A method for synthesizing a full carbon quaternary carbon cyclic ketone spirocyclic pseudoindole derivative

Abstract

This invention discloses a method for synthesizing a full-carbon quaternary carbocyclic ketone-spirocyclic pseudoindole derivative. This method uses a metal carbonyl compound as a safe carbonyl source and involves a catalytic cycle from zero-valent palladium to divalent palladium. Specifically, it involves the oxidative addition of palladium(O) via a carbon-halogen bond, the coordination and migration insertion of CO to form a carbonyl palladium species, followed by nucleophilic attack of the indole C3 ring to achieve dearomatization of the indole ring, and then reductive elimination to obtain the full-carbon quaternary carbocyclic ketone-spirocyclic pseudoindole derivative. Specifically, compound 1 and the metal carbonyl compound Co2(CO)8 are reacted under heating conditions with palladium as a catalyst, organophosphine as a ligand, and sodium salt as a base to obtain the full-carbon quaternary carbocyclic ketone-spirocyclic pseudoindole molecule. This method is a novel synthetic method for full-carbon quaternary carbocyclic ketone-spirocyclic pseudoindole derivatives, solving the problems of existing technologies such as the need for multiple reaction steps, harsh reaction conditions, narrow substrate range, and high toxicity of starting materials.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthesis method of a compound, in particular to a synthesis method of a per-carbon quaternary carbocyclic ketospiro pseudoindole derivative. BACKGROUND

[0002] Per-carbon quaternary carbocyclic ketospiro pseudoindole derivatives are widely distributed in natural products and bioactive molecules, and are the core skeleton of many drug molecules. In addition, per-carbon quaternary carbocyclic ketospiro pseudoindole derivatives are also important synthetic intermediates of some pesticides, dyes and functional materials. Organic chemists have been constantly exploring simple and direct methods to synthesize such carbonyl cyclic ketospiro molecules. Most of the reported synthesis methods have some shortcomings, and it is difficult to effectively integrate the introduction of carbonyl group and the construction of per-carbon quaternary carbocyclic ring. Often, it needs to be completed in steps, that is, to construct the spiro ring and introduce the carbonyl group respectively. For example: Franz, A. K.; Hanhan, N. V.; Ball-Jones, N. R. ACS Catal. 2013, 3, 540-553; Qiu, B.; Xu, D.; Sun, Q.; Miao, C.; Lee, Y.-M.; Li, X.-X.; Nam, W.; Sun, W. ACS Catal. 2018, 8, 2479-2487; Suzuki, Y.; Vatmurge, N.; Tanaka, S.; Kitamura, M.; Suzuki, Y.; Vatmurge, N.; Tanaka, S.; Kitamura, M. Chem. Asian J. 2017, 12, 633-637; Ramachary, D. B.; Krishna, P. M. Asian J. Org. Chem. 2016, 5, 729-734; Bera, S.; Daniliuc, G. C.; Studer, A. Angew. Chem. Int. Ed. 2017, 56, 7402-7406; Jiang, H.; Gschwend, B.; Albrecht, L.; Hansen, S. G.; Jorgensen, K. A. Chem.-Eur. J. 2011, 17, 9032-9036. Or the reaction conditions are harsh, the substrate range is narrow, and toxic carbon monoxide gas is used as a carbonyl source, which does not meet the basic concepts of green chemistry and sustainable development. Therefore, how to find a raw material easy to obtain, safe and efficient method to realize the synchronous construction of carbonyl group introduction and per-carbon quaternary carbocyclic ring, so as to realize the efficient synthesis of per-carbon quaternary carbocyclic ketospiro pseudoindole derivatives, is still one of the problems to be solved in the field of organic chemistry. SUMMARY

[0003] Invention purposes: The present application aims to provide a simple and efficient synthesis method of all-carbon quaternary carbocyclic ketone spirocyclic pseudoindole derivatives.

