Ultrasound-assisted synthesis of 3-(arylamino)-1-ferrocenylpropan-1-ones

Article abstract of DOI:10.1002/hlca.201200009

A successful aza-Michael addition of arylamines to a conjugated enone, acryloylferrocene, has been achieved by ultrasonic irradiation of the mixture of these reactants and the catalyst, i.e., montmorillonite K-10. This solvent-free reaction, yielding ferr

Full text of DOI:10.1002/hlca.201200009

Helvetica Chimica Acta – Vol. 95 (2012)
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Ultrasound-Assisted Synthesis of 3-(Arylamino)-1-ferrocenylpropan-1-ones
by Anka Pejovic´ a), Dragana Stevanovic´ a), Ivan Damljanovic´ a), Mirjana Vukic´evic´ b),
Sladjana B. Novakovic´ c), Goran A. Bogdanovic´ c), Tatjana Mihajilov-Krstevd), Niko Radulovic´*e), and
Rastko D. Vukic´evic´*a)
a
´
) Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovica 12, RS-34000
Kragujevac (e-mail: vuk@kg.ac.rs)
) Department of Pharmacy, Faculty of Medicine, University of Kragujevac, S. Markovica 69,
b
´
RS-34000 Kragujevac
c
ˇ
) Vinca Institute of Nuclear Sciences, Laboratory of Theoretical Physics and Condensed Matter Physics,
University of Belgrade, P.O. Box 522, RS-11001 Belgrade
) Department of Biology and Ecology, Faculty of Science and Mathematics, University of Nis,
d
ˇ
ˇ
ˇ
Visegradska 33, RS-18000 Nis
e
ˇ
ˇ
) Department of Chemistry, Faculty of Science and Mathematics, University of Nis, Visegradska 33,
ˇ
RS-18000 Nis (phone: þ 381-628049210; fax: þ 381-18533014; e-mail: nikoradulovic@yahoo.com)
A successful aza-Michael addition of arylamines to a conjugated enone, acryloylferrocene, has been
achieved by ultrasonic irradiation of the mixture of these reactants and the catalyst, i.e., montmorillonite
K-10. This solvent-free reaction, yielding ferrocene containing Mannich bases, 3-(arylamino)-1-
ferrocenylpropan-1-ones, considered as valuable precursors in organic synthesis, has been performed
by using a simple ultrasonic cleaner. Among 17 synthesized b-amino ketones, three were new ones, and
these were fully characterized by spectroscopic means. X-Ray crystallographic analysis of three of these
crystalline products enabled the insight into the conformational details of these compounds. All
compounds were evaluated for their antibacterial activities against six Gram-positive and five Gram-
negative strains in a microdilution assay. The observed promising antibacterial activity (with a MIC value
of 25 mg/ml (ca. 0.07 mmol/ml) as the best result for almost all tested compounds against Micrococcus
flavus) seems not only to be compound but also bacterial species-specific.
Introduction. – Ferrocene, an unusually stable metalorganic compound, has
attracted the most widespread attention of chemists among all non-natural compounds.
Since its discovery in 1951 [1][2], a plethora of studies dealing with ferrocene (which is
now commercially available, and a relatively non-expensive compound), and/or its
derivatives were carried out. This unprecedented interest is a consequence of several
unique features of these compounds. By classical methods of organic chemistry,
ferrocene could be easily functionalized to derivatives that possess an outstanding
stability in both aqueous and non-aqueous media. Thus, ferrocenes have applications in
numerous fields, particularly in those such as organic synthesis, catalysis, electronic
absorption, and nonlinear optical materials [3][4]. Since the iron core of these
compounds is able to exist in both Fe2þ and Fe3þ, they possess very interesting redox
properties and, therefore, offer interesting possibilities for the formation of electro-
chemical actuators or switches [5]. Furthermore, bioconjugates containing ferrocene
represent a new class of biomaterials, with the organometallic unit serving as a
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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molecular scaffold, a sensitive probe, a chromophore, a biological marker, a redox-
active site, a catalytic site, etc. [6]. Biological properties of this class of compounds are
particularly interesting. The earliest attempts to apply ferrocenes in medicine were
unsuccessful [7][8], but it did not discourage chemists to search for new possibly
biologically active derivatives of this metallocene. Several new compounds of this kind
have been synthesized and biologically evaluated against certain diseases, and it turned
out that many ferrocenyl compounds display interesting cytotoxic, antitumor,
antimalarial, and antimicrobial activities [9 – 18]. All these investigations were
prompted by the known fact that a formal substitution of an aromatic group from a
compound possessing a certain property (e.g., biological/pharmacological activity)
might lead to a product with this feature being much more manifested. It was the main
drawing force in many synthetic projects concerning ferrocenes: a plethora of new
molecules were designed to be derivatives or analogs of known compounds (that
already possess desired properties) in which a certain group was replaced with the
ferrocene unit (expecting an improved property). The present study also follows this
strategy. Namely, in the scope of a broader synthetic project, we needed recently some
3-(arylamino)-1-ferrocenylpropan-1-ones. In general, such compounds (b-amino
ketones) have many applications, among which the most important ones are surely
the synthesis of pharmaceuticals [19 – 22]. The introduction of a ferrocene nucleus into
these molecules could be of a particular interest. The most frequently used general
synthetic approach to these compounds is the Mannich reaction [19][23][24], but
serious disadvantages of this approach exist and mostly encompass the drastic reaction
conditions, long reaction times (causing many side reactions), and an inability of the
use of primary amines in the synthesis of secondary ones (since the latter are also good
substrates of the same reaction giving tertiary amines containing two 3-oxo groups). A
very good alternative to this reaction is the aza-Michael addition, i.e., the conjugate
addition of amines to the olefinic bond of a,b-unsaturated CO groups [25]. The
literature survey revealed that the addition of aliphatic amines to Michael acceptors
proceeds readily (even without a catalyst [26][27]), whereas aromatic ones do not
undergo this reaction easily because of their lower nucleophilicity, particularly when
mild conditions and environmentally friendly catalysts were used [28 – 32]. Considering
these literature findings, we developed recently a suitable method for the synthesis of
3-(arylamino)-1-ferrocenylpropan-1-ones by microwave irradiation of acryloyl ferro-
cene and the corresponding arylamines at the surface of montmorillonite K-10, without
a solvent in good-to-excellent yields [33]. In continuation of our permanent interest in
the synthesis of different ferrocene derivatives containing two or more heteroatoms
(interesting from both synthetic and medicinal chemistry points of view) [18][34 – 36],
herein we wish to report that this synthesis might be accomplished using a simple and
cheap ultrasonic cleaner instead of the microwave oven. Since almost all products are
crystal substances, suitable for X-ray analysis, in addition to the spectral data of newly
synthesized compounds, we will compare here the structural features (molecular
structure and ability to form intermolecular interactions) of some of the obtained
Mannich bases with those of recently reported derivatives [33]. Our previous results on
the antibacterial activity of these compounds encouraged us to screen the synthesized
compounds against a broader panel of bacterial strains (in total eleven different
bacteria) in order to provide a better understanding of the intrinsic features of these

