Synlett 2014; 25(19): 2769-2772
DOI: 10.1055/s-0034-1379183
letter
© Georg Thieme Verlag Stuttgart · New York

One-Pot Synthesis of Pyrrolo[1,2-c]quinazolinone Derivatives

Matija Petrovčić
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, 10 000 Zagreb, Croatia   Fax: +385(1)4680195   Email: majerski@irb.hr
,
Marija Alešković
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, 10 000 Zagreb, Croatia   Fax: +385(1)4680195   Email: majerski@irb.hr
,
Kata Mlinarić-Majerski*
Department of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, 10 000 Zagreb, Croatia   Fax: +385(1)4680195   Email: majerski@irb.hr
› Author Affiliations
Further Information

Publication History

Received: 25 July 2014

Accepted after revision: 29 August 2014

Publication Date:
07 October 2014 (online)

Abstract

A fast and simple one-pot synthesis of pyrrolo[1,2-c]-quinazolinones is reported. The tandem Suzuki coupling of N-Boc-pyrrol-2-yl boronic acid and ortho-substituted aminoaryl halogenides with subsequent cyclization of the third ring yields a variety of pyrroloquinazolinone scaffolds in good to moderate yields. The palladium-catalyzed cross-coupling reaction is applicable to a wide range of substituted aminoaryl halogenides.

