Efficient N- and C-functionalisation of cyclam macrocycles utilising bisaminal methodology

Article abstract of DOI:10.1016/j.tetlet.2004.02.108

An efficient synthesis of C-functionalised cyclam macrocycles that employs bisaminal intermediates and allows N-substitution to be controlled is reported.

Full text of DOI:10.1016/j.tetlet.2004.02.108

Tetrahedron
Letters
Tetrahedron Letters 45(2004) 3059–3062
Efficient N- and C-functionalisation of cyclam macrocycles
utilising bisaminal methodology
Elizabeth A. Lewis, Cheryll C. Allan, Ross W. Boyle and Stephen J. Archibald*
Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, UK
Received 15January 2004; revised 12 February 2004; accepted 19 February 2004
Abstract—An efficient synthesis of C-functionalised cyclam macrocycles that employs bisaminal intermediates and allows N-
substitution to be controlled is reported.
ꢀ 2004 Elsevier Ltd. All rights reserved.
There is much current interest in the applications of
bifunctional chelators based on tetraazamacrocycles
such as 1,4,8,11-tetraazacyclotetradecane (cyclam) to
biology and medicine, for example, MRI contrast agents
and radioimmunotherapy.1;2 In particular, a great deal
of research effort in this area has been focused on 6-(4-
aminobenzyl)-1,4,8,11-tetraazacyclotetradecane-N,N,N,
N-tetraacetic acid and its analogues.3 Consequently,
there is an increasing requirement for versatile and
efficient routes to the 4-nitrobenzyl- or 4-cyanobenzyl
derivatives of 6-C-functionalised 1,4,8,11-tetraazacyclo-
tetradecane (cyclam), both of which can be reduced and
further reacted to form suitable precursors for conju-
gation to biomolecules.3;4 The ideal synthetic strategy
will include a number of key aspects: an efficient cycli-
sation step involving inexpensive, readily available
starting materials, the ability to produce gram quantities
of C-functionalised cyclam macrocycles, and lastly,
provide straightforward access to a range of selectively
N-substituted systems. Towards this goal we present
herein a novel and efficient route to N- and C-func-
tionalised cyclam macrocycles in which a 4-nitrobenzyl
group is appended at the 6-position.
butanedione to form a bisaminal 1 prior to reaction with
1,3-dibromopropane.5 Compared to other published
routes the method is very attractive, requiring only mild
conditions and having a relatively short reaction time
(6 h at rt).6 Regioselective N-functionalisation of cyclam
macrocycles is a continuing synthetic challenge, although
there are a number of different strategies proposed.7 One
common method involves addition of a large excess of
macrocycle relative to the electrophile in order to limit
N-derivatisation to one, two or three sites. Even if the
remaining macrocycle can be recovered at the end of the
reaction, this is not an efficient approach to N-derivati-
sation of C-functionalised cyclam, which is prepared
synthetically rather than being commercially available.8
Alternatively, protecting groups are frequently employed
to block one or more nitrogen sites on the macrocycle
and so allow the remaining ones to be derivatised selec-
tively. Although traditionally, tert-butyloxycarbonyl
(Boc) or tosyl (Ts) groups have been used to protect the
nitrogen positions of the macrocycle, new methodology
with bisaminal derivatives has been developed.9;10 On
reaction of a bisaminal intermediate with an electrophile,
sterically controlled N-substitution occurs cleanly and
in high yield.10 In this paper we demonstrate that by
utilising bisaminals both as templates in cyclisation
reactions and as protecting groups for selective N-func-
tionalisation, an efficient method of C- and N-function-
alisation is achieved. To our knowledge this is the first
example of bisaminal methodology being adapted to the
preparation of C-functionalised macrocycles.
Recently, the use of bisaminal intermediates both as
organic templates for cyclisation reactions and as a
protecting group for selective N-functionalisation has
been highly successful.5–10 In a novel approach to the
preparation of cyclam, N,N-bis(2-aminoethyl)-1,3-
propanediamine was rigidified by condensation with
The synthesis initially involves the preparation of
2-(4-nitrobenzyl)-1,3-dibromopropane 2 according to three
published steps from 4-nitrobenzyl bromide and diethyl
malonate, in high overall yield (66%).12 Treatment of
Keywords: Bifunctional macrocycles; Cyclam; Cyclisation; Bisaminal.
* Corresponding author. Tel.: +44-01482465488; fax: +44-014824664-
10; e-mail: s.j.archibald@hull.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.108

