Functionalized N-aryl-substituted cyclens by nucleophilic aromatic substitution

Article abstract of DOI:10.1080/00397910500278552

The reaction of trifold protected cyclen with fluorinated dinitroarenes yields aryl-substituted or aryl-bridged cyclen derivatives in good yield. The two arene nitro groups, necessary for the nucleophilic aromatic substitution, are subsequently selectivel

Full text of DOI:10.1080/00397910500278552

Synthetic Communicationsw, 35: 3003–3019, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278552
Functionalized N-Aryl-Substituted Cyclens
by Nucleophilic Aromatic Substitution
Michael Subat, Hans-Christoph Gallmeier, Andreas Fuchs,
¨
and Burkhard Konig
Institute for Organic Chemistry, University of Regensburg,
Regensburg, Germany
Abstract: The reaction of trifold protected cyclen with fluorinated dinitroarenes yields
aryl-substituted or aryl-bridged cyclen derivatives in good yield. The two arene nitro
groups, necessary for the nucleophilic aromatic substitution, are subsequently
selectively reduced to amines and further functionalized by amide formation. As an
example, a cyclen derivative bearing a heterocyclic oligoamide with potential DNA
binding ability was prepared.
Keywords: Azamacrocycles, DNA binding, ionophore, nucleophilic aromatic
substitution
INTRODUCTION
Metal complexes with open coordination sites have found wide use in
molecular recognition. They serve as binding sites in the development of
chemosensors,[1] study metalloenzyme function in bioinorganic chemistry,[2]
or direct supramolecular self-assembly.[3] Metal complexes of cyclen are
particular useful because of their high binding affinity to many transition
metal ions, the kinetic inertness and high stability of many of their metal
complexes, and the variety of methods for functionalization of the ligand.
Starting from the commercially available parent cyclen macrocycle,
alkylation,[4] acylation,[5] and arylation[6] ofthenitrogenatomsinaregioselective
Received in Poland May 30, 2005
Address correspondence to Burkhard Konig, Institute for Organic Chemistry,
¨
University of Regensburg, D-93040, Regensburg, Germany. Fax: þ49-941-943-
1717; E-mail: burkhard.koenig@chemie.uni-regensburg.de
3003

3004
M. Subat et al.
manner using peptide protecting groups has been described. In this article, we
describe the extension of cyclen arylation by nucleophilic aromatic substi-
tution to the preparation of selectively functionalized arene substituents.
RESULTS AND DISCUSSION
Koike et al.[7] have reported the reaction of a threefold protected cyclen with
Sangers reagent, 2,4-dinitrofluorobenzene. This reaction can be extended to
difluoro-dinitrobenzene (2), giving aryl-bridged bis-cyclen (3-Boc) in nearly
quantitative yield. The use of ultrasound to promote the reaction is advan-
tageous. Boc protecting groups are removed quantitatively by trifluoroacetic
acid (TFA), and eluation from a basic ion-exchange resin gives ligand 3-H
(Scheme 1). Alternatively, reduction of the nitro groups in 3-Boc by
hydrogenation on Pd/C yields 4, which now allows further functionalization,
for example by acylation giving 5-Boc. Deprotection with TFA and eluation
from basic ion-exchange resin as described for 3-Boc gives ligand 5-H,
which was transformed into bis-zinc(II) complex 6 to illustrate its metal ion
complexing properties (Scheme 2).
The reaction of compound 1 with 2,4-dinitrofluorobenzene (7) also
benefits from ultrasound agitation, and 8-Boc is obtained in nearly quantitative
yield. Deprotection with TFA affords 8-H, and reduction of both nitro substi-
tuents gives 9-Boc (Scheme 3). A reduction of one of the nitro groups, leaving
the other untouched, is possible using milder reduction conditions. Method A,
according to a previously published procedure by Chambers,[8] uses six
equivalents of sulphur and sodium sulphide in water/ethanol. After 30 min,
the starting material was completely converted and 11-Boc obtained as the
major reaction product. Nearly equal amounts of 10-Boc and 9-Boc were
isolated as side products. Method B employs Pd/C and triethylammonium
formiate as reducing agent in acetonitrile under reflux. These conditions
give diamino compound 9-Boc as the major product and the nitro amino
compounds 10-Boc and 11-Boc in only 28 and 12% yield, respectively
(Scheme 4).
Scheme 1.

Functionalized N-Aryl-Substituted Cyclens
3005
Scheme 2.
The isomers 10-Boc and 11-Boc were assigned from their aromatic proton
chemical shifts by comparison with calculated increment values. In particular,
the chemical shift of proton H-5 is indicative. Table 1 summarizes the
measured and calculated chemical shifts, which are in very good agreement.
The reduction of the nitro groups is reflected in changes of the absorption
spectra of the compounds. Figure 1 shows the UV absorption spectra of 8-Boc,
10-Boc, and 11-Boc, in acetonitrile. The longest wavelength absorption of
10-Boc shifts 26 nm bathochromic compared to 8-Boc, and the extinction
coefficient of 11-Boc at 391 nm (lg 1 ¼ 3.44) is much weaker that that of
10-Boc (397 nm, lg 1 ¼ 4.14).
Deprotection of 10-Boc and 11-Boc with TFA gave amines 10-H and
11-H. To probe the effect of the isomeric position of nitro and amino
groups on the protonation equilibria of the cyclen nitrogen atoms, the pKa
values were determined by potentiometric titration. The data (10-H: lg
Scheme 3.

3006
M. Subat et al.
Scheme 4.
K1 ¼ 10.74 + 0.03; lg K2 ¼ 8.13 + 0.05; 11-H: lg K1 ¼ 10.42 + 0.04;
lg K2 ¼ 8.20 + 0.06; for comparison, 8-H: lg K1 ¼ 11.04 + 0.05; lg
K2 ¼ 9.86 + 0.03) (lg K3 and lg K4 for all systems ,2) showed no or very
little effect of the position of the arene substituents on the cyclen pKa values.
To demonstrate the use of compounds 10-Boc and 11-Boc in the synthesis
of functionalized cyclens, we describe the preparation of cobalt complex 14,
with potential DNA binding ability (Scheme 5). Compound 11-Boc was
coupled with dipyrrole 12 using standard peptide coupling conditions.
Dipyrrol 12 is a substructure found in natural DNA binding agents, such as
distamycin or netropsin.[9] Compound 13-Boc, isolated in 82% yield, was
deprotected to 13-H and transformed into the target complex 14. Preliminary
DNA binding studies showed high affinity of 14 to dDNA in an ethidium
bromide displacement assay.[10]
EXPERIMENTAL
General
Solvents and chemicals were purified and dried according to standard labora-
tory procedures. If not otherwise stated, commercially available solvents of
the highest purity were used. UV-VIS spectra were measured using a
Table 1. Calculated and observed chemical shifts of compounds 8-Boc, 10-
Boc, and 11-Boc (400 MHz, CDCl3, TMS as internal standard)
8-Boc
dobserved
10-Boc
dobserved
11-Boc
dobserved
Proton
dcalcd.
dcalcd.
dcalcd.
H-6
H-5
H-3
7.12
8.41
8.98
7.17
8.20
8.56
6.61
7.38
7.28
6.98
7.58
7.54
6.61
6.71
7.28
7.08
6.77
6.90