 
  • References and Notes

    • 2a Kumar A, Rajput CB, Bhati SK. Bioorg. Med. Chem. 2007; 15: 3089
    • 2b Coombs RV, Danna RP, Denzer M, Hardtmann GE, Huegi B, Koletar G, Koletar J, Ott H, Jukniewicz E. J. Med. Chem. 1973; 16: 1237
    • 2c Cohen E, Klarberg B, Vaughan JR. Jr. J. Am. Chem. Soc. 1960; 82: 2731
    • 2d Maarouf AR, El-Bendary ER, Goda FE. Arch. Pharm. Pharm. Med. Chem. 2004; 337: 527
    • 2e Wolfe JF, Rathman TL, Sleevi MC, Campbell JA, Greenwood TD. J. Med. Chem. 1990; 33: 161
    • 3a Bandurco VT, Wong EM, Levine SD, Hajos ZG. J. Med. Chem. 1981; 24: 1455
    • 3b Helissey P, Parrot-Lopezi H, Renault J, Cros S. Eur. J. Med. Chem. 1987; 22: 366
  • 4 Cotter ML, Bandurco V, Wong E, Hajos ZG. J. Heterocycl. Chem. 1979; 16: 623
  • 5 Beccalli EM, Marchesini A, Pilati T. Tetrahedron 2005; 48: 5359
  • 6 Molina P, Alajarín M, Vidal A. Tetrahedron 1995; 51: 5351
  • 7 Molina P, Aller E, Lorenzo A. Synthesis 1998; 283
  • 8 Dörr AA, Lubell WD. Heterocycles 2014; 88: 1149
    • 9a Caron S, Massett SS, Bogle DE, Castaldi MJ, Braish TF. Org. Process Res. Dev. 2001; 5: 254
    • 9b Dajka-Halász B, Monsieurs K, Éliás O, Károlyházy L, Tapolcsányi P, Maes BU. W, Riedl Z, Hajós G, Dommisse RA, Lemière GL. F, Košmrlj J, Mátyus P. Tetrahedron 2004; 60: 2283
    • 10a Thompson AE, Batsanov AS, Bryce MR, Saygili N, Parryc PR, Tarbit B. Tetrahedron 2005; 61: 5131
    • 10b Thompson AE, Hughes G, Batsanov AS, Bryce MR, Parry PR, Tarbit B. J. Org. Chem. 2005; 70: 388
    • 10c Maes BU. W, Lemière GL. F, Dommisse R, Augustyns K, Haemers A. Tetrahedron 2000; 56: 1777
    • 10d Itoh T, Mase T. Tetrahedron Lett. 2005; 46: 3573
    • 10e Schulz T, Torborg C, Enthaler S, Schäffner B, Dumrath A, Spannenberg A, Neumann H, Börner A, Beller M. Chem. Eur. J. 2009; 15: 4528
    • 10f Vuoti S, Autio J, Laitila M, Haukka M, Pursiainen J. Eur. J. Inorg. Chem. 2008; 397
    • 10g Youn SW, Bihn JH. Tetrahedron Lett. 2009; 50: 4598
  • 11 Alešković M, Basarić N, Mlinarić-Majerski K. J. Heterocycl. Chem. 2011; 48: 1329
  • 12 General Procedure To a stirred solution of the corresponding aniline (1 mmol), Cs2CO3 (2 mmol), and Pd(PPh3)4 (5 mol%) in toluene (20 mL) at reflux and under nitrogen atmosphere, a solution of N-Boc-pyrrol-2-yl boronic acid17 (1 mmol) in a mixture of toluene (10 mL) and MeOH (3 mL) was added over 7 h. The mixture was stirred at reflux for 17 h, cooled, and the MeOH was removed under reduced pressure. To the resultant toluene suspension H2O (30 mL) was added, and the layers were separated. The water layer was extracted with CH2Cl2 (3 × 25 mL; or EtOAc for compound 5), the combined organic extracts were washed with H2O (30 mL), dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a suitable eluent as indicated below. Pyrrolo[1,2-c]quinazolin-5(6H)-one (1) and 2-(1H-Pyrrol-2-yl)aniline (1a) 11 Purified by chromatography with a mixture of n-hexane–Et2O (3:2). Analytical Data Compound 1: grey powder. 