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E. A. Lewis et al. / Tetrahedron Letters 45 (2004) 3059–3062
2-(4-nitrobenzyl)-1,3-dibromopropane with the butane-
dione derived bisaminal, 1, in dry acetonitrile, in the
presence of excess potassium carbonate and heated to
60 ꢁC for 5d gives rise to the cyclisation product, 3, [74%
yield after column chromatography on flash silica, 10%
methanol/(3% Et3N in CH2Cl2), Rf ¼ 0:4].13 The reac-
its 4-cyanobenzyl analogues, the scheme described
herein is far more efficient. The two key steps, that is
cyclisation followed by bisaminal bridge removal, result
in formation of 6 in good overall yield (67%) and after a
total reaction time of only 8 d. Tetra-N-substitution of 6
is straightforward, typically involving addition of an
excess of the appropriate alkyl halide compound to a
solution of the macrocycle.15 In order to achieve di-N-
substitution however, 6 can be condensed with glyoxal
in cold acetonitrile to give bisaminal, 7, quantitatively.16
It is well established that on reaction of glyoxal with
cyclam, only the cis-diastereoisomer is obtained.14 As
detailed earlier with respect to 3, C-functionalisation at
the 6-position gives rise to two possible diastereoisomers
in which the bisaminal bridge is in the cis-configuration
(Scheme 2c). Unlike 3, where only one diastereoisomer
1
tion mixture was monitored by H NMR spectroscopy
and thin layer chromatography (TLC) in order to
determine the optimum conditions. It was noted that
cyclisation can be achieved at rt but occurs more slowly,
for example, less than 20% product was obtained after
stirring the reaction mixture for 3 d. Handel and
co-workers have shown that 1 exists as only the
cis-diastereoisomer in solution, and that this bridge
configuration is retained upon cyclisation using 1,3-
dibromopropane.5 By using a C-functionalised dib-
romo-derivative in the cyclisation step there are now
two possible cis-diastereoisomers that can be obtained,
dependent on the relative position of the hydrogen and
the 4-nitrobenzyl moieties at the 6-position (Scheme 2c).
1
exists in solution, the H and 13C NMR spectra of 7
exhibit two sets of signals, in approximately 1:1 ratio,
indicating the formation of both diastereoisomers (7a
and 7b) in approximately equal amounts. The single-
crystal X-ray structure (Scheme 2b) of 7a was obtained,
showing the 4-nitrobenzyl moiety in position R3, as in 3.
A comparison of the N2–N4 distance across the mac-
rocyclic ring revealed a slight compression in 3 relative
to 7a, attributed to the steric influence of the methyl
1
The H and 13C NMR spectra exhibit a single set of
signals for the cyclisation product, indicating that only
one diastereoisomer is obtained. The single-crystal
X-ray structure of 3 (Scheme 2a) confirms that the
4-nitrobenzyl moiety is in the sterically more favourable
position, directed away from the methyl groups, which
in turn retain their cis-configuration.
ꢀ
ꢀ
groups (3.038(7) A for 3 and 3.142(8) A for 7a).
Weisman and co-workers have demonstrated that the
bisaminal obtained from condensation of glyoxal with
cyclam undergoes highly regioselective di-N-function-
alisation and that the substitution pattern is dictated by
the macrocycle conformation.14 It follows that very
similar reactivity towards electrophiles will be observed
using the C-functionalised bisaminal analogue, 7. After
stirring 7 with an excess of benzyl bromide (ca. 10 equiv)
for 14 d, highly regioselective di-N-substitution at non-
adjacent N positions was achieved to give 8 (60%).17
Furthermore, Weisman and co-workers have developed
a series of Ôcross-bridgedÕ macrocycles by reduction of
the bisaminal bridge.14 Potentially, 8 can be used as a
precursor in the formation of novel C-functionalised
Ôcross-bridgedÕ macrocycles and experiments are in
progress to probe this. Conversely, in a similar manner
to 3 and 4, the bisaminal bridge of 8 can easily be
removed by acid hydrolysis to yield the C- and di-N-
functionalised cyclam macrocycle, 9.5
The addition of excess benzyl bromide (ca. 10 equiv) to a
solution of 3 in dry acetonitrile resulted in quantitative
formation of the mono-benzylated bisaminal, 4. The
1H and 13C NMR spectra indicate that benzylation
occurred selectively at one of two nitrogens on the
bisaminal, and that no other diastereoisomers, or
products arising from multiple substitution are obtained
even after 14 d of stirring at rt. The isomer obtained is
depicted in Scheme 1, in which steric repulsions between
the N- and C-benzyl moieties are minimised. Other
groups have observed exceptional selectivity for mono
N-benzylation, but in these cases steric control was
exerted by an asymmetric bisaminal bridge and not by
C-functionalisation at the 6-position of the macrocycle
backbone.10a;b Removal of the bisaminal bridge was
achieved quantitatively by acid hydrolysis under mild
conditions to yield the C- and N-substituted macrocycle,
5.5 Furthermore, 5 can be considered a useful precursor
to tri-N-substitution. After derivatisation of the
remaining three secondary amines of the macrocycle, the
benzyl group can easily be removed by hydrogenolysis.14
In summary we have shown that bisaminal methodology
can be utilised effectively for the preparation of C- and
N-functionalised cyclam macrocycles. The synthetic
strategy not only offers a more efficient pathway to the
cyclisation step but also incorporates synthons that
provide convenient routes to controlled N-substitution.
If di- or tetra-N-substitution of the C-functionalised
macrocycle is required, then the bisaminal bridge of 3
can be removed to afford 6-(4-nitrobenzyl)-1,4,8,11-tet-
raazacyclotetradecane, 6 (i.e., C-functionalised cyclam),
in excellent yield (>90%).5 In the procedures published
to date, C-functionalisation at the 6-position was
introduced by heating a mixture of the appropriate
malonate derivative and the linear tetraamine, N,N-
bis(2-aminoethyl)-1,3-propanediamine to reflux in eth-
anol to give a cyclic diamide, which was then subse-
quently reduced with borane in tetrahydrofuran.12a;15 In
comparison with this time-consuming (13–18 d) and
low-yielding (ca. 20%) strategy for the synthesis of 6 or
Supplementary material: Crystallographic data (exclud-
ing structure factors) for the structures in this paper,
have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication
numbers CCDC 227998 and 227999. Copies of the data
can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.
ac.uk).

