A convenient modified short route for the preparation of [32]ane-N 8 hydrochloride

Article abstract of DOI:10.1002/jccs.200500111

A conve nient modified short-cut route for the prep a ration of a 32-membered octaazamacrocyclic mol ecule, 1,5,9,13,17,21,25,29- octaazacyclodotriacontane hydrochlo ride, [32]ane-N₈·8HCl has been de scribed. The proper tetramine has been con t

Full text of DOI:10.1002/jccs.200500111

Journal of the Chinese Chemical Society, 2005, 52, 793-797
793
A Convenient Modified Short Route for the Preparation of [32]ane-N8
Hydrochloride
Tarun Kumar Misra, Tse-Shien Chen (
Ken-Tsung Wong ( ) and Chuen-Ying Liu* (
Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan, R.O.C.
),
)
A convenient modified short-cut route for the preparation of a 32-membered octaazamacrocyclic mole-
cule, 1,5,9,13,17,21,25,29-octaazacyclodotriacontane hydrochloride, [32]ane-N8·8HCl has been described.
The proper tetramine has been contemplated to go this new pathway which propagates [32]-N8·8HCl more ef-
fectively.
Keywords: Macrocyclic polyamines; [32]ane-N8·8HCl; Convenient way.
INTRODUCTION
Macrocyclic polyaza ligands have shown their double
The chemical force which exists in between the cationic bind-
ing sites (ammonium groups) of the receptors and the nega-
tively charged polyphosphate groups is the electrostatic force
of attraction.8-10,31
roles in coordination chemistry. They afford stable com-
plexes with transition metal ions1-5 as well as with inorganic
or organic anions.6-14 Anions play important roles in both
chemical and biochemical processes15 and their complexa-
tion by synthetic macropolycyclic polyammonium receptor
molecules is an area of intense research interest.6-14 In some
instances, these ligands have shown their capability to cata-
lyze biologically significant reactions of the bound sub-
stances.16-19 The protonated forms of polyazamacrocycles
having highly positive charges act as anionic receptors in
aqueous solution even at neutral pH, and they have an ability
to form multisided hydrogen-bonding networks. The result of
second sphere interaction between anionic receptors and
complex, neutral or charged species provides complexes
called ‘super-complexes’. Recently, anion receptors have
been applied in anion transport in construction of ion selec-
tive electrodes and in separation science.14,20-30 Our labora-
tory has prepared macrocyclic polyamine bonded phases and
applied them in the electrophoretic separation of organic and
inorganic anions and metal ion speciation.12,22-29 The biologi-
cally relevant anions neucleotide polyphosphates, in particu-
lar adenosine mono-, di- and tri-phosphates are basic compo-
nents in the bioenergetics of all living organisms31,32 as well
as being the centre for chemical energy storage and transfer
being their polyphosphate chains, are selectively and strongly
bound with the protonated form of macrocyclic polyamines.
The macrocyclic polyamine 1,5,9,13,17,21,25,29-octa-
azacyclodotriacontane, [32]ane-N8 can be octaprotonated in
weakly acidic solution to give [32]ane-N8H88+ and has acted
as a molecular receptor which binds strongly a number of or-
ganic and inorganic anions, forming stable complexes espe-
cially with the anionic metal hexacyanides.33-35 Electrochem-
ical modification35,36 and photochemical37 properties of the
complexed anion has been reported. It has been shown to in-
duce the dimerization of negatively charged porphyrins in
micromolar concentrations.38 Another useful application has
been reported where it converted into unimolecular poly-
amine-polyhydroxy cores for the accommodation of polar
guests as a consequence of solubilization of sugars in apolar
organic media via flexible intramolecular polar microsolva-
tion.39 The advent of new methodologies for the synthesis of
macrocyclic polyamines is the consequence of their versatil-
ity.40 Due to the potential applications of [32]ane-N8 in a vari-
ety of areas, an efficient and convenient synthetic route to-
wards this compound is in high demand.
The first synthesis of [32]ane-N8 was reported by Jean-
Marie Lehn et al.33,34 They took proper triamine as the start-
ing material; the triamine was initially functionalized by the
tosyl groups (Ts), affording tosylated triamine (3N, where N
is amine-N). The obtained tosylated triamine was then di-
vided into two parts. One part was successively converted to
Dedicated to Professor Ching-Erh Lin on the Occasion of his 66th Birthday and his Retirement from National Taiwan University
* Corresponding author. Tel: +886-2-23630231 ext. 2338; Fax: +886-2-23638543; E-mail: cyliu@ntu.edu.tw

