Journal of Chemistry

Volume 2013 (2013), Article ID 106908, 9 pages

http://dx.doi.org/10.1155/2013/106908

Research Article

Synthetic Studies on Potent Marine Drugs: Synthesis and the Crystal Structure of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic Acid

Hui-Jing Li,¹ Jun-Li Wang,¹ Rui Wang,¹ Dong-Hui Luo,¹ and Yan-Chao Wu1,2

¹School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, China

²Stake Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China

Received 24 May 2013; Revised 10 September 2013; Accepted 12 September 2013

Academic Editor: John C. G. Zhao

Copyright © 2013 Hui-Jing Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

4H-Chromene-2-carboxylic acid ester derivatives of renieramycin M might be of use for the structural-activity relationship studies of antitumor antibiotic tetrahydroisoquinoline natural products. Accordingly, 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic acid, one key intermediate, was synthesized via the condensation of (3E)-2-oxo-4-phenylbut-3-enoate methyl ester with 4-tert-butylphenol in the presence of AuCl₃/3AgOTf (5 mol%), followed by cyclodehydration and aqueous hydrolysis. The product was unambiguously shown to the 4H-chromene-2-carboxylic acid by spectroscopy and X-ray crystallographic analysis. A packing diagram of the crystal structure shows that aromatic -stacking interactions and O–H⋯O hydrogen bond stabilize the structure in the solid.

1. Introduction

Antitumor antibiotic renieramycin M (5, Figure 1) has been isolated from the marine sponge Xestospongia sp. in 2003 [1–3], which belongs to a family of tetrahydroisoquinoline natural products including ecteinascidin 743 (1, Et-743, yondelis, trabectedin), saframycin A (3), quinocarcin, and so forth [4–20]. These natural products show potent antitumor antibiotic activities, and Et-743 has received European approval for the treatment of soft tissue sarcoma and ovarian carcinoma [21]. The remarkable clinical results of Et-743 have stimulated the discovery of zalypsis (2) that is currently in advanced human clinical trials for treating Ewing’s sarcoma [22, 23]. It is noteworthy that quinoline-2-carboxylic acid amide derivative of saframycin A (QAD, 4) was shown to possess single-digit picomolar potency against three human sarcoma cell lines 100 times more potent than Et-743 [24]. On the other hand, the ester side chain structure of renieramycin M was also found to have a critical impact on its antitumor activities [25]. We envisioned that 4H-chromene-2-carboxylic acid ester derivatives of renieramycin M (6) might be of some use for the structural-activity relationship studies of this antitumor antibiotic marine natural product. Compound 6 was thought to be prepared from pentacyclic alcohol 7 by the selective acylation of the primary alcohol with 4H-chromene-2-carboxylic acids (8, Scheme 1). We have already reported the synthesis of compound 7 in our asymmetric total synthesis of renieramycin M and jorumycin [9]. Herein, we would like to report our endeavors on the synthesis of 4-phenyl-4H-chromene-2-carboxylic acid 8a. As the structure of this product might be possible 4-phenyl-2H-chromene-2-carboxylic acid 9a or 2-phenyl-2H-chromene-4-carboxylic acid 10a, X-ray crystallographic analysis was used to elucidate the product as compound 8a.

Scheme 1: Retrosynthetic analysis.

Figure 1: Structures of tetrahydroisoquinoline compounds.

2. Materials and Methods

2.1. General Experimental Details

NMR spectra were measured on a Bruker XL-300 (¹H, 300 MHz and ¹³C, 75 MHz) and a Bruker XL-400 (¹H, 400 MHz and ¹³C, 100 MHz). Data for ¹H are reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), integration, coupling constant (Hz), and number. Data for ¹³C NMR are reported in terms of chemical shift (δ, ppm). Infrared (IR) spectra were recorded on a Perkin Elmer 500 FTIR spectrophotometer and are reported in terms of frequency of absorption (cm⁻¹). Elemental analyses were performed on Carlo-Mod 1102 instrument. The X-ray structure analysis was performed on a Bruker Smart-1000 X-ray Diffraction meter. Melting points were measured using a Beijing-Taike X-4 apparatus.

