Preparation method of N1-and N2-alkyl indazole

Abstract

The invention discloses a preparation method of N1-and N2-alkyl indazole compounds as shown in formulas (3) and (4), which is characterized in that the N1-and N2-alkyl indazole compounds are synthesized by utilizing nucleophilic ring-opening reaction between D-A cyclopropane and indazole compounds catalyzed by lewis acids with different properties; the process is simple to operate, the catalyst is cheap and easy to obtain, the reaction substrate is wide in universality, the regioselectivity is high, atom economy and step economy are high, byproducts are few, products are easy to separate and purify, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry and relates to the selectivity of indazole N -Alkylation reaction. Indazole and DA cyclopropane undergo a regioselective nucleophilic ring-opening reaction under the catalysis of Lewis acid, and the high yield and high selectivity preparation N 1 -Alkyl indazole and N 2 -Alkyl indazole compounds. Background Art

[0002] Indazole compounds have a wide range of pharmaceutical and biological activities, such as anti-inflammatory, antiarrhythmic, anti-tumor, antifungal, antibacterial and anti-HIV activities ( Mini-Rev. Med. Chem. , 2012,12, 1293-1300). In medicinal chemistry, indazole is an effective bio-isomer of indole and benzimidazole ( J. Med. Chem. , 1991,34, 1492−1503), is an important core skeleton of many marketed drugs, such as gamendazole MK-4827 (anticancer agent), pazopanib (votrient, tyrosine kinase inhibitor) and bendazole ( ACS Med. Chem. Lett. , 2016,7, 374−378; Drugs , 2011,71, 443−454; Bioorg. Med. Chem. Lett. , 2010,20, 2115−2118; J. Med. Chem. , 2005,48, 1132−1144; ur. J. Cancer , 2001,37, 364−368). Given the importance of indazole as a superior drug skeleton, great efforts have been made in the synthesis and functionalization of indazole ( Eur. J. Med. Chem. , 2015,90, 707−731; Adv. Synth. Catal. , 2020, 362, 3768−3794). The alkylation reaction of indazole is one of the most direct and practical methods for synthesizing indazole derivatives. However, indazole is a typical amphiphilic nucleophile. N 1 and N 2 The alkylation of indazoles usually yields N 1 -and N 2 -Mixture of alkyl indazoles, poor reaction selectivity ( Synth. Commun. , 1996,26, 2443−2447; J. Org. Chem., 2009,74, 6331−6334; Chem. Asian J. , 2018,13, 2109−2116.). In addition, due to its structural characteristics, indazole has relatively weak nucleophilicity. Therefore, developing efficient and highly regioselective alkylation reactions of indazole remains a challenging research task ( ACS Catal. , 2020,10, 4983−4989; J. Am. Chem. Soc. ,2022,144, 2994−3004; Org. Process Res. Dev. , 2007,11, 30−38; Bioorg. Med. Chem. Lett., 2019,29, 1854−1858.). To date, highly active and highly selective alkylation agents and methods are still very limited ( Org. Lett. , 2009,11, 5054−5057; Org. Lett. , 2021,23,1000−1004; Tetrahedron, 2020,76, 131338; Org. Lett. ,2024,26, 5646−5651; Chem. Commun. , 2022,58, 6429−6432; Org. Biomol. Chem. , 2015,13, ​​11376−11381; J. Org. Chem. , 2006,71, 5392−5395; J. Org. Chem. , 2003,68, 4093−4095; Angew. Chem., Int. Ed. , 2021,60, 8321−8328).

[0003] DA cyclopropane is an important organic synthon, but it has not been reported in the functionalization of indazole. This method aims to report the nucleophilic ring opening of indazole with DA cyclopropane under Lewis acid catalysis to generate N 1 -and N 2 -alkyl indazole derivatives. Compared with the existing methods, this method uses a new alkylating agent, DA cyclopropane, which has simple reaction operation, wide substrate universality, and high reaction regioselectivity. Summary of the invention

[0004] The present invention successfully achieves highly regioselective ring opening of indazole and DA cyclopropane by adjusting the properties of Lewis acid, providing a new method for the synthesis of diverse N 1 andN 2 -Alkylated indazole derivatives provide an efficient and concise route to facilitate the generation of indazole lead compounds.

[0005] The reaction formula of the preparation method is:

[0006] In formula (I): R is an alkyl group or an aryl group, such as a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a phenyl group, etc.; R1 is an aryl group, an alkenyl group, an alkyl group, or a heteroatom substituent, such as 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 4-chlorophenyl, 4-esterphenyl, 4-cyanophenyl, 1-naphthyl, 2-furyl, styryl, n-propyl, or phthalimide; R2 is a hydrogen atom, 3-methyl, 3-bromo, 4-methyl, 5-methyl, 5-chloro, 5-trifluoromethyl, 6-methoxy, 6-methyl, 6-ester, 7-fluoro, and the like.

[0007] In formula (II): R is an alkyl group or an aryl group, such as a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a phenyl group, etc.; R1 is an aryl group, an alkenyl group, an alkyl group, or a heteroatom substituent, such as 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 4-chlorophenyl, 4-esterphenyl, 4-cyanophenyl, 1-naphthalene, furan, styryl, n-propyl, or phthalimide; R2 is a hydrogen atom, 3-methyl, 4-methyl, 5-methyl, 5-chloro, 5-trifluoromethyl, 6-methoxy, 6-methyl, 6-ester, 7-methyl, 7-fluoro or the like.

[0008] The present invention N 1 -and N 2 The specific steps of the preparation method of -alkyl indazole are as follows: indazole, DA cyclopropane and the corresponding Lewis acid (hard Lewis acid or soft Lewis acid) are added to a reaction bottle, and a solvent is added under nitrogen protection, and the reaction is stirred at an appropriate temperature. The reaction is detected by thin layer chromatography. After the raw materials react completely, the reaction solution is concentrated to obtain a crude product, and the crude product is purified by column chromatography to obtain the target compound.

[0009] Wherein, the DA cyclopropane can be prepared from malonic acid ester, corresponding aldehyde and trimethyl sulfoxide iodide (see Angew. Chem. Int. Ed. 2012, 51, 11620-11623).

[0010] The above aldehydes are aromatic aldehydes, α, β unsaturated aldehydes, and aliphatic aldehydes, such as 4-methoxybenzaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde, 4-methylbenzaldehyde, phenyl, 4-chlorobenzaldehyde, 4-ester benzaldehyde, 4-cyanobenzaldehyde, furanaldehyde, 1-naphthaldehyde, and benzaldehyde. All of the above compounds are purchased from the market.

[0011] Among them, indazole is a 3-, 4-, 5-, 6-, and 7-substituted indazole derivative, all of which can be purchased from the market.

