The Baylis-Hillman Bromides as Versatile Synthons: A Facile One-Pot Synthesis of Indolizine and Benzofused Indolizine Frameworks

Abstract

A facile one-pot synthesis of indolizine, benzofused indolizines {pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]isoquinoline} derivatives from the Baylis-Hillman (B-H) bromides, via an interesting strategy involving 1,5-cyclization of nitrogen ylides has been described.

Key words

Baylis-Hillman bromides - 1,5-cyclization strategy - indolizines - benzofused indolizines - quinoline - isoquinoline

References and Notes

• 1 Comprehensive Heterocyclic Chemistry   Vol. 4:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.476 
• 2a Lotter ANC. Pathak R. Sello TS. Fernandes MA. Van Otterlo WAL. de Koning CB. Tetrahedron  2007,  63:  2263 
• 2b Ewing J. Hughes GK. Ritchie E. Taylor WC. Nature (London)  1952,  169:  618 
• 3a Gundersen LL. Charnock C. Negussie AH. Rise F. Teklu S. Eur. J. Pharm. Sci.  2007,  30:  26 
• 3b Wiede T. Arve L. Prinz H. Waldmann H. Kessler H. Bioorg. Med. Chem. Lett.  2006,  16:  59 
• 3c Sonnet P. Dallemagne P. Guillon J. Enguehard C. Stiebing S. Tanguy J. Bureau R. Rault S. Auvray P. Moslemi S. Sourdaine P. Seralini GE. Bioorg. Med. Chem. Lett.  2000,  8:  945 
• 3d Ostby OB. Dalhus B. Gundersen LL. Rise F. Bast A. Haenen GRMM. Eur. J. Org. Chem.  2000,  3763 
• 3e Gubin J. Vogelaer HD. Inion H. Houben C. Lucchetti J. Mahaux J. Rosseels G. Peiren M. Clinet M. Polster P. Chatelain P. J. Med. Chem.  1993,  36:  1425 
• 3f Bermudez J. Fake CS. Joiner GF. Joiner KA. King FD. Miner WD. Sanger GJ. J. Med. Chem.  1990,  33:  1924 
• 3g Maryanoff BE. Vaught JL. Shank RP. McComsey DF. Costanzo MJ. Nortey SO. J. Med. Chem.  1990,  33:  2793 
• 3h Anderson WK. Heider AR. Raju N. Yucht JA. J. Med. Chem.  1988,  31:  2097 
• 4a Zhu L. Vimolratna M. Brown SP. Medina JC. Tetrahedron Lett.  2008,  49:  1768 
• 4b Hardin AR. Sarpong R. Org. Lett.  2007,  9:  4547 
• 4c Chuprakov S. Gevorgyan V. Org. Lett.  2007,  9:  4463 
• 4d Smith CR. Bunnelle EM. Rhodes AJ. Sarpong R. Org. Lett.  2007,  9:  1169 
• 4e Przewloka T. Chen S. Xia Z. Li H. Zhang S. Chimmananmada D. Kostik E. James D. Koya K. Sun L. Tetrahedron Lett.  2007,  48:  5739 
• 4f Seregin IV. Gevorgyan V. J. Am. Chem. Soc.  2006,  128:  12050 
• 4g Tielmann P. Hoenke C. Tetrahedron Lett.  2006,  47:  261 
• 4h Marchalin S. Baumlova B. Baran P. Oulyadi H. Daich A. J. Org. Chem.  2006,  71:  9114 
• 4i Kaloko J. Hayford A. Org. Lett.  2005,  7:  4305 
• 4j Bora U. Saikia A. Boruah RC. Org. Lett.  2003,  5:  435 
• 4k Katritzky AR. Qiu G. Yang B. He HY. J. Org. Chem.  1999,  64:  7618 
• 4l Troll T. Beckel H. Bohm CL. Tetrahedron  1997,  53:  81 
• 4m Bonneau R. Romashin YN. Liu MTH. MacPherson SE. J. Chem. Soc., Chem Commun.  1994,  509 
• 4n Eberbach W. Maier W. Tetrahedron Lett.  1989,  30:  5591 
• 4o Matsumoto K. Uchida T. Konshi H. Watanabe Y. Aoyama K. Asahi M. Chem. Lett.  1987,  807 
• 4p Andeson WK. DeRuiter J. Heider AR. J. Org. Chem.  1985,  50:  722 
• 4q Pohjala E. Tetrahedron Lett.  1972,  13:  2585 
• 4r Tamura Y. Tsujimoto N. Sumida Y. Ikeda M. Tetrahedron  1972,  28:  21 
• 4s Basketter N. Plunkett AO. J. Chem. Soc., Chem. Commun.  1971,  1578 
• 4t Krock FW. Krohnke F. Chem. Ber.  1971,  104:  1645 
• 5a Basavaiah D. Roy S. Org. Lett.  2008,  10:  1819 
• 5b Basavaiah D. Reddy RJ. Org. Biomol. Chem.  2008,  6:  1034 
• 5c Basavaiah D. Aravindu K. Org. Lett.  2007,  9:  2453 
• 5d Basavaiah D. Reddy KR. Org. Lett.  2007,  9:  57 
• 5e Basavaiah D. Reddy RJ. Rao JS. Tetrahedron Lett.  2006,  47:  73 
• 5f Basavaiah D. Rao JS. Reddy RJ. Rao AJ. Chem Commun.  2005,  2621 
