A remarkably efficient and direct route for the synthesis of binucleating 1,4,7-triazacyclononane ligands

Article abstract of DOI:10.1055/s-2001-18706

An extremely efficient and direct route towards a range of binucleating analogues of 1,4,7-triazacyclononane 5a-f, has been developed. In all cases the reactions of benzylic and aliphatic diamines with ditosylate ester 3 proceed to give the target binucleating ligands ahnost exclusively and in excellent yield.

Full text of DOI:10.1055/s-2001-18706

SHORT PAPER
2381
A Remarkably Efficient and Direct Route for the Synthesis of Binucleating
1,4,7-Triazacyclononane Ligands
Synthesis of
B
o
inucleating 1
n
,4,7-Triaza
c
i
yclono
a
a
Department of Chemistry, Queen Mary, University of London, Mile End Road, London, E1 4NS, U.K.
Fax +44(0)2078827794; E-mail: m.watkinson@qmul.ac.uk
b
Warwick International Limited, Mostyn, Flintshire, North Wales, CH8 9HE, U.K.
Received 14 August 2001
ing potassium carbonate as the base in acetonitrile. We
wondered whether this could also provide a considerably
more direct and efficient synthesis of binucleating ana-
logues like 5a and 5b. We therefore decided to investigate
the reaction of the commercially available m- and p-xy-
lenediamines with 3 under identical reaction conditions
(Scheme). Intuitively one might expect a complex mixture
of products to be formed under such reaction conditions
viz. larger marcocycles, higher order macrocycles e.g.
Abstract: An extremely efficient and direct route towards a range
of binucleating analogues of 1,4,7-triazacyclononane 5a–f, has
been developed. In all cases the reactions of benzylic and aliphatic
diamines with ditosylate ester 3 proceed to give the target binucle-
ating ligands almost exclusively and in excellent yield.
Key words: macrocycles, azamacrocycles, binucleating ligands,
polyazacycloalkanes, 1,4,7-triazacyclononane
1
2+2, oligomers and polymeric species. However, H
The synthesis and application of triazamacrocyclic
ligands such as 1, has been an area of enormous interest
and diversity in recent years.2 Included in this generic
class of ligands is a series of binucleating analogues, for
example 2, that have been of particular utility in bioinor-
ganic chemistry3 and catalysis.4 Metal complexes of these
triazacyclononane ligands have found application e.g. as
oxidation catalysts5 and as hydrolase enzyme mimics, e.g.
capable of the non-oxidative cleavage of RNA and DNA.6
In both of these cases, dramatic increases in the effective-
ness of the catalysts were observed when a binucleating
variant of the triazacyclononane ligand, like 2, was used
rather than its mononucleating analogue, like 1.4,8a There
is particularly strong spectroscopic evidence, for manga-
nese oxidation catalysts based on triazacyclononane
ligands, that a binuclear metal complex is formed during
the catalytic cycle.7 It is therefore not surprising that, by
forcing two metal centres into close proximity by using
such binucleating ligands, the catalytic properties in the
resultant complexes are enhanced. Unfortunately, in spite
of the remarkable properties and catalytic activity that
these ligands incur on their metal complexes, there are
considerable difficulties associated with their syntheses;
two general procedures have been reported,8 both of
which involve the synthesis and subsequent derivatisation
of the preformed 1,4,7-triazacyclononane system (Fig-
ure).
NMR analysis of the crude reaction mixtures indicated
that the formation of single compounds had almost exclu-
sively occurred and their spectra were consistent with the
target binucleating ligands 5a and 5b. This was corrobo-
rated by infrared spectroscopy, which revealed that the
highly characteristic bands of the tosylamide protected
1,4,7-triazacyclononane ring were present at 1599, 1495,
1450, 1090, 996, 815, 712 and 692 cm–1. The structural in-
tegrity of the products was further supported by 13C NMR
and mass spectral analysis. Analytically pure materials
could be readily prepared by simple recrystallisation from
acetonitrile to give 5a and 5b in 76% and 66% isolated
yield respectively. This is a remarkable result and reflects
that the formation of the nine-membered triaza-ring is
highly favoured under the reaction conditions we have de-
veloped. That this combined intermolecular and intramo-
lecular
reaction
involving
four
nucleophilic
displacements should occur in such high yield is impres-
sive in itself; that it should occur exclusively to form the
binucleating ligands 5a and 5b, when many other reac-
tions are possible is, in our view, quite remarkable.
