Azine Activation via Silylium Catalysis

Practical, efficient, and general methods for the diversification of N-heterocycles have been a recurrent goal in chemical synthesis due to the ubiquitous influence of these motifs within bioactive frameworks. Here, we describe a direct, catalytic, and selective functionalization of azines via silylium activation. Our catalyst design enables mild conditions and a remarkable functional group tolerance in a one-pot setup.


-benzoquinone (DDQ)
Weigh the catalyst (1 mol %) and the substrate if solid (0.2 mmol) in a vial charged with a magnetic stirring bar and place it under argon atmosphere. Unless stated otherwise, add the corresponding silyl ketene acetal (2 equiv) via Hamilton syringe followed by MeCN (5 M) and the substrate if liquid. Then, seal with Teflon/parafilm and stir the mixture overnight at the specified temperature. Check the crude by 1 H NMR in order to determine the conversion of the addition step (shown in parenthesis). Alternatively, quench the reaction dropwise with dry DDQ (1 M in MeCN) and stir 3 h at room temperature. Add triethylamine (1 equiv) and filter the crude through a long pad of silica eluting with DCM/MeOH (1%). Purify the desired product using chromatography techniques.

Oxidative quenching using (bis(trifluoroacetoxy)iodo)benzene (PIFA)
The addition step is independent on the oxidant used for the rearomatization of 3. Quench the reaction via dilution of the crude with DCM followed by slow addition of PIFA. Keep stirring at room temperature and add triethylamine (1 equiv). Purify the desired product using chromatography techniques. General procedure with pyridazine and S-1 performed at room temperature (93%). Quench overnight with 2 equiv PIFA (0.2 M). In this case, extract with DCM/sat. NaHCO3 and dry the combined organic layers with Na2SO4. Purify by prep-TLC using MTBE as eluent (Rf = 0.33). The desired product 5a was obtained as a pale yellow solid (35 mg, 80% yield). 1

Oxidative quenching using diisopropyl azodicarboxylate (DIAD)
The addition step is independent on the oxidant used for the rearomatization of 3. Quench the reaction via dilution of the crude with DCM followed by addition of DIAD and keep stirring at room temperature. Purify the desired product using chromatography techniques.

Oxidative quenching using potassium permanganate (KMnO4)
The addition step is independent on the oxidant used for the rearomatization of 3. Quench the reaction with AcOH (1 equiv) and dilute the crude with THF/MeCN 5:1. Add KMnO4 and keep stirring at room temperature. Extract with EtOAc/sat. NaHCO3 followed by brine and dry the combined organic layers with Na2SO4. Purify the desired product using chromatography techniques.

Oxidative quenching using palladium on carbon (Pd/C 10 mol%)
The addition step is independent on the oxidant used for the rearomatization of 3. Quench the reaction via dilution of the crude with AcOH followed by addition of Pd/C 10 mol% and keep stirring at 70 °C. Filter through Celite, extract with EtOAc/sat. NaHCO3 and dry the combined organic layers with Na2SO4. Purify the desired product using chromatography techniques.

Dihydropyridine Derivatives
Weigh substrate 1c (1 equiv, 20.8 mg, 0.2 mmol) in a vial charged with a magnetic stirring bar and place it under inert atmosphere. Dissolve it in Et2O (0.4 ml) and add silyl ketene acetal 2a (2 equiv, 80 l, 0.4 mmol) via Hamilton syringe followed by Tf2NH 0.1 M in DCM (1 mol%, 20 l, 2 mol). Then, seal with Teflon/parafilm and stir the mixture overnight at room temperature. Quench the reaction with 10 l of triethylamine and add 4-fluorobenzoyl chloride (2 equiv, 48 l, 0.4 mmol) followed by TBAF 1 M in THF (2 equiv, 0.4 ml, 0.4 mmol). Keep stirring for another hour. Dilute the mixture with ethyl acetate and wash the solution with saturated aqueous NaHCO3 and brine. Then, dry the combined organic layers with Na2SO4 and concentrate the crude under reduced pressure. Purify by prep-TLC using hexanes/ethyl acetate 2:1 as eluent (Rf = 0.57). The desired product 10 was obtained as a colorless thick oil (66 mg, 99% yield). 1

