Iron-catalyzed four-member multicomponent reaction for assembly of (E)-6-arylvinyl-3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1016/j.tet.2015.07.039

A novel iron-catalyzed one-pot multi-component tandem reaction of acetoacetamide, urea, and two molecules of aryl aldehydes has been developed. This reaction provides a general, straightforward, practical and useful method for the preparation of potential

Full text of DOI:10.1016/j.tet.2015.07.039

Tetrahedron xxx (2015) 1e7
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Tetrahedron
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Iron-catalyzed four-member multicomponent reaction for assembly
of (E)-6-arylvinyl-3,4-dihydropyrimidin-2(1H)-ones
*
Zhiguo Zhang , Lianqiang Zhang, Xinyu Duan, Xiangqian Yan, Yan Yan, Qingfeng Liu,
*
Tongxin Liu, Guisheng Zhang
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel iron-catalyzed one-pot multi-component tandem reaction of acetoacetamide, urea, and two
molecules of aryl aldehydes has been developed. This reaction provides a general, straightforward,
practical and useful method for the preparation of potential bioactive (E)-6-arylvinyl-3,4-
dihydropyrimidin-2(1H)-ones. They are also versatile precursors leading to diverse drug-like dihy-
dropyrimidin-2(1H)-one derivative. The characters of avoiding protonic acid and using a single in-
expensive and environmentally benign catalyst make this method more valuable.
Received 3 June 2015
Received in revised form 11 July 2015
Accepted 14 July 2015
Available online xxx
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Four-component reaction
Biginelli-type reaction
Aldol condensation reaction
Iron-catalyzed
Vinylogous aldol condensation
1. Introduction
3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) are identified
a broad range of biological activities, such as antitumor,1 antihy-
pertensive,2 antiHIV,3 antimicrobials, antiinflammatory, antibacte-
rial, antifungal, and anthelmintic activities.4 6-Arylvinyl DHPMs are
not only potential bioactive compounds, but also potential versatile
precursors of preparing diverse drug-like DHMP derivatives, e.g.,
pyrido[4,3-d]pyrimidines,5 through conjugate-addition, in-
termolecular and intramolecular cycloadditions, halogenations,
hydrogenations, hydrations, oxidations, and other reactions based
on the newly formed carbonecarbon double bond. It is well-known
that DHPMs can be obtained from the classical Biginelli reaction or
Biginelli-like reaction,6 but, highly functional DHPM derivatives7
including 6-arylvinyl DHPMs5 have to be prepared by a de-
rivatization of Biginelli products although it would be a better
choice to obtain them from one-pot multi-component Biginelli-
type reaction.8 Very recently, we achieved an iron-catalyzed
vinylogous aldol condensation of Biginelli products with alde-
hydes for the synthesis of 6-arylvinyl DHPMs (Eq. 1),5 which in-
spired us to hypothesize that a Lewis acid catalyzed one-pot four-
component strategy for assembly of 6-arylvinyl DHPMs should be
feasible (Eq. 2).
A literature review disclosed that only three papers had focused
on the four-component Biginelli-like multi-component reactions
(MCRs) (with one molecule of b-dicarbonyl compounds, one mol-
ecule of urea and two molecules of aldehyde) since Biginelli re-
action was discovered. In 2000, Byk and co-works found that a five-
member ring b-keto ester (lactone) could react with one molecule
of urea and two of aldehyde to give a new family of spiro hetero-
bicyclic aliphatic rings in good yields without traces of the expected
DHMP (Biginelli) products.9 Soon after, they extended the four-
component Biginelli-type reaction to the condensation between
cyclic b-keto lactams with two molecules of aldehyde and urea, and
the reaction produced exclusively syn spiro-fused pyrimidine iso-
* Corresponding authors. Fax: þ86 373 332 5250; e-mail addresses: zhangzg@
htu.edu.cn (Z. Zhang), zgs6668@yahoo.com (G. Zhang).
mers in a 1:1 mixture.10 And similar spiro-fused ring syntheses
http://dx.doi.org/10.1016/j.tet.2015.07.039
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
could also be obtained when annular cyclopentane-1,3-dione and
dimethylbarbituric acid (or their analogues) were used as the
special 1,3-dicarbonyl compounds.11 However, it must be noted that
all of these MCR methods9e11 afforded a spiro compound instead of
the 6-arylvinyl DHMPs (Eq. 3). Herein, we report an effective and
practical iron-catalyzed one-pot four-component Biginelli-type
condensation for the straightforward assembly of 6-arylvinyl
DHPMs from acetoacetamide, urea, and two molecules of aldehyde.
