Jeanne Fichez

Dorian Dupommier

Tatiana Besset
email: tatiana.besset@insa-rouen.fr

Direct Synthesis of Disubstituted Trifluoromethylthiolated Alkenes

Keywords:

In the field of organofluorine chemistry, the quest for emergent fluorinated groups is in high demand. In particular, the scientific community has shown special interest in the SCF3 residue thanks to its unique properties. Indeed, over the last decade, the SCF3 group has become a pivotal fluorinated moiety as demonstrated by several SCF3-containing compounds of interest and related to that, the steadily increasing synthetic methods to access such molecules. In this Short Review, the main advances made for the synthesis of trifluoromethylthiolated disubstituted alkenes will be discussed and highlighted. 1 Introduction 2 Trifluoromethylthiolation of pre-functionalized alkenes 3 Direct C-H Trifluoromethylthiolation of alkenes 4 Trifluoromethylthiolation of miscellaneous derivatives 5 Conclusion

Introduction

Since the 50's, fluorinated compounds have emerged as pivotal molecules for medicinal chemistry, material sciences, agrochemical and pharmaceutical industries 1 thanks to the unique properties of the fluorine atom and fluorinated groups. 2,3 Therefore the field of organofluorine chemistry has been steadily evolving over the years, by means of the development of original and efficient synthetic methods to access fluorinated molecules. 4 Among the wide diversity of fluorinated residues, the SCF3 group has already shown attractive and unique properties. Indeed, it has been established that this group displays a strong electron-withdrawing effect, comparable to the one of the CF3 moiety. It is also known to impact the lipophilicity of the molecules in which it is incorporated with a high Hansch parameter (π = 1.44), in comparison with those of other fluorinated groups like the CF3 (π = 0.88) and the OCF3 (π = 1.04) residues. 5 Over the last years, this emergent fluorinated group has aroused the interest of the scientific community and a large panel of straightforward synthetic methodologies to access SCF3containing compounds has been developed. 6,[START_REF] Boiko | For selected examples[END_REF] Generally, their synthesis relied on two mains approaches: a) the construction of the SCF3 moiety [START_REF] Xu | Indirect Trifluoromethylthiolation Methods[END_REF] including the fluorination of trichloromethylthioether compounds 9 and the trifluoromethylation of thiol derivatives, 10 and b) the direct introduction of a SCF3 moiety on various classes of molecules. In the latter case, albeit the trifluoromethylthiolation of (hetero)arenes 11 and to some extent of aliphatic derivatives 12 was well studied, the number of reports dealing with the synthesis of 1,1-and 1,2-disubstituted olefins remains rather limited. Nevertheless, disubstituted alkenes are common scaffolds found in several compounds of interest in medicinal chemistry and agrochemicals (Figure 1,A). 13 Among these alkenes, two trifluoromethylthiolated compounds demonstrated interesting properties as weed killer 14 and insecticide 15 (Figure 1,B). Herein, this Short Review will provide an overview of the different approaches for the synthesis of disubstituted trifluoromethylthiolated alkenes by direct trifluoromethylthiolation reaction and the main advances will be discussed and highlighted. 16

Trifluoromethylthiolation of pre-functionalized alkenes

Starting from boronic acids

In 2012, Vicic and co-workers reported a copper-mediated synthesis of trifluoromethylthiolated derivatives (Scheme 1). 17 During their investigations on the trifluoromethylthiolation of (hetero)aromatic boronic acids as a potent alternative to the use of aryl chlorides, the functionalization of vinyl boronic acids was studied. Indeed, under mild conditions (room temperature, air as oxidant), the synthesis of four trifluoromethylthioethers was achieved using this copper-mediated transformation in the presence of NMe4SCF3. Note that the transformation was completely selective towards the formation of the E-isomer. Both styrenes substituted with electron-donating groups and halogens (1a-c) were smoothly trifluoromethylthiolated. The (cyclohexylvinyl)boronic acid was more reactive, as 2d was prepared in 70% yield.

In 2013, Shen, Lu and co-workers developed an alternative approach for the trifluoromethylthiolation of aryl, vinyl boronic acids and alkynes (Scheme 2). 18 Using the electrophilic reagent II 19 as an electrophilic source, the copper-catalyzed trifluoromethylthiolation reaction went smoothly, although restricted to the selective synthesis of the compounds 4a and 4b as E-isomers.

Scheme 2 Trifluoromethylthiolation reaction using the electrophilic reagent II. bpy = 2,2'-bipyridine.

In 2015, the group of Shibata used their in-home reagent, the trifluoromethanesulfonyl hypervalent iodonium ylide III, for the functionalization of various substrates (Scheme 3). 20 In this study, both allyl alcohols and boronic acids were trifluoromethylthiolated including two examples of vinyl boronic acids, which were trifluoromethylthiolated in moderate yields (6a and 6b, 45% yield and 55% yield, respectively).

Scheme 3 Copper-mediated trifluoromethylthiolation reaction using the reagent of Shibata.

A complementary approach to get trifluoromethylthiolated 1,2-disubstituted alkenes relied on the use of the Munavalli reagent V. 22 In 2014, Rueping 23 and Shen 24 independently reported the trifluoromethylthiolation of boronic acid derivatives (Scheme 4). The copper-catalyzed methodology described by Rueping was effective for the trifluoromethylthiolation of various vinyl boronic acids substituted with a naphthyl, a phenyl and an alkyl moiety (7a-7c) and the corresponding products were isolated in good to excellent yields (8a-8c, up to 85% yield). In case of Shen, a single example was depicted and the compound 8d was obtained in 50% yield. The copper-catalyzed cross-coupling reaction of boronic acids with the Billard reagent VI was also reported (Scheme 5). 25 Under these reaction conditions, both aromatic and benzylic vinyl boronic acids were functionalized at room temperature under air. In this transformation, the presence of water (7 equivalents) was crucial, although its role was not clear.

Scheme 5 Trifluoromethylthiolation of boronic derivatives using the Billard reagent. 4,4'-diMe-2-2'-bpy = 4,4'-dimethyl-2,2'-bipyridine.

More recently, in 2020, Zhang and co-workers developed an electrophilic hypervalent trifluoromethylthio-iodine(III) reagent IV (Scheme 6). 21 The synthetic utility of IV was demonstrated with the functionalization of several nucleophiles, including bio-relevant thio-containing compounds and vinyl boronic acids. Hence, the trifluoromethylthiolated styrenes 12a and 12b were synthesized in high yields using CuI as a catalyst.

Scheme 6 Copper-catalyzed trifluoromethylthiolation using the reagent IV. a Reaction was carried out at 0 °C. phen = 1,10-phenanthroline.

Starting from α,β-unsaturated carboxylic acids

Among the other classes of precursors for the synthesis of trifluoromethylthiolated difunctionalized alkenes, the group of Huang was the first to develop, in 2016, a copper-mediated decarboxylative trifluoromethylthiolation of α,β-unsaturated carboxylic acids using AgSCF3 (VII, Scheme 7). 26 Cinnamic acids with various substituents 13 were functionalized and the expected vinyl trifluoromethyl thioethers 14 were obtained in moderate to good yields with a good E:Z selectivity in favour of the Eisomer. Note however, that in case of the pyridyl α,β-unsaturated carboxylic acid 13c, a complete selectivity for the Z-isomer was noticed. Although efficient, the method suffered from some limitations as the reaction was completely inefficient with cinnamic acids bearing a strong electron-withdrawing group or aliphatic substituted ones.

Scheme 7 Copper-mediated decarboxylative trifluoromethylthiolation of α,β-unsaturated carboxylic acids. E:Z ratios are given in parenthesis and were determined by 19 F NMR. Only the major isomer was depicted.

Using similar reaction conditions (no need of silver salt), Xu, Feng and co-workers reported in 2018 the preparation of a panel of disubstituted trifluoromethylthiolated alkenes 16, with yields up to 73% starting from cinnamic acids 15 (Scheme 8). 27 Worth to mention that the E:Z ratios were in favour to the Eisomer.

Scheme 8 Copper-mediated decarboxylative trifluoromethylthiolation of cinnamic acid derivatives. E:Z ratios are given in parenthesis and were determined by 19 F NMR. a Reaction was carried out at 80 °C. Only the major isomer was depicted.

Starting from halogenated alkenes

The trifluoromethylthiolation reaction has also been developed starting from halogenated alkenes. The group of Rueping, inspired by the nucleophilic S-addition of thiols on vinyl iodides and bromides, 28 was the first to propose the synthesis of trifluoromethylthioethers starting from a halogenated vinyl compound (Scheme 9). 29 In that purpose, two methods have been reported for the trifluoromethylthiolation of vinyl iodides. The first one, using two equivalents of CuSCF3, allowed the functionalization of aryl-and alkyl-substituted vinyl iodides (17a-17h) and the expected products (18a-18h) were isolated in high yields (up to 97% yield). Note that compounds 18f, 18g and 18h were also obtained using [Bu4N][SCF3] as the SCF3 source via a copper catalyzed reaction. Few years later, Zheng and Weng developed the copper-mediated trifluoromethylthiolation of vinyl halides (Scheme 10). 30 In the presence of the (bpy)Cu(SCF3) complex, the functionalization of aromatic vinyl bromides bearing electron-donating (19b-19d) or electron-withdrawing groups (19e) as well as a halogen (19f-19h) led to the 1,2-disubstituted alkenes in excellent yields (up to 93% yield). The synthesis of 1,1-trifluoromethylthiolated alkenes was also successively achieved starting from thebromostyrene (21a), the (1-iodovinyl)cyclohexane (21b) and 2-iodooct-1-ene (21c) and afforded the corresponding products 22a-22c. Note that the stereochemistry of the substrate (E:Z ratios) was retained in the course of the reaction.

