Synthesis of C2-functionalized pyrimidines from 3,4-dihydropyrimidin-2(1H)- ones by the Mitsunobu coupling reaction

Article abstract of DOI:10.1016/j.tet.2011.02.046

The Biginelli 3,4-dihydropyrimidin-2(1H)-one was converted to various C2-multifunctionalized pyrimidines via the dehydrogenation and Mitsunobu reaction using amines, alcohols, phenols and carboxylic acids as nucleophiles. A possible mechanism was also proposed to rationalize the formation of products.

Full text of DOI:10.1016/j.tet.2011.02.046

Tetrahedron 67 (2011) 3267e3272
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Tetrahedron
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Synthesis of C2-functionalized pyrimidines from 3,4-dihydropyrimidin-2(1H)-
ones by the Mitsunobu coupling reaction
,
b
,
a
,
,
,
,
,b,
*
Xi-Cun Wang a , Guo-Jun Yang b, Xiao-Dong Jia a b, Zhang Zhang a b, Yu-Xia Da a b, Zheng-Jun Quan a
*
a Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, Gansu 730070, PR China
b Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Anning East Road 967#, Lanzhou,
Gansu 730070, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The Biginelli 3,4-dihydropyrimidin-2(1H)-one was converted to various C2-multifunctionalized pyrimi-
dines via the dehydrogenation and Mitsunobu reaction using amines, alcohols, phenols and carboxylic
acids as nucleophiles. A possible mechanism was also proposed to rationalize the formation of products.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 10 December 2010
Received in revised form 26 January 2011
Accepted 15 February 2011
Available online 22 February 2011
Keywords:
C2-Functionalized pyrimidines
Mitsunobu coupling reaction
3,4-Dihydropyrimidin-2(1H)-ones
Dehydrogenation
Nucleophiles
1. Introduction
Dehydrogenation of the Biginelli DHPMs is also a well known dif-
ficult process leading to low yield, when oxidizing agents, such as
Biginelli 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)1 are cen-
tral subunits in a broad range of medicinal agents, which display
interesting pharmacological and biological properties, such as cal-
cium channel modulators, a1a-adrenergic receptor antagonists,
mitotic kinesin inhibitors and hepatitis B virus replication in-
hibitors.2 The DHPM core was also found in several marine derived
natural products, such as Crambine, Batzelladine B (potent HIV gp-
120CD4 inhibitors) and Ptilomycalin alkaloids.3 Additionally, the
Biginelli DHPMs are important building blocks in synthesis of
multifunctionalized pyrimidines. Although much effort has been
paid on the development of methods for the synthesis of the py-
rimidine derivatives,4 few methodologies are available towards
efficiently synthesis of 2-substituted pyrimidines. In general,
C2-substituted pyrimidines were obtained from Biginelli DHPMs by
a four-step strategy involving sequentially dehydrogenation, tau-
SeO2, DDQ or HNO3 were used.7 It was not until 2005 that a more
efficient approach was achieved by Kang et al., in which8 Biginelli
DHPMs were converted to the C2-functionalized pyrimidines via
Kappe dehydrogenation7c and PyBroP-mediated coupling with
nucleophiles at rt for 24 h (Scheme 1, Eq. 3). At the same time,
Yamamoto et al.9 developed a mild and practical procedure for
dehydrogenation of DHPMs using tert-butylhydroperoxide (TBHP),
which can be applied on a large scale.
However, some limitations still exist in the synthesis of C2-
functionalized pyrimidines based on the methodologies mentioned
above, such as elevating temperature, using of expensive catalyst,
needing long reaction time or multistep. Thus, it is necessary to
develop simpler and more efficient methods under mild reaction
conditions to construct these compounds. To address this problem,
we have developed a mild and rapid procedure to the synthesis of
C2-substituted pyrimidines by sequential functionalization of 3,4-
dihydropyrimidine-2(1H)-ones via oxidation and esterification
followed by cross-coupling reaction with N, S and O nucleophiles at
rt (Scheme 1, Eq. 4).10 The results showed that the method is not
essential for the reaction of pyrimidin-2-yl sulfonates with phenols
to provide phenolic pyrimidine derivative. Herein we report
a general and comprehensive strategy for the preparation of highly
C2-functionalized pyrimidines (4, 6, 8) including phenolic pyrimi-
dines through direct functionalization of the 2-hydroxy pyrimidine
tomerization, activation and coupling with
a
nucleophile5,6
(Scheme 1). However, the harsh condition in chlorination using
POCl3 at high temperatures would threaten those substrates with
sensitive functional groups (Scheme 1, Eq. 1).5 Besides, S-alkylation
was absolutely necessary for sulfide oxidation (Scheme 1, Eq. 2).6b,e
* Corresponding authors. Tel./fax: þ86 931 7971971; e-mail address: wangxicun@
nwnu.edu.cn (X.-C. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.046

3268
X.-C. Wang et al. / Tetrahedron 67 (2011) 3267e3272
O
Ar
O
Ar
R2
N
MeO
Me
NuH
N
O
Ar
N
H
R1
N
Cl
O
ref. 8
ref. 5
O
Ar
NuH
Pd cat.
Oxadiation
O
Ar
N
R2
NH
1. Oxidation
Chlorination
(1)
R2
NH
(3)
(4)
PyBroP
2.
R2
N
R1
N
H
O
R1
O
N
H
Ar
O
R1
Nu
O
Ar
NuH
Base
NuH
(2) R2
NH
Base
R2
NH
O
Ar
R1
N
H
S
ref. 6
O
Ar
R1
N
H
O
ref. 10
R2
N
R2
N
Me
1. S-Methylation
2. Aromatzation
3. Sulfide Oxidation
1. Oxidation
2. Esterification
R1
N
S
O
R1
N
OTs
O
Scheme 1. Synthesis of the C-2 functionalized pyrimidines deriving from DHPMs.
core 2, which obtained from Biginelli 3,4-dihydropyrimidine-2
(1H)-ones 1 (Scheme 2). The OH group of the 2-hydroxy pyrimidine
can be replaced by different nitrogen, oxygen and acid nucleophiles
using amines 3, alcohols (or phenols) 5 and benzoic acids 7 via
Mitsunobu reaction.
Mitsunobu reaction. The results were summarized in Table 2. No
matter what substituent groups were on the aromatic rings of 2-
hydroxy pyrimidine, the reactions proceeded smoothly, and the
cross-coupling products were isolated in good yields. Cyclic sec-
ondary amines were the most successful in this process (entries
O
Ar
N
O
Ar
N
O
Ar
O
Ar
N
O
Ar
N
NuH 3, 5, 7
TBHP
R2
+
N
R2
N
+
R2
NH
R2
N
R2
N
DIAD, Ph3P
OH
R1
OC(O)Ar
R1
OR(Ar)
R1
N
H
O
1
R1
R1
NRR
4
8
6
2
Scheme 2. Preparation of C2-multifunctionalized pyrimidines.
