2 General procedure for the trifluormethylation of 4-methoxyphenyl boronic acid .... 2 Copper-mediated radical trifluoromethylation of boronic acids .... Copper-mediated oxidative triflu
LITERATURE REVIEW
Trifluoromethylation
Fluorination chemistry has been an attractive field for many scientists due to its widespread applications in pharmaceuticals, 1 agrochemicals, 2 materials, 3 and radiotracers for positron emission tomography (PET) 4 It has been reported that 20% of pharmaceuticals and up to 30% of agrochemicals on the market are fluorine-containing compounds, 1a which indicates the vital role of these compounds in numerous areas In pharmaceutical research, introducing fluorine atom(s) into an organic compound can change its physical, distribution, metabolism and excretion properties 1a while remaining the molecular size due to the similar atomic radius of fluorine to hydrogen atom Despite fluorine is the 13 th most abundant element found in the earth’s crust, the amount of natural fluorinated compounds known is very low (Figure 1.1) 5 Therefore, there is a large interest in methodology to introduce selectively fluorine and fluorine-containing groups into organic compounds for improvements of biological activities
Figure 1 1 Natural occurring fluoro-organic compounds
The first metal-mediated direct perfluoroalkyllation was invented by McLoughlin and Thrower in 1965 They successfully introduced perfluoroalkyl group into the
9 predetermined position of aromatic compounds bearing a wide variety of substituent (carboxy, nitro, amino, hydroxyl, etc.) with the presence of copper under 110-130 o C (Scheme 1.1) It was also clearly demonstrated that the copper perfluoroalkyl Cu-Rf was formed as a mediated species, which then reacted with aryl halide to produce the desired product 6 However, it was not until 1986 that the copper perfluoroalkyl comple x was first identified via spectroscopic studies 7
Scheme 1 1 Copper-mediated perfluoroalkylation of aromatic compounds
Since 1960’s, further developments have been continuously reported, regarding the use of various transition-metal-based catalysts 8 Among that, copper-mediated trifluoromethylation has been studied most extensively because of the high efficiency and low cost of copper 8
One of the most important classes of fluorinated substances consists of compounds bearing a trifluormethyl group The effects of trifluormethyl introduction into molecules are similar to that of fluorine, including enhancing chemical and metabolism stability, lipophilicity and binding selectivity of initial compounds 9 Hence, such these compounds are used widely as active ingredients in drugs as well as agrochemicals, some examples of them are shown in Figure 1.2
Figure 1.2 Several active ingredients containing trifluormethyl group 10 Looking for new methods to introduce trifluormethyl group into organic molecules is also an attractive field owing to their important applications in many areas 10 Molecules bearing a trifluormethylation group represent one of the most important classes of selectively fluorinated compound 11
In 2012, Standford and co-workers reported the copper-mediated radical trifluoromethylation of aryl boronic acids with the radical reagent sodium trifluoromethanesulfinate NaSO2CF3, in conjunction with tert-butyl hydroperoxide, proceeding under ambient conditions at room temperature (Scheme 1.2) 12 Herein, trifluoromethyl radical could be generated from the radical reagent to participate in the reaction as a reactive species 13 One limitation of this method is the use of stoichiometric amounts of copper salt
Scheme 1 2 Copper-mediated radical trifluoromethylation of boronic acids
11 The merger of photoredox catalyst ruthenium(II) and copper catalysis was also described by Sanford et al., 14 which developed a mild protocol to carry out the cross- coupling reaction of boronic acids and CF3I in radical pathway (Scheme 1.3) Although this work employed readily available reagents and provide simple experimental procedure, the high cost of metal catalysis made it less favorable
