One-pot, three-component synthesis of highly functionalized pyrimidone derivatives and access to indole fused pyrimidones via palladium-catalyzed intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tet.2014.04.023

A simple and facile approach to highly functionalized pyrimidone derivatives and indole fused pyrimidones has been developed. The synthesis of substituted pyrimidone derivatives in moderate to good yields involves [4+2] cycloaddition of 1,4-dipoles generated from α,β-unsarurated imines and dimethyl acetylenedicarboxylate (DMAD) with isocyanates as dipolarophiles. Furthermore, the pyrimidones resulted from 2-bromophenyl isocyanate could be transformed into various indole fused pyrimidones via intramolecular palladium-catalyzed Heck reaction under different conditions.

Full text of DOI:10.1016/j.tet.2014.04.023

Tetrahedron xxx (2014) 1e10
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot, three-component synthesis of highly functionalized
pyrimidone derivatives and access to indole fused pyrimidones
via palladium-catalyzed intramolecular Heck reaction
*
Ming Lei , Wan Tian, Wei Li, Ping Lu, Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and facile approach to highly functionalized pyrimidone derivatives and indole fused pyr-
imidones has been developed. The synthesis of substituted pyrimidone derivatives in moderate to good
Received 10 January 2014
Received in revised form 4 April 2014
Accepted 8 April 2014
Available online xxx
yields involves [4þ2] cycloaddition of 1,4-dipoles generated from
a,b-unsarurated imines and dimethyl
acetylenedicarboxylate (DMAD) with isocyanates as dipolarophiles. Furthermore, the pyrimidones re-
sulted from 2-bromophenyl isocyanate could be transformed into various indole fused pyrimidones via
intramolecular palladium-catalyzed Heck reaction under different conditions.
Ó 2014 Published by Elsevier Ltd.
Keywords:
Multi-component reactions
Pyrimidone derivatives
Indole fused pyrimidones
[4þ2] cycloaddition
Intramolecular Heck reaction
1. Introduction
biologically potent alkaloids have been isolated from the roots of
Isatis indigotica, which is commonly used in traditional Chinese
Multi-component reactions are defined as a kind of reactions
involving at least three different substrates to form products via
a tandem process. These methodologies allow molecular com-
plexity and diversity to be created by the facile formation of several
new covalent bonds in one-pot manner without isolation of the
intermediates, which combine two major principles of organic
synthesis, convergence and atom economy. Consequently, these
classes of reactions have found extensive applications in organic,
combinatorial, and medicinal chemistry for fast generation of
compound libraries.1
medicine to help overcome various diseases, especially for treating
influenza, cold, fever, and infections (Fig. 1).11 Therefore, it is highly
desirable to develop efficient synthetic methods for this class of
compound and expand their structure diversity for current me-
dicinal chemistry demands. Although several methods for
The pyrimidone skeletons exist in the core structure of several
biologically active compounds, such as PPAR agonist,2 calcium re-
ceptor (CaR) antagonist,3 methaqualone,4 GnRH receptor antago-
nist,5 angiotensin II (A II) receptor antagonist.6 Evodiamine, a major
quinazolinocarbolin alkaloid isolated from the fruit of Evodia
rutaecarpa Bentham, has been reported exhibiting vasorelaxant7
and cardiotonic effects.8 Furthermore, indole fused pyrimidones
derivatives, such as tryptanthrin and phaitanthrin E, possess vari-
ous bioactivities, such as anticancer, antimalarial, antibacterial,
antifungal and antileishmanial, respectively.9,10 Recently,
* Corresponding author. Tel.: þ86 571 87952359; fax: þ86 571 87951895; e-mail
address: leiming@zju.edu.cn (M. Lei).
Fig. 1. Some pyrimidone derivatives.
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.04.023
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2
M. Lei et al. / Tetrahedron xxx (2014) 1e10
synthesis of pyrimidone and indole fused pyrimidones derivatives
have been developed,3,12 most of these protocols suffer from te-
dious procedures, poor precursor scopes, and/or low efficiency.
Therefore the development of the facile methodologies for the
generation of highly functionalized pyrimidone derivatives library
is still challenging in organic synthetic chemistry and medicinal
chemistry.
Our previous work had successfully demonstrated that the 1,4-
dipoles generated from a,b-unsaturated imines and DMAD could
react efficiently with benzylaldehyde dipolarophiles in one-pot
[4þ2] annulations resulting in the diversity oriented synthesis of
1,3-oxazine derivatives in good to excellent yields.13 Therefore, we
from 1.1:1.1:1 to 1.2:1.2:1, better yields were obtained under the
same reaction condition (Table 1, entries 4 and 5). When the solvent
was changed to THF, DCM, methylbenzene, and dioxane, the yields
decreased significantly (Table 1, entries 6e9). In DMF or ethanol,
only trace amount of 4a were detected by TLC (Table 1, entries 10
and 11). When altering the reaction temperature to 0 ꢀC, 30 ꢀC,
50 ꢀC, and under reflux, the yields decreased slightly as compared
with at room temperature (Table 1, entries 12e15). The yield was
still maintained in 60% when the reaction time was shortened to
12 h (Table 1, entry 16). However, the yield decreased to 54% as the
time was reduced to 10 h (Table 1, entry 17). In all these cases,
byproduct 9 was observed, which generated from the side reaction
of 1,4-dipolar intermediate with DMAD. Even under the optimized
reaction conditions 9 was still obtained in 12% yield, which is
consistent with our previous observation.16 In general, in
1.2:1.2:1 M ratio of 1a, 2a, and 3a, at room temperature in aceto-
nitrile for 12 h, the reaction could give best yield in 60%.
envisioned that the
a,b-unsaturated imine-DMAD dipole would
react with isocyanates to afford pyrimidone derivatives bearing
styryl moiety. Moreover, those pyrimidones resulted from 2-
bromine phenyl isocyanate could be further transformed into in-
dole fused pyrimidones via intramolecular palladium-catalyzed
Heck reaction.14,15 These protocols well extend our ongoing re-
search on constructing diverse heterocycle compounds. Herein, we
would like to report the detailed results of our investigation.
With the optimized reaction conditions in hand, the scope and
limitations of this methodology have been examined using various
a
,
b
-unsaturated imines 1, 2 and substituted isocyanates 3 on
a 0.5 mmol scale and the results are summarized in Scheme 1. The
results revealed that the aniline moiety of -unsaturated imines
a,b
2. Results and discussion
bearing electron-donating groups tend to result in higher yield
(Scheme 1, 4s) than those bearing electron-withdrawing group
(Scheme 1, 4b and 4c). However, the electronic effect on cinna-
With the above idea in mind, we investigated the model re-
action of imine (1a), DMAD (2a), 4-methyl phenyl isocyanate (3a) in
1:1:1 ratio on a 0.5 mmol scale in acetonitrile. Fortunately, we
found that after 24 h at room temperature, the expected compound
4a accompanied with byproduct (E)-1-phenyl-6-styryl-1,6-
dihydropyridine-2,3,4,5-tetracarboxylic acid tetramethyl ester (9)
were obtained in 51% (Table 1, entry 1) and 15% isolated yield,
respectively.
maldehyde part of
resulted 54e67% yields (Scheme 1, 4deh). The steric effect of
substituent on the carbon of -unsaturated imine is significant
a,b-unsaturated imines are not significant and
a,b
and decrease the yield to 30% (Scheme 1, 4i).
Isocyanates with various functional groups are well tolerated
and those bearing electron-withdrawing groups (Scheme 1, 4j, 4k,
and 4m), which facilitate the nucleophilic attack to DMAD exhibi-
ted better activity than those bearing electron-donating groups
(Scheme 1, 4nep). Unexpectedly, low yield (30%) is observed for 2-
nitro phenyl isocyanate, which is likely due to its poor solubility
(Scheme 1, 4l). Furthermore, we studied other combinations of the
three kinds of substrate and found that all of these reactions pro-
ceeded smoothly in moderate to good yields (Scheme 1, 4qez).
While, in the case of methyl propiolate (2c), the loss of one of the
electron-withdrawing carboxylate groups led to lower activity and
afforded the product 4A in only 24% yield (Scheme 1, 4A). The
structure of compound 4r has been confirmed by single crystal X-
ray analysis (Fig. 2).
Table 1
Optimization of reaction conditions
Entrya
1a:2a:3ab
Solvent
Temp (ꢀC)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
1:1:1
1:1:1.1
1:1:1.2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
30
50
Reflux
rt
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
10
51
55
52
52
60
44
41
33
On the basis of the above results, a plausible mechanism of this
reaction is illustrated in Scheme 2.15,17 The reaction may be con-
sidered for via the initial formation of the 1,4-dipolar intermediate
1.1:1.1:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
1.2:1.2:1
I, which is generated through nucleophilic attack of
a,b-un-
saturated imines 1 to the electron-deficient triple bond of 2. Then I
was trapped by isocyanates 3, presumably by the process of [4þ2]
cycloaddition to give the final products 4.
DCM
Toluene
Dioxane
DMF
9
24
In order to access indole fused pyrimidones, we further expand
the scope of our methodology, in which compound 4j was chosen
to proceed intramolecular Heck reaction. Various catalytic systems
were tested and the results were summarized in Table 2. When we
used 10 mol % Pd(OAc)2 as catalyst, 40 mol % PPh3 as ligand,
2.5 equiv of K2CO3 as the base in DMF under N2 at 100 ꢀC for 4 h,
the expected products 5a and 6a were isolated in 40% and 5%
yields, respectively and accompanied with trace amount of de-
carboxylation product 7a (Table 2, entry 1). We also observed that
compound 5a could be transformed to 6a via the base-mediated
isomerization in presence of K2CO3 in DMF at 100 ꢀC. When us-
ing Et3N as base in DMF or toluene, the products could be obtained
in yields of close level (Table 2, entries 2 and 3). In CH3CN at 80 ꢀC
for 72 h, the reaction afforded 5a as a sole product in 35% yield
with 58% recovery of 4j (Table 2, entry 4). While in toluene at
100 ꢀC for same time, only 11% of 4j was recovered in almost same
10
11
12
13
14
15
16
17
Trace
Trace
52
58
55
54
60
54
EtOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
a
0.5 mmol scale in 2 mL of solvent.
