N-heterocyclic carbene catalyzed decarboxylation coupling method

Abstract

The invention relates to a decarboxylation coupling method catalyzed by N-heterocyclic carbene. Small organic molecule N-heterocyclic carbene is used as an organic catalyst, manganese is used as a reducing agent, aromatic acid or derivatives thereof and an electrophilic reagent are subjected to cross coupling, and multi-structure ketone is prepared. Small organic molecule N-heterocyclic carbene is used as an organic catalyst, manganese is combined as a reducing agent, cross coupling of aromatic acid or derivatives thereof and some cheap and easily available electrophilic reagents can be promoted, ketones with various structures can be provided at high yield, and the method is especially suitable for preparation of high-steric-hindrance ketone compounds and has wide application prospects. The method has the advantages of high yield, convenience in separation, high efficiency, mildness, low-cost economy and high industrial application value, and the requirement on transition metal catalysis can be reduced.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of ketone compounds, and more specifically to a decarboxylation coupling method catalyzed by an azacarbene. Background Art

[0002] Cross-electrophilic coupling reaction is a powerful tool for forming carbon-carbon (CC) bonds. This method avoids the use of pre-prepared highly active carbon nucleophilic organometallic reagents used under harsh conditions (such as Grignard reagents, organozinc or organoboron reagents). Moreover, since carbon electrophiles are more easily commercially available than carbon nucleophiles, the range of substrates that can be used in cross-electrophilic coupling reactions to construct CC bonds is very wide. At the same time, this protocol also provides excellent functional group compatibility, but the reaction is usually catalyzed by 3d and 4d transition metals such as nickel, cobalt and palladium.

[0003] Reactions catalyzed by transition metals generally have problems with heavy metal residues to a certain extent, as well as the corresponding cumbersome processes and high costs brought about by heavy metal catalysis. In addition, there has been no realization of a reaction mode that replaces metal catalysis with organic catalysis, which limits the application of reductive coupling reactions to a certain extent. Summary of the invention

[0004] The invention provides a decarboxylation coupling method catalyzed by azacarbene. The invention utilizes an organic small molecule azacyclic carbene as an organic catalyst and combines manganese as a reducing agent to promote the cross-coupling of aromatic acids or their derivatives with some inexpensive and readily available electrophilic reagents, and can provide ketones with diverse structures in high yield. The method is particularly suitable for the preparation of large sterically hindered ketone compounds and can reduce the demand for transition metal catalysis. The method has the advantages of high yield and convenient separation, high efficiency, mildness and low-cost economy, and has great industrial application value.

[0005] The invention provides a decarboxylation coupling method catalyzed by azacarbene, which uses an organic small molecule azacyclic carbene as an organic catalyst and manganese or tetrakis(dimethylamino)ethylene as a reducing agent to cross-couple an aromatic acid or a derivative thereof with an electrophilic reagent to prepare a multi-structure ketone.

[0006] Preferably, the electrophilic reagent comprises N-hydroxyphthalimide ester and alkyl bromide.

[0007] Preferably, the specific process is: adding compound 1, compound 2, solvent, catalyst, and reducing agent into a reactor, reacting at 25-80° C. for 1-24 hours, and monitoring the reaction progress by thin layer chromatography until the reaction is complete; then extracting with ethyl acetate and water for 3-4 times, collecting and merging the organic phases and washing with saturated brine, collecting the organic phases and drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying with silica gel column chromatography to obtain compound 3. The reaction equation in the synthesis process is:

[0008]

[0009] Preferably, the molar ratio of compound 1 to compound 2 is 1:1-4.

[0010] Preferably, R 1 is selected from substituted or unsubstituted aryl, heteroaryl, alkyl, styryl; R 2 One selected from the group consisting of a fluorine atom, a pyrrol-1-yl group, a pyrazol-1-yl group, an imidazole-1-yl group, and a pyridine-2-thiol group;

[0011] R 2 R is selected from fluorine atom, pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, pyridine-2-thiol; 3 One selected from a secondary or tertiary alkyl group, a tertiary alkyl group substituted with an α-oxygen, nitrogen or bromine atom;

[0012] R 3 Selected from secondary or tertiary alkyl, tertiary alkyl substituted with α-oxygen, nitrogen or bromine atom;

[0013] R 4 One selected from the group consisting of a hydrogen atom, a 1,3-dioxoisoindolin-2-yl group, a 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl group, and a 1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl group.

[0014] Preferably, the molar ratio of compound 1 to catalyst is 1:0.01-0.5; the molar ratio of compound 1 to base is 1:0-0.5; the molar ratio of compound 1 to reducing agent is 1:0.5-3; the concentration range of compound 1 to solvent is 0.05M-1M.

[0015] Preferably, no alkaline substance is added to compound 1, but a catalyst, a reducing agent and a solvent are added.

[0016] Preferably, the salt catalyst anion is selected from one of perchlorate anion, tetrafluoroborate anion, hexafluorophosphate anion, chloride anion, iodine anion, and bromide anion;

[0017] The salt catalyst cation is selected from 3-(2,6-diisopropylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-neopentyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-(2,6-diisopropylphenyl)-4,5,6,7-tetrahydro-phenyl One of 3-benzene-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-mesityl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-phenyl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-neopentyl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 6,7-dihydro-2-phenyl-5H-pyrrolo[2,1-c]-1,2,4-triazole, and 6,7-dihydro-2-mesityl-5H-pyrrolo[2,1-c]-1,2,4-triazole.

[0018] Preferably, the base is selected from cesium carbonate, cesium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, dipotassium phosphate, monopotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, cesium fluoride, lithium fluoride, sodium fluoride, triethylamine, pyridine, tetramethylguanidine, and N,N-diisopropylethylamine.

[0019] Preferably, the reducing agent is selected from manganese or tetrakis(dimethylamino)ethylene;

[0020] The solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, acetone, xylene and ethyl acetate.

[0021] Preferably, R 4 is a hydrogen atom, N,N-carbonyldiimidazole is added to the system, and the molar ratio of compound 1 to N,N-carbonyldiimidazole is 1 to 1.5; R 3 is a tertiary alkyl group substituted with an α-bromine atom, R 4 It is one of alkyl, alkenyl, alkynyl, aryl and heteroaryl.

[0022] In summary, the present invention has the following beneficial effects:

[0023] 1. The cross-electrophilic coupling reaction used in the present invention is catalyzed by an organic small molecule nitrogen heterocyclic carbene, which can avoid the use of transition metals;

[0024] 2. The raw materials of the method of the present invention are widely available and easy to obtain, and the operation is safe and simple;

[0025] 3. The synthesis method of the present invention is simple and efficient, and the target product is constructed by one-step reaction. The reaction conditions are mild, the operation is simple, the environment is friendly, the yield is high, and the gram-level reaction yield is good, which has the potential for industrial production;

[0026] 4. The target product compounds obtained by the present invention have rich structural diversity and are also applicable to substrates with special structures.

