CN110724040B - Method for synthesizing iodo-trifluoromethoxyl compound - Google Patents

Method for synthesizing iodo-trifluoromethoxyl compound Download PDF

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CN110724040B
CN110724040B CN201910995410.7A CN201910995410A CN110724040B CN 110724040 B CN110724040 B CN 110724040B CN 201910995410 A CN201910995410 A CN 201910995410A CN 110724040 B CN110724040 B CN 110724040B
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trifluoromethoxy
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CN110724040A (en
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汤平平
黄庆云
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Nankai University
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Abstract

The embodiment of the invention provides a method for synthesizing a trifluoromethoxy compound, which is characterized by comprising the following steps of: (1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent; (2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I). The synthesis method of the iodo-trifluoromethoxy compound provided by the invention can construct a functional group compound simultaneously having iodo and trifluoromethoxy.

Description

Method for synthesizing iodo-trifluoromethoxyl compound
Technical Field
The invention relates to the field of organic chemistry, in particular to a synthetic method of an iodo-trifluoromethoxy compound.
Background
Fluorine-containing drugs have been rapidly developed in recent 30 years, accounting for 36% of small molecule drugs in the market, and the directional fluorination of drug molecules has become the most important part of drug design, and the specific gravity of fluorine-containing molecules in pesticide molecules has also increased year by year. In addition, in the related art of materials, fluorine-containing materials account for nearly half of the military tip materials due to their unique stability and physical properties. Fluorine-containing compounds have been widely used in the fields of medicinal chemistry, agricultural chemicals, organic synthesis, materials, PET, and the like. However, due to the specific nature of fluoride, how to construct such compounds has been the subject of synthetic and pharmaceutical chemistry research. In recent years, a plurality of mild and simple methods for constructing small-molecule fluorine-containing compounds are developed, wherein fluorine elements or fluorine-containing functional groups (OCF)3Etc.) has become an important strategy to improve materials and develop new drugs. Due to trifluoromethoxy group (OCF)3) Has the characteristics of stronger electroabsorbability and extremely high lipophilicity, and the synthesis of the compounds is concerned by fluorine chemists.
Iodo compounds play an important role in organic synthesis, and can undergo various types of organic reactions, including S, due to the strong activity of iodine atomsN2 nucleophilic substitution reactions, free radical type reactions, and metal catalyzed coupling reactions, among others, are important intermediates in organic synthesis. The iodo reaction and the trifluoromethoxy reaction are combined, and the synthesis method of the fluoro compound is enriched whileStarting from the product, other fluoro compounds with more complex structures and higher application values can be further synthesized.
Disclosure of Invention
The embodiment of the invention aims to provide a method for synthesizing iodo-trifluoromethoxy compounds, so as to realize the construction of functional compounds with iodo groups and trifluoromethoxy groups. The specific technical scheme is as follows:
1. a method for synthesizing a trifluoromethoxy compound, comprising the steps of:
(1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent;
(2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I);
Figure BDA0002239569170000021
wherein R is1、R2、R3And R4Each independently represents H, halogen, hydroxyl, nitro, cyano, mercapto, amino, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl, C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z radical, said C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl, C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,
Figure BDA0002239569170000022
Said C is5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);
the Z radical is
Figure BDA0002239569170000023
And R is1、R2、R3And R4At most one of which is said C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z group;
or, at R1、R2、R3And R4The method comprises the following steps:
R1、R2one of (1) and R3、R4One of them together with the carbon atom to which each is attached in formula (I) forms C5-8Monocyclic or bicyclic; r1、R2、R3、R4Wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl radical, said C5-8Monocyclic or bicyclic ring, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, benzyloxy;
R5representative H, C1-6Alkyl, halogen, nitro, cyano, mercapto, amino, C1-6An alkyloxy group; said C is1-6Alkyl and C1-6The alkyloxy group is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl and nitro.