NH HN
N
N
N
N
N
H
N
N
2
1
We are currently interested in developing efficient routes
to both unsymmetrically and symmetrically substituted
triazamacrocyclic ligands and recently reported an effi-
cient route for their syntheses (Scheme).9 We observed
that formation of the desired nine-membered ring of 4 was
highly favoured when benzylamine was reacted with 3 us-
Figure
As a result of the efficiency of the reactions with benzylic
diamines, we extended our study to a series of other ali-
phatic diamines. These were similarly found to be high
yielding and extremely clean reactions with the desired bi-
nucleating ligands 5c–5f being almost exclusively
formed. Purification by column chromatography was re-
quired in these cases to provide analytically pure materi-
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2381,2383,ftx,en;E15501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2382
S. Pulacchini et al.
SHORT PAPER
in procedure were in the reaction times, which were 5 days for 5a
and 5b and 10 days for 5c–5f.
Ts
Ts
Ts
N
N
N
N
(i)
N
1,3-Bis[N,N’-bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-1-
ylmethyl]benzene (5a)
The off white solid produced from the crude reaction mixture was
recrystallised from hot CH3CN to yield 5a as a white crystalline sol-
id (0.93 g, 76%); mp 192–194 °C.
Ts
N
Ts
Bn
N
4
OTs TsO
R
Ts
(ii)
3
N
N
IR: 1597, 1494, 1446, 1317 (SO2)NTs, 1148 (SO2)NTs, 1090, 950,
816, 710, 689 cm–1.
N
N
Ts
Ts
1H NMR: = 2.42 (s, 12 H, ArCH3), 3.00 (b s, 8 H, TsNCH2CH2N),
3.17 (bs, 8 H, TsNCH2CH2N), 3.50 (s, 8 H, TsNCH2CH2NTs), 3.76
(s, 4 H, NCH2Ar), 7.30 (m, 12 H, J = 8.3, CH2C6H4CH2 and
CH3CCH), 7.66 (d, 8 H, J = 8.3, SO2CCH).
5
Scheme Reagents and conditions: (i) BnNH2, CH3CN, K2CO3, 5
days, 70% (ii) NH2(R)NH2, CH3CN, K2CO3
13C NMR: = 21.48, 51.50, 52.51, 54.69, 61.00, 127.20, 127.88,
128.23, 129.75, 135.53, 139.03, 143.37.
als, however, the crude products of the reactions were
sufficiently pure for use in subsequent reactions.
MS m/z: 977 (100%) (M+H), 822 (60) (M+H–Ts), 665 (19) (M–H–
+
+
The remarkable efficiency of this reaction route towards
the direct synthesis of a range of binucleating triazacy-
clononane ligands 5a–f, has been clearly demonstrated. It
is hoped that this procedure will allow such ligands to be
readily prepared so that a thorough investigation of the
catalytic properties of their complexes can be undertaken.
Investigations along these lines are currently underway in
our laboratories.
2Ts), 539 (17) (C28H33N3O4S2 ), 450 (8) (C21H28N3O4S2 ), 385 (6)
(C21H27N3O2S+).
HRMS (m/z): calcd for C48H61N6O8S4, 977.3434; found, 977.3391.
Anal. Calcd for 5a H2 O, C48H62N6O9S4: C, 57.9; H, 6.3; N, 8.4.
Found: C, 58.2; H, 6.0; N, 8.4.
1,4-Bis[N,N’-bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-1-
ylmethyl]benzene (5b)
The off white solid produced from the crude reaction mixture was
recrystallised from hot CH3CN to yield 5b as a white crystalline sol-
id (0.81 g, 66%); mp 217–218 °C.
Table Binucleating ligands prepared by the Direct Reaction of Di-
amines with 3.
IR: 1597, 1451, 1324 (SO2)NTs, 1150 (SO2)NTs, 1088, 950, 812, 710,
689 cm–1.
