CN116730896A - Synthesis method for introducing trans-isopentenyl into C3 position of indole - Google Patents
Synthesis method for introducing trans-isopentenyl into C3 position of indole Download PDFInfo
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- CN116730896A CN116730896A CN202310367975.7A CN202310367975A CN116730896A CN 116730896 A CN116730896 A CN 116730896A CN 202310367975 A CN202310367975 A CN 202310367975A CN 116730896 A CN116730896 A CN 116730896A
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- indole
- isopentenyl
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 25
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 19
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 125000001041 indolyl group Chemical group 0.000 title claims abstract description 13
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 150000002941 palladium compounds Chemical class 0.000 claims abstract description 5
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 4
- 238000005859 coupling reaction Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 31
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 13
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 12
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 12
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 9
- -1 trans-isopentenyl indole compound Chemical class 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 54
- 239000007858 starting material Substances 0.000 abstract description 13
- 238000007306 functionalization reaction Methods 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- PJEDQEWEWIHEHN-UHFFFAOYSA-N 2-(3-methylbut-3-enyl)-1h-indole Chemical class C1=CC=C2NC(CCC(=C)C)=CC2=C1 PJEDQEWEWIHEHN-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YBFCBQMICVOSRW-UHFFFAOYSA-N 1-phenylindole Chemical compound C1=CC2=CC=CC=C2N1C1=CC=CC=C1 YBFCBQMICVOSRW-UHFFFAOYSA-N 0.000 description 2
- ADZUEEUKBYCSEY-UHFFFAOYSA-N 1h-indole-5-carbaldehyde Chemical compound O=CC1=CC=C2NC=CC2=C1 ADZUEEUKBYCSEY-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- RTOYKOQOXPAKPD-UHFFFAOYSA-N 5-chloro-1-phenylindole Chemical compound C1=CC2=CC(Cl)=CC=C2N1C1=CC=CC=C1 RTOYKOQOXPAKPD-UHFFFAOYSA-N 0.000 description 1
- OOCUGGYSDYJACZ-UHFFFAOYSA-N 5-methoxy-1-phenylindole Chemical compound C1=CC2=CC(OC)=CC=C2N1C1=CC=CC=C1 OOCUGGYSDYJACZ-UHFFFAOYSA-N 0.000 description 1
- PBEQDISFTDAYCG-UHFFFAOYSA-N 6-bromo-1-phenylindole Chemical compound C12=CC(Br)=CC=C2C=CN1C1=CC=CC=C1 PBEQDISFTDAYCG-UHFFFAOYSA-N 0.000 description 1
- HAPBEDLLNHVEHW-UHFFFAOYSA-N 6-methyl-1-phenylindole Chemical compound C12=CC(C)=CC=C2C=CN1C1=CC=CC=C1 HAPBEDLLNHVEHW-UHFFFAOYSA-N 0.000 description 1
- DEKFKHAGUJJGBA-UHFFFAOYSA-N 6-nitro-1-phenylindole Chemical compound C12=CC([N+](=O)[O-])=CC=C2C=CN1C1=CC=CC=C1 DEKFKHAGUJJGBA-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a synthesis method for introducing trans-isopentenyl into an indole C3 position, which takes indole and 2-methyl-2-butene as starting materials, palladium compounds as catalysts, and can introduce trans-isopentenyl into the indole C3 position with high regioselectivity and chemical selectivity through direct oxidative dehydrogenation coupling reaction. Compared with the traditional method for introducing trans-isopentenyl into the C3 position of indole, the method provided by the invention has the advantages of simplicity in operation, low price of used reagents, mild reaction conditions, no need of pre-functionalization of a substrate, no need of using a ligand and high atom utilization rate.
Description
Technical Field
The invention relates to a novel synthesis method for introducing trans-isopentenyl into an indole C3 position, and belongs to the field of organic synthesis.
Background
Isopentenyl indole alkaloids are an important class of organic compounds, which are widely found in plants, fungi, bacteria and marine organisms and which generally have excellent biological and medicinal activities. Isopentenyl indole alkaloids as drugs often exhibit a distinct and more diverse drug and pharmacological activity than their non-isopentenyl indole alkaloid precursors. Studies have shown that the introduction of isopentenyl building blocks into drug molecules can enhance their lipophilicity and permeability across cell membranes. Currently, strategies for introducing isopentenyl into the C3 position of indole are mainly realized through nucleophilic substitution, friedel-Crafts alkylation reaction and metal-catalyzed allylation reaction. These strategies either require pre-functionalization of the substrate or use a leaving group containing C5 olefin as starting material, which does not meet the economic requirements of atoms and steps and results in higher reaction costs. Therefore, these conventional methods have a great improvement in terms of step simplicity, atom economy, cost reduction, and the like.
