Chemical design and synthesis of unsymmetrical diamino proligands employing a flexible route

Article abstract of DOI:10.1016/j.tetlet.2012.08.057

Three new unsymmetrical diamino proligands with a central alcohol group and four different pendant arms were obtained, employing a five step synthesis. The synthesis of these compounds involves inexpensive and commercially available reagents. The versatility of the synthetic route allows accessing to compartmental diamines with two chemically different adjacent coordination chambers.

Full text of DOI:10.1016/j.tetlet.2012.08.057

Tetrahedron Letters 53 (2012) 5699–5702
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemical design and synthesis of unsymmetrical diamino proligands employing
a flexible route
⇑
Gabriela N. Ledesma, Sandra R. Signorella
IQUIR (Instituto de Química Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario, Suipacha 531, (S2002LRK) Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new unsymmetrical diamino proligands with a central alcohol group and four different pendant
arms were obtained, employing a five step synthesis. The synthesis of these compounds involves inex-
pensive and commercially available reagents. The versatility of the synthetic route allows accessing to
compartmental diamines with two chemically different adjacent coordination chambers.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 24 July 2012
Revised 11 August 2012
Accepted 13 August 2012
Available online 19 August 2012
Keywords:
Binucleating ligands
Chemical design
Biomimetics
Compartmental diamines
12,13
Numerous examples of active site of binuclear metalloenzymes
show that each metal atom may have chemically different environ-
ments, with coordination number asymmetry (dissimilar number
of donor atoms) and/or donor asymmetry (different types of donor
atoms), even in homodinuclear species.1–3 The coordination asym-
metry around the two metal ions often leaves vacant coordination
sites and facilitates the interaction of the metal center with specific
substrates.
A large number of dinucleating ligands have been prepared and
used to synthesize metal complexes that mimic binuclear metallo-
proteins.4 However, the limited number of model systems that em-
ploy non-symmetric ligands reveals the need of developing
efficient routes toward this class of ligands.4–6
With the goal of obtaining dimanganese complexes as models
of manganese catalases (MnCAT), we and others have found that
polydentate ligands with a central bridging alkoxide can be used
to emulate some key features of the active site of these en-
zymes.7–11 In particular, symmetrical ligands derived from 1,3-dia-
minopropan-2-ol afford dimanganese complexes that reproduce
the intermetallic distance of the enzyme (Fig. 1a).7,8 However,
while in MnCAT the two metal ions differ in the number of
exchangeable solvent ligands (only one of the manganese ions is
bound to a labile water molecule), symmetrical alkoxo-bridging li-
gands afford synthetic models with identical environment around
the two metal centers, leading to a less efficient catalytic reaction.
Two types of unsymmetrical phenoxo-bridged dimanganese
complexes have also been studied as MnCAT mimics (Fig. 1b)
;
but in these compounds, the phenoxide bridge leads to Mnꢀ ꢀ ꢀMn
separation longer than found in the enzyme and, thus, these com-
plexes are less relevant as MnCAT models. Therefore, the chemical
design of novel unsymmetrical ligands with a central alkoxide
group turns out to be essential for improving the efficiency of ana-
logues of these metalloenzymes.
As a part of our synthetic effort toward preparing proligands for
obtaining mimics of dinuclear metalloproteins, we report here on
the synthesis of three novel unsymmetrical ligands with N3
O3-donor set: 1-[N-(2-pyridylmethyl),N-(2-hydroxybenzyl)amino]-
3-[N0-(2-hydroxybenzyl),N0-(benzyl)amino]propan-2-ol (H3L1),
1-[N-(2-pyridylmethyl),N-(2-hydroxybenzyl)amino]-3-[N0-(2-hyd-
roxybenzyl),N0-(4-methyl-benzyl)amino]propan-2-ol (H3L2), and
1-[N-(2-pyridylmethyl),N-(2-hydroxybenzyl)amino]-3-[N0-(2-hy-
droxy-5-chloro-benzyl),N0-(benzyl)amino]propan-2-ol (H3L3), de-
picted in Scheme 1.
