Application of Biginelli reaction to the synthesis of ferrocenylpyrimidones and [3]-ferrocenophane-containing pyrimido[4,5-d]pyrimidinediones

Article abstract of DOI:10.1016/j.jorganchem.2009.06.017

A series of ferrocene-containing mono- and bis-dihydropyrimidines (DHP's) were prepared by boric acid mediated three-component Biginelli reactions of formyl- and 1,1′-diformylferrocene, 1,3-dioxo-components and urea. A few further transformations includin

Full text of DOI:10.1016/j.jorganchem.2009.06.017

Journal of Organometallic Chemistry 694 (2009) 3667–3673
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Application of Biginelli reaction to the synthesis of ferrocenylpyrimidones and
[3]-ferrocenophane-containing pyrimido[4,5-d]pyrimidinediones
A. Csámpai a, A.Z. Györfi b, Gy.I. Túrós c, P. Sohár a,c,
*
a Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest, Pázmány Péter sétány 1/A, Hungary
b Department of Organic Chemistry, Babeßs-Bolyai University, RO-40028 Cluj-Napoca, Str. Arany János 11, Romania
c Research Group for Structural Chemistry and Spectroscopy, 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 ferrocene-containing mono- and bis-dihydropyrimidines (DHP’s) were prepared by boric acid
mediated three-component Biginelli reactions of formyl- and 1,10-diformylferrocene, 1,3-dioxo-compo-
nents and urea. A few further transformations including hydrogenolysis of a benzyl 4-ferrocenyl-DHP-
5-carboxylate were also performed. Novel cis-fused saturated pyrimido[4,5-d]pyrimidine-2,7(1H,3H)-
diones incorporating [3]-ferrocenophane moiety were constructed by means of iron(III)-catalyzed Bigi-
nelli-like condensations of 1,10-diformylferrocene with urea and in situ generated methyl ketone-derived
silyl enol ethers. The structures of the new compounds were established by IR and NMR spectroscopy,
including HMQC, HMBC and DEPT measurements.
Received 17 April 2009
Accepted 15 June 2009
Available online 18 June 2009
Keywords:
Ferrocene
Dihydropyrimidine
Biginelli reaction
[3]-Ferrocenophane
NMR spectroscopy
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
2. Results and discussion
3,4-Dihydropyrimidin-2(1H)-ones and their derivatives (DHP’s)
have attracted great attention recently due to their pharmacologi-
cal and therapeutic properties such as antibacterial–antihyperten-
sive and calcium channel blocker activity as well as behaving as
neuropeptide antagonists [1]. Biginelli reaction is a simple one-pot
method for the synthesis of DHP’s. The low-yielding condensations
of b-dicarbonyl compounds with aldehydes and urea or thiourea
can be improved using Lewis acids such as BF3ꢀOEt2, LaCl3,
La(OTf)3, Yb(OTf)3, InX3 (X = Cl, Br), ZrCl4, BiCl3, LiClO4 as catalyst
[2]. Microwave technique [3] and ultrasound irradiation [4] were
also applied to increase the yields. In spite of the relative simplicity
of the available methodologies and a wide range of biological ef-
fects found for simple ferrocene derivatives [5], only a few ferroce-
nyl-substituted DHPs including ethyl ester 2b (Scheme 1) have
been prepared by indium(III)-mediated synthesis [6]. Encouraged
by their promising pharmaceutical properties we started to search
for expedient synthetic routes to a variety of further DHP’s contain-
ing ferrocenes.
First, we applied boric acid as catalyst (0.2 equiv.) in acetic acid
solution containing 1,3-dioxo components (1 equiv.) and urea
(1.2 equiv.) [7] to convert formylferrocene (1) at 100 °C (Method
A) into the corresponding 4-ferrocenyl DHP (2a–c, Scheme 1).
Within a relatively short reaction time (1 h) good yields were
achieved for 2a and 2b (83% and 77%, respectively), but a mediocre
yield (51%) was obtained for benzyl ester 2c contaminated by a
substantial amount of ferrocenylvinyl derivative 3 (18%) which
was formed by aldol condensation of the activated 6-methyl group
with unreacted 1. When 2c was condensed with 1 under the con-
ditions of Method B employing 0.2 equiv. of boric acid and pro-
longed reaction time (4 h) (Scheme 1) 3 formed in higher yield
(74%). The exclusive formation of C@C double bond with ‘‘E”-con-
figuration in 3 can be attributed to the much higher degree of steric
crowding which would be accumulated in the ‘‘Z”-isomer. In order
to get carboxylic acid 5, suitable to coupling with a variety of bio-
molecules, a mild hydrolysis of 2b was attempted under PTC con-
ditions using Bu4NOH in a 20:1 mixture of DCM–MeOH (Method
C). Instead of esther-hydrolysis consuming the whole amount of
the applied base (1 equiv.) methoxymethylation on the more acidic
1-NH group took place with the participation of both components
of the solvent mixture selectively resulting DHP 4 in good yield
(85%). Finally, facile debenzylation of 2c was carried out by cata-
lytic hydrogenation over Pd(C) in EtOAc–AcOH (3:1) solution to
give carboxylic acid 5 in almost quantitative yield (Scheme 1).
Combination of these two supplementary reactions of these two
* Corresponding author. Address: Research Group for Structural Chemistry and
Spectroscopy, Hungarian Academy of Sciences – Eötvös Loránd University, H-1117
Budapest, Pázmány Péter sétány 1/A, Hungary. Tel.: +36 1 209 0555 1900; fax: +36
1 209 0602.
