Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (−CF₂H) Motifs

Abstract

An emerging class of C–C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbon-ickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene’s intrinsic electronic bias.

Introduction

The backbone of many natural products and synthetic entities consists of saturated carbon-carbon (C–C) bonds.^[1–3] Increasing the degree of molecular saturation also offers the opportunity to incorporate out-of-plane substituents and tune molecular shape, whichis crucial for enhancing receptor/ligand complementarity in drug development.^[4,5] In this vein, transition metal-catalyzed alkene hydrocarbonation provides an expeditious route to saturated organic molecules from readily available starting materials, through simultaneous incorporation of hydrogen and a carbon-based functional group.^[6–8] In particular, an effective way of generating stereogenic carbon centers involves the branched (Markovnikov)-selective hydroarylation of α-olefins.^[9–11] Although related processes with activated alkenes^[12,13] (such as styrenes) and unactivated alkenes^[14] using common hydride sources such as hydrosilanes,^[15,16] alcohols^[17,18] and metal alkoxides^[19,20] are well-documented, the corresponding transformations of fluorinated olefins^[21] which would afford prized F-containing products are exceedingly rare. Organofluorine molecules are ubiquitous in various fields, most notably in the preparation of drugs^[22,23] and agrochemicals.^[24] Fluorine is also employed in niche applications such as radioactive labeling for positron emission tomography (PET).^[25]

In this regard, enacting regioselective hydroarylation(alkenylation) of geminal or 1,1-difluoroalkenes to afford molecular architectures with difluoromethyl (CF₂H)-substituted carbon centers^[26,27] is especially compelling, given that such moieties are known to impart beneficial properties such as improved bioavailability, lipophilicity and metabolic stability to biologically active molecules.^[28–30] Importantly, CF₂H groups prevalently serve as lipophilic hydrogen-bond donors and bioisosteres for alcohols, thiols and amines in medicine^[28] and agriculture^[24] (Scheme 1A). Currently, common ways to introduce the CF₂H group involve the deoxyfluorination of aldehydes,^[31,32] or the insertion of difluorocarbenes into X–H bonds (X=C, N, S etc.) to deliver CF₂H-substituted motifs adjacent to a heteroatom.^[33,34] Other methods such as radical-based approaches,^[35,36] electrochemistry,^[37,38] and cross-coupling,^[39–43] have also been successful in installing the difluoromethyl functional group. A comprehensive review by Zafrani et al. covers a wide range of methods for accessing the difluoromethyl group.^[44] Access to difluoromethylated compounds via alkene hydrofunctionalization represents a distinct approach. However, most reported hydrofunctionalization methods to date rely on pre-installing electronically stabilizing arenes to the olefin, presumably to increase π-bond reactivity towards hydrometallation^[21,45] (Scheme 1B). Lower reaction efficiency is typically observed with the more general alkyl-substituted (but less-activated) gem-difluoroalkenes, engendering other side reactions such as hydrodefluorination^[46–48] to become competitive (Scheme 1C).

Scheme 1.

The significance and challenges of accessing difluoromethylated compounds by catalytic hydrofunctionalization of 1,1-difluoroalkenes.

Of the established protocols that afford CF₂H-substituted carbon centers, hydroboration and hydrosilylation^[26] have been disclosed to give aryl-substituted fluoroalkylborane and fluoroalkylsilane products, respectively, which still need to be subjected to another C–C cross-coupling to form the desired hydrocarbonation products.^[49,50] On the other hand, site-selective hydrocarbonation of styrenyl difluoroalkenes by Pd-catalyzed hydroalkoxycarbonylation was recently demonstrated, although the scope was restricted to ester formation and undesired isomerization was found with alkyl-substituted gem-difluoro substrates.^[27] Thus, a general hydroarylation(alkenylation) protocol that retains the two fluorine atoms using nonprecious metal catalysis remains largely obscure.

