Synthesis, characterization and anti-Trypanosoma cruzi evaluation of ferrocenyl and cyrhetrenyl imines derived from 5-nitrofurane

Article abstract of DOI:10.1016/j.jorganchem.2011.06.038

A series of new cyrhetrenyl and ferrocenylimines complexes derived from 5-nitrofurane were designed, synthesized and characterized. The ¹H and ¹³C NMR spectra indicate that these compounds adopt an anti-(E) conformation in solution, and confirmed for 1b by the X-ray crystal crystallography. The electronic effects of cyrhetrenyl (1b) and ferrocenyl (1a) bound directly to nitrogen have been correlated with the chemical shift of the iminic carbon. The trypanocidal activity (Tulahuen strain of Trypanosoma cruzi) of these compounds has been studied with respect to the substituent on the nitrogen atom of the 5-nitrofurfurylideneamino pharmacophore. Even though all the resulting derivatives were less active than Nifurtimox, the cyrhetrenyl complex (1b), compared with ferrocenyl (1a) or purely organic (4a and 4b) analogues, was more efficient as antichagasic agent. This result is likely due to the enhanced lipophilic character of the molecules or from a possible synergy between the cyrhetrenyl and 5-nitrofurane groups.

Full text of DOI:10.1016/j.jorganchem.2011.06.038

Journal of Organometallic Chemistry 696 (2011) 3238e3244
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis, characterization and anti-Trypanosoma cruzi evaluation of ferrocenyl
and cyrhetrenyl imines derived from 5-nitrofurane
,
a
b
Rodrigo Arancibia a, A. Hugo Klahn a , Gonzalo E. Buono-Core , Enrique Gutierrez-Puebla ,
*
Angeles Monge b, Manuela E. Medina b, Claudio Olea-Azar c, Juan D. Maya d, Fernando Godoy e
a Instituto de Quimica, Pontificia Universidad Catolica de Valparaíso, Casilla 4059, Valparaíso, Chile
b Instituto de Ciencias de Materiales de Madrid, Consejo Superior de Investigaciones, Cientificas, Sor Juana Inés de la Cruz 3, 28049 Madrid, Spain
c Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y, Farmacéuticas, Universidad de Chile, Casilla 233, Santiago, Chile
d Programa de Farmacología Clínica y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
e Departamento de Química de los Materiales, Facultad de Química y Biología, Universidad de Santiago de Chile, Casilla 40, Santiago, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new cyrhetrenyl and ferrocenylimines complexes derived from 5-nitrofurane were designed,
synthesized and characterized. The 1H and 13C NMR spectra indicate that these compounds adopt an
anti-(E) conformation in solution, and confirmed for 1b by the X-ray crystal crystallography. The elec-
tronic effects of cyrhetrenyl (1b) and ferrocenyl (1a) bound directly to nitrogen have been correlated
with the chemical shift of the iminic carbon. The trypanocidal activity (Tulahuen strain of Trypanosoma
cruzi) of these compounds has been studied with respect to the substituent on the nitrogen atom of the
5-nitrofurfurylideneamino pharmacophore. Even though all the resulting derivatives were less active
than Nifurtimox, the cyrhetrenyl complex (1b), compared with ferrocenyl (1a) or purely organic (4a and
4b) analogues, was more efficient as antichagasic agent. This result is likely due to the enhanced lipo-
philic character of the molecules or from a possible synergy between the cyrhetrenyl and 5-nitrofurane
groups.
Received 17 June 2011
Received in revised form
29 June 2011
Accepted 30 June 2011
Keywords:
Cyrhetrenylimines
Ferrocenylimines
5-Nitrofurane
Antichagasic activity
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
[3,4]. Nfx may act by generating free radicals toxic species through
a
redox-cycling process, and Bnz may cause reactions with
American Trypanosomiasis (Chagas disease) is one of the most
common endemic parasitic diseases in Central and South America
and is caused by the protozoa Trypanosoma cruzi (T. cruzi). The most
recent data from the WHO indicate that over 24 million people, or
8% of the Latin-American population, are infected or are serologi-
cally positive for T. cruzi [1]. Current pharmacological treatments
have been based on dated and nonspecific drugs such as
NifurtimoxÒ (Nfx, a nitrofuran derivative, Fig. 1) and BenznidazoleÒ
(Bnz, a nitroimidazole derivative, Fig. 1).
Both drugs produce significant side effects such as peripheral
neuropathy, anorexia, vomiting and allergies, as well as consider-
able cardiac and renal toxicity [2]. While the toxic effects and the
mechanisms of action of Nfx and Bnz are not yet fully understood
[3,4], a large number of new antitrypanosomal agents have been
developed with derivatives structurally related to these drugs
[5e8]. It has been proposed in several studies that the bioreduction
of the nitro group during metabolism causes activity in these drugs
macromolecules, including the DNA, lipids and proteins of the
parasite.
The nonselective bioreduction of these drugs are believed to
cause the toxic side effects in the mammalian host. For these
reasons, there is an urgent need for the development of new
effective and nontoxic antichagasic compounds.
Different strategies have been used to search for new anti-
trypanosomal agents. Several organic compounds containing
a nitro-aromatic system have been proposed as anti-T. cruzi agents,
including nitroimidazole [9], nitrofurane [10] and nitroindazole
[11]. Metal complexes also appear to be a promising alternative in
the search for a pharmacological solution to Chagas disease [12].
