Method for synthesizing olefin furan compound from eneyne ketone under catalysis of rhodium

Abstract

The invention provides a method for synthesizing an olefin furan compound by catalyzing eneyne ketone through rhodium metal. The synthesis method of the alkenyl furan comprises the following step: reacting an eneyne ketone compound with alkenyl azide under the catalysis of cheap metal rhodium to generate the alkenyl furan compound. The synthesis method is simple and rapid, mild in condition, neutral in reaction condition, free of hidden danger of equipment corrosion, and capable of reacting under air condition without inert gas protection. Therefore, the method has potential industrial application value. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for synthesizing an olefin furan compound by using rhodium to catalyze enynone. Background Art

[0002] Alkenylfurans are versatile synthetic molecules that serve as building blocks for natural products and pharmaceuticals. Their preparation has garnered extensive research and attention. However, current technology for preparing alkenylfuran molecules from enynones requires catalytic conditions that are sensitive to water and oxygen, requiring inert gas protection and air sensitivity. Furthermore, the synthesized compounds carry the risk of heavy metal residues. For example:

[0003] Method 1 (J.Org.Chem.2024,89,7275-7279)

[0004]

[0005] Method 2 (J.Am.Chem.Soc.2013,135,13502-13511)

[0006]

[0007] Method 1 requires the synthesis of alkenylfuran compounds through two steps using an enynone compound, using palladium as a catalyst, and requires operation in a glove box (strictly anhydrous and oxygen-free). Method 2 also uses a palladium catalyst to prepare alkenylfuran, requires operation under an argon atmosphere, and the reaction needs to be carried out under alkaline conditions.

[0008] The present invention provides a method for mildly preparing alkenylfurans, which utilizes an alkenyl ketone compound and a transition metal rhodium as a catalyst. The method reacts under neutral conditions without the need for inert gas protection, has high conversion efficiency, does not require the assistance of strong acids or bases in catalysis, and has no hidden dangers of equipment corrosion, thus having potential industrial application value. Summary of the Invention

[0009] The present invention discloses a method for preparing an alkenylfuran compound. This method utilizes neutral reaction conditions, eliminates the need for inert gas protection, achieves high conversion efficiency, eliminates the need for strong acid or base catalysis, and eliminates the risk of equipment corrosion. The raw material, an inexpensive and readily available enynone compound, allows for the one-step construction of the alkenylfuran compound. The synthesized alkenylfuran compound is compatible with carbonyl substituents.

[0010] The present invention is an original method for synthesizing alkenylfuran compounds by rhodium catalysis, which has not been reported in the literature before the application date.

[0011] A rhodium-catalyzed synthesis of olefin furan compounds from enynone is characterized by the following:

[0012] Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect;

[0013] Wherein: X is a carbon or phosphine group;

[0014] Where: R 3 C1~C 12 alkyl, aryl or heteroaryl; wherein R 3 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent;

[0015] The present invention is achieved through the following technical solutions:

[0016] The alkenyl ketone compound 1 is dissolved in a solvent, a catalyst and alkenyl azide 2 are added, and after the reaction, the alkenyl furan compound 3 is separated and purified.

[0017] Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect;

[0018] Wherein: X is a carbon or phosphine group;

[0019] Where: R 3 C1~C 12 alkyl, aryl or heteroaryl; wherein R 3 Any one or more hydrogen atoms of the upper aromatic ring may be replaced by a substituent;

[0020] Where: R is C1~C 12 Alkyl, aryl and heteroaryl; any one or more hydrogen atoms of the aromatic ring on R may be replaced by a substituent;

[0021] The catalyst is one of Rh2(OAc)4, Rh2(OPiv)4, Rh2(esp)2, [Rh(Cp*)Cl2]2, Rh2(TPA)4, Rh2(oct)4, and Rh2(TFA)4; the preferred catalyst is Rh2(OAc)4.

[0022] The molar ratio of the metal catalyst to the alkenyl ketone compound is preferably 0.001 to 1:1, preferably 0.02:1.

