CN117886759A - A method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F - Google Patents

Abstract

The invention reports a new free radical mediated [3+2+1]]Cyclizing the α -polyfluoromethyl olefins, including α -trifluoromethyl 1, 3-ene, including α -difluoromethyl 1, 3-ene and α -trifluoromethyl 1, 3-diene and the common 2-aryl-2-trifluoromethylalkenes, and the like, aryl isocyanates activate C-F by XAT to produce high value monofluoro 3, 4-dihydropyrimidin-2 (1H) -ones. The method is carried out by base-mediated organic solvents (e.g. DMF (Rradal= -1.95V vs. SCE)) and bases (e.g. Na) ₂ CO ₃ ) Is subjected to thermochemical cleavage to generate methyl carbamate free radical, and alpha-polyfluoromethyl olefin is transferred with fluorine atoms of the methyl carbamate free radical to form polyfluoromethyl free radical for cyclization and fluorine eliminationBesides cascade reaction, a brand new synthetic approach is provided for direct functionalization of alpha-trifluoromethyl olefin C (sp 3) -F.

Description

A method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F

Technical Field

The invention belongs to the technical field of organic synthesis, and specifically relates to a method for selective C(sp3)-F activation reaction of a carbamoyl radical on a halogen atom to cause [3+2+1] cyclization of an alpha-polyfluoromethyl olefin and an aromatic isocyanate to generate monofluorinated 3,4-dihydropyrimidin-2(1H)-one.

Background Art

The construction of fluorinated organic molecules, especially fluorinated ring compounds, is an important topic in the fields of organic chemistry, medicinal chemistry and materials chemistry, because the introduction of fluorinated groups into these structures can significantly affect their solubility, lipophilicity and metabolic stability, which is conducive to paving the way for the innovation of drugs and functional materials. Typical methods for the synthesis of fluorinated molecules by introducing external fluorine sources include fluorination, fluoroalkylation and fluoroalkoxylation. In order to avoid the use of highly toxic conventional fluorine reagents and achieve satisfactory selectivity, these reactions usually require the pre-preparation of active fluorine sources and the pre-functionalization of fluorine receiving reagents. In addition, the CF functionalization of readily available fluorinated molecules represents a particularly promising and powerful method for the construction of a variety of new fluorinated structures, because it avoids the use of external fluorine sources and provides a reliable strategy for further modification and degradation of environmentally persistent fluorinated molecules. In this field, the method of selective C(sp3)-F functionalization of alkyl fluorides, including aryl- _CF3 , carbonyl- _CF3 and easily accessible alkyl- _CF3 , is particularly attractive and has become a powerful platform for forging bonds and simplifying the synthesis of complex fluorinated molecules. Compared with the remarkable progress in the C(sp3)-F functionalization of aryl- _CF3 and carbonyl- _CF3 using transition metal catalysis and free radical strategies in recent years, the direct C(sp3)-F functionalization of alkynyl- _CF3 has made relatively little progress. This is because the highly reactive olefin moiety in alkynyl- _CF3 makes the synthesis of geminal difluoroolefins susceptible to competition from γ-selective functionalization and fluorine elimination cascade reactions. To date, two feasible strategies for the direct C(sp3)-F functionalization of α-trifluoromethyl olefins have been developed: one was first reported by Zhu, Jiang, and co-workers, and their strategy is a direct anionic _SN2' -type substitution reaction of the C(sp3)-F bond mediated by nucleophiles (such as oximes), and the other was first established by Feng and co-workers and involves the use of transient activators (amine traceless mediators) to generate highly reactive geminal difluoropropenyl intermediates, and the C(sp3)-F functionalization is indirectly completed by a _SN2' -amination, ammonium and palladium-catalyzed regioselective allylic arylation cascade. Although the methods for the direct C(sp3)-F functionalization of α-trifluoromethyl olefins are efficient and highly selective, they have remained scarce to date, which may be related to the limited availability of nucleophiles and transient activating reagents in addition to the problem of competition with the γ-selective functionalization mentioned above. Therefore, it is highly desirable to develop an effective strategy to selectively achieve C(sp3)-F activation for the transformation of α-trifluoromethyl olefins using readily available starting materials.

Halogen atom transfer (XAT) has emerged as one of the most powerful strategies for the innovation of various radical synthesis methods, which involve the activation of organic halides (usually iodides and bromides) to form the corresponding carbon-centered radicals to construct different bonds and increase the complexity of molecules. In general, these methods are mainly based on effective XAT reagents, including classical organic compounds, Mn _x (CO) _y silicon reagents or trialkylborane-oxygen and recently developed tertiary amines using thermochemical photoredox or metal redox strategies. Despite the significant progress in this field, to the best of our knowledge, the formation of alkyl carbon-centered radicals by fluorine atom transfer to enable direct activation of C(sp3)-F is still an unexplored area, which may be due to the unusually high negative reduction potential of alkyl fluorides (CF ₃ CH＝CH ₂ :Rradical＝−5.11V vs.SCE) and the rather low negative reduction potential of existing XAT reagent systems (Et ₃ N:ROX1/2-radical＝−1.12V vs.SCE). Recently, the XAT strategy independently reported by Wang, Zhang/Wang, Glorius, and Huang/Leid was applicable to the γ-selective radical functionalization and defluorination cascade reaction of (trifluoromethyl)olefins with iodinated alkyl groups via photoredox catalysis or electrochemical strategies, in which tertiary amines or silanols were used as XAT agents to preferentially activate the C(sp3)-I bond of the iodinated alkyl group rather than the C(sp3)-F bond of the (trifluoromethyl)olefin to generate alkyl radicals.

Summary of the invention

The purpose of the present invention is to provide a method for the direct functionalization of α-trifluoromethyl olefin C(sp3)-F, which is a new base-mediated thermally induced fluorine atom transfer strategy to selectively contact the polyfluoromethyl C(sp3) central free radical, so that the α-polyfluoromethyl olefin and isocyanate form a [3+2+1] ring under transition metal-free and photocatalytic conditions, thereby providing a new synthetic route for the direct functionalization of α-trifluoromethyl olefin C(sp3)-F.

In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

A method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F, wherein the α-polyfluoromethyl olefin is heated under an inert atmosphere in the presence of a base and an organic solvent to cause [3+2+1] cyclization of the α-polyfluoromethyl olefin with an isocyanate to generate a monofluorinated 3,4-dihydropyrimidin-2(1H)-one, wherein the reaction equation is shown in Formula 1:

In the formula, ^R1 is selected from one of phenyl, substituted phenyl, substituted alkenyl or substituted alkynyl;

^R2 is selected from hydrogen or fluorine;

Ar ¹ and Ar ² are independently substituted phenyl groups. The position and number of the substituents are not limited. Ar ¹ and Ar ² may be the same or different.

Furthermore, when the R ¹ is a substituted phenyl group, the substituted phenyl group is a phenyl group containing at least one substituent selected from the group consisting of an alkyl group and a halogen group.

Furthermore, when the R ¹ is an alkenyl group containing a substituent, the alkenyl group containing a substituent is an alkenyl group containing a phenyl substituent, such as a phenyl group.

Furthermore, when ^R1 is an alkynyl group containing a substituent, the alkynyl group containing a substituent is an alkynyl group containing at least one substituent selected from the group consisting of an aryl group and a heterocyclic aromatic group, the aryl group is a phenyl group, a substituted phenyl group or a naphthyl group, the substituted phenyl group is a phenyl group containing at least one substituent selected from the group consisting of an alkyl group, a (N,N-dimethyl)amino group, a phenyl group, a halogen group, a cyano group, a trifluoromethyl group or a methyl formate group; the heterocyclic aromatic group is a thiophene, a ferrocene, a tazarotene derivative group, an ibuprofen derivative group, an estrone derivative group or an estradiol heptanoate derivative group.

Furthermore, the substituted phenyl groups of Ar ¹ and Ar ² are phenyl groups containing at least one substituent selected from the group consisting of alkyl, phenoxy, trifluoromethyl, trifluoromethoxy and halogen.

