A selective one-step synthesis of tris N-alkylated cyclens

Article abstract of DOI:10.1016/j.tet.2004.04.086

A general one-step synthesis for tris N-alkylated cyclens with good yield and unprecedented selectivity is presented. Tris and 1,4-bis N-alkylated cyclens, as the only two major products are isolated. Furthermore, according to the single crystal X-ray str

Full text of DOI:10.1016/j.tet.2004.04.086

Tetrahedron 60 (2004) 5595–5601
A selective one-step synthesis of tris N-alkylated cyclensq
*
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, People’s Republic of China
Received 12 March 2004; revised 19 April 2004; accepted 22 April 2004
Abstract—A general one-step synthesis for tris N-alkylated cyclens with good yield and unprecedented selectivity is presented. Tris and 1,4-
bis N-alkylated cyclens, as the only two major products are isolated. Furthermore, according to the single crystal X-ray structures of tris and
1,4-bis N-alkylated cyclen 1 and 1a, one nitrogen atom on the cyclen ring can be protonated under this reaction condition, which prevents its
further alkylation, and gives rise to the regioselectivity ultimately.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
or increase the enzymatic responding ability.8 Secondly, a
maximum of two coordinated sites is left for the binding of
water molecules in these heptadentate Ln3þ complexes,
which makes the relaxivity of Gd3þ complexes increase
effectively because the inner-sphere proton relaxivity is
linearly proportional to the number of directly coordinated
water molecules.9 Lastly, three chelating moieties with
negative charges such as carboxylate can neutralize the
Ln3þ; the resulting neutral complexes with low osmolality
can effectively reduce the pain and tissue sloughing during
the injection process.
Ln3þ complexes that are based on multidentate 1,4,7,10-
tetraazacyclododecane (cyclen) show high thermodynamic
and kinetic stabilities in aqueous solution, and have been
widely used as Magnetic Resonance Imaging (MRI)
contrast agents (CAs),1 radio-pharmaceuticals,2 lumines-
cence probes or switches,3 and RNA cleavers,4 etc. For
example, the octacoordinate Gd3þ complex, [Gd-DOTA
(H2O)]2 (Dotareme)5, is one of the most widely used
contrast agents in clinics (Fig. 1). Compared to octacoordi-
nate Ln3þ complexes, there has been a growing interest in
macrocyclic heptacoordinate Ln3þ complexes, especially
the tris N-carboxymethyl-1,4,7,10-tetraazacyclodecane
(DO3A) derivatives. Firstly, in DO3A derivatives, with
the exception of three pendant chelating moieties that are
utilized for strong lanthanide chelation, the remaining NH
can be derivatized freely to improve the organ/tissue
selectivity,6 fine tune the intramolecular energy transfer,7
Several selective functionalizations of cyclen to prepare
DO3A derivatives have been reported. Before the alkylation
is performed, three amines in the cyclen can be temporarily
protected by the protective groups such as tert-butyloxy-
carbonyl,10 tosyl11, formyl,12 trifluoroacetyl,13 or by the
sterically hindered reagents including phosphoryl species,14
glyoxal aminal,15 and metal carbonyls M(CO)6 (M¼Cr, Mo,
Figure 1. Structures of DOTA, Gd-DOTA and DO3A derivatives.
q Supplementary data associated with this article can be found in the online version, at doi: 10.1016/j.tet.2004.04.086
Keywords: One-step synthesis; Alkylation; Cyclen.
*
Corresponding author. Tel.: þ852-2859-2157; fax: þ852-2547-2933; e-mail address: wtwong@hkucc.hku.hk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.086

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C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
W)16 from the inside of the tetraazamacrocycles in a
stoichiometric ratio. Therefore, all the procedures above
involve a protection, alkylation, deprotection, and alkyl-
ation sequence. Even in the recent work of Welch, tris
N-alkylated cyclens were prepared from cyclen through four
such steps.17 In principle, the most efficient method to
prepare tris N-alkylated cyclens is selective alkylation of
three NH on the cycle with chelating agents (such as acetic
acid, amides, etc.) directly, after which selected functional
groups can be introduced to the remaining amine. Even
though several synthetic procedures for tris N-alkylated
cyclens through one-step alkylation were reported,18
unfortunately they are not always general, and the yields
of tris N-alkylated cyclens fluctuate between 20 and 50%
due to the formation of tetra N-alkylated byproducts. Hence,
the challenge still remains in exploiting a straightforward
procedure to prepare tris N-alkylated cyclens with high
selectivity.
different solvents with various auxiliary bases (Table 1).
