Efficient synthesis of new C-functionalized macrocyclic polyamines

Article abstract of DOI:10.1002/ejoc.200901183

A powerful synthetic route for the preparation of new polyazamacrocycles, valuable precursors of afunctional chelating agents with applications in nuclear medicine, is reported. The desired functional group was introduced onto the macrocycle backbone during the cyclization step, thus avoiding the tedious preparation of a C-functionalized synthon. The regioselective reaction of macrocycles bearing an aminomethyl pendant arm with aldehydes is also described.

Full text of DOI:10.1002/ejoc.200901183

FULL PAPER
DOI: 10.1002/ejoc.200901183
Efficient Synthesis of New C-Functionalized Macrocyclic Polyamines
Yoann Rousselin,[a] Nicolas Sok,[a] Frédéric Boschetti,[b] Roger Guilard,[a] and
Franck Denat*[a]
Keywords: Amines / N ligands / Bifunctional chelating agents / Macrocycles
A powerful synthetic route for the preparation of new poly-
azamacrocycles, valuable precursors of bifunctional chelat-
ing agents with applications in nuclear medicine, is reported.
The desired functional group was introduced onto the macro-
cycle backbone during the cyclization step, thus avoiding the
tedious preparation of a C-functionalized synthon. The re-
gioselective reaction of macrocycles bearing an aminomethyl
pendant arm with aldehydes is also described.
cursor bearing the desired function on a carbon atom,
which can be tedious in some cases. The size of the macro-
cycle is also very important for tuning the coordination
properties of the chelating agent. [13]aneN4 derivatives have
been much less investigated than their smaller and larger
analogues, cyclen and cyclam derivatives, respectively, al-
though it has been reported that such 13-membered ring
compounds could show original properties.[8] The selective
alkylation of [13]aneN4 is clearly more difficult than that
of the more symmetrical cyclen and cyclam macrocycles,
which may explain why less attention has been paid to this
tetraazacycloalkane.
We wish to report in this paper a powerful route for the
synthesis of new macrocyclic tetraamines bearing an ad-
ditional aminomethyl group on a carbon atom in both the
cyclen and [13]aneN4 series. These macrocycles represent a
new class of ligands, the coordination properties of which
are currently under investigation. These compounds are
also valuable precursors of new bifunctional chelating
agents for labeling biomolecules. Indeed, the four secondary
amine groups of the ring can be further functionalized, for
instance, with acetate groups, after selective protection of
the primary amine function. A second approach is to intro-
duce another functionality onto the pendant amino group
by using a suitable reagent prior to ring functionalization.
We will also report herein an example of such a regioselec-
tive reaction, that is, the condensation with various alde-
hydes, which after reduction yield exclusively the compound
N-alkylated on the exocyclic nitrogen atom.
Introduction
Cyclic tetraamines (cyclen, cyclam, and [13]aneN4 and
their derivatives) have attracted increasing attention owing
to their versatile coordination properties which allow their
use in many fields, especially for medical purposes.[1] In-
deed, gadolinium chelates based on cyclen (e.g., DOTA-like
ligands) are widely used for magnetic resonance imaging
(MRI),[2] macrocyclic complexes with radioactive metals
(64Cu, 111In, 68Ga, and 90Y ...) are good candidates for la-
beling biological vectors for either diagnosis or therapeutic
purposes,[3] and macrocycles incorporating EuIII and TbIII
are very useful as fluorescent probes and labels.[4]
