# The revival of Enantioselective Perfluoroalkylation – Update of New Synthetic Approaches from 2015–2022

Marina Briand, Elsa Anselmi, Guillaume Dagousset, Emmanuel Magnier

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Marina Briand, Elsa Anselmi, Guillaume Dagousset, Emmanuel Magnier. The revival of Enantioselective Perfluoroalkylation – Update of New Synthetic Approaches from 2015–2022. Chemical Record, 2023, 10.1002/tcr.202300114 . hal-04125052

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# The Revival of Enantioselective Perfluoroalkylation – Update of New Synthetic Approaches from 2015–2022

Marina Briand,[a] Elsa Anselmi,[*a, b] Guillaume Dagousset,[*a] and Emmanuel Magnier*[a]

**Abstract:** Over the last years, methods devoted to the synthesis of asymmetric molecules bearing a perfluoroalkylated chain have been limited in number. Among them, only a few can be used on a large variety of scaffolds. This microreview aims at summarizing these recent advances in enantioselective perfluoroalkylation (–CF₃, –CF₂H, –CₙF₂n+1) and highlights the need for new enantioselective methods to easily synthesize chiral fluorinated molecules which would be useful for the pharmaceutical and agrochemical industries. Some perspectives are also mentioned.

**Keywords:** Enantioselectivity, Fluorine, Perfluoroalkyl chains, Asymmetric catalysis

## 1. Introduction

Asymmetric synthesis has always been of great interest among medicinal chemists and to the pharmaceutical industry. Indeed, chirally pure molecules display a high potential for the development of biologically active drugs.[1,2] At the same time, the incorporation of fluorine in molecules has become increasingly important for the design of new potent pharmaceuticals and agrochemicals over the past decade.[3–7] However, due to the many issues raised by the complexity of organofluorine chemistry, methods to access chiral fluorinated compounds have been slower to develop. In the pharmaceutical field, drugs containing perfluoroalkylated or perfluorinated aromatic moieties are numerous. Among them, compounds

with an asymmetric carbon bearing a perfluoroalkyl group are rare.[8]

On top of that, most methods to access perfluoroalkylated stereogenic centers rely on protocols using already fluorinated building blocks (hydrogenation of fluorinated molecules for instance)[9] rather than procedures involving direct enantiocentrilled incorporation of the desired perfluoroalkyl entity into the final molecule.[10] Nevertheless, direct enantioselective introduction of the perfluoroalkyl group in organic compounds remains an appealing synthetic pathway in the framework of late-stage functionalization strategies for drug discovery.[11,12]

To that extent, the lack of methods for asymmetric insertion of perfluoroalkyl chains has been progressively addressed by organic chemists who have envisioned the importance of chirality and fluorine incorporation into molecules designed for the pharmaceutical industry. As an example, it should be noted that the number of publications devoted to enantioselective perfluoroalkylation was extremely low until the end of the 20th century. After a long period of latency, the year 2000 saw a real change in this field.

Regarding the increasing interest in this area since the beginning of the 21st century, reviews on enantioselective organofluorine chemistry have also flourished over the last two decades. Reviews on asymmetric monofluorination are especially numerous.[13–16] Nonetheless, reviews examining asymmetric perfluoroalkylation reactions are rare. To date, the latest comprehensive ones were written by Cahard in 2008,[17] and Toste in 2015.[18]

<footnote>[a] M. Briand, E. Anselmi, G. Dagousset, E. Magnier</footnote>

<footnote>Université Paris-Saclay, UVSQ, CNRS, UMR 8180 Institut Lavoisier de Versailles, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France</footnote>

<footnote>E-mail: elsa.anselmi@univ-tours.fr
guillaume.dagousset@uvsq.fr
emmanuel.magnier@uvsq.fr</footnote>

<footnote>[b] E. Anselmi</footnote>

<footnote>Université de Tours, Faculté des Sciences et Techniques, Parc Grandmont, Avenue Monge, 37200 Tours, France</footnote>

<footnote>© 2023 The Authors. The Chemical Record published by The Chemical Society of Japan and Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</footnote>
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Emmanuel Magnier was born in 1970 in Rue (France). He prepared his PhD under the guidance of Prof. Yves Langlois in the Université Paris-Sud (Orsay). His thesis work was devoted to synthetic approaches to manzamine alkaloids. As a holder of a Bourse Lavoisier, he worked for one year on Pauson-Khand reactions with Prof. William Motherwell at University College, London. He then came back to Orsay for one year as a lecturer in the laboratory of Profs. Henri Kagan and Jean-Claude Fiaud. In 1999, he was appointed as a CNRS permanent researcher in the group of Claude Wakselman in Versailles. He is now director of Institut Lavoisier at Versailles and in charge of the fluorine group. The research works of the group are the synthesis and development of perfluoroalkylating reagents (electrophilic and radical by photoredox catalysis), fluorinated analogues of natural compounds or of therapeutic interest, emerging fluorinated substituents (chalcogens and perfluoroalkylated chains), and the use of new media for green chemistry purposes (ionic liquids).

<figure><img src="image_3.png" /></figure>

Guillaume Dagousset was born in 1984 in Paris. After graduating from Cachan and Chimie ParisTech, he received in 2011 his PhD at ICSN under the supervision of Pr. Jieping Zhu and Dr. Géraldine Masson, working on the Povarov reaction and the phosphoric-acid catalyzed enantioselective synthesis of diamino compounds. He then completed an Alexander von Humboldt post-doctoral fellowship in the research group of Prof. Knochel at the Ludwig Maximilians University in Munich (Germany) where he studied iodine-lithium exchange reactions. In 2013, he joined the group of Dr. Géraldine Masson as a post-doctoral fellow, working on photoredox catalyzed reactions involving enecarbamates. He is currently a permanent CNRS researcher in the Institut Lavoisier at Versailles. His research work involves fluoroalkylation via photoredox catalysis and pyridinium salt chemistry.