Functionalized N-Aryl-Substituted Cyclens
3007
25
.
Figure 1. UV/vis spectra of 8-Boc (3), 10-Boc (11), and 11-Boc (12) (c ¼ 2 10
mol/L) in acetonitrile.
Varian Cary BIO 50 UV/VIS/NIR spectrometer, with a 1-cm quartz cell
(Hellma) and Uvasol solvents (Merck), reported as lmax in nm (1). IR
spectra were measured using a Bio-Rad FT-IR spectrometer FTS 155. NMR
spectra were measured using a Bruker Avance 300 (1H: 300.1 MHz, 13C:
75.5 MHz) and Bruker Avance 600 (1H: 600.1 MHz, 13C: 150.1 MHz). The
chemical shifts are in d values relative to the internal (or external) standard
TMS and are reported as chemical shift (multiplicity, coupling constant,
number of protons, assignment). Mass spectra were measured using a
Varian CH-5 (EI), Finnigan MAT 95 (CI; FAB and FD), and Finnigan
MAT TSQ 7000 (ESI). Melting points are uncorrected and were determined
according to Tottoli using instrumentation from Bu¨chi. The microanalytical
laboratory of the School of Chemistry and Pharmacy, University of Regens-
burg, determined all elemental analyses. CC means column chromatography;
PE means petrol ether with a boiling range from 60 to 70 8C, and EA means
ethyl acetate.
Potentiometric Titrations
Potentiometric titrations were performed in aqueous 0.1 M tetraethyl
ammonium perchlorate solution to assure a constant ionic strength of
I ¼ 0.1. Tetraethylammonium hydroxide (0.1 M) was added as base by an
automatic burette (Dosimat 665 bzw. 765, Metrohm) at 258C to a solution
hold at the same temperature. The base solution was calibrated with sodium

3008
M. Subat et al.
Scheme 5.
phthalate. A microprocessor pH meter (pH 3000, WTW, Wiss.-tech.
¨
Werkstatten Weilheim) recorded the pH values during titration. The self-
dissociation of water log Kw was calculated from titration of 0.1 M perchloric
acid, and the program Hyperquad 2000 (vers. 2.1) was used to determine
pKa values.[11]
The following solution equilibria were considered for data fitting:
log K1
½Lꢀ þ Hþ
H½Lꢀþ
ð1Þ
ð2Þ
ð3Þ
ð4Þ
log K2
log K3
log K4
2þ
H½Lꢀþ þ Hþ
H2½Lꢀ
H3½Lꢀ
H4½Lꢀ
2þ
3þ
4þ
H2½Lꢀ þ Hþ
H3½Lꢀ3þ þ Hþ

Functionalized N-Aryl-Substituted Cyclens
Synthesis of Compounds
3009
1,3-Bis-(1,4,7-tris[tert-butyloxycarbonyl]-1,4,7,10-tetraaza-cyclododecane)-
4,6-dinitro-benzene (3-Boc): NaHCO3 (0.45 g, 5.33 mmol) was suspended in
dry acetonitrile (30 mL) by sonification using an ultrasound bath under dinitro-
gen atmosphere at 308C for 20 min. 1,3-Difluoro-4,6-dinitrobenzene (0.26 g,
1.27 mmol) and tri-tert-butyl 1,4,7,10-tetraaza cyclododecan-1,4,7-tricarbo-
nate (1.20 g, 2.54 mmol) were added, and the reaction mixture was
sonicated for 18 h at 308C. Monitoring of the reaction shows quantitative
formation of a monosubstituted derivative (Rf ¼ 0.48, EA/PE ¼ 1:1) after
90 min. After complete reaction, acetonitrile (30 mL) was added, and the
mixture was filtered to remove insoluble salts. The solvent was removed
and CC on silica gel (EA/PE ¼ 1:1) gave 1.39 g (98%) 3-Boc (Rf ¼ 0.22,
EE/PE ¼ 1:1), mp 1058C. IR (KBr): n (cm21) ¼ 2974, 2932, 1703, 1561,
˜
1366, 1164, 859, 776; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 229
1
(4.206), 365 (4.239); H NMR (250 MHz, CDCl3): d ¼ 1.41 (s, 36H, CH3-
Boc), 1.44 (s, 18H, CH3-Boc), 3.39–3.55 (m, 32H, CH2-cyclen), 6.59 (bs,
1H, CH 1), 8.44 (s, 1H, CH 4); 13C NMR (63 MHz, CDCl3): d ¼ 28.4, 28.5
(þ, CH3-Boc), 47.6, 49.5, 50.5, 51.4 (2, CH2-cyclen), 80.3, 80.4 (Cquat
,
C-Boc), 106.9 (þ, Caryl-H 1), 129.0 (þ, Caryl-H 4), 130.9 (Cquat, Caryl-N 2
and 6), 149.1 (Cquat, Caryl-N 3 and 5), 156.4, 156.6 (Cquat, C55O Boc); MS
(ESI, CH2Cl2/MeOH þ 1% AcOH): m/z (%) ¼ 1109 (100) [MH]þ, 1009
(20) [MH-Boc]þ; elemental analysis (C52H88N10O16): calcd. C, 56.30; H,
8.00; N, 12.63; found: C, 55.85; H, 7.94; N, 11.98.
1,3-Di-(1,4,7,10-tetraaza cyclododecane-1-yl)-4,6-dinitrobenzene (3-H):
Compound 3-Boc (1.97 g, 1.78 mmol) was dissolved in CH2Cl2 (40 mL),
trifluoro acetic acid (TFA) (11.5 mL, 17.02 g, 149.3 mmol) was added, and
the reaction mixture stirred for 16 h at room temp. Solvent and excess TFA
were removed in vacuum to give 2.13 g (quantitative) 1,3-bis-(10-aza-1,4,7-
hexaazonium-cyclododec-10-yl)-4,6-dinitrobenzene hexakis-trifluoroacetate
as a yellow solid, mp 125–1278C. IR (KBr): n (cm21) ¼ 3431, 2991, 2872,
˜
1572, 1194, 857, 774; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 223 (3.932),
1
361 (4.161); H NMR (400 MHz, CD3CN): d ¼ 3.02–3.05 (m, 8H, CH2-
cyclen), 3.12–3.21 (m, 16H, CH2-cyclen), 3.46–3.48 (m, 8H, CH2-cyclen),
7.18 (bs, 12H, NHþ2 ), 7.80 (s, 1H, CH 2), 8.56 (s, 1H, CH 5); 13C NMR
(100 MHz, CD3CN): d ¼ 43.5, 44.9, 46.5, 51.1 (2, CH2-cyclen), 117.1
1
(Cquat, q, JC,F ¼ 290.0 Hz, CF3COO2), 127.2 (þ, Caryl-H 5), 130.8 (þ,
2
C
aryl-H 2), 143.8, 148.7 (Cquat, Caryl-N), 160.9 (Cquat, q, JC,F ¼ 36.7 Hz,
CF3COO2); MS (ESI, MeOH þ 1% AcOH): m/z (%) ¼ 509 (100)
[M6þ25H]þ, 255 (90) [M6þ–4H]2þ
.
The obtained salt (1.56 g, 1.31 mmol) was dissolved in water (30 mL) and
eluated over 90 mL of a strong basic ion-exchange resin (OH2 capacity:
0.9 mmol/mL) with 200 mL of water and 50 mL of CH3CN. The organic
solvent was removed from the combined eluates and the aqueous phase was

