Reactions of Fluoroalkanes with Mg−Mg Bonds: Scope, sp3C−F/sp2C−F Coupling and Mechanism

Abstract sp3C−F Bonds of fluoroalkanes (7 examples; 1°, 2° and 3°) undergo addition to a low‐valent Mg−Mg species generating reactive organomagnesium reagents. Further reactions with a series of electrophiles results in a net C−F to C−B, C−Si, C−Sn or C−C bond transformation (11 examples, diversity). The new reactivity has been exploited in an unprecedented one‐pot magnesium‐mediated coupling of sp3C−F and sp2C−F bonds. Calculations suggest that the sp3C−F bond activation step occurs by frontside nucleophilic attack of the Mg−Mg reagent on the fluoroalkane.

The activation and functionalization of sp 3 CÀFb onds of fluoroalkanes represents an important and largely unsolvedc hallenge. [1][2][3] Transformations that use sp 3 CÀFb onds as reactive functional groupsc ould potentially open up new avenues in synthesis, including upgrading refrigerantsa nd the late-stage functionalisation of agrochemicals and pharmaceuticals. Slow progress in this area of research can, in part, be traced to the difficultiesa ssociated with the oxidative addition of sp 3 CÀF bonds to transition metals.T he high sp 3 CÀFb ond dissociation energy along with the lack of charges tabilisation in the transition state for bond breaking means that definedoxidative addition reactions are incredibly scarce. [4] In casesw here oxidative addition can occur,t he resulting metal alkyl complexes are liable to undergo fast b-hydridee limination. Main group reagents and catalysts offer acomplementary approach to transition metal systems.E lectrophilic silyliumi ons, [5,6] and related species, [7][8][9] have proven remarkably adept catalysts for fluoride abstraction from fluoroalkanes,w hileanucleophilic boryl anion hasj ust emerged as ar eagent capable of CÀFc leavage of CF 3 H( HFC-23). [10] Although we, and others, demonstrated that sp 3 CÀFb onds of fluoroalkanes undergoo xidative addition to single-site Al I complexes, [11][12][13] no further reactivity of the resultant Group13 reagents has been reported. In related studies we have shown that the reactiono ff luoroarenesw ith 1a occurs by ac oncerted S N Ar-like addition of the sp 2 CÀFb ond acrosst he MgÀMg bond (Scheme 1). [14,15] Fluorocarbonsa re often considered inert toward Grignard formation.There is,however,aseries of somewhat contradictory reports that metallic magnesium can be used to generate Grignardr eagents from fluoroalkanes, provided as uitable initiator( e.g.,I 2 ,B r 2 ,E tBr)i sp resent. [16,17] Captivated by these studies, we becamei nterested in the reactivity of 1a [18][19][20][21][22][23] towardsf luoroalkanes.H ere we show that these reagents activate av arietyo fs p 3 CÀFb onds under mild conditions. The resultant organomagnesium reagents can be used to transfer the alkyl group to boron-, silicon-, tin-and carbon-based electrophiles. The latter carbonÀcarbon bond forming reactioni s an unprecedented example of at ransition metal free crosscoupling reaction of two CÀFbonds. [24] Addition of 1.1 equiv of 1-fluorohexane to a0 .02 m solution of 1a in C 6 D 6 at 80 8Cl ed to the consumption of the Mg-Mg reagent over 1h and formation of the magnesium alkyl 2a in 92 %y ield. 2a wasc haracterised by ah igh-field triplet resonancei nt he 1 HNMR spectrum (d = À0.22 ppm, 3 J H-H = 7.9 Hz) assignedt ot he methylene group adjacent to magnesium and formed alongside the previously characterised magnesium fluoride 3a. [25] The scope of the reaction was considered. As eries of substratesw as investigated and the organomagnesium complexes 2b-e were formedi ng ood yields (Scheme 1). The reaction tolerates 18,2 8 and 38 fluoroalkanes along with chain-branching both adjacentt oa nd remote from the active site. Related organomagnesium complexes crystallise as bridgedd imers (18 alkyl) or 3-coordinate monomers (28/38 alkyl). [26][27][28] In the solidstate 2a forms ad imer,b ridged by 3-centre, 2-electron bonds ( Figure 1a). DFT calculations show that the solid-state structures likelyp ersist in solution and dimerization of these organomagnesiums only becomes unfavourable with branching of the chain (Figure 1b). Although 1a did not react cleanly with 38 alkyl fluorides, the analogue 1b mediates the CÀFb ond activation of 1-fluoroadamantane. In this case, the resulting b-diketiminate stabilised organomagnesium is unstablew ith respect to Schlenk-like ligand redistribution preventing its characterisation in solution.T rapping of the organomagnesium with HBpin resulted in direct formation of 1-adamantylBpini n 69 %y ield from 1b (Bpin = pinacolatoborane, Figure 1c).
