An organic template approach for the synthesis of selectively functionalised tetraazacycloalkanes

Article abstract of DOI:10.1039/b108244b

Selectively functionalised tetraazacycloalkanes are obtained from the open-chain tetraamine by using a bisaminal moiety acting both as a template agent and as a N-protecting group.

Full text of DOI:10.1039/b108244b

An organic template approach for the synthesis of selectively
functionalised tetraazacycloalkanes
Frédéric Boschetti, Franck Denat, Enrique Espinosa and Roger Guilard*
Laboratoire d’Ingénierie Moléculaire pour la Séparation et les Applications des Gaz, LIMSAG UMR 5633,
Faculté des Sciences Gabriel, 6 Bd Gabriel 21100. Dijon, France. E-mail: limsag@u-bourgogne.fr
Received (in Cambridge, UK) 12th September 2001, Accepted 6th December 2001
First published as an Advance Article on the web 18th January 2002
Selectively functionalised tetraazacycloalkanes are obtained
from the open-chain tetraamine by using a bisaminal moiety
acting both as a template agent and as a N-protecting
group.
Cyclic tetraamines have received considerable attention owing
to their coordination properties towards various metal cations.1
The increasing need of finely tuned macrocycles requires the
development of new synthetic tools for the preparation of such
ligands. The research in this field has been focused on the
synthesis of bifunctional chelating agents (BFCs or BCAs)
based on a cyclic amine containing two kinds of functional
groups, one for the coordination of the guest, another one for the
anchoring of the macrocycle onto a solid support or an
antibody.2 In a recent review, we have described the different
Scheme 1
strategies for the regioselective functionalisation of tetra-
azacycloalkanes.3 Besides some typical procedures developed
for the synthesis of some target molecules, mono-N-functional-
isation of cyclic tetraamines usually involves the use of a large
excess of macrocycle relative to the electrophile agent, typically
five equivalents in the cyclam series. Although the excess of the
ligand might be recovered and re-used in most cases, such an
approach is macrocycle consuming and the formation of small
amounts of polysubstituted macrocycles may not be completely
avoided. Another method consists of protecting three nitrogen
atoms with Boc groups prior to the functionalisation of the
remaining secondary amine.4 This procedure has been success-
fully used for the synthesis of many different ligands but its
main drawback is the chromatographic work-up necessary to
separate the triprotected macrocycle from the reaction mixture.
Finally, the above methods involve the use of a high cost
macrocycle, i.e. cyclam or cyclen, as starting material and they
cannot be utilized in the case of unsymmetrical macrocycles
such as 1,4,7,10-tetraazacyclotridecane for which two different
mono- or tri-N-functionalised compounds may be formed.
Substituting the hydrogen atom of one secondary amine of a
cyclic tetraamine by a benzyl group is also a convenient method
for synthesis of trifunctionalised cyclams, since the benzylic C–
N bond is easily hydrogenolysed. The mild conditions used to
remove the protecting group allow the survival of many
different functionalities. Conveniently substituted benzene
rings, such as nitrobenzene, may allow a further functionalisa-
tion of the arm to graft, for example, the macrocycle on an
antibody. Moreover, such benzylated tetraazacycloalkanes, and
especially bismacrocycles containing two cyclam units linked
together through a xylyl spacer, are highly potent anti-HIV
compounds.5
very mild conditions to yield the desired monobenzylated
1,4,7,10-tetraazacyclotridecane 4a and cyclam 4b. These de-
protection conditions might slightly differ depending on the
nature of the macrocycle. Thus, while refluxing NaOH solution
is necessary to remove the bisaminal bridge from 3a, the
benzylcyclam 4b is already released at rt, proving that the
quaternary ammonium salt 3a is more stable than 3b. The yields
for each step are nearly identical in both series and the
monobenzylated macrocycles, 4a and 4b, can be readily
obtained from the linear tetraamine in overall yields close to
30%. The structures of compounds 1 and 3b have been
