Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

Summary The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described.

The microwave-assisted reactions were performed by setting the temperature at reported number and the maximum power and pressure at 250 W and 200 psi respectively. The power is automatically altered by the device to maintain the set temperature for the reported duration of time. A ramp period of 10 min is set to reach the desired temperature and the device automatically starts the emission period as soon as the set temperature is obtained. During the reactions the stirring option is on and a stream of nitrogen cools the reactor. The Max Power option is also on to maintain the reaction temperature while cooling. This option should not be used for polar solvents.
The N-aryl-aromatic imines 1 were prepared by mixing the amine and carbonyl components in ACN, in the presence of 4 Å MS at room temperature, according to a standard method. N-alkyl imines and activated substrates were prepared following the described procedures (see below).

Preparation of imines and related compounds (1)
General procedure Equimolar amounts of the corresponding aldehyde and amine (1:1, 2 mmol) together with 2 g of activated MS 4 Å were placed in a 50 mL flask, 10 mL of dry ACN were added and the solution was stirred under nitrogen for 24 h or until all the starting material was consumed. The reaction progress was monitored by TLC or HPLC. After the reaction was complete, 10 mL of saturated aqueous NaHCO 3 solution were added. Molecular sieves were filtered and washed with 20 mL of EtOAc. The aqueous layer was extracted with 3 × 10 mL of EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude imine was used without further purification.

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General procedure for isatin imines Equimolar amounts of isatin and the corresponding amine (1:1, 5 mmol) were placed in a 100 mL flask, 20 mL of absolute EtOH and 0.2 mL glacial acetic acid were added and the mixture was refluxed for 12 h or until all the starting material was consumed.
The reaction progress was monitored by TLC or HPLC. After the reaction was complete, the solution was set aside to gradually cool down overnight. The formed crystals were filtered, washed with cold EtOH and dried in vacuo [1] .

General procedures for the azetidine formation
General procedure A 0.5 mmol (1 equiv) of imine 1 were dissolved in 2 mL of dry THF. To this solution was dropwise syringed 0.5 mmol (1 equiv) of BF 3 Et 2 O while stirring. In case of using a solid isocyanide, it was first dissolved in 1 mL of THF. After 2 min, 1.5 mmol (3 equiv.) of the corresponding isocyanide was gradually added. The solution was stirred for 24 h or until the reaction was complete or showed no evolution. The reaction was quenched with 10 mL of saturated NaHCO 3 solution and extracted with 3 × 10 mL of AcOEt. The combined organic phases were dried over Na 2 SO 4 , concentrated in vacuo and purified by flash chromatography (Hexanes/EtOAc).

General procedure B
In a microwave reactor tube, 0.5 mmol (1 equiv) of imine 1 were dissolved in 2 mL of dry THF .To this solution was dropwise syringed 0.5 mmol (1 equiv) of BF 3 Et 2 O while stirring. After 2 minutes, 1.5 mmol (3 equiv) of the corresponding isocyanide was gradually added. In case of using a solid isocyanide, it was first dissolved in 1 mL of THF. The solution was irradiated in the microwave for 30 min at 65 °C. Then it was allowed to cool to room temperature. The reaction was quenched with 10 mL of saturated NaHCO 3 solution and extracted with 3 × 10 mL of EtOAc. The combined organic phases were dried over Na 2 SO 4 , concentrated in vacuo and purified by flash chromatography (hexanes/EtOAc).

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According to procedure B, azetidine 3k was obtained as a brown paste (14%).