Synthesis, characterization, and anti-amoebic screening of core-modified 5,20-bis{2-{[(alkyl)(alkyl′)amino]methyl}ferrocen-1-yl}-10,15-diphenyl-21, 23-dithiaporphyrin (=1,1″-(10,15-diphenyl-21,23-dithiaporphine-5,20-diyl) bis[2-{[(alkyl)(alkyl′)amino]methyl}ferrocene]) derivatives

Article abstract of DOI:10.1002/hlca.200800461

The synthesis of the first bis-ferrocenyl-substituted core-modified porphyrins, 5,20-bis{2-{[(alkyl)-(alkyl′)amino]methyl}ferrocen-1-yl}-10, 15-diphenyl-21,23-dithiaporphyrin derivatives 6a - 6j, via a multistep route is reported (Schemes 1, 2, and 4). The synthesis was carried out through acid-catalyzed (BF₃ ? Et2O) condensation of 1,1″- [thiophene-2,5-diylbis(hydroxymethyl)]bis[2-{[(alkyl)(alkyl′)amino]methyl} ferrocenes] 4a - 4j with 2,2′-[thiophene-2,5-diylbis(phenylmethylene)] bis[1H-pyrrole] (5b) in presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (=4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile; DDQ). Characterization of the compounds was done at each step by means of various spectroscopic techniques. The final compounds were screened for in vitro anti-amoebic activity against the strain HM1:IMSS of E. histolytica (Table 2).

Full text of DOI:10.1002/hlca.200800461

1644
Helvetica Chimica Acta – Vol. 92 (2009)
Synthesis, Characterization, and Anti-amoebic Screening of Core-Modified
5,20-Bis{2-{[(alkyl)(alkyl’)amino]methyl}ferrocen-1-yl}-10,15-diphenyl-21,23-
dithiaporphyrin (¼1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-
{[(alkyl)(alkyl’)amino]methyl}ferrocene]) Derivatives
by Abdul R. Bhat, Asif I. Bhat, Fareeda Athar1), and Amir Azam*
Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
(fax: þ 91-11-26980229; e-mail: amir_sumbul@yahoo.co.in)
The synthesis of the first bis-ferrocenyl-substituted core-modified porphyrins, 5,20-bis{2-{[(alkyl)-
(alkyl’)amino]methyl}ferrocen-1-yl}-10,15-diphenyl-21,23-dithiaporphyrin derivatives 6a – 6j, via a multi-
step route is reported (Schemes 1, 2, and 4). The synthesis was carried out through acid-catalyzed (BF3 ·
Et2O) condensation of 1,1’’-[thiophene-2,5-diylbis(hydroxymethyl)]bis[2-{[(alkyl)(alkyl’)amino]me-
thyl}ferrocenes] 4a – 4j with 2,2’-[thiophene-2,5-diylbis(phenylmethylene)]bis[1H-pyrrole] (5b) in
presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (¼4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-
1,2-dicarbonitrile; DDQ). Characterization of the compounds was done at each step by means of various
spectroscopic techniques. The final compounds were screened for in vitro anti-amoebic activity against
the strain HM1:IMSS of E. histolytica (Table 2).
Introduction. – The ferrocene is an important structural motif in a great number of
biologically active compounds and functional molecules [1 – 4]. The chemistry of bis-
ferrocenyl-substituted core-modified porphyrins (¼1,1’’-(core-modified porphyrin-
diyl)bis[ferrocenes] has remained quite unexplored, in contrast to the well-developed
chemistry of ferrocene and its numerous applications in organic synthesis, homogenous
catalysis, and material science [5 – 7]. Recently, core-modified porphyrins or modified
porphyrin macrocycles obtained by replacing one of the N-atoms with a chalcogen- or
C-atom has led to flurry of research activity [8 – 11]. The electronic environment of the
porphyrin p system is expected to change by insertion of these atoms into the porphyrin
core [12]. In addition, they impart different biological properties and are used as
potential agents in photodynamic therapy (PDT) due to their ability to absorb long-
wavelength radiation. Although the literature provides the synthesis of several
ferrocenyl-substituted porphyrins [13 – 15], to the best of our knowledge there are no
reports in the literature on the direct substitution by 2-(aminomethyl)ferrocen-1-yl
groups at the meso position of a core-modified porphyrin ring. Herein, we report the
first successful synthesis of the core-modified porphyrins 6a – 6j bearing two ferrocenyl
moieties, each one substituted with an aminomethyl group. The synthetic methodology
involves a multistep synthesis before the final condensation step. Characterization of
the compounds was done at each step by means of various spectroscopic techniques.
1
)
Present address: Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia,
Jamia Nagar, New Delhi-110025, India
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
1645
The final compounds were evaluated for their in vitro activity in anti-amoebic studies,
globally the second leading cause of death [16][17], i.e., for their in vitro activity,
against the strain HM1:IMSS of E. histolytica.
Results and Discussion. – Synthesis. The synthesis of bis-ferrocenyl-substituted
core-modified porphyrins 6a – 6j required the bis[ferrocenes] 4a – 4j which were
prepared in various steps starting by a well-known reaction of secondary amines
R’NHR and HCHO to give the corresponding N,N,N’,N’-tetrasubstituted methanedi-
amines 1a – 1j (Scheme 1).
Scheme 1
Then the 1-(aminomethyl)ferrocenes 2a – 2j were prepared by treating ferrocene
with the corresponding diamine 1a – 1j in the presence of phosphoric acid (Scheme 2).
The increase in molar ratio of phosphoric acid resulted in increasing yields of 2a – 2j.
As ferrocene and many of its derivatives are easily oxidized in air, the reactions were
1
carried out under Ar. The ferrocenes 2a – 2j were characterized by IR and H-NMR
Scheme 2

1646
Helvetica Chimica Acta – Vol. 92 (2009)
1
spectroscopy. The H-NMR spectra showed a s in the range of d 3.16 – 4.31 for the
CH2N group and two d in the range of d 3.97 – 4.39 and 4.42 – 4.91 with a coupling
constant J value around 12.6, and one s for five ferrocene H-atoms at d 4.23 – 5.12.
The synthesis of the 1-(aminomethyl)-2-formylferrocenes 3a – 3j was carried out by
metallation of the ferrocene ring of 2a – 2j in the presence of BuLi (Scheme 2). The
lithium derivative was then condensed with DMF at room temperature under Ar in
good yields. The structure of the corresponding formylferrocenes 3a – 3j was
established on the basis of IR and 1H-NMR data. The 1,2-substitution of the ferrocenes
was established unambiguously by comparison of the IR data [18 – 20]: The IR
absorption at 1000 and 1105 cmꢀ1 are typical for the presence of an unsubstituted
cyclopentadienyl moiety in 3a – 3j; indeed, these two bands are absent if both
cyclopentadienyl moieties are substituted. The structures of 3a – 3j were further
confirmed by the 1H-NMR data, i.e, by four signals in the range for ferrocene H-atoms
(2 d at d 4.01 – 4.69 and 4.17 – 5.29 with coupling constant J ¼ 12.3 – 12.9 Hz, one m at d
3.89 – 5.29, and one s at d 4.82 – 6.63), and by the s for the aldehydic H-atom at d 8.93 –
9.71. Thus, the 1H-NMR data confirmed the exclusive 1,2-substitution of the ferrocenes
3a – 3j as expected from the intermediate {2-[(amino-kN)methyl]ferrocen-1-yl}lithium
compounds 2’a – 2’j. Indeed, this 1,2-substituted intermediate should have the
maximum stability due to the possible coordination of the Li by the adjacent amino
group, resulting in the formation of a 5-membered ring.
Subsequent addition of the formylferrocenes 3a – 3j to (thiophene-2,5-diyl)dilithi-
um, obtained by 2,5-dilithiation of thiophene with excess of BuLi/TMEDA
(¼ N,N,N’,N’-tetramethylethane-1,2-diamine) in excess of hexane, gave 1,1’’-
[thiophene-2,5-diylbis(hydroxymethylene)]bis[2-(aminomethyl)ferrocenes]
4a – 4j
(Scheme 2) which were purified by column chromatography and recrystallization.
The bis-ferrocenes 4a – 4j were single isomers as confirmed by a s at d 6.64 – 7.51 for the
thiophene H-atoms and another s for the hydroxymethylene moiety at d 5.49 – 6.51 in
the 1H-NMR spectra.
The addition of benzaldehyde to (thiophene-2,5-diyl)dilithium resulted in the
formation of a2,a5-diphenylthiophene-2,5-dimethanol (5a), and 2,2’-[thiophene-2,5-
diylbis(phenylmethylene)]bis[1H-pyrrole] (5b) was prepared by treating 5a with
excess of 1H-pyrrole in the presence of BF3 · Et2O (Scheme 3). The data of 5a and 5b
were in accordance with the literature [11].
Scheme 3
The compounds 6a – 6j, having a meso-substituted porphyrin moiety with the
substituted ferrocenyl groups at the 5 and 20 position and the Ph groups at the 10 and 15
position, were prepared in the dark and under Ar by the condensation of 4a – 4j with 5b