The retrosynthetic analysis of the H3Ln family yielded two dif-
ferent approaches that share the same initial steps. As shown in
Scheme 1, the proligands can be accessed through two key discon-
nections: the reaction of a chlorohydrin and a secondary amine
involving a nucleophilic displacement (path A); and the reductive
amination of salicylaldehyde (properly substituted) with the sec-
ondary amine derived from coupling between an epoxide and pic-
olylamine (path B).
The synthesis of the polypodal ligands was first attempted
employing path A. The reductive amination of salicylaldehyde 1
with commercially available amines (benzylamine, p-toluidine,
and 2-picolylamine), rendered the secondary amines 2a–c in
⇑
Corresponding author. Tel.: +54 341 4350214; fax: +54 341 4370477.
E-mail address: signorella@iquir-conicet.gov.ar (S.R. Signorella).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.057

5700
G. N. Ledesma, S. R. Signorella / Tetrahedron Letters 53 (2012) 5699–5702
Figure 1. Dimanganese complexes with symmetrical (a) and unsymmetrical (b) ligands.
Scheme 1. Retrosynthesis of proligands H3Ln.
excellent yield. The subsequent condensation of 2a,b with epichlo-
rohydrin (3) gave chlorohydrins 4a,b almost quantitatively. The
reaction of 4a,b with 2c introduced two new potential donor sites
(N,O), leading to the desired proligands H3L1 and H3L2 in moderate
yield (H3L1: 41% from 4a, H3L2: 44% from 4b), by using conditions
of nucleophilic displacement (Scheme 2).
Although the route outlined in Scheme 2 yielded the desired
H3L1 and H3L2, the final step generates a mixture of products diffi-
cult to separate through column chromatography and the yield of
this step was quite low. Tilmans et al. devised a similar approach to
synthesize a phos-tag ligand with two bis(pyridylmethyl)amino
units.14 However, when Tilmans’ conditions were employed for
the nucleophilic substitution (DIPEA, neat, 70 °C), instead of those
of step c in Scheme 2, H3L1 and H3L2 were not achieved, probably
because phenols strongly modify the reactivity of the system.
In order to circumvent the previous drawbacks, the alternative
strategy of path B was explored. In this approach, epoxides were
chosen as the activated form of the electrophiles. Nucleophilic
opening of oxiranes is a powerful and effective tool for obtaining
new carbon-heteroatom bonds with a carbinol in adjacent posi-
tion. This highly flexible route to polypodal ligands starts
from chlorohydrins 4a–c, which upon reaction with potassium
Scheme 2. Synthesis of unsymmetrical ligands—Path A. Reagents and conditions: (a) (i) benzylamine/p-toluidine/picolylamine, EtOH, reflux for 2 h; (ii) NaBH4, EtOH
0 °C?80 °C, 2 h (2a:87%; 2b:90%; 2c:82%), (b) 3, MeOH, rt, 48 h (4a:95%; 4b:99%), (c) 2c, THF, TEA, KI, reflux for 3 d (H3L1: 41% from 4a; H3L2: 44% from 4b).

G. N. Ledesma, S. R. Signorella / Tetrahedron Letters 53 (2012) 5699–5702
5701
Scheme 3. Synthesis of unsymmetrical ligands—Path B. Reagents and conditions: (a) tBuOK, dioxane, rt, 3 h (5a:98%; 5b:98%; 5c:99%); (b) 2-picolylamine, rt, 24 h (6a:88%;
6b:78%; 6c:70%); (c) (i) salicylaldehyde, MeOH, reflux for 18 h; (ii) NaBH(OAc)3, CH2Cl2, rt, 24 h (H3L1:52% from 6a; H3L2:66% from 6b; H3L3:52% from 6c).
