Bis-aminals: Efficient tools for bis-macrocycle synthesis

Article abstract of DOI:10.1039/b103995b

Tetraazamacrocyclic bis-aminals prove to be excellent tools for the synthesis of symmetrical, dissymmetrical or functionalized bis-tetraazamacrocycles. The key feature of the process is the separation of insoluble mono- or bis-quaternary ammonium salts from solution during the course of the alkylation reaction.

Full text of DOI:10.1039/b103995b

View Online / Journal Homepage / Table of Contents for this issue
Bis-aminals: efficient tools for bis-macrocycle synthesis
Michel Le Baccon,a Francoise Chuburu,a Lo•c Toupet,b Henri Handel,*a Mathieu Soibinet,c
Isabelle Dechamps-Olivier,c Jean-Pierre Barbierc and Michel Aplincourtc
a L aboratoire de Chimie, Electrochimie Moleculaires et Chimie Analytique (CNRS UMR 6521),
Universite de Bretagne Occidentale, BP 809, 29285 Brest cedex, France.
E-mail: henri.handel=univ-brest.fr
b Groupe de la Matiere Condensee et Materiaux (CNRS UMR 6626), Universite de Rennes 1,
Campus de Beaulieu, 35042 Rennes cedex, France
c Groupe de Recherche en Chimie Inorganique, Universite de Reims Champagne Ardenne, BP
1039, 51687 Reims cedex 2, France
Received (in Montpellier, France) 3rd May 2001, Accepted 6th June 2001
First published as an Advance Article on the web 17th August 2001
Tetraazamacrocyclic bis-aminals prove to be excellent tools for the synthesis of symmetrical, dissymmetrical or
functionalized bis-tetraazamacrocycles. The key feature of the process is the separation of insoluble mono- or
bis-quaternary ammonium salts from solution during the course of the alkylation reaction.
Macrocyclic saturated tetraamines constitute versatile ligands
whose high binding affinity for transition metals is now well
documented.1 Their complexation ability can be modulated
by ligand functionalization and derivatives with tailored
properties can be synthesized.2 Among these derivatives, bis-
macrocycles represent noteworthy examples. In particular,
bis-cyclams were described as a new class of antiviral agents
that exhibit potent inhibitory e†ects on HIV-1 and HIV-2 rep-
lication along with high selectivity.3
From a chemical point of view, their synthesis requires a
subsequent mono-N alkylation of the starting macrocycle and
the methods previously reported have been based either on
classical temporary techniques4h6 or on the use of triprotected
groups.7h10 Recently, new methods using an aminal interme-
diate have been developed for cyclen11 and cyclam12 mono-N
functionalization. But surprisingly, to our knowledge no
extension of this route to bis-tetraazamacrocycles has been
developed.
fused rings and the cis conÐguration of the central two-carbon
bridge is revealed by the temperature-dependent 13C NMR
spectrum. The cis isomers are indeed known to exhibit
exchange phenomena whereas the more rigid trans isomers do
not allow such a process.14
As a result of the cis conÐguration, the bis-aminals possess
a folded geometry that governs nitrogen reactivity. Thus, for
bis-aminal 2 the nitrogen atoms whose lone pairs are directed
towards the convex side of the molecular structure are strong-
er nucleophiles.12,15 AM1 molecular orbital calculations of
bis-aminals 1, 2 and 3 are in favor of this analysis since what-
ever the macrocycle, N and N lone pairs directed towards
2
4
the concave fold were involved in aminal bridge bonds; on the
other hand, the lone pairs that pointed out from the convex
side remained localized on N and N (Fig. 1). Therefore, the
1
3
action of an electrophile on bis-aminals leads to N function-
1
alization and these adducts can further be alkylated on the
opposing N atom to obtain a diquat salt11b,12 (Scheme 2).
3
In this paper, we report on a new strategy for the synthesis
of symmetrical and dissymmetrical bis-tetraazamacrocycles
and propose an extension to functionalized bis-tetra-
azamacrocycles.
SigniÐcant results on the mono-N and di-N ,N alkylation of
1
1
3
cyclen glyoxal and cyclam glyoxal are gathered in Table 1.
The comparison of bis-aminal reactivity is complicated by
the more or less complete precipitation of the ammonium salts
under experimental conditions. The above-mentioned results
highlight the higher reactivity of cyclen glyoxal due to its
more constrained topology and thus to the better accessibility
of the corresponding nitrogen lone pairs. However, di-N ,N
alkylation of 1 and 2 can be reached providing that, with non
activated electrophiles, the reaction is allowed to run over
longer times.
Results and discussion
Macrocyclic bis-aminals, synthesized from the condensation of
glyoxal with tetraazamacrocycles such as cyclen, cyclam or
homocyclam, have been known for more than twenty years.13
When the reaction is carried out in methanol, compounds 1, 2
and 3 are obtained quantitatively (Scheme 1). Their respective
structures are characterized by a maximum of six-membered
1
3
The precipitation of the monoalkylated cationic products
allows one to selectively synthesize mono-N alkylated com-
pounds; it constitutes the key feature of the process.11b Fur-
thermore, control of this step enabled us to use the bis-aminal
as an intermediate for bis-macrocycle synthesis, all the more
so as deprotection of compounds 1 and 3 in hydrazine mono-
hydrate16 and compound 2 in hydroxylamine17 is easy to
achieve.
