Cross-coupling reactions of pyrimidin-2-yl sulfonates with phenols and anilines: An efficient approach to C2-functionalized pyrimidines

Article abstract of DOI:10.1002/cjoc.201300536

Pyrimidin-2-yl sulfonates, as an efficient reaction partner, which can be easily prepared from cheap commercial materials, were coupled with phenols and anilines to give a wide array of C2-aryloxy- and arylaminopyrimidines in good to excellent yields under mild reaction conditions. Copyright

Full text of DOI:10.1002/cjoc.201300536

FULL PAPER
DOI: 10.1002/cjoc.201300536
Cross-Coupling Reactions of Pyrimidin-2-yl Sulfonates with
Phenols and Anilines: An Efficient Approach to
C2-Functionalized Pyrimidines
Zhengjun Quan,* Fuqiang Jing, Zhang Zhang, Yuxia Da, and Xicun Wang*
Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China;
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal
University, Anning East Road 967#, Lanzhou, Gansu 730070, China
Pyrimidin-2-yl sulfonates, as an efficient reaction partner, which can be easily prepared from cheap commercial
materials, were coupled with phenols and anilines to give a wide array of C2-aryloxy- and arylaminopyrimidines in
good to excellent yields under mild reaction conditions.
Keywords cross-coupling, pyrimindine-2-yl sulfonates, C2-aryloxypyrimidines, C2-arylaminopyrimidines
Introduction
mediated coupling with nucleophiles. More recently, we
have developed a approach to highly substituted and
functionalized pyrimidines by a domino desulfitative
coupling/acylation/hydration process cocatalyzed by
copper(I) and palladium(II).[9]
Heterobiaryl compounds as a prevalent structural
motif in many pharmaceuticals and other biologically
active molecules, have been focused on the develop-
ment of significant nature’s heterocyclic products.[1]
Dihydropyrimidinones (DHPMs), a class of heterocyclic
compounds that have been previously established
N-acyl-/N-benzoyl- and C2-DHPM derivatives display
more interesting pharmacological properties than other
derivatives.[2] C2-DHPM derivatives have attracted
considerable interest due to their interesting pharma-
cological properties, such as calcium channel modulator,
antihypertensive activity, α1a-adrenergic agonists mitotic
kinesin inhibitor and hepatitis B virus replication sup-
pressor.[3]
Although some synthetic approaches have now been
established, the methods to synthesize C2-DHPM de-
rivatives are still limited.[4] In the conversion of pyrimi-
din-2(1H)-one to C2-substituted pyrimidine, conven-
tional tautomerization-activation-coupling process would
normally include chlorination or sulfonylation, followed by
coupling with a nucleophile.[5] Chlorination using
POCl3 at high temperatures could be problematic for
substrates with sensitive functionalities,[5b,5c] and S-al-
kylation was necessary for sulfide oxidation.[5e,5h] Kappe
group have developed an efficient carbon-carbon cou-
pling reaction between 3,4-dihydropyrimidine-2-thiones
and boronic acids under modified Liebeskind-Srogl
reaction conditions.[6,7] Kang et al.[8] have reported a
novel and efficient synthesis of multifunctionalized py-
rimidines through Kappe dehydrogenation and PyBroP-
Therefore, a method easily available for the starting
materials generating small amount of by-product to
streamline organic synthesis and to improve the diver-
sity of product is still needed in this area. In 2010, we
have developed a mild and rapid procedure to the syn-
thesis of C2-substituted pyrimidines by cross-coupling
reaction of pyrimidin-2-yl sulfonates, which were easily
available from DHPMs via oxidation, esterification,[10]
with N, S and O nucleophiles at room temperature. The
results showed that the method is not essential for phe-
nols to provide phenolic pyrimidines. Alternatively, in
2011, we have developed a novel and efficient synthetic
method to prepare C2-multifunctionalized pyrimidines
by the Mitsunobu reaction between 2-hydroxy pyrim-
idine and N, S and O nucleophiles.[11] Unfortunately, it
was unefficient to afford aniline pyrimidine derivative
via these two approaches.
Herein, we report a general process for the synthesis
of C2-aryloxy- and arylaminopyrimidines by cross-
coupling reactions of pyrimidin-2-yl sulfonates with
phenols and anilines.