confirmed by single crystal X-ray analyses (Fig. 1). The
compound 1 is obtained as the sole product and no trace of the
other seven possible isomers has been detected in the NMR
spectra. An interesting characteristic of compound 3b is the
exceptional length of the bond between the ammonium nitrogen
atom and the aminal-type carbon atom (N1–C41 = 1.582 (4) Å)
when compared to similar ammonium salts (1.547 (6) Å in the
glyoxal adduct).6
In this paper, we wish to report a convenient and general
synthesis of mono-N-benzylated tetraazacycloalkanes starting
from the suitable open-chain tetraamine. The reaction proceeds
as depicted in Scheme 1. The first step involves the reaction of
the linear tetraamine with pyruvic aldehyde to form the
bisaminal derivative 1. Cyclisation occurs in a second step, by
condensation of the bisaminal compound with the convenient
biselectrophile, leading to 2a and 2b in good yields. The
addition of benzyl bromide to 2a and 2b gives the mono-
benzylated bisaminal protected tetraazamacrocycles as quater-
nary salts 3a and 3b. These compounds are easily deprotected in
Fig. 1 ORTEP13 views of (a) cis-9a-methyloctahydro-1H,4H,7H-1,3a,6a,9-
tetraazaphenalene (1) and (b) the cis-3a-benzyl-10b-methyldecahydro-
1H,6H-5a,8a,10a-triaza-3a-azoniapyrene cation of (3b), showing thermal
ellipsoids at the 50% probability level. Selected bond distances: N1–C41 =
1.455 (2) and 1.582 (4) Å, N2–C21 = 1.478 (2) and 1.480 (4) Å, N3–C21
= 1.463 (2) and 1.460 (4) Å, N4–C41 = 1.491 (2) and 1.482 (5) Å, C21–
C41 = 1.544 (2) and 1.561 (5) Å, for (a) and (b), respectively. H-atoms
omitted for clarity.†
312
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solution was extracted with chloroform, the organic phase was dried over
The interest of the method lies in the use of a bisaminal
moiety both as an organic template and as a protecting group for
selective functionalisation. Indeed, the rigidity of the bisaminal
type tricyclic adduct 1 enables the cyclisation key step to occur
in very good yields without any high dilution conditions. The
formation of 1 as the unique product of the condensation of the
tetraamine with pyruvic aldehyde is consistent with the results
reported with glyoxal or butanedione which have already been
used as dicarbonyl compounds for the synthesis of cyclen,
cyclam and 1,4,7,10-tetraazacyclotridecane after removal of the
bisaminal group.7 Indeed, the formation of three six-membered
fused rings is favoured, as well as the cis configuration of the
bisaminal bridge. Yet, there are still two possible isomers in the
case of pyruvic aldehyde, depending on the relative position of
the hydrogen atom and the methyl group on the bisaminal
moiety. As evidenced by the crystallographic structure, only the
isomer in which the methyl group is connected to the aminal-
type carbon atom between the two secondary amines is
obtained. The X-ray structure of 3b shows that the quaterniza-
tion of the bisaminal protected macrocycle occurs selectively on
the nitrogen atom linked to the aminal carbon bearing the
methyl group. In fact, the steric repulsions between the methyl
and the benzyl groups are minimized in this case as shown by a
simple model examination. This feature is responsible for the
exceptional selectivity of our method since trans di-N-
quaternization of 2b does not occur, unlike the results reported
with other aminal type macrocyclic compounds.6,8,9 For similar
reasons, attempts to quaternize the butanedione protected
cyclam failed, due to the presence of two methyl groups on the
bisaminal bridge which hinder the two nitrogen atoms available
for quaternization. When using glyoxal instead of butanedione,
it is known that two isomers are obtained, depending on whether
the glyoxal is condensed with cyclam or with the linear
tetraamine prior to the cyclisation.9,10 In the latter case,
although quaternization of the glyoxal protected cyclam occurs
in good yield, the bisaminal bridge cannot easily be removed in
the ultimate step. Conversely, the bisaminal bridge in 3a and 3b
can be readily removed in mild conditions to release the
monobenzylated macrocycles, owing mainly to the large
distance between the ammonium nitrogen atom and the aminal-
type carbon atom.