When bis-electrophiles and molecules that possess two
alkylation sites are involved, the main drawback arises from
the side reaction consisting of oligomer formation. In the syn-
thesis of symmetrical bis-tetraazamacrocycles, the best results
Scheme 1
were obtained on running the reaction in CH CN: in this
3
1168
New J. Chem., 2001, 25, 1168È1174
DOI: 10.1039/b103995b
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

View Online
Fig. 1 Calculated AM1 geometries and molecular orbitals of compounds 1, 2 and 3.
solvent, the protected bis-macrocyclic salts precipitate as soon
as formed, which avoids the formation of polymers (Table 2).
Due to the chirality of aminal carbons and ammonium
nitrogens, several stereoisomers were expected for protected
bis-macrocycles. Moreover, for homocyclam, its lower sym-
metry leads to three potential structures, 10e , 10e and 10e ,
1
2
3
for the corresponding disalt (Scheme 3). The simplicity of the
13C NMR spectrum suggested the existence of a symmetrical
form such as 10e or 10e . Resolution of the X-ray structure
1
2
for single crystals of the corresponding deprotected bis-
macrocycle indicated that the disalt obtained had structure
10e (Fig. 2).
1
The preparation of dissymmetrical bis-tetraazamacrocycles
implies additional constraints that make their synthesis tricky.
The Ðrst attack of the electrophile by one of its ends must be
controlled prior to the introduction of the second macrocycle.
The use of bis-electrophiles that bear two functions of well
di†erentiated reactivities was previously proposed.7 Bis-
aminals o†er an alternative solution: symmetrical bis-
electrophiles can indeed be used, which requires that the
anchoring of the link on the Ðrst macrocycle be controlled.
This means that the reactive mono-N salt has to be rapidly
isolated. This can be done in an appropriate solvent in which
the solubility of this monosalt is low. Salts 11e and 11f were
found to precipitate in THF or benzene and were subse-
quently isolated by Ðltration.18 In a second step, dissym-
metrical bis-tetraazamacrocycles were obtained after partial
solubilization of the mono-salts 11 in CH CN in the presence
3
of a slight excess of the second macrocyclic aminal (Scheme 4).
This strategy is very successful on condition that, in the Ðrst
step, the less reactive bis-aminal is allowed to react with the
bis-electrophile; if not, oligomers are mainly obtained.
Finally, this strategy can be extended to obtain bis-
macrocycles with additional pendant arms: for example the
scorpioid bis-macrocycle 13º was obtained from compound 4d
Scheme 2
Table 1 Synthesis of mono-N and di-N ,N alkylated cyclen and cyclam glyoxals at room temperature
1
1
3
Stoichiometry
bis-aminal : RX
Reaction
time
Bis-aminal
RX
Solvent
Product
Yield (%)
Ref.
1
1
1
1
1
1
1
2
2
CH I
1 : 1
1 : 1
1 : 2.5
1 : 1
1 : 2.5
1 : 1
1 : 2.1
1 : 2
1 : 6
THF
Toluene
3 h
1 h
24 h
3 h
24 h
10 days
3 d
4a
4a
6a
4b
6b
4c
4d
5b
7b
97
98
90
96
98
65
75
90
73
This work
11b
3
CH I
3
CH I
CH CN
This work
This work
This work
This work
This work
12
3
3
C H CH Br
THF
6
5
2
C H CH Br
CH CN
6
5
2
3
CH CH CH CH Br
THF
3
2
2
2
N-(3-Bromopropyl) phthalimide
CH CN
3
C H CH Br
CH CN
2 h
3 weeks
6
5
2
3
CH CN
3
C H CH Br
12
6
5
2
New J. Chem., 2001, 25, 1168È1174
1169

View Online
Table 2 Bis-macrocyclic salt syntheses carried out in CH CN at room temperature
3
Reaction
time/days
XRX
Bis-aminal
Product
Yield (%)
1
2
3
1
7
7
8e
9e
97
100
80
e
f
10e
1
2a
1
7
8f
9f
90
85
1
2
1
7
8g
9g
95
95
g
h
i
1
1
7
7
8h
8i
80
78
1
2
3
7
22
22
8j
9j
10j
75
Èb
88
j
a In CH CNÈTHF (1 : 1). b See Experimental.
3
after reaction with a,a@-dibromo-p-xylene and deprotection
pathway is easy to run, quasi-quantitative and for these
reasons constitutes an attractive alternative to the previously
published methods. Furthermore, the control of the mono-N
alkylation allows the design of more sophisticated bis-
macrocycles or of bis-macrocycles possessing two cavities of
di†erent sizes.
with hydrazine monohydrate (Scheme 5).
Conclusion
According to the nature of the solvent, the alkylation reaction
can be orientated either to an unequivocal mono-N alkylation
or to a speciÐc di-N ,N alkylation. The choice of the solvent
Experimental
1
3
constitutes the key feature of the process. The high-yield syn-
theses of bis-macrocycles reported here are not only the
straightforward outcome of these considerations, but also
demonstrate the powerful utility of bis-aminals. This synthesis
General
All 1H and 13C NMR spectra were recorded on Bruker
AC300 and Bruker AMX400 spectrometers (respectively 75.47
and 100.62 MHz for 13C). Chemical shifts are given downÐeld
from external TMS. Elemental analysis were performed at the
Centre de Microanalyses du CNRS (Gif sur Yvette). All the
reactions were run using freshly distilled and dry solvents.
Molecular modelling was performed with Spartan19 soft-
ware on a Silicon Graphics station. Trial structures of com-
pounds 1, 2 and 3 were generated and a conformational
search was made to Ðnd the global minimum of each surface.
Semi-empirical calculations were then performed, geometries
Fig. 2 Crystal structure of compound 10ºe with crystallographic
numbering scheme.
Scheme 3
1170
New J. Chem., 2001, 25, 1168È1174

View Online
solvent, bis-aminals were isolated as white solids and used as
such in the following steps.
