The synthesis of C2-symmetric 1,4,7-triazacyclononane ligands derived from chiral aziridines

Article abstract of DOI:10.1039/b204818c

An efficient synthetic route for the synthesis of C₂-symmetric derivatives of 1,4,7-triazacyclononanes 14 from chiral pool amino acids has been developed. These investigations have shown that competitive formation of piperazines 7 occurs when i

Full text of DOI:10.1039/b204818c

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The synthesis of C2-symmetric 1,4,7-triazacyclononane ligands
derived from chiral aziridines
J. Erik W. Scheuermann, Fiona Ronketti, Majid Motevalli, D. Vaughan Griffiths and
Michael Watkinson*
Department of Chemistry, Queen Mary, University of London, Mile End Road, London,
UK E1 4NS. E-mail: m.watkinson@qmul.ac.uk; Fax: +44(0)20 7882 7794
Received (in London, UK) 17th May 2002, Accepted 30th May 2002
First published as an Advance Article on the web 4th July 2002
An efficient synthetic route for the synthesis of C2-symmetric derivatives of 1,4,7-triazacyclononanes 14 from
chiral pool amino acids has been developed. These investigations have shown that competitive formation of
piperazines 7 occurs when inappropriate nitrogen protecting groups are employed. It is apparent that the
formation of the piperazines occurs as a result of an intramolecular nucleophilic attack followed by a b-
elimination. This appears to only be relevant for the formation of the [9]-N3 ring, as the larger [12]-N4
macrocycle, 11, is formed via a Richman–Atkins cyclisation in the presence of the same benzylic protected
nitrogen atom. The single crystal X-ray structures of piperazine 7a and 1,4,7-triazacyclononanes 14a both
=
reveal that weak intermolecular C–Hꢀ ꢀ ꢀO S interactions occur in the solid state in these systems.
meric excesses were moderate the potential of these systems in
catalysis was clearly demonstrated.
Introduction
Manganese complexes of a number of derivatives of 1,4,7-tria-
zacyclononane or TACN, 1 (R ¼ H), have been shown to be
extremely potent oxidation catalysts. Arguably the most
famous, and also notorious, example was the Accelerator2
catalyst marketed by Unilever in the early nineties as a low-
temperature bleaching additive for washing powders.1
Although excellent bleaching properties were observed, these
were associated with unwanted fabric damage following pro-
longed washing cycles. Despite this negative outcome, the
potential of this powerful oxidant was soon demonstrated in
a synthetic context and examples of the use of manganese com-
plexes, principally of 1 (R ¼ Me), soon appeared. A wide
range of substrates has subsequently been shown to be effec-
tively oxidised, principally using the environmentally benign
oxidant hydrogen peroxide, including benzylic alcohols,2 sul-
fides,3 phenols4 and even hydrocarbons.5 Potentially of great-
est synthetic utility and interest are the reports of the
efficient epoxidation, and most recently cis-dihydroxylation,
of a range of alkenes.6
In view of this array of activity and the recent interest in effi-
cient catalysts for the formation of enantiomerically pure
epoxides, it is perhaps a little surprising that examples of chiral
analogues of 1 are so limited. The first reports of chiral analo-
gues of 1 appeared in patents,7 with the first example of an
application in asymmetric synthesis being reported by Bolm.8
In this case chirality was incorporated into the ligand system
through the alkylation of the secondary amine nitrogen atoms
in 1 to generate the C3-symmetric analogue 2 (R ¼ Me or Pri).
Complexes prepared in situ using manganese(II) acetate were
shown to catalyse the asymmetric epoxidation of a range of
olefins with hydrogen peroxide; the highest levels of asym-
metric induction were observed for the benchmark cis-b-
methylstyrene which led to the production of the 1R,2R-
trans-epoxide with 55% ee. More recently Bolm has also
reported the application of a second class of C3-symmetric
derivative of 1 in which the chirality was incorporated into
the macrocyclic framework by reduction of a tricylic peptide
derived from L-proline, 3.9 Although conversions and enantio-
Our interest in this area has focussed on the preparation of
C2-symmetric analogues. Our initial investigations10 centred
on the application of the previously reported macrocyclic
ligand 4,11 however, due to the difficulties associated with its
synthesis and the general lack of easily accessible vicinal dia-
mines, we decided to adopt an alternative approach utilising
chiral pool amino acids. Although our initial investigations
in this area have only just appeared,12 a recent related
account13 prompts us to now report our other efforts in this
area.y
Results and discussion
We have recently reported an extremely selective means of
effecting the selective ring-opening of N-tosyl activated aziri-
y Note added in proof: a further related study appeared after submis-
sion of this manuscript: G. Argouarch, C. L. Gibson, G. Stones and
D. C. Sherrington, Tetrahedron Lett., 2002, 43, 3795.
1054
New J. Chem., 2002, 26, 1054–1059
DOI: 10.1039/b204818c
This journal is # The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2002

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Scheme 2 Proposed mechanism for the formation of piperazines 7
via an intramolecular elimination reaction.
