A Practical Synthetic Route to Benzofuro[2,3-b]pyridine and Trifluoromethyl-α-carbolines

Viktor O. Iaroshenko; Ulrich Groth; Nadiya V. Kryvokhyzha; Samra Obeid; Andrei A. Tolmachev; Thomas Wesch

doi:10.1055/s-2008-1032042

LETTER

A Practical Synthetic Route to Benzofuro[2,3-b]pyridine and Trifluoromethyl-α-carbolines

Viktor O. Iaroshenko*^a,b, Ulrich Groth^a, Nadiya V. Kryvokhyzha^c, Samra Obeid^a, Andrei A. Tolmachev^b,d, Thomas Wesch^a
^a Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstraße 10, 78457 Konstanz, Germany
Fax: +49(7531)884424; e-Mail: yva108@yahoo.co.uk;
^b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv 33, 01033, Ukraine
^c Department of Chemistry, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK
^d ‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine

Abstract

All articles of this category

Abstract

In situ generated benzofuran-2-amine reacts with 1,3-CCC-dielectrophiles, such as CF₃-containing β-diketones, 3-formylchromone, methyl-2,4-dioxopentanoate and pentafluorobenzaldehyde, and the reaction leads to the formation of benzofuro[2,3-b]pyridine ring system. By using a similar approach 4-trifluoromethyl-α-carbolines were synthesized starting from indole-2-amine.

Key words

furanamine - indoleamine - pyridine - annulation - electrophilic aromatic substitution

Full Text

References

References and Notes

<A NAME="RG30207ST-1A">1a</A> Kovtunenko VO. Drug Methods Acting on the Central Nervous System [in Ukrainian] Perun; Kiev: 1997. p.373

<A NAME="RG30207ST-1B">1b</A> Silverman RB. The Organic Chemistry of Drug Design, and Drug Action 2nd ed.: Elsevier/Academic Press; New York: 2004. p.617

<A NAME="RG30207ST-2A">2a</A> Kleemann A. Engel J. Kutscher B. Reichert D. Pharmaceutical Substances: Syntheses, Patents, Applications Thieme; Stuttgart: 2001.

<A NAME="RG30207ST-2B">2b</A> Ismail FMD. J. Fluorine Chem. 2002, 118: 27

<A NAME="RG30207ST-3A">3a</A> Venkat RG, Qi L, Pierce M, Robbins PB, Sahasrabudhe SR, and Selliah R. inventors; Int. Patent WO2007076085. ; Chem. Abstr. 2007, 147, 143456

<A NAME="RG30207ST-3B">3b</A> Arakawa H, Monden Y, Nakatsuru Y, and Kodera T. inventors; Int. Patent WO2003080077. ; Chem. Abstr. 2003, 139, 286323

<A NAME="RG30207ST-3C">3c</A> Burstein HJ. Overmoyer B. Gelman R. Silverman P. Savoie J. Clarke K. Dumadag L. Younger J. Ivy P. Winer EP. Invest. New Drugs 2007, 25: 161

<A NAME="RG30207ST-4A">4a</A> Yan H. Mizutani TC. Nomura N. Takakura T. Kitamura Y. Miura H. Nishizawa M. Tatsumi M. Yamamoto N. Sugiura W. Antiviral Chem. Chemother. 2005, 16: 363

<A NAME="RG30207ST-4B">4b</A> Li X. Vince R. Bioorg. Med. Chem. 2006, 14: 2942

<A NAME="RG30207ST-4C">4c</A> Zhao G. Wang C. Liu C. Lou H. Mini-Rev. Med. Chem. 2007, 7: 707

<A NAME="RG30207ST-5A">5a</A> Gelbard HA, Maggirwar SB, Dewhurst S, and Schifitto GP. inventors; Int. Patent WO2007076372. ; Chem. Abstr. 2007, 147, 134456

<A NAME="RG30207ST-5B">5b</A> Mellman I, and Jiang A. inventors; Int. Patent WO2007075911. ; Chem. Abstr. 2007, 147, 134427

<A NAME="RG30207ST-6A">6a</A> Stubbs MC. Armstrong SA. Curr. Drug Targets 2007, 8: 703