2. Results and discussion
Table 1
Optimization of reaction conditions for product 4dAa
The Biginelli DHPM 1 and their dehydrogenated compounds 2
were readily prepared according to the procedures reported by Fu
et al.11 and Yamamoto et al.9 As a starting point in our in-
vestigations, we examined the Mitsunobu reaction between model
substrate 2-hydroxy pyrimidine 2d and piperidine 3a. Firstly, we
chose diethyl azodicarboxylate (DEAD) and triphenylphosphine
(TPP) as Mitsunobu regents.12 As expected, when the reaction was
performed at rt for 12 h, the cross-coupling product 4dA was
obtained in low yield together with the isolation of a C2 ethoxy
substituted pyrimidine 4dB (Table 1, entries 1 and 2). When the
reaction was performed at 0 ꢀC to rt, the yield of 4dA was increased
obviously (entry 3). Diisopropyl azodicarboxylate (DIAD) exhibited
the best activity and higher yields of 4dA were obtained with
shorter reaction time (entries 7 and 8). Survey of various conditions
indicates that the optimum ratio of 2d:3a:DIAD:Ph3P is
1:1.5:1.5:1.5.
Next, the addition order of the reactants and solvents was
evaluated. Initially, the reaction was conducted under the typical
procedure of the Mitsunobu reaction as follows: DIAD was added
dropwise to the mixture of TPP, 2d, and 3a, but the reaction did not
occur smoothly and only 56% yield of 4dA was achieved (entry 9). A
survey of the adding order showed that the yield could be improved
significantly according to the following order: at 0 ꢀC, DIAD
(1.5 mmol) was dissolved in THF (3 mL), followed by the addition of
TPP with the formation of a suspension, then 2d and 3a were added
(entry 8). The mixture was warmed to rt, and stirred for further
2.5 h to give 4dA in 78% yield.
Cl
Cl
Cl
N
O
O
O
+
Conditions
EtO
Me
N
EtO
Me
N
EtO
Me
N
+
N
H
N
2d
OH
N
4dA
N
O
3a
4dB
Entry Equiv of 2d:3a Reagent Temp (ꢀC) Time (h) Isolated yield (%)
4dA
4dB
1
2
3
4
1:1
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DIAD
DIAD
DIAD
25
25
0e25
60
0e25
0e25
0e25
0e25
0e25
12
12
12
12
2.5
2.5
12
10
11
50
10
56
53
56
78
56
60
63
40
68
35
39
d
d
d
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1
5
6b
7
8
1:1.5
1:1.5
2.5
2.5
9c
a
Reaction conditions: at 0 ꢀC, DIAD (1.5 mmol) was first dissolved in THF (3 mL),
followed by the addition of TPP (1.5 mmol) with the forming of a suspension, then
2d (1.0 mmol) and 3a (1.5 mmol) were added. The temperature was increased to rt.
b
CH2Cl2 was used as solvent.
Reaction conditions: DIAD (1.5 mmol) was added dropwise to the mixture of TPP
c
(1.5 mmol), 3a (1.5 mmol) and 2d (1.0 mmol).
1e14). Acyclic amines also gave promising results (completed
within 5 h), albeit a bit longer time was needed (entries 15).
However, when aromatic amine was involved, the reaction became
complicated, and most of the starting 2-hydroxy pyrimidine 2 was
recovered (not shown in Table 2).
With the optimized conditions in hand, we then examined the
scope of 2-hydroxy pyrimidine substrates by varying the sub-
stituents on the aromatic ring to explore the generality of this

X.-C. Wang et al. / Tetrahedron 67 (2011) 3267e3272
3269
Table 2
Table 3
Coupling of 2-hydroxy pyrimidines 2 with NH nucleophiles 3a
Coupling of 2-hydroxy pyrimidines 2 with OH nucleophiles 5a
O
Ar
O
Ar
N
O
Ar
N
O
Ar
R2
N
R2
N
R2
N
ROH 5
R2
N
NH NuH 3
DIAD, Ph3P, THF
R1
N
OH
R1
OR
6
DIAD, Ph3P, THF
R1
NR2
R1
N
OH
2
4
2
Entry Ar
R1
R2
Time (h) ROH 5
6
Yield (%)b
Entry
Ar/2
Ph/2a
R1
R2
NH
4
Yield
(%)b
84
1
2
3
4
5
Ph
Ph
Ph
4-ClePh
Ph
Me OEt
Me OEt
Me OEt
Me OEt
Me OEt
2
2
2
2
6
CH3CH2OH
(CH3)2CHOH
PhCH2OH
6a 95
6b 93
6c 90
6d 96
6e 82
1
Me
OEt
4a
HN
CH3CH2OH
3a
2
3
4
5
6
7
8
4-MeOePh/2b
4-MeePh/2c
4-ClePh/2d
4-BrePh/2e
4-FePh/2f
4-FePh/2g
Ph/2a
Me
Me
Me
Me
Me
i-Pr
Me
OEt
OEt
OEt
OEt
OEt
OMe
OEt
3a
3a
3a
3a
3a
3a
4b
4c
4d
4e
4f
81
83
78
85
86
80
82
6
4-MeOePh Me OEt
6
6
6f 95
6g 86
6h 80
6i 78
6j 60c
7
4-ClePh
4-FePh
4-ClePh
4-ClePh
Me OEt
i-Pr OMe
Me OEt
Me OEt
4g
4h
8
6
HN
O
3b
9
6
9
4-MeOePh/2b
4-MeePh/2c
4-ClePh/2d
4-BrePh/2e
4-FePh/2f
4-FePh/2g
Ph/2a
Me
Me
Me
Me
Me
i-Pr
Me
OEt
OEt
OEt
OEt
OEt
OMe
OEt
3b
3b
3b
3b
3b
3b
4i
4j
80
80
83
80
82
84
77
HO
Cl
10
11
12
13
14
15c
4k
4l
4m
4n
4o
10
12
HO
11
4-ClePh
Me OEt
12
6k Traced
HO
OMe
CH3CH2NH2 3c
a
a
Reaction conditions: at 0 ꢀC, DIAD (1.5 mmol) was first dissolved in THF (3 mL),
followed by the addition of TPP (1.5 mmol) with the forming of a suspension, then 2
(1.0 mmol) and 5 (1.5 mmol) was added. The temperature was increased to rt and
stirred for another 6 h.
