial [1], enzyme inhibition [2], antifungal [3], and antipheromonal effects [4], as well as anticancer [5] and anti-HIV properties [6]. Additionally, there are important applications in organic light-emitting materials [7,8,9,10,11,12,13]. Given their great importance, substantial efforts have been dedicated to developing new synthetic methods for the preparation of isocoumarins, driven by their potential applications (Scheme 1) [14]. Classical methods for synthesizing these 3-substituted isocoumarins were reported by Barry in 1964, Oliver in 1984, and Pal in 2011 [15,16,17]. These synthetic pathways involved multiple reactions, the use of toxic reagents, and harsh reaction conditions. Subsequently, the synthesis of these molecules gained popularity through metal-catalyzed cyclization (Scheme 1) [18,19,20,21]. For instance, 3-substituted isocoumarins were prepared either by Rh (III)-catalyzed oxidative coupling of benzoic acids with geminal substituted vinyl acetates [18] or by a CuI-catalyzed domino coupling/addition/deacylation process [19]. In addition, 3-substituted isocoumarins were recently found to be reported via sequential Rh(III)-catalyzed C–H activation/annulation [20]. These synthetic methodologies still necessitated the use of hazardous metallic reagents and multipart procedures or exhibited limited functional group tolerance. Furthermore, the same possible synthesis strategy for the construction of the isocoumarin nucleus has hardly been proposed under metal-free conditions (Scheme 1) [22,23]. Consequently, to overcome these limitations and to prepare various isocoumarins, a new metal-free and efficient synthetic method for variable isocoumarins is still desirable in synthetic organic and fluorescent molecule research.
The Wittig reaction is considered to be a powerful method for constructing carbon-carbon unsaturated bonds by converting the C=O double bond of an aldehyde or ketone to a C=C double bond [24,25,26]. Since its discovery more than half a century ago, the Wittig reaction has been widely utilized in organic synthesis due to its simple synthesis, excellent functional group tolerance, and environmental friendliness. Moreover, intramolecular Wittig reactions have been recognized as a valuable strategy for the synthesis of a variety of heterocycles [27,28], although a Wittig reaction involving a variety of carbonyl reagents (e.g., aldehydes, ketones, esters, and amides) has found widespread application in the synthesis of structurally diverse compounds [29,30,31,32]. Intermolecular Wittig reactions incorporating acid anhydrides as carbonyl components have been less commonly reported [33,34]. Continuing our exploration of heterocycle synthesis through Wittig reactions [35,36,37,38,39,40], we propose a novel, metal-free, and efficient method for the synthesis of 3-substituted isocoumarins by O-acylation/Wittig reaction, utilizing readily available (2-carboxybenzyl)triphenylphosphonium bromide 3 as the starting material. Finally, we evaluate the fluorescence properties of isocoumarin derivative 4 at both theoretical and experimental levels to assess its potential application in fluorescent materials.