Molar ratio.
Isolated yields of 4a based on 3a.
b
c
In order to optimize the reaction conditions, a series of reactions
of 1a, 2a, and 3a were conducted and the results were shown in
Table 1. Increasing the amount of 3a failed to improve the yield
significantly (Table 1, entries 2 and 3), while adding more 1a and 2a,
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M. Lei et al. / Tetrahedron xxx (2014) 1e10
3
a 0.5 mmol scale based on 3 in 2 mL of CH3CN at room temperature for 12 h.
b Isolated yields of 4 based on 3.
Scheme 1. Synthesis of pyrimidone derivatives by the [4þ2] cycloadditiona,b
.
level of product yield (Table 2, entry 3). So substrate 4j may be not
stable under high temperature. Other bases, such as CsF, DBU, and
Cs2CO3, were also been examined for Pd(OAc)2ePPh3 system,
these reaction afforded 7a as major product but in low yields and
selectivity (Table 2, entries 5e7). Thus, we speculated that strong
base and high temperature could able to promote the de-
carboxylation to generate 7a. It is ineffective when water was
added as co-solvent to improve the solubility of K2CO3 (Table 2,
entry 8), while adding n-Bu4NCl (1 equiv) as an additive could give
7a as major product in 51% yield with trace amount of 5a and 6a
(Table 2, entry 9). When the ligand was changed to dppf, 5a was
obtained as major product in low yield and selectivity (Table 2,
entry 10). Furthermore, other palladium sources, such as
PdCl2(PPh3)2, PdCl2, and Pd(PPh3)4, combined with various bases
and solvents, were screened (Table 2, entries 11e21) and the
highest yield of 5a for this reaction is 66% (Table 2, entry 13).
When toluene-H2O was used as solvent, Pd(PPh3)4 as catalyst and
K2CO3 as base, no 5a was observed and afforded 7a in 28% yield
(Table 2, entry 22). Herein, structures of compounds 5a, 6a, and 7a
were confirmed by single crystal X-ray analysis (Fig. 3).
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4
M. Lei et al. / Tetrahedron xxx (2014) 1e10
Originally, we believed that the generation of 7a may be in-
volved with Pd-mediated coupling. To testify our guess, we used 4-
methphenylboronic acid to trap the intermediate generated from
6a, expecting to afford compound 8. However, the result revealed
that 6a was transformed to 7a rather than coupling with 4-
methphenyl. On the other hand, 7a could be obtained without
Pd(OAc)2 and ligand (Scheme 3). So we speculated that 6a may
undergo base-induced decarboxylation and the result demon-
strated that n-Bu4NCl plays crucial role as phase transfer catalyst in
this process resulting 7a as major product (Table 2, entries 9, 15 and
22). In addition, in DMF at 100 ꢀC and in presence of 2.5 equiv
K2CO3, 5a could transform to 7a in 95% isolated yield within 4 h
(Scheme 4).
With the optimized reaction conditions in hand, the scope and
limitation of this transformation were further explored. Several
pyrimidone derivatives were investigated using Pd(PPh3)4
(10 mol %) and K2CO3 (2.5 equiv) in DMF under 100 ꢀC. The results
in Table 3 show that various substituted groups are compatible with
the reaction conditions, providing the desired 5aed as major
product in moderate to good yields (Table 3, entries 1e4). While for
substrates 4w and 4x, decarboxylation products 7e and 7f were
obtained as major product in low yields, 35% and 30%, respectively,
under the same condition (Table 3, entries 5 and 6). The low yields
may be relevant to the strong electron-withdrawing nitro group.
We also examined the condition for transformation of the above
pyrimidone derivatives to the corresponding decarboxylation
products and the results shown in Table 4. For 4j, 4t, 4v, and 4r,
using Pd(OAc)2, n-Bu4NCl, K2CO3, PPh3 in DMF, corresponding de-
carboxylation products 7aed were obtained as major product in
45e59% yields (Table 4, entries 1e4). While for substrates 4w and
Fig. 2. X-ray structure of compound 4r.
Scheme 2. Plausible reaction mechanism.
Table 2
Optimization of intramolecular Heck conditionsa
Entry
Catalyst
Ligand
Additive
Base
Solvent
T (ꢀC)
Time (h)
Yield (%)
5a
6a
7a
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
dppf
PPh3
PPh3
K2CO3
Et3N
Et3N
Et3N
CsF
DMF
DMF
100
120
100
80
4
4
72
72
4
4
4
4
4
4
4
4
4
76
4
10
72
12
18
18
72
6
40
39
37
35
Trace
0
Trace
22
Trace
21
15
57
66
41
Trace
52
43
31
5
4
5
Trace
Trace
0
0
30
36
42
6
51
Trace
Trace
Trace
Trace
0
19
0
0
Trace
Trace
0
12
Trace
21
3b
4b
5
Toluene
CH3CN
DMF
m-Xylene
DMF
DMFeH2O
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene-H2O
DMF
DMF
DMF
DMF
DMF
TolueneeH2O
110
130
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
6
7
8
9
DBU
CsCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
K2CO3
K2CO3
DIEA
Na2CO3
NaOAc
K3PO4
K2CO3
K2CO3
4
n-Bu4NCl
n-Bu4NCl
Trace
14
11
11
14
10
11
12
13
14
15
16
17
18
19
20
21b
22
0
Trace
7
0
3
Trace
34
28
Trace
28
Trace
Trace
11
41
0
n-Bu4NCl
100
3
a
Unless otherwise stated, all reactions have been carried out on a 0.25 mmol scale in 2 mL solvent.
The reactions performed incompletely with recovery of 4j in 58%, 11%, 35%, respectively.
b
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Fig. 3. X-ray structure of compound 5a, 6a, and 7a.
Table 3
Palladium-catalyzed intramolecular Heck reactiona
Scheme 3. Decarboxylation of 6a.
Entry
4 (R1/R2)
Time (h)
Yield (%)
5
6
7
1
2
3
4
5
6
4j
4t
4v
4r
4w
4x
4
4
6
12
10
11
5a:66
5b:70
5c:65
5d:59
5e:trace
5f:trace
6a:14
7a:trace
7b:trace
7c:trace
7d:13
7e:35
7f:30
6b:trace
6c:trace
6d:trace
6e:trace
6f:trace
a
Reaction conditions: 4 (0.25 mmol), Pd(PPh3)4 (10 mol %), K2CO3 (0.625 mmol),
DMF(2 mL), N2, 100 ꢀC.
Table 4
Scheme 4. Transformation of 5ae7a.
Palladium-catalyzed intramolecular Heck reactiona
4x bearing deactivating group, under the same condition, trace
amount of products were observed (Table 4, entries 5 and 6).
The mechanism (Scheme 4) for the formation of 5a can be
regarded as the reductive Heck type reaction involving the in-
termediate I, which might be converted to 6a via 1,3-H shift. Then
6a undergoes base-induced decarboxylation to afford 7a.18
3. Conclusions
In conclusion, we have developed a facile method for synthesis
of highly functionalized pyrimidone derivatives from
a,b-un-
saturated imines, DMAD and isocyanates via 1,4-dipolar cycload-
dition. Various substitutes are tolerated in this reaction, which
proceeds smoothly in moderate to good yields. Furthermore, the
pyrimidones derived from 2-bromophenyl isocyanate could be
transformed to various indole fused pyrimidones when they were
subjected to different palladium-catalyzed intramolecular Heck
reaction conditions. The mechanisms of the series of trans-
formation also have been proposed. The present method offers
direct pathway to the diversified pyrimidone and indole fused
pyrimidones compounds, which may possess potential bioactivity.
Entry
4 (R1/R2)
Time (h)
Yield (%)
5
6
7
1
2
3
4
5
6
4j
4t
4v
4r
4w
4x
4
6
7
12
11
11
5a:trace
5b:trace
5c:trace
5d:trace
5e:trace
5f:trace
6a:trace
6b:trace
6c:trace
6d:trace
6e:trace
6f:trace
7a:51
7b:45
7c:47
7d:59
7e:trace
7f:trace
a
Reaction conditions: 4 (0.25 mmol), Pd(OAc)2(10 mol %), n-Bu4NCl (1 equiv),
K2CO3 (0.625 mmol), PPh3(40 mol %), DMF (2.0 mL), N2, 100 ꢀC.
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6
M. Lei et al. / Tetrahedron xxx (2014) 1e10
Detailed mechanistic study and synthetic application of these
methods are underway.
134.7, 133.2, 132.5, 129.4, 129.0, 128.0, 127.4, 126.7, 122.5, 120.9,
120.8, 103.3, 80.7, 53.5, 52.5; IR (KBr): 3028, 2950, 1742, 1660, 1548,
1488,1271,1229,1194,1158,1071, 968, 910, 833, 769, 731, 692 cmꢁ1
;
4. Experimental
HRMS (ESI): m/z [M] calcd for C28H22N2O5Br2: 623.9895, found:
623.9907.