There is clearly a strong need for finely tailored ligands
that are multifunctional [so-called BFCs or bifunctional
chelating agents (BCAs)] and have very specific properties,
and the search for powerful synthetic routes towards tetra-
azacycloalkanes and their N- and/or C-functionalized de-
rivatives has become a real economic challenge. To date,
many routes have been proposed for the selective N-func-
tionalization of such frameworks.[5] However, the attach-
ment of the targeting biomolecule to a carbon atom of the
macrocyclic BFC may be preferred because the four nitro-
gen atoms then remain available for further functionaliza-
tion with chelating arms. This approach also avoids the pre-
vious multistep syntheses of sophisticated pendant arms
bearing both a chelating group and a grafting function-
ality.[6] Several strategies have been used for the synthesis
of such C-functionalized tetraazacycloalkanes.[7] The main
drawback of these approaches is the preparation of the pre-
[a] Institut de Chimie Moléculaire de l’Université de Bourgogne,
UMR 5260, CNRS-Univ. Bourgogne,
Results and Discussion
9 Avenue Alain Savary, 21078 Dijon Cedex, France
Fax: +33-3-80396117
The conditions used for the cyclization step in the pro-
cedure described herein allow the introduction of a func-
tional group onto a carbon atom of the cyclic backbone
without needing to prepare a sophisticated precursor. The
starting linear tetraamines, triethylenetetraamine and N,N-
E-mail: Franck.Denat@u-bourgogne.fr
[b] CheMatech,
9 Avenue Alain Savary, 21078 Dijon Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901183.
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Synthesis of New C-Functionalized Macrocyclic Polyamines
Scheme 1. Synthesis of the C-aminomethyl macrocycles 7 and 8.
bis(aminoethyl)propane-1,3-diamine, were first rigidified by
reaction with 2,3-butanedione to give the bis-aminal com-
pounds 1 and 2 (Scheme 1).[5b,9] This “bis-aminal ap-
proach” has been widely used in the last decade to prepare
macrocyclic tetraamines in high yields without using high-
dilution conditions or a metal cation as a template.[9b,10] It
has also been shown that C-functionalized and regioselec-
tively N-functionalized derivatives as well as cross-bridged
macrocycles can readily be obtained via such bis-aminal in-
termediates.[5b,7,11]
Condensation of chloroacetaldehyde with the bis-aminal
compounds 1 and 2 in the presence of 1 equiv. of benzotri-
azole and potassium carbonate in acetonitrile gave the cor- Figure 1. ORTEP[14] views of one anti stereoisomer of 3 (left) and
one syn stereoisomer of 4 (right), showing thermal ellipsoids at
responding cyclic adducts, which were not isolated
the 50% probability level. Hydrogen atoms have been omitted for
(Scheme 1). The benzotriazole-assisted reaction of second-
clarity.
ary amines with aldehydes has been extensively studied by
Katritzky et al.[12] and we have previously successfully used
this very convenient method for the synthesis of macro-
Reduction of compounds 3 and 4 with 2 equiv. of LiAlH4
cyclic polyamines.[13] Indeed, the reaction of a suitable bis- gave the corresponding aminomethyl bis-aminal derivatives
aminal compound with glyoxal assisted by benzotriazole 5 and 6, respectively, which were converted into the target
has proved to be a powerful route for the large-scale prepa- macrocycles 7 and 8 after removal of the bis-aminal bridge
ration of cyclen. The benzotriazole moiety in these adducts by acidic hydrolysis.
can be displaced by any kind of nucleophilic reagent. In this
The structure of the penta-protonated form of the new
work we chose cyanide ions as the nucleophilic agent and cyclen derivative 7 is shown in Figure 2. According to Da-
compounds 3 and 4 were isolated in 30 and 49% yields, le’s nomenclature the macrocycle adopts a (3,3,3,3)-A con-
respectively, after the addition of sodium cyanide. The formation, the four nitrogen atoms being located at the ver-
NMR spectra of these compounds are quite complicated tices of a square. Note that this structure resembles that of
because both 3 and 4 were obtained as pairs of enantiomers cyclen tetrahydrochloride. In the structure shown in Fig-
that have a diastereomeric cross-relation. Moreover, the ure 2, the absolute configuration of the carbon atom bear-
presence of many diastereotopic protons in these polycyclic ing the aminomethyl group is S, but compound 7 is ob-
1
derivatives gives rise to a large number of signals in the H tained as a racemic mixture.
NMR spectra. However, we were able to recrystallize a cou-
The crystal structure of compound 8 presented in Fig-
ple of enantiomers in both series. The crystal structures of ure 3 shows that two macrocycles, held together in a head-
these compounds are shown in Figure 1. In the cyclen de- to-tail arrangement by intermolecular hydrogen bonds, are
rivative 3, the cyanide group is pointing away from the bis- present in the unit cell with N–H···N distances of 3.208 and
aminal bridge, whereas the cyanide and the two methyl 3.346 Å for N3A–N4B and N5A–N4B, and 3.329 and
groups on the bis-aminal carbon atoms in compound 4 are 3.282 Å for N5B–N4A and N3B–N4A, respectively. The
located on the same side of the mean plane.
conformation of this macrocycle is thus imposed by inter-
Eur. J. Org. Chem. 2010, 1688–1693
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Y. Rousselin, N. Sok, F. Boschetti, R. Guilard, F. Denat
FULL PAPER
To protect the primary amine group for appending ad-
ditional coordinating arms onto the four nitrogen atoms of
the macrocycle, compound 8 was treated with 1 equiv. of
benzaldehyde. Only traces of the expected Schiff base were
1
observed, with both H and 13C NMR spectra exhibiting
signals characteristic of the presence of an aminal moiety.
