Nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole derivatives: Synthesis of pyrrolopyrazinone, pyrrolotriazinone, and pyrrolooxazinone moieties

Intramolecular nucleophilic and electrophilic cyclization of N-alkyne-substituted pyrrole esters is described. Efficient routes towards the synthesis of pyrrolopyrazinone, pyrrolotriazinone and pyrrolooxazinone have been developed. First, N-alkyne-substituted pyrrole ester derivatives were synthesized. Introduction of various substituents into the alkyne functionality was accomplished by a copper-catalyzed cross-coupling reaction. Nucleophilic cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with hydrazine afforded the 6-exo-dig/6-endo-dig cyclization products depending on the electronic nature of the substituents attached to the alkyne. On the other hand, cyclization of N-alkyne-substituted methyl 1H-pyrrole-2-carboxylates with iodine only resulted in the formation of the 6-endo-dig cyclization product regardless of the substitution of the alkyne functionality.


General remarks
All reagents were used as purchased from commercial suppliers without further purification.
Proton nuclear magnetic resonance spectra ( 1 H NMR) were recorded on a 400 MHz instrument, and chemical shifts are reported in parts per million (ppm) downfield from TMS, using residual CDCl 3 as an internal standard. The 13 C NMR spectra were recorded on a 100 MHz instrument and are reported in ppm using solvent as an internal standard (CDCl 3 ).

1-Ethynyl-4-methoxybenzene (10a)
After completion of the reaction, the reaction mixture was concentrated in vacuum. The residue was diluted with EtOAc (50 mL) and washed with HCl (4 N, 40 mL) then with brine (3 × 40 mL). The resulting crude mixture was eluted through a SiO 2 column (hexane) and S5 concentrated in vacuum to obtain 10a (0.487 g, 98%) as a colorless oil. 1  General procedure for synthesis of bromoalkyne derivatives (11). To a solution of terminal alkyne derivatives 10 (1.0 equiv) in acetone (30 mL) were added NBS (1.1 equiv) and AgNO 3 (0.1 equiv) and the resulting mixture was stirred at room temperature for 4 hours.
After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuum. Then, the resulting crude mixture was added to distilled water (20 mL) and extracted with diethyl ether (3 × 25 mL) and washed with brine. Then the organic phase was dried over Na 2 SO 4 and concentrated in vacuum. The crude product was purified via column chromatography (SiO 2 , hexane) and concentrated in vacuum to obtain bromoalkyne derivatives. [7,8].  [7,8]. A solution of 1-hexyne (3.50 g, 42.6 mmol) in acetone (150 mL) were added AgNO 3 (0.84 g 4.30 mmol) and stirred for 5 minutes. To the resulting mixture was added NBS (9.09 g, 51.1 mmol) and stirred at room temperature for 90 min and 11d (6.38 g, 39.6 g, 93%) was obtained as a colorless liquid as described above. 1

Methodology
Frequency calculations and geometrical optimizations of reactants, transition states (TS) and products were performed at the polarizable continuum model [9] (PCM) in dichloromethane with the M06 [10] method using the GEN basis set combination 6-31+G(d) and LANL2DZ (I) in Gaussian 09 [11]. The intrinsic reaction coordinates [11] (IRC) were computed to make sure that each transition state connects the corresponding reactant and the product in dichloromethane. The total electronic energies including zero point energy corrections, enthalpy corrections and Gibbs free energy corrections were extracted from the output of the frequency calculations in dichloromethane.