A method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorocyclization

Abstract

This invention relates to the field of organic synthesis and discloses a method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization. This method utilizes the intramolecular defluorination cyclization reaction of γ,γ-difluoroallylimine substrates under palladium catalysis to achieve the efficient preparation of 3-fluoropyrrole compounds. Compared with traditional methods for synthesizing 3-fluoropyrrole compounds, this invention has the following advantages: inexpensive and readily available raw materials; simple experimental operation; high reaction yield; wide applicability; and the ability to obtain a series of 3-fluoropyrrole derivatives.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and specifically to a novel method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization reaction. Background Technology

[0002] Nitrogen-containing heterocyclic compounds are important components in the structures of bioactive molecules, natural products, and drugs. 3-Fluoropyrrole, as a key structure in this group, holds significant value in pharmaceutical research and drug development due to its unique electronic properties and chemical stability. However, most existing synthetic methods for 3-fluoropyrrole require multiple steps, have low yields, are often accompanied by side reactions, and have limited applicability.

[0003] Reference 1 (Eur. J. Org. Chem. 2019, 2339) discloses a method for synthesizing polysubstituted 2-fluoropyrrole and 3-fluoropyrrole from 2,3,4,5-tetrabromopyrrole. The specific reaction process is shown below:

[0004]

[0005] Reference 2 (Org. Biomol. Chem. 2016, 14, 183) discloses a method for synthesizing multifunctionalized 3-fluoropyrroles from commercial aldehydes. This method enables the modular and systematic assembly of multisubstituted 3-fluoropyrroles. The specific reaction process is shown below:

[0006]

[0007] Reference 3 (Org. Lett. 2009, 11, 2920) discloses a method for synthesizing 2-aryl-3-fluoropyrrole compounds via the cyclization and dehydrogenation reaction of γ,γ-difluoropropargylamine catalyzed by gold trichloride. The specific reaction process is shown below:

[0008]

[0009] While the above synthetic methods can achieve the synthesis of 3-fluoropyrrole compounds, they still have many limitations: for example, long synthetic routes, numerous steps, harsh reaction conditions, high cost of raw materials and reagents, and limited applicability of raw materials. Therefore, there is an urgent need to develop a new synthetic method that can more universally and efficiently construct 3-fluoropyrrole compounds. This invention mainly studies a method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization reactions. Starting from commercially available or inexpensive raw materials, this method first prepares γ,γ-difluoroallyl ketone compounds with different functional groups, and then performs a one-step condensation to obtain various types of γ,γ-difluoroallyl imine reaction substrates. Under alkaline conditions, these substrates undergo intramolecular defluorination cyclization reactions under palladium catalysis, yielding 3-fluoropyrrole compounds with broad functional group compatibility and good yields. Summary of the Invention

[0010] This invention provides a method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization. This method offers advantages such as simple operation, wide substrate applicability, and high yield. The method involves first condensing γ,γ-difluoroallyl ketone compounds to obtain γ,γ-difluoroallyl imine substrates. Under alkaline conditions, these substrates undergo intramolecular defluorination cyclization using a palladium catalyst to yield 3-fluoropyrrole compounds.

[0011] To solve the technical problem of this invention, the proposed technical solution is: a novel method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization reaction, comprising the following steps:

[0012] Step 1: Under a nitrogen atmosphere, aryltriphenylamine phosphine compound (Formula 2) and γ,γ-difluoroallyl ketone compound (Formula 1) are added to toluene to obtain a mixture.

[0013] Step 2: Stir the mixture described in Step 1 at 110°C until the reaction is complete. Filter the crude product through a short silica gel column and concentrate it under reduced pressure to obtain γ,γ-difluoroallylimine compounds (Formula 3).

[0014] Step 3: Under a nitrogen atmosphere, palladium catalyst, base, and γ,γ-difluoroallylimide obtained in Step 2 are added to a solvent. The resulting mixture is stirred at a suitable temperature until the reaction is complete, extracted, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 3-fluoropyrrole compound (Formula 4);

[0015] The specific reaction route is as follows:

[0016]

[0017] Where R 1 For: aryl, ester, alkyl, cinnamyl, phenylethynyl, and myrtleenal related fragments; R 2The components are: hydrogen, 4-methoxy, 4-trifluoromethyl, 4-chloro, 3,5-dimethoxy, and 2-methyl.

[0018] Preferably, the γ,γ-difluoroallylimine compounds are derived from the dehydration condensation of various γ,γ-difluoroallyl ketone compounds.

[0019] Preferably, the palladium catalyst is tetra(triphenylphosphine)palladium.

[0020] Preferably, the alkali is potassium carbonate.

[0021] Preferably, the solvent is anhydrous N,N-dimethylacetamide.

[0022] Preferably, the reaction temperature is 120°C and the reaction time is 12h to 16h.