[0004] Technical scheme: The synthesis method of all-carbon quaternary carbocyclic ketone spirocyclic pseudoindole derivatives provided by the present application uses carbonyl metal compounds as a safe carbonyl source, and completes the introduction of carbonyl and the construction of spiro ring in one step. The reaction is carried out according to the following steps: compound 1 is mixed with carbonyl metal compound Co2(CO)8, a palladium catalyst, a phosphine ligand and a base are added, and the target compound 2 is obtained after reaction in a solvent, and the reaction formula is as follows:

[0005]

[0006] The present application relates to a preparation method of multifunctional all-carbon quaternary carbocyclic ketone spirocyclic pseudoindole. Compound 1 is used as a reaction raw material, carbonyl metal compound Co2(CO)8 is used as a safe carbonyl source, a palladium catalyst and an appropriate amount of phosphine ligand are added, and the multifunctional all-carbon quaternary carbocyclic ketone spirocyclic pseudoindole compound is synthesized through the processes of oxidative addition, CO migration insertion and de- aromatization.

[0007] Among them, R 1 is hydrogen, fluorine, chlorine, alkyl or alkoxy; R 2 is hydrogen, fluorine, chlorine, nitro, trifluoromethyl, phenyl, alkyl or alkoxy; R 3 is alkyl, phenyl or halogenated phenyl. Preferably, the substituent R 1 of the raw material indole derivative is hydrogen, methyl, methoxy or chlorine; R 2 is hydrogen, fluorine, chlorine, nitro, trifluoromethyl, phenyl, methyl or methoxy; R 3 is methyl, phenyl or 4-fluoro-substituted phenyl.

[0008]

[0009] Preferably, the molar ratio of compound 1 to carbonyl metal compound is 1:0.5-100.

[0010] Preferably, the palladium catalyst is palladium chloride, palladium acetate, palladium hydroxide, palladium trifluoroacetate, palladium tetraphenylphosphine, bis(acetonitrile) palladium chloride, palladium acetylacetone or palladium tetraphenylphosphine; the solvent is toluene, chlorobenzene, fluorobenzene, xylene or trifluorotoluene; the phosphine ligand is bistriphenylphosphine propane, triphenylphosphine, adamantyl phosphine, bistriphenylphosphine butane, tricyclohexylphosphine, tris(o-methylphenyl) phosphine, tri-tert-butyl phosphine or 1,1'-binaphthalene-2,2'-diphenylphosphine; and the base is potassium hydroxide, sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, sodium ethoxide, sodium hydroxide, n-butyllithium, triethylamine or diethylamine.

[0011] Preferably, the reaction is carried out at room temperature to 150°C for 1-48 hours, and the yield of the target compound is 69-85%.

[0012] Preferably, the amount of alkali used is 1-20 times the molar number of 2-methyl-3-(o-bromobenzyl)indole.

[0013] Preferably, the molar ratio of compound 1 to catalyst is 1:0.005-0.3.

[0014] Multifunctionalized all-carbon quaternary carbon cyclic ketone spirocyclic pseudoindole compounds can be successfully constructed under the above reaction conditions.

[0015] The post-reaction processing is simple, requiring only a simple column chromatography separation method, using a mixed solvent of petroleum ether and ethyl acetate as the eluent to obtain pure all-carbon quaternary cyclic ketone spirocyclic pseudoindole derivatives.

[0016] This invention utilizes a novel synthetic method for all-carbon quaternary carboxycyclic ketone-spirocyclic pseudoindole derivatives. This method employs a metal carbonyl compound as a safe carbonyl source and a zero-valent palladium catalytic cycle system, involving the oxidative addition of palladium(O) via a carbon-halogen bond, followed by carbon monoxide coordination and migration insertion to form an acyl palladium species. The indole ring is then dearomatized via nucleophilic attack at C3 of the indole ring. This invention surpasses previously reported synthetic methods by using a metal carbonyl compound as a safe carbonyl source and avoiding the use of highly toxic carbon monoxide gas. It employs a one-pot method, is simple to operate, and uses readily available and inexpensive raw materials to synthesize 2-methyl-3-(o-bromobenzyl)indole as the reactant.