The CHCl3/(Et)3N system afforded the most satisfactory
result (entry 4, Table 1). The effect of solvents on the yield
and selectivity is obvious. Weakly polar and aprotic
solvents like CH3Cl and CH2Cl2 are preferable to polar,
aprotic solvents such as DMF, CH3CN, and polar, protic
solvents such as CH3OH, which lead to substantial losses in
yield and selectivity22 (entries 6–8, Table 1). Auxiliary
bases also play an important role in determining the
regioselectivity (entries 1–4, Table 1). A yield of only
35% of tris N-alkylated cyclen 1 was achieved if (Et)3N was
replaced by K2CO3. Furthermore, in the presence of K2CO3,
nearly all cyclen was tetra N-alkylated in the presence of
8.0 equiv. of electrophile.
To further investigate the regioselectivity and distribution of
different N-alkylated products in the CHCl3/(Et)3N system,
a series of experiments was conducted in the presence of
tert-butyl bromoacetate from 2.0 to 8.0 equiv. (Fig. 2). 1,4-
Bis N-alkylated cyclen 1a and tris N-alkylated cyclen 1 were
the only two products that were isolated in the whole
reaction process. The yield of 1 increased gradually and
reached approximately 77% in the presence of about
3.5 equiv. of alkylating agent. At the same time, the yield
of 1a decreased from 81 to 20%. Interestingly, the
regioselectivity was kept nearly constant, and no tetra
N-alkylated cyclen was found even in a large excess of
8.0 equiv. of electrophile.
2. Results and discussion
In our previous studies, we described direct methods for the
preparations of mono N-alkylated cyclen,19 and 1,4-bis
N-alkylated cyclen.20 1,4-Bis(tert-butoxycarbonylmethyl)-
1,4,7,10-tetraazacyclododecane 1a as the only bis N-alkyl-
ated isomer was isolated in good yield by the treatment of
2.0 equiv. of tert-butyl bromoacetate with cyclen in chloro-
form. As reported, 6–10% of tris (tert-butoxycarbonyl-
methyl)-1,4,7,10-tetraazacyclododecane 1 was developed
as a side-product in this circumstance.20 To promote the
yield of this important precursor of DO3A chelate, an
additional electrophile was added under similar reaction
conditions. The yield of 1 increased dramatically, and an
optimal value of 77% was achieved in the presence of
3.5 equiv. of electrophile, much higher than that previously
reported.18 Surprisingly, apart from about 20% of 1,4-bis
N-alkylated product 1a, no other alkylated products were
isolated.
To clarify the solvent and auxiliary base’s effect on the
regioselectivity, this reaction was also performed in
Figure 2. Plot of yields of tris and 1,4-bis N-alkylated cyclens 1 (X) and 1a
(W) as a function of the number of equivalents of tert-butyl bromoacetate
added (298 K, CHCl3/(Et)3N).
Table 1. Effect of solvent and auxiliary base on the yield and
regioselectivity
Entry
Cond.a
Base
Yield (%)b
Bis Tetra
Tris
rc
To demonstrate the generality of this protocol in the
CHCl3/(Et)3N system, selected alkylating agents, especially
those that have been widely used as chelating moieties
2b–7b, were examined with cyclen, respectively (Table 2).
As expected, corresponding tris N-alkylated cyclens 2–7
and 1,4-bis N-alkylated cyclens 2a–7a were obtained with
good yields in the presence of 3.5 and 2.0 equiv. of
electrophiles, respectively, with no detection of 1,7-bis
and tetra N-alkylated cyclens at the same time.
1
2
3
4
5
6
7
8
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
DMF
Free
Pyridinee
K2CO3
(Et)3Ne
(Et)3Ne
(Et)3Ne
(Et)3Ne
(Et)3Ne
51
63
35
77
62
54
48
42
40
28
32
20
32
31
25
31
n.d.d
n.d.d
27
.99
.99
.99
.99
.99
3.7
f
n.d.d
n.d.d
,7
CH3CN
MeOH
21
22
2.4
2.8
a
3.5 equiv. tert-butyl bromoacetate, 14–20 h, 298 K.
Isolated yield of purified product.
b
c
Ratio of 1,4/1,7 bis-alkylated cyclen determined by 1H NMR and 13C
Compounds 1 and 1a were crystallized from a mixture of
9:1 acetone/H2O by slow evaporation. Interestingly, single
crystal X-ray structures demonstrated that both 1 and 1a
were in the form of their mono hydrochloride salts. In
NMR.21
Not detect.
d
e
f
10.0 equiv. of (Et)3N or pyridine.
5.0 equiv. of K2CO3.