4.1. General information
4.3.3. 1-(4-Bromo-phenyl)-3-(4-nitro-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4c). Yellow solid (102 mg, 35%); mp: 169e171 ꢀC; 1H NMR
All commercially available reagents and solvents were used
without further purification unless otherwise stated. TLC was per-
formed using GF254 silica gel glass plates and silica gel 60
(300e400 mesh) was used in column chromatography separations.
(400 MHz, CDCl3):
d
¼8.28 (d, J¼8.8 Hz, 2H), 7.49e7.45 (m, 4H),
7.41e7.34 (m, 5H), 7.16 (d, J¼8.4 Hz, 2H), 6.83 (d, J¼15.6 Hz, 1H),
6.59 (dd, J¼16.0, 5.6 Hz, 1H), 5.88 (d, J¼4.8 Hz, 1H), 3.84 (s, 3H), 3.74
Petroleum ether (PE) refers to the fraction boiling in the 60e90 ꢀ
C
range. Melting points were obtained using a micro melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a FT-IR spectrometer taken as KBr discs. 1H NMR and 13C NMR
spectra were recorded on 400 MHz and 100 MHz or 500 MHz and
125 MHz instruments using CDCl3 solvent with tetramethylsilane
as the internal standard. HRMS were recorded using electron spray
ionization method.
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼164.3, 162.8, 158.7, 147.5,
146.4, 146.1, 138.7, 135.8, 134.7, 132.8, 129.6, 129.2, 127.8, 127.5,
125.8,123.3,121.2,120.9,110.1, 80.3, 53.9, 52.9; IR (KBr): 3348, 2961,
2924, 2853, 1732, 1589, 1512, 1495, 1435, 1259, 1111, 1012, 958, 853,
750, 733, 698 cmꢁ1. HRMS (ESI): m/z [M] calcd for C28H22N3O7Br:
591.0641, found: 591.0645.
4.3.4. 1-(4-Bromo-phenyl)-6-oxo-3-phenyl-2-styryl-1,2,3,6-
4.2. General procedure for the synthesis of highly function-
alized pyrimidone derivatives 4 via three-component cascade
reaction
tetrahydro-pyrimidine-4,5-dicarboxylic
(4d). Yellow solid (186 mg, 68%); mp: 85e86 ꢀC; 1H NMR
(400 MHz, CDCl3):
¼7.45e7.26 (m,12H), 7.19 (d, J¼8.4 Hz, 2H), 6.73
(d, J¼16.0 Hz, 1H), 6.67 (dd, J¼16.0, 5.2 Hz, 1H), 5.73 (d, J¼4.8 Hz,
1H), 3.81 (s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3):
acid
dimethyl
ester
d
a,
b-Unsaturated imines 1 (0.6 mmol), acetylenedicarboxylate 2
d
¼165.2,
(0.6 mmol) and isocyanates 3 (0.5 mmol) were mixed in acetonitrile
(2 mL). The reaction mixture was stirred at room temperature for
12 h. After completion of the reaction, the solvent was removed
under vacuum, the residue was subject to flash chromatography on
silica gel (petroleum ether/ethyl acetate, 4:1 to 2:1) to afford pure 4.
163.1,159.4,151.6,141.3,139.1,135.3,134.8,132.3,130.0,129.2,128.9,
128.7, 128.0, 127.3, 125.1, 121.1, 120.5, 101.7, 80.6, 53.2, 52.3; IR (KBr):
3028, 2950, 2836, 1745, 1659, 1538, 1488, 1270,1230, 1070, 968, 910,
809, 758, 731, 695 cmꢁ1
;
HRMS (ESI): m/z [M] calcd for
C28H23N2O5Br: 546.0790, found: 546.0797.
4.3. Typical procedure for the synthesis of 5 via intra-
molecular Heck reaction
4.3.5. 1-(4-Bromo-phenyl)-2-[2-(4-nitro-phenyl)-vinyl]-6-oxo-3-
phenyl-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl
ester (4e). White solid (174 mg, 59%); mp: 207e208 ꢀC; 1H NMR
Pyrimidone derivatives 4 (0.25 mmol), Pd(PPh3)4 (28.9 mg,
10 mol %), and K2CO3 (86.3 mg, 0.625 mmol) were mixed in DMF
(2.0 mL). Then the mixture was stirred at 100 ꢀC under nitrogen
atmosphere for the indicated time until complete consumption of
starting material as monitored by TLC. After completion, the re-
action mixture was cooled to room temperature, diluted in ethyl
acetate, and washed with brine. The aqueous phase was re-
extracted with ethyl acetate for twice. The combined organic
phase were dried over anhydrous Na2SO4 and then concentrated
under vacuum, and the resulting residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate, 4:1 to 2:1)
to afford the corresponding product 5.
(400 MHz, CDCl3):
d
¼8.23 (d, J¼8.4 Hz, 2H), 7.59 (d, J¼8.4 Hz, 2H),
7.49e7.37 (m, 5H), 7.29e7.27 (m, 2H), 7.18 (d, J¼8.4 Hz, 2H), 6.84
(d, J¼16.0 Hz, 1H), 6.77 (dd, J¼16.0, 5.2 Hz, 1H), 5.81 (d, J¼4.8 Hz,
1H), 3.82 (s, 3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼165.1,
163.2,159.6,151.3,148.1, 141.5, 141.2, 139.0, 132.9,132.7, 130.3, 129.0,
128.2, 127.9, 126.1, 124.9, 124.4, 120.9, 103.3, 80.1, 53.5, 52.6; IR
(KBr): 3062, 2950, 2853, 1742, 1595, 1519, 1489, 1344, 1233, 1070,
972, 833, 756, 741, 696 cmꢁ1; HRMS (ESI): m/z [M] calcd for
C28H22N3O7Br: 591.0641, found: 591.0623.
4.3.6. 1-(4-Bromo-phenyl)-2-[2-(4-methoxy-phenyl)-vinyl]-6-oxo-3-
phenyl-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl
ester (4f). White solid (156 mg, 54%); mp: 186e188 ꢀC; 1H NMR
4.3.1. 1-(4-Methyl-phenyl)-6-oxo-3-phenyl-2-styryl-1,2,3,6-
(400 MHz, CDCl3):
d
¼7.45e7.34 (m, 7H), 7.31e7.27 (m, 2H), 7.19
tetrahydro-pyrimidine-4,5-dicarboxylic
(4a). Yellow solid (145 mg, 60%); mp: 87e89 ꢀC; 1H NMR
(400 MHz, CDCl3):
acid
dimethyl
ester
(d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H), 6.64 (d, J¼16.0 Hz, 1H), 6.55
(dd, J¼16.0, 6.0 Hz, 1H), 5.69 (d, J¼6.0 Hz, 1H), 3.82 (s, 6H), 3.64
d
¼7.47e7.31 (m, 10H), 7.21 (d, J¼8.4 Hz, 2H), 7.16
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼165.3, 163.2, 160.5, 159.6,
(d, J¼8.0 Hz, 1H), 6.78e6.69 (m, 2H), 5.75 (d, J¼4.0 Hz, 1H), 3.83
151.7, 141.4,139.2,134.9,132.3,130.0,128.8,128.7, 128.1,127.5, 125.3,
120.5, 118.7, 114.3, 101.5, 80.9, 55.5, 53.2, 52.3; IR (KBr): 3003, 2951,
2837, 1746, 1606, 1512, 1488, 1257, 1069, 1011, 968, 910, 828, 731,
696 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H25N2O6Br: 576.0896,
found: 576.0900.
(s, 3H), 3.66 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼165.4, 163.3, 159.6, 151.2, 141.5, 137.6, 137.0, 135.0, 134.9, 129.9,
129.0, 128.8, 128.5, 127.2, 126.3, 125.0, 121.6, 102.2, 80.8, 53.1, 52.2,
21.1. IR (KBr): 3056, 2951, 2839, 1742, 1659, 1547, 1508, 1434, 1230,
1158, 1073, 969, 832, 793, 735, 693 cmꢁ1; HRMS (ESI): m/z [M] calcd
for C29H26N2O5: 482.1842; found: 482.1841.
4.3.7. 1-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-2-[2-(4-methoxy-
phenyl)-vinyl]-6-oxo-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic
acid dimethyl ester (4g). Yellow solid (208 mg, 69%); mp: 90e91 ꢀC;
4.3.2. 1,3-Bis-(4-bromo-phenyl)-6-oxo-2-styryl-1,2,3,6-tetrahydro-
pyrimidine-4,5-dicarboxylic acid dimethyl ester (4b). Yellow solid
1H NMR (400 MHz, CDCl3):
d¼7.44 (d, J¼8.8 Hz, 2H), 7.37
(122 mg, 39%); mp: 132e134 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼7.53
(d, J¼8.8 Hz, 2H), 7.28e7.18 (m, 4H), 6.88 (d, J¼8.8 Hz, 4H),
(d, J¼8.8 Hz, 2H), 7.46e7.42 (m, 4H), 7.39e7.35 (m, 3H), 7.17
(d, J¼8.8 Hz, 4H), 6.71 (d, J¼16.0 Hz, 1H), 6.64 (dd, J¼16.0, 5.6 Hz,
1H), 5.68 (d, J¼5.6 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H); 13C NMR
6.61e6.53 (m, 2H), 5.58e5.57 (m, 1H), 3.81e3.79 (m, 9H), 3.64
(s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.3, 163.0, 160.4, 159.8,
159.6, 153.0, 139.1, 135.0, 133.6, 132.2, 128.6, 128.2, 127.5, 127.4,
120.4, 118.4, 114.8, 114.2, 99.1, 81.2, 55.6, 55.4, 53.1, 52.0; IR (KBr):
(100 MHz, CDCl3):
d¼165.0, 163.0, 159.2, 150.7, 140.5, 139.0, 135.6,
Please cite this article in press as: Lei, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.023

M. Lei et al. / Tetrahedron xxx (2014) 1e10
7
3003, 2951, 2838, 1742, 1606, 1510, 1488, 1254, 1159, 1029, 969, 910,
831, 795, 730, 645 cmꢁ1
HRMS (ESI): m/z [M] calcd for
30H27N2O7Br: 606.1002, found: 606.1007.