3010
M. Subat et al.
lyophilized yielding 0.67 g (quantitative) of 3-H as a yellow solid; mp 918C.
IR (KBr): n (cm21) ¼ 3411, 2926, 2848, 1599, 1558, 1348, 1282, 1118, 823,
˜
1
761; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 230 (4.575), 368 (4.188); H
NMR (300 MHz, CDCl3): d ¼ 2.36 (bs, 6H, NH), 2.57–2.61 (m, 8H, CH2-
cyclen), 2.66–2.74 (m, 16H, CH2-cyclen), 3.31–3.38 (m, 8H, CH2-cyclen),
7.58 (s, 1H, CH 2), 8.22 (s, 1H, CH 5); (300 MHz, CD3CN): d ¼ 2.58–2.60
(m, 8H, CH2-cyclen), 2.67–2.72 (m, 8H, CH2-cyclen), 2.75–2.91 (m, 14H,
CH2-cyclen und NH), 3.36–3.40 (m, 8H, CH2-cyclen), 7.65 (s, 1H, CH 2),
8.23 (s, 1H, CH 5); 13C NMR (75 MHz, CDCl3): d ¼ 46.1, 46.3, 47.8, 49.4
(2, CH2-cyclen), 120.2 (þ, Caryl-H 2), 125.4 (þ, Caryl-H 5), 136.0, 149.1
(Cquat, Caryl-N); (75 MHz, CD3CN): d ¼ 46.5, 47.2, 48.8, 53.2 (2, CH2-
cyclen), 121.4 (þ, Caryl-H 2), 126.8 (þ, Caryl-H 5), 136.0, 149.5 (Cquat
,
C
aryl-N); MS (ESI, MeOH/CH2Cl2 þ 1% AcOH): m/z (%) ¼ 255 (100)
[M þ 2 H]2þ
,
509 (70) [MH]þ, 1017 (3) [2M þ H]þ; HRMS
(C22H41N10O4): calcd. 509.3312 [MH]þ, found: 509.3317 [MH]þ + 1.02ppm.
1,3-Bis-(1,4,7-tris[tert-butyloxycarbonyl]-1,4,7,10-tetraazacyclododecane)-
4,6-diamino-benzene (4): After dissolving 3-H (2 g, 1.81 mmol) in dry ethanol
(25 mL), 0.50 g of Pd/C (10% palladium) were added and the mixture was
pressurized with 10 bar dihydrogen for 48 h at room temp. The catalyst was
filtered off over Celitew and washed with ethanol. The combined solvents
were evaporated in vacuum, and the remaining crude product was purified
by CC on silica gel (EA/PE ¼ 1:1) yielding 4 (1.73 g, 91%; (Rf ¼ 0.12,
EA/PE ¼ 1:1) as a yellow solid, mp 938C. IR (KBr): n (cm21) ¼ 3466,
˜
3364, 2975, 2931, 1698, 1463, 1248, 1176, 861, 774; UV/Vis (CH3CN):
lmax (nm) (lg 1) ¼ 212 (4.471), 249 (3.905), 316 (3.763); 1H NMR
(300 MHz, CDCl3): d ¼ 1.41 (s, 36H, CH3-Boc), 1.49 (s, 18H, CH3-Boc),
2.85–3.01 (m, 8H, CH2-cyclen), 3.24–3.35 (m, 8H, CH2-cyclen), 3.43–
3.72 (m, 16H, CH2-cyclen), 6.10 (s, 1H, CH 5), 6.69 (s, 1H, CH 2); 13C
NMR (75 MHz, CDCl3): d ¼ 28.4, 28.6 (þ, CH3-Boc), 47.0, 49.4, 53.4 (2,
CH2-cyclen), 79.7, 79.8 (Cquat, C-Boc), 103.5 (þ, Caryl-H 5), 114.4 (þ,
Caryl-H 2), 128.0, 140.6 (Cquat, CAryl-N), 155.7, 156.2 (Cquat, C55O Boc);
MS (ESI, MeOH/CH2Cl2 þ 1% AcOH): m/z (%) ¼ 1050 (100) [MH]þ,
950 (5) [MH-Boc]þ; elemental analysis (C52H92N10O12): calcd. C, 59.52;
H, 8.84; N, 13.35; found: C, 59.20; H, 8.79; N, 13.28.
1,3-Bis-(1,4,7-tris[tert-butyloxycarbonyl]-1,4,7,10-tetraazacyclododecane)-4,6-
di-(acetyl-amino)-benzene (5-Boc): Compound 4 (1.20 g, 1.14 mmol) was
dissolved in CH2Cl2 (50 mL) and freshly distilled (from P2O5) acetic
anhydride (430 ml, 0.47 g, 4.56 mmol) was added. The reaction mixture was
stirred for 24 h at room temp. under nitrogen, the solvent and excess acetic
anhydride were removed in vacuum, and the crude product was purified by
CC on silica gel (EA/PE ¼ 4 : 1) to give 5-Boc (1.01 g, 78%) as a yellow
solid (R ¼ 0.21, EA), mp 106–1088C. IR (KBr): n (cm21) ¼ 3508, 3372,
˜
f
2976, 2932, 1703, 1523, 1247, 1163, 860, 773; UV/Vis (CH3CN): lmax