[0012] Wherein, the Lewis acid in formula (I) is a soft Lewis acid, such as: copper trifluoromethanesulfonate (Cu(OTf)2), zinc trifluoromethanesulfonate (Zn(OTf)2), nickel trifluoromethanesulfonate (Ni(OTf)2), cobalt trifluoromethanesulfonate (Co(OTf)2), bis(trifluoromethylsulfonyl)imide cobalt (Co(NTf2)2), etc.

[0013] Among them, the Lewis acid in formula (II) is a hard Lewis acid, such as rare earth metal salts such as yttrium trifluoromethanesulfonate (Y(OTf)3), lanthanum trifluoromethanesulfonate (La(OTf)3), samarium trifluoromethanesulfonate (Sm(OTf)3), europium trifluoromethanesulfonate (Eu(OTf)3), magnesium perchlorate (Mg(ClO4)2), aluminum trifluoromethanesulfonate (Al(OTf)3), etc.

[0014] The solvent is a halogenated hydrocarbon, aromatic hydrocarbon, ether, ester or other solvent, such as dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, ether, tetrahydrofuran or the like.

[0015] The indazole, aldehyde, organic solvent, thin layer chromatography plate and silica gel used in the present invention can all be purchased from the market.

[0016] The present invention aims to provide a method for synthesizing a novel nanostructured carbon nanotube ... N 1 and N 2 -A method for preparing alkyl indazole derivatives. The present invention successfully achieves efficient and highly regioselective alkylation of indazole by Lewis acid-catalyzed nucleophilic ring opening of indazole and DA cyclopropane. N 1 and N 2 The synthesis of -alkyl indazole derivatives provides an efficient and concise path, which facilitates the preparation of indazole lead compounds. The process is simple to operate, the reaction conditions are mild, there are few by-products, the products are easy to separate and purify, and the method is widely applicable. At the same time, the obtained products are easy to derive and have high added value. DETAILED DESCRIPTION

[0017] The present invention is further described in detail in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not particularly limit the content.

[0018] Preparation of the present invention N 1 The specific steps of the method for the alkyl indazole compound include: weighing an indazole compound and DA cyclopropane in a molar ratio of 1:1.2 and placing them in a reaction bottle, adding 10 mol% of a soft Lewis acid under nitrogen protection, adding a solvent (1.0 mL / mmol), and heating at 40 o C, and the reaction was stirred and detected by thin layer chromatography. After the reaction was complete, the reaction solvent was removed by concentration to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1~2:1) to obtain N 1 -Alkyl indazole compounds pure product.

[0019] Preparation of the present invention N 2 The specific steps of the method for the alkyl indazole compound include: weighing an indazole compound and DA cyclopropane in a molar ratio of 1.2:1 and placing them in a reaction bottle, adding 10 mol% of a hard Lewis acid, adding a solvent (1.0 mL / mmol) under nitrogen protection, and heating at 40 o C, and the reaction was stirred and detected by thin layer chromatography. After the reaction was complete, the reaction solvent was removed by concentration to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1~2:1) to obtain N 2 -Alkyl indazole compounds pure product.

[0020]

[0021] Example 1: 2-(2-(1 HPreparation of dimethyl 2-(2-(1H-indazol-1-yl)-2-(4-methoxyphenyl)ethyl)malonate (3a): DA cyclopropane 1a (31.7 mg, 0.12 mmol) and indazole 2a (11.8 mg, 0.10 mmol) were added to a reaction flask, and bis(trifluoromethylsulfonyl)imide cobalt (Co(NTf2)2) (6.2 mg, 10 mol%) was added. Under nitrogen protection, 1.0 mL of 1,2-dichloroethane was added, and 40 o C and stirred for 18 h, and the reaction was detected by thin layer chromatography. After the reaction was complete, the reaction solvent was removed by concentration to obtain a crude product. The obtained crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1~2:1) to obtain N 1 -Alkyl indazole compound 3a pure product (35.6 mg, yield 93%). Crude product 1 H NMR analysis reveals regioselectivity of indazole alkylation N 1 : N 2 >20:1.

[0022] Implement 2-23 to prepare compounds (3b ~ 3w).

[0023] Examples 2-23 are the same as Example 1. The changes in substituents, compound numbers, yields, etc. in the reactions are shown in Table 1.

[0024]

[0025]

[0026] Example 24: 2-(2-(2 H Preparation of dimethyl 2-(2-(2H-indazol-2-yl)-2-(4-methoxyphenyl)ethyl)malonate (4a): DA cyclopropane 1a (26.4 mg, 0.10 mmol) and indazole 2a (14.2 mg, 0.12 mmol) were added to a reaction flask, and aluminum trifluoromethanesulfonate (Al(OTf)3) (4.7 mg, 10 mol%) was added. Under nitrogen protection, 1.0 mL of 1,2-dichloroethane was added, and 40 oC and stirred for 18 h, and the reaction was detected by thin layer chromatography. After the reaction was complete, the reaction solvent was removed by concentration to obtain a crude product. The obtained crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1~2:1) to obtain N 1 -Alkyl indazole compound 4a pure product (34.8 mg, yield 91%). Crude product 1 H NMR analysis reveals regioselectivity of indazole alkylation N 1 : N 2 =20:1.

[0027] Compounds (4b to 4w) were prepared by performing 25-46.

[0028] Examples 25-46 are the same as Example 24. The changes in substituents, compound numbers, yields, etc. in the reactions are shown in Table 2.

[0029]

