Catalytic etherification of N-protected tris(hydroxymethyl)aminomethane for the synthesis of ligands with C3 symmetry

Article abstract of DOI:10.1016/j.tetlet.2006.01.026

The synthesis of two nonadentate ligands based on a N,N-dibenzylated- tris(hydroxy)methylaminomethane framework is described. The key step consists in tris-etherification of the precursor with elaborated pyridine and bipyridine derivatives and this was greatly improved by the introduction of catalytic amounts of tetrabutylammoniumiodide to the reaction mixture in DMF at room temperature. Analysis of the alkylation rates and an X-ray crystal structure of a bis-alkylated intermediate strongly support the presence of a tight intramolecular hydrogen bond, preventing a fast third alkylation step. The two acidic ligands were successfully prepared by combining a sequence of carboalkoxylation and hydrolysis of the corresponding esters. Both ligands react with europium and terbium chloride salts to generate water luminescent mononuclear complexes.

Full text of DOI:10.1016/j.tetlet.2006.01.026

Tetrahedron Letters 47 (2006) 1793–1796
Catalytic etherification of
N-protected tris(hydroxymethyl)aminomethane for the synthesis
of ligands with C3 symmetry
*
*
`
Nicolas Weibel, Loıc Charbonniere and Raymond Ziessel
¨
Laboratoire de Chimie Mole´culaire, associe´ 7509 au CNRS, ECPM-ULP, 25 rue Becquerel, 67087 Strasbourg Cedex, France
Received 28 November 2005; revised 21 December 2005; accepted 9 January 2006
Available online 26 January 2006
Abstract—The synthesis of two nonadentate ligands based on a N,N-dibenzylated-tris(hydroxy)methylaminomethane framework is
described. The key step consists in tris-etherification of the precursor with elaborated pyridine and bipyridine derivatives and this
was greatly improved by the introduction of catalytic amounts of tetrabutylammoniumiodide to the reaction mixture in DMF at
room temperature. Analysis of the alkylation rates and an X-ray crystal structure of a bis-alkylated intermediate strongly support
the presence of a tight intramolecular hydrogen bond, preventing a fast third alkylation step. The two acidic ligands were success-
fully prepared by combining a sequence of carboalkoxylation and hydrolysis of the corresponding esters. Both ligands react with
europium and terbium chloride salts to generate water luminescent mononuclear complexes.
Ó 2006 Elsevier Ltd. All rights reserved.
Gathering coordinating entities on a C3 symmetrical
podand type of structure is an elegant way to achieve in-
creased stability for metal coordination. Providing that
the link which connects the coordinating moieties to
the central node is neither too short, avoiding steric con-
gestion, nor too long, generating entropic disorder,1 the
improved thermodynamic control can result in superior
efficiency regarding photo-chemical stability and photo-
physical properties.2 In the case of lanthanide coordina-
tion chemistry, for which coordination numbers of nine
are targeted for optimum photo-physical properties,
tris-tridentate podand type structures can saturate the
first coordination sphere of the lanthanide. Owing to
their exceptional luminescence properties, such com-
plexes are used as luminescent labels,3 and thereby re-
quire the introduction of an activated group for
labeling biological materials. The use of tris(hydroxy-
methyl)aminomethane (TRIS) is particularly attractive
as this starting material provides both a C3 symmetrical
frame of alkoxy groups and an amino residue that
should give access to orthogonal chemistry,4 and poten-
tially to the introduction of a labelling group.
Relatively few examples dealing with the use of TRIS as
a starting material for C3 symmetric ligands have been
reported, and most of them rely on the nucleophilic at-
tack of the hydroxy groups on sp2 carbon atoms such as
acyl chlorides5 or a,b-unsaturated carbonyl compounds
in 1,4 additions.6 Williamson etherification reaction are
more rare and require the use of severe experimental
conditions and afford modest yields of trisalkylation.7
In an effort to introduce elaborated tridentate coordina-
tion sites containing chromophoric units, we have inves-
tigated activation by alkylation of TRIS under various
experimental conditions and with catalytic mediators.
Results concerning the synthesis of two new C3 symmet-
ric ligands, L1H3 and L2H3, are described (Chart 1).
After deprotonation, both ligands have tris-tridentate
anionic arms able to compensate for the +III charge
of the lanthanide cations. During the coordination, the
formation of two five-membered chelate rings per arm
appears to be a favorable option. L1H3 is designed so
that the ether linkages are expected to take part in the
coordination (mode A), whereas in L2H3 these groups
are only envisaged as spacers in the C3 framework
(mode B).
Ligand L1H3 is based on tridentate units made of 2-alk-
oxymethylene-6-carboxy-pyridine. The synthetic proto-
col to obtain L1H3 is described in Scheme 1. Starting
from commercially available 2-amino-6-methyl-pyridine
*
Corresponding authors. Tel.: +33 3 90 24 26 89; fax: +33 3 90 24 26
35; e-mail: ziessel@chimie.u-strasbg.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.026

