An efficient route to symmetrically and unsymmetrically substituted azamacrocyclic ligands

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4233::AID-EJOC4233>3.0.CO;2-L

An extremely efficient cyclisation protocol has been developed for the synthesis of symmetrically (6) and unsymmetrically substituted (7) derivatives of 1,4,7-triazacyclononane (2). The optimised conditions can be successfully applied to the synthesis of larger macrocycles 15a and 18a. In contrast, the protocol is not generally applicable with benzylamine, and the cyclic carbamates 16 and 19, rather than larger azamacrocycles, are formed, indicating that cyclisation in CH₃CN using K₂CO₃ is highly specific to the formation of 7.

Full text of DOI:10.1002/1099-0690(200111)2001:22<4233::AID-EJOC4233>3.0.CO;2-L

FULL PAPER
An Efficient Route to Symmetrically and Unsymmetrically Substituted
Azamacrocyclic Ligands
Sonia Pulacchini[a] and Michael Watkinson*[a]
Keywords: Macrocycles / Aza compounds / Polyazacycloalkanes / Nitrogen heterocycles
An extremely efficient cyclisation protocol has been de-
veloped for the synthesis of symmetrically (6) and unsymmet-
the protocol is not generally applicable with benzylamine,
and the cyclic carbamates 16 and 19, rather than larger aza-
rically substituted (7) derivatives of 1,4,7-triazacyclononane macrocycles, are formed, indicating that cyclisation in
(2). The optimised conditions can be successfully applied to
the synthesis of larger macrocycles 15a and 18a. In contrast,
CH3CN using K2CO3 is highly specific to the formation of 7.
Introduction
The synthesis and application of N-functionalised nitro-
gen macrocycles continues to be an area of considerable
interest.[1,2] This is due to the diverse array of properties
that their metal complexes have found; for example, in coor-
dination chemistry,[3] catalysis,[4] and medical applica-
tions.[5] Although such ligands are known, their syntheses
are not always trivial, as they frequently rely on statistical
reactions and the separation of complex reaction mixtures.
In addition, the preparation of suitable open-chain starting
materials can often be more difficult than the subsequent
cyclisation reactions, as has recently been noted.[6] Arguably
the greatest success in this diverse area has been achieved in
the selective alkylation of tetraazamacrocycles, particularly
cyclen (1), through judicious control of reaction conditions
such as pH.[7,8] Considerably less success has been achieved
with the related triazamacrocycles, particularly 1,4,7-triaza-
cyclononane (2). Several procedures have been reported
based on the statistical alkylation of the free macrocy-
cle,[9,10] dialkylation of the mono-tosylamide[4,11,12] or deri-
vitisation of the orthoamide 3.[13Ϫ15] Although successful,
we felt that a more appealing strategy would be to use a
cyclisation protocol that would lead directly to the desired
substitution pattern in the macrocyclic ring, rather than
these reported procedures.
Scheme 1. Reagents and conditions: (i) ethylene carbonate, K2CO3,
DMF, 94%; (ii) TsCl, Et3N, DMAP(cat), CH2Cl2, 88%; (iii) TsNH2,
K2CO3, CH3CN, 97%
the desired macrocycle, 6, in acceptable yield, although it
was contaminated with other unidentified side products
(Scheme 1). This was not much improved by the use of
K2CO3 in the same solvent, which gave an isolated yield
of the macrocycle of 52%, after flash chromatography. The
synthetic route proved to be incredibly efficient, however,
when the solvent was changed to acetonitrile, with 6 being
1
formed quantitatively as judged by H NMR spectroscopy.
Simple filtration followed by crystallisation from ethanol
led to analytically pure 6 in 97% yield. The advantages of
this protocol lie in the clean reaction and the ease of
workup when acetonitrile is used rather than DMF. This
appears to be one of the most efficient methods that has
been reported for the synthesis of 6 with an overall yield of
80% in four steps.
The analogous reaction using benzylamine was less
straightforward (Scheme 2). The attempted displacement
and cyclisation of 5b with benzylamine in DMF gave, in
addition to small quantities of the desired unsymmetrically
substituted macrocycle 7a, a number of other identifiable
materials, 5a and 8, 9a, 10 and 11, in varying quantities.
These materials were always isolated no matter what efforts
were made to dry the solvent.[17] The formation of all of
these materials can be readily rationalised as there is pre-
cedent for the formation of analogous species; however, we
are not aware of any reports of them being formed in such
significant quantities under such standard reaction condi-
tions for the formation of azamacrocycles. We have been
unable to prevent hydrolysis reactions occurring under these
reaction conditions and, as a consequence, 5a is always
formed. The formation of enamines 8 and 9a presumably
Results and Discussion
By adapting reported procedures that use Cs2CO3 as the
base in DMF,[16] cyclisation of tosylamide with 5b produced
[a]
Department of Chemistry, Queen Mary, University of London,
Mile End Road, London, E1 4NS, UK
E-mail m.watkinson@qmul.ac.uk
Eur. J. Org. Chem. 2001, 4233Ϫ4238
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/1122Ϫ4233 $ 17.50ϩ.50/0
4233

S. Pulacchini, M. Watkinson
FULL PAPER
Following the effectiveness of the combination of aceton-
itrile and K2CO3 for the formation of 6 we investigated
whether a similarly favourable improvement for the syn-
1
thesis of 7a might be observed. To our delight a H NMR
spectrum of the crude reaction mixture indicated that 7a
had been produced exclusively and could be readily purified
by crystallisation from ethanol in 70% yield. The benzyl-
protected amine in 7a was readily deprotected under stand-
ard conditions[6,24] to yield the required unsymmetrically
substituted derivative 7b in high yield. Solvent purity ap-
pears to be the key to this reaction; no sign of any of the
previous unwanted side-products 5a or 8؊11 were observed
with freshly distilled dry acetonitrile.