Functionalized N-Aryl-Substituted Cyclens
3011
(nm) (lg 1) ¼ 253 (3.985), 349 (3.634); 1H NMR (250MHz, CDCl3): d ¼ 1.32
(s, 36H, CH3-Boc), 1.44 (s, 18H, CH3-Boc), 2.04 (s, 6H, CH3-amide), 2.78–
2.93 (m, 8H, CH2-cyclen), 3.27–3.68 (m, 24H, CH2-cyclen), 6.93 (s, 1H, CH2),
8.12 (bs, 2H, NH-amide), 9.05 (s, 1H, CH 5); 13C NMR (63 MHz, CDCl3):
d ¼ 24.7 (þ, CH3-amide), 28.4, 28.5 (þ, CH3-Boc), 45.7, 48.9, 50.9 (2, CH2-
cyclen), 80.2, 80.3 (Cquat, C-Boc), 113.6 (þ, Caryl-H 2), 115.5 ( þ , Caryl-H 5),
132.4, 136.5 (Cquat, Caryl-N), 155.9, 156.2 (Cquat, C55O Boc), 168.0 (Cquat
,
C55O amide); MS (ESI, MeOH/CH2Cl2 þ 1% AcOH): m/z (%) ¼ 1156 (100)
[M þ Na]þ, 1134 (55) [MH]þ; elemental analysis (C56H96N10O14): calcd. C,
59.34; H, 8.54; N, 12.36; found: C, 59.52; H, 8.59; N 12.16.
1,3-Di-(1,4,7,10-tetraazacyclododecane-1-yl)-4,6-di-(acetylamino)-benzene (5-
H): A solution of 5-Boc (700 mg, 0.62 mmol) in CH2Cl2 (25 mL) and TFA
(2.8 mL, 4.14 g, 36.35 mmol) was stirred for 18 h at room temp., the solvent
and excess TFA was removed in vacuum, and the oily residue was
dissolved in a small amount of acetonitrile and again evaporated in vacuum
to remove traces of TFA. 1,3-Bis-(10-aza-1,4,7-hexazonium-cyclododec-10-
yl)-4,6-di-(acetylamino)-benzene hexakis-trifluoroacetate (763 mg, quantitat-
ive) was obtained as a yellow solid, mp 118–1208C. IR (KBr): n
˜
(cm21) ¼ 3628, 3372, 2936, 1523, 1252, 1162, 862, 773; UV/Vis (CH3CN):
1
lmax (nm) (lg 1) ¼ 242 (3.732), 342 (3.544); H NMR (300MHz, CD3CN):
d ¼ 1.96 (s, 6H, CH3-amide), 3.11–3.17 (m, 8H, CH2-cyclen), 3.23–3.31
(m, 16H, CH2-cyclen), 3.48–3.55 (m, 8H, CH2-cyclen), 6.87 (s, 1H, CH 2),
7.39 (bs, 14H, NH2þ und NH-amide), 8.89 (s, 1H, CH 5); 13C NMR
(75 MHz, CD3CN): d ¼ 25.1 (þ, CH3 amide), 42.9, 44.2, 45.7, 50.2 (2, CH2-
cyclen), 113.1 (þ, Caryl-H 2), 114.9 (þ, Caryl-H 5), 117.6 (Cquat, q,
1JC,F ¼ 290.3 Hz, CF3COO2), 131.3, 135.0 (Cquat, Caryl-N), 161.2 (Cquat, q,
2JC,F ¼ 36.5Hz, CF3COO2), 169.6 (Cquat, C55O amide); MS (ESI, MeOH þ
1% AcOH): m/z (%) ¼ 533 (100) [M6þ 2 5H]þ, 267 (65) [M6þ 2 4H]2þ
.
The TFA salt (600 mg, 0.49 mmol) was dissolved in water (10 mL) and
was passed through 30 mL of a strong basic ion-exchange resin (OH2
capacity 0.9 mmol/mL) followed by water (120 mL) and acetonitrile
(30 mL). The organic solvent was removed from the eluate and the aqueous
phase lyophilized to yield 5-H (262 mg, quantitative) as a yellow solid, mp
968C. IR (KBr): n (cm21) ¼ 3618, 3381, 2986, 2928 1503, 1222, 1161,
˜
864, 771; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 249 (3.796), 349 (3.618);
1H NMR (250 MHz, CD3CN): d ¼ 1.99 (s, 6H, CH3-amide), 2.61–2.65
(m, 8H, CH2-cyclen), 2.73–2.81 (m, 8H, CH2-cyclen), 2.96–3.11 (m, 14H,
CH2-cyclen und NH), 3.38–3.44 (m, 8H, CH2-cyclen), 6.91 (s, 1H, CH 2),
8.23 (bs, 2H, NH-amide), 8.92 (s, 1H, CH 5); 13C NMR (63 MHz, CD3CN):
d ¼ 24.8 (þ, CH3-amide), 44.6, 45.5, 47.2, 51.1 (2, CH2-cyclen), 114.9
(þ, Caryl-H 2), 116.7 (þ, Caryl-H 5), 131.9, 136.0 (Cquat, Caryl-N), 169.2
(Cquat, C55O amide); MS (ESI, MeOH/CH2Cl2 þ 1% AcOH): m/z
(%) ¼ 533 (100) [MH]þ, 267 (35) [M þ 2H]2þ; HRMS (C26H49N10O2):
calcd. 533.4040 [MH]þ, found: 533.4037 [MH]þ + 0.96 ppm.

3012
M. Subat et al.
1,3-Di-(zinc (II)-1,4,7,10-tetraazacyclododecane-1-yl)-4,6-di-(acetylamino)-
.
benzol-tetra-perchlorate (6): Zn(ClO4)2 6H2O in methanol (10 mL) was
added to a solution of ligand 5-H (195 mg, 0.37 mmol), dissolved in
methanol (15 mL), and the mixture was stirred for 24 h at room temp. The
product precipitates from solution. The mixture was heated to reflux for
30 min to ensure complete reaction, the solvent was removed in vacuum
and the crude product recrystallized from CH3CN/water (3 : 1) to give 6
(264 mg, 67%) as yellow crystals, mp 2198C (dec). IR (KBr): n
˜
(cm21) ¼ 3609, 3372, 2991, 2919 1513, 1170, 865, 777; UV/Vis (CH3CN):
1
lmax (nm) (lg 1) ¼ 245 (3.709), 346 (3.562); H NMR (300 MHz, CD3CN):
d (ppm) ¼ 2.09 (s, 6H, CH3-amide), 2.78–2.83 (m, 4H, CH2-cyclen), 2.97–
3.20 (m, 8H, CH2-cyclen), 3.35–3.45 (m, 8H, CH2-cyclen), 3.58–3.74
(m, 14H, CH2-cyclen und NH), 4.24–4.38 (m, 4H, CH2-cyclen), 7.12
(s, 1H, CH 2), 8.31 (bs, 2H, NH-amide), 9.28 (s, 1H, CH 5); 13C NMR
(75 MHz, CD3CN): d (ppm) ¼ 24.4 (þ, CH3-amide), 44.0, 45.1, 46.5, 49.8
( 2 , CH2-cyclen), 114.9 (þ, Caryl-H 2), 116.7 (þ, Caryl-H 5), 133.1, 139.3
(Cquat, Caryl-N), 170.6 (Cquat, C55O amide); MS (ESI, CH3CN): m/z
(%) ¼ 409 (100) [M4þ þ CH3COO2 þ ClO24 ]2þ, 389 (60) [M4þ þ2
CH3COO2]2þ; (ESI, neg., CH3CN): m/z (%) ¼ 1115 (100) [M4þ þ4
ClO24 þ CH3COO2]2.
Tri-tert-butyl 10-(2,4-dinitrobenzene-1-yl)-1,4,7,10-tetraaza cyclododecane-
1,4,7-tricarbamate (8-Boc):[7]
A
suspension of NaHCO3 (1.07 g,
12.72 mmol) in dry CH3CN (80 mL) was sonicated at 408C under nitrogen
for 15 min, 1-fluoro-2,4-dinitrobenzene (7, 1.18 g, 6.36 mmol) and 1 (3.00 g,
6.36 mmol) were added, and the reaction mixture was heated for 8 h in the
sonicator bath to 408C. The mixture was filtered through Celitew, the filter
was washed with CH3CN (30 mL) and the combined eluates were evaporated
in vacuum. The crude product was chromatographed on silica gel (EA/
PE ¼ 1 : 1, Rf ¼ 0.37) giving 8-Boc (3.98 g, 98%) as a yellow solid, mp
1
708C, H NMR (250 MHz, CDCl3): d (ppm) ¼ 1.47 (s, 9H, CH3-Boc), 1.48
(s, 18H, CH3-Boc), 3.39–3.62 (m, 16H, CH2-cyclen), 7.17 (d, 1H,
3
4
3J ¼ 9.5 Hz, CH 6), 8.20 (dd, 1H, J ¼ 9.5 Hz, J ¼ 2.7 Hz, CH 5), 8.56
(d, 1H, J ¼ 2.7 Hz, CH 3); 13C NMR (63 MHz, CDCl3): d (ppm) ¼ 28.4,
4
28.5 (þ, CH3-Boc), 47.8, 49.6, 50.5, 52.2 (2, CH2-cyclen), 80.6, 80.8
(Cquat, C-Boc), 118.2 (þ, Caryl-H 6), 123.7, 127.8 (þ, Caryl-H 3 und 5),
137.5 (Cquat, Caryl-N 2 und 4), 147.7 (Cquat, Caryl-N 1), 156.3, 156.9 (Cquat
C55O Boc).
,
1-(2,4-Dinitrobenzene-1-yl)-1,4,7,10-tetraaza cyclododecane (8-H): TFA
(4.3 mL, 6.36 g, 55.79 mmol) was added to a solution of compound 8-Boc
(1.20 g, 1.88 mmol) in 50 mL of CH2Cl2. The reaction mixture was stirred
for 4 h at room temp., and all volatile components were removed in vacuum
to give 10-(2,4-dinitrobenenel-1-yl)-10-aza-1,4,7-triazonium-cyclododecane
tris-trifluoroacetate (1.29 g, 1.88 mmol, quantitative) after drying in high