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Elsa Anselmi received her PhD in organic chemistry from the University of Versailles under the supervision of Dr. C. Wakselman and Dr. J.-C.Blazejewski dealing with fluorine chemistry. She then joined the CEA Le Ripault working on the synthesis of deuterated polyimides and the CNRS in Lyon for a second postdoctoral position. where she worked on hyperbranched sulfonated PEEK for PEMFC. In 2005, she obtained an assistant professor position at the University of Tours. Her research interests include organometallic chemistry on polyhalogenated synths for the synthesis of heterocycles. Since 2018, she integrated the Institut Lavoisier at Versailles to combine fluorine chemistry and methodology in the synthesis of heterocycles.

<figure><img src="image_5.png" /></figure>

Marina Briand graduated from Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris) in 2020. She performed two Master internships in organic chemistry, one about quinoline chemistry in the group of Prof. M. D'Hooghe in Gent (Belgium) in 2019, and the other in the biotechnology company Galapagos in Romainville (France) in 2020. Since October 2020, she is preparing a PhD in the research group of Dr. E. Magnier under the guidance of Dr. G. Dagousset and Dr. E. Anselmi. Her research work involves enantioselective perfluoroalkylation under photoredox catalysis and organocatalysis.
Since these last reviews, some efforts have been made to develop new methods for direct creation of asymmetric motifs bearing a perfluoroalkyl moiety by the enantiocontrolled introduction of the perfluoroalkyl chain into molecules of interest. This short review aims at highlighting all of these recent enantioselective processes developed since 2015 and outlines the most recent and significant papers devoted to enantioselective perfluoroalkylation, including the asymmetric insertion of -CF₃, -CF₂H, and -CₙF₂n+1 moieties. This microreview focuses on results that have appeared in the literature since the review written by Toste *et al.* in 2015. The recently developed reactions can be classified as nucleophilic, radical and electrophilic, and will be introduced following these categories.

## 2. Nucleophilic Perfluoroalkylation

In the field of asymmetric perfluoroalkylation, nucleophilic approaches have been more widely investigated than radical or electrophilic pathways. Alongside metal-catalyzed procedures which are largely employed for nucleophilic perfluoroalkylation, original and innovative metal-free strategies have also appeared.

### 2.1. Nucleophilic Perfluoroalkylation using Trimethyl(perfluoroalkyl)silanes

Among scientists who significantly contributed to investigating enantioselective nucleophilic trifluoromethylation, Shibata and co-workers used their expertise in asymmetric trifluoromethylation of aryl ketones and aryl aldehydes[19–21] to improve the synthesis of the drug Efavirenz. The group implemented a new procedure for incorporation of the -CF₃ group into key Efavirenz intermediates.[22] The proposed enantioselective method involves organocatalyst **2** and the Ruppert-Prakash reagent. The route provides the Efavirenz intermediates **3a-c** with high enantiomeric excesses (Scheme 1). Interestingly, this procedure required unknown ethynyl cinchona alkaloid catalysts **2a** and **2b** which proved to be highly effective for this reaction. This strategy is all the more relevant in that it represents an alternative to the use of an organometallic complex which is needed for the classic synthetic routes proposed by Merck and Lonsa.[23,24]

The previous strategy is a rare example of nucleophilic metal-free enantioselective perfluoroalkylation. Indeed, direct asymmetric perfluoroalkylation procedures involving metal-catalysis are more numerous. A procedure was reported by Trost *et al.* in 2019 for nucleophilic asymmetric trifluoromethylation of selected six-membered ring molecules with the Ruppert-Prakash reagent (Scheme 2a). The route delivered with high enantiomeric ratios of 80:20 to 97:3 (Scheme 2b).[25] As the ethynyl cinchona alkaloid catalysts

<figure><img src="image_6.png" /><figcaption>**Scheme 1.** Enantioselective trifluoromethylation by Shibata *et al.* for the preparation of key intermediates of Efavirenz.[22]</figcaption></figure>

**(a) General procedure**

<figure><img src="image_7.png" /></figure>

**(b) Selected examples**

<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Enantioselective perfluoroalkylation of six-membered rings by Trost *et al.*[25]</figcaption></figure>

which were revealed by the work of Shibata *et al.*, Trost and co-workers also shed light on an uncommon class of chirality-inducing agents. Optimization of the proposed reaction led to
the use of chiral diamidophosphite ligand **5** since traditional
phosphines designed for allylic alkylation such as S-Phos,
BINAP, or the triisopropyl phosphite gave no results. The
reaction was applied both to carbon rings and heterocycles. As
a variant of the Ruppert-Prakash reagent, other perfluoroalkyl-
lated trimethylsilanes were used to introduce a wide range of
perfluoroalkyl moieties. Trost and co-workers managed to
incorporate $-C_2F_5$, $-C_3F_7$ and $-CF_2CO_2Et$ groups in their
model substrates without any loss of enantioselectivity.