The prenylation reaction of the C3 position of indole is a long-standing research topic in organic chemistry and has attracted considerable attention from chemists. The transition metal catalyzed direct oxidative dehydrogenation cross-coupling reaction can directly construct a new C-C bond by breaking two C-H bonds, and the reaction can avoid the pre-functionalization of raw materials, thereby simplifying the synthesis scheme and simultaneously conforming to the atomic economy principle. The invention firstly proposes that the large-scale chemical 2-methyl-2-butene with huge absolute yield generated by the petroleum hydrocarbon high-temperature cracking process is used as a C5 source for directly dehydrogenating and introducing trans-isoamylene at the C3 position of indole, thereby realizing the value-added development and utilization of the 2-methyl-2-butene in the C5 distillate, simultaneously reducing the cost of introducing trans-isoamylene at the C3 position of indole, reducing the resource waste and meeting the synthesis requirements of the green process. The reaction has the characteristics of mild reaction conditions, avoidance of ligand addition, high regioselectivity and site selectivity, and is considered to be an ideal chemical reaction.
Disclosure of Invention
The invention aims to provide a synthesis method for introducing trans-isopentenyl into an indole C3 position, which has the advantages of simple operation, low cost, high efficiency, high atom utilization rate and high regioselectivity.
The implementation process of the invention is as follows:
a method for introducing trans-isopentenyl at the C3 position of indole: the compound (A) and 2-methyl-2-butene (B) are used as initial raw materials, palladium compound is used as catalyst, copper sulfate is used as oxidant, acetonitrile, acetic acid and hexafluoroisopropanol are used as mixed solvent, the trans-isopentenyl indole compound (C) is prepared through direct oxidative dehydrogenation coupling reaction,
wherein R is 1 Phenyl, naphthyl or hydrogen; r is R 2 Is H, C1-C20 alkyl, alkoxy or aldehyde, C2-C20 ester, halogen or nitro.
The above mentioned materials are takenThe substituents are preferably: r is R 1 Phenyl, naphthyl or hydrogen; r is R 2 Is H, C1-C5 alkyl, alkoxy or aldehyde, C2-C6 ester, halogen or nitro.
The palladium compound catalyst is tris (dibenzylideneacetone) dipalladium or palladium trifluoroacetate.
In the mixed solvent, the volume ratio of acetonitrile, acetic acid and hexafluoroisopropanol is 1.4: (0.2-0.6): (0.2-0.6).
The invention has the advantages that: compared with the traditional synthesis method for introducing trans-isopentenyl into the C3 position of indole, the method has the advantages of mild reaction conditions, low raw material cost, high efficiency, high atom utilization rate and high product regioselectivity.
Detailed Description
The synthesis method of the invention comprises the following steps: palladium catalyst (10 mol%) and an oxidant, indole, were added sequentially to the sealed tube, followed by the solvent, 2-methyl-2-butene. And then sealing the reaction tube, and putting the reaction tube into an oil bath pot with the temperature of 60 ℃ to stir for 6-18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the trans-isopentenyl indole compound.
Examples
Compound C-1
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 6-methyl-1-phenyl-1HIndole (41.4 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 6 hours.The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-1. (31 mg, 56%).
Compound C-1: yellow oil; IR 2964, 2922, 2360, 2341, 1597, 1501, 1459, 1276, 1261, 765, 751, 699 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d,J= 8.2 Hz, 1H), 7.50 (d,J= 1.7 Hz, 2H), 7.51-7.47 (m, 2H), 7.36 – 7.30 (m, 2H), 7.05 (s, 1H), 6.95 (d,J= 8.1 Hz, 1H), 6.16 (dd,J= 17.4, 10.5 Hz, 1H), 5.12 (d,J= 17.4 Hz, 1H), 5.05 (d,J= 10.5 Hz, 1H), 2.43 (s, 3H), 1.54 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 147.7, 140.2, 137.5, 132.0, 129.6 (2C), 126.2, 125.4, 124.8, 124.5 (2C), 123.8, 121.5, 121.3, 110.9, 110.6, 37.7, 28.2 (2C), 21.9; HRMS (ESI) m/z calculated for for C 20 H 21 NNa [M+Na] + : 298.1566; Found: 298.1553。
Examples
Compound C-2
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 5-methoxy-1-phenyl-1HIndole (44.6 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.4 mL) and hexafluoroisopropanol (0.4 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 6 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, followed by addition of ethyl acetate, washing with water and brine, respectivelyAnd (3) a mixture. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-2. (36 mg, 61%).