Functionalized N-Aryl-Substituted Cyclens
3013
vacuum as a yellow solid, mp 1378C. IR (KBr):n (cm21) ¼ 3588, 3420, 2950,
˜
1531, 1467, 1346, 1288, 1070, 954, 741; UV/Vis (CH3CN): lmax (nm) (lg
1) ¼ 210 (3.858), 371 (3.903); 1H NMR (250 MHz, CD3CN):
d
(ppm) ¼ 3.06–3.27 (m, 12H, CH2-cyclen), 3.46–3.54 (m, 4H, CH2-cyclen),
7.25 (bs, 6H, NHþ2 ), 7.77 (d, 1H, 3J ¼ 9.1 Hz, CH 6), 8.43 (d, 1H,
4
3J ¼ 9.1 Hz, J ¼ 2.7 Hz, CH 5), 8.67 (d, 1H, 4J ¼ 2.7 Hz, CH 3); 13C NMR
(63 MHz, CD3CN): d (ppm) ¼ 43.7, 44.9, 45.6, 51.6 (2, CH2-cyclen), 117.3
1
(Cquat, q, JC,F ¼ 290.9 Hz, CF3COO2), 123.1, 127.5, 129.5 (þ, Caryl-H),
2
144.7, 145.6, 148.8 (Cquat, Caryl-N), 161.2 (Cquat, q, JC,F ¼ 36.1 Hz,
CF3COO2); MS (ESI, CH3CN): m/z (%) ¼ 339 (100) [M3þ 2 2H]þ.
The ammonium salt (1.00 g, 1.46 mmol) was dissolved in water (25 mL)
and eluated over a strong basic ion-exchange resin (30 mL, capacity: 0.9 mmol
OH2/mL) with water. The eluate was lyophilized yielding 8-H (0.46 g, 93%),
as a yellow solid, mp 948C. IR (KBr): n (cm21) ¼ 3426, 3097, 2925,
˜
1604, 1326, 1170, 742, 714; UV/Vis (CH3CN): lmax [nm] (lg 1) ¼ 218
1
(4.033), 378 (3.962); H NMR (250 MHz, CDCl3): d (ppm) ¼ 2.04 (bs, 3H,
NH), 2.61–2.70 (m, 4H, CH2-cyclen), 2.74–2.84 (m, 8H, CH2-cyclen),
3.50–3.58 (m, 4H, CH2-cyclen), 7.66 (s, 1H, 3J ¼ 9.4 Hz, CH 6), 8.23
3
4
4
(d, 1H, J ¼ 9.4 Hz, J ¼ 2.7 Hz, CH 5), 8.56 (d, 1H, J ¼ 2.7 Hz, CH 3);
13C NMR (63 MHz, CDCl3): d (ppm) ¼ 46.1, 46.2, 48.1, 52.7 (2, CH2-
cyclen), 122.5, 123.7, 127.4 (þ, Caryl-H), 139.0, 140.7, 148.9 (Cquat
,
C
aryl-N); MS (ESI, MeOH þ 1% AcOH): m/z (%) ¼ 339 (100) [MH]þ, 361
(15) [M þ Na]þ; HRMS (C14H23N6O4): calcd. 339.1781 [MH]þ, found:
339.1877 [MH]þ + 1.19 ppm.
Tri-tert-butyl 10-(2,4-diamionbenzene-1-yl)-1,4,7,10-tetraaza cyclododecane-
1,4,7-tricarbamate (9-Boc): To a solution of 8-Boc (1 g, 1.57 mmol) in EtOH
(10 mL), 250 mg of Pd/C (10% palladium) was added and the mixture was
pressurized by H2 (10 bar) for 48 h at room temp. The catalyst was removed
by filtration through Celitew, the solvent was removed in vacuum, and the
crude product was chromatographed (EA/PE ¼ 4 : 1; Rf ¼ 0.25, EA/
PE ¼ 1 : 1). Yield: 668 mg (74%) of 9-Boc, as a solid, mp 1108C (dec.). IR
(KBr): n (cm21) ¼ 3363, 3458, 2976, 2930, 1685, 1529, 1417, 1366, 1249,
˜
1168, 861, 774; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 217 (4.395), 307
1
(3.491); H NMR (300 MHz, CDCl3): d (ppm) ¼ 1.41 (s, 18H, CH3-Boc),
1.49 (s, 9H, CH3-Boc), 2.81–3.16 (m, 4H, CH2-cyclen), 3.18–3.41 (m, 4H,
CH2-cyclen), 3.47–3.82 (m, 8H, CH2-cyclen), 6.02–6.07 (m, 2H, CH-
3
arene), 6.78 (d, 1H, J ¼ 7.9 Hz, CH-arene); 13C NMR (75 MHz, CDCl3): d
(ppm) ¼ 28.4, 28.5 (þ, CH3-Boc), 47.3, 49.5, 51.0, 52.9 (2, CH2-cyclen),
79.4, 79.7 (Cquat, C-Boc), 102.8, 105.0, 122.2 (þ, Caryl-H), 128.9 (Cquat
,
aryl-N 2 und 4) 143.9 (Cquat, Caryl-N 1), 155.8, 156.3 (Cquat, C55O Boc);
C
MS (ESI, MeOH þ 1% AcOH): m/z (%) ¼ 579 (100) [MH]þ.
Tri-tert-butyl 10-(2-amino-4-nitrophenyl)-1,4,7,10-tetraaza cyclododecane-
1,4,7-tricarbamate (10-Boc) and Tri-tert-butyl 10-(4-amino-2-nitrophenyl)-
1,4,7,10-tetraaza cyclododecane-1,4,7-tricarbamate (11-Boc) and Tri-tert-butyl

