CN112624908B - Method for dibromo-trifluoromethoxylation of terminal alkyne - Google Patents

Method for dibromo-trifluoromethoxylation of terminal alkyne Download PDF

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CN112624908B
CN112624908B CN202011542145.6A CN202011542145A CN112624908B CN 112624908 B CN112624908 B CN 112624908B CN 202011542145 A CN202011542145 A CN 202011542145A CN 112624908 B CN112624908 B CN 112624908B
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dichloromethane
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汤平平
王丰
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Nankai University
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Abstract

The embodiment of the invention provides a method for dibromo-trifluoromethoxylation reaction of terminal alkyne, which comprises the following steps: in an organic solvent, enabling terminal alkyne to perform electrophilic addition reaction in the presence of fluorine anions, a trifluoromethoxy reagent and a bromination reagent so as to perform dibromo-trifluoromethoxylation reaction of the terminal alkyne; wherein the brominating reagent is selected from at least one of N-Br type electrophilic brominating reagents; the trifluoromethoxylation reagent is at least one of substituted or unsubstituted benzene sulfonic acid trifluoromethyl ester. The application provides a novel method for dibromo-trifluoromethoxylation reaction of terminal alkyne, which can synthesize alkenyl trifluoromethyl ether through one-step reaction; the product can be further functionalized, thereby obtaining a series of compounds containing alkenyl trifluoromethoxy ether structures. The preparation method has mild reaction conditions and can tolerate various functional groups; more importantly, the complex molecule can also successfully carry out the dibromo-trifluoromethoxylation reaction.

Description

Method for dibromo-trifluoromethoxylation of terminal alkyne
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for carrying out dibromo-trifluoromethoxylation reaction on terminal alkyne.
Background
In recent years, the synthesis of fluorine-containing compounds has become the subject of organic chemistry and medicinal chemistry research, and a plurality of mild and simple methods for constructing small-molecule fluorine-containing compounds are developed. Wherein a fluorine-containing functional group (OCF) 3 Etc.) has become an important strategy to improve materials and develop new drugs.
A large number of direct introduction OCFs have been developed 3 Radical strategy. This includes C (sp) 3 )-OCF 3 Bond and aryl C (sp) 2 )-OCF 3 A method of construction. However, direct construction of alkenyl C (sp) 2 )-OCF 3 Key strategies are also less common.
In 1978, the Dolty project group utilized "AgOCF 3 "achieve the hydrogen-trifluoromethoxy addition reaction of activated alkyne. "AgOCF 3 "species is formed by AgF, COF 2 Generated in situ in acetonitrile solution. The method realizes C (sp) for the first time 2 )-OCF 3 And (5) constructing a key. However, the reaction has a low yield and narrow substrate applicability.
In 2018, the Liu national topic group reported the bistrifluoromethoxylation reaction of non-activated olefins. They found alkenyl trifluoromethyl ether as a by-product in the reaction. The by-product yield is low.
In 2018, the Shibata project group takes o-hydroxy ketone as a substrate, and reacts with a trifluoromethyl reagent to form o-trifluoromethoxy substituted ketone, and further reacts with allyl carbonyl chloride in the presence of NaHMDS and TMEDA to form carbonate containing an alkenyl trifluoromethyl ether structure. However, the synthesis of the carbonate requires two steps and is complicated.
In 2020, the Toping project group reported a silver-promoted iodo-trifluoromethoxy addition reaction of styrene. They subsequently derivatize the resulting product to form, by elimination, an alkenyltrifluoromethyl ether compound. The preparation of the compound also needs two steps, and the process is complicated.
Disclosure of Invention
The inventor finds that alkenyl bromide species are good synthetic intermediates, and a series of subsequent transformations can be realized by modifying a C-Br bond through a coupling reaction in which transition metal participates. Therefore, the present application aims to synthesize an olefin having both an alkenyl bromide structure and an alkenyl trifluoromethyl ether structure.
The application provides a method for dibromo-trifluoromethoxylation reaction of terminal alkyne, which comprises the following steps:
in an organic solvent, enabling terminal alkyne to perform electrophilic addition reaction in the presence of fluorine anions, a trifluoromethoxy reagent and a bromination reagent so as to perform dibromo-trifluoromethoxylation reaction of the terminal alkyne;
wherein the brominating reagent is selected from at least one of N-Br type electrophilic brominating reagents;
the trifluoromethoxy reagent is selected from at least one substituted or unsubstituted benzene sulfonic acid trifluoromethyl ester.
The application provides a novel method for dibromo-trifluoromethoxylation reaction of terminal alkyne, which can synthesize alkenyl trifluoromethyl ether through one-step reaction; the product can be further functionalized, thereby obtaining a series of compounds containing alkenyl trifluoromethoxy ether structures. The preparation method has mild reaction conditions and can tolerate various functional groups; more importantly, the complex molecule can also successfully carry out the dibromo-trifluoromethoxylation reaction.
Further, by adjusting the contents of the respective components in the reaction system, and by adding a silver salt and/or an additive, a higher yield can be obtained.
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, and not all embodiments. All other embodiments obtained by a person skilled in the art based on the embodiments of the present invention are within the scope of protection of the present invention.
Chemical group abbreviations:
ph phenyl
t Bu tert-butyl
Me methyl group
Bz benzoyl
TMS trimethylsilyl group
Bu n-butyl
OAc acetoxy
NPhth phthalimido group
iPr isopropyl group
The application provides a method for dibromo-trifluoromethoxylation reaction of terminal alkyne, which comprises the following steps:
in an organic solvent, enabling terminal alkyne to perform electrophilic addition reaction in the presence of fluorine anions, a trifluoromethoxy reagent and a bromination reagent so as to perform dibromo-trifluoromethoxylation reaction of the terminal alkyne;
wherein the brominating reagent is selected from at least one of N-Br type electrophilic brominating reagents;
the trifluoromethoxy reagent is selected from at least one substituted or unsubstituted benzene sulfonic acid trifluoromethyl ester.
The method for the dibromo-trifluoromethoxylation of the terminal alkyne refers to that the terminal alkyne obtains the olefin containing alkenyl bromide and alkenyl trifluoromethyl ether structures through electrophilic addition reaction.
The inventor finds in research that the type and structure of the terminal alkyne have little influence on the reaction of the application, and the electrophilic addition reaction of the application can be realized by simple molecules and complex molecules.
In this application, "terminal alkyne" refers to a compound in which the triple bond of the alkyne is at the end of the carbon chain, and its structure can be represented by formula I:
Figure BDA0002855003320000021
wherein, the structure and composition of R has little influence on the reaction, so that R is not limited in this application, and may be hydrogen, substituted or unsubstituted aliphatic organic group, alicyclic organic group, aromatic organic group, heterocyclic group, etc., specifically, the aliphatic organic group may include alkyl, alkenyl, alkynyl, etc.; the alicyclic organic group may include cycloalkyl, cycloalkenyl, cycloalkynyl and the like, and further specifically, there may be monocyclic, linked, fused, cyclic, bridged hydrocarbon and the like; the aromatic compound may specifically include benzene series and polycyclic aromatic hydrocarbons, and more specifically, the benzene series includes monocyclic and polycyclic aromatic hydrocarbons, the polycyclic aromatic hydrocarbons include biphenyls and the like, the polycyclic aromatic hydrocarbons may include polycyclic aromatic hydrocarbons which are completely condensed by benzene rings, such as naphthalenes, anthracenes, phenanthrenes, polyacene, and the like, and may further include polycyclic aromatic structures which are condensed by benzene rings and cycloalkyl groups, such as indene, fluorene, acenaphthene, and the like; the heterocyclic group includes aliphatic and aromatic heterocycles, i.e., at least one heteroatom selected from the group consisting of O, S, N, P, si, and combinations thereof, is included in the ring. The substituent on R is not limited in the present application, and may be, for example, a substituent containing at least one group of a hydrocarbon group, an alkoxy group, a hydroxyl group, a carboxyl group, a carbonyl group, an amino group, and a halogen.
In some embodiments of the first aspect of the present application, the terminal alkynyl group is linked to an alkyl group, preferably a C3-C20 alkyl group.
In other embodiments of the first aspect of the present application, the terminal alkynyl group is attached to a substituted or unsubstituted cyclic group through a linker, optionally the cyclic group comprises a heteroatom; preferably, the cyclic group is an aryl group;
wherein the connecting group is a single bond or- (CH) 2 ) n N is a positive integer of 1 to 10, said- (CH) 2 ) n in-CH 2 Optionally substituted by-CO-, -O-, -SO 2 -、-NR 1 -、-CHR 2 -substitution, R 1 、R 2 Each independently selected from at least one of hydrogen, C1-C5 alkyl or NPhth; preferably, the C1-C5 alkyl group is selected from methyl or n-butyl;
the heteroatoms on the cyclic groups are independently from each other selected from O, S or N;
the substituent on the substituted cyclic group is not limited, and may be selected from at least one of alkyl, cycloalkyl, alkoxy, aryl, halogen, trifluoromethyl, trifluoromethoxy, benzoyl, cyano, nitro, and acetoxy, and preferably from at least one of methyl, methoxy, phenyl, phenoxy, tert-butyl, fluoro, chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, benzoyl, cyano, nitro, and acetoxy.