In the above-mentioned reactions, chirality was induced by
a ligand and/or a catalyst. Some processes rely on the use of
chiral substrates for enantiocontrol. This is the case for the
reaction proposed by Zhang *et al*. in 2018 for the synthesis of
trifluoromethylated and difluoroalkylated propargylic com-
pounds starting from optically active secondary propargyl
sulfonates **7** (Scheme 3a).[26] The procedure involves trimeth-
yl(perfluoroalkyl)silanes as sources of perfluoroalkyl chains.
Several leaving groups were tested for the starting material.
Acetate, pivalate or trifluoroacetate gave no reaction. Among
the various sulfonate leaving groups which were tested, the *p*-
methoxyphenyl proved to be the best candidate. Notably, it is
the first example of stereospecific perfluoroalkylation in this
category of substrates. The inversion of absolute configuration
can be mechanistically explained by a first step of oxidative
addition providing an intermediate with inversed configura-
tion, and a stereoretentive reductive elimination (Scheme 3b).
The reaction provides highly enantioenriched trifluorometh-
ylated and difluoroalkylated molecules with enantiomeric
excesses from 93% to 99% (Scheme 3c).

## 2.2. Nucleophilic Perfluoroalkylation using Difluoroenolates or Difluoroenoxysilanes

Recently, in combination with copper catalysis, specific
reagents were used for enantioselective nucleophilic introduc-
tion of difluoroalkyl moieties, the difluoroenolates **9** and
difluoroenoxysilanes **10** (Figure 1).

Difluoroenolates have especially the advantage of being
quite, while reactive enough for difluoroalkylation in a wide
range of reactions.[27] They also provide an easy access to the
difluoromethyl group and can be an alternative to TMSCF₂H
when this reagent does not work. In this way, in 2019, Zhang
et al. adapted the method that they developed in 2018 for
propargyl sulfonates to the asymmetric incorporation of
$-CF_2COAr$ into the same class of compounds, using
difluoroenoxysilanes **12** as fluorine reagents (Scheme 4a).[28]

In this case, difluoroenoxysilanes constitute masked di-
fluoroalkyl anions. The mechanism involves a chiral allene
intermediate **A** which undergoes a nucleophilic asymmetric
attack by the fluorinated anion (Scheme 4b). As for the
synthetic route developed in 2018, this methodology still
affords products **14** with excellent yields of 55–91% and high

(a) General procedure

<figure><img src="image_9.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_10.png" /></figure>

(c) Selected examples

<figure><img src="image_11.png" /><figcaption>**Scheme 3.** Enantioselective perfluoroalkylation of secondary propargyl sulfo-
nates by Zhang *et al.*[26]</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>**Figure 1.** Difluoroenolates and difluoroenoxysilanes for enantioselective nucleophilic difluoroalkylation.</figcaption></figure>

enantioselectivities of 91.5:8.5 to 99:1 *e.r.* (Scheme 4c). As
before, several leaving groups were tested as substrates.
Increasing the steric hindrance of the leaving group proved to
give higher enantioselectivities but lower yields than less-bulky
groups. Moreover, different difluoroenoxysilanes were engaged
(a) General procedure

<figure><img src="image_13.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_14.png" /></figure>

(c) Selected examples

<figure><img src="image_15.png" /><figcaption>**Scheme 4.** Enantioselective difluoroalkylation of secondary propargyl sulfo-nates by Zhang *et al.* [28]</figcaption></figure>

to assess their benefits for the reaction. The –OTES group appeared to be more stable than the –OTMS difluorooxen-ysilane. Finally, the synthesized molecules represent interesting building blocks as the difluoroalkyl group can be transformed into a –CF₂H moiety by employing KOH and heating the medium.

In 2020, Zhang, Ma *et al.* also used difluorooenoxysilanes **17** to prepare asymmetric difluoroalkylated tetrasubstituted isoindolones through an enantioselective Mukaiyama-Mannich reaction, by means of novel chiral spirocyclic phosphoric acids **18** and HFIP as an additive (Scheme 5a).[29]

The authors noticed that the presence of a fluorinated solvent as additive was necessary to implement their enantioselective strategy. Indeed, HFIP is required for dissolution of the phosphoric acid and the starting material. Thanks to the

(a) General procedure

<figure><img src="image_16.png" /></figure>

(b) Transition state

<figure><img src="image_17.png" /></figure>

(c) Selected examples

<figure><img src="image_18.png" /><figcaption>**Scheme 5.** Enantioselective difluoromethylation of isoindolones by Zhang, Ma *et al.* [29]</figcaption></figure>

coordination of the bifunctional chiral phosphoric acid **18** to the –TMS group and the isoindolone **16** simultaneously (Scheme 5b), asymmetric addition of the fluorinated reagent **17** is possible. The difluoroalkylated isoindolones **19** were obtained with yields of 55–97% and enantioselectivities of 48–99% ee (Scheme 5c). As mentioned above for the molecules synthesized through the methodology of Zhang *et al.*, the difluoroalkyl chain of the synthesized isoindolones can be reduced to a difluoromethyl group to obtain the products **21** without any loss of enantioselectivity.
Unlike difluoroenoxysilanes which need to be previously prepared, difluoroenolates are often generated in situ. Wolf and co-workers used difluoroenolates to implement a strategy to prepare α,α-difluoro-β-hydroxyketones 25 from trifluoromethyl α,α-difluorinated β-keto gem-diol (Scheme 6a).[30] The purpose was to target the complexity of asymmetric reactions with fluorinated carbanions by forming the α,α-difluoroenolates 26 in situ. The difluoroenolate 26 is generated after deprotonation of alcohol in 23b which also leads to the formation of CF₃CO₂Et (Scheme 6b). With the help of a new chiral bisoxazoline ligand 24, this copper-catalyzed process led to the synthesis of enantioenriched α,α-difluoro-β-hydroxyketones with yields of 55–99% and satisfying enantioselectivities of 73–92% ee (Scheme 6c).