2.2. Synthesis of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylate Methyl Ester (13a, Scheme 2)

Scheme 2: Synthesis of 4H-chromene-2-carboxylic acid 8a.

The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with (3E)-2-oxo-4-phenylbut-3-enoate methyl ester (11a, 190.2 mg, 1.0 mmol) [26, 27] and 4-tert-butylphenol (12a, 150.2 mg, 1.0 mmol). The resulting mixture was stirred at reflux for 6 hours, cooled to room temperature, and filtered through Celite. The filtrate was added with a drop of concentrated sulfuric acid and stirred at room temperature for 0.5 hour. The obtained mixture was added with water (20 mL) and extracted with 1,2-dichloroethane (20 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylate methyl ester (13a, 138.6 mg) in 43% overall yield. White solid; mp = 176-177°C; FTIR (KBr), ν, cm⁻¹: 3028, 2961, 1738 (C=O), 1665, 1497, 1286, 1233, 1137, 1083, 700; ¹H NMR (300 MHz, CDCl₃), δ, ppm, (J, Hz): 7.34 (d, J = 6.8, 2H, C₆H₅), 7.29 (d, J = 8.6, 1H, H-8), 7.26–7.20 (m, 3H, C₆H₅), 7.09 (dd, J = 8.6, 2.2, 1H, H-7), 6.93 (d, J = 2.2, 1H, H-5), 6.27 (d, J = 4.5, 1H, H-3), 4.82 (d, J = 4.4, 1H, H-4), 3.85 (s, 3H, CO₂CH₃), 1.20 [s, 9H, C(CH₃)₃]; ¹³C NMR (75 MHz, CDCl₃), δ, ppm: 162.4 (C=O), 148.3 (C-9), 147.2 (C-2), 145.0 (C-6), 140.1 (C₆H₅), 128.8 (C₆H₅), 128.3 (C₆H₅), 127.0 (C₆H₅), 126.3 (C-5), 125.3 (C-10), 120.9 (C-7), 116.5 (C-8), 114.0 (C-3), 52.4 (CO₂CH₃), 41.3 (C-4), 34.3 [C(CH₃)₃], 31.3 [C(CH₃)₃]; elemental analysis. Found, %: C, 78.14; H, 6.97. C₂₁H₂₂O3. Calculated, %: C, 78.23; H, 6.88.

2.3. Synthesis of 1-Phenyl-1H-benzo[f]chromene-3-carboxylate Methyl Ester (13b)

The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with (3E)-2-oxo-4-phenylbut-3-enoate methyl ester (11a, 190.2 mg, 1.0 mmol) and 2-naphthol (12c, 144.2 mg, 1.0 mmol). The resulting mixture was stirred at reflux for 6 hours, cooled to room temperature, and filtered through Celite. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford 1-phenyl-1H-benzo[f]chromene-3-carboxylate methyl ester (13b, 291.0 mg) in 92% yield. White solid; mp = 177-178°C; FTIR (KBr), ν, cm⁻¹: 1725 (C=O), 1674, 1622, 1599, 1516, 1443, 1335, 1231, 1190, 1113, 1070, 1037, 764, 748, 705; ¹H NMR (400 MHz, CDCl₃), δ, ppm, (J, Hz): 7.79 (d, J = 6.8, 2H), 7.64 (d, J = 2.8, 1H), 7.41–7.17 (m, 8H), 6.46 (d, 1H), 5.35 (d, 1H), 3.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃), δ, ppm: 162.3, 149.1, 144.4, 139.1, 131.3, 129.4, 129.0, 128.5, 127.8, 126.9, 126.8, 124.5, 123.6, 118.0, 115.0, 113.1, 52.4, 39.1; Elemental analysis. Found, %: C, 79.64; H, 5.37. C₂₁H₁₆O3. Calculated, %: C, 79.73; H, 5.10.