• 5g Basavaiah D. Rao JS. Reddy RJ. J. Org. Chem.  2004,  69:  7379 
• 5h Basavaiah D. Satyanarayana T. Chem Commun.  2004,  32 
• 5i Basavaiah D. Sharada DS. Veerendhar A. Tetrahedron Lett.  2004,  45:  3081 
• 5j Basavaiah D. Kumaragurubaran N. Sharada DS. Reddy RM. Tetrahedron  2001,  57:  8167 
• 5k Basavaiah D. Sreenivasulu B. Rao JS. Tetrahedron Lett.  2001,  42:  1147 
• 5l Basavaiah D. Satyanarayana T. Org. Lett.  2001,  3:  3619 
• 6a Basavaiah D. Rao AJ. Tetrahedron Lett.  2003,  44:  4365 
• 6b Basavaiah D. Rao AJ. Chem Commun.  2003,  604 
• For leading reviews on the Baylis-Hillman reaction, see:
• 7a Singh V. Batra S. Tetrahedron  2008,  64:  4511 
• 7b Basavaiah D. Rao KV. Reddy RJ. Chem. Soc. Rev.  2007,  36:  1581 
• 7c Masson G. Housseman C. Zhu J. Angew. Chem. Int. Ed.  2007,  46:  4614 
• 7d Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev.  2003,  103:  811 
• 7e Ciganek E. Organic Reactions   Vol. 51:  Paquette LA. Wiley; New York: 1997.  p.201 
• 7f Basavaiah D. Dharma Rao P. Suguna Hyma R. Tetrahedron  1996,  52:  8001 
• 7g Drewes SE. Roos GHP. Tetrahedron  1988,  44:  4653 
• 8a Zhang Y. Liu Y.-K. Kang T.-R. Hu Z.-K. Chen Y.-C. J. Am. Chem. Soc.  2008,  130:  2456 
• 8b Winbush SM. Mergott DJ. Roush WR. J. Org. Chem.  2008,  73:  1818 
• 8c Shi M. Liu X.-G. Org. Lett.  2008,  10:  1043 
• 8d Amarante GW. Rezende P. Cavallaro M. Coelho F. Tetrahedron Lett.  2008,  49:  3744 
• 8e Davoust M. Cantagrel F. Metzner P. Briere J.-F. Org. Biomol. Chem.  2008,  6:  1981 
• 8f Utsumi N. Zhang H. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2007,  46:  1878 
• 8g Shafiq Z. Liu L. Liu Z. Wang D. Chen Y.-J. Org. Lett.  2007,  9:  2525 
• 8h Chuprakov S. Malyshev DA. Trofimov A. Gevorgyan V. J. Am. Chem. Soc.  2007,  129:  14868 
• 8i Pigge FC. Dhanya R. Hoefgen ER. Angew. Chem. Int. Ed.  2007,  46:  2887 
• 8j Myers EL. Butts CP. Aggarwal VK. Chem. Commun.  2006,  4434 
• 8k Dadwal M. Mohan R. Panda D. Mobin SM. Namboothiri INN. Chem. Commun.  2006,  338 
• 8l Krafft ME. Wright JA. Chem. Commun.  2006,  2977 
• 8m Rao JS. Briere J.-F. Metzner P. Basavaiah D. Tetrahedron Lett.  2006,  47:  3553 
• 8n Berkessel A. Roland K. Neudorfl JM. Org. Lett.  2006,  8:  4195 
• 8o Wang J. Li H. Yu X. Zu L. Wang W. Org. Lett.  2005,  7:  4293 
• 8p Turki T. Villieras J. Amri H. Tetrahedron Lett.  2005,  46:  3071 
• 8q Kabalka GW. Venkataiah B. Tetrahedron Lett.  2005,  46:  7325 
• 8r Gowri Shankar S. Lee KY. Lee CG. Kim JN. Tetrahedron Lett.  2004,  45:  6141 
• 8s Jellerichs BG. Kong JR. Krische MJ. J. Am. Chem. Soc.  2003,  125:  7758 
• 8t McDougal NT. Schaus SE. J. Am. Chem. Soc.  2003,  125:  12094 
• 8u Pei W. Wei HX. Li G. Chem. Commun.  2002,  17:  1856 
• 8v Lee WD. Yang KS. Chen K. Chem. Commun.  2001,  1612 
• 8w Basavaiah D. Muthukumaran K. Sreenivasulu B. Synthesis  2000,  545 
• 8x Basavaiah D. Suguna Hyma R. Padmaja K. Krishnamacharyulu M. Tetrahedron  1999,  55:  6971 
• 8y Basavaiah D. Gowriswari VVL. Sarma PKS. Rao PD. Tetrahedron Lett.  1990,  31:  1621 
• 8z Basavaiah D. Gowriswari VVL. Synth. Commun.  1987,  17:  587 
• 9a Bode ML. Kaye PT. J. Chem. Soc., Perkin Trans. 1  1993,  1809 
• 9b Bode ML. Kaye PT. J. Chem. Soc., Perkin Trans. 1  1990,  2612 
• Allyl bromides (as a mixture of E- and Z-isomers) were prepared by treatment of the Baylis-Hillman alcohols with HBr in the presence of H₂SO₄ following the literature procedure. See:
• 10a Buchholz R. Hoffmann HMR. Helv. Chim. Acta  1991,  74:  1213 
• 10b Ameer F. Drewes SE. Emslie ND. Kaye PT. Mann RL. J. Chem. Soc., Perkin Trans. 1  1983,  2293 

