Photoredox-catalyzed oxo-amination of aryl cyclopropanes

Cyclopropanes represent a class of versatile building blocks in modern organic synthesis. While the release of ring strain offers a thermodynamic driving force, the control of selectivity for C–C bond cleavage and the subsequent regiochemistry of the functionalization remains difficult, especially for unactivated cyclopropanes. Here we report a photoredox-coupled ring-opening oxo-amination of electronically unbiased cyclopropanes, which enables the expedient construction of a host of structurally diverse β-amino ketone derivatives. Through one electron oxidation, the relatively inert aryl cyclopropanes are readily converted into reactive radical cation intermediates, which in turn participate in the ensuing ring-opening functionalizations. Based on mechanistic studies, the present oxo-amination is proposed to proceed through an SN2-like nucleophilic attack/ring-opening manifold. This protocol features wide substrate scope, mild reaction conditions, and use of dioxygen as an oxidant both for catalyst regeneration and oxygen-incorporation. Moreover, a one-pot formal aminoacylation of olefins is described through a sequential cyclopropanation/oxo-amination.


General Information
Unless otherwise noted, all reactions were carried out under oxygen atmosphere. All commercially available reagents were used directly without further purification unless noted. All solvents were dried by passing through a column of neutral alumina under nitrogen prior to use. Organic solutions were concentrated under reduced pressure on an IKA RV 10 rotary evaporator. Chromatography was performed using silica gel with distilled solvents. Thin-layer chromatography (TLC) was performed on Silicycle 250 μm silica gel plates visualized under UV light (254 nm) and dyed with cerous molybdate solution by heating.
HRMS spectra were recorded on a Xevo G2-XS QTof (Waters Corporation). 1 H NMR and 13 C NMR spectra were recorded using Bruker Avance 400 MHz spectrometers.
Chemical shifts for 1 H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet).

Substrates Preparation
Compounds 1a, 1c, 1e, 1f, 1g, 1n, 1u, 1x, 1y, 1ab, 1ak, 1am, 1ao-1aq, 1as, 1au and 1av were prepared according to the literature procedures, and all the spectroscopic data are in agreement with the literature reports. 4 a) To a 150 mL oven-dried round-bottom flask equiped with a stir bar, the isopropyltriphenylphosphonium iodide (6.0 g, 13.88 mmol, 1.2 equiv) and anhydrous THF (70 mL, 0.2 M) was added. The reaction flask was capped with rubber septum and charged with N2 balloon and then the reaction mixture was cooled to 0 °C. n-BuLi (2.5 M, 5.6 mL, 14 mmol, 1.2 equiv) was added dropwise by syringe and the reaction mixture was stirred at this temperature for 30 min. The corresponding solution of aldehyde (11.6 mmol, 1.0 equiv) in THF (20 mL) was added by syringe and the reaction mixture was allowed to warm to room temperature, and then stirred for 16 h. After the reaction reached completion according to the TLC analysis, the reaction mixture was quenched by sat. NH4Cl (30 mL) and extracted with EtOAc (100mL) for 3 times. The combined organic layers were washed with H2O2 (10 wt% in water, 10 mL) and brine (20 mL), dried over Na2SO4 (20 g), and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the desired alkene.

