Photoinduced site-selective alkenylation of alkanes and aldehydes with aryl alkenes

The dehydrogenative alkenylation of C-H bonds with alkenes represents an atom- and step-economical approach for olefin synthesis and molecular editing. Site-selective alkenylation of alkanes and aldehydes with the C-H substrate as the limiting reagent holds significant synthetic value. We herein report a photocatalytic method for the direct alkenylation of alkanes and aldehydes with aryl alkenes in the absence of any external oxidant. A diverse range of commodity feedstocks and pharmaceutical compounds are smoothly alkenylated in useful yields with the C-H partner as the limiting reagent. The late-stage alkenylation of complex molecules occurs with high levels of site selectivity for sterically accessible and electron-rich C-H bonds. This strategy relies on the synergistic combination of direct hydrogen atom transfer photocatalysis with cobaloxime-mediated hydrogen-evolution cross-coupling, which promises to inspire additional perspectives for selective C-H functionalizations in a green manner. Dehydrogenative alkenylation of C-H bonds is an atom-economical approach to prepare more complex olefins. Here, the authors use a combination of decatungstate and a cobaloxime catalyst for the photocatalytic dehydrogenative alkenylation of alkanes and aliphatic aldehydes with aryl alkenes.

Transition-metal-catalyzed dehydrogenative alkenylation of alkanes and aldehydes through an auxiliary-assisted metal insertion was recently disclosed (Fig. 1a) [7][8][9][10][11][12][13] . However, these transformations usually require stoichiometric Cu II or Ag I salts as oxidants. Moreover, the heteroatom-containing directing groups can undergo intramolecular Michael addition and give cyclized products instead of the desired alkenylated products [7][8][9][10][11][12][13] . In 2019, Gevorgyan and coworkers disclosed an elegant radical relay strategy for the alkenylation of alcohols with visible-lightmediated palladium catalysis 14 . Nonetheless, the requirement of a silicon-based auxiliary lowers the atom economy of this strategy, and the substrate scope is limited to alcohols. On the other hand, auxiliary-free dehydrogenative alkenylation offers practical advantages and has attracted substantial interest (Fig. 1b) [15][16][17][18][19][20] . Although much progress has been achieved, the developed systems usually require stoichiometric peroxides and a large excess of the C-H partner (over 40 equivalents of the alkanes), and the substrate scopes are limited to simple hydrocarbons and aromatic aldehydes. In pursuing methods for olefin construction [25][26][27] and photomediated C-H bond functionalization [28][29][30][31] , we aspired to develop an auxiliary-free and oxidant-free strategy for C sp3 -H and C sp2 (O)-H alkenylation with the C-H substrate as the limiting reagent (Fig. 1c). Importantly, this would allow the late-stage functionalization of advanced synthetic intermediates and pharmaceutical relevant molecules without de novo synthesis 32 .
In this context, we were inspired by direct hydrogen atom transfer (HAT) photocatalysts that could achieve the straightforward activation of C-H bonds 33 [40][41][42][43][44] . Inspired by these studies, we proposed that the combination of decatungstate anion and a cobaloxime catalyst could enable the direct activation and alkenylation of alkanes and aldehydes using alkenes as the feedstocks. We herein report that by incorporating decatungstate catalysis and cobaloxime catalysis, direct alkenylation of alkanes and aldehydes with aryl alkenes can be achieved in the absence of hydrogen acceptors. This strategy features a broad substrate scope, high C-H site selectivity, excellent E selectivity of the alkene products, and the use of the C-H substrate as the limiting reagent. Application of this strategy in late-stage functionalization was demonstrated by the selective alkenylation of natural products and pharmaceutically important molecules.

