A Sterically Tuned Directing Auxiliary Promotes Catalytic 1,2‐Carbofluorination of Alkenyl Carbonyl Compounds

Abstract

The site‐selective palladium‐catalyzed three‐component coupling of unactivated alkenyl carbonyl compounds, aryl‐ or alkenylboronic acids, and N‐fluorobenzenesulfonimide is described herein. Tuning of the steric environment on the bidentate directing auxiliary enhances regioselectivity and facilitates challenging C(sp³)−F reductive elimination from a Pd^IV intermediate to afford 1,2‐carbofluorination products in moderate to good yields.

Judicious tuning of the steric environment on the bidentate directing auxiliary is proposed to facilitate challenging C(sp³)−F reductive elimination from a Pd^IV intermediate in the site‐selective palladium‐catalyzed three‐component coupling of unactivated alkenyl carbonyl compounds, aryl‐ or alkenylboronic acids, and N‐fluorobenzenesulfonimide.

The incorporation of carbon‐fluorine (C−F) bonds can impart favorable properties into small molecules for applications in the pharmaceutical, agrochemical, and material sectors. ^[1] As such, the development of strategies that enable the formation of C−F bonds has become a major research area of both industrial and academic importance in recent years. ^[2] In particular, multicomponent intermolecular carbofluorination of alkenes is an attractive transformation as it combines C−C skeletal formation and C−F installation into a single chemical operation. ^[3] In this context, carbofluorination allows for the conversion of readily accessible alkene feedstocks into structurally complex fluorinated molecules; however, achieving regio‐ and chemoselectivity in these transformations remains challenging.

Building on early work in alkene fluorocyclization processes, ^[4] Toste and co‐workers have reported intermolecular three‐component 1,1‐arylfluorination reactions ^[5] (where regioselectivity is governed by substrate electronics) (Scheme 1A) and 1,2‐arylfluorination reactions ^[6] (where selectivity is governed by substrate directivity) to construct chiral benzyl fluorides using palladium/N,N‐ligand systems (Scheme 1B). Chen and co‐workers recently extended the scope of this method to include doubly activated internal enamides. ^[7] Our group has reported a transient directing group approach for the arylfluorination of ortho‐alkenylbenzaldehydes using arylboronic acids and an electrophilic fluorine source. ^[3]

Scheme 1.

a) State of the art in palladium‐catalyzed alkene arylfluorination using electronic control. b) Recent examples in palladium‐catalyzed alkene arylfluorination using directing groups. c) Directed carbofluorination utilizing a novel directing group for alkene functionalization.

While the aforementioned work represents a great deal of progress, significant limitations in alkene carbofluorination remain. Only aryl derivatives have been found to be competent nucleophiles in palladium‐catalyzed 1,2‐carbofluorinations, and only a single example of intermolecular arylfluorination of unactivated alkene substrates has been reported to date (with 1,1‐selectivity observed). ^[5a] Alternative radical processes require up to 12 equivalents of alkene to provide synthetically useful yields and necessitate the use of aryldiazonium salts or related radical precursors. ^[8]

With the previous efforts in mind, we recognized an opportunity to design a complementary method for selective 1,2‐carbofluorination of unactivated alkenes. During the past five years, our group and others have developed a suite of palladium‐catalyzed, three‐component directed alkene 1,2‐difunctionalization reactions facilitated by the bidentate 8‐aminoquinoline (AQ) auxiliary. ^[9] Considering the potential for 1,2‐carbofluorination via this strategy, we questioned whether alkylpalladium intermediates arising from directed migratory insertion could be intercepted via oxidation with an electrophilic fluorine source. Given that directing groups are well‐established to help overcome the inherent kinetic challenges associated with C(sp³)−F reductive elimination,[ ³ , ¹⁰ ] we hypothesized that effective reaction conditions for the 1,2‐carbofluorination of unactivated alkenes could be identified through optimization of a specifically tailored N,N‐bidentate directing auxiliary that enables regioselective arylpalladium migratory insertion, prevents β‐H elimination, and facilitates C(sp³)−F reductive elimination. To this end, herein we disclose the discovery and development of 1,2‐aryl‐ and 1,2‐alkenylfluorination reactions of unactivated 3‐butenoic acid derivatives (Scheme 1C).

