New Pyrrolo[2,1-a]phthalazine Derivatives by One-Pot Three-Component Synthesis

Abstract

The synthesis of the pyrrolo[2,1-a]phthalazine derivatives was performed by an efficient one-pot three-component reaction starting from phthalazine, 2-bromoacetophenones and nonsymmetrical and symmetrical acetylenic dipolarophiles in 1,2-epoxybutane as both reaction medium and HBr scavenger. The structure of the compounds was assigned by IR and NMR spectroscopy.

Key words

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

References and Notes

• 1a Ashton MC, Bridge AW, Dron DI, Fenton G, Lythgoe DJ, and Newton CG. inventors; Eur. Patent Appl., EP  319330.  ; Chem. Abstr. 1989, 111, 232846u
• 1b Caprosu M. Stefanescu E. Ungureanu M. Petrovanu M. Rev. Roum. Chim.  1991,  36:  657 
• 1c Kidena H, Hirayama N, Hotsuta M, Meguro S, Yoshizuka N, Ichinose S, and Nishizawa Y. inventors; Jpn. Kokai Tokkyo Koho Jpn. Patent,  JP0565215.  ; Chem. Abstr. 1993, 119, 34097c
• 1d Cheng Y. Ma B. Wudl F. J. Mater. Chem.  1999,  9:  2183 
• 1e Mitsumori T. Bendikov M. Sedó J. Wudl F. Chem. Mater.  2003,  15:  3759 
• 1f Uff BC. Ghaem-Maghami G. Budhram RS. Wilson CL. Apatu JO. J. Heterocycl. Chem.  1989,  26:  571 
• 1g Butnariu RM. Caprosu MD. Bejan V. Ungureanu M. Poiata A. Tuchilus C. Florescu M. Mangalagiu I. J. Heterocycl. Chem.  2007,  44:  1 
• 1h Dorweiler C. Holderbaum M. Munzmay T. Spang P. Durr H. Kruger C. Raabe E. Chem. Ber.  1988,  121:  843 
• 2a Uff BC. Budhram RS. Synthesis  1978,  206 
• 2b Potts KT. Bordeaux KG. Kuehnling WR. Salsbury RL. J. Org. Chem.  1985,  50:  1677 
• 2c Weidner CH. Michaels FM. Beltman DJ. Montgomery CJ. Wadsworth DH. Briggs BT. Picone ML. J. Org. Chem.  1991,  56:  5594 
• 2d Bridge AW. Hursthouse MB. Lehmann CW. Lythgoe DJ. Newton CG. J. Chem. Soc., Perkin Trans. 1  1993,  1839 
• 2e Siriwardana AI. Nakamura I. Yamamoto Y. J. Org. Chem.  2004,  69:  3202 
• 2f Galin FZ. Sakhautdinov IM. Tukhavatullin OR. Russ. Chem. Bull. Int. Ed.  2007,  53:  2305 
• 3 Sharp JT. Wilson P. Parsons S. Gould RO. J. Chem. Soc., Perkin Trans. 1  2000,  1139 
• 4a Khlebnikov AF. Kostik EI. Kostikov RR. Synthesis  1993,  568 
• 4b Butler RN. Coyne AG. Burke LA. J. Chem. Soc., Perkin Trans. 2  2001,  1781 
• 4c Komatsu M. Kasano Y. Yamaoka S. Minakata S. Synthesis  2003,  1398 
• 4d Dumitrascu F. Mitan CI. Draghici C. Caproiu MT. Raileanu D. Tetrahedron Lett.  2001,  42:  8379 
• 4e Dumitrascu F. Alecu M. Badoiu A. Vuluga D. Rev. Chim. (Bucharest)  2003,  54:  974 
