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CN109776295B - Aryl iodine compound containing difluoromethylene at ortho-position and preparation method thereof - Google Patents

Aryl iodine compound containing difluoromethylene at ortho-position and preparation method thereof Download PDF

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CN109776295B
CN109776295B CN201910119196.9A CN201910119196A CN109776295B CN 109776295 B CN109776295 B CN 109776295B CN 201910119196 A CN201910119196 A CN 201910119196A CN 109776295 B CN109776295 B CN 109776295B
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aryl iodide
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CN109776295A (en
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黄鑫
张亚鸽
许滢
彭勃
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Zhejiang Normal University CJNU
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Abstract

The invention discloses a method for preparing an aryl iodide compound containing difluoromethylene at the ortho-position, which is characterized in that in the presence of trimethylsilyl trifluoromethanesulfonate, aryl iodide diacetate shown in a structural formula (I) and difluoroacetophenone enol silyl ether shown in a structural formula (II) are subjected to rearrangement reaction to obtain an aryl iodide compound containing difluoromethylene shown in a structural formula (III); wherein R is1Selected from hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl, haloalkyl, haloalkoxy, alkyl substituted by alkoxycarbonyl, alkyl substituted by amino, alkoxycarbonyl and alkyl substituted by amino, cyano or nitro, and Ar is selected from benzene ring, naphthalene ring and thiophene ring. The method has the advantages of mild reaction conditions, good selectivity, high yield, easy product separation, simple operation and the like.

Description

Aryl iodine compound containing difluoromethylene at ortho-position and preparation method thereof
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a method for preparing an aryl iodide compound containing difluoromethylene at the ortho-position and a compound.
Background
Difluoromethylene is generally considered as a bioisostere of oxygen atoms, carbonyl groups and methylene groups, has good metabolic stability and high lipophilicity, and the enhancement of lipophilicity is beneficial to improving the permeability and absorptivity of organic molecules, so that the compound containing difluoromethylene functional groups has wide application in the fields of medicines, pesticides and materials (chem biochem2004,5,570; chem. eur.j.2017,23,14676).
Among these difluoromethylene-containing compounds, difluoromethylene-containing aromatic compounds are of great interest because these compounds are widely present in a wide variety of biologically important molecules (chem. rev.2016,2,422). For example, the drug ledipasvir for the treatment of hepatitis c (j.med.chem.2014,57,2033); nitric oxide synthase selective inhibitors for the treatment of neurodegenerative diseases (j.am. chem. soc.2010,132, 14229). Therefore, the research and development of a new method for preparing the aromatic compound containing the difluoromethylene group have important practical significance.
The Synthesis of aromatic compounds containing difluoromethylene groups is generally achieved by deoxofluorination of aromatic aldehydes (Synthesis1973,12,787; j.org.chem.1975,40,574) or difluoromethyleneization with the participation of transition metals (Asian j.org.chem.2017,6,139; chem.eur.j.2015,21,12836; top. organomet.chem.2014,52,113). The former has the disadvantage that not only is the functional group compatibility poor, but the fluorination reagents used are generally somewhat hazardous. In the latter case, the reaction often relies on the use of expensive transition metal catalysts, and certain reactions must be carried out under severe conditions.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a novel method for preparing an aryl iodide compound containing difluoromethylene at the ortho-position, and the method has the advantages of mild reaction conditions, good selectivity, high yield, easy separation of products, simple operation, wide space for further functionalization and the like, wherein iodine reserved in the product structure can be used as a leaving group.
The technical scheme adopted by the invention is as follows:
a method for preparing aryl iodide compounds containing difluoromethylene at the ortho-position comprises the following steps of carrying out rearrangement reaction on aryl iodide diacetate shown in a structural formula (I) and difluoroacetophenone enol silyl ether shown in a structural formula (II) in the presence of trimethylsilyl trifluoromethanesulfonate to synthesize aryl iodide compounds containing difluoromethylene at the ortho-position shown in a structural formula (III), wherein the general formula of the reaction is as follows:
Figure BDA0001971266340000021
the diacetic acid aryl iodide shown in the structural formula (I) and the ortho-position difluoro methylene containing aryl iodide compound shown in the structural formula (III) can also be represented by the following structures:
Figure BDA0001971266340000022
wherein R is1Selected from hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl (including ester group), haloalkyl, haloalkoxy, alkyl substituted by alkoxycarbonyl, alkyl substituted by amino, alkoxycarbonyl and alkyl substituted by amino, cyano or nitro, and Ar is selected from benzene ring, naphthalene ring and thiophene ring.