E-mail address: sohar@chem.elte.hu (P. Sohár).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.06.017

3668
A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
CHO
Ph
O
Fe
O
NH
O
Fe
N
H
1
Fe
A
3
Me
(18% from 1; 74 % from 2c)
O
O
NH2
O
NH2
OEt
Me
B
R
O
N
+1
OMe
from 2c
R
N
O
H
Me
NH
O
Fe
5'
4 (85 %)
C
N
H
O
2'
from 2b
Fe
OH
Me
NH
O
O
2a: R = Me (83 %)
2b: R = OEt (77 %)
D
N
H
from 2c
Fe
2c: R = OCH2Ph (51 %)
5 (95 %)
A: H3BO3 ( 0.2 equiv.), 1,3-dicarbonyl component (1 equiv.), urea (1.2 equiv.), AcOH, 100 oC, 1 h
B: H3BO3 (0.2 equiv), AcOH,100 oC: 4 h;
C: Bu4NOH, DCM-MeOH (20:1), rt, 5 h;
D: H2/Pd(C) EtOAc-AcOH (3-1), 1h
Scheme 1.
esters may open up ways to a number of selectively polyfunction-
alized DHP’s.
(12%)] derived from incomplete reactions on one of the Cp rings.
In an attempt to increase the ratio of the target compound we em-
ployed four equivalents of urea with 6 h reaction time (Method F,
Scheme 2) and 7 could be isolated in 70% yield with decreased
amount of mono-DHP’s 8, (Z)-9 and (E)-9 (4%, 10% and 7%). The com-
parable yields of the latter two products can be reasoned by the
similar size of the acetyl- and ethoxycarbonyl groups. It is worth
Using 0.4 equiv. of boric acid, an analogous cyclization reaction
of 1,10-diformyl-ferrocene (6) was also attempted with ethyl aceto-
acetate (2 equiv.) and 2.4 equiv. of urea (Method E). The reaction
afforded bis-DHP 7 as a single diastereomer (Scheme 2) in moderate
yield (42%) along with mono-DHP’s [8 (10%), (Z)-9 (18%) and (E)-9
CHO
EtO
H2N
O
O
O
Fe
H2N
E, F
Me
CHO
6
OEt
Me
NH
OEt
OEt
Me
Me
NH
OEt
O
Me
NH
O
O
NH
N
O
O
N
N
H
O
O
H
H
N
O
Fe
O
H
Fe
O
Fe
H
N
O
Fe
H
H
NH
Me
O
O
O
CHO
OEt
Me
OEt
OEt
Me
8 [10% (E); 4% (F)]
(Z)-9 [18% (E);10% (F)]
(E)-9 [12% (E); 7% (F)]
7 [42% (E); 70% (F)]
E: H3BO3 ( 0.4 equiv.), 1,3-dicarbonyl component (2 equiv.), urea (2.4 equiv.), AcOH, 100 oC, 4 h
F: H3BO3 ( 0.4 equiv.), 1,3-dicarbonyl component (2 equiv.), urea (4 equiv.), AcOH, 100 oC, 6 h
Scheme 2.

A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
3669
to point out that the formation of the alternative diastereomer of 7
was not observed at all. So far we have failed to grow crystals suit-
able for X-ray analysis and the relative configuration could not be
determined on the basis of NMR data.
from the two NH-signals in 1H NMR between 6.3 and 7.6 ppm
(NH-3) and 7.6 and 9.2 ppm (NH-1), respectively, removable by
adding heavy water.
Due to smaller
a
-effect of a C(sp2) atom as compared to that
In order to get 2,4-diferrocenyl-DHP without substituent at po-
sition 5 we resorted to a Biginelli-like protocol developed by Wang
et al. [8] reacting formylferrocene (1) with acetylferrocene (10) and
urea in the presence of catalytic amount of FeCl3ꢀ6H2O (0.1 equiv.)
and TMSCl (1 equiv.) in refluxing MeCN (Method G, Scheme 3).
Although the reaction was conducted under argon, we could iso-
late only 2,4-diferrocenyl-2-hydroxypyrimidine (11) in moderate
yield (38%). We assume that in the course of work-up the primarily
formed target compound underwent facile aromatization pro-
moted by two ferrocenyl groups.
An interesting bridging reaction associated with the formation
of cis-anellated hexahydropyrimido[4,5-d]pyrimidine ring system
(12a–d, Scheme 4) took place when the reaction of 1,10-diformyl-
ferrocene (6) was conducted in the presence of doubled amount
of the keton component (2 equiv.), urea (3 equiv.), FeCl3ꢀ6H2O
(0.2 equiv.) and TMSCl (2 equiv.) (Method H). The facile formation
of this ring system incorporating [3]-ferrocenophane unit can be
rationalized by two subsequent aldol reactions followed by con-
densation with two molecules of urea. The new tetraazadecalines
of type 12 accessible by our reactions can be explored as precur-
sors for the synthesis of a wide variety of new saturated heterocy-
cle-bridged ferrocene derivatives due to the presence of four non-
equivalent NH groups.
of C(sp3) (by >10 ppm) [9] the C-10 signal of the Fc moiety at-
tached to the vinyl group in 3 appears at 82.1 ppm, while this
line falls in the interval of 92.7–95.2 ppm for compounds 2a–c,
4,5, 7 and 8.