794 J. Chin. Chem. Soc., Vol. 52, No. 4, 2005
Misra et al.
tosylated pentamine (5N) following these steps: (1) Michael
addition of acrylnitrile by tritosylated triamine, (2) reduction
of the corresponding nitrile groups to amines and (3) further
N-tosylation of the newly formed amines. To get the desired
[32]ane-N8, the final cyclization step involved a (3N + 5N)
combination where the tosylated triamine (3N) was brought
after alkylation with 3-chloropropanol; then converted the
hydroxy groups of the resulting diol into good leaving groups
by methanesulfonylchloride (MsCl), and further reacted with
the dianion of tosylated pentamine. This synthetic pathway is
a quite lengthy and time consuming process. In this contribu-
tion, we would like to report a new synthetic strategy for the
preparation of [32]ane-N8 under the consideration of a proper
tetramine as a starting material. Our new (4N + 4N) pathway
will lead to [32]ane-N8 more efficiently.
amine which is commercially available at a reasonable price,
affording N,N¢,4,8-tetra(p-toluenesulfonyl)-4,8-diazaunde-
cane-1,11-diamine (1) with a yield of 84%. Alkylation of
compound (1) on the terminal tosylated-N with 3-chloro-1-
propanol in DMF at 110 °C gave 4,8,12,16-tetra(p-toluene-
sulfonyl)-4,8,12,16-tetraazanonadecane-1,19-diol (2) in
66% yield. The two hydroxyl groups in diol 2 were further
converted to be the good leaving groups with methanesul-
fonylchloride (MsCl) to give 1,19-di(methanesulfonyl)-
4,8,12,16-tetra(p-toluenesulfonyl)-4,8,12,16-tetraazanona-
decane (3) with an isolated yield of 97%. Compound 3 was
then subjected for the final cyclization with the dianion of
compound 1.
As a consequence tosylated cyclic 32-membered,
[32]ane-N8(Ts)8 was obtained in 45% yield. Detosylation
with 33% HBr-AcOH/PhOH at 80 °C provided the bromide
salt of 1,5,9,13,17,21,25,29-octaazacyclodotriacontane. Pass-
-
RESULTS AND DISCUSSION
ing through anion exchanger resin Dowex 1X8/Cl gave the
chloride salt of 32-membered macrocyclicpolyamine, [32]ane-
-
The advantages of our innovative route over the previ-
ously reported method by Jean-Marie Lehn et al.,33,34 are sim-
plicity, short length of time and convenience for the prepa-
rating of [32]ane-N8. The way of preparation of [32]ane-N8 is
depicted in Scheme I. The synthesis started with the tosyla-
tion34 of tetramine, N,N¢-bis(3-aminopropyl)-1,3-propanedi-
N8H88+·8HCl , with a yield of 82%. Our simple and more effi-
cient synthetic pathways took measured with proper tetra-
mine as a starting material. The final cyclization step was
guided by a (4N + 4N) combination. Thus, in our attempt,
there is no need to endeavor to increase the amine-contain-
ing chain length. This minor modification has been signifi-
Scheme I
Ts
Ts
N
N
Ts
Ts
Ts
Ts
N
N
iii
NH HN
NH HN
ii
i
Ts
Ts
N
N
NH HN
OH
HO
H
H
2
1
Ts
Ts
N
Ts
Ts
N
N
N
Ts
Ts
Ts
N
N
vi
v
.
Ts
Ts
[32]ane-N8 8HBr
N
N
N
N
Ts
OMS
MsO
vii
iv
N
N
Ts
Ts
3
.
[32]ane-N8 8HCl
4
1
5
Reagents: (i) TsCl/K2CO3/H2O; (ii) 3-chloro-1-propanol/K2CO3/DMF; (iii) MsCl/Et3N/dry CH2Cl2/-18 °C; (iv) NaH/DMF/stir
-
at rt; (v) DMF/110 °C; (vi) 33% HBr-AcOH/PhOH/80 °C; (vii) Dowex 1X8/Cl .

