Synthesis of pyridine-based polyaminocarboxylic ligands bearing a thioalkyl anchor

Article abstract of DOI:10.1016/j.tetlet.2007.03.024

A bicyclic tetraazatriacetic chelating agent containing a thioalkyl pendant group was prepared. Four synthetic routes have been investigated via a Mitsunobu reaction from 2,4-[bishydroxymethyl]-3-hydroxy-pyridine 1. Deprotection of trityl thioether compound 5c led to ligand 6c in 22% overall yield from the starting 3-hydroxypyridine.

Full text of DOI:10.1016/j.tetlet.2007.03.024

Tetrahedron Letters 48 (2007) 3463–3466
Synthesis of pyridine-based polyaminocarboxylic ligands
bearing a thioalkyl anchor
a
b
a,
a
*
´
´
Yi Lin, Alain Favre-Reguillon, Stephane Pellet-Rostaing and Marc Lemaire
a
`
ICBMS, Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires, Laboratoire de Catalyse et Synthese Organique,
43 boulevard du 11 novembre 1918, Villeurbanne F-69622, France; CNRS, UMR5246, Villeurbanne F-69622, France;
Universite´ de Lyon, Lyon F-69622, France; Universite´ Lyon 1, Lyon F-69622, France; INSA-Lyon, Villeurbanne F-69622, France;
CPE Lyon, Villeurbanne F-69616, France
bLaboratoire de Chimie organique, UMR CNRS 7084, Conservatoire des Arts et Me´tiers, 2 rue Conte´, 75003 Paris, France
Received 31 January 2007; revised 28 February 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—A bicyclic tetraazatriacetic chelating agent containing a thioalkyl pendant group was prepared. Four synthetic routes
have been investigated via a Mitsunobu reaction from 2,4-[bishydroxymethyl]-3-hydroxy-pyridine 1. Deprotection of trityl thioether
compound 5c led to ligand 6c in 22% overall yield from the starting 3-hydroxypyridine.
Ó 2007 Elsevier Ltd. All rights reserved.
MRI is an imaging technique and now one of the most
important diagnostic tools available in clinical practice.
Nowadays, most of the MRI contrast agents approved
for clinical use involve Gd3+–poly(aminocarboxy-
late) complexes.1 Among them, Gd(III)(DTPA) and
Gd(III)(DOTA) are the most efficient, ensuring nontox-
icity due to their kinetic inertness and high thermody-
namic stability. Although it produces highly resolved
images, MRI requires elevated concentrations of con-
trast agents. To reach the required local concentration,
the majority of the potential contrast agents involves
macromolecular carriers such as dendrimers,2,3 linear
polymer,4–7 proteins,8–10 or micelles.11–14 Recently, we
described a dithiolate DTPA derivative anchored on
gold nanoparticles as a very attractive and a higher con-
trast agent than the Gd3+–DTPA complex widely
used.15
MRI contrast agent.20 With a very high stability con-
stant21 (logGd–PCTA-[12] = 20.8) and an improved perfor-
mance in terms of relaxivity as discussed in detail in a
previous review,1 the corresponding Gd3+ complex was
proved to be an efficient contrast agent.
Generally, the synthesis of the polyazamacrocyclic ring
is the crucial step in the preparation of PCTA-[12] deriv-
atives. Commonly, azamacrocycles were synthesised
via the condensation of 2,6-bis(halomethyl)-pyridine
and disodium salt of 1,4,7-trinosyl-1,4,7-triazaheptane
according to the modified method of Richman and At-
kins.22 Moreover, 3-substituted-pyridine azacrowns
were also prepared via this procedure.14,23 Although
effective, it suffers from a number of drawbacks involv-
ing, among others, harsh conditions of deprotection and
purification of the final carboxylate derivatives. There-
fore, alternative and easier strategies are desirable. The
Mannich reaction was then successfully employed to ob-
tain a 12-membered 3,5-dihydroxy pyridine-containing
macrocycle24 but was unfortunately not effective for
the access to the 3-hydroxypyridine derivative. More re-
cently, Hovinen and Sillanpa¨a¨25 proposed a new route
for the synthesis of pernosylated azamacrocycles via a
Mitsunobu reaction, which we chose to use for the prep-
aration of precursors 3a–c (Scheme 1).