The OCH2 signal is downfield shifted (66.0 and 66.5 ppm) both
in 1H and 13C NMR spectra of 2c and 3 (for the PhCH2O groups) rel-
ative to the ethyl esters 2b, 4, 7, 8 and 9 (E and Z) (60.2–62.4 ppm).
The N(1)-substitution in 4 is revealed by the upfield shift of
NH(3) signal (to 5.74 ppm), probably due to the absence of H-
bonds which reduces the electron attracting property of the neigh-
bouring carbonyl group forming dimeric cyclic association with the
NH(1) group in the other compounds.
The symmetric (aromatic iminohydrine) form of 11 follows
from the identical shifts of C-4 and C-6 as well as of the C-10
(and all further) lines of both Fc substituents.
Similarly, the identical shifts of all H/C-signals of the two pyr-
imidone moieties and Cp rings, respectively, in 7 confirm the sym-
metric structure of this compound.
The structure of 8 is evidenced by the presence of the formyl H/
C signals in both the 1H and 13C NMR spectra (10.03 and
195.0 ppm).
The E and Z configurations, resp., of the isomers 9 are unambig-
uous because of the field effects [10] on C@O and CH3 lines of the
acetyl group in E and on ester C@O in Z isomer: 194.2 and
27.0 ppm for (E)-9, while 205.5 and 31.5 ppm for (Z)-9 and
164.9 ppm for (Z)-9, while 170.0 for (E)-9, respectively.
The structures of 12a–d are supported by the following facts:
3. Structure
The spectral data proving the postulated structures of the new
compounds are given in Tables 1A, B, 2A, B and 3. Only the follow-
ing additional remarks are necessary.
The formation of the dihydropyrimidone ring (Biginelli-prod-
uct) follows straightforwardly from the presence of a carbonyl line
in the 13C NMR spectra of compounds 2–5 and 7–9, from the chem-
ical shifts characteristic [9] for urethanes (153.9–154.9 ppm) and
(1) The signals of R1 group (e.g., the H/C signals of the phenyl
substituent in case of 12a, the OCH3 and CH3(Ac) signals
for 12b and 12d, respectively, and the signals of a second
ferrocenyl moiety for 12c and 12d) are present in the 1H
and 13C NMR spectra.
OH
N
N
CHO
COCH3
G
+
Fe
Fe
Fe
Fe
1
11 (38 %)
10
.
G: urea (1.5 equiv.), FeCl3 6H2O (0.1 equiv.), TMSCl (1 equiv.), MeCN, reflux: Ar, 24 h
Scheme 3.
O
yield (%)
R1
HN
a
b
c
d
Ph-
p-anisyl-
59
68
reflux:
15 h
O
HN
CHO
R1Ac /
H
8a
N
H
R1
ferrocenyl-
AcFc-
46
36
reflux:
24 h
H
HN
5
4
Fe
H
4a
H
H2NCONH2
Ac
Fe
CHO
AcFc-:
Fe
6
12a-d
.
H: R1Ac (2 equiv.), urea (3 equiv.), FeCl3 6H2O (0.2 equiv.), TMSCl (2 equiv.), MeCN, reflux
Scheme 4.

3670
A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
Table 1A
The most important 1H NMR dataa of compounds 2a–c, 3–5, 7, 8, (E)-9, (Z)-9 and 11.b
CH2 qae (2H)
H4e d (1H)
H-2,5 (2H or 2 ꢁ 1H)
H-3,4 (2H or 2 ꢁ 1H)
CHf
s (5H)
NH-1
br (1H)
NH-3
br (1H)
c
d
Compound
CH3 (Pos 6) s (3H)
CH3 t (3H)
Substituted c-pentane ring
2ag
2b
2cg
3
4
5
7
8
(E)-9
(Z)-9
11
2.19
2.15
2.25
–
2.45
2.13
2.16
2.26
2.22
2.23
–
–
1.23
–
–
1.34
–
1.23
1.32
5.05
4.95
ꢂ5.15h
5.07
5.16i
4.92
4.95
5.11
5.17
5.18
–
3.92, 4.10
3.94, 4.09
4.08, 4.14
4.35 (4H)
4.05
4.07, 4.08
4.05
4.18
4.18
4.17
4.14, 4.17
4.20
4.17
–
–
–
–
4.20
9.10
9.10
8.46
9.17
7.58
7.47
6.45
7.57
5.74
ꢂ 7.4
7.49
6.34
6.74
6.81
–
4.10
ꢂ5.15h
5.21
4.22
4.00, 4.07 (2H), 4.09
4.10 4.13
4.09, 4.24
–
3.95j, 4.10
4.05 (4H)j
9.00
9.09
8.29
7.68
7.66
–
ꢂ4.1h
4.19
ꢂ4.1h
ꢂ4.1h
4.30, 4.47, 4.80, 4.95
4.22h, 4.36, 4.58 (2H)k
4.23, 4.37, 4.49k, 4.54k
5.03 (4H)
4.16, 4.21, 4.67 (2H)
4.15, 4.16, 4.56 (2H)k
4.13, 4.14, 4.52 (2H)k
4.63 (4H)
1.34, 1.37
1.33, 1.35
–
4.21h, 4.40
4.21, 4.28
–
a
In DMSO-d6 or CDCl3 (for 4 and 8) solution, for 11 in CDCl3 + CD3OD at 500 MHz. Chemical shifts in ppm (dTMS = 0 ppm), coupling constants in Hz.
