Nucleophilic Substitution Reaction of Pyrimidin-2-yl Phosphates Using Amines and Thiols as Nucleophiles Mediated by PEG-400 as an Environmentally Friendly Solvent

Article abstract of DOI:10.1055/s-0035-1560175

A metal-free synthesis of C2-functionalized pyrimidines via the reaction of pyrimidin-2-yl phosphates with amines and thiophenols in PEG-400 has been developed. The desired products can be generated in good to excellent yields in the environmentally friendly PEG-400, without any catalysts or other additives.

Full text of DOI:10.1055/s-0035-1560175

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3925–3935
paper
3925
T. Xing et al.
Paper
Synthesis
Nucleophilic Substitution Reaction of Pyrimidin-2-yl Phosphates
Using Amines and Thiols as Nucleophiles Mediated by PEG-400 as
an Environmentally Friendly Solvent
Ting Xinga,b
Kai-Jie Weia,b
Zheng-Jun Quan*a,b
Xi-Cun Wang*a,b
O
Ar
O
Ar
N or S nucleophile
PEG-400
R1
N
R1
N
R2
N
OP(O)(OEt)2
R2
N
Nu
1. mild conditions
2. no catalyst or base
3. 26 examples, up to 89% yield
a Key Laboratory of Eco-Environment-Related Polymer Materials,
Ministry of Education of China, Gansu 730070, P. R. of China
b Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Gansu
730070, P. R. of China
wangxicun@nwnu.edu.cn
Received: 03.07.2015
Accepted after revision: 23.07.2015
Published online: 02.09.2015
ties,10 such as activity as calcium channel modulators, α1a-
adrenergic receptor antagonists, mitotic kinesin inhibitors,
and hepatitis B virus replication inhibitors.11 Among the
DHPM derivatives, most of the pharmacologically attractive
derivatives are N3- and C2-functionalized analogues.12 The
synthesis of pyrimidine derivatives13 has attracted much at-
tention among the many scientific research workers. How-
ever, there are only a few reports in the literature for the ef-
ficient synthesis of C2-substituted pyrimidines. In the tra-
ditional methods, C2-substituted pyrimidines have been
obtained by a multistep strategy involving sequential dehy-
drogenation, tautomerization, activation, and base-, palla-
dium-, or iron-catalyzed cross-coupling with a nucleophile
(Scheme 1, a).14–17 Thus, developing a new and simple
methodology to prepare C2-substituted pyrimidines from
the easily available Biginelli DHPM is more attractive than
other methods. In 2008, Srinivasan and co-workers report-
ed an efficient regioselective approach to the synthesis of
tetrasubstituted pyrimidines by sequential functionaliza-
tion of easily available Biginelli DHPMs via dehydrogenation
and chlorination, followed by a palladium-catalyzed Suzuki/
Sonogashira coupling reaction (Scheme 1, a).14c In 2010, our
group reported the synthesis of 4-arylpyrimidin-2-yl to-
sylates and their utilization in the formation of C2-substi-
tuted pyrimidines.16a Then, we developed procedures for
the synthesis of C2-substituted pyrimidines via the cross-
coupling reactions of pyrimidin-2-yl sulfonates.16b–d We
also developed the iron- or palladium-catalyzed C–S or C–C
cross-coupling reaction of 1,2-di(pyrimidin-2-yl) disulfides
with Grignard reagents (Scheme 1, b).17
DOI: 10.1055/s-0035-1560175; Art ID: ss-2015-h0413.op
Abstract A metal-free synthesis of C2-functionalized pyrimidines via
the reaction of pyrimidin-2-yl phosphates with amines and thiophenols
in PEG-400 has been developed. The desired products can be generated
in good to excellent yields in the environmentally friendly PEG-400,
without any catalysts or other additives.
Key words C2-functionalized pyrimidines, pyrimidin-2-yl phosphates,
amines, thiophenols, cross-coupling, metal-free
Developing green chemical reactions is one of the most
important aims of modern organic synthesis. Poly(ethylene
glycol) 400 (PEG-400) is an interesting solvent system
which has many advantages over other solvents, such as
thermal stability, commercial availability, nonvolatility, and
immiscibility with a number of organic solvents. PEG is in-
expensive, non-halogenated, and easily degradable, and
possesses low toxicity.1 Thus, PEG has received consider-
able attention in synthetic organic chemistry as a green or-
ganic solvent.1d,2
In recent years, much attention has been paid to cou-
pling with C–O electrophiles3 due to their ready availability
from natural sources and chemical synthesis. So far, unreac-
tive substrates such as phosphates have been identified as
competent coupling partners in cross-coupling reactions.
The use of phosphates has various advantages such as easy
preparation and environmental friendliness. In addition,
phosphates can be involved in a series of reactions, such as
the Stille,4 Negishi,5 Suzuki–Miyaura,6 Kumada,7 Sonogashira,8
and Heck reactions,9 providing a reliable alternative to envi-
ronmentally unfriendly halides.
More recently, we expanded the synthetic method for
C2-substituted pyrimidines by a Kumada cross-coupling re-
action of pyrimidin-2-yl phosphates with Grignard re-
agents (Scheme 1, c).18 Herein, we explored the possible ap-
plication of pyrimidin-2-yl phosphates in the diversifica-
tion of the pyrimidine motif by functionalization with
3,4-Dihydropyrimidin-2(1H)-one (DHPM) is a privi-
leged heterocyclic scaffold. Compounds containing this
scaffold exhibit a wide range of pharmacological proper-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935

3926
T. Xing et al.
Paper
Synthesis
a)
O
Ar
O
Ar
N
O
Ar
N
O
Ar
N, O, S, or C nucleophile
Fe or Pd (cat.)
oxidation
R1
NH
R1
N
R1
N
R1
N
functionalization
C–N, C–O, C–S, C–C
coupling reaction
R2
N
H
O
R2
LG
R2
Nu
R2
N
OH
LG = Cl, OTs, SO2Me
Nu = ROH, RSH, NHR2, ArB(OH)2
alkyne, RMgBr
b)
Ar
O
Ar
O
Ar
N
R1
N
N
R1
NH
R1
N
oxidation
RMgBr
S
O
Fe or Pd (cat.)
R2
N
H
S
R2
R
N
R2
2
c)
O
Ar
N
O
Ar
N
O
Ar
N
N or S nucleophile
R1
N
RMgBr
R1
N
R1
Fe (cat.)
PEG-400
no catalyst or base
R2
R
R2
OP(O)(OEt)2
R2
Nu
this work
Scheme 1 Synthesis of C2-functionalized pyrimidines derived from DHPMs
amino and thioether groups (Scheme 1, c). Notably, the re-
action delivered the desired C2-substituted pyrimidines un-
der mild reaction conditions, with no requirement for cata-
lysts, additives, or bases, and an easy-to-handle procedure
which make this method more attractive than other meth-
ods.
According to our previous report,18 the pyrimidin-2-yl
phosphates 3 were prepared by the reaction of 2-hydroxy-
pyrimidines 1 with diethyl phosphonate (2) in the presence
of a triethylamine in carbon tetrachloride system (Table 1).
Initially, the cross-coupling reaction between pyrimi-
din-2-yl phosphate 3a and piperidine (4a) was explored as
the model reaction (Table 2). At first, we tested a diverse set
of temperatures (Table 2, entries 1–4). When the reaction
was carried out at room temperature, the starting material
Table 1 Preparation of the Pyrimidin-2-yl Phosphates 3a
O
Ar
O
Ar
Table 2 Optimization of the Reaction of Pyrimidin-2-yl Phosphate 3a
with Piperidine (4a)a
O
R1
N
R1
N
Et3N
O
+
H
P
OEt
CCl4, r.t.
R2
N
OP(OEt)2
O
Ph
R2
N
OH
OEt
2
O
Ph
1
3
EtO
N
EtO
N
+
R1
R2
Product 3
Yieldb (%)
N
H
Entry
Ar
Me
N
N
Me
N
OP(O)(OEt)2
1
2
Ph
4-Tol
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
Me
3a
3b
3c
3d
3e
3f
82
76
70
79
84
75
80
82
83
78
88
3a
4a
5i
En- Solvent
try
Temp
(°C)
Yieldb Entry Solvent
(%)
Temp Yieldb
(°C)
3
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
2-Tol
(%)
65
4
1
2
3
4
5
6
7
PEG-400
r.t.