[0030] The characterization of indazole derivatives 3a~4w is as follows: Characterization of product 3a: 1 H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.64 (d, J = 7.8Hz, 1H), 7.31 – 7.21 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.04 (t, J = 7.2 Hz, 1H),6.73 (d, J = 8.4 Hz, 2H), 5.66 (dd, J = 10.2, 5.4 Hz, 1H), 3.66 (s, 3H), 3.61 (s,3H), 3.57 (s, 3H), 3.22 (dd, J = 9.0, 5.4 Hz, 1H), 3.19 – 3.09 (m, 1H), 2.81(ddd, J = 14.4, 9.0, 5.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 169.48, 169.35,159.24, 139.82, 133.74, 132.19, 127.91, 126.32, 124.24, 121.08, 120.84,114.06, 109.14, 59.07, 55.24, 52.65, 52.56, 48.66, 34.25. HRMS (ESI) Calcdfor C 21 H 22 N2O5[M + H] + 383.1601; Found 383.1597. Characterization of product 3b: 1 H NMR (600 MHz, CDCl3) δ 8.11 (s, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.34 – 7.20 (m, 3H), 7.18 – 7.01 (m, 4H), 6.03 (dd, J = 10.8, 4.2 Hz,1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.44 (dd, J = 10.2, 4.2 Hz, 1H), 3.27 – 3.15(m, 1H), 2.74 (ddd, J = 14.4, 10.2, 4.2 Hz, 1H), 2.51 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 169.60, 169.38, 139.88, 138.70, 134.77, 133.68, 130.60, 127.80,126.60, 126.38, 126.24, 124.30, 121.10, 120.89, 109.01, 56.01, 52.68, 52.55,48.67, 33.80, 19.28. HRMS (ESI) Calcd for C 21 H 22 N2O4[M + H] + 367.1652; Found367.1652. Characterization of product 3c: 1 H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.72 (d, J= 7.8Hz, 1H), 7.36 – 7.28 (m, 2H), 7.18 – 7.10 (m, 3H), 7.08 (d, J = 7.8 Hz, 1H),7.04 (d, J = 7.2 Hz, 1H), 5.74 (dd, J = 10.2, 4.8 Hz, 1H), 3.68 (s, 3H), 3.64 (s,3H), 3.31 (dd, J = 9.6, 5.4 Hz, 1H), 3.25 (ddd, J = 14.4, 10.8, 5.4 Hz, 1H), 2.89(ddd, J = 14.4, 9.6, 5.0 Hz, 1H), 2.28 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ169.50, 169.36, 140.11, 139.96, 138.43, 133.80, 128.75, 128.61, 127.28,126.37, 124.23, 123.70, 121.09, 120.88, 109.15, 59.54, 52.68, 52.57, 48.65,34.26, 21.46. HRMS (ESI) Calcd for C 21 H 22 N2O4[M + H] + 367.1652; Found 367.1650. Characterization of product 3d: 1 H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.36 – 7.27 (m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H),7.08 (d, J = 7.8 Hz, 2H), 5.74 (dd, J = 10.2, 5.4 Hz, 1H), 3.68 (s, 3H), 3.64 (s,3H), 3.31 (dd, J= 9.6, 5.4 Hz, 1H), 3.28 – 3.18 (m, 1H), 2.89 (ddd, J = 14.4, 9.6, 5.4 Hz, 1H), 2.27 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 169.49, 169.36, 139.89, 137.70, 137.11, 133.75, 129.38, 126.56, 126.34, 124.25, 121.08, 120.85, 109.15, 59.36, 52.66, 52.56, 48.67, 34.17, 21.05. HRMS (ESI) Calcd for C 21 H 22 N2O4[M + H] + 367.1652; Found 367.1650. Characterization of Product 3e: 1 H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.36 – 7.25 (m, 6H), 7.23 (t, J = 7.2 Hz, 1H), 7.15 – 7.10 (m, 1H), 5.78 (dd, J = 10.4, 4.8 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.32 (dd, J = 9.6, 5.4 Hz, 1H), 3.29 – 3.21 (m, 1H), 2.91 (ddd, J = 14.4, 9.6, 5.4 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.47, 169.33, 140.16, 139.96, 133.86, 128.73, 127.96, 126.63, 126.40, 124.25, 121.11, 120.92, 109.11, 59.55, 52.69, 52.59, 48.63, 34.21. HRMS (ESI) Calcd for C 26 H 25 ClNO4[M + H] +Found 353.1493. Characterization of product 3f: 1 H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.36 – 7.28 (m, 2H), 7.27 – 7.22 (m, 4H), 7.14 (t, J = 7.2 Hz, 1H),5.77 (dd, J = 10.2, 4.8 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.30 (dd, J = 9.6,5.4 Hz, 1H), 3.27 – 3.18 (m, 1H), 2.86 (ddd, J = 14.4, 9.6, 4.8 Hz, 1H). 13 C NMR(150 MHz, CDCl3) δ 169.38, 169.22, 139.92, 138.70, 134.15, 133.83, 128.91,128.05, 126.58, 124.28, 121.21, 121.09, 108.91, 58.85, 52.75, 52.63, 48.48,34.15. HRMS (ESI) Calcd for C 20 H 19 ClN2O4[M + H] + 387.1106; Found 387.1108. Characterization of product 3g: 1 H NMR (600 MHz, CDCl3) δ 8.12 (s, 1H), 7.95 (d, J = 7.8Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.34 – 7.28 (m, 2H),7.14 (t, J = 7.2 Hz, 1H), 5.85 (dd, J = 10.8, 4.8 Hz, 1H), 3.87 (s, 3H), 3.69 (s,3H), 3.64 (s, 3H), 3.33 (dd,J = 9.6, 4.8 Hz, 1H), 3.30 – 3.23 (m, 1H), 2.89(ddd, J = 14.4, 9.6, 4.8 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.37, 169.19,166.61, 145.19, 140.04, 134.26, 130.07, 129.80, 126.64, 124.30, 121.23,121.14, 108.90, 59.21, 52.76, 52.64, 52.15, 48.46, 34.03. HRMS (ESI) Calcdfor C 22 H 22 N2O6[M + H] + Found 411.1550. Characterization of product 3h: 1 H NMR (600 MHz, CDCl3) δ 8.15 (s, 1H), 7.77 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.39 – 7.35 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 5.89 (dd, J = 10.8, 4.2 Hz,1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.32 (dd, J = 10.2, 4.8 Hz, 1H), 3.30 – 3.22(m, 1H), 2.88 (ddd, J = 14.4, 10.2, 4.2 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ169.27, 169.04, 145.52, 140.10, 134.61, 132.59, 127.41, 126.85, 124.32,121.34, 118.42, 111.95, 108.66, 58.93, 52.80, 52.67, 48.31, 34.03. HRMS (ESI)Calcd for C 21 H 19 N3O4[M + H] + Found 378.1447. Characterization of product 3i: 1 H NMR (600 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 8.19(s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 7.2 Hz,1H), 7.53 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 3.6 Hz, 2H),7.15 (d, J = 7.2 Hz, 1H), 7.13 – 7.05 (m, 1H), 6.69 (dd, J = 11.2, 3.6 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.56 (dd, J = 10.8, 4.2 Hz, 1H), 3.38 – 3.28 (m,1H), 3.03 (ddd, J = 14.4, 10.8, 3.6 Hz, 1H). 1313C NMR (150 MHz, CDCl3) δ 169.84, 169.41, 140.02, 136.65, 133.88, 133.76, 130.47, 129.08, 128.50, 126.94, 126.46, 125.82, 125.53, 124.44, 123.73, 122.47, 121.08, 121.02, 109.22, 56.04, 52.70, 52.65, 48.76, 33.90. HRMS (ESI) Calcd for C 24 H 22 N2O4[M + H] + 403.1652; Found 403.1648. Characterization of Product 3j: 1 1H NMR (600 MHz, CDCl3) δ 8.05 (s, 1H), 7.72 (d, J J = 8.4 Hz, 1H), 7.43 (d, J J = 8.4 Hz, 1H), 7.37 (t, J J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.15 (t, J J = 7.2 Hz, 1H), 6.30 (s, 2H), 5.92 (dd, J J = 10.2, 5.4 Hz, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.21 (dd, J J = 9.0, 5.4 Hz, 1H), 3.14 (ddd, J J = 15.6, 10.2, 5.4 Hz, 1H), 2.98 (ddd, J J = 14.4, 9.0, 5.4 Hz, 1H). 