A method for the synthesis of structurally diverse pyrano coumarins with hydrogen functionality

Abstract

The application relates to a method for synthesizing structural divergent pyrano coumarin analogues by continuous hydrogen functionalization. Specifically, under the catalysis of a transition metal and a double ligand, 4-hydroxyl coumarin derivatives are used as raw materials to react with 1,3-alkyne, and under the action of 4-methoxy benzene sulfonic acid and triethylenediamine, two kinds of pyrano coumarin analogues can be obtained in structural divergence. The application uses cheap and easily obtained 4-hydroxyl coumarin and 1,3-alkyne, and a series of heterocyclic compounds with potential medicinal value are selectively obtained under simple and mild conditions.

Description

Technical Field

[0001] This invention relates to a novel method for the continuous hydrogen functionalization synthesis of pyranocoumarin analogs. Background Technology

[0002] Pyranocoumarin analogues are a class of oxygen-containing heterocyclic compounds fused with pyran and coumarin. They are rare secondary metabolites in plants, widely distributed in the plant kingdom, found in the roots, bark, leaves, and seeds of various plants. They possess significant biological and therapeutic properties, including anti-inflammatory, anti-HIV, anti-tuberculosis, and antibacterial effects, and hold immense potential in medicinal chemistry. However, traditional synthetic methods typically require multiple reaction steps and purification processes under harsh conditions, and may generate other byproducts, leading to low yields of the target product. Given the enormous potential application value of pyranocoumarins in novel drug synthesis, we have developed a novel continuous hydrogen functionalization reaction, using simple and readily available starting materials, enabling efficient, atom-economical, and highly selective synthesis of the target product.

[0003] In summary, this work describes an innovative method for the highly selective synthesis of a high-value-added pyranocoumarin and dihydropyran[2,3-c]pyrazole analogues using inexpensive and readily available raw materials and alkenynes under transition metal catalysis. Summary of the Invention

[0004] 1. The purpose of this invention is to provide a method for highly selective synthesis of pyranocoumarins by rhodium-catalyzed continuous hydrogen functionalization.

[0005]

[0006] Reaction Equation 1: Continuous Hydrogen Functionalization Reaction of Enynes

[0007] The specific operating steps are as follows (reaction equation 1):

[0008] Under a nitrogen atmosphere, substrates 1 and 2, a rhodium catalyst, phosphine ligands (4-FC6H4)3P and BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), DABCO (triethylenediamine), and solvents dichloromethane and methanol were added to a pressure-resistant tube and reacted at 70 degrees Celsius for 24 hours. After the reaction was completed, pyranocoumarin analog 3 was isolated.

[0009] [Rh(cod)Cl]2 is preferably used as the reaction catalyst, and the amount used is 0.02-0.04 molar equivalents (relative to raw material 1), preferably 0.025-0.03 molar equivalents.

[0010] (4-FC6H4)3P is preferably a monophosphine ligand L1, and the amount used is 0.08-0.16 molar equivalents (relative to raw material 1), preferably 0.10-0.12 molar equivalents.

[0011] BINAP is preferably a bisphosphine ligand L2, used in an amount of 0.04-0.08 molar equivalents (relative to raw material 1), preferably 0.05-0.06 molar equivalents.

[0012] DABCO (triethylenediamine) is preferred, and the amount used is 0.4-0.7 molar equivalents (relative to raw material 1), preferably 0.5-0.6 molar equivalents.

[0013] Solvents: 1,2-dichloroethane, 0.2 mL; methanol, 0.3 mL.

[0014] The reaction temperature is 70℃.

[0015] Under a nitrogen atmosphere, substrates 1 and 2, a rhodium catalyst, phosphine ligand Dppb (1,4-bis(diphenylphosphine)butane), 4-methoxybenzenesulfonic acid, and solvents 1,2-dichloroethane and ethylene glycol dimethyl ether were added to a pressure-resistant tube, and the reaction was carried out at 70 degrees Celsius for 24 hours. After the reaction was completed, pyranocoumarin analog 4 was isolated.

[0016] [Rh(cod)Cl]2 is preferably used as the reaction catalyst, and the amount used is 0.02-0.04 molar equivalents (relative to raw material 1), preferably 0.025-0.03 molar equivalents.

[0017] (4-FC6H4)3P is preferably a monophosphine ligand L1, and the amount used is 0.08-0.16 molar equivalents (relative to raw material 1), preferably 0.10-0.12 molar equivalents.

[0018] BINAP is preferably a bisphosphine ligand L2, used in an amount of 0.04-0.08 molar equivalents (relative to raw material 1), preferably 0.05-0.06 molar equivalents.

[0019] 4-Methoxybenzenesulfonic acid is preferred, and the amount used is 0.4-0.7 molar equivalents (relative to raw material 1), preferably 0.5-0.6 molar equivalents.