Difluoroenoxysilanes and difluoroenolates represent an alternative to the direct formation of fluorinated carbanions whose reactivity is difficult to control. In this framework, zinc-

based perfluoroalkylated reagents are also relevant to avoid the presence of very reactive fluorinated carbanions.

## 2.3. Nucleophilic Perfluoroalkylation using Zinc based Difluoroalkylating Reagents

Zinc difluoroalkylating reagents have a complementary reactivity to that of the difluoroenoxysilanes as we will discuss in this section.

In 2012, Stuart et al. took advantage of the potential of these zinc-based reagents to propose a one-pot procedure for an enantioselective difluoroalkylating Reformatsky reaction applied to ketones (Scheme 7a).[31] Optimization showed that ethyl iododifluoroacetate was more efficient than ethyl bromodifluoroacetate to perform the halogen-zinc exchange with diethylzinc and generate the intermediate 30. Moreover, a low temperature was required to achieve high enantioselectivities. A heterogeneous two-step procedure of the reaction in

**(a) General procedure**

<figure><img src="image_19.png" /></figure>

**(b) Reaction mechanism: formation of the difluoroenolate**

<figure><img src="image_20.png" /></figure>

**(c) Selected examples**

<figure><img src="image_21.png" /><figcaption>**Scheme 6.** Enantioselective difluoroalkylation of ketones by Wolf and co-workers.[30]</figcaption></figure>

**(a) One-pot homogeneous procedure**

<figure><img src="image_22.png" /></figure>

**(b) Two-step heterogeneous procedure**

<figure><img src="image_23.png" /></figure>

**(c) Selected examples (synthesized via the one-pot procedure)**

<figure><img src="image_24.png" /><figcaption>**Scheme 7.** Enantioselective Reformatsky reaction by Stuart and co-workers.[31]</figcaption></figure>
which the reagent **30** was first prepared with zinc dust was also investigated to prove the potency of the one-pot pathway (Scheme 7b). The authors showed that this two-step route led to lower enantioselectivities. The one-step reaction provided satisfying yields of 62–90% and enantioselectivities of 76–91% *ee* for a range of aryl ketones (Scheme 7c).

Other difluoromethylated reagents are also at the disposal of the chemists. This is the case for the Zn(CF₂H)₂(DMPU)₂ reagent **35** which was employed in 2019 by Mikami and co-workers to perform the enantioselective copper-catalyzed difluoromethylation of arylidene Meldrum's acid derivatives (Scheme 8a).[32] After complexation of the chiral phosphoramidite ligand **32** with copper, zinc coordination on the carbonyl group to form intermediate **A** promotes oxidative addition in the catalytic cycle by playing the role of a Lewis acid, leading to intermediate **B**. Reductive elimination affords intermediate **C** which undergoes hydrolysis to access the enantioenriched difluoromethylated product **33** (Scheme 8b). The methodology for enantioselective difluoromethylation proposed by Mikami *et al.* provides β-difluoromethyl esters **34** (Scheme 8c) with satisfying yields of 80–89% and promising enantiomeric excesses of up to 82% (*ee* were calculated only for final esters **34**). The zinc reagent is prepared with diethylzinc, dimethylformamide (DMF) and iododifluoromethane in hexane as it is not commercially available (Scheme 8d).[33] The compound of interest is obtained after a ligand exchange between DMF and DMPU. Another preparation of this reagent was reported meanwhile by Vicic *et al.* in 2016.[34] Recently, a continuous process for gram-scale preparation of **35** has also been reported.[35]

Over the last decade, nucleophilic approaches were investigated for asymmetric perfluoroalkylation. Attention was also paid to radical or electrophilic pathways, with efforts to find new and innovative procedures using easily-handled reagents.

### 3. Radical Perfluoroalkylation

Most of the recent radical perfluoroalkylation techniques employed X-CF₂R reagents which include perfluoroiodoalkanes and bromodifluoroacetamides, but also new emerging trifluoromethylation reagents such as Togni's hypervalent iodine derivatives. Featuring an electrophilic character, perfluoroalkyl radicals have set the stage for innovative enantioselective perfluoroalkylation methods.

#### 3.1. Radical Perfluoroalkylation using X-CF₂R Reagents

Inspired by the previous methodologies employing chiral enamine intermediates such as asymmetric perfluoroalkylation by MacMillan *et al.*,[36] Yajima and co-workers proposed a promising procedure for enantioselective α-perfluoroalkylation

<figure><img src="image_25.png" /><figcaption>**Scheme 8.** Enantioselective synthesis of β-difluoromethyl esters by Mikami and co-workers.[32]</figcaption></figure>
of aldehydes.[37] By the use of a chiral organocatalyst such as Jørgensen's pyrrolidine **37**, the authors implemented an interesting enantioselective process for the incorporation of C₃F₇, C₄F₉ and C₆F₁₃ moieties to synthesize α-perfluoroalkylated aldehydes **38** (Scheme 9a). This metal-free process is based on the formation of an electron donor-acceptor (EDA) complex **39** between the enamine intermediate (the donor) and the perfluoroiodoalkyl reagent RfI (the acceptor, Scheme 9b). Under visible light excitation, this complex **39** undergoes a single electron transfer.[38] This process generates radical intermediates which can combine in an enantioselective manner, leading to the corresponding α-perfluoroalkyl iminium. Final hydrolysis of the resulting iminium affords the α-

perfluoroalkylated aldehydes **38** together with the regenerated organocatalyst **37**.