13 13C NMR (150 MHz, CDCl3) δ 169.20, 169.05, 152.11, 142.48, 139.75, 134.31, 126.58, 124.21, 121.18, 121.01, 110.39, 109.13, 107.57, 53.86, 52.71, 52.69, 48.10, 31.48. HRMS (ESI) Calcd for C 18 H 18 N2O5[M + H]+ Found 343.1280. Characterization of product 3k: 1 H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.74 (d, J = 7.8Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.2 Hz,2H), 7.30 – 7.25 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.57 – 6.42 (m, 2H), 5.39 (dt, J = 9.6, 6.0 Hz, 1H), 3.67 (s, 3H), 3.65 (s,3H), 3.26 (dd, J = 9.0, 5.4 Hz, 1H), 2.95 (ddd, J = 14.4, 9.6, 5.4 Hz, 1H), 2.75(ddd, J = 14.4, 9.0, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.40, 169.26,139.62, 135.97, 134.03, 132.45, 128.57, 128.05, 127.47, 126.63, 126.41,124.14, 121.20, 120.91, 109.10, 58.39, 52.70, 52.63, 48.29, 33.37. HRMS (ESI)Calcd for C 22 H 22 N2O4[M + H] + 379.1652; Found 379.1653. Characterization of product 3l: 1 H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.39 – 7.28 (m, 2H), 7.13 (t,J = 7.2 Hz, 1H), 4.72 – 4.60 (m, 1H), 3.61 (s, 3H), 3.59 (s, 3H), 2.93 (dd, J = 10.8, 4.2 Hz, 1H), 2.76 – 2.67 (m, 1H), 2.51 (ddd, J = 14.2, 10.8, 3.6 Hz, 1H), 2.13 – 2.05 (m, 1H), 1.90 – 1.79 (m, 1H), 1.19 – 1.09 (m, 1H), 1.02 – 0.94 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 169.50, 169.32, 140.53, 133.90, 126.15, 123.61, 121.12, 120.60, 108.79, 56.10, 52.52, 52.44, 48.30, 37.75, 34.06, 19.43, 13.64. HRMS (ESI) Calcd for C 17 H 22 N2O4[M + H] + 319.1652; Found 450.1657. Characterization of product 3m: 1 H NMR (600 MHz, CDCl3) δ 8.14 (s, 1H), 7.85 – 7.83 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.73 – 7.70 (m, 3H), 7.43 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.05 – 6.97 (m, 1H), 4.42 – 4.02 (m, 4H), 3.83 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 3.41 – 3.33 (m, 2H), 1.28 (t, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 3H). 1313C NMR (150 MHz, CDCl3) δ 168.43, 168.29, 167.29, 139.80, 135.20, 134.44, 131.40, 127.06, 124.24, 123.76, 121.57, 121.02, 109.57, 61.89, 61.85, 60.33, 48.60, 29.65, 14.01, 13.94. HRMS (ESI) Calcd for C 24 H 23 N3O6[M + H] + 450.1660; Found 450.1659. Characterization of Product 3n: 1 1H NMR (600 MHz, CDCl3) δ 7.62 (d, J J = 7.8 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.25 (d, J J = 9.0 Hz, 3H), 7.08 (t, J J = 7.2 Hz, 1H), 6.80 (d, J J = 8.4 Hz, 2H), 5.64 (dd, J J = 10.2, 5.4 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.64 (s, 3H), 3.30 (dd, J J = 9.6, 5.4 Hz, 1H), 3.24 – 3.12 (m, 1H), 2.87 (ddd, J J = 14.4, 9.6, 5.4 Hz, 1H), 2.59 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 169.56, 169.42, 159.11, 142.15, 140.70, 132.50, 127.92, 126.21, 123.66, 120.35, 119.94, 113.96, 109.00, 58.69, 55.24, 52.62, 52.53, 48.71, 34.11, 12.15. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1756. Characterization of product 3o: 1 H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.38 –7.34 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.2Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 5.69 (dd, J = 9.6, 6.0 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H), 3.31 (dd, J = 9.0, 6.0 Hz, 1H), 3.18 (ddd, J = 14.4,9.6, 6.0 Hz, 1H), 2.88 (ddd, J = 14.4, 9.0, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3)δ 169.39, 169.20, 159.42, 140.89, 131.49, 128.02, 127.57, 124.03, 121.64,121.29, 120.45, 114.14, 109.44, 59.84, 55.26, 52.70, 52.61, 48.62, 34.01.HRMS (ESI) Calcd for C 21 H 21 BrN2O5[M + H] + 461.0707; Found 461.0699. Characterization of product 3p: 1 H NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.24 (d, J = 9.0Hz, 2H), 7.22 – 7.19 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 6.6 Hz, 1H),6.80 (d, J = 8.4 Hz, 2H), 5.70 (dd,J = 10.2, 5.4 Hz, 1H), 3.74 (s, 3H), 3.69 (s,3H), 3.65 (s, 3H), 3.28 (dd, J = 9.6, 5.4 Hz, 1H), 3.21 (ddd, J = 15.6, 10.2, 5.4Hz, 1H), 2.88 (ddd, J = 14.4, 9.6, 5.4 Hz, 1H), 2.58 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 169.50, 169.38, 159.20, 139.78, 132.62, 132.26, 131.54, 127.89,126.52, 124.68, 120.83, 114.03, 106.58, 59.11, 55.25, 52.67, 52.58, 48.65,34.21, 18.59. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1758. Characterization of product 3q: 1 H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.47 (s, 1H),7.24 – 7.19 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 5.69(dd, J = 10.2, 5.4 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 3.30 (dd, J = 9.0, 5.4 Hz, 1H), 3.26 – 3.16 (m, 1H), 2.87 (ddd, J = 14.4, 9.6, 5.4 Hz,1H), 2.42 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 169.52, 169.39, 159.19, 138.54,133.08, 132.28, 130.29, 128.46, 127.85, 124.61, 120.07, 114.03, 108.84,59.09, 55.25, 52.67, 52.58, 48.66, 34.17, 21.25. HRMS (ESI) Calcd forC 22 H 24 N2O5[M + H] + 397.1758; Found 397.1754. Characterization of product 3r: 1 H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.67 (s, 1H),7.29 – 7.18 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H), 5.69 (dd, J = 9.6, 5.4 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 3.29 (dd, J = 9.0, 6.0 Hz, 1H), 3.24– 3.14 (m, 1H), 2.91 – 2.83 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 169.40, 169.25,159.38, 138.26, 133.05, 131.74, 127.86, 127.03, 126.54, 125.04, 120.25,114.15, 110.29, 59.45, 55.25, 52.70, 52.63, 48.60, 34.16. HRMS (ESI) Calcdfor C 21 H 21 ClN2O5[M + H] + 417.1212; Found 417.1208. Characterization of product 3s: 1 H NMR (600 MHz, CDCl3) δ 8.17 (s, 1H), 8.03 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.43 (d,J = 9.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.82(d, J = 8.4 Hz, 2H), 5.77 (dd, J = 9.6, 5.4 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H), 3.29 (dd, J = 9.0, 6.0 Hz, 1H), 3.25 – 3.18 (m, 1H), 2.90 (ddd, J =14.4, 9.0, 5.4 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.36, 169.19, 159.47, 140.60, 134.72, 131.49, 127.91, 124.64 (q, J = 270.0 Hz), 123.49 (q, J = 32.1Hz), 123.41, 122.96 (q, J = 3.2 Hz), 119.35 (q, J = 4.4 Hz), 114.20, 109.85, 59.60, 55.25, 52.71, 52.64, 48.58, 34.14. 