E. A. Lewis et al. / Tetrahedron Letters 45 (2004) 3059–3062
3061
Scheme 1. Reagents and conditions:11 (i) NaH, DME, rt, 1 h, N2; (ii) BH3SMe2, THF, reflux, 3 d, N2; (iii) PBr3, pyridine (cat.), rt, o/n, 90–100 ꢁC, 1 h;
(iv) 10 equiv K2CO3, CH3CN, 60 ꢁC, 5d, N 2; (v) 10% HCl/H2O, EtOH, 60 ꢁC, 3 d; (vi) 40% aq glyoxal, MeOH, ꢀ5 ꢁC, 2 h, rt, 3 h; (vii) 10 equiv benzyl
bromide, CH3CN, rt, 3 d; (viii) 10 equiv benzyl bromide, CH3CN, rt, 14 d.
Scheme 2. Reagents and conditions: (a) ORTEP plot of the single-crystal X-ray crystal structure of 3 where: R1¼CH3, R2¼H, R3¼4-nitrobenzyl; (b)
ORTEP plot of the single-crystal X-ray crystal structure of 7a where: R1¼H, R2¼H, R3¼4-nitrobenzyl; (c) general schematic: R1¼H, CH3; R2¼H,
R3¼4-nitrobenzyl or R2¼4-nitrobenzyl, R3¼H.
Acknowledgements
References and notes
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We acknowledge the University of Hull and the Well-
come Trust (E.A.L., grant no 069719) for funding. We also
thank the EPSRC National Mass Spectrometry Service.
ꢁ
Chichester, 2001.