Reaction conditions: at 0 ꢀC, DIAD (1.5 mmol) was first dissolved in THF (3 mL),
followed by the addition of TPP (1.5 mmol) with the forming of a suspension, then 2
(1.0 mmol) and 3 (1.5 mmol) was added. The temperature was increased to rt and
stirred for another 2.5 h.
b
b
Isolated yields.
Isolated yields.
Reaction was completed within 6 h.
c
NMR yield is determined by 1H NMR spectroscopy.
c
d
Detected by TLC and 1H NMR.
When this procedure was applied to the reaction between
2-hydroxy pyrimidine 2 and alcohols 5, to our delight, the target
molecules were obtained in excellent isolated yields (Table 3). As
indicated in Table 3, the reaction could proceed smoothly (entries
1e4). Then alcohol was changed to phenols, and the reaction could
also occur smoothly with phenols bearing electron-withdrawing
groups, such as nitro and chloro, affording desired products 6eei
good to excellent isolated yields (entries 5e9) with prolonged re-
action time. Unfortunately, product 6j could not be isolated from
the reaction mixture by column chromatography and the corre-
sponding yield was determined by 1H NMR (entry 10). When
phenols with an electron-donating group (such as CH3O) were
used, the reaction gave the desired product in trace yield (detected
by TLC and 1H NMR) (entry 11). The results implied that the phenols
bearing electron-withdrawing groups were preferred in this re-
action, which was in agreement with other Mitsunobu reactions. It
is because that the phenols with lower pKa value can accelerate this
cross-coupling reaction.12a
To further demonstrate the utility of the Mitsunobu reaction, we
also tested the reaction between 2-hydroxy pyrimidine 2 and car-
boxylic acids 7. As we expected, Mitsunobu reaction occurred
smoothly giving C2 benzoyloxy pyrimidines 8aeg (Table 4). All sub-
strates, either 2-hydroxy pyrimidines or carboxylic acids, with either
electron-rich (CH3O) or electron-deficient (NO2, Cl) aryl groups,
afforded the corresponding C2 benzoyloxy pyrimidines 8aeg in good
to high yields, in favor of the one with electron-deficient groups.
As mentioned above, the nuclephiles, such as phenols and car-
boxylic acids with lower pKa prefer the cross-coupling reaction.
Thus the mechanism was proposed for the formation of C2-multi-
functionalized pyrimidines via the Mitsunobu reaction based on
a general pathway as shown in Scheme 3. The first step is the
irreversible formation of the MorrisoneBrunneHuisgen (MBH)
betaine 9.13 In step 2, this betaine 9 deprotonates the nucleophile to
form the ionic specie 10, which reacted with the 2-hydroxy
Table 4
Coupling of 2-hydroxy pyrimidines 2 with carboxylic nucleophlies 7a
O
Ar
O
Ar
R2
N
R2
N
ArCOOH 7
DIAD, Ph3P, THF
OH
R1
N
R1
N
OOCAr
2
8
Entry
Ar
Ph
R1
R2
7
8
Yield (%)b
1
2
3
4
5
6
7
Me
Me
Me
i-Pr
Me
Me
Me
OEt
OEt
OEt
OMe
OEt
OEt
OEt
PhCOOH
PhCOOH
PhCOOH
PhCOOH
4-MeOePhCOOH
4-NO2ePhCOOH
4-ClePhCOOH
8a
8b
8c
8d
8e
8f
70
68
69
63
72
80
79
4-MeOePh
4-ClePh
4-FePh
4-ClePh
4-ClePh
4-ClePh
8g
a
Reaction conditions: at 0 ꢀC, DIAD (1.5 mmol) was first dissolved in THF (3 mL),
followed by the addition of TPP (1.5 mmol) with the forming of a suspension, then 2
(1.0 mmol) and 7 (1.5 mmol) was added. The temperature was increased to rt and
stirred for another 6 h.
b
Isolated yields.
pyrimidine 2 providing the key alkoxyphosphonium salt 11 and the
hydrazine RO2CNHeNHCO2R. After nucleophilic substitution and
releasing of a molecule of triphenylphosphine oxide, the product,
C2-multifunctionalized pyrimidine, is formed.
It is noteworthy that the study reported above, to our best
knowledge, is the first general exploration of cross-coupling
reaction of 2-hydroxy pyrimidines with N, O and acid nucleophiles
to give C2-substituted pyrimidines under Mitsunobu reaction
conditions. This cross-coupling reaction, in which only two steps
needed using 3,4-dihydropyrimidinones as starting material, was
superior to other reported processes.

3270
X.-C. Wang et al. / Tetrahedron 67 (2011) 3267e3272
CO2R
O
Ph3P
Ph3P
H
Ph3P
Ar
NuH
N N
RO2C
N N
N N
Nu
10
RO2C
CO2R
RO2C
CO2R
Ar
9
O
R2
N
2
- Ph3P=O
R2
N
Nu
11
R1
N
O-PPh3
R1
N
Nu
Scheme 3. A proposed mechanism for the formation of C2-multifunctionalized pyrimidines.
3. Conclusion
160.1, 139.7, 129.2, 128.0, 113.1, 60.7, 44.6, 25.8, 24.8, 23.2, 13.5.
ESI-MS: m/z 326 ([MþHþ]).
In conclusion, we have developed a novel and efficient synthetic
method to prepare C2-multifunctionalized pyrimidines by the
Mitsunobu reaction between 2-hydroxy pyrimidine and alcohols,
amines, phenols and carboxylic acids nucleophiles. Compared to
previously known approaches, the simplicity (only two-step needed
using 3,4-dihydropyrimidinones as starting material) and higher
efficiency make this method particularly attractive. These results
provided, as well as other reported studies, that Mitsunobu reaction
conditions could be potentially applicable to other electron-de-
ficient heterocyclic or aromatic systems. The present study also
4.2.2. Ethyl 4-(4-methoxyphenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (4b). Obtained 287 mg, yield 81%, white solid, mp
87e88 ꢀC.1HNMR (400 MHz, CDCl3)
d
¼7.56 (d, J¼8.8 Hz, 2H), 6.91 (d,
J¼8.8 Hz, 2H), 4.11 (q, J¼7.6 Hz, 2H), 3.88(t, J¼5.2 Hz, 4H), 3.84(s, 3H),
2.47 (s, 3H), 1.60e1.68 (m, 6H), 1.03 (t, J¼7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d
¼169.5, 166.5, 164.7, 160.7, 132.0, 129.7, 113.5,
60.8, 55.3, 44.6, 25.8, 24.8, 23.1, 13.7. ESI-MS: m/z 356 ([MþHþ]).
