Regio-and Stereoselective Hydroelementation of SF5-Alkynes and Further Functionalizations

: Herein is described a fully regio-and stereoselective hydroelementation reaction of SF 5 -alkynes with N, O and S-nucleophiles and further functionalization of the corresponding Z-(hetero)vinyl-SF 5 intermediates, a suitable platform to access α-SF 5 ketones and esters, β-SF 5 amines and alcohols under mild reaction conditions. Experimental and computational comparative studies between SF 5 - and CF 3 -alkynes have been performed to highlight and explain the difference of reactivity and selectivity observed between these two fluorinated motifs.


Introduction
Enamine is a privileged functional group in organic chemistry and it has been worldwide spotlighted with the 2021 Nobel prize in Chemistry about organocatalysis. [1,2]Enamine chemistry has been widely used in organofluorine chemistry, especially for the stereoselective introduction of fluorine atoms and CF3 group. [3]On the other hand, fluorinated enamines are also of great interest and can be readily prepared by fluoroalkylation, [4] fluorination of ynamides, [5] dehaloamination of haloalkenes, [6] Michael addition, [7] hydroamination of alkynes, [8] and other methods. [9]owadays, the pentafluorosulfanyl group (SF5) [10] is growing in interest in many fields such as heterocyclic synthesis, [11] material science, [12] and medicinal chemistry, [13] and drug development are in progress. [14]However, synthetic routes to SF5 compounds with structural diversity remain highly challenging and rely mainly on two general methods : the direct radical pentafluorosulfanylation of alkenes, alkynes, diazo ketones or [1.1.1]propelane, [15]or the oxidative fluorination of aromatic thiols, disulfide or derivatives. [16]F5-alkynes are readily accessible substrates which can be used in various transformations, such as cycloadditions, heterocyclic synthesis and hydrofunctionalization. [17] Great discoveries are also under investigation with the closely related R-SF4-alkynes another class of promising SFn subunits. [18]Surprisingly, the hydrofunctionalization of SF5-alkynes has been poorly explored and is mainly limited to hydration and hydrofluorination. [19]Until recently, hydroamination of SF5-alkynes was unknown, [20] but analogous reaction with CF3-alkynes was studied by Trofimov and Nenajdenko (Scheme 1,a). [8]They observed that addition of imidazole derivatives on CF3-alkynes was fully stereoselective, forming exclusively Z-isomers but the regioselectivity of the amination, in α-or β-position with respect to the CF3, is highly dependent on the substitution of the aromatic ring of the CF3-alkynes ranging from 45:55 to 5:95, but without a clear trend.Other syntheses of CF3-enamines are known but rely mainly in addition/elimination strategies (Scheme 1,b-c). [6]Herein is reported a general procedure for the hydroamination of SF5 alkynes 2 with a wide variety of nitrogen-nucleophiles, leading exclusively to a single β,Z regio-and stereoisomer, and this methodology can easily be extended to hydroetherification and hydrothioetherification reactions.Furthermore, it is demonstrated that these vinyl-SF5 scaffolds are suitable platforms to access α-SF5-ketones and esters, β-SF5-amines and alcohols.

Results and Discussion
15j, 21] We started the study by the reaction of biphenyl-4-ethynyl pentafluorosulfane 2a with 1.2 equiv. of imidazole at r.t. in THF that delivers the product 3aa with a full conversion and 68% yield (Scheme 2).Compared to the analogous reaction with CF3 alkynes, [8] we were delighted to note that an additional base was not required with SF5-alkynes, and the reaction gave a single regio-and stereoisomer with introduction of the imidazole exclusively in β-position of the SF5 with a Z-configuration, as confirmed by the X-ray diffraction of compound 3ca (CCDC 2221093), 3ae (CCDC 2221162), 3ae' (CCDC 2235645) and 4ab (CCDC 2221641). [22]Encouraged by this result we investigated the scope and the limitation of hydroamination of SF5-alkynes by screening different amines and other N-containing nucleophiles.Unlike imidazole, we found that using a base achieved complete conversion in all cases.After a short optimization, we found that the combination of NaH in DMSO was compatible with a wide variety of nucleophiles, securing a good solubility of the system, a full conversion and still a perfect regio-and stereoselectivity.Several nitrogen-containing heteraromatic compounds can easily be introduced on SF5alkynes such as indole (3ab), benzotriazole (3ad), tetrazole (3ae), carbazole (3af), 6-or 7-aza-indazoles (3ag-h, 3dh) [23] with yields ranging from 43 to 73%.In addition, the 2-SF5-indole [21] is also a competent nucleophile in these conditions and provide compound 3ac in 50% yield bearing two SF5 motifs.Natural products such as adenine and theophylline are well tolerated and underwent the reaction smoothly to give 3al and 3aj in good 72 and 56% yield, respectively.Secondary anilines protected with mesyl (3al), acetyl (3am), tosyl (3an) or even tert-butylcarbamate (3ap) are well tolerated with yields ranging from 38 to 68%.Aliphatic secondary amines such as N-Ts allyl amine (3ar) and N-Boc benzylamine (3as) can be introduced with a moderate 42 to 48% yield.Other N-nucleophiles such as phtalimide (3at), oxazolidinones (3au-v), sulfoximine (3aw) or even an imine (3ax) can be introduced easily in yields ranging from 35 to 78%.Interestingly, the addition of hydroxylamine in THF in the presence of KOH gave the oxime 3ay with a decent yield of 45%.Furthermore, when NaN3 was used as nucleophile in DMSO, it resulted in a mixture of the β,Z-N3 addition product 3az in 35% yield along with the corresponding cycloaddition triazole 3az' in 48% yield.In this case, heating of the reaction at 60 °C and/or extended reaction time did not improve the 3az:3az' ratio.Surprisingly, the use of CuI as additive suppressed the formation of 3az' and 3az was isolated in 60% yield as single SF5-containing product.We then capitalized on this reaction and extended the scope of this transformation to sulfur-and oxygen-containing nucleophiles.Aromatic (4aa) and heteroaromatic thiols (4ab-d) were successfully introduced at the sulfur atom with yields ranging from 39 to 85%.Various phenols can also be introduced, with pnitro (5aa), with o-halogens (5ac-d) or even with a bulky 1,1'binapthyl structure (5ae).Noteworthy, substitution of the alkyne is also tolerated as in the case of heteroaromatic groups (5dd) or N-Boc piperidine (5ed) for instance.The reaction can be extended to a CF3-alkyne, where 67% conversion was obtained with the formation of compound 5ad' as single regio-and stereoisomer isolated in 43% yield.Interestingly, the introduction of oxygen nucleophile is not limited to phenols since an oxime (5af) can also be introduced in 60 % yield, and the addition of aliphatic alcohols such as MeOH (5ag) and t-BuOH (5ah) proceeds also well in these conditions.With MeOH, we observed for the first time a mixture of E:Z isomers (50:50) in NMR but the introduction of the MeOH only takes place in β-position of the SF5, while only the β,Z isomer is observed with t-BuOH.In 1964, Hoover and co-workers described a similar nucleophilic addition of methanol in the presence of KOH as base towards SF5-acetylene 2f leading mainly to the Z isomer in 65% yield (Scheme 3, eq.1).In contrast, nucleophilic addition of MeOH to the β,E-chloro-olefin 1f provided mainly the E isomer in 40% yield suggesting mainly a substitution of the chlorine atom (Scheme 3, eq.2). [24]As a comparison, we tested these conditions with the SF5-alkyne 2a and corresponding β,E-chloro-olefin 1a (Scheme 3, eq.3-4).Similar results were obtained in both cases with a Z:E mixture ranging from 50:50 to 40:60, which seems to indicate that a similar reaction pathway takes place by addition of methoxide onto SF5-alkyne 2a (as substrate or generated in-situ from 1a).However, we noticed a clear difference of stability between the Z:E isomers 5ag.Both E:Z isomers can easily be purified by silica gel column chromatography, however Z isomer is stable over time while degradation of the E isomer was observed in the NMR tube (See ESI for details, Figure S11). [25]During the investigation of the hydroamination of SF5-alkynes, we found that some secondary amines such as pyrrolidine and piperidine were effectively transformed into corresponding enamines 6 as a single regio-and stereoisomer (Scheme 4), but they were somehow sensitive to purification and prone to partial hydrolysis over silica gel, delivering a mixture of SF5-enamine 6 and SF5-ketone 7.For a long time, the α-SF5-ketones were known in the literature but remained mostly anecdotal. [26]More recently, specific procedures for the synthesis of α-SF5-ketones have been reported, such as gold catalyzed regioselective hydration of SF5 Scheme 3. Nucleophilic addition of alcoholates, MeOH vs t-BuOH.a E:Z ratio determined by 19 F and 1 H NMR, b Isolated yield into brackets, c Only the Z isomer was isolated after silica gel chromatography, while E isomer degraded overtime.
alkynes, [19b] direct pentafluorosulfanylation of α-diazo ketones, [15g] or ozonolysis of allylic SF5 products. [27]The procedure described herein is a complementary approach and had the advantage of using mild reaction conditions and being a metal-free procedure.After some optimization, we found that pyrrolidine (2 equiv.)yielded enamine 6a 1 in 30 min at r.t. in THF, while the kinetic was slower with piperidine (2 equiv., r.t.5h).Then, we found that acidic treatment either with diluted H2SO4 (10% in water) or HBF4 (50% in water) were efficient conditions to fully hydrolyze the enamines 6a 1 and 6a 2 with good overall yields of 76% (7a) in both cases.In contrast, we observed that the hydrolysis was slower for 6a 1 (6 h) than for 6a 2 (30 min).For the scope of this transformation (Scheme 4), we used the pyrrolidine for 2h at r.t. and then HBF4 50% in water for 6h at r.t.The reaction proceeded smoothly with aromatic, heteroaromatic and alkyl substituted alkynes in moderate to high yields.Surprisingly, substitution with a 2-naphtyl delivers the ketone 7b in 67% yields while the 1-napthyl substitution (2g) stopped at the enamine form without full conversion.It rather looks like a special case because several examples of bulky ortho-substituted aryl ketones (7d, 7h-j) were obtained in yields ranging from 35 to 75%.Nitrogen-heterocycles (7d, 7m) are well tolerated and the reaction is also compatible with alkyl substrates although corresponding ketone 7n and 7o are quite volatile.Unlike the closely related RSF4-alkyne derivatives, [18d] the hydrolysis of SF5-alkynes directly with an acidic aqueous solution is unknown.Following recommendation from referee, we checked that hydrolysis of SF5-alkynes 2a was not possible using H2SO4 (10 mol%) or HBF4 (50% in H2O), thus showing the benefit to pass by the formation of enamine 6. [25] In contrast, much more concentrated solution of H2SO4 proved to be effective to hydrolyze 2a into 7a, and after a short optimization we found that using 80% aq.solution of H2SO4 in THF at r.t.give 94% of 7a after 5 min, isolated in 68 % yield.Since SF5-alkynes 2 are prepared from 1 by a base-mediated dehydrochlorination, we anticipated that the basic conditions we used for the hydroelementation would be suitable for both the dehydrochlorination step and the hydroelementation step, so we could perform this hydroelementation directly from 1 via a telescoped procedure (Scheme 5).So, we tested the hydroetherification from β,E-chloro-olefins 1a and 1d in the presence of LiOH, DMSO and 2-iodophenol as nucleophile and we obtained products 5ad and 5dd in 79 and 74% yield respectively over a two-step sequence.Similarly, hydroamination of 1c with imidazole in the