Table 1
Rates of H2O2 disproportionation catalyzed by alkoxo-bridged dimanganese complexesa
Catalyst
Rate (mmol H2O2 mmol catꢁ1 sꢁ1
)
Solvent, T (°C)
Reference
H3L1 + Mn(OAc)3
3.3
3.0
2.6
0.95
0.89
CH3CN, 20
DMF, 25
MeOH:H2O, 25
DMF, 10
This work
9
16
8
17
[Mn2(
[Mn2(
[Mn2(
[Mn2(
l
l
l
l
-OAc)(
l
-OMe)(hppnO)]+
-O)(OAc)(OH)(benzimpnO)]+
-OMe)(OAc)(hppentO)]+
-OMe)(
l
-OAc)(salpentO)]+
MeOH, 25
a
[H2O2]0 = 140 mM. hppnOH = 1,3-bis[(2-hydroxybenzyl)(2-pyridylmethyl)amino]propan-2-ol; hppentOH = 1,5-bis[(2-hydroxybenzyl)(2-pyridylmethyl)amino]pentan-
3-ol; benzimpnOH = N,N,N0,N0-tetrakis(2-methylenebenzimidazolyl)-1,3-diaminopropan-2-ol; salpentOH = 1,5-bis(salicylidenamino)pentan-3-ol.
tert-butoxide in dioxane gave 5a–c in almost quantitative yield,
without the necessity of further purification. Nucleophilic opening
of 5a–c with neat 2-picolylamine led to diamines 6a–c. After the
reaction was completed, the extra amount of amine was removed
under reduced pressure, recovering the excess of reagent for fur-
ther use, and the residue was purified by column chromatography,
to afford 6a–c as pure oils. Finally, the three N3O3-donor ligands
H3L1, H3L2, and H3L3 were obtained by a one pot-two step reduc-
tive amination of salicylaldehyde with 6a–c (Scheme 3).
metallobiosites where the two metal ions possess chemically dis-
tinct surroundings. Reproduction of these features is essential for
obtaining efficient biomimetic compounds.
Acknowledgments
We gratefully acknowledge CONICET (Consejo Nacional de
Investigaciones Científicas y Técnicas) and UNR (Universidad Nac-
ional de Rosario) for financial support.
The structure of all compounds presented in this study was con-
firmed by 1H NMR, 13C NMR, and high-resolution mass spectra (see
Supplementary data).15
Supplementary data
Several improvements can be highlighted for path B over path
A and Tilman’s approach: the two first steps of this novel route
(a and b) do not require chromatographic purification and the total
yield is higher than the synthetic route described in path A. These
facts make this approach the method of choice to obtain unsym-
metrical polypodal diamines. Because this route avoids the use of
protective groups, it enables incorporation of broad chemofunc-
tional diversity.
Supplementary data (experimental procedures, analytical data,
spectra and catalase-like activity) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.08.057.
References and notes
The coordinating ability of H3L1 was explored by reacting
1.4 mM H3L1 with 2 equiv of manganese(III) acetate in acetonitrile,
and the catalase-like activity of the complex formed in situ was
tested by measuring the O2 evolved after addition of 100 equiv of
H2O2 to the complex solution (see Supplementary data). The cata-
lyst was able to dismutate all H2O2 within 7 min with retention of
activity after successive additions of H2O2, and the measured rate
of H2O2 disproportionation is similar or higher than reported for
Mn complexes of symmetrical alkoxide bridging ligands (Table 1).
This result exemplifies the capacity of the present ligands to form
efficient biomimetic catalysts.
In conclusion, we provided a versatile and flexible route, leading
to new diamino proligands with a central alcohol group and
unsymmetrical pendant binding sites. This is a general synthetic
strategy that may allow the design of a number of dinucleating li-
gands with two chemically different coordination environments.
These unsymmetrical polypodal proligands are of great interest,
since they can be used to mimic a large number of binuclear
1. Carboni, M.; Latour, J. M. Coord. Chem. Rev. 2011, 255, 186.
2. Belle, C.; Pierre, J. L. Eur. J. Inorg. Chem. 2003, 4137.
3. Bertini, I., Sigel, A., Sigel, H., Eds.; Handbook on Metalloproteins; M. Dekker Inc.:
New York, 2001.
