A short and efficient synthesis of mono-substituted 1,4,7-Triazacyclononanes

Article abstract of DOI:10.1081/SCC-120017190

A convenient synthesis of 1,4,7-Triazacyclononane (tacn) derivatives substituted with a single pendant donor group is described. Monosubstituted tacns with a hydroxylalkyl, an aminoalkyl, or a benzyl group are synthesized via efficient cyclization of inex

Full text of DOI:10.1081/SCC-120017190

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A Short and Efficient Synthesis of Mono-substituted
1,4,7-Triazacyclononanes
Hyun-soon Chong a & Martin W. Brechbiel a
a Chemistry Section , Radiation Oncology Branch , National Cancer Institute , Bethesda,
Maryland, USA
Published online: 21 Aug 2006.
To cite this article: Hyun-soon Chong & Martin W. Brechbiel (2003) A Short and Efficient Synthesis of Mono-substituted 1,4,7-
Triazacyclononanes, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:7, 1147-1154, DOI: 10.1081/SCC-120017190
To link to this article: http://dx.doi.org/10.1081/SCC-120017190
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 7, pp. 1147–1154, 2003
A Short and Efficient Synthesis of
Mono-substituted 1,4,7-Triazacyclononanes
*
Hyun-soon Chong and Martin W. Brechbiel
Chemistry Section, Radiation Oncology Branch,
National Cancer Institute, Bethesda,
Maryland, USA
ABSTRACT
A convenient synthesis of 1,4,7-Triazacyclononane (tacn) derivatives
substituted with a single pendant donor group is described. Mono-
substituted tacns with a hydroxylalkyl, an aminoalkyl, or a benzyl
group are synthesized via efficient cyclization of inexpensive starting
materialsfollowed by detosylation.
Key Words: Triazacyclononane; Pendant substituted macrocycle;
Mono-substituted tacn.
*Correspondence: Martin W. Brechbiel, Chemistry Section, Radiation Oncology
Branch, National Cancer Institute, 10 Center Drive, Building 10, Rm B3B69,
NIH, Bethesda, Maryland, USA; E-mail: martinwb@mail.nih.gov.
1147
DOI: 10.1081/SCC-120017190
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1148
Chong and Brechbiel
1,4,7-triazacyclononane (tacn) derivatives substituted with a variety
of donor groupsare known to form stable complexeswith transition and
lanthanide metals.[1] The resulting metal complexes have been explored
for use in biomimetic studies,[2] biomedical applications,[3] DNA cleav-
[5]
age,[4] and ascatalytssfor oxidative cleavage.
Currently, there isa
significant interest in the synthesis of mono-substituted tacn derivatives
aseither intermediatesor astarget moleculesfor diveres areasof
research.[6] In our continuing effortsto develop potential novel chelators
for radioimmunotherapy applicationswith Yttrium or lanthanidesios-
topes,[7] we required an efficient entry to mono-substituted tacn deriva-
tivesbearing either an amino or a hydroxyl donor group that wasalso
amenable to being performed on a reasonably large scale.
Although a few synthetic routes to mono-substituted tacns bearing a
pendant hydroxyl group are reported,[8,9] there seems to be no straight-
forward general synthetic route available. Moreover, there also seems to
be no example of a simple synthesis of pendant amino-armed tacns. One
of the synthetic routes to mono-substituted tacns involves the reaction of
di-Boc protected tacn[10] with suitable alkylating agents followed by
deprotection of the secondary ring amines.[11] However, unless a very
reactive alkylating agent isuesd, alkylation of di-protected tacn is
known to result in low yields due to the presence of the bulky Boc
[8,11]
groupsin the macrocyclic intermediate.
The orthoamide derivative
1,4,7-triazatricyclo[5.2.1.0.][4,10] decane derived from tacn also has been
employed as a key intermediate for the mono-substituted tacn synthesis.
Recently, Pyke and co-workershave published a general method for the
preparation of hydroxylalkyl-armed tacn from the orthoamide, which
consisted of multiple steps including the use of ethylene oxides as alkylat-
[8]
ing agentsand inconvenient chromatographic purification.
In this paper, we present a convenient synthetic route to mono-
substituted tacn derivatives bearing a hydroxylalkyl, an aminoalkyl, or
a benzyl group. To the best of our knowledge, this synthetic procedure for
mono-substituted tacns is the first example that occurs via direct cycliza-
tion of readily available starting materials rather than starting with tacn,
which is an expensive reagent, and to date has exclusively been used as a
starting point for the preparation of mono-substituted tacns.
Thisdirect cyclization route employsprimary aminesbearing a vari-
ety of substitution that then provide pendant arms as starting materials
which are reacted with an N,N0-ditosyl protected ditosylate ester to pro-
vide the desired 1,4,7-triazacyclononane macrocyclic ring (Sch. 1). Thus,
reaction of readily available ditosylate 1[12] with primary aminesin the
presence of Na2CO3 in acetonitrile afforded the N,N0-ditosyl-protected
macrocycles 2a–g in high yield (81–92%). The reactionsof 1 with a

