One-Pot, Three-Component Synthesis of a Library of New Pyrrolo[1,2-a]quinoline Derivatives

Abstract

The synthesis of a library of pyrrolo[1,2-a]quinoline derivatives 4-33 was performed by an efficient one-pot, three-component reaction from quinolines 1a-c, 2-bromoacetophenones 2 and non-symmetrical acetylenic dipolarophiles 3a-c in 1,2-epoxypropane as both reaction medium and HBr scavenger. As this approach was unsuccessful in the case of DMAD, a different method was used for the synthesis of pyrrolo[1,2-a]quinolines 35-44. The structural features of the cycloadducts 19 and 44 were investigated by X-ray analysis.

Key words

1,3-dipolar cycloaddition - N-ylide - pyrrolo[1,2-a]quinoline - multicomponent reaction

References and Notes

• 1a Butin AV. Tsiunchik FA. Abaev VT. Bosikova KV. ARKIVOC  2009,  (iv):  79 
• 1b Liu X.-Y. Che C.-M. Angew. Chem. Int. Ed.  2008,  47:  3805 
• 1c Cho SH. Chang S. Angew. Chem. Int. Ed.  2008,  47:  2836 
• 1d Nair V. Devipriya S. Suresh E. Synthesis  2008,  551 
• 1e Jones CP. Anderson KW. Buchwald SL. J. Org. Chem.  2007,  72:  7968 
• 1f Kobayashi K. Takanohashi A. Himei Y. Sano T. Fukamachi S. Morikawa O. Konishi H. Heterocycles  2007,  7:  2717 
• 1g Liu Y. Song Z. Yan B. Org. Lett.  2007,  9:  409 
• 1h McNab H. Reed D. Tipping ID. Tyas RG. ARKIVOC  2007,  (xi):  85 
• 1i Seregin IV. Ryabova V. Gevorgyan V. J. Am. Chem. Soc.  2007,  129:  7742 
• 1j Hulcoop DG. Lautens M. Org. Lett.  2007,  9:  1761 
• 1k Cadogan JIG. Hewage CM. McNab H. MacPherson AD. Nicolson IS. Reed D. Sadler IH. Org. Biomol. Chem.  2006,  4:  2446 
• 1l Fujita R. Hoshino M. Tomishava H. Chem. Pharm. Bull.  2006,  54:  334 
• 1m Kobayashi K. Takanohashi A. Hashimoto K. Morikawa O. Konishi H. Tetrahedron  2006,  62:  10379 
• 1n Tverdokhlebov AV. Gorulya AP. Tolmachev AA. Kostyuk AN. Chernega AN. Rusanov EB. Synthesis  2005,  2161 
• 1o Komatsu M. Kasano Y. Yamaoka S. Minakata S. Synthesis  2003,  1398 
• 1p Fürstner A. Mamane V. J. Org. Chem.  2002,  67:  6264 
• 2a Cappelli A. Giuliani G. Anzini M. Riitano D. Giorgi G. Vomero S. Bioorg. Med. Chem.  2008,  16:  6850 
• 2b Anderson WK. De Ruiter J. Heider AR. J. Org. Chem.  1985,  50:  722 
• 2c Ager IR. Barnes AC. Danswan GW. Hairsine PW. Kay DP. Kennewell PD. Matharu SS. Miller P. Robson P. Rowlands DA. Tully WR. Westwood R. J. Med. Chem.  1988,  31:  1098 
• 2d Anderson WK. Heider AR. Raju N. Yucht JA. J. Med. Chem.  1988,  31:  2097 
• 2e Cai SX, Drewe JA, Jiang S, Kasibhatla S, Kuemmerle JD, Sirisoma NS, and Zhang HZ. inventors; WO  2004055163. 
• 2f Hayford A, and Kaloko J. inventors; US Pat  20070293456. 
• 2g Jones DT. Harris AL. Mol. Cancer Ther.  2007,  5:  2193 
• 3a Dürr H. Gross H. Zils K.-D. Hauck G. Klauck G. Hermann H. Chem. Ber.  1983,  116:  3915 
• 3b Kelderman E. Verboom W. Engbersen JFJ. Harkema S. Heesink GJT. Lehmusvaara E. Van Hulst NF. Reinhoudt DN. Derhaeg L. Persoons A. Chem. Mater.  1992,  4:  626 
• 3c Nakatsuka M, and Shimamura T. inventors; JP  2000277263. 
• 3d Ahmed SA. J. Phys. Org. Chem.  2006,  19:  402 
• 4 Toyuyama T. Unoyama D. Brown G. Daly JW. Witkop B. Helv. Chim. Acta  1974,  57:  2597 
• 5a Pearson WH. Fang W. J. Org. Chem.  2000,  65:  7158 
• 5b Wei L.-L. Hsung RP. Sklenicka HM. Gerasyuto AI. Angew. Chem. Int. Ed.  2001,  40:  1516 
• 5c Santarem M. Vanucci-Bacqué C. Lhommet G. J. Org. Chem.  2008,  73:  6466 
• 6 El-Sayed II. El-Sayed HE.-A. Adv. Heterocycl. Chem.  2003,  84:  83 
• 7a Henrick CA. Ritchie E. Taylor WC. Aust. J. Chem.  1967,  20:  2467 
• 7b Tewari RS. Dubey AK. Misra NK. J. Chem. Eng. Data  1982,  27:  101 
• 7c Tewari RS. Dixit PD. Dubey AK. J. Chem. Eng. Data  1983,  28:  283 
• 7d Wei X. Hu Y. Li T. Hu H. J. Chem. Soc., Perkin Trans. 1  1993,  2487 
• 7e Dumitrascu F. Mitan CI. Drãghici C. Cãproiu MT. Rãileanu D. Tetrahedron Lett.  2001,  42:  8379 
• 7f Wu K. Chen Q.-Y. Synthesis  2003,  35 
• 7g Yue G. Wan Y. Song S. Yang G. Chen Z. Bioorg. Med. Chem. Lett.  2005,  15:  453 
• 8a Dömling A. Chem. Rev.  2006,  106:  17 
• 8b Multicomponent Reactions   Zhu J. Bienayme H. Wiley-VCH; Weinheim: 2005. 
• 8c Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  3180 
• 8d Xie C. Zhang Y. Xua P. Synlett  2008,  3115 
• 8e Olimpieria F. Volonterio A. Zanda M. Synlett  2008,  3016 
• 8f Krasavin M. Parchinsky V. Synlett  2008,  645 
• 8g Nguyen R.-V. Li C.-J. Synlett  2008,  1897 
• 8h Sotoca E. Constantieux T. Rodriguez J. Synlett  2008,  1313 
• 8i Willy B. Müller TJJ. ARKIVOC  2008,  (i):  195 
• 8j Yavari I. Souri S. Sirouspour M. Synlett  2008,  1633 
• 8k El Kaim L. Gizolme M. Grimaud L. Synlett  2007,  227 
• 8l Stonehouse JP. Chekmarev DS. Ivanova NV. Lang S. Pairaudeau G. Smith N. Stocks MJ. Sviridov SI. Utkina LM. Synlett  2008,  100 
• 13a Tayyari F. Wood DE. Fanwick PE. Sammelson RE. Synthesis  2008,  279 
• 13b Yan B. Zhou Y. Zhang H. Chen J. Liu Y. J. Org. Chem.  2007,  72:  7783 

