Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines

Abstract

With the purpose to synthesize novel ADAs (adenosine deaminase) and IMPDH (inosine 5′-monophosphate dehydroge­nase) inhibitors the reaction of 5-amino-1-tert-butyl-1H-pyrrolo-3-carbonitrile with fluorinated 1,3 -biselectrophiles was studied. An efficient and convenient synthetical approach to obtain fluorinated pyrrolo[2,3-b]pyridines was developed. tert-Butyl protecting group was successfully cleaved by treating of synthesized pyrrolo­pyridines with concentrated sulfuric acid.

pyrrol - amine - fluorine - pyridine - annulation - electrophilic aromatic substitution

References and Notes

1a Ugarkar BG. DaRe JM. Kopcho JJ. Browne CE. Schanzer JM. Wiesner JB. Erion MD.
J. Med. Chem.  2000,  43:  2883 

1b Erion MD. Ugarkar BG. DaRe JM. Castellino AJ. Fujitaki JM. Dixon R. Appleman JR. Wiesner JB. Nucleosides, Nucleotides Nucleic Acids  1997,  16:  1013 

2a Seela F. Zulauf M. Nucleosides, Nucleotides Nucleic Acids  1999,  18:  2697 

2b Renau TE. Kennedy C. Ptak RG. Breitenbach JM. Drach JC. Townsend LB. J. Med. Chem.  1996,  39:  3470 

2c Crawczyk SH. Renau TE. Nassiri MR. Westerman AC. Wotring LL. Drach JC. Townsend LB. J. Med. Chem.  1995,  38:  4115 

2d Crawczyk SH. Nassiri MR. Kucera LS. Kern ER. Ptak RG. Wotring LL. Drach JC. Townsend LB. J. Med. Chem.  1995,  38:  4106 

3a Nekhai S. Bhat UG. Ammosova T. Radhakrishnan SK. Jerebtsova M. Niu X. Foster A. Layden TJ. Gartel AL. Oncogene  2007,  26:  3899 

3b Mohapatra S, and Pledger WJ. inventors; US  2007238745.  ; Chem. Abstr. 2007, 147, 420059

3c Fujiwara Y. Hosokawa Y. Watanabe K. Tanimura S. Ozaki K.-I. Kohno M. Mol. Cancer Ther.  2007,  6:  1133 

4a Porcari AR. Ptak RG. Borysko KZ. Breitenbach JM. Drach JC. Townsend L. J. Med. Chem.  2000,  43:  2457 

4b Gartel AL, and Radhakrishnan SK. inventors; WO  2006116512.  ; Chem. Abstr. 2006, 145, 465765

4c Gordon RK. Ginalski K. Rudnicki WR. Rychlewski L. Pankaskie MC. Bujnicki JM. Chiang PK. Eur. J. Biochem.  2003,  270:  3507 

5a Mekouar K, Deziel R, Mounir S, and Iyer RP. inventors; WO  2003055896.  ; Chem. Abstr. 2003, 139, 53249

5b Schul W. Liu W. Xu H.-Y. Flamand M. Vasudevan SG. J. Infect. Dis.  2007,  195:  665 

5c Maccoss M, Olsen DB, Leone J, and Durette PL. inventors; WO  2006065335.  ; Chem. Abstr. 2006, 145, 76603

5d Maccoss M, and Olsen DB. inventors; WO  2006012078.  ; Chem. Abstr. 2006, 144, 192451

6a Hoffman K. Holmes FA. Fraschini G. Esparza L. Frye D. Raber MN. Newman RA. Hortobagyi GN. Cancer Chemother. Pharmacol.  1996,  37:  254 

6b O’Connell MJ. Rubin J. Hahn RG. Kvols LK. Moertel CG. Cancer Treat. Rep.  1987,  71:  333 

6c Lyss AP. Morrell LE. Perry MC. Proc. Am. Soc. Clin. Oncol.  1991,  10:  120 

6d Feun LG. Blessing JA. Barrett RJ. Hanjani PA. Am. J. Clin. Oncol.  1993,  16:  506 