60
80
110
60
60
60
75
82
83
85
82d
68
73
8
9
PEG-6000c
DMSO
DMF
60
60
60
60
60
60
60
5
PEG-400
PEG-400
PEG-400
PEG-400
80
81
70
72
50
78
6
10
11
12
13
14
7
3g
3h
3i
dioxane
THF
8
9
2-ClC6H4
Ph
PEG-2000c
PEG-4000c
H2O
10
11
3j
EtOH
Ph
OMe
3k
a Reaction conditions: 3a (1.0 mmol), 4a (1.5 mmol), solvent (3 mL), 1 h.
b Isolated yield after column chromatography.
c PEG (2 g) was used.
a Reaction conditions: 1 (0.6 mmol), 2 (0.9 mmol), Et3N (1.8 mmol), CCl4 (2
mL), r.t., 20 min.
b Isolated yield after column chromatography.
d Reaction time was prolonged to 2 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935

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T. Xing et al.
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Synthesis
was not completely consumed and the yield was only 75%.
The starting material was consumed when the temperature
was increased to 60 °C, 80 °C, or 110 °C; however, increas-
ing the temperature to 80 °C or 110 °C only resulted in a
slight further increase in the yield. So, we chose 60 °C as the
optimum temperature. Then, when the reaction time was
prolonged from 1 hour to 2 hours, the yield was unchanged
(Table 2, entry 5 vs 2). Finally, the effect of the solvent on
O
Ar
O
Ar
PEG-400
60 °C, 1 h
R1
N
R1
N
NuH
+
R2
N
Nu
R2
N
OP(O)(OEt)2
4
5
3
OMe
Me
Cl
O
O
O
O
O
EtO
N
MeO
N
EtO
N
N
EtO
N
EtO
O
N
Me
N
N
Me
N
N
Me
N
Me
N
N
Me
N
N
O
O
O
O
5a, 81%
Br
5b, 89%
5e, 87%
5c, 79%
NO2
5d, 80%
F
OMe
O
O
O
O
O
EtO
N
EtO
Me
N
EtO
N
EtO
Me
N
EtO
Me
N
Me
N
N
N
N
Me
N
N
N
N
N
N
O
O
O
5i, 82%
5h, 86%
Br
5g, 83%
5f, 85%
5j, 78%
Me
Cl
F
O
O
O
Cl
N
O
O
EtO
N
N
EtO
N
EtO
EtO
N
EtO
N
Me
N
Me
N
N
Me
N
N
Me
N
N
Me
N
N
5o, 82%
5k, 80%
5l, 88%
5n, 86%
5m, 85%
O
Ph
N
O
Ph
O
Ph
O
Ph
N
O
Ph
EtO
i-Pr
EtO
OH
N
EtO
N
EtO
EtO
N
Et
N
N
Me
N
N
Me
N
NHn-Bu
Me
N
N
Me
N
NHBn
H
Et
5s, 84%
5p, 84%
5r, 80%
5t, 85%
5q, 83%
Cl
OMe
O
O
O
Me
S
O
O
EtO
N
EtO
N
EtO
Me
N
EtO
Me
N
n-Bu
EtO
N
Me
N
N
4-Tol
4-Tol
4-Tol
4-Tol
Me
N
S
N
N
S
n-Bu
Me
N
S
5u, 82%
5v, 75%
5x, 73%
5w, 70%
5y, 81%
Scheme 2 Cross-coupling reactions of pyrimidin-2-yl phosphates 3 with N and S nucleophiles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935

3928
T. Xing et al.
Paper
Synthesis
this reaction was also investigated. Different kinds of sol-
vents (such as PEG-2000, DMSO, DMF, dioxane, THF, H2O,
and EtOH) were tested, as well as PEG-400 which proved
superior (Table 2, entry 2 vs 6–14). From the perspective of
environmental protection and the productivity, we finally
selected PEG-400 as the best solvent. Thus, on the basis of
all of these results, PEG-400 as solvent at 60 °C for 1 hour
was selected as our optimized reaction conditions for the
cross-coupling reaction between pyrimidin-2-yl phosphate
3a and piperidine (4a).
action time and the use of strongly basic conditions; how-
ever, the hydrolysis of phosphates can take place in the
presence of alkali.
We also examined the cross-coupling reactions of py-
rimidin-2-yl phosphates 3 with other nitrogenated nucleo-
philes, such as benzamide, carbamates, and sulfonamides.
Unfortunately, we found that we could not obtain the target
products in PEG-400, even when different kinds of bases
were added to the system.19
In summary, we have developed a simple, rapid, and en-
vironmentally benign methodology for the synthesis of C2-
substituted pyrimidines via the nucleophilic substitution
reaction of reactive pyrimidin-2-yl phosphates with differ-
ent nitrogen and sulfur nucleophiles. The reaction is carried
out in PEG-400 as an environmentally friendly solvent and
proceeds efficiently to give various C2–N- and C2–S-func-
tionalized products in high yields under catalyst-, base-,
and ligand-free conditions.
With the optimized conditions in hand, various pyrimi-
din-2-yl phosphates 3 and a diverse set of nucleophiles 4
were used to test the scope of the reaction (Scheme 2). In
general, moderate to good yields (70–89%) of the C2-func-
tionalized pyrimidines 5 were obtained under the standard
reaction conditions. The nature of substituents on the het-
erocyclic fragment of the phosphate esters did not play a
significant role in this reaction. We found that pyrimidin-2-
yl phosphates 3 bearing an electron-withdrawing group (Cl,
Br, F, NO2) on the phenyl ring provided higher yields than
those compounds containing an electron-donating group
(OMe, Me). Cyclic secondary amines (morpholine or piperi-
dine) as the nucleophile were the most successful in this
process, being completely consumed to provide 5a–p. Acy-
clic amines also gave promising results; thus, primary
amines and secondary amines gave satisfactory results (see
5q–u). However, aromatic amines failed to react, even un-
der higher temperatures and longer reaction times (not
shown in Scheme 2). We next turned our attention to sulfur
and oxygen nucleophiles by treating pyrimidin-2-yl phos-
phates 3 with 1.5 equivalents of S and O nucleophiles in
PEG-400 at 60 °C. The reaction of phosphates 3 and p-thio-
cresol proceeded smoothly without base, to give 5v–y.
Furthermore, diethyl 6-methyl-2-(phenylamino)pyrimi-
din-4-yl phosphate (3l) was prepared18 and treated with p-
thiocresol, giving the C–S coupling product 5z in 80% yield
(Scheme 3).
Commercially available reagents were used without further purifica-
tion, unless otherwise stated. Melting points were measured on an
XT-4 apparatus and are uncorrected. IR spectra were recorded using
1
KBr pellets on a Nicolet Avatar 360 FT-IR spectrophotometer. H, 13C,
and 31P NMR spectra were recorded on either a Varian V-NMRS 600 or
Mercury Plus-400 instrument using CDCl3 as solvent and TMS as in-
ternal standard. High-resolution mass spectra (HRMS) were obtained
on a Bruker Daltonics APEX II 47e mass spectrometer. Column chro-
matography was generally performed on silica gel (200–300 mesh)
and TLC inspections were performed on silica gel GF254 plates.
Pyrimidin-2-yl Phosphates 3a–3l; General Procedure
Et3N (0.25 mL, 1.8 mmol) was slowly added to a mixture of a 2-hy-
droxypyrimidine 1 (0.6 mmol), diethyl phosphonate (2; 124.3 mg, 0.9
mmol), and CCl4 (2 mL), and then the mixture was stirred at r.t. for 20
min. After the starting material 1 had been consumed (monitored by
TLC), the product was purified by flash chromatography on silica gel
using petroleum ether–EtOAc (4:1) to EtOAc as eluent to provide the
corresponding pyrimidin-2-yl phosphate 3.
When alcohols were involved, the reaction with pyrimi-
din-2-yl phosphates 3 failed. When sodium tert-butoxide,
potassium carbonate, or tripotassium phosphate was added
to the system, most of the corresponding starting 2-hy-
droxypyrimidine 1 was recovered, which shows that hydro-
lysis of the phosphates may occur. From our previous
work,16a the cross-coupling reactions of pyrimidin-2-yl sul-
fonates with alcohols can proceed upon prolonging the re-
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-methyl-6-phenylpyrimi-
dine-5-carboxylate (3a)18
Yield: 194 mg (82%); yellow oil.