Helvetica Chimica Acta – Vol. 95 (2012)
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compounds, responsible for their activity, and to possibly point out to the ones with
higher or improved activity (in this context, the currently obtained minimal inhibitory
concentrations (MIC) data together with those reported in [33] were subjected to an
agglomerative hierarchical clustering analysis).
Results and Discussion. – Synthesis. The main advantages of the method described
in our previous work for the synthesis of the title compounds over the classical ones are
the simplicity, high efficiency, and the use of an environmentally friendly catalyst [33].
Even better results with respect to these parameters have been reported recently for
the catalyst-free addition of aliphatic amines to conjugate systems of ferrocene analogs
of chalcones supported by the ultrasonic irradiation [30]. However, as the authors
reported, this reaction failed when aromatic amines were used as the nucleophiles. In
our hands, on the other hand, the addition of aniline (2a) to acryloylferrocene (1) under
conditions described in [33] gave the corresponding b-amino ketone (3a; Scheme), but
in a relatively poor yield (<40%). Since our microwave-assisted synthesis of the same
compound starting from the same reactants was successful only in the presence of the
catalyst (montmorillonite K-10) [33], we assumed that the addition of less nucleophilic
aromatic amines to the conjugate system of enones might be facilitated also by the
simultaneous action of this environmentally benign catalyst and ultrasonic irradiation.
A very recent report, demonstrating once again that ultrasound has a positive effect on
the conjugate addition of amines to Michael acceptors (appeared when the present
manuscript has already been finished), confirms validity of this idea [37]. Thus, when a
mixture of 1 (1 mmol), 2a (2 mmol), and montmorillonite K-10 (100 mg) was
irradiated in an ultrasonic cleaner for 1 h, b-amino ketone 3a was obtained in high
yield (80%). To check the generality of this reaction, additional 16 arylamines, 2b – 2q
(Scheme), have been submitted to the same reaction conditions. The results are
compiled in Table 1, and show that a simple and cheap ultrasonic cleaner can be used to
accomplish the aza-Michael reaction as successfully as a microwave oven.
Scheme. Ultrasound-Assisted Synthesis of 3-(Arylamino)-1-ferrocenylpropan-1-ones
An overview of the data collected in Table 1 reveals that the yields of the
corresponding b-amino ketones 3a – 3q depend on the structure of the starting amines
2a – 2q in an expected manner. Namely, when the starting amines contain an electron-
withdrawing group, the yield of the corresponding Mannich base is lower. Thus, in the
case of amines containing a C¼O group (i.e., 2l – 2n), the corresponding b-amino
ketones were obtained in slightly lower yields (Table 1, Entries 12 – 14) than in the case
of aniline, whereas the presence of a strong electron-withdrawing group, i.e., the NO2
group (amines 2o – 2q), causes a more considerable decrease of the yields (Table 1,
Entries 15 – 17).

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Helvetica Chimica Acta – Vol. 95 (2012)
Table 1. Structures of 3-(Arylamino)-1-ferrocenylpropan-1-ones, 3a – 3q, and the Corresponding Starting
Amines 2a – 2q, Respectively, as Well as the Yields of the Reaction
Entry
1
Amine
Product
Yielda)
80
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
2
3
4
5
90
80
85
82
6
7
8
9
2f
2g
2h
2i
3f
3g
3h
3i
90
91
95
93

Helvetica Chimica Acta – Vol. 95 (2012)
1429
Table 1 (cont.)
Entry
10
Amine
Product
Yielda)
90
2j
3j
11
12
13
2k
2l
3k
3l
89
77
75
2m
3m
14
15
16
17
2n
2o
2p
2q
3n
3o
3p
3q
70
35
61
59
a) Yields of isolated products based on the starting acryloylferrocene.
Spectral Characterization. The three newly synthesized compounds, 3l – 3n,
described in this work (the rest of the compounds from Table 1, 3a – 3k and 3o – 3q,
have been already reported in [33] including their spectral data) have been fully
1
characterized by standard spectroscopic techniques (IR, and H- and 13C-NMR), as

