Michael-Type Adducts of 3-Carbethoxycoumarins via Diels-Alder Reaction: Tandem Ring Construction of Furopyranochroman-2-one Skeletons

Abstract

Diels-Alder reaction of furan with electron-deficient 3-carbethoxycoumarins gave the Michael-type adducts obtained from the rearrangement of the intermediate Diels-Alder adducts, instead of the Diels-Alder cycloadducts. Trapping of the dipolar intermediate with electron-deficient aromatic aldehydes gave a one-pot access to fused furo[3,2-b]pyranochroman-2-ones with multiple stereogenic centers. Ring opening of the lactone moiety gave a facile route to generate diverse scaffolds.

Key words

coumarins - substituted furans - fused furopyranochroman-2-ones - Michael products - Diels-Alder reaction - MCR - scaffold hopping reaction

References and Notes

• 1 Rastogi RP. Mehrotra BN. In Compendium of Indian Medicinal Plants   Vol. 3:  Rastogi RP. CDRI and P & I Directorate; Lucknow and New Delhi: 1993.  p.273 
• 2a Beletskaya IP. Ganina OG. Tsvetkov AV. Fedorov AYu. Finet JP. Synlett  2004,  2797 
• 2b Darbarwar M. Sundaramurthy V. Synthesis  1982,  337 
• 2c Tollari S. Palmisano G. Cenini S. Cravotto G. Giovenzana GB. Penoni A. Synthesis  2001,  735 
• 2d Borges F. Roleira F. Milhazes N. Santana L. Uriarte E. Curr. Med. Chem.  2005,  12:  887 
• 2e Appendino G. Cravotto G. Toma L. Annunziata R. Palmisano G. J. Org. Chem.  1994,  59:  5556 
• 3a Iinuma M. Tanaka T. Mizuno M. Katsuzaki T. Ogawa H. Chem. Pharm. Bull.  1989,  37:  1813 
• 3b Hsu F.-L. Nonaka G.-I. Nishioka I. Chem. Pharm. Bull.  1985,  33:  3142 
• 4 Takechi M. Tanaka Y. Takehara M. Nonaka G.-I. Nishioka I. Phytochemistry  1985,  24:  2245 
• 5 Tillekeratne LMV. Sherette A. Grossman P. Hupe L. Hupe D. Hudson RA. Bioorg. Med. Chem. Lett.  2001,  11:  2763 
• 6 Dean RM. Adv. Heterocycl. Chem.  1982,  30:  169 
• 7 Vogel P. Cossy J. Plumet J. Arjona O. Tetrahedron  1999,  55:  13521 ; and references cited therein
• 8a Itoh K. Kitoh K. Sera A. Heterocycles  1999,  51:  243 
• 8b Alder RW. Hyland NP. Jeffery JC. Riis-Johannessen T. Riley DJ. Org. Biomol. Chem.  2009,  7:  2704 
• 8c Pinto RMA. Salvador JAR. Le Roux C. Catal. Commun.  2008,  9:  465 
• 8d Sera A. Ohara M. Kubo T. Itoh K. Yamada H. Mikata Y. Kaneko C. Katagiri N. J. Org. Chem.  1988,  53:  5460 
• 8e Avalos M. Babiano R. Bravo JL. Cintas P. Jemenez JL. Palacios JC. Tetrahedron Lett.  1998,  39:  930 
• 10 Girotti R. Marrocchi A. Minuti L. Piermatti O. Pizzo F. Vaccaro L. J. Org. Chem.  2006,  71:  70 
• 11a Itoh K. Kitoh K. Kishimoto S. Can. J. Chem.  2006,  84:  392 
• 11b Itoh K. Kishimoto S. Sagi K. Can. J. Chem.  2009,  87:  760 
• 11c Itoh K. Kishimoto S. New J. Chem.  2000,  347 
• 12 JAGUAR 7.6   2007 ed.:  Shrodinger LLC; Portland: 2007.  http://www.schrodinger.com