In certain embodiments of the first aspect of the present application, the terminal alkyne is selected from the compounds shown below:
Figure BDA0002855003320000031
Figure BDA0002855003320000041
Figure BDA0002855003320000051
accordingly, when the dibromotrifluoromethoxy reaction of the present application is carried out using the above-mentioned terminal alkyne as a reaction substrate, the reaction product includes the compounds shown below:
Figure BDA0002855003320000052
Figure BDA0002855003320000061
Figure BDA0002855003320000071
the inventors have found that increasing the concentration of the terminal alkyne in the organic solvent to some extent increases the yield, and that the increase in yield is less affected by the terminal alkyne concentration when the concentration is above 0.6mol/L, and thus, in some embodiments of the present application, the concentration of the terminal alkyne in the organic solvent is from 0.15 to 0.8mol/L, preferably from 0.2 to 0.6mol/L.
The brominating reagent in this application is selected from at least one of electrophilic brominating reagent of N-Br type, wherein said electrophilic brominating reagent of N-Br type means that at least one bromine atom is linked to a nitrogen atom in said brominating reagent, in some embodiments of this application, said electrophilic brominating reagent of N-Br type is selected from at least one of NBP, DBDMH and NBS. The structural formula is as follows:
Figure BDA0002855003320000072
the inventors have also found that NBP can give higher yields in several brominating reagents.
The inventors have also found that increasing the amount of brominating reagent can increase the yield of product within certain limits, but when the molar ratio of bromine in the brominating reagent to the terminal alkyne reaches 3, and then increasing the amount of brominating reagent, the yield of product does not increase significantly any more, in some embodiments of the present application, the molar ratio of bromine in the brominating reagent to the terminal alkyne is (2-4): 1.
The inventors have found in their studies that the type and position of the substituents have some effect on the yield when using a substituted trifluoromethyl benzene sulfonate as a trifluoromethoxy reagent, e.g., when a bulky steric group is present in the ortho position to the sulfonate group, which in some embodiments of the present application is para to the sulfonate group; in addition, the inventors have found in the research that when the substituent in the substituted benzene sulfonic acid trifluoromethyl ester is a strong electron-donating group, the yield of the product is also reduced.
In some preferred embodiments herein, the substituted or unsubstituted triflate is selected from the group consisting of
Figure BDA0002855003320000073
At least one of (a).
The inventors have also found that an increase in the amount of trifluoromethoxylating agent can also improve the yield, and in some embodiments of the application, the molar ratio of the terminal alkyne to the trifluoromethoxylating agent is 1 (3-7).
The organic solvent is not limited to a specific type as long as the object of the present invention can be achieved, and may be selected from, for example, acetonitrile (MeCN), tetrahydrofuran (THF), acetone (Acetone), 1,4-dioxane (1, 4-dioxane), dichloromethane (DCM), anisole (Anisole), 1, 2-Dichloroethane (DCE), hexane (Hexane), ethyl acetate (EtOAc), toluene (tolene), dimethyl carbonate (DMC), and Dimethylacetamide (DMA). The inventors have found that different organic solvents give different yields under the same reaction conditions, and in some preferred embodiments of the present application, the organic solvent is selected from at least one of acetonitrile, 1,4-dioxane, dichloromethane, 1, 2-dichloroethane, ethyl acetate, dimethyl carbonate, toluene, anisole; more preferably, the organic solvent is selected from at least one of acetonitrile, 1,4-dioxane, or toluene.
The reaction system of the application also contains fluorine anions which can be used for activating the trifluoromethoxy reagent so as to release the trifluoromethoxy anions.
The counter ion of the fluorine anion is not limited as long as the purpose of the present invention can be achieved, and may be, for example, a metal ion such as Na + 、Fe 3+ 、Ag + 、K + 、Rb + Or Cs + In the research, the inventor finds that different fluorine salts have different solubilities in organic solvents, and the solubility is different under the same dosageThe lower fluoride salt gives lower fluoride anion concentration, and the efficiency of activating the trifluoromethoxy reagent is low; on the other hand, different cations will influence the main reaction, in some preferred embodiments of the present application, the counter-ion of the fluorine anion is selected from K + Or Cs + 。
The inventors have also found that the molar ratio of fluoride anion to terminal alkyne also affects the yield of product, to the extent that the yield increases with increasing fluoride anion content. In some embodiments herein, the molar ratio of the fluoride anion to the terminal alkyne is (1-5): 1.
The inventors have unexpectedly discovered in their research that the yield is significantly improved when a silver salt is added to the reaction system, which in some embodiments of the present application is selected from AgSbF 6 、Ag 2 CO 3 、AgF、Ag 2 O、AgOCOCF 3 、AgBF 4 At least one of (1).
The inventors have also found that the molar ratio of silver salt to terminal alkyne affects the yield of product, in some embodiments of the present application the molar ratio of silver in the silver salt to the terminal alkyne is (0.1-1): 1, preferably (0.3-0.6): 1.
The inventors have also found that the addition of crown ethers also contributes to an increase in the product yield. In some embodiments of the present application, the reaction system further comprises substituted or unsubstituted C 8 -C 24 Preferably 18-crown-6 (18-crown-6) or 15-crown-5 (15-crown-5).
In some embodiments herein, the molar ratio of the crown ether to the terminal alkyne is (0.5-1.5): 1.
The inventors also found that when the reaction temperature is lower than 60 ℃, the yield gradually decreases as the temperature decreases, and when the reaction temperature is higher than 60 ℃, the yield changes less with temperature. In some embodiments of the present application, the reaction temperature is 20-80 ℃.
In some embodiments of the present application, the reaction time is 3 to 5 hours.
In some embodiments of the present application, the reaction is carried out in an atmosphere of air, oxygen, or nitrogen. Invention of the inventionIt was found that the yield of the reaction in oxygen and nitrogen was substantially the same, whereas the yield was slightly decreased when the reaction was carried out under an air atmosphere. Without being bound by any theory, the inventors believe that this may be due to the presence of traces of water vapor in the air, which to some extent destroys the OCF 3 Stability of the negative ion.
The present application will be specifically described below with reference to examples, but the present application is not limited to these examples.
EXAMPLE 1 Synthesis of Compound 1
Synthesis path:
Figure BDA0002855003320000091
in a glove box (N) 2 Atmosphere), 0.500mmol of terminal alkyne (83mg, 1.00eq.), 2.00mmol of KF (116mg, 2.0mmol,4.00eq, 4.00 eq.), 0.500mmol of 18-crown-6 (132mg, 1.00eq.), 0.100mmol of Ag in turn are added into a 15mL sealed tube 2 CO 3 (27.5mg, 0.200eq.), 1.500mmol of NBP (339mg, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 2.00mmol of trifluoromethyl 4-fluorobenzenesulfonate (489mg, 4.00eq.) were added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. Then, dichloromethane is added to dissolve the sample, the mixture is filtered through kieselguhr, and after spin-drying, the mixture is separated by preparative HPLC as MeCN: H 2 And O is eluent for separation. Elution conditions: (9 mL/min, detector UV. Lamda. Max 210nm, meCN/H 2 O＝90/0(0min),MeCN/H 2 O＝100:0(10min),MeCN/H 2 O =100 (40 min)). Retention time: 29.5min. The corresponding product was obtained as 163mg as a colorless liquid (yield 80%).
R f ＝0.98(hexanes).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ2.55(t,J＝7.5Hz,2H),1.63–1.53(m,2H),1.37–1.20(m,14H),0.89(t,J＝5.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ149.5,119.9(q,J＝260.9Hz),87.8,32.1,32.1,29.7,29.6,29.5,29.3,28.9,26.0,22.9,14.3. 19 F NMR(376MHz,CDCl 3 )δ-55.81(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 13 H 21 Br 2 F 3 O[M] + ,407.9911.Found,407.9910.
EXAMPLE 2 Synthesis of Compound 2
Figure BDA0002855003320000092
In a glove box, terminal alkynes (116mg, 2.0mmol,4.00eq.,0.500mmol, 1.00eq.), KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. 176mg of the corresponding product are obtained as a colorless liquid (yield 74%).
R f ＝0.11(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝7.7Hz,1H),7.59–7.52(m,1H),7.34(t,J＝7.9Hz,1H),7.10(dd,J＝7.6,2.5Hz,1H),4.34(t,J＝6.1Hz,2H),3.85(s,3H),2.65(t,J＝7.1Hz,2H),1.92–1.71(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.5,159.7,148.7,131.6,129.5,122.0,119.9(q,J＝261.0Hz),119.5,114.2,88.6,64.3,55.5,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.29(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 16 Br 2 F 3 O 4 [M+H] + ,474.9362.Found,474.9358。
EXAMPLE 3 Synthesis of Compound 3
Figure BDA0002855003320000101
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained as a colorless liquid (yield 82%) at 220 mg.