It was proven by X-ray analysis of the [13]aneN4 derivative
10 (Figure 4) that the initial reaction of the primary amine
with the aldehyde was followed by the thermodynamically
favored formation of a hexahydropyrimidine six-membered
ring (Scheme 2). Similar results were obtained with other
aldehydes as well as with the cyclen series. The X-ray struc-
ture of the cyclen derivative 9 containing an anthracene
moiety is shown in Figure 4.
Figure 2. ORTEP[14] view of the penta-protonated form of 7, show-
ing thermal ellipsoids at the 50% probability level. Hydrogen atoms
attached to carbon atoms of the cyclic backbone, water molecules,
and counterions have been omitted for clarity.
molecular hydrogen bonds as well as by intramolecular hy-
drogen bonds, as shown by the following N–H···N dis-
tances: N2A–N3A 2.815 Å, N2A–N1A 2.879 Å, N2B–N3B
2.832 Å, N2B–N1B 2.870 Å, N4A–N1A 3.129 Å, N4B–
N1B 3.146 Å.
Figure 4. ORTEP[14] view of compounds 9 (left) and 10 (right),
showing thermal ellipsoids at the 50% probability level. Hydrogen
atoms attached to carbon atoms of the cyclic backbone have been
omitted for clarity. Hydrogen bonds are indicated by dashed lines.
Intramolecular N–H···N distances are 2.897, 2.904, and 2.964 Å
for N1–N2, N3–N4, and N3–N2, respectively, in 9 and 3.142,
2.903, and 2.984 Å for N1–N4, N3–N2, and N3–N4, respectively,
in 10.
The aminal intermediates were quantitatively reduced by
sodium borohydride in ethanol. Because two compounds
could result from the opening of the aminal bridge, com-
pound 13 was synthesized following another route, that is,
the bis-aminal intermediate 6 was first treated with benzal-
Figure 3. ORTEP[14] view of compound 8, showing thermal ellip-
soids at the 50% probability level. Hydrogen atoms attached to
carbon atoms of the cyclic backbone have been omitted for clarity.
Hydrogen bonds are indicated by dashed lines.
The C-aminomethyl macrocycles 7 and 8 represent a new dehyde before reduction and removal of the protecting bis-
class of ligands, which by themselves may exhibit original aminal group in the last step (Scheme 3).
chelating properties towards metal cations. Several com-
The superimposition of the NMR spectra of the two
plexes have already been prepared and the study of the co- compounds prepared by the two different routes proved un-
ordination properties of these cyclic pentaamines will be re- ambiguously that the cleavage of the aminal group in
ported elsewhere.
10 occurred selectively leading to the formation of the
Scheme 2. Selective N-alkylation of macrocycles 7 and 8.
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Synthesis of New C-Functionalized Macrocyclic Polyamines
in acetonitrile (2 L) at 0 °C. The mixture was stirred at this tem-
perature for 2 h. After filtration, an orange solution was obtained
and benzotriazole (46.4 g, 0.39 mol, 1 equiv.) and K2CO3 (107.6 g,
0.78 mol, 2 equiv.) were added at 0 °C. A solution of chloroacetal-
dehyde dried with MgSO4 (60.84 g, 0.39 mol) in acetonitrile
(500 mL) was slowly added at 0 °C and the resulting mixture was
stirred for 3 h. NaCN (19.21 g, 1 equiv.) was added. The mixture
was stirred overnight at room temperature. The solution was fil-
tered through Celite and the solid was washed with acetonitrile
(500 mL). The filtrate was evaporated. The resulting solid was dis-
solved in chloroform (1 L). After filtration, the solvent was re-
moved and the residual brown solid was taken up in diethyl ether
(2 L) and stirred at room temperature overnight. The impurities
were eliminated by filtration and the solvent was removed. The
residual solid was purified by aluminium oxide chromatography
[solvent: CH2Cl2/pentane (95:5)]. Two diastereoisomers were ob-
tained as a yellow oil (yield 28.5 g, 0.12 mol, 29 %). 1H NMR
(300 MHz, CDCl3, 300 K): δ = 1.07 (m, 9 H), 1.31 (s, 3 H), 2.48–
3.22 (m, 26 H), 3.34–3.52 (m, 3 H), 4.21 (m, 1 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3, 300 K): δ = 13.8, 14.0, 14.4, 16.4 (CH3),
42.6, 42.8, 43.8, 44.2, 45.8, 46.5, 47.4, 47.9, 49.6, 49.7, 50.3, 50.7,
51.1, 53.4 (CH2-α), 55.7, 56.5 (CH), 78.0, 78.3, 79.5, 80.0 (N-C-N),
Scheme 3. Alternative route to macrocycle 13.