We were interested to see whether this route could be
extended to larger macrocyclic rings and investigated the
synthesis of other N3 and N4 azamacrocycles using these
optimised conditions (Scheme 4). The tosylamides 14[25]
Scheme 2. Reagents and conditions: (i) BnNH2, K2CO3, CH3CN,
70%; (ii) Pd/C, H2, AcOH, 96%; (iii) BnNH2, M2CO3 (M ϭ K or
Cs), DMF
results from competitive elimination and hydrolysis reac-
tions of 5b,[18] and the formation of species like 10 and 11
by the known reaction of amine nucleophiles with
carbonate.[19Ϫ22] Similarly, when K2CO3 was used in DMF
the same materials could be identified. We are confident
that the structure is 9a rather than the similar amine 9b,[23]
confirmation of which came from the intramolecular cyclis-
ation of 9a to hemiaminal 12. We were keen to further sub-
stantiate our proposal that the cyclisation reaction proceeds
via a mechanism involving general acid catalysis. Isotopic
studies into the intramolecular cyclisation of enamine 9a in
the presence of Dϩ did lend support to our previous pro-
posal that the cyclisation reaction proceeds via the iminium
ion 13a, as shown in Scheme 3. The quadruplet of the
CHCH3 for hemiaminal 12 in the 1H NMR spectrum
rapidly became extremely complex on addition of Dϩ, sug-
gesting that a number of species were formed. Multiple in-
corporation of deuterium in 12aϪc was confirmed by high
resolution mass spectrometry, and this presumably results
from the reversible addition of Dϩ to enamine 9a prior to
the cyclisation step as shown.
Scheme 4. Investigations into the synthesis of larger N3- and N4-
azamacrocycles
Scheme 3. Proposed mechanism to account for the multiple incorporation of deuterium during the cyclisation of 9a to 12
4234 Eur. J. Org. Chem. 2001, 4233Ϫ4238

An Efficient Route to Substituted Azamacrocyclic Ligands
FULL PAPER
and 17[26] were prepared as reported and then reacted with
tosylamide or benzylamine. Cyclisation reactions using tos-
ylamide proved to be incredibly efficient for both the 10-
Conclusion
We have developed an incredibly efficient cyclisation pro-
membered N3-macrocycle 15a[27] and the cyclen derivative cedure for the synthesis of symmetrically (6) and unsym-
18a,[28] which were both isolated in 95% yield. Unfortu- metrically substituted (7) nine-membered azamacrocycles. It
nately, when the analogous reactions were investigated with appears that the reaction conditions can be readily applied
benzylamine the results were less impressive. For the reac- to the preparation of larger macrocyclic rings when tosyla-
tion with 14 the macrocycle 15b[29] could be isolated by col- mide is used in the ring closing step. However, when benzyl-
umn chromatography in low yield. In addition, other insep- amine is used, the reaction proves to be highly sensitive to
arable side products were present, one of which we believe the size of the macrocyclic ring, with nine-membered rings
to be the carbamate 16 (HRMS gives M ϩ Hϩ 586.2063, being highly favoured. When attempts are made to increase
ϩ
C29H36N3O6S2 requires 586.2046). For the analogous re- the ring size by even a single CH2 unit, the yield of the
action with 17, none of the desired N4-macrocycle 18b[30] desired macrocycle is reduced to 25%.
could be obtained. However, carbamate 19 was isolated in
63% yield. It seems clear from these results that the cyclis-
Experimental Section
ation protocol developed for benzylamine is specific to the
synthesis of the unsymmetrically substituted nine-mem-
bered macrocycle 7a.
General Remarks: All reagents were purchased from either Aldrich
or Lancaster and were used without further purification unless
otherwise stated. For high yielding and efficient cyclisation reac-
tions it is essential that both DMF and acetonitrile are dry and
freshly distilled. DMF was refluxed overnight with triphenylchloro-
In view of the adventitious hydrolysis reactions that per-
sistently occurred in DMF, despite extensive efforts to pre-
vent them, we wondered whether it might be possible to use
this to our advantage and develop a direct route to 7b. We
thus investigated whether the phthalimide lone pair in 20
might be sufficiently nucleophilic to undergo the desired
cyclisation step; facile hydrolysis would then give 7b directly
(Scheme 5). Potassium phthalimide was thus reacted with
5b in DMF. The desired reaction did not occur, although
we were rather surprised to find that not only was the pre-
dictable substitution product 22 produced, but that other
unexpected materials (23 and 25) were also isolated. The
complex reaction mixture was extremely difficult to separ-
ate by column chromatography and 23 and 25 were largely
inseparable. However, by converting 23 to 24 (and 25 to
5a) they could be unambiguously identified. Although it is
known that formates can be formed from tosylates in DMF,
these reports are largely isolated to steroid chemistry.[31]
Furthermore we have never observed the formation of
formates in any other reactions performed in DMF in the
absence of phthalimide. We therefore believe that phthalim-
ide is integral to the formation of the formate, and investi-
gations into its role are currently underway in our laborat-
ories.
