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Direct Allylic C–H Alkylation of Enol Silyl Ethers Enabled by Photoredox–

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Direct Allylic C–H Alkylation of Enol Silyl Ethers Enabled by Photoredox– ARTICLE https://doi.org/10.1038/s41467-019-10641-y OPEN Direct allylic C–H alkylation of enol silyl ethers enabled by photoredox–Brønsted base hybrid catalysis Kohsuke Ohmatsu 1, Tsubasa Nakashima1, Makoto Sato1 & Takashi Ooi 1,2 Strategies for altering the reaction pathway of reactive intermediates are of significant importance in diversifying organic synthesis. Enol silyl ethers, versatile enolate equivalents, 1234567890():,; are known to undergo one-electron oxidation to generate the radical cations that sponta- neously form electrophilic α-carbonyl radicals via elimination of the silyl groups. Here, we demonstrate that close scrutiny of the property of the radical cations as strong C–H acids enables the identification of a catalyst system consisting of an iridium-based photosensitizer and 2,4,6-collidine for the generation of nucleophilic allylic radicals from enol silyl ethers through one-electron oxidation-deprotonation sequence under light irradiation without the desilylation of the radical cation intermediates. The resultant allylic radicals engage in the addition to electron-deficient olefins, establishing the selective allylic C-H alkylation of enol silyl ethers. This strategy is broadly applicable, and the alkylated enol silyl ethers can be transformed into highly functionalized carbonyl compounds by exploiting their common polar reactivity. 1 Institute of Transformative Bio-Molecules (WPI-ITbM), and Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8601, Japan. 2 CREST, Japan Science and Technology Agency (JST), Nagoya 464-8601, Japan. Correspondence and requests for materials should be addressed to T.O. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:2706 | https://doi.org/10.1038/s41467-019-10641-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-10641-y nol silyl ethers and their analogs are one of the most ver- construction exclusively at the allylic carbon, leaving the enol silyl satile substrate classes and enjoy widespread applications in ether component intact for further synthetic manipulations. Here, E 1–3 organic synthesis (Fig. 1a) . They can be prepared from we disclose the successful implementation of this strategy through carbonyl compounds of all oxidation states, such as aldehydes, the development of a direct allylic C–H functionalization of a ketones, esters and amides, by reliable protocols and exhibit variety of enol silyl ethers with electron-deficient olefins under preeminent reactivity as enolate anion equivalents amenable to hybrid catalysis of an iridium-based photosensitizer and pyridine various catalysis manifolds. These distinct features render enol derivative with the irradiation of visible light. The utility of this silyl ethers attractive yet powerful handles for selective α- unique C–H alkylation protocol is also demonstrated. functionalization of a wide array of carbonyl entities. 3 On the other hand, the allylic sp -hybridized carbons of the Results enol silyl ethers are potential reaction sites as the electron-rich Analysis of the property of enol silyl ether and its radical enol moiety contributes to decreasing bond-dissociation enthalpy cation. We selected the cyclohexanone-derived enol silyl ether 1a of the allylic C–H bonds. In particular, selective bond formation as a model substrate and investigated the physical properties at the allylic carbons4 with preservation of the enol silyl ether requisite to establish a catalytic system for effecting the component offers an opportunity to harness the reactivity of the target allylic functionalization. First, the oxidation potential (E ) resulting functionalized enol silyl ethers for the conventional ox of 1a was determined to be 1.52 V vs. saturated calomel electrode polar reactions, enabling access to α,β-difunctionalized carbonyl – (SCE) by square wave voltammetry measurement in MeCN, compounds5 7. However, despite their potential synthetic utility, which led us to use a IrIII photocatalyst bearing ligands suitable only a few catalytic systems are available for direct allylic C–H for imparting sufficient single-electron oxidation ability to the functionalization of enol silyl ethers or their analogs, which rely visible light-excited *IrIII to generate a radical cation from 1a. on transition metal catalysis and synergistic photoredox-thiol •+ Second, the pK value of the resulting radical cation [1a] in catalysis8,9. a MeCN was estimated from the calculated reaction free energy In addition to the common polar reactivity useful for a diverse (ΔG) of deprotonation process. Since the direct determination of set of transformations, it has long been recognized that enol silyl pK from the calculated free energy is liable