CN115028655B - 2-trifluoromethyl-3-iodo-indole compound and preparation method thereof - Google Patents

2-trifluoromethyl-3-iodo-indole compound and preparation method thereof Download PDF

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CN115028655B
CN115028655B CN202210554864.2A CN202210554864A CN115028655B CN 115028655 B CN115028655 B CN 115028655B CN 202210554864 A CN202210554864 A CN 202210554864A CN 115028655 B CN115028655 B CN 115028655B
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indole
trifluoromethyl
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trimethylsilyl
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CN115028655A (en
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许斌
戴微微
高明春
鲍晟元
丁昌华
刘秉新
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University of Shanghai for Science and Technology
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention discloses a 2-trifluoromethyl-3-iodine-indole compound and a synthesis method thereof, wherein the structural formula of the compound is as follows:wherein R is 1 =hydrogen, methyl, methoxy, fluoro, bromo, chloro, iodo; r is R 2 =hydrogen, 2- (trimethylsilyl) ethoxymethyl, methyl, benzyl, n-butyl. According to the invention, indole is used as a raw material, potassium iodide is used as an iodine source, 1- (trifluoromethyl) -1, 2-phenyliodiyl-3 (1H) -ketone is used as a trifluoromethyl source, and a series of 2-trifluoromethyl-3-iodoindole compounds are efficiently constructed under the action of copper nitrate. Has the advantages of simple and easily obtained raw materials, simple reaction operation, mild conditions, environmental friendliness and the like. The 2-trifluoromethyl-3-iodoindole compound synthesized by the method has wide application prospect in the related fields of organic synthesis, pharmaceutical chemistry and the like.

Description

2-trifluoromethyl-3-iodo-indole compound and preparation method thereof
Technical Field
The invention relates to a 2-trifluoromethyl-3-iodo-indole compound and a synthesis method thereof.
Background
Indole compounds are compounds having a benzopyrrole skeleton and have been widely used in the fields of biological medicine, materials, foods, agricultural chemicals, dyes and the like (see literature: anna, j.k. -k.et, chem.rev.2010,110, 4489-4497). Tryptophan, for example, is one of the amino acids essential to the human body; 5-hydroxytryptamine, found in serum, is an inhibitory neurotransmitter; indomethacin is one of the strongest prostaglandins and synthesis inhibitors; sumatriptan is an anti-migraine agent.
On the other hand, the introduction of fluorine atoms or fluorine-containing groups into molecules strongly influences their solubility, lipophilicity, metabolic stability (see, e.g., wang, J.et al. Chem. Rev.2014,114, 2432-2506). Of the fluorine-containing molecular substituents, trifluoromethyl has unique physical, chemical and biological properties, and trifluoromethyl compounds play an important role in agriculture and medicinal chemistry (see: muller, K.et al science 2007,317,1881-1886).
Aromatic iodides have strong physiological and pharmacological activities, and the structures of the aromatic iodides are contained in a plurality of medicinal molecules or bioactive substances, such as Amiodarone (Amiodarone) class III antiarrhythmic drugs; the cydiodine tablet can be used for treating chronic pharyngolaryngitis, oral ulcer, etc.; thyroxine (Thyroxine) has effects of promoting metabolism of substances and energy in vivo, mainly metabolism of saccharide, protein and fat, and has structural formula of(see literature:Veluri,R.et al.J.Nat.Prod.2003,66,1520-1523)。
aromatic iodides are important chemical intermediates in organic synthesis, both as precursors for the synthesis of organometallic reagents (e.g., grignard reagents and organolithiates) and as cross-coupling reactants (see: fauvarque, j. Pureappl. Chem.1996,68, 1713-1720). In 1941 Kharasch reported the first transition metal catalyzed C (sp 2 )-C(sp 2 ) Coupling reactions (see: kharasch, m.s.j.am.chem.soc.1941,63, 2316-2320). Beginning in the seventies of the twentieth century, a number of classical coupling reactions have emerged, such as Kumada coupling, heck coupling, sonogashira coupling, negishi coupling, stiller coupling, suzuki coupling, hiyama coupling, and the like.
It follows that indole, trifluoromethyl substituents and aromatic iodides play an important role in organic chemistry. The synthetic methods of 2-trifluoromethylindole and 3-iodoindole have received great attention over the last decades (see Xie, J.—J. Et al, RSCAdv.2019,9, 35098-35101), but there is no precedent for the simultaneous introduction of 3-iodo and two substituents of 2-trifluoromethyl into pyrrole units in indoles. Therefore, from the aspects of a synthetic method and application prospect, research on introducing iodine and trifluoromethyl functional groups into indole simultaneously has great significance. The synthesis methods of 2-trifluoromethyl indole and 3-iodo indole compounds reported in the literature mainly comprise the following steps:
synthesis of (one) 2-trifluoromethyl indole
In 2010, sodeoka et al selectively obtained 2-trifluoromethylindole in good yield in MeOH solvent using CuOAc as a catalyst and 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one as a trifluoromethylating agent under mild conditions (see: shimizu, R.tetrahedron Lett.2010,51, 5947-5949).