2. Results and Discussion

The readily accessible starting material (2-carboxybenzyl)triphenylphosphonium bromide 3 was synthesized as depicted in Scheme 2 [35]. In this process, the reaction between 2-methylbenzoic acid 1 and N-Bromosuccinimide (NBS) in CCl4 took place at reflux temperature over a duration of 4–8 h, yielding 2-(bromomethyl)benzoic acid 2 in 80% yield. Next, the 2-(bromomethyl)benzoic acid 2 reacted with triphenylphosphine in acetone at room temperature, producing (2-carboxybenzyl)triphenylphosphonium bromide 3 in 90% yield.
In order to optimize the conditions for the O-acylation–Wittig reaction sequence, (2-carboxybenzyl)triphenylphosphonium bromide 3a and benzoyl chloride were selected as model substrates (Table 1). When the reaction was conducted in the presence of DMAP (2 equiv) in CH2Cl2 at room temperature for 12 h, the expected 3-phenyl-1H-isochromen-1-one 4a was not obtained (Table 1, Entry 1). Subsequently, we screened different bases including NEt3, DBU, t-BuOK, K2CO3, and NaOH (Table 1, Entries 2–6), and the reaction gave comparably better yields of 4a using Et3N (Entry 2, 79%). The suitable basicity of NEt3 may influence both the Wittig reaction and the O-acylation reaction steps. Subsequently, NEt3 was employed as the base to investigate the impact of alternative solvents, including THF, CH3CN, DCE, 1,4-dioxane, and toluene, on the reaction (Table 1, Entries 7–11), the results indicated that 3-phenyl-1H-isochromen-1-one 4a were obtained in the better-isolated yield (79%, Table 1, Entry 2). To examine the temperature-dependent effects on the reaction, toluene was employed as the solvent, and the reaction was conducted at 80 °C or 110 °C for 2–6 h, respectively (Table 1, Entries 12–13). The product was obtained with a higher yield of 82% (Table 1, Entry 13). This suggests that the reaction temperature influences both the reaction rate and the efficacy of the Wittig reaction. Thus, the optimum reaction condition for the preparation of 3-phenyl-1H-isochromen-1-one 4a was found (Table 1, Entry 13).
Under optimal conditions, we initiated an investigation into the reaction’s scope, observing that the yields of product 4 were primarily influenced by the R2 group (Table 2). When R2 was an aromatic moiety (Table 2, compounds 4a–4t), good yields (72–90%) were achieved with various electrono-accepting and electron-withdrawing groups (CH3, t-Bu, CH3O, 3,4,5-(CH3O)3, F, Cl, and Br) on the benzene ring. Notably, compounds were successfully synthesized even with a strong electron-withdrawing group (CF3) on the benzene ring. Furthermore, when R2 comprised an ortho-substituted phenyl group, compounds 4j and 4s were synthesized successfully (Table 2, 75% and 79%). Using Cinnamoyl chloride as an acyl chloride reactant, the preparation of 1H-isochromen-1-ones was also accomplished successfully (Table 2, 4h and 4r). It is noteworthy that R2 consisted of a thiophene ring or naphthalene ring, and both yielded satisfactorily (Table 2, 80-86%, compounds 4k, 4q, and 4t). Moderate yields (60%) were obtained when R2 is an alkyl group, likely due to its relatively lower reactivity (Table 2, compounds 4u). In summary, high functional group tolerance for this reaction was proved.
Based on the presented observation and previous literature reports [27,33,35], Scheme 3 depicts a plausible mechanism for the sequential O-acylation/Wittig process. In the presence of the base NEt3, phosphonium salt 3 is converted into conjugate base 5, which undergoes O-acylation with an acyl chloride to form an anhydride 6. This process releases one equivalent of HBr, which is captured by NEt3. Then, a second equivalent of triethylamine deprotonnates the anhydride 6 to phosphorus ylide 7. This process releases one equivalent of HBr, which is also captured by NEt3. Subsequently, phosphorus ylide 7 undergoes an intramolecular Wittig reaction to form oxaphosphetane intermediate 8, accompanied by [2+2] cycloaddition. Intermediate 8 then converts to 1H isochrom-1-one 4, releasing equimolar amounts of oxygen and phosphorus.
Coumarin, a typical fluorophore, has been widely studied in dyes, pigments, fluorescent probes, and other fields due to its favorable optical properties. Isocoumarins are no exception, owing to their similar conjugated structures. Therefore, to further demonstrate the synthetic utility of our approach, isocoumarin derivatives 4 with different structures were screened to assess their optical properties. Considering the conjugated structure and substituent types of these derivatives, 4a, 4h, 4j, 4k, 4p, and 4u were specially selected as a representative for further investigation (Table 3).
