New ferrocenyl-substituted heterocycles. Formation under Biginelli conditions, DFT modelling, and structure determination

Article abstract of DOI:10.1016/j.jorganchem.2010.04.036

A series of novel ferrocene-containing-dihydropyrimidines (DHPs) were prepared by three-component Biginelli reactions of formylferrocene, 1,3-dioxo-components and thiourea catalyzed by boric acid and ytterbium triflate, respectively. When cyclic-1,3-diones were employed as dioxo component in the reactions promoted by boric acid, besides one expected 4-ferrocenyl-2-thioxoquinazoline, 9-ferrocenyl-2H-xanthene-1,8-dione and 9-ferrocenylcyclopenta[b]chromen-8-ones could also be isolated as products. By means of control reactions and B3LYP/6-31 G(d) modelling the formation of the chromenone was interpreted by hetero-Diels-Alder addition involving the Knoevenagel intermediate and the cyclopentadiene resulted in situ from acid-catalyzed decomposition of formylferrocene. The enhanced tendency of the acyclic dioxo components to undergo Biginelli reaction avoiding cycloaddition was reasoned by the formation of Knoevenagel intermediates capable of chelating proton or Lewis acids. The structures of the new compounds were established by IR and NMR spectroscopy, including HMQC, HMBC, DEPT and DNOE measurements. Some structural characteristics were disclosed by B3LYP/6-31 G(d) method. Novel ferrocenyl-2-thioxo-dihydropyrimi-dines, and condensed heterocycles were formed in the Biginelli reactions of formylferrocene, 1,3-dioxo-components and thiourea catalyzed by boric acid and ytterbium triflate, respectively. The interpretation of reactions were supported by B3LYP/6-31 G(d) modelling studies. The structures of the new compounds were established by IR and NMR spectroscopy.

Full text of DOI:10.1016/j.jorganchem.2010.04.036

Journal of Organometallic Chemistry 695 (2010) 1852e1857
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
New ferrocenyl-substituted heterocycles. Formation under Biginelli conditions,
DFT modelling, and structure determination
,
a,b
K. Kiss a, A. Csámpai a , P. Sohár
*
a Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest, Pázmány Péter sétány 1/A, Hungary
b Protein Modelling Group, Hungarian Academy of Sciences, Eötvös Loránd University, H-1117 Budapest, Pázmány Péter sétány 1/A, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel ferrocene-containing-dihydropyrimidines (DHPs) were prepared by three-component
Biginelli reactions of formylferrocene, 1,3-dioxo-components and thiourea catalyzed by boric acid and
ytterbium triflate, respectively. When cyclic-1,3-diones were employed as dioxo component in the
reactions promoted by boric acid, besides one expected 4-ferrocenyl-2-thioxoquinazoline, 9-ferrocenyl-
2H-xanthene-1,8-dione and 9-ferrocenylcyclopenta[b]chromen-8-ones could also be isolated as prod-
ucts. By means of control reactions and B3LYP/6-31 G(d) modelling the formation of the chromenone was
interpreted by hetero-DielseAlder addition involving the Knoevenagel intermediate and the cyclo-
pentadiene resulted in situ from acid-catalyzed decomposition of formylferrocene. The enhanced
tendency of the acyclic dioxo components to undergo Biginelli reaction avoiding cycloaddition was
reasoned by the formation of Knoevenagel intermediates capable of chelating proton or Lewis acids. The
structures of the new compounds were established by IR and NMR spectroscopy, including HMQC,
HMBC, DEPT and DNOE measurements. Some structural characteristics were disclosed by B3LYP/6-31 G
(d) method.
Received 18 March 2010
Received in revised form
26 April 2010
Accepted 29 April 2010
Available online 6 May 2010
Keywords:
Ferrocene
Biginelli reaction
DielseAlder addition
DFT calculations
NMR spectroscopy
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
Biginelli products [5] exploring H3BO3/AcOH and FeCl3/TMSCl/
MeCN systems introduced by Tu et al. [6] and Wang et al. [7],
There is considerable current interest in the Biginelli reaction,
because 3,4-dihydropyrimidin-2(1H)-ones (DHP’s) and their
derivatives have attracted great attention recently in synthetic
organic chemistry due to their valuable pharmacological and
therapeutic potential [1]. For a characteristic example, dihy-
dropyrimidinone C-5 amides were prepared and assayed as potent
respectively. As a continuation of our ongoing research aiming at
the extension of ferrocene-containing heterocycles to be tested in
biological assays we attempted the preparation of a group of novel
4-ferrocenyl-DHP’s and quinoxalines with variably transformable
2-thioxo substituent allowing to obtain further biologically relevant
scaffolds or bioconjugates.
and selective
prostatic hyperplasia [1d]. Biginelli reactions are simple one-pot
condensations of -dicarbonyl compounds with aldehydes and
a1A receptor antagonists for the treatment of benign
2. Results and discussion
b
urea or thiourea most commonly catalyzed by mineral acid, but
many synthetic modifications have been reported including
a variety of Lewis and protic acids [2]. In spite of the relative
simplicity of the available methodologies and a wide range of
promising biological effects detected for simple ferrocene deriva-
tives [3], there are only a few examples of ferrocenyl-substituted
DHPs of which first representatives have been prepared by Fu et al.