We were able to obtain crystals of 7a suitable for single crys-
tal X-ray diffraction, Table 1. These crystals revealed that the
piperazine ring adopts the expected chair-like conformation,
which is slightly flattened by the almost planar sulfonamide
nitrogen atom, Fig. 1; the sum of the angles about this atom
being 358.3ꢁ [C(8)–N(1)–C(11) ¼ 114.7(3)ꢁ, C(8)–N(1)–
S(1) ¼ 121.9(3)ꢁ, C(11)–N(1)–S(1) ¼ 121.7(2)ꢁ]. The nitrogen
Scheme 1 The synthesis of piperazines 7.
dines, to selectively yield single and double ring-opened mate-
rials.12 The double ring-opened materials 5 were of particular
interest to us as we expected that they could be used directly
in the synthesis of new analogues of 1 using standard Rich-
man–Atkins conditions,14 Scheme 1. A particularly appealing
feature of this synthetic route lay in the generation of the
unsymmetrically substituted triazacyclononane 6 which might
lead to novel binucleating ligands following the removal of the
benzylic protecting group.15 Unfortunately the reaction did
not proceed as hoped under a range of standard cyclisation
conditions and piperazines 7 were isolated. Piperazine forma-
tion is presumably thermodynamically driven by the creation
of the six-membered ring, as has previously been observed in
related polyamine systems.16 We believe that this reaction pro-
ceeds as depicted in Scheme 2 via an intramolecular elimina-
tion of the N-tosylaziridine. It is noteworthy that in the
related report,13 formation of larger polyamine macrocycles
could be effected in the presence of a p-methoxybenzene pro-
tected nitrogen atom, but that an amide protecting group
was required when the 1,4,7-triazacyclononane ring system
was synthesised.
˚
sulfur bond length of S(1)–N(1) ¼ 1.600(3) A is slightly
shorter than those observed in structurally related pipera-
zines.17 Finally the tetrahedral sulfur atom shows slight asym-
˚
metry in the sulfur oxygen bonds, S(1)–O(1) ¼ 1.424(3) A and
˚
S(1)–O(2) ¼ 1.433(3) A. In contrast to the nine other related
structures which all exist as discrete monomers, the piperazine
rings in 7a are linked into polymeric arrays via interactions
˚
between C(9)–H and O(2) of the next molecule of 3.488(5) A
as shown in Fig. 1.
In view of this outcome we wondered whether such an intra-
molecular elimination reaction could be used as a direct route
towards C-chiral macrocycles, 10. We therefore investigated
this possibility for 5a, Scheme 3, in which an analogous intra-
molecular elimination reaction would lead to the C-chiral ana-
logue, 10. In this case however, the elimination reaction did
not occur and only the 12-membered N4-macrocycle 11 that
would be expected to form via a classical Richman–Atkins
cyclisation14 could be isolated. This and the related report13
Table 1 Details of crystal structures and refinement for 7a and 14a
7a
14a
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
C21H28N2O2S
372.51
293(2)
C33H45N3O6S3
675.90
160(2)
Orthorhombic
P212121
Orthorhombic
P212121
˚
Unit cell dimensions/A
a ¼ 8.180(5)
b ¼ 23.468(8)
c ¼ 10.149(4)
1948.4(16)
4
a ¼ 11.261(2)
b ¼ 13.805(3)
c ¼ 21.546(4)
3349.5(11)
4
3
˚
Volume/A
Z
r
calc./mg mꢂ3
1.270
0.184
1.340
0.270
Absorption coefficient/mmꢂ1
F(000)
Crystal size/mm
800
0.4 ꢃ 0.4 ꢃ 0.2
1.74 to 24.99
1440
0.20 ꢃ 0.15 ꢃ 0.10
1.75 to 24.99
y range/ꢁ
Index ranges
ꢂ2 p h p 9, ꢂ2 p k p 27, ꢂ5 p l p 12
2031
ꢂ2 p h p 13, ꢂ7 p k p 16, ꢂ10 p l p 25
Reflections collected
Independent reflections
Completeness to y ¼ 24.99ꢁ (%)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
3415
3319 [R(int) ¼ 0.0047]
1977 [R(int) ¼ 0.0053]
99.9
99.9
Full-matrix least-squares on F2
1977/0/214
1.106
Full-matrix least-squares on F2
3319/1/413
1.037
R1 ¼ 0.0384, wR2 ¼ 0.1116
R1 ¼ 0.0506, wR2 ¼ 0.1288
ꢂ0.04(16)
R1 ¼ 0.0569, wR2 ¼ 0.1036
R1 ¼ 0.1912, wR2 ¼ 0.1327
0.18(19)
Absolute structure parameter
Largest diff. peak and hole/e A
ꢂ3
˚
0.337 and ꢂ0.391
0.481 and ꢂ0.440
New J. Chem., 2002, 26, 1054–1059
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Fig. 2 The single crystal structure of 14a with selected bond lengths
ꢁ
˚
(A) and angles( ): S(1)–O(2) 1.436(6), S(1)–O(1) 1.438(6), S(1)–N(1)
1.621(7), S(2)–O(4) 1.438(7), S(2)–O(3) 1.439(6), S(2)–N(2) 1.633(7),
S(3)–O(5) 1.438(7), S(3)–O(6) 1.438(6), S(3)–N(3) 1.649(7), N(1)–C(1)
1.473(10), N(1)–C(6) 1.514(10), N(2)–C(2) 1.481(10), N(2)–C(3)
1.481(10), N(3)–C(5) 1.482(10), N(3)–C(4) 1.485(10), C(1)–C(2)
1.550(12); C(1)–N(1)–C(6) 122.8(7), C(1)–N(1)–S(1) 115.5(6), C(6)–
N(1)–S(1) 118.0(6), C(2)–N(2)–C(3) 118.0(7), C(2)–N(2)–S(2)
116.4(6), C(3)–N(2)–S(2) 119.6(6), C(5)–N(3)–C(4) 113.6(6), C(5)–
N(3)–S(3) 114.7(5), C(4)–N(3)–S(3) 114.0(5); C(18)ꢀ ꢀ ꢀO(2a) 3.2571.
