Indium(III) bromide-catalyzed preparation of dihydropyrimidinones: Improved protocol conditions for the Biginelli reaction

Article abstract of DOI:10.1016/S0040-4020(02)00455-6

Indium(III) bromide efficiently catalyzes the three-component coupling of β-keto esters, aldehydes and urea (or thiourea) to afford the corresponding dihydropyrimidinones. This new protocol for the Biginelli reaction includes the following important features: produces excellent yields, allows the recycling of catalyst with no loss in its activity, and leads to zero-discharge during the process. The reaction of ethyl acetoacetate, salicylaldehyde and thiuourea produced 13-ethoxycarbonyl-9-methyl-11-thioxo-8-oxa-10,12-diazatricyclo [7.3.1.0^2,7]-trideca-2,4-6-triene, which had its crystal structure determined by X-ray crystallography.

Full text of DOI:10.1016/S0040-4020(02)00455-6

TETRAHEDRON
Pergamon
Tetrahedron 58 *2002) 4801±4807
IndiumꢀIII) bromide-catalyzed preparation
of dihydropyrimidinones: improved protocol conditions
for the Biginelli reaction
Nan-Yan Fu,a Yao-Feng Yuan,a Zhong Cao,a Shan-Wei Wang,a Ji-Tao Wanga and Clovis Peppeb,p
aDepartment of Chemistry, State Key Laboratory for Elemento-organic Chemistry, Nankai University,
Tianjin 300071, People's Republic of China
 à Â
Laboratorio de Materiais Inorganicos, Departamento de Quõmica, Universidade Federal de Santa Maria, RS, Campus UFSM,
b
97105-900 Santa Maria, Brazil
Received 19 February2002; accepted 23 April 2002
AbstractÐIndium*III) bromide ef®cientlycatalyzes the three-component coupling of b-keto esters, aldehydes and urea *or thiourea) to
afford the corresponding dihydropyrimidinones. This new protocol for the Biginelli reaction includes the following important features:
produces excellent yields, allows the recycling of catalyst with no loss in its activity, and leads to zero-discharge during the process. The
reaction of ethyl acetoacetate, salicylaldehyde and thiuourea produced 13-ethoxycarbonyl-9-methyl-11-thioxo-8-oxa-10,12-diazatricyclo
[7.3.1.02,7]-trideca-2,4-6-triene, which had its crystal structure determined by X-ray crystallography. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
our experiments, Ranu and co-workers reported the prepara-
tion of DHPMs catalyzed by InCl3.10 As in the case of the
trichloride catalyst, we have found that indium*III) bromide
is also ef®cient for preparing the DHPMs. However, the
present protocol, involving the tribromide, includes new
features related to Ranu's work, particularlyfrom the
preparative point of view. Remarkable advantages are:
anhydrous conditions are no longer necessary during the
process; in fact, the reactions were carried out in 95%
ethanol; the catalyst can be re-used for several times without
anydecrease in reaction yields; and the procedure can be
repeated with zero-discharge to the environment. Lastly, we
have observed that in our hands the product from reactions
involving salicylaldehyde, ethylacetoacetate and urea *or
thiourea) is in fact the diazatricyclic compound 13-ethoxy-
carbonyl-9-methyl-11-oxo*or thioxo)-8-oxa-10,12-diazatri-
cyclo[7.3.1.02,7]trideca-2,4,6-triene. The crystal structure of
the thiourea derivative was solved bysingle crystal X-ray
diffraction techniques.
Biginelli-type dihydropyrimidinones *DHPMs), 4 *Eq. *1))
have interesting pharmacological properties, such as
ef®cacyas calcium channel modulators and a1a adreno-
aceptor-selective antagonists;1 use as an anticancer drug
capable of inhibiting kinesin motor protein;2 and anti-HIV
activityin some marine natural products, containing the
DHPM skeleton, such as the alkaloid batzelladine B.3 The
original Biginelli protocol for the preparation of the DHPMs
consisted of heating a mixture of the three components
*b-keto-ester 1, aldehyde 2, and urea 3) in ethanol contain-
ing a catalytic amount of HCl.4 This procedure leads in one
step-one pot to the desired DHPM. The major drawback
associated with this protocol is the low yields, particularly
for substituted aromatic and aliphatic aldehydes. Recently,
there was considerable activityaiming to improve the
ef®ciencyof the Biginelli DHPMs synthesis. Yields have
been improved compared to the original procedure by
re¯uxing a mixture of the three starting materials in THF
containing polyphosphate ester *PPE).5 Use of Lewis acid
catalysts *BF3´OEt2,6 FeCl3 and HCl,7 LaCl3´7H2O,8 and
ytterbium tri¯ate9) also gave improved yields.
We wish to report here a new studyon the Biginelli reaction
catalyzed by indium*III) compounds. After we had initiate
ꢀ1†
Keywords: indium*III) bromide; green Lewis acid catalyst; Biginelli
reaction.
p
Corresponding author. Tel.: 155-55-2208868; fax: 155-55-2208031;
e-mail: peppe@quimica.ufsm.br
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*02)00455-6

4802
N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
Table 1. InBr3-catalyzed synthesis of 4a under different reaction conditions
EntrySolvent
Amount of InBr
3 *mol%)
Re¯uxing time *h)
Yield *%)a
1
2
3
4
5
6
7
8
9
10
THF
Toluene
Benzene
Dichloromethane
Water
Water/ethanol *1:1, v/v)
Ethanol
Ethanol
Ethanol
Ethanol
10
10
10
10
10
10
10
5
7
0.5
5.5
7
0.5
7
7
7
7
7
83
56
94
35
Trace
17
95, 98, 97, 96b
74c
66d
13
2.5
0
a
Isolated yield.