The isocoumarin derivatives exhibit very similar absorption spectra in THF (Figure 1a), with a maximum absorption peak (λa) of about around 280 nm and one or multiple bands in the range of 300–400 nm. The molar extinction coefficients (ε) of these absorption peaks are greater than 104 L·mol−1·cm−1, confirming that intramolecular electron transitions are permitted [41]. The absorption at shorter wavelengths mainly arises from π-π* transition absorption, while the absorption at longer wavelengths is primarily attributed to n-π* transition absorption and intramolecular charge transfer absorption generated by the donor–acceptor (D-A) system [42]. The long-wavelength, lower-energy band absorption is attributed to the transition of the dominant H (HOMO) → L (LUMO), while the maximum absorption peak is mainly attributed to the H → L+1 or H-2 → L+1 transition. The difference in absorption intensity is related to the various oscillator strengths (fosc). Like most molecules, derivatives 4 with larger conjugated structures have larger and broader UV absorption spectra, with 4h > 4a > 4u. Furthermore, fluorescence emission spectra were used to roughly assess the photoluminescence behavior of these compounds (Figure 1b). Their emission wavelengths are primarily concentrated around 420 nm, resulting in purple emission. Notably, the emission wavelength of 4p is 457 nm with blue fluorescence. Their Stokes shift values range from 3978 to 6678 cm−1. This value is comparable to that of most small-molecule fluorescent compounds at this stage [43]. This may facilitate the material’s ability to overcome self-absorption and be effectively applied to probes or imaging. Of course, subsequent studies can also prepare isocoumarin derivatives with larger Stokes shifts by molecular design (i.e., introducing electron-withdrawing groups, extending conjugated systems, etc.) [44]. In THF, the absolute fluorescence quantum yields of 4h can reach 14%, while 4u, with the smallest conjugated structure, exhibits a hardly detectable fluorescence quantum yield.
Additionally, the photophysical properties of isocoumarin derivatives 4 were evaluated at the theoretical level (Figure 2). Structure optimization, frequency calculation, and calculation of the electron cloud distribution of frontier molecular orbitals for isocoumarin derivatives 4 were conducted using Gaussian 09 with the theoretical level of B3LYP, 6-31g (d). From the perspective of optimized structure, almost all molecules maintain good planarity, except for the naphthalene-substituted 4k. The large volume of naphthalene unavoidably leads to distorted dihedral angles. Despite this, the relatively planar structures ensure a certain rigidity, which is conducive to fluorescence emission. The Highest Occupied Molecular Orbital (HOMO) electron cloud of these derivatives is predominantly distributed on the conjugated benzene skeleton, while the Lowest Unoccupied Molecular Orbital (LUMO) exhibits an intramolecular charge transfer (ICT) effect due to the influence of the ester group and electron-withdrawing substitutions (such as -Cl, -CF3, etc.). However, this intramolecular charge transfer (ICT) is relatively weak due to the small size of the structure and the limited separation between electron-withdrawing and electron-donating groups. Therefore, if we aim to modulate the rich fluorescence behavior through ICT (i.e., stimulus-responsive luminescence, etc.), these aspects must be improved upon. From the perspective of the transition band gap, electron-withdrawing groups can effectively reduce the band gap level more, whether they are located on the side group benzene (compared 4b and 4i) or on the fused benzene (compared 4a and 4l). In addition, a larger conjugated structure, compared to compounds 4a with 4k, also significantly reduces the band gap. Indeed, a low band gap is beneficial for electron transition and the improvement of semiconductor properties [45]. In summary, these theoretical data provide the necessary theoretical basis for the subsequent design and development of fluorescent materials derived from isocoumarin.

