Selective mono N-alkylations of cyclen in one step syntheses

Article abstract of DOI:10.1016/j.tetlet.2007.09.022

In this Letter, we describe selective one step mono N-alkylations of cyclen (1,4,7,10-tetraazacyclododecane) using a range of functionalized alkyl halides. This 'easy to use' synthesis gives rise to mono-derivatives of cyclen from various alkyl halides or

Full text of DOI:10.1016/j.tetlet.2007.09.022

Tetrahedron Letters 48 (2007) 8052–8055
Selective mono N-alkylations of cyclen in one step syntheses
´
Julien Massue, Sally E. Plush, Celia S. Bonnet, Doireann A. Moore and
Thorfinnur Gunnlaugsson*
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
Received 17 July 2007; revised 27 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—In this Letter, we describe selective one step mono N-alkylations of cyclen (1,4,7,10-tetraazacyclododecane) using a range
of functionalized alkyl halides. This ‘easy to use’ synthesis gives rise to mono-derivatives of cyclen from various alkyl halides or,
when using alkyl dihalides, bis-cyclen derivatives, where the alkyl group links two cyclen macrocycles together. While the reaction
conditions require the use of 1:4 stoichiometry (alkyl halide:cyclen), any unreacted cyclen can be recovered with an aqueous extrac-
tion and successfully reused. This procedure was found to be quite versatile, being particularly well-suited for cyclen targets bearing
protected thiol groups, as well as a-chloroamide-derived chromophores; such cyclen pendant chromophores are employed as ante-
nnae for lanthanide luminescence probes and sensors.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Selective N-alkylation is an important step in the prepa-
ration of functionalized nitrogenous macrocycles such
as cyclens or cyclams. To date, several synthetic routes
have been reported for the selective mono N-alkylation
of such frameworks. However, these usually involve
multi-step syntheses, which often require the temporary
protection of several of the amines in the cyclic frame-
work prior to the selective alkylation. Examples of such
synthetic strategies involve the use of common protect-
ing groups such as tert-butyloxycarbonyl (Boc),1 p-tolu-
enesulfonyl (tosyl)2 or the formyl3 group in the 1, 4 and
7 positions of cyclen, followed by the alkylation of the
remaining amino moiety and then deprotection. An
alternative method often employed is the introduction
of bulky substituents on three of the nitrogens of the
macrocycle. Glyoxal4 or transition metal carbonyls
M(CO)6,5 such as Mo(CO)6, are the most commonly
used for this kind of protection. However, boron or
phosphorus derivatives have also been used for this pur-
pose.6 Again, a final deprotection step is necessary to
provide the desired mono N-alkylated product.
to the need for purification by column chromatography,
which is a real drawback in macrocyclic chemistry.
Furthermore, the expensive cyclen, used in excess as
the starting material, was not recovered. Hence, there
exists a need for an improved strategy for the introduction
of alkyl groups into such macrocycles in both high yields
and in a versatile manner.
Here, we describe a general method for the mono
N-alkylation of cyclen to obtain either mono-cyclen or
bis-cyclen systems depending on the nature of the pen-
dant arm. This improved synthesis involves the use of
a four fold excess of cyclen, which can be alkylated using
a variety of alkyl halides to give the mono product in
high yield. While this method involves the use of excess
cyclen, the unreacted macrocycle is easily removed
during the work-up stage and can be recycled. In this
Letter, we demonstrate the formation of several mono
N-alkylated cyclen derivatives, which are obtained in
high purity in moderate to good yields without the use
of lengthy column chromatography (Scheme 1).
Direct alkylation of cyclen or cyclam has been much
more rarely observed. Won and co-workers recently
reported the preparation of various mono N-alkylated
derivatives of such macrocycles.7 However, both bis
and tris-substitutions were often observed, which led
H
H
H
H
N
N
N
N
N
N
N
N
i) NEt3 / RX
ii) NaOH
H
H
H
R
Scheme 1. The synthesis of mono N-alkylated systems, from cyclen.
The cyclen moiety was reacted in 4:1 ratio with the alkyl halide RX,
where X = Cl or Br.
*
Corresponding author. Tel.: +353 1896 3459; fax: +353 1671 2826;
e-mail: gunnlaut@tcd.ie
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.022