R f ＝0.15(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.02(d,J＝8.7Hz,2H),7.39(t,J＝7.2Hz,2H),7.19(t,J＝6.9Hz,1H),7.07(d,J＝7.9Hz,2H),7.00(d,J＝8.6Hz,2H),4.34(t,J＝5.9Hz,2H),2.78(t,J＝7.4Hz,2H),2.18–1.97(m,2H). 13 C NMR(101MHz,CDCl 3 )δ165.9,162.0,155.6,148.1,131.7,130.1,124.6,124.3,120.2,119.8(q,J＝261.0Hz),117.3,89.0,63.3,29.1,25.2. 19 F NMR(376MHz,CDCl 3 )δ-56.70(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 19 H 16 Br 2 F 3 O 4 [M+H] + ,522.9362.Found,522.9362。
EXAMPLE 4 Synthesis of Compound 4
Figure BDA0002855003320000102
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489 mg) was added2.00mmol, 4.00eq.). After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, and spin-dried before separation using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained as 214mg as a colorless liquid (yield 82%).
R f ＝0.11(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝8.3Hz,2H),7.68(d,J＝8.3Hz,2H),7.64(d,J＝7.3Hz,2H),7.48(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),4.39(t,J＝6.0Hz,2H),2.69(t,J＝7.0Hz,2H),1.91–1.76(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.5,148.7,145.8,140.1,130.2,129.0,128.3,127.4,127.2,119.9(q,J＝261.2Hz),88.6,64.2,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.20(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 20 H 18 Br 2 F 3 O 3 [M+H] + ,520.9569.Found,520.9567。
EXAMPLE 5 Synthesis of Compound 5
Figure BDA0002855003320000111
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained as 184mg as a colorless liquid (yield 80%).
R f ＝0.18(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.88–7.80(m,2H),7.40–7.29(m,2H),4.34(t,J＝5.8Hz,2H),2.66(t,J＝6.9Hz,2H),2.41(s,3H),1.89–1.71(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.8,148.7,138.3,133.8,130.3,130.2,128.4,126.8,119.9(q,J＝260.9Hz),88.6,64.2,31.7,27.9,22.6,21.4. 19 F NMR(376MHz,CDCl 3 )δ-56.35(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 16 Br 2 F 3 O 3 [M+H] + ,458.9413.Found,458.9408。
EXAMPLE 6 Synthesis of Compound 6
Figure BDA0002855003320000112
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and separated after spin-drying using a thin layer chromatography silica gel plate with hexane/EtOAc 40 (v/v). 206mg of the corresponding product are obtained as a colorless liquid (yield 82%).
R f ＝0.18(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.01–7.92(m,2H),7.52–7.40(m,2H),4.34(t,J＝6.1Hz,2H),2.66(t,J＝7.1Hz,2H),1.88–1.71(m,4H),1.34(s,9H). 13 C NMR(101MHz,CDCl 3 )δ166.7,156.8,148.7,129.6,127.6,125.5,119.9(d,J＝261.2Hz),88.6,64.0,35.2,31.7,31.2,28.0,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.20(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 18 H 22 Br 2 F 3 O 3 [M+H] + ,500.9882.Found,500.9878。
EXAMPLE 7 Synthesis of Compound 7
Figure BDA0002855003320000121
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product, 178mg, was obtained as a colorless liquid (yield 80%).
R f ＝0.18(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝7.6Hz,2H),7.56(t,J＝7.4Hz,1H),7.45(t,J＝7.5Hz,2H),4.35(t,J＝5.9Hz,2H),2.66(t,J＝7.0Hz,2H),1.89–1.71(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.7,148.7,133.1,130.4,129.7,128.5,119.9(q,J＝261.0Hz),88.6,64.3,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.14(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 14 H 13 Br 2 F 3 O 3 [M] + ,443.9184.Found,443.9179。
EXAMPLE 8 Synthesis of Compound 8
Figure BDA0002855003320000131
In a glove box, 15mL of the mixture is sealedTerminal alkyne (0.500mmol, 1.00eq.), KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag are sequentially added into the sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained 183mg as a colorless liquid (yield 78%).
R f ＝0.18(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.13–7.96(m,2H),7.18–7.06(m,2H),4.34(t,J＝6.2Hz,2H),2.66(t,J＝7.1Hz,2H),1.89–1.71(m,4H). 13 C NMR(101MHz,CDCl 3 )δ165.9(d,J＝254.0Hz),165.7,148.7,132.2(d,J＝9.3Hz),126.6(d,J＝2.8Hz),119.9(q,J＝261.0Hz),115.7(d,J＝22.0Hz),88.7,64.4,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.21(s,3F),-105.86–-105.76(m,1F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 14 H 13 Br 2 F 4 O 3 [M+H] + ,462.9162.Found,462.9143。
EXAMPLE 9 Synthesis of Compound 9
Figure BDA0002855003320000132
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. Reaction(s) ofAt the end, the mixture was transferred with dichloromethane to a round bottom flask and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained as 184mg as a colorless liquid (yield 81%).
R f ＝0.20(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),4.34(t,J＝6.1Hz,2H),2.65(t,J＝7.1Hz,2H),1.90–1.70(m,4H). 13 C NMR(101MHz,CDCl 3 )δ165.8,148.6,139.6,131.1,128.9,128.8,119.9(q,J＝261.1Hz),88.7,64.5,31.7,27.8,22.5. 19 F NMR(376MHz,CDCl 3 )δ-56.60(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 14 H 13 Br 2 ClF 3 O 3 [M+H] + ,478.8867.Found,478.8861。
EXAMPLE 10 Synthesis of Compound 10
Figure BDA0002855003320000141
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained in the form of 204mg as a colorless liquid (yield 80%).
R f ＝0.30(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.89(d,J＝8.5Hz,2H),7.58(d,J＝8.5Hz,2H),4.34(t,J＝6.1Hz,2H),2.76(t,J＝7.4Hz,2H),2.11–2.03(m,2H). 13 C NMR(101MHz,CDCl 3 )δ165.8,148.0,131.9,131.2,129.0,128.3,119.9(q,J＝261.1Hz),89.1,63.8,29.2,25.2. 19 F NMR(376MHz,CDCl 3 )δ-56.02(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 13 H 11 Br 3 F 3 O 3 [M+H] + ,508.8205.Found,508.8203。
EXAMPLE 11 Synthesis of Compound 11
Figure BDA0002855003320000142
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained 235mg as a colorless liquid (yield 82%).
R f ＝0.27(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.3Hz,2H),7.73(d,J＝8.4Hz,2H),4.33(t,J＝6.1Hz,2H),2.65(t,J＝7.1Hz,2H),1.87–1.71(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.1,148.6,137.9,131.1,129.8,119.9(q,J＝260.9 Hz),100.9,88.7,64.5,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.23(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 14 H 12 Br 2 F 3 IO 3 [M] + ,569.8150.Found,569.8159。
EXAMPLE 12 Synthesis of Compound 12
Figure BDA0002855003320000151
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained as 203mg of a colorless liquid (yield 79%).
R f ＝0.20(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.15(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),4.38(t,J＝6.2Hz,2H),2.66(t,J＝7.2Hz,2H),1.90–1.73(m,4H). 13 C NMR(101MHz,CDCl 3 )δ165.4,148.6,134.6(q,J＝32.5Hz),133.6,130.1,125.6(q,J＝3.5Hz),123.8(q,J＝272.7Hz),119.9(q,J＝261.2Hz),88.7,64.8,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.63(s,3F),-62.62(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 15 H 12 Br 2 F 6 O 3 [M] + ,511.9057.Found,511.9046。
EXAMPLE 13 Synthesis of Compound 13
Figure BDA0002855003320000152
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg,0.100mmol，0.200eq.)，NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained as 207mg as a colorless liquid (yield 78%).
R f ＝0.20(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝8.6Hz,2H),7.27(d,J＝8.2Hz,2H),4.36(t,J＝5.9Hz,2H),2.66(t,J＝7.0Hz,2H),1.89–1.73(m,4H). 13 C NMR(101MHz,CDCl 3 )δ165.4,152.8,148.7,131.7,128.8,120.5(q,J＝258.8Hz),120.4,120.0(q,J＝261.0Hz),88.7,64.6,31.7,27.9,22.6. 19 F NMR(376MHz,CDCl 3 )δ-56.19(s,3F),-57.12(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 13 Br 2 F 6 O 4 [M+H] + ,528.9079.Found,528.9085。
EXAMPLE 14 Synthesis of Compound 14
Figure BDA0002855003320000161
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 20. To obtainTo the corresponding product, 215mg, as a white solid (78% yield).
R f ＝0.25(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝8.3Hz,2H),7.84(d,J＝8.3Hz,2H),7.80(d,J＝8.3Hz,2H),7.61(t,J＝7.4Hz,1H),7.53–7.46(m,2H),4.40(t,J＝6.1Hz,2H),2.79(t,J＝7.4Hz,2H),2.16–2.04(m,2H). 13 C NMR(101MHz,CDCl 3 )δ196.1,165.7,148.0,141.6,137.0,133.1,133.1,130.2,129.9,129.6,128.6,119.9(q,J＝261.3Hz),89.2,64.0,29.2,25.2. 19 F NMR(376MHz,CDCl 3 )δ-56.50(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 20 H 16 Br 2 F 3 O 4 [M+H] + ,534.9362.Found,534.9358。
EXAMPLE 15 Synthesis of Compound 15
Figure BDA0002855003320000162
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and separated after spin-drying using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained as 186mg as a colorless liquid (yield 79%).