(benzylamino)methyl-[13]aneN4 derivative 13. This remark-
able reaction provides a convenient access to new macro-
cycles functionalized on the exocyclic nitrogen atom. In-
deed, any aliphatic or aromatic aldehyde, such as 2-pyr-
idinecarbaldehyde or ferrocenecarbaldehyde, can be used.
Conclusions
We have devised a very efficient synthesis of C-function-
alized tetraazacycloalkanes. Aminomethyl derivatives of cy- 119.7, 120.4 (CN) ppm. IR: ν = 2233 (CN) cm–1. MS (MALDI-
˜
TOF): m/z = 247.76 [M]+.
clen and [13]aneN4 have been prepared in quite good over-
all yields. We are currently investigating the reactivity of the
benzotriazole bis-aminal adduct with nucleophilic agents
cis-9b,9c-Dimethyldecahydro-2a,4a,7a,9a-tetraazacyclopenta[cd]-
phenylene-1-carbonitrile (4): A solution of 2,3-butanedione (27.45 g,
other than the cyanide ion. Preliminary results have shown 0.319 mol) in acetonitrile (10 mL) was added to a solution of N,N-
bis(aminoethyl)propane-1,3-diamine (51.1 g, 0.319 mmol) in aceto-
nitrile (1.5 L) at 0 °C. The mixture was stirred at this temperature
for 2 h. Benzotriazole (38.1 g, 1 equiv.) and K2CO3 (88.2 g,
2 equiv.) were added. A solution of 50 % chloroacetaldehyde in
water (50.1 g, 0.319 mol) was slowly added at 0 °C and the resulting
mixture was stirred for 3 h. NaCN (15.6 g, 1 equiv.) was added and
the mixture was stirred overnight at room temperature. Then the
solution was filtered through Celite and washed with acetonitrile
(100 mL). The filtrate was evaporated. The resulting solid was dis-
solved in CH2Cl2 (500 mL). After filtration, the organic phase was
washed with a 3  NaOH solution (200 mL). After extraction, the
organic phase was dried with MgSO4 and the solvent was evapo-
rated. The residual brown solid was purified by aluminium oxide
chromatography (eluent: CH2Cl2). Compound 4 was obtained as a
white powder; m.p. 152.1(5) °C; yield 40.73 g, 0.156 mol, 49%. Sin-
gle crystals of 4 were obtained by slow evaporation of cyclohexane.
1H NMR (300 MHz, CDCl3, 300 K): δ = 1.03 (s, 3 H), 1.12 (m, 2
H), 1.29 (s, 6 H), 1.31 (s, 3 H), 2.26–3.69 (m, 32 H) ppm. 13C{1H}
NMR (75 MHz, CDCl3, 300 K): δ = 11.5, 11.7, 13.5, 14.9 (CH3),
18.1 (ϫ2) (CH2-β), 42.3, 43.9, 45.4 (ϫ2), 45.5, 45.6, 47.3, 47.4, 47.6,
47.9, 48.0, 49.5, 49.6, 49.7 (CH2-α), 56.3 (ϫ2) (CH), 72.6, 72.9,
that various Grignard reagents as well as other carbanions,
such as the malonate ion, could be successfully used, which
means that the scope of this reaction is not limited to the
preparation of compounds described herein. We would also
like to point out the peculiar reactivity of the C-ami-
nomethyl macrocycles with aldehydes, which results in the
highly regioselective N-functionalization of the pendant pri-
mary amine group. This reaction provides a very efficient
access to a wide range of valuable bifunctional chelating
agents based on the cyclen and [13]aneN4 macrocycles.