Bis-aminal 1: perhydro-2a,4a,6a,8a-tetraazacyclopenta[ f,g]
acenaphthylene (cyclen glyoxal). 95% yield, mp \ 94 ¡C, 13C
NMR(CDCl ): d 77.5 (C
), 51.1, 50.3 (CH N).
3
aminal
2
Bis-aminal
2:
cis-3a,5a,8a,10a-tetraazaperhydropyrene
(cyclam glyoxal). 89% yield, mp \ 82 ¡C, 13C NMR (CDCl ):
3
d 77.1 (C
), 56.0, 54.3, 52.4, 44.7 (CH N), 19.6 (CH CH N).
aminal
2
2
2
Bis-aminal 3: perhydro-3a,5a,8a,11a-tetraazacyclohepta-
[d,e,f ]phenanthrene (homocyclam glyoxal). 90% yield,
mp \ 74 ¡C, 13C NMR (CDCl ): d 80.6 (C
), 55.6, 54.6,
3
aminal
49.6, 49.4 (CH N), 22.7, 20.5 (CH CH N).
2
2
2
Syntheses of mono-N and di-N ,N alkylated cyclen and
1
1
3
cyclam glyoxals. Compounds 4aÈd and 6a, b were synthesized
according to a slightly modiÐed Lukes procedure.11 Spectro-
scopic data and elemental analysis of derivatives 4aÈc and 6a,
b were in good agreement with the previously reported data.11
Compound 4d. To a stirred solution of 970 mg of bis-aminal
1 (5 mmol) dissolved in 5 ml of dry acetonitrile, a solution of
2.8 g (10.5 mmol) of N-(3-bromopropyl)phthalimide in 10 ml
of dry acetonitrile was added. The mixture was stirred at
room temperature for 3 days. The precipitate was collected by
Ðltration, washed with acetonitrile and dried in vacuo, giving
Scheme 4 e: (i) a,a@-Dibromo-p-xylene in THF at RT; (ii) 1 in
CH CN at RT; (iii) H NOH in ethanol. f: (i) a,a@-Dibromo-m-xylene
3
2
4d (75%) as a white powder. 13C NMR (D O): d 173.0 (CO),
in toluene at RT; (ii) 1 in CH CN at RT; (iii) H NOH in ethanol. j:
2
3
2
137.7, 133.9, 126.3 (C ), 86.8, 74.5 (C
), 65.0, 59.9, 58.6,
(i) 1,5-Dibromopentane in CH CN at RT; (ii) 1 in CH CN at RT; (iii)
ar
aminal
3
3
54.1, 51.2, 51.0, 50.6, 50.4, 46.5 (CH N), 37.6
H NOH in ethanol.
2
2
(N`CH CH CH N), 25.2 (N`CH CH CH N).
2
2
2
2
2
2
were fully optimized and minima characterized by the number
of negative eigenvalues (none) of the Hessian matrix.
Typical procedure for symmetrical bis-macrocycle syntheses
Bis-salts 8, 9 and 10. Due to the chirality of aminal carbons
and ammonium nitrogens, several stereoisomers can be
observed. Consequently, the signal splitting is indicated in
italics.
Synthesis of the monomeric starting materials
Bis-aminal 1, 2, 3 syntheses. A methanolic solution of 25
mmol of glyoxal (40% aqueous) was added dropwise, between
[5 and 0 ¡C, to a cooled methanolic solution of 25 mmol of
the tetraazamacrocycle (cyclen, cyclam or homocyclam). The
mixture was stirred for 3 h at room temperature. After solvent
Compound 8e. a,a@-Dibromo-p-xylene (5 mmol) was added
to a stirred solution of cyclen glyoxal 1 (11 mmol) in dry ace-
tonitrile (20 ml). The mixture was stirred at room temperature
for 24 h. The precipitate was collected by Ðltration, washed
with acetonitrile and dried in vacuo, giving 8e (98%) as a white
powder. 13C NMR (D O): d 136.4, 132.6 (C ), 85.9, 74.5
evaporation, the residue was dissolved in Et O and the solu-
2
2
ar
tion Ðltered to remove polymers. After evaporation of the
(C
), 64.5, 63.7, 60.4, 54.2, 51.1, 50.9, 50.4, 46.6 (CH N).
aminal
2
Scheme 5 (i) a,a@-Dibromo-p-xylene in DMF at RT; (ii) H NNH , H O reÑux overnight.
2
2
2
New J. Chem., 2001, 25, 1168È1174
1171

View Online
(D O): d 53.9, 51.6, 46.5, 45.2, (CH N), 20.7 (CH CH CH ).
Compound 8f. White powder (90%). 13C NMR (D O): d
2
2
2
2
2
2
138.9, 138.2, 133.8, 131.5 (C ), 86.0, 85.9, 74.5 (C
), 64.3,
C H N É 6HCl É 4H O (675.43): calc. C 33.79, H 8.66, N
ar
aminal
19 44
8
2
63.7, 59.9, 59.8, 54.2, 51.2, 51.1, 50.4, 46.6 (CH N).
16.59, Cl 31.49; found C 33.51, H 8.62, N 16.44, Cl 31.28%.
1-[4-(1,4,7,10-T etraazacyclododecan-1-yl)butyl]-1,4,7,10-
tetraazacyclododecane (8ºi). White crystals (72%). 13C NMR
2
Compound 8g. White powder (95%). 13C NMR (D O): d
138.1, 135.0, (C ), 85.6, 74.4 (C
2
), 65.2, 60.1, 58.4, 54.2, 51.2,
ar
aminal
51.0, 50.7, 50.5, 46.4 (CH N).
