Trifluoroethylation and Pentafluoropropylation of C(sp³)–H Bonds

Abstract

Polyfluorinated substituents often enhance effectiveness, improve the stability within metabolic processes, and boost the lipophilicity of biologically active compounds. However, methods for their introduction into aliphatic carbon chains remain very limited. A potentially general route to integrate the fluorinated scaffolds into organic molecules involves insertion of fluorine-containing carbenes into C(sp³)–H bonds. The electron-withdrawing characteristics of perfluoroalkyl groups enhances the reactivity of these carbenes which should enable the functionalization of unactivated C(sp³)–H bonds. Curiously, it appears that use of perfluoroalkyl-containing carbenes in alkane C–H functionalization is exceedingly rare. This concept describes photolysis, enzymatic catalysis, and transition metal catalysis as three primary approaches to C(sp³)–H functionalization by trifluoromethylcarbene and its homologues.

Graphical Abstract

The Concept summarizes photolysis, enzymatic catalysis, and transition metal catalysis as three primary approaches to C(sp³)–H functionalization by trifluoromethylcarbene and its homologues. These reactions result in selective functionalization of saturated molecules allowing access to greater chemical space which is advantageous in medicinal chemistry. However, progress thus far appears to be limited, and further methodology improvements are needed.

1. Introduction

Polyfluorinated groups play a significant role as functional units capable of amplifying the effectiveness, bolstering resilience against metabolic processes, and increasing lipophilicity of biologically active compounds.^[1] Among pharmaceuticals, about twenty percent contain fluorine, including many crucial medications.^[2] The integration of fluorine into drug molecules is a common practice during the drug development process, owing to the fact that the introduction of a single atom of fluorine can substantially and advantageously alter the biochemical attributes of the molecule (Figure 1).

Figure 1.

Polyfluorinated scaffolds in drugs

The use of carbon-hydrogen bonds as functional groups for introduction of fluorinated moieties stands out as an attractive approach for the synthesis of fluorine-containing compounds and efficient late-stage modification of biologically active substances.^[3] While C(sp²)–H bond trifluoroethylation is quite common,^[4] the corresponding transformations of C(sp³)–H bonds are very rare. Aminoquinoline-directed, palladium-catalyzed C(sp³)–H alkylation by trifluoroethyl iodide was reported to give product in 5% yield.^[5] Reaction of perfluoroalkyl carbenes with C(sp³)–H bonds is a promising way for preparation of polyfluorinated compounds. Carbenes generated from the polyfluorinated diazo compounds shown in Figure 2 are expected to be highly electrophilic and undergo insertion into alkane C–H bonds.^[6] Ethyl diazoacetate and donor-acceptor diazocompounds are routinely used in C(sp³)–H bond functionalization under tris(pyrazolyl)borate-Group 11 metal and dirhodium complex catalysis. Currently, dirhodium complexes are the most widely employed catalysts, allowing for highly enantioselective transformations and high selectivities for functionalizing the desired C-H bonds. These catalysts have been used in key steps of total syntheses of natural products.^[7] In contrast, C(sp³)–H bond functionalization by using trifluoromethylcarbene and its homologues has not received widespread attention. Metal-catalyzed reactions of trifluoromethylcarbene sources with X–H (X = O, S, N, Si, B, P) and multiple bonds are well-explored.^[8][9] This concept will review the trifluoroethylation and pentafluoropropylation of C(sp³)–H bonds.

Figure 2.

Fluorinated diazo compounds

2. Trifluoroethylation of C(sp³)–H bonds mediated by light

The first examples of trifluoromethylcarbene insertion into C(sp³)–H bonds were reported by Atherton and Fields in 1967 during their study of its reaction with cis- and trans-but-2-enes.^[10] They noted that when 2,2,2-trifluorodiazoethane and an excess of trans-but-2-ene were irradiated with ultraviolet light in the liquid phase, a mixture of cyclopropane 3 and two alkenes 4 and 5 were formed in addition to other minor products (Scheme 1). Alkene 4 was formed by carbene insertion in the allylic C–H bond, while 5 originates from reaction with a C(sp²)–H bond. Authors propose that carbene reacts in a singlet state affording cyclopropanation and C–H insertion products.

Scheme 1.