In some embodiments of the invention, R1、R2、R3And R4Each represents H, C respectively1-13Alkyl radical, C5-12Cycloalkenyl radical, C6-10Aryl radical, C6-10Heteroaryl or Z radical, said C1-13Alkyl radical, C5-12CycloalkenesBase, C6-10Aryl radical, C6-10Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, C1-4Alkyl radical, C1-4Alkylcarbonyloxy, C1-4Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,
Figure BDA0002239569170000031
Said C is5-12Cycloalkenyl radical, C6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);
the Z radical is
Figure BDA0002239569170000032
And R is1、R2、R3And R4At most one of which is said C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z group;
or, at R1、R2、R3And R4The method comprises the following steps:
R1、R2one of (1) and R3、R4One of them together with the carbon atom to which each is attached in formula (I) forms C5-8A single ring;
R1、R2、R3、R4wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl radical, said C5-8Monocyclic ring, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, C1-4Alkyl radical, C1-4Alkylcarbonyloxy, C1-4An alkoxycarbonyl group;
R5represents H, halogen, C1-6Alkyl radical, C1-6An alkyloxy group; said C is1-6Alkyl radical, C1-6The alkyloxy group is unsubstituted or optionally substituted with one or more halo.
During the experiment, the inventors of the present invention unexpectedly found that the addition sequence of the compound of formula (III) and the compound of formula (II) affects the yield of the compound of formula (I); specifically, the compound of the formula (I) obtained by the reaction is high in generation yield after the compound of the formula (II) is mixed with other reactants such as a solvent and the like and then the compound of the formula (III) is added; on the contrary, the compound of formula (I) obtained by the reaction is low in yield when the compound of formula (III) is mixed with other reactants such as solvent and the like and stirred for a period of time in the absence of light.
In some embodiments of the invention, R1、R2、R3And R4At least one of them represents H.
In some embodiments of the invention, the compound of formula (ii) is selected from the following compounds:
Figure BDA0002239569170000041
Figure BDA0002239569170000051
in some embodiments of the invention, the compound of formula (iii) is selected from the following compounds:
Figure BDA0002239569170000052
in some embodiments of the present invention, the compound of formula (iii) is in molar excess of the compound of formula (ii), preferably the molar ratio of the compound of formula (iii) to the compound of formula (ii) is 3 to 5: 1.
in some embodiments of the invention, the solvent is selected from one or at least two of dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, chloroform, acetonitrile; preferably, the solvent is a mixture of acetonitrile and dichloromethane, and more preferably, the volume ratio of acetonitrile to dichloromethane is (1:2) to (2: 1).
In some embodiments of the invention, the fluoride salt is selected from LiF, NaF, KF, CsF, ZnF2、MgF2、CaF2、NMe4One or at least two of F; preferably, the molar ratio of the fluorine salt to the compound of formula (II) is (0.5-1): 1.
in some embodiments of the invention, the iodinating agent is selected from one or at least two of N-iodosuccinimide, N-iodophthalimide, diiodohydantoin, elemental iodine; preferably, the molar ratio of the iodinating agent to the compound of formula (II) is (1-5): 1, preferably (3-5): 1.
the structural formula of each iodinating agent is as follows:
Figure BDA0002239569170000061
in some embodiments of the invention, in step (1), the pre-reaction system further comprises a chiral catalyst; preferably, the chiral catalyst is selected from one or at least two of hydrogenated quinine 1,4- (2, 3-naphthyridine) diether, hydrogenated quinine (anthraquinone-1, 4-diyl) diether or hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether; more preferably, the molar ratio of the chiral catalyst to the compound of formula (II) is (0.05-0.2): 1, preferably (0.1 to 0.15): 1. each chiral catalyst is commercially available and the molecular formula of the chiral catalyst is shown in table 1.