Preferably, in the formulae (I) to (III), R1Selected from hydrogen, halogen, C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Haloalkyl, C1～C4Haloalkoxy, C1～C4Alkoxycarbonyl substituted C1～C4Alkyl, amino substituted C1～C4Alkyl radical, C1～C4Alkoxycarbonyl and amino substituted C1～C4Alkyl or cyano, Ar is selected from benzene ring, naphthalene ring and thiophene ring, and the amino comprises H2N-or C1～C4Alkyl-substituted amino groups.
In the present invention, the halogen is preferably F, Cl, Br; c1～C4The alkyl group includes methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl and the like, and preferably methyl or ethyl. C1～C4Alkoxy includes methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, preferably methoxy, ethoxy. C1～C4Haloalkyl includes methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, and the like, preferably methyl, ethyl, substituted with one or more of F, Cl, Br (preferably Cl). C1～C4The haloalkoxy group comprises one or moreMethoxy, ethoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, etc., each substituted with F, Cl, Br, etc., preferably methoxy, ethoxy. The alkoxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl and the like.
Preferably, R1Selected from hydrogen, cyano, methyl, ethyl, chloromethyl, methoxycarbonyl, 2-methoxycarbonyl-2-tert-butoxycarbonylaminoethyl.
As a further preference, the aryl iodide diacetate represented by structural formula (I) is selected from one of the following compounds:
Figure BDA0001971266340000031
taking iodobenzene diacetate and difluoroacetophenone enol silyl ether as an example of the rearrangement reaction, the reaction mechanism is as follows:
Figure BDA0001971266340000032
the activated diacetic acid aryl iodine is converted into bis (trifluoromethanesulfonic) iodobenzene 1 with extremely strong electrophilicity, and can be subjected to nucleophilic attack by difluoroacetophenone enol silyl ether in a system to obtain an intermediate 2, then [3,3] rearrangement is carried out to obtain an intermediate 3, and finally the target product is obtained after aromaticity is recovered. By the assembling mode, the reaction time is greatly shortened, and the functional group compatibility of a reaction substrate is greatly improved due to the high identification of difluoroacetophenone enol silyl ether on the active intermediate 1.
Preferably, the adding molar ratio of the aryl iodide diacetate to the difluoroacetophenone enol silyl ether is 1: (1-3), more preferably 1: (1.2 to 2.2), more preferably 1: 2.
preferably, the adding molar ratio of the trimethylsilyl trifluoromethanesulfonate to the aryl iodide diacetate is (1-3): 1, more preferably (1.2 to 2.2): 1, more preferably 2: 1.
Preferably, the rearrangement reaction is carried out in a solvent selected from one or more of dichloromethane, chloroform, methanol, acetonitrile, acetone. More preferably, the reaction solvent is dichloromethane. The volume mol ratio of the reaction solvent to the aryl iodide diacetate is 8-20 mL: 1 mmol.
Preferably, the difluoroacetophenone enol silyl ether is added into a solution dissolved with iodobenzene diacetate and trimethylsilyl trifluoromethanesulfonate at a low temperature of-70 to-85 ℃.
Preferably, the temperature of the rearrangement reaction is-60 to-90 ℃, more preferably-70 to-85 ℃, more preferably-75 to-80 ℃, and the reaction time is 5 to 30min, more preferably 5 to 10 min.
After the rearrangement reaction is finished, the target product can be obtained through post-treatment. The preferred post-treatment method is as follows:
and after the rearrangement reaction is finished, adding saturated sodium bicarbonate to quench the reaction, heating to room temperature, extracting, drying an organic phase, and concentrating to obtain a concentrated solution, wherein the obtained concentrated solution is subjected to recrystallization or column chromatography to obtain a high-purity target product. The extractant can be dichloromethane.
