Dehydrosulfurative arylation with concomitant oxidative dehydrogenation for rapid access to pyrimidine derivatives

Article abstract of DOI:10.1016/j.tet.2017.10.010

This report describes a cascade reaction method for the synthesis of 2-arylpyrimidine derivatives via dehydrosulfurative carbon-carbon cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system. It provides rapid and general access to a diverse range of 2-arylpyrimidines in a single step from a wide range of 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) and arylboronic acids.

Full text of DOI:10.1016/j.tet.2017.10.010

Accepted Manuscript
Dehydrosulfurative arylation with concomitant oxidative dehydrogenation for rapid
access to pyrimidine derivatives
Hyeji Kim, Nguyen Huu Trong Phan, Hyunik Shin, Hee-Seung Lee, Jeong-Hun Sohn
PII:
S0040-4020(17)31025-6
10.1016/j.tet.2017.10.010
TET 29013
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 August 2017
Revised Date: 29 September 2017
Accepted Date: 6 October 2017
Please cite this article as: Kim H, Phan NHT, Shin H, Lee H-S, Sohn J-H, Dehydrosulfurative arylation
with concomitant oxidative dehydrogenation for rapid access to pyrimidine derivatives, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.10.010.
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Dehydrosulfurative Arylation with
Leave this area blank for abstract info.
Concomitant Oxidative Dehydrogenation for
Rapid Access to Pyrimidine Derivatives
Hyeji Kim,a Nguyen Huu Trong Phan,a Hyunik Shin,b Hee-Seung Lee,c and Jeong-Hun Sohna*
aDepartment of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764 Korea;
c
bYonsung Fine Chemicals R&D Center, Suwon 443-380 Korea, Department of Chemistry, KAIST, Daejeon 305-701
Korea
Ar
Ar
Pd(PPh3)4
CO2R
R'
CuTC, K3PO4
CO2R
R'
HN
+ ArBH(OH)2
N
PhMe, 100 oC
16-18 h
S
N
H
Ar
N
52-89%, 49 examples

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Dehydrosulfurative Arylation with Concomitant Oxidative Dehydrogenation for
Rapid Access to Pyrimidine Derivatives
Hyeji Kim,a Nguyen Huu Trong Phan,a Hyunik Shin,b Hee-Seung Lee,c and Jeong-Hun Sohna*
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764 Korea, bYonsung Fine Chemicals R&D Center, Suwon
443-380 Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This report describes a cascade reaction method for the synthesis of 2-arylpyrimidine derivatives
via dehydrosulfurative carbon-carbon cross-coupling and concomitant oxidative
dehydrogenation under a Pd/Cu catalytic system. It provides rapid and general access to a
diverse range of 2-arylpyrimidines in a single step from a wide range of 3,4-dihydropyrimidin-
1H-2-thiones (DHPMs) and arylboronic acids.
Available online
2017 Elsevier Ltd. All rights reserved
.
Keywords:
C-S bond cleavage
dehydrosulfurative coupling
oxidative dehydrogenation
pyrimidine
3,4-dihydropyrimidin-1H-2-thione
1. Introduction
system (Scheme 1). This method could provide the means for
rapid generation of fully substituted 2-arylpyrimidine derivatives
in a single step.
Organosulfur compounds are promising electrophilic partners
and alternatives to the most common organohalides or related
substrates in metal-catalyzed coupling reactions.1 In 2000,
Liebeskind and Srogl reported mechanistically unprecedented Pd-
catalyzed/Cu-mediated cross-coupling of thioesters with boronic
acids to generate ketones.2 This desulfurative cross-coupling has
extended the use of organosulfur compounds as electrophilic
partners for coupling with diverse nucleophilic partners to
produce unparalleled outcomes, which are unattainable by the
traditional carbon-carbon bond formation.3 A notable example is
the direct dehydrosulfurative carbon-carbon cross-coupling of
thioamide fragments, containing latent free-thiol functionalities
with boronic acids under microwave conditions.4 Applications of
this reaction protocol to thioamide, thiourea, or thiourethane
compounds with boronic acids, stannanes, siloxanes or terminal
alkynes have been successful.5,6 The results are unusual given that
C-S cross-coupling is typically favored in traditional cross-
coupling reactions with such substrates.7
Scheme 1. Synthetic strategy for 2-arylpyrimidines
Recently, we found that the oxidative dehydrogenation of 2-
alkylthiodihydropyrimidines to produce 2-alkylthiopyrimidines
proceeded well in the presence of a Cu catalyst with no additional
reagents.8 This reaction protocol was applied to 3,4-
dihydropyrimidin-1H-2-thiones (DHPMs) to produce 2-
arylthiopyrimidines via Cu-catalyzed C-S cross-coupling and
concomitant oxidative dehydrogenation.9 Based on these results,
we envisioned a cascade reaction combining dehydrosulfurative
arylation of the DHPM (DHPM tautomer I1) with arylboronic
acid and oxidative dehydrogenation using a Pd/Cu catalytic
The pyrimidine motifs are embedded as a privileged scaffold
of many valuable drugs, such as the hypocholesterolemic agent
rosuvastatin (Crestor) and potent anticancer drug imatinib
(Gleevec).10 Despite their prominent biological importance, the
reported synthetic strategies toward various pyrimidine
derivatives are not well developed particularly for rapid
generation of useful diversity. Most synthetic approaches to fully
substituted 2-arylpyrimidines rely on the arylation of pyrimidines
containing halides or related leaving groups at the C2 position,
Corresponding author. Tel.: +82-42-821-5479; fax: +82-42-821-8896; e-mail: sohnjh@cnu.ac.kr

2
Tetrahedron
ACCEPTED MANUSCRIPT
which require multi-step synthesis of the pyrimidine coupling the Pd source, Pd(PPh3)4 was superior to other Pd(0) or Pd(II)
partners.11,12 We report herein a one-step synthesis of fully complexes, such as Pd2(dba)3 and Pd(dba)2 or Pd(OAc)2 and
substituted 2-arylaminopyrimidines from DHPMs using a Pd/Cu PdCl2, respectively, (entries 6–9). In the absence of a base, the
catalytic system, which offers very rapid diversification, given reaction also produced the desired product (entry 10); however,
that the DHPMs possessing diverse substituents at C4-C6 (R1-R3 the base was shown to be an important factor with regards to
in Scheme 1) can be easily prepared by the Biginelli three increasing the reaction yield. The highest efficacy among the
component reaction, with versatile β-ketoesters, aldehydes, and bases examined in the studies was found for K3PO4, which gave
thiourea.13
the product 3a, with an 85% yield (entries 5 and 11-13). Lesser
amount of either Pd(PPh3)4 or CuTC reduced the reaction yield
(entries 17 and 18), and the variation of the reaction temperature
did not improve the result (entries 19 and 20). When the reaction
was performed under air, only a trace amount of the desired
product was obtained (entry 21). In all cases, we did not observe
the compounds I2.
2. Results and Discussion
The study commenced with an examination of the reaction
with DHPM 1a and 4-MeOC6H4B(OH)2 (2a) in the presence of
Pd(PPh3)4 (15 mol%), Cu(I)-thiophene-2-carboxylate (CuTC, 3.0
equiv) and K2CO3 (2.0 equiv) in dimethylformamide (DMF) at
100 °C for 16 h under Ar. The reaction afforded the desired
product 3a12a in 44% yield, which enabled further optimization
(Table 1).14,15
Table 2. Scope of the reaction with respect to
aryl(heteroaryl)boronic acida,b
Ph
Ph
Pd(PPh3)4
CO2Et
CuTC, K3PO4
CO2Et
HN
ArB(OH)2
+
N
PhMe, 100 oC
16-18 h
Table 1. Optimization of reaction conditionsa
S
N
H
Ar
N
Ph
1a
2
3
B(OH)2
Ph
CO2Et
Conditions
CO2Et
N
HN
+
Ph
N
Ph
Ph
N
S
N
H
CO2Et
CO2Et
CO2Et
N
N
N
OMe
MeO
1a
2a
3a
N
N
Yield
(%)b
Entry [Pd]
[Cu]
Base
Solvent
3b, 89%
Ph
3c, 81%
3d, 68%
1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
CuTC
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
44
Ph
N
Ph
N
CO2Et
CO2Et
2
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuI
dioxane
NMP
46
CO2Et
N
3
52
N
N
N
4
DMA
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
50
R
5
67
3e, R = F, 88%
3f, R = Cl, 68%
R
3j
, R = OMe, 78%
3k, R = Cl, 67%
3l
6
64
3n, 79%
3g
, R = Br, 74%
7
62
3h, R = NO2, 74%
, R = NO2, 52%
8
Pd(OAc)2/PPh3
PdCl2/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
45
3i
3m, R = CF3, 67%
, R = CF3, 73%
9
trace
54
Ph
N
Ph
Ph
N
CO2Et
MeO
CO2Et
CO2Et
10
11
12
13
14
15
16
17
18
19
20
21
-
N
Cs2CO3
tBuOK
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
40
Cl
N
N
N
70
MeO
85
Cl
OMe
3p, 72%
F
3o, 53%
3q, 57%
27
Ph
Ph
Ph
CuBr
21
CO2Et
CO2Et
CO2Et
Cu(OAc)2
CuTC
CuTC
CuTC
CuTC
CuTC
10
N
N
N
N
63c
40d
64e
73f
traceg
O
N
S
O
N
3r, 61%
3s, 58%
3t, 72%
aReaction conditions
: 1 (0.14 mmol), ArB(OH)2 (0.17 mmol), Pd(PPh3)4
(15 mol%), CuTC (0.42 mmol), K3PO4 (0.28 mmol) in toluene (0.8 mL) at
100 °C for 16-18 h under Ar. bIsolated yields.
aReaction conditions: 1a (0.14 mmol), 2a (0.17 mmol), [Pd] (15 mol%),
CuTC (3.0 equiv), base (2.0 equiv), and solvent (0.8 mL) at 100 °C for 16 h
c
d
under Ar. bIsolated yields. With 10 mol% of Pd(PPh3)4. With 1.5 equiv of
Under optimal reaction conditions, we investigated the
reaction with various DHPMs and arylboronic acids. With respect
to arylboronic acid, the reaction method was compatible with a
wide range of aryl- and heteroarylboronic acids (Table 2). When
the electronic effect or the substituent position at the arylboronic
acid was examined, the reaction did not vary due to either factor.
