Trifluoromethylation of (hetero)aryl iodides and bromides with copper(I) chlorodifluoroacetate complexes

Abstract

A new copper-mediated trifluoromethylation reaction using copper(I) chlorodifluoroacetate complexes as reagents is reported. The complex [L₂Cu][O₂CCF₂Cl] (L = bpy, dmbpy, phen) reacted with (hetero)aryl iodides and bromides in the presence of CsF in DMF at 75 °C to afford the trifluoromethylarenes in good to excellent yields. High compatibility with various chemical functions or (hetero)cycles was also observed in the reaction. A reaction mechanism involving a difluorocarbene intermediate, along with a subsequent formation of a –CF₃ anion was proposed.

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Introduction

Trifluoromethylated compounds exhibit extensive applications in the pharmaceutical, agrochemical, and advanced materials.^1–3 This is because of their unique behavior arising from the unusual properties of the trifluoromethyl (–CF₃) group, such as its high lipophilicity, and strong electron-withdrawing character.^4,5 Therefore, it is not surprising that a number of methods for their synthesis have been developed over several decades.^6–14 These methods include nucleophilic, electrophilic, and radical trifluoromethylation of arene substrates with trifluoromethylation reagents, such as Ruppert–Prakash reagent (Me₃SiCF₃)¹⁵ and its ethyl derivative (Et₃SiCF₃), Togni's¹⁶ and Umemoto's^17,18 reagents, and the perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical.¹⁹ Nevertheless, these reagents are expensive, and, therefore, the utility of these compounds in large-scale trifluoromethylation reactions may be limited.

The discovery of new economically viable alternatives for trifluoromethylation reaction is of current interest, especially for large-scale application.^20–23 Vicic and co-workers reported the synthesis of (NHC) copper-trifluoroacetate and chlorodifluoroacetate complexes, which underwent decarboxylative trifluoromethylation of aryl halides at 160 °C.²⁴ Beller and co-workers also reported the copper-catalyzed trifluoromethylation of aryl iodides with methyl trifluoroacetate at 160 °C.²³ Very recently, Zhang and co-workers developed a silver-catalyzed radical trifluoromethylation of arenes at 120 °C using trifluoroacetic acid as the trifluoromethylating reagent.²⁵ However, the necessity of high reaction temperatures, poor substrate scope, and low regioselectivities are the inevitable drawbacks of these reactions.

Copper-mediated trifluoromethylation via a difluorocarbene intermediate followed by the formation of a –CF₃ anion either by the decomposition of difluorocarbene or in the presence of KF and CuI, often offers an efficient method for the formation of trifluoromethylated compounds (eqn (1)).^26–28

:CF₂ + F⁻ ⇌ CF₃⁻ (1)

For example, Chen, and Burton, and co-workers reported the use of methyl fluorosulfonyldifluoroacetate (FSO₂CF₂CO₂CH₃) and methyl chlorodifluoroacetate (ClCF₂CO₂CH₃) as trifluoromethylating reagent (Scheme 1).^29–31 Recently, Xiao and co-workers described a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-promoted decomposition of difluorocarbene derived from various carbene precursors and the subsequent trifluoromethylation.³² Zhang and co-workers invented a new reagent trimethylsilyl chlorodifluoroacetate for trifluoromethylation.^33,34 Qing and co-workers reported a copper-mediated trifluoromethylation of diaryliodonium salts with difluoromethyltriflate at room temperature.³⁵ These reactions provide trifluoromethyl-substituted arenes and heteroarenes in good yields with excellent functional group tolerance.

Scheme 1 Trifluoromethylation via a difluorocarbene intermediate.

Very recently, Chen and Liu, and co-workers developed a new trifluoromethylating reagent Cu(O₂CCF₂SO₂F)₂ for the trifluoromethylation of haloarenes under mild conditions.³⁶ We reported the preparation of copper(I) chlorodifluoroacetate complexes [L₂Cu][O₂CCF₂Cl] (1a–c; L = bpy, Me2bpy, phen) from readily available and inexpensive chlorodifluoroacetic acid.³⁷ These complexes can serve as difluorocarbene precursor for difluoromethylation of phenols and hydroxypyridines to form (hetero)aryl difluoromethyl ethers. As a continuation of our investigations into synthetic pathways to trifluoromethyled arenes,^37,38 we began the search for the ideal conditions for the trifluoromethylation of haloarenes using complexes 1.