TABLE 2 molecular formulae of the chiral catalysts
Figure BDA0002239569170000062
Figure BDA0002239569170000071
In some embodiments of the invention, in step (1), the pre-reaction system further comprises a silver salt; preferably, the silver salt is selected from one or at least two of silver fluoride, silver carbonate, silver trifluoromethanesulfonate, silver oxide, silver tetrafluoroborate, silver nitrate, silver sulfate and silver benzoate; more preferably, the molar ratio of silver salt to compound of formula (II) (0.2-1.5): 1, preferably (1.0 to 1.5): 1.
in some embodiments of the invention, in step (2), the reaction temperature is from 30 to-20 ℃, preferably from 0 to-20 ℃, more preferably-10 ℃; the reaction time is 8-20 hours; preferably, the compound of formula (III) is added to the pre-reaction system in step (2) when the temperature of the pre-reaction system is from 30 ℃ to-20 ℃, preferably from 0 ℃ to-20 ℃, more preferably-10 ℃.
Herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.
Herein, the term "C1-13Alkyl "refers to straight or branched chain saturated hydrocarbon groups containing 1 to 13 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and n-undecyl. "C1-6Alkyl group "," C1-4Alkyl "refers to the above examples containing 1 to 6 carbon atoms, 1 to 4 carbon atoms, respectively.
Herein, the term "C2-13Alkenyl "refers to straight or branched chain hydrocarbon radicals containing from 2 to 13 carbon atoms and having one or more carbon-carbon double bonds, including but not limited to ethenyl, 2-propenyl, and 3-dodecene. "C2-6Alkenyl "refers to the above examples containing 2 to 6 carbon atoms.
Herein, the term "C2-13Alkynyl "refers to a straight or branched chain hydrocarbon group containing 2 to 13 carbon atoms and having one or more carbon-carbon triple bonds, and may optionally also include one or more carbon-carbon double bonds, including but not limited to ethynyl, propynyl, and 3-dodecynyl. "C2-6Alkynyl "refers to the above examples containing 2 to 6 carbon atoms.
Herein, the term "C5-12Cycloalkyl "means a saturated cyclic hydrocarbon group containing 5 to 12 carbon atoms, which may have one or more rings, preferably one or two rings, including but not limited to cyclopentyl, cyclohexyl, and cyclooctyl.
Herein, the term "C5-12Cycloalkenyl "means containing 5-12 carbon atoms, and having one or more carbon-carbon double bonds, which may have one or more rings, preferably one or two rings, including but not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclooctenyl.
Herein, the term "C6-14Aryl "refers to a cyclic carbocyclic hydrocarbon group containing from 6 to 14 ring carbon atoms consisting of one or more fused rings, at least one of which is aromatic, including but not limited to phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, and indenyl.
The term "C" as used herein6-14Heteroaryl "means an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, N, preferably 1 to 3 heteroatoms. Heteroaryl groups include mono-heteroaryl and fused heteroaryl groups, representative examples of which include, but are not limited to: furyl, imidazolyl, isoxazolyl, thiazolyl, benzothienyl, benzopyranyl and the like.
Herein, the term "substituted with … …" means that one or more hydrogen atoms on a given atom or group are replaced with one or more substituents selected from the group given, provided that the normal valence of the given atom is not exceeded.
Herein, the term "substituted with one or more substituents" means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from the given group.
In the present invention, in the radical structural formula
Figure BDA0002239569170000091
Indicates the point of attachment of the group to the rest of the molecule.
Abbreviations
Abbreviations referred to herein are as follows, and for abbreviations referred to herein but not listed, they have the ordinary meaning in the art.