Helvetica Chimica Acta – Vol. 92 (2009)
1647
in the presence of a catalytic amount of BF3 · Et2O and subsequent oxidation with
DDQ (¼4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile) (Scheme 4).
The products 6a – 6j were purified via chromatography (basic alumina) and recrystal-
1
lization and characterized by means of elemental analysis, IR, H-NMR, electronic
spectroscopy and mass spectrometry. All the compounds 6a – 6j are soluble in CHCl3,
MeOH, EtOH, DMF, and DMSO; and their purity was established by means of the
elemental analyses and the mass spectra.
Scheme 4
The IR spectra of 6a – 6i exhibited some prominent signals which were very helpful
to deduce their structure. These include absorptions at 1652 – 1615 (C¼N), 1211 – 1256
(CꢀN), 1110 – 1115 (ferrocene), 1001 – 1005 (ferrocene), and 907 – 895 cmꢀ1 (ferro-
cene), and a very weak band at 865 – 845 cmꢀ1 (CꢀS). The absence of the band near
3500 – 3100 cmꢀ1 showed that the N-atom of the pyrrole moieties does not carry any H-
atom, as expected from the aromatization of the molecule. The strong signal around
1110 cmꢀ1 and a weak one around 1000 cmꢀ1 established that the ferrocene moiety is
present and possesses one unsubstituted cyclopentadienyl moiety [18 – 20]. The signal
around 900 cmꢀ1 was also indicative of the presence of the ferrocene moiety, and the
weak band around 850 cmꢀ1 confirmed the presence of the thiophene moiety.
1
The formation of the porphyrins 6a – 6j was further supported by the H-NMR
spectra. Besides the usual signals of the amino substituents, well-resolved ferrocene
signals and two d at d 6.31 – 6.57 and 6.54 – 6.81 with a coupling constant J ranging
between 7.3 and 7.6 Hz of the four pyrrole H-atoms (different environment) were
present. The two s at d 7.31 – 7.91 and 7.55 – 805 were assigned to the four thiophene H-
atoms (similar environment). The absence of signals either on the right hand side of the
SiMe4 signal (as found in 5,10,15,20-tetrakis[4-(tert-butyl)phenyl]porphyrins (TBPPs))
or beyond d 8.69 (aromatic-NH signals are expected at d > 10) also suggested the
absence of pyrrole NH atoms, in accord with the proposed structures.
The formation of the porphyrin derivatives 6a – 6j was further supported by the
typical electronic spectra of porphyrins with one Soret band (lmax 416 – 456 nm) and
four Q bands (Table 1). Out of the four Q bands, two were intense (lmax 510 – 520 nm
and 535 – 576 nm), and two were less intense (lmax 575 – 601 nm and 630 – 657 nm);

1648
Helvetica Chimica Acta – Vol. 92 (2009)
Table 1. UV/VIS Band Maxima and Extinction Coefficients for meso-Substituted Porphyrins 6a – 6j. In
MeOH; lmax in nm (e · 10ꢀ3 in cmꢀ1 molꢀ1 l).
Compound
Soret 1
Q IV
Q III
Q II
Q I
6a
6b
6c
6d
6e
6f
6g
6h
6i
416a) (102.3)b)
429 (120.8)
515 (39.4)
517 (29.5)
517 (18.5)
510 (35.3)
519 (26.4)
518 (30.5)
513 (32.5)
514 (31.2)
511 (27.6)
520 (20.4)
555 (27.3)
537 (16.3)
536 (13.3)
536 (29.3)
535 (19.1)
538 (15.5)
545 (28.4)
565 (20.2)
576 (18.7)
567 (17.3)
595 (4.5)
586 (3.2)
587 (5.1)
583 (5.8)
586 (2.1)
585 (7.9)
575 (6.2)
582 (3.5)
593 (4.1)
601 (7.1)
630 (2.3)
–
433
429
448
452
436
424
456
421
(95.5)
(87.6)
(89.2)
(87.4)
(91.3)
(84.6)
(79.5)
(87.1)
636 (1.8)
635 (2.8)
642 (3.5)
632 (6.8)
655 (5.1)
652 (4.1)
–
6j
657 (6.2)
a) Absorption wavelength lmax b) Molar absorption coefficient e (formerly called molar extinction
.
coefficient).
even in the cases of 6b and 6i, the fourth Q band was not recognized. Except for 6b, 6e,
and 6i, all the meso-substituted porphyrin derivatives gave etui spectra (eIV > eIII > eII >
eI), and the relative intensities of the QI and QII bands exhibited a standard behavior
(eII/eI < 1).
Anti-amoebic Activity. Preliminary experiments were carried out to determine the
in vitro antiamoebic activity of all the compounds 6a – 6j against strain HM1:IMSS of
E. histolytica, and the results were compared with the activity of metronidazole
(MNZ). The IC50 values are shown in Table 2. The percent inhibition of amoebal
growth was calculated from the optical densities of the control and test wells and was
plotted against the logarithm of the dose of the drugs. Metronidazole had a 50%
inhibitory concentration IC50 of 1.81 mm in our experiments (Fig.). The IC50 values for
compounds 6b (0.59 mm), 6c (1.41 mm), 6d (0.72 mm), 6f (1.57 mm), 6h (1.71 mm), and 6j
(1.56 mm) were considerably lower than that of metronidazole, corresponding to a 1.05-
Table 2. In vitro Anti-amoebic Activity of 6a – 6j against the Strain HM1 :IMSS of E. histolytica
Compound
IC50 [mm]
S.D.a) (ꢁ)
6a
6b
6c
6d
6e
6f
6g
6h
> 1.8
0.59
1.41
0.72
> 1.8
1.57
> 1.8
1.71
> 1.8
1.56
1.81
0.31
0.51
0.25
0.30
0.63
0.24
0.53
0.18
0.21
0.35
0.13
6i
6j
Metronidazole (MNZ)
a) Standard deviation.

Helvetica Chimica Acta – Vol. 92 (2009)
1649
Figure. In vitro anti-amoebic activity of metronidazole (MNZ) and compounds 6b and 6e against the
Strain HM1:IMSS of E. histolytica
to 3.05-fold increase in activity. The results were statistically evaluated by analyses of
the variance. The null hypothesis was tested by the T-test, and the significance of the
differences between the IC50 value(s) of metronidazole vs. 6a – 6j was evaluated. The
calculated T-values were higher than the table values at the 4% level. Hence, the
character under study was significantly influenced by the treatment. Thus, from the
data available, we can say that porphyrins can act as better anti-amoebic drugs.
Conclusion. – Bis-ferrocenyl-substituted core-modified porphyrins ( ¼ 1,1’’-(core-
modified porphyrindiyl)bis[ferrocenes]) 6a – 6j were synthesized via an acid-catalyzed
condensation of 4a – 4j and 5b and subsequent oxidation with DDQ. All the
compounds were characterized by spectroscopic techniques. The cell-culture studies
showed that some compounds, 6a – 6j, possessed high in vitro anti-amoebic activity
against E. histolytica. The IC50 values for compounds 6b, 6c, 6d, 6f, 6h, and 6j were
considerably lower than that of metronidazole (1.81 mm), corresponding to a 1.05- to
3.05-fold increase in activity, thus these compound proved to be better inhibitors of E.
histolytica growth.
We are grateful to the Department of Science & Technology (Grant No. VII-PRDSF/44/2004-05/TT)
for funding the work. We thank Dr. Sudha Bhattacharya, School of Environmental Science, and Dr. Alok
Bhattacharya, School of Life Sciences, Jawaharlal Nehru University, New Delhi, for providing the
facilities for biological studies.
Experimental Part
1. General. Ferrocene ¼ fc; thiophene-2,5-diyl ¼ tp. All the reactions were carried out in the dark
under Ar. All the chemicals were purchased from Aldrich Chemical Company (USA), and CH2Cl2 was