Fig. 1 Single crystal structure of 7a showing the polymeric network
ꢁ
˚
with selected bond lengths (A) and angles ( ) [a ¼ ꢂ1 + x, y, z]:
S(1)–O(1) 1.424(3), S(1)–O(2) 1.433(3), S(1)–N(1) 1.600(3), N(1)–C(8)
1.477(5), N(1)–C(11) 1.497(5), N(2)–C(9) 1.466(5), N(2)–C(10)
1.467(5), C(8)–C(9) 1.507(6), C(10)–C(11) 1.510(5); O(1)–S(1)–O(2)
120.18(19), O(1)–S(1)–N(1) 106.53(18), O(2)–S(1)–N(1) 107.01(17),
O(1)–S(1)–C(1) 106.76(16), O(2)–S(1)–C(1) 106.75(17), N(1)–S(1)–
C(1) 109.32(17), C(8)–N(1)–C(11) 114.7(3), C(8)–N(1)–S(1) 121.9(3);
C(9)ꢀ ꢀ ꢀO(2a) 3.488(3).
second was to remove the benzylic protecting groups in 5 and
to reprotect the nitrogen atoms with an alternative protecting
group that suppressed the nitrogen nucleophilicity sufficiently
to prevent intramolecular cyclisation occurring. We decided
to investigate the latter approach and found that the benzylic
protecting group could be readily removed in almost quantita-
tive yield giving 12 as shown in Scheme 4. We elected to use the
tosyl protecting group to protect the secondary nitrogen atoms
in 12 as we were confident 13 would undergo the desired cycli-
sation reaction. This indeed proved to be the case and the new
C2-symmetric macrocycles 14 were prepared in good yield.
Crystals of 14a suitable for single crystal X-ray diffraction con-
firmed the structure and absolute stereochemistry of 14a, Table
1 and Fig. 2. The structure reveals that the two sulfonamide
groups adjacent to the stereogenic centres N(1) and N(2) are
similar with comparable sulfur–nitrogen bond lengths [S(1)–
˚
˚
Scheme 3 The synthesis of the [12]-N4 C2-symmetric ligand 11.
N(1) ¼ 1.621(7)A and S(2)–N(2) ¼ 1.633(7) A] and relatively
planar geometries; the sum of the angles about each nitrogen
being 356.3ꢁ and 354.0ꢁ, Table 1. The third sulfonamide centre
is slightly different with a slightly longer bond length between
strongly suggest that polyamine macrocycles, with the excep-
tion of 1,4,7-triazacyclononanes, are available via this metho-
dology, but that an alternative strategy is required for the
synthesis of the nine-membered triaza ring.
As a result of this finding we were faced with two choices.
The first was to reinvestigate the ring opening of N-tosylaziri-
dines with alternative less nucleophilic amines that might pre-
vent intramoleculear attack as in 8, Scheme 2, occurring. The
˚
the sulfur and nitrogen atoms of 1.649(7) A and a greater
deviation from planarity; the sum of the angles about nitrogen
is 342.3ꢁ. This is comparable with our observations in the
related macrocyclic system 4 (R ¼ Ts) in which the sulfona-
mide nitrogen atoms adjacent to the stereogenic centres remain
essentially planar, whilst the third sulfonamide nitrogen devi-
ates markedly from planarity.10 In both cases we assume that
Scheme 4 The synthesis of the target C2-symmetric azamacrocyclic ligands 14.
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(S)-4-Benzyl-2-(1-methylethyl)-1-(4-methylbenzenesulfonyl)-
piperazine 7a
Tertiary amine 5a (3.00 g, 5.09 mmol), ethylene glycol 1,2-dito-
lyl-4-sulfonic acid ester (2.45 g, 6.62 mmol) and potassium car-
bonate (2.11 g, 15.27 mmol) were dissolved in acetonitrile (60
cm3) and refluxed for 3 d. The resulting white solid was
removed by filtration and washed with acetonitrile (60 cm3).
