Unexpected and Divergent Reactions of N-Formyl-1,2-dihydroquinolines with Sodium Azide: Highly Chemoselective Formation of 2-Substituted Quinolines and Isoxazolo[4,3-c]quinolines

Abstract

Efficient and divergent synthesis of 2-substituted quinolines and isoxazolo[4,3-c]quinolines was achieved from N-formyl-1,2-dihydroquinolines with the aid of sodium azide. The synthesis is substituent-dependent. Thus N-formyl-1,2-dihydroquinolines with a hydrogen atom at the 3-position afforded 2-substituted quinolines in good to excellent yields, while with a 3-formyl group, N-formyl-1,2-dihydroquinolines unexpectedly gave isoxazolo[4,3-c]quinolines in high yields.

Key words

azides - quinolines - chemoselectivity - deformylation heterocycles

References and Notes

• 1a Kleeman A. Engel J. Kutscher B. Reichert D. Pharmaceutical Substances, Synthesis, Patents, Applications   Thieme; Stuttgart, New York: 2001. 
• 1b Michael JP. Nat. Prod. Rep.  2001,  18:  543 
• 1c Funayama S. Murata K. Noshita T. Heterocycles  2001,  54:  1139 
• 2 Huang LJ. Hsieh MC. Teng CM. Lee KH. Kuo SC. Bioorg. Med. Chem.  1998,  6:  1657 
• 3 Musser JH. Chakraborty UR. Sciortino S. Gordon RJ. Khandwala A. Neiss ES. Pruss TP. Van Inwegen R. Weinryb I. Coutts SM. J. Med. Chem.  1987,  30:  96 
• 4 Gauthier JY. Jones T. Champion E. Charette L. Dehaven R. Ford-Hutchinson AW. Hoogsteen K. Lord A. Masson P. Piechuta H. Pong SS. Springer JP. Therien M. Zamboni R. Young RN. J. Med. Chem.  1990,  33:  2841 
• For example:
• 5a Majumder S. Gipson KR. Odom AL. Org. Lett.  2009,  11:  4720 
• 5b Martinez R. Ramon DJ. Yus M. J. Org. Chem.  2008,  73:  9778 
• 5c Schramm OG. Oeser T. Kaiser M. Brun R. Müller TJJ. Synlett  2008,  359 
• 5d Zhang ZH. Tan JJ. Wang ZY. Org. Lett.  2008,  10:  173 
• 5e Horn J. Marsden SP. Nelson A. House D. Weingarten GG. Org. Lett.  2008,  10:  4117 
• 5f Li L. Jones WD. J. Am. Chem. Soc.  2007,  129:  10707 
• 5g Sandelier MJ. DeShong P. Org. Lett.  2007,  9:  3209 
• 6 Li H. Zheng C. Chen RE. Su WK. Org. Prep. Proced. Int.  2009,  41:  156 
• 7a Wolf C. Lerebours R. J. Org. Chem.  2003,  68:  7077 
• 7b Pierce AC. ter Haar E. Binch HM. Kay DP. Patel SR. Li P. J. Med. Chem.  2005,  48:  1278 
• 7c Andersen KE. Lundt BF. Jorgensen AS. Braestrup C. Eur. J. Med. Chem.  1996,  31:  417 
• 7d Holla BS. Mahalinga M. Karthikeyan MS. Poojary B. Akberali PM. Kumari NS. Eur. J. Med. Chem.  2005,  40:  1173 
• 7e Zhong BY. Al-Awar RS. Shih C. Grimes JH. Vieth M. Hamdouchi C. Tetrahedron Lett.  2006,  47:  2161 
• 7f Lim J. Stock N. Pracitto R. Boueres JK. Munoz B. Chaudhary A. Santini AM. Orr K. Schaffhauser H. Bezverkov RE. Aiyar J. Venkatraman S. Bioorg. Med. Chem. Lett.  2004,  14:  1913 
• 8 Sashida H. Fujii A. Tsuchiya T. Chem. Pharm. Bull.  1987,  35:  3182 
• 9 Smith KM. Miura M. Tabba HD. J. Org. Chem.  1983,  48:  4779 
• 10 Kumar KH. Peruma PT. J. Heterocycl. Chem.  2008,  45:  597 
• 11 Delfourne E. Darro F. Bontemps-Subielos N. Decaestecker C. Bastide J. Frydman A. Kiss R. J. Med. Chem.  2001,  44:  3275 
• 12 Ismail MM. Abass M. Hassan MM. Molecules  2000,  5:  1224 
• 14a Brahma S. Ray JK. J. Heterocycl. Chem.  2008,  45:  311 
• 14b Brahma S. Ray JK. Tetrahedron Lett.  2005,  46:  6575 
• 14c Becher J. Jorgensen PL. Pluta K. Krake NJ. Falt-Hansen B. J. Org. Chem.  1991,  57:  2127 