Assignments were supported by HMQC and HMBC (except for 2c, 5, 7 and 11), for 2a, c, d also by 2D-COSY measurements. Further signals, CH3(Ac), s (3H): 2.23 (2a), 2.38
b
[(E)-9], 2.42 [(Z)-9]; OCH3, s (3H): 3.37 (4), OH, br (1H): 11.95 (5), 7.39 (11), CHO, s (1H): 10.03 (8); @CH (
(3); H-5 s (1H): 6.53 (11).
a to Cp): 7.20, d, J: 16.4 (3), 7.46 s [(E)-9, (Z)-9], @CH (b to Cp): 7.35, d
c
Ethyl group, t (3H), J: 7.1, for 7 6.9 and for (Z)-9 7.3.
s (2c and 3).
d (J: 4.0 for 2a,b, 3, 5, 3.1 for 7 and 8, 3.6 for (E)-9, (Z)-9.
Unsubstituted Cp ring in ferrocene.
Contaminated: 0.5 mol CH2Cl2 (2a, d: 5.74 ppm) and H3BO3 (2c, d: 4.73 ppm).
Overlapping signals.
In overlap with the NCH2 signal (3H).
Interchangeable assignments.
d
e
f
g
h
i
j
k
With the CH@C(Ac)COOEt group substituted Cp ring.
Table 1B
The most important 1H NMR dataa of compounds 12a–d.b
Compound
H-4a d (1H)
H-5 s (1H)
H-4c d (1H)
H-2,5 (2H)
H-3,4 (2H)
CHd
NH-1
NH-3
Substituted c-pentane ring
s (5H)
br (1H)
br (1H)
12a
12b
12c
12d
2.77
2.74
2.34
2.35
3.64
3.69
3.97f
3.97
4.13
4.12e
4.04
4.03e
3.90, 4.47, 4.24, 4.60
3.92, 4.48, 4.23, 4.59
3.91, 4.47, 4.22, 4.44
3.89, 4.47, 4.22, 4.41fp
3.95, 4.03e, 4.04e, 4.12
3.95, 4.03e, 4.04e, 4.12e
3.95, 4.03e, 4.03e, 4.09
3.95, 4.03 e, 4.02e, 4.08
7.00, 6.81
7.04, 6.83
7.27, 6.95
7.22, 6.94
6.28, 6.56
6.25, 6.16
5.39, 6.50
5.38, 6.50
4.41
a
In DMSO-d6 solution at 500 MHz. Chemical shifts in ppm (dTMS = 0 ppm), coupling constants in Hz.
b
Assignments were supported by HMQC and HMBC measurements. Further signals, CH3(Ac), s (3H): 2.38 (12d), H(Fc-8a): 4.41d (12c), H25 (Fc-8a,subst. Cp in 12c): ꢂ4.3
(2H), 4.33 and 4.07; H(Cp attached to the skeleton in Pos. 8a, 12d), H2,5: 4.06, 4.30, H3,4: 4.32, 4.40f, H(Ac-subst.Cp, 12d): H2,5: 5.02, 5.06, H3,4: 4.80 (2H).
c
d (J: 10.7 for 12a,c and 10.4 for 12b).
Unsubstituted Cp ring in ferrocene.
Overlapping signals.
d, J: 3.
d
e
f
Table 2A
The most important 13C NMR chemical shiftsa of compounds 2a–c, 3–5, 7, 8 and (E)-9, (Z)-9.b,c
Compound CH3 (Pos.
6)
CH3 (Et) CH3
(Ac)
CH2 (R)
C@O(2) C-4
C-5
C-6
Cp d (Fc) C-10
C-20,50
C-30,40
C@O (R)
Pyrimidone ring
Substituted c-pentane ring
2a
2b
2c
3
19.7
18.5
18.8
–
–
15.2
–
31.3
–
153.9
153.9
154.5
154.3
49.4 112.5 147.7 69.4
49.6 101.7 148.3 69.3
50.3 102.0 147.6 68.8
49.8 101.8 137.2 69.4,
70.2
95.0
94.6
93.6
94.1,
82.1
92.7
94.6
94.8
95.2
94.8,
76.4
94.8,
76.6
66.3, 66.9
65.9, 66.8
65.5, 67.4
66.1, 66.5, 66.9,
67.8
65.5, 67.8
66.1, 66.8
66.9, 67.4
67.3, 68.8
67.8, 68.5, 71.4,
71.7
67.6, 68.0
67.8, 68.1
67.7, 68.0
194.9
166.4
166.0
–
–
–
60.2
66.0
66.5
–
68.0, 68.1, 68.8, 70.8 166.2
4
5
7
8
15.9
18.5
18.5
19.2
19.3
14.8
–
–
–
–
–
60.8
–
154.9
154.2
154.0
154.7
154.5
50.1 107.2 147.1 69.0
68.3, 68.5
68.0, 69.4e
68.8, 69.2
69.3, 70.1
69.1, 70.2, 73.18,
73.21
166.5
168.2f
166.4
166.1
166.2,
170.0
49.9 102.2 147.4 69.4e
15.1
14.8
14.5,
14.9
14.6,
14.8
60.2
60.6
60.5,
62.4
60.4,
61.6
101.4 148.5
50.1 120.8 146.7
49.7 103.0 146.6
–
–
–
g
g
(E)-9
27.0
(Z)-9
19.3
31.5
154.5
49.7 102.9 146.7
–
67.6, 68.5, 71.1,
72.0
69.0, 70.2, 72.9, 73.0 166.1,
164.9
a
In DMSO-d6 or CDCl3 (for 4 and 8) solution at 125 MHz. Chemical shifts in ppm (dTMS = 0 ppm).
