Synthesis of 2-organylselenopheno[2,3-b ]pyridines and 1,6-diazaselenanthrenes via radical cascade reactions using tert -butyl nitrite

We describe herein an alternative method to prepare 2-organylselenopheno[2,3-b ]pyridines starting from bis(3-amino-2-pyridyl) diselenide and aryl-and alkylacetylenes in the presence of t BuONO in CH 3 NO 2 as solvent. The reactions were conducted at 80 °C for 2 hours

Our group has been dedicated to developing new synthetic methodologies to prepare pharmacologically promising organochalcogen compounds.Recently, we reported the preparation of bis(2-pyridyl) diselenide derivatives and their antioxidant and anticholinesterasic activities. 35Based on our previous findings and in those from Zang and coworkers, 36 we hypothesize that these compounds could be ideal starting materials to synthesize fused selenopheno [2,3-b]pyridines by the reaction with terminal alkynes in the presence of a nitrosating agent (Scheme 2).Scheme 2. General scheme of the present work.

Results and Discussion
Initially, we selected different 2-alkylselanyl-pyridin-3-amine 1a-b and bis(3-amino-2-pyridyl) diselenide 2a as substrates to react with phenylacetylene 3a using tert-butyl nitrite as a nitrosating agent under argon atmosphere to evaluate our hypothesis.Still, to establish the best reaction conditions, other variables were also studied, such as the nature of the solvent and the temperature of the reaction, and these results are summarized in Table 1.For the synthesis of the starting materials 1 and 2 we followed the procedures recently described by us. 35hus, our preliminary experiment consisted in stirring a mixture of 0.25 mmol of 2-(methylselanyl)pyridin-3amine 1a, 0.75 mmol of phenylacetylene 3a and 0.5 mmol of tert-butyl nitrite in nitromethane (1.0 mL) as solvent at 80 °C for 2 h under argon atmosphere.Under these conditions, the desired 2phenylselenopheno[2,3-b]pyridine 4a was obtained in 27% yield (Table 1, entry 1).Due to the low yield, we decided to employ 2-(butylselanyl)pyridin-3-amine 1b as starting material, which gave the expected product in only 23% (Table 1, entry 2).To our satisfaction, when the reaction was performed directly with bis(3-amino-2pyridyl) diselenide 2a, the product 4a was obtained in 40% yield, almost the double that using selenides 1a and 1b.This outcome represents a reduction of waste production and time consuming (Table 1, entry 3).Furthermore, it was obtained 11% of 1,6-diazaselenanthrene 5a, an unpublished product so far.Thus, aiming to increase the reaction yield, bis(3-amino-2-pyridyl) diselenide 2a was chosen as standard starting material and other reaction parameters were evaluated in the reaction with phenylacetylene 3a, such as reaction time (entry 4), the nitrosating agent (isopentyl nitrite, entry 5) and different temperatures (entries 6-8).However, after performing these reactions, no increments in the yield of 4a was observed.Then, our attention was focused on the evaluation of the nature of the solvent, and it was observed that neither DMSO or PEG-400 were more effective than nitromethane (entries 9 and 10).Finally, the reduction of the amount of phenylacetylene 3a and tert-butyl nitrite was evaluated (entries 11 and 12).When the phenylacetylene quantity was reduced to 2 equiv (0.5 mmol), 2-phenylselenopheno [2,3-b]pyridine 4a was obtained in comparable yield (entry 3 vs 11).However, the reduction of the nitrite amount from 2.0 equiv to 1.0 equiv (0.25 mmol) resulted in an incomplete consumption of 2a.Thus, the optimized reaction condition was stablished as stirring a mixture of bis(3-amino-2-pyridyl) diselenide 2a (0.125 mmol), phenylacetylene 3a (0.5 mmol) and tert-butyl nitrite (0.5 mmol) in CH 3 NO 2 (1.0 mL), under argon atmosphere at 80 °C during 2 h.This reaction afforded 2-phenylselenopheno [2,3-b]pyridine 4a in 41% yield and the new 1,6-diazaselenanthrene 5a in 11% yield.a The mixture of compound 2 (0.125 mmol), phenylacetylene 3a (0.75 mmol), and t BuONO (0.5 mmol) in the respective solvent (1.0 mL) was stirred at 80 °C under Ar.b Yield are given for isolated products 4a and 5a.c 0.25 mmol of 1. d 0.50 mmol of phenylacetylene 3a was used.e 0.25 mmol of t BuONO was used.