General Procedure A for Aryl Cyclopropanes Synthesis
b) In a 150 mL oven-dried round-bottom flask with a stir bar, was added 2,4,6trichlorophenol (1.18 g, 6.0 mmol, 2.5 equiv ) under nitrogen atmosphere. DCM (60 mL, 0.1 M) was added into the flask and the reaction mixture was cooled to -40 °C.
ZnEt2 (1.0 M, 6.0 mL, 6.0 mmol, 2.5 equiv) was added slowly into the flask by syringe and the reaction mixture was stirred at this temperature for 15 min. CH2I2 (2.57 g, 9.6 mmol, 4.0 equiv) was added slowly by syringe and the reaction mixture was stirred at this temperature for another 15 min. Next, the corresponding solution of alkene (2.4 mmol, 1.0 equiv) in DCM (10 mL) was added by syringe and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. After the reaction reached completion (as judged by 1 H-NMR of an alloquat removed from the reaction vessel and worked up by evaporation), the reaction mixture was quenched with sat. NH4Cl (30 mL) and extracted with DCM (100mL) for 3 times. The combined organic layers were washed with aq. NaOH (1.0 M, 30 mL) and brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the desired compound. To a 50 mL oven-dried round-bottom flask equipped with a stir bar, was added DCM (3 mL, 0.67 M) under nitrogen atmosphere and was cooled to -40 °C. ZnEt2 (2.0 M, 2.5 mL, 5.0 mmol, 2.5 equiv) was added followed by slow addition of a solution of CH2I2 (2.68 g, 10.0 mmol, 5.0 equiv) in DCM (1 mL) by syringe. The reaction mixture was stirred at this temperature for 1 h followed by warming to -10 °C . Next, a the solution of trichloroacetic acid (60 mg, 0.4 mmol, 0.2 equiv) and DME (224 mg, 2.4 mmol, 1.2 equiv) in DCM (1 mL) was added dropwise into and the reaction mixture by syringe and the resulting solution was allowed to stir at -10 °C for another 1 h. A solution of corresponding alkene (2.0 mmol, 1.0 equiv) in DCM (1 mL) was then added by syringe and the reaction mixture was allowed to warmed to room temperature and stirred for 16 h. After the reaction reached completion (as judged by 1 H-NMR of an alloquat removed from the reaction vessel and worked up by evaporation), the reaction mixture was quenched with sat. NH4Cl (30 mL) and extracted with DCM (20 mL) for 3 times. The combined organic layers were washed with aq. NaOH (1.0 M, 30 mL) and brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the corresponding title compound.
To a 50 mL oven-dried round-bottom flask equipped with a stir bar was added the solution of (4-methoxyphenyl)(tributylstannyl)methyl methyl carbonate 8 (486 mg, 1.0 mmol, 1.0 equiv) and the corresponding alkene (1.1 mmol, 1.0 equiv) in toluene (3.5 mL) under nitrogen atmosphere at room temperature. The reaction vessel was cooled to -23 °C . BF3· OEt2 (156 mg, 1.1 mmol, 1.1 equiv) was added by syringe and stirred at this temperature for 2 h. After the reaction reached completion according to the TLC analysis, the reaction mixture was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (30 mL) for 3 times. The combined organic layers were washed with brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the target compound.

Synthetic Procedure for 1ab
Compound 1ab was prepared from (E)-1-methoxy-4-(prop-1-en-1-yl)benzene following the cyclopropanation method in General Procedure A and obtained in 73% yield as a colorless liquid.

Synthetic Procedure for 1aa
The compound 1aa was prepared from 1-methoxy-4-vinylbenzene following the cyclopropanation method in General Procedure A and obtained in 77% yield as a colorless liquid.
To this stirring solution at room temperature, EtMgBr (1.0 M in THF,4.8 mL,4.8 mmol,2.4 equiv) was added slowly by syringe and the resulting mixture was stirred for an additional 2 h. Once the reaction was judged to be complete by TLC analysis, the reaction mixture was quenched with sat. NH4Cl (20 mL) and extracted with EtOAc (30 mL) for 3 times. The combined organic layers were washed with sat. NaHCO3 (30 mL) and brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford 1-(2-ethylbut-1-en-1-yl)-4methoxybenzene as colorless oil (294 mg, 1.54 mmol, yield 77%).