In 2011, the Baran group used the common trifluoromethylating reagent CF 3 SO 2 Na, a variety of electron-deficient and electron-rich heterocyclic ring systems undergo a trifluoromethylation reaction. The reaction conditions are mild, and the functional group is highly tolerant and can be carried out in an air atmosphere (see, ji, Y.et al Proc.Natl. Acad. Sci.2011,108, 14411-14415).
In the same year, the MacMillan group developed a highly efficient photocatalytic technique in which non-activated aromatic and heteroaromatic hydrocarbons can be directly subjected to trifluoromethylation under mild irradiation of visible light. The method is also applicable to heterocycles such as pyrrole, thiophene, furan and pyridine (see: nagib, d.a. et al nature 2011,480,224-228).
In 2012, cho and colleagues reported a mild, simple to operate and environmentally friendly trifluoromethylation process. The reaction is carried out byCF 3 I is trifluoromethyl radical source, ru (bpy) 3 Cl 2 Trifluoromethyl derivatization was performed on a variety of electron-rich heterocycles as photocatalysts (see, iqbal, N.et al tetrahedron Lett.,2012,53,2005-2008).
Synthesis of (di) 3-iodoindole
In 2015, the Rao group reported a mild approach to selectively halogenate at the C3 position of indole. The method is suitable for various substituted indoles, and can carry out selective chlorination, bromination and iodination on the C-H bond at the 3 position of the indole, and the yield is medium to excellent (see literature: himabindi, V.et al, newJ.chem.2018,42, 18889-18893).
In 2018, cai et al reported a method for iodinated decarboxylation of aryl carboxylic acids. The method uses Cu (OAc) 2 As a catalyst, 1, 10-phenanthroline as a ligand and sodium iodide as an iodinating agent, aryl iodides can be obtained in moderate to good yields (see, fu, Z.et al tetrahedron Lett.2018,59, 4458-4461). The reaction is applicable to various electron-deficient and electron-rich indole compounds, but requires a higher temperature.
In 2019, satkar et al reported an electrophilic iodination reaction of aromatic compounds with iodoxybenzene (PhIO) and ammonium iodide as iodine sources (see, satkar, Y.et al J.Org.chem.2019,84, 4149-4164). The method has short reaction time and mild conditions.
In 2019 Sun et al reported an electrochemically induced tandem reaction for selective N-alkylation and C3-halogenation of indole compounds. This electrochemical process avoids the traditional multi-step procedure and effectively produces N-alkyl-3-haloindoles under more environmentally friendly conditions. The reaction does not use any oxidant, alkali or transition metal, and has excellent atom economy by fully using alkyl halide as an alkylating and halogenating agent without generating atom waste (see Sun L.et al Green chem.2019,21, 2732-2738).
In the same year, iida et al reported a method for the electrophilic iodination of aromatic compounds using 1, 3-diiodo-5, 5-Dimethylhydantoin (DIH). The reaction uses disulfide activated DIH as a Lewis base and the iodination reaction can be carried out under mild conditions. The reaction is applicable to a variety of electron-rich aromatic compounds including acetanilide, anisole, imidazole, pyrazole derivatives, and the like (see, iida k.j. Org. Chem.2019,84, 7411-7417). The reaction formula is as follows:
in summary, the synthesis methods of 2-trifluoromethyl indole and 3-iodo indole mainly include the above methods, but in these reactions, a part of the reactions use expensive ruthenium reagent and cuprous acetate, or the reaction conditions are relatively severe, such as a high temperature of 160 ℃. In addition, there is no report in the prior art that trifluoromethyl and iodine are simultaneously incorporated into the pyrrole units in the indole.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to overcome the defects in the prior art and provide a 2-trifluoromethyl-3-iodo-indole compound and a preparation method thereof, and the 2-trifluoromethyl-3-iodo-indole compound is efficiently prepared. Has the advantages of simple and easily obtained raw materials, simple reaction operation, mild conditions, environmental friendliness and the like. The 2-trifluoromethyl-3-iodoindole compound synthesized by the method has wide application prospect in the field of organic synthesis.
In order to achieve the aim of the invention, the invention adopts the following inventive concept:
the reaction mechanism adopted by the method is as follows:
wherein,
R 1 =hydrogen, methyl, methoxy, fluoro, bromo, chloro, iodo;
R 2 =hydrogen, 2- (trimethylsilyl) ethoxymethyl, methyl, benzyl, n-butyl.
According to the invention, indole is used as a raw material, potassium iodide is used as an iodine source, 1- (trifluoromethyl) -1, 2-phenyliodiyl-3 (1H) -ketone is used as a trifluoromethyl source, and a series of 2-trifluoromethyl-3-iodoindole compounds are efficiently constructed under the action of copper nitrate. Has the advantages of simple and easily obtained raw materials, simple reaction operation, mild conditions, environmental friendliness and the like.
According to the inventive concept, the invention adopts the following technical scheme:
a 2-trifluoromethyl-3-iodo-indole compound, which has a structural formula:
wherein R is 1 Is any one of hydrogen, methyl, methoxy, fluorine, bromine, chlorine and iodine;
R 2 is any one of hydrogen, 2- (trimethylsilyl) ethoxymethyl, methyl, benzyl and n-butyl.
