TMSCl-Catalyzed Aza-Diels-Alder Reaction: A Simple and Efficient ­Synthesis of Pyrano- and Furanoquinolines

Abstract

An efficient TMSCl-catalyzed synthesis of pyrano- and furanoquinolines and phenanthridinone derivative has been developed. In the presence of TMSCl (20 mol%), various aliphatic, ­aromatic and heteroaromatic aldehydes reacted with different anilines in the presence of either 2,3-dihydrofuran, 3,4-dihydro-2H-pyran or cyclohexenone to afford the aza-Diels-Alder adducts in excellent yield at room temperature. The ambient conditions, fast reaction rates, and excellent product yields are important characteristics of this reaction.

aza-Diels-Alder reaction - one-pot - TMSCl - pyrano- and furanoquinolines - excellent yields

References and Notes

1a Ramesh M. Mohan PS. Shanmugam P. Tetrahedron  1984,  40:  4041 

1b Witherup KM, Ranson RW, Varga SL, Lotti VJ, and Lumma WJ. inventors; U.S. Patent US  5288725.  ; Chem. Abstr. 1994, 121, 91779s

1c Johnson JV. Eauckman S. Baccanari PD. Roth B. J. Med. Chem.  1989,  32:  1942 

1d Biller SA, and Misra RN. inventors; U.S. Patent US  4843082.  ; Chem. Abstr. 1989, 111, 232600j

1e Perry NB. Blunt JW. McComb JD. Munro MHG. J. Org. Chem.  1986,  51:  5476 

1f Yamada N. Kadowaki S. Takahashi K. Umezu K. Biochem. Pharmacol.  1992,  44:  1211 

1g Faber K. Stuckler H. Kappe T. J. Heterocyl. Chem.  1984,  21:  1177 

1h Michael ZH. Roger LX. Richard FR. Sylvia M. Alban S. Gregory DC. James RH. Bioorg. Med. Chem. Lett.  2002,  12:  129 

1i Lin H.-ML. Liu F.-W. Zou D.-P. Dai G.-F. Bioorg. Med. Chem. Lett.  2005,  15:  1821 

2 Katritzky AR. Rachwal S. Rachwal B. Tetrahedron  1996,  48:  15031 ; and references cited therein

3a Povarov LS. Russ. Chem. Rev. (Engl. Transl.)  1967,  36:  656 

3b Boger DL. Weinreb SM. Hetero Diels-Alder Methodology in Organic Synthesis   Academic Press; San Diego: 1987.  Chap. 2.

3c Boger DL. Weinreb SM. Hetero Diels-Alder Methodology in Organic Synthesis   Academic Press; San Diego: 1987.  Chap. 9.

3d Weinreb SM. In Comprehensive Organic Synthesis   Vol. 5:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.401 

3e Buonora P. Olsen JC. Oh T. Tetrahedron  2001,  57:  6099 

3f Jayakumar S. Ishar MPS. Mahajan MP. Tetrahedron  2002,  58:  379 

3g Zang J. Li C.-J. J. Org. Chem.  2002,  67:  3969 

3h Cheng D. Zhou J. Saiah E. Beaton G. Org. Lett.  2002,  4:  4411 

3i Sundarajan G. Prabagaran N. Varghese B. Org. Lett.  2001,  3:  1973 

3j Lavilla R. Bernabeu MC. Carranco I. Diaz JL. Org. Lett.  2003,  5:  717 

3k Yadav JS. Reddy BVS. Reddy JSS. Rao S. Tetrahedron  2003,  59:  1599 

3l Jose B. Monica T. Eduardo R. Jose MG. J. Am. Chem. Soc.  2004,  126:  3416 

3m Xia M. Lu Y.-D. Synlett  2005,  2357 

4a Zhang W. Jia X. Yang Li. Liu Z.-L. Tetrahedron Lett.  2002,  43:  9433 

4b Zhang W. Guo Y. Liu Z. Jin X. Yang Li. Liu Z.-L. Tetrahedron  2005,  61:  1325 

