Cytotoxicity of (2,2′:6′,2′′-Terpyridine)platinum(II)
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1003
filtrate and extracts were then concentrated in vacuo, and the
white solid so obtained was collected by filtration and recrys-
tallized from dichloromethane to afford white needles of 4′-
(N,N-bis(2-hydroxyethyl)amino)-2,2′:6′,2′′-terpyridine (352 mg,
31%): mp 171-172 °C. δH (500 MHz, CD3OD): 8.61 (dd, 4J (6,4)
5′); 7.84 (2H, td, J ) 1.8, 7.7, terpy H4/4′′); 8.60 (2H, d, J )
8.0, terpy H3/3′′); 8.66-8.69 (2H, m, terpy H6/6′′). m/z
(+ESI): 249 (MH+).
4′-F lu or o-2,2′:6′,2′′-ter p yr id in e. A suspension of 4′-amino-
2,2′:6′,6′′-terpyridine (0.185 g, 0.75 mmol) in fluoroboric acid
(50%; 1.0 mL) was stirred and treated dropwise at 0 °C with
a cold solution of sodium nitrite (0.10 g, 1.4 mmol) in water
(0.5 mL). Most of the solid dissolved to give a bright-yellow
solution. The mixture was stirred at 0 °C for 1 h and then
allowed to warm to room temperature and stirred for a further
1 h. The mixture was cooled again to 0 °C and basified with
aqueous sodium hydroxide (50%). A yellow solid was precipi-
tated, and the mixture was extracted with chloroform (3 × 10
mL). The organic extracts were dried and evaporated and the
residual brown gum flash chromatographed over alumina
eluting with light petroleum-ether (10:1). The fractions
containing terpyridine were combined and evaporated and the
material was further purified by preparative TLC on alumina
to remove 4′-chloroterpyridine formed as a byproduct (7%).
Elution six times with light petroleum-ether (50:1) afforded
the title compound as a colorless solid (0.043 g, 23%). Crystal-
lization from light petroleum-dichloromethane gave colorless
needles: mp 114-115 °C. Anal. (C15H10FN3) C, 71.4; H, 4.0;
N, 16.5. νmax(Nujol)/cm-1: 1597, 1581, 1468, 1403, 1173, 931,
and 790. δH(200 MHz, CDCl3): 7.36 (2H, ddd, J ) 0.9, 4.8,
and 7.4 Hz, terpy H5/5′′); 7.86 (2H, td, J ) 1.8, 7.7, terpy H4/
4′′); 8.19 (2H, d, J HF ) 9.7, terpy H3′/5′); 8.61 (2H, d, J ) 8.6,
terpy H3/3′′); 8.70 (2H, d, J 4.5, terpy H6/6′′). δC(50 MHz,
CDCl3): 108.5 (d, J CF ) 19.5, C3′/5′); 121.3 and 124.3 (C3/3′′
and C5/5′′); 136.9 (C4/4′′); 149.2 (C6/6′′); 155.0 (C2/2′′); 158.6
(d, J CF 7.3, C2′/6′); 170.77 (d, J CF ) 259.8, C4′); δF(235 MHz,
CDCl3) -102.0; m/z (APCI+) 252(MH+).
3
3
) 1.4, J (6,5) ) 4.5, 2H, H-C(6), H-C(6′′)); 8.52 (d, J (3,4) )
8.0, 2H, H-C(3), H-C(3′′)); 7.93 (dt, 4J (4,6) ) 1.8, 3J (4,3) )
3J (4,5) ) 7.7, 2H, H-C(4), H-C(4′′)); 7.68 (s, 2H, H-C(3′),
4
3
3
H-C(5′)); 7.42 (ddd, J (5,3) ) 1.2, J (5,6) ) 4.9, J (5,4) ) 7.5,
2H, H-C(5), H-C(5′′)); 3.85 (t, 3J vic ) 5.9, 4H, H2-COH); 3.75
(t, J vic ) 5.9, 4H, H2-CNterpy). δC (50.3 MHz, CD3OD):
3
156.92 (C(4′)); 155.66 (C(2)/C(2′), C(6′)/C(2′′)); 155.25 (C(2)/
C(2′), C(6′)/C(2′′)); 148.55 (C(6)/C(6′′)); 137.49 (C(4)/C(4′′));
123.49 (C(5)/C(5′′)); 121.94 (C(3)/C(3′′)); 103.91 (C(3′)/C(5′));
58.72 (H2COH); 52.86 (H2CNterpy). m/z (+ESI): 377 (MH+).
Anal. (C19H20N4O2) C, 67.6; H, 6.0; N, 16.4%.
