Palladium‐Catalyzed Fluorination of Cyclic Vinyl Triflates: Effect of TESCF₃ as an Additive

Abstract

A method for the palladium-catalyzed fluorination of cyclic vinyl triflates has been developed. As with several previous palladium-catalyzed fluorination reactions using fluoride salts, controlling the regioselectivity was nontrivial and presented a challenge in developing a practical synthetic procedure. The addition of triethyl(trifluoromethyl)silane (TESCF 3 ) was found to effectively address this problem and resulted in dramatically improved regioselectivities in this palladiumcatalyzed fluorination reaction. This discovery, along with the use of a new biarylphosphine ligand, allowed for the development of an efficient and highly regioselective protocol for the fluorination of vinyl triflates. This method is compatible with a range of sensitive functional groups and provides access to cyclic (five, six, and seven-membered) vinyl fluorides Graphical AbstractA technique for the palladium-catalyzed fluorination of cyclic vinyl triflates has been developed. The reaction exhibited good functional group tolerance and proceeded efficiently for five, six and seven-membered vinyl triflate substrates, as well as a few acyclic substrates. The addition of Correspondence to: Stephen L. Buchwald. Supporting information for this article is given via a link at the end of the document. (Figure 1). [1,2] The alkenyl fluoride group resembles an amide linkage in terms of both steric demand and charge distribution, [3] but fluoroalkenes exhibit substantially enhanced stability towards hydrolysis compared to amides. Moreover, in contrast to amides, which often exist as equilibrating s-cis and s-trans rotamers, fluoroalkenes are configurationally stable. As a result, they have been investigated as amide bioisosteres with improved lipophilicity and metabolic stability in pharmaceutical applications and as tools for probing the conformational properties of biologically active amides. [4] In addition to these applications, fluoroalkenes also serve as versatile starting materials for a variety of transformations, including the Diels-Alder reaction, [5a] cyclopropanation, [5b,5c] and epoxidation, [5d] allowing for the construction of other classes of fluorine-containing molecules. HHS Public AccessDespite considerable potential, fluoroalkenes are underutilized due to challenges in their synthesis. Current approaches for their preparation generally require multistep functional group manipulations or the use of harsh reaction conditions, which limit the functional group compatibility of these techniques. [6][7][8][9][10][11] The development of a mild and general method for fluoroalkene synthesis would therefore be highly desirable. Due to the challenge of preparing suitable precursors, cyclic fluoroalkenes are particularly difficult to access using existing methods, and new methods that provide access to these compounds would be especially useful.In this context, the palladium-catalyzed coupling of cyclic vinyl triflates with simple metal fluoride salts represents a particularly attractive strategy to access fluoroalkenes....

Studying Regioisomer Formation in the Pd‐Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification**

“…Because the preparation of Pd II complexes supported by L1 is difficult, presumably due to the large size of L1 , we employed L2 as the supporting ligand for these stoichiometric studies (Scheme 4). As previously reported, L2 was also effective in vinyl fluorination, although the regioselectivity of the process was slightly lower than that when L1 was employed [12] . We initially sought to prepare trans ‐ L2 Pd(vinyl)F ( C2 ) from trans ‐ L2 Pd(vinyl)Br ( C1 ) via salt metathesis with AgF.…”

“…In 2016, motivated by the broad utility of vinyl fluorides as amide bioisosteres in medicinal chemistry and chemical biology, [10, 11] we developed a Pd 0/II ‐catalyzed fluorination of cyclic vinyl triflates [12] . The addition of TESCF 3 to the reaction mixture was found to significantly improve the regioselectivity of the fluorination process.…”

Mechanistic Studies of Pd-Catalyzed Fluorination of Cyclic Vinyl Triflates: Evidence for in situ Ligand Modification

“…As previously reported, L2 was also effective in vinyl fluorination, although the regioselectivity of the process was slightly lower than that using L1. 12 We initially sought to prepare trans-L2Pd(vinyl)F (C2) from trans-L2Pd(vinyl)Br (C1) via salt metathesis with AgF. When C1 was treated with AgF, fluorinated products A and B were readily formed, even at room temperature.…”

“…8d,8e In 2016, motivated by the utility of fluorine-substituted olefins as amide surrogates in medicinal chemistry and chemical biology, 10,11 we developed a Pd 0/II -catalyzed fluorination of cyclic vinyl triflates. 12 The addition of TESCF3 to the reaction mixture was found to significantly improve both the yield and regioselectivity of the fluorination process. Under the standard reaction conditions using 30 mol% TESCF3 as the additive, the desired fluorinated product A was generated in high yield with excellent regioselectivity (Scheme 1, with TESCF3, 74% yield, A:B > 99:1).…”

Stereodivergent Alkyne Hydrofluorination Using a Simple Practical Reagent

“…One direct approach for vinyl fluoride synthesis involves the coupling of fluoride ion with vinyl triflates catalyzed by biaryldialkylphosphine complexes of palladium (Fig. 1B, a) 8 . The metal-catalyzed and noncatalytic fluorination of vinyl metal species under oxidative conditions constitutes another approach (Fig.…”