Experimental Section
General: NMR spectra were recorded with a Bruker 300, 500, or
600 spectrometer (300, 500, or 600 MHz for 1H; 75, 125, or
150 MHz for 13C). Chemical shifts are reported in δ ppm referenced
to the residual peak of [D]chloroform (δ = 7.25 or 77.00 ppm for
1H or 13C). The following abbreviations are used; s: singlet, d:
doublet, t: triplet, q: quartet, m: multiplet, br.: broad. Elemental
analyses were performed at the PACSMUB at the University of
Burgundy. Mass spectra were obtained by the MALDI-TOF (ma-
trix-assisted laser desorption ionization time of flight) method with
a Bruker DALTONICS Proflex III spectrometer or by ESI (electro-
spray ionization) with a Bruker MicroTOF-Q spectrometer. Infra-
red spectra were recorded with a Bruker Vector 22 spectrometer in
ATR mode. CCDC-749971 (for 3), -749972 (for 4), -749973 (for
7), -749974 (for 8), -749975 (for 9), and -749976 (for 10) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
80.2, 80.4 (N-C-N), 119.2, 120.3 (CN) ppm. IR: ν = 2228
˜
(CN) cm–1. MS (MALDI-TOF): m/z = 261.97 [M]+.
cis-(9b,9c-Dimethyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]ace-
naphthylen-1-yl)methanamine (5): A solution of 3 (28.5 g, 0.12 mol)
in dry THF was slowly added to a suspension of LiAlH4 (5.25 g,
0.14 mol) in THF (250 mL) under nitrogen at –78 °C. The resulting
mixture was stirred overnight. Water (50 mL) was carefully added
at –78 °C to the mixture to neutralize the excess LiAlH4. After
removal of the solvent, the residual white solid was taken up in
chloroform (500 mL), insoluble impurities were eliminated by fil-
tration and washed with NaOH (8 ) solution. Two diastereoiso-
mers were obtained as a yellow oil (yield 28.0 g, 0.11 mol, 96%).
1H NMR (300 MHz, CDCl3, 300 K): δ = 1.05–1.55 (m, 16 H),
2.36–3.44 (m, 34 H) ppm. 13C{1H} NMR (75 MHz, CDCl3,
300 K): δ = 13.9, 14.0, 16.6, 23.0 (CH3), 43.3, 43.9, 44.4 (ϫ2), 44.8,
cis-9b,9c-Dimethyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg]ace-
naphthylene-1-carbonitrile (3): A solution of 2,3-butanedione
(33.5 g, 0.39 mol) was added to a solution of dry triethylenetetraa-
mine (57.0 g, 0.39 mol) and calcium hydroxide (57.70 g, 0.78 mol)
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Y. Rousselin, N. Sok, F. Boschetti, R. Guilard, F. Denat
45.2, 45.6, 46.1, 46.4, 48.6, 50.1, 50.5, 51.3, 51.4, 52.3, 55.7 (CH2- 46.8, 48.3, 48.6, 50.0, 50.2, 52.2, 52.7, 52.9, 55.5, 66.2 (CH2-α),
FULL PAPER
α), 60.5, 63.3 (CH), 77.3, 78.4, 79.4, 80.3 (N-C-N) ppm. MS
77.9, 81.5 (CH-aminal), 123.2, 124.5, 124.6, 124.8 (ϫ2), 125.2,
125.3 (ϫ2), 125.4 (ϫ2), 125.6, 126.2, 126.8 (ϫ2), 128.3, 128.7, 128.9
(ϫ2), 129.0, 129.3, 129.4, 129.6, 129.7, 130.0, 130.5, 130.7, 131.5,
132.2 (Car) ppm. ESI: m/z = 390.26 [M+ + H]. C24H31N5 (389.54):
calcd. C 74.00, H 8.02, N 17.98; found C 73.61, H 8.80, N 18.26.