presence of LiHMDS delivered product 3ca in 65% yield.We also confirmed it was possible to make the α-SF5-ketone 7c in 71% yield directly from 1c by reaction with pyrrolidine in the presence of LiHMDS, followed by hydrolysis with aqueous HBF4.In the literature, the SF5 group is often called "super CF3" since many of its physicochemical properties are enhanced compared to CF3. [10] However, the synthesis and reactivity of SF5 compounds differ significantly from the CF3 analogs.During the present study, we wondered why the hydroelementation of SF5 alkynes was perfectly regio-and stereoselective, whereas the hydroamination of CF3 alkynes in similar conditions yielded a mixture of regioisomers. [8]As comparison, Nenajdenko and coworkers described in 2016 the addition of imidazole and derivatives on CF3-alkynes forming exclusively Z-stereoisomers but with α:β regioselectivity ranging from 45:55 to 5:95 without a clear trend about the influence of the alkyne substitution.Since our group also has a strong interest in the synthesis and reactivity of CF3 alkynes, [28] we decided to reinvestigate this transformation experimentally on both CF3-and SF5-alkynes, using reactions conditions X (no base, THF, r.t., 2h) from the present report and conditions Y (20 mol% of KOH, MeCN, r.t., 24h) from Nenajdenko (See ESI, Figure S1). [8]We first observed that in conditions X or Y, the addition of imidazole on the SF5-alkyne 2a leads to a perfect β,Z-selectivity (B1).Surprisingly, with the analogous CF3alkyne 2a' no reaction occurs in conditions X, even after 24h, but the reaction proceeds in conditions Y yielding a 25:75 A1:B1 ratio in favor the β,Z-isomer (B1).Looking for a substrate giving a lower selectivity, we identified the CF3-alkyne 2b' which gave a 40:60 A1:B1 ratio. [8]heme 5. Telescoped procedures As expected, no reaction takes place in condition X with 2b', but only conditions Y are suitable to produce a 30:70 A1:B1 ratio which is closely related to what they observed.With the analogous SF5-alkyne 2b, a perfect β,Z selectivity (B1) was observed in conditions X, while a 92:8 B1:B2 mixture of stereoisomers was observed for the first time in conditions Y, and the structure was confirmed by NOE experiments. [25]However, we noticed that the β,E-isomer B2 was poorly stable overtime.For instance, after keeping the mixture of isomers in an NMR tube under sunlight for a couple of days, B1 remains intact whereas B2 evolves to the corresponding ketone 7 and other by-products.In contrast with CF3-alkynes, nucleophilic addition onto SF5alkynes always takes place at the β-position of the SF5 motif, but how to explain this difference of regioselectivity?One could say that SF5 (with an electronegativity of 3.65 vs 3.36 for CF3) polarizes more the alkyne than CF3 making the C≡C bond a better nucleophile acceptor.This is supported by the calculations of the NPA charges of the carbon atoms of the triple bond, C and C, for the fluorinated-alkynes 2a and 2a'.C bears a slightly positive charge (0.09 for 2a and 0.07 for 2a') whereas for C it is negative (-0.30 for 2a and -0.15 for 2a'), leading to a more polarized bond in 2a (q : 0.39 and 0.22 respectively, See ESI, table S3).On the other hand, the larger van der Waals volume of SF5 (55.4 Å 3 vs Figure 1.Energy profiles (G in kcal/mol) computed at PCM(THF)-M06-2X/6-311+G**//M06-2X/def2-SVP level of theory for the hydroamination of SF5/CF3-alkynes (2a/2a') with imidazole, affording A1 (, Z) and B1 (, Z) products.Activation barriers for the formation of all plausible hydroamination products (A1, A2, B1 and B2) are also reported.34.6 Å 3 for CF3) closer to a tert-butyl group would argue more in favor of steric preferences.To elucidate the origin of the observed selectivity for SF5-alkynes i.e. privileged nucleophilic attack on carbon, as well as the higher reactivity of SF5-alkynes over CF3alkynes in conditions X, we computed the different energy profiles (PCM(THF)/M06-2X/6-311+G**//M06-2X/def2-SVP) for the hydroamination reaction over SF5/CF3-alkyne 2a/2a' with imidazole in absence of base.The more relevant energy profiles associated to the formation of Z-isomers (A1, B1) are depicted in Figure 1 and the whole panorama (Z-and E-isomers) are reported in ESI, Figures S2-3).As displayed in Figure 