A preparation method of a 2-trifluoromethyl-3-iodo-indole compound comprises the following steps:
(1) In nitrogen atmosphereAdding indole compound, 1- (trifluoromethyl) -1, 2-phenyliodic acid-3 (1H) -ketone, copper nitrate trihydrate and potassium iodide into acetonitrile (CH) according to the mole ratio of 1.0-2.0:1.0-1.5 3 CN), stirring the mixed solution for 1-2 hours at 40-50 ℃, monitoring the reaction until the raw materials disappear through TLC, and determining that the reaction is finished to obtain a product mixed solution;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) And separating and purifying the obtained crude product by column chromatography to obtain the 2-trifluoromethyl-3-iodo-indole compound.
Preferably, in the step (1), the indole compound employs at least one of 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methoxy-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 1-methylindole, 1-benzyl indole, 5-bromo-1-methyl-indole, and 1-n-butyl indole.
Preferably, in the step (1), indole compounds, 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -ketone, copper nitrate trihydrate and potassium iodide are added into acetonitrile according to a molar ratio of 1.0:2.0:2.0:1.5 for mixing.
In said step (1), 0.6mmol of indole compound is added to at least 3.0mg of acetonitrile.
Preferably, in the step (3), when the separation and purification are performed by column chromatography, a silica gel column chromatography separation method is adopted, and the developing agent adopts a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 150-300:1, or adopts petroleum ether.
Compared with the prior art, the invention has the following obvious prominent substantive features and obvious advantages:
1. according to the invention, indole is used as a raw material, potassium iodide is used as an iodine source, 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -ketone is used as a trifluoromethyl source, and a series of 2-trifluoromethyl-3-iodoindole compounds are efficiently constructed under the action of copper nitrate;
2. the method has the advantages of simple and easily obtained raw materials, simple reaction operation, mild conditions, environmental friendliness and the like;
3. the 2-trifluoromethyl-3-iodoindole compound synthesized by the method has wide application prospect in the field of organic synthesis.
Detailed Description
The foregoing aspects are further described in conjunction with specific embodiments, and the following detailed description of preferred embodiments of the present invention is provided:
embodiment one:
in this example, a process for the preparation of 2-trifluoromethyl-3-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, comprising the steps of:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (74.1 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, the disappearance of the reaction starting material was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1, to obtain yellow oily 2-trifluoromethyl-3-iodo-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (93)9 mg, 71% yield) of the formula
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2956,1731,1532,1456,1393,1345,1299,1254,1211,1172,1123,927,846,747,694；
1 H NMR(CDCl 3 ,500MHz):δ7.58(d,J＝8.0Hz,1H),7.54(d,J＝8.4Hz,1H),7.43(t,J＝7.7Hz,1H),7.33-7.28(m,1H),5.63(s,2H),3.55-3.50(m,2H),0.92-0.87(m,2H),-0.05(s,8H)； 19 FNMR(CDCl 3 ,471MHz):δ-54.46；
13 C NMR(CDCl 3 ,126MHz):δ138.13,130.10,126.73(q, 2 J C-F ＝35.6Hz),126.32,123.56,122.41,121.14(q, 1 J C-F ＝271.5Hz),74.47(q, 4 J C-F ＝2.6Hz),66.43,62.92(q, 3 J C-F ＝3.7Hz),17.92,-1.36；
HRMS(DART)m/z:calcd for C 15 H 19 F 3 INOSi[M+H] + 442.0305,found 442.0306.
embodiment two:
a preparation method of 2-trifluoromethyl-3-iodo-5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) The synthesis of 2-trifluoromethyl-3-iodo-5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole employs the following steps: copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (78.3 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, and the disappearance of the reaction material was monitored by TLC to determine the end of the reaction to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1 to obtain yellow oily 2-trifluoromethyl-3-iodo-5-methyl-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (88.7 mg, 65% yield) of the formula
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2953,2908,1531,1441,1398,1338,1252,1176,1112,926,846,797,752,694； 1 H NMR(CDCl 3 ,400MHz):δ7.45(d,J＝8.5Hz,1H),7.37(s,1H),7.28(s,1H),5.62(s,2H),3.57-3.51(m,2H),2.53(s,3H),0.90(d,J＝8.1Hz,2H),-0.03(s,9H)；
19 FNMR(CDCl 3 ,376MHz):δ-54.26；
13 C NMR(CDCl 3 ,101MHz):δ136.45,132.02,130.15,128.10,126.52(d, 2 J C-F ＝35.6Hz),122.86,121.13(q, 1 J C-F ＝270.9Hz),111.14,74.44(q, 4 J C-F ＝2.6Hz),66.32,62.31(q, 3 J C-F ＝3.6Hz),21.46,17.87,-1.39.