7 Mantovanini M, Melillo G, and Daffonchio L. inventors; WO  9504742.  ; Chem. Abstr. 1995, 122, 314537

8 Easterwood LM. Veliz EA. Beal PA. J. Am. Chem. Soc.  2000,  122:  11537 

9 Veliz EA. Easterwood LM. Beal PA. J. Am. Chem. Soc.  2003,  125:  10867 

10 Cristalli G. Eleuteri A. Vittori S. Volpini R. Camaioni E. Lupidi G. Drug Dev. Res.  1993,  28:  253 

11a Lupidi G. Marmocchi F. Cristalli G. Biochem. Mol. Biol.  1998,  46:  1071 

11b Lupidi G. Cristalli G. Marmocchi F. Riva F. Grifantini M. J. Enzyme Inhib. Med. Chem.  1985,  1:  67 

11c Okamoto A. Tanaka K. Saito I. Bioorg. Med. Chem. Lett.  2002,  12:  97 

12 Erion MD. Reddy MR. J. Am. Chem. Soc.  1998,  120:  3295 

13a Begue J.-P. Bonnet-Delpon D. Chimie bioorganique et médecinal du fluor   EDP Sciences; Paris: 2005.  p.366 

13b Silverman RB. The Organic Chemistry of Drug Design, and Drug Action   2nd ed.:  Elsevier Academic Press; London: 2004.  p.617 ; ISBN 0-12-643732-7

14 Agarwal RP. Spector T. Parks RE. Biochem. Pharmacol.  1977,  26:  359 

15 Pankiewicz KW. Goldstein BM. Inosine Monophosphate Dehydrogenase: ACS Symposium Series 839   American Chemical Society; Washington DC: 2003. 

16a Iaroshenko VO. Volochnyuk DM. Wang Y. Vovk MV. Boiko VJ. Rusanov EB. Groth UM. Tolmachev AO. Synthesis  2007,  3309 

16b Iaroshenko VO. Groth U. Kryvokhyzha NV. Obeid S. Tolmachev AA. Wesch T. Synlett  2008,  343 

16c Volochnyuk DM. Pushechnikov AO. Krotko DG. Sibgatulin DA. Kovalyova SA. Tolmachev AA. Synthesis  2003,  1531 

16d Vovk MV. Bolbut AV. Boiko VI. Pirozhenko VV. Chernega AN. Tolmachev AA. Chem. Heterocycl. Compd. (N.Y.)  2004,  40:  370 

16e Vovk MV. Bol’but AV. Dorokhov VI. Pyrozhenko VV. Synth. Commun.  2002,  32:  3749 

16f Wesch T. Iaroshenko VO. Groth U. Synlett  2008,  1459 

17 De Rosa M. Issac RP. Houghton G. Tetrahedron Lett.  1995,  36:  9261 

18 Allegretti M. Anacardio R. Cesta MC. Curti R. Mantovanini M. Nano G. Topai A. Zampella G. Org. Process Res. Dev.  2003,  7:  209 

19a Brodrick A. Wibberley DG. J. Chem Soc., Perkin Trans. 1  1975,  19:  1910 

19b Benoit R. Dupas G. Bourguignon J. Queguiner G. Synthesis  1987,  1124 

20

1- tert -Butyl-4-[chloro(difluoro)methyl]-6-phenyl-1 H -pyrrolo[2,3- b ]pyridine-3-carbonitrile (11e)
Colorless solid (0.65g, 90%); mp 234 ˚C (from EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.87 (9 H, s, CH₃), 7.53
(3 H, br m), 8.07 (1 H, s), 8.18 (2 H, d, ^³ J _CH = 7.8 Hz), 8.70 (1 H, s). ^¹³C NMR (100.5 MHz, DMSO-d ₆): δ = 28.9, 59.5, 81.9, 109.4 (t, ^³ J _CF = 6.4 Hz), 112.8 (t, ^³ J _CF = 2.4 Hz), 114.9, 124.6, (t, ^¹ J _CF = 290 Hz), 126.9, 129.0, 129.6, 135.2 (t, ^² J _CF = 30 Hz), 137.8, 139.7, 148.0, 151.3. MS: m/z (%) = 361(13) [M⁺ + 2], 359(36) [M⁺], 304(23), 303(100), 269(16), 268(75), 57(13). Anal. Calcd for C₁₉H₁₆ClF₂N₃: C, 63.42; H, 4.48; Cl, 9.85; F, 10.56; N, 11.68. Found: C, 63.50; H, 4.53; N, 11.75.