Experimental
General methods
Melting points were measured on an XT-4 apparatus
and are uncorrected. NMR spectra were recorded at 400
*
E-mail: wangxicun@nwnu.edu.cn or quanzhengjun@hotmail.com; Tel./Fax: 0086-931-7972626
Received July 12, 2013; accepted September 3, 2013; published online October 17, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300536 or from the author.
Chin. J. Chem. 2013, 31, 1495—1502
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Quan et al.
FULL PAPER
(1H) and 100 (13C) MHz, respectively, on a Varian Mer-
cury plus-400 instrument using CDCl3 as solvent and
TMS as internal standard. High-resolution mass spectra
(HRMS) were obtained on a Bruker Daltonics APEX II
47e mass spectrometer. Column chromatography was
generally performed on silica gel (200－300 mesh) and
TLC inspections were on silica gel GF254 plates. Sol-
vent was purified and dried by standard methods prior
to use. All commercially available reagents were used
without further purification unless otherwise noted.
－68 ℃. 1H NMR (400 MHz, CDCl3) δ: 7.64－7.54 (m,
2H), 7.50－7.33 (m, 5H), 7.24－7.14 (m, 2H), 4.21－
4.16 (m, 2H), 2.57 (s, 3H), 1.08－1.06 (m, 3H); 13C
NMR (101 MHz, CDCl3) δ: 169.23, 167.87, 166.61,
163.59, 151.25, 137.09, 130.41, 130.38, 129.37, 128.43,
128.28, 122.94, 121.28, 61.81, 22.69, 13.57. HRMS
calcd for C20H17ClN2O3 [M＋H]＋ 369.1006; found
369.1009.
Ethyl
2-(2-chlorophenoxy)-4-methyl-6-phenyl-
pyrimidine-5-carboxylate (3f) White solid, m.p. 76
1
－78 ℃. H NMR (400 MHz, CDCl3) δ: 7.57 (d, J＝
General procedure for the synthesis of 2-aryloxypy-
rimidines (3a－3k)
6.9 Hz, 2H), 7.51－7.34 (m, 4H), 7.28 (dd, J＝11.5, 5.7
Hz, 2H), 7.23－7.13 (m, 1H), 4.23－4.11 (m, 2H), 2.56
(d, J＝3.0 Hz, 3H), 1.11－0.96 (m, 3H); 13C NMR (101
MHz, CDCl3) δ: 169.25, 167.97, 166.51, 163.26, 148.85,
137.13, 130.32, 128.49, 128.34, 128.13, 127.73, 127.35,
126.49, 123.71, 121.23, 61.79, 22.67, 13.58. HRMS
calcd for C20H17ClN2O3 [M＋H]＋ 369.1006; found
369.1003.
Ethyl 2-(4-chlorophenoxy)-4-(4-methoxyphenyl)-
6-methylpyrimidine-5-carboxylate (3k) White solid,
m.p. 70－72 ℃. 1H NMR (400 MHz, CDCl3) δ: 7.58 (d,
J＝8.8 Hz, 2H), 7.36 (d, J＝8.8 Hz, 2H), 7.18 (d, J＝
8.8 Hz, 2H), 6.92 (d, J＝8.8 Hz, 2H), 4.25 (q, J＝7.1 Hz,
2H), 3.83 (s, 3H), 2.55 (s, 3H), 1.16 (t, J＝7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ: 168.40, 165.70, 163.56,
161.68, 151.32, 130.41, 130.23, 130.02, 129.26, 123.01,
120.69, 114.18, 113.77, 61.93, 55.67, 22.55, 14.01.
HRMS calcd for C21H19ClN2O4 [M＋H]＋ 399.1112;
found 399.1114.
A mixture of pyrimidin-2-yl sulfonates (1, 1.0
mmol), phenols (2, 1.5 mmol), K2CO3 (2.5 mmol) and
acetone (4 mL) was stirred at 60 ℃ for 7 h until the 1
were completely consumed (monitored by TLC). The
mixture was cooled to r.t. and quenched with saturated
NH4Cl aqueous solution (3 mL), extracted with diethyl
ether (10 mL×2). The organic solvents were combined
and washed with NaOH aqueous solution (2 mmol/mL,
2 mL), brine and dried over MgSO4. The crude product
was purified by column chromatography (SiO2), eluting
with petroleum ether/EtOAc (30∶1) to afford the cor-
responding 2-aryloxypyrimidines 3. The spectroscopic
data for compounds 3d, 3g, 3h, 3i and 3j were consis-
tent with those reported in the literature.[11]
Ethyl 4-methyl-2-phenoxy-6-phenylpyrimidine-5-
1
carboxylate (3a) Colourless oil. H NMR (400 MHz,
CDCl3) δ: 7.49－7.47 (m, 2H), 7.31－7.25 (m, 5H),
7.16－7.08 (m, 3H), 4.05 (q, J＝7.1 Hz, 2H), 2.45 (s,
3H), 0.92 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ: 168.91, 167.77, 166.36, 163.69, 152.52,
136.98, 130.06, 129.11, 128.17, 128.08, 124.96, 121.31,
115.20, 61.57, 22.46, 13.35; HRMS calcd for
C20H18N2O3 [M＋H]＋ 335.1396; found 335.1399.