3014
M. Subat et al.
10-(2,4-diamionbenzene-1-yl)-1,4,7,10-tetraaza cyclododecane-1,4,7-tricarba-
mate (9-Boc): Method A (reduction with sulphur and sodium sulphide). A
solution of 8-Boc (2.44 g, 3.82 mmol, 1.0 equiv.) was heated to reflux in EtOH
(50 mL); sodium sulphide (5.50 g, 22.92 mmol, 6 equiv.) and sulphur (0.73 g,
22.92 mmol, 6 equiv.) were added in water (10 mL) in one portion causing a
color change from yellow to dark brown. The reaction mixture was heated for
20 min to reflux, the solvent was removed in vacuum, and the red-brown solid
dissolved in water (40 mL) and EA (40 mL). The aqueous phase was extracted
with EA (3ꢁ), the combined organic phases were dried over sodium sulphate,
the solvent was removed in vacuum, and the crude product was chromatographed
on silica gel (PE:EA 50 : 50) giving 11-Boc (1.48 g, 64%, Rf ¼ 0.20), 10-Boc
(425 mg, 18%, Rf ¼ 0.25 in PE:EA 30 : 70), and 9-Boc (350 mg, 16%,
Rf ¼ 0.23 in PE:EA 10 : 90).
Method B (reduction by transfer hydrogenation using triethylammonium
formiate). A mixture of 8-Boc (200 mg, 0.31 mmol, 1.0 equiv.), triethyl amine
(0.2 mL, 1.35 mmol, 4.3 equiv.), and 15 mg of Pd/C in 20 mL of acetonitrile
was heated to reflux. Formic acid (0.05 mL, 1.35 mmol, 4.3 equiv.) was
added; the mixture was heated to reflux for 2 h and, after cooling to room
temp., filtered through Celite. The solvent was removed in vacuum and the
crude product was purified by column chromatography on silica gel to yield
53 mg (28%) of 10-Boc (Rf ¼ 0.20), 23 mg (12%) of 11-Boc (Rf ¼ 0.25 in
PE:EE 30 : 70), and 108 mg (60%) of 9-Boc (Rf ¼ 0.23 in PE:EE 10 : 90).
Tris-tert-Butyl-10-(2-amino-4-nitrophenyl)-1,4,7,10-tetraaza cyclododecane-
1,4,7-tricarbamate (10-Boc): mp1058C. IR (KBr): n ¼ 2975 cm21, 2924,
˜
1698, 1685, 1508, 1458, 1365, 1250, 1166. UV/Vis (acetonitrile): lmax
1
(lg 1) ¼ 189 nm (5.00), 231 (4.51), 261 (4.42), 325 (4.06), 397 (4.14). H
NMR (250 MHz, CDCl3): d ¼ 1.38–1.50 (m, 27H, BOC-CH3), 3.11 (bs,
4H, cyclen-CH2), 3.43 (bs, 4H, cyclen-CH2), 3.56 (bs, 8H, cyclen-CH2),
3
4.22 (bs, 2H, –NH2), 6.98 (d, 1H, H-6, J ¼ 8.60 Hz), 7.54 (d, 1H, H-3,
3
4
4J ¼ 2.60 Hz), 7.58 (dd, 1H, H-5, J ¼ 8.60 Hz, J ¼ 2.60 Hz). 13C NMR
(100 MHz, CDCl3): d ¼ 28.3 (þ, BOC-CH3), 28.5 (þ, BOC-CH3), 46.1
(2, cyclen-CH2, 2C), 49.3 (2, cyclen-CH2, 2C), 50.1 (2, cyclen-CH2, 2C),
51.3 (2, cyclen-CH2, 2C), 80.1 (Cquat, BOC-C[CH3]3), 80.2 (Cquat, BOC-
C[CH3]3), 110.0 (þ, arene-CH), 113.4 (þ, arene-CH), 119.4 (þ, arene-
CH), 142.7 (Cquat), 142.8 (Cquat), 144.4 (Cquat), 155.9 (Cquat), 156.2 (Cquat).
MS (ESI, CH2Cl2), m/z (%): 609.3 (100) [MHþ], 1239.6 (2.4)
[2 M þ Naþ]. C29H46N6O10 (608.8): calcd. C, 57.22; H, 7.95; N, 13.81;
found: C, 57.27; H, 8.19; N, 12.89.
Tris-tert-butyl-10-(4-amino-2-nitrophenyl)-1,4,7,10-tetraaza cyclododecane-
˜
1,4,7-tricarbamate (11-Boc), mp1018C. IR (KBr): n ¼ 2976 cm21, 2930,
1685, 1529, 1478, 1417, 1366, 1249, 1168, 858, 774, 620. UV/Vis (aceto-
nitrile): lmax (lg 1) ¼ 191 nm (4.97), 245 (4.52), 391 (3.44). 1H NMR
(250 MHz, CDCl3): d ¼ 1.42 (s, 18H, BOC-CH3), 1.46 (s, 9H, BOC-CH3),

Functionalized N-Aryl-Substituted Cyclens
3015
3.16 (m, 4H, cyclen-CH2), 3.30 (m, 4H, cyclen-CH2), 3.41 (m, 4H, cyclen-
CH2), 3.53 (m, 4H, cyclen-CH2), 3.92 (bs, 2H, 2NH2), 6.77 (dd, 1H, H-5,
4
4
3J ¼ 8.69 Hz, J ¼ 2.75 Hz), 6.90 (d, 1H, H-3, J ¼ 2.75 Hz), 7.08 (d, 1H,
H-6, J ¼ 8.69 Hz). 13C NMR (100 MHz, CDCl3): d ¼ 28.4 (þ, BOC-CH3),
3
28.5 (þ, BOC-CH3), 47.8–49.3 (2, cyclen-CH2), 79.6 (Cquat, BOC-
C[CH3]3), 79.7 (Cquat, BOC-C[CH3]3), 109.9 (þ, arene-CH), 118.9 (þ,
arene-CH), 127.8 (þ, arene-CH), 134.5 (Cquat), 144.1 (Cquat), 148.7 (Cquat),
155.7 (Cquat), 156.0 (Cquat). MS (ESI, CH2Cl2), m/z (%): 609.3 (100)
[MHþ], 1239.6 (2.4) [2 M þ Naþ]. C29H46N6O10 (608.8): calcd. C, 57.22;
H, 7.95; N, 13.81; found: C, 57.11; H, 8.17; N, 13.26.
5-Nitro-2-(1,4,7,10-tetraazacyclododec-1-yl)-phenylamine (10-H): TFA
(2.3 mL, 30.0 mmol, 42 equiv.) was added to a solution of 10-Boc (425 mg,
0.7 mmol, 1 equiv.) in dichloromethane (10 mL), and the mixture was stirred
at room temp. overnight. The solvent and excess of TFA was removed in
vacuum to give the yellowish TFA salt of the compound. IR (KBr):
n ¼ 3007 cm21, 2863, 1677, 1524, 1352, 1203, 1140, 836, 799, 722. H
1
˜
NMR (250 MHz, CD3CN): d ¼ 2.95–3.00 (m, 4H, cyclen-CH2), 3.08–3.25
3
(m, 12H, cyclen-CH2), 7.40 (d, 1H, H-3, J ¼ 8.78 Hz), 7.69 (dd, 1H, H-4,
3J ¼ 8.77 Hz, 4J ¼ 2.67 Hz), 7.77 (d, 1H, H-6, 4J ¼ 2.66 Hz). 13C NMR
(62 MHz, CD3CN): d ¼ 43.2 (2, cyclen-CH2), 43.4 (2, cyclen-CH2), 46.7
(2, cyclen-CH2), 50.3 (2, cyclen-CH2), 114.2 (þ, arene-CH), 116.4 (þ,
arene-CH), 116.8 (q, F3C–CHOO2, J ¼ 288,69 Hz), 125.8 (þ, arene-CH),
144.2 (Cquat), 145.4 (Cquat), 147.5 (Cquat), 160.5 (q, F3C–CHOO2, J ¼
37.77 Hz).
The TFA salt was dissolved in methanol and eluated over a strong basic
ion exchange resin. The solvent was removed in vacuum and the product dried
in high vacuum to yield 10-H (400 mg, quantitative) as a yellow solid,
mp938C. IR (KBr): n ¼ 2920 cm21, 2883, 2840, 1628, 1580, 1513, 1450,
˜
1334, 1285, 1195, 1111, 954, 813, 731. UV/Vis (acetonitrile): lmax (lg
1) ¼ 189 nm (7.05), 207 (4.67), 237 (4.42), 269 (4.34), 339 (4.04), 413
(4.17). 1H NMR (250 MHz, CD3CN): d ¼ 2.53–2.69 (m, 12H, cyclen-
CH2), 3.02–3.06 (m, 4H, cyclen-CH2), 7.07 (d, 1H, H-3, 3J ¼ 8.60 Hz),
7.41 (dd, 1H, H-4, 3J ¼ 8.60 Hz, 4J ¼ 2.71 Hz), 7.46 (d, 1H, H-6,
4J ¼ 2.71 Hz). 13C NMR (62 MHz, CD3CN): d ¼ 45.7 (2, cyclen-CH2),
47.1 (2, cyclen-CH2), 47.5 (2, cyclen-CH2), 50.4 (2, cyclen-CH2), 109.7
(þ, arene-CH), 112.8 (þ, arene-CH), 121.7 (þ, arene-CH), 143.3 (Cquat),
145.0 (Cquat), 145.1 (Cquat). MS (ESI, CH2Cl2), m/z (%): 309.1 (100)
[MHþ], 331.1 (6) [MNaþ].
3-Nitro-4-(1,4,7,10-tetraazacyclododec-1-yl)-phenylamine (11-H): TFA
(7.9 mL, 103.0 mmol, 42 equiv.) was added to 11-Boc (1.48 g, 2.44 mmol,
1 equiv.) in dichloromethane (25 mL), the mixture was stirred overnight at
room temp., and the solvent and excess TFA was removed in vacuum to
yield the TFA salt. IR (KBr): n ¼ 3131 cm21, 2984, 2875, 2791, 1779,
˜