Here, we address the aforementioned challenges by designing a N-heterocyclic carbene (NHC)-nickel-catalyzed regime that is capable of mediating direct 1,2-selective hydroaryl(alkenyl) additions to readily accessible non-styrenyl gem-difluoroalkenes, using bench-stable reagents, to deliver a wide array of compounds containing difluoromethylated carbon centers (Scheme 1C, grey inset). The present system is complementary to previously reported Cu-catalyzed radical relay reactions^[51] for alkene carbo-difluoromethylation,^[52–54] in which reactive aryl diazonium salts or N-hydroxyphthalimide esters in combination with an air- and moisture-sensitive difluoromethyl-zinc complex (large-scale synthesis in the laboratory is non-trivial) were employed.

Results and Discussion

Previous efforts in branched-selective hydroarylation often involve the generation of a catalytically active metal hydride species, triggering regioselective hydrometallation of the alkene substrate followed by arylation.^[15,55] However, extension of this reaction manifold to electronically biased gem-difluoroalkenes is expected to be problematic, since β-F elimination of the alkylmetal intermediate derived from hydrometallation would be difficult to avoid^[56] (Scheme 2A). To this end, we wondered if a size-programmable NHC-nickel catalytic species could be leveraged to induce site-selective arylnickelation under steric control.^[19,20] Subsequent transformation of the C–Ni bond to C–H via hydride transfer would deliver the desired difluoromethylated product. Through this mechanistic reversal of events, defluorinative side reactions can be potentially suppressed. However, unlike a non-fluorinated alkene, the corresponding 1,1-difluoro π-bond is significantly more polarized, making it more challenging to overcome the substrate’s strong electronic bias and achieve sterically controlled arylnickelation (Scheme 2A, inset).

Scheme 2.

Reaction design to achieve site-selective 1,2-hydroarylation(alkenylation) of 1,1-difluoroalkenes and the beneficial effect of tuning the metal alkoxide. Yields and regioisomeric ratios (r.r.) were determined by GC with tridecane as an internal standard. Value in parentheses denotes isolated yield.

Initial studies revealed that 10 mol% of the in situ-generated Ni-based complex derived from Ni(cod)₂ and imidazolium chloride L1 promoted hydroarylation of unactivated alkene 1 in the presence of commercially available bromoarene 2 and NaOiPr (5 equiv.) as the hydride donor (which forms the requisite Ni-hydride by β-H elimination of a Ni-alkoxide species^[19,20]), furnishing the desired adduct 3 in 90% GC yield and >98:2 regioisomeric ratio (r.r.) at 40°C in toluene within three hours (Scheme 2B). In stark contrast, no desired hydroarylation product 5 was detected in the analogous reaction of gem-difluoroalkene 4. Instead, a complicated mixture of arylated alkanes (6, 7) and alkenes (8–10) with different degrees of mono- and bis hydrodefluorination^[57] was observed. Through control experiments with a separately synthesized monofluoro-analogue of 1 (Supporting Information section 4.5), we found that adventitious hydrodefluorination^[46–48] of 4 (leading to 10 and 1) likely occurred before any events of hydroarylation^[19,20] (leading to 6 and 7) or Heck reaction^[58–60] (leading to 8 and 9). Evidently, undesired hydrodefluorination and/or β-H elimination processes must be suppressed to achieve successful 1,2-hydroarylation.

Previous computational studies on NHC-nickel-catalyzed alkene functionalization reactions revealed that coordination of the alkoxide to the organonickel complex is involved in key steps.^[61] On this basis, we wondered if tuning the steric environment around the Ni center by modulating the alkoxide could inhibit undesired side reactions of 4. After an extensive evaluation of various conditions (SI Section 5), we found that replacing NaOiPr with a sterically more encumbered NaOCHPhMe as hydride donor significantly suppressed defluorinative side reactions, and the desired difluoromethylated adduct 5 was finally secured in 40% GC yield (60% conversion (conv.)) as a single regioisomer (Table S8). Full substrate conv. was attained by increasing the catalyst loading to 20 mol%, affording 5 in 80% GC (74% isolated) yield (Scheme 2C).