The EDA complex properties for synthetic applications have also been employed by Melchiorre *et al*. In 2015, the group performed the enantioselective perfluoroalkylation of β-ketoesters (Scheme 10a) involving EDA complex **43** (Scheme 10b).[39] Using cinchonine derivatives as phase-transfer catalysts, the process works both for -CF₃ and longer

**(a) General procedure**

<figure><img src="image_26.png" /></figure>

**(b) Reaction mechanism**

<figure><img src="image_27.png" /><figcaption>**Scheme 9.** Enantioselective α-perfluoroalkylation of aldehydes by Yajima *et al.*[38]</figcaption></figure>

**(a) General procedure**

<figure><img src="image_28.png" /></figure>

**(b) Reaction mechanism**

<figure><img src="image_29.png" /></figure>

**(c) Selected examples**

<figure><img src="image_30.png" /><figcaption>**Scheme 10.** Enantioselective perfluoroalkylation of β-ketoesters by Melchiorre *et al.*[39]</figcaption></figure>
perfluoroalkyl chains such as -C₄F₉, -C₆F₁₃, -C₈F₁₇ and -C₁₀F₂₁, to afford perfluoroalkylated β-ketoesters 42 in 38-71% yield and high enantioselectivities of 78-96% ee (Scheme 10c). Through this method, Melchiorre and co-workers proved that chiral enolates can constitute efficient electron donors as partners in an EDA complex.

Shortly after, Xiao and co-workers developed a similar enantioselective perfluoroalkylation procedure for the synthesis of perfluoroalkylated β-ketoesters 45 (Scheme 11a). [40]

This time, the process combines both visible-light photo-catalysis and Lewis acid catalysis. Changing the ligand of the Lewis acid and using ethereal solvents such as DME induced an improvement in enantioselectivities. An increase of the Lewis acid catalyst loading to 20 mol% was necessary to achieve satisfactory enantiomeric ratios. The mechanism of the reaction was also investigated. It is worth noting that the nickel complex C must be oxidized to give the starting nickel complex A back and close the photocatalytic cycle. This oxidation can be performed either by the iridium catalyst in its excited state or by the nickel complex B whose formation was required to generate the Ir(II) state (Scheme 11b). This methodology led to satisfying yields of 45-67% and enantiomeric ratios of 55:45 to 94.5:4.5. The reaction is applicable to -CF₂CO₂Et, -C₃F₇ and -C₄F₉ moieties (Scheme 11c).

Inspired by these methodologies which combine photo-redox and asymmetric catalyses, Meggers et al. implemented a strategy in which the metal plays both the role of the catalyst and of the chirality-inducing reagent (Scheme 12a). [41]

By designing a metal catalyst with a dual functionality, Meggers and co-workers proposed an innovative reaction to introduce a wide range of perfluoroalkyl chains. The compound 47 serves as a chirality inductor and as a Lewis acid catalyst simultaneously. Tert-butyl substituents on the photo-catalyst 47 enable a notable increase in the yield. From a mechanistic point of view, formation of the enolate intermediate complex B is the key step of the catalytic cycle. After addition of the perfluoroalkyl radical coming from the photo-redox cycle onto intermediate B, oxidation of the resulting intermediate C releases the final product coordinated to the catalyst (intermediate D). Coordination of the iridium metal to another substrate molecule 46 closes the catalytic cycle (Scheme 12b). The procedure is all the more remarkable given the enantioselectivities obtained for the perfluoroalkylated 2-acyl imidazoles 48 which are all at least of 90% ee (Scheme 12c).

Our group has very recently introduced preliminary results for a novel procedure for enantioselective remote perfluoroalkylation of α,β-unsaturated carbonyl compounds 49. By combining photoredox catalysis and organocatalysis, the reaction affords γ-perfluoroalkylated enal 51 as an intermediate which is then derivatized to 52 through a Wittig reaction to avoid partial racemization (Scheme 13). [42] The method

provides access to compound 52 with a moderate yield of 28% but a satisfying enantioselectivity of 86% ee. It is worth mentioning that this is the first example of catalytic enantioselective remote C-H perfluoroalkylation. The authors tested several organocatalysts. While MacMillan's catalyst 50a led to no desired product, Jørgensen's pyrrolidine 50b proved

(a) General procedure

<figure><img src="image_31.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_32.png" /></figure>

(c) Selected examples

<figure><img src="image_33.png" /><figcaption>**Scheme 11.** Enantioselective perfluoroalkylation of β-ketoesters by Xiao *et al.* [40]</figcaption></figure>
(a) General procedure

<figure><img src="image_34.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_35.png" /></figure>

(c) Selected examples

<figure><img src="image_36.png" /><figcaption>**Scheme 12.** Enantioselective perfluoroalkylation of 2-acyl imidazoles by Meggers *et al.*[41]</figcaption></figure>

<figure><img src="image_37.png" /><figcaption>**Scheme 13.** Enantioselective remote C–H perfluoroalkylation by Dagousset *et al.*[42]</figcaption></figure>

to be effective for the process. After optimization of the reaction conditions with C₄F₉I, the authors performed an attempt with CF₃I which led to a result of only 53% ee. The authors explain this observation by the small size of the –CF₃ radical.