Starting from nitroalkenes

The denitrative trifluoromethylthiolation reaction is also an interesting way to prepare trifluoromethylthiolated alkenes. The group of Hong reported in 2020 the efficient preparation of several SCF3-containing difunctionalized alkenes (Scheme 11). 31 The copper-promoted denitrative trifluoromethylthiolation of monosubstituted -nitrostyrenes (23a-23c) was achieved in good yields (up to 87% yield) using the reagent VII as the SCF3 source. Interestingly, in case of 23b, the reaction proceeded selectively leaving the nitro group on the aromatic part intact and the expected product 24b

was obtained in 58% yield in a 96:4 E:Z ratio. Di-and tri-substituted -nitrostyrenes were also suitable substrates (23d and 23e) but afforded the desired compounds with slightly lower yields than their monosubstituted analogues. The diene 23f was also smoothly functionalized in this transformation.

Scheme 11 Copper-catalyzed denitrative trifluoromethylthiolation of nitroalkenes. E:Z ratios are given in parenthesis and were determined by 19 F NMR. Only the major isomer was depicted.

Direct C-H Trifluoromethylthiolation of alkenes

Recently an alternative to the above depicted approaches relied on the synthesis of disubstituted trifluoromethylthiolated olefins by direct C-H trifluoromethylthiolation. Such approach offered efficient and original retrosynthetic disconnections towards these fluorinated molecules. The recent breakthroughs for the synthesis of both 1,2-and 1,1-disubstituted trifluoromethylthiolated olefins will be summarized in that part.

Preparation of 1,2-disubstituted trifluoromethylthiolated olefins

In 2016, Glorius group reported a visible-light photoredox catalyzed process for the trifluoromethylthiolation of (hetero)aromatic substituted alkenes using the electrophilic Munavalli reagent V (Scheme 12) and the fac-[Ir(ppy)3] as photocatalyst. 32 With this dual photoredox/halide catalysis, the preparation of various di-and tri-substituted alkenes was possible. Among them, the synthesis of eight disubstituted compounds was described. The stereoselectivity of this transformation was in favor of the E-isomer (26a-26f). However, a Z-favored transformation was achieved in case of 26g and the benzo [b]thiophene derivative 26h.

Scheme 12 Trifluoromethylthiolation of styrene derivatives using a dual halide/ photoredox catalysis. E:Z ratios are given in parenthesis and were determined by 19 F NMR. Only the major isomer was depicted. ppy = 2-phenyl-pyridine.

The same year, the group of Shen depicted the synthesis of a new electrophilic SCF3 source, (PhSO2)2NSCF3 XI and showed that it allowed the preparation of various trifluoromethylthiolated derivatives (Scheme 13). 33 Among them, the direct trifluoromethylthiolation of styrene derivatives such as 27a was efficiently achieved and the desired products were obtained as E-isomers (17 examples, up to 96% yield). To further demonstrate the synthetic utility of their methodology, the functionalization of the ferrocene derivative 27b and the steroid 27c was reported and the expected products (28b and 28c) were isolated in 52% yield and 85% yield, respectively.

Scheme 13 Trifluoromethylthiolation reaction using the reagent XI.

Preparation of 1,1-disubstituted trifluoromethylthiolated olefins

In contrast with the synthesis of 1,2-disubstituted olefins by direct C-H trifluoromethylthiolation of alkenes, the access to 1,1-disubstituted trifluoromethylthiolated olefins starting from the nonprefunctionalized substrates is highly challenging. So far such transformation was restricted to activated olefins such as α,β-unsaturated carbonyl compounds, which can act as a Michael acceptor in Baylis-Hillman conditions. 34 Cho and co-workers described the synthesis of these 1,1-trifluoromethylthiolated difunctionalized alkenes by means of a DABCO-mediated electrophilic trifluoromethylthiolation reaction using the reagent XI (Scheme 14). 35 With this methodology, the trifluoromethylthiolation of α,β-unsaturated ketones (19 examples, up to 88% yield) and α,β-unsaturated esters (6 examples, up to 87% yield) was smoothly achieved. In the first case, the reaction was tolerant to (hetero)aromatic and aliphatic α,βunsaturated ketones (29a, 29b and 29c respectively), but also regioselective in the case of the ketone 29d in which the cyclohexene moiety remained intact. Even if the scope of the acrylates was substantially narrower, Cho and co-workers proved that substrates bearing a para-substituted electron-poor and electron-rich arene (29e and 29f) as well as an ortho-brominated arene (29g) were efficiently functionalized.

Scheme 14 Synthesis of trifluoromethylthiolated 1,1-disubstituted alkenes starting from α,β-unsaturated ketones and esters.

Trifluoromethylthiolation of miscellaneous derivatives

Over the years, several complementary approaches were developed to access 1,2-disubstituted alkenes starting from various classes of compounds. In this section, the main advances were summarized.

In 2016, the group of Cao described the hydrotrifluoromethylthiolation of terminal alkynes using AgSCF3 VII and K2S2O8 along with catalytic amounts of HMPA and phenanthroline (Scheme 15). 36 Under these conditions, the synthesis of the anti-Markovnikov selective trifluoromethylthiolated 1,2alkenes was possible in good to high yields, with a wide functional tolerance (22 examples, up to 82% yield). Both aromatic (31a and 31b) and alkyl (31c) substituted alkynes were suitable substrates. Note that the regioselectivity of the transformation was good although products were obtained as an inseparable E:Z mixture. Using slightly modified reaction conditions (H2O and a catalytic amount of CuCl instead of HMPA and phenanthroline in DCE at 100°C), the Markovnikov-selective hydrotrifluoromethylthiolation occurred (8 examples, up to 81% yield). It is interesting to mention that this reaction was limited to para-alkoxy-substituted phenylacetylene derivatives affording the corresponding 1,1-trifluoromethylthiolated styrenes in very good yields (33a and 33b, Scheme 15), while the benzo [d]oxolane derivative 33c was prepared with a lower yield (41%).

Scheme 15 Hydrotrifluoromethylthiolation of terminal alkynes using AgSCF3. E:Z ratios are given in parenthesis and were determined by 19 F NMR and 1 H NMR. Only the major isomer was depicted. phen = 1,10-phenanthroline.

Three years after this initial report, Qing and co-workers developed a complementary approach for the hydrotrifluoromethylthiolation of unactivated alkenes and alkynes for the preparation of trifluoromethylthiolated alkanes and alkenes, respectively, under visible-light photoredox-catalysis (Scheme 16). 37 In this transformation, the trifluoromethanesulfonic anhydride (Tf2O) is playing a key role as a radical trifluoromethylthiolating reagent. Both terminal aliphatic alkynes with linear and cyclic alkane as substituents (34a-34c) were suitable in this transformation leading to the products as a mixture of E:Z isomers, the Z-isomer being the major one.

Scheme 16 Hydrotrifluoromethylthiolation of terminal alkynes under visible-light photoredox-catalysis. E:Z ratios are given in parenthesis and were determined by 19 F NMR. Only the major isomer was depicted. dF-ppy= 2-(2,4-difluorophenyl)pyridine.

One year after, in the course of their study concerning the synthesis of functionalized allylic gemdifluorides, Zhao and co-workers proposed an elegant synthetic pathway to gemtrifluoromethylthiolated disubstituted alkenes via a catalytic fluorinative Meyer-Schuster-like rearrangement, using the saccharin derivative XIII as the trifluoromethylthiolating reagent (Scheme 17). 38 In the presence of XIII, HBF4•OEt2 and using a catalytic amount of a symmetric aryl sulfide, the functionalization of α-fluorinated alkynes afforded the corresponding 1,1-disubstituted SCF3-containing alkenes 37a-37c in good to high yields (3 examples, up to 89% yield).

Scheme 17 Diarylsulfide-catalyzed synthesis of trifluoromethylthiolated 1,1-disubstituted alkenes via a Meyer-Schuster-like rearrangement.

Finally, in 2020, the group of Xu reported the synthesis of the 1,2-disubstituted trifluoromethylthiolated compounds starting from epoxides and AgSCF3 in the presence of n-Bu4NI and KI (Scheme 17). 39 The functionalization of a large panel of aliphatic and aromatic epoxides was smoothly achieved. Note that in the case of aromatic epoxides, a better selectivity towards the E-isomer was generally observed (39a), while an almost 1:1 mixture was obtained with aliphatic epoxides (39b-39e). Among the latter compounds, worth to mention that both Oand N-substituted alkyl epoxides were suitable substrates providing the corresponding products in 67% yield and 74% yield, respectively. These conditions also allowed the preparation of natural product derivatives such as the functionalized tyrosine 39e in a good yield.

Scheme 17 Trifluoromethylthiolation of epoxides using AgSCF3. E:Z ratios are given in parenthesis and were determined by 19 F NMR. Only the major isomer was depicted.

