Photo-mediated selective deconstructive geminal dihalogenation of trisubstituted alkenes

Selective deconstructive functionalization of alkenes, other than the well-established olefin metathesis and ozonolysis, to produce densely functionalized molecular scaffolds is highly attractive but challenging. Here we report an efficient photo-mediated deconstructive germinal dihalogenation of carbon-carbon double bonds. A wide range of geminal diiodoalkanes and bromo(iodo)alkanes (>40 examples) are directly prepared from various trisubstituted alkenes, including both cyclic and acyclic olefins. This C=C cleavage is highly chemoselective and produces geminal dihalide ketones in good yields. Mechanistic investigations suggest a formation of alkyl hypoiodites from benzyl alcohols and N-iodoimides, which undergo light-induced homolytic cleavage to generate active oxygen radical species.

Following the general procedure C afforded the product as a colourless oil (58 mg, 70% yield). 1

Deconstructive bromo-iodination General procedure of the deconstructive bromo-iodination
General procedure D: Alkene (0.2 mmol) and N-bromosuccinimide (0.21 mmol, 1 equiv), H2O (10 mmol, 50 equiv), and MeCN (2 mL) were added to a schlenk tube (10 mL) equipped with a magnetic stirring bar. The reaction mixture was operated by freeze-pump-thaw procedures for three times and backfilled with argon. The resulting solution was magnetically stirred at 50 o C for 12 hours. Then, 1,3-diiodo-5,5-dimethylhydantoin (0.3 mmol, 1.5 equiv) was added to the reaction mixture under inert condition. The reaction mixture was irradiated by blue LED lamps (2*40 W) and magnetically stirred at 50 o C. After 24 hours, the reaction solution was concentrated, and the product was purified by column chromatography (SiO2). The diastereomeric ratio was determined by 1 H NMR of the crude product mixture. General procedure E: Alkene (0.2 mmol) and N-bromosuccinimide (0.21 mmol, 1 equiv), H2O (10 mmol, 50 equiv), and MeCN (2 mL) were added to a schlenk tube (10 mL) equipped with a magnetic stirring bar. The reaction mixture was operated by freeze-pump-thaw procedures for three times and backfilled with argon. The resulting solution was magnetically stirred in an ice-bath and slowly warmed to room temperature. After 12 hours, 1,3-diiodo-5,5-dimethylhydantoin (0.3 mmol, 1.5 equiv) was added to the reaction mixture under inert condition. The reaction mixture was irradiated by blue LED lamps (2*40 W) and magnetically stirred at 50 o C. After 24 hours, the reaction solution was concentrated, and the product was purified by column chromatography (SiO2).

S9
Following the general procedure D afforded the product as a yellow oil (59 mg, 67% yield). 1

S10
Following the general procedure D afforded the product as a yellow oil (50 mg, 63% yield). 1

Investigation of other trisubstituted alkenes a) Trialkyl-substituted cyclohexene
Following general procedure A, treatment of 42 with DIH in the presence of H2O under blue LED irradiation, could not produce the corresponding diiodination product. Following general procedure D, treatment of 42 with NBS and DIH in the presence of H2O under blue LED irradiation, could not produce the corresponding bromo-iodination product.
80 o C conditions: 42 (0.2 mmol) and N-bromosuccinimide (0.21 mmol, 1.05 equiv), H2O (10 mmol, 50 equiv), and MeCN (2 mL) were added to a 10 mL schlenk tube (10 mL) equipped with a magnetic stirring bar. The reaction mixture was operated by freeze-pump-thaw procedures for three times and backfilled with argon. The resulting solution was magnetically stirred at room temperature for 12 hours. Then, 1,3-diiodo-5,5dimethylhydantoin (0.3 mmol, 1.5 equiv) was added to the reaction mixture, and the reaction mixture was irradiated by blue LED lamps (2*40 W) and magnetically stirred at 80 o C. After 24 hours, the reaction solution was concentrated, and the product was purified by column chromatography (SiO2). Product 43 was obtained as in 22% yield. The generation and stability of the halohydrin and hypoiodite intermediates are the keys for the success of geminal diiodination and bromo-iodination. Control experiments were performed to evaluate the temperature effect on the halohydrin formation and deconstructive iodination with both aryl substituted and trialkyl substituted cyclic alkenes. As illustrated in Supplementary Figure 2, the formation of halohydrins was sensitive to the reaction temperature, and bromohydrins possessed better thermal stability than that with iodohydrins. On the other hand, higher temperature would accelerate the deconstructive halogenation. However, compared to aryl substituted alcohols, the trialkyl substituted alcohols were not effective in the deconstructive iodination step. A suitable reaction temperature was therefore important to achieve an effective deconstructive geminal dihalogenation.
Product 47 was obtained as colorless oil: 1   Time profile of the transformation with the light ON/OFF over time. Yields were determined by crude 1 H NMR spectra using dibromomethane as an internal standard. To examine the impact of light, we conducted experiments under alternating periods of irradiation and darkness following the general procedure A. These resulted in total interruption of the reaction progress in the absence of light and recuperation of reactivity on further illumination. The results demonstrated that light was a necessary component of the reaction. Even though we could not fully rule out a radical-chain process, the data shown that any chain-propagation process must be short-lived. Before irradiation, the sample cell was stirred for 2 hours and the EPR spectra were recorded (Supplementary Figure 9). Then the sample cavity was irradiated by 80 W blue light for 3 hours at 323 K. After the irradiation, the sample cell was cooled to 298 K and the EPR spectra were recorded (Supplementary Figure 10). The ESR results demonstrated that there is no radical formation in the dark, but radical species was formed after light irradiation.