Assignments were suppported by DEPT (except for 2c and 5), HMQC (except for 2c, 5 and 7) and HMBC (except for 2c, 3, 5 and 7).
b
c
Further lines: Olefinic @CH’s
a and b to Fc: 136.5 and 117.5 (3), 142.2 and 129.5 [(Z)-9], 142.9 and 130.6 [(E)-9]; NCH2: 74.0 (4); OCH3: 56.7 (4); C@O (formyl, 8): 195.0;
C-10, C-20,50 and C-30,40 for formyl substituted Cp: 79.9, 70.2 and 71.5, 74.3 and 74.4 (8); C@O(Ac): 194.2 (9E), 205.5 (9Z).
d
C-10-50 (unsubstituted Cp).
Overlapping lines.
Carboxyl group.
e
f
g
The data in the first row refer to the pyrimidone substituted Cp ring, in the second row to the side chain [(E)-9, (Z)-9].

A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
3671
Table 2B
The most important 13C NMR chemical shifts of compounds 11 and 12a–d.b,c
a
Compound
CH3 (Ac)
CH2 (R)
C@O(2)
C-4
C-5
C-6
Cpd (Fc)
C-10
C-20,50
C-30,40
72.5
68.1, 70.3, 69.3, 70.8
68.1, 70.3, 69.3, 70.8
68.1, 70.4, 69.3, 70.8
68.05, 69.4, 67.6, 70.89
Pyrimidone ring
Substituted c-pentane ringe
11
–
–
–
–
–
–
–
–
–
159.0
146.2f
98.3
52.9
53.1
53.9
53.5
146.2f
71.6
71.2
67.3
67.3
70.8
–
–
69.5
–
68.7
12a
12b
12c
12d
154.7, 155.7
154.8, 155.8
154.0, 155.4
154.0, 155.2
46.2, 46.3
46.2, 46.3
46.4, 46.5
46.3, 46.5
86.6, 84.8
86.6, 84.9
86.8, 84.7
86.6, 84.6
66.3, 69.1, 67.9, 72.2
66.3, 69.1, 67.8, 72.2
66.3, 69.2, 67.7, 72.2
66.3, 69.2, 67.6, 72.2
28.4
a
In DMSO-d6 solution, for 11 in CDCl3 + CD3OD at 125 MHz. Chemical shifts in ppm (dTMS = 0 ppm).
Assignments were supported by DEPT (except for 11), HMQC and HMBC (except for 11).
b
c
Further lines: OCH3: 56.1 (12b); C-10, C-20,50 and C-30,40 for Cp in Pos. 8a (12c,d): 97.9, 68.4 and 68.7, 65.9 and 70.1 (12c, Cp attached to the HC), 99.1, 68.11 and 69.6, 70.5
and 72.1 (12d, Cp attached to the HC), 80.7, 70.85 and 71.4, 73.8e (12d, Ac-substituted. Cp).
d
C-10-50 (unsubstituted Cp).
The data in the first row refer to the Cp ring attached to C-4, in the second row to C-5.
Because of molecular symmetry C-4 and C-6 have common lines in 11.
e
f
Table 3
The most important characteristic IR frequencies [cmꢃ1] of compounds 2a–c, 3–5, 7, 8, (E)-9, (Z)-9, 11 and 12a d (in KBr discs).*
Compound
m
NH band broad or diffuse (df)
m
C@O (ester)
Amide-I banda
mC@O ketone or aldehyde
masCp–Fe–Cp and tilt of Cp
2a
2b
2c
3
4
5
7
8
(E)-9
(Z)-9
11
12a
12b
12c
12d
3500–2500 df
3500–2500 df
3250, 3110
3419, 3235, 3090
3320, 3226
3600–2700 df
3240, 3110
3248, 3113
–
1609
1647
1685
1687
1691
1656
1648
1644
1653
1651
–
1701
–
–
–
–
–
–
1684
1688
1701b
–
–
–
497
489
498, 486
485
504
499, 484
488
526, 495, 485
482
1702
1710
–
1706
1684
1702
1701
1699
1701b
–
3375, 3235
3250, 3115
522
3350–2600 df
3405, 3215, 3085
3500–2800 df
3415, 3310, 3220
3500–2700 df
502, 483
524, 509
522
523, 513, 489
525
–
–
1689
1681
1670
1670b
–
–
1670b
*
Further bands,
m
C@N-type aromtic skeletal band (11): 1622, mC@C band: 1645 (2c), 1624 (5), 1611 (9Z), m :cCArH and cCArCAr
C@O: 1–3 bands between 1029 and 1242 cmꢃ1
bands: 757 and 697 (2c), 762 and 700 (12a).
a
Splitted band, with the second maximum at 1662 (12b).
Overlapped maxima.
b
(2) The chemically non-equivalent H/C pairs in positions 2,5 and
3,4 in both Cp rings of the skeleton give separated signals in
contrast to 7, where the two not condensed pyrimidone moi-
eties give chemically equivalent signals with doubled
intensity.
[14a,15a] HMQC [14b,15b] and HMBC [16,17] spectra were ob-
tained by using the standard Bruker pulse programs.
4.1. Three-component condensations of formylferrocene (1) by Method
A
(3) The H/C signals of three C(sp3)H groups (in positions 4, 4a
and 5) and the signal of a saturated quaternary carbon (C-
8a) are observable in the 1H and 13C NMR spectra.
