Catalysis of the Biginelli reaction by ferric and nickel chloride hexahydrates. One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1055/s-2002-20956

An efficient synthesis of 3,4-dihydropyrimidinones from the aldehyde, β-keto ester and urea in ethanol, using ferric chloride hexahydrate or nickel chloride hexahydrate as the catalyst, is described. Compared with the classical Biginelli reaction conditio

Full text of DOI:10.1055/s-2002-20956

4
66
PAPER
Catalysis of the Biginelli Reaction by Ferric and Nickel Chloride
Hexahydrates. One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
O
J
ne-Pot
S
u
ynthesis of
3
n
,4-Dihydropyrimid
L
in-2(1
H
)-ones u,* Yinjuan Bai
Department of Chemistry, Northwest University, Shaanxi Province Key Laboratory of Physico-inorganic Chemistry. Xi’an, Shaanxi
10069, P. R. China
7
E-mail: lujunyue@hotmail.com
Received 19 November 2001
ed for Biginelli reactions carried out under microwave
irradition.12 Several combinatorial approaches towards
DHPMs 4 have been also advanced, using solid phase or
Abstract: An efficient synthesis of 3,4-dihydropyrimidinones from
the aldehyde, -keto ester and urea in ethanol, using ferric chloride
hexahydrate or nickel chloride hexahydrate as the catalyst, is de-
scribed. Compared with the classical Biginelli reaction conditions,
13
fluorous phase reaction conditions. More recently, sev-
this new method has the advantage of excellent yields (53–97%) eral other conditions for the one-pot syntheses of dihydro-
pyrimidinones have also been reported.1
4–18
In recent
and short reaction time (4 5 hours).
Key words: Biginelli reaction, dihydropyrimidine-2(1H)-ones, years, ferric chloride hexahydrate and nickel chloride
nickel chloride hexahydrate, ferric chloride hexahydrate
hexahydrate have emerged as extraordinarily efficient cat-
alysts in carbon-carbon bond forming reactions, such as
the Michael reaction of 1,3-dicarbonyl compounds and
19
20
In the past decade, dihydropyrimidine derivatives have enones. In a previous communication, we had reported
exhibited important pharmacological properties, as the in- that ferric chloride hexahydrate can catalyze Biginelli re-
tegral backbone of several calcium channel blockers, an- action. However, the use of nickel chloride hexahydrate as
tihypertensive agents, alpha-1a-antagonists, and neuro- a catalyst in the synthesis of pyrimidinones has not been
1
reported yet. Herein, we report a general and practical
route for the Biginelli cyclocondensation reaction using
either ferric chloride hexahydrate or nickel chloride
hexahydrate as a mild catalyst. The 3,4-dihydropyrimi-
din-2(1H)-one (4a) can be obtained from the reaction of
benzaldehyde, ethyl acetoacetate and urea in the presence
peptide Y (NPY) antagonists. Recently, several isolated
marine alkaloids with interesting biological activities
were also found to contain the dihydropyrimidinone-5-
2
carboxylate core. Most notably among them are the bat-
zelladine alkaloids, which have been found to be potent
3
HIV gp-120-CD4 inhibitors. Consequently, synthesis of
the heterocyclic nucleus contained in such compounds has of ferric chloride hexahydrate or nickel chloride hexahy-
gained importance.
drate in 94% and 97% yield, respectively. Similarly, the
treatment of several aromatic, aliphatic and heterocyclic
aldehydes with ethyl acetoacetate and urea also gave the
corresponding dihydropyrimidinones in excellent yields
The Biginelli reaction, first reported more than a century
ago and recently reviewed, involves the acid-catalyzed
cyclocondensation reaction of ethyl acetoacetate (1),
benzaldehyde (2) and urea (3). This reaction is carried out
4
(
Scheme 1).