General procedure for the synthesis of 2-arylamino-
pyrimidines (5a－5h)
All reactions were conducted under nitrogen atmos-
phere in a dual-manifold Schlenk tube. A seal tube (15
mL) initially fitted with a septum containing PdCl2 (8.8
mg, 0.05 mmol) and PPh3 (52.0 mg, 0.2 mmol) was
evacuated and purged with nitrogen gas three times.
Pyrimidin-2-yl sulfonates (1, 1.0 mmol), anilines (4, 1.5
mmol), K3PO4 (2.5 mmol) and 1.4-dioxane (4 mL),
were added to the system and the reaction mixture was
stirred at 110 ℃ for 10 h until complete consumption
of 1 (based on TLC monitoring). Then, the mixture was
cooled to r.t. and quenched with saturated NH4Cl aque-
ous solution (3 mL), extracted with ethoxyethane (10
mL×2). The organic solvents were combined and
washed with NaOH aqueous solution (2 mmol/mL, 2
mL), brine and dried over MgSO4. The crude product
was purified by column chromatography (SiO2), eluting
with EtOH/EtOAc (1∶100) to afford the corresponding
2-arylaminopyrimidins 5. The spectroscopic data for
compound 5a were consistent with those reported in the
literature.[5h]
Ethyl
4-methyl-6-phenyl-2-(p-tolyloxy)pyrimi-
dine-5-carboxylate (3b) Colourless oil. 1H NMR
(400 MHz, CDCl3) δ: 7.65－7.55 (m, 2H), 7.50－7.36
(m, 3H), 7.23－7.18 (m, 2H), 7.16－7.10 (m, 2H),
4.23－4.13 (m, 2H), 2.63－2.51 (m, 3H), 2.36 (s, 3H),
1.08－1.03 (m, 3H); 13C NMR (101 MHz, CDCl3) δ:
169.03, 168.05, 166.56, 164.02, 150.51, 137.32, 134.64,
130.18, 129.80, 128.34, 128.16, 121.18, 120.87, 61.71,
22.60, 20.73, 13.57. HRMS calcd for C21H20N2O3 [M＋
H]＋ 349.1552; found 349.1550.
Ethyl
4-methyl-6-phenyl-2-(m-tolyloxy)pyrimi-
dine-5-carboxylate (3c) Colourless oil. 1H NMR (400
MHz, CDCl3) δ: 7.64－7.54 (m, 2H), 7.48－7.35 (m,
3H), 7.29－7.21 (m, 2H), 7.20－7.10 (m, 2H), 4.22－
4.13 (m, 2H), 2.60－2.51 (m, 3H), 2.28－2.17 (m, 3H),
1.12－1.00 (m, 3H); 13C NMR (101 MHz, CDCl3) δ:
169.12, 168.13, 166.59, 163.83, 151.29, 137.29, 131.07,
130.52, 130.18, 128.36, 128.31, 126.77, 125.41, 121.82,
120.78, 61.74, 22.68, 16.37, 13.58. HRMS calcd for
C21H20N2O3 [M＋H]＋ 349.1552; found 349.1549.