1H NMR: = 2.40 (s, 12 H, ArCH3), 2.94 (bs, 8 H, TsNCH2CH2N),
3.11 (bs, 8 H, TsNCH2CH2N), 3.48 (s, 8 H, TsNCH2CH2TsN), 3.70
(s, 4 H, NCH2Ar), 7.28 (m, 12 H, J = 8.3, CH2C6H4CH2 and
CH3CCH), 7.64 (d, 8 H, J = 8.3, SO2CCH).
Entry
R
Time (d) Compound Yield
(mol%)
1
2
3
4
5
6
m-CH2C6H4CH2-
p-CH2C6H4CH2
(CH2)2
5
5
5a
5b
5c
5d
5e
5f
76
66
81
89
82
51
13C NMR: = 21.48, 51.43, 52.40, 54.75, 60.68, 127.19, 129.06,
129.75, 135.54, 138.11, 143.38.
10
10
10
10
(CH2)3
MS m/z: 977 (100%) (M+H), 822 (40) (M+H-Ts), 665 (15) (M+H-
+
+
2Ts), 540 (22) (C28H34N3O4S2 ), 450 (20) (C21H28N3O4S2 ), 385
(CH2)4
(72) (C21H27N3O2S+) .
CH2CH(OH)CH2
HRMS (m/z): calcd for C48H61N6O8S4, 977.3434.; found, 977.3391.
Anal. Calcd for C48H60N6O8S4: C, 59.0; H, 6.2; N, 8.6. Found: C,
58.6; H, 6.2; N, 8.4.
Reagents and solvents were standard grade commercial products
and were used without further purification unless otherwise stated.
Diamines were purified by distillation from KOH prior to use.
CH3CN was refluxed overnight with CaH2 in an atmosphere of ni-
trogen and then distilled from CaH2. Melting points were deter-
mined using an Electrothermal melting point apparatus and are
uncorrected. Elemental analyses were obtained using a Carlo Erba
1,2-Bis[N,N’- bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-
yl]ethane (5c)
To a stirred suspension of 3 (2.00 g, 2.60 mmol), potassium carbon-
ate (1.08 g, 7.80 mmol) in anhyd CH3CN (20 mL) was added ethyl-
enediamine (87 L, 1.30 mmol) dropwise under a N2 atmosphere.
The resultant mixture was heated at 85 °C under reflux for 10 d. The
inorganic salts were removed by filtration and the filtrate concen-
trated in vacuo to yield the crude product as an off-white solid
which was purified by column chromatography (ethyl acetate–pe-
troleum spirits b.p.40–60 °C, 2:1) to yield 5c (0.95 g, 81%);10 mp
250–252 °C.
1
1106 elemental analyser. H NMR and 13C NMR spectra were re-
corded as CDCl3 solutions on a JEOL JNM-EX spectrometer at 270
MHz and at 67.9 MHz respectively and were referenced to residual
CHCl3 as the internal standard. J values are given in Hertz. IR spec-
tra were recorded on a Perkin-Elmer 1720X FT-IR spectrometer
with a solid state ATR attachment. UV-Spectra were recorded on a
Hewlett-Packard 8453 diode array UV-vis spectrophotometer.
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).
IR: 1597, 1492, 1449, 1321 (SO2)NTs, 1149 (SO2)NTs, 1088, 961,
811, 709, 694 cm–1.
1H NMR: = 2.40 (s, 12 H, ArCH3), 2.71 (s, 4 H, NCH2CH2N), 2.92
(bs, 8 H, TsNCH2CH2N), 3.17 (bs, 8 H, TsNCH2CH2N), 3.47 (bs, 8
H, TsNCH2CH2TsN), 7.30 (d, 8 H, J = 8.3, CH3CCH), 7.64 (d, 8 H,
J = 8.3, SO2CCH).
All binucleating macrocyclic ligands were prepared in an identical
manner, which is typified by the synthesis of 5c. The only variations
13C NMR: = 21.49, 51.39, 52.61, 55.31, 55.69, 127.36, 129.79,
135.44, 143.41.