1H NMR (300 MHz, DMSO-d 6): δ = 6.67 (t, J = 3.3 Hz, 1 H), 7.01 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 7.18–7.36 (m, 3 H), 7.59 (dd, J 1 = 3.1 Hz, J 2 = 1.5 Hz, 1 H), 7.89–7.92 (m, 1 H), 11.48 (br s, 1 H). Compound 1a: white crystals. 1H NMR (600 MHz, CDCl3): δ = 3.94 (s, 2 H), 6.30–6.33 (m, 1 H), 6.40–6.44 (m, 1 H), 6.75–6.77 (m, 1 H), 6.79–6.83 (m, 1 H), 6.85–6.87 (m, 1 H), 7.06–7.10 (m, 1 H), 7.24 (s, 1 H), 8.58 (br s, 1 H). 9-Methylpyrrolo[1,2-c]quinazolin-5(6H)-one (2) Purified by chromatography with a mixture CH2Cl2–MeOH (98:2). Fractions were rechromatographed using 0 → 35% Et2O in CH2Cl2 as eluent to obtain analytically pure 2. Analytical Data Grey powder; mp 255–258 °C; IR (KBr): ν = 2921, 1701, 1508, 1411, 721 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.35 (s, 3 H), 6.66 (t, J = 3.3 Hz, 1 H), 6.97 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 7.13–7.16 (m, 2 H), 7.58 (dd, J 1 = 3.0 Hz, J 2 = 1.5 Hz, 1 H), 7.73 (s, 1 H), 11.40 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 20.5 (CH3), 104.3 (CH), 113.7 (CH), 114.1 (C), 115.3 (CH), 115.4 (CH), 122.0 (CH), 128.8 (CH), 129.2 (C), 130.3 (C), 132.1 (C), 145.4 (C). HRMS: m/z [M]+ calcd for C12H10N2O: 198.0788; found: 198.0788. 9-Isopropylpyrrolo[1,2-c]quinazolin-5(6H)-one (3) and 4-Isopropyl-2-(1H-pyrrol-2-yl)aniline (3a) Purified by chromatography with a mixture CH2Cl2–MeOH (99:1). Fractions were rechromatographed using CH2Cl2–Et2O (7:3) as eluent to obtain analytically pure compounds. Analytical Data Compound 3: grey powder; mp 170–173 °C. IR (KBr): ν = 2954, 1701, 1508, 1407, 715 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.23 (s, 3 H), 1.26 (s, 3 H), 2.94 (sept, J = 6.9 Hz, 1 H), 6.66 (t, J = 3.3 Hz, 1 H), 7.03 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 7.15–7.24 (m, 2 H), 7.57 (dd, J 1 = 3.0 Hz, J 2 = 1.5 Hz, 1 H), 7.76–7.78 (m, 1 H), 11.40 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 23.9, 33.1, 104.3, 113.7, 114.2, 115.3, 115.5, 119.4, 125.9, 129.4, 130.7, 143.3, 145.5. HRMS: m/z [M]+ calcd for C14H14N2O: 226.11; found: 226.1101. Compound 3a: white crystals; mp 90–91 °C. IR (KBr): ν = 3384, 3305, 3178, 2962, 1500, 825, 725 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.21 (s, 3 H), 1.23 (s, 3 H), 2.82 (sept, J = 6.9 Hz, 1 H), 3.81 (br s, 2 H), 6.31 (dd, J 1 = 5.8 Hz, J 2 = 2.8 Hz, 1 H), 6.39–6.45 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.84–6.88 (m, 1 H), 6.96 (dd, J 1 = 2.2 Hz, J 2 = 8.2 Hz, 1 H), 7.11 (d, J = 2.2 Hz, 1 H), 8.68 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 24.1 (2 × CH3), 33.2 (CH), 107.2 (CH), 109.2 (CH), 116.7 (CH), 117.7 (CH), 119.6 (C), 125.7 (CH), 126.3 (CH), 129.9 (C), 139.7 (C), 140.9 (C). HRMS: m/z [M]+ calcd for C13H16N2: 200.1308; found: 200.1311. 7,9-Dimethylpyrrolo[1,2-c]quinazolin-5(6H)-one (4) Purified by chromatography with a mixture CH2Cl2–Et2O (7:3). Analytical Data Grey powder; mp 254–256 °C. IR (KBr): ν = 3224, 2916, 1689, 1498, 1348, 719 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 2.30 (s, 3 H), 2.37 (s, 3 H), 6.65 (t, J = 3.3 Hz, 1 H), 6.94 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 6.98 (s, 1 H), 7.56–7.59 (m, 2 H), 10.55 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 17.5 (CH3), 20.4 (CH3), 104.1 (CH), 113.9 (CH), 114.2 (C), 115.2 (CH), 119.9 (CH), 123.9 (C), 128.7 (C), 129.4 (C), 130.1 (CH), 131.8 (C), 145.8 (C). HRMS: m/z [M]+ calcd for C13H12N2O: 212.0944; found: 212.0936. 