[0017] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) It uses solid metal carbonyl compounds as a safe carbonyl source to replace highly toxic carbon monoxide gas; (2) It completes the introduction of carbonyl and the construction of spirocyclic rings in a one-pot process, which is simple and convenient to operate; (3) It has a wide compatibility of functional groups; (4) It does not produce polluting byproducts; (5) It uses recyclable palladium catalysts to promote the formation of carbon-carbon new bonds under mild conditions, and constructs multifunctional all-carbon quaternary carbon cyclic ketone spirocyclic pseudoindole derivatives through intermolecular carbonylation and dearomatization, which is highly practical. Attached Figure Description

[0018] Figure 1 The 1H NMR spectra of compounds 2-8 are shown.

[0019] Figure 2 The carbon NMR spectra of compounds 2-8 are shown below.

[0020] Figure 3 The above are the 1H NMR spectra of compounds 2-9.

[0021] Figure 4NMR chart of compound 2-9;

[0022] Figure 5 NMR chart of compound 2-10;

[0023] Figure 6 NMR chart of compound 2-10;

[0024] Figure 7 NMR chart of compound 2-11;

[0025] Figure 8 NMR chart of compound 2-11;

[0026] Figure 9 NMR chart of compound 2-12;

[0027] Figure 10 NMR chart of compound 2-12;

[0028] Figure 11 NMR chart of compound 2-13;

[0029] Figure 12 NMR chart of compound 2-13;

[0030] Figure 13 NMR chart of compound 2-14;

[0031] Figure 14 NMR chart of compound 2-14;

[0032] Figure 15 NMR chart of compound 2-15;

[0033] Figure 16 NMR chart of compound 2-15;

[0034] Figure 17 NMR chart of compound 2-16;

[0035] Figure 18 NMR chart of compound 2-16;

[0036] Figure 19 General reaction process of the method of the present application. DETAILED DESCRIPTION

[0037] The technical solutions of the present application are further described below in combination with specific examples.

[0038] Example 1

[0039]

[0040] The 2-methyl-3-(o-bromobenzyl)indole derivative 1-1 (0.1 mmol), Co2(CO)8(0.1 mmol), 0.5% of palladium acetate (0.0005 mmol), bistrifurylphosphine butane (0.001 mmol) and potassium hydroxide (0.1 mmol) were mixed and reacted under heating, the reaction time being of 36 hours. The conversion of 1-1 was 95% and the yield of 2-1 was 80%. Figure 19 1 H NMR (500 MHz, CDC13) δ 7.85 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.5, 1H), 7.66 - 7.59 (m, 2H), 7.52 - 7.44 (m, 1H), 7.35 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 7.13 (td, J1= 7.5 Hz, J2= 1.1 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 3.62 (d, J = 17.7 Hz, 1H), 3.49 (d, J = 17.7 Hz, 1H), 2.16 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDC13) δ 200.3, 179.3, 156.4, 152.7, 140.6, 136.4, 135.8, 128.7, 128.2, 126.9, 125.8, 125.4, 121.1, 120.3, 72.4, 35.2, 16.4. HRMS (ESI) m / z: [M + H] + Calcd. for C 17 H 14 NO + 248.1070, Found 248.1076.

[0041] Example 2

[0042]

[0043] The 2-methyl-3-(o-bromobenzyl)indole derivative 1-2 (0.1 mmol), Co2(CO)8(2.5 mmol), 1% of palladium hydroxide (0.001 mmol), tricyclohexylphosphine (0.002 mmol) and sodium tert-butoxide (0.2 mmol) were mixed and reacted under heating, the reaction time being of 18 hours. The conversion of 1-2 was 95% and the yield of 2-2 was 78%. 1 ​H NMR (500 MHz, CDC13) δ 7.85 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.14 (d, J = 7.9 Hz, 1H), 6.80 (s, 1H), 3.60 (d, J = 17.6 Hz, 1H), 3.47 (d, J = 17.6 Hz, 1H), 2.28 (s, 3H), 2.13 (s, 3H). 13 C{ 1 H} NMR (125 MHz, CDC13) δ 200.7, 178.3, 154.2, 152.8, 140.8, 136.5, 135.78, 135.76, 129.3, 128.3, 126.9, 125.4, 121.9, 119.8, 72.3, 35.3, 21.3, 16.4. HRMS (ESI) m / z: [M + H] + Calcd. for C 18 H 16 NO + 262.1226, Found 262.1235.