by simply heating a mixture of the above three compo- This is a novel, one-pot combination that not only pre-
nents dissolved in ethanol with a catalytic amount of hy- serves the simplicity of Biginelli’s one-pot reaction but
drochloric acid at reflux temperature for 18 hours. also consistently produces excellent yields of the dihydro-
However, this one-pot, one step protocol often provides pyrimidin-2(1H)-ones. In the presence of the ferric or
only low to moderate yields of the desired target mole- nickel chloride hexahydrates (2.5 mmol), the reaction of
–
keto ester 1 (10 mmol), aldehyde 2 (10 mmol), and urea
cules 4 (20 50%), in particular when substituted aromatic
or aliphatic aldehydes are employed. Therefore, the dis-
covery of milder and practical routes for the synthesis of
dihydropyrimidin-2(1H)-ones by the Biginelli reaction
continues to attract the attention of researchers. Recently,
several improved procedures for the preparation of
3
(15 mmol) was carried out in a one-pot condensation
employing refluxing ethanol, which has previously been
employed successfully in the Biginelli condensation as
solvent. In the experiment, we found that the correspond-
ing compound 4n cannot be obtained when the aldehyde
DHPMs (‘Biginelli compounds’) have been reported, ei- was furfuraldehyde and ferric chloride hexahydrate was
ther by modification of the classical one-pot Biginelli ap- used as a catalyst. However, when nickel chloride hexahy-
5
proach itself, such as polyphosphate ester (PPE), Lewis drate was used as a catalyst in this one-pot procedure, 4n
6
–8
9,10
acids, lanthanide compounds
or by the development was obtained in 56% yield. Meanwhile, even for aliphatic
1
1
of novel but more complex multistep strategies. In addi- aldehydes such as butyraldehyde and iso-butyraldehyde,
tion, significant rate and yield enhancements were report- which normally show extremely poor yields in the Bigi-
nelli reaction,21 the corresponding dihydropyrimidin-
2
(1H)-ones 4j and 4k could be obtained in moderate
Synthesis 2002, No. 4, 15 03 2002. Article Identifier:
437-210X,E;2002,0,04,0466,0470,ftx,en;F08501SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
1
©
yields (Table). Under these conditions, the yields of the
one-pot Biginelli reaction can be increased to 53 97%

PAPER
One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
467
R1
2
R O2C
H
O
O
O
O
N
Catalyst
NH2 EtOH, reflux 4-5 h
R1 CHO
Me
OR2
+
+
H2N
Me
N
H
1
2a-s
3
4a-s
Catalyst: NiCl 6H O or FeCl3 6H O
2
2
2
Scheme 1
and the reaction time can also be shortened from 18 to terception of the iminium ion by ethyl acetoacetate pro-
4
5 hours.
duces an open-chain ureide 7 which subsequently cyclizes
to the dihydropyrimidinone 4. Owing to the empty orbital
in the iron and nickel ion, a complex 6 can be formed
through a coordinative bond and stabilized by iron and
nickel. We have proposed a mechanism for the iron(III)
and nickel(II) promoted Biginelli reaction in Scheme 2.