Conclusion

In summary, this Short Review provides an overview of the major advances made to access 1,2-and 1,1-disubstituted trifluoromethylthiolated alkenes. Taking benefit from a myriad of SCF3-containing sources (both nucleophilic and electrophilic reagents), a panel of original methodologies was developed starting from diverse classes of compounds. Note that in contrast with 1,2-disubstituted SCF3containing alkenes, the trifluoromethylthiolation of 1,1-disubstituted alkenes is still challenging, often restricted to the functionalization of acrylate or electron-rich styrene derivatives and the design of new approaches is of high demand. In addition, the quest for additional modern synthetic solutions towards the preparation of this class of compounds involving for instance, electrochemistry and photocatalyzed reactions will definitively be an asset. Appealing for the organofluorine chemistry research field, this ShortReview will have a strong impact on both academia and industry by providing an overview of original disconnections to access trifluoromethylthiolated disubstituted olefins. We do believe that this Short Review will be inspiring for further developments in a near future regarding the synthesis of trifluoromethylthiolated alkenes, extending further the chemical space of these fluorinated molecules and potentially giving access to new lead compounds.

Figure 1 A

 1 Figure 1 A: Selected examples of bioactive derivatives possessing a 1,2-disubstituted alkene pattern. B: Key compounds containing a 1,2-disubstituted trifluoromethylthiolated alkene.

Scheme 4

 4 Scheme 4 Trifluoromethylthiolation using the Munavalli reagent V. bpy = 2,2'-bipyridine. a Using Rueping's conditions. b Using Shen's conditions.

Scheme 9

 9 Scheme 9 Trifluoromethylthiolation using CuSCF3 or [Bu4N][SCF3] as nucleophilic SCF3-sources. a Using method A. b Using method B. c Reaction was carried out at 25 °C for 3 h. d Reaction was carried out at 25 °C for 24 h.

Acknowledgements

This work has been partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM), and by Region Normandie. E.N. and T.B. thank the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 758710). E.N. thanks the Region Normandy for a doctoral fellowship.

Funding Information

We thank Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM), and by Region Normandie. D.D. and T.B. thank the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 758710). J.F. thanks the Fondation de la Maison de la Chimie for the financial support (no 212420).


Fabien Petit-Cancelier

Samuel Couve-Bonnaire

Tatiana Besset
email: tatiana.besset@insa-rouen.fr

Synthesis of a Library of SCF2CO2Et Reagents: An Access To Original (Ethoxycarbonyl)difluoromethylthioesters

Keywords: Difluoromethylthioester derivatives, Fluorine chemistry, Radical process, Mild reaction conditions, Aldehydes

A library of original and shelf-stable reagents, source of the (ethoxycarbonyl)difluoromethylthio group, is reported. These reagents are applied to the functionalization of a large panel of aldehydes via a transition metal-free protocol under mild reaction conditions. This approach offers an efficient access to valuable difluoromethylthioester derivatives.

Introduction

Over the years, the organofluorine chemistry field became a compulsory research area as fluorinated compounds are of paramount importance in material science, pharmaceutical and agrochemical industries. 1 Indeed, thanks to the specific properties of the fluorine atom and the fluorinated groups, their presence on a molecule generally modulate its physico-chemical and biological properties, offering an efficient tool for the discovery of compounds of interest. 2 Therefore, the development of original strategies to expand the portfolio of original fluorinated molecules is of major concern. 3 Over the year, a special attention was paid to fluorinated groups such as SCF3 and SCF2H groups, 4 thanks to their unique properties such as a strong withdrawing character and interesting lipophilicity (Hansch parameter πR = 1.44 and 0.68, respectively). 5 More recently, the design of original SCF2FG groups (FG = CO2R, (R = Me, Et), PO(OEt)2, SO2Ph) has aroused the interest of the scientific community, as the physico-chemical properties of the molecules bearing such fluorinated groups might be fine-tuned. 6 Among them, the SCF2CO2R residue was recently studied and, thanks to the remarkable contributions of Shen 7 and Billard 8 who independently designed electrophilic reagents, its incorporation onto various molecules became possible. Besides, considerable attention was paid to fluorinated thioesters, 4f,4g,6b-d especially trifluoromethylthioesters. These later were synthesized by the direct introduction of the SCF3 group onto acid chlorides, 9 aldehydes 10 or carboxylic acids. 11 In contrast, methods for the synthesis of difluoromethylthioesters remain limited. In 2018, Wang developed a new methodology for the difluoromethylthiolation of aldehydes using the PhSO2SCF2H reagent 6b in the presence of di-tert-butyl peroxide (TBHP, (Scheme 1, eq. a). 12 The same year, taking benefit from the versatility of the PhSO2SRf (Rf = CF3, CH2F, CF2H and CF2CF3) reagent, Shen reported the synthesis of various fluorinated thioesters (Scheme 1, eq. b). 10b More recently, the group of Hopkinson developed an access to difluoromethylthioesters starting from carboxylic acids and the BT-SCF2H reagent (BT = benzothiazolium) (Scheme 1, eq.c). 11b Then, a visible light-mediated synthesis of difluoromethylthioesters was depicted by the group of Wang using the tetrabutylammonium decatungstate (TBADT) photocatalyst with the PhSO2SCF2H reagent under oxidant-free reaction conditions (Scheme 1, eq. d). 13 Finally, our group developed a methodology for the direct introduction of the SCF2PO(OEt)2 moiety onto aldehydes with the TolSO2SCF2PO(OEt)2 reagent (Scheme 1, eq. e). 14 Despite these recent advances, the preparation of difluoromethylthioesters was restricted to few examples related to the incorporation of the SCF2H, SCF2CF3 and SCF2PO(OEt)2 motifs onto molecules and the quest for original tools to access novel fluorinated thioesters is really appealing. Herein, we report a straightforward methodology for the synthesis of original (ethoxycarbonyl)difluoromethyl-thioesters via a radical process. In that purpose, a library of reagents was synthesized and the direct introduction of the SCF2CO2Et moiety onto readily available aldehydes was then investigated. Scheme 1. State of the Art: Approaches for the synthesis of difluoromethylthioesters. TBHP = di-tert-butyl peroxide; PIFA = (bistrifluoroacetoxy)iodobenzene; BT = benzothiazolium; TBADT = tetrabutylammonium decatungstate.

Results and Discussion

At the outset of this study, we explored the synthesis of the ((ethoxycarbonyl)difluoromethyl)benzenesulfonothioate 2a. We imagined that this latter might be prepared starting from sodium benzenesulfinate and a suitable electrophilic SCF2CO2Et-containing source. Indeed, when the sodium benzenesulfinate 1a was reacted with the (ethoxycarbonyl)difluoromethylsulfenamide I in presence of para-toluene sulfonic acid monohydrate, 2a was isolated in 91% yield. 15 Note that the synthesis of the new reagent I employed in this transformation was successfully achieved following the procedure previously described by the group of Billard. 8 With these preliminary results in hand, we examined the scope of the reaction. It turned out that the transformation was versatile as a library of original SCF2CO2Et reagents was obtained starting from various sodium arylsulfinates 1 (Scheme 2). Scheme 2. (Ethoxycarbonyl)difluoromethylthiolation of sodium sulfinates 1. Reaction conditions: Sodium sulfinate 1 (0.2 mmol, 1 equiv.), I (0.24 mmol, 1.2 equiv.), pTSA . H2O (1 mmol, 5.0 equiv.), CH2Cl2 (0.08 M), 22 °C, 15 h, argon. a The reaction was carried out using 4.1 mmol of 1e.

Pleasingly, several sodium arylsulfinates reacted well with the reagent I to give the desired difluoromethylated arylsulfonothioates 2. Sodium benzenesulfinate (1a) and sodium naphthalenesulfinate (1b) turned out be suitable substrates in this transformation. When arylsulfinates substituted at the para position with electron-donating groups (1c-1d) were reacted with I, the expected products (2c-2d) were obtained in high yields. The functionalization of arylsulfinates bearing halogens (1e-1f) and electron-withdrawing groups (1g-1i) went smoothly. Worth to mention that the transformation was tolerant to the presence of several functional groups such as cyano (1h), ketone (1i) and halogens (1e and 1f), an asset for post-functionalization reactions. The reaction with the sodium 4chlorobenzene sulfinate (1e) was successfully scaled up from 0.2 mmol to 4.1 mmol, giving the expected product 2e in an excellent 98% yield. Finally, the functionalization of 1j and 1k went smoothly, suggesting that the substitution pattern of the arene did not have a significant impact on the outcome of the reaction.

Then, we focused on the synthesis of (ethoxycarbonyl)difluoromethylthioesters 4. Pleasingly, when the benzaldehyde 3a was reacted with the reagent 2a in the presence of PIFA and sodium azide, the expected product 4a was obtained in a promising 56% yield (table 1, entry 1). To further optimize the reaction conditions, we wondered whether the electronic properties of the reagent 2 might have an influence on the outcome of the reaction (Table 1), the PhSO2SRf or TolSO2SRf being the most common reagents used in these transformations. 6b When the reagent 2c or the TolSO2SCF2CO2Et 2d were used, 4a was obtained in encouraging 76% and 64% yields, respectively (Table 1, entries 2 and3). In contrast, the reagent 2g turned out to be much less efficient providing 4a in only 16% yield (Table 1, entry 4). Pleasingly, when the reaction was carried out with the reagent 2e (Table 1, entry 5), 4a was isolated in 93% yield, and we pursued our investigations using 2e as the coupling partner. Reaction conditions: 3a (0.2 mmol, 1 equiv.), 2 (0.3 mmol, 1.5 equiv.), PIFA (0.4 mmol, 2 equiv.), NaN3 (0.4 mmol, 2 equiv.), EtOAc (0.4 M), 3 h, argon.