HRMS(DART)m/z:calcd for C 16 H 21 F 3 INOSi[M+H] + 456.0462,found 456.0463.
embodiment III:
a preparation method of 2-trifluoromethyl-3-iodo-4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol), potassium iodide (75.0 mg, 0.45 mmol) and, after 3 substitutions of nitrogen, acetonitrile (3.0 ml), 4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (82.6 mg, 0.3 mmol) were added sequentially to a 30 ml tube; heating to 40 ℃ and stirring for 1 hour, monitoring by TLC until the reaction raw materials disappear, and determining that the reaction is finished to obtain a product mixed solution;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1, to obtain yellow oily 2-trifluoromethyl-3-iodo-4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (88.7 mg, 63% yield) of the formula
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2956,1614,1563,1520,1403,1365,1234,1166,1114,1036,926,840,760,696,603；
1 H NMR(CDCl 3 ,400MHz):δ7.24(s,1H),6.83(s,1H),5.56(s,2H),3.55-3.49(m,2H),2.90(s,3H),2.44(s,3H),0.94-0.88(m,2H),-0.04(s,9H)；
19 FNMR(CDCl 3 ,376MHz):δ-53.32；
13 C NMR(CDCl 3 ,101MHz):δ139.07,135.79,133.05,126.63,126.08(q, 2 J C-F ＝34.7Hz),124.23,121.50(q, 1 J C-F ＝271.1Hz),109.48,74.34(q, 4 J C-F ＝3.0Hz),66.24,58.69(q, 3 J C-F ＝3.5Hz),21.85,20.74,17.93,-1.36；
HRMS(DART)m/z:calcd for C 17 H 23 F 3 INOSi[M+H] + 470.0618,found 470.0618.
embodiment four:
a preparation method of 2-trifluoromethyl-3-iodo-5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (79.5 mg, 0.3 mmol) were added, and the mixture was heated to 50 ℃ and stirred for 2 hours, and the reaction material was monitored to disappear by TLC to determine the end of the reaction, thereby obtaining a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by the reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1 by using a developing agent to obtain yellow oily 2-trifluoromethyl-3-iodo-5-fluoro-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (71.7 mg, 52% yield) of the formula:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2953,2908,1531,1441,1398,1338,1252,1176,1112,927,846,797,752；695； 1 H NMR(CDCl 3 ,500MHz):7.51(dd,J＝9.0,4.1Hz,1H),7.26-7.22(m,1H),7.17(td,J＝9.0,2.5Hz,1H),5.61(s,2H),3.58-3.48(m,2H),0.95-0.87(m,2H),-0.04(s,9H)；
19 FNMR(CDCl 3 ,471MHz):δ-54.63,-120.47(s,Ar-F)；
13 C NMR(CDCl 3 ,126MHz):δ159.32(d, 1 J C-F ＝239.5Hz,Ar-F),134.57,130.92(d, 3 J C-F ＝10.4Hz,Ar-F),128.12(q, 2 J C-F ＝36.0Hz),120.86(q, 1 J C-F ＝271.2Hz),115.33(d, 2 J C-F ＝26.6Hz,Ar-F),112.95(d, 3 J C-F ＝9.3Hz,Ar-F),108.46(d, 2 J C-F ＝24.8Hz,Ar-F),74.80(q, 4 J C-F ＝2.7Hz),66.52,61.75(q, 3 J C-F ＝5.1,3.7Hz),17.91,-1.36；
HRMS(DART)m/z:calcd for C 15 H 18 F 4 INOSi[M+H] + 459.0133,found 459.0134.
fifth embodiment:
a preparation method of 2-trifluoromethyl-3-iodo-5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol), potassium iodide (75.0 mg, 0.45 mmol) and, after 3 substitutions of nitrogen, acetonitrile (3.0 ml), 5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (84.3 mg, 0.3 mmol) were added sequentially to a 30 ml tube; heating to 50 ℃ and stirring for 2 hours, monitoring by TLC until the reaction raw materials disappear, and determining that the reaction is finished to obtain a product mixed solution;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1 to obtain yellow oily 2-trifluoromethyl-3-iodo-5-chloro-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (69.8 mg, 49% yield) of the formula:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2954,2901,1530,1445,1395,1339,1250,1207,1175,1117,1083,848,797；693； 1 H NMR(CDCl 3 ,500MHz):δ7.56(d,J＝2.0Hz,1H),7.48(d,J＝8.8Hz,1H),7.37(dd,J＝8.8,2.0Hz,1H),5.60(s,2H),3.53-3.49(m,2H),0.90-0.87(m,2H),-0.05(s,9H)；
19 FNMR(CDCl 3 ,471MHz):δ-54.67；
13 C NMR(CDCl 3 ,125MHz):136.48,131.25,128.42,127.92(q, 2 J C-F ＝35.8Hz),126.88,123.03,120.82(q, 1 J C-F ＝271.3Hz),112.91,74.78(q, 4 J C-F ＝2.7Hz),66.60,61.54(q, 3 J C-F ＝3.6Hz),17.91,-1.36；
HRMS(DART)m/z:calcd for C 15 H 18 F 3 IClNOSi[M+H] + 475.9916,found 475.9917.
