Novel chiral Schiff base ligands from amino acid amides and salicylaldehyde

Article abstract of DOI:10.1016/S0040-4039(02)00687-1

A novel type of symmetric chiral Schiff base ligands has been synthesized in good yield using an easy and good yielding stepwise approach from o-phenylenediamine, amino acids and salicylaldehyde.

Full text of DOI:10.1016/S0040-4039(02)00687-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3821–3823
Novel chiral Schiff base ligands from amino acid amides and
salicylaldehyde
Massimo Curini,* Francesco Epifano,* Federica Maltese and Maria C. Marcotullio
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Facolta` di Farmacia, Universita` degli Studi,
Via del Liceo, 06123 Perugia, Italy
Received 21 March 2002; revised 2 April 2002; accepted 8 April 2002
Abstract—A novel type of symmetric chiral Schiff base ligands has been synthesized in good yield using an easy and good yielding
stepwise approach from o-phenylenediamine, amino acids and salicylaldehyde. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
scopic characterization of novel symmetric N-salicyl-
aldehyde ligands based on chiral amino acid-derived
subunits of general structure 1.
The synthesis of new kinds of chiral ligands represents
one of the most important factors in the field of asym-
metric catalysis. The major part of the most common
ligands are bidentate and neutral, like DIOP and
BINAP,1 or dianionic, like TADDOL2 and BINOL.3
Among higher denticity ligands are the tetradentate
salen ligands, used for example in asymmetric epoxida-
tion,4 epoxide ring opening5 and aziridination.6,7
Salen-type chiral Schiff base ligands have received con-
siderable attention during the last decades, mainly
because their steric and electronic properties can be
easily adapted by choosing the right chiral amine and
aldehyde precursors. In this context, for example,
Jacobsen catalyst and other similar transition metal
complexes with symmetric or unsymmetric ligands have
been developed and used as catalysts for many kinds of
processes.8
Complexes of trivalent lanthanides aminoacidato com-
plexes have been the subject of several physicochemical
studies,15 but very few reports on the catalytic activity
of such complexes have been found in the literature.16
Ligand 1 contains from four up to six coordination
sites; its core is based upon two nitrogen imine atoms
and two hydroxyl functions, which are known to coor-
dinate strongly to transition metal centers,10 and two
amide moieties. The synthesis was carried out in three
easy steps, each with excellent or good yields, as out-
lined in Scheme 1.
An interesting class of salen analogue transition metal
complexes is that one having N-salicylaldehyde chiral
aminoacidatos as ligands; studied as non-enzymatic
models for pyridoxal-amino acid system.9 To this aim
several copper(II),10 zinc(II)10 and vanadium(IV) or
(V)11 salicylaldehyde aminoacidatos have been synthe-
sized and structurally characterized.
Starting from N-Boc-protected amino acids, prepared
by standard methods,17 the coupling reaction with o-
phenylenediamine (2:1 ratio) was made by using 2
equiv. of dicyclohexyl carbodiimide (DCC) as conden-
sating agent in EtOAc at room temperature. Employing
As a part of our ongoing studies on using lanthanide
salts as catalysts in synthetic organic chemistry,12–14 we
report in the present work the synthesis and spectro-
N-Boc protected
-valine as starting materials, the corresponding
diamide adduct 4 was obtained in 90% (R=-CH2Ph,
L-phenylalanine, D-phenylglycine and
L
* Corresponding authors. Tel.: +39075585511; fax: +390755855116;
e-mail: epifano@unipg.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00687-1