Scheme 3. Functionalization of aldehydes using the reagent 2e. Reaction conditions: 3 (0.2 mmol, 1 equiv.), 2e (0.3 mmol, 1.5 equiv.), PIFA (0.4 mmol, 2 equiv.), NaN3 (0.4 mmol, 2 equiv.), EtOAc (0.4 M), 22 °C, 3 h, argon.

With the best reaction conditions in hand, we next investigated the scope of the reaction with various aldehydes (Scheme 3). Pleasingly, the (ethoxycarbonyl)difluoromethylthiolation of a myriad of aldehydes including (hetero)aromatic and aliphatic aldehydes was achieved. Indeed, benzaldehyde (3a) and naphthaldehyde (3b) were smoothly functionalized, leading to the corresponding products (4a) and (4b) in 93% yield and 80% yield, respectively. Aromatic aldehydes bearing an electron-donating group (3c), halogen (3d) and electron-withdrawing groups, such as CF3 (3e) and ester (3f) at the para position were suitable substrates, the reaction being more efficient with electron-enriched compounds. When the 3-bromobenzaldehyde (3g) and the 2-methylbenzaldehyde (3h) reacted with 2e, the expected products were obtained in 59% and 73% yields, respectively. The reaction using the 3,4-dimethoxybenzaldehyde (3i) proceeded also smoothly with a high yield. Gratifyingly, heteroaromatic and aliphatic substrates such as the indole-3-carboxaldehyde (3j) and the cyclohexanecarboxaldehyde (3k) were also well converted to the corresponding products (4j and 4k) with moderate to good yields.

In order to get a better understanding of the reaction mechanism, radical-trapping experiments were carried out. When the reaction was carried out under standard reaction conditions in the presence of 2 or 4 equivalents of TEMPO (2,2,6,6-tetramethy-l-piperidinyloxy), no expected product 4a was detected and the TEMPO-adduct was observed in GC-HRMS. 16 These results suggested that a radical process might be involved and based on the literature data, 12,13,14,17 a possible acyl radical might be generated from 3 in the presence of PIFA and NaN3, which would then react with the reagent 2e to afford the expected compound 4.

Conclusion

In summary, we successfully synthesized a library of [(ethoxycarbonyl)difluoromethyl]arylsulfonothioate reagents (11 examples, up to 98% yield). These latter were applied to the (ethoxycarbonyl)difluoromethylthiolation of aldehyde derivatives. We demonstrated that the nature of the substituents on these reagents has a strong impact on the efficiency of the transformation.

Hence, a straightforward synthetic route to (ethoxycarbonyl)difluoromethylthioesters was developed, affording the expected products in moderate to excellent yields (11 examples, up to 93% yield). Worth mentioning that this transition metal-free transformation was tolerant to halogens and functional groups such as ester. This approach offers an efficient and operationally simple tool for the construction of SCF2CO2Et-containing molecules We do believe that this library of reagents will expand the portfolio of SCF2CO2Et-containing reagents and will, beyond doubt, open new avenues towards the synthesis of high-value added SCF2CO2Et-containing molecules.

Experimental section

Material and instrumentation

All reactions were carried out using oven-dried glassware and magnetic stirring under argon unless otherwise stated. Reaction temperatures are reported as the temperature of the bath surrounding the vessel unless otherwise stated. Analytical thin layer chromatography was performed on silica gel aluminum plates with F-254 indicator and visualized by UV light (254 nm) and/or chemical staining with a KMnO4 solution. Flash column chromatography was performed using 0.040 -0.063 nm silica gel. Reverse-phase chromatography was performed on InterchimS215 with Nacheray Magel PFP 21 × 250 mm as a column system. 1 H NMR spectra were recorded on a Bruker DXP 300 MHz spectrometer at 300.1 MHz, 13 C NMR spectra at 75.5 MHz, 19 F NMR spectra at 282.4 MHz. Chemical shifts (δ) are quoted in ppm relative to TMS ( 1 H) and CFCl3 ( 19 F). Coupling constants (J) are quoted in Hz. The following abbreviations were used to show the multiplicities: bs: broad singlet, s: singlet, d: doublet, t: triplet, q: quadruplet, dd: doublet of doublet, td, triplet of doublet and m: multiplet. The residual solvent signals were used as references (CDCl3: δH = 7.26 ppm, δC = 77.00 ppm or relative to external CFCl3, δF = 0 ppm). High-resolution mass spectrometry (HRMS) were recorded on a Waters LCT Premier spectrometer with a micro-TOF analyzer. IR spectra were recorded on a PerkinElmer Spectrum 100, the wave numbers (υ) of recorded IR-signals (ATR) are quoted in cm -1 .

Aniline was distillated over CaH2. Ethyl acetate (EtOAc) and dichloromethane (CH2Cl2) were purified by distillation over CaH2 and stored over Molecular Sieves (3Å). The sodium sulfinates 1b, 1h and 1j were synthesis according the to the litterature. 15 The reagent I was prepared according to the litterature procedure. 8 2. General Experimental Procedures:

General procedure for the synthesis of ethyl 2,2-difluoro-2-[(phenylamino)sulfanyl)]acetate I:

The procedure was adapted from a previously reported procedure. 8 To a solution of DIPEA (3.4 mL, 19.8 mmol, 1.1 equiv.) in CH2Cl2 (36 mL), DAST (2.6 mL, 19.8 mmol, 1.1 equiv.) was slowly added under argon at -25 °C during 20 min. Then, TMSCF2CO2Et (3.4 mL, 18 mmol, 1 equiv.) was slowly added and the reaction mixture was stirred for 1.5 h at 25 °C. Once the aniline (1.6 mL, 18 mmol, 1 equiv.) was added, the reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted in 100 mL of water and the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The combined organic phases were washed with an aqueous saturated NaCl solution (100 mL), dried under Na2SO4, filtered and concentrated under reduce pressure. Purification of the crude reaction mixture by flash column chromatography on silica gel (height 15 cm, width 8 cm, pentane/diethyl ether = 95:5) afforded the desired product I (2.3 g, 52 %).

General procedure for the synthesis of the derivatives 2:

The procedure was adapted from a previously reported procedure. 15a The reagent I (60 mg, 0.24 mmol, 1.2 equiv.), sodium sulfinate 1 (0.2 mmol, 1 equiv.) and pTSA.H2O (190 mg ,1 mmol, 5 equiv.) were charged in an oven-dried 10 mL tube equipped with a stirring bar and filled under argon. Then, 2.5 mL of distilled dichloromethane was added, and the resulting mixture was stirred at 25 °C for 16 h. The reaction completion was checked by 19 F NMR and then the reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to afford the product 2.

General procedure for the synthesis of the derivatives 4:

The aldehyde 3 (0.2 mmol, 1 equiv.) was charged in an oven-dried 10 mL tube equipped with a stirring bar and filled under argon followed by the reagent 2 (99.3 mg, 0.3 mmol, 1.5 equiv.), PIFA (172.0 mg, 0.4 mmol, 2 equiv.) and freshly distilled ethyl acetate (0.8 mL). Then, NaN3 (26.8 mg, 0.4 mmol, 2 equiv.) was finally introduced. The reaction mixture was stirred at 22 °C for 3 h before removing the solvent under reduced pressure. The crude mixture was directly purified by flash column chromatography on silica gel to afford the desired product 4.

Physical and spectral data

Ethyl 2,2-difluoro-2-[(phenylamino)sulfanyl]-acetate I: Rf (Petroleum ether/EtOAc=90/10): 0.41. 1 H NMR (300.1 MHz, CDCl3) δ 7.31 -7.29 (m, 2H), 7.09 -7.03 (m, 2H), 6.97 -6.90 (m, 1H), 5.04 (bs, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -92.9 (s). 13 C NMR (75.5 MHz, CDCl3) δ 161.8 (t, J = 31.9 Hz), 145. 5,129.0,121.2,120.0 (t,J = 289.8 Hz),114.9,63.6,13.4. IR (neat, cm -1 ) υ: 3366,2987,1752,1600,1495,1373,1283,1227,1102,1012,917,855,749,691,596. HRMS (API + ) for C10H12NO2F2S m/z 248.0557 [M+H] + , Found 248.0547 (Δ = -4.0 ppm).

S-(Ethoxycarbonyl)difluoromethyl-benzenesulfonothioate 2a:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2a as a colorless oil (54.1 mg, 91%). Rf (Petroleum ether/EtOAc=90/10): 0.51. 1 H NMR (300.1 MHz, CDCl3) δ 7.99 (d,J = 7.9 Hz,2H),1H),2H), 4.37 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.9 (s). 13 C NMR (75.5 MHz, CDCl3) δ 160.0 (t, J = 31.0 Hz), 145. 1,134.8,129.4,127.5,119.2 (t,J = 294.5 Hz),64.7,13.7. IR (neat, cm -1 ) υ: 2988,1772,1582,1449,1352,1294,1152,1078,1013,969,714,577. HRMS (ESI + ) calcd for C10H10F2O4S2K m/z 334.9626 [M+K] + , Found 334.9634 (Δ = 2.4 ppm).

