Method for synthesizing 3-fluoropyrrole compound through palladium-catalyzed defluorination cyclization

Abstract

The invention relates to the technical field of organic synthesis, and discloses a method for synthesizing a 3-fluoropyrrole compound through palladium-catalyzed defluorination cyclization reaction. According to the method, high-efficiency preparation of the 3-fluoropyrrole compound is realized through intramolecular defluorination cyclization reaction of a gamma, gamma-difluoroallyl imine substrate under the action of a palladium catalyst. Compared with the traditional method for synthesizing the 3-fluoropyrrole compound, the method disclosed by the invention has the advantages that the raw materials are cheap and easy to obtain; the experiment operation is simple; the reaction yield is high; the method is wide in application range; a series of 3-fluoropyrrole derivatives can be obtained.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a new method for synthesizing 3-fluoropyrrole compounds through palladium-catalyzed defluorination cyclization reaction. Background Art

[0002] Nitrogen-containing heterocyclic compounds are important components of bioactive molecules, natural products and drug structures. 3-Fluoropyrrole, as an important structure among them, has important value in medical research and drug development due to its unique electronic properties and chemical stability. However, most existing 3-fluoropyrrole synthesis methods require multi-step synthesis, with low yields, often accompanied by side reactions, and poor applicability.

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

[0004]

[0005] Reference 2 (Org. Biomol. Chem. 2016, 14, 183) discloses a method for synthesizing multifunctionalized 3-fluoropyrrole from commercial aldehydes. This method can realize modular and systematic assembly of multi-substituted 3-fluoropyrrole. The specific reaction process is as follows:

[0006]

[0007] Document 3 (Org. Lett. 2009, 11, 2920) discloses a method for synthesizing 2-aryl-3-fluoropyrrole compounds by cyclization and dehydrogenation of γ,γ-difluorohomopropargylamine catalyzed by gold trichloride. The specific reaction process is as follows:

[0008]

[0009] Although the above synthesis methods can realize the synthesis of 3-fluoropyrrole compounds, there are still many limitations: for example, the synthesis route is long, there are many steps, the reaction conditions are harsh, the cost of raw materials and reagents is high, the application range of raw materials is limited, etc. Therefore, it is urgent to develop a new synthesis method to realize the construction of 3-fluoropyrrole compounds more universally and efficiently. The present invention mainly studies the method of synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction. This method starts from commercial or cheap and readily available raw materials, first prepares γ, γ-difluoroallyl ketone compounds with different functional groups, and then obtains various types of γ, γ-difluoroallyl imine reaction substrates through one-step condensation. Under alkaline conditions, the substrate undergoes intramolecular defluorination cyclization reaction under palladium catalysis, and 3-fluoropyrrole compounds are obtained with wide functional group compatibility and good yield. Summary of the invention

[0010] The invention provides a method for synthesizing a 3-fluoropyrrole compound by palladium-catalyzed defluorination cyclization reaction, which has the advantages of simple operation, wide substrate application range, high yield, etc. In the method, a γ,γ-difluoroallyl ketone compound is first condensed to obtain a γ,γ-difluoroallylimine reaction substrate, and a palladium catalyst is used to perform intramolecular defluorination cyclization on the substrate under alkaline conditions to obtain a 3-fluoropyrrole compound.

[0011] In order to solve the technical problem of the present invention, the proposed technical solution is: a new method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction, comprising the following steps:

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

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

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

[0015] The specific reaction route is as follows:

[0016]

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

[0018] Preferably, the γ,γ-difluoroallylimidamine compounds are derived from the dehydration condensation of various γ,γ-difluoroallylimidone compounds.

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

[0020] Preferably, the base is potassium carbonate.

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

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

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

[0024] Compared with the prior art, the present invention has the following beneficial effects:

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

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

[0027] 3. The present invention can obtain the target compound with a higher yield by optimizing the reaction conditions, thereby reducing costs and improving efficiency.

