Palladium-catalyzed multi components oxy-aminofluorination and aminofluorination of gem-difluoroalkenes

Fen Wu ,Xin Li ,Junbio Chng ,Dchng Bi,b,*

a State Key Laboratory of Antiviral Drugs,NMPA Key Laboratory for Research and Evaluation of Innovative Drug,Key Laboratory of Green Chemical Media and Reactions,Ministry of Education,School of Chemistry and Chemical Engineering,Pingyuan Laboratory,Henan Normal University,Xinxiang 453007,China

b State Key Laboratory of Organometallic Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China

Keywords: Palladium Multi components Aminofluorination Oxy-aminofluorination C(sp3)-O bond cleavage

ABSTRACT Organofluorine compounds are widely used in the realm of drug discovery and material science.Herein,we developed palladium catalyzed intermolecular aminofluorination and oxy-aminofluorination of gemdifluoroalkenes with N-fluorobenzenesulfonimide (NFSI),in which NFSI was used as the nitrogen source and oxidant.The reaction provides an efficient and straightforward synthesis route of a series of αtrifluoromethyl benzylic amines.Notably,three/four components oxy-aminofluorination processes were realized to give α-trifluoromethyl benzylic ether with a terminal amino group,which proceed through C(sp3)-O bond cleavage of easily available ether and simultaneous introduced a fluorine,an amino and an oxy substituent in one pot with excellent regioselectivity.The divergent reactivity not only included the incorporation of one ether molecular,but also much more challenged two ether insertion with excellent selectivity through succession C(sp3)-O bonds cleavage.This protocol allows for concise synthesis of high value amines with fluoroalkyl-substituents and selectively transformation of easily available ethers by high-valent palladium catalysis.

The incorporation of fluoroalkyl group into organic molecules has been widely applied in pharmaceuticals and agrochemicals development [1-5].In this context,the synthesis of bioactive molecules with C(sp3)-CF3scaffold is particularly sought after[6-15].The amine or ether bearingα-CF3group is highly attractive for lead candidate study in medicinal chemistry.While,existing methods to give these compounds mainly focus on the nucleophilic addition of trifluoromethyl reagent or transformation of CF3-substituted imines (ketones) [16-19].These methods usually need multistep transformations or expensive reagents.An efficient and direct synthetic route is still highly desirable.

In the last two decades,thegem-difluoroalkenes have been used as one type of ideal substrates for the synthesis of highvalue-added organofluorine compounds [20-23].However,these reports usually gave the monofluoroalkenes and derivativesviaβ-F elimination by transition-metal catalyst [20-30].Recently,the fluorine retentive reaction to access functionalα-fluoroalkyl containing products has been disclosed [31-43].The nucleophilic addition of fluoride ion togem-difluoroalkenes is a novel strategy to generateα-CF3-containing products [35-39],which was applied in the palladium-catalyzed allylation and arylation [40-42].In 2019,the Malcolmson group developed the synthesis ofα-trifluoromethyl benzylic amines by using N-containinggemdifluoroalkenes through palladium catalyzed arylation (Scheme 1A)[43].All of these reactions proceeded through C-C bond formation fromα-CF3organopalladium intermediate,the C-N or C-O bond formation is still unexplored.

Scheme 1.The synthesis of α-fluoroalkyl containing amines with transition-metal catalyst.

On the other hand,the aminofluorination of simple olefins with transition metal catalysis is a powerful strategy for the synthesis of fluorine-containing amines [44-52].Liu group developed pioneer and attractive palladium-catalyzed aminofluorination of simple styrenes [53].The more steric hindrance trifluoromethyl products and the cleavage of C(sp3)-O bond by high valent Pd species has not been discovered.Later,Zhang group developed the radical aminofluorination by copper catalysis with regioselectivities opposite to that of palladium catalysis (Scheme 1B) [54].Inspired by these remarkable works and our continuous interest in the synthesis ofα-fluoroalkyl containing compounds,herein,we report the palladium catalyzed aminofluorination and multi The ligand structure plays an important role to deliver product4a(entries 9-16).The PdCl2and Pd(dba)2exhibited similar reactivity to the Pd(OAc)2catalyst (entries 17 and 18).Low yield of3awas observed when the reaction proceeded at 40 °C (entry 19).Furthermore,4acould be obtained in 99% yield when the Pd catalysis loading decreased to 2 mol% (entry 20).The use of chiral ligandsL1-L5were found with low levels of enantiocontrol (for more details see Tables S4 and S5 in Supporting information).

