Improved and Practical Procedures for the Preparation of Highly Substituted Pyridines and Pyridazines via Silica-Mediated Aromatisation

Abstract

A new and straightforward procedure is described for the preparation of highly substituted pyridines and pyridazines. The method involves a Diels-Alder/retro-Diels-Alder sequence leading to dihydropyridine or related intermediates, which can be aromatized to pyridines and pyridazines by treatment with silica gel. The value of this procedure has been demonstrated with a one-step ­synthesis of an E-ring-modified steroid.

Key words

Diels-Alder reaction - heterocycles - pyridines - pyrid­azines - fused-ring systems - silica-mediated aromatization

References and Notes

• For recent references, see:
• 1a Bagley MC. Glover C. Tetrahedron  2006,  62:  66 
• 1b Belhadj T. Nowicki C. Moody CJ. Synlett  2006,  3033 
• 1c Kozhevnikov VN. Kozhevnikov DN. Shabunina OV. Rusinov VL. Chupakhin ON. Tetrahedron Lett.  2005,  46:  1521 
• 1d Kozhevnikov VN. Kozhevnikov DN. Shabunina OV. Rusinov VL. Chupakhin ON. Tetrahedron Lett.  2005,  46:  1791 
• 1e Altuna-Urquijo M. Stanforth SP. Tarbit B. Tetrahedron Lett.  2005,  46:  6111 ; and references therein
• 2a Raw SA. Taylor RJK. Chem. Commun.  2004,  508 
• 2b Fernandez Sainz Y. Raw SA. Taylor RJK. J. Org. Chem.  2005,  70:  10086 
• 2c Laphookhieo S. Jones S. Raw SA. Fernández Sainz Y. Taylor RJK. Tetrahedron Lett.  2006,  47:  3865 
• 2d See also (pyridazine synthesis) Geyelin PH. Raw SA. Taylor RJK. ARKIVOC  2007,  (xi):  37 
• For recent applications of triazines, see:
• 3a Vzorov AN. Bhattacharyya D. Marzilli LG. Compans RW. Antiviral Res.  2005,  65:  57 
• 3b Wang X.-L. Chao H. Li H. Hong X.-L. Liu Y.-J. Tan L.-F. Ji L.-N. Inorg. Biochem.  2004,  98:  1143 
• 3c Hudson MJ. Drew MGB. Foreman MRStJ. Hill C. Huet N. Madic C. Youngs TGA. Dalton Trans.  2003,  1675 
• 3d Abdel-Rahman RM. Pharmazie  2001,  56:  195 
• 3e Croot PL. Hunter KA. Anal. Chim. Acta  2000,  406:  289 
• 4a Boger DL. Weinreb SN. Hetero Diels-Alder Methodology in Organic Synthesis   Academic Press; London: 1987.  Chap. 10. p.300 
• 4b Boger DL. Chem. Rev.  1986,  86:  781 
• 4c Boger DL. Tetrahedron  1983,  39:  2869 
• 4d Boger DL. Panek JS. J. Org. Chem.  1981,  46:  2179 
• 4e Boger DL. Panek JS. Meier MM. J. Org. Chem.  1982,  47:  895 
• 5 Chenard BL. Ronau RT. Schulte GA. J. Org. Chem.  1988,  53:  5175 
• 7 Banerjee AK. Laya MS. Vera WJ. Russ. Chem. Rev.  2001,  70:  971 
• 9a Helm MD. Moore JE. Plant A. Harrity JPA. Angew. Chem. Int. Ed.  2005,  44:  3889 
• 9b Atfah MA. J. Heterocycl. Chem.  1989,  26:  717 
• 10 Fischer DS. Allan GM. Bubert C. Vicker N. Smith A. Tutill HJ. Wood APL. Packham G. Mahon MF. Reed MJ. Potter BVL. J. Med. Chem.  2005,  48:  5749 ; and references therein