˚
silane in an atmosphere of nitrogen and then distilled from 4 A
molecular sieves under reduced pressure. CH3CN was refluxed
overnight with CaH2 in an atmosphere of nitrogen and then dis-
tilled from CaH2. Benzylamine was dried over KOH pellets prior
to use. Nitrogen for inert atmosphere use was purified by passing
˚
it through anhydrous manganese(II) oxide, 3 A molecular sieves
and highly reduced chromium adsorbed onto a silica support. Thin
layer chromatography (TLC) was performed on either silica gel 60
F254 plates (Merck) or neutral aluminium oxide 60 F254150 plates
(Merck). Flash chromatography was performed on either silica gel
60 F254, 230Ϫ400 mesh (Merck) or neutral aluminium oxide 60
F254 (Merck). Melting points were determined using an Electro-
thermal melting point apparatus and are uncorrected. Elemental
analyses were obtained using a Carlo Erba 1106 elemental analyser.
1H and 13C NMR spectra were recorded as CDCl3 solutions on a
JEOL JNM-EX spectrometer at 270 MHz and at 67.9 MHz re-
spectively, unless otherwise stated, and were referenced to residual
CHCl3 as the internal standard. J values are given in Hertz. IR
spectra were recorded on a PerkinϪElmer 1720X FT-IR spectro-
meter with a solid state ATR attachment. UV spectra were re-
corded on a HewlettϪPackard 8453 diode array UV/Vis spectro-
photometer. Mass spectra were recorded on a VG Instruments
ZAB-SE using xenon gas at 8 kV in a matrix of 3-nitrobenzyl alco-
hol (MNBA) and sodium iodide (FAB) or on a V.G. BIO-Q instru-
ment (CI, NH3).
Tosylamide 4 was prepared as previously reported.[27] The macro-
cyclic precursors 5,[29] 14[25] and 17[26] have previously been re-
ported although the procedure described herein is considerably
more efficient, particularly for 5. These were prepared in an ident-
ical manner that is typified by the preparation of 5a and 5b. Com-
pounds 6,[27] 15a,[27] 15b,[6] 18a[27] and 18b[30] were checked for their
integrity by comparison with the data which have previously been
reported. Analytical data are presented for any compound for
which incomplete characterization was originally reported.
3,6-Di(tosyl)-3,6-diazaoctane-1,8-diol (5a): A solution of 4 (40.00 g,
108.6 mmol), ethylene carbonate (38.24 g, 434.2 mmol) and potas-
sium carbonate (33.01 g, 238.8 mmol) in DMF (220 cm3) was
heated at reflux overnight. After cooling to room temperature, the
solvent was evaporated under reduced pressure and the yellow solid
Scheme 5. Reagents and conditions: (i) KNPhth, DMF; (ii) KOH,
MeOH
Eur. J. Org. Chem. 2001, 4233Ϫ4238
4235

S. Pulacchini, M. Watkinson
FULL PAPER
obtained triturated with distilled water (200 cm3). The white pow-
372 (74) [Mϩ Ϫ Ts], 216 (100). Ϫ HRMS: calcd. for C27H34N3O4S2
der that formed was separated by filtration and recrystallised from 528.1991; found 528.1982 [M ϩ Hϩ]. ϪC27H33N3O4S2 (527.70):
boiling ethanol to yield 5a as white crystals (46.6 g, 94%). m.p.
153Ϫ155 °C. H NMR: δ ϭ 2.42 (s, 6 H, Ar-CH3), 2.94 (br. s, 2 S 11.9.
H, OH), 3.23 (t, J ϭ 5.0 Hz, 4 H, TsN-CH2-CH2-OH), 3.39 (s, 4
calcd. C 61.4, H 6.3, N 7.9, S 12.1; found C 61.1, H 6.4, N 7.7,
1
1,4-Di(tosyl)-1,4,7-triazacyclononane
(7b):
Pd/C
(41 mg,
H, TsN-CH2-CH2-NTs), 3.80 (t, J ϭ 5.0 Hz, 4 H, CH2-OH), 7.30
(d, J ϭ 8.5 Hz, 4 H, CH3CC-H), 7.70 (d, J ϭ 8.5 Hz, 4 H, SO2CC-
H). Ϫ 13C NMR: δ ϭ 21.5 (2 ϫ s), 50.3 (2 ϫ d), 53.1 (2 ϫ d), 61.0
(2 ϫ d), 127.3 (4 ϫ t), 129.8 (4 ϫ t), 134.9 (2 ϫ q), 143.8 (2 ϫ q).
Ϫ IR: ν˜max ϭ 3345 (OH), 1326 (SO2), 1146 (SO2) cmϪ1. Ϫ MS
(FAB): m/z (%) ϭ 589 (26) [M ϩ Csϩ], 479 (80) [M ϩ Naϩ], 457
(80) [M ϩ Hϩ], 439 (10) [Mϩ Ϫ OH], 286 (100). Ϫ HRMS: calcd.
for C20H29N2O6S2 457.1467; found 457.1481 [M ϩ Hϩ]. Ϫ
C20H28N2O6S2 (456.58): calcd. C 52.6, H 6.2, N 6.1; found C 52.8,
H 6.3, N 6.3.