8-Nitropyrrolo[1,2-c]quinazolin-5(6H)-one (5) and 5-Nitro-2-(1H-pyrrol-2-yl)aniline (5a) The general workup procedure was slightly changed because of solubility problems. In this case, product 5a was extracted from the water layer with CH2Cl2 and 5 with EtOAc. Chromatography with a mixture CH2Cl2–MeOH (99:1) furnished analytically pure 5a and chromatography with a mixture CH2Cl2–EtOAc (9:1) furnished pure 5. Analytical Data Compound 5: yellow crystals; mp 312–313 °C. IR (KBr): ν = 3255, 1720, 1521, 1340, 723 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.78 (dd, J 1 = 3.1 Hz, J 2 = 3.6 Hz, 1 H), 7.30 (dd, J 1 = 3.6 Hz, J 2 = 1.5 Hz, 1 H), 7.74 (dd, J 1 = 3.1 Hz, J 2 = 1.5 Hz, 1 H), 8.01 (dd, J 1 = 8.7 Hz, J 2 = 2.2 Hz, 1 H), 8.06–8.08 (m, 1 H), 8.14 (d, J = 8.7 Hz, 1 H), 11.87 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 108.6, 110.7, 114.7, 117.8, 117.9, 119.8, 122.9, 127.6, 132.6, 145.0, 145.4. HRMS: m/z [M + H]+ calcd for C11H8N3O3: 230.0561; found: 230.0565. Compound 5a: red crystals; mp 159–161 °C. IR (KBr): ν = 3392, 1618, 1514, 1336, 877, 744 cm–1. 1H NMR (600 MHz, DMSO-d 6): δ = 5.57 (s, 2 H), 6.21–6.23 (m, 1 H), 6.57–6.60 (m, 1 H), 6.94–6.96 (m, 1 H), 7.41–7.46 (m, 2 H), 7.65 (d, J = 2.2 Hz, 1 H), 11.27 (s, 1 H). 13C NMR (150 MHz, DMSO-d 6): δ = 108.9, 109.1, 109.3, 111.1, 120.2, 124.2, 127.0, 127.5, 145.1; 145.6. HRMS: m/z [M]+ calcd for C10H9N3O2: 203.0688; found: 203.0691. 7,9-Dinitropyrrolo[1,2-c]quinazolin-5(6H)-one (6) Purified by chromatography with CH2Cl2. Analytical Data Orange crystals; mp 291–293 °C. IR (KBr): ν = 3436, 3257, 1718, 1612, 1529, 1307, 750 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.83 (t, J = 3.3 Hz, 1 H), 7.58 (dd, J 1 = 3.6 Hz, J 2 = 1.5 Hz, 1 H), 7.77 (dd, J 1 = 3.0 Hz, J 2 = 1.5 Hz, 1 H), 8.75 (d, J = 2.4 Hz, 1 H), 9,14 (d, J = 2.4 Hz, 1 H), 11.18 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 109.4 (CH), 115.3 (CH), 117.8 (CH), 117.9 (C), 118.5 (CH), 122.2 (CH), 126.4 (C), 131.0 (C), 134.6 (C), 141.4 (C), 143.9 (C). HRMS: m/z [M]+ calcd for C11H6N4O5: 274.0338; found: 274.0333. 8-Chloropyrrolo[1,2-c]quinazolin-5(6H)-one (7) and 5-Chloro-2-(1H-pyrrol-2-yl)aniline (7a) Purified by chromatography with a CH2Cl2–EtOAc (96:4). Analytical Data Compound 7: dark grey powder; mp 257–259 °C. IR (KBr): ν = 2360, 1710, 1587, 1409, 721 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.69 (t, J = 3.3 Hz, 1 H), 7.05 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 7.22–7.27 (m, 2 H), 7.60 (dd, J 1 = 3.1 Hz, J 2 = 1.5 Hz, 1 H), 7.95 (d, J = 8.2 Hz, 1 H), 11.57 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 105.2 (CH), 113.3 (C), 114.0 (CH), 114.8 (CH), 115.9 (CH), 122.9 (CH), 123.9 (CH), 128.3 (C), 131.2 (C), 133.6 (C), 145.2 (C). HRMS: m/z [M]+ calcd for C11H7ClN2O: 218.0242; found: 218.0249. 