Synthesis, structural and electrochemical characterization of novel ferrocene-containing tetrahydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.jorganchem.2020.121422

Herein, we report an easy performable method for the synthesis of ferrocene-containing tetrahydropyrimidin-2(1H)-ones starting from the corresponding 3-arylamino-1-ferrocenylpropan-1-ols and sodium cyanate (NaOCN) in the presence of glacial acetic acid. T

Full text of DOI:10.1016/j.jorganchem.2020.121422

Journal Pre-proof
Synthesis, structural and electrochemical characterization of novel ferrocene-
containing tetrahydropyrimidin-2(1H)-ones
Aleksandra Minić, Marko S. Pešić, Sladjana B. Novaković, Goran A. Bogdanović,
Anka Todosijević, Danijela Ilić Komatina, Dragana Stevanović
PII:
S0022-328X(20)30324-7
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121422
JOM 121422
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 3 June 2020
Revised Date: 28 June 2020
Accepted Date: 5 July 2020
Please cite this article as: A. Minić, M.S. Pešić, S.B. Novaković, G.A. Bogdanović, A. Todosijević,
Danijela.Ilić. Komatina, D. Stevanović, Synthesis, structural and electrochemical characterization of
novel ferrocene-containing tetrahydropyrimidin-2(1H)-ones, Journal of Organometallic Chemistry (2020),
doi: https://doi.org/10.1016/j.jorganchem.2020.121422.
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Synthesis, structural and electrochemical characterization of novel
ferrocene-containing tetrahydropyrimidin-2(1H)-ones
Aleksandra Minić,*a Marko S. Pešić,b Sladjana B. Novaković,c Goran A. Bogdanović,c Anka
Todosijević,d Danijela Ilić Komatina,a Dragana Stevanovićb
aFaculty of Technical Sciences, University of Priština, Knjaza Miloša 7, 38220 Kosovska
Mitrovica, Serbia
bDepartment of Chemistry, Faculty of Science, University of Kragujevac, Radoja
Domanovića 12, 34000 Kragujevac, Serbia
c„VINČA” Institute of Nuclear Sciences - National Institute of thе Republic of Serbia,
University of Belgrade, PO Box 522, 11001 Belgrade, Serbia
dFaculty of Agriculture, University of Niš, Kosančićeva 4, 37000 Kruševac, Serbia
*Corresponding author: aleksandra.minic.989@gmail.com (aleksandra.minic@pr.ac.rs)
Abstract: Herein, we report an easy performable method for the synthesis of ferrocene-
containing tetrahydropyrimidin-2(1H)-ones starting from the corresponding 3-arylamino-1-
ferrocenylpropan-1-ols and sodium cyanate (NaOCN) in the presence of glacial acetic acid.
The protocol is included an intramolecular cyclization of an in situ generated 1,3-
hydroxyurea. The scope of the reaction towards eleven ferrocene-containing 1,3-amino
alcohols has been explored and the targeted 1-aryl-4-ferrocenyltetrahidropyrimidin-2(1H)-
ones were obtained in good to high yields (up to 93%). All products have been isolated in
high purity >95%. In addition, we have provided a detailed structural characterization of the
new compounds, which has been performed by IR and NMR spectroscopy. The single-crystal
X-ray diffraction analysis was successfully performed on three representative examples, as
well as elemental analysis. Moreover, molecular structure properties and intermolecular
interactions of these three structures have been compared and analyzed in detail.
Electrochemical properties of products were investigated by cyclic voltammetry. This
investigation revealed the quasi-reversible one-electron redox process.
Keywords: Ferrocene, Tetrahydropyrimidin-2(1H)-ones, One-pot reaction, Crystal structure,
Electrochemistry.

1. Introduction
In recent years we have seen an increased interest of both chemists and biologists for
urea derivatives, which have been synthesized extensively since. This specific class of
compounds is characterized by a wide range of biological activities, therefore, urea
derivatives represent promising candidates as anticonvulsant [1], antibacterial [2], antitumor
[3], anti-HIV [4], antagonistic [5], anti-proliferative [6], anticancer (renal cancer, colon
cancer, lungs cancer, prostate cancer, and breast cancer) [7], and antifungal [8] agents.
Besides, urea derivatives have been used as organocatalysts in organic synthesis [9] and have
been applied in material science [10], which has consequently resulted in a heightened
interest for their synthesis.
Since its discovery in 1951 [11], ferrocene (Fc) and its derivatives have found
applications in many areas, among which the most important are in material science,
asymmetric catalysis, bioorganometallic chemistry, and organic synthesis [12]. The
incorporation of ferrocene nucleus into biologically relevant molecules can significantly
enhance molecular properties such as solubility, hydrophobicity and lipophilicity of ’parent
compounds’ [13]. Consequently, many Fc-containing compounds exhibit antimalarial [14],
antifungal [15], anti-HIV, and DNA cleaving activity [16], as well as antitumor activity [17–
20]. Thus, the ferrocene moiety was recognized as an attractive pharmacophore in drug
design [21] and a multitude of reports dealing with derivatives of this metallocene have been
appeared in the literature.
In continuation of our long-standing interest toward the synthesis of Fc-containing
compounds [22–24], particularly those that contain heterocyclic core and represent
potentially bioactive agents [25–31], we developed protocols for obtaining 3-(arylamino)-1-
ferrocenylproran-1-ones [32, 33]. 3-(Arylamino)-1-ferrocenylproran-1-ones – Mannich bases
have demonstrated the great results in the synthesis of Fc derivatives, giving rise to five
different series of novel acyclic and heterocyclic ferrocene compounds (see Scheme 1). Thus,
using Mannich bases as starting material we successfully designed strategies and optimized
reaction conditions for the synthesis of 1-aryl-1-(3-ferrocenyl-3-oxopropyl)-3-phenylureas
(2a-k) [34], 3-aryl-6-ferrocenyl-N-phenyl-1,3-thiazinan-2-imines (4a-k) [35], 1-aryl-4-
ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones (5a-k) [36, 37], 4-ferrocenyl-1,2,3,4-
tetrahydroquinolines (6a-k) and 4-ferrocenylquinolines (7a-k) (see Scheme 1) [38, 39].
Notably, as it can be seen on Scheme 1, particular attention of our research group has been
paid to the reaction between reduced Mannich bases 3a-k and organic iso(thio)cyanate [35–

37]. Bearing in mind all above mentioned, previously obtained experience, we have been
encouraged to expand our studies and test the application of the corresponding 1,3-amino
alcohol 3a-k in reaction with cyanate salt (see Scheme 1). Therefore, in this paper the focus
was on designing
a
synthetic strategy for the preparation of Fc-containing
tetrahydropyrimidin-2(1H)-ones by reaction between reduced Mannich base 3a-k and
cyanate salt.
Scheme 1. Synthesis of Fc-containing compounds starting from Mannich bases. Reagents
and conditions: i) PhNCO, ultrasound irradiation for 1h; ii) NaBH4, MeOH, stirring for 2h;
iii) PhNCS, ultrasound irradiation (1-7 h), then AcOH, ultrasound irradiation, 1 h; iv)
PhNCO, ultrasound irradiation, 1 h, and then AcOH, ultrasound irradiation, 1 h; v) AcOH,
ultrasound irradiation, 2 h; vi) DDQ, toluene, reflux for 2 h.
In view of this, growing interest in urea derivatives has prompted the development of
protocols for their synthesis and most of them are based on the reaction of carbon dioxide
(CO2), carbon monoxide (CO) and phosgene (COCl2) with amines [40]. However, a
numerous of other synthetic pathways have been developed to obtain this class of
compounds. Among them, reactions of amines with organic isocyanates characterized by
mild conditions and high product yields have been identified as the most effective and widely
applied strategy for the synthesis of urea derivatives [41, 42]. In accordance with that, in the
present
paper,
we
report
the
preparation
of
eleven
novel
1-aryl-4-
ferrocenyltetrahydropyrimidin-2(1H)-ones achieved via a one-pot reaction between

