“Sandwich” Diimine-Copper Catalyzed Trifluoroethylation and Pentafluoropropylation of Unactivated C(sp³)–H Bonds by Carbene Insertion

Abstract

We report here “sandwich”-diimine copper complex-catalyzed trifluoroethylation and pentafluoropropylation of unactivated C(sp³)–H bonds in alkyl esters, halides, and protected amines by employing CF₃CHN₂ and CF₃CF₂CHN₂ reagents. Reactions proceed in dichloromethane solvent at room temperature. Identical C-H functionalization conditions and stoichiometries are employed for generality and convenience. Selectivities for C–H insertions are higher for compounds possessing stronger electron-withdrawing substituents. Preliminary mechanistic studies point to a mechanism involving a pre-equilibrium forming a “sandwich”-diimine copper-CF₃CHN₂ complex followed by rate-determining loss of nitrogen affording the reactive copper carbene. It reacts with trifluoromethyldiazomethane about 6.5 times faster than with 1-fluoroadamantane explaining the need for slow addition of the diazo compound.

Graphical Absract

“Sandwich” diimine-copper (I) complex catalyzes reactions of CF₃CHN₂ and CF₃CF₂CHN₂ reagents with C(sp³)–H bonds in a large panel of alkyl esters, halides, and protected amines resulting in introduction of trifluoroethyl- and pentafluoropropyl groups with predictable regioselectivities. Identical C-H functionalization conditions and stoichiometries are employed for generality and synthetic convenience. Preliminary mechanistic studies point to a mechanism involving a pre-equilibrium forming a “sandwich”-diimine copper-CF₃CHN₂ complex followed by rate-determining loss of nitrogen affording the reactive copper carbene which reacts with trifluoromethyldiazomethane about 6.5 times faster than with 1-fluoroadamantane explaining the need for slow addition of the diazo compound.

Introduction

Polyfluoroalkyl groups are important moieties that can increase the potency, enhance the metabolic stability, and improve the lipophilicity of biologically active molecules.¹ In contrast to the trifluoromethylation strategies which have been extensively investigated in recent years,² the incorporation of 2,2,2-trifluoroethyl and related substituents has received less attention.³ Three main strategies have been employed for formation of carbon-trifluoroethyl bonds. First, cross-coupling of aryl boronic acids or aryl halides with CF₃CH₂I under transition metal catalysis gives 2,2,2-trifluoroethyl arenes.⁴ In some cases, benzyl or allyl electrophiles can be used, resulting in C(sp³)– C(sp³) bond formation.⁴ⁱ Second, C–H bond functionalization strategies have been employed for the trifluoroethylation of aromatic and heterocyclic compounds.⁵ Third, reactions of 2,2,2-trifluoroethyl radicals with alkenes have been reported.⁶

Reactions proceeding via metal carbenes have been extensively used for C(sp³)–H bond functionalization.⁷ The electrophilic carbene generated from 2,2,2-trifluorodiazoethane should insert into alkane C–H bonds producing trifluoroethyl-containing molecules.⁸ Somewhat unexpectedly, this transformation has not been widely explored. While reactions of CF₃CHN₂ with X–H bonds (X = N, S, O, P, B, Si) have been extensively investigated,⁹ only three publications report metal-catalyzed insertion of trifluoroethylcarbene into C(sp³)–H bonds. An early report by Duan and Gu discloses iron-catalyzed trifluoroethylation of cyclohexane in 20% yield, along with two examples of insertion into benzylic C–H bonds (Scheme 1A).¹⁰ In 2019, Arnold and co-workers developed a highly enatioselective, activated C(sp³)–H bond trifluoroethylation in tertiary amines catalyzed by engineered cytochrome P450 enzyme analogue (Scheme 1B).¹¹ Our group recently disclosed “sandwich” diimine-copper catalysts 1 and 2 for hydrocarbon C–H functionalization with a number of diazoalkanes. Adamantane, cyclooctane, cyclodecane, and cyclododecane trifluoroethylation was reported (Scheme 1C).¹² Key to the success of these transformations is axial steric bulk around the reactive center as well as high electrophilicity of the cationic copper complex which allows the use of unactivated diazocompounds. However, trifluoroethylation of synthetically relevant substrates was not explored. We report here that diimine-copper catalyst 2 allows for site-selective unactivated C(sp³)–H trifluoroethylation in protected carboxylic acids, alcohols, amines, and alkyl halides. Reactions occur at room temperature under uniform conditions by using C–H insertion substrates as limiting reagents, which should facilitate use of these transformations in synthesis.