3. Materials and Methods

3.1. General Information

Melting points were determined using an X-4 model apparatus and were uncorrected. 1H NMR were recorded in CDCl3 on a Varian Mercury 600 spectrometer and resonances were relative to TMS. 13C NMR spectra were recorded in CDCl3 on a Varian Mercury 600 (150 MHz) with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm). HRMS was measured on an Agilent 6224 TOF LC/MS spectrometer. UV-vis absorption spectra were measured on a TU-1901 spectrophotometer. Fluorescence spectra were measured on the F97pro fluorescence spectrometer and HORIBA Fluoromax-4p. Density functional theory (DFT) calculations were conducted to determine the optimized conformation, oscillator strength (fosc), and UV absorption properties at Gaussian 09. The optimized conformation and frequency calculations were performed at the B3LYP/6-31g (d) theoretical level, while the excited state properties were investigated using time-dependent density functional theory (TDDFT) at the B3LYP/6-31g (d) level.

3.2. General Procedure for the Synthesis of 1H-isochromen-1-ones 4

Anhydrous toluene (6 mL), NEt3 (0.28 mL, 2.0 mmol), and (2-carboxybenzyl)triphenylphosphonium bromide 3 (1 mmol) were initially added into a dry reaction flask. Subsequently, acyl chloride (1.1 mmol) in anhydrous toluene (2 mL) was added dropwise over a time period of approximately 30 min. The mixture was maintained at 110 °C for 2–4 h, with the reaction progress monitored by TLC. The solvent was then evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 60:1–15:1, V/V) to yield compound 4.
3-phenyl-1H-isochromen-1-one (4a) [19]. (Rf = 0.65, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.182 g, 82%), mp 84–85 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.28 (d, J = 6.8 Hz, 1H), 7.86 (d, J = 6.0 Hz, 2H), 7.69 (s, 1H), 7.51–7.39 (m, 5H), 6.92 (s, 1H).; 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.27, 153.43, 137.41, 134.84, 131.80, 129.91, 129.51, 128.77, 128.09, 125.97, 125.13, 120.38, 101.77. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C15H11O2 223.0754; found 223.0754.
3-(p-tolyl)-1H-isochromen-1-one (4b) [18]. (Rf = 0.66, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.198 g, 84%), mp 88–89 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.28 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.48–7.43 (m, 2H), 7.25 (d, J = 7.8 Hz, 2H), 6.88 (s, 1H), 2.39 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) δ 162.27, 153.57, 140.07, 137.50, 134.65, 129.39, 129.35, 128.92, 127.71, 125.68, 124.95, 120.15, 100.89, 21.23. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H13O2 237.0910; found 237.0909.
3-(4-fluorophenyl)-1H-isochromen-1-one (4c) [46]. (Rf = 0.64, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.216g, 90%), mp 105–106 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.18 (s, 1H), 7.75 (s, 2H), 7.61 (s, 1H), 7.38 (s, 2H), 7.03 (s, 2H), 6.77 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 164.34, 162.68, 161.97, 152.45, 137.19, 134.78, 129.43, 128.02, 127.07, 127.02, 125.77, 120.10, 115.84, 115.69, 101.38. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C15H10FO2 241.0659; found 241.0646.
3-(4-methoxyphenyl)-1H-isochromen-1-one (4d) [18]. (Rf = 0.61, petroleum ether/ethyl acetate = 8:1, V/V), white solid (yield 0.209 g, 83%), mp 128–129 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.26 (d, J = 7.0 Hz, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.67 (s, 1H), 7.43 (s, 2H), 6.95 (d, J = 7.4 Hz, 2H), 6.80 (s, 1H), 3.84 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 164.76, 163.74, 162.94, 162.44, 161.49, 161.01, 153.63, 137.84, 134.77, 129.54, 127.60, 126.74, 125.66, 124.45, 120.06, 114.18, 100.18, 55.36. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H13O3 253.0859; found 253.0859.
3-(m-tolyl)-1H-isochromen-1-one (4e) [46]. (Rf = 0.67, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.193 g, 82%), mp 100-101 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.28 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 7.2, 4.3 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.91 (s, 1H), 2.40 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.37, 153.72, 140.04, 138.54, 137.55, 134.81, 131.80, 130.73, 129.57, 128.66, 128.01, 125.89, 125.81, 122.33, 120.43, 101.66, 21.42. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H13O2 237.0910; found 237.0910.