[0044] Example 3

[0045]

[0046] Example 3 2-methyl-3-(o-bromobenzyl)indole derivative 1-3 (0.1 mmol), Co2(CO)8 (0.35 mmol), 10% palladium chloride (0.01 mmol), bistrifurylphosphine propane (0.024 mmol) and sodium tert-butoxide (0.2 mmol) were mixed and reacted under heating for 24 hours. The conversion of 1-3 was 92% and the yield of 2-3 was 82%. 1 H NMR (500 MHz, CDC13) δ 7.82 (d, J = 7.8 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.50 - 7.45 (m, 2H), 6.84 (dd, Ji = 8.5 Hz, J2= 2.6 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 3.70 (s, 3H), 3.59 (d, J = 17.6 Hz, 1H), 3.44 (d, J = 17.6 Hz, 1H), 2.10 (s, 3H). 13 C{ 1H NMR (125 MHz, CDC13) δ 200.4, 177.1, 158.4, 152.8, 150.0, 142.1, 136.4, 135.8, 128.3, 127.0, 125.4, 120.5, 113.3, 108.0, 72.5, 55.7, 35.5, 16.3. HRMS (ESI) m / z: [M + H] + Calcd. for C 18 H 16 NO2 + 278.1176, Found 278.1183.

[0047] Example 4

[0048]

[0049] Example 5 The 2-methyl-3-(o-bromobenzyl)indole derivative 1-4 (0.1 mmol), Co2(CO)8(0.05 mmol), 1% palladium trifluoroacetate (0.001 mmol), bis-triphenylphosphine propane (0.0016 mmol) and potassium hydroxide (0.2 mmol) were mixed and reacted under heating for 30 hours. The conversion of 1-4 was 95% and the yield of 2-4 was 81%. 1 H NMR (125 MHz, CDC13) δ 200.4, 177.1, 158.4, 152.8, 150.0, 142.1, 136.4, 135.8, 128.3, 127.0, 125.4, 120.5, 113.3, 108.0, 72.5, 55.7, 35.5, 16.3. HRMS (ESI) m / z: [M + H] 13 C{ 1 H NMR (125 MHz, CDC13) δ 200.4, 177.1, 158.4, 152.8, 150.0, 142.1, 136.4, 135.8, 128.3, 127.0, 125.4, 120.5, 113.3, 108.0, 72.5, 55.7, 35.5, 16.3. HRMS (ESI) m / z: [M + H] + Calcd. for C 18 H 16 ClNO + 282.0680, Found 282.0691.

[0050] Example 5 The 2-methyl-3-(o-bromobenzyl)indole derivative 1-4 (0.1 mmol), Co2(CO)8(0.05 mmol), 1% palladium trifluoroacetate (0.001 mmol), bis-triphenylphosphine propane (0.0016 mmol) and potassium hydroxide (0.2 mmol) were mixed and reacted under heating for 30 hours. The conversion of 1-4 was 95% and the yield of 2-4 was 81%.

[0051]

[0052] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivatives 1-5 (0.1 mmol), Co2(CO)8 (0.05 mmol), 10% palladium bis(acetonitrile)chloride (0.01 mmol), triphenylphosphine (0.02 mmol), and sodium methoxide (0.5 mmol) was reacted under heating for 24 hours. The conversion of 1-5 was 90%, and the yield of 2-5 was 76%. 1 H NMR(500MHz, CDCl3)δ7.62(s,1H),7.58(d,J=7.8Hz,1H),7.56–7.50(m,2H),7.34–7.30(m,1H),7.11(t,J=7 .5Hz,1H),6.98(d,J=7.4Hz,1H),3.54(d,J=17.5Hz,1H),3.42(d,J=17.5Hz,1H),2.45(s,3H),2.14(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ200.4,179.5,156.4,150.2,140.8,138.4,137.1,136.6,128 .6,126.6,125.8,125.3,121.1,120.2,72.8,34.9,21.1,16.4.HRMS(ESI)m / z:[M+H] + Calcd.for C 18 H 16 NO + 262.1226, Found 262.1235.