3-arylamino-1-ferrocenylpropan-1-ols and sodium cyanate (NaOCN) in the presence of
glacial acetic acid. All products were purified by column chromatography and their structures
13
were confirmed by spectroscopic data (1H NMR, C NMR, 2D NMR and IR). Moreover, a
detailed single-crystal X-ray diffraction analysis has been successfully performed on three
representative examples, as well as elemental analysis. In addition, electrochemical behavior
of all synthesized compounds has been investigated using cyclic voltammetry technique.
2. Results and Discussion
2.1. Synthesis of 1-aryl-4-ferrocenyltetrahydropyrimidin-2(1H)-ones (9a-k)
Within the first phase of this study, we made sure to establish an appropriate method for
the synthesis of 1-aryl-4-ferrocenyltetrahydropyrimidin-2(1H)-ones. Our research team has
been already designed a strategy and optimized reaction conditions for the synthesis of Fc-
derivatives of six-membered cyclic ureas in high-to-excellent yields [36, 37]. This synthesis
involved the reaction between the corresponding 1,3-amino alcohols 3a-k and phenyl
isocyanate and the subsequent intramolecular cyclization of generated 1,3-hydroxyureas in
the presence of glacial acetic acid. According to literature [43, 44], the reaction between the
amino group and the cyanate salt undergoes in acidic medium building the corresponding
urea derivatives. In this manner, we designed the protocol for the synthesis of cyclic ureas
9a-k through the usage of sodium cyanate. Thus, we set “order of events” – 3-(arylamino)-1-
ferrocenylproran-1-ones → 3-(arylamino)-1-ferrocenylproran-1-ols → 1-aryl-1-(3-ferrocenyl-
3-hydroxypropyl)ureas → 1-aryl-4-ferrocenyltetrahydropyrimidin-2(1H)-ones (see Scheme 2).
O
R
R
R
H
O
HN
OH HN
OH
N
N
R
NaNCO
AcOH
N
NaBH4
MeOH
AcOH
H2N
O
Fe
Fe
Fe
Fe
9a-k
1a-k
3a-k
8a-k
o,o,p
R = H, CH3,
-(CH3)3, F, Cl
Scheme 2. A synthetic strategy to 1-aryl-4-ferrocenyltetrahydropyrimidin-2(1H)-ones (9a-k)

A synthetic strategy included the preparation of 1,3-amino alcohols 3a-k by reduction of 3-
(arylamino)-1-ferrocenylproran-1-ones (1a-k), and then an intramolecular cyclization of in
situ generated 1,3-hydroxyureas 8a-k (see Scheme 2). The reduction of Mannich bases 1a-k
was performed very smoothly and the corresponding 1,3-amino alcohols 3a-k were obtained
in high yields [36]. In order to establish optimal conditions, we set up the reaction between 3a
(1 mmol) and sodium cyanate (1.5 mmol). The reaction mixture was placed in an ultrasound
bath for 2 hours at ambient temperature. Sequentially, glacial acetic acid (1 ml) was added in
the well homogenized mixture and the irradiation was continued for 2 hours. After the usual
workup and column chromatography (SiO2/n-hexane–EtOAc, 1:1, v/v), these reaction
conditions successfully yielded 9a and the promised heterocyclic scaffold is isolated in 77%
yield. This result suggested that the reaction proceeds in a one-pot manner via 1,3-
hydroxyurea 8a. Further, these reaction conditions have not required additional screening and
have been accepted as optimal ones. The scope of the reaction has been investigated
employing ten additional 3-(arylamino)-1-ferrocenylproran-1-ols 3b-k. The desired products
9a-k have been obtained in moderate to excellent yields (up to 93%) after the purification by
means of column chromatography (see Scheme 3). Structural characterization has been
confirmed by spectroscopic methods (NMR, IR), as well as elemental analysis, and revealed
a purity of >95% for all prepared compounds.
We have observed that the electronic properties of the substituents of the phenyl
group have a significant influence on reaction outcomes (see Scheme 3). Regarding that, the
products obtained from substrates with an electron-withdrawing group on the phenyl ring, as
well as ortho-substituted phenyl group were isolated in lower yield (see Scheme 3).
Consequently, the steric hindrance also has an influence on the reaction outcome since 1,3-
amino alcohols with a bulky substituent in the ortho-position of the phenyl group leads to
moderate yield (see Scheme 3, products 9b and 9i). In addition, 1,3-amino alcohol 3b with a
methyl group in the ortho-position of the phenyl group gives 9b which exists in two pairs of
enantiomers due to the presence of atropoisomerism. This observation is consistent with our
previous reports [36, 37]. The isomerism is caused by the resonance of the carbonyl diamide
functional group which restricts rotation around the single bond between the nitrogen of the
1
heterocyclic ring and the carbon of the aryl group [36, 37]. Based on the H NMR spectrum
of 9b, the ratio of diastereoisomers is approximately 1:1. A comparison of results obtained
within this study with previous results suggests that the substituent on the second nitrogen
atom of the cyclic urea fragment has a significant influence on the rigidity of the ring [36,

37]. Therefore, a more flexible tetrahydropyrimidinone ring of 9a-k can explain the absence
of the expected atropoisomerism in product 9i.
Scheme 3. An overview of newly Fc-containing tetrahydropyrimidin-2(1H)-ones 9a-k
Reaction mechanism has been discussed to get a more comprehensive insight into the in
situ generation of 1,3-hydroxyureas, as well as the role of α-ferrocenyl carbocation in
intramolecular cyclization. Initially, cyanic acid is generated from sodium cyanate in acidic
medium (see Scheme 4). In the next step, the amino group of 1,3-amino alcohols 3a-k is
added to cyanic acid building the corresponding 1,3-hydroxyureas 8a-k [43–45]. The reaction
pathway continues with the protonation of 1,3-hydroxyureas giving oxonium ions I. Further,
α-ferrocenyl carbocations II were formed by dehydration of oxonium ions I. Noteworthy, α-
ferrocenyl carbocations II are known as very stable due to the participation of ferrocenyl
moiety in the delocalization of positive charge [12, 46]. In the last step, a nucleophilic attack
of the carbamide nitrogen on the positive center of cations II affords products 9a-k.

R
OH HN
NaNCO
H+
Fe
H-NCO
3a-k
O
O
O
O
R
H
R
H
N
R
R
H
H
H
N
N
N
N
N
H2N
N
H+
-H2O
H2O
-H+
OH2
OH
-H+
Fe
Fe
Fe
Fe
9a-k
II
8a-k
R = H, CH3, o,o,p-(CH3)3, F, Cl
I
Scheme 4. Plausible schematic mechanism for the synthesis of titled compounds 9a-k
2.2. Spectral characterization
The newly synthesized 1-aryl-4-ferrocenyltetrahydropyrimidin-2(1H)-ones (9a-k) were
found to be stable at the room temperature for a prolonged time and could safely be handled
in air, but like other ferrocene derivatives, they should be stored in closed containers. To
confirm their structure, a detailed characterization has been done by standard spectroscopic
1
13
techniques (IR, H and C NMR), as well as elemental analysis. All collected spectral data
were fully consistent with the proposed structures (for more data see Experimental part and
ESI).
The IR spectra of Fc-derivatives 9a-k contain the medium intensity absorptions of NH
stretching vibrations at 3419–3438 cm-1, indicating that all NH groups are involved in the H-
bonding interactions. The characteristic bands at 1646–1670, 1495–1610 and 1448–1590 cm-1
have been most likely originated from carbonyl diamide group. Moreover, the IR spectra of
example 9a have been presented on the Figure 1 (for more data see Experimental part and for
copies of IR spectrums for all prepared compounds see ESI).
1
Three sets of signals have been observed in the H NMR spectra. The first belongs to
protons of the tetrahydropyrimidinone moieties, the second to the aromatic protons and the
third to protons of the ferrocene units (see Figure 2). The signals at ~ 3.28–3.84 and 1.76–
2.34 ppm originate from the protons of the methylene groups (H-6a, H-6b, H-5a, and H-5b,
respectively), while the characteristic doublets of doublets at ~ 4.40 ppm belong to the
protons of the methine groups (H-4) in the heterocyclic rings. Also, the broad singlets at ~
5.30 ppm assigned to the corresponding protons of NH fragments in the ring (H-3). The
overlapped multiplets at 4.11–4.33 ppm originate from the protons of the substituted