Cerecetto and co-workers used an interesting approach to develop
transition metal complexes by combining ligands showing anti-
trypanosomal activity with pharmacologically active metals. On the
basis of this approach, a series of ligands derived from the 5-
nitrofuryl pharmacophore (5-nitro-2-furaldehyde semicarbazone,
N4-n-butyl-5-nitrofuraldehyde semicarbazone, 3-(5-nitrofuryl)
acroleine semicarbazone and nitrofurylthiosemicarbazones) coor-
dinated to rhenium [13], ruthenium [14] and palladium [15,16]
* Corresponding author. Fax: þ56 32 273422.
E-mail address: hklahn@ucv.cl (A.H. Klahn).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.06.038

R. Arancibia et al. / Journal of Organometallic Chemistry 696 (2011) 3238e3244
3239
spectrum (based on 187Re) m/z: 365 [Mþ]; 337 [Mþ ꢂ CO]; 309
[Mþ ꢂ 2CO]; 281 [Mþ ꢂ 3CO].
2.2.2. N1-(Ferrocenylmethyl)-1,4-phenylendiamine (5b)
The ferrocenecarboxaldehyde (214.0 mg, 1.0 mmol) and 1,4-
phenylendiamine (108.0 mg, 1.0 mmol) were dissolved in anhy-
drous methanol (20.0 mL). The solution was refluxed in a nitrogen
atmosphere for 3 h. After this time, the solvent was removed in
a vacuum, and the resulting red solid was dissolved in anhydrous
THF (30.0 mL) followed by the addition of an excess of solid LiAlH4
(152.0 mg, 4.0 mmol). The mixture was stirred and refluxed in
a nitrogen atmosphere for 1 h. The reaction mixture was quenched
with methanol (20.0 mL) and filtered, and the solvents were
removed in a vacuum. The residual solid was dissolved in a minimal
amount of dichloromethane and transferred to a chromatography
column packed with silica gel in hexane. Elution with CH2Cl2/
hexane (1:1) separated a red band, which was evaporated to until it
was dry. A red microcrystalline solid was obtained after crystalli-
Fig. 1. Drugs commercially available for the treatment of Chagas disease: Nifurtimox
(Nfx) and Benznidazole (Bnz).
centres have been prepared. Some of these complexes are more
active against T. cruzi than the corresponding free ligands.
To the best of our knowledge, organometallic complexes bearing
antitrypanosomal groups have not yet been reported. While the
synthesis of 5-nitrofurfurylidenaminoferrocene has been briefly
described, its potential biological activity was not studied [17]. This
lack of research is in sharp contrast to the vast literature detailing
biomolecules covalently bound to ferrocene and their applications
[18].
In this work, we report the synthesis, characterization and
biological evaluation of new bioorganometallic compounds con-
taining the 5-nitrofuryl group attached to cyrhetrenyl and ferro-
cenyl fragments through conjugated and nonconjugated bridges.
zation with
a dichloromethane-hexane mixture (1:2). This
compound was characterized by 1H NMR and MS as bis-
ferrocenylmethyl-phenylendiamine [24]. Elution with pure CH2Cl2
moved a second red band. From this band red microcrystals of 5b
were obtained after the removal of the solvent and after crystalli-
zation with CH2Cl2/hexane (1:5) at ꢂ18 ꢀC (yield: 122.0 mg,
2. Experimental
0.40 mmol, 40%). 1H NMR:
d 3.36 (s, 3H, NH, NH2); 3.90 (s, 2H, CH2);
4.13 (t, J ¼ 2.4 Hz, 2H, C5H4); 4.17 (s, 5H, C5H5); 4.24 (t, J ¼ 2.4 Hz, 2H,
C5H4); 6.57 (d, 2H, J ¼ 8.3 Hz, C6H4); 6.63 (d, 2H, J ¼ 8.3 Hz, C6H4).
Mass spectrum m/z: 306 [Mþ].
2.1. Materials
Ferrocene (98%), ferrocenecarboxaldehyde (98%), 5-nitro-2-
furaldehyde (99%), p-nitro-aniline (99%), 1,4-phenylendiamine
(98%), NH2OH$HCl, LiAlH4 and NaBH4 were obtained from
Aldrich. The solvents such as CH2Cl2, C6H6, MeOH and THF were
obtained commercially and were purified using standard methods.
2.2.3. N1-(Cyrhetrenylmethyl)-1,4-phenylendiamine (5c)
The 1,4-phenylendiamine 54.0 mg (0.5 mmol) was added to
a solution of (h
5-C5H4CHO)Re(CO)3 181.0 mg (0.5 mmol) in anhy-
drous methanol (10.0 mL). The mixture was refluxed in a nitrogen
atmosphere for 3 h. After this time, the solution was cooled, and an
excess of solid NaBH4 (76.0 mg, 2.0 mmol) was added in a nitrogen
atmosphere and stirred for 2 h. After this time, the IR spectrum
Complexes (
5-C5H4CN)Re(CO)3 [21], (
Fc [23] (Fc ¼ Fe(
5-C5H5)) were prepared according to a procedure
h
5-C5H4CHO)Re(CO)3 [19], (
h
5-C5H4NH2)Re(CO)3 [20],
5-C5H4NH2)
(h
h
5-C5H4CH2NH2)Fc [22], (
h
h
in the literature. The infrared spectra were recorded in solution
(NaCl cell) or as solid (KBr pellets) on a PerkineElmer FT-1605
spectrophotometer. The 1H and 13C NMR spectra were measured
in CDCl3 solution on a Bruker AVANCE 400 spectrometer. The 1H
NMR chemical shifts were referenced using the chemicals shifts of
residual solvent resonances, and 13C chemical shifts to solvent
peaks. The mass spectra were obtained on a Thermo-Finnigan MAT
900XP, at the Facultad de Ciencias Químicas y Farmacéuticas, Uni-
versidad de Chile. The elemental analyses were conducted on
a PerkineElmer 2400 series II, CHNS/O Analyzer.