21

The General Procedure for Synthesis of Pyrrolo[2,3- b ]pyridines 11 and 13 5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.33 g, 2 mmol) and diketone 10 (or 12, 2.2 mmol) were dissolved in AcOH (20 mL) and heated under reflux in the inert atmosphere during 1 h. Then this solution was evaporated under reduced pressure, treated with H₂O, filtrated, and dried on the air and recrystallized from an appropriate solvent, or was subjected to column chromatography over SiO₂.

22a Zanatta N. Amaral SS. Esteves-Souza A. Echevarria A. Brondani PB. Flores DC. Bonacorso HG. Flores AFC. Martins MAP. Synthesis  2006,  2305 

22b Kondratov IS. Gerus II. Kacharov AD. Gorbunova MG. Kukhar VP. Froehlich R. J. Fluorine Chem.  2005,  126:  543 

22c Matsumoto N. Takahashi M. Tetrahedron Lett.  2005,  46:  5551 

23

The Procedure for the Synthesis of ( E )-1- tert -Butyl-5-(4,4,4-trifluoro-3-oxobut-1-enylamino)-1 H -pyrrole-3-carbonitrile (15) 5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.66 g,
4 mmol) and 14 (0.68 g, 4.4 mmol) were dissolved in abs. DMF (10 mL) and heated under inert atmosphere at 85 ˚C for 12 h. The solution was evaporated under reduced pressure, treated with H₂O, and dried under reduced pressure. Afterwards, the residue was subjected to column chromatography over SiO₂. Colorless solid (0.78 g, 68%); mp 116-118 ˚C; R _f = 0.75 (hexane-EtOAc, 5:1). ^¹H NMR (400 MHz, CDCl₃): d = 1.59 (9 H, s, CH₃), 5.68 (1 H, d, ^³ J _HH = 8 Hz), 6.20 (1 H, s.), 7.13 (1 H, s), 7.29 (1 H, dd, ^³ J _HH = 8 Hz, ^³ J _HH = 4 Hz), 11.80
(1 H, d, ^³ J _HH = 4 Hz, NH). ^¹³C NMR (100.5 MHz, CDCl₃): d = 29.9, 58.1, 90.7, 91.0, 103.7, 119.8 (d, ^¹ J _CF = 285 Hz), 117.7, 131.0, 140.7, 153.3, 180.2 (q, ^² J _CF = 33 Hz). MS: m/z (%) = 286(11) [M⁺ + 1], 285(56) [M⁺], 239(22), 229(77), 170(11), 160(90), 57(100), 41(37). Anal. Calcd for C₁₃H₁₄F₃N₃O: C, 54.73; H, 4.95; F, 19.98; N, 14.73; O, 5.61. Found: C, 54.80; H, 4.98; N, 14.78.

24

Procedure for the Synthesis of 1- tert -Butyl-4-(trifluoro-methyl)-1 H -pyrrolo[2,3- b ]pyridine-3-carbonitrile (16)
1-tert-Butyl-5-(4,4,4-trifluoro-3-oxobut-1-enylamino)-1H-pyrrole-3-carbonitrile (15, 0.57 g, 2 mmol) in a 10 mL flask was melted for 5 h under inert atmosphere at 180 ˚C (temperature of the oil bath), then the dark-green residue formed was subjected to column chromatography over SiO₂.
Colorless solid (0.38 g, 71%); mp 161-163 ˚C. R _f = 0.75 (hexane-EtOAc, 5:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.78 (9 H, s, CH₃), 7.41 (1 H, d, ^³ J _HH = 4.7 Hz, H), 7.99 (1 H, s), 8.49 (1 H, d, ^³ J _HH = 4.7 Hz). ^¹³C NMR (100.5 MHz, CDCl₃): δ = 29.0, 59.3, 82.8, 113.8 (q, ^³ J _CF = 4.7 Hz), 114.5, 115.7, 122.8 (q, ^² J _CF = 270 Hz), 129.8 (q, ^² J _CF = 35 Hz), 136.3, 143.7, 148.3. MS: m/z (%) = 267(48) [M⁺], 212(58), 211(100), 192(24), 57(39), 56(10), 41(25). Anal. Calcd for C₁₃H₁₂F₃N₃: C, 58.42; H, 4.53; F, 21.33; N, 15.72. Found: C, 58.50; H, 4.59; N, 15.71.

25

Crystallographic data (excluding structure factors) for the structure11c reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 683574 and can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; email: [e-mail], or via www.ccdc.cam.ac.uk/data_request/cif.