0.038 mmol) was added to a solution of 7a (101 mg, 0.19 mmol) in
glacial acetic acid (5 cm3) and the atmosphere saturated with hydro-
gen. The mixture was stirred at room temperature overnight. The
reaction mixture was filtered through a Celite pad which was then
washed with methanol (5 cm3) and ethyl acetate (5 cm3). The fil-
trate was concentrated under reduced pressure and the yellow solid
obtained was dissolved in CHCl3 (10 cm3) and stirred vigorously
with a 10% solution of NaOH (10 cm3). After 1 hour the two layers
were separated and the aqueous layer extracted with CHCl3 (3 ϫ
5 cm3). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure to give 7b (80 mg, 96%) as a
white solid whose analytical data were consistent with the re-
ported data.[32]
3,6-Di(tosyl)-3,6-diazaoctane-1,8-di(toluene-4-sulfonate) (5b): A so-
lution of 5a (38.68 g, 84.71 mmol), p-toluenesulfonyl chloride
(35.53 g, 186.37 mmol), triethylamine (28.40 mL, 203.31 mmol)
and DMAP (103 mg, 0.85 mmol) in CH2Cl2 (1000 cm3) was stirred
at room temperature for 24 hours. The solvent was evaporated un-
der reduced pressure and the yellow solid obtained triturated with
a 10% solution of HCl (400 cm3). The solid was collected by filtra-
tion, washed with distilled water and purified by crystallisation
from hot ethanol to give 5b as white crystals (57.03 g, 88%). m.p.
Alternative Procedure for the Synthesis of 7a: A solution of 5b
(1.00 g, 1.30 mmol), benzylamine (157 µL, 1.43 mmol) and cesium
carbonate (940 mg, 2.86 mmol) in dry DMF (15 cm3) was stirred
at reflux under an atmosphere of nitrogen for six days. After cool-
ing to room temperature, the inorganic salts were removed by filtra-
tion and the filtrate evaporated under reduced pressure to leave a
yellow solid which was purified by column chromatography on sil-
ica gel [petroleum ether (40:60)/ethyl acetate, 3:1] to give 7a (20 mg,
3%) as a white solid. In addition to 7a the following compounds
could also be isolated: 5a (160 mg, 28%), 8 (20 mg, 2%), 9a (60 mg,
11%), 10 (200 mg, 27%), 11 (traces)[33,34] and 12 (90 mg, 15%).
1
144Ϫ146 °C. Ϫ H NMR: δ ϭ 2.44 (s, 12 H, Ar-CH3), 3.30 (s, 4
H, TsN-CH2-CH2-NTs), 3.35 (t, J ϭ 5.3 Hz, 4 H, TsN-CH2-CH2-
OTs), 4.13 (t, J ϭ 5.2 Hz, 4 H, TsN-CH2-CH2-OTs), 7.33 (d, J ϭ
8.3 Hz, 8 H, CH3CCH), 7.71 (d, J ϭ 8.3 Hz, 4 H, SO2CCH), 7.76
(d, J ϭ 8.3 Hz, 4 H, SO2CCH). Ϫ 13C NMR: δ ϭ 21.5 (2 ϫ s),
21.6 (2 ϫ s), 49.4 (2 ϫ d), 49.8 (2 ϫ d), 69.0 (2 ϫ d), 127.4 (4 ϫ
t), 128.0 (4 ϫ t), 130.0 (8 ϫ t), 132.3 (2 ϫ q), 134.9 (2 ϫ q), 144.0
3,6-Di(tosyl)-3,6-diaza-1,7-octadiene (8): The dielimination product
8 could also be prepared directly: Potassium tert-butoxide (322 mg,
2.87 mmol) was added to a solution of 5b (1.00 g, 1.31 mmol) in
DMF (20 cm3) and the resultant mixture was stirred at 100 °C
under an atmosphere of nitrogen for 20 hours. After cooling to
room temperature, the solvent was evaporated. The yellow solid
obtained was dissolved in CH2Cl2 (20 cm3) and washed with a 10%
solution of HCl (20 cm3). The aqueous layer was extracted with
CH2Cl2 (3 ϫ 15 cm3). The combined organic layers were dried over
MgSO4 and concentrated. The solid obtained was recrystallised
from ethyl acetate to give 8 as white crystals (510 mg, 93%). m.p.
˜
(2 ϫ q), 145.2 (2 ϫ q). Ϫ IR: νmax ϭ 1355 (OSO2), 1326 (NSO2),
1173 (OSO2), 1149 (NSO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 897
(100) [M ϩ Csϩ], 787 (28) [M ϩ Naϩ], 765 (34) [M ϩ Hϩ], 593
(53) [Mϩ Ϫ OTs]. Ϫ HRMS: calcd. for C34H41N2O10S2 765.1644;
found 765.1674 [M ϩ Hϩ]. Ϫ C34H40N2O10S4 (764.95): calcd. C
53.4, H 5.3, N 3.7; found C 53.4, H 5.6, N 3.1.