[0023] Preferably, the reaction molar ratio is γ,γ-difluoroallylimine compound: tetra(triphenylphosphine)palladium: potassium carbonate = 1:0.05:2.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] 1. This invention simplifies the synthesis steps of 3-fluoropyrrole compounds, making the entire synthesis process more direct and easier to operate.

[0026] 2. The reaction system of the present invention is clean, has a high conversion rate, and the products are easy to separate.

[0027] 3. By optimizing reaction conditions, this invention can obtain the target compound in high yield, thereby reducing costs and improving efficiency.

[0028] 4. This invention directly constructs pyrrole rings through palladium-catalyzed intramolecular defluorination cyclization, avoiding unnecessary side reactions and waste generation, and improving the utilization rate of raw materials and atom economy.

[0029] 5. This invention is carried out under relatively mild reaction conditions, and the tetra(triphenylphosphine)palladium used is relatively inexpensive and readily available among transition metal catalysts, which helps to reduce potential environmental impact and may reduce the requirements for reaction equipment. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0031] Figure 1 The nuclear magnetic resonance of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of this invention. 1 H spectrum;

[0032] Figure 2 The nuclear magnetic resonance of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of this invention. 19 F-spectrum;

[0033] Figure 3 The nuclear magnetic resonance of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of this invention. 13 C spectrum;

[0034] Figure 4 The nuclear magnetic resonance of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of this invention. 1 H spectrum;

[0035] Figure 5 The nuclear magnetic resonance of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of this invention. 19 F-spectrum;

[0036] Figure 6 The nuclear magnetic resonance of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of this invention. 13 C-spectrum. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0038] The method of this invention can synthesize various types of 3-fluoropyrrole compounds through the same mechanism, depending on the different structures of the reaction substrates.

[0039] (1) Using tetraphenylphosphine as a template substrate, the practicality of the method was discussed using different types of γ,γ-difluoroallylimine compounds. The specific reaction equations are as follows:

[0040]

[0041] The R group can be aryl, ester, alkyl, cinnamyl, phenylethynyl, or myrtol-related fragments.

[0042] The target product has the following structural formula:

[0043]

[0044] (2) Using 2,2-difluoro-1-(4-methoxyphenyl)but-3-en-1-one as a template substrate, the practicality of the method was discussed using different types of aryltriphenylphosphine compounds. The specific reaction equations are as follows:

[0045]

[0046] The R group is 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2-methylphenyl, 4-chlorophenyl, or 4-trifluoromethylphenyl.

[0047] The specific structure of the target product is as follows:

[0048]

[0049] 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole

[0050]

[0051] (4a) 1 H NMR (400MHz, CDCl3): δ7.35-7.26(m,3H),7.15-7.09(m,2H),7.08-6.98(m,2H),6 .84-6.74(m,2H),6.64(dd,J=5.1,3.3Hz,1H),6.16(d,J=3.3Hz,1H),3.77(s,3H). 19 F NMR (376MHz, CDCl3): δ-164.20 (d, J=5.8Hz). 13 C NMR (100MHz, CDCl3): δ158.29, 149.97 (d, J = 242.1Hz), 140.36, 130.20 (d, J = 2.3Hz), 129.19, 126.73, 125.44, 122.07 (d,J=3.2Hz),118.96(d,J=6.3Hz),116.64(d,J=21.9Hz),113.77,98.07(d,J=16.8Hz),55.27.HRMS(ESI,m / z):calcd for C 17 H 15 FNO,[M+H] + :268.1138,found:269.1139.

[0052] 4-(3-fluoro-1-phenyl-1H-pyrrol-2-yl)benzonitrile

[0053]

[0054] (4b) 1 H NMR(400MHz,CDCl3):δ7.52-7.46(m,2H),7.41-7.29(m,3H),7.22-7.16(m,2H),7.14-7.09(m,2H),6.73(dd,J=5.2,3.3Hz,1H),6.19(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-158.75(d,J=4.6Hz). 13 C NMR(100MHz,CDCl3):δ151.83(d,J=248.7Hz),139.81,134.11(d,J=3.9Hz),132.02,129.66,128.40(d,J=3.6Hz),127.60,125.49,122.23(d,J=6.2Hz),119.13,115.20(d,J=20.0Hz),109.31,98.69(d,J=16.7Hz).HRMS(ESI,m / z):calcd for C 17 H 12 FN2,[M+H] + :263.0985,found:263.0994.

[0055] 3-fluoro-1-phenyl-2-(p-tolyl)-1H-pyrrole

[0056]

[0057] (4c) 1 H NMR(400MHz,CDCl3):δ7.37-7.21(m,3H),7.16-7.10(m,2H),7.08-6.97(m,4H),6.65(dd,J=5.1,3.2Hz,1H),6.16(d,J=3.3Hz,1H),2.29(s,3H). 19 F NMR(376MHz,CDCl3):δ-163.37(d,J=5.2Hz). 13C NMR(100MHz,CDCl3):δ150.26(d,J=243.2Hz),140.42,136.27,129.20,128.98,128.73(d,J=2.4Hz),126.76,126.62(d,J=3.6Hz),125.45,119.39(d,J=6.3Hz),116.89(d,J=21.8Hz),98.14(d,J=16.9Hz),21.28.HRMS(ESI,m / z):calcd for C 17 H 15 FN,[M+H] + :252.1189,found:252.1189.