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1,4,7-Triazacyclononanes
1149
Scheme 1. 2a. R=CH2CH2OH; 2b. R=CH2CH2CH2OH; 2c. R=Ben; 2d.
R=CH2CH2CO2tBu 2e. R=CH2CHOHCH2OH; 2f. R=CH2CHOHCH3 2g.
R= CH(CH2OH)2
Table 1. Reactionsof 1 with R-NH2.
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
CH2CH2OH
CH2CH2CH2OH
Ben
2a
2b
2c
2d
2e
2f
86
92
82
84
86
91
81
CH3CH2CO2t-Bu
CH2CHOHCH2OH
CH2CHOHCH3
CH(CH2OH)2
2g
variety of primary aminesare us mmarized in Table 1. Thiscyclization
method is convenient, clean, and a high yield route using highly cost
effective starting materials. This strategy can be applied to the
construction of a wide range of macrocyclic rings by using modified
primary amines.
The desired mono-substituted tacns having a hydroxylalkyl pendant
arm (3a and 3b) were obtained from deprotection of the tosyl groups in
compound 2a[13] and 2b[13] (Sch. 2). Thus, deprotection was effected with
concentrated sulfuric acid at 115ꢀC for 72 h. Tacn derivatives 3a and
3b were obtained in high yield (>90%) without any further purification
procedures. The overall yields for synthesis of 3a and 3b were 89% and
94%, respectively. Tacn derivatives bearing an aminoalkyl group (6 and
7) were prepared in high yield after conversion of the hydroxyl group in
2a and 2b to an amino group and subsequent detosylation.[13]
Deprotection of the tosyl groups in 2c wasattempted under the
same conditions used for the preparation of 3a and 3b to generate
the mono-benzyl tacn. However, treatment of 2c with sulfuric acid
failed to afford 5. Acid hydrolysis of tosyl groups in 2c with a hydro-
bromic acid/acetic acid mixture in the presence of phenol was attempted
at lower temperature (90ꢀC). Thisreaction provided a mixture of

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1150
Chong and Brechbiel
Scheme 2.
compounds 4 and 5 asa 3:1 ratio, which were esparated by column
chromatography (see Experimental section). While not entirely as suc-
cessful in providing a single chromatography free route to the desired 5,
the ability to access 4 asa potential intermediate for further dervatization
of tacn seems an attractive side benefit.
In summary, mono-substituted tacn derivatives with an amino,
a hydroxyl, or a benzyl pendant group were prepared via an efficient
direct cyclization procedure using inexpensive starting materials followed
by detosylation. This synthetic procedure allows for a cost-efficient and
high yield production of mono-substituted tacns in a large scale that may
be employed for a variety of applicationsvia further modification.
EXPERIMENTAL
Melting pointswere recorded on a ThomasHoover capillary melting
point apparatusand were uncorrected. Elemental microanaleys
were performed by Galbraith Laboratories, Knoxville, TN. Fast
atom bombardment (FAB-MS) mass spectra were obtained on
an Extrel 4000 in the positive ion detection mode.
General Procedure For Reaction of 1 With Amines (2c–2g)
To a mixture of primary amines(10 mmol) and Na 2CO3 (10.6 g,
[12]
100 mmol) in CH3CN (300 mL) wasadded 1
(7.65 g, 10 mmol) and