[4] using indium(III)-halides as catalyst. In our previous work we
reported on facile synthetic routes to further ferrocene-containing
Two catalytic systems, namely H3BO3/AcOH (Method A) and Yb
(OTf)3/MeCN (Method B), respectively (Scheme 1), were evaluated
in comparative manner. According to the first protocol employed
for the first time to targeting 2-thioxo-DHPs, the mixture of for-
mylferrocene (1, 1 equiv.), the corresponding 1,3-dioxo component
(2aei 1 equiv.), thiourea (1.2 equiv.) and boric acid (0.2 equiv.) were
heated in acetic acid for 5 h at 100 ꢀC [6] affording 4-ferrocenyl
DHP’s (3aei) in mediocre yields (21e55%, see Section 4).
The cyclizations were also carried out in refluxing acetonitrile by
Method B employing the reagents in the same ratio and ytterbium
triflate (0.05 equiv.) as catalyst, but 3aei could be isolated in lower
yields (3e53%, see Section 4). The most significant differences in
the yields (53/4% for 3f and 36/10% for 3g by Methods A/B) were
* Corresponding author.
E-mail address: csampai@chem.elte.hu (A. Csámpai).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.04.036

K. Kiss et al. / Journal of Organometallic Chemistry 695 (2010) 1852e1857
1853
S
2, 3 R1
R2
Fe
O
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Ph
Me
H2N
NH2
O
CHO
H
R2
OMe
OEt
1.2 equiv.
A or B
Fe
H
S
4
+
R2
N
O
R1
t
6
2
OBu
NEt2
Ph
N
H
R1
1 (1 equiv.)
2a-i (1 equiv.)
g
h
i
OEt
3a-i
Method A : H3BO3 (0.2 equiv.), AcOH, 100 oC, 5 h, Ar
Method B : Yb(OTf)3 (0.05 equiv.) , MeCN, reflux, 6 h, Ar
CH2CO2Me OMe
CH2CO2Et
OEt
Scheme 1.
detected for the reactions involving aromatic derivatives 2f, g
potentially capable of bonding to the Yb(III) species by h6
yield (10%) and a considerable amount of 1 could also be recovered
by column chromatography from the reaction mixture contami-
nated by tarry substances. Conversion of 4b attempted by Method B
gave only undefined decomposition products.
-
complexation with the participation of the phenyl substituent [8].
The low yields of the reactions with diesters 2h, i performed by
either procedures (21/3% for 3h and 21/7% for 3i by Methods A/B)
can probably be ascribed to uncontrolled condensations involving
two highly activated methylene groups. It is also worth to point out
that the reaction of 2f by Method A proved to be regioselective
affording 5-benzoyl-6-methyl-substituted DHP 3f, but the product
with alternative substitution pattern could not be isolated in accord
with the expected enhanced reactivity of the aliphatic ketone
relative to that of the aromatic one.
1,3-Cyclohexane-dione and dimedone (4a, b) were additional
choices to target the preparation of 4-ferrocenyl-2-thio-
xoquinoxalines employing the conditions of Method A which
produced higher yields in the reactions of acyclic dioxo compo-
nents 2aei (Scheme 2). Under these conditions 4a got partially
converted into the mixture of the expected bicyclic product 5a
(10%), 9-ferrocenylcyclopenta[b]chromenone 6a (10%) and 9-fer-
rocenylxanthene-dione 7a (7%), but 4b afforded cyclopenta[b]
chromenone 6b (25%) as exclusively isolable product. Although
these reactions were conducted under argon, rather low yields
could be achieved due to the formation of substantial amount of
tarry materials. In order to increase the yield of quinoxaline 5a, we
attempted to carry out the reaction of 4a and thiourea by Method B
(Scheme 2). Under these conditions 5a was formed again in low
The formation of 6a, b can be interpreted by formal [4 þ 2]
cycloaddition of Knoevenagel-intermediates Ia,
b and cyclo-
pentadiene (Cp) resulted from the acid-catalyzed decomposition of
1 (Scheme 3). This view gains support from the following experi-
mental observations and theoretical considerations: (i) the green
colour of the hydrated iron(II) ions was observable on aqueous
workup of the reaction mixtures, while the formation of tarry
substances under protic conditions can at least partly be attributed
to the polymerization of hydroxyfulvene, the other possible
decomposition product of 1; (ii) on treatment of 1 (1 equiv.) with 4a
(1.5 equiv.), boric acid (0.2 equiv.) and Cp (2 equiv.) in acetic acid at
100 ꢀC for 5 h (Method C) 6a was obtained in good yield (70%,
Scheme 3). According to general expectations the overall [4 þ 2]
cycloadditions might competitively proceed via two pathways
involving inverse electron-demand hetero DielseAlder (DA) reac-
tion with Ia,b as oxadiene component (Scheme 3) and by “normal”
DA reaction with Cp as diene component followed by [3,30] oxa-
Cope rearrangement (Ia, b þ Cp / endo-IIa,b / 6a, b), respec-
tively. Taking into account the elementary steps which in principle
might also afford diastereomeric products 6*a, b (Scheme 3), the
energetics of the two possible pathways were disclosed by DFT
calculations [9] carried out at B3LYP level of theory [10] using 6-31
S
Fe
O
(1.2 equiv.)
