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DOI: 10.1055/s-2004-832851
Fluorescent 7-Deazapurine Derivatives from 5-Iodocytosine via a Tandem Cross-Coupling-Annulation Reaction with Terminal Alkynes
Publication History
Publication Date:
28 September 2004 (online)
Abstract
Fluorescent bicyclic analogs of cytosine have been synthesized directly from derivatives of 5-iodocytosine by a one-pot sequential Sonogashira cross-coupling and annulation with terminal alkynes. The spectral properties of these compounds depend on the identity of the alkyne. 7-Deazapurines synthesized from substituted phenylacetylenes possess greater fluorescence than those derived from alkyl substituted alkynes.
Key words
annulation - cross-coupling - nucleobase - pyrrolocytosine - peptide nucleic acid
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Robins MJ.Barr PJ. J. Org. Chem. 1983, 48: 1854 -
3a
Woo J.Meyer RB.Gamper HB. Nucleic Acids Res. 1996, 24: 2470 -
3b
Berry DA.Jung K.-Y.Wise DS.Sercel AD.Pearson WH.Mackie H.Randolph JB.Somers RL. Tetrahedron Lett. 2004, 45: 2457 - 4
Liu C.Martin CT. J. Mol. Biol. 2001, 308: 465 - Recent examples of the use of pC include:
-
5a
Dash C.Rausch JW.Le Grice Stuart FJ. Nucleic Acids Res. 2004, 32: 1539 -
5b
Chen P.He C. J. Am. Chem. Soc. 2004, 126: 728 - 6
Hudson RHE.Li G.Tse J. Tetrahedron Lett. 2002, 43: 1381 - 7
Hudson RHE.Viirre RD.McCourt N.Tse J. Nucleosides, Nucleotides Nucleic Acids 2003, 22: 1029 - 8
Froehler BC.Jones RJ.Cao X.Terhorst TJ. Tetrahedron Lett. 1993, 34: 1003 -
9a
Hobbs FW. J. Org. Chem. 1989, 54: 3420 -
9b For a recent example see:
Roychowdhury A.Illangkoon H.Hendrickson CL.Benner SA. Org. Lett. 2004, 6: 489 -
10a
Sonogashira K.Tohda Y.Hagihara N. Tetrahedron Lett. 1975, 4467 -
10b
Stephens RD.Castro CE. J. Org. Chem. 1963, 28: 3313 - 11 A similar result has been observed in the synthesis of 2-substituted indoles:
Kabalka GW.Wang L.Pagni RM. Tetrahedron 2001, 57: 8017 - 12
Hudson RHE.Viirre RD.Liu YH.Wojciechowski F.Dambenieks AK. Pure Appl. Chem. 2004, in press - 14
Inoue H.Imura A.Ohtsuka E. Nippon Kagaku Kaishi 1987, 7: 1214 - 15
Larock RC.Yum EK.Refvik MD. J. Org. Chem. 1998, 63: 7652 ; and references therein - 16
Seela F.Chen Y.Bindig U.Kazimierczuk Z. Helv. Chim. Acta 1994, 77: 194 - 17
Balogh L.Blumstein A. Macromolecules 1995, 28: 5691 - 20 Ferrocenyl-substituted furanouridine has been prepared but no mention was made of its fluorescence properties:
Yu CJ.Yowanto H.Wan Y.Meade TJ.Chong Y.Strong M.Donilon LH.Kayyem JF.Gozin M.Blackburn GF. J. Am. Chem. Soc. 2000, 122: 6767 - 21
Yoshimoto K.Xu C.-Y.Nishizawa S.Haga T.Satake H.Teramae N. Chem. Commun. 2003, 2960
References
Current address: Department of Chemistry, 80 St. George Street, University of Toronto, Toronto, ON, M5S 3H6, Canada.