(4) The high value (>10.5 Hz) of the H-4,H-4a vicinal coupling
refers to a diaxial interaction [11] and a small H-4a,H-5 cou-
pling proves ca. 60° dihedral angle of the latter H’s in accord
with their axial–equatorial interaction giving unambiguous
support to the cis-annealation of the two saturated pyrimi-
dine rings.
A solution of 1 (0.642 g, 3 mmol), 1,3-dicarbonyl compound
(3 mmol), urea (0.216 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 1 h. After the reaction mixture was cooled to r.t. and
was poured into ice-water (50 mL). The precipitated solid was fil-
tered, washed with ice-water, dried and subjected to flash column
chromatography on silica using DCM–eOH (80:1) as eluent to ob-
tain the products which were recrystallized from EtOH.
4.2. 5-Acetyl 3,4-dihydro-4-ferrocenyl-6-methylpyrimidin-2(1H)-one
(2a)
4. Experimental
Yellow microcrystals; yield: 0.842 g, 83%; mp 243–245 °C (de-
comp.); Anal. Calc. for C17H18FeN2O2 (338.18): C, 60.38; H, 5.36;
N, 8.28. Found: C, 60.50; H, 5.54; N, 8.16%.
Melting points were determined with a Boethius microstage and
are uncorrected. The IR spectra were run in KBr discs 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
4.3. Ethyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-methyl-2-oxopyrimidine-
5-carboxylate (2b)
(
13C) MHz, with the deuterium signal of the solvent as the lock and
TMS as internal standard. DEPT spectra [12] were run in a standard
manner [13] using only a = 135° pulse to separate the CH/CH3
and CH2 lines phased ‘‘up” and ‘‘down”, respectively. The 2D-COSY
Yellow powder; yield: 0.850 g, 77%; mp 227–230 °C (decomp.)
(229–231 °C [6]); Anal. Calc. for C18H20FeN2O3 (368.21): C, 58.71;
H, 5.47; N, 7.61. Found: C, 58.56; H, 5.54; N, 7.72%.
H

3672
A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
4.4. Benzyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-methyl-2-
4.10. 1,10-Bis-(1,2,3,4-tetrahydro-5-ethoxycarbonyl-6-methyl-2-
oxopyrimidine-5-carboxylate (2c)
oxopyrimidine-4-yl)ferrocene (7)
Yellow powder; yield: 0.636 g, 51%; mp 285–288 °C (decomp.);
Anal. Calc. for C22H20FeN2O3 (416.25): C, 63.48; H, 4.84; N, 6.73.
Found: C, 63.40; H, 4.91; N, 6.65%.
Yellow powder; yield: 0.462 g, 42% (by Method E) and 0.771 g,
70% (by Method F); mp > 310 °C; Anal. Calc. for C26H30FeN4O6
(550.38): C, 56.74; H, 5.49; N, 10.18. Found: C, 56.62; H, 5.42; N,
10.32%.
4.5. Benzyl 1,2,3,4-tetrahydro-4-ferrocenyl-6-(2-ferrocenylvinyl)-2-
oxopyrimidine-5-carboxylate (3)
4.11. Ethyl 1,2,3,4-tetrahydro-4-(10-formylferrocenyl)-6-methyl-2-
oxopyrimidine-5-carboxylate (8)
Orange needles; yield: 0.338 g, 18%; mp 234–238 °C(decomp.);
Anal. Calc. for C34H30Fe2N2O3 (626.30): C, 65.20; H, 4.83; N, 4.47.
Found: C, 65.32; H, 4.95; N, 4.55%.
Orange powder; yield: 0.079 g, 10% (by Method E) and 0.032 g,
4% (by Method F); mp 260–264 °C (decomp.); Anal. Calc. for
C19H20FeN2O4 (396.22): C, 57.60; H, 5.09; N, 7.07. Found: C,
57.72; H, 5.12; N, 7.18%.
4.6. Aldol condensation of 2c with 1 by Method B
A solution of 2c (0.416 g, 1 mmol), 1 (0.214 g, 1 mmol) and
H3BO3 (0.013 g, 0.2 mmol) in glacial acetic acid (4 mL) was heated
under Ar at 100 °C, while stirring for 4 h. The reaction mixture was
cooled to r.t. and was poured into ice-water (20 mL). The precipi-
tated yellowish-grey solid was filtered, washed with ice-water,
dried and purified by flash column chromatography on silica using
DCM–MeOH (80:1) as eluent to separate the tarry substances from
3 which was recrystallized from EtOH. Yield: 0.463 g, 74%. Within
experimental error the analytical and spectral data were identical
with those listed under Method A.
4.12. Ethyl 4-(10-((Z)-2-(ethoxycarbonyl)-3-oxobut-1-enyl)ferroceny-
l)-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate ((Z)-
9)
Red powder; yield: 0.183 g, 18% (by Method E) and 0.102 g, 10%
(by Method F); mp 252–256 °C (decomp.); Anal. Calc. for C25H28Fe-
N2O6 (508.34): C, 59.07; H, 5.55; N, 5.51. Found: C, 58.96; H, 5.72;
N, 5.59%.