suitable media for this multicomponent condensation (Table 1,
entry 1). The use of EtOH resulted in the formation of 4ad in 29%
yield together with 47% 5a, and the yield of 4ad could not be further
increased by prolonging the reaction times (Table 1, entry 2). In
solvents CH2Cl2 and DMSO, the desired product 4ad was not ob-
tained, especially in DMSO, the only isolated compound was Bigi-
nelli product 5a (82%) (Table 1, entries 3 and 4). The temperature
has a great influence on the reaction. It was found that the yield of
4ad would decrease significantly along with the decreased tem-
perature (Table 1, entries 5 and 6). At reflux, increasing or de-
creasing the amount of the FeCl3$6H2O would only provide
a slightly lower yield of 4ad (Table 1, entry 1 vs. entries 7,8). In-
terestingly, we did not obtain a satisfied result when 2.0 equiv of 2a
was used for the reaction, although it seems it is enough for the
protocol (Table 1, entry 9). Moreover, the experimental results
disclosed that increasing the amount of 2a to 4.0 equiv entirely
could not improve the yield of the 4ad (Table 1, entry 10). In ad-
dition, iron salts screening showed that the multicomponent cou-
pling reaction could be catalyzed by FeIII salts or FeII salts, such as
FeCl3$6H2O, Fe2(SO4)3$xH2O, anhydrous FeCl3, Fe(NO3)3$9H2O, and
FeSO4$7H2O, in the absence of any acid (such as HCl) (Table 1, en-
tries 1, 11e14). But it is obvious that FeCl3$6H2O was the most ef-
fective catalyst for the reaction (Table 1, entry 1). More importantly,
this tandem reaction is very efficient, compared with the stepwise
reaction of Biginelli reaction (5a: 92% yield) and vinylogous aldol
condensation (4ad: 88% yield) (total yield: 81%),5 the yield of 4ad
can be obtained up to 86% in the presence of sole FeCl3$6H2O via
the one-pot strategy (Table 1, entry 1). It is noteworthy that,
according to the 1H NMR data, the C]C double bond at the 6-
position was assigned as an E configuration based on the magni-
tude of the coupling constant (16.4 Hz).9
2. Results and discussion
Over the past decade, iron-catalyzed MCRs have drawn much
attention due to the nontoxicity, low cost, sustainability, ready
availability, stability, and environmentally friendly properties.12
Several literature have successfully achieved the iron-catalyzed
Biginelli reactions.6e-l Combined with our recent work on the
synthesis of 6-arylvinyl DHPMs,5 iron salts were selected as the
catalyst for the effective and practical preparation of p-conjugated
6-arylvinyl DHPMs. Some key results of the conditions screening
are summarized in Table 1. Our initial investigation focused on the
effect of solvents on the four-component coupling reactions of 1, 2,
and 3. Initially, several solvents were screened in a model reaction
of acetoacetanilide (1a) (0.5 mmol),13 benzaldehyde (2a)
(1.5 mmol), and urea (3a) (0.5 mmol) by using FeCl3$6H2O
(0.05 mmol) as catalyst, and CH3CN was found to be the most
The optimized reaction condition was established (Table 1, entry
1), the scope of this protocol was investigated next (Table 2). We
first explored the scope of the reaction by using various acetoace-
tanilides (1aeh) and 2a. As expected, 1aeh worked well and gave
Table 1
Survey of reaction conditionsa
Entry
Catalyst
T/ꢀC
Time/h
Products
Yieldb/%
1
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
FeCl3$6H2O
Fe2(SO4)3$xH2O
FeCl3
Reflux
Reflux
Reflux
82
60
40
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
22
24
20
6
24
4
46
21
12
23
33
36
3
4ad
86
2c
3d
4e
5
4adþ5a
4adþ5a
5a
29þ47
0þ0
82
4adþ5a
47þ46
6
5a
90
7f
4ad
4ad
4ad
4ad
4ad
4ad
74
72
11
88
84
73
8g
9h
10i
11
12
13
14
Fe(NO3)3$9H2O
FeSO4$7H2O
4adþ5a
Traceþ79
40
4ad
76
a
Unless otherwise indicated, all reactions were carried out with 1a (0.5 mmol), 2a (1.5 mmol), and 3a (0.5 mmol) in CH3CN (3.0 mL) in the presence of 0.1 equiv iron salt.
Isolated yield.
b
c
d
e
f
Reaction was performed in EtOH.
Reaction was performed in CH2Cl2.
Reaction was performed in DMSO.
FeCl3$6H2O (0.05 equiv) was used.
FeCl3$6H2O (0.2 equiv) was used.
Compound 2a (2.0 equiv) was used and 85% of 5a was obtained.
Compound 2a (4.0 equiv) was used.
g
h
i
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Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
3
Table 2
Four-component one-pot condensation strategy for the synthesis of 4aa,b
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
a Unless otherwise indicated, all reactions were carried out with 1 (0.5 mmol), 2 (1.5 mmol), 3 (0.5
mmol) and FeCl3·6H2O (10 mol%) in CH3CN (3.0 mL).
b Isolated yield.
c 4.0 Equiv of aldehyde was used.
d 4.0 Equiv of aldehyde 2 and 0.2 equiv FeCl3·6H2O was used.
e 0.1 Equiv of Fe2(SO4)3·xH2O was used, 38% of 5p was obtained, and prolonged reaction time could
not improve the yield of 4ap.
f 54% of 5q was obtained.
g 73% of 5r was obtained.
h 53% of 5s was obtained along with the recovered 1a 40%.
i 59% of 3-oxo-N-phenyl-2-(pyridin-4-ylmethylene)butanamide was obtained.
the target products 4aaeh in good to excellent yields (72e91%)
regardless of the electronic nature of the diverse substituents and
the position of the substituents. In these cases, it took a little longer
time for the substrates 1e and 1h with electron-withdrawing
groups (EWG) (eCl, eCO2Et) on the ortho-position of the benzene
ring to afford compounds 4ae (40 h) and 4ah (36 h), respectively.