1,4,7-Tri(tosyl)-1,4,7-triazacyclononane (6):
A solution of 5b
(1.00 g, 1.30 mmol), tosylamide (0.25 g, 1.43 mmol) and potassium
carbonate (396 mg, 2.87 mmol) in dry acetonitrile (15 cm3) was
stirred at reflux under an atmosphere of nitrogen for six days. After
cooling to room temperature, the inorganic salts were removed by
filtration and the filtrate evaporated under reduced pressure to
leave a white powder. This was purified by crystallisation from hot
ethanol to give 6 as white crystals (750 mg, 97%).
1
184Ϫ186 °C. Ϫ H NMR: δ ϭ 2.42 (s, 6 H, ArCH3), 3.51 (s, 4 H,
TsNCH2), 4.40 (dd, J ϭ 9.3, 1.8 Hz, 2 H, TsN-CHϭCHcis), 4.58
(dd, J ϭ 15.7, 1.8 Hz, 2 H, TsN-CHϭCHtrans), 6.88 (dd, J ϭ 15.7,
9.3 Hz, 2 H, TsN-CHϭC), 7.30 (d, J ϭ 8.3 Hz, 4 H, CH3CCH),
7.64 (d, J ϭ 8.3 Hz, 4 H, SO2CCH). Ϫ 13C NMR: δ ϭ 21.5 (2 ϫ
s), 41.4 (2 ϫ d), 92.7 (2 ϫ d), 126.8 (4 ϫ t), 129.9 (4 ϫ t), 131.6 (2
1-Benzyl-4,7-di(tosyl)-1,4,7-triazacyclononane (7a): A solution of 5b
(1.00 g, 1.30 mmol), benzylamine (157 µL, 1.43 mmol) and potas-
sium carbonate (396 mg, 2.87 mmol) in dry acetonitrile (15 cm3)
was stirred at reflux under an atmosphere of nitrogen for six days.
After cooling to room temperature, the inorganic salts were re-
moved by filtration and the filtrate evaporated under reduced pres-
sure to leave a white powder. This was purified by crystallisation
˜
ϫ t), 135.5 (2 ϫ q), 144.1 (2 ϫ q). Ϫ IR: νmax ϭ 1624 (CϭC), 1352
(SO2), 1152 (SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 443 (10) [M ϩ
Naϩ], 421 (90) [M ϩ Hϩ], 265 (100) [Mϩ Ϫ Ts]. Ϫ HRMS calcd.
for C20H25N2O4S2 421.1243; found 421.1256 [M ϩ Hϩ]. Ϫ
C20H24N2O4S2 (420.55): calcd. C 57.1, H 5.8, N 6.7; found C 57.8,
H 6.0, N 6.7.
from hot ethanol to give 7a as white crystals (480 mg, 70%). m.p.
1
1
149Ϫ151 °C. Ϫ H NMR: δ ϭ 2.36 (s, 6 H, ArCH3), 3.09 (br. m, 3,6-Di(tosyl)-3,6-diaza-8-octen-1-ol (9): H NMR: δ ϭ 2.43 (s, 6 H,
4 H, TsNCH2CH2NBn), 3.20 (br. m, 4 H, TsNCH2CH2NBn), 3.42
ArCH3), 3.12Ϫ3.40 (m, 4 H, TsNCH2CH2NTs), 3.52Ϫ3.67 (m, 2
(s, 4 H, TsNCH2CH2NTs), 3.71 (s, 2 H, NCH2Ph), 7.16Ϫ7.31 (m, H, TsNCH2CH2OH), 3.79 (t, J ϭ 5.1 Hz, 2 H, CH2OH), 4.39 (dd,
9 H, Ar-H), 7.59 (d, J ϭ 8.3 Hz, 4 H, SO2CCH). Ϫ 13C NMR δ ϭ J ϭ 9.3, 1.8 Hz, 1 H, TsNCHϭCHcis), 4.58 (dd, J ϭ 15.7, 1.8 Hz,
21.5 (2 ϫ s), 51.5 (2 ϫ d), 52.4 (2 ϫ d), 54.6 (2 ϫ d), 62.0 (d), 1 H, TsNCHϭCHtrans), 6.87 (dd, J ϭ 15.7, 9.3 Hz, 1 H, TsNCHϭ
127.1 (5 ϫ t), 128.3 (2 ϫ t), 129.1 (2 ϫ t), 129.7 (4 ϫ t), 135.3 (2 CH2), 7.26Ϫ7.42 (m, 4 H, Ar-H), 7.51Ϫ7.79 (m, 4 H, Ar-H). Ϫ13C
ϫ q), 139.5 (q), 143.4 (2 ϫ q). Ϫ UV/Vis (CH2Cl2): λmax (ε) ϭ
NMR: δ ϭ 21.6 (2 ϫ s), 44.4 (d), 47.6 (d), 53.0 (d), 61.3 (d), 92.3
232 nm (24800). Ϫ IR: ν˜max ϭ 1339 (SO2), 1153 (SO2) cmϪ1. Ϫ (d), 126.9 (2 ϫ t), 127.3 (2 ϫ t), 129.9 (2 ϫ t), 130.0 (2 ϫ t), 131.8
MS (FAB): m/z (%) ϭ 550 (11) [M ϩ Naϩ], 528 (62) [M ϩ Hϩ], (t), 135.1 (q), 135.4 (q), 143.9 (q), 144.2 (q). Ϫ IR: νmax ϭ 3317
˜
4236
Eur. J. Org. Chem. 2001, 4233Ϫ4238

An Efficient Route to Substituted Azamacrocyclic Ligands
FULL PAPER
(OH), 1623 (CϭC), 1334 (SO2), 1153 (SO2) cmϪ1. Ϫ MS (FAB): boiling solution of 5b (1.00 g, 1.30 mmol) in DMF (150 cm3) under
m/z (%) ϭ 461 (100) [M ϩ Naϩ], 439 (47) [M ϩ Hϩ]. Ϫ HRMS: nitrogen. The mixture was stirred at reflux for 3 days and, after
calcd. for C20H26N2NaO5S2 461.1181; found 461.1169 [M ϩ Naϩ].