Initial experiments suggest that, in ac ase that forms two energetically dissimilar diastereomers, the reaction is stereoconvergent. Hence, cis and trans 4-tert-butylcyclohexyl fluoride both react with 1a to give as ingle diastereomer assigned as trans-2e based on the 3 J H-H valueso ft he NMR resonance of the protons adjacent to Mg (Scheme 1). By DFT the trans isomer is calculated to be 5.4 kcal mol À1 more stable than the cis isomer and they likely interconvert by epimerisation of the stereocentre adjacentt om agnesium.
Insight into the functional group compatibility of the new transformationw as gained by running the reaction of 1a with 1-fluorohexane in the presence of external reagents containing alkenes, alkynes,e thers, 38 amine and pyridine moieties. These additivesh ad little or no impact on the yield of 2a (Supporting Information, Scheme S3). In the case of THF and DMAP this experiment led to the formation of the solvates 2a·THF and 2a·DMAP,r espectively.S ubstrates including an additional halogen atom on the hydrocarbon chain, such as 1-iodo-3-fluoropropaneo r1 -bromo-5-fluoropentane,u nderwent cyclisation to form three-or five-membered hydrocarbon rings (Supporting Information, Scheme S4). [29] The utility of the new organomagnesium complexes was investigated and specifically the polar Mg d + ÀC dÀ bond derived from sp 3 CÀFa ctivation was used as an ucleophilic source of the carbanion. Reaction of mixturesc ontaining 2a,f ormed from CÀFa ctivation of 1-fluorohexane, with HBpin,B 2 pin 2 , B 2 nep 2 ,9 -BBN, H 3 SiPh, HSnBu 3 ,o rC lSnBu 3 leads to transfer of the alkyl group from magnesium to the electrophile and results in sp 3 CÀB, sp 3 CÀSi, and sp 3 CÀSn bond formation, respectively (Bnep = 5,5-dimethyl-1,3,2-dioxaborolane, 9-BBN = 9-borabicyclo[3.3.1]nonane). These reactions are highly efficient, with most proceeding in > 80 %y ield over the two steps as measured by 1 HNMR spectroscopy.A ne xception is the reaction of 2a with B 2 nep 2 whichf orms n-HexBnep in only 50 % yield (Scheme 2). [30] Encouraged by the ease of nucleophilic addition to main group electrophiles, we turned our attention to intermolecular carbonÀcarbon bond formation by the heterocoupling of two CÀFb onds. 2a,g enerated directly from 1-fluorohexane, adds to perfluoroarenes under forcing conditions (Scheme 3). The reactiono fi ns itu generated 2a with hexafluorobenzene forms 4a as evidenced by the emergence of an ew triplet resonance in the 1 HNMR spectrum (d = 2.29 ppm, 3 J H-H = 7.7 Hz) assigned to the methylenep rotons adjacentt ot he aromatic ring. The scope of this reaction was expanded and the overall yields of cross-coupled products 4a-e while modest, 34-72 %, represent ac ombinationo ft wo steps and an average 60-85 %y ield for each CÀFb ond cleavager eaction. Althoughr elated reactions of organomagnesium reagents with perfluoroarenes are known, [31][32][33] this represents the first transition metal free procedure forC ÀCb ond formation by the coupling of two CÀF bonds.