R f ＝0.08(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝8.0Hz,2H),7.74(d,J＝8.1Hz,2H),4.37(t,J＝6.2Hz,2H),2.65(t,J＝7.2Hz,2H),1.91–1.70(m,4H). 13 C NMR(101MHz,CDCl 3 )δ165.0,148.5,134.1,132.3,130.2,119.9(q,J＝261.1Hz),118.0,116.6,88.7,65.0,31.6,27.7,22.5. 19 F NMR(376MHz,CDCl 3 )δ-55.67(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 15 H 12 Br 2 F 3 NO 3 [M] + ,468.9136.Found,468.9134。
EXAMPLE 16 Synthesis of Compound 16
Figure BDA0002855003320000171
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 30. The corresponding product was obtained 199mg as a pale yellow liquid (yield 79%).
R f ＝0.30(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.28(d,J＝8.8Hz,2H),8.20(d,J＝8.8Hz,2H),4.40(t,J＝6.2Hz,2H),2.66(t,J＝7.3Hz,2H),1.90–1.72(m,4H). 13 C NMR(101MHz,CDCl 3 )δ164.7,150.7,148.5(d,J＝1.2Hz),135.7,130.8,123.7,119.9(q,J＝261.1Hz),88.8,65.2,31.6,27.8,22.5. 19 F NMR(376MHz,CDCl 3 )δ-56.49(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 14 H 12 Br 2 F 3 NO 5 [M] + ,488.9034.Found,488.9042。
EXAMPLE 17 Synthesis of Compound 17
Figure BDA0002855003320000172
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 8. The corresponding product was obtained as a colorless liquid (yield 81%).
R f ＝0.05(hexanes/EtOAc 8:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.18(d,J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H),4.36(t,J＝6.2Hz,2H),3.05(s,3H),2.62(t,J＝7.2Hz,2H),1.90–1.65(m,4H). 13 C NMR(101MHz,CDCl 3 )δ164.9,148.4(d,J＝1.2Hz),144.3,134.9,130.5,127.5,119.8(q,J＝261.0Hz),88.6,65.0,44.3,31.5,27.6,22.4. 19 F NMR(376MHz,CDCl 3 )δ-56.56(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 16 Br 2 F 3 O 5 S[M+H] + ,522.9032.Found,522.9028。
EXAMPLE 18 Synthesis of Compound 18
Figure BDA0002855003320000181
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. End of additionAfter that, the lid was closed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 30. The corresponding product was obtained as 127mg as a colorless liquid (yield 63%).
R f ＝0.10(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ9.90(s,1H),7.86(d,J＝8.6Hz,2H),7.03(d,J＝8.5Hz,2H),4.92(s,2H). 13 C NMR(101MHz,CDCl 3 )δ190.8,162.5,143.2,143.2,132.1,131.0,119.9(q,J＝262.3Hz),115.1,95.7,65.3. 19 F NMR(376MHz,CDCl 3 )δ-56.12(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 11 H 8 Br 2 F 3 O 3 [M+H] + ,402.8787.Found,402.8782。
EXAMPLE 19 Synthesis of Compound 19
Figure BDA0002855003320000191
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 1. The corresponding product was obtained as a white solid (yield 37%) 78 mg.
R f ＝0.78(hexanes/EtOAc 1:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.10(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),4.92(s,2H). 13 C NMR(101MHz,CDCl 3 )δ162.1,143.4,132.6,123.8,123.1,119.9(q,J＝262.4 Hz),116.0,114.6,95.6,65.3. 19 F NMR(376MHz,CDCl 3 )δ-56.01(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 11 H 6 Br 2 F 3 O 4 [M-H] - ,416.8590.Found,416.8589。
EXAMPLE 20 preparation of Compound 20
Figure BDA0002855003320000192
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained in the form of 204mg as a colorless liquid (yield 80%).
R f ＝0.08(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.00(d,J＝8.8Hz,2H),6.94(d,J＝8.8Hz,2H),4.89(s,2H),4.37–4.27(m,2H),3.59(t,J＝5.8Hz,2H),1.99–1.82(m,4H). 13 C NMR(101MHz,CDCl 3 )δ166.0,161.4,143.4,131.7,124.0,119.8(q,J＝262.1Hz),114.5,95.4,65.2,64.0,44.6,29.3,26.2. 19 F NMR(376MHz,CDCl 3 )δ-56.66(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 15 Br 2 ClF 3 O 4 [M+H] + ,508.8972.Found,508.8967。
EXAMPLE 21 Synthesis of Compound 21
Figure BDA0002855003320000201
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained 171mg as a colorless liquid (yield 72%).
R f ＝0.07(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝8.7Hz,2H),6.95(d,J＝8.7Hz,2H),4.90(s,2H),4.63(dd,J＝12.3,2.7Hz,1H),4.13(dd,J＝12.3,6.3Hz,1H),3.36–3.28(m,1H),2.88(t,J＝4.4Hz,1H),2.74–2.69(m,1H). 13 C NMR(101MHz,CDCl 3 )δ165.8,161.6,143.4,132.0,123.4,119.9(q,J＝262.3Hz),114.6,95.5,65.4,65.3,49.6,44.8. 19 F NMR(376MHz,CDCl 3 )δ-56.57(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 14 H 12 Br 2 F 3 O 5 [M+H] + ,474.8998.Found,474.8994。
EXAMPLE 22 Synthesis of Compound 22
Figure BDA0002855003320000202
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg,0.100mmol，0.200eq.)，NBP(339mg,1.500mmol，3.00 eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. 177mg of the corresponding product were obtained as a colorless liquid (yield 68%).
R f ＝0.18(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝8.9Hz,2H),6.94(d,J＝8.9Hz,2H),4.89(s,2H),4.43–4.36(m,2H),1.15–1.08(m,2H),0.08(s,9H). 13 C NMR(101MHz,CDCl 3 )δ166.3,161.3,143.6,131.7,124.6,119.9(q,J＝262.3Hz),114.5,95.4,65.3,63.2,17.6,-1.3. 19 F NMR(376MHz,CDCl 3 )δ-56.54(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 16 H 19 Br 2 F 3 NaO 4 Si[M+Na] + ,540.9264.Found,540.9262。
EXAMPLE 23 Synthesis of Compound 23
Figure BDA0002855003320000211
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained as 141mg as a colorless liquid (yield 60%).
R f ＝0.11(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.82–7.74(m,2H),7.70–7.63(m,2H),3.66(t,J＝6.9Hz,2H),2.57(t,J＝7.2Hz,2H),1.74–1.64(m,2H),1.64–1.54(m,2H). 13 C NMR(101MHz,CDCl 3 )δ168.3,148.5,134.0,132.1,123.2,119.8(q,J＝261.1Hz),88.5,37.4,31.5,27.7,23.2. 19 F NMR(376MHz,CDCl 3 )δ-56.22(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 15 H 13 Br 2 F 3 NO 3 [M+H] + ,469.9209.Found,469.9205。
EXAMPLE 24 Synthesis of Compound 24
Figure BDA0002855003320000212
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained 183mg as a colorless liquid (yield 72%).
R f ＝0.06(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝6.9Hz,1H),7.93–7.88(m,1H),7.87–7.77(m,2H),3.78(t,J＝7.2Hz,2H),2.62(t,J＝7.5Hz,2H),1.93–1.83(m,2H),1.75–1.65(m,2H). 13 C NMR(101MHz,CDCl 3 )δ159.0,148.4,137.7,134.9,134.4,127.3,125.2,121.0,119.8(q,J＝261.2Hz),88.7,38.8,31.5,27.5,23.1. 19 F NMR(376MHz,CDCl 3 )δ-56.14(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 14 H 13 Br 2 F 3 NO 4 S[M+H] + ,505.8879.Found,505.8873。
EXAMPLE 25 Synthesis of Compound 25
Figure BDA0002855003320000221
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and spin-dried before separation using a thin layer chromatography silica gel plate with hexane/EtOAc 12. The corresponding product was obtained as 218mg as a colorless liquid (yield 81%).
R f ＝0.15(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J＝7.4Hz,2H),7.58–7.51(m,1H),7.48(t,J＝7.4Hz,2H),3.16–3.02(m,4H),2.60–2.50(m,2H),1.64–1.41(m,6H),1.32–1.22(m,2H),0.87(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ148.6,139.9,132.5,129.1,127.1,119.8(q,J＝260.8Hz),88.5,48.3,47.9,31.6,30.9,27.8,23.1,20.0,13.7. 19 F NMR(376MHz,CDCl 3 )δ-56.12(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 17 H 23 Br 2 F 3 NO 3 S[M+H] + ,535.9712.Found,535.9708。
EXAMPLE 26 Synthesis of Compound 26
Figure BDA0002855003320000222
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and separated after spin-drying using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product, 201mg, was obtained as a colorless liquid (yield 81%).
