Designer ligands. VII. Synthesis of biomimetic Schiff-base ligands

Article abstract of DOI:10.1081/SCC-100105116

The preparation of a series of novel acyclic and macrocyclic Schiff-base ligands, designed to model the tyrosinase receptor, is described.

Full text of DOI:10.1081/SCC-100105116

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1
DESIGNER LIGANDS. VII. SYNTHESIS OF BIOMIMETIC
SCHIFF-BASE LIGANDS
a
a
Perry T. Kaye & Kevin W. Wellington
a
Department of Chemistry , Rhodes University , Grahamstown, 6140, South Africa
Published online: 09 Nov 2006.
1
To cite this article: Perry T. Kaye & Kevin W. Wellington (2001) DESIGNER LIGANDS. VII. SYNTHESIS OF BIOMIMETIC
SCHIFF-BASE LIGANDS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:16, 2405-2411, DOI: 10.1081/SCC-100105116
To link to this article: http://dx.doi.org/10.1081/SCC-100105116
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SYNTHETIC COMMUNICATIONS, 31(16), 2405–2411 (2001)
1
DESIGNER LIGANDS. VII. SYNTHESIS OF
BIOMIMETIC SCHIFF-BASE LIGANDS
Perry T. Kaye* and Kevin W. Wellington
Department of Chemistry, Rhodes University,
Grahamstown, 6140, South Africa
ABSTRACT
The preparation of a series of novel acyclic and macrocyclic
Schiff-base ligands, designed to model the tyrosinase receptor,
is described.
Tyrosinase, a metalloenzyme whose phenolase and catecholase activity
2
is responsible for the browning of injured fruit and vegetables, is considered
3
to contain appropriately coordinated copper(I) ions in its active site. There
has been considerable interest in the development of synthetic copper com-
4
plexes as biomimetic tyrosinase analogues, the primary aim being to design
ligands capable of forming dinuclear copper complexes in which a Cu-Cu
5
separation of ca 3.5 A permits dioxygen binding. To that end, the nature of
˚
the ‘‘spacer’’ (Figure 1) is expected to play a crucial role. We have previously
6
reported the synthesis of polydentate ligands containing flexible biphenyl
1
and rigid 1,10-phenanthroline spacers. We now describe the preparation of
a series of acyclic and macrocyclic Schiff-base ligands with biomimetic
potential.
*
Corresponding author.
2
405
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
2
406
KAYE AND WELLINGTON
Figure 1. Generalised representation of dinuclear complex prior to dioxygen
bridging.
Scheme 1.
The target ligands 3a–f and 5 (Scheme 1) contain acyclic spacers which
3
1
2
were expected to illustrate substituent (R , R , R ) and chain-length effects.
Although the active site in tyrosinase is believed to contain imidazolyl
7
donors, imidazole-containing imino ligands are prone to intramolecular
8
cyclisation and, consequently, 2-(2-aminoethyl)pyridine 2 was chosen to
provide the ‘‘coordinating arms’’ of the ligand systems. The relative posi-
tions of the imine and pyridine nitrogen donors are expected to favour the
formation of 6-membered chelates (as illustrated in Figure 1), which are
9
known to permit changes in the oxidation state of copper.

ORDER
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DESIGNER LIGANDS. VII
2407
The ligands 3a–f were obtained by reacting 2-(2-aminoethyl)pyridine 2
with the corresponding diketones 1a–f which, with the exception of the
benzylated system 1d, were available commercially. (The diketone 1d was
obtained by standard benzylation of acetylacetone with benzyl bromide in
the presence of sodium methoxide.) Similar condensation of 2,5-hexane-
dione 4 with 2-(2-aminoethyl)pyridine 2 afforded the tetradentate ligand
5
by NMR spectroscopy and high-resolution FAB-MS analysis.
. The ligands were all purified by flash chromatography and characterised
1
The H NMR spectra of CDCl solutions of the ligands 3a–f, in which
3
the imino groups are separated by a single carbon atom, reveal the presence
of extensive tautomerism. On the addition of D O, the characteristic, broad
2
signal at d12–13 ppm [attributed to the hydrogen-bonded amino proton in
tautomer II (Figure 2)] disappears and the multiplet at ca. d3.7 ppm becomes
a triplet, permitting its assignment to the adjacent methylene group. As
conjugated, 6-membered, hydrogen-bonded chelates, the imino-enamine
tautomers II are well stabilised; the corresponding tautomer of the diimine
5 would enjoy none of these advantages and, not surprisingly, exhibits no
evidence of tautomerism.
The novel dibenzo macrocycle 9 was obtained by condensing
,10-phenanthroline-2,9-dicarbaldehyde 7 with 1,2-diaminobenzene 8 in
1
refluxing methanol (Scheme 2). The FAB-MS spectrum revealed the
þ
expected MH peak at m/z 616 and high resolution analysis confirmed
1
the molecular formula. The H NMR spectrum of the recrystallised macro-
ꢀ
cycle 9 in DMSO-d at 30 C is characterised by a complex series of multi-
6
plets in the region, d6.0–9.0 ppm, consistent with the expected structure but
indicative of a loss of symmetry due to ring-puckering. The C NMR
spectrum displays corresponding complexity with a multiplicity of signals
1
3
1
in excess of the expected number. H NMR spectra were run at elevated
ꢀ
temperatures, and the increasing simplification observed at 75 C and at
ꢀ
90 C supports a slow equilibration between ring-puckered conformers.
Figure 2. Tautomerism in the Schiff-base ligands 3a–f.