Based on our past work, we initiated our investigation using AQ‐masked 3‐butenoic acid as the alkene substrate and (4‐methoxyphenyl)boronic acid as the nucleophile (Table 1). We observed the desired arylfluorination product in up to 33 % yield, establishing the feasibility of this reaction; however, attempts to further improve the yield proved unsuccessful. Hence, we turned to tuning of the directing auxiliary itself, based on the hypothesis that a more strongly σ‐donating and sterically bulky DG would give rise to improved results in this Pd^II/Pd^IV redox process. The Chatani lab has developed a picolinyl amine auxiliary in which the planar ring structure in AQ instead contains a sp³‐hybridized carbon linker, which allows for bidentate chelation with conformational flexibility. ^[11] The Shi group has pioneered gem‐dimethyl‐substitution as a means of restricting conformationally flexibility and tuning bite angle through the Thorpe–Ingold effect. ^[12] We thus explored these and other bidentate directing groups to test their efficacy in the envisioned arylfluorination. ^[13]

Table 1.

Optimization of the intermolcular arylfluorination reaction.

[a] Combined yield of regioisomers and r.r. based on ¹H NMR and ¹⁹F NMR of crude reaction mixture using benzyl 4‐fluorobenzoate as an internal standard. [b] Isolated yield of major regioisomer in parentheses. [c]  Me₃PyF(BF₄)=1‐fluoro‐2,4,6‐trimethylpyridinium tetrafluoroborate.

Analogously to trends in C−H activation chemistry, replacement of the AQ directing group with a PIP auxiliary increased both the reactivity and selectivity of the reaction. We hypothesized that increasing the steric demand of the gem‐dialkyl substitution within the backbone of the PIP directing group might lead to further improvements through the Thorpe–Ingold effect ^[14] in addition to tuning the level of steric hindrance within the secondary coordination sphere of the palladium center. Indeed, the replacement of the gem‐dimethyl group with a gem‐diethyl group gave an increase in isolated yield and a decrease in observed side products while maintaining excellent regioselectivity. ^[15] Replacement with a gem‐dipropyl group gave further improvements in regioselectivity, albeit with lower isolated yields. Substitutions on the pyridyl ring were found to influence r.r., but led to slightly diminished isolated yields; thus, we selected the picolinyl‐α,α‐gem‐diethyl amine (PDE) as our standard directing group. Additionally, we found that the improvement in yield when using PDE instead of AQ or PIP was consistent across a representative panel of substrates with different alkene substitution patterns (see Supporting Information for details).

Following a screening campaign investigating a variety of solvents, palladium sources, and catalyst loadings (see Supporting Information for details), we identified conditions shown in Table 1. In the presence of Pd(MeCN)₄(BF₄)₂ and Et₃N ⋅ 3HF, (4‐methoxyphenyl)boronic acid, an electrophilic fluorine source, and model alkenyl substrate (DG=PDE) underwent efficient three‐component coupling to generate the desired product (Entry 1). Control experiments revealed that NFSI was necessary for product formation while exclusion of Et₃N ⋅ 3HF led to slightly reduced selectivity and yield (Entries 2–3). We hypothesize that Et₃N ⋅ 3HF aids in transmetalation. Alternative bases were also operable with diminished yields (Entries 4–5). While alternative electrophilic fluorine sources gave increased selectivity (Entries 6–7), they led a significant decrease in yield. The catalyst loading could be lowered to 7.5 % without a significant decrease in yield or r.r. (see Supporting Information).