Scheme 1 3 Ruthenium(II) and copper-catalyzed radical trifluoromethylation of boronic acids Trifluoromethylated arenes were also synthesized from boronic acids via electrophilic pathway, utilizing electrophilic reagents which produce trifluoromethyl cation as a reactive species to react with nucleophiles In these cases, Togni’s reagent 15 and Umemoto’s reagent 16 were used (Scheme 1.4) Considerably, despite comprising of the same substrate scope, the method employing Togni’s reagent (Scheme 4a) displayed better yields when using a low loading of copper catalysts The employment of extremely expensive electrophilic reagents is the main disadvantage of these reports
Scheme 1 4 Copper-catalyzed electrophilic trifluoromethylation of boronic acids
The development in this field over last few decades involved the use of transition-metal catalyst via nucleophilic, electrophilic, and radical pathway 11 Among these strategies, the Ruppert-Prakash reagent Me3SiCF3 has made nucleophilic approach a method of choice due to its low-cost, stability, and easy to handling over related trifluormethylated reagents 17 In particular, studies in the formation of trifluormethylated (hetero) arenes by utilizing Me 3 SiCF 3 have been intensively reported using expensive palladium catalysts 18
Recently, a copper-mediated oxidative trifluormethylation of alkynes and aryl boronic acids was disclosed Quing and Chu first focused their efforts towards oxidative trifluormethylation of boronic acids 19 (Scheme 1.5a), wherein a nucleophilic reagent in conjunction with an oxidant was used to carry out the transformation In 2012, they developed the procedure to reduce the amount of copper to a catalytic amount (10 mol%) (Scheme 1.5b) However, the slow addition of boronic acid as well as nucleophilic reagent made this process less practical
13 Scheme 1 5 Copper-catalyzed oxidative trifluormethylation of boronic acids
Following the idea, a more economical protocol was then studied by Buchwald’s group, which employed Cu(OAc)2 as a copper source and dry O2 as the oxidant (Scheme 1.6) 20 However, the utilizing of hazardous solvent isobutyronitrile and a stoichiometric amount of copper has limited the application of this method
Scheme 1 6 Copper-mediated oxidative trifluoromethylation of boronic acids
Regarding to the trifluoromethylation of sp 3 -hybridized carbon centers, Fu and co-wokers reported their work on copper-promoted oxidative trifluoromethylation of primary and secondary alkyl boronic acids (Scheme 1.7) 21 The use of expensive silver catalyst made this method less practical
14 Scheme 1 7 Copper-promoted oxidative trifluoromethylation of alkyl boronic acids
Later, an alternative low-cost reagent fluoroform-derived CuCF3 for oxidative trifluormethylation was recommended by Grushin et al in 2012 22 A wide range of trifluormethylated aromatic compounds were obtained in up to 99% yield under mild condition (Scheme 1.8) However, the need of a complex multiple-step process to generate CuCF3 was one limitation of this method
Scheme 1 8 Fluoroform-derivated CuCF3 for trifluoromethylation of boronic acids
In general, all of these approaches have successfully conducted the trifluormethylation of boronic acids to obtain the trifluormethylated compounds
However, either stoichiometric amount of copper salts or slow addition of reagents by syringe pump was required to achieve good yields Furthermore, to the best of our knowledge, reports using heterogeneous catalysts for trifluormethylation reactions have not been described yet Due to the presence of fluorine in 20% of pharmaceuticals and
15 30% of agrochemicals, 1a the development of more practical and efficient protocols using recyclable catalytic systems is highly needed especially for industrial applications.