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2
408
KAYE AND WELLINGTON
Scheme 2.
Biomimetic studies, using 2,4-di-tert-butylphenol (DTBP) and 3,5-di-
tert-butylcatechol (DTBC) as substrates, indicate that the copper(II) com-
plexes of selected Schiff-base ligands exhibit both phenolase (DTBP ! the
coupled, biphenyl derivative) and catecholase (DTBC ! the quinone deri-
vative) activity. The results of these studies will be reported elsewhere.
EXPERIMENTAL
Infrared spectra were recorded on a Perkin Elmer 2000 spectrophoto-
meter using potassium bromide discs. NMR spectra were recorded on a
Bruker AMX 400 spectrometer, and chemical shifts are reported relative
to the solvent peaks. Low-resolution mass spectra were obtained on a
Hewlett Packard 5988A mass spectrometer, and high-resolution FAB
mass spectra were obtained on a VG Micromass 70-70E spectrometer
(
Ion tech B11N FAB-gun), using Xe as bombarding gas (University of
Potchefstroom). The diketone 1d was prepared by a standard procedure,
the remaining diketones 1a–c,e,f and 4 were available commercially. The
1
dialdehyde 7 was obtained via SeO oxidation of neocuproine 8. Prepara-
0
2
tion of the acyclic ligands 3a–f is illustrated by the following example.