Additionally, the use of N-aliphatic substituted acetoacetamide 1i
resulted in a slightly lower yield of target product 4ai (74%). Next,
the electronic effects of various aromatic aldehydes with an
electron-donating groups (EDG) (OMe) or EWG (eF, eCOOEt) were
examined, and the experimental data showed that all tested aro-
used. Similarly, heteroaryl aldehydes 2-thenaldehyde (1s) and
isonicotinaldehyde (1t) also did not convert to the expected 6-
arylvinyl DHPMs 4as and 4at, respectively.
In order to enlarge the available drug-like library of the diverse 4
(using different aldehydes 2 at the two stages of Biginelli reaction
and vinylogous aldol condensation) for the bioactivity screening as
well as verify the universality of the approach, one-pot stepwise
strategy for the synthesis of 4b was performed by using several
randomly selected 1, 2, and 3. To our delight, a series of
p-conju-
gated 3,4-dihydropyrimidin-2(1H)-one analogues (4baeg) with
a variety of different substituent groups could be achieved in
67e80% yield via the multi-step one-pot process (Table 3). It worth
noting that the amount of the aldehydes 2 should not be added
more than 1.1 equiv at the first step in the synthesis of 5, otherwise,
it would give the yield of 4a more than 5%. It is noteworthy that as
one of the most important applications, very recently, we have used
compounds 4 to prepare potential bioactive pyrido[4,3-d]pyrimi-
dines 6 in the presence of NaOH in EtOH at reflux.5
matic aldehydes were transformed into the highly substituted
p-
conjugated 3,4-dihydropyrimidin-2(1H)-one analogues 4ajeo very
well except for the 3-methoxybenzaldehyde, which only gave
a moderate yield of 4ak (58%) for some reasons. The expansion of
urea seemed to be limited, only 43% 4ap was obtained under the
optimized condition. Finally, although the yield of 4ap could be
obtained in 43% by using the catalyst of Fe2(SO4)3$xH2O (0.1 equiv),
it could not be further improved by prolonging the reaction times
or increasing the amount of aldehyde. It only afforded the Biginelli
products 5q (54%) and 5r (73%) instead of the desired 6-arylvinyl
DHPMs 4aq and 4ar when aliphatic aldehydes 1q and 1r were
This chemistry was also extended to the other
b-dicarbonyl
compounds such as ethyl acetoacetate (1u) and acetylacetone (1v),
but they only gave the corresponding Biginelli products 5u and 5v
in 85% and 81% yields, respectively (Eq. 4). Even we increased the
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4
Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
Table 3
One-pot stepwise strategy for the synthesis of 4ba,b
a Unless otherwise indicated, the first step were carried out with 1 (0.5 mmol), 2 (0.55 mmol), 3 (0.75
mmol) and FeCl3·6H2O (10 mol%) in CH3CN (2.0 mL) and another different aldehydes 2 (1.0 mmol)
was added to the mixture at the second step.
b Isolated yield.
amount of the benzaldehyde to 3 equiv or carried out the reactions
addition of the reactive species C to aldehydes 2 with the terminal
in the presence of molecular sieve under anhydrous condition. The
Biginelli products bearing 5-ester or 5-acyl group are not the sub-
strates of vinylogous aldol reaction under present conditions. These
results indicate that the electron-rich amide moiety at the 5-
position of DHPMs (5) is very important for this vinylogous aldol
condensation reaction.5 A possible mechanism of the tandem
Biginelli reaction/vinylogous aldol condensation is proposed in
Scheme 1. We proposed a mechanism for the first stage (1 to 5)
similar to that of Folkers and Johnson,6k Kappe,6j Hu,6i and Lu6d for
Biginelli reaction.14 The first step in this reaction involves the for-
mation of the highly reactive N-acyliminium species B, formed by
the reaction of the aldehyde with urea and stabilized by either iron
carbon of its double-bond system (the g-carbon/position), followed
by dehydration to afford the products 4.16d,17
In order to demonstrate the easy use of the multi-component
condensation, a large-scale reaction of 1a, 2a with 3a was con-
ducted in CH3CN. After vigorously stirring the mixture of 1a (100 g,
0.565 mol), 2a (172 mL, 1.695 mol), 3a (33.9 g, 0.565 mol), and
FeCl3$6H2O (15.3 g, 0.057 mol) in CH3CN (1 L) for 48 h at reflux, the
desired compound 4ad was isolated as a white solid in 80% yield
(179 g, 0.453 mol) without purification by silica gel column chro-
matography, and 0.9 L CH3CN was recovered after distilled under
reduced pressure.18
or proton (produced in situ). Subsequent addition of a
p-nucleo-
phile A, i.e., the enol tautomer of acetoacetamide 1 to the electron-
deficient N-acyliminium species B, followed by the cyclization and
dehydration, would produce the DHPMs 5. For the vinylogous-aldol
reaction stage, the vinylogous enolate C12a,15 was firstly formed in
the presence of FeCl3. The nitrogen of the amide moiety contributed
its lone-pair electrons to the conjugated system, which would en-
hance the nucleophilicity of the vinylogous enolate C.5,16 The
3. Conclusions
In summary, we have achieved an iron-catalyzed multi-com-
ponent condensation reaction of
b-keto amides, aldehydes and
ureas for the synthesis of the useful 6-arylvinyl DHPMs in good to
excellent yields via a tandem reaction of Biginelli reaction and
vinylogous aldol condensation using a sole iron catalyst, four
chemical bonds were constructed at once in this process, including
two CeN bonds, one CeC single bond, and a CeC double bond.