J. Massue et al. / Tetrahedron Letters 48 (2007) 8052–8055
8053
The synthesis involved the use of an alkyl halide
(1 mmol), which was added to a solution of cyclen
(4 mmol, 4 equiv) and triethylamine (1.2 mmol,
1.2 equiv) in one portion, in freshly distilled CHCl3
(15 mL). The resulting solution was then refluxed gently
for 15 h, under argon. After cooling to room tempe-
rature, the organic solution was washed three times with
5 mL of a 1 M sodium hydroxide solution to remove the
excess of cyclen and then three times with water, dried
(MgSO4) and evaporated to yield colourless oils or white
powders. The unreacted cyclen could be recycled by con-
centrating the above alkaline solution under reduced
pressure and adjusting the pH of this concentrate to
neutral pH using HCl (1 M). This gave a white precipi-
products obtained in this investigation are summarized
in Table 1). Firstly, we used alkyl halides of several
lengths, such as propyl, n-hexyl and n-dodecyl, 1a–c,
onto the cyclen framework. Such derivatives are partic-
ularly important for magnetic resonance imaging
(MRI), since the Gd(III) complexes of such derivatives
have been used in the past as lipophilic paramagnetic
contrast agents.8 These compounds were all formed
successfully (e.g., cyclen mono N-alkylated compounds
1d–f, Table 1), and obtained in moderate to good yields
and in high purity, as demonstrated by 1H NMR analy-
sis, the 1H NMR data matching that reported in the lit-
erature.9 This was followed by the synthesis of several
cyclen derivatives bearing a pendant chromophore.
Examples include phenyl 2a, naphthalene 3a and acet-
amidoquinoline 4a, since such groups are commonly
used as antennae in sensitized lanthanide lumines-
cence.10 This gave compounds 2b, 3b and 4b, respec-
tively, in good yields. All characterizations were
consistent with the literature data previously reported.11
These results clearly demonstrate the versatility of this
1
tate, which when analyzed using H NMR (600 MHz,
CDCl3) showed the presence of a single signal, a singlet,
at 2.67 ppm, consistent with the chemical shifts of the
methylene groups of the cyclen framework.
We first tested this simple method by making several
mono-systems with various pendant arms (the resulting
Table 1. Alkylation of cyclen with alkyl bromide or chloride via Scheme 1
Entry
RX
Product
Yield (%)
H
H
N
N
N
Cl(CH2)nCH3
1a n = 11
1b n = 5
69
75
38
N
1
H
H
(CH2)nCH3
1d n = 11
1e n = 5
1f n = 2
1c n = 2
H
N
N
N
Br
2
3
4
63
59
60
N
2a
H
H
2b
H
N
N
N
Br
N
3a
H
H
3b
H
N
N
N
N
O
N
O
N
Cl
N
H
H
N
H
4a
4b
H
H
H
H
H
N
N
N
N
O
5
6
68
59
Br(CH2)12
S
O
5a
(CH2)12
5b
S
H
N
N
N
N
O
O
O
O
Cl
O(CH2)11
S
O(CH2)11
S
6a
6b

8054
J. Massue et al. / Tetrahedron Letters 48 (2007) 8052–8055
simple method. Most importantly, it excludes the use of
additional synthetic steps. We also investigated the
formation of several mono-systems, functionalized with
various alkyl halides, which had terminal acetyl pro-
tected thiol groups, as such groups could be employed
to graft lanthanide ion complexes of such cyclen deriva-
tives onto surfaces to give monolayers (SAMs) or
Langmuir–Blodgett (LB) films.12 A convenient way to
attach those entities onto these surfaces is to chemically
functionalize the pendant arms of the macrocycles with
an electrophilic entity capable of adsorbing onto the sur-
face, such as thiols.13 Halides 5a and 6a were used with
acetyl protected thiols, which can later be hydrolyzed to
give the desired thiol functionalities.14 Again here, the
one step reaction worked well, and the corresponding
cyclen derivatives 5b and 6b were synthesized in good
yields as colourless oils.15 We also investigated the
synthesis of several bis-cyclen systems, where two mono
N-alkylated cyclen macrocycles were linked together by
an alkyl spacer, as demonstrated in Scheme 2. This was
simply achieved by using alkyl dihalides. However, a
twofold increase in cyclen was required; an 8:1 stoichio-
metry was used; again any unreacted cyclen was easily
recovered.
procedure.14a The reaction of 8a with 8 equiv of cyclen
in chloroform in the presence of triethylamine afforded
N-alkylated bis-system 8b as a colourless sticky oil with-
out the need for column chromatographic purification.18
In summary, we have successfully improved the method
for the mono N-alkylation of the cyclen framework, by
using a 4:1 stoichiometry of cyclen to alkyl halides, in an
‘easy to use’ one step synthesis. We have also shown that
the excess cyclen can be easily recovered at the work-up
stage and subsequently recycled. We have also demon-
strated that alkyl dihalides can be used to give corres-
ponding bis-cyclens and that this method tolerates
several important functional groups such as disulfide
or protected thiol groups. We are currently exploring
the use of this method further for the synthesis of both
lanthanide-based ribonuclease mimics and in the synthe-
sis of lanthanide-based luminescence devices.
Acknowledgements
We thank TCD, SFI and IRCSET for financial support
and Drs. John E. O’Brien and Manuel Reuthers for
assisting with NMR analyses.
Examples of the products of this modification are shown
in Table 2. Compound 7b has previously been reported
as an important starting material for the formation of
various transition metal ion complexes, and for the
formation of bis-Gd(III) complexes for use as MRI
contrast agents,5,16 and as ribonuclease mimics for the
hydrolysis of phosphodiesters.17 Starting from the
commercially available 1,4-bis(bromomethyl)benzene
7a gave the desired bis-system 7b as a white powder, in
excellent yield. The incorporation of a di-sulfide bridge
was also achieved using 1,2-bis(12-bromododecyl)di-
sulfane, 8a, and was made according to a reported
References and notes
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N
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N
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N
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N
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N
i) NEt3 / RX2
ii) NaOH
Spacer
Scheme 2. General reaction for the synthesis of mono N-alkylated
cyclen bis-systems.
Table 2. Alkylation of cyclen with alkyl bromide via Scheme 2
Entry
RX
Product
Yield (%)
78
H
H
H
H
N
H
Br
N
N
N
N
N
N
1
Br
N
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7a
7b
H
H
H
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H
N
N
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N
N
N
N
2
Br(CH2)12S–S(CH2)12Br
8a
70
N
H
(CH2)12S-S(CH2)12
8b