4. Gavrilova, A. L.; Bosnich, B. Chem. Rev. 2004, 104, 349.
5. Rossi, L. M.; Neves, A.; Bortoluzzi, A. J.; Hörner, R.; Szpoganicz, B.; Terenzi, H.;
Mangrich, A. S.; Pereira-Maia, E.; Castellano, E. E.; Haase, W. Inorg. Chim. Acta
1807, 2005, 358.
6. Jarenmark, M.; Carlsson, H.; Nordlander, E. C. R. Chimie 2007, 10, 433.
7. Wu, A. J.; Penner-Hahn, J. E.; Pecoraro, V. L. Chem. Rev. 2004, 104, 903.
8. Signorella, S.; Tuchagues, J.-P.; Moreno, D.; Palopoli, C. In Inorganic Biochemistry
Research Progress; Hughes, J. G., Robinson, A. J., Eds.; Nova. Sci. Publ. Inc.: New
York, 2008; pp 243–279.
9. Biava, H.; Palopoli, C.; Duhayon, C.; Tuchagues, J.-P.; Signorella, S. Inorg. Chem.
2009, 48, 3205.
10. Palopoli, C.; Bruzzo, N.; Hureau, C.; Ladeira, S.; Murgida, D.; Signorella, S. Inorg.
Chem. 2011, 50, 8973.
11. Signorella, S.; Hureau, C. Coord. Chem. Rev. 2012, 256, 1229.
12. Neves, A.; de Brito, M. A.; Drago, V.; Griesar, K.; Haase, W. Inorg. Chim. Acta
1995, 237, 131.
13. Lambert, E.; Chabut, B.; Chardon-Noblat, S.; Deronzier, A.; Chottard, G.;
Bousseksou, A.; Tuchagues, J.-P.; Laugier, J.; Bardet, M.; Latour, J. M. J. Am.
Chem. Soc. 1997, 119, 9424.

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G. N. Ledesma, S. R. Signorella / Tetrahedron Letters 53 (2012) 5699–5702
14. Tilmans, N. P.; Krusemark, C. J.; Harbury, P. A. B. Bioconjugate Chem. 2010, 21,
1010.
136.5, 129.6, 129.0, 128.9, 128.7, 127.8, 121.7, 119.4, 116.2, 58.8, 58.0, 55.3,
49.8, 44.9; ESI-HRMS: calcd. for [C17H19NO2+H]+ = 270.1494, found 270.1491.
Compound 6a: yellowish oil; 1H NMR (d): 8.53 (d, J = 4.9, 1 H), 7.61 (dt, J = 7.7,
1.7, 1 H), 7.34–7.25 (m, 5 H), 7.21–7.13 (m, 3 H), 6.99 (dd, J = 7.4, 1.2, 1 H), 6.84
(dd, J = 8.0, 0.9, 1 H), 6.76 (dt, J = 7.4, 0.8, 1 H), 3.96–3.90 (m, 1 H), 3.86 (s, 2H),
3.84 (d, J = 5.0, 2 H), 3.69 (s, 2H), 2.73–2.42 (m, 4 H). 13C NMR (d): 159.4, 157.6,
149.2, 136.9, 136.6, 129.7, 128.9, 128.8, 128.5, 127.6, 122.33, 122.27, 122.1,
119.2, 116.2, 67.2, 58.7, 58.1, 57.1, 54.5, 53.3; ESI-HRMS: calcd. for
[C23H27N3O2+H]+ = 378.21815, found 378.21760.