Furthermore, the base is selected from any one or more of Na ₃ PO 4 , t-BuONa, t-BuOK, Et ₃ N, DBU, DABCO NaHCO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ and Na ₂ CO ₃ ; preferably Na ₂ CO ₃ .

Furthermore, the organic solvent is selected from any one or more of DMSO, DMF, NMP, 1,4-dioxane, MeCN and PhMe; preferably DMF.

Furthermore, the The molar ratio of Ar ¹ NCO, Ar ² NCO and the base is 1:(1-2):(1-2):(4-10); preferably 1:2:2:5.

Furthermore, the heating temperature is 90-150°C, preferably 120-130°C.

Furthermore, the inert atmosphere is a nitrogen or argon atmosphere.

Furthermore, after the cyclization is completed, ethyl acetate is used as the eluent, filtered through a coarse column, concentrated in vacuo, and then purified by silica gel column chromatography to obtain monofluorinated 3,4-dihydropyrimidin-2(1H)-one.

The advantages of the present invention are:

The present invention reports for the first time a new free radical-mediated [3+2+1] cyclization of α-polyfluoromethyl olefins, including α-trifluoromethyl 1,3-ene, including α-difluoromethyl 1,3-ene and α-trifluoromethyl 1,3-dienes and common 2-aryl-2-trifluoromethyl olefins, etc., and aryl isocyanates activate CF through XAT to produce high-value monofluoro 3,4-dihydropyrimidin-2(1H)-ones. The method generates carbamate methyl radicals through base-mediated thermal chemical cracking of organic solvents (such as DMF (Rradical＝-1.95V vs.SCE)) and bases (such as Na ₂ CO ₃ ), and α-polyfluoromethyl olefins transfer fluorine atoms with carbamate methyl radicals to form polyfluoromethyl radicals, which undergo cyclization and fluorine elimination cascade reactions, providing a new synthetic route for the direct functionalization of α-trifluoromethyl olefins C(sp3)-F.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a reaction equation of the present invention.

DETAILED DESCRIPTION

The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the reagents and raw materials used are all purchased through conventional commercial channels in the art and/or prepared by conventional methods.

Preparation Example 1 of Reaction Raw Materials:

CuI (57.2 mg, 10 mol%) and Pd(PPh ₃ ) ₂ Cl ₂ (105.3 mg, 5 mol%) were dissolved in Et ₃ N (30 mL) at room temperature under argon. 2-Bromo-3,3,3-trifluoroprop-1-ene (0.498 mL, 4.8 mmol, 1.6 eq) and alkyne (3.0 mmol, 1.0 eq) were added to the solution. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with saturated aqueous NH ₄ Cl (20 mL) and then extracted with CH ₂ Cl ₂ (3×20 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=100:1) to give the desired enyne.

Preparation Example 2 of Reaction Raw Materials:

1-Ethynyl-4-methoxybenzene (1.1 mL, 10 mmol) in THF (25 mL) was cooled to -78°C and n-butyl lithium (5 mL, 2.5 M, 12.5 mmol) was added dropwise. The solution was stirred at this temperature for 30 minutes and ethyl trifluoroacetate (1.75 mL, 10 mmol) and Et ₂ O·BF ₃ (1.4 mL, 10 mmol) were added dropwise. The solution was stirred at -78°C for 1 hour and then warmed to room temperature. The reaction mixture was washed with water (3×25 mL) and saturated aqueous ammonium chloride solution (2×20 mL), and the combined aqueous phases were extracted with Et ₂ O. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by distillation under reduced pressure (20°C, 7.5×10 ^-2 mbar) to give 1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-yn-2-one as a yellow oil.

To a solution of methyl-d3-triphenylphosphine iodide (2.35 g, 5 mmol) in THF (20 mL) was added n-BuLi (3.2 mL, 1.6 M in THF) at -78 °C for 5 minutes. The solution was stirred at -78 °C for 15 minutes and then warmed to room temperature. The mixture was stirred for 30 minutes. The reaction mixture was cooled back to -78 °C and 1,1,1-trifluoro-4-(4-methoxyphenyl)but-3-yn-2-one (1.14 g, 5 mmol) was added dropwise over 5 minutes. After 20 minutes, the solution was heated to room temperature and stirred for 18 hours. The reaction mixture was filtered through silica gel and concentrated in vacuo. The residue was purified by flash column chromatography (100% n-pentane) to give the target compound 1a- _d2 (91%-D) as a colorless oil.

Examples 1-15

The compound shown in formula 1a and the aromatic isocyanate shown in formula 2a and 2a' were used to activate the C-F bond by XAT to prepare the monofluoro 3,4-dihydropyrimidin-2(1H)-one shown in formula 3aa. The effect of different synthesis conditions on the yield of the target product was discussed. The results are shown in Table 1. The reaction formula is as follows:

Table 1 Effect of different synthesis conditions on the yield of target products

^a Standard reaction conditions: 1a (0.2 mmol), 2a (4 equiv), Na ₂ CO ₃ (5 equiv), DMF (0.1 M; 1 mL), argon, 120°C, reaction time 2 h; ^b 1a (5 mmol; 1.13 g), 2 h

Taking Example 1 as an example, the typical test operation is as follows:

1-Methoxy-4-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)benzene 1a (1.14 g; 5 mmol), 1-isocyanate-4-methylbenzene 2a (2.66 g; 20 mmol; 4.0 equiv), Na ₂ CO ₃ (2.65 g; 25 mmol; 5 equiv) and DMF (0.1 M; 50 mL) were added to a Schlenk tube. The tube was then filled with argon (1 atm) and stirred at 120° C. for 4 hours until the starting material was completely consumed as monitored by TLC and/or GC-MS analysis. After the reaction was completed, the reaction mixture was filtered through a coarse column, eluted with ethyl acetate, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give the desired 6-fluoro-5-((4-methoxyphenyl)ethynyl)-1,3-di-p-tolyl-3,4-dihydropyrimidin-2(1H)-one 3aa (75%; 1.60 g).

¹ H NMR (500MHz, CDCl ₃ ) δ: 7.34 (d, J = 8.0 Hz, 2H), 7.23-7.17 (m, 8H), 6.82 (d, J = 8.0 Hz, 2H), 4.42 (d, J = 5.5Hz, 2H), 3.78 (s, 3H), 2.34 (d, J = 13.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.6,151.4(d,J＝263.75Hz),151.7,139.1,138.3,136.6,132.7,131.4,129.8,129.6,128.6,125.4,115.2,114.0,94.4(d,J＝5.0Hz),78.9 (d, J=1.25Hz), 73.0 (d, J=17.5Hz), 55.3, 49.4 (d, J=2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.93 (s ,1F); HRMS m/z(ESI)calcd for C ₂₇ H ₂₄ FN ₂ O ₂ ([M+H] ⁺ )427.1816,found427.1817.

Example 16-42 Substrate Extension Test 1

The same as Example 1 or Example 15, except that different α-polyfluoromethyl olefins were used. The results are shown in Table 2:

Table 2 Reaction results of different α-polyfluoromethyl olefins

^a Standard reaction conditions: 1 (0.2 mmol), 2a (4 equiv), Na ₂ CO ₃ (5 equiv), DMF (0.1 M; 1 mL), argon, 120°C, reaction time 2 h; ^b 1 (5 mmol; 1.13 g), 2 h;

In Example 16-41, Ar ¹ is 4-MeC ₆ H ₄ . In Example 42, Ar ¹ is 4-MeOC ₆ H ₄ .

Product structure characterization:

Compound 3ba: 64.9 mg, 82%; Brown yellow solid, mp 118.5-120.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.40 (d, J = 4.5 Hz, 2H), 7.29 (d, J =5.0Hz, 2H), 7.24-7.18 (m, 8H), 4.44 (d, J = 5.5Hz, 2H), 2.35 (d, J = 13.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.8(d,J＝265.0Hz),151.6,139.0,138.4,136.7,131.3,131.2,129.8,129.6,128.6,128.4,128.2,125.5,123.1,94.5(d,J＝5.0Hz),80.4 (d, J＝2.5Hz), 72.7 (d, J＝17.5Hz), 49.4 (d, J＝3.75Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.07 (s, 1F ); HRMS m/z(ESI)calcd for C ₂₆ H ₂₂ FN ₂ O([M+H] ⁺ )397.1711,found 397.1712.

