Green chemistry approaches to the synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones by a three-component coupling of one-pot condensation reaction: Comparison of ethanol, water, and solvent-free conditions

Article abstract of DOI:10.1021/jo0205199

A general and practical green chemistry route to the Biginelli cyclocondensation reaction using cerium(III) chloride as the catalyst (25% mol) is described under three different sets of reaction conditions. This method provides an efficient and much impro

Full text of DOI:10.1021/jo0205199

alkaloids containing the dihydropyrimidine core unit
have been isolated from marine sources, which also
exhibit interesting biological properties.6 Most notably
among these are the batzelladine alkaloids, which were
found to be potent HIV gp-120-CD4 inhibitors.7 Thus,
synthesis of this heterocyclic nucleus is of much current
importance. The most simple and straightforward pro-
cedure, first reported by Biginelli in 1893, involves three-
component, one-pot condensation of a â-ketoester with
an aldehyde and urea under strongly acidic conditions.4
One major drawback of this so-called Biginelli reaction,
however, is the low to moderate yields (20-60%) that are
frequently encountered when using substituted aromatic
or aliphatic aldehydes.8 This has led to the development
of more complex multistep strategies that produce some-
what higher overall yields but lack the simplicity of the
one-pot Biginelli protocol.8,9
Gr een Ch em istr y Ap p r oa ch es to th e
Syn th esis of 5-Alk oxyca r bon yl-4-a r yl-3,4-
d ih yd r op yr im id in -2(1H)-on es by a
Th r ee-Com p on en t Cou p lin g of On e-P ot
Con d en sa tion Rea ction : Com p a r ison of
Eth a n ol, Wa ter , a n d Solven t-fr ee
Con d ition s
D. Subhas Bose,* Liyakat Fatima, and
Hari Babu Mereyala
Organic Chemistry Division III, Fine Chemicals Laboratory,
Indian Institute of Chemical Technology,
Hyderabad 500 007, India
dsb@iict.ap.nic.in
Received August 6, 2002
The art of performing efficient chemical transformation
coupling three or more components in a single operation
by a catalytic process avoiding stoichiometric toxic re-
agents, large amounts of solvents, and expensive puri-
fication techniques represents a fundamental target of
the modern organic synthesis.10 Thus, Biginelli’s reaction
for the synthesis of dihydropyrimidinone has received
renewed interest, and several improved procedures have
recently been reported,4b,11 although some of these meth-
ods involve strong Lewis acids such as BF3‚OEt2,11d protic
acids such as HCl,11g AcOH,11d and additives.11d Conse-
quently, there is scope for further renovation toward mild
reaction conditions, increased variation of the substitu-
ents in all three components, and better yields.
Abstr a ct: A general and practical green chemistry route
to the Biginelli cyclocondensation reaction using cerium(III)
chloride as the catalyst (25% mol) is described under three
different sets of reaction conditions. This method provides
an efficient and much improved modification of original
Biginelli reaction reported in 1893, in terms of high yields,
short reaction times, and simple work-up procedure, and it
has the ability to tolerate a wide variety of substitutions in
all three components, which is lacking in existing proce-
dures.
At the beginning of the new century, a shift in
emphasis in chemistry is apparent with the desire to
develop environmentally benign routes to a myriad of
materials.1 Green chemistry approaches hold out signifi-
cant potential not only for reduction of byproducts, a
reduction in the waste produced, and lowering of energy
costs but also in the development of new methodologies
toward previously unobtainable materials, using existing
technologies.2 Of all of the existing areas of chemistry,
medicinal and pharmaceutical chemistry, with their
traditionally large volume of waste/product ratio, are
perhaps the most ripe for greening.3
In recent years, dihydropyrimidinones and their de-
rivatives occupy an important place in the realm of
natural and synthetic organic chemistry because of their
therapeutic and pharmacological properties.4 They have
emerged as integral backbones of several calcium channel
blockers, antihypertensive agents, R-1a-antagonists, and
neuropeptide Y (NPY) antagonists.5 Moreover, several
Over recent years, lanthanide salt mediated Lewis acid
reactions have attracted tremendous interest throughout
scientific communities due to their low toxicity, ease of
handling, low cost, stability, and recoverability of the
reagent from water.12 In this paper, we describe a general
(5) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.;
Moreland, S.; Swanson, B. N.; Gougoutas, J . Z.; Schwartz, J .; Smillie,
K. M.; Malley, M. F. J . Med. Chem. 1990, 33, 2629. (b) Rovnyak, G.
C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; DiMarco, J . D.; Gougoutas,
J . Z.; Hedberg, A.; Malley, M F.; McCarthy, J . P.; Zhang, R.; Moreland,
S. J . Med. Chem. 1995, 38, 119 and references therein.
(6) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J . Am. Chem.
Soc. 1995, 117, 2657.
(7) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J .; DeBrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J . J . Org. Chem.
1995, 60, 1182.
(8) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J . J . Org.
Chem. 1989, 54, 5898. (b) Barluenga, J .; Tomas, M.; Ballesteros, A.;
Lopez, L. A. Tetrahedron Lett. 1989, 30, 4573.
(9) O’ Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
(10) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(11) Gupta, R.; Gupta, A.; Paul, S.; Kachroo, P. Indian J . Chem.
1995, 34B, 151. (b) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995,
36, 7819. (c) Studer, A.; J eger, P.; Wipf, P.; Curran, D. P. J . Org. Chem.
1997, 62, 2917. (d) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J . Org. Chem.
1998, 63, 3454. (e) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718. (f)
Singh, K.; Singh, J .; Deb, P. K.; Singh, H. Tetrahedron 1999, 55, 12873.
(g) Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron
Lett. 1999, 40, 3465. (h) Ranu, B. C.; Hajra, A.; J ana, U. J . Org. Chem.
2000, 65, 6270. (i) Lu, J .; Ma, H. R. Synlett 2000, 63. (j) Dondoni, A.;
Massi, A. Tetrahedron Lett. 2001, 42, 7975. (k) Kumar, A. K.;
Kasthuraiah, M.; Reddy, S. C.; Reddy, D. C. Tetrahedron Lett. 2001,
42, 7873.
* To whom correspondence should be addressed. Fax: +91-40-
7160387. Telephone: +91-40-7193275. E-mail: dsb@iict.ap.nic.in.
(1) Anastas, P.; Williamson, T. Green Chemistry, Frontiers in Benign
Chemical Synthesis and Procedures; Oxford Science Publications:
1998.
(2) Cave, G. W. V.; Raston, C. L.; Scott, J . L. Chem. Commun. 2001,
2159-2169.
(3) As estimated by determination of E-factor: Sheldon, R. A. Chem.
Ind. 1997, 12.
(4) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Kappe, C. O.
Tetrahedron 1993, 49, 6937.
10.1021/jo0205199 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002
J . Org. Chem. 2003, 68, 587-590
587

TABLE 1. CeCl3-Ca ta lyzed Syn th esis of Dih yd r op yr im id in on es
yieldb (%)
H2O
entry
R
R1
R2
CH3
C2H5
CH3
CH3
CH3
X
time (h)
product (4)a
EtOH reflux
solvent-free
ref
1
2
3
4
5
6
7
8
Ph
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
O
O
O
S
O
O
O
S
O
O
O
O
O
3
2.5
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
95
88
86
95
90
91
95
88
83
80
95
93
88
90 (3 h)
82
84
90
84
89
86
83
76
73
90
85
70
80 (10 h)
68
69
75
70
73
71
77
73
65
80
70
11f
11d
4-(OCH3)-C6H4
4-(NCH3)2-C6H4
4-(NCH3)2-C6H4
2,4-(OCH3)2-C6H3
2,4-(Cl)2-C6H3
3,4-(OCH3)2-C2H3
3,4-(OCH3)2-C2H3
C6H5-CHdCH
CH3CH2CH2
4
2.5
4.0
3.0
3.0
4.5
4.0
5.0
2.5
3.0
CH3
C2H5
C(CH3)3
C2H5
C2H5
C2H5
C(CH3)3
C(CH3)3
9
13
14
14
10
11
12
13
4j
4k
4l
(CH3)2CH
3,4,5-(OCH3)3-C6H2
4m
14
2-(NO2)-C6H4
CH3
C2H5
O
5.0
4n
82
78
65
11e
a
b
All products were characterized by 1H NMR, IR, and mass spectroscopy. Isolated and unoptimized yields.
SCHEME 1
stituents afforded high yields of products in high purity.
Acid sensitive aldehydes such as furfural worked well
without the formation of any side products. Thiourea has
been used with similar success to provide the correspond-
ing dihydropyrimidine-(2H)-thiones, which are also of
much interest with regard to biological activity.4b Thus,
variations in all three components have been accom-
modated very comfortably. However, under the present
reaction conditions â-ketoaldehydes do not produce the
corresponding dihydropyrimidinones; instead they lead
to multiple products whose identities are yet to be
established.
and practical route for the Biginelli cyclocondensation
reaction using cerium(III) chloride heptahydrate as the
catalyst. Three different sets of reaction conditions were
examined: (i) traditional ethanol reflux; (ii) water reflux;
and (iii) solvent-free conditions. This is a novel, one-pot
combination that not only preserves the simplicity of
Biginelli’s one-pot reaction but also consistently produces
excellent yields of the dihydropyrimidine-2(1H)-ones
(Scheme 1).
In a typical general experimental procedure by using
traditional conditions, a solution of â-dicarbonyl com-
pound, an aldehyde, and urea in ethanol was heated
under reflux in the presence of a catalytic amount of
CeCl3‚7H2O (25 mol %) for a certain period of time
required to complete the reaction (TLC), resulting in the
formation of dihydropyrimidinone. The reaction mixture
was then poured into crushed ice, and the solid product
separated was filtered and recrystallized.
To study the generality of this process, several ex-
amples illustrating this novel and general method for the
synthesis of dihydropyrimidinones were studied and are
summarized in Table 1. Many of the pharmacologically
relevant substitution patterns on the aromatic ring could
be introduced with high efficiency. A variety of substi-
tuted aromatic, aliphatic, and heterocyclic aldehydes
carrying either electron-donating or -withdrawing sub-
Use of just 25 mol % CeCl3‚7H2O in refluxing EtOH is
sufficient to push the reaction forward. Higher amounts
of CeCl3 did not improve the result to a greater extent.
No additive or protic/Lewis acid is necessary in this
procedure. The yields are, in general, very high regard-
less of the structural variations in dicarbonyl compound,
aldehyde, or urea. The crude products obtained are of
high purity (>95% by 1H NMR). Another important
aspect of this procedure is survival of a variety of
functional groups such as NO2, Cl, OH, OCH3, and
conjugated CdC double bond under the reaction condi-
tions. Presumably, the reaction may proceed through the
acid-catalyzed formation of an acyl imine intermediate
or N-alkylidene urea formed by reaction of the aldehyde
with urea, the key rate-determining step. Interception
of the iminium ion by ethyl acetoactate produces an open-
chain ureide 6 which subsequently cyclizes to the dihy-
dropyrimidinones 4. Because of the 4f empty orbital in
the cerium ion, a complex 5 can be formed through a
coordinative bond and stabilized by cerium. So we
propose a mechanism similar to that of Kappe11e for the
cerium promoted Biginelli reaction as in Scheme 2.
To reduce the employment of ecologically suspected
solvents, we have chosen to carry out the reactions in
water. Indeed water is recognized as an attractive
medium for many organic reactions. Biginelli reaction
using water as a solvent showed a significant improve-
ment upon the isolated product yields ranging from 73
to 90% in the presence of CeCl3‚7H2O (1 mmol). Ad-
ditionally, difficulties were still encountered in the use
of -NO2-substituted benzaldehydes. However, these
(12) Molander, G. A. Chem. Rev. 1992, 92, 29. (b) Marshman, R.
Aldrichim. Acta 1995, 28, 77. (c) Bartoli, G.; Bosco, M.; Marcantoni,
E.; Nobili, F.; Sambri, L. J . Org. Chem. 1997, 62, 4183. (d) Cappa, A.;
Marcantoni, E.; Torregiani, E.; Bartoli, G.; Bellucci, C. M.; Bosco, M.;
Sambri, L. J . Org. Chem. 1999, 64, 5696.
(13) Folkers, K.; Harwood, H. J .; J ohnson, T. B. J . Am. Chem. Soc.
1932, 54, 3751.
(14) Eynde, J . J . V.; Audiart, N.; Canonne, N.; Michel, S.; Haverbeke,
Y. V.; Kappe, C. O. Heterocycles 1997, 45, 1967.
588 J . Org. Chem., Vol. 68, No. 2, 2003

and the chemical shifts are reported in ppm (δ unit) downfield
from tetramethylsilane as the internal standard (CDCl3, δ 77.0).
Mass spectra were obtained utilizing electron impact (EI) at an
ionizing potential of 70 eV.
SCHEME 2
Rep r esen ta tive P r oced u r e for 5-Eth oxyca r bon yl-4-(4-
m et h oxyp h en yl)-6-m et h yl-3,4-d ih yd r op yr im id in -2(1H )-
on e (En tr y 2). A solution of methyl acetoacetate (1.16 g, 10
mmol), 4-methoxybenzaldehyde (1.36 g, 10 mmol), and urea (1.8
g, 30 mmol) in ethanol (5 mL) was heated under reflux in the
presence of CeCl3‚7H2O (931 mg, 25 mol %) for 2.5 h (monitored
by TLC). The reaction mixture (after being cooled to room
temperature) was poured onto crushed ice (30 g) and stirred for
5-10 min. The solid separated was filtered under suction (water
aspirator), washed with ice-cold water (50 mL), and then
recrystallized from hot ethanol to afford pure product (2.62 g,
95%), mp 198-200 °C (lit.11d mp 201-203 °C). IR (KBr): 3225,
1
3098, 2928, 2835, 1710, 1651, 1613, 1583, 1513 cm-1. H NMR
δ 8.95 (br s, N1-H), 7.24 (br s, N3-H), 7.18 (d, J ) 8.7 Hz, 2H),
6.78 (d, J ) 8.7 Hz, 2H), 5.09 (d, J ) 3.2 Hz, 1H), 3.98 (q, J )
7.1 Hz, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 1.16 (t, J ) 7.1 Hz, 3H).
13C NMR δ 165.0, 158.2, 152.0, 147.4, 136.9, 127.1, 113.2, 99.5,
58.6, 54.6, 53.3, 17.5, 13.8. EIMS: m/z (%) 290 (M+, 23), 261
(100), 217 (80), 155 (60), 77 (35), 42 (98). Anal. Calcd for
reactions were confounded from the green perspectives,
by the requirements for extractive isolation followed by
recrystallization to afford material of a suitable quality.
In our final series of experiments we set out to examine
the solvent-free reaction. â-Ketoester, aldehyde, urea, and
CeCl3‚7H2O (30 mol %) were mixed together, and the
heterogeneous mixture was stirred rapidly and refluxed
for 10 h. The corresponding dihydropyrimidinones were
afforded in a typically good yield (65-80%) with the
notable exception of the reaction with 2-nitrobenzalde-
hyde. The solvent-free approach afforded good yields of
most of the other nitrobenzaldehydes examined during
the course of this study. In the majority of instances, our
solvent-free approaches generated dihydropyrimidinones
of good purity.
In conclusion, the present procedure of the synthesis
of dihydropyrimidin-2(1H)-ones by cerium(III) chloride
catalyzed, three-component condensation provides an
efficient and much improved modification of Biginelli’s
reaction. In addition, it is possible to apply the tenets of
green chemistry to the generation of biologically interest-
ing Biginelli products using aqueous medium approaches,
which are less expensive and less toxic than those with
organic solvents. Moreover, this method offers several
advantages including high yields, short reaction times,
and a simple work-up procedure, and it also has the
ability to tolerate a wide variety of substitutions in all
three components, which is lacking in existing proce-
dures. Furthermore, the present procedure is readily
amenable to parallel synthesis and the generation of
combinatorial dihydropyrimidinone libraries.
C
14H16N2O4: C, 60.86; H, 5.83; N, 10.14. Found: C, 60.69; H,
5.76; N, 10.02.
This procedure was followed for the preparation of all the
dihydropyrimidinones and thiones listed in Table 1. The known
compounds have been identified by comparison of spectral data
and mp with those reported. The mp, spectral, and analytical
data of the new compounds have been presented below in order
of their entries.
Wa ter Reflu x. 4-Methoxybenzaldehyde (1.36 g, 10 mmol) was
suspended in water (15 mL) along with urea (1.8 g, 30 mmol),
methyl acetoacetate (1.16 g, 10 mmol) and CeCl3‚7H2O (3.72 g,
10 mmol), and the heterogeneous mixture was stirred rapidly
and refluxed for 3 h (monitored by TLC). The reaction mixture
after being cooled to room temperature was poured onto crushed
ice (40 g) and stirred for 5-10 min. The solid separated was
filtered under suction (water aspirator), washed with ice-cold
water (20 mL), and then recrystallized from hot ethanol to afford
pure product (2.48 g, 90%).
Solven t F r ee. To a mixture of 4-methoxybenzaldehyde (1.36
g, 10 mmol), urea (1.8 g, 30 mmol), and methyl acetoacetate (1.16
g, 10 mmol) (15 mL) was added CeCl3‚7H2O (1.11 g, 30 mol %)
at room temperature. After it was stirred for 5 min, the resulting
mixture was heated at 90 °C in a preheated oil bath for 10 h
(monitored by TLC). The reaction mixture (after being cooled to
room temperature) was poured onto crushed ice (40 g) and
stirred for 5-10 min. The solid separated was filtered under
suction (water aspirator), washed with ice-cold water (40 mL),
and then recrystallized from hot ethanol to afford pure product
(2.20 g, 80%).
5-Meth oxyca r bon yl-4-(4-d im eth yla m in op h en yl)-6-m eth -
yl-3,4-d ih yd r op yr im id in -2(1H)-on e (En tr y 3). mp 213-215
°C. IR (KBr): 3250, 3120, 2928, 2835, 1700, 1651, 1613, 1583,
1
1230 cm-1. H NMR δ 8.98 (br s, N1-H), 7.31 (br s, N3-H), 7.18
(d, J ) 9.1 Hz, 2H), 6.63 (d, J ) 9.1 Hz, 2H), 5.18 (s, 1H), 3.62
(s, 3H), 2.91 (s, 6H), 2.30 (s, 3H). EIMS: m/z (%) 289 (M+, 33),
274 (66), 260 (37), 216 (65), 183 (25), 169 (36), 121 (80), 120 (100),
69 (43), 43 (68). Anal. Calcd for C15H19N3O3: C, 62.27; H, 6.61;
N, 14.52. Found: C, 62.01; H, 6.54; N, 14.06.
Exp er im en ta l Section
Gen er a l Meth od s. All solvents and reagents were obtained
from commercial sources and used without further purification
unless otherwise stated. Analytical thin layer chromatography
(TLC) was performed on Silica Gel 60 F254 precoated plates.
Melting points are uncorrected. Infrared spectra were recorded
as thin films on KBr plates with νmax in inverse centimeters. 1H
NMR spectra were taken in commercial deuterated solvents on
a multinuclear spectrometer with all chemical shifts being
reported in parts per million (δ) relative to internal tetrameth-
ylsilane (TMS, δ 0.0) or with the solvent reference relative to
TMS employed as the internal standard (CDCl3, δ 7.26 ppm).
Data are reported as follows: chemical shift (multiplicity [singlet
(s), doublet (d), triplet (t), quartet (q), broad (br), and multiplet
(m)], coupling constants [Hz], integration). 13C NMR spectra
were taken on a multinuclear spectrometer (200 MHz), using
diluted solutions of each compound in DMSO-d6 as the solvent,
5-Meth oxyca r bon yl-4-(4-d im eth yla m in op h en yl)-6-m eth -
yl-3,4-d ih yd r op yr im id in e-2(1H)-th ion e (En tr y 4). mp 152-
155 °C. IR (KBr): 3280, 3185, 2928, 1710, 1651, 1613, 1583 cm-1
.
1H NMR δ 9.98 (br s, N1-H), 9.31 (br s, N3-H), 7.16 (d, J ) 9.1
Hz, 2H), 6.62 (d, J ) 9.1 Hz, 2H), 5.13 (s, 1H), 3.60 (s, 3H), 2.92
(s, 6H), 2.30 (s, 3H). 13C NMR δ 174.1, 166.2, 150.3, 144.9, 131.2,
127.4, 112.6, 101.3, 53.7, 51.3, 17.4. EIMS: m/z (%) 305 (M+,
21), 246 (25), 231 (8), 185 (22), 171 (18), 141(37), 120 (32), 78-
(100), 43 (87). Anal. Calcd for C15H19N3O2S: C, 58.99; H, 6.27;
N, 13.76. Found: C, 58.78; H, 6.18; N, 13.68.
5-Meth oxyca r bon yl-4-(2,4-d im eth oxyp h en yl)-6-m eth yl-
3,4-d ih yd r op yr im id in -2(1H)-on e (En tr y 5). mp 225-227 °C.
IR (KBr): 3400, 3220, 3110, 2958, 1710, 1650, 1613, 1583, 1450,
J . Org. Chem, Vol. 68, No. 2, 2003 589

1
1320, 1220 cm-1
.
1H NMR δ 9.10 (br s, N1-H), 6.93 (d, J ) 8.7
195 °C. IR (KBr): 3157, 3122, 2980, 1710, 1651, 1596 cm-1. H
Hz, 2H), 6.80 (br s, N3-H), 6.49 (s, 1H), 6.38 (d, J ) 8.7 Hz, 2H),
5.44 (s, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.55 (s, 3H), 2.32 (s, 3H).
13C NMR δ 159.0, 158.2, 137.3, 128.2, 125.1, 115.7, 104.0, 98.6,
96.3, 55.2, 55.0, 39.0, 37.2. EIMS: m/z (%) 306 (M+, 62), 291
(76), 274 (51), 247 (100), 228 (32), 192 (12), 169 (71), 138 (40),
110 (25), 77 (9), 42 (19). Anal. Calcd for C15H18N2O5: C, 58.81;
H, 5.92; N, 9.14. Found: C, 58.64; H, 5.82; N, 9.05.
NMR δ 8.10 (br s, N1-H), 7.58 (br s, N3-H), 6.80 (s, 3H), 5.33 (s,
1H), 3.88 (s, 6H), 2.38 (s, 3H), 1.85 (s, 9H). 13C NMR δ 173.9,
164.5, 149.0, 148.9, 141.6, 135.1, 118.9, 111.3, 110.1, 104.2, 81.0,
55.9, 28.0, 17.9. EIMS: m/z (%) 364 (M+), 307 (100, -57, t-But),
263 (52), 248 (9), 171 (46), 138 (29), 57 (35). Anal. Calcd for
C18H24N2O4S: C, 59.3; H, 6.63; N, 7.67. Found: C, 59.15; H, 6.61;
N, 7.63.
5-Meth oxyca r bon yl-4-(2,4-d ich lor op h en yl)-6-m eth yl-3,4-
d ih yd r op yr im id in -2(1H)-on e (En tr y 6). mp 242-244 °C. IR
(KBr): 3380, 3230, 3104, 2960, 1700, 1641, 1613 cm-1. 1H NMR
δ 9.13 (br s, N1-H), 7.31 (s, 1H), 7.12-7.24 (m, 2H), 6.98 (br s,
N3-H), 5.63 (s, 1H), 3.55 (s, 3H), 2.33 (s, 3H). EIMS: m/z (%)
314 (M+, 26), 299 (85), 279 (100), 255 (98), 219 (8), 183 (66), 170
(100), 137 (93), 110 (32), 67 (11), 42 (50). Anal. Calcd for
C13H12N2O3Cl2: C, 49.54; H, 3.83; N, 8.89. Found: C, 49.51; H,
3.76; N, 8.78.
5-Eth oxyca r bon yl-4-(3,4-d im eth oxyp h en yl)-6-eth yl-3,4-
d ih yd r op yr im id in -2(1H)-on e (En tr y 7). mp 163-165 °C. IR
(KBr): 3340, 3230, 3106, 2980, 1700, 1651, 1613 cm-1. 1H NMR
δ 8.90 (br s, N1-H), 7.11 (br s, N3-H), 6.72-6.89 (m, 3H), 5.23
(s, 1H), 4.02-4.18 (m, 2H), 3.85 (s, 6H), 2.73-2.78 (m, 2H), 1.15-
1.35 (m, 6H). 13C NMR δ 164.4, 152.6, 152.0, 147.6, 147.1, 136.3,
117.5, 110.2, 109.2, 98.4, 58.4, 54.7, 54.6, 53.2, 23.7, 13.0, 11.8.
EIMS: m/z (%) 334 (M+, 67), 305 (100), 261 (45), 260 (22), 197
(37), 169 (7). Anal. Calcd for C17H22N2O5: C, 61.06; H, 6.63; N,
8.37. Found: C, 60.83; H, 6.51; N, 8.18.
5-ter t-Bu toxycar bon yl-4-(3,4,5-tr im eth oxyph en yl)-6-m eth -
yl-3,4-d ih yd r op yr im id in -2(1H)-on e (En tr y 12). mp 196-198
°C. IR (KBr): 3260, 3140, 2920, 1710, 1651, 1613, 1265, 1130
cm-1 1H NMR δ 8.75 (br s, N1-H), 7.09 (br s, N3-H), 6.55 (s,
.
2H), 5.22 (s, 1H), 3.88 (s, 6H), 3.75 (s, 3H), 2.28 (s, 3H), 1.38 (s,
9H). 13C NMR δ 163.7, 151.6, 151.3, 145.4, 138.9, 135.4, 102.1,
99.5, 58.7, 57.9, 54.3, 53.1, 26.5, 16.4. EIMS: m/z (%) 378 (M+,
19), 322 (100), 292 (12), 278 (20), 156 (75), 141 (27). Anal. Calcd
for C19H26N2O6: C, 60.37; H, 6.92; N, 7.40. Found: C, 60.22; H,
6.89; N, 7.32.
5-ter t-Bu toxyca r bon yl-4-(3-fu r fu r yl)-6-m eth yl-3,4-d ih y-
d r op yr im id in -2(1H)-on e (En tr y 13). mp 169-171 °C. IR
(KBr): 3278, 3140, 2920, 1716, 1655, 1585, 1265, 1130 cm-1
.
1H NMR δ 8.82 (br s, N1-H), 7.31 (s, 1H), 7.18 (s, 1H), 6.51 (br
s, N3-H), 6.40 (s, 1H), 5.26 (s, 2H), 2.23 (s, 3H), 2.45 (s, 9H).
EIMS: m/z (%) 278 (M+), 222 (100, -56, t-But), 205 (33), 178
(100), 155 (40), 122 (10), 94 (7), 44 (52). Anal. Calcd for
C14H18N2O4: C, 60.42; H, 6.52; N, 10.06. Found: C, 60.19; H,
6.50; N, 9.95.
5-ter t-Bu toxyca r bon yl-4-(3,4-d im eth oxyp h en yl)-6-m eth -
yl-3,4-d ih yd r op yr im id in e-2(1H)-th ion e (En tr y 8). mp 193-
J O0205199
590 J . Org. Chem., Vol. 68, No. 2, 2003