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N. Weibel et al. / Tetrahedron Letters 47 (2006) 1793–1796
ammonium iodide (TBAI) substantially improved the
yield of the reaction, similar to what was observed for
the TBAI assisted synthesis of phosphonates.11 Under
these conditions, the starting alkylating agent was con-
sumed in one hour without the need to heat the solution.
In the next step, the bromine groups in 6 were converted
into butyl esters by a carboalkoxylation procedure cata-
lyzed by low valent palladium.12
N
CO2H
CO2H
N
N
O
O
Bz2N
Bz2N
N
O
N
O
CO2H
N
O
O
CO2H
CO2H
N
CO2H
N
N
N
L1H3
L2H3
Compound 7 was isolated in 44% yield. In contrast to
the case of the carboethoxylation of bromo-bipyridine
derivatives,12,13 the reaction with bromo-pyridines re-
quired higher reaction temperatures, provided by chang-
ing the nature of the alcohol (n-butanol instead of
ethanol). Finally, ligand L1H3 was obtained quantita-
tively as its tetrahydrochloride salt after acidic hydroly-
sis of the ester groups.14 A similar procedure was
applied for the synthesis of ligand L2H3 (Scheme 2).
Here again, the use of catalytic amounts of TBAI in
DMF at room temperature proved to be very effective
in improving the yield of the tris-etherification of 2
(Table 1). Insight into an understanding of the diffi-
culties to achieve the third alkylation was gained by
X-ray diffraction. Single crystals of compound 9 were
obtained by slow diffusion of Et2O into a CH2Cl2
solution of the compound (Fig. 1).
O
N
O
N
O-
O
O
Ln
O-
Ln
coordination mode A
coordination mode B
3, a Sandmeyer reaction8 gave the intermediate 2-bro-
mo-6-methyl-pyridine which is transformed into 4 by a
radical bromination.9 The N-protected TRIS derivative
envisaged was the N,N-dibenzyl compound 2, obtained
by an adaptation of a literature procedure.10 These pro-
tecting groups support acidic and basic conditions, and
can in principle be deprotected by hydrogenolysis.
As described in Table 1, alkylation of 2 according to
conventional procedures using NaH in dry THF at
65 °C led to a poor yield (41%) of the tris-alkylated
product, 6, and a substantial amount of the bis-alkyl-
ated intermediate 5 (22%). Changing the solvent to
DMF in the presence of a catalytic amount of tetrabutyl-
An interesting feature of the structure is the formation
of a tight intramolecular hydrogen bond between the
hydrogen atom of the remaining hydroxy group and
OH
OH
OH
OH
i) 30%
H2N
Bz2N
OH
OH
Br
N
N
Br
2
1
iv)
O
O
Bz2N
Bz2N
N
Br
+
N
O
OH
O
Br
O
N
Br
ii) 79%
iii) 67%
5
6
Br
N
NH2
N
Br
4
3
v) 44%
CO2Bu
N
vi) quant.
O
O
Bz2N
N
L1H3
CO2Bu
CO2Bu
O
N
7
Scheme 1. Reagents and conditions: (i) benzyl bromide (2.2 equiv), NaHCO3 (2.2 equiv), TBAI (0.1 equiv), H2O, 100 °C, 30%;10 (ii) HBr 48%, Br2
À20 °C/NaNO2 (4 equiv), 0 °C, 79%;8 (iii) NBS (1.1 equiv), AIBN (cat.), hm, CH2Cl2/H2O (1/1), reflux, 67%;9 (iv) see Table 1 for experimental
conditions; (v) n-BuOH/(iPr)2EtN/CH2Cl2 (10/5/3), [Pd(PPh)3Cl2] (0.05 mol equiv per Br), CO (1 atm.), 120 °C, 44%; (vi) HCl 6 N, 60 °C, quant.
Table 1. Reaction conditions for the etherification of 2 with compounds 4 and 8
Entry
Alkylating
agent
Solvent
Temperature
(°C)
Reaction
time (h)
Number of
NaH (equiv)
Number of
TBAI (equiv)
Yields of
ethers formed
1
2
3
4
5
4
4
8
8
8
THF
DMF
THF
DMF
DMF
65
25
70
70
25
28
1
25
24
19
4
4.5
9
9
4.5
—
0.1
—
—
0.1
6 (41%)
5 (22%)
6 (75%)
10 (55%)
10 (19%)
10 (87%)
9 (25%)