(MALDI-TOF): m/z = 251.32 [M]+.
cis-(9b,9c-Dimethyldecahydro-2a,4a,7a,9a-tetraazacyclopenta[cd]-
phenylen-1-yl)methanamine (6): A solution of 4 (40.73 g, 0.156 mol)
in dry THF (50 mL) was slowly added to a suspension of LiAlH4
(11.8 g, 0.31 mol, 2 equiv.) in THF (200 mL) under nitrogen at 15-Phenyl-1,4,8,11,14-pentaazabicyclo[10.3.1]hexadecane (10):
–78 °C. The resulting mixture was stirred overnight. Ethyl acetate
(100 mL) and then water (25 mL) were carefully added. After re-
moval of the solvent, the residual white-grey solid was taken up in
Benzaldehyde (0.3 mL, 3.5 mmol) was added at 0 °C to a solution
of 8 (0.76 g, 3.5 mmol) in ethanol (50 mL). The mixture was stirred
at this temperature for 5 h. The solvent was evaporated and the
chloroform (2ϫ200 mL) and insoluble products were eliminated residual oil was taken up in pentane (50 mL). The insoluble impuri-
by filtration. Compound 6 was obtained as a colorless oil (yield
32.16 g, 78 %) as two diastereoisomers. 1H NMR (300 MHz,
CDCl3, 300 K): δ = 1.04 (s, 3 H), 1.12 (s, 3 H), 1.27 (s, 2.9 H), 1.28
ties were removed by filtration. Compound 10 was obtained as col-
orless crystals upon slow evaporation of the solvent; m.p.
93.8(5) °C; yield 0.74 g, 2.4 mmol, 70%. Two diastereoisomers were
1
(s, 2.9 H), 1.76 (m, 1.3 H), 2.2–3.6 (m, 26.6 H) ppm. 13C{1H} NMR obtained. H NMR (300 MHz, CDCl3, 300 K): δ = 1.43–3.30 (m,
(75 MHz, CDCl3, 300 K): δ = 11.9, 12.3 (ϫ2), 13.4 (CH3), 18.7, 46 H), 3.96 (s, 1 H), 4.37 (s, 1 H), 7.26–7.56 (m, 10 H) ppm.
25.8 (CH2-β), 44.8, 44.9, 45.7, 45.9, 46.5, 46.6, 47.2 (ϫ2), 48.0,
48.3, 48.4, 49.4, 50.0, 50.1, 51.0, 51.1 (CH2-α), 61.8, 68.1 (C-H), 51.0 (ϫ2), 51.7, 51.8, 53.0, 53.1, 53.7, 54.6, 54.7, 54.9, 55.5, 55.6,
13C{1H} NMR (75 MHz, CDCl3, 300 K): δ = 32.0, 32.5 (CH2-β),
73.2, 73.4, 79.3, 80.5 (N-C-N) ppm. MS (MALDI-TOF): m/z =
56.1, 56.5, 57.1, 57.2 (CH2-α), 67.9 (ϫ2) (CH), 85.8, 90.0 (N-C-N),
131.0 (ϫ3), 131.8, 132.1, 132.2 (ϫ3), 132.5 (ϫ2) (CHar), 145.0,
145.4 (Car) ppm. MS (MALDI-TOF): m/z = 304.09 [M + H]+.
C17H29N5 (303.45): calcd. C 67.09, H 9.63, N 23.08; found C 67.31,
H 9.66, N 22.40.
265.82 [M]+.
(1,4,7,10-Tetraazacyclododecan-2-yl)methanamine (7): A solution of
35% hydrochloric acid (40 mL, 0.4 mol, 7 equiv.) was slowly added
to compound 5 (15.0 g, 0.06 mol). The mixture was heated at reflux
overnight. After cooling at room temperature, a precipitate was
formed. The light-brown solid was filtered and washed successively
with ethanol and with diethyl ether. A white powder was obtained.
Then the solid was taken up in a 16  NaOH solution (20 mL) and
extracted with chloroform. Compound 7 was obtained as a yellow
oil (yield 4.3 g, 0.02 mol, 39 %). 1H NMR (300 MHz, CDCl3,
15-(Pyridin-2-yl)-1,4,8,11,14-pentaazabicyclo[10.3.1]hexadecane
(11): 2-Pyridinecarbaldehyde (0.22 g, 2 mmol) was added at 0 °C to
a solution of 8 (0.44 g, 2 mmol) in ethanol (50 mL). The mixture
was stirred at this temperature overnight. The solvent was evapo-
rated, and the residual oil was taken up in pentane (50 mL). The
insoluble impurities were removed by filtration. After evaporation
300 K): δ = 1.75 (s, 6 H), 2.49–2.66 (m, 17 H) ppm. 13C{1H} NMR of the solvent, compound 11 was obtained as a colorless oil; yield
(75 MHz, CDCl3, 300 K): δ = 44.1, 44.6, 46.0, 46.3, 46.4, 46.7,
46.8, 48.9 (CH2-α), 57.2 (CH) ppm. MS (MALDI-TOF): m/z =
201.75 [M]+.