O
H
H2N
NH2
H
S
1
+
4
N
5
6
R
A or B (from 4a)
Methods A and B :
see Scheme 1
2
O
R
N
H
4a,b (1 equiv.)
5a (10% by A)
(10% by B)
a: R=H
b: R=Me
Fe
Fe
O
O
O
H
H
H
4
(The atomic numbers given for 5a, 6a,b
and 7a are used for NMR assignments in
Tables 1 and 2 and do not correspond to
IUPAC rules.)
4
5
6
3
2
R
R
O
O
H
6a (10% by A)
6b (25% by A)
7a (7% by A)
Scheme 2.

1854
K. Kiss et al. / Journal of Organometallic Chemistry 695 (2010) 1852e1857
Fc
H
O
Fc
O
H
H
H
H
H
C
a: R=H
b: R=Me
1
4a
ΔE(R=H)=
−38.6 kJ/mol
70% for 6a
R
R
R
R
O
O
(Fc=ferrocenyl)
6a,b
6*a,b
ΔE= −35.2 kJ/mol
ΔE= −76.3 kJ/mol
(R=H)
(R=H)
ΔE= −38.0 kJ/mol
ΔE= −76.6 kJ/mol
(R=H)
(R=H)
Fc
O
O
H
ΔE= −2.8 kJ/mol
O
ΔE= −0.3 kJ/mol
(R=H)
H
Fc
Fc
(R=H)
+
R
O
O
O
R
R
R
R
R
exo−IIa,b
Ia,b
endo−IIa,b
Method C: 1 (1 equiv.), 4a (1.5 equiv.), H3BO3 (0.2 equiv.), AcOH, 100 oC, 1 h, then Cp (2 equiv.) 7 h, Ar
Scheme 3.
G(d) basis set [11] on the optimized structures of the reactants and
the potential spirocyclic intermediates endo-IIa and exo-IIa
unsubstituted on the cyclohexanone unit (R ¼ H). The changes in
energy represented on Scheme 3 show that both studied hetero-DA
reactions are highly exothermic and, in accord with the preparative
results, 6a carrying the bulky ferrocenyl group in exo-position is
more stable by 38.6 kJ/mol than 6a* with endo-positioned ferro-
cenyl substituent. The contribution of the alternative pathway can
practically be ruled out by the similar slightly exothermic ener-
getics obtained for the DA additions affording in preequilibrium
diastereomeric spirocycles of which oxa-Cope rearrangements e
contrary to the observed diastereoselectivity e would afford 6a and
6*a in comparable yields as suggested by their similar activation
these are the cationic chelated intermediates which undergo
conjugate addition with thiourea followed by cyclization affording
DHP ring.
The spectral data (1H and 13C NMR and IR) given in Tables 1e3
unambiguously confirm the supposed structures. Only the
following additional remarks are necessary.
Because of asymmetric structures (chiral C-4 atom), the atom
pairs H/C-2,5 and H/C-3,4 in the substituted Cp rings are chemically
non-equivalent and they give separated signals in the spectra of
3aei, 5a and also of 6a, b (having two further chiral centra). In case
of the symmetric 7a, of course, common signals were observed for
these atom pairs.
In case of compounds 6a, b the position of the C]C double bond
in the cyclopentene ring with its cis or trans annelation and the
relative orientation of H-2 to H-3 and H-4, respectively, were to be
elucidated.
barriers (
D
Ez ¼ 63.2 kJ/mol for endo-IIa / 6a and 68.2 kJ/mol for
exo-IIa / 6*a, respectively). The transition states of these intra-
molecular processes were located by using QST2 calculations [12] at
B3LYP/6-31 G(d) level of DFT.
The position of the double bond in 6a, b follows straightfor-
wardly from the multiplicity of the H-2 signals at 5.12 ppm (for 6a)
and 5.16 ppm (for 6b), respectively, (and also from the HMBC
Since the formation of pyran scaffold was not observed in the
boric acid-mediated reactions of acyclic 1,3-dioxo components
2aei it is plausible to assume that their Knoevenagel intermediates
IVaei readily undergo protonation to give chelate-stabilized
cations Vaei (Scheme 4) preventing to adopt single-cis conforma-
tion, the prerequisite of the inverse electron-demand hetero DA
reaction. On the other hand, it seems that the acid-mediated
decomposition of 1 resulting in Cp may be supressed by IVaei
having significantly increased basicity relative to that of cyclic dioxo
compounds Ia, b. This view was also supported by B3LYP/6-31 G(d)
calculations on equilibrium-protonation reactions of two selected
simple models [Ia þ Hþ 4 IIIa (1, R ¼ H) and IVa þ Hþ 4 Va (2,
R1 ¼ R2 ¼ Me), respectively, Scheme 4] affording a considerable
H
R
R
R
R
O
O
ΔE1 (R=H)
Fc
Fc
H
+
H
O
H
O
a: R=H
b: R=Me
Ia,b
IIIa,b
R2
R2
O
ΔE2 (R1=R2=Me, R3=Fc)
ΔE3 (R1=R2=Me, R3=Ph)
O
O
O
H
difference in the energetics
[
D
E1(IIIa ꢁ Ia)ꢁ E2(Va ꢁ IVa) ¼ þ
D
R3
H
R3
H
41.8 kJ/mol] irrespectively of the acid component. Besides chelation
it is the highly electron-donating ferrocenyl group [13] located at
the terminal of the push-pull system which significantly stabilizes
cations Va-i as evidenced by the difference in the calculated ener-
getics of the equilibrium-protonation of IVa and its phenyl
H
+
R1
R1
Designation a-i: see Scheme 1
Va−i (R3=Fc)
VIIa (R1=R2=Me, R3=Ph)
IVa−i (R3=Fc)
VIa (R1=R2=Me, R3=Ph)
Fc=ferrocenyl
analogue
VIa
[
D
E3(VIIa ꢁ VIa)ꢁ E2(Va ꢁ IVa) ¼ þ25.3 kJ/mol,
D
For any proton source [calculated by B3LYP/6-31 G(d) method] :
ΔE1(IIIa−Ia) − ΔE2(Va−IVa)= + 41.8 kJ/mol
ΔE3(VIIa−VIa) − ΔE2(Va−IVa)= + 25.3 kJ/mol
Scheme 4]. Finally, on the basis of the previous considerations it is
reasonable to assume that IVa-i show increased affinity to Lewis
acids, too, including boron and Yb(III) capable of replacing proton in
the chelated structures. It must also be pointed out that presumably
Scheme 4.