Compound 3ca: 76.3 mg, 93%; Brown yellow solid, mp 123.4-125.6°C (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.299 (d, J = 8.0 Hz, 2H), 7.208 (t, J =5.2Hz, 8H), 7.103 (d, J = 8.0Hz, 2H), 4.437 (d, J = 5.6Hz, 2H), 2.349 (d, J = 11.2Hz, 9H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.6(d,J＝263.75Hz),139.0,138.4,138.3,136.7,131.4,131.1,129.8,129.6,129.1,128.6,125.5,120.1,94.6(d,J＝5.0Hz),79.7 (d, J＝2.5Hz), 72.9 (d, J＝17.5Hz), 49.4 (d, J＝2.5Hz), 21.5, 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.53 (s ,1F); HRMS m/z(ESI)calcd for C ₂₇ H ₂₄ FN ₂ O([M+H] ⁺ )411.1867, found 411.1867.

Compound 3da: 26.3mg, 30%; Brown yellow solid, mp 176.3-178.8℃ (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.282 (d, J = 8.8Hz, 2H), 7.229-7.154 (m ,8H),6.591(d,J＝8.8Hz,2H),4.410(d,J＝5.6Hz,2H),2.928(s,6H),2.334(d,J＝10.0Hz,6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.8,150.8(d,J＝263.75Hz),150.1,139.1,138.2,136.5,132.4,131.6,129.7,129.5,128.6,125.4,111.8,109.8,95.5(d,J＝5.0Hz),77.9 (d, J=2.5Hz), 73.5 (d, J=17.5Hz), 49.6 (d, J=3.75Hz), 40.2, 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -96.93 (s ,1F); HRMS m/z(ESI)calcd for C ₂₈ H ₂₇ FN ₃ O([M+H] ⁺ )440.2133,found440.2128.

Compound 3ea: 53.8 mg, 57%; Brown yellow solid, mp 211.5-213.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.58-7.53 (m, 4H), 7.47 (d, J=8.0Hz ,2H),7.43(d,J＝7.5Hz,2H),7.34(d,J＝7.5Hz,1H),7.25-7.18(m,8H),4.46(d,J＝5.5Hz,2H),2.35 (d, J=13.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.8(d,J＝263.75Hz),151.7,140.9,140.3,139.0,138.4,136.7,131.6,131.3,129.8,129.6,128.9,128.6,127.7,127.0(2C),125.5,122.0, 94.4( d, J＝5.0Hz), 81.1 (d, J＝2.5Hz), 72.8 (d, J＝16.25Hz), 49.4 (d, J＝2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-94.92(s,1F); HRMS m/z(ESI)calcd forC ₃₂ H ₂₆ FN ₂ O([M+H] ⁺ )473.2024,found473.2026.

Compound 3fa: 65.4 mg, 79%; Brown yellow solid, mp 142.0-144.2°C (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.38 (t, J=6.5Hz, 2H), 7.24-7.18 (m ,8H),6.99(t,J＝8.5Hz,2H),4.43(d,J＝5.5Hz,2H),2.35(d,J＝13.5Hz,6H); ¹³ C NMR (100MHz, CDCl ₃ )δ:162.4(d,J＝248.75Hz),151.6,151.9(d,J＝265.0Hz),139.0,138.4,136.7,133.1(d,J＝7.5Hz),131.3,129.8129.6,128.6,125.4,119.2 (d,J＝3.75Hz),115.7(d,J＝22.5Hz),93.3(d,J＝5.0Hz),80.1(d,J＝1.25Hz),72.5(d,J＝16.25Hz),49.3 (d, J=3.75Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-94.99(t,J＝4.71Hz,1F),-110.9--111.0(q,J＝9.42Hz,1F); HRMS m/z(ESI)calcd for C ₂₆ H ₂₁ F ₂ N ₂ O ([M+H] ⁺ )415.1616,found 415.1617.

Compound 3ga: 73.9 mg, 77%; Brown yellow solid, mp 201.5-203.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.32 (d, J = 8.0 Hz, 2H), 7.27 (d, J =8.0Hz, 2H), 7.24-7.18 (m, 8H), 4.43 (d, J = 5.5Hz, 2H), 2.35 (d, J = 13.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.6,151.1(d,J＝263.75Hz),139.0,138.5,136.8,134.2,132.4,131.3,129.8,129.7,128.8,128.7,125.5,121.7,93.4(d,J＝5.0Hz),81.6 (d, J＝2.5Hz), 72.5 (d, J＝16.25Hz), 49.2 (d, J＝2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -94.45 (s, 1F ); HRMS m/z(ESI)calcd for C ₂₆ H ₂₁ ClFN ₂ O([M+H] ⁺ )431.1321, found 431.1319.

Compound 3ha: 80.6 mg, 85%; Brown yellow solid, mp 189.5-190.3°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.42 (d, J=8.0Hz, 2H), 7.26-7.18 (m ,10H),4.43(d,J＝5.5Hz,2H),2.35(d,J＝13.5Hz,6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:152.1(d,J＝265.0Hz),151.6,138.9,138.5,136.8,132.6,131.6,131.2,129.8,129.6,128.6,125.4,122.3,122.1,93.4(d,J＝6.25Hz),81.7 (d, J＝2.5Hz), 72.4 (d, J＝17.5Hz), 49.2 (d, J＝2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -94.38 (s, 1F ); HRMS m/z(ESI)calcd forC ₂₆ H ₂₁ BrFN ₂ O([M+H] ⁺ )475.0816,found475.0819.

Compound 3ia: 50.5 mg, 60%; Brown yellow solid, mp 240.5-243.3°C (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.55 (d, J = 8.0 Hz, 2H), 7.44 (d, J =8.0Hz, 2H), 7.24-7.18 (m, 8H), 4.45 (d, J = 5.6Hz, 2H), 2.35 (d, J = 10.0Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:152.9(d,J＝266.25Hz),151.4,138.8,138.7,136.9,132.1,131.4,131.0,129.8,129.7,128.6,128.1,125.4,118.6,111.1,93.1(d,J＝5.0Hz) , 85.4 (d, J = 2.5Hz), 71.9 (d, J = 16.25Hz), 49.0 (d, J = 3.75Hz), 21.2, 21.1; ¹⁹ F NMR (376MHz, CDCl ₃ ) δ: -92.54 (s ,1F); HRMSm/z(ESI)calcd for C ₂₇ H ₂₁ FN ₃ O([M+H] ⁺ )422.1663, found 422.1663.

Compound 3ja: 63.1 mg, 68%; Brown yellow solid, mp 245.3-247.2°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.55 (d, J = 8.0 Hz, 2H), 7.49 (d, J =8.0Hz, 2H), 7.25-7.19 (m, 8H), 4.46 (d, J = 5.5Hz, 2H), 2.36 (d, J = 14.0Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:153.6,151.5,138.9,138.6,136.9,131.3,131.1,129.8,129.7,128.6,127.0,125.4,125.3(d,J＝3.75Hz),125.0,122.9,93.2(d,J＝5.0Hz) ,83.2,72.1(d,J＝17.5Hz),49.1(d,J＝2.5Hz),21.2,21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-62.78(s,3F),-93.50(s ,1F); HRMSm/z(ESI)calcd for C ₂₇ H ₂₁ F ₄ N ₂ O([M+H] ⁺ )465.1585, found 465.1582.

Compound 3ka: 61.7 mg, 68%; Brown yellow solid, mp>250°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.966 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0Hz, 2H), 7.24-7.18 (m, 8H), 4.45 (d, J = 5.5Hz, 2H), 3.89 (s, 3H), 2.35 (d, J = 13.5Hz, 6H); ¹³ C NMR ( 125MHz,CDCl ₃ )δ:166.5,152.4(d,J＝266.25Hz),151.5,138.9,138.5,136.8,131.1,130.9,129.8,129.7,129.5,129.2,128.6,127.8,125.4,93.9(d,J＝5.0Hz) , 83.8 (d, J = 1.25Hz), 72.2 (d, J = 16.25Hz), 52.3, 49.1 (d, J = 3.75Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -96.53 (s,1F); HRMS m/z(ESI)calcd for C ₂₈ H ₂₄ FN ₂ O ₃ ([M+H] ⁺ )455.1765,found455.1763.