Catalyst was reused for four times.
b
c
After ®ltering the product, the ®ltrate was heated under re¯ux for another 24 h, more product was obtained and the total yield came upto 97%.
After ®ltering the product, the ®ltrate was heated under re¯ux for another 24 h, more product was obtained, the total yield came upto 98%.
d
2. Results and discussion
A summaryof the optimization experiments is provided in
Table 1. Entries 1±7 show the effect of various solvents on
the reaction. THF *entry1, 83%), benzene *entry3, 94%)
and 95% ethanol *entry7, 98%) gave the highest yields.
Ethanol was chosen as the solvent with consideration to
the reaction yields and environmental impact. The optimum
amount of catalyst *10 mol%) was determined from the
experiments corresponding to entries 7±10. Entry7 also
describes the yields of four consecutive condensations
leading to 4a. In these experiments, the product 4a was
isolated by®ltration, the ®ltered solution containing the
10 mol% of catalyst was reloaded with the initial reagents
and this solution was re-submitted to a new period of re¯ux.
No decrease in the yield was observed, demonstrating that
InBr3 can be reused as catalyst in a Biginelli condensation
with zero-discharge to the environment.
We started to studythe three component Biginelli conden-
sation catalyzed by InBr3 *Eq. *1)) byexamining the con-
ditions for the reaction involving benzaldehyde, urea and
ethylacetoatate to afford the DHPM 4a *R1ˆEt, R2ˆPh,
XˆO).
Table 2. Indium *III) bromide catalyzed synthesis of dihydropyrimidinones
4
Product
R1
Et
R2
X
Yield *%)a
4a
4b
4c
4d
4e
4f
Ph
O
O
O
O
O
O
O
O
O
O
O
98, *92, 96, 94)b
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4-*OMe)±C6H4
2-*Me)±C6H4
4-*Me)±C6H4
3-*OH)±C6H4
4-*OH)±C6H4
2-*Cl)±C6H4
3-*Cl)±C6H4
4-*Cl)±C6H4
3-*NO2)±C6H4
4-*NO2)±C6H4
97
94
98
90
93
75
70
86
95
86
Table 2 shows the generalityof the present protocol, which
is equallyeffective for urea and thiourea. In most cases, the
reactions proceeded smoothlyto produce the corresponding
DHPMs in high yields. Aromatic aldehydes containing
either electron-donating or electron-withdrawing sub-
stituents and aliphatic aldehydes all produced improved
yields as compared to the classical Biginelli protocol.
Surprisingly, even paraformaldehyde gave the correspond-
ing DHPMs 4q and 4c0.
4g
4h
4i
4jc
4kc
4l
Et
Et
O
O
95
90
4m
4n
4od
4p
4q
4r
Et
Et
Et
Et
Me
Me
Me
Me
Me
Et
Ph-CHvCH
Me
n-Bu
H
Ph
4-*OMe)±C6H4
4-*Me)±C6H4
4-*Cl)±C6H4
4-*NO2)±C6H4
Ph
4-*OMe)±C6H4
4-*Me)±C6H4
4-*Cl)±C6H4
4-*NO2)±C6H4
O
O
O
O
O
O
O
O
O
S
68
75
92
80
98
94
97
93
72
94
98
94
79
70
In the course of our work, we have observed that the
products derived from the condensation reactions involving
salicylaldehyde *Table 3) showed NMR spectra inconsistent
with the expected DHPM structure. A single crystal X-ray
structural analysis of the thiourea and ethylacetoacetate
derivative, 5a was conducted. Fig. 1 shows the molecular
structure, proposed in earlier studies and based on NMR
spectroscopy.11,12
4s
4t
4u
4v
4w
4x
4y
4a
4a0
Et
Et
Et
Et
S
S
S
S
Table 3. Indium*III) tribromide catalyzed synthesis of diazatricyclo
compounds,
thiourea)
5 from alkylacetoacetate, salicylaldehyde and urea *or
4b0
Et
Et
S
S
86
70
Product
R1
X
Yield *%)a
4c0
H
5a
5b
5c
C2H5
C2H5
CH3
S
O
O
70
75, 48b
72
a
Isolated yield.
b
c
d
Three consecutive condensations catalyzed by InCl3´4H2O *10 mol%).
The re¯uxing time extended to 36 h in order to get satisfactoryyield.
From 40% acetaldehyde.
a
Isolated yield.
Catalyzed by InCl3´4H2O *10 mol%).
b

N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
4803
Figure 1. The molecular structure of C14H16O3N2S, 5a, *ORTEP diagram), with non-hydrogen atoms shown as 30% probability ellipsoids.
The production of compounds 5a±c can be explained by
the isomerization reaction of the DHPM's, 4 which were
initiallyformed *Scheme 1).
The interest to develop new protocols to prepare organic
compounds in aqueous media is growing during the last
few years, since water is a non-toxic and environmentally
benign solvent.14 In this context, Lewis acid catalyzed
processes is one of these challenges, particularlydue to
the fact that manyLewis acids promptlyreact with water,
restricting their use. We had shown that InBr3 acts as a
catalyst in dithioacetalization of carbonyl compounds in
aqueous media;15 and in order to demonstrate the use of
indium trihalides as `green Lewis acid' catalysts for the
Biginelli condensation, we have carried out: the preparation
of 4o from aqueous *40%) acetaldehyde; three consecutive
condensations, catalyzed by InCl3´4H2O, which produced
4a in 92, 96 and 94% of yields; and the synthesis of 5b in
48% using the hydrated catalyst. The experimental con-
ditions for these experiments were those described in Tables
2 and 3, respectively. The sum of these results clearly indi-
cates that InX3 *XˆCl, Br) are equallyef®cient as catalysts
in the Biginelli condensation reaction and that both can
tolerate the presence of water in the media with no sign of
deactivation.