2.4. Synthesis of 1-p-tolyl-1H-benzo[f]chromene-3-carboxylate Methyl Ester (13c)

The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added (3E)-2-oxo-4-p-tolylbut-3-enoate methyl ester (11b, 204.2 mg, 1.0 mmol) and 2-naphthol (12c, 144.2 mg, 1.0 mmol). The resulting mixture was stirred at reflux for 6 hours, cooled to room temperature, and filtered through Celite. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford 1-p-tolyl-1H-benzo[f]chromene-3-carboxylate methyl ester (13c, 297.3 mg) in 90% yield. White solid; mp = 180-181°C; FTIR (KBr), ν, cm⁻¹: 1726, 1623, 1598, 1515, 1433, 1337, 1230, 1114, 1071, 1036, 765, 745, 704; ¹H NMR (400 MHz, CDCl₃), δ, ppm, (J, Hz): 7.79–7.68 (m, 3H), 7.42–7.36 (m, 3H), 7.15–7.05 (m, 3H), 6.47 (d, 1H), 5.31 (d, 1H), 3.86 (s, 3H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃), δ, ppm: 162.2, 148.9, 141.4, 138.9, 136.5, 131.4, 131.2, 129.7, 129.3, 128.4, 127.6, 126.7, 124.4, 123.5, 117.9, 115.2, 113.3, 52.3, 38.6, 20.9; Elemental analysis. Found, %: C, 79.91; H, 5.35. C₂₂H₁₈O₃. Calculated, %: C, 79.98; H, 5.49.

2.5. Synthesis of 1-(4-Methoxyphenyl)-1H-benzo[f]chromene-3-carboxylate Methyl Ester (13d)

The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with (3E)-2-oxo-4-(4-methoxyphenyl)but-3-enoate methyl ester (11c, 220.2 mg, 1.0 mmol) and 2-naphthol (12c, 144.2 mg, 1.0 mmol). The resulting mixture was stirred at reflux for 6 hours, cooled to room temperature, and filtered through Celite. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford 1-(4-methoxyphenyl)-1H-benzo[f]chromene-3-carboxylate methyl ester (13d, 303.4 mg) in 87% yield. White solid; mp = 157-158°C; FTIR (KBr), ν, cm⁻¹: 1736 (C=O), 1673, 1608, 1598, 1509, 1340, 1302, 1253, 1230, 1117, 817, 753; ¹H NMR (400 MHz, CDCl₃), δ, ppm, (J, Hz): 7.79–7.68 (m, 3H), 7.41–6.79 (m, 7H), 6.46 (d, 1H), 5.29 (d, 1H), 3.86 (s, 3H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃), δ, ppm: 162.3, 158.4, 148.9, 138.8, 136.6, 131.3, 129.3, 128.7, 128.4, 126.7, 124.4, 123.5, 117.9, 115.2, 114.4, 113.4, 55.1, 52.3, 38.1; Elemental analysis. Found, %: C, 76.47; H, 5.36. C₂₂H₁₈O4. Calculated, %: C, 76.29; H, 5.24.