Photolysis of 2,2,2-trifluorodiazoethane in butene

Expanding on their previous results, Atherton and Fields investigated the insertion of trifluoromethylcarbene into simple alkane C–H bonds.^[11] The photolysis of 2,2,2-trifluorodiazoethane in excess of liquid cyclohexane yielded 76% of the insertion product 6. When 2,2,2-trifluorodiazoethane in an excess of n-butane were irradiated with UV light at −78 °C, 61% of a mixture of 7 and 8 in a 1.4:1 ratio was obtained. Similar lack of selectivity was observed in reaction with isobutane, resulting in a 73% yield of isomers 9 and 10 in a 7.85:1 ratio (Scheme 2). Accounting for the number of hydrogens, ratio of insertion rates k(_tert)/k(_prim) was found to be 1.3±0.2. The insertion of free carbene into a tertiary C–H bond is thus only slightly faster than reaction with a primary C–H bond. Lack of selectivity is common for C-H insertion reactions of free carbenes.^[12] Use of metal carbene intermediates allows for higher selectivity due to their attenuated reactivity. Tuning of reactivity and selectivity can be achieved by varying metal and its ligand environment as seen below.

Scheme 2.

Trifluoroethylation of alkane C(sp³)–H bonds

3. Trifluoroethylation and pentafluoropropylation of C(sp³)–H bonds using enzyme catalysis

In 2019, Arnold and co-workers reported a methodology for direct, highly enantioselective C(sp³)–H fluoroalkylation of tertiary amines at the activated α-positions (Scheme 3).^[13] The authors employed engineered cytochrome P450 enzyme analogues that incorporate trifluoroethyl group into a variety of substituted pyrrolidines and N, N-dimethylanilines α to the nitrogen atom. The regioselectivity of the reaction was highlighted through exclusive functionalization of the N-alkyl groups in the presence of weak benzylic C–H bonds. Authors propose that the observed selectivity is due to the strong electron-donating properties of nitrogen which renders α-amino C–H bonds more reactive with the electrophilic iron-carbene intermediates. Additionally, the P450 enzyme analogue demonstrated high reactivity towards the introduction of pentafluoropropyl group into acyclic and cyclic amine substrates with outstanding activities and enantioselectivities. At this point, only weak C(sp³)–H bonds can be functionalized by using this methodology; however, this is compensated for by exquisite selectivities which cannot be achieved in metal-catalyzed transformations.

Scheme 3.

Functionalization of tertiary amine C(sp³)–H bonds

4. Trifluoroethylation of C(sp³)–H bonds using metal catalysts

In 2017, Duan and Gu disclosed three examples of FeCl(TPP) -catalyzed trifluoroethylation of C(sp³)–H bonds (Scheme 4, TPP = 5,10,15,20-tetraphenyl-21H, 23H-porphine).^[14] While two examples involve functionalization of benzylic C–H bonds, trifluoroethylation of cyclohexane gave 17 in a 20% yield. This appears to be the first example of a metal-catalyzed trifluoroethylation of an unactivated C(sp³)–H bond. Trifluoromethyl sulfonium ylide 16 was used as a convenient carbene precursor. Addition of Na₂S₂O₄ reductant increased yields of the reactions.

Scheme 4.

Iron-catalyzed trifluoroethylation of C(sp³)−H bonds

A recent paper from our group describes the use of copper “sandwich”-diimine complex 20 in C(sp³)–H functionalization by donor, donor-acceptor, and acceptor diazocompounds. Reactions employing trimethylsilyldiazomethane, ethyl diazoacetate, diazomethane, phenyldiazometane, and 2,2,2-trifluorodi-azoethane were disclosed. The latter diazo compound was used in trifluoroethylation of simple alkanes such as adamantane, cyclooctane, cyclodecane, and cyclododecane (Scheme 5).^[15] Adamantane C–H bond functionalization yielded a mixture of 21 and 22 in a 6:1 ratio and a combined yield of 79%. Only 5 equivalents of alkane substrate and short addition times were used in the trifluoroethylation reactions. The high efficiency of the copper catalyst can be attributed to the axial shielding provided by two 3,5-dichloroaryl groups arranged in a “sandwich” configuration.

Scheme 5.