The solvent was removed from the combined filtrates and
the resulting yellow semi-solid purified by column chromato-
graphy (eluents: petroleum spirits (bp 40–60 ꢁC)–ethyl acetate,
3:1) to give the piperazine 7a (1.13 g, 60%) as colourless crys-
25
tals, mp 141–142 ꢁC (from acetonitrile); [a]D +32.6 (c 0.5 in
CHCl3); Found: C, 68.0; H, 7.5; N, 7.7. C21H28N2O2S requires
C, 67.7; H, 7.53; N, 7.68 %; nmax/cmꢂ1 2966, 2361, 1596, 1454,
1319, 1305, 1235, 1156, 1092, 978, 921, 887, 814, 755, 745, 726,
677, 662, 599, 561, 543, 501, 449; dH 0.75 (3H, d, J 6.4,
CH(CH3)2), 0.91 (3H, d, J 6.9, CH(CH3)2), 1.66–1.78 (2H,
m, CH(CH3)2 and piperazine ring-H), 2.32–2.40 (1H, m, piper-
azine ring-H), 2.42 (3H, s, Ar-CH3), 2.49–2.54 (1H, m, piper-
azine ring-H), 2.69 (1H, d, J 11.9, piperazine ring-H), 3.16
(1H, d, J 13.1, Ar-CH2-N), 3.18–3.43 (2H, complex m, piper-
azine ring-H), 3.36 (1H, d, J 13.1, Ar-CH2-N), 3.67–3.74
(1H, m, piperazine ring-H), 7.18–7.28 (7H, m, Ar-H), 7.69
(2H, d, J 8.4, Ar-H); dC 19.9, 20.0, 21.6, 26.2, 41.6, 52.0,
52.4, 60.6, 63.0, 127.1, 127.2, 128.3, 128.9, 129.7, 138.1,
139.3, 142.9; m/z (FAB): 373 (54%, M + H), 217 (100, M ꢂ Ts)
(Found: (M + H) 373.1958. C21H29N2O2S requires 373.1950).
Fig. 3 The polymeric array in 14a.
this is a steric effect resulting from an effort to reduce ring
strain, the magnitude of which is greater in the fused bicyclic
system 4. As was observed for piperazine 7a, a polymeric array
exists in the solid state (Fig. 3). The monomer units are joined
by long interactions between the sulfonamide oxygen atom
O(2)a and the H(18) atom of a neighbouring sulfonamide
˚
group O(2)aꢀ ꢀ ꢀC(18) ¼ 3.2571 A. The interaction is clearly
restricted to the solid state as none of the shielding effects in
1
the H NMR of 7a that we have observed in related sulfona-
mide systems10 are seen in this case.
(S)-4-Benzyl-2-(1-methylpropyl)-1-(4-methylbenzenesulfonyl)-
piperazine 7b
Conclusion
7b was prepared in an identical manner to 7a and was isolated
as a waxy solid (200 mg, 67%), mp ¼ 59–62 ꢁC (from ethanol);
[a]D25 +33.2 (c 0.5, CHCl3); nmax/cmꢂ1 2966, 2964, 2362, 2238,
1596, 1451, 1377, 1340, 1326, 1275, 1149, 1116, 1095, 1015,
963, 917, 812, 751, 740, 702, 642, 598, 562, 552, 540; dH 0.70
(3H, d, J 6.7, CH3-CH(CH)-CH2), 0.87 (3H, t, J 7.3, CH2-
CH3), 0.94–1.10 (1H, m, CH2-CH3), 1.59–1.76 (3H, m, piper-
azine ring-H and CH2-CH3), 2.01–2.18 (1H, m, CH3-
CH(CH)-CH2), 2.42 (3H, s, Ar-CH3), 2.47–2.52 (1H, m, piper-
azine ring-H), 2.69 (1H, d, J 11.9, piperazine ring-H), 3.15 (1H,
d, J 13.0, Ar-CH2-N), 3.19–3.29 (1H, m, piperazine ring-H),
3.35 (1H, d, J 13.0, Ar-CH2-N), 3.41–3.56 (1H, m, piperazine
ring-H), 3.66–3.72 (1H, m, piperazine ring-H), 7.19–7.28 (7H,
m, Ar-H), 7.68 (2H, d, J 8.2, Ar-H); dC 11.4, 15.7, 21.6, 25.4,
32.4, 41.7, 51.9, 52.3, 59.2, 63.0, 127.1, 127.2, 128.3, 129.0,
129.7, 137.9, 139.3, 143.0; m/z (FAB): 387 (52%, M + H,
231) 231 (100%, M ꢂ Ts) (Found: (M + H) 387.2106.
C22H30N2O2S requires 387.2094).
We have developed a new synthetic route for the synthesis of
C2-symmetric macrocyclic 1,4,7-triazacyclononane ligands,
14, derived from chiral pool amino acids. We are currently
actively engaged in an investigation of their coordination
chemistry and their application in asymmetric catalysis.
