N-Azinylpyridinium N-Aminides: An Approach to Pyrazolopyridines via an Intramolecular Radical Pathway

Abstract

Intramolecular radical arylation, under thermal conditions, to a π-deficient pyridinium, linked to a π-excessive 2-azinyliminopyridine moiety is described. The method allows a new entry to pyrazolo[1,5-a]pyridine nucleus.

aminides - pyrazolopyridines - intramolecular radical reactions - ylides

References

1a Curran DP. Fevig TP. Jasperse CP. Chem. Rev.  1991,  91:  1237 

1b Giese B. Kopping B. Göbel T. Dickhaut J. Thoma G. Kulicke KJ. Trach F. Org. React.  1996,  48:  301 

2a Dobbs AP. Jones K. Veal KT. Tetrahedron Lett.  1995,  36:  4857 ; and references therein

2b Dobbs AP. Jones K. Veal KT. Tetrahedron  1998,  54:  2149 ; and references therein

2c Fiumana A. Jones K. Tetrahedron Lett.  2000,  41:  4209 

3a Shankaran K. Sloan CP. Snieckus V. Tetrahedron Lett.  1985,  26:  6001 

3b Snieckus V. Bull. Soc. Chim. Fr.  1988,  67 

4 Nadin A. Harrison T. Tetrahedron Lett.  1999,  40:  4073 

5a Harrowven DC. Browne R. Tetrahedron Lett.  1994,  35:  5301 

5b Harrowven DC. Nunn MIT. Tetrahedron Lett.  1998,  39:  5875 

5c Harrowven DC. Nunn MIT. Blumire NJ. Fenwick DR. Tetrahedron Lett.  2000,  41:  6681 

5d Harrowven DC. Sutton BJ. Coulton S. Tetrahedron Lett.  2001,  42:  9061 

5e Harrowven DC. Nunn MIT. Blumire NJ. Fenwick DR. Tetrahedron  2001,  57:  4447 

6a Jones K. Fiumana A. Tetrahedron Lett.  1996,  37:  8049 

6b Jones K. Fiumana A. Escudero-Hernandez ML. Tetrahedron  2000,  56:  397 

7 Dobbs AP. Jones K. Veal KT. Tetrahedron Lett.  1997,  38:  5383 

8a Minisci F. Vismara E. Fontana F. Heterocycles  1989,  28:  489 

8b Fontana F. Minisci F. Barbosa MCN. Vismara E. J. Org. Chem.  1991,  56:  2866 

8c Minisci F. Vismara E. Fontana F. J. Heterocycl. Chem.  1990,  27:  79 

9 Minisci F. Fontana F. Pianese G. Yan YM. J. Org. Chem.  1993,  58:  4207 

10a Togo H. Hayashi K. Yokoyama M. Chem. Lett.  1991,  2063 

10b Togo H. Hayashi K. Yokoyama M. Chem. Lett.  1993,  641 

11a Murphy JA. Sherburn MS. Tetrahedron Lett.  1990,  31:  1625 

11b Murphy JA. Sherburn MS. Tetrahedron Lett.  1990,  31:  3495 

12a Da Mata MLEN. Motherwell WB. Ujjainwalla F. Tetrahedron Lett.  1997,  38:  137 

12b Da Mata MLEN. Motherwell WB. Ujjainwalla F. Tetrahedron Lett.  1997,  38:  141 

12c Clive DL. Kang S. Tetrahedron Lett.  2000,  41:  1315 

12d Bonfand E. Forslund L. Motherwell WB. Vazquez S. Synlett  2000,  475 

12e Studer A. Bossart M. Steen H. Tetrahedron Lett.  1998,  39:  8829 

13a Carceller R. García-Navío JL. Izquierdo ML. Alvarez-Builla J. Fajardo M. Gomez-Sal P. Gago F. Tetrahedron  1994,  50:  4995 

13b Burgos C. Delgado F. García-Navío JL. Izquierdo ML. Alvarez-Builla J. Tetrahedron  1995,  51:  8649 

13c García de Viedma A. Martínez-Barrasa V. Burgos C. Izquierdo ML. Alvarez-Builla J. J. Org. Chem.  1999,  64:  1007 

13d Martínez-Barrasa V. Delgado F. Burgos C. García-Navío JL. Izquierdo ML. Alvarez-Builla J. Tetrahedron  2000,  56:  2481 

14a Kakehi A. Ito S. Ono T. Miyazima T. Chem. Lett.  1979,  205 

14b Kakehi A. Ito S. Ono T. Miyazima T. J. Chem. Res., Synop.  1980,  18 

14c Kakehi A. Kitajima J. Ito S. Tagusagawa N. Acta Cryst.  1995,  942 

14d Phadke RC. Rangnekar DW. Synthesis  1987,  484 

14e Bast K. Behrens M. Durst T. Grashey R. Huisgen R. Schiffer R. Temme R. Eur. J. Org. Chem.  1998,  379 