cyclopentadiene rings (H-2'', H-3'', H-4'' and H-5''), and the singlets at ~ 4.22 ppm belong to
1
the protons of unsubstituted ferrocene cyclopentadiene rings (H-1''') in the H NMR spectra.
The signals of aromatic protons (H-2', H-3', H-4', H-5' and H-6') are located at the expected
chemical shifts (> 6.80 ppm) in the spectra (see Experimental part and ESI). Further, signals
assigned to the corresponding carbons of the synthesized compounds 9a-k appear in the
expected regions of the 13C NMR spectra. Moreover, the presence of signal at around 155
13
ppm (C-2) in the C NMR spectra of 9a-k unambiguously confirmed the proposed product
structure and intramolecular N-alkylation, since this signal belongs to carbon of the
carbamide functional group (for more data see Experimental part and ESI).
Figure 1. The IR spectra (800-3600cm-1) for compound 9a
Figure 2. Labeled carbons atoms for NMR characterization

2.3. Crystal structures of 9d, 9h and 9j
The compounds 9d, 9h and 9j have been characterized by single-crystal X-ray
diffraction analysis. The molecular structure and the atom labelling scheme are presented in
Figure 3, while the selected bond lengths and angles are listed in Table 1. The X-ray analysis
reveals similar composition of the three compounds where the central six-membered cyclic
urea links the ferrocene moiety in position C11 and p-CH3, p-F and m-Cl substituted phenyl
ring in position N1 (Figure 3). The ferrocene units display only slight geometrical distortion.
Each pair of cyclopentadienyl (Cp) rings takes close to parallel orientation, with the
maximum dihedral angle between the mean planes of 2.0(1)° found in compound 9j. The
Cg1–Fe–Cg2 angle of the same compound (177.9°) also shows the maximum deviation from
the ideal geometry (Cg1 and Cg2 are centroids of the substituted and unsubstituted Cp rings,
respectively). The distances between the Fe atom and the Cg1 and Cg2 centroids are:
1.654/1.645, 1.648/1.641, 1.649/1.644 Å in 9d, 9h and 9j, respectively. The more
pronounced difference between the Fc units is observed for the C1–Cg1–Cg2–C6 torsion
angle which indicates the conformational changes from almost eclipsed in 9d (−7.0°) to
staggered in 9h and 9j (−21.9 and 27.0°, respectively).
In all cases, the cyclic urea is significantly rotated with respect to the Cp1 plane. This
is illustrated by the large dihedral angle between the best plane through the five
approximately coplanar atoms of the heterocycle, N1−N2−C11−C12−C13 and the
corresponding Cp1 ring which is 66.7(1), 67.9(1) and 70.7(1)° in 9d, 9h and 9j, respectively.
The displacement of the remaining C14 atom from the N1−N2−C11−C12−C13 plane is
significant and equals to 0.621(4), 0.623(4), 0.640(3) Å in 9d, 9h and 9j, respectively. The
dihedral angle between the planes of cyclic urea and the phenyl ring in position N1 is 27.7(1),
28.3(1) and 21.6(1)° in 9d, 9h and 9j, respectively. All these parameters indicate a great
structural similarity of the three compounds, which is also confirmed by an overlay of their
molecular structures presented in Figure 4a.
It is interesting to compare the conformational features of the present compounds with
those of the four previously reported ferrocene-containing six-membered cyclic ureas where
the H atom in position N2 is replaced with an additional phenyl substituent [36, 37]. Apart
from the increased dihedral angle between the N1−N2−C11−C12−C13 and Cp1 planes,
which in the N2-substituted structures approaches to 90°, these structures are characterized
by a completely different orientation of the urea ring. The overlay of molecular structures of
the compound 9d and one of the previously reported N2-substituted derivatives presented in
Figure 4b emphasizes the conformational difference in two groups of compounds. Thus, in

the N2-substituted structures [36, 37], the ureido N2 lies approximately in the level of Cp1
plane (average displacement of 0.07 Å) dissimilar to 9d, 9h and 9j, where the same atom
deviates up to 1.42 Å from this plane. Opposite was found for C14 (average displacement of
1.37 in N2-substitued and 0.30 Å in current structures). Also, in N2-substitued structures the
carbonyl O atom points away from the Fc moiety, with the average displacement from the
Cp1 plane of 1.14, while in 9d, 9h and 9j, the same atom orients orthogonally to Cp1 with the
extreme deviation of 3.06 Å in average (see Figure 4b).
Additional overlay of the derivatives, based on the atoms of cyclic urea, is given in
Figure S1 (see ESI). It actually reveals that the altered orientation of the cyclic urea with
respect to the Cp1 ring results from the fact that Fc moiety occupies the axial position of the
heterocycle in 9d, 9h and 9j, while the equatorial position in N2- substituted derivatives. The
same overlay also indicates a considerable conformational similarity of the heterocycle in all
crystal structures. Namely, each heterocycle is characterized by an approximately planar
N1−N2−C11−C12−C13 fragment resulting from the trigonal character of the two N atoms
and the delocalization of electron density in the ureido fragment. The atom C14 shows
significant displacement from the N1−N2−C11−C12−C13 plane which ranges from 0.621(4)
in 9d to 0.709(5) [37]. Also, the valence angles in the cyclic urea show wide range of values
from 107 at sp3 C up to 127 at sp2 N atoms.
The geometrical parameters listed in Table 1 show only minor mutual differences
between the 9d, 9h and 9j. The maximum variations are observed in N1−C12 bond (0.008 Å)
and in the C12−N1−C15 angle involving the phenyl substituent (1.3°). In comparison to the
values in Table 1, the N2-substituted derivatives display small but systematic differences,
especially in the half of the ring bearing the additional phenyl substituent. Thus, compared to
title compounds, the C12−N2 and C11−C14 bonds in N2-substituted structures are longer for
0.04 and 0.02 Å in average, respectively. Also, the C12−N2−C11 angle is larger for 4° in
average, mainly on expense of the C12−N1−C13 angle which narrows for the same average
value.
The crystal structures of 9d, 9h and 9j display similar packing features. The hydrogen
bond formed between the N2-donor and the ureido oxygen acceptor represents the dominate
interaction in three crystal structures (see Table 2). By this interaction, the inversion related
molecules arrange into pairs generating the cyclic R2 (8) motifs (see Figure 5). The
2
ferrocenyl units of the N2−H...O1 bonded molecules, self-organize into additional pairs
forming the rigid ferrocene-ferrocene dimers. Through the combination of N2–H...O1
hydrogen bonding and Fc...Fc interaction the molecules arrange into double chain which