• 4f Dumitrascu F. Draghici C. Caproiu MT. Dumitrescu D. Badoiu A. Rev. Roum. Chim.  2006,  51:  643 
• 4g Dumitrascu F. Caira MR. Draghici C. Barbu L. Anal. Sci. X  2005,  21:  x133 ; doi: 10.2116/analscix.21.x133
• 4h Butler RN. Coyne AG. Moloney EM. Tetrahedron Lett.  2007,  48:  3501 
• 5a Dömling A. Chem. Rev.  2006,  106:  17 
• 5b Zhu J. Bienayme H. Multicomponent Reactions   Wiley-VCH; Weinheim: 2005. 
• 5c Olimpieria F. Volonterio A. Zanda M. Synlett  2008,  3016 
• 5d Barthelon A. Legoff X.-F. El-Kaim L. Grimaud L. Synlett  2010,  153 
• 5e Kantevari S. Yempala T. Vuppalapati SVN. Synthesis  2010,  959 
• 5f Gan S.-F. Wan J.-P. Pan Y.-J. Sun C.-R. Synlett  2010,  973 
• 5g Willy B. Müller TJJ. ARKIVOC  2008,  (i):  195 
• 5h Esmaeili AA. Hosseinabadi R. Habibi A. Synlett  2010,  1477 
• 5i Kobayashi K. Fujita S. Fukamachi S. Konishi H. Synthesis  2009,  3378 
• 5j Alizadeh A. Noaparast Z. Sabahnoo H. Zohreh N. Synlett  2010,  1469 
• 5k Zhao K. Xu X.-P. Zhu S.-L. Shi D.-Q. Zhang Y. Ji S.-J. Synthesis  2009,  2697 
• 5l Maisonneuve S. Xie J. Synlett  2009,  2977 
• 5m Zhang W. Kuang C. Yang Q. Synthesis  2010,  283 
• 5n Reddy Udagandla C. Saikia Anil K. Synlett  2010,  1027 
• 6a Dumitrascu F. Caira MR. Draghici B. Caproiu MT. Dumitrescu DG. Synlett  2008,  813 
• 6b Vasilescu M. Bandula R. Cramariuc O. Hukka T. Lemmetyinen H. Rantala TT. Dumitrascu F. J. Photochem. Photobiol., A  2008,  194:  308 
• 6c Georgescu E. Caira MR. Georgescu F. Draghici B. Popa MM. Dumitrascu F. Synlett  2009,  1795 
• 6d Caira MR. Georgescu E. Georgescu F. Draghici B. Popa MM. Dumitrascu F. ARKIVOC  2009,  (xii):  242 
• 6e Dumitrascu F. Georgescu E. Caira MR. Georgescu F. Popa M. Draghici B. Dumitrescu DG. Synlett  2009,  3336 
• 6f Georgescu E. Dumitrascu F. Georgescu F. Draghici C. Popa MM. Rev. Roum. Chim.  2010,  55:  217 
• 9 Huntress EH. Lesslie TE. Bornstein J. Org. Synth., Coll. Vol. IV   John Wiley & Sons; London: 1963.  p.329 
• 10a Zugrãvescu I. Petrovanu M. N-Ylid Chemistry   McGraw-Hill; New York: 1976.  p.239 
• 10b Caprosu MC. Zbancioc GN. Moldoveanu CC. Mangalagiu I. Collect. Czech. Chem. Commun.  2004,  69:  426 
• 11a Wei X. Hu Y. Li T. Hu H. J. Chem. Soc., Perkin Trans. 1  1993,  2487 
• 11b Wang B. Hu J. Zhang X. Hu Y. Hu H. J. Heterocycl. Chem.  2000,  37:  1533 
• 11c Zhou J. Hu Y. Hu H. J. Heterocycl. Chem.  2000,  37:  1165 
• 11d Dumitrascu F. Draghici C. Miu B. Caproiu MT. Barbu L. Dumitrescu DG. Rev. Roum. Chim.  2008,  53:  261 