R f ＝0.30(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.94(d,J＝8.7Hz,1H),8.20(d,J＝7.2Hz,1H),8.03(d,J＝8.2Hz,1H),7.90(d,J＝8.1Hz,1H),7.64(t,J＝7.7Hz,1H),7.58–7.48(m,2H),4.46(t,J＝5.9Hz,2H),2.69(t,J＝7.1Hz,2H),1.94–1.77(m,4H). 13 C NMR(101MHz,CDCl 3 )δ167.6,148.7,134.0,133.5,131.5,130.3,128.7,127.9,127.3,126.3,125.9,124.6,119.9(q,J＝260.8Hz),88.6,64.3,31.8,28.0,22.7. 19 F NMR(376MHz,CDCl 3 )δ-56.23(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 18 H 16 Br 2 F 3 O 3 [M+H] + ,494.9413.Found,494.9409。
EXAMPLE 27 Synthesis of Compound 27
Figure BDA0002855003320000231
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). Stirring for five minutes at room temperature, and adding 4-fluorobenzene sulfonic acid trisFluoromethyl ester (489mg, 2.00mmol, 4.00eq.). After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 30. The corresponding product was obtained as 170mg as a colorless liquid (yield 70%).
R f ＝0.11(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝7.8Hz,1H),7.58(dd,J＝8.4,0.7Hz,1H),7.52(d,J＝0.9Hz,1H),7.47–7.41(m,1H),7.33–7.27(m,1H),4.40(t,J＝6.3Hz,2H),2.66(t,J＝7.2Hz,2H),1.90–1.70(m,4H). 13 C NMR(101MHz,CDCl 3 )δ159.6,155.8,148.6(q,J＝1.1Hz),145.5,127.8,127.0,123.9,122.9,119.9(q,J＝261.1Hz),114.0,112.4,88.7,64.7,31.6,31.6,27.8,22.4. 19 F NMR(376MHz,CDCl 3 )δ-56.22(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 16 H 13 Br 2 F 3 NaO 4 [M+Na] + ,506.9025.Found,506.9020。
EXAMPLE 28 Synthesis of Compound 28
Figure BDA0002855003320000241
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained in the form of 202mg,as a colorless liquid (76% yield).
R f ＝0.30(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝3.6Hz,1H),7.06(d,J＝3.6Hz,1H),4.29(t,J＝5.6Hz,2H),2.63(t,J＝6.6Hz,2H),1.90–1.58(m,4H). 13 C NMR(101MHz,CDCl 3 )δ161.1,148.6(q,J＝1.1Hz),134.9,133.8,131.0,120.4,119.9(q,J＝261.1Hz),88.7,64.6,31.6,27.8,22.4. 19 F NMR(376MHz,CDCl 3 )δ-56.31(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 12 H 11 B r3 F 3 O 3 S[M+H] + ,528.7926.Found,528.7920。
EXAMPLE 29 Synthesis of Compound 29
Figure BDA0002855003320000242
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by the addition of dichloromethane, filtered through celite, and spun dry with hexane/EtOAc/Et 3 N15 (v/v) as a developing solvent, and separating by using a thin layer chromatography silica gel plate. The corresponding product was obtained as 191mg as a colorless liquid (yield 77%).
R f ＝0.19(hexanes/EtOAc 8:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.31–8.15(m,2H),8.09(d,J＝8.3Hz,1H),7.79(d,J＝8.1Hz,1H),7.71(t,J＝7.6Hz,1H),7.56(t,J＝7.4Hz,1H),4.45(t,J＝6.3Hz,2H),2.62(t,J＝7.3Hz,2H),1.94–1.80(m,2H),1.80–1.63(m,2H). 13 C NMR(101MHz,CDCl 3 )δ165.3,148.6,148.0,147.7,137.2,130.8,130.2,129.3,128.6,127.5,120.9,119.8(q,J＝261.1Hz),88.5,65.2,31.6,27.7,22.4. 19 F NMR(376MHz,CDCl 3 )δ-56.09(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 17 H 15 Br 2 F 3 NO 3 [M+H] + ,495.9365.Found,495.9362。
EXAMPLE 30 Synthesis of Compound 30
Figure BDA0002855003320000251
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by the addition of dichloromethane, filtered through celite, and spun dry with hexane/EtOAc/Et 3 N15 (v/v) as a developing solvent, and separating by using a thin layer chromatography silica gel plate. The corresponding product, 172mg, was obtained as a colorless liquid (yield 74%).
R f ＝0.22(hexanes/EtOAc 8:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.04–7.88(m,2H),7.13(d,J＝7.9Hz,1H),4.39(t,J＝6.4Hz,2H),2.62(t,J＝7.3Hz,2H),1.89–1.78(m,2H),1.77–1.66(m,2H). 13 C NMR(101MHz,CDCl 3 )δ163.8,162.9(d,J＝242.8Hz),148.4,146.3(d,J＝12.3Hz),142.1(d,J＝7.5Hz),122.7(d,J＝3.5Hz),119.7(d,J＝261.3Hz),113.9(d,J＝37.0Hz),88.5,65.3,31.5,27.6,22.3. 19 F NMR(376MHz,CDCl 3 )δ-56.16(s,3F),-64.70(s,1F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 13 H 12 Br 2 F 4 NO 3 [M+H] + ,463.9115.Found,463.9110.
EXAMPLE 31 Synthesis of Compound 31
Figure BDA0002855003320000252
In a glove box, terminal alkynes (66mg, 0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.) 18-crown-6 (132mg, 0.500mmol, 1.00eq.) Ag-were added to a 15mL sealed tube in this order 2 CO 3 (34.4 mg,0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained as 158mg as a colorless liquid (yield 84%).
R f ＝0.40(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.37(d,J＝8.7Hz,2H),6.83(d,J＝8.6Hz,2H),3.74(s,3H). 13 C NMR(101MHz,CDCl 3 )δ161.1,146.5(q,J＝1.5Hz),131.0,123.6,120.1(q,J＝261.9Hz),113.9,88.1,55.4. 19 F NMR(376MHz,CDCl 3 )δ-55.67(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 10 H 7 Br 2 F 3 O 2 [M] + ,373.8765.Found,373.8759。
EXAMPLE 32 Synthesis of Compound 32
Figure BDA0002855003320000261
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). Stirring for five minutes at room temperature, and adding 4-fluorobenzene sulfonic acid trifluoroMethyl ester (612mg, 2.50mmol, 5.00eq.). After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 100. The corresponding product was obtained as a colorless liquid (yield 71%) at 150 mg.
R f ＝0.63(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.78–7.62(m,6H),7.57–7.48(m,2H),7.48–7.40(m,1H). 13 C NMR(101MHz,CDCl 3 )δ146.3,143.2,134.0,130.4,129.8,129.1,128.2,127.3,127.1,120.2(q,J＝262.3Hz),89.4. 19 F NMR(376MHz,CDCl 3 )δ-56.77(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 15 H 9 Br 2 F 3 O[M] + ,419.8972.Found,419.8967。
EXAMPLE 33 Synthesis of Compound 33
Figure BDA0002855003320000262
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 100. The corresponding product was obtained as 127mg as a colorless liquid (yield 63%).
R f ＝0.46(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.50–7.45(m,2H),7.45–7.40(m,2H),1.35(s,9H). 13 C NMR(101MHz,CDCl 3 )δ153.8,146.7,129.1,128.6,125.4,120.1(q,J＝262.0Hz),88.7,35.6,31.3. 19 F NMR(376MHz,CDCl 3 )δ-56.41(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 13 H 13 Br 2 F 3 O[M] + ,399.9285.Found,399.9280。
EXAMPLE 34 Synthesis of Compound 34
Figure BDA0002855003320000271
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 100. The corresponding product, 107mg, was obtained as a colorless liquid (62% yield).
R f ＝0.43(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.57–7.48(m,2H),7.46–7.38(m,3H). 13 C NMR(101MHz,CDCl 3 )δ146.6(q,J＝1.8Hz),131.7,130.5,129.4,128.6,120.1(q,J＝262.2Hz),89.3. 19 F NMR(376 MHz,CDCl 3 )δ-56.44(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 9 H 5 Br 2 F 3 O[M] + ,343.8659.Found,343.8650。
EXAMPLE 35 Synthesis of Compound 35
Figure BDA0002855003320000272
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and separated after spin-drying using a thin layer chromatography silica gel plate with hexane/EtOAc 50. The corresponding product was obtained in the form of 99mg as a colorless liquid (yield 52%).
R f ＝0.45(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.5Hz,2H),7.40(d,J＝8.5Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ145.4,136.7,130.7,130.2,129.0,120.1(q,J＝262.4Hz),90.1. 19 F NMR(376MHz,CDCl 3 )δ-56.65(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 9 H 4 Br 2 ClF 3 O[M] + ,377.8270.Found,377.8261。
EXAMPLE 36 Synthesis of Compound 36
Figure BDA0002855003320000281
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (34.4 mg,0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. Then add intoThe sample was dissolved in dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 50 (v/v). The corresponding product was obtained as 90mg as a pale yellow liquid (yield 46%).