Scheme 1.

Trifluoroethylation of C(sp³)–H bonds by metal carbenes.

Results and Discussion

Reaction optimization.

We previously used diazo compounds as limiting reagents.¹² This is acceptable for reactions with easily accessible hydrocarbon or ether substrates such as cyclohexane or dioxane. However, in case of more complex structures, C–H insertion substrate should be used as the limiting reagent. We examined the reaction of 5-methyl-2-hexanol acetate 3 with 2,2,2-trifluorodiazoethane (Table 1). Trifluoroethylation occurs exclusively at the remote tertiary position. Screening with respect to amount of diazo reagent showed that best results are obtained with 6 equivalents of 2,2,2-trifluorodiazoethane (entries 1–5). Entries 4, 6, and 9 demonstrate that product 4 is formed in the highest yield if 5 mol% of catalyst is used, while 2 and 10 mol% loading affords lower conversions. Interestingly, the product yield is dependent on the concentration of the diazo reagent. We could reproducibly obtain about 1.2 M concentration of 2,2,2-trifluorodiazoethane which gave 77% NMR (62% isolated) yield of 4 (entry 4). However, if 0.84 M solution of diazo reagent was used under otherwise identical conditions, 64% NMR yield of 4 was observed (entry 7). Lowering concentration of 2,2,2-trifluorodiazoethane to 0.4 M further decreased the product yield to 58% (entry 8). Control experiment with simple diphenyl imine catalyst 5 gave only 22% yield of 4, while use of Cu(MeCN)₄PF₆ did not result in formation of C–H insertion product. The best results were obtained under conditions of entry 4, which were used in all subsequent experiments. Excess of diazo reagent is converted to a mixture of isomeric bis(trifluoromethyl)ethylenes.

Table 1.

Reaction optimization studies^a

Entry	CF3CHN2 (M, equiv)	Catalyst (mol%)	Yield [%]
1	1.2, 1	2 (5)	22
2	1.2, 2	2 (5)	47
3	1.2, 4	2 (5)	58
4	1.2, 6	2 (5)	77(62)b,c
5	1.2, 8	2 (5)	67
6	1.2, 6	2 (10)	72
7	0.84, 6	2 (5)	64
8	0.4, 6	2 (5)	58
9	1.2, 6	2 (2)	21
10	1.2, 6	5 (5)	22
11	1.2, 6	Cu(MeCN)4PF6 (5)	NR

^aReaction conditions: neat 3 (0.2 mmol, 1.0 equiv), add CF₃CH=N₂ as a solution in CH₂Cl₂ in 10 hours by syringe pump at RT (20–23 °C), then stir for 12 hours. Yields determined by ¹⁹F NMR spectroscopy with trifluorotoluene as an internal standard.

^bIsolated yield. NR = no C-H insertion.

^cNMR yield of 77% was obtained also if reaction was stirred 2 hours after addition.

Acyl group effect on insertion into tertiary C(sp³)–H bonds.

After establishing the optimal reaction conditions, we explored the effect of acyl group on selectivity and yield of C–H insertion (Scheme 2). Please note that reaction conditions in all subsequent schemes are identical unless otherwise noted. 4-Methyl-1-pentanol acetate 6 was trifluoroethylated at the tertiary position in 75% yield.

Scheme 2.

Alcohol protecting group effect.

The pivalate ester 7 gave 9 in 61% yield. 5-Methyl-2-hexanol trifluoroacetate 10 gave 12 in 53% yield, while the corresponding acetate and pivalate afforded 4 and 13 in 62 and 70% yields, respectively. Presumably, strongly electron-withdrawing trifluoroacetate deactivates the proximal C–H bonds towards carbene insertion. Conversely, for more distant C–H bonds use of trifluoroacetate esters should increase the selectivity by deactivating the proximal C–H bonds. Functionalization of 3,7-dimethyl-1-octanol acetate 15 gave a 50% isolated yield of a mixture of five isomers in 33:3:1:1:2.7 ratio, with the major isomer derived from insertion in distal tertiary position. The corresponding trifluoroacetate 14 gave a mixture of three isomers in 27:1:1 ratio in 68% isolated yield. Thus, overall selectivity (4.3/1 vs. 13.5/1 major/minor isomers) and yield was higher for the trifluoroacetate ester substrate. For functionalization of proximal C–H bonds one should use acetate or pivalate ester, while for distal bonds trifluoroacetate protecting group gives better yields and selectivities.