5 Yadav JS. Reddy BVS. Sadasiv K. Reddy PSR. Tetrahedron Lett.  2002,  43:  3853 

6a Kobayashi S. Nagayama S. J. Am. Chem. Soc.  1996,  118:  8977 

6b Kiselyov A. Smith L. Virgilio A. Armstrong RW. Tetrahedron  1998,  54:  7987 

6c Kobayashi S. Akiyama R. Pure Appl. Chem.  2001,  73:  1103 

7 Powell DA. Batey RA. Tetrahedron Lett.  2003,  44:  7569 

8a Dilman AD. Loffe SL. Chem. Rev.  2003,  103:  733 

8b Lee PH. Seomoon D. Lee K. Heo Y. J. Org. Chem.  2003,  68:  2510 

8c Wang L.-S. Hollis TK. Org. Lett.  2003,  14:  2543 

8d Liu Y. Xu X. Zhang Y. Tetrahedron  2004,  60:  4867 

8e Sabitha G. Reddy GSK. Reddy KB. Yadav JS. Synthesis  2004,  263 

8f Sabitha S. Reddy KS. Reddy GSK. Fatima N. Yadav JS. Synlett  2005,  2347 

8g Barga AL. Vargas F. Sehnem JA. Barga RC. J. Org. Chem.  2005,  70:  9021 

8h Xu L.-W. Xia C.-G. Synthesis  2004,  2191 

9 Wang T. Zhang Z. Meanwell NA. Tetrahedron Lett.  1999,  40:  6745 

10 Tsuji R. Nakagawa M. Nishida A. Tetrahedron: Asymmetry  2003,  14:  177 

11

General Procedure for the Synthesis of Pyrano- and Furanoquinolines 8a and 8b.
A mixture of aldehyde 5 (1 mmol), aniline 6 (1.2 mmol), olefin 7 (1.2 mmol) and TMSCl (20 mol%) in MeCN (1 mL) was stirred at r.t. for an appropriate time (Table [2] ). After completion of the reaction (monitored by TLC), the reaction mixture diluted with EtOAc (25 mL) and washed with H₂O (2 × 20 mL) followed by brine (2 × 15 mL). The organic layer was dried over anhyd MgSO₄, followed by evaporation of solvent to obtain the crude product. Pure product 8 was obtained by flash column chromatography on silica gel using eluent (hexane-EtOAc, 95:5).
Synthesis of Pyranoquinolines 11a and 11b.
A mixture of aniline 2 (1 mmol), 3,4-dihydro-2H-pyran (3, 2.2 mmol) and TMSCl (20 mol%) in MeCN (1 mL) was stirred at r.t. for 3 h. The products were obtained as above.
Compound 8a from Table 2, Entry 17.
White solid, mp 108-110 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.78-1.81 (1 H, m), 2.30-2.33 (1 H, m), 2.80-2.83 (1 H, m), 3.78-3.81 (2 H, m), 3.96 (1 H, br s), 4.95 (1 H, d, J = 2.6 Hz), 5.25 (1 H, d, J = 7.6 Hz), 6.58 (1 H, d, J = 8.0 Hz), 6.84 (1 H, t, J = 7.4 Hz), 7.04-7.06 (3 H, m), 7.24 (1 H, d, J = 5.2 Hz), 7.34 (1 H, d, J = 7.2 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 145.36, 144.30, 129.97, 128.26, 126.53, 124.12, 123.95, 122.61, 119.45, 114.85, 75.61, 66.50, 53.53, 45.85, 25.07. MS (70 eV): m/z (%) = 258 (8) [M + 1]⁺, 257 (55) [M⁺], 212 (100), 178 (25), 130 (23), 115 (22), 91 (25), 77 (28). HRMS: m/z calcd for C₁₅H₁₅NOS: 257.0874; found: 257.0869.
Compound 8b from Table 2, Entry 17.