PADI
In a flame-dried Schlenk, dissolve compound S-4 (1 equiv, 50 mg, 0.15 mmol) in DCM (5 ml) under inert conditions. Add N-trifluoromethylsulfonyl-P,P,P-trichlorophosphazene (1 equiv, 30 l, 0.15 mmol) and triethylamine (5.7 equiv, 120 l, 0.86 mmol). Stir for 1.5 h at room temperature and add trifluoromethanesulfonamide in one portion (2 equiv, 50 mg, 0.3 mmol). Stir for 3 h more and concentrate the crude. Purify by column chromatography using hexanes/ethyl acetate 4:1 as eluent (Rf (pentane/acetone 1:1) = 0.28). Acidify with DOWEX 50Wx8 in MeOH, dry under high vacuum for 24 h and store under argon at -20°C. Ph PADI was obtained as a beige powder (79 mg, 81% yield). 1   To a solution of 2-(methoxymethoxy)-1,1'-biphenyl (1 equiv, 180 l, 0.9 mmol) 11 in THF (6 ml) under inert conditions cooled down to 0 °C, add dropwise n-butyllithium 2.5 M in hexanes (1.1 equiv, 0.4 ml, 1.0 mmol) and stir for 30 min. Then, add this solution in one portion over anhydrous FeCl3 (1 equiv, 150 mg, 0.9 mmol) previously dissolved in THF (2 ml) under inert conditions and cooled down to 0 °C. Stir vigorously overnight while warming up to room temperature. Dilute the mixture with Et2O and wash it with brine. Extract the aqueous phase and then dry the combined organic layers with Na2SO4. Concentrate the crude under reduced pressure and  without further purification  dissolve it in 2 ml HCl 4 M in dioxane. Stir at room temperature overnight. Dilute the mixture with Et2O and wash it with water. Extract the aqueous phase and then dry the combined organic layers with Na2SO4. Concentrate and purify by column chromatography using hexanes/ethyl acetate 9:1 as eluent (Rf = 0.31). Dry the sample further as an azeotropic mixture with toluene. The desired product S-4 was obtained as a white crystalline solid (106 mg, 70 % yield). 1

CF3 PADI
In a flame-dried Schlenk, dissolve compound S-12 (1 equiv, 26 mg, 0.03 mmol) in DCM (0.8 ml) under inert conditions. Add N-trifluoromethylsulfonyl-P,P,P-trichlorophosphazene (1 equiv, 5 l, 0.03 mmol) and triethylamine (5 equiv, 20 l, 0.14 mmol). Stir for 30 min at room temperature and add trifluoromethanesulfonamide in one portion (2 equiv, 10 mg, 0.06 mmol). Stir for 2 h more and purify by preparative TLC using pentane/acetone 1:1 as eluent (Rf = 0.73) and then wash with EtOAc. Acidify with DOWEX 50Wx8 in MeOH, dry under high vacuum for 24 h and store under argon at -20°C. CF3 PADI was obtained as a brownish powder (31 mg, 86% yield). 1   Prepare a solution of bis(tri-tert-butylphosphine)palladium (20 mol%, 20 mg, 0.04 mmol) and 3,5-bistrifluoromethyl)-5-bromobenzene (10 equiv, 0.35 ml, 2 mmol) in THF (2 ml) under inert conditions in a flame-dried Schlenk. Note: solvent previously degassed by bubbling argon for 15 min. Add the zincate solution from S-10 (0.2 mmol, see synthesis of S-9), seal and reflux the mixture at 70 °C overnight. Dilute the mixture with Et2O and quench with sat. NH4Cl. Extract, wash the combined organic layers with brine and dry with Na2SO4. Concentrate the crude under reduced pressure and  without further purification  dissolve it in 2 ml HCl 0.4 M in dioxane. Stir at room temperature overnight. Dilute the mixture with Et2O and wash it with water. Extract the aqueous phase and then dry the combined organic layers with Na2SO4. Concentrate the crude under reduced pressure and purify by column chromatography using hexanes/ethyl acetate 30:1 as eluent (Rf (9:1) = 0.59). Dry the sample further as an azeotropic mixture with toluene. The desired product S-12 was obtained as a yellowish crystalline solid (88 mg, 50% yield). 1