2840, 1743, 1661, 1531, 1510, 1434, 1233, 1100, 1026, 970, 932, 835,
783, 737, 695 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H25N3O8:
543.1642, found: 543.1634.
;
C
4.3.8. 1-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-2-[2-(4-nitro-
phenyl)-vinyl]-6-oxo-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic
acid dimethyl ester (4h). Yellow solid (207 mg, 67%); mp:
4.3.13. 1-(3-Chloro-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4m). Yellow solid (178 mg, 67%); mp: 87e88 ꢀC; 1H NMR
184e185 ꢀC; 1H NMR (400 MHz, CDCl3):
d
¼8.22 (d, J¼8.8 Hz, 2H),
(400 MHz, CDCl3):
d
¼7.44 (d, J¼6.8 Hz, 2H), 7.39e7.33 (m, 4H),
7.58 (d, J¼8.8 Hz, 2H), 7.47 (d, J¼8.4 Hz, 2H), 7.24 (d, J¼8.8 Hz, 2H),
7.18 (d, J¼8.4 Hz, 2H), 6.91 (d, J¼8.8 Hz, 2H), 6.81 (dd, J¼16.0, 4.8 Hz,
1H), 6.76 (d, J¼15.6 Hz, 1H), 5.70 (d, J¼4.8 Hz, 1H), 3.82e3.81
7.27e7.25 (m, 3H), 7.20 (d, J¼8.0 Hz, 2H), 6.90 (d, J¼8.8 Hz, 2H),
6.73e6.65 (m, 2H), 5.65 (d, J¼4.4 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H),
3.65 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.4,163.1,159.9,159.6,
(m, 6H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼165.3, 163.2,
153.0, 141.2, 135.5, 134.8, 134.5, 133.7, 130.2, 129.2, 128.9, 127.5,
127.3, 127.1, 126.7, 124.4, 120.9, 115.0, 99.5, 80.9, 55.6, 53.2, 52.2; IR
(KBr): 3024, 2951, 2839, 1746, 1660, 1538, 1510, 1434, 1256, 1160,
1073, 968, 910, 836, 793, 730, 691 cmꢁ1; HRMS (ESI): m/z [M] calcd
for C29H25N2O6Cl: 532.1401, found: 532.1402.
160.0, 159.4, 152.7, 148.0, 141.2, 139.0, 133.8, 132.9, 132.6, 128.1,
128.0,127.2,125.9,124.3,120.8,115.2,100.8, 80.5, 55.8, 53.4, 52.4; IR
(KBr): 3013, 2951, 2830, 1739, 1596, 1510, 1488, 1344, 1246, 1108,
973, 836, 735, 698 cmꢁ1
;
HRMS (ESI): m/z [M] calcd for
C
29H24N3O8Br: 621.0747, found: 621.0775.
4.3.14. 1,3-Bis-(4-methoxy-phenyl)-6-oxo-2-styryl-1,2,3,6-
4.3.9. 1-(4-Bromo-phenyl)-6-oxo-3-phenyl-2-(2-phenyl-propenyl)-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4i). Yellow solid (83 mg, 30%); mp: 193e195 ꢀC; 1H NMR
tetrahydro-pyrimidine-4,5-dicarboxylic
(4n). Yellow solid (161 mg, 61%); mp: 100e102 ꢀC; 1H NMR
(400 MHz, CDCl3):
acid
dimethyl
ester
d
¼7.43 (d, J¼7.6 Hz, 2H), 7.39e7.31 (m, 3H),
(400 MHz, CDCl3):
(s, 1H), 5.68 (s, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 2.15 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼7.48e7.28 (m, 10H), 7.20e7.16 (m, 4H), 6.45
7.27e7.20 (m, 4H), 6.89e6.84 (m, 4H), 6.73 (dd, J¼15.6, 6.8 Hz, 1H),
6.60 (d, J¼15.6 Hz, 1H), 5.55 (d, J¼6.8 Hz, 1H), 3.81e3.76 (m, 9H),
d¼165.1, 163.2, 159.4, 151.2, 141.7, 139.4, 135.9,
3.64 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼165.7, 163.3, 160.0,
132.4, 132.3, 131.5, 130.0, 129.2, 128.7, 128.5, 128.2, 127.7, 125.6,
120.6, 103.7, 85.2, 53.2, 52.4, 14.3; IR (KBr): 3056, 2950, 2834, 1745,
1660, 1556, 1488, 1434, 1260, 1071, 1011, 923, 830, 792, 758,
697 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H25N2O5Br: 560.0947,
found: 560.0960.
159.8, 158.6, 152.9, 135.2, 135.1, 133.9, 133.0, 129.1, 128.9, 128.4,
127.6, 127.3, 121.3, 114.9, 114.5, 99.6, 81.7, 55.7, 55.6, 53.1, 52.2; IR
(KBr): 3003, 2951, 2838, 1747, 1660, 1538, 1506, 1434, 1249, 1158,
1073, 968, 911, 836, 794, 730, 693 cmꢁ1; HRMS (ESI): m/z [M] calcd
for C30H28N2O7: 528.1897, found: 528.1893.
4.3.10. 1-(2-Bromo-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4j). Yellow solid (198 mg, 69%); mp: 166e168 ꢀC; 1H NMR
4.3.15. 3-(4-Methoxy-phenyl)-6-oxo-2-styryl-1-p-tolyl-1,2,3,6-
tetrahydro-pyrimidine-4,5-dicarboxylic
(4o). Yellow solid (163 mg, 64%); mp: 143e145 ꢀC; 1H NMR
(400 MHz, CDCl3):
acid
dimethyl
ester
(500 MHz, CDCl3):
d
¼7.64 (d, J¼9.0 Hz, 1H), 7.43e7.28 (m, 9H),
d
¼7.43 (d, J¼7.2 Hz, 2H), 7.38e7.30 (m, 3H), 7.25
7.20e7.17 (m, 1H), 6.86 (d, J¼9.0 Hz, 2H), 6.79 (dd, J¼16.0, 8.5 Hz,
(d, J¼8.4 Hz, 2H), 7.19 (d, J¼8.4 Hz, 2H), 7.13 (d, J¼8.0 Hz, 2H), 6.88
(d, J¼8.8 Hz, 2H), 6.72 (dd, J¼16.0, 6.4 Hz, 1H), 6.64 (d, J¼15.6 Hz,
1H), 5.60 (d, J¼6.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.64 (s, 3H),
1H), 6.48 (d, J¼16.0 Hz, 1H), 5.37 (d, J¼9.0 Hz, 1H), 3.83 (s, 3H), 3.80
(s, 3H), 3.64 (s, 3H); 13C NMR (125 MHz, CDCl3):
d¼165.9, 163.3,
159.9, 159.4, 154.5, 138.3, 135.6, 135.0, 133.8, 133.6, 132.9, 129.9,
129.3, 129.0, 128.4, 128.3, 127.3, 122.8, 120.6, 114.7, 97.5, 80.8, 55.7,
53.2, 52.2; IR (KBr): 3030, 2950, 2839, 1746, 1660, 1510, 1474, 1234,
1162,1076,1028, 967, 911, 835, 794, 729, 693 cmꢁ1; HRMS (ESI): m/z
[M] calcd for C29H25N2O6Br: 576.0896, found: 576.0896.
2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.7,163.3,159.8,159.7,
152.8, 137.7, 137.0, 135.10, 135.06, 134.0, 129.9, 129.1, 128.9, 127.5,
127.3, 126.6, 121.5, 114.9, 99.9, 81.4, 55.7, 53.1, 52.2, 21.2; IR (KBr):
3028, 2950, 2839,1743,1660, 1548,1511,1434,1231, 1158,1073, 968,
911, 837, 794, 731, 693 cmꢁ1; HRMS (ESI): m/z [M] calcd for
C30H28N2O6: 512.1947, found: 512.1952.
4.3.11. 1-(4-Fluoro-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4k). Yellow solid (193 mg, 75%); mp: 182e183 ꢀC; 1H NMR
4.3.16. 3-(4-Methoxy-phenyl)-6-oxo-1-phenyl-2-styryl-1,2,3,6-
tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4p). Yellow solid (165 mg, 66%); mp: 148e149 ꢀC; 1H NMR
(400 MHz, CDCl3):
(400 MHz, CDCl3):
d
¼7.43 (d, J¼7.2 Hz, 2H), 7.39e7.34 (m, 3H),
7.29e7.24 (m, 4H), 7.02 (t, J¼8.4 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H), 6.73
(dd, J¼16.0, 7.2 Hz, 1H), 6.60 (d, J¼16.0 Hz, 1H), 5.56 (d, J¼6.8 Hz,
1H), 3.82e3.81 (m, 6H), 3.64 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼7.44 (d, J¼7.2 Hz, 2H), 7.39e7.30 (m, 7H),
7.26e7.24 (m, 3H), 6.88 (d, J¼9.2 Hz, 2H), 6.73 (dd, J¼16.0, 6.4 Hz,
1H), 6.65 (d, J¼15.6 Hz, 1H), 5.64 (d, J¼6.4 Hz, 1H), 3.82e3.80
d
¼165.6, 163.2, 161.4 (d, J¼246.0 Hz), 159.9, 153.2, 136.1 (d,
(m, 6H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.7, 163.4,
J¼2.0 Hz), 135.5, 135.0, 133.8, 129.3, 129.0, 128.9, 128.8, 127.7, 127.4,
121.0,116.2 (d, J¼22.0 Hz),115.0, 99.4, 81.6, 55.7, 53.2, 52.3; IR (KBr):
3029, 2950, 1747, 1667, 1557, 1515, 1428, 1269, 1157, 1072, 968, 911,
159.82, 159.79, 152.9, 140.4, 135.2, 135.1, 134.0, 129.3, 129.2, 129.0,
127.6, 127.4, 127.2, 126.7, 121.5, 115.0, 100.0, 81.3, 55.7, 53.2, 52.2; IR
(KBr): 3028, 2950, 2839, 1743, 1659, 1538, 1510, 1434, 1232, 1159,
1073, 968, 911, 835, 794, 730, 694 cmꢁ1; HRMS (ESI): m/z [M] calcd
for C29H26N2O6: 498.1791, found: 498.1798.