1, the nucleophilic attack of the imidazole over the fluorinated-alkyne first forms a zwitterionic intermediate (INT), followed by a presumed fast and solvent-mediated proton transfer, leading to the final hydroamination product in a highly exothermic process (G < -19 kcal/mol).This nucleophilic addition is the step governing the regioselectivity.In line with the experimentally observed regioselectivity, DFT calculations have shown that the attack at the -carbon of SF5-alkyne 2a and leading to Z-isomer B1 is kinetically favored over the attack at the -carbon, affording Zisomer A1 (G ǂ = 21.7 vs 24.6 kcal/mol for TS1 and TS2, respectively).Closer inspection of the optimized transition states suggests that TS1 is an earlier TS than TS2, with a C•••N distance of 1.908 Å and 1.765 Å, respectively.It is noteworthy that formation of E-isomers (A2, B2) are less kinetically favorable (G # ~5 kcal/mol compared to TS1).
On the other hand, by comparing the processes involving 2a and 2a', we found that the replacement of the SF5 with CF3 produces a considerable increase of the activation barrier of the nucleophilic attack at -carbon (G ǂ = 21.7 vs 30.1 kcal/mol, respectively).This finding perfectly matches with the fact that the hydroamination reaction of SF5-alkyne 2a with imidazole occurs at r.t.but fails employing the analogous CF3-alkyne 2a'.As revealed by the C•••N distance, the highest activation barrier for TS1' corresponds to a later TS with a C•••N distance of 1.832 Å vs 1.908 Å, for respectively TS1' and TS1.
In order to further understand the origin of the -selectivity observed for the SF5-alkyne 2a, we applied two powerful computational tools to quantitatively analyze the physical factors behind the reactivity trends, namely, the Activation Strain Model of reactivity (ASM) and the Energy Decomposition Analysis (EDA). [25]The Activation Strain Model (ASM) approach was used to assess the relative contributions of the strain (Estrain) and interaction (Eint) terms upon attack of imidazole at -carbon and -carbon of the alkyne.Figure 2 shows the corresponding activation strain diagrams along the entire reaction coordination  (selected as the C•••N bond-forming distance) for the nucleophilic attack of imidazole on alkyne 2a at -carbon (dashed lines) and -carbon (solid lines).As observed in Figure 2, the Estrain term, which quantifies the required energy to distort the reactants, is considerably smaller for the nucleophilic attack at the -carbon compared to the same attack at the -carbon (at a quasi-similar C•••N distance of about 1.9 Å, close to TS1, Estrain : 10.4 for C and 24.6 kcal/mol for C see Table S1).Consequently, this term is not at all responsible for the -selectivity.In sharp contrast, the interaction term (Eint) between the reactants is much more stabilizing for the process involving the -carbon along the whole reaction coordinate, meaning that Eint term is solely responsible for the experimentally observed -selectivity.With the help of the EDA method (M06-2X/TZ2P//M06-2X/def2-SVP), we further analyzed the Eint term by decomposing it into three different chemically meaningful terms: (i) the Pauli repulsion term, Epauli, that quantifies destabilizing interactions between occupied orbitals and is a measure for any steric repulsion, (ii) the Velstat term corresponding to the quasi-classical electrostatic interaction between the reactants and (iii) the Eorb accounting for the stabilizing orbital interactions between occupied orbital of one reactant with unoccupied orbital of the other reactant.Although we computed the EDA terms along the whole reaction coordinate (see ESI, figure S5), for a direct comparison between the attack at -or -carbon, we analyzed the EDA terms at a consistent similar distance C•••N distance of ~1.9 Å, close to TS1.At this point, Eorb and Velstat terms are relatively small (Eorb = 3.7 and Velstat = 2.7 kcal/mol, in favor of C).The largest difference between the two attacks finds its origin in the destabilizing Pauli repulsion term (EPauli = 8.5 kcal, see ESI Table S2), which is much larger for C attack.This result suggests that the origin of the -selectivity observed for 2a is mainly due to a larger steric repulsion upon attack at Cthuspreventing the formation of hydroaminated -isomer.