An aryl iodide compound containing difluoromethylene at the ortho-position has a structure shown as the following general formula:
Figure BDA0001971266340000041
wherein R is1Selected from hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl, haloalkyl, haloalkoxy, alkyl substituted by alkoxycarbonyl, alkyl substituted by amino, alkoxycarbonyl and alkyl substituted by amino, cyano or nitro, and Ar is selected from benzene ring, naphthalene ring and thiophene ring.
Preferably, R1Selected from hydrogen, halogen, C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Haloalkyl, C1～C4Haloalkoxy, C1～C4Alkoxycarbonyl substituted C1～C4Alkyl, amino substituted C1～C4Alkyl radical, C1～C4Alkoxycarbonyl and amino substituted C1～C4Alkyl or cyano, Ar is selected from benzene ring, naphthalene ring and thiophene ring, and the amino comprises H2N-or C1～C4Alkyl-substituted amino groups.
Preferably, R1Selected from hydrogen, cyano, methyl, ethyl, chloromethyl, methoxycarbonyl, 2-methoxycarbonyl-2-tert-butoxycarbonylaminoethyl.
Preferably, the compound has a structure represented by the following structural formula:
Figure BDA0001971266340000042
Figure BDA0001971266340000051
preferably, the structure is as follows:
Figure BDA0001971266340000052
compared with the prior art, the method synthesizes the aryl iodide compound containing difluoromethylene at the ortho position under mild conditions by using aryl iodide diacetate and difluoroacetophenone enol silyl ether, and has the advantages that:
(1) the method has the advantages of mild reaction conditions, good selectivity, high yield, easy product separation and simple operation;
(2) the raw materials used in the method are cheap and easy to obtain, and the defects that a dangerous fluorinating reagent or an expensive metal catalyst is used in the traditional method, the reaction condition is strict, and the reaction substrate is limited are avoided;
(3) the obtained product contains aryl iodine, can be further subjected to coupling reaction, and opens up a new synthetic way for synthesizing the aryl compound with wider functional groups and multi-substituted ortho-position containing difluoromethylene;
(4) the obtained product contains benzoyl, and the benzoyl can be further removed under alkaline conditions to obtain difluoromethyl.
Detailed Description
Example 1
Figure BDA0001971266340000053
N2Redistilled dichloromethane (5mL) was added to a 25mL reaction tube under protection, then iodobenzene diacetate 161mg (0.5mmol) was added, then trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol) was added in 180 μ l, the reaction mixture was stirred at room temperature for 5min, finally difluoroacetophenone enolsilyl ether 228mg (1.0mmol) was added at-78 ℃, stirred for 5min, the reaction progress was followed by thin layer chromatography, after the reaction was finished, saturated sodium bicarbonate solution (3mL) was added to quench the reaction, the temperature was slowly raised to room temperature, then dichloromethane (3mL × 3) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, separated by column chromatography (Rf 0.19, developer: petroleum ether/ethyl acetate 40/1, v/v), and the product was obtained as a colorless oil with a purity of 99.78% and a yield of 83%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.14(dd,J＝8.4,1.1Hz,2H),7.96(dd,J＝7.9,0.8Hz,1H),7.73(dd,J＝7.9,1.6Hz,1H),7.67–7.62(m,1H),7.53–7.48(m,3H),7.22–7.15(m,1H)。
13C NMR(151MHz,CDCl3):δ188.1(t,J＝31.7Hz),141.4,136.9(t,J＝22.7Hz),134.2,133.2,132.1,130.3(t,J＝3.0Hz),128.8,128.11,128.08(t,J＝9.1Hz),117.1(t,J＝256.7Hz),93.4(t,J＝4.5Hz)。
19F NMR(565MHz,CDCl3):δ-96.1。
IR(neat):3060,2978,2919,2846,1710,1597,1448,1232,1052,1009,758。