In order to improve these contrast-enhanced properties,
we focused our attention on the synthesis of PCTA-[12]
macrocycles (pyridine containing triaza macrocycle)
containing a thiol group. Among the polyazamacrocy-
clic ligands such as 12-membered N4 pyridine-contain-
ing macrocycles1,16–18 (PC-type ligands), PCTA-[12]19
was already synthesised and evaluated as potential
O-Alkylation of 126 in the presence of dry K2CO3 in
DMF gave 2a–c in good yields. Compounds 2a,b were,
Keywords: Azamacrocycle; PCTA; Mitsunobu reaction; Thiol.
*
Corresponding author. E-mail: pellet@univ-lyon1.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.024

3464
Y. Lin et al. / Tetrahedron Letters 48 (2007) 3463–3466
OR
N
H
N
H
N
Ns
N
Ns
N
N
OH
OH
1) CH2 O
NaOH
OR
OH
7
CO2t-Bu
OH
RX
Ns
N
Ns
N
N
K2CO3
DMF
2) HCl 6N
50%
PBu3, DIAD
N
OH
.HCl
OH
O
t
-BuO
1
a: R: CH3
b: R: CH2=CHCH2
c: R: TrS(CH2)3
2a. 62%
2b. 80%
2c. 56%
O2N
O
3a. 54%
3b. 75%
3c. 93%
Ns:
S
O
Scheme 1.
respectively, obtained from the commercially available
methyl iodide and allyl bromide. Compound 2c was ob-
tained from bromopropylene trityl thioether.27 Alkyl-
ation of 718 with an equimolar amount of diol 2b was
preliminary performed with the classical Mitsunobu
diisopropyl azodicarboxylate (DIAD)–PPh3 tandem
(3.0 equiv of each of the reagents) in THF.25 After
4 h at room temperature, 3b was obtained in 65%
moiety. Unfortunately, whatever the conditions (TMSI
or BBr3 in chloroform) the deprotection of 5a failed.
Tested with RhCl3 in ethanol31 or Pd/C in methanol
with APTS,32 the cleavage of allyl substituent from 5b
also failed. As described by Broxterman et al.,33 the rad-
ical addition of thiolacetic acid with AIBN on 5b fol-
lowed by the hydrolysis of the thioacetate intermediate
could give the corresponding thiol derivative. Neverthe-
less, degradation of the starting material was solely
observed under these conditions.
yield. 1,10-(Azodicarbonyl)dipiperidine (ADDP)–P(tBu)3
combination did not have the expected efficiency28
affording the desired product in 67% yield. Finally, the
highest conversion of 2b!3b was achieved (75%) when
DIAD was used with PBu3 instead of PPh3. These con-
ditions (DIAD–PBu3, rt, 4 h, THF) were applied to the
preparation of derivatives 3a,c29 from 2a,c.
From 5c, simultaneous removal of trityl and tert-butyl
groups was also tested by the treatment with TFA/
TES in THF.34 Under these conditions, the removal of
the trityl group easily occurred accompanied by a partial
hydrolysis of ester functions. Even in more concentrated
TFA or in longer reaction times, the monoester deriva-
tive was obtained. Finally, preliminary reaction of 5c
with HCl in ether (1 M), followed by the treatment with
TFA/TES afforded macrocycle 6c which was purified by
precipitation in ether in 93% yield (Scheme 3).35
Deprotection of nosyl groups (Scheme 2) was performed
with 2-mercaptoethanol in DMF and Cs2CO3 as bases30
affording 4a–c in good yields. Alkylation of 4a–c deriv-
atives performed with bromomethyl tert-butyl ester and
K2CO3 or Ag2CO3 as a base gave a mixture of polyalky-
lated macrocycles. When triethylamine (TEA) was used,
the expected product 5a–c were obtained in high yields.