Compound C-2: yellow oil; IR 2962, 2923, 2361, 2341, 1597, 1503, 1478, 1157, 796, 751, 700 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 5.8 Hz, 4H), 7.46 (d, J = 9.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 9.0, 2.3 Hz, 1H), 6.12 (dd, J = 17.4, 10.5 Hz, 1H), 5.12 (d, J = 17.4 Hz, 1H), 5.05 (d, J = 10.5 Hz, 1H), 3.76 (s, 3H), 1.50 (s, 6H); 13 C NMR (101 MHz, DMSO-d6) δ 153.7, 147.6, 139.7, 131.6, 130.2 (2C), 128.1, 126.3, 125.4, 123.9, 123.8 (2C), 111.8, 111.7, 111.3, 104.1, 55.9, 37.5, 28.1 (2C); HRMS (ESI) m/z calculatedfor C 20 H 22 NO [M+H] + : 292.1696; Found: 292.1684。
Examples
Compound C-3
In a 15mL sealed tube, sequentially: palladium trifluoroacetate (6.6 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), indole-5-carbaldehyde (29.0 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.25 mL) and hexafluoroisopropanol (0.25 mL) were added separately, followed by 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-3. (26.9 mg, 63%).
Compound C-3: yellow solid, melting point 81-82 o C；IR: 1673, 1606, 1573, 1413, 1377, 1261, 749, 689 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.75 (dd, J = 8.5, 1.4 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.14 (dd, J = 17.4, 10.5 Hz, 1H), 5.10 (d, J = 13.6 Hz, 1H), 5.06 (d, J = 6.7 Hz, 1H), 1.54 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 192.9, 147.4, 140.8, 129.0, 127.2, 126.1, 126.0, 122.2, 122.0, 112.0, 111.5, 37.7, 28.4 (2C); HRMS (ESI) m/z calculated for C 14 H 14 NO [M-H] - : 212.1081; Found: 212.1072。
Examples
Compound C-4
In a 15mL sealed tube, sequentially: palladium trifluoroacetate (6.6 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), indole-6-carboxylic acid methyl ester (35.0 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.4 mL) and hexafluoroisopropanol (0.5 mL) were added separately, followed by the final addition of 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-4. (37.9 mg, 78%).
Compound C-4: yellow solid, melting point 141-142 o C；IR (KBr): 3347, 2960, 2925, 1692, 1435, 1318, 1276, 1217, 1088, 765, 750 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 8.12 (s, 1H), 7.74 (d, J = 2.1 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.11 (dd, J = 17.4, 10.5 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 3.4 Hz, 1H), 3.93 (s, 3H), 1.51 (s, 6H); 13 C NMR (101MHz, CDCl 3 ) δ 168.5, 147.4, 136.5, 129.7, 124.3, 123.9, 123.2, 121.0, 119.9, 113.8, 111.1, 52.1, 37.6, 28.2 (2C); HRMS (ESI) m/z calculated for C 15 H 17 NNaO 2 [M+Na] + : 266.1151; Found: 266.1142。
Examples
Compound C-5
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv),N- (2-naphthalene) -indole (48.6 mg,0.2 mmol,1 equiv), followed by addition of acetonitrile (1.4 mL), acetic acid (0.5 mL) and hexafluoroisopropanol (0.4 mL), respectively, and finally addition of 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 6 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-5. (33 mg, 53%).