Recently, the mechanism of the Biginelli reaction was re-
2
3
investigated in detail by Kappe. He proposed and estab-
lished that the first step in this reaction, the acid-catalyzed
formation of acyl imine intermediate formed by reaction
of the aldehyde with urea, is the key rate-limiting step. In-
Table Iron (III) and Nickel (II) Catalyzed Synthesis of Dihydropyrimidinonesa
Entry
R1
R2
Yield (%)
Ab
Mp (°C)e
Found
Bc
97
90
82
81
87
86
82
95
94
64
62
58
91
56
88
94
90
85
92
Cd
78
61
49
–
Reported
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
C H
Et
94
94
82
80
84
83
93
82
83
72
53
61
92
–
202 203
201 202
188 189
256 258
226 228
208 209
215 216
192 193
185 186
152 154
170 171
201 203
249 250
202 204
231 232
204 205
236 238
192 194
209 211
202.422
6
5
4-(CH O)-C H
4
Et
201 20222
187 18822
256 25722
227 22922
207 208.522
213 2156
192 19320
185 18620
153~15522
170~17222
201 20222
249 2509
204.5 20522
232 23322
204 2076
235 2376
192 1946
209 2126
3
6
3,4-(OCH O)-C H
Et
2
6
3
4-(NMe )-C H
4
Et
2
6
4-(OH)-C H
Et
67
58
56
56
58
15
10
19
69
36
42
56
41
28
42
6
4
4-(NO )-C H
4
Et
2
6
g
h
i
4-(Cl)-C H
Et
6
4
4
3-(Cl)-C H
Et
6
3-(Br)-C H
Et
6
4
j
CH CH CH
2
Et
3
2
k
l
(CH ) CH
Et
3
2
2-(OH)-C H
Et
6
4
m
n
o
p
q
r
s
2,4-(Cl) -C H
3
Et
2
6
Furyl-
4-(OH)-3-(OCH )-C H
3
Et
Et
86
96
87
88
86
3
6
4-(Cl)-C H
Me
Me
Me
Me
6
4
4-(NO )-C H
4
2
6
4-(CH O)-C H
4
3
6
C H
6
5
a
b
c
d
e
All the products were characterized by IR and H NMR and 13C NMR spectral and their mps compared with literature mps.
1
Method A: new reaction conditions (cat. FeCl 6H O in EtOH, reflux 4 h).
3
2
Method B: new reaction conditions (cat. NiCl 6H O/HCl in EtOH, reflux 5 h).
Method C: classical Biginelli conditions (cat. HCl in EtOH, reflux 18 h).
Melting points were uncorrected.
2
2
Synthesis 2002, No. 4, 466–470 ISSN 0039-7881 © Thieme Stuttgart · New York

4
68
J. Lu, Y. Bai
PAPER
H
N
OH
N
O
Ph
Ph
H+
2
NH2
NH2
Ph CHO
+
2
H N
NH2
-H O
M
H
2
3
O
O
6
5
M
O
O
Ph
Ph
Ph
EtO2C
Me
Me
OEt
EtO2C
Me
H
O
NH
EtO2C
HO
H
1
N
-H2O
N
H+
O
O
-
N
H
4
NH2
N
O
Me
H
8
7
M = Fe3+ , Ni2+
Scheme 2
In conclusion, the use of ferric chloride hexahydrate or 13C NMR (DMSO-d
): = 165.4, 158.4, 152.2, 148.0, 137.1, 127.4,
13.7, 99.6, 59.1, 55.0, 53.3, 17.7, 14.1.
6
1
nickel chloride hexahydrate as a catalyst provides an effi-
cient and much improved modification of Biginelli reac-
tion. The yields of the one-pot Biginelli reaction increased
from 20 50% to 53 97% while the reaction time short-
ened from 18 hours to 4 5 hours. This improved modifi-
cation of Biginelli reaction is a simple, high-yielding,
timesaving, and environmentally friendly process.
4
c
2
1
Solid, mp 188 189 °C (Lit. mp 187 188 °C).
IR (KBr): 3414, 3233, 3107, 2965, 1696, 1638, 1495 cm 1.
1H NMR (DMSO-d6): = 9.16 (s, 1 H), 7.66 (s, 1 H), 6.83 (d,
J = 8.0 Hz, 1 H), 6.73 (s, 1 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.96 (s, 2
H), 5.05 (d, J = 3.2 Hz, 1 H), 3.97 (q, J = 7.2 Hz, 2 H), 2.23 (s, 3 H),
1
.09 (t, J = 7.2 Hz, 3 H).
Melting points were determined in a capillary tube and are not cor-
13
C NMR (DMSO-d ): = 165.3, 152.0, 148.2, 147.2, 146.3, 138.8,
6
1
13
rected. H NMR and C NMR spectra were recorded on an
INOVA-400 NMR spectrometer using TMS as internal standard.
