One-pot Synthesis of a 1,3,7,9-Tetraazacyclododecane Derivative and an Investigation of its Complexation Properties

Article abstract of DOI:10.1039/a804077j

A one-pot synthesis of a 1,3,7,9-tetraazacyclododecane macrocycle in 37% yield from inexpensive starting materials is described, and its complexation properties with metal cations are investigated.

Full text of DOI:10.1039/a804077j

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7
12 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
One-pot Synthesis of a 1,3,7,9-Tetraazacyclododecane
Derivative and an Investigation of its Complexation
Properties$
1998, 712±713$
Andreas Axen, Helena Grennberg and Adolf Gogoll*
Â
Department of Organic Chemistry, University of Uppsala, Box 531 751 21 Uppsala, Sweden
A one-pot synthesis of a 1,3,7,9-tetraazacyclododecane macrocycle in 37% yield from inexpensive starting materials is
described, and its complexation properties with metal cations are investigated.
Aza-crown macrocycles have been investigated for their
properties as strong and selective complexing agents for
metal cations and other charged and uncharged guest
deprotection scheme or addition of template ions is needed,
and since the starting materials are all cheap and readily
available chemicals, the moderate yield (37%) should be
acceptable for most purposes.
1
molecules. Practical applications include their use as phase
2
transfer agents, NMR shift reagents, MRI contrast
3
Attempts to improve the yield by increasing the excesses
of N-methylenebenzylamine or formaldehyde gave no
improvement. Prolonged reaction times lead only to
increased polymer formation. Increasing the amount of
solvent had no e€ect. Addition of formaldehyde in the form
of aqueous solution instead of paraformaldehyde increased
the yield considerably (from ca. 20 to 37%).
4
reagents or as catalysts. They often also show a wide
5
6
range of biological activity. This has motivated the
synthesis of a great variety of aza-crown macrocycles
with varying ring size and di€erent spacers between the
7
heteroatoms.
1
The room temperature H NMR spectrum of the macro-
cycle 1 shows broad methylene proton signals due to a slow
conformational equilibrium, probably similar to those of
1
5
other tetraazacyclododecanes.
The complexing properties of this new macrocycle 1 have
been tested with sodium and cobalt(II) ions in non-aqueous
1
6
solvents using NMR methods. For sodium ions (solvent
2
3
acetone or THF) the Na chemical shift variation with
ligand concentration was measured. No complexation at
all could be detected in acetone solution whereas in THF a
1
7
weak complexation was indicated. For the paramagnetic
cobalt(II) ion the chemical shift change of the macrocycle
ring methylene protons (DdCH2) upon variation of the metal
ion concentration in acetone solution was measured. A plot
of the relative concentration of the metal ion and ligand
versus dCH2 (Fig. 1) shows a linear increase of dCH2 until a
ratio of approximately 1:1 is reached. Further addition of
metal ion does not change the resonance frequency. This
Scheme 1 Synthesis of 1,3,7,9-tetrabenzyl-5,5,11,11-
tetramethoxycarbonyl-1,3,7,9-tetraazacyclododecane
In general, synthesis is performed by cyclisation of
diamines with dialdehydes, diepoxides, dihalides or activated
8
diacid derivatives. In spite of the many preparation
18
behaviour indicates the formation of a stable 1:1 complex.
methods, the NCH
considered a challenge due to its low stability. A common
way to overcome this problem is to complex the amine to a
2
N linkage in such macrocycles is still
8
Chemical shift changes (ambient temperature, 300 MHz) for
the other protons in the molecule were negligible.
Polyamine macrocycles often show a reduced ability
to complex alkali and alkaline earth metal cations, and
are more e€ective in complexing divalent transition
9
transition metal cation which is used as a template. This
19
seems to be a limitation, since the only preparation of