showed the presence of two new n(CO) absorption bands that were
shifted to low energy in comparison to the aldehyde precursor. The
reaction was quenched with H2O (2 drops). The pale-yellow oily
solid obtained after the methanol was evaporated was chromato-
graphed on a silica gel column that had been previously washed
with hexane. The product eluted with CH2Cl2. Complex 5c was
isolated as a yellow oil after purification from CH2Cl2/hexane (1:5)
at ꢂ18 ꢀC (yield: 204.0 mg, 0.45 mmol, 90%). IR (CH2Cl2, cmꢂ1
, nCO):
2022 (s), 1924 (vs). 1H NMR:
d
4.1 (s, 2H, CH2); 5.25 (t, J ¼ 2.4 Hz, 2H,
C5H4); 5.40 (t, J ¼ 2.4 Hz, 2H, C5H4); 6.55 (d, 2H, J ¼ 8.1 Hz, C6H4);
6.62 (d, 2H, J ¼ 8.1 Hz, C6H4), NH (not observed).
2.2. Synthesis of cyrhetrenyl and ferrocenylamines
2.3. Synthesis of ferrocenyl and cyrhetrenyl imines
2.2.1. Cyrhetrenylmethylamine (5a)
The cyanocyrhetrene [21] (170.0 mg, 0.50 mmol) was dissolved
in dry THF (20.0 mL) at 0 ꢀC, and an excess of LiAlH4 (2.0 mL, 1 M in
THF, 2.0 mmol) was added dropwise. The mixture was then stirred
for 1 h in a nitrogen atmosphere. A mixture of benzene (10.0 mL)
and CH2Cl2 (15.0 mL) was added with caution, and then a few drops
of 5 M NaOH were added. The mixture was filtered through Celite,
and the solution was evaporated under reduced pressure until it
was dry. The residue was extracted with CH2Cl2 (5 ꢁ 10.0 mL) and
washed with water and brine. After drying over MgSO4, the solvent
was removed in a rotary evaporator. Crystallization with CH2Cl2/
hexane (1:5) at ꢂ18 ꢀC gave a brown solid of 5a (yield: 127.0 mg,
0.35 mmol, 70%). This compound was quite unstable in solution and
in solid state and should be prepared immediately before use. IR
The imine compounds were prepared by modifying a procedure
described by Pudova et al. [23]. Equimolar amounts of the amino
complexes and 5-nitrofuraldehyde were dissolved in anhydrous
benzene (20.0 mL) and were heated in a water bath for 1 h, in
a nitrogen atmosphere. The solvent was then removed under
vacuum, and the resulting coloured solids were purified by crys-
tallization with CH2Cl2/hexane (1:5) at ꢂ18 ꢀC.
2.3.1. (5-Nitro-2-furfurylideneamino)ferrocene (1a)
Purple solid, yield: 90% (291.0 mg, 0.85 mmol). IR (KBr): (
nC]N
cmꢂ1): 1610 (w). 1H NMR:
d
4.22 (s, 5H, C5H5); 4.37 (t, J ¼ 2.2 Hz, 2H,
C5H4); 4.67 (t, J ¼ 2.2 Hz, 2H, C5H4); 7.11(d, J ¼ 3.8 Hz, 1H, C4H2O);
7.40 (d, J ¼ 3.8 Hz, 1H, C4H2O); 8.48 (s, 1H, CH]N). 13C NMR:
d 63.7
(CH2Cl2, cmꢂ1
,
n
CO): 2022 (s), 1924 (vs). 1H NMR:
d
4.42 (s, 2H, CH2);
(C5H4); 69.0 (C5H4); 70.1 (C5H5); 102.0 (C5H4ipso); 112.3 (C4H2O);
5.32 (t, J ¼ 2.4 Hz, 2H, C5H4); 5.45 (t, J ¼ 2.4 Hz, 2H, C5H4). Mass
113.5 (C4H2O); 114.6 (C4H2Oipso); 143.6 (CH]N); 154.5 (C4H2Oipso).

3240
R. Arancibia et al. / Journal of Organometallic Chemistry 696 (2011) 3238e3244
Mass spectrum (m/z): 324 [Mþ]. Anal.(%) Calc. for C15H12N2O3Fe: C,
55.56; H, 3.70 and N, 8.64; found: C, 55.60; H, 3.71 and N, 8.62.