(D O):
d
56.8, 52.3, 46.6, 45.8, 45.3 (CH N), 23.6
2
2
2
Compound 8h. White powder (80%). 13C NMR (D O): d
(CH CH CH CH ). C
H
N É 7HCl É 5H O (743.93): calc.
2
2
2
2
2
20 46
8
2
87.2, 74.4 (C
aminal
50.4, 46.5 (CH N), 21.0, (CH CH CH ).
), 65.2, 60.2, 60.1, 57.1, 54.1, 51.2, 51.0, 50.6,
C 32.29, H 8.54, N 15.06, Cl 33.36; found C 32.12, H 8.47, N
14.71, Cl 33.20%.
2
2
2
2
Compound 8i. White powder (78%). 13C NMR (D O): d
1-[5-(1,4,7,10-T etraazacyclododecan-1-yl)pentyl]-1,4,7,10-
tetraazacyclododecane (8ºj). White crystals (81%). 13C NMR
2
84.6, 72.4 (C
aminal
44.4 (CH N), 20.8 (CH CH CH CH ).
), 62.9, 58.0, 57.8, 52.0, 49.1, 48.9, 48.5, 48.3,
(D O):
d
57.9, 53.0, 46.4, 46.2, 45.3 (CH N), 28.2
2
2
2
2
2
2
2
Compound 8j. White powder (75%). 13C NMR (D O): d
(CH CH CH CH CH ),
25.7
(CH CH CH CH CH ).
2
2
H
2
8
2
2
2
2
2
2
2
2
2
86.6, 74.5 (C
), 65.0, 60.7, 59.8, 54.1, 51.3, 51.1, 50.6, 50.5,
C
N É 6HCl É 3H O (685.47): calc. C 36.80, H 8.82, N
aminal
21 48
46.6
(CH N),
25.8
(CH CH CH CH CH ),
25.3
16.35, Cl 31.03; found C 36.56, H 8.86, N 16.24, Cl 30.86%.
1-[4-(1,4,8,12-T etraazacyclopentadecan-1-ylmethyl)benzyl]-
1,4,8,12-tetraazacyclopentadecane (10ºe). White crystals (93%).
13C NMR (D O): d 135.0, 133.5, (C ), 61.8, 51.7, 48.9, 45.7,
2
2
2
2
2
2
(CH CH CH CH CH ).
2
2
2
2
2
Compound 9e. White powder (100%). 13C NMR (D O): d
2
137.0, 131.5 (C ), 85.2, 72.3 (C
54.2, 51.4, 49.4, 44.8 (CH N), 21.3, 20.9 (NCH CH ).
), 64.5, 62.9, 56.8, 56.1, 54.8,
ar
aminal
2
ar
44.9, 44.7, 44.3, 41.7 (CH N), 23.1, 22.7, 22.0
2
2
2
2
Compound 9f. White powder (85%). 13C NMR (D O): d
(NCH CH CH N). C
H
N É 6HCl É 4H O (821.66): calc. C
2
2
2
2
30 58
8
2
140.6, 138.6, 133.2, 129.9 (C ), 84.9, 72.3 (C
), 64.6, 62.7,
43.85, H 8.83, N 13.64, Cl 25.89; found C 44.02, H 8.82, N
13.72, Cl 26.01%.
ar
aminal
56.7, 56.2, 54.7, 54.2, 51.7, 49.4, 44.8 (CH N), 21.2, 20.8
2
(NCH CH ).
1-[5-(1,4,8,12-T etraazacyclopentadecan-1-yl)pentyl]-1,4,8,12-
2
2
Compound 9g. White powder (95%). 13C NMR (D O): d
tetraazacyclopentadecane (10ºj ). White crystals (95%). 13C
2
138.9, 133.8 (C ), 84.8, 72.3 (C
54.2, 51.6, 49.3, 44.8 (CH N), 21.4, 20.9 (NCH CH ).
), 63.1, 59.4, 56.7, 56.1, 54.8,
NMR (D O): d 58.5, 52.2, 49.5, 45.9, 45.0, 44.9, 44.5, 41.8,
ar
aminal
2
(CH N),
23.2, 22.8, 22.1 (NCH CH CH N), 26.2
2
2
2
2
2 2 2
(CH CH CH CH CH ).
Compound 9j. The low reactivity of cyclam glyoxal 2
towards 1,5-dibromopentane leads after evaporation of the
solvent to the sole monosalt 11j (vide infra).
Compound 10e. White powder (80%). 13C NMR (D O): d
136.7, 132.4 (C ), 86.0, 85.9, 78.2 (C
(CH CH CH CH CH ),
25.5
2
2
8
2
2
2
2
2
2
2
2
C
H
N É 6HCl É 4H O (787.64): calc. C 41.17, H 9.47, N
27 60
2
14.23, Cl 27.01; found C 41.33, H 9.44, N 14.32, Cl 27.11%.
2
Representative deprotection procedure with hydroxylamine.
Bis-cyclam 9 (1.4 mmol) was dissolved in 20 ml of dry ethanol
with 3 g of hydroxylamine hydrochloride and 2.9 g of sodium
ethoxide. The mixture was reÑuxed under nitrogen for 4 h.
After cooling, the solvent was evaporated, the resulting solid
was dissolved in 10 ml of 10 M NaOH and extracted four
times with chloroform. The combined organic phases were
evaporated and dropwise addition of an HClÈethanol solution
induced precipitation of the hydrochloride salt. Acetone was
then added to complete precipitation. After standing in a
refrigerator overnight, a white solid was Ðltered o†, washed
with acetone and dried in vacuo.