[0020] Solvents: 1,2-dichloroethane, 0.2 mL; methanol, 0.3 mL.

[0021] The reaction temperature is 70℃

[0022] This invention uses inexpensive and readily available raw materials to react 4-hydroxycoumarin derivatives with 1,3-enyne under rhodium catalysis to selectively obtain two pyrancoumarin analogs.

[0023] This invention utilizes the catalysis of transition metals and dual ligands to react 4-hydroxycoumarin derivatives with 1,3-enyne, yielding two pyrancoumarin analogs through structural divergence under the action of 4-methoxybenzenesulfonic acid and triethylenediamine, respectively. This invention employs inexpensive and readily available 4-hydroxycoumarin and 1,3-enyne, achieving high selectivity and yielding a series of heterocyclic compounds with potential pharmaceutical value under simple and mild conditions.

[0024] The present invention has the following advantages:

[0025] First, the raw materials are widely available and easily obtained. Second, the selective and continuous hydrogen functionalization reaction catalyzed by diligand-regulated rhodium metal enables highly efficient and atom-economical generation of regioselective products. Third, the reaction conditions are mild; the addition of acid or base can yield products with two different structures, making the operation simple and easy to scale up. Finally, the resulting pyranocoumarin analogues may possess biological activity and have potential applications in medicinal chemistry and pharmaceutical synthesis. Detailed Implementation

[0026] To better understand the present invention, the following examples are provided. The reaction materials and results of Examples 1-28 are shown in Table 1.

[0027] Table 1. Reaction results for different olefin substrates

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] Example 1

[0034] Under nitrogen protection, substrate 1a (0.20 mmol), [Rh(cod)Cl]2 (0.005 mmol), BINAP (0.01 mmol), (4-FC6H4)3P (0.02 mmol), DABCO (0.10 mmol), 1,2-dichloroethane (0.2 mL), and methanol (0.3 mL) were added sequentially to a 4 mL pressure-resistant tube. Enyne substrate 2 (0.40 mmol) was then added using a microsyringe. The tube was sealed tightly and the reaction was carried out at 70°C for 24 hours. After the reaction was completed, the target product 3a was obtained by column chromatography with a yield of 76%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0035] The test data is as follows:

[0036]

[0037] 4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3a)Lightyellow oil, 34.8mg, 76% yield. 1 H NMR (400MHz, Chloroform-d) δ7.72 (dd, J=7.9, 1.4Hz, 1H), 7.49 (ddd, J=8.6, 7.3, 1.6 Hz,1H),7.29–7.21(m,2H),6.47(d,J=6.2Hz,1H),4.94(d,J=6.2Hz,1H),1.51(s,6H). 13 C NMR (101MHz, CDCl3) δ161.07,155.40,152.41,135.32,131.71,123.87,123.00,116.28,116.05,114.32,107.87,30.02,29.62.HRMS Calculated forC 14 H 12 O3[M+H] + 229.0865, found 229.0857.

[0038] Example 2:

[0039] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1b. The yield of product 3b was 74%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0040]

[0041] 4,4-dimethyl-9-nitro-4H,5H-pyrano[3,2-c]chromen-5-one(3b)Lightyellowsolid(mpxx oC), 40.4 mg, 74% yield. 1 H NMR(400MHz,Chloroform-d)δ7.87(d,J=2.3Hz,1H),7.59(dd,J=8.8,2.4Hz,1H), 7.17(d,J=8.8Hz,1H),6.48(d,J=6.2Hz,1H),4.96(d,J=6.2Hz,1H),1.52(s,6H). 13C NMR (101MHz, CDCl3) δ160.40,154.33,151.25,135.26,134.55,125.69,118.06,116.66,116.07,115.91,108.73,30.12,29.58.

[0042] Example 3:

[0043] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1c, the product 3c yield was 77%, and the structure of the compound was identified by NMR (H1N, C1N and fluorine spectra) and high-resolution mass spectrometry.

[0044]

[0045] 9-fluoro-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3c)Lightyellowsolid(mpxx oC), 37.7 mg, 77% yield. 1 H NMR (400MHz, Chloroform-d) δ7.41(dd,J=8.5,2.9Hz,1H),7.30–7.20(m,2H),6.49(d,J=6.2Hz,1H),4.97(d,J=6.2Hz,1H),1.54(s,6H). 13 C NMR (101MHz, CDCl3) δ160.70, 158.61 (d, J = 243.5Hz), 154.68 (d, J = 2.8Hz), 148.53 (d, J = 1.9Hz), 135.26, 119.26(d,J=24.6Hz),117.91(d,J=8.3Hz),116.06,115.23(d,J=9.2Hz),108.92,108.66,30.09,29.56. 19 F NMR(376MHz,CDCl3)δ-117.36.HRMSCalculated forC 14 H 12 FO3[M+H] + 247.0770, found 247.0768.