Results and discussion

Initial test reactions focused on screening the trifluoromethylation of 4-iodobenzonitrile 2k with [(bpy)₂Cu][O₂CCF₂Cl] 1a and NaOH in the presence of various metal fluorides in DMF at 75 °C for 18 h (Table 1). The nature of the metal fluorides was found to affect the observed reactivity. CsF seemed to be the most effective and the trifluoromethylated product 4-(trifluoromethyl)benzonitrile 3k was obtained in 96% NMR yield (Table 1, entry 4). The use of LiF, NaF, and KF produced the product 3l in moderate or low yields (Table 1, entries 1–3). AgF and CuF₂ were found to increase the desired product yields to 70% and 75%, respectively (Table 1, entries 5 and 6). Furthermore, it turned out that no product was observed in the presence of n-Bu₄NF (Table 1, entry 7). Next, the influence of the solvent was examined. DMF has been proven to be the solvent of choice: the reaction in other solvents, such as DMSO, NMP, CH₃CN, THF, and toluene gave inferior results (Table 1, entries 8–12).

Table 1 Optimization of the trifluoromethylation of 4-iodobenzonitrile 2k^a

Entry	MF	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 1 (0.25 mmol), 2k (0.10 mmol), NaOH (0.30 mmol), MF (0.30 mmol), DMF (1.5 mL), under N2 atmosphere.b The yield was determined by ^19F NMR spectroscopy with PhOCF3 as internal standard.
1	LiF	DMF	75	3	5<
2	NaF	DMF	75	3	30
3	KF	DMF	75	3	47
4	CsF	DMF	75	3	96
5	AgF	DMF	75	3	70
6	CuF2	DMF	75	3	75
7	n-Bu4NF	DMF	75	3	0
8	CsF	DMSO	75	3	6
9	CsF	NMP	75	3	73
10	CsF	CH3CN	75	3	74
11	CsF	THF	75	3	26
12	CsF	Toluene	75	3	5
13	CsF	DMF	50	3	62
14	CsF	DMF	100	3	80
15	CsF	DMF	75	1	31

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Consistent with our previous observations,³⁷ a reaction temperature of 75 °C was essential to overcome the energy barrier for decarboxylation of the copper chlorodifluoroacetate complexes (Table 1, entry 4). When this trifluoromethylation reaction was conducted at 50 °C, lower yield of 3k was obtained (Table 1, entry 13). Increasing the temperature to 100 °C resulted in a drop in yield of 3k to 80%, probably due to the thermal instability of –CF₃ species (Table 1, entry 14). Moreover, shorter reaction time to 1 h led to a lower yield of product 3k (Table 1, entry 15).

Given that variation in the structure of the diimine ligands is known to significantly alter the behaviour of copper complexes, we then studied the trifluoromethylation reaction mediated by a series of copper(I) chlorodifluoroacetate complexes (Table 2). The results indicated that the diimine ligands strongly affected the formation of trifluoromethylated products. For example, complex 1a, ligated by 2,2′-bipyridine, reacted with 4-iodobenzonitrile 2k to afford the product 3k in 96% yield (Table 2, entry 1). Under similar reaction conditions, complex 1b, ligated by 4,4′-dimethyl-2,2′-bipyridine, gave the desired product 3k in relatively lower yield (Table 2, entry 2). Similarly inferior results were obtained when using complex 1c ligated by 1,10-phenanthroline (Table 2, entry 3), a ligand that has proven to be effective in copper-catalyzed or -mediated trifluoromethylation reactions of aryl halides.^39–42 In addition, complex 1d ligated by a monodentate ligand (4-methylpyridine) furnished the corresponding product 3k in only 30% yield (Table 2, entry 4). These results indicated that 2,2′-bipyridine was the most effective ligand for the trifluoromethylation.