Synthetic Procedure for 1x
a) To a 150 mL oven-dried round-bottom flask equipped with a stir bar was added bromo(3-bromopropyl)triphenylphosphorane (7.0 g, 15.
Synthetic Procedure for 1am 10 Compound 1am was prepared according to the literature procedure 10 and obtained with an overall yield of 39% as a white solid.
The following protocol for the synthesis of compound 1t follows the General Procedure B, which allows the generation of desired product in 55% yield as a white solid. sat.NH4Cl (10 mL) and extracted with EtOAc (50 mL) for 3 times. The combined organic layers were washed with H2O2 (10 wt% in water, 10 mL) and brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the 1-methoxy-4-(2-methoxyvinyl)benzene as a yellow oil (1.19 g, 7.25 mmol, yield 72.5%).

Synthetic
b) To an oven-dried 50 mL round-bottom flask with a stir bar, AcOH (10 mL) was warm ed 80 °C , then AgAcO (10 mg) was added with stirring soon it became a clear solution.
Then Zn powder (2.0 g) was added into the solution and stirred at 80 °C for 30 seconds.
The resultant mixture was cooled down to room temperature and then solvent was decant, the residue solids were washed with ether (10 mL) for 5 times. To the residue solids was added 1-methoxy-4-(2-methoxyvinyl)benzene (820 mg, 5.0 mmol, 1.0 equiv) followed by anhydrous ether (10 mL) under nitrogen atmosphere at room temperature, then CH2I2 (2.0 g, 7.5 mmole, 1.5 equiv) was dropped into with stirring and then the reaction solution was stirred under reflux for 16 h. After the reaction reached completion according to the TLC analysis, the reaction mixture was quenched with sat.NH4Cl (10 mL) and extracted with EtOAc (50 mL) for 3 times. The combined organic layers were washed with H2O (50 mL) and brine (20 mL), dried over Na2SO4 (20 g) and filtered. After the volatile materials were removed under reduced pressure, the crude residue was purified by column chromatography (PE : EtOAc = 50 : 1 to 10 : 1) to afford the 1an as a colorless oil (580 mg, 3.25 mmol, yield 65.0%, D,R = 1: 0.8).

Synthesis of (1R,2R)-1,2-diphenylcyclopropane
a) To an oven-dried 100 mL round-bottom flask equipped with a stir bar, (E)styrylboronic acid (0.75 g, 5 mmol, 1.0 equiv), +TMTA (1.05 g, 5 mmol, 1.0equiv) and dry DCM (20 mL) was added at room temperature. The reaction mixture was stirred for 2h and then cooled to -78°C. In a separate 100 mL flask, Et2Zn ( Synthetic procedure for 2e 14 Compound 2e was prepared according to the literature 14 with an overall yield of 68% as a white solid.  atmosphere at room temperature for certain h. Yield and conversion were determined by 1 H-NMR using 1,1,2,2-tetrachloroethane as internal standard.

General Procedure E for Oxo-Amination of Aryl Cyclopropanes
To an oven-dried 10 mL tube equipped with a stir bar, cyclopropanes 1 (0. and then the reaction tube was capped and charged with O2 using a balloon, and the resulting mixture was irradiated under 15W blue LEDs at room temperature. When the reaction was determined to be completed by TLC analysis, the mixture was passed through a short pad of celite and rinsed with DCM (20 mL). The filtrate was evaporated to dryness under reduced pressure and the crude residue was purified by column chromatography on silica gel (PE : EtOAc = 9 : 1 to 4 : 1) to afford the desired product 3.

General Procedure F for One-pot Aminoacylation of Olefins
To an oven-dried 50 mL round-bottom flask equipped with a stir bar was added a solution of (4-methoxyphenyl)(tributylstannyl)methyl methyl carbonate (486 mg

Light On/Off Experiment
To an over dried 5 mm NMR tube equipped with a stir bar, were added 1b ( Recorded using a F-4600 FL Spectrophotometer (λmax= 459 nm).

Determination of the Light Intensity at 459 nm
Following a modified procedure reported by Melchiorre and co-workers, 16 Where: :

Determination of the Reaction Quantum Yield
To a 3 mL quartz cuvette with two sides taped over with electrical tape, 1a ( The reaction quantum yield (Φ) was thus determined to be 0.14.
Supplementary Figure 10. Absorbance of the reaction mixture solution.