R f ＝0.30(hexanes/EtOAc 20:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.28(d,J＝8.8Hz,2H),7.75(d,J＝8.8Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ148.6,144.2(q,J＝1.9Hz),138.0,130.5,123.8,120.0(q,J＝263.2Hz),92.6. 19 F NMR(376MHz,CDCl 3 )δ-56.78(s,3F).Mass Spectrometry:HRMS-EI(m/z):Calcd for C 9 H 4 Br 2 F 3 NO 3 [M] + ,388.8510.Found,388.8503。
EXAMPLE 37 Synthesis of Compound 37
Figure BDA0002855003320000282
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained as a white solid (yield 80%) 304 mg.
R f ＝0.36(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.4Hz,2H),7.48(d,J＝8.4Hz,2H),7.17(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,2H),6.75(s,1H),3.22–3.06(m,4H),2.60(t,J＝6.0Hz,2H),2.37(s,3H),1.70–1.55(m,4H),1.50(dt,J＝15.1,7.6Hz,2H),1.28(dt,J＝14.5,7.3Hz,3H),0.90(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ148.5,145.2,144.0(q,J＝38.5Hz),142.3,139.8,139.4,129.7,128.7,128.0,125.7,125.5,121.1(q,J＝269.2Hz),119.7(q,J＝261.0Hz),106.2,88.5,48.3,47.8,31.4,30.7,27.7,22.9,21.2,19.9,13.6. 19 F NMR(376MHz,CDCl 3 )δ-56.12(s,3F),-62.37(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 28 H 30 Br 2 F 6 N 3 O 3 S[M+H] + ,760.0273.Found,760.0270。
EXAMPLE 38 Synthesis of Compound 38
Figure BDA0002855003320000291
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 3. The corresponding product was obtained as a white solid (yield 34%) in the form of 143 mg.
R f ＝0.65(hexanes/EtOAc 1:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ6.86(s,1H),6.71(s,1H),6.27(s,1H),6.06(d,J＝3.5Hz,1H),5.92(dd,J＝13.5,1.3Hz,2H),4.56(d,J＝5.0Hz,1H),4.47(dd,J＝9.8,7.2Hz,1H),4.36(dd,J＝9.8,1.5Hz,1H),4.04(t,J＝5.0Hz,2H),3.88(s,3H),3.83(s,3H),3.46(dd,J＝10.1,5.2Hz,1H),3.14–3.04(m,1H),2.66(t,J＝6.7Hz,2H),2.06(s,3H),1.89–1.79(m,4H). 13 C NMR(101MHz,CDCl 3 )δ178.5,170.6,153.1,152.1,149.1,148.8,146.5,141.7,136.2,131.6,126.4,119.9(q,J＝260.9Hz),110.5,108.7,108.3,101.4,88.3,73.2,72.0,68.9,61.2,56.3,45.5,42.5,38.7,31.9,29.4,22.7,21.0. 19 F NMR(376MHz,CDCl 3 )δ-56.03(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 30 H 28 Br 3 F 3 NaO 10 [M+Na] + ,864.9077.Found,864.9078。
EXAMPLE 39 Synthesis of Compound 39
Figure BDA0002855003320000301
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 3. The corresponding product was obtained as 107mg as a colorless oily liquid (yield 33%).
R f ＝0.25(hexanes/EtOAc 4:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ5.12(s,2H),4.26(t,J＝6.1Hz,2H),3.79(s,3H),3.66(s,3H),2.90–2.81(m,2H),2.71–2.57(m,2H),2.40–2.25(m,2H),2.17(s,3H),2.14–2.06(m,2H),1.80–1.70(m,1H),1.58–1.44(m,3H),1.41–1.29(m,1H),0.98(d,J＝6.1Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ174.5,169.2,163.0,155.4,148.8,146.7,130.3,120.1,119.9(q,J＝260.7Hz),112.6,88.5,74.0,68.4,61.2,51.6,37.5,33.0,31.9,31.7,29.3,26.9,22.3,19.3,11.7. 19 F NMR(376MHz,CDCl 3 )δ-56.07(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 24 H 30 Br 2 F 3 O 7 [M+H] + ,645.0305.Found,645.0308。
EXAMPLE 40 Synthesis of Compound 40
Figure BDA0002855003320000311
In a glove box, terminal alkynes (0.500mmol, 1.00eq., KF (116mg, 2.0mmol,4.00eq.,2.00mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag-were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. Then, dichloromethane is added to dissolve the sample, the mixture is filtered through kieselguhr, and after spin-drying, the mixture is separated by preparative HPLC as MeCN: H 2 And O is eluent for separation. Elution conditions: (9 mL/min, detector UV. Lamda. Max 210nm, meCN/H 2 O＝70:30(0min),MeCN/H 2 O＝100:0(30min),MeCN/H 2 O =100 (40 min)). Retention time: 30.4min. The corresponding product was obtained in the form of 246mg as a colorless oily liquid (yield 71%).
R f ＝0.38(hexanes/EtOAc 4:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ5.76(d,J＝9.8Hz,1H),5.40(s,1H),4.09(t,J＝5.6Hz,2H),2.76–2.46(m,7H),2.34(td,J＝14.0,3.8Hz,1H),2.04–1.96(m,1H),1.94–1.81(m,3H),1.79–1.65(m,2H),1.59(dt,J＝13.7,4.3Hz,1H),1.46(dd,J＝20.5,9.2Hz,1H),1.39(s,3H),1.37–1.19(m,3H),1.05–0.96(m,1H),0.93(d,J＝5.9Hz,3H),0.82(d,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.0,171.1,148.0,119.8(q,J＝261.0Hz),104.5,92.2,91.6,88.9,80.2,63.2,51.6,45.3,37.3,36.3,34.1,31.8,29.2,28.9,26.0,24.9,24.6,22.0,20.3,12.1. 19 F NMR(376MHz,CDCl 3 )δ-56.17(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 25 H 33 Br 2 F 3 NaO 9 [M+Na] + ,715.0336.Found,715.0336。
EXAMPLE 41 Compound 41
Figure BDA0002855003320000312
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 8. The corresponding product was obtained as a white solid (yield 57%) at 208 mg.
R f ＝0.34(hexanes/EtOAc 4:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.36–7.17(m,6H),6.99(t,J＝7.9Hz,2H),6.96–6.82(m,4H),5.71(t,J＝6.1Hz,1H),4.84(s,2H),4.59(s,1H),3.06(t,J＝7.4Hz,1H),2.10–2.00(m,5H),1.92–1.77(m,2H). 13 C NMR(101MHz,CDCl 3 )δ170.1,166.9,162.3(d,J＝246.5Hz),158.9(d,J＝243.3Hz),157.9,143.7,135.8(d,J＝3.2Hz),133.8(d,J＝2.6Hz),130.8,128.2(d,J＝8.2Hz),127.3,119.7(q,J＝262.1Hz),118.3(d,J＝7.8Hz),115.7(d,J＝23.9Hz),115.6,115.4(d,J＝21.5Hz),95.0,74.7,65.2,60.6,60.1,33.6,24.8,21.0. 19 F NMR(376MHz,CDCl 3 )δ-56.41(s,3F),-113.67–-113.74(m,1F),-117.79–-117.86(m.1F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 30 H 24 Br 2 F 5 NNaO 5 [M+Na] + ,753.9834.Found,753.9831。
EXAMPLE 42 Synthesis of Compound 42
Figure BDA0002855003320000321
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol,4.00eq., 2.00eq., 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. Then adding dichloromethane to dissolve the sample, filtering with diatomaceous earth, spin drying, separating with preparative HPLC using MeCN: H 2 And O is eluent for separation. Elution conditions: (9 mL/min, detector UV. Lamda. Max 210nm, meCN/H 2 O＝50:50(0min),MeCN/H 2 O＝70:30(20min),MeCN/H 2 O＝90:10(30min),MeCN/H 2 O =100 (40 min)). Retention time: 17.1min. The corresponding product, 178mg, was obtained as an oily liquid (yield 70%).
R f ＝0.14(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy:NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ4.27–4.16(m,2H),2.65(t,J＝7.6Hz,2H),2.44–2.32(m,1H),2.03–1.84(m,4H),1.69–1.59(m,1H),1.07(s,3H),1.02(s,3H),0.92(s,3H). 13 C NMR(101MHz,CDCl 3 )δ178.0,167.4,147.6(d,J＝1.0Hz),119.8(q,J＝261.3Hz),91.0,89.2,64.0,54.8,54.2,30.7,28.9,28.9,25.0,16.8,16.8,9.7,9.7. 19 F NMR(376MHz,CDCl 3 )δ-56.22(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 16 H 20 Br 2 F 3 O 5 [M+H] + ,506.9624.Found,506.9619。
EXAMPLE 43 Synthesis of Compound 43
Figure BDA0002855003320000331
In a glove box, terminal alkynes (0.500mmol, 1.0) were added sequentially to a 15mL sealed tube0 eq.), KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, and separated after spin-drying using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product was obtained as a white solid (yield 67%) 210 mg.
