CN117384133A - 2-bromo-1- (pyridin-2-yl) indole compound and preparation method thereof - Google Patents
2-bromo-1- (pyridin-2-yl) indole compound and preparation method thereof Download PDFInfo
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- -1 2-bromo-1- (pyridin-2-yl) indole compound Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000003446 ligand Substances 0.000 claims description 24
- 239000007800 oxidant agent Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 16
- 230000001590 oxidative effect Effects 0.000 claims description 15
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 13
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 9
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 claims description 9
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- CWPKTBMRVATCBL-UHFFFAOYSA-N 3-[1-[1-[(2-methylphenyl)methyl]piperidin-4-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound CC1=CC=CC=C1CN1CCC(N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)CC1 CWPKTBMRVATCBL-UHFFFAOYSA-N 0.000 claims description 4
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 4
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims description 3
- NFRYVRNCDXULEX-UHFFFAOYSA-N (2-diphenylphosphanylphenyl)-diphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C(=CC=CC=1)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 NFRYVRNCDXULEX-UHFFFAOYSA-N 0.000 claims description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 claims description 2
- YGUPAQDKOAPZHC-UHFFFAOYSA-N tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 YGUPAQDKOAPZHC-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- VSKZGHVPGOMFAV-UHFFFAOYSA-N 1-pyridin-2-ylindole Chemical compound C1=CC2=CC=CC=C2N1C1=CC=CC=N1 VSKZGHVPGOMFAV-UHFFFAOYSA-N 0.000 description 13
- 239000002994 raw material Substances 0.000 description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 241000894007 species Species 0.000 description 6
- QONJVZMMPRYTSY-UHFFFAOYSA-N 2-methyl-1-pyridin-2-ylindole Chemical compound CC1=CC2=CC=CC=C2N1C1=CC=CC=N1 QONJVZMMPRYTSY-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- IEBQZJXMAOMNBO-UHFFFAOYSA-N 1h-indole;pyridine Chemical compound C1=CC=NC=C1.C1=CC=C2NC=CC2=C1 IEBQZJXMAOMNBO-UHFFFAOYSA-N 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
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- 238000004440 column chromatography Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QEQBMZQFDDDTPN-UHFFFAOYSA-N (2-methylpropan-2-yl)oxy benzenecarboperoxoate Chemical compound CC(C)(C)OOOC(=O)C1=CC=CC=C1 QEQBMZQFDDDTPN-UHFFFAOYSA-N 0.000 description 1
- JNETYVLEGPSOFY-UHFFFAOYSA-N 3-bromopyrrolidine-2,5-dione Chemical compound BrC1CC(=O)NC1=O JNETYVLEGPSOFY-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000005885 boration reaction Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
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- 238000005457 optimization Methods 0.000 description 1
- 238000013386 optimize process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and provides a 2-bromo-1- (pyridine-2-yl) indole compound and a preparation method thereof. The structural formula is shown as formula (1):the method comprises the steps of carrying out a first treatment on the surface of the R in formula (1) 1 、R 2 、R 3 Each independently is methyl or methoxy. The invention discloses a synthesis method of a 2-bromo-1- (pyridine-2-yl) indole compound. The 2-bromo-1- (pyridin-2-yl) indole was found to be a novel compound by two professional database searches using Reaxys, sciFinder, and no reports have been made on its structure and synthesis. With CuBr 2 As a brominating reagent, the brominating reagent which is irritated in taste and is not friendly to the environment and human body is avoided, the yield of the obtained target product is high and can reach 95%, the position selectivity of the synthesis method is very high, and only the C2 position is subjected to monobromination reaction, but other positions are not subjected to reaction.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 2-bromo-1- (pyridin-2-yl) indole compound and a preparation method thereof.
Background
Indole is a very important nitrogenous heterocyclic compound, widely exists in various bioactive molecules and medical intermediate structures, and particularly plays an important role in drug research as a platform framework molecule, so that the compound has wide market demands. By modifying the indole structure and introducing different groups into different positions of the molecular structure, the application of indole derivatives in the fields of medicines, pesticides and the like can be further expanded, and particularly, the indole derivatives are expected to obtain compounds with antibacterial activity through structural modification.