The preparation of the DHPM 4 derived from salicyl-
aldehyde was ®rst decribed in 1932.13 Its structure was
disproved in 1991, when exclusive formation of 5b was
obtained under HCl catalysis.12 This ®nding suggests that
this DHPM promptlyisomerizes to its cyclic isomer in the
presence of a Lewis acid. In support of this, we have demon-
strated the abilityof InBr to catalyze the cyclization of
3
a related system: lapachol was isomerized into a and
b-lapachones *Scheme 2) in 87% of yield *a/bˆ1:5).
In conclusion, the present procedure described useful
improvements in the protocol conditions for the Biginelli
condensations catalyzed by indium*III) halides. It intro-
duced indium*III) bromide as a new catalyst, as ef®cient
as the chloride analogue. Excellent reactional yields,
recycling of the catalyst with no loss in its activity,
Scheme 1. The isomerization of DHPMs to diazatricyclic compounds.
Scheme 2. The isomerization of lapachol±lapachone catalyzed by InBr3.

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N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
zero-discharge to the environment, use of aqueous solvent
and the elimination of anhydrous atmosphere during the
reactions, are important features of this new protocol to
prepare the Biginelli-type dihydropyrimidinones.
3.1.4. 5-Ethoxycarbonyl-6-methyl-4-ꢀ4-methylphenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4d. Mp 215±2168C;
1H NMR: dˆ9.15 *s, 1H, NH), 7.80 *s, 1H, NH), 7.10 *s,
4H, C6H4), 5.09 *s, 1H, CH), 3.96 *q, Jˆ7.1 Hz, 2H,
OCH2CH3), 2.23 *s, 3H, C6H5±CH3), 1.08 *t, Jˆ7.1 Hz,
3H, OCH2CH3); 13C NMR: dˆ165.3, 152.2, 148.1, 141.9,
136.3, 128.8, 126.1, 99.5, 59.1, 53.7, 20.6, 17.7, 14.1; IR
*KBr): 3165, 1688, 1633 cm21; MS *70 eV, EI): m/z *%):
274 *M, 28), 183 *100); Anal. *%): calcd for C15H18O3N2: C,
65.66; H, 6.62; N, 10.22. Found: C, 65.39; H, 6.69; N, 10.13.
3. Experimental
Melting points were determined on a glass disk and are
1
uncorrected. H and 13C NMR spectra were recorded in
DMSO-d6 solutions, unless otherwise indicated, on a
BRUKER AC-P-200 spectrometer with TMS as internal
standard. IR spectra were obtained on a FTS-135 spectro-
meter with KBr plates. Mass spectra were determined under
EI *70 eV) on a VG-ZAB-HS spectrometer. Elemental
analyses were carried out on a Perkin-Elmer 240 C analyzer.
Indium*III) bromide was prepared bypassing a ¯ow of
bromine gas through melted indium.16 b-Keto esters, alde-
hydes, urea and thiourea were all commercial products and
were used without further puri®cation. All liquid reagents
were distilled before use.
3.1.5. 5-Ethoxycarbonyl-4-ꢀ3-hydroxyphenyl)-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4e. Mp 163±1658C,
1
lit.10 164±1668C; H NMR: dˆ9.38 *s, 1H, OH), 9.15 *s,
1H, NH), 7.64 *s, 1H, NH), 7.09±6.64 *m, 4H, C6H4), 5.04
*s, 1H, CH), 3.98 *q, Jˆ7.0 Hz, 2H, OCH2CH3), 2.22 *s, 3H,
CH3), 1.11 *t, Jˆ7.0 Hz, 3H, OCH2CH3).
3.1.6. 5-Ethoxycarbonyl-4-ꢀ4-hydroxyphenyl)-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4f. Mp 230±2328C,
1
lit.6 230±2328C; H NMR: dˆ9.34 *s, 1H, OH), 9.10 *s,
1H, NH), 7.64 *s, 1H, NH), 7.03±6.65 *m, 4H, C6H4),
5.02 *s, 1H, CH), 3.96 *q, Jˆ7.0 Hz, 2H, OCH2CH3), 2.21
*s, 3H, CH3), 1.08 *t, Jˆ7.0 Hz, 3H, OCH2CH3).
3.1. General procedure for the synthesis of DHPMs
Representative procedure for 5-ethoxycarbonyl-6-methyl-4-
phenyl-3,4-dihydropyrimidin-2*1H)-one, 4a: a solution of
ethyl acetoacetate *520 mg, 4 mmol), benzaldehyde
*424 mg, 4 mmol), urea *312 mg, 5.2 mmol), InBr3
*142 mg, 0.4 mmol) in 95% ethanol *10 mL) was heated
under re¯ux for 7 h. On cooling, the product spontaneously
crystallized from the solution. The pure solid 4a *1.02 g,
3.92 mmol, 98%, mp 202±2048C, lit.6 202±2048C) was
®ltered, washed with ethanol *3£10 mL) and dried under
vacuum. This procedure was followed for the preparation
of all compounds 4 and 5 listed in Tables 2 and 3, respec-
tively. Melting points, spectral and analytical data for these
products are given below.
