Synthesis of β‐Diamine Building Blocks by Photocatalytic Hydroamination of Enecarbamates with Amines, Ammonia and N−H Heterocycles

Abstract 3‐Amino‐substituted saturated nitrogen heterocycles are an important subclass of β‐diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox‐mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.


General method A: Hydroamination with primary amines
To an 8mL vial equipped with a septum and stirrer bar was added enecarbamate (0.25 mmol; 1 eq.), 2,4,6-triisopropylthiophenol (0.125 mmol; 50 mol%) and iridium photocatalyst A or B (0.005 mmol; 2 mol%). The vial was purged with nitrogen for 5 minutes followed by the addition of anhydrous toluene (5 mL) and primary amine (1.25 mmol; 5 eq.). The reaction was irradiated with a 32W blue LED for 16 hours. The solvent was removed in vacuo and the compound was purified by column chromatography or strong cation exchange chromatography.

General method B: Hydroamination with amine hydrochloride salts
To an 8 mL reaction vial equipped with a septum and stirrer bar was added enecarbamate (0.25 mmol; 1eq.), 2,4,6-triisopropylthiophenol (0.125 mmol; 50 mol%), iridium photocatalyst A or B (0.005 mmol; 2 mol%), amine hydrochloride salt (0.5mmol; 2 eq.) and lithium hydroxide monohydrate (0.50 mmol; 2eq.). The vial was purged with nitrogen for 5 minutes followed by the addition of anhydrous toluene (5 mL). The reaction was irradiated with a 32W blue LED for 16 hours. The solvent was removed in vacuo and the compound was purified by column chromatography.

General method C: Hydroamination with heteroaromatic and aromatic amines
To an 8 mL reaction vial equipped with a septum and stirrer bar was added enecarbamate (0.25 mmol; 1eq.), 2,4,6-triisopropylthiophenol (0.125 mmol; 50 mol%), iridium photocatalyst A or B (0.005 mmol; 2 mol%) and (hetero)aromatic amine (0.50 mmol; 2eq.). The vial was purged with nitrogen for 5 minutes followed by the addition of anhydrous toluene (5 mL). The reaction was irradiated with a 32W blue LED for 16 or 40 hours. The solvent was removed in vacuo and the compound was purified by column chromatography.
The reaction was irradiated with a 32W blue LED for 16 hours. The solvent was removed in vacuo and the compound was purified by column chromatography or strong cation exchange chromatography.
The reaction was irradiated with a 32W blue LED for 16 hours. The solvent was removed in vacuo followed by the addition of electrophile (0.5 mmol; 2eq.), DIPEA (0.5 mmol, 2eq.) and DCM (2 mL). The mixture was stirred at room temperate for 4-16 hours. The solvent was removed in vacuo followed by purification by column chromatography.

Reaction optimisation A: Primary amines
Reactions were set up as for general method A, with deviations from the general method listed in the table below. Conversion was measured by consumption of starting enecarbamate. Isolated yields were recorded after compound purification.   , 9.6 mL, 9.6 mmol).
The mixture was allowed to stir at -78ºC for 45 minutes followed by the sequential dropwise addition of DIPEA (6.9 mL 40.0 mmol ), trifluoroacetic anhydride ( brine (1 x 20 mL) and dried over MgSO 4 ; evaporation of the solvent in vacuo gave the crude aminoacetal. The crude material was dissolved in anhydrous DCM (20 mL) and DIPEA (1.7 mL, 10.0 mmol) was added. The solution was cooled to 0ºC followed by the dropwise addition of TMS triflate (1.88 mL, 10.0 mmol) over 2 minutes. The reaction was immediately quenched by the addition of hexane (20 mL) followed by filtration through celite eluting with hexane , The filtrate was evaporated in vacuo and the residue purified by column chromatography (10% ethyl acetate in hexane) and isolated as a colourless oil (358mg, 37%) as a mixture of rotamers which was used immediately in the next step.
Compound was eluted with 10x column volumes of methanolic ammonia (7M)) and isolated as a colourless oil (42 mg, 63%) as a mixture of rotamers.  Sample loaded in methanol (ca 2ml) and washed with 10x column volumes of methanol.