Metal-organic frameworks (MOFs)
Metal organic frameworks (MOFs) are a class of porous crystalline materials of one-, two- or three-dimensional networks constructed from metal ions/clusters and organic ligands 23 With enormous surface areas and high pore volumes in uniformly- sized pores, MOFs are favorable materials for various applications in energy storage 24 , CO2 adsorption 25 , hydrocarbon adsorption/separation 26 , catalysis 27 , magnetism 28 , sensor 29 , drug delivery 30 , luminescene 31 , and others First published in 1990 32 , these novel materials have attracted lots of attention of various research groups, with the remarkable increase in the number of papers published in this field during recent years 33 and more than 20 000 different MOFs being reported and studied within the past decade 34
In general, the MOFs are constructed by joining the metal-containing units, so- called SBUs (secondary building unit), with organic linkers through coordination bonds 34 Normally, SBUs are molecular clusters (rather than single atoms) of simple geometrical shapes such as triangle, square, tetrahedra, and octahedra, etc 35 These clusters are linked by organic polytopic linkers, which could be categorized as ditopic, tritopic or above, into periodic structures 36
So far, the main routes to synthesize MOFs are hydrothermal or solvothermal methods, wherein MOFs are prepared in small scales by electrical heating 23 However, this pathway requires long reaction time, up to several days, which limits large-scale synthesis Alternatively, to reduce the reaction time and obtain smaller as well as uniform crystals, several strategies were studied such as microwave-assisted 37 , sonochemical 38 , electrochemical 39 , mechanochemical methods 40 , etc Despite huge improvements in MOFs synthesis methods during recent years, further investigations are required for scale-up synthesis 23
With their high surface area and ultrahigh porosity 41 , MOFs are employed in numerous fields 23 One of the most promising applications is utilizing MOFs as
16 heterogeneous catalysis, due to their high intrinsic metal content 42 and uniform, periodically aligned active sites 33 Besides that, large pore size is one of the properties that make MOFs more suitable as catalysts for liquid-phase reactions than classical zeolites 43 Due to these benefits, there is a vast potential for MOFs in application as catalysts in organic reactions
Cu(INA)2 (INA = isonicotinate) is a single-net three-dimensional sprial open- framework combined by the square pyramidal Cu(II) and IN (isonicotinate) ligand The structure of the material consists of copper atom coordinated by two pyridyl groups and three carboxylate groups of five IN units 44 It can be synthesized from copper salts as a source of copper and isonicotinic acid (HINA) as a ligand, according to a literature procedure 45
Figure 1 3 View of the crystal structure of Cu(INA)2
The discovery of Cu(INA) 2 framework with Cu(II) square-pyramidal geometry possessing exceptionally high chemical ability and hydrophobicity opens its application especially in catalysis 46 Moreover, structure elucidation indicated the weak interaction between copper centers, which is structurally rare for metal organic framework Lately, Cu(INA)2 was successfully used as catalyst for the ligand-free N-arylation of heterocycles, 46 which demonstrated the efficiency of this MOF as heterogeneous catalyst for organic reactions
17 Scheme 1 9 Cu(INA)2 as an efficient heterogeneous catalyst for the ligand-free N- arylation of heteroarenes Mechanistic studies in trifluormethylation disclosed that flexibility in copper center favors the reductive elimination forming C-CF 3 bond 11, 47 Herein, we report the first heterogeneous protocol for trifluormethylation of aryl boronic acids under Cu(INA) 2 catalysis It is worth mentioning that this is also the first catalytic route from this transformation under copper-based system.
Our approach
Transition-metal mediated trifluoromethyl chemistry has improved significantly to become a focus of numerous researches, especially in the last five years 48 However, the use of homogeneous catalysts has limited their industrial applications, especially in pharmaceutical industry Difficulties in isolating process 49 may lead to the poor purity of products, which is the important consideration in bioactive compound synthesis
In contrast, the recoverability and the demand of simple separation process makes heterogeneous catalysis the better option for industrial applications Metal-organic frameworks (MOFs), one of the most favorable transition metal heterogeneous catalysts, are promising candidates due to their high catalytic activity 50