Compound 3la: 54.9 mg, 67%; Brown yellow solid, mp 124.9-126.3°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.25-7.18 (m, 11H), 7.10 (d, J=7.5Hz ,1H),4.44(d,J＝5.5Hz,2H),2.34(t,J＝13.5Hz,9H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.6(d,J＝263.75Hz),139.0,138.4,138.0,136.7,131.8,131.3,129.8,129.6,129.1,128.6,128.3,128.2,125.5,122.9,94.7(d,J＝5 .0 Hz), 80.0 (d, J = 2.5Hz), 72.8 (d, J = 17.5Hz), 49.4 (d, J = 2.5Hz), 21.2, 21.1; ¹⁹ F NMR (; MHz, CDCl ₃ ) δ:- 95.29(s,1F); HRMS m/z(ESI)calcd forC ₂₇ H ₂₄ FN ₂ O([M+H] ⁺ )411.1867,found411.1872.

Compound 3ma: 47.3mg, 55%; Brown yellow solid, mp 223.6-225.9℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.39 (s, 1H), 7.28-7.18 (m, 11H), 4.44 (d, J＝5.5Hz, 2H), 2.35 (d, J＝13.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:152.3(d,J＝265.0Hz),151.5,138.9,138.5,136.8,134.2,131.2,130.9,129.8,129.7,129.6,129.3,128.6,128.4,125.4,124.9,93.1(d,J＝5.0 Hz), 81.8 (d, J = 2.5 Hz), 72.3 (d, J = 17.5 Hz), 49.2 (d, J = 2.5 Hz), 21.2, 21.1; ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ: -94.08 (s,1F); HRMS m/z(ESI)calcd forC ₂₆ H ₂₁ ClFN ₂ O([M+H] ⁺ )431.1321,found431.1319.

Compound 3na: 63.1 mg, 77%; Brown yellow solid, mp 131.6-133.2°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.36 (d, J=7.5Hz, 1H), 7.25-7.19 (m ,10H),7.13-7.11(m,1H),4.46(d,J＝5.5Hz,2H),2.37(t,J＝15.0Hz,9H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.6(d,J＝263.75Hz),139.7,139.0,138.4,136.8,131.4,131.3,129.8,129.6,129.5,128.7,128.2,125.6,125.5,122.9,93.5(d,J＝5 .0 Hz), 84.3 (d, J = 2.5 Hz), 72.9 (d, J = 17.5 Hz), 49.4 (d, J = 3.75 Hz), 21.2, 21.1, 20.7; ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ: -95.35(s,1F); HRMS m/z(ESI)calcd for C ₂₇ H ₂₄ FN ₂ O([M+H] ⁺ )411.1867, found 411.1866.

Compound 3oa: 74.8 mg, 87%; Brown yellow solid, mp 232.3-236.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.42 (d, J = 7.0 Hz, 2H), 7.37 (d, J =7.5Hz, 2H), 7.25-7.18 (m, 10H), 4.47 (d, J = 5.5Hz, 2H), 2.35 (d, J = 12.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:152.3(d,J＝265.0Hz),151.6,139.0,138.5,136.8,135.3,132.7,131.2,129.8,129.7,129.3,129.1,128.7,126.5,125.5,123.1,91.4(d,J＝5.0 Hz), 85.8 (d, J = 2.5 Hz), 72.4 (d, J = 16.25 Hz), 49.2 (d, J = 2.5 Hz), 21.2, 21.1; ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ: -93.72 (s,1F); HRMS m/z(ESI)calcd for C ₂₆ H ₂₁ ClFN ₂ O([M+H] ⁺ )431.1321, found 431.1317.

Compound 3pa: 70.2 mg, 74%; Brown yellow solid, mp 243.6-244.8°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.553 (d, J = 8.0 Hz, 1H), 7.417 (d, J ＝7.5Hz,1H),7.25-7.18(m,9H),7.11(t,J＝8.0Hz,1H),4.48(d,J＝5.5Hz,2H),2.35(d,J＝12.0Hz,6H ); ¹³ C NMR (125MHz, CDCl ₃ )δ:152.3(d,J＝266.25Hz),151.5,139.0,138.5,136.8,132.7,132.4,131.2,129.8,129.7,129.2,128.7,127.1,125.5,125.3,125.0,93.2(d,J＝5 .0 Hz), 85.3 (d, J = 2.5 Hz), 72.4 (d, J = 17.5 Hz), 49.1 (d, J = 2.5 Hz), 21.2, 21.1; ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ: -93.59 (s,1F); HRMS m/z(ESI)calcd for C ₂₆ H ₂₁ BrFN ₂ O([M+H]+)475.0816,found475.0813.

Compound 3qa: 62.4 mg, 70%; Brown yellow solid, mp>250°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.92 (s, 1H), 7.79-7.74 (m, 2H), 7.58- 7.41 (m, 4H), 7.25-7.18 (m, 8H), 4.48 (d, J = 5.0Hz, 2H), 2.35 (d, J = 15.0Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.9(d,J＝263.75Hz),151.7,139.0,138.4,136.7,133.0,132.7,131.6,131.4,130.9,129.8,129.6,128.9,128.6,128.1,127.8(d,J＝5.0Hz) ,127.0(d,J＝5.0Hz),126.6(d,J＝5.0Hz),125.5,120.4,95.0(d,J＝6.25Hz),80.9(d,J＝1.25Hz),72.8(d,J =17.5Hz), 49.4 (d, J = 2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-94.81(s,1F); HRMS m/z(ESI)calcd forC ₃₀ H ₂₄ FN ₂ O([M+H] ⁺ )447.1867, found 447.1867.

Compound 3ra: 41.0 mg, 51%; Brown yellow solid, mp 222.9-225.1°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.41 (s, 1H), 7.26-7.18 (m, 9H), 7.09 (d, J=5.0Hz, 1H), 4.43 (d, J=5.0Hz, 2H), 2.36 (d, J=15.0Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.8(d,J＝263.75Hz),151.6,139.0,138.4,136.7,131.3,129.8,129.7,129.6,128.6,128.3,125.4,122.1,89.5(d,J＝6.25Hz),79.8(d , J=2.5Hz), 72.6 (d, J=17.5Hz), 49.3 (d, J=2.5Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.17 (s, 1F); HRMS m/z(ESI)calcdfor C ₂₄ H ₂₀ FN ₂ OS([M+H] ⁺ )403.1275,found403.1274.

Compound 3sa: 95.8 mg, 95%; Brownish red solid, mp>250°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.25-7.18 (m, 8H), 4.41 (s, 4H), 4.19 ( d, J＝3.5Hz, 7H), 2.36 (d, J＝15.0Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.4(d,J＝262.5Hz),139.0,138.3,136.7,131.4,129.8,129.6,128.6,125.4,92.2(d,J＝5.0Hz),76.1(d,J＝2.5Hz) ,73.2(d,J＝17.5Hz),71.4,70.1,68.9,64.9,49.4(d,J＝2.5Hz),21.2,21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-96.24(s, 1F ); HRMS m/z(ESI)calcd for C ₃₀ H ₂₆ FFeN ₂ O([M+H] ⁺ )505.1073,found505.1074.