[0053] Example 6

[0054]

[0055] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivatives 1-6 (0.1 mmol), Co₂(CO)₈ (0.2 mmol), 2.5% palladium acetate (0.0025 mmol), bis(triphenylphosphine)butane (0.005 mmol), and potassium tert-butoxide (0.2 mmol) was reacted under heating for 24 hours. The conversion of 1-6 was 95%, and the yield of 2-6 was 81%. 1 H NMR (500MHz, CDCl3) 1H NMR (500MHz, CDCl3) δ7.73(d,J=7.8Hz,1H),7.59(d,J=7.7Hz,1H),7.44(s,1H),7.36–7.28(m,2H),7.12(t,J =7.5Hz,1H),7.00(d,J=7.3Hz,1H),3.56(d,J=17.6Hz,1H),3.43(d,J=17.6Hz,1H),2.52(s,3H),2.15(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ199.7,179.6,156.4,153.3,147.4,140.8,134.2,129.6,128 .6,127.3,125.8,125.3,121.1,120.3,72.6,35.1,22.2,16.4.HRMS(ESI)m / z:[M+H] + Calcd.for C 18 H 16 NO + 262.1226, Found 262.1234.

[0056] Example 7

[0057]

[0058] The following were added: 2-methyl-3-(o-bromobenzyl)indole derivative 1-7 (0.1 mmol), Co2(CO)8 (0.3 mmol), 1% palladium acetate (0.001 mmol), and Ad2P. n Bu (0.0024 mmol) and sodium ethoxide (0.8 mmol) were mixed and reacted under heating for 18 hours. The conversion of 1-7 was 95%, and the yield of 2-7 was 76%. 1 H NMR (500MHz, CDCl3) δ7.58(d,J=7.7Hz,1H),7.51(d,J=8.4Hz,1H),7.35–7.30(m,2H),7.25(d,J=2.5Hz,1H),7.12 (t,J=7.5Hz,1H),7.00(d,J=7.4Hz,1H),3.85(s,3H),3.51(d,J=17.3Hz,1H),3.39(d,J=17.3Hz,1H),2.14(s,3H). 13 C{ 1H}NMR (125MHz, CDCl3) δ200.3,179.4,160.1,156.4,145.6,140.7,137.7,128.7,127 .6,125.8,125.3,121.1,120.3,106.4,73.2,55.7,34.5,16.4.HRMS(ESI)m / z:[M+H] + Calcd.for C 18 H 16 NO2 + 278.1176, Found 278.1184.

[0059] Example 8

[0060]

[0061] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivative 1-8 (0.1 mmol), Co₂(CO)₈ (0.85 mmol), 1% palladium acetate (0.001 mmol), bis(triphenylphosphine)butane (0.002 mmol), and potassium hydroxide (0.3 mmol) was reacted under heating for 36 hours. The conversion of 1-8 was 95%, and the yield of 2-8 was 71%. The 1H and 1C NMR spectra are shown below. Figures 1-2 As shown. 1 H NMR (500MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.64(s,1H),7.59(d,J=Hz,1H),7.48-7.46(m,1H),7.34(dt,J1=7.6Hz,J2=1.2Hz ,1H),7.12(dt,J1=8.7Hz,J2=1.1Hz,1H),6.98(d,J=7.4Hz,1H),3.57(d,J=17.9Hz,1H),3.45(d,J=17.9Hz,1H),2.15(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ198.8,178.7,156.3,154.1,142.5,140.2,134.8,129.1, 128.8,127.1,126.3,125.9,121.0,120.3,72.3,34.7,16.3.HRMS(ESI)m / z:[M+H] + Calcd.for C 17 H 13 ClNO + 282.0680, Found 282.0689.

[0062] Example 9

[0063]

[0064] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivatives 1-9 (0.1 mmol), Co₂(CO)₈ (0.5 mmol), 5% palladium hydroxide (0.005 mmol), tricyclohexylphosphine (0.012 mmol), and sodium hydroxide (0.2 mmol) was reacted under heating for 28 hours. The conversion of 1-9 was 96%, and the yield of 2-9 was 73%. The 1H and 1C NMR spectra are shown below. Figures 3-4 As shown. 1 H NMR (500MHz, CDCl3) δ7.64-7.52(m,3H),7.44(d,J=7.6Hz,1H),7.34(dt,J1=7.7Hz,J2=1.3Hz,1H),7.1 2(t,J=7.6Hz,1H),6.98(d,J=7.4Hz,1H),3.58(d,J=17.7Hz,1H),3.42(d,J=17.7Hz,1H),2.18(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ196.8,178.8,156.2,154.8,140.4,135.9,133.4,132.4, 129.9,128.8,125.8,125.2,121.0,120.3,72.7,34.4,16.5.HRMS(ESI)m / z:[M+H] + Calcd.for C 17 H 13 ClNO + 282.0680, Found282.0683.