(C6H4); 113.8 (C4H2O); 123.0 (C6H4); 140.0 (C6H4); 141.2
(C4H2Oipso); 147.3 (CH]N); 154.5 (C4H2Oipso); 193 (CO). Mass
spectrum (based on 187Re) m/z: 579 [Mþ]; 349 [Mþ ꢂ C11H8N3O3];
321 [Mþ ꢂ C11H8N3O3 ꢂ CO]; 293 [Mþ ꢂ C11H8N3O3 ꢂ 2CO]; 265
2.3.2. (5-Nitro-2-furfurylideneamino)cyrhetrene (1b)
Orange crystal, yield: 90% (58.7 mg, 0.13 mmol). IR (CH2Cl2,
[Mþ
ꢂ C11H8N3O3 ꢂ 3CO]. Anal. (%) Calc. for C20H14N3O6Re: C,
cmꢂ1): 2025 (s) (
d
n
CO); 1929 (vs) (
5.33 (t, 2H, J ¼ 2.3 Hz, C5H4); 5.65 (t, 2H, J ¼ 2.3 Hz, C5H4); 7.16 (d,
1H, J ¼ 3.8 Hz, C4H2O); 7.40 (d, 1H, J ¼ 3.8 Hz, C4H2O); 8.35 (s, 1H,
CH]N). 13C NMR:
78.6 (C5H4); 82.5 (C5H4); 112.8 (C4H2O); 114.6
n
CO); 1625 (w) (
n
C]N). 1H NMR:
41.45; H, 2.42 and N, 7.25; found: C, 40.98; H, 2.40 and N, 7.30.
2.3.7. N-[(5-Nitrofuran-2-yl)methylen]-benzene-1,4-diamine (4a)
d
Purple crystals, yield: 90% (208.0 mg, 0.9 mmol). IR (KBr): (
nC]
(C5H4ipso); 115.7 (C4H2O); 122.2 (C4H2Oipso); 149.0 (CH]N); 152.1
(C4H2Oipso); 193.2 (CO). Mass spectrum (based on 187Re) m/z: 474
[Mþ], 446 [Mþ ꢂ CO], 418 [Mþ ꢂ 2CO], 390 [Mþ ꢂ 3CO]. Anal. (%)
Calc. for C13H7N2O6Re: C, 32.91; H, 1.47 and N, 5.91; found: C, 32.69;
H, 1.41 and N, 5.82.
N cmꢂ1): 1628 (w). 1H NMR:
d
6.70 (d, J ¼ 8.2 Hz, 2H, C6H4); 7.11 (d,
J ¼ 3.8 Hz, 1H, C4H2O); 7.20 (d, J ¼ 8.2 Hz, 2H, C6H4); 7.41 (d,
J ¼ 3.8 Hz, 1H, C4H2O); 8.50 (s, 1H, CH]N). 13C NMR:
d: 112.6
(C4H2O); 114.1 (C4H2O); 123.5 (C6H4); 139.0 (C6H4); 147.3 (CH]N);
154.5 (C4H2Oipso). Mass spectrum m/z: 231 [Mþ]. Anal. (%) Calc. for
C11H9N3O3: C, 57.14; H, 3.90 and N, 18.18; found: C, 57.14; H, 3.89
and N, 18.20.
2.3.3. (5-Nitro-furfurylideneaminomethyl)ferrocene (2a)
The synthesis of complex 2a was carried out similarly to that
described for the general procedure, but by refluxing for 6 h using
a DeaneStark apparatus. Compound 2a was obtained as a red solid,
2.3.8. 4-Nitro-N-((5-nitrofuran-2-yl)methylene)benzenamine (4b)
Yellow crystals, yield: 90% (235.0 mg, 0.9 mmol). IR (KBr): (
nC]
yield: 90% (304.0 mg, 0.9 mmol). IR (KBr): (
1H NMR:
4.17 (s, 5H, C5H5); 4.18 (s, 4H, C5H4); 4.63 (d, J ¼ 1.5 Hz,
2H, CH2); 6.99 (d, J ¼ 3.8 Hz, 1H, C4H2O); 7.35 (d, J ¼ 3.8 Hz, 1H,
C4H2O); 8.07 (s, 1H, CH]N). 13C NMR:
60.0 (CH2); 68.4 (C5H4);
n
C]N cmꢂ1): 1628 (w).
N cmꢂ1): 1632 (w). 1H NMR:
d
7.28 (d, J ¼ 3.9 Hz, 1H, C4H2O); 7.34
d
(d, J ¼ 8.8 Hz, 2H, C6H4); 7.41 (d, J ¼ 3.9 Hz, 1H, C4H2O); 8.30 (d,
J ¼ 8.8 Hz, 2H, C6H4); 8.37 (s, 1H, CH]N). 13C NMR:
d 112.5 (C4H2O);
d
116.3 (C4H2O); 121.5 (C6H4); 125.2 (C6H4); 148.9 (CH]N); 152.1
(C4H2Oipso); 155.5 (C4H2Oipso). Mass spectrum m/z: 261 [Mþ]. Anal.
(%) Calc. for C11H7N3O5: C, 50.57; H, 2.68 and N, 16.09; found: C,
50.58; H, 2.69 and N, 16.02.
68.6 (C5H5); 68.7 (C5H4); 83.6 (C5H4ipso); 112.7 (C4H2O); 112.9
(C4H2O); 114.6 (C4H2Oipso); 148.2 (CH]N); 153.0 (C4H2Oipso). Mass
spectrum m/z: 338 [Mþ]. Anal. (%) Calc. for C16H14N2O3Fe: C, 56.80;
H, 4.14 and N, 8.28; found: C, 56.70; H, 4.10 and N, 8.32.