White solid, mp 146-148 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.86-1.89 (1 H, m), 2.12-2.16 (1 H, m), 2.45-2.48 (1 H, m), 3.85-3.89 (1 H, m), 4.04-4.08 (1 H, m), 4.14 (1 H, d, J = 11.0 Hz), 4.31 (1 H, br s), 4.60 (1 H, d, J = 4.6 Hz), 6.65 (1 H, d, J = 8.0 Hz), 6.84 (1 H, t, J = 7.4 Hz), 6.99-7.16 (3 H, m), 7.29-7.40 (2 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 145.34, 144.63, 131.07, 128.90, 126.41, 125.80, 125.27, 120.05, 118.75, 114.79, 76.02, 65.15, 53.47, 44.72, 29.03.
Compound 8a from Table 2, Entry 18. White solid, mp 155-156 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.55-1.58 (4 H, m), 2.18-2.22 (1 H, m), 3.40-3.43 (1 H, m), 3.55-3.59 (1 H, m), 4.11-4.14 (1 H, m), 4.96 (1 H, d, J = 2.6 Hz), 5.29 (1 H, d, J = 5.6 Hz), 6.10 (1 H, d, J = 8.2 Hz), 6.84 (1 H, t, J = 7.4 Hz), 7.03-7.08 (3 H, m), 7.23 (1 H, d, J = 3.4 Hz), 7.43 (1 H, d, J = 7.6 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 144.33, 144.28, 127.75, 127.29, 126.41, 123.61, 123.50, 119.84, 118.46, 114.27, 60.32, 55.35, 39.31, 25.07, 18.12. MS (70 eV): m/z (%) = 272 (5) [M + 1]⁺, 271 (28) [M⁺], 212 (100), 178 (20), 130 (22), 91 (20), 77 (22), 70 (24). HRMS: m/z calcd for C₁₆H₁₇NOS: 271.1031; found: 271.1025.
Compound 8b from Table 2, Entry 18.
White solid, mp 135-137 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.35-1.37 (1 H, m), 1.61-1.83 (3 H, m), 2.02-2.06 (1 H, m), 3.70 (1 H, t), 4.07 (1 H, d, J = 9.8 Hz), 4.37 (1 H, d, J = 2.6 Hz), 5.03 (1 H, d, J = 10.6 Hz), 6.52 (1 H, d, J = 8.2 Hz), 6.73 (1 H, t, J = 7.4 Hz), 6.95-6.97 (3 H, m), 7.21-7.24 (2 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 146.04, 144.01, 130.70, 129.21, 126.25, 125.27, 124.89, 120.67, 117.79, 114.24, 68.64, 50.58, 40.12, 24.05, 21.80.
Compound 8a from Table 2, Entry 19. Pale yellow solid, mp 75-77 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.85-1.88 (1 H, m), 2.22-2.26 (1 H, m), 2.96-2.99 (1 H, m), 3.78-3.82 (2 H, m), 3.89 (1 H, br s), 4.69 (1 H, d, J = 3.0 Hz), 5.23 (1 H, d, J = 7.6 Hz), 6.26-6.36 (2 H, m), 6.60 (1 H, d, J = 8.0 Hz), 6.83 (1 H, t, J = 7.2 Hz), 7.10 (1 H, t, J = 7.6 Hz), 7.36-7.39 (2 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 154.80, 144.34, 141.60, 130.05, 128.31, 122.58, 119.31, 114.82, 110.19, 105.63, 75.36, 66.42, 51.48, 42.24, 25.25. MS (70 eV): m/z (%) = 242 (9) [M + 1⁺], 241 (55) [M⁺], 196 (100), 178 (25), 167 (25), 130 (22), 91 (18), 77 (27). HRMS: m/z calcd for C₁₅H₁₅NO₂: 241.1103; found: 241.1097.
Compound 8b from Table 2, Entry 19.
Pale yellow solid, mp 62-64 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.83-1.86 (1 H, m), 2.12-2.16 (1 H, m), 2.63-2.65 (1 H, m), 3.84-3.87 (1 H, m), 4.01-4.05 (2 H, m), 4.29 (1 H, br s), 4.61 (1 H, d, J = 5.0 Hz), 6.34-6.38 (2 H, m), 6.63 (1 H, d, J = 8.0 Hz), 6.80 (1 H, t, J = 7.2 Hz), 7.13 (1 H, t, J = 7.2 Hz), 7.40-7.43 (2 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 154.50, 144.40, 142.27, 130.97, 128.84, 119.99, 118.59, 114.85, 110.17, 107.41, 75.72, 65.21, 51.08, 40.66, 29.10.