[0065] Example 10

[0066]

[0067] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivative 1-10 (0.1 mmol), Co₂(CO)₈ (0.8 mmol), 10% palladium chloride (0.01 mmol), bis(triphenylphosphine propane) (0.016 mmol), and n-butyllithium (0.5 mmol) was reacted under heating for 18 hours. The conversion of 1-10 was 90%, and the yield of 2-10 was 69%. The 1H and 1C NMR spectra are shown below. Figures 5-6 As shown. 1H NMR (500MHz, CDCl3) δ7.76-7.73(m,2H),7.61(d,J=7.8Hz,1H),7.48(t,J=7.7Hz,1H),7.36(dt,J1=7.7Hz,J2=1.2 Hz,1H),7.15(t,J=7.5Hz,1H),7.0(d,J=7.5Hz,1H),3.59(d,J=18.3Hz,1H),3.48(d,J=18.3Hz,1H),2.17(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ199.4,178.6,156.3,150.3,140.2,138.2,135.4,133.2, 129.9,128.9,126.0,123.6,121.1,120.4,72.1,34.1,16.4.HRMS(ESI)m / z:[M+H] + Calcd.for C 17 H 13 ClNO + 282.0680, Found 282.0686.

[0068] Example 11

[0069]

[0070] A mixture of 0.1 mmol of 2-methyl-3-(o-bromobenzyl)indole derivative 1-11, 1.0 mmol of Co₂(CO)₈, 0.001 mmol of 1% palladium trifluoroacetate, 0.002 mmol of bis(triphenylphosphine propane), and 0.5 mmol of potassium hydroxide was reacted under heating for 18 hours. The conversion of 1-11 was 95%, and the yield of 2-11 was 72%. The 1H and 1C NMR spectra are shown below. Figures 7-8 As shown. 1 H NMR (500MHz, CDCl3) δ7.96-7.94(m,2H),7.76(d,J=8.0Hz,1H),7.61(d,J=7.8Hz,1H),7.36(dt,J1=7.8Hz,J2=1.3 Hz,1H),7.14(t,J=7.5Hz,1H),6.94(d,J=7.4Hz,1H),3.68(d,J=17.9Hz,1H),3.55(d,J=17.9Hz,1H),2.16(s,3H). 13 C{ 1H}NMR(125MHz,CDCl3)δ199.4,178.3,156.3,152.8,140.0,138.9,137.0(q,J C-F =32.5Hz),129.0,126.0,125.9,125.4(q,J C-F =3.8Hz), 124.1, (q, J C-F =3.8Hz), 123.4(q,J C-F =271.3Hz),121.0,120.5,72.4,35.1,16.4.HRMS(ESI)m / z:[M+H] + Calcd.for C 18 H 13 F3NO + 316.0944, Found 316.0952.

[0071] Example 12

[0072]

[0073] A mixture of 0.1 mmol of 2-methyl-3-(o-bromobenzyl)indole derivative 1-12, 0.5 mmol of Co2(CO)8, 0.01 mmol of 10% bis(acetonitrile)palladium chloride, 0.018 mmol of triphenylphosphine, and 0.6 mmol of diethylamine was reacted under heating for 48 hours. The conversion of 1-12 was 93%, and the yield of 2-12 was 79%. The 1H and 1C NMR spectra are shown below. Figures 9-10 As shown. 1 H NMR (500MHz, CDCl3) δ8.51(s,1H),8.36-8.33(m,1H),7.99(d,J=8.3Hz,1H),7.61(d,J=7.8Hz,1H),7.39-7.36(m ,1H),7.15(t,J=7.15Hz,1H),6.97(d,J=7.4Hz,1H),3.59(d,J=18.0Hz,1H),3.72(d,J=18.0Hz,1H),2.17(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ198.8,177.9,156.2,153.4,152.4,140.3,139.7,129.2, 126.3,126.1,123.7,122.3,120.9,120.6,72.6,35.0,16.5.HRMS(ESI)m / z:[M+H] + Calcd.for C17 H 13 N2O3 + 293.0921, Found 293.0929.