extends along the c crystallographic axis of the corresponding unit cells (Figure 5, see ESI:
Figure S2 and Figure S3). One should notice that the Fc...Fc dimer represents the only
interaction which exists in current as well as in N2-substituted derivatives. This confirms the
stability and persistence of the Fc...Fc building blocks [47], regardless the different
conformation of ferrocene derivatives or the presence of strong hydrogen bonds.
In contrast to 9d, 9h and 9j, the lack of an adequate hydrogen bonding donor in N2-
substituted derivatives [36, 37] prevents the formation of strong hydrogen bond, hence the
ureido O1 serves as an acceptor only in weak C−H...O interactions. The Hirshfeld fingerprint
plots [48] presented in Figure. S4 (see ESI) emphasize the difference in intermolecular
interactions for the two groups of derivatives. The most prominent feature of the mutually
similar plots of 9d, 9h and 9j is a pair of sharp spikes belonging to N2−H...O1 hydrogen
bond. Contrary, in the plots of N2-substituted derivatives the spikes of C–H...O are weakly
expressed. The presence of lateral ‘wings’ in each plot (see ESI Figure S4) indicates the
importance of weak C–H...π interactions for both types of derivatives. Nevertheless, the
different molecular conformations employ dissimilar C–H donors and π-acceptors for this
type of interactions. The 9d, 9h and 9j, form equivalent set of C–H...π interactions (see Table
2). The most important interaction of this type is C4–H...π which employs C–H donor from
the substituted Cp ring and the phenyl ring as π-acceptor. This interaction leads to the further
paring of the centrosymmetric molecules and interconnection of the above described double
chains (see ESI Figure S5).

Table 1. Selected bond lengths (Å) and angles (°) in crystal structure of 9d, 9h and 9j.
9d
9h
9j
O1−C12
1.231(3)
1.235(3)
1.380(3)
1.425(3)
1.472(3)
1.347(3)
1.459(3)
1.503(3)
1.510(4)
1.514(4)
121.1(2)
120.2(2)
117.6(2)
126.8(2)
129.0(2)
123.5(2)
108.0(2)
107.0(2)
115.6(2)
120.5(2)
122.1(2)
117.4(2)
110.8(2)
110.2(2)
1.228(2)
N1−C12
1.383(3)
1.391(2)
N1−C15
1.428(3)
1.422(2)
N1−C13
1.473(3)
1.474(2)
N2−C12
1.343(3)
1.348(2)
N2−C11
1.462(3)
1.464(2)
C1−C11
1.503(3)
1.504(2)
C11−C14
1.504(3)
1.503(3)
C13−C14
1.516(3)
1.517(3)
C12−N1−C15
C12−N1−C13
C15−N1−C13
C12−N2−C11
C5−C1−C11
C2−C1−C11
N2−C11−C1
N2−C11−C14
C1−C11−C14
O1−C12−N2
O1−C12−N1
N2−C12−N1
N1−C13−C14
C11−C14−C13
120.59(18)
120.32(18)
118.35(17)
126.9(2)
121.90(14)
120.28(14)
117.33(14)
126.69(15)
128.56(17)
124.17(17)
108.47(14)
107.01(15)
114.96(16)
120.75(16)
122.06(16)
117.17(15)
111.12(14)
109.72(16)
128.8(2)
124.2(2)
107.72(18)
107.25(18)
115.71(19)
120.8(2)
121.9(2)
117.22(19)
110.80(18)
110.19(19)

Table 2. Geometry of intermolecular interactions in crystal structure of 9d, 9h and 9j.
D−H (Å)
0.76(3)
0.93
H...A (Å)
2.14(3)
2.83
D−H...A (°) Symmetry code:
N2–H2...O1
176(3)
145
−x+1, −y+2, −z+1
x, y, z+1
9d
C4–H4...Cg3
C11–H11...Cg3
C17–H17...Cg2
N2–H2...O1
0.98
3.14
139
−x+2, −y+2, −z+1
x, y, z−1
0.93
3.18
159
0.78(3)
0.93
2.17(3)
2.90
172(3)
144
−x+1, −y+2, −z
−x+1, −y+1, −z
−x, −y+2, −z
x+1, y, z
9h
C4–H4...Cg3
C11–H11...Cg3
C13–H13a...Cg1
C17–H17...Cg2
N2–H2...O1
0.98
3.15
136
0.97
3.15
128
0.93
2.82
179
x, y, z+1
0.83(3)
0.93
2.10(3)
2.80
176(2)
142
−x+2, −y+1, −z+1
−x+2, −y, −z+1
−x+1, −y+1,−z+1
x+1, y, z
9j
C4–H4...Cg3
C11–H11...Cg3
C13–H13a...Cg1
0.98
3.13
130
0.97
3.07
130
Cg1 and Cg2 are centroids of the substituted and unsubstituted Cp rings, respectively; Cg3 is
centroid of phenyl ring.

Figure 3. The molecular structure with the atom-labelling scheme: (a) 9d, (b) 9h and (c) 9j.
Displacement ellipsoids are drawn at the 30% probability level.

Figure 4. (a) Overlay of 9d, 9h and 9j (blue, green and red, respectively) based on the atoms of
Cp1 ring. Overlay of 9d (blue) and the N2-substituted derivative [36] (yellow); atom-labelling
scheme in (b) corresponds only to the yellow colored molecule, atom-labelling of 9d is as in (a)
where this molecule is presented in the same orientation. H atoms are excluded for clarity.
Figure 5. Double chain of 9d molecules formed by N2−H…O1 hydrogen bond, Fc...Fc pairing
and C17–H...π interaction. Equivalent chains for 9h and 9j are presented in Figure S2 and Figure
S3 (see ESI).

2.4. Electrochemistry
It is well known that the Fe2+/Fe3+ redox chemistry contributes to the bioactivity of
ferrocene derivatives [26-31, 49 and 50]. Leaded by this fact, we opted to evaluate the
electrochemical properties of all newly prepared compounds 9a-k. This has been done by
means of cyclic voltammetry (CV) in dichloromethane containing 0.1 mol/L
tetrabutylammonium perchlorate as a supporting electrolyte. The working electrode was a
polished platinum disk (2 mm diameter; Metrohm). The counter electrode was a platinum
wire, whereas an Ag/AgCl electrode was used as the reference. The peak potentials (Ep) of
the anodic and cathodic potentials (Epa and Epc, respectively, at 0.1 V s-1), their half-wave
potentials (E1/2 = (Epa + Epc)/2), and the differences between anodic and cathodic peak
potentials (ΔE = Epa ‒ Epc) of Fc-derivatives 9a-k, have been measured and evaluated as
important electrochemical data [52]. All measurements have been carried out using ferrocene
as internal standard. Besides, an additional proof of purity for all synthesized compounds has
been provided by CV measurements.
2.4.1. Redox behavior of prepared 1-aryl-4-ferrocenyltetrahidropyrimidin-2(1H)-ones (9a-k)
The redox behavior of the products 9a-k has been determined using cyclic voltammetry
(CV) under the same conditions mentioned above, and the results of this study have been
listed in Table 3. Based on collected data, we have determined that all novel Fc-containing
derivatives 9a-k exhibited one well-defined oxidation wave on the forward-potential sweep
(0.662 – 0.729 V) and one reduction wave during the back-potential sweep (0.461 – 0.543 V)
assigned to the ferrocene nucleus. It appears that the oxidation potentials of 9a-k have been
more positive than the ones of the unsubstituted ferrocenes (for representative example see
Figure 6), which shows significant electronic contact between the ferrocene unit and the rest
of the molecule. Due to the reversibility of this electron transfer, even at low scan speed, the
produced radical anion is stable within the time scale of cyclic voltammetry (see Figure 7)
[51]. Both anodic and cathodic peak currents are proportional to the square root of the scan
rate (see Figure 8), and their ratio is independent of the scan rate, indicating a diffusion-
controlled process. Moreover, the average of anodic and cathodic current was not unity and
the difference between the oxidation and reduction maxima (ΔE = Epa ‒ Epc) was around
0.168 V. Compared with the theoretical value ΔE = 0.150 V, we can determine that the redox
process is quasi-reversible nature [51].