IR (KBr): 2980 (m), 1718 (s), 1595 (s), 1570 (s), 1492 (s), 1448 (s),
1386 (s), 1208 (s), 1163 (m), 1080 (s), 1030 (vs) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 6.8 Hz, 2 H, ArH), 7.40–7.37
(m, 3 H, ArH), 4.32 [q, J = 7.6 Hz, 4 H, P(O)(OCH2CH3)2], 4.14–4.10 (m,
2 H, OCH2), 2.54 (s, 3 H, CH3), 1.31 [t, J = 6.4 Hz, 6 H, P(O)(OCH2CH3)2],
0.99 (t, J = 7.2 Hz, 3 H, CH2CH3).
Me
Me
Me
HS
PEG-400
60 °C, 1 h
N
N
+
N
N
S
N
N
OP(O)(OEt)2
Me
H
H
5z, 80%
3l
Scheme 3 Cross-coupling reaction of pyrimidin-2-yl phosphate 3l with p-thiocresol
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935

3929
T. Xing et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 168.94, 166.92, 166.47, 158.55,
136.43, 130.15, 128.12 (2 C), 128.01 (2 C), 122.65, 64.87, 64.81, 61.56,
22.08, 15.62, 15.55, 13.13.
31P NMR (162 MHz, CDCl3): δ = –7.37.
HRMS (EI): m/z [M + H]+ calcd for C18H24N2O6P: 395.1366; found:
Ethyl 4-(4-Chlorophenyl)-2-[(diethoxyphosphoryl)oxy]-6-meth-
ylpyrimidine-5-carboxylate (3e)18
Yield: 215 mg (84%); yellow solid; mp 80–82 °C.
IR (KBr): 2984 (m), 1720 (s), 1596 (s), 1544 (s), 1492 (w), 1438 (s),
1396 (s), 1090 (s), 1032 (vs), 578 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.65–7.62 (m, 2 H, ArH), 7.45–7.42 (m,
2 H, ArH), 4.42–4.35 [m, 4 H, P(O)(OCH2CH3)2], 4.25–4.21 (m, 2 H,
OCH2), 2.62 (s, 3 H, CH3), 1.39 [t, J = 6.8 Hz, 6 H, P(O)(OCH2CH3)2], 1.13
(t, J = 6.8 Hz, 3 H, CH2CH3).
395.1368.
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-methyl-6-(p-tolyl)pyrimi-
dine-5-carboxylate (3b)18
13C NMR (100 MHz, CDCl3): δ = 169.55, 167.18, 165.40, 158.87,
136.89, 135.10, 129.76 (2 C), 128.73 (2 C), 122.73, 65.26, 65.20, 62.06,
22.54, 16.00, 15.93, 13.59.
31P NMR (162 MHz, CDCl3): δ = –7.15.
HRMS (EI): m/z [M + H]+ calcd for C18H23ClN2O6P: 429.0977; found:
Yield: 192 mg (76%); yellow oil.
IR (KBr): 2980 (m), 1720 (s), 1610 (w), 1560 (s), 1510 (s), 1438 (s),
1038 (vs), 576 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 7.6 Hz, 2 H, ArH), 7.25 (d, J =
7.2 Hz, 2 H, ArH), 4.41–4.36 [m, 4 H, P(O)(OCH2CH3)2], 4.22 (q, J = 7.2
Hz, 2 H, OCH2), 2.60 (s, 3 H, Ar-CH3), 2.40 (s, 3 H, CH3), 1.38 [t, J = 6.8
Hz, 6 H, P(O)(OCH2CH3)2], 1.11 (t, J = 6.8 Hz, 3 H, CH2CH3).
429.0980.
13C NMR (100 MHz, CDCl3): δ = 168.85, 167.43, 166.46, 158.67,
140.74, 133.65, 128.98 (2 C), 128.20 (2 C), 122.52, 65.05, 64.99, 61.72,
22.30, 21.14, 15.85, 15.78, 13.42.
31P NMR (162 MHz, CDCl3): δ = –7.12.
HRMS (EI): m/z [M + H]+ calcd for C19H26N2O6P: 409.1523; found:
Ethyl 4-(4-Bromophenyl)-2-[(diethoxyphosphoryl)oxy]-6-meth-
ylpyrimidine-5-carboxylate (3f)18
Yield: 211 mg (75%); white solid; mp 93–95 °C.
IR (KBr): 2980 (m), 1715 (s), 1594 (s), 1580 (s), 1514 (s), 1448 (s),
1255 (s), 1035 (vs), 690 (m), 575 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.61–7.54 (m, 4 H, ArH), 4.40–4.38 [m,
4 H, P(O)(OCH2CH3)2], 4.22 (q, J = 6.8 Hz, 2 H, OCH2), 2.62 (s, 3 H, CH3),
1.39 [t, J = 6.4 Hz, 6 H, P(O)(OCH2CH3)2], 1.13 (t, J = 7.2 Hz, 3 H,
CH2CH3).
409.1525.
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-(4-methoxyphenyl)-6-
methylpyrimidine-5-carboxylate (3c)18
13C NMR (100 MHz, CDCl3): δ = 169.58, 167.14, 165.46, 158.87,
135.53, 131.69 (2 C), 129.94 (2 C), 125.26, 122.68, 65.26, 65.20, 62.07,
22.55, 16.00, 15.93, 13.59.
31P NMR (162 MHz, CDCl3): δ = –7.17.
HRMS (EI): m/z [M + H]+ calcd for C18H23BrN2O6P: 473.0472; found:
Yield: 177 mg (70%); yellow oil.
IR (KBr): 2983 (m), 1716 (s), 1610 (s), 1580 (s), 1510 (s), 1476 (w),
1448 (s), 1260 (s), 1034 (vs), 958 (m), 570 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 7.2 Hz, 2 H, ArH), 6.95 (d, J =
7.2 Hz, 2 H, ArH), 4.39 [q, J = 7.2 Hz, 4 H, P(O)(OCH2CH3)2], 4.24 (q, J =
7.2 Hz, 2 H, OCH2), 3.86 (s, 3 H, OCH3), 2.59 (s, 3 H, CH3), 1.38 [t, J = 6.8
Hz, 6 H, P(O)(OCH2CH3)2], 1.15 (t, J = 6.0 Hz, 3 H, CH2CH3).
473.0476.
13C NMR (100 MHz, CDCl3): δ = 168.77, 167.72, 165.76, 161.53,
158.64, 130.04 (2 C), 128.73, 122.09, 113.75 (2 C), 65.11, 65.05, 61.82,
55.19, 22.36, 15.92, 15.84, 13.58.
31P NMR (162 MHz, CDCl3): δ = –7.10.
HRMS (EI): m/z [M + H]+ calcd for C19H26N2O7P: 425.1472; found:
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-methyl-6-(4-nitrophe-
nyl)pyrimidine-5-carboxylate (3g)
Yield: 210 mg (80%); white solid; mp 70–72 °C.
IR (KBr): 2984 (m), 1720 (s), 1560 (m), 1544 (m), 1256 (s), 1032 (m),
580 (m), 508 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.34–8.32 (m, 2 H, ArH), 7.86–7.84 (m,
2 H, ArH), 4.42–4.39 [m, 4 H, P(O)(OCH2CH3)2], 4.24 (q, J = 7.2 Hz, 2 H,
OCH2), 2.67 (s, 3 H, CH3), 1.41 [t, J = 7.2 Hz, 6 H, P(O)(OCH2CH3)2], 1.13
(t, J = 7.2 Hz, 3 H, CH2CH3).
425.1470.
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-(4-fluorophenyl)-6-meth-
ylpyrimidine-5-carboxylate (3d)18
13C NMR (150 MHz, CDCl3): δ = 170.32, 166.51, 164.51, 158.94,
148.84, 142.64, 129.51 (2 C), 123.59 (2 C), 123.08, 65.37, 65.33, 62.30,
22.75, 16.01, 15.96, 13.61.
31P NMR (162 MHz, CDCl3): δ = –7.27.
HRMS (EI): m/z [M + H]+ calcd for C18H23N3O8P: 440.1217; found:
Yield: 194 mg (79%); yellow oil.
IR (KBr): 2984 (m), 1716 (s), 1610 (s), 1560 (s), 1544 (s), 1448 (s),
1090 (s), 1034 (vs), 560 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 4.0 Hz, 2 H, ArH), 7.14 (t, J =
7.6 Hz, 2 H, ArH), 4.39 [q, J = 7.2 Hz, 4 H, P(O)(OCH2CH3)2], 4.22 (q, J =
7.2 Hz, 2 H, OCH2), 2.61 (s, 3 H, CH3), 1.38 [t, J = 6.8 Hz, 6 H,
P(O)(OCH2CH3)2], 1.12 (t, J = 6.0 Hz, 3 H, CH2CH3).