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1,4,7-Triazacyclononanes
1151
the resulting mixture was refluxed for 72 h. The reaction mixture was
allowed to cool to ambient temperature and filtered, and washed with
CH2Cl2 (100 mL) and the filtrate wasconcentrated in vacuo.
1-benzyl-4,7-bis-(toluene-4-sulfonyl)-[1,4,7]triazonane (2c). The crude
product waspurified via column chromatography on silica gel by eluting
with 25% EtOAc-hexane. Pure 2c (4.31 g, 82%) wasthereby obtained as
a colorless micro-crystalline solid: M.p. 144ꢀC; H NMR (CDCl3) ꢀ 2.51
1
(s, 6 H), 3.11 (t, 4 H), 3.24 (t, 4 H), 3.85 (s, 4 H), 7.23 À 7.49 (m, 9 H), 7.76
(d, 2 H); 13C NMR (CDCl3) ꢀ 21.3 (q), 51.3 (t), 52.2 (t), 54.5 (t), 61.1
(t), 126.8 (d), 126.9 (d), 128.1 (d), 128.9 (d), 129.6 (d), 135.2 (s), 139.2
(s), 143.2 (s); Anal. Calcd. for C27H33N3S2O4: C, 61.46; H, 6.30; Found:
C, 61.13; H, 6.56.
1-(3-tert-butoxycarboethyl)-(4,7-bis-(toluene-4-sulfonyl)-[1,4,7]triazo-
nane (2d). The crude product waspurified via column chromatography on
silica gel by eluting with 25% EtOAc-hexane. Pure 2d (4.70 g, 84%) was
thereby obtained as a colorless micro-crystalline solid: M.p. 147–148ꢀC;
1H NMR (CDCl3) ꢀ 1.46 (s, 9 H), 2.47 (s, 6 H), 2.88–2.95 (m, 4 H), 3.23
(t, 4 H), 3.54 (s, 4 H), 7.36 (d, JAB ¼ 8.0 Hz, 4 H), 7.72 (d, JAB ¼ 8.0 Hz, 4
H); 13C NMR (CDCl3) ꢀ 21.2 (q), 27.8 (q), 34.0 (t), 50.8 (t), 52.1 (t), 52.5
(t), 55.7 (t), 80.1 (s), 127.0 (d), 129.5 (d), 135.0 (s), 143.2 (s), 171.8 (s);
Anal. Calcd. for C27H39N3S2O6: C, 57.32; H, 6.95; N, 7.43; Found:
C, 57.19; H, 6.98; N, 7.20; MS (positive ion FAB) m/z 566 [Mrþ H]þ.
1-[(2R)-2,3-Dihydroxypropyl]-4,7-bis-(toluene-4-sulfonyl)-[1,4,7]tria-
zonane (2e). The crude product waspurified via column chromatography
on silica gel by eluting with EtOAc. Pure 2e (4.4 g, 86%) wasthereby
obtained as a colorless micro-crystalline solid: M.p. 116ꢀC; 1H NMR
(CDCl3) ꢀ 2.50 (s, 6 H), 2.64–2.90 (m, 4 H), 3.10–3.57 (m, 8 H),
3.78–3.85(m, 4 H), 7.39 (d, JAB ¼ 7.7 Hz, 4 H), 7.73 (d, JAB ¼ 7.7 Hz,
4 H); 13C NMR (CDCl3) ꢀ 21.4 (q), 52.6 (t), 53.0 (t), 55.3 (t), 60.7
(t), 64.2 (t), 68.6 (d), 127.0 (d), 129.7 (d), 135.0 (s), 143.6 (s); Anal. Calcd.
for C27H33N3S2O4: C, 53.99; H, 6.50; Found: C, 52.06; H, 6.19.
1-[(2s)-2-Hydroxypropyl)]-4,7-bis-(toluene-4-sulfonyl)-[1,4,7]triazo-
nane (2f). The crude product waspurified via column chromatography
on silica gel by eluting with 50% EtOAc-hexane. Pure 2f (4.65 g, 91%)
was thereby obtained as a colorless micro-crystalline solid: M.p.
102–103ꢀC; 1H NMR (CDCl3) ꢀ 2.53 (s, 6 H), 3.05 (d, 2 H), 3.13
(t, 4 H), 3.10–3.89 (m, 4 H), 7.42 (d, JAB ¼ 8.4 Hz, 4 H), 7.76 (d,
JAB ¼ 8.4 Hz, 4 H); 13C NMR (CDCl3) ꢀ 19.8 (q), 21.4 (q), 52.8 (t), 53.0
(t), 55.3 (t), 63.8 (d), 66.9 (t), 127.1 (d), 129.8 (d), 135.0 (s), 143.6 (s);
Anal. Calcd. for C23H33N3S2O5(H2O)0.5: C, 54.74; H, 6.84; N, 8.33;
Found: C, 55.07; H, 6.79; N, 7.76; MS (positive ion FAB) m/z 496
[Mrþ H]þ.