K. Kiss et al. / Journal of Organometallic Chemistry 695 (2010) 1852e1857
1855
Table 1
1H NMR dataa, b of compounds 3aei, 5a, 6a,b and 7a.c
CH3 or CH2 (Pos. 6)d
CH3 (R2)e
CH2 (R2 or R1)
H-4 df
C5H5
H-2,5
H-3,4
NH, s, br (Pos. 1)
NH, d, br (Pos. 3)
c-Pentene rings in ferrocenyl
group
3a
3b
2.23
2.20
2.25
3.66
ꢁ
ꢁ
5.02
4.92
4.24
4.23
3.91, w4.8 (4H)
3.93, 4.07, 4.09
(2H)
10.26
10.34
9.48
9.38
3c
3d
3e
3f
2.20
2.17
1.22
1.44
0.98
ꢁ
w4.1g
4.92
4.88
4.72
5.10
5.04
4.94
4.94
4.94
3.95
3.75
4.38
4.24
4.25
4.25
4.08g
4.27
4.22
4.24
4.21
4.14g
4.13
4.03
3.92 (1H), w4.09
10.32
10.22
9.87
10.29
10.45
10.40
10.36
10.58
ꢁ
9.36
9.33
8.66
9.47
9.53
9.48
9.44
9.44
ꢁ
(3H)g
ꢁ
3.93 (1H), w4.09
(3H)
1.67
3.20 broad
ꢁ
4.02, 4.10, 4.11,
4.14 (4ꢂ 1H)
4.02, 4.05, 4.08,g
4.13 (4ꢂ1H)
4.10 (1H), 4.16
(2H), 4.19 (1H)
4.00, 4.11, 4.12,
4.18 (4ꢂ 1H)
4.00 (1H), w4.08
(2H),g 4.18 (1H)
3.89 (1H), w4.07
(3H)
1.74
3g
3h
3i
ꢁ
0.82
3.83 qa
3.64g
1.18h
w2.48
w2.35
2.18
3.64
3.72 s (R1)
w4.08 (R1, R2)g
1.79,i 1.94i
1.87,i 1.94i
2.11, 2.17j
w2.00 m (4H)
g
1.19h
5a
6a
6b
7a
w2.28
w2.32, w2.43
0.91, 0.96
w2.35, w2.48
4.04, 4.05, 4.13,g
4.20 (4ꢂ1H)
4.02, 4.06 (2H),
4.21
3.99 (2H), 3.75
(2H)
ꢁ
ꢁ
w2.65
ꢁ
ꢁ
a
In DMSO-d6 or CDCl3 (3a, 6a) solution at 500 MHz. Chemical shifts in ppm (dTMS ¼ 0 ppm), coupling constants in Hz.
b
Further 1H NMR signals: CH2 (Pos. 6, 3i): 3.69, CH2 (c-pentene ring): 2.14 and 2.55, 2ꢂ qadd (J: 17.7, 7.8 and 2.3 and 17.7, 8.0 and 1.7, resp., 6a), 1.96 and 2.60, ddd and dd (J:
15.7, 7.5 and 1.4 and 16.6 and 8.0, resp., 6b); H-2,6 (Ph), wd (2H): 7.64 (3f), 7.24 (3g); H-3,5 (Ph), wt (2H): 7.51 (3f), 7.38 (3g); H-4 (Ph), wt (1H): 7.59 (3f), 7.41 (3g); ]CH(CH),
m (1H): 5.91(6a, b); ]CH(CH2), td (1H): 6.10 (6a, J: 5.5, 2.3), m (6b); H-2, dt (1H): 5.12 (6a, J: 7.2 and 2.0), wd (1H): 5.16 (6b, J: 7.1).
c
Assignments were supported by HMQC and H,C-HMBC (except for 3b), for 6a, b also by 2D-COSY and DIFFNOE measurements.
s (3/2H) for 3aef/3h, i, 6b, m (2H, 5a, 6a) (4H, 7a).
d
e
s (3H) for 3a, b, d, h, t [J: 7.1 (3c, g), 6.7 (3e)], m (2H) for 5a or 2ꢂ m (2ꢂ 1H, 6a, 2ꢂ 2H, 7a), 2ꢂ s (2ꢂ 3H, 6b).
f
J: 4.4 ꢃ 0.2 (3aed, g), 3.4 ꢃ 0.1 (3e, h), 4.0 ꢃ 0.1(3f, 5a), 3.7 (3i), s (6a,b, 7a).
g
Overlapping signals.
h
Interchangeable assignments.