Compound 3ta: 39.7mg, 40%; Brown yellow solid, mp 216.3-217.3℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.39 (s, 1H), 7.25-7.18 (m, 8H), 7.06 (d,J＝8.0Hz,1H),7.01(d,J＝8.5Hz,1H),4.45(d,J＝5.5Hz,2H),3.03-3.01(m,2H),2.36(d,J＝ 14.0Hz, 6H), 1.92 (d, J = 5.0Hz, 2H), 1.30 (s, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.5(d,J＝263.75Hz),142.0,139.0,138.3,136.7,133.0,131.4,129.8,129.6,129.3,128.6,126.5,125.4,118.3,94.8(d,J＝5.0Hz) ,79.5(d,J＝1.25Hz),72.9(d,J＝17.5Hz),49.4(d,J＝2.5Hz),37.2,32.9,30.0,23.2,21.2,21.1; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-95.53(s,1F); HRMS m/z(ESI)calcd for C ₃₁ H ₃₀ FN ₂ OS([M+H] ⁺ )497.2057,found 497.2055.

Compound 3ua: 79.8mg, 65%; Brown yellow solid, mp>250℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.32 (d, J=8.0Hz, 2H), 7.24-7.17 (m, 10H),7.13(d,J＝8.0Hz,2H),7.08(d,J＝7.5Hz,2H),5.07(s,2H),4.44(d,J＝5.5Hz,2H),3.76-3.71( m,2H),2.44(d,J＝7.0Hz,2H),2.35(d,J＝13.0Hz,6H),1.88-1.80(m,1H),1.49(d,J＝7.0Hz,3H), 0.89(d,J=6.5Hz,6H); ¹³ C NMR (125MHz, CDCl ₃ ) δ: 174.4, 151.9 (d, J = 265Hz), 151.6, 140.7, 139.0, 138.4, 137.5, 136.7, 136.1, 131.3, 131.2, 129.8, 129.6, 129.4, 128.6, 127. 7, 127.2,125.4,122.8,94.2(d,J＝5.0Hz),80.8(d,J＝2.5Hz),72.6(d,J＝16.25Hz),65.8,49.3(d,J＝3.75Hz),45.1( 2C),30.2,22.4,21.2,21.1,18.4; ¹⁹ F NMR (471MHz, CDCl ₃ )δ: -94.83 (s, 1F); HRMS m/z (ESI)calcd for C ₄₀ H ₄₀ FN ₂ O ₃ ([M+H] ⁺ )615.3017, found 615.3020.

Compound 3va: 93.8mg, 82%; Brown yellow solid, mp>250℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.24-7.16 (m, 11H), 4.43 (d, J = 5.5Hz, 2H),2.86(t,J＝4.5Hz,2H),2.52-2.46(m,1H),2.35(d,J＝13.5Hz,6H),2.16-2.09(m,1H),2.07-1.94(m ,3H),1.66-1.40(m,7H),0.90(s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ:220.7,151.7,151.6(d,J=263.75Hz),140.3,139.0,138.4,136.7(2C),131.6,131.4,129.8,129.6,128.6,128.5,125.4,120.4,120.1,94.6(d, J＝5.0Hz),79.7(d,J＝1.25Hz),72.9(d,J＝16.25Hz),50.5,49.4(d,J＝3.75Hz),47.9,44.5,38.0,35.8,31.6,29.1, 26.3,25.6,21.6,21.2,21.1,13.9; ¹⁹ F NMR (471MHz, CDCl ₃ )δ: -95.47 (s, 1F); HRMS m/z (ESI)calcd for C ₃₈ H ₃₈ FN ₂ O ₂ ([M+H] ⁺ )573.2912, found 573.2910.

Compound 3wa: 110.5mg, 84%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.26-7.18 (m, 10H), 7.14 (s, 1H), 4.713-4.43 (m,3H),2.82(t,J＝4.5Hz,2H),2.37-2.21(m,11H),1.89-1.71(m,4H),1.55-1.26(m,10H),0.92(s,4H ),0.82(s,3H); ¹³ C NMR(125MHz, CDCl ₃ )δ:174.0,151.7,151.5(d,J＝263.75Hz),140.8,139.0,138.3,136.8,136.7,131.6,131.4,129.7,129.6,128.6,128.4,125.4,120.2,94.7(d,J＝5 .0 Hz),82.3,7 9.5(d,J＝1.25Hz),72.9(d,J＝16.25Hz),49.9,49.4(d,J＝2.5Hz),44.3,42.9,38.2,36.9,34.3,29.2,27.6,27.2,27.0, 25.9,23.3,22.3,21.2,21.0,13.8,12.1; ¹⁹ FNMR (471MHz, CDCl ₃ )δ: -95.47 (s, 1F); HRMS m/z (ESI)calcd for C ₄₃ H ₄₈ FN ₂ O ₃ ( [M+H] ⁺ )659.3643, found 659.3645.

Compound 3xa: 46.4 mg, 55%; Brown yellow solid, mp 111.3-112.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.26 (d, J=7.5Hz, 2H), 7.23-7.16 (m ,11H),4.28(d,J＝5.5Hz,2H),2.84(t,J＝7.5Hz,2H),2.63(t,J＝8.0Hz,2H),2.34(d J＝11.5Hz,6H) ; ¹³ C NMR (125MHz, CDCl ₃ )δ:151.7,151.4(d,J＝261.25Hz),140.5,19.1,138.2,136.6,131.5,129.7,129.6,128.6,128.5,128.4,126.4,125.4,94.7(d,J＝5.0Hz),72.9 (d, J=17.5Hz), 72.1 (d, J=2.5Hz), 49.6 (d, J=3.75Hz), 35.14, 22.0, 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -97.74 (s,1F); HRMS m/z(ESI)calcd for C ₂₈ H ₂₆ FN ₂ O([M+H] ⁺ )425.2024,found425.2025.

Compound 3ya: 35.0 mg, 44%; Brown yellow solid, mp 119.3-120.6°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.37 (d, J = 8.0 Hz, 2H), 7.29 (d, J ＝7.5Hz,4H),7.24-7.20(m,7H),7.06(d,J＝16.5Hz,1H),6.11(d,J＝16.5Hz,1H),4.55(s,2H),2.370(s ,6H); ¹³ C NMR (125MHz, CDCl ₃ )δ:151.6,146.2(d,J＝262.5Hz),139.6,138.1,137.4,136.9,131.7,129.9,129.5,128.7,128.6,127.2,125.9(2C),124.4(d,J＝3.75Hz), 118.5, 88.2 (d, J = 13.75Hz), 47.9 (d, J = 3.75Hz), 21.2, 21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -106.71 (s, 1F); HRMS m/z ( ESI)calcd for C ₂₆ H ₂₄ FN ₂ O([M+H] ⁺ )399.1867,found 399.1866.

Compound 3za: 38.7 mg, 52%; Brown yellow solid, mp 121.6-123.1°C (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.36-7.31 (m, 4H), 7.28-7.25 (m, 4H) ,7.20(t,J＝10.4Hz,5H),4.65(d,J＝6.0Hz,2H),2.36(s,3H),2.33(s,3H); ¹³ C NMR (100MHz, CDCl ₃ )δ: 152.2, 145.5 (d, J = 261.2Hz), 139.5, 137.9, 136.5, 133.0 (d, J = 4.6Hz), 132.0 (d, J = 1.2Hz), 129.7, 129.5, 128.7 (d, J =1.2Hz), 128.6, 126.6 (d, J = 1.3Hz), 126.3 (d, J = 6.0Hz), 125.5, 88.0 (d, J = 13.2Hz), 49.9 (d, J = 4.9Hz), 21.2 ,21.0; ¹⁹ F NMR (376.5MHz, CDCl ₃ )δ: -105.26 (s, 1F); HRMS m/z (ESI)calcd for C ₂₄ H ₂₂ FN ₂ O([M+H] ⁺ )373.1711,found373.1712.

Compound 3aaa: 46.7mg, 55%; Brown yellow solid, mp 135.9-137.2℃ (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.28-7.22 (m, 8H), 7.21-7.16 (m, 4H) ,4.58(d,J＝5.6Hz,2H),2.33(d,J＝9.2Hz,6H); ¹³ C NMR (100MHz, CDCl ₃ )δ: 150.1, 145.9 (d, J = 261.3Hz), 139.4, 138.2, 136.6, 132.2 (d, J = 2.1Hz), 131.9, 131.5 (d, J = 4.8Hz), 129.7 (d, J = 17.9 Hz), 128.8, 127.5 (d, J = 6.3 Hz), 125.5, 87.0 (d, J = 12.9 Hz), 49.7 (d, J = 4.9 Hz), 21.2, 21.1; ¹⁹ F NMR (376.5 MHz, CDCl ₃ )δ:-106.05(s,1F); HRMS m/z(ESI)calcd forC ₂₄ H ₂₁ ClFN ₂ O([M+H] ⁺ )407.1321, found407.1322.