1650
Helvetica Chimica Acta – Vol. 92 (2009)
purified by treating with molecular sieves. TLC: precoated silica gel (SiO2) 60 F254 aluminium plates.
Flash column chromatography (FC): SiO2 60 ꢂ (240 – 400 mesh) and basic alumina. CC ¼ Column
chromatography. UV/VIS Spectra: Shimadzu UV-1601-PC UV/VIS spectrophotometer; in MeOH. IR
.
Spectra: Perkin-Elmer 1620 FT-IR spectrophotometer; KBr pellets; ˜nmax in cmꢀ1 1H-NMR Spectra:
Bruker Spectrospin-DPX-300 spectrophotometer; CDCl3/DMSO solns. at r.t.; d in ppm rel. to Me4Si as
internal standard, J in Hz. FAB-MS: Jeol SX-102/DA-6000 mass spectrometer/data system; Ar/Xe (6 kV,
10 mA) as the FAB gas and 3-nitrobenzyl alcohol (NBA) as the matrix; in m/z. Elemental analyses:
Heraeus Vario-EL-III analyzer; performed in the Central Drug Research Institute, Luckhnow; results
within 0.3% of the theoretical values.
2. Synthesis of 1a – 1j. General Procedure. A secondary amine R’NHR’’ (300 mmol) was added
dropwise to a stirred 37% HCHO (150 mmol) soln. in H2O at 08. Subsequently, the mixture was stirred
for 2 h at r.t., followed by addition of KOH pellets until two layers were separated. The org. layer was
extracted with Et2O, and the extract dried (Na2SO4) and concentrated: oil. The structures of the methane
diamines 1a – 1j were confirmed by IR spectroscopy.
3. Synthesis of 2a – 2j: General Procedure. A mixture of ferrocene (1 equiv.), each diamine 1a – 1j (1
equiv.), and phosphoric acid (H3PO4; 1.5 equiv.) was heated in AcOH for 5 h. After cooling, the mixture
was diluted with H2O/Et2O 5 :15 (20 ml). NaOH was added to the aq. layer until the pH reached 12. The
free-base derivative was extracted with CH2Cl2, the org. layer dried (Na2SO4) and concentrated, and the
residue subjected to CC (SiO2, hexane/Et2O): 2a – 2j as red oils.
1-[(Butylmethylamino)methyl]ferrocene (2a). Yield 72%. IR: 2936 (arom. CꢀH), 2858 (CꢀH),
1638, 1582, 1450 (C¼C), 1239 (CꢀN), 1104 (fc), 1000 (fc), 815 (fc). 1H-NMR (CDCl3): 1.26 – 1.39 (m,
1 Me); 1.52 – 1.61 (m, 1 CH2); 2.71 (m, 1 CH2); 3.20 (t, 1 CH2); 3.34 (s, 1 CH2N); 3.56 (s, 1 Me); 3.73 (s,
1 CH2N); 4.16 (d, J ¼ 12.6, 2 H of fc); 4.30 (d, J ¼ 12.6, 2 H of fc); 5.30 (s, 5 H of fc).
1-{[Methyl(phenylmethyl)amino]methyl}ferrocene (2b): Yield 69%. IR: 3094 (arom. CꢀH), 2931
(CꢀH), 1650, 1558, 1456 (C¼C), 1255 (CꢀN), 1105 (fc), 1000 (fc), 813 (fc). 1H-NMR (CDCl3): 2.68 (s,
MeN); 3.56 (s, 1 CH2N); 3.61 (s, 1 CH2N); 4.34 (d, J ¼ 12.6, 2 H of fc); 4.96 (d, J ¼ 12.6, 2 H of fc); 5.18 (s,
5 H of fc); 6.91 – 7.13 (m, 5 arom. H).
1-[(4-Methylpiperidin-1-yl)methyl]ferrocene (2c): Yield 65%. IR: 3074 (arom. CꢀH), 2926 (CꢀH),
1580, 1537, 1408 (C¼C), 1204 (CꢀN), 1103 (fc), 1002 (fc), 815 (fc). 1H-NMR (CDCl3): 1.99 (Me); 2.45
(m, CH); 2.60 – 2.69 (m, CH(CH2)2); 3.16 (s, 1 CH2N); 3.55 – 3.63 (m, CH2NCH2); 3.97 (d, J ¼ 12.8, 2 H
of fc); 4.32 (d, J ¼ 12.8, 2 H of fc); 4.72 (s, 5 H of fc).
1-[(Hexahydro-1H-azepin-1-yl)methyl]ferrocene (2d): Yield 67%. IR: 3038 (arom. CꢀH), 2903
(CH2 stretch), 2893 (CH2), 1569, 1493, 1483 (C¼C), 1230 (CꢀN), 1104 (fc), 1000 (fc), 811 (fc).
1H-NMR (CDCl3): 2.85 – 2.98 (m, 4 CH2); 3.82 (s, 1 CH2); 4.13 (d, J ¼ 12.9, 2 H of fc); 4.23 (s, 5 H of fc);
4.53 – 4.61 (m, CH2NCH2); 4.81 (d, J ¼ 12.9, 2 H of fc).
1-[(Cyclohexylmethylamino)methyl]ferrocene (2e): Yield 79%. IR: 3007 (arom. CꢀH), 2905 (Me
1
stretch), 2892 (CH2), 1592, 1561, 1494 (C¼C), 1216 (CꢀN), 1105 (fc), 1002 (fc), 817 (fc). H-NMR
(CDCl3): 2.43 – 2.52 (m, (CH2)5); 2.71 (s, Me); 3.89 (s, 1 CH2); 4.08 – 4.17 (m, CHNꢀ); 4.32 (s, 5 H of fc);
4.47 (d, J ¼ 12.3, 2 H of fc); 4.52 (d, J ¼ 12.3, 2 H of fc).
1-[(Diethylamino)methyl]ferrocene (2f): Yield 75%. IR: 3032 (arom. CꢀH), 2937 (Me stretch),
2893 (CH2), 1602, 1586, 1430 (C¼C), 1205 (CꢀN), 1101 (fc), 1002 (fc), 817 (fc). 1H-NMR (CDCl3): 1.94
(t, 2 Me); 3.4 (m, (CH2)2N); 3.8 (s, CH2); 4.12 (d, J ¼ 12.4, 2 H of fc); 4.42 (d, J ¼ 12.4, 2 H of fc); 4.81 (s,
5 H of fc).
1-[(Dipropylamino)methyl]ferrocene (2g): Yield 68%. IR: 3025 (arom. CꢀH), 2928 (Me stretch),
2840 (CH2), 1593, 1548, 1410 (C¼C), 1215 (CꢀN), 1104 (fc), 1000 (fc), 815 (fc). 1H-NMR (CDCl3): 1.92
(t, 2 Me); 2.52 – 2.63 (m, 2 CH2); 3.37 (t, (CH2)2N); 4.31 (s, 1 CH2N); 4.31 (d, J ¼ 12.6, 2 H of fc); 4.82 (d,
J ¼ 12.6, 2 H of fc); 5.12 (s, 5 H of fc).
1-[(Pyrrolidin-1-yl)methyl]ferrocene (2h): Yield 77%. IR: 3063 (arom. CꢀH), 2890 (CH2), 1610,
1559, 1435 (C¼C), 1238 (CꢀN), 1107 (fc), 1000 (fc), 813 (fc). 1H-NMR (CDCl3): 2.63 – 2.72 (m,
(CH2)2); 3.89 – 3.95 (m, (CH2)2N); 4.1 (s, 1 CH2N); 4.39 (d, J ¼ 12.6, 2 H of fc); 4.82 (s, 5 H of fc); 4.91 (d,
J ¼ 12.6, 2 H of fc).
1-[(2-Ethylpiperidin-1-yl)methyl]ferrocene (2i): Yield 67%. IR: 3078 (arom. CꢀH), 2956 (Me),
2841 (CH2), 1613, 1586, 1513 (C¼C), 1221 (CꢀN), 1103 (fc), 1001 (fc), 815 (fc). 1H-NMR (CDCl3): 1.75