Elemental analyses were performed on a Perkin Elmer 2400 mi-
croanalyser and IR spectra were recorded on an EQUINOX55 spec-
trophotometer using KBr pellets.
1
19.3, 107.9, 106.6, 100.9, 99.3, 59.1, 53.6, 17.7, 14.1.
4
d
21
Solid, mp 256 258 °C (Lit. mp 257 258 °C).
IR (KBr): 3420, 3245, 3117, 2976, 1704, 1647, 1527cm 1.
1H NMR (DMSO-d6): = 9.07 (s, 1 H), 7.57 (s, 1 H), 7.02 (d,
J = 8.4 Hz, 2 H), 6.64 (d, J = 8.4 Hz, 2 H), 5.02 (d, J = 3.2 Hz, 1 H),
3.96 (q, J = 7.2 Hz, 2 H), 2.83 (s, 6 H), 2.22 (s, 3 H), 1.10 (t, J = 7.2
Hz, 3 H).
Preparation of 3,4-Dihydropyrimidinones Using FeCl 6H O or
3
2
NiCl 6H O as a Catalyst; Typical Procedure
2
2
A soln of -keto ester (10 mmol), the appropriate aldehyde (10
mmol), urea (15 mmol), catalyst (FeCl 6H O or NiCl 6H O, 2.5
3
2
2
2
mmol) and conc. HCl (1 2 drops) in EtOH (20 mL) was heated un-
der reflux for 4 5 h. After cooling, the reaction mixture was poured
onto crushed ice (100 g). Stirring was continued for several min, the
1
3
C NMR (DMSO-d ): = 165.5, 152.3, 149.7, 147.5, 132.6, 126.9,
6
1
12.2, 99.9, 59.1, 53.3, 17.7, 14.1.
solid products were filtered, washed with cold H O (2 50 mL) and
Anal. Calcd for C16
63.55; H, 6.80; N, 13.72.
H N O : C, 63.37; H, 6.93; N 13.86. Found: C,
21 3 3
2
a mixture of EtOH H O, 1:1 (3 20 mL). The solids were dried and
2
recrystallised from hot EtOH to afford pure products.
4
e
2
1
4
a
Solid, mp 226 228 °C (Lit. mp 227 229 °C).
2
1
Solid, mp 202 203 °C (lit. mp 202.4 °C).
IR (KBr): 3414, 3230, 3109, 2936, 1702, 1649, 1599 cm 1.
IR (KBr): 3417, 3241, 3120, 2984, 1687, 1649, 1512 cm 1.
1H NMR (DMSO-d6): = 9.32 (s, 1 H), 9.11 (s, 1 H), 7.61 (s, 1 H),
7.02 (d, J = 8.4 Hz, 2 H), 6.69 (d, J = 8.4 Hz, 2 H), 5.04 (d, J = 3.2
Hz, 1 H), 3.97 (q, J = 7.2 Hz, 2 H), 2.23 (s, 3 H), 1.08 (t, J = 7.2 Hz,
3 H).
1
H NMR (DMSO-d ): = 9.17 (s, 1 H), 7.72 (s, 1 H), 7.21–7.32 (m,
6
5
H), 5.14 (s, 1 H), 3.98 (q, J = 7.2 Hz, 2 H), 2.24 (s, 3 H), 1.08 (t,
J = 7.2 Hz, 3 H).
1
3
13C NMR (DMSO-d
115.0, 99.8, 59.1, 53.5, 17.8, 14.1.
C NMR (DMSO-d ): = 165.4, 152.2, 148.4, 144.9, 128.4, 127.3,
6
): = 165.4, 156.6, 152.2, 147.8, 135.5, 127.4,
6
1
26.3, 99.3, 59.2, 54.0, 17.8, 14.1.
