D
C. E. Miron, A. Petitjean
Letter
Synlett
comparison to the 21% overall yield reported in the previ-
ous synthesis of Phen-DC3.7 The alternate synthetic route,
which eliminates the need for three explosive, toxic, or car-
cinogenic reagents, should allow research laboratories to
more readily implement large-scale syntheses of Phen-
DC3, thereby enabling its widespread use as a benchmark
compound against which novel G4 ligands can be com-
pared.
Teulade-Fichou, M.-P.; Vesnaver, G.; Haider, S.; Lah, J. Biophys. J.
2015, 108, 2903. (d) Lacroix, L.; Séosse, A.; Mergny, J.-L. Nucleic
Acids Res. 2011, 39, e21. (e) Guilbaud, G.; Murat, P.; Recolin, B.;
Campbell, B. C.; Maiter, A.; Sale, J. E.; Balasubramanian, S. Nat.
Chem. 2017, 9, 1110. (f) Gomez, D.; Guédin, A.; Mergny, J.-L.;
Salles, B.; Riou, J.-F.; Teulade-Fichou, M.-P.; Calsou, P. Nucleic
Acids Res. 2010, 38, 7187.
(10) Larsen, A. F.; Ulven, T. Org. Lett. 2011, 13, 3546.
(11) (a) Albrecht, M. Chem. Eur J. 2000, 6, 3485. (b) Qi, H.; Teesdale, J.
J.; Pupillo, R. C.; Rosenthal, J.; Bard, A. J. J. Am. Chem. Soc. 2013,
135, 13558. (c) Jun, L.; Zheng, M.; Li, W.; Wang, H.; Zhang, H.;
Wu, H.; Jia, Z.; Zheng, L.; Tian, J. CN 102040608, 2011. (d) Qi, D.;
Wang, X. CN 105884683, 2014.
Funding Information
Funding from the Natural Sciences and Engineering Research Council
(NSERC-DG, grant number 315311-2013; NSERC PGS-D), the Canada
(12) (a) Beer, R. H.; Jimenez, J.; Drago, R. S. J. Org. Chem. 1993, 58,
1746. (b) Lamarque, L.; Bazin, H.; Blanche, E. WO 2010070232,
2010. (c) Goswami, S.; Maity, A. C.; Fun, H.-K. Chem. Lett. 2007,
36, 552. (d) This observation is consistent with oxygen acting as
both oxidant and radical scavenger, thereby impeding progress
along the chlorinating radical reaction pathway, see: Anderson,
A. G.; Tober, T. Y. J. Org. Chem. 1980, 45, 1695.
(13) Holbrook, M. T. Carbon Tetrachloride, In Kirk-Othmer Encyclope-
dia of Chemical Technology; John Wiley and Sons: New York,
2000, 1.
Foundation for Innovation, and Queen’s University is acknowledged.
N
a
utarSelcnicesa
n
d
E
n
gn
i
e
enri
g
R
esearch
C
o
u
noClfic
a
n
a
d
a
3(
1
5
3
1
1-2
0
1
3)
Supporting Information
Supporting information for this article is available online at
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(14) Experimental
References and Notes
Commercially available compounds were used as received.
Reagents for reactions requiring anhydrous conditions were
pre-dried under vacuum and P2O5. Column chromatography
was performed with Silica-P flash silica gel (40–63 μm particle
size, 60 Å pore diameter). NMR data was obtained with 300
MHz, 400 MHz, and 500 MHz Bruker instruments at 25 °C.
CDCl3 was neutralized before use by passing through a short
column of basic alumina. Peak listings for all spectra are given
in ppm and referenced against the signal of the residual solvent
signal (1H NMR) or internal standard (19F NMR).
(1) (a) Neidle, S. J. Med. Chem. 2016, 59, 5987. (b) Brooks, T. A.;
Kendrick, S.; Hurley, L. FEBS J. 2010, 277, 3459. (c) Müller, S.;
Rodriguez, R. Expert Rev. Clin. Pharmacol. 2014, 7, 663. (d) Patel,
D. J.; Phan, A. T.; Kuryavyi, V. Nucleic Acids Res. 2007, 35, 7429.
(2) Harris, L. M.; Merrick, C. J. PLoS Pathog. 2015, 11, e1004562.
(3) (a) Huppert, J. L. Chem. Soc. Rev. 2008, 37, 1375. (b) Burge, S.;
Parkinson, G. N.; Hazel, P.; Todd, A. K.; Neidle, S. Nucleic Acids
Res. 2006, 34, 5402.
(4) Kim, N. W.; Piatyszek, M. A.; Prowse, K. R.; Harley, C. B.; West,
M. D.; Ho, P. L. C.; Coviello, G. M.; Wright, W. E.; Weinrich, S. L.;
Shay, J. W. Science 1994, 266, 2011.