), 65.9, 59.7, 57.9, 55.5,
ar
aminal
54.5, 53.7, 53.4, 53.3, 49.0, 45.4 (CH N), 31.1, 25.0, 22.2
2
(NCH CH CH N).
2
2
2
Compound 10j. Soluble in CH CN, this compound was iso-
lated by evaporation of the solvent. The resulting solid was
3
washed with THF and dried in vacuo. White powder (88%).
13C NMR (D O): d 87.1, 77.5 (C
), 63.2, 60.2, 57.9, 55.6,
54.9, 53.5, 52.3, 49.3, 45.5 (CH N), 31.8, 25.0, 22.3
2
aminal
2
(NCH CH CH N), 25.8 (CH CH CH CH CH ), 23.3
2
2
2
2
2
2
2
2
(CH CH CH CH CH ).
2
2
2
2
2
Bis-salts deprotection: bis-macrocycles 8º,9º,10º
1-[4-(1,4,8,11-T etraazacyclotetradecan-1-ylmethyl)benzyl]-
1,4,8,11-tetraazacyclotetradecane (9ºe). White crystals (93%).
13C NMR (D O): d 135.0, 133.5 (C ), 61.4, 50.5, 47.2, 44.0,
Representative deprotection procedure in hydrazine mono-
hydrate. Compound 8 or 10 (4.6 mmol) and 20 ml of hydrazine
monohydrate were heated at 120 ¡C overnight. After cooling,
the solid was Ðltered, dissolved in ethanol and the solvent was
rotary evaporated. The solid was recrystallized in acetone and
precipitated as the hydrochloride salt for elemental analysis
and NMR spectra.
2
ar
43.8, 40.4, 39.9 (CH N), 21.4, 20.9 (NCH CH ).
2
2
2
C
H
N É 6HCl É 4H O (793.61): calc. C 42.38, H 8.64, N
28 54
8
2
14.12, Cl 26.80; found C 42.06, H 8.70, N 14.02, Cl 26.63%.
1-[3-(1,4,8,11-T etraazacyclotetradecan-1-ylmethyl)benzyl]-
1,4,8,11-tetraazacyclotetradecane (9ºf ). White crystals (91%).
13C NMR (D O): d 136.6, 136.1, 133.7, 132.3 (C ), 61.6, 50.5,
1-[4-(1,4,7,10-T etraazacyclododecan-1-ylmethyl)benzyl]-
1,4,7,10-tetraazacyclododecane (8ºe). White crystals (91%). 13C
NMR (D O): d 136.6, 133.8 (C ), 59.7, 51.1, 46.7, 45.1
2
ar
47.2, 44.3, 43.7, 40.4, 40.3, 39.8 (CH N), 21.3, 20.8 (NCH CH ).
2
2
2
C
H
N É 6HCl É 4H O (793.61): calc. C 42.38, H 8.64, N
28 54
8
2
2
(CH N). C
2
ar
14.12, Cl 26.80; found C 42.23, H 8.64, N 14.08, Cl 26.69%.
1-M[5-(1,4,8,11-T etraazacyclotetradecan-1-ylmethyl)-2-
H
N É 6HCl É 3H O (719.49): calc. C 40.06, H
24 46
8
2
8.13, N 15.57, Cl 29.57; found C 39.39, H 7.87, N 15.22, Cl
29.46%.
thienyl]methylN-1,4,8,11-tetraazacyclotetradecane (9ºg). White
crystals (88%). 13C NMR (D O): d 136.5, 136.0, (C ), 55.2,
1-[3-(1,4,7,10-T etraazacyclododecan-1-ylmethyl)benzyl]-
1,4,7,10-tetraazacyclododecane (8ºf ). White crystals (85%). 13C
NMR (D O): d 137.6, 135.1, 133.0, 132.4 (C ), 59.6, 50.8, 46.9,
2
ar
50.5, 47.4, 44.4, 44.1, 44.0, 40.8, 40.6, 40.5 (CH N), 21.6, 21.5
2
(NCH CH ).
C
H
N S É 6HCl É 3H O (781.62): calc.
C
2
2
26 52
8
2
2
ar
39.95, H 8.25, N 14.34, S 4.10, Cl 27.21; found C 39.53, H 8.27,
N 14.17, S 4.13, Cl 26.98%.
44.9, 44.8 (CH N). C
H
N É 7HCl É 4H O (773.96): calc. C
2
24 46
8
2
37.24, H 7.94, N 14.48, Cl 32.06; found C 37.27, H 7.67, N
14.04, Cl 31.94%.
Dissymmetrical bis-macrocycle syntheses
1-M[5-(1,4,7,10-T etraazacyclododecan-1-ylmethyl)-2-thienyl]-
methylN-1,4,7,10-tetraazacyclododecane (8ºg). White crystals
(90%). 13C NMR (D O): d 139.7, 132.2, (C ), 53.2, 50.1, 47.0,
Monosalts 11. Compound 11e. A solution of a,a@-dibromo-p-
xylene (1.18 g) in 10 ml of dry THF was added dropwise to a
THF solution of cyclam glyoxal 2 (1 g, 15 ml) and the mixture
was stirred for 10 days at room temperature. The precipitate
was Ðltered o†, washed with dry THF and dried in vacuo.
2
ar
45.0, 44.6 (CH N). C
H N S É 6HCl É 4H O (743.53): calc. C
2
22 44
8
2
35.54, H 7.86, N 15.07, S 4.31, Cl 28.61; found C 35.82, H 7.59,
N 15.04, S 4.37, Cl 28.40%.