440.1215.
13C NMR (100 MHz, CDCl3): δ = 169.46, 167.40, 165.54, 162.96,
158.88, 132.84, 130.66 (2 C), 130.58 (2 C), 122.74, 115.78 (2 C), 115.56
(2 C), 65.32, 65.26, 62.07, 22.59, 16.06, 15.99, 13.66.
31P NMR (162 MHz, CDCl3): δ = –7.14.
HRMS (EI): m/z [M + H]+ calcd for C18H23FN2O6P: 413.1272; found:
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-methyl-6-(o-tolyl)pyrimi-
dine-5-carboxylate (3h)
Yield: 200 mg (82%); yellow oil.
IR (KBr): 2950 (w), 1718 (s), 1610 (s), 1565 (s), 1516 (s), 1448 (s),
1034 (vs), 575 (m) cm–1
.
413.1278.
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1H NMR (600 MHz, CDCl3): δ = 7.31–7.28 (m, 1 H, ArH), 7.25–7.23 (m,
1 H, ArH), 7.19–7.16 (m, 1 H, ArH), 7.10 (d, J = 5.2 Hz, 1 H, ArH), 4.36–
4.33 [m, 4 H, P(O)(OCH2CH3)2], 4.01–3.99 (m, 2 H, OCH2), 2.63 (s, 3 H,
Ar-CH3), 2.25 (s, 3 H, CH3), 1.36–1.33 [m, 6 H, P(O)(OCH2CH3)2], 0.86–
0.84 (m, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.62, 169.38, 166.47, 136.76,
135.93, 130.38 (2 C), 129.34 (2 C), 127.88 (2 C), 125.39 (2 C), 65.35,
65.29, 61.62, 22.86, 19.55, 16.04, 15.97, 13.34.
31P NMR (162 MHz, CDCl3): δ = –7.15.
HRMS (EI): m/z [M + H]+ calcd for C17H22N2O6P: 381.1210; found:
381.1214.
Diethyl 6-Methyl-2-(phenylamino)pyrimidin-4-yl Phosphate (3l)18
Yield: 172 mg (85%); white solid; mp 100–102 °C.
IR (KBr): 3215 (s), 2980 (m), 1715 (s), 1610 (s), 1575 (s), 1498 (s),
1440 (s), 1350 (s), 1030 (vs), 585 (s) cm–1
.
31P NMR (243 MHz, CDCl3): δ = –7.07.
HRMS (EI): m/z [M + H]+ calcd for C19H26N2O6P: 409.1523; found:
1H NMR (400 MHz, CDCl3): δ = 7.66–7.64 (m, 2 H, ArH), 7.35–7.27 (m,
2 H, ArH), 7.20 (s, 1 H, ArH), 7.06–7.03 (m, 1 H, ArH), 6.31 (s, 1 H, NH),
4.30–4.25 [m, 4 H, (OCH2CH3)2], 2.40 (s, 3 H, CH3), 1.35 [t, J = 7.2 Hz, 6
H, (OCH2CH3)2].
13C NMR (100 MHz, CDCl3): δ = 171.20, 164.73, 164.68, 159.42,
138.98, 128.78 (2 C), 122.73, 119.48 (2 C), 99.53, 99.46, 64.99, 64.93,
24.15, 16.04, 15.97.
409.1520.
Ethyl 4-(2-Chlorophenyl)-2-[(diethoxyphosphoryl)oxy]-6-meth-
ylpyrimidine-5-carboxylate (3i)
Yield: 212 mg (83%); yellow oil.
IR (KBr): 2980 (m), 1715 (s), 1603 (s), 1565 (s), 1544 (s), 1252 (m),
31P NMR (162 MHz, CDCl3): δ = –6.86.
HRMS (EI): m/z [M + H]+ calcd for C15H20N3O4P: 338.1254; found:
1098 (s), 1032 (vs), 556 (m) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.40 (d, J = 5.2 Hz, 1 H, ArH), 7.35–7.34
(m, 1 H, ArH), 7.31 (s, 2 H, ArH), 4.35 [q, J = 4.8 Hz, 4 H,
P(O)(OCH2CH3)2], 4.04 (q, J = 4.8 Hz, 2 H, OCH2), 2.68 (s, 3 H, CH3), 1.34
[t, J = 4.4 Hz, 6 H, P(O)(OCH2CH3)2], 0.89 (t, J = 4.8 Hz, 3 H, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 170.72, 167.12, 165.53, 158.81,
136.70, 131.89, 130.45 (2 C), 129.98 (2 C), 129.38 (2 C), 126.64 (2 C),
123.51, 65.42, 65.38, 61.64, 23.47, 16.02, 15.97, 13.34.
338.1251.
C2-Functionalized Pyrimidines 5a–z; General Procedure
To a stirred mixture of a pyrimidin-2-yl phosphate 318 (0.4 mmol) in
PEG-400 (3 mL) was added a nucleophile (0.6 mmol) at 60 °C. After
the reaction mixture was stirred at 60 °C for 1 h (TLC monitoring), it
was extracted with water (10 mL) and EtOAc (30 mL). Then, the or-
ganic layers were dried over Na2SO4. The crude product was purified
by flash chromatography using petroleum ether–EtOAc (15:1) to
EtOAc as eluent for 5a–u, and petroleum ether–EtOAc (30:1) to EtOAc
as eluent for 5v–z, to give the pure product 5.
31P NMR (243 MHz, CDCl3): δ = –7.30.
HRMS (EI): m/z [M + H]+ calcd for C18H23ClN2O6P: 429.0977; found:
429.0982.
Ethyl 2-[(Diethoxyphosphoryl)oxy]-4-isopropyl-6-phenylpyrimi-
dine-5-carboxylate (3j)
Ethyl 4-Methyl-2-morpholino-6-phenylpyrimidine-5-carboxylate
(5a)16a
Yield: 197 mg (78%); colorless oil.
Yield: 106 mg (81%); white solid; mp 118–119 °C.
IR (KBr): 2976 (w), 1720 (s), 1544 (s), 1398 (m), 1244 (s), 1030 (s),
828 (w), 622 (w) cm–1
.
IR (KBr): 2964 (w), 1718 (vs), 1560 (s), 1512 (s), 1492 (s), 1444 (s),
1232 (s), 690 (vw), 576 (vw) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.64–7.62 (m, 2 H, ArH), 7.43–7.38 (m,
3 H, ArH), 4.36–4.32 [m, 4 H, O(CH2CH3)2], 4.14 (q, J = 4.8 Hz, 2 H,
OCH2), 3.22–3.15 (m, 1 H, CH), 1.34 [t, J = 4.8 Hz, 6 H, CH(CH3)2], 1.30
[d, J = 4.8 Hz, 6 H, P(O)(OCH2CH3)2], 1.02 (t, J = 4.8 Hz, 3 H, CH2CH3).
1H NMR (400 MHz, CDCl3): δ = 7.58–7.40 (m, 5 H, ArH), 4.08–4.03 (m,
2 H, OCH2), 3.94–3.92 [m, 4 H, N(CH2)2], 3.76 [t, J = 4.80 Hz, 4 H,
O(CH2)2], 2.50 (s, 3 H, CH3), 0.95 (t, J = 7.60 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.96, 167.03, 165.66, 160.20,
139.30, 129.46, 128.16 (2 C), 128.06 (2 C), 114.48, 66.87 (2 C), 60.99,
44.10 (2 C), 23.14, 13.54.
HRMS (EI): m/z [M + H]+ calcd for C18H22N3O3: 328.1656; found:
328.1661.
13C NMR (150 MHz, CDCl3): δ = 177.09, 167.58, 167.56, 166.78,
159.39, 159.37, 136.90, 130.32, 128.41 (2 C), 128.33 (2 C), 122.32,
65.06, 65.02, 61.92, 33.29, 21.55 (2 C), 16.05, 16.00, 13.53.
31P NMR (243 MHz, CDCl3): δ = –8.13.
HRMS (EI): m/z [M + H]+ calcd for C20H28N2O6P: 423.1679; found:
423.1685.
Methyl 4-Methyl-2-morpholino-6-phenylpyrimidine-5-carboxyl-
ate (5b)
Methyl 2-[(Diethoxyphosphoryl)oxy]-4-methyl-6-phenylpyrimi-
dine-5-carboxylate (3k)18
Yield: 111 mg (89%); colorless oil.