The 2-bromo-1- (pyridine-2-yl) indole compound is taken as one of indole compounds, the molecular structure of the compound contains parent rings with potential biological or pharmaceutical activities such as indole and pyridine, the compound has strong structural modification, and other functional groups can be introduced into the indole or pyridine structure by constructing proper reactions, particularly C-H activation, so that the compound has specific functions. In particular, bromine atoms can further undergo reactions such as methylation, nitration, amination, boration, coupling and the like, and can further construct downstream products with special properties and purposes in the fields of medicines, pesticides and the like.
According to the traditional method of organic synthesis, 1- (pyridine-2-yl) indole is used as a raw material to synthesize 2-bromo-1- (pyridine-2-yl) indole, and two key problems are mainly needed to be solved: firstly, the choice of brominating reagent is commonly usedNBromosuccinimide (NBS), bromine, hydrobromic acid, phosphorus tribromide as brominating agent, which has the main problems of extremely great taste and irritation, and is not friendly to human body and environment in the processes of feeding, reaction, post-treatment and the like; secondly, the raw material 1- (pyridine-2-yl) indole contains two heterocycles of pyridine and indole in the structure, and has position selectivity in the substitution reactionThere is a possibility that the di-substitution occurs.
Disclosure of Invention
In view of the above problems, the present invention provides a 2-bromo-1- (pyridin-2-yl) indole compound and a method for preparing the same.
The invention is realized by the following technical scheme: a2-bromo-1- (pyridin-2-yl) indole compound has a structural formula shown in formula (1):the method comprises the steps of carrying out a first treatment on the surface of the R in formula (1) 1 、R 2 、R 3 Each independently is methyl or methoxy.
Further, the compound is one of the following:
。
process for preparing the 2-bromo-1- (pyridin-2-yl) indole compound, 0.1mmol of 1- (pyridin-2-yl) indole compound, 0.03-0.05mmol of CuBr 2 Mixing 0.02-0.1mmol of ligand and 0.2mmol of oxidant in 2mL of solvent, and reacting for 12h at 90-110 ℃;
wherein: the oxidant is any one of tert-butyl peroxybenzoate TBPB, di-tert-butyl peroxyDTBP and tert-butyl hydroperoxide TBHP;
the ligand is 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl, namelyt-Bu Xphos, 1, 4-bis (diphenylphosphine) butane dppb, 1, 3-bis (diphenylphosphine) propane dppp, tricyclohexylphosphine pcy 3 Any one of 2-dicyclohexylphosphorus-2 ',4',6 '-triisopropylbiphenyl (xphos), 2-dicyclohexylphosphorus-2' -methylbiphenyl (mephos), 1, 2-bis (diphenylphosphino) benzene (dppbz), 2 '-diphenylphosphine-1, 1' -Binaphthyl (BINAP), L1, L3, L4-L6, L8-L12, L14-L17;
the structural formulas of L1, L3, L4-L6, L8-L12 and L14-L17 are shown as follows:
；
the solvent is dimethyl sulfoxide DMSO or tetrahydrofuran THF;
the 1- (pyridin-2-yl) indole compound is one of the following:
。
further, the oxidant is DTBP, and the dosage is 0.2 mmol. The ligand is 1, 3-bis (diphenylphosphine) propane dppp ort-Bu·Xphos。
Further, the ligand ist-Bu Xphos in an amount of 0.03mmol.
Further, the solvent is DMSO. The reaction temperature is 100 ℃; cuBr 2 The amount of (C) is 0.05mmol; the ligand was used in an amount of 0.05mmol.
The product obtained by the invention is separated and purified by column chromatography and is determined to be 2-bromo-1- (pyridin-2-yl) indole by nuclear magnetic resonance analysis instead of the expected 2-methyl-1- (pyridin-2-yl) indole. Based on this, the present invention creatively discovers a synthetic method of 2-bromo-1- (pyridin-2-yl) indole compounds. It was found by searching using two specialized databases of Reaxys, sciFinder that 2-bromo-NPyridine indole is a novel compound, and has not been reported on the structure and synthesis of the novel compound.