Compound 8a from Table 2, Entry 20.
Brown solid, mp 151-152 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.44-1.60 (4 H, m), 2.30-2.40 (1 H, m), 3.40-3.51 (2 H, m), 3.89-4.02 (1 H, m), 4.71 (1 H, d, J = 2.3 Hz), 5.25 (1 H, d, J = 5.6 Hz), 6.29-6.32 (1 H, m), 6.36-6.40 (1 H, m), 6.62 (1 H, d, J = 8.0 Hz), 6.83 (1 H, t, J = 6.6 Hz), 7.08 (1 H, t, J = 6.4 Hz), 7.43 (2 H, d, J = 8.6 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 154.03, 144.40, 141.60, 128.09, 127.69, 120.08, 118.59, 114.50, 110.16, 105.98, 71.80, 60.65, 53.74, 36.22, 25.28, 18.76. MS (70 eV): m/z (%) = 256 (7) [M + 1⁺], 255 (42) [M⁺], 196 (100), 167 (23), 130 (33), 91 (15), 81 (24), 77 (25), 70 (20). HRMS: m/z calcd for C₁₆H₁₇NO₂: 255.1259; found: 255.1254.
Compound 8b from Table 2, Entry 20.
Pale brown solid, mp 92-94 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.40-1.43 (1 H, m), 1.51-1.54 (1 H, m), 1.74-1.78 (2 H, m), 2.20-2.24 (1 H, m), 3.64-3.69 (1 H, m), 4.01-4.05 (1 H, m), 4.40 (1 H, d, J = 3.0 Hz), 4.81 (1 H, d, J = 10.6 Hz), 6.31-6.35 (2 H, m), 6.53 (1 H, d, J = 8.0 Hz), 6.69 (1 H, t, J = 7.4 Hz), 7.06 (1 H, t, J = 7.6 Hz), 7.21 (1 H, d, J = 7.6 Hz), 7.38 (1 H, s). ¹³C NMR (50 MHz, CDCl₃): δ = 155.01, 143.97, 142.00, 130.46, 129.09, 120.45, 117.64, 114.33, 110.04, 107.32, 73.89, 67.90, 48.84, 36.96, 24.18, 22.03.
Compound 8a from Table 2, Entry 23. Pale yellow solid, mp 170-172 °C. ¹H NMR (200 MHz, CDCl₃): δ = 0.92-0.96 (2 H, m), 1.19-1.29 (3 H, m), 1.40-1.50 (3 H, m), 1.58-1.65 (1 H, m), 1.67-1.71 (2 H, m), 1.76-1.83 (3 H, m), 1.90-1.93 (1 H, m), 2.18-2.22 (1 H, m), 2.97 (1 H, dd, J = 7.6, 2.0 Hz), 3.38-3.45 (1 H, m), 3.56-3.60 (1 H, m), 5.02 (1 H, d, J = 5.5 Hz), 6.51 (1 H, d, J = 8.0 Hz), 6.72 (1 H, t, J = 7.3 Hz), 7.03 (1 H, t, J = 7.1 Hz), 7.36 (1 H, d, J = 7.6 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 144.95, 127.81, 127.40, 120.06, 117.68, 113.91, 72.56, 60.58, 59.15, 37.45, 33.15, 30.20, 28.46, 26.27, 25.90, 25.83, 25.52, 17.93.
Compound 8b from Table 2, Entry 23. Pale yellow solid, mp 115-117 °C. ¹H NMR (200 MHz, CDCl₃): δ = 1.13-1.20 (5 H, m), 1.49-1.53 (2 H, m), 1.64-1.84 (8 H, m), 1.95-1.97 (1 H, m), 3.23-3.27 (1 H, m), 3.63-3.69 (1 H, m), 3.83-3.87 (1 H, m), 4.50 (1 H, d, J = 3.5 Hz), 6.51 (1 H, d, J = 8.0 Hz), 6.64 (1 H, t, J = 7.8 Hz), 7.04 (1 H, t, J = 7.8 Hz), 7.24 (1 H, d, J = 7.2 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 144.85, 129.71, 128.73, 119.91, 116.78, 114.05, 73.35, 66.12, 55.60, 38.61, 33.22, 30.23, 26.81, 26.71, 26.56, 26.28, 24.18, 23.35.