NIS N-iodosuccinimide
Ac2O acetic anhydride
DMA N, N-dimethylacetamide
DMAP 4-dimethylaminopyridine
EtOAc ethyl acetate
Et3N-Triethylamine
Me methyl group
MeCN acetonitrile
Ph phenyl
Phth phthaloyl group
Bn benzyl group
t-Bu tert-butyl
Boc tert-butoxycarbonyl
THF tetrahydrofuran
Tol toluene
The embodiment of the invention provides a method for synthesizing iodo-trifluoromethoxy compounds, which can be used for constructing functional compounds with iodo and trifluoromethoxy simultaneously. The method has the advantages of simple operation, mild reaction conditions and high yield. The substrate of the method has wide application range, and the aromatic ring has electron withdrawing groups and electron donating groups, and the olefin substrate comprising ortho-position or meta-position substituent and aliphatic olefin substrate can obtain corresponding products with high yield. Meanwhile, the method can be well suitable for double-bond double-functionalization reaction of the complex natural product in the later period of molecules to prepare the corresponding trifluoromethoxy product, and provides abundant substrate diversity for bioactivity research.
Detailed Description
The technical solutions of the present invention will be described below with reference to specific embodiments, and the described embodiments are only a part of embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Synthesis example of Compound of formula (II)
Preparation of tiamulin diethyl ester
Figure BDA0002239569170000101
A100 mL reaction flask was taken, and tiamulin (700mg,1.85mmol,1.00equiv) and DMAP (4-dimethylaminepyrdine) (22.0mg,0.185mmol,0.1equiv) were added thereto with dried CH2Cl2(20.0mL) and Et was added3N (1.50mL,11.1mmol,6.00equiv) and Ac2O (0.700mL,7.40mmol,4.00equiv), reacted at room temperature for 4 h. After the reaction was complete, saturated NaHCO was used3(20.0mL) quenching, CH2Cl2(25.0 mL. times.3) extraction, combined organic phases, anhydrous MgSO4Drying, suction filtration removed solids, concentration, and column chromatography with n-hexane/EtOAc 4:1(v/v) afforded 429mg of product, 54% yield.
Rf＝0.2(n-hexane:EtOAc＝4:1).NMR Spectroscopy:1H NMR(400MHz,CDCl3)6.28(dd,J＝17.6,11.2Hz,1H),5.71(d,J＝8.2Hz,1H),5.27(d,J＝11.2Hz,1H),5.19(d,J＝17.6Hz,1H),4.88(d,J＝6.6Hz,1H),4.56–4.38(m,2H),2.52–2.41(m,1H),2.28–2.35(m,1H),2.24–2.06(m,9H),1.86–1.94(m,1H),1.64–1.74(m,2H),1.50–1.53(m,1H),1.44(s,3H),1.31–1.41(m,3H),1.13(td,J＝13.9,4.2Hz,1H),1.01(s,3H),0.80(d,J＝7.0Hz,3H),0.73(d,J＝6.9Hz,3H).13C NMR(101MHz,CDCl3)217.2,170.6,170.3,166.6,139.4,116.7,76.7,70.0,61.5,58.6,45.4,44.7,43.2,42.1,36.7,36.3,34.6,30.4,27.8,26.9,25.1,20.9,20.6,16.4,14.9,11.9.Mass Spectrometry:HRMS-ESI(m/z):Calcd for C26H38NaO7[M+Na]+,485.2510.Found,485.2513.
In addition to the above-mentioned tiamulin diethyl ester, the compounds of formula (ii) and formula (iii) used in the following examples can be prepared by the prior art or obtained commercially.
Synthesis examples of Compounds of formula (I)
Example 1Synthesis of 1- (2-iodo-1- (trifluoromethoxy) ethyl) -4-fluorobenzene (formula I-1)
Figure BDA0002239569170000111
In a glove boxTo a 4.0mL sealed tube was added AgF (21.3mg,0.168mmol,1.00equiv), (DHQD)2PHAL (13.1mg,0.0168mmol,0.100equiv), CsF (12.8mg,0.0840mmol,0.500equiv) and NIS (113mg,0.504mmol,3.00equiv), followed by addition of solvent CH3CN (0.800mL) and CH2Cl2(0.800mL) was dissolved. After the glove box was taken out, 4-fluorostyrene (formula II-1, 20.0. mu.L, 0.168mmol,1.00equiv) as a substrate was added, the reaction system was placed in a low-temperature reactor at-10 ℃ and stirred for 5min, and then a fluorinating agent TFMS (formula III-1, 130. mu.L, 0.840mmol,5.00equiv) was slowly added and reacted at-10 ℃ overnight (12 hours). After the reaction is completed, saturated Na is used2S2O3Quench the reaction (3.00mL), extract with dichloromethane, combine the organic phases, anhydrous MgSO4Drying, suction filtration, concentration and chromatography on n-hexane column gave 51mg of oily product in 90% yield.