N. Weibel et al. / Tetrahedron Letters 47 (2006) 1793–1796
1795
Br
OH
OH
N
Br
N
Bz2N
OH
N
O
N
2
N
Bz2N
i)
O
O
+
Bz2N
N
N
O
O
OH
N
Br
N
Br
Br
N
Br
N
N
9
Br
10
ii) 81%
8
CO2Et
N
N
iii) 65%
O
N
L2H3.4HCl
Bz2N
O
N
O
N
CO2Et
N
11
CO2Et
Scheme 2. Reagents and conditions: (i) see Table 1; (ii) EtOH/Et3N/CH2ClCH2Cl (4/4/1), [Pd(PPh3)2Cl2] (7% mol equiv per Br), CO (1 atm.), 70 °C,
81%; (iii) NaOH (4 equiv), MeOH/H2O (4/1), 60 °C, dil HCl, 65%.
could be avoided. Finally, 11 was saponified with meth-
anolic NaOH to afford L2H3 as a tetrahydrochloride salt
after acidification of the medium.17 Preliminary investi-
gations of the complexation of L1H3 and L2H3 with lan-
thanide chloride salts (Ln = Eu and Tb) in water clearly
indicate the formation of luminescent mononuclear
complexes and complexes of [Ln(L2)]ÆxH2O formulae
were isolated with L2 and characterized by elemental
analysis, IR and FAB mass spectrometry. As evidenced
on Figure 2, the complexation of L2 by europium leads
to a bathochromic shift of the ligand centered p–p* tran-
sitions (from k = 290 nm (e = 32,800 MÀ1 cmÀ1) for L2
Figure 1. ORTEP view of compound 9 (ellipsoids drawn at 50%
probability).
to 305 nm (e = 23,400 MÀ1 cmÀ1) for [Eu(L2)]) with
appearance of the europium centered emission upon li-
gand excitation (quantum yield = 1.2%).18 Nevertheless,
˚
the central nitrogen atom (dN19–H18 = 2.084 A, angle
fluorescence spectra revealed the presence of the remain-
ing ligand centred fluorescence around 450 nm that can
(OHN) = 107.0°). It is surmised that this hydrogen bond
is responsible for the difficulty to effect the etherification
be attributed either to a bad intersystem crossing effi-
reaction on the third hydroxy group of the TRIS. The
ciency or to a partial decoordination of the ligand. Deep-
er photo-physical studies, in particular the examination
of the excited state lifetimes in water and deuterated
two bipyridyl arms of 9 are co-facially arranged in an
anti-conformation, but at a rather long distance
˚
(4.77 A), and no particular p-stacking interaction is
foreseen.
40000
30000
20000
10000
Catalytic enhancement of nucleophilic substitution by
iodide, a better nucleophile and electrophile than bro-
mide15 is well established, but should be tempered in
that case, as the nucleophilic power of halides has been
shown to be reversed within the series when using apro-
tic polar solvents.16 In our case, the catalytic activity of
TBAI is clearly demonstrated (see Table 1, entry 4), but
the exact influence may arise from a subtle balance be-
tween hydrogen bonding disruption and nucleophilicity
enhancement.
The tris-bromobipyridine intermediate 10 was then con-
verted into the tris-ester 11 by the above mentioned car-
boethoxylation procedure,12 under conventional
conditions of solvent and temperature. Note that the
carboalkoxylation is more efficient compared to the
preparation of 7 and the use of a high boiling solvent
0
650
220
320
420
Wavelengths (nm)
550
Figure 2. Absorption spectra of L2H3 (dashed line) and [EuL2] (bold
line) and emission spectra of [Eu(L2)] in water (TRIS/HCl buffer,
0.01 M, pH = 7.0).