MgSO4 and evaporated to give the compound 4a as a colorless oil. dH 1.56
(m, 2H), 2.20 (bs, 3H), 2.46–2.69 (m, 16H), 3.50 (s, 2H), 7.16 (m, 5H), dC
28.9; 47.2; 47.9; 48.4 (2C); 49.4; 50.7; 54.3; 54.4; 60.4; 127.3; 128.5; 129.4;
139.7. [M+] 276.7.
X-Ray suitable crystals of 1 and 3b were grown from chloroform. In both
cases the structure was solved using direct methods11 and refined by full
matrix least-squares on F2.12 H-Atoms were observed in the Fourier
synthesis and refined with a global isotropic thermal factor in each
structure.
Crystal data for C10H20N4 (1): M = 196.30, monoclinic, a = 9.3721(4),
b = 7.8942(4), c = 14.4579(7) Å, b = 91.1640(2) Å, U = 1069.23(9) Å3,
T = 110(2) K, space group P21/n, Z = 4, m(Mo-Ka) = 0.077 mm21, 4135
reflections measured, 2448 unique (Rint = 0.0303) which were used in all
calculations. The final wR(F2) was 0.1043 (all data). CCDC 172982.
Crystal data for C23H34BrCl9N4 for (3b): M = 765.50, monoclinic, a =
10.4280(2), b = 28.2670(7), c = 11.6960(4) Å, b = 110.544(1) Å, U =
3228.35(15) Å3, T = 110(2) K, space group P21/n, Z = 4, m(Mo-Ka) =
2.040 mm21, 12777 reflections measured, 7271 unique (Rint = 0.0999)
which were used in all calculations. The final wR(F2) was 0.0958 (all data).
CCDC 172981. See http://www.rsc.org/suppdata/cc/b1/b108244b/ for crys-
tallographic files in .cif or other format.
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The method reported here represents a very powerful route
from a linear tetraamine towards monobenzylated cyclam and
1,4,7,10-tetraazacyclotridecane, and indirectly to BFCs based
on these macrocycles. In contrast to glyoxal or butanedione,
pyruvic aldehyde allows the selective mono-N-functionalisa-
tion of the protected macrocycle before removal of the
bisaminal bridge. In order to obtain various mono-N-function-
alised tetraazacycloalkanes, we are currently extending the
scope of this method to the cyclen series and to different
quaternizing agents. For example, methyl iodide or ethyl
iodoacetate have been successfully employed. Biselectrophilic
reagents such as a,a’-dibromo-p-xylene can also be used, thus
providing a much better alternative synthesis of highly potent
antiviral bisazamacrocycles when compared to the existing
ones.
Notes and references
† Typical experimental procedure: synthesis of 4-benzyl-1,4,7,10-tetra-
azacyclotridecane 4a. To a solution of N,NA-bis(2-aminoethyl)-1,3-propane-
diamine (1.22 g; 7.65 mmol) in 50 ml of acetonitrile cooled to 4 °C was
added dropwise a solution of pyruvic aldehyde (40 wt% solution in water;
1.38 g; 7.65 mmol). After completion of the reaction (4 h) the solution was
heated under reflux, potassium carbonate (5.28 g; 38.25 mmol) and
1,2-dibromoethane (1.43 g; 7.65 mmol) were added. After 48 h, the mixture
was filtered, the filtrate was evaporated and the residue was chromato-
graphed over an alumina plug using dichloromethane as eluent to give 2a as
a colorless oil (1.17 g; 5.27 mmol; yield 69%). A mixture of 2a and benzyl
bromide (0.90 g; 5.27 mmol) in 10 ml of acetonitrile was stirred at rt for 24
h, the white precipitate formed was filtered off and washed with diethyl
ether and salt 3a was obtained as a white powder (1.10 g; 2.80 mmol; yield
53%). The solid was dissolved in 10 ml of water, 100 ml of 3M aqueous
NaOH solution was added and the mixture was refluxed for 12 h. The
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