4
b
4f
2
1
21
Solid, mp 201 202 °C (Lit. mp 201 202 °C).
Solid, mp 208 209 °C (Lit. mp 207 208.5 °C).
IR (KBr): 3415, 3241, 3114, 2954, 1708, 1646, 1512 cm 1.
IR (KBr): 3416, 3237, 3085, 2941, 1728, 1694, 1588, 1509 cm 1.
1H NMR (DMSO-d6): = 9.14 (s, 1 H), 7.66 (s, 1 H), 7.14 (d,
J = 8.4 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.08 (d, J = 2.8 Hz, 1 H),
1H NMR (DMSO-d
7.89 (s, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 5.26 (d, J = 3.2 Hz, 1 H),
3.94 (q, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.07 (t, J = 7.2 Hz, 3 H).
): = 9.32 (s, 1 H), 8.28 (d, J = 8.4 Hz, 2 H),
6
3
.97 (q, J = 7.2 Hz, 2 H), 3.71 (s, 3 H), 2.23 (s, 3 H), 1.09 (t, J = 7.2
Hz, 3 H).
13
C NMR (DMSO-d ): = 165.3, 152.2, 152.1, 149.6, 146.9, 127.9,
6
1
24.0, 98.5, 59.7, 53.9, 18.0, 14.2.
Synthesis 2002, No. 4, 466–470 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
469
4
g
4m
6
9
Solid, mp 215 216 °C (Lit. mp 213 215 °C).
Solid, mp 249 250 °C (Lit. mp 249 250 °C).
IR (KBr): 3419, 3246, 3112, 2980, 1708, 1646, 1487 cm 1.
IR (KBr): 3415, 3219, 3104, 2969, 1699, 1641 cm 1.
1H NMR (DMSO-d6): = 9.23 (s, 1 H), 7.75 (s, 1 H), 7.38 (d,
J = 8.8 Hz, 2 H), 7.24 (d, J = 8.8 Hz, 2 H), 5.14 (d, J = 2.8 Hz, 1 H),
1
H NMR (DMSO-d ): = 9.33 (s, 1 H), 7.77 (s, 1 H), 7.31–7.57 (m,
6
3 H), 5.59 (d, J = 2.8 Hz, 1 H), 3.90 (q, J = 7.2 Hz, 2 H), 2.29 (s, 3
3
.97 (q, J = 7.2 Hz, 2 H), 2.24 (s, 3 H), 1.08 (t, J = 7.2 Hz, 3 H).
H), 1.00 (t, J = 7.2 Hz, 3 H).
1
3
13
C NMR (DMSO-d ): = 165.2, 151.9, 148.7, 143.8, 131.8, 128.4,
C NMR (DMSO-d ): = 164.7, 151.0, 149.5, 140.9, 132.6, 132.5,
6
6
1
28.2, 98.8, 59.3, 53.4, 17.8, 14.1.
130.2, 128.6, 127.9, 97.4, 59.0, 51.1, 17.6, 13.8.
+
+
MS: m/z (%) = 328 (M , 6.69), 330 (M + 2, 4.10), 299 (47.18), 293
68.72), 255 (40.00), 183 (100.00), 155 (32.82), 137 (25.64).
4
h
(
2
0
Solid, mp 192 193 °C (Lit. mp 192 193 °C).
IR (KBr): 3416, 3224, 3098, 2980, 2926, 1704, 1651, 1593 cm 1.
4n
2
1
1
Solid, mp 202 204 °C (Lit. mp 204.5 205 °C).
IR (KBr): 3413, 3239, 3119, 2984, 1702, 1644, 1457 cm 1.
H NMR (CD COCD ): = 8.31 (s, 1 H), 7.26–7.37 (m, 4 H), 6.93
3
3
(
s, 1 H), 5.37 (d, J = 3.2 Hz, 1 H), 4.05 (q, J = 7.2 Hz, 2 H), 2.39 (s,
3
H), 1.15 (t, J = 7.2 Hz, 3 H).