Compound 3aba: 66.9 mg, 82%; Brown yellow solid, mp 109.2-110.8°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.32 (d, J = 8.0 Hz, 2H), 7.26 (t, J ＝8.0Hz,4H),7.18(t,J＝6.5Hz,4H),6.83(d,J＝8.0Hz,2H),6.75(s,1H),4.51(s,2H),3.80(s,3H ),2.34(s,6H); ¹³ CNMR(125MHz,CDCl ₃ )δ:159.5,151.8,139.7,138.2,136.8,136.3,134.8,132.7,129.6,129.5,126.4,125.5,115.2,114.0,94.4,91.2,83.6,55.3,52.6,21.0; HRMS m/z( ESI) calcd for C ₂₇ H ₂₅ N ₂ O ₂ ([M+H] ⁺ )409.1911,found 409.1913.

Example 43-54 Substrate Extension Test 2

The same as Example 1 or Example 15, except that different aromatic isocyanates were used. The results are shown in Table 3:

Table 3 Reaction results of different aromatic isocyanates

Standard reaction conditions: 1 (0.2 mmol), 2a (4 equiv), Na ₂ CO ₃ (5 equiv), DMF (0.1 M; 1 mL), argon, 120°C, reaction time 2 h.

Product structure characterization:

Compound 3ab: 71.4 mg, 70%; Brown yellow solid, mp 236.5-238.3°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.41 (t, J = 8.5 Hz, 4H), 7.35 (d, J ＝8.0Hz,2H),7.29-7.24(m,4H),6.83(t,J＝7.0Hz,2H),4.46(d,J＝4.0Hz,2H),3.80(s,3H),1.32(s ,18H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.6,151.4(d,J＝263.75Hz),151.7,151.2,149.7,138.9,132.7,128.2,126.0,125.9,125.1,115.2,114.0,94.4(d,J＝5.0Hz),79.0(d , J＝2.5Hz), 73.2 (d, J＝16.25Hz), 55.3, 49.4 (d, J＝2.5Hz), 34.7, 34.6, 31.4; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.84 (s ,1F); HRMS m/z(ESI)calcd for C ₃₃ H ₃₆ FN ₂ O ₂ ([M+H] ⁺ )511.2755,found511.2761.

Compound 3ac: 98.9mg, 85%; Brown yellow solid, mp>250℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.37-7.31 (m, 7H), 7.28 (d, J = 8.5Hz, 2H),7.15-7.09(m,2H),7.04(t,J＝9.5Hz,7H),6.84(d,J＝8.5Hz,2H),4.45(d,J＝5.0Hz,2H),3.80( s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.7, 157.4, 157.0, 156.6, 155.9, 151.8, 151.2 (d, J = 263.75Hz), 136.5, 132.7, 130.2, 129.9, 129.8, 128.7, 127.3, 123.8, 123.6, 119.4, 119. 3,119.0,118.7 ,115.1,114.1,94.6(d,J＝5.0Hz),78.7(d,J＝1.25Hz),73.2(d,J＝16.25Hz),55.3,49.6(d,J＝2.5Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-96.02(s,1F); HRMS m/z(ESI)calcd for C ₃₇ H ₂₈ FN ₂ O ₄ ([M+H] ⁺ )583.2028,found 583.2029.

Compound 3ad: 101.9mg, 90%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.40-7.35 (m, 6H), 7.27 (t, J = 10.0Hz, 4H ), 6.84 (d, J = 7.0Hz, 2H), 4.46 (d, J = 4.0Hz, 2H), 3.80 (s, 3H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.8,151.3,150.6(d,J＝265.0Hz),148.2(d,J＝171.25Hz),139.7,132.8,132.2,130.3,130.2(d,J＝37.5Hz),129.0(d,J ＝23.75Hz),127.0,121,8,121.4,119.4(d,J＝3.75Hz),114.8,114.1,95.2(d,J＝6.25Hz),78.1(d,J＝2.5Hz),74.2(d,J =17.5Hz), 55.3, 49.3 (d, J = 2.5Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-57.95(d,J＝47.1Hz,6F),-96.56(s,1F); HRMS m/z(ESI)calcd forC ₂₇ H ₁₈ F ₇ N ₂ O ₄ ([M+H] ⁺ ) 567.1149, found 567.1139.

Compound 3ae: 80.7mg, 93%; Brown yellow solid, mp 143.5-145.2℃ (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.36-7.30 (m, 6H), 7.12-7.06 (m, 4H) ,6.84(d,J＝8.5Hz,2H),4.42(d,J＝5.5Hz,2H),3.79(s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 162.3 (d, J = 246.25Hz), 161.2 (d, J = 245.0Hz), 159.8, 150.9 (d, J = 263.75Hz), 151.6, 137.3 (d, J = 3.75Hz), 132.8, 130.7 (d,J＝8.75Hz),130.3(d,J＝8.75Hz),129.8(d, J＝2.5Hz),127.6(d,J＝8.75Hz),116.2,116.1(d,J＝3.75Hz),115.9,114.9,114.1,94.9(d,J＝5.0Hz),78.4(d,J＝ 1.25Hz),73.5(d,J＝16.25Hz),55.3,49.6(d,J＝3.75Hz); ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -96.29 (s, 1F), -112.75 (d, J = 9.42Hz, 1F), -114.36 (d, J = 4.71Hz, 1F); HRMS m/z ( ESI)calcd for C ₂₅ H ₁₈ F ₃ N ₂ O ₂ ([M+H] ⁺ )435.1315,found435.1318.

Compound 3af: 84.8 mg, 91%; Brown yellow solid, mp 209.1-211.3°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.38-7.32 (m, 7H), 7.26 (d, J=5.5Hz ,3H),6.84(d,J＝8.0Hz,2H),4.45(d,J＝5.5Hz,2H),3.80(s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.8, 151.2, 150.6 (d, J = 265Hz), 148.1, 139.8, 135.6, 134.4, 132.8, 132.4 (d, J = 11.25Hz), 131.8, 130.1, 129.7 (d, J = 1.25Hz), 129.3,129.2,126.8,114.8,114.1,95.1(d,J＝6.25Hz),78.2(d,J＝2.5Hz),74.0(d,J＝16.25Hz),55.3,49.2(d,J＝2.5Hz ); ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -96.65 (s, 1F); HRMS m/z (ESI)calcd for C ₂₅ H ₁₈ Cl ₂ FN ₂ O ₂ ([M+H] ⁺ )467.0724,found467.0726.

Compound 3ag: 108.4mg, 98%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.56-7.50 (m, 4H), 7.36 (d, J = 8.5Hz, 2H ),7.21(t,J＝8.5Hz,4H),6.84(d,J＝8.0Hz,2H),4.42(d,J＝5.5Hz,2H),3.80(s,3H); ¹³ C NMR (125MHz ,CDCl ₃ )δ:159.8,151.1,150.6(d,J＝265.0Hz),148.0,140.3,132.9,132.8,132.7,132.3(d,J＝11.25Hz),130.4,130.0,127.1,122.4,120.3,114.8,114.1 ,95.1(d,J＝5.0Hz),78.3(d,J＝2.5Hz),74.1(d,J＝17.5Hz),55.3,49.1(d,J＝3.75Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-96.52(s,1F); HRMS m/z(ESI)calcd for C ₂₅ H ₁₈ Br ₂ FN ₂ O ₂ ([M+H] ⁺ )554.9714,found554.9717.