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DESIGNER LIGANDS. VII
2409
0
N,N -Bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 3a
Acetylacetone 1a (0.41 mL, 4.0 mmol) was dissolved in CHCl (5 mL).
3
To this solution, 2-(2-aminoethyl)pyridine 2 (0.95 mL, 7.9 mmol) was added
and the resulting mixture was boiled under reflux for 2 h, and then stirred
at room temperature for 48 h. The completion of the reaction was con-
firmed by TLC. The solvent was removed under reduced pressure and the
residue purified by chromatography [flash chromatography on silica; elution
0
wih MeOH-benzene-EtOAc (1:4:4)] to afford, as a brown oil, N,N -bis[2-(2-
1
1
þ
pyridyl)ethyl]pentane-2,4-diimine 3a
þ
(0.70 g, 57%) (Found: MH ,
09.2079. C H N requires MH , 309.2079); d (400 MHz; CDCl ) 1.82
3
1
9
24
4
H
3
(
3H, s, CH ), 1.95 (3H, s, CH ), 3.01 (4H, t, NHCH CH ), 3.65 (4H, q,
3 3 2 2
NHCH CH ), 4.89 (1H, s, NHC¼CH), 7.09–7.14 (2H, m, ArH), 7.16 (2H,
2
2
d, ArH), 7.59 (2H, t, ArH), 8.53 (2H, d, ArH), 10.86 (1H, br s, D O
2
exchangeable, NH); dC (100 MHz; CDCl ) 18.7 (CH ), 28.7 (CH ), 38.8
3
3
3
(
1
NHCH CH ), 42.7 (NHCH CH ), 95.3 (NHC¼CH), 121.7, 123.7, 136.5,
2
2
2
2
49.6, 158.2, 162.9 and 194.8 (ArC, NHC¼C and C¼N).
Analytical data for the other new ligands prepared in this study are as
follows.
3
brown oil, (0.48 g, 43%); (Found: MH , 323.2235. C H N requires
0
11
-Methyl-N,N -bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 3b, as a
þ
2
0
26
4
þ
MH , 323.2236); dH (400 MHz; CDCl ) 1.77 (3H, s, CH ), 1.90 (3H, s,
3
3
CH ), 2.08 (3H, s, CH ), 3.01 (4H, t, NHCH CH ), 3.65 (4H, q,
NHCH CH ), 7.11 (2H, m, ArH), 7.18 (2H, d, ArH), 7.58 (2H, td, ArH),
3
3
2
2
2
2
8
.52 (2H, d, ArH), 12.00 (1H, br s, NH); d (100 MHz; CDCl ) 14.7 (CH ),
C
3
3
1
5.0 (CH ), 28.4 (CH ), 39.0 (NHCH CH ), 43.1 (NHCH CH ), 98.1
3
3
2
2
2
2
(
NHC¼C), 121.6, 123.6, 136.5, 149.5, 158.5, 161.9 and 194.6 (ArC,
NHC¼C and C¼N).
0
11
3
-Ethyl-N,N -bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 3c,
þ
as a
brown oil, (0.73 g, 35%) (Found: MH , 337.2392. C H N requires
2
0
28
4
þ
MH , 337.2392); dH (400 MHz; CDCl ) 0.94 (3H, t, CH CH ), 1.90 (3H,
3
2
3
s, CH ), 2.10 (3H, s, CH ), 2.20 (2H, q, CH CH ), 3.01 (4H, NHCH CH ),
3.65 (4H, q, NHCH CH ), 7.10 (2H, t, ArH), 7.17 (2H, d, ArH), 7.57 (2H, t,
3
3
2
3
2
2
2 2
ArH), 8.52 (2H, d, ArH), 12.14 (1H, br s, NH); d (100 MHz; CDCl ) 14.3
C
3
(
CH CH ), 15.5 (CH ), 22.0 (CH CH ), 27.3(CH ), 38.9 (NHCH CH ),
2 3 3 2 3 3 2 2
4
1
3.1 (NHCH CH ), 105.5 (NHC¼C), 121.6, 123.6, 136.5, 149.5, 158.5,
2
2
62.2 and 194.6 (ArC, NHC¼C and C¼N).
0
11
-Benzyl-N,N -bis[2-(2-pyridyl)ethyl]pentane-2,4-diimine 3d, as a
3
brown oil, (0.35 g, 25%) (Found: MH , 399.2548. C H N requires
MH , 399.2549); dH (400 MHz; CDCl ) 1.80 (3H, s, CH ), 2.03 (3H, s,
þ
2
6
30
4
þ
3
3
CH ), 3.07 (4H, t, NHCH CH ), 3.63 (2H, s, CH Ph), 3.71 (4H, q,
NHCH CH ), 7.10 (2H, d, ArH), 7.07–7.18 (4H, m, ArH), 7.19–7.29 (3H,
3
2
2
2
2
2