1-[3-(1,4,7,10-T etraazacyclododecan-1-yl)propyl]-1,4,7,10-
tetraazacyclododecane (8ºh). White crystals (68%). 13C NMR
White solid (87%). 13C NMR (CDCl ): d 139.9, 134.1, 129.3,
3
126.5 (C ), 80.9, 69.5 (C
), 60.1, 58.2, 54.2, 54.1, 52.0,
ar
aminal
1172
New J. Chem., 2001, 25, 1168È1174

View Online
N É 6HCl É 3H O
(713.52): calc. C 38.72, H 9.04, N 15.70, Cl 29.81; found C
38.41, H 9.10, N 15.58, Cl 29.60%.
49.0, 46.6, 42.5 (CH N), 32.3 (CH Br), 19.1, 18.7,
21.2, 20.8 (NCH CH CH N).
C
H
2
2
2
2
2
23 52
8
2
(NCH CH CH N).
2
2
2
Compound 11f. A solution of a,a@-dibromo-m-xylene (1.18 g)
in 10 ml of dry toluene was added dropwise to a toluene solu-
tion of 2 (1 g, 10 ml) and the mixture was stirred for 10 days at
room temperature. The precipitate was Ðltered o†, washed
with dry toluene and dried in vacuo. White solid (59%). 13C
NMR (CDCl ): d 138.7, 133.7, 133.5, 131.2, 129.4, 126.9 (C ),
Synthesis of the functionalized bis-macrocycle 13º
Compound 13. A solution of 650 mg (2.38 mmol) of a,a@-
dibromo-p-xylene in 50 ml of dry DMF was added dropwise
to a suspension of 2.2 g of 4d (4.76 mmol) in 100 ml of dry
DMF. The mixture was stirred at room temperature for 2
weeks. The solvent was evaporated, 10 ml of dry acetonitrile
were added to the residue and the mixture was stirred for
several minutes. The precipitate was collected by Ðltration,
washed with acetonitrile and dried in vacuo, giving 13 (85%).
3
ar
), 60.2, 58.3, 54.3, 54.0, 51.9, 48.8, 46.6, 42.4
81.1, 69.6 (C
aminal
(CH N), 32.4 (CH Br), 19.0, 18.7, (NCH CH CH N).
2
2
2
2
2
Compound 11j. A solution of cyclam glyoxal 2 (2 g) and 1.2
ml of 1,5-dibromopentane in 10 ml of dry acetonitrile was
stirred for 3 weeks at room temperature. The solvent was
rotary evaporated and the residue was washed three times
13C NMR (D O): d 173.0 (CO), 137.7, 136.6, 134.1, 134.0,
with diethyl ether. White solid (29%). 13C NMR (CDCl ): d
2
ar
3
132.1, 126.3 (C ), 81.6, 80.4 (C
), 64.5, 63.9, 63.1, 58.4, 58.2,
85.2, 72.2 (C
), 63.1, 62.2, 56.7, 56.1, 54.9, 54.1, 51.3, 49.1,
aminal
2
aminal
49.1, 48.8, 45.5, 45.3, 37.6 (NCH ), 25.1 (CH CH CH ).
44.8, (CH N), 37.1 (CH Br), 34.2 (CH CH Br), 27.2
(CH CH CH Br), 22.6 (CH CH CH CH Br), 21.4, 20.9
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Deprotection of 13 to give 3-[7-(4-{ [7-(3-aminopropyl)-
1,4,7,10-tetraazacyclododecan-1-yl]methyl}benzyl)-1,4,7,10-
tetraazacyclododecan-1-yl]propylamine (13º). Compound 13
(2.4 g, 2 mmol) and 6 ml of hydrazine monohydrate were
heated at 120 ¡C for 5 h. After cooling, the solid was Ðltered
o†, dissolved in ethanol and the solvent was evaporated. The
resulting oil was dissolved in 10 ml ethanol and 10 ml concen-
trated HCl were added dropwise. Acetone was then added to
complete precipitation. After standing in a refrigerator over-
night, a white solid was Ðltered o†, washed with acetone and
(NCH CH CH N).
2
2
2
Dissymmetrical bis-salts 12. To a suspension of compound
11e or 11f (1.41 g) in 10 ml of dry acetonitrile, 0.65 g of bis-
aminal 1 was added and the mixture was stirred for 5 days at
room temperature. The precipitate was Ðltered and washed
with acetonitrile and dried in vacuo. White solids 12e or 12f
were obtained.
Due to the chirality of aminal carbons and ammonium
nitrogens, several stereoisomers can be observed. Consequent-
ly, the signal splitting is indicated in italics.
dried in vacuo. White solid (82%). 13C NMR (D O): d 137.4,
2
133.4 (C ), 58.6, 51.9, 49.8, 49.6, 45.4, 45.3, 40.4 (NCH ), 23.9
ar
2
Compound 12e. (86%). 13C NMR (D O): d 137.3, 136.2,
(CH CH CH ). C
H
N
É 7HCl É 2H O (852.12): calc. C
2
2
2
2
30 60 10
2
132.6, 131.5 (C ), 85.9, 85.2, 74.5, 72.3 (C
), 64.5, 64.4, 63.5,
42.29, H 8.40, N 16.44, Cl 29.12; found C 42.41, H 8.31, N
16.35, Cl 29.52%.
ar
aminal
63.0, 60.0, 56.8, 56.2, 54.8, 54.2, 51.4, 51.2, 51.1, 50.5, 49.4, 46.6,
44.8 (CH N), 21.3, 20.9 (NCH CH CH N).