4.2.3. Ethyl 4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidine-5-carboxylate
provides
a
readily accessible approach to construct multi-
(4c). Obtained 281 mg, yield 83%, white solid, mp 68e69 ꢀC. 1H
functionalized pyrimidinetemplate fordiversity-oriented synthesis.
NMR (400 MHz, CDCl3)
d
¼7.47 (d, J¼8.0 Hz, 2H), 7.19 (d, J¼8.0 Hz,
2H), 4.08 (q, J¼6.8 Hz, 2H), 3.88 (t, J¼5.2 Hz, 4H), 2.47 (s, 3H), 2.38
(s, 3H), 1.59e1.67 (m, 6H), 0.99 (t, J¼7.2 Hz, 3H). 13C NMR
4. Experimental section
4.1. General information
(100 MHz, CDCl3)
d
¼169.4, 166.6, 165.5, 139.3, 136.8, 128.7, 128.0,
60.7, 44.6, 25.8, 24.8, 23.1, 21.3, 13.6. ESI-MS: m/z 340 ([MþHþ]).
4.2.4. Ethyl 4-(4-chlorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
Commercially available reagents were used without further
purification. Solvents were treated prior to use according to the
standard methods. Column chromatography was performed on
silica gel (300e400 mesh). Melting points were determined on an
XT-4 electrothermal micromelting point apparatus and are un-
corrected. NMR spectra were recorded at 400 (1H) and 100 (13C)
MHz, respectively, on a Varian Mercury plus-400 instrument using
CDCl3 as solvent and TMS as an internal standard. Mass spectra
were obtained on a Bruker Daltonics APEXII 47e FT-ICR spectrom-
eter. The Biginelli DHPM 1 and their dehydrogenated compounds 2
were readily prepared according to the procedures by Fu et al.11 and
Yamamoto et al.9
5-carboxylate (4d). Obtained 280 mg, yield 78%, white solid, mp
54e55 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.50 (d, J¼8.4 Hz, 2H), 7.36
(d, J¼8.4 Hz, 2H), 4.07 (m, J¼6.8 Hz, 2H), 3.88 (t, J¼5.2 Hz, 4H), 2.48
(s, 3H), 1.60e1.68 (m, 6H), 1.01 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3)
d
¼169.4, 166.6, 165.5, 139.3, 136.8, 128.7, 128.0, 113.1, 60.7,
44.6, 25.8, 24.8, 23.1. ESI-MS: m/z 360 ([MþHþ]).
4.2.5. Ethyl 4-(4-bromophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (4e). Obtained 342 mg, yield 85%, white solid, mp
61e62 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.52 (d, J¼8.4 Hz, 2H), 7.43
(d, J¼8.0 Hz, 2H), 4.05 (q, J¼7.2 Hz, 2H), 3.88 (t, J¼5.2 Hz, 4H), 2.49
(s, 3H), 1.60e1.68 (m, 6H), 1.00 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3)
d
¼168.8, 167.2, 164.5, 160.0, 138.7, 131.2, 129.7, 123.6, 60.8,
44.6, 25.8, 24.8, 23.2, 13.6. ESI-MS: m/z 404 ([MþHþ]).
4.2. General procedure for the synthesis of C2-functionalized
4.2.6. Ethyl 4-(4-fluorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (4f). Obtained 295 mg, yield 86%, white solid, mp
pyrimidines
51e52 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.06e7.59 (m, 4H), 4.06
At 0 ꢀC, DIAD (1.5 mmol) was dissolved in THF (3 mL), fol-
lowed by the addition of TPP (1.5 mmol) with the forming of
a suspension, then 2-hydroxy pyrimidine (1.0 mmol) and nucle-
ophile (1.5 mmol) were added. The mixture was warmed to rt and
stirred for further 2e6 h. After completion of the reaction mon-
itored by thin layer chromatography (TLC), the solvent was
evaporated under reduced pressure, and then the crude product
was purified by column chromatography over silica gel with ethyl
acetate and petroleum ether as the eluent, to give target product
4, 6 or 8.
(q, J¼6.8 Hz, 2H), 3.88 (t, J¼5.6 Hz, 4H), 2.48 (s, 3H), 1.61 (m,
6H), 1.00 (t, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼169.3,
d
167.3, 165.0, 164.7, 162.5, 160.3, 136.0, 130.4, 130.2, 115.4, 115.1,
113.2, 61.1, 44.9, 26.1, 25.0, 23.4, 13.8. ESI-MS: m/z 344 ([MþHþ]).
4.2.7. Methyl 4-(4-fluorophenyl)-6-isopropyl-2-(piperidin-1-yl)py-
rimidine-5-carboxylate (4g). Obtained 286 mg, yield 80%, white
solid, mp 96e97 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.06e7.60 (m,
4H), 3.89 (t, J¼5.2 Hz, 4H), 3.59 (s, 3H), 3.19 (m, 1H), 1.58e1.68 (m,
6H), 1.24 (d, J¼6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3)
¼174.4,
d
170.0, 164.7, 163.8, 162.2, 160.5, 135.7, 129.9, 115.2, 115.0, 112.4, 51.9,
4.2.1. Ethyl 4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidine-5-car-
44.7, 32.7, 25.7, 24.8, 21.7. ESI-MS: m/z 358 ([MþHþ]).
boxylate (4a). Obtained 273 mg, yield 84%, white solid, mp
69e70 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.37e7.58 (m, 5H), 4.02 (q,
4.2.8. Ethyl 4-methyl-2-morpholino-6-phenylpyrimidine-5-carboxyl-
J¼6.8 Hz, 2H), 3.89 (t, J¼5.6 Hz, 4H), 2.49 (s, 3H), 1.62 (m, 6H), 0.93
ate (4h). Obtained 268 mg, yield 82%, white solid, mp 118e119 ꢀC.1H
(t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼169.2, 166.9, 165.7,
d

X.-C. Wang et al. / Tetrahedron 67 (2011) 3267e3272
3271
NMR (400 MHz, CDCl3)
d
¼7.40e7.58 (m, 5H), 4.04 (q, J¼7.2 Hz, 2H),
128.1, 128.0, 119.4, 63.4, 61.3, 22.5, 14.2, 13.3. ESI-MS: m/z 287
([MþHþ]).
3.76 (t, J¼4.8 Hz, 4H), 2.50 (s, 3H), 0.95 (t, J¼7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d¼168.9, 167.0, 165.7, 160.2, 139.3, 129.5, 128.2,
128.1, 114.5, 66.9, 60.9, 44.1, 23.1, 13.5. ESI-MS: m/z 328 ([MþHþ]).