Table 2 Effect of ligand on the trifluoromethylation of 4-iodobenzonitrile 2k^a

Entry	Complexes 1	L(n)	Yield^b (%)
a Reaction conditions: 1 (0.25 mmol), 2k (0.10 mmol), NaOH (0.30 mmol), CsF (0.30 mmol), DMF (1.5 mL), under N2 atmosphere; bpy = 2,2′-bipyridine, dmbpy = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, 4-MePy = 4-methylpyridine.b The yield was determined by ^19F NMR spectroscopy with PhOCF3 as internal standard.
1	1a	bpy(2)	96
2	1b	dmbpy(2)	81
3	1c	phen(2)	80
4	1d	4-MePy(4)	30

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After attaining the optimised conditions, the scope of this methodology was assessed using different functionalized aryl iodide for the trifluoromethylation with 1a (Table 3). We established that this method could be applied to the trifluoromethylation of an array of aryl iodides, generating the desired trifluoromethyl arenes in good yield. Generally, the reactions were successful for both electron-withdrawing (3b–3k) and electron-donating (3l) aryl iodides, with the latter exhibiting a slight decrease in yield. Various reactive functionalities, such as formyl, acetyl, ester, trifluoromethyl, nitro, cyano, and methoxy are well tolerated. Additionally, bromide, chloride, and fluoride substituents, in various positions on the aromatic ring, were also proved to be compatible with the reaction. Each halogen substituted aryl iodides gave the desired products (3m–3q) in good to excellent NMR yields (60–89%). Moreover, 1-iodonaphthalene could also be used in the reaction with the corresponding trifluoromethylated product (3r) being obtained in good yield of 64% (NMR yield).

Table 3 Trifluoromethylation of aryl iodides by [(bpy)₂Cu][O₂CCF₂Cl] 1a and CsF^a,b

a Reaction conditions: 1a (1.25 mmol, 2.5 equiv.), 2 (0.50 mmol), NaOH (1.50 mmol), CsF (1.50 mmol), DMF (6 mL), N₂.b The yield was determined by ¹⁹F NMR spectroscopy with PhOCF₃ as internal standard.

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To extend the scope of this methodology, we focused on the trifluoromethylation reaction with heteroaryl halides (Table 4). 2-Iodopyridine was readily converted to 5a in 97% NMR yield. Importantly, the procedure remained successful with heteroarylbromides. For example, the formyl, ester, acetyl, nitro, and chloro substituted 2-bromopyridines underwent the trifluoromethylation to afford the trifluoromethylation of 3-iodopyridine and 4-iodopyridine proceeded highly efficiently to furnish the desired products 5h–5j in good to high yields. It is worth noting that the heteroaryl chloride and bromide functionality remained unaffected during the reactions. This is useful to introduce further various substituents on the aromatic unit to design new precursors for biologically-active substances through transition metal-catalyzed cross-coupling reactions. The trifluoromethylation protocol was further accomplished with other halogenated nitrogen-containing heterocycles. The reaction with 2-bromoquinoline led to the trifluoromethylated product 5k in 81% NMR yield. Likewise, 2-iodopyrazine and 2-bromoquinoxaline provided the desired products (5e and 5f) with 73% and 69% NMR yields, respectively. In the case of the reaction using 2-bromopyrimidine as substrate, product (5n) was formed in 75% NMR yield. Finally, 2-iodothiophene underwent the trifluoromethylation reaction with 1a and CsF affording the product (5o) in 51% NMR yield.

Table 4 Trifluoromethylation of heteroaryl iodides and bromides by [(bpy)₂Cu][O₂CCF₂Cl] 1a and CsF^a,b

a Reaction conditions: 1a (1.25 mmol, 2.5 equiv.), 4 (0.50 mmol), NaOH (1.50 mmol), CsF (1.50 mmol), DMF (6 mL), N₂.b The yield was determined by ¹⁹F NMR spectroscopy with PhOCF₃ as internal standard.c 1c was used instead of 1a.