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Helvetica Chimica Acta – Vol. 95 (2012)
well as elemental analyses. All spectral data were fully consistent with the proposed
structures and with those reported in [33].
In the IR spectra of 3l – 3n, sharp, medium intensity absorptions of NH stretching
vibrations are observed below 3400 cmꢀ1, indicating that all NH groups are involved in
H-bonding interactions. The CO stretching vibration band of the 1’-ferrocene-carbonyl
group appears in the range 1667 – 1677 cmꢀ1, suggesting the existence of inter- and/or
intramolecular H-bonds to the CO functional group. The C¼O absorptions of the Ac
group show a similar trend and are all at higher frequencies when compared to the
corresponding aminoacetophenones.
The 1H- and 13C-NMR spectra of compounds 3l – 3n display all signals expected for
the proposed composition. With few exceptions (typically, the CH2 C-atom signals
having close values of their chemical shifts and overlapped signals), the H- and C-atom
resonances could be assigned on the basis of chemical-shift theory, signal intensities and
multiplicities, substituent effects, and by comparison with literature data [38] for the
corresponding aminoacetophenones.
1
The H-NMR data for the three newly synthesized compounds are typical of
monosubstituted ferrocene (a characteristic intensity pattern of 2 :2 :5 for the
cyclopentadienyl (Cp) H-atoms of ferrocene). Two slightly deshielded ꢂtripletsꢃ (or
better pseudotriplets) are observed for the Cp ring H-atoms at 4.51 – 4.53 and 4.77 –
4.80 ppm. The low-field pseudotriplet is assigned to the H-atoms at C(2) and C(5),
whereas the high-field pseudotriplet is assigned to the ring H-atoms at C(3) and C(4).
These are downfield of the singlets assigned to the unsubstituted Cp ring at d(H) 4.11 –
4.17, which is characteristic for ferrocenes with electron-withdrawing substituents (due
to deshielding with the increased delocalization of electron density toward the C¼O
substituent [39]).
The involvement of the NH H-atom in 3l in intramolecular H-bonding may be
1
inferred from the chemical shift of this H-atom (9.01 ppm) in its H-NMR spectrum,
while, in the other two compounds, the NH is more probably involved in intermolecular
H-bonding, and their signals are shifted upfield (d(H) 4.43 and 4.81, for 3m and 3n,
resp.). These slightly acidic H-atoms undergo a slow exchange reaction in CDCl3 and
the signal splits by coupling to the H-atoms of the adjacent CH2 group (resulting in
broad triplets with a coupling constant of ca. 6 Hz). The slow exchange on the NMR
time scale of these NH H-atoms seems to be a characteristic of these ferrocene
containing compounds rather than of the Ph analogs (compounds obtained when the
ferrocene nucleus is interchanged with a benzene ring), since the latter do not show this
coupling and give broad singlets for the NH H-atoms [33].
The off-resonance H-atom decoupled 13C-NMR spectra of 3l – 3n exhibited the
expected number of peaks in the aliphatic, aromatic, and CO regions. The CO C-atom
signals appear at d(C) 202.1 – 203.4 and 196.3 – 200.8 (for the FcCO and MeCO group,
resp.). The 13C resonances of the ꢀCH2CH2ꢀ fragment in all three compounds were
relatively non-sensitive to the position of the acyl substituent on neighboring
phenylamino group and could be found in the following ranges: d(C) 37.4 – 37.9 and
38.0 – 38.8. The same applies for the chemical shifts of the substituted Cp ring (d(C)
69.2 – 69.3 (C(3’) and C(4’)) and 72.4 – 72.6 (C(2’) and C(5’))). The chemical
equivalence of HꢀC(2’,5’) and HꢀC(3’,4’) atom pairs evidences a free and fast rotation
around the CꢀC bond between the Cp rings and their substituents.

Helvetica Chimica Acta – Vol. 95 (2012)
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X-Ray Crystal Structure of 3c, 3k, and 3l. The three 3-(arylamino)-1-ferrocenyl-
propan-1-ones, presented in Fig. 1, crystallize in different crystal systems: monoclinic
¯
(space group C2/c), triclinic (P1), and orthorhombic (P212121) for 3c, 3k, and 3l,
respectively. The Cp rings within their ferrocene units are nearly parallel (the maximum
dihedral angle of 1.6(2)8 is found in 3c) and exhibit conformations which are close to
the eclipsed ones. The torsion angle C1ꢀCg1ꢀCg2ꢀC6, relating the eclipsed C-atoms
through the corresponding Cp centroids, is equal to 13.1(5), 6.4(5), and 1.2(5)8 for 3c,
3k, and 3l, respectively. In each of the structures, the Fe ··· Cg1 distance (Cg1 is centroid
Fig. 1. Molecular structures of 3c (a), 3k (b), and 3l (c) with the atom numbering scheme. Displacement
ellipsoids are drawn at the 40% probability level. Dashed lines in 3l indicate N1ꢀH ··· O2 and C6ꢀH ···
O2 intramolecular interactions

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of the substituted Cp ring) is, in average, by 0.01 ꢄ shorter than the distance toward the
unsubstituted ring (Fe ··· Cg2). This is in accordance with the previously observed trend
for similar ferrocene derivatives [33][40].
As defined by the O1ꢀC11ꢀC1ꢀC5 torsion angle (ꢀ 5.8(4), 1.9(5), and ꢀ 5.3(4)8 in
3c, 3k, and 3l, resp.), the corresponding C1¼O1 carbonyl fragment is almost co-planar
with the substituted Cp ring. A similar co-planarity between the aromatic ring and the
closely attached atoms can also be observed within the arylamino moiety. The torsion
angle N1ꢀC14ꢀC15ꢀC16 is equal to 176.2(3), 174.9(3), and 179.9(3)8 in 3c, 3k, and 3l,
respectively. A number of selected structural parameters (Table 2) show values closely
comparable with those recently reported for crystal structures of compounds 3j, 3p, and
3o [33]. It is interesting to notice that, despite the allowed free rotation around the
constituting single bonds, and the variation in type and position of the arylamino
substituents, the C1ꢀC11ꢀC12ꢀC13ꢀN1 fragment within all six crystal structures
displays a rather similar conformation. This is indicated by the similarity of the torsion
angles C1ꢀC11ꢀC12ꢀC13 and C11ꢀC12ꢀC13ꢀN1, whose values of ꢀ 165.6(2)/76.2(3),
ꢀ 172.5(3)/76.4(4), and ꢀ 178.6(2)/71.1(3)8 in 3c, 3k, and 3l, respectively, are
consistent with those reported for 3j, 3p, and 3o [33].
Table 2. Selected Bond Lengths and Angles of 3c, 3k, and 3l
3c
3k
3l
Bond lengths [ꢄ]
O1ꢀC11
1.222(3)
1.389(4)
1.439(4)
1.477(3)
1.506(3)
1.524(3)
1.510(5)
–
1.218(4)
1.373(4)
1.445(5)
1.468(4)
1.509(4)
1.516(5)
–
1.738(4)
–
–
1.227(3)
1.355(4)
1.448(4)
1.469(4)
1.510(4)
1.505(4)
–
N1ꢀC14
N1ꢀC13
C1ꢀC11
C11ꢀC12
C12ꢀC13
C16ꢀC20
C17ꢀCl1
C15ꢀC20
C20ꢀO2
–
–
–
1.471(4)
1.223(3)
Bond angles [8]
O1ꢀC11ꢀC1
120.9(2)
121.1(2)
117.9(2)
112.9(2)
113.6(2)
122.2(2)
121.8(3)
121.6(3)
116.6(3)
112.8(3)
114.4(3)
121.5(3)
120.4(3)
121.4(3)
118.2(3)
113.5(3)
111.3(2)
124.7(3)
O1ꢀC11ꢀC12
C1ꢀC11ꢀC12
C11ꢀC12ꢀC13
N1ꢀC13ꢀC12
C14ꢀN1ꢀC13
Among the presently discussed compounds, the most significant difference can be
detected by a comparison of the C12ꢀC13ꢀN1ꢀC14 torsion angle, which indicates a
different orientation of the arylamino moiety in 3l (ꢀ176.4(3)8) with respect to its
orientation in 3c and 3k (69.4(4) and 70.6 (4)8). The corresponding dihedral angle
between the Fe1/C1/Cg1 plane (dividing the substituted Cp ring) and the best plane of
the Ph ring has the values 85.1(5), 87.4(5), and 32.2(5)8 in 3c, 3k, and 3l, respectively. In
comparison with the previously described structures, one can observe that the