4.2.17. Ethyl 2-isopropoxy-4-methyl-6-phenylpyrimidine-5-carbox-
ylate (6b). Obtained 279 mg, yield 93%, colorless oil. 1H NMR
(400 MHz, CDCl3)
d
¼7.38e7.65 (m, 5H), 5.41 (m, 1H), 4.14 (m, 2H),
4.2.9. Ethyl 4-(4-methoxyphenyl)-6-methyl-2-morpholinopyrimidine-
5-carboxylate (4i). Obtained 286 mg, yield 80%, white solid, mp
2.55 (s, 3H), 1.38 (m, 6H), 1.06 (t, J¼6.8 Hz, 3H). 13C NMR (100 MHz,
72e74 ꢀC.1H NMR (400 MHz, CDCl3)
d
¼7.58(d, J¼9.2 Hz, 2H), 6.93 (d,
CDCl3)
d
¼168.4, 168.1, 166.2, 163.5, 137.7, 129.7, 128.1, 128.0, 119.2,
61.3, 22.6, 22.5, 21.6, 21.3, 13.3. ESI-MS: m/z 301 ([MþHþ]).
J¼8.4 Hz, 2H), 4.13 (q, J¼6.8 Hz, 2H), 3.84 (s, J¼4.8 Hz, 3H), 3.75 (t,
J¼4.8 Hz, 4H), 2.47 (s, 3H), 1.05 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
4.2.18. Ethyl 2-(benzyloxy)-4-methyl-6-phenylpyrimidine-5-carbox-
CDCl3)
d
¼169.3, 166.6, 164.7, 160.9, 160.2, 131.5, 129.7, 114.2, 113.6,
ylate (6c). Obtained 313 mg, yield 90%, colorless oil. 1H NMR
66.9, 61.0, 55.3, 55.3, 44.1, 23.1, 13.7. ESI-MS: m/z 358 ([MþHþ]).
(400 MHz, CDCl3)
d
¼7.30e7.63 (m,10H), 5.51 (s, 2H), 4.15 (q, J¼7.2 Hz,
2H), 2.58 (s, 3H), 1.02 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
4.2.10. Ethyl 4-methyl-2-morpholino-6-p-tolylpyrimidine-5-carbox-
d
¼168.6, 168.1, 166.3, 163.7, 137.6, 136.2, 129.9, 128.4, 128.2, 128.2,
ylate (4j). Obtained 273 mg, yield 80%, white solid, mp 68e70 ꢀC.1H
128.1, 127.9, 119.9, 69.2, 61.5, 22.6, 13.4. ESI-MS: m/z 349 ([MþHþ]).
NMR (400 MHz, CDCl3)
d
¼7.49 (d, J¼8.0 Hz, 2H), 7.22 (d, J¼8.0 Hz,
2H), 4.10 (q, J¼7.2 Hz, 2H), 3.92 (t, J¼4.4 Hz, 4H), 3.75 (t, J¼4.4 Hz, 4H),
4.2.19. Ethyl
carboxylate (6d). Obtained 307 mg, yield 96%, pale yellow oil. 1H
NMR (400 MHz, CDCl3)
4-(4-chlorophenyl)-2-ethoxy-6-methylpyrimidine-5-
2.48 (s, 4H), 2.38 (s, 3H), 1.01 (t, J¼6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3)
d
¼169.2, 166.7, 165.4, 160.2, 139.6, 136.4, 128.9, 128.1, 128.0,
d
¼7.69 (dd, J¼2 Hz, 6.4 Hz, 2H), 7.41 (dd,
114.5, 66.9, 60.9, 44.1, 23.0, 21.3, 13.6. ESI-MS: m/z 342 ([MþHþ]).
J¼2 Hz, 6.0 Hz, 2H), 4.50 (q, J¼6.8 Hz, 2H), 4.5018 (q, J¼6.8 Hz, 2H),
2.57 (s, 3H), 1.45 (t, J¼6.8 Hz, 3H), 1.10 (t, J¼6.8 Hz, 3H). 13C NMR
4.2.11. Ethyl 4-(4-chlorophenyl)-6-methyl-2-morpholinopyrimidine-
5-carboxylate (4k). Obtained 299 mg, yield 83%, white solid, mp
(100 MHz, CDCl3)
d
¼168.8, 168.0, 165.2, 164.0, 136.3, 136.3, 129.6,
128.5, 119.5, 63.7, 61.6, 22.7, 14.3, 13.6. ESI-MS: m/z 320 Mþ, 322
[Mþ2]þ. Anal. Calcd for C16H17ClN2O3: C, 59.91; H, 5.34; N, 8.73.
Found: C, 59.69; H, 5.31; N, 8.70.
80e83 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.37e7.52 (m, 4H), 4.10 (m,
J¼7.2 Hz, 2H), 3.92 (t, J¼5.6 Hz, 4H), 3.76 (t, J¼5.2 Hz, 4H), 2.50 (s,
3H), 1.02 (t, J¼7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼168.7, 167.2,
d
164.5, 160.0, 137.7, 135.7, 129.5, 128.4, 114.3, 66.8, 61.1, 44.1, 23.2,
4.2.20. Ethyl 2-(4-nitrophenoxy)-4-methyl-6-phenylpyrimidine-5-
13.7. ESI-MS: m/z 362 ([MþHþ]).
carboxylate (6e). Obtained 310 mg, yield 82%, white solid, mp
118e119 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼8.33e8.29 (m, 2H),
7.60e7.50 (m, 2H), 7.49e7.27 (m, 5H), 4.23e4.18 (m, 2H), 2.59 (s,
3H), 1.09e1.06 (m, 3H). 13C NMR (100 MHz, CDCl3)
4.2.12. Ethyl 4-(4-bromophenyl)-6-methyl-2-morpholinopyrimidine-
5-carboxylate (4l). Obtained 324 mg, yield 80%, white solid, mp
d¼169.6, 167.6,
92e93 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.43e7.55 (m, 4H), 4.08 (q,
166.8,162.9, 157.6,144.8,136.8, 130.6, 128.6,128.3, 125.3, 122.1, 62.0,
22.7, 13.6. ESI-MS: m/z 379 Mþ. Anal. Calcd for C20H17N3O5: C,
63.32; H, 4.52; N, 11.08. Found: C, 63.02; H, 4.50; N, 11.02.