Phenylboronic acid was also suitable as a reaction partner to
CuTC. eAt 80 °C. fAt 120 °C. gUnder air.
For further optimization of the reaction, we investigated the
solvent effect and observed that PhMe was better than other
solvents such as DMF, dioxane, N-methyl-2-pyrrolidone (NMP),
or N,N-dimethylacetamide (DMA) (entries 1–5). With respect to

3
produce 3b12a in 89% yield. In addition to the initially tested 4- substituents at the C4-Ph group in the DHPMs 1 (Table 3).
ACCEPTED MANUSCRIPT
OMe group, the electron-donating 2- or 4-Me group also afforded Halide groups, F and Br produced the desired products with
good results (3c12a and 3d,12a respectively), although steric
similar yields, regardless of their positions at the C4-Ph group
hindrance might cause a lower reaction yield for the 2-Me group (4aa,11c 4ab-ac and 4ad,12a 71-79%). The electron-donating
than for the 4-Me group. Halide groups, F, Cl, and Br at the para substituent OMe group at the para or meta position also provided
position, resulted in the corresponding products 3e,f12a and 3g, the corresponding product 4ae11c (72%) or 4af16 (85%),
respectively, in 68-88% yields. Other electron-withdrawing respectively. DHPMs possessing bicycle and heteroarenes at the
substituents, such as NO2 and CF3, also yielded the desired C4 position, such as 2-naphthyl, 2-pyridinyl, and 2- and 3-
products 3h (74%) and 3i11c (73%), respectively. The arylboronic
thiophenyl groups, were also shown to be compatible for the
acids substituted at the meta position afforded the corresponding reaction method (4b, 4c,16 and 4d-e). When the DHPMs
products with moderate to good yields (3j12b and 3k-m, 52-78%), containing the Ph group at the C6 position and Ar at the C4
and bicyclic naphthalenylboronic acid resulted in 3n in 79% yield. position were treated with C6H5B(OH)2 under the optimal reaction
Disubstituted arylboronic acids were also investigated as coupling conditions the desired products 4fa17 and 4fb-fe were produced in
partners, with desired products, 3o (53%), 3p (72%), and 3q 63-87% yields. The cross-coupling reactions of DHPMs
(57%) for 3,5-dichloro-, 3,4-dimethoxy-, and 3-fluoro-4- possessing various aryl groups at the C4 position with a range of
methoxyphenylboronic acid, respectively. When the reaction arylboronic acids were also carried out to expand the scope of the
condition was applied to heteroarylboronic acids, the desired reaction method. The reaction of DHPM having 3- or 4-MeOC6H4
products 3r-t were produced in 58-72% yields.
group at the C4 position with the para-substituted boronic acids,
such as MeOC6H4B(OH)2, F3CC6H4B(OH)2, or BrC6H4B(OH)2,
resulted in 4ga-gd in 60-68% yields. In the case of the 4-FPh
group at the C4 position of DHPM, the cross-coupling reaction
with diverse arylboronic acids produced 4ha-hh in 56-76%
yields. The reactions of these DHPM substrates with 2-
naphthylboronic acid also delivered the desired products 4ia-ic in
64-73% yields.
Table 3. Scope of the reaction with respect to DHPM and
aryl(heteroaryl)boronic acida,b
Ar
Ar
Pd(PPh3)4
CuTC, K3PO4
CO2Et
CO2Et
R
HN
+
Ar
B(OH)2
N
PhMe, 100 o
16-18 h
C
S
N
H
R
Ar
N
1
2
4
According to the reaction mechanism proposed by Kappe et al.
for the dehydrosulfurative carbon–carbon cross-coupling of the
substrate possessing a thioamide fragment with boronic acid, 2-3
equivalents of CuTC are needed to enhance the polarization of the
Pd-S bond through Cu(I) coordination to S for facile ligand
exchange.4b Our result for the reaction using 1.5 equivalents of
CuTC gave a much lower reaction yield than that with 3
equivalents of CuTC, which is in agreement with this mechanistic
proposal. Regarding the mechanism of the oxidative
dehydrogenation step, we also performed the reaction of the
DHPM possessing t-Bu group at the C4 position (Scheme 2).
Previous reports of the oxidative dehydrogenation of 2-
alkylthiodihydropyrimidine containing t-Bu group at the C4
position exhibited the debutylated product as the predominant
product, which was explained by the radical mechanism.18 The
current reaction of DHPM 5 with PhB(OH)2 also produced the
debutylated product 6 as the major product (68%), which suggests
that the reaction proceeds via a radical mechanism for oxidative
dehydrogenation, presumably by Cu species present in the
reaction mixture. Based on these results a plausible reaction
mechanism of the current cascade reaction is depicted in
Supporting Information.
R
N
CO2Et
N
CO2Et
N
CO2Et
N
N
N
N
4aa, R = 4-F, 74%
4ab, R = 3-F, 79%
4ac, R = 2-F, 78%
4ad, R = 4-Br, 71%
4ae, R = 4-OMe, 72%
4af, R = 3-OMe, 85%
4c, 77%
4b, 69%
S
R
CO2Et
CO2Et
S
N
N
N
CO2Et
N
N
4e, 57%
N
4fa, R = H, 63%
4fb, R = 2-NO2, 69%
4fc, R = 3-NO2, 87%
, R = 4-NO2, 73%
4fe, R = 4-F, 71%
4d, 79%
F
4fd
X
CO2Et
CO2Et
N
N
N
X
N
CO2Et
N
R
R
N
4ga, X = 4-OMe,
R = OMe, 68%
4gb, X = 4-OMe,
R = CF3, 63%
4gc, X = 4-OMe,
R = Br, 60%
4ha, R = 3-OMe, 70%
4hb, R = 3-CF3, 74%
4hc
, R = 3-NO2, 56%
4hd, R = 4-OMe, 74%
4he, R = 4-F, 74%
4hf, R = 4-CF3, 63%
4hg, R = 4-NO2, 76%
4hh, R = 4-Br, 76%
Scheme 2. Reaction of DHPM possessing t-Bu group at the
C4 position with PhB(OH)2
4ia
, X = 4-F, 64%
4ib, X = 4-OMe, 69%
4ic, X = 3-OMe, 73%
4gd, X = 3-OMe,
R = CF3, 63%
3. Conclusion
aReaction conditions
: 1a (0.14 mmol), ArB(OH)2 (0.17 mmol), Pd(PPh3)4
We have developed a cascade reaction method for the
conversion of DHPMs to the 2-arylpyrimidines via
(15 mol%), CuTC (0.42 mmol), K3PO4 (0.28 mmol) in toluene (0.8 mL) at
100 °C for 16-18 h under Ar. bIsolated yields.
dehydrosulfurative
concomitant oxidative dehydrogenation under a Pd/Cu catalytic
system. The reaction method was compatible with a wide range of
carbon–carbon
cross-coupling
and
To determine the scope of the reaction with respect to the
DHPM substrates, the reaction was carried out with various

4
Tetrahedron
ACCEPTED MANUSCRIPT
3H); 13C NMR (75 MHz, CDCl3): δ 168.5, 165.3, 163.7, 163.5,
141.3, 138.3, 134.5, 132.3, 132.2, 131.5, 129.9, 129.2, 128.6,
128.4, 123.0, 61.7, 22.8, 21.5, 13.6.
DHPM compounds and arylboronic acids as reaction partners.
Considering the easy synthesis of DHPM substrates by the
Biginelli three component reaction, the reaction method offers a
shortcut to the preparation of 2-arylpyrimidines with rapid
diversification. Due to the biological importance of the
pyrimidine derivatives, this chemistry could serve as a platform
for rapid and general access to important substructures of
valuable drug candidates.
4.2.4.
Ethyl
4-methyl-6-phenyl-2-(o-tolyl)pyrimidine-5-
carboxylate (3d)12a (68%): White solid; mp 76-78 (lit. 77-78 ).
1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 7.3 Hz, 1H), 7.75 –
7.68 (m, 2H), 7.48 – 7.41 (m, 3H), 7.35 – 7.24 (m, 3H), 4.22 (q, J
= 7.1 Hz, 2H), 2.68 (s, 3H), 2.61 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 168.4, 166.8, 165.0, 163.2, 138.0,
137.7, 137.5, 131.4, 130.6, 130.0, 129.7, 128.5, 128.4, 126.0, 61.9,
22.8, 21.3, 13.7.
4. Experimental
4.1. General information
Common solvents were purified before use. Tolene (PhCH3) was
purified by distillation from sodium-benzophenone ketyl. N,N-
Dimethylformamide (DMF, AcroSeal), N-methyl-2-pyrrolidone
(NMP, Aldrich Sure/Seal), N,N-dimethylacetamide (DMA,
Aldrich Sure/Seal) and 1,4-dioxane (Aldrich Sure/Seal) were used
as received. All reagents were reagent grade and purified where
necessary. ‘Water’ refers to distilled water. Reactions were
monitored by thin layer chromatography (TLC) using Whatman
precoated silica gel plates. Flash column chromatography was
performed over ultra pure silica gel (230-400 mesh) from Merck.