815, 794, 733, 695 cmꢁ1
;
HRMS (ESI): m/z [M] calcd for
C
29H25N2O6F: 516.1697, found: 516.1694.
4.3.12. 3-(4-Methoxy-phenyl)-1-(2-nitro-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4l). Yellow solid (79 mg, 30%); mp: 120e122 ꢀC; 1H NMR
4.3.17. 1-(4-Fluoro-phenyl)-6-oxo-3-phenyl-2-styryl-1,2,3,6-
tetrahydro-pyrimidine-4,5-dicarboxylic
(4q). Yellow solid (175 mg, 72%); mp: 68e70 ꢀC; 1H NMR
(400 MHz, CDCl3):
¼7.44e7.25 (m, 12H), 7.01 (t, J¼8.4 Hz, 2H),
6.75e6.67 (m, 2H), 5.74e5.66 (m, 1H), 3.81 (s, 3H), 3.63 (s, 3H); 13
NMR (100 MHz, CDCl3):
acid
dimethyl
ester
(400 MHz, CDCl3):
d
¼7.98 (d, J¼8.0 Hz, 1H), 7.60e7.56 (m, 1H),
d
7.48e7.38 (m, 9H), 6.91e6.86 (m, 3H), 6.56 (d, J¼16.0 Hz, 1H), 5.58
C
(d, J¼8.0 Hz, 1H), 3.80e3.79 (m, 6H), 3.63 (s, 3H); 13C NMR
d
¼165.3, 163.1, 161.3 (d, J¼245.0 Hz), 159.6,
(100 MHz, CDCl3):
d
¼165.6, 163.1, 160.1, 160.0, 155.0, 146.9, 136.2,
151.7, 141.3, 136.0 (d, J¼3.0 Hz), 135.2, 134.8, 129.9, 129.2, 128.9,
128.7 (d, J¼6.0 Hz), 128.6, 127.3, 125.2, 121.1, 116.1 (d, J¼23.0 Hz),
101.5, 81.0, 53.2, 52.2; IR (KBr): 3028, 2951, 1747, 1660, 1538, 1506,
134.9, 134.0, 133.5, 133.1, 132.9, 129.5, 129.3, 129.1, 128.7, 127.4,
125.6, 120.7, 114.7, 97.0, 81.4, 55.7, 53.2, 52.2; IR (KBr): 3003, 2951,
Please cite this article in press as: Lei, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.023

8
M. Lei et al. / Tetrahedron xxx (2014) 1e10
1428, 1230, 1157, 1073, 968, 911, 837, 796, 731, 695 cmꢁ1; HRMS
1162, 1074, 968, 911, 829, 793, 733, 696 cmꢁ1; HRMS (ESI): m/z [M]
(ESI): m/z [M] calcd for C28H23N2O5F: 486.1591, found: 486.1589.
calcd for C29H25N2O6Br: 576.0896, found: 576.0897.
4.3.18. 1-(2-Bromo-phenyl)-6-oxo-3-phenyl-2-styryl-1,2,3,6-
4.3.23. 1-(2-Bromo-phenyl)-3-(4-methoxy-phenyl)-2-[2-(4-nitro-
phenyl)-vinyl]-6-oxo-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic
acid dimethyl ester (4w). Yellow solid (165 mg, 53%); mp:
tetrahydro-pyrimidine-4,5-dicarboxylic
(4r). White solid (180 mg, 66%); mp: 192e194 ꢀC; 1H NMR
(400 MHz, CDCl3):
acid
dimethyl
ester
d
¼7.63 (d, J¼8.0 Hz, 1H), 7.44e7.26 (m, 12H), 7.19
207e209 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼8.22 (d, J¼8.8 Hz, 2H),
(t, J¼7.6 Hz,1H), 6.79 (dd, J¼16.0, 7.6 Hz,1H), 6.57 (d, J¼15.6 Hz,1H),
7.65 (d, J¼8.4 Hz, 1H), 7.57 (d, J¼8.8 Hz, 2H), 7.34e7.19 (m, 5H),
6.93e6.87 (m, 3H), 6.65 (d, J¼15.6 Hz, 1H), 5.48 (d, J¼7.2 Hz, 1H),
3.82e3.81 (m, 6H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3):
5.48 (d, J¼7.6 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼165.6, 163.3, 159.3, 153.3, 141.5, 138.4, 135.4, 135.1, 133.7,
132.7, 130.0, 129.8, 129.3, 129.0, 128.9, 128.4, 127.4, 126.1, 122.7,
120.8, 99.5, 80.4, 53.2, 52.3; IR (KBr): 3059, 2950, 1746, 1667, 1556,
d
¼165.5, 163.2, 159.9, 159.2, 154.0, 148.0, 141.3, 138.1, 133.81, 133.76,
132.9, 132.6, 130.1, 128.5, 128.0, 127.8, 125.3, 124.3, 122.6, 114.9, 98.6,
79.9, 55.7, 53.3, 52.3; IR (KBr): 3062, 2951, 2834, 1739, 1658, 1545,
1511, 1436, 1343, 1235, 1162, 1028, 969, 840, 790, 754, 730,
690 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H24N3O8Br: 621.0747,
found: 621.0745.
1494, 1434, 1278, 1162, 1075, 967, 932, 840, 792, 756, 696 cmꢁ1
;
HRMS (ESI): m/z [M] calcd for C28H23N2O5Br: 546.0790, found:
546.0789.
4.3.19. 1-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl ester
(4s). Yellow solid (204 mg, 71%); mp: 99e101 ꢀC; 1H NMR
4.3.24. 1-(2-Bromo-phenyl)-2-[2-(4-nitro-phenyl)-vinyl]-6-oxo-3-
phenyl-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid dimethyl
ester (4x). Yellow solid (142 mg, 48%); mp: 156e157 ꢀC; 1H NMR
(400 MHz, CDCl3):
d
¼7.45e7.42 (m, 4H), 7.38e7.32 (m, 3H),
7.27e7.24 (m, 2H), 7.20 (d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H),
6.71 (dd, J¼16.0, 6.4 Hz, 1H), 6.64 (d, J¼16.0 Hz, 1H), 5.61
(d, J¼6.0 Hz, 1H), 3.81e3.79 (m, 6H), 3.64 (s, 3H); 13C NMR
(500 MHz, CDCl3):
d
¼8.23 (d, J¼8.0 Hz, 2H), 7.64 (d, J¼8.0 Hz, 1H),
7.58 (d, J¼8.5 Hz, 2H), 7.42e7.34 (m, 7H), 7.23e7.21 (m, 1H), 6.87
(dd, J¼16.0, 7.0 Hz, 1H), 6.73 (d, J¼16.0 Hz, 1H), 5.59 (d, J¼7.0 Hz,
(100 MHz, CDCl3):
d
¼165.3, 163.0, 159.8, 159.5, 152.9, 139.1, 135.4,
1H), 3.83 (s, 3H), 3.67 (s, 3H); 13C NMR (125 MHz, CDCl3):
d¼165.4,
134.7, 133.6, 132.2, 129.2, 128.9, 128.1, 127.4, 127.2, 120.8, 120.4,
114.9, 99.4, 81.0, 55.6, 53.1, 52.1; IR (KBr): 3024, 2950, 2837, 1743,
1688, 1586, 1538, 1510, 1434, 1234, 1195, 1070, 968, 910, 762, 730,
694 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H25N2O6Br: 576.0896,
found: 576.0900.
163.3, 159.1, 152.9, 148.1, 141.5, 141.4, 138.2, 133.9, 132.7, 132.5, 130.2,
130.0, 128.9, 128.6, 128.1, 125.61, 125.55, 124.4, 122.6, 100.7, 79.6,
53.4, 52.4; IR (KBr): 3071, 2950, 2847, 1734, 1653, 1545, 1512, 1435,
1343, 1232, 1153, 1074, 973, 857, 788, 748, 690 cmꢁ1; HRMS (ESI):
m/z [M] calcd for C28H22N3O7Br: 591.0641, found: 591.0638.