Isola tion a n d Ch a r a cter iza tion of th e Tw o Alk oxy
Sid e P r od u cts. When 2-propanol is replaced by ethanol/
methanol (1:1, v/v, 80 mL) in the previous experiment, the
dichloromethane filtrate remaining from the recrystallization
when evaporated in vacuo gave a solid residue which on
chromatography on an alumina preparative plate using pe-
troleum ether (bp 40-60 °C)/EtOAc (7:1) as eluant gave three
bands identified as 4′-chloro-2,2′:6′,2′′-terpyridine, 4′-methoxy-
2,2′:6′,2′′-terpyridine, and 4′-ethoxy-2,2′:6′,2′′-terpyridine.
4′-Met h oxy-2,2′:6′,2′′-t er p yr id in e: mp 56-57 °C. Anal.
(C16H13N3O) C, 72.8; H, 5.0; N, 15.8. TLC (alumina, petroleum
ether (40-60 °C)/EtOAc, 3:1): Rf ) 0.53. δH (200 MHz,
CDCl3): 8.71 (d, 3J (6,5) ) 4.7, 2H, H-C(6), H-C(6′′)); 8.64 (d,
3J (3,4) ) 8.0, 2H, H-C(3), H-C(3′′)); 8.04 (s, 2H, H-C(3′),
4
3
3
H-C(5′)); 7.87 (dt, J (4,6) ) 1.8, J (4,3) ) J (4,5) ) 7.8, 2H,
H-C(4), H-C(4′′)); 7.34 (ddd, 4J (5,3) ) 1.1, 3J (5,6) ) 4.8,
3J (5,4) ) 7.5, 2H, H-C(5), H-C(5′′)); 4.05 (s, 3H, H3-COterpy).
δC (50.3 MHz, CDCl3): 168.15 (C(4′)); 157.35 (C(2)/C(2′), C(6′)/
C(2′′)); 156.33 (C(2)/C(2′), C(6′)/C(2′′)); 149.28 (C(6)/C(6′′));
137.04 (C(4)/C(4′′)); 124.03 (C(5)/C(5′′)); 121.54 (C(3)/C(3′′));
107.05 (C(3′)/C(5′)); 55.55 (H3COterpy). m/z (+ESI): 264 (MH+).
This compound can be prepared in excellent yield by metha-
nolysis of 4′-chloro-2,2′:6′,2′′-terpyridine activated by FeCl2‚
4H2O or by reaction of sodium methoxide with 4′-chloro-2,2′:
6′,2′′-terpyridine without activation.
4′-(N-2-H yd r oxyet h yl-N-m et h yla m in o)-2,2′:6′,2′′-t er -
p yr id in e. A solution of 4′-chloro-2,2′:6′,2′′-terpyridine (1.61 g,
6 mmol) in 20 mL of dichloromethane was added to a solution
of FeCl2‚4H2O (1.35 g, 6.8 mmol) in 2-propanol (100 mL). An
excess of N-methylethanolamine (20 mL) was then added to
the purple solution. The mixture was heated to reflux for 22
h under an atmosphere of argon and with stirring. It was then
concentrated by removal of solvent in vacuo to leave a viscous
purple oil. Addition of [NH4][PF6] (1.66 g, 10 mmol) in
methanol (10 mL) followed by diethyl ether (50 mL) gave a
purple gum [HOCH2CH2N(Me)terpy)2Fe][PF6] which was
worked up as for 4′-(N,N-bis(2-hydroxyethyl)amino)-2,2′:6′,2′′-
terpyridine (see above). The title product was recrystallized
from acetone/petroleum ether (bp 40-60 °C) to give 4′-(N-2-
hydroxyethyl-N-methylamino)-2,2′:6′,2′′-terpyridine (1.44 g,
78%): mp 148-150 °C. Anal. (C18H18N4O) C, 70.8; H, 5.6; N,
18.4. νmax (KBr)/cm-1: 3219(m,br), 2880-2820(m,br), 1609(m),
1592(s), 1567(s), 1459(m), 1412(m), 1228(w), 1055(s), 1006(m)
851(w), 790(s). δH (200 MHz, CDCl3): 8.65 (d, 3J (6,5) ) 4.5
Hz, 2H, H-C(6)/H-C(6′′)); 8.60 (d, 3J (3,4) ) 8.5, 2H, H-C(3)/
4′-E t h oxy-2,2′:6′,2′′-t er p yr id in e: mp 85-86 °C. Anal.