HRMS(ESI-TOF):calculated for[C14H9F2IONa(M+Na+)]:380.9558,found:380.9566。
example 2
Figure BDA0001971266340000061
N2Redistilled dichloromethane (5mL) was added to a 25mL reaction tube under protection, 178mg (0.5mmol) of para-chlorinated iodobenzene diacetate was added, then adding 180 microliter trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction solution at room temperature for 5min, finally adding 228mg (1.0mmol) of difluoroacetophenone enol silyl ether at-78 ℃, stirring for 5min, tracking the reaction progress by using a thin layer chromatography, adding a saturated sodium bicarbonate solution (3ml) after the reaction is finished to quench the reaction, slowly heating to room temperature, then extracted with dichloromethane (3 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, separation by column chromatography (Rf 0.20, developing solvent: petroleum ether/ethyl acetate 40/1, v/v) gave the product as a pale yellow solid with a purity of greater than 99% and a yield of 65%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.15(d,J＝7.5Hz,2H),7.86(d,J＝8.4Hz,1H),7.70(d,J＝2.5Hz,1H),7.67(t,J＝7.5Hz,1H),7.53(t,J＝7.8Hz,2H),7.17(dd,J＝8.4,2.4Hz,1H)。
13C NMR(151MHz,CDCl3):δ187.5(t,J＝31.7Hz),142.3,138.5(t,J＝24.2Hz),134.9,134.4,132.8,132.1,130.3(t,J＝4.5Hz),128.8,128.4(t,J＝10.5Hz),116.5(t,J＝258.2Hz),90.5(t,J＝4.5Hz)。
19F NMR(565MHz,CDCl3):δ-96.4。
IR(neat):3089,3071,1691,1596,1577,1447,1223,1104,1077,1006,869,820。
HRMS(ESI-TOF):calculated for[C14H8ClF2IONa(M+Na+)]:414.9169,found:414.9171。
example 3
Figure BDA0001971266340000071
N2Under protection, will weigh heavilyDistilled dichloromethane (5mL) was added to a 25mL reaction tube, and 173mg (0.5mmol) of para-cyano-substituted iodobenzene diacetate was added, then adding 180 microliter trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction solution at room temperature for 5min, finally adding 228mg (1.0mmol) of difluoroacetophenone enol silyl ether at-78 ℃, stirring for 5min, tracking the reaction progress by using a thin layer chromatography, adding a saturated sodium bicarbonate solution (3ml) after the reaction is finished to quench the reaction, slowly heating to room temperature, then extracted with dichloromethane (3 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, separation by column chromatography (Rf 0.25, developing solvent: petroleum ether/ethyl acetate 20/1, v/v) gave the product as a pale yellow solid with a purity of greater than 99% and a yield of 56%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.16(d,J＝7.7Hz,2H),8.10(d,J＝8.1Hz,1H),7.94(d,J＝1.4Hz,1H),7.69(t,J＝7.5Hz,1H),7.55(t,J＝7.8Hz,2H),7.46–7.41(m,1H)。
13C NMR(151MHz,CDCl3):δ187.2(t,J＝31.7Hz),142.4,138.8(t,J＝22.7Hz),134.8,134.5,131.0(t,J＝9.0Hz),130.3(t,J＝6.0Hz),129.4,128.9,128.7,117.6(t,J＝256.7Hz),112.6,90.4(t,J＝4.5Hz)。
19F NMR(565MHz,CDCl3):δ-96.6。
IR(neat):3079,2956,2233,1704,1592,1459,1235,1125,1012,893,829。
HRMS(ESI-TOF):calculated for[C15H8F2INONa(M+Na+)]:405.9511,found:405.9514。
example 4
Figure BDA0001971266340000081
N2Redistilled dichloromethane (5mL) was added to a 25mL reaction tube, followed by 185mg (0.5mmol) of iodobenzene p-chloromethyldiacetate, followed by 180. mu.L trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), and reaction, under protectionThe reaction solution is stirred for 5min at room temperature, and finally difluoroacetophenone enol silyl ether 228mg (1.0mmol) is added at-78 ℃, the reaction is stirred for 5min, the reaction process is tracked by thin layer chromatography, saturated sodium bicarbonate solution (3mL) is added after the reaction is finished, the reaction is quenched, the temperature is slowly raised to the room temperature, then dichloromethane (3mL × 3) is used for extraction, an organic phase is dried by anhydrous sodium sulfate, vacuum concentration is carried out, and separation is carried out by column chromatography (Rf is equal to 0.20, a developing solvent is petroleum ether/ethyl acetate is equal to 50/1, v/v), so that the obtained product is light yellow oily matter, the purity is more than 99%, and the yield is 59%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.05(d,J＝7.6Hz,2H),7.84(d,J＝8.1Hz,1H),7.63(d,J＝2.1Hz,1H),7.58–7.54(m,1H),7.44–7.40(m,2H),7.13(dd,J＝8.1,2.1Hz,1H),4.50(s,2H)。
