A convenient method for the preparation of mono N-alkylated cyclams and cyclens in high yields

Article abstract of DOI:10.1016/S0040-4039(02)00497-5

Selective and high yield synthesis of mono N-substituted derivatives of cyclam and cyclen can be achieved by using a direct and general synthetic method with very mild reaction conditions.

Full text of DOI:10.1016/S0040-4039(02)00497-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3217–3220
A convenient method for the preparation of mono N-alkylated
cyclams and cyclens in high yields
Cong Li and Wing-Tak Wong*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug
Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
Received 23 October 2001; revised 28 February 2002; accepted 7 March 2002
Abstract—Selective and high yield synthesis of mono N-substituted derivatives of cyclam and cyclen can be achieved by using a
direct and general synthetic method with very mild reaction conditions. © 2002 Elsevier Science Ltd. All rights reserved.
The complexation chemistry of functionalized cyclams
and cyclens has been extensively studied in recent years.
The main reasons are that these macrocycles have
strong coordination ability towards a wide range of
cations, including transition metal ions and lanthanide
ions, and their complexes demonstrate high thermody-
namic stability and kinetic inertness.1a,b Hence cyclam
and cyclen have become the two most important tetra-
azamacrocycles in application and research, and their
complexes have been widely used as MRI contrast
agents,1b,c luminescent probes,2 DNA cleavers3 and
medicines for radioimmunotherapy.4 Currently, one
approach in MRI contrast agents focuses on the feasi-
bility of introducing some special functional groups
into the macrocycles, which can improve tissue selectiv-
ity, modify biodistribution, and give the molecule the
ability to sense pH value, temperature, and even enzy-
matic activity.5
atoms from the inside of the tetraazamacrocycles. How-
ever, all these procedures involve a protection, mono
functionalization, and deprotection sequence. Such
multiple step routes are divergent and not always appli-
cable; special reagents and extreme reaction conditions
are needed in some cases. This prompted us to look for
a more convenient and straightforward procedure with
high selectivity and high yield.
As a general synthetic method, the tetraazamacrocycles
should be able to react with different activated or
non-activated alkyl bromides, and bromides containing
functional groups that play an important role in
enhancing the molecule’s special performance. Here, we
describe a general and convenient route for obtaining
the mono N-alkylated derivatives of cyclam and cyclen.
Under these reaction conditions, satisfactory selectivity
and yield were achieved (Scheme 1).
Selective mono N-alkylation is an important step in the
preparation of functionalized macrocycles. Several
routes for mono N-alkylation have been reported.
Direct N-alkylations have been attempted, but a large
excess amount of costly polyazacrowns are needed.6
Three amines in the cyclic tetraamine are temporarily
protected by protective groups such as tert-butyloxy-
carbonyl, tosyl and formyl, before the alkylation is
performed.7 Another method is the introduction of
some sterically hindered reagents including boron,8
phosphoryl species,9 glyoxal aminal,10 and metal car-
bonyls M(CO)6 (M=Cr, Mo, W)11 in a stoichiometric
ratio, which can temporarily block three of the nitrogen
A typical procedure is as follows: alkylating agent (0.2
mmol) in 10 mL acetonitrile was added dropwise under
nitrogen to a solution of the tetraazamacrocycle
(cyclam or cyclen, 0.4 mmol) in 40 mL of acetonitrile
with 1.0 mmol anhydrous K2CO3 at 55–60°C. This
process lasted for about half an hour. The mixture was
Keywords: cyclam; cyclen; alkylation; synthesis.