[0046] Example 4:

[0047] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1d, and the product yield was 66% after 3d. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0048]

[0049] 9-chloro-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3d)Lightyellowsolid(mpxx oC), 34.9 mg, 66% yield. 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=2.5Hz,1H),7.38(dd,J=8.8,2.5Hz,1H), 7.16(d,J=8.8Hz,1H),6.41(d,J=6.2Hz,1H),4.89(d,J=6.2Hz,1H),1.46(s,6H). 13 C NMR(101MHz, CDCl3)δ160.45,154.42,150.78,135.26,131.73,129.40,122.63,117.76,116.07,115.47,108.73,30.11,29.57.HRMSCalculated forC 14 H 12 ClO3[M+H] + 263.0475, found 263.0481.

[0050] Example 5:

[0051] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1e, and the yield of product 3e was 47%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0052]

[0053] 9-bromo-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3e)Lightyellowsolid(mpxx oC), 28.6 mg, 47% yield. 1 H NMR (400MHz, Chloroform-d) δ7.73 (dd, J=7.9, 1.5Hz, 1H), 7.50 (ddd, J=8.6, 7.3, 1.6 Hz,1H),7.29–7.23(m,2H),6.48(d,J=6.2Hz,1H),4.95(d,J=6.2Hz,1H),1.53(s,6H). 13HRMSCalculated for C 14 H 12 BrO3[M+H] + 306.9970, found 306.9963.

[0054] Example 6:

[0055] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1f, the yield of 3f product was 90%, and the structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0056]

[0057] 4,4,9-trimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3f)Lightyellow solid(mpxx oC), 43.8 mg, 90% yield. 1 H NMR(400MHz,Chloroform-d)δ7.54–7.51(d,J=1.7Hz,1H),7.31(dd,J=8.4,1.7Hz,1H),7.1 8(d,J=8.4Hz,1H),6.48(d,J=6.2Hz,1H),4.95(d,J=6.2Hz,1H),2.40(s,3H),1.53(s,6H). 13 HRMS Calculated for C 15 H 15 O3[M+H] + 243.1021, found 243.1017.

[0058] Example 7:

[0059] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1g, the product was 3g, and the yield was 82%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0060]

[0061] 9-methoxy-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one (3g) Lightyellow solid (mpxx oC), 42.4mg, 82% yield. 1 H NMR(400MHz,Chloroform-d)δ7.20(d,J=9.0Hz,1H),7.14(d,J=2.9Hz,1H),7.07(dd,J= 9.0,3.0Hz,1H),6.48(d,J=6.2Hz,1H),4.94(d,J=6.2Hz,1H),3.83(s,3H),1.52(s,6H). 13 HRMS Calculated for C 15 H 15 O4[M+H] + 259.0970, found 259.0957.

[0062] Example 8:

[0063] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1h, and the product yield was 88% after 3h. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0064]

[0065] 4,4,8,9-tetramethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3h)Light yellowsolid(mpxx oC), 45.2mg, 88% yield. 1 H NMR (400MHz, Chloroform-d) δ7.45(s,1H),7.04(s,1H),6.47(d,J=6.2Hz,1H),4.94(d,J=6.2Hz,1H),2.33(s,3H),2.29(s,3H),1.52(s,6H). 13C NMR (101MHz, CDCl3) δ161.49,155.56,150.85,141.68,135.26,132.64,122.87,116.71,116.05,111.78,106.81,29.93,29.62,20.27,19.35.HRMS Calculated forC 16 H 17 O3[M+H] + 257.1178, found 257.1160.

[0066] Example 9:

[0067] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1i, and the yield of product 3i was 53%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0068]

[0069] 8-fluoro-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3i)Lightyellow solid(mpxx oC), 27.7 mg, 53% yield. 1 H NMR (400MHz, Chloroform-d) δ7.73(dd,J=9.5,6.1Hz,1H),7.03–6.98(m,2H),6.48(d,J=6.2Hz,1H),4.96(d,J=6.2Hz,1H),1.52(s,6H). 13 C NMR (101MHz, CDCl3) δ163.44 (d, J = 253.3Hz), 159.77, 154.09, 152.52 (d, J = 13.2Hz), 134.22, 123.84 (d, J = 10.2Hz ), 115.13, 111.02 (d, J = 22.8Hz), 109.94 (d, J = 2.7Hz), 105.85 (d, J = 2.5Hz), 102.69 (d, J = 25.6Hz), 28.89, 28.51. 19 F NMR(376MHz,CDCl3)δ-105.64.HRMS Calculated for C 14 H 12 FO3[M+H] + 247.0770, found 247.0763.