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1152
Chong and Brechbiel
1-[(2R)-1,3-Dihydroxy-iso-propyl]-4,7-bis-(toluene-4-sulfonyl)-[1,4,7]
triazonane (2g). The crude product waspurified via column chromatog-
raphy on silica gel by eluting with 50% EtOAc-hexane. Pure 2g (4.14 g,
81%) was thereby obtained as a colorless micro-crystalline solid: M.p.
133ꢀC; 1H NMR (CDCl3) ꢀ 2.13 (s, 1H), 2.51 (s, 6 H), 2.89–3.89 (m, 8 H),
7.42 (d, JAB ¼ 8.0 Hz, 4 H), 7.76 (d, JAB ¼ 8.0 Hz, 4 H); 13C NMR
(CDCl3) ꢀ 21.4 (q), 51.8 (t), 53.0 (t), 53.3 (t), 60.4 (t), 66.2 (d), 127.1
(d), 129.8 (d), 134.7 (s), 143.6 (s); Anal. Calcd. for C27H33N3S2O4: C,
54.84; H, 6.71; Found: C, 54.01; H, 6.92.
General Procedure for Detosylation
Compound 2a or 2b (1 mmol) was dissolved in concentrated H2SO4
(5 mL) and heated to 115ꢀC for 72 h under argon. The resulting solution
wascooled to ambient temperature and added in portionsto Et 2O
(150 mL) at À60ꢀC. The resulting precipitate was collected, washed
with Et2O (20 mL), and immediately dissolved in H2O (25 mL). The aque-
oussolution wasextracted with Et 2O (10 mL), concentrated to 5 mL, and
neutralized with 50% NaOH. The resulting mixture was extracted with
CHCl3 (3 ꢁ 50 mL) and the combined organic layerswere dried (MgSO 4),
filtered, and the filtrate wasconcentrated in vacuo to afford 3a or 3b.
2-[1,4,7]Triazonan-1-yl-ethanol (3a). Pure 3a (158 mg, 91%) was
thereby obtained as a colorless viscous oil. Melting point of 3a asan
HCl salt was obtained: M.p. 209–211ꢀC; H NMR (CDCl3) ꢀ 2.79–2.83
1
(m, 4 H), 2.92–3.03 (m, 10 H), 4.06 (t, 2 H), 4.88 (s, 1 H); 13C NMR
(CDOD3) ꢀ 44.74 (t), 45.92 (t), 51.86 (t), 56.74 (t), 67.65 (t); HRMS
(positive ion FAB) Calcd. for C9H19N3O: [Mþ H]þ m/z 174.1606;
1
Found: [Mþ H]þ m/z 174.1604. The H NMR, 13C NMR, Mass spectra
of the material thereby obtained is essentially identical with the cor-
responding spectral data that has been reported previously for authentic
3a.[9]
(3-[1,4,7]Triazonan-1-yl-propan-1-ol (3b). Pure 3b (179 mg, 96%) was
thereby obtained as a colorless viscous oil. Melting point of 3b asan HCl
salt was obtained: M.p. 245–248ꢀC; H NMR (CDCl3) ꢀ 1.50–1.56 (m,
1
2 H), 2.32–2.64 (m, 14 H), 3.84 (t, 2 H), 4.35 (s, 1 H); 13C NMR (CDCl3) ꢀ
27.40 (t), 43.99 (t), 45.02 (t), 50.53 (t), 53.43 (t), 66.43 (t); HRMS (positive
ion FAB) Calcd. for C10H21N3O: [Mþ H]þ m/z 189.1140; Found:
[Mþ H]þ m/z 189.1134.
Deprotection of tosyl groups in 2c. 1-benzyl-4-(toluene-4-sulfonyl)-
[1,4,7]triazonane (4) and 1-benzyl-[1,4,7]triazonane (5). A mixture of 2c
(1.85 g, 3.52 mmol) and phenol (2.47 g) was dissolved into 30% HBr in