(C17H15N3O) C, 73.3; H, 5.5; N, 15.1. TLC (alumina, petroleum
ether (40-60 °C)/EtOAc, 3:1): Rf ) 0.59. δH (200 MHz, CDCl3):
3
3
8.70 (d, J (6,5) ) 4.1, 2H, H-C(6), H-C(6′′)); 8.63 (d, J (3,4)
) 8.1, 2H, H-C(3), H-C(3′′)); 8.02 (s, 2H, H-C(3′), H-C(5′));
7.86 (dt, 4J (4,6) ) 1.8, 3J (4,3) ) 3J (4,5) ) 7.3, 2H, H-C(4),
H-C(4′′)); 7.34 (ddd, 4J (5,3) ) 1.2, 3J (5,6) ) 4.8, 3J (5,4) ) 7.5,
3
2H, H-C(5), H-C(5′′)); 4.32 (q, 2H, J vic ) 7.1, 2H, H2-
3
COterpy); 1.50 (t, J vic ) 6.9,H3-CCH2). m/z (+ESI): 278
(MH+). This compound can be prepared in excellent yield by
ethanolysis of 4′-chloro-2,2′:6′,2′′-terpyridine activated by FeCl2‚
4H2O or by reaction of sodium ethoxide with 4′-chloro-2,2′:6′,2′′-
terpyridine without activation.
3
4
H-C(3′′)); 7.83 (dt, J (4,5) ) 7.77, J (4,6) ) 1.8, 2H, H-C(4)/
3
H-C(4′′)); 7.78 (s, 2H, H-C(3′)/H-C(5′)); 7.30 (ddd, J (5,4) )
4′-Am in o-2,2′:6′,2′′-ter p yr id in e. A solution of 4′-azido-2,2′:
6′,6′′-terpyridine (0.453 g; 1.65 mmol, prepared from 4′-
hydrazino-2,2′:6′,6′′-terpyridine, vide infra, by treatment with
nitrous acid) in dichloromethane (5.0 mL) and methanol (5.0
mL) was saturated with hydrogen sulfide at 0 °C and the
solution kept at room temperature for 4h by which time TLC
showed no azide to remain. The solution was degassed with
argon to remove hydrogen sulfide and then evaporated to
dryness. The residue was treated with sulfuric acid (2M, 3.0
mL) and the aqueous mixture filtered and washed with
dichloromethane to remove elemental sulfur. The solution was
basified by the dropwise addition of sodium hydroxide (50%)
and extracted with dichloromethane (3 × 20 mL). The com-
bined organic layers were dried and evaporated to give the
title compound as a pale yellow solid (0.398 g, 97%). Crystal-
lization from light petroleum-dichloromethane gave pale-
yellow brown needles: mp 228-230 °C. Anal. (C19H20N4O2) C,
72.5; H, 4.7; N, 22.2. νmax(Nujol)/cm-1: 3414, 3344, and 3226
(NH2). δH(200 MHz, CDCl3): 4.36 (2H, br s, NH2); 7.32 (2H,
ddd, J 1.2, 4.8, and 6.0, terpy H5/5′′); 7.75 (2H, s, terpyH3′/
7.4, 3J (5,6) ) 4.8, 4J (5,3) ) 1.1, 2H, H-C(5)/H-C(5′′));
3
3
3.9 (t, J vic ) 5.8, 2H, terpyNMe‚CH2CH2OH); 3.7 (t, J vic
)
5.8, 2H, terpyNMe‚CH2CH2OH); 3.2 (s, 3H, terpyNCH3‚
CH2CH2OH).
4′-(1-Meth ylh yd r a zin o)-2,2′:6′,2′′-ter p yr id in e. 4′-Chloro-
2,2′:6′,2′′-terpyridine (148 mg, 0.55 mmol) was dissolved in
isobutanol (3 mL) with warming. Excess methylhydrazine (0.8
mL) was added. The mixture was then heated to reflux, with
stirring, for 28 h. On cooling white needles crystallized out of
solution. The solid was collected by filtration and washed with
diethyl ether to yield analytically pure 4′-(1-methylhydrazino)-
2,2′:6′,2′′-terpyridine (132 mg, 86%): mp 217-219 °C. Anal.
(C16H15N5) C, 69.5; H, 5.1; N, 25.2. νmax(KBr)/cm-1: 3323(m),
3100-2700(w,br), 2359(w,br), 1562(s), 1582(s), 1470(s), 1408-
(s), 1093(m), 1005(m), 826(w). δH (200 MHz, CDCl3): 8.70 (d,
3J (6,5) ) 4.7, 2H, H-C(6)/H-C(6′′)); 8.64 (d, 3J (3,4) ) 7.98,
2H, H-C(3)/H-C(3′′)); 7.98 (s, 2H, H-C(3′)/H-C(5′)); 7.85 (dt,
3J (4,5) ) 7.56, 4J (4,6) ) 1.77, 2H, H-C(4)/H-C(4′′)); 7.33 (ddd,
3J (5,4) ) 7.4, 3J (5,6) ) 4.8, 4J (5,3) ) 1.2, 2H, H-C(5)/H-C(5′′));