C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
5597
Table 2. Yield and regioselectivity of selected electrophiles with cyclen in the condition of CHCl3/(Et)3N
Entry
Electrophiles
Product
Yield (%)a
1. R¼CH2COOBut Tris: 77b
1a. R¼H 1,4-Bis: 81c, r.99d
1
1b
2b
3b
2. R¼CH2Ph Tris: 86%b
2a. R¼H 1,4-Bis: 78c, r.99d
2
3
4
5
3. R¼CH2CHvCH2 Tris: 76%b
3a. R¼H 1,4-Bis: 73c, r.99d
4. R¼CH2CONHCH(Ph)2 Tris: 81b
4a. R¼H 1,4-Bis: 71c, r.99d
4b
5b
p
5. R¼CH2CONHCHMePh Tris: 71b
5a. R¼H 1,4-Bis: 73c, r.99d
6. R¼CH2CONH(CH2)5CH3 Tris: 84b
6a. R¼H 1,4-Bis: 75c, r.99d
6
6b
7b
7. R¼CHMeCOOEt Tris: 65b
7a. R¼H 1,4-Bis: 70c
7
a
Isolated yield of purified product.
In presence of 3.5 equiv. of halides.
In presence of 2.0 equiv. of halides.
Ratio of 1,4/1,7 N-alkylated cyclen.
b
c
d
previous reports of the crystal structure of DO3A23 or
DOTA derivatives24, the 12-membered cyclen rings usually
adopted a square [3333] conformation (A, Fig. 5). However,
the common feature of both 1 and 1a is that an unalkylated
N atom on the cyclen ring is protonated, and H-bonds with
the opposite N atom. This H-bonding results in the square
macrocycle ring being ‘pressed’ to the rectangular [2424]
conformations (B, Fig. 5). In the structure of 1·HCl25
(Fig. 3), hydrogen bonding interaction was found between
N(1) and protonated N(3), with a bonding distance of
meanwhile, the nucleophilicity of N(4) decreased substan-
tially due to its intraannular lone pair, which might explain
why part of 1,4-bis N-alkylated products can not be
transformed to the tris or tetra N-alkylated products even
in excess of electrophiles.
3. Conclusion
In conclusion, we developed a general one-step synthetic
strategy to prepare the tris N-alkylated cyclens in a yield of
up to 86%. This unique regioselectivity can be well
understood by the single crystal structures of 1 and 1a.
Under the CHCl3/(Et)3N reaction condition, nitrogen atoms
in the macrocycle can be selectively protonated, which
prevents its further alkylation even in a large excess of
electrophile, and ultimately gives rise to this regio-
selectivity. As far as we are aware, this is the first time
that the 12-membered cyclen ring has been observed to
˚
3.032 A, and the N–H· · ·N angle was 150.28. We propose
that its protonation prevents N(3) on the cyclen from being
alkylated, even in the presence of a large excess of
electrophiles. In the structure of 1a·HCl26 (Fig. 4),
H-bonding developed between the unalkylated N(3) and
˚
opposite N(1), with a distance of 2.867 A, which was even
shorter than that in 1·HCl, and the N–H· · ·N angle was
153.58. For the two neighboring unalkylated amines in 1a,
N(3) was protonated and H-bonded with opposite N(1);

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C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
Figure 3. X-ray crystal structure of 1.
Figure 4. X-ray crystal structure of 1a.
change from square to rectangular conformations via
intraannular H-bonding (Fig. 5). The attractive features of
this method such as high yield, operational convenience,
cost and labor economy will provide more opportunities to
create novel ligands based on tris N-alkylated cyclen
derivatives, and thus facilitate the application of lanthanide
complexes in drug discovery.
4. Experimental
4.1. General methods
All reactions were carried out under an argon atmosphere
using oven-dried glassware. CHCl3 and CH2Cl2 were
˚
distilled from calcium hydride and stored over 4 A

C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
5599
J¼6.8 Hz), 3.65 (4H, s), 3.35 (2H, s), 2.83–2.57 (16H, br,
m); 13C NMR (100 MHz, CDCl3): d 138.8 (2£C), 138.1 (C),
129.6 (2£CH), 129.5 (4£CH), 128.2 (4£CH), 128.1
(2£CH), 127.6 (2£CH), 127.0 (CH), 62.2 (2£CH2), 51.8
(CH2), 51.2 (2£CH2), 50.8 (2£CH2), 50.2 (2£CH2), 48.2
(2£CH2); ESI-MS m/z 443 (MþH)þ; HRFAB-MS calcd for
C29H39N4 (MþH)þ 443.3175, found 443.3171. Anal. calcd
for C29H39N4Cl: C, 72.70; H, 8.20; N, 11.69. Found: C,
72.56; H, 8.36; N, 11.42.