Having optimized the conditions, we next investigated the scope of the organoboronic acid coupling partner using 1 as our standard alkene substrate. As shown in Table 2, both electron‐donating and ‐withdrawing substituents at various positions on the aryl ring of the boronic acid were readily accommodated in the transformation, giving useful to good yields. Yields were generally better for electron‐donating groups compared with electron‐withdrawing groups at the para‐ and meta‐ positions. ortho‐Substituted arylboronic acids were also found to serve as competent coupling partners. Additionally, boronic acids incorporating protected functional groups were successfully introduced, including phenols (2 p) and anilines (2 c and 2 d). In terms of heterocyclic coupling partners, the reaction proceeded with furan, benzodioxole, and isoindolinone (giving 2 n, 2 s, and 2 v, respectively), but it did not tolerate those containing basic N(sp²) atoms, such as pyridines and pyrazoles. Gratifyingly, the reaction was also compatible with a handful of aryl‐substituted alkenylboronic acids (2 w–2 y), although alkenylboronic acids did result in comparatively lower yields. Unfortunately, extension to simple alkyl‐substituted alkenylboronic acids did not prove successful.

Table 2.

Scope of the boronic acid coupling partner.

[a] Combined yield of regioisomers and r.r. based on ¹H NMR and ¹⁹F NMR of crude reaction mixture using benzyl 4‐fluorobenzoate as an internal standard. [b] Isolated yield of major regioisomer in parentheses.

With respect to the alkene coupling partner, substituents were tolerated at the α‐, β‐, and γ‐positions (Table 3). Notably, substituted alkenes containing synthetically useful functional handles, such as nitrile (3 d) and protected aldehyde (3 f), were tolerated, albeit with modest yield. Only a single regioisomer was observed for simple alkyl substitutions at the β‐position. Diminished regioselectivity was observed in the presence of substitution at the γ‐position (3 j). With the scope of the carbofluorination established, we next sought to demonstrate that the PDE auxiliary could subsequently be removed to give a versatile carboxylic acid. Indeed, the PDE directing group could be effectively cleaved according to the sequence at the bottom of Table 3 in which nitrosylation with NaNO₂ under acidic conditions is followed by hydrolysis with in situ generated LiOOH to give the corresponding acid (3 k). ^[10c]

Table 3.

Scope of the alkene substrate.

[a] Combined yield of regioisomers, r.r., and d.r. based on ¹H NMR and ¹⁹F NMR of crude reaction mixture using benzyl 4‐fluorobenzoate as an internal standard. [b] Combined isolated yields of diastereomers of major regioisomer in parentheses. [c] r.r. >20 : 1. [d] Combined isolated yield of regioisomers.

We sought to understand the reaction mechanism and in particular the beneficial effect of the PDE directing auxiliary. While the PIP group has previously been found to promote C(sp³)−H fluorination, a control experiment ruled out an alternative mechanistic pathway involving sequential alkene hydroarylation followed by C(sp³)−H fluorination (see Supporting Information). Additionally, the diastereoselectivity of product 3 j indicates syn‐addition of the Ar and F groups across the alkene (see S‐3 in the Supporting Information for an example with relative stereochemistry confirmed by X‐ray crystallographic analysis), ^[16] consistent with 1,2‐migratory insertion followed by stereoretentive C(sp³)−F reductive elimination.

Regarding the role of the PDE group, as previously mentioned, the Thorpe–Ingold effect can play a significant role in the reactivity of organometallic intermediates, especially in reductive elimination processes. In the PIP‐directed fluorination of unactivated C−H bonds at the β‐position relative to the directing group, both the groups of Shi ^[10b] and Ge ^[10c] proposed that the sterically bulky gem‐dimethyl moiety in PIP amine may facilitate the typically challenging C−F reductive elimination from Pd^IV. Hoping to gain insight into the properties of the PDE directing group that result in higher selectivity and yield compared with more commonly used PIP and AQ directing groups, we performed DFT calculations on the alkene bound palladium complexes as well as the postulated Pd^IV intermediates. The geometry obtained was evaluated using SambVca, ^[17] an online tool for the calculation of buried volume ^[18] and steric maps. ^[19]