example six:
a preparation method of 2-trifluoromethyl-3-iodo-5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (97.5 mg, 0.3 mmol) were added, and the mixture was heated to 50 ℃ and stirred for 2 hours, and the reaction material was monitored to disappear by TLC to determine the end of the reaction, thereby obtaining a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1 to obtain yellow oily 2-trifluoromethyl-3-iodo-5-bromo-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (60.7 mg, 39% yield) of the formula:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2953,1530,1443,1393,1338,1249,1207,1175,1117,935,846,795；695； 1 H NMR(CDCl 3 ,500MHz):δ7.72(d,J＝1.9Hz,1H),7.50(d,J＝7.1Hz,1H),7.43(d,J＝8.8Hz,1H),5.60(s,2H),3.53-3.48(m,2H),0.92-0.85(m,2H),-0.05(s,9H)；
19 FNMR(CDCl 3 ,471MHz):δ-54.67；
13 C NMR(CDCl 3 ,125MHz):δ136.64,131.63,129.25,127.59(q, 2 J C-F ＝36.0Hz),126.01,120.62(q, 1 J C-F ＝271.3Hz),115.65,113.06,74.60(q, 4 J C-F ＝2.7Hz),66.44,61.24(q, 3 J C-F ＝3.7Hz),17.75,-1.52；
HRMS(DART)m/z:calcd for C 15 H 18 F 3 IBrNOSi[M+H] + 519.9411,found 519.9408
embodiment seven:
a preparation method of 2-trifluoromethyl-3-iodo-5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (111.9 mg, 0.3 mmol) were added, and the mixture was heated to 50 ℃ and stirred for 2 hours, and the disappearance of the reaction material was monitored by TLC to determine the end of the reaction to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1, to obtain yellow oily 2-trifluoromethyl-3-iodo-5-iodo-1- [ [2- (trimethylsilyl) ethoxyBase group]Methyl group]-1H-indole (54.4 mg, 32% yield) of the formula:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2954,2897,1530,1464,1435,1392,1339,1249,1208,1175,1120,937,840,796,695；
1 H NMR(CDCl 3 ,500MHz):δ7.92(d,J＝1.6Hz,1H),7.67(dd,J＝8.7,1.6Hz,1H),7.32(d,J＝8.7Hz,1H),5.59(s,2H),3.52-3.48(m,2H),0.89-0.86(m,2H),-0.05(s,9H)；
19 FNMR(CDCl 3 ,471MHz):δ-54.65；
13 C NMR(CDCl 3 ,125MHz):δ137.28,134.79,132.44,132.38,127.35(q, 2 J C-F ＝35.9Hz),120.73(q, 1 J C-F ＝271.3Hz),113.51,85.94,74.70(q, 4 J C-F ＝2.6Hz),66.60,61.15(q, 3 J C-F ＝3.6Hz),17.90,-1.35；
HRMS(DART)m/z:calcd for C 15 H 18 F 3 I 2 NOSi[M+H] + 556.9194,found 556.9195.
example eight:
a preparation method of 2-trifluoromethyl-3-iodo-5-methoxy-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times nitrogen substitution, acetonitrile (3.0 ml) and 5-methoxy-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (83.1 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, and the disappearance of the reaction material was monitored by TLC to determine the end of the reaction to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent by reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1 to obtain yellow oily 2-trifluoromethyl-3-iodo-5-methoxy-1- [ [2- (trimethylsilyl) ethoxy group]Methyl group]-1H-indole (59.3 mg, 42% yield). The structural formula is as follows:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2954,2897,1530,1463,1435,1392,1339,1250,1208,1175,1120,937,840,796,695；
1 H NMR(CDCl 3 ,400MHz):δ7.44(d,J＝9.0Hz,1H),7.07(d,J＝9.1Hz,1H),6.95(d,J＝2.5Hz,1H),5.59(s,2H),3.91(s,3H),3.54-3.49(m,2H),0.92-0.86(m,2H),-0.05(s,9H)；
19 FNMR(CDCl 3 ,376MHz):δ-54.24；
13 C NMR(CDCl 3 ,101MHz):δ156.14,133.07,130.62,126.79(q, 2 J C-F ＝35.7Hz),121.10(q, 1 J C-F ＝270.9Hz),117.55,112.60,103.83,74.61(q, 4 J C-F ＝2.6Hz),66.36,62.14(q, 3 J C-F ＝3.6Hz),55.90,17.91,-1.36.
HRMS(DART)m/z:calcd for C 15 H 21 F 3 IO 2 NSi[M+H] + 472.0411,found 475.0412
example nine:
a preparation method of 2-trifluoromethyl-3-iodo-1-methylindole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and 1-methylindole (39.3 mg, 0.3 mmol) were added, and the mixture was stirred for 1 hour under heating to 40 ℃, the disappearance of the reaction raw materials was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by silica gel column chromatography, and petroleum ether was used as a developing solvent to obtain 2-trifluoromethyl-3-iodo-1-methylindole (67.3 mg, yield 69%) as a yellow solid. The structural formula is as follows:melting point: 40-41 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3058,2953,1531,1466,1393,1357,1314,1247,1168,1115,1071,934,741；695；
1 H NMR(CDCl 3 ,600MHz):δ7.56(d,J＝8.1Hz,1H),7.42(t,J＝7.7Hz,1H),7.35(d,J＝8.4Hz,1H),7.29-7.26(m,1H),3.91(s,3H)；
19 FNMR(CDCl 3 ,471MHz):δ-55.92；
13 C NMR(CDCl 3 ,125MHz):δ138.23,129.76,126.87(q, 2 J C-F ＝35.2Hz),125.85,123.52,121.71,121.27(q, 1 J C-F ＝270.7Hz),110.13,59.62(q, 3 J C-F ＝3.6Hz),32.01；
HRMS(DART)m/z:calcd for C 10 H 7 F 3 IN[M+H] + 324.9570,found 324.9567.