CH2CH2CH2.
2ꢂ d (J: 16.0): AB-type spectrum (6b).
i
j
spectrum), which are triple doublets split by ca. 7, 2 and 2 Hz,
originating from one vicinal and two allylic-type couplings.
The relative position of the three methine hydrogens in 6a, b were
determined by DIFFNOE measurements. Irradiating the H-2,5 signal
of the substituted cyclopentene ring both H-2 and H-3 signals gave
responses. This means that the two latter H’s lie on the same side of
the molecular skeleton, thus they are in cis position, on the same side
with the ferrocenyl moiety and, consequently, trans to H-4.
The structures of four representative 4-ferrocenyl-DHP’s (3a, b,
e, f) were also analyzed by B3LYP/6-31 G(d) method. Geometry
optimization carried out for 3a, b disclosed nearly coplanar C-5,C-6
bond and C]O group at Pos. 5 (interplanar angles: 0.9ꢀ for 3a and
10.0ꢀ for 3b) allowing efficient enone conjugation. In 3e and 3f the
bulky COR2 substituents at pos. 5 were found to turn out of the
plane of C-5,C-6 bond (interplanar angles: 51.2ꢀ for 3e and 40.6ꢀ for
3b) separating ferrocenyl- and R2 groups on the opposite sides of
the DHP ring.
synthesis of monocyclic 4-ferrocenyl-DHP’s of which formation
presumably proceeds via ferrocenyl-stabilized Knoevenagel inter-
mediates of chelated structure. On the other hand, on the use of
cyclic 1,3-dioxo components partial acid-catalyzed degradation of
formylferrocene followed by inverse electron-demand DA reaction
of the resulted cyclopentadiene with the Knoevenagel intermedi-
ates must also be taken into account. From the aspect of synthetic
utilization, the extension of this transformation to other electron-
donor dienophilic components may serve as an easy access to
a series of novel tricyclic ferrocenyl-substituted pyrane derivatives
of potential biological interest.
4. Experimental
Melting points were determined with a Boethius microstage
and are uncorrected. All calculations were performed by the
Gaussian03 suite of programs [14]. The structures of the located
stationary points are available from the authors on request. The IR
spectra were run in KBr disks on a Bruker IFS-55 FT-spectrometer
controlled by Opus 3.0 software. The 1H and 13C NMR spectra were
recorded in CDCl3 solution in 5 mm tubes at RT, on a Bruker DRX-
500 spectrometer at 500.13 (1H) and 125.76 (13C) MHz, with the
deuterium signal of the solvent as the lock and TMS as internal
standard. DEPT spectra were run in a standard manner, using only
3. Conclusion
The Biginelli reactions of formylferrocene, thiourea and a variety
of 1,3-dioxo components performed in comparative manner under
two conditions point to the preference of the method employing
the cheaper and more efficient H3BO3/AcOH system. However, the
extension of this simple protocol seems to be limited to the
a
Q
¼ 135ꢀ pulse to separate the CH/CH3 and CH2 lines phased “up”

1856
K. Kiss et al. / Journal of Organometallic Chemistry 695 (2010) 1852e1857
Table 2
13C NMR chemical shiftsa of compounds 3aei, 5a, 6a, b and 7a.b, c
CH3 (R1)
CH3 (R2)
C]S (C-2)
C]O Pos. 5
C-4
C-5
C-6
CH2
C-10
C-20,50
C-30,40
C5H5
Substituted Cp ring (Fc-group)
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
6a
6b
7a
19.0
17.9
17.9
18.0
16.1
18.3
ꢁ
31.4
52.0
15.1
28.8
14.0
ꢁ
175.5
175.7
175.7
175.8
175.4
175.5
175.7
175.4
175.5
175.8
82.6i
82.7
195.4
166.6
166.1
165.5
168.1
195.2
165.9
166.3
165.8
194.6
197.5
196.5
197.5
49.7
49.9
49.9
50.0
52.7
51.6
50.4
50.0
50.0
47.5
29.0
29.3
23.4
113.4
102.8
103.1
104.6
108.8
111.9
103.6
104.1
104.5
110.8
113.7
112.4
117.0
144.3
145.3
145.1
144.3
130.3
142.0
146.0
141.7
141.4
151.3
173.2
171.5
166.6
ꢁ
93.7
93.3
93.4
93.7
92.7
92.7
92.7
92.7
92.8
93.5
93.8
93.9
95.2
66.2, 67.2
66.0, 67.0
68.0, 68.1
68.2, 68.3
69.5
69.5
69.5
69.5
69.4
69.5
69.6
69.5
69.5
69.5
69.1
69.2
69.2
ꢁ
60.5
80.8d
40.8
ꢁ
66.0, 67.1, 68.1, 68.2
66.0, 66.9, 68.0, 68.1
65.9, 67.6, 68.0, 68.7
66.4, 66.9, 68.2, 68.6
66.4, 67.1, 68.3, 68.4
66.5, 67.1, 68.2, 68.4
66.4, 67.2, 68.2, 68.3
66.4, 66.8, 68.0, 68.1
14.4
52.7e
14.9f
37.2g
37.3g
51g
60.4
36.8
60.9, 61.3
52.2e
14.9f
26.1g
30.0g
27.8, 29.2
27.5g
h
21.4
20.9h 38.3k
38.6k
66.4, 67.45
66.6, 67.4, 67.8, 68.4
67.1
67.51, 68.5
37.4g
ꢁ
20.8h
67.4
a
In DMSO-d6 or CDCl3 (3a, 6a, b) solution at 125 MHz. Chemical shifts in ppm (dTMS ¼ 0 ppm).
