Visible-Light Photoredox Catalyzed Dehydrogenative Synthesis of Allylic Carboxylates from Styrenes

The visible-light photoredox/[Co(III)] cocatalyzed dehydrogenative functionalization of cyclic and acyclic styryl derivatives with carboxylic acids is documented. The methodology enables the chemo- and regioselective allylic functionalization of styryl compounds, leading to allylic carboxylates (32 examples) under stoichiometric acceptorless conditions. Intermolecular as well as intramolecular variants are documented in high yields (up to 82%). A mechanistic rationale is also proposed on the basis of a combined experimental and spectroscopic investigation.

U nactivated olefins are convenient feedstocks in organic synthesis due to their large availability and intrinsic wide chemical flexibility. 1 Generally, the chemical manipulation of alkenes requires site-selective electrophilic activation of the πsystem using noble transition metals or harsh Brønsted acidic conditions. Very recently, radical variants started flanking these approaches 2 with the use of dedicated visible-light induced generation of radical cations that could evolve into chemical diversity/complexity via subsequent stoichiometric oxidantfree dehydrogenative couplings.
In this context, the combined use of Fukuzumi acridinium salts (visible-light photoredox abstractors of electrons from olefins) 3 and [Co(II)/(III)] oximine proton acceptors (i.e., cobaloximes) 4 has recently received extensive attention in the direct functionalization of unactivated alkenes under a catalytic hydrogen evolution regime (Figure 1a). 5,6 In the realm of photoredox acceptorless dehydrogenation reactions, Lei documented the anti-Markovnikov oxidation of styrenes with water, 5a alcohols, and azoles. 5b In addition, an elegant [4 + 2]type cycloaddition between alkenes and aromatic ketoimines to deliver dihydroisoquinolines was also reported. 5c Subsequently, Wu extended this approach to the formation of alkenylphosphines via a dehydrogenative C−P bond forming process under photosensitizer-free conditions. 5d In a continuation of our ongoing interests toward the realization of visible-light photoredox promoted synthetic protocols 7 and metal mediated allylic nucleophilic substitutions, 8 we envisioned the opportunity to apply the visible-light induced cobaloxime/acridinium dual catalysis to the preparation of allylic esters via dehydrogenation of Csp 3 −H bonds under stoichiometric oxidant-free conditions (Figure 1b). Such an approach would represent a significant improvement with respect to the known oxidant-based synthesis of allylic carboxylates (Figure 1c). 9 In this scenario, 1-phenyl-1-cyclohexene (1a) and butanoic acid (2a) were elected as model substrates in order to tackle the intrinsic regioselective issues of the protocol (see compounds 5aa/5aa′/5aa″ in the Table 1 graphic). In addition, rigorous base-free conditions were targeted in order to prevent undesired photoinduced decarboxylative events. 10 At the outset of the optimization stage, we discovered that the combined use of [Co(III)(dmgH) 2 pyCl] (3a) (5 mol %, dmgH = dimethylglyoximate, py = pyridine) and Fukuzumi 9mesityl-10-methylacridinium perchlorate (4a) (2.5 mol %) promoted the chemoselective anti-Markovnikov (5aa vs 5aa″) 5a,11,12 formation of the butyrate 5aa in 63% yield (blue LED 23 W 465 nm, rt, DCM, entry 1, Table 1). Furthermore, high allylic ester (5aa) vs enolester (5aa′) chemoselectivity (generally >25:1) was observed as well (see mechanistic discussion for details).
With the aim of further improving the performance of the dehydrogenative cross-coupling process, we reasoned that the employment of a photosensitizer featuring a longer excited state lifetime (4a τ = 6.4 ns) 13 and higher thermal stability (side dealkylation events have been documented with N-alkyl acridinuim derivatives) 14 could provide a higher concentration of the key radical cation (Figure 1a). Therefore, in line with the recent discoveries by Nicewicz, 14 the new N-phenyl dye 4c was synthesized and fully characterized spectroscopically: (i) singlet excited state energy = 2.64 eV; (ii) singlet excited state lifetime = 17.6 ns; (iii) cyclic voltammetry revealed that two reversible one-electron reductions were observed at −0.59 and −1.65 V (vs SCE see Figure S1). 15 Finally, the excited state reduction potential was estimated to be 2.05 V and hence comparable to that of 4a.
Interestingly, the N-phenyl acridinium 4c provided 5aa in a similar extent to 4a (60% yield) but with a shorter reaction time (48 h, entry 7 vs entry 1), enabling also the reactivity of several inert substrates with 4a to be unlocked. As a partial explanation of the recorded outcomes, we compared the relative decrease of the singlet excited state lifetime of 4a and 4c in the presence of the same concentration of 1a (21 mM) in CH 2 Cl 2 . The results revealed that the singlet excited state of 4a was quenched only by 55%. However, in the case of 4c, quenching was as high as 71%. Accompanied by the previous results, the Stern−Volmer quenching constants were found to be k Q = 8.6 × 10 9 M −1 s −1 and k Q = 6.6 × 10 9 M −1 s −1 for 4a and 4c, respectively. 16 Having established the optimal reaction conditions, we faced the substrate scope of the methodology by subjecting to the model photoredox cross-coupling conditions a range of carboxylic acids 2b−m and alkene 1a (Scheme 1).