Short Route for the Preparation of [32]ane-N8 Hydrochloride
J. Chin. Chem. Soc., Vol. 52, No. 4, 2005 795
cant for the omission of three tedious steps: Michael addi-
tion of tritosylated triamines (3N) on acrylnitrile, reduction
of corresponding nitrile groups to amines and further N-
tosylation; those were compulsory in the previously reported
method for the synthesis of [32]ane-N8.
(t, J = 12.0 Hz, 12H), 7.60 (d, J = 8.0 Hz, 8H), 7.70 (d, J = 8.0
Hz, 8H); 13C-NMR (75 MHz, CDCl3) d 143.5, 143.2, 136.6,
135.3, 129.7, 129.6, 126.9, 126.8, 47.4, 46.5, 40.2, 29.5,
28.7, 21.6.
4,8,12,16-Tetra(p-toluenesulfonyl)-4,8,12,16-tetraazanona-
decane-1,19-diol (2)
CONCLUSION
Compound 1 (10 g, 120 mmol) and K2CO3 (9 g, 60
mmol) in DMF (80 mL) were heated and stirred at 100 °C. A
solution of 3-chloro-1-propanol (3.4 g, 36 mmol) in 20 mL
DMF was added dropwise over a period of ½ h. The reaction
mixture continued to be stirred at 110 °C overnight. Thereaf-
ter, the mixture was cooled down and filtered; the solid was
washed with CH2Cl2. The organic solutions evaporated to
dryness. The crude material was dissolved in CH2Cl2, washed
with H2O, and dried over MgSO4. The pure compound was
obtained as an oil after column chromatography on alumina
and eluted with 1% MeOH in CH2Cl2. Yield: 7.5 g, 66%. IR
(KBr) n 3418, 2932, 2875, 1661, 1596, 1493, 1454, 1384,
1330, 1153, 1088, 1019, 968, 926, 840, 817, 761, 719, 655
We have established a convenient short-cut route to
prepare the 32-membered macrocyclicpolyamine, 1,5,9,
13,17,21,25,29-octaazacyclodotriacontane hydrochloride,
[32]ane-N8·8HCl, starting with a proper tetramine instead of
a triamine. Our present contribution has made the synthesis
of this intriguing macrocyclicpolyamine more convenient
and efficient.
EXPERIMENTAL
1
DMF and triethylamine were distilled from CaH2 and
KOH, respectively, and stored over 4 Å molecular sieves. All
other chemicals were analytical reagent grade used as re-
cm-1; H-NMR (400 MHz, CDCl3) d 1.70-1.76 (m, 4H),
1.82-1.90 (m, 6H), 2.38 (s, 12H), 3.08-3.18 (m, 16H), 3.63-
3.67 (m, 4H), 7.23-7.29 (m, 8H), 7.60-7.67 (m, 8H); 13C-
NMR (75 MHz, CDCl3) d 143.4, 143.3, 135.5, 129.7, 129.6,
126.8, 59.1, 47.4, 47.2, 47.1, 46.2, 31.8, 29.1, 29.0, 21.6; MS
(m/z) 921.3 (100, M + 1), 863.3 (28), 765.3 (40); HRMS calcd
for C43H61O10N4S4 (M + H) 921.3271, found 921.3267.
ceived without any further purification. H NMR and 13C
1
NMR spectra were recorded at 400 MHz on a Bruker AC-400
spectrometer. IR spectra were obtained on a Perkin-Elmer
Model 983 spectrophotometer. Mass spectra were measured
with a JEOL SX-102 mass spectrometer. HRMS were per-
formed in the same spectrometer in FAB mode.
1,19-Di(methanesulfonyl)-4,8,12,16-tetra(p-toluenesulfo-
nyl)-4,8,12,16-tetraazanonadecane (3)
N,N¢,4,8-tetra(p-toluenesulfonyl)-4,8-diazaundecane-1,11-
diamine (1)34
Compound 2 (7.5 g, 8 mmol) in 200 mL dry CH2Cl2 was
stirred, cooled down at -18 °C; Et3N (5 g, 50 mmol) was
added. A solution of methanesulfonyl chloride (2 g, 17
mmol) in 10 mL dry CH2Cl2 was added dropwise over a pe-
riod of ½ h. The resulting mixture was stirred for another 2 h
at the same temperature, and then allowed to warm up to
room temperature for ½ h. The mixture was washed with 1M
HCl and with brine. The organic solution was dried over
MgSO4 and evaporated to dryness. This gave the desired
waxy solid compound. Yield: 8.5 g, 97%. IR (KBr): n 3029,
2938, 2873, 1596, 1494, 1459, 1336, 1157, 1089, 1018, 973,
925, 815, 717, 696, 655, 549, 528 cm-1; 1H-NMR (400 MHz,
CDCl3) d 1.84-1.91 (m, 6H), 1.96-2.03 (m, 4H), 2.40 (s,
12H), 2.99 (s, 6H), 3.01- 3.19 (m, 16H), 4.26 (t, J = 11.6 Hz,
4H), 7.26-7.31 (m, 8H), 7.60-7.64 (m, 8H); 13C-NMR (75
MHz, CDCl3) d 143.5, 143.4, 135.5, 135.4, 129.7, 127.0,
67.5, 47.4, 47.2, 45.8, 37.4, 29.1, 28.9, 21.6; MS (m/z) 1077.3
N,N¢-Bis-(3-aminopropyl)-1,3-propane diamine (5 g,
27 mmol) and K2CO3 (14 g, 10 mmol) were taken in 500 mL
water and stirred vigorously at 70 °C, then p-toluenesulfonyl
chloride (35 g, 180 mmol) was added in several portions over
a period of 1 h. Stirring was continued at 70 °C for 4 h. The re-
action mixture was allowed to cool overnight. The precipitate
was filtered off and washed thoroughly with water. The resi-
due was dissolved in 250 mL of CH2Cl2 and washed with 1M
HCl and H2O thoroughly. The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was dissolved
in EtOAc-MeOH (1:5 v/v) and slow evaporation resulted in a
white solid. The solid was filtered off and dried in a vacuum
to afford N,N¢,4,8-tetra(p-toluenesulfonyl)-4,8-diazaunde-
cane-1,11-diamine (18 g, 84%). m.p. 130-132 °C; 1H-NMR
(400 MHz, CDCl3) d 1.74-1.85 (m, 6H), 2.41 (s, 12H), 2.97