19 F NMR (565 MHz, CDCl3) δ -60.96. HRMS (ESI) Calcd for C 22 H 21 F3N2O5[M + H] + 451.1475; Found 451.1472. Characterization of Product 3t: 1 H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.56 (d, J = 9.0Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 9.0 Hz,1H), 6.64 (s, 1H), 5.66 (dd, J= 10.2, 5.4 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.32 (dd, J = 9.0, 5.4 Hz, 1H), 3.23 – 3.15 (m,1H), 2.87 (ddd, J = 14.4, 9.6, 5.4 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.56,169.42, 159.40, 159.20, 141.09, 133.77, 132.21, 127.89, 121.78, 119.00,114.05, 112.81, 90.44, 58.83, 55.51, 55.25, 52.68, 52.57, 48.62, 34.24. HRMS(ESI) Calcd for C 22 H 24 N2O6[M + H] + 413.1707; Found 413.1702. Characterization of product 3u: 1 H NMR (600 MHz, CDCl3) δ 8.01 (s, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.25 (d, J = 9.0 Hz, 2H), 7.10 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.81(d, J = 8.4 Hz, 2H), 5.69 (dd, J = 10.2, 5.4 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 3.30 (dd, J = 9.0, 5.4 Hz, 1H), 3.19 (ddd, J = 15.0, 10.2, 5.4 Hz,1H), 2.87 (ddd, J = 14.4, 9.0, 5.4 Hz, 1H), 2.44 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 169.53, 169.40, 159.19, 140.45, 136.73, 133.58, 132.33, 127.89,123.20, 122.38, 120.62, 114.04, 108.55, 58.82, 55.25, 52.68, 52.56, 48.65,34.30, 22.11. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1754. Characterization of product 3v: 1 H NMR (600 MHz, CDCl3) δ 8.13 (s, 1H), 8.12 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.81(d, J = 8.4 Hz, 2H), 5.79 (dd, J = 9.6, 5.4 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.24 (ddd, J = 15.0, 12.0, 5.4 Hz, 2H), 2.95 – 2.88(m, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.37, 169.18, 167.22, 159.40, 139.36,133.78, 131.75, 128.15, 127.93, 126.73, 121.46, 120.96, 114.14, 111.46,59.42, 55.24, 52.70, 52.65, 52.33, 48.67, 34.33. HRMS (ESI) Calcd forC 23 H 24 N2O7[M + H] + 441.1656; Found 441.1660. Characterization of product 3w: 11H NMR (600 MHz, CDCl3) δ 8.07 (d, J J = 1.2 Hz, 1H), 7.49 –7.42 (m, 1H), 7.32 (d, J J = 8.4 Hz, 2H), 7.04 – 6.95 (m, 2H), 6.81 (d, J J = 8.4 Hz,2H), 5.94 (dd, J J = 10.2, 5.4 Hz, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H),3.35 – 3.24 (m, 2H), 2.86 (ddd, J J = 14.4, 9.0, 5.4 Hz, 1H). 13 13C NMR (151 MHz,CDCl3) δ 169.41, 169.23, 159.32, 148.44 (d, J J = 245.3 Hz), 134.50, 132.41,129.28 (d, J J = 11.9 Hz), 128.11, 128.00 (d, J J = 4.4 Hz), 121.18 (d, J J = 5.7 Hz),116.82 (d, J J = 4.2 Hz), 113.99, 111.29 (d, J J = 17.7 Hz), 61.39 (d, J J = 5.9 Hz),55.23, 52.64, 52.58, 48.99, 34.43. 19 19F NMR (565 MHz, CDCl3) δ -132.68. HRMS(ESI) Calcd for C 21 18H 21 19FN2O5[M + H] + 401.1507; Found 401.1505. Characterization of Product 4a: 1 1H NMR (600 MHz, CDCl3) δ 7.90 (s, 1H), 7.73 (d, J J = 8.4Hz, 1H), 7.60 (d, J J = 8.4 Hz, 1H), 7.32 (d, J= 7.8 Hz, 2H), 7.26 (t, J = 7.8 Hz,1H), 7.05 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 7.8 Hz, 2H), 5.72 – 5.63 (m, 1H),3.77 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H), 3.28 (t, J = 7.2 Hz, 1H), 3.24 – 3.14(m, 1H), 2.90 (dt, J = 14.4, 7.2 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.24,169.08, 159.73, 148.81, 131.20, 128.27, 125.86, 122.28, 121.77, 121.74,120.18, 117.85, 114.27, 64.57, 55.28, 52.63, 52.61, 48.72, 34.46. HRMS (ESI)Calcd for C 21 H 22 N2O5[M + H] + 383.1601; Found 383.1599. Characterization of Product 4b: 1 H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.74 (d, J = 9.0Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 – 7.40 (m, 1H), 7.29 – 7.26 (m, 1H),7.23 – 7.16 (m, 3H), 7.08 – 7.03 (m, 1H), 6.00 (dd, J = 10.2, 4.8 Hz, 1H), 3.74(s, 3H), 3.65 (s, 3H), 3.47 (dd, J = 9.0, 5.4 Hz, 1H), 3.17 (ddd, J = 14.4, 10.2,5.4 Hz, 1H), 2.82 (ddd, J= 14.4, 9.0, 4.8 Hz, 1H), 2.38 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 169.38, 169.15, 148.57, 137.28, 135.92, 130.96, 128.46, 126.70, 126.12, 125.93, 122.49, 121.82, 120.24, 117.83, 61.19, 52.75, 52.72, 48.73, 34.02, 19.19. HRMS (ESI) Calcd for C 21 H 22 N2O4[M + H] + 367.1652; Found 367.1652. Characterization of Product 4c: 1 H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 5.68 (dd, J = 9.6, 5.4 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 3H), 3.29 (dd, J = 8.4, 6.0 Hz, 1H), 3.24 – 3.16 (m, 1H), 2.91 (ddd, J = 14.4, 9.0, 6.0 Hz, 1H), 2.31 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 169.29; 121.76, 120.26, 117.88, 65.02, 52.74, 52.72, 48.64, 34.34, 21.43. HRMS (ESI) Calcdfor C 21 H 22 N2O4[M + H] + 367.1652; Found 367.1652. Buy 4d installation: 1 H NMR (600 MHz, CDCl3) δ 7.91 (s, 1H), 7.73 (d, 11). J = 9.0Hz, 1H), 7.60(d, J = 8.4 Hz, 1H), 7.30 – 7.24 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 – 7.03 (m, 1H), 5.68 (dd, J = 9.6, 6.0 Hz, 1H), 3.72 (s, 3H), 3.66 (s,3H), 3.29 (dd, 1). J = 8.4, 6.0 Hz, 1H), 3.19 (ddd, J = 15.6, 9.6, 6.0 Hz, 1H), 2.91(ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.31(s, 3H). 13 C NMR (150 MHz, CDCl3) δ169.29, 169.14, 148.78, 138.38, 136.13, 129.57, 126.85, 125.93; 117.85, 64.79, 52.76, 52.73, 48.65, 34.32, 21.11.HRMS (ESI) Calcd for C 21 H 22 N2O4[M + H] +367.1652; Found 367.1648. Characterization of product 4e: 1 H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.74 (d, J = 9.0Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz,2H), 7.31 – 7.24 (m, 2H), 7.07 (dd, J = 7.8, 7.2 Hz, 1H), 5.72 (dd, J = 10.2, 5.4Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.30 (dd, J = 9.0, 5.4 Hz, 1H), 3.25 –3.18 (m, 1H), 2.93 (ddd, J = 14.4, 9.0, 5.4 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ169.27, 169.11, 148.83, 139.22, 128.91, 128.50, 126.85, 126.01, 122.67,121.89, 121.75, 120.26, 117.87, 65.00, 52.77, 52.75, 48.61, 34.36. HRMS (ESI)Calcd for C 26 H 25 ClNO4[M + H] + 353.1496; Found 353.1494. Characterization of product 4f: 1 H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.73 (d, J = 9.0Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.33 – 7.25 (m, 5H), 7.10 – 7.06 (m, 1H), 5.70 (dd, J= 10.2, 5.4 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.25 (dd, J = 9.0,5.4 Hz, 1H), 3.23 – 3.15 (m, 1H), 2.88 (ddd, J = 14.4, 9.0, 5.4 Hz, 1H). 