3-Benzyl-6,9-di(tosyl)-1-oxa-3,6,9-triazacycloundecan-2-one (10):
cooling to room temperature, the solvent was evaporated. The res-
idue was dissolved in CH2Cl2 (50 cm3) and washed with a 10%
solution of hydrochloric acid (50 cm3). The aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 30 cm3) and the combined organic layers
were dried over MgSO4 and concentrated. The crude material was
purified by column chromatography on silica gel [petroleum ether
(40:60)/ethyl acetate, 3:2] to yield 22 (130 mg, 14%), 23 (160 mg,
23%), 25 (20 mg, 5%), and unchanged 5b (300 mg, 30%). Amide 23
could not be separated from 25 by column chromatography, al-
though early fractions did contain pure 25. The signals due to 23
could be identified by elimination of signals due to 25 from the
spectra of the mixture. Moreover the structural integrity of 23 was
further clarified by hydrolysis to produce 24 which was readily sep-
arable by column chromatography from 5a (produced by hydrolysis
of 25).
M.p. 117Ϫ118 °C. Ϫ 1H NMR: δ ϭ 2.45 (s, 6 H, ArCH3),
2.98Ϫ3.22 (s, 2 H, BnNCH2), 3.27Ϫ3.61 (m, 8 H, CH2NTs),
4.30Ϫ4.48 (m, 2 H, CH2OCO), 4.56 (br. s, 2 H, NCH2Ph),
7.30Ϫ7.52 (m, 9 H, Ar-H), 7.66Ϫ7.73 (m, 4 H, Ar-H). Ϫ 13C
NMR: δ ϭ 21.5 (2 ϫ s), 42.6 (d), 48.0 (d), 49.0 (d), 49.9 (d), 51.1
(d), 53.2 (d), 65.7 (d), 127.1 (2 ϫ t), 127.5 (2 ϫ t), 127.6 (2 ϫ t),
128.0 (2 ϫ t), 128.7 (2 ϫ t), 129.9 (t), 129.9 (2 ϫ t), 133.7 (q), 135.1
˜
(q), 136.8 (q), 143.8 (q), 143.9 (q), 155.6 (q). Ϫ IR: νmax ϭ 1698
(CϭO), 1333 (SO2), 1155 (SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ
594 (71) [M ϩ Naϩ], 572 (100) [M ϩ Hϩ], 416 (59) [Mϩ Ϫ Ts].
Ϫ HRMS: calcd. for C28H34N3O6S2 572.1889; found 572.1869 [M
ϩ Hϩ].
2-Methyl-3,6-di(tosyl)-1-oxa-3,6-diazacyclooctane
(12):
M.p.
3,6-Di(tosyl)-3,6-diazaoctane-1,8-diphthalimide (22): M.p. 210Ϫ211
°C. Ϫ1H NMR: δ ϭ 2.36 (s, 6 H, ArCH3), 3.43 (t, J ϭ 5.5 Hz, 4
H, TsNCH2CH2NPhth), 3.61 (s, 4 H, TsNCH2CH2NTs), 3.94 (t,
J ϭ 5.5 Hz, 4 H, TsNCH2CH2NPhth), 7.25 (d, J ϭ 8.9 Hz, 4 H,
Ar-H), 7.68Ϫ7.95 (m, 12 H, Ar-H). Ϫ 13C NMR: δ ϭ 21.5 (2 ϫ
s), 36.7 (2 ϫ d), 48.2 (2 ϫ d), 49.3 (2 ϫ d), 123.3 (4 ϫ t), 127.4 (4
ϫ t), 129.8 (2 ϫ q, 4 ϫ t), 132.0 (2 ϫ q), 133.9 (4 ϫ t), 135.2 (2 ϫ
124Ϫ127 °C. Ϫ1H NMR: δ ϭ 1.01 (d, J ϭ 5.8 Hz, 3 H, CHCH3),
2.42 (s, 6 H, ArCH3), 3.14Ϫ3.50 (m, 4 H, CH2), 3.56Ϫ3.80 (m, 3
H), 3.87Ϫ4.06 (m, 1 H), 5.26 (q, J ϭ 5.8 Hz, 1 H, CHCH3), 7.30 (d,
J ϭ 7.9 Hz, 4 H, CH3CCH), 7.68 (d, J ϭ 8.1 Hz, 4 H, SO2CCH). Ϫ
13C NMR: δ ϭ 18.6 (s), 21.5 (2 ϫ s), 43.4 (d), 49.0 (d), 49.2 (d),
67.2 (d), 84.7 (t), 126.8 (2 ϫ t), 127.0 (2 ϫ t), 129.7 (2 ϫ t), 129.8
(2 ϫ t), 136.3 (q), 137.3 (q), 143.3 (q), 143.7 (q). Ϫ IR: ν˜max
ϭ
˜
q), 143.5 (2 ϫ q), 168.2 (4 ϫ q). Ϫ IR: νmax ϭ 1710 (CO), 1330
1318 (SO2), 1153 (SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 461 (15)
[M ϩ Naϩ], 439 (41), [M ϩ Hϩ], 283 (14) [Mϩ Ϫ Ts], 241 (100).