Helvetica Chimica Acta – Vol. 92 (2009)
1651
(t, 1 Me); 2.13 (m, 4 CH2); 3.61 (m, CHN); 3.89 (t, 1 CH2N); 4.44 (s, 1 CH2N); 4.52 (d, J ¼ 12.8, 2 H of
fc); 4.87 (s, 5 H of fc); 4.95 (d, J ¼ 12.8, 2 H of fc).
1-[(4-Phenylpiperazin-1-yl)methyl]ferrocene (2j): Yield 77%. IR: 3051 (arom. CꢀH), 2880 (CH2),
1615, 1549, 1432 (C¼C), 1256 (CꢀN), 1106 (fc), 1002 (fc), 811 (fc). 1H-NMR (CDCl3): 2.38 – 2.70 (m,
2 CH2NCH2); 4.7 (s, 1 NCH2); 4.63 (d, J ¼ 12.8, 2 H of fc); 4.91 (s, 5 H of fc); 5.32 (d, J ¼ 12.8, 2 H of fc);
6.53 – 7.12 (m, 5 H of Ph).
3. Synthesis of 3a – 3j. General Procedure. Each ferrocene 2a – 2j (1 equiv.) in anh. Et2O (20 ml) was
treated with BuLi in hexane (1.25 equiv.) under Ar at r.t. with continous stirring. The reaction was
completed in 16 h. The soln. obtained was treated with N,N-dimethylformamide (1.25 equiv.) under Ar at
r.t. After 4 h, the compound was hydrolyzed by addition of H2O. The aq. phase was washed with small
portions of Et2O, the combined Et2O extract dried (Na2SO4) and concentrated, and the obtained red oil
purified by CC (SiO2, Et2O/hexane): 3a – 3j as red oils.
1-[(Butylmethylamino)methyl]-2-formylferrocene (3a): Yield 53%. IR: 2916 (arom. CꢀH), 2867
1
(CꢀH), 1723 (C¼O), 1630, 1542, 1435 (C¼C), 1234 (CꢀN), 1114 (fc), 1003 (fc), 903 (fc). H-NMR
(CDCl3): 1.28 – 1.37 (m, 1 Me); 1.43 – 1.49 (m, 1 CH2); 1.92 – 2.05 (m, 1 CH2); 3.32 (t, 1 CH2); 3.47 (s,
1 Me); 3.58 (s, 1 CH2N); 4.01 (d, J ¼ 12.8, 1 H of fc); 4.17 (d, J ¼ 12.8, 1 H of fc); 5.15 – 5.29 (m, 1 H of fc);
6.63 (s, 5 H of fc); 9.35 (s, CHO).
1-Formyl-2-{[methyl(phenylmethyl)amino]methyl}ferrocene (3b): Yield 69%. IR: 3086 (arom.
CꢀH), 2976 (CꢀH), 1721 (C¼O), 1630, 1535, 1474 (C¼C), 1237 (CꢀN), 1112 (fc), 1002 (fc), 905
(fc). 1H-NMR (CDCl3): 2.73 (s, MeN); 3.23 (s, 1 CH2N); 3.48 (s, 1 CH2N); 3.92 – 4.03 (m, 1 H of fc); 4.25
(d, J ¼ 12.9, 1 H of fc); 4.39 (d, J ¼ 12.9, 1 H of fc); 5.92 (s, 5 H of fc); 9.36 (s, CHO).
1-Formyl-2-[(4-methylpiperidin-1-yl)methyl]ferrocene (3c): Yield 69%. IR: 3035 (arom. CꢀH),
2963 (CꢀH), 1733 (C¼O), 1586, 1533, 1426 (C¼C), 1227 (CꢀN), 1113 (fc), 1002 (fc), 899 (fc).
1H-NMR (CDCl3): 1.43 (d, Me); 2.41 (m, 1 CH); 2.52 – 2.61 (m, CH(CH2)2); 3.23 – 3.37 (m, CH2NCH2);
3.43 (s, 1 CH2); 4.13 (d, J ¼ 12.4, 1 H of fc); 4.19 (d, J ¼ 12.4, 1 H of fc); 4.52 – 4.61 (m, 1 H of fc); 5.13 (s,
5 H of fc); 8.93 (s, CHO).
1-Formyl-2-[(hexahydro-1H-azepin-1-yl)methyl]ferrocene (3d): Yield 68%. IR: 3046 (arom. CꢀH),
2923 (CH2 stretch), 2884 (CH2), 1728 (C¼O), 1576, 1498, 1480 (C¼C), 1246 (CꢀN), 1113 (fc), 1004
1
(fc), 903 (fc). H-NMR (CDCl3): 2.73 – 2.87 (m, 4 CH2); 3.49 (s, 1 CH2N); 4.43 – 4.50 (m, CH2NCH2);
4.52 – 4.61 (m, 1 H of fc); 4.63 (d, J ¼ 12.4, 1 H of fc); 4.79 (d, J ¼ 12.4, 1 H of fc); 5.61 (s, 5 H of fc); 9.71 (s,
CHO).
1-[(Cyclohexylmethylamino)methyl]-2-formylferrocene (3e): Yield 58%. IR: 3036 (arom. CꢀH),
2938 (Me stretch), 2897 (CH2), 1729 (C¼O), 1613, 1573, 1467 (C¼C), 1234 (CꢀN), 1114 (fc), 1002 (fc),
901 (fc). 1H-NMR (CDCl3): 2.33 – 2.47 (m, (CH2)5); 2.64 (s, Me); 3.67 (s, CH2N); 3.92 – 3.98 (m, CHN);
4.49 (d, J ¼ 12.8, 1 H of fc); 4.57 (d, J ¼ 12.8, 1 H of fc); 4.63 – 4.71 (m, 1 Hof fc); 5.12 (s, 5 H of fc); 9.25 (s,
CHO).
1-[(Diethylamino)methyl]-2-formylferrocene (3f): Yield 69%. IR: 3036 (arom. CꢀH), 2916 (Me
stretch), 2894 (CH2), 1732 (C¼O), 1613, 1597, 1447 (C¼C), 1238 (CꢀN), 1115 (fc), 1004 (fc), 904 (fc).
1H-NMR (CDCl3): 1.83 (t, 2 Me); 3.53 (m, N(CH2)2); 3.72 (s, CH2N); 4.43 – 4.59 (m, 1 H of fc); 4.69 (d,
J ¼ 12.3, 1 H of fc); 4.83 (d, J ¼ 12.3, 1 H of fc); 5.31 (s, 5 H of fc); 9.61 (s, CHO).
1-[(Dipropylamino)methyl]-2-formylferrocene (3g): Yield 52%. IR: 3067 (arom. CꢀH), 2956 (Me
stretch), 2826 (CH2), 1727 (C¼O), 1586, 1567, 1428 (C¼C), 1231 (CꢀN), 1113 (fc), 1001 (fc), 905 (fc).
1H-NMR (CDCl3): 1.86 (t, 2 Me); 2.69 – 2.78 (m, 2 CH2); 3.58 (t, (CH2)2N); 4.21 (s, CH2N); 4.44 (d, J ¼
12.8, 1 H of fc); 4.78 – 4.86 (m, 1 H of fc); 4.93 (d, J ¼ 12.8, 1 H of fc); 5.95 (s, 5 H of fc); 9.09 (s, CHO).
1-Formyl-2-[(pyrrolidin-1-yl)methyl]ferrocene (3h): Yield 58%. IR: 3037 (arom. CꢀH), 2873
1
(CH2), 1731 (C¼O), 1593, 1578, 1426 (C¼C), 1228 (CꢀN), 1112 (fc), 1003 (fc), 905 (fc). H-NMR
(CDCl3): 2.39 – 2.47 (m, (CH2)2); 4.02 – 4.11 (m, (CH2)2N); 4.17 (s, 1 CH2N); 4.23 (d, J ¼ 12.4, 1 H of fc);
4.63 – 4.71 (m, 1 H of fc); 5.03 (d, J ¼ 12.4, 1 H of fc); 6.23 (s, 5 H of fc); 9.39 (s, CHO).
1-[(2-Ethylpiperidin-1-yl)methyl]-2-formylferrocene (3i): Yield 54%. IR: 3069 (arom. CꢀH), 2913
(Me), 2886 (CH2), 1733 (C¼O), 1618, 1572, 1487 (C¼C), 1234 (CꢀN), 1115 (fc), 1000 (fc), 902 (fc).
1H-NMR (CDCl3): 1.79 (t, Me); 2.32 (m, 4 CH2); 3.48 (m, CHN); 3.91 (t, 1 CH2N); 4.16 (s, 1 CH2N);
4.43 – 4.49 (m, 1 H of fc); 4.39 (d, J ¼ 12.6, 1 H of fc); 4.82 (s, 5 H of fc); 4.91 (d, J ¼ 12.6, 1 H of fc); 9.71 (s,
CHO).