<A NAME="RG30207ST-6B">6b</A> Shenoy S. Vasania VS. Gopal M. Mehta A. Toxicol. Appl. Pharmacol. 2007, 222: 80

<A NAME="RG30207ST-6C">6c</A> Seedhouse CH. Hunter HM. Lloyd-Lewis B. Massip A.-M. Pallis M. Carter GI. Grundy M. Shang S. Russell NH. Leukemia 2006, 20: 2130

<A NAME="RG30207ST-7A">7a</A> Joseph J, Meijer L, and Liger F. inventors; Fr. Patent FR2876377. ; Chem. Abstr. 2006, 144, 390900

<A NAME="RG30207ST-7B">7b</A> Sennhenn P, Mantoulidis A, Treu M, Tontsch-Grunt U, Spevak W, McConnell D, Schoop A, Brueckner R, Jacobi A, Guertler U, Schnapp G, Klein C, Himmelsbach F, Pautsch A, Betzemeier B, Herfurth L, Mack J, Wiedenmayer D, Bader G, and Reiser U. inventors; Int. Patent WO2006131552. ; Chem. Abstr. 2006, 146, 62695

<A NAME="RG30207ST-7C">7c</A> Das S, Brown JW, Dong Q, Gong X, Kaldor SW, Liu Y, Paraselli BR, Scorah N, Stafford JA, and Wallace MB. inventors; Int. Patent W02007044779. Chem. Abstr. 2007, 146, 441771

<A NAME="RG30207ST-8">8</A> Fong TM, Erondu NE, Macneil DJ, Mcintyre JH, and Van der Ploeg LHT. inventors; Int. Patent WO2004110368. ; Chem. Abstr. 2004, 142, 69181

<A NAME="RG30207ST-9A">9a</A> Voigt B. Meijer L. Lozach O. Schaechtele C. Totzke F. Hilgeroth A. Bioorg. Med. Chem. Lett. 2005, 15: 823

<A NAME="RG30207ST-9B">9b</A> Xie Y, Zhang G, Wang X, Gray NS, and Liu Y. inventors; Int. Patent WO2007021795. ; Chem. Abstr. 2007, 146, 274386

<A NAME="RG30207ST-10">10</A> Brachwitz K. Hilgeroth A. Bioorg. Med. Chem. Lett. 2002, 12: 411

<A NAME="RG30207ST-11">11</A> Resnati G. Tetrahedron 1993, 49: 9385

<A NAME="RG30207ST-12A">12a</A> Mueller U, Connell R, Goldmann S, Gruetzmann R, Beuck M, Bischoff H, Denzer D, Domdey-Bette A, and Wohlfeil S. inventors; Eur. Patent EP705831. ; Chem. Abstr. 1996, 125, 58487

<A NAME="RG30207ST-12B">12b</A> Gruetzmann R, Mueller U, Bischoff H, and Zaiss S. inventors; Int. Patent WO2001097787. ; Chem. Abstr. 2001, 136, 64132

<A NAME="RG30207ST-13A">13a</A> Volochnyuk DM. Pushechnikov AO. Krotko DG. Sibgatulin DA. Kovalyova SA. Tolmachev AA. Synthesis 2003, 1531

<A NAME="RG30207ST-13B">13b</A> Volochnyuk DM. Kostyuk AN. Sibgatulin DA. Chernega AN. Tetrahedron 2005, 61: 2839

<A NAME="RG30207ST-13C">13c</A> Iaroshenko VO. Volochnyuk DM. Wang Y. Vovk MV. Boiko VJ. Rusanov EB. Groth UM. Tolmachev AO. Synthesis 2007, 3309

<A NAME="RG30207ST-14">14</A> Glenn RW, Lim M, Gardlik JM, Jones SD, Murphy BP, and Rees CW. inventors; US Patent US2005193504. ; Chem. Abstr. 2005, 143, 292010

<A NAME="RG30207ST-15">15</A> Cruz F. Quijano L. Gomez-Garibay F. Rios T. J. Nat. Prod. 1990, 53: 543

<A NAME="RG30207ST-16A">16a</A> Pschorr R. Hoppe G. Ber. Dtsch. Chem. Ges. 1910, 43: 2543

<A NAME="RG30207ST-16B">16b</A> Matsumoto T. Yoshida D. Tomita H. Agric. Biol. Chem. 1981, 45: 2031

<A NAME="RG30207ST-16C">16c</A> Sagitullin RS. Mel’nikova TV. Kost AN. Snegirev VF. Frenkel EN. Khim. Geterotsikl. Soedin. 1973, 8: 1043

<A NAME="RG30207ST-16D">16d</A> Portnov YN, Golubeva GA, and Kost AN. inventors; SU Patent SU331060. ; Chem. Abstr. 1972, 77, 19720307

<A NAME="RG30207ST-16E">16e</A> Kebrle J. Hoffmann K. Helv. Chim. Acta 1956, 39: 116

<A NAME="RG30207ST-17A">17a</A> Pfister JR. Wyman WE. Synthesis 1983, 38

<A NAME="RG30207ST-17B">17b</A> Capson TL. Poulter CD. Tetrahedron Lett. 1984, 25: 3515

<A NAME="RG30207ST-17C">17c</A> Wang X.-C. Chai L.-Q. Wang M.-G. Quan Z.-Q. Li Z. Synth. Commun. 2006, 36: 645

<A NAME="RG30207ST-17D">17d</A> Hu Y.-H. Xiang JS. Di-Grandi MJ. Du X. Ipek M. Laakso LM. Li J. Li W. Rush TS. Schmid J. Skotnicki JS. Bioorg. Med. Chem. 2005, 13: 6629

2-Methyl-4-(trifluoromethyl)benzofuro[2,3- b ]pyridine (5a): colorless solid (1.13 g, 90%); mp 115-117 °C; R _f = 0.65 (EtOAc-hexane, 1:2). ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.68 (s, 3 H), 7.50 (t, ³ J _HH = 8.0 Hz, 1 H), 7.66 (t, ³ J _HH = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.83 (d, ³ J _HH = 8.0 Hz, 1 H), 7.99 (d, ³ J _HH = 8.0 Hz, 1 H). ¹³C NMR (100.5 MHz, DMSO-d ₆): δ = 24.4, 109.8, 112.7, 115.5, 119.7, 123.4, 123.7 (¹ J _CF = 275 Hz), 124.7, 126.7, 129.9 (² J _CF = 35 Hz), 154.5, 158.1, 163.1. ¹⁹F NMR (376.2 MHz, DMSO-d ₆): δ = -63.5. MS: m/z (%) = 242 (14) [M⁺ + 1], 241 (100) [M⁺], 210 (37), 182 (41). Anal. Calcd for C₁₃H₈F₃NO: C, 62.16; H, 3.21; N, 5.58. Found: C, 62.18; H, 3.20; N, 5.57.

General Procedure for the Synthesis of Furo[2,3- b ]pyridines 5, 9, 11, and benzofuro[2,3- b ]quinoline 13: To a boiling solution of AcOH (250 mL) and H₂O (10 mL; temperature in the oil bath was about 135 °), a mixture of a dielectrophile (5 mmol) and 2-isocyanatobenzofuran (1.99 g, 12.5 mmol) in absolute DMF (50 mL) was dropped very slowly through the condenser. After the addition was completed the mixture was refluxed for further 3 h. After evaporation of the solvent, the residue was subjected to column chromatography over silica gel, or recrystallized from appropriate solvent.

<A NAME="RG30207ST-20A">20a</A> Kost AN. Men’shikov VV. Sagitullin RS. Zh. Org. Khim. 1976, 12: 2234

<A NAME="RG30207ST-20B">20b</A> Sadovoy AV. Golubev GA. Nasakin OE. Chem. Heterocycl. Compd. (Engl. Transl.) 2001, 37: 1145

<A NAME="RG30207ST-20C">20c</A> Muller U, Eckenberg P, Grutzmann R, Bischoff H, Denzer D, Wohlfeil S, Lohmer S, Nielsch U, and Kolkhof P. inventors; Eur. Patent EP799828. ; Chem. Abstr. 1997, 127, 678930

<A NAME="RG30207ST-21A">21a</A> Gowravaram S. Aldrichimica Acta 1996, 29: 15

<A NAME="RG30207ST-21B">21b</A> Ghosh T. Bandyopadhyay C. J. Heterocycl. Chem. 2006, 43: 1431

<A NAME="RG30207ST-21C">21c</A> Quiroga J. Mejia D. Insuasty B. Abonia R. Nogueras M. Sanchez A. Cobo J. Low JN. J. Heterocycl. Chem. 2002, 39: 51

<A NAME="RG30207ST-21D">21d</A> Ghosh CK. Ray A. Patra A. J. Heterocycl. Chem. 2001, 38: 1459

<A NAME="RG30207ST-22A">22a</A> Jiang JB. Roberts J. J. Heterocycl. Chem. 1985, 22: 159

<A NAME="RG30207ST-22B">22b</A> Jiang JB, and Isaacson D. inventors; US Patent US4656274. ; Chem. Abstr. 1987, 127, 318979

7,8,9,10-Tetrafluorobenzofuro[2,3- b ]quinoline (13): colorless solid (1.05 g, 72%); mp 235-237 °C (i-PrOH). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.55 (t, ³ J _HH = 8.0 Hz, 1 H), 7.74 (t, ³ J _HH = 8.0 Hz, 1 H), 7.81 (d, ³ J _HH = 8.0 Hz, 1 H), 8.40 (d, ³ J _HH = 8.0 Hz, 1 H), 9.35 (s, 1 H). MS: m/z (%) = 292 (17) [M⁺ + 1], 291 (100) [M⁺], 262 (10), 145 (10). Anal. Calcd for C₁₅H₅F₄NO: C, 61.87; H, 1.73; N, 4.81. Found: C, 61.85; H, 1.74; N, 4.82.

<A NAME="RG30207ST-24">24</A> Pento J. T., Li P.-K., Brueggemeier R. W., Hackett J.; Int. Patent WO2006119148, 2006; Chem. Abstr. 2006, 145, 489214

4-(Difluoromethyl)-2-methylbenzofuro[2,3- b ]pyridine (14a): colorless solid (0.99 g, 85%); mp 112-113 °C; R _f = 0.5 (EtOAc-hexane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 2.72 (s, 3 H), 7.04 (t, ² J _HF = 56 Hz, 1 H), 7.31 (s, 1 H), 7.39 (t, ³ J _HH = 8.0 Hz, 1 H), 7.53 (t, ³ J _HH = 8.0 Hz, 1 H), 7.63 (d, ³ J _HH = 8.0 Hz, 1 H), 8.01 (d, ³ J _HH = 8.0 Hz, 1 H). ¹³C NMR (100.5 MHz, CDCl₃): δ = 24.5, 110.8, 112.4 (¹ J _CF = 240 Hz), 113.1, 115.5, 120.9, 123.4, 124.3, 128.6, 136.8 (² J _CF = 26 Hz), 154.6, 157.0, 163.4. ¹⁹F NMR (376.2 MHz, DMSO-d ₆): δ = -115.3 (d, ² J _HF = 56 Hz, 2 F). MS: m/z (%) = 234 (15) [M⁺ + 1], 233 (100) [M⁺], 182 (16). Anal. Calcd for C₁₃H₉F₂NO: C, 66.95; H, 3.89; N, 6.01. Found: C, 66.94; H, 3.89; N, 6.02.

<A NAME="RG30207ST-26A">26a</A> Muthian S, Mnich SJ, Burgos LAC, and Naiman BM. inventors; Int. Patent WO2007039797. ; Chem. Abstr. 2007, 146, 375738

<A NAME="RG30207ST-26B">26b</A> Nunes JJ, Milne J, Bemis J, Xie R, Vu CB, Ng PY, Disch JS, Salzmann T, and Armistead D. inventors; Int. Patent WO2007019346. ; Chem. Abstr. 2007, 146, 274349

<A NAME="RG30207ST-26C">26c</A> Taltavull MJ, Pages S, and Luis M. inventors; Int. Patent WO2007017078. ; Chem. Abstr. 2007, 146, 229376