Indium(III) halides-catalyzed preparation of ferrocene-dihydropyrimidinones

Article abstract of DOI:10.1016/S0022-328X(03)00139-6

Indium(III) halides (chloride and bromide) catalyse the three-component Biginelli coupling of ferrocenyl-1,3-diketones, aldehydes and urea (or thiourea) to give 5-ferrocenoyl-3,4-dihydropyrimidinones. 4-Ferrocenyl-3,4-dihydropyrimidinones were obtained fr

Full text of DOI:10.1016/S0022-328X(03)00139-6

Journal of Organometallic Chemistry 672 (2003) 52Á57
/
www.elsevier.com/locate/jorganchem
Indium(III) halides-catalyzed preparation of ferrocene-
dihydropyrimidinones
Nan-Yan Fu a, Yao-Feng Yuan a, Mei-Li Pang a, Ji-Tao Wang a, Clovis Peppe b,*
a Department of Chemistry, State Key Laboratory for Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
b Departamento de Qu´ımica, Laborato´rio de Materiais Inorgaˆnicos, Universidade Federal de Santa Maria, Santa Maria 97105-900, RS, Brazil
Received 31 January 2003; received in revised form 24 February 2003; accepted 24 February 2003
Abstract
Indium(III) halides (chloride and bromide) catalyse the three-component Biginelli coupling of ferrocenyl-1,3-diketones, aldehydes
and urea (or thiourea) to give 5-ferrocenoyl-3,4-dihydropyrimidinones. 4-Ferrocenyl-3,4-dihydropyrimidinones were obtained from
alkyl-acetoacetates, formylferrocene and urea. The tricyclic compound, 13-ferrocenecarbonyl-9-methyl-11-oxo-8-oxa-10,12-
diazatricyclo [7.3.1.02,7]trideca-2,4-6-triene, was synthesized from 1-ferrocenyl-1,3-butanedione, salicilaldehyde and urea.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Indium(III) halides; Biginelli coupling; Ferrocene-dihydropyrimidinones
1. Introduction
Dihydropyrimidinones (DHPMs) are substances de-
rived from the condensation of b-keto-esters, aldehydes
and urea (Eq. (1)). They were firstly prepared by
Biginelli more than one century ago [15]. Recently, the
DHPMs have attracted considerable attention, mainly
because of their use as calcium channel modulators,
anti-cancer and anti-HIV activity [16]. The original
protocol for the DHPMs synthesis consisted of heating
the three-component mixture in ethanol containing HCl
as catalyst. The efficiency of the synthesis was improved
The use of ferrocene as an equivalent to phenyl
groups in organic synthesis is employed when is desired
a low toxic and stable three-dimensional bulky metal
containing substituent capable of acting as an electro-
chemical probe for electron transfer processes [1,2].
Recently, there is a growing interest in the preparation
of ferrocene-substituted heterocycles to use them as
functionalised ligands and for biological purposes [3Á
/
11]. In fact, some of these compounds have been
employed as electrochemical sensors to study redox
by several Lewis acid catalysts, such as BF3×
/
OEt2, FeCl3
and HCl, LaCl3×
/
7H2O, ytterbium triflate.
processes through DNA structures [12Á
/
14].
Recently, we have demonstrated that indium triha-
(1)
lides, InY3 (YꢀCl, Br) are superior catalysts for the
Biginelli reaction (Eq. (1)) [17], and as a consequence of
this finding, we describe here the preparation of some
/
* Corresponding author. Tel.: ꢁ
031.
E-mail address: peppe@quimica.ufsm.br (C. Peppe).
/
55-55-2208-868; fax: ꢁ55-55-2208-
/
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00139-6

N.-Y. Fu et al. / Journal of Organometallic Chemistry 672 (2003) 52Á
/57
53
ferrocene-dihydropyrimidinones catalyzed by indium
trihalides.
2.3. General experimental procedure for preparation of
ferrocene-dihydropyrimidinones (1Á9) and the
diazatricyclic compound (10) (see Table 1)
/
A solution of 2 mmol of the diketone (or alkyl
acetoacetate), 2 mmol of the aldehyde, 2.6 mmol of
urea (or thiourea) and 0.2 mmol (10 mol%) of InBr3 (or
2. Experimental
InCl3×
/
4H2O) in ethanol-95% (10 ml) was stirred at room
temperature (r.t.) for 4 h, then heated under reflux for
the required time (Table 1). On cooling, the product
spontaneously crystallises from the solution. The solid
was filtered, washed with ethanol and dried under
vacuo. The yields in Table 1 refer to isolated analytically
pure compounds. Purity criteria were melting tempera-
tures, molecular formulae are based on microanalysis
and mass spectrometry and structural assignments based
on 1H-NMR spectroscopy and cyclic voltammetry.