Inspired by those reasons, this thesis aims to investigate the possibility of employing heterogenous catalysts - in particular MOFs - in trifluoromethylation.So far, no trifluoromethylation reactions have been reported using heterogeneous catalysis
Therefore, a novel methodology to introduce trifluoromethyl groups into organic compounds – immersing transition metal heterogeneous catalysis – is worth being presented, leading to a more convenient and practical strategy for direct trifluoromethylation Following the idea, the objective of our approach is conducting
18 trifluoromethylation reations of boronic acids using copper-based MOF since copper is relatively cheap and usually acts efficiently 8
The work of Buchwald’s group exhibited a simple, mild, and high efficiency procedure 20 The use of stoichiometric amounts of copper catalyst was the only limitation of this method Hence, this thesis aims to replace the homogeneous catalyst with copper-based MOF with a lower amount to overcome this drawback
Scheme 1 10 Trifluoromethylation of boronic acids over Cu-MOF
EXPERIMENTAL
Synthesis and characterization of the metal-organic frame work Cu(INA) 2
All reagents and starting materials were obtained commercially from Sigma- Aldrich, Merck, Xilong, and were used as received without any further purification
Table 1 1 List of chemicals for MOF synthesis
A Netzsh Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 o C/min under a nitrogen atmosphere Powder X-ray diffraction (PXRD) patterns were recorded using a Cu K radiation source on a D8 Advance Bruker powder diffractometer Scanning electron microscopy studies were conducted on a S4800 Scanning Electron Microscope (SEM) Fourier transform infrared (FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets
2.1.2 Synthesis of MOF Cu(INA) 2 :
Figure 2.1 Synthesized procedure of MOF Cu(INA)2
MOF Cu(INA)2 was synthesized following a literature procedure 45 In a typical experiment, solution of Cu(NO3)2.3H2O (1.93 g, 8 mmol) in N-Methyl-2-pyrrolidone
(NMP, 70 mL) was added to a beaker containing solution of HINA (isonicotinic acid) (0.492 g, 4 mmol) in N,N’-dimethylformamide (DMF, 170 mL) under stirring condition at room temperature Pyridine (15 mL) was then added to the mixture The resulting solution was distributed to twenty 10 mL vials The vials were then heated at 100 o C in an isothermal oven for 72 h After cooling the vial to room temperature, the solid
15 mL pyridine 1.93 g Cu(NO 3 ) 2 3H 2 O in 70 mL NMP
21 product was removed by decanting with mother liquor and washed in DMF for 3 days
Solvent exchange was then carried out with dichloromethane (DCM) at room temperature for 3 days The material was then evacuated under vacuum at 140 o C for 6 hours and stored.
Catalytic study
All reagents and starting materials were obtained commercially from Sigma-Aldrich, Fisher, and Merck, and were used as received without any further purification unless otherwise noted
Table 2 1List of chemicals for trifluormethylation of boronic acids
Tetrabutyl ammonium fluoride (TBAF) Acros
Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-
Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) The temperature program for GC analysis heated sample at 100 o C for 1 minute; heated from 100 to 280 o C at 40 oC/min and held them at 280 o C for 2 minutes 30 seconds Dodecane was used as an internal standard
The products were indicated by gas chromatography mass spectroscopy (GC-
MS), analysis data were recorded on a Shimadzu GCMS-QP2010 Ultrawith a ZB-5MS column (length = 30 m, inner diameter = 0.25 mm, film thickness = 0.25 μm) The temperature program for GC-MS analysis heated samples at 50 °C for 2 min, from 50 °C to 280 °C at rate of 10 °C/min, then held at 280 °C for 5 min MS spectra were compared with the spectra gathered in the NIST library
The 1 H and 13 C NMR spectra were recorded on a Bruker AV 500 MHz spectrometer operating at 500 MHz for 1 H and 125 MHz for 13 C, respectively, using tetramethylsilane as standard The chemical shifts (δ) are expressed as values in parts per million (ppm) and the coupling constant (J) is given in hertz (Hz) Spin
23 multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet)
2.2.2 General procedure for the trifluormethylation of 4-methoxyphenyl boronic acid
Figure 2 2 General procedure for the trifluormethylation of 4-methoxyphenyl boronic acid
Cu-MOF (30% mol) 1,10 – phenanthroline (30% mol)
TMSCF3 (4 quiv.) 4-methoxyphenylboronic acid ( 1 quiv.)
