Direct allylic acylation via cross-coupling involving cooperative N‑heterocyclic carbene, hydrogen atom transfer, and photoredox catalysis

Herein, we report a mild, operationally simple, multicatalytic method for the synthesis of β,γ-unsaturated ketones via allylic acylation of alkenes. Specifically, the method combines N‑heterocyclic carbene catalysis, hydrogen atom transfer catalysis, and photoredox catalysis for cross-coupling reactions between a wide range of feedstock carboxylic acids and readily available olefins to afford structurally diverse β,γ-unsaturated ketones without olefin transposition. The method could be used to install acyl groups on highly functionalized natural-product-derived compounds with no need for substrate pre-activation, and C–H functionalization proceed with excellent site selectivity. To demonstrate the potential applications of the method, we convert a representative coupling product into various useful olefin synthons.


Supplementary Notes
Reagents were purchased from commercial sources and were used as received. 1 H and 13 C Nuclear Magnetic Resonance (NMR) spectra were recorded on Bruker Avance 400 Ultrashield NMR spectrometers. Chemical shifts (δ) were given in parts per million (ppm) and were measured downfield from internal tetramethylsilane. High-resolution mass spectrometry (HRMS) data were obtained on an FTICR-MS instrument (Ionspec 7.0 T). The melting points were determined on an X-4 microscope melting point apparatus and are uncorrected. Conversion was monitored by thin layer chromatography (TLC). Flash column chromatography was performed over silica gel (100-200 mesh). Blue LED (36 W, λmax = 470 nm) purchased from JIADENG (LS) was used for blue light irradiation. A fan attached to the apparatus was used to maintain the reaction temperature at room temperature 2. Supplementary Discussion 2.1 Investigation of the key reaction parameters.

Exploration the role of K3PO4 and Cs2CO3
In order to infer the effect of each base, we performed the following experiments:

Supplementary Figure 6 The role of Cs2CO3
When we use a single potassium phosphate as a catalyst in the template reaction, we can separate a large amount of unreacted substrate 1a (49%), but when using a single cesium carbonate as a catalyst, the amount of substrate remaining is less (11%). It's reflected from the side that Cs2CO3 probably acts on reaction of NHC precursor and acylimidazole to form acyl azolium intermediate which means Cs2CO3 mainly played the role in facilitating NHC precatalyst to NHC catalyst.

Supplementary Figure 7 The role of K3PO4
In mechanistic experiments we found that reaction of 2a with acyl azolium ion 59 under photoredox catalysis conditions provided ketone 3 in 41% yield, this experiment was carried out under the condition of K3PO4 as base. But when we removed K3PO4, the reaction cannot be carried out and the product was not obtained, this result showed that K3PO4 mainly acts on deprotonation of thiol to generate sulfur anion to mediate the formation of allyl radicals. In summary, Cs2CO3 mainly acts on the formation of NHC catalyst, that is, the production of azolium radical, while K3PO4 mainly acts on the deprotonation process of thiols, that is, the formation of allyl radicals. However, in the reaction system, two bases cannot completely act independently, and our experiment is only to prove the main role of two bases, and it cannot be absolutely said that one base only plays an independent role, a mixture of both bases provided the best result, as discussed in the manuscript.

Supplementary Figure 8 Synthesis of acyl imidazoles
Acyl imidazoles were prepared based on the literature 2 : The appropriate acid (10 mmol, 1.0 equiv) was dissolved in dry dichloromethane (0.3 M), and CDI (carbonyldiimidazole, 15 mmol, 1.5 equiv) was added slowly (caution, exothermic). The resulting mixture was stirred for 12 h at room temperature. Upon completion, the solution was transferred to a separatory funnel and washed with deionized water (2 x 25 mL), and then the organic layer was dried over MgSO4. Concentration under reduced pressure afforded the acyl imidazole, which was used in the following reaction without further purification. 3.2 General procedure for the synthesis of NHC A 3 A mixture of 1,2,4-triazole (1.0 g, 14.5 mmol), iodomethane (6.2 g, 43.5 mmol), and potassium carbonate (3.0 g, 21.7 mmol) in acetonitrile (8 mL) and methanol (2 mL) was heated at 40 °C for 3 days. The white mixture was filtered with a Buckner funnel, and the white solid was washed with CH2Cl2. The filtrate was concentrated to give 2,4-dimethyl-1,2,4-triazolium iodide (white solid, 3.28 g, 100%)