2.6. Synthesis of 1-(4-Chlorophenyl)-1H-benzo[f]chromene-3-carboxylate Methyl Ester (13e)

The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with (3E)-2-oxo-4-(4-chlorophenyl)but-3-enoate methyl ester (11d, 224.6 mg, 1.0 mmol) and 2-naphthol (12c, 144.2 mg, 1.0 mmol). The resulting mixture was stirred at reflux for 6 hours, cooled to room temperature, and filtered through Celite. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford 1-(4-chlorophenyl)-1H-benzo[f]chromene-3-carboxylate methyl ester (13e, 319.2 mg) in 91% yield. White solid; mp = 144-145°C; FTIR (KBr), ν, cm⁻¹: 1737, 1673, 1448, 1436, 1263, 1252, 1121, 821, 765, 748; ¹H NMR (400 MHz, CDCl₃), δ, ppm, (J, Hz): 7.71–7.28 (m, 6H), 7.14–7.04 (m, 4H), 6.33 (d, 1H), 5.25 (d, 1H), 3.77 (s, 3H); ¹³C NMR (100 MHz, CDCl₃), δ, ppm: 162.1, 149.0, 142.9, 139.3, 132.8, 131.3, 131.2, 129.7, 129.2, 129.1, 128.6, 126.9, 124.6, 123.3, 118.0, 114.3, 112.6, 52.4, 38.5; Elemental analysis. Found, %: C, 71.81; H, 4.39. C₂₁H₁₅ClO3. Calculated, %: C, 71.90; H, 4.31.

2.7. Synthesis of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic Acid (8a)

To a solution of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylate (13a, 483.6 mg, 1.5 mmol) in the mixture of tetrahydrofuran (THF, 21 mL) and water (H₂O, 7 mL), lithium hydroxide monohydrate (LiOH·H₂O, 254.6 mg, 6.1 mmol) was added at 0°C. The mixture was stirred at 0°C for 6 hour and added with 20 mL of water. The obtained mixture was neutralized with 2 N hydrochloric acid until pH = 6, and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200–300 mesh) to afford 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic acid (8a, 453.3 mg) in 98% yield. White solid; mp = 335–337°C; FTIR (KBr), ν, cm⁻¹: 3318 (O–H), 1692 (C=O), 1495, 1256, 1130, 758; ¹H NMR (300 MHz, DMSO-d6), δ, ppm, (J, Hz): 7.34 (d, J = 6.8, 2H, C₆H₅), 7.30 (d, J = 8.6, 1H, H-8), 7.26–7.20 (m, 3H, C₆H₅), 7.08 (dd, J = 8.6, 2.1, 1H, H-7), 6.93 (d, J = 2.1, 1H, H-5), 6.41 (d, J = 4.5, 1H, H-3), 4.85 (d, J = 4.5, 1H, H-4), 1.19 [s, 9H, C(CH₃)₃]; ¹³C NMR (75 MHz, DMSO-d6), δ, ppm: 162.9 (C=O), 148.4 (C-9), 147.0 (C-2), 145.7 (C-6), 140.9 (C₆H₅), 129.2 (C₆H₅), 128.4 (C₆H₅), 127.3 (C₆H₅), 126.4 (C-5), 125.6 (C-10), 121.8 (C-7), 116.6 (C-8), 113.7 (C-3), 34.4 [C(CH₃)₃], 31.5 [C(CH₃)₃]; Elemental analysis. Found, %: C, 77.86; H, 6.57%. C₂₀H₂₀O₃. Calculated, %: C, 77.90; H, 6.54%.

2.8. The X-Ray Structural Investigation of Compound 8a

Colorless single crystals of compound 8a suitable for X-ray analysis were obtained by slow evaporation of an ethanol solution. The X-ray structure analysis was performed on a Bruker Smart-1000 X-ray Diffraction. Data collection: Rapid Auto [28]. Cell refinement: Rapid Auto [28]. Data reduction: Rapid Auto [28]. Program(s) used to solve structure: SHELXS-97 [29]. Program(s) used to refine structure: SHELXL-97[29]. Molecular graphics: SHELXTL [30]. Software used to prepare material for publication: SHELXTL. Crystals 0.29 × 0.23 × 0.10 mm, colorless, grown in EtOH, triclinic, space group, P-1, unit cell parameters: a 6.2690(13), b 10.230(2), c 2.839(3)Å; Z 16. The number of reflections collected was 6621, independent 3485 ( 0.0328). The final probability parameters were 0.0580, 0.1452 (for reflections with ) with Goodness-of-fit 1.020. The results of the X-ray structural investigation were deposited at the Cambridge Crystallographic Data Center (deposit CCDC 917764).