7-Chloro-9-nitropyrrolo[1,2-c]quinazolin-5(6H)-one (8) and 2-Chloro-4-nitro-6-(1H-pyrrol-2-yl)aniline (8a) Separation of products 8 and 8a was unsuccessful even after several repeated chromatography. The yields were estimated from 1H NMR spectroscopic analysis of the mixture of 8 (11%) and 8a (8%). 7-(Chloro-9-fluoropyrrolo[1,2-c]quinazolin-5(6H)-one (9) Purified by chromatography with CH2Cl2. Analytical Data White crystals; mp 236–238 °C. IR (KBr): ν = 3247, 1698, 1573, 1499, 724 cm–1. 1H NMR (300 MHz, DMSO-d 6): δ = 6.73 (t, J = 3.3 Hz, 1 H), 7.17 (dd, J 1 = 3.6 Hz, J 2 = 1.5 Hz, 1 H), 7.44 (dd, J 1(HF) = 8.5 Hz, J 2 = 2.7 Hz, 1 H), 7.67 (dd, J 1 = 3.1 Hz, J 2 = 1.5 Hz, 1 H), 7.87 (dd, J 1(HF) = 9.1 Hz, J 2 = 2.7 Hz, 1 H), 10.91 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 107.0 (CH), 107.4 (d, J CF = 24.6 Hz, CH), 114.4 (CH), 115.1 (d, J CF = 27.2 Hz, CH), 116.7 (CH), 116.7 (d, J CF = 11.7 Hz, C), 119.8 (d, J CF = 10.3 Hz, C), 126.1 (d, J CF = 2.2 Hz, C), 127.6 (d, J CF = 3.5 Hz, C), 145.0 (C), 157.2 (d, J CF = 241.6 Hz, C). HRMS: m/z [M]+ calcd for C11H6ClFN2O: 236.0153; found: 236.0148. 7,9-Difluoropyrrolo[1,2-c]quinazolin-5(6H)-one (10) Purified by chromatography with a mixture CH2Cl2–MeOH (99.5:0.5). Fractions were rechromatographed using CH2Cl2–EtOAc (97:3) as eluent to obtain analytically pure 10. Analytical Data White crystals; mp 270–271 °C. IR (KBr): ν = 3087, 1697, 1510, 1400, 1301, 727 cm–1. 1H NMR (600 MHz, DMSO-d 6): δ = 6.71 (t, J = 3.3 Hz, 1 H), 7.14 (dd, J 1 = 3.5 Hz, J 2 = 1.5 Hz, 1 H), 7.26–7.30 (m, 1 H), 7.67 (dd, J 1 = 3.0 Hz, J 2 = 1.5 Hz, 1 H), 7.68–7.71 (m, 1 H), 11.56 (br s, 1 H). 13C NMR (150 MHz, DMSO-d 6): δ = 102.2 [dd, J 1(CF) = 28.2 Hz, J 2(CF) = 22.0 Hz, CH], 103.8 [dd, J 1(CF) = 24.7 Hz, J 2(CF) = 3.2 Hz, CH], 106.7 (CH), 114.0 (CH), 116.7 [dd, J 1(CF) = 11.2 Hz, J 2(CF) = 4.7 Hz, C], 117.8 (CH), 117.8 [dd, J 1(CF) = 14.2 Hz, J 1(CF) = 2.8 Hz, C], 127.7 (t, J CF = 3.5 Hz, C), 144.8 (C), 148.8 [dd, J 1(CF) = 248.4 Hz, J 2(CF) = 13.3 Hz, C], 156.6 [dd, J 1(CF) = 240.5 Hz, J 2(CF) = 11.4 Hz, C]. 19F NMR (565 MHz, DMSO-d 6): δ = –106.6 (dt, J 1 = 9.2 Hz, J 2 = 4.5 Hz, 1 F), –114.4 (m, 1 F). HRMS: m/z [M]+ calcd for C11H6F2N2O: 220.0443; found: 220.0448.
  • 13 Johnson CN, Stemp G, Anand N, Stephen SC, Gallagher T. Synlett 1998; 1025
  • 14 Tom NJ, Simon WM, Frost HN, Ewing M. Tetrahedron Lett. 2004; 45: 905
  • 15 Rawal VH, Jones RJ, Cava MP. J. Org. Chem. 1987; 52: 19
  • 16 Hegedus LS. Organopalladium Chemistry . In Organometallics in Synthesis . Schlosser M. John Wiley and Sons; Chichester: 2002

    • N-Boc-pyrrole, N-Boc-pyrrol-2-yl boronic acid, and 2-bromo-5-chloroaniline were prepared according to the procedures described in the literature:
    • 17a Grehn L, Ragnarsson U. Angew. Chem., Int. Ed. Engl. 1984; 23: 296
    • 17b Martina S, Enkelmann V, Wegner G, Schlüter A.-D. Synthesis 1991; 613
    • 17c Allen JR, Biswas K, Bryan MC, Burli R, Cao G.-Q, Frohn MJ, Golden JE, Mercede S, Peterkin T, Pickrell AJ, Reed A, Tegley CM, Wang X. WO 2008076427, 2008