3016
M. Subat et al.
1678, 1531, 1204, 1171, 835, 797, 722. 1H NMR (250 MHz, CD3CN):
d ¼ 2.93–2.97 (m, 4H, cyclen-CH2), 3.05–3.11 (m, 4H, cyclen-CH2),
3.14–3.24 (m, 8H, cyclen-CH2), 7.00 (dd, 1H, H-6, 3J ¼ 8.75 Hz,
4J ¼ 2.76 Hz), 7.17 (d, 1H, H-2, 4J ¼ 2.74 Hz), 7.42 (d, 1H, H-5,
3J ¼ 8.78 Hz). 13C NMR (62 MHz, CD3CN): d ¼ 42.7 (2, cyclen-CH2),
44.0 (2, cyclen-CH2), 45.8 (2, cyclen-CH2), 51.3 (2, cyclen-CH2), 110.6
(þ, arene-CH), 116.8 (q, F3C–CHOO2, J ¼ 288.54 Hz), 121.6 (þ, arene-
CH), 128.6 (þ, arene-CH), 131.7 (Cquat), 148.7 (Cquat), 148.8 (Cquat), 160.4
(q, F3C–CHOO2, J ¼ 37.86 Hz).
The TFA salt was dissolved in methanol and eluated over a strong basic
ion-exchange resin, the solvent was removed in vacuum, and the product dried
in high vacuum to yield 11-H (610 mg, 82%), as a dark yellow solid, mp 908C.
IR (KBr): n ¼ 3432 cm21, 2925, 2846, 1653, 1523, 1457, 1363. UV/Vis
˜
1
(acetonitrile): lmax (lg 1) ¼ 195 nm (4.90), 243 (4.59), 375 (3.44). H NMR
(250 MHz, CD3CN): d ¼ 2.46–2.50 (m, 8H, cyclen-CH2), 2.66–2.69
(m, 4H, cyclen-CH2), 2.89–2.93 (m, 4H, cyclen-CH2), 4.45 (bs, 2H,
4
3
–NH2), 6.77 (d, 1H, H-2, J ¼ 2.65 Hz), 6.83 (dd, 1H, H-6, J ¼ 8.69 Hz,
4J ¼ 2.73 Hz), 7.27 (d, 1H, H-5, 4J ¼ 8.60 Hz). 13C NMR (62 MHz,
CD3CN): d ¼ 45.5 (2, cyclen-CH2), 46.2 (2, cyclen-CH2), 47.0 (2,
cyclen-CH2), 54.0 (2, cyclen-CH2), 108.8 (þ, arene-CH), 119.8 (þ, arene-
CH), 128.8 (þ, arene-CH), 134.2 (Cquat), 148.6 (Cquat), 152.1 (Cquat). MS
(ESI, CH2Cl2), m/z (%): 309.1 (100) [MHþ], 331.1 (8) [MNaþ].
Tris-tert-butyl-10-[4-(f1-methyl-4[(1-methyl-4-nitro-1H-pyrrole-2-carbo-
nyl)-amino]-1H-pyrrole-2-carbonylg-amino)-2-nitro-phenyl]-1,4,7,10-tetraaza
cyclododecane-1,4,7-tricarbamate (13-Boc): A mixture of 11-Boc (242 mg,
0.40 mmol), 12[12] (128 mg (0.44 mmol), HATU (181 mg, 0.48 mmol),
HOAt (65 mg, 0.48 mmol), and collidine (481 mg, 3.98 mmol) in DMF
(6 mL) was stirred 48 h at 608C. Water (3 mL) was added, and the mixture
was extracted three times with dichloromethane. The combined organic
phases were dried over Na2SO4, the solvents were removed in vacuum, and
the crude product was chromatographed on silica gel (EA/PE ¼ 1 : 1) to
give 13-Boc (198 mg, 82%, Rf ¼ 0.22, EE/PE ¼ 7 : 3) as a yellow solid, mp
1868C (dec.). IR (KBr): n (cm21) ¼ 3460, 2927, 1668, 1504, 1419, 1367,
˜
1167, 850; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 201 (4.672), 238 (4.369),
272 (4.421), 307 (4.527); 1H NMR (400 MHz, DMSO-d6): d ¼ 1.43
(s, 18H, CH3-Boc), 1.46 (s, 9H, CH3-Boc), 3.19–3.27 (m, 4H, CH2-cyclen),
3.34–3.41 (m, 4H, CH2-cyclen), 3.42–3.49 (m, 4H, CH2-cyclen), 3.50–
3.58 (m, 4H, CH2-cyclen), 3.95 (s, 3H, CH3-pyrrole), 4.05 (s, 3H, CH3-
4
4
pyrrole), 7.22 (d, 1H, J ¼ 1.9 Hz, CH-pyrrole), 7.33 (d, 1H, J ¼ 1.7 Hz,
CH-pyrrole), 7.40 (d, 1H, 3J ¼ 8.9 Hz, CH 2), 7.60 (d, 1H, 4J ¼ 1.9 Hz,
3
4
CH-pyrrole), 7.90 (dd, 1H, J ¼ 8.9 Hz, J ¼ 2.5 Hz, CH 3), 8.19 (d, 1H,
4J ¼ 1.7 Hz, CH-pyrrole), 8.30 (d, 1H, J ¼ 2.5 Hz, CH 5), 10.17 (bs, 1H,
4
NH), 10.32 (bs, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d ¼ 27.9, 28.0
(þ, CH3-Boc), 36.2, 37.4 (þ, CH3-pyrrole), 46.3, 47.2, 48.0