24 In a typical experiment, a vial contained a magnetic stir bar was purged with argon To the vial was added cesium fluoride (304 mg, 2.0 mmol, 2.0 equiv), which was activated under vacuum at 200 o C, 1, 10-phenanthroline (59.5 mg, 0.33 mmol, 1.1 equiv, and Cu-MOF (0.3 mmol, 30 mol%) The vial was backfilled with argon Dried dichloroethane (DCE, 5 mL) were then added to the reaction vial, which was then stirred vigorously for 5 minutes TMSCF3 (0.6 mL, 4.0 mmol, 4.0 equiv) and 4- methoxyphenylboronic acid (152 mg, 1 mmol, 1 equiv) was quickly added to the reaction vessel, before purging the vial with oxygen gas The reaction yield was monitored by withdrawing aliquots from the reaction mixture at different time intervals, diluting with ethylacetate (2 mL), quenching with an aqueous KOH solution (1%, 1 mL), and then drying over anhydrous Na 2 SO 4 before analyzing by GC with dodecane used as internal standard, and further confirming product identity by GC–MS and NMR
For the leaching test, a catalytic reaction was stopped at 15 min, analyzed by GC, and filtered to remove the solid catalyst The reaction solution was then stirred for a further 105 min Reaction progress, if any, was monitored by GC as previously described
When the reaction was completed, a sample was withdrawn and quenched with water before being eluted with ethyl acetate The organic layer was then dried over anhydrous Na2SO4 and analyzed by GC GC yield of the trifluormethylated products was calculated using the following formula:
S Pr : Peak area of 4-trifluormethyl anisole in the sample
S IS : Peak area of internal standard in the sample
The above formula was calculated based on the calibration curve, prepared by the following procedure: 4-trifluormethyl anisole (22.4 mg, 0.127 mmol) and dodecane (23 mg, 0.135 mmol) were weighted into two distinct 10 mL volumetric flasks Ethyl acetate was added into the flasks until the volume reached 10 mL Portions of the 4-
25 trifluormethyl anisole solution (1) were withdrawn and added into five 10 mL vials as showed in Table 2.2 Ethyl acetate was added into all these flasks to reach the volume of 10 mL
Table 2 2 Dilution preparation for 4-trifluormethyl anisole
Flask number Volume withdrawn Dilution ratio
Six vials containing corresponding amount of each solution was analyzed by GC, as shown in Table 2.3
Table 2 3 Calibration curve preparation for 4-trifluormethyl anisole
Volumn withdrawn (mL) Molar ratio
4-trifluormethyl (%) anisole solutions Dodecane solution
Ratio between peak areas of 4-trifluormethyl anisole and dodecane were observed via GC Following that, the calibration curve was shown in Figure 2.1
Figure 2 3 Calibration curve of 4-trifluormethyl anisole
When the reaction was completed, the reaction mixture was quenched with water, eluted with diethyl ether and dried over anhydrous Na2SO4 The organic layer was then dried in vacuo and purified via column chromatography on silica gel with 3 hexane: 1 dichloromethane (DCM) to yield the benzotrifluoride product Isolated yield of the product was calculated using the following formula:
Where: m Pr : Mass of 4-trifluormethyl anisole obtained after isolation y = 204.05x + 2.5242 R² = 0.9979
27 m’ Pr : Mass of 4-trifluormethyl anisole when yield is 100%
Beside the room temperature method of Buchwald’s group, another research reported the trifluormethylation of boronic acid at 45 o C in DMF 19 To investigate the most suitable temperature for the reaction condition, the procedure was conducted at 5 oC, 50 o C, 70 o C, and room temperature over the use of 30 mol% Cu(INA)2, 2 equivalent of CsF and 4 equivalent of TMSCF3 After 2 hours of reaction, samples were taken for GC analysis
The recoverability and reusability of the Cu(INA)2 catalyst were investigated by repeatedly separating the solid catalyst from the reaction mixture after the reaction
Specifically, the Cu(INA)2 catalyst was separated from the reaction mixture by simple centrifugation, washed with copious amounts of DCE, ethylacetate, water and THF, dried at 140 °C under vacuum in 8 h and reused in further reactions under identical conditions to the first run
RESULTS AND DISCUSSIONS
The Cu(INA)2 was synthesized following the procedure in section 2.1.2 to obtain dark blue crystals with 52.2% yield (calculated based on the molar ratio of HINA)
Highly crystalline material was formed as confirmed by X-ray diffraction measurements (XRD), Fourier transform infrared (FT-IR), transmission electron microscopy (SEM), and thermogravimetric analysis (TGA)
The powder X-ray diffraction patterns of the synthesized Cu(INA)2 is shown in Figure 3.1