S-(Ethoxycarbonyl)difluoromethyl-2-naphtalene-sulfonothioate 2b:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2b as a colorless oil (33.1 mg, 47%). Rf (Petroleum ether/EtOAc=90/10): 0.54. 1 H NMR (300.1 MHz, CDCl3) δ 8.56 (s, 1H), 8.07 -7.90 (m, 4H), 7.77 -7.62 (m, 2H), 7.25 -7.18 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -81.0 (s). 13 C NMR (75.5 MHz, CDCl3) δ 160.1 (t,J = 31.2 Hz),141.9,135.6,131.8,130.1,129.9,129.9,129.8,128.1,128.1,121.9,119.2 (t,J = 294.5 Hz),64.7,13.7. IR (neat, cm -1 ) υ: 2926,1772,1338,1291,1151,1067,811,746,650,564. HRMS (ESI + ) calcd for C14H16NF2O4S2 m/z 364.0489 [M+NH4] + , Found 364.0501 (Δ = 3.3 ppm)

S-(Ethoxycarbonyl)difluoromethyl-4-methoxybenzene-sulfonothioate 2c:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2c as a colorless oil (53.5 mg, 82%). Rf (Petroleum ether/EtOAc=90/10): 0.48. 1 H NMR (300.1 MHz, CDCl3) δ 7.91 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.1 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -81.4 (s). 13 C NMR (75.5 MHz, CDCl3) δ 164. 6,160.2 (t,J = 31.2 Hz),136.8,130.2,119.2 (t,J = 293.7 Hz),114.5,64.6,55.9,13.8. IR (neat, cm -1 ) υ: 2986,1771,1591,1496,1347,1264,1142,1016,833,658,570. HRMS (API + ) calcd for C11H13O5F2S2 m/z 327.0172 [M+H] + , Found 327,0173 (Δ = 0.3 ppm).

S-(Ethoxycarbonyl)difluoromethyl-4-methylbenzene-sulfonothioate 2d:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2d as a colorless oil (53.9 mg, 83%). Rf (Petroleum ether/EtOAc=90/10): 0.45. 1 H NMR (300.1 MHz, CDCl3) δ 7.87 (d,J = 8.4 Hz,2H),7.38 (d,J = 8.6 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -81.1 (s). 13 C NMR (75.5 MHz, CDCl3) δ 160.1 (t,J = 31.1 Hz),146.2,142.3,130.0,127.6,119.2 (t,J = 294.1 Hz),64.6,21.7,13.7. IR (neat, cm - 1 ) υ: 2980,1773,1593,1448,1294,1149,1015,971,812,700,650,572. HRMS (ESI + ) calcd for C11H12O4F2S2K m/z 348.8782 [M+K] + , Found 348.9793 (Δ = 3.2 ppm).

S-(Ethoxycarbonyl)difluoromethyl-4-chlorobenzene-sulfonothioate 2e:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2e as a colorless oil (58.2 mg, 87%) The reaction was also performed on 4.1 mmol scale starting from 794.4 mg of 1e leading to the corresponding product 2e (1.3 g, 98%). Rf (Petroleum ether/EtOAc=90/10): 0.37. 1 H NMR (300.1 MHz, CDCl3) δ 7.92 (d,J = 8.8 Hz,2H),7.56 (d,J = 8.8 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.8 (s). 13 C NMR (75.5 MHz, CDCl3) δ 159.9 (t,J = 30.8 Hz),143.5,141.6,129.8,129.1,119.2 (t,J = 294.8 Hz),64.8,13.7. IR (neat, cm -1 ) υ: 2927,1757,1571,1475,1348,1302,1157,1089,1010,826,752,561. HRMS (ESI + ) calcd for C10H13F2NO4S2Cl m/z 347.9943 [M+NH4] + , Found 347.9946 (Δ = 0.9 ppm).

S-(Ethoxycarbonyl)difluoromethyl-4-fluorobenzene-sulfonothioate 2f:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2e as a colorless oil (37.7 mg, 60%). Rf (Petroleum ether/EtOAc=90/10): 0.41. 1 H NMR (300.1 MHz, CDCl3) δ 8. 08 -7.95 (m, 2H), 7.31 -7.21 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.38 (t,J = 7.2 Hz,3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -81.0 (s), -101.1 (s). 13 C NMR (75.5 MHz, CDCl3) δ 167.7 (d,J = 259.1 Hz),160.0 (t,J = 30.9 Hz),141.1,130.8 (d,J = 9.9 Hz),119.2 (t,J = 294.6 Hz),116.8 (d,J = 23.1 Hz),64.8,13.7. IR (neat, cm -1 ) υ: 2989,1772,1588,1492,1354,1294,1241,1146,970,838,656,571. HRMS (ESI + ) calcd for C10H13NF3O4S2 m/z 332.0238 [M+NH4] + , Found 332.0234 (Δ = -1.2 ppm).

S-(Ethoxycarbonyl)difluoromethyl-4-trifluoromethyl-benzenesulfonothioate 2g:

Purification by flash chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2g as a colorless oil (50.3 mg, 69%). Rf (Petroleum ether/EtOAc=90/10): 0.32. 1 H NMR (300.1 MHz, CDCl3) δ 8.13 (d,J = 8.3 Hz,2H),7.86 (d,J = 8.4 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.38 (t,J = 7.1 Hz,3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -63.8 (s), -80.4 (s). 13 C NMR (75.5 MHz, CDCl3) δ 159.8 (t,J = 30.7 Hz),148.2,136.2 (q,J = 33.4 Hz),128.2,126.7 (q,J = 3.7 Hz), 122.9 (q, J = 273.4 Hz), 119.2 (t,J = 295.4 Hz),65.0,13.7. IR (neat, cm -1 ) υ: 3107,2996,1761,1407,1350,1303,1210,1123,1059,1012,847,709,549 (t,J = 30.5 Hz),148.5,133.3,128.2,119.2 (t,J = 295.8 Hz),118.4,116.7,65.0,13.8. IR (neat, cm -1 ) υ: 2987,2237,1772,1355,1288,1154,1015,967,837,570. HRMS (API -) calcd for C11H9F2NO4S2 m/z 320.9941 [M] -, Found 320.9946 (Δ = 1.6 ppm).

S-(Ethoxycarbonyl)difluoromethyl-4-acetyl-benzene-sulfonothioate 2i:

Purification by reverse flash column chromatography (35 g column, 50 mL/min, H2O/MeCN=50/50 until H2O/MeCN=0/100) afforded 2i as a colorless oil (48.7 mg, 72%). Rf (Petroleum ether/EtOAc=90/10): 0.45. 1 H NMR (300.1 MHz, CDCl3) δ 8.17 -8.04 (m, 4H), 4.39 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.5 (s). 13 C NMR (75.5 MHz, CDCl3) δ 196.3, 159.9 (t, J = 30.9 Hz), 148. 4,141.3,129.2,128.0,119.2 (t,J = 295.4 Hz),64.9,27.0,13.8. IR (neat, cm -1 ) : 2925,1775,1692,1652,1399,1352,1260,1155,965,833,594. HRMS (API -) calcd for C12H12F2O5S2Cl m/z 372.9783 [M+Cl] -, Found 372.9781 (Δ = -0.5 ppm). 0,146.1,130.4,121.6,119.7,119.2 (t,J = 294.4 Hz),111.7,64.7,55.8,13.8. IR (neat, cm -1 ) υ: 2943,1772,1596,1480,1289,1244,1139,969,851,783,677,608. HRMS (ESI + ) calcd for C11H16NO5F2S2 m/z 344.0438 [M+NH4] + , Found 344.0448 (Δ = 2.9 ppm).

S-(Ethoxycarbonyl

S-(Ethoxycarbonyl)difluoromethyl-2-iodobenzene-sulfonothioate 2k:

Purification by reverse flash column chromatography (35 g column, 50 mL/min, H2O/MeCN=50/50 until H2O/MeCN=0/100) afforded 2k as a colorless oil (66.7 mg, 79%). Rf (Petroleum ether/EtOAc=90/10): 0.38. 1 H NMR (300.1 MHz,2H),1H),7.31 (td,J = 7.7 Hz and J = 1.5 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.38 (t,J = 7.1 Hz,3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.9 (s). 13 C NMR (75.5 MHz, CDCl3) δ 160.1 (t,J = 31.0 Hz),146.3,143.1,135.0,130.9,128.8,119.2 (t,J = 294.9 Hz),92.7,64.7,13.8. IR (neat, cm -1 ) υ: 2988,1770,1566,1446,1350,1298,1156,1011,968,759,579. HRMS (ESI + ) calcd for C10H10O4F2S2I m/z 422.9033 [M+H] + , Found 422.9024 (Δ = -2.1 ppm).

