Electrochemical synthesis of functionalized gem-difluoroalkenes with diverse alkyl sources via a defluorinative alkylation process

Abstract

An electrochemical defluorinative alkylation protocol of α-trifluoromethyl alkenes is described. This reaction enables the preparation of functionalized gem-difluoroalkenes with the use of diverse alkyl sources including organohalides, N-hydroxyphthalimide (NHP) esters and Katritzky salts. This method exhibits lots of synthetic advantages including mild conditions, simple operation, and convenience of amplification, and provides a new route for the synthesis of gem-difluoroalkenes.

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Introduction

Gem-difluoroalkenes are privileged structural motifs present in many bioactive molecules and drug candidates. This fascinating functionality features unique properties that affect the metabolic stability, absorbability and lipophilicity of organic molecules.¹ The strong electronegative nature of fluorine and the chemical reactivity of the gem-difluorovinyl moiety make gem-difluoroalkenes formidable electrophiles that act as irreversible inhibitors of specific enzymes.² In addition, as gem-difluoroalkenes are bioisosteres of carbonyl groups (aldehydes and ketones), they can mimic the chemical reactivity of a carbonyl group, providing new opportunities in the drug discovery pipeline.³Fig. 1 shows some representative organic molecules containing the gem-difluorovinyl scaffold with various pharmacological activities, such as antiepilepsy and antitubulin.

Fig. 1 Representative applications of gem-difluoroalkenes in medicinal chemistry.

During the past few decades, chemists have synthesized a series of structurally diverse gem-difluoroalkenes by a variety of simple and efficient methods. In addition to the direct conversion of carbonyl compounds into the corresponding gem-difluoroalkenes via the Wittig, Horner–Wadsworth–Emmons or Julia–Kocienski reactions,⁴ more common synthetic routes to these valuable compounds are through a defluorinative coupling reaction of α-trifluoromethyl alkenes owing to the ready availability of substrates as well as its high efficiency. Traditionally, gem-difluoroalkenes are prepared by a S_N2′-type reaction involving highly reactive and hazardous organometallic reagents, such as organolithiums, Grignard reagents, N-lithiated amines, ester enolates, and silyl lithium reagents (Scheme 1a).⁵ Despite their high efficiency in certain instances, many of these protocols suffer from narrow substrate scope concerning structural diversity or functional group tolerance. In order to overcome these disadvantages, great efforts have been made to develop efficient methods for the construction of the gem-difluoroethylene motif, and two major synthetic strategies have been established. On one hand, visible light photoredox catalysis as an eco-friendly synthetic approach has provided an array of protocols for the radical defluorinative cross-coupling reaction under user-friendly conditions, with the aid of visible light-excitable metal complexes or conjugated organic molecules (Scheme 1b).⁶ On the other hand, considerable progress has been made in the field of transition metal (mainly nickel) catalyzed defluorinative reductive cross-coupling with organohalides and prefunctionalized backbones, affording diverse gem-difluoroalkenes bearing sensitive functional groups with high efficiency (Scheme 1c).⁷

Scheme 1 Synthesis of gem-difluoroalkenes from α-trifluoromethyl alkenes.

As a widely acknowledged sustainable synthetic methodology, the reviving organic electrochemistry has recently emerged as a powerful synthetic tool that enables a vast variety of mild reductive transformations, which can be readily achieved via direct electrolysis without the requirement of catalysts or reducing agents.⁸ Driven by the prevalence of the gem-difluorovinyl moiety in a myriad of biologically relevant molecules, we envisioned that the exploration of a new and sustainable synthetic approach to gem-difluoroalkenes from α-trifluoromethyl alkenes under electrolysis would be highly rewarding. To date, there are very few examples on the electrochemical synthesis of gem-difluoroalkenes, although recently, Zhou and co-workers reported an electrochemical defluorinative carboxylation of α-trifluoromethyl alkenes with CO₂,^9a and Fu, Lu, and co-workers developed a nickel promoted electrochemical reductive cross-coupling to access functionalized gem-difluoroalkenes.^9b While these works undoubtedly bring new space in this research field, these electrochemical strategies are still at their infancy in terms of diverse alkyl sources that can be introduced. As part of our ongoing interest in the electrochemical reactions,¹⁰ we reported herein a sustainable electrochemical system that allows defluorinative cross-coupling of α-trifluoromethyl alkenes to proceed smoothly (Scheme 1d). The successful coupling partners include organohalides (iodides and bromides) as well as simple prefunctionalized compounds such as N-hydroxyphthalimide (NHP) esters and Katritzky salts.

