Regio- and Diastereoselective 1,3-Dipolar Cycloadditions of 1,2,4-Triazin-1-ium Ylides: a Straightforward Synthetic Route to Polysubstituted Pyrrolo[2,1-f][1,2,4]triazines

A synthetic strategy to pyrrolo[2,1-f][1,2,4]triazines is reported. We show that various synthetically easily accessible 1,2,4-triazines can be efficiently alkylated under mild conditions to provide the corresponding 1-alkyl-1,2,4-triazinium salts. These bench-stable salts serve as precursors to triazinium ylides, which react in 1,3-dipolar cycloadditions with electron-poor dipolarophiles to yield polysubstituted pyrrolotriazines in a single step.


Alkylation of 1,2,4-triazines
General procedure B: Substituted triazine (2.00 mmol) was dissolved in anhydrous toluene (20 mL) under argon and this mixture was cooled to 0 °C. Then, methyl or ethyl triflate (1.2 equiv., 2.40 mmol) was added dropwise (≈ 5 min) and the cooling bath was removed. Progress of the reaction was followed by HPLC. When finished, usually the products precipitated from toluene and can be easily filtered off and washed with Et2O. In some cases, we observed only partial precipitation or no precipitation at all. In such cases, we either added Et2O directly to the mixture and cool it in an ice bath or we evaporated toluene and the residue was sonicated with Et2O, which always produced fine powders. We used these products as such (always mixtures with minor N2 alkylated isomer) but it can be separated on a reverse phase flash column chromatography, if wanted. Note 1: we used anhydrous DCM as solvent in case of simple 3-aryl triazines (as shown in the maintext) but such derivatives are not productive during the cycloaddition step, and we omitted them from further study. Our theory is that the free position 5, which attracts nucleophiles, causes a ring opening and further chemical decomposition. The only evidence in our hands would be a simple TLC, which always showed just a huge brown/black spot at the start, and only traces of products were observed in all cases. Note 2: in case of electron donating substituents (p-OMe, p-piperidyl) we also observed the minor formation of 6-substituted triazines (not 5-substituted). These can be easily separated from each other. However, such products were alkylated at position 3 and, since position 5 was free, we also tried these intermediates in cycloaddition with DMAD. However, only starting material was observed in the reaction, which was therefore not investigated further.

Cycloadditions with DMAD
General procedure C: Alkylated triazine 2d-2m (0.50 mmol) was dissolved in THF (10 mL) and DMAD (2.0 equiv.) was added. The mixture was cooled to 0 °C and DIPEA (1.5 equiv.) was added dropwise (≈ 5 min). Then, the cooling bath was removed and the mixture was stirred at room temperature for 5 h. We followed the reaction progress by HPLC and, usually, the oxidation was slower with ethylated derivatives. In such cases, we just opened the flask and stirred the mixture like that for the final 15 -20 min. Then, the volatiles were evaporated under reduced pressure and the crude products were purified by column chromatography (the solvent mixtures are specified for each derivative separately). The yields are normalized for major N1 alkylated triazines. -1-yl)

Methods
The studied structures were subjected to geometry optimization at the DFT level using the B3LYP functional 9, 10 with the standard 6-31+G(2d,p) basis set and the polarizable continuum model SMD used for implicit toluene solvation. 11 Empirical dispersion correction GD3BJ was used in all calculations. 12 The vibrational frequencies and free energies were calculated for all of the optimized structures, and the stationary-point character was thus confirmed (minimumno negative frequency or transition stateone negative frequency). Zero-point energy, enthalpy and free energy corrections were also obtained at this level of theory, using a standard state of p = 1 atm and T = 298 K. The Gaussian16 program package was used throughout this study. 13 The visualization of molecular structures and electrostatic potentials was done with GaussView 6.0.16.

Electrostatic potential
The electrostatic potential plots (Figure S1) of 3-methylthiotriazine and 3-phenyltriazine show that the most electronegative site in both triazines is nitrogen N1 followed by N2. However, the access to nitrogen N2 is partially hindered by the presence of the substituent at position 3. Figure S1. The electrostatic potential plots of two conformers of 3-methylthiotriazine (left and middle) and of 3-phenyltriazine (right).

S25
Energies of the transition state for the reaction of 2g-Me with methyl propiolate We found two different transition-state structures for this reaction (depicted in Figure S3). TS1 leading to the experimentally observed regioisomer 4g-H has lower calculated free energy by 5 kcal/mol. The DFT calculations thus rationalize the observation of a single product in the reaction. Figure S3. The transition-state structures for the reaction of 2g-Me with methyl propiolate. The free energy of the structure on the left-hand side is 5.0 kcal/mol lower.

Energies of the transition state for the reaction of 2g-Me with N-ethylmaleimide
The reaction of 2g-Me with N-ethylmaleimide provided two products, which differ in the configuration of the newly formed pyrrolidine ring. The structure of the two products was elucidated by a combination of 1D and 2D NMR experiments and by a comparison of experimental and calculated J-coupling constants (Table S2). We found transition-state structures leading to the two products ( Figure S4). The TS structure leading to the major product has lower calculated energy by 0.9 kcal/mol.    Copies of 1 H and 13 C NMR spectra