Results
Proposed reaction mechanism. A hypothesized catalytic cycle is depicted in Fig. 2 Reaction optimization. Our investigation began with the alkenylation of cyclooctane with cyclooctane as the limiting reagent and styrene as the alkene partner. After extensive evaluation (Table 1 and Supplementary Tables 1-10), we established that the combination of tetra-n-butylammonium decatungstate (TBADT, 9, 4 mol%), Co(dmgH)(dmgH) 2 Cl 2 (10, 1 mol%), and 2,6-lutidine (L5, 10 mol%) in acetonitrile (0.1 M) at 60°C were the optimal conditions, affording alkenylated product 11 in 69% isolated yield with exclusive E selectivity ( Table 1, entry 1). Reducing the amount of styrene from 10 equiv. to 5 equiv. resulted in a much lower yield (Table 1, entry 2). After careful analysis of the crude product mixture using GC-MS and 1 H NMR spectroscopy (see Supplementary Discussion), it was found that cobalt hydride, a key intermediate in the proposed catalytic cycle (Fig. 2), also promoted the oligomerization of styrene 53 . Due to this competing side reaction, 10 equiv of styrene is needed to achieve a high yield of the desired product. Nonetheless, considering the abundance of alkene feedstocks ($ 0.002/mmol for styrene) and the versatile reactivity of olefins, this method is still highly valuable. Hydrogen gas was produced in 64% yield by GC analysis of the crude product mixture (Supplementary Figs. 3-5), which supported our mechanistic hypothesis. The possibility of styrene or styrene oligomers serving as hydrogen acceptors 54 was excluded since byproducts from olefin hydrogenation were not detected (Supplementary Figs. [6][7][8][9]. During the reaction optimization, we found that the ligand had a large impact on the dehydrogenative alkenylation (Table 1, entries 3-12). Axial ligands on cobaloxime can readily dissociate, and recoordination of these ligands facilitates β-H elimination 55,56 . Moreover, the electronic and steric properties of axial ligands could dramatically influence the reactivity of cobaloxime complexes 56,57 . A survey of heterocyclic ligands (Supplementary Table 8) revealed that 2,6-lutidine (L5) was most effective among all the pyridine ligands evaluated, most probably because it provided a suitable steric environment around the cobalt center. In addition, the use of 50 mol% of 2methylbenzimidazole (L9) was also effective. The use of inorganic bases such as sodium bicarbonate failed to increase reaction yield, confirming that these heterocycles function as ligands rather than bases (Table 1, entry 13 and Supplementary Table 9). No product was detected in the absence of TBADT 9, cobaloxime 10 or light (  Fig. 2 Proposed mechanism for the dehydrogenative alkenylation of alkanes and aldehydes. The plausible mechanism involves a hydrogen atom transfer process, a single electron transfer process, and cobalt-catalyzed alkene formation and hydrogen evolution. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-15878-6 ARTICLE to 12 gave alkenylated products 11-15 in good yields (54-78%). The alkenylation reaction was amenable to scale-up, delivering alkene 16 in 71% yield on a 5.0-mmol scale. Interestingly, this dual-catalytic system exhibits a strong preference for the functionalization of sterically accessible and electron-rich C-H sites. For instance, the secondary C-H bonds in norbornane (16), 1,4epoxycyclohexane (17) and trans-1,4-dimethylcyclohexane (18) were selectively alkenylated, while the sterically hindered tertiary C-H bonds were not reactive despite their relatively lower bond dissociation energies (BDEs) 58 . Primary C-H bonds, owing to their high BDEs 58 , were barely functionalized in the presence of secondary C-H bonds (18)(19). The steric preference of this transformation is also illustrated by the regiospecific alkenylation of 1-methylcyclopentanol (19) at the remote methylene site. Similarly, the least hindered and most electron-rich methylene site of azaspirodecanedione (20) was selectively alkenylated. The reaction of adamantane (21) furnished two regioisomers (1.3:1) in 82% yield, while the reaction of adamantane derivatives bearing electron-withdrawing groups (22)(23)(24) occurred predominantly at the tertiary sites. This unique selectivity observed among adamantane derivatives probably originated from the steric accessibility of the tertiary C-H bond due to its equatorial character 59 and the remarkably long life-time of 1-adamantyl radicals compared to 2-adamantyl radicals 60 . For linear alkanes, pentane (25, α:β:γ 1.1:4.2:1) and hexane (26, α:β:γ 1:3.7:1.7) were preferentially functionalized at the internal secondary positions. Hexamethyldisilane, which possesses one of the strongest C sp3 -H bonds (BDE = 101.3 kcal/mol, see Supplementary Discussion), underwent alkenylation to afford product 27 in 50% yield. Activated C sp3 -H bonds were also examined. Ethers (28)(29)(30), amides (31) and alkylbenzenes (32) were all found to be competent substrates (38-67%). Notably, substituted tetrahydropyrans afforded alkenylation products (29 and 30) with excellent regio-and diastereoselectivity. α,β-Unsaturated ketones are core structures in a wide variety of naturally occurring and man-made molecules that are of synthetic, biological and pharmaceutical importance 61 . The direct alkenylation of aldehydes represents a highly attractive and sustainable strategy for the synthesis of this important family of compounds. We were excited to find that various primary and secondary aldehydes were effective substrates under the optimal alkenylation conditions, providing α,β-unsaturated ketones in decent yields with exclusive E selectivity (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Notably, excellent site selectivity was observed for aldehyde C-H bonds, while other activated C-H bonds, such as benzylic (34), allylic (38), propargylic (39) and α-heteroatom C-H bonds (42 and 43), were not functionalized. The preference of formyl C-H abstraction by decatungstate anion can be explained by the polar transition state due to the partial positive charge on the carbonyl carbon ( Supplementary Fig. 21) 62 . A tertiary aldehyde (44), 2- Eosin Y c or benzophenone instead of 9 < 5 a Reactions were performed under the irradiation of a 24 W 370 nm LED. b Yields were determined from the crude 1H NMR spectra using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields in parentheses. Only E alkenes were generated. c 18 W blue LED was used.
Late-stage selective C-H alkenylation of complex molecules. The potential of this protocol for the late-stage site-selective alkenylation of complex molecules was subsequently investigated. As illustrated in Fig. 4, a number of natural products and derivatives were successfully alkenylated under the optimal conditions. The observed regioselectivities were in accordance with the R′ R-H R′ R TBADT (4 mol%) Co(dmgH)(dmgH 2 )Cl 2 (1 mol%) 2,6-lutidine (10 mol%)  Fig. 2 (see Supplementary Discussion). The presence of radical intermediates was evidenced by radical trapping experiments using 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO, Supplementary Fig. 10). Light on-off experiments demonstrated that continuous light irradiation was necessary for the transformation ( Supplementary Fig. 13). We measured the kinetic isotope effect (KIE) from two parallel reactions and an intermolecular competition experiment, and the KIE values were calculated to be 1.0 and 2.0 respectively (Supplementary Figs. 14-16). These results indicated that C-H cleavage may not be the rate-determining step 66 . The UV-Vis absorption of the reaction mixture was also monitored. Two absorption bands at 440-500 nm and 550-700 nm were observed after 10 min light irradiation and subsequent exposure to air (Supplementary Figs. 17-18), which indicates the presence of Co II and Co I intermediates respectively 48,49 .