2.1. General
Indium(III) bromide was prepared by passing a flow
of bromine gas through melted indium. Formylferro-
cene [18], 1-ferroceny-1,3-butanedione [19] and 1-ferro-
cenyl-3-phenyl-1,3-propanedione [20] were prepared
according to literature. InCl3×
/
4H2O, urea, thiourea
and aldehydes were commercial products. All liquid
reagents were distilled and all solid reagents were
recrystalized before use. Melting points were determined
Analytical and spectroscopic data for compounds 1Á
/
10 are as follow:
1
on a glass disk and are uncorrected. H-NMR spectra
2.3.1. 5-Ferrocenylcarbonyl-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one (1)
were recorded in DMSO-d6 solutions on a BRUKER
AC-P-200 spectrometer with TMS as internal standard.
IR spectra (KBr plates) were obtained on a Bio-Rad
FTS-135 spectrometer. Mass spectra were determined
under EI (70 eV) on a VG-ZAB-HS spectrometer.
Elemental analyses were carried out on a CHN-COR-
DERM 7-3 automated analyser.
1
M.p. 262Á
/
268 8C (dec.); H-NMR: dꢀ
/
8.86 (s, 1H,
7.28 (m, 5H, C6H5), 5.41
4.52 (m, 4H, FcÁH), 3.79 (s, 5H, FcÁ
NH), 7.64 (s, 1H, NH), 7.38Á
/
(s, 1H, CH), 4.75Á
/
/
/
H), 1.83 (s, 3H, CH3); IR (KBr): 3200, 3010, 1674, 1642,
1599 cmꢂ1; MS (70 eV, EI): m/z (%): 400 (M, 12), 44
(100). Anal. Calc. for C22H20O2N2Fe: C, 66.03, H, 5.04,
N, 7.00. Found: C, 66.13, H, 4.99, N, 7.05%.
2.3.2. 5-Ferrocenylcarbonyl-6-methyl-4-(4-
methylphenyl)-3,4-dihydropyrimidin-2(1H)-one (2)
2.2. Electrochemical measurements
1
M.p. 157Á
/
160 8C (dec.); H-NMR: dꢀ
/
8.79 (s, 1H,
7.16 (m, 4H, C6H4), 5.38
4.40 (m, 4H, FcÁH), 3.83 (s, 5H, FcÁ
CH3), 1.83 (s, 3H, CH3); IR (KBr):
Cyclic voltammograms were obtained from a BAS-
100 B electrochemical analyzer (Purdue Research Park,
West Lafayette, IN) equipped with a three-electrode
assembly. The solutions were 0.1 mol lꢂ1, in DMF
containing n-Bu4NPF4 as supporting electrolyte. Amine
free DMF was obtained by drying an analytical grade
NH), 7.57 (s, 1H, NH), 7.22Á
(s, 1H, CH), 4.74Á
H), 2.26 (s, 3H, PhÁ
/
/
/
/
/
3435, 3238, 3111, 1697, 1657, 1613 cmꢂ1; MS (70 eV,
EI): m/z (%): 414 (M, 100), 330 (74). Anal. Calc. for
C23H22O2N2Fe: C, 66.69, H, 5.35, N, 6.76. Found: C,
66.41, H, 5.27, N, 6.89%.
˚
sample over Linde type 4-A molecular sieves for 72 h
and distilled at reduced pressure under N2, minutes
before use. The working electrode was a platinum disk
2.3.3. 4-(4-Chlorophenyl)-5-ferrocenylcarbonyl-6-
methyl-3,4-dihydropyrimidin-2(1H)-one (3)
of Fꢀ200 mm in diameter embedded in a cobalt glass
/
seal and it was polished consecutively with polishing
alumina and diamond suspensions (supplied by BAS as
a kit), rinsed with ethanol and dried in air before each
run. The reference electrode was a KCl saturated
calomel electrode (SCE). A platinum wire (BAS) was
used as a counter electrode. The solutions were satu-
rated and blanketed with N2 before the first scan.