1H NMR and 13C NMR spectra were recorded on a Bruker
AVANCE 300 (300 MHz) spectrometer using residual solvent
4.2.5. Ethyl 2-(4-fluorophenyl)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3e)12a (88%): Pale yellow solid; mp 93-95 (lit. 95-
96 ). 1H NMR (300 MHz, CDCl3): δ 8.60 – 8.50 (m, 2H), 7.77 –
7.70 (m, 2H), 7.47 (dd, J = 5.0, 1.6 Hz, 3H), 7.15 (t, J = 8.6 Hz,
2H), 4.19 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.06 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 168.4, 166.3, 165.6, 163.8,
162.8, 138.2, 133.3, 130.94, 130.86, 130.1, 128.6, 128.5, 123.3,
115.6, 115.4, 61.8, 22.7, 13.6.
4.2.6. Ethyl 2-(4-chlorophenyl)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3f)12a (68%): Pale yellow solid; mp 85-86 (lit. 84-
1
86 ). H NMR (300 MHz, CDCl3): δ 8.49 (d, J = 8.6 Hz, 2H),
peaks as an internal standard (CHCl3: δ 7.24 ppm for proton and δ
7.72 (dt, J = 5.2, 2.1 Hz, 2H), 7.49 – 7.41 (m, 5H), 4.20 (q, J =
7.1 Hz, 2H), 2.68 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 168.2, 165.5, 163.7, 162.6, 138.0, 137.4, 135.5,
132.2, 130.1, 128.7, 128.5, 128.4, 123.5, 61.8, 22.8, 13.6.
1
77.0 ppm for carbon). Multiplicities for H NMR are designated
as: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of
doublets, dt = doublet of triplets, td = triplet of doublets, m =
multiplet. Infrared spectra (IR) were recorded on JASCO FT/IR-
4100 spectrometer and are reported in reciprocal centimeter (cm-
1). High resolution mass spectra (HRMS) were obtained on
BrukermicroTOF-Q.
4.2.7. Ethyl 2-(4-bromophenyl)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3g) (74%): White solid; mp 94-95 . 1H NMR (300
MHz, CDCl3): δ 8.42 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 6.5, 3.0
Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 5.2, 1.6 Hz, 1H),
4.19 (q, J = 7.1 Hz, 1H), 2.67 (s, 1H), 1.06 (t, J = 7.1 Hz, 1H); 13
C
4.2. General procedure for synthesis of 2-arylpyrimidines 3
and 4 from DHPMs 1.
NMR (75 MHz, CDCl3): δ 168.3, 165.5, 163.7, 162.7, 138.0,
136.0, 131.7, 130.2, 130.1, 128.5, 128.4, 125.9, 123.6, 61.8, 22.8,
13.6; IR (film) cm-1: 3062, 2981, 2931, 2356, 1724, 1577, 1538,
1434, 1392, 1261, 1172, 1072, 1010, 921, 852, 809, 763, 694, 574,
536, 478, 455; HRMS (ESI) (m/z): calcd for C20H18BrN2O2
[M+H]+ 397.0522, found 397.0519.
To a mixture of DHPM 1 (0.14 mmol), CuTC (0.42 mmol),
Pd(PPh3)4 (15 mol%) and K3PO4 (0.28 mmol) in PhCH3 (0.8 mL)
was added arylboronic acid (0.17 mmol), and the mixture was
degassed with Ar. After stirring at 100 °C for 16–18 h under Ar,
the resulting mixture was filtered through a silica gel pad and
washed with EtOAc (20 mL). The filtrate was washed with water
(2 mL) and brine (2 mL), dried with MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (ethyl
acetate/hexane, 1/10) to give 2-arylpyrimidine 3 or 4.
4.2.8. Ethyl 4-methyl-2-(4-nitrophenyl)-6-phenylpyrimidine-5-
1
carboxylate (3h) (74%): Pale yellow solid; mp 113-114 . H
NMR (300 MHz, CDCl3): δ 8.71 (d, J = 8.8 Hz, 2H), 8.30 (d, J =
8.9 Hz, 2H), 7.78 – 7.68 (m, 2H), 7.53 – 7.42 (m, 3H), 4.22 (q, J
= 7.1 Hz, 2H), 2.69 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 168.1, 166.0, 163.9, 161.6, 149.5, 142.9,
137.7, 130.4, 129.5, 128.7, 128.5, 124.5, 123.7, 62.0, 22.7, 13.6;
IR (film) cm-1: 3386, 2985, 2086, 1724, 1643, 1538, 1434, 1346,
1261, 1172, 1079, 1010, 852, 771, 744, 698, 647, 578, 501, 455,
412; HRMS (ESI) (m/z): calcd for C20H17N3O4Na [M+Na]+
386.1117, found 386.1113.
4.2.1. Ethyl 2-(4-methoxyphenyl)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3a)12a (85 %): White solid; mp 57-59
(lit. 57-
1
59 )) H NMR (300 MHz, CDCl3): δ 8.50 (d, J = 8.8 Hz, 2H),
7.73 (dd, J = 6.6, 2.6 Hz, 2H), 7.48 – 7.43 (m, 3H), 6.98 (d, J =
8.8 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.66 (s, 3H),
1.05 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.9,
165.2, 163.9, 163.2, 162.34, 138.2, 130.6, 130.1, 128.5, 128.5,
122.6, 113.9, 61.8, 55.4, 22.7, 13.7.
4.2.9.
Ethyl
4-methyl-6-phenyl-2-(4-
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (3i)11c (73%):
Colourless oil. 1H NMR (300 MHz, CDCl3): δ 8.66 (d, J = 8.3 Hz,
2H), 7.78 – 7.67 (m, 4H), 7.52 – 7.44 (m, 3H), 4.21 (q, J = 7.1 Hz,
2H), 2.71 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.3, 165.8, 163.8, 162.4, 140.5, 138.0, 132.8, 132.5,
130.3, 129.0, 128.6, 128.5, 125.52, 125.48, 125.44, 124.1, 122.8,
61.9, 22.7, 13.6.
4.2.2.
Ethyl
4-methyl-2,6-diphenylpyrimidine-5-carboxylate
1
(3b)12a (89 %): White solid; mp 66-67 (lit. 66-67 ). H NMR
(300 MHz, CDCl3): δ 8.55 (dd, J = 6.7, 3.0 Hz, 2H), 7.75 (dd, J =
6.5, 3.1 Hz, 2H), 7.47 (dt, J = 5.6, 4.2 Hz, 6H), 4.20 (q, J = 7.1
Hz, 2H), 2.70 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 168.3, 165.3, 163.9, 163.5, 138.1, 136.7, 131.3,
130.2, 128.8, 128.6, 128.5, 123.4, 61.9, 22.7, 13.7.
4.2.10. Ethyl 2-(3-chlorophenyl)-4-methyl-6-phenylpyrimidine-5-
carboxylate (3k) (67%): White solid; mp 90-92 . 1H NMR (300
MHz, CDCl3): δ 8.53 (d, J = 1.8 Hz, 1H), 8.43 (dt, J = 7.3, 1.5 Hz,
1H), 7.77 – 7.68 (m, 2H), 7.50 – 7.39 (m, 5H), 4.20 (q, J = 7.1 Hz,
2H), 2.68 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.3, 165.7, 163.8, 162.5, 139.0, 138.0, 134.7, 131.0,
130.2, 129.8, 128.7, 128.6, 128.5, 126.8, 123.9, 61.8, 22.7, 13.6;
4.2.3.
Ethyl
4-methyl-6-phenyl-2-(p-tolyl)pyrimidine-5-
carboxylate (3c)12a (81%): White solid; mp 61-63 (lit. 61-63 ).
1H NMR (300 MHz, CDCl3): δ 8.44 (d, J = 8.0 Hz, 2H), 7.76 –
7.71 (m, 2H), 7.50 – 7.44 (m, 3H), 7.27 (t, J = 7.2 Hz, 2H), 4.19
(q, J = 7.0 Hz, 2H), 2.69 (s, 3H), 2.41 (s, 3H), 1.06 (t, J = 6.9 Hz,

5
IR (film) cm-1: 3066, 2981, 2931, 1955, 1724, 1538, 1434, 1369,
4.2.16.
Ethyl
2-(3-fluoro-4-methoxyphenyl)-4-methyl-6-
ACCEPTED MANUSCRIPT
1253, 1168, 1083, 1014, 902, 833, 763, 694, 578, 532, 466; phenylpyrimidine-5-carboxylate (3q) (57%): White solid; mp 64-
HRMS (ESI) (m/z): calcd for C20H17ClN2O2Na [M+Na]+ 66 . H NMR (300 MHz, CDCl3): δ 8.29 (dd, J = 15.5, 4.8 Hz,
1
375.0876, found 375.0869.
2H), 7.72 (dd, J = 6.5, 3.0 Hz, 2H), 7.50 – 7.41 (m, 3H), 7.02 (t, J
= 8.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.66 (s, 3H),
1.06 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.4,
165.4, 163.7, 162.3, 153.9, 150.7, 150.4, 138.1, 130.1, 128.54,
128.45, 125.2, 123.0, 116.4, 116.2, 112.6, 61.9, 56.2, 22.8, 13.7;
IR (film) cm-1: 3066, 2973, 2935, 2040, 1893, 1724, 1616, 1538,
1442, 1392, 1272, 1234, 1211, 1180, 1133, 1079, 1022, 960, 890,
856, 809, 767, 698, 647, 609, 559, 501, 420; HRMS (ESI) (m/z):
calcd for C21H19FN2O3Na [M+Na]+ 389.1277, found 389.1272.