R f ＝0.14(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ8.11(d,J＝1.7Hz,1H),8.03(dd,J＝8.8,1.7Hz,1H),6.98(d,J＝8.9Hz,1H),4.30(t,J＝6.0Hz,2H),3.87(d,J＝6.5Hz,2H),2.84–2.66(m,5H),2.23–2.11(m,1H),2.10–1.99(m,2H),1.06(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ167.4,162.5,161.8,161.5,147.8(q,J＝1.1Hz),132.6,132.0,125.9,121.3,119.8(q,J＝261.2Hz),115.4,112.7,102.9,89.2,75.7,63.7,29.0,28.2,25.0,19.1,17.5. 19 F NMR(376MHz,CDCl 3 )δ-56.10(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 22 H 22 Br 2 F 3 N 2 O 4 S[M+H] + ,624.9614.Found,624.9611。
EXAMPLE 44 Synthesis of Compound 44
Figure BDA0002855003320000332
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring for five minutes at room temperature, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the material feeding is finished, the cover is sealed and the glove is turned toThe reaction was carried out outside the chamber at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 10. The corresponding product, 220mg, was obtained as a colorless oily liquid (73% yield).
R f ＝0.18(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.81–7.74(m,2H),7.73–7.65(m,2H),7.22–7.09(m,5H),5.16(dd,J＝11.3,5.2Hz,1H),4.31–4.15(m,2H),3.57(ddd,J＝25.6,14.3,8.4Hz,2H),2.64–2.53(m,2H),1.97–1.85(m,2H). 13 C NMR(101MHz,CDCl 3 )δ168.9,167.5,147.8,136.7,134.3,131.6,128.9,128.7,127.0,123.6,119.8(d,J＝261.6Hz),89.1,64.5,53.4,34.8,28.9,25.0. 19 F NMR(376MHz,CDCl 3 )δ-56.17(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 23 H 19 Br 2 F 3 NO 5 [M+H] + ,603.9577.Found,603.9572。
EXAMPLE 45 Synthesis of Compound 45
Figure BDA0002855003320000341
In a glove box, terminal alkynes (0.500mmol, 1.00eq., KF (116mg, 2.0mmol,4.00eq.,2.00mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag-were added to a 15mL sealed tube in this order 2 CO 3 (27.5mg, 0.100mmol, 0.200eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (489mg, 2.00mmol, 4.00eq.) was added. After the addition was completed, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. Then, dichloromethane is added to dissolve the sample, the mixture is filtered through kieselguhr, and after spin-drying, the mixture is separated by preparative HPLC as MeCN: H 2 And O is eluent for separation. Elution conditions: (9 mL/min, detector UV. Lamda. Max 210nm, meCN/H 2 O＝70:30(0min),MeCN/H 2 O＝90:10(30min),MeCN/H 2 O =100 (0 (80 min)). Retention time: 77.05min. The corresponding product, 258mg, was obtained as a colorless oily liquid (yield 71%).
R f ＝0.35(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ4.77–4.63(m,1H),4.08(t,J＝6.1Hz,2H),2.66(t,J＝7.5Hz,2H),2.38–2.30(m,1H),2.24–2.16(m,1H),2.01(s,3H),1.99–1.88(m,3H),1.88–1.75(m,5H),1.69–1.63(m,1H),1.60–1.50(m,2H),1.46–1.34(m,7H),1.30–1.20(m,4H),1.15–0.95(m,6H),0.94–0.86(m,6H),0.63(s,3H). 13 C NMR(101MHz,CDCl 3 )δ174.3,170.8,148.2,119.9(q,J＝261.0Hz),88.9,74.5,62.8,56.6,56.1,42.7,42.0,40.5,40.3,35.9,35.5,35.2,34.7,32.4,31.3,31.1,29.1,28.3,27.1,26.8,26.4,25.1,24.3,23.4,21.6,21.0,18.4,12.2. 19 F NMR(376MHz,CDCl 3 )δ-56.16(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 32 H 47 Br 2 F 3 NaO 5 [M+Na] + ,749.1635.Found,749.1633。
EXAMPLE 46 Synthesis of Compound 46
Figure BDA0002855003320000351
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag (Packoo) and the like were added to a 15mL sealed tube in this order 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spun dry. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 1. The corresponding product was obtained as a white solid (yield 88%) 305 mg.
R f ＝0.74(hexanes/EtOAc 1:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝8.4Hz,2H),6.99(d,J＝8.5Hz,2H),5.34–5.23(m,2H),5.20–5.10(m,2H),4.28(dd,J＝12.3,5.4Hz,1H),4.16(d,J＝12.1Hz,1H),3.94–3.84(m,1H),2.14–1.94(m,12H). 13 C NMR(101MHz,CDCl 3 )δ170.6,170.3,169.5,169.3,157.9,145.9(q,J＝1.7Hz),131.0,126.3,120.0(q,J＝262.1Hz),116.6,98.4,89.0,72.7,72.3,71.2,68.3,62.0,20.7,20.7,20.7,20.6. 19 F NMR(376MHz,CDCl 3 )δ-56.68(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 23 H 23 Br 2 F 3 NaO 11 [M+Na] + ,712.9451.Found,712.9447。
EXAMPLE 47 Synthesis of Compound 47
Figure BDA0002855003320000352
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4mg, 0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 40. The corresponding product was obtained 161mg as a white solid (yield 57%).
R f ＝0.38(hexanes/EtOAc 10:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.36–7.28(m,2H),7.25(s,1H),4.12–3.85(m,4H),2.94–2.87(m,2H),2.42–2.26(m,2H),2.12–2.02(m,1H),2.00–1.75(m,4H),1.74–1.37(m,6H),0.92(s,3H). 13 C NMR(101MHz,CDCl 3 )δ146.8,143.2,137.1,129.6,128.7,126.5,125.4,120.1(q,J＝262.0Hz),119.5,88.5,65.4,64.7,49.6,46.2,44.3,38.6,34.3,30.8,29.5,26.7,25.8,22.5,14.5. 19 F NMR(376MHz,CDCl 3 )δ-55.59(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 23 H 26 Br 2 F 3 O 3 [M+H] + ,565.0195.Found,565.0191。
EXAMPLE 48 Synthesis of Compound 48
Figure BDA0002855003320000361
In a glove box, terminal alkynes (0.500mmol, 1.00eq.) and KF (116mg, 2.0mmol, 4.00eq.), 18-crown-6 (132mg, 0.500mmol, 1.00eq.), ag, were sequentially added to a 15mL sealed tube 2 CO 3 (34.4 mg,0.125mmol, 0.250eq.), NBP (339mg, 1.500mmol, 3.00eq.), meCN (1.00 mL). After stirring at room temperature for five minutes, 4-fluorobenzenesulfonic acid trifluoromethyl ester (612mg, 2.50mmol, 5.00eq.) was added. After the addition, the lid was sealed, and the reaction was carried out outside the glove box at 60 ℃ for 4 hours. After the reaction was complete, the mixture was transferred to a round bottom flask with dichloromethane and spin dried. The sample was then dissolved by addition of dichloromethane, filtered through celite, spun dry and separated using a thin layer chromatography silica gel plate with hexane/EtOAc 100. The corresponding product, 213mg, was obtained as a colorless oily liquid (yield 65%).
R f ＝0.79(hexanes/EtOAc 40:1(v/v)).NMR Spectroscopy: 1 H NMR(400MHz,CDCl 3 )δ7.10(s,1H),7.07(s,1H),2.83–2.68(m,2H),2.16(s,3H),1.87–1.73(m,2H),1.64–1.57(m,2H),1.55–1.49(m,1H),1.46–1.19(m,15H),1.17–1.02(m,6H),0.91–0.80(m,12H). 13 C NMR(101MHz,CDCl 3 )δ154.1,147.2,129.3,128.4,126.4,121.5,120.3,120.1(q,J＝261.7Hz),87.0,77.1,40.6,39.6,37.6,37.6,37.5,33.0,32.8,31.0,28.2,25.0,24.6,24.4,22.9,22.8,22.3,21.1,19.9,19.8,16.2. 19 F NMR(376MHz,CDCl 3 )δ-55.90(s,3F).Mass Spectrometry:HRMS-ESI(m/z):Calcd for C 30 H 46 Br 2 F 3 O 2 [M+H] + ,653.1811.Found,653.1811.
Example 49
Except that no Ag is added 2 CO 3 Otherwise, the same procedure as in example 1 was repeated.
Examples 50 to 54
Except that Ag is added separately 2 CO 3 Replacement is AgSbF 6 、AgBF 4 、Ag 2 O、AgF、AgOCOCF 3 Otherwise, the same procedure as in example 1 was repeated.
Examples 55 to 61
The same as in example 1 except that 18-crown-6 was replaced with 12-crown-4 (12-crown-4), 15-crown-5 (15-crown-5), benzo-18-crown-6 (Benzo-18-crown-6), dibenzo-18-crown-6 (Dibenzo-18-crown-6), dicyclohexano-18-crown-6, dibenzo-24-crown-8 (Dibenzo-24-crown-8), and Benzo-21-crown-7 (Benzo-21-crown-7), respectively.
Example 62
The procedure was as in example 1 except that 18-crown-6 was not added.
Examples 63 to 64
The procedure of example 1 was repeated except that NBP was replaced with NBS and DBDMH.
Examples 65 to 69
Except that KF is replaced by RbF and AgF 2 、NaF、FeF 3 CsF, the rest being the same as in example 1.
Examples 70 to 80
The procedure was as in example 1 except that MeCN was replaced with THF, acetone, 1,4-dioxane, DCM, anisole, DCE, hexane, etOAc, toluene, DMC, DMA, respectively.
