Reversed reactivity of anilines with alkynes in the rhodium-catalysed C–H activation/carbonylation tandem

Development of multicatalytic approach consisting of two or more mechanistically distinct catalytic steps using a single-site catalyst for rapid and straightforward access of structurally complex molecules under eco-benign conditions has significance in contemporary science. We have developed herein a rhodium-catalysed C–H activation strategy which uses an unprotected anilines and an electron-deficient alkynes to C–C bonded products as a potential intermediate in contrast to the archetypical C–N bonded products with high levels of regioselectivity. This is followed by carbonylation of C–H bond activated intermediate and subsequent annulation into quinolines has been described. This rhodium-catalysed auto-tandem reaction operates under mild, environmentally benign conditions using water as the solvent and CO surrogates as the carbonyl source with the concomitant generation of hydrogen gas. The strategy may facilitate the development of new synthetic protocols for the efficient and sustainable production of chemicals in an atom-economic way from simple, abundant starting materials.

products. This is because in the catalytic reaction water was produced as the byproduct and there is a possibility of formation of phosphine oxide (observed by 31 P NMR in few cases). Thus, we can hardly believe that 10 mol% of phosphine liagnd (5 fold excess w.r.t per Rh atom) is required for the effective catalytic transformation.

General Information
All catalytic experiments were carried out using standard Schlenk techniques or using J. Young NMR tubes. All solvents were reagent grade or better. Deuterated solvents were used as received. All non-deutrated solvents were dried according to standard procedure. 1 Most of the starting materials (anilines and alkynes), and ligands used in catalytic reactions were purified according to standard procedure. 2

Synthesis of 1h and 1i
Procedure (Method A): A mixture of 1g (5 mmol), allyl or propargyl bromide (15 mmol), K 2 CO 3 (20 mmol), EtOH (25 mL), and water (5 mL) was added to a 100 mL round bottom flask and stirred at 70°C for the desired time until complete consumption of 1g as judged by TLC. Then, the solvent was removed under reduced pressure and the product was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 . The solvent was removed by evaporation under reduced pressure to afford the crude products of both mono-and bis-alkylated derivatives of 1g. The crude products were subjected for hydrolysis of acetyl group without further purification.
Procedure (Method B): To a 15 mL oven dried screw capped tube were added alkylated products of 1g and 17% of HCl (H 2 O:THF = 1:1by v/v) at room temperature. This reaction mixture was heated to 70 o C for 15 h. After cooling to room temperature the reaction mixture was neutralised with saturated NaHCO 3 followed by extraction with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and the solvent was removed by evaporation under reduced pressure. The crude products were isolated by silica gel column chromatography using petroleum ether and ethyl acetate as an eluent.
Procedure (Method C): 3 In a 15 mL oven dry screw cap tube [RuCl 2 (p-cymene)] 2 (0.25 mmol, 5 mol%) and AgSbF 6 (1 mmol, 20 mol%) were added under argon atmosphere. To that tube acetanilide (5 mmol), alkyne (5.5 mmol), pivolic acid (25 mmol, 5 equiv) and isopropanol (2.5 mL) were added. After that the reaction mixture was heated up to 100 o C for 12 h. Then the reaction mixture was cooling to room temperature and diluted by dichloromethane. Diluted reaction mixture then passed through celite pad and concentrated on rotavapor under reduce pressure. The crude product was purified through silica gel column chromatography by using pet ether and ethyl acetate as an eluent.
After cooling to ~5 ο C (ice/water), the excess CO was vented carefully and the reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated. The crude product was purified by silica gel column chromatography (230-400 mesh size) using petroleum-ether/ethyl acetate as an eluent.
Procedure: A 100 mL Fischer-Porter tube was charged under nitrogen with [Rh(cod)Cl] 2 (2.5 mol%), dppm (10 mol%), 5a (0.25 mmol), and water (500 µL). The Fischer-Porter tube was purged by three successive cycles of pressurization/venting with CO (5 psi), then pressurized with CO (3atm). The solution was heated at 100 ºC with stirring for 24 h. After cooling to ~5 ο C (ice/water), the excess CO was vented carefully and the reaction mixture was diluted with water (6 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and the solvent was evaporated. The crude product was purified by silica gel column chromatography (230-400 mesh size) using petroleum-ether/ethyl acetate as an eluent.
Procedure: To an oven dried 15 mL screw cap reaction vial were added 4o (264 mg, 1 mmol), NH 4 Cl (53 mg, 1 mmol) followed by a saturated solution of NH 3 in methanol.
The reaction mixture was heated at 70 o C for 72 h. After cooling to ambient temperature and triturated with water to get analytically pure compound 7. 4 Procedure: To an oven dried 25 mL round bottle flask 87 mg of 6,7dimethoxyquinoline-3-carboxamide (7) and 850 mg of pyridine.HCl were added and then the reaction mixture was kept for heating at 170 o C for 30 minutes. After heating the excess amount of pyridine.HCl was removed under high vacuum and the resulting solid was washed with ice cold water. The crude mixture was subjected for HRMS analysis ( Supplementary Fig 92) to confirm the formation of 6,7-Dihydroxyquinoline-

Mechanistic Studies
Procedure: To a J.YOUNG NMR tube were added aniline 1a or 1a' (0.  Fig 97). The hydride ligand may originated via ortho C-H activation of aniline (1c) followed by proto-demetallation.
These experiment results implied that auto-tandem approach should proceed through carbonylation path and not via either N-formylation, imine intermediate, and [3,3] rearrangement.