4.2.11. Ethyl 4-methyl-2-(3-nitrophenyl)-6-phenylpyrimidine-5-
1
carboxylate (3l) (52%): Pale yellow solid; mp 101-103 . H
NMR (300 MHz, CDCl3): δ 9.42 – 9.31 (m, 1H), 8.89 (d, J = 7.8
Hz, 1H), 8.33 (dd, J = 8.1, 1.5 Hz, 1H), 7.79 – 7.70 (m, 2H), 7.65
(t, J = 8.0 Hz, 1H), 7.53 – 7.45 (m, 3H), 4.22 (q, J = 7.1 Hz, 2H),
2.70 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 168.0, 165.9, 163.9, 161.4, 148.8, 139.0, 137.7, 134.4,
130.3, 129.5, 128.6, 125.5, 124.4, 123.6, 62.0, 22.8, 13.7; IR
(film) cm-1: 3432, 3085, 2981, 2931, 2869, 1724, 1581, 1535, 4.2.17. Ethyl 2-(benzofuran-2-yl)-4-methyl-6-phenylpyrimidine-5-
1438, 1349, 1257, 1168, 1079, 1014, 921, 860, 809, 771, 732, 694, carboxylate (3r) (61%): Pale yellow solid; mp 147-149 . H
1
655, 586, 468, 416; HRMS (ESI) (m/z): calcd for C20H17N3O4Na NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.73 (dd, J = 5.6, 2.0 Hz,
[M+Na]+ 386.1117, found 386.1109.
2H), 7.67 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 5.1 Hz, 3H), 7.38 (t, J =
7.8 Hz, 1H), 7.31 – 7.24 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.72 (s,
3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
167.9, 165.8, 164.1, 157.1, 156.1, 153.1, 137.7, 130.2, 128.6,
128.4, 128.2, 126.5, 123.4, 122.2, 112.4, 111.0, 61.9, 22.9, 13.6;
IR (film) cm-1: 4057, 3941, 3791, 3656, 3062, 2981, 2935, 2680,
2591, 2487, 2402, 2348, 2260, 2186, 2144, 2090, 1943, 1897,
1859, 1724, 1581, 1528, 1438, 1407, 1268, 1226, 1087, 1010, 960,
929, 856, 813, 748, 698, 651, 613, 574, 497, 416; HRMS (ESI)
(m/z): calcd for C22H19N2O3Na [M+Na]+ 381.1215, found
381.1199.
4.2.12.
Ethyl
4-methyl-6-phenyl-2-(3-
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (3m) (67%):
White solid; mp 77-79 . 1H NMR (300 MHz, CDCl3): δ 8.82 (s,
1H), 8.75 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 6.4, 3.2 Hz, 3H), 7.58
(dd, J = 17.2, 9.4 Hz, 1H), 7.51 – 7.46 (m, 3H), 4.21 (q, J = 7.1
Hz, 2H), 2.70 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 168.2, 165.7, 163.8, 162.2, 137.9, 131.8, 131.2,
130.8, 130.3, 129.1, 128.6, 128.5, 127.6, 125.5, 124.0, 122.4, 62.0,
22.9, 13.7; IR (film) cm-1: 3066, 2985, 2935, 1959, 1909, 1812,
1727, 1542, 1496, 1442, 1396, 1319, 1257, 1168, 1126, 1083,
1014, 925, 840, 806, 767, 694, 651, 570, 466, 412; HRMS (ESI) 4.2.18.
Ethyl
2-(benzo[b]thiophen-2-yl)-4-methyl-6-
(m/z): calcd for C21H17F3N2O2Na [M+Na]+ 409.1140, found phenylpyrimidine-5-carboxylate (3s) (58%): Pale yellow solid;
409.1137.
mp 154-156 . 1H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 7.91
– 7.81 (m, 2H), 7.75 (dd, J = 7.0, 2.6 Hz, 2H), 7.51 – 7.46 (m,
3H), 7.40 – 7.35 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H),
1.07 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.20,
165.73, 163.83, 160.76, 142.80, 142.24, 140.16, 137.80, 130.25,
128.59, 128.53, 126.82, 125.95, 125.04, 124.66, 123.38, 122.72,
61.83, 22.61, 13.55; IR (film) cm-1: 3413, 2985, 2337, 2098, 1720,
1643, 1531, 1438, 1388, 1257, 1180, 1087, 1014, 848, 806, 759,
694, 647, 559, 470, 443; HRMS (ESI) (m/z): calcd for
C22H18N2O2SNa [M+Na]+ 397.0987, found 397.1008.
4.2.13. Ethyl 4-methyl-2-(naphthalen-2-yl)-6-phenylpyrimidine-5-
1
carboxylate (3n) (79%): Pale yellow solid; mp 148-150 . H
NMR (300 MHz, CDCl3): δ 9.11 (s, 1H), 8.65 (d, J = 8.5 Hz, 1H),
7.90 (ddd, J = 26.1, 20.7, 5.8 Hz, 5H), 7.50 (s, 5H), 4.22 (q, J =
7.0 Hz, 2H), 2.74 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H),; 13C NMR (75
MHz, CDCl3): δ 168.3, 165.4, 163.8, 163.6, 138.2, 134.9, 134.2,
133.2, 132.3, 132.2, 131.5, 130.1, 129.3, 129.2, 128.53, 128.48,
128.40, 127.7, 127.3, 126.2, 125.3, 123.4, 61.8, 22.8, 13.7; IR
(film) cm-1: 3058, 2981, 2931, 1724, 1538, 1473, 1438, 1392,
1265, 1238, 1199, 1160, 1087, 1014, 956, 914, 860, 813, 771, 701, 4.2.19.
Ethyl 2-(furan-2-yl)-4-methyl-6-phenylpyrimidine-5-
1
640, 570, 509, 470, 412; HRMS (ESI) (m/z): calcd for carboxylate (3t) (72%): Brown viscous oil. H NMR (300 MHz,
C24H20N2O2Na [M+Na]+ 391.1422, found 391.1407.
CDCl3): δ 7.72 – 7.60 (m, 3H), 7.49 – 7.39 (m, 4H), 6.57 (dd, J =
3.4, 1.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.04 (t, J
= 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.0, 165.6, 164.1,
156.7, 151.8, 145.6, 137.9, 130.1, 128.5, 128.4, 114.9, 112.3, 61.8,
22.8, 13.6; IR (film) cm-1: 3309, 3120, 3066, 2981, 2931, 2753,
2649, 2564, 2356, 2090, 1955, 1893, 1724, 1581, 1538, 1488,
1434, 1373, 1268, 1187, 1083, 1010, 948, 887, 856, 809, 763, 698,
651, 509, 474, 435, 420; HRMS (ESI) (m/z): calcd for
C18H16N2O3 [M+Na]+ 331.1059, found 331.1055.
4.2.14.
Ethyl
2-(3,5-dichlorophenyl)-4-methyl-6-
phenylpyrimidine-5-carboxylate (3o) (53%): White solid; mp 86-
1
87 . H NMR (300 MHz, CDCl3): δ 8.43 (d, J = 1.9 Hz, 2H),
7.78 – 7.63 (m, 2H), 7.55 – 7.36 (m, 4H), 4.21 (q, J = 7.1 Hz, 2H),
2.67 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.1, 165.9, 163.9, 161.3, 140.2, 137.8, 135.4, 130.8,
130.3, 128.6, 128.5, 127.0, 124.3, 61.9, 22.7, 13.6; IR (film) cm-1:
3444, 3085, 2981, 2356, 1959, 1724, 1646, 1538, 1442, 1361,
1261, 1176, 1083, 1014, 860, 840, 798, 767, 694, 659, 578, 516, 4.2.20. Ethyl 4-(4-fluorophenyl)-6-methyl-2-phenylpyrimidine-5-
482, 431; HRMS (ESI) (m/z): calcd for C20H16Cl2N2O2Na carboxylate (4aa)11c (74%): White solid; mp 84-86
(lit. 85-
[M+Na]+ 409.0487, found 409.0474.
86 ). H NMR (300 MHz, CDCl3): δ 8.53 (dt, J = 3.7, 2.8 Hz,
1
2H), 7.81 – 7.69 (m, 2H), 7.49 (dd, J = 6.4, 3.9 Hz, 3H), 7.21 –
7.10 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.68 (s, 2H), 1.13 (t, J =
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.4, 165.5, 163.7,
162.3, 136.9, 134.2, 131.1, 130.6, 128.6, 128.5 123.2, 115.8,
115.5, 61.9, 22.8, 14.1.
4.2.15.