Discussion
In summary, we disclosed a general strategy for the dehydrogenative alkenylation of alkanes and aliphatic aldehydes with aryl alkenes using the C-H substrates as the limiting reagent. The late-stage functionalization of complex pharmaceutically important molecules was achieved with high levels of site selectivity, and a broad scope of functional groups were tolerated, providing a unique method for olefin synthesis and molecular diversification. The sterically and electronically dictated site selectivity originates from the dual effect of both the decatungstate and cobaloxime catalysts. Our future efforts will be directed toward further expanding the alkene scope and developing strategies to further tune the site-selectivity of the C-H alkenylation.

Methods
General procedure for dehydrogenative alkenylation of alkanes and aldehydes with alkenes. To a 10 mL oven-dried Schlenk tube equipped with a magnetic stir bar was added the corresponding C-H nucleophile (0.2 mmol, 1.0 equiv.), alkene (2.0 mmol, 10 equiv.), TBADT (26.6 mg, 0.008 mmol, 4 mol%), Co(dmgH) (dmgH 2 )Cl 2 (0.7 mg, 0.002 mmol, 1 mol%), 2,6-lutidine (2.1 mg, 0.02 mmol, 10 mol %) and dry acetonitrile (2 mL). The resulting mixture was cooled to 0 o C using an ice-water bath, and bubbled with argon balloon for 10 min (if the C-H nucleophile was volatile, it was added after argon bubbling). After that, the reaction was placed under a 370 nm LED (2.5 meter strips, 24 W), stirred and irradiated under argon atmosphere. The temperature was maintained at 60°C using a water bath. The reaction mixture was removed from light and quenched by stirring open to air for 5 minutes. The solvent was removed on a rotary evaporator under reduced pressure and the residue was subjected to column chromatography isolation over silica gel or preparative thin layer chromatography to obtain the corresponding product.