In the previous strategies, perfluoroiodoalkanes were used as perfluoroalkyl radical sources, but other reagents can be used to introduce perfluoroalkyl moieties in an enantioselective manner *via* a radical pathway. Influenced by the process proposed by Meggers *et al.*, Xu and co-workers reported in 2019 a dual catalytic system to synthesize enantioenriched fluorinated 2-acyl imidazoles **57** using commercial bromodifluoroacetamides **55** as perfluoroalkylating agents (Scheme 14a).[43] Combining photoredox and Lewis acid catalyses through the bifunctional chiral photocatalyst **56a**, the reaction led to good yields of 71–97% and enantioselectivities of up to 99% ee (Scheme 14b). The reaction pathway is consistent with the mechanism previously proposed by Meggers *et al.* (cf. Scheme 12b). The only mechanistic change is the requirement of a base. DIPEA was selected, as inorganic bases gave no result. Surprisingly, iridium complex **56b** failed to catalyze the reaction in contrast to rhodium complex **56a**. The authors explained this observation by the faster kinetics of the ligand exchange for rhodium complexes compared to the iridium catalysts.[44] Finally, an interesting aspect of the reaction was its extension to the synthesis of enantioenriched monofluoroalkylated 2-acyl imidazoles.

Previous methods introduced in this microreview employed perfluoroiodoalkanes or X-CF₂R type reagents as perfluoroalkyl chain sources. However, these are not the most easily-handled fluorine agents when it comes to trifluoromethylation. Indeed, trifluoroiodomethane is somewhat difficult to manip-
(a) General procedure

<figure><img src="image_38.png" /></figure>

(b) Selected examples

<figure><img src="image_39.png" /><figcaption>**Scheme 14.** Enantioselective perfluoroalkylation of 2-acyl imidazoles by Xu *et al.*[43]</figcaption></figure>

ulate as it is gaseous at room temperature under atmospheric pressure. Addition of an exact volume of such a reagent can be problematic. Therefore, new reagents have been designed to address this issue.

## 3.2. Radical Perfluoroalkylation using Togni's Reagents

The synthesis of hypervalent iodine derivatives, known as Togni's reagents **58** and **59**, was reported for the first time in 2006 (Figure 2).[45] Since then, they have been very useful for the development of various new radical perfluoroalkylation reactions.

In 2019, through a Lewis acid catalysis combined with the use of chiral PyBOX-type ligands, Katayev and co-workers efficiently obtained enantioenriched trifluoromethylated oxinolides and were the first to perform asymmetric trifluorometh-

ylation thanks to the fluorinated hypervalent iodine reagent **59** (Scheme 15).[46] This innovative approach allowed them to achieve excellent yields and remarkable enantioselectivities. In light of these encouraging results, the reaction conditions were also applied to two other perfluoroalkyl groups, $-C_2F_5$ and $-C_3F_7$, leading to the same outstanding outcomes.

In 2020, Liu *et al.* took advantage of these new sources of the trifluoromethyl radical for the synthesis of enantioenriched β-ketones **65** starting from cyclopropanols **63** (Scheme 16a).[47] The targets **65** were obtained in 42–77% yield and satisfying enantioselectivities of 59–95% ee (Scheme 16b). The first step of the cycle is an oxidation of copper complex **A** by Togni's reagent **59** activated by complexation with the starting material **63** (complex **B**). Reaction of compound **63** with intermediate **C** provides complex **D** which undergoes a homolytic cleavage of the Cu–O bond leading to the formation of an alkoxide radical **F**. After a ring-opening process, trapping of the formed benzylic radical by copper complex **E** allows enantioselective trifluoromethylation providing the enantioenriched product **65** (Scheme 16c). However, an analysis of the crude mixture revealed that a lot of side products were formed and are derived from complex **C**, which partly explains the rate-determining step of the reaction. The authors also proved the essential role played by the quinoline moiety in bisoxazoline ligand **64** to achieve an enantioselective process. Indeed, the quinoline moiety interacts weakly with the copper in $Cu(CH_3CN)_4$ leading to hindered complex **E** and provides highly enantioselective trapping in the last step of the cycle. Finally, the authors observed that an excess of $-CF_3$ anion engenders a significant drop in enantiomeric excess because of the competitive coordination of $-CF_3$ moiety on copper. Therefore, reagents such as $(DMPU)_2Zn(CF_3)_2$ or TMSCF$_3$ proved to be incompatible with the reaction.

Taking advantage of the stability of benzylic radicals, in continuity of the research in the field of enantioselective radical reactions, Liu *et al.* proposed very recently a procedure for enantioselective radical C–H trifluoromethylation at the benzylic position (Scheme 17a).[48] Concerning the mechanistic pathway, the key step is trapping of the benzylic radical by complex **B** which leads to asymmetric trifluoromethylation (Scheme 17b). It is worth noting that addition of $MeB(OH)_2$ resulted in better yields because of the possible activation of Togni's reagent **58** thanks to the boronic acid. The proposed

<figure><img src="image_40.png" /><figcaption>**Figure 2.** Hypervalent-iodine trifluoromethylating reagents synthesized by Togni *et al.*</figcaption></figure>
(a) General procedure

<figure><img src="image_41.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_42.png" /></figure>

(c) Selected examples

<figure><img src="image_43.png" /><figcaption>**Scheme 15.** Enantioselective trifluoromethylation of oxindoles by Katayev *et al.*[46]</figcaption></figure>

process is all the more interesting as it employs metal-free photocatalysts **68** and **69** and represents an opportunity for late-stage functionalization of bioactive molecules as shown with **70g** and **70h**. This multicatalytic process combines copper and photoredox catalyses to afford benzylic trifluoromethylated products in 41–78% yield and satisfying enantioselectivities of 82–94% ee (Scheme 17c). Togni's re-

(a) General procedure

<figure><img src="image_44.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_45.png" /></figure>

(c) Selected examples

<figure><img src="image_46.png" /><figcaption>**Scheme 16.** Enantioselective trifluoromethylation of benzylic radicals *via* ring-opening of cyclopropanols by Liu *et al.*[47]</figcaption></figure>

agent **58** showed effectiveness for this reaction again in contrast to the Ruppert-Prakash reagent. Moreover, cationic copper species (Cu(I) salts, such as CuCl or CuOAc) are required.