3. Results and Discussion

During our ongoing interest aiming at the synthesis of functional heterocycles [31–34], we have developed several synthetic strategies for the preparation various 2H-chromenes [35–38]. In one case, we isolated a trace of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylate methyl ester (13a) whose structure has been determined by single-crystal X-ray analysis. However, the formation of 13a was not completely finished when the transformation of this 4H-chromene-2-carboxylate methyl ester into the corresponding 2H-chromene took place [36]. Thus, herein we use an improved synthetic method for the synthesis of 4H-chromene-2-carboxylate methyl ester 13a along with the corresponding acid.

As shown in Scheme 2, 4-phenyl-4H-chromene-2-carboxylic acid 8a was smoothly synthesized from (3E)-2-oxo-4-phenylbut-3-enoate methyl ester (11a) and 4-tert-butylphenol (12a). Accordingly, condensation of β,γ-unsaturated α-ketoester 11a with phenol 12a in the presence of AuCl₃/3AgOTf (5 mol%) [39] in refluxing 1,2-dichloroethane for 6 hours gave a mixture, which was filtered through Celite and the resulting mixture was further condensed in 1,2-dichloroethane with a drop of concentrated sulfuric acid [40] to afford 4-phenyl-4H-chromene-2-carboxylate methyl ester 13a in 43% overall yield. Aqueous hydrolysis of ester 13a with lithium hydroxide in THF/H₂O (v/v = 3 : 1) afforded 4-phenyl-4H-chromene-2-carboxylic acid 8a in 98% yield. The structure of compound 8a was assigned from spectral and single crystal data [41].

A series of other conditions for the synthesis of 4H-chromene-2-carboxylate methyl ester 13a were also screened, and the representative results are shown in Table 1. Either AuCl₃ (5 mol %) or AgOTf (15 mol%) was not the suitable promoter for the condensation of β,γ-unsaturated α-ketoester 11a with phenol 12a in refluxing 1,2-dichloroethane; however, the reaction went smoothly in the presence of 5 mol% of AuCl₃ and 15 mol% of AgOTf (entries 1–3). As this reaction did not work in the presence of AgCl (15 mol%, entry 4), Au(OTf)₃ should be actually the effective promoter. LiCl, Mg(OTf)₂, Sc(OTf)₃, Yb(OTf)₃, PtCl₂, Cu(OTf)₂, Zn(OTf)₂, and Al(OTf)₃ were not effective promoters for the reaction mentioned previously (entries 5–8, and entries 12–15). Treatment of 11a and 12a in refluxing 1,2-dichloroethane for 12 hours in the presence of these salts did not generate isolable products and the starting materials were recovered. Otherwise, Hf(OTf)₄, Fe(OTf)₃, FeCl₃, and Bi(OTf)₃ displayed some efficiency for this reaction, which afforded 4H-chromene-2-carboxylate methyl ester 13a in 4–8% yields under the same conditions (entries 9–11, and entry 16). When the catalyst loading of AuCl₃/3AgOTf was decreased to 1 mol%, only 13% yield of 13a was isolated (entry 17). Decreased yields were observed when the reaction was performed in refluxing tetrahydrofuran or acetonitrile, reflecting the temperature factor effect on this reaction (entries 18-19, and entry 1). As expected, increased yields were observed when the reaction was performed in toluene or nitromethane at 83°C (entries 20-21). When the reaction was performed in refluxing toluene (110°C), degradation was observed.

Table 1: Survey of conditions for the condensation of 11a with 12a a.

