Mono-benzyl substituted cis,cis-1,3,5-triaminocyclohexanes

Article abstract of DOI:10.1016/j.tetlet.2005.07.112

Unsymmetrical derivatives of the versatile molecule cis,cis-1,3,5- triaminocyclohexane (tach) have been prepared using a new metal-promoted synthesis to give the mono N-substituted tach ligands. This new method enables the synthesis of these molecules sel

Full text of DOI:10.1016/j.tetlet.2005.07.112

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6441–6443
Mono-benzyl substituted cis,cis-1,3,5-triaminocyclohexanes
Stephen J. Archibald, Alison K. Nairn, Phillipa Timmins and Paul H. Walton*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 27 May 2005; revised 14 July 2005; accepted 22 July 2005
Abstract—Unsymmetrical derivatives of the versatile molecule cis,cis-1,3,5-triaminocyclohexane (tach) have been prepared using a
new metal-promoted synthesis to give the mono N-substituted tach ligands. This new method enables the synthesis of these mole-
cules selectively and in good yields and purity.
Ó 2005 Elsevier Ltd. All rights reserved.
Small molecules which can coordinate to metal ions and
which enforce an N3 face-capping geometry at the metal
are used extensively in coordination chemistry, particu-
larly as catalysts and biomimetic complexes. The most
widely used ligands are those based on triazacyclo-
nonane, trispyrazolylborates, trisimidazoylmethanes
and cis,cis-1,3,5-triaminocyclohexane (tach). Of these
ligands, tach–metal complexes are attracting increased
attention due to their potential application as imaging
agents and metal chelating agents,1–6 as cata- lysts for
the hydrolysis of DNA7 and peptides8,9 and in biomi-
metic complexes.10–12 Despite the wide interest in tach,
there are few reports for the general synthesis of unsym-
metrically N,N0,N00-substituted tach ligands. The exist-
ing synthetic methods tend to produce a mixture of
products, which require complex separation.13,14 Build-
ing on our previous work in which we demonstrated that
N-substituted tach molecules acted as ligands in metal
complexes,15–17 we present here a general synthesis and
characterisation of unsymmetrical N,N0,N00-substituted
tach ligands, significantly extending the range of possi-
ble tach derivatives. To prepare N-substituted tach, we
carbamate, which is then cleaved with HBr/acetic acid
to yield the triamine.
The general synthesis of the unsymmetrically N,N0,N00-
substituted tach is as follows: neutralisation of the hydro-
bromide salt of tach with aqueous sodium hydroxide
followed by reaction with three equivalents of a benz-
aldehyde gave the tris-imine, 1 (Scheme 1), in excellent
yield (>95%). Compound 1 was then reacted with one
equivalent of Ni(NO3)2Æ6H2O resulting in a remarkable
selective hydrolysis of two of the three imines to afford
a mono-substituted imine metal complex. This hydroly-
sis is highly selective for the mono-imine compound.
This complex was reduced in situ using NaBH4 to give
the amine derivatised Ni complex 2 (Scheme 1). [Ni-
(tach)2]2+ is a by-product of the reaction (<5% yield),
however, it is known that [Ni(tach)2]2+ is stable and it
could easily be removed by extraction of 2 into THF.
Compound 2 was typically isolated in >70% yield. From
2, the mono N-benzylated triamino cyclohexane, 3 was
produced by treatment of 2 with NaCN in H2O to liber-
ate the metal as [Ni(CN)4]2ꢀ. The N-benzyl derivatives
of cis,cis-1,3,5-triaminocyclohexane were isolated as vis-
cous oils in overall yields for the three steps of >55% for
both derivatives (Table 1).
have used
a simple and reliable metal-catalysed
controlled hydrolysis of tri-imine derivatives of tach.
The hydrobromide salt of tach was synthesized from
the corresponding cis,cis-1,3,5-cyclohexanetricarboxylic
acid using the route of Brechbiel et al.18 The reaction
proceeds via a Curtius rearrangement to form a benzyl
A demonstration of the ability of the new unsymmetri-
cal tach molecules to be further derivatised and then
act as ligands for metal ions was shown in the prepara-
tion of salicylaldehyde derivatised ligand L (Scheme 2).
Due to the hygroscopic nature of the product it was nec-
essary to store it under nitrogen, however complexation
with Cu(BF4)2Æ6H2O resulted in the formation of an
air-stable copper complex in 70% yield, CuII L.
Keywords: Triaminocyclohexane; Nickel; Biomimetic.
*
Corresponding author. Tel.: +44 1904 432500; fax: +44 1904
432516; e-mail: phw2@york.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.112

6442
S. J. Archibald et al. / Tetrahedron Letters 46 (2005) 6441–6443
Scheme 1. Synthetic route to the new N3O2 donor ligands (1a, 2a, 3a; R1 = H, R2 = OMe: 1b, 2b, 3b; R1 = tBu, R2 = H). Conditions: (i) Et2O,
NaOH/H2O, (ii) Ni(NO3)2Æ6H2O, NaBH4 in MeOH, (iii) NaCN in H2O.
Table 1. Summary of derivatives prepared and yields obtained of new unsymmetrically N,N0,N00-substituted tach species
Compound
Number
Substitution pattern
Yield/%
cis,cis-1,3,5-Tris(benzylidene amino)cyclohexane
1a
1b
2a
2b
3a
3b
R1 = H, R2 = OMe
R1 = tBu, R2 = H
R1 = H, R2 = OMe
R1 = tBu, R2 = H
R1 = H, R2 = OMe
R1 = tBu, R2 = H
97
96
73
92
89
63
1-[Benzylamino]-3,5-(diaminocyclohexane)Ni(NO3)2
1-(Benzylamino)-3,5-diaminocyclohexane
Scheme 2. Synthetic route to the new N3O2 donor ligand (L, where R1 = H, R2 = OMe, R3 = tBu). Conditions: 2 equiv of 3,5-di-tBu-salicylaldehyde,
–H2O.
In summary, we have prepared a novel N-benzyl
substituted cis,cis-1,3,5-triaminocyclohexane molecules
using a new synthesis, which selectively produces the
mono substituted species. The route has the potential
to accommodate a wide range of functional groups
and offers an alternative to tosylation procedures,
which result in low-yielding deprotection steps limiting
the functional groups present in the target molecule,
without the use of further protective group strategies.
Moreover, the general strategy allows for acid-sensi-
tive functional groups to be included in the benzyl
moiety.

S. J. Archibald et al. / Tetrahedron Letters 46 (2005) 6441–6443
6443
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Supplementary data
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Synthetic and characterization details for the com-
pounds 1a, 1b, 2a, 2b, 3a, 3b, L and CuII L are available
as supplementary data in the online version at doi:
10.1016/j.tetlet.2005.07.112.
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