[0070] Example 10:

[0071] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1j, and the yield of product 3j was 53%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0072]

[0073] 8-chloro-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3j)Lightyellow solid(mpxx oC), 27.7 mg, 53% yield. 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.24( dd,J=8.5,2.0Hz,1H),6.48(d,J=6.1Hz,1H),4.96(d,J=6.1Hz,1H),1.52(s,6H). 13 HRMSCalculated for C 14 H 12 ClO3[M+H] + 263.0475, found 263.0480.

[0074] Example 11:

[0075] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1k, and the yield of product 3k was 76%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0076]

[0077] 8-bromo-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3k)Light yellowsolid(mpxx oC), 39.8mg, 76% yield. 1H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.5Hz,1H),7.46(d,J=1.7Hz,1H),7.39( dd,J=8.5,1.8Hz,1H),6.47(d,J=6.2Hz,1H),4.96(d,J=6.2Hz,1H),1.52(s,6H). 13 HRMSCalculated for C 14 H 12 BrO3[M+H] + 306.9970, found 306.9977.

[0078] Example 12:

[0079] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1L, and the product yield was 87%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0080]

[0081] 8-methoxy-4,4-dimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3l)Lightyellow solid(mpxx oC), 44.8mg, 87% yield. 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.8Hz,1H),6.83(dd,J=8.8,2.3Hz,1H),6.76( d,J=2.3Hz,1H),6.47(d,J=6.2Hz,1H),4.95(d,J=6.2Hz,1H),3.86(s,3H),1.52(s,6H). 13 HRMS Calculated for C 15 H 15 O4[M+H]+ 259.0970, found 259.0970.

[0082] Example 13:

[0083] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1m, and the yield of the 3m product was 82%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0084]

[0085] 4,4,8-trimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3m)Light yellowsolid(mpxx oC), 39.7mg, 82% yield. 1 H NMR (400MHz, Chloroform-d) δ7.60(d,J=7.9Hz,1H),7.07(m,2H),6.47(d,J=6.2Hz,1H),4.94(d,J=6.2Hz,1H),2.43(s,3H),1.52(s,6H). 13 HRMS Calculated for C 15 H 15 O3[M+H] + 243.1021, found 243.1011.

[0086] Example 14:

[0087] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1n, and the yield of product 3n was 91%. The structure of the compound was identified by NMR (H1N, C1N and fluorine spectra) and high-resolution mass spectrometry.

[0088]

[0089] 4,4,7-trimethyl-4H,5H-pyrano[3,2-c]chromen-5-one(3n)Light yellowsolid (mpxx oC), 43.9 mg, 91% yield. 1H NMR(400MHz,Chloroform-d)δ7.57(d,J=7.9Hz,1H),7.35(d,J=7.3Hz,1H),7.15(t,J =7.7Hz,1H),6.48(d,J=6.2Hz,1H),4.95(d,J=6.2Hz,1H),2.44(s,3H),1.54(s,6H). 13 HRMS Calculated for C 15 H 15 O3[M+H] + 243.1021, found 243.1004.

[0090] Example 15:

[0091] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1O, and the yield of product 3O was 45%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0092]

[0093] 4,4-dimethyl-4H,5H-benzo[f]pyrano[3,2-c]chromen-5-one(3o)Light yellowsolid(mpxx oC), 24.9 mg, 45% yield. 1 H NMR(400MHz,Chloroform-d)δ9.04(d,J=8.8Hz,1H),7.94(d,J=8.9Hz,1H),7.86(d,J=7.8Hz,1H),7.62(t,J=7.2 Hz,1H),7.53(t,J=7.5Hz,1H),7.41(d,J=8.9Hz,1H),6.65(d,J=6.1Hz,1H),5.05(d,J=6.1Hz,1H),1.61(s,6H). 13C NMR (101MHz, CDCl3) δ160.75,159.13,153.38,134.70,133.73,130.96,129.15,128.92, 128.18,126.29,125.59,116.94,116.11,107.81,107.69,29.96,29.82.HRMSCalculated forC 18 H 15 O3[M+H] + 279.1021, found 279.1014.

[0094] Example 16:

[0095] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1p, and the yield of the 3p product was 77%. The structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0096]

[0097] 1,1-dimethyl-1H,12H-benzo[h]pyrano[3,2-c]chromen-12-one(3p)Lightyellow solid(mpxx oC), 42.8 mg, 77% yield. 1 H NMR (400MHz, Chloroform-d) δ8.54–8.48(m,1H),7.87–7.82(m,1H),7.74–7.59(m,4H),6.53(d,J=6.1Hz,1H),4.99(d,J=6.2Hz,1H),1.58(s,6H). 13 C NMR (101MHz, CDCl3) δ161.11,156.34,149.75,135.41,134.74,128.55,127.75,12 6.99,123.84,122.67,122.41,118.59,116.09,109.53,107.34,30.01,29.58.HRMS Calculated for C 18 H 15 O3[M+H] + 279.1021, found 279.1029.