4.13. Ethyl 4-(10-((E)-2-(ethoxycarbonyl)-3-oxobut-1-enyl)ferrocenyl)
-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylate ((E)-9)
4.7. Attempted hydrolysis of 2b: formation of ethyl 1,2,3,4-tetrahydro-
4-ferrocenyl-1-(methoxymethyl)-6-methyl-2-oxopyrimidine-5-carbo-
xylate (4) (Method C)
Red powder; yield: 0.122 g, 12% (by Method E) and 0.071 g, 7%
(by Method F); mp 274–278 °C (decomp.); Anal. Calc. for C25H28Fe-
N2O6 (508.34): C, 59.07; H, 5.55; N, 5.51. Found: C, 59.21; H, 5.60;
N, 5.67%.
To the suspension made of 2b (0.736 g, 2 mmol) and DCM
(40 mL) 1 M methanolic solution of Bu4NOH (2 mL) was added un-
der Ar. The reaction mixture was stirred at r.t. under Ar for 5 h and
extracted with water (3 ꢁ 50 mL). The organic phase was dried
(Na2SO4) and evaporated. The solid residue was recrystallized from
EtOH to obtain 4 as yellow microcrystals. Yield: 0.700 g, 85%; mp
184–187 °C; Anal. Calc. for C20H24FeN2O4 (412.26): C, 58.27; H,
5.87; N, 6.80. Found: C, 58.45; H, 5.65; N, 6.64%.
4.14. Iron(III)-mediated condensation of formylferrocene (1), acetylfe-
rrocene (10) and urea: preparation of 4,6-diferrocenylpyrimidin-2-ol
(11) by Method G
Under Ar urea (0182 g, 3 mmol), 10 (0.456 g, 2 mmol) and
TMSCl (0.218 g, 2 mmol) were added successively to a solution of
1 (0.428 g, 2 mmol) and FeCl3ꢀ6H2O (0.054 g, 0.2 mmol) in MeCN
(6 mL). The reaction mixture was refluxed for 24 h under Ar then
cooled to r.t. and quenched with water (40 mL). The precipitated
dark solid was filtered off, dried and purified by flash column chro-
matography on silica using n-hexane–EtOAc (3:1) as eluent to ob-
tain 11 separated from tarry substances. The solid product was
recrystallized from EtOH affording deep red microcrystals. Yield:
0.353 g, 38%; mp 297–300 °C (decomp.); Anal. Calc. for C24H20Fe2-
N2O (464.12): C, 62.11; H, 4.34; N, 6.04. Found: C, 62.21; H, 4.21;
N, 5.97%.
4.8. 1,2,3,4-Tetrahydro-4-ferrocenyl-6-(2-ferrocenylvinyl)-2-oxopyri-
midine-5-carboxylic acid (5) (Method D)
In the solution of 2c (0.416 g, 1 mmol) in the mixture of EtOAc–
AcOH (24–8 mL) Pd/C (0.2 g) was suspended. The mixture was
hydrogenated at atmospheric pressure for 1 h and the catalyst
was removed by filtration. The yellow solution was evaporated
and the residue was recrystallized from EtOH to obtain 5 as yellow
powder. Yield: 0.323 g, 95%; mp 295–298 °C (decomp.); Anal. Calc.
for C16H16FeN2O3 (340.15): C, 56.50; H, 4.74; N, 8.24. Found: C,
56.65; H, 4.83; N, 8.27%.
4.9. Three-component condensations of 1,10-diformylferrocene (6) by
Methods E and F
4.15. Iron(III)-mediated condensations of 1,10-diformylferrocene (6),
methyl-ketones and urea Method H
A solution of 6 (0.484 g, 2 mmol), ethyl acetoacetate (0.520 g,
4 mmol), urea (0.290 g, 4.8 mmol by Method E and 0.480 g, 8 mmol
by Method F, resp.) and H3BO3 (0.025 g, 0.4 mmol) in glacial acetic
acid (20 mL) was heated under Ar at 100 °C, while stirring (for 4 h
by Method E and for 6 h by Method F, respectively).After the reac-
tion mixture was cooled to r.t. and was poured into ice-water
(100 mL). The precipitated solid was filtered, washed with ice-
water, dried and subjected to flash column chromatography on sil-
ica using DCM–MeOH (50:1) as eluent to obtain the products
which were recrystallized from EtOH.
Under Ar urea (0364 g, 6 mmol), the corresponding ketone
(4 mmol) and TMSCl (0.436 g, 4 mmol) were added successively
to a solution of 6 (0.484 g, 2 mmol) and FeCl3ꢀ6H2O (0.108 g,
0.4 mmol) in MeCN (10 mL). The reaction mixture was refluxed
for the time given in Scheme 4 then cooled to r.t. and quenched
with water (70 mL). The precipitated dark solid was filtered
off, dried and purified by flash column chromatography
(silica DCM–MeOH (25:1)) and subsequent crystallization from
EtOH.

A. Csámpai et al. / Journal of Organometallic Chemistry 694 (2009) 3667–3673
3673
4.16. (4R*,4aS*,5R*,8aS*)-Hexahydro-4,5-(ferrocene-1,10-diyl)-8a-
phenylpyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione (12a)
[2] (a) J.S. Yadav, B.V.S. Reedy, R. Srinivas, C. Venugopal, T. Ramalingam, Synthesis
(2001) 1341;
(b) A.K. Kumar, M. Kasturaiah, S.C. Reedy, C.D. Reddy, Tetrahedron Lett. 42
(2001) 7873;
(c) J. Peng, Y.Q. Deng, Tetrahedron Lett. 42 (2001) 5917;
(d) N. Fu, Y. Yuan, Z. Cao, S. Wang, J. Wang, C. Peppe, Tetrahedron 58 (2002)
4801;
(e) M. Xia, Y. Wang, Tetrahedron Lett. 43 (2002) 7703;
(f) K.R. Reddy, C.V. Reddy, M. Mahesh, P.V.K. Raju, V.V.N. Reddy, Tetrahedron
Lett. 44 (2003) 8173;
(g) G. Maiti, P. Kundu, C. Guin, Tetrahedron Lett. 44 (2003) 2757;
(h) R. Varala, M.M. Alam, S.R. Adapa, Synlett (2003) 67;
(i) A. Dondoni, A. Massi, E. Minghini, S. Sabbatini, V. Bertolasi, J. Org. Chem. 68
(2003) 6172.