IR (KBr): 2952 (w), 1718 (vs), 1638 (s), 1560 (s), 1490 (s), 1458 (s),
Yield: 200 mg (88%); colorless oil.
1068 (s), 1024 (m), 766 (vw) cm–1
.
IR (KBr): 2983 (m), 1716 (s), 1598 (s), 1498 (s), 1445 (s), 1383 (s),
1H NMR (400 MHz, CDCl3): δ = 7.59–7.58 (m, 2 H, ArH), 7.41 (d, J = 4.8
Hz, 3 H, ArH), 3.93–3.91 [m, 4 H, N(CH2)2], 3.76–3.74 [m, 4 H,
O(CH2)2], 3.58 (s, 3 H, OCH3), 2.49 (s, 3 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 169.51, 167.05, 165.41, 160.29,
139.17, 129.54, 128.19 (2 C), 128.00 (2 C), 114.19, 66.84 (2 C), 51.86,
44.13 (2 C), 23.16.
1218 (s), 1160 (m), 1050 (s), 1035 (vs), 802 (m), 585 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.66 (m, 2 H, ArH), 7.48–7.45 (m,
3 H, ArH), 4.41–4.37 [m, 4 H, (OCH2CH3)2], 3.71 (s, 3 H, OCH3), 2.61 (s,
3 H, CH3), 1.40–1.37 [m, 6 H, (OCH2CH3)2].
13C NMR (100 MHz, CDCl3): δ = 169.26, 167.86, 166.60, 158.84,
136.46, 130.49, 128.41 (2 C), 128.13 (2 C), 122.41, 65.18, 65.12, 52.56,
22.48, 15.92, 15.84.
HRMS (EI): m/z [M + H]+ calcd for C17H20N3O3: 314.1499; found:
314.1501.
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Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-morpholinopyrimidine-5-
carboxylate (5c)16a
Ethyl 4-(4-Fluorophenyl)-6-methyl-2-morpholinopyrimidine-5-
carboxylate (5g)16a
Yield: 113 mg (79%); white solid; mp 72–74 °C.
Yield: 114 mg (83%); white solid; mp 86–88 °C.
IR (KBr): 2960 (w), 1715 (vs), 1592 (s), 1581 (s), 1492 (s), 1446 (s),
IR (KBr): 2964 (s), 1716 (vs), 1602 (s), 1560 (vs), 1508 (s), 1448 (s),
1230 (s), 1050 (s), 1034 (s), 850 (s) cm–1
.
1226 (vs), 848 (s), 800 (s), 592 (m), 566 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 9.20 Hz, 2 H, ArH), 6.93 (d,
J = 8.40 Hz, 2 H, ArH), 4.11–4.10 (m, 2 H, OCH2), 3.93–3.91 [m, 4 H,
N(CH2)2], 3.84 (s, 3 H, OCH3), 3.75 [t, J = 4.80 Hz, 4 H, O(CH2)2], 2.47 (s,
3 H, CH3), 1.05 (t, J = 7.20 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.32, 166.63, 164.68, 160.88,
160.15, 131.50, 129.69 (2 C), 114.19, 113.58 (2 C), 66.86 (2 C), 55.34,
55.30, 44.10 (2 C), 23.05, 13.74.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.07 (m, 4 H, ArH), 4.12–4.06 (m,
2 H, OCH2), 3.92 [t, J = 4.80 Hz, 4 H, N(CH2)2], 3.76 [t, J = 4.80 Hz, 4 H,
O(CH2)2], 2.49 (s, 3 H, CH3), 1.02 (t, J = 7.20 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.85, 167.12, 164.86, 164.41,
162.38, 160.12, 135.33, 130.14 (2 C), 130.05, 115.31 (2 C), 114.34,
66.84 (2 C), 61.07, 44.10 (2 C), 23.15, 13.66.
HRMS (EI): m/z [M + H]+ calcd for C18H21FN3O3: 346.1561; found:
346.1556.
HRMS (EI): m/z [M + H]+ calcd for C19H24N3O4: 358.1761; found:
358.1768.
Ethyl 4-Methyl-2-morpholino-6-(4-nitrophenyl)pyrimidine-5-
carboxylate (5h)
Ethyl 4-Methyl-2-morpholino-6-(p-tolyl)pyrimidine-5-carboxyl-
ate (5d)16a
Yield: 128 mg (86%); yellow solid; mp 100–102 °C.
Yield: 109 mg (80%); white solid; mp 68–70 °C.
IR (KBr): 2856 (w), 1718 (vs), 1560 (m), 1522 (m), 1446 (m), 1348 (s),
IR (KBr): 2964 (s), 1716 (vs), 1584 (s), 1560 (vs), 1510 (s), 1448 (m),
1236 (vs), 864 (m), 802 (w) cm–1
.
1234 (s), 1016 (s), 796 (s), 594 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29–8.26 (m, 2 H, ArH), 7.73–7.70 (m,
2 H, ArH), 4.08 (q, J = 7.2 Hz, 2 H, OCH2), 3.93 [t, J = 4.8 Hz, 4 H,
N(CH2)2], 3.78–3.76 [m, 4 H, O(CH2)2], 2.54 (s, 3 H, CH3), 1.01 (t, J = 7.2
Hz, 3 H, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 168.02, 167.95, 163.82, 160.04,
148.20, 145.77, 129.10 (2 C), 123.28 (2 C), 114.20, 66.76 (2 C), 61.16,
44.12 (2 C), 23.47, 13.66.
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 8.00 Hz, 2 H, ArH), 7.22 (d,
J = 8.00 Hz, 2 H, ArH), 4.12–4.07 (m, 2 H, OCH2), 3.92 [t, J = 4.40 Hz, 4
H, N(CH2)2], 3.75 [t, J = 4.40 Hz, 4 H, O(CH2)2], 2.48 (s, 3 H, Ar-CH3),
2.38 (s, 3 H, CH3), 1.01 (t, J = 6.80 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.16, 166.74, 165.43, 160.22,
139.64, 136.36, 128.86 (2 C), 128.03 (2 C), 114.45, 66.86 (2 C), 60.98,
44.12 (2 C), 23.04, 21.29, 13.61.
HRMS (EI): m/z [M + H]+ calcd for C18H21N4O5: 373.1506; found:
373.1510.
HRMS (EI): m/z [M + H]+ calcd for C19H24N3O3: 342.1812; found:
342.1815.
Ethyl 4-Methyl-6-phenyl-2-(piperidin-1-yl)pyrimidine-5-carbox-
ylate (5i)16a
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-morpholinopyrimidine-5-
carboxylate (5e)16a
Yield: 107 mg (82%); white solid; mp 69–70 °C.
Yield: 126 mg (87%); white solid; mp 80–83 °C.
IR (KBr): 2950 (w), 1715 (vs), 1565 (s), 1550 (s), 1495 (s), 1450 (s),
IR (KBr): 2950 (w), 1715 (vs), 1605 (s), 1580 (s), 1490 (s), 1454 (s),
1270 (s), 1164 (m) cm–1
.
1050 (s), 1025 (m), 830 (s), 650 (s), 540 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.56 (m, 2 H, ArH), 7.42–7.38 (m,
3 H, ArH), 4.06–4.01 (m, 2 H, OCH2), 3.89 [t, J = 5.60 Hz, 4 H, N(CH2)2],
2.49 (s, 3 H, CH3), 1.68–1.60 [m, 6 H, (CH2)3], 0.93 (t, J = 7.2 Hz, 3 H,
CH2CH3).
1H NMR (400 MHz, CDCl3): δ = 7.52–7.37 (m, 4 H, ArH), 4.12–4.07 (m,
2 H, OCH2), 3.92 [t, J = 5.6 Hz, 4 H, N(CH2)2], 3.76 [t, J = 5.20 Hz, 4 H,
O(CH2)2], 2.50 (s, 3 H, CH3), 1.02 (t, J = 7.60 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.68, 167.23, 164.45, 160.04,
137.70, 135.65, 129.47 (2 C), 128.40 (2 C), 114.27, 66.82 (2 C), 61.14,
44.10 (2 C), 23.17, 13.65.
13C NMR (100 MHz, CDCl3): δ = 169.20, 166.91, 165.73, 160.15,
139.75, 129.20, 128.06 (2 C), 113.18 (2 C), 60.77, 44.64, 25.84 (2 C),
24.83, 23.20 (2 C), 13.51.