Examples 81 to 86
Except that
Figure BDA0002855003320000371
(4-Fluorobenzenesulfonic acid trifluoromethyl ester) was replaced with
Figure BDA0002855003320000372
Figure BDA0002855003320000373
The rest was the same as in example 1.
Examples 87 to 89
The same procedure as in example 1 was repeated, except that the amounts of the terminal alkynes were adjusted to 0.25mmol, 0.125mmol and 0.0625mmol, respectively.
Examples 90 to 91
The procedure of example 1 was repeated, except that NBP was used in an amount of 1mmol or 2 mmol.
Examples 92 to 93
Except for adjusting Ag 2 CO 3 The amount of (B) was 0.05mmol, 0.25mmol and the same as in example 1.
Examples 94 to 95
The procedure was repeated as in example 1 except that the amount of KF used was changed to 1.5mmol and 1 mmol.
Examples 96 to 98
In addition to adjusting
Figure BDA0002855003320000381
The amount of (B) was 1mmol, 1.5mmol and 2.5mmol, and the rest was the same as in example 1.
Examples 99 to 102
The procedure of example 1 was repeated, except that the reaction temperature was adjusted to 40 ℃, 50 ℃, 70 ℃ and 80 ℃.
Examples 103 to 104
Except that the reaction is separately carried out at O 2 Atmosphere and air atmosphere, and the rest was the same as in example 1.
Comparative example 1
The procedure was as in example 1 except that NBP was replaced with liquid bromine.
Comparative example 2
The procedure was as in example 1 except that KF was not added.
The parameters and yields of the examples and comparative examples are shown in tables 1 and 2.
Figure BDA0002855003320000391
Figure BDA0002855003320000401
TABLE 2
Figure BDA0002855003320000411
It can be seen from examples 1-48 that the method of dibromotrifluoromethoxylation of terminal alkynes of the present application is applicable to different terminal alkynes, and the dibromotrifluoromethoxylation can be smoothly performed on both terminal alkynes with simple structure and terminal alkyne molecules with complex structure, so as to obtain olefins containing both alkenyl bromide and alkenyl trifluoromethyl ether structures.
As can be seen from example 1 and examples 49 to 54, the yield was low, about 33%, when no silver salt was added to the reaction system, and the yield was improved by adding a different silver salt, wherein the yield was improved to more than 80% by adding silver fluoride or silver carbonate, and AgSbF 6 、Ag 2 O and AgOCOCOCF 3 The yield can be improved to more than 60%.
As can be seen from example 1 and examples 55 to 62, crown ethers having different numbers of carbon atoms, and crown ethers having substituents, were able to improve the yield of the reaction, with 18-crown-6 giving a yield of up to 80%.
It can be seen from examples 1, 63, 64 and comparative example 1 that when electrophilic brominating reagents of the N-Br type are used, the reaction is able to produce dibromotrifluoromethoxy products, and furthermore, different yields of products are obtained with different brominating reagents, DBDMH and NBP being preferred in this application, and NBP being more preferred.
As can be seen from examples 1, 65-69 and comparative example 2, fluoride anions are necessary in the reaction, wherein different fluoride anions can affect the yield differently, wherein the yield can reach more than 60% by adding CsF, and the yield can reach 80% by adding KF.
As can be seen from example 1 and examples 70-80, the kind of organic solvent influences the yield of the reaction, wherein, when dichloromethane, anisole and ethyl acetate are used as the organic solvent of the reaction, the yield can reach more than 40%; when 1, 2-dichloroethane or dimethyl carbonate is used as the organic solvent for the reaction, the yield can reach more than 60 percent; when acetonitrile or 1,4-dioxane is adopted, the yield can reach 80 percent.
It can be seen from example 1 and from examples 81 to 86 that different trifluoromethoxylating reagents give different yields and that, in addition, when the position of the substituent on the benzene ring in the trifluoromethane benzene sulphonate is para to the sulphonate group, this is advantageous in giving higher yields and, without being bound by any theory, the inventors believe that this may be due to the hindrance of the fluoride anion to the sulphonyl group if a bulky sterically hindered group is present in the ortho position to the sulphonate group.
As can be seen from example 1 and examples 87 to 89, the product yield increases with the molar concentration of the terminal alkyne in the reaction system, and can reach 80% when the molar concentration of the terminal alkyne reaches 0.5mol/L, so that in some embodiments of the present application, the concentration of the terminal alkyne in the organic solvent is 0.15 to 0.8mol/L, and at this time, the yield can reach 40% or more; preferably, the concentration of the terminal alkyne in the organic solvent is 0.2-0.6mol/L, and the yield can reach more than 60%.
As can be seen from example 1 and examples 90 and 91, within certain limits, increasing the amount of brominating reagent used increases the product yield, and after the molar ratio of bromine in the brominating reagent to the terminal alkyne reaches 3 (brominating reagent amount is 1.5mmol, terminal alkyne amount is 0.5 mmol), and increasing the amount of brominating reagent, the product yield no longer increases significantly, in some embodiments of the present application, the molar ratio of bromine in the brominating reagent to the terminal alkyne is (2-4): 1.
It can be seen from example 1 and examples 92 and 93 that increasing the amount of silver salt used increases the product yield. In some embodiments herein, the molar ratio of silver in the silver salt to the terminal alkyne is (0.1-1): 1.
As can be seen from example 1 and examples 94 and 95, an increase in the concentration of the fluoride anion can improve the yield, and in some embodiments of the present application, the molar ratio of the fluoride anion to the terminal alkyne is (1-5): 1.
As can be seen from example 1 and examples 96-98, an increase in the concentration of the trifluoromethoxy reagent can increase the yield, which in some embodiments of the present application is greater than 50% at a molar ratio of the terminal alkyne to the trifluoromethoxy reagent of 1 (3-7).
As can be seen from example 1 and examples 99-102, the yield can reach 80% at a reaction temperature of about 60 ℃, and the yield decreases with decreasing reaction temperature below 60 ℃; above 60 ℃, the yield is not greatly changed along with the rise of the temperature; in some preferred embodiments of the present application, the reaction temperature is 50 to 70 ℃ in view of productivity and production cost.
As can be seen from example 1 and examples 103 and 104, the reaction yields were higher in nitrogen, oxygen and air, with a slight decrease in yield in air, and without being bound to any theory, the inventors believe that this may be due to a small amount of water vapor in air that has somewhat destroyed the OCF 3 The stability of the negative ions.
The above description is only a preferred embodiment of the present application and should not be taken as limiting the present application, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims (7)

1. A method for the dibromotrifluoromethoxylation of a terminal alkyne, comprising:
in an organic solvent, enabling terminal alkyne to perform electrophilic addition reaction in the presence of fluorine anions, a trifluoromethoxy reagent and a bromination reagent so as to perform dibromo-trifluoromethoxylation reaction of the terminal alkyne;
wherein the brominating reagent is selected from at least one of N-Br type electrophilic brominating reagents; the trifluoromethoxylation reagent is selected from at least one of substituted or unsubstituted benzene sulfonic acid trifluoromethyl ester; the N-Br type electrophilic brominating reagent is selected from at least one of NBP, DBDMH and NBS; counter-balancing of said fluorine anionsThe ion is a metal ion selected from K + Or Cs + (ii) a The reaction system also comprises substituted or unsubstituted C 8 -C 24 At least one of the crown ethers of (a);
the concentration of the terminal alkyne in the organic solvent is 0.15-0.8mol/L; the molar ratio of bromine in the brominating reagent to the terminal alkyne is (2-4) to 1; the organic solvent is at least one selected from acetonitrile, 1,4-dioxane, dichloromethane, 1, 2-dichloroethane, ethyl acetate, dimethyl carbonate, toluene and anisole; the reaction temperature is 20-80 ℃; the reaction time is 3-5 hours.
2. The method of claim 1, wherein the reaction system further comprises a silver salt selected from AgSbF 6 、Ag 2 CO 3 、AgF、Ag 2 O、AgOCOCF 3 、AgBF 4 At least one of (a).
3. The process according to claim 2, wherein the molar ratio of silver in the silver salt to the terminal alkyne is (0.1-1): 1.
4. The process of claim 1, wherein the molar ratio of the crown ether to the terminal alkyne is (0.5-1.5): 1.
5. The method of claim 1, wherein the method has at least one of the following features:
(a) The molar ratio of the terminal alkyne to the trifluoromethoxy reagent is 1 (3-7);
(b) The concentration of the terminal alkyne in the organic solvent is 0.2-0.6mol/L;
(d) The molar ratio of the fluorine anions to the terminal alkyne is (1-5): 1;
(e) In the substituted benzene sulfonic acid trifluoromethyl ester, a substituent is positioned at the para position of a sulfonate group;
(i) The reaction is carried out in an atmosphere of air, oxygen or nitrogen.
6. The method of claim 1, wherein the terminal alkyne is selected from the group consisting of:
Figure FDA0003859114200000011
Figure FDA0003859114200000021
Figure FDA0003859114200000031
7. the method of claim 1, wherein the reaction product is selected from the group consisting of:
Figure FDA0003859114200000032
Figure FDA0003859114200000041
Figure FDA0003859114200000051
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