K2CO3-Promoted oxy-Michael Addition/Cyclization of α,β-Unsaturated Carbonyl Compounds with Naphthols: Synthesis of Naphthopyrans

A potassium carbonate promoted tandem oxy-Michael addition/cyclization of α,β-unsaturated carbonyl compounds with naphthol derivatives for the synthesis of 2-substituted naphthopyrans was developed. Using the readily available, inexpensive potassium carbonate as the promoter, a range of different substituted naphthopyrans were prepared.


Introduction
Naphthopyran derivatives are widely used in medicine and industry. Many naphthopyran derivatives have important biological and pharmacological activities. Natural products with a naphthopyran core, busseihydroquinones C-D, have been isolated from the roots of Pentas bussei, a plant found in Kenya, and a decoction of the roots is used as a remedy for gonorrhea, syphilis, and dysentery [1,2]. Compound A has shown antibacterial activity against some gram-positive and gram-negative bacteria [3,4]. Compound B showed low cytotoxicity toward KB cells in vitro and was inactive against bacteria and fungi [5,6]. In addition, naphthopyran analogs of LY290181 can act as tumor vascular disrupting agents [7]. Compound C with a naphthopyran core exhibits photochromic properties, which are useful for many applications, e.g., in the manufacture of ophthalmic lenses, contact lenses, solar protection glasses, filters, camera optics, transmission devices, agrochemical films, glazes, decorative objects, and in information storage using optical inscription ( Figure 1) [5,6,[8][9][10][11]].

Introduction
Naphthopyran derivatives are widely used in medicine and industry. Many naphthopyran derivatives have important biological and pharmacological activities. Natural products with a naphthopyran core, busseihydroquinones C-D, have been isolated from the roots of Pentas bussei, a plant found in Kenya, and a decoction of the roots is used as a remedy for gonorrhea, syphilis, and dysentery [1,2]. Compound A has shown anti-bacterial activity against some gram-positive and gram-negative bacteria [3,4]. Compound B showed low cytotoxicity toward KB cells in vitro and was inactive against bacteria and fungi [5,6]. In addition, naphthopyran analogs of LY290181 can act as tumor vascular disrupting agents [7]. Compound C with a naphthopyran core exhibits photochromic properties, which are useful for many applications, e.g., in the manufacture of ophthalmic lenses, contact lenses, solar protection glasses, filters, camera optics, transmission devices, agrochemical films, glazes, decorative objects, and in information storage using optical inscription ( Figure 1) [5,6,[8][9][10][11]. Therefore, efficient methods toward the synthesis of the naphthopyran skeleton have long been valued by synthetic chemists, and many synthetic strategies have been reported. The main route involves the reaction of naphthols and olefins catalyzed by a Lewis acid, including the reaction of naphthols with conjugated dienes [4,[12][13][14][15] and the reaction of naphthols with analogs, such as allyl alcohol [5,9,[16][17][18][19][20][21][22][23][24]. In these strategies, precious-metal catalysts or a large amount of acid catalysts are used. More importantly, this type of reaction is not suitable for the synthesis of acid-sensitive natural products. Therefore, it is desirable to develop a method to obtain naphthopyran compounds using alkali base (Scheme 1a).
Therefore, efficient methods toward the synthesis of the naphthopyran skeleton have long been valued by synthetic chemists, and many synthetic strategies have been reported. The main route involves the reaction of naphthols and olefins catalyzed by a Lewis acid, including the reaction of naphthols with conjugated dienes [4,[12][13][14][15] and the reaction of naphthols with analogs, such as allyl alcohol [5,9,[16][17][18][19][20][21][22][23][24]. In these strategies, preciousmetal catalysts or a large amount of acid catalysts are used. More importantly, this type of reaction is not suitable for the synthesis of acid-sensitive natural products. Therefore, it is desirable to develop a method to obtain naphthopyran compounds using alkali base (Scheme 1a).
We speculated that the reaction sites of phenolic hydroxyl groups and unsaturated ketones can be subjected to a base [25] to obtain naphthopyran products, while the remaining carbonyl group in the product would allow for further structural modification, enabling the synthesis of various pharmacological compounds (Scheme 1b). Scheme 1. Approaches to naphthopyrans.