Assignments were supported by DEPT, HMQC and H,C-HMBC (except for 3b) measurements.
b
c
Further 13C-NMR signals: ]CH(CH): 130.9 (6a), 131.7 (6b); ]CH(CH2): 138.7 (6a), 138.8 (6b); C-1 (Ph): 140.5 (3f), 134.9 (3g); C-2,6 (Ph): 129.1 (3f), 129.6 (3g); C-3,5 (Ph):
129.6 (3f), 128.5 (3g); C-4 (Ph): 133.1 (3f), 129.9 (3g); C]O (CH2COOMe, Pos. 6, 3h): 169.9; C(sp3)quat.: 32.3.
d
Cquat.(t-Bu).
Interchangeable assignments.
Overlapping lines.
CH2.
CH2CH2CH2.
OCH.
CH2 in c-pentene ring.
e
f
g
h
i
k
and “down”, respectively. The 2D-COSY, HMQC and HMBC spectra
were obtained by using the standard Bruker pulse programs.
4.2. Three-component condensations of formylferrocene (1) by
Method B
A mixture of 1 (0.643 g, 3 mmol), 1,3-dioxo reagent (3 mmol),
4.1. Three-component condensations of formylferrocene (1) by
Method A
thiourea (0.274 g, 3.6 mmol), and ytterbium-triflate (0.093 g,
0.15 mmol) in acetonitrile (10 mL) was stirred and heated at reflux
for 6 h. After cooling, water (100 mL) was added to the mixture. The
precipitate was filtered and thoroughly washed with water and
dried. The crude product was chromatographed on silica gel using
DCMeMeOH (100:1) as eluent to obtain the products as yellowish
powders which were crystallized with cold EtOH. Within experi-
mental errors the mps and analytical data of the products were
identical to those obtained by Method A.
A solution of 1 (0.642 g, 3 mmol), 1,3-dicarbonyl compound
(3 mmol), thiourea (0.274 g, 3.6 mmol) and H3BO3 (0.037 g,
0.6 mmol) in glacial acetic acid (10 mL) was heated under Ar at
100 ꢀC, while stirring for 5 h. After cooling, water (100 mL) was
added to the mixture. The precipitate was filtered and thoroughly
washed with water and dried. The crude product was chromatho-
graphed on silica gel using DCMeMeOH (100:1) as eluent to obtain
the products as yellowish powders which were crystallized with
cold EtOH (description of the products: see after the next section).
4.2.1. 5-Acetyl-3,4-dihydro-4-ferrocenyl-6-methylpyrimidin-2
(1H)-thione (3a)
Yield: 46/31% (A/B); mp 244-245 ꢀC; anal. calcd. for C17H18Fe-
N2OS (354.25) C 57.64, H 5.12, N 7.91, S 9.05%; found C 57.77, H 5.11,
N 7.86, S 9.12%.
Table 3
Characteristic IR frequencies [cmꢁ1] of compounds 3aei, 5a, 6b and 7a (in KBr discs).
n
NH band (broad
or diffuse)
3a w3270
n
C]O
n
C]C
n
CeO ester or
nasCpeFeeCp and
tilt of Cp
4.2.2. Methyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-methyl-2-
thioxopyrimidine-5-carboxylate (3b)
b
banda,
band
ether bands
1610
1667
1670
1704
1690
1572
1570
1570
1589
1608
1619
1573
1563
1569
1570
1605
1619
1613
e
482
496
w500
487
482, 501
504, 480, 469
494
486
497
523, 489
509, 495
480
Yield: 55/53% (A/B); mp 233e235 ꢀC; anal. calcd. for C17H18Fe-
N2O2S (370.25) C 55.15, H 4.90, N 7.57, S 8.66%; found C 55.23, H
4.79, N 7.48, S 8.74%.
3b 3380e2800
3c 3300e2500
3d 3300e2700
3e 3500e2500
1182, 1108
1185, 1120
1156, 1095
e
3fc 3406, 3300e2700 1656
e
4.2.3. Ethyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-methyl-2-
thioxopyrimidine-5-carboxylate (3c)
3gc 3400e2700
3h w3320
1692
1746
1736
1620
1643
1650
1669d
1197, 1138,
1189, 1112
1187, 1108
e
Yield: 37/30% (A/B); mp 229e231 ꢀC; anal. calcd. for C18H20Fe-
N2O2S (384.27) C 56.26, H 5.25, N 7.29, S 8.34%; found C 56.32, H
5.20, N 7.21, S 8.42%.