Radical Inhibition Experiment with TEMPO
To an oven-dried 10 mL Schlenk tube equipped with a stir bar, 1b (0.

Evidence of Alkyl Hydroperoxide Intermediate
To an oven-dried 10 mL Schlenk tube equipped with a stir bar was added 1 (0. To a flask with a stir bar, Int-3ha/Int-3pa was added dimethylaminopyridine (DMAP) (10 mol%), Ac2O (1.0 equiv) and DCE (0.5 mL). The reaction mixture was stirred at rt for 3 h after which TLC showed all of the starting material was consumed. The reaction mixture was diluted with ethyl acetate (20 mL) and brine (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (20 mL×2). The combine organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was separated from the residue by column chromatography on silica gel ((PE : EtOAc = 4 : 1 , Rf3ha = 0.55, 70% yield; Rf3pa = 0.40, 60% yield), and the structure of the obtained compound was confirmed to be identical to 3ha/3pa by NMR.

The Examination of Reactions Between Pyrazole and 1ak, 1ba and 1bb
Following the General Procedure E, 3aka and 5aka was obtained from 1ak in 22%, 35% yields, respectively, 6baa was obtained from 1ba in 30% yield and 5bba was obtained from 1bb in 50% yield.
As we can obtain the desired products of to 3aka, the SET oxidation of respective substrates for the generation of radical cation intermediates therefore is accomplished.
The present reaction predominately proceeded through a concerted nucleophilic attack/ring-opening manifold, and the positive charge is believed to be delocalized over the whole molecule, not only the aryl moiety but also the cyclopropyl ring system. Therefore, the installation of electronically negative substituent proximal to the cyclopropyl ring would inevitably affect the charge distribution, thus making the carbon atom of cyclopropane proximal to those electron-withdrawing functionalities less positively charged and in turn more reluctant to undergo nucleophilic attack by azaarenes. Furthermore, in addition to the formation of desired product 3aka, the demethoxyamination product 5aka was also obtained in 35% yield in the reaction of 1ak. In this case, the nucleophilic aromatic substitution by azaarene compares favorably with ring-opening functionalization of cyclopropane ring because of the proximity of -OAc functionality.
This phenomenon is consistent with the observation of Nicewicz that in the case of photoredox catalyzed hemolytic aromatic substitution of electron-rich arene derivatives, the nucleophile tends to attack the para-position of arenes with electron-donating substituents (J. Am. Chem. Soc. 2017, 139, 11288). Therefore, the experimental result from 1ba indicates that after one electron oxidation the positive charge reside mainly on the aryl ring, with the cyclopropyl ring embed in oxo-bicyclic system poorly participated in charge delocalization, probably because of poor orbit overlap.
In the case of 1bb, the reaction selectively underwent nucleophilic aromatic substitution to afford 5bba in 50% yield.

The Examination of Aza-Nucleophiles with Different Oxidation Potentials
The prerequisite for the success of this reaction is the efficient and selective SET oxidation of aryl cyclopropane substrates, therefore, the selected aza-nucleophile should tolerate the oxidation potentials that enable smooth SET oxidation of cyclopropane derivatives. On the other hand, the success of ring opening of cyclopropane radical cation intermediate is also directly affected by the nucleophilicity of azaarenes. This issue we faced is that nucleophiles with high nucleophilicity are always more easily undergo SET oxidation. We have tested a set of aza-nucleophiles with varying oxidation potentials and found that nucleophiles with oxidation potentails lower than aryl cyclopropane substrate are not viable in the present reaction.

Experiment with Enantiometically Enriched Diphenyl Cyclopropane
The reaction of 1ao with 90% ee led to the generation of the product 3aoa in 65% yield with 60% ee after 24 h. This result indicates that the oxo-amination maninly proceed