6

Representative Procedure
A suspension of triazine 1a (50 mg, 0.21 mmol), pyrrolidine (6, 26 µL, 0.31 mmol), cyclopentanone (2a, 27 µL, 0.31 mmol) and silica (Fluka, flash chromatography silica gel 60, 220-440 mesh, 200 mg) in toluene (4 mL) was heated under reflux for 5 h. The reaction mixture was cooled to r.t., diluted with EtOAc (6 mL), and stirred an additional 20 min at the same temperature. The mixture was then filtered through a Celite pad, concentrated and the residue obtained was eluted from a column of silica (PE-EtOAc, 5:1) yielding the desired pyridine 5a (57 mg, 99%); data were consistent with those reported in ref. 2b.

8

Similar reactions were carried out in which the silica gel was replaced by stoichiometric amounts of HCl, MeCOOH, Et₃N, or 1,5-diazabicyclo[4.3.0]non-5-ene (DBU). None of these reactions produced pyridines 5 in significant quantities.

11

The structure of the cycloaddition product 10 was assigned using NOE and HMBC NMR experiments.

12

A solution of triazine 1a (100 mg, 0.43 mmol), pyrrolidine (6, 52 µL, 0.64 mmol) and estrone (9) (113 mg, 0.42 mmol) in xylene (4 mL) was heated in a screwcapped tube at 160 °C for 10 h. The reaction mixture was cooled to r.t., silica (Fluka, flash chromatography silica gel 60, 220-440 mesh) was added and the yellow suspension obtained refluxed for an additional 5 h. The mixture was then cooled to r.t., filtered through a Celite pad, concentrated and the residue obtained was eluted from a column of silica (CHCl₃-EtOAc, 7:1) yielding the desired 3-hydroxy-estra-1,3,5 (10)-triene-[17,16-c]-(2′-pyrid-2-yl)-(6′-phenyl)-pyridine (10, 129 mg, 67%) as a white solid, mp 261-262 °C (toluene-hexane); [α]_D ²⁵ -50.0 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.71 (1 H, ddd, J = 0.9, 1.8, 4.8 Hz, C-9′-H), 8.43 (1 H, ddd, J = 0.9, 1.0, 7.9 Hz, C-12′-H), 8.13 (2 H, m, C-14′-H, C-18′-H), 7.83 (1 H, ddd, J = 1.8, 7.6, 7.9 Hz, C-11′-H), 7.56 (1 H, s, C-5′-H), 7.49 (2 H, m, C-15′-H, C-17′-H), 7.41 (1 H, m, C-16′-H), 7.29 (1 H, ddd, J = 1.0, 4.8, 7.6 Hz, C-10′-H), 7.18 (1 H, d, J = 8.4 Hz, C-1-H), 6.63 (1 H, dd, J = 2.6, 8.4 Hz, C-2-H), 6.57 (1 H, d, J = 2.6 Hz, C-4-H), 4.80 (1 H, s, OH), 3.45 (1 H, dd, J = 5.8, 16.1 Hz, H-12a), 3.04 (1 H, dd, J = 11.9, 16.1 Hz, H-12b), 2.90 (2 H, m, H-6a,b) 2.47 (1 H, m), 2.35 (2 H, m), 2.12 (1 H, m), 1.77 (4 H, m), 1.50 (1 H, m), 1.07 (3 H, s, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 166.2, 158.6, 155.2, 153.8, 151.6, 148.5, 140.0, 138.71, 136.7, 136.4, 132.3, 128.6, 127.1, 126.3, 123.6, 122.9, 115.4, 113.3, 112.9, 56.1, 45.8, 44.3, 37.8, 34.6, 32.2, 29.6, 27.7, 26.4, 19.0. MS (EI): m/z (%) = 459.2 (100) [M + 1]. HRMS (EI): m/z calcd for C₃₂H₃₁N₂O [M + 1]: 459.2436; found: 459.2431 (-3.2 ppm error).