13C NMR(151MHz,CDCl3):δ188.0(t,J＝31.7Hz),141.8,137.9,137.5(t,J＝24.2Hz),134.4,133.0,132.1,130.4(t,J＝3.0Hz),128.9,128.2(t,J＝9.0Hz),117.0(t,J＝256.7Hz),93.3(t,J＝4.5Hz),45.1。
19F NMR(565MHz,CDCl3):δ-96.4。
IR(neat):3061,295,1697,1596,1448,1239,1124,1010,856,820。
HRMS(ESI-TOF):calculated for[C15H10ClF2IONa(M+Na+)]:428.9325,found:428.9337。
example 5
Figure BDA0001971266340000091
N2Adding redistilled dichloromethane (5mL) into a 25mL reaction tube under protection, adding 190mg (0.5mmol) of para-methoxycarbonyl substituted iodobenzene diacetate, adding 180 microliter trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction solution at room temperature for 5min, adding 228mg (1.0mmol) of difluoroacetophenone enol silyl ether at-78 ℃, stirring for 5min, tracking the reaction progress by thin layer chromatography, and after the reaction is finished, addingThe reaction was quenched by addition of saturated sodium bicarbonate solution (3mL), slowly warmed to room temperature, then extracted with dichloromethane (3mL × 3), the organic phase dried over anhydrous sodium sulfate, concentrated in vacuo, and isolated by column chromatography (Rf ═ 0.22, developing solvent: petroleum ether/ethyl acetate ═ 20/1, v/v) to give the product as a pale yellow oil with a purity of greater than 99% and a yield of 57%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.35(d,J＝2.0Hz,1H),8.15(d,J＝7.5Hz,2H),8.04(d,J＝8.2Hz,1H),7.80(dd,J＝8.2,2.0Hz,1H),7.69–7.61(m,1H),7.55–7.49(m,2H),3.94(s,3H)。
13C NMR(151MHz,CDCl3):δ187.7(t,J＝31.7Hz),165.9,141.8,137.5(t,J＝24.2Hz),134.4,132.8,132.6,130.3(t,J＝3.0Hz),128.9(t,J＝9.0Hz),128.8,128.7,117.0(t,J＝256.7Hz),99.7(t,J＝4.5Hz),52.6。
19F NMR(565MHz,CDCl3):δ-96.1。
IR(neat):3102,3074,2999,1716,1699,1594,1445,1220,1112,1010,856,820,763,718。
HRMS(ESI-TOF):calculated for[C16H11F2IO3Na(M+Na+)]:438.9613,found:438.9622。
example 6
Figure BDA0001971266340000101
N2Adding redistilled dichloromethane (5mL) into a 25mL reaction tube under protection, adding 262mg (0.5mmol) of 4- ((2S) -2-tert-butoxycarbonylamino-2-methoxycarbonyl ethyl diacetic acid iodobenzene (the structure is shown as the formula), then adding 180 microliter of trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction liquid at room temperature for 5min, finally adding 228mg (1.0mmol) of difluoroacetophenone enol silyl ether at-78 ℃, stirring for 5min, tracking the reaction progress by thin layer chromatography, adding saturated sodium bicarbonate solution (3mL) after the reaction is finished, quenching the reaction, slowly heating to room temperature, and then adding difluoroacetophenone enol silyl ether (1.0mmol) into the reaction tube by using a solvent of the mixtureMethyl chloride (3mL × 3) was extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo and isolated by column chromatography (Rf ═ 0.23, developing solvent: petroleum ether/ethyl acetate ═ 10/1, v/v) to give the product as a pale yellow oil with a purity of greater than 99% and a yield of 65%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.08(d,J＝7.6Hz,2H),7.83(d,J＝8.0Hz,1H),7.64–7.59(m,1H),7.52–7.44(m,3H),6.96(d,J＝7.9Hz,1H),5.12(d,J＝7.6Hz,1H),4.60(d,J＝6.8Hz,1H),3.70(s,3H),3.25–3.05(m,2H),1.41(s,9H)。
