Palladium(II) catalyzed Suzuki/Sonogashira cross-coupling reactions of sulfonates: An efficient approach to C2-functionalized pyrimidines and pyridines

Article abstract of DOI:10.1002/ejoc.201300592

Pyrimidin-2-yl sulfonates, as a reaction partner, can be easily prepared from inexpensive commercial materials and are efficiently cross-coupled with arylboronic acids and terminal alkynes by using Pd(OAc)₂-catalyzed Suzuki and Sonogashira reactions. A wide array of C2-functionalized pyrimidines have been prepared in good to excellent yields. 2-Arylpyridines and 2-(oct-1-ynyl)pyridine were also synthesized. An efficient means to synthesize expanded pyrimidin-2-yl conjugated systems was developed by using Pd(OAc) ₂-catalyzed cross-coupling reaction of pyrimidin/pyridin-2-yl sulfonates with arylboronic acids and terminal alkynes. Compared with 2-chloropyrimidines, pyrimidin-2-yl sulfonates can be easily prepared from inexpensive commercial materials and the reactions are more efficient. Copyright

Full text of DOI:10.1002/ejoc.201300592

FULL PAPER
DOI: 10.1002/ejoc.201300592
Palladium(II) Catalyzed Suzuki/Sonogashira Cross-Coupling Reactions of
Sulfonates: An Efficient Approach to C2-Functionalized Pyrimidines and
Pyridines
Zheng-Jun Quan,*[a] Fu-Qiang Jing,[a] Zhang Zhang,[a] Yu-Xia Da,[a] and Xi-Cun Wang*[a]
Keywords: Synthetic methods / C–C coupling / Cross-coupling / Nitrogen heterocycles / Palladium / Alkynes
Pyrimidin-2-yl sulfonates, as a reaction partner, can be easily
prepared from inexpensive commercial materials and are ef-
ficiently cross-coupled with arylboronic acids and terminal
alkynes by using Pd(OAc)2-catalyzed Suzuki and Sonoga-
shira reactions. A wide array of C2-functionalized pyrimid-
ines have been prepared in good to excellent yields. 2-Aryl-
pyridines and 2-(oct-1-ynyl)pyridine were also synthesized.
cursors for natural products, pharmaceuticals, and optical
and electronic materials. Usually, these methods require the
use of sterically bulky phosphanes.[9]
Introduction
Transition-metal-catalyzed coupling reactions provide
versatile methods for the formation of carbon–carbon
bonds.[1] Among such reactions, palladium is extensively
used for the synthesis of small molecules because of its ex-
ceptional reactivity, tolerance towards many functional
groups, low toxicity, and attractiveness from the viewpoint
of assembly efficiency.[2] The palladium-catalyzed Suzuki–
Miyaura reaction (SMC) is particularly attractive among
the various cross-coupling reactions, and has been widely
applied to the synthesis of important drugs, polymers, and
materials in both academic and industrial laboratories;[3–5]
in these reactions the electrophiles are predominantly aryl/
alkenyl halides,[4a,4b] carboxylates,[4c,4d,5b] phosphonium
salts,[4e] triflates,[4f] phosphates,[4f] or sulfonates.[4c,5] N-Het-
erocyclic compounds, which are typically synthesized by
using the Suzuki–Miyaura reaction of (hetero)aryl halides
and pseudo halides with (hetero)arylboronic acids, have
aroused wide attention in organic synthesis and pharmacy
because of their bioactivity. In recent years, sulfonates have
been used as reaction partners; these can be easily prepared
from inexpensive commercial materials, and have been
widely used in organic synthesis.[5,6]
Heterobiaryl compounds as a prevalent structural motif
in many pharmaceuticals and other biologically active mo-
lecules, have been a focus for the development of significant
heterocyclic
products.[10]
3,4-Dihydropyrimidinone
(DHPM) is a privileged heterocyclic scaffold exhibiting a
wide range of pharmacological properties[11] such as cal-
cium channel modulator, antihypertensive, α1a-adrenergic
agonists, mitotic kinesin inhibitors, and hepatitis B virus