Results and discussion

Our study began by the investigation of the reaction between trifluoromethyl-substituted alkene 1a and 4-iodotetrahydro-2H-pyran (2a) in a simple undivided cell equipped with an iron plate anode and a nickel plate cathode as the working electrodes (Table 1). After the initial evaluation of reaction parameters, we obtained a promising result when employing nBu₄NPF₆ as the supporting electrolyte and triethylamine as the base under 3 mA constant current electrolysis at room temperature, affording the desired gem-difluoroalkene product 5a in 32% yield (entry 1). Replacing nBu₄NPF₆ with nBu₄NI as the supporting electrolyte under otherwise identical reaction conditions greatly improved the yield (entry 3), while the use of other electrolytes gave lower yields (entries 2 and 4) or no yield (entry 5). Further optimizations were conducted by screening a variety of reaction solvents, such as DMA, ethanol, acetonitrile, and a mixed solvent of THF/CH₃CN (1 : 1, 2.5 mL/2.5 mL), but they all provided unsatisfactory results (entries 6–9, respectively). Moreover, changing the reaction time to 6 h or 14 h reduced the reaction efficiency (entries 10 and 11). During the optimization studies, we found that the concentration of the electrolyte was critical: a low concentration of nBu₄NI (0.013 M) improved the yield to 78% (with 76% isolated yield), but a high concentration (0.1 M or 0.2 M) greatly reduced the efficiency (entries 12–14). As anticipated, the control experiment revealed that electric current was critical for the reaction (entry 15).

Table 1 Optimization studies^a

Entry	Electrolyte	Solvent	Time (h)	5a (%)
a Standard conditions: iron plate anode (10 × 10 × 0.15, mm), Pt plate cathode (10 × 10 × 0.15, mm), 1a (0.5 mmol), 2a (0.9 mmol, 1.8 equiv.), Et3N (1.0 mmol, 2.0 equiv.), electrolyte (0.1 mmol, 0.02 M), anhydrous DMF (5.0 mL), constant current = 3 mA under air at room temperature for 12 h (2.7 F mol^−1). b Yield determined by ^1H NMR using 1,3,5-trimethoxybenzene as an internal standard. c nBu4NI (0.50 mmol, 0.1 M). d nBu4NI (1.0 mmol, 0.2 M). e nBu4NI (0.13 mmol, 0.013 M) in DMF (10 mL). f Yield of the isolated product. g Reaction was performed without constant current. N.R.: no reaction.
1	nBu4NPF6	DMF	12	32
2	nBu4NOAc	DMF	12	17
3	nBu4NI	DMF	12	60
4	nBu4NBF4	DMF	12	29
5	NaIO4	DMF	12	N.R.
6	nBu4NI	DMA	12	37
7	nBu4NI	EtOH	12	Trace
8	nBu4NI	CH3CN	12	Trace
9	nBu4NI	THF/CH3CN	12	20
10	nBu4NI	DMF	6	26
11	nBu4NI	DMF	14	45
12^c	nBu4NI	DMF	12	47
13^d	nBu4NI	DMF	12	22
14	nBu 4 NI	DMF	12	78 (76)
15^g	nBu4NI	DMF	12	N.R.