Optimization studies
To a solution of triflimide in MeCN-d3 in a vial under argon atmosphere was added SKA 2a or 2b and the resulting mixture was stirred for 30 min at room temperature. Then, the substrate was added at the specified temperature (0.05 mmol) and the stirring continued overnight. The reaction was quenched with 5 l of triethylamine and the crude was analyzed by 1  In order to expand further the chemoselectivity, we explored the reactivity of less acidic catalysts such as bis-arylsulfonimides or diphenyl phosphate.
To a vial charged with the disulfonimide under argon atmosphere was added silyl ketene acetal 2b followed by the substrate (0.05 mmol). Then, the mixture was stirred overnight at room temperature. The reaction was quenched with 5 l of triethylamine, dissolved in CDCl3 and analyzed by 1 H NMR. Based on these results, we then designed the novel scaffold.
To a vial charged with Ph PADI under argon atmosphere was added silyl ketene acetal 2b or 2c followed by the substrate (0.05 mmol). Then, the mixture was stirred overnight at the specified temperature. The reaction was quenched with 5 l of triethylamine, dissolved in CDCl3 and analyzed by 1 H NMR. Note: several unidentified by-products observed in the case of triflimide. Catalyst analog without 3,3´-substituents proved to be rather unstable.
Substrates with ortho-substituton are still rather challenging due to arduous coordination of the silylated catalyst in the sterically hindered nitrogen atom. Similarly, C2 addition to para-substituted substrates shows little reactivity.

Mechanistic Insights
In the optimization studies, no addition of 2a to 1c was observed in the absence of catalyst. Otherwise, catalytic Tf2NH led to complete dearomatization of the substrate towards 3c-2. Analogous results were obtained with 1a towards 3a. Note: color change is slower without presilylation.
In the case of reaction between 1e and 2c, direct analysis of the crude reaction mixture by MS (ESI + ) revealed traces of the functionalized Nmethylated 3-bromodihydropyridine.
Initial 19 F NMR studies suggest that electronically different pyridines interact with the silylated catalyst; Tf2NH  shown in spectra (a)  reacts both with pyridine via protonation (b) or with trimethylphenylsilane towards Tf2NTMS (c). In the case of silyl ketene acetal 2a, the resulting ester partially stabilizes the silicon (d) and slowly forms Tf2NMe. 15 Then, addition of 3-cyanopyridine (e), ethyl nicotinate (f) or pyridine (g) implied also a slight variation of the chemical shift (1c‹1d‹1g). Furthermore, a well-defined cross-peak in 29 Si HMBC was observed in the last example (41.48 ppm in d-PhMe), which reasonably corresponds to the substrate coordinated to the activated catalyst. Generation of the proposed intermediate occurs in parallel with the formation of TMS-siloxane, rearranged silyl ketene acetal and TMS-isobutyric acid; but does not lead to the desired addition product 3g-3.   Several low-angle reflections were shadowed by the beamstop and omitted from the data set before the final refinement cycles. The structure was solved by direct methods (SHELXT) and refined by full-matrix leastsquares (SHELXL). The H atoms were calculated and refined using a riding model. CSD number: CCDC-2055772.

Table S1b. Atomic coordinates and equivalent isotropic displacement parameters (Å 2 ).
Ueq is defined as one third of the trace of the orthogonalized Uij tensor.      Figure S3b. Superposition of the PO2N2 units of the two independent anions, showing the slightly different conformations in the crystal. View from the side and from above.