To understand the higher reactivity of the SF5-alkyne 2a compared to the CF3-alkyne 2a', we applied again the ASM/EDA methodology for the privileged nucleophilic attack at -carbon.We found that the Estrain term for the process involving 2a and the process involving 2a' are nearly identical along the reaction coordinate (Figure 3).However, the Eint term is more stabilizing for the nucleophilic addition of imidazole on SF5-alkyne than CF3alkyne.According to EDA analysis, at a similar distance close to TS1 (C•••N ~ 1.91 Å), the largest difference between the attacks on 2a and 2a' is found in the orbital term (Eorb), which is more stabilizing for 2a [EPauli : 3.2, Velstat= -2.3 and Eorb= -5.8 kcal/mol, see ESI table S4 and Figure S7].The Natural Orbital for Chemical Valence (NOCV) extension of the EDA method shows that the main orbital interaction Eorb1 comes from the charge flow of the density from the nitrogen lone pair of imidazole to the empty *CC orbital of alkyne (See Figure 4).The highest orbital stabilization for 2a (Eorb1 : -47.5 kcal/mol vs -42.7 kcal/mol in 2a') can be correlated to a more accessible LUMO (*CC/*CC aryl (alkyne)) in SF5-alkyne compared to CF3-alkyne (-1.2 eV in 2a vs -1.0 eV in 2a', see Figure S10).In order to generalize our study, we computed the activation barriers for the attack at the -carbons of SF5-alkyne 2a and affording Z-isomers A1/B1, for two other nucleophiles experimentally reported in Scheme 4 and involving similar experimental conditions (without base) i.e. pyrrolidine and piperidine.DFT calculations (see ESI for details, Table S6) indicate the attack at C is still kinetically favored, in line with the experimental results.The activation barriers for the nucleophilic attack at -carbon were computed lower in energy than for imidazole, at G ǂ = 15.5 and 15.2 kcal/mol, respectively for pyrrolidine and piperidine, suggesting more reactive nucleophiles.In addition, a lower energy difference between the two transition states associated with the attacks in  and  was found for pyrrolidine and piperidine (G # : -1.5 and -1.0 kcal/mol, respectively) compared to imidazole (G # : -2.9 kcal/mol) but did not impact the selectivity.As these DFT studies fully support the experimental selectivities, we then embarked in control experiments to gain further insights into the mechanism (Scheme 6). [8,29]he reaction proceeds smoothly in the presence of 4 equiv. of TEMPO and gave the desired product 5ab without inhibition of the reaction.When DMSO-d6 was used as solvent a mixture of deuterated and not deuterated product was obtained in a 50:50 ratio, showing the crucial role of the solvent in this reaction acting as a H/D-donor.Moreover, the incorporation of deuterium took place only on the olefin in α-position of the SF5.Finally, we studied some downstream functionalizations.Palladium-catalyzed Negishi cross-coupling with diethylzinc delivered 8a in 49% yield.Suzuki-Miyaura cross-coupling with phenyl boronic acid (8b) and Sonogashira cross-coupling with TMS-acetylene (8c) were also performed in 75 and 57% yields, respectively (Scheme 7,a).Intermediate enamine 6a 1 can react with an electrophilic halogen source such as NCS or NBS to form α-chloro or α-bromo α-SF5-ketones (9a, 10a) in presence of water to quench the intermediate iminium (Scheme 7,b).Enamine 6a 1 can also be reduced with BH3.SMe2 to form the corresponding amine 11a in decent 55% yield.Finally, reduction of the α-SF5ketone 7a was performed in high yield (94% 13a) using sodium borohydride in ethanol.Moreover, we succeeded to perform a Baeyer-Villiger oxidation on the ketone 7a leading to the corresponding ester 12a in 71% yield (Scheme 7,c).