Measurements were made at 20 8C. The voltammo-
1
M.p. 242Á
/
245 8C (dec.); H-NMR: dꢀ
/
8.85 (s, 1H,
7.33 (m, 4H, C6H4), 5.40 (s,
4.42 (m, 4H, FcÁH), 3.84 (s, 5H, FcÁH),
NH), 7.66 (s, 1H, NH), 7.43Á
/
1H, CH), 4.74Á
/
/
/
1.82 (s, 3H, CH3); IR (KBr): 3434, 3240, 3111, 1694, 1657,
1613 cmꢂ1; MS (70 eV, EI): m/z (%): 434 (M, 67), 350
(10), 28 (100). Anal. Calc. for C22H19O2N2ClFe: C, 60.79,
H, 4.41, N, 6.44. Found: C, 60.91, H, 4.26, N, 6.58%.
grams were scanned over the potential range 0Á1.0 V
(positive potential direction in forward mode) at 200 mV
sꢂ1. The redox potentials (E1/2 values) were reproduci-
/
2.3.4. 5-Ferrocenylcarbonyl-6-methyl-4-(4-nitrophenyl)-
3,4-dihydropyrimidin-2(1H)-one (4)
1
M.p. 238Á
/
242 8C (dec.); H-NMR: dꢀ
/
9.07 (s, 1H,
7.61 (m, 4H, C6H4), 5.53
4.46 (m, 4H, FcÁH), 3.87 (s, 5H, FcÁ
ble to 9
ing an inherent error of 5Á
/
10 mV, ]
/
5 mV for consecutive scans suggest-
10 mV.
NH), 7.84 (s, 1H, NH), 8.30Á
/
/
(s, 1H, CH), 4.77Á
/
/
/

54
N.-Y. Fu et al. / Journal of Organometallic Chemistry 672 (2003) 52Á57
/
Table 1
Indium(III) halides-catalyzed preparation of ferrocene-dihydropyrimidinones
DHPM
R1
R2
R3
Ph
X
Time (h)
Yield a (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Ph
Fc b
Fc
O
O
O
O
S
14
36, 14
36
86c
p-CH3 Á
p-ClÁC6H4
p-NO2 ÁC6H4
Ph
Ph
Fc
Fc
Fc
/
C6H4
73 c, 82 d
62 c
Fc
Fc
/
/
36
12
70 d
Fc
Fc
96 c
O
O
O
S
36
42 c
Me
Me
Me
OEt
OMe
OEt
7, 7
6
86 c, 69 d
68 d
10
79 d
a
Isolated yield.
C5H4FeC5H5.
10 mol% of InBr3.
b
c
d
10 mol% of InCl3×4 H2O under N2 atmosphere.
/
H), 1.86 (s, 3H, CH3); IR (KBr): 3396, 3237, 3109, 1699,
1652, 1609 cmꢂ1; MS (70 eV, EI): m/z (%): 445 (M, 8),
121 (57), 28 (100). Anal. Calc. for C22H19O4N3Fe: C,
59.35, H, 4.30, N, 9.43. Found: C, 59.47, H, 4.41, N,
9.35%.
2.3.5. 5-Ferrocenylcarbonyl-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-thione (5)
1
M.p. 233Á
/
237 8C (dec.); H-NMR: dꢀ
/
9.48 (s, 1H,
7.35 (m, 5H, C6H5), 5.49
4.48 (m, 4H, FcÁH), 3.84 (s, 5H, FcÁ
NH), 7.46 (s, 1H, NH), 7.38Á
/
(s, 1H, CH), 4.80Á
/
/
/
Scheme 1.

N.-Y. Fu et al. / Journal of Organometallic Chemistry 672 (2003) 52Á
/57
55
H), 1.89 (s, 3H, CH3); IR (KBr): 3298, 3182, 3111, 3014,
1657, 1614, 1579, 1473, 1449 cmꢂ1; MS (70 eV, EI): m/z
(%): 416 (M, 44), 352 (5), 317 (9), 213 (7), 121 (13), 31
(100). Anal. Calc. for C22H20ON2FeS: C, 63.49, H, 4.84,
N, 6.73. Found: C, 63.21, H, 4.77, N, 6.65%.