[0027] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of protection of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the hydrogen spectrum of compound 3a in the present invention;

[0029] Figure 2 is the carbon spectrum of compound 3a in the present invention;

[0030] Figure 3 is the hydrogen spectrum of compound 3af of the present invention;

[0031] Figure 4 It is the carbon spectrum of compound 3af in the present invention. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with the examples. It is particularly noted that if no specific conditions are specified in the following examples, the reactions are carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0033] Example

[0034] Example 1

[0035] (1) In a glove box filled with nitrogen, a magnetron, substrate 1 (1,3-dioxoisoindolin-2-yl 2,2-dimethylhex-5-enoate, 0.2 mmol), substrate 2 ((1H-imidazol-1-yl)(pyridin-2-yl)methanone, 0.26 mmol) and a nitrogen heterocyclic carbene catalyst NHC-1 (3-(2,6-diisopropylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium perchlorate, 0.04 mmol) were added to a 4 ml reaction bottle dried in advance.

[0036] (2) Then, manganese powder (0.4 mmol), cesium carbonate (0.01 mmol) and dimethyl sulfoxide (1 ml) were added. After the addition was completed, the reaction bottle was removed from the glove box and placed at 60° C. with vigorous stirring for 24 h.

[0037] (3) The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature and 1 mL of saturated aqueous ammonium chloride solution was added to quench the reaction. The reaction mixture was transferred to a separation funnel with ethyl acetate, and then the mixture was washed with water and saturated brine. The organic phase was then concentrated in vacuo and purified by silica gel column chromatography to obtain product 3a (2,2-dimethyl-1-(pyridin-2-yl)hex-5-en-1-one). The reaction formula is as follows:

[0038]

[0039] The morphology, yield, NMR, and high-resolution mass spectrometry data of product 3a are as follows:

[0040] Yellow oil (34 mg, yield 84%). 1 H NMR(400MHz,Chloroform-d)δ8.61(m,1H),7.87(m,1H),7.78(m,1H),7.38(m,1H), 5.73(m,1H),4.98-4.82(m,2H),2.20-2.09(m,2H),1.99-1.89(m,2H),1.42(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ206.7,155.1,147.9,139.0,136.8,126.0,123.6,114.3,47.7,39.6,29.5,25.7.HRMS(ESI)m / z:[M+Na] + Calculate for C 13 H 17 N NaO + 226.1202, found 226.1184.

[0041] Example 2

[0042] Compared with Example 1, the difference is that Compound 1 is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0043]

[0044] The corresponding product 3b is 5-(2,5-dimethylphenoxy)-2,2-dimethyl-1-(pyridin-2-yl)pentan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0045]

[0046] Yellow oil (42 mg, yield 70%). 1H NMR(400MHz,Chloroform-d)δ8.63-8.55(m,1H),7.87(dt,J=8.0,1.1Hz,1H), 7.76(td,J=7.7,1.8Hz,1H),7.35(ddd,J=7.6,4.7,1.3Hz,1H),7.00-6.92(m, 1H),6.62(dd,J=7.4,1.6Hz,1H),6.53(d,J=1.6Hz,1H),3.85(t,J=6.4Hz,2H) ,2.27(s,3H),2.26-2.20(m,2H),2.10(s,3H),1.72-1.62(m,2H),1.45(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ206.7,157.0,155.0,147.9,136.8,136.5,130.3,126.0,123.6,123.6,12 0.6,111.9,68.1,47.7,36.9,25.7,25.3,21.5,15.9.HRMS(ESI)m / z:[M+Na] + Calculate for C 20 H 25 NNaO 2 + 334.1778, found 334.1779.

[0047] Example 3

[0048] Compared with Example 1, the difference is that compound 1 is 2-methyl-2-phenylpropionic acid 1,3-dioxoisoindoline-2-ester, and its structure is:

[0049]

[0050] The corresponding product 3c is 2-methyl-2-phenyl-1-(pyridin-2-yl)propan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0051]

[0052] Yellow oil (29 mg, yield 65%). 1H NMR(400MHz,Chloroform-d)δ8.34(ddd,J=4.7,1.8,0.9Hz,1H),7.86(dt,J=7.9,1.1H z,1H),7.66(td,J=7.7,1.8Hz,1H),7.29-7.22(m,4H),7.21-7.11(m,2H),1.75(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ203.8,153.6,148.1,145.9,136.4,128.3,126.0,126.0,125.7,124.0,51.3,27.4.HRMS(ESI)m / z:[M+Na] + calcdfor C 15 H 15 NNaO + 248.1046, found 248.1053.

[0053] Example 4

[0054] Compared with Example 1, the difference is that compound 1 is 2,2-dimethyl-4-phenoxybutyric acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0055]

[0056] The corresponding product 3d is 2,2-dimethyl-4-phenoxy-1-(pyridin-2-yl)butan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0057]

[0058] White solid (35 mg, yield 65%). 1 H NMR(400MHz,Chloroform-d)δ8.59(ddd,J=4.8,1.9,0.9Hz,1H),7.97(dt,J=7.9,1.1Hz,1H),7.79(td,J=7.7,1.8Hz,1H),7.36(ddd,J=7.6,4 .7,1.3Hz,1H),7.22-7.14(m,2H),6.86(tt,J=7.4,1.1Hz,1H),6.72-6.63(m,2H),3.96(t,J=6.7Hz,2H),2.65(t,J=6.7Hz,2H),1.50(s,6H). 13 C NMR (101 MHz, CDCl 3)δ205.3,158.8,154.9,147.8,136.8,129.4,126.0,123.7,120.6,114.4,64.8,46.4,39.5,26.1.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 20 NO 2 + 270.1489, found 270.1461.

[0059] Example 5

[0060] Compared with Example 1, the difference is that Compound 1 is 1,3-dioxoisoindolin-2-yl 4-((tert-butyldimethylsilyl)oxy)-2,2-dimethylbutyrate, and its structure is:

[0061]

[0062] The corresponding product 3e is 4-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-1-(pyridin-2-yl)butan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0063]

[0064] Yellow oil (48 mg, yield 78%). 1 H NMR(400MHz,Chloroform-d)δ8.72(ddd,J=4.7,1.8,0.9Hz,1H),8.04(dt,J=8.0,1.1Hz,1H),7.88(td,J=7.8,1.9Hz,1H) ,7.47(ddd,J=7.6,4.7,1.3Hz,1H),3.71(t,J=7.0Hz,2H),2.53(t,J=7.0Hz,2H),1.53(s,6H),0.86(s,9H),0.00(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ205.6,154.9,147.7,136.6,125.8,123.7,60.3,46.3,43.0,26.1,26.0,18.4,-5.4.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 30 NO 2 Si + 308.2040, found 308.2040.