15

Typical Procedure, Method A: 3-Chloro-dipyrido[1,2- b; 3′2′- d ]pyrazole 5a: A solution of tris(trimethylsilyl)silane (TTMSS) (0.149 g 0.6 mmol) and AIBN (0.099 g, 0.6 mmol) in 6 mL of dry benzene was diluted with 14 mL of dry acetonitrile. The resulting solution was added dropwise by a syringe pump during 16 h, to a dispersion of potassium carbonate (0.083 g, 0.6 mmol) and the aminide 1c (0.062 g, 0.3 mmol) in 50 mL of dry acetonitrile, stirred at 80ºC (bath temperature), under an atmosphere of dry argon. After being stirred at the same temperature until 24 h, full consumption of 1c was observed (TLC analysis). The reaction mixture was allowed to warm to r.t. and distilled water (5 mL) was added. The organic extracts were dried (Na₂SO₄) and concentrated in vacuo, providing a crude product that was purified by flash chromatography [silicagel, ethyl acetate:hexane (1:1) (R_f ≈ 0.30)]. Yellow solid (0.034 g, 56% yield, toluene, mp = 212-214 ºC). ¹H NMR (300 MHz, CDCl₃): δ = 8.87 (ddd, 1 H, J = 6.9, 1.2 and 1.1 Hz), 8.80 (d, 1 H, J = 2.4 Hz), 8.39 (d, 1 H, J = 2.4 Hz), 8.11 (ddd, 1 H, J = 8.5, 1.4 and 1.1 Hz), 7.51 (ddd, 1 H, J = 8.5, 7.3 and 1.2 Hz), 7.33 (ddd, 1 H, J = 7.3, 6.9 and 1.4 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 157.7, 152.2, 146.5, 134.4, 129.0, 127.7, 124.0, 122.8, 118.5, 117.8. IR (KBr): 2922, 1706, 1641, 1437 cm^-1. MS (CI): m/z = 204, 206 ([M⁺ + 1], 100, 32). EIMS HR: calcd for C₁₀H₆ ³⁵ClN₃: [M⁺] 203.0246. Found: 203.0240.

15a Loss of a proton from a dihydropyridine radical cation is a key step in the oxidative homolytic alkylation of pyridinium salts, in aqueous or Me₂SO solutions: Minisci F. Fontana F. Morini G. Serravalle M. Giordano C. J. Org. Chem.  1987,  52:  730 

15b Rusell and co-workers have reported previously the use of bases to promote the substitutive reactions of aromatics: Rusell GA. Chen P. Kim BH. Rajaratnam R. J. Am. Chem. Soc.  1997,  119:  8795 

15c Wang C. Rusell GA. Trahanovsky WS. J. Org. Chem.  1998,  63:  9956 

17

Potassium carbonate could abstract a proton from the substituted dihydropyridine radical 6 (Scheme [2] ), to form the radical 7, that would be converted in the arylated compound 5 (see ref. [15b] [c] ). In the absence of potassium carbonate, dihydropyridine radical 6 did not evolve to 5, and only decomposition products and N-N reduction compounds were observed.

18 Martínez-Barrasa V. García de Viedma A. Burgos C. Alvarez-Builla J. Org. Lett.  2000,  2:  3933 

19

Typical Procedure, Method E: Pyridinium N -(3′-bromo-5′-chloropyrazin-2′-yl)aminide 1e: To a solution of pyridinium (N-(2′-pyrazinyl)aminide 1b (0.172 g, 1 mmol) in dry dichloromethane (5 mL) stirred at 0 ºC was added dropwise a solution of N-chlorosuccinimide (NCS) (0.160 g, 1.2 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred for 1 h at the same temperature, allowed to warm up to r.t. and stirring for a further 24 h. The solvent was evaporated and the residue was purified by flash chromatography [silicagel, ethanol, (R_f ≈ 0.25)] to yield 0.149 g (72%) of pyridinium N-(5′-chloropyrazin-2′-yl)aminide 8b: Yellow solid (ethyl acetate, mp = 158-161 ºC). ¹H NMR (300 MHz, CD₃OD): δ = 8.76 (dd, 2 H, J = 5.7 and 1.3 Hz), 8.13 (tt, 1 H, J = 8.2 and 1.3 Hz), 7.86 (dd, 2 H, J = 8.2 and 5.7 Hz), 7.62 (d, 1 H, J = 1.4 Hz), 7.60 (d, 1 H, J = 1.4 Hz). ¹³C NMR (75 MHz, CD₃ OD): δ = 160.8, 145.0, 140.3, 139.5, 135.4, 132.1, 128.7. Anal. Calcd for C₉H₇ClN₄: C, 52.31; H, 3.41; N, 27.11. Found: C, 52.32; H, 3.69; N, 27.31. To a solution of pyridinium N-(5′-chloro-pyrazin-2′-yl)aminide 8b (0.206 g, 1 mmol) in dry dichloro-methane (5 mL) stirred at r.t., was added dropwise a solution of N-bromosuccinimide (NBS) (0.214 g, 1.2 mmol) in dry dichlorometane (10 mL). The reaction mixture was stirred until 24 h at the same temperature, the solvent was eva-porated and the residue was purified by flash chromato-graphy [silicagel, ethanol (R_f ≈ 0.75)] to yield 0.231 g (81%) of pyridinium N-(3′-bromo-5′-chloropyrazin-2′-yl)aminide 1e: Yellow-orange solid (ethyl acetate, mp = 203-205 ºC). ¹H NMR (300 MHz, CD₃OD): δ = 8.70 (dd, 2 H, J = 6.9 and 1.4 Hz), 8.25 (tt, 1 H, J = 7.8 and 1.4 Hz), 7.93 (dd, 2 H, J = 7.8 and 6.9 Hz), 7.60 (s, 1 H). ¹³C NMR (75 MHz, CD₃OD): δ = 158.4, 146.2, 141.4, 139.6, 130.8, 129.0, 126.0; Anal. Calcd for C₉H₆BrClN₄: C, 37.86; H, 2.12; N, 19.62. Found: C, 38.01; H, 2.43; N, 19.31.