2.4. Biological assays
2.3.4. (5-Nitro-furfurylideneaminomethyl)cyrhetrene (2b)
A suspension of 3 ꢁ 106 epimastigotes of the Tulahuen strain of
T. cruzi was cultured at 28 ꢀC in monophasic Diamond’s culture
medium and was supplemented with 4 mM haemin and inactivated
bovine calf serum at a final concentration of 4%. Drugs dissolved in
DMSO (final concentration of 1%) were added to the culture media
to give 0.5e150 mM final concentrations. The parasite growth was
followed by nephelometry for 7e10 days. The nephelometry
readings were directly proportional to the concentration of para-
sites. No toxic effect of the DMSO alone was observed [24]. The
growth culture constant (k) for each drug concentration employed
was calculated using an exponential epimastigote growth curve
(regression coefficient > 0:97, P < 0:05). The slope resulting from
plotting the natural logarithm (Ln) of the nephelometry reading
versus time (hours) corresponds to k (hrꢂ1). The IC50 is defined as
the drug concentration needed to diminish k by 50%. It is calculated
by a linear regression analysis from the k values and the tested
concentrations. Reported values are the means of three indepen-
dent experiments.
The synthesis of complex 2b was carried out similarly to that
described for 2a. Complex 2b was obtained as brown solid, yield:
60% (78.0 mg, 0.16 mmol). IR (CH2Cl2, cmꢂ1): 2022 (s) (
n
CO); 1926
(s) (nCO); 1622 (w) (n d 4.60 (s, 2H, CH2); 5.32 (t, 2H,
C]N). 1H NMR:
J ¼ 2.3 Hz, C5H4); 5.45 (t, 2H, J ¼ 2.3 Hz, C5H4); 7.07 (d,1H, J ¼ 3.8 Hz,
C4H2O); 7.40 (d, 1H, J ¼ 3.8 Hz, C4H2O); 8.17 (s, 1H, CH]N). 13C
NMR:
d 41.4 (CH2); 83.5 (C5H4); 83.7 (C5H4); 112.8 (C4H2O); 114.6
(C5H4ipso); 115.7 (C4H2O); 122.2 (C4H2Oipso); 147.1 (CH]N); 152.1
(C4H2Oipso); 193.2 (CO). Mass spectrum (based on 187Re) m/z: 488
[Mþ]; 460 [Mþ ꢂ CO]; 432 [Mþ ꢂ 2CO]; 404 [Mþ ꢂ 3CO]. Anal. (%)
Calc. for C14H9N2O6Re: C, 34.43; H, 2.87 and N, 5.74; found: C, 34.60;
H, 2.91 and N, 5.80.
2.3.5. (N1-(Ferrocenylmethyl)-N2-(5-nitrofuran-2-yl)methylen)-
1,4-phenylendiamine (3a)
Complex 3a was isolated as red solid, yield: 90% (128.7 mg,
0.3 mmol). IR (KBr): (n d 4.00 (s, 2H,
C]N cmꢂ1): 1625 (w). 1H NMR:
CH2); 4.17 (t, J ¼ 2.4 Hz, 2H, C5H4); 4.20 (s, 5H, C5H5); 4.25 (t,
J ¼ 2.4 Hz, 2H, C5H4); 6.67 (d, J ¼ 8.2 Hz, 2H, C6H4); 7.11 (d, J ¼ 3.1 Hz,
1H, C4H2O); 7.31 (d, J ¼ 8.2 Hz, 2H, C6H4); 7.41 (d, J ¼ 3.1 Hz, 1H,
2.5. Crystal structure determination
C4H2O); 8.42 (s, 1H, CH]N). 13C NMR:
d 43.2 (CH2); 68.0 (C5H4);
68.1 (C5H5); 68.5 (C5H4); 85.6 (C5H4ipso); 112.6 (C4H2O); 112.8
(C4H2O); 113.0 (C4H2Oipso); 123.5 (C6H4); 139.0 (C6H4); 140.2
(C6H4); 148.7 (CH]N); 154.0 (C4H2O ipso). Mass spectrum m/z: 429
[Mþ], 200 [Mþ ꢂ C11H8N3O3]. Anal. (%) Calc. for C22H19N3O3Fe: C,
61.54; H, 4.43 and N, 9.79; found: C, 61.30; H, 4.20 and N, 9.72.
A summary of the fundamental crystal and refinement data for
1b are given in Table 2. Crystals of 1b were selected under a polar-
izing optical microscope and were glued on a glass fibre for a single-
Table 1
13C NMR shifts for Schiff bases.
Compound
13C NMRa (CH]N)
2.3.6. (N1-(Cyrhetrenylmethyl)-N2-(5-nitrofuran-2-yl)methylen)-
1,4-phenylendiamine (3b)
1a
1b
2a
2b
3a
3b
4a
4b
143.6
149.0
148.2
147.1
148.7
147.3
147.3
148.9
Complex 3b was isolated as red crystals, yield: 90% (114.4 mg,
0.2 mmol). IR (CH2Cl2, cmꢂ1): 2022 (s) (
nCO); 1924 (s) (nCO); 1630
(w) (
n
C]N). 1H NMR:
d
4.20 (s, 2H, CH2); 5.31 (t, J ¼ 2.1 Hz, 2H,
C5H4); 5.45 (t, J ¼ 2.1 Hz, 2H, C5H4); 6.69 (d, J ¼ 8.5 Hz, 2H, C6H4);
7.11 (d, J ¼ 3.8 Hz, 1H, C4H2O); 7.30 (d, J ¼ 8.5 Hz, 2H, C6H4); 7.41 (d,
J ¼ 3.8 Hz, 1H, C4H2O); 8.41 (s, 1H, CH]N). 13C NMR:
d: 41.2 (CH2);
a
83.6 (C5H4); 83.8 (C5H4); 107.7 (C5H4ipso); 112.9 (C4H2O); 113.3
ppm, CDCl3.