[0065] Example 6

[0066] Compared with Example 1, the difference is that Compound 1 is 3-(1,3-dioxolane-2-yl)-2,2-dimethylpropionic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0067]

[0068] The corresponding product 3f is 3-(1,3-dioxolane-22-yl)-2,2-dimethyl-1-(pyridin-2-yl)propan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0069]

[0070] Yellow oil (35 mg, yield 74%). 1 H NMR (400MHz, Chloroform-d) δ8.60 (ddd, J=4.8, 1.9, 1.0Hz, 1H), 7.93 (dt, J=7.9, 1.1Hz, 1H), 7.79 (td, J=7.7, 1.8 Hz,1H),7.36(ddd,J=7.5,4.8,1.3Hz,1H),4.95(t,J=5.2Hz,1H),3.67(s,4H),2.57(d,J=5.1Hz,2H),1.48(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ205.2,155.1,147.6,136.7,125.7,123.7,103.0,64.6,45.9,44.0,26.4.HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 18 NO 3 + 236.1281, found 236.1279.

[0071] Example 7

[0072] Compared with Example 1, the difference is that compound 1 is 1-(1,3-dioxoisoindoline-2-yl)-2,2-dimethylglutaric acid methyl ester, and its structure is:

[0073]

[0074] The corresponding product 3g is 4,4-dimethyl-5-oxo-5-(pyridin-2-yl)pentanoic acid methyl ester, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0075]

[0076] Yellow oil (29 mg, yield 62%). 1 H NMR (400MHz, Chloroform-d) δ8.61 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 7.88 (dt, J=7.9, 1.1Hz, 1H), 7.79 (td, J=7.7, 1.8Hz,1H),7.39(ddd,J=7.5,4.8,1.3Hz,1H),3.62(s,3H),2.42-2.36(m,2H),2.28-2.21(m,2H),1.42(s,6H). 13 CNMR (101MHz, CDCl 3 )δ205.9,174.3,154.7,148.0,136.8,126.2,123.6,51.7,47.2,35.2,30.1,25.4.HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 18 NO 3 + 236.1281, found 236.1259.

[0077] Example 8

[0078] Compared with Example 1, the difference is that Compound 1 is 3-((tert-butyloxycarbonyl)amino)-2,2-dimethylpropionic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0079]

[0080] The corresponding product 3h is tert-butyl (2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propyl)carbamate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0081]

[0082] Yellow oil (46 mg, yield 83%). 1H NMR (400MHz, Chloroform-d) δ8.63 (ddd, J=4.8, 1.8, 0.9Hz, 1H), 7.89 (dt, J=7.9, 1.1Hz, 1H), 7.81 (td, J=7.7, 1.8 Hz,1H),7.42(ddd,J=7.5,4.8,1.3Hz,1H),5.27(d,J=6.7Hz,1H),3.53(d,J=6.6Hz,2H),1.47(s,6H),1.42(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ206.1,156.4,154.4,148.0,137.0,126.3,123.8,79.0,49.3,49.2,28.5,23.3.HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 23 N 2 O 3 + 279.1703, found 279.1677.

[0083] Example 9

[0084] Compared with Example 1, the difference is that compound 1 is 2,2-dimethyloct-7-enoic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0085]

[0086] The corresponding product 3i is 2,2-dimethyl-1-(pyridin-2-yl)oct-7-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0087]

[0088] Yellow oil (33 mg, yield 71%). 1H NMR (400MHz, Chloroform-d) δ8.61(ddd,J=4.7,1.8,1.0Hz,1H),7.86(dt,J=7.9,1.1Hz,1H),7.78(td,J=7.7,1.8Hz,1H),7.37(ddd,J=7.5,4.8,1.4Hz ,1H),5.72(ddt,J=16.9,10.2,6.6Hz,1H),4.97-4.82(m,2H),2.06-2.00(m ,2H),1.99-1.92(m,2H),1.39(s,6H),1.33-1.25(m,2H),1.22-1.12(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ207.0,155.2,147.8,139.1,136.7,125.9,123.5,114.3,47.9,40.2,33.6,29.6,25.8,24.6.HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 22 NO + 232.1696, found 232.1676.

[0089] Example 10

[0090] Compared with Example 1, the difference is that compound 1 is 2-(4-isobutylphenyl)propionic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0091]

[0092] The corresponding product 3j is 2-(4-isobutylphenyl)-1-(pyridin-2-yl)propan-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0093]

[0094] Yellow oil (21 mg, yield 40%). 1H NMR (400MHz, Chloroform-d) δ8.66 (ddd, J=4.7, 1.8, 0.9Hz, 1H), 8.00 (dt, J=7.9, 1.1Hz,1H),7.76(td,J=7.7,1.7Hz,1H),7.39(ddd,J=7.5,4.8,1.3Hz,1H),7.28( dd,J=8.6,2.3Hz,2H),7.05-7.01(m,2H),5.46(q,J=7.1Hz,1H),2.38(d,J=7.2Hz ,2H),1.80(dp,J=13.6,6.8Hz,1H),1.54(d,J=7.0Hz,3H),0.86(d,J=6.6Hz,6H). 13 C NMR (101 MHz, CDCl 3 )δ201.9,152.8,148.6,139.9,137.8,136.6,129.0,127.9,126.7,122.6,44.8,44.2,30.0,22.2,18.0.HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 22 NO + 268.1696, found 268.1700.

[0095] Embodiment 11

[0096] Compared with Example 1, the difference is that Compound 1 is 1-methylcyclohexane-1-carboxylic acid 1,3-dioxoisoindolin-2-yl ester, and its structure is:

[0097]

[0098] The corresponding product 3k is (1-methylcyclohexyl)(pyridin-2-yl)methanone, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0099]

[0100] Yellow oil (27 mg, yield 64%). 1 H NMR(400MHz,Chloroform-d)δ8.59(ddd,J=4.7,1.7,0.9Hz,1H),7.86-7.73(m,2H),7.3 6(ddd,J=7.3,4.8,1.6Hz,1H),2.44-2.33(m,2H),1.59-1.45(m,9H),1.37-1.32(m,2H). 13C NMR (101 MHz, CDCl 3 )δ207.7,155.8,147.7,136.8,125.7,123.6,48.4,35.8,26.2,25.5,23.2. 13 C NMR (101 MHz, CDCl 3 )δ207.7,155.8,147.7,136.8,125.7,123.6,48.4,35.8,26.2,25.5,23.2.HRMS(ESI)m / z:[M+Na] + calcdfor C 13 H 17 NNaO + 226.1202, found 226.1204.

[0101] Example 12

[0102] Compared with Example 1, the difference is that Compound 2 is 1H-imidazole-1-yl-(5-methylpyridin-2-yl)methanone, and its structure is:

[0103]

[0104] The corresponding product 3l is 2,2-dimethyl-1-(5-methylpyridin-2-yl)hex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0105]

[0106] Yellow oil (35 mg, yield 81%). 1 H NMR(400MHz,Chloroform-d)δ8.43(dd,J=2.0,1.2Hz,1H),7.87-7.76(m,1H),7.58(ddd,J=8.1,2.3,0.9Hz,1H),5.73(ddt,J=16 .7,10.1,6.4Hz,1H),4.98-4.79(m,2H),2.38(s,3H),2.19-2.10(m,2H),1.92(dddt,J=10.4,7.6,6.3,1.6Hz,2H),1.41(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ206.3,152.5,148.3,139.1,137.1,136.2,123.4,114.2,47.7,39.6,29.5,25.8,18.7.HRMS(ESI)m / z:[M+Na] +calcdfor C 14 H 19 NNaO + 240.1359, found 240.1365.