replication suppressor. Among the DHPM derivatives, most
of the pharmacologically attractive derivatives are N3-sub-
stituted and C2-functionalized analogues.[12] A few meth-
ods have been developed to efficiently convert DHPM to 2-
substituted pyrimidines.[13] In the conversion of DHPM
into 2-substituted pyrimidine, conventional tautomeriza-
tion-activation-coupling processes would normally include
chlorination[14] or sulfonylation,[15] followed by coupling
with a nucleophile. Chlorination by using POCl3 at high
temperatures could be problematic for substrates with sensi-
tive functionalities, and S-alkylation is absolutely necessar-
ily for sulfide oxidation. The Kappe group have developed
an efficient carbon–carbon coupling reaction between 3,4-
dihydropyrimidine-2-thiones and boronic acids under
modified Liebeskind–Srogl reaction conditions.[16] Kang et
al.[17] have reported a novel and efficient synthesis of multi-
functionalized pyrimidines through Kappe dehydrogenation
and PyBroP-mediated coupling reaction with nucleophiles,
however, only a few C2-aryl- or alkynyl-substituted pyrim-
idines were synthesized. More recently, we have developed
an approach to highly substituted and functionalized pyr-
imidines by a domino desulfitative coupling/acylation/hy-
dration process cocatalyzed by copper(I) and palladi-
um(II).[18] Nevertheless, a method employing easily avail-
able starting materials and generating small amounts of by-
Similarly,
the
palladium-catalyzed
Sonogashira–
Hagihara cross (SHC) reaction is one of the most important
and widely used methods for preparing aryl- and alkyl
acetylenes as well as conjugated enynes,[7–9] which are pre-
[a] Laboratory of Eco-Environment-Related Polymer Materials,
Ministry of Education, China, Gansu Key Laboratory of
Polymer Materials, College of Chemistry and Chemical
Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, P. R. China
E-mail: wangxicun@nwnu.edu.cn
quanzhengjun@hotmail.com
www.nwnu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300592.
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Scheme 1. Synthesis of C2-substituted pyrimidines from DHPMs [Suzuki–Miyaura reaction (SMC), Sonogashira–Hagihara cross reaction
(SHC)].
product to streamline the organic synthesis and to improve phane) (DPE-Phos) as ligand, and 2.5 equivalents of K3PO4
the range of C2-functionalized products is still needed in as base, 1,4-dioxane as solvent at 110 °C for 7 h, which af-
this area. Although a few reports are available on the use forded the desired product in an isolated yield of 86 or 87%,
of palladium-catalyzed Heck[19] and Sonogashira[20] reac- respectively (entries 4–9).
tion of halo-substituted pyrimidines and pyridines with ar-
ylboronic acids and terminal alkynes, to the best of our
Table 1. Optimization of the Suzuki–Miyaura reaction of pyrim-
idin-2-yl sulfonates with arylboronic acid.[a]
knowledge, only one report details the cross-coupling syn-
thesis of multiply substituted pyrimidines; that report was
limited to the use of two arylboronic acids and two alkynes,
which limited the diversity of the products (Scheme 1,
A).[21] Moreover, the chlorination step in the preparation of
2-chloro pyrimidines using POCl3 at high temperatures
could be problematic for substrates with sensitive function-
alities and may be accompanied by the formation unexpec-
ted byproducts.
In 2010, we reported a mild and rapid procedure with
which to synthesize C2-substituted pyrimidines by cross-
coupling reaction of pyrimidin-2-yl sulfonates, which were
easily available from Biginelli 3,4-dihydropyrimidine-2(1H)-
ones through oxidation and esterification under mild condi-
tions,[22] with N, S and O nucleophiles at room temperature.