13C NMR(151MHz,CDCl3):δ187.9(t,J＝33.2Hz),171.8,155.3,141.4,137.2(t,J＝22.6Hz),136.7,134.2,133.1,131.4,130.2,129.1(t,J＝12.1Hz),128.8,116.8(t,J＝383.5Hz),91.4(t,J＝6.0Hz),80.3,60.5,54.2,52.5,37.9,28.3,21.1,14.3。
19F NMR(565MHz,CDCl3):δ-96.0。
IR(neat):2977,1741,1700,1597,1498,1448,1241,1159,1125,1009,853,817。
HRMS(ESI-TOF):calculated for[C23H24F2INO5Na(M+Na+)]:582.0559,found:582.0558。
example 7
Figure BDA0001971266340000102
N2Adding redistilled dichloromethane (5mL) into a 25mL reaction tube under protection, adding iodonaphthalene diacetate 186mg (0.5mmol), adding 180 microliter trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction solution at room temperature for 5min, adding difluoroacetophenone enol silyl ether 228mg (1.0mmol) at-78 ℃, stirring for 5min, tracking the reaction progress by thin layer chromatography, adding saturated sodium bicarbonate solution (3mL) after the reaction is finished, quenching the reaction, slowly heating to room temperature, extracting with dichloromethane (3mL x 3), drying the organic phase with anhydrous sodium sulfate, vacuum concentrating, passing through a column layer, and filtering to obtain the final productSeparation by chromatography (Rf 0.72, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) gave the product as a pale yellow oil with a purity of greater than 99% and a yield of 53%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ78.32–78.27(m,1H),78.14(d,J＝7.5Hz,2H),77.99(d,J＝8.6Hz,1H),77.86–77.82(m,2H),77.65–77.58(m,3H),77.52–77.47(m,2H)。
13C NMR(151MHz,CDCl3):δ188.5(t,J＝33.2Hz),136.6(t,J＝24.2Hz),135.1,134.7,134.1,133.53,133.48,130.3(t,J＝3.0Hz),129.5,128.8,128.7,128.6,128.3,124.0(t,J＝9.0Hz),117.7(t,J＝256.7Hz),101.8(t,J＝4.5Hz)。
19F NMR(565MHz,CDCl3):δ-93.9。
IR(neat):3059,2920,1685,1595,1448,1224,1129,1066。
HRMS(ESI-TOF):calculated for[C18H11F2IONa(M+Na+)]:430.9715,found:430.9722。
example 8
Figure BDA0001971266340000111
N2Redistilled dichloromethane (5mL) was added to a 25mL reaction tube under protection, 163mg (0.5mmol) iodothiophene diacetate was added, then adding 180 microliter trimethylsilyl trifluoromethanesulfonate (TMSOTf,1.0mmol), stirring the reaction solution at room temperature for 5min, finally adding 228mg (1.0mmol) of difluoroacetophenone enol silyl ether at-78 ℃, stirring for 5min, tracking the reaction progress by using a thin layer chromatography, adding a saturated sodium bicarbonate solution (3ml) after the reaction is finished to quench the reaction, slowly heating to room temperature, then extracted with dichloromethane (3 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, separation by column chromatography (Rf 0.69, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) gave the product as a pale yellow solid with a purity of greater than 99% and a yield of 72%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.09(d,J＝7.6Hz,2H),7.68–7.60(m,1H),7.52–7.46(m,2H),7.39(d,J＝5.1Hz,1H),7.17–7.13(m,1H)。
13C NMR(151MHz,CDCl3):δ186.1(t,J＝33.2Hz),138.0,134.5,134.1,132.2,130.4(t,J＝3.0Hz),129.2,128.8,115.3(t,J＝256.7Hz),80.4(t,J＝6.4Hz)。
19F NMR(565MHz,CDCl3):δ-88.0。
IR(neat):3106,2919,1697,1594,1415,1219,1127,1078,715。
HRMS(ESI-TOF):calculated for[C12H7F2IOSNa(M+Na+)]:386.9123,found:386.9129。
example 9
Figure BDA0001971266340000121
The rearrangement product obtained in the example 1 can further realize debenzoylation under the alkaline (KOH is taken as an example) condition and methanol is taken as a solvent under the reflux condition for 1 hour, and the aryl iodine compound containing difluoromethyl can be finally obtained after the conventional post-treatment (the yield is about 90%). The chemical is an important drug intermediate (CAS1214334-19-6), which is not sold at home at present, and the price is up to 1g thousands of dollars abroad.