R. Arancibia et al. / Journal of Organometallic Chemistry 696 (2011) 3238e3244
3241
Table 2
3.1. Synthesis
Crystal data and structure refinement for 1b.
To prepare some of the Schiff bases described below, it was
necessary to synthesize the organometallic amine precursors (h5
C5H4CH2NH2)Re(CO)3 (5a),
5-C5H4CH2eNHe1,4-C6H4NH2)M,
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C13H7N2O6Re
473.41
296(2) K
1.54178 Å
Monoclinic
P2(1)/c
-
(
h
M ¼ Fc (5b), and Re(CO)3 (5c) (Scheme 1). The unreported 5a was
obtained by the reduction of cyanocyrhetrene [21] with LiAlH4. This
compound is quite unstable and should be prepared immediately
prior to use. The compounds 5b and 5c were prepared by first
condensing the organometallic aldehyde with 1,4-phenyldiamine
(1:1 ratio), followed by an in situ reduction with LiAlH4. These
complexes were characterized only by spectroscopy (see
Experimental section).
The imine complexes were synthesized following the same
procedure as described for analogous ferrocenylimines [29] and
cyrhetrenyl imines [30], that is, by the condensation of equimolar
amounts of the corresponding organometalliceamine complex
with 5-nitro-furaldehyde (Scheme 2) [31].
Unit cell dimensions
a ¼ 6.5287(11) Å
a
¼ 90ꢀ.
b ¼ 20.005(3) Å
c ¼ 11.263(2) Å
1407.9(4) Å3
4
b
¼ 106.85ꢀ.
¼ 90ꢀ.
g
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
Theta range for data collection
Index ranges
2.233 Mg/m3
17.201 mmꢂ1
888
4.66e54.02ꢀ
ꢂ5 ꢃ h ꢃ 6, ꢂ21 ꢃ k ꢃ 20, ꢂ10 ꢃ l ꢃ 11
Reflections collected
Independent reflections
3986
1586 [R(int) ¼ 0.1187]
93.3%
0.2781 and 0.1303
Full-matrix least-squares on F2
1586/0/200
Completeness to
q
¼ 54.02ꢀ
Max. and min. Transmission
Refinement method
In all cases, the products were isolated as solids after crystalli-
zation with the CH2Cl2/hexane mixture. They are air-stable and are
soluble in most organic solvents.
Data/restraints/parameters
Goodness-of-fit on F2
1.062
Final R indices [I > 2
R indices (all data)
s(I)]
R1 ¼ 0.0835, wR2 ¼ 0.1956
The IR spectra of these compounds showed the expected
R1 ¼ 0.0855, wR2 ¼ 0.1981
absorption band for the
n
C]N stretch in the range of
C]N
1610e1630 cmꢂ1 in CH2Cl2 solution or KBr disc. Similar
n
frequency values have been reported for Schiff bases derived from
formylferrocene [29] and formylcyrhetrene [30]. The stoichiometry
of the complexes was established by elemental analysis and mass
spectrometry. Each of the imine complexes showed a strong
molecular ion in their mass spectra. For the cyrhetrenyl derivatives,
the successive losses of CO ligands were also present in the spectra.
For all complexes, the 1H NMR spectra showed the presence of
a single compound. A sharp singlet near 8.00e8.50 ppm was
crystal X-ray diffraction experiment. X-ray intensity data were
collected in a Bruker SMART CCD diffractometer equipped with
a normal focus, 2.4 kW sealed tube X-ray source (MoKa radi-
ation ¼ 0.71073 Å). The data were collected at room temperature in
a hemisphere of the reciprocal space by a combination of three sets
of exposures. Each exposure of 20 s covered 0.3ꢀ in
detector distance was 5.08 cm.
u. The crystal to
The unit cell dimensions were determined by a least-squares fit
of reflections collected with I > 2 (I). The first 100 frames were
assigned to the iminic proton, and the two doublets at
d 7.11e7.42
s
were assigned to the hydrogen atoms of the furfuryl ring. For the
ferrocene derivatives 1a, 2a and 3a, the resonances assigned to the
protons of unsubstituted cyclopentadienyl appeared as a singlet in
recollected at the end of the data acquisition to monitor crystal
decay. Data were integrated and scaled using the SAINTplus
program [25]. A semi-empirical absorption and scale correction
based on the equivalent reflection was carried out using SADABS
[26]. Space group determinations were determined using XPREP
[27]. Calculations were performed with the SMART software for
data collection and data reduction and SHELXTL [27]. The struc-
tures were solved by direct methods. The final cycles of refinement
were carried out by full-matrix least-squares analyses with aniso-
tropic thermal parameters for all nonhydrogen atoms. The
hydrogen atoms of the organic ligands were situated at their
calculated positions. Weighted R factors (Rw) and all goodness-of-
fit (S) are based on F2. Conventional R factors (R) are based on F.
the region
d 4.0e4.2. The two triplets observed at 4.27 ppm and
4.62e4.65 ppm are assigned to the hydrogen nuclei of the
substituted ring. These results are in agreement with the values
reported for several analogous iminoferrocene complexes [29,32].