2.3.9. 5-Ethoxycarbonyl-4-ferrocenyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-thione (9)
1
M.p. 215Á
/
219 8C (dec.); H-NMR: dꢀ/10.37 (s, 1H,
NH), 9.41 (s, 1H, NH), 4.92 (s, 1H, CH), 4.25 (s, 5H,
FcÁH), 4.15Á3.92 (m, 6H, FcÁH, OCH2CH3), 2.20 (s,
3H, CH3), 1.23 (t, Jꢀ7.1Hz, 3H, OCH2CH3); IR (KBr):
/
/
/
/
3422, 3323, 3161, 3094, 1672, 1570, 1454 cmꢂ1; MS (70
eV, EI): m/z (%): 384 (M, 100), 350 (14), 186 (19), 121
(19). Anal. Calc. for C18H20O2N2FeS: C, 56.28, H, 5.25,
N, 7.29. Found: C, 56.37, H, 5.33, N, 7.18%.
2.3.6. 5-Ferrocenylcarbonyl-4,6-diphenyl-3,4-
dihydropyrimidin-2(1H)-one (6)
1
M.p. 217Á
/
223 8C (dec.); H-NMR: dꢀ
/
9.07 (s, 1H,
7.18 (s, 10H, two C6H5),
4.09 (m, 4H, FcÁH), 3.72 (s, 5H,
H); IR (KBr): 3436, 3211, 3103, 1932, 1681, 1640,
NH), 7.80 (s, 1H, NH), 7.49Á
5.34 (s, 1H, CH), 4.31Á
FcÁ
/
2.3.10. 13-Ferrocenylcarbonyl-9-methyl-11-oxo-8-oxa-
10,12-diazatricyclo [7.3.1.02,7] trideca-2,4,6-triene (10)
/
/
/
1
1611, 1444 cmꢂ1; MS (70 eV, EI): m/z (%): 462 (M,
100), 396 (21), 332 (12), 247 (19), 186 (12), 121 (22).
Anal. Calc. for C27H22O2N2Fe: C, 70.15, H, 4.80, N,
6.06. Found: C, 70.32, H, 4.89, N, 6.11%.
M.p. 250Á
/
254 8C; H-NMR: dꢀ
/
7.55 (s, 1H, NH),
6.81 (m, 4H, C6H4), 4.90Á4.47
4.28 (m, 5H, FcÁH), 3.74 (s, 1H,
CH), 3.32 (s, 1H, CH), 1.72 (s, 3H, CH3); IR (KBr):
3434, 3254, 3090, 1689, 1667, 1588, 1495, 1452 cmꢂ1
7.01 (s, 1H, NH), 7.25Á
/
/
(m, 4H, FcÁH), 4.32Á
/
/
/
;
MS (70 eV, EI): m/z (%): 416 (M, 100), 308 (7), 229 (14),
213 (68), 121 (34). Anal. Calc. for C22H20O3N2Fe: C,
63.49; H, 4.84; N, 6.73. Found: C, 63.61; H, 4.77; N,
6.76%.
2.3.7. 5-Ethoxycarbonyl-4-ferrocenyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (7)
1
M.p. 229Á
/
233 8C (dec.); H-NMR: dꢀ
/
9.11 (s, 1H,
NH), 7.49 (s, 1H, NH), 4.94 (s, 1H, CH), 4.18 (s, 5H,
FcÁH), 4.12Á3.94 (m, 6H, FcÁH, OCH2CH3), 2.15 (s,
3H, CH3), 1.23 (t, Jꢀ7.1Hz, 3H, OCH2CH3); IR (KBr):
/
/
/
3. Results and discussion
/
3365, 3252, 3117, 1704, 1647, 1457 cmꢂ1; MS (70 eV,
EI): m/z (%): 368 (M, 100), 258 (52), 186 (38), 121 (22).
Anal. Calc. for C18H20O3N2Fe: C, 58.72, H, 5.48, N,
7.61. Found: C, 58.53, H, 5.25, N, 7.81%.
3.1. Preparative, analytical and spectroscopic studies
A variety of ferrocene-containing DHPMs were
synthesized in good to excellent yields (Table 1), from
a Biginelli reaction catalysed by InBr3 and/or InCl3×
4H2O in aqueous ethanol
5-Ferrocenoyl substituted DHPM, 1Á6 were prepared
from the corresponding 1-ferrocenyl-1,3-propanedione.
Formylferrocene leads to the 4-ferrocenyl substituted
/
2.3.8. 4-Ferrocenyl-5-methoxycarbonyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-one (8)
/
1
M.p. 237Á
/
241 8C (dec.); H-NMR: dꢀ
/
9.18 (s, 1H,
NH), 7.53 (s, 1H, NH), 4.95 (s, 1H, CH), 4.18 (s, 5H,
DHPMs, 7Á9 (Scheme 1).