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This methodology was successfully applied to the synthesis of the CF₃ containing pirfenidone, which was recently filed under patent for possessing activity against fibrotic disorders.^43–45 Reaction of 1a with 5-iodo-2H-[1,2′-bipyridin]-2-one 6 in the presence of CsF afforded the trifluoromethylated product 7 in 75% NMR yield (Scheme 2). The result illustrates the great potential of this protocol in the synthesis of pharmaceutically relevant molecules.

Scheme 2 Synthesis of CF₃-pirfenidone 7.

To assess the scalability of the protocol, the trifluoromethylation reaction was performed on a 5.0 mmol scale with methyl 4-iodobenzoate 2e, affording the desired product 3e (0.86 g) in 85% isolated yield, albeit at a slightly higher reaction temperature of 80 °C (Scheme 3).

Scheme 3 Scalability of the trifluoromethylation of 2e.

A mechanism for this copper-mediated trifluoromethylation reaction with copper(I) chlorodifluoroacetate complex is proposed (Scheme 4). The reaction is initiated by the decarboxylative reaction of 1 with NaOH to generate difluorocarbene, together with CO₂ and L_nCuCl.³⁷ Subsequently, the CF₂ carbene reacts with fluoride provided by CsF to form trifluoromethyl anion –CF₃,⁴⁶ which then undergoes the transmetalation with L_nCuCl to form the trifluoromethylcopper species. Indeed, a reaction of 1a with CsF in the presence of NaOH in DMF at 75 °C for 80 min affords L_nCuCF₃ in 49% (δ = −25.9 ppm), detected by ¹⁹F NMR spectroscopy (see ESI†). Finally, the oxidative addition of aryl halide to L_nCuCF₃ species would give a copper(III) species A, which undergoes reductive elimination to furnish the Ar–CF₃ coupling products.^21,47–49

Scheme 4 Proposed reaction mechanism.

Conclusions

In summary, we have identified a copper-mediated decarboxylative trifluoromethylation reaction of aryl halides with copper(I) chlorodifluoroacetate complexes and CsF to generate trifluoromethylarenes. These reactions were operated under relatively mild conditions and the trifluoromethylated products were obtained in good to excellent yields. A variety of functional groups were tolerated well under the present reaction conditions.

Experimental section

General information

All manipulations were carried out under an inert atmosphere using a nitrogen-filled glovebox or standard Schlenk techniques. All glassware was oven or flame dried immediately prior to use. Solvents were freshly dried and degassed according to the procedures in purification of laboratory chemicals prior to use. Deuterated solvents were purchased from Cambridge Isotope Laboratories, Inc., and were degassed and stored over activated 4 Å molecular sieves. Complexes 1a–1c³⁷ and 5-iodo-2H-[1,2′-bipyridin]-2-one 6⁴⁵ were prepared according to the published procedures. All other reagents were obtained from commercial sources and used without further purification. The ¹H, ¹⁹F and ¹³C{¹H} NMR spectra were obtained at 293 K on a Bruker Avance 400 spectrometer, and chemical shifts were recorded relative to the solvent resonance. ¹⁹F NMR chemical shifts were determined relative to CFCl₃ as outside standard and low field is positive. GC-MS measurements were conducted on a Shimadzu QP2010SE.

General procedure for trifluoromethylation of aryl iodides and bromides with [(bpy)₂Cu][O₂CCF₂Cl] 1a

Aryl iodides or bromides (0.50 mmol), [(bpy)₂Cu][O₂CCF₂Cl] 1a (631 mg, 1.25 mmol, 2.5 equiv.), NaOH (60 mg, 1.5 mmol), CsF (228 mg, 1.50 mmol), and DMF (6 mL) were added to a reaction tube with teflon screw cap equipped with a stir bar. The tube was sealed and the solution was placed into a preheated 75 °C oil bath for 3 h. The tube was removed from the oil bath and cooled to room temperature, and then (trifluoromethoxy)benzene (65 μL, 0.50 mmol) was added as an internal standard. The reaction mixture was then filtered through a layer of celite. The filtrate was analyzed by ¹⁹F NMR and GC-MS.

Acknowledgements

Financial support from National Natural Science Foundation of China (21372044), and Fuzhou University (022494) is gratefully acknowledged.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra15547b

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