Perspective pubs.acs.org/acscatalysis
Catalytic, Vicinal Difluorination of Olefins: Creating a Hybrid, Chiral Bioisostere of the Trifluoromethyl and Ethyl Groups István G. Molnár, Christian Thiehoff, Mareike C. Holland, and Ryan Gilmour* Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany ABSTRACT: Contemporaneous reports describing the vicinal difluorination of olefins relying on I(I)/I(III) catalysis have augmented the arsenal of dihalogenation methods and provided a solution to this longstanding challenge in olefin functionalization. In both studies, success was contingent on the in situ generation of ArIF2 from a simple aryl iodide, HF source, and suitable terminal oxidant. The first report by Jacobsen and co-workers employed a resorcinol-derived aryl iodide/m-CPBA oxidant combination, while this laboratory relied on p-iodotoluene and Selectfluor. The complementarity of these approaches ensures that a wide variety of electronically distinct olefins are viable substrates for this transformation. This perspective describes our development of a catalytic difluorination of terminal olefins as a means to efficiently construct a hybrid, chiral bioisostere of the trifluoromethyl and ethyl groups in the broader context of molecular design and highlights key reports from other laboratories that accelerated the study. KEYWORDS: bioisostere design, catalysis, gauche effect, hypervalent iodine, vicinal difluorination
1. INTRODUCTION The intrinsic polarity of the carbon−fluorine bond (Cδ+−Fδ−) manifests itself in a permanent localized dipole, enabling a plethora of well-described, noncovalent interactions with proximal groups in both inter- and intramolecular ensembles.1 The electronegativity of the fluorine substituent lowers the energy of the corresponding molecular orbital of the C−F bond,2 thereby creating a low-lying antibonding orbital (σC−F*) that can participate in stabilizing donor−acceptor interactions when the geometric requirements are satisfied. Hyperconjugative processes engaging donor orbitals range from nonbonding electron pairs (nO → σC−F*), in the case of the anomeric effect,3 to reinforcing σC−H → σC−F* interactions that constitute the stereoelectronic basis of the gauche effect in 1,2difluoroethane (1) (Scheme 1, upper).1,4 In this latter case, stabilization due to effective orbital mixing is contingent on
reaching the antiperiplanar alignment between donor and acceptor orbitals; this gives rise to the characteristic synclinal alignment of the C−F bonds (φFCCF = 60°) and dipole vectors (Scheme 1, bottom).5 When more highly substituted difluoroethylene units are considered, this simple vector treatment is didactically valuable, since the gauche effect can be utilized to determine the relative special orientation of substituents on these fluorine-bearing carbon atoms.6 The more intuitive anti conformer, in which the localized dipoles are opposed, is consequently a higher energy scenario.7 Early studies determined that the equilibrium dipole moment of 1,2difluoroethane (1) displays an inverse temperature dependence (dμ/dT < 0).8 Thus, bonding models and physical descriptions of 1,2-difluoroethane have evolved with a high degree of mutual consistency to account for this intriguing characteristic.4d Perhaps unsurprisingly, the two regioisomers of difluoroethane differ in their overall dipole moment (μ), where geminal difluorination patterns (−CF2−) give rise to smaller dipole moments than the corresponding vicinal motifs (−CHFCHF−).9 This is particularly noteworthy considering that the C(sp3)−F centers in the vicinal motif can be rendered stereogenic. The electronic disparity between regioisomers is easily demonstrated by comparison of the overall molecular dipoles calculated for a series of propane derivatives (i.e., R = CH3 in the simple monosubstituted olefin precursor) (Figure 1, I−VI). The benchmark values calculated for propane and propene of 0.09 and 0.043 D (II and III, respectively) contrast starkly with those for the difluorinated systems (I, IV−VI). This is clearly
Scheme 1. Fluorine Gauche Effect in 1,2-Difluoroethane 1 (Top) and a Vector Analysis To Rationalize the Temperature-Dependent Dipole Moment of This Moiety (Bottom)