Ethyl 4-methyl-6-phenyl-2-(p-tolylamino)pyrimi-
1
dine-5-carboxylate (5b) Brown oil. H NMR (400
MHz, CDCl3) δ: 7.67 (s, 1H), 7.64－7.56 (m, 2H), 7.50
(dd, J＝8.3, 1.5 Hz, 2H), 7.42 (dd, J＝4.3, 2.6 Hz, 3H),
7.10 (d, J＝7.5 Hz, 2H), 4.12－4.06 (m, 2H), 2.55 (d,
Ethyl
2-(4-chlorophenoxy)-4-methyl-6-phenyl-
pyrimidine-5-carboxylate (3e) White solid, m.p. 66
1496
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1495—1502

An Efficient Approach to C2-Functionalized Pyrimidines
J＝1.8 Hz, 3H), 2.30 (s, 3H), 0.99－0.95 (m, 3H); 13C
NMR (101 MHz, CDCl3) δ: 168.48, 167.17, 165.76,
158.79, 138.62, 136.38, 132.19, 129.55, 129.22, 128.21,
127.96, 119.42, 116.64, 61.15, 22.91, 20.70, 13.47.
HRMS calcd for C21H21N3O2 [M ＋ H] ＋ 348.1712;
found 348.1708.
C21H18ClN3O2 [M＋H]＋ 368.1166; found 368.1168.
Ethyl 4-methyl-2-(2-nitrophenylamino)-6-phenyl-
pyrimidine-5-carboxylate (5h) Yellow solid, m.p.
1
177－180 ℃. H NMR (400 MHz, CDCl3) δ: 10.58 (s,
1H), 9.12 (dd, J＝8.7, 1.0 Hz, 1H), 8.27 (dd, J＝8.5, 1.5
Hz, 1H), 7.69－7.63 (m, 3H), 7.57－7.45 (m, 3H),
7.16－7.05 (m, 1H), 4.17 (q, J＝7.1 Hz, 2H), 2.63 (s,
3H), 1.06 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ: 168.13, 167.32, 165.46, 158.18, 138.06,
136.70, 135.98, 135.43, 130.04, 128.47, 128.22, 126.08,
121.22, 121.20, 119.34, 61.59, 22.86, 13.61. HRMS
calcd for C20H18N4O4 [M ＋ H] ＋ 379.1006; found
379.1408.
Ethyl 4-methyl-6-phenyl-2-(o-tolylamino)pyrimi-
1
dine-5-carboxylate (5c) Brown oil. H NMR (400
MHz, CDCl3) δ: 8.07 (d, J＝8.1 Hz, 1H), 7.61－7.46 (m,
2H), 7.35 (dd, J＝5.1, 1.8 Hz, 3H), 7.20－7.10 (m, 2H),
6.97 (dd, J＝8.5, 11.1 Hz, 2H), 4.02 (q, J＝7.1 Hz, 2H),
2.47 (s, 3H), 2.26 (s, 3H), 0.91 (t, J＝7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ: 168.51, 167.26, 165.88,
159.09, 138.59, 136.98, 130.40, 129.63, 128.30, 127.99,
126.50, 121.51, 117.02, 61.23, 22.92, 18.16, 13.53.
HRMS calcd for C21H21N3O2 [M ＋ H] ＋ 348.1712;
found 348.1715.
Results and Discussion
C－O coupling reaction of pyrimidin-2-yl sulfonates
with phenols
Ethyl 2-(4-chlorophenylamino)-4-methyl-6-phe-
1
nylpyrimidine-5-carboxylate (5d) Colourless oil. H
We began this study by choosing pyrimidin-2-yl
sulfonate (1a) and phenol (2a) as model substrates
(Table 1). Initially, different bases were tested at r.t. In
the presence of K2CO3 or K3PO4, no reaction was de-
tected. The strong bases NaOH and NaOtBu resulted in
a low conversion to give only a trace of the target cou-
pling compound 3a, but with formation of the O－S
cleavage product 3ab in high yield (Table 1, Entries 1－
6). To our delight, using acetone as solvent and K2CO3
or K3PO4 as base under refluxing for 7 h obtained the
cross-coupling product 3a in 86% isolated yield (Table
1, Entries 7 and 8). The reaction could also conduct
smoothly in THF and dioxane as solvents using K2CO3
as base to give product 3a (Table 1, Entries 11－12). It
revealed that the reaction was best conducted in the
presence of 2.5 equivalents of K2CO3 in acetone at 60
℃ for 7 h, and the desired product was isolated in the
best yield. It is noteworthy that O－S cleavage products
(3ab) were obtained under strong bases (Table 1,
Entries 3, 4, 9, 10) and high temperature (Table 1, Entry
6). Our previous work has reported analogous results,[10]
and Lee et al. disclosed the competitive reaction path-
ways in the nucleophilic substitution reactions of aryl
benzenesulfonates with benzylamines in acetonitrile.[12]
In this study, we have also observed two competitive
reaction pathways (i.e., C－O bond cleavage path vs.
the S － O bond-cleavage path). The S － O bond
cleavage reaction is favored with strong base and high
temperature. Reaction of 1a with phenols produced
C2-substituted pyrimidines via cleavage of C－O bond
in high yields.