Other NHC ligands besides L1 led to lower yields, while reactions using N- or P-based ligands were unproductive (Table S4). Increasing or decreasing the temperature did not improve reaction efficiency (Table S5). Substrate conv. to product was lower when the metal alkoxide loading was reduced to <5 equiv., although the degree of defluorinative side product formation remained fairly constant (Table S6). It is worth noting that replacing NaOCHPhMe with other hydride sources such as hydrosilane/fluoride^[15,16] or alcohol^[17,18] inhibited the trans-formation (<5% conv.; (Table S3), hinting that binding of ⁻OCHPhMe is crucial during the catalytic cycle. Notably, in situ generation of the metal alkoxide by mixing an alcohol and base led to diminished yields (Tables S11, S12). On the other hand, hydroarylation with other aryl-substituted halide/pseudohalide reagents were less efficient (Table S2).

Additional studies were performed to obtain more mechanistic insights (Scheme 3). Under the standard conditions, the reaction of difluoro-vinylcyclopropane 11 and 12 delivered the expected hydroarylation product 13 in 81% yield (3 : 1 d.r.) as a single regioisomer with no traces of ring-opening detected (Scheme 3A). Computations studies suggest that if the putative radical is formed, radical ring-opening is extremely fast (barrier is only 2.2 kcal/mol and irreversible (downhill by 11.2 kcal/mol). The addition of a radical scavenger such as butylated hydroxytoluene (BHT) also did not inhibit the reaction (SI Section 4.4). Taken together, these suggest that long-lived radical species are unlikely to be involved in the present reaction system, which is in contrast to alkene hydroarylations promoted by metal-hydride hydrogen atom transfer.^[14,16,55] In another study, the origin of the hydride source was ascertained through the analogous deuteroarylation of gem-difluoroalkene 14 in the presence of 2 and NaOCDPhMe, furnishing 15 in 70% yield with ≈1.0 deuterium incorporation on the difluorinated carbon as well as acetophenone as by-product (Scheme 3B). This result provides strong evidence that NaOCHPhMe served as a hydride donor during the course of the reaction.

Scheme 3.

Mechanistic studies.

A key mechanistic question that we sought to address relates to why changing the hydride source from NaOiPr to the sterically more demanding NaOCHPhMe facilitates the desired hydroarylation and suppresses hydrodefluorination (Scheme 2B). To gain a better understanding, we turned to unrestricted open-shell dispersion-corrected density functional theory (DFT) calculations. Overall, based on our studies as well as previous works,^[19,20,61] extensive mechanistic scenarios were considered, but for simplicity, only the lowest energy productive catalytic pathway are discussed (see Supporting Information Section 7 for full computational details and alternative mechanisms considered). Specifically, as shown in Scheme 4A, in the presence of L1 and Ni(cod)₂, reaction with aryl bromide could lead to ii (downhill in energy by 16.9 kcal/mol) via a low barrier oxidative addition (ΔG^‡=2.6 kcal/mol). Complex ii would then undergo a branched-selective π-complexation/1,2-migratory insertion (barrier of 10.9 kcal/mol with respect to ii via TS_ii-iii) across the gem-difluoroalkene A to generate iii. Notably, the competing linear-selective migratory insertion (via TSii’-iii_branched) pathways is less favored (ΔG^‡_rel=12.7 kcal/mol versus 10.9 kcal/mol; see SI). Distortion/interaction analysis revealed that the lower barrier associated TSii’-iii_branched is due to a much stronger interaction energy (ΔE_int) between the two fragments compared to TSii-iii_linear (Scheme 4B). In addition, Natural Bond Orbital (NBO) analysis showed that TSii-iii_branched benefits from favorable donor-acceptor interaction energy from the bonding orbital (BD) of the C1–C2 bond to the LP* (antibonding orbital) on the nickel atom (Scheme S27).