Protonic acid-free, and the use of sole FeCl3$6H2O as the catalyst in
the tandem processes make the protocol more effective and prac-
tical. This straightforward strategy combines the advantages of
both MCRs and tandem reactions, thus significantly enhance its
green characteristic and the operational convenience. A variety of
Scheme 1. Proposed mechanism.
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Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
5
cheap and readily available reactants, a wide range of substrate
scopes, dense and flexible substituted patterns, significantly higher
yields, and important synthetic potential of the products are ad-
vantages of the present method.
2H), 7.41e7.26 (m, 11H), 7.22 (d, J¼16.8 Hz, 1H), 6.85 (d, J¼8.8 Hz,
2H), 5.47 (d, J¼2.4 Hz, 1H), 3.70 (s, 3H).
4.2.4. (E)-N-(3-Methoxyphenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4ab). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼100:1) as a white solid (161.5 mg, 76%); 1H NMR (400 MHz,
4. Experimental
4.1. General
DMSO-d6)
d 10.02 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.42e7.26 (m,
12H), 7.19e7.15 (m, 3H), 6.63 (td, J1¼7.6 Hz, J2¼2.0 Hz, 1H), 5.47 (d,
J¼2.8 Hz, 1H), 3.70 (s, 3H).
All reagents were purchased from commercial sources and used
without further treatment. All reactions were carried out under air
atmosphere. The known compounds 4aae4aj, 4ap, and 4b were
identified by comparison of their 1H NMR with those of authentic
samples.5 The new compounds (4ake4ao) listed in Table 2 were
properly characterized by melting point, 1H NMR, 13C NMR, and
HRMS. 1H NMR and 13C NMR spectra were recorded on a 400 MHz
NMR spectrometer (1H: 400 MHz, 13C: 100 MHz at 25 ꢀC). Coupling
constants are reported in hertz (Hz). All high-resolution mass
spectra (HRMS) were measured on a mass spectrometer by using
electrospray ionization (ESI). Melting points were measured on
a melting point apparatus equipped with a thermometer and were
uncorrected. All reactions were monitored by TLC with GF254 silica
gel coated plates. Flash chromatography was carried out on SiO2
(silica gel 200e300 mesh).
4.2.5. (E)-N-(2-Methoxyphenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4ac). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼100:1) as
a
yellow solid (182.8 mg, 86%); 1H NMR
(400 MHz, DMSO-d6)
d
8.92 (s, 1H), 8.80 (s, 1H), 7.80e7.70 (m, 2H),
7.49 (t, J¼7.2 Hz, 2H), 7.44e7.27 (m, 10H), 7.07 (t, J¼7.6 Hz, 1H),
6.98 (d, J¼8.0 Hz, 1H), 6.88 (t, J¼7.6 Hz, 1H), 5.39 (s, 1H), 3.60 (s,
3H).
4 . 2 . 6 . ( E ) - 2 - O x o - N , 4 - d i p h e n y l - 6 - s t y r y l - 1, 2 , 3 , 4 -
tetrahydropyrimidine-5-carboxamide (4ad). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼80:1) as a white solid (169.8 mg, 86%); 1H NMR (400 MHz,
DMSO-d6)
d
10.03 (s, 1H), 8.83 (s, 1H), 7.76 (s, 1H), 7.58 (d, J¼8.0 Hz,
2H), 7.44e7.25 (m, 13H), 7.21 (d, J¼16.4 Hz, 1H), 7.04 (t, J¼7.2 Hz,
1H), 5.51 (s, 1H).
4.2. General procedure for the synthesis of compounds 4a
and 4b
4.2.7. (E)-N-(4-Chlorophenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4ae). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼80:1) as a white solid (186.6 mg, 87%); 1H NMR (400 MHz,
4.2.1. For 4a (4ad as an example). To a round-bottom flask (25 mL)
equipped with a spherical condenser (40 cm length) were added 3-
oxo-N-phenylbutanamide (89 mg, 0.5 mmol), urea (30 mg,
0.5 mmol), benzaldehyde (159 mg, 1.5 mmol), FeCl3$6H2O (14 mg,
0.05 mmol), and CH3CN (3 mL). Then, the mixture was well stirred
under reflux for 22 h (The whole process was closely monitored by
TLC.). After cooling off, water (3 mL) was added to the mixture.
Then, the mixture was filtered and the insoluble material was pu-
rified by a short flash silica gel column chromatography to give oxo-
4-phenyl-6-styryl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid
phenylamide 4ad (169.8 mg, 86%) as white solid (eluent:
dichloromethane/methanol¼80:1).