Compound 3ah: 107.0 mg, 82%; Brown yellow solid, mp 243.3-244.6°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.75-7.69 (m, 4H), 7.35 (d, J=8.5Hz ,2H),7.08(t,J＝9.5Hz,4H),6.84(d,J＝8.0Hz,2H),4.40(d,J＝5.5Hz,2H),3.79(s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.8,151.0,150.5(d,J＝265.0Hz),141.1,138.2(d,J＝6.25Hz),133.7,132.8,130.6,127.2,114.8,114.1,95.1(d,J＝5.0Hz) ,94.0,91.5,78.3(d,J＝2.5Hz),74.1(d,J＝16.25Hz),55.4,48.9(d,J＝2.5Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-96.50 (s,1F); HRMS m/z(ESI)calcd for C ₂₅ H ₁₈ I ₂ FN ₂ O ₂ ([M+H] ⁺ )650.9436, found 650.9437.

Compound 3ai: 72.6 mg, 68%; Brown yellow solid, mp>250°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.717-7.658 (m, 4H), 7.489 (d, J = 7.6Hz, 4H), 7.369 (d, J = 8.4Hz, 2H), 6.848 (d, J = 8.4Hz, 2H), 4.505 (d, J = 5.6Hz, 2H), 3.800 (s, 3H); ¹³ C NMR ( 125MHz,CDCl ₃ )δ: 159.9, 151.0, 150.3 (d, J = 266.25Hz), 144.3, 137.0, 132.8, 130.5 (d, J = 32.5Hz), 129.1, 128.7 (d, J = 32.5Hz), 126.3 (q, J ＝3.75Hz),126.1(q,J＝3.75Hz),125.3,124.8(d,J＝10.0Hz),122.7(d,J＝11.25Hz),114.7,114.1,95.5(d,J＝5.0Hz) ,77.9(d,J＝2.5Hz),74.9(d,J＝17.5Hz),55.3,48.8(d,J＝2.5Hz); ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -62.56 (d, J = 70.65Hz, 6F), -96.89 (d, J = 4.71Hz, 1F); HRMS m/z (ESI)calcd for C ₂₇ H ₁₈ F ₇ N ₂ O ₂ ([M+H] ⁺ )535.1251, found 535.1244.

Compound 3aj: 57.9 mg, 68%; Brown yellow solid, mp 120.8-122.8°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.35 (d, J = 8.5 Hz, 2H), 7.28 (d, J ＝10.5Hz,2H),7.18-7.13(m,5H),7.07(d,J＝7.5Hz,1H),6.83(d,J＝8.0Hz,2H),4.45(d,J＝5.5Hz,2H ), 3.78 (s, 3H), 2.35 (d, J = 8.5Hz, 6H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.6, 151.7, 151.3 (d, J = 263.75Hz), 141.5, 139.1, 138.9, 133.9, 132.7, 129.5, 129.2, 129.0, 128.7, 127.7, 126.4, 125.9, 122.6, 115.2, 114. 0,94.5(d , J=5.0Hz), 78.8 (d, J=1.25Hz), 73.2 (d, J=16.25Hz), 55.3, 49.4 (d, J=2.5Hz), 21.4, 21.3; ¹⁹ F NMR (471MHz, CDCl ₃ )δ:-96.00(s,1F); HRMS m/z(ESI)calcd for C ₂₇ H ₂₄ FN ₂ O ₂ ([M+H] ⁺ )427.1816,found 427.1816.

Compound 3ak: 62.4 mg, 67%; Brown yellow solid, mp 229.3-230.4°C (uncorrected); ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.369-7.280 (m, 7H), 7.225 (d, J=7.6Hz ,3H),6.831(d,J＝8.8Hz,2H),4.411(d,J＝5.6Hz,2H),3.766(s,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.8,151.1,150.5(d,J＝265.0Hz),142.4,134.9,134.6,134.5,132.8,130.1,129.9,129.2,128.8,127.1(2C),125.8,123.7,114.8,114.1,9 5.2( d, J＝5.0Hz), 78.2 (d, J＝1.25Hz), 74.3 (d, J＝16.25Hz), 55.3, 49.1 (d, J＝2.5Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ :-96.65(s,1F); HRMS m/z(ESI)calcd for C ₂₅ H ₁₈ Cl ₂ FN ₂ O ₂ ([M+H] ⁺ )467.0724,found467.0721.

Compound 3al: 63.9 mg, 75%; Brown yellow solid, mp 1°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.34 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 7.0 Hz,8H),6.82(d,J=8.5Hz,2H),4.51-4.46(m,1H),4.26-4.22(m,1H),3.78(s,3H),2.33(s,6H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.6, 151.6 (d, J = 261.25Hz), 150.5, 150.3, 140.0, 137.4, 137.1, 135.7 (d, J = 10.0Hz), 133.0 (d, J = 7.5Hz), 132.7, 131.3, 130.8 (d,J＝3.75Hz),129.8(d,J＝10.0Hz),129 .1(d,J＝12.5Hz),128.2,127.3,127.2(d,J＝8.75Hz),126.7,115.2,114.0,94.4(d,J＝5.0Hz),78.8(d,J＝1.25Hz) ,72.0 (d, J=17.5Hz), 55.3, 49.5 (d, J=3.75Hz), 17.7, 17.6; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -96.93 (s, 1F); HRMS m/z (ESI)calcd for C ₂₇ H ₂₄ FN ₂ O ₂ ([M+H] ⁺ )427.1816,found427.1817.

Compound 3am: 72.6 mg, 80%; Brown yellow solid, mp 215.5-217.5°C (uncorrected); ¹ H NMR (500MHz, CDCl ₃ ) δ: 7.35 (d, J = 8.0 Hz, 2H), 6.9735 (t, J ＝7.0Hz,5H),6.89(s,1H),6.83(d,J＝8.0Hz,2H),4.44(d,J＝4.5Hz,2H),3.79(s,3H),2.31(d,J =7.0Hz, 12H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.6, 151.7, 151.4 (d, J = 263.75Hz), 148.9, 141.4, 139.1, 138.9, 138.6, 133.8, 133.4, 132.7, 131.0, 130.1, 128.6, 126.5, 125.9, 123.4, 115. 3,114.0,94.3 (d, J=6.25Hz), 79.0 (d, J=5.0Hz), 73.0 (d, J=16.25Hz), 55.3, 49.5 (d, J=3.75Hz), 21.3, 21.2; ¹⁹ F NMR (471MHz ,CDCl ₃ )δ:-95.95(s,1F); HRMS m/z(ESI)calcd for C ₂₉ H ₂₈ FN ₂ O ₂ ([M+H] ⁺ )455.2129,found455.2134.

Embodiment 55

The reaction process is the same as in Example 1, and the reaction equation is as follows:

Compound 3aag: 65.7mg, 67%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.56-7.49 (m, 2H), 7.35 (d, J = 8.0Hz, 2H ),7.24-7.17(m,6H),6.83(d,J＝8.0Hz,2H),4.42(d,J＝4.5Hz,2H),3.79(s,3H),2.35(d,J＝12.5Hz ,3H); ¹³ C NMR (125MHz, CDCl ₃ )δ:159.7(d,J＝11.25Hz), 159.7(d,J＝12.5Hz), 152.4(d,J＝23.75Hz), 151.7(d,J＝21.25Hz), 151.6(d,J＝22.5 Hz),151.2(d,J＝22.5Hz),151.3(d,J＝23.75Hz),149.6(d,J＝21.25Hz),148.2(d ,J＝42.5Hz),140.5(d,J＝32.5Hz),138.9(d,J＝32.5Hz),138.4(d,J＝33.75Hz),136.8(d,J＝38.75Hz),133.0(d ,J＝30.0Hz),132.8(q,J＝5.0Hz),132.2(d,J＝11.25Hz),132.1(d,J＝10.0Hz),13 1.3(d,J＝30.0Hz),130.4(d,J＝7.5Hz),130.1,129.8(d,J＝10.0Hz),129.7(d,J＝15.0Hz),128.6(d,J＝7.5Hz ),127.1(d,J＝7.5Hz),125.5(d,J＝3.75Hz),123.7,122.3(d,J＝32.5Hz),120.2(d, J＝40.0Hz),115.1(d,J＝20.0Hz),114.9(d,J＝20.0Hz),114.1(t,J＝3.75Hz),94.7(q,J＝20.0Hz),78.6(q, J＝26.25Hz),74.0(q,J＝16.25Hz),73.1(d,J＝17.5Hz),55.3,49.5,49.0,21.2,21.1; ¹⁹ F NMR (471MHz, CDCl ₃ ) δ: -95.92 (t, J = 4.71Hz, 1F), -96.00 (t, J = 4.71Hz, 1F), -96.47 (t, J = 4.71Hz, 1F), -96.53(t,J＝4.71Hz,1F); HRMS m/z(ESI)calcd forC ₂₆ H ₂₁ BrFN ₂ O ₂ ([M+H] ⁺ )491.0765, found491.0767.