To gain ad eeper understanding of the CÀFb ond cleavage steps involved in the carbonÀcarbon bond forming sequence, as eries of calculations were undertaken on the reaction of 1fluoropropane [34] with hexafluorobenzene using the B3PW91 functional and ah ybrid basis set (Figure 2a). We have previously benchmarked the computational methodsu sed herein against experimentally determined activation parameters. [15] The initial endergonicc oordination of 1-fluoropropane at 1a to form Int-1,i sf ollowedb yC ÀFb ond cleavage in TS-1 ultimately leadingt ot he formation of Int-2/3. [35] Schlenk-like redistribution of two equivalents of Int-2/3 forms the experimentally observed products Int-2 2 and Int-3 2 .W hile the dissociation of Int-2/3 into the monomeric fragments Int-2 and Int-3 required for redistribution is endergonic DG o 298 K = 25.3 kcal mol À1 ,t his energy barrierr epresentsc omplete dissociation and, as such, is an upper limit of the activation energy.O verall this Schlenk-like redistribution is thermoneutral. The second CÀFb ond cleavages tep forms the carbonÀcarbon bond and proceeds by nucleophilic addition of the newly formed magnesium alkyl complext ot he electron-deficient arene. Dissociation of Int-2 2 is required to access the reactive three-coordinate magnesium alkyl species Int-2,a nd is on the way to the concerted S N Ar transition state TS-2. [36,37] In combination these steps lead to ah igh activation barrier forc arbonÀcarbon bond formation, DG°2 98 K = 26.2 kcal mol À1 . [38] The unusual geometry of TS-1 warrants further discussion. TS-1 contains an ear planar arrangemento fM g, Ca nd Fa toms in which the CÀFb ond orientates itself perpendicular to the MgÀMg bond with the fluorine atom approaching head-on. The CÀFb ond stretches to 1.84 from 1.39 in 1-fluoropropane, the MgÀFd istances are short(% 2.1 )w hile both Mg-C distances are long (> 3.6 ). Asimilar transition state was located for the reaction of 1a with 2-fluoropropane. TS-1 bears all the hallmarks of front-side nucleophilic attack in an S N 2mechanism;t he carbon substituent takes the role of the leaving group and the electron-pair between the magnesium atoms of 1a the role of the nucleophile. [39][40][41][42] This geometry is starkly different to that observed in the side-on and S N Ar like transition states calculated for the reaction of 1a with CO 2 and C 6 F 6 ,r espectively. [15,43] While all these processes can be classified as oxidative additions from the perspective of the main group reagent there are significant deviations in the TS geometries ( Figure 2c).
Frontside nucleophilic attack, taught as an unfavourable pathway to undergraduate students, has been modelled in dynamics calculations on nucleophilic substitution reactions of alkyl halides. [39][40][41] These pathways have been shown, universally,t ob ep rohibitively high in energy when compared to backside nucleophilic attack. In the current case, it appears the unusual nature of 1a overrides the standard selectivity.T here is limitedp recedentf or the geometry of TS-1.E isenstein and coworkers have postulated that ac erocene hydride attacks C 6 F 6 Scheme3.CarbonÀcarbon bond formation by double carbonÀfluorineb ond activation. Yields measured by 1 HNMR by comparison against an internal standard. through at ransition state involving an end-on H-FÀCi nteraction. [44] The MgÀMg reagent 1a possesses an on-nuclear local maximum in electron density at the centre of the metalÀmetal bond that acts as ah ighly nucleophilic electron-pair. [45,46] Second-order perturbation calculations on TS-1 show donoracceptori nteractionsf rom not only the MgÀMg s-bond to the low-lying s*(F-C) orbitalo ft he fluoroalkane (37 kcal mol À1 )b ut also from the filled F p-orbitals to the empty s*(Mg-Mg) orbital (7 kcal mol À1 ). This latter interaction contributes to the stabilisation of the frontside TS as the electrostatic interactions between fluorine and magnesiuma toms anchort he CÀFb ond in place and polarise it.I nTS-1,t he hydrocarbonc hain acts as a leaving group. This moietya dopts carbanion charactera nd following breaking of the CÀFbond migrates directly to magnesium (Supporting Information, movie). The carbanion character is evidencedb yt he NPAc harges on the carbon atom in TS-1 which is more negative than that in Int-1 alongside the deviation of the carbon centre from sp 3 to sp 2 hybridised (degree of pyramidalization; Int-1 = 42 %, TS-1 = 12.5 %). [47] In summary,w er eport an ew reaction that transforms sp 3 CÀ Fb onds into reactive sp 3 CÀMg bonds. This methodology can be considered as an equivalent of Grignard formation that occurs in homogeneous solutiona nd allows expansion of the substrate scope to include fluorocarbons. The organomagnesium products react with as eries of electrophiles leading to the development of an unprecedented carbonÀcarbon bond forming reaction that couplest wo CÀFb onds. Ap reliminarya ssessment of the mechanism hints that sp 3 CÀFb onda ctivation occurs by ar emarkable pathway involving frontside nucleophilic attack. We are currently investigating the stereospecifity of the reaction of 1a (and relatedr eagents) with fluoroalkanes alongside am ore detailed study of the stereointegrityo ft he resultingo rganometallics.