ORDER
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2
410
KAYE AND WELLINGTON
m, ArH), 7.61 (2H, td, ArH), 8.54 (2H, d, ArH), 12.36 (1H, br s, NH); dC
(
(
100 MHz; CDCl3) 15.0 (CH3), 27.9 (CH3), 34.6 (CH Ph), 39.0
NHCH CH ), 43.2 (NHCH CH ), 101.4 (CCH Ph), 121.7, 123.8, 125.7,
2
2
2
2
2
2
1
27.5, 128.4, 136.5, 141.7, 149.6, 158.4, 163.7 and 195.4 (ArC, NHC¼C
and C¼N).
0
11
,3-Diphenyl-N,N -bis[2-(2-pyridyl)ethyl]propane-1,3-diimine 3e, as
1
a yellow-green oil, (0.90 g, 58%) (Found: MH , 433.2392. C H N
þ
2
9
28
4
þ
requires MH , 433.2392); d (400 MHz; CDCl ) 3.02 (4H, t, NHCH CH ),
H
3
2
2
3
.64 (4H, q, NHCH CH ), 5.69 (1H, s, NHC¼CH), 7.09–7.17 (4H, m,
2
2
ArH), 7.26–7.28 (2H, m, ArH), 7.33–7.43 (6H, m, ArH), 7.53–7.60 (2H,
m, ArH), 7.83–7.87 (2H, m, ArH), 8.49 (2H, d, ArH), 11.41 (1H, br s,
NH); dC (100 MHz; CDCl ) 39.4 (NHCH CH ), 44.4 (NHCH CH ), 93.6
3
2
2
2
2
(
1
NHC¼CH), 121.6, 123.6, 127.0, 127.6, 128.1, 128.5, 129.4, 130.6, 135.6,
36.4, 140.4, 149.5, 158.2, 166.7 and 188.4 (ArC, NHC¼C and C¼N).
0
11
1
-Phenyl-N,N -bis[2-(2-pyridyl)ethyl]butane-1,3-diimine 3f,
as a
light-brown oil, (0.77 g, 43%) (Found: MH , 371.2235. C H N requires
MH , 371.2236); dH (400 MHz; CDCl ) 1.97 (3H, s, CH ), 3.09 (4H, t,
þ
2
4
26
4
þ
3
3
NHCH CH ), 3.76 (4H, q, NHCH CH ), 5.60 (1H, s, NHC¼CH), 7.14
2
2
2
2
(
2H, m, ArH), 7.20 (2H, d, ArH), 7.33–7.43 (3H, m, ArH), 7.59 (2H, td,
ArH), 7.82 (2H, m, ArH), 8.56 (2H, d, ArH), 11.49 (1H, br s, NH); dC
(
100 MHz; CDCl ) 19.2 (CH ), 38.8 (NHCH CH ), 42.9 (NHCH CH ),
3 3 2 2 2 2
9
1
2.1 (NHC¼CH), 121.7, 123.7, 126.8, 128.0, 130.3, 136.5, 140.4, 149.6,
58.2, 164.7 and 187.7 (ArC, NHC¼C and C¼N).
0
N,N -Bis[2-(2-pyridyl)ethyl]hexane-2,5-diimine 5, as a brown oil,
þ þ
0.68 g, 60%) (Found: MH , 323.2236. C H N requires MH ,
20 26 4
(
ꢁ
1
3
23.2236); vmax(NaCl/cm ) 1652 (C¼N); d (400 MHz; CDCl ) 2.13 (6H,
H
3
s, CH ), 3.06 (4H, t, CH CH N), 4.13 (4H, t, CH CH N), 5.74 (4H, s,
3 2 2 2 2
N¼CCH ), 6.92 (2H, d, ArH), 7.12–7.18 (2H, m, ArH), 7.55 (2H, td,
2
ArH), 8.57 (2H, d, ArH); dC (100 MHz; CDCl ) 12.3 (CH ), 39.6
3
3
(
1
CH CH C¼N), 43.4 (CH CH C¼N), 105.2 (N¼CCH ), 121.7, 123.6,
2
2
2
2
2
27.4, 136.5, 149.5 and 158.6 (ArC and C¼N).
The Dibenzo Macrocycle 9
A stirred mixture of 1,10-phenanthroline-2,9-dicarbaldehyde 7 (0.70 g,
.0 mmol) and 1,2-diaminobenzene (0.35 g, 3.0 mmol) in MeOH (85 mL) was
3
boiled under reflux for 5 min. The mixture was then stirred at room tem-
perature for 12 h during which time a yellow solid precipitated, which was
filtered off and recrystallised from THF-hexane to give, as a cream powder,
ꢀ
þ
the dibenzo macrocycle 9 (0.56 g, 30%), mp 239–241 C (Found: MH
þ
6
16.2122. C H N requires MH , 616.2124); vmax(KBr/cmꢁ1)1619 (C¼N).
4
0
24
8

ORDER
REPRINTS
DESIGNER LIGANDS. VII
ACKNOWLEDGMENTS
2411
The authors thank MINTEK for a bursary (to K.W.W.), and
MINTEK, Rhodes University and the National Research Foundation for
generous financial support.
REFERENCES
1
2
3
. Kaye, P.T.; Wellington, K.W. Synth. Commun. Part VI, 2001, 31, 799.
. Karlin, K.D.; Gultneh, Y. J. Chem. Ed. 1985, 62, 983.
. Solomon, E.I.; Sundaram, U.M.; Machonkin, T.E. Chem. Rev. 1996,
96, 2563.
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4, 727.
. Burton, S.G.; Kaye, P.T.; Wellington, K. W. Synth. Commun. in press.
. Tyeklar, Z.; Karlin, K.D. Acc. Chem. Res. 1989, 22, 241.
. Sorrell, T.N. Tetrahedron 1989, 45, 3; Casella, L., Gullotti, M.;
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6
7
8
´
9
1
0. Chandler, C.J.; Deady, L.W.; Reiss, J.A. J. Heterocycl. Chem. 1981,
8, 599.
1
1. In CDCl , the compound exists as the imino-enamine tautomer, and
the NMR data are cited for this tautomer.
1
3
Received in the USA November 6, 2000

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