[0058] 3-fluoro-2-phenethyl-1-phenyl-1H-pyrrole

[0059]

[0060] (4d) 1 H NMR(400MHz,CDCl3):δ7.50-7.32(m,3H),7.22-7.10(m,5H),6.99-6.94(m,2H),6.45(dd,J=5.0,3.3Hz,1H),6.01(d,J=3.3Hz,1H),2.97-2.76(m,2H),2.71-2.64(m,2H). 19 F NMR(376MHz,CDCl3):δ-166.57(d,J=5.6Hz). 13 C NMR(100MHz,CDCl3):δ150.15(d,J=237.1Hz),141.40,140.15,129.33,128.45,128.39,127.49,126.07,117.24(d,J=6.2Hz),115.68(d,J=24.7Hz),96.98(d,J=16.8Hz),35.30,25.55(d,J=2.8Hz).HRMS(ESI,m / z):calcd for C 18 H 16 FNNa,[M+Na] + :288.1164,found:288.1165.

[0061] 4-(3-fluoro-1-phenyl-1H-pyrrol-2-yl)-N,N-dimethylaniline

[0062]

[0063] (4e) 1 H NMR(400MHz,CDCl3):δ7.35-7.27(m,2H),7.26-7.21(m,1H),7.18-7.12(m,2H),7.03-6.97(m,2H),6.66-6.57(m,3H),6.15(d,J=3.3Hz,1H),2.91(s,6H). 19 F NMR(376MHz,CDCl3):δ-164.78(d,J=5.6Hz). 13 C NMR(100MHz,CDCl3):δ149.63(d,J=241.0Hz),149.08,140.60,129.87(d,J=2.2Hz),129.12,126.51,125.42,118.30(d,J=6.3Hz),117.54(d,J=3.6Hz),117.27(d,J=22.0Hz),112.14,98.01(d,J=17.0Hz),40.52.HRMS(ESI,m / z):calcd for C 18 H 18 FN2,[M+H] + :281.1454,found:281.1459.

[0064] 3-fluoro-2-(4-(methylsulfonyl)phenyl)-1-phenyl-1H-pyrrole

[0065]

[0066] (4f) 1 H NMR(400MHz,CDCl3):δ7.76(d,J=8.6Hz,2H),7.41-7.31(m,3H),7.27(dd,J=8.7,0.9Hz,2H),7.16-7.09(m,2H),6.74(dd,J=5.2,3.3Hz,1H),6.19(d,J=3.3Hz,1H),3.02(s,3H). 19 F NMR(376MHz,CDCl3):δ-159.00(d,J=5.8Hz). 13C NMR(100MHz,CDCl3):δ151.91(d,J=248.9Hz),139.77,137.47,135.10(d,J=3.9Hz),129.70,128.59(d,J=3.3Hz),127.60,127.35,125.50,122.24(d,J=6.1Hz),115.11(d,J=20.0Hz),98.65(d,J=16.6Hz),44.58.HRMS(ESI,m / z):calcd for C 17 H 15 FNO2S,[M+H] + :316.0808,found:316.0798.

[0067] 3-fluoro-2-(4-nitrophenyl)-1-phenyl-1H-pyrrole

[0068]

[0069] (4g) 1 H NMR(400MHz,CDCl3):δ8.07(dd,J=9.0,2.2Hz,2H),7.36(ddd,J=8.1,5.9,3.2Hz,3H),7.30-7.21(m,2H),7.14(dt,J=6.0,1.8Hz,2H),6.76(ddd,J=5.3,3.3,2.1Hz,1H),6.21(dd,J=3.3,2.1Hz,1H). 19 F NMR(376MHz,CDCl3):δ-157.70(d,J=5.3Hz). 13 C NMR(100MHz,CDCl3):δ152.22(d,J=249.8Hz),145.50,139.78,136.10(d,J=3.6Hz),129.74,128.23(d,J=3.4Hz),127.73,125.54,123.67,122.80(d,J=6.0Hz),115.06(d,J=19.9Hz),98.81(d,J=16.7Hz).HRMS(ESI,m / z):calcd for C 16 H 12 FN2O2,[M+H] + :283.0883,found:283.0891.