As previously mentioned, Togni's reagents represent efficient sources of the –CF₃ radical. Meanwhile, new method-
(a) General procedure

<figure><img src="image_47.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_48.png" /></figure>

(c) Selected examples

<figure><img src="image_49.png" /><figcaption>**Scheme 17.** Enantioselective trifluoromethylation of benzylic radicals by Liu *et al.*[48]</figcaption></figure>

ologies have shown that these hypervalent iodine reagents can
also be used as electrophilic sources of the CF₃ moiety and

thus be involved in electrophilic pathways for enantioselective
perfluoroalkylation.

4. Electrophilic Perfluoroalkylation

4.1. Electrophilic Perfluoroalkylation using Togni's Reagents

Inspired by the work of MacMillan *et al.* combining chiral organocatalysis and chiral Lewis acid catalysis, Vallribera and co-workers proposed in 2019 a new electrophilic approach for enantioselective α-trifluoromethylation of β-ketoesters, which is based on the use of lanthanum (III) triflate and a PyBOX-type chiral ligand **72** (Scheme 18a).[49]

Among electrophilic perfluoroalkylating reagents, Umemoto's reagent showed low efficiency compared to Togni's reagent **59**. Moreover, the authors explain the enantioselectivity of the reaction by the constrained structure of the complex **C** engendered by one of the prochiral faces of ligand **72**. They observed that the enantioselectivity is also dependent on the steric hindrance of the substrate. It is important to mention that ligand **72** plays the role of both the chiral agent and the base to generate the corresponding enolate **B** (Scheme 18b). 3-Oxo ester derivatives are obtained in good yields of 65–85% and enantioselectivities of 53–99% *ee* (Scheme 18c).

4.2. Electrophilic Perfluoroalkylation using Difluorocarbene Reagents

Enantioselective perfluoroalkylation *via* electrophilic pathways involving difluorocarbene species were reported quite recently.

In 2021, Guo *et al.* developed a suitable asymmetric difluoromethylation method for amino acids (Scheme 19a) and ketimines (Scheme 19b).[50] The process displays both good yields of 50–76% and enantioselectivities of 80–97% *ee*. Having proved effective for the synthesis of difluoromethyl amino acids **76**, the methodology was extended to the synthesis of perfluoroalkylated ketimine esters **78** with high enantioselectivities (Scheme 19c). Concerning the mechanism of the reaction, after coordination of the substrate on the copper leading to complex **B**, *N*-metalated azomethine ylide intermediate **C** is formed through the deprotonation of **B**. The electrophilic difluorocarbene species reacts with chiral intermediate **C** through a nucleophilic addition affording intermediate **D**. This carbanion undergoes hydrolysis under acidic conditions to give product **76** (Scheme 19d). While the authors recognize that the use of Freon 22 (ClCF₂H) as a difluoromethyl source is arguable, the procedure is useful for the design of new pharmaceuticals.

In the field of difluorocarbene as fluorine agent for
enantioselective difluoromethylation, Wang *et al.* also pro-
posed a procedure for the synthesis of enantioenriched
(a) General procedure

<figure><img src="image_50.png" /></figure>

(b) Reaction mechanism

<figure><img src="image_51.png" /></figure>

(c) Selected examples

<figure><img src="image_52.png" /><figcaption>**Scheme 18.** Enantioselective trifluoromethylation of β-ketoesters by Vallribera *et al.*[49]</figcaption></figure>

difluoromethylated β-ketoesters by phase-transfer catalysis (Scheme 20a). By combining chiral cinchona-derived aryl-substituted phase-transfer catalysts **80** and TMSCF₂Br as a difluorocarbene precursor, the methodology affords products **81** with satisfying yields of 63–92% and good enantioselectivities of up to 83% ee (Scheme 20b).[51] TMSCF₂Cl was also tested as a difluoromethylating agent but showed low reactivity. For product **81h**, the use of K₂CO₃ as a reaction promotor did not work, and replacement by KOH was required in this case which resulted in a decrease in the

(a) General procedure for aldimine esters

<figure><img src="image_53.png" /></figure>

(b) General procedure for ketimine esters

<figure><img src="image_54.png" /></figure>

(c) Selected examples

<figure><img src="image_55.png" /><figcaption>76a 76%, 96% ee</figcaption></figure>

<caption>76b 66%, 90% ee</caption>

<figure><img src="image_56.png" /><figcaption>76d 65%, 90% ee</figcaption></figure>

<caption>76e 67%, 96% ee</caption>

<figure><img src="image_57.png" /><figcaption>78a 54%, 97% ee</figcaption></figure>