[0098] Example 17:

[0099] The operation process and conditions were the same as in Example 1. The difference from Example 1 was that the substrate was changed to 1q, the product 3q yield was 64%, and the structure of the compound was identified by NMR (H1N, C1N, and fluorine spectra) and high-resolution mass spectrometry.

[0100]

[0101] 4,4,7-trimethyl-4H,5H-pyrano[4,3-b]pyran-5-one(3q)Light yellow solid(mpxx oC), 24.5mg, 64% yield. 1 H NMR (400MHz, Chloroform-d) δ6.27(d,J=6.2Hz,1H),5.70(s,1H),4.84(d,J=6.2Hz,1H),2.17(d,J=0.8Hz,3H),1.43(s,6H). 13 C NMR(101MHz, CDCl3)δ162.99,160.67,160.03,135.25,115.99,104.86,99.05,29.30,19.69.HRMSCalculated for C 11 H 13 O3[M+H] + 193.0865, found 193.0866.

[0102] Example 18:

[0103] Under nitrogen protection, substrate 1a (0.20 mmol), [Rh(cod)Cl]2 (0.005 mmol), Dppb (0.01 mmol), 4-MeOC6H4SO3H (0.10 mmol), ethylene glycol dimethyl ether (0.4 mL), and dichloromethane (0.5 mL) were sequentially added to a 4 mL pressure-resistant tube. Enyne substrate 2 was added using a microsyringe. The tube was then sealed and the reaction was carried out at 70°C for 24 hours. After the reaction was completed, the target product 4a was obtained by column chromatography with a yield of 80%. The structure of the compound was identified by NMR (1H and 1C spectra).

[0104]

[0105] 2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4a)Known compound, lightyellow solid, 36.4mg, 80% yield. 1H NMR(400MHz,Chloroform-d)δ7.80(dd,J=7.9,1.5Hz,1H),7.52(ddd,J=8.7,7.3,1.6H z,1H),7.34–7.23(m,2H),6.54(d,J=10.0Hz,1H),5.54(d,J=10.0Hz,1H),1.55(s,6H). 13 C NMR (101MHz, CDCl3) δ160.96,158.83,153.15,132.08,126.19,123.97,122.74,116.74,115.56,100.26,80.57,28.58.

[0106] Example 19:

[0107] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1b, the yield of product 4b was 65%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0108]

[0109] 2,2-dimethyl-9-nitro-2H,5H-pyrano[3,2-c]chromen-5-one(4b)Known compound, light yellow solid, 35.6 mg, 65% yield. 1 H NMR(400MHz,Chloroform-d)δ7.79(dd,J=7.9,1.5Hz,1H),7.51(ddd,J=8.6,7.3,1.6H z,1H),7.31–7.24(m,2H),6.53(d,J=10.0Hz,1H),5.52(d,J=10.0Hz,1H),1.54(s,6H). 13 C NMR (101MHz, CDCl3) δ160.96,158.83,153.14,132.09,126.19,123.97,122.74,116.73,115.55,100.25,80.57,28.58.

[0110] Example 20:

[0111] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1c, the yield of product 4c was 51%, and the structure of the compound was identified by NMR (H1N, C1N and fluorine NMR).

[0112]

[0113] 9-fluoro-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4c)Known compound, light yellow solid, 25.2 mg, 51% yield. 1 H NMR(400MHz,Chloroform-d)δ7.44(dd,J=8.3,2.9Hz,1H),7.31–7.23(dd,J=9.0,4.5Hz,1H),7 .22(ddd,J=9.1,7.7,2.9Hz,1H),6.52(d,J=10.0Hz,1H),5.56(d,J=10.0Hz,1H),1.55(s,6H). 13 C NMR (101MHz, CDCl3) δ160.63, 158.72 (d, J = 242.3Hz), 157.92 (d, J = 2.8Hz), 149.22 (d, J = 1.9Hz), 126.84, 119.53 (d,J=24.6Hz),118.35(d,J=8.2Hz),116.49,116.48(d,J=6.3Hz),108.35(d,J=25.3Hz),100.85,80.95,28.60. 19 F NMR (376MHz, CDCl3) δ-117.30.

[0114] Example 21:

[0115] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1d and the product yield was 57% after 4d. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0116]

[0117] 9-chloro-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4d)Known compound, light yellow solid, 31.6 mg, 57% yield. 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=2.5Hz,1H),7.46(dd,J=8.8,2.5Hz,1H),7 .24(d,J=8.8Hz,1H),6.52(d,J=10.0Hz,1H),5.57(d,J=10.0Hz,1H),1.56(s,6H).13 C NMR (101MHz, CDCl3) δ160.34,157.59,151.45,131.96,129.54,126.87,122.20,118.19,116.69,116.44,100.89,81.02,28.60.