1652
Helvetica Chimica Acta – Vol. 92 (2009)
1-Formyl-2-[(4-phenylpiperazin-1-yl)methyl]ferrocene (3j): Yield 64%. IR: 3043 (arom. CꢀH),
2897 (CH2), 1710 (C¼O), 1615, 1553, 1422 (C¼C), 1234 (CꢀN), 1101 (fc), 1004 (fc), 902 (fc). 1H-NMR
(CDCl3): 2.30 – 2.65 (m, 2 CH2NCH2); 4.5 (s, 1 CH2N); 4.75 (d, J ¼ 12.8, 2 H of fc); 4.70 – 4.78 (m, 1 H of
fc); 4.85 (s, 5 H of fc); 5.12 (d, J ¼ 12.8, 2 H of fc); 6.20 – 6.33 (m, 5 H of Ph); 9.89 (s, CHO).
4. Synthesis of 4a – 4j. General Procedure. Thiophene (1 equiv.) was added to a soln. of BuLi (3
equiv.) and N,N,N’,N’-tetramethylethane-1,2-diamine (TMEDA; 3 equiv.) in hexane under Ar. The
mixture was heated under reflux for 2 h, cooled to r.t., and transferred to a dropping funnel. The
(thiophene-2,5-diyl)dilithium suspension was then added dropwise, at 08 under Ar, to a formylferrocene
3a – 3j (3 equiv.) in THF (dried over basic alumina and degassed with Ar for 15 min). After the addition,
the mixture was allowed to warm to r.t. followed by the addition of 1m aq. NH4Cl. The aq. phase was
extracted with Et2O (3ꢂ), the combined org. phase washed with H2O and brine, dried (MgSO4), and
concentrated, and the crude red oil purified by CC (SiO2, Et2O/hexane): 4a – 4j as red oils.
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(butylmethylamino)methyl]ferrocene] (4a):
Yield 17%. IR: 3237 (OꢀH), 2915 (arom. CꢀH), 2885 (CꢀH), 1602, 1583, 1495 (C¼C), 1237
1
(CꢀN), 1112 (fc), 1001 (fc), 901 (fc). H-NMR (CDCl3): 1.16 – 1.23 (m, 2 Me); 1.28 – 1.33 (m, 2 CH2);
1.69 – 1.76 (m, 2 CH2); 3.53 (s, 2 Me); 3.64 (t, 2 CH2); 4.01 (s, 2 CH2); 4.08 (d, J ¼ 12.3, 2 H of fc); 4.23 (d,
J ¼ 12.3, 2 H of fc); 4.39 (s, 2 CHOH); 5.32 – 5.39 (m, 2 H of fc); 5.93 (s, 10 H of fc); 6.11 (s, 2 CHOH);
6.64 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-{[methyl(phenylmethyl)amino]methyl}ferro-
cene] (4b): Yield 22%. IR: 3320 (OꢀH), 3065 (arom. CꢀH), 2935 (CꢀH), 1595, 1574, 1501 (C¼C),
1228 (CꢀN), 1113 (fc), 1004 (fc), 903 (fc). 1H-NMR (CDCl3): 2.94 (s, 2 MeN); 3.16 (s, 2 CH2N); 3.51 (s,
2 CH2N); 3.81 – 3.93 (m, 2 H of fc); 4.12 (d, J ¼ 12.2, 2 H of fc); 4.31 (d, J ¼ 12.2, 2 H of fc); 5.39 (s, 10 H
of fc); 5.21 (s, 2 CHOH); 6.12 (s, 2 CHOH); 7.23 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(4-methylpiperidin-1-yl)methyl]ferrocene]
(4c): Yield 25%. IR: 3320 (OꢀH), 3076 (arom. CꢀH), 2934 (CꢀH), 1605, 1583, 1495 (C¼C), 1210
(CꢀN), 1115 (fc), 1001 (fc), 902 (fc). 1H-NMR (CDCl3): 1.21 (d, 2 Me); 1.91 (m, 2 CH); 2.36 – 2.51 (m,
2 CH(CH2)2); 3.05 – 3.21 (m, 2 CH2NCH2); 3.56 (s, 2 CH2N); 4.10 (d, J ¼ 12.5, 2 H of fc); 4.27 (d, J ¼ 12.5,
2 H of fc); 4.53 (s, 2 CHOH); 4.71 – 4.78 (m, 2 H of fc); 5.49 (s, 10 H of fc); 5.49 (s, 2 CHOH); 7.31 (s, 2 H
of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(hexahydro-1H-azepin-1-yl)methyl]ferro-
cene] (4d): Yield 19%. IR: 3250 (OꢀH), 3018 (arom. CꢀH), 2956 (CH2 stretch), 2905 (CH2), 1593,
1520, 1465 (C¼C), 1235 (CꢀN), 1115 (fc), 1001 (fc), 907 (fc). 1H-NMR (CDCl3): 1.69 – 1.81 (m, 8 CH2);
3.95 (s, 2 CH2N); 4.13 – 4.20 (m, 2 CH2NCH2); 4.32 – 4.40 (m, 2 H of fc); 4.49 (d, J ¼ 12.9, 2 H of fc); 4.81
(d, J ¼ 12.9, 2 H of fc); 5.31 (s, 10 H of fc); 5.43 (s, 2 CHOH); 6.19 (s, 2 CHOH); 6.97 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(cyclohexylmethylamino)methyl]ferrocene]
(4e): Yield 15%. IR: 3356 (OꢀH), 3057 (arom. CꢀH), 2940 (Me stretch), 2886 (CH2), 1615, 1575, 1567
(C¼C), 1225 (CꢀN), 1113 (fc), 1005 (fc), 903 (fc). 1H-NMR (CDCl3): 1.93 – 2.07 (m, 2 (CH2)5); 2.34 (s,
2 Me); 3.87 (s, 2 CH2N); 4.12 – 4.19 (m, CHN); 4.32 (d, J ¼ 12.2, 2 H of fc); 4.48 (d, J ¼ 12.2, 2 H of fc);
4.51 – 4.59 (m, 2 H of fc); 4.97 (s, 10 H of fc); 5.43 (s, 2 CHOH); 6.71 (s, 2 CHOH); 7.05 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(diethylamino)methyl]ferrocene] (4f): Yield
16%. IR: 3410 (OꢀH), 3018 (arom. CꢀH), 2936 (Me stretch), 2886 (CH2), 1633, 1576, 1513 (C¼C),
1247 (CꢀN), 1113 (fc), 1002 (fc), 904 (fc). 1H-NMR (CDCl3): 1.73 (t, 4 Me); 3.19 (m, 2 (CH2)2N); 3.75
(s, 2 CH2N); 4.51 – 4.58 (m, 2 H of fc); 4.65 (d, J ¼ 12.4, 2 H of fc); 4.73 (s, 2 CHOH); 4.79 (d, J ¼ 12.4, 2 H
of fc); 5.21 (s, 10 H of fc); 6.15 (s, 2 CHOH); 6.95 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(dipropylamino)methyl]ferrocene] (4g):
Yield 19%. IR: 3313 (OꢀH), 3045 (arom. CꢀH), 2956 (Me stretch), 2854 (CH2), 1565, 1510, 1438
1
(C¼C), 1241 (CꢀN), 1115 (fc), 1004 (fc), 906 (fc). H-NMR (CDCl3): 1.32 (t, 4 Me); 2.51 – 2.58 (m,
4 CH2); 3.25 (t, 2 (CH2)2N); 4.03 (s, 2 CH2N); 4.23 (d, J ¼ 12.2, 2 H of fc); 4.62 – 4.73 (m, 2 H of fc); 4.81
(d, J ¼ 12.2, 4 H of fc); 5.09 (s, 2 CHOH); 5.32 (s, 10 H of fc); 6.51 (s, 2 CHOH); 7.51 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(pyrrolidin-1-yl)methyl]ferrocene] (4h): IR:
3276 (OꢀH), 3031 (arom. CꢀH), 2895 (CH2), 1597, 1536, 1481 (C¼C), 1235 (CꢀN), 1110 (fc), 1006
1
(fc), 899 (fc). H-NMR (CDCl3): 2.13 – 2.27 (m, (CH2)2); 3.71 – 3.85 (m, 2 (CH2)2N); 4.03 (s, 2 CH2N);