1H NMR (DMSO-d6): = 9.22 (s, 1 H), 7.74 (s, 1 H), 7.53 (s, 1 H),
6.33 (d, J = 2.8 Hz, 1 H), 6.07 (d, J = 2.8 Hz, 1 H), 5.20 (d, J = 3.6
Hz, 1 H), 4.00 (q, J = 7.2 Hz, 2 H), 2.22 (s, 3 H), 1.12 (t, J = 7.2 Hz,
3 H).
1
3
C NMR (CD COCD ): = 166.1, 152.6, 149.1, 148.3, 134.5,
3
3
1
31.1, 128.2, 127.5, 125.9, 100.8, 60.2, 55.6, 18.4, 14.5.
+
MS: m/z (%) = 294 (M , 5.63), 265 (37.47), 221 (24.01), 183
1
3
(
100.00), 155 (39.33), 137 (33.51).
C NMR (DMSO-d ): = 165.0, 155.9, 152.4, 149.3, 142.1, 110.3,
6
1
05.3, 96.8, 59.2, 47.7, 17.7, 14.1.
4
i
2
0
Solid, mp 185 186 °C (Lit. mp 185 186 °C).
4o
2
1
Solid, mp 231 232 °C (Lit. mp 232 233 °C).
IR (KBr): 3416, 3228, 3113, 2976, 2932, 1705, 1654, 1613,
1
IR (KBr): 3536, 3243, 3116, 2971, 2934, 1700, 1644, 1515 cm 1.
1
589cm .
1
1H NMR (DMSO-d6): = 9.15 (s, 1 H), 8.95 (s, 1 H), 7.66 (s, 1 H),
6.80 (s, 1 H), 6.75 (d, J = 8.4 Hz, 2 H), 6.60 (d, J = 8.4 Hz, 1 H),
5.05 (d, J = 2.8 Hz, 1 H), 3.98 (q, J = 7.2 Hz, 2 H), 3.72 (s, 3 H),
2.22 (s, 3 H), 1.11 (t, J = 7.2 Hz, 3 H).
H NMR (DMSO-d ): = 9.26 (s, 1 H), 7.78 (s, 1 H), 7.22–7.45 (m,
H), 5.14 (d, J = 3.2 Hz, 1 H), 3.95 (q, J = 7.2 Hz, 2 H), 2.25 (s, 3
6
4
H), 1.09 (t, J = 7.2 Hz, 3 H).
1
3
C NMR (DMSO-d ): = 165.2, 151.9, 148.9, 147.5, 130.8, 130.2,
6
1
3
1
29.2, 125.3, 121.5, 98.6, 59.3, 53.6, 17.8, 14.1.
C NMR (DMSO-d ): = 165.3, 152.1, 147.8, 145.6, 135.8, 118.1,
6
+
+
115.1, 110.7, 99.4, 59.0, 55.4, 53.4, 17.6, 14.0.
MS: m/z (%) = 339 (M + H, 22.23), 341 (M + 2 + H, 20.48), 309
(
(
20.70), 311 (19.88), 265 (13.96), 267 (11.73), 183 (100.00), 155
30.64), 137 (21.34).
4
p
6
Solid, mp 204 205 °C (Lit. mp 205 207 °C).
4
j
IR (KBr): 3364, 3221, 3103, 2947, 1712, 1636, 1494 cm 1.
2
1
Solid, mp 152 154 °C (Lit. mp 153 155 °C).
1H NMR (DMSO-d6): = 9.30 (s, 1 H), 7.82 (s, 1 H), 7.40 (d,
J = 8.4 Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 5.14 (d, J = 2.8 Hz, 1 H),
3.53 (s, 3 H), 2.25 (s, 3 H).
IR (KBr): 3414, 3247, 3119, 1709, 1676, 1646 cm 1.