[0074] Example 13

[0075]

[0076] A mixture of 2-methyl-3-(o-bromobenzyl)indole derivative 1-13 (0.1 mmol), Co₂(CO)₈ (0.05 mmol), 1% palladium acetate (0.001 mmol), bis(triphenylphosphine)butane (0.0024 mmol), and diethylamine (0.2 mmol) was reacted under heating for 30 hours. The conversion of 1-13 was 95%, and the yield of 2-13 was 83%. The 1H and 1C NMR spectra are shown below. Figures 11-12 As shown. 1 H NMR(500MHz, CDCl3)δ7.60(d,J=7.8Hz,1H),7.34(dt,J1=7.6Hz,J2=1.3Hz,1H),7.24(s,1H),7.14(t,J=7.5Hz, 1H),7.04-7.02(m,2H),4.04(s,3H),3.94(s,3H),3.51(d,J=17.5Hz,1H),3.40(d,J=17.5Hz,1H),2.15(s,3H). 13 C{ 1 H}NMR (125MHz, CDCl3) δ198.6,179.7,156.4,156.3,150.1,148.2,140.7,129.3,128.6 ,125.8,121.1,120.2,107.5,105.5,72.7,56.4,56.2,34.9,16.2.HRMS(ESI)m / z:[M+H] + Calcd.forC 19 H 18 NO3 + 308.1281, Found 308.1286.

[0077] Example 14

[0078]

[0079] The following were added: 2-methyl-3-(o-bromobenzyl)indole derivative 1-14 (0.1 mmol), Co2(CO)8 (0.3 mmol), 10% palladium acetate (0.01 mmol), and Ad2P. nBu (0.02 mmol) and sodium ethoxide (0.5 mmol) were mixed and reacted under heating for 12 hours. The conversion of 1-14 was 95%, and the yield of 2-14 was 85%. The 1H and 1C NMR spectra are shown below. Figures 13-14 As shown. 1 H NMR (500MHz, CDCl3) δ9.02(d,J=8.3Hz,1H),8.20(dJ=8.4Hz,1H),7.98(d,J=8.2Hz,1H),7.71-7.41(m,4H),7.36(dt,J1=7.8 Hz,J2=1.3Hz,1H),7.13(t,J=7.5Hz,1H),7.03(d,J=7.4Hz,1H),3.71(d,J=18.1Hz,1H),3.59(d,J=18.0Hz,1H),2.19(s,3H) 13 C{ 1 H}NMR(125MHz, CDCl3)δ200.2,179.5,156.5,156.4,140.6,137.0,133.0,130.8,129.8,129.6, 128.6,128.3,127.3,125.8,124.0,123.7,121.0,120.2,72.8,35.4,16.3.HRMS(ESI)m / z:[M+H] + Calcd.for C 21 H 16 NO + 298.1226, Found298.1234.

[0080] Example 15

[0081]

[0082] 0.1 mmol of 2-phenyl-3-(o-bromobenzyl)indole 1-15, 0.05 mmol of Co₂(CO)₈, 0.005 mmol of 5% palladium acetylacetonate, 0.008 mmol of tricyclohexylphosphine, and 0.5 mmol of triethylamine were mixed and reacted under heating for 42 hours. The conversion of 1-15 was 92%, and the yield of 2-15 was 71%. The 1H and 1C NMR spectra are shown below. Figures 15-16 As shown. 1H NMR (500MHz, CDCl3) δ7.96 (d, J=7.7Hz, 1H), 7.81-7.76 (m, 2H), 7.69-7.66 (m, 3H), 7.57 (t, J=7.8Hz, 1H), 7.43-7.3 3(m,4H),7.13(dt,J1=7.5Hz,J2=1.1Hz,1H),6.91(d,J=7.4Hz,1H),3.84(d,J=17.7Hz,1H),3.51(d,J=17.7Hz,1H) 13 C{ 1 H}NMR (125MHz, CDCl3) δ200.2,177.2,155.8,152.5,142.0,136.4,135.8,131.7,131.1,128. 9,128.8,128.4,127.9,127.3,126.3,125.9,121.3,120.1,70.5,37.6.HRMS(ESI)m / z:[M+H] + Calcd.for C 22 H 16 NO + 310.1226, Found 310.1232.

