Hydrogen Bonding Networks Enable Brønsted Acid‐Catalyzed Carbonyl‐Olefin Metathesis

Abstract Synthetic chemists have learned to mimic nature in using hydrogen bonds and other weak interactions to dictate the spatial arrangement of reaction substrates and to stabilize transition states to enable highly efficient and selective reactions. The activation of a catalyst molecule itself by hydrogen‐bonding networks, in order to enhance its catalytic activity to achieve a desired reaction outcome, is less explored in organic synthesis, despite being a commonly found phenomenon in nature. Herein, we show our investigation into this underexplored area by studying the promotion of carbonyl‐olefin metathesis reactions by hydrogen‐bonding‐assisted Brønsted acid catalysis, using hexafluoroisopropanol (HFIP) solvent in combination with para‐toluenesulfonic acid (pTSA). Our experimental and computational mechanistic studies reveal not only an interesting role of HFIP solvent in assisting pTSA Brønsted acid catalyst, but also insightful knowledge about the current limitations of the carbonyl‐olefin metathesis reaction.


Introduction
To study such novel catalyst systems, we embarked on the investigation of their efficiency on the 48 carbonyl olefin metathesis (COM) reaction. 9 The COM reaction has been identified as an attractive 49 replacement to overcome challenges in traditional approaches for the olefination of carbonyl groups, 50 such as pre-functionalization of substrates, reagent synthesis, or the separation of by-products from 51 reaction mixtures. 10 The majority of approaches towards COM reactions are based on Lewis acid 52 catalysts, 11 ranging from transition metal salts such as FeCl3 first reported by Schindler et al. 9c,12 and 53 Li et al. 9d and subsequently salts of Ga(III) by Schindler 13 and Bour, 9f AuCl3 by Lin et al. 14 or bimetallic 54 systems such as AlCl3/AgSF6 and AlCl3/AgSF6 by Schindler 15 . Further, more specialized approaches 55 harness the reactivity of hydrazines as organocatalysts as reported by the Lambert group 9a, 16 and a 56 special photocatalytic strategy by the Glorius group. 9e There have also been notable applications of 57 metal-free Lewis acids in promoting COM reactions such as the tritylium catalysts by Franzén and co-58 workers 9b, 17 as well as tropylium salts 18 and iodonium ion 19 reported by our Nguyen group. Silylium or 59 phosphonium-based Lewis acids also showed potential catalytic activity for COM reactions. 20 Despite 60 recent advances in COM reactions with various Lewis acid catalysts, 10 the field is still in its infancy and 61 a generalized approach towards Brønsted acid-catalyzed COM reactions remains elusive. Up to this  To probe our hypothesis on hydrogen bond network-assisted, Brønsted acid-catalyzed COM reactions, 73 we studied the influence of solvent on the reaction substrate 1a using pTSA as a simple readily available 74 Brønsted acid catalyst. Pleasingly, the reaction worked optimally with 10 mol% of pTSA catalyst in 100 75 µL HFIP for the 0.2 mmol scale reaction, giving the product 2a in 80% yield after 4 hours at ambient 76 temperature (entry 1, Table 1). 24 Solvents such as 1,2-dichloroethane (DCE), iPrOH or linear fluorinated 77 alcohols, which are weaker hydrogen-bonding agents than HFIP, proved to be inefficient (entries 2-6, 78 Table 1). 1 H NMR studies on the perturbation of the pTSA acidic proton signal in the presence of a 79 varying amount of HFIP showed clear evidence of such a hydrogen-bonding network, and this effect 80 was stronger with HFIP than iPrOH or TFE (see page S4-S7 in the experimental SI for further details).

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The respective 1 H NMR studies on the interaction of HFIP with substrate 1a showed no evidence on 82 potential solvent-substrate interaction (see page S8 in the experimental SI).

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Entry [a] Variations from optimal conditions [b] Yield [c]  For further understanding of the reaction mechanism and the role of HFIP and the hydrogen bond 104 network on the reaction, we carried out a series of kinetic studies with substrate 1a and 5 mol% of 105 pTSA in varying amount of HFIP from 2 to 6 equivalents with respect to 1a in CDCl3 (Figure 1). The conversion of 1a was monitored by 1 H NMR spectroscopy over time (see pages S11-S12 in the 107 experimental SI for more details). The kinetic data for initial reactions rates after ~ 10% conversions 108 was analyzed and showed that the reaction order in HFIP was ~2.5 ( Figure 1), which suggested that 109 only a small number of HFIP solvent molecules were directly involved in the rate determining step of 110 the COM reaction under investigation.

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The optimized conditions developed in Table 1 were then applied to a range of intramolecular COM 181 substrates (Scheme 3b). -Substituted ketoester substrates reacted smoothly to form their 182 corresponding cyclopentene products in moderate to high yields (2a-i). For some substrates, the 183 isomerized cyclopentenes were obtained as major products (2'e and 2'h), which was expected in this 184 Brønsted acidic environment. Five-membered N-heterocyclic products could also be formed by this 185 method in good to high yields, although the reactions on non -substituted systems (2l-m) were less 186 efficient than those of a-substituted ones (2j-k). The reaction worked particularly well to form indene 187 derivatives (2n-q and 2'r), which can be attributed to the stability of the conjugate indene ring that 188 formed (Scheme 3). Similarly, a range of naphthalene products (2s-u) could be efficiently synthesized 189 using our developed conditions. There were also competing carbonyl-ene side processes in these 190 reactions. The application of these conditions to the formation of six-membered carbocyclic or N-191 heterocyclic products only led to moderate reaction outcomes (2v-y, Scheme 3b).

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As discussed earlier, the directed Brønsted acid catalyzed COM reaction in homogeneous conditions is 193 often problematic in that several side processes such as carbonyl-ene, Prins or interrupted carbonyl-194 olefin metathesis reactions can occur. 23 As our pTSA/HFIP catalytic system marked the first time COM 195 reactions can be carried out in this manner without much of those issues, we would like to expand the work to investigate the scope of its catalytic activity on analogous cyclization reactions. We decided to  (e) 5-exo-trig (d) 5-exo-dig (c) 6-endo-trig (b) COM reaction (a)   length of the alkenyl carbon skeleton (Scheme 4). The analysis of the first reaction step showed a 261 distinct effect of the carbon chain length on the activation free energy for C-C bond formation (TS1).

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This step is energetically favored for the hexene (1, n = 2) and heptene (3, n = 3) substrates, while being 263 energetically highly unfavorable for the shorter pentene derivative (5, n = 1) due to the high ring strain  to allow for a novel and practical method for the direct Brønsted acid catalyzed carbonyl-olefin 293 metathesis reaction. Interesting insights into the effect of the alkenyl moiety chain length on the 294 reaction outcomes were also revealed, which give the rationalization for the current ring-size limitation 295 of COM cyclization reaction products. These results will not only advance the catalytic scope of the 296 COM reaction further into homogeneous Brønsted acid catalysis but also pave the way for further 297 investigations and applications of hydrogen bonding network assisted catalysis in organic synthesis.

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The Supporting Information is available free of charge: Experimental details and spectroscopic data for 301 all products, full Gaussian reference, Cartesian coordinates, electronic and free energies.