NMR (400 MHz, CDCl3) δ: 7.97 (s, 1H), 7.71－7.57 (m,
2H), 7.56－7.47 (m, 2H), 7.41 (d, J＝5.8 Hz, 3H), 7.24
－7.17 (m, 2H), 4.11 (q, J＝7.1 Hz, 2H), 2.55 (s, 3H),
0.98 (dd, J＝7.7, 6.6 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ: 168.28, 167.24, 165.70, 158.53, 138.30,
137.63, 129.75, 128.60, 128.29, 127.95, 127.32, 120.40,
117.25, 61.30, 22.88, 13.52. HRMS calcd for
C20H18ClN3O2 [M＋H]＋ 368.1166; found 368.1169.
Ethyl 4-methyl-2-(4-nitrophenylamino)-6-p-tolyl-
pyrimidine-5-carboxylate (5e) Yellow solid, m.p.
1
175－177 ℃. H NMR (300 MHz, CDCl3) δ: 8.17 (d,
J＝6.9 Hz, 2H), 8.03 (s, 1H), 7.80 (d, J＝6.9 Hz, 2H),
7.54 (d, J＝6.3 Hz, 2H), 7.25 (d, J＝6.3 Hz, 2H), 4.22
－4.17 (m, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 1.11－1.08 (t,
J＝5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.20,
167.15, 165.47, 157.95, 145.34, 141.92, 140.55, 134.95,
129.22, 128.06, 125.08, 118.81, 117.87, 61.63, 22.81,
21.32, 13.64. HRMS calcd for C21H20N4O4 [M＋H]＋
393.1563; found 393.1566.
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-(phenyl-
amino)pyrimidine-5-carboxylate (5f) Claybank oil.
1H NMR (300 MHz, CDCl3) δ: 7.56 (d, J＝10.1 Hz,
1H), 7.34 (d, J＝8.5 Hz, 4H), 7.06－6.95 (m, 2H), 6.72
(t, J＝7.4 Hz, 1H), 6.68－6.61 (m, 2H), 3.88 (q, J＝7.1
Hz, 2H), 3.52 (s, 3H), 2.24 (s, 3H), 0.80 (t, J＝7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ: 168.90, 166.83,
164.88, 161.05, 158.78, 139.26, 130.80, 129.77, 128.75,
122.55, 119.27, 116.67, 113.75, 61.30, 55.28, 22.83,
＋
13.75. HRMS calcd for C21H21N3O3 [M ＋ H]
364.1661; found 364.1659.
Ethyl
4-(4-chlorophenyl)-6-methyl-2-(phenyl-
Under the optimized conditions, various pyrimidin-
2-yl sulfonates (1) with a diverse set of phenols (2) were
tested in the reaction scope (Table 2). In general, good
to excellent yields (67%－92%) were obtained under
the standard reaction conditions (Table 2, Entries 1－
11). The reaction tolerated a variety of pyrimidin-2-yl
sulfonates and phenols containing an electron-with-
drawing group (Cl and NO2) as well as an electron-do-
nating group (Me) on the phenyl ring.
amino)pyrimidine-5-carboxylate (5g) White solid,
m.p. 129－130. 1H NMR (300 MHz, CDCl3) δ: 7.54 (s,
1H), 7.46－7.27 (m, 4H), 7.19－7.14 (m, 2H), 7.09－
7.04 (m, 2H), 6.87－6.75 (m, 1H), 3.98－3.86 (m, 2H),
2.42－2.26 (m, 3H), 0.92－0.74 (m, 3H); 13C NMR (75
MHz, CDCl3) δ: 168.38, 167.60, 164.61, 158.92, 139.08,
137.15, 136.02, 129.62, 128.93, 128.65, 122.98, 119.50,
116.97, 61.52, 23.12, 13.78. HRMS calcd for
Chin. J. Chem. 2013, 31, 1495—1502
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Quan et al.