/
FcÁH), 4.10Á3.94 (m, 4H, FcÁH), 3.65 (s, 3H, OCH3),
/
/
/
In our previous paper [17], we have described the
synthesis and the complete characterization by X-ray
means of diazatricyclic compounds from Biginelli con-
densations involving salicylaldehyde. As in that case, we
have now prepared 13-ferrocenecarbonyl-9-methyl-11-
oxo-8-oxa-10,12-diazatricyclo [7.3.1.02,7]trideca-2,4-6-
2.16 (s, 3H, CH3); IR (KBr): 3416, 3244, 3114, 1704,
1656, 1645 cmꢂ1; MS (70 eV, EI): m/z (%): 354 (M,
100), 256 (28), 186 (45), 121 (33). Anal. Calc. for
C17H18O3N2Fe: C, 57.66, H, 5.12, N, 7.91. Found: C,
57.48, H, 5.11, N, 7.89%.
(2)

56
N.-Y. Fu et al. / Journal of Organometallic Chemistry 672 (2003) 52Á57
/
Table 2
Cyclic voltammetric data (in DMF) for DHPMs a
were observed for DHPMs 1, 5 and 6, respectively, and
this is consistent with a conjugated ferrocenoyl ligand
attached to carbon 5 of the DHPM ring. For compound
10, the observed E1/2 (679.5 mV) is very close to the
potential measured for its parent 1-ferrocenyl-1,3-buta-
nedione (663 mV); this result is in keeping with a non-
conjugated ferrocenoyl substituent as indeed is observed
for the proposed tryciclic ring structure. Finally, we
notice no appreciable change in the E1/2 for 7 (454.5 mV)
compared to the value of ferrocene (450 mV), again
consistent with the proposed structure containing a non-
conjugated ferrocenyl substituent attached to position 4
of the DHPM ring.
Compound
Epa
Epc
E1/2
ꢀ/1/2(Epa
ꢁ/
EpaꢂEpc
(mV)
/
(mV)
(mV)
Epc) (mV)
Ferrocene
FcCHO
506
764
488
394
628
339
602
595
553
564
503
412
604
450
696
112
136
149
122
110
102
106
99
413.5
663
650
FcCOCH2COCH3 724
FcCOCH2COPh
1
705
655
670
602
497
755
604
617
5
6
552.5
454.5
679.5
7
10
85
151
a
In DMF solutions at 200 mV sꢂ1
.
4. Conclusion
triene (10) (62% with InBr3, 58% with InCl3×
/4H2O) as
the result of the cyclization of the DHPM derived from
salicylaldehyde and 1-ferrocenyl-1,3-butanedione (Eq.
(2)).
In summary, we have described the route for introdu-
cing ferrocenyl substituents at different positions of the
DHPMs ring system. We have also demonstrated how
cyclic voltammetry is easily applied for determining the
position of the substitution at the DHPM ring. The
products comprise a valuable class of compounds
especially for those interested on the study of ferrocenyl
derivatives as an electrochemical probe in biological
systems and those interested in the development of new
drugs containing the DHPM ring system.
Molecular formulae (see Section 2) for 1Á10 were
/
determined from microanalysis (C, H and N) and
1
confirmed by mass spectrometry. The H-NMR spectra
of compounds 1Á
/
9 (except 6) exhibit two sets of singlets
2.2 ppm), which are characteristic
(at 4.9Á5.5 and 1.8Á
/
/
for the hydrogen and methyl substituents at position 4
and 6 of the DHPM ring, respectively. For compound
10, the two methyne resonances of the tetrahydro-
pyrimidinone were detected at 3.74 and 3.32 ppm.
Acknowledgements
3.2. Electrochemical results
We thank the National Natural Science Foundation
of China (grant no. 29972026 and 29872018), the State
Key Laboratory of Elemento-Organic Chemistry, Nan-
kai University and RFDP, China’s Ministry of Higher
Education (1999005520), and FAPERGS-Brazil (C.P.)
for financial support.
Cyclic voltammetry is a useful tool to determine the
substitution pattern of ferrocenyl substituents at the
DHPM ring. The relevant electrochemical data for
ferrocene, the parent ferrocenyl derivatives and products
are given at Table 2. The electrochemical studies were
carried out in DMF solutions since the DHPMs 1Á10
/
are unsoluble in most common organic solvents. It is
well documented that DMF reacts slowly with the
FeCp2ꢁ cation leading to its decomposition; accordingly
we have observed quasi-reversible electrochemical be-
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/
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/
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/
ipc"
/
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/
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