3.1.7. 4-ꢀ2-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-
1
3,4-dihydropyrimidin-2ꢀ1H)-one, 4g. Mp 222±2248C; H
NMR: dˆ9.25 *s, 1H, NH), 7.70 *s, 1H, NH), 7.37±7.29 *m,
4H, C6H4), 5.61 *s, 1H, CH), 3.87 *q, Jˆ6.9 Hz, 2H,
OCH2CH3), 2.28 *s, 3H, CH3), 0.97 *t, Jˆ6.9 Hz, 3H,
OCH2CH3); 13C NMR: dˆ165.0, 151.4, 149.3, 141.7,
131.8, 129.4, 129.1, 128.8, 127.7, 98.0, 59.1, 51.6, 17.7,
13.9; IR *KBr): 3150, 1688, 1626 cm21; MS *70 eV, EI):
m/z *%): 294 *M, 14), 183 *100); Anal. *%): calcd for
C14H15O3N2Cl: C, 57.03; H, 5.13; N, 9.51. Found: C,
56.89; H, 5.44; N, 9.30.
3.1.8. 4-ꢀ3-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4h. Mp 193±1958C;
1H NMR: dˆ9.24 *s, 1H, NH), 7.77 *s, 1H, NH), 7.36±
7.17 *m, 4H, C6H4), 5.14 *s, 1H, CH), 3.98 *q, Jˆ7.0 Hz,
2H, OCH2CH3), 2.24 *s, 3H, CH3), 1.08 *t, Jˆ7.0 Hz, 3H,
OCH2CH3); 13C NMR: dˆ165.2, 151.9, 148.9, 147.2,
132.9, 130.4, 127.2, 126.2, 124.9, 98.7, 59.3, 53.6, 17.8,
14.0; IR *KBr): 3350, 3140, 1692, 1635 cm21; MS *70 eV,
EI): m/z *%): 294 *M, 18), 183 *100); Anal. *%): calcd for
C14H15O3N2Cl: C, 57.03; H, 5.13; N, 9.51. Found: C, 56.96;
H, 5.34; N, 9.34.
3.1.1. 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-
pyrimidin-2ꢀ1H)-one, 4a. Mp 202±2048C, lit.6 202±
1
2048C; H NMR: dˆ9.20 *s, 1H, NH), 7.74 *s, 1H, NH),
7.25 *s, 5H, C6H5), 5.14 *s, 1H, CH), 3.97 *q, Jˆ6.5 Hz, 2H,
OCH2CH3), 2.24 *s, 3H, CH3), 1.08 *t, Jˆ6.5 Hz, 3H,
OCH2CH3).
3.1.2. 5-Ethoxycarbonyl-4-ꢀ4-methoxyphenyl)-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4b. Mp 202±2048C, lit.6
1
201±2038C; H NMR: dˆ9.14 *s, 1H, NH), 7.66 *s, 1H,
NH), 7.15±6.84 *m, 4H, C6H4), 5.07 *s, 1H, CH), 3.96 *q,
Jˆ6.8 Hz, 2H, OCH2CH3), 3.70 *s, 3H, OCH3), 2.23 *s, 3H,
CH3), 1.09 *t, Jˆ6.8 Hz, 3H, OCH2CH3).
3.1.9. 4-ꢀ4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4i. Mp 212±2148C,
1
lit.6 213±2158C; H NMR: dˆ9.24 *s, 1H, NH), 7.78 *s,
1H, NH), 7.40±7.21 *m, 4H, C6H4), 5.12 *s, 1H, CH),
3.97 *q, Jˆ6.9 Hz, 2H, OCH2CH3), 2.24 *s, 3H, CH3),
1.08 *t, Jˆ6.9 Hz, 3H, OCH2CH3).
3.1.3. 5-Ethoxycarbonyl-6-methyl-4-ꢀ2-methylphenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4c. Mp 208±2108C; H
1
NMR: dˆ9.15 *s, 1H, NH), 7.84 *s, 1H, NH), 7.15±7.11 *m,
4H, C6H4), 5.39 *s, 1H, CH), 3.87 *q, Jˆ7.0 Hz, 2H,
OCH2CH3), 2.40 *s, 3H, C6H5±CH3), 2.28 *s, 3H, CH3),
0.98 *t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR: dˆ165.3,
151.6, 148.4, 143.3, 134.7, 130.1, 127.2, 126.6, 99.3, 59.1,
3.1.10. 5-Ethoxycarbonyl-6-methyl-4-ꢀ3-nitrophenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4j. Mp 229±2318C; H
1
NMR: dˆ9.37 *s, 1H, NH), 7.90 *s, 1H, NH), 8.10±7.64 *m,
4H, C6H4), 5.29 *s, 1H, CH), 3.98 *q, Jˆ6.9 Hz, 2H,
OCH2CH3), 2.26 *s, 3H, CH3), 1.08 *t, Jˆ6.9 Hz, 3H,
OCH2CH3); 13C NMR: dˆ165.1, 151.9, 149.4, 147.8,
147.0, 133.0, 130.2, 122.3, 121.1, 98.4, 59.4, 53.6, 17.9,
50.6, 18.7, 17.7, 13.9; IR *KBr): 3155, 1686, 1628 cm21
;
MS *70 eV, EI): m/z *%): 274 *M, 41), 183 *100); Anal. *%):
calcd for C15H18O3N2: C, 65.66; H, 6.62; N, 10.22. Found:
C, 65.50; H, 6.85; N, 10.30.

N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
4805
14.0; IR *KBr): 3270, 1691, 1676, 1615, 1513 cm21; MS
*70 eV, EI): m/z *%): 305 *M, 12), 183 *100); Anal. *%):
calcd for C14H15O5N3: C, 55.06; H, 4.96; N, 13.77. Found:
C, 55.11; H, 4.83; N, 13.81.
dˆ8.84 *s, 1H, NH), 6.96 *s, 1H, NH), 4.03 *q, Jˆ6.9 Hz,
2H, OCH2CH3), 3.86 *s, 2H, CH2), 2.13 *s, 3H, CH3), 1.16
*t, Jˆ6.9 Hz, 3H, OCH2CH3); 13C NMR *d6-DMSO1
CDCl3): dˆ165.3, 152.8, 148.4, 94.5, 59.0, 17.4, 14.2; IR
*KBr): 3200, 3180, 1724, 1696, 1648 cm21; MS *70 eV, EI):
m/z *%): 184 *M, 48), 155 *M2C2H5, 100), 111 *84); Anal.
*%): calcd for C8H12O3N2: C, 52.17; H, 6.57; N, 15.22.
Found: C, 52.31; H, 6.62; N, 15.07.
3.1.11. 5-Ethoxycarbonyl-6-methyl-4-ꢀ4-nitrophenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4k. Mp 207±2098C,
1
lit.6 208±2118C; H NMR: dˆ9.35 *s, 1H, NH), 7.89 *s,
1H, NH), 8.23±7.47 *m, 4H, C6H4), 5.26 *s, 1H, CH),
3.97 *q, Jˆ7.0 Hz, 2H, OCH2CH3), 2.25 *s, 3H, CH3),
1.08 *t, Jˆ7.0 Hz, 3H, OCH2CH3).
3.1.18.
5-Methoxycarbonyl-6-methyl-4-phenyl-3,4-di-
hydropyrimidin-2ꢀ1H)-one, 4r. Mp 206±2088C, lit.6
1
209±2128C; H NMR: dˆ9.20 *s, 1H, NH), 7.78 *s, 1H,
3.1.12. 5-Ethoxycarbonyl-4-ꢀ2-furfuryl)-6-methyl-3,4-
dihydropyrimidin-2ꢀ1H)-one, 4l. Mp 209±2118C; 1H
NMR: dˆ9.24 *s, 1H, NH), 7.75 *s, 1H, NH), 7.54 *s, 1H,
CHar.), 6.34 *s, 1H, CHar.), 6.08 *s, 1H, CHar.), 5.19 *s, 1H,
CH), 4.01 *q, Jˆ6.9 Hz, 2H, OCH2CH3), 2.22 *s, 3H, CH3),
1.12 *t, Jˆ6.9 Hz, 3H, OCH2CH3); 13C NMR: dˆ165.0,
155.9, 152.4, 149.2, 142.1, 110.3, 105.2, 96.8, 59.2, 47.7,
NH), 7.28±7.23 *m, 5H, C6H5), 5.12 *s, 1H, CH), 3.51 *s,
3H, OCH3), 2.23 *s, 3H, CH3).
3.1.19. 5-Methoxycarbonyl-4-ꢀ4-methoxyphenyl)-6-
methyl-3,4-dihydropyrimidin-2ꢀ1H)-one, 4s. Mp 190±
1
1928C, lit.6 192±1948C; H NMR: dˆ9.17 *s, 1H, NH),
7.68 *s, 1H, NH), 7.14±6.83 *m, 4H, C6H4), 5.07 *s, 1H,
CH), 3.70 *s, 3H, C6H5±OCH3), 3.51 *s, 3H, OCH3), 2.23 *s,
3H, CH3).
17.7, 14.1; IR *KBr): 3320, 3225, 3100, 1695, 1640 cm21
;
MS *70 eV, EI): m/z *%): 250 *M, 80), 221 *M2C2H5, 99),
177 *100); Anal. *%): calcd for C12H14O4N2: C, 57.57; H,
5.64; N, 11.20. Found: C, 57.63; H, 5.59; N, 11.28.
3.1.20. 5-Methoxycarbonyl-6-methyl-4-ꢀ4-methylphenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4t. Mp 204±2068C; H
1
3.1.13. 5-Ethoxycarbonyl-6-methyl-4-ꢀ2-thienyl)-3,4-di-
hydropyrimidin-2ꢀ1H)-one, 4m. Mp 215±2178C; 1H
NMR: dˆ9.31 *s, 1H, NH), 7.88 *s, 1H, NH), 7.34 *d,
Jˆ5.3 Hz, 1H, CHar.), 6.93±6.88 *m, 2H, CHar.), 5.39 *s,
1H, CH), 4.05 *q, Jˆ7.1 Hz, 2H, OCH2CH3), 2.20 *s, 3H,
CH3), 1.15 *t, Jˆ7.1 Hz, 3H, OCH2CH3); 13C NMR: dˆ
165.0, 152.2, 148.8, 148.6, 126.6, 124.6, 123.5, 99.8, 59.3,
49.4, 17.7, 14.1; IR *KBr): 3165, 1680, 1633 cm21; MS
*70 eV, EI): m/z *%): 266 *M, 84), 237 *M2C2H5, 100),
193 *91); Anal. *%): calcd for C12H14O3N2S: C, 54.10; H,
5.30; N, 10.52. Found: C, 54.27; H, 5.19; N, 10.33.
NMR: dˆ9.18 *s, 1H, NH), 7.10 *s, 4H, C6H4), 5.08 *s, 1H,
CH), 3.51 *s, 3H, OCH3), 2.24 *s, 6H, C6H5±CH3, CH3); 13
C
NMR: dˆ185.9, 152.2, 148.4, 141.8, 136.4, 129.0, 126.1,
99.2, 53.6, 50.7, 20.6, 17.8; IR *KBr): 3175, 1691,
1634 cm21; MS *70 eV, EI): m/z *%): 260 *M, 4), 245
*M2CH3, 8), 201 *M2CO2CH3, 8), 169 *18), 31 *100);
Anal.*%): calcd for C14H16O3N2: C, 64.58; H, 6.20; N,
10.77. Found: C, 64.39; H, 6.12; N, 10.58.
3.1.21. 4-ꢀ4-Chlorophenyl)-5-methoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4u. Mp 179±1818C, lit.6
1
179±1818C; H NMR: dˆ9.28 *s, 1H, NH), 7.76 *s, 1H,
3.1.14. 5-Ethoxycarbonyl-6-methyl-4-styryl-3,4-dihydro-
NH), 7.40±7.21 *m, 4H, C6H4), 5.12 *s, 1H, CH), 3.51 *s,
3H, OCH3), 2.23 *s, 3H, CH3).
pyrimidin-2ꢀ1H)-one, 4n. Mp 225±2278C *dec.), lit.13
1
2258C *dec.); H NMR: dˆ9.09 *s, 1H, NH), 7.40 *s, 1H,
NH), 7.37±7.21 *m, 5H, C6H5), 6.32 *d, Jˆ12.0 Hz, 1H,
vCH), 6.21 *dd, Jˆ12.0, 5.8 Hz, 1H, vC±H), 4.72 *d,
Jˆ5.5 Hz, 1H, CH), 4.08 *q, Jˆ7.0 Hz, 2H, OCH2CH3),
2.19 *s, 3H, CH3), 1.19 *t, Jˆ7.0 Hz, 3H, OCH2CH3).
3.1.22. 5-Methoxycarbonyl-6-methyl-4-ꢀ4-nitrophenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-one, 4v. Mp 214±2158C,
1
lit.6 204±2078C; H NMR: dˆ9.38 *s, 1H, NH), 7.91 *s,
1H, NH), 8.22±7.47 *m, 4H, C6H4), 5.26 *s, 1H, CH),
3.52 *s, 3H, OCH3), 2.25 *s, 3H, CH3).
3.1.15. 5-Ethoxycarbonyl-4,6-dimethyl-3,4-dihydropyri-
1
midin-2ꢀ1H)-one, 4o. Mp 194±1958C; H NMR: dˆ8.97
3.1.23. 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydro-
pyrimidin-2ꢀ1H)-thione, 4w. Mp 208±2108C; H NMR:
dˆ10.33 *s, 1H, NH), 9.64 *s, 1H, NH), 7.35±7.19 *m,
5H, C6H5), 5.16 *d, Jˆ3.5 Hz, 1H, CH), 4.00 *q, Jˆ
7.0 Hz, 2H, OCH2CH3), 2.28 *s, 3H, CH3), 1.09 *t, Jˆ
7.0 Hz, 3H, OCH2CH3).
1
*s, 1H, NH), 7.19 *s, 1H, NH), 4.06 *q, Jˆ6.9 Hz, 3H, over-
lapped signals OCH2CH3 and CHCH3), 2.15 *s, 3H, CH3),
1.18 *t, Jˆ6.9 Hz, 3H, OCH2CH3), 1.09 *d, Jˆ6.0 Hz, 3H,
CH3); 13C NMR: dˆ165.3, 152.7, 147.6, 100.6, 59.1, 46.4,
23.3, 17.6, 14.2; IR *KBr): 3252, 3118, 1707, 1657 cm21
;
MS *70 eV, EI): m/z *%): 198 *M, 10), 237 *M2CH3, 100),
193 *91); Anal. *%): calcd for C9H14O3N2: C, 54.51; H,
7.12; N, 14.14. Found: C, 54.65; H, 7.07; N, 14.23.
3.1.24. 5-Ethoxycarbonyl-4-ꢀ4-methoxyphenyl)-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-thione, 4x. Mp 150±1528C;
1H NMR: dˆ10.29 *s, 1H, NH), 9.59 *s, 1H, NH), 7.14±
6.87 *m, 4H, C6H4), 5.10 *s, 1H, CH), 3.99 *q, Jˆ7.0 Hz,
2H, OCH2CH3), 3.71 *s, 3H, OCH3), 2.27 *s, 3H, CH3), 1.09
*t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR: dˆ174.0, 165.2,
158.8, 144.7, 135.8, 127.7, 113.9, 101.1, 59.6, 55.1, 53.5,
17.2, 14.1; IR *KBr): 3250, 1651, 1598, 1561 cm21; MS
*70 eV, EI): m/z *%): 306 *M, 82), 277 *M2C2H5, 80), 32
*100); Anal. *%): calcd for C15H18O3N2S: C, 58.78; H, 5.93;
N, 9.15. Found: C, 58.83; H, 5.77; N, 9.03.
3.1.16. 4-Butyl-5-ethoxycarbonyl-6-methyl-3,4-dihydro-
pyrimidin-2ꢀ1H)-one, 4p. Mp 164±1668C, lit.9 157±
1
1588C; H NMR: dˆ8.92 *s, 1H, NH), 7.30 *s, 1H, NH),
4.03 *m, 3H, CH, OCH2CH3), 2.14 *s, 3H, CH3), 1.36±1.13
*m, 9H, ±*CH2)3, OCH2CH3), 0.83 *t, 3H, CH3).
3.1.17. 5-Ethoxycarbonyl-6-methyl-3,4-dihydropyrimi-
din-2ꢀ1H)-one, 4q. Mp 242±2448C *dec.); 1H NMR:

4806
N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
3.1.25. 5-Ethoxycarbonyl-6-methyl-4-ꢀ4-methylphenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-thione, 4y. Mp 192±1948C;
1H NMR: dˆ10.27 *s, 1H, NH), 9.58 *s, 1H, NH), 7.16±
7.07 *m, 4H, C6H4), 5.12 *s, 1H, CH), 4.00 *q, Jˆ7.0 Hz,
2H, OCH2CH3), 2.27 *s, 3H, C6H5±CH3), 2.25 *s, 3H, CH3),
1.10 *t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR: dˆ174.2,
165.2, 144.9, 140.6, 136.9, 129.1, 126.3, 100.9, 59.6, 53.8,
20.7, 17.2, 14.1; IR *KBr): 3255, 1659, 1562 cm21; MS
*70 eV, EI): m/z *%): 290 *M, 100), 261 *M2C2H5, 77);
Anal. *%): calcd for C15H18O2N2S: C, 62.02; H, 6.25; N,
9.65. Found: C, 62.00; H, 6.47; N, 9.62.
292 *M, 100), 263 *M2C2H5, 67), 219 *M2CO2C2H5,
51), 199 *71); Anal.*%): calcd for C14H16O3N2S: C, 57.49;
H, 5.52; N, 9.59. Found: C, 57.71; H, 5.64; N, 9.38.
3.1.31.
13-Ethoxycarbonyl-9-methyl-11-oxo-8-oxa-10,
12-diazatricyclo [7.3.1.02,7] trideca-2,4,6-triene, 5b. Mp
200±2028C; 1H NMR: dˆ7.61 *s, 1H, NH), 7.21±6.75
*m, 4H, C6H4), 4.46 *d, Jˆ2.1 Hz, 1H, CH), 4.15 *q, Jˆ
7.0 Hz, 2H, OCH2CH3), 3.25 *d, Jˆ2.1 Hz, 1H, CH), 1.73
*s, 3H, CH3), 1.22 *t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR:
dˆ168.5, 154.9, 150.7, 129.5, 128.7, 125.5, 120.7, 116.7,
83.2, 60.7, 47.8, 44.1, 24.1, 14.1; IR *KBr): 3220, 3082,
1749, 1689 cm21; MS *70 eV, EI): m/z *%): 276 *M, 35),
247 *M2C2H5, 73), 203 *M2CO2C2H5, 61), 183 *100);
Anal. *%): calcd for C14H16O4N2: C, 60.84; H, 5.84; N,
10.14. Found: C, 60.77; H, 5.90; N, 10.19.
3.1.26. 4-ꢀ4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2ꢀ1H)-thione, 4z. Mp 192±1948C;
1H NMR: dˆ10.36 *s, 1H, NH), 9.65 *s, 1H, NH), 7.43±
7.19 *m, 4H, C6H4), 5.16 *s, 1H, CH), 4.00 *q, Jˆ6.6 Hz,
2H, OCH2CH3), 2.28 *s, 3H, CH3), 1.08 *t, Jˆ6.6 Hz, 3H,
OCH2CH3); 13C NMR: dˆ174.3, 165.0, 145.3, 142.4,
132.3, 128.6, 128.4, 100.4, 59.7, 53.5, 17.2, 14.0; IR
*KBr): 3255, 1657, 1560 cm21; MS *70 eV, EI): m/z *%):
310 *M, 99), 281 *M2C2H5, 82), 199 *100); Anal. *%):
calcd for C14H15O2N2ClS: C, 54.08; H, 4.87; N, 9.02.
Found: C, 54.23; H, 4.71; N, 8.99.
3.1.32. 13-Methoxycarbonyl-9-methyl-11-oxo-8-oxa-10,
12-diazatricyclo [7.3.1.02,7] trideca-2,4,6-triene, 5c. Mp
195±1978C; 1H NMR: dˆ7.60 *s, 1H, NH), 7.21±6.74
*m, 4H, C6H4), 4.46 *d, Jˆ2.4 Hz, 1H, CH), 3.68 *s, 3H,
OCH3), 3.28 *d, Jˆ2.4 Hz, 1H, CH), 1.72 *s, 3H, CH3); 13
C
NMR: dˆ169.0, 154.6, 150.7, 129.5, 128.8, 125.4, 120.7,
116.7, 83.2, 52.1, 47.7, 44.0, 24.1; IR *KBr): 3228, 3085,
1750, 1698 cm21; MS *70 eV, EI): m/z *%): 262 *M, 36),
247 *M2CH3, 38), 203 *M2CO2CH3, 46), 169 *100); Anal.
*%): calcd for C13H14O4N2: C, 59.51; H, 5.38; N, 10.69.
Found: C, 59.48; H, 5.21; N, 10.77.
3.1.27. 5-Ethoxycarbonyl-6-methyl-4-ꢀ4-nitrophenyl)-
3,4-dihydropyrimidin-2ꢀ1H)-thione, 4a0. Mp 109±
1
1118C; H NMR: dˆ10.40 *s, 1H, NH), 9.62 *s, 1H, NH),
8.25±7.45 *m, 4H, C6H4), 5.26 *s, 1H, CH), 4.00 *q, Jˆ
7.1 Hz, 2H, OCH2CH3), 2.30 *s, 3H, CH3), 1.12 *t, Jˆ
7.1 Hz, 3H, OCH2CH3).
3.1.33. The isomerization lapachol±lapachones. Lapa-
chol *193 mg, 0.79 mmol) was added to a stirred solution
of InBr3 *282 mg, 0.79 mmol) in CH2Cl2. After 24 h, the
reaction was quenched with 10 mL of water and extracted
with CH2Cl2 *2£10 mL). The extract was dried *Na2SO4),
®ltered and evaporated to dryness. The residue was
separated bycolumn chromatographyon silica gel
*hexane±acetate) to give 27.8 mg *0.11 mmol) of a-lapa-
chone and 139 mg *0.57 mmol) of b-lapachone *total
yield 87%, a/bˆ1:5). a-lapachone: mp: 119±1218C, lit.17
3.1.28. 5-Ethoxycarbonyl-6-methyl-4-ꢀ2-thienyl)-3,4-di-
hydropyrimidin-2ꢀ1H)-thione, 4b0. Mp 215±2168C; 1H
NMR: dˆ10.46 *s, 1H, NH), 9.76 *s, 1H, NH), 7.39 *d,
Jˆ4.1 Hz, 1H, CHar.), 6.95±6.89 *m, 2H, CHar.), 5.41 *s,
1H, CH), 4.07 *q, Jˆ6.7 Hz, 2H, OCH2CH3), 2.26 *s, 3H,
CH3), 1.15 *t, Jˆ6.7 Hz, 3H, OCH2CH3); 13C NMR:
dˆ174.7, 164.8, 147.0, 145.3, 126.8, 125.3, 124.2, 101.3,
59.8, 49.4, 17.1, 14.1; IR *KBr): 3245, 1650, 1555 cm21
;
1
1178C; H NMR *CDCl3): dˆ7.94 *dd, Jˆ7.5, 1.2 Hz, 1H,
MS *70 eV, EI): m/z *%): 282 *M, 99), 253 *M2C2H5, 50),
109 *100); Anal. *%): calcd for C12H14O2N2S2: C, 51.02; H,
5.00; N, 9.93. Found: C, 51.24; H, 4.91; N, 9.71.
C´Har.), 7.72 *dd, Jˆ7.5, 1.2 Hz, 1H, C´Har.), 7.56 *td, Jˆ7.5,
1.2 Hz, 1H, C´Har.), 7.42 *td, Jˆ7.5, 1.2 Hz, 1H, C´Har.),
2.47 *t, Jˆ6.9 Hz, 2H, CH2), 1.77 *t, Jˆ6.9 Hz, 2H, CH2),
1.39 *s, 6H, CH3); b-lapachone: mp: 154±1558C, lit.17
3.1.29. 5-Ethoxycarbonyl-6-methyl-3,4-dihydropyrimi-
1
1
din-2ꢀ1H)-thione, 4c0. Mp 232±2348C *dec.); H NMR:
1548C; H NMR *CDCl3): dˆ7.90 *m, 2H, C´Har.), 7.54
*m, 2H, C´Har.), 2.50 *t, Jˆ6.6 Hz, 2H, CH2), 1.73 *t, Jˆ
6.6 Hz, 2H, CH2), 1.38 *s, 6H, CH3).
dˆ9.95 *s, 1H, NH), 8.93 *s, 1H, NH), 4.07 *q, Jˆ7.0 Hz,
2H, OCH2CH3), 3.87 *s, 2H, CH2), 2.17 *s, 3H, CH3), 1.18
*t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR *d6-DMSO1
CDCl3): dˆ175.8, 165.0, 145.1, 96.0, 59.3, 16.8, 14.2; IR
*KBr): 3145, 1701, 1646, 1599 cm21; MS *70 eV, EI): m/z
*%): 200 *M, 99), 271 *M2C2H5, 100); Anal. *%): calcd for
C8H12O2N2S: C, 47.96; H, 6.04; N, 13.99. Found: C, 48.12;
H, 6.21; N, 14.07.
3.2. Supporting information available
Crystallographic data *CIF ®le) for the crystal structure
determination of compound 5a has been deposited with
the Cambridge Crystallographic Data Centre, CCDC no.
171589. Copies maybe obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
*Fax: 144-1223-336033; e-mail: deposit@ccdc.cam.ac.uk
or web: http://www.ccdc.cam.ac.uk).
3.1.30. 13-Ethoxycarbonyl-9-methyl-11-thioxo-8-oxa-10,
12-diazatricyclo [7.3.1.02,7] trideca-2,4,6-triene, 5a. Mp
1
203±2058C; H NMR: dˆ9.12 *s, 2H, 2NH), 7.20±6.84
*m, 4H, C6H4), 4.57 *d, Jˆ2.2 Hz, 1H, CH), 4.15 *q, Jˆ
7.0 Hz, 2H, OCH2CH3), 3.30 *d, Jˆ2.2 Hz, 1H, CH), 1.77
*s, 3H, CH3), 1.22 *t, Jˆ7.0 Hz, 3H, OCH2CH3); 13C NMR:
dˆ176.6, 167.9, 150.5, 129.7, 128.6, 123.8, 121.0, 116.5,
81.5, 60.9, 48.3, 42.5, 23.5, 14.1; IR *KBr): 3367, 3171,
3086, 1730, 1590, 1565 cm21; MS *70 eV, EI): m/z *%):
Acknowledgements
We thank the National Natural Science Foundation of China
*Grant No. 29972026 and 29872018), the KeyLaboratoryof

N.-Y. Fu et al. / Tetrahedron 58 92002) 4801±4807
4807
8. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett.
2000, 41, 9075±9078.
Elemento-organic Chemistry, Nankai University and RFDP,
China's Ministryof Higher Education *1999005520), and
FAPERGS-Brazil *C. P.) for ®nancial support.
9. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65,
3864±3868.
10. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270±6272.
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