Conclusion
In summary, we have developed an efficient and general hydroelementation reaction on SF5-alkynes.The reaction tolerates a wide range of N-, O-, and S-nucleophiles and gives the corresponding adducts in good yields and in all the cases as a single regio-and stereoisomer.A complementary synthesis of α-SF5-ketones was performed under mild condition and without any use of metals.Moreover, it was shown that these transformations can also be performed directly from the corresponding β,E-chloroolefins which shorten the synthesis by one step.A selection of downstream functionalizations was demonstrated, including C-C cross coupling, halogenation, reduction and Baeyer-Villiger oxidation.DFT calculations were also performed to better understand the impact on reactivity of the SF5 compared to the CF3 group, which nuance the comparison of SF5 as a super CF3, but seems to indicate that they have very distinct properties and reactivities.DFT calculations combined with ASM/EDA analyses were performed to have better insight on the -selectivity for SF5alkyne and the impact of the fluorinated group (SF5 vs CF3) for the hydroamination reaction with imidazole.The origin of the selectivity for the SF5-alkyne is related to a lower steric repulsion (EPauli) upon attack at C. Compared to CF3-alkyne, the Cnucleophilic attack of imidazole on SF5-alkyne occurs in the absence of base thanks to better orbital interaction between the nitrogen lone pair of imidazole and the empty *CC (alkyne), which is more accessible in energy than in CF3-alkyne.

Scheme 1 .
Scheme 1. State of the art and proposed strategy for the hydroelementation of SF5-alkynes.

Scheme 2 .
Scheme 2. Scope and limitation for the N, O and S-nucleophilic addition.The reaction was performed from SF5-alkyne 2 unless otherwise noted.a THF was used instead of DMSO with 2 equiv. of nucleophile without base, b Obtained from the reaction with NaN3 as nucleophile, c KOH was used instead of NaH, d Same yield on 0.03, 0.3 and 0.6 mmol scale, e Reaction performed from the corresponding β,E-chloro-olefin 1, f Only the Z-isomer was recovered after silica gel chromatography.
Scheme 4. Scope and limitation for the formation of α-SF5-ketones.a H2SO4 10% was used instead of HBF4, b Enamine 6g was partially obtained but not isolated.

Figure 2 .
Figure 2. Activation strain diagrams computed along the IRC for the paths to TS1 (attack at C, dashed lines) and TS2 (attack at C, solid lines) of the hydroamination reaction of SF5-alkyne 2a with imidazole.Energy level: M06-2X/def2-SVP.

Figure 3 .
Figure 3. Activation strain diagrams computed along the IRC for the privileged path through TS1 (attack at C for 2a, dashed lines) and TS1' (attack at C for 2a', solid lines) of the hydroamination reaction of the fluorinated alkynes with imidazole.Energy level: M06-2X/def2-SVP.

Figure 4 .
Figure 4. Plot of the evolution of the orbital interaction energy contribution (ΔEorb,1 in kcal/mol) of the main pairwise orbital interaction between the fluorinated-alkynes and imidazole all along the process for the attack at C.TS1 is in solid line and TS1' in dashed line.Plot of the contours of deformation density contribution (Δρorb,1) of the main pairwise orbital interaction and associated orbital interaction energy contribution (ΔEorb1 in kcal/mol).
Scheme 6.Control experiments and proposed mechanism