Table 3. The electrochemical data for compounds 9a-k
Entry
Compound
Epaa (V)
0.729
0.659
0.665
0.668
0.684
0.668
0.720
0.662
0.687
0.684
0.668
Epca (V)
0.461
0.510
0.522
0.528
0.497
0.513
0.491
0.543
0.504
0.528
0.543
E1/2b (V)
0.595
0.585
0.594
0.598
0.591
0.591
0.606
0.603
0.596
0.606
0.606
ΔEc (V)
0.268
0.149
0.143
0.140
0.187
0.155
0.229
0.119
0.183
0.156
0.125
1
2
9a
9b
9c
9d
9e
9f
3
4
5
6
7
9g
9h
9i
8
9
10
11
9j
9k
a Epa and Epc anodic and cathodic peak potentials, respectively, at 0.1 V s-1.
b E1/2 = (Epa + Epc)/2.
c ΔE = Epa ‒ Epc.
Figure 6. Cyclic voltammograms at the platinum disk (d = 2 mm) by a 0.1 V s-1 scan rate in
0.1 M dichloromethane solution of Bu4NClO4: (a) electrolyte, (b) 1 mM solution of
4-ferrocenyl-1-phenyltetrahydropyrimidin-2(1H)-one (9a) (c) ferrocene.

Figure 7. Cyclic voltammograms of
1
mM solution of 4-ferrocenyl-1-
phenyltetrahydropyrimidin-2(1H)-one (9a) at the platinum disk (d = 2 mm) in 0.1 M
dichloromethane solution of Bu4NClO4 on a different scan rates: a) 0.01 V s-1 b) 0.1 V s-1 c)
0.3 V s-1 d) 0.5 V s-1
Figure 8. Anodic and cathodic peak currents of product 9a obtained at different scan rates at
the platinum disk (d = 2 mm) in 0.1 M dichloromethane solution of Bu4NClO4.

3. Conclusion
In summary, we have described a new, easily performable one-pot procedure for the
synthesis of Fc-containing tetrahydropyrimidin-2(1H)-ones in good to excellent yields (up to
93%) starting from 3-(arylamino)-1-ferrocenylproran-1-ols and sodium cyanate (NaNCO) in
acidic medium. The reported protocol is practical and convenient and proceeds under
relatively mild conditions – an ultrasound irradiation has been used as reaction promoter and
acetic acid has been applied as catalyst. The structures of novel compounds are determined
using standard spectroscopic methods (IR and NMR). The proposed structures of three
representative products 9d, 9h and 9j are confirmed by single-crystal X-ray diffraction
analysis, as well as by elemental analysis. Further, the cyclic voltammetry studies were done
in order to evaluate electrochemical behavior of the prepared ferrocenes. This investigation
has been reviled that all products 9a-k exhibit only one well-defined redox couple (attributed
to the ferrocene nucleus). In addition, the presented synthetic approach, besides practical
application, gives rise to new potentially biologically relevant Fc-containing six-membered
cyclic ureas.

4. Experimental
4.1. General information
All chemicals were commercially available and used as received, except the solvents,
which were purified by distillation. Ultrasonic cleaner Elmasonic S 10 (Elma, Germany),
30W was used for the ultrasonically supported synthesis. Chromatographic separations were
carried out using silica gel 60 (Merck, 230–400 mesh ASTM), whereas silica gel 60 on Al
1
13
plates, (Merck, layer thickness 0.2 mm) was used for TLC. The H and C NMR spectra of
the samples in CDCl3 were recorded on a Bruker Avance III 400 MHz (1H at 400 MHz, 13C at
101 MHz) and Varian Gemini (1H at 200 MHz, 13C at 50 MHz) NMR spectrometers.
Chemical shifts are expressed in δ (ppm), relative to residual solvent protons as the internal
1
standard (CDCl3: 7.26 ppm for H and 77 ppm for 13C). The coupling constants (J) are
reported in Hz. Multiplicities of proton resonance are designated as singlet (s), broad singlet
(br s), doublet (d), broad double (br d), doublet of doublets (dd), triplet (t), doublet of triplets
(dt), doublet of doublets of doublets (ddd), quartet (q) and multiplets (m). 2D NMR
experiments (1H-1H COSY, NOESY, HSQC and HMBC) are performed on the same
instrument with a standard pulse sequence. IR measurements were carried out with a Perkin–
Elmer FTIR 31725-X spectrophotometer. Microanalyses of carbon, hydrogen and nitrogen
were carried out with a Carlo Erba 1106 model microanalyzer; these results agreed favorably
with the calculated values. Melting points were determined on a Mel-Temp capillary melting
points apparatus, model 1001, and the given values are uncorrected.
4.2. Crystal structure determination
Single-crystal X-ray diffraction data for compounds 9d, 9h and 9j were collected at Oxford
Gemini S diffractometer, using monochromatized MoKα radiation (λ = 0.71073 Å). Data
reduction and empirical absorption correction were performed with CrysAlisPRO [52]. The
crystal structures were solved by direct methods using SHELXS [53] and refined on F2 by
full-matrix least-squares using SHELXL [53]. All non-hydrogen atoms were refined
anisotropically. The H atoms bonded to C atoms were placed in geometrically calculated
positions and refined using the riding model with Uiso values constrained to 1.2Ueq or 1.5Ueq
of the parent C atoms. The H atoms bonded to N atoms were located in difference Fourier
map and refined isotropically. The PLATON [54] software was used to perform geometrical
calculation and the Mercury [55] was employed for molecular graphics. Crystallographic
details are summarized in Table 4.

Table 4. Crystal data and structure refinement parameters.
Compound
9d
C21H22FeN2O
374.26
9h
C20H19FeN2OF
378.22
9j
C20H19FeN2OCl
394.67
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
293(2)
293(2)
293(2)
0.71073
Triclinic
P−1
0.71073
Triclinic
P−1
0.71073
Triclinic
P−1
Unit cell dimensions
7.1329(4)
9.2412(4)
14.3951(6)
104.462(4)
98.613(4)
103.414(4)
871.74(7)
2
7.1095(4)
9.2090(6)
13.8244(9)
75.131(6)
97.298(5)
77.021(5)
835.90(9)
2
7.0364(4)
9.0305(5)
14.0744(10)
76.501(5)
88.962(5)
76.732(4)
845.81(9)
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
V (Å3)
Z
1.426
1.503
1.550
Dcalc (Mg/m3)
0.876
0.922
1.060
μ (mm−1)
F(000)
392
392
408
Crystal size (mm3)
0.51 x 0.26 x
0.09
0.46 x 0.20 x
0.10
0.46 x 0.43 x
0.12
11450
6391
12871
Reflections collected
4061, 0.0249
4061 / 0 / 231
1.050
3769, 0.0240
3769 / 0 / 230
1.128
3983, 0.0264
3983 / 0 / 230
1.036
Independent reflections, Rint
Data / restraints / parameters
Goodness-of-fit on F2
0.0417, 0.1004
0.0419, 0.0929
0.0342, 0.0781
Final R1/wR2 indices [I >2σ(I)]
Largest diff. peak and hole (e
Å−3)
0.619 and
−0.344
0.367 and
−0.323
0.301 and
−0.363
4.3. Electrochemical measurements
Cyclic voltammetry (CV) experiments were performed at ambient temperature in
dichloromethane (CH2Cl2) containing 0.1 M tetrabutylammonium perchlorate (Bu4NClO4) as
the supporting electrolyte. Autolab potentiostat (PGSTAT 302N) and three-electrode cell