[0107] Example 13

[0108] Compared with Example 1, the difference is that Compound 2 is (1H-imidazole-1-yl)(4-methoxypyridin-2-yl)methanone, and its structure is:

[0109]

[0110] The corresponding product 3m is 1-(4-methoxypyridin-2-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0111]

[0112] Yellow oil (35 mg, yield 75%). 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J=5.6Hz,1H),7.40(d,J=2.6Hz,1H),6.89(dd,J=5.6,2.6Hz,1H),5.74(ddt,J=16.7, 10.2,6.5Hz,1H),5.00-4.82(m,2H),3.88(s,3H),2.18-2.08(m,2H),1.93(dddt,J=10.6,7.7,6.4,1.4Hz,2H),1.41(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ206.6,166.3,156.9,149.3,139.0,114.3,112.7,108.8,55.4,47.8,39.6,29.5,25.7.HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 20 NO 2 + 234.1489, found 234.1484.

[0113] Embodiment 14

[0114] Compared with Example 1, the difference is that Compound 2 is (3-chloropyridin-2-yl)(1H-imidazole-1-yl)methanone, and its structure is:

[0115]

[0116] The corresponding product 3n is 1-(3-chloropyridin-2-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0117]

[0118] Yellow oil (26 mg, yield 55%). 1 H NMR(400MHz,Chloroform-d)δ7.84-7.73(m,2H),7.44(dd,J=7.7,1.2Hz,1H),5.74(ddt,J=16.7,10.2,6 .5Hz,1H),4.99-4.84(m,2H),2.15-2.07(m,2H),1.93(dddd,J=12.2,6.4,2.8,1.4Hz,2H),1.41(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ205.0,154.7,149.5,139.5,138.8,127.0,122.2,114.5,47.9,39.6,29.5,25.7.HRMS(ESI)m / z:[M+H] + Calculate for C 13 H 17 ClNO + 238.0993, found 238.0993.

[0119] Embodiment 15

[0120] Compared with Example 1, the difference is that Compound 2 is (1H-imidazol-1-yl)(quinoline-2-yl)methanone, and its structure is:

[0121]

[0122] The corresponding product 3o is 2,2-dimethyl-1-(quinolin-2-yl)hex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0123]

[0124] Yellow oil (40 mg, yield 79%). 1H NMR(400MHz,Chloroform-d)δ8.22(dd,J=8.6,0.9Hz,1H),8.14(dq,J=8.5,1.0Hz,1 H),7.97(d,J=8.5Hz,1H),7.84(dd,J=8.1,1.5Hz,1H),7.75(ddd,J=8.4,6.9,1.5Hz, 1H),7.61(ddd,J=8.2,6.9,1.2Hz,1H),5.73(ddt,J=16.8,10.1,6.5Hz,1H),4.98-4. 80(m,2H),2.34-2.23(m,2H),1.99(dddd,J=11.9,6.5,2.9,1.4Hz,2H),1.51(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ207.0,154.3,146.5,139.0,136.7,130.6,129.9,128.9,128.3,127.7,120.1,114.3,48.1,40.0,29.7,26.0.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 20 NO + 254.1539, found 254.1542.

[0125] Example 16

[0126] Compared with Example 1, the difference is that Compound 2 is benzo[b]thiophene-2-yl(1H-imidazole-1-yl)methanone, and its structure is:

[0127]

[0128] The corresponding product 3p is 1-(benzo[b]thiophene-2-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0129]

[0130] Yellow oil (25 mg, yield 49%). 1H NMR(400MHz,Chloroform-d)δ8.02(d,J=0.9Hz,1H),7.91-7.83(m,2H),7.42(dddd,J=21.4, 8.2,7.1,1.3Hz,2H),5.83-5.65(m,1H),5.03-4.84(m,2H),2.06-1.95(m,4H),1.43(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ200.0,142.4,141.7,139.3,138.3,128.6,127.2,126.0,124.9,122.7,114.8,47.8,40.8,29.2,26.3.HRMS(ESI)m / z:[M+Na] + Calculate for C 16 H 18 NaOS + 281.0971, found 281.0970.

[0131] Embodiment 17

[0132] Compared with Example 1, the difference is that Compound 2 is (1H-imidazole-1-yl)(7-methoxybenzofuran-2-yl)methanone, and its structure is:

[0133]

[0134] The corresponding product 3q is 1-(7-methoxybenzofuran-2-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0135]

[0136] Yellow oil (32 mg, yield 59%). 1 H NMR(400MHz,Chloroform-d)δ7.52(s,1H),7.26(dd,J=7.9,1.2Hz,1H),7.20(t,J=7.8Hz,1H),6.93(dd ,J=7.8,1.2Hz,1H),5.84-5.66(m,1H),5.01-4.84(m,2H),4.03(s,3H),2.07-1.93(m,4H),1.41(s,6H). 13 C NMR (101 MHz, CDCl 3)δ196.3,153.2,146.1,144.9,138.6,128.5,124.5,114.9,114.7,113.9,109.5,56.3,47.0,39.1,29.3,24.9.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 21 O 3 + 273.1485, found 273.1502.

[0137] Embodiment 18

[0138] Compared with Example 1, the difference is that Compound 2 is (1H-imidazole-1-yl)(3-methylbenzofuran-2-yl)methanone, and its structure is:

[0139]

[0140] The corresponding product 3r is 1-(3-methylbenzofuran-2-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0141]

[0142] Yellow oil (34 mg, yield 66%). 1 H NMR(400MHz,Chloroform-d)δ7.65(d,J=7.9Hz,1H),7.53-7.44(m,2H),7.31(td,J=7.3,6.8,1.3Hz,1H ),5.75(ddt,J=16.0,9.8,5.9Hz,1H),5.01-4.83(m,2H),2.59(s,3H),2.09-1.91(m,4H),1.39(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ198.5,153.5,148.3,138.8,129.0,128.0,126.3,123.2,121.4,114.5,112.2,47.6,38.7,29.4,24.7,10.2.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 21 O 2 + 257.1536, found 257.1549.

[0143] Embodiment 19

[0144] Compared with Example 1, the difference is that Compound 2 is (1H-imidazole-1-yl)(thiophene-2-yl)methanone, and its structure is:

[0145]

[0146] The corresponding product 3s is 2,2-dimethyl-1-(thiophen-2-yl)hex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0147]

[0148] Yellow oil (26 mg, yield 63%). 1 H NMR(400MHz,Chloroform-d)δ7.79(dd,J=3.9,1.1Hz,1H),7.56(dd,J=5.0,1.1Hz,1H),7.11( dd,J=5.0,3.9Hz,1H),5.81-5.68(m,1H),5.01-4.84(m,2H),2.02-1.88(m,4H),1.38(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ198.6,142.9,138.4,132.5,131.7,127.8,114.7,47.4,40.8,29.2,26.3.HRMS(ESI)m / z:[M+Na] + calcdfor C 12 H 16 NaOS + 231.0814, found 231.0829.