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

[0029] 5. The present invention is carried out under relatively mild reaction conditions, and the selected tetrakis(triphenylphosphine)palladium is relatively cheap and readily available among transition metal catalysts, which helps to reduce potential impacts on the environment and may reduce requirements for reaction equipment. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0031] Figure 1 The NMR of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of the present invention is 1 H spectrum;

[0032] Figure 2 The NMR of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of the present invention is 19 F spectrum;

[0033] Figure 3 The NMR of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole provided in Example 1 of the present invention is 13 C spectrum;

[0034] Figure 4 The NMR of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of the present invention is 1 H spectrum;

[0035] Figure 5 The NMR of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of the present invention is 19 F spectrum;

[0036] Figure 6 The NMR of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole provided in Example 19 of the present invention is 13 C spectrum. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

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

[0039] (1) Using tetraphenylphosphine amide as a template substrate, different types of γ,γ-difluoroallylimidamine compounds were used to discuss the practicality of the method. The specific reaction equation is as follows:

[0040]

[0041] The R groups are: aryl, ester, alkyl, cinnamyl, phenylethynyl and myrtenal 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, different types of aryl triphenylphosphine amide compounds were used to discuss the practicality of the method. The specific reaction equation is 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 is used to prepare 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole. The specific operation is as follows:

[0120]

[0121] Tetraphenylphosphine (0.3 mmol, 1.5 eq.) was added to the reaction tube, and the nitrogen was replaced three times. Toluene (2 mL) and 2,2-difluoro-1-(4-methoxyphenyl)but-3-ene-1-one (0.2 mmol, 1 eq.) were added under nitrogen atmosphere, and the reaction was carried out at 110°C for 12 h. TLC spot plate monitoring was performed, and after the reaction was complete, the mixture was cooled to room temperature, and quickly filtered through a short silica gel column, and washed with dichloromethane to remove excess tetraphenylphosphine and the generated triphenylphosphine. After reduced pressure concentration, the crude product was obtained for use without further purification.

[0122] Add tetrakis(triphenylphosphine)palladium (11.6mg, 0.2mmol, 1.0eq) and potassium carbonate (55.3mg, 0.4mmol, 2.0eq.) to the reaction tube, replace nitrogen three times, dissolve the crude product in the previous step in 2mL anhydrous N, N-dimethylacetamide, and add it to the reaction tube under nitrogen. Put it into an oil bath preheated to 120℃ and stir for 12h. When the reaction is complete, add ethyl acetate to dilute, add water to separate, extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography to obtain the final target product. The product is a colorless to slightly yellow oily liquid with a two-step yield of 60%.

[0123] The results of the hydrogen nuclear magnetic resonance spectrum of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole are as follows: 1 HNMR (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, 3.3 Hz, 1H), 6.16 (d, J = 3.3 Hz, 1H), 3.77 (s, 3H). The results of the determination of the nuclear magnetic resonance fluorine spectrum of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole are as follows: 19 F NMR (376MHz, CDCl3): δ-164.20 (d, J = 5.8Hz). The results of the determination of the carbon nuclear magnetic resonance spectrum of 3-fluoro-2-(4-methoxyphenyl)-1-phenyl-1H-pyrrole are: 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 H-NMR, F-NMR and C-NMR spectra of compound 4a are shown in Figure 1 , Figure 2 and Figure 3 shown.

[0125] Embodiments 2 to 18

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

[0127] Table 1 Examples 2 to 18

[0128]

[0129]

[0130] Embodiment 19

[0131] This example is used to prepare 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole. The specific operation is as follows:

[0132]

[0133] 4-methoxyphenyl triphenylphosphine amide (0.3mmol, 1.5eq.) was added to the reaction tube, and nitrogen was replaced three times. Toluene (2mL) and 2,2-difluoro-1-(4-methoxyphenyl) but-3-ene-1-one (0.2mmol, 1eq.) were added under nitrogen atmosphere, and stirred overnight at 110°C. TLC spot plate monitoring was performed, and after the reaction was complete, the mixture was cooled to room temperature, and quickly filtered through a short silica gel column, and washed with dichloromethane to remove excess 4-methoxyphenyl triphenylphosphine amide and the generated triphenylphosphine. The solvent was evaporated by a rotary evaporator, and the crude product was obtained after reduced pressure concentration for use without further purification.