9

Synthesis of Pyrrolo[1,2- a ]quinolines 4-33; General Procedure: Quinoline 1 (5 mmol), phenacyl bromide 2 (5 mmol) and non-symmetrical acetylene 3 (ethyl propiolate, 3-butyn-2-one or benzoylacetylene; 7 mmol) in 1,2-epoxy-propane (40 mL) were stirred at room temperature for 30 h. The solvent was partly removed by evaporation, then methanol (10 mL) was added and the mixture was left overnight at room temperature. The solid was filtered, washed with a mixture of MeOH-Et₂O (1:1) and recrystallised from CHCl₃-MeOH. Ethyl 1-(4-Methyl-benzoyl)-7-methyl-pyrrolo[1,2- a ]quinoline-3-carboxy-late (19): Yellow crystals with mp 173-175 ˚C were obtained by recrystallization from CHCl₃-MeOH. Yield: 54%; Anal. Calcd for C₂₄H₂₁NO₃: C, 77.61; H, 5.70; N, 3.77. Found: C, 77.91; H, 5.94; N, 3.98. FT-IR: 1617, 1654, 1704, 2976 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.39 (t, J = 7.1 Hz, 3 H, MeCH₂), 2.47 (s, 3 H, MeAr), 2.50 (s, 3 H, 7-Me), 4.39 (q, J = 7.1 Hz, 2 H, CH₂), 7.35-7.38 (m, 3 H, H-8, H-3′, H-5′), 7.57 (d, J = 2.1 Hz, 1 H, H-6), 7.62 (s, 1 H, H-2), 7.60 (d, J = 9.3 Hz, 1 H, H-5), 7.87 (d, J = 8.9 Hz, 1 H, H-9), 7.95 (d, J = 8.8 Hz, 2 H, H-2′, H-6′), 8.23 (d, J = 9.3 Hz, 1 H, H-4). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.5 (MeCH₂), 20.8, 21.6 (7-Me, MeAr), 59.9 (OCH₂), 107.4 (C-3), 117.6 (C-4), 119.9 (C-9), 125.1, 128.0, 131.4, 135.9, 139.7 (C-1, C-3a, C-5a, C-9a, C-7), 128.3 (C-6), 129.4 (C-5), 128.6 (C-8), 129.1 (C-3′, C-5′), 129.9 (C-2), 130.2 (C-2′, C-6′), 135.1 (C-1′), 143.4 (C-4′), 164.1 (COO), 184.8 (COAr).