1H NMR (CDCl3): = 8.55 (s, 1 H), 6.30 (s, 1 H), 4.31 (s, 1 H), 4.15
1
3
(
q, J = 7.2 Hz, 2 H), 2.28 (s, 3 H), 1.40–1.59 (m, 4 H), 1.28 (t,
C NMR (DMSO-d ): = 165.6, 151.9, 148.9, 143.5, 131.7, 128.4,
6
J = 7.2 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H).
128.0, 98.4, 53.1, 50.7, 17.7.
1
3
C NMR (CDCl ): = 165.9, 154.9, 146.8, 101.5, 59.8, 51.2, 39.1,
Anal. Calcd for C H N O Cl: C, 55.61; H, 4.63; N, 9.98. Found:
3
13 13
2
3
1
8.4, 17.5, 14.3, 13.7.
C, 55.80; H, 4.32; N, 9.72.
4
k
4q
2
1
6
Solid, mp 170 171 °C (Lit. mp 170–172 °C).
Solid, mp 236 238 °C (Lit. mp 235 237 °C).
IR (KBr): 3413, 3237, 3106, 1700, 1646 cm 1.
IR (KBr): 3364, 3222, 3113, 2949, 1717, 1640, 1516 cm 1.
1H NMR (CDCl3): = 8.61 (s, 1 H), 6.31 (s, 1 H), 4.23 (s, 1 H), 4.16
1H NMR (DMSO-d6): = 9.41 (s, 1 H), 8.22 (d, J = 8.4 Hz, 2 H),
(
q, J = 7.2 Hz, 2 H), 2.29 (s, 3 H), 1.85 (m, 1 H), 1.28 (t, J = 7.2 Hz,
7.93 (s, 1 H), 7.51 (d, J = 8.4 Hz, 2 H), 5.27 (d, J = 2.8 Hz, 1 H),
3
H), 0.91 (d, J = 6.4 Hz, 3 H), 0.86 (d, J = 6.4 Hz, 3 H).
3.54 (s, 3 H), 2.27 (s, 3 H).
1
3
13
C NMR (CDCl ): = 166.2, 155.3, 147.1, 100.2, 59.8, 56.8, 34.5,
C NMR (DMSO-d ): = 165.5, 151.7, 149.5, 146.6, 127.5, 123.8,
3
6
1
8.4, 15.6, 14.3.
109.2, 97.8, 53.4, 50.8, 17.8.
4
l
4r
6
6
Solid, mp 201 203 °C (Lit. mp 201 202 °C).
Solid, mp 192 194 °C (Lit. mp 192 194 °C).
IR (KBr): 3414, 3236, 3119, 2984, 1720, 1702, 1644, 1521 cm 1.
1H NMR (DMSO-d6): = 9.33 (s, 1 H), 8.20 (d, J = 8.4 Hz, 2 H),
IR (KBr): 3415, 3247, 3111, 2953, 1719, 1683, 1512 cm 1.
1H NMR (DMSO-d6): = 9.20 (s, 1 H), 7.70 (s, 1 H), 7.14 (d,
J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 5.08 (d, J = 2.8 Hz, 1 H),
3.72 (s, 3 H), 3.52 (s, 3 H), 2.24 (s, 3 H).
13
7
3
.87 (s, 1 H), 7.49 (d, J = 8.4 Hz, 2 H), 5.26 (d, J = 3.2 Hz, 1 H),
.97 (q, J = 7.2 Hz, 2 H), 2.26 (s, 3 H), 1.08 (t, J = 7.2 Hz, 3 H).
1
3
C NMR (DMSO-d ): = 165.1, 152.0, 151.8, 149.4, 146.7, 127.7,
C NMR (DMSO-d ): = 165.7, 158.3, 152.0, 148.3, 136.7, 127.2,
6
6
1
23.8, 98.2, 59.4, 53.7, 17.9, 14.1.
113.6, 99.1, 54.9, 53.0, 50.7, 17.7.