were used. The working electrode was the platinum disk (d = 2 mm), and the counter
electrode was platinum wire. Ag/AgCl reference electrode (double junction) for nonaqueous
systems was used. The working electrode was polished with alumina slurry and rinsed with
dichloromethane. The potentials are relative to Fc+/Fc.
4.4.1 General procedure for the preparation of 3-(arylamino)-1-ferrocenylpropan-1-ones
(1a-k) and 3-(arylamino)-1-ferrocenylpropan-1-ols (3a-k)
The 1,3-amino ketones 1a-kwere prepared following the previously reported procedure
[32-38]. A test tube containing a well homogenized mixture of 1-ferrocenylpropenone (240
mg, 1 mmol), the corresponding aniline (2 mmol) and montmorillonite K-10 (100 mg) was
placed in the ultrasonic cleaner and irradiated for 1h. Then, CH2Cl2 (10 ml) was added to the
mixture, and the contents were filtered off. The solid residue was washed with water and
brine, followed by drying over anh. Na2SO4 overnight. After the evaporation of the solvent,
the crude mixture was fractioned by flash chromatography on a SiO2 column. The
corresponding aniline was eluted with toluene, whereas 3-(arylamino)-1-ferrocenylproran-1-
ones (1a-k) were washed from the column by a mixture of hexane and AcOEt 8 : 2 (v/v). The
complete excess of the anilines was recovered. The obtained spectral data for 3-(arylamino)-
1-ferrocenylpropan-1-ones (1a-k) were in complete agreement with literature data [32-39].
The 1,3-amino alcohols 3a-k were prepared following the previously reported procedure
[35-38]. To a stirred solution of the corresponding Mannich base (1 mmol) in MeOH (20 ml)
at room temperature, an excess of NaBH4 (5 mmol) was added in several portions (up to 190
mg) and the reaction progress was monitored by TLC. After complete reduction (ca. 2 h),
methanol was distilled off and the residue diluted with water (20 ml). The mixture was
extracted with CH2Cl2 (two 20 ml portions) and the combined organic layers were washed
with water and brine, as well as dried over anh. Na2SO4. After filtering off the drying agent
and evaporation of the solvent, the crude product (without purification) was used in the next
reaction. The obtained spectral data for 3-(arylamino)-1-ferrocenylpropan-1-ols (3a-k) were
in complete agreement with literature data [35-38].
4.4.2
General
one-pot
procedure
for
the
preparation
of
1-aryl-4-
ferrocenyltetrahydropyrimidin-2(1H)-ones (9a–k)
In a test tube, 1 mmol of 1,3-amino alcohol (3a-k) was homogenized with 1.5 mmol sodium
cyanate (NaNCO), placed in an ultrasonic cleaner and irradiated for 2 hours. Subsequently, 1
ml of glacial acetic acid was added, and the irradiation continued for additional 2 hours. The

reaction mixture was neutralized with NaHCO3 (litmus paper) and extracted with CH2Cl2
(two 20 ml portions). The combined organic layers were washed with water and brine, as
well as dried over anh. Na2SO4. The solvent was removed by evaporation and the crude
product was purified by column chromatography (SiO2) to afford pure product 9a-k.
4-Ferrocenyl-1-phenyltetrahydropyrimidin-2(1H)-one (9a).* Yellow solid; mp 162 °C.
Rf = 0.3 (EtOAc/Hexane, 1:1 (v/v)). Yield 82%. 1H NMR (200 MHz, CDCl3) δ = 7.41 – 7.30
(m, 4H, H-2' and H-3'), 7.23 – 7.14 (m, 1H, 1H, H-4'), 5.22 (br s, 1H, H-3), 4.51 – 4.34 (m,
1H, H-4), 4.31 – 4.16 (overlapped m, 4H, H-2'', H-3'', H-4'' and H-5''), 4.23 (overlapped s,
5H, H-1'''), 3.84 – 3.55 (m, 2H, H-6a and H-6b), 2.34 – 2.13 (m, 1H, H-5a), 2.07 – 1.82 (m,
1H, H-5b). 13C NMR (50 MHz, CDCl3) δ = 154.9 (C-2), 143.4 (C-1'), 128.7 (C-3'), 125.5 (C-
2'), 125.4 (C-4'), 90.4 (C-1''), 68.5 (C-1'''), 68.3 (C-3''), 67.9 (C-5''), 66.2 (C-4''), 65.3 (C-2''),
51.0 (C-4), 47.4 (C-6), 31.5 (C-5). *The assignation for H and C atoms has been done using
analogy with examples 9d, 9h and 9k and our previous studies [see references 36, 37]. IR
(KBr, cm-1) ν = 3424, 1663, 1594, 1575, 753.
4-Ferrocenyl-1-o-tolyltetrahydropyrimidin-2(1H)-one
(9b).*
Noteworthy,
for
examples 9b we have been obtained a mixture of two atropoisomers, therefore, most of the
signals in the NMR spectra were double, which was in agreement with our previous studies
1
13
(for figures of H NMR and C NMR spectra for compound 9b see ESI) [36, 37]. Yellow
1
solid; mp 167 °C. Rf = 0.3 (EtOAc/Hexane, 1:1 (v/v)). Yield 70%. H NMR (200 MHz,
CDCl3) δ = 7.29 – 7.12 (m, 4H, H-3', H-4', H-5' and H-6'), 5.27 (br s, 1H, H-3,
diastereoisomer A), 5.22 (br s, 1H, H-3 diastereoisomer B), 4.44 (dd, J = 8.8, 3.5 Hz, 1H, H-
3), 4.34 – 4.28 (m, 1H, H-5''), 4.27 – 4.15 (overlapped m, 3H, H-2'', H-3''and H-4''), 4.23
(overlapped s, 5H, H-1'''), 3.73 – 3.29 (m, 2H, H-6a and H-6b), 2.31 (s, 3H, CH3,
diastereoisomer A), 2.28 (s, 3H, CH3, diastereoisomer B), 2.12 – 1.85 (m, 2H, H-5a and H-
13
5b). C NMR (50 MHz, CDCl3)** δ = 154.8 (C-2), 142.0 (C'), 136.1 (C'), 130.9 (C'), 129.2
(C'), 127.9 (C'), 127.6 (C'), 127.3 (C'), 126.8 (C'), 126.1 (C'), 90.7 (C''), 90.4 (C''), 68.6 (C-
1'''), 68.3 (C''), 67.7 (C''), 67.7 (C''), 67.4 (C''), 66.2 (C''), 65.5 (C''), 65.2 (C''), 51.2 (C-4),
51.0 (C-4), 47.7 (C-6), 47.3 (C-6), 31.9 (C-5), 31.5 (C-5), 17.8 (CH3). *The assignation for H
and C atoms has been done using analogy with example 9d and our previous studies [see
**
references 36, 37]. The signals originated from aromatic carbons and substituted Cp ring
cannot be assigned based on obtained data. IR (KBr, cm-1): ν = 3434, 1660, 1585, 1540, 755.
4-Ferrocenyl-1-m-tolyltetrahydropyrimidin-2(1H)-one (9c).* Yellow solid; mp 154
°C. Rf = 0.3 (EtOAc/Hexane, 1:1 (v/v)). Yield 81%. 1H NMR (200 MHz, CDCl3) δ = 7.27 –
6.97 (m, 4H, H-2', H-4', H-5' and H-6'), 5.21 (br s, 1H, H-3), 4.39 (dd, J = 8.5, 3.9 Hz, 1H, H-