Results and Discussion
Here, we investigated the activity of readily available, inexpensive potassium carbonate as a promoter for the synthesis of naphthopyran compounds by the reaction of naphthol with unsaturated ketones. The results indicated that this method may be an economic, efficient, and practical synthesis for naphthopyran natural products.
In the first set of experiments, we used tert-butyldimethylsilyl (TBS) as the protecting group for the screening of subsequent reaction conditions. Different solvents, THF, DMSO, MeOH, 1,4-dioxane, DCE, and EtOAc, were then examined; only low yields were obtained and most of the raw materials did not react (Table 1, entries 1-7). The reaction proceeded efficiently in the strong polar solvent DMF and provided the product 4aa in 41% yield (Table 1, entry 8). We then examined different bases for the reaction in DMF. However, no desired product 4aa was obtained when t-BuOK or pyridine were used (Table 1, entries 9-10). When CsF or K3PO4 were used, only a trace amount of product was obtained (Table 1, entries [11][12]. K2CO3 was found to be the optimal base and 4aa was obtained in an excellent yield of 91% and was successfully isolated in 88% yield (Table 1, entry 13). Raising the temperature to 80 °C increased the reaction rate. We speculated that the reaction sites of phenolic hydroxyl groups and unsaturated ketones can be subjected to a base [25] to obtain naphthopyran products, while the remaining carbonyl group in the product would allow for further structural modification, enabling the synthesis of various pharmacological compounds (Scheme 1b).