With the optimized reaction conditions,we first explored the generality of the three components oxy-aminofluorination reaction.To our delight,the substrate scope was found to be very broad,and gave correspondingα-trifluoromethyl benzylic ethers with terminal amino groups in moderate to high yield.As shown in Scheme 2,the reaction was tolerated with an array of substituents at thepara-,meta-orortho-position and produced the corresponding products2b-2jin 34%-93% yield.The (hetero)aryl-substituted alkenes and biarylgem-difluoroalkenes were also briefly investigated and yielded the oxy-aminofluorination products2k-2oin 52%-88% yield.The structure of2kwas confirmed by X-ray crystallography (CCDC: 2215518).Subsequently,we examined C(sp3)-O cleavage process of other cyclic ethers.Delightedly,when dioxane was used instead of THF,the correspondingα-trifluoromethyl benzylic ether could be obtained in moderate yield through C(sp3)-O cleavage in dioxane (2p,66% yield and2q,60% yield).The six number ring pyran was also successfully applied in this oxycomponents oxy-aminofluorination ofgem-difluoroalkenes withNfluorobenzenesulfonimide (NFSI),which was used as the nitrogen source as well as the oxidant,affording various functionalα-CF3containing amines (Scheme 1C).Noteworthy,the three components oxy-aminofluorination reaction involved the cleavage of C(sp3)-O bonds in easily available alkyl ethers (such as THF,dioxane,DME),providing theα-CF3benzylic ethers bearing terminal amino groups with excellent regioselectivity.We also realized the succession C(sp3)-O bond cleavage,affording two ethers insertion products with excellent selectivity by addition of Lewis acids,which might be benefit for the coordination of ether to the Pd(IV) center.We suggested that the C(sp3)-O bond cleavage initiated by the coordination of ether to the Pd(IV) center would be one attractive strategy for the transformation of ethers [55-58].Additionally,this reaction could access toα-CF2H containing amines from monofluoroalkenes.The challenge of this catalytic system does not just include the steric hindrance of trifluoromethyl group andβ-fluorine elimination,the one pot incorporation of a fluorine,an amino and an oxy substituent with high regioselectivity is also an important synthetic challenge.

Scheme 2.Substrate scope of oxy-aminofluorination reaction with one ether insertion.Reaction conditions: 1 (0.20 mmol),NFSI (0.40 mmol),Pd(OAc)2 (10 mol%),L1(10 mol%),ether (2.0 mL),80 °C,36 h,isolated yields.

We began our studies by examining the reaction parameters ofgem-difluoroalkene1aand NFSI in the presence of Pd(OAc)2catalysis (Table 1).We found that the ligandL1was efficient to give the oxy-aminofluorination product2ain 47% yield with high chemoselectivity through C(sp3)-O cleavage in THF (entry 1).The yield of2acould be increased to 75% when NaF was added (entry 2).Very interesting,the more challenged two THF insertion product3acould be obtained in 60% yield when AgSbF6was used as an additive (entry 3,for more details see Table S1 in Supporting information).The addition of AgSbF6might be favored for the coordination of THF to Palladium center and accelerated the succession cleavage of C(sp3)-O bond [59-61].Trace amount of three THF insertion products observed under the reaction conditions of entry 3 (3a:3a’=93:7).We next examined the solvent effect and found that the aminofluorination product4awas obtained (entries 4-8,for more details see Table S2 in Supporting information).The product4acould be obtained in 99% yield when MeOtBu was used as solvent at 80 °C (entry 4).The DCE gave the comparative result,while DMF andiPrOH gave no desired product (entries 5-8).aminofluorination reaction,giving the corresponding product2rin 68% yield.Low efficiency for the seven number cyclic ether and gave the corresponding product2sin 12% yield.Theαtrifluoromethyl benzylic ether without terminal amino group2twas obtained in 52% yield when linear ether DME was used instead of cyclic ether.The monofluoroalkene delivered theα-CF2H benzylic amine2uin 50% yield with THF.Other ethers such as 2-phenyloxirane and phenyl methyl ether failed to give desired products.