Synthetic diversification
To a stirring suspension of anhydrous CrCl2 (98 mg, 0.8 mmol) in THF (2 mL), DMF is added (62 uL, 0.8 mmol) at 25 °C under an argon atmosphere. After 30 min of stirring, a solution of cyclohexanecarboxaldehyde (0.1 mmol) and 2 (0.2 mmol) in THF (0.3 mL) is added at 25 °C. The pale green suspension turns to dark green and then to a dark brown solution. The resulting mixture is stirred at 25 °C for 12 hours. The mixture is subjected to aqueous workup. E/Z Ratio was determined by GC analysis of the crude mixture. Purification by column chromatography gave the desired olefin 57.
Product 57 was obtained as colourless oil (20 mg, 74%). 1  2 (0.2 mmol), DBU (0.2 mmol) and benzene (3 mL) were added to a sealed tube equipped with a magnetic stirring bar. The reaction mixture was heated to 60 °C for 4 hours. The mixture is subjected to aqueous workup. E/Z Ratio was determined by GC analysis of the crude mixture. Purification by column chromatography gave the desired olefin 58.
Product 59 was obtained as colourless oil (62 mg, 72%). 1  In a glovebox, 2 (0.1 mmol), Hantzsch ester (0.3 mmol), Ru(bpy)3Cl2 and MeCN (2 mL) were added to a Schlenk tube equipped with a stirring bar. Then the reaction mixture was irradiated by blue LED strips and magnetically stirred. After 24 hours, the reaction solution was concentrated, and the product 60 was purified by column chromatography (SiO2).
Product 60 was obtained as colourless oil (15 mg, 85%). 1 [5] In a glovebox, 24 (0.1 mmol), Hantzsch ester (0.3 mmol), Ru(bpy)3Cl2 and MeCN (2 mL) were added to a Schlenk tube equipped with a stirring bar. Then the reaction mixture was irradiated by blue LED strips and magnetically stirred. After 24 hours, the reaction solution was concentrated, and the product was purified by column chromatography (SiO2).
Product 61 was obtained as colourless oil (23 mg, 90%). 1  24 (0.2 mmol), NaN3 (0.8 mmol) and DMF (2 mL) were added to a sealed tube equipped with a magnetic stirring bar. The reaction mixture was heated to 70 °C for 18 hours. Purification by column chromatography gave the product 63.
Product 63 was obtained as a white solid (51 mg, 86%). 1  Following reported procedure, [6] 63 (0.2 mmol) and phenylacetylene (0.2 mmol) were suspended in 4 mL of a 1:1 water/tert-butanol mixture. Sodium ascorbate (0.02 mmol, in 0.2mL water) was added, followed by copper(II) sulfate pentahydrate (0.01 mmol, in 0.1mL water). The heterogeneous mixture was stirred vigorously overnight at ambient temperature. The reaction mixture was diluted with 20 mL of S26 water and cooled in ice to obtain white precipitate which was collected by filtration and used directly in next step. The white solid, which was obtained from above reaction, was added to a solution of H2O (10 mmol) and Ag2CO3 (0.2 mmol) in toluene (4 mL). Then, the reaction mixture was stirred at 70 o C. After 10 hours, the reaction was concentrated, and the corresponding product was purified by column chromatography.
Density functional theory (DFT) calculations were performed for the verification of the mechanism. The geometries optimization in this study (except 56 and 56*) was performed at the (u)B3LYP-D3(BJ) level of theory. The 6-311+g(d,p) basis set was used for all H, C, N, and O atoms, and the Stuttgart-Dresden basis set (SDD) was employed for Br and I atoms. The nature of the stationary points (minima with no imaginary frequency or transition states with one imaginary frequency) was confirmed. The free energies of the optimized geometries were calculated at the same level of theory, taking into account the solvent effect of acetonitrile using Solvent Polarizable Continuum Model (PCM). Unless specified otherwise, the Gibbs free energy was used throughout. Considering the deviation in the free energies is ~1.89 kcal/mol from the standard state (1 atm) to 1 M in solution, we reduced by 1.89 kcal/mol to the free energy for additional steps and added by 1.89 kcal/mol for the dissociation steps. [7] For transition state, intrinsic reaction coordinate (IRC) calculations were performed to verify whether it connected with correct reactants and products or intermediates. Time-dependent density functional theory (TD-DFT) was performed to calculate the vertical excitation energies of the photodissociation process, using the CAM-B3LYP-D3(BJ) [8] level of theory with the same basis set. All calculations were performed using the Gaussian 16 Rev. A.03 software suite. [9] The geometries were realized using CYLview, 1.0. [10] Supplementary Figure