3-(4-bromophenyl)-1H-isochromen-1-one (4f) [47]. (Rf = 0.64, petroleum ether/ethyl acetate = 7:1, V/V), white solid (yield 0.267 g, 89%); mp 158–159 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.29 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 9.3 Hz, 3H), 7.58 (d, J = 8.3 Hz, 2H), 7.50 (dd, J = 14.6, 7.6 Hz, 2H), 6.93 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.96, 152.50, 137.17, 134.95, 132.01, 130.82, 129.68, 128.40, 126.63, 126.02, 124.28, 120.74, 120.52, 102.08. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C15H10BrO2 300.9859; found 300.9859.
3-(4-(tert-butyl)phenyl)-1H-isochromen-1-one (4g) [47]. (Rf = 0.72, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.217 g, 78%), mp 80–81 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.30 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.70 (t, J = 7.3 Hz, 1H), 7.48 (dd, J = 14.6, 7.9 Hz, 4H), 6.92 (s, 1H), 1.37 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.24, 153.56, 153.20, 137.50, 134.64, 129.39, 128.92, 127.71, 125.72, 125.61, 124.84, 120.19, 101.00, 31.02. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H19O2 279.1380; found 279.1379.
(E)-3-styryl-1H-isochromen-1-one (4h). (Rf = 0.63, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.201 g, 81%); mp 116–117 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.24 (s, 1H), 7.64 (s, 1H), 7.48 (d, J = 6.0 Hz, 2H), 7.38 (dd, J = 24.4, 13.5 Hz, 5H), 7.30 (s, 1H), 6.65 (d, J = 15.9 Hz, 1H), 6.41 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.90, 152.33, 137.33, 135.57, 134.66, 132.64, 129.56, 128.67, 127.87, 126.96, 125.63, 120.57, 119.20, 105.64. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C17H13O2 249.0910; found 249.0911.
3-(4-(trifluoromethyl)phenyl)-1H-isochromen-1-one (4i) [47]. (Rf = 0.58, petroleum ether/ethyl acetate = 6:1, V/V), white solid (yield 0.206 g, 72%), mp 214–215 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.29 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.73 (t, J = 7.3 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.02 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.75, 151.87, 136.83, 135.17, 135.03, 131.60, 131.39, 129.71, 128.81, 126.25, 125.78, 125.37, 120.77, 103.37. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H10F3O2 291.0627; found 291.0631.
3-(o-tolyl)-1H-isochromen-1-one (4j). (Rf = 0.70, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.186 g, 79%), mp 90–91 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.32 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 6.60 (s, 1H), 2.50 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.55, 155.52, 137.45, 136.72, 134.81, 132.72, 131.02, 129.76, 129.54, 129.14, 128.89, 128.20, 125.95, 125.81, 120.28, 105.89, 20.57. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H13O2 237.0910; found 237.0910.
3-(naphthalen-1-yl)-1H-isochromen-1-one (4k) [47]. (Rf = 0.65, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.231 g, 85%), mp 148–149 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.37 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 21.7, 7.4 Hz, 2H), 7.74 (d, J = 7.0 Hz, 2H), 7.53 (d, J = 17.2 Hz, 5H), 6.80 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.63, 154.70, 137.42, 134.91, 133.74, 130.73, 130.52, 129.65, 128.57, 128.40, 127.69, 127.08, 126.26, 125.89, 125.09, 125.02, 120.50, 120.29, 107.11, 103.85. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H13O2 273.0910; found 237.0916.
7-chloro-3-phenyl-1H-isochromen-1-one (4l). (Rf = 0.63, petroleum ether/ethyl acetate = 9:1, V/V), white solid (yield 0.220 g, 86%), mp 138–139 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.19 (s, 1H), 7.80 (d, J = 5.3 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.41 (s, 4H), 6.87 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 160.95, 153.67, 135.66, 135.04, 133.59, 131.27, 130.04, 128.84, 128.69, 127.29, 125.00, 121.35, 100.78. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C15H10ClO2 257.0364; found 257.0365.
7-chloro-3-(p-tolyl)-1H-isochromen-1-one (4m). (Rf = 0.64, petroleum ether/ethyl acetate = 9:1, V/V), white solid (yield 0.227 g, 84%), mp 205–206 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.16 (s, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 7.3 Hz, 2H), 6.80 (s, 1H), 2.36 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.03, 153.83, 140.37, 135.83, 134.93, 133.25, 129.37, 128.74, 128.42, 127.14, 124.87, 121.15, 99.98, 21.23. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H12ClO2 271.0520; found 271.0522.