7

General Procedure for the Synthesis of Pyrrolo[2,1- a ]phthalazines 4: Phthalazine 1 (5 mmol), phenacyl bromide 2 (5 mmol)and nonsymmetrical acetylene 3 (5 mmol; methyl propiolate, ethyl propiolate, 3-butyn-2-one) in 1,2-epoxybutane (20 mL) were refluxed with stirring for 12 h. The solvent was partly removed by evaporation, MeOH (10 mL) was added and the mixture was left overnight at r.t. The solid was filtered, washed with a small quantity of cold EtOH and crystallized from a suitable solvent. 3-Acetyl-1-(4-methoxybenzoyl)pyrrolo[2,1- a ]phthalazine (4c): colorless crystals with mp 158-160 ˚C were obtained by recrystallization from MeOH. Yield: 71%. Anal. Calcd C₂₁H₁₆N₂O₃: C, 73.24; H, 4.68; N, 8.13. Found: C, 73.51; H, 4.97; N, 8.38. ATR-IR: 1089, 1256, 1659, 1672, 2986, 3050 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.68 (s, 3 H, MeCO), 3.90 (s, 3 H, OMe), 7.00 (d, 2 H, J = 9.0 Hz, H-3′, H-5′), 7.60 (s, 1 H, H-2), 7.71-7.76 (m, 1 H, H-8), 7.85-7.91 (m, 2 H, H-7, H-9), 7.97 (d, 2 H, J = 9.0 Hz, H-2′, H-6′), 8.72 (d, 1 H, J = 0.8 Hz, H-6), 9.82-9.85 (m, 1 H, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 29.7 (MeCO), 55.7 (OMe), 113.9 (C-3′, C-5′), 117.0 (C-1), 123.5 (C-2), 127.6, 127.7 (C-7, C-10), 122.3, 127.3, 129.2, 131.5 (C-3, C-6a, C-10a, C-10b), 130.0 (C-8), 132.3 (C-2′, C-6′), 132.9 (C-9), 132.9 (C-1′), 146.9 (C-6), 163.5 (C-4′), 183.7 (COAr), 193.8 (COMe).

8

General Procedure for the Synthesis of Pyrrolo[2,1- a ]phthalazines 5; Method A: Phthalazine 1 (5 mmol)and phenacyl bromide 2 (5 mmol) were stirred for 30 min in 1,2-epoxybutane (20 mL) and then acetylenic dipolarophile (DMAD, DEAD, DIPAD; 7 mmol) was added and the reaction was kept under reflux for 12 h. The solvent was partly removed by evaporation, MeOH (10 mL) was added and the mixture was left overnight at r.t. The solid was filtered, washed on a filter with cold EtOH and crystallized from a suitable solvent. Method B: Phthalazinium bromide 2 (5 mmol) and symmetrical acetylenic dipolarophile 3 (7 mmol) in 1,2-epoxybutane (20 mL) were refluxed for 24 h. The workup of the reaction mixture was similar to method A. Diethyl 1-(4-Chlorobenzoyl)pyrrolo[2,1- a ]phthalazine-1,2-dicarboxylate (5h): colorless crystals with mp 153-154 ˚C were obtained by recrystallization from MeOH. Yield: 77%. Anal. Calcd C₂₄H₁₉ClN₂O₅: C, 63.93; H, 4.25; Cl, 7.86; N, 6.21. Found: C, 64.27; H, 4.61; Cl, 8.19; N, 6.01. ATR-IR: 1086, 1234, 1682, 1694, 1725, 2956, 3036 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.01 (t, 3 H, J = 7.1 Hz, Me), 1.40 (t, 3 H, J = 7.1 Hz, Me), 4.10 (q, 2 H, J = 7.1 Hz, CH₂), 4.47 (q, 2 H, J = 7.1 Hz, CH₂), 7.42 (d, 2 H, J = 8.6 Hz, H-3′, H-5′), 7.62-7.67 (m, 1 H, H-8), 7.77-7.84 (m, 2 H, H-7, H-9), 7.81 (d, 2 H, J = 8.9 Hz, H-2′, H-6′), 8.45 (s, 1 H, H-6), 8.90-8.93 (m, 1 H, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.6, 14.0 (2 × Me), 61.3, 62.7 (2 × CH₂), 108.0 (C-1), 119.5, 121.1, 124.4, 126.6, 128.0 (C-2, C-3, C-6a, C-10a, C-10b), 124.5 (C-10), 128.2, 133.4 (C-7, C-9), 128.8 (C-3′, C-5′), 129.0 (C-8), 130.1 (C-2′, C-6′), 136.0 (C-4′), 140.6 (C-1′), 147.0 (C-6), 163.2, 165.2 (2 × COO), 185.8 (COAr).