Iodine-catalyzed diazo activation to access radical reactivity

Transition-metal-catalyzed diazo activation is a classical way to generate metal carbene, which are valuable intermediates in synthetic organic chemistry. An alternative iodine-catalyzed diazo activation is disclosed herein under either photo-initiated or thermal-initiated conditions, which represents an approach to enable carbene radical reactivity. This metal-free diazo activation strategy were successfully applied into olefin cyclopropanation and epoxidation, and applying this method to pyrrole synthesis under thermal-initiated conditions further demonstrates the unique reactivity using this method over typical metal-catalyzed conditions.


Supplementary Table 1. Optimization of Reaction under Photo-initiated Conditions
Addition of 1 equiv. of TEMPO 0% n.d.
Reaction conditions: 1 mol% photocatalyst and 10 mol% I 2 were added to a DCE solution (3 mL) of 2a (0.3 mmol) and EDA 1a (0.3 mmol), and reaction was kept under argon (degassed) at room temperature under blue light for 24 h. Conversion and yield were determined by 1 H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal standard.
The Schlenk tube was vacuumed and purged with argon three times before it was tightly screw-capped. The reaction mixture was stirred at 100 o C for 24 h, and cooled to room temperature. The reaction solution was evaporated, and the residue was purified by column chromatography (PE/EA) to afford the desired product 4 in 80% yield (E/Z = 4:1).

Radical Trapping Experiment under Thermal-initiated Conditions
To a 50 mL Schlenk tubes with a stir bar was added olefin 2a (55 mg, 0.3 mmol), diazo compound 1a (35 mg, 0.3 mmol), TEMPO (47 mg, 0.3 mmol) and 3 mL of DCE, then I 2 (8 mg, 0.03 mmol) was added. The Schlenk tube was vacuumed and purged with argon three times before it was tightly screw-capped. The reaction mixture was stirred at 100 o C for 24 h, and cooled to room temperature. No 3a was observed via the crude HNMR. And

Control Experiment under Photo-initiated Conditions
Control experiment 1. Photocatalyst would deactivate in the presence of some alkenes, such as vinyl ferrocene, p-NO 2 -styrene and enamide. Control experiments displayed that EDA would decompose slowly in the presence of I 2 and Ru(bpy) 3 Cl 2 . However, some alkenes (such as vinyl ferrocene, p-NO 2 -styrene and enamide) added the above reaction, we don't observe decomposition of EDA (except the formation of diiodide 1a'), which supported our hypothesis that these alkene substrates indeed deactivated the photo catalyst. Besides, the model reaction would be inhibited completely when these alkenes were added. And these results strongly indicated that photocatalyst would deactivate in the presence of these alkenes, see Supplementary  Conversion and yield were determined by 1 H NMR spectroscopy using 1,3,5trimethoxybenzene as internal standard. Isolated yield in parentheses.

Catalytic amount of iodine and EDA under argon using MNP (2-methyl-2-nitros opropane) as a spin trapping reagent.
To a 50 mL Schlenk tubes with a stir bar was added EDA (23 mg, 0.2 mmol), MNP (3.5 mg, 0.04 mmol) and 2 mL of DCE. Then iodine (5 mg, 0.02 mmol) was added to the above solution. The Schlenk tube was vacuumed and purged with argon three times before it was tightly screw-capped. The mixture was stirred at 100 ºC for 1 h, and cooled to room temperature. Then 20 uL of this solution was taken out into a small tube and analyzed by EPR at room temperature (Supplementary Two radical signals were clearly observed. Data analysis suggested that the seven Lorentzian lines (g = 2.0066, a ( 14 N1) = 9.14 G, a ( 14 N2) = 4.56 G) displayed characteristic resonance of adduct from nitrogen radical and MNP. We believe that the nitrogen radical may be generated from iodine and EDA. The other six Lorentzian lines (g = 2.0063, a ( 14 N) = 14.41 G, a ( 1 H) = 4.19 G) displayed a characteristic resonance of adduct from carbon radical and MNP, which we speculated was generated from denitrogenation product of the nitrogen radical.
Catalytic amount of iodine and EDA under oxygen using DMPO (5,5-dimethyl-1pyrroline N-oxide) as a spin trapping reagent. To a 50 mL Schlenk tubes with a stir bar was added EDA (23 mg, 0.2 mmol), DMPO (4.5 mg, 0.04 mmol) and 2 mL of DCE. Then iodine (5 mg, 0.02 mmol) was added to the above solution. The Schlenk tube was vacuumed and purged with oxygen three times before it was tightly screw-capped. The mixture was stirred at 80 ºC for 30 min, and cooled to room temperature. Then 20 uL of this solution was taken out into a small tube and analyzed by EPR at room temperature We observed clearly the peroxy radical signal with six Lorentzian lines. Other weak signals came form DMPO itself signal under oxygen. We speculated that the iodosubstituted alkyl radical would further react with oxygen to generate the peroxy radical which was easily captured by DMPO.

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The reaction mixture was stirred at room temperature under blue light for 24 h. The reaction solution was evaporated, and the residue was purified by column chromatography (PE/EA) to afford the desired product 3a-3n.

Control experiment 2:
To a 10 mL tube with a stir bar was added acetamidocyclopropane 6c´ (20 mg) and 1 mL of DCE. The reaction mixture was stirred at 100 ºC for 24 h, and cooled to room temperature. The reaction solution was evaporated to obtain the pure product 6c (18 mg) in nearly quantitative yield. The results of experiment 3 and 4 indicated that acetamidocyclopropane was the key intermediate.

Gram Synthesis of Pyrroles
To a 250 mL Schlenk tube with a stir bar was added enamides 5a (1.61 g, 10 mmol), diazo compound 1a (1.14 g, 10 mmol) and 100 mL of DCE, then iodine (254 mg, 1 mmol) was added. The Schlenk tube was vacuumed and purged with argon three times before it was tightly screw-capped. The reaction mixture was stirred at 100 ºC for 24 h, and cooled to room temperature. The reaction solution was evaporated, and the residue was purified by column chromatography (PE/EA) to afford the desired product 6a in 80% yield (1.83 g).

Experimental Procedure and Date for Olefin Epoxidation
To a 50 mL Schlenk tube with a stir bar was added olefin 2 (0.3 mmol), ethyl diazoacetate 1a (35 mg, 0.3 mmol) and DCE (3 mL), followed by iodine (4 mg, 0.015 mmol). The Schlenk tube was vacuumed and purged with oxygen three times before it was tightly screw-capped. The reaction mixture was stirred at 80 ºC for 2 h, and cooled to room temperature. Then the reaction solution was evaporated, and the residue was purified by column chromatography (PE/EA) to afford the desired epoxide 7a-7e.