Experimental
General methods
All reagents were commercially available and were used with-
out further purification, unless otherwise stated. CH3CN was
heated under reflux overnight with CaH2 in an atmosphere
of nitrogen and then distilled from CaH2 . CH2Cl2 was distilled
from P2O5 . Triethylamine was distilled from KOH pellets
prior to use. Nitrogen for inert atmosphere use was purified
˚
by passing it through anhydrous manganese(II) oxide, 3A
molecular sieves and highly reduced chromium adsorbed onto
a silica support. Thin layer chromatography (TLC) was per-
formed on silica gel 60 F254 plates (Merck). Melting points
were determined using an Electrothermal melting point appa-
ratus and are uncorrected. Elemental analyses were obtained
using a Carlo Erba 1106 elemental analyser. All 1H-NMR
and 13C-NMR spectra were recorded as CDCl3 solutions on
a JEOL JNM-EX spectrometer at 270 MHz and at 67.9
MHz respectively unless otherwise stated. All spectra were
referenced to residual CHCl3 as the internal standard with J
values given in Hertz. IR spectra were recorded on a Perkin-
Elmer 1720X FT-IR spectrometer with a solid state ATR
attachment. Fast atom bombardment (FAB) mass spectra
were recorded on a VG Instruments ZAB-SE using xenon
gas at 8 kV in a matrix of 3-nitrobenzyl alcohol (MNBA)
and sodium iodide (FAB). Optical rotations were recorded
on an Optical Activity Ltd AA1000 polarimeter using the
sodium D line (589 nm) and are given in units of 10ꢂ1 deg
dm2 gꢂ1. All samples were homogeneous by TLC.
(S,S)-4-Benzyl-2,6-bis(1-methylpropyl)-1,7,10-tris(4-methyl-
benzenesulfonyl)-1,4,7,10-tetraazacyclododecane 11
Tertiary amine 5a (1.00 g, 1.71 mmol), N,O,O0-tris(4-methyl-
benzenesulfonyl)diethanolamine (1.26 g, 2.22 mmol) and cae-
sium carbonate (1.67 g, 5.13 mmol) were dissolved in dry
acetonitrile (50 cm3) and refluxed for 6 d under N2 . The white
solid was filtered off and washed with acetonitrile (50 cm3).
The filtrates were combined, the solvent was removed and
the resulting product purified by column chromatography (elu-
ents: petroleum spirits–ethyl acetate, 75:25) to give macrocycle
25
11 (463 mg, 34%) as colourless crystals, mp 108–110 ꢁC; [a]D
+24.2 (c 0.5, CHCl3); Found: C, 61.1; H, 6.7; N, 6.6.
C42H56N4O6S3 .H2O requires: C, 61.0; H, 7.1; N, 6.8 %;
n
max/cmꢂ1: 2961, 2360, 2341, 1597, 1494, 1454, 1322, 1262,
1154, 1089, 1019, 942, 912, 890, 814, 722, 699, 661, 582, 571,
548, 515, 486, 461; dH 0.70 (6H, d, J 6.7, CH(CH3)2), 0.82
(6H, d, J 6.6, CH(CH3)2), 1.82–1.91 (2H, m, CH(CH3)2),
2.39 (6H, s, Ar-CH3), 2.42 (3H, s, Ar-CH3), 2.94–2.98 (2H,
New J. Chem., 2002, 26, 1054–1059
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m, ring N-CHn), 3.26–3.84 (14H, m, ring N-CHn), 7.10–7.35
(11H, m, Ar-H) 7.60–7.65 (2H, m, Ar-H), 7.73 (4H, d, J 8.4,
Ar-H); dC 20.0, 21.6, 21.8, 30.8, 46.1, 50.7, 57.5, 64.3, 66.2,
127.2, 127.8, 128.0, 128.2, 129.7, 129.8, 130.4, 134.3, 136.5,
137.8, 143.3, 144.0; m/z (FAB): 809 (23%, M + H), 653 (55,
M ꢂ Ts) (Found: (M + H) 809.3466. C42H57N4O6S3 requires
809.3448).
137.5, 143.5, 144.3; m/z (FAB) 650 (13.5%, M + H); (Found:
M + H 650.2373. C31H44N3O6S6 requires 650.2392).
N,N-Bis(2-[4-methylbenzenesulfonylamino]-3-methylpentyl)-4-
methylbenzenesulfonamide 13b
13b was prepared in an identical manner to 13a to yield colour-
less crystals (5.11 g, 88%), mp 191–192 ꢁC (from ethanol);
N-(1-{N0-[(2-{4-methylbenzenesulfonylamino}-3-methylbutyl]-
aminoethyl}-2-methylpropyl-4-methylbenzenesulfonamide 12a
[a]D ꢂ10.4 (c 0.5, CHCl3); nmax/cmꢂ1 3255, 2957, 2920,
25
2367, 1596, 1453, 1351, 1325, 1306, 1163, 1092, 1039, 1020,
967, 903, 812, 744, 688, 666, 603, 555, 548, 521; dH 0.59 (6H,
d, J 7.2 CH3-CH(CH)-CH2), 0.77–0.94 (8H, m, CH3-CH2
and CH(CH)-CH2-CH3), 1.08–1.24 (2H, m, CH(CH)-CH2-
CH3), 1.55–1.65 (2H, m, CH3-CH(CH)-CH2), 2.39 (6H, s,
Ar-CH3), 2.43 (3H, s, Ar-CH3), 2.70 (2H, dd, J 14.8 and J
5.0, SO2NH-CH2-CH(CH)), 3.04 (2H, dd, J 14.6 and J 8.8,
SO2NH-CH2-CH(CH)), 3.11–3.22 (2H, m, CH2-CH(CH)-
NHSO2), 5.02 (2H, d, J 6.1, CH(CH)-NH-SO2), 7.25 (4H, d,
J 8.0, Ar-H), 7.35 (2H, d, J 8.2, Ar-H), 7.50–7.69 (6H, m,
Ar-H); dC 12.2, 13.8, 21.6, 24.8, 36.1, 48.0, 55.5, 127.3, 127.5,
129.7, 130.3, 135.6, 137.7, 143.5, 144.4; m/z (FAB): 700
(16%, M + Na), 678 (52, M + H) (Found: M + H 678.2694.