Compound C-5: yellow oil; IR 3357, 2962, 2922, 2853, 1703, 1439, 1279, 1212, 1140, 903, 747 cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ 7.96 (d,J= 8.7 Hz, 1H), 7.93 – 7.85 (m, 3H), 7.80 (d,J= 8.0 Hz, 1H), 7.66 (dd,J= 8.7, 2.2 Hz, 1H), 7.62 (d,J= 8.2 Hz, 1H), 7.52 (m, 2H), 7.24 – 7.19 (m, 2H), 7.16 – 7.12 (m, 1H), 6.20 (dd,J= 17.4, 10.5 Hz, 1H), 5.16 (dd,J= 17.4, 1.3 Hz, 1H), 5.08 (dd,J= 10.5, 1.3 Hz, 1H), 1.59 (s, 6H). 13 C NMR (101 MHz, CDCl 3 )δ 147.6, 137.5, 137.2, 134.0, 131.8, 129.6, 128.0, 127.8, 127.7, 127.0, 126.1, 125.2, 124.5, 123.5, 122.3, 122.0, 121.9, 119.7, 111.1, 110.8, 37.7, 28.2 (2C). HRMS (ESI) m/z calculated for C 23 H 22 N [M+H] + : 312.1747, Found: 312.1749。
Examples
Compound C-6
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 6-bromo-1-phenyl-1HIndole (54.2 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-6. (34 mg, 50%).
Compound C-6: yellow oil, IR 2962, 2925, 1595, 1502, 1459, 1439, 1226, 1145, 914, 801, 760, 697 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (s, 1H), 7.61 (d,J= 8.6 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.46 (d,J= 7.4 Hz, 2H), 7.38 – 7.34 (m, 1H), 7.21 (d,J= 8.6 Hz, 1H), 7.09 (s, 1H), 6.13 (dd,J= 17.4, 10.5 Hz, 1H), 5.11 (d,J= 17.6 Hz, 1H), 5.07 (d,J= 11.0 Hz, 1H), 1.53 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 147.3, 139.4, 137.8, 129.9 (2C), 126.8, 126.3, 124.97, 124.95, 124.6 (2C), 123.1, 122.8, 116.0, 113.6, 111.3, 37.6, 28.2 (2C). HRMS (ESI) m/z calculated for C 19 H 18 BrNNa [M+Na] + : 362.0515, Found: 362.0521。
Examples
Compound C-7
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 5-chloro-1-phenyl-1HIndole (45.4 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.5 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-7. (29 mg, 50%).
Compound C-7: yellow solid, melting point 141-142 o C; IR: 3431, 2965, 2927, 2361, 2342, 1463, 1276, 1261, 1070, 915, 764, 751 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (d,J= 1.9 Hz, 1H), 7.52 – 7.40 (m, 6H), 7.35 (d,J= 7.1 Hz, 1H), 7.14 (s, 1H), 6.13 (dd,J= 17.4, 10.5 Hz, 1H), 5.13 (dd,J= 17.4, 1.3 Hz, 1H), 5.08 (dd,J= 10.5, 1.3 Hz, 1H), 1.53 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 147.2, 139.6, 135.4, 129. 8 (2C), 128.5, 126.7, 125.6, 125.1, 124.5, 124.4 (2C), 122.4, 121.2, 111.7, 111.5, 37.6, 28.2 (2C). HRMS (ESI) m/z calculated for C 19 H 18 ClNNa [M+Na] + : 318.1020, Found: 318.1024。
Examples
Compound C-8
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 6-nitro-1-phenyl-1HIndole (38.6 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.5 mL) and hexafluoroisopropanol (0.3 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-8. (41 mg, 68%).
Compound C-8: yellow oil, IR 2956, 2924, 2360, 1502, 1462, 1336, 1276, 1261, 764, 750 cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ 8.41 (d,J= 2.0 Hz, 1H), 8.00 (dd,J= 8.9, 2.1 Hz, 1H), 7.81 (d,J= 8.9 Hz, 1H), 7.56 (d,J= 7.4 Hz, 2H), 7.52 – 7.48 (m, 2H), 7.45 (d,J= 7.3 Hz, 1H), 7.40 (s, 1H), 6.14 (dd,J= 17.4, 10.6 Hz, 1H), 5.14 (dd,J= 10.2, 1.2 Hz, 1H), 5.10 (dd,J= 3.5, 1.2 Hz, 1H), 1.57 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 146.8, 142.9, 138.6, 135.8, 132.0, 130.2, 130.1 (2C), 127.7, 125.6, 124.8 (2C), 121.8, 114.9, 111.8, 107.7, 38.3, 28.2 (2C). HRMS (ESI) m/z calculated for C 19 H 19 N 2 O 2 [M+H] + : 307.1441, Found: 307.1446。
Examples
Compound C-9
In a 15mL sealed tube, sequentially: palladium acetate (3.3 mg,10 m)Mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 1-phenyl-1HIndole (35.0 mg,0.2 mmol,1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL) were added separately, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 ℃ for stirring for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, separating and purifying by column chromatography to obtain the compound C-9. (32 mg, 42%).