3i 3350e2800
5a w3260, w3163
6a
6b
7a
e
e
e
1020
1207, 1086
1129
486
4.2.4. Tert-butyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-methyl-2-
thioxopyrimidine-5-carboxylate (3d)
a
Ester or ketone (for 3a, f, 5a, 6a, b, 7a) group, amide-I band for 3e (amide-II
band: 1655).
Yield: 36/25% (A/B); mp 239e240 ꢀC; anal. calcd. for C20H24Fe-
N2O2S (412.33) C 58.26, H 5.87, N 6.79, S 7.78%; found C 58.37, H
5.79, N 6.70, S 7.73%.
b
c
CH2COOMe/Et group for 3h, i,
CArH and CArCAr band: 731, 698 (3f), 698, 765 (3g).
Split band-pair with the second maximum at 1649.
nC]O conjugated ester: 1682 (3h, i).
g
g
d

K. Kiss et al. / Journal of Organometallic Chemistry 695 (2010) 1852e1857
1857
4.2.5. N,N-Diethyl-1,2,3,4-tetrahydro-6-methyl-4-ferrocenyl-2-
thioxopyrimidine-5-carboxamide (3e)
Within experimental error the mp and analytical data were iden-
tical to those of the sample obtained by Method A.
Yield: 50/40% (A/B); mp 232e234 ꢀC; anal. calcd. for C20H25Fe-
N3OS (411.34) C 58.40, H 6.13, N 10.22, S 7.80%; found C 58.50, H
6.15, N 10.30, S 7.91%.
Acknowledgements
This work was supported by the Hungarian Scientific Research
Fund (OTKA T-043634). The authors are indebted to Dr. Hedvig
Medzihradszky-Schweiger for analyses.
4.2.6. 5-Benzoyl-3,4-dihydro-4-ferrocenyl-6-methylpyrimidin-2
(1H)-thione (3f)
Yield: 53/4% (A/B); mp 251e253 ꢀC; anal. calcd. for C22H20Fe-
N2OS (416.32) C 63.47, H 4.84, N 6.73, S 7.70%; found C 63.55, H 4.76,
N 6.67, S 7.74%.
References
[1] (a) P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360e416;
(b) E.H. Hu, D.R. Sidler, U.J. Dolling, Org. Chem. 63 (1998) 3454;
(c) A. Kappe, Acc. Chem. Res. 33 (2000) 879;
4.2.7. Ethyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-phenyl-2-
thioxopyrimidine-5-carboxylate (3g)
(d) J.C. Barrow, P.G. Nantermet, H.G. Selnick, K.L. Glass, K.E. Rittle, K.F. Gilbert,
T.G. Steele, C.F. Homnick, R.M. Freidinger, R.W. Ransom, P. Kling, D. Reiss, T.
P. Broten, T.W. Schorn, R.S.L. Chang, S.S. O’Malley, T.V. Olah, J.D. Ellis,
A. Barrish, K. Kassahun, P. Leppert, D. Nagarathnam, C. Forray, J. Med. Chem.
43 (2000) 2703e2718.
Yield: 36/10% (A/B); mp 223e225 ꢀC; anal. calcd. for C23H22Fe-
N2O2S (446.34) C 61.89, H 4.97, N 6.28, S 7.18%; found C 61.95, H
4.90, N 6.21, S 7.15%.
[2] (a) J.S. Yadav, B.V.S. Reedy, R. Srinivas, C. Venugopal, T. Ramalingam, Synthesis
(2001) 1341;
4.2.8. Methyl 6-[(methoxycarbonyl)methyl]-1,2,3,4-tetrahydro-4-
ferrocenyl-2-thioxopyrimidine-5-carboxylate (3h)
Yield: 21/3% (A/B); mp 194e195 ꢀC; anal. calcd. for C19H20Fe-
N2O4S (428.28) C 53.28, H 4.71, N 6.54, S 7.49%; found C 53.32, H
4.66, N 6.50, S 7.40%.
(b) A.K. Kumar, M. Kasturaiah, S.C. Reedy, C.D. Reddy, Tetrahedron Lett. 42
(2001) 7873;
(c) N. Fu, Y. Yuan, Z. Cao, S. Wang, J. Wang, C. Peppe, Tetrahedron 58 (2002)
4801;
(d) K.R. Reddy, C.V. Reddy, M. Mahesh, P.V.K. Raju, V.V.N. Reddy, Tetrahedron
Lett. 44 (2003) 8173;
(e) R. Varala, M.M. Alam, S.R. Adapa, Synlett 67 (2003);
(f) A. Dondoni, A. Massi, E. Minghini, S. Sabbatini, V. Bertolasi, J. Org. Chem. 68
(2003) 6172.
4.2.9. Ethyl 6-[(ethoxycarbonyl)methyl]-1,2,3,4-tetrahydro-4-
ferrocenyl-2-thioxopyrimidine-5-carboxylate (3i)
Yield: 21/7% (A/B); mp 161e163 ꢀC; anal. calcd. for C21H24Fe-
N2O4S (456.34) C 55.27, H 5.30, N 6.14, S 7.03%; found C 55.33, H
5.21, N 6.11, S 7.11%.