J. Massue et al. / Tetrahedron Letters 48 (2007) 8052–8055
8055
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2H, CH2), 2.82 (t, 2H, CH2, J = 7 Hz), 2.28 (s, 3H, CH3),
1.62 (qt, 2H, CH2, J = 7 Hz), 1.52 (qt, 2H, CH2,
J = 7 Hz), 1.23 (m, 14H, CH2). dC (100 MHz, CDCl3)
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M = 415.3471. Found M = 415.3469. dH (400 MHz,
CDCl3): 2.84 (t, 2H, CH2, J = 7 Hz), 2.77 (m, 4H, CH2),
2.62 (m, 4H, CH2), 2.55 (m, 4H, CH2), 2.50 (m, 4H, CH2),
2.38 (t, 2H, CH2, J = 7 Hz), 2.30 (s, 3H, CH3), 1.54 (qt,
2H, CH2, J = 7 Hz), 1.44 (qt, 2H, CH2, J = 7 Hz), 1.23
(m, 16H, CH2). dC (100 MHz, CDCl3) 195.43, 53.99,
50.99, 46.51, 45.57, 44.66, 30.11, 29.15, 29.11, 29.05, 29.03,
28.99, 28.95, 28.60, 28.58, 28.18, 26.93, 26.78; (b) Data for
6b, Mass spectrum (MeOH, ES+): Expected M = 458.0.
Found M = 417.3245 (MÀAc+H). dH (400 MHz, CDCl3):
4.05 (t, 2H, CH2, J = 7 Hz), 3.38 (s, 2H, CH2), 2.82 (t, 2H,
CH2, J = 7 Hz), 2.76 (m, 8H, CH2), 2.60 (m, 4H, CH2),
2.56 (m, 4H, CH2), 2.28 (s, 3H, CH3), 1.58 (m, 2H, CH2),
1.52 (m, 2H, CH2), 1.22 (m, 14H, CH2). dC (100 MHz,
CDCl3): 195.25, 171.04, 63.94, 61.18, 55.25, 51.12, 46.42,
45.64, 45.56, 45.48, 44.69, 32.52, 30.02, 28.89, 28.84, 28.81,
28.60, 28.50, 28.18, 27.99, 25.44, 25.30.
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dodecyl)disulfane (100 mg; 0.18 mmol) was added to a
solution of cyclen (247 mg; 1.43 mmol) and NEt3
(0.06 mL; 0.43 mmol) in CHCl3 (15 mL) and the resulting
mixture was refluxed overnight. After cooling down, the
crude mixture was diluted with 30 mL of CHCl3 and then
washed with NaOH 1 M (3 · 20 mL) and H2O (2 ·
20 mL), dried (MgSO4) and evaporated under vacuum
to afford a colourless oil (186 mg, 70%). Calcd for
C40H87N8S2Æ0.5CHCl3: C, 60.58; H, 10.86; N, 13.95.
Found: C, 60.68; H, 10.66; N. 13.96. Calcd for
C40H87N8S2 [M+H]: M = 743.6523. Found M =
743.6495. dH (400 MHz, CDCl3): 2.67 (br s, 8H, CH2),
2.57 (t, 4H, CH2, J = 7 Hz), 2.52 (br s, 8H, CH2), 2.46 (br
s, 8H, CH2), 2.41 (br s, 8H, CH2), 2.30 (m, 4H, CH2), 1.56
(m, 4H, CH2), 1.35 (m, 4H, CH2), 1.27 (m, 4H, CH2), 1.16
(m, 28H, CH2). dC (100 MHz, CDCl3) 54.0, 51.0, 46.5,
45.7, 45.6, 44.7, 38.6, 29.2, 29.1, 29.1, 29.0, 28.7, 28.7, 28.0,
27.0, 26.9, 26.8. m(KBr)/cmÀ1: 3290, 2923, 2852, 2808,
1642, 1491, 1464, 1352, 1201, 1149, 1043, 943, 721, 658.
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1-Bromoundecanol (1 g, 3.98 mmol) was dissolved in
40 mL of absolute ethanol. Potassium thioacetate