HRMS (EI): m/z [M + H]+ calcd for C18H21ClN3O3: 362.1266; found:
HRMS (EI): m/z [M + H]+ calcd for C19H24N3O2: 326.1863; found:
362.1268.
326.1867.
Ethyl 4-(4-Bromophenyl)-6-methyl-2-morpholinopyrimidine-5-
carboxylate (5f)16a
Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-(piperidin-1-yl)pyrimi-
dine-5-carboxylate (5j)16a
Yield: 138 mg (85%); white solid; mp 92–93 °C.
Yield: 111 mg (78%); white solid; mp 87–88 °C.
IR (KBr): 2950 (w), 1718 (vs), 1596 (s), 1575 (s), 1482 (s), 1456 (s),
IR (KBr): 2922 (s), 1270 (s), 1235 (m), 1080 (s), 1065 (s), 1045 (s),
1034 (m), 650 (s), 585 (s) cm–1
.
1024 (m), 564 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.43 (m, 4 H, ArH), 4.12–4.06 (m,
2 H, OCH2), 3.91 [t, J = 4.4 Hz, 4 H, N(CH2)2], 3.75 [t, J = 4.8 Hz, 4 H,
O(CH2)2], 2.49 (s, 3 H, CH3), 1.02 (t, J = 6.8 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.65, 167.30, 164.53, 160.11,
138.25, 131.35 (2 C), 129.75 (2 C), 123.95, 114.28, 66.83 (2 C), 61.12,
44.15 (2 C), 23.17, 13.66.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.8 Hz, 2 H, ArH), 6.91 (d, J =
8.8 Hz, 2 H, ArH), 4.13–4.07 (m, 2 H, OCH2), 3.88 [t, J = 5.2 Hz, 4 H,
N(CH2)2], 3.84 (s, 3 H, OCH3), 2.47 (s, 3 H, CH3), 1.68–1.60 [m, 6 H,
(CH2)3], 1.03 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.57, 166.55, 164.77, 160.75,
132.03, 129.72 (2 C), 113.52 (2 C), 60.82, 55.32, 44.65 (2 C), 25.85 (2
C), 24.87, 23.13, 13.75.
HRMS (EI): m/z [M + H]+ calcd for C18H21BrN3O3: 406.0761; found:
406.0765.
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HRMS (EI): m/z [M + H]+ calcd for C20H26N3O3: 356.1969; found:
356.1970.
13C NMR (100 MHz, CDCl3): δ = 169.37, 165.00, 164.74, 162.53,
160.35, 136.05, 130.49, 130.22, 115.45, 115.40, 113.28, 61.12, 44.90
(2 C), 26.10 (2 C), 25.08, 23.47, 13.87.
HRMS (EI): m/z [M + H]+ calcd for C19H23FN3O2: 344.1769; found:
344.1775.
Ethyl 4-Methyl-2-(piperidin-1-yl)-6-(p-tolyl)pyrimidine-5-carbox-
ylate (5k)16a
Yield: 109 mg (80%); white solid; mp 68–69 °C.
Ethyl 4-(2-Chlorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (5o)
IR (KBr): 2925 (w), 1718 (vs), 1598 (s), 1568 (s), 1540 (s), 1230 (s),
1063 (s) cm–1
.
Yield: 118 mg (82%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.0 Hz, 2 H, ArH), 7.19 (d, J =
8.0 Hz, 2 H, ArH), 4.10–4.04 (m, 2 H, OCH2), 3.88 [t, J = 5.2 Hz, 4 H,
N(CH2)2], 2.47 (s, 3 H, Ar-CH3), 2.38 (s, 3 H, CH3), 1.67–1.59 [m, 6 H,
(CH2)3], 0.99 (t, J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.42, 166.61, 165.52, 139.35,
136.83, 128.77 (2 C), 128.08 (2 C), 60.79, 44.67 (2 C), 25.85 (2 C),
24.87, 23.19, 21.32, 13.63.
IR (KBr): 2932 (s), 1716 (vs), 1560 (s), 1542 (s), 1510 (s), 1458 (s),
1092 (s), 1066 (s), 806 (s), 760 (s), 574 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.38–7.37 (m, 1 H, ArH), 7.28 (d, J = 2.4
Hz, 3 H, ArH), 3.94 (q, J = 4.8 Hz, 2 H, OCH2), 3.85 [t, J = 3.6 Hz, 4 H,
N(CH2)2], 2.58 (s, 3 H, CH3), 1.68–1.56 [m, 6 H, (CH2)3], 0.83 (t, J = 4.8
Hz, 3 H, CH2CH3).
HRMS (EI): m/z [M + H]+ calcd for C20H26N3O2: 340.2020; found:
340.2015.
13C NMR (150 MHz, CDCl3): δ = 168.54, 167.20, 165.69, 159.97,
139.89, 131.94, 129.72 (2 C), 129.17 (2 C), 129.15 (2 C), 126.34 (2 C),
113.07, 60.34, 44.70 (2 C), 25.82 (2 C), 24.80, 24.40, 13.38.
HRMS (EI): m/z [M + H]+ calcd for C19H23ClN3O2: 360.1473; found:
360.1475.
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (5l)16a
Yield: 126 mg (88%); white solid; mp 54–55 °C.
Ethyl 4-Isopropyl-6-phenyl-2-(piperidin-1-yl)pyrimidine-5-car-
boxylate (5p)
IR (KBr): 2948 (w), 1716 (vs), 1594 (s), 1588 (s), 1520 (s), 1455 (s),
1230 (m), 845 (s), 550 (s) cm–1
.
Yield: 119 mg (84%); white solid; mp 92–94 °C.
IR (KBr): 2932 (s), 1718 (s), 1560 (s), 1524 (s), 1446 (s), 1236 (s) cm–1
1H NMR (400 MHz, CDCl3): δ = 7.60–7.57 (m, 2 H, ArH), 7.39–7.38 (m,
3 H, ArH), 4.03 (q, J = 7.2 Hz, 2 H, OCH2), 3.89 [t, J = 5.6 Hz, 4 H,
N(CH2)2], 3.31–3.21 (m, 1 H, CH), 1.68–1.64 (m, 2 H, CH2), 1.62–1.58
[m, 4 H, (CH2)2], 1.27 [s, 3 H, CH(CH3)2], 1.26 [s, 3 H, CH(CH3)2], 0.94 (t,
J = 7.2 Hz, 3 H, CH2CH3).
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.4 Hz, 2 H, ArH), 7.36 (d, J =
8.4 Hz, 2 H, ArH), 4.10–4.04 (m, 2 H, OCH2), 3.88 [t, J = 5.2 Hz, 4 H,
N(CH2)2], 2.48 (s, 3 H, CH3), 1.68–1.60 [m, 6 H, (CH2)3], 1.01 (t, J = 7.2
Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 169.42, 166.61, 165.52, 139.35,
136.83, 128.77 (2 C), 128.09 (2 C), 113.19, 60.79, 44.67 (2 C), 25.85 (2
C), 24.88, 23.19, 13.63.
.
HRMS (EI): m/z [M + H]+ calcd for C19H23ClN3O2: 360.1473; found:
360.1471.
13C NMR (150 MHz, CDCl3): δ = 174.26, 169.53, 165.33, 160.65,
139.91, 129.11, 128.09 (2 C), 128.07 (2 C), 112.93, 60.88, 44.70 (2 C),
32.63, 25.80 (2 C), 24.94, 21.74 (2 C), 13.56.
HRMS (EI): m/z [M + H]+ calcd for C21H28N3O2: 354.2176; found:
354.2179.
Ethyl 4-(4-Bromophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (5m)16a
Yield: 137 mg (85%); white solid; mp 61–62 °C.
Ethyl 2-(Butylamino)-4-methyl-6-phenylpyrimidine-5-carboxyl-
ate (5q)
IR (KBr): 2928 (w), 1714 (vs), 1578 (s), 1558 (s), 1510 (s), 1458 (s),
1064 (s), 645 (m), 573 (s) cm–1
.
Yield: 104 mg (83%); white solid; mp 76–78 °C.
1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.4 Hz, 2 H, ArH), 7.43 (d, J =
8.0 Hz, 2 H, ArH), 4.09–4.04 (m, 2 H, OCH2), 3.88 [t, J = 5.2 Hz, 4 H,
N(CH2)2], 2.49 (s, 3 H, CH3), 1.68–1.60 [m, 6 H, (CH2)3], 1.00 (t, J = 7.2
Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.89, 167.21, 164.59, 160.04,
138.70, 131.21 (2 C), 129.76 (2 C), 123.67, 60.89, 44.67 (2 C), 25.85 (2
C), 24.82, 23.29, 13.66.