Helvetica Chimica Acta – Vol. 95 (2012)
1433
structural features of 3c and 3k closely resemble those of 3j and 3p. Accordingly, it can
be suggested that the conformation observed for these four compounds is favorable in
the cases where the arylamino moiety has the substituent at C(3’’’) or C(4’’’). The
conformation of 3l is, on the other hand, similar to that of 3o and quite different from
those of 3c, 3k, 3j, and 3p. One possible explanation for the different orientations of the
arylamino moieties in 3l and 3o structures (comparing to 3c, 3k, 3j, and 3p) could be
found in their ability to form an intramolecular H-bond between the substituent at
C(2’’’) and the rest of the molecule (see Fig. 1, c).
Regardless of the type of substituents present in the arylamino moiety, conforma-
tionally similar derivatives possess a similar way of the intermolecular arrangement. As
previously described for 3j and 3p, the crystal packing of 3c and 3k is also characterized
by the formation of discrete H-bonding dimers where centrosymmetrically related
molecules associate through pairs of strong NꢀH ··· O interactions (Table 3, Fig. S11)).
This is not the case with 3l where the corresponding C¼O O-atom is engaged in two
weak CꢀH ··· O interactions which lead to a more extended, chain-like molecular
arrangement (Table 3). The crystal packing of 3l is, however, comparable to that of 3o,
which, although containing additional acceptor sites (two O-atoms of the NO2
substituent), involves exactly the same sets of atoms in intermolecular H-bonding
(Fig. S21)). The arylamino NꢀH donor of 3l (Fig. 1,c), as well as that of 3o, is engaged
only in the intramolecular H-bonding to the corresponding Ac and NO2 substituents,
respectively.
Table 3. Geometrical Parameters of H-Bonds, and Selected CꢀH ··· O Interactions of 3c, 3k, and 3l. The
CꢀH ··· O interactions are given, if H ··· O distance is shorter than 2.7 ꢄ, and CꢀH ··· O angle is larger
than 1008.
DꢀH ··· A
d(DꢀH) [ꢄ]
d(D ··· A) [ꢄ]
d(H ··· A) [ꢄ]
/(DꢀH ··· A) [8]
3ca)
N1ꢀH1N ··· O1i
0.77(3)
0.93
3.036(3)
3.483(4)
2.27(3)
2.62
172(3)
156
C4ꢀH4 ··· N1ii
3kb)
N1ꢀH1N ··· O1i
0.82(4)
3.054(4)
2.26(4)
162(3)
3lc)
N1ꢀH1N ··· O2
C6ꢀH6 ··· O2
C2ꢀH2 ··· O1i
C12ꢀH2b ··· O1ii
0.75(3)
0.93
0.93
2.669(4)
3.487 (5)
3.326 (3)
3.235(4)
2.07(3)
2.60
2.54
2.57
b
137(3)
159
143
0.97
126
a) Symmetry codes: i ꢀ x þ 1/2, ꢀ y þ 1/2, ꢀ z; ii x þ 1/2, y þ 1/2, z. ) Symmetry codes: i ꢀ x þ 2, ꢀ y þ 1,
c
ꢀ z þ 2. ) Symmetry codes: i x ꢀ 1, y, z; ii x ꢀ 1/2, ꢀ y þ 1/2, ꢀ z þ 2.
Biology. Several ferrocenyl compounds display interesting cytotoxic, antitumor,
antimalarial, antifungal, antibacterial, and DNA-cleaving activities [16]. In our
previous work, we have demostrated that 3-(arylamino)-1-ferrocenylpropan-1-ones
possess a certain degree of antibacterial potential, especially against an important
human pathogen S. aureus [33]. This time we have retested compounds 3a – 3k and 3o –
1
)
Supplementary Material may be obtained upon request from the authors.