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M. Curini et al. / Tetrahedron Letters 43 (2002) 3821–3823
in progress in our laboratories. In fact coordinating our
ligands to lanthanides would not only have great sig-
nificance in the fundamental chemistry of these rare
earth elements but could also have an important role in
the field of MRI contrast agents, biological probes or
NMR chiral shift reagents.
2. Experimental
2.1. Synthesis of diamide 4
To a stirred solution of N-tbutoxycarbonyl amino acid
2 (2.44 mmol) and o-phenylenediamine 3 (1.22 mmol)
in EtOAc (6 mL), a solution of DCC (2.44 mmol) in
EtOAc (4 mL) was added dropwise over a period of 20
min at room temperature. After the addition was com-
plete the mixture was stirred for 6 h, the white precipi-
tate formed was filtered under reduced pressure, the
filtrate was washed twice with a 5% solution of citric
acid (10 mL) and evaporated. The residue was purified
by SiO2 gel column chromatography (eluent CH2Cl2/
MeOH, 99:1) to give the desired compound 4.
Scheme 1.
Data for compound 4a: Mp 222–224°C; [h]D=+20.24
1
(c=1.0 g/mL, CHCl3); H NMR (CDCl3, 200 MHz) l
4a), 88% (R=-Ph, 4b) and 87% (R=-iPr, 4c) yield,
respectively, after SiO2 gel column chromatography
using CH2Cl2/MeOH (99:1) as eluent. The carbamate
functions of 4 were cleaved (98% yield in all cases,
R=-CH2Ph, 5a, R=-Ph, 5b, R=-iPr, 5c) with a 50%
solution of CF3COOH (TFA) in CH2Cl2 at room tem-
perature. This high yielding two-step synthesis of
diamino diamides of structure like 5 needs to be
pointed out as they represent useful synthons for tetra-
and pentadentate macrocyclic tetramide ligands.18 The
synthesis of the desired ligands was then completed by
condensation of chiral diamine 5 with salicylaldehyde in
refluxing MeOH for 2 h, followed by crystallization of
the corresponding Schiff base 1. Yields were as follows:
57% (R=-CH2Ph, 1a), 58% (R=-Ph, 1b), 53% (R=-
iPr, 1c).
1.42 (s, 18H), 2.89–3.34 (m, 4H), 4.39–4.64 (m, 2H),
7.06–7.49 (m, 14H) ppm; 13C NMR (CDCl3, 50 MHz)
l 28.3, 38.1, 56.2, 80.5, 125.3, 126.4, 126.9, 128.6, 129.4,
130.0, 136.7, 155.9, 170.9 ppm. IR (neat) 3300 (br),
1674 cm−1.
Data for compound 4b: Mp 202–203°C; [h]D=−60.93
1
(c=1.0 g/mL, CHCl3); H NMR (CDCl3, 200 MHz) l
1.45 (s, 18H), 5.25 (d, 2H, J=6.9 Hz), 5.81 (d, 2H,
J=6.9 Hz), 6.90–7.48 (m, 14H) ppm; 13C NMR
(CDCl3, 50 MHz) l 28.3, 59.0, 80.2, 125.2, 126.4, 127.3,
128.5, 129.0, 130.0, 137.7, 155.2, 170.0 ppm. IR (neat)
3300 (br), 1672 cm−1.
Data for compound 4c: Mp 176–178°C; [h]D=+15.38
1
(c=1.0 g/mL, CHCl3); H NMR (CDCl3, 200 MHz) l
0.94 (d, 6H, J=6.8 Hz), 1.01 (d, 6H, J=6.8 Hz), 1.42
(s, 18H), 2.09–2.30 (m, 2H), 4.04–4.24 (m, 2H), 5.51 (d,
2H, J=8.2 Hz), 7.02–7.14 (m, 4H) ppm; 13C NMR
(CDCl3, 50 MHz) l 17.8, 19.3, 28.5, 30.9, 60.4, 79.8,
125.2, 126.0, 129.9, 155.9, 171.2 ppm. IR (neat) 3300
(br), 1670 cm−1.
These ligands are insoluble at room temperature in
apolar solvents such as n-hexane, benzene or toluene,
but exhibit a very good solubility in slightly polar
solvents such as dichloromethane, acetonitrile, acetone
or tetrahydrofuran, for example; solubility tends to
diminish with increasing solvent polarity (e.g. they are
sparingly soluble in methanol and insoluble in water),
but in such solvents, increases by raising the tempera-
ture. These compounds are also stable for several days
at room temperature in the solid state.
2.2. Boc deprotection
Compound 4 (3.4 mmol) was added to a stirred solu-
tion of CF3COOH (5.0 mL) in CH2Cl2 (10 mL) at
room temperature; the mixture was allowed to react for
30 min, diluted with CH2Cl2 (30 mL), basified with
0.5N NaOH and the organic layer was separated, dried
over anhydrous Na2SO4 and evaporated to give the
desired diamine 5.
In conclusion, we have developed a short synthesis of a
new class of chiral polydentate Schiff base ligands,
which contain mixed N,O donors. These ligands were
easily prepared in good yield starting from low-cost
commercially available materials. The work to obtain
the corresponding transition metal complexes to
provide new chiral Lewis acids to use in asymmetric
catalytic processes and for possible use with lanthanides
and for multimetallic application in general, is currently
Data for compound 5a: Mp 265–266°C; [h]D=−22.43
1
(c=1.0 g/mL, MeOH); H NMR (CDCl3, 200 MHz) l
2.76 (dd, 2H, J1–2=8.8 Hz, J1–3=14.6 Hz), 3.33 (dd,
2H, J1–2=4.2 Hz, J1–3=14.6 Hz), 3.74 (dd, 2H, J1–2
=

M. Curini et al. / Tetrahedron Letters 43 (2002) 3821–3823
3823
4.2 Hz, J1–3=8.8 Hz) 7.14–7.64 (m, 14H) ppm; 13C
NMR (CDCl3, 50 MHz) l 40.7, 56.5, 124.6, 125.9,
126.9, 128.7, 129.3, 129.9, 137.9, 173.5 ppm. IR (neat)
3300 (br), 1682 cm−1.
132.2, 133.2, 160.5, 167.8, 170.7 ppm. IR (neat) 3300
(br), 1660, 1628 cm−1.
Acknowledgements
Data for compound 5b: Mp 226–228°C; [h]D=−101.42
1
(c=1.0 g/mL, MeOH); H NMR (CDCl3, 200 MHz) l
4.48 (s, 2H), 7.12–7.58 (m, 14H) ppm; 13C NMR
(CDCl3, 50 MHz) l 60.0 124.8, 126.2, 126.2, 126.9,
128.1, 128.9, 130.0, 140.8, 172.1 ppm. IR (neat) 3300
(br), 1680 cm−1.
Financial support from MIUR (Rome, Italy) is grate-
fully acknowledged.
References
Data for compound 5c: Mp 185–187°C; [h]D=+97.37
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(c=1.0 g/mL, MeOH); H NMR (CDCl3, 200 MHz) l
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(c=1.0 g/mL, CHCl3); H NMR (CDCl3, 200 MHz) l
1.01 (d, 6H, J=6.4 Hz), 1.07 (d, 6H, J=6.4 Hz),
2.40–2.62 (m, 2H), 3.76 (d, J=3.8 Hz), 6.90–7.55 (m,
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32.4, 80.4, 117.0, 118.6, 119.2, 125.1, 126.3, 129.8,