Yellow powder; 0.505 g, 59%; mp 299–302 °C (decomp); Anal.
Calc. for C22H20FeN4O2 (428.26): C, 61.70; H, 4.71; N, 13.08. Found:
C, 61.79; H, 4.64; N, 13.19%.
4.17. (4R*,4aS*,5R*,8aS*)-Hexahydro-4,5-(ferrocene-1,10-diyl)-8a-(4-
methoxy-phenyl)pyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione (12b)
Yellow powder; 0.623 g, 68%; mp > 310 °C; Anal. Calc. for
C23H22FeN4O2 (458.29): C, 60.28; H, 4.84; N, 12.23. Found: C,
60.22; H, 4.69; N, 12.16%.
[3] M.S. Manhas, S.N. Ganguly, S . Mukherjee, A.K. Jain, A.K. Bose, Tetrahedron Lett.
47 (2006) 2423.
[4] H.A. Stefani, C.B. Oliveira, R.B. Almeida, C.M.P. Pereira, R.C. Braga, R. Cella, V.C.
Borges, L. Savegnago, C.W. Nogueira, Eur. J. Med. Chem. 41 (2006) 513.
[5] (a) S. Top, A. Vessiéres, C. Cabestaing, I. Laios, G. Leclerq, C. Provot, G. Jaouen, J.
Organomet. Chem. 637–639 (2001) 500;
4.18. (4R*,4aS*,5R*,8aS*)-Hexahydro-4,5-(ferrocene-1,10-diyl)-8a-
ferrocenylpyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione (12c)
(b) 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;
(c) B. Weber, A. Serafin, J. Michie, C. Van Rensburg, J.C. Swarts, L. Bohm,
Anticancer Res. 24 (2B) (2004) 763;
(d) G. Jaouen, S. Top, A. Vessieres, G. Leclercq, M.J. McGlinchey, Curr. Med.
Chem. 11 (2004) 2505;
Yellow powder; 0.493 g, 46%; mp > 310 °C; Anal. Calc. for
C26H24Fe2N4O2 (536.18): C, 58.24; H, 4.51; N, 10.45. Found: C,
58.41; H, 4.60; N, 10.37%.
(e) E. Hillard, A. Vessieres, L. Thouin, G. Jaouen, C. Amatore, Angew. Chem., Int.
Ed. 45 (2006) 285.
4.19. (4R*,4aS*,5R*,8aS*)-Hexahydro-4,5-(ferrocene-1,10-diyl)-8a-(10-
acetylferro-cenyl)pyrimido[4,5-d]pyrimidine-2,7(1H,3H)-dione (12d)
[6] N.-Y. Fu, Y.-F. Yuan, M.-L. Pang, J.-T. Wang, C. Peppe, J. Organomet. Chem. 672
(2003) 52–57.
[7] S. Tu, F. Fang, C. Miao, H. Jiang, Y. Feng, D. Shi, X. Wang, Tetrahedron Lett. 44
(2003) 6153.
[8] Z.-T. Wang, L.-W. Xu, C.-G. Xia, H.-Q. Wang, Tetrahedron Lett. 45 (2004) 7951.
[9] (a) E. Pretsch, T. Clerc, J. Seibl, N. Simon, Tabellen zur Strukturaufklärung
organischer Verbindungen mit spektroskopischen Methoden, Springer Verlag,
Berlin, 1976. p. C 185.
Orange powder; 0.416 g, 36%; mp > 310 °C; Anal. Calc. for
C28H26Fe2N4O2 (578.22): C, 58.16; H, 4.53; N, 9.69. Found: C,
58.02; H, 4.64; N, 9.59%.
[10] P. Sohár, Nuclear Magnetic Resonance Spectroscopy, vol. 2, CRC Press, Boca
Raton, FL, 1983. pp. 164–166.
[11] M. Karplus, J. Chem. Phys. 30 (1959) 11;
Acknowledgements
M. Karplus, J. Chem. Phys. 33 (1960) 1842.
This work was supported by the Hungarian Scientific Research
Fund (OTKA T-043634). The authors are indebted to Dr. Hedvig
Medzihradszky-Schweiger for analyses.
[12] D.T. Pegg, D.M. Doddrell, M.R. Bendall, J. Chem. Phys. 77 (1982) 2745.
[13] M.R. Bendall, D.M. Doddrell, D.T. Pegg, W.E. Hull, High Resolution Multipulse
NMR Spectrum Editing and DEPT, Bruker, Karlsruhe, 1982.
[14] (a) R.R. Ernst, G. Bodenhausen, A. Wokaun, Principles of Nuclear Magnetic
Resonance in One and Two Dimensions, Clarendon Press, Oxford, UK, 1987. pp.
400–448;
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