The substrates of examples 2 to 8 can also be subjected to similar reactions to obtain the corresponding difluoromethyl group-containing aryl iodide compounds with a yield of about 80 to 95%.
Example 10
Figure BDA0001971266340000122
Under the conditions of palladium catalyst and alkalinity (taking potassium tert-butoxide as an example), 1, 4-dioxane as a solvent is taken as a solvent, and the reaction is carried out for 1 hour under the reflux condition, the rearrangement product obtained in the example 1 and the bis (pinacolato) borate react (the molar ratio is 1: 1) to realize the coupling of C-B bond and the removal of debenzoyl by a one-pot method, the synthesized product is an important medicine intermediate (the yield is 87 percent), and the product has the price of 1g of 6000 Yuan (CAS 879275-72-6) after Shanghai Biao.
The substrates of examples 2-8 can also be subjected to similar reactions to obtain corresponding drug intermediates, with yields of about 80-90%.

Claims (7)

1. A method for preparing aryl iodide compounds containing difluoromethylene at ortho-position is characterized in that aryl iodide diacetate shown in a structural formula (I) and difluoroacetophenone enol silyl ether shown in a structural formula (II) are subjected to rearrangement reaction in the presence of trimethylsilyl trifluoromethanesulfonate to obtain aryl iodide compounds containing difluoromethylene shown in a structural formula (III);
the structural formula (I), the structural formula (II) and the structural formula (III) are respectively as follows:
Figure FDA0003140958710000011
wherein R is1Selected from hydrogen, halogen, alkyl, alkoxy, alkoxycarbonyl, haloalkyl, haloalkoxy, alkyl substituted by alkoxycarbonyl, alkyl substituted by amino, alkoxycarbonyl and alkyl substituted by amino, cyano or nitro, and Ar is selected from benzene ring, naphthalene ring and thiophene ring.
2. The method of claim 1, wherein R is selected from the group consisting of1Selected from hydrogen, halogen, C1～C4Alkyl radical, C1～C4Alkoxy radical, C1～C4Haloalkyl, C1～C4Haloalkoxy, C1～C4Alkoxycarbonyl substituted C1～C4Alkyl, amino substituted C1～C4Alkyl radical, C1～C4Alkoxycarbonyl and amino substituted C1～C4Alkyl or cyano, Ar is selected from benzene ring, naphthalene ring and thiophene.
3. The method of claim 1, wherein R is selected from the group consisting of1Selected from hydrogen, cyano, methyl, ethyl, chloromethyl, methoxycarbonyl, 2-methoxycarbonyl-2-tert-butoxycarbonylaminoethyl.
4. The method of claim 1, wherein the molar ratio of aryl iodide diacetate to difluoroacetophenone enol silyl ether is 1: 1 to 3.
5. The method for preparing aryl iodide compounds containing difluoromethylene at the ortho-position according to claim 1, wherein the molar ratio of trimethylsilyl trifluoromethanesulfonate to aryl iodide diacetate is 1-3: 1.
6. the method for preparing an aryl iodide compound containing a difluoromethylene group at the ortho-position according to claim 1, wherein the rearrangement reaction is carried out in a solvent selected from one or more of dichloromethane, chloroform, acetonitrile and acetone.
7. The method for preparing an aryl iodide compound containing a difluoromethylene group at the ortho-position as claimed in claim 1, wherein the temperature of the rearrangement reaction is-60 to-90 ℃.
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