[3] (a) T. Klimova, E.I. Klimova, M. Martinez Garcia, E.A. Vázquez López, C. Alvarez
Toledano, A.R. Toscano, L. Ruíz Ramírez, J. Organomet. Chem. 628 (2001) 107;
(b) B. Weber, A. Serafin, J. Michie, C. Van Rensburg, J.C. Swarts, L. Bohm,
Anticancer Res. 24 (2B) (2004) 763;
(c) G. Jaouen, S. Top, A. Vessieres, G. Leclercq, M.J. McGlinchey, Curr. Med.
Chem. 11 (2004) 2505;
(d) E. Hillard, A. Vessieres, L. Thouin, G. Jaouen, C. Amatore, Angew. Chem. Int.
Ed. 45 (2006) 285.
4.2.10. 1,2,3,4,7,8-Hexahydro-4-ferrocenyl-2-thioxoquinazolin-5
(6H)-one (5a)
[4] (a) Y.N. Fu, Y.-F. Yuan, M.-L. Pang, J.-T. Wang, C. Peppe, J. Organomet. Chem.
672 (2003) 52e57.
Yield: 10/10% (A/B); mp 260e261 ꢀC; anal. calcd. for C18H18Fe-
N2OS (366.26) C 59.03, H 4.95, N 7.65, S 8.75%; found C 59.10, H
4.88, N 7.62, S 8.68%.
}
[5] A. Csámpai, Gy. I. Túrós, A. Gyorfi, P. Sohár, J. Organomet. Chem. 694 (2009)
3667e3673.
[6] S. Tu, F. Fang, C. Miao, H. Jiang, Y. Feng, D. Shi, X. Wang, Tetrahedron Lett. 44
(2003) 6153.
[7] T. Z-Wang, L.-W. Xu, C.-G. Xia, H.-Q. Wang, Tetrahedron Lett. 45 (2004) 7951.
[8] G.B. Deacon, Q. Shen, J. Organomet. Chem. 506 (1996) 1e17.
[9] (a) P. Hohenberg, W. Kohn, Phys. Rev. 136 (1964) B864;
(b) W. Kohn, L.J. Sham, Phys. Rev. 140 (1965) A1133;
4.2.11. (3aR*,9S*,9aR*)-6,7,9,9a-Tetrahydro-9-ferrocenylcyclopenta
[b]chromen-8(1H,3aH,5H)-one (6a)
Yield: 10% (A); mp 169e170 ꢀC; anal. calcd. for C22H22FeO2
(374.25) C 70.60, H 5.93%; found C 70.64, H 5.90%.
(c) R.G. Parr, W. Yang, Density-functional Theory Of Atoms and Molecules.
Oxford University Press, Oxford, 1989.
[10] (a) A.D. Becke, J. Chem. Phys. 98 (1993) 1372;
(b) C. Lee, W. Yang, R.G. Parr, Phys. Rev. 37 (1988) B785.
[11] W.J. Hehre, L. Radom, P.V.R. Schleyer, J.A. Pople, Ab initio Molecular Orbital
Theory. Wiley, New York, 1986.
[12] C. Peng, P.Y. Ayala, H.B. Schlegel, M.J. Frisch, J. Comp. Chem. 17 (1996) 49.
[13] (a) U. Beherens, J. Organomet. Chem. 182 (1979) 89;
(b) M. Rosenblum, Chemistry of the Iron Group Metallocenes. Part 1. Inter-
science, New York, 1975, 120 pp.;
4.2.12. (3aR*,9S*,9aR*)-6,7,9,9a-Tetrahydro-6,6-dimethyl-9-
ferrocenylcyclopenta[b]chromen-8(1H,3aH,5H)-one (6b)
Yield: 25% (A); mp 189e190 ꢀC; anal. calcd. for C24H26FeO2
(402.31) C 71.65, H 6.51%; found C 71.70, H 6.47%.
4.2.13. 3,4,6,7-Tetrahydro-9-ferrocenyl-2H-xanthene-1,8(5H,9H)-
dione (7a)
(c) J.J. Dannenberg, M.K. Levenberg, J.H. Richards, Tetrahedron 29 (1973)
1575;
(d) J. Silver, D.A. Davies, R.M.G. Roberts, M. Herberhold, U. Dörfler,
B. Wrackmeyer, J. Organomet. Chem. 590 (1999) 71.
Yield: 7% (A); mp 217e219 ꢀC; anal. calcd. for C23H22FeO3
(402.26) C 68.67, H 5.51%; found C 68.73, H 5.49%.
[14] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.
R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.
M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo,
J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi,
C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.
J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain,
O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz,
Q. Cui, A.G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng,
A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.
W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision A.1. Gaussian, Inc.,
Pittsburgh, PA, 2003.
4.3. Preparation of 6a using hetero-DA reaction by Method C
A solution of 1 (1000 g, 4.67 mmol), 4a (0.785 g, 7 mmol) and
H3BO3 (0.058 g, 0.94 mmol) in glacial acetic acid (10 mL) was
heated and stirred under Ar at 100 ꢀC for 1 h, then freshly distilled
cyclopentadiene (0.647 g, 9.34 mmol) was added to the reaction
mixture which was kept at 100 ꢀC. After 7 h water (100 mL) was
added to the mixture. The precipitate was thoroughly washed with
cold EtOH to obtain 6a as yellowish powder. Yield: 1.23 g (70%).