[0070] 2-(2,5-difluorophenyl)-3-fluoro-1-phenyl-1H-pyrrole

[0071]

[0072] (4h) 1 H NMR(400MHz,CDCl3):δ7.41-7.20(m,3H),7.15-7.07(m,2H),6.98-6.83(m,3H),6.77(dd,J=5.1,3.3Hz,1H),6.19(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-118.77--118.95(m),-118.97--119.14(m),-159.51(dd,J=10.5,5.7Hz). 13 C NMR(100MHz,CDCl3):δ158.35(dd,J=246.3,6.5Hz),155.61(dd,J=246.3,3.7Hz),151.21(d,J=246.2Hz),140.09,129.31,127.02,124.46,120.59(d,J=6.1Hz),118.95(ddd,J=17.8,9.2,3.2Hz),118.26-117.67(m),116.89(dd,J=24.8,9.3Hz),115.76(dd,J=23.8,8.6Hz),110.18(d,J=23.6Hz),98.23(d,J=16.4Hz).HRMS(ESI,m / z):calcd forC 16 H 11 F3N,[M+H] + :274.0844,found:274.0848.

[0073] 3-fluoro-2-(2-fluorophenyl)-1-phenyl-1H-pyrrole

[0074]

[0075] (4i) 1H NMR(400MHz,CDCl3):δ7.35-7.27(m,2H),7.27-7.20(m,2H),7.17(td,J=7.6,1.7Hz,1H),7.13-7.03(m,3H),6.99(ddd,J=9.7,8.2,1.2Hz,1H),6.77(dd,J=5.1,3.3Hz,1H),6.20(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-112.86(d,J=10.9Hz),-160.59(dd,J=10.4,4.6Hz). 13 C NMR(100MHz,CDCl3):δ159.69(d,J=248.9Hz),150.95(d,J=244.7Hz),140.36,132.02,129.48(d,J=8.1Hz),129.17,126.75,124.51,124.00(d,J=3.7Hz),119.92(d,J=6.1Hz),117.63(dd,J=15.0,3.4Hz),115.93(d,J=22.0Hz),111.10(d,J=23.8Hz),98.13(d,J=16.7Hz).HRMS(ESI,m / z):calcd for C 16 H 12 F2N,[M+H] + :256.0938,found:256.0941.

[0076] 3-fluoro-2-(3-methoxyphenyl)-1-phenyl-1H-pyrrole

[0077]

[0078] (4j) 1 H NMR(400MHz,CDCl3):δ7.38-7.23(m,3H),7.18-7.10(m,3H),6.76-6.70(m,2H),6.69-6.64(m,2H),6.17(d,J=3.3Hz,1H),3.62(s,3H). 19 F NMR(376MHz,CDCl3):δ-63.10(d,J=3.2Hz). 13C NMR(100MHz,CDCl3):δ159.31,150.58(d,J=244.6Hz),140.40,130.74(d,J=3.7Hz),129.26,129.21,126.93,125.54,121.30(d,J=2.7Hz),119.93(d,J=6.2Hz),116.74(d,J=21.2Hz),113.87(d,J=2.7Hz),112.66,98.21(d,J=16.9Hz),55.11.HRMS(ESI,m / z):calcd for C 17 H 15 FNO,[M+H] + :268.1138,found:268.1141.

[0079] (E)-3-fluoro-1-phenyl-2-styryl-1H-pyrrole

[0080]

[0081] (4k) 1 H NMR(400MHz,CDCl3):δ7.48(dd,J=8.3,6.6Hz,2H),7.44-7.38(m,1H),7.38-7.23(m,6H),7.21-7.15(m,1H),6.98(d,J=16.6Hz,1H),6.72(d,J=16.5Hz,1H),6.61(dd,J=5.1,3.2Hz,1H),6.14(d,J=3.2Hz,1H). 19 F NMR(376MHz,CDCl3):δ-157.08(d,J=5.5Hz). 13 C NMR(100MHz,CDCl3):δ151.61(d,J=247.3Hz),139.70,138.06,129.51,128.68,127.69,127.27(d,J=9.8Hz),127.12,126.17,125.96,119.06(d,J=6.1Hz),116.11(d,J=20.3Hz),115.40(d,J=5.3Hz),98.39(d,J=16.1Hz).HRMS(ESI,m / z):calcdfor C 18 H 15 FN,[M+H] + :264.1189,found:264.1187.

[0082] 3-fluoro-1-phenyl-2-(phenylethynyl)-1H-pyrrole

[0083]

[0084] (4l) 1 H NMR(400MHz,CDCl3):δ7.53(d,J=7.5Hz,2H),7.49-7.43(m,2H),7.39-7.32(m,3H),7.31-7.25(m,3H),6.73(dd,J=5.1,3.3Hz,1H),6.09(d,J=3.3Hz,1H). 19 FNMR(376MHz,CDCl3):δ-153.24(d,J=5.8Hz). 13 C NMR(100MHz,CDCl3):δ155.96(d,J=250.7Hz),139.58,130.89,129.17,128.37,128.12,127.30,124.41,123.24,119.85(d,J=5.8Hz),98.04(d,J=15.5Hz),97.57(d,J=3.6Hz),77.83(d,J=4.7Hz).HRMS(ESI,m / z):calcd for C 18 H 13 FN,[M+H] + :262.1032,found:262.1033.

