A Direct Synthesis of Octahydropyrrolo[2,1,5-cd]indolizin-6-one Derivatives

Abstract

A direct and highly selective synthesis of octahydropyrrolo[2,1,5-cd]indolizin-6-one derivatives has been accomplished by a double dipolar cycloaddition of olefinic dipolarophiles to p-(di­methylamino)pyridinium ylides.

Key words

pyrrolo[2,1,5-cd]indolizine - cycloaddition - enamines - ylides - hydrogen transfer

References and Notes

• 1a Flitsch W. Comprehensive Heterocyclic Chemistry   Vol. 4:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.478 
• 1b Tominaga Y. Shiroshita Y. Hosomi A. Heterocycles  1988,  27:  2251 
• 1c Bird CW. Tetrahedron  1998,  54:  10179 
• 2a Jørgensen AS. Jacobsen P. Christiansen LB. Bury PS. Kanstrup A. Thorpe SM. Bain S. Nerum L. Wassermann K. Bioorg. Med. Chem. Lett.  2000,  10:  399 
• 2b Jørgensen AS. Jacobsen P. Christiansen LB. Bury PS. Kanstrup A. Thorpe SM. Bain S. Nerum L. Wassermann K. Bioorg. Med. Chem. Lett.  2000,  10:  2383 
• 3a Schröder F. Sinnwell V. Baumann H. Kaib M. J. Chem. Soc., Chem. Commun.  1996,  2139 
• 3b Schröder F. Franke S. Francke W. Baumann H. Kaib M. Pasteels JM. Tetrahedron  1996,  52:  13539 
• 3c Schröder F. Sinnwell V. Baumann H. Kaib M. Francke W. Angew. Chem., Int. Ed. Engl.  1997,  36:  77 
• 3d Schröder F. Francke W. Tetrahedron  1998,  54:  5259 
• 3e Thanh GV. Celerier JP. Lhommet G. Tetrahedron Lett.  1999,  40:  2824 
• 3f Sayah B. Pelloux-Leon N. Vallee Y. J. Org. Chem.  2000,  65:  2824 
• 4a Gibson WK. Leaver D. Roff JE. Cummings CW. J. Chem. Soc., Chem. Commun.  1967,  214 
• 4b Acheson RM. Woollard J. J. Chem. Soc., C  1971,  3296 
• 4c Johnson D. Jones G. J. Chem. Soc., Perkin Trans. 1  1972,  840 
• 4d Pohjala E. Heterocycles  1974,  2:  585 
• 4e Babaev EV. Simonyan VV. Pasichnichenko KY. Nosova VM. Kisin AV. Jug K. J. Org. Chem.  1999,  64:  9057 
• 5a Blake AJ. Dick JW. Leaver D. Strachan P. J. Chem. Soc., Perkin Trans. 1  1991,  2991 
• 5b Kojima H. Kinoshita Y. Matsumura N. Inoue H. J. Heterocycl. Chem.  1991,  28:  2059 
• 5c Kojima H. Yamamoto K. J. Heterocycl. Chem.  1992,  29:  1473 
• 5d Matsumoto K. Uchida T. Yoshida H. Toda M. Kakehi A. J. Chem. Soc., Perkin Trans. 1  1992,  2437 
• 5e Matsuda Y. Kohra S. Katou K. Itou T. Uemura T. Heterocycles  1997,  45:  2223 
• 5f Smith JO. Mandal BK. J. Heterocycl. Chem.  1997,  34:  1441 
• 5g Tominaga Y. Komiya K. Kataoka S. Shigemitsu Y. Hirota T. Sasaki K. Heterocycles  1998,  48:  1985 
• 5h Tominaga Y. Sasaki K. Castle RN.
  J. Heterocycl. Chem.  1998,  35:  1219 
• 6 Hu J. Jiang X. He T. Zhou J. Hu Y. Hu H. J. Chem. Soc., Perkin Trans. 1  2001,  1820 
• 7 Liang F. Hu J. Zhang L. Hu Y. Hu H. J. Heterocycl. Chem.  2001,  38:  853 
• 8a Cui P. Xu L. Shi Z. Gan L. J. Org. Chem.  2011,  76:  4210 
• 8b Cui P. Xu L. Cheng H. Gan L. Tetrahedron  2012,  68:  152 
• 9 Diaz-Gavilan M. Galloway WRJD. O’Connell KMG. Hodkingson JT. Spring DR. Chem. Commun.  2010,  46:  776 
• 10 Snyder SA. ElSohly AM. Kontes F. Angew. Chem. Int. Ed.  2010,  49:  9693 
• 11a Johnson AW. Ylide Chemistry   Academic Press; New York: 1966. 
• 11b Zugravescu I. Petrovanu M. N-Ylide Chemistry   McGraw Hill; New York: 1976. 
• 11c Tufariello JJ. In 1,3-Dipolar Cycloaddition Chemistry   Vol. 2:  Padwa A. Wiley; New York: 1984.  p.83 
• 11d Song P. Lander SW. Leginus JM. Dicken CM. In Advances in Cycloaddition   Vol. 1:  Curran DP. JAI Press; London: 1988.  p.93 
• 12 Tsuge O. Kanemasa S. Adv. Heterocycl. Chem.  1989,  45:  231 
• 13 Surpateanu G. Catteau JP. Karafiloglou P. Lablache-Combier A. Tetrahedron  1976,  32:  2647 ; and references cited therein
• 14 Sarkunam K. Nallu M. J. Heterocycl. Chem.  2005,  42:  5 
• 16a Paulmier C. Lerouge P. Tetrahedron Lett.  1982,  23:  1557 
• 16b Yan M. Zhao W.-J. Huang D. Ji S.-J. Tetrahedron Lett.  2004,  45:  6365 
• 16c Zhao W.-J. Yan M. Huang D. Ji S.-J. Tetrahedron  2005,  61:  5585 
• 17 Kanemasa S. Takenaka S. Watanabe H. Tsuge O. J. Org. Chem.  1989,  54:  420 
• 20a Tsuge O. Kanemasa S. Takenaka S. Chem. Lett.  1985,  355 
• 20b Tsuge O. Kanemasa S. Takenaka S. Bull. Chem. Soc. Jpn.  1985,  58:  3137 

