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C. M. Reid et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2455–2458
In order to probe further the anti-protozoal activity of
1,4,7,10-tetraazacyclododecanes, we now report the syn-
thesis and biological testing of a focused library of C2-
substituted polyazamacrocycles 3, which are compounds
that lack reactive carbamate side-chains but still retain
significant in vivo activity against bloodstream form
African trypanosomes. The toxicity of these compounds
against malaria parasites from Plasmodium falciparum is
also described.
NH
NH
NH2
NH2
R
O
4
a
b
NH
Our first aim in this study was the synthesis of the parent,
unsubstituted 1,4,7,10-tetraazacyclododecane, cyclen 8.
Many different approaches for the synthesis of cyclen
have been reported due to its importance as an interme-
diate for the preparation of diagnostic and therapeutic
pharmaceutical agents.8–10 These methods include high
dilution conditions,11 Richman–Atkins cyclisations,12
as well as phase transfer conditions.13 All these processes
involve the condensation of terminal halides with bis-sul-
fonamide sodium salts. We recently used the phase trans-
fer approach for the synthesis of our carbamate-derived
polyazamacrocycles.7 However, for the preparation of
cyclen 8 on a large scale with reproducibly high yields,
a three-step approach involving bis-imidazoline 6 proved
the most efficient.14 Reaction of triethylenetetraamine 4
with N,N-dimethylformamide dimethyl acetal 5 under
neat conditions gave bis-imidazoline 6 in quantitative
yield (Scheme 1). Macrocyclisation of 6 with 1,2-dibro-
moethane in the presence of potassium carbonate gave
the imidazolinium compound 7 in quantitative yield.
Hydrolysis of 7 using potassium hydroxide gave cyclen
8 in 71% overall yield in only 3 steps.
O
NH
NH
Cl
Cl
R
Fe
NH
+
H
O
9
10-20
Cl
H
H
N
N
N
N
R
Fe
c
Cl
NH HN
R
NH HN
Having synthesised the parent 1,4,7,10-tetraazacyclod-
odecane, a series of C2-substituted analogues were then
prepared using a metal-templated approach involving
condensation of cis-iron dichloride complex 9 with a ser-
ies of glyoxals 10–20, followed by the reductive removal
of the metal template (Scheme 2).15 Glyoxals 10–20 were
easily prepared in one step by selenium dioxide oxida-
tion of the corresponding methyl ketone.16 This gave
glyoxals 10–20 in generally high yield and the majority
21-32
Scheme 2. Reagents and conditions: (a) FeCl3, MeOH; (b) SeO2, 1,4-
dioxane, H2O, R = tBu (10), 100%; 4-NO2–Ph (11), 80%; 4-MeO–Ph
(12), 100%; 4-Cl–Ph (13), 100%; 4-Br–Ph (14), 100%; 4-CF3–Ph (15),
100%; thiophen-2-yl (16), 100%; naphthalen-2-yl (17), 83%; 3,5-
bis(trifluoromethyl)phenyl (18), 100%; 2-fluorenyl (19), 42%; phenan-
thren-2-yl (20), 99%; (c) i—NaBH4, MeOH, D, ii—HCl then NaOH,
R = tBu (21), 63%; Ph (22), 84%; 4-NO2–Ph (23), 67%; 4-MeO–Ph (24),
83%; 4-Cl–Ph (25), 78%; 4-Br–Ph (26), 71%; 4-CF3–Ph (27), 64%;
thiophen-2-yl (28), 79%; naphthalen-2-yl (29), 77%; 3,5-bis(trifluoro-
methyl)phenyl (30), 54%; 2-fluorenyl (31), 100%; phenanthren-2-yl
(32), 79%.
OMe
OMe
N
N
N
N
NH
NH
NH2
NH2
a
+
N
of these were stored as their hydrates prior to the con-
densation reaction. Attempts were made to prepare
these glyoxals using solvent-free microwave condi-
tions.17 However, conversions were generally poor,
and thus the longer solvent-based approach was pre-
ferred. The glyoxals were then treated with cis-iron
dichloride complex 9 which was prepared using triethyl-
enetetraamine 4 and iron(III) chloride. Reduction of the
resulting diimine with sodium borohydride gave the de-
4
6
5
b
N
N
N
N
NH HN
c
sired
C2-substituted-1,4,7,10-tetraazacyclododecanes
21–32 in good overall yield (Scheme 2).18
NH HN
Br
8
7
The library of C2-substituted polyazamacrocycles was
tested for anti-protozoal activity against bloodstream
form Trypanosoma brucei using a derivative of the Alamar
Scheme 1. Reagents and conditions: (a) neat, D, 100%; (b) 1,2-
dibromoethane, K2CO3, MeCN, D, 100%; (c) KOH, H2O, D, 71%.