The invention is discovered accidentally during the study of the synthesis of 2-methyl-1- (pyridin-2-yl) indole, 1- (pyridin-2-yl) indole (19.4 mg, 0.1 mmol) and CuBr 2 (6.7 mg, 0.03 mmol), ligand 1, 3-bis (diphenylphosphine) propane (dppp, 24.8 mg, 0.06 mmol), oxidant tert-butyl peroxybenzoate (TBPB, 38.8 mg, 0.2 mmol) were dissolved in 2.0 mL dimethyl sulfoxide (DMSO), reacted at 100℃with 12h, the product was purified by column chromatography, and nuclear magnetic resonance analysis was estimated to be 2-bromo-NPyridine indole, rather than the envisioned 2-methyl-1- (pyridin-2-yl) indole. Based on this, the present invention creatively discovers a synthetic method of 2-bromo-1- (pyridin-2-yl) indole compounds.
The invention creatively uses CuBr 2 As brominating agent, the method avoids the use of NBS, bromine, hydrobromic acid, phosphorus tribromide and other taste stimulus and is not harmful to environment and human bodyThe synthesis method of the invention is used for synthesizing the 2-bromo-1- (pyridin-2-yl) indole compound with a friendly brominating reagent, the yield of the obtained target product is high and can reach 95%, and the position selectivity of the synthesis method is very high only whenCMonobromination occurs at the 2-position and does not occur at the other positions.
Drawings
FIG. 1 is a schematic illustration of a synthetic reaction process according to the present invention;
FIG. 2 is a synthetic reaction equation for 2-bromo-1- (pyridin-2-yl) indole;
FIG. 3 is a structural formula of L1-L17;
FIG. 4 is a nuclear magnetic resonance spectrum of product 1;
FIG. 5 is a nuclear magnetic resonance spectrum of product 2;
FIG. 6 is a nuclear magnetic resonance spectrum of product 3;
FIG. 7 is a nuclear magnetic resonance spectrum of product 4.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments; all other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, the disclosure of which is incorporated herein by reference as is commonly understood by reference.
Those skilled in the art will recognize that equivalents of the specific embodiments described, as well as those known by routine experimentation, are intended to be encompassed within the present application.
The experimental methods in the following examples are conventional methods unless otherwise specified. The instruments used in the following examples are laboratory conventional instruments unless otherwise specified; the experimental materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores.
Example 1: when the synthesis of 2-methyl-1- (pyridin-2-yl) indole was studied, it was found by accident that 1- (pyridin-2-yl) indole (19.4 mg, 0.1 mmol), cuBr 2 (6.7 mg, 0.03 mmol), ligand 1, 3-bis (diphenylphosphine) propane (dppp, 24.8 mg, 0.06 mmol), oxidant t-butyl peroxybenzoate (TBPB, 38.8 mg, 0.2 mmol) were dissolved in 2.0 mL dimethyl sulfoxide (DMSO), reacted at 100℃for 12h, the product was isolated and purified by column chromatography, nuclear magnetic resonance analysis was estimated to be 2-bromo-1- (pyridin-2-yl) indole, rather than the expected 2-methyl-1- (pyridin-2-yl) indole. The specific synthetic reaction process is shown in figure 1.
Example 2: the reaction conditions were optimized with reference to fig. 2.
1. Optimization of reaction conditions
(1) Influence of the type of oxidizing agent: the dosage of the fixed raw material 1- (pyridine-2-yl) indole is 19.4mg (0.1 mmol) and CuBr 2 The amount was 6.7. 6.7 mg (0.03 mmol), the amount of ligand dppp was 24.8. 24.8 mg (0.06 mmol), the amount of solvent DMSO was 2. 2mL, and the reaction was conducted at 100℃for 12. 12h, and the effect of the type of oxidizing agent on the yield was examined, and the results are shown in Table 1. And determining the DTBP as the optimal oxidant according to experimental results.
Table 1: influence of the oxidant species on yield
(2) Influence of ligand species: the dosage of the immobilized raw material 1- (pyridin-2-yl) indole is 19.4mg (0.1 mmol) and CuBr 2 The amount of (B) was 6.7. 6.7 mg (0.03 mmol), the amount of DTBP as an oxidizing agent was 29.2. 29.2mg (0.2 mmol), the amount of DMSO as a solvent was 2mL, the reaction was conducted at 100℃for 12h, the influence of the ligand species on the yield was examined, the results are shown in Table 2, and the structural formulae of L1 to L17 in the Table are shown in FIG. 3. From the experimental resultst-Bu Xphos is the best ligand.