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Helvetica Chimica Acta – Vol. 95 (2012)
3q against additional three Gram-positive (Listeria monocytogenes, Micrococcus
flavus, and Sarcina lutea) and two Gram-negative (Klebsiella pneumoniae and Shigella
sonnei) bacteria, while the remaining, newly synthesized compounds 3l – 3n were
evaluated against the full panel of eleven bacterial strains. The results of the MIC
determination as well as of the minimal bactericidal activity (MBC) are presented in
Tables 4 and 5 as the averages of five repetitions. The compounds have again been
shown to possess inhibitory action on the growth of all bacteria with MIC values in the
range of 0.025 and 25.00 mg/ml. Almost as a rule, MBC values were several folds higher
than those of MIC, suggesting a better inhibitory than bactericidal activity. The only
exception was the case of P. aeruginosa where the MIC against all tested strains was a
cidal one. The most sensitive bacterium turned out to be a Gram-positive M. flavus with
MIC value lower than 25 mg/ml and MBC being 25 mg/ml, but even this best result was
one hundred times lower compared to the effect caused by tetracycline on the same
bacterium. Once more, a Gram-positive strain, Bacillus cereus, was the most resistant
one among the assayed, with the highest MIC values (66.5 mmol/ml) for 3l – 3n.
Although having the least significant action on the growth of B. cereus, these three
compounds were generally among the most active ones against all other bacteria,
including the pathogenic K. pneumoniae (MIC 2.08 – 8.32 mmol/ml), L. monocytogenes
(MIC 8.32 – 16.6 mmol/ml), and S. soneii (MIC 4.16 – 8.32 mmol/ml).
Table 4. Minimal Inhibitory (MIC) and Minimal Bactericidal Concentrations (MBC) of the Synthesized
Compounds 3a – 3k and 3o – 3q
Compound
MIC/MBC [mmol/ml]
Gram (ꢀ) bacteria
Gram (þ) bacteria
Klebsiella
Shigella sonnei
Listeria
Micrococcus
Sarcina lutea
pneumoniae
monocytogenes
flavus
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3o
3p
3q
9.36/75.0
8.99/36.0
2.25/18.0
8.99/36.0
4.16/66.6
8.88/35.5
17.8/35.5
4.44/35.5
2.12/33.9
8.49/136
8.49/33.9
2.06/66.0
4.12/33.0
0.529/16.5
2.25/2.25
18.8/37.5
18.0/72.0
18.0/72.0
4.50/36.0
16.6/66.6
2.22/35.5
17.8/35.5
17.8/35.5
17.0/33.9
8.49/67.9
2.12/33.9
16.5/66.0
8.25/33.0
16.5/66.0
2.25/2.25
9.36/37.5
8.99/36.0
2.25/4.50
1.12/4.50
4.16/66.6
8.88/35.5
17.8/35.5
4.44/35.5
2.12/17.0
4.24/17.0
2.12/33.9
2.06/4.12
4.12/33.0
0.529/8.25
36.0/36.0
< 0.0750/0.0750
< 0.0720/0.0720
< 0.0720/0.0720
< 0.0720/0.0720
< 0.0666/0.0666
< 0.0712/0.0712
< 0.0712/0.0712
< 0.0712/0.0712
< 0.0680/0.0680
< 0.0680/0.0680
< 0.0680/0.0680
< 0.0661/0.0661
< 0.0661/0.0661
< 0.0661/0.0661
0.563/0.563
0.150/0.150
0.144/0.144
0.144/0.144
0.144/0.144
0.133/0.133
0.142/0.142
0.142/0.142
0.142/0.142
0.136/0.136
0.136/0.136
0.136/0.136
0.132/0.132
0.0661/0.132
0.132/0.132
55.4/55.4
Tetracyclinea)
a) MIC/MBC values are given in nmol/ml.
To better interpret the results obtained in antibacterial assays, we have statistically
compared the obtained MIC values of compounds 3a – 3q against all eleven bacteria
(results from the current work and those obtained in our previous study [33]). The

Helvetica Chimica Acta – Vol. 95 (2012)
1435
Table 5. Minimal Inhibitory (MIC) and Minimal Bactericidal Concentrations (MBC) of the Synthesized
Compounds 3l – 3n
Bacterial strains
MIC/MBC [mmol/ml]
3l 3m
3n
Tetracycinea)
Gram (ꢀ) bacteria
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Salmonella enterica
Shigella sonnei
0.533/0.533
2.08/16.6
0.533/0.533
1.07/1.07
0.533/0.533
2.08/8.32
1.07/1.07
2.08/2.08
4.16/8.32
0.267/0.533
8.32/16.6
0.533/0.533
0.267/0.533
8.32/8.32
3.51/3.51
2.25/2.25
7.02/7.02
7.02/7.02
2.25/2.25
4.16/16.6
Gram (þ) bacteria
Bacillus cereus
Clostridium perfringens
Listeria monocytogenes
Micrococcus flavus
Sarcina lutea
66.5/66.5
16.6/33.3
8.32/16.6
< 0.0666/0.0666
0.267/0.533
0.267/0.533
66.5/66.5
16.6/33.3
16.6/16.6
< 0.0666/0.0666
0.267/0.533
0.267/0.533
66.5/66.5
66.5/66.5
8.32/8.32
< 0.0666/0.0666
0.0666/0.0666
1.07/1.07
3.51/3.51
3.51/3.51
36.0/36.0
0.563/0.563
55.4/55.4
0.202/0.202
Staphylococcus aureus
a) MIC/MBC values are given in nmol/ml.
results of agglomerative hierarchical clustering (AHC) analyses are presented in Fig. 2.
The dendrogram indicates the existence of six groups of compounds. Compounds 3l –
3n were separated from the rest of the compounds, making the two highly related clades
C5 and C6. The presence of an additional CO (AcO) group seems to have
differentiated them from the other compounds, and resulted in the greatest decrease
in activity against B. cereus, while retaining a significant degree of activity towards
other bacteria as mentioned above (this is clearly observable from the centroid
characteristics of these clades). The rest of the groups do not have such a clear-cut
subdivision of the compounds. A number of subclades consist of compounds having
substituents of similar electronic character, e.g., electron-withdrawing ones in 3h, 3q, 3i,
and 3o of class C3 second, and that are regiochemically the same (having substituents in
the same position on the benzene ring), e.g., 3i and 3o, C3 class; 3j and 3p, class C4; and
3d and 3k, the same class. This analysis also showed that clade C1 (a single compound,
3b, making up this group) is the most related to, but still statistically different, from,
clade C2 (again only one compound in this class, i.e. 3g). The two compounds appear to
be differentiated by the activity against Salmonella enterica, the latter being less active.
These observations confirm the notion that, in general, compounds having an electron-
acceptor functionality appeared not to be more or less effective in inhibiting the growth
of all bacteria than compounds possessing an electron-donating substituent or no
substituent at all. Although it is reasonable to expect that the ortho-regioisomers could
have a steric impediment towards an interaction with the receptor of the test organisms,
and this is substantiated by the corresponding mentioned grouping of these isomers, the
extent of the activity does not seem to hold out on this hypothesis. The activity seems
not only to be compound but also bacterial species-specific. It seems worthwhile to note
that the activity of the compounds does not follow a trend of decreasing hydrophilic
character (estimated [41] log Po/w values for the Ph analogs of compounds were used for