[0149] Embodiment 20

[0150] Compared with Example 1, the difference is that Compound 2 is 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl(1H-imidazole-1-yl)methanone, and its structure is:

[0151]

[0152] The corresponding product 3t is 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0153]

[0154] Yellow oil (42 mg, yield 45%). 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=2.3Hz,1H),7.32-7.28(m,2H),7.27-7.23(m,1H),7.15(d,J=8.4Hz,1H),7.07-7.03(m ,2H),5.75(ddt,J=16.6,10.2,6.3Hz,1H),4.99-4.84(m,2H),2.27(s,3H),2.13-2.06(m,2H),2.01-1.93(m,2H),1.40(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ203.1,148.1,141.7,139.2,136.3,135.8,134.9,133.2,131.1,130.5,130.4,12 9.0,127.8,127.5,119.4,114.2,48.3,39.7,29.5,25.7,10.4.HRMS(ESI)m / z:[M+H] + Calculate for C 24 H 24 Cl 3 NO 2 + 461.0949,found461.0974.

[0155] Embodiment 21

[0156] Compared with Example 1, the difference is that Compound 2 is (4-fluorophenyl)(1H-imidazole-1-yl)methanone, and its structure is:

[0157]

[0158] The corresponding product 3u is 1-(4-fluorophenyl)-2,2-dimethylhex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0159]

[0160] Yellow oil (33 mg, yield 58%). 1H NMR(400MHz,Chloroform-d)δ7.82-7.71(m,2H),7.13-7.03(m,2H),5.74(ddt,J=16.7, 10.1,6.4Hz,1H),5.02-4.87(m,2H),2.03-1.94(m,2H),1.89-1.81(m,2H),1.33(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ207.0,164.4(d,J=252.5Hz),138.4,134.9,130.6(d,J=9.1Hz),115.3(d,J=22.2Hz),114.8,47.7,40.4,29.3,26.4. 19 F NMR (376 MHz, CDCl 3 )δ-108.2.HRMS(ESI)m / z:[M+Na] + Calculate for C 14 H 17 FNaO + 243.1156, found 243.1181.

[0161] Embodiment 22

[0162] Compared with Example 1, the difference is that Compound 2 is (1H-imidazole-1-yl)(4-(trifluoromethoxy)phenyl)methanone, and its structure is:

[0163]

[0164] The corresponding product 3v is 2,2-dimethyl-1-(4-(trifluoromethoxy)phenyl)hex-5-en-1-one, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0165]

[0166] Yellow oil (36 mg, yield 62%). 1 H NMR(400MHz,Chloroform-d)δ7.78-7.72(m,2H),7.30-7.20(m,2H),5.75(ddt,J=16.8, 10.1,6.4Hz,1H),5.01-4.89(m,2H),2.03-1.94(m,2H),1.88-1.82(m,2H),1.33(s,6H). 13 C NMR (101 MHz, CDCl 3)δ207.4,151.1,138.3,137.2,129.8,120.5(q,J=260.0Hz),120.3,114.9,47.8,40.2,29.3,26.2. 19 F NMR (376 MHz, CDCl 3 )δ-57.7.HRMS(ESI)m / z:[M+Na] + Calculate for C 15 H 17 F 3 NaO 2 + 309.1073, found 309.1091.

[0167] Embodiment 23

[0168] Compared with Example 1, the difference is that compound 1 is 1-bromocyclobutane-1-carboxylic acid ethyl ester, and its structure is:

[0169]

[0170] The corresponding product 3w is ethyl 1-(pyridine-2-formyl)cyclobutanecarboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0171]

[0172] Yellow oil (29 mg, yield 66%). 1 H NMR (400MHz, Chloroform-d) δ8.58(ddd,J=4.8,1.7,0.9Hz,1H),8.11(dt,J=7.9,1.1Hz,1H),7.84(td,J=7.7,1.7Hz,1H),7.42(ddd,J=7.6,4.7,1 .3Hz,1H),4.07(q,J=7.1Hz,2H),2.71-2.54(m,4H),2.14(dtt,J=11.4,9 .4, 6.7Hz, 1H), 1.91 (dtt, J=11.4, 9.4, 6.8Hz, 1H), 0.99 (t, J=7.1Hz, 3H). 13 C NMR (101 MHz, CDCl 3 )δ196.5,173.0,151.4,148.7,137.0,126.9,122.9,60.8,55.9,27.8,16.2,13.9.HRMS(ESI)m / z:[M+Na] + Calculate for C 13 H15 NNaO 3 + 256.0944, found 256.0962.

[0173] Embodiment 24

[0174] Compared with Example 1, the difference is that compound 1 is 1-bromocyclohexane-1-methyl carboxylate, and its structure is:

[0175]

[0176] The corresponding product 3x is 1-(pyridine-2-formyl)cyclohexane-1-carboxylic acid methyl ester, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0177]

[0178] Yellow oil (30 mg, yield 60%). 1 H NMR(400MHz,Chloroform-d)δ8.59(ddd,J=4.7,1.8,0.9Hz,1H),8.03(dt,J=7.9,1.1Hz,1H),7.83(td,J=7.7,1.7Hz,1H),7.41( ddd,J=7.6,4.7,1.2Hz,1H),3.57(s,3H),2.10(dd,J=6.9,5.3Hz,4H),1.77-1.67(m,2H),1.61-1.52(m,2H),1.51-1.43(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ198.9,174.4,152.0,148.2,137.1,126.8,123.2,56.0,52.0,31.6,25.7,22.2.HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 18 NO 3 + 248.1281, found 248.1301.

[0179] Embodiment 25

[0180] Compared with Example 1, the difference is that compound 1 is methyl 2-bromo-2-methylpropionate, and its structure is:

[0181]

[0182] The corresponding product 3y is methyl 2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propanoate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0183]

[0184] Yellow oil (17 mg, yield 40%). 1 H NMR (400MHz, Chloroform-d) δ8.61 (ddd, J=4.6, 1.7, 0.9Hz, 1H), 8.08 (dt, J=7.9, 1.1Hz, 1H ),7.84(td,J=7.7,1.7Hz,1H),7.42(ddd,J=7.6,4.7,1.2Hz,1H),3.58(s,3H),1.53(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ198.9,175.3,151.4,148.3,137.1,126.9,123.2,52.1,51.9,23.2.HRMS(ESI)m / z:[M+Na] + Calculate for C 11 H 13 NNaO 3 + 230.0788, found 230.0789.