IR (KBr): 3242 (vs), 1715 (vs), 1598 (s), 1570 (s), 1512 (s), 1446 (s),
1250 (s), 1085 (vs), 1028 (s), 775 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55 (s, 2 H, ArH), 7.42 (s, 3 H, ArH),
5.53 (s, 1 H, NH), 4.04 (q, J = 7.2 Hz, 2 H, OCH2), 3.47 (q, J = 6.4 Hz, 2 H,
NHCH2), 2.49 (s, 3 H, CH3), 1.61–1.54 (m, 2 H, CH2CH2CH3), 1.44–1.35
(m, 2 H, CH2CH2CH3), 0.94 [t, J = 7.2 Hz, 6 H, OCH2CH3 (3 H), CH2CH3 (3
H)].
13C NMR (100 MHz, CDCl3): δ = 168.80, 166.11, 161.19, 139.28,
139.25, 129.27, 128.11 (2 C), 127.90 (2 C), 114.94, 60.88, 40.98, 31.68,
19.97, 13.78, 13.74, 13.49.
HRMS (EI): m/z [M + H]+ calcd for C19H23BrN3O2: 404.0968; found:
404.0970.
Ethyl 4-(4-Fluorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidine-
5-carboxylate (5n)16a
HRMS (EI): m/z [M + H]+ calcd for C18H24N3O2: 314.1863; found:
314.1865.
Yield: 118 mg (86%); white solid; mp 51–52 °C.
IR (KBr): 2938 (w), 1715 (vs), 1598 (s), 1578 (s), 1505 (s), 1455 (s),
1350 (s), 1060 (s), 730 (s), 640 (m), 575 (s) cm–1
.
Ethyl 2-(Benzylamino)-4-methyl-6-phenylpyrimidine-5-carboxyl-
ate (5r)14c
1H NMR (400 MHz, CDCl3): δ = 7.59–7.06 (m, 4 H, ArH), 4.10–4.04 (m,
2 H, OCH2), 3.88 [t, J = 5.60 Hz, 4 H, N(CH2)2], 2.48 (s, 3 H, CH3), 1.69–
1.54 [m, 6 H, (CH2)3], 1.00 (t, J = 6.80 Hz, 3 H, CH2CH3).
Yield: 111 mg (80%); colorless oil.
IR (KBr): 3252 (vs), 1716 (vs), 1598 (s), 1560 (s), 1532 (s), 1448 (s),
1256 (vs), 1166 (w), 1080 (vs), 1026 (s), 770 (s) cm–1
.
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1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 4.4 Hz, 2 H, ArH), 7.41–7.39
(m, 3 H, ArH), 7.32–7.30 (m, 4 H, ArH), 7.26–7.25 (m, 1 H, ArH), 6.12
(s, 1 H, NH), 4.66 (d, J = 4.0 Hz, 2 H, CH2), 4.06 (q, J = 4.8 Hz, 2 H, OCH2),
2.48 (s, 3 H, CH3), 0.95 (t, J = 4.4 Hz, 3 H, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 168.80, 161.12, 139.10, 129.43, 128.49
(2 C), 128.31 (2 C), 128.19, 128.05, 128.00, 127.80, 127.52 (2 C),
127.16 (2 C), 115.51, 61.03, 45.25, 22.69, 13.55.
IR (KBr): 2930 (s), 1714 (vs), 1591 (s), 1582 (s), 1510 (s), 1455 (s),
1370 (w), 1070 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 4.8 Hz, 4 H, ArH), 7.40 (d, J =
4.8 Hz, 1 H, ArH), 7.37–7.34 (m, 2 H, ArH), 7.21 (d, J = 5.2 Hz, 2 H,
ArH), 4.15 (q, J = 4.4 Hz, 2 H, OCH2), 2.49 (s, 3 H, Ar-CH3), 2.39 (s, 3 H,
CH3), 1.04 (t, J = 4.8 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 172.37, 168.10, 165.82, 163.51,
139.16, 137.40, 135.07 (2 C), 130.07, 129.68 (2 C), 128.38 (2 C), 128.31
(2 C), 125.89, 121.37, 61.70, 22.59, 21.33, 13.58.
HRMS (EI): m/z [M + H]+ calcd for C21H22N3O2: 348.1707; found:
348.1712.
HRMS (EI): m/z [M + H]+ calcd for C21H21N2O2S: 365.1318; found:
365.1315.
Ethyl 2-[(2-Hydroxyethyl)amino]-4-methyl-6-phenylpyrimidine-
5-carboxylate (5s)16a
Yield: 101 mg (84%); white solid; mp 100–102 °C.
Ethyl 4-(4-Methoxyphenyl)-6-methyl-2-(p-tolylthio)pyrimidine-5-
carboxylate (5w)16a
IR (KBr): 3420 (s), 3260 (vs), 1714 (vs), 1598 (s), 1558 (s), 1524 (s),
1438 (s), 1258 (vs), 1082 (s), 708 (s), 620 (vw) cm–1
.
Yield: 110 mg (70%); white solid; mp 85–87 °C.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.38 (m, 5 H, ArH), 6.02 (s, 1 H,
NH), 4.08–4.02 (m, 2 H, OCH2), 3.78 (t, J = 4.0 Hz, 2 H, CH2), 3.56 (d, J =
4.4 Hz, 2 H, NHCH2), 2.48 (s, 3 H, CH3), 0.94 (t, J = 6.8 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 168.43, 167.39, 161.62, 138.76,
129.58, 128.30 (2 C), 127.82 (2 C), 115.77, 63.39, 61.11, 44.56, 22.87,
13.50.
IR (KBr): 2935 (s), 1717 (vs), 1595 (s), 1581 (s), 1505 (s), 1453 (s),
1265 (s), 1150 (m), 1040 (s) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.53–6.85 (m, 8 H, ArH), 4.21–4.19 (m,
2 H, OCH2), 3.82 (s, 3 H, OCH3), 2.48 (s, 3 H, Ar-CH3), 2.40 (s, 3 H, CH3),
1.13 (t, J = 6.8 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 172.01, 168.50, 165.49, 162.55,
161.38, 139.11, 135.10 (2 C), 130.11 (2 C), 129.66 (2 C), 129.53,
125.90, 120.69, 113.76 (2 C), 61.73, 55.31, 22.50, 21.35, 13.76.
HRMS (EI): m/z [M + H]+ calcd for C16H20N3O3: 302.1499; found:
302.1501.
HRMS (EI): m/z [M + H]+ calcd for C22H23N2O3S: 395.1424; found:
395.1428.
Ethyl 2-(Diethylamino)-4-methyl-6-phenylpyrimidine-5-carbox-
ylate (5t)
Yield: 106 mg (85%); colorless oil.
Ethyl 4-Methyl-6-(o-tolyl)-2-(p-tolylthio)pyrimidine-5-carboxyl-
ate (5x)
IR (KBr): 2972 (s), 1718 (s), 1560 (m), 1522 (m), 1494 (m), 1458 (m),
1438 (m), 1260 (s), 1194 (m), 1080 (s), 1046 (m) cm–1
.
Yield: 110 mg (73%); colorless oil.
1H NMR (600 MHz, CDCl3): δ = 7.59–7.57 (m, 2 H, ArH), 7.40–7.39 (m,
3 H, ArH), 4.03 (q, J = 4.8 Hz, 2 H, OCH2), 3.70 [q, J = 4.8 Hz, 4 H,
N(CH2CH3)2], 2.49 (s, 3 H, CH3), 1.20 [t, J = 4.8 Hz, 6 H, N(CH2CH3)2],
0.94 (t, J = 4.8 Hz, 3 H, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 169.46, 166.77, 165.52, 159.87,
139.94, 129.08, 128.08 (2 C), 128.00 (2 C), 113.09, 60.73, 41.82 (2 C),
23.28, 13.55, 13.16 (2 C).
IR (KBr): 2980 (s), 1722 (vs), 1524 (s), 1491 (s), 1440 (s), 1377 (s),
1218 (vs), 1182 (m), 1086 (s), 807 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.50–7.48 (m, 2 H, ArH), 7.26–7.23 (m,
1 H, ArH), 7.18 (d, J = 5.2 Hz, 3 H, ArH), 7.15–7.12 (m, 1 H, ArH), 7.08
(d, J = 5.2 Hz, 1 H, ArH), 3.98–3.95 (m, 2 H, OCH2), 2.52 (s, 3 H, Ar-
CH3), 2.36 (s, 3 H, CH3), 2.13 (s, 3 H, Ph-CH3), 0.85–0.83 (m, 3 H,
CH2CH3).