15

Crystal structure data of 5a (CCDC 852712), 5e (CCDC 852711), and 6b (CCDC 852713) are available in the Supporting Information.

18

General Procedure for the Synthesis of Octahydropyrrolo[2,1,5- cd ]indolizin-6-ones To a suspension of p-dimethylaminopyridinium phenacyl bromide (4a, 1.6 g, 5 mmol) in CH₂Cl₂ (75 mL) DBU (0.15 mL, 1 mmol) was added. The reaction slurry turns yellow, and then acrylonitrile (0.65 mL, 10 mmol) was added dropwise. The reaction mixture was stirred at r.t. for 24 h and then evaporated under vacuum. Purification by column chromatography (silica gel, EtOAc-cyclohexane = 1:1) provided compound 5a as colorless crystals in 65% (1.03 g) yield. R _f  = 0.13, 65%, mp 193-195 ˚C. IR (ATR): 2945, 2243, 1726, 1684, 1448, 1223, 1115, 974, 803, 719 cm^-¹. ^¹H NMR (400 MHz, DMSO-d6): δ = 2.45-2.57 (m, 2 H, H7 + H9), 2.70-2.91 (m, 5 H, 2 H2 + H4 + H7 + H9), 3.05 (m, 1 H, H4), 3.49 (m, 1 H, H1), 3.63 (m, 1 H, H5), 3.73 (m, 2 H, H6 + H10), 7.54 (dd, ^³ J = 7.6, 7.6 Hz, 2 H, 2 CH_ar), 7.66 (dd, ^³ J = 7.6, 7.6 Hz, 1 H, CH_ar), 7.95 (d, ^³ J = 7.6 Hz, 2 H, 2 CH_ar). ^¹³C NMR (100 MHz, DMSO-d6): δ = 33.0 (C1), 33.3 (C5), 39.2 (C2), 39.7 (C4), 40.5 (C7), 43.0 (C9), 56.5 (C6), 57.6 (C10), 78.0 (C), 119.7 (CN), 121.5 (CN), 128.6 (CH_ar), 129.3 (CH_ar), 133.0 (CH_ar), 133.1 (C_ar) 197.8 (CO), 205.5 (CO). MS (EI): m/z (%) = 319 (2) [M⁺], 266 (6), 214 (100), 172 (12). Anal. Calcd for C₁₉H₁₇N₃O₂: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.26; H, 5.25; N, 13.33.

19

General Procedure for the Synthesis of Tricyclic Enamines 6 To a suspension of p-dimethylaminopyridinium p-methoxy-phenacyl bromide (4b, 0.443 g, 1 mmol) in CH₂Cl₂ (15 mL) DBU (0.03 mL, 0.2 mmol) was added. The reaction slurry turns yellow, and then acrylonitrile (0.13 mL, 2 mmol) was added dropwise. The reaction mixture was stirred at r.t. for 24 h and then evaporated under vacuum. The residue was purified by crystallization from EtOH providing compound 6b as colorless crystals in 70% (0.26 g) yield; mp 245-246 ˚C. IR (ATR): 2932, 2232, 1665, 1668, 1594, 1484, 1393, 1319, 1266, 1155, 1024, 976, 843, 690 cm^-¹. ^¹H NMR (400 MHz, DMSO-d6): δ = 2.33 (m, 1 H, H2), 2.44-2.58 (m, 3 H, H2 + 2 H4), 2.68 (s, 6 H, 2 CH₃), 2.88 (m, 1 H, H9), 2.99 (m, 1 H, H9), 3.18 (m, 1 H, H1), 3.34-3.40 (m, 1 H, H5), 3.62 (m, 1 H, H10), 3.86 (s, 3 H, OCH₃), 3.89 (m, 1 H, H6), 4.37 (br s, 1 H, H7), 7.01 (d, ^³ J = 7.8 Hz, 2 H, 2 CH_ar), 8.04 (d, ^³ J = 7.8 Hz, 2 H, 2 CH_ar). ^¹³C NMR (100 MHz, DMSO-d6): δ = 29.8 (C9), 32.3 (C1), 33.9 (C5), 39.1 (NCH₃), 39.4 (C2), 40.6 (C4), 55.2 (OCH₃), 57.2 (C6), 60.3 (C10), 78.2 (C3), 91.2 (C7), 113.4 (CH_ar), 119.9 (CN), 121.7 (CN), 126.1 (C_ar), 131.4 (CH_ar), 145.7 (C8), 162.6 (C_ar), 196.7 (CO). MS (EI): m/z (%) = 375 (6) [M⁺ - H], 323 (100), 188 (38), 147 (16), 135 (25). Anal. Calcd for C₂₂H₂₄N₄O₂: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.38; H, 6.67; N, 15.13.