4.3.20. 1-(2-Bromo-phenyl)-3-(4-methoxy-phenyl)-2-[2-(4-
methoxy-phenyl)-vinyl]-6-oxo-1,2,3,6-tetrahydro-pyrimidine-4,5-
dicarboxylic acid dimethyl ester (4t). White solid (202 mg, 67%);
4.3.25. 1-(4-Bromo-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylic acid diethyl ester
(4y). Yellow solid (169 mg, 56%); mp: 76e77 ꢀC; 1H NMR (400 MHz,
mp: 194e196 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼7.63 (d, J¼7.6 Hz,
CDCl3):
d
¼7.45e7.33 (m, 7H), 7.26e7.19 (m, 4H), 6.88 (d, J¼8.4 Hz,
1H), 7.37e7.25 (m, 6H), 7.18 (t, J¼7.6 Hz, 1H), 6.90e6.85 (m, 4H),
6.67 (dd, J¼16.0, 8.4 Hz, 1H), 6.41 (d, J¼16.0 Hz, 1H), 5.34
(d, J¼8.0 Hz, 1H), 3.83e3.82 (m, 6H), 3.79 (s, 3H), 3.63 (s, 3H); 13C
2H), 6.73 (dd, J¼15.6, 6.4 Hz, 1H), 6.63 (d, J¼15.6 Hz, 1H), 5.58
(d, J¼6.4 Hz, 1H), 4.30e4.25 (m, 2H), 4.09 (q, J¼7.2 Hz, 2H), 3.80
(s, 3H), 1.32 (t, J¼7.2 Hz, 3H), 1.06 (t, J¼7.2 Hz, 3H); 13C NMR
NMR (100 MHz, CDCl3):
d
¼165.8, 163.2, 160.4, 159.7, 159.3, 154.3,
(100 MHz, CDCl3):
d¼164.8, 162.6, 159.8, 159.7, 152.7, 139.3, 135.4,
138.2, 135.1, 133.6, 133.5, 132.8, 129.8, 128.6, 128.3, 128.2, 127.5,
122.6, 118.0, 114.6, 114.3, 97.1, 80.9, 55.6, 55.4, 53.0, 52.1; IR (KBr):
3006, 2951, 2838,1744,1660, 1538,1511,1434,1253,1162, 1076, 968,
911, 832, 794, 731, 682 cmꢁ1; HRMS (ESI): m/z [M] calcd for
134.9, 134.0, 132.3, 129.2, 128.9, 128.2, 127.7, 127.3, 121.2, 120.5,
114.9, 100.1, 81.1, 62.5, 61.0, 55.7, 14.3, 13.7; IR (KBr): 3053, 2981,
2838, 1738, 1660, 1538, 1511, 1454, 1257, 1170, 1068, 968, 910, 836,
785, 731, 694 cmꢁ1; HRMS (ESI): m/z [M] calcd for C31H29N2O6Br:
604.1209, found: 604.1221.
C
30H27N2O7Br: 606.1002, found: 606.0998.
4.3.21. 3-(4-Methoxy-phenyl)-2-[2-(4-methoxy-phenyl)-vinyl]-6-
oxo-1-p-tolyl-1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid di-
methyl ester (4u). Yellow solid (168 mg, 62%); mp: 87e89 ꢀC; 1H
4.3.26. 1-(4-Fluoro-phenyl)-3-(4-methoxy-phenyl)-6-oxo-2-styryl-
1,2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid diethyl ester
(4z). Yellow solid (158 mg, 58%); mp: 67e69 ꢀC; 1H NMR (400 MHz,
NMR (400 MHz, CDCl3):
6.63e6.54 (m, 2H), 5.57 (d, J¼4.8 Hz, 1H), 3.81e3.78 (m, 9H), 3.64
(s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
160.3, 159.8, 159.7, 152.8, 137.7, 136.9, 134.6, 133.9, 129.8, 128.6,
127.7, 127.5, 126.5,119.0,114.8,114.2, 99.5, 81.6, 55.6, 55.4, 53.0, 52.1,
21.1; IR (KBr): 3003, 2951, 2838, 1747, 1660, 1538, 1515, 1434, 1257,
1158, 1072, 969, 911, 834, 795, 731, 645 cmꢁ1; HRMS (ESI): m/z [M]
calcd for C31H30N2O7: 542.2053, found: 542.2050.
d
¼7.38e7.12 (m, 8H), 6.90e6.86 (m, 4H),
CDCl3):
d
¼7.44 (d, J¼6.8 Hz, 2H), 7.39e7.31 (m, 3H), 7.29e7.24
(m, 4H), 7.02 (t, J¼8.4 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 6.75 (dd,
J¼16.0, 7.2 Hz, 1H), 6.61 (d, J¼15.6 Hz, 1H), 5.55 (d, J¼7.2 Hz, 1H),
4.33e4.22 (m, 2H), 4.09 (q, J¼7.2 Hz, 2H), 3.80 (s, 3H), 1.32
(t, J¼7.2 Hz, 3H), 1.06 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.7, 163.3,
d
¼164.8, 162.6, 161.3 (d, J¼246.0 Hz), 160.0, 159.8, 152.7, 136.2
(d, J¼3.0 Hz), 135.3, 135.0, 134.0, 129.2, 128.93, 128.85 (d, J¼8.0 Hz),
127.8, 127.3, 121.3, 116.1 (d, J¼22.0 Hz), 114.8, 99.9, 81.5, 62.4, 61.0,
55.7, 14.3, 13.7; IR (KBr): 3058, 2981, 2839, 1737, 1659, 1547, 1510,
1450, 1227, 1156, 1070, 969, 834, 781, 735, 693 cmꢁ1; HRMS (ESI):
m/z [M] calcd for C31H29N2O6F: 544.2010, found: 544.2007.
4.3.22. 1-(2-Bromo-phenyl)-2-[2-(4-methoxy-phenyl)-vinyl]-6-oxo-
3-phenyl-1, 2,3,6-tetrahydro-pyrimidine-4,5-dicarboxylic acid di-
methyl ester (4v). Yellow solid (162 mg, 55%); mp: 168e169 ꢀC; 1H
NMR (400 MHz, CDCl3):
d
¼7.61 (d, J¼8.0 Hz, 1H), 7.37e7.26 (m, 9H),
4.3.27. 3-(4-Bromo-phenyl)-1-(4-methoxy-phenyl)-4-oxo-2-styryl-
7.18 (t, J¼7.6 Hz, 1H), 6.89 (d, J¼8.4 Hz, 2H), 6.67 (dd, J¼15.6 Hz,
7.6 Hz, 1H), 6.50 (d, J¼15.6 Hz, 1H), 5.45 (d, J¼7.6 Hz, 1H), 3.83e3.81
1,2,3,4-tetrahydropyrimidine-5-carboxylic
(4A). White solid (63 mg, 24%); mp: 98e100 ꢀC; 1H NMR (400 MHz,
CDCl3):
acid
methyl
ester
(m, 6H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.4, 163.0,
d
¼8.25 (s, 1H), 7.47 (d, J¼8.8 Hz, 2H), 7.39e7.31 (m, 5H),
160.3, 159.1, 153.0, 141.1, 138.1, 134.7, 133.3, 132.4, 129.7, 129.5, 128.6,
128.4, 128.1, 127.3, 125.8, 122.4, 118.0, 114.1, 98.8, 80.4, 55.3, 52.9,
52.0; IR (KBr): 3003, 2950, 2837, 1743, 1661, 1539, 1512, 1435, 1253,
7.23e7.19 (m, 4H), 6.94 (d, J¼8.8 Hz, 2H), 6.60 (dd, J¼16.0, 6.4 Hz,
1H), 6.53 (d, J¼16.0 Hz, 1H), 5.83 (d, J¼5.6 Hz, 1H), 3.84e3.82
(m, 6H); 13C NMR (100 MHz, CDCl3):
d
¼166.1, 160.0, 158.8, 150.5,
Please cite this article in press as: Lei, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.023

M. Lei et al. / Tetrahedron xxx (2014) 1e10
9
139.7,135.6,135.1,134.9,132.4,129.3,129.1,128.8,127.3,122.6,121.3,
120.6, 115.4, 99.3, 79.4, 55.9, 52.0; IR (KBr): 3328, 2949, 2842, 1734,
1616, 1596, 1511, 1438, 1244, 1179, 1033, 826, 745, 691 cmꢁ1; HRMS
(ESI): m/z [M] calcd for C27H23N2O4Br: 518.0841, found: 518.0844.
1420, 1233, 1151, 1097, 1021, 925, 804, 760, 731, 695 cmꢁ1; HRMS
(ESI): m/z [M] calcd for C28H22N2O5: 466.1529, found: 466.1531.