C33H48N3O6S3 requires 678.2705)
To a solution of 5a (3.00 g, 5.13 mmol) in glacial acetic acid (60
cm3) was added palladium dispersion on carbon (280 mg, 10%
w/w) and the reaction was stirred under an atmosphere of
hydrogen for 18 hours. The solid was removed by filtration
and the solid washed with ethanol (60 cm3) and ethyl acetate
(60 cm3). The organic phases were combined and the solvents
removed under reduced pressure to yield a yellow oil. The oil
was redissolved in CH2Cl2 and stirred with potassium hydro-
xide solution (60 cm3, 1 M) for 30 min. The layers were seper-
ated and the aqueous layer washed with CH2Cl2 (2 ꢃ 30 cm3).
The organic phases were combined, dried over anhydrous
magnesium sulfate and the solvent removed under reduced
pressure to yield an off-white solid (2.48 g, 97.5%). All spectro-
scopic data were consistent with those previously reported.18
In addition HRMS, found (M + H) 496.2311. C24H38N3O4S2
requires 496.2304.
(2S,6S)-2,6-Bis(1-methylethyl)-1,4,7-tris(4-methylbenzene-
sulfonyl)-1,4,7-triazacyclononane 14a
N-(1-{N0-[(2-{4-methylbenzenesulfonylamino}-3-methylpentyl]-
aminoethyl}-2-methylbutyl-4-methylbenzenesulfonamide 12b
Tosylamide 13a (4.50 g, 6.93 mmol), ethylene glycol 1,2-dito-
lyl-4-sulfonic acid ester (3.34 g, 9.01 mmol) and caesium carbo-
nate (6.77 g, 20.79 mmol) were dissolved in dry acetonitrile (10
cm3) and refluxed under nitrogen for 6 d. The resulting white
solid was filtered off and washed with acetonitrile (10 cm3).
The solvent was removed from the combined filtrates and
the resulting yellow semisolid was recrystallised from acetoni-
trile to yield macrocycle 14a (3.00 g, 64%) as colourless crys-
12b was prepared in an identical manner to 12a to yield a yel-
25
low solid (4.84 g, 95%), mp 99–101 ꢁC; [a]D ꢂ2.2 (c 0.5,
CHCl3); nmax/cmꢂ1: 3291, 3168, 2360, 2338, 1596, 1457,
1419, 1326, 1156, 1092, 1076, 1017, 952, 856, 816, 700, 655,
571, 547, 496, 436; dH 0.70 (6H, d, J 6.9, CH3-CH(CH)-
CH2), 0.77 (6H, t, J 7.3, CH2-CH3), 0.83–1.07 (2H, m, CH-
CH(CH2)-CH3), 1.18–1.31 (2H, m, CH-CH(CH2)-CH3),
1.33–1.50 (2H, m, CH-CH(CH2)-CH3), 2.18 (2H, dd, J 12.6
and J 4.0, NH-CH2-CH(CH)), 2.34 (2H, dd, J 12.9 and J
7.9, NH-CH2-CH(CH)), 2.41 (6H, s, Ar-CH3), 3.02–3.08
(2H, m, CH2-CH(CH)-NHSO2), 7.28 (4H, d, J 8.1, Ar-H),
7.75 (4H, d, J 8.1, Ar-H); dC 11.8, 14.4, 21.6, 25.7, 37.1,
48.2, 56.8, 127.2, 129.7, 138.1, 143.3; m/z (FAB): 524 (100%,
M + H); (Found: M + H 524.2631. C26H42N3O4S2 requires
524.2617).
25
tals, mp 214–215 ꢁC (from acetonitrile); [a]D ꢂ7.4 (c 0.5,
CHCl3); nmax/cmꢂ1 2964, 2360, 1597, 1452, 1395, 1336, 1305,
1154, 1089, 1018, 972, 909, 843, 815, 730, 714, 697, 665, 649,
633, 574, 549; dH 0.35 (6H, br s, CH(CH3)2), 0.85 (6H, d, J
6.0, CH(CH3)2), 0.93–1.16 (2H, bm, CH(CH3)2), 2.38 (6H, s,
Ar-CH3), 2.45 (3H, s, Ar-CH3), 3.04–3.29 (4H, m, ring-CHn),
3.30–3.48 (2H, m, ring-CHn), 3.53–3.88 (4H, m, ring-CHn),
7.26 (4H, d, J 8.3, Ar-H), 7.35 (2H, d, J 8.3, Ar-H), 7.67–
7.72 (6H, m, Ar-H); dC (Bruker AMX400, 100.6 MHz) 20.0,
20.4, 21.8, 28.2, 45.6, 51.7, 64.5, 127.2, 127.6, 128.1, 129.7,
129.8, 143.4, 143.9; m/z: 698 (52, M + Na), 676 (65, M + H),
520 (69%, M ꢂ Ts) (Found: M + H 676.2575. C33H46N3O6S3
requires M + H 676.2549).