Similarly, complexes 1b, 2b and 3b showed two set of resonances
around 5.31e5.65 ppm for cyrhetrenyl group.
The 13C NMR data also indicate the existence of a single
compound. Despite that these type of compounds could adopt two
different forms (E- or Z-), their 1H and 13C NMR spectra agreed with
those reported for related ferrocenyl and cyrhetrenyl Schiff bases
[29,30,32]; this finding indicates that only one isomer (E-form) was
3. Results and discussion
Our initial goal in preparing organometallic derivatives of
nitrofurane was to compare the electronic effects of ferrocenyl and
cyrhetrenyl groups in the biological activity of these systems
against T. cruzi. For that purpose, we designed the following two
types of compounds: i) those connected electronically between the
two groups through
a simple imine (1a and 1b) and 1,4-
phenyldimine bridge and ii) those containing nitrofurylimine
without any electronic communication with the organometallic
fragment (2a and 2b).
In the first case, we succeed with the synthesis of 1a and 1b;
however, attempts to form the corresponding 1,4-phenyldimine
were unsuccessful because of the instability of such compounds,
which have precedent in the literature [28]. For that reason, we also
included compounds 3a and 3b, which can be considered to be type
ii compounds.
Scheme 1. Synthesis of organometallic amine precursors.

3242
R. Arancibia et al. / Journal of Organometallic Chemistry 696 (2011) 3238e3244
Scheme 2. Synthesis of cyrhetrenyl and ferrocenylimines complexes.
present in the solution. Further proof was provided by an X-ray
crystal structure determination of 1b (see below). The most
important feature of these spectra is the presence of a low field
(1.266 Å) is markedly localized and resembles those measured for
several organometallic imines [29e31]. It is slightly shorter than
those reported for the other compound possessing the 5-
nitrofurane group bound to iminyl carbon [36e38]. The C(6)eC(7)
resonance (
d
143e148) assigned to the iminyl carbon. This reso-
as those reported for other Schiff
ꢀ
nance occurs at almost the same
d
distance (1.439(19) A) is within the range found in O2Ne5-
bases mentioned above. These assignments were confirmed by
1He13C NMR HMBC. It is worth nothing that both the 1H and 13C
NMR spectra of derivatives 2 and 3 showed the presence of
a methylene group and C6H4 and CH2 groups, respectively.
The 13C shifts of the iminyl carbons of 1a and 1b show clear
dependence on the presence of ferrocenyl or cyrhetrenyl bound to
the nitrogen atom. This phenomenon is not observed in
compounds 2 and 3 for which the electronic communication is
impeded by a methylene group (Table 1).
C4H2Oe2-CH]NeR: R ¼ OH (1.441 Å) [36], R ¼ C11H11N2O
(1.438 Å) [37] and R ¼ N3C2H2 (1.430 Å) [38]. However, the internal
ꢀ
ꢀ
CeC (C(7)eC(8), 1.361 A; C(8)eC(9), 1.38(2) A and C(9)eC(10),
The upfield shift observed for the ferrocenyl derivative (1a)
compared with 1b (Dd ¼ 5.4 ppm) can be related to the opposite
electronic effects of these organometallic fragments [33]. Thus, the
known electron-acceptor properties of cyrhetrenyl group [34] are
therefore better than ferrocenyl at stabilizing any positive charge
built up on the iminyl carbon and producing a marked deshielding
of the carbon resonance. Similar results have been reported by
Houlton for
a -
series of ferrocenylimines of the type ((h5
C5H4CHNAr)Fc, Ar ¼ Ph, C6H4X-p, X ¼ H, F, Cl, CN, NO2, OMe) [35].
Furthermore, the dependence of the electronic effects on the aryl
ring substituent in purely organic compounds 4a and 4b are also in
agreement with the above observation (see Table 1).
With the aim of comparing structural parameters of these
compounds with the crystallographic data reported for several
ferrocenyl and cyrhetrenyl imines [30], we undertook a crystallo-
graphic study of complex 1b. Fig. 2 shows an Ortep view of 1b and
the most relevant bond length and angles. Table 2 reports the
crystal structure and refinement data. The structure confirms the E
configuration assigned tentatively by NMR.
Taking into account the internal CeC distances of the cyclo-
pentadienyl ring, a h2 3-coordination mode can be considered for
-h
1b because it possesses three short and two long CeC distances:
C(1)eC(2) 1.380 Å; C(1)eC(5) 1.380 Å; C(4)eC(3) 1.380 Å; C(2)eC(3)
1.410 Å; and C(4)eC(5) 1.430 Å. The dihedral angle between the C5
ring plane and the iminyl group plane is 6.30ꢀ. Thus, the imine
moiety is nearly coplanar with the ring plane. Nevertheless, there is
no appreciable delocalization within these two fragments, as
indicated by the remarkable single bond character of C(1)eN(2)
(1.449(16) Å). Alternatively, the iminic double bond N(1)eC(6)
ꢀ
Fig. 2. Ortep plot of the asymmetrical unit of 1b. Relevant bond length (A): C(1)eN(2)
1.449(16); N(2)eC(6) 1.266(15); C(6)eC(7) 1.439(19); Cp(centroid)eRe(1) 1.961(6) and
angles (ꢀ): N(2)eC(6)eC(7) 122.8(12); C(6)eN(2)eC(5) 120.1(11).

