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Hydrodefluorination of fluoroaromatics by isopropanol catalyzed by a ruthenium NHC complex. An unusual role of the carbene ligand. Van Hung Mai, and Georgii I. Nikonov ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02004 • Publication Date (Web): 12 Oct 2016 Downloaded from http://pubs.acs.org on October 12, 2016
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ACS Catalysis
Hydrodefluorination of fluoroaromatics by isopropanol catalyzed by a ruthenium NHC complex. An unusual role of the carbene ligand. Van Hung Mai, Georgii I. Nikonov* Department of Chemistry, Brock University, Niagara Region, 1812 Sir Isaac Brock Way, ON L2S 3A1, Canada. *E-mail:
[email protected]; Tel: +1 905 688 5550 ext 3350 Supporting Information Placeholder ABSTRACT: The NHC (NHC = N-Heterocyclic Carbene) complex Cp*(IPr)RuH3 catalyzes hydrodefluorination of aromatic fluorides at 70°C by isopropanol as reducing reagent. The reaction is selective for aromatic fluorides, as almost negligible C(sp3)-F bond reduction takes place. The activity decreases from more to less fluorinated substrates, but polyaromatic monofluorides, such as 1-fluoronaphthalene and 6fluoro-2-methyl quinoline, can be also reduced in moderate to good yields. Kinetic studies are consistent with a mechanism based on elimination NHC, reversible substrate coordination, followed by coordination of alcohol.
KEYWORDS: hydrodefluorination, transfer hydrogenation, Nheterocyclic carbene, ruthenium catalysis, mechanism
INTRODUCTION The C-F bond is a prevailing motif in many important organic molecules,1 with the estimated contribution of organofluorine compounds totalling to 40% of agrochemical and 25% of pharmaceutical products, including three out of five topselling drugs.2 Most of these compounds feature only a few fluorine atoms,2a.b and therefore the installation of the C-F bond in a specific position (selective fluorination) has recently received significant attention.3 Although selective fluorination is promising for the preparation of compounds with increased functional complexity and is almost inevitable for the installation of unstable 18F labels,4 it is not yet well suited for large scale synthesis.5 An alternative approach, applicable to the more common 19F organofluorides, is to start with the more accessible perfluorinated substrates and then replace some of the fluorine atoms with hydrogen in a process known as hydrodefluorination (HDF).6 Due to the high strengths of the C-F single bond (105 kcal.mol-1) and the large kinetic hurdle for its activation, effective defluorination usually requires significant heating in the presence of both a catalyst and a good fluorine scavenger, such as silane7,8 borane,9 or phosphine10 which leads to the production of a voluminous waste. A more environmentally benign method is to use hydrogen gas as reductant, but due to the gaseous nature of this reagent and its high flammability this approach requires high-pressure equipment and may present a serious hazard.11 The practical alternative to hydrogenation is transfer hydro-
genation (TH) from alcohols (e.g. isopropanol), which usually takes place at lower temperatures and pressures, is less prone to explosions, and produces low boiling point organic coproduct(s), such as acetone.12 However, so far there have been only a very few reports on the application of alcohols as reductants in the HDF chemistry (Scheme 1).13 Thus, Fort et al. reported reduction of fluoroarenes by alkoxide catalyzed by a Ni carbene complex14 and Sajiki et al. further extended this methodology towards the use of isopropanol over Pd/C at 120 °C.15 Peris et al. reported the first homogeneous HDF by isopropanol catalyzed by a Ru/Pd bimetallic complex (1%, 1h, 80 °C).16 Interestingly, in the latter reaction the presence of both Group 8 and 10 metals was required to achieve significant activity. Here we report a Ru-only catalyzed HDF which occurs under mild conditions, at low catalyst load, is selective towards C(aryl)-F bonds and uses isopropanol as the reducing reagent. Our mechanistic studies further suggest that the NHC ligand plays an unusual role of a leaving group. During the revision process a referee draw our attention to a recently published paper by Kayaki et al. who reported an Ir-catalyzed HDF in isopropanol.17
Scheme 1. Examples of HDF reactions using isopropanol as hydrogen source.
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RESULTS AND DISCUSSION
11
no catalyst, no base
0
0
0
Catalyst screening. Our discovery of a HDF process was purely accidental. In the course of studying the TH of heteroaromatic substrates18 catalysed by an NHC-supported ruthenium complex Cp(IPr)RuH3 (1, IPr=1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene))19 we noticed partial hydrodefluorination of 6-fluoro-2-methyl quinoline. Since the activation of C-F bonds in monofluoroarenes is particularly challenging due to the increased strength of this bond,20 we became interested in the scope of this catalytic process. To establish optimal reactions condition, we chose pentafluorobenzene as the substrate and tested its reduction by a series of ruthenium catalysts prepared in our laboratory (Table 1). The neutral NHC complex 1 (entries 1 and 2) was more effective than cationic complexes, both containing an NHC ligand (entries 4-6 and 9) and free of carbene (entries 7 and 8). Complexes without the NHC ligand showed very little if any activity. A blank experiment with free NHC ligand did not result in any HDF process either, thus ruling out the possibility that the reaction can be mediated by the carbene dissociated from the catalyst (entry 10). We also noticed that effective reduction is facilitated by the presence of a substoichiometric amount of a base (entry 1 vs entries 2 and 3), but the base alone cannot mediate this reaction (entry 12). Our previous studies on transfer hydrogenation of nitriles and heterocycles catalyzed by the trihydride 1 showed that a base is not required for these reactions. But the special feature of HDF in isopropanol is that it produces HF as one of the co-products, which when accumulated in the reaction mixture results in inhibition of catalysis.
12
no catalyst
0
120
0
Table 1. Optimization of catalytic conditions for the HDF of pentaflurobenzene.a
Entry
Catalyst
1
Cp(IPr)RuH3 (1)
2
Cp(IPr)RuH3 (1)
% % cat base 0.5 0.5
0
Yields, % A/B/C
a
10 eq of IPA was used for all catalytic screening trials. b KOtBu
was used as base.
Based on the results of this preliminary screening, we decided to focus on a family of trihydride catalysts (Table 2). Pentafluorobenzene was again used as a test substrate. Complex 1 was found to be more active than the less sterically encumbered NHC complex Cp(IMes)RuH3 (entry 1 vs entry 3) and more active than related phosphine derivatives Cp(Ph3P)RuH3 and Cp(iPr3P)RuH3 (entries 5 and 6, respectively). Further bulking up the cyclopentadienyl group to Cp*, as in Cp*(IPr)RuH3 (7), increases the yield of hydrodefluorinated products A-C (entry 2 vs entry 1). Reduced sterics of the carbene, such as in Cp*(IMes)RuH3(9), again resulted in decreased activity (entry 4 vs entry 2), and interestingly, the Cp* complex 9 is even less active than its Cp analogue 8, but shows greater preference towards the tetrafluoro-substituted product A. Thus, the A/B ratio changes from 19/28 to 23/7 upon switching from 8 to 9. Variation of the catalyst load for 7 showed that decrease to 0.1 and 0.25 mol% results in a noticeable decrease of efficacy (entries 7 and 8), whereas the increase of catalyst load up to 5% brings about only a marginal increase of activity (entries 9-11). Therefore, we determined that complex 7 at 0.5 mol% load is the optimal choice of the catalyst. Table 2. Screening of catalytic activity of tris(hydride) complexes of Ru in the HDF of pentafluorobenzene.
1.5
1
Cp(IPr)RuH3 (1)
0.5
120
45/