Nolan and Cavallo have pioneered %V_Bur (the fraction of the volume of a sphere centered on the metal atom occupied by a given ligand, or in this case, directing group) as a powerful descriptor for designing and understanding the performance of transition metal complexes. While %V_Bur has been applied in a wide variety of catalyst and reaction classes, to the best our knowledge it has not been directly applied towards the understanding of intramolecular directing group chemistry. ^[20] We observed a trend between yield/selectivity and the calculated %V_Bur for the AQ, PIP, and PDE directing groups in both the alkene and Pd^IV complexes (Scheme 2). We hypothesize that this trend is a result of increasing steric density around the palladium center, which would be consistent with previous studies suggesting that steric bulk can help to overcome the kinetic barriers posed by C−F reductive elimination from Pd^IV. Taken together, the results of our mechanistic investigations and prior literature precedent are consistent with the mechanism outlined in Scheme 3.

Scheme 2.

Correlation between selectivity/yield and the percentage of buried volume, %V_Bur, (the fraction of the volume of a sphere centered on the palladium atom occupied by a given ligand, or in this case, directing group) calculated for AQ, PIP, and PDE; (L¹=N(SO₂Ph)₂, L²=MeCN).

Scheme 3.

Proposed catalytic cycle.

With this mechanistic model in mind, we concluded this study by exploring the potential for enantioinduction. Several groups, including Toste, ^[6] Chen, ^[9g] Zhao, ^[9h] Shi,[ ¹⁵ , ²¹ ] and our lab, ^[22] have demonstrated that palladium‐catalyzed directed functionalizations of alkenes and C(sp³)−H bonds can be rendered asymmetric through judicious selection of chiral ligands. Based on these results, we screened a library of chiral ligands, including amino acids, amines, BINOL, CPA, MOXin, Pyrox, BOX, and BiOX ligands (see Supporting Information for details). Following an initial hit with commercially available 2,2′‐bis[(4S)‐4‐benzyl‐2‐oxazoline] which afforded 2 a in 63 % yield (r.r.=3 : 1, e.r.=81 : 19 (major)), additional BiOX ligands were synthesized and tested, with ligand (R,R)‐L15 giving the best enantioselectivity but lower regioselectivity (76 % yield, r.r.=2 : 1, e.r.=16 : 84 (major)) (Scheme 4). Diminished r.r. values in these experiments may stem from the BiOX ligand partially or completely displacing the PDE auxiliary during the migratory insertion step. These preliminary results establish the viability of enantioinduction in the three‐component carbofluorination of unactivated alkenes, while underscoring the challenges of simultaneously controlling both regio‐ and enantioselectivity with these substrates (see Supporting Information for details).

Scheme 4.

Extension to enantioselective 1,2‐arylfluorination.

In conclusion, we have disclosed a site‐selective palladium‐catalyzed three‐component coupling of unactivated alkenyl carbonyl compounds, aryl‐ or alkenylboronic acids, and N‐fluorobenzenesulfonimide to afford 1,2‐carbofluorination products in modest to good yields and with moderate to high regioselectivity. The data presented herein suggest that tuning of the steric environment on the bidentate directing auxiliary is key to facilitating the challenging C(sp³)−F reductive elimination from a Pd^IV intermediate.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

Supporting Information

Liu Z., Oxtoby L. J., Sun J., Li Z.-Q., Kim N., Davies G. H. M., Engle K. M., Angew. Chem. Int. Ed. 2023, 62, e202214153; Angew. Chem. 2023, 135, e202214153.

Data Availability Statement

The data that support the findings of this study are openly available at www.ccdc.cam.ac.uk/data_request/cif, reference number 2168001.