example ten:
a preparation method of 2-trifluoromethyl-3-iodo-1-benzylindole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and 1-benzylindole 62.1 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, the disappearance of the reaction materials was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by silica gel column chromatography, and petroleum ether was used as a developing solvent to give 2-trifluoromethyl-3-iodo-1-benzylindole (58.8 mg, yield 49%) as a yellow oil. The structural formula is as follows:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3036,2933,1605,1575,1527,1455,1401,1355,1314,1255,1171,1118,1028,986,932,836,792,738,695,646,588,560,451；
1 H NMR(CDCl 3 ,500MHz):δ7.63(t,J＝8.8Hz,1H),7.35(d,J＝6.9Hz,1H),7.33-7.26(m,4H),7.22(d,J＝8.2Hz,1H),7.01(d,J＝7.2Hz,2H),5.55(d,J＝3.1Hz,2H)；
19 FNMR(CDCl 3 ,471MHz):δ-55.10；
13 C NMR(CDCl 3 ,101MHz):δ138.02,136.64,130.01,128.91,127.76,126.94(q, 2 J C-F ＝35.4Hz),126.19,125.84,123.65,122.05,121.2159(q, 1 J C-F ＝271.1Hz),60.82(q, 3 J C-F ＝3.6Hz),49.24(q, 4 J C-F ＝2.4Hz)；
HRMS(DART)m/z:calcd for C 16 H 11 F 3 IN[M+H] + 400.9883,found 400.9882.
example eleven:
a preparation method of 2-trifluoromethyl-3-iodine-1H-indole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -ketone (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and indole (35.1 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, the disappearance of the reaction raw materials was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by column chromatography on silica gel with a volume ratio of petroleum ether to ethyl acetate of 150:1 to give 2-trifluoromethyl-3-iodo-1H-indole as a yellow solid (49.3 mg, yield 53%). The structural formula is as follows:melting point: 44-46 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):3364,1548,1424,1373,1328,1254,1163,1124,975,839,748,680,575,504； 1 H NMR(CDCl 3 ,400MHz):δ8.70(s,1H),7.56(d,J＝8.1Hz,1H),7.40(s,1H),7.39(s,1H),7.30(ddd,J＝8.0,4.7,3.3Hz,1H)；
19 FNMR(CDCl 3 ,471MHz):δ-59.24；
13 C NMR(CDCl 3 ,101MHz):δ135.12,130.51,126.57(q, 2 J C-F ＝37.2Hz),126.08,122.75,122.18,120.94(d, 1 J C-F ＝269.5Hz),112.05,60.03(q, 3 J C-F ＝3.5Hz)；
HRMS(DART)m/z:calcd for C 9 H 5 F 3 IN[M+H] + 310.9413,found 310.9412
embodiment twelve:
a preparation method of 2-trifluoromethyl-3-iodo-5-bromo-1-methylindole comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and 5-bromo-1-methyl-indole (62.7 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, the disappearance of the reaction starting material was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by silica gel column chromatography, and petroleum ether was used as a developing solvent to give 2-trifluoromethyl-3-iodo-5-bromo-1-methylindole (51.9 mg, yield 43%) as a white solid. The structural formula is as follows:melting point: 43-44 ℃.
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):1527,1471,1290,1253,1159,1112,1071,939,853,792,578；
1 H NMR(CDCl 3 ,500MHz):δ7.67(d,J＝3.5Hz,1H),7.50-7.41(m,1H),7.19(d,J＝8.7Hz,1H),3.87(s,3H)；
19 FNMR(CDCl 3 ,471MHz):δ-56.18；
13 C NMR(CDCl 3 ,125MHz):δ136.88,131.29,127.85(q, 2 J C-F ＝35.4Hz),126.02,120.84(q, 1 J C-F ＝271.1Hz),115.00,111.76,58.33(q, 3 J C-F ＝3.6Hz),32.27(q, 4 J C-F ＝2.8Hz)；
HRMS(DART)m/z:calcd for C 10 H 6 F 3 IBrN[M+H] + 402.8675,found 402.8674
embodiment thirteen:
a preparation method of a 2-trifluoromethyl-3-iodo-indole compound comprises the following steps:
(1) Copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (75.0 mg, 0.45 mmol) were sequentially added to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and 1-n-butylindole (51.9 mg, 0.3 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, the disappearance of the reaction raw materials was monitored by TLC, and the end of the reaction was determined to give a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by silica gel column chromatography, and petroleum ether was used as a developing solvent to give 2-trifluoromethyl-3-iodo-1-n-butylindole (47.3 mg, yield 43%) as a yellow oil. The structural formula is as follows:
the basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2961,2871,1526,1461,1402,1355,1308,1249,1168,1116,1080,741；
1 H NMR(CDCl 3 ,500MHz):δ7.56(d,J＝8.1Hz,1H),7.42-7.32(m,2H),7.27(d,J＝7.7Hz,1H),4.30-4.24(m,2H),1.79(p,J＝7.8Hz,2H),1.45-1.40(m,2H),0.98(t,J＝7.4Hz,3H)；
19 FNMR(CDCl 3 ,471MHz):δ-55.32；
13 C NMR(CDCl 3 ,101MHz):δ137.53,129.92,126.35(q, 2 J C-F ＝35.3Hz),125.70,123.62,121.64,121.32(q, 1 J C-F ＝270.8Hz),59.79(q, 3 J C-F ＝3.5Hz),46.00(q, 4 J C-F ＝2.2Hz),32.29,20.24,13.79；
HRMS(DART)m/z:calcd for C 13 H 13 F 3 IN[M+H] + 367.0039,found 367.0039.