4), 4.32 – 4.14 (overlapped m, 4H, H-2'', H-3'', H-4'' and H-5''), 4.23 (overlapped s, 5H, H-
1'''), 3.77 – 3.52 (m, 2H, H-6a and H-6b), 2.35 (s, 3H, CH3), 2.20 (dd, J = 13.1, 4.5 Hz, 1H,
H-5a), 1.94 (ddd, J = 13.1, 8.8, 4.3 Hz, 1H, H-5b). 13C NMR (50 MHz, CDCl3) δ = 155.0 (C-
2), 143.4 (C-1'), 138.6 (C-3'), 128.6 (C-5'), 126.5 (C-2'), 126.4 (C-4'), 122.6 (C-6'), 90.5 (C-
1''), 68.5 (C-1'''), 68.3 (C-3''), 67.9 (C-5''), 66.2 (C-4''), 65.3 (C-2''), 51.0 (C-4), 47.5 (C-6),
31.5 (C-5), 21.3 (CH3). *The assignation for H and C atoms has been done using analogy with
example 9d and our previous studies [see references 36, 37]. IR (KBr, cm-1): ν = 3429, 1656,
1608, 1588, 697.
4-Ferrocenyl-1-p-tolyltetrahydropyrimidin-2(1H)-one (9d). Yellow solid; mp 191 °C.
Rf = 0.3 (EtOAc/Hexane, 1:1 (v/v)). Yield 72%. 1H NMR (400 MHz, CDCl3) δ = 7.19 (q, J =
8.2 Hz, 4H, H-2' and H-3'), 5.13 (br s, 1H, H-3), 4.40 (br d, J = 5.1 Hz, 1H, H-4), 4.30 – 4.16
(overlapped m, 4H, H-2'', H-3'', H-4'' and H-5''), 4.25 (overlapped s, 5H, H-1'''), 3.72 (t, J =
9.5 Hz, 1H, H-6a), 3.64 – 3.54 (m, 1H, H-6b), 2.34 (s, 3H, CH3), 2.26 – 2.14 (m, 1H, H-5a),
2.01 – 1.86 (m, 1H, H-5b). 13C NMR (101 MHz, CDCl3) δ = 155.2 (C-2), 140.9 (C-1'), 135.4
(C-4'), 129.5 (C-3'), 125.7 (C-2'), 90.5 (C-1''), 68.6 (C-1'''), 68.3 (C-3''), 67.9 (C-5''), 66.3 (C-
4''), 65.3 (C-2''), 51.1 (C-4), 47.7 (C-6), 31.6 (C-5), 21.0 (CH3). IR (KBr, cm-1): ν = 3422,
1670, 1589, 1565, 692. Anal. Calc. for C21H22FeN2O: C, 67.39; H, 5.93; Fe, 14.92; N, 7.49;
O, 4.27. Found: C, 67.42; H, 5.90; N, 7.45%.
4-Ferrocenyl-1-mesityltetrahydropyrimidin-2(1H)-one (9e).* Yellow solid; mp 214
°C. Rf = 0.3 (EtOAc/Hexane, 1:1 (v/v)). Yield 77%. 1H NMR (200 MHz, CDCl3) δ = 6.90 (s,
2H, H-3'), 5.21 (br s, 1H, H-3), 4.42 (dd, J = 8.5, 4.0 Hz, 1H, H-4), 4.33 – 4.27 (m, 1H, H-
5''), 4.25 – 4.14 (overlapped m, 3H, H-2'', H-3''and H-4''), 4.22 (overlapped s, 5H, H-1'''), 3.54
– 3.37 (m, 1H, H-6a), 3.26 (dt, J = 12.2, 4.8 Hz, 1H, H-6b), 2.26 (overlapped s, 6H, 2 × CH3),
2.20 (overlapped s, 3H, CH3), 2.32 – 2.11 (overlapped m, 1H, H-5a), 2.06 – 1.79 (m, 1H, H-
5b). 13C NMR (50 MHz, CDCl3) δ = 154.5 (C-2), 137.7 (C-1'), 136.9 (C-4'), 135.8 (C-2'),
129.1 (C-3'), 90.5 (C-1''), 68.5 (C-1'''), 68.2 (C-3''), 67.7 (C-5''), 66.0 (C-4''), 65.3 (C-2''), 51.0
*
(C-4), 47.8 (C-6), 31.5 (C-5), 21.8 (CH3), 17.71 (2 × CH3). The assignation for H and C
atoms has been done using analogy with example 9d and our previous studies [see references
36, 37]. IR (KBr, cm-1): ν = 3432, 1656, 1496, 1453, 813.
4-Ferrocenyl-1-(2-fluorophenyl)tetrahydropyrimidin-2(1H)-one (9f).* Yellow solid;
mp 179 °C. Rf = 0.4 (EtOAc/Hexane, 1:1 (v/v)). Yield 89%. 1H NMR (200 MHz, CDCl3) δ =
7.39 – 7.05 (m, 4H, H-3', H-4', H-5' and H-6'), 5.59 (br s, 1H, H-3), 4.42 (dd, J = 8.1, 4.1 Hz,
1H, H-4), 4.33 – 4.11 (overlapped m, 4H, H-2'', H-3'', H-4'' and H-5''), 4.22 (overlapped s,
5H, H-1'''), 3.72 – 3.43 (m, 2H, H-6a and H-6b), 2.30 – 2.13 (m, 1H, H-5a), 2.04 – 1.83 (m,