7-chloro-3-(4-methoxyphenyl)-1H-isochromen-1-one (4n). (Rf = 0.59, petroleum ether/ethyl acetate = 9:1, V/V), white solid (yield 0.235 g, 82%), mp 183–184 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.16 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.1 Hz, 2H), 6.73 (s, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.10, 160.99, 153.73, 136.04, 134.94, 132.97, 128.74, 127.00, 126.56, 123.76, 120.88, 114.04, 99.13, 55.21. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H12ClO3 287.0469; found 287.0468.
3-(4-(tert-butyl)phenyl)-7-chloro-1H-isochromen-1-one (4o). (Rf = 0.63, petroleum ether/ethyl acetate = 10:1, V/V), white solid (yield 0.253 g, 81%), mp 236–237 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.24 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 1.35 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.24, 161.00, 154.12, 153.71, 136.06, 135.13, 133.50, 129.03, 128.70, 127.31, 125.83, 125.01, 121.48, 100.30, 34.85, 31.12. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H18ClO2 313.0990; found 313.0991.
7-chloro-3-(3,4,5-trimethoxyphenyl)-1H-isochromen-1-one (4p). (Rf = 0.60, petroleum ether/ethyl acetate = 3:1, V/V), white solid (yield 0.277 g, 80%), mp 168–169 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.22 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.04 (s, 2H), 6.84 (s, 1H), 3.95 (s, 6H), 3.91 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 13C NMR 161.05, 153.65, 153.46, 139.96, 139.63, 135.83, 135.22, 133.64, 129.01, 127.28, 126.93, 121.30, 102.52, 100.64, 60.95, 56.29. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C18H16ClO5 347.0681; found 347.0681.
7-chloro-3-(naphthalen-1-yl)-1H-isochromen-1-one (4q). (Rf = 0.64, petroleum ether/ethyl acetate = 9:1, V/V), white solid (yield 0.263 g, 86%), mp 195–196 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.31 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 24.2, 7.9 Hz, 2H), 7.70 (dd, J = 23.4, 7.6 Hz, 2H), 7.52 (dd, J = 14.5, 6.9 Hz, 3H), 7.44 (d, J = 8.2 Hz, 1H), 6.77 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.45, 155.05, 135.77, 135.24, 134.05, 133.72, 130.74, 130.53, 130.34, 129.09, 128.63, 127.74, 127.39, 127.18, 126.33, 125.00, 124.92, 121.62, 106.31. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C19H12ClO2 307.0520; found 307.0520.
(E)-7-chloro-3-styryl-1H-isochromen-1-one (4r). (Rf = 0.65, petroleum ether/ethyl acetate = 9:1, V/V), light yellow solid (yield 0.228 g, 81%), mp 205–206 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.18 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 7.4 Hz, 2H), 7.45 (d, J = 15.9 Hz, 1H), 7.38 (t, J = 8.3 Hz, 4H), 7.32 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.36 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 160.87, 152.83, 135.89, 135.56, 135.15, 133.68, 133.45, 129.26, 129.00, 128.84, 127.16, 121.87, 119.01, 104.80. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C17H11ClO2 283.0520; found 283.0519.
7-chloro-3-(o-tolyl)-1H-isochromen-1-one (4s). (Rf = 0.67, petroleum ether/ethyl acetate = 9:1, V/V), white solid (yield 0.204 g, 75%), mp 100–101 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.29 (s, 1H), 7.67 (d, J = 6.7 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 6.59 (s, 1H), 2.49 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.53, 161.39, 155.92, 155.80, 136.73, 135.82, 135.15, 133.89, 132.36, 131.10, 129.97, 129.11, 129.04, 127.29, 126.01, 105.10, 20.74. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C16H14ClO2 273.0677; found 273.0676.
6-chloro-3-(thiophen-2-yl)-1H-isochromen-1-one (4t). (Rf = 0.58, petroleum ether/ethyl acetate = 8:1, V/V), white solid (yield 0.210 g, 80%), mp 188–189 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.17 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.44-7.32 (m, 3H), 7.10 (s, 1H), 6.67 (s, 1H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 160.84, 150.64, 141.60, 138.80, 135.13, 131.40, 128.27, 128.20, 127.99, 126.69, 125.10, 118.46, 99.66. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C13H8ClO2S 262.9928; found 262.9928.
6-chloro-3-ethyl-1H-isochromen-1-one (4u). (Rf = 0.69, petroleum ether/ethyl acetate = 25:1, V/V), white solid (yield 0.125 g, 60%), mp 77–78 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.16 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 6.19 (s, 1H), 2.62–2.49 (m, 2H), 1.28 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.14, 160.94, 141.27, 138.95, 131.11, 127.97, 124.55, 118.35, 101.07, 26.68, 11.07. HRMS (ESI-TOF) m/z [M+H]+ Calcd for C11H10ClO2 209.0364; found 209.0364.