to give deviated value, ethers undergo single-electron oxidation to generate the corre- a we conducted statistical manipulation using experimentally sponding radical cations10. Yet, previous efforts for exploiting this available values. Specifically, the pK of [1a]•+ was obtained by radical reactivity in reaction development have been restricted to a – considering acid–base equilibria with a series of substituted ani- coupling with concomitantly generated heteroatom radicals11 15 lines (Fig. 2), whose pK values were experimentally determined or tethered olefins at the α-carbon of the carbonyl group; this is a (5–12 in MeCN)32. As shown in Fig. 2, the values for the reaction largely due to the strong propensity of the radical cation to free energy calculated at the SMD(MeCN)-(U)CAM-B3LYP/6- undergo elimination of a silyl cation to produce parent carbonyls – 311 + G(d,p) level and the experimental pK values of anilines (Fig. 1b)10,16 22. Under these circumstances, we considered the a showed excellent linear correlation. The intercept of this plot intrinsic properties of this class of radical cations, specifically the •+ – corresponded to the pK of [1a] and was determined to be 8.4, presumed high acidity of allylic protons23 27. For instance, a – which is close to that of TsOH [pK (MeCN) = 8.6]33, meaning MacMillan28 31 reported that radical cations generated from a that [1a]•+ can be readily deprotonated by an appropriate aldehyde- or cyclic ketone-derived enamines underwent depro- Brønsted base. In view of structural tunability, we sought to tonation to form allylic radicals that were susceptible to radical employ an organic base with recognition that essential require- addition reactions for β-functionalizations of the parent carbo- ments for ensuring the function of the base are not only the pK nyls. With this profile in mind, we envisioned that the allylic a value but also the redox potential not to be involved in the single- proton of the radical cation derived from an enol silyl ether could electron redox processes operated by the photocatalyst. be readily deprotonated to generate an allylic radical nucleophilic enough to be captured by an external electrophile (Fig. 1c). If the employment of an appropriate Brønsted base allows this proton Design of catalysis and optimization of reaction conditions. abstraction event to occur predominantly over the desilylation, Based on these initial results and considerations, we began to the single-electron oxidation–deprotonation sequence would evaluate the viability of our strategy in the reaction of 1a with provide a broadly applicable platform to execute bond benzalmalononitrile (2a) as an acceptor in the presence of [Ir(dF a General reactions of enol silyl ethers b Electron transfer-induced desilylation R3Si R Si R Si O O 3 O 3 O + O O Electrophile –e– –R Si E + 3 H X X X X X X R1 R1 R1 SET R1 R1 R1 c Electron transfer-initiated deprotonation–alkylation R Si R Si R Si R3Si 3 3 O 3 O + O O O –e– Electrophile + –H R X X X X X SET 2 2 2 2 R 2 R H R H R E R E Leaving silyl enol ether moiety intact Rapid access to Applicable for further transformations complex carbonyl compounds Fig. 1 Transformations of enol silyl ethers. a General reaction pathway. b Known desilylation reaction initiated by single-electron oxidation. c The reaction design of allylic C–H alkylation 2 NATURE COMMUNICATIONS | (2019) 10:2706 | https://doi.org/10.1038/s41467-019-10641-y | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-10641-y ARTICLE a TBSO TBSO + X X + + ° H MeCN, 25 C + NH2 ΔG NH3 [1a]•+ b 13 C) ° (X = 4-OMe) 12 X 11 (X = H) (MeCN at 25 a K NH 10 p 2 (X = 4-Br) 9 (X = 2,4-F2) 8 (X = 2-Cl) 7 y = –0.6x + 8.4 (X = 2,5-Cl2) R 2 = 0.9883 6 5 (X = 2,6-Cl2) 4 –8 –6 –4 –2 0 2 4 6 8 Δ ° –1 Gcalc (MeCN at 25 C) /kcal mol •+ •+ Fig. 2 Estimation of pKa of radical cation [1a] .aAcid–base equilibria between [1a] and substituted anilines. b Linear free energy plot for the acid–base equilibria ′ red = (CF3)ppy)2(4,4 -dCF3bpy)]PF6 (4a, 2 mol%) (*E1/2 1.65 V vs. 34 = SCE) and 2,4,6-collidine (1 equiv) (pKa 14.98 in MeCN, Table 1 Optimization of conditions for reaction of enol silyl ox = ≥ 32 E1/2 2.0 V vs. SCE) in MeCN at ambient temperature. ether 1a with benzalmalononitrile (2a) Under the irradiation of a blue light-emitting diode (LED), bond formation occurred at the allylic carbon (β-position to the TBSO TBSO latent carbonyl) to give the alkylated enol silyl ether 3a in 78% 4 (2 mol%) CN base CN nuclear magnetic resonance (NMR) yield (Table 1, entry 1). The + Ph MeCN CN nature of the Brønsted base was of critical importance as the use H CN blue LED, 25 °C of the sterically demanding 2,6-di-tert-butyl-4-methylpyridine 1a 2a 3a Ph (DTBMP) substantially decreased the yield of 3a and inorganic CF bases, such as potassium phosphate, were totally ineffective F 3 III 4a (R1 =H,R2 =CF ) (entries 2 and 3).
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