NMR Spectroscopy:1H NMR(400MHz,CDCl3)7.37–7.30(m,2H),7.13–7.06(m,2H),5.21(t,J＝6.4Hz,1H),3.50(dd,J＝10.8,7.2Hz,1H),3.41(dd,J＝10.8,6.0Hz,1H).13C NMR(101MHz,CDCl3)163.2(d,J＝249.6Hz),133.3(d,J＝3.1Hz),128.3(d,J＝8.5Hz),121.4(q,J＝257.3Hz),116.0(d,J＝21.8Hz).,79.5(q,J＝2.3Hz),6.5.19F NMR(376MHz,CDCl3)-58.29(s,3F),-111.62–-111.69(m,1F).Mass Spectrometry:HRMS-CI(m/z):Calcd for C9H7F4O[M-I]+,207.0428.Found,207.0429.
Examples 2 to 28
Referring to the synthesis procedure of example 1, a series of compounds of formula (I) was synthesized as shown in Table 2 using the compound of formula (II) in Table 2 and the fluorinating agent TFMS (formula III-1).
Figure BDA0002239569170000121
Figure BDA0002239569170000131
Figure BDA0002239569170000141
Figure BDA0002239569170000151
Figure BDA0002239569170000161
Figure BDA0002239569170000171
Figure BDA0002239569170000181
Figure BDA0002239569170000191
Examples 28 to 35
The compound of formula I-1 was synthesized according to the synthesis method of example 1, examples 28-35 differ from example 1 in that: in examples 28 to 35, the amount of AgF added was 0.0672mmol (0.4equiv), the amount of CsF added was 0.168mmol (1.0equiv), and the amount of fluorinating agent TFMS added was 0.504mmol (3.0 equiv); the reaction temperature is 0 ℃; the solvents in table 3 below were used; the yields of the compounds of formula I-1 are shown in Table 3.
TABLE 3 Effect of different solvents
Figure BDA0002239569170000201
Note: CH in Table 33CN/CH2Cl2The ratio is volume ratio.
Examples 36 to 43
The compound of formula I-1 was synthesized by reference to the synthesis of example 1, examples 36-43 differing from example 1 in that: in examples 36 to 43, the amount of AgF added was 0.0672mmol (0.4equiv), and the amount of fluorinating agent TFMS added was 0.504mmol (3.0 equiv); the reaction temperature is 0 ℃; and the fluorine salts and their equivalents in table 4 below were used; the yields of the compounds of formula I-1 are shown in Table 4.
TABLE 4 influence of different fluorine salts and their equivalents
Figure BDA0002239569170000202
Note: eq in table 4 is equiv, which represents the equivalent.
Examples 44 to 51
The compound of formula I-1 was synthesized by reference to the synthesis of example 1, examples 44-51 differed from example 1 in that: in examples 44 to 51, the amount of AgF added was 0.0672mmol (0.4 equiv); the reaction temperature is 0 ℃; and the compounds of formula (III) and their equivalents in Table 5 below were used; the yields of the compounds of formula I-1 are shown in Table 5.