13 C NMR(150 MHz, CDCl3) δ 169.18, 168.98, 148.99, 137.85, 134.39, 129.05, 128.24,126.18, 122.76, 122.07, 121.73, 120.24, 117.88, 64.26, 52.79, 52.78, 48.45,34.35. HRMS (ESI) Calcd for C 20 H 19 ClN2O4[M + H] + 387.1106; Found 387.1104. Characterization of Product 4g: 1 H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.4 Hz, 2H), 7.97(s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz,2H), 7.30 (dd, J = 7.8, 7.2 Hz, 1H), 7.09 (dd, J = 7.8, 7.2 Hz, 1H), 5.80 (dd, J =10.2, 4.8 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 3.31 – 3.19 (m,2H), 2.92 (ddd, J = 14.4, 9.0, 4.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 169.16,168.95, 166.48, 148.96, 144.17, 130.25, 130.17, 126.79, 126.29, 123.03,122.15, 121.74, 120.27, 117.86, 64.57, 52.81, 52.79, 52.20, 48.41, 34.24.HRMS (ESI) Calcd for C 22 H 22 N2O6[M + H] + 411.1551; Found 411.1549. Characterization of product 4h: 1 H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.74 (d, J = 9.0Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz,2H), 7.33 – 7.29 (m, 1H), 7.10 (t, J = 7.2 Hz, 1H), 5.80 (dd, J = 10.8, 4.2 Hz,1H), 3.72 (s, 3H), 3.68 (s, 3H), 3.29 – 3.17 (m, 2H), 2.87 (dt, J = 13.8, 7.8 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.10, 168.82, 149.23, 144.66, 132.67,127.48, 126.47, 123.26, 122.35, 121.74, 120.26, 118.31, 117.91, 112.36,64.28, 52.86, 48.24, 34.23. HRMS (ESI) Calcd for C 21 H 19 N3O4[M + H] + 378.1448;Found 378.1447. Characterization of product 4i: 1H NMR (600 MHz, CDCl3) δ 8.23 ​​(d, J = 8.4 Hz, 1H), 7.89 –7.84 (m, 2H), 7.81 (dd, J = 10.8, 9.0 Hz, 2H), 7.56 (t, J = 9.0 Hz, 2H), 7.52 –7.45 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.08 – 7.02 (m,1H), 6.63 (dd, J = 10.8, 4.2 Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 3.55 (dd, J =9.6, 4.8 Hz, 1H), 3.28 (ddd, J = 15.4, 10.8, 4.8 Hz, 1H), 3.06 (ddd, J = 14.4,9.6, 4.2 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 169.59, 169.18, 148.66, 135.17,133.87, 130.63, 129.25, 128.99, 127.11, 126.04, 126.02, 125.42, 123.92,122.97, 122.60, 121.98, 121.90, 120.34, 117.89, 61.07, 52.83, 52.73, 48.77,34.23. 24 H 22 N2O4[M + H] + Found 403.1652. Characterization of product 4j: 1 H NMR (600 MHz, CDCl3) δ 7.96 (s, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.40 (d, J= 1.2 Hz, 1H), 7.31 – 7.23 (m, 1H),7.08 – 7.04 (m, 1H), 6.46 (d, J = 3.2 Hz, 1H), 6.36 (dd, J = 3.2, 1.8 Hz, 1H),5.83 (dd, J = 9.6, 6.0 Hz, 1H), 3.74 (s, 3H), 3.64 (s, 3H), 3.25 (dd, J = 8.4,6.0 Hz, 1H), 3.08 (ddd, J = 15.6, 9.6, 6.0 Hz, 1H), 2.96 (ddd, J = 14.4, 8.4, 6.0Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.00, 168.85, 150.82, 148.78, 143.10,126.13, 122.15, 121.94, 121.82, 120.30, 117.81, 110.60, 108.83, 58.77, 52.84,52.75, 48.23, 32.65. HRMS (ESI) Calcd for C 18 H 18 N2O5[M + H] + 343.1288; Found343.1285. Characterization of Product 4k: 1 H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.73 (d, J = 9.0Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.33 – 7.22 (m, 4H),7.11 – 7.05 (m, 1H), 6.61 (d, J = 15.6 Hz, 1H), 6.52 (dd, J = 15.6, 7.2 Hz, 1H),5.28 (dd, J = 15.6, 7.2 Hz, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.27 (dd,J = 9.0, 6.0 Hz, 1H), 2.91 (ddd, J = 14.4, 9.0, 6.0 Hz, 1H), 2.77 (ddd, J = 14.4, 9.0, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.08, 168.89, 148.91, 141.61, 126.83, 126.17, 122.19, 122.01, 121.74, 120.31, 117.89, 60.63, 52.83, 52.76, 48.44, 35.54. HRMS (ESI) Calcd for C 22 H 22 N2O4 [M + H] + 379.1652; Found 379.1651. Characterization of Product 4l: 1 H NMR (600 MHz, CDCl3) δ 7.89 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.13 – 7.07 (m, 1H), 4.57 – 4.44 (m, 1H), 3.75 (s, 3H), 3.60 (s, 3H), 2.99 (dd, J = 10.2, 4.2 Hz, 1H), 2.76 – 2.63 (m, 1H), 2.55 (ddd, J = 14.4, 10.2, 3.6 Hz, 1H), 2.27 – 2.04 (m, 1H), 1.96 – 1.81 (m, 1H), 1.32 – 1.17 (m, 1H), 1.17 – 1.03 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 169.38, 169.13, 148.90, 125.92,122.84, 121.72, 121.19, 120.22, 117.65, 62.06, 52.70, 52.60, 48.25, 37.98,34.61, 19.28, 13.54. HRMS (ESI) Calcd for C 17 H 22 N2O4[M + H] + 319.1652; Found450.1647. Characterization of product 4m: 1 H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.86 (dd, J = 5.4,3.0 Hz, 2H), 7.73 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.63 (d, J =8.4 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.08 – 7.03 (m, 1H), 6.90 (t, J = 7.8 Hz,1H), 4.22 – 4.11 (m, 4H), 3.54 (dt, J = 14.4, 7.2 Hz, 1H), 3.44 – 3.32 (m, 2H), 1.24 (q, J = 7.2 Hz, 6H). 13 C NMR (150 MHz, CDCl3) δ 168.04, 168.00, 166.88,148.63, 134.66, 131.30, 126.65, 123.91, 122.84, 122.34, 121.91, 120.53,118.12, 65.33, 62.08, 62.04, 48.66, 30.32, 13.96, 13.95. HRMS (ESI) Calcd forC 24 H 23 N3O6[M + H] + 450.1660; Found 450.1657. Characterization of product 4n: 11H NMR (600 MHz, CDCl3) δ 7.70 (d, J J = 8.4 Hz, 1H), 7.53(d, J J = 8.4 Hz, 1H), 7.29 – 7.21 (m, 3H), 7.04 – 6.98 (m, 1H), 6.80 (t, J J = 9.0Hz, 2H), 5.71 – 5.65 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.69 (s, 3H), 3.35– 3.25 (m, 2H), 2.85 (ddd, J J = 14.4, 9.0, 5.4 Hz, 1H), 2.51 (s, 3H). 13 13C NMR (150MHz, CDCl3) δ 169.56, 169.29, 159.34, 147.93, 131.77, 131.66, 128.02, 125.99,121.09, 120.46, 119.75, 117.65, 114.16, 60.10, 55.28, 52.65, 52.62, 48.62,34.68, 9.81. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1756. Characterization of Product 4o: 1 1H NMR (600 MHz, CDCl3) δ 7.89 (s, 1H), 7.56 (d, J J = 8.4Hz, 1H), 7.33 (d, J J = 8.4 Hz, 2H), 7.20 – 7.15 (m, 1H), 6.86 (d, J J = 8.4 Hz, 2H),6.81 (d, J J = 6.6 Hz, 1H), 5.68 (dd, J J = 9.6, 6.0 Hz, 1H), 3.77 (s, 3H), 3.72 (s,3H), 3.67 (s, 3H), 3.30 (dd, J J = 8.4, 6.0 Hz, 1H), 3.23 – 3.14 (m, 1H), 2.90(ddd,J = 14.4, 8.4, 6.0 Hz, 1H), 2.47 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ169.32, 169.15, 159.66, 148.72, 131.20, 130.38, 128.27, 126.36, 123.06,121.50, 121.04, 115.09, 114.24, 64.49, 55.31, 52.75, 52.73, 48.67, 34.42,19.14. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1753. Characterization of product 4p: 1 H NMR (600 MHz, CDCl3) δ 7.79 (s, 1H), 7.63 (d, J = 9.0Hz, 1H), 7.34 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.13 – 7.07 (dd, J = 9.0, 1.2Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 5.63 (dd, J = 9.6, 6.0 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H), 3.27 (dd, J = 8.4, 6.0 Hz, 1H), 3.16 (ddd, J = 15.6,9.6, 6.0 Hz, 1H), 2.88 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.38 (s, 3H). 13C NMR(150 MHz, CDCl3) δ 169.31, 169.15, 159.61, 147.73, 131.34, 131.10, 128.82, 128.20, 122.02, 121.49, 118.30, 117.49. 114.20, 64.38, 55.30, 52.71, 52.70, 48.68, 34.43, 21.71. HRMS (ESI) Calcd 22 H 24 N2O5[M+H] + 397.1758; Found397.1760. Buy 4q application: 1 H NMR (600 MHz, CDCl3) δ 7.84 (s, 1H), 7.66 (d, 11). J = 9.0Hz, 1H), 7.57(d, J = 1.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.20 (dd, J = 9.0, 1.8Hz, 1H), 6.86(d, J = 9.0 Hz, 2H), 5.64 (dd, J = 9.0, 6.0 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.26 (dd, J = 8.4, 6.6 Hz, 1H), 3.16 (ddd, J = 15.6,9.6, 6.6 Hz, 1H), 2.88 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3)δ 169.19, 169.03, 159.79, 147.11, 130.74, 128.30, 127.49, 127.31, 122.07, 122.05, 119.37, 118.92,000; 114.31, 64.73, 55.32, 52.78, 52.75, 48.64, 34.34.HRMS (ESI) Calcd for C 21 H 21 ClN2O5[M+H]+ 417.1212; Found 417.1205. Characterization of product 4r: 1 H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 7.96 (s, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.48 – 7.39 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.69 (dd, J = 9.0, 6.0 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.68 (s, 3H), 3.27 (dd, J = 8.4, 6.0 Hz, 1H), 3.19 (ddd, J = 15.6, 9.0, 6.6 Hz,1H), 2.91 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.15,168.98, 159.90, 149.11, 130.49, 128.36, 124.71 (q, J = 269.9 Hz), 124.33,124.17 (q, J = 31.7 Hz), 121.92 (d, J = 2.9 Hz), 120.27, 119.16 (q, J = 5.0 Hz), 118.90, 114.38, 64.98, 55.32, 52.78, 52.75, 48.62, 34.34. 19 F NMR (565 MHz, CDCl3) δ -61.87. HRMS (ESI) Calcd for C 22 H 21 F3N2O5[M + H] + 451.1475; Found451.1472. Characterization of product 4s: 1 H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.45 (d, J= 9.0Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.75(dd, J = 9.0, 1.8 Hz, 1H), 5.57 (dd, J = 9.6, 6.0 Hz, 1H), 3.85 (s, 3H), 3.77 (s,3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.29 (dd, J = 8.4, 6.0 Hz, 1H), 3.22 – 3.10(m, 1H), 2.86 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ169.31, 169.16, 159.60, 158.74, 149.83, 131.32, 128.22, 122.56, 121.00,117.15, 116.82, 114.21, 94.92, 64.18, 55.30, 55.18, 52.73, 52.71, 48.69,34.37. HRMS (ESI) Calcd for C 22 H 24 N2O6[M + H] + 413.1707; Found 413.1703. Characterization of Product 4t: 1 H NMR (600 MHz, CDCl3) δ 7.83 (s, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.48 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H), 6.84(d, J = 8.4 Hz, 2H), 5.62 (dd, J = 9.6, 6.0 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H),3.66 (s, 3H), 3.28 (dd, J = 9.0, 6.0 Hz, 1H), 3.16 (ddd,J = 15.6, 9.6, 6.0 Hz,1H), 2.88 (ddd, J = 14.4, 9.0, 6.0 Hz, 1H), 2.43 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 169.32, 169.16, 159.60, 149.41, 135.74, 131.34, 128.21, 124.70,122.21, 120.02, 119.73, 116.21, 114.19, 64.32, 55.30, 52.72, 52.70, 48.67,34.42, 22.17. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] + 397.1758; Found 397.1756. Characterization of product 4u: 1 H NMR (600 MHz, CDCl3) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.69 (dd, J = 9.0, 1.2 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H),6.87 (d, J = 8.4 Hz, 2H), 5.69 (dd, J = 9.0, 6.0 Hz, 1H), 3.94 (s, 3H), 3.78 (s,3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.28 (dd, J = 8.4, 6.6 Hz, 1H), 3.19 (ddd, J =15.6, 9.6, 6.6 Hz, 1H), 2.91 (ddd, J = 14.4, 8.4, 6.6 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 169.19, 169.03, 167.55, 159.84, 147.98, 130.65, 128.37, 127.84,123.77, 122.66, 121.72, 121.49, 120.26, 114.33, 65.01, 55.32, 52.78, 52.75,52.16, 48.64, 34.40. HRMS (ESI) Calcd for C 23 H 24 N2O7[M + H] + 441.1656; Found 441.1653. Characterization of product 4v: 1 H NMR (600 MHz, CDCl3) δ 7.83 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 5.4 Hz, 1H), 6.95 (t, J = 7.2 Hz,1H), 6.85 (d, J = 8.4 Hz, 2H), 5.68 (dd, J = 9.0, 5.6 Hz, 1H), 3.77 (s, 3H), 3.72(s, 3H), 3.64 (s, 3H), 3.32 (dd, J = 8.4, 6.0 Hz, 1H), 3.23 – 3.07 (m, 1H), 2.88 (ddd, J = 14.4, 8.4, 6.0 Hz, 1H), 2.63 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ169.38, 169.23, 159.65, 148.98, 131.31, 128.37, 127.98, 124.79, 122.13,122.02, 121.59, 117.59, 114.19, 64.48, 55.31, 52.70, 52.66, 48.79, 34.67,17.14. HRMS (ESI) Calcd for C 22 H 24 N2O5[M + H] +397.1758; Found 397.1756. Characterization of product 4w: 1 H NMR (600 MHz, CDCl3) δ 7.94 (s, 1H), 7.36 (d, J = 6.6Hz, 3H), 6.99 – 6.84 (m, 4H), 5.70 (dd, J = 9.0, 6.6 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.67 (s, 3H), 3.29 (t, J = 7.2 Hz, 1H), 3.19 (dt, J = 9.0, 7.8 Hz,1H), 2.98 – 2.85 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ 169.20, 169.04, 159.83,153.04 (d, J = 255.4 Hz), 139.83 (d, J = 15.5 Hz), 130.69, 128.42, 124.98 (d, J =5.9 Hz), 123.02, 121.73 (d, J = 5.9 Hz), 116.18 (d, J = 4.6 Hz), 114.30, 108.80(d, J = 16.3 Hz), 64.93, 55.32, 52.75, 52.71, 48.69, 34.34. 19 F NMR (565 MHz, CDCl3) δ -128.48. HRMS (ESI) Calcd for C 21 H 21 FN2O5[M + H] + 401.1507; Found401.1502. Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. N 1 -and N 2 - The preparation method of alkyl indazole compounds is to synthesize the nucleophilic ring-opening reaction of indazole (2) and DA cyclopropane (1) under the catalysis of Lewis acid. N 1 -Alkyl indazole compounds (3) and N 2 -Alkyl indazole compounds (4); The reaction formula of the preparation method is shown in formula (I) and (II):