<caption>78b 60%, 95% ee</caption>

<caption>78c 70%, 97% ee</caption>

(d) Reaction mechanism

<figure><img src="image_58.png" /><figcaption>**Scheme 19.** Asymmetric difluoromethylation of amino acids by Guo *et al.*[50]</figcaption></figure>
<figure><img src="image_59.png" /></figure>

**(b) Selected examples**

<figure><img src="image_60.png" /></figure>

81a 92%, 83% ee

<figure><img src="image_61.png" /></figure>

81b 78%, 67% ee

<figure><img src="image_62.png" /></figure>

81c 78%, 67% ee

<figure><img src="image_63.png" /></figure>

81d 88%, 78% ee

<figure><img src="image_64.png" /></figure>

81e 76%, 63% ee

<figure><img src="image_65.png" /></figure>

81f 74%, 73% ee

<figure><img src="image_66.png" /></figure>

81g 77%, 63% ee

<figure><img src="image_67.png" /></figure>

81h 63%, 58% ee

**(c) Reaction mechanism**

<figure><img src="image_68.png" /><figcaption>**Scheme 20.** Enantioselective difluoromethylation of β-ketoesters by Wang *et al.*[51]</figcaption></figure>

enantiomeric excess. It is worth mentioning that the formation of the –OCF₂H side product **81'** *via* O-difluoromethylation is also possible during the reaction. With a C/O selectivity of at least 93:7, the method is selective for the C–CF₂H product. For C-difluoromethylation, after deprotonation of the ester **79**, the enolate forms a complex with the phase transfer catalyst (Scheme 20c). Once the difluorocarbene is formed after desilylation and fragmentation, there are two possibilities, either O-difluoromethylation or the formation of a cyclopropane as shown in intermediate **C**. According to the authors, formation of intermediate **C** is favored thanks to the affinity between the phase transfer catalyst as a cation PTC⁺ and the oxygen. This prevents O-difluoromethylation and the formation of side product **81'**. The authors also showed that the C/O selectivity can be controlled by using a different reaction promotor. For instance, addition of KHF₂ favors the formation of side product **81'**.

**5. Conclusion and Perspectives**

The last years have seen a remarkable renewal in enantioselective perfluoroalkylation. A wide range of methods were developed to directly access chiral perfluoroalkylated products. This represents a real opportunity in the framework of late-stage functionalization of pharmaceutical and agrochemical molecules. This upsurge in studies in enantioselective perfluoroalkylation has gone hand in hand with the development of original and innovative perfluoroalkylating reagents which are practical to handle, stable and easy to synthesize (see Figure 3). For instance, hypervalent iodine reagents such as Togni's reagents **58** and **59** proved to be effective for several asymmetric perfluoroalkylation reactions while they are synthesized *via* a one-pot procedure with satisfying yields.[52] As another example, zinc fluorinated reagents have appeared such as (DMPU)₂Zn(CF₂H)₂ which was synthesized with a high yield of 94% and represents a formidable advance for asymmetric difluoromethyl incorporation. This zinc reagent is a solid, therefore easy to handle, and it is also stable and compatible with a wide range of substrates.[34] In the same way, the use of difluorocarbene reagents and difluoromethyl precursors led to a slight increase in proposed procedures for direct enantioselective difluoromethylation and difluoroalkylation than before 2015. Among other notable breakthroughs during the last years, new reagents featuring a dual role in the reaction including chiral induction were designed. As an illustration, the chiral compound **47** designed by Meggers *et al.* as well as the catalysts **56a–b** employed by Xu and coworkers are consistent examples of dual-functional reagents playing both the roles of chiral-inducing agents and photocatalysts. Finally, some reactions introduced in this microreview have represented an opportunity to synthesize new chiral ligands. This is the case for the synthesis of Efavirenz
<figure><img src="image_69.png" /><figcaption>**Figure 3.** Improvements and advances in enantioselective C–H perfluoroalkylation during the last five years.</figcaption></figure>

intermediates proposed by Shibata *et al.* which led to the design of unknown ethynyl cinchona alkaloid catalysts **2a** and **2b** for chiral induction.[22]

Nevertheless, there are some advances which are still missing in the framework of direct enantioselective perfluoroalkylation. Among these, chiral reagents bearing a perfluoroalkyl moiety and capable of asymmetric induction while being the perfluoroalkyl source of the reaction are absent from the list of all improvements made during the last decade. Additionally, enantioselective difluoromethylation was less studied compared to other perfluoroalkyl chains. However, the –CF₂H moiety represents a key functionality for drugs or drug candidates. Indeed, the difluoromethyl group displays a C–H acidic bond which makes it a potent hydrogen-bond donor. The –CF₂H group can also be useful as a bioisostere of the hydroxyl group or thiol group in therapeutic studies.[53] Therefore, this perfluoroalkyl chain must be one of the main targets for fluorine incorporation into bioactive molecules. Finally, in an effort to tend to a greener chemistry, more metal-free procedures are required in the near future even if an

increase of such procedures has been observed for enantioselective perfluoroalkylation in the last five years.

Regarding all these major developments over the past years, it is undeniable that enantioselective incorporation of fluoroalkyl moieties is at the top of the list of priorities in the field of asymmetric synthesis.

### Acknowledgements

This work was supported by a grant from the Agence Nationale de la Recherche with JCJC funding (ANR-20-CE07-0008-01). M. B. thanks UVSQ and the French ministry of research for a PhD scholarship. Dr. Karen Wright is warmly acknowledged for improvement of the text as well as the GIS Fluor is also acknowledged.

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Manuscript received: March 30, 2023

Revised manuscript received: May 2, 2023

Version of record online: May 23, 2023