[0118] Example 22:

[0119] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1f, the yield of product 4f was 69%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0120]

[0121] 2,2,9-trimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4f)Known compound, light yellow solid, 33.4mg, 69% yield. 1 H NMR(400MHz,Chloroform-d)δ7.59–7.54(d,J=1.9Hz,1H),7.32(dd,J=8.5,1.9Hz,1H),7.19 (d,J=8.4Hz,1H),6.54(d,J=10.0Hz,1H),5.52(d,J=10.0Hz,1H),2.42(s,3H),1.56(s,6H). 13 C NMR (101MHz, CDCl3) δ161.16,158.84,151.33,133.71,133.15,126.02,122.34,116.86,116.49,115.19,100.19,80.45,28.56,20.92.

[0122] Example 23:

[0123] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1g and the product yield was 4g with a yield of 22%. The structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0124]

[0125] 9-methoxy-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one (4g)Known compound, light yellow solid, 11.2mg, 22% yield.1 H NMR(400MHz,Chloroform-d)δ7.23(d,J=9.0Hz,1H),7.18(d,J=3.0Hz,1H),7.10(dd,J=9 .0,3.0Hz,1H),6.54(d,J=10.0Hz,1H),5.53(d,J=10.0Hz,1H),3.87(s,3H),1.55(s,6H). 13 C NMR (101MHz, CDCl3) δ161.12,158.58,155.91,147.68,126.23,120.17,117.90,116.87,115.88,104.43,100.47,80.61,55.91,28.58.

[0126] Example 24:

[0127] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1h, the product yield was 59% after 4h, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0128]

[0129] 2,2,8,9-tetramethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4i)Known compound, light yellow solid, 28.5mg, 59% yield. 1 H NMR (400MHz, Chloroform-d) δ7.51(s,1H),7.07(s,1H),6.53(d,J=10.0Hz,1H),5.49(d,J=10.0Hz,1H),2.34(s,3H),2.32(s,3H),1.54(s,6H). 13 C NMR (101MHz, CDCl3) δ161.34,159.13,151.66,142.28,132.81,125.52,122.61,117.27,116.99,113.05,99.46,80.31,28.52,20.35,19.28.

[0130] Example 25:

[0131] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1i, the product 4i yield was 37%, and the structure of the compound was identified by NMR (H1N, C1N, and fluorine NMR).

[0132]

[0133] 8-fluoro-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4i)Known compound, light yellow solid (mpxx oC), 18.2 mg, 37% yield. 1 H NMR (400MHz, Chloroform-d) δ7.79(dd,J=9.5,6.1Hz,1H),7.00(m,2H),6.51(d,J=10.0Hz,1H),5.52(d,J=10.0Hz,1H),1.55(s,6H). 13 C NMR (101MHz, CDCl3) δ164.80 (d, J = 253.7Hz), 160.67, 158.51, 154.30 (d, J = 13.2Hz), 126.03, 124.57 (d, J = 10.3H z), 116.54, 112.21 (d, J = 2.6Hz), 112.17 (d, J = 22.9Hz), 104.24 (d, J = 25.6Hz), 99.27 (d, J = 2.2Hz), 80.84, 28.59. 19 F NMR (376MHz, CDCl3) δ -104.86.

[0134] Example 26:

[0135] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1j and the yield of product 4j was 57%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0136]

[0137] 8-chloro-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4j)Lightyellow solid(mpxx oC), 29.9 mg, 57% yield. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.24(d d,J=8.5,1.9Hz,1H),6.50(d,J=10.0Hz,1H),5.54(d,J=10.0Hz,1H),1.54(s,6H). 13HRMS Calculated for C 14 H 12 ClO3[M+H] + 263.0475, found 263.0477.

[0138] Example 27:

[0139] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1k and the product 4k yield was 68%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0140]

[0141] 8-bromo-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4k)Light yellowsolid(mpxx oC), 41.5mg, 68% yield. 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.5Hz,1H),7.45(d,J=1.8Hz,1H),7.38(d d,J=8.5,1.8Hz,1H),6.49(d,J=10.0Hz,1H),5.54(d,J=10.0Hz,1H),1.53(s,6H). 13 HRMSCalculated for C 14 H 12 BrO3[M+H] + 306.9970, found 306.9977.

[0142] Example 28:

[0143] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1L, the product yield was 56%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0144]

[0145] 8-methoxy-2,2-dimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4l)Known compound, light yellow solid (mpxx oC), 28.9mg, 56% yield. 1 H NMR(400MHz,Chloroform-d)δ7.69(d,J=8.8Hz,1H),6.85(d,J=2.4Hz,1H),6.77(d,J= 2.4Hz,1H),6.51(d,J=10.0Hz,1H),5.46(d,J=10.0Hz,1H),3.86(s,3H),1.52(s,6H). 13 C NMR (101MHz, CDCl3) δ163.15,161.32,159.45,155.03,125.04,123.88,116.88,112.41,108.77,100.50,97.88,80.43,55.78,28.56.