Results and Discussion
Here, we investigated the activity of readily available, inexpensive potassium carbonate as a promoter for the synthesis of naphthopyran compounds by the reaction of naphthol with unsaturated ketones. The results indicated that this method may be an economic, efficient, and practical synthesis for naphthopyran natural products.
In the first set of experiments, we used tert-butyldimethylsilyl (TBS) as the protecting group for the screening of subsequent reaction conditions. Different solvents, THF, DMSO, MeOH, 1,4-dioxane, DCE, and EtOAc, were then examined; only low yields were obtained and most of the raw materials did not react ( Table 1, entries 1-7). The reaction proceeded efficiently in the strong polar solvent DMF and provided the product 4aa in 41% yield ( Table 1, entry 8). We then examined different bases for the reaction in DMF. However, no desired product 4aa was obtained when t-BuOK or pyridine were used (Table 1, entries 9-10). When CsF or K 3 PO 4 were used, only a trace amount of product was obtained ( Table 1, entries 11-12). K 2 CO 3 was found to be the optimal base and 4aa was obtained in an excellent yield of 91% and was successfully isolated in 88% yield (Table 1, entry 13). Raising the temperature to 80 • C increased the reaction rate.
Having established the optimized reaction conditions, we investigated the substrate scope of the reaction with various α,β-unsaturated carbonyls and naphthalens. As summarized in Scheme 2, we first investigated the reaction of naphthalen-2-ol 2a with a variety of α,β-unsaturated carbonyls 1 under the optimal conditions. Substituted α,β-unsaturated carbonyls, with both electron-donating (4ad-4ag) and electron-withdrawing (4ah and 4ai) groups at different positions on the benzene ring, were suitable substrates and gave the desired 2-substituted naphthopyran products. The structure of 4ag was unambiguously determined by single-crystal X-ray diffraction analysis (CCDC 2171562 (4ag) contains the supplementary crystallographic data for this paper. For details, see the supporting information). A cyclopropane-substituted, α,β-unsaturated carbonyl compound was also tolerated, giving the corresponding product in 70% yield (4ab). In addition, esters could also react with naphthol and gave the naphthopyran products (4aj-4ak) in good yields. Having established the optimized reaction conditions, we investigated the substrate scope of the reaction with various α,β-unsaturated carbonyls and naphthalens. As summarized in Scheme 2, we first investigated the reaction of naphthalen-2-ol 2a with a variety of α,β-unsaturated carbonyls 1 under the optimal conditions. Substituted α,β-unsaturated carbonyls, with both electron-donating (4ad-4ag) and electron-withdrawing (4ah and 4ai) groups at different positions on the benzene ring, were suitable substrates and gave the desired 2-substituted naphthopyran products. The structure of 4ag was unambiguously determined by single-crystal X-ray diffraction analysis (CCDC 2171562 (4ag) contains the supplementary crystallographic data for this paper. For details, see the supporting information). A cyclopropane-substituted, α,β-unsaturated carbonyl compound was also tolerated, giving the corresponding product in 70% yield (4ab). In addition, esters could also react with naphthol and gave the naphthopyran products (4aj-4ak) in good yields. We further investigated the scope of the naphthalens for this reaction. As illustrated in Scheme 3, a series of different naphthalens 2 were reacted with α,β-unsaturated carbonyl 1a under the optimized conditions. This transformation showed good generality Scheme 2. Substrate scope of α,β-unsaturated carbonyls in the synthesis of 2-substituted naphthopyrans. Reaction conditions: naphthalen-2-ol (1.5 equiv), K 2 CO 3 (2 equiv), DMF (0.5 mL), 80 • C, 10 h. Isolated yields.
We further investigated the scope of the naphthalens for this reaction. As illustrated in Scheme 3, a series of different naphthalens 2 were reacted with α,β-unsaturated carbonyl 1a under the optimized conditions. This transformation showed good generality and reactivity; all the tested naphthalens were tolerated and produced the corresponding 2substituted naphthopyran 4. Starting materials bearing electron-withdrawing and electrondonating groups afforded the corresponding products (Scheme 3, 4ba-4ga). Moreover, 4-hydroxycoumarin and 1,3-cyclohexanedione were also tolerated and provided the desired products in 48% and 79% yield, respectively (Scheme 4, 5aa and 5ab). and reactivity; all the tested naphthalens were tolerated and produced the corresponding 2-substituted naphthopyran 4. Starting materials bearing electron-withdrawing and electron-donating groups afforded the corresponding products (Scheme 3, 4ba-4ga). Moreover, 4-hydroxycoumarin and 1,3-cyclohexanedione were also tolerated and provided the desired products in 48% and 79% yield, respectively (Scheme 4, 5aa and 5ab).  Subsequently, we explored a gram-scale reaction. α,β-Unsaturated carbonyl 1a was treated with naphthalen-2-ol 2a under the standard conditions (Scheme 5). The corresponding naphthopyran product 4aa was obtained in 81% yield, slightly lower than the small-scale reaction yield. The reaction of α,β-Unsaturated carbonyl 1a and 1-naphthol was checked as well, which produced the desired product in 31% yield (See NMR spectra in Supplementary Materials). Herein, we proposed an immature process. Initially, deprotonation of the OH group of 2-naphthol 2a with K2CO3 generated 2-naphtholanion I, which undergoes an oxy-Michael addition reaction to the α,β-unsaturated carbonyl compound 1 to afford the alkylated naphthol intermediate III. This intermediate then might undergo an intramolecular SN2-type cyclization process to form the 2-substituted naphthopyran product 4aa and reactivity; all the tested naphthalens were tolerated and produced the corresponding 2-substituted naphthopyran 4. Starting materials bearing electron-withdrawing and electron-donating groups afforded the corresponding products (Scheme 3, 4ba-4ga). Moreover, 4-hydroxycoumarin and 1,3-cyclohexanedione were also tolerated and provided the desired products in 48% and 79% yield, respectively (Scheme 4, 5aa and 5ab).  Subsequently, we explored a gram-scale reaction. α,β-Unsaturated carbonyl 1a was treated with naphthalen-2-ol 2a under the standard conditions (Scheme 5). The corresponding naphthopyran product 4aa was obtained in 81% yield, slightly lower than the small-scale reaction yield. The reaction of α,β-Unsaturated carbonyl 1a and 1-naphthol was checked as well, which produced the desired product in 31% yield (See NMR spectra in Supplementary Materials). Herein, we proposed an immature process. Initially, deprotonation of the OH group of 2-naphthol 2a with K2CO3 generated 2-naphtholanion I, which undergoes an oxy-Michael addition reaction to the α,β-unsaturated carbonyl compound 1 to afford the alkylated naphthol intermediate III. This intermediate then might undergo an intramolecular SN2-type cyclization process to form the 2-substituted naphthopyran product 4aa Subsequently, we explored a gram-scale reaction. α,β-Unsaturated carbonyl 1a was treated with naphthalen-2-ol 2a under the standard conditions (Scheme 5). The corresponding naphthopyran product 4aa was obtained in 81% yield, slightly lower than the small-scale reaction yield.
and reactivity; all the tested naphthalens were tolerated and produced the corresponding 2-substituted naphthopyran 4. Starting materials bearing electron-withdrawing and electron-donating groups afforded the corresponding products (Scheme 3, 4ba-4ga). Moreover, 4-hydroxycoumarin and 1,3-cyclohexanedione were also tolerated and provided the desired products in 48% and 79% yield, respectively (Scheme 4, 5aa and 5ab).  Subsequently, we explored a gram-scale reaction. α,β-Unsaturated carbonyl 1a was treated with naphthalen-2-ol 2a under the standard conditions (Scheme 5). The corresponding naphthopyran product 4aa was obtained in 81% yield, slightly lower than the small-scale reaction yield. The reaction of α,β-Unsaturated carbonyl 1a and 1-naphthol was checked as well, which produced the desired product in 31% yield (See NMR spectra in Supplementary Materials). Herein, we proposed an immature process. Initially, deprotonation of the OH group of 2-naphthol 2a with K 2 CO 3 generated 2-naphtholanion I, which undergoes an oxy-Michael addition reaction to the α,β-unsaturated carbonyl compound 1 to afford the alkylated naphthol intermediate III. This intermediate then might undergo an intramolecular S N 2-type cyclization process to form the 2-substituted naphthopyran product 4aa along with the loss of TBSOH (Scheme 6). However, we have to realize that the mechanism of the reaction is unclear at this stage. along with the loss of TBSOH (Scheme 6). However, we have to realize that the mechanism of the reaction is unclear at this stage.