13
1H, H-5b). C NMR (50 MHz, CDCl3) δ = 158.2 (d, JC-F = 249.3 Hz, C-2'), 154.7 (C-2),
130.5 (d, JC-F = 12.2 Hz, C-1'), 129.7 (d, JC-F = 1.3 Hz, C-6'), 128.1 (d, JC-F = 7.9 Hz, C-4'),
124.2 (d, JC-F = 3.7 Hz, C-5'), 116.3 (d, JC-F = 20.2 Hz, C-3'), 90.3 (C-1''), 68.4 (C-1'''), 68.1
*
(C-4''), 67.7 (C-2''), 66.1 (C-3''), 65.3 (C-5''), 50.8 (C-4), 47.2 (C-6), 31.1 (C-5). The
assignation for H and C atoms has been done using analogy with example 9h and our
previous studies [see references 36, 37]. IR (KBr, cm-1): ν = 3424, 1659, 1503, 1488, 753.
4-Ferrocenyl-1-(3-fluorophenyl)tetrahydropyrimidin-2(1H)-one (9g).* Yellow solid;
mp 140 °C. Rf = 0.4 (EtOAc/Hexane, 1:1 (v/v)). Yield 93%. 1H NMR (200 MHz, CDCl3) δ =
7.37 – 7.23 (m, 1H, H-5'), 7.16 – 7.06 (m, 2H, H-2' and H-6'), 6.93 – 6.81 (m, 1H, H-4'), 5.35
(br s, 1H, H-3), 4.47 – 4.33 (m, 1H, H-4), 4.28 – 4.14 (overlapped m, 4H, H-2'', H-3'', H-4''
and H-5''), 4.23 (overlapped s, 5H, H-1'''), 3.81 – 3.55 (m, 2H, H-6a and H-6b), 2.34 – 2.14
13
(m, 1H, H-5a), 2.05 – 1.84 (m, 1H, H-5a). C NMR (50 MHz, CDCl3) δ = 162.6 (d, JC-F
=
245.3 Hz, C-3'), 154.6 (C-2), 144.9 (d, JC-F = 9.9 Hz, C-1'), 129.5 (d, JC-F = 9.2 Hz, C-5'),
120.5 (d, JC-F = 3.0 Hz, C-6'), 112.6 (d, JC-F = 23.6 Hz, C-2'), 112.0 (d, JC-F = 21.1 Hz, C-4'),
90.2 (C-1''), 68.5 (C-1'''), 68.3 (C-3''), 67.9 (C-5''), 66.2 (C-4''), 65.3 (C-2''), 50.9 (C-4), 47.1
*
(C-6), 31.3 (C-5). The assignation for H and C atoms has been done using analogy with
example 9h and our previous studies [see references 36, 37]. IR (KBr, cm-1): ν = 3419, 1654,
1609, 1590, 693.
4-Ferrocenyl-1-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (9h). Yellow solid;
mp 187 °C. Rf = 0.4 (EtOAc/Hexane, 1:1 (v/v)). Yield 56%. 1H NMR (400 MHz, CDCl3) δ =
7.33 – 7.28 (m, 2H, H-2'), 7.10 – 7.03 (m, 2H, H-3'), 5.28 (br s, 1H, H-3), 4.42 (dd, J = 8.6,
4.0 Hz, 1H, H-4), 4.30 – 4.27 (m, 1H, H-2''), 4.27 – 4.23 (overlapped m, 1H, C-4''), 4.23
(overlapped s, 5H, H-1'''), 4.20 – 4.16 (m, 2H, C-3'' and C-5''), 3.71 (ddd, J = 11.9, 9.9, 3.7
Hz, 1H, H-6a), 3.59 (dt, J = 11.8, 4.7 Hz, 1H, H-6b), 2.23 (dq, J = 13.1, 4.0 Hz, 1H, H-5a),
2.00 – 1.91 (m, 1H, H-5b). 13C NMR (101 MHz, CDCl3) δ = 160.4 (d, JC-F = 244.8.1 Hz, C-
4'), 155.1 (C-2), 139.4 (d, JC-F = 3.0 Hz, C-1'), 127.5 (d, JC-F = 8.4 Hz, C-2'), 115.6 (d, JC-F
=
22.5 Hz, C-3'), 90.3 (C-1''), 68.6 (C-1'''), 68.4 (C-3''), 68.0 (C-5''), 66.3 (C-4''), 65.3 (C-2''),
51.1 (C-4), 47.7 (C-6), 31.5 (C-5). IR (KBr, cm-1): ν = 3418, 1664, 1508, 1483, 822. Anal.
Calc. for C20H19FFeN2O: C, 63.51; H, 5.06; F, 5.02; Fe, 14.76; N, 7.41; O, 4.23. Found: C,
63.55; H, 5.01; N, 7.38%.
1-(2-Chlorophenyl)-4-ferrocenyltetrahydropyrimidin-2(1H)-one (9i).* Yellow oil. Rf
= 0.2 (EtOAc/Hexane, 1:1 (v/v)). Yield 60%. 1H NMR (200 MHz, CDCl3) δ = 7.46 (dd, J =
6.7, 2.3 Hz, 1H, H-5'), 7.38 – 7.19 (m, 3H, H-2', H-4' and H-6'), 5.37 (br d, J = 9.2 Hz, 1H,
H-3), 4.42 (dd, J = 9.9, 6.0 Hz, 1H, H-4), 4.37 – 4.26 (m, 1H, H-5''), 4.26 – 4.13 (overlapped

m, 3H, H-2'', H-3'' and H-4''), 4.23 (overlapped s, 5H, H-1'''), 3.84 – 3.28 (m, 2H, H-6a and
13
H-6b), 2.35 – 1.88 (m, 2H, H-5a and H-5b). C NMR (50 MHz, CDCl3)** δ = 154.6 (C-2),
140.4 (C'), 133.1 (C'), 130.3 (C'), (C'), 128.5 (C'), 127.7 (C'), 90.4 (C-1''), 68.5 (C-1'''), 68.2
*
(C-3''), 67.8 (C-5''), 66.2 (C-4''), 65.4 (C-2''), 50.1 (C-4), 47.2 (C-6), 31.3 (C-5). The
assignation for H and C atoms has been done using analogy with example 9k and our
previous studies [see references 36, 37]. **The signals originated from aromatic carbons
cannot be assigned based on obtained data. IR (KBr, cm-1): ν = 3438, 1646, 1495, 1448, 755.
1-(3-Chlorophenyl)-4-ferrocenyltetrahydropyrimidin-2(1H)-one (9j).* Yellow solid;
mp 169 °C. Rf = 0.4 (EtOAc/Hexane, 1:1 (v/v)). Yield 83%. 1H NMR (200 MHz, CDCl3) δ =
7.35 (s, 1H, H-2'), 7.28 – 7.23 (m, 2H, H-4' and H-6'), 7.19 – 7.12 (m, 1H, H-5'), 5.43 (br s,
1H, H-3), 4.40 (dd, J = 8.7, 3.7 Hz, 1H, H-4), 4.29 – 4.16 (overlapped m, 4H, H-2'', H-3'', H-
4'' and H-5''), 4.23 (overlapped s, 5H, H-1'''), 3.78 – 3.54 (m, 2H, H-6a and H-6b), 2.29 – 2.15
(m, 1H, H-5a), 2.09 – 1.84 (m, 1H, H-5b). 13C NMR (50 MHz, CDCl3) δ = 154.6 (C-2), 144.5
(C-1'), 134.0 (C-3'), 129.5 (C-6'), 125.5 (C-2'), 125.4 (C-5'), 123.5 (C-4'), 90.2 (C-1''), 68.5
(C-1'''), 68.3 (C-3''), 67.9 (C-5''), 66.2 (C-4''), 65.3 (C-2''), 50.9 (C-4), 47.1 (C-6), 31.2 (C-5).
*The assignation for H and C atoms has been done using analogy with example 9k and our
previous studies [see references 36, 37]. IR (KBr, cm-1): ν = 3424, 1667, 1590, 1570, 755.
Anal. Calc. for C20H19ClFeN2O: C, 60.86; H, 4.85; Cl, 8.98; Fe, 14.15; N, 7.10; O, 4.05.
Found: C, 60.90; H, 4.90; N, 7.15%.
1-(4-Chlorophenyl)-4-ferrocenyltetrahydropyrimidin-2(1H)-one (9k). Yellow solid;
mp 183 °C. Rf = 0.4 (EtOAc/Hexane, 1:1 (v/v)). Yield 76%. 1H NMR (400 MHz, CDCl3) δ =
7.38 – 7.21 (m, 4H, H-2', H-3', H-5' and H-6'), 5.24 (br s, 1H, H-3), 4.44 (br s, 1H, H-4), 4.32
– 4.15 (overlapped m, 4H, H-2'', H-3'', H-4'' and H-5''), 4.23 (overlapped s, 5H, H-1'''), 3.82 –
3.56 (m, 2H, H-6a and H-6b), 2.22 (br d, J = 10.7 Hz, 1H, H-5a), 2.02 – 1.85 (m, 1H, H-5b).
13C NMR (101 MHz, CDCl3) δ = 141.7 (C-2), 130.8 (C-1'), 128.7 (C-4'), 126.7 (C-2'), 120.8
(C-3'), 90.1 (C-1''), 68.5 (C-1'''), 68.3 (C-3'') 67.9 (C-5''), 66.2 (C-4''), 65.1 (C-2''), 50.9 (C-4),
47.3 (C-6), 31.3 (C-5). IR (KBr, cm-1): ν = 3420, 1665, 1610, 1568, 750.

Acknowledgement
This work was supported by the Ministry of Education, Science and Technological
development of the Republic of Serbia (Agreement No. 451-03-68/2020-14/200122).
Supporting Information
X-ray crystallographic data in CIF format and copies of IR and NMR (1H NMR and 13C NMR)
spectra.
Appendix A. Supplementary data
Crystallographicdataforstructural analysis havebeen deposited with theCambridge Crystallographic
DataCentre, CCDC No. 2000137-2000139. Thesedata can beobtained freeof chargevia
www.ccdc.cam.ac.uk.
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