[0134] Add tetrakis(triphenylphosphine)palladium (11.6mg, 0.2mmol, 1.0eq) and potassium carbonate (55.3mg, 0.4mmol, 2.0eq.) to the reaction tube, replace nitrogen three times, dissolve the crude product in the previous step in 2mL anhydrous N, N-dimethylacetamide, and add it to the reaction tube under nitrogen. Put it into an oil bath preheated to 120℃ and stir for 12h. When the reaction is complete, add ethyl acetate to dilute, add water to separate, extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by column chromatography to obtain the final target product. The product is a colorless to slightly yellow oily liquid with a two-step yield of 55%.

[0135] The results of the hydrogen nuclear magnetic resonance spectrum of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole are as follows: 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). The results of the determination of the fluorine nuclear magnetic resonance spectrum of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole are as follows: 19 F NMR (376MHz, CDCl3): δ-164.61 (d, J = 5.2Hz). The results of the determination of the carbon nuclear magnetic resonance spectrum of 3-fluoro-1,2-bis(4-methoxyphenyl)-1H-pyrrole are: 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 H NMR, F NMR and C NMR spectra of compound 4s are shown in Figure 4 , Figure 5 and Figure 6 shown.

[0137] Embodiments 20 to 23

[0138] Examples 20 to 23 are substantially the same as Example 19, except that R2 in the aryl triphenylphosphine amide compounds is different. The specific structures thereof are shown in the table below:

[0139] Table 2 Examples 20 to 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction, characterized in that: First, γ,γ-difluoroallyl ketone compounds are prepared, and γ,γ-difluoroallylimine compounds are obtained by condensation. Then, under alkaline conditions, the structure is subjected to intramolecular defluorination cyclization using a palladium catalyst to obtain 3-fluoropyrrole compounds.

2. The method for preparing 3-fluoropyrrole compounds according to claim 1, characterized in that: The following steps are involved: Step 1: Under a nitrogen atmosphere, an aryl triphenylphosphine amide compound (Formula 2) and a γ,γ-difluoroallyl ketone compound (Formula 1) are added to toluene to obtain a mixture. Step 2: Stir the mixture in step 1 at 110° C. until the reaction is complete, filter the crude product through a short silica gel column, and concentrate under reduced pressure to obtain a γ,γ-difluoroallylimidamine compound (Formula 3). Step 3: under nitrogen atmosphere, palladium catalyst, base, and γ,γ-difluoroallylimine (Formula 3) obtained in Step 2 are added to a solvent, and the obtained mixture is stirred at a suitable temperature until the reaction is complete, extracted, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain a 3-fluoropyrrole compound (Formula 4); The specific reaction route is as follows: Where R 1 The fragments are: aryl, ester, alkyl, cinnamyl, phenylethynyl and myrtenal related fragments; R 2 are: hydrogen, 4-methoxy, 4-trifluoromethyl, 4-chloro, 3,5-dimethoxy and 2-methyl.

3. The method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction according to claim 1, characterized in that: The palladium catalyst in step 3 is tetrakis(triphenylphosphine)palladium.

4. The method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction according to claim 1, characterized in that: The base in step 3 is one of potassium carbonate and cesium carbonate.

5. The method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction according to claim 1, characterized in that: The reaction temperature in step 3 is 120° C.; the reaction time is 12 h to 16 h.

6. The method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction according to claim 1, characterized in that: The reaction solvent in step 3 is one of acetonitrile, N,N-dimethylacetamide and N,N-dimethylacetamide.

7. The method for synthesizing 3-fluoropyrrole compounds by palladium-catalyzed defluorination cyclization reaction according to claim 1, characterized in that: The reaction molar ratio in step 3 is γ,γ-difluoroallylimidamine compound:tetrakis(triphenylphosphine)palladium:base=1:0.05:2.

Images