11

1-Aza-8-cyano-7-phenylbicyclo[4.3.0]nona-2,4,6,8-tetraene (2a) - Representative Procedure
To 2-(bromomethyl)-3-phenylprop-2-enenitrile [¹0] (1 mmol, 0.222 g) pyridine (3 mL) was added and stirred for 15 min (formation of pyridinium salt was observed as shown by TLC) at r.t. The reaction mixture was diluted with DMF (3 mL) and K₂CO₃ (5 mmol, 0.690 g) was added. The reaction mixture was then heated at 80 ˚C for 3 h and was allowed to cool to r.t. Saturated aq NaCl soln (5 mL) was added and extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layer was dried over anhyd Na₂SO₄. Solvent was evaporated, and the residue, thus obtained, was purified by column chromatography (SiO₂, 5% EtOAc in hexanes) to furnish the pure compound 2a as a colorless solid. Yield 52% (0.114 g); mp 128-130 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 6.60-6.70 (m, 1 H), 6.77-6.86 (m, 1 H), 7.32-7.40 (m, 1 H), 7.46-7.53 (m, 2 H), 7.56-7.68 (m, 3 H), 7.74 (s, 1 H), 7.88 (d, 1 H, J = 7.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 96.94, 113.60, 116.22, 117.46, 118.16, 118.92, 120.05, 125.31, 127.15, 128.67, 129.00, 129.68, 132.56. IR (KBr): ν = 2222 cm^-¹. LC-MS: m/z = 219 [M + H]⁺. Anal. Calcd for C₁₅H₁₀N₂: C, 82.55; H, 4.62; N, 12.84. Found: C, 82.51; H, 4.65; N, 12.70.

12

Detailed X-ray crystallographic data are available from the CCDC, 12 Union road, Cambridge CB2 1EZ, UK; for compounds 2a (CCDC # 693505), 3a (CCDC # 693506), 4a (CCDC # 693507).

13

1-Aza-12-cyano-11-phenyltricyclo[8.3.0.0 ^²,7 ]trideca-2,4,-6,8,10,12-hexaene (3a) - Representative Procedure
To a stirred solution of 2-(bromomethyl)-3-phenylprop-2-enenitrile (1 mmol, 0.222 g) in DMF (3 mL) was added quinoline (2 mmol, 0.258 g) at r.t. After stirring for 1 h (salt formation was observed as evidenced by TLC), K₂CO₃ (5 mmol, 0.690 g) was added and heated for 5 h at 80 ˚C. The reaction mixture was allowed to cool to r.t. and diluted with sat. aq NaCl soln (5 mL) and extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layers were dried over anhyd Na₂SO₄. Solvent was evaporated, and the residue, thus obtained, was purified by column chromatography (SiO₂, 8% EtOAc in hexanes) to furnish the pure compound 3a as a colorless solid. Yield 45% (0.120 g); mp 160-162 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, 1 H, J = 9.6 Hz), 7.34-7.68 (m, 9 H), 7.85 (d, 1 H, J = 8.4 Hz), 8.26 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 96.68, 114.43, 116.19, 117.35, 118.04, 120.39, 122.03, 124.52, 125.64, 127.50, 128.10, 128.84, 128.92, 129.00, 129.05, 132.28, 132.38.
IR (KBr): ν = 2226 cm^-¹. LC-MS: m/z = 269 [M + H]⁺. Anal. Calcd for C₁₉H₁₂N_2: C, 85.05; H, 4.51; N, 10.44. Found: C, 85.11; H, 4.54; N, 10.57.

14

The single crystal X-ray structure revealed the presence of two molecules in the asymmetric unit. For clarity we have shown one molecule in the ORTEP diagram.