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At each stage of the synthesis, the chain can be either elongated or cyclised to the macrocycle of
interest. The use of two orthogonal protective groups on either side of the oligomers allows control
of the length of the triazine–piperazine chain. Furthermore, it is possible to functionalise each triazine
unit in the chain with different amines as the chain is elongated. In the synthesis described below, only
cyclic trimers were considered and piperazine was used as a linker, in order to create relatively rigid
macrocycles. However, in due course, larger rings may be prepared and other diamines might be used as
linkers, thereby increasing the diversity even further.5
The synthesis of the required building blocks commenced with mono-Boc protection of piperazine
2 using a modification of a literature procedure6 (Scheme 1). Reaction of monoprotected piperazine 3
with cyanuric chloride gave monosubstituted product 4 in 93% yield, using a procedure described by
Koopman et al.7 Compound 4 could be used throughout the synthesis as a convenient building block
for the elongation of triazine–piperazine oligomers. Mono-Z-protected piperazine was chosen as the
second substituent on triazine 4, since it provides a second orthogonally protected piperazine moiety. The
mono-Z-protected piperazine 6 was obtained in a quantitative yield by a subsequent reaction of 3 with
Z-chloride and TFA. This route was preferred to literature procedures8 because of its convenience and
high yield. In addition, the reaction of piperazine with Z-chloride, gave only the bisubstituted product.
Scheme 1. Synthesis of building blocks. Reaction conditions and yields: (i) Boc2O, CH2Cl2, 83%; (ii) cyanuric chloride,
NaHCO3, H2O/acetone, 93%; (iii) Z-Cl, Et3N, CH2Cl2; (iv) TFA, DCM, quantitative from 3
As is shown in Scheme 2, a reaction of Z-protected piperazine 6 with 4 afforded bisubstituted triazine 7
in 85% yield.7 Subsequently, the third substituent was introduced by refluxing 7 with an excess of amine
to give trisubstituted triazines 8a–f in 75–99% yield.9 These reactions show that a plethora of amines
may be used in this reaction to provide the desired diversity. The triazines 8 are the starting point for the
preparation of a series of functionalised triazine–piperazine oligomers that can be eventually cyclised.
At this point, compounds 8a–c were selected to continue the synthesis: either the Boc or the Z-group
could be removed to functionalise these compounds further. Preliminary results had revealed that higher
yields of macrocycles could be obtained if the last protective group to be removed before cyclisation was
a Boc- rather than a Z-group. Thus, in order to obtain oligomers containing two triazines, compounds
8a–c were treated with TFA, followed by a reaction with dichloride 4, using triethylamine as a base to
give bistriazines 9a–c10 in 78–100% yield. The remaining chloride was then substituted using an excess
of a second amine to afford compounds 10a–f in 92–96% yield, providing further diversity. Removal of
the Z-group and reaction with cyanuric chloride gave dichlorides 11a–f in 54–85% yield, as a precursor
for synthesis of tristriazine–piperazine macrocycles.
The respective macrocycles 12a–f were prepared from the triazine–piperazine oligomers 11a–f by
subsequent treatment with acid and base. All compounds were converted to their corresponding macro-
cycles in fair yields (40–85%). Insignificant dimer formation was observed under the reaction conditions
employed. It is worth noting that compounds 11c and 11d afford macrocycles 12c and 12d, respectively,
which are identical, as was confirmed by both their spectral11 and chromatographic properties. Finally,
the remaining chlorine in 12a–f was substituted using an excess of a third amine to give the fully
L?wik, Dennis W. P. M.