S-(Ethoxycarbonyl)difluoromethylbenzothioate 4a:

Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=95/05) afforded 4a as a colorless oil (48.4 mg, 93%). Rf (Petroleum ether/EtOAc=90/10): 0.35. 1 H NMR (300.1 MHz, CDCl3) δ 7.89 -7.82 (m, 2H), 1H),2H),4.43 (q,J = 7.1 Hz,2H),1.38 (t,J = 7.1 Hz,3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -85.8 (s). 13 C NMR (75.5 MHz, CDCl3) δ 187.3 (t, J = 3.5 Hz), 161.2 (t, J = 30.9 Hz), 135.2 (t, J = 2.9 Hz), 134.9,129.1,127.6,120.4 (t,J = 284.9 Hz),64.1,13.8. IR (neat, cm -1 ) υ: 2987,2130,1767,1683,1583,1450,1372,1301,1210,1131,1026,894,772,683. HRMS (CI + ) calcd for C11H11F2O3S m/z 261.0397 [M+H] + , Found 261.0405 (Δ = 3.2 ppm). (t,J = 30.9 Hz),136.3,132.4 (t,J = 2.8 Hz),132.2,129.8,129.7,129.4,129.1,127.9,127.4,122.5,120.5 (t,J = 284.9 Hz),64.1,13.8. IR (neat, cm -1 ) υ: 2986, 1766, 1681, 1626, 1466, 1370, 1300,

S-(Ethoxycarbonyl

  )difluoromethyl-3-methoxybenzene-sulfonothioate 2j: Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=90/10) afforded 2j as a colorless oil (45.7 mg, 70%). Rf (Petroleum ether/EtOAc=90/10): 0.53. 1 H NMR (300.1 MHz, CDCl3) δ 7.61 -7.55 (m, 1H), 7.53 -7.44 (m, 2H), 7.25 -7.18 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.89 (s, H), 1.38 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.8 (s). 13 C NMR (75.5 MHz, CDCl3) δ 160.1 (t, J = 31.0 Hz), 160.

  )difluoromethyl-2-naphtothioate 4b: Purification by flash column chromatography (height: 15 cm, width: 3 cm, pentane/diethyl ether=95/05) afforded 4b as a colorless oil (49.6 mg, 80%). Rf (Petroleum ether/EtOAc=90/10): 0.38. 1 H NMR (300.1 MHz, CDCl3) δ 8.42 (s, 1H), 8.01 -7.80 (m, 4H), 7.70 -7.51 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -85.6 (s). 13 C NMR (75.5 MHz, CDCl3) δ 187.1 (t, J = 3.2 Hz), 161.3

Table 1 .

 1 Study of the influence of the nature of the reagents 2 on the (ethoxycarbonyl)difluoromethylthiolation of the aldehyde 3a

	Entry	R	Yield (%)
	1	H (2a)	56
	2	OMe (2c)	76
	3	Me (2d)	64
	4	CF3 (2g)	16
	5	Cl (2e)	93

  . HRMS (API -) calcd for m/z 398.9551 [M+Cl] -, Found 398.9550 (Δ = -0.3 ppm). Petroleum ether/EtOAc=90/10): 0.35. 1 H NMR (300.1 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 19 F{ 1 H} NMR (282.4 MHz, CDCl3) δ -80.2 (s). 13 C NMR (75.5 MHz, CDCl3) δ 159.7

	S-(Ethoxycarbonyl)difluoromethyl-4-cyanobenzene-sulfonothioate 2h: Purification by reverse flash chromatography
	(35 g column, 50 mL/min, H2O/MeCN=50/50 until H2O/MeCN=0/100) afforded 2h as a colorless oil (32.0 mg, 50%).
	Rf (

Acknowledgements

This work has been partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM), and by Region Normandie. F.P.-C. and T.B. thank the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 758710). F.P.-C. thanks the Region Normandy for a doctoral fellowship.


Pierre Gay

Bastien Genet

Audrey Rouet

Rana Alkouri

Judith Cohen-Bittan

Boddaert Jacques

Dr Lorène Zerah
email: lorene.zerah@aphp.fr

BLOOD TRANSFUSION AND DELAYED SURGERY ASSOCIATED WITH POSTOPERATIVE ATRIAL FIBRILLATION IN OLDER PATIENTS WITH HIP FRACTURE IN A DEDICATED ORTHOGERIATRIC CARE PATHWAY: A NESTED CASE-CONTROL STUDY

Keywords: arrhythmia, orthopedic surgery, geriatrics

Background Few data are available regarding post-operative atrial fibrillation (POAF) in noncardiothoracic surgery, particularly orthopedic surgery. Hence, given the frequent incidence of POAF after surgery and its marked impact, we need to identify modifiable risk factors associated with POAF after hip fracture surgery in older patients.

Methods

We conducted a nested case-control study in the unit for perioperative geriatric care of an academic hospital in Paris from July 1, 2009 to December 31, 2019, enrolling all consecutive patients aged ≥ 70 years with hip fracture surgery and no history of permanent atrial fibrillation before admission. Patients with and without POAF were matched 1:5 on 5 baseline characteristics (age, hypertension, diabetes, coronary artery disease, cardiac failure).

Results

Of the 757 patients included, 384 were matched, and 64 had POAF. The incidence of POAF was 8.5%. The mean age was 86 ± 6 years, 298 (78%) patients were female, and the median Charlson Comorbidity Index was 6 (interquartile range IQR 4-8). The median time between surgery and the occurrence of POAF was 2 days (1-4). On multivariable logistic regression analysis (matched cohort), the modifiable factors present at admission associated with POAF were time to surgery greater than 48 hr (odds ratio OR= 1.66, 95% Confidence interval ) and more than 2 transfusions of packed red blood cells (OR = 3.94,).

Conclusions This study provides new information about POAF in older patients with hip fracture surgery, a surgical emergency whose complexity requires multidisciplinary care.

INTRODUCTION

Hip fracture, with the total number of cases increasing in line with the ageing population, is a major public health concern associated with poor vital and functional outcomes. [START_REF] Berry | Hip fractures in older adults in 2019[END_REF][START_REF] Brauer | Incidence and mortality of hip fractures in the United States[END_REF][START_REF] Hannan | Mortality and locomotion 6 months after hospitalization for hip fracture: risk factors and risk-adjusted hospital outcomes[END_REF] In parallel, atrial fibrillation (AF), the most common sustained cardiac arrhythmia in adults, is particularly common in older patients,(4) reaching 10% in patients over 80 years of age. [START_REF] Go | Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study[END_REF] An increase in the number of surgical populations among older people over the last decade has increased the overall prevalence of postoperative AF (POAF), defined as new-onset AF in the immediate postoperative period: 20% to 50% of patients after cardiac surgery and 10% to 30% after non-cardiac thoracic surgery.(4) POAF, whose usual peak of incidence is between day 2 and 4 postoperatively,( 6) is associated with numerous complications such as cardioembolic stroke, acute coronary syndrome, and acute heart failure, with an impact on in-hospital mortality, length of hospital stay and medical health costs. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Subramaniam | Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial[END_REF][START_REF] Lin | Perioperative/Postoperative Atrial Fibrillation and Risk of Subsequent Stroke and/or Mortality[END_REF][START_REF] Bhave | Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery[END_REF] Several studies, largely focused on POAF after cardiothoracic surgery, identified triggering factors including baseline characteristics (age, male sex, hypertension, chronic heart failure, ischemic heart disease, chronic kidney disease), and perioperative and postoperative complications (hypovolemia, electrolyte disorders, hypoxemia). [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Dobrev | Postoperative atrial fibrillation: mechanisms, manifestations and management[END_REF][START_REF] Bhave | Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery[END_REF][START_REF] Rostagno | Postoperative atrial fibrillation is related to a worse outcome in patients undergoing surgery for hip fracture[END_REF][START_REF] Leibowitz | Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture[END_REF][START_REF] Bessissow | Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview[END_REF] However, few data are available regarding POAF after noncardiothoracic surgery, particularly emergent orthopedic surgery. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Subramani | Incidence, Risk Factors, and Outcomes of Perioperative Atrial Fibrillation following Noncardiothoracic Surgery: A Systematic Review and Meta-Regression Analysis of Observational Studies[END_REF] Hence, given the frequent incidence of POAF after surgery and its marked impact, we need to identify risk factors, particularly modifiable risk factors, associated with POAF after orthopedic surgery. We previously demonstrated that optimizing patient care by improving the management of peri-operative factors and thus decreasing postoperative complications could reduce by a maximum of one quarter the 6-month mortality rate after hip fracture. [START_REF] Zerah | Attributable Mortality of Hip Fracture in Older Patients: A Retrospective Observational Study[END_REF] Identifying the modifiable factors associated with the occurrence of POAF in a population with multimorbidity and polypharmacy would be an essential step that could indicate the future directions for care improvement.

Our primary objective was to identify the modifiable acute risk factors (triggers) or protective factors associated with the occurrence of POAF in older patients with hip fracture surgery in a dedicated orthogeriatric pathway.

MATERIAL AND METHODS

The database was declared to the French National Commission on Computing and Liberty (CNIL) of the Assistance Publique-Hôpitaux de Paris (APHP) for this study (no.

