Synthesis of Acridines through Alkyne Addition to Diarylamines

A new synthesis of substituted acridines is achieved by palladium-catalyzed addition of terminal acetylenes between the aryl rings of bis(2-bromophenyl)amine. By including a diamine base and elevating the temperature, the reaction pathway favors the formation of acridine over a double Sonogashira reaction to form bis(tolan)amine. This method is demonstrated with several aryl-alkynes and alkyl-alkynes.


Synthesis of bis(bromophenyl)amine (3):
To a flame dried 35 mL microwave vial with a teflon cap, 16 mL of anhydrous toluene was added followed by 3.18 g (33.1 mmol) of sodium tert-butoxide then 2.6 mL (23 mmol) of 2bromoaniline (1) and 3.0 mL (23 mmol) of 2-bromoiodobenzene (2) dropwise and stirred. The ligand DPEPhos, 103 mg (0.190 mmol), and 29.8 mg (0.133 mmol) Pd(OAc) 2 were added then heated 30 minutes at 150 °C in a microwave reactor. The product was extracted with 3 x 35 mL of dichloromethane and the combined organic layer was washed with water (3 x 150mL). The organic layer was dried over magnesium sulfate and concentrated in vacuuo. The resulting product was recrystallized from ethanol to yield white or gray needlelike crystals in 68 % yield.

Synthesis of bis(tolan)amine (4a):
To a flame dried 35mL microwave vial with a teflon cap, 25 mL of diisopropylamine was added via syringe and degassed with nitrogen for ten minutes. To this vessel 510 mg (1.6 mmol) of bis(2-bromophenyl)amine (3), 140 mg (0.74 mmol) CuI, and 111 mg Pd(PPh 3 ) 2 Cl 2 (0.16 mmol) were added sequentially while stirring under nitrogen. Subsequently 0.84 mL of phenyl acetylene was added dropwise via syringe over 30 min followed by heating for 2.5 hours at 120 °C in a microwave reactor. Upon completion, the reaction was poured over ice and extracted into dichloromethane (3 × 50mL). The combined organic layer was washed with water (3 × 100mL) then concentrated in vacuuo. The reaction was then purified using a KP-NH™ flash column using hexanes and ethyl acetate to produce a yellow solid in 63% yield.

Microwave Heating:
To a flame dried 35 mL microwave vial with a teflon coated cap, 25 mL of ethylene diamine was added via syringe and degassed with nitrogen for 20 minutes. To this vessel was added 504 mg (1.5 mmol) of bis(2-bromophenyl)amine (3), 66 mg (0.30 mmol) of copper iodide, and 219 mg (0.30 mmol) of bis(triphenylphosphine)palladium dichloride sequentially while stirring under nitrogen. Next 3.0 mmol of aryl acetylene was added dropwise via syringe. The reaction flask was heated for 1.5 hours at 180 ºC in a microwave reactor. Upon completion, the reaction was then poured over ice, extracted into dichloromethane (3 x 35 mL) and the combined organic layers were washed with water three times before purifying on an amine treated KP-NH™ silica flash column using hexanes and ethyl acetate as eluent. Fractions include primarily bis(tolan)amines (4a-f), 9-substituted acridines (5a-f), and carbazole (6) depending on conditions.

Conventional Heating:
To a flame dried 150 mL pressure vessel, 25 mL of ethylene diamine was added via syringe and degassed with nitrogen for 20 minutes. To this vessel was added 504 mg (1.5 mmol) of bis(2-bromophenyl)amine (3), 66 mg (0.30 mmol) of copper iodide, and 219 mg (0.30 mmol) of bis(triphenylphosphine)palladium dichloride sequentially while stirring under nitrogen. Next 3.0 mmol of aryl acetylene was added dropwise via syringe. The reaction flask was heated for 1.5 hours in an oil bath set to 180 ºC. Upon completion, the reaction was then poured over ice, extracted into dichloromethane (3 × 35 mL) and the combined organic layers were washed with water three times before purifying on an amine treated KP-NH™ silica flash column using hexanes and ethyl acetate as eluent. Fractions include primarily bis(tolan)amines (4a-f), 9-substituted acridines (5a-d), and carbazole (6) depending on conditions.

Preparation of 9-benzylacridine (5a):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.33 mL (3.0 mmol) phenyl acetylene. The reaction produced a mustard yellow solid in 203 mg (53%) yield by microwave heating. Conventional heating produces 217 mg (55%) yield.