Table 1Investigation of reaction conditions.a

Then,we investigated the generality of the much more challenged four components oxy-aminofluorination reaction,giving two THF insertion products (Scheme 3).A series of functionalgem-difluoroalkenes with electron-donating groups were well tolerated to give two THF insertion products with high selectivity through the succession double C(sp3)-O cleavage (3a,60%yield,3f,45% yield,3g,54% yield and3h,59% yield).Trace amount of desired product observed for the Cl-substituted alkene.The substituents atmeta-orortho-position and the (hetero)arylsubstituted alkenes were compatible (3i-3k,34%-42% yield).Some biarylgem-difluoroalkenes were briefly investigated (3m-3p,41%-54% yield).Other cyclic ether such as pyran was successfully to deliver the desired two ether insertion product (3r,26%yield).No desired products obtained when dioxane or seven number ether were used.The conjugatedgem-difluoroalkene only gave the aminofluorination product4yin 35% yield.

Scheme 3.Substrate scope of oxy-aminofluorination reaction with two ether insertion.Reaction conditions: 1 (0.20 mmol),NFSI (0.40 mmol),Pd(OAc)2 (10 mol%),L1 (10 mol%),AgSbF6 (0.02 mmol),hexane (1.5 mL),ether (0.5 mL),80 °C,15 h,isolated yields.a PdCl2 (10 mol%) was used instead of Pd(OAc)2.

Finally,we turned our attention to study the substrate scope of aminofluorination reaction (Scheme 4).The reaction also tolerated with various functional groups at thepara-position of the benzene ring ofgem-difluoroalkenes (4b-4g,72%-99% yield).The reaction showed high efficiency for the electron rich substrates.While the electron-withdrawing substituted alkene (CF3group atpara-position) could not give the desired product (4h),only with starting materials recovered.Low reactivity might be due to the coordination of electron-deficient alkene to low-valent palladium,which would stabilize the low oxidation state and not benefit for the generation of high-valent Pd(IV) species [62,63].The alkenes with substituents at themeta-position were also tolerated to yield theα-trifluoromethyl benzylic amines4i-4lin 48%-95%yield.Theortho-substituted alkenes with methyl group needed higher temperature to produce the amine product4m,possibly due to steric effect.While,the electron-rich alkene with MeOgroup at theortho-position delivered the product4nin 80% yield even with 2 mol% Pd catalysis loading.The structure of4mwas confirmed by X-ray crystallography (CCDC: 2212514).(Hetero)arylsubstituted alkene gave the corresponding products4oin 68%yield.Furthermore,the biarylgem-difluoroalkenes with electrondonating groups,electron-withdrawing groups or halo-groups at the benzene ring worked smoothly to deliver the products4p-4xin 53%-99% yield.The conjugatedgem-difluoroalkene was also compatible to afford the trifluoromethylated allylic amine4yin 60% yield with excellent regioselectivity.However,the reaction of (1,1-difluoroprop-1-en-2-yl)benzene or (4,4-difluorobut-3-en-1-yl)benzene all failed to give the desired products,only with starting materials recovered.

Scheme 4.Substrate scope of aminofluorination reaction.Reaction conditions: 1(0.20 mmol),NFSI (0.40 mmol),Pd(OAc)2 (10 mol%),L1 (10 mol%),MeOtBu (2.0 mL),80 °C,24 h,isolated yields.a Pd(OAc)2 (2 mol%),L1 (2 mol%).b Pd(OAc)2 (10 mol%),L1 (10 mol%),48 h,120 °C.

The CF3-containing amine products could undergo several transformations (Scheme 5).These reactions were successfully scaled up to 2.0 mmol without the erosion of yield,giving product2ain 74% yield and4ain 99% yield (Scheme 5A).Theαtrifluoromethyl ether2acould be reduced to product5in 84%yield.Theα-trifluoromethyl benzylic amine4aalso could be reduced to product6in 85% yield.Furthermore,the primary amine7was obtained in 65% yield and could be combined with aldehydeviareductive amination to obtain the product8in 53% yield(Scheme 5B).