15. Typical procedure for the preparation of proligand H3L1 (Path B): A mixture of 2a
(1.582 g; 7.4 mmol) and epichloro hydrin 3 (2.9 mL; 37.0 mmol) in methanol
(5 mL) was stirred at room temperature for 48 h. The resulting colorless
solution was evaporated under vacuum and the crude solid was purified by
recrystallization from MeOH, to afford 4a as a white solid (2.155 g; 7.0 mmol;
95% yield). Chloro hydrin 4a (0.195 g, 0.64 mmol) and tBuOK (0.197 g,
1.75 mmol) were stirred in 5 mL of 1,4-dioxane at room temperature for 2 h
and purged with dry Argon. The reaction was quenched with saturated
NaHCO3 solution, extracted with AcOEt (3 ꢂ 5 mL), and dried with MgSO4,
filtered and concentrated under vacuum to afford 5a (0.168 g; 0.62 mmol;
Compound H3L1: colorless oil; 1H NMR (d): 8.58 (d, J = 4.5, 1 H), 7.64 (dt, J = 7.7,
1.7, 1 H), 7.32–7.27 (m, 2 H), 7.23–7.18 (m, 4 H), 7.16–7.09 (m, 2 H), 6.98–6.95
(m, 2 H), 6.83 (d, J = 8.1, 2 H), 6.76 (t, J = 7.4, 2 H), 4.16–3.71 (m, 6 H), 3.67–3.59
(m, 3 H), 2.54–2.43 (m, 4 H); 13C NMR (d): 157.5, 157.4, 157.3, 148.8, 137.2,
136.8, 129.7, 129.6, 129.2, 128.9, 128.7, 128.5, 127.5, 123.1, 122.6, 122.4, 122.3,
119.2, 119.1, 116.7, 116.1, 66.6, 58.8, 58.7, 58.6, 58.5, 58.2, 57.3; IR (KBr):
yield 98%) as
a colorless oil. A mixture of 5a (0.182 g; 0.7 mmol) and
2-picolylamine (1 mL; 9.7 mmol) was stirred in a warm water bath (40 °C)
overnight. After the total consumption of 5a, the remaining 2-picolylamine
was recovered by distillation at reduced pressure (50 °C; 2 mmHg). The crude
product obtained was purified by column chromatography (hexane/AcOEt
100:0 to AcOEt/EtOH/TEA 90:7:3) to afford 6a as a yellowish oil (0.233 g;
0.62 mmol; yield 88%). To a solution of 6a (0.128 g; 0.34 mmol) in 2 mL of
methanol was added salicylaldehyde (0.046 g; 0.38 mmol) and stirred at room
temperature for 6 h. After removal of solvent the obtained pale orange oil was
dissolved in 3 mL of dichloromethane and sodium triacetoxyborohydride
m
= 3058, 3028, 2830, 1614, 1588, 1488, 1374, 1255, 1183, 1151, 1035, 979,
870, 802, 754, 701, 636, 455, 405 cmꢁ1
[C30H33N3O3+H]+ = 484.2600, found 484.2589.
;
ESI-HRMS: calcd. for
Compound H3L2: colorless oil; 1H NMR (d): 8.58 (d, J = 4.5, 1 H), 7.63 (dt, J = 7.7,
1.8, 1 H), 7.23–7.13 (m, 4 H), 7.11 (s, 4 H), 6.99–6.95 (m, 2 H), 6.84 (dd, J = 8.2,
0.9, 2 H), 6.79–6.73 (m, 2 H), 4.16–3.77 (m, 6 H), 3.73–3.57 (m, 3 H), 2.54–2.48
(m, 4 H), 2.31 (s, 3 H); 13C NMR (d): 157.5, 157.4, 157.3, 148,8, 137.3, 133.4,
129.74, 129.69, 129.2, 129.0, 128.8, 123.2, 122.6, 122.4, 122.2, 119.2, 119.1,
(0.108 g; 0.49 mmol) was added. The mixture was stirred for 12 h and 120 lL
of saturated solution of KF (0.114 g; 1.96 mmol) was added. Solvent was
removed and the solid residue was extracted with AcOEt (3 ꢂ 10 mL), dried,
filtered, and purified by column chromatography (AcOEt/EtOH/TEA 90:7:3) to
afford H3L1 as a colorless oil (0.086 g; 0.18 mmol; yield 52%). H3L2–3 were
synthesized similarly, and the selected spectroscopic data of 4a, 5a, 6a, and
H3L1–3 are as follows.