4.2.3. Tris-(allyl)-1,4,7,10-tetraazacyclododecane·HCl
(3).
3 was prepared as a colorless oil (579 mg,
1.76 mmol), yield 76% 1H NMR (400 MHz, CDCl3): d
5.80–5.70 (3H, m), 5.14–5.06 (6H, m), 3.11 (6H, d,
J¼6.4 Hz), 2.73–2.50 (16H, br, m); 13C NMR (100 MHz,
CDCl3): d 134.7 (2£CH), 130.8 (CH), 119.8 (CH2), 118.6
(2£CH2), 60.7 (2£CH2), 50.3 (2£CH2), 49.7 (2£CH2), 49.0
(2£CH2), 48.7 (2£CH2), 47.9 (CH2); ESI-MS m/z 293
(MþH)þ; HRFAB-MS calcd for C17H33N4 (MþH)þ,
293.2705, found 293.2714. Anal. calcd for C17H33N4Cl:
C, 62.08; H, 10.11; N, 17.03. Found: C, 62.16; H, 10.36; N,
16.82.
Figure 5. Conformations of 12-membered cyclen ring.
molecular sieves. Triethylamine were distilled from calcium
hydride and stored over sodium hydroxide. Flash chroma-
tography was performed on aluminum oxide 90 active
neutral (particle size 70–230 mesh) using CHCl3/CH3OH as
eluting solvents. NMR spectra were measured in CDCl3 or
CD3OD with SiMe4 as an internal standard at ambient
temperature on a Bruker Avance DPX 300 or 400 Fourier
Transform Spectrometer. Mass spectra were obtained at a
Finnigan MAT 95 mass spectrometer for high resolution
Fast Atom Bombardment (FAB) mass spectra, and at a LCQ
quadrupole ion trap mass spectrometer for low resolution
Electron Spray Ionization source (ESI) mass spectra.
Elemental analyses were performed in the Department of
Chemistry, City University of Hong Kong.
4.2.4. Tris-[(diphenyl)methylcarbamoylmethyl]-1,4,
7,10-tetraazacyclododecane·HCl (4). 4 was prepared as a
colorless oil (1.65 g, 1.88 mmol), yield 81% 1H NMR
(400 MHz, CDCl3): d 8.66–8.60 (2H, br), 7.85–7.82 (1H,
br), 7.22–7.06 (30H, m), 6.18 (2H, d, J¼6.3 Hz), 5.97 (1H,
d, J¼6.3 Hz), 3.27–3.17 (6H, m), 2.72–2.25 (16H, br, m);
13C NMR (100 MHz, CDCl3): d 171.5 (2£C), 171.3 (C),
141.8 (4£C), 141.7 (2£C), 129.1 (12£CH), 128.1 (12£CH),
127.8 (6£CH), 59.7 (3£CH), 58.2 (3£CH2), 51.3 (2£CH2),
51.1 (2£CH2), 49.2 (2£CH2), 47.5 (2£CH2); ESI-MS m/z
842 (MþH)þ; HRFAB-MS calcd for C53H60N7O3
(MþH)þ, 842.4758, found 842.4776. Anal. calcd for
C53H60N7O3Cl: C, 72.46; H, 6.88; N, 11.16. Found: C,
72.25; H, 6.65; N, 11.12.
4.2. General method for tris-N alkylated-1,4,7,10-
tetraazacyclododecane (1–7)
3.5 equiv. of appropriate electrophile (7.6 mmol) dissolved
in 10.0 mL of anhydrous chloroform was added dropwise to
a mixture of 1,4,7,10-tetraazacyclododecane (cyclen)
(400.0 mg, 2.32 mmol) and 10.0 equiv. triethylamine
(2.3 g, 23.2 mmol) in 40 mL of anhydrous chloroform
under argon atmosphere. The reaction mixture was stirred
for a further 16–20 h. The resulting solution was washed by
water (3£40 mL), and the organic phase was dried by
Na2SO4. The solvent was removed, and the crude products
were purified by column chromatography on Al2O3 to afford
the products 1–7.