Synthesis 2002, No. 4, 466–470 ISSN 0039-7881 © Thieme Stuttgart · New York

4
70
J. Lu, Y. Bai
PAPER
(9) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
4
s
6
Solid, mp 209 211 °C (Lit. mp 209 211 °C).
Lett. 2000, 41, 9075.
IR (KBr): 3332, 3223, 3105, 2948, 1697, 1666 cm 1.
(10) Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
65, 3864.
1
H NMR (DMSO-d ): = 9.24 (s, 1 H), 7.70 (s, 1 H), 7.34–7.22 (m,
6
(11) Atwal, K. S.; Rovnyak, G. C.; O' Reilly, B. C.; Schwartz, J.
J. Org. Chem. 1989, 54, 5898.
(12) (a) Stadler, A.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1
5
H), 5.14 (d, J = 2.8 Hz, 1 H), 3.53 (s, 3 H), 2.25 (s, 3 H).
1
3
C NMR (DMSO-d ): = 165.8, 152.2, 148.7, 144.7, 128.5, 127.3,
6
2
2
000, 1363. (b) Stefani, H. A.; Gatti, P. M. Synth. Commun.
000, 30, 2165. (c) Kappe, C. O.; Kumar, D.; Varma, R. S.
1
26.2, 98.9, 53.8, 50.8, 17.9.
Synthesis 1999, 1799.
Acknowledgements
(13) (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819. (b) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J.
This work was supported by the Nature Science Foundation of
Shaan’xi Province.
Org. Chem. 1997, 62, 2917.
(
(
14) Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341.
15) Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D.
Tetrahedron Lett. 2001, 42, 7873.
References
(
1) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
(16) Dondoni, A.; Massi, A. Tetrahedron Lett. 2001, 42, 7975.
(17) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K. S.;
Prasad, A. R. J. Chem. Soc., Perkin Trans. 1 2001, 1939.
(18) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917.
(19) (a) Nelson, J. H.; Howells, P. N.; DeLullo, G. C.; Landen, G.
L.; Henry, R. A. J. Org. Chem. 1980, 45, 1246.
1995, 38, 119.
(
(
2) Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828; and
references therein.
3) (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner,
D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R.
K.; Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60,
(b) Christoffers, J. Chem. Commun. 1997, 943.
(c) Christoffers, J.; Rößler, U.; Werner, T. Eur. J. Org.
Chem. 2000, 701. (d) Christoffers, J. Synlett 2001, 723.
(20) Lu, J.; Ma, H. Synlett 2000, 63.
1
182. (b) Rama Rao, A. V.; Gujar, M. K.; Vasudevan, J. J.
(21) Eynde, J. J. V.; Audiart, N.; Canonne, V.; Michel, S.;
Haverbeke, Y. V.; Kapple, C. O. Heterocycles 1997, 45,
1967.
Chem. Soc., Chem. Commun. 1995, 1369. (c) Snider, B. B.;
Chen, J.; Patil, A. D.; Freyer, A. Tetrahedron Lett. 1996, 37,
6
977.
(22) (a) Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem.
Soc. 1932, 54, 3751. (b) Folkers, K.; Johnson, T. B. J. Am.
Chem. Soc. 1933, 55, 3361. (c) Eynde, J. J. V.; Audiart, N.;
Canonne, V.; Michel, S.; Haverbeke, Y. V.; Kapple, C. O.
Heterocycles 1997, 45, 1967. (d) Singh, K.; Singh, J.; Deb,
P. K.; Singh, H. Tetrahedron 1999, 55, 12873.
(
(
(
4) Kappe, C. O. Tetrahedron 1993, 49, 6937.
5) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
6) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998,
6
3, 3454.
7) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
270.
8) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Synlett
001, 863.
(
(
6
(23) Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
2
Synthesis 2002, No. 4, 466–470 ISSN 0039-7881 © Thieme Stuttgart · New York