Ethyl
2-(3,4-dimethoxyphenyl)-4-methyl-6-
phenylpyrimidine-5-carboxylate (3p) (72%): Pale yellow solid;
mp 91-93 . 1H NMR (300 MHz, CDCl3): δ 8.19 (dd, J = 8.5, 2.0
Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.49 –
7.43 (m, 3H), 6.95 (d, J = 8.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
4.00 (s, 3H), 3.94 (s, 3H), 2.68 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H); 4.2.21. Ethyl 4-(3-fluorophenyl)-6-methyl-2-phenylpyrimidine-5-
1
13C NMR (75 MHz, CDCl3): δ 168.5, 165.3, 163.8, 163.2, 151.8, carboxylate (4ab) (79%): White solid; mp 64-65 . H NMR
148.9, 138.3, 130.9, 129.8, 128.51, 128.46, 122.7, 122.4, 111.2, (300 MHz, CDCl3): δ 8.57 – 8.49 (m, 2H), 7.71 (dd, J = 13.3, 7.3
110.7, 61.8, 56.0, 22.8, 13.7; IR (film) cm-1: 4057, 3424, 3062, Hz, 2H), 7.50 – 7.47 (m, 4H), 7.23 – 7.13 (m, 1H), 4.23 (q, J =
2938, 2838, 2734, 2684, 2638, 2588, 2464, 2341, 2275, 2032, 6.9 Hz, 2H), 2.69 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (75
1959, 1889, 1724, 1596, 1535, 1454, 1430, 1392, 1268, 1180, MHz, CDCl3): δ 167.8, 165.5, 163.5, 140.1, 136.4, 133.4, 132.3,
1141, 1083, 1025, 956, 921, 875, 860, 767, 617, 563, 501, 458, 132.2, 131.54, 131.50, 131.46, 130.2, 130.1, 128.8, 128.60,
412; HRMS (ESI) (m/z): calcd for C22H22N2O4Na [M+Na]+ 128.57, 128.4, 124.2, 117.3, 117.0, 115.8, 115.5, 62.0, 22.6, 13.7;
401.1477, found 401.1459.
IR (film) cm-1: 3372, 2994, 2082, 1643, 1542, 1484, 1434, 1392,
1369, 1265, 1222, 1172, 1141, 1079, 752, 690, 512; HRMS (ESI)

6
Tetrahedron
ACCEPTED MANUSCRIPT
(m/z): calcd for C20H17FN2O2Na [M+Na]+ 359.1172, found 128.3, 120.6, 62.2, 22.6, 13.9; IR (film) cm-1: 3436, 3104, 3073,
359.1163.
2981, 2938, 2480, 2360, 2337, 2105, 1967, 1913, 1724, 1646,
1538, 1430, 1265, 1168, 1145, 1076, 1018, 917, 852, 767, 701,
605, 566, 539, 443, 416; HRMS (ESI) (m/z): calcd for
C18H16N2O2SNa [M+Na]+ 347.0830, found 347.0817.
4.2.22. Ethyl 4-(2-fluorophenyl)-6-methyl-2-phenylpyrimidine-5-
1
carboxylate (4ac) (78%): White solid; mp 84-85 . H NMR
(300 MHz, CDCl3): δ 8.53 (dt, J = 7.7, 3.9 Hz, 2H), 7.69 (td, J =
7.5, 1.7 Hz, 1H), 7.50 – 7.42 (m, 4H), 7.28 (td, J = 7.5, 1.0 Hz, 4.2.29. Ethyl 4-methyl-2-phenyl-6-(thiophen-3-yl)pyrimidine-5-
1H), 7.15 – 7.07 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.78 (s, 3H),
carboxylate (4e) (57%): Pale yellow solid; mp 48-50 . 1H NMR
1.06 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.0, (300 MHz, CDCl3): δ 8.56 – 8.46 (m, 2H), 7.58 – 7.44 (m, 5H),
166.5, 164.0, 161.5, 160.5, 158.2, 136.9, 131.5, 131.4, 131.2, 7.11 (dd, J = 4.7, 4.2 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.61 (s,
128.7, 128.5, 124.43, 124.38, 115.6, 115.3, 61.5, 23.7, 13.6; IR
3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
(film) cm-1: 3436, 2989, 2078, 1724, 1643, 1538, 1496, 1434, 168.6, 164.8, 163.4, 154.9, 141.6, 136.7, 131.1, 130.7, 128.7,
1369, 1261, 1172, 1079, 1014, 921, 759, 694, 536, 497, 439; 128.5, 128.3, 120.5, 62.3, 22.5, 13.9; IR (film) cm-1: 3428, 3174,
HRMS (ESI) (m/z): calcd for C20H17FN2O2Na [M+Na]+ 359.1172, 3070, 2981, 2931, 2749, 2480, 2360, 2337, 2105, 1909, 1724,
found 359.1169.
1538, 1430, 1261, 1168, 1145, 1076, 1018, 917, 856, 763, 701,
605, 566, 528, 478, 439; HRMS (ESI) (m/z): calcd for
C18H16N2O2SNa [M+Na]+ 347.0830, found 347.0821.
4.2.23. Ethyl 4-(4-bromophenyl)-6-methyl-2-phenylpyrimidine-5-
carboxylate (4ad)12a (71%): Pale yellow solid; mp 86-88
(lit.
1
87-88 ). H NMR (300 MHz, CDCl3): δ 8.52 (dd, J = 6.6, 3.1 4.2.30. Ethyl 2,4,6-triphenylpyrimidine-5-carboxylate (4fa)17
1
Hz, 2H), 7.66 – 7.57 (m, 4H), 7.51 – 7.47 (m, 3H), 4.23 (q, J = (63%): Pale yellow solid; mp 106-108 . H NMR (300 MHz,
7.1 Hz, 2H), 2.69 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (75 CDCl3): δ 8.62 (dt, J = 7.6, 3.7 Hz, 2H), 7.83 – 7.75 (m, 4H), 7.52
MHz, CDCl3): δ 168.2, 165.6, 163.7, 162.4, 137.0, 136.8, 131.7, – 7.45 (m, 9H), 4.08 (q, J = 7.1 Hz, 2H), 0.96 (t, J = 7.1 Hz, 3H);
131.2, 130.1, 128.64, 128.56, 124.7, 123.2, 62.0, 22.8, 13.8.
13C NMR (75 MHz, CDCl3): δ 168.4, 164.5, 163.8, 137.9, 137.0,
132.3, 131.2, 130.0, 128.8, 128.54, 128.48, 123.1, 61.9, 13.5.
4.2.24. Ethyl 4-(4-methoxyphenyl)-6-methyl-2-phenylpyrimidine-
5-carboxylate (4ae)11c (72%): Pale yellow solid; mp 64-65 (lit. 4.2.31.
Ethyl
4-(2-nitrophenyl)-2,6-diphenylpyrimidine-5-
1
1
61-63 ). H NMR (300 MHz, CDCl3): δ 8.57 – 8.49 (m, 2H), carboxylate (4fb) (69%): Pale yellow solid; mp 159-161 . H
7.75 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 4.4, 2.0 Hz, 3H), 6.98 (d, J NMR (300 MHz, CDCl3): δ 8.53 (dd, J = 7.6, 2.1 Hz, 2H), 8.21 (d,
= 8.6 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.66 (s, 3H), J = 8.1 Hz, 1H), 7.81 (dd, J = 7.1, 2.4 Hz, 2H), 7.68 (dtd, J = 15.5,
1.16 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.9, 7.5, 3.9 Hz, 2H), 7.55 – 7.40 (m, 7H), 3.93 (q, J = 7.1 Hz, 2H),
165.2, 163.6, 162.8, 161.4, 137.3, 131.0, 130.5, 130.2, 128.6, 0.83 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.1,
128.5, 122.9, 114.0, 61.8, 55.3, 22.7, 13.7.
164.9, 164.0, 163.8, 148.0, 137.9, 136.7, 133.6, 133.2, 131.4,
130.9, 130.3, 130.1, 128.9, 128.7, 128.54, 128.51, 124.5, 122.2,
61.8, 13.3; IR (film) cm-1: 3436, 2086, 1694, 1531, 1446, 1353,
1265, 1172, 1068, 748, 694, 543, 501, 487; HRMS (ESI) (m/z):
calcd for C25H19N3O4Na [M+Na]+ 448.1273, found 448.1251.
4.2.25. Ethyl 4-(3-methoxyphenyl)-6-methyl-2-phenylpyrimidine-
5-carboxylate (4af)16 (85%): White solid; mp 97-99 . H NMR
1
(300 MHz, CDCl3): δ 8.57 – 8.46 (m, 2H), 7.63 (dt, J = 7.5, 1.8
Hz, 1H), 7.50 – 7.37 (m, 4H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 6.90
(d, J = 8.3 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 2.76 (s, 4.2.32.
Ethyl
4-(3-nitrophenyl)-2,6-diphenylpyrimidine-5-
1
2H), 1.00 (t, J = 7.1, Hz, 3H); 13C NMR (75 MHz, CDCl3): δ carboxylate (4fc) (87%): Pale yellow solid; mp 121-123 . H
167.2, 165.7, 164.0, 163.0, 156.4, 137.3, 130.94, 130.90, 128.6, NMR (300 MHz, CDCl3): δ 8.68 (d, J = 1.5 Hz, 1H), 8.61 (dd, J =
128.4, 128.2, 124.0, 120.9, 110.2, 60.9, 55.1, 23.6, 13.6.
5.7, 2.2 Hz, 2H), 8.37 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.7 Hz,
1H), 7.79 (dd, J = 5.6, 2.1 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.55
– 7.46 (m, 6H), 4.12 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 168.0, 165.1, 164.1, 161.9, 148.2,
139.4, 137.6, 136.5, 134.7, 131.6, 130.3, 129.6, 128.8, 128.63,
128.60, 128.5, 124.7, 123.8, 123.0, 62.3, 13.5; IR (film) cm-1:
3432, 3066, 2977, 2927, 2861, 2684, 2557, 2445, 2337, 2256,
2132, 2078, 1967, 1913, 1816, 1727, 1581, 1531, 1442, 1353,
1265, 1172, 1072,m 1014, 910, 863, 813, 740, 694, 628, 539, 478,
455; HRMS (ESI) (m/z): calcd for C25H19N3O4Na [M+Na]+
448.1273, found 448.1261.