[0083] Example 16

[0084]

[0085] 2-(4-fluorophenyl)-3-(o-bromobenzyl)indole 1-16 (0.1 mmol), Co2(CO)8 (0.2 mmol), 10% tetraphenylphosphine palladium (0.01 mmol), and sodium ethoxide (0.9 mmol) were mixed and reacted under heating for 46 hours. The conversion of 1-16 was 93%, and the yield of 2-16 was 72%. The 1H and 1C NMR spectra are shown below. Figures 17-18 As shown. 1 H NMR (500MHz, CDCl3) δ7.95 (d, J = 7.7Hz, 1H), 7.81-7.56 (m, 5H), 7.57 (t, J = 7.3Hz, 1H), 7.39 (dt, J1 = 7.8Hz, J2 = 1.2Hz, 1H), 7 .13(dt,J1=7.5Hz,J2=1.1Hz,1H),7.05-7.02(m,2H),6.91(d,J=7.3Hz,1H),3.79(d,J=17.7Hz,1H),3.52(d,J=17.7Hz,1H). 13 C{ 1H}NMR(125MHz,CDCl3)δ200.0,175.9,164.5(d,J C-F =251.3Hz),155.7,152.4,141.9,136.2,136.0,130.0(d,J C-F =8.8Hz),128.9,128.5,128.1(d,J C-F =2.5Hz),127.3,126.3,125.9,121.2,120.1,116.1(d,J C-F =21.3Hz),70.4,37.6.HRMS(ESI)m / z:[M+H] + Calcd.for C 22 H 15 FNO + 328.1132,Found 328.1143。

Claims

1. A method for the synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives, characterized by, Using a carbonyl metal compound as a safe carbonyl source, a one-step reaction is employed to simultaneously introduce the carbonyl group and construct the spirocyclic ring. The reaction proceeds as follows: Compound 1 is mixed with the carbonyl metal compound Co2(CO)8, and a palladium catalyst, a phosphine ligand, and a base are added. The palladium catalyst is any one of palladium acetate, palladium hydroxide, palladium chloride, palladium trifluoroacetate, palladium bis(acetonitrile)chloride, palladium tetrate-triphenylphosphine, or palladium acetylacetonate. The phosphine ligand is any one of adamantanephosphine, bis(triphenylphosphine propane), tricyclohexylphosphine, or bis(triphenylphosphine butane). The base is any one of potassium hydroxide, sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, sodium hydroxide, n-butyllithium, sodium ethoxide, triethylamine, or diethylamine. After reacting in a solvent, the target compound 2 is obtained, as shown in the following reaction formula: ； wherein R 1 is hydrogen, fluorine, chlorine, alkyl or alkoxy; R 2 is hydrogen, fluorine, chlorine, nitro, trifluoromethyl, phenyl, alkyl or alkoxy; R 3 is alkyl, phenyl or halogenated phenyl.

2. The process for the synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, characterized in that, The molar ratio of compound 1 to the carbonyl metal compound is 1:0.5~100.

3. The process for the synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, characterized in that, The solvent is toluene, chlorobenzene, xylene, fluorobenzene, or trifluorotoluene.

4. The process for the synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, characterized in that, The molar ratio of compound 1 to the catalyst is 1:0.005 to 1:0.

3.

5. The method of synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, wherein, The reaction is carried out at room temperature to 150 o C.

6. The method of synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, wherein, The reaction time is 1-48 hours.

7. The method of synthesis of all-carbon quaternary carbon cyclic ketospiro pseudoindole derivatives according to claim 1, wherein, The yield of the target compound was 69-85%.

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