Preparation of carboxylic acids, derived from diacetone-D-glucose, pregnenolone, L-Menthol
Supplementary Figure 9 Preparation of carboxylic acids S12 Step 1 4 : To a solution of 4-formylbenzoic acid (1.0 equiv) in dichloromethane (0.3 M) was added oxalyl chloride (1.5 equiv) dropwise at 0 ℃, and one drop of DMF was subsequently added to the solution. Then the mixture was transferred to room temperature and stirred at the same temperature overnight. After the indicated time, the mixture was evaporated to dry under reduced pressure, and the crude acyl chloride was used directly for the next step without further purification.
Step 2 5 : To the mixture of ROH (1.0 equiv), Et3N (1.0 equiv) and DMAP (0.05 equiv) in DCM (1.0 M) was added TsCl (1.l equiv) dropwise at 0 ℃. The temperature was maintained at 0 °C for 3 h, and stirred at room temperature overnight, after which the reaction was quenched by saturated NaHCO3 (20 mL) and extracted by DCM (20 mL × 3). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography with silica gel column, affording the corresponding aromatic aldehydes.
Step 3 6 : To a solution of aromatic aldehyde (1 equiv), NaH2PO4 (1 equiv), 2-methyl-2-butene (4.42 equiv) in tert-BuOH (0.16 M) and water (0.6 M) was added NaClO2 (3.4 equiv) and the mixture was stirred for 50 min at room temperature. The reaction mixture was adjusted to pH of 4 by addition of 1 M HCl. The aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4. Purification by flash chromatography (petroleum ether/EtOAc), afforded the corresponding aromatic carboxylic acids. . The organic layers were dried over Na2SO4. The solvent was removed under vacuum and purified by silica gel chromatography (gradient of 10:1 PE: EA) to afford 52 as a yellow oil with 83% yield. c) General procedure for the synthesis of isoxazolines 8 A flame dry 8 mL tube was charged with oxime (43.2 mg, 0.2 mmol, 1.0 equiv), Na2CO3 (31.8 mg, 0.3 mmol, 1.5 equiv), fac-[Ir(ppy3)] (2.6 mg, 0.004mmol, 1.5 mol%) in anhydrous CHCl3 (2.5 mL) under argon atmosphere. Then, the resulting mixture was degassed via argon bubbling. The resulting suspension was stirred 36 h with the irradiation of 460 nm blue LEDs at room temperature. The mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were dried over Na2SO4. The solvent was removed under vacuum and purified by silica gel chromatography (gradient of 20:1 PE: EA) to afford 53 as a yellow oil with 49% yield. d) General procedure for reaction with Pd/C, H2 9 To a Schlenk tube fulfilled with argon were added Pd/C (8.5 mg, 0.004 mmol, 2 mol%) and the ketone 3 (40.4 mg, 0.2 mmol, 1.0 equiv) sequentially. After addition of these chemicals, the tube was degassed and refilled with H2 by a balloon of H2. Then EtOAc (2 mL) was added and the resulting mixture was stirred at room temperature for 60 h. The H2 balloon was removed and the S14 resulting mixture was filtered through a short column of silica gel (2 cm), eluted with ethyl acetate (5 mL x 3). The solvent was removed under vacuum and purified by silica gel chromatography (gradient of 20:1 PE: EA) to afford 54 as a colorless oil with 81% yield. e) General procedure for Wittig reaction 10 To an oven dried round bottom flask under argon was added methyl triphenylphosphonium iodide (162.4 mg, 0.4 mmol, 2.0 equiv) followed by THF (3.6 mL) and reaction cooled to 0 °C. n-BuLi (2.5 M in hexanes, 160 µL, 0.4 mmol, 2.0 equiv) was added dropwise and solution turned yellow. The reaction was stirred for 15 min. The ketone 3 (40.4 mg, 0.2 mmol, 1.0 equiv) in THF (0.4 mL) was added dropwise. The reaction was allowed to warm up to 25 °C over 30 min and stirring continued for an additional hour. The reaction was quenched by the addition of aq. NaCl. The aqueous phase was extracted with Et2O (10 mL ×3), and the combined organic layers were dried over MgSO4. The solvent was removed under vacuum and purified by silica gel chromatography (gradient of PE) to afford 55 as a colorless oil with 80% yield. f) General procedure for reduction with NaBH4 11 A methanolic solution (1 mL) of the ketone 3 (40.4 mg, 0.2 mmol, 1.0 equiv) was cooled to 0 °C, charged with NaBH4 (11.3 mg, 0.3 mmol, 1.5 equiv) portion wise, and allowed to warm to rt over 30 min. The reaction mixture was quenched with 2M HCl, concentrated in vacuo to a slurry and alkalized to pH 8 with sat. NaHCO3 (2 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient of 10:1 PE: EA) to afford 56 as a colorless oil with 76% yield. g) Reductive amination of 3 12 To a solution of 3 (40.4 mg, 0.2 mmol, 1.0 equiv) in MeOH (2.0 mL) were added PMPNH2 (70.2 mg, 0.6 mmol, 3.0 equiv), NaBH3CN (37.8 mg, 0.6 mmol, 3.0 equiv), and two drops of HOAc sequentially. The mixture was stirred at room temperature and monitored by TLC. After the completion of the reaction, the solvent was removed under reduced pressure. Next, the residue was purified by flash column chromatography (PE/EA = 15: 1) to give 57 in 79% yield as colorless oil.

Examples of unsuccessful substrates
Supplementary Figure 12 Examples of unsuccessful substrates S15