4 . 3 . 3 3 . 10 - B e n z yl - 1 - ( 4 - m e t h o x y- p h e n yl ) - 4 - o x o - 1, 4 -
dihydropyrimido-[1,2-a] indole-3-carboxylic acid methyl ester
(7a). Yellow solid (56 mg, 51%); mp: 175e177 ꢀC; 1H NMR
4.3.28. 10-Benzylidene-1-(4-methoxy-phenyl)-4-oxo-1,4,10,10a-tet-
rahydropyrimido[1,2-a]indole-2,3-dicarboxylic acid dimethyl ester
(5a). Yellow solid (82 mg, 66%); mp: 101e103 ꢀC; 1H NMR
(500 MHz, CDCl3):
d
¼8.91 (d, J¼8.0 Hz, 1H), 8.22 (s, 1H), 7.37e7.30
(m, 3H), 7.19 (d, J¼8.5 Hz, 2H), 7.10e7.09 (m, 3H), 6.81 (d, J¼9.0 Hz,
(500 MHz, CDCl3):
d
¼8.13 (d, J¼8.0 Hz, 1H), 7.44e7.29 (m, 7H), 7.06
2H), 6.73e6.72 (m, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.50 (s, 2H); 13C
(t, J¼7.5 Hz, 1H), 6.91 (s, 1H), 6.63 (s, 1H), 6.54 (d, J¼9.0 Hz, 2H), 6.42
NMR (125 MHz, CDCl3):
d
¼165.4, 160.8, 157.1, 150.2, 139.8, 133.0,
(d, J¼9.0 Hz, 2H), 3.90 (s, 3H), 3.65 (s, 3H), 3.57 (s, 3H); 13C NMR
132.3, 130.6, 130.3, 128.4, 128.2, 127.8, 126.1, 124.3, 123.3, 118.0,
(125 MHz, CDCl3):
d
¼165.3, 163.7, 159.7, 158.1, 155.7, 141.9, 135.2,
117.0, 115.1, 99.0, 98.4, 55.9, 52.3, 28.8; DEPT135 13C NMR (125 MHz,
130.6, 130.0, 129.7, 129.5, 129.4, 129.3, 129.1, 128.8, 126.2, 124.2,
120.0, 115.4, 113.6, 106.7, 75.8, 55.5, 53.3, 52.5; IR (KBr): 3058, 2951,
2840, 1746, 1704, 1667, 1557, 1509, 1442, 1249, 1168, 1097, 1026, 921,
845, 795, 761, 734, 698 cmꢁ1; HRMS (ESI): m/z [M] calcd for
CDCl3):
d
¼165.4, 160.8, 157.1, 150.2, 133.0, 132.3, 130.6, 130.3, 128.4,
128.2, 127.8, 126.1, 124.3, 123.3, 118.0, 117.0, 115.1, 55.9, 52.3, 28.8; IR
(KBr): 3059, 2949, 2838, 1741, 1699, 1617, 1588, 1511, 1459, 1436,
1242, 1190, 1055, 1030, 840, 768, 731, 708 cmꢁ1; HRMS(ESI): m/z
[M] calcd for C27H22N2O4: 438.1580, found: 438.1575.
C
29H24N2O6: 496.1634, found: 496.1645.
4.3.29. 10-Benzyl-1-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-pyr-
imido[1,2-a]in- dole-2,3-dicarboxylic acid dimethyl ester
(6a). Yellow solid (17 mg, 14%); mp: 79e80 ꢀC; 1H NMR (500 MHz,
CDCl3):
4.3.34. 10-(4-Methoxy-benzyl)-1-(4-methoxy-phenyl)-4-oxo-1,4-
dihydropyrimido[1,2-a]indole-3-carboxylic
(7b). Yellow solid (53 mg, 45%); mp: 200e201 ꢀC; 1H NMR
(500 MHz, CDCl3):
acid
methyl
ester
d
¼8.90 (d, J¼8.5 Hz, 1H), 7.36e7.26 (m, 3H), 7.19e7.17
d
¼8.91 (d, J¼8.0 Hz, 1H), 8.22 (s, 1H), 7.38e7.26
(m, 2H), 7.11e7.09 (m, 3H), 6.75e6.70 (m, 4H), 3.95 (s, 3H), 3.81
(m, 3H), 7.20 (d, J¼8.5 Hz, 2H), 6.84 (d, J¼9.0 Hz, 2H), 6.67e6.62
(s, 3H), 3.55 (s, 3H), 3.35 (s, 2H); 13C NMR (125 MHz, CDCl3):
(m, 4H), 3.92 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H), 3.43 (s, 2H); 13C NMR
d
¼165.4, 162.0, 161.2, 156.8, 151.6, 139.8, 131.8, 130.9, 130.6, 130.4,
(125 MHz, CDCl3):
d
¼165.5, 160.8, 158.1, 157.1, 150.2, 133.1, 132.2,
129.0, 128.2, 127.8, 126.1, 124.6, 123.6, 118.1, 117.1, 114.5, 99.9, 97.0,
55.9, 53.3, 52.9, 28.6; IR (KBr): 3025, 2951, 2840, 1746, 1704, 1614,
1547, 1510, 1462, 1443, 1253, 1168, 1064, 1027, 955, 910, 848, 793,
731, 696 cmꢁ1; HRMS (ESI): m/z [M] calcd for C29H24N2O6:
496.1634, found: 496.1633.
131.9, 130.7, 130.3, 128.8, 128.4, 124.3, 123.3, 118.0, 117.1, 115.1, 113.7,
99.5, 98.5, 55.9, 55.5, 52.4, 27.9; IR (KBr): 3071, 2989, 2950, 2836,
1740, 1700, 1617, 1588, 1510, 1459, 1437, 1293, 1243, 1175, 1115, 1033,
910, 839, 786, 734 cmꢁ1; HRMS (ESI): m/z [M] calcd for C28H24N2O5:
468.1685, found: 468.1688.
4.3.30. 10-(4-Methoxy-benzylidene)-1-(4-methoxy-phenyl)-4-oxo-
1,4,10,10a-tetrahydro-pyrimido[1,2-a]indole-2,3-dicarboxylic acid di-
methyl ester (5b). Yellow solid (92 mg, 70%); mp: 103e105 ꢀC; 1H
4 . 3 . 3 5 . 10 - ( 4 - M e t h o x y- b e n z yl ) - 4 - o x o - 1 - p h e nyl - 1, 4 -
dihydropyrimido-[1,2-a] indole-3-carboxylic acid methyl ester
(7c). Yellow solid (52 mg, 47%); mp: 232e233 ꢀC; 1H NMR
NMR (500 MHz, CDCl3):
d
¼8.11 (d, J¼7.5 Hz, 1H), 7.39e7.33 (m, 3H),
(500 MHz, CDCl3):
d
¼8.92 (d, J¼8.0 Hz, 1H), 8.24 (s, 1H), 7.50
7.28e7.25 (m, 1H), 7.05e6.96 (m, 3H), 6.85 (s, 1H), 6.61 (d, J¼8.5 Hz,
2H), 6.53 (s, 1H), 6.45 (d, J¼9.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H),
(t, J¼7.5 Hz, 1H), 7.40e7.35 (m, 4H), 7.33e7.30 (m, 3H), 6.65e6.58
(m, 4H), 3.92 (s, 3H), 3.73 (s, 3H), 3.38 (s, 2H); 13C NMR (125 MHz,
3.65 (s, 3H), 3.59 (s, 3H); 13C NMR (125 MHz, CDCl3):
d
¼165.3,163.9,
CDCl3):
d
¼165.4, 158.1, 157.0, 149.8, 140.4, 131.8, 131.6, 130.7, 130.34,
160.1, 159.7, 158.1, 155.4, 141.5, 131.0, 130.0, 129.8, 127.9, 126.8, 126.0,
124.2, 119.6, 115.3, 114.6, 113.7, 107.4, 76.0, 55.6, 55.5, 53.3, 52.5; IR
(KBr): 3055, 2951, 2838, 1743, 1694, 1662, 1605, 1511, 1437, 1248,
1179, 1119, 1028, 921, 831, 787, 753, 722, 696 cmꢁ1; HRMS (ESI): m/z
[M] calcd for C30H26N2O7: 526.1740, found: 526.1747.
130.29, 130.2, 128.7, 127.1, 124.4, 123.4, 118.1, 117.1, 113.7, 99.6, 98.7,
55.4, 52.4, 28.0; IR (KBr): 3058, 2949, 2843, 1740, 1700, 1617, 1582,
1510, 1494, 1436, 1244, 1115, 1055, 1033, 853, 784, 732, 705 cmꢁ1
;
HRMS (ESI): m/z [M] calcd for C27H22N2O4: 438.1580, found:
438.1582.
4.3.31. 10-(4-Methoxy-benzylidene)-4-oxo-1-phenyl-1,4,10,10a-tet-
rahydropyrimido[1,2-a]indole-2,3-dicarboxylic acid dimethyl ester
(5c). Yellow solid (81 mg, 65%); mp: 101e102 ꢀC; 1H NMR
4.3.36. 10-Benzyl-4-oxo-1-phenyl-1,4-dihydro-pyrimido[1,2-a]in-
dole-3-carboxylic acid methyl ester (7d). Yellow solid (60 mg, 59%);
mp: 217e219 ꢀC; 1H NMR (500 MHz, CDCl3):
d¼8.93 (d, J¼8.5 Hz,
(500 MHz, CDCl3):
d
¼8.11 (d, J¼8.0 Hz, 1H), 7.34e7.28 (m, 3H),
1H), 8.25 (s, 1H), 7.49 (t, J¼7.5 Hz, 1H), 7.40e7.28 (m, 7H), 7.10e7.09
7.27e7.26 (m,1H), 7.13e7.10 (m,1H), 7.05e6.95 (m, 5H), 6.82 (s,1H),
6.69 (d, J¼7.5 Hz, 2H), 6.56 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.56
(m, 3H), 6.68 (s, 2H), 6.73e6.72 (m, 2H), 3.93 (s, 3H), 3.46 (s, 2H);
13C NMR (125 MHz, CDCl3):
d
¼165.5, 157.1, 149.8, 140.4,139.6, 132.0,
(s, 3H); 13C NMR (125 MHz, CDCl3):
d¼165.2, 163.8, 160.1, 157.9,
130.7, 130.4, 130.3, 130.2, 128.3, 127.8, 127.2, 126.2, 124.4, 123.5,
118.1, 117.1, 99.1, 98.8, 52.5, 28.9; IR (KBr): 3317, 3059, 2949, 2847,
1740,1700,1664,1617,1582,1493,1461,1437,1293,1244,1153,1055,
926, 789, 752, 726, 695 cmꢁ1; HRMS (ESI): m/z [M] calcd for
154.9, 141.3, 137.3, 130.9, 130.0, 129.9, 129.0, 128.6, 128.5, 127.8,
126.7, 126.0, 124.3, 119.6, 115.3, 114.6, 107.9, 76.0, 55.6, 53.3, 52.5; IR
(KBr): 3062, 2950, 2830, 1740, 1700, 1685, 1604, 1512, 1466, 1437,
1250, 1178, 1096, 1032, 917, 804, 755, 697 cmꢁ1; HRMS (ESI): m/z
[M] calcd for C29H24N2O6: 496.1634, found: 496.1639.