4. Conclusions

In summary, we have introduced a novel approach for the synthesis of 3-substituted isocoumarins through a sequential O-acylation/Wittig reaction, utilizing the readily accessible (2-carboxybenzyl)triphenylphosphonium bromide. Our method holds considerable significance for the synthesis of diverse fluorescent 3-substituted isocoumarins under environmentally friendly metal-free conditions, demonstrating notable functional group tolerance and good yields. Furthermore, the photophysical properties of some isocoumarin derivatives 4 at the experimental and theoretical levels were investigated and proved that these derivatives have further research and development value in the field of fluorescent materials.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29112449/s1.

Author Contributions

M.S. and C.-Y.Z. contributed equally to this work. Conceptualization, J.-X.H. and M.-W.D.; Formal Analysis, L.-L.B., M.X. and K.C.; Investigation, J.-L.L., T.Z. and L.-L.B.; Data Curation, M.S., C.-Y.Z., L.-L.B., M.X., K.C., J.-L.L., T.Z. and J.-Y.D.; Writing—Original Draft, M.S. and C.-Y.Z.; Writing—Review and Editing, J.-X.H. and M.-W.D.; Funding Acquisition, M.S., L.-L.B. and M.-W.D. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (No. 21572075), the 111 Project B17019, Science and Technology Plan Project of Huainan City (No. 2023A319), the Natural Science Foundation Department of Education of Anhui Province (No. 2023AH051545) and the Natural Science Foundation of Huainan Normal University (No. 2023XJZD013).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 02449 sch001
Scheme 1. Synthesis of isocoumarins.
Scheme 1. Synthesis of isocoumarins.
Molecules 29 02449 sch001
Molecules 29 02449 sch002
Scheme 2. Synthesis of of (2-carboxybenzyl)triphenylphosphonium bromide 3.
Scheme 2. Synthesis of of (2-carboxybenzyl)triphenylphosphonium bromide 3.
Molecules 29 02449 sch002
Molecules 29 02449 sch003
Scheme 3. Proposed mechanism for the formation of 4.
Scheme 3. Proposed mechanism for the formation of 4.
Molecules 29 02449 sch003
Molecules 29 02449 g001
Figure 1. UV-vis absorption spectra (a) and fluorescence emission spectra (b) of isocoumarin derivatives 4 in THF (c = 10−5 mol/L).
Figure 1. UV-vis absorption spectra (a) and fluorescence emission spectra (b) of isocoumarin derivatives 4 in THF (c = 10−5 mol/L).
Molecules 29 02449 g001
Molecules 29 02449 g002
Figure 2. Optimized conformation, frontier molecular orbital electron cloud distribution, energy level and band gap of isocoumarin derivatives 4.
Figure 2. Optimized conformation, frontier molecular orbital electron cloud distribution, energy level and band gap of isocoumarin derivatives 4.
Molecules 29 02449 g002
Table 1. Optimization of reaction conditions a,b.
Table 1. Optimization of reaction conditions a,b.
Molecules 29 02449 i001
EntrySolventTemp (°C)BaseTimeYield (%)
1DCM25DMAP12 h0
2DCM25NEt312 h79
3DCM25DBU12 h20
4DCM25t-BuOK12 h10
5DCM25K2CO312 h50
6DCM25NaOH12 h10