DMSO-d6)
d
10.15 (s, 1H), 8.87 (d, J¼6.4 Hz, 1H), 7.78 (s, 1H), 7.62 (d,
J¼8.4 Hz, 2H), 7.47e7.23 (m, 13H), 7.20 (d, J¼16.8 Hz, 1H), 5.50 (s,
1H).
4.2.8. (E)-N-(3-Chlorophenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4af). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼80:1) as a white solid (156.6 mg, 73%); 1H NMR (400 MHz,
DMSO-d6)
d
10.19 (s, 1H), 8.88 (s, 1H), 7.79 (s, 1H), 7.78 (t, J¼2.0 Hz,
1H), 7.47e7.26 (m, 13H), 7.18 (d, J¼16.4 Hz, 1H), 7.09 (d, J¼8.0 Hz,
1H), 5.48 (d, J¼2.8 Hz, 1H).
4.2.2. One-pot stepwise strategy for the synthesis of 4b (4ba as an
example). In a three necked flask (50 mL) with a reflux condenser
(40 cm), 4-fluorobenzaldehyde [186 mg, 0.55 mmol, dissolved in
CH3CN (2 mL) in a pressure equalizing dropping funnel] was
4.2.9. (E)-N-(2-Chlorophenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4ag). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼100:1) as a white solid (195.2 mg, 91%); 1H NMR (400 MHz,
dropwise added to
a mixture of N-(4-methoxyphenyl)-3-
DMSO-d6) d 9.56 (s, 1H), 8.89 (s,1H), 7.78 (s,1H), 7.51e7.34 (m,12H),
oxobutanamide (104 mg, 0.5 mmol), urea (45 mg, 0.75 mmol),
FeCl3$6H2O (14 mg, 0.05 mmol), and CH3CN (1 mL). The mixture
was refluxed for 5 h before benzaldehyde (106 mg, 1.0 mmol) was
added in. After 20 h at reflux, the mixture was cooled off, and water
(3 mL) was added in, then the mixture was filtered and the in-
soluble material was purified by a short flash silica gel column
7.33e7.28 (m, 3H), 7.20 (t, J¼8.0 Hz, 1H), 5.47 (d, J¼2.4 Hz, 1H).
4. 2.10. (E)-Ethyl 4-(2-oxo-4-phenyl-6-styryl-1, 2, 3, 4-
tetrahydropyrimidine-5-carboxamido)benzoate (4ah). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼80:1) as a white solid (168.2 mg, 72%); 1H NMR
chromatography
to
give
(E)-4-(4-fluorophenyl)-N-(4-
(400 MHz, DMSO-d6)
2H), 7.81 (s, 1H), 7.73 (d, J¼8.8 Hz, 2H), 7.51e7.16 (m, 12H), 5.51 (s,
1H), 4.27 (q, J¼7.2 Hz, 2H), 1.30 (t, J¼7.2 Hz, 3H).
d
10.34 (s, 1H), 8.91 (s, 1H), 7.88 (d, J¼8.4 Hz,
methoxyphenyl)-2-oxo-6-styryl-1,2,3,4-tetrahydropyrimidine-5-
carboxamide 4ba (148 mg, 67%) as white solid (eluent: dichloro-
methane/methanol¼80:1).
4. 2.11. (E)-N-Benzyl-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4ai). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼60:1) as a white solid (151.3 mg, 74%); 1H NMR (400 MHz,
4.2.3. (E)-N-(4-Methoxyphenyl)-2-oxo-4-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4aa). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼80:1) as a white solid (176.4 mg, 83%); 1H NMR (400 MHz,
DMSO-d6)
d
8.68 (s,1H), 8.56 (t, J¼6.0 Hz,1H), 7.65 (s,1H), 7.37e7.25
DMSO-d6)
d
9.90 (s, 1H), 8.79 (s, 1H), 7.73 (s, 1H), 7.46 (d, J¼8.8 Hz,
Please cite this article in press as: Zhang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.039

6
Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
(m, 14H), 7.20 (d, J¼16.4 Hz, 1H), 7.13 (d, J¼7.6 Hz, 2H), 5.37 (s, 1H),
4.39 (dd, J¼14.8, 6.0 Hz, 1H), 4.20 (dd, J¼14.8, 5.6 Hz, 1H).
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼60:1) as a white solid (202.6 mg, 94%). Mp: 249e251 ꢀC;
1H NMR (400 MHz, DMSO-d6)
d 10.09 (s, 1H), 9.02 (s, 1H), 7.67 (s,
4.2.12. (E)-4-(4-Methoxyphenyl)-6-(4-methoxystyryl)-2-oxo-N-phe-
nyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4aj). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼60:1) as a white solid (193.3 mg, 85%); 1H NMR (400 MHz,
1H), 7.55e7.45 (m, 3H), 7.41e7.13 (m, 11H), 7.03 (t, J¼7.2 Hz, 1H),
5.76 (d, J¼2.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d 164.5, 161.0
(d, J¼68.8 Hz), 158.5 (d, J¼65.9 Hz), 152.8, 139.0, 136.0, 130.2 (d,
J¼13.6 Hz), 129.8 (d, J¼8.2 Hz), 128.9 (d, J¼3.9 Hz), 128.7, 128.3 (d,
J¼3.2 Hz), 125.0, 124.8, 124.4, 124.0 (d, J¼11.7 Hz), 123.5, 122.1 (d,
J¼5.9 Hz), 119.9, 119.5, 116.1 (d, J¼21.5 Hz), 115.7 (d, J¼21.7 Hz),
109.8, 50.5. HRMS (ESI), m/z calcd for C25H19F2N3O2 ([MþNa]þ)
454.1338, found: 454.1316.
