Synthesis of thioether derivatives of ethidium bromide

Article abstract of DOI:10.1016/S0040-4039(00)93416-6

3,8-Dithiocyanato-5-ethyl-6-phenylphenanthridinium iodide was prepared via diazotization of ethidium bromide. Reduction with aqueous Na₂S followed by alkalation gave cationic thioether derivatives.

Full text of DOI:10.1016/S0040-4039(00)93416-6

T~trahedron Letters, Vol.32, No.38, pp 5019-5020, 1991
Printed inGreat Britain
0040~t039/91 $3.00 +.00
Pergamon Press plc
SYNTHESIS OF THIOETHER DERIVATIVES OF ETHIDIUM BROMIDE
Gregory T. Whiteker and Stephen J. Lippard*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, MA 02139
Abstract. 3,8-Dithiocyanato-5-ethyl-6-phenylphenanthridinium iodide was
diazotization
cationic thioether
of
bromide. Reduction with aqueous
followed by
derivatives.
which intercalate into
important uses
chemotherapy and molecular
In conjunction with ongoing studies metallointercalator complexes,3
sought to prepare
intercalators with exocyclic thioether substituents for coordination to thiophilic, late transition metals.
The resulting compounds and procedure are of potential value to medicinal chemists interested in
intercalator based antibiotics.4
H
2
N
~
-
~
'
- NH2
a,b ~- N C S ~ ~ ~ - - S C N
_ 2 =N*_
_
1
phTN;
Pli
Et
EtdBr
C
H
a
S
-
~
~ SCH3
d
H
S
~
S
ph/~= NEt
3
2
Conditions. (a) NaNO2,HC1, 0 °C. (b) K S C(c)NNa.2S, H20-acetone. (d) CH3I.
Diazotization of the DNA i n t e r c aEl ta dt5oBwrars followed by reaction with KSCN to give 3,8-
dithiocyanato-5-ethyl-6-phenylphenanthridinium
(1) in
electrophilic phenanthridinium
Aqueous 8 however,
yield.9 of the
yield after
exchange.6
which
reduced the
of 1
underwent
thiocyanate, 1,
gave thioether in 74%
procedure described
via diazotization an aromatic
reduction of thiocyanates, n
complicated by
reduction with
give air-sensitive
presence of
7
2 in
yield.1°
thiol with
a general
The use
for the
the non-nucleophilic
of heterocyclic
Na2S, allows

5020
(1) Remers, W. A. J. Nat. Prod. 1985, 48, 173.
(2) Dervan, P. B. Science 1986, 232, 464.
(3) Bowler, B. E.; Ahmed, K. J.; Sundquist, W. I.; Hollis, L. S.; Whang, E. E.; Lippard, S. J. J. Am. Chem.
Soc. 1989, 111, 1299.
(4) Gale, E. F.; Cundliffe, E.; Reynolds, P. E.; Richmond, M. H.; Waring, M. J. The Molecular Basis oJ
Antibiotic Action; 2nd ed.; John Wiley & Sons: New York, 1981.
(5) Firth, W. J.; Watkins, C. L.; Graves, D. E.; Yielding, L. W. J. Heterocyclic Chem. 1983, 20, 759.
(6) 1H NMR (acetone-d6) 8 9.48 (d, J=9.6 Hz, 1H, H1);~9.42 (d, J=9.0 Hz, ! H, H!O); 9.11 (d, j=l.5 Hz, H4);
8.60 (dd, J=9.0, 1.4 Hz, 1H, Hg); 8.44 (dd, J=8.7, 1.2 Hz, 1H, H2); 7.96 (d, J=1.4 Hz, 1H, H7); 7.94 (m, 5H, Ph);
5.17 (q, J=7 Hz, 2H, CH2); 1.73 (t, J=7 Hz, 3H, CH3). IR (KBr) 2161 (m) cm-1. HRMS (FAB, m-nitrobenzyl
alcohol matrix) Calcd for C23H16N3S2+: 398.0786, Obsd 398.0783.
(7) Patai, S. The Chemistry of the Thiol Group; Wiley Interscience: London, 1974, pp 232.
(8) Davies, W. H.; Sexton, W. A. J. Chem. Soc. 1944, 11.
(9) 1FI NMR (CD3OD) 8 8.39 (d, J=8.9 Hz, 1H, H1); 8.34 (d, J=8.9 Hz, 1H, H10); 8.19 (d, J=2 Hz, 1H, H4);
8.05 (dd, J=8.9, 2 Hz, 1H, H9); 7.88 (dd, J=8.9, 2 Hz, 1H, H2); 7.74 - 7.60 (m, 5H, Ph), 7.38 (d, J=2 Hz, 1H, H7);
4.63 (q, J=7 Hz, 2H, CH2); 1.53 (t, J=7Hz, 3H, CH3). Mass Spectrum: m/e : 347, [m]+.
(10) 1H NMR (DMF-d7) 8 9.22 (d, J=8.9 Hz, 1H, H1); 9.18 (d, J=9.0 Hz, 1H, H10); 8.39 (d, J=1.5 Hz, 1H, H4);
8.28 (dd, J=8.7, 2.0 Hz, 1H, H9); 8.09 (dd, J=8.8, 1.5 I/z, 1H, H2); 7.90 (m, 5H, Ph); 7.15 (d, J=2 Hz, 1H, H7);
5.08 (q, J=7 Hz, 2H, CH2); 2.90 (s, 3H, SCH3); 2.50 (s, 3H, SCH3); 1.65 (t, J=7 Hz, 3H, CH3). HRMS (FAB, m-
nitrobenzyl alcohol matrix) Calcd for C23H22NS2+: 376.1194, Obsd 376.1192.
(11) This work was supported by a grant from the National Cancer Institute. G.T.W. thanks the
National Institutes of Health and the American Cancer Society for postdoctoral fellowships.
(Received in USA 3 June 1991)