0.45 g, 1.5 mmol, 74%. Two diastereoisomers were obtained. 1H
NMR (300 MHz, CDCl3, 300 K): δ = 1.15–3.19 (m, 46 H), 4.06 (s,
1 H), 4.41 (s, 1 H), 7.15 (m, 2 H), 7.36 (m, 2 H), 7.51 (m, 2 H),
8.49 (m, 2 H) ppm. 13C{1H} NMR (75 MHz, CDCl3, 300 K): δ =
28.2, 28.8 (CH2-β), 47.1, 47.2, 48.0, 49.2 (ϫ2), 49.5, 50.6, 50.8,
51.1, 51.6, 51.7, 51.8, 52.3, 52.6, 53.5, 53.6 (CH2-α), 64.5 (ϫ2)
(CH), 82.8, 86.2 (N-C-N), 122.1, 122.2, 123.2, 123.3, 136.6, 137.0,
149.4, 149.5 (CHar), 160.0, 160.7 (Car) ppm.
(1,4,7,10-Tetraazacyclotridecan-5-yl)methanamine (8): A solution of
35% hydrochloric acid (107 mL, 1.2 mol, 10 equiv.) was added to a
solution of 6 (32.16 g, 0.12 mol) in ethanol (200 mL). The resulting
mixture was heated at reflux for 4 h. After cooling, the solution was
filtered and washed with ethanol (50 mL) and then diethyl ether
(100 mL). The solid was dissolved in a saturated 15  NaOH solu-
tion (10 mL). After extraction with chloroform (2ϫ150 mL), the
organic phase was dried with MgSO4 and the solvent was evapo-
rated. Compound 8 was obtained as a white solid; m.p. 78.8(5) °C;
yield 11.02 g, 42%. Single crystals of 8 were obtained by slow evap-
N-[(1,4,7,10-Tetraazacyclododecan-2-yl)methyl]-1-(anthracen-9-yl)-
methanamine (12): NaBH4 (0.15 g, 3.84 mmol) was added to a solu-
tion of 9 (0.3 g, 0.77 mmol) in ethanol (10 mL) at room tempera-
ture. The mixture was stirred at room temperature for 12 h. The
solvent was then removed and the residual orange oil was taken up
in diethyl ether (20 mL). The insoluble salts were removed by fil-
1
oration of pentane. H NMR (300 MHz, CDCl3, 300 K): δ = 1.63
(m, 2 H), 1.87 (s, 6 H), 2.67–2.76 (m, 17 H) ppm. 13C{1H} NMR tration through CLARCEL®. After evaporation of the solvent
(75 MHz, CDCl3, 300 K): δ = 28.9 (CH2-β), 44.3, 46.2, 47.7, 49.0, compound 12 was obtained as a yellow oil; yield 0.20 g, 0.51 mmol,
49.0, 49.7, 49.8, 50.8 (CH2-α), 59.0 (CH) ppm. MS (MALDI-
67%. 1H NMR (500 MHz, CDCl3, 300 K): δ = 1.89 (br. s, 4 H),
TOF): m/z = 215.68 [M]+. C10H25N5·0.2H2O (221.62): calcd. C 2.25–2.73 (m, 18 H), 4.50 (m, 2 H), 7.31 (m, 4 H), 7.80 (m, 2 H),
54.86, H 11.69, N 31.99; found C 55, H 11.57, N 31.81.
8.19 (m, 3 H) ppm. 13C{1H} NMR (125 MHz, CDCl3, 300 K): δ =
44.3, 45.9 (ϫ2), 46.0, 46.3, 46.8, 47.0, 49.0, 52.7 (CH2-α), 55.1
(CH), 124.3, 124.9, 126.0, 127.0, 129.0, 130.3, 131.5, 131.9
(Car) ppm.
14-(Anthracen-9-yl)-1,4,7,10,13-pentaazabicyclo[9.3.1]pentadecane
(9): Anthracene-9-carbaldehyde (0.25 g, 1.25 mmol) was added to
a solution of 7 (0.25 g, 1.25 mmol) in ethanol (20 mL) at room
temperature. The mixture was stirred at room temperature for 12 h.