Acyl group effect on insertion into secondary C(sp³)–H bonds.

Next, we explored insertion into methylene C–H bonds (Scheme 3). Reaction of 2,2,2-trifluorodiazoethane with 1-pentanol acetate 18 gave a 60% isolated yield of three isomer mixture in 17:2:1 ratio with 21 as the major one. Trifluoroacetate-containing substrate 19 afforded a 26:2.6:1 ratio of isomer mixture in 55% NMR yield. Two most abundant isomers 22a and 22b were isolated and fully characterized after derivatization.¹³ The highest selectivity was observed for pentafluorophenyl ester 20. A 14:1 ratio of isomers was obtained with 23 as the major product in 62% yield. Next, reactions with 1-hexanol esters were explored. Trifluoroacetate 24 gave a 17:3:1 ratio of products in 89% NMR and 65% isolated yield. Using a more electron-withdrawing triflate ester 26 marginally increased C–H insertion selectivity to afford 20:2.5:1 ratio of products in 50% yield. It is likely that for longer alkyl chains the selectivities will not be synthetically useful if catalyst 2 is employed.

Scheme 3.

Selectivity dependence on distance from ester.

Trifluoroethylation of acyl moiety C(sp³)–H bonds in esters.

Scheme 4 shows C(sp³)–H bond functionalizations of the acyl linkage of carboxylic esters. For methyl, ethyl, and propyl esters the C–H insertion can be directed to the acyl group if it contains at least a three-carbon chain. Propyl isovalerate 28 was trifluoroethylated to give a 60% yield of 29. 4-Methylvaleric acid ester 30 reacted selectively at the tertiary position affording a 59% yield of 31. Isoheptanoic acid methyl ester 32 was trifluoroethylated in 70% yield. Methyl ester of valeric acid 34 reacted selectively at the most remote methylene position to afford 35 in 65% yield. For longer chain carboxylic acids, such as caproic acid ester 36, selectivity decreases and an 80% yield of three isomer mixture (68.5:12:1) was isolated. The two most abundant isomers were identified as 37a and 37b after derivatization and separation.¹³ Interestingly, α–halocarboxylic acid esters are compatible with the reaction conditions. Thus, α-bromocaproic acid methyl ester 38 was trifluoroethylated to give 39 in 42% yield as a 1:1 diastereomer ratio. Functionalization of α-bromoheptanoic acid ethyl ester 40 was less selective, affording a 25:1:1 isomer ratio in 60% yield. The major isomer 41 was formed as a 1:1 diastereomer mixture.

Scheme 4.

Substrate scope with respect to carboxylic acid moiety in esters.

Trifluoroethylation of alcohol moiety C(sp³)–H bonds in esters.

Scheme 5 shows functionalization of alcohol derivative C(sp³)–H bonds. Isoamyl acetate 42 reacted selectively at the tertiary position giving 39% isolated and 50% NMR yield of 43. The lower isolated yield is due to volatility of the product. 2,5-Dimethyl-2-hexanol trifluoroacetate 44 gave a 62% yield of 45, while tetrahydrolinalool trifluoroacetate 46 reacted to form 60% of 47. For longer chain esters such as 48, minor amount of insertion into secondary C–H bonds was observed along the expected product 49 arising from functionalization of the tertiary C–H bond. Trifluoroethylation of 2-methyl-2-hexanol trifluoroacetate 50 afforded a 40% yield of a 10:1 isomer mixture with 51 as a major product.

Scheme 5.

Scope with respect to alcohol moiety in esters.

Trifluoroethylation of the adamantane scaffold.

Scheme 6 shows trifluoroethylation of 1-adamantanecarboxylic acid methyl ester 52. Under the standard conditions, a separable mixture of mono-, bis-, and tris-trifluoroethylated products was obtained, with 17% of 53, 63% of 54, and 12% of 55 isolated. The reaction could be forced to completion by performing it under standard conditions, evaporating the volatiles, and adding another portion of 2,2,2-trifluorodiazoethane and catalyst. Under these conditions, 72% of tris-trifluoroethylated 55 was isolated.

Scheme 6.

Adamantanecarboxylic acid ester reactions.

Trifluoroethylation of amine and halogen-containing substrate C(sp³)–H bonds.

Scheme 7 shows compatibility of other functional groups with the trifluoroethylation protocol. Phthaloyl-protected isoamylamine 56 was trifluoroethylated in 60 % yield affording 57. Protected amylamine 58 gave an 87% yield of isomer mixture (25:1:1), with 59 as a major product. Phthaloyl-protected memantine 60 reacted to give 61 in 95% yield. 1-Bromo-pentane 62 was trifluoroethylated affording a 31:2:1 isomer mixture in 62% yield, with 63 as a major product. The carbon-bromine bond was not affected under these conditions.¹⁴ Fluorohydrocarbons can also be trifluoroethylated affording polyfluorinated products. Reaction of 64 gave a 76% isolated yield of an isomer mixture (37:4:2:1:1) with 65 as a major product. 1-Fluoroadamantane 66 was bis(trifluoroethylated) to afford 67 in 86% yield.

Scheme 7.

Compatibility with other functional groups.

Pentafluoropropylation of C(sp³)–H bonds.

Pentafluoropropylation of unactivated C(sp³)–H bonds has not been reported.¹¹ We explored the reactions of 2,2,3,3,3-pentafluoro-1-diazopropane with a number of esters (Table 2). The yields are somewhat lower than those obtained in reactions with 2,2,2-trifluorodiazoethane, likely due to higher steric demand of the intermediate metallocarbene, and lower concentration of 2,2,3,3,3-pentafluoro-1-diazopropane solution. Esters 3 and 10 were pentafluoropropylated to give 68 and 69 in nearly identical 32 and 30% yields (entries 1 and 2). These yields are about twice lower than those obtained in reactions with 2,2,2-trifluorodiazoethane. Trifluoroacetate 48 reacted to give a 36% yield of 70 (entry 3). In contrast to trifluoroethylation, only one isomer of product was observed in crude reaction mixture. Propyl 4-methylvalerate 30 gave 71 in a 30% yield, and isoheptanoic acid methyl ester 32 was pentafluoropropylated in 35% yield to afford 72 (entries 4 and 5).

Table 2.

Pentafluoropropylation of C(sp³)–H bonds.

^aReaction conditions: ester (0.2 mmol, 1.0 equiv), add CF₃CF₂CH=N₂ as a solution in CH₂Cl₂ in 10 hours by syringe pump at RT (20–23 °C), then stir for 12 hours. Yields are isolated yields.

Trifluoroethylation of 5β-cholestan-3β-ol trifluoro-acetate.

To demonstrate the amenability of trifluoroethylation strategy for late-stage synthetic applications, we subjected 5β-cholestan-3β-ol trifluoroacetate 73 to the standard trifluoroethylation conditions (Scheme 8). A 60% NMR and 45% isolated yield of 74 was obtained, with trifluoroethylation predominately occurring at the isopropyl group.

Scheme 8.

Cholestanol derivative trifluoroethylation.

Mechanistic considerations.

Low temperature NMR studies were performed to observe reaction intermediates and interrogate their reactivities. Catalyst 75 was combined with 5 or 10 equivalents of 2,2,2-trifluorodiazoethane in CD₂Cl₂ solvent at –70 °C (Scheme 9) and ¹⁹F spectra were recorded every five minutes. The only species observed in ¹⁹F spectra were the PF₆ anion, CF₃CHN₂, and cis/trans isomers of bis(trifluoromethyl)ethylene dimers arising from decomposition of the diazo compound. Pseudo-first order rate constants for the dimer formation are dependent on concentration of CF₃CHN₂ implying an associative exchange mechanism for ethylene displacement by the diazo compound.^13,17 The calculated second order rate constant corresponds to ΔG^≠ = 13.5 kcal/mol. In related copper complex 1 associative ethylene self-exchange proceeds with ΔG^≠ = 12.9 kcal/mol.¹⁵ The generally accepted mechanism for metal-catalyzed formation of alkenes from diazocompounds is presented in Scheme 9.¹⁶ Ethylene ligand exchange for the diazocompound is followed by nitrogen extrusion producing the copper carbene, which reacts with another equivalent of diazo species affording nitrogen and bis(trifluoromethyl)ethylene isomers. The addition of 4 equivalents of ethylene completely shuts down the dimer formation. Trifluoromethylcyclopropane is not formed under these conditions. This points to a mechanism involving preequilibrium forming 76 followed by rate-determining loss of nitrogen affording 77 (N₂ is unlikely to recapture 77 and re-form 76).

Scheme 9.

Mechanistic considerations.

Next, the relative reactivity of copper carbene intermediate with 1-fluoroadamantane and 2,2,2-trifluorodiazoethane was determined. Catalyst 75 was combined with 1-fluoroadamantane and 2,2,2-trifluorodiazoethane in CD₂Cl₂ solvent at –80 °C and ¹⁹F spectra were recorded every five minutes. Interestingly, C–H functionalization of 1-fluoroadamantane occurs at –80 °C. Copper carbene intermediate 77 can react either with another molecule of 2,2,2-trifluorodiazoethane affording bis(trifluoromethyl)ethylene isomers, or with 1-fluoroadamantane giving C–H functionalization product 78. Ratio between the bis(trifluoromethyl)ethylene and 78 shows that reaction of 77 with trifluoromethyldiazomethane is about 6.5 times faster than 1-fluoroadamantane functionalization. High reactivity of copper carbene 77 with 2,2,2-trifluorodiazoethane explains necessity for slow addition of the diazocompound to substrate/catalyst mixture. The comparative reactivity of a tertiary and secondary C(sp³)–H bonds in 30 and 34 is consistent with that reported earlier.¹⁸

Conclusions

In conclusion, we have shown that “sandwich” diimine-copper(I) complexes are efficient catalysts for C(sp³)–H trifluoroethylation and pentafluoropropylation. Alkyl esters, halides, and protected amines react with CF₃CHN₂ and CF₃CF₂CHN₂ in dichloromethane at room temperature affording products in moderate to high yields. In all reactions, 5 mol% catalyst 2, six equivalents of the diazo compound, and 10–hour addition time was used. General reaction conditions should allow for easy extension of the methodology to other substrates. Selectivities for C–H insertions are higher for esters possessing stronger electron-withdrawing substituents such as trifluoroacetate or pentafluorobenzoate. Acceptable regioselectivities can be achieved for up to 5–6 carbon long methylene chains provided that an electron-withdrawing moiety is present. Preliminary mechanistic studies suggest a mechanism involving ligand exchange that reversibly forms a copper-CF₃CHN₂ complex followed by rate-determining loss of nitrogen affording the reactive copper carbene. Addition of external ligands such as ethylene inhibits the formation of copper carbene. Intrinsic reactivity of intermediate copper carbene with trifluoromethyldiazomethane is about 6.5 times higher than that with 1-fluoroadamantane explaining the need for slow addition of the diazo compound.

Experimental Section

General Procedure for 2,2,2-Trifluoroethylation Reactions:

Outside the glovebox, one 35 mL borosilicate vial was equipped with a magnetic stir bar. The vial was placed inside the glovebox. To the vial was added solid copper catalyst 2 (25 mg, 5 mol%) and substrate (0.5 mmol, 1.0 equiv). 0.2 mL of CH₂Cl₂ was added to this vial if substrate is solid. The vial was then sealed with a cap containing a septum and taken out of the glovebox. Outside the glovebox, CF₃CHN₂ (1.2 M in CH₂Cl₂, 6 equiv) was added with an aid of a syringe pump equipped with a plastic syringe over 10 hours at room temperature. The grease was then applied to the top of the septa to maintain an inert atmosphere. After addition was complete, stirring was continued for 12 hours. After that, glacial acetic acid (0.5 mL) was added to quench unreacted diazo compound. Silica gel was then added and mixture was concentrated on rotary evaporator at RT and subjected to flash chromatography using an appropriate eluent to obtain the products. After concentrating the fractions containing the product, the residue was dried under reduced pressure to yield pure product. The product was characterized by ¹H, ¹³C, ¹⁹F NMR and HR-MS. Due to the UV inactive property, these products were identified and isolated based on the GC-MS and ¹⁹F NMR for each fraction.