FULL PAPER
Table 1 Optimization of reaction conditions for compound 3aa
C－N coupling reaction of pyrimidin-2-yl sulfonates
with anilines
O
Ph
O
Ph
Next, coupling reaction of pyrimidin-2-yl sulfonates
with anilines was examined. In our preliminary study to
optimize the reaction conditions, the coupling of pyrimi-
din-2-yl sulfonates (1a) and aniline (4a) was selected as
the model reaction in the presence of various bases
(Table 3). It indicated that the bases play an important
role in the coupling reaction.[13] Among the tested bases,
only K3PO4 gave the product in dioxane or DMSO, al-
beit in low yield (Table 3, Entries 1－9). To our delight,
the yield was dramatically increased to 88% when PdCl2
(5 mol%) was used as the catalyst and PPh3 (20 mol%)
was used as ligand (Table 3, Entry 10). Further study
showed that the catalysts and ligands have slight
influence on the yield (Table 3, Entries 11－14). In
summary, the optimal conditions for cross-coupling
reaction of pyrimidin-2-yl sulfonates with aniline were
achieved by using 5 mol% PdCl2, 20 mol% PPh3, 2.5
equiv. K3PO4 in 1,4-dioxane at 110 ℃ for 10 h.
+
EtO
Me
N
EtO
Me
N
PhOTs
3ab
conditions
+
PhOH
2a
Ph
N
OTs
N
3a
O
1a
Yieldb/%
Entry
Base
Solvent Temp./℃ Time/h
3a 3ab
1
2
K2CO3
K3PO4
NaOH
Acetone
Acetone
Dioxane
r.t.
r.t.
r.t.
r.t
48
48
48
48
48
48
7
0
0
0
0
3
12
85
4
NaOtBu Dioxane
trace 87
5
K2CO3
K2CO3
K2CO3
K3PO4
NaOH
THF
r.t.
110
60
60
60
60
70
60
trace
0
0
65
8
6
Dioxane
Acetone
Acetone
Acetone
7
86
8
7
80 trace
9
7
0
0
56
60
10
11
12
NaOt-Bu Acetone
7
K2CO3
K2CO3
THF
7
85 trace
82 trace
The generality of the optimized reaction conditions
was examined by treating various pyrimidin-2-yl
sulfonates with different anilines. In general, good to
excellent yields of C2-arylaminopryrimindes 5a－5h
Dioxane
7
a
Reactants and reaction conditions: 1a (1.0 mmol), 2a (1.5
mmol), base (2.5 equiv.), and solvent (4 mL). b Isolated yield of
pure product after column chromatography.
Table 2 C－O coupling of pyrimidin-2-yl sulfonates with phenols
O
Ar
O
Ar
EtO
Me
N
EtO
Me
N
K2CO3 2.5 equiv.
acetone 4 mL
60 oC, 7 h
+ Ar'OH
Ar'
N
N
1
OTs
O
2
3
Entry
1
Sulfonate 1
Ar'OH 2
Product 3
Yielda/%
86
OH
O
O
EtO
Me
N
EtO
Me
N
N
OTs
N
O
2a
1a
3a
OH
O
Me
2
92
89
1a
1a
1a
EtO
N
Me
Me
N
3b
O
2b
OH
O
Me
3
4
EtO
N
Me
Me
N
O
2c
3c
OH
O
NO2
80
EtO
N
NO2
2d
Me
N
O
3d
1498
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1495—1502

An Efficient Approach to C2-Functionalized Pyrimidines
Continued
Yielda/%
Entry
Sulfonate 1
Ar'OH 2
Product 3
OH
O
Cl
5
85
70
1a
EtO
Me
N
Cl
N
O
2e
3e
OH
Cl
O
6
7
1a
EtO
Me
N
2f
N
O
3f
Cl
OMe
OMe
O
O
2d
67
NO2
EtO
Me
N
EtO
Me
N
N
O
N
OTs
3g
1b
Cl
Cl
O
O
2d
2d
2e
8
72
NO2
EtO
Me
N
EtO
Me
N
N
O
N
1c
OTs
3h
F
F
O
O
9
76
NO2
MeO
Me
N
MeO
N
Me
N
OTs
N
O
Me
Me
3i
1d
Cl
O
10
75
1c
Cl
EtO
N
Me
N
O
3j
OMe
O
11
70
1b
2e
Cl
EtO
Me
N
N
O
3k
a Isolated yield of pure product after column chromatography.
Chin. J. Chem. 2013, 31, 1495—1502
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1499

Quan et al.