Received: July 29, 2016 Revised: September 8, 2016 Published: September 14, 2016 © 2016 American Chemical Society
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DOI: 10.1021/acscatal.6b02155 ACS Catal. 2016, 6, 7167−7173
Perspective
ACS Catalysis
highlights the conspicuous absence of catalytic, vicinal difluorination methods and advocates investment in developing selective dihalogenation technologies in a broader sense.16 Responding to this deficiency in the dihalogenation ordnance, contemporaneous studies by this laboratory17 and by Jacobsen and co-workers18 have demonstrated that I(I)/I(III) catalysis19 is ideally suited to process olefins to the corresponding difluoroethylene systems. Common to both approaches are (i) an aryl iodide catalyst, (ii) an inexpensive fluoride source that may also act as a Brønsted acid, and (iii) a terminal oxidant (Scheme 2). Interestingly, subtle differences in the parameters Scheme 2. Parameters To Consider in the Development of a Catalytic Vicinal Difluorination Reaction and the Stoichiometric Precedent Set by Hara, Yoneda, and CoWorkers using p-Iodotoluene Difluoride (2) and Et3N·5HF20
Figure 1. Comparison of the molecular dipole moments of propane (II), propene (III), and the four regioisomeric relationships of difluoropropane (I and IV−VI). The propane scaffold was chosen as the simplest monosubstituted system (R = CH3). Electrostatic potential maps (ESP) and molecular dipole moments in Debye comparing the global minima of fluorinated and nonfluorinated threecarbon derivatives (I, 1,2-difluoropropane; II, propane; III, propene; IV, 1,3-difluoropropane; V, 1,1-difluoropropane; VI, 2,2-difluoropropane). Computational method: B3LYP/6-311+G(d,p). Isosurfaces correspond to an electron density of 0.004 au. Color range of the electrostatic potential: −0.04 (red) to +0.04 (blue).
evident from the associated electrostatic potential (ESP) maps (Figure 1, lower). The differing electronic signatures of the difluorinated series are reflected by the dipole moments, which display the trend I (1,2) > VI (2,2) ≈ V (1,1) > IV (1,3) (μ = 3.32, 2.66, 2.59, and 2.31 D, respectively). That fluorine incorporation augments the localized dipole so significantly with minimal steric impact presents a valuable opportunity in bioisostere design.10 Since fluorinated and partially fluorinated units have steric volumes that are often similar to those of comparable molecular weight hydrocarbon fragments, they are commonly employed in drug discovery to interrogate noncovalent interactions or enhance metabolic stability.11 The trifluoromethyl group, for instance, is often considered as a bioisostere equivalent of the isopropyl group.12 However, comparison of the calculated van der Waals volumes reveals that the trifluoromethyl group is significantly smaller (VvdW(CF3) = 39.8 Å3 vs VvdW(iPr) = 56.2 Å3). Indeed, comparison with an ethyl group (VvdW = 38.9 Å3) appears to be more appropriate, with the caveat that the shapes differ.13 This notion of ethyl/trifluoromethyl bioisosterism was corroborated by Zanda and co-workers.14 In contrast to these achiral functionalities, the difluoroethylene unit contains stereochemical information. Collectively, these factors constitute a persuasive argument for considering the vicinal difluoride derived from terminal olefins as a chiral bioisostere hybrid of the ethyl and trifluoromethyl groups (Figure 1, top). Despite this unique profile, strategic application of the vicinal difluoroethylene unit in focused molecular design remains relatively uncommon9,15 and is most likely a consequence of preparative difficulties associated with the direct difluorination of unactivated olefins. Indeed, a recent review by Denmark
used by the two groups revealed remarkable substrate scope and functional group tolerance overall. In this perspective, we delineate the development of our catalytic difluorination strategy inspired by a single stoichiometric precedent set by Hara, Yoneda, and co-workers in 1998 using reagent 2 (Scheme 2, bottom, compounds 3−6).20 How this study complements the elegant approach by Jacobsen and co-workers to provide rapid access to an important functional group is also briefly highlighted.