In conclusion, we have synthesised a new thiol PCTA
type ligand in 22% overall yield from 3-hydroxypyridine
in six synthetic steps via a Mitsunobu reaction and a
deprotection of the thiol group. Immobilisation onto
Further functionalisation of 5a and 5b involved the pre-
liminary deprotection of the residual OH of the pyridine
OR
OR
OR
NH
N
N
2-mercaptoethanol
Cs2CO3, DMF
N
N
BrCH2CO2tBu
Ns
N
N Ns
t
-BuO
Ot-Bu
N
N
NH
TEA, CH3CN
N
N
O
O
4a: 84%
4b: 72%
4c: 97%
5a: 78%
5b: 80%
5c: 92%
O
O
O
t-BuO
t-BuO
t
-BuO
3a-c
5a-c
4a-c
Scheme 2.
O
N
SH
O
SH
1) HCl/Et2O, THF, 0˚C
2) TFA, (Et)3SiH
N
N
N
N
O
O
N
HO
OH
N
N
93%
O
O
O
O
O
O
O
HO
6c
5c
Scheme 3.

Y. Lin et al. / Tetrahedron Letters 48 (2007) 3463–3466
3465
22. Richman, J. E.; Atkins, T. J. J. Am. Chem. Soc. 1974, 96,
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Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti, M.
Chem. Eur. J. 1999, 5, 1253–1260.
gold nanoparticles and MRI properties are under
investigations.
24. Aime, S.; Cavallotti, C.; Gianolio, E.; Giovenzana, G. B.;
Palmisano, G.; Sisti, M. Org. Lett. 2004, 6, 1201–
1204.
25. Hovinen, J.; Sillanpa¨a¨, R. Tetrahedron Lett. 2005, 46,
4387–4389.
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Synthesis 1987, 720–723.
27. Bromopropylene trityl thioether: To a suspension of
lithium aluminium hydride (0.38 g, 10 mmol) in 15 mL
of THF was added dropwise a solution of 3-tritylsulfanyl-
propionic acid (3.5 g, 10 mmol) in THF (30 mL). The
mixture was then refluxed for 3 h. After cooling, 2 mL of
20% NaOH was added and the precipitate was filtered off.
Pure 3-tritylsulfanyl-propanol (2.75 g, 82%) was obtained
as a white solid by purification on chromatography
column (SiO2, ethyl acetate/cyclohexane: 1/2). 3-Trityl-
sulfanyl-propanol (0.34 g, 1 mmol) was then dissolved at
0 °C in dry CH2Cl2 (5 mL) with triphenylphosphine
(0.29 g, 1.1 mmol). NBS (0.2 g, 1.1 mmol) was added in
portion and the mixture was stirred over night at room
temperature. The solvent was evaporated and the residue
was treated with Et2O. After filtration, the crude product
was purified by chromatography on silica gel (CH2Cl2/
cyclohexane: 1/1) to give the bromopropylene trityl
thioether as a colorless oil (0.25 g, 62%). 1H NMR
(CDCl3): 1.92 (q, 2H, J = 6.78 Hz); 2.48 (t, 2H,
J = 6.45 Hz); 3.42 (t, 2H, J = 6.59 Hz); 7.31–7.61 (m,
15ArH). 13C NMR: 30.82, 32.15, 32.87 (CH2); 67.25 (C);
127.2, 128.4, 130.1 (ArCH); 145.2 (ArC).
28. (a) Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett.
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Cordi, A.; Marchand-Brynaert, J. Tetrahedron Lett. 2003,
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29. General procedure: 2a–c (1 mmol), 7 (1 mmol) and tribut-
ylphosphine (3 mmol) were dissolved in dry THF (25 mL).
DIAD (3 mmol) was added in four portions during
15 min, and the reaction was stirred at room temperature
for 4 h. All volatiles were removed in vacuum, and the
residue was purified by chromatography on silica gel (ethyl
acetate/heptane: 1/1–100/0) to give a light yellow solid.
30. Nihei, K.-I.; Kato, T. Y.; Yamane, T.; Palma, M. S.;
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2001, 335, 283–289.
32. Li, Q.; Li, S.-C.; Li, H.; Cai, M.-S.; Li, Z.-J. Carbohydr.
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Beuf, O.; Favre-Reguillon, A.; Pellet-Rostaing, S.; Lamar-
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´ ´
16. Dioury, F.; Sambou, S.; Guene, E.; Sabatou, M.; Ferroud,
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Ferroud, C.; Favre-Reguillon, A.; Guy, A. Eur. J. Org.