DMSO-d6)
d
9.96 (s, 1H), 8.72 (s, 1H), 7.66 (s, 1H), 7.57 (d, J¼7.6 Hz,
2H), 7.34 (d, J¼8.8 Hz, 2H), 7.29e7.21 (m, 5H), 7.11e7.01 (m, 2H),
6.95e6.88 (m, 4H), 5.42 (d, J¼2.8 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H).
4.2.13. (E)-4-(3-Methoxyphenyl)-6-(3-methoxystyryl)-2-oxo-N-phe-
nyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4ak). The product
was isolated by flash chromatography (eluent: dichloromethane/
4 . 2 .18 . ( E ) - N , 4 - D i p h e n yl - 6 - s t y r yl - 2 - t h i o x o - 1, 2 , 3 , 4 -
tetrahydropyrimidine-5-carboxamide (4ap). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼500:1) as a yellow solid (88.4 mg, 43%); 1H NMR (400 MHz,
methanol¼100:1) as
a
white solid (122.8 mg, 54%). Mp:
10.08 (s, 1H), 8.85 (s,
238e240 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
1H), 7.78 (s, 1H), 7.61 (d, J¼7.6 Hz, 2H), 7.35 (d, J¼16.8 Hz, 1H),
7.31e7.26 (m, 4H), 7.20 (d, J¼16.4 Hz, 1H), 7.07e7.00 (m, 2H),
6.93e6.84 (m, 5H), 5.48 (d, J¼2.4 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H).
DMSO-d6)
d
10.16 (s, 1H), 9.95 (s, 1H), 9.65 (s, 1H), 7.58 (d, J¼8.0 Hz,
2H), 7.50e7.25 (m, 13H), 7.15 (d, J¼16.4 Hz, 1H), 7.05 (t, J¼7.2 Hz,
1H), 5.48 (d, J¼2.8 Hz, 1H).
13C NMR (100 MHz, DMSO-d6)
d 164.9, 159.6, 159.4, 153.0, 145.1,
139.1, 137.8, 136.2, 131.5, 130.1, 129.8, 128.7, 123.6, 119.9, 119.7,
119.3, 118.6, 114.2, 112.6, 112.5, 111.9, 110.1, 55.6, 55.04, 55.01.
HRMS (ESI), m/z calcd for C27H25N3O4 ([MþNa]þ) 478.1737, found:
478.1734.
4.2.19. (E)-4-(4-Fluorophenyl)-N-(4-methoxyphenyl)-2-oxo-6-
styryl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(4ba). The
product was isolated by flash chromatography (eluent: dichloro-
methane/methanol¼80:1) as a white solid (148.4 mg, 67%); 1H
NMR (400 MHz, DMSO-d6)
d 9.88 (s, 1H), 8.82 (s, 1H), 7.74 (s, 1H),
4.2.14. (E)-4-(2-Methoxyphenyl)-6-(2-methoxystyryl)-2-oxo-N-phe-
nyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4 al). The product
was isolated by flash chromatography (eluent: dichloromethane/
7.46 (d, J¼8.4 Hz, 2H), 7.43e7.32 (m, 7H), 7.30 (t, J¼7.2 Hz, 1H),
7.24e7.14 (m, 3H), 6.86 (d, J¼8.0 Hz, 2H), 5.48 (s, 1H), 3.71 (s, 3H).
methanol¼100:1) as
a
white solid (159.3 mg, 70%). Mp:
10.02 (s, 1H), 8.83 (s,
4.2.20. (E)-4-(4-Fluorophenyl)-2-oxo-N-phenyl-6-styryl-1,2,3,4-
tetrahydropyrimidine-5-carboxamide (4bb). The product was iso-
lated by flash chromatography (eluent: dichloromethane/meth-
anol¼80:1) as a white solid (165.2 mg, 80%); 1H NMR (400 MHz,
233e235 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d
1H), 7.66 (d, J¼8.4 Hz, 2H), 7.43 (d, J¼16.8 Hz, 1H), 7.39e7.25 (m,
8H), 7.06e6.93 (m, 5H), 5.74 (d, J¼2.4 Hz, 1H), 3.69 (s, 3H), 3.67 (s,
3H). 13C NMR (100 MHz, DMSO-d6)
d
165.1, 157.2, 156.1, 153.7, 139.4,
DMSO-d6)
d
10.04 (s, 1H), 8.90 (s, 1H), 7.80 (s, 1H), 7.58 (d, J¼8.0 Hz,
136.3, 130.9,129.5,128.7, 128.5, 128.0, 127.1, 127.0, 125.1, 123.1, 120.7,
120.6, 120.3, 119.4, 111.6, 111.04, 109.98, 55.4, 55.2, 50.1. HRMS (ESI),
m/z calcd for C27H25N3O4 ([MþNa]þ) 478.1737, found: 478.1711.