Table 2: influence of ligand species on yield
(3) Influence of the reaction temperature: the amount of 1- (pyridin-2-yl) indole as a fixed starting material was 19.4. 19.4mg (0.1 mmol), cuBr 2 In an amount of 6.7. 6.7 mg (0.03 mmol), the oxidant DTBP in an amount of 29.2. 29.2mg (0.2 mmol), ligandt-Bu Xphos was used in an amount of 25.4. 25.4mg (0.06 mmol), DMSO was used in an amount of 2. 2mL, the reaction time was 12. 12h, and the effect of the reaction temperature on the yield was examined, and the results are shown in Table 3. The optimum reaction temperature was determined to be 100℃from the experimental results.
Table 3: influence of the reaction temperature on the yield
(4) Raw material CuBr 2 Effect of the amount used: immobilized starting 1- (pyridin-2-yl) indole 19.4mg (0.1 mmol), oxidant DTBP 29.2mg (0.2 mmol) ligandt-Bu Xphos 25.4mg (0.06 mmol), solvent DMSO 2mL, reaction temperature 100 ℃ and reaction time 12h, examine raw material CuBr 2 The effect of the amount on the yield was shown in Table 4. Determination of raw material CuBr from experimental results 2 The optimum amount of the component (relative to the raw material) is 0.5equivN-moles of pyridine indole).
Table 4: raw material CuBr 2 Influence of the amount used on the yield
(5) Influence of ligand usage: the amount of 1- (pyridin-2-yl) indole as a fixed starting material was 19.4. 19.4mg (0.1 mmol), cuBr 2 The amount was 11.2. 11.2 mg (0.05 mmol), the amount of oxidant DTBP was 29.2mg (0.2 mmol), the amount of solvent DMSO was 2mL, the reaction temperature was 100deg.C, the reaction time was 12h, and the ligand was examinedt-The effect of Bu Xphos amount on yield is shown in Table 5. Determination of ligand from experimental resultst-The optimum amount of Bu Xphos is 0.3 equiv. (relative to the starting materialsN-moles of pyridine indole).
Table 5: ligandt-Bu Xphos dose vs. yield shadowSound box
(6) Influence of the solvent species: the amount of 1- (pyridin-2-yl) indole as a fixed starting material was 19.4. 19.4mg (0.1 mmol), cuBr 2 In an amount of 11.2 mg (0.05 mmol), the oxidant DTBP in an amount of 29.2mg (0.2 mmol), ligandt-Bu Xphos was used in an amount of 12.7. 12.7 mg (0.03 mmol), the reaction temperature was 100℃and the reaction time was 12h, the solvent was used in an amount of 2mL, and the effect of the solvent type on the yield was examined, and the results are shown in Table 6. The best solvent was determined to be DMSO from the experimental results.
Table 6: influence of solvent species on yield
In combination, 1- (pyridin-2-yl) indole and CuBr 2 The optimized process conditions for synthesizing 2-bromo-1- (pyridin-2-yl) indole from raw materials are: the amount of 1- (pyridin-2-yl) indole was 19.4mg (0.1 mmol), cuBr 2 In an amount of 11.2 mg (0.05 mmol), the oxidant DTBP in an amount of 29.2mg (0.2 mmol), ligandt-Bu Xphos was used in an amount of 12.7. 12.7 mg (0.03 mmol), the reaction temperature was 100℃and the reaction time was 12. 12h, and the solvent DMSO was used in an amount of 2.0. 2.0 mL. Under this condition, the yield of 2-bromo-1- (pyridin-2-yl) indole can reach 83%.
(7) Reaction broad spectrum study: under the optimal reaction conditions, the broad spectrum of the synthesis method was examined by changing the compound containing 1- (pyridin-2-yl) indole structure, and the results are shown in Table 7.