[0023] The molar ratio of the alkenyl azide to the alkenyl ketone compound is 1 to 10:1, preferably 1.5:1.

[0024] The solvent is selected from the group consisting of 1,2-dichloroethane, 1,1-dichloromethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, and xylene. The preferred solvent is 1,2-dichloroethane.

[0025] The ratio of the solvent to the enynone compound is 1 to 20 mL:1 mmol, preferably 10 mL:1 mmol.

[0026] The reaction conditions are 0°C to 120°C for 0.5h to 48h, preferably 40°C for 24h.

[0027] The enynone compound can be prepared by referring to known literature. (J.Am.Chem.Soc.2013,135,13502–13511)

[0028] Method 1

[0029] Method 2

[0030] Method 3

[0031] Alkenylfuran compounds are important molecular building blocks, and their derivatives, benzofuran compounds, are important anticancer drugs, such as the marketed metastatic colorectal cancer drug Fruquintinib. The benzofuran skeleton is also the active skeleton of important hypnotic drugs, such as the marketed sleep disorder drug Tasimelteon. Alkenylfuran compounds are important intermediates in the synthesis of benzofuran compounds, and therefore, methods for synthesizing alkenylfuran compounds and their derivatives have significant potential applications. This invention provides a method for efficiently constructing alkenylfuran compounds using inexpensive metals.

[0032]

[0033] Examples of alkenyl furan compounds that can be prepared by the present invention are as follows:

[0034]

[0035] Compared with the prior art, the present invention has the following advantages and effects:

[0036] The preparation process of the present invention operates under neutral conditions, eliminating the need for inert gas protection, resulting in efficient conversion, no need for strong acid or base catalysis, and no potential for equipment corrosion. The raw material, the enynone compound, is inexpensive and readily available, allowing the construction of an alkenylfuran compound in a single step. The synthesized alkenylfuran compound is molecularly compatible with carbonyl substituents. DETAILED DESCRIPTION

[0037] The present invention is further described below with reference to specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art and can be directly purchased or synthesized by known literature methods.

[0038] Example 1

[0039]

[0040] In a reaction tube equipped with a stirrer, Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1a (42.4 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol) and 1,2-dichloroethane (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate 20:1 by volume) to obtain product 3a (80%) as a yellow oily liquid. 1 H NMR (400MHz, Chloroform-d) δ7.47–7.36(m,5H),6.36(s,1H),5.75(s,1H),5.25(s,1H),2.65(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.2,158.6,151.7,139.1,138.5,128.4,128.3,122.9,112.6,109.3,29.2,14.6; HRMS(ESI)Calcd for C 15 H 15 O2(M+H) + 227.1067,found227.1076.

[0041] Example 2

[0042]

[0043] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1b (48.4 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain product 3b (87%) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ7.37(d,J=8.9Hz,2H),6.93(d,J=8.8Hz,2H),6.37(s,1H),5.68(s,1H),5.20(s,1H),3.85(s,3H),2.64(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.2,159.7,158.6,152.0,137.9,131.5,129.4,122.9,113.8,111.8,109.1,55.3,29.1,14.6; HRMS(ESI)Calcd for C 16 H 16 O3(M+H) + 257.1172, found 257.1173.

[0044] Example 3

[0045]

[0046] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1c (49.2 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to afford product 3c (99%) as a yellow solid with a melting point of 53-55°C. 1 H NMR(400MHz,Chloroform-d)δ7.37(s,4H),6.34(s,1H),5.75(s,1H),5.23(s,1H),2.64(s,3H),2.36(s,3H); 13C NMR(101MHz, CDCl3)δ194.0,158.8,151.3,137.5,134.2,129.6,128.6,122.9,113.0,109.3,29.1,14.6; HRMS(ESI)Calcd forC 15 H 13 ClO2(M+H) + 261.0677,found 261.0686.