Herein, we report a general and novel process for the syn-
thesis of C2-substituted pyrimidines by cross-coupling reac-
tion of pyrimidin-2-yl sulfonates with arylboronic acids and
terminal alkynes under the modified Suzuki/Sonogashira
conditions (Scheme 1, B). This method provides a powerful
means of expanding pyrimidin-2-yl π-conjugated systems
utilizing the C–C cross-coupling reaction.
Entry
Base
Solvent Temp. Catal.
[°C]
Time Yield
[h]
[%][b]
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
Na2CO3 THF
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
THF
THF
r.t.
60
60
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
NiCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
48
48
48
48
7
48
7
0
15
Ͻ 5
55
80
dioxane 110
dioxane 110
dioxane 110
dioxane 110
dioxane 110
dioxane 110
0
86
7
7
68[c]
87[d]
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), catalyst
(5 mol-%), PPh3 (20 mol-%), base (2.5 equiv.), solvent (4 mL).
[b] Isolated yield after column chromatography. [c] Pd(OAc)2
(2.5 mol-%) and PPh3 (10 mol-%) were used. [d] Pd(OAc)2
(2.5 mol-%) and DPE-Phos (3 mol-%) were used.
Results and Discussion
Under the optimized conditions, various pyrimidin-2-yl
sulfonates (1) and a diverse set of arylboronic acids (2) were
used to test the scope of the reaction (Table 2). In general,
good to excellent yields (63–96%) were obtained under the
Coupling Reaction of Pyrimidin/Pyridin-2-yl Sulfonates
with Arylboronic Acid
Initially, the Suzuki–Miyaura cross-coupling reaction be- standard reaction conditions using PPh3 as the ligand (en-
tween pyrimidin-2-yl sulfonate (1a) and phenylboronic acid tries 1–16). The reaction conditions were suitable for a vari-
(2a) was tested as the model reaction (Table 1). To our de- ety of pyrimidin-2-yl sulfonates and arylboronic acids con-
light, the C–C cross-coupling product 3a was isolated in taining electron-withdrawing (Cl and Br) as well as elec-
80% yield (entry 5). Lower yield of 3a was obtained when tron-donating groups (Me and MeO) on the phenyl ring.
tetrahydrofuran (THF) was used as solvent (entries 1–3). The reaction of electron-deficient thiophene boronic acid
This revealed that the reaction was best conducted with and 1-naphthalene boronic acid also gave the cross-cou-
5 mol-% Pd(OAc)2 as the catalyst and either 20 mol-% PPh3 pling products 3h, 3i, 3o, and 3p in good yields (entries 8,
or 6 mol-% 2,2Ј-oxybis(2,1-phenylene)bis(diphenylphos- 9, 15 and 16).
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C2-Functionalized Pyrimidines and Pyridines
Table 2. Suzuki–Miyaura coupling of pyrimidin/pyridin-2-yl sulf-
onates with arylboronic acids.[a]
Table 2. (Continued)
[a] Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Pd(OAc)2
(5 mol-%), PPh3 (20 mol-%), K3PO4 (2.5 equiv.), 1,4-dioxane
(4 mL), 110 °C, 7 h. [b] Isolated yield after column chromatog-
raphy. [c] 1 (1.0 mmol) and 2a (3.0 mmol) were used.