J¼7.2 Hz, 2H), 3.91 (t, J¼4.4 Hz, 4H), 3.75 (t, J¼4.8 Hz, 4H), 2.49 (s,
3H),1.02 (t, J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼168.7,167.3,
d
164.5, 160.1, 138.3, 131.4, 129.8, 123.9, 114.3, 66.8, 61.1, 44.2, 23.2,
13.7. ESI-MS: m/z 406 ([MþHþ]).
4.2.21. Ethyl
pyrimidine-5-carboxylate (6f). Obtained 388 mg, yield 95%, white
solid, mp 105e107 ꢀC. 1H NMR (400 MHz, CDCl3)
2-(4-nitrophenoxy)-4-(4-methoxyphenyl)-6-methyl-
4.2.13. Ethyl 4-(4-fluorophenyl)-6-methyl-2-morpholinopyrimidine-
5-carboxylate (4m). Obtained 283 mg, yield 82%, white solid, mp
d¼8.30 (dd, J¼2 Hz,
6.8 Hz, 2H), 7.59 (dd, J¼2 Hz, 6.8 Hz, 2H), 7.41 (dd, J¼2 Hz, 6.8 Hz, 2H),
86e89 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.07e7.59 (m, 4H), 4.10 (q,
6.93 (dd, J¼2 Hz, 6.8 Hz, 2H), 4.27 (q, J¼7.2 Hz, 2H), 3.85 (s, 3H), 2.57 (s,
3H), 1.17 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d¼169.2, 168.1,
J¼7.2 Hz, 2H), 3.92 (t, J¼4.8 Hz, 4H), 3.76 (t, J¼4.8 Hz, 4H), 2.49 (s,
3H), 1.02 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼168.8, 167.1,
d
165.8, 162.8, 161.8, 157.7, 144.7, 130.1, 128.9, 125.3, 122.1, 121.4, 114.0,
62.0, 55.4, 22.6, 13.8. ESI-MS: m/z 409 Mþ. Anal. Calcd for C21H19N3O6:
C, 61.61; H, 4.68; N, 10.26. Found: C, 61.29; H, 4.65; N, 10.20.
164.9, 164.4, 162.4, 160.1, 135.3, 130.1, 130.1, 115.3, 115.1, 114.3, 66.8,
61.1, 44.1, 23.2, 13.7. ESI-MS: m/z 346 ([MþHþ]).
4.2.22. Ethyl 2-(4-nitrophenoxy)-4-(4-chlorophenyl)-6-methylpyr-
imidine-5-carboxylate (6g). Obtained 355 mg, yield 86%, white
4.2.14. Methyl 4-(4-fluorophenyl)-6-isopropyl-2-morpholinopyrimidine-
5-carboxylate (4n). Obtained 301 mg, yield 84%, white solid, mp
solid, mp 121e123 ꢀC. 1H NMR (400 MHz, CDCl3)
d¼8.31 (dd,
102e103 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.08e7.61 (m, 4H), 3.92
J¼2 Hz, 6.8 Hz, 2H), 7.54 (dd, J¼1.6 Hz, 6.8 Hz, 2H), 7.43e7.39 (m,
(t, J¼4.4 Hz, 4H), 3.77 (t, J¼5.2 Hz, 4H), 3.61 (s, 3H), 3.19 (m,1H),1.26
4H), 4.23 (q, J¼7.2 Hz, 2H), 2.59 (s, 3H), 1.14 (t, J¼7.2 Hz, 3H). 13C
(d, J¼6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3)
¼174.6, 169.7, 164.9,
d
NMR (100 MHz, CDCl3)
d
¼169.8, 167.4, 165.5, 162.9, 157.5, 144.9,
163.9, 162.4, 160.6, 135.3, 130.0, 115.4, 115.2, 113.7, 66.8, 52.1, 44.2,
32.9, 21.7. ESI-MS: m/z 360 ([MþHþ]).
137.1, 135.2, 129.7, 128.9, 125.4, 122.1, 121.9, 62.2, 22.8, 13.7. ESI-MS:
m/z 413 Mþ, 415 [Mþ2]þ. Anal. Calcd for C20H16ClN3O5: C, 58.05; H,
3.90; N, 10.15. Found: C, 58.28; H, 3.93; N, 10.20.
4.2.15. Ethyl 2-(ethylamino)-4-methyl-6-phenylpyrimidine-5-carbox-
ylate (4o). Obtained 219 mg, yield 77%, white solid, mp 70e72 ꢀC. 1H
4.2.23. Ethyl 2-(4-nitrophenoxy)-4-(4-fluorophenyl)-6-isopropylpyri-
midine-5-carboxylate (6h). Obtained 329 mg, yield 80%, colourless oil.
NMR (400 MHz, CDCl3)
d
¼7.38e7.54 (m, 5H), 5.39 (s, 1H), 4.05 (q,
J¼6.8 Hz, 2H), 3.51 (m, 2H), 2.49 (s, 3H), 1.22 (t, J¼7.6 Hz, 3H), 0.94 (t,
1H NMR (400 MHz, CDCl3)
d
¼8.34e8.30 (m, 2H), 7.65e7.60 (m, 2H),
7.45e7.42 (m, 2H), 7.28e7.10 (m, 2H), 3.74 (s, 3H), 3.22e3.15 (m, 1H),
1.32e1.14 (m, 6H). 13C NMR (100 MHz, CDCl3)
J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼168.8, 167.1, 166.1, 161.1,
d
139.2,129.3,128.1,127.9,115.0, 60.9, 36.2, 22.9,14.8,13.5. ESI-MS: m/z
286 ([MþHþ]).
d¼177.5, 168.3, 165.5,
163.4, 162.9, 157.6, 144.8, 132.9, 130.4, 125.2, 122.1, 120.9, 115.9, 115.7,
52.9, 33.5, 21.6. ESI-MS: m/z 411 Mþ. Anal. Calcd for C22H20FN3O5: C,
62.11; H, 4.74; N, 9.88. Found: C, 62.36; H, 4.72; N, 9.83.
4.2.16. Ethyl 2-ethoxy-4-methyl-6-phenylpyrimidine-5-carboxylate
(6a). Obtained 271 mg, yield 95%, colorless oil. 1H NMR
(400 MHz, CDCl3)
d
¼7.30e7.56 (m, 5H), 4.40 (m, 2H), 4.05 (m,
2H), 2.47 (s, 3H), 1.34 (t, J¼6.8 Hz, 3H), 0.92 (t, J¼7.2 Hz, 3H). 13C
4.2.24. Ethyl 2-(4-chlorophenoxy)-4-(4-chlorophenyl)-6-methylpyr-
imidine-5-carboxylate (6i). Obtained 313 mg, yield 78%, white solid,
NMR (100 MHz, CDCl3)
d
¼168.4, 168.0, 166.2, 163.8, 137.6, 129.7,

3272
X.-C. Wang et al. / Tetrahedron 67 (2011) 3267e3272
mp 97e99 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼7.55e7.52 (m, 2H),
4.2.31. Ethyl 2-(4-chlorobenzoyloxy)-4-(4-chlorophenyl)-6-methyl-
pyrimidine-5-carboxylate (8g). Obtained 339 mg, yield 79%, yellow
oil. 1H NMR (400 MHz, CDCl3)
7.41e7.35 (m, 4H), 7.18e7.16 (m, 2H), 4.24e4.19 (m, 2H), 2.56 (s, 3H),
1.15e1.11 (m, 3H). 13C NMR (100 MHz, CDCl3)
d¼169.5, 167.7, 165.3,
d¼8.16 (dd, J¼2 Hz, 4.8 Hz, 2H), 7.63
163.7, 151.2, 136.8, 135.5, 130.6, 129.7, 129.5, 128.8, 122.9, 121.1, 62.0,
22.8, 13.7. ESI-MS: m/z 402 Mþ, 404 [Mþ2]þ. Anal. Calcd for
C20H16Cl2N2O3: C, 59.57; H, 4.00; N, 6.95. Found: C, 59.82; H, 4.02; N,
6.98.