Ϫ HRMS: (FAB) calcd. for C20H26N2O5S2Cs 571.0337; found
571.0304 [M ϩ Csϩ]; (CI) calcd. for C20H27N2O5S2 439.1361;
found 439.1350 [M ϩ Hϩ].
(SO2), 1146 (SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 737 (42) [M ϩ
Naϩ], 715 (52) [M ϩ Hϩ], 307 (100). Ϫ HRMS: calcd. for
C36H35N4O8S2 715.1896; found 715.1906 [M ϩ Hϩ].
3,6-Di(tosyl)-3,6-diazaoctane-1,8-diformate (25): M.p. 151Ϫ153 °C.
Ϫ1H NMR:
δ ϭ 2.44 (s, 6 H, ArCH3), 3.39 (s, 4 H,
Deuterium Labelling Study: [D4]acetic acid (0.18 cm3 of a 0.13 
solution in CDCl3) was added to a solution of 9a (10 mg, 23 µmol)
in CDCl3 (0.5 cm3) and the reaction mixture monitored by NMR
intermittently for a period of several hours. The solvent was evap-
orated and the resultant oil analysed by mass spectrometry.Ϫ MS
(FAB): m/z (%) ϭ 572 (100), [M ϩ Csϩ], 461 (19), [M ϩ Naϩ]. Ϫ
HRMS: m/z (FAB): 12a: calcd. for C20H25DN2O5S2Cs 572.0400;
found 572.0374 [M ϩ Csϩ]. 12b: calcd. for C20H24D2N2O5S2Cs
TsNCH2CH2NTs), 3.43 (t, J ϭ 5.4 Hz, 4 H, TsNCH2CH2OCHO),
4.33 (t, J ϭ 5.4 Hz, 4 H, CH2OCHO), 7.32 (d, J ϭ 8.4 Hz, 4 H,
CH3CCH), 7.70 (d, J ϭ 8.4 Hz, 4 H, SO2CCH), 8.02 (s, 2 H,
HCOO). Ϫ 13C NMR: δ ϭ 21.5 (2 ϫ s), 48.8 (2 ϫ d), 49.6 (2 ϫ
d), 62.1 (2 ϫ d), 127.2 (4 ϫ t), 129.9 (4 ϫ t), 135.3 (2 ϫ q), 144.0
˜
(2 ϫ q), 160.6 (2 ϫ t). Ϫ IR: νmax ϭ 1715 (CO), 1340 (SO2), 1149
(SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 535 (47) [M ϩ Naϩ], 513 (57)
[M ϩ Hϩ], 256 (100) [M2ϩ]. Ϫ HRMS: calcd. for C22H29N2O8S2
513.1365; found 513.1345 [M ϩ Hϩ].
573.0463; found 573.0500 [M
ϩ
Csϩ]. 12c: calcd. for
C20H23D3N2O5S2Cs 574.0526; found 574.0514 [M ϩ Csϩ].
3,6-Di(tosyl)-3,6-diaza-8-phthalimido-1-octyl formate (23): M.p.
208Ϫ210 °C. Ϫ1H NMR: δ ϭ 2.32 (s, 3 H, ArCH3), 2.44 (s, 3 H,
ArCH3), 3.25Ϫ3.61 (m, 8 H, NTsCH2), 3.85 (t, J ϭ 5.6 Hz, 2 H,
CH2NPhth), 4.35 (t, J ϭ 5.3 Hz, 2 H, CH2OCOH), 7.18 (d, J ϭ
8.5 Hz, 2 H, Ar-H), 7.36 (d, J ϭ 8.1 Hz, 2 H, Ar-H), 7.62 (d, J ϭ
8.3 Hz, 2 H, Ar-H), 7.66Ϫ7.92 (m, 6 H, Ar-H), 8.05 (s, 1 H,
HCOO). Ϫ 13C NMR: δ ϭ 21.6 (2 ϫ s), 21.6 (d), 36.6 (d), 48.0
(d), 48.8 (d), 49.2 (d), 62.2 (d), 123.3 (2 ϫ t), 127.2 (2 ϫ t), 127.4
(2 ϫ t), 129.8 (2 ϫ t), 130.0 (2 ϫ t), 132.0 (2 ϫ q), 134.0 (2 ϫ t),
135.4 (2 ϫ q), 143.7 (q), 143.9 (q), 164.7 (t), 168.2 (2 ϫ q). Ϫ IR:
3-Benzyl-6,9,12-tri(tosyl)-1-oxa-3,6,9,12-tetrazacyclotetradecan-2-
one (19): Tosylamide 14 (600 mg, 6.2 ϫ 10Ϫ4 mol) was reacted with
benzylamine (75 µL, 6.9 ϫ 10Ϫ4 mol) under identical conditions to
those described for 5a (vide infra). The crude reaction mixture was
purified by column chromatography on silica gel [ethyl acetate/
petroleum ether (40:60), 1:1]. The major fractions containing 19
were combined and the solvents evaporated. The solid which re-
sulted was purified by recrystallisation from ethanol giving 19 as a