With the optimized conditions in hand, we investigated the substrate scope, performing reactions with different aryl-and alkylacetylenes 3b-f and the results are presented in Table 2.In general, all reactions proceeded smoothly, providing the desired products in moderate yields.
When the reaction was performed with arylacetylenes with electron-donating groups at the para-position of the aromatic ring (3b-d), the obtained results were similar to that obtained using the neutral phenylacetylene 3a (Table 2, entries 2-4 vs entry 1).In contrast, in the presence of the electron-withdrawing Cl-substituent at the aromatic ring (3e) the reaction was faster, but the yield was not satisfactory (10%) and many by-products were observed (Table 2, entry 5).
The aliphatic heptyne 3f was also used and the respective 2-pentylselenopheno[2,3-b]pyridine 4f was obtained after 2 h in 17% yield.In all cases 1,6-diazaselenanthrene 5a was formed and isolated, as depicted in Table 2. Interestingly, for all the conducted reactions the yield of 5a was similar, ranging from 7% to 13%. a The mixture of compound 2a (0.125 mmol), acetylene 3 (0.5 mmol), and t BuONO (0.5 mmol) was added in CH 3 NO 2 (1.0 mL) under argon atmosphere and stirred for the indicated time at 80 °C.b Yields are given for isolated products 4a-f and 5a.
To confirm the chemical structure of 1,6-diazaselenanthrene 5a, in addition to NMR collected data, the compound was recrystallized and analyzed by single-crystal X-ray diffraction analysis.The molecular structure obtained is demonstrated in Figure 2. Once the structure of 1,6-diazaselenanthrene 5a was confirmed, we turn to carried out reactions in absence of acetylene 3, under the same conditions, to allow the selective formation of product 5a.When bis(3-amino-2pyridyl) diselenide 2a was allowed to react with tert-butyl nitrite in nitromethane at 80 °C, 1,6diazaselenanthrene 5a was obtained in 47% yield after 2 h (Table 3, entry 1).After this test, different amounts of the nitrosating agent were evaluated, but lower yields were observed.Subsequently, the performance of bis(3-amino-2-pyridyl) diselenide 2b, containing a methyl group at the aromatic pyridine ring and the chloro-substituted compound 2c, was evaluated.In these reactions, the expected products 5b and 5c were obtained in 41% and 43% yields, respectively (Table 3, entries 2 and 3).Aiming to collect evidences into the reaction pathway, a control experiment was conducted.Thus, the radical trapping experiment was conducted in the presence of the radical inhibitor 2,2,6,6-tetramethyl-1piperidinyloxy (TEMPO) under the standard conditions.Under this condition, a complex mixture was obtained and only traces of compounds 4a and 5a were detected by GC/MS analysis.Through this experiment, and based in our findings and reports, 8,36 a mechanism is proposed in Scheme 4. Firstly, the reaction between pyridylamine and tert-butyl nitrite results in radical species A. From this intermediate A the reaction can follow two paths, depending on the interaction or not with acetylene.In Path I, the reaction occurs without the presence of acetylene 3 via two intramolecular radical reactions to afford the product 5.In Path II, however, occurs the reaction between the radical intermediate A and the acetylene 3, affording the vinyl radical B, which reacts via intramolecular homolytic substitution at the selenium atom, leading to the final product 4.