[0085] 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-3-yl)-3-fluoro-1-phenyl-1H-pyrrole

[0086]

[0087] (4m) 1H NMR(400MHz,CDCl3):δ7.40-7.34(m,2H),7.30-7.24(m,3H),6.51(dd,J=5.1,3.3Hz,1H),6.04(d,J=3.3Hz,1H),5.60(td,J=3.2,1.6Hz,1H),2.42-2.24(m,2H),2.17(dt,J=8.9,5.7Hz,1H),2.01(ddt,J=6.0,4.4,2.7Hz,1H),1.91(t,J=5.7Hz,1H),1.17(d,J=8.8Hz,1H),1.11(s,3H),0.86(s,3H). 19 F NMR(376MHz,CDCl3):δ-162.42(d,J=5.1Hz). 13 C NMR(100MHz,CDCl3):δ148.41(d,J=242.0Hz),141.07,135.98(d,J=3.7Hz),129.09,126.67,124.75,123.93(d,J=3.3Hz),118.44(d,J=21.5Hz),118.08(d,J=6.3Hz),97.84(d,J=17.3Hz),45.69,40.24,37.97,32.12,31.73,26.27,21.02.HRMS(ESI,m / z):calcd for C 19 H 21 FN,[M+H] + :282.1658,found:282.1648.

[0088] 3-fluoro-1-phenyl-2-(thiophen-3-yl)-1H-pyrrole

[0089]

[0090] (4n) 1 H NMR(400MHz,CDCl3):δ7.41-7.31(m,3H),7.23-7.15(m,3H),6.88-6.83(m,2H),6.60(dd,J=5.1,3.3Hz,1H),6.14(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-161.05(d,J=5.2Hz). 13C NMR(100MHz,CDCl3):δ150.14(d,J=243.8Hz),140.41,129.64(d,J=4.2Hz),129.28,127.42,127.37(d,J=3.0Hz),125.99,124.83,121.23(d,J=3.3Hz),119.37(d,J=6.2Hz),113.39(d,J=21.8Hz),97.94(d,J=16.7Hz).HRMS(ESI,m / z):calcd for C 14 H 11 FNS,[M+H] + :244.0596,found:244.0599.

[0091] 2-(dec-9-en-1-yl)-3-fluoro-1-phenyl-1H-pyrrole

[0092]

[0093] (4o) 1 H NMR(400MHz,CDCl3):δ7.46-7.39(m,2H),7.38-7.31(m,1H),7.29-7.23(m,2H),6.44(dd,J=5.0,3.3Hz,1H),6.00(d,J=3.2Hz,1H),5.79(ddt,J=16.9,10.2,6.7Hz,1H),4.97(dq,J=17.1,1.7Hz,1H),4.91(ddt,J=10.1,2.3,1.2Hz,1H),2.65-2.49(m,2H),2.10-1.91(m,2H),1.38-1.09(m,12H). 19 F NMR(376MHz,CDCl3):δ-167.14(d,J=4.5Hz). 13 CNMR(100MHz,CDCl3):δ149.99(d,J=236.5Hz),140.44,139.35,129.27,127.34,126.01,116.95,116.88,114.19,96.93(d,J=17.1Hz),33.88,29.37,29.13,29.09,28.97,28.93,28.91,23.13(d,J=2.3Hz).HRMS(ESI,m / z):calcd for C 20 H 27 FN,[M+H] +:300.2128,found:300.2134.

[0094] ethyl 3-fluoro-1-phenyl-1H-pyrrole-2-carboxylate

[0095]

[0096] (4p) 1 H NMR(400MHz,CDCl3):δ7.46-7.38(m,3H),7.31-7.25(m,2H),6.71(dd,J=5.1,3.2Hz,1H),6.06(d,J=3.1Hz,1H),4.18(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H). 19 FNMR(376MHz,CDCl3):δ-144.23(d,J=5.0Hz). 13 C NMR(100MHz,CDCl3):δ159.59(d,J=3.9Hz),156.74(d,J=259.8Hz),140.35,128.79,128.16,126.39,126.03(d,J=5.8Hz),109.03(d,J=17.9Hz),97.91(d,J=16.0Hz),60.18,14.29.HRMS(ESI,m / z):calcd forC 13 H 13 FNO2,[M+H] + :234.0930,found:234.0927.

[0097] 2-(benzofuran-2-yl)-3-fluoro-1-phenyl-1H-pyrrole

[0098]

[0099] (4q) 1 H NMR(400MHz,CDCl3):δ7.50-7.44(m,1H),7.42-7.36(m,3H),7.33-7.28(m,3H),7.22-7.14(m,2H),6.72(dd,J=5.1,3.2Hz,1H),6.38(d,J=0.9Hz,1H),6.19(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-155.93(d,J=4.4Hz). 13C NMR(100MHz,CDCl3):δ154.28,151.83(d,J=249.8Hz),146.31(d,J=5.0Hz),140.28,129.20,128.66,127.79,125.79,123.83,122.88,121.58(d,J=5.8Hz),120.64,111.10,109.08(d,J=20.9Hz),103.66(d,J=3.8Hz),98.38(d,J=15.8Hz).HRMS(ESI,m / z):calcd for C 18 H 13 FNO,[M+H] + :278.0981,found:278.0975.