Helvetica Chimica Acta – Vol. 92 (2009)
1653
4.19 (d, J ¼ 12.4, 2 H of fc); 4.42 – 4.51 (m, 2 H of fc); 5.17 (d, J ¼ 12.4, 2 H of fc); 5.42 (s, 2 CHOH); 5.49
(s, 10 H of fc); 6.38 (s, 2 CHOH); 7.19 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(2-ethylpiperidin-1-yl)methyl]ferrocene]
(4i): Yield 16%. IR: 3319 (OꢀH), 3053 (arom. CꢀH), 2905 (CH2), 1635, 1546, 1483 (C¼C), 1235
(CꢀN), 1109 (fc), 1005 (fc), 901 (fc). 1H-NMR (CDCl3): 1.56 (t, Me); 2.43 (m, 4 CH2); 3.71 (m, CHN);
3.82 (t, 1 CH2N); 4.31 (s, 1 CH2N); 4.47 (d, J ¼ 12.6, 2 H of fc); 4.53 (d, J ¼ 12.6, 2 H of fc); 4.61 – 4.68 (m,
2 H of fc); 4.79 (s, 2 CHOH); 4.83 (s, 10 H of fc); 6.42 (s, 2 CHOH); 6.97 (s, 2 H of tp).
1,1’’-[Thiophene-2,5-diylbis(hydroxymethylene)]bis[2-[(4-phenylpiperazin-1-yl)methyl]ferrocene]
(4j): Yield 21%. IR: 3236 (OꢀH), 3011 (arom. CꢀH), 2885 (CH2), 1591, 1533, 1482 (C¼C), 1233
(CꢀN), 1112 (fc), 1004 (fc), 903 (fc). 1H-NMR (CDCl3): 2.28 – 2.55 (m, 2 CH2NCH2); 4.27 (s, 1 CH2N);
4.39 (d, J ¼ 12.7, 2 H of fc); 4.50 – 4.62 (m, 2 H of fc); 4.82 (s, 10 H of fc); 4.91 (d, J ¼ 12.7, 2 H of fc); 4.96
(s, 2 CHOH); 6.38 (s, 2 CHOH); 6.49 – 6.74 (m, 5 H of Ph); 7.08 (s, 2 H of tp).
5. a2,a5-Diphenylthiophene-2,5-dimethanol (5a). As described in Sect. 4, with benzaldehyde instead
of a formylferrocene 3a – 3j. Concentration of the dried org. phase gave 5a (32%). White crystals. IR:
3033 (arom. CꢀH), 2928 (Me stretch), 1536, 1511, 1468 (C¼C). 1H-NMR (CDCl3): 2.93 (s, 2 CHOH);
4.92 (s, 2 CHOH); 7.03 (s, 2 H of tp); 7.14 (t, 2 H of Ph); 7.49 (d, 4 H of Ph); 7.52 (dd, 4 H of Ph).
6. 2,2’-[Thiophene-2,5-diylbis(phenylmethylene)]bis[1H-pyrrole] (5b). Compound 5a was dissolved
in excess 1H-pyrrole (10.6 ml), and Ar was bubbled through it. BF3 · Et2O (0.1 ml) was added, and the
resulting mixture was stirred for 1 h. The reaction was stopped by the addition of CH2Cl2 (100 ml)
followed by 40% NaOH soln. (25 ml). The org. layer was washed with H2O (3 ꢂ 100 ml) and brine
(100 ml), dried (MgSO4), and concentrated. The excess 1H-pyrrole was removed in vacuo at r.t. The
residual oil was purified by CC (SiO2, hexane/AcOEt 75 :25) to give a yellow oil, which was recrystallized
from AcOEt/hexane: 0.74 g (46%) of 5b. White solid. M.p. 98 – 1008. IR: 3411 (OH), 3045 (arom. CꢀH),
1
1576, 1532, 1401 (C¼C). H-NMR (CDCl3): 3.87 (s, 2 CH); 5.79 (d, 2 H of pyr); 6.06 – 6.10 (m, 2 H of
pyr); 6.37 – 6.42 (m, 2 H of pyr); 7.04 (s, 2 H of tp); 7.16 – 7.27 (m, 10 H of Ph). FAB-MS: 395 ([M þ H]þ,
C26H23N2Sþ).
7. Synthesis of 6a – 6j. General Procedure. Compounds 5b (1 equiv.) was dissolved in CH2Cl2 (1 l) and
degassed under Ar for 20 min. DDQ (0.5 equiv.) was added, and the reaction vessel was covered with Al
foil followed by purging the system with Ar. In the dark, BF3 · Et2O (0.2 ml) was added, and the resulting
mixture was heated at reflux for 1 h. The mixture was allowed to cool and concentrated, and the residue
was redissolved in a minimum of CH2Cl2. The resulting soln. was purified by chromatography on basic
Al2O3 eluted with CH2Cl2. The first red band was collected, and the product was washed with acetone.
The crude product was then recrystallized from CH2Cl2/MeOH to gave 6a – 6j as purple solids. M.p. >
3008.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(butylmethylamino)methyl]ferrocene]
(6a): Yield 16%. IR: 2947 (arom. CꢀH), 2836 (CꢀH), 1652 (C¼N), 1596, 1565, 1495 (C¼C), 1256
1
(CꢀN), 1110 (fc), 1001 (fc), 895 (fc). H-NMR (CDCl3): 1.34 – 1.39 (m, 2 Me); 1.45 – 1.51 (m, 2 CH2);
2.13 – 2.18 (m, 2 CH2); 3.05 (t, 2 CH2); 3.56 (s, 2 Me); 3.78 (s, CH2N); 4.05 (d, J ¼ 12.8, 2 H of fc); 4.10 (d,
J ¼ 12.8, 2 H of fc); 5.20 – 5.28 (m, 2 H of fc); 5.93 (s, 10 H of fc); 6.56 (d, J ¼ 7.3, 2 H of pyr); 6.63 (d, J ¼
7.3, 2 H of pyr); 7.82 (s, 2 H of tp); 7.94 (s, 2 H of tp); 8.51 – 8.69 (m, 10 arom. H). FAB-MS: 1063.25
([M þ H]þ; calc. 1062.17). Anal. calc. for C64H62Fe2N4S2: C 72.30, H 5.88, N 5.27; found: C 72.38, H 5.97,
N 5.32.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-{[methyl(phenylmethyl)amino]methyl}-
ferrocene] (6b): Yield 9%. IR: 3056 (arom. CꢀH), 2925 (CꢀH), 1635 (C¼N), 1576, 1549, 1510 (C¼C),
1211 (CꢀN), 1114 (fc), 1003 (fc), 903 (fc). 1H-NMR (CDCl3): 2.71 (s, 2 MeN); 3.38 (s, 2 CH2N); 3.76 (s,
2 CH2N); 4.35 (d, J ¼ 12.9, 2 H of fc); 4.65 – 4.76 (m, 2 H of fc); 4.82 (d, J ¼ 12.9, 2 H of fc); 5.03 (s, 10 H
of fc); 6.46 (d, J ¼ 7.6, 2 H of pyr); 6.54 (d, J ¼ 7.6, 2 H of pyr); 7.87 (s, 2 H of tp); 7.93 (s, 2 H of tp); 8.49 –
8.58 (m, 10 arom. H). FAB-MS: 1131.46 ([M þ H]þ; calc. 1130.14). Anal. calc. for C70H58Fe2N4S2: C
74.32, H 5.17, N 4.95; found: C 74.43, H 5.31, N 5.14.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(4-methylpiperidin-1-yl)methyl]ferro-
cene] (6c): Yield 7%. IR: 3065 (arom. CꢀH), 2943 (CꢀH), 1648 (C¼N), 15605, 1583, 1465 (C¼C), 1248
(CꢀN), 1111 (fc), 1002 (fc), 901 (fc). 1H-NMR (CDCl3): 1.65 (d, 2 Me); 2.68 (m, 2 CH); 2.38 – 2.46 (m,
2 CH(CH2)2); 2.30 – 3.41 (m, 2 CH2NCH2); 3.99 (s, 2 CH2N); 4.29 (d, J ¼ 12.9, 2 H of fc); 4.35 – 4.44 (m,