10

Synthesis of Pyrrolo[1,2- a ]quinolines 35-44; General Procedure: Quaternary salt 34a-j (5 mmol) and DMAD or DEAD (7 mmol) in 1,2-epoxypropane (40 mL) were stirred at room temperature for 24 h. The solvent was partly removed by evaporation, then methanol (10 mL) was added and the mixture was left overnight at room temperature. The solid was filtered, washed on filter with a mixture of MeOH-Et₂O (1:1) and recrystallised from CHCl₃-MeOH. Dimethyl 1-(3-Bromobenzoyl)-7-methylpyrrolo[1,2- a ]quinoline-2,3-dicarboxylate (39): Yellow crystals with mp 192-194 ˚C were obtained by recrystallization from MeOH-CHCl₃. Yield: 44%. Anal. Calcd for C₂₃H₁₈BrNO₃: C, 63.32; H, 4.16; Br, 18.31; N, 3.21. Found: C, 63.44; H, 4.39; Br, 18.66; N, 3.56. FT-IR: 1617, 1654, 1704, 2976 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.54 (s, 3 H, 7-Me), 3.50, 3.90 (s, 6 H, 2-CO₂Me, 3-CO₂Me), 7.27 (dd, J = 8.8, 2.1 Hz, 1 H, H-8), 7.36 (t, J = 7.8 Hz, 1 H, H-5′), 7.51 (d, J = 8.9 Hz, 1 H, H-9), 7.57 (d, J = 2.1 Hz, 1 H, H-6), 7.58 (d, J = 9.3 Hz, 1 H, H-5), 7.73-7.77 (m, 1 H, H-4′), 7.84-7.87 (m, 1 H, H-6′), 8.15 (t, J = 2.0 Hz, 1 H, H-2′), 8.23 (d, J = 9.3 Hz, 1 H, H-4). ^¹³C NMR (75 MHz, CDCl₃): δ = 20.9 (7-Me), 51.7, 52.8 (CO₂CH₃), 105.5 (C-3), 117.7 (C-4), 118.8 (C-9), 122.7 (C-3′), 125.3, 127.2, 128.8, 131.2, 135.7, 140.3 (C-1, C-3a, C-5a, C-9a, C-7, C-2), 128.4 (C-6), 128.5 (C-2′), 128.9 (C-5), 130.2 (C-5′), 130.4 (C-8), 132.7 (C-2′), 136.5 (C-4′), 139.5 (C-1′), 163.5, 165.1 (2 × COO), 185.7 (COAr).

11

X-ray crystal data for 19: C₂₄H₂₁NO₃; yellow plate; M = 371.42; triclinic; P(-1); a = 9.3086 (5) Å, b = 10.4631 (5) Å, c = 10.9389 (5) Å, α = 91.153 (2)˚, β = 112.900(3)˚, γ = 104.195 (3)˚; V = 943.48 (7) Å^³; Z = 2; T = 173 (2) K; F ₀₀₀  = 392; R1 = 0.0428, wR2 = 0.1170. The CCDC deposition number: 718544.

12

X-ray crystal data for 44: C₂₈H₂₇NO₇; pale-yellow plate; M = 489.51; triclinic; P(-1); a = 7.5730 (3) Å, b = 13.0161 (3) Å, c = 13.4416 (6) Å, α = 97.269 (2)˚, β = 104.946 (2)˚, γ = 102.512 (3)˚; V = 1226.13 (8) Å^³; Z = 2; T = 173 (2) K; F ₀₀₀  = 516; R1 = 0.0414, wR2 = 0.1132. The CCDC depo-sition number: 718545.