796 J. Chin. Chem. Soc., Vol. 52, No. 4, 2005
Misra et al.
(100, M + 1), 941.3 (28), 921.2 (33), 785.3 (15), 730 (10);
HRMS calcd for C45H65O14N4S6 (M + H) 1077.2822, found
1077.2809.
ACKNOWLEDGEMENT
Authors thank the National Science Council of Taiwan
for financial support.
1,5,9,13,17,21,25,29-Octa(p-toluenesulfonyl)-
1,5,9,13,17,21,25,29-octaazacyclodotriacontane (4)34
Compound 1 (8.9 g, 11 mmol) was dissolved in DMF
(200 mL) and then NaH (1.5 g, 63 mmol) was added wholly at
the same time. After stirring for 2 h at room temperature the
excess NaH was discarded by filtration and the filtrate having
dianion of compound 1 was stirred at 110 °C. A solution of
compound 3 (12 g, 11 mmol) in 30 mL DMF was added
dropwise within 10 min. to the solution of dianion. After
complete addition, the resulting mixture was maintained un-
der the same conditions for another 3 h. Thereafter the solu-
tion was evaporated and the residue was partitioned between
400 mL CH2Cl2 and 1M HCl. The organic layer was washed
with brine, dried over MgSO4 and concentrated to dryness
thus providing the crude product. The desired compound was
purified by column chromatography on silica gel and eluted
with 1% MeOH in CH2Cl2. Solid crystalline product was ob-
tained from CH2Cl2EtOH (1:2 v/v). Yield 8 g, 45%. m.p.
186-188 °C; 1H-NMR (400 MHz, CDCl3) d 1.85 (br, 16H),
2.38 (s, 24H), 3.08 (m, 32H), 7.26-7.32 (m, 16H), 7.58-7.65
(m, 16H); 13C-NMR (75 MHz, CDCl3) d 143.5, 143.2,
135.7, 129.9, 129.6, 127.1, 126.9, 49.1, 47.1, 31.6, 28.9,
21.6; MS (m/z) 1090.6 (100, M+1), 1533.6 (84), 1379.5
(40), 845.3 (116), 689.3 (60).
Received December 30, 2004.
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