4.2.5. Tris-[(R)-1-(1-phenyl)ethylcarbamoylmethyl]-
1,4,7,10-tetraazacyclododecane·HCl (5). 5 was prepared
1
as a colorless oil (1.14 g, 1.65 mmol), yield 71% H NMR
(400 MHz, CDCl3): d 8.51–8.45 (2H, br), 8.16–8.12 (1H,
br), 7.39–7.04 (15H, m), 5.04–4.80 (3H, m), 3.28–3.03
(6H, br, s), 2.73–2.22 (16H, br, m), 1.45 (9H, br, s); 13C
NMR (100 MHz, CDCl3): d 171.0 (C), 170.8 (C), 170.6 (C),
144.1 (C), 143.8 (2£C), 128.4 (6£CH), 127.1 (3£CH),
126.4 (6£CH), 60.7 (2£CH2), 60.6 (CH2), 54.2 (2£CH2),
53.2 (2£CH2), 52.1 (2£CH2), 48.9 (CH), 48.7 (2£CH), 46.7
(2£CH2), 22.5 (CH3), 21.8 (2£CH3); ESI-MS m/z 656
(MþH)þ; HRFAB-MS calcd for C38H54N7O3 (MþH)þ,
656.4288, found 656.4284. Anal. calcd for C38H54N7O3-
Cl·H2O: C, 64.25; H, 7.95; N, 13.80. Found: C, 64.44; H,
7.79; N, 13.99.
4.2.1. Tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetra-
azacyclododecane·HCl (1). 1 was prepared as a white
solid (0.98 g, 1.79 mmol); yield 77% mp 178–180 8C. H
1
NMR (400 MHz, CDCl3): d 3.34 (4H, s), 3.26 (2H, s), 3.05
(4H, s), 2.89–2.85 (12H, m), 1.47 (27H, s); 13C NMR
(100 MHz, CDCl3): d 170.5 (2£C), 169.6 (C), 81.6 (3£C),
58.2 (3£CH2), 51.3 (2£CH2), 51.1 (2£CH2), 49.2 (2£CH2),
47.5 (2£CH2), 28.2 (3£CH3), 28.1 (6£CH3); ESI-MS m/z
515 (MþH)þ; HRFAB-MS calcd for C26H51N4O6 (MþH)þ
515.3809; found 515.3811. Anal. calcd for C26H51N4O6Cl:
C, 56.66; H, 9.33; N, 10.17. Found: C, 56.41; H, 9.61; N,
10.34.
4.2.6. Tris-(hexylcarbamoylmethyl)-1,4,7,10-tetraaza-
cyclododecane·HCl (6). 6 was prepared as a colorless oil
(1.23 g, 1.95 mmol), yield 84% 1H NMR (400 MHz,
CDCl3): d 7.95–7.72 (3H, br, m), 3.14–3.10 (12H, br, s),
2.75–2.63 (8H, br, m), 2.60–2.46 (8H, br, m), 1.43–1.41
(6H, br, m), 1.23–1.10 (18H, br, s), 0.77 (9H, br, s); 13C
NMR (100 MHz, CDCl3): d 171.2 (C), 170.9 (2£C), 60.7
(3£CH2), 56.2 (CH2), 55.1 (CH2), 53.2 (2£CH2), 52.6
(2£CH2), 47.1 (2£CH2), 39.5 (CH2), 39.4 (2£CH2), 31.4
4.2.2. Tris-(benzyl)-1,4,7,10-tetraazacyclododecane·HCl
(2). 2 was prepared as a colorless oil (0.96 g, 2.00 mmol),
1
yield 86% H NMR (400 MHz, CDCl3): d 7.38–7.30 (8H,
m), 7.28–7.22 (2H, m), 7.21–7.13 (3H, m), 6.90 (2H, d,

5600
C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
(2£CH2), 31.3 (CH2), 29.5 (2£CH2), 29.4 (CH2), 26.6
(2£CH2), 26.4 (CH2), 22.4 (3£CH2), 13.8 (3£CH3); ESI-
MS m/z 596 (MþH)þ; HRFAB-MS calcd for C32H66N7O3
(MþH)þ, 596.5227, found 596.5235. Anal. calcd for
C32H66N7O3Cl: C, 60.78; H, 10.52; N, 15.50. Found: C,
60.94; H, 10.69; N, 15.55.
J¼6.4 Hz), 2.62 (4H, br, s), 2.52–2.47 (4H, m), 2.38–2.35
(4H, m), 2.31 (4H, br, s); 13C NMR (100 MHz, CDCl3): d
133.9 (2£CH), 118.1 (2£CH2), 55.4 (2£CH2), 50.5
(2£CH2), 50.0 (2£CH2), 46.6 (2£CH2), 45.5 (2£CH2);
ESI-MS m/z 253 (MþH)þ; HRFAB-MS calcd for C14H29N4
(MþH)þ, 253.2392, found 253.2384. Anal. calcd for
C14H29N4Cl: C, 58.21; H, 10.12; N, 19.40. Found: C,
58.41; H, 9.89; N, 19.22.
