Rh(iii)-catalyzed double C–H activation of aldehyde hydrazones: a route for functionalized 1H-indazole synthesis

An unprecedented strategy for functionalized 1H-indazoles via C–C bond construction was realized by the Rh(iii)-catalyzed C–H/C–H cross coupling of aldehyde hydrazones.


General Information
All reactions were carried out under an atmosphere of argon atmosphere in flame-dried glassware unless otherwise noted. Reactions were monitored by TLC on silica gel plates (GF254), and the analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica gel plates. 1 H NMR, 13 C NMR spectra were recorded on on a Bruker AVANCE Ⅲ-400 spectrometer at room temperature. Chemical shifts (δ) are reported in ppm downfield from tetramethylsilane. Abbreviations for signal couplings are: s, singlet; d, doublet; t, triplet; m, multiplet. The high and low resolution mass spectra were recorded in a positive and negative ion mode on a hybrid quadrupole time-off light mass spectrometer with an Electrospray Ionization (ESI) ion source. Hydrazine was obtained from commercial sources or prepared following the previous literature. 1 Solvents and all other reagents were obtained from commercial sources and used as received.

General Procedure for the Aldehyde Hydrazones
General procedure A: A mixture of hydrazine (2.4 mmol), aldehyde (2.0 mmol) and anhydrous MgSO 4 (0.5 g) in CH 2 Cl 2 (10 mL) was stirred overnight at room temperature. After filtration of MgSO 4 , CH 2 Cl 2 was removed under reduced pressure and the residue was subjected to column chromatography to give the desired product

1.
General procedure B 2 : To a solution of aldehyde hydrazone (5 mmol) in dry THF (20 mL) was added NaH (60%, 50 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min, and then MeI (7.5 mmol) was added dropwise. The reaction mixture was stirring at room temperature for 3 h then refluxed for another 2 h. The reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure with a rotary evaporator. The residue was diluted with water, extracted with ethyl acetate, and dried over MgSO 4 . After removal of the solvent, the residue was purified by silica gel column chromatography to give the product 1.

Deuterium labeling experiment
1. Synthesis of deuterated N-nitrosoaniline substrate 1j-d 3 : 1j-d 3 was prepared from p-tolualdehyde and deuterated hydrazine 1c according to the general procedure A.
H H H

Computational Details
All calculations were performed with the Gaussian 09 package. 3 All of the geometries were optimized by the M06-2X functional 4 with the basis set BS1. In BS1, for Rh atom, the effective core potential (ECP) 5 was employed for Rh, and the basis set for Rh is a modified LANL2DZ plus a set of f-type functions, 6 in which the two 5p and 6p functions of the standard LANL2DZ are replaced by the optimized 5p and 6p functions from Couty and Hall,7 respectively. For other atoms, the 6-31G(d,p) basis set was used. To get more accurate energies, we performed single-point energy calculations for all the species at the M062x/BS2 level. In BS2, we employed the same basis set for Rh atom as in BS1, and the cc-pVTZ basis set for other atoms. The calculated Gibbs free energies refer to 298.15 K and 1 atm. For each transition state, the intrinsic reaction coordinate (IRC) 8 analysis was performed to verify whether the transition state truly connects the reactant and the product. The solvent effect was treated with the polarizable continuum model (PCM). 9 In calculating the free energies for species in the 1,2-dichloroethane solvent, we have used the method developed by Whitesides et al. 10 to calculate the entropic contributions. This method was designed to better describe the suppression of the translational entropy upon moving from gas phase to a solvent for each species. 11 Activation free energy barriers here are defined as the free energy difference between the transition state and the lowest-energy stationary point before it in the reaction pathways.
1. The alternative pathway for C=N double insertion (path 2) Direct formation of intermediate IV from II via C=N insertion reaction is possible. We have tried our best to locate the transition state of C=N insertion II or its rotation isomer (II). However, all attempts failed. We performed a relaxed potential energy scan by fixing the C-C distance at a series of values to estimate the approximate barrier. As shown in Figure S1, the generation of the C=N bond insertion intermediate (IV) is endothermic by about 40 kcal mol -1 in electronic energy (the relative free energy is 48.8 kcal mol -1 above above the active catalyst I and reactant 1a), which suggests that the path 2 could be excluded. Figure S1. The relaxed potential energy scan for the C=N bond insertion step from II to IV.

Computational investigations of the steric effects on the proposed C-H/C-H cross coupling protocol
To investigate the influence of steric effects on this reaction, we calculated the corresponding Gibbs Free Energy Barriers of substrate 1A and 1B. The Second C-H bond activation step and reductive elimination step, are shown in Table S2. For substrates 5 and 6, the corresponding reductive elimination barriers are 37.6 and 38.9 kcal mol -1 , respectively, which are much higher than that of substrate 1a. These results can account for the experimental observations that no desired product was observed for substrate 1A and 1B. n.d. and corrected free energies (G, in a.u.) for all stationary points in Figure 1 and Table   S1. TSW stands for the corrected entropy using the Whitesides' method.     Number