Synthesis 2001, No. 16, 2381–2383 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Binucleating 1,4,7-Triazacyclononane Ligands
2383
MS, m/z: 923 (6%) (M+Na), 901 (16) (M+H), 745 (6) (M–Ts), 464
(65) (C22H30N3O4S2 ), 450 (100) (C21H28N3O4S2 ), 294 (14),
(C14H20N3O2S+).
MS m/z: 1063 (47%) (M+Cs), 953 (54), (M+Na), 931 (59) (M+H),
775 (14) (M–Ts), 450 (100) (C21H28N3O4S2 ).
+
+
+
HRMS (m/z): calcd for C43H59N6O9S4,931.3226; found, 931.3250.
HRMS (m/z): calcd for C42H57N6O8S4, 901.3121; found, 901.3126.
Anal. Calcd for C43H58N6O9S4: C, 55.5; H, 6.3; N, 9.0. Found: C,
55.2; H, 6.4; N,8.7.
Anal. Calcd for: C, 56.0; H, 6.3; N, 9.3. Found: C, 56.2; H, 6.5; N,
9.0.
Acknowledgement
1,3-Bis [N, N’- bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-
yl]propane (5d)
We are grateful to the following bodies for financial support: EPS-
RC (CASE awards for New Academics, Award 00800316, KS),
Queen Mary, University of London for the provision of a stu-
dentship (SP), The Royal Society, The Nuffield Foundation, The
University of London Central Research Fund and Warwick Interna-
tional Limited.
The crude reaction mixture was purified by column chromatogra-
phy (Et2O–CH2Cl2, 2:1) to yield 5d (1.01 g, 89%) as a white crys-
talline solid;10 mp 144–146 °C.
IR: 1597, 1492, 1448, 1327 (SO2)NTs, 1152 (SO2)NTs, 1088, 976,
814, 711, 690 cm–1.
1H NMR: =1.65 (br, 2 H, NCH2CH2CH2N), 2.40 (s, 12 H, ArCH3),
2.58 (t, 4 H, J = 7.0, NCH2CH2CH2N), 2.85 (s, 8 H, TsNCH2CH2N),
3.16 (s, 8 H, TsNCH2CH2N), 3.46 (s, 8H, TsNCH2CH2TsN), 7.28
(d, 8 H, J = 8.3, CH3CCH), 7.64 (d, 8 H, J = 8.3, SO2CCH).
13C NMR: = 21.46, 26.23, 51.54, 52.69, 55.46, 55.83, 127.22,
129.77, 135.47, 143.34.
References
(1) Present address: Associated Octel, Oil Sites Road, Ellesmere
Port, Merseyside, U.K.
(2) Wainwright, K. P. Coord. Chem. Rev. 1997, 166, 35.
(3) (a) Sessler, J. L.; Sibert, J. W.; Lynch, L.; Markert, J. T.;
Wooten, C. L. Inorg. Chem. 1993, 32, 621. (b) Brudenell,
S. J.; Spiccia, L.; Bond, A. M.; Fallon, G. D.; Hockless, D.
C. R.; Lazarev, G.; Mahon, P. J.; Tiekink, E. R. T. Inorg.
Chem. 2000, 39, 881.
MS m/z: 937 (16%) (M+Na), 915 (54), (M+H), 760 (23) (M–Ts),
+
+
478 (17) (C23H32N3O4S2 ), 464 (7) (C22H30N3O4S2 ), 450 (100)
+
(C21H28N3O4S2 ), 296 (28), (C14H22N3O2S+).
HRMS (m/z): calcd for C43H59N6O8S4, 915.3277; found, 915.3301.
(4) Hage, R.; Iburg, J. E.; Kerschner, J.; Koek, J. H.; Lempers,
E. L. M.; Martens, R. J.; Racherla, U. S.; Russell, S. W.;
Swarthoff, T.; van Vliet, M. R. P.; Warnaar, J. B.; van der
Wolf, L.; Krijnen, B. Nature 1994, 369, 637.
Anal. Calcd for 5d H2O, C43H60N6O9S4: C, 55.3; H, 6.4; N, 9.0.
Found: C, 55.4; H, 6.2; N, 8.7.
1,4-Bis [N, N’- bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-
yl]butane (5e)
The crude reaction mixture was recrystallised from hot EtOH to
yield 5e (0.61 g, 82%).