N,N-Bis(2-[4-methylbenzenesulfonylamino]-3-methylbutyl)-4-
methylbenzenesulfonamide 13a
p-Toluenesulfonyl chloride (462 mg, 2.42 mmol) and 12a (1.00
g, 2.02 mmol) were dissolved in dry CH2Cl2 (20 cm3) under
nitrogen. Triethylamine (613 mg, 6.06 mmol) and DMAP (49
mg, 0.4 mmol) were added and the yellow solution stirred
for 12 h. The solvent was removed under reduced pressure
and the resulting yellow oil stirred with H2O (20 cm3) for 1
h. The water was decanted and the remaining yellow semi-solid
recrystallised from EtOH to give 13a (1.00 g, 76%) as colour-
(2S,6S)-2,6-Bis(1-methylpropyl)-1,4,7-tris(toluene-4-sulfonyl)-
1,4,7-triazacyclononane 14b
13b was prepared in identical manner to 13a to give colourless
crystals of 14b (4.40 g, 53%), mp 95–97 ꢁC (from acetonitrile);
25
[a]D +24.1 (c 0.5, CHCl3); Found: C, 59.8; H, 7.0; N, 6.0.
25
less crystals, mp 205–207 ꢁC (from ethanol), [a]D ꢂ30.4 (c
C35H49N3O6S3 requires: C, 59.7; H, 7.0; N, 6.0%; nmax/cmꢂ1
3203, 2963, 2931, 1596, 1453, 1381, 1340, 1303, 1112, 1151,
1112, 1088, 979, 962, 891, 855, 816, 736, 715, 696, 664, 649,
631, 574, 544; dH 0.55–0.64 (8H, m), 0.77–0.80 (8H, m),
0.91–1.06 (2H, m, CH3-CH(CH)-CH2), 2.39 (6H, s, Ar-CH3),
2.44 (3H, s, Ar-CH3), 3.19–3.72 (8H, m, ring-CHn), 3.75–
3.92 (2H, bm, ring-CHn) 7.25 (4H, d, J 8.3, Ar-H), 7.34 (2H,
d, J 8.0, Ar-H), 7.73–7.66 (6H, m, Ar-H); dC 11.6, 15.7, 21.6,
26.7, 35.8, 46.1, 48.7, 63.3, 127.5, 127.8, 129.8, 129.9, 137.7,
143.6, 143.7; m/z (FAB): 726 (32%, M + Na), 704 (39,
M + H) (Found M + H 704.2850. C35H50N3O6S3 requires
704.2862).
0.5, CHCl3); Found C, 57.8; H, 6.8; N, 6.5. C31H43N3O6S3
requires C, 57.3; H 6.7; N, 6.5%; nmax/cmꢂ1 3244, 2958,
1597, 1454, 1353, 1320, 1160, 1127, 1092, 1037, 1019, 964,
891, 813, 737, 665, 617, 587, 553, 513, 460; dH 0.55 (6H, d, J
7.2, CH(CH3)2), 0.71 (6H, d, J 6.9, CH(CH3)2), 1.65–1.85
(2H, m, CH(CH3)2), 2.39 (6H, s, Ar-CH3), 2.43 (3H, s, Ar-
CH3), 2.87–3.02 (4H, m, SO2N-CH2-CH(CH)), 3.08–3.19
(2H, m, CH2-CH(CH)-NHSO2), 5.07 (2H, d, J 6.6, CH-NH-
SO2), 7.25 (4H, d, J 8.0, Ar-H), 7.33 (2H, d, J 8.0, Ar-H),
7.65 (2H, d, J 8.3, Ar-H), 7.72 (4H, d, J 8.3, Ar-H); dC 16.5,
17.9, 21.6, 28.4, 51.0, 57.1, 127.3, 127.6, 129.7, 130.1, 134.6,
1058
New J. Chem., 2002, 26, 1054–1059

View Article Online
R. Nasser, G. E. Hawkes, R. T. Kroemer, M. Motevalli and M.
Watkinson, manuscript in preparation.
11 S. W. Golding, T. W. Hambley, G. A. Lawrance, S. M. Luther,
M. Maeder and P. Turner, J. Chem. Soc., Dalton Trans., 1999,
1975.