[0100] 2-([1,1'-biphenyl]-4-yl)-3-fluoro-1-phenyl-1H-pyrrole

[0101]

[0102] (4r) 1 H NMR(400MHz,CDCl3):δ7.61-7.55(m,2H),7.51-7.46(m,2H),7.44-7.39(m,2H),7.38-7.26(m,4H),7.23-7.16(m,4H),6.70(dd,J=5.1,3.3Hz,1H),6.21(d,J=3.3Hz,1H). 19 F NMR(376MHz,CDCl3):δ-162.17(d,J=5.3Hz). 13 C NMR(100MHz,CDCl3):δ150.72(d,J=244.6Hz),140.69,140.40,139.01,129.33,129.00(d,J=2.7Hz),128.86,128.57(d,J=3.7Hz),127.35,127.00,126.95,126.89,125.53,120.08(d,J=6.2Hz),116.56(d,J=21.3Hz),98.33(d,J=16.9Hz).HRMS(ESI,m / z):calcd for C 22 H 17 FN,[M+H] + :314.1345,found:314.1336.

[0103] 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole

[0104]

[0105] (4s) 1 H NMR(400MHz,CDCl3):δ7.09-7.02(m,4H),6.89-6.74(m,4H),6.58(dd,J=5.2,3.3Hz,1H),6.13(d,J=3.2Hz,1H),3.79(s,3H),3.77(s,3H). 19 F NMR(376MHz,CDCl3):δ-164.61(d,J=5.2Hz). 13 C NMR(100MHz,CDCl3):δ158.32,158.22,149.66(d,J=241.6Hz),133.55,130.16(d,J=2.3Hz),126.80,122.19(d,J=3.7Hz),118.99(d,J=6.2Hz),116.77(d,J=21.6Hz),114.30,113.76,97.55(d,J=16.8Hz),55.54,55.26.HRMS(ESI,m / z):calcd for C 18 H 17 FNO2,[M+H] + :298.1243,found:298.1238.

[0106] 1-(3,5-dimethoxyphenyl)-3-fiuoro-2-(4-methoxyphenyl)-1H-pyrrole

[0107]

[0108] (4t) 1 H NMR(400MHz,CDCl3):δ7.10(m,2H),6.91-6.77(m,2H),6.65(dd,J=5.2,3.3Hz,1H),6.34(t,J=2.2Hz,1H),6.26(d,J=2.3Hz,1H),6.14(d,J=3.1Hz,1H),3.78(s,3H),3.64(s,6H). 19 F NMR(376MHz,CDCl3):δ-164.05(d,J=5.3Hz). 13C NMR(100MHz,CDCl3):δ160.90,158.36,149.95(d,J=242.4Hz),141.96,130.17(d,J=2.3Hz),122.09(d,J=3.5Hz),118.87(d,J=6.1Hz),116.66(d,J=22.3Hz),113.77,103.78,98.93,98.04(d,J=17.0Hz),55.52,55.32.HRMS(ESI,m / z):calcd for C 19 H 18 FNO3Na,[M+Na] + :350.1168,found:350.1169.

[0109] 3-fluoro-2-(4-methoxyphenyl)-1-(o-tolyl)-1H-pyrrole

[0110]

[0111] (4u) 1 H NMR(400MHz,CDCl3):δ7.29-7.20(m,3H),7.18-7.13(m,1H),7.07-6.97(m,2H),6.74-6.69(m,2H),6.44(dd,J=5.1,3.2Hz,1H),6.15(d,J=3.2Hz,1H),3.73(s,3H),1.90(s,3H). 19 F NMR(376MHz,CDCl3):δ-165.38(d,J=5.3Hz). 13 C NMR(100MHz,CDCl3):δ157.98,149.07(d,J=241.5Hz),139.61,135.77,130.90,129.05,129.03,128.20(d,J=1.8Hz),126.61,122.48(d,J=3.8Hz),118.86(d,J=6.4Hz),117.57(d,J=20.6Hz),113.66,97.40(d,J=16.8Hz),55.13,17.54.HRMS(ESI,m / z):calcd for C 18 H 17 FNO,[M+H] + :282.1294,found:282.1297.

[0112] 1-(4-chlorophenyl)-3-fluoro-2-(4-methoxyphenyl)-1H-pyrrole

[0113]

[0114] (4v) 1 H NMR(400MHz,CDCl3):δ7.30-7.24(m,2H),7.09-6.99(m,4H),6.85-6.76(m,2H),6.60(dd,J=5.1,3.3Hz,1H),6.16(d,J=3.3Hz,1H),3.78(s,3H). 19 F NMR(376MHz,CDCl3):δ-163.74(d,J=4.6Hz). 13 C NMR(100MHz,CDCl3):δ158.45,150.04(d,J=242.8Hz),138.86,132.37,130.27(d,J=2.2Hz),129.39,126.51,121.63(d,J=3.5Hz),118.86(d,J=6.2Hz),116.69(d,J=22.4Hz),113.92,98.57(d,J=16.9Hz),55.32.HRMS(ESI,m / z):calcd for C 17 H 14 ClFNO,[M+H] + :302.0748,found:302.0755.