[0185] Embodiment 26

[0186] Compared with Example 1, the difference is that Compound 1 is tert-butyl 4-((2-bromo-2-methylpropionyl)oxy)piperidine-1-carboxylate, and its structure is:

[0187]

[0188] The corresponding product 3z is tert-butyl 4-((2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propionyl)oxy)piperidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0189]

[0190] Yellow oil (51 mg, yield 68%). 1H NMR(400MHz,Chloroform-d)δ8.55(ddd,J=4.8,1.7,0.9Hz,1H),8.06(dt,J=7.9,1.1Hz,1H),7.83(td,J=7.7,1.7Hz,1H),7.41(ddd,J=7 .6,4.7,1.3Hz,1H),4.94(tt,J=7.2,3.6Hz,1H),3.19(t,J=5.8Hz,4H),1.66-1.57(m,2H),1.52(s,6H),1.39(s,9H),1.37-1.29(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ198.8,173.9,154.7,151.4,148.1,137.2,127.1,123.2,79.7,69.4,52.2,40.6,29.8,28.5,23.2.HRMS(ESI)m / z:[M+H] + Calculate for C 20 H 29 N 2 O 5 + 377.2071, found 377.2095.

[0191] Embodiment 27

[0192] Compared with Example 1, the difference is that compound 1 is 2-bromo-2-methylpropionic acid (2-methylallyl) ester, and its structure is:

[0193]

[0194] The corresponding product 3aa is 2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propionic acid (2-methylallyl) ester, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0195]

[0196] Yellow oil (43 mg, yield 87%). 1H NMR (400MHz, Chloroform-d) δ8.52 (ddd, J=4.7, 1.8, 0.9Hz, 1H), 8.01 (dt, J=7.9, 1.1Hz, 1H), 7.76 (td, J=7.7, 1. 7Hz,1H),7.34(ddd,J=7.6,4.7,1.3Hz,1H),4.73-4.66(m,2H),4.34(s,2H),1.49(s,6H),1.36(t,J=1.2Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ198.8,174.5,151.4,148.3,139.8,137.1,126.9,123.1,113.2,68.3,52.1,23.3,19.2.HRMS(ESI)m / z:[M+Na] + Calculate for C 14 H 17 NNaO 3 + 270.1101, found 270.1122.

[0197] Embodiment 28

[0198] Compared with Example 1, the difference is that compound 1 is 2-bromo-2-methyl cinnamyl propionate, and its structure is:

[0199]

[0200] The corresponding product 3ab is 2,2-dimethyl-3-oxo-3-(pyridin-2-yl)cinnamyl propionate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0201]

[0202] Yellow oil (38 mg, yield 61%). 1 H NMR(400MHz,Chloroform-d)δ8.52(ddd,J=4.7,1.8,0.9Hz,1H),8.08(dt,J=7.9,1.1Hz,1H),7.80(td,J=7.7,1.7Hz,1H) ,7.35-7.19(m,6H),6.42(dt,J=15.9,1.4Hz,1H),6.02(dt,J=15.9,6.4Hz,1H),4.67(dd,J=6.4,1.4Hz,2H),1.58(s,6H). 13 C NMR (101 MHz, CDCl 3)δ198.9,174.5,151.4,148.3,137.0,136.4,133.8,128.6,128.0,126.9,126.6,123.1,65.3,52.1,23.3.HRMS(ESI)m / z:[M+H] + Calculate for C 19 H 20 NO 3 + 310.1438, found 310.1430.

[0203] Embodiment 29

[0204] Compared with Example 1, the difference is that compound 1 is bis(2-bromo-2-methylpropionic acid) but-2-yne-1,4-diester, and its structure is:

[0205]

[0206] The corresponding product 3ac is bis(2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propanoic acid)but-2-yne-1,4-diester, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0207]

[0208] Yellow oil (56 mg, yield 64%). 1 H NMR(400MHz,Chloroform-d)δ8.48(ddd,J=4.7,1.7,0.9Hz,2H),7.98(dt,J=7.9,1.1Hz,2H) ,7.75(td,J=7.7,1.7Hz,2H),7.34(ddd,J=7.6,4.7,1.3Hz,2H),4.49(s,4H),1.45(s,12H). 13 C NMR (101 MHz, CDCl 3 )δ198.4,173.8,151.0,148.4,137.1,127.0,123.1,80.2,52.2,51.8,23.1.HRMS(ESI)m / z:[M+H] + calcdfor C 24 H 25 N 2 O 6 + 437.1707, found 437.1737.

[0209] Embodiment 30

[0210] Compared with Example 1, the difference is that Compound 1 is (3S, 8S, 9S, 10R, 13R, 14S, 17R)-10,13-dimethyl-17-((R)-6-methylhept-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 2-bromo-2-methylpropanoate, and its structure is:

[0211]

[0212] The corresponding product 3ad is (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylhept-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3-yl 2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propanoate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0213]

[0214] Yellow oil (64 mg, yield 57%). 1 H NMR(400MHz,Chloroform-d)8.63-8.55(m,1H),8.09-8.02(m,1H),7.87-7.76(m,1H),7.40(ddd,J=7.6,4.7,1.3Hz,1H),5.28 -5.25(m,1H),4.64-4.51(m,1H),2.09-1.69(m,7H),1.61-1.29(m,16H),1.20-0.94(m,10H),0.92-0.81(m,13H),0.63(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ199.2,174.1,151.6,148.1,139.8,137.0,126.9,123.0,122.6,74.1,56.8,56.2,52.2,50.1,42.4,39.8,39.6,37.7,37. 0,36.6,36.3,35.9,32.0,31.9,28.3,28.1,27.3,24.4,23.9,23.3,22.9,22.7,21.1,19.3,18.8,11.9.HRMS(ESI)m / z:[M+H] + Calculate for C 37 H 56 NO 3+ 562.4255, found 562.4289.

[0215] Embodiment 31

[0216] Compared with Example 1, the difference is that compound 1 is ((3aR, 5R, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxole)[4,5-b:4',5'-d]pyran-5-yl)methyl 2-bromo-2-methylpropanoate, and its structure is:

[0217]

[0218] The corresponding product 3ae is ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxol)[4,5-b:4',5'-d]pyran-5-yl)methyl 2,2-dimethyl-3-oxo-3-(pyridin-2-yl)propanoate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0219]

[0220] Yellow oil (83 mg, yield 95%). 1 H NMR(400MHz,Chloroform-d)δ8.59(ddd,J=4.7,1.7,0.9Hz,1H),8.06(dt,J=7.9,1.1Hz,1H), 7.82(td,J=7.7,1.7Hz,1H),7.40(ddd,J=7.6,4.7,1.2Hz,1H),5.43(d,J=4.9Hz,1H),4.47(dd ,J=7.8,2.5Hz,1H),4.24(dd,J=5.0,2.5Hz,1H),4.15(qd,J=11.2,6.4Hz,2H),3.85(ddt,J=6. 9,3.7,1.9Hz,2H),1.54(d,J=4.5Hz,6H),1.41(s,3H),1.37(s,3H),1.29(s,3H),1.22(s,3H). 13 C NMR (101 MHz, CDCl 3 )δ198.7,174.5,151.3,148.4,137.0,126.8,123.1,109.4,108.8,96.2,70.7,7 0.6,65.5,63.2,52.0,26.1,26.0,25.1,24.4,23.3,23.2.HRMS(ESI)m / z:[M+Na]+ Calculate for C 22 H 29 NNaO 8 + 458.1785, found 458.1816.