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1,4,7-Triazacyclononanes
1153
AcOH (30 mL) and washeated to 90 ꢀC for 72 h under argon. The result-
ing solution was cooled to ambient temperature and added in portions to
Et2O (150 mL) at À60ꢀC. The resulting precipitate was collected, washed
with Et2O (20 mL), and immediately dissolved in H2O (25 mL). The aque-
ousoslution wasextracted with Et 2O (10 mL), concentrated to 5 mL,
and neutralized with 50% NaOH. The resulting mixture was extracted
with CHCl3 (3 ꢁ 50 mL) and the combined organic layerswere dried
(MgSO4), filtered, and the filtrate wasconcentrated in vacuo. The
crude product waspurified via column chromatography on neutral alu-
mina by eluting with 10% MeOH–CH2Cl2. Pure 4 (830 mg, 63%) was
thereby obtained asa colorlessoil. Melting point of 4 asan HCl salt was
obtained: M.p. 186–188ꢀC; 1H NMR (CDCl3) ꢀ 2.84–3.04 (m, 6 H),
3.17–3.35 (m, 6 H), 3.79 (s, 2 H), 7.22–7.44 (m, 5 H), 7.76 (d, 2 H);
13C NMR (CDCl3) ꢀ 21.3 (q), 47.5 (t), 49.0 (t), 51.6 (t), 51.8 (t), 54.0
(t), 55.5 (t), 61.6 (t), 126.9 (d), 127.0 (d), 128.2 (d), 128.9 (d), 129.5 (d),
135.4 (s), 139.3 (s), 143.1 (s); HRMS (positive ion FAB) Calcd. for
C10H21N3O: [Mþ H]þ m/z 374.1902; Found: [Mþ H]þ m/z 374.1885.
Further elution with 20% NH4OH-MeOH afforded 5 (250 mg, 33%)
asa colorlesoil. Melting point of 5 asan HCl salt wasobtained: M.p.
134–137ꢀC; 1H NMR (CDCl3) ꢀ 2.46–2.59 (m, 12 H), 3.53 (s, 2 H),
7.32–7.43 (m, 5 H); 13C NMR (CDCl3) ꢀ 46.06 (2t), 52.3 (t), 61.5 (t),
127.1 (d), 128.3 (d), 128.9 (d), 139.3 (s); MS (positive ion FAB) m/z
220 [Mrþ H]þ. The 1H NMR, 13C NMR, and mass spectra of the
obtained oil are essentially identical with the corresponding spectral
data that hasbeen reported previously for authentic 5.
ACKNOWLEDGMENT
We thank the structural Mass Spectra Group (Dr. L. Pannell,
NIDDK, Bethesda, MD) for obtaining the mass spectra of compounds.
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