Pd(OAc)2-catalyzed dehydrogenative C–H activation: An expedient synthesis of uracil-annulated β-carbolinones

Summary An intramolecular dehydrogenative C–H activation enabled an efficient synthesis of an uracil-annulated β-carbolinone ring system. The reaction is simple, efficient and high yielding (85–92%).


Results and Discussion
We started our investigation with the preparation of amide precursors 4 from N-substituted indole-2-carboxylic acids 1 (Scheme 1). The acids were treated with oxalyl chloride at room temperature [33] and the resulting acid chloride obtained was transformed to the amide by the reaction with amine 3 in dry THF using NaH as a base.
The amide precursor was then subjected to a series of reactions in pursuit of the best reaction conditions for the dehydrogenative cross-coupling process. Assuming that the reaction goes through an electrophilic metallation pathway, it was projected that Pd(OAc) 2 would be an excellent starting point for catalyst screening. The amide 4a (R 1 = R 2 = R 3 = R 4 = Me) was used as a model substrate for this dehydrogenative coupling reaction. The reaction was set up in the presence of Pd(OAc) 2 (10 mol %), Cu(OAc) 2   All reactions were performed with 1 equiv starting material (4) Pd(PPh 3 ) 2 Cl 2 presumably be due to the less electrophilic nature of these catalysts (Table 1, entries 15,16,18).
With the optimized reaction conditions in hand (10 mol % Pd(OAc) 2 , 2 equiv AgOAc in DMF at 90 °C for 8 h), we further explored the substrate scope of the reaction (Scheme 2).
All the reactions went very smoothly giving excellent yields in the range of (85-92%). No distinct steric influence was noticed when the indole-N-methyl group was replaced by ethyl, butyl or benzyl groups. However, the reaction did not proceed at all with the unsubstituted indole precursor (R 1 = H, 4m), this result may be explained with potential coordination of the Pd catalyst between the indole nitrogen and amide carbonyl oxygen. A representative X-ray crystal structure of β-carbolinone derivative 5h was obtained [57] (Figure 2).
The inactivity of Pd(0) ( Table 1, entry 17), and inferior reactivity of other less electrophilic Pd catalysts indicates a mechanistic pathway that commence with electrophilic metalation at mediate then undergoes a σ-bond metathesis reaction to form a seven membered palladacycle B which in turn produces the product β-carbolinones after reductive elimination from the 7-membered palladacycle B. The catalytic cycle is completed by AgOAc.

Conclusion
In conclusion we have developed an elegant method for the preparation of uracil annulated β-carbolinones via a high yielding dehydrogenative C-H activation process. The key to the success of this reaction is the complementary elec- tronic properties of the indole C3-H bond and the uracil C6-H bond. It is anticipated this efficient and atom economic approach can be emulated for the preparation of other β-carbolinones as well, and further results in this regard will be reported in due course.

Experimental
Representative procedure for the preparation of uracil annulated β-carbolinones (5a-m): In a flame-dried round bottomed flask equipped with a magnetic bar, a mixture of 1 equiv starting material 4, 5 mL dry DMF, 2 equiv of AgOAc and 10 mol % Pd(OAc) 2 was taken and stirred at room temperature for 5 min. Then the reaction mixture was heated in an oil bath fixed at 90 °C for 8 h under air. Completion of the reaction was monitored by checking TLC. The reaction mixture was cooled to room temperature, diluted with water and 50 mL of EtOAc and passed through a pad of celite. The organic layer was washed with H 2 O (2 × 10 mL) and saturated NaCl (aq) (1 × 10 mL). The organic part was dried over Na 2 SO 4 , evaporated and purified by flash chromatography, using ethyl acetate/petroleum ether (2:8) as the eluent to afford product 5. For details see Supporting Information File 1.

Supporting Information
Supporting Information File 1 Experimental and analytical data.