[0047] Example 4

[0048]

[0049] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1d (58.0 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to afford product 3d (89%) as a yellow solid with a melting point of 56-58°C. 1 H NMR (400MHz, Chloroform-d) δ7.52(d,J=8.4Hz,2H),7.30(d,J=8.4Hz,2H),6.34(s,1H),5.75(s,1H),5.24(s,1H),2.64(s,3H),2.35(s,3H); 13 C NMR(101MHz, CDCl3)δ194.0,158.8,151.2,137.9,137.5,131.6,129.9,122.9,122.3,113.0,109.3,29.1,14.6; HRMS(ESI)Calcd for C 15 H 13 BrO2(M+H) + 305.0172,found 305.0182.

[0050] Example 5

[0051]

[0052] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1e (50.8 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain product 3e (69%) as a yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.99(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,2H),6.36(s,1H),5.82(s,1H),5.32(s,1H),2.65(s,3H),2.64(s,3H),2.36(s,3H); 13 C NMR(101MHz, CDCl3)δ197.6,194.0,158.8,151.0,143.7,137.7,136.9,128.5,128.5,123.0,113.8,109.4,29.1,26.7,14.6; HRMS(ESI)Calcd for C 17 H 16 O3(M+H) + 269.1172,found269.1181.

[0053] Example 6

[0054]

[0055] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1f (54.0 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 10:1 by volume) to yield product 3f (99%) as a yellow solid with a melting point of 120-122°C. 1 H NMR (400MHz, Chloroform-d) δ8.07(d,J=8.5Hz,2H),7.51(d,J=8.4Hz,2H),6.35(s,1H),5.81(s,1H),5.31(s,1H),3.95(s,3H),2.65(s,3H),2.35(s,3H); 13C NMR(101MHz, CDCl3)δ194.0,166.8,158.8,151.0,143.6,137.8,130.0,129.8,128.3,122.9,113.7,109.4,52.2,29.1,14.6; HRMS(ESI)Calcd for C 17 H 16 O4(M+H) + 285.1121, found 285.1124.

[0056] Example 7

[0057]

[0058] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1g (56.0 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 10:1 by volume) to obtain 3 g (77%) of the product as a yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.66(d,J=8.3Hz,2H),7.55(d,J=7.9Hz,2H),6.34(s,1H),5.82(s,1H),5.29(s,1H),2.65(s,3H),2.36(s,3H); 13 C NMR (101MHz, CDCl3) δ194.0,158.9,151.0,142.6,137.5,130.4(d,J2=33.3Hz),12 8.6,127.4(d,J3=10.1Hz),125.4(q,J1=11.1Hz),123.0,113.8,109.4,29.1,14.6; 19 F NMR(376MHz, CDCl3)δ-62.59; HRMS(ESI)Calcd for C 16 H 13 F3O2(M+H) + 295.0940,found 295.0939.

[0059] Example 8

[0060]

[0061] In a reaction tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1h (52.4 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to yield product 3h (75%) as a yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.88–7.83(m,3H),7.55–7.49(m,3H),6.39(s,1H),5.83(s,1H),5.36(s,1H),2.66(s,3H),2.33(s,3H); 13 C NMR (101MHz, CDCl3) δ194.2,158.7,151.8,138.6,136.5,133.3,133.2,132.1,129.9,128.2, 128.0,127.7,127.2,126.4,126.4,126.3,122.9,113.1,109.4,29.1,14.6; HRMS(ESI)Calcd forC 19 H 16 O2(M+H) + 277.1223, found 277.1227.