[0115] 3-fluoro-2-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrole

[0116]

[0117] (4w) 1 H NMR(400MHz,CDCl3):δ7.67-7.48(m,2H),7.23-7.18(m,2H),7.05(dd,J=8.9,0.8Hz,2H),6.90-6.71(m,2H),6.67(dd,J=5.0,3.3Hz,1H),6.21(dd,J=3.4,0.6Hz,1H),3.79(s,3H). 19 F NMR(376MHz,CDCl3):δ-62.18,-163.06(d,J=5.2Hz).13 C NMR (100MHz, CDCl3): δ158.58, 150.34 (d, J = 243.7Hz), 143.10, 130.27 (d, J = 2.1Hz), 128.44 (q, J = 32.8Hz), 126.36 (q, J = 3.8Hz), 125.03, 122.5 2(q,J=272.2Hz),121.37(d,J=3.4Hz),118.86(d,J=6.1Hz),116.72(d,J=22.7Hz),113.97,99.22(d,J=17.2Hz),55.23.HRMS(ESI,m / z):calcd for C 18 H 14 F4NO,[M+H] + :336.1012,found:336.1011.

[0118] Example 1

[0119] This example describes the preparation of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole. The specific procedures are as follows:

[0120]

[0121] Tetraphenylphosphine (0.3 mmol, 1.5 eq.) was added to the reaction tube, and nitrogen was purged three times. Toluene (2 mL) and 2,2-difluoro-1-(4-methoxyphenyl)but-3-en-1-one (0.2 mmol, 1 eq.) were added under a nitrogen atmosphere, and the reaction was carried out at 110 °C for 12 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature and quickly filtered through a short silica gel column. The mixture was eluted with dichloromethane to remove excess tetraphenylphosphine and the generated triphenylphosphine oxide. The crude product was concentrated under reduced pressure and used for later use. No further purification was required.

[0122] Tetra(triphenylphosphine)palladium (11.6 mg, 0.2 mmol, 1.0 eq) and potassium carbonate (55.3 mg, 0.4 mmol, 2.0 eq.) were added to a reaction tube, purging with nitrogen three times. The crude product from the previous step was dissolved in 2 mL of anhydrous N,N-dimethylacetamide and added to the reaction tube under nitrogen atmosphere. The mixture was placed in an oil bath preheated to 120 °C and stirred for 12 h until the reaction was complete. Ethyl acetate was added for dilution, followed by water extraction. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was then separated by column chromatography to obtain the final target product. The product was a colorless to slightly yellow oily liquid, with a two-step yield of 60%.

[0123] The results of the 1H NMR spectrum determination of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole are as follows: 1 ¹H NMR (400 MHz, CDCl₃): δ 7.35–7.26 (m, 3H), 7.15–7.09 (m, 2H), 7.08–6.98 (m, 2H), 6.84–6.74 (m, 2H), 6.64 (dd, J = 5.1, 3.3 Hz, 1H), 6.16 (d, J = 3.3 Hz, 1H), 3.77 (s, 3H). The results of the NMR fluorine spectrum determination of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole were as follows: 19 F NMR (376 MHz, CDCl3): δ -164.20 (d, J = 5.8 Hz). The results of the carbon NMR spectrum determination of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole are as follows: 13 C NMR (100MHz, CDCl3): δ158.29, 149.97 (d, J=242.1Hz), 140.36, 130.20 (d, J=2.3Hz), 129.19, 126.73, 125. 44, 122.07 (d, J = 3.2Hz), 118.96 (d, J = 6.3Hz), 116.64 (d, J = 21.9Hz), 113.77, 98.07 (d, J = 16.8Hz), 55.27.

[0124] The 1H NMR spectrum, fluorine NMR spectrum, and 3C NMR spectrum of compound 4a are as follows: Figure 1 , Figure 2 and Figure 3 As shown.

[0125] Examples 2-18

[0126] Examples 2-18 are basically the same as Example 1, except that the substituent R1 in the γ,γ-difluoroallyl ketone compounds are different. The specific structures of the γ,γ-difluoroallyl ketone compounds are shown in the table below:

[0127] Table 1 Examples 2-18

[0128]

[0129]

[0130] Example 19

[0131] This example describes the preparation of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole. The specific procedures are as follows:

[0132]

[0133] 4-Methoxyphenyltriphenylamine phosphine (0.3 mmol, 1.5 eq.) was added to the reaction tube, and nitrogen was purged three times. Toluene (2 mL) and 2,2-difluoro-1-(4-methoxyphenyl)but-3-en-1-one (0.2 mmol, 1 eq.) were added under a nitrogen atmosphere, and the mixture was stirred overnight at 110 °C. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and quickly filtered through a short silica gel column. The mixture was washed with dichloromethane to remove excess 4-methoxyphenyltriphenylamine phosphine and the generated triphenylphosphine oxide. The solvent was evaporated using a rotary evaporator, and the crude product was concentrated under reduced pressure for later use; no further purification was required.