20190822165316

). This report follows the STROBE recommendations (eMethods 1 in the Supplement).( 15)

Study design, study setting and eligibility criteria

A nested case-control study was conducted in the unit for perioperative geriatric care of an academic hospital. The unit for perioperative geriatric care is part of a dedicated orthogeriatric care pathway including coordination between the department of emergency medicine and surgery, department of anaesthesiology and critical care, department of orthopaedic surgery and department of rehabilitation. This dedicated orthogeriatric care pathway is defined as 1) an early alert from the emergency department (ED), 2) considering hip fracture as requiring surgery as soon as feasible (i.e., 24 hr/day), 3) rapid transfer to the unit for perioperative geriatric care after surgery, and 4) rapid transfer of stable patients to a dedicated rehabilitation unit. [START_REF] Boddaert | Postoperative admission to a dedicated geriatric unit decreases mortality in elderly patients with hip fracture[END_REF][START_REF] Boddaert | Perioperative management of elderly patients with hip fracture[END_REF] The management strategy in this unit for perioperative geriatric care, previously described [START_REF] Boddaert | Postoperative admission to a dedicated geriatric unit decreases mortality in elderly patients with hip fracture[END_REF], focused on early mobilization with the aim of chair-sitting and walking within 24 and 48 hr after arrival, respectively; pain management; the provision of air-filled mattresses for patients with pressure sores or at high risk of pressure sores; swallowing disorders detected using a systematic medical survey; detection of stool impaction and urinary retention using bedside ultrasonography; correction of anemia with transfusion of packed red blood cells (usually when haemoglobin level is <8 g.L -1 ); and detection of delirium, AF and malnutrition.

From July 1, 2009 to December 31, 2019, all consecutive patients with hip fracture admitted to the unit for perioperative geriatric care were evaluated for eligibility. Patients were included if they were ≥70 years old and their primary presentation was hip fracture (first hospitalization after surgery in the unit for perioperative geriatric care). We excluded patients with multiple or metastatic or periprosthetic fractures, a history of permanent AF before admission in the unit for perioperative geriatric care, post-operative supraventricular arrhythmia other than AF; and missing data (missing anesthesia records, missing data from the ED, no electrocardiogram before admission in the unit for perioperative geriatric care). Patients were followed until death or the end of hospitalization in the unit for perioperative geriatric care. Some patients had been included in previous studies. [START_REF] Zerah | Attributable Mortality of Hip Fracture in Older Patients: A Retrospective Observational Study[END_REF][START_REF] Boddaert | Postoperative admission to a dedicated geriatric unit decreases mortality in elderly patients with hip fracture[END_REF][START_REF] Boddaert | Perioperative management of elderly patients with hip fracture[END_REF][START_REF] Vallet | Prognostic Value of Serum Procalcitonin After Orthopedic Surgery in the Elderly Population[END_REF][START_REF] Zerah | Retrospective evaluation of a restrictive transfusion strategy in older adults with hip fracture[END_REF][START_REF] Boddaert | Prediction of postoperative mortality in elderly patients with hip fracture: are specific and geriatric scores better than general scores?[END_REF][START_REF] Vallet | Isolated cardiac troponin rise does not modify the prognosis in elderly patients with hip fracture[END_REF][START_REF] Magny | Pressure ulcers are associated with 6-month mortality in elderly patients with hip fracture managed in orthogeriatric care pathway[END_REF][START_REF] Zerah | Association between Cognitive Status before Surgery and Outcomes in Elderly Patients with Hip Fracture in a Dedicated Orthogeriatric Care Pathway[END_REF][START_REF] Genet | Lack of Association Between Perioperative Medication and Postoperative Delirium in Hip Fracture Patients in an Orthogeriatric Care Pathway[END_REF][START_REF] Thietart | Short-term administration of nonsteroidal antiinflammatory drugs in older patients with hip fracture: A cohort study[END_REF]

Outcomes

Our main outcome measure was the occurrence of POAF defined as new-onset AF in the immediate period after surgery (until the end of hospitalization in the unit for perioperative geriatric care). The occurrence of POAF was retrospectively adjudicated by 2 geriatricians (AR, PG) who independently reviewed medical charts (kappa = 0.948, 95% confidence interval [CI] 0.87-0.99). In case of disagreement, consensus was reached with a third independent senior expert (JB).

Data collection methods

Since the opening of the unit for perioperative geriatric care in 2009, we have created a dedicated research database that is prospectively implemented by 3 senior geriatricians (JB, JCB, LZ), experts in orthogeriatrics, and that integrates all the data from the orthogeriatric care pathway for each patient.

The following variables were collected prospectively by interviewing patients, their family members or their physicians and pharmacists during the hospital stay and were defined as baseline characteristics before hip fracture: age, sex, home or nursing home living conditions, walking ability, previous medical history including cardiovascular and neurologic diseases, chronic medications, and type of fracture (radiological definition by an orthopedic surgeon).

Co-morbidity severity was assessed with the Charlson Comorbidity Index( 26) because all comorbidity scores are equivalent in predicting mortality in this population [START_REF] Boddaert | Prediction of postoperative mortality in elderly patients with hip fracture: are specific and geriatric scores better than general scores?[END_REF]. Functional status was evaluated with an activities of daily living scale [START_REF] Katz | Index of ADL[END_REF]. Repeated falls was defined as 2 or more falls in the previous year, chronic renal failure as Cockcroft creatinine clearance < 30 ml.min -1 , hypokalemia as potassium level < 3.5 mmol/L and anemia as haemoglobin level < 12 g.dL -1 for women and 13 g.dL -1 for men.

During the perioperative period, we prospectively recorded the surgical treatment, the delay and duration of surgery, the anesthetic drugs used and all drugs and transfusions administered from the ED to the unit for perioperative geriatric care. Cardiovascular drugs taken at baseline and their suspension were recorded retrospectively.

After surgery, delays to first sitting and first walking, destination (home or rehabilitation) at discharge from the unit for perioperative geriatric care and length of stay in acute care were recorded. All postoperative complications during the acute care period were prospectively recorded.

Statistical analysis

Because the database was prospectively supplemented, all authors were "blinded" to the research question at the time of data collection. The study is based on data for all available patients during the study period, and thus no a priori power calculation was conducted. Data are presented as mean ± SD or median (interquartile range) for continuous variables and number Patients with (cases) and without POAF (controls) were matched 1:5 on 5 baseline characteristics (age, hypertension, diabetes, coronary artery disease, cardiac failure). We selected those 5 factors from a literature review(4) and deliberations of a panel of 9 independent experts. This panel included 3 geriatricians, 4 cardiologists and 2 anesthesiologists who were all blinded to the research question at this time and to the other experts' answers. We asked each expert the following standardized question: "According to you, what are the 9-10 main baseline predisposing factors of POAF among patients of 70 and more undergoing hip fracture surgery?" The 4 most frequently given answers were age (89%), diabetes (89%), hypertension (89%) and coronary artery disease (78%) (eMethods 2 in the Supplement). Then, 4 other factors were mentioned with equal frequency: history of paroxystic AF, chronic heart failure, chronic kidney disease, and valvular disease. We chose to keep chronic heart failure because it was most homogenously proposed by the 3 represented medical specialties and was previously described as a strong predisposing factor in this specific context [START_REF] Gupta | Clinical presentation and outcome of perioperative myocardial infarction in the very elderly following hip fracture surgery[END_REF][START_REF] Leibowitz | Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture[END_REF][START_REF] Khormaee | Risk of Ischemic Stroke After Perioperative Atrial Fibrillation in Total Knee and Hip Arthroplasty Patients[END_REF].

Then, using the matched dataset, we performed a logistic conditional regression analysis to assess independent modifiable variables present at admission in the unit for perioperative geriatric care that were associated with POAF; adjusted odds ratios (ORs) and their 95% CIs were calculated. To avoid overestimation, a conservative approach was used [START_REF] Sun | Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis[END_REF][START_REF] Harrell | Regression models for prognostic prediction: advantages, problems, and suggested solutions[END_REF]: all variables with P <.20 on univariate analyses and all clinically relevant variables were included.

Statistical analyses were performed with R v 1.4.1717 (package Matchlt). All p-values were two-tailed and p < .05 was considered statistically significant.

RESULTS

Demographic data, patient baseline characteristics, surgery and biology

We included 757 patients, and 384 were matched; 64 had POAF (Figure 1). Excluded patients (n = 607, 45%) had similar characteristics as patients included with one exception: fewer patients excluded had haemoglobin level < 10 g.dL -1 before surgery (68% vs 74%, p = 0.03) (eMethods 3 in the Supplement).

Baseline characteristics are reported in Table 1 (matched cohort). The mean age was 86 ± 6 years; 298 (78%) patients were female; the median Charlson Comorbidity Index was 6 (IQR 4-8); and 17% were living in a nursing home before the hip fracture.

The incidence of POAF was 8.5% in our cohort (Figure 1), with a median time between hospitalization in our unit and the occurrence of POAF of 2 days (1-4). On univariate analysis (matched cohort), patients with and without POAF did not differ in comorbidities (except for history of paroxystic AF), autonomy, type of hip fracture or surgery (Table 1). The median time to surgery was 26 hr (20-47), and for more patients with than without POAF, the time to surgery was longer than 48 hr: 23 (36%) versus 62 (19%) (p = 0.004). The groups did not differ in biologic factors on the first day of hospitalization (haemoglobin and potassium levels) (Table 1).

Perioperative therapeutics

On univariate analysis (matched cohort), patients with and without POAF did not differ in use of anesthetic drugs or techniques (Table 2). Patients with POAF more frequently received more than 2 transfusions of packed red blood cells in the emergency room or recovery room than patients without POAF: 8 (13%) versus 9 (3%) (p = 0.003) (Table 2). The groups did not differ in cardiovascular drug use (treatment at baseline and suspension of treatment before surgery), with the exception of flecainide, used more at baseline in the POAF than non-POAF group (eMethods 4 in the Supplement).