2. Among them, R is an alkyl group or an aryl group, such as a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a phenyl group, etc.; R1 is an aryl group, an alkenyl group, an alkyl group, or a heteroatom substituent, such as 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 4-chlorophenyl, 4-esterphenyl, 4-cyanophenyl, 1-naphthyl, 2-furyl, styryl, n-propyl, or phthalimide; R2 is a hydrogen atom, 3-methyl, 3-bromo, 4-methyl, 5-methyl, 5-chloro, 5-trifluoromethyl, 6-methoxy, 6-methyl, 6-ester, 7-fluoro, and the like.

3. The preparation method according to claim 1, characterized in that The catalyst, (I) wherein the catalyst is a soft Lewis acid, such as copper trifluoromethanesulfonate (Cu(OTf)2), zinc trifluoromethanesulfonate (Zn(OTf)2), nickel trifluoromethanesulfonate (Ni(OTf)2), cobalt trifluoromethanesulfonate (Co(OTf)2), bis(trifluoromethylsulfonyl)imide cobalt (Co(NTf2)2), etc., (II) wherein the catalyst is a hard Lewis acid, such as yttrium trifluoromethanesulfonate (Y(OTf)3), trifluoromethanesulfonate (T(OTf)3), trifluoromethanesulfonate (T(OTf)2), etc. Lanthanum fluoromethanesulfonate (La(OTf)3), samarium trifluoromethanesulfonate (Sm(OTf)3), europium trifluoromethanesulfonate (Eu(OTf)3) and other rare earth metal salts, magnesium perchlorate (Mg(ClO4)2), aluminum trifluoromethanesulfonate (Al(OTf)3) and other quaternary phosphonium salts, alkyl sulfonates, etc. The reaction solvent is a halogenated hydrocarbon, aromatic hydrocarbon, ether, ester and other solvents, such as: dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, ether, tetrahydrofuran, etc.

4. The preparation method according to claim 1, characterized in that The following steps are involved: Step (1), weighing raw materials DA cyclopropane and indazole, and weighing a Lewis acid catalyst; Step (2), under nitrogen protection, add a solvent in an amount of 1-2 mL / mmol, dissolve and stir to react; Step (3), after the reaction is completed, the solvent is removed by concentration, and the crude product is purified by column chromatography to obtain the corresponding N 1 and N 2 -Alkyl indazole compounds.

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