(dd, J¼1.6 Hz, 5.6 Hz, 2H), 7.49 (dd, J¼2.4 Hz, 4.8 Hz, 2H), 7.44 (dd,
J¼2.0 Hz, 4.8 Hz, 2H), 4.29e4.21 (m, 2H), 2.67 (s, 3H), 1.18e1.08 (m,
3H). 13C NMR (100 MHz, CDCl3)
d
¼169.7, 167.1, 165.7, 163.2, 160.0,
140.8, 137.1, 134.9, 131.9, 129.8, 129.6, 129.0, 128.9, 128.6, 126.9,
124.3, 62.3, 22.6, 13.7. ESI-MS: m/z 430 Mþ, 432 [Mþ2]þ. Anal. Calcd
for C21H16Cl2N2O4: C, 58.48; H, 3.74; N, 6.50. Found: C, 58.20; H,
3.71; N, 6.53.
4.2.25. Ethyl 2-(benzoyloxy)-4-methyl-6-phenylpyrimidine-5-carbox-
ylate (8a). Obtained 254 mg, yield 70%, white solid, mp 89e90 ꢀC. 1H
NMR (400 MHz, CDCl3)
7.51e7.43 (m, 5H), 4.23 (q, J¼7.2 Hz, 2H), 2.67 (s, 3H),1.09 (t, J¼7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3)
d¼8.25e8.23 (m, 2H), 7.69e7.63 (m, 3H),
Acknowledgements
d
¼169.3, 167.4, 167.1, 164.1, 160.3,
136.7, 134.1, 130.6, 130.5, 128.6, 128.5, 128.4, 124.3, 62.1, 22.6, 13.6.
ESI-MS: m/z 363 Mþ. Anal. Calcd for C21H18N2O4: C, 69.60; H, 5.01; N,
7.73. Found: C, 69.86; H, 5.00; N, 7.76.
We are thankful for the financial support from the National
Nature Science Foundation of China (No. 20902073 and 21062017),
the Natural Science Foundation of Gansu Province (No. 096RJZA116),
and Scientific and Technological Innovation Engineering program
of Northwest Normal University (nwnu-kjcxgc-03-64).
4.2.26. Ethyl
imidine-5-carboxylate (8b). Obtained 267 mg, yield 68%, colourless
oil. 1H NMR (400 MHz, CDCl3)
2-(benzoyloxy)-4-(4-methoxyphenyl)-6-methylpyr-
d
¼8.25e8.23 (m, 2H), 7.72e7.66 (m,
2H), 7.64e7.62 (m, 1H), 7.52e7.49 (m, 2H), 6.98e6.95 (m, 2H), 4.28
(q, J¼6.8 Hz, 2H), 3.84 (s, 3H), 2.65 (s, 3H), 1.18 (t, J¼6.8 Hz, 3H). 13C
Supplementary data
NMR (100 MHz, CDCl3)
d
¼168.9, 167.8, 166.1, 164.1, 161.7, 160.2,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.046. These data include MOL files and
InChIKeys of the most important compounds described in this article.
134.0, 130.5, 130.2, 128.9, 128.6, 128.5, 123.6, 114.0, 62.0, 55.3, 22.5,
13.7. ESI-MS: m/z 392 Mþ. Anal. Calcd for C22H20N2O5: C, 67.34; H,
5.14; N, 7.14. Found: C, 67.04; H, 5.13; N, 7.17.
References and notes
4.2.27. Ethyl 2-(benzoyloxy)-4-(4-chlorophenyl)-6-methylpyrimidine-
5-carboxylate (8c). Obtained 273 mg, yield 69%, colourless oil. 1H NMR
1. (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360; (b) Kappe, C. O. Tetrahedron 1993,
49, 6937; (c) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879; (d) Kappe, C. O.; Stadler,
A. Org. React. 2004, 63, 1; (e) Dallinger, D.; Stadler, A.; Kappe, C. O. Pure Appl.
Chem. 2004, 76, 1017; (f) Gong, L. Z.; Chen, X. H.; Xu, X. Y. Chem.dEur. J. 2007, 13,
8920; (g) Kolosov, M. A.; Orlov, V. D. Mol. Diversity 2009, 13, 5; (h) Quan, Z.-J.;
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2. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043; (b) Deres, K.; Schroder, C. H.;
Paessens, A.; Goldmann, S.; Hacker, H. J.; Weber, O.; Kraemer, T.; Niewoehner, U.;
Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.; Masantschek, R. N. A.; Reimann, A.;
(400 MHz, CDCl3)
d
¼8.25e8.22 (m, 2H), 7.67e7.63 (m, 3H), 7.53e7.49
(m, 2H), 7.45e7.43 (m, 2H), 4.26 (q, J¼6.8 Hz, 2H), 2.67 (s, 3H), 1.16 (t,
J¼6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
¼169.6, 167.2, 165.6, 164.1,
d
160.3, 137.0, 135.1, 130.6, 129.9, 128.9, 128.6, 128.5, 124.1, 62.3, 22.6,
13.7. ESI-MS: m/z 396 Mþ, 398 [Mþ2]þ. Anal. Calcd for C21H17ClN2O4:
C, 63.56; H, 4.32; N, 7.06. Found: C, 63.86; H, 4.34; N, 7.08.
Jaeger, R.; Grob, R.; Beckermann, B.; Schlemmer, K.-H.; Haebich, D.; Rubsamen
4.2.28. Ethyl 2-(benzoyloxy)-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-
carboxylate (8d). Obtained 248 mg, yield 63%, colourless oil. 1H NMR
Waigmann, H. Science 2003, 299, 893; (c) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6,
771; (d) Sing, K.; Arora, D.; Poremsky, E.; Lowery, J.; Moreland, R. S. Eur. J. Med.