Main outcome

On multivariable logistic regression analysis (matched cohort; all variables detailed in

Table 3), the modifiable factors associated with POAF, present at admission in the unit for perioperative geriatric care, were time to surgery greater than 48 hr (OR = 1.66 [1.01-2.81]) and more than 2 transfusions of packed red blood cells (OR = 3.94 [1.50-10.03]).

Post-operative complications

On univariate analysis (matched cohort), stroke, acute heart failure and infection were more frequent in patients with than without POAF (Table 2). In 5 patients with acute heart failure, the heart failure occurred before the discovery of POAF. Also, in 3 patients with acute coronary syndrome, the acute coronary syndrome occurred before the discovery of POAF.

DISCUSSION

This study aimed to identify modifiable risk factors associated with POAF after hip fracture surgery in a geriatric population receiving treatment in a dedicated orthogeriatric care pathway. The incidence of POAF was 8.5% in our cohort. The occurrence of POAF was associated with time to surgery greater than 48 hr and more than 2 transfusions of packed red blood cells before hospitalization in the unit for perioperative geriatric care.

The reported incidence of POAF after non-thoracic non-cardiac surgery varies widely, from 0.5% to 15%, which reflects the heterogeneity in definitions (inclusion or not of patients with a history of AF), methods used to identify POAF, study populations (geriatric or not) and settings (type of surgeries). [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Dobrev | Postoperative atrial fibrillation: mechanisms, manifestations and management[END_REF][START_REF] Subramani | Incidence, Risk Factors, and Outcomes of Perioperative Atrial Fibrillation following Noncardiothoracic Surgery: A Systematic Review and Meta-Regression Analysis of Observational Studies[END_REF] We chose to include in this cohort patients with a history of paroxystic AF, as for previous cohorts of patients with hip fracture, [START_REF] Rostagno | Postoperative atrial fibrillation is related to a worse outcome in patients undergoing surgery for hip fracture[END_REF][START_REF] Leibowitz | Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture[END_REF] to minimize classification bias. In studies by Leibowitz et al. [START_REF] Leibowitz | Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture[END_REF] (n = 410, mean age 80 ± 7.8 years) and Rostagno et al. [START_REF] Rostagno | Postoperative atrial fibrillation is related to a worse outcome in patients undergoing surgery for hip fracture[END_REF] (n = 2922, mean age 83.7 ± 8.2 years), the incidence of newly diagnosed AF among older comorbid patients undergoing hip fracture surgery was 3.7% and 3.6%, respectively. Because the definition of POAF and the populations were similar to our cohort, [START_REF] Rostagno | Postoperative atrial fibrillation is related to a worse outcome in patients undergoing surgery for hip fracture[END_REF][START_REF] Leibowitz | Perioperative atrial fibrillation is associated with increased one-year mortality in elderly patients after repair of hip fracture[END_REF] the higher incidence we found in our cohort may have been related to differences in monitoring and screening POAF in this highly specialized environment. [START_REF] Zerah | Attributable Mortality of Hip Fracture in Older Patients: A Retrospective Observational Study[END_REF][START_REF] Boddaert | Postoperative admission to a dedicated geriatric unit decreases mortality in elderly patients with hip fracture[END_REF] We found delayed surgery associated with the occurrence of POAF, which agrees with the study of Rostagno et al., finding a time to surgery less than 48 hr for 80% of patients in the control group versus 49% in the AF group (p = 0.0001). [START_REF] Rostagno | Postoperative atrial fibrillation is related to a worse outcome in patients undergoing surgery for hip fracture[END_REF] Once again, surgery for a hip fracture should be considered an emergency. A meta-analysis including 191 873 patients found that early hip fracture surgery (cut-off between 24 and 48 hr) was associated with significantly reduced risk of death (OR = 0.74 [0.67-0.81]).( 33) Of note, reducing the time to surgery is not included in the European Society of Cardiology recommendations to prevent POAF. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF] We also found the occurrence of POAF associated with more than 2 transfusions of packed of red blood cells before hospitalization in the unit for perioperative geriatric care, which may reflect complications of anemia or the transfusion itself. [START_REF] Carson | Liberal or restrictive transfusion in high-risk patients after hip surgery[END_REF][START_REF] Willett | Management of postoperative complications: anemia[END_REF] Perioperative anemia is a known risk factor of POAF. Anemia may lead to relative ischemia of atrial cells and myocardial conduction tissue, thus altering the cell electric properties and leading to arrhythmias. [START_REF] Bessissow | Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview[END_REF][START_REF] Chelazzi | Postoperative atrial fibrillation[END_REF] In addition, anemia, especially acute anemia, produces an intense adrenergic activation that may trigger POAF in predisposed patients. [START_REF] Bessissow | Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview[END_REF][START_REF] Chelazzi | Postoperative atrial fibrillation[END_REF] However, in cardiothoracic surgery, there is evidence that packed red blood cell transfusion increases the incidence of POAF. [START_REF] Sood | The association among blood transfusions, white blood cell count, and the frequency of post-cardiothoracic surgery atrial fibrillation: a nested cohort study from the Atrial Fibrillation Suppression Trials I, II, and III[END_REF] We previously found in our unit that a restrictive transfusion strategy was associated with fewer in-hospital cardiovascular complications (including AF, coronary syndrome, heart failure and stroke) with no significant difference in long-term mortality. [START_REF] Zerah | Retrospective evaluation of a restrictive transfusion strategy in older adults with hip fracture[END_REF] We found no association between hypokalemia and POAF in our cohort, [START_REF] Chelazzi | Postoperative atrial fibrillation[END_REF] nor with cardiovascular drug use (beta-blocker interruption), [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Dobrev | Postoperative atrial fibrillation: mechanisms, manifestations and management[END_REF] possibly owing to lack of power. In addition, we collected the serum potassium level only on the first day of hospitalization, which could explain why we did not find an association of hypokalemia with POAF occurring later during the hospital stay.

Our study has several limitations. First, it was an observational study, and causality cannot be demonstrated. Second, it was a retrospective study, and bias due to other procedural changes, which may have influenced the occurrence of POAF during the same time cannot be excluded. Third, many patients had to be excluded because of missing preoperative electrocardiogram results (including missing anesthesia or emergency records) to fully meet the definition (exclusion of permanent AF). However, these patients had the same characteristics as included patients with the exception that they had less aenemia before surgery (potential trigger for POAF). Fourth, patients were not continuously monitored, which may have resulted in an under-diagnosis of the incidence of paroxysmal POAF and misclassification bias. Fifth, because our study was conducted in a highly specialized environment that is associated with reduced mortality and postoperative complications as compared with patients admitted to an orthopaedic department,(14,16) our results may not be extrapolated to other wards. This study may have significant implications for the care of perioperative patients. The complexity of POAF, in particular in a population with multimorbidity and polypharmacy, requires a multifaceted, holistic, and multidisciplinary approach to the management of AF patients, with active involvement in partnership with geriatricians, surgeons, anesthetists and emergency physicians.(4)

CONCLUSIONS

Among older patients hospitalized in a dedicated orthogeriatric care pathway for hip fracture surgery, the occurrence of POAF was associated with 2 modifiable factors: time to surgery greater than 48 hr and more than 2 transfusions of packed of red blood cells before the hospitalization in the unit for perioperative geriatric care. Further studies are needed to demonstrate a possible causal link between these factors and POAF.

Tables Legends

Table 1: Demographic data and baseline characteristics of older patients with and without postoperative atrial fibrillation (POAF) (matched population)

  (percentage) for categorical variables. Comparison of quantitative variables involved unpaired Student t test or Mann-Whitney test depending on the normal distribution of data. Normality was assessed by graphical representation of the data distribution. Comparison of categorical variables involved chi-squared or Fisher's exact test, as appropriate.

Figure 1 :

 1 Figure 1: Flow chart of participants in the study.

  (cases: 54, controls: 267), Concordance = 0.69 Hypokalemia = potassium level <3.5 mmol.l -1 at admission in unit for perioperative geriatric care Abbreviations: OR = odds ratio, CI: confidence interval; CCI = Charlson Comorbidity Index; RBC = red blood cell

Table 2 :

 2 Management, complications and in-hospital outcomes of older patients with and without POAF (matched population)

Table 3 :

 3 Logistic regression analysis of factors associated with occurrence of POAF (matched population)

Table 3 : Logistic regression analysis of factors associated with occurrence of postoperative atrial fibrillation (POAF) (matched population)

 3

	Univariate analysis	P value	Multivariable analysis	P value
	OR (95% CI)		OR (95% CI)

: Paired by age, diabetes, ischemic cardiopathy, hypertension, chronic heart failure

Acknowledgments:

We thank Dr Guillaume Coutance, Dr Sabine Drevet, Dr Thomas Gilbert, Dr Jules Greze, Dr Romuald Henry, Dr Léopold Oliver, Dr Cyril Sellier, Dr Francesca Santi, Dr Arnaud Savoure for their expertise (9 independent experts for matching).

Funding/support: This work was supported only by institutional sources

Transparency statement: The lead author affirms that this manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

Data sharing: Data can be obtained on request to Pr Jacques Boddaert (Jacques.boddaert@aphp.fr).

Authors' contributions:

Study concept and design: Boddaert, Zerah, Rouet, Genet, Gay B Genet had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.