fourteen examples:
in this example, in step (1), copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (189.6 mg, 0.6 mmol) and potassium iodide (1.0 mg, 0.6 mmol) were sequentially added to a 30 ml test tube, nitrogen was replaced 3 times, acetonitrile (3.0 ml) and indole (0.6 mmol) were added, and the mixture was stirred for 1 hour under heating to 40 ℃, and the reaction mixture was confirmed to be completed by TLC monitoring the disappearance of the reaction material.
Indole compounds employ at least one of 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methoxy-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 1-methylindole, 1-benzyl indole, 5-bromo-1-methyl-indole, 1-n-butylindole.
The yield of the various 2-trifluoromethyl-3-iodo-indole compounds prepared in this example was not lower than 39%.
Example fifteen:
in this example, in step (1), copper nitrate trihydrate (145.1 mg, 0.6 mmol), 1- (trifluoromethyl) -1, 2-phenyliodiyl-3 (1H) -ketone (189.6 mg, 0.6 mmol) and potassium iodide (1.5 mg, 0.9 mmol) were sequentially added to a 30 ml test tube, nitrogen was replaced 3 times, acetonitrile (3.0 ml) and indole (0.6 mmol) were added, and the mixture was stirred for 1 hour under heating to 40 ℃, and the reaction mixture was monitored by TLC until the reaction material disappeared, and the end of the reaction was determined.
Indole compounds employ at least one of 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methoxy-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 1-methylindole, 1-benzyl indole, 5-bromo-1-methyl-indole, 1-n-butylindole.
The yield of the various 2-trifluoromethyl-3-iodo-indole compounds prepared in this example was not lower than 47%.
Application test analysis of the use of the compounds synthesized in the above examples of the invention:
the synthesis scale of the above example 2-trifluoromethyl-3-iodo-indole compound can be successfully scaled up to gram scale, comprising the steps of:
(1) Copper nitrate trihydrate (2.4160 g, 10.0 mmol), 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -one (3.2160 g, 10.0 mmol) and potassium iodide (1.2515 g, 7.5 mmol) were added sequentially to a 30 ml test tube, after 3 times of nitrogen substitution, acetonitrile (3.0 ml) and 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole (1.2355 g, 5.0 mmol) were added, and the mixture was heated to 40 ℃ and stirred for 1 hour, and the disappearance of the reaction material was monitored by TLC to determine the end of the reaction, thereby obtaining a product mixture;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) The crude product obtained after the solvent was removed from the reaction system was separated by column chromatography on silica gel with a volume ratio of petroleum ether to ethyl acetate of 300:1 to give 2-trifluoromethyl-3-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole as a yellow oil (1.1907 g, yield 54%).
Further derivatization of the above example 2-trifluoromethyl-3-iodo-indole may also take place. The method comprises the following steps:
(1) Palladium acetate (3.4 mg, 3 mmol%), cesium carbonate (16.2 mg, 6 mmol%), cesium carbonate (325.8 mg, 1.0 mmol) and, after three nitrogen substitutions, dimethyl sulfoxide (2.0 ml), 2-trifluoromethyl-3-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole 2a (220.5 mg, 0.5 mmol), t-butylisonitrile (68. Mu.l, 0.6 mmol) and p-tolane (76. Mu.l, 0.6 mmol) were added in sequence to a 15 ml dry tube, and stirred at 100℃for 2 hours.