Trifluoroethylation of simple alkanes

A further report broadens the applicability of “sandwich” diimine-copper(I) complexes and explores the functional group tolerance and regioselectivity in trifluoroethylation and pen-tafluoropropylation of unactivated C(sp³)–H bonds (Table 1).^[16] These reactions occur at room temperature. Furthermore, in contrast to most metal-catalyzed carbene insertion reactions, substrates are used as limiting reagents. This feature should facilitate application of the methodology in late-stage drug modification where use of tens of equivalents of substrate is not economically viable. Alkyl esters (entries 1–2, 4–5, 9–10), halides (entries 5, 7, 8), and protected amines (entry 6) react with CF₃CHN₂ and CF₃CF₂CHN₂ in the presence of catalyst 26 yielding C–H insertion products in moderate to high yields. Triflate group is compatible with the reaction conditions (entry 3). The reaction conditions are uniform, with 5 mol% of the copper catalyst, six equivalents of the diazo compound, and 10-hour addition time employed. Tris(trifluoroethyl)adamantanecarboxylic acid methyl ester could be obtained in a good yield by performing reaction under standard conditions, evaporating the volatiles, and adding another portion of 2,2,2-trifluorodiazoethane and catalyst (entry 4). Enhanced selectivity for C–H insertions are observed in compounds containing more potent electron-withdrawing substituents such as trifluoroacetate, pentafluorobenzoate, or triflate. Satisfactory regioselectivities are achieved for up to six-carbon long methylene chains, provided that an electron-withdrawing functional group is present.

Table 1.

Trifluoroethylation and pentafluoropropylation of C(sp³)–H bonds^a

Entry	Substrate	Diazo compound	Product	Yield (%)
1				62
2				80
3				50
4b				72
5				42
6				87
7				62
8				86
9				30
10				35

^aStandard conditions: alkane (0.2 mmol, 1 equiv), catalyst 26 (5 mol%), add diazo compound (6 equiv, CF₃CHN₂ or CF₃CF₂CHN₂) as a solution in CH₂Cl₂ in 10 hours by syringe pump at 20–23 °C, then stir for 12 hours.

^bReaction performed under standard condition, volatiles removed, catalyst, solvent, and CF₃CHN₂ added once more.

More complex structures can be functionalized with reasonable regioselectivities. 5β-Cholestan-3β-ol trifluoroacetate 27 gave 60% NMR and 45% of isolated yield of 28 under standard trifluoethylation conditions (Scheme 6). The trifluoroethylation occurred primarily at the least hindered tertiary position.

Scheme 6.

Trifluoroethylation of a cholestanol derivative

Copper “sandwich”-diimine catalyzed C(sp³)–H functionalizations by fluorinated diazocompounds exhibit selectivities which are comparable to those obtained by using ethyl diazoacetate. While many functional groups are compatible with trifluoroethylation, ketone functionality and carbon-carbon multiple bonds are not tolerated. Aromatic rings which do not contain electron-withdrawing substituents undergo Buchner ring expansion. The reaction follows the commonly accepted mechanism, involving a pre-equilibrium forming a “sandwich”-diimine copper-CF₃CHN₂ complex followed by rate-determining loss of nitrogen affording the reactive copper carbene.^[16]

5. Summary and Outlook

While C(sp²)–H trifluoroethylation is common, corresponding reactions of C(sp³)–H bonds are very rare. Development of methods for selective functionalization of saturated molecules is quite important since this allows access to greater chemical space which is advantageous in medicinal chemistry.^[17] A promising strategy for introducing fluorinated substituents in saturated scaffolds involves reaction of C(sp³)–H bonds with trifluoromethylcarbene and its homologues under photolysis, enzymatic, and transition metal catalysis. However, progress thus far appears to be limited, and further methodology improvements are needed. First, the ability to tune and direct trifluoroethylation selectivity depending on C(sp³)–H bond steric and electronic properties would be very useful. Second, methods for enantioselective trifluoroethylation of unactivated C(sp³)–H bonds are still unknown. Third, safer diazo compound alternatives should be developed.

Biographies

Thanh Le earned a B.S. degree in Chemical Engineering at the University of Technology in Ho Chi Minh City, Vietnam in 2018. He is currently a fifth-year Ph.D. candidate in Prof. Daugulis’ lab. He contributed to the development of the ortho-functionalization of pentafluorosulfanyl arenes and is currently working on copper-catalyzed C(sp³)–H bond functionalization.

Girish Gowda Ramachandru graduated from SDM College in Karnataka, India, with a M.Sc. degree in Organic Chemistry. He then moved to Texas in Fall 2021 and joined Prof. Daugulis’ lab. His work focuses on using Group-11 metals for carbon- hydrogen bond functionalization.

Olafs Daugulis received an undergraduate degree from Riga Technical University in Latvia. After earning a PhD from University of Wisconsin under the guidance of Prof. Edwin Vedejs and postdoctoral studies with Prof. Maurice Brookhart at University of North Carolina at Chapel Hill, he joined the chemistry faculty at the University of Houston in 2003. He was promoted to full Professor and awarded Robert A. Welch Chair in Chemistry in 2014. He is interested in developing methods for C–H bond functionalization, application of organometallic chemistry to organic chemistry problems, and using late transition metals for olefin polymerization.