116.7, 116.2, 66.5, 58.8, 58.6, 58.5, 58.3, 57.9, 57.3, 21.1; IR (KBr): m = 3048,
2924, 2828, 1715, 1588, 1488, 1375, 1254, 1184, 1151, 1036, 970, 871,
803, 755, 703, 636, 485, 455, 407 cmꢁ1
[C31H35N3O3+H]+ = 498.2757, found 498.2771.
;
ESI-HRMS: calcd. for
Compound H3L3: yellow oil; 1H NMR (d): 8.58 (d, J = 4.9, 1 H), 7.65 (dt, J = 7.7,
1.8, 1 H), 7.36 (s, 3 H), 7.36–7.14 (m, 3 H), 7.10 (dd, J = 8.5, 2.3, 2 H), 6.98–6.93
(m, 2 H), 6.87–6.83 (m, 2 H), 6.80–6.74 (m, 2 H), 4.00–3.75 (m, 6 H), 3.69–3.59
(m, 3 H), 2.56–2.40 (m, 4 H); 13C NMR (d):157.4, 157.2, 156.3, 148.8, 137.3,
136.6, 129.7, 129.6, 129.3, 128.6, 128.5, 128.3, 127.62, 123.9, 123.6, 123.1,
122.6, 122.3, 119.2, 117.5, 116.8, 66.6, 58.8, 58.6, 58.5, 57.6, 57.1; IR (KBr):
Compound 4a: white solid; mp: 94–96 °C; 1H NMR (d): 7.35–7.25 (m, 5H), 7.17
(dt, J = 7.6, 1.4, 1H), 7.01 (dd, J = 7.6, 1.3, 1 H), 6.86 (dd, J = 8.2, 0.9, 1 H), 6.79 (dt,
J = 7.5, 1.2, 1 H), 4.07–4.00 (m, 1H), 3.93 (d, J = 13.9, 1 H), 3.76 (d, J = 13.7, 2 H),
3.63 (d, J = 13.2 Hz, 1 H), 3.50–3.33 (m, 2H), 2.73–2.59 (m, 2H); 13C (d): 157.3,
136.5, 129.6, 129.1, 129.0, 128.7, 127.8, 122.0, 119.5, 116.3, 69.1, 58.8, 58.3,
56.5, 48.2; ESI-HRMS: calcd. for [C17H20ClNO2+H]+ = 306.1261, found 306.1255.
Compound 5a: colorless oil; 1H NMR (d): 7.38–7.28 (m, 5 H), 7.17 (dt, J = 7.7,
1.5, 1 H), 7.00 (dd, J = 7.4, 1.3, 1 H), 6.86 (dd, J = 8.1, 1.0, 1 H), 6.78 (dt, J = 7.4,
1.2, 1 H), 4.09–3.90 (m, 2 H), 3.73–3.62 (m, 2 H), 3.17–3.11 (m, 1 H), 2.92 (dd,
J = 13.9, 3.4, 1 H), 2.75–2.72 (m, 1 H), 2.44–2.37 (m, 2H); 13C NMR (d): 157.6,
m
= 3051, 2924, 2837, 1595, 1585, 1481, 1375, 1265, 1251, 1180, 1151, 1029,
979, 908, 819, 736, 703, 669, 642 cmꢁ1
[C30H32ClN3O3+H]+ = 518.2210, found 518.2196.
;
ESI-HRMS: calcd. for
16. Boelrijk, A. E. M.; Dismukes, G. C. Inorg. Chem. 2000, 39, 3020.
17. Palopoli, C.; Chansou, B.; Tuchagues, J.-P.; Signorella, S. Inorg. Chem. 2000, 39,
1458.