[0134] Tetra(triphenylphosphine)palladium (11.6 mg, 0.2 mmol, 1.0 eq) and potassium carbonate (55.3 mg, 0.4 mmol, 2.0 eq.) were added to a reaction tube, and the mixture was purged with nitrogen three times. The crude product from the previous step was dissolved in 2 mL of anhydrous N,N-dimethylacetamide and added to the reaction tube under nitrogen atmosphere. The mixture was placed in an oil bath preheated to 120 °C and stirred for 12 h until the reaction was complete. Ethyl acetate was added for dilution, followed by water extraction. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was then separated by column chromatography to obtain the final target product. The product was a colorless to slightly yellow oily liquid, with a two-step yield of 55%.

[0135] The results of the 1H NMR spectrum determination of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole are as follows: 1 ¹H NMR (400MHz, CDCl₃): δ 7.09–7.02 (m, 4H), 6.89–6.74 (m, 4H), 6.58 (dd, J = 5.2, 3.3 Hz, 1H), 6.13 (d, J = 3.2 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H). The results of the fluorine NMR spectrum determination of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole were as follows: 19 F NMR (376 MHz, CDCl3): δ -164.61 (d, J = 5.2 Hz). The results of the carbon NMR spectrum determination of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole are as follows: 13C NMR (100MHz, CDCl3): δ158.32, 158.22, 149.66 (d, J=241.6Hz), 133.55, 130.16 (d, J=2.3Hz), 126.80, 122.19 ( d, J=3.7Hz), 118.99 (d, J=6.2Hz), 116.77 (d, J=21.6Hz), 114.30, 113.76, 97.55 (d, J=16.8Hz), 55.54, 55.26.

[0136] The 1H NMR spectrum, fluorine NMR spectrum, and 1C NMR spectrum of this compound are as follows: Figure 4 , Figure 5 and Figure 6 As shown.

[0137] Examples 20-23

[0138] Examples 20-23 are basically the same as Example 19, except that R2 in the aryltriphenylphosphine compounds are different. Their specific structures are detailed in the table below:

[0139] Table 2 Examples 20-23

[0140]

[0141]

[0142] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-fluoropyrrole compounds via palladium-catalyzed defluorination cyclization, characterized in that, γ,γ-difluoroallylimine compounds were obtained by condensation; under alkaline conditions, the structure was subjected to intramolecular defluorination cyclization using a palladium catalyst to obtain 3-fluoropyrrole compounds. The specific reaction route is as follows: The molecular structural formula of the 3-fluoropyrrole compound is shown in formula (I) below: The molecular structural formula of the γ,γ-difluoroallylimine compound is shown in formula (II) below: In equations (I) and (II), R 1 Selected from phenyl, cinnamyl, phenylethynyl; R 2 Selected from hydrogen, 4-methoxy, 4-trifluoromethyl, 4-chloro, 3,5-dimethoxy, and 2-methyl; The palladium catalyst is one of tetra(triphenylphosphine)palladium, palladium acetate, and di(triphenylphosphine)palladium dichloride; The alkali is either potassium carbonate or cesium carbonate, and the solvent is either acetonitrile, N,N-dimethylformamide, or N,N-dimethylacetamide.

2. The method for preparing the 3-fluoropyrrole compound according to claim 1, characterized in that, The method includes the following steps: (1) In a nitrogen atmosphere, aryltriphenylamine phosphine compound and γ,γ-difluoroallyl ketone compound were added to toluene to obtain a mixture; The molar ratio of aryltriphenylamine phosphine compound to γ,γ-difluoroallyl ketone compound is 1.5:1; (2) The mixture described in step (1) was stirred at 110 °C for 12 hours. The crude product was filtered through a short silica gel column and concentrated under reduced pressure to obtain γ,γ-difluoroallylimine compounds. (3) Under a nitrogen atmosphere, palladium catalyst, base, and γ,γ-difluoroallylimide obtained in step (2) were added to a solvent. The mixture was stirred at a suitable temperature until the reaction was complete, extracted, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 3-fluoropyrrole compound. The molar ratio of the palladium catalyst, the base, and the γ,γ-difluoroallylimide is 0.05:2.0:1.0; the mixture is stirred at 120 °C for 12 hours.

3. The method for preparing a 3-fluoropyrrole compound according to claim 2, characterized in that, In step (3), the reaction solvent is N,N-dimethylacetamide; the base is potassium carbonate.

Images