TABLE 5 influence of different compounds of the formula (III) and their equivalents
Figure BDA0002239569170000211
Examples 52 to 55
The compound of formula I-1 was synthesized according to the synthesis method of example 1, examples 52-55 differed from example 1 in that: in examples 52 to 55, the amount of AgF added was 0.0672mmol (0.4 equiv); and the reaction temperatures in table 6 below were used; the yields of the compounds of formula I-1 are shown in Table 6.
TABLE 6 Effect of different reaction temperatures
Figure BDA0002239569170000221
Examples 56 to 59
The compound of formula I-1 was synthesized according to the synthesis method of example 1, examples 56-59 being different from example 1 in that: in examples 56 to 59, the amount of AgF added was 0.0672mmol (0.4 equiv); and the NIS equivalents in table 7 below were used; the yields of the compounds of formula I-1 are shown in Table 7.
TABLE 7 Effect of different NIS equivalents
Figure BDA0002239569170000222
Examples 60 to 64
The compound of formula I-1 was synthesized with reference to the synthesis of example 1, examples 60-64 differed from example 1 in that: in examples 60 to 64, the amount of AgF added was 0.0672mmol (0.4 equiv); and using the (DHQD) in Table 8 below2PHAL equivalent; the yields of the compounds of formula I-1 are shown in Table 8.
TABLE 8 Difference (DHQD)2Effect of PHAL equivalent
Figure BDA0002239569170000223
Figure BDA0002239569170000231
Examples 65 to 69
The compound of formula I-1 was synthesized according to the synthesis method of example 1, examples 65-69 differed from example 1 in that: examples 65-69 the AgF equivalent weights in Table 9 below were used; the yields of the compounds of formula I-1 are shown in Table 9.
TABLE 9 Effect of different AgF equivalents
Figure BDA0002239569170000232
Comparative example 1Synthesis of 1- (2-iodo-1- (trifluoromethoxy) ethyl) -4-fluorobenzene (formula I-1)
In a glove box, to a 4.0mL sealed tube was added AgF (21.3mg,0.168mmol,1.00equiv), (DHQD)2PHAL (13.1mg,0.0168mmol,0.100equiv), CsF (12.8mg,0.0840mmol,0.500equiv) and NIS (113mg,0.504mmol,3.00equiv), followed by additionSolvent CH3CN (0.800mL) and CH2Cl2(0.800mL) was dissolved. After removal from the glove box, the fluorinating reagent TFMS (formula III-1, 130. mu.L, 0.840mmol,5.00equiv) was added slowly and stirred for 30 minutes in the absence of light. Then, the reaction system was placed in a low temperature reactor at-10 ℃ and stirred for 5min, followed by addition of 4-fluorostyrene (formula II-1, 20.0. mu.L, 0.168mmol,1.00equiv) as a substrate and reaction at-10 ℃ overnight. After the reaction is completed, saturated Na is used2S2O3Quench the reaction (3.00mL), extract with dichloromethane, combine the organic phases, anhydrous MgSO4Drying, suction filtration, concentration and chromatography on n-hexane column gave 38mg of oily product in 68% yield.
The compound of formula (I) was synthesized according to the synthesis method of comparative example 1 using the compound of formula (II) in Table 10 below; the yields of the compound of formula (I) obtained are shown in Table 10.
TABLE 10 yield of the compound of formula (I) for the different syntheses
Figure BDA0002239569170000241
As can be seen from Table 10, the compound of formula (I) obtained by the reaction of the compound of formula (II) with the other reactants such as solvent and the like, which were mixed together, and then the compound of formula (III) was added by the method of example 1 was obtained in a high yield; on the contrary, the compound of formula (I) obtained by the reaction is produced in a low yield by the method of comparative example 1 in which the compound of formula (III) is mixed with other reactants such as a solvent and the like and stirred for a certain period of time and then the compound of formula (II) is added.
The synthesis method of the trifluoromethoxy compound provided by the invention is described in detail above. The principles and embodiments of the present invention are explained herein using specific examples, which are presented only to assist in understanding the method and its central concept. It should be noted that it would be apparent to those skilled in the art that various changes and modifications can be made in the invention without departing from the principles of the invention, and such changes and modifications are intended to be covered by the appended claims.