* Corresponding author. Tel.: +852 2859 2157; fax: +852 2547 2933;
e-mail: wtwong@hkucc.hku.hk
Scheme 1. Reagents and conditions: (i) 0.4–0.5 equiv. of
alkylating reagents, CH3CN, 55–60°C, K2CO3, N2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00497-5

3218
C. Li, W.-T. Wong / Tetrahedron Letters 43 (2002) 3217–3220
then stirred for another 3–10 h at the same tempera-
ture. The reaction was monitored by TLC (Al2O3,
chloroform/methanol) until all of the alkylating agent
was consumed. After cooling down to room tempera-
ture, the excess macrocycles and K2CO3 were filtered
and the solvent was evaporated below 30°C to leave the
crude products, which were purified by flash chro-
matography on aluminum oxide (neutral, 70–230 mesh)
with a chloroform/methanol (or ethyl acetate/hexane)
mixed solvent system. A small amount of bis-alkylated
macrocycles and tri-alkylated macrocycles were
observed together with mono N-alkylated products.
Various selected alkylating reagents and their mono
N-alkylated products are listed in Table 1.
Accordingly, 2 equiv. of tetraazamacrocycles versus
alkylating agents is necessary to maintain the high yield
of mono N-alkylated products. From Table 1, under
the same reaction conditions, cyclam shows better
mono N-alkylation selectivity and yield than cyclen.
We found that the solubility of cyclam and cyclen in
acetonitrile is different. The limited solubility of cyclam
and the high solubility of mono N-alkylated cyclam in
acetonitrile are presumed to afford the driving force for
the reaction.
Previously Kruper and co-workers found that a high
yield of mono N-alkylated products in the form of
monohydrohalide salts can be obtained from the reac-
tion of a stoichiometric amount of cyclen with a-bromo
acid esters in a nonpolar, aprotic solvent.12 Unfortu-
nately, we found that the high yield cannot be main-
tained in the case of some less active bromides or alkyl
bromides with special functional groups. Moreover,
From Table 1 we find that the macrocycle:alkylating
agents ratio of 2–2.5:1 is the best choice for these
reactions; increasing the amount of tetraazamacrocycles
does not further improve the selectivity and yield.
Table 1. Alkylation of cyclam and cyclen with alkyl bromides
% Isolated yield a
Electrophile
Product
Time (h)
mono-subs bis-subs tris-subs m/z (MH+)b
n
R
BrCH2COOCH2CH3
4
1 n = 0
1 n = 1
2 n = 0
2 n = 1
3 n = 0
3 n = 1
79
85
81
88
84
91
~5
~3
~3
~3
~2
~2
~2
259.3
287.3
263.4
291.4
213.3
241.4
NH
NH
N
1a
Br
4
~1
n = 0, cyclen
n = 1, cyclam
HN
n
4
~1
n. d.c
2a
3.5
4
R = CH2COOCH2CH3,
PhCH2, CH2=CHCH2
~1
n. d.c
CH2= CHCH2Br
3a
4
n
CH2CH2OH
NH
NH
N
Br CH2CH2OH
6
6
4 n = 0
4 n = 1
83
90
~3
n. d.c
n. d.c
n. d.c
217.3
245.4
HN
4a
n
n
OH
NH
NH
N
Br
Br
OH
6.5
6.5
5 n = 0
5 n = 1
83
93
~2
n. d.c
~1
n. d.c
343.5
371.4
5a
HN
n
n
O
OAc
O
AcO
OAc
NH
NH
N
O
OAc
OAc
O
8.5
8.5
6 n = 0
6 n = 1
75
83
~4
~3
~1
~1
547.6
575.4
AcO
OAc
OAc
HN
6a13
n
n
O
O
O O
O
O
NH
NH
N
O
449.5, 471.5d
477.5, 499.5d
O
8.5
8.5
7 n = 0
7 n = 1
72
81
~5
~5
~2
~1
O
O
Br
Br
HN
O
O
7a14
n
n
O O
O
O O
O
O
NH
NH
N
O
O
O
8a15
10
10
8 n = 0
8 n = 1
66
78
~5
~3
~3
~2
493.7, 515.6d
521.7, 543.6d
O
O
HN
n
O
O
a
All the reactions were conducted at 55–60°C in dry acetonitrile under a N2 atmosphere; selectivity and yield were based on products isolated
by flash column chromatography. The two starting materials were in the ratio of macrocycle:alkylating agents=2–2.5:1 and 5.0 equiv. of
anhydrous potassium carbonate was added to the base. b ESI-MS m/z [MH+]. c Product was not detected. d ESI-MS m/z [M+Na]+.