1436
Helvetica Chimica Acta – Vol. 95 (2012)
this purpose), hence, indicating that the well-known fact that the solubility of
antimicrobials in the bilipid cell membranes may play a significant role in the activity,
here has little if any importance. Thus, further work is necessary to establish the true
mechanism of action of these ferrocenyl derivatives. Overall, these results are highly
promising and suggest that a more detailed study of the antimicrobial (including the
antifungal one) activity of this class of compounds could identify further derivatives
with improved antibacterial properties.
Fig. 2. Dendrogram (AHC analysis) and its expansion (left) representing antibacterial activity (the MIC
values of compounds 3a – 3q against eleven bacterial strains) dissimilarity relationships of the seventeen
compounds 3a – 3q obtained by Euclidean distance dissimilarity, using aggregation criterion-Wardꢀs
method. Six groups of the compounds were found: C1 – C6 (from left to right).
Conclusions. – We described, herein, a new, easily performable procedure for the
conjugate addition of arylamines to acryloylferrocene to yield the corresponding N-
aryl-3-amino-1-ferrocenylpropan-1-ones in good to excellent yields. This synthesis was

Helvetica Chimica Acta – Vol. 95 (2012)
1437
performed with montmorillonite K-10 as the catalyst, supported by ultrasonic
irradiation. We unambiguously showed that both the catalyst and the irradiation play
an important role in this synthesis. The procedure requires short reaction times,
employs an environmentally friendly and non-expensive catalyst, as well as an
ultrasonic cleaner, a cheap and simple apparatus, which almost every laboratory
possesses. Among 17 compounds synthesized in this way, three were also characterized
by single-crystal X-ray analysis. The investigation of their crystal structures and the
comparison with recently reported ones suggest two favored conformations for 3-
(arylamino)-1-ferrocenylpropan-1-ones. One of the factors influencing the conforma-
tion could be the position of the substituent in the arylamino moiety. The conforma-
tionally similar derivatives show considerable similarity in their manner of crystal
packing. The results of antibacterial assays are highly promising and urge for a more
mechanistic-oriented study of antimicrobial (both antibacterial and antifungal)
activities of such compounds that could possibly identify further derivatives with
improved activity. The observed antibacterial activity seems not only to be compound-
(position of the substituent on the ring and its electron-donating/accepting properties)
but also bacterial species-specific.
This work was supported by the Ministry of Education and Science of the Republic of Serbia (grant
´
172034). We thank Prof. Vladimir Divjakovic for the diffraction data of compounds 3k and 3l.
Experimental Part
General Remarks. All chemicals were commercially available and used as received, except that the
solvents were purified by distillation. Column chromatography (CC): silica gel 60 (230 – 400 mesh
ASTM; Merck). TLC: silica gel 60 on Al plates, layer thickness 0.2 mm (Merck). M.p. (uncorrected):
Mel-Temp cap. melting-point apparatus, model 1001. IR Spectra: Perkin-Elmer FTIR 31725-X
spectrophotometer. 1H- and 13C-NMR spectra: in CDCl3, Varian Gemini (200 MHz) spectrometer;
chemical shifts in d(H) [ppm], rel. to the residual solvent H-atoms or 13CDCl3 as the internal standards
1
(CDCl3: 7.26 ppm for H and 77.0 ppm for 13C). Elemental analysis of C, H, and N: Carlo Erba 1106
microanalyser; results in agreement with the calculated values. The reactions (ultrasonic-assisted
syntheses) were performed by placing the probe with the reactants and the catalyst in an ultrasonic
cleaner. An Elmasonic S30 (Elma, Germany) ultrasound bath was used at a frequency of 37 kHz, with an
effective ultrasonic power of 30 W and a peak of 240 W.
General Procedure for the Synthesis of the Mannich Bases 3a – 3q. A test tube containing a well-
homogenized mixture of 240 mg (1 mmol) of acryloylferocene, 2 mmol of the corresponding arylamine,
and 100 mg of montmorillonite K-10 was placed in the ultrasonic cleaner and irradiated for 1 h. Then,
CH2Cl2 (10 ml) was added to the mixture, and the contents were filtered off. The solid residue was
washed with CH2Cl2, and the collected org. solns. were dried (Na2SO4) overnight. After the evaporation
of the solvent, the crude mixture was fractioned by flash chromatography on a SiO2 column. The amines
eluted with toluene, whereas the Mannich bases 3a – 3q were washed from the column by a mixture of
hexane and AcOEt 9 :1 (v/v). In all cases, the complete excess of the amines was recovered. The spectral
data of compounds 3a – 3k and 3o – 3q can be found in [33], whereas the data of the newly synthesized
ones 3l – 3n are given below.
3-[(2-Acetylphenyl)amino]-1-ferrocenylpropan-1-one (3l). M.p. 1198. IR (KBr): 3322, 1667, 1630,
1567, 1515, 1503, 1458, 1250, 1228, 1205, 1168, 1146, 1107, 949, 752, 609. 1H-NMR (200 MHz, CDCl3): 9.01
(t, J ¼ 5.8, NH); 7.75 (dd, J ¼ 8.1, 1.6, HꢀC(3’’’)); 7.40 (ddd, J ¼ 8.6, 7.1, 1.6, HꢀC(5’’’)); 6.83 (br. d, J ¼ 8.6,
HꢀC(6’’’)); 6.61 (ddd, J ¼ 8.1, 7.1, 1.1, HꢀC(4’’’)); 4.80 (pseudo-t, HꢀC(2’), HꢀC(5’)); 4.51 (pseudo-t,
HꢀC(3’), HꢀC(4’)); 4.17 (s, HꢀC(1’’), HꢀC(2’’), HꢀC(3’’), HꢀC(4’’), HꢀC(5’’)); 3.68 (dt, J ¼ 6.9, 5.8,
CH2(3)); 3.08 (br. t, J ¼ 7.0, CH2(2)); 2.57 (s, Me). 13C-NMR (50 MHz, CDCl3): 202.1 (C(1)); 200.8