4.2.7. Tris-[ethyloxycarbonyl-1-methylmethyl]-1,4,7,10-
tetraazacyclododecane·HCl (7) (racemic mixture). 7 was
prepared as a colorless oil (0.71 g, 1.51 mmol), yield 65%.
1H NMR (400 MHz, CDCl3): d 4.04 (6H, br, s), 3.54–3.50
(1H, m), 3.36–3.32 (2H, m), 3.03–2.36 (16H, br, m), 1.28–
1.06 (18H, m); ESI-MS m/z 473 (MþH)þ; HRFAB-MS
calcd for C23H45N4O6 (MþH)þ, 473.3339, found 473.3336.
Anal. calcd for C23H45N4O6Cl·H2O: C, 52.41; H, 8.99; N,
10.63. Found: C, 52.15; H, 8.79; N, 10.47.
4.3.4. 1,4-Bis-[(diphenyl)methylcarbamoylmethyl]-
1,4,7,10-tetraazacyclododecane·HCl (4a). 4a was pre-
1
pared as a colorless oil (1.13 g, 1.65 mmol); yield 71% H
NMR (400 MHz, CDCl3): d 7.25–7.07 (20H, m), 6.21 (2H,
m), 3.19 (4H, s), 2.64–2.17 (16H, m); 13C NMR (100 MHz,
CDCl3): d 171.3 (2£C), 142.1 (4£C), 128.9 (8£CH), 128.1
(4£CH), 127.7 (8£CH), 59.4 (2£CH2), 52.5 (2£CH2), 51.3
(2£CH2), 50.3 (2£CH), 48.5 (2£CH2), 47.5 (2£CH2); ESI-
MS m/z 647 (MþH)þ; HRFAB-MS calcd for C38H47N8O2
(MþH)þ, 647.3822, found 647.3829. Anal. calcd for
C38H47N8O2Cl: C, 66.80; H, 6.93; N, 16.40. Found: C,
66.51; H, 6.66; N, 16.11.
4.3. General method for 1,4-bis N-alkylated-1,4,7,10-
tetraazacyclododecane 1a–7a
2.0 equiv. of appropriate electrophiles (4.64 mmol) dis-
solved in 10.0 mL anhydrous chloroform was added
dropwise to a mixture of 1.0 equiv. 1,4,7,10-tetraazacyclo-
dodecane (cyclen) (400.0 mg, 2.32 mmol) and 10.0 equiv.
triethylamine (2.32 g, 23.20 mmol) in 40 mL anhydrous
chloroform under a N2 atmosphere for approximately half
an hour. The reaction mixture was allowed to continuously
stir for a further 12–14 h. The resulting solution was
washed by water (3£40 mL) then the organic phase was
dried by Na2SO4. The solvent was removed, and the crude
products were purified by column chromatography on
Al2O3 to afford the products 1a–7a.
4.3.5. 1,4-Bis-[(R)-1-(1-phenyl)ethylcarbamoylmethyl]-
1,4,7,10-tetraazacyclododecane·HCl (5a). 5a was pre-
pared as a colorless oil (898 mg, 1.69 mmol); yield 73%
1H NMR (400 MHz, CD3OD): d 7.37–7.10 (10H, m),
5.04–4.92 (2H, m), 3.26–3.07 (4H, q, J¼8.2, 6.3 Hz),
2.75–2.60 (16H, m), 1.52 (6H, d, J¼7.0 Hz); 13C NMR
(100 MHz, CD3OD): d 171.6 (2£C), 143.8 (2£C), 128.6
(4£CH), 127.0 (2£CH), 126.1 (4£CH), 57.3 (2£CH2), 52.7
(2£CH2), 48.6 (2£CH2), 48.0 (2£CH), 45.7 (2£CH2), 44.9
(2£CH2), 21.1 (2£CH3); ESI-MS m/z 495 (MþH)þ;
HRFAB-MS calcd for C28H43N6O2 (MþH)þ, 495.3447,
found 495.3451. Anal. calcd for C28H43N6O2Cl: C, 63.32;
H, 8.16; N, 15.82. Found: C, 63.57; H, 8.27; N, 15.77.
