Reaction of Nitrogen‐Radicals with Organometallics Under Ni‐Catalysis: N‐Arylations and Amino‐Functionalization Cascades

Abstract Herein, we report a strategy for the generation of nitrogen‐radicals by ground‐state single electron transfer with organyl–NiI species. Depending on the philicity of the N‐radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N‐arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N‐cyclization–alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.

The filtrate was evaporated to give 5 (75%) as an oil. 1

SI-7
Compounds S13- 18 have been prepared according to previously reported procedures. 8

Synthesis of 28 and 60. General Procedure 1 -GP1
The appropriate carboxylic acid (20 mmol) was loaded in a 150 mL flask equipped with a condenser and a stirring bar, then SOCl 2 (14.5 mL, 200 mmol, 10 equiv.) was slowly added in one portion and the reaction mixture was refluxed for 3 h. After cooling to room temperature, the mixture was treated with ice (100 g) under vigorous stirring, the organic fraction was extracted with pentane (100 mL, 3×), then the combined organic layers were washed with brine, dried over magnesium sulphate and concentrate under reduced pressure to provide a crude oil. To a solution of the former oil in THF (67 mL, 0.3 M) Nmethylhydroxylamine hydrochloride (2.00 g, 24 mmol, 1.2 equiv.) and NaHCO 3 (3.36 g, 40 mmol, 2.0 equiv.) were loaded and the reaction was stirred at room temperature for 16 h.
After this time, the solvent was evaporated, then the crude was diluted with EtOAc (250 mL), the organic phase was washed with NaHCO 3 (5×), brine, dried over magnesium sulphate and concentrate under reduced pressure to provide a crude oil. To a solution of the former crude oil in THF (100 mL), NaH (60%, 1.01 g, 30 mmol, 1.5 equiv.) was added portionwise at 0 °C. After the addition, the reaction was continued stirring for additional 30 min at 0 °C, then 1-fluoro-2,4-dinitrobenzene was slowly added in one portion and the reaction mixture  h and then evaporated. The residue was purified by column chromatography to give the desired product.

Preparation of Organozinc Reagents
Stock solutions of the following organozincs have been prepared according to the procedures reported in the literature, from the corresponding commercially available Grignard reagents 11 . Tridecylmagnesium bromide has been prepared from the corresponding 1-bromotridecane following a reported procedure. 12     Upon completion, the crude was diluted with water and extracted with EtOAc (3×) and then purified by column chromatography.

GP5 -General Procedure for N-arylation and cyclization-arylation with organo silanes
A dry tube equipped with a stirring bar was charged with the aryloxyamine/amide (0.1 mmol, 1.0 equiv.), sealed, evacuated and refilled with N 2 for three times. Then a stock solution of NiCl 2 ·6H 2 O:dtbpy 1:1 in DMF were added (1.0 µmol, 10 mol%), followed by the addition of a stock solution of the arylsilane and TBAT in DMSO (0.2 mmol, 2.0 equiv.). The reaction was stirred at 50 o C for 15h, the crude was then absorbed on silica and purified on silica gel column.

Analysis of Chan-Lam Couplings with Heteroaromatic Organometallics
As the use of arylboronic acids and, to a lesser extent, arylsilanes and arylzincs in this methodology would deliver products identical to the widely used Chan-Lam coupling, we performed a literature survey to identify potential areas of complementarity ( Figure S1). We realized that amination of C-3 and C-4-zincated pyridines and C-2-zincated 5-membered ring heterocyles (e.g. thiophene) has not been reported. In the case of aryl boronic acids no precedent was found to access C-4 aminated pyridines. Aryl silanes are considerably less used in aromatic amination.

Mechanistic Considerations
The following experiments using substrates 3-5 were performed following the general procedures GP3, GP4 or GP5. As shown in Table S4, although the N-arylation product 6 was obtained in several cases, product 7, which would result from a radical 5-exo-trig cyclisation, was exclusively obtained when using 3, regardless from the nature of the organometallic partner (entries 1-6). The presence of both 6 and 7 in these reactions suggests that the rates of cyclisation (1.9 10 5 s -1 ) and N-arylation are comparable. 1 Indeed, the ratio between 6 and 7 varies in favor of 7 at low Ni-catalyst loading (Table S5, entries 1-4) and also at higher dilution (entries 5-8), which further supports the intermediacy of a N-radical in our process. 1 The C-radical formed upon N-radical cyclization could intercept the Ni(II)-aryl complex. However, as this radical is di-benzylic we believe other pathways might be operative (e.g. 1,5-HAT, oxidation…). Furthermore, the addition of benzylic radicals to Ni-complexes has been described to be   We subjected precursors 3 and 4 to the optimum conditions identified in Table S5 favouring cyclization over N-arylation (Table S5, entry 8). As shown in Table S6 precursor 3 only led to the cyclized product 7 (entry 1) while 6 underwent N-arylation in poor yield. (entry 2). Table S6.
OBz 10 -Using precursor 3 product 7 was detected in 29% yield and no 6 was found. Using precursor 2 no cyclization was found and only 10% of N-arylated product 6 was found.

tert-Butyl 2-Isopropylpyrrolidine-1-carboxylate (71)
Following GP3, S19 (38 mg, 0.1 mmol) gave 71 (53%) as an oil. 1   Thermal corrections were computed from unscaled frequencies, assuming a standard state of 298.15 K and 1 atm. For substrates having more than one conformations, low energy conformation of the transition state could possibly be different from the low energy ground state. 45 The structures described herein are the lowest energy-optimized conformers. SI-52