[0221] In addition to the novel coupling reactions of Examples 1 to 31, the coupling reactions developed in the present invention can be successfully used for the preparation of some active molecules. Compared with the previously reported routes, the method used in the present invention simplifies the routes.

[0222] Embodiment 32

[0223] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0224]

[0225] Compound 2 is (5-chloropyridin-2-yl)(1H-imidazole-1-yl)methanone, and its structure is:

[0226]

[0227] The corresponding product 3af is tert-butyl 3-(5-chloropyridine-22-carbonyl)-3-propylpyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0228]

[0229] Yellow oil (55 mg, yield 78%). 1 H NMR(400MHz,Chloroform-d)δ8.63-8.55(m,1H),7.98(dd,J=8.5,3.0Hz,1H),7.84-7.77(m,1H),4.00-3.87(m,1H),3.78-3.53 (m,1H),3.48-3.30(m,2H),2.57-2.45(m,1H),2.30-1.89(m,3H),1.46(d,J=3.3Hz,9H),1.23-0.96(m,2H),0.83-0.76(m,3H). 13 C NMR (101 MHz, CDCl 3)δ201.4,154.6,151.1,147.3,136.9,135.7,124.6,79.3,58.4,53.8,44.5,39.1,33.1,28.6,18.9,14.6.HRMS(ESI)m / z:[M+Na] + Calculate for C 18 H 25 C1N 2 NaO 3 + 375.1446, found 375.1466.

[0230] Embodiment 33

[0231] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0232]

[0233] Compound 2 is benzo[b]thiophene-2-yl(1H-imidazol-1-yl)methanone, and its structure is:

[0234]

[0235] The corresponding product 3ag is tert-butyl 3-(benzo[b]thiophene-2-carbonyl)-3-propylpyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0236]

[0237] Yellow oil (35 mg, yield 47%). 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=3.0Hz,1H),7.93-7.83(m,2H),7.51-7.37(m,2H),4.13-3.97(m,1H),3.7 3-3.33(m,3H),2.66-2.51(m,1H),2.17-1.88(m,3H),1.47(d,J=4.2Hz,9H),1.31-1.19(m,2H),0.89-0.82(m,3H). 13 C NMR (101 MHz, CDCl 3)δ196.5,154.6,142.0,141.8,139.3,128.8,127.6,126.2,125.2,122.8,7 9.6,58.7,54.1,44.5,40.8,33.9,28.6,18.8,14.5.HRMS(ESI)m / z:[M+Na] + Calculate for C 21 H 27 NNaO 3 S + 396.1604, found 396.1631.

[0238] Embodiment 34

[0239] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0240]

[0241] Compound 2 is (3,4-dichlorophenyl)(1H-imidazol-1-yl)methanone, and its structure is:

[0242]

[0243] The corresponding product 3ah is tert-butyl 3-(3,4-dichlorobenzoyl)-3-propylpyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0244]

[0245] Yellow oil (34 mg, yield 44%). 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=2.1Hz,1H),7.69(d,J=8.5Hz,1H),7.53(t,J=7.7Hz,1H),3.88(dd,J=11.4,4.9Hz,1H), 3.64-3.31(m,3H),2.55-2.39(m,1H),2.03-1.94(m,1H),1.94-1.78(m,2H),1.46(s,9H),1.24-1.11(m,2H),0.89-0.80(m,3H). 13 C NMR (101 MHz, CDCl 3)δ200.7,154.5,137.2,135.9,133.4,130.8,130.7,127.7,79.8,58.8,53.8,44.5,40.1,33.9,28.6,18.8,14.6.HRMS(ESI)m / z:[M+Na] + Calculate for C 19 H 25 Cl 2 NNaO 3 + 408.1104, found 408.1124.

[0246] Embodiment 35

[0247] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0248]

[0249] Compound 2 is (5-bromonaphthalene-2-yl)(1H-imidazole-1-yl)methanone, and its structure is:

[0250]

[0251] The corresponding product 3ai is tert-butyl 3-(5-bromo-2-naphthoyl)-3-propylpyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0252]

[0253] Yellow oil (36 mg, yield 40%). 1 H NMR(400MHz,Chloroform-d)δ8.35(d,J=1.8Hz,1H),8.28(t,J=7.9Hz,1H),8.02(t,J=7.2Hz,1H),7.95-7.86(m,2H),7.41(t,J=7.9Hz,1 H),3.99(t,J=12.2Hz,1H),3.78-3.37(m,3H),2.67-2.48(m,1H),2.18-1.88(m,3H),1.46(s,9H),1.22-1.07(m,2H),0.87-0.79(m,3H). 13 C NMR (101 MHz, CDCl 3)δ202.5,154.6,134.2,133.8,132.4,129.9,129.6,127.8,127.3,126.3,126.1, 122.8,79.7,59.0,54.1,44.6,40.3,34.0,28.6,18.8,14.6.HRMS(ESI)m / z:[M+H] + Calculate for C 23 H 29 BrNO 3 + 446.1325, found 446.1276.

[0254] Embodiment 36

[0255] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0256]

[0257] Compound 2 is (1H-imidazol-1-yl)(quinoline-2-yl)methanone, and its structure is:

[0258]

[0259] The corresponding product 3aj is tert-butyl 3-propyl-3-(quinoline-2-carbonyl)pyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0260]

[0261] Yellow oil (59 mg, yield 80%). 1 H NMR(400MHz,Chloroform-d)δ8.26(t,J=7.5Hz,1H),8.17(t,J=7.6Hz,1H),8.0 7(d,J=8.5Hz,1H),7.87(t,J=8.4Hz,1H),7.82-7.74(m,1H),7.65(q,J=7.5Hz, 1H),4.13-4.00(m,1H),3.97-3.74(m,1H),3.52-3.38(m,2H),2.69-2.56(m,1H ),2.48-2.02(m,3H),1.50-1.44(m,9H),1.22-1.03(m,2H),0.82-0.75(m,3H). 13 C NMR (101 MHz, CDCl 3)δ202.9,154.9,152.6,146.6,137.0,130.9,130.1,129.3,128.8,127.8,119 .7,79.3,58.6,54.2,44.6,39.8,33.3,28.6,19.0,14.7.HRMS(ESI)m / z:[M+H] + Calculate for C 22 H 29 N 2 O 3 + 369.2173, found 369.2185.