(5) See for example (a) De Vos, D.; Bein, T. Chem. Commun.
1996, 917. (b) Zondervan, C.; Hage, R.; Feringa, B. L.
Chem. Commun. 1997, 419. (c) De Vos, D. E.; Sels, B. F.;
Reynaers, M.; Subba Rao, Y. V.; Jacobs, P. A. Tetrahedron
Lett. 1998, 3221. (d) Barton, D. H. R.; Li, W.; Smith, J. A.
Tetrahedron Lett. 1998, 39, 7055. (e) Shul’pin, G. B.; Süss-
Fink, G.; Lindsay Smith, J. R. Tetrahedron 1999, 55, 5345.
(6) (a) Young, M. J.; Chin, J. J. Am. Chem. Soc. 1995, 117,
10577. (b) Hegg, E. L.; Burstyn, J. N. Inorg. Chem. 1996,
35, 7474. (c) McCue, K. P.; Voss, D. A.; Marks, C.;
Morrow, J. R. J. Chem. Soc., Dalton Trans. 1998, 2961.
(7) (a) De Vos, D. E.; Meinershagen, J. L.; Bein, T. Angew.
Chem. Int. Ed. Engl. 1996, 35, 2211. (b) Gilbert, B. C.;
Kamp, N. W. J.; Lindsay Smith, J. R.; Oakes, J. J. Chem.
Soc., Perkin Trans 2. 1997, 2161. (c) De Vos, D. E.; de
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Angew. Chem. Int. Ed. 1999, 38, 980.
(8) (a) Weisman, G. R.; Vachon, D. J.; Johnson, V. B.;
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(b) Sessler, J. L.; Sibert, J. W.; Lynch, V. Inorg. Chem. 1990,
29, 4143. (c) Blake, A. J.; Danks, J. P.; Li, W.-S.; Lippolis,
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for publication.
IR: 1597, 1492, 1448, 1328 (SO2)NTs, 1151 (SO2)NTs, 1088, 979,
814, 711, 691 cm–1.
Mp, 1H NMR and 13C NMR spectra were consistent with the report-
ed data.8b
MS m/z: 929 (15%) (M+H), 774 (16), (M+H–Ts), 490 (100),
+
+
(C24H32N3O4S2 ),
478
(7)
(C23H32N3O4S2 ),
464
(5)
+
(C22H30N3O4S2 ).
HRMS (m/z): calcd for C44H61N6O8S4, 929.3434; found, 929.3475.
1,3-Bis [N, N’- bis(p-toluenesulfonyl)-1,4,7-triaza-1-cyclonon-
yl]propan-2-ol (5f)
The crude reaction mixture was purified by column chromatogra-
phy (EtOAc– petroleum spirits, b.p. 40–60 °C, 2:1) to yield 5f (0.58
g, 51%); mp 105 °C.
IR: 1597, 1492, 1450, 1350 (SO2)NTs, 1149 (SO2)NTs, 1088, 982,
813, 710, 689 cm–1.
1H NMR: = 2.39 (s, 12 H, ArCH3), 2.59 (dd, 2 H, J = 12.9 and 8.2,
NHCHCHOH), 2.73 (dd, 2 H, J = 12.9 and 2.5, NHCHCHOH),
3.00 (bs, 8 H, NCH2CH2NTs), 3.23 (bs, 8 H, NCH2CH2NTs), 3.45
(bs, 8 H, TsNCH2CH2NTs), 3.75 (bm, 1 H, CH2CHOHCH2), 7.28
(d, 4 H, J = 8.3, CH3CH), 7.64 (d, 4 H, J = 8.3, SO2CCH).
(10) Wieghardt K., Tolksdorf I., Herrmann W.; Inorg. Chem.;
1985, 24: 1230-1235; the original report of these compounds
provides no experimental data and indicates that the
compounds contain impurities as judged by 13C NMR.
(11) Sessler, J. L.; Sibert, J. W.; Burrell, A. K.; Lynch, V.;
Markert, J. T.; Wooten, C. L. Inorg. Chem. 1993, 32, 4277.
13C NMR were consistent with the reported data.11
Synthesis 2001, No. 16, 2381–2383 ISSN 0039-7881 © Thieme Stuttgart · New York