Scheme 6.
Possible mechanism for the formation of 4aa.
In summary, we have developed an approach to access 2-substituted naphthopyrans using α,β-unsaturated carbonyl compounds and naphthol derivatives in DMF at 80 °C with K2CO3 as the promoter. The reaction is proposed to undergo a tandem oxy-Michael addition/cyclization process, and various substitutions on both reaction partners were tolerated. This reaction is the first method for synthesizing naphthopyran compounds using basic medium.

General Information
Unless otherwise noted, all reactions were carried out under air atmosphere. 1,2-dichloroethane, N,N-Dimethylformamide, naphthols, ferric chloride, and potassium carbonate were from commercial sources and used as received without further purification. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.20 mm silica gel plates using UV light as the visualizing agent, and iodine and an acidic solution of phosphomolybdic acid (PMA) with heat as the stains. Column chromatography was performed on silica gel (200-300 meshes) using petroleum ether and ethyl acetate as eluent. All new compounds were characterized by means of 1 H NMR, 13 C NMR and HRMS. NMR spectra were recorded using a Bruker AVANCE NEO 500 MHz NMR spectrometer and can be found at the end of the paper. All 1 HNMR data are reported in δ units, parts per million (ppm), and were calibrated relative to the signals for residual chloroform (7.26 ppm) in deuterochloroform (CDCl3). All 13 C NMR data are reported in ppm relative to CDCl3 (77.16 ppm) and were obtained with 1 H decoupling. The following abbreviations or combinations, thereof, were used to explain the multiplicities: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Single crystal X-ray diffraction (SCXRD) of 4ag was carried out at 100(2) K on a Bruker D8 VENTURE diffractometer using Mo-Kα radiation (λ = 0.71073 Å). Integration and scaling of intensity data was performed using the SAINT program. Data were corrected for the effects of absorption using SADABS. The structures were solved by direct method and refined with the full-matrix least-squares technique using SHELX-2014 software. Non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms were placed in calculated positions and refined with a riding model.

General Information
α,β-Unsaturated carbonyl compound 1 (0.2 mmol, 1.0 equiv), naphthol 2 (0.3 mmol, 1.5 equiv), and K2CO3 (0.4 mmol, 2.0 equiv) were added into a 15 mL tube under N2 atmosphere. DMF (1.5 mL) was added to the reaction tube. Then, the reaction mixture was heated to 80 °C. After a time period of 10 h, the solution was diluted with EtOAc (2 mL × 3), washed with brine (1 mL × 1), and concentrated in vacuo. The crude product was purified by a flash chromatography on silica gel to afford the corresponding product 4. In summary, we have developed an approach to access 2-substituted naphthopyrans using α,β-unsaturated carbonyl compounds and naphthol derivatives in DMF at 80 • C with K 2 CO 3 as the promoter. The reaction is proposed to undergo a tandem oxy-Michael addition/cyclization process, and various substitutions on both reaction partners were tolerated. This reaction is the first method for synthesizing naphthopyran compounds using basic medium.

General Information
Unless otherwise noted, all reactions were carried out under air atmosphere. 1,2dichloroethane, N,N-Dimethylformamide, naphthols, ferric chloride, and potassium carbonate were from commercial sources and used as received without further purification. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.20 mm silica gel plates using UV light as the visualizing agent, and iodine and an acidic solution of phosphomolybdic acid (PMA) with heat as the stains. Column chromatography was performed on silica gel (200-300 meshes) using petroleum ether and ethyl acetate as eluent. All new compounds were characterized by means of 1 H NMR, 13 C NMR and HRMS. NMR spectra were recorded using a Bruker AVANCE NEO 500 MHz NMR spectrometer and can be found at the end of the paper. All 1 HNMR data are reported in δ units, parts per million (ppm), and were calibrated relative to the signals for residual chloroform (7.26 ppm) in deuterochloroform (CDCl 3 ). All 13 C NMR data are reported in ppm relative to CDCl 3 (77.16 ppm) and were obtained with 1 H decoupling. The following abbreviations or combinations, thereof, were used to explain the multiplicities: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Single crystal X-ray diffraction (SCXRD) of 4ag was carried out at 100(2) K on a Bruker D8 VENTURE diffractometer using Mo-Kα radiation (λ = 0.71073 Å). Integration and scaling of intensity data was performed using the SAINT program. Data were corrected for the effects of absorption using SADABS. The structures were solved by direct method and refined with the full-matrix least-squares technique using SHELX-2014 software. Non-hydrogen atoms were refined with anisotropic displacement parameters, and hydrogen atoms were placed in calculated positions and refined with a riding model.