FULL PAPER
Table 3 Optimization of reaction conditions for compound 5aa
O
Ph
O
Ph
conditions
EtO
Me
N
EtO
Me
N
PhNH2
+
Ph
N
OTs
N
N
H
1a
4a
5a
Entry
Base
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaAc
Solvent
Acetone
THF
Temp./℃
60
Time/h
48
Yieldb/% Entry
Base
K3PO4 Dioxane
K3PO4 DMSO
K3PO4 Dioxane
K3PO4 DMSO
Solvent
Temp./℃
110
Time/h
48
Yieldb/%
55
1
2
3
4
5
6
7
0
0
0
0
0
0
0
8
68
48
9
110
48
40
88c
86c
80d
60e
65f
Dioxane
DMSO
Dioxane
Dioxane
Dioxane
110
48
10
11
12
13
14
110
10
110
48
120
10
110
48
K3PO4 Dioxane
K3PO4 Dioxane
K3PO4 Dioxane
110
10
110
48
110
10
DBU
110
48
110
10
a Reactants and reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), base (2.5 equiv.), and solvent (4 mL). b Isolated yield of pure product
c
after column chromatography. 5 mol% PdCl2 and 20 mol% PPh3. d 2.5 mol% PdCl2 and 10 mol% PPh3. e 5 mol% NiCl2 and 20 mol%
PPh3. f 10 mol% CuI2 and 20 mol% PPh3.
were obtained (Table 4). The reaction tolerated a variety
of anilines containing an electron-withdrawing group
(Cl and NO2) as well as an electron-donating group (Me)
on the phenyl ring, although the reaction of electro-
deficient nitroanilines 4e and 4f gave lower yields of the
products (Table 4, Entries 5 and 8).
Table 4 C－N coupling of pyrimidin-2-yl sulfonates with anilines
PdCl2 (5 mol%)
PPh3 (20 mol%)
K3PO4 (2.5 equiv.)
O
Ar
O
Ar
EtO
Me
N
EtO
Me
N
+ Ar'NH2
Ar'
1,4-dioxane (4 mL)
110 oC, 10 h
N
N
4
N
1
OTs
H
5
Entry
1
Sulfonate 1
Ar'NH2 4
Produt 5
Yielda/%
NH2
O
88
1a
EtO
Me
N
4a
N
N
H
5a
NH2
O
Me
2
3
4
96
68
1a
1a
1a
EtO
N
Me
Me
N
N
H
4b
5b
NH2
Me
O
EtO
N
4c
Me
N
N
H
Me
5c
NH2
O
Cl
84
EtO
Me
N
Cl
N
N
H
4d
5d
1500
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 1495—1502

An Efficient Approach to C2-Functionalized Pyrimidines
Continued
Yielda/%
Entry
Sulfonate 1
Ar'NH2 4
Produt 5
Me
Me
NH2
O
O
5
55
NO2
EtO
Me
N
EtO
N
NO2
N
OTs
Me
N
N
4e
H
1e
5e
OMe
O
6
80
1b
4a
EtO
N
Me
N
N
H
5f
Cl
O
7
90
1c
4a
EtO
Me
N
N
N
H
5g
NH2
NO2
O
8
78
1a
EtO
Me
N
N
N
H
4f
5h
NO2
a Isolated yield of pure product after column chromatography.
Conclusions
20902073 and 21062017), the Natural Science
Foundation of Gansu Province (No. 1208RJYA083),
and the Scientific and Technological Innovation
Engineering Program of Northwest Normal University
(Nos. nwnu-kjcxgc-03-64, nwnulkqn-10-15).
In summary, we have developed a general approach
to C2-substituted pyrimidines via the cross-coupling of
pyrimidin-2-yl sulfonates. A wide range of C2-sub-
stituted pyrimidines were obtained in good to excellent
yields. Noteworthy is the use of easily prepared pyrimi-
din-2-yl sulfonates as an attractive reaction partner for
the synthesis of novel C2-substituted C－O/C －N
systems. Compared with previous procedures,[10,11] this
method avoids the formation of S－O bond-cleavage
by-product to give phenolic pyrimidine as the sole
product. Furthermore, some novel structures of aniline
pyrimidine derivatives, which are difficultly obtained by
the classical methods, were prepared, which make this
approach attractive. Synthesis and screening of desired
compounds based on pyrimidine scaffolds may lead to
the discovery of interesting biological activities.
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