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We also examined several pyridin-2-yl sulfonates, includ- Table 3. Coupling of pyrimidin/pyridin-2-yl sulfonates with ter-
minal alkynes.[a]
ing pyridin-2-yl sulfonate (1g), and 5-bromo-, 5-methyl- and
5-nitro substituted pyridin-2-yl sulfonates (1h–j) as sub-
strates in the Suzuki–Miyaura coupling reaction with four
arylboronic acids (Table 2, entries 17–26). The reactions of
pyridin-2-yl sulfonates with arylboronic acids proceeded
smoothly, giving the products 3q–z in moderate to good
yields (entries 17–26). Arylboronic acids with electron-rich
functional groups (Me, MeO) have significantly higher ac-
tivity than the unsubstituted arylboronic acids (entries 17–
26). It is noteworthy that 5-bromo-substituted pyridin-2-yl
sulfonate gave 2,5-diphenylpyridine and 5-phenylpyridin-2-
yl 4-methylbenzenesulfonate in yields of 48 and 30%,
respectively, under the optimal conditions (entry 21). When
3.0 equiv. 2a was used, 2,5-diphenylpyridine was formed in
87% yield (entry 22). These results indicated that the Br
group at the 5-position on the pyridine ring has priority
over the OTs group in coupling with arylboronic acid.
Coupling Reaction of Pyrimidin/Pyridin-2-yl Sulfonates
with Terminal Alkynes
The coupling reaction of pyrimidin-2-yl sulfonates with
terminal acetylene derivatives was then examined. In our
preliminary study to optimize the reaction conditions, the
coupling of ethyl 4-methyl-6-phenyl-2-(tosyloxy)pyrimid-
ine-5-carboxylate (1a) and phenyl acetylene (4a) was se-
lected as the model reaction. Our previous optimized condi-
tions were applied to the bimetallic catalytic system, using
a combination of Pd(OAc)2 (5 mol-%) and CuI (10 mol-%),
PPh3 (20 mol-%), and K3PO4 (2.5 equiv.) in 1.4-dioxane
(4 mL) at 110 °C for 48 h. Unfortunately, under these con-
ditions, the alkynylation gave a low yield (36%) and starting
materials were recovered. The choice of ligand was critical
to the success of the reaction, and improved yields were
obtained when DPE-Phos was screened as ligand using
Pd(OAc)2 as catalyst, which gave up to 80% yield of Sono-
gashira product 5a. Reducing the catalyst and base loading
led to a decrease in yield. In summary, the optimal condi-
tions for palladium/copper cross-coupling reaction of pyr-
imidin-2-yl sulfonates with terminal acetylene was achieved
by using a combination of Pd(OAc)2 (5 mol-%), CuI
(10 mol-%), DPE-Phos (6 mol-%), and Et3N (1.0 mL) in
1,4-dioxane at 110 °C for 48 h.
The generality of the optimized Sonogashira reaction
conditions was explored by treating various pyrimidin-2-yl
sulfonates with a range of terminal alkynes. In general,
good to excellent yields were obtained (Table 3, entries 1–
6), halogen-substituted pyrimidin-2-yl sulfonates gave
higher yield (Table 3, entries 5–6) than substrates with elec-
tron-donating substituents (Table 3, entries 7–8). It is worth
noting that the desired compounds contain an alkynyl
group, which increases the diversity of the molecule and can
allow the preparation of other interesting libraries.[17]
Finally, we examined pyridin-2-yl sulfonates 1g–j as sub-
strates in the Sonogashira coupling reaction with alkynes.
We were pleased to note that under the previously described
[a] Reaction conditions: 1 (1.0 mmol), 4 (1.5 mmol), Pd(OAc)2
(5 mol-%), DPE-Phos (6 mol-%), CuI (10 mol-%), Et3N (1.0 mL),
1,4-dioxane (4 mL), 110 °C, 48 h. [b] Isolated yield after column
chromatography. [c] Reaction conditions:
1
(1.0 mmol),
4
(1.5 mmol), [Pd(PPh3)4] (5 mol-%), CuTC (10 mol-%), DBU
(2.5 equiv.), 1,4-dioxane (4 mL), 110 °C, 48 h.
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C2-Functionalized Pyrimidines and Pyridines
Scheme 2. Synthesis of di(oct-1-ynyl)pyridine.
noted. Melting points were measured with an XT-4 apparatus and
are uncorrected. NMR spectra were recorded at 400 (1H) and 100
(13C) MHz, respectively, with a Varian Mercury plus-400 