1438
Helvetica Chimica Acta – Vol. 95 (2012)
(COMe); 150.6 (C(1’’’)); 135.1, 132.8 (C(3’’’), C(5’’’)); 117.8 (C(2’’’)); 114.2, 111.5 (C(4’’’), C(6’’’)); 78.8
(C(1’)); 72.4 (C(2’), C(5’)); 69.8 (C(1’’), C(2’’), C(3’’), C(4’’), C(5’’)); 69.3 (C(3’), C(4’)); 38.8, 37.4 (C(2),
C(3)); 27.9 (Me). Anal. calc. for C21H21FeNO2 (375.2419): C 67.22, H 5.64, N 3.73; found: C 67.30, H 5.67,
N 3.71.
3-[(3-Acetylphenyl)amino]-1-ferrocenylpropan-1-one (3m). M.p. 1068. IR (KBr): 3363, 1677, 1652,
1600, 1519, 1473, 1453, 1283, 1263, 1106, 826, 782, 688. 1H-NMR (200 MHz, CDCl3): 7.30 – 7.22 (m,
overlapping peaks, HꢀC(2’’’), HꢀC(4’’’), HꢀC(5’’’)); 6.84 (ddd, J ¼ 8.2, 2.6, 1.3, HꢀC(6’’’)); 4.77 (pseudo-t,
J ¼ 2.0, HꢀC(2’), HꢀC(5’)); 4.51 (pseudo-t, J ¼ 2.0, HꢀC(3’), HꢀC(4’)); 4.43 (br. t, J ¼ 5.9, NH); 4.11 (s,
HꢀC(1’’), HꢀC(2’’), HꢀC(3’’), HꢀC(4’’), HꢀC(5’’)); 3.62 (pseudo-q, J ¼ 5.9, CH2(3)); 3.04 (t, J ¼ 5.9,
CH2(2)); 2.57 (s, Me).13C-NMR (50 MHz, CDCl3): 203.4 (C(1)); 198.7 (COMe); 147.9 (C(1’’’)); 138.2
(C(3’’’)); 129.4 (C(5’’’)); 118.2, 118.0 (C(4’’’),C(6’’’)); 111.1 (C(2’’’)); 78.7 (C(1’)); 72.5 (C(2’), C(5’)); 69.8
(C(1’’), C(2’’), C(3’’), C(4’’), C(5’’)); 69.2 (C(3’), C(4’)); 38.6, 37.9 (C(2), C(3)); 26.7 (Me). Anal. calc. for
C21H21FeNO2 (375.2419): C 67.22, H 5.64, N 3.73; found: C 67.23, H 5.60, N 3.72.
3-[(4-Acetylphenyl)amino]-1-ferrocenylpropan-1-one (3n): M.p. 1828. IR (KBr): 3330, 1665, 1647,
1600, 1584, 1456, 1361, 1283, 1263, 1180, 1042, 959, 825, 584. 1H-NMR (200 MHz, CDCl3): 7.84 (AA’XX’,
Jo ¼ 8.9, Jm ¼ 2.4, HꢀC(3’’’), HꢀC(5’’’)); 6.61 (AA’XX’, Jo ¼ 8.9, Jm ¼ 2.4, HꢀC(2’’’), HꢀC(6’’’)); 4.81 (br. t,
J ¼ 5.9, NH); 4.78 (pseudo-t, J ¼ 2.0, HꢀC(2’), HꢀC(5’)); 4.53 (pseudo-t, J ¼ 2.0, HꢀC(3’), HꢀC(4’)); 4.11
(s, HꢀC(1’’), HꢀC(2’’), HꢀC(3’’), HꢀC(4’’), HꢀC(5’’)); 3.66 (pseudo-q, J ¼ 5.9, CH2(3)); 3.04 (t, J ¼ 5.9,
CH2(2)); 2.49 (s, Me).13C-NMR (50 MHz, CDCl3): 203.0 (C(1)); 196.3 (COMe); 151.6 (C(1’’’)); 130.9
(C(3’’’), C(5’’’)); 126.8 (C(4’’’)); 111.4 (C(2’’’), C(6’’’)); 78.6 (C(1’)); 72.6 (C(2’), C(5’)); 69.8 (C(1’’),
C(2’’), C(3’’), C(4’’), C(5’’)); 69.2 (C(3’), C(4’)); 38.0, 37.9 (C(2), C(3)); 26.0 (Me). Anal. calc. for
C21H21FeNO2 (375.2419): C 67.22, H 5.64, N 3.73; found: C 67.18, H 5.59, N 3.70.
X-Ray Crystallography. Single crystals suitable for X-ray-analysis of 3c, 3k, and 3l were obtained by
a slow evaporation from a mixture of CH2Cl2 and hexane. The diffraction data for 3k and 3l were
collected on Oxford Diffraction Xcalibur Sapphire3 Gemini, while those for 3c were collected on Enraf
Nonius CAD4 diffractometer, both equipped with MoKa radiation (l ¼ 0.71073 ꢄ). In the case of 3k and
3l, data were processed with CrysAlis software [42] with multi-scan absorption corrections applied using
SCALE3 ABSPACK [42]. The data for 3c were processed with XCAD4-CAD4 data reduction program
[43]. All three crystal structures were solved with SHELXS [44] and refined using SHELXL [44]. The
refinement of the crystal structure 3k revealed the presence of a disordered solvent molecule which could
not be reliably modeled. The examination of the structure with SQUEEZE/SOLV procedures included
in PLATON [45] indicated the presence of one solvent-accessible void per unit cell with the estimated
volume of 205 ꢄ3. The volume of the cavity and the shape of the residual electron density suggest the
incorporation of one toluene molecule. This solvent was used during the synthetic procedure for the
chromatographic elution of the amine. The contribution of the solvent to the scattering factors was
suppressed using the SQUEEZE procedure. A new data set, free of solvent contribution, was then used
in the final refinement.
In all three structures, the H1-atom attached to N1 was located by difference Fourier synthesis and
refined isotropically. All other H-atoms were placed at geometrically calculated positions with the CꢀH
distances fixed to 0.93 from C(sp2); 0.96 and 0.97 ꢄ from Me and CH2 C(sp3), resp. The corresponding
isotropic displacement parameters of the H-atoms were equal to 1.2 Ueq and 1.5 Ueq of the parent C(sp2)
and C(sp3), resp.
The crystallographic data are compiled in Table 6. Figures were produced using ORTEP-3 [46] and
MERCURY, Version 2.4 [47]. The software used for the preparation of the materials for publication:
WinGX [48], PARST [49], PLATON [45].
Crystallographic data for 3c, 3k, and 3l have been deposited at the Cambridge Crystallographic Data
Centre (CCDC) with the deposition Nos. CCDC-846998, 846999, and 847000, resp. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ 44 1223 336033; e-
mail: deposit@ccdc.cam.ac.uk).
Biology. Test Microorganisms. The synthesized 3-(arylamino)-1-ferrocenylpropan-1-ones, 3a – 3q,
were assayed for antibacterial activity against a panel of strains belonging to the American Type Culture
Collection (ATCC). Compounds 3a – 3q were tested against three Gram-positive (Listeria monocyto-