2H), 7.45e7.33 (m, 7H), 7.28 (t, J¼8.0 Hz, 3H), 7.15e7.25 (m, 3H),
7.04 (t, J¼7.2 Hz, 1H), 5.52 (s, 1H).
4.2.21. (E)-Methyl
4-(2-(6-(4-methoxyphenyl)-2-oxo-5-(phenyl-
4.2.15. (E)-4-(4-Fluorophenyl)-6-(4-fluorostyryl)-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4am). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼60:1) as a white solid (176.7 mg, 82%). Mp: 237e239 ꢀC;
carbamoyl)-1,2,3,6-tetrahydropyrimidin-4-yl)vinyl)benzoate
(4bc). The product was isolated by flash chromatography (eluent:
dichloromethane/methanol¼80:1) as a white solid (164.2 mg,
68%); 1H NMR (400 MHz, DMSO-d6)
d 10.01 (s, 1H), 8.81 (s, 1H), 7.93
1H NMR (400 MHz, DMSO-d6)
d
9.97 (s, 1H), 8.81 (s, 1H), 7.75 (s, 1H),
(d, J¼8.4 Hz, 2H), 7.70 (s, 1H), 7.53 (t, J¼8.4 Hz, 4H), 7.40 (d,
J¼16.4 Hz, 1H), 7.32 (d, J¼16.8 Hz, 1H), 7.28e7.19 (m, 4H), 7.02 (t,
J¼7.2 Hz, 1H), 6.88 (d, J¼8.8 Hz, 2H), 5.45 (d, J¼2.8 Hz, 1H), 3.82 (s,
3H), 3.69 (s, 3H).
7.57 (d, J¼7.6 Hz, 2H), 7.46e7.36 (m, 5H), 7.29e7.13 (m, 7H), 7.04 (t,
J¼6.8 Hz, 1H), 5.52 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
d 164.7,
163.0 (d, J¼62.4 Hz), 160.6 (d, J¼59.9 Hz), 152.6, 139.8 (d, J¼1.8 Hz),
138.9, 136.3, 132.8 (d, J¼3.3 Hz), 130.5, 128.6 (d, J¼8.4 Hz), 128.5,
128.4, 123.5, 120.0, 119.2 (d, J¼1.5 Hz), 115.8 (d, J¼21.7 Hz), 115.3 (d,
J¼21.3 Hz), 109.7, 55.1. HRMS (ESI), m/z calcd for C25H19F2N3O2
([MþNa]þ) 454.1338, found: 454.1345.
4.2.22. (E)-Methyl
4-(2-(2-oxo-6-phenyl-5-(phenylcarbamoyl)-
1,2,3,6-tetrahydropyrimidin-4-yl)vinyl)benzoate (4bd). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼80:1) as a white solid (160.8 mg, 71%); 1H NMR
4.2.16. (E)-4-(3-Fluorophenyl)-6-(3-fluorostyryl)-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4an). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼60:1) as a white solid (206.9 mg, 96%). Mp: 252e254 ꢀC;
(400 MHz, DMSO-d6)
2H), 7.79 (s, 1H), 7.55 (t, J¼8.4 Hz, 4H), 7.47e7.25 (m, 9H), 7.04 (t,
J¼7.2 Hz, 1H), 5.54 (s, 1H), 3.83 (s, 3H).
d
10.06 (s, 1H), 8.87 (s, 1H), 7.95 (d, J¼8.0 Hz,
1H NMR (400 MHz, DMSO-d6)
d
10.10 (s, 1H), 8.98 (s, 1H), 7.91 (s,
4.2.23. (E)-Methyl4-(2-(6-(4-fluorophenyl)-2-oxo-5-(phenyl-
carbamoyl)-1,2,3,6-tetrahydropyrimidin-4-yl)vinyl)benzoate
(4be). The product was isolated by flash chromatography (eluent:
dichloromethane/methanol¼80:1) as a white solid (181.5 mg, 77%);
1H), 7.61 (d, J¼8.0 Hz, 2H), 7.45e7.39 (m, 3H), 7.32e7.20 (m, 6H),
7.17e7.12 (m, 3H), 7.07 (t, J¼7.2 Hz, 1H), 5.55 (d, J¼2.4 Hz, 1H). 13
C
NMR (100 MHz, DMSO-d6)
d
164.7, 163.6 (d, J¼22.5 Hz), 161.2 (d,
J¼22.8 Hz), 152.8, 146.3 (d, J¼6.0 Hz), 139.0, 138.9 (d, J¼7.8 Hz),
136.4, 131.0 (d, J¼8.4 Hz), 130.7 (d, J¼8.1 Hz), 128.7, 123.7, 123.1 (d,
J¼2.0 Hz),122.6 (d, J¼2.5 Hz),120.9,120.0,115.3 (d, J¼21.2 Hz),114.5
(d, J¼20.9 Hz), 113.3, 113.1, 112.8, 110.0, 55.2. HRMS (ESI), m/z calcd
for C25H19F2N3O2 ([MþNa]þ) 454.1338, found: 454.1318.