2
2
2
2
Crystal structure determination of 10ºe
Compound 12f. (91%). 13C NMR (D O): d 139.8, 138.6,
2
137.9, 133.5, 131.0, 130.1 (C ), 85.9, 85.7, 85.1, 74.4, 72.2
ar
The structure is presented in Fig. 2. Monocrystals of com-
(C
), 64.6, 64.2, 63.5, 62.7, 60.0, 59.7, 56.7, 56.1, 54.7, 54.1,
51.4, 51.1, 51.0, 50.4, 49.4, 46.6, 44.7 (CH N), 21.2, 20.8
aminal
pound 10ºe were isolated by recrystallization from dry
2
acetone:
C
H
N , M \ 530.84, triclinic, P1 (no. 2),
(NCH CH CH N).
30 58
8
2
2
2
a \ 8.7740(5), b \ 9.4790(5), c \ 18.8510(7) A, a \ 80.211(2),
Compound 12j. To a solution of compound 11j (1.0 g) in 10
ml of dry acetonitrile, 0.5 g of bis-aminal 1 was added and the
mixture was stirred for 10 days at room temperature. The
solvent was rotary evaporated and the residue was washed
three times with diethyl ether. White solid (84%). 13C NMR
b \ 82.197(2), c \ 67.030(3)¡, U \ 816.41(8) A
Ž
3, Z \ 1, D \
x
1.080 Mg m~3, j(Mo-Ka) \ 0.710 73 A, k \ 0.66 cm~1,
F(000) \ 294, T \ 290 K. The sample was studied on a
NONIUS Kappa CCD with graphite monochromated
Mo-Ka radiation. The cell parameters are obtained with
Denzo and Scalepack20 with 10 frames (phi rotation: 1¡ per
frame). The data collection21 gave 3798 integrated reÑections.
The data reduction with Denzo and Scalepack20 led to 3724
independent reÑections (2191 with I [ 2.0p(I). The structure
was solved with SIR-97,22 which reveals all the non-hydrogen
atoms of the compound and the solvent. After anisotropic
reÐnement, the hydrogen atoms were found with a Fourier
di†erence map. The whole structure was reÐned with
SHELXL9723 by the full-matrix least-square techniques (use
(D O): d 86.5, 85.2, 74.5, 72.1 (C
), 65.0, 63.2, 62.0,
2
aminal
60.7, 59.8, 56.6, 56.1, 54.9, 54.2, 54.1, 51.4, 51.3, 50.9,
50.6, 50.4, 49.1, 46.5, 44.8 (CH N), 25.8, 25.3, 23.2
2
(NCH CH CH CH CH N), 21.2, 20.8 (NCH CH CH N)
2
2
2
2
2
2
2
2
Bis-salt deprotection: bis-macrocycles 12º. Compounds 12e,
12f and 12j were deprotected with a ethanolic solution of
hydroxylamine, as previously described. The corresponding
compounds 12º were isolated as hydrochloride salts.
1-[4-(1,4,7,10-T etraazacyclododecan-1-ylmethyl)benzyl]-
1,4,8,11-tetraazacyclotetradecane (12ºe). White solid (92%). 13C
NMR (D O): d 140.0, 134.3, 134.0, 131.0, (C ), 61.9, 59.0, 50.5,
of F square magnitude; x, y, z, b for C and N atoms and
ij
riding mode for
H
atoms; calc. w \ 1/[p2(F 2) ] (0.104
o
2
ar
P)2 ] 0.073 P] where P \ (F 2 ] 2 F2)/3 with the resulting
50.2, 47.0, 44.9, 44.6, 44.1, 43.6, 40.0, 39.5 (CH N), 21.2, 20.6
o
c
2
R \ 0.0613, R \ 0.174.
(NCH CH CH N). C
39.85, H 8.49, N 14.30, Cl 27.15; found C 40.23, H 8.44, N
14.40, Cl 27.31%.
H
N É 6HCl É 5H O (783.57): calc. C
w
2
2
2
26 50
8
2
Atomic scattering factors were taken from ref. 24. ORTEP
views were realized with PLATON98.25 All the calculations
were performed on a Pentium NT Server computer.
CCDC reference number 166637. See http://www.rsc.org/
suppdata/nj/b1/b103995b/ for crystallographic data in CIF or
other electronic format.
1-[3-(1,4,7,10-T etraazacyclododecan-1-ylmethyl)benzyl]-
1,4,8,11-tetraazacyclotetradecane (12ºf ). White solid (89%).
13C NMR (D O):
d 138.2, 135.6, 133.8, 133.0, 132.3,
2
131.6, (C ), 62.0, 59.3, 50.6, 50.2, 46.8, 45.3, 45.0, 44.0, 43.5,
ar
39.9, 39.4 (CH N), 21.1, 20.6 (NCH CH CH N).
2
2
2
2
C
H
N É 7HCl É 3H O (784.00): calc. C 39.83, H 8.10, N
References and notes
1
26 50
8
2
14.29, Cl 31.65; found C 40.33, H 8.24, N 14.40, Cl 30.82%.
1-[5-(1,4,7,10-T etraazacyclododecan-1-yl)pentyl]-1,4,8,11-
tetraazacyclotetradecane (12ºj ). White solid (87%). 13C NMR
A. Bianchi, M. Micheloni and P. Paoletti, Coord. Chem. Rev.,
1991, 110, 17.
K. P. Wainwright, Coord. Chem. Rev., 1997, 166, 35.
(a) E. De Clercq, N. Yamamoto, R. Pauwels, M. Baba, D. Scols,
H. Nakashima, J. Balzarini, Z. Debyser, B. A. Murrer, D.
2
3
(D O): d 59.4, 58.4, 54.1, 50.6, 47.3, 46.9, 46.4, 45.8, 44.1, 43.6,
2
40.1, 39.4, (CH N), 26.3, 25.6 (NCH CH CH CH CH N),
2
2
2
2
2
2
New J. Chem., 2001, 25, 1168È1174
1173

View Online
Schwartz, D. Thornton, G. Bridger, S. Fricker, G. Henson, M.