Claims (25)

1. The synthesis method of the iodo-trifluoromethoxyl compound is characterized by comprising the following steps of:
(1) preparing a pre-reaction system, wherein the pre-reaction system comprises villiaumite, an iodizing agent, a compound shown in a formula (II) and a solvent;
(2) adding a compound of formula (III) to the pre-reaction system to react the compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I);
Figure FDA0002595535940000011
wherein R is1、R2、R3And R4Each independently represents H, halogen, hydroxyl, nitro, cyano, mercapto, amino, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl, C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z radical, said C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl, C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,
Figure FDA0002595535940000012
Said C is5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);
the Z radical is
Figure FDA0002595535940000013
Figure FDA0002595535940000021
And R is1、R2、R3And R4At most one of which is said C5-12Cycloalkyl radical, C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z group;
or, at R1、R2、R3And R4The method comprises the following steps:
R1、R2one of (1) and R3、R4One of them together with the carbon atom to which each is attached forms C5-8Monocyclic or bicyclic;
R1、R2、R3、R4wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl radical, said C5-8Monocyclic or bicyclic ring, C1-13Alkyl radical, C2-13Alkenyl radical, C2-13Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, mercapto, amino, carbonyl, phenyl, C1-6Alkyl radical, C1-6Alkylcarbonyloxy, C1-6Alkoxycarbonyl, benzyloxy;
R5representative H, C1-6Alkyl, halogen, nitro, cyano, mercapto, amino, C1-6An alkyloxy group; said C is1-6Alkyl and C1-6The alkyloxy group is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxyl and nitro.
2. The method of synthesizing iodo-trifluoromethoxy compounds of claim 1, wherein R is1、R2、R3And R4Each represents H, C respectively1-13Alkyl radical, C5-12Cycloalkenyl radical, C6-10Aryl radical, C6-10Heteroaryl or Z radical, said C1-13Alkyl radical, C5-12Cycloalkenyl radical, C6-10Aryl radical, C6-10Heteroaryl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, nitro, cyano, phenyl, C1-4Alkyl radical, C1-4Alkylcarbonyloxy, C1-4Alkoxycarbonyl, benzyloxy, alkoxycarbonyl, or benzyloxy,
Figure FDA0002595535940000022
Said C is5-12Cycloalkenyl radical, C6-14The ring-forming carbon atoms of the heteroaryl group may be optionally oxidized to c (o);
the Z radical is
Figure FDA0002595535940000031
Figure FDA0002595535940000032
And R is1、R2、R3And R4At most one of which is said C5-12Cycloalkenyl radical, C6-14Aryl radical, C6-14Heteroaryl or Z group;
or, at R1、R2、R3And R4The method comprises the following steps:
R1、R2one of (1) and R3、R4One of them together with the carbon atom to which each is attached in formula (I) forms C5-8A single ring; r1、R2、R3、R4Wherein the other groups represent H, halogen, hydroxy, nitro, cyano, mercapto, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl radical, said C5-8Monocyclic ring, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl is unsubstituted or optionally substituted with one or more substituents selected from: halogen, hydroxy, nitro, C1-4Alkyl radical, C1-4Alkylcarbonyloxy, C1-4An alkoxycarbonyl group;
R5represents H, halogen, C1-6Alkyl radical, C1-6An alkyloxy group; said C is1-6Alkyl radical, C1-6The alkyloxy group is unsubstituted or optionally substituted with one or more halo.
3. The method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein R is1、R2、R3And R4At least one of them represents H.
4. The method for the synthesis of iodo-trifluoromethoxy compounds according to claim 1 or 2, wherein the compound of formula (ii) is selected from the following compounds:
Figure FDA0002595535940000033
Figure FDA0002595535940000041
5. the method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein the compound of formula (iii) is selected from the group consisting of:
Figure FDA0002595535940000042
6. the method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein the compound of formula (iii) is in molar excess with respect to the compound of formula (ii).