13

Experimental Procedure for the Synthesis of 4-Chloro-2-substituted Quinolines; 1,3-(2 H )-dicarbaldehyde 1o-r: To an ice-cold magnetically stirred solution of DMF (10 mL) and 2-arylquinoline (5.0 mmol), POCl₃ (30 mmol, 2.8 mL) was added dropwise. The reaction mixture was heated to
50 ˚C for 3 h. After which it was poured into the crush ice, neutralized with sat. K₂CO₃ solution and extracted with EtOAc. After drying and condensation of the organic layer , the crude reaction product was purified by column chromatography using 5% EtOAc in PE as eluent to afford pure 1o-r.

15

General Procedure for the Synthesis of 2-Substituted Quinolines 2a-n: To a solution of DMSO (5 mL) and 4-chloro-N-formyl-1,2-dihydroquinolines 1a-n (1.0 mmol), NaN₃ (1 mmol, 0.065 g) was added at r.t. The solution was then heated at the indicated temperature (90 ˚C or 120 ˚C or 150 ˚C) for the indicated time. After completion of the reaction (monitored by TLC) the mixture was treated with ice-water and extracted with EtOAc. The organic layer was washed with H₂O, and then with brine. After condensation of the organic layer, the products 2a-n were obtained by column chromatography (PE-EtOAc).
2-(2-Chloro-6-fluorophenyl)quinoline (2f)
New compound. Yield: 99%; light yellow oil; R _f 0.53 (PE-EtOAc, 5:1). ^¹H NMR (400 MHz, CDCl₃): δ = 8.27 (1 H, d, J = 8.0 Hz), 8.20 (1 H, d, J = 8.4 Hz), 7.89 (1 H, d, J = 8.0 Hz), 7.74-7.79 (1 H, m), 7.60 (1 H, t, J = 8.0 Hz), 7.50 (1 H, d, J = 8.0 Hz), 7.32-7.38 (2 H, m), 7.11-7.16 (1 H, m). ^¹³C NMR (100 MHz, CDCl₃): δ = 160.7 (d, ^¹ J _C-F = 248.7 Hz), 152.5, 147.9, 136.4, 134.3, 130.2 (d, ^³ J _C-F = 9.9 Hz), 129.8, 129.6, 127.6, 127.3, 127.1, 125.6 (d, ⁴ J _C-F = 3.1 Hz), 123.0, 114.6 (d, ^² J _C-F = 22.0 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₀ClFN: 258.0408; found: 258.0477.

16

General Procedure for the Synthesis of 4-Substituted Isoxazolo[4,3- c ]quinolines-5-(4 H )-carbaldehyde 3o-r: To a solution of DMSO (5 mL) and 4-chloro-2-substituted quinolines-1,3 (2H)-dicarbaldehyde 1o-r (1.0 mmol), NaN₃ (1.5 mmol, 0.098 g) was added at r.t. and the reaction mixture was kept at this temperature for 0.5 h. After completion of the reaction (monitored by TLC) the mixture was treated with ice-water and extracted with EtOAc. The organic layer was washed with H₂O, and then with brine. After condensation of the organic layer, the products 3o-r were obtained by column chromatography (PE-EtOAc).
4-Phenylisoxazolo[4,3- c ]quinoline-5-(4 H )-carbaldehyde (3o)
New compound. Yield: 88%; white crystals; mp 176-178 ˚C; R _f 0.46 (PE-EtOAc, 3:1). IR (KBr): 3121, 3057, 2851, 1677, 1609, 1574, 1475 cm^-¹. ^¹H NMR (400 MHz, DMSO): δ = 9.21 (1 H, s), 8.86 (1 H, s), 7.94 (1 H, d, J = 8.0 Hz), 7.73 (1 H, d, J = 8.0 Hz), 7.54-7.59 (1 H, m), 7.37-7.41 (1 H, m), 7.22-7.30 (3 H, m), 7.16 (2 H, d, J = 8.0 Hz), 7.10 (1 H, s). ^¹³C NMR (100 MHz, DMSO): δ = 162.4, 156.0, 153.8, 138.8, 136.1, 132.2, 128.7, 127.8, 126.3, 126.1, 124.6, 121.2, 117.1, 114.7, 46.9. HRMS (EI): m/z [M⁺] calcd for C₁₇H₁₂N₂O₂: 276.0899; found: 276.0899.