7THF25NEt312 h38
8CH3CN25NEt312 h42
9DCE25NEt312 h53
101,4-dioxane25NEt312 h57
11toluene25NEt312 h77
12toluene80NEt36 h80
13toluene110NEt32 h82
a (2-carboxybenzyl)triphenylphosphonium bromide 3a (1.0 mmol), benzoyl chloride (1.1 mmol), base (2.0 mmol), solvent (8.0 mL), 2–12 h; DCM = dichloromethane, DCE = dichloroethane, THF = tetrahydrofuran, DMAP = 4-dimethylaminopyridine, DBU = 1,8-diazabicyclo [5.4.0]undec-7-ene. b isolated yields.
Table 2. Preparation of 1H-isochromen-1-ones 4 a.
Table 2. Preparation of 1H-isochromen-1-ones 4 a.
Molecules 29 02449 i002
EntryR1R2TimeYield (%)EntryR1R2TimeYield (%)
4aHPh2 h854l4-ClPh2 h86
4bH4-CH3C6H42 h844m4-Cl4-CH3C6H42 h84
4cH4-FC6H42 h904n4-Cl4-CH3OC6H42.5 h82
4dH4-CH3OC6H42.5 h834o4-Cl4-t-BuC6H42.5 h81
4eH3-CH3C6H42 h824p4-Cl3,4,5-(CH3O)3C6H43 h80
4fH4-BrC6H41.5 h894q4-Clnaphthalen-1-yl2 h86
4gH4-t-BuC6H42.5 h784r4-ClC6H4CH=CH3 h81
4hHC6H4CH=CH3 h814s4-Cl2-CH3C6H4 3 h75
4iH4-CF3C6H41 h724t5-Clthiophene-2-yl2.5 h80
4jH2-CH3C6H43 h794u5-ClCH3CH24 h60
4kHnaphthalen-1-yl2 h85
a Isolated yields based on the 1H-isochromen-1-ones 4.
Table 3. Linear photophysical parameters of isocoumarin derivatives 4.
Table 3. Linear photophysical parameters of isocoumarin derivatives 4.
Comps.Experimental ValueTheoretical Value
λaελe∆νΦλcalcfoscMajor Contribution
4a3321.040956701%3380.3801H → L (89%)
2893.83000.4871H → L+1 (85%)
4h3651.8427397814%3730.9345H → L (89%)
3222.33260.5218H → L+1 (87%)
2783.22770.0204H-2 → L+1 (61%)
4j3350.840450982%3420.4632H → L (92%)
2902.93050.5353H → L+1 (90%)
4k3292.641663565%3250.1213H → L+1 (92%)
2803.22760.0827H-2 → L+1 (50%)
4p3611.7458586612%3670.4832H → L (92%)
3152.43200.5485H → L+1 (87%)
2813.12870.3640H-2 → L+1 (95%)
4u3280.54206678---3080.1048H → L (90%)
2763.42660.1759H → L+1 (77%)
λa: UV absorption wavelength (nm); ε: molar extinction coefficient (×104, L·mol−1·cm−1); λe: emission wavelength (nm); ∆ν: Stokes shift (cm−1); Φ: absolute fluorescence quantum yield; λcalc: theoretical value of absorption wavelength (nm); fosc: oscillator strength.
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Sun, M.; Zeng, C.-Y.; Bu, L.-L.; Xu, M.; Chen, K.; Liu, J.-L.; Zhang, T.; Dai, J.-Y.; Hong, J.-X.; Ding, M.-W. Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications. Molecules 2024, 29, 2449. https://doi.org/10.3390/molecules29112449

AMA Style

Sun M, Zeng C-Y, Bu L-L, Xu M, Chen K, Liu J-L, Zhang T, Dai J-Y, Hong J-X, Ding M-W. Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications. Molecules. 2024; 29(11):2449. https://doi.org/10.3390/molecules29112449

Chicago/Turabian Style

Sun, Mei, Chong-Yang Zeng, Lu-Lu Bu, Mai Xu, Kai Chen, Jia-Lin Liu, Tao Zhang, Jia-You Dai, Jia-Xin Hong, and Ming-Wu Ding. 2024. "Novel Metal-Free Synthesis of 3-Substituted Isocoumarins and Evaluation of Their Fluorescence Properties for Potential Applications" Molecules 29, no. 11: 2449. https://doi.org/10.3390/molecules29112449

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