[0146] Example 29:

[0147] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1m and the product 4m yield was 39%. The structure of the compound was identified by NMR (H1N and C1N spectra).

[0148]

[0149] 2,2,8-trimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4m)Known compound, yellow solid (mpxx oC), 19.1 mg, 39% yield. 1 H NMR (400MHz, Chloroform-d) δ7.66(d,J=7.9Hz,1H),7.07(m,2H),6.52(d,J=10.0Hz,1H),5.49(d,J=10.0Hz,1H),2.43(s,3H),1.53(s,6H). 13 C NMR (101MHz, CDCl3) δ161.15,159.12,153.30,143.37,125.68,125.19,122.46,116.86,113.05,99.43,80.40,28.54,21.80.

[0150] Example 30:

[0151] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1n, the yield of product 4n was 43%, and the structure of the compound was identified by NMR (H1N and C1N spectra).

[0152]

[0153] 2,2,7-trimethyl-2H,5H-pyrano[3,2-c]chromen-5-one(4n)Known compound, light yellow solid, 20.6 mg, 43% yield. 1 H NMR(400MHz,Chloroform-d)δ7.65(d,J=7.9Hz,1H),7.37(d,J=7.3Hz,1H),7.17(t,J= 7.6Hz,1H),6.56(d,J=10.4Hz,1H),5.53(d,J=10.0Hz,1H),2.45(s,3H),1.55(s,6H). 13 C NMR (101MHz, CDCl3) δ160.97,159.14,151.52,133.34,126.12,126.03,123.47,120.36,116.86,115.29,100.01,80.39,28.52,15.69.

[0154] Example 31:

[0155] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1O and the product 4O yield was 62%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0156]

[0157] 2,2-dimethyl-2H,5H-benzo[f]pyrano[3,2-c]chromen-5-one(4o)Light yellowsolid(mpxx oC), 34.4mg, 62% yield. 1H NMR(400MHz,Chloroform-d)δ9.22(d,J=8.8Hz,1H),7.93(d,J=9.0Hz,1H),7.86(d,J=7.9Hz,1H),7.63(t,J=7.8 Hz,1H),7.54(t,J=7.5Hz,1H),7.41(d,J=9.0Hz,1H),6.63(d,J=9.9Hz,1H),5.58(d,J=9.9Hz,1H),1.68(s,6H). 13 C NMR (101MHz, CDCl3) δ162.37,160.63,154.16,133.88,130.85,129.04,129.01,128.23, 126.15,125.76,125.57,117.42,117.30,109.04,101.03,81.02,28.56.HRMSCalculated for C 18 H 15 O3[M+H] + 279.1021, found 279.1024.

[0158] Example 32:

[0159] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1p and the yield of the 4p product was 67%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0160]

[0161] 3,3-dimethyl-3H,12H-benzo[h]pyrano[3,2-c]chromen-12-one(4n)Lightyellow solid(mpxx oC), 37.2mg, 67% yield. 1 H NMR(400MHz,Chloroform-d)δ8.55–8.48(m,1H),7.86–7.81(m,1H),7.76(d,J=8.7Hz ,1H),7.66–7.58(m,3H),6.59(d,J=10.0Hz,1H),5.54(d,J=10.0Hz,1H),1.58(s,6H). 13C NMR (101MHz, CDCl3) δ160.92,159.87,150.57,135.05,128.66,127.82,127.04,12 5.88,123.95,122.95,122.60,118.31,116.86,110.76,99.94,80.66,28.64.HRMS Calculated for C 18 H 15 O3[M+H] + 279.1021, found 279.1014.

[0162] Example 33:

[0163] The operation process and conditions were the same as in Example 18, except that the substrate was changed to 1q and the yield of product 4q was 62%. The structure of the compound was identified by NMR (H1N and C1N) and high-resolution mass spectrometry.

[0164]

[0165] 2,2,7-trimethyl-2H,5H-pyrano[4,3-b]pyran-5-one(4q)Known compound, light yellow solid, 8.1 mg, 21% yield. 1 H NMR (400MHz, Chloroform-d) δ6.38(d,J=10.0Hz,1H),5.77(s,1H),5.36(d,J=10.0Hz,1H),2.21(d,J=1.0Hz,3H),1.44(s,6H). 13 CNMR (101MHz, CDCl3) δ164.16,162.38,124.84,116.33,100.33,97.90,80.11,28.53,20.21.