Scheme 4.

Proposed mechanism for NHC–Ni-catalyzed 1,2-hydroarylation(alkenylation) of 1,1-difluoroalkenes supported by DFT calculations. A. Computational studies were performed at the UM06L-D3/def2tzvpp-CPCM(toluene)//UB3LYP-D3/def2svp-CPCM(toluene) level of theory for the catalytic 1,2-hydroarylation(alkenylation) of 1,1-difluoroprop-1-ene (model system) and free energies are reported in kcalmol⁻¹ (298 K). B. Key transition state structures show that branched-selective 1,2-migratory insertion is kinetically favored over the linear-selective 1,2-migratory insertion.

Notably, we also considered the mechanistic scenario in which early formation of Ni-alkoxide from ii (via transmetallation with the exogenous alkoxide) in the catalytic cycle could occur prior to migratory insertion. However, inconsistent with experiments, this mechanistic scenario predicted poor site selectivity and a much higher energy barrier for the 1,2-migratory insertion step (Scheme S28). Instead, transmetallation of ii with the exogenous alkoxide reagent (NaOCHPhMe) could lead to the Ni-alkoxide species iv. In turn, iv could undergo regioselective β-H elimination with the alkoxide to deliver Ni-hydride v (barrier of 13.2 kcal/mol with respect to iv) with concomitant formation of the experimentally observed acetophenone by-product. We also considered the early formation of Ni-hydride from ii via transmetallation/β-H elimination with NaOCHPhMe, but we found that this process is not thermodynamically favored and leads to defluorinative side products (see SI). Finally, compound v would undergo reductive elimination (barrier of 17.5 kcal/mol with respect to v) to generate the desired hydroarylation product and restart the catalytic cycle. Consistent with the need for excess alkoxide, calculations showed that coordination of the acetophenone by-product from β-hydride elimination also plays an important role in lowering the energy barrier in the reductive elimination. Thus, as the reaction proceeds, more acetophenone is produced which, in turn, increases the concentration of acetophenone to assist in promoting this high energy step.

Next, we turned our attention to using computations to gain insights into the dramatic effect of the hydride source (i.e., NaOiPr versus sterically more demanding NaOCHPhMe) in facilitating the desired 1,2-hydroarylation of gem-difluoroalkenes. As shown in Scheme 5, the thermo-dynamic drive for the transmetallation of Ni-bromide iii with both alkoxide reagents to form iv is essentially the same (downhill in energy by ≈21.0 kcal/mol). However, calculations showed that the β-H elimination proceeds 10 times faster with Ni-OCHPhMe compared to Ni-OiPr via TS_iv-v’ (ΔG^‡=14.2 kcal/mol versus 13.2 kcal/mol) to form Ni-hydride v with concomitant formation of the corresponding ketone, presumably due to the favorable π–π stacking interaction between the phenyl group in the acetophenone and the ligand fragments (Scheme S31). We also considered the alternative elimination of from iv to form the corresponding gem-difluoroalkene, but the energy barrier for this process was much higher (ΔG^‡≈40.0 kcal/mol, Scheme S32).

Scheme 5.

Comparison between NaOiPr and NaOCHPhMe on Ni-hydride formation and reductive elimination supported by DFT calculations at the UM06L-D3/def2tzvpp-CPCM(toluene)//UB3LYP-D3/def2svp-CPCM(toluene) level of theory.

Finally, compound v would undergo reductive elimination to generate the desired hydroarylation adduct via TS_v-vi. Overall, calculations showed a much higher energy barrier for the system that leads to acetone (R=Me) formation as a by-product than that of the system that leads to acetophenone (R=Ph) during the Ni-hydride formation likely due to the greater capacity of acetophenone to stabilize the nickel complex (Scheme S33) and, as revealed from NBO analysis, a more favorable donor-acceptor interaction energy from the lone pair (LP) orbital of the oxygen to the LP* (antibonding orbital) on the nickel atom in the TS_v–vi (R=Ph) compared with TS_v-vi (R=Me). This conclusion is supported by experimental observations showing that the generation of acetophenone is faster than that of acetone (Scheme S8).