7. The method for synthesizing iodo-trifluoromethoxy compound according to claim 6, wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is 3-5: 1.
8. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein the solvent is selected from one or at least two of dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, chloroform, acetonitrile.
9. The method of synthesizing iodo-trifluoromethoxy compound of claim 8, wherein the solvent is a mixture of acetonitrile and dichloromethane.
10. The method of synthesizing iodo-trifluoromethoxy compound according to claim 9, wherein the volume ratio of acetonitrile to dichloromethane is (1:2) to (2: 1).
11. The method of synthesizing iodo-trifluoromethoxy compound of claim 1 or 2, wherein the fluoro salt is selected from LiF, NaF, KF, CsF, ZnF2、MgF2、CaF2、NMe4One or at least two of F.
12. The method for synthesizing iodo-trifluoromethoxy compound according to claim 11, wherein the molar ratio of fluoro salt to the compound of formula (ii) is (0.5-1): 1.
13. the method for synthesizing iodo trifluoromethoxy compound according to claim 1 or 2, wherein the iodinating agent is one or at least two selected from the group consisting of N-iodo succinimide, N-iodo phthalimide, diiodohydantoin, and iodine.
14. The method for synthesizing iodo-trifluoromethoxy compound according to claim 13, wherein the molar ratio of the iodinating agent to the compound of formula (ii) is (1-5): 1.
15. the method for synthesizing iodo-trifluoromethoxy compound according to claim 14, wherein the molar ratio of the iodinating agent to the compound of formula (ii) is (3-5): 1.
16. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein in step (1), the pre-reaction system further comprises a chiral catalyst; the chiral catalyst is one or at least two selected from hydrogenated quinine 1,4- (2, 3-naphthyridine) diether, hydrogenated quinine (anthraquinone-1, 4-diyl) diether or hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether.
17. The method for synthesizing iodo-trifluoromethoxy compound according to claim 16, wherein the molar ratio of the chiral catalyst to the compound of formula (ii) is (0.05-0.2): 1.
18. the method for synthesizing iodo-trifluoromethoxy compound according to claim 17, wherein the molar ratio of the chiral catalyst to the compound of formula (ii) is (0.1-0.15): 1.
19. the method for synthesizing an iodotrifluoromethoxy compound according to claim 1 or 2, wherein in step (1), the pre-reaction system further comprises a silver salt; the silver salt is one or at least two of silver fluoride, silver carbonate, silver trifluoromethanesulfonate, silver oxide, silver tetrafluoroborate, silver nitrate, silver sulfate and silver benzoate.
20. The method of synthesizing an iodotrifluoromethoxy compound of claim 19, wherein the molar ratio of silver salt to compound of formula (ii) (0.2-1.5): 1.
21. the method of synthesizing an iodotrifluoromethoxy compound of claim 20, wherein the molar ratio of silver salt to compound of formula (ii) is (1.0-1.5): 1.
22. the method for synthesizing iodo-trifluoromethoxy compound according to claim 1 or 2, wherein in step (2), the reaction temperature is 30 to-20 ℃; the reaction time is 8-20 hours.
23. The method for synthesizing iodo-trifluoromethoxy compound according to claim 22, wherein in step (2), the reaction temperature is 0 to-20 ℃.
24. The method for synthesizing an iodo-trifluoromethoxy compound according to claim 1 or 2, wherein in step (2), the compound of formula (III) is added to the pre-reaction system until the temperature of the pre-reaction system is 30 to-20 ℃.
25. The method for synthesizing an iodo-trifluoromethoxy compound according to claim 24, wherein in step (2), the compound of formula (iii) is added to the pre-reaction system until the temperature of the pre-reaction system is 0 to-20 ℃.
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