[0062] Example 9

[0063]

[0064] To a dry Schlenk tube with a stirring bar, Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1i (55.6 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL) were added and stirred at 40°C for 14 h. After the reaction was complete, the solvent was removed and the product was purified by flash column chromatography (eluent: petroleum ether: ethyl acetate 2:1 by volume) to obtain the product 3i (77%) as a yellow oily liquid. 1 H NMR(400MHz,Chloroform-d)δ7.43–7.40(m,2H),7.39–7.36(m,3H),6.22(d,J=3.4 Hz,1H),5.75(s,1H),5.25(s,1H),3.74(s,3H),3.71(s,3H),2.58(d,J=2.1Hz,3H); 13CNMR(101MHz,CDCl3)δ160.7(d,J3=27.3Hz),153.1(d,J2=15.2Hz),138.9,138.4,12 8.4,128.2,112.7,111.1(d,J2=12.1Hz),107.3(d,J1=217.2Hz),52.43,52.38,13.7; 31 P NMR (162MHz, CDCl3) δ17.58; HRMS (ESI) Calcd for C 15 H 17 O4P(M+H) + 293.0937,found 293.0940.

[0065] Example 23

[0066]

[0067] To a dry Schlenk tube equipped with a stirrer, add Rh2(OAc)4 (1.8 mg, 0.004 mmol), 1j (47.6 mg, 0.2 mmol), 2a (47.7 mg, 0.3 mmol), and 1,2-dichloroethane (2 mL). Stir at 40°C for 14 h. Once the reaction is complete, remove the solvent and purify by flash column chromatography (eluent: petroleum ether:ethyl acetate 20:1 by volume) to obtain product 3j (41%) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.43–7.39(m,2H),7.37–7.34(m,3H),6.50(s,1H),5.73(s,1H),5 .25(s,1H),3.08(t,J=6.3Hz,2H),2.75–2.72(m,2H),2.07–2.02(m,2H),1.97–1.92(m,2H); 13C NMR(101MHz, CDCl3)δ196.6,161.8,152.5,138.9,138.6,128.3,128.2,125.1,112.6,109.3,44.5,29.8,24.9,22.9; HRMS(ESI)Calcdfor C 17 H 16 O2(M+H) + 253.1223, found 253.1231.

[0068] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for synthesizing an olefin furan compound by using rhodium-catalyzed enynones, characterized in that: Where: R is C1~C 12 Alkyl, aryl and heteroaryl; any one or more hydrogen atoms of the aromatic ring on R may be replaced by a substituent; Where: R 1 , R 2 All are C1~C 12 Alkyl, aryl, heteroaryl; R 1 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent; R 1 , R 2 To connect or not to connect; Wherein: X is a carbon or phosphine group; Where: R 3 C1~C 12 Alkyl, aryl or heteroaryl; wherein, R 3 Any one or more hydrogen atoms on the aromatic ring may be replaced by a substituent.

2. The method for synthesizing an olefin furan compound by using rhodium-catalyzed enynone according to claim 1, wherein: The steps include: Under air conditions, the enynone compound is dissolved in a solvent, a catalyst and alkenyl azide are added, and after the reaction, the alkenyl furan compound is separated and purified to obtain the alkenyl furan compound.

3. The preparation method according to claim 2, wherein: The catalyst is one of Rh2(OAc)4, Rh2(OPiv)4, Rh2(esp)2, [Rh(Cp*)Cl2]2, Rh2(TPA)4, Rh2(oct)4, and Rh2(TFA)4.

4. The preparation method according to claim 2, wherein: The molar ratio of the catalyst to the enynone compound is 0.001 to 1:

1.

5. The preparation method according to claim 2, wherein: The reaction is carried out at 0°C-120°C.

6. The preparation method according to claim 2, wherein: 0.5h~48h; the preferred time is 24h.

7. The preparation method according to claim 2, characterized in that: The solvent is selected from one of 1,1-dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, trifluorotoluene, 1,4-dioxane, acetonitrile, toluene, chlorobenzene, and xylene; the preferred solvent is 1,2-dichloroethane.

8. The preparation method according to claim 2, wherein: The volume molar ratio of the solvent to the enynone compound is 1-20 mL:1 mmol, and the preferred ratio is 10 mL:1 mmol.

9. The molar ratio of the alkenyl azide to the alkenyl ketone compound according to claim 2 is 0.1:1 to 10:1.

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