2. DIRECT, VICINAL DIFLUORINATION OF OLEFINS The growing demand for partially fluorinated materials is a powerful incentive for the development of direct methods to access vicinal difluorides.21 The most atom economical strategy involves the use of elemental fluorine,22 as is exemplified by the direct addition across olefins reported by Rozen and Brand (Scheme 3, 7 → 8 and 9 → 10).23 However, generalizing this approach is hindered by considerations regarding handling, reactivity, and toxicity. To some extent, these concerns have been mitigated by the introduction of F2 in N2 as a carrier gas, thus rendering this approach more palatable from a preparative perspective. Microreactor technology and reactor engineering24 continue to have a significant impact on popularizing this reagent, but limited functional group tolerance remains an issue. Stoichiometric reagents, including XeF2, have also found application but tend to be prohibitive due to cost on scale-up.25 7168
DOI: 10.1021/acscatal.6b02155 ACS Catal. 2016, 6, 7167−7173
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ACS Catalysis Scheme 3. Direct Addition of F2 to Olefins Reported by Rozen and Brand23
Scheme 5. Postulated Catalytic Cycle
In contemplating possible catalysis paradigms to realize the title transformation, the stoichiometric vicinal difluorination of olefins reported by Hara, Yoneda, and co-workers proved invaluable.20 In their report, commercial p-iodotoluene difluoride (2) and Et3N·5HF was shown to be an effective reagent combination to install the vicinal difluoro motif without the need for olefin prefunctionalization. The authors demonstrated that terminal olefins can be smoothly and efficiently converted to the difluoroethylene unit, thereby providing a solid foundation for this work (Scheme 2, bottom). Moreover, that the difluorination of disubstituted olefins proceeds in a highly syn-stereospecific process gives valuable mechanistic insights (Scheme 2).16a,19a,20 While the authors themselves highlighted some constraints of these conditions, including reagent availability and capriciousness of the reaction, this seminal study constitutes the conceptual framework for the two catalytic variants reported earlier this year.
prove to be critical on account of its perceived role in Brønsted acid activation of p-iodotoluene difluoride (2) and the ensuing displacement reactions. 3.1. Oxidation (11 → 2). We began our investigations by surveying approaches to generate p-iodotoluene difluoride in situ. This logically requires p-iodotoluene (11) as a catalyst and a suitable terminal oxidant and fluoride source. Cognizant of a report by Shreeve and co-workers describing the syntheses of I(III) systems using Selectfluor,28 we selected this reagent as the oxidant of choice (Scheme 6, 14 → 15). Moreover, this Scheme 6. Generating TolIF2 (2) in Situ
3. DEVELOPMENT OF A DIRECT, CATALYTIC, VICINAL DIFLUORINATION OF OLEFINS Achieving an efficient catalytic transformation hinged on our ability to generate p-iodotoluene difluoride (2) in situ from 11. Should this prove successful, it would likely constitute an expansive approach to developing catalytic fluorination processes proceeding via an initial nucleophilic addition to the activated alkene; this in turn would complement the numerous formal electrophilic fluorination processes (Scheme 4).26 In the case of the title transformation, some specific issues Scheme 4. Generating p-Iodotoluene Difluoride (2) in Situ
terminal oxidant had previously found application in the vicinal diacetoxylation of olefins using I(I)/I(III) catalysis.29 In contrast, the study by Jacobsen and co-workers demonstrates that m-CPBA is a competent oxidant for the vicinal difluorination of olefins utilizing a resorcinol-based catalyst system.18 3.2. Brønsted Acid Activation. On the basis of Hara and Yoneda’s study,20 it was envisaged that efficient catalysis would be conditional on activation of p-iodotoluene difluoride by H bonding, thereby polarizing the F−I−F moiety. The authors report a high degree of sensitivity to changes in the HF:amine ratio that supports this notion. This is further reinforced by a recent study by Kitamura on generation and activation of (difluoroiodo)arenes.30 An analogous effect has also been reported by Cotter et al. in the reaction of iodobenzene dichloride catalyzed by trifluoroacetic acid.31 3.3. Sequential Displacement Steps (12 → 13). It is interesting to note that the stoichiometric difluorination of cyclohexene derivative 16 proceeds in a highly diastereoselective manner to furnish the syn product 17 in 55% yield. This