Helvetica Chimica Acta – Vol. 95 (2012)
1439
Table 6. Crystallographic Data for 3c, 3k, and 3l
3c
3k
3l
Empirical formula
Formula weight
Color
Crystal size [mm3]
Temp. [K]
Wavelength [ꢄ]
Crystal system
Space group
Unit cell parameters
a [ꢄ]
C20H21FeNO
347.23
Dark-orange
0.30 ꢁ 0.26 ꢁ 0.22
293(2)
0.7107
Monoclinic
C2/c
C22.5H22ClFeNO
413.71
Dark-orange
0.22 ꢁ 0.19 ꢁ 0.12
293(2)
C21H21FeNO2
375.24
Dark-orange
0.23 ꢁ 0.20 ꢁ 0.18
293(2)
0.71073
0.71073
Orthorhombic
P212121
Triclinic
¯
P1
18.365(4)
7.3680(10)
25.355(2)
90
97.908(13)
90
3398.2(9)
8
1.357
7.3916(4)
10.2424(5)
13.8640(7)
95.634(4)
102.539(4)
99.872(4)
999.4(3)
5.8045(2)
14.7344(5)
20.2616(9)
90
90
90
1732.9(1)
4
1.438
b [ꢄ]
c [ꢄ]
a [8]
b [8]
g [8]
V [ꢄ3]
Z
2
Dcalc [Mg/m3]
1.375
0.899
m [mmꢀ1
]
0.891
0.884
q Range for data collection [8]
Reflections collected
1.62 to 25.97
3320
3.04 to 29.08
7398
3.32 to 29.03
5655
Independent reflections, Rint
Refinement method
3320
4497, 0.0235
Full-matrix
least-squares on F2
4497/0/212
3447, 0.0284
Full-matrix
least-squares on F2
3447/0/231
ꢀ 0.01(2)
1.030
Full-matrix
least-squares on F2
3320/0/212
Data/restraints/parameters
Flack parameter [50]
Goodness-of-fit on F2
0.995
1.028
R1/wR2 indices [I > 2s(I)]
R1/wR2 indices (all data)
Largest diff. peak and hole [e Aꢀ3
0.0421/0.1076
0.0736/0.1161
0.358/ ꢀ 0.389
0.0613/0.1621
0.0829/0.1759
0.609/ ꢀ 0.254
0.0429/0.0735
0.0563/0.0792
0.265/ ꢀ 0.272
]
genes ATCC 7644, Micrococcus flavus ATCC 40240, and Sarcina lutea ATCC 9341) and two Gram-
negative bacteria (Klebsiella pneumoniae ATCC 10031 and Shigella sonnei ATCC 25931). The three
newly synthesized compounds, 3l – 3n, were additionally tested against three Gram-positive (Bacillus
cereus ATCC 10876, Clostridium perfringens ATCC 19404, and Staphylococcus aureus ATCC 6538) and
three Gram-negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853,
and Salmonella enterica ATCC 13076). All of these bacterial strains were maintained on nutrient agar at
378.
Screening of Antibacterial Activity. Antibacterial activity was evaluated using a broth microdilution
method according to NCCLS [51]. Minimum inhibitory concentrations (MICs) and minimal bactericidal
concentrations (MBCs) were determined as described in [52]. Stock solns. of the compounds 3a – 3q were
prepared in 10% (v/v) aq. DMSO in the concentration range of 0.025 – 50.00 mg/ml (the diluting factor
2). Tetracycline served as a positive control, while the solvent (10% DMSO(aq.)) was used as the
negative one.
Statistical Analyses. Agglomerative hierarchical clustering (AHC) was performed using the Excel
program plug-in XLSTAT (version 2011.4.04). The method was applied utilizing the MIC values of
compounds 3a – 3q from this work and those reported in [33] against eleven bacterial strains as original
variables without any recalculation. AHC was performed using Pearson dissimilarity (as aggregation

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Helvetica Chimica Acta – Vol. 95 (2012)
criteria simple linkage, unweighted pair-group average, and complete linkage were used) and Euclidean
distance (aggregation criterion: weighted pair-group average, unweighted pair-group average and Wardꢃs
method). The definition of the groups was based on Pearson correlation, using complete linkage and
unweighted pair-group average method.
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