such 1,3,7,9-tetraazacyclododecane derivatives found in the
literature was for N,N',N0,N1-tetramethyl-1,3,7,9-tetraaza-
cyclododecane which could not be fully characterised due to
1
0
its low stability. In contrast, the corresponding 1,4,7,10-
1
1
tetraaza macrocycles are well characterised.
In the course of our investigations aimed at ®nding
ligands suitable for NMR investigations of organic
1
2
palladium complexes we serendipitously found a one-pot
synthesis for the backbone of 1,3,7,9-tetraazacyclo-
dodecane derivative. The compound, 1,3,7,9-tetrabenzyl-
a
5
,5,11,11-tetramethoxycarbonyl-1,3,7,9-tetraazacyclododecane
1
3
1,
is stable, can be chromatographed on silica, and stored
in solution for weeks without any notable decomposition.
Our synthesis (Scheme 1) is based on a Mannich reaction,
1
4
mixing the preformed Schi€ base
with dimethyl malonate and formaldehyde. No protection/
2
of benzylamine
*
To receive any correspondence.
Fig. 1 Chemical shift variation for 2,8-methylene protons
(dCH2) of compound 1 as a function of the cobalt(II)
concentration. Addition of cobalt(II) chloride solution (0.01M)
to a solution of 1 (0.001M) in acetone
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1998 713
2
metal cations. However, 1,4,7,10-tetraazacyclododecane-
0
1
1
1 M. K. Moi and C. F. Meares, J. Am. Chem. Soc., 1988, 110,
6
266; M. L. Garrity, G. M. Brown, J. E. Elbert and R. A.
Sachleben, Tetrahedron Lett., 1993, 34, 5531.
2 A. Gogoll, H. Grennberg and A. Axen, Organometallics, 1997,
6, 1167.
N,N',N0,N1-tetraacetic acid (DOTA) does complex sodium
2
1
ions,
and mixed nitrogen±oxygen ligands commonly
2
Â
2
complex alkali metal cations. A model for the size-match
relation between the ion and the macrocyclic ligand has
been proposed,
1
13 Synthesis: N-methylenebenzylamine (0.60 g, 5 mmol), dimethyl
malonate (0.33 g, 2.5 mmol) and paraformaldehyde (30% aq.
solution) (0.5 g, 5 mmol) were mixed in ethanol (30 mL) then
re¯uxed with stirring for 20 h. The solvent was removed and
the product 1 puri®ed by column chromatography (Silica 60;
2
3
although it can be dicult to apply
because of the many variables (nature of the donor atom,
ring size and number of chelating atoms, relative position
of the donor atoms, nature of the ligand backbone) that
1
pentane±diethyl ether, 7:3); yield 0.7 g, 37%, clear oil. H NMR
3
a€ect the system. In conclusion, the new macrocycle 1
(
400 MHz, CDCl
(s, 8 H), 3.22 (br s, 4 H), 3.02 (br s, 8 H); C NMR
(100.6 MHz, CDCl ) ꢀ 169.4, 137.5, 128.7, 123.0, 126.9, 74.3,
3
) ꢀ 7.40±7.20 (m, 20 H), 3.71 (s, 12 H), 3.61
13
should be of general interest as a model compound due to
its simple synthesis and unexpected stability as well as that
of its metal complex.
3
5
1
C
9.0, 55.5, 54.0, 52.4; IR (CDCl ) 3061, 2819, 1736, 1495, 1453,
52 4 8
H N O C 69.09, H 6.85, N 7.32; found
3
�
1
263 cm ; calc. for C44
69.00, H. 6.87,
N
7.22%; MS (electrospray, methanol
The Swedish Natural Science Research Council and
Magn. Bergvalls Stiftelse are gratefully acknowledged for
‡
solution), m/z ˆ 765 ([M ‡ H] ).
1
4 Synthesis: Benzylamine (10.9 mL, 0.1 mol) and formaldehyde
(0.1 mol, 8.6 mL 35% aq. solution) were mixed in ethanol
®nancial support.
(50 mL) and re¯uxed overnight. The solvent was removed yield-
ing compound 2 as a clear oil that crystallised over time (10.1 g,
1
Received, 1st June 1998; Accepted, 20th July 1998
Paper E/8/04077J
85%), mp 49±50 8C. H NMR (400 MHz, CDCl
(
3
) ꢀ 7.40±7.20
m, 5 H), 3.70 (s, 2 H), 3.45 (s br, 2 H); C NMR (100.6 MHz,
CDCl ) ꢀ 138.3, 128.8, 128.1, 126.9, 73.7, 57.0; IR (CDCl
050, 2900, 1490, 1450 cm
5 At lower temperatures (�60 8C) the methylene proton signals
two br s) separate into two pairs of doublets. Compare, e.g.,
13
3
3
)
�
1
3
.
1
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(
1
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23
6
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23
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18
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1