(15) 2,9-Bis(trichloromethyl)-1,10-phenanthroline (2)
To a solution of 2,9-dimethyl-1,10-phenanthroline (430 mg, 2.1
mmol, 1.0 equiv) in chloroform (17 mL) under argon atmo-
sphere at room temperature was added dropwise a solution of
N-chlorosuccinimide (NCS, 2.2 g, 0.017 mol, 8.0 equiv) in chlo-
roform (72 mL). The reaction mixture was protected from light
while stirring and heating under reflux (6 h). The reaction
mixture was then cooled to 4 °C and filtered. The filtrate was
concentrated under reduced pressure to yield the crude prod-
uct. Purification by column chromatography using gradient
CHCl3/hexanes (1:1 to 2:1) afforded pure compound 2 (590 mg,
68%). CH2Cl2/hexanes was also tested as eluent but gave a
slightly poorer separation by TLC. 1H NMR (400 MHz, CDCl3):
(5) Merle, P.; Evrard, B.; Petitjean, A.; Lehn, J.-M.; Teulade-Fichou,
M.-P.; Chautard, E.; De Cian, A.; Guittat, L.; Tran, P. L. T.; Mergny,
J.-L.; Verrelle, P.; Tchirkov, A. Mol. Cancer Ther. 2011, 10, 1784.
(6) (a) Perrone, R.; Nadai, M.; Frasson, I.; Poe, J. A.; Butovskaya, E.;
Smithgall, T. E.; Palumbo, M.; Palù, G.; Richter, S. N. J. Med.
Chem. 2013, 56, 6521. (b) Amrane, S.; Kerkour, A.; Bedrat, A.;
Vialet, B.; Andreola, M.-L.; Mergny, J.-L. J. Am. Chem. Soc. 2014,
136, 5249. (c) Lista, M. J.; Martins, R. P.; Billant, O.; Contesse, M.-
A.; Findakly, S.; Pochard, P.; Daskalogianni, C.; Beauvineau, C.;
Guetta, C.; Jamin, C.; Teulade-Fichou, M.-P.; Fåhraeus, R.;
Voisset, C.; Blondel, M. Nat. Commun. 2017, 8, 16043.
(d) Madireddy, A.; Purushothaman, P.; Loosbroock, C. P.;
Robertson, E. S.; Schildkraut, C. L.; Verma, S. C. Nucleic Acids Res.
2016, 44, 3675. (e) Biswas, B.; Kandpal, M.; Jauhari, U. K.;
Vivekanandan, P. BMC Genomics 2016, 17, 949. (f) Fleming, A.
M.; Ding, Y.; Alenko, A.; Burrows, C. J. ACS Infect. Dis. 2016, 2, 674.
(7) De Cian, A.; DeLemos, E.; Mergny, J.-L.; Teulade-Fichou, M.-P.;
Monchaud, D. J. Am. Chem. Soc. 2007, 129, 1856.
(8) (a) Chung, W. J.; Heddi, B.; Hamon, F.; Teulade-Fichou, M.-P.;
Phan, A. T. Angew. Chem. Int. Ed. 2014, 53, 999. (b) Quadruplex
graphic generated using the PyMOL Molecular Graphics System,
version 1.3, Schroedinger.
(9) (a) De Rache, A.; Mergny, J.-L. Biochimie 2015, 115, 194.
(b) Monchaud, D.; Allain, C.; Bertrand, H.; Smargiasso, N.; Rosu,
F.; Gabelica, V.; De Cian, A.; Mergny, J.-L.; Teulade-Fichou, M.-P.
Biochimie 2008, 90, 1207. (c) Bončina, M.; Hamon, F.; Islam, B.;
3
3
δ =7.96 (s, 2 H), 8.32 (d, J = 8 Hz, 2 H), 8.44 (d, J = 8 Hz, 2 H).
Rf = 0.26 (1:1 CHCl3/hexanes); mp. 227 °C (lit. 225–227°C).11c
(16) 1,10-Phenanthroline-2,9-dicarboxylic acid (3)
A solution of 2 (540 mg, 1.3 mmol, 1.0 equiv) in concentrated
aqueous sulfuric acid (95–98%, 17 mL) was stirred at 85 °C for 7
h. Following this, the brown solution was cooled to room tem-
perature and poured over crushed ice. The ice was allowed to
melt and the resulting white suspension filtered under vacuum,
washed with water, and air-dried to afford pure compound 3
(360 mg, quant. yield). 1H NMR (300 MHz, DMSO-d6): δ = 8.22
3
3
(s, 2 H), 8.42 (d, J = 8.4 Hz, 2 H), 8.74 (d, J = 8.4 Hz, 2 H); mp
215–216 °C (dec.).
(17) Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J. Hazard Mater.
2005, 126, 1.
(18) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
(b) Nakajima, N.; Ikada, Y. Bioconjugate Chem. 1995, 6, 123.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E