9

General Synthetic Procedure for 5a-f To a mixture of 3-carbethoxycoumarin 1a-f (3 mmol) and furan 2 (30 mmol), AlCl₃ catalyst (10 mol%) was added and stirred at r.t. for 20-26 h. After the completion of reaction, excess of furan was distilled off, diluted with H₂O and extracted with CH₂Cl₂ (3 × 25 mL). The combined extracts were dried over anhyd Na₂SO₄, filtered, evaporated under reduced pressure, and purified by column chromatography on silica gel (hexane-EtOAc). This was further recrystal-lized from CH₂Cl₂ to afford 5a-f.
5a: White solid; yield 83%; mp 56-58 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.37-7.30 (m, 3 H), 7.12-7.09 (m, 2 H), 6.28-6.23 (m, 1 H), 6.06 (d, J = 2.4 Hz, 1 H), 4.8 (d, J = 5.6 Hz, 1 H), 4.19-4.12 (m, 3 H), 1.10 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 166.3, 163.7, 150.9, 143.0, 129.5, 128.5, 127.3, 125.0, 121.4, 117.1, 110.4, 108.0, 62.3, 51.1, 38.6, 13.8. FTIR (KBr pellet): 3142, 3123, 2945, 1770, 1732, 1614, 1487, 1460, 1222, 1161, 1012, 935, 756, 661, 570, 524 cm^-¹. HRMS (EI): m/z calcd for C₁₆H₁₄O₅ [M⁺]: 286.0899; found: 286.0903.
5b: White solid; yield 78%; mp 80-82 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.38 (m, 3 H), 7.20 (d, J = 2.4 Hz, 1 H), 6.99-6.93 (m, 1 H), 6.30-6.26 (m, 1 H), 6.10 (d, J = 3.2 Hz, 1 H), 4.18-4.11 (m, 3 H), 1.14 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 166.1, 163.0, 150.2, 150.0, 143.5, 132.7, 131.4, 123.6, 119.0, 117.7, 110.7, 108.4, 62.7, 50.8, 38.4, 14.3. FTIR (neat): 3319, 2982, 1780, 1739, 1602, 1477, 1408, 1371, 1319, 1265, 1222, 1153, 1116, 1072, 1014, 904, 819, 742 cm^-¹. HRMS (EI): m/z calcd for C₁₆H₁₃O₅Br [M⁺]: 365.0023; found: 365.0029.
Synthesis of Diels-Alder Adduct 7 To a mixture of 3-carbethoxycoumarin 1a (1 mmol) and cyclopentadiene (6, 1 mmol) in CH₂Cl₂ (20 mL), AlCl₃ catalyst (10 mol%) was added and stirred at r.t. for 4 h. After the completion of reaction, the reaction mixture was washed with H₂O (2 × 5 mL), brine (5 mL), dried over anhyd Na₂SO₄, concentrated over reduced pressure, and purified by column chromatography to afford 7.
7: Light-yellow liquid; yield 60%. ^¹H NMR (400 MHz, CDCl₃): δ = 7.28-6.96 (m, 4 H), 6.22 (dd, J = 2.8, 5.6 Hz, 1 H), 5.95 (dd, J = 2.8, 5.6 Hz, 1 H), 4.26-4.13 (m, 2 H), 3.79-3.72 (m, 1 H), 3.62 (d, J = 3.6 Hz, 1 H), 2.03 (d, J = 5.6 Hz, 1 H), 1.93 (d, J = 8.0 Hz, 1 H), 1.68 (d, J = 8.0 Hz, 1 H), 1.28-1.23 (m, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 171.0, 165.9, 149.5, 138.1, 136.5, 128.6, 128.1, 124.8, 121.2, 117.0, 62.1, 58.1, 52.9, 50.4, 47.4, 30.9, 13.6. FTIR (neat): 3046, 2924, 2851, 1781, 1739, 1615, 1488, 1456, 1363, 1224, 1157, 1080, 968, 756 cm^-¹. HRMS (EI): m/z calcd for C₁₇H₁₆O₄ [M⁺]: 284.1023; found: 284.1026.
Synthesis of 10a To a mixture of 3-carbethoxycoumarin (1a, 3 mmol) and furan (2, 30 mmol) at 10 ˚C, 3-chlorobenzaldehyde (3 mmol), and AlCl₃ (10 mol%) were added and stirred for 24 h. After completion of the reaction, excess of furan was distilled off, diluted with H₂O, and extracted with CH₂Cl₂ (3 × 25 mL). The combined extracts were dried over anhyd Na₂SO₄, filtered, evaporated under reduced pressure, and purified by column chromatography on silica gel (hexane-EtOAc) to afford 10a.
10a: Colorless liquid; yield 68%. ^¹H NMR (400 MHz, CDCl₃): δ = 7.35-7.11 (m, 9 H), 6.30 (d, J = 8.0 Hz, 1 H), 6.06 (d, J = 4.0 Hz, 1 H), 5.97-5.89 (m, 1 H), 5.35 (s, 1 H), 4.80 (d, J = 4.0 Hz, 1 H), 4.17-4.10 (m, 2 H), 1.13-1.10 (m, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 167.2, 163.7, 151.9, 142.7, 134.4, 128.6, 128.2, 124.8, 123.3, 121.4, 117.3, 110.3, 108.5, 107.8, 106.9, 106.3, 62.3, 51.1, 44.6, 38.6, 34.4, 30.9, 13.8. FTIR (neat): 3121, 3065, 2984, 2926, 1772, 1743, 1591, 1487, 1456, 1371, 1219, 1149, 1107, 1014, 941, 760, 686 cm^-¹. HRMS (EI): m/z calcd for C₂₃H₁₉O₆Cl [M⁺]: 426.0916; found: 426.0913.
10b: Colorless liquid; yield 62%. ^¹H NMR (400 MHz, CDCl₃): δ = 8.21-8.17 (m, 2 H), 7.13-7.09 (m, 7 H), 6.40 (s, 1 H), 6.05 (d, J = 4.0 Hz, 1 H), 5.45 (s, 1 H), 4.15-4.12 (m, 2 H), 3.05-3.01 (m, 2 H), 1.25-1.19 (m, 3 H). ^¹³C NMR (400 MHz, CDCl₃): δ = 166.8, 163.3, 153.0, 152.1, 150.9, 146.3, 142.3, 129.0, 128.3, 127.9, 124.4, 122.8, 121.0, 117.1, 109.0, 107.6, 62.2, 51.0, 44.5, 38.5, 34.6, 33.8, 29.5. FTIR (neat): 3121, 3078, 2921, 2850, 1774, 1740, 1593, 1487, 1456, 1348, 1218, 1148, 1015, 773 cm^-¹. HRMS (EI): m/z calcd for C₂₃H₁₉NO₈ [M⁺]: 437.1124; found: 437.1129.

