2-Oxo-2 H -chromen-7-yl 4-chlorobenzoate

: We describe the synthesis of 2-oxo-2 H -chromen-7-yl 4-chlorobenzoate 3 in 88% yield by the O -acylation reaction of 7-hydroxy-2 H -chromen-2-one 1 with 4-chlorobenzoyl chloride 2 in dichloromethane using a slight excess of triethylamine at 20 ◦ C for 1 h. The ester 3 was completely characterized by mass spectrometry, IR, UV–Vis, 1D, and 2D NMR spectroscopy.


Introduction
The coumarin was first isolated from tonka beans by A. Vogel in 1820 [1], while W. H. Perkin described the first chemical synthesis in 1868 by heating acetic acid with the sodium salt of salicylaldehyde [2]. The coumarin is also known as 2H-chromen-2-one (1,2-benzopyrone or 2H-1-benzopyran-2-one) according to the IUPAC nomenclature. This oxa-heterocycle is a two-ring system, consisting of a benzene ring fused with a α-pyrone nucleus. It should be noted that coumarin-based fluorescent chemosensors have been widely employed in bioorganic chemistry, molecular recognition, and materials science [3]. Over the last decades, synthetic and naturally occurring coumarins have received considerable attention from organic and medicinal chemists due to their huge diversity of biological and pharmacological activities, including anti-inflammatory [4], antibacterial [5], antifungal [6], anticoagulant [7], antioxidant [8], antiviral [9], cholinesterase (ChE), and monoamine oxidase (MAO) inhibitory properties [10]. Besides, coumarins exhibited significant anticancer activity through diverse mechanisms of action, including inhibition of carbonic anhydrase, inhibition of microtubule polymerization, inhibition of tumor angiogenesis, regulating the reactive oxygen species, among others [11][12][13][14].
In particular, 7-hydroxycoumarin derivatives have been widely used as valuable building blocks for the preparation of novel coumarin-based anticancer agents [15][16][17]. For instance, umbelliferone analogs (I) and (II) had excellent activity against MCF-7 cells with IC 50 values of 9.54 and 16.1 µM, respectively, as illustrated in Figure 1 [15]. Interestingly, the coumarin-containing ketone (III) showed potent activity against breast cancer MCF-7 cells, with an IC 50 value of 0.47 µM [16]. In contrast, the coumarin-containing ester (IV) exhibited high selectivity towards tumor-associated hCA IX over the cytosolic hCA I isoform, with a value of 21.8 nM [17].
It should be noted that the post-functionalization of the 7-hydroxycoumarin skeleton has been scarcely studied in synthetic and medicinal chemistry [18]. Interestingly, the hydroxyl group at the 7-position of the coumarin skeleton can be exploited to perform alkylation and acylation reactions [19][20][21][22]. Herein, we describe the synthesis and complete characterization of 2-oxo-2H-chromen-7-yl 4-chlorobenzoate 3 through an O-acylation reaction of 7-hydroxy-2H-chromen-2-one 1 with 4-chlorobenzoyl chloride 2 in the presence of triethylamine under mild reaction conditions.

Results and Discussion
In connection with the ongoing development of efficient and simple protocols for the acylation of heterocyclic compounds of biological interest [23,24], we describe an expeditious approach to synthesize 2-oxo-2H-chromen-7-yl 4-chlorobenzoate 3 through an O-acylation reaction between equimolar amounts of 7-hydroxy-2H-chromen-2-one 1 and 4-chlorobenzoyl chloride 2 in dichloromethane, using a slight excess of triethylamine with vigorous stirring at 20 • C for 1 h under normal atmospheric conditions (Scheme 1). After the specified reaction time, the solvent was removed under vacuum using a rotary evaporator. The resulting crude product was purified by flash chromatography on silica gel using dichloromethane as an eluent to furnish ester 3 in 88% yield. This procedure is distinguished by its short reaction times, high yield, clean reaction profile, and operational simplicity. Albeit the compound 3 was synthesized nine years ago [19], the structural and electronic information obtained from spectroscopic and spectrometry data has not been explained yet. For that reason, a complete spectroscopic and analytical characterization was performed in this work (see Section 3). Initially, the structure of 3 was determined by mass spectrometry, IR, UV-Vis, and 1D NMR spectroscopy (Figures S1-S7). Later, the analysis of 2D NMR spectra, including HSQC ( Figure   The absorption bands at 1728 and 1589/1620 cm −1 are assigned to the C=O and C=C stretching vibrations in the IR spectrum, respectively. The absorption bands at 1068/1092 and 1231/1261 cm −1 are attributed to the C-O-C asymmetric stretching vibrations. It should be noted that the C-Cl stretching band is normally expected around 580-750 cm −1 [25]; thus, a strong band at 744 cm −1 is assigned to the C-Cl stretching vibration. The 1 H-NMR spectrum of 3 recorded in DMSO-d 6 showed one doublet of doublets at 7.34 ppm and four doublets at 6.51, 7.48, 7.83, and 8.11 ppm for the coumarin ring, as well as two doublets at 7.70 and 8.15 ppm for the benzene ring ( Table 1). The proton signal of the hydroxyl group attached to the coumarin ring was not observed, indicating that the O-acylation process was successful. The 13 C{ 1 H} NMR and DEPT spectra of 3 showed 14 carbon signals, consisting of seven aromatic methines, five quaternary aromatic carbons, and two carbonyl carbons (Table 1 and Figure 2A). The complete assignment of the proton and carbon signals of 3 is described in Section 3, while the correlations 1 H-1 H and 1 H-13 C observed in COSY and HMBC experiments, respectively, are illustrated in Figure 2B. In the MS spectrum, two molecular peaks are observed at m/z 300 and 302 complying with the Cl-rule, along with two peaks at m/z 141 and 139 with 32% and 100% intensity, respectively, corresponding to the (4-chlorobenzylidyne)oxonium ion (C 7 H 4 ClO + ). Additionally, the accurate mass (m/z 301.0261) of the pseudo-molecular ion ([M + H] + ) and the elemental formula (C 16 H 10 ClO 4 + ) is confirmed by HRMS measurements, obtaining an error mass of 1.33 ppm.     In summary, we described the expeditious and ambient-temperature synthesis of 2-oxo-2H-chromen-7-yl 4-chlorobenzoate 3 through an O-acylation reaction of 7-hydroxy-2H-chromen-2-one 1 with 4-chlorobenzoyl chloride 2 in dichloromethane, using a slight excess of triethylamine. This protocol is distinguished by its short reaction times, high yield, clean reaction profile, and operational simplicity.
Author Contributions: Investigation, data curation, writing-original draft preparation, D.B.; writing-review and editing, resources, J.P.; conceptualization, data curation, writing-original draft preparation, J.-C.C. All authors have read and agreed to the published version of the manuscript.
Funding: The APC was sponsored by MDPI.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available in this article.