C. Li, W.-T. Wong / Tetrahedron Letters 43 (2002) 3217–3220
Table 2. Alkylation of cyclam and cyclen in the different solvents
3219
Macrocycle
Alkylating agent
% Isolated yield
CH3CNa
b
a
CHCl3
CHCl3
EtOHa
Cyclen
PhCH2Br
CH2ꢀCHCH2Br
BrCH2COOEt
Br(CH2)11OH
BrCH2CH2OCH2-15-crown-5
81
84
79
83
72
75
88
91
85
93
81
83
84
81
85
43
38
32
55
53
43
51
47
32
21
31
47
55
44
37
24
36
ꢀ3
ꢀ5
ꢀ3
ꢀ6
ꢀ2
ꢀ1
ꢀ4
ꢀ6
ꢀ5
ꢀ7
ꢀ2
ꢀ2
BrCH2CH2O-b-
PhCH2Br
D
-glucopyranoside
Cyclam
CH2ꢀCHCH2Br
BrCH2COOEt
Br(CH2)11OH
BrCH2CH2OCH2-15-crown-5
BrCH2CH2O-b- -glucopyranoside
49
28
n.d.c
n.d.c
D
a Isolated yield of purified product after flash chromatography. All reactions were conducted at 55–60°C; reaction time ranged from 3 to 10 h.
All the reactions were conducted at the ratio of macrocycle:alkylating agent=2–2.5:1, and 5.0 equiv. of anhydrous potassium carbonate was
added as base.
b Using similar reaction conditions as in Ref. 12.
c Product was not detected.
under these reaction conditions, the yields of mono
N-alkylated cyclams dropped sharply, even for the
active N-alkylating agents and almost no N-alkylated
products were observed for the alkylating agents with
some large functional groups. In order to clarify the
effect of the reaction conditions on the yield of mono
N-alkylated products of these two important polyaza-
macrocycles, we conducted experiments using selected
N-alkylating agents under different conditions. The
following observations were made from the data shown
in Table 2: (1) In the acetonitrile/K2CO3 reaction sys-
tem, not only high selectivity and yield of mono N-
alkylated products can be gained for active bromides,
but also for less active bromides such as the special
spectra. This straightforward one-step process provides
a convenient preparative method for mono N-alkylated
tetraazamacrocycles such as cyclam and cyclen. The
mild and general reaction conditions also allow the
possibility of adding macromolecules or biomolecules
to tetraazamacrocycles with high efficiency.
Acknowledgements
We gratefully acknowledge financial support from the
Hong Kong Research Grants Council and the Univer-
sity of Hong Kong. This work is also supported by
Area of Excellence Scheme of University Grants Com-
mittee (Hong Kong), Li Cong acknowledges the receipt
of a postgraduate studentship administered by the Uni-
versity of Hong Kong.
alkyl bromides containing b-D
-glucopyranoside,13 long
aliphatic chain and different size crown ethers.14,15 (2)
Under these reaction conditions, satisfactory results
were achieved for both cyclen and cyclam, and to our
surprise, nearly all the N-alkylating agents show high
activity and selectivity to cyclam, especially in the case
of the bromide with a long carbon chain. It is also clear
that solvents play an important role in this reaction
because poor selectivity and yield resulted in either
chloroform or ethanol under the same conditions.