HRMS (EI): m/z [M + H]+ calcd for C18H24N3O2: 314.1863; found:
314.1860.
13C NMR (150 MHz, CDCl3): δ = 172.17, 167.14, 166.14, 166.05,
139.21, 137.33, 136.12, 135.14 (2 C), 130.35, 129.74 (2 C), 129.01,
128.18, 125.70, 125.29, 122.75, 61.32, 22.84, 21.32, 19.62, 13.37.
HRMS (EI): m/z [M + H]+ calcd for C22H23N2O2S: 379.1475; found:
379.1478.
Ethyl 2-(Dibutylamino)-4-methyl-6-phenylpyrimidine-5-carbox-
ylate (5u)
Yield: 121 mg (82%); colorless oil.
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-(p-tolylthio)pyrimidine-5-
IR (KBr): 2928 (s), 1718 (vs), 1560 (m), 1544 (m), 1524 (m), 1492 (m),
carboxylate (5y)16a
1458 (m), 1438 (s), 1226 (vs), 1180 (m), 1088 (s), 1058 (s), 775 (s) cm–1
.
Yield: 129 mg (81%); white solid; mp 92–93 °C.
1H NMR (600 MHz, CDCl3): δ = 7.59–7.58 (m, 2 H, ArH), 7.40–7.39 (m,
3 H, ArH), 4.05–4.04 (m, 2 H, OCH2), 3.65–3.64 [m, 4 H, N(CH2)2], 2.49
(s, 3 H, CH3), 1.63–1.59 [m, 4 H, (CH2CH2CH3)2], 1.37–1.34 [m, 4 H,
(CH2CH2CH3)2], 0.96–0.94 [m, 9 H, OCH2CH3 (3 H), (CH2CH3)2 (6 H)].
13C NMR (150 MHz, CDCl3): δ = 169.51, 166.68, 165.37, 160.34,
139.96, 129.07, 128.11 (2 C), 127.97 (2 C), 112.92, 60.71 (2 C), 47.16
(2 C), 29.99, 23.30, 20.17 (2 C), 13.98 (2 C), 13.56.
IR (KBr): 2935 (s), 1716 (vs), 1590 (s), 1583 (s), 1515 (s), 1454 (s),
1024 (s), 595 (m) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.49 (m, 2 H, ArH), 7.46–7.44 (m,
2 H, ArH), 7.34–7.32 (m, 2 H, ArH), 7.21 (d, J = 5.2 Hz, 2 H, ArH), 4.18
(q, J = 4.8 Hz, 2 H, OCH2), 2.49 (s, 3 H, Ar-CH3), 2.39 (s, 3 H, CH3), 1.10
(t, J = 4.8 Hz, 3 H, CH2CH3).
HRMS (ESI): m/z [M + H]+ calcd for C22H32N3O2: 370.2489; found:
370.2495.
13C NMR (100 MHz, CDCl3): δ = 172.59, 167.91, 166.02, 162.11,
139.31, 136.47, 135.79, 135.13 (2 C), 129.76 (2 C), 129.72 (2 C), 128.59
(2 C), 125.70, 121.15, 61.86, 22.61, 21.34, 13.69.
HRMS (EI): m/z [M + H]+ calcd for C21H20ClN2O2S: 399.0929; found:
399.0932.
Ethyl 4-Methyl-6-phenyl-2-(p-tolylthio)pyrimidine-5-carboxylate
(5v)16a
Yield: 109 mg (75%); white solid; mp 65–66 °C.
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3934
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4-Methyl-N-phenyl-6-(p-tolylthio)pyrimidin-2-amine (5z)
(7) (a) Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M. Tetrahe-
dron Lett. 1981, 22, 4449. (b) Karlstrom, A. S. E.; Itami, K.;
Backvall, J. E. J. Org. Chem. 1999, 64, 1745. (c) Miller, J. A. Tetra-
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Commun. 1998, 1757. (b) Galbo, F. L.; Occhiato, E. G.; Guarna, A.;
Faggi, C. J. Org. Chem. 2003, 68, 6360.
Yield: 98 mg (80%); colorless oil.
IR (KBr): 3430 (s), 2920 (s), 1640 (s), 1593 (s), 1585 (s), 1510 (s), 1265
(s), 1240 (s), 1040 (s), 880 (s) cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.49 (d, J = 5.6 Hz, 2 H, ArH), 7.39–7.38
(m, 2 H, ArH), 7.28 (s, 1 H, ArH), 7.17–7.15 (m, 2 H, ArH), 7.08 (s, 1 H,
ArH), 6.95–6.93 (m, 1 H, ArH), 6.23 (s, 1 H, ArH), 2.45 (s, 3 H, Ar-CH3),
2.25 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 172.56, 166.53, 158.83, 139.91,
139.53, 136.10 (2 C), 130.35 (2 C), 128.62 (2 C), 124.80, 121.85, 118.52
(2 C), 107.76, 23.93, 21.40.
(9) (a) Ebran, J. P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup, T. J. Am.
Chem. Soc. 2007, 129, 6931. (b) Lindhardt, A. T.; Skrydstrup, T.
Chem. Eur. J. 2008, 14, 8756.
HRMS (EI): m/z [M + H]+ calcd for C18H18N3S: 308.1216; found:
308.1221.
(10) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(11) (a) Deres, K.; Schröder, C. H.; Paessens, A.; Goldmann, S.;
Hacker, H. J.; Weber, O.; Krämer, T.; Niewöhner, U.; Pleiss, U.;
Stoltefuss, J.; Graef, E.; Koletzki, D.; Masantschek, R. N. A.;
Reimann, A.; Jaeger, R.; Groß, R.; Beckermann, B.; Schlemmer,
K.-H.; Haebich, D.; Rübsamen-Waigmann, H. Science 2003, 299,
893. (b) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 6, 771. (c) Sing,
K.; Arora, D.; Poremsky, E.; Lowery, J.; Moreland, R. S. Eur. J. Med.
Chem. 2009, 44, 1997.
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Moreland, S.; Hedberg, A.; Reilly, B. C. O. J. Med. Chem. 1991, 34,
806. (b) Singh, K.; Arora, D.; Singh, K.; Singh, S. Mini-Rev. Med.
Chem. 2009, 9, 95.
Acknowledgment
We are thankful for financial support from the National Natural Sci-
ence Foundation of China (Nos. 21362032 and 21362031), the Gansu
Provincial Department of Finance, and the Natural Science Founda-
tion of Gansu Province (No. 1308RJZA299).
Supporting Information
(13) (a) Undheim, K.; Benneche, T. In Comprehensive Heterocyclic
Chemistry II; Vol. 6; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.;
McKillop, A., Eds.; Pergamon: Oxford, 1996, 93. (b) Joule, J. A.;
Mills, K. In Heterocyclic Chemistry; Blackwell Science Ltd: Cam-
bridge, 2000, 4th ed. 194. (c) Lagoja, I. M. Chem. Biodiversity
2005, 2, 1. (d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627. (e) Hill,
M. D.; Movassaghi, M. Chem. Eur. J. 2008, 14, 6836.
(14) (a) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 55.
(b) Matloobi, M.; Kappe, C. O. ACS Comb. Sci. 2007, 9, 275.
(c) Gholap, A. R.; Toti, K. S.; Shirazi, F.; Deshpande, M. V.;
Srinivasan, K. V. Tetrahedron 2008, 64, 10214.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560175.
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(19) We can obtain satisfactory results via the CuSO4·5H2O-catalyzed
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with amides 4. Using this method, we have successfully
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935

3935
T. Xing et al.
Paper
Synthesis
O
Ph
N
MeO
MeO
N
O
O
Me
O
N
H
6a, 70%
H2N
H2N
4i
Ph
N
O
Ph
N
O
CuSO4•5H2O, NaAsc
O
S
S
O
4j
MeO
N
+
t-BuONa, DMSO
100 °C, 7 h
Me
N
N
H
Me
OP(O)(OEt)2
O
Me
6b, 65%
3k
O
Me
O
Ph
N
H2N
OEt
4k
MeO
Me
O
N
N
H
OEt
6c, 68%
Scheme 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3925–3935