General Synthetic Procedure for 11a-f To the 3-carbethoxy-4-(2-furanyl)chroman-2-one 5a-f (1 mmol) a solution of NaOH (3 mmol) in H₂O (15 mL) was added and stirred at 80 ˚C for 4 h. The reaction mixture was neutralized with concd HCl and heated at 80 ˚C for 2-4 h (Table  [²] ). The reaction mixture was cooled, extracted with CH₂Cl₂ (3 × 25 mL). The combined extracts were concentrated to dryness and recrystallized from CH₂Cl₂.
11a: White solid; yield 86%; mp 141-143 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.33 (s, 1 H), 7.15-7.06 (m, 2 H), 6.90-6.83 (m, 2 H), 6.30 (d, J = 1.2 Hz, 1 H), 6.12 (d, J = 2.4 Hz, 1 H), 4.84 (t, J = 7.2 Hz, 1 H), 3.23-3.08 (m, 2 H). ^¹³C NMR (400 MHz, CDCl₃/CD₃OD): δ = 174.5, 156.0, 153.8, 141.0, 127.6, 124.5, 119.6, 116.9, 115.5, 109.7, 105.5, 38.0, 34.3. FTIR (KBr pellet): 3443, 3148, 2991, 2604, 1676, 1593, 1502, 1456, 1334, 1307, 1211, 1161, 1093, 1008, 943, 823, 758, 742, 638, 596, 530, 497 cm^-¹. HRMS (EI): m/z calcd for C₁₃H₁₂O₄ [M⁺]: 232.0829; found: 232.0825.