Interestingly, good yields were obtained for linear (5ac,d), branched (5ae) and hydrocinnamic carboxylates 5af (58%). Analogously, acetic acid proved competent in the dehydrogenative coupling, delivering the desired acetate 5ab in 58% yield. α,β-Unsaturated carboxylic acids worked also satisfyingly, providing the carboxylates 5ag−h in moderate yield (43%) but without appreciable erosion on the stereochemical information on the pristine carboxylic acid. Additionally, Optimal conditions were then applied to a series of cyclic as well as acyclic styryl derivatives in order to assess the generality of the protocol toward unsaturated hydrocarbons (Scheme 2).
First, a range of functionalized 1-aryl-cyclohexenes (1b−n) were subjected to the oxidative photocatalyzed intermolecular derivatization. Substituents can be effectively accommodated at the C-4 position of the cyclohexenyl scaffold (i.e., tBu, Me, and gem-dimethyl), generating the corresponding carboxylates 5 in a yield up to 71%.
In this direction, a library of carboxylic acids 6a−d were readily obtained via Suzuki cross-coupling and directly subjected to optimal reaction parameters (Scheme 3). Additionally, the adoption of 1-aryl-cyclohexenyl units, carrying both EWGs (i.e., CO 2 Me, COMe, F) and EDGs (i.e., Me and di-Me, tBu) at the ortho-, meta-, and parapositions of the arene, led to the allylic carboxylates 5 in moderate to good yields (up to 69%) via anti-Markovnikov condensation. The generality of the protocol was also ascertained for the cycloeptenyl compound 1o that generated the desired benzoate 5oa in 43% yield. 17 Finally, C7, C9 and diphenyl-substituted C5 acyclic styryl compounds 1p,q were conveniently synthesized as an E:Z-mixture via Suzuki crosscoupling of the corresponding enol triflates or Grignard addition/dehydration sequences (see SI) and subjected to the oxidative coupling in the presence of 4c. 18 Also, in these cases, the allylic esters were isolated in satisfying yields (up to 52%) and marked allylic ester vs enol ester selectivity.
Moreover, the synthetic versatility of the procedure was further emphasized by implementing an intramolecular variant. In particular, the photoredox procedure was applied to the direct synthesis of isocoumarin scaffolds 7 19 via an unprecedented intramolecular dehydrogenative formal Csp 2 − H functionalization. 20 Interestingly, the desired isocoumarins 7 were obtained from moderate to excellent yields (up to 82%) accompanied by a high selectivity toward the 3,4-unsaturated scaffold (up to >25:1). 21 Differently, the corresponding pyranyl core 7d was isolated in 40% yield as a mixture (ca. 1:1) of the 1,4-and 1,10b-dihydropyranyl isomers. Therefore, the synthetic flexibility of the allylic carboxylates was examined ( Figure 2a). First, the epoxidation of the cyclohexenyl core was carried out effectively (mCPBA, CH 2 Cl 2 , 0°C, 16 h) delivering the cyclohexene oxide 8ab in 88% yield. In addition, the acetyl group of 5ab could be conveniently saponified (NaOH, MeOH, rt) to release the corresponding allylic alcohol 9ab in 89% yield, proposing the present methodology as a catalytic indirect hydroxylation of allylic Csp 3 −H bonds.
In order to get some insight into the reaction machinery, several dedicated control experiments were carried out. First, the on/off irradiation experiment (Schemes S1 and S2) revealed that, upon a relatively short induction period, the  Organic Letters pubs.acs.org/OrgLett Letter reaction proceeded smoothly under blue LED irradiation, which showed negligible advancements during the light-free stages. Radical trap experiments with TEMPO led to contrasting results with respect to similar processes previously investigated. 3d, 6,22 In particular, attempts to replace the cobaloxime 3a with stoichiometric amounts of TEMPO failed in promoting the photoredox condensation, and no overall inhibition was observed when the radical trap was added to optimal conditions. Mechanistically, the schematic representation depicted in Figure 2b 27,28 It is worth mentioning that, as the β-H elimination of alkyl− Co species is subjected to rigid stereochemical constraints (i.e., syn periplanar conformations are required), 29 we can speculate that the β-CH−OCO 2 R cannot arrange syn periplanar with respect to the C−Co linkage, making the formation of the enolester 5′ unlikely. Last, protonation of [Co(III)−H] would restore the catalytically active [Co(III)] adduct via a hydrogen evolution reaction (HER). 30 Finally, a kinetic isotope effect (KIE) experiment was carried out with deuterated phenyl-cyclohexene d 3 -1a (Figure 2c). 31 In the intermolecular competition experiment, a 1a/d 3 -1a 1:1 mixture was utilized under optimal conditions (32 h, yield = 21%). Interestingly, no isotopic effect was observed (5aa:d 2 -5aa = 1:1), excluding the β-elimination from the ratedetermining step of the catalytic cycle.
In conclusion, in this study, we have documented an unprecedented dual visible-light/cobalt catalyzed redox protocol for the preparation of cyclic and acyclic allylic carboxylates via direct Csp 3 −H oxidation of styryl compounds with carboxylic acids. The oxidant-free methodology showed peculiar anti-Markovnikov regiochemistry. An intramolecular variant was also realized, resulting in the direct preparation of isocoumarin scaffolds in up to 82% yield . Studies toward the extension of the present methodology to the realization of direct allylic C−H activation protocols are underway in our laboratories.