4.2.26. Ethyl 4-methyl-6-(naphthalen-2-yl)-2-phenylpyrimidine-5-
carboxylate (4b) (60%): Yellow solid; mp 127-129 . H NMR
1
(300 MHz, CDCl3): δ 8.57 (dd, J = 6.3, 2.7 Hz, 2H), 8.24 (s, 1H),
7.99 – 7.82 (m, 4H), 7.57 – 7.44 (m, 5H), 4.19 (q, J = 7.2 Hz, 2H),
2.71 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 168.6, 165.4, 163.7, 163.4, 137.2, 135.5, 133.9, 133.0,
131.1, 128.69, 128.65, 128.5, 128.3, 127.7, 127.2, 126.5, 125.6,
123.6, 61.8, 22.9, 13.7; IR (film) cm-1: 3417, 3054, 2981, 2935,
2564, 2418, 2345, 2306, 2113, 1959, 1920, 1724, 1635, 1538,
1434, 1396, 1365, 1261, 1164, 1079, 960, 898, 863, 817, 771, 701,
647, 563, 474, 443; HRMS (ESI) (m/z): calcd for C24H20N2O2Na 4.2.33.
Ethyl
4-(4-nitrophenyl)-2,6-diphenylpyrimidine-5-
1
[M+Na]+ 391.1422, found 391.1422.
carboxylate (4fd) (73%): White solid; mp 149-151 . H NMR
(300 MHz, CDCl3): δ 8.60 (dd, J = 7.3, 2.2 Hz, 2H), 8.35 (d, J =
8.7 Hz, 2H), 7.94 (d, J = 8.7 Hz, 2H), 7.78 (dd, J = 7.2, 2.2 Hz,
2H), 7.56 – 7.47 (m, 6H), 4.08 (q, J = 7.1 Hz, 2H), 0.98 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.8, 165.1, 164.1,
162.3, 148.7, 144.0, 137.6, 136.5, 132.3, 132.2, 131.6, 130.4,
129.7, 128.8, 128.63, 128.61, 128.5, 123.6, 123.2, 62.2, 13.5; IR
(film) cm-1: 3387, 2977, 2927, 2857, 2360, 1913, 1820, 1727,
1531, 1450, 1349, 1268, 1172, 1068, 1014, 860, 829, 752, 694,
640, 609, 539, 509, 470, 428; HRMS (ESI) (m/z): calcd for
C25H19N3O4Na [M+Na]+ 448.1273, found 448.1257.
4.2.27. Ethyl 4-methyl-2-phenyl-6-(pyridin-2-yl)pyrimidine-5-
1
carboxylate (4c)16 (77%): White solid; mp 95-97 . H NMR
(300 MHz, CDCl3): δ 8.69 – 8.45 (m, 4H), 7.87 (td, J = 7.8, 1.6
Hz, 1H), 7.57 – 7.44 (m, 3H), 7.37 (dd, J = 6.7, 4.9 Hz, 1H), 4.41
(q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 168.8, 165.9, 163.4, 159.7, 154.2,
148.4, 137.2, 137.1, 131.0, 128.6, 128.5, 125.1, 123.1, 123.1, 61.5,
22.4, 13.9.
4.2.28. Ethyl 4-methyl-2-phenyl-6-(thiophen-2-yl)pyrimidine-5-
1
4.2.34.
Ethyl
4-(4-fluorophenyl)-2,6-diphenylpyrimidine-5-
1
carboxylate (4d) (79%): Pale yellow viscous oil. H NMR (300
carboxylate (4fe) (71%): White solid; mp 106-108 . H NMR
(300 MHz, CDCl3): δ 8.60 (dd, J = 6.5, 2.9 Hz, 2H), 7.79 (ddd, J
= 11.3, 6.1, 2.8 Hz, 4H), 7.49 (dd, J = 7.0, 3.5 Hz, 6H), 7.18 (t, J
= 8.6 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 0.98 (t, J = 7.1 Hz, 3H);
MHz, CDCl3): δ 8.58 – 8.44 (m, 2H), 7.58 – 7.44 (m, 5H), 7.11
(dd, J = 5.0, 3.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H),
1.35 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.7,
164.8, 163.4, 154.9, 141.6, 136.8, 131.1, 130.7, 128.7, 128.5,

7
13C NMR (75 MHz, CDCl3): δ 168.4, 165.7, 164.6, 163.8, 163.2, 593, 555, 509, 431; HRMS (ESI) (m/z): calcd for
ACCEPTED MANUSCRIPT
162.3, 137.9, 136.9, 134.0, 131.3, 130.8, 130.6, 130.1, 128.7, C21H19FN2O3Na [M+Na]+ 389.1277, found 389.1279.
128.52, 128.49, 122.9, 115.8, 115.5, 62.0, 13.5 IR (film) cm-1:
3328, 2800, 2360, 1909, 1731, 1531, 1450, 1373, 1265, 1168,
1068, 1014, 698, 532, 482, 404; HRMS (ESI) (m/z): calcd for
C25H19FN2O2Na [M+Na]+ 421.1328, found 421.1315.
4.2.40.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-(3-
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (4hb) (74%):
1
Pale yellow solid; mp 51-53 . H NMR (300 MHz, CDCl3): δ
8.80 (s, 1H), 8.73 (d, J = 7.8 Hz, 1H), 7.81 – 7.70 (m, 3H), 7.60 (t,
4.2.35. Ethyl 2,4-bis(4-methoxyphenyl)-6-methylpyrimidine-5- J = 7.8 Hz, 1H), 7.17 (t, J = 8.5 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H),
carboxylate (4ga) (68%): Yellow viscous oil. 1H NMR (300 MHz, 2.69 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 8.49 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 6.97 CDCl3): δ 168.23, 165.91, 162.57, 162.31, 137.85, 134.01, 131.81,
(d, J = 7.6 Hz, 4H), 4.23 (q, J = 7.1 Hz, 2H), 3.86 (d, J = 3.0 Hz, 130.94, 130.69, 130.61, 129.08, 127.65, 125.52, 123.88, 123.85,
6H), 2.63 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, 115.85, 115.64, 61.98, 22.73, 13.66; IR (film) cm-1: 3077, 2981,
CDCl3): δ 169.0, 165.0, 163.2, 162.7, 162.1, 161.2, 130.7, 130.3, 2935, 2356, 1909, 1727, 1604, 1542, 1515, 1446, 1369, 1322,
130.1, 129.9, 122.1, 113.9, 113.8, 61.7, 55.3, 22.8, 13.8; IR (film) 1253, 1164, 1126, 1079, 1014, 925, 848, 802, 755, 694, 651, 590,
cm-1: 3423, 2931, 2838, 2699, 2337, 2040, 1901, 1724, 1604, 563, 509, 455; HRMS (ESI) (m/z): calcd for C21H16F4N2O2Na
1581, 1535, 1427, 1396, 1257, 1172, 1076, 1029, 844, 806, 755, [M+Na]+ 427.1046, found 427.1041.
593, 563, 493, 451, 416; HRMS (ESI) (m/z): calcd for
C22H22N2O4Na [M+Na]+ 401.1477, found 401.1459.
4.2.41.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-(3-
nitrophenyl)pyrimidine-5-carboxylate (4hc) (56%): White solid;
1
4.2.36.
Ethyl
4-(4-methoxyphenyl)-6-methyl-2-(4- mp 106-107 . H NMR (300 MHz, CDCl3): δ 9.41 – 9.35 (m,
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (4gb) (63%): 1H), 8.89 (d, J = 7.8 Hz, 1H), 8.39 – 8.27 (m, 1H), 7.78 – 7.71 (m,
White solid; mp 82-83 . 1H NMR (300 MHz, CDCl3): δ 8.65 (d, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.49 (dd, J = 5.1, 1.9 Hz, 2H), 4.22
J = 8.2 Hz, 2H), 7.74 (t, J = 8.4 Hz, 4H), 6.99 (d, J = 8.8 Hz, 2H),
(q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C
4.27 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.67 (s, 3H), 1.17 (t, J = 7.1 NMR (75 MHz, CDCl3): δ 167.94, 166.00, 162.58, 161.35,
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.7, 165.5, 162.9, 148.74, 138.81, 134.27, 133.70, 130.66, 130.55, 129.51, 125.53,
162.2, 161.6, 140.6, 132.6, 132.3, 130.2, 130.1, 128.9, 125.5, 124.19, 123.55, 115.91, 115.62, 62.10, 22.79, 13.75; IR (film) cm-
123.5, 123.8, 114.1, 61.9, 55.4, 22.7, 13.7; IR (film) cm-1: 3440, 1: 3444, 2985, 2360, 1724, 1646, 1585, 1535, 1438, 1349, 1257,
3004, 2842, 2553, 2086, 1724, 1643, 1619, 1538, 1438, 1373, 1168, 1079, 1010, 917, 852, 809, 740, 694, 655, 505, 478, 443,
1322, 1261, 1168, 1122, 1068, 1025, 844, 802, 682, 597, 566, 520, 416; HRMS (ESI) (m/z): calcd for C20H16FN3O4Na [M+Na]+
451; HRMS (ESI) (m/z): calcd for C22H19F3N2O3Na [M+Na]+ 404.1023, found 404.1207
439.1245, found 439.1226.
4.2.42.
Ethyl
4-(4-fluorophenyl)-2-(4-methoxyphenyl)-6-
4.2.37.