1H NMR (400 MHz, DMSO-d6)
d 10.04 (s, 1H), 8.89 (s, 1H), 7.94 (d,
J¼8.4 Hz, 2H), 7.79 (s, 1H), 7.54 (d, J¼8.0 Hz, 4H), 7.43 (d, J¼16.8 Hz,
1H), 7.38e7.25 (m, 5H), 7.19 (t, J¼8.8 Hz, 2H), 7.05 (t, J¼7.2 Hz, 1H),
5.52 (s, 1H), 3.84 (s, 3H).
4.2.24. (E)-N-(4-Chlorophenyl)-6-(4-methoxystyryl)-2-oxo-4-
4.2.17. (E)-4-(2-Fluorophenyl)-6-(2-fluorostyryl)-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4ao). The product
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
product was isolated by flash chromatography (eluent:
(4bf). The
Please cite this article in press as: Zhang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.039

Z. Zhang et al. / Tetrahedron xxx (2015) 1e7
7
4. Ramesh, B.; Bhalgat, C. M. Eur. J. Med. Chem. 2011, 46, 1882e1891.
dichloromethane/methanol¼80:1) as a white solid (160.6 mg,
70%); 1H NMR (400 MHz, DMSO-d6)
10.09 (s, 1H), 8.78 (s, 1H), 7.74
5. Zhang, L.; Zhang, Z.; Liu, Q.; Liu, T.; Zhang, G. J. Org. Chem. 2014, 79, 2281e2288.
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Dtsch. Chem. Ges. 1891, 24, 1317e1319; (c) Kappe, C. O. Acc. Chem. Res. 2000, 33,
879e888; For recent iron-catalyzed Biginelli reactions, please see: (d) Lu, J.; Ma,
H. Synlett 2000, 63e64; (e) Martínez, S.; Meseguer, M.; Casas, L. S.; Rodríguez,
d
(s, 1H), 7.61 (d, J¼8.8 Hz, 2H), 7.20e7.43 (m, 10H), 7.07 (d, J¼16.4 Hz,
1H), 6.94 (d, J¼8.4 Hz, 2H), 5.47 (s, 1H), 3.75 (s, 3H).
~
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E.; Molins, E.; Moreno-Manas, M.; Roig, A.; Sebasftian, R. M.; Vallribera, A.
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nyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4bg). The product
was isolated by flash chromatography (eluent: dichloromethane/
methanol¼80:1) as a white solid (159.5 mg, 72%); 1H NMR
(400 MHz, DMSO-d6) d 9.98 (s, 1H), 8.79 (s, 1H), 7.74 (s, 1H), 7.56 (d,
J¼7.2 Hz, 2H), 7.34 (s, 4H), 7.31e7.13 (m, 5H), 7.06 (d, J¼17.2 Hz, 2H),
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I.; Tellitu, I.; Domínguez, E. J. Org. Chem. 2010, 75, 7954e7957; (c) Dallinger, D.;
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8. Suresh; Sandhu, J. S. Arkivoc 2012, 66e133.
6.94 (d, J¼7.6 Hz, 2H), 5.47 (s, 1H), 3.75 (s, 3H).
Acknowledgements
We thank the National Natural Science Foundation of China
(21172056, 21272057, and 21372065), PCSIRT (IRT1061), China
Postdoctoral Science Foundation funded project (2013M530339
and 2015M572109), the Program of Foundation and Frontier
Technology Research of Henan Province (122300410296) and In-
novation Scientists and Technicians Troop Construction Projects of
Henan Province (134200510016).
9. Byk, G.; Gottlieb, H. E.; Herscovici, J.; Mirkin, F. J. Comb. Chem. 2000, 2, 732e735.
10. Byk, G.; Kabha, E. J. Comb. Chem. 2004, 6, 596e603.
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4559e4562; (b) Shaabani, A.; Bazgir, A.; Bijanzadeh, H. R. Mol. Divers. 2004, 8,
141e145; (c) Shaabani, A.; Bazgir, A. Tetrahedron Lett. 2004, 45, 2575e2577; (d)
Prajapati, D.; Bhuyan, D.; Gohain, M.; Hu, W. Mol. Divers. 2011, 15, 257e261.
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€
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Furstner, A. Acc. Chem. Res. 2008, 41, 1500e1511; (e) Diaz, D. D.; Miranda, P. O.;
Padron, J. I.; Martin, V. S. Curr. Org. Chem. 2006, 10, 457e476.
Supplementary data
13. Alvim, H. G. O.; Lima, T. B.; de Oliveira, A. L.; de Oliveira, H. C. B.; Silva, F. M.;
Gozzo, F. C.; Souza, R. Y.; da Silva, W. A.; Neto, B. A. D. J. Org. Chem. 2014, 79,
3383e3397.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.07.039.
14. (a) Ramos, L. M.; Guido, B. C.; Nobrega, C. C.; Correa, J. R.; Silva, R. G.; de Oli-
veira, H. C.; Gomes, A. F.; Gozzo, F. C.; Neto, B. A. Chem.dEur. J. 2013, 19,
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Please cite this article in press as: Zhang, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.039