X-Ray crystallography
The intensity data were collected on a CAD-4 diffractometer
˚
using MoKa radiation (l 0.71069 A) with o–2y scans. The unit
cell parameters were determined by least-squares refinement
on diffractometer angles [(Piperazine 7a) 10.22 p y p 12.41 ꢁ
and (Macrocycle 14a) 8.23 p y p 12.78 ꢁ] for 25 automatically
centred reflections.19 All data were corrected for absorption by
empirical methods (C scan)20 and for Lorentz-polarization
effects by XCAD4.21 The structures were solved by the
heavy-atom method using the programs SHELXS-9722 and
DIRDIF-9923 and refined anisotropically (non-hydrogen
atoms) by full-matrix least-squares on F2 using SHELXL-
97.22 The H atom positions were calculated geometrically
and refined with a riding model. In the final stage of refinement
data were correct for absorption by DIFABS.24 The programs
ORTEP-3,25 PLATON26 were used for drawing the molecules
and WINGX27 was used to prepare material for publication.
CCDC reference numbers 185531 (14a) and 185532 (7a).
See http://www.rsc.org/suppdata/nj/b2/b204818c/ for
crystallographic data in CIF or other electronic format.
12 J. E. W. Scheuermann, G. Ilyashenko, D. V. Griffiths and M.
Watkinson, Tetrahedron: Asymmetry, 2002, 13, 269.
13 B. M. Kim, S. M. So and H. J. Choi, Org. Lett., 2002, 4, 949.
14 G. H. Searle and R. J. Geve, Aust. J. Chem., 1984, 37, 959.
15 S. Pulacchini and M. Watkinson, Eur. J. Org. Chem., 2001, 4233.
16 S. Buøen and J. Dale, Acta Chem. Scand. B, 1986, 40, 278.
17 (a) I. L. Karle, Z. Kristallog., Kristallg., Kristallp., Kristallch.,
1973, 138, 184; (b) A. Perales, F. H. Cano and S. Garcia-Blanco,
Acta Crystallogr., Sect. B, 1977, 33, 3172; (c) P. D. Williams, P. S.
Anderson, R. G. Ball, M. G. Bock, L. Carroll, S.-H. L. Chiu,
B. V. Clineschmidt, J. C. Culberson, J. M. Erb, B. E. Evans,
S. L. Fitzpatrick, R. M. Freidinger, M. J. Kaufman, G. F. Lun-
dell, J. S. Murphy, J. S. Pawluczyk, D. S. Perlow, D. J. Pettibone,
S. M. Pitzenberger, K. L. Thompson and D. F. Veber, J. Med.
Chem., 1994, 37, 565; (d ) P. D. Williams, R. G. Ball, B. V. Clin-
eschmidt, J. C. Culberson, J. M. Erb, R. M. Freidinger, J. M.
Pawluczyk, D. S. Perlow, D. J. Pettibone and D. F. Veber, Bioorg.
Med. Chem., 1994, 2, 971; (e) M. M. El-Abadelah, S. S. Sabri,
M. A. Khanfar, W. Voelter and C. Maichle-Moessmer, Z. Natur-
forsch., Teil B, 1999, 54, 1323; ( f ) W. Voelter, C. Maichle-Moss-
mer, M. A. Khanfar, M. M. El-Abadelah and S. S. Sabri, Z.
Naturforsch., Teil B, 1999, 54, 1602; (g) M. M. El-Abadelah,
S. S. Sabri, M. A. Khanfar, W. Voelter and C. Maichle-Mossmer,
Z. Naturforsch., Teil B, 2000, 55, 1079; (h) M. M. El-Abadelah,
S. S. Sabri, M. A. Khanfar, W. Voelter, R. J. Abdel-Jalil, C.
Maichle-Mossmer and Y. Al-Abed, Heterocycles, 2000, 53, 2643.
18 (a) R. Alul, M. B. Cleaver and J.-S. Taylor, Inorg. Chem., 1992,
31, 3636; (b) J.-Q. Wang, M. Zhong and G.-Q. Lin, Chin. J.
Chem., 1998, 16, 65.
19 Enraf-Nonius, CAD-4/PC Software, Version 1.5c, Enraf-Nonius,
Delft, The Netherlands, 1994.
20 A. C. T. North, D. C. Phillips and F. S. Mathews, Acta Crystal-
logr., Sect. A, 1968, 24, 351.
21 XCAD4-CAD4 Data Reduction, K. Harms and S. Wocadlo, Uni-
versity of Marburg, Marburg, Germany, 1995.
22 G. M. Sheldrick, SHELX-97, Program for Solution and Refine-
ment of Crystal Structures, University of Go¨ttingen, Germany,
1997.
23 N. Walker and D. Stuart, Acta Crystallogr., Sect. A, 1983, 39,
158.
24 DIRDIF-99 program system, P. T. Beurskens, G. Beurskens,
W. P. Bosman, R. de Gelder, S. Garcia-Granda, R. O. Gould,
R. Israel, J. M. M. Smits, Crystallography Laboratory, University
of Nijmegen, The Netherlands, 1999.
25 ORTEP-3 for Windows, L. J. Farrugia, J. Appl. Crystallogr.,
1997, 30, 565.
26 PLATON/PLUTON: (a) A. L. Spek, Acta Crystallogr., Sect. A,
1990, 46, 34; (b) PLATON, A Multipurpose Crystallographic
Tool, A. L. Spek, Utrecht University, Utrecht, The Netherlands,
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