[0166] Comparative Example 1:

[0167] The operation process and conditions were the same as in Example 1, except that no alkali was added, the yield of product 3a was 1%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0168] Comparative Example 2:

[0169] The operation process and conditions were the same as in Example 1, except that no rhodium catalyst and ligand were added, the yield of product 3a was 0%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0170] Comparative Example 3:

[0171] The operation process and conditions were the same as in Example 18, except that no rhodium catalyst was added, the yield of product 4a was 0%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0172] Comparative Example 4:

[0173] The operation process and conditions were the same as in Example 18, except that a rhodium catalyst was added but no phosphine ligand was added. The yield of product 4a was 0%, and the structure of the compound was identified by nuclear magnetic resonance (H1N and C1N spectra).

[0174] Comparative Example 5:

[0175] The operation process and conditions are the same as in Example 18, except that benzoic acid is used instead of acid, and no product 4a is generated.

Claims

1. A method for synthesizing diffusing pyranocoumarins using hydrogen functionalization, characterized in that: The reaction formula is as follows: Where R 1 It can be one or more of the following groups: halogen atom substituents (such as one or more of fluorine, chlorine, and bromine), C1-C5 alkyl substituents (such as one or more of methyl, ethyl, and tert-butyl), oxygen-containing substituents (such as one or more of methoxy, ethoxy, and tert-butoxy), and nitro groups. Alternatively, the starting compound of Formula 1 may also be one or more of the following: fused-ring compounds such as benzocoumarin (e.g., if the starting compound of Formula 1 is one or two of 1O or 1P, the corresponding product is 4O or 4P) or simple pyranone substrates (e.g., if the starting compound of Formula 1 is 1Q, the corresponding product is 4Q).

2. The method according to claim 1, characterized in that: The specific operating steps are as follows: Under an inert atmosphere (e.g., nitrogen and / or argon), substrates 1 and 2, a rhodium catalyst, a phosphine ligand, a base, and a solvent were added to a container and reacted at 60-70 degrees Celsius for 18-24 hours. After the reaction was completed, pyranocoumarin analog 3 was isolated. Alternatively, under an inert atmosphere (e.g., nitrogen and / or argon), substrates 1 and 2, a rhodium catalyst, a phosphine ligand, an acid, and a solvent are added to a container, and the reaction is carried out at 60-70 degrees Celsius for 18-24 hours; after the reaction is completed, pyranocoumarin analog 4 is isolated.

3. The method according to claim 1 or 2, characterized in that: The preferred molar ratio of substrate 1, substrate 2, rhodium catalyst [Rh(cod)Cl]2, monodentate phosphine ligand L1, bidentate phosphine ligand L2, and acid or base is 1.0:2.0:0.025:0.05:0.1:0.

5.

4. The method according to claim 1 or 2, characterized in that: The rhodium catalyst used can be one or more of [Rh(cod)Cl]2, [Rh(CH2CH2)Cl]2, and [Rh(coe)2Cl]2, preferably [Rh(cod)Cl]2 as the reaction catalyst, and the amount used is 0.02-0.04 molar equivalents (relative to raw material 1), preferably 0.025-0.03 molar equivalents.

5. The method according to claim 1 or 2, characterized in that: The L1 ligand used can be one of the monophosphine ligands PPh3, (4-MeC6H4)3P, (4-MeOC6H4)3P, (4-FC6H4)3P, (4-ClC6H4)3P, and (4-CF3C6H4)3P, preferably (4-FC6H4)3P, and the amount used is 0.08-0.16 molar equivalents (relative to raw material 1), preferably 0.10-0.12 molar equivalents.

6. The method according to claim 1 or 2, characterized in that: The L2 ligand used can be one or more of the following phosphine ligands: BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine)), Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene), Dppb (1,4-bis(diphenylphosphine)butane), Dppf (1,1'-bis(diphenylphosphine)ferrocene), DppBz (1,2-bis(diphenylphosphino)benzene), and Dppe (1,2-bis(diphenylphosphine)ethane). Preferably, BINAP or Dppe is the bisphosphine ligand L2, and the amount used is 0.04-0.08 molar equivalents (relative to feedstock 1), preferably 0.05-0.06 molar equivalents.

7. The method according to claim 1 or 2, characterized in that: The acid used can be one or more of benzenesulfonic acid, 4-methoxybenzenesulfonic acid, and diphenyl phosphate, preferably 4-methoxybenzenesulfonic acid, and the amount used is 0.4-0.7 molar equivalents (relative to raw material 1), preferably 0.5-0.6 molar equivalents; The base used can be one or more of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (triethylenediamine), and triethylamine, preferably DABCO (triethylenediamine), and the amount used is 0.4-0.7 molar equivalents (relative to raw material 1), preferably 0.5-0.6 molar equivalents.

8. The method according to claim 1 or 2, characterized in that: The solvent used can be one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methanol, and ethanol; the amount used is 0.5-1.0 ml relative to 0.20 mmol of raw material 1.

9. The method according to claim 1 or 2, characterized in that: The molar ratio of substrate 1 to substrate 2 is 1.0:1.5-2.0.

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