Then the solvent was removed and the residual oil was taken up in
diethyl ether (50 mL). The insoluble salts were removed by fil-
tration and after 12 h crystals appeared. After filtration, compound
9 was obtained as yellow needles; m.p. 153.4(5) °C; yield 0.3 g,
0.5 mmol, 61%. 1H NMR (600 MHz, CDCl3, 300 K): δ = 2.08–
3.06 (m, 36 H), 3.14–3.25 (m, 4 H), 3.53 (m, 1 H), 3.84–4.08 (m, 2
N-[(1,4,7,10-Tetraazacyclotridecan-5-yl)methyl]-1-phenylmethan-
amine (13): NaBH4 (0.11 g, 3 mmol, 10 equiv.) was added at 0 °C
to a solution of 10 (90 mg, 297 µmol) in ethanol (25 mL). The mix-
ture was heated at reflux overnight. The solvent was evaporated
and the residual solid was taken up in chloroform (50 mL). After
filtration and evaporation of the solvent, the residual oil was taken
up in pentane (30 mL). The insoluble impurities were removed by
H), 5.64–5.86 (m, 1 H), 7.40–7.51 (m, 8 H), 7.92–8.08 (m, 4 H), filtration. After evaporation of the solvent, compound 13 was ob-
8.47 (m, 4 H), 9.43 (m, 2 H) ppm. 13C{1H} NMR (150 MHz,
CDCl3, 300 K): δ = 43.3, 44.9, 45.2, 46.0, 46.2, 46.6, 46.7, 46.7,
tained as a colorless oil; yield 90 mg, 297 µmol, 98%. 1H NMR
(300 MHz, CDCl3, 300 K): δ = 1.60 (m, 2 H), 2.19 (s, 5 H), 2.44–
1692
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1688–1693

Synthesis of New C-Functionalized Macrocyclic Polyamines
2.72 (m, 17 H), 3.70 (s, 2 H), 7.22 (m, 5 H) ppm. 13C{1H} NMR
(75 MHz, CDCl3, 300 K): δ = 32.5 (CH2-β), 49.8, 51.3, 52.4, 52.8,
53.3 (ϫ2), 54.7, 55.5, 57.8 (CH2-α), 60.7 (CH), 130.4, 131.6 (ϫ2),
131.9 (ϫ2) (CHar), 139.5 (Car) ppm. MS (MALDI-TOF): m/z =
306.10 [M]+.
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS), the French Ministry of Research, and the
Regional Council of Burgundy. Y. R. and N. S. especially acknowl-
edge the French Ministry for Research for Ph. D. grants.
N-[(1,4,7,10-Tetraazacyclotridecan-5-yl)methyl]-1-(pyridin-2-yl)-
methanamine (14): NaBH4 (0.55 g, 14 mmol, 10 equiv.) was added
to a solution of 11 (0.44 g, 1.4 mmol) in ethanol (50 mL) at room
temperature. The mixture was heated at reflux overnight. The sol-
vent was evaporated and the residual solid was taken up in chloro-
form (50 mL). After filtration and evaporation of the solvent, com-
pound 14 was obtained as a colorless oil (yield 0.44 g, 1.4 mmol,
100%). 1H NMR (300 MHz, CDCl3, 300 K): δ = 1.63 (m, 2 H),
2.4–2.6 (m, 18 H), 3.84 (s, 2 H), 7.06 (s, 1 H), 7.22 (s, 1 H), 7.56 (s,
1 H), 8.49 (s, 1 H) ppm. 13C{1H} NMR (75 MHz, CDCl3, 300 K): δ
= 32.8 (CH2-β), 49.8, 51.4, 52.4, 52.8, 53.3 (ϫ2), 54.8, 55.8, 59.1
(CH2-α), 60.7 (CH), 125.5, 125.8, 140.0, 152.9 (CHar), 163.6
(Car) ppm. MS (MALDI-TOF): m/z = 307.03 [M]+.
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yield 1.16 g, 2.8 mmol, 56%. H NMR (300 MHz, CDCl3, 300 K):
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Received: October 19, 2009
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis of all compounds
and X-ray data for compounds 3, 4, and 7–10.
Published Online: February 16, 2010
Eur. J. Org. Chem. 2010, 1688–1693
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1693