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Typical Procedure for Cross-Coupling without Cyclization:
Compound 1 (1.0 mmol) was suspended in dry, deoxygenated DMF (7 mL) to which CuI (0.2 mmol), Et3N (2.0 mmol), alkyne (3.0 mmol) and Pd(PPh3)4 (0.1 mmol) were sequentially added. The reaction mixtures were stirred in the dark at r.t. for 24 h and products were isolated by precipitation in EtOAc or by flash chromatography. All NMR spectra were obtained at 400.1 MHz (1H) or 100.6 MHz (13C) in d
6-DMSO. Compound 3a: white solid, mp 211-213 °C (dec). 1H NMR: δ = 8.06 (s, 1 H), 7.77 (s, 1 H), 7.38-7.33 (m, 5 H), 6.98 (s, 1 H), 5.16 (s, 2 H), 4.54 (s, 2 H), 4.28 (s, 2 H), 3.28 (s, 3 H). 13C NMR: δ = 168.4, 160.1, 154.6, 142.0, 137.9, 108.2, 99.3, 66.4, 61.0, 57.4, 51.9, 14.0. HRMS: m/z calcd for C17H17N3O4: 327.1219; found: 327.1217. Compound 3b: white solid, mp 205-214 °C (dec). 1H NMR: δ = 7.94 (s, 1 H), 7.72 (s, 1 H), 7.39-7.31 (m, 5 H), 6.79 (s, 1 H), 5.16 (s, 2 H), 4.54 (s, 2 H), 2.39 (t, J = 6.9 Hz, 2 H), 1.54-1.47 (m, 2 H), 1.39-1.30 (m, 2 H), 1.27-1.26 (m, 4 H), 0.85 (t, J = 5.8 Hz, 3 H). 13C NMR: δ = 168.4, 165.1, 154.2, 148.9, 135.7, 128.4, 128.1, 127.9, 95.8, 90.1, 71.5, 66.2, 49.9, 30.8, 28.1, 28.0, 22.0, 19.0, 14.0. HRMS: m/z calcd for C21H25N3O3: 367.1896; found: 367.1888. Compound 3c: off-white solid, mp 214-216 °C (dec). 1H NMR: δ = 8.11 (s, 1 H), 7.82 (s, 1 H), 7.37-7.32 (m, 5 H), 6.72 (s, 1 H), 5.16 (s, 2 H), 4.54 (s, 2 H), 0.20 (s, 9 H). 13C NMR: δ = 168.3, 164.6, 153.9, 150.8, 135.6, 128.5, 128.2, 127.9, 99.7, 96.4, 89.3, 66.3, 50.0, -0.1. HRMS: m/z calcd for C18H21N3O3Si: 355.1352; found: 355.1360. Compound 3d: beige solid, mp 235 °C (dec). 1H NMR: δ = 8.18 (s, 1 H), 7.85 (s, 1 H), 7.60-7.58 (m, 2 H), 7.42-7.31 (m, 8 H), 7.14 (s, 1 H), 5.18 (s, 2 H), 4.60 (s, 2 H). 13C NMR: δ = 168.3, 164.5, 154.1, 150.2, 135.7, 131.4, 131.2, 128.5, 128.5, 127.9, 122.4, 93.9, 89.2, 81.1, 66.3, 50.1. HRMS: m/z calcd for C21H17N3O3: 359.1270; found: 359.1281.