Functionalized N-Aryl-Substituted Cyclens
3017
(2, CH2-cyclen), 78.5 (Cquat, C-Boc), 105.7 (þ, CH-pyrrole), 107.5 (þ, CH-
pyrrole), 115.4 (þ, Caryl-H 5), 119.7 (þ, CH-pyrrole), 123.9 (þ, Caryl-H 3),
126.1 (þ, Caryl-H 2), 128.2 (þ, CH-pyrrole), 121.4, 122.2, 125.6, 133.7.
135.5, 138.9 (Cquat), 154.7, 154.9 (Cquat, C55O Boc), 156.8, 159.6 (Cquat
,
C55O amide); MS (ESI, MeOH þ 10 mmol NH4Ac): m/z (%) ¼ 883 (100)
[MH]þ, 392 (80) [M-Boc þ 2H]2þ
,
783 (30) [MH-Boc]þ; HRMS
(C41H59N10O12): calcd. 883.4314 [MH]þ, found: 883.4322 [MH]þ + 1.19ppm.
1-[4-(f1-Methyl-4[(1-methyl-4-nitro-1H-pyrrole-2-carbonyl)-amino]-1H-
pyrrole-2-carbonylg-amino)-2-nitro-phenyl]-1,4,7,10-tetraaza cyclododecane
(13-H): A solution of compound 13-Boc (150 mg, 0.18 mmol) in 20 mL of
TFA/CH2Cl2 (60:40, v/v) with a small amount methanol was stirred for
36 h at room temp. All solvents were removed in vacuum, and the
remaining solid was dried in high vacuum to yield the TFA salt (156 mg, quan-
titative) as a yellow solid, mp 147–1498C; IR (KBr): n (cm21) ¼ 3430, 2951,
˜
1667, 1515, 1423, 1161, 853; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 202
1
(4.551), 239 (4.457), 273 (4.583), 305 (4.605); H NMR (400 MHz, D2O):
d ¼ 2.92–3.03 (m, 4H, CH2-cyclen), 3.10–3.25 (m, 8H, CH2-cyclen),
3.25–3.36 (m, 4H, CH2-cyclen), 3.58 (s, 3H, CH3-pyrrole), 3.68 (s, 3H,
CH3-pyrrole), 6.64 (s, 1H, CH-pyrrole), 6.89 (s, 1H, CH-pyrrole), 6.97
4
(d, 1H, J ¼ 1.9 Hz, CH-pyrrole), 7.44 (d, 1H, 4J ¼ 1.6 Hz, CH-pyrrole),
3
4
3
7.53 (dd, 1H, J ¼ 8.9 Hz, J ¼ 1.9 Hz, CH 3), 7.58 (d, 1H, J ¼ 8.9 HZ,
CH 2), 8.01 (d, 1H, 4J ¼ 2.1 Hz, CH 5); 13C NMR (100 MHz, D2O):
d ¼ 36.4, 37.6 (þ, CH3-pyrrole), 41.5, 42.6, 44.6, 49.9 (2, CH2-cyclen),
105.9, 108.1, 115.6 (þ, CH-pyrrole), 116.1 (þ, Caryl-H 5), 116.4 (Cquat, q,
1JC,F ¼ 291.5 Hz, CF3COO2), 126.1 (þ, Caryl-H 3), 127.0 (þ, Caryl-H 2),
128.7 (þ, CH-pyrrole), 120.8, 125.2, 125.7, 133.7, 136.9, 137.6, 146.9
2
(Cquat), 157.8, 160.5 (Cquat, C55O amide), 162.9 (Cquat, q, JC,F ¼ 36.6 Hz,
CF3COO2); MS (ESI, CH3CN): m/z (%) ¼ 583 (100) [M3þ 2 2H]þ.
The TFA salt (118 mg, 0.13 mmol) was dissolved in 12 mL of H2O and
1 mL of CH3CN, and eluated over a strong basic ion exchange resin. The
organic solvent was removed from the eluate in vacuum and the remaining
aqueous phase was lyophylized to give 13-H (76 mg, quantitative) as a
yellow solid, mp 1568C (dec.). IR (KBr): n (cm21) ¼ 3441, 2913, 1661,
˜
1506, 1417, 1159, 854; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 203 (4.724),
236 (4.546), 279 (4.634), 306 (4.716); 1H NMR (400 MHz, DMSO-d6):
d ¼ 2.42–2.48 (m, 8H, CH2-cyclen), 2.60–2.66 (m, 4 H, CH2-cyclen),
2.96–3.03 (m, 4H, CH2-cyclen), 3.87 (s, 3H, CH3-pyrrole), 3.97 (s, 3H,
CH3-pyrrole), 7.21 (d, 1H, 4J ¼ 1.9 Hz, CH-pyrrole), 7.33 (d, 1H,
4J ¼ 1.7 Hz, CH-pyrrole), 7.60 (d, 1H, 4J ¼ 1.9 Hz, CH-pyrrole), 7.61
3
3
4
(d, 1H, J ¼ 8.9 HZ, CH 2), 7.88 (dd, 1H, J ¼ 8.9 Hz, J ¼ 2.4 Hz, CH 3),
8.17 (d, 1H, 4J ¼ 2.4 Hz, CH 5), 8.18 (d, 1H, 4J ¼ 1.7 Hz, CH-pyrrole),
10.19 (bs, 1H, NH), 10.34 (bs, 1H, NH); 13C NMR (100 MHz, DMSO-d6):
d ¼ 36.2, 37.4 (þ, CH3-pyrrole), 44.9, 45.4, 46.5, 52.0 (2, CH2-cyclen),
105.8, 107.5 (þ, CH-pyrrole), 114.3 (þ, Caryl-H 5), 119.7 (þ, CH-pyrrol),

3018
M. Subat et al.
123.9 (þ, Caryl-H 3), 127.0 (þ, Caryl-H 2), 128.1 (þ, CH-pyrrole), 121.6,
122.2, 126.1, 133.7, 136.2, 139.0, 147.8 (Cquat), 156.9, 159.7 (Cquat, C55O
amide), MS (ESI, CH3CN): m/z (%) ¼ 583 (100) [MH]þ.
1-[4-(f1-Methyl-4[(1-methyl-4-nitro-1H-pyrrole-2-carbonyl)-amino]-1H-
pyrrole-2-carbonylg-amino)-2-nitro-phenyl]-1,4,7,10-tetraaza cyclododecane
.
cobalt (III)-tri-chloride (14): Na3[Co)CO3)2] 3H2O (12 mg, 0.03 mmol was
added to a solution of 13-H (20 mg, 0.03 mmol) in 6 mL of H2O/MeOH
(1:1). The mixture was heated to 708C for 30 min. After cooling to room
temp., five to seven drops of conc. HCl were added, causing a color change
of the solution to green-yellow. Organic solvents were removed in vacuum
and the aqueous phase was lyophylized, yielding 14 (25 mg, quantitative) as
a yellow-green solid, mp 177–1798C, IR (KBr): n (cm21) ¼ 3437, 2934,
˜
1668, 1549, 1093, 740; UV/Vis (CH3CN): lmax (nm) (lg 1) ¼ 298 (3.902);
1H NMR (400 MHz, D2O): d ¼ 297–306 (m, 4H, CH2-cyclen), 3.13–3.28
(m, 8H, CH2-cyclen), 3.29-3.41 (m, 4H, CH2-cyclen), 3.56 (s, 3H, CH3-
pyrrole), 3.65 (s, 3H, CH3-pyrrole), 6.77 (bs, 1H, CH), 6.87 (bs, 1H, CH),
7.09 (bs, 1H, CH), 7.48 (bs, 1H, CH), 7.60 (bs, 2H, CH), 8.03 (bs, 1H,
CH); MS (ESI, MeOH/H2O þ 10 mmol NH4Ac): m/z (%) ¼ 701 (100)
[L þ Co3þ þ CO232]þ, 350 (25) [L þ Co3þ þ CH3COO2]2þ
.
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