(2) After the reaction was completed, the product mixture was cooled to room temperature, and it was necessary to carefully open the tube to decompress. Extracting the product with ethyl acetate, washing with equal amount of saturated saline for at least 3 times, drying, and removing solvent to obtain a crude product;
(3) Separating the crude product by silica gel column chromatography after removing solvent from the reaction system, wherein the volume ratio of petroleum ether to ethyl acetate is 300:1, to obtain yellow oily (E) -N- (tert-butyl) -3- (p-tolyl) -1- (2-trifluoromethyl) -1- [2- (trifluoromethyl) ethoxy]methyl-1H-indol-3-propyl-2-alkyne-1-imine (96.8 mg, 65% yield) of the formula
The basic parameters of this compound are as follows:
IR(KBr,cm -1 ):2962,2196,1563,1508,1421,1341,1245,1173,1119,1074,970,926,843,748,700；
1 H NMR(CDCl 3 ,500MHz):δ7.83(d,J＝8.0Hz,1H),7.57(d,J＝8.4Hz,1H),7.39(d,J＝7.5Hz,1H),7.35(d,J＝8.1Hz,2H),7.24(d,J＝7.4Hz,1H),7.15(d,J＝7.9Hz,2H),5.63(s,2H),3.62-3.56(m,2H),2.36(s,3H),0.95-0.90(m,2H),-0.03(s,9H)；
19 FNMR(CDCl 3 ,471MHz):δ-53.88；
13 C NMR(CDCl 3 ,101MHz):δ142.28,140.18,137.71,131.64,131.43,129.36,128.87,125.79,125.55,123.26(q, 2 J C-F ＝36.9Hz),122.04,121.75(q, 3 J C-F ＝2.6Hz),121.58(q, 1 J C-F ＝271.8Hz),121.36,118.87,111.19,98.88,85.21,74.17(d, 4 J C-F ＝2.2Hz),66.34,57.90,29.59,21.73,17.94,-1.33；
HRMS(DART)m/z:calcd for C 29 H 36 F 3 N 2 OSi[M+H] + 513.2544,found 513.2540.
in summary, the structural formula of the 2-trifluoromethyl-3-iodo-indole compound and the synthetic method thereof in the above embodiment of the invention is as follows:
wherein R is 1 =hydrogen, methyl, methoxy, fluoro, bromo, chloro, iodo;
R 2 =hydrogen, 2- (trimethylsilyl) ethoxymethyl, methyl, benzyl, n-butyl.
According to the embodiment of the invention, indole is used as a raw material, potassium iodide is used as an iodine source, 1- (trifluoromethyl) -1, 2-phenyliodiyl-3 (1H) -ketone is used as a trifluoromethyl source, and a series of 2-trifluoromethyl-3-iodoindole compounds are efficiently constructed under the action of copper nitrate. Has the advantages of simple and easily obtained raw materials, simple reaction operation, mild conditions, environmental friendliness and the like. The 2-trifluoromethyl-3-iodoindole compound synthesized by the method has wide application prospect in the fields of organic synthesis, pharmaceutical chemistry and the like.
The embodiments of the present invention have been described above, but the present invention is not limited to the above embodiments, and various changes, modifications, substitutions, combinations or simplifications can be made according to the spirit and principles of the technical solution of the present invention, and the present invention is not limited to the above embodiments, but is limited to the protection scope of the present invention as long as the technical principles and the inventive concept of the present invention are not deviated.

Claims (5)

1. A preparation method of a 2-trifluoromethyl-3-iodo-indole compound is characterized by comprising the following steps:
(1) Under the nitrogen atmosphere, adding indole compound, 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -ketone, copper nitrate trihydrate and potassium iodide into acetonitrile (CH) according to the mole ratio of 1.0-2.0:1.0-1.5 3 CN), stirring the mixed solution for 1-2 hours at 40-50 ℃, monitoring the reaction until the raw materials disappear through TLC, and determining that the reaction is finished to obtain a product mixed solution;
(2) After the reaction is finished, cooling the product mixed solution to room temperature, extracting a product by using ethyl acetate, washing at least 3 times by using saturated saline with equal quantity, drying, and removing a solvent to obtain a crude product;
(3) Separating and purifying the crude product by column chromatography to obtain 2-trifluoromethyl-3-iodine-indole compounds; the structural formula is as follows:
wherein R is 1 Is any one of hydrogen, methyl, methoxy, fluorine, bromine, chlorine and iodine;
R 2 is any one of hydrogen, 2- (trimethylsilyl) ethoxymethyl, methyl, benzyl and n-butyl.
2. The method for producing 2-trifluoromethyl-3-iodo-indole compound according to claim 1, wherein: in the step (1), the indole compound employs at least one of 1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 4, 6-dimethyl-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-fluoro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-chloro-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-bromo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-iodo-1- [ [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 5-methoxy-1- [2- (trimethylsilyl) ethoxy ] methyl ] -1H-indole, 1-methylindole, 1-benzyl indole, 5-bromo-1-methyl-indole, and 1-n-butylindole.
3. The method for producing 2-trifluoromethyl-3-iodo-indole compound according to claim 1, wherein: in the step (1), indole compounds, 1- (trifluoromethyl) -1, 2-phenyliodic-3 (1H) -ketone, copper nitrate trihydrate and potassium iodide are added into acetonitrile according to a molar ratio of 1.0:2.0:2.0:1.5 for mixing.
4. The method for producing 2-trifluoromethyl-3-iodo-indole compound according to claim 1, wherein: in said step (1), 0.6mmol of indole compound is added to at least 3.0mg of acetonitrile.
5. The method for producing 2-trifluoromethyl-3-iodo-indole compound according to claim 1, wherein: in the step (3), when column chromatography is used for separation and purification, a silica gel column chromatography separation method is adopted, and a developing agent adopts a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 150-300:1, or adopts petroleum ether.
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