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With the optimized conditions in hand, we next sought to examine the scope of this electrochemical defluorinative cross-coupling reaction. At the outset, a variety of α-trifluoromethyl alkenes were examined with 4-iodotetrahydro-2H-pyran (2a) under the standard conditions, affording the desired gem-difluoroalkene products in good to moderate yields (Table 2, 5a–5o). We found that not only the benzene ring system can be applied to this protocol, but also naphthalene and anthracene were well compatible (5b–5d). Next, different substitution patterns on the benzene ring of trifluoromethyl-substituted alkenes were studied, all of which selectively gave the desired gem-difluoro olefins in decent yields. For example, substrates with phenyl (5e), methyl (5f and 5g), ether (5h), thioether (5i), ketone (5j), and dioxole (5k) at different positions on the aromatic ring were tolerated well under the optimized conditions. It is worth noting that α-trifluoromethyl alkenes bearing heterocycles, such as thianthrene (5l), dibenzothiophene (5m), indole (5n), and indazole (5o), were also effectively transformed into the corresponding products. The scope with respect to the analogues of organohalides (2) as the coupling partner was further explored. Herein, alkyl iodides were mainly tested, as iodides exhibit a less negative redox potential in comparison with the corresponding alkyl bromides.¹¹ Secondary alkyl iodides were found to be suitable substrates for this reaction. Cyclic iodides with different ring sizes were all converted into the corresponding gem-difluoroalkenes (5p–5t) in good to moderate yields. Iodides bearing acyclic hydrocarbons also worked well (5u). In addition, tertiary and primary aliphatic iodides could also be employed as suitable reaction partners, and again the formation of the corresponding products was observed (5v–5y). Notably, the reaction with respect to alkyl bromides as the coupling partner was further tested. Secondary and tertiary alkyl bromides were capable of proceeding the electrochemical defluorinative coupling with 1a to furnish the desired products with lower yields (5s and 5v), whereas the employment of a primary alkyl bromide gave no desired product (5w).

Table 2 Scope of the electrochemical defluorinative cross-coupling of α-trifluoromethyl alkenes with organohalides^a,c, NHP esters^b,c, and Katritzky salts^b,c

a Reaction conditions: iron plate anode (10 × 10 × 0.15, mm), Pt plate cathode (10 × 10 × 0.15, mm), 1 (0.5 mmol), 2 (0.9 mmol, 1.8 equiv.), nBu₄NI (0.13 mmol, 0.013 M), Et₃N (1.0 mmol, 2.0 equiv.), anhydrous DMF (10.0 mL), constant current = 3 mA under air at room temperature for 12 h. b Reaction conditions: iron plate anode (10 × 10 × 0.15, mm), Pt plate cathode (10 × 10 × 0.15, mm), 1 (0.50 mmol), 3 or 4 (0.90 mmol, 1.8 equiv.), nBu₄NI (0.13 mmol, 0.013 M), Et₃N (1.0 mmol, 2.0 equiv.), anhydrous DMF (10.0 mL), constant current = 6 mA under air at room temperature for 12 h. c Yield of the isolated product. d Reaction time: 10 h.

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To further demonstrate the compatibility and applicability of our protocol, we expanded the substrate scope to carboxylic acid derivatives instead of organohalides, because carboxylic acids are among the most prevalent organic molecules found in nature. They can be simply activated to form redox-active N-hydroxyphthalimide esters (NHP esters, 3), which is known in many other synthetic transformations,^7g,12 then generate alkyl radicals via facile single-electron reduction, and undergo the designed electrochemical defluorinative reaction with trifluoromethyl-substituted alkenes (1). As shown in Table 2, using the NHP ester of tetrahydro-2H-pyran-4-carboxylic acid as the model substrate, several trifluoromethyl alkenes were evaluated under the optimized conditions. These results revealed that trifluoromethyl alkenes bearing different functional groups and heterocyclic functionalities could be successfully converted into the desired products (6a, 6b, 6h, 6k, 6m and 6n), affording similar yields in comparison tothe reactions using alkyl halides. Moreover, it could be applied to a variety of secondary (6r and 6z), tertiary (6v), and primary (6x and 6aa–6cc) aliphatic redox-active esters. Both cyclic and acyclic esters were suitable substrates in this transformation. Notably, carboxylic acid-containing medicinal compounds bearing multiple reactive functional groups, such as chlorambucil that has antineoplastic properties, provided the desired coupling product 6dd in 41% yield, which greatly highlights our methodology.