Ethyl
2-(4-bromophenyl)-4-(4-methoxyphenyl)-6- methylpyrimidine-5-carboxylate (4hd) (74%): Pale yellow solid;
1
methylpyrimidine-5-carboxylate (4gc) (60%): White solid; mp 86- mp 56-58 . H NMR (300 MHz, CDCl3): δ 8.48 (d, J = 7.4 Hz,
1
88 . H NMR (300 MHz, CDCl3): δ 8.41 (d, J = 8.5 Hz, 2H), 2H), 7.74 (ddd, J = 7.2, 4.5, 1.9 Hz, 2H), 7.15 (t, J = 8.7 Hz, 2H),
7.73 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.7 6.98 (d, J = 8.9 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H),
Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.64 (s, J = 5.5 Hz, 2.65 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ δ 168.54, 165.40, 163.45, 162.22, 130.56, 130.45, 130.34, 129.70,
168.70, 165.24, 162.74, 162.59, 161.37, 136.20, 131.65, 130.26, 122.41, 115.67, 115.38, 113.85, 61.76, 55.38, 22.89, 13.75; IR
130.14, 130.10, 125.78, 123.03, 113.97, 61.83, 55.39, 22.76, (film) cm-1: 3428, 2985, 2935, 2842, 2051, 1913, 1724, 1643,
13.82; IR (film) cm-1: 3444, 2090, 1716, 1643, 1535, 14340, 1369, 1609, 1538, 1515, 1415, 1257, 1168, 1079, 1029, 844, 806, 674,
1257, 1176, 1099, 1072, 1014, 985, 794, 744, 593, 524, 485, 435; 586, 509, 439; HRMS (ESI) (m/z): calcd for C21H19FN2O3Na
HRMS (ESI) (m/z): calcd for C21H19BrN2O3Na [M+Na]+ [M+Na]+ 389.1277, found 389.1281.
456.0477, found 456.0467.
4.2.43.
Ethyl
2,4-bis(4-fluorophenyl)-6-methylpyrimidine-5-
1
4.2.38.
Ethyl
4-(3-methoxyphenyl)-6-methyl-2-(4- carboxylate (4he) (74%): Pale yellow solid; mp 83-84 . H
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (4gd) (63%): NMR (300 MHz, CDCl3): δ 8.59 – 8.49 (m, 2H), 7.78 – 7.70 (m,
1
White solid; mp 128-129 . H NMR (300 MHz, CDCl3): δ 8.63 2H), 7.20 – 7.10 (m, 4H), 4.22 (q, J = 7.1 Hz, 2H), 2.66 (s, 3H),
(d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 7.5, 1.4 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.35,
Hz, 1H), 7.48 – 7.39 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.92 (d, J 166.35, 165.66, 165.38, 163.84, 162.88, 162.76, 162.54, 134.23,
= 8.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 2.77 (s, 3H), 134.20, 133.15, 133.12, 133.27, 130.94, 130.61, 123.16, 115.62,
1.01 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 166.93, 61.89, 22.70, 13.66; IR (film) cm-1: 3436, 3077, 2985, 2576, 2360,
165.92, 163.23, 162.53, 156.45, 140.50, 131.16, 130.92, 128.95, 2032, 1913, 1724, 1639, 1604, 1542, 1511, 1415, 1369, 1261,
127.83, 125.94, 125.37, 125.32, 124.78, 121.01, 110.27, 61.11, 1234, 1160, 1079, 1014, 925, 848, 806, 767, 713, 682, 586, 559,
55.11, 23.57, 13.58; IR (film) cm-1: 3070, 2977, 2938, 2842, 1936, 462, 416; HRMS (ESI) (m/z): calcd for C20H16F2N2O2Na [M+Na]+
1727, 1596, 1538, 1496, 1457, 1438, 1373, 1322, 1261, 1164, 377.1078, found 377.1056.
1126, 1064, 1022, 929, 860, 813, 755, 682, 636, 593, 580, 532,
493, 447, 416; HRMS (ESI) (m/z): calcd for C22H19F3N2O3Na
4.2.44.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-(4-
[M+Na]+ 439.1245, found 439.1249.
(trifluoromethyl)phenyl)pyrimidine-5-carboxylate (4hf) (63%):
Pale yellow solid; mp 83-84 . H NMR (300 MHz, CDCl3): δ
1
4.2.39.
Ethyl
4-(4-fluorophenyl)-2-(3-methoxyphenyl)-6- 8.64 (d, J = 8.1 Hz, 2H), 7.80 – 7.67 (m, 4H), 7.21 – 7.11 (m, 2H),
methylpyrimidine-5-carboxylate (4ha) (70%): Pale yellow solid; 4.24 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13
C
1
mp 48-50 . H NMR (300 MHz, CDCl3): δ 8.11 (dd, J = 11.6, NMR (100 MHz, CDCl3): δ 168.20, 165.89, 165.45, 162.95,
5.0 Hz, 2H), 7.79 – 7.71 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.20 – 162.56, 162.38, 140.30, 133.97, 130.69, 130.60, 128.94, 125.55,
7.11 (m, 2H), 7.05 (dd, J = 8.1, 2.3 Hz, 1H), 4.23 (q, J = 7.1 Hz, 125.48, 123.97, 115.87, 115.65 62.01, 22.74, 13.67; IR (film) cm-
2H), 3.90 (s, 3H), 2.70 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR 1: 3633, 3232, 3085, 2985, 2935, 2360, 1905, 1727, 1604, 1542,
(100 MHz, CDCl3): δ 168.44, 165.55, 165.34, 163.54, 162.84, 1515, 1434, 1373, 1322, 1261, 1164, 1126, 1064, 1014, 852, 806,
162.38, 159.98, 138.48, 134.30, 130.27, 132.20, 132.11, 130.68, 682, 593, 563, 520, 489, 458; HRMS (ESI) (m/z): calcd for
130.60, 129.60, 128.60, 128.48, 123.32, 121.23, 117.34, 115.73, C21H16F4N2O2Na [M+Na]+ 427.1046, found 427.1041.
113.51, 113.50, 61.85, 55.38, 22.73, 13.65; IR (film) cm-1: 3428,
3073, 2981, 2838, 2333, 2256, 1897, 1724, 1604, 1542, 1511,
1454, 1373, 1268, 1234, 1157, 1087, 1045, 848, 790, 755, 701,

8
Tetrahedron
ACCEPTED MANUSCRIPT
4.2.45.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-(4-
Acknowledgement
nitrophenyl)pyrimidine-5-carboxylate (4hg) (68%): Yellow solid;
1
mp 124-126 . H NMR (300 MHz, CDCl3): δ 8.70 (d, J = 8.8
This
work
was
supported
by
the
NRF
grant
Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H), 7.75 (dd, J = 8.5, 5.3 Hz, 2H),
7.18 (t, J = 8.5 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.69 (s, 3H),
1.14 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 167.90,
165.97, 162.52, 161.48, 149.49, 142.68, 133.66, 130.64, 130.53,
129.45, 124.37, 124.23, 123.66, 115.92, 115.63, 62.13, 22.81,
13.75; IR (film) cm-1: 3436, 3029, 2082, 1720, 1643, 1542, 1423,
1346, 1261, 1079, 1010, 844, 785, 698, 501, 431; HRMS (ESI)
(m/z): calcd for C20H16FN3O4Na [M+Na]+ 404.1023, found
404.1027.
(2017R1A2B2003614, 2016R1A2A1A05005509) and the
research fund of Chungnam National University.
Supplementary data
Supplementary data related with this article can be found at
http://
References and notes
4.2.46.
Ethyl
2-(4-bromophenyl)-4-(4-fluorophenyl)-6-
1. For selected recent reviews, see: a) D. H. Ortgies, A. Hassanpour,
methylpyrimidine-5-carboxylate (4hh) (76%): Pale yellow solid;
mp 80-82 . 1H NMR (300 MHz, CDCl3): δ 8.44 – 8.37 (m, 2H),
7.78 – 7.70 (m, 2H), 7.64 – 7.54 (m, 2H), 7.15 (ddd, J = 9.8, 5.9,
2.5 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.66 (s, J = 5.7 Hz, 3H),
1.13 (t, J = 7.1 Hz, 3H); ); 13C NMR (75 MHz, CDCl3): δ 168.34,
165.74, 165.38, 162.88, 162.85, 162.48, 135.97, 134.15, 134.12,
131.79, 130.65, 130.56, 130.23, 126.09, 123.47, 115.80, 115.58,
61.91, 22.75, 13.66; IR (film) cm-1: 3428, 2985, 2078, 1920, 1724,
1643, 1608, 1538, 1427, 1369, 1261, 1168, 1095, 1072, 1010, 917,
844, 802, 701, 563, 497, 412; HRMS (ESI) (m/z): calcd for
C20H16BrFN2O2Na [M+Na]+ 444.0277, found 444.0256.
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7297; i) T. D. Ngoc, N. Moons, Y. Kim, W. D. Borggraeve, A.
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2286; k) F. A. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G.
Guillaumet, Synlett 2002, 447-450; l) F. A. Alphonse, F. Suzenet,
A. Keromnes, B. Lebret, G. Guillaumet, Org. Lett. 2003, 5, 803-
805.
4.2.47.
