Visible-light-induced cross-coupling of aryl iodides with hydrazones via an EDA-complex

A visible-light-induced, transition-metal and photosensitizer-free cross-coupling of aryl iodides with hydrazones was developed. In this strategy, hydrazones were used as alternatives to organometallic reagents, in the absence of a transition metal or an external photosensitizer, making this cross-coupling mild and green. The protocol was compatible with a variety of functionalities, including methyl, methoxy, trifluoromethyl, halogen, and heteroaromatic rings. Mechanistic investigations showed that the association of the hydrazone anion with aryl halides formed an electron donor–acceptor complex, which when excited with visible light generated an aryl radical via single-electron transfer.


General information
All reagents were purchased from commercial sources and used without further purification unless otherwise stated. 1 H, 19 F and 13 C NMR spectra were recorded at room temperature on Varian Mercury plus 300 MHz, Bruker AV400 MHz and Agilent INOVA 600 MHz with TMS as an internal standard and CDCl 3 (unless otherwise stated) as solvent. All reactions were carried out in argon atmosphere unless otherwise stated. Silica gel (300-400 mesh) was used for flash column chromatograph, eluting (unless otherwise stated) with an ethyl acetate/ petroleum ether (v/v =1/250) mixture.
GC-MS analyses were made by Thermo Scientific Trace 1300 by means of EI. HRMS analyses were made at Lanzhou University, and Technical Institute of Physics and Chemistry & University of Chinese Academy of Sciences by means of ESI and EI.
Melting points were measured on micro melting point apparatus and uncorrected. All solvents were purified and dried by standard techniques.

2.3) Effects of ratio of substrates a
Entry Conditions Yield(%) b   °C. b Yields were determined by 1 H NMR using nitromethane as internal standard.

General procedure for C-C coupling
In the glove box, NaOH (0.4 mmol 16.0 mg) was added into a test tube (20.0 mL) charged with a magnetic stir bar. Then, the tube was moved out of the glovebox, followed by the addition of DMSO (1.0 mL), DMF (50.0 µL), hydrazone (0. 8 mmol) and alkyl halide (0.2 mmol), sealed and the mixture was irradiated by 425 nm 3Wˣ2 blue LED for 24 h under an air atmosphere at 15 °C. Brine (10.0 mL) was added to the reaction system. The mixture was extracted with EA (20.0 mL × 3), and the combined organic phase was dried over Na 2 SO 4 , filtered and concentrated. The product diphenylmethane (3a) was isolated by flash chromatography on silica gel with PE/EA (250/1(v/v)).

The promotion of light on the reaction
23% yield of 3a was obtained in dark indicating that nucleophilic substitution process was possible. To further investigate this pathway, different substrates were reacted at high temperature in absence of light, obtaining very low yield of products (2% yield of 3v, trace amounts of 3m) (Scheme S1). We increased the reaction's temperature without light, and the yield of 3a increased at first and then decreased. The highest yield (50%) was obtained when heated at 60 ºC, which was also lower than visible-light induced condition at 15 ºC (73%). Further increasing the temperature lowered the yield because of competitive Wolff-Kishner-Huang reaction of 1a under basic conditions.
For product 3v and 3m, when increasing the reaction temperature in dark, the yields were much lower than visible-light induced condition at 15 ºC (60% for 3v and 50% for 3m, respectively). These results indicated that light was important for this transformation. On the other hand, the DFT calculations indicated that free energy barrier of an intermolecular aromatic nucleophilic substitution was as high as 30.0 kcal mol -1 (see Figure S2 in SI). Therefore, in the absence of light, the experimental results can only obtain low to trace yields. These controlling experiments and DFT calculations results indicated that visible light has a great promoting effect on the reaction. Scheme S1 Control experiments of different substrates under dark conditions.

Deuterium labelling experiment
We have carried out several deuterium labeling experiments, 0.4 mmol D 2 O was added to the reaction system under the standard conditions (DMSO solvent), the yield was deceased to 44%. However, no deuterated product was detected. The same result was obtained using NaOD (40% in D 2 O) instead of NaOH (Scheme S2a). Considering that the deuterium atom at the benzyl position may be exchanged with DMSO solvent under basic conditions leading to the above results, to further confirm this hypothesis, DMSO-d6 (1.0 mL) was used as solvent instead of DMSO, and obtained the deuterated product 3v-d 2 (70% D) in 48% yield under standard conditions (Scheme S2b). Directly using diphenylmethane 3v as starting material in DMSO-d6 (1.0 mL) under basic conditions, the hydrogen atoms at the benzylic position were completely exchanged with/without light (Scheme S2c). These results can explain why no deuterated products were obtained when adding D 2 O or using NaOD (due to the hydrogen/deuterium atoms at the benzyl position can easily exchange with DMSO solvent under basic condition). The similar results for α-trideuteration of methylarenes have been reported with DMSO-d6 in the presence of NaOH (Org. Chem. Front., 2021Front., , 8, 2981 In glove box, NaOH (3.0 mmol, 120.0 mg) were added into a round bottom flask (25.0 mL) charged with a magnetic stir bar. Then, the flask was moved out of the glovebox, followed by the addition of DMSO (7.5 mL), DMF (0.35 mL), hydrazone 1a (6.0 mmol) and aryl halide 2a (1.5 mmol), sealed, and the mixture was irradiated by 425 nm blue LEDs (3Wˣ4) for 24 h under an air atmosphere at 15 °C. Brine (10.0 mL) was added to the reaction system. The mixture was extracted with EA (30.0 mL × 3), and the combined organic phase was dried over Na 2 SO 4 , filtered and concentrated. The product 3a (colorless liquid, 180 mg, 55% yield) was isolated by flash chromatography on silica gel with PE/EA (250/1 (v/v)).

Complete reference for Gaussian 09
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Computational methods.
All DFT calculations were carried out using Gaussian 09 program. All geometry optimizations and frequency calculations in this paper were performed with the B3LYP functional [1,2] including Grimme's D3 (BJ-damping) dispersion corrections [3] in implicit dimethylsulfoxide using at 6-31G(d) basis set (SDD basis set [4] for I and Na) by using the Solvation Model Based on Density (SMD) [5] with the keyword in the Gaussian code route section "SCRF=(SMD,Solvent=dimethylsulfoxide). The vibrational frequencies were computed at the same level of theory as for the geometry optimizations to confirm whether each optimized structure is an energy minimum or a transition state and to evaluate the zero-point vibrational energy (ZPVE) and thermal corrections. The single-point energies were computed with the M062X functional [6] including Grimme's D3 dispersion corrections [7] using a higher-level basis set 6-311+G(d,p) basis set (SDD basis set for I and Na). The TDDFT/B3LYP-D3(BJ)/6-31G(d)-SDD/SMD(DMSO) method was applied to optimize the geometry of the lowest singlet excited state. The frontier molecular orbital (FMO) analyses were generated using VMD [8] and Multiwfn [9] . The 3D diagrams of molecules were generated using CYLView [10] .

DFT calculations for the radical substitution (SRN)
As shown in Figure S3, when hydrazone radical C is formed, the calculated activation free energy for the direct radical substitution between hydrazone radical and iodobenzene 2b via 16-ts is 31.4 kcal mol -1 , leading to the iodine radical and benzhydryldiazene intermediate E. Moreover, the calculated activation free energy for the radical substitution between 7 and iodobenzene 2b through transition state 17-ts is as high as 28.1 kcal mol -1 . The activation energies of these two pathways are much higher than the corresponding radical coupling pathway via transition states 8-ts. Therefore, the radical coupling of C with D is a favorable pathway due to the low energy barriers.