R. Arancibia et al. / Journal of Organometallic Chemistry 696 (2011) 3238e3244
3243
ꢀ
1.360(19)) and CeN(NO2) (1.380(18) A) bond distances of the
nitrofurane group are much shorter than those reported for the
above compounds and may suggest some delocalization of electron
density over the furaneeCH]N moiety. Within the cyrhetrenyl
group, the average ReeC(O) distance and the ReeCeO angle are
concordant with related tricarbonyl cyclopentadienyl rhenium(I)
complexes [39].
Accordingly, we believe that the substantial improvement in the
cytotoxicity of 5-nitrofurfuryl group bearing organometallic
moieties compared with their purely organic analogues could
proceed from two sources: the increase in the lipophilic character
of the drug by incorporating the organometallic entity or by
possible synergism between the two moieties.
4. Conclusion
3.2. Biological assays
Ferrocenyl and cyrhetrenyl Schiff bases containing 5-nitrofurane
pharmacophore were successfully synthesized. Like many other
organometallic imine derivatives, these complexes adopt an anti
configuration for the iminyl moiety, which was confirmed by NMR
data and X-ray crystallography. The electron-donor (ferrocene and
aminophenyl) and electron-withdrawing (cyrhetrene and nitro-
phenyl) capability of the substituents on the iminyl nitrogen
correlate properly with the 13C shift of the carbon nuclei of the C]
N bridging group. The results of an in vitro antitrypanosomal assay
of the compounds against strains of T. cruzi indicate that they are
less active than Nifurtimox. However, some interesting observa-
tions can be reported. Compounds possessing electronic commu-
nication between the organometallic and 5-nitrofurane groups,
such as the cyrhetrenyl derivative, show a better antichagasic
activity. This result is likely due to its electron-withdrawing effects
that are efficiently transferred to the furane group facilitating the
To study the influence of the ferrocene and cyrhetrene incor-
poration in 5-nitrofurfuryl antitrypanosomal compounds, 1a,b,
3a,b and 4a,b were measured against the Tulahuen strain of T. cruzi
(epimastigote). Table 3 shows the IC50 values found for the new
compounds. For comparison, we include the values for the drugs
that are in clinical use.
From the analysis of Table 3, it can be observed that the activity
of the compounds that possess electronic communication between
nitrofurane and the organometallic groups, the cyrhetrenyl deriv-
ative 1b was considerably better than the ferrocenyl analogue 1a,
suggesting that the electron-withdrawing and bulky carbonyl
ligands stabilize a large electron density on the metal in compar-
ison to 1a. If these electronic changes are efficiently transferred
through resonance or polarization [40] to the furane group, then
the reduction of NO2 group should proceed to more easily to form
reduction of NO2 to NO2 ꢂ. This situation contrasts the higher IC50
ꢄ
ꢄꢂ
the radical NO2 and therefore improve its antitrypanosomal
values found for the ferrocene analogue. Therefore, the electronic
effects should be considered an influencing factor in designing new
molecules with potential antitrypanosomal activity. When
compared with their purely organic derivatives, the presence of the
organometallic moieties dramatically enhanced the cytotoxicity,
probably by increasing the lipophilic character or by a possible
synergism between the organometallic and 5-nitrofurfuryl groups.
activity [2].
To confirm this hypothesis, the IC50 of the closely related organic
derivatives 4a (containing an electron-donor aminophenyl) and 4b
(containing an electron-withdrawing nitrophenyl) were measured
under the same experimental conditions. Unfortunately, both
compounds showed remarkably less activity than their organo-
metallic analogues because their IC50 values (>150
mM) were
higher than the limit of the drug concentration.
Acknowledgements
For type ii compounds (2 and 3), the IC50 values appear to be
independent of the presence of the organometallic fragment
because comparable antitrypanosomal activity is observed within
each series. However, clear differences are observed when the IC50
of the two series are compared (2a,b vs 3a,b). The lower values
found for the compounds 3a and 3b that possess an aryl bridge
between the imine and methylcyclopentadienyl metal fragment
can be explained by the increase of the electronic delocalization
between the furane and the aryl ring through the imine bridge.
Considering the IC50 values shown in Table 3, an obvious ques-
tion emergesdwhy do the purely organic derivatives (4a and 4b)
show a remarkably lower activity than 3a and 3b? The literature
reports dealing with the lipophilic enhancement observed in some
drugs by incorporating an organometallic fragment offer insight
[41,42]. On this respect, we have recently demonstrated that the
introduction of the cyrhetrenyl moiety at the end of the lateral
chain of a 4-aminoquinoline scaffold dramatically increased lip-
ophilicity when compared with their pure organic analogues [43].
A.H.K. acknowledges FONDECYT (Project 1110669) and D.I.
Pontificia Universidad Católica de Valparaiso. R.A. acknowledges
MECESUP and FONDECYT for a Doctoral scholarship and D.I.-PUCV
for a Postdoctoral position. The loan of NH4ReO4 from MOLYMET e
Chile is also much appreciated. J.D.M acknowledges project Anillo
ACT112, Programa de Investigacion Asociativa CONICYT and
FONDECYT 1090078.
Appendix A. Supplementary material
CCDC 781523 contains the supplementary crystallographic data
for complex 1b. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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