Abrams and D. Picker, Proc. Natl. Acad. Sci. U.S.A., 1992, 89,
5286; (b) E. De Clercq, N. Yamamoto, R. Pauwels, J. Balzarini,
M. Witvrouw, K. De Vreese, Z. Debyser, B. Rosenwirth, P.
Peichl, R. Datema, D. Thornton, R. Skerlj, F. Gaul, S. Padama-
nabhan, G. Bridger, G. Henson and M. Abrams, Antimicrob.
Agents Chemother., 1994, 98, 366.
I. C•sarova, J. Rudovsky and I. Lukes, T etrahedron L ett., 2000,
41, 1249.
12 J. Kotek, P. Herman, P. Vojt•sek, J. Rohovec and I. Lukes,
Collect. Czech. Chem. Commun., 2000, 65, 243.
13 G. R. Weisman, S. C. H. Ho and V. Johnson, T etrahedron L ett.,
1980, 21, 335.
14 (a) R. A. Kolinski and F. G. Riddell, T etrahedron L ett., 1981, 22,
2217; (b) F. G. Riddell, P. Murray-Rust, R. Kolinski and P.
Gluzinski, T etrahedron, 1982, 38, 673.
15 T. J. Hubin, J. M. McCormick, N. W. Alcock, H. J. Clase and
D. H. Busch, Inorg. Chem., 1999, 38, 4435.
16 (a) R. W. Sanders, M. Gacek and K. Undheim, Acta Chim.
Scand., 1998, 52, 1402; (b) R. W. Sanders, J. Vasilevskis, K.
Undheim and M. Gacek, W orld Pat., WO96/28432, 1996.
17 G. Herve, H. Bernard, N. Le Bris, M. Le Baccon, J.-J. Yaouanc
and H. Handel, T etrahedron L ett., 1999, 40, 2517.
18 Compound 11j, less reactive than 11e and 11f, was synthesized in
the homogeneous phase.
19 Spartan SGI v 5.1.3 62, Wavefunction Inc., Irvine, CA 92612,
USA.
20 Z. Otwinowski and W. Minor, in Methods in Enzymology, vol.
276, Macromolecular Crystallography, Part A, ed. C. W. Carter
and R. M. Sweet, Academic Press, London, 1997, pp. 307È326.
21 KappaCCD Software, Nonius BV, Delft, The Netherlands, 1999.
22 A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Giaco-
vazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori and R.
Spagna, J. Appl. Crystallogr., 1999, 32, 115.
23 G. M. Sheldrick, SHELX97, Program for the ReÐnement of
Crystal Structures, University of Gottingen, Germany, 1997.
24 International T ables for X-ray Crystallography, ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, vol. C.
25 A. L. Spek, PLATON, A Multipurpose Crystallographic Tool,
Utrecht University, The Netherlands, 1998.
4
(a) G. J. Bridger, R. T. Skerlj, S. Padmanabhan, S. A. Martellucci,
G. W. Henson, S. Struyf, M. Witvrouw, D. Schols and E. De
Clercq, J. Med. Chem., 1999, 42, 3971; (b) G. J. Bridger, R. T.
Skerlj, D. Thornton, S. Padmanabhan, S. A. Martellucci, G. W.
Henson, M. J. Abrams, N. Yamamoto, K. De Vreese, R. Pauwels
and E. De Clercq, J. Med. Chem., 1995, 38, 366; (c) A. Urfer and
T. A. Kaden, Helv. Chim. Acta, 1994, 77, 23; (d) M. Ciampolini, L.
Fabbrizzi, A. Perotti, A. Poggi, B. Seghi and F. Zanobini, Inorg.
Chem., 1987, 26, 3527; (e) D. Xu, P. G. Mattner, K. Prasad, O.
Repic and T. J. Blacklock, T etrahedron L ett., 1996, 37, 5301.
(a) S. Brandes, C. Gros, F. Denat, P. Pullumbi and R. Guilard,
Bull. Soc. Chim. Fr., 1996, 133, 65; (b) B. Boitrel, B. Andrioletti,
M. Lachkar and R. Guilard, T etrahedron L ett., 1995, 36, 4995; (c)
F. Denat, S. Brandes and R. Guilard, Synlett, 2000, 5, 561.
V. Boldrini, G. B. Giovenzana, R. Pagliarin, G. Palmisano and
M. Sisti, T etrahedron L ett., 2000, 41, 6527.
5
6
7
8
9
I. Gardinier, A. Roignant, N. Oget, H. Bernard, J. J. Yaouanc
and H. Handel, T etrahedron L ett., 1996, 37, 7711.
N. Oget, F. Chuburu, J. J. Yaouanc and H. Handel, T etrahedron,
1996, 52, 2995.
H. Bernard, J. J. Yaouanc, J. C. Clement, H. Des Abbayes and H.
Handel, T etrahedron L ett., 1991, 32, 639.
10 A. Roignant, I. Gardinier, H. Bernard, J. J. Yaouanc and H.
Handel, J. Chem. Soc., Chem. Commun., 1995, 1233.
11 (a) W. C. Baker, M. J. Choi, D. C. Hill, J. L. Thompson and P. A.
Petillo, J. Org. Chem., 1999, 64, 2683; (b) J. Rohovec, R. Gyepes,
1174
New J. Chem., 2001, 25, 1168È1174