Compound C-9: yellow oil, IR 2923, 2868, 1597, 1502, 1458, 1376, 1229, 911, 742, 697 and 697 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d,J= 7.9 Hz, 1H), 7.54 (d,J= 8.2 Hz, 1H), 7.51 – 7.45 (m, 4H), 7.33 – 7.28 (m, 1H), 7.19 (d,J= 6.9 Hz, 1H), 7.15 – 7.09 (m, 2H), 6.17 (dd,J= 17.4, 10.5 Hz, 1H), 5.14 (dd,J= 17.4, 1.4 Hz, 1H), 5.06 (dd,J= 10.5, 1.0 Hz, 1H), 1.56 (s, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 147.6, 140.0, 136.9, 129.7 (2C), 127.6, 126.3, 124.9, 124.4 (2C), 124.3, 122.1, 121.9, 119.6, 111.0, 110.7, 37.7, 28.2 (2C). HRMS (ESI) m/z calculated for C 19 H 19 NNa [M+Na] + : 284.1410, Found: 284.1404。
Examples
Taking the synthesis of the compound C-9 as an example, different solvents are selected for carrying out synthesis experiments.
In a 15mL sealed tube, sequentially: tris (dibenzylideneacetone) dipalladium (18.3 mg,10 mol%), copper sulfate (63.8 mg,0.4 mmol,2 equiv), 1-phenyl-1HIndole (35.0 mg,0.2 mmol,1 equiv), then 2mL of the solvents listed below (see brackets for ratios of solvents), respectively, were added, and finally 2-methyl-2-butene (84)μL,1.0 mmol,5 equiv). Then sealing the reaction tube, and placing the reaction tube into an oil bath with the temperature of 60 DEG CThe mixture was stirred in the pan for 18 hours. The reaction was checked by TLC plate until the starting material was complete. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added, and the mixture was washed with water and brine, respectively. Then using anhydrous Na 2 SO 4 The organic phase was dried and then concentrated in vacuo. Finally, the compound C-9 is obtained by column chromatography separation and purification, and the yield is shown in table 1.
TABLE 1 Experimental results of Synthesis Using different solvents
| Numbering device | Solvent (volume ratio) | Yield (%) |
| 1 | CH 3 CN:HOAc:HFIP (7:1.5:1.5) | 62 |
| 2 | HOAc:DMSO (9:1) | A small amount of |
| 3 | CH 3 CN:HFIP (10:1) | 48 |
| 4 | CH 3 CN:HOAc (10:1) | 46 |
| 5 | CH 3 CN | No product |
| 6 | HOAc | No product |
| 7 | CH 3 CN:HCOOH (10:1) | A small amount of |
Claims (4)
1. A method for introducing trans-isopentenyl into the C3 position of indole, comprising the steps of: the compound (A) and 2-methyl-2-butene (B) are used as initial raw materials, palladium compound is used as catalyst, copper sulfate is used as oxidant, acetonitrile, acetic acid and hexafluoroisopropanol are used as mixed solvent, the trans-isopentenyl indole compound (C) is prepared through direct oxidative dehydrogenation coupling reaction,
wherein R is 1 Phenyl, naphthyl or hydrogen; r is R 2 Is H, C1-C20 alkyl, alkoxy or aldehyde, C2-C20 ester, halogen or nitro.
2. The method for synthesizing the trans-isopentenyl introduced into the C3 position of indole according to claim 1, wherein the method comprises the following steps of: r is R 1 Phenyl, naphthyl or hydrogen; r is R 2 Is H, C1-C5 alkyl, alkoxy or aldehyde, C2-C6 ester, halogen or nitro.
3. The method for synthesizing the trans-isopentenyl introduced into the C3 position of indole according to claim 1, wherein the method comprises the following steps of: the palladium compound catalyst is tris (dibenzylideneacetone) dipalladium or palladium trifluoroacetate.
4. The method for synthesizing the trans-isopentenyl introduced into the C3 position of indole according to claim 1, wherein the method comprises the following steps of: in the mixed solvent, the volume ratio of acetonitrile, acetic acid and hexafluoroisopropanol is 1.4: (0.2-0.6): (0.2-0.6).
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