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35. Synthesis of 6c: A solution of bromopropylene trityl
thioether (0.25 g, 0.6 mmol) in 2 mL of DMF was added
to a solution of 1 (0.1 g, 0.5 mmol) in 2 mL of DMF with
K2CO3 (0.16 g, 1.1 mmol). The resulting mixture was
stirred overnight at 60 °C. After cooling, the solvent was
evaporated and the residue was triturated with CH2Cl2
and filtered. The filtrate was concentrated and purified by
chromatography (SiO2, CH2Cl2–CH2Cl2/CH3OH: 100/2),
18. Siaugue, J.-M.; Segat-Dioury, F.; Sylvestre, I.; Favre-
´
Reguillon, A.; Madic, C.; Guy, A. Tetrahedron 2001, 57,
4713–4718.
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Jommi, G.; Pagliarin, R.; Sisti, M. J. Chem. Soc., Chem.
Commun. 1995, 1885–1886; (b) Won, D. K.; Garry, E. K.;
Maton, F.; McMillan, K.; Muller, N. R.; Sherry, A. D.
Inorg. Chem. 1995, 34, 2233–2243.
20. Aime, S.; Gianolio, E.; Corpillo, D.; Cavallotti, C.;
Palmisano, G.; Sisti, M.; Giovenzana, G. B.; Pagliarin,
R. Helv. Chim. Acta 2003, 86, 615–632.
1
affording pure 2c as a white solid (0.2 g, 81%). H NMR
(CDCl3): 1.85 (q, 2H, J = 6.3 Hz); 2.39 (t, 2H,
J = 7.07 Hz); 3.94 (t, 2H, J = 5.94 Hz); 4.61 (s, 2H); 4.72
(s, 2H); 7.05 (d, H, J = 8.28 Hz); 7.18–7.30 (m, 10H);
7.41–7.44 (m, 6H). 13C NMR (CDCl3): 28.48, 28.73, 60.40,
64.96, 66.82, 67.10 (CH2); 118.5, 120.1 (CH); 127.1, 128.3,
21. Aime, S.; Botta, M.; Crich, S. G.; Giovenzana, G. B.;
Jommi, G.; Pagliarin, R.; Sisti, M. Inorg. Chem. 1997, 36,
2992–3000.

3466
Y. Lin et al. / Tetrahedron Letters 48 (2007) 3463–3466
129.9 (ArCH); 145.1 (ArC), 148.0, 149.9, 150.9 (C).
was stirred at 70 °C for 1 h and evaporated in vacuum.
The residue was dissolved in CH2Cl2 and the organic layer
was washed with water and brine. The solution was dried
over Na2SO4 and evaporated to dryness to give pure 5c as
a yellow solid (1.16 g, 92%). 1H NMR (CDCl3): 1.32–1.43
(m, 27H); 1.71 (t, 2H, J = 6.5 Hz); 2.28 (t, 2H,
J = 6.87 Hz); 3.09–3.11 (br, 4H); 3.32 (s, 4H); 3.61 (t,
2H, J = 5.28 Hz); 3.79–3.89 (m, 8H); 4.26 (s, 2H); 6.97 (s,
2H); 7.11–7.22 (m, 9H); 7.30–7.35 (m, 6H). 13C NMR
(CDCl3): 28.46, 28.51 (CH3); 28.74, 50.13, 50.72, 51.14,
53.08, 53.68, 54.24, 55.43, 56.85, 58.75, 59.14, 67.15, 67.38
(CH2); 82.32, 84.51 (C); 119.4, 121.7 (CH); 127.1, 128.3,
129.9 (ArCH); 145.1 (ArC); 148.6, 149.1, 151.7 (C); 166.1,
170.3, 170.4 (C@O). 35 mL of a solution of HCl in
diethylether was added dropwise to a solution of 5c (0.6 g,
0.68 mmol) in 10 mL of anhydrous THF. The reaction
mixture was stirred overnight and the white precipitate
was filtered off. The residue was then dissolved in 3 mL of
TFA. After 1 h, 0.32 mL of triethylsilane was added and
the mixture was stirred for 1 h. Pure 6c was obtained by
the addition of diethylether, filtration of the precipitate
and washing with diethylether. Compound 6c was
obtained as a light yellow solid (0.3 g, 93%). 1H NMR
(CD3OD) : 2.11–2.26 (m, 2H); 2.71–2.77 (m, H); 2.92–2.97
(m, H); 3.24 (s, 4H); 3.47–3.54 (m, 4H); 3.89 (s, 2H); 4.06–
4.10 (m, 4H); 4.25 (s, 2H); 4.52 (s, 2H); 4.62 (s, 2H); 7.41
(s, lH); 7.57 (d, H). 13C NMR (CD3OD): 28.27, 30.13;
51.42, 51.98, 52.09, 52.30, 52.42, 52.95, 54.63, 56.34, 56.55,
57.86, 65.66, 66.96, 67.04 (CH2); 119.9, 121.5 (CH); 147.9,
149.0, 151.0 (C); 168.0, 172.3 (C@O). MS: ESI: 471.2
[M+H].