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were characterized by H NMR, 13C NMR and MS

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C. Li, W.-T. Wong / Tetrahedron Letters 43 (2002) 3217–3220
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(1H, t, J=10 Hz, Glc-H2), 4.57 (1H, d, J=8 Hz, Glc-
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m, a-b), 3.46 (2 H, t, J=6 Hz, b-a, b), 2.09 (3H, s, Ac),
2.07 (3H, s, Ac), 2.03 (3H, s, Ac), 2.01 (3H, s, Ac); 13C
NMR (75 MHz, CDCl3): l 170.5, 170.1, 169.3, 100.9,
72.5, 71.8, 70.9, 69.7, 68.2, 61.7, 29.8, 20.6, 20.5. FAB-
MS: m/z 455 [M]+, 477 [M+Na]+. Anal. Calcd for
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5.34%.
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14. Synthesis of 2-(2-bromoethoxy)methyl-15-crown-5 (7a):
300 mg (1.2 mmol) hydromethyl-15-crown-5 and 75 mg
(0.4 mmol) triethylbenzyl ammonium chloride were
added to dibromoethane (10 mL) at the same time. An
aqueous solution of 50% sodium hydroxide (5 mL) was
added and stirred at 60°C for about 12 h. After cooling,
dichloromethane (10 mL) and H2O (10 mL) were added
and collected separately after extraction. The aqueous
phase was further extracted with dichloromethane (3×10
mL), the combined organic fractions were evaporated to
give the crude product as a yellow oil, which was purified
by column chromatography on aluminum oxide (neutral,
70–230 mesh) with ethyl acetate:hexane=7:3 as eluent.
Yield: 67% as a pale viscous oil. 1H NMR (400 MHz,
CDCl3): l 3.86–3.54 (23H, m, 11×O-CH2 and 1×O-CH),
3.44 (2H, t, J=6 Hz, CH2-CH2-Br); 13C NMR (100
MHz, CDCl3): l 78.7, 71.5, 71.4, 71.2, 71.1, 70.9, 70.8,
70.7, 70.6, 70.5. 70.4, 70.3, 30.5. ESI-MS: m/z 357.5
[MH]+, 379.5 [M+Na]+. Anal. Calcd for C13H25O6Br: C,
43.71; H, 7.05. Found: C, 43.56; H, 7.35%.
12. Kruper, W. J., Jr.; Rudolf, P. R.; Langhoff, C. A. J. Org.
Chem. 1993, 58, 3869–3876.
13. Synthesis of 2,3,4,6-tetraacetyl-1-(2-bromoethoxy)-D-gluco-
pyranoside (6a): 1.5 equivalents of 2-bromoethanol (5.6 g,
45 mmol) was added to the solution of the penta-O-acetyl
D
-glucopyranose (11.7 g, 30 mmol) in dichloromethane
(80 mL). Boron trifluoride etherate (28.5 mL, 225 mmol)
was added to the stirred solution at 0°C for 1 h and then
at 35°C overnight. The solution was washed with water,
aqueous sodium carbonate and saturated aqueous
sodium chloride, respectively, dried with magnesium sul-
fate and evaporated in vacuo to give the crude product
(12.02 g, 26.4 mmol) as a yellow oil, yield: 88%. Diethyl
ether (50 mL) was added and the mixture was placed in
a refrigerator overnight during which time a white solid
precipitated. The white solid was recrystallized from
diethyl ether to yield white needle-like single crystals. mp:
15. Synthesis of 2-(2-bromoethoxy)methyl-18-crown-6 (8a):
the synthesis of 2-(2-bromoethoxy)-methyl-18-crown 6 is
1
similar to that of 7a. Yield: 65% as a pale viscous oil. H
NMR (400 MHz, CDCl3): l 3.81–3.54 (27H, m, 13×O-
CH2 and 1×O-CH), 3.45 (2H, t, J=6 Hz, CH2-CH2-Br);
13C NMR (100 MHz, CDCl3): l 78.7, 71.5, 71.4, 71.3,
71.2, 71.1, 71.0, 70.9, 70.8, 70.7, 70.6, 70.5. 70.4, 70.3,
30.5. ESI-MS: m/z 401.4 [MH]+, 423.4 [M+Na]+. Anal.
Calcd for C15H29O7Br: C, 44.90; H, 7.28. Found: C,
44.66; H, 7.57%.