white solid (300 mg, 63%). m.p. 105Ϫ106 °C. Ϫ1H NMR: δ ϭ 2.37
(s, 3 H, ArCH3), 2.38 (s, 3 H, ArCH3), 2.40 (s, 3 H, ArCH3),
3.05Ϫ3.51 (m, 14 H, NCH2), 4.28Ϫ4.30 (m, 2 H, OCH2), 4.47 (s,
2 H, NCH2Ph), 7.20Ϫ7.45 (m, 11 H, Ar-H), 7.52Ϫ7.86 (m, 6 H,
Ar-H). Ϫ 13C NMR (250 MHz): δ ϭ 21.4 (3 ϫ s), 45.4 (d), 47.7
(d), 48.5 (d), 49.8 (3 ϫ d), 50.6 (d), 51.3 (d), 65.2 (d), 127.2 (3 ϫ
t), 127.4 (3 ϫ t), 127.6 (2 ϫ t), 128.2 (t), 128.7 (3 ϫ t), 129.8 (5 ϫ
t), 134.5 (q), 135.3 (q), 137.0 (q), 143.7 (2 ϫ q), 143.9 (2 ϫ q),
νmax ϭ 1707 (CO), 1335 (SO2) cmϪ1. 1150 (SO2) ϭ MS (FAB): m/z
(%) ϭ 636 (47) [M ϩ Naϩ] 614 (100) [M ϩ Hϩ], 458 (24) [Mϩ
˜
Ϫ
Ts]. Ϫ HRMS calcd. for C28H32N3O8S2 614.1631; found 614.1651
[M ϩ Hϩ].
3,6-Di(tosyl)-3,6-diaza-8-phthalimido-octan-1-ol (24): Solid KOH
(16 mg, 0.29 mmol) was added to a solution of 23 (160 mg,
0.26 mmol) in methanol (5 cm3) and the mixture was stirred at
room temperature for 1 hour. The solvent was evaporated and the
residue dissolved in CH2Cl2 (10 cm3) and washed with a 10% solu-
tion of HCl (10 cm3). The aqueous layer was extracted with CH2Cl2
(3 ϫ 10 cm3) and the combined organic layers dried over MgSO4
and concentrated under reduced pressure. The solid obtained was
155.7 (q). Ϫ IR: ν˜max ϭ 1698 (CO), 1337 (SO2), 1152 (SO2) cmϪ1
.
Ϫ MS (FAB): m/z (%) ϭ 791 (100) [M ϩ Naϩ], 769 (26) [M ϩ
Hϩ]. Ϫ HRMS: calcd. for C37H45N4O8S3 769.2400; found 769.2423
[M ϩ Hϩ].
Reaction of Potassium Phthalimide with 5b: Potassium phthalimide
(266 mg, 1.43 mmol) was added portionwise within 3 hours to a
Eur. J. Org. Chem. 2001, 4233Ϫ4238
4237

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FULL PAPER
[11]
[12]
recrystallised from boiling ethanol to give 24 as a white powder
1
(130 mg, 85%). H NMR: δ ϭ 2.34 (s, 3 H, ArCH3), 2.45 (s, 3 H,
ArCH3), 3.30 (t, J ϭ 5.0 Hz, 2 H, TsNCH2), 3.42 (t, J ϭ 5.7 Hz,
2 H, TsNCH2), 3.52 (s, 4 H, 2 ϫ TsNCH2), 3.72Ϫ3.90 (m, 4 H,
CH2OH and PhthNCH2), 7.20 (d, J ϭ 8.1 Hz, 2 H, Ar-H), 7.36
(d, J ϭ 8.1 Hz, 2 H, Ar-H), 7.65 (d, J ϭ 8.3 Hz, 2 H, Ar-H),
7.68Ϫ7.84 (m, 6 H, Ar-H). Ϫ 13C NMR: δ ϭ 21.6 (2 ϫ s), 36.5
(d), 47.7 (d), 49.3 (d), 50.0 (d), 52.9 (d), 61.8 (d), 123.3 (2 ϫ t),
127.2 (2 ϫ t), 127.4 (2 ϫ t), 129.8 (2 ϫ t), 129.9 (2 ϫ t), 131.9 (2
ϫ q), 134.0 (2 ϫ t), 135.3 (q), 135.4 (q), 143.6 (q), 143.7 (q), 168.2
[13]
[14]
[15]
[16]
[17]
˜
(2 ϫ q). Ϫ IR: νmax ϭ 3494 (OH), 1711 (CO), 1333 (SO2), 1142
(SO2) cmϪ1. Ϫ MS (FAB): m/z (%) ϭ 608 (100) [M ϩ Naϩ], 586
(70) [M ϩ Hϩ]. Ϫ HRMS: calcd. for C28H32N3O7S2 586.1682;
found 586.1685 [M ϩ Hϩ].
[18]
[19]
[20]
[21]
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´
V. G o mez-Parra, F. Sanchez, T. Torres, Synthesis 1985,
282Ϫ285.
´
´
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