We assessed the generality of the catalytic method with different functionalized substrates. The scope of sp²-hybridized carbon electrophiles (sp³-variants are ineffective in the system) was explored under our established conditions (Table 1). Various haloarenes (X=Br or I) containing electron-rich or electron-deficient groups at the ortho-, meta- and/or para-positions underwent hydroarylation to furnish 16–40 in 40–87% yield. These include products bearing a Lewis basic amine (26), an amide (27) as well as those with a triflate (25), chloride (29, 35, 36) or bromide (34) moiety that can be orthogonally functionalized to give a broader assortment of synthetically useful compounds. Remarkably, access to 25 underscores the exceptional chemoselectivity observed, allowing preferential transformation of a C–Br bond in the presence of a C–OTf unit, which is distinct from hydroarylations of non-fluorinated alkenes.^[19]

Table 1:

The scope of organohalides in NHC–Ni-catalyzed 1,2-hydroarylation(alkenylation).

Regioisomeric ratios (r.r.) were determined by GC and ¹H NMR analysis. Yields denote isolated yields. ^aIodide was used. ^bTriflate was used.

Sterically hindered arenes (38, 39) and heteroarenes (40) could also be successfully installed through this regime. However, reactions with aryl halides bearing pyridine, aldehyde/ketone as well as congested 2,6-disubstituted arenes were not productive (see Supporting Information Section 2 for details). Hydroalkenylation could be achieved to deliver allylic-CF₂H compounds 41–43 in 56–80% yield. No adventitious hydrogenation of the pendant C=C bonds was detected. In these cases, alkenyl triflates served as more effective reagents compared to their bromo-analogues. Across the board, 1,2-hydrocarbonation adducts bearing difluoromethylated carbon centers were isolated with >98% site selectivity.

Next, we examined the alkene scope by subjecting a range of functionalized gem-difluoroalkenes to hydroarylation with 12 (Table 2). Gratifyingly, 44–55 were generated in 56–90% yield with complete site selectivity. gem-Difluoroalkenes with aromatic (50) or saturated heterocycles (54) and those with branching at the allylic (53–55) or homoallylic (51) position were tolerated. The transformation leading to 52 bearing a linear (unfunctionalized) alkyl chain shows that electronic activation is unnecessary, as opposed to most established systems that employed styrenyl substrates (Scheme 1B). Diastereoselective hydroarylation of an enantioenriched substrate could be accomplished to deliver sterically congested 55 in 7:1 diastereomeric ratio (d.r.). The major diastereomer of 55 was ascertained by X-ray crystallographic analysis (see SI).^[62] Besides alkyl-substituted substrates, reaction with styrenyl difluoroalkene also proceeded to give 56.^[63]

Table 2:

The scope of 1,1-difluoroalkenes in NHC–Ni-catalyzed 1,2-hydroarylation.

Regioisomeric ratios (r.r.) and diastereomeric ratios (d.r.) were determined by GC and ¹H NMR analysis. Yields denote isolated yields.

Conclusion

We have built a catalytic solution that overcomes a prevailing challenge involving 1,2-hydroarylation(alkenylation) of alkyl-substituted gem-difluoroalkenes, which are notoriously difficult substrates owing to low reactivity and susceptibility to defluorinative side reactions. Through the combination of a sizeable NHC-nickel catalyst and a sterically demanding metal alkoxide as hydride donor, defluorination was considerably suppressed, providing straightforward access to a wide variety of medicinally valuable saturated entities with CF₂H-functionalized carbon centers. The mechanistic insights derived from our studies are expected to fuel the design of new catalytic transformations that address other problems related to the synthesis of multifunctional organofluorides.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.