Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles

Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry. Herein, we present a family of metal-free intermolecular formal cycloaddition reactions that enable highly selective and orthogonal access to isoquinolines and pyrimidines at will. Applications of the products are complemented by a density functional theory mechanistic analysis that pinpoints the crucial factors responsible for the selectivity observed, including stoichiometry and the nature of the heteroalkyne.

off in vacuum, the product was isolated by silicagel chromatography.
Step b, cross coupling of oxazolidinone: A 15 mL pressure tube was charged with oxazolidinone (1.6 mmol), 1,1-dibromo-1-alkene (2.4 mmol), Cs 2 CO 3 (2.1 g, 6.4 mmol), and copper(I) iodide (38 mg, 0.2 mmol). The tube was fitted with a rubber septum, evacuated under high vacuum and backfilled with argon. Dry and degassed 1,4-dioxane or DMF (3 mL) and N,N'-dimethylethylenediamine (30 μL, 0.3 mmol) were next added, the rubber septa was replaced by Teflon-coated screw cap and the light bluegreen suspension was heated at the temperature. The brownish suspension was cooled to rt. When the reaction was run in 1,4-dioxane, the crude reaction mixture was filtered over a plug of silica gel (washed with EtOAc), and concentrated. When the reaction was run in DMF, the crude reaction mixture was diluted with water, extracted with diethyl ether and the combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated. The crude residue was in both cases purified by flash chromatography over silica gel.

General procedure for the synthesis of isoquinolines
Under Argon atmosphere, mixture of ynamide (0.22 mmol, 1.1 eq.) and nitrile (0.2 mmol, 1.0 eq.) in dichloroethane (4 mL) was added dropwise of TfOH (0.22 mmol, 1.1 eq.) at 0 °C. The reaction was warm up immediately to RT for 30 min. Then the reaction was irradiated with microwave at 120 °C for 1 h or reflux at 120 °C for 16 h. The reaction was quenched with Na 2 CO 3 sat. sol. (5 mL) after cooled to rt, extracted with DCM (3 x 5 mL), dried over Na 2 SO 4 and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel with hexane/ethyl acetate (7/3 or 1/1).

General procedure for the synthesis of thioalkynes
In a dry argon-flushed Schlenk flask, alkyne (5 mmol) was dissolved in THF (5 mL). The solution was cooled to -78 °C and nBuLi (5.5 mmol, 3.44 mL, 1.6 M in hexane) was added dropwise. After 10 min of stirring at -78 °C, dimethyl disulfide (565 mg, 6 mmol) was added and the solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl-solution and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na 2 SO 4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Al 2 O 3 netural, pentane).
Under Argon, TfOH (0.20 mmol, 1.0 eq.) was slowly added to a cold (0 ˚C) solution of thio-alkyne (0.2 mmol, 1.0 eq) and nitrile (1.0 mmol, 5.0 eq.) in DCM (2 mL). The result mixture was warm up to rt and stirred for 16 h at ambient temperature. The reaction was quenched with NaHCO 3 sat. sol. (5 mL) after cooled to rt, extracted with DCM (3 x 5 mL), dried over Na 2 SO 4 . 4-Dimethylaminopyridine (12.2 mg, 0.1 mmol) was added before the filtration. Then the solvent was removed in vacuo. After obtain the crude proton nmr, the crude product was purified by column chromatography on silica gel with hexane/ethyl acetate (20:1 or 5:1).

General procedure for the synthesis of pyrimidines with acetonitrile
Under Argon, TfOH (0.20 mmol, 1.0 eq.) was slowly added to a cold (0 ˚C) solution of thio-alkyne (0.2 mmol, 1.0 eq) in acetonitrile (2 mL). The result mixture was warm up to rt and stirred for 16 h at ambient temperature. The reaction was quenched with NaHCO 3 sat. sol. (5 mL) after cooled to rt, extracted with DCM (3 x 5 mL), dried over Na 2 SO 4 . 4-Dimethylaminopyridine (12.2 mg, 0.1 mmol) was added before the filtration. Then the solvent was removed in vacuo. After obtain the crude proton nmr, the crude product was purified by column chromatography on silica gel with hexane/ethyl acetate (5:1).

Further manipulation of isoquinoline and pyrimidine products.
Compound 3di (212 mg, 0.5 mmol) was dissolved in AcOH (10 mL). The solution was submitted to a preset H-Cube reactor cyclically (H 2 100 bar, 40 ˚C) and was analyzed by TLC. After completely consuming of the starting material (1 h), the reactor was rinsed in succession by AcOH (10 mL) and Methonal (10 mL). Combined solution was evaporated under vacuum. The crude product was protected by TsCl in DCM, with triethylamine as the base. After filtration, the residue was purified by flash column chromatography (Hexane/ethyl acetate = 1:1) on silica gel to afford compound rac-8-Ts (246 mg, 99%).