Compound 3c then was prepared as described in Ref. 29
from 7. Yield: 93%. 1H (CDCl3) NMR: 1.32–1.35 (m,
27H); 1.62–1.68 (m, 2H); 2.28 (t, 2H, J = 6.78); 2.35 (t,
2H, J = 7.73); 2.55 (t, 2H, J = 7.64); 3.10–3.14 (s+t, 4H);
3.27 (t, 2H, J = 7.71); 3.80 (t, 2H, J = 6.12); 4.43 (s, 2H);
4.49 (s, 2H); 7.05–7.20 (m, 10H); 7.30–7.35 (m, 7H); 7.50–
7.64 (m, 6H); 7.89–7.95 (m, 2H). 13C NMR (CDCl3): 28.46
(CH3); 27.32, 28.13, 44.38, 45.47, 49.74, 50.30, 51.04,
51.88, 54.35, 57.90, 67.11, 67.17 (CH2); 81.48 (C); 120.3,
126.1 (CH); 124.5, 124.65, 127.1, 128.3, 130.0, 131.0,
131.2, 131.9, 132.1, 133.7, 134.0 (ArCH); 143.6, 145.2,
146.0, 148.6, 148.7, 154.0 (C); 171.4 (C@O). To a solution
of 3c (1.5 g, 1.5 mmol) in 5 mL DMF were added Cs2CO3
(1.15 g, 3.5 mmol) and 2-mercaptoethanol (0.57 g,
7.3 mmol). The resulting mixture was stirred for 2 h. The
solvent was evaporated in vacuum and the residue was
triturated with CH2Cl2. After filtration, pure 4c was
obtained by chromatography (SiO2, CH2Cl2/CH3OH: 10/
1—CH3OH—CH3OH/NH3 aq: 10/1) as a yellow oil
(0.93 g, 97%). 1H NMR (CDCl3): 1.48 (s, 9H); 1.84 (t,
2H, J = 6.32 Hz); 2.39 (t, 2H, J = 6.87 Hz); 2.62 (s, br,
4H); 2.79–2.84 (m, 4H); 3.51 (s, 2H); 3.90–3.94 (m, 4H);
4.07 (s, 2H); 7.01 (s, 2H); 7.18–7.30 (m, 9ArH); 7.40–7.43
(m, 6H). 13C NMR (CDCl3): 28.55 (CH3); 28.47, 28.73,
47.60, 48.71, 48.94, 51.93, 53.90, 56.60, 57.54, 59.96, 64.22,
66.75, 68.46 (CH2); 118.5, 120.7 (CH); 127.0, 128.2, 129.8
(ArCH); 145.1 (ArC); 147.4, 151.7 (C);171.7 (C@O). To a
solution of 4c (0.93, 1.4 mmol) in 20 mL CH3CN, were
added triethylamine (0.44 g, 4.4 mmol) and tert-butyl
bromoacetate (0.85 g, 4.4 mmol). The resulting mixture