1796
N. Weibel et al. / Tetrahedron Letters 47 (2006) 1793–1796
7. Dupuis, C.; Viguier, R.; Dupraz, A. Synth. Commun. 2001,
31, 1307.
8. Adams, R.; Miyano, S. J. Am. Chem. Soc. 1954, 76, 3168.
9. Bedel, S.; Ulrich, G.; Picard, C. Tetrahedron Lett. 2002,
43, 1697.
10. Dupraz, A.; Guy, P.; Dupuy, C. Tetrahedron Lett. 1996,
37, 1237.
11. Cohen, R. J.; Fox, D. L.; Eubank, D. L.; Salvatore, R. N.
Tetrahedron Lett. 2003, 44, 8617.
water, point to the presence of two species in solution.
In the case of L2, the longest lived species
(s = 1.23 ms, 25%) corresponds to the expected complex
with the tris-tridentate units wrapping around the first
coordination sphere of the europium atom, while the
shortest one (s = 0.27 ms, 75%) contains three coordi-
nated water molecules in the first coordination sphere,
pointing to the decoordination of one of the three tri-
dentate arm.19
12. El Ghayoury, A.; Ziessel, R. J. Org. Chem. 2000, 65, 7757.
`
13. Charbonniere, L.; Weibel, N.; Ziessel, R. J. Org. Chem.
2002, 67, 3933.
In short, we succeeded in alkylating a di-N-protected
trishydroxymethylaminomethane framework with bro-
minated pyridine or bipyridine modules. Alkylation is,
however, partially inhibited by an intramolecular hydro-
gen bond in the bis-alkylated intermediate species. The
resulting bromo groups were adequately transformed
into the ester and acid forms via a carboalkoxylation/
hydrolysis sequence. These new C3-like podands form
mononuclear complexes with europium with ligand
centred sensitization of the europium emission (antenna
effect). Work in progress concentrates on the
determination of the structure of the complexes in solu-
tion and on the complexation of other lanthanide
cations.
14. Compound L1H3Æ4HClÆ2H2O: 1H NMR (CD3OD,
200 MHz): d 4.30 (s, 6H), 4.87 (s, 4H), 4.94 (s, 6H),
7.17–7.28 (m, 10H), 7.80–7.84 (m, 3H), 8.18–8.24 (m, 6H);
13C NMR (CD3OD, 50 MHz): d 57.9, 69.7, 71.6, 74.1,
127.1, 129.3, 130.2, 130.7, 131.4, 132.5, 145.2, 145.8, 156.7,
163.7; FAB+/MS: m/z 707.3 ([L1H3+H]+, 100%). Anal.
Calcd for C39H38N4O9Æ4HClÆ2H2O: C, 52.71; H, 5.22; N,
6.30. Found: C, 52.52; H, 4.98; N, 6.14; IR (KBr, cmÀ1):
3435 (s), 2966 (w), 2933 (w), 1636 (m, mCOO, asym.), 1439
(w), 1384 (m, mCOO, sym.), 1275 (w), 1076 (w), 1010 (w);
UV–vis (0.01 M Tris/HCl buffer, pH = 7.0, kmax, nm
(emax, MÀ1 cmÀ1)): 268 (14,600).
15. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley
Interscience, 1985; p 304.
16. Weaver, W. M.; Hutchison, J. D. J. Am. Chem. Soc. 1964,
86, 261.
17. Compound L2H3Æ4HClÆH2O: 1H NMR (CD3OD,
400 MHz): d 3.74 (s, 6H), 4.08 (s, 4H), 4.51 (s, 6H),
7.04–7.15 (m, 6H), 7.24–7.30 (m, 4H), 7.76 (dd, 3H,
3J = 8.5 Hz, 4J = 2.0 Hz), 7.94 (t, 3H, 3J = 8.0 Hz), 8.03
(d, 3H, 3J = 7.0 Hz), 8.30 (d, 3H, 3J = 8.0 Hz), 8.32 (d,
3H, 3J = 8.5 Hz), 7.49 (s, 3H); FAB+/MS: m/z 847.2
([L2H3–C7H7+H]+, 25%), 938.2 ([L2H3+H]+, 100%).
Anal. Calcd for C54H47N7O9Æ4HClÆH2O: C, 58.86; H,
4.85; N, 8.90. Found: C, 58.69; H, 4.88; N, 8.82; IR (KBr,
cmÀ1): 3445 (s), 1635 (m, mCOO, asym.), 1384 (m, mCOO, sym.),
1262 (w), 1096 (w); UV–vis (0.01 M Tris/HCl buffer,
pH = 7.0, kmax, nm (emax, MÀ1 cmÀ1)): 242 (27,600), 290
(32,800).
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`
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`
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