Conclusions
In summary, we have developed a simple method for the synthesis of 2-organylselenopheno[2,3-b]pyridines in short reaction times and mild conditions.To allow these synthesis bis(3-amino-2-pyridyl) diselenide was reacted with terminal alkynes in the presence of tert-butyl nitrite as nitrosating agent.Also, it was possible to obtain a new class of 1,6-diazaselenanthrenes, which were obtained in good yields when the reaction was conducted without the presence of alkynes.In addition, the applicability of selenopheno [2,3-b]pyridines was demonstrated by bromination and direct selanylation reactions to obtain versatile substrates for further organic transformations capable to produce promising drugs or precursors for new materials.

Experimental Section
General.The reactions were monitored by TLC carried out on Merk silica gel (60 F254) by using UV light as visualization agent and the mixture between 5% of vanillin in 10% of H 2 SO 4 under heating conditions as developing agents.Merck silica gel (particle size 0.040-0.063mm) was used to flash chromatography.Hydrogen nuclear magnetic resonance spectra ( 1 H NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broadband probe at 400 MHz.The spectra were recorded in CDCl 3 solutions.The chemical shifts are reported in ppm, referenced to tetramethylsilane (TMS) as the internal reference.
Coupling constants (J) are reported in Hertz.Abbreviations to denote the multiplicity of a particular signal are brs (broad singlet) s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), qui nt (quintet) and m (multiplet).Carbon-13 nuclear magnetic resonance spectra ( 13 C NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broadband probe at 100 MHz.The chemical shifts are reported in ppm, referenced to the solvent peak of CDCl 3 .Selenium-77 nuclear magnetic resonance spectra ( 77 Se NMR) were obtained on Bruker Avance III HD 400 MHz employing a direct broadband probe at 76 MHz.The chemical shifts are reported in ppm using as solvent the CDCl 3 and as an internal standard the diphenyl diselenide.The high-resolution electrospray ionization mass spectrometry (ESI-QTOF) analysis were performed on a Bruker Daltonics microTOF-Q II instrument in positive mode.The samples were solubilized in HPLC-grade acetonitrile and injected into the APCI source by means of a syringe pump at a flow rate of 5.0 µL min -1 .The follow instrument parameters were applied: capillary and cone voltages were set to +3500 V and -500 V, respectively, with a desolvation temperature of 180 °C.For data acquisition and processing, Compass 1.3 for microTOF-Q II software (Bruker daltonics, USA) was used.The data were collected in the m/z range of 50-1200 at the speed of two scans per second.Low-resolution mass spectra were obtained with a Shimadzu GC-MS-QP2010P mass spectrometer.Melting point (mp) values were measured in a Marte PFD III instrument with a 0.1 °C precision.
General procedure for synthesis of 2-aryl-or 2-alkylselenopheno[2,3-b]pyridines 4a-f.In a Schlenk tube was prepared a mixture of bis(3-amino-2-pyridyl) diselenide 2a (0.125 mmol), alkyne 3a-f (0.5 mmol), and t C 4 H 9 ONO (0.5 mmol) in CH 3 NO 2 (1.0 mL) under argon atmosphere.This reaction mixture was stirred at 80 °C for the time indicated in Table 2.Then, water was added (25.0 mL) and the reaction was extracted with ethyl acetate (3x 10.0 mL).The organic phase was separated, dried over MgSO 4 , and the solvent was evaporated under reduced pressure.The product was isolated by column chromatography using hexane/ethyl acetate as eluent.

Table 3 .
Synthesis of 1,6-diazaselenanthrenes 5a-c a a The mixture of compound 2a-c (0.125 mmol) and t C 4 H 9 ONO (0.5 mmol) was added in CH 3 NO 2 (1.0 mL) under argon atmosphere and stirred for 2 hours at 80 °C.b The yield is given for isolated products 5a-c.Scheme 3. Control experiment.