Table 7: broad-spectrum study of synthetic methods
Structural analysis of the product:
1. product 1： 1 H NMR (400 MHz, CDCl3): δ 8.70 (dd,J= 1.2, 4.8 Hz, 1H), 7.94 (td,J= 2.0, 7.6 Hz, 1H), 7.59-7.56 (m, 1H), 7.47 (d,J= 8.0 Hz, 1H), 7.44-7.38 (m, 2H), 7.27-7.16 (m, 3H) ppm。
2. Product 2： 1 H NMR (400 MHz, CDCl3): δ 8.71-8.69 (m, 1H), 7.91 (td,J= 2.0, 8.0 Hz, 1H), 7.46 (d,J= 8.0 Hz, 1H), 7.41-7.37 (m, 1H), 7.10 (t,J= 8.0 Hz, 1H), 6.98 (d,J= 8.0 Hz, 1H), 6.88(s, 1H), 6.58 (d,J= 7.6 Hz, 1H), 3.96(s, 3H) ppm。
3. Product 3： 1 H NMR (400 MHz, CDCl3): δ 8.68 (t,J= 2.4 Hz, 1H), 7.93-7.89 (m, 1H), 7.45 (d,J= 8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.32 (d,J= 8.8 Hz, 1H), 7.03-6.98 (m, 1H), 6.88-6.81 (m, 1H), 6.69 (s, 0.4H), 3.89-3.85(m, 3H) ppm。
4. Product 4： 1 H NMR (400 MHz, CDCl3): δ 8.69 (dd,J= 1.2, 4.8 Hz, 1H), 7.89 (td,J= 2.0, 7.6 Hz, 1H), 7.57-7.54 (m, 1H), 7.46-7.41 (m, 1H), 7.38-7.34 (m, 1H), 7.19-7.17 (m, 1H), 2.37 (s, 3H) ppm。
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (8)
1. A 2-bromo-1- (pyridin-2-yl) indole compound, characterized in that: the structural formula is shown as formula (1):
the method comprises the steps of carrying out a first treatment on the surface of the R in formula (1) 1 、R 2 、R 3 Each independently is methyl or methoxy.
2. A 2-bromo-1- (pyridin-2-yl) indole compound according to claim 1, characterised in that: the compound is one of the following:
。
3. a process for preparing a 2-bromo-1- (pyridin-2-yl) indole compound according to claim 1 or 2, characterized in that: 0.1mmol of 1- (pyridin-2-yl) indole compound and 0.03-0.05mmol of CuBr 2 Mixing 0.02-0.1mmol of ligand and 0.2mmol of oxidant in 2mL of solvent, and reacting for 12h at 90-110 ℃;
wherein: the oxidant is any one of tert-butyl peroxybenzoate TBPB, di-tert-butyl peroxyDTBP and tert-butyl hydroperoxide TBHP;
the ligand is 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl, namelyt-Bu Xphos, 1, 4-bis (diphenylphosphine) butane dppb, 1, 3-bis (diphenylphosphine) propane dppp, tricyclohexylphosphine pcy 3 Any one of 2-dicyclohexylphosphorus-2 ',4',6 '-triisopropylbiphenyl (xphos), 2-dicyclohexylphosphorus-2' -methylbiphenyl (mephos), 1, 2-bis (diphenylphosphino) benzene (dppbz), 2 '-diphenylphosphine-1, 1' -Binaphthyl (BINAP), L1, L3, L4-L6, L8-L12, L14-L17;
the structural formulas of L1, L3, L4-L6, L8-L12 and L14-L17 are shown as follows:
；
the solvent is dimethyl sulfoxide DMSO or tetrahydrofuran THF;
the 1- (pyridin-2-yl) indole compound is one of the following:
。
4. a process according to claim 3, characterized in that: the oxidant is DTBP, and the dosage is 0.2 mmol.
5. A process according to claim 3, characterized in that: the ligand is 1, 3-bis (diphenylphosphine) propane dppp ort-Bu·Xphos。
6. The preparation method according to claim 5, characterized in that: the ligand ist-Bu Xphos in an amount of 0.03mmol.
7. A process according to claim 3, characterized in that: the solvent is DMSO.
8. A process according to claim 3, characterized in that: the reaction temperature is 100 ℃; cuBr 2 The amount of (C) was 0.05mmol.
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