1654
Helvetica Chimica Acta – Vol. 92 (2009)
2 H of fc); 4.68 (d, J ¼ 12.9, 2 H of fc); 5.39 (s, 10 H of fc); 6.31 (d, J ¼ 7.6, 2 H of pyr); 6.61 (d, J ¼ 7.6, 2 H
of pyr); 7.91 (s, 2 H of tp); 8.05 (s, 2 H of tp); 8.36 – 8.48 (m, 10 arom. H). FAB-MS: 1085.37 ([M þ H]þ;
calc. 1084.15). Anal. calc. for C66H60Fe2N4S2: C 73.05, H 5.57, N 5.16; found: C 73.18, H 5.71, N 5.36.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]fer-
rocene] (6d): Yield 13%. IR: 3065 (arom. CꢀH), 2953 (CH2 stretch), 2893 (CH2), 1628 (C¼N), 1597,
1545, 1595 (C¼C), 1233 (CꢀN), 1115 (fc), 1002 (fc), 899 (fc). 1H-NMR (CDCl3): 2.49 – 2.56 (m, 8 CH2);
3.94 (s, 2 CH2); 4.35 – 4.45 (m, 2 CH2NCH2); 4.55 – 4.62 (m, 2 H of fc); 4.74 (d, J ¼ 12.4, 2 H of fc); 4.84 (d,
J ¼ 12.4, 2 H of fc); 5.19 (s, 10 H of fc); 6.57 (d, J ¼ 7.4, 2 H of pyr); 6.72 (d, J ¼ 7.4, 2 H of pyr); 7.51 (s, 2 H
of tp); 7.55 (s, 2 H of tp); 8.06 – 8.19 (m, 10 arom. H). FAB-MS: 1087.43 ([M þ H]þ; calc. 1086.17). Anal.
calc. for C66H62Fe2N4S2: C 72.91, H 5.75, N 5.15; found: C 72.98, H 5.83, N 5.27.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(cyclohexylmethylamino)methyl]ferro-
cene] (6e): Yield 8%. IR: 3013 (arom. CꢀH), 2945 (Me stretch), 2868 (CH2), 1633 (C¼N), 1605, 1545,
1
1508 (C¼C), 1219 (CꢀN), 1113 (fc), 1002 (fc), 903 (fc). H-NMR (CDCl3): 2.35 – 2.43 (m, 2 (CH2)5);
2.61 (s, 2 Me); 3.56 (s, 2 CH2); 3.81 – 3.89 (m, 2 CHN); 4.39 – 4.47 (m, 2 H of fc); 4.65 (d, J ¼ 12.9, 2 H of
fc); 4.71 (d, J ¼ 12.9, 2 H of fc); 5.36 (s, 10 H of fc); 6.42 (d, J ¼ 7.5, 2 H of pyr); 6.58 (d, J ¼ 7.5, 2 H of
pyr); 7.31 (s, 2 H of tp); 7.81 (s, 2 H of tp); 8.36 – 8.48 (m, 10 arom. H). FAB-MS: 1115.41 ([M þ H]þ; calc.
1114.20). Anal. calc. for C68H66Fe2N4S2: C 73.23, H 5.97, N 5.02; found: C 73.61, H 6.13, N 5.13.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(diethylamino)methyl]ferrocene] (6f):
Yield 11%. IR: 3054 (arom. CꢀH), 2857 (Me stretch), 2857 (CH2), 1633 (C¼N), 1580, 1536, 1485
(C¼C), 1248 (CꢀN), 1115 (fc), 1004 (fc), 904 (fc). 1H-NMR (CDCl3): 1.72 (t, 4 Me); 3.58 (m,
2 (CH2)2N); 3.60 (s, 2 CH2); 4.25 (d, J ¼ 12.3, 2 H of fc); 4.56 (d, J ¼ 12.3, 2 H of fc); 4.62 (s, 10 H of fc);
4.71 – 4.79 (m, 2 H of fc); 6.49 (d, J ¼ 12.6, 2 H of pyr); 6.69 (d, J ¼ 12.6, 2 H of pyr); 7.53 (s, 2 H of tp); 7.67
(s, 2 H of tp); 8.13 – 8.25 (m, 10 arom. H). FAB-MS: 1035.56 ([M þ H]þ; calc. 1034.14). Anal. calc. for
C62H58Fe2N4S2: C 71.94, H 5.65, N 5.41; found: C 71.88, H 5.74, N 5.49.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(dipropylamino)methyl]ferrocene] (6g):
Yield 13%. IR: 3048 (arom. CꢀH), 2920 (Me stretch), 2865 (CH2), 1642 (C¼N), 1505, 1536, 1498
1
(C¼C), 1223 (CꢀN), 1115 (fc), 1005 (fc), 905 (fc). H-NMR (CDCl3): 1.65 (t, 4 Me); 2.88 – 2.96 (m,
4 CH2); 3.11 (t, 2 (CH2)2N); 4.05 (s, 2 CH2N); 4.35 (d, J ¼ 12.8, 2 H of fc); 4.56 (d, J ¼ 12.8, 4 H of fc);
4.73 – 4.79 (m, 2 H of fc); 4.97 (s, 10 H of fc); 6.51 (d, J ¼ 7.3, 2 H of pyr); 6.81 (d, J ¼ 7.3, 2 H of pyr); 7.43
(s, 2 H of tp); 7.82 (s, 2 H of tp); 8.19 – 8.32 (m, 10 arom. H). FAB-MS: 1091.62 ([M þ H]þ; calc. 1090.20).
Anal. calc. for C66H66Fe2N4S2: C 72.64, H 6.10, N 5.13; found: C 72.56, H 6.23, N 5.18.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(pyrrolidin-1-yl)methyl]ferrocene] (6h):
Yield 9%. IR: 3038 (arom. CꢀH), 2895 (CH2), 1628 (C¼N), 1610, 1511, 1472 (C¼C), 1215 (CꢀN), 1115
(fc), 1005 (fc), 905 (fc). 1H-NMR (CDCl3): 2.57 – 2.61 (m, 2 (CH2)2); 4.19 – 4.25 (m, 2 (CH2)2N); 4.36 (s,
2 CH2N); 4.39 (d, J ¼ 12.4, 2 H of fc); 4.55 – 4.64 (m, 2 H of fc); 4.95 (d, J ¼ 12.4, 2 H of fc); 5.92 (s, 10 H
of fc); 6.39 (d, J ¼ 7.4, 2 H of pyr); 6.74 (d, J ¼ 7.4, 2 H of pyr); 7.54 (s, 2 H of tp); 7.86 (s, 2 H of tp); 8.21 –
8.35 (m, 10 arom. H). FAB-MS: 1031.57 ([M þ H]þ; calc. 1030.10). Anal. calc. for C62H54Fe2N4S2: C
72.22, H 5.28, N 5.43; found: C 72.32, H 5.43, N 5.56.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(ethylpiperidin-1-yl)methyl]ferrocene]
(6i): Yield 8%. IR: 3069 (arom. CꢀH), 2913 (CH2), 1618, 1572, 1487 (C¼C), 1234 (CꢀN), 1115 (fc),
1000 (fc), 902 (fc). 1H-NMR (CDCl3): 1.63 (t, 2 Me); 2.28 (m, 8 CH2); 3.76 (m, 2 CHN); 3.82 (t,
2 CH2N); 4.39 (d, J ¼ 12.6, 2 H of fc); 4.53 (s, 2 CH2N); 4.61 – 4.68 (m, 2 H of fc); 4.82 (d, J ¼ 12.6, 2 H of
fc); 4.91 (s, 10 H of fc); 6.48 (d, J ¼ 7.5, 2 H of pyr); 6.78 (d, J ¼ 7.5, 2 H of pyr); 7.37 (s, 2 H of tp); 7.76 (s,
2 H of tp); 8.39 – 8.47 (m, 10 arom. H). FAB-MS: 1115.48 ([M þ H]þ; calc. 1114.20). Anal. calc. for
C68H66Fe2N4S2: C 73.23, H 5.97, N 5.02; found: C 73.34, H 6.09, N 5.15.
1,1’’-(10,15-Diphenyl-21,23-dithiaporphine-5,20-diyl)bis[2-[(4-phenylpiperazin-1-yl)methyl]ferro-
cene] (6j): Yield 12%. IR: 3011 (arom. CꢀH), 2885 (CH2), 1591, 1533, 1482 (C¼C), 1233 (CꢀN), 1112
(fc), 1004 (fc), 903 (fc). 1H-NMR (CDCl3): 2.30 – 2.64 (m, 4 CH2NCH2); 4.30 (s, 2 CH2N); 4.41 (d, J ¼
12.7, 2 H of fc); 4.58 – 4.71 (m, 2 H of fc); 4.91 (s, 10 H of fc); 5.01 (d, J ¼ 12.7, 2 H of fc); 6.39 (d, J ¼ 7.4,
2 H of pyr); 6.68 (d, J ¼ 7.4, 2 H of pyr); 7.44 (s, 2 H of tp); 7.89 (s, 2 H of tp); 8.36 – 8.45 (m, 10 arom. H).
FAB-MS: 1213.33 ([M þ H]þ; calc. 1212.08). Anal. calc. for C74H64Fe2N6S2: C 73.26, H 5.32, N 6.93;
found: C 73.41, H 5.39, N 7.06.