On the basis of our existing work, we envisaged that under the appropriate conditions, an electrochemical cross-coupling of trifluoromethyl alkenes with alkyl radicals generated from amine derivatives via a deaminative manner would facilitate the production of gem-difluoroalkenes. Such a sustainable synthetic pathway is highly attractive as amines, especially primary amines, are readily available in nature. Inspired by the works of Watson, Wang, and others,^7h,13 we began to investigate the reaction of trifluoromethyl-substituted alkenes (1) with Katritzky salts 4 by electrolysis (Table 2). To our delight, all α-trifluoromethyl alkenes bearing various functional groups turned out to be suitable substrates for this electrochemical defluorinative cross-coupling under slightly amended reaction conditions, providing the desired gem-difluoroalkene products (7a–7b, 7f–7h, 7k) in acceptable yields. Additionally, diverse aliphatic Katritzky salts, including primary, secondary, and tertiary alkyl-substituted ones, were reacted with α-trifluoromethyl alkenes to furnish 7v and 7ee-7ii with ease. All these results in Table 2 have well demonstrated the broad applicability of our electrochemical method, which is suitable not only for a wide variety of α-trifluoromethyl alkenes, but also for diverse alkyl radical precursors including organohalides, N-hydroxyphthalimide (NHP) esters, and Katritzky salts.

In order to demonstrate the practicability of the developed electrochemical defluorinative cross-coupling, a gram-scale experiment of 1a and 2a has been performed on a 4.5 mmol scale, and the corresponding gem-difluoroalkene product 5a was isolated in 67% yield (Scheme 2a). To further evaluate this electrochemical process, a series of cyclic voltammetry (CV) experiments were carried out. The E_p values of 4-iodotetrahydro-2H-pyran, NHP ester and Katritzky salt were measured and determined to be −2.58 V, −1.35 V, and −1.26 V, respectively (see the ESI† for details), which indicated that all of these substrates are likely to undergo cathodic reduction to produce the corresponding aliphatic carbon-centered radicals. Moreover, a divided-cell experiment was later carried out in order to gain more insight into the reaction mechanism. Substrates 1a and 2a as well as triethylamine were placed into the cathode chamber with an iron plate anode and a nickel plate cathode as the working electrodes. As expected, the desired product 5a was detected in the cathode chamber with 71% isolated yield (Scheme 2b), suggesting that the electrochemical defluorinative reaction occurred around the nickel plate cathode, and the iron plate anode was used as a sacrificial anode.

Scheme 2 Gram-scale synthesis and divided-cell experiment.

On the basis of the above experimental results and previous literature, a plausible mechanism for this electrochemical defluorinative cross-coupling reaction was proposed, as depicted in Scheme 3. Substrate 2 (including organohalides, NHP esters, and Katritzky salts) undergoes a single electron transfer (SET) process by cathodic electrolysis to provide a crucial aliphatic carbon-centered radical intermediate A, which further reacts with α-trifluoromethyl alkene 1 to form an α-CF₃ carbon radical B. Cathodic reduction of this radical furnishes α-CF₃ carbanion C. Finally, a β-fluoride elimination process of intermediate C affords the gem-difluoroalkene 5 as the desired product.

Scheme 3 Proposed reaction mechanism.

Conclusions

We have developed a highly efficient, green, and concise system for the electrochemical synthesis of diverse gem-difluoroalkenes. This protocol is applicable not only to a wide variety of α-trifluoromethyl alkenes, but also to different kinds of alkyl radical precursors such as organohalides, N-hydroxyphthalimide (NHP) esters, and Katritzky salts. This method has many significant advantages including mild conditions, high reaction efficiency, low cost, and convenience of purification and amplification. We believe that this sustainable, convenient and environmentally friendly system will find wide application in high value-added transformations, and provide novel inspiration for late-stage functionalization of pharmaceutical intermediates. Further development of new electrochemical reactions is underway in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (no. 21672047 and 22101066), the State Key Laboratory of Urban Water Resource and Environment (no. 2018DX02), the Science and Technology Plan of Shenzhen (JCYJ20210324133001004), and the Natural Science Foundation of Guangdong (no. 2020A1515010564). W. X. is grateful for the Talent Plan of the Pearl River in Guangdong, a starting up fund from the Shenzhen Government and the financial support from the Guangdong Province Covid-19 Pandemic Control Research Fund (no. 2020KZDZX1218). The project was also supported by the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1qo01460a

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