3062
E. A. Lewis et al. / Tetrahedron Letters 45 (2004) 3059–3062
2. (a) Parker, D.; Morphy, J. R.; Jankowski, K.; Cox, J. Pure
NMR (400 MHz, CD2Cl2): d 8.08 (d, J ¼ 8:6 Hz, 2H,
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CH2-a-N · 8, CH2-c-N · 1), 1.80–1.70 (m, 2H, CH2-b-N),
1.25(s, 3H, C H3), 1.20 (s, 3H, CH3), 1.20–1.00 (m, 1H,
CH-b-N); 13C NMR (100 MHz, CD2Cl2): d 150.47 (ArC),
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(NCN), 74.35(N CN), 52.94 (br, CH2-a-N), 51.33 (br,
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49.22 (br, CH2-a-N), 47.07 (br, CH2-a-N), 45.30 (br, CH2-
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11.27 (CH3), 9.89 (CH3); 1H COSY, 1H–13C HETCOR
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3a,5a,8a,10a-tetraazapyrene 7: Integration of the 1H
NMR spectrum indicates that two diastereoisomers are
present in approx. 1:1 ratio; 1H NMR (400 MHz,
CD2Cl2): d 8.09 (d, J ¼ 8:8 Hz, 2H, ArH), 8.08 (d,
J ¼ 8:8 Hz, ArH), 7.27 (d, J ¼ 8:8 Hz, 2H, ArH), 7.22
(d, J ¼ 8:8 Hz, 2H, ArH), 3.35–1.50 (2m, 21H · 2, CH2-a-
N · 8, CH2-c-N · 1, CH · 2), 1.30–1.00 (2m, 2H · 2, CH2-
b-N); 13C NMR [100 MHz, (CD3)2SO2]: d 150.04 (ArC),
148.28 (ArC), 145.94 (ArC), 145.82 (ArC), 130.08 (ArCH),
130.03 (ArCH), 123.46 (ArCH), 123.39 (ArCH), 77.12
(CH), 76.51 (CH), 76.48 (CH), 76.34 (CH), 61.08 (br,
CH2-a-N), 57.97 (br, CH2-a-N), 55.56 (br, CH2-a-N),
53.81 (br, CH2-a-N), 53.69 (br, CH2-a-N), 52.02 (br, CH2-
a-N), 45.26 (br, CH2-a-N), 44.32 (br, CH2-a-N), 40.58
(CH2-c-N), 37.31 (CH2-c-N), 36.08 (CH-b-N), 30.12 (CH-
ꢁ
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consistent with those reported: (a) Moreau, P.; Tinkl, M.;
Tsukazaki, M.; Bury, P. S.; Griffen, E. J.; Sniekus, V.;
Maharajh, R. B.; Kwon, C. S.; Somayajii, V. V.; Peng, Z.;
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1
1
b-N), 19.65( CH2-b-N), 19.48 (CH2-b-N); H COSY, H–
13C HETCOR, 13C DEPT and variable temperature
experiments were used to make resonance assignments;
HR ESMSꢀ m=z: calcd for C19H27H5O2 356.2092
[(MꢀH)ꢀ]; found 356.2088.
13. Spectroscopic data for cis-10b,10c-dimethyl-2-(4-nitro-
1H
17. Efforts to compare reactivity of 7a and 7b are in
progress.
benzyl)decahydro-3a,5a,8a,10a-tetraazapyrene
3: