An efficient protocol for the liquid-phase synthesis of methyl 3,4-dihydropyrimidin-2(1H)-one-5-carboxylate derivatives

Article abstract of DOI:10.1055/s-2003-36816

Methyl 3,4-dihydropyrimidin-2(1H)-one-5-carboxylate derivatives 7 were effectively synthesized on the soluble polymer of polyethylene glycol (PEG) 4000 by heating or solvent-free microwave irradiation through the Biginelli three-component cyclocondensation. Compared with the classical solution-phase Biginelli reactions, the yields could be considerably improved and the reaction time could be shortened dramatically under microwave promotion in a liquid-phase protocol. Moreover, the polymer-supported synthesis provided the target compounds in high purity.

Full text of DOI:10.1055/s-2003-36816

262
PAPER
An Efficient Protocol for the Liquid-Phase Synthesis of Methyl 3,4-Dihydro-
pyrimidin-2(1H)-one-5-carboxylate Derivatives
Methyl 3,4-Dihydropyi
n
-2(1
H
)
-one-5-carbo
X
xylate Derivative
i
a,*a Yan-guang Wangb
a
Department of Applied Chemistry, Zhejiang Institute of Science and Technology, Hangzhou 310033, P. R. China
Fax 0086(0571)88802212; E-mail: chchxm@21cn.com
b
Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. China
Received 19 August 2002; revised 30 October 2002
the advantages of homogeneous solution chemistry (high
reactivity, lack of diffusion phenomena and ease of anal-
ysis without the cleavage-and-check procedure) with
those of solid-phase chemistry (use of excessive reagents
Abstract: Methyl 3,4-dihydropyrimidin-2(1H)-one-5-carboxylate
derivatives 7 were effectively synthesized on the soluble polymer of
polyethylene glycol (PEG) 4000 by heating or solvent-free micro-
wave irradiation through the Biginelli three-component cyclocon-
densation. Compared with the classical solution-phase Biginelli and easy isolation and purification of products). More-
reactions, the yields could be considerably improved and the reac-
over, owing to the homogeneity of liquid-phase reactions,
tion time could be shortened dramatically under microwave promo-
the reaction conditions can be readily shifted from solu-
tion in a liquid-phase protocol. Moreover, the polymer-supported
tion-phase systems without large changes, and the amount
synthesis provided the target compounds in high purity.
of the excessive reagents is less than that in solid-phase re-
Key words: Biginelli reaction, condensation, polymers, cycliza-
actions. Among the various soluble polymers, polyethyl-
tions, heterocycles, liquid-phase synthesis, polyethylene glycol, mi-
ene glycol (PEG) is the most useful and promising. In
crowave irradiation
connection with our work on the synthesis of small molec-
ular compounds on soluble polymer,9 we herein devel-
oped the Biginelli reaction on PEG 4000 (1) that offers the
3,4-Dihydropyrimidin-2(1H)-one derivatives 7 (named as
Biginelli compounds, DHPMs) represent a heterocyclic
desired products i.e. 3,4-dihydropyrimidinone derivatives
7 in good to excellent yields and high purity after the di-
system of remarkable pharmacological efficacy.1 Recent-
rect cleavage from PEG, maintaining the simplicity of the
ly, appropriately functionalized DHPMs have emerged as
one-pot procedure (Scheme1). To our knowledge, this is
potent calcium channel blockers,2 antihypertensive
the first report of a liquid-phase synthesis of Biginelli
compounds.
agents,3
adrenergic antagonists4 and neuropeptide Y
1a
antagonists.5 The most straightforward protocol to synthe-
size DHPMs 7 involves the one-pot and one-step conden-
sation of a -keto ester, an aldehyde and urea under
strongly acidic conditions, termed as Biginelli cyclocon-
densation.6 Unfortunately, one major drawback of this
protocol lies in the fact that it often provides only low to
moderate yields (20–50%) of the desired target products,
in particular when substituted aromatic aldehydes are em-
ployed. Generally, in order to drive the reaction to com-
pletion, an excess of two of the three components has to
be used for solution-phase synthesis. So far, problems
with the workup, recrystallization or chromatography
steps are inevitable, and the resultant loss of products can-
not be neglected in some cases. Although the solid-phase
strategy on insoluble polymers has appeared to solve the
problem of separation and purification,7 their drawbacks
of long-step modification and linkage on resins, high cost,
and complicated cleavage-and-analysis techniques hinder
their further developments in combinatorial and parallel
synthesis.
The PEG 4000 linked acetoacetate 3 was prepared by re-
acting of PEG 4000 (1) with 2,2,6-trimethyl-4H-1,3-diox-
in-4-one (2) (i.e. diketene acetone adduct, TKD)10 in
anhydrous toluene under reflux for 5 hours. The conver-
sion of the terminal hydroxyl groups on PEG 4000 was
1
determined by H NMR to be quantitative. The liquid-
phase synthesis of DHPMs 7 was achieved as follows: the
PEG 4000 linked acetoacetate 3, urea 4 and corresponding
aldehyde 5 were mixed in the ratio of 1:4:4 in MeCN with
2–3 drops of concd hydrochloric acid as the catalyst. The
resulting mixture was refluxed for 18 hours and the sol-
vent was removed. The residue was dissolved in a small
volume of CH2Cl2 and Et2O was poured with stirring to
precipitate the solid, which was washed several times with
Et2O and EtOAc. The target compounds 7 were obtained
by cleavage from the PEG support under the treatment of
the polymer bound products 6 with NaOMe (1 N) in
MeOH. Complete cleavage of the products was deter-
mined by the observation of the downfield shift of the -
methylene protons at the polymer attached site from
=
Recently, organic synthesis of small molecular com-
pounds on soluble polymers, i.e. liquid-phase chemistry,
has increasingly become the attractive field.8 It couples
4.4 to 3.6 in the 1H NMR. If the peak of the -methylene
protons was still present after NMR checking, the recov-
ered PEG bound products could be resubmitted to the
same reaction conditions until a completed scission was
reached. Normally, it was enough for complete cleavage
in NaOMe (1 N)–MeOH overnight.
Synthesis 2003, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2003,0,02,0262,0266,ftx,en;F06502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Methyl 3,4-Dihydropyrimidin-2(1H)-one-5-carboxylate Derivatives
263
Scheme 1
The results are indicated in Table 1. It can be seen from progress without following the cleavage-and-check pro-
Table 1 that the yields were much improved over those in cedure.
classical solution-phase Biginelli reactions, due to the
It appeared that there was no apparent electronic effect on
ability to use excess of reagents to drive the reaction in liq-
the Biginelli reaction in that aryl aldehydes with electron-
uid-phase strategy. Also, thanks to the adoption of poly-
withdrawing or electron-donating groups offered good
mer-supported synthesis, the complicated separation was
yields. In addition to aryl aldehydes, heterocyclic and , -
simplified and the excessive reagents could be removed
unsaturated aldehydes were both effective substrates.
by ready washing and filtration before the deprotection
Another shortcoming of the classical Biginelli reactions
step to provide the crude products in high purity (>91%,
was the long time (18–36 h) they took for completion. Al-
though there have been some modifications to reduce the
reaction time to within several hours using Lewis acids,
such as FeCl3,11 Yb(OTf)3,12 InCl3,13 LaCl3,14 etc., these
condition could not be transferred to the PEG supported
reaction system, since the Lewis acids would become in-
effective due to the strong coordination between Lewis
acids and the oxygen atoms on the PEG chain. In recent
years, the application of microwave (MW) irradiation in
organic synthesis has been the focus of considerable atten-
tion and is becoming an increasingly popular technolo-
gy.15 The prominent features of the microwave approach
are the rapid reaction rates, clean reaction conditions and
ease of manipulation. Reactions in ‘dry media’ or under
solvent-free conditions are especially appealing as they
provide an opportunity to work with open vessels, thus
avoiding the risk of high pressure development. Recently,
we have reported that PEG 4000 could be utilized as a
polymeric support and solvent as well under microwave-
assisted reaction.16 Herein we described the microwave-
induced Biginelli cyclocondensation on PEG 4000 sup-
port.
Stefani et al. has reported17 that DHPMs 7 could be syn-
thesized with methyl acetoacetate, urea and correspond-
ing aldehyde under MW heating. However, due to the
absence of acidic catalyst, this protocol could only offer
low to moderate yields. It appeared that in order to obtain
good yields, acidic catalyst was indispensable in spite of
the MW promotion. Considering several protonic acids,
such as HCl, H2SO4, CF3CO2H, CF3SO3H, etc., we chose
the non-volatile, high boiling point and non-oxidant poly-
phosphoric acid (PPA) as the catalyst. Kappe et al.
reported18 that PPA was an effective catalyst in solution-
phase Biginelli reactions because it favored the formation
of an N-acyliminium ion intermediate, which was the key
intermediate in the one-pot synthesis according to its
determined by HPLC).26 More importantly, crude prod-
ucts of high purity obtained from the liquid-phase proto-
col were especially valuable since libraries were usually
not purified before pharmaceutical screening. It was wor-
thy to note that, in contrast to the various restrictions on
the analysis of reaction developed in the solid-phase syn-
thesis, the liquid-phase protocol allowed routine analyti-
cal instruments (UV, NMR, TLC, etc.) to monitor reaction
Table 1 Liquid-Phase Synthesis of DHPM Derivatives on a PEG
Support
Entry ArCHO
Yield (%)
Aa
Purity (%)c
Bb
7a
7b
7c
7d
7e
7f
PhCHO
91
82
4221
6722,d
2821
5123,d
5124,d
–
99.37
99.80
99.17
91.85
99.52
98.12
95.27
91.60
93.47
p-HOC6H4CHO
p-CH3 OC6H4CHO 88
o-ClC6H4CHO
m-O2NC6H4CHO
PhCH=CHCHO
o-HOC6H4CHO
(2-Furyl)CHO
85
94
89
70
72
83
7g
7h
7i
1922,d
3622,d
4121
p-NO2C6H4CHO
a Method A: PEG supported liquid-phase reaction (concd aq HCl, re-
flux 18 h) with yield relating to product isolated and purified after
cleavage from polymer.
b Method B: classical solution-phase reaction (concd aq HCl or concd
H2SO4, reflux 18 h).
c Determined on HPLC analysis of crude products before purification.
d Yield referred to ethyl 3,4-dihydropyrimidin-2(1H)-one-5-carboxy-
late.
Synthesis 2003, No. 2, 262–266 ISSN 0039-7881 © Thieme Stuttgart · New York

264
M. Xia, Y-g. Wang
PAPER
Table 2 PEG Supported Biginelli Reaction Under MW Irradiationa
mechanism.19 We put the PEG 4000 bound acetoacetate 3,
urea (4) and corresponding aldehyde 5 together and dis-
persed them completely. Then the reaction vessel was
placed inside a large container filled with alumina, which
acted as a heat sink. After cooling, a small volume of
dichloromethane was added to the reaction mixture and
the filtrate was poured into diethyl ether to precipitate the
solid, which was washed several times with Et2O and
EtOAc. The target compounds 7 were obtained by cleav-
age from the PEG polymer in NaOMe (1 N)–MeOH solu-
tion. After a series of experiments, we found 400 W
irradiation power was the most suitable energy for the
MW assisted reaction on the PEG support and the time
needed was varied according to the property of the corre-
sponding aldehyde. During MW heating the PEG linked
acetoacetate 3 was melted into a liquid, in which sub-
strates were ensured to react with each other in homoge-
neity, especially in the cases that solid aldehydes were
used. As we knew that PEG with low molecular weight
has received attention as solvent in a wide range of reac-
Entry ArCHO
Time
(min)
Yield
(%)b
Purity
(%)c
7a
7b
7c
7d
7e
7f
PhCHO
1.5
1.5
2.0
2.0
1.5
2.5
85
82
85
77
85
71
99.23
98.89
98.57
94.13
96.55
90.46
p-CH3OC6H4CHO
m-O2NC6H4CHO
o-ClC6H4CHO
PhCH=CHCHO
a PEG supported liquid-phase reaction without solvent.
b Yield referred to product isolated and purified after cleavage from
PEG.
c Determined on HPLC analysis of crude products before purification.
tions,20 PEG 4000 in our case acted simultaneously as a a combinatorial library. Further applications of liquid-
polymeric support and as a solvent under MW irradiation, phase multicomponent synthesis of heterocycles will be
transporting energy and making the reaction system ho- reported in due course.
mogenous. The results are shown in Table 2. It indicates
that the MW-induced protocol could achieve significantly
Mps were determined on X4 mp apparatus and the thermometer was
1
improved yields over those under traditional Biginelli re-
action conditions. At the same time, the reaction time was
decreased from several hours to a few minutes.
uncorrected. H NMR spectra were obtained on a Bruker Avance
DMX 500MHz instrument. FT-IR spectra were recorded on Perkin–
Elmer 298 spectrophotometer. MS data were recorded on HP5989B
instrument. HPLC analysis was carried out on Agilent 1100
(250 4.6mm C18 Column, gradient elution 50% MeCN and 50%
H2O, 1 mL/min, UV detection at = 254 nm). MW experiments
were performed on a Galaz WP800J-823 domestic microwave ov-
en. All the chemicals were used without further purification.
Based on the MS data, we proposed a possible mechanism
of fragmentation in Scheme 2.
In conclusion, we herein described a novel and efficient
liquid-phase method of Biginelli multicomponent reac-
tion on soluble polymer. All three reactions involved
(linker attachment, cyclocondensation and resin cleavage)
allowed the synthesis of DHPM derivatives in high purity
and improved yields over those in classical solution-phase
reaction, simplifying the procedure of isolation and puri-
fication. Furthermore, the MW-promoted protocol pro-
vided a rapid and solvent-free preparation of DHPMs in
an environmentally benign and safe way. These versatile
methods produce compounds with known pharmaco-
phoric scaffolds and are thus suitable for the generation of
PEG Bound Acetoacetate 3; General Procedure
Under a flow of nitrogen, PEG4000 (1) (4 g, 2 mmol terminal hy-
droxyl groups) and TKD (2) (5 mmol) were added to anhyd toluene
(20 mL). The resulted mixture was refluxed under stirring for 5 h.
After cooling, anhyd Et2O (100 mL) was poured onto the mixture to
precipitate the yellow solid, which was washed with Et2O and
EtOAc several times. After drying in vacuo, the solid was stored for
the next step of the synthesis.
1H NMR (500 MHz, CDCl3): = 2.27 (s, 3 H, CH3), 3.49 (s, 2 H,
COCH2CO), 3.53–3.79 (m, PEG backbone, OCH2CH2O), 4.30 (t, 2
H, J = 5 Hz, PEG-OCH2CH2OCO).
Scheme 2
Synthesis 2003, No. 2, 262–266 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Methyl 3,4-Dihydropyrimidin-2(1H)-one-5-carboxylate Derivatives
265
DHPMs 7; General Procedure
Methyl 6-Methyl-4-(2-chlorophenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (7d)
White, crystalline solid; mp 224–225 ºC.
1H NMR (500 MHz, DMSO-d6): = 2.29 (s, 3 H), 3.45 (s, 3 H), 5.61
(s, 1 H), 7.31–7.39(m, 4 H), 7.71 (s, 1 H), 9.31 (s, 1 H).
At r.t., PEG 4000 linked acetoacetate 3 (1 g, 0.5 mmol), urea (4) (2.0
mmol) and corresponding aldehyde 5 (2.0 mmol) were added to the
MeCN (10 mL) containing 2–3 drops of concd aq HCl and the mix-
ture was refluxed for 18 h. After cooling, the solvent was removed
under reduced pressure and the residue was dissolved in a small vol-
ume of CH2Cl2 (3 mL), then Et2O (20 mL) was added under stirring
to precipitate the solid, which was washed with Et2O (2 10 mL)
and EtOAc (2 10 mL). After drying in vacuo, the solid was added
to the NaOMe (1 N)–MeOH solution (15 mL) to cleave the products
at r.t. overnight (checked by TLC). The target compounds 7 were
obtained by extraction from the reaction mixture with EtOAc (2 10
mL), dilution with H2O (30 mL) and then removal of the solvent.
The samples were purified by recrystallization from EtOH.
FT-IR (KBr): 3227, 3098, 2955, 1699, 1645, 1427, 1221, 1087, 760
cm–1.
MS: m/z (%) = 280 (M+, 4.07), 265 (11.68), 245 (59.21), 221
(24.50), 169 (100.00), 137 (62.35), 102 (13.98), 75 (25.33), 42
(42.07).
Methyl 6-Methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (7e)
Pale yellow, crystalline solid; mp 278–279 ºC.
DHPMs 7 by MW Irradiation; General Procedure
1H NMR (500 MHz, DMSO-d6): = 2.28 (s, 3 H), 3.54 (s, 3 H), 5.30
(d, J = 3 Hz, 1 H), 7.65–7.68 (m, 2 H), 7.93 (s, 1 H), 8.09 (s, 1 H),
8.13 (d, J = 8 Hz, 1 H), 9.41 (s, 1 H).
At r.t., PPA (2–3 drops) was added to the completely ground pow-
ders of PEG 4000 linked acetoacetate 3 (1 g, 0.5 mmol), urea (4)
(1.0 mmol) and corresponding aldehyde 5 (1.0 mmol). The resulting
mixture was added into an open vessel and stirred with a spatular for
30 s, and then the vessel was placed inside a large container filled
with alumina at the center of the domestic microwave oven. After
irradiated at 400 W for the necessary time, the mixture was cooled
to r.t. and a small volume of CH2Cl2 (5 mL) was added into it. After
filtration, Et2O (20 mL) was poured under stirring to precipitate the
solid, which was washed several times with Et2O (2 10 mL) and
EtOAc (2 10 mL). The cleavage step was performed according to
the above procedure. The samples were purified by recrystallization
from EtOH.
FT-IR (KBr): 3357, 3221, 3103, 2957, 1700, 1642, 1535, 1435,
1348, 1230, 1098, 824, 693 cm–1.
MS: m/z (%) = 291 (M+, 43.67), 276 (58.99), 232 (86.13), 186
(20.06), 169 (100.00), 137 (78.76), 110 (17.33), 76 (34.55), 42
(61.32).
Methyl 6-Methyl-4-styryl-3,4-dihydropyrimidin-2(1H)-one-5-
carboxylate (7f)
Pale yellow, crystalline solid; mp 216 ºC (decomp.).
FT-IR (KBr): 3245, 3114, 2952, 1722, 1684, 1645, 1433,
1319,1248, 1099, 976, 777, 757, 693 cm–1.
1H NMR (500 MHz, DMSO-d6): = 2.19 (s, 3 H), 3.63 (s, 3 H), 4.72
(t, J = 4 Hz, 1 H), 6.19 (dd, J = 5.5, 6 Hz, 1 H), 6.34 (d, J = 16 Hz,
1 H), 7.23 (t, J = 7 Hz, 1 H), 7.31 (t, J = 8 Hz, 2 H), 7.39 (d, J = 7.5
Hz, 2 H), 7.56 (s, 1 H), 9.17 (s, 1 H).
Methyl 6-Methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one-5-
carboxylate (7a)
White, crystalline solid; mp 213–214 ºC (lit.21 209–212 ºC).
FT-IR (KBr): 3334,3222, 3105, 2950, 1699, 1667, 1639, 1433,
1342, 1238, 11092, 937, 793, 755, 698 cm–1.
MS: m/z (%) = 272 (M+, 100.00), 257 (48.07), 240 (37.64), 213
(87.63), 195 (19.96), 169 (70.70), 137 (91.10), 128 (24.69), 110
(42.93), 103 (20.85), 91 (23.60), 77 (55.82), 51 (37.01), 42 (97.74).
1H NMR (500 MHz, DMSO-d6): = 2.25 (s, 3 H), 3.52 (s, 3 H), 5.13
(d, J = 3 Hz, 1 H), 7.22–7.25 (m, 3 H), 7.30–7.33 (m, 2 H), 7.76 (s,
1 H), 9.23 (s, 1 H).
MS: m/z (%) = 246 (M+, 13.51), 231 (25.55), 214 (17.42), 187
(25.24), 169 (100.00), 137 (62.14), 77 (24.98), 42 (36.99).
Methyl 6-Methyl-4-(2-hydroxyphenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (7g)
White, crystalline solid; mp 243–244 ºC.
Methyl 6-Methyl-4-(4-hydroxylphenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (7b)
White, crystalline solid; mp 231–233 ºC.
FT-IR (KBr): 3415, 3224, 3110, 2952, 1749, 1682, 1644, 1604,
1459, 1229, 1090, 755 cm–1.
1H NMR (500 MHz, DMSO-d6): = 2.27 (s, 3 H), 3.47 (s, 3 H), 5.44
(s, 1 H), 6.71–7.18 (m, 4 H), 7.61 (s, 1 H), 9.14 (s, 1 H), 9.63 (s, 1
H).
MS: m/z (%) = 262 (M+, 42.77), 247 (45.66), 230 (82.87), 203
(47.15), 185 (18.32), 169 (100.00), 137 (55.98), 110 (17.83), 65
(33.20), 59 (30.74), 42 (94.88).
FT-IR (KBr): 3588, 3371, 3270, 3119, 2955, 1702, 1681, 1639,
1431, 1318, 1230, 1088, 759, 658 cm–1.
1H NMR (500 MHz, DMSO-d6): = 2.23 (s, 3 H), 3.52 (s, 3 H), 5.03
(s, 1 H), 6.67 (d, J = 7.5 Hz, 2 H), 7.02 (d, J = 7.5 Hz, 2 H), 7.65 (s,
1 H), 9.15 (s, 1 H), 9.35 (s, 1 H).
MS: m/z (%) = 262 (M+, 22.71), 247 (56.99), 230 (20.07), 203
(58.91), 169 (100.00), 137 (99.38), 110 (30.48), 65 (35.70), 42
(76.78).
Methyl 6-Methyl-4-(2-furyl)-3,4-dihydropyrimidin-2(1H)-one-
5-carboxylate (7h)
Pale red, crystalline solid; mp 196–198 ºC.
Methyl 6-Methyl-4-(4-methyoxylphenyl)-3,4-dihydropyrimi-
din-2(1H)-one-5-carboxylate (7c)
FT-IR (KBr): 3316, 3118, 2954, 1708, 1673, 1638, 1433, 1341,
1239, 1088, 762 cm–1.
1H NMR (500 MHz, DMSO-d6): = 2.23 (s, 3 H), 3.56 (s, 3 H), 5.19
(d, J = 3 Hz, 1 H), 6.09 (d, J = 3 Hz, 1 H), 6.34 (m, 1 H), 7.55 (d,
J = 1 Hz, 1 H), 7.78 (s, 1 H), 9.27 (s, 1 H).
MS: m/z (%) = 236 (M+, 30.24), 219 (23.12), 208 (14.79), 193
(13.47), 182 (12.80), 177 (60.89), 137 (18.81), 124 (18.61), 110
(12.23), 94 (18.91), 77 (14.76), 66 (24.34), 59 (20.62), 52 (29.52),
42 (100.00)
White, crystalline solid; mp 193–194 ºC (lit.21 192–194 ºC).
FT-IR (KBr): 3245, 3116, 2951, 1699, 1649, 1511, 1435, 1241, 196,
794 cm–1.
1H NMR (500 MHz, DMSO-d6): = 2.24 (s, 3 H), 3.52 (s, 3 H), 3.71
(s, 3 H), 5.08 (d, J = 2.5 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 2 H), 7.15 (d,
J = 8.5 Hz, 2 H), 7.70 (s, 1 H), 9.19 (s, 1 H).
MS: m/z (%) = 276 (M+, 33.43), 261 (82.43), 244 (37.73), 217
(87.29), 169 (100.00), 137 (90.42), 110 (37.21), 77 (31.42), 42
(60.59).
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M. Xia, Y-g. Wang
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Methyl 6-Methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (7i)
(8) (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489.
(b) Wentworth, P.; Janda, K. D. Chem. Commun. 1999,
1917. (c) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33,
546.
(9) Shang, Y. J.; Wang, Y. G. Tetrahedron Lett. 2002, 43, 2247.
(10) Birney, D. M.; Xu, X. L.; Ham, S. J. Org. Chem. 1997, 62,
7114.
(11) Lu, J.; Ma, H. Synlett 2000, 63.
(12) Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
65, 3864.
Pale yellow, crystalline solid; mp 250–251 ºC (lit.25 246–248 ºC).
1H NMR (500 MHz, DMSO-d6): = 2.27 (s, 3 H), 3.54 (s, 3 H), 5.28
(s, 1 H), 7.50 (d, J = 7.5 Hz, 2 H), 7.93 (s, 1 H), 8.21(d, J = 7.5 Hz,
2 H), 9.40 (s,1 H).
FT-IR (KBr): 3367, 3223, 3115, 2950, 2834, 1717, 1688, 1636,
1517, 1434, 1354, 1228, 1095, 803 cm–1.
MS: m/z (%) = 291 (M+, 8.08), 276 (25.66), 232 (13.34), 186
(15.95), 169 (100.00), 137 (76.74), 110 (11.34), 76 (12.96), 50
(13.00), 42 (48.89).
(13) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
(14) Lu, J.; Bai, Y. J.; Wang, Z. J.; Yang, B. Q.; Ma, H. R.
Tetrahedron Lett. 2000, 41, 9075.
References
(15) (a) Varma, R. S. Green Chem. 1999, 43. (b) Loupy, A.;
Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.;
Mathe, D. Synthesis 1998, 1213.
(1) (a) Kappe, C. O. Tetrahedron 1993, 49, 6937. (b)Kappe, C.
O. Eur. J. Med. Chem. 2000, 35, 1043. (c) Kappe, C. O.
Acc. Chem. Res. 2000, 33, 879. (d) Lu, J.; Yang, B. Q.; Bai,
Y. J. Chin. J. Org. Chem. 2001, 21, 640.
(2) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, D. J.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
1995, 38, 119.
(3) Grover, G. J.; Dzwomczyk, S.; McMullen, D. M.;
Normadinam, C. S.; Sleph, P. G.; Moreland, S. J. J.
Cardiovasc. Pharmacol. 1995, 26, 289.
(4) Silder, D. R.; Larsen, R. D.; Chartrain, M.; Ikemote, N.;
Roberge, C. M.; Taylor, C. S.; Li, W.; Bills, G. F. PCT Int.
WO 99 07695, 1999.
(16) Xia, M.; Wang, Y. G. J. Chem. Res. 2002, 173.
(17) Stefani, H. A.; Gatti, D. M. Synth. Commun. 2000, 30, 2165.
(18) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
(19) Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
(20) (a) Totten, G. E.; Clinton, N. A. J. M. S. Rev. Macromol.
Chem. Phys. 1988, C28, 293. (b) Totten, G. E.; Clinton, N.
A. J. M. S. Rev. Macromol. Chem. Phys. 1998, C38, 77.
(21) Hu, E. H.; Sidler, D.; Dolling, U. H. J. Org. Chem. 1998, 63,
3454.
(22) Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55,
2886.
(23) McKinstry, D. W.; Reading, E. H. J. Franklin Inst. 1944,
237, 203.
(24) Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem.
Soc. 1932, 54, 3751.
(25) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799.
(26) The purity was determined by HPLC analysis on Agilent
1100 (250 4.6 mm C18 Column, gradient elution 50%
MeCN and 50% H2O, 1 mL/min, UV detection at = 254
nm).
(5) Bruce, M. A.; Pointdexter, G. S.; Johnson, G. PCT Int. Appl.
WO 98 33791, 1998.
(6) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(7) (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819. (b) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J.
Org. Chem. 1997, 62, 2917. (c) Kappe, C. O. Bioorg. Med.
Chem. Lett. 2000, 10, 49.
Synthesis 2003, No. 2, 262–266 ISSN 0039-7881 © Thieme Stuttgart · New York