had to be considered, including the robustness of the catalyst on exposure to HF and the mitigation of uncatalyzed reactions involving the substrate and reagent set. Since Weinland and Stille’s seminal report describing the treatment of PhIO2 with aqueous HF to yield PhIOF2,27 the preparation and application of hypervalent-iodine-based fluorination reagents has evolved at an astonishing pace.19 This rich history made it possible to make an informed choice regarding suitable oxidants and fluoride sources. A conceptual overview of the catalytic cycle envisaged is shown in Scheme 5. Importantly, a prudent choice of the hydrogen fluoride source would likely 7169
DOI: 10.1021/acscatal.6b02155 ACS Catal. 2016, 6, 7167−7173
Perspective
ACS Catalysis insightful finding is fully consistent with formation of an intermediate iodiranium ion followed by sequential SN2 displacement steps (Scheme 7, 18 → 19). Scheme 7. Difluorination of Disubstituted Olefin 16 and an Explanation To Account for the Relative Syn Configuration16a,19a,20
Figure 2. Reaction of electron-rich olefins with Selectfluor and an I(III)-catalyzed rearrangement.
limited, the commonly used reagents Et3N·3HF and Olah’s reagent (Pyr(HF)x) were explored. Selected entries from the initial investigation are given in Table 1 and demonstrate the capriciousness of the amine to HF ratio in a set of reactions optimized in DCE at 40 °C. Despite the initial challenges, a 1:4.5 ratio proved to be optimal, thereby allowing for the smooth difluorination of the model substrate in a synthetically useful 76% isolated yield. With a view to generalizing this transformation and demonstrating broad functional group tolerance, the ester moiety (27) was systematically substituted by other groups while retaining the spacer (Figure 3). Using method A (HF:amine 4.5:1, 14 h), a relatively diverse class of substrates proved to be viable. These include free alcohols (29b), phthalimides (29c), and α,β-unsaturated esters (29d). The chemoselectivity of this last entry is particularly noteworthy, given that the scope reported in the Jacobsen study includes a variety of electron-deficient olefins. Interestingly, acetates (29e) and tosylates (29f) also tolerated the reaction conditions. In the case of tosylate 29g, reducing the chain length required slight adjustment of the HF to amine ratio (method B) to achieve synthetically useful yields. This facilitated the conversion of allylic alcohol ethers to their difluorinated congeners (29h−m). Although quinine is a classic substrate often used to explore vicinal difunctionalization of terminal olefins, it proved challenging. However, using Olah’s reagent exclusively (method C) it was possible to isolate the product in 80% yield as a 5:1 mixture of diastereoisomers (29n). The phenol derivative explored in this study proved intriguing on account of intramolecular cyclization leading to chromane formation (29p) that dominated. The expected difluoride 29p was isolated in trace amounts. Interestingly, during our initial efforts to render the difluorination enantioselective, it was this latter transformation that gave the most encouraging enantioselectivities (29p, er 70.5:29.5) using aryl iodide 30. The catalyst choice was inspired by an elegant study in which Ishihara and Muñiz showed it to be highly competent for the vicinal dioxygenation of terminal olefins.35 However, when the catalyst was employed in the vicinal difluorination using substrate 28k, only modest enantioselectivity was recorded (29k, er 61:39). While this result does constitute a proof of concept, it reflects the
4. OPTIMIZED REACTION CONDITIONS As an initial optimization platform, the vicinal difluorination of a terminal olefin with remote functionality was chosen to minimize steric or electronic interference (Table 1, 26 → 27). Table 1. Investigating Et3N·3HF and Olah’s Reagent as Convenient, Widely Available Fluoride Sourcesa
entry
HF source (amine:HF)a
conversn (%)b
time (h)
yield (%)c
1 2 3 4
A (1:3) B (1:9.23) A+B (1:4.5)
95
14 24 14 14