Scheme 5.Scale-up reaction and derivatization.

We then performed several experiments to investigate the influence of substituent in the alkene and ether (Scheme 6).When the simple styrene was used,only starting materials were recovered with Pd/L1catalysis.The reaction worked smoothly for the monofluoroalkene(Z)-9,affording theα-difluoromethyl benzylic amine products10in 90% yield.The monofluoroalkene(E)-9was also successfully converted to10in 87% yield.These results indicated the importance of fluorine atom at the alkenes,but irrelevant with the alkene configuration.When methyln-butyl ether was used instead of cyclic ether,α-trifluoromethyl benzylic ether11was obtained in 24% yield and12was obtained in 8% yield.This result suggested that the C(sp3)-O cleavage prior occurred at the position with small steric hindrance substituent.When different amount of THF was added in MeOtBu solvent,the THF insertion product was the major product after 50 equiv.THF was added(for more details see Table S3 in Supporting information).Several kinetic studies of the reaction ofgem-difluoroalkene1a,NFSI,[Pd]catalysis and ligand effect by the method of initial rates were performed (Scheme 6C).This reaction exhibited a first-order dependence on the concentration ofgem-difluoroalkene1a,[Pd] catalysis and NFSI (for more details in Supporting information).Notably,these kinetic data are consistent withgem-difluoroalkene into Pd(II)-F,but are inconsistent with the Pd(IV)-F insertion[53,64-66].

Scheme 6.Mechanistic studies.(a) Influence of substituents at the alkenes.(b) Influence of substituents at the ether.(c) Kinetic studies.

Based on these above results and previous studies in palladiumcatalyzed aminofluorination of alkenes [44-52,64-72],we proposed a plausible mechanism in Scheme 7.The reaction was initiated by the generation of Pd(II) intermediateA.After the coordination ofgem-difluoroalkene1ato the Pd(II)-F species (TS1),Pd(II)-F inserted or F-nucleophilic addition to the1aand formed the intermediateB,which would undergo oxidative addition of intermediateBto NFSI and gave the Pd(IV) speciesC.The oxidation of intermediateBto give the Pd(IV) intermediateCis consistent with our kinetic studies in Scheme 6C.The reductive elimination from the intermediateCdelivered theα-trifluoromethyl benzylic amine product4a.When the cyclic ether was used,the cyclic ether (THF)coordinated to the Pd(IV) center and the C(sp3)-O bond cleavage occurred to form the Pd(IV)-O species from Pd(IV)-N species intermediateC(TS2) and gave the intermediateD,which would undergo reductive elimination to give theα-trifluoromethyl benzylic ether product2a.Alternatively,another THF would coordinated to the Pd(IV) center (TS3) and C(sp3)-O bond cleavage from the Pd(IV)-O species to give the intermediateE,which undergo reductive elimination to deliver the two THF insertion product3a.

Scheme 7.Proposed mechanism.

In summary,we have developed a novel palladiumcatalyzed aminofluorination and three/four components oxyaminofluorination ofgem-difluoroalkenes,in which the NFSI was served not only as the fluorine and nitrogen source but also the oxidant.The reaction proceeded with excellent regioselectivity and atom economy,affording a variety of functionalizedα-trifluoromethyl benzylic amines and ethers.Particularly,the intermolecular oxy-aminofluorination simultaneously introduced a fluorine,an amino and an oxy substituent in one pot through C(sp3)-O bonds cleavage of the easily available ethers.We not only realized one ether insertion process,but also two ether insertion process through succession C(sp3)-O bonds cleavage.This study contributed to the rapid and divergent synthesis ofα-fluoroalkyl containing compounds,and provided insight for further development of functionalization of olefins.

Acknowledgments

This work is supported by the National Natural Science Foundation of China (Nos.82130103,U1804283,21801067),the Central Plains Scholars and Scientists Studio Fund (No.2018002),and the Project funded by the Natural Science Foundation of Henan Province (Nos.202300410225,222102310562) and Henan Postdoctoral Science Foundation (No.202103087).We also thank the financial support from Henan Key Laboratory of Organic Functional Molecules and Drug Innovation.

Supplementary materials

Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.cclet.2023.109155.