Helvetica Chimica Acta – Vol. 92 (2009)
1655
8. Anti-amoebic Activity. The compounds 6a – 6j were screened in vitro for anti-amoebic activity
against the strain HM1:IMSS of E. histolytica by the microdilution method [21]. E. histolytica
trophozoites were cultured in TYIS-33 growth medium [22], in wells of a 96 microtiter plate (Costar).
The test compounds were dissolved in DMSO (40 ml). The maximum concentration of DMSO in the test
did not exceed 0.1% at which level no inhibition of amoebal growth occurred [23][24]. Enough culture
medium was added to obtain a concentration of 1 mg/ml. Stock solns. of the compounds were prepared
freshly before use at a concentration of 0.1 mg/ml. Two-fold serial dilutions were made. Each test
included metronidazole as a standard amoebic drug, control wells (culture medium plus amoeba), and a
blank (culture medium only). The number of amoeba per milliliter was estimated with a haemocy-
tometer, and trypan blue exclusion was used to confirm viability. The cell suspension used was diluted to
105 organisms/ml by adding fresh medium, and 170 ml of this suspension was added to the test and control
wells in the plate. An inoculum of 1.7 · 104 organisms/well was chosen, so that confluent but not excessive
growth took place. The plates were sealed, gassed for 10 min with N2, and incubated at 378 for 72 h. After
incubation, the growth of the amoeba was checked with a low-power microscope. The culture medium
was removed by inverting the plate and shaking gently. The plates were immediately washed with 0.9%
aq. NaCl soln. at 378. This procedure was performed quickly, and the plate was not allowed to cool, to
prevent the detachment of amoebae. The plate was allowed to dry at r.t., and the amoebae were fixed
with chilled MeOH by keeping it in an ice bath for 15 min, dried, and stained with 0.5% aq. eosin soln. for
15 min. The stained plate was washed once with ordinary H2O, and then twice with dist. H2O, and allowed
to dry. Then, 0.1n aq. NaOH soln. (200 ml) was added to each well to dissolve the protein and to release
the dye (eosine). The optical density of the resulting soln. in each well was determined at 490 nm with a
microplate reader. The inhibition (%) of amoebal growth was calculated from the optical densities of the
control and test wells, and plotted against the logarithm of the dose of the drug tested. Linear-regression
analysis was used to determine the best-fitting straight line (Fig.) from which IC50 values were
determined. The experiments were performed thrice for each compound tested.
REFERENCES
[1] N. Farrell, ꢃTransition Metal Complexes as Drugs and Chemotherapeutic Agentsꢄ, Reidel-Kluwer
Academic Publishers, Dordrecht, 1989, Vol. 11.
[2] H. Kopf, P. Kopf-Maier, Angew. Chem. 1979, 91, 509.
[3] P. Kopf-Maier, H. Kopf, E. W. Neuse, Angew. Chem., Int. Ed. 1984, 23, 456.
[4] C. E. D. Chidsey, Science (Washington, DC, U.S.) 1991, 251, 919.
[5] A. Togni, T. Hyashi, ꢃFerrocenesꢄ, VCH Verlagsgesellschaft mbH, Weinheim, Germany, 1995, refs.
cit. therein.
[6] M. Hobi, O. Ruppert, V. Gremlich, A. Togni, Organometallics 1997, 16, 1384.
[7] S. Barlow, H. E. Bumting, C. Ringham, J. C. Green, G. U. Bubliz, S. G. Boxer, J. W. Perry, S. R.
Marder, J. Am. Chem. Soc. 1999, 121, 3715.
[8] Y. Shimizu, Z. Shen, T. Okujima, H. Uno, N. Ono, Chem. Commun. 2004, 374.
[9] N. Agarwal, S. P. Mishra, A. Kumar, C. H. Hung, N. Ravikanth, Chem. Commun. 2002, 2642.
[10] D. Kumaresan, N. Agarwal, N. Ravikanth, Perkin Trans. 1 2001, 1644.
[11] D. G. Hilmey, N. Abe, M. I. Nelem, C. E. Stilts, G. A. Baker, S. N. Baker, F. P. Bright, S. R. Davies,
S. O. Gollnick, A. R. Oseroff, S. L. Gibson, R. Hilf, M. R. Detty, J. Med. Chem. 2002, 45, 449.
[12] N. Ravikanth, T. K. Chandrashekar, Struct. Bonding (Berlin) 1995, 82, 105.
[13] D. T. Gryko, F. Zhao, A. A. Yasseri, K. M. Roth, D. F. Bocian, W. J. Kuhr, J. S. Lindsey, J. Org. Chem.
2000, 65, 7356.
[14] C. Bucher, C. H. Devillers, J. C. Moutet, J. Royal, E. Saint-Aman, Chem. Commun. 2003, 888.
[15] J. Kim, S. W. Rhee, H. Y. Na, K. P. Lee, Y. Do, S. C. Jeoung, Bull. Korean Chem. Soc. 2001, 22, 1316.
[16] S. L. Stanley Jr., Lancet 2003, 361, 1025.
[17] L. S. Diamond, ꢃLumen Dwelling Protozoa: Entamoeba, Trichomonads, and Giardiaꢄ, in ꢃIn vitro
Cultivation of Protozoan Parasitesꢄ, Ed. J. B. Jensen, CRC Press, Boca Raton, 1983, pp. 65 – 110.
[18] M. Rosenblum, R. B. Woodward, J. Am. Chem. Soc. 1958, 80, 5443.

1656
Helvetica Chimica Acta – Vol. 92 (2009)
[19] M. A. L. Blackie, P. Beagley, K. Chibale, C. Clarkson, J. R. Moss, P. J. Smith, J. Organomet. Chem.
2003, 688, 144.
[20] M. A. Sierra, M. J. Mancheno, R. Vicente, M. Gomez-Gallego, J. Org. Chem. 2001, 66, 8920.
[21] C. W. Wright, M. J. OꢄNeill, J. D. Phillipson, D. C. Warhurst, Antimicrob. Agents Chemother. 1988,
32, 1725.
[22] L. S. Diamond, D. R. Harlow, C. C. Cunnick, Trans. R. Soc. Trop. Med. Hyg. 1978, 72, 431.
[23] F. D. Gillin, D. S. Reiner, M. Suffness, Antimicrob. Agents Chemother. 1982, 22, 342.
[24] A. T. Keen, A. Harris, J. D. Phillipson, D. C. Warhurst, Planta Med. 1986, 278.
Received December 31, 2008