Compound 3adg: 71.7mg, 64%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.557-7.504 (m, 2H), 7.36 (d, J = 8.0Hz, 4H ), 7.28-7.20 (m, 4H), 6.84 (d, J = 8.0Hz, 2H), 4.46-4.41 (m, 2H), 3.79 (s, 3H); ¹³ C NMR (125MHz, CDCl ₃ )δ: 159.8, 150.6 (d, J = 265.0Hz), 151.3 (d, J = 11.25Hz), 151.1 (d, J = 11.25Hz), 148.8, 147.4, 144.1 (d, J = 2.5Hz), 140.3 (d,J＝3.75Hz),139.8(d,J＝3.75Hz),134.0(d,J＝1.25Hz),133.2,132.9(d,J＝2.5Hz),132.8,132.6(d,J＝8.75 Hz),132.5,132.3(d,J＝11.25Hz),130.3(d,J＝12.5Hz),130.0(d,J＝2.5 Hz), 128.0 (d, J = 13.75Hz), 127.3 (d, J = 5.0Hz), 127.1 (d, J = 3.75Hz), 127.0 (d, J = 5.0Hz), 122.4, 122.0 (d, J ＝3.75Hz),121.8,121.6,121.5(d,J＝3.75Hz),121.4,120.4(d,J＝6.25Hz),119.4(d,J＝3.75Hz),114.8,114.4,114.1,95.2(q ,J＝5.0Hz),78.2(d,J＝2.5Hz),74.1(m),55.3,49.2(d,J＝18.75Hz); ¹⁹ F NMR (471MHz, CDCl ₃ )δ: -57.86 (s, 3F), -57.95 (s, 3F), -96.57 (s, 2F); HRMS m/z (ESI)calcd forC ₂₆ H ₁₈ BrF ₄ N ₂ O ₃ ([M+H] ⁺ )561.0431,found561.0432.

Compound 3age: 71.3mg, 72%; Brown yellow solid, mp>250℃ (uncorrected); ¹ HNMR (500MHz, CDCl ₃ ) δ: 7.56-7.51 (m, 2H), 7.36 (d, J = 8.5Hz, 2H ),7.32-7.29(m,2H),7.25-7.20(m,2H),7.13-7.07(m,2H),6.84(t,J＝8.0Hz,2H),4.43(t,J＝4.5Hz, 2H),3.40(s,3H); ¹³ CNMR(125MHz, CDCl ₃ )δ:163.3(d,J＝3.75Hz), 162.2(d,J＝3.75Hz), 161.3(d,J＝3.75Hz), 160.2(d,J＝3.75Hz), 159.8(t,J＝3.75 Hz), 151.9 (d, J = 11.25Hz), 151.7, 151.6 (d, J = 5.0Hz), 151.3 (d, J = 8.75Hz), 151.1, 149.8 (d, J = 11.25Hz), 149.5 (d ,J＝11.25 Hz),140.4(d,J＝7.5 Hz),137.3(d,J＝2.5 Hz),137.3(d,J＝3.75 Hz), 132.9 (d, J = 8.75 Hz), 132.8, 132.3 (d, J = 3.75 Hz), 132.2 (d, J = 6.25 Hz), 130.6 (d, J = 8.75 Hz), 129.8 (d, J =3.75 Hz), 129.7 (d, J = 3.75 Hz), 127.6 (d, J = 8.75 Hz), 127.1, 122.4 (d, J = 11.25 Hz), 120.3 (d, J = 8.75 Hz), 116.3 (d ,J＝5.0 Hz),116.1(t,J＝6.25 Hz),115.9(d,J＝6.25 Hz),114.9(t,J＝6.25 Hz),114.1,95.1(q,J＝5.0 Hz),94.9(q,J＝5.0 Hz),78.4(d,J＝3.75 Hz),78.3(t,J＝2.5 Hz),78.2(d,J =2.5 Hz), 74.0 (q, J = 5.0 Hz), 73.6 (q, J = 5.0 Hz), 55.3, 49.6, 49.1; ¹⁹ F NMR (471 MHz, CDCl ₃ ) δ: -96.27 (t, J = 9.42 Hz, 1F), -96.40 (q, J＝4.71 Hz, 1F), -96.53 (t, J＝4.71 Hz, 1F), -112.62 (q, J＝4.71 Hz,1F),-112.76(t,J＝4.71Hz,1F),-114.27(q,J＝9.42 Hz,1F),-114.35(d,J＝4.71Hz,1F).HRMSm/z(ESI) calcd for C ₂₅ H ₁₈ BrF ₂ N ₂ O ₂ ([M+H] ⁺ )495.0514, found 495.0515.

Claims (10)

1. A method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F, characterized in that, under an inert atmosphere, in the presence of a base and an organic solvent, heating is performed to allow α-polyfluoromethyl olefin to undergo [3+2+1] cyclization with isocyanate to generate monofluorinated 3,4-dihydropyrimidin-2(1H)-one, wherein the reaction equation is shown in Formula 1: In the formula, ^R1 is selected from one of phenyl, substituted phenyl, substituted alkenyl or substituted alkynyl; ^R2 is selected from hydrogen or fluorine; Ar ¹ and Ar ² are independently substituted phenyl groups, the position and number of the substituents are not limited, and Ar ¹ and Ar ² may be the same or different. 2. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that when the ^R1 is a substituted phenyl group, the substituted phenyl group is a phenyl group containing at least one substituent selected from the group consisting of an alkyl group and a halogen group. 3. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that when the ^R1 is an alkenyl group containing a substituent, the alkenyl group containing a substituent is an alkenyl group containing a phenyl substituent. 4. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that when ^R1 is an alkynyl group containing a substituent, the alkynyl group containing a substituent is an alkynyl group containing at least one substituent selected from the group consisting of an aryl group and a heterocyclic aromatic group, the aryl group is a phenyl group, a substituted phenyl group or a naphthyl group, the substituted phenyl group is a phenyl group containing at least one substituent selected from the group consisting of an alkyl group, a (N,N-dimethyl)amino group, a phenyl group, a halogen group, a cyano group, a trifluoromethyl group or a methyl formate group; the heterocyclic aromatic group is a thiophene, a ferrocene, a tazarotene derivative group, an ibuprofen derivative group, an estrone derivative group or an estradiol heptanoate derivative group. 5. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that the substituted phenyl groups of Ar ¹ and Ar ² are phenyl groups containing at least one substituent selected from the group consisting of alkyl, phenoxy, trifluoromethyl, trifluoromethoxy, and halogen. 6. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim ₁ , characterized in that the base is selected from any one or more of _Na3PO4 , t-BuONa, t-BuOK, _Et3N , _DBU , DABCO _NaHCO3 , _{K2CO3 , Cs2CO3} and _Na2CO3 . 7. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that the organic solvent is selected from any one or more of DMSO, DMF, NMP, 1,4-dioxane, MeCN and PhMe. 8. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that The molar ratio of Ar ¹ NCO, Ar ² NCO and the base is 1:(1-2):(1-2):(4-10). 9. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that the heating temperature is 90 to 150°C. 10. The method for direct functionalization of α-trifluoromethyl olefin C(sp3)-F according to claim 1, characterized in that after the cyclization is completed, ethyl acetate is used as the eluent, filtered through a coarse column, concentrated in vacuo, and then purified by silica gel column chromatography to obtain monofluorinated 3,4-dihydropyrimidin-2(1H)-one.