Entry
Catalyst
Temperature
Solvent
Time
Yield

1
5 mol% AuCl₃/3AgOTf
83°C
DCE
6 h
43%

2
5 mol% AuCl₃
83°C
DCE
12 h
0

3
15 mol% AgOTf
83°C
DCE
12 h
trace

4
15 mol% AgCl
83°C
DCE
12 h
0

5
10 mol% LiCl
83°C
DCE
12 h
0

6
10 mol% Mg(OTf)₂
83°C
DCE
12 h
0

7
10 mol% Sc(OTf)₃
83°C
DCE
12 h
trace

8
10 mol% Yb(OTf)₃
83°C
DCE
12 h
trace

9
10 mol% Hf(OTf)₄
83°C
DCE
12 h
4%

10
10 mol% Fe(OTf)₃
83°C
DCE
12 h
8%

11
10 mol% FeCl₃
83°C
DCE
12 h
5%

12
10 mol% PtCl₂
83°C
DCE
12 h
0

13
10 mol% Cu(OTf)₂
83°C
DCE
12 h
trace

14
10 mol% Zn(OTf)₂
83°C
DCE
12 h
0

15
10 mol% Al(OTf)₃
83°C
DCE
12 h
trace

16
10 mol% Bi(OTf)₃
83°C
DCE
12 h
5%

17
1 mol% AuCl₃/3AgOTf
83°C
DCE
12 h
13%

18
5 mol% AuCl₃/3AgOTf
66°C
THF
6 h
15%

19
5 mol% AuCl₃/3AgOTf
76°C
CH₃CN
6 h
19%

20
5 mol% AuCl₃/3AgOTf
83°C
PhCH₃
6 h
39%

21
5 mol% AuCl₃/3AgOTf
83°C
CH₃NO₂
6 h
41%

General conditions: the mixture of 11a (1.0 mmol), 12a (1.0 mmol), and catalyst (1–15 mol%) in solvent (5 mL, c = 1.0 M) was stirred at 66–83°C for 6–12 hours, cooled to room temperature, and filtered through Celite. The filtrate was added with a drop of concentrated sulfuric acid and stirred at room temperature for 0.5 hour.

With the optimized reaction conditions in hand, the scope of the reaction with respect to various β,γ-unsaturated α-ketoesters 11 and phenols 12 was subsequently investigated (Table 2). Deactivated phenols, such as 4-nitrophenol (12b) and 4-chlorophenol (12c), prevented any reaction (entries 3-4), indicating that there is an electronic effect on this tandem reaction. To our delight, activated phenols, such as 4-tert-butylphenol (12a) and 2-naphthol (12d), could react smoothly with β,γ-unsaturated α-ketoesters. Further condensation of the crude products in the presence of a drop of concentrated sulfuric acid helps to improve the yield of 4H-chromene-2-carboxylate methyl ester 13a (entries 1-2). However, this additional step is of little use when 2-naphthol (12d) was used as one starting material (entries 5-6). By treating 2-naphthol with β,γ-unsaturated α-ketoester 11a in 1,2-dichloroethane under reflux for 6 hours, 4H-chromene-2-carboxylate methyl ester 13b was obtained in 92% yield (entry 6). With a weak electron-donating group such as a methyl group at the para position of the β,γ-unsaturated α-ketoester, β,γ-unsaturated α-ketoester 11b reacted with 12d to afford product 13c in 90% yield (entry 7). With a strong electron-donating group such as a methoxy group at the para position of the β,γ-unsaturated α-ketoester, the corresponding reaction under standard conditions afforded the desired product in 87% yield (entry 8). With the para position of the β,γ-unsaturated α-ketoester bearing an electron-withdrawing group such as a chloro group, β,γ-unsaturated α-ketoester 11d reacted equally well with 12d to afford 4H-chromene-2-carboxylate methyl ester 13e in an excellent yield (91%, entry 9).

Table 2: Condensation of an β,γ-unsaturated α-ketoester 11 with phenol 12 a.