Ethyl
4-(4-fluorophenyl)-6-methyl-2-(naphthalen-2-
yl)pyrimidine-5-carboxylate (4ia) (64%): White solid; mp 82-
1
83 . H NMR (300 MHz, CDCl3): δ 9.09 (s, 1H), 8.61 (d, J =
8.7 Hz, 1H), 7.94 (ddd, J = 18.4, 9.0, 6.7 Hz, 3H), 7.83 – 7.76 (m,
2H), 7.55 – 7.49 (m, 2H), 7.19 (t, J = 8.6 Hz, 2H), 4.24 (q, J = 7.1
Hz, 2H), 2.73 (s, J = 3.4 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 168.40, 165.57, 163.71, 162.42,
134.91, 134.36, 133.22, 130.66, 130.55, 129.32, 129.15, 128.19,
127.72, 127.32, 126.27, 125.27, 115.78, 115.50, 61.89, 22.91,
13.77; IR (film) cm-1: 3467, 2356, 2333, 2094, 1643, 1542, 1511,
1430, 1388, 1265, 1230, 1199, 1157, 1083, 1010, 802, 752, 555,
524, 478, 420; HRMS (ESI) (m/z): calcd for C23H20FN2O2
[M+H]+ 387.1509, found 387.1500.
4. a) A. Lengar, C. O. Kappe, Org. Lett. 2004, 6, 771-774; b) H.
Prokopcova, C. O. Kappe, J. Org. Chem. 2007, 72, 4440-4448; c)
N. Arshad, J. Hashim, C. O. Kappe, J. Org. Chem. 2009, 74,
5118-5121.
4.2.48. Ethyl 4-(4-methoxyphenyl)-6-methyl-2-(naphthalen-2-
yl)pyrimidine-5-carboxylate (4ib) (69%): Yellow solid; mp 94-
1
96 . H NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 8.63 (dd, J =
8.7, 1.1 Hz, 1H), 7.93 (ddd, J = 17.7, 9.1, 6.4 Hz, 3H), 7.80 (d, J
= 8.6 Hz, 2H), 7.56 – 7.46 (m, 2H), 7.01 (d, J = 8.6 Hz, 2H), 4.27
(q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 2.71 (s, 3H), 1.17 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 168.84, 165.16, 163.50,
162.77, 161.32, 134.82, 134.62, 133.22, 130.52, 130.15, 129.28,
129.01, 128.09, 127.68, 127.17, 126.17, 125.34, 122.82, 113.97,
61.77, 55.38, 22.84, 13.83; IR (film) cm-1: 3042, 2969, 2931,
2838, 2553, 2294, 1905, 1816, 1724, 1608, 1538, 1434, 1388,
1261, 1180, 1079, 1029, 960, 917, 844, 806, 755, 593, 566, 516,
470, 431; HRMS (ESI) (m/z): calcd for C25H23N2O3 [M+H]+
399.1709, found 399.1692.
5. a) S. Silva, B. Sylla, F. Suzenet, A. Tatibouët, A. P. Rauter, P.
Rollin, Org. Lett. 2008, 10, 853-856; b) S. Silva, S. Tardy, S.
Routier, F. Suzenet, A. Tatibouët, A. P. Rauter, P. Rollin,
Tetrahedron Lett. 2008, 49, 5583-5586; c) X. Guinchard, E.
Roulland, Org. Lett. 2009, 11, 4700-4703; d) Q. Sun, F. Suzenet,
G. Guillaumet, J. Org. Chem. 2010, 75, 3473-3476; e) Q. Sun, F.
Suzenet, G. Guillaumet, Tetrahedron Lett. 2012, 53, 2694-2698;
f) Z. –J. Quan, W. –H. Hu, X. –D. Jia, Z. Zhang, Y. –X. Da, X. –
C. Wang, Adv. Synth. Catal. 2012, 354, 2939-2948; g) Z. –F. Yan,
Z. –J. Quan, Y. –X. Da, Z. Zhang, X. –C. Wang, Chem. Commun.
2014, 50, 13555-13558.
6. For
the
dehydrosulfurative
C-C
cross-couplings
of
mercaptopyrimidines with terminal alkynes, see: O. V. Maltsev,
A. Pöthig, L. Hintermann, Org. Lett. 2014, 16, 1282-1285.
7. a) G. Y. Li, G. Zheng, A. F. Noonan, J. Org. Chem. 2001, 66,
8677-8681; b) F. Y. Kwong, S. L. Buchwald, Org. Lett. 2002, 4,
3517-3520; c) T. Itoh, T. Mase, Org. Lett. 2004, 6, 4587-4590; d)
M. A. Fernández-Rodriges, Q. Shen, J. F. Hartwig, J. Am. Chem.
Soc. 2006, 128, 2180-2181.
8. N. H. T. Phan, J. -H. Sohn, Tetrahedron 2014, 70, 7929-7935.
9. a) O. S. Lee, H. Lee, H. Kim, H. Shin, J. –H. Sohn, Tetrahedron
2015, 71, 2936-2944; b) O. K. Lee, H. Kim, H. –S. Lee, H. Shin,
J. –H. Sohn, Bull. Korean Chem. Soc. 2016, 37, 242-245.
4.2.49. Ethyl 4-(3-methoxyphenyl)-6-methyl-2-(naphthalen-2-
yl)pyrimidine-5-carboxylate (4ic) (73%): Yellow solid; mp 161-
1
163 . H NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 8.62 (d, J =
8.6 Hz, 1H), 7.92 (ddd, J = 16.4, 9.1, 6.6 Hz, 3H), 7.70 (dd, J =
7.5, 1.6 Hz, 1H), 7.55 – 7.40 (m, 3H), 7.14 (t, J = 7.2 Hz, 1H),
6.92 (d, J = 8.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H),
2.81 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H); ); 13C NMR (75 MHz,
CDCl3): δ 167.31, 165.82, 164.03, 163.24, 156.56, 134.91, 134.61,
133.28, 131.08, 129.39, 129.24, 128.23, 128.14, 127.74, 127.26,
126.21, 125.49, 121.06, 110.25, 60.98, 55.08, 23.58, 13.51; IR
(film) cm-1: 3436, 2981, 2842, 2090, 1724, 1643, 1535, 1496,
1461, 1434, 1392, 1261, 1199, 1157, 1083, 1022, 809, 755, 636,
516, 478, 439; HRMS (ESI) (m/z): calcd for C25H22N2O3Na
[M+Na]+ 421.1528, found 421.1516.
10. R. Capdeville, E. Buchdunger, J. Zimmermann, A. Matter, Nat.
Rev. Drug. Discov. 2002, 1, 493-502.
11. For recent selected examples, see: a) A. R. Gholap, K. S. Toti, F.
Shirazi, M. V. Deshpande, K. V. Srinivasan, Tetrahedron 2008,
64, 10214-10223; b) Z. –J. Quan, F. –Q. Jing, Z. Zhang, Y. –X.
Da, X. –C. Wang, Eur. J. Org. Chem. 2013, 7175-7183; c) T.
Xing, Z. Zhang, Y. –X. Da, Z. –J. Quan, X. –C. Wang,

9
Tetrahedron Lett. 2015, 56, 6495-6498; d) Q. Yang, Z. Quan, S.
Wu, B. Du, M. Wang, P. Li, Y. Zhang, X. Wang, Tetrahedron
2015, 71, 6124-6131; e) T. Xing, Z. Zhang, Y. –X. Da, Z. –J.
Quan, X. –C. Wang, Asian J. Org. Chem. 2015, 4, 538-544; f) Q.
–L. Yang, Z. –J. Quan, B. –X. Du, S. Wu, Y. –P. Zhang, P. –D.
Li, M. –M. Wang, Z. –Q. Lei, X. –C. Wang, RSC Adv. 2015, 5,
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G. Meyer, K. L. Tuck, Tetrahedron 2016, 72, 1151-1160.
13. For selected reviews, see: a) K. Singh, K. Singh, Adv.
ACCEPTED MANUSCRIPT
Heterocycl. Chem. 2012, 105, 223-308; b) Suresh, J. S. Sandhu,
ARKIVOC 2012, 66-133; c) J. -P. Wan, Y. Liu, Synthesis 2010,
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14. Although Kappe group reported six examples of I2 production
with 14-82% of the reaction yields when the reaction of DHPM
with ArB(OH)2 using microwave irradiation in the presence of
Pd(PPh3)4 and CuTC in tetrahydrofuran (THF) at 100 °C was
carried out,4a we could not observe the compound I2.
15. Such intermediates I2 were not observed either in our previous
studies on the dehydrosulfurative C-N cross-coupling with
concomitant oxidative dehydrogenation under Ar. See: N. H. T.
Phan, H. Kim, H. Shin, H. –S. Lee, J. –H. Sohn, Org. Lett. 2016,
18, 5154-5157.
12. Recently, Quan and Wang et al. reported a two-step synthesis of
2-arylpyrimdines from two equivalents of the DHPMs via
oxidation
using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) to produce disulfides, which was then converted to 2-
arylpyrimidines by Pd-catalyzed/Cu-mediated cross-coupling with
arylboronic acids, see: a) Z. –J. Quan, Y. Lv, F. –Q. Jing, X. –D.
Jia, C. –D. Huo, X. –C. Wang, Adv. Synth. Catal. 2014, 356, 325-
332; b) B. –X. Du, Z. –J. Quan, Y. –X. Da, Z. Zhang, X. –C.
Wang, Adv. Synth. Catal. 2015, 357, 1270-1276. Lu et al. reported
copper-catalyzed one-pot synthesis of the trisubstituted 2-
arylpyrimidines from primary amides as building blocks with
N,N-dimethylformamide dimethylacetal and enamines, see: c) H.
B. Jalani, W. Cai, H. Lu, Adv. Synth. Catal. 2017, 359, 2509-
2513.
16. A. Kuno, Y. Sugiyama, K. Katsuta, T. Kamitani, H. Takasugi,
Chem. Pharm. Bull. 1992, 40, 1452-1461.
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