C26H20N2O3: 408.1474, found: 408.1479.
4.3.37. 1-(4-Methoxy-phenyl)-10-(4-nitro-benzyl)-4-oxo-1,4-
dihydropyrimido[1,2-a]indole-3-carboxylic acid methyl ester
(7e). Yellow solid (42 mg, 35%); mp: 207e209 ꢀC; 1H NMR
(400 MHz, CDCl3):
4.3.32. 10-Benzylidene-4-oxo-1-phenyl-1,4,10,10a-tetrahydro-pyr-
imido[1,2-a]indole-2,3-dicarboxylic acid dimethyl ester (5d). Yellow
solid (69 mg, 59%); mp: 198e200 ꢀC; 1H NMR (500 MHz, CDCl3):
d
¼8.94 (d, J¼8.4 Hz, 1H), 8.23 (s, 1H), 7.98
d
¼8.14 (d, J¼8.0 Hz, 1H), 7.42e7.32 (m, 7H), 7.13e7.05 (m, 2H),
6.96e6.93 (m, 2H), 6.89 (s, 1H), 6.69 (s, 1H), 6.63 (d, J¼7.5 Hz, 2H),
3.91 (s, 3H), 3.55 (s, 3H); 13C NMR (125 MHz, CDCl3):
(d, J¼8.8 Hz, 2H), 7.40e7.30 (m, 3H), 7.20 (d, J¼8.8 Hz, 2H), 6.90
(d, J¼8.8 Hz, 2H), 6.83 (d, J¼8.8 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H),
d¼165.2,163.7,
3.61 (s, 2H); 13C NMR (100 MHz, CDCl3):
150.2, 147.8, 146.7, 132.8, 130.8, 129.8, 128.6, 128.5, 124.7, 123.7,
123.6, 117.4, 117.3, 115.3, 99.1, 97.1, 56.1, 52.5, 29.0; IR (KBr): 3114,
3062, 2946, 2838, 1743, 1667, 1590, 1511, 1458, 1435, 1343, 1291,
d
¼174.8, 165.3, 161.1, 156.9,
158.0, 155.2, 141.8, 137.2, 135.1, 130.6, 129.5, 129.3, 129.2, 129.1,
129.0, 128.9, 128.7, 128.6, 126.2, 124.3, 120.0, 115.6, 107.3, 75.7, 53.2,
52.5. IR (KBr): 3058, 2950, 2855, 1743, 1700, 1663, 1595, 1526, 1493,
Please cite this article in press as: Lei, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.023

10
M. Lei et al. / Tetrahedron xxx (2014) 1e10
1241, 1177, 1106, 1027, 838, 784, 745, 735, 715 cmꢁ1; HRMS (ESI): m/
z [M] calcd for C27H21N3O6: 483.1430, found: 483.1436.
4. Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campell, J. A.; Greenwood, T. D. J. Med.
Chem. 1990, 33, 161.
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Chem. Lett. 2002, 12, 403.
6. Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma, D.; Caliari, S.; Fici, F.; Cirillo, R.;
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7. Chiou, W. F.; Liao, J. F.; Chen, C. F. J. Nat. Prod. 1996, 59, 374.
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2001, 67, 244.
9. (a) Sharma, V. M.; Prasanna, P.; Seshu, K. V. A.; Renuka, B.; Rao, C. V. L.; Kumar,
G. S.; Narasimhulu, C. P.; Babu, P. A.; Puranik, R. C.; Subramanyam, D.; Ven-
kateswarlu, A.; Rajagopal, S.; Kumar, K. B. S.; Rao, C. S.; Mamidi, N. V. S.; Deevi,
D. S.; Ajaykumar, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett. 2002, 12, 2303; (b)
Xia, Z. M.; Wang, K.; Zheng, J. N.; Ma, Z. Y.; Jiang, Z. G.; Wang, X. X.; Lv, X. Org.
Biomol. Chem. 2012, 10, 1602; (c) Bhattacharjee, A. K.; Skanchy, D. J.; Jennings,
B.; Hudson, T. H.; Brendle, J. J.; Werbovetz, K. A. Bioorg. Med. Chem. 2002, 10,
1979.
4.3.38. 10-(4-Nitro-benzyl)-4-oxo-1-phenyl-1,4-dihydropyrimido
[1,2-a]indole-3-carboxylic acid methyl ester (7f). Yellow solid
(34 mg, 30%); mp: 156e157 ꢀC; 1H NMR (400 MHz, CDCl3):
d¼8.95
(d, J¼8.4 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J¼8.8 Hz, 2H), 7.55e7.52
(m, 1H), 7.41e7.29 (m, 7H), 6.85 (d, J¼8.4 Hz, 2H), 3.94 (s, 3H), 3.56
(s, 2H); 13C NMR (125 MHz, CDCl3):
d
¼165.2, 156.8, 149.7, 147.6,
146.7, 140.2, 132.5, 130.8, 130.5, 129.8, 128.6, 127.3, 124.8, 123.8,
123.7, 117.5, 117.3, 99.3, 97.1, 52.6, 29.1; IR (KBr): 3071, 2946, 1739,
1700, 1662, 1620, 1589, 1508, 1454, 1435, 1342, 1288, 1244, 1106,
1054, 933, 855, 785, 746, 691 cmꢁ1; HRMS (ESI): m/z [M] calcd for
C
26H19N3O5: 453.1325, found: 453.1321.
10. Jao, C. W.; Lin, W. C.; Wu, Y. T.; Wu, P. L. J. Nat. Prod. 2008, 71, 1275.
11. Chen, M. H.; Gan, L. S.; Lin, S.; Wang, X. L.; Li, L.; Li, Y. H.; Zhu, C. G.; Wang, Y. A.;
Jiang, B. Y.; Jiang, J. D.; Yang, Y. C.; Shi, J. G. J. Nat. Prod. 2012, 75, 1167.
12. (a) Zhang, Z. G.; Xue, C.; Liu, X.; Zhang, Q.; Liu, Q. Tetrahedron 2011, 67, 7081; (b)
Jeong, J. U.; Chen, X.; Rahman, A.; Yamashita, D. S.; Luengo, J. I. Org. Lett. 2004, 6,
1013; (c) Jezewski, A.; Jurczak, J.; Lidert, Z.; Tice, C. M. J. Heterocycl. Chem. 2001,
38, 645; (d) Sitte, A.; Paul, H. Chem. Ber. 1969, 102, 615; (e) Taylor, E. C.; Zhou, P.;
Tice, C. M. Tetrahedron Lett. 1997, 38, 4343; (f) Adib, M.; Yavari, H.; Molla-
hosseini, M. Tetrahedron Lett. 2004, 45, 1803.
13. For reviews of Heck reaction see: (a) Ruan, J. W.; Xiao, J. L. Acc. Chem. Res. 2011,
44, 614; (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945; (c)
Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449.
14. For examples of intramolecular Heck reaction see: (a) Firmansjah, L.; Fu, G. C. J.
Am. Chem. Soc. 2007, 129, 11340; (b) Ma, S. M.; Ni, B. K. J. Org. Chem. 2002, 67,
8280; (c) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc. 2011,
133, 20146; (d) Zang, Q.; Javed, S.; Porubsky, P.; Ullah, F.; Neuenswander, B.;
Lushington, G. H.; Basha, F. Z.; Organ, M. G.; Hanson, P. R. ACS Comb. Sci. 2012,
14, 211; (e) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581; (f) Pinho, P.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 259;
(g) Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003, 68, 7625;
(h) Liu, Y.; Yao, B.; Deng, C. L.; Tang, R. Y.; Zhang, X. G.; Li, J. H. Org. Lett. 2011, 13,
1126.
4.3.39. 1-Phenyl-6-styryl-1,6-dihydro-pyridine-2,3,4,5-tetracarboxy-
lic acid tetramethyl ester (9). Yellow oil (15 mg, 12%); 1H NMR
(400 MHz, CDCl3):
d
¼7.45e7.27 (m, 10H), 6.78 (d, J¼15.6 Hz, 1H),
6.31 (dd, J¼16.0, 6.0 Hz, 1H), 5.50 (d, J¼4.2 Hz, 1H), 3.92 (s, 3H), 3.75
(s, 3H), 3.70 (s, 3H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼167.9, 164.3, 163.8, 148.4, 142.9, 137.6, 136.0, 132.1, 129.5, 128.8,
128.5, 128.4, 127.2, 125.2, 123.0, 109.4, 103.6, 62.0, 53.1, 52.8, 52.6,
52.2; IR (KBr): 2953, 2923, 2851, 1740, 1598, 1493, 1436, 1235, 1121,
1076, 964, 763, 735, 700 cmꢁ1; HRMS (ESI): m/z [M] calcd for
C
27H25NO8: 491.1580, found: 491.1582.
References and notes
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2009, 42, 463; (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169; (c)
Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Ba-
€
lagopal, A. L. Acc. Chem. Res. 2003, 36, 899; (d) Domling, A. Chem. Rev. 2006, 106,
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15. Lei, M.; Zhan, Z. J.; Tian, W.; Lu, P. Tetrahedron 2012, 68, 3361.
16. Lei, M.; Tian, W.; Hu, R. J.; Li, W.; Zhang, H. Synthesis 2012, 44, 2519.
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Please cite this article in press as: Lei, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.023