Figure 3 1 Powder X-ray diffraction patterns of the synthesized Cu(INA)2 (a); and the calculated pattern (b) The pattern was similar to the calculated PXRD pattern for Cu(INA)2.2H2O from its single-crystal diffraction data provided by L.James et al., 51 Sharp peak at 2θ = 10 and a range of peak between 2 θ = 20 and 2 θ = 25 were observed from the XPRD pattern, which indicated that Cu(INA)2 crystal was successfully formed
Figure 3 2 FT–IR spectra of the Cu(INA)2 The FT–IR spectra of the Cu(INA)2 showed the presence of C=O vibration of the carboxylic group via a strong peak at about 1600 cm -1 (asymmetric) and 1550 cm -1 (symmetric stretch), while the absence of a band between 1730 and 1650 cm -1 suggested that the HINA was fully coordinated with copper ions In addition, an absorbance band at 775 cm -1 confirmed the formation of Cu-O bond in the material The shift of the C=N stretch from 1555 cm -1 to 1550 cm -1 could be explained by the contribution of nitrogen of the pyridine ring, as presented in the literature 52
SEM micrograph of the Cu(INA)2 indicated the formation of the crystalline powder Cu(INA)2, as well as the uniform morphologies and sizes of the crystals obtained (Figure 3.3)
30 Figure 3 3 SEM micrograph of the Cu(INA)2
Figure 3 4 TGA curve of the Cu(INA)2
Due to hydrogen bonding with carboxylate groups, guest water molecules were trapped inside the tunnel and extruded into the cavities of the material 53 Thermogravimetric analysis of the Cu(INA)2 (after being activated at 140 o C for 6 hours) indicated a weight loss of 1.4% between 30 and 296 o C, proving that a large amount of guest water molecules were removed after activation The framework started to collapse around 300 o C, showing the thermal stability below 300 o C of the Cu(INA)2
According to these analytical results, the formation of Cu(INA)2 prepared under solvothermal synthesis conditions has been confirmed
The trifluormethylation of boronic acids was carried out over homogeneous copper-based catalyst, as reported by Buchwald and co-workers 20 This work presented a simple, mild protocol for the transformation of 4-phenoxyphenyl boronic acid into
31 benzotrifluoride product (Scheme 3.1) Beside the trifluormethylated product (2), several byproducts also obtained from the reaction including the proto-deboronation (1), the halogenation (3), and the homocoupling products (4)
Scheme 3 1 Copper-mediated trifluoromethylation of 4-phenoxyphenyl boronic acid
For further understanding of the reaction, a proposed mechanism was suggested on the basis of the Chan-Lam coupling reaction 54 According to that, the CF3 - moiety was generated in the existence of fluoride anion and combine with copper to form the reactive Cu-CF3 complex, followed by the transmetalation with aryl boronic acid (Scheme 3.2) Wherein, the oxidation of Cu-CF3 complex occurred to transfer into Cu(III) complex, which then underwent facile reductive elimination to deliver the desired product The use of ligand would stabilize the reactive Cu-CF3 mediate
Scheme 3 2 Proposed mechanism for the copper-mediated oxidative trifluoromethylation of boronic acids
3.2.1 Effect of catalyst loading on the reaction yield
Figure 3 5 Effect of catalyst loading on reaction yield
By mimicking the homogeneous counterpart, in reaction screening, the catalytic activity of Cu (INA) 2 was investigated in oxidative trifluormethylation of 4- methoxyphenyl boronic acids using 4 equivalent of TMSCF3, 2 equivalent of CsF, and a corresponding amount of 1,10-phenanthroline under O2 atmosphere in DCE solvent
33 With respect to catalyst amount, low reaction yields of 5% and 13% were obtained when 10% and 20% catalyst were employed, respectively, due to the substantial formation of homocoupling by-products Gratifyingly, the requirement for stoichiometric amount of copper, which was observed in homogeneous conditions, is not necessary since the use of 30% catalyst offered 79% yield Increasing the catalyst loading did not lead to higher efficiency It was previously hypothesized that the reductive elimination of aryl-Cu-CF3 complexes generated aryl-CF 3 products and catalytically inactive Cu species 55 Thus, the use of catalytic amount of copper for this transformation is mechanistically unprecedented
3.2.2 Effect of different fluoride anion to the reaction yield
It is also necessary to elect the most efficient fluoride anion source as an initiator for the triluoromethylation of boronic acids Therefore, 2 equivalent of TBAF (tetrabutylammonium fluoride), KF (potassium fluoride) and CsF (cesium fluoride) were utilized in the reaction, with 30 mol% of Cu(INA)2 and 4 equivalent of TMSCF3, at room temperature for 2 hours
Figure 3 6 Effect of different fluoride anion to the reaction yield It can be seen from Figure 3.6 that ,