Typical Procedure for the Heteroannulation Reaction:
Compound 3 (1.0 mmol) was dissolved in dry, deoxygenated DMF (7 mL) to which CuI (0.2 mmol), Et3N (2.0 mmol), alkyne (3.0 mmol) and Pd(PPh3)4 (0.1 mmol) were sequentially added. The reaction mixtures were stirred in the dark at 50 °C for 24 h after which the solvent was removed under vacuum. The reaction mixture was redissolved in absolute EtOH and refluxed for 18 h. All products were isolated by silica gel column chromatography. All NMR spectra were obtained at 400.1 MHz (1H) or 100.6 MHz (13C) in d
6-DMSO. Compound 4a: pale yellow solid, mp 205-207 °C (dec). 1H NMR: δ = 11.37 (1 H, br s), 8.39 (1 H, s), 6.22 (1 H, s), 4.69 (2 H, s), 4.33 (2 H, s), 4.13 (2 H, q, J = 7.1 Hz), 3.26 (3 H, s), 1.19 (3 H, t, J = 7.2 Hz). 13C NMR: δ = 168.4, 141.9, 137.9, 108.6, 99.4, 66.4, 61.0, 57.4, 14.0. HRMS: m/z calcd for C12H15N3O4: 265.1063; found: 265.1057. Compound 4b: pale yellow solid, mp 134-139 °C. 1H NMR: δ = 11.15 (1 H, s), 8.24 (1 H, s), 5.93 (1 H, s), 4.67 (2 H, s), 4.12 (2 H, q, J = 7.1 Hz), 1.16 (16 H, overlapping signals). HRMS: m/z calcd for C16H23N3O3: 305.17394; found: 305.17383. Compound 4c: pale yellow solid, mp 211-218 °C (dec). 1H NMR: δ = 11.24 (1 H, s), 8.46 (1 H, s), 6.46 (1 H, s), 4.71 (2 H, s), 4.13 (2 H, q, J = 7.1 Hz), 1.19 (3 H, t, J = 7.2 Hz), 0.25 (9 H, s). HRMS: m/z calcd for C13H19N3O3Si: 293.1196; found: 293.1197. Compound 4d: green solid, mp 335-338 °C (dec). 1H NMR: δ = 11.83 (1 H, br s), 8.46 (1 H, s), 7.83 (2 H, d, J = 7.4 Hz), 7.44 (2 H, t, J = 7.7 Hz), 7.34 (1 H, t, J = 7.5 Hz), 6.78 (1 H, s), 4.72 (2 H, s), 4.14 (2 H, q, J = 7.1 Hz), 1.20 (3 H, t, J = 7.1 Hz). HRMS: m/z calcd for C16H15N3O3: 297.1113; found: 297.1119. Compound 4e: yellow solid, mp 279-284 °C (dec). 1H NMR: δ = 11.74 (1 H, s), 8.38 (1 H, s), 7.77 (2 H, d, J = 6.9 Hz), 7.00 (2 H, d, J = 6.9 Hz), 6.62 (1 H, s), 4.71 (2 H, s), 4.14 (2 H, q, J = 7.1 Hz), 3.79 (3 H, s), 1.20 (3 H, t, J = 7.1 Hz). HRMS: m/z calcd for C17H17N3O4: 327.1219; found: 327.1223. Compound 4f: orange solid, mp 280-285 °C (dec). 1H NMR: δ = 12.08 (1 H, br s), 8.63 (1 H, s), 8.28 (2 H, d, J = 9.0 Hz), 8.09 (2 H, d, J = 8.8 Hz), 7.13 (1 H, s), 4.75 (2 H, s), 4.15 (2 H, q, J = 7.1 Hz), 1.21 (3 H, t, J = 7.1 Hz). HRMS: m/z calcd for C16H14N4O5: 342.0964; found: 342.0972. Compound 4g: yellow solid mp 154-158 °C (dec). 1H NMR: δ = 11.61 (1 H, br s), 8.27 (1 H, s), 7.64 (2 H, d, J = 9.0 Hz), 6.74 (2 H, d, J = 9.0 Hz), 6.46 (1 H, s), 4.68 (2 H, s), 4.13 (2 H, q, J = 7.0 Hz), 2.94 (6 H, s), 1.20 (3 H, t, J = 7.0 Hz). LR ESI-TOF: m/e (%) = 381.1 (75) [K adduct], 325.0(100) [-CH3], 268.9 (15), 147.1 (25); calcd for C18H20N4O3: 340.4. Compound 4h: red-brown solid, mp 136-141 °C. 1H NMR: δ = 11.48 (1 H, br s), 8.27 (1 H, s), 6.28 (1 H, s), 4.85 (2 H, br t, J = 1.7 Hz), 4.68 (2 H, s), 4.38 (2 H, br t, J = 1.7 Hz), 4.14 (2 H, q, J = 7.1 Hz), 4.09 (5 H, s), 1.21 (3 H, t, J = 7.1 Hz). HRMS: m/z calcd for C20H19FeN3O3: 405.0775; found: 405.0768.
The electron-rich substituted pyrroles 4e and 4g were markedly less stable than the parent phenyl-substituted (4d) or p-nitrophenyl substituted (4f) compounds. Whilst 4d and 4f are stable in solution for months, 4e (p-methoxy) slowly decomposed to non-fluorescent products over the same timeframe and 4g was isolated with difficulty.