Chem. 2009, 44, 1997; (e) Singh, K.; Arora, D.; Singh, K.; Singh, S. Mini-Rev. Med.
Chem. 2009, 9, 95.
3. (a) Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828; (b) Patil, A. D.; Kumar, N. V.;
Kokke, W. C.; Bean, M. F.; Freyer, A. J.; DeBrosse, C.; Mai, S.; Truneh, A.; Gaulkner,
D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westly, J. W.; Potts, B. C.
J. Org. Chem. 1995, 60, 1182; (c) Aron, Z. D.; Overman, L. E. Chem. Commun. 2004,
253.
4. For reviews, see: (a) Undheim, K.; Benneche, T. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.;
Pergamon: Oxford, UK, 1996; Vol. 6; p 93; (b) Lagoja, I. M. Chem. Biodiversity
2005, 2, 1; (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627; (d) Joule, J. A.; Mills, K.
Heterocyclic Chemistry, 4th ed.; Blackwell Science Ltd.: Cambridge, MA, 2000; p
194; (e) Hill, M. D.; Movassaghi, M. Chem.dEur. J. 2008, 14, 6836.
5. (a) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 55; (b) Gholap, A. R.;
Toti, K. S.; Shirazi, F.; Deshpande, M. V.; Srinivasan, K. V. Tetrahedron 2008, 64,
10214.
6. (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.; Hirai, K. Bioorg. Med.
Chem. 1997, 5, 437; (b) Kim, D. C.; Lee, Y. R.; Yang, B.-S.; Shin, K. J.; Kim, D. J.;
Chung, B. Y.; Yoo, K. H. Eur. J. Med. Chem. 2003, 38, 525; (c) Kasparec, J.; Adams,
J. L.; Sisko, J.; Silva, D. J. Tetrahedron Lett. 2003, 44, 4567; (d) Gayo, L. M.; Suto,
M. J. Tetrahedron Lett. 1997, 38, 211; (e) Matloobi, M.; Kappe, C. O. J. Comb. Chem.
2007, 9, 275; (f) Obrecht, D.; Abrecht, C.; Grieder, A.; Villalgordo, J. M. Helv.
Chim. Acta 1997, 80, 65; (g) Vanden Eynde, J. J.; Labuche, N.; Van Haverbeke, Y.;
Tietze, L. ARKIVOC 2003, xv, 22.
7. (a) Kappe, C. O. Tetrahedron Lett. 1993, 49, 6937; (b) Vanden Eynde, J. J.; Audiart,
N.; Canonne, V.; Michel, S.; Van Haverbeke, Y.; Kappe, C. O. Heterocycles 1997,
45, 1967; (c) Puchala, A.; Belaj, F.; Bergman, J.; Kappe, C. O. J. Heterocycl. Chem.
2001, 38, 1345.
8. Kang, F. A.; Kodah, J.; Guan, Q. Y.; Li, X. B.; Murray, W. V. J. Org. Chem. 2005,
70, 1957.
9. Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005, 7, 4673.
10. Wang, X.-C.; Yang, G.-J.; Quan, Z.-J.; Ji, P.-Y.; Liang, J.-L.; Ren, R.-G. Synlett 2010,
1657.
11. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C. Tetrahedron 2002,
58, 4801.
(400 MHz, CDCl3)
d
¼8.26e8.24 (m, 2H), 7.73e7.69 (m, 2H), 7.67e7.63
(m, 1H), 7.54e7.49 (m, 2H), 7.17e7.12 (m, 2H), 3.78 (s, 3H), 3.20 (t,
J¼7.2 Hz, 2H), 1.36 (s, 3H), 1.34 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
¼177.4, 168.2, 165.5, 165.4, 164.0, 162.9, 160.9, 134.1, 132.9, 130.6, 130.5,
128.6, 128.5, 123.0, 115.9, 115.7, 52.9, 33.6, 21.6. ESI-MS: m/z 394 Mþ,
396 [Mþ2]þ. Anal. Calcd for C23H21FN2O4: C, 67.64; H, 5.18; N, 6.86.
Found: C, 67.89; H, 5.21; N, 6.89.
4.2.29. Ethyl 2-(4-methoxybenzoyloxy)-4-(4-chlorophenyl)-6-methyl-
pyrimidine-5-carboxylate (8e). Obtained 307 mg, yield 72%, white
solid, mp 99e100 ꢀC. 1H NMR (400 MHz, CDCl3)
d
¼8.18 (dd, J¼2 Hz,
6.8 Hz, 2H), 7.64 (dd, J¼2 Hz, 4.8 Hz, 2H), 7.43 (dd, J¼2 Hz, 4.8 Hz,
2H), 6.98 (dd, J¼1.6 Hz, 7.2 Hz, 2H), 4.28e4.23 (m, 2H), 3.90 (s, 3H),
2.66 (s, 3H), 1.18e1.14 (m, 3H). 13C NMR (100 MHz, CDCl3)
d¼169.5,
167.3, 165.6, 164.4, 160.5, 136.9, 135.1, 132.9, 129.9, 128.9, 123.9,
120.6, 113.9, 62.2, 55.5, 22.7, 13.7. ESI-MS: m/z 426 Mþ, 428 [Mþ2]þ.
Anal. Calcd for C22H19ClN2O5: C, 61.90; H, 4.49; N, 6.56. Found: C,
61.61; H, 4.45; N, 6.51.
4.2.30. Ethyl
pyrimidine-5-carboxylate (8f). Obtained 353 mg, yield 80%, pale
yellow oil. 1H NMR (400 MHz, CDCl3)
2-(4-nitrobenzoyloxy)-4-(4-chlorophenyl)-6-methyl-
d
¼8.43e8.36 (m, 4H), 7.65
(dd, J¼2 Hz, 6.8 Hz, 2H), 7.45 (dd, J¼2 Hz, 6.4 Hz, 2H), 4.28 (q,
J¼6.8 Hz, 2H), 2.69 (s, 3H), 1.17 (t, J¼6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3)
d
¼169.9, 166.9, 165.8, 162.2, 159.7, 151.2, 137.3, 134.8, 133.9,
131.7, 129.8, 129.0, 124.6, 123.8, 62.4, 22.7, 13.7.
12. (a) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E. Chem. Rev. 2009, 109, 2551;
(b) Sze, T. Y.; Toy, P. H. Chem.dAsian J. 2007, 2, 1340.
13. Wilson, S. R.; Perez, J.; Pasternak, A. J. Am. Chem. Soc. 1993, 115, 1994.
ESI-MS: m/z 441 Mþ, 443 [Mþ2]þ. Anal. Calcd for C21H16ClN3O6:
C, 57.09; H, 3.65; N, 9.51. Found: C, 57.30; H, 3.67; N, 9.56.