[0262] Embodiment 37

[0263] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-3-(1,3-dioxoisoindolin-2-yl)-3-propylpyrrolidine-1,3-dicarboxylate, and its structure is:

[0264]

[0265] Compound 2 is (1H-imidazol-1-yl)(4-iodophenyl)methanone, and its structure is:

[0266]

[0267] The corresponding product 3ak is tert-butyl 3-propyl-3-(4-iodobenzoyl)pyrrolidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0268]

[0269] Yellow oil (42 mg, yield 47%). 1 H NMR(400MHz,Chloroform-d)δ7.87-7.77(m,2H),7.61-7.51(m,2H),3.93-3.81(m,1H),3.66-3.29( m,3H),2.55-2.39(m,1H),2.08-1.78(m,3H),1.45(s,9H),1.23-1.09(m,2H),0.83(q,J=7.0Hz,3H). 13 C NMR (101 MHz, CDCl 3)δ202.2,154.5,137.9,130.0,128.6,100.3,79.7,58.7,53.8,44.5,40.1,33.9,28.6,18.8,14.6.HRMS(ESI)m / z:[M+Na] + Calculate for C 19 H 26 INaO 3 + 466.0850, found 466.0849.

[0270] Embodiment 38

[0271] Compared with Example 1, the difference is that Compound 1 is 1-(tert-butyl)-4-(1,3-dioxoisoindolin-2-yl)-4-methylpiperidine-1,4-dicarboxylate, and its structure is:

[0272]

[0273] Compound 2 is (1H-imidazol-1-yl)(4-(quinolin-3-yl)phenyl)methanone, and its structure is:

[0274]

[0275] The corresponding product 3al is tert-butyl 4-methyl-4-(4-(quinolin-3-yl)benzoyl)piperidine-1-carboxylate, and its structure, morphology, yield, NMR, and high-resolution mass spectrometry data are as follows:

[0276]

[0277] White solid (46 mg, yield 53%). 1 H NMR(400MHz,Chloroform-d)δ9.18(d,J=2.3Hz,1H),8.33(d,J=2.4Hz,1H),8.16(d,J=8.5Hz,1H),7.91-7.83(m,3H),7.78-7.70( m,3H),7.63-7.55(m,1H),3.77-3.55(m,2H),3.17-2.99(m,2H),2.36-2.23(m,2H),1.65-1.52(m,2H),1.49(s,3H),1.43(s,9H). 13 C NMR (101 MHz, CDCl 3)δ22407.2,155.0,149.6,147.7,140.8,137.7,133.8,132.7,130.1,129.4,129.0,1 28.3,128.0,127.4,127.3,79.6,46.8,40.9,35.4,28.6,25.5.HRMS(ESI)m / z:[M+H] + Calculate for C 27 H 30 N 2 NaO 3 + 453.2149, found 453.2179.

[0278] The above is only an exemplary embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. An azacarbene-catalyzed decarboxylation coupling method, characterized in that: The method uses an organic small molecule nitrogen heterocyclic carbene as an organic catalyst and manganese or tetrakis(dimethylamino)ethylene as a reducing agent to cross-couple aromatic acids or their derivatives with electrophilic reagents to prepare multi-structure ketones.

2. The decarboxylation coupling method catalyzed by azacarbene according to claim 1, characterized in that: Such electrophiles include N-hydroxyphthalimide esters and alkyl bromides.

3. The decarboxylation coupling method catalyzed by azacarbene according to claim 1, characterized in that: The specific process is as follows: Compound 1, Compound 2, solvent, catalyst and reducing agent are added to the reactor, and the mixture is heated at 25 to 80° C. for 1 to 24 hours, and the reaction progress is monitored by thin layer chromatography until the reaction is complete; then, the mixture is extracted with ethyl acetate and water for 3 to 4 times, and the organic phase is collected and combined and washed with saturated brine. After the organic phase is collected, it is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified with silica gel column chromatography to obtain Compound 3. The reaction equation in the synthesis process is:

4. The decarboxylation coupling method catalyzed by azacarbene according to claim 3, characterized in that: The molar ratio of compound 1 to compound 2 is 1:1-4.

5. The decarboxylation coupling method catalyzed by azacarbene according to claim 3, characterized in that: R 1 is selected from substituted or unsubstituted aryl, heteroaryl, alkyl, styryl; R 2 One selected from the group consisting of a fluorine atom, a pyrrol-1-yl group, a pyrazol-1-yl group, an imidazole-1-yl group, and a pyridine-2-thiol group; R 2 R is selected from fluorine atom, pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, pyridine-2-thiol; 3 One selected from a secondary or tertiary alkyl group, a tertiary alkyl group substituted with an α-oxygen, nitrogen or bromine atom; R 3 Selected from secondary or tertiary alkyl, tertiary alkyl substituted with α-oxygen, nitrogen or bromine atom; R 4 One selected from the group consisting of a hydrogen atom, a 1,3-dioxoisoindolin-2-yl group, a 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl group, and a 1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl group.

6. The azacarbene-catalyzed decarboxylation coupling method according to claim 3, characterized in that: The molar ratio of compound 1 to the catalyst is 1:0.01-0.5; the molar ratio of compound 1 to the base is 1:0-0.5; the molar ratio of compound 1 to the reducing agent is 1:0.5-3; the concentration range of compound 1 to the solvent is 0.05M-1M.

7. The azacarbene-catalyzed decarboxylation coupling method according to claim 3, characterized in that: The salt catalyst anion is selected from one of perchlorate anion, tetrafluoroborate anion, hexafluorophosphate anion, chloride anion, iodine anion and bromide anion; The salt catalyst cation is selected from 3-(2,6-diisopropylphenyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-mesityl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-neopentyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-3-ium, 3-(2,6-diisopropylphenyl)-4,5,6,7-tetrahydro-phenyl One of 3-benzene-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-mesityl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-phenyl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 3-neopentyl-4,5,6,7-tetrahydro-benzo[d]thiazol-3-ium, 6,7-dihydro-2-phenyl-5H-pyrrolo[2,1-c]-1,2,4-triazole, and 6,7-dihydro-2-mesityl-5H-pyrrolo[2,1-c]-1,2,4-triazole.

8. The azacarbene-catalyzed decarboxylation coupling method according to claim 3, characterized in that: The base is selected from one of cesium carbonate, cesium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, dipotassium phosphate, monopotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, cesium fluoride, lithium fluoride, sodium fluoride, triethylamine, pyridine, tetramethylguanidine, and N,N-diisopropylethylamine.

9. The azacarbene-catalyzed decarboxylation coupling method according to claim 3, characterized in that: The reducing agent is selected from manganese or tetrakis(dimethylamino)ethylene; The solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, acetone, xylene and ethyl acetate.

10. The azacarbene-catalyzed decarboxylation coupling method according to claim 3, characterized in that: R 4 is a hydrogen atom, N,N-carbonyldiimidazole is added to the system, and the molar ratio of compound 1 to N,N-carbonyldiimidazole is 1 to 1.5; R 3 is a tertiary alkyl group substituted with an α-bromine atom, R 4 It is one of alkyl, alkenyl, alkynyl, aryl and heteroaryl.

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