Entry
11
12
13
Yield

1

43%b

2
11a
12a
13a
37%

3
11a

0

4
11a

0

5
11a

92%b

6
11a
12d
13b
92%

7

12d

90%

8

12d

87%

9

12d

91%

General conditions: The mixture of AuCl₃ (15.2 mg, 0.05 mmol) and AgOTf (38.6 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was stirred at room temperature for 0.5 hour and then was added with a β,γ-unsaturated α-ketoester 11 (1.0 mmol) and a phenol 12 (1.0 mmol). The resulting mixture was stirred at reflux for 6 hours.

The crude products in 1,2-dichloroethane (5 mL) were filtered through Celite, added with a drop of concentrated sulfuric acid, and stirred at room temperature for 0.5 hour.

It is noteworthy that β,γ-unsaturated α-ketoesters can react with phenols through Friedel-Crafts alkylation, Friedel-Crafts hydroxyalkylation, oxa-Michael addition, transesterification, hemiacetalization, acetalization, and so on [36]. It might be possible that the oxa-Michael addition/Friedel-Crafts hydroxyalkylation of β,γ-unsaturated α-ketoester 11a with phenol 12a afford chromane 14a [42], which might be in turn converted to 2-phenyl-2H-chromene-4-carboxylate methyl ester 15a by condensation with sulfuric acid (Scheme 2). Aqueous hydrolysis of ester 15a with lithium hydroxide in THF/H₂O (v/v = 3 : 1) system might afford 2-phenyl-2H-chromene-4-carboxylic acid 10a (Schemes 1 and 2). It might be also possible that aqueous hydrolysis of ester 13a, under basic reaction conditions, affords 4-phenyl-2H-chromene-2-carboxylic acid 9a (Schemes 1 and 2). Thus, the colorless single crystals of compound 8a suitable for X-ray analysis were obtained by slow evaporation of an ethanol solution, which was shown to the 4-phenyl-4H-chromene-2-carboxylic acid by spectroscopy and X-ray crystallographic analysis [41].

The structure of 4H-chromene-2-carboxylic acid 8a was shown in Figure 2, in which hydrogen atoms are represented by circles of arbitrary size. The molecule contains two planar groups, a trisubstituted benzene ring and a phenyl group.

Figure 2: The X-ray structure of 4H-chromene-2-carboxylic acid 8a.

A packing diagram of the crystal structure of 4H-chromene-2-carboxylic acid 8a was shown in Figure 3, in which dashed lines indicate hydrogen bonds. This diagram showed that aromatic -stacking interactions and O–H⋯O hydrogen bond stabilize the structure in the solid state.

Figure 3: A molecular packing of 4H-chromene-2-carboxylic acid 8a.

4. Conclusion

In summary, we have reported an efficient synthesis of 6-tert-butyl-4-phenyl-4H-chromene-2-carboxylic acid from (3E)-2-oxo-4-phenylbut-3-enoate methyl ester and 4-tert-butylphenol via the processes of Friedel-Crafts alkylation, cyclodehydration, and aqueous hydrolysis. The reactions were found to have high selectivity and the potential by-products were not detected in these reactions. The product was confirmed from its spectra and by single-crystal X-ray analysis. Our synthesis paves the way for the preparation of 4H-chromene-2-carboxylic acid ester derivatives of renieramycin M, as well as the corresponding structural-activity relationship studies.

Conflict of Interests

The authors declare that they do not have any financial relations with any of the commercial entities mentioned in the paper that could lead to a conflict of interests.

Acknowledgments

The financial support from the Science and Technology Development Project of Weihai (2011DXGJ13, 2012DXGJ02), the Science and Technology Development Project of Shandong Province (2013GGA10075), the Natural Science Foundation of Shandong Province (ZR2012BM002), the Natural Scientific Research Innovation Foundation in Harbin Institute of Technology (HIT.NSRIF.2011097, 2011098), the Scientific Research Foundation of Harbin Institute of Technology at Weihai (HIT (WH) 201105, 201106), the National Natural Science Foundation of China (21272046, 21202028, 21372054), and the State Key Laboratory of Natural and Biomimetic Drugs in China (K20120210) is gratefully acknowledged.

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