4.3.1. 1,4-Bis (tert-butoxycarbonylmethyl)-1,4,7,10-tetra-
azacyclododecane·HCl (1a). 1a was prepared as a white
power solid (821 mg, 1.88 mmol); yield 81% 1H NMR
(400 MHz, CDCl3): d 3.32 (4H, s), 2.98–2.96 (8H, m),
2.89–2.87 (8H, m), 1.41 (18H, s); 13C NMR (100 MHz,
CDCl3): d 170.1 (C), 81.6 (2£C), 53.4 (2£CH2), 51.1
(2£CH2), 49.9 (2£CH2), 46.5 (2£CH2), 46.1 (2£CH2), 28.2
(6£CH3); IR (KBr, cm21) 2976, 1732, 1715, 1636, 1559,
1457, 1167; ESI-MS m/z 401 (MþH)þ; HRFAB-MS calcd
for C20H41N4O4 (MþH)þ, 401.3128, found 401.3130. Anal.
calcd for C20H41N4O4Cl: C, 54.97; H, 9.46; N, 12.82.
Found: C, 55.07; H, 9.76; N, 12.57.
4.3.6. 1,4-Bis-[(hexylcarbamoylmethyl)-1,4,7,10-tetra-
azacyclododecane·HCl (6a). 6a was prepared as a colorless
1
oil (886 mg, 1.74 mmol); yield 75% H NMR (400 MHz,
CDCl3): d 3.32 (4H, s), 3.22–3.11 (4H, br, m), 2.85–2.70
(8H, m), 2.63–2.47 (8H, m), 1.61–1.47 (4H, br, s), 1.40–
1.27 (12H, br, s), 0.88 (6H, br, s); 13C NMR (100 MHz,
CDCl3): d 173.2 (C), 172.2 (C), 57.5 (CH2), 56.3 (CH2),
52.5 (2£CH2), 52.0 (2£CH2), 45.3 (2£CH2), 44.3 (2£CH2),
39.2 (CH2), 39.0 (CH2), 31.2 (CH2), 31.1 (CH2), 29.1 (CH2),
28.9 (CH2), 26.3 (CH2), 26.1 (CH2), 22.2 (2£CH2), 13.0
(CH2), 12.9(CH2); ESI-MS m/z 455 (MþH)þ; HRFAB-MS
calcd for C24H51N6O2 (MþH)þ, 455.4074, found 455.4065.
Anal. calcd for C24H51N6O2Cl·H2O: C, 56.61; H, 10.49; N,
16.51. Found: C, 56.38; H, 10.42; N, 16.33.
4.3.2. 1,4-Bis (benzyl)-1,4,7,10-tetraazacyclodode-
cane·HCl (2a). 2a was prepared as a colourless oil
(704 mg, 1.81 mmol); yield 78%. 1H NMR (400 MHz,
CDCl3): d 7.28–7.16 (10H, m), 3.51 (4H, s), 2.85 (4H, br,
s), 2.80–2.74 (4H, m), 2.67–2.61 (4H, m), 2.57 (4H, br, s);
13C NMR (100 MHz, CDCl3): d 138.0 (2£C), 129.9
(4£CH), 128.8 (4£CH), 127.6 (2£CH), 57.6 (2£CH2),
51.5 (2£CH2), 51.2 (2£CH2), 47.1 (2£CH2), 46.2 (2£CH3);
ESI-MS m/z 353 (MþH)þ; HRFAB-MS calcd for C22H33N4
(MþH)þ, 353.2705, found 353.2711. Anal. calcd for
C22H33N4Cl: C, 67.93; H, 8.55; N, 14.40. Found: C,
67.66; H, 8.51; N, 14.71.
4.3.7. 1,4-Bis-(ethyloxycarbonyl-1-methylmethyl)-
1,4,7,10-tetraazacyclododecane·HCl (7a) (racemic
mixture). 7a was prepared as a colorless oil (677 mg,
1.62 mmol); yield 70% 1H NMR (400 MHz, CDCl3): d 4.01
(4H, br, s), 3.43–3.40 (2H, m), 3.03–2.36 (16H, br, m),
1.28–1.06 (12H, m); ESI-MS m/z 373.3 (MþH)þ; HRFAB-
MS calcd for C18H37N4O4 (MþH)þ, 373.2815, found
373.2825. Anal. calcd for C18H37N4O4Cl·0.5 H2O: C,
51.73; H, 9.16; N, 13.40. Found: C, 51.59; H, 9.33 N, 13.12.
4.3.3. 1,4-Bis (allyl)-1,4,7,10-tetraazacyclododecane·HCl
(3a). 3a was prepared as a white power solid (488 mg,
1
1.69 mmol); yield 73%. H NMR (400 MHz, CDCl3): d
5.62–5.51 (2H, m), 4.92–4.86 (4H, m), 2.89–2.87 (4H, d,
4.3.8. X-ray crystallography. Data collections were
performed at 20 8C with a Bruker AXS SMART 1000

C. Li, W.-T. Wong / Tetrahedron 60 (2004) 5595–5601
5601
11. Dischino, D. D.; Delaney, E. J.; Emswiler, J. E.; Gaughan,
G. T.; Prasad, J. S.; Srivastava, S. K.; Tweedle, M. F. Inorg.
Chem. 1991, 30, 1265–1269.
CCD diffractometer that was interfaced with a Silicon
Graphics INDYe workstation using the program package
TeXsan from MSC (version 1.7–2.0). The structures were
solved by direct methods (SIR92 or ORIENT), and refined
by full-matrix least-squares methods on F (teXsan).
Crystallographic data for compound 1 and 1a have been
deposited with the Cambridge Crystallographic Data Centre
(Deposition numbers CCDC 206158 and 206159). Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email:
deposit@ccdc.cam).
12. Boldrini, V.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.;
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We gratefully acknowledge financial support from the Hong
Kong Research Grants Council and the University of Hong
Kong. This work was also supported by the Area of
Excellence Scheme of the University Grants Committee
(Hong Kong).
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References and notes
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20. Li, C.; Wong, W. T. J. Org. Chem. 2003, 68, 2956–2959.
21. In the 13C NMR spectral, 1,7 bis N-alkylated adduct displays
two carbon signals for the eight carbons of the cyclen ring
indicating a D2h symmetry whereas 1,4 bis N-alkylated adduct
displays four carbon signals indicating C2v symmetry.
22. Kruper, W. J., Jr.; Rudolf, P. R.; Langhoff, C. A. J. Org. Chem.
1993, 58, 3869–3876.
3. (a) Parker, D.; Senanayake, P. K.; Williams, J. A. G. J. Chem.
Soc. Perkin Trans. 2 1998, 2129–2140. (b) Gunnlaugsson, T.;
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Leonard, J. P.; Senechal, K.; Harte, A.; J, J. Am. Chem. Soc.
2003, 125, 12062–12063. (c) Gunnlaugsson, T.; Leonard, J. P.
Chem. Commun. 2003, 2424–2425.
23. (a) Kumar, K.; Chang, C. A.; Francesconi, L. C.; Dischino,
D. D.; Malley, M. F.; Gougoutas, J. Z.; Tweedle, M. F. Inorg.
Chem. 1994, 33, 3567–3575. (b) Kang, S. I.; Ranganathan,
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Chappell, L. L.; Khalili, H.; Supkowski, R. M.; Horrocks,
W. D.; Morrow, J. R. Inorg. Chem. 2000, 39, 2130–2134.
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25. Crystal data for 1·HCl: C26H52ClN4O6.50, M¼561.18, mono-
clinic, space group P2/c (#13), a¼22.076(4), b¼6.699(1),
3
˚
˚
c¼23.700(4) A, b¼111.55(1)8, V¼3259.9(9) A , Z¼4,
Dcalc.¼1.143 g/cm3, m(Mo Ka)¼0.159 cm21, T¼298 K,
20143 reflections collected, 7922 unique (Rint¼0.023).
Refinement on F, final R1¼0.0459 (for 4274 reflections with
I$2.00s (I)), wR2¼0.0562.
7. (a) Gunnlaugsson, T.; Mac Donaill, D. A.; Parker, D. J. Am.
Chem. Soc. 2001, 123, 12866–12876. (b) Faulkner, S.; Pope,
S. J. A. J. Am. Chem. Soc. 2003, 125, 10526–10527.
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Ed. Engl. 1997, 36, 726–728. (b) Nivorozhkin, A. L.;
Kolodziej, A. F.; Caravan, P.; Greenfield, M. T.; Lauffer,
R. B.; McMurry, T. J. Angew. Chem., Int. Ed. Engl. 2001, 40,
2903–2906.
26. Crystal data for 1a·HCl: C40H88Cl2N8O11, M¼928.09,
tetragonal, space group P4¯ (#81), a¼28.798(3), b¼28.798
3
˚
˚
(3), c¼6.407(1) A, V¼5313.5(10) A , Z¼4, Dcalc¼1.160
g/cm3, m (Mo Ka)¼0.179 cm21, T¼298 K, 33108 reflections
collected, 6576 unique (Rint¼0.051). Refinement on F, final
R1¼0.0735 (for 3768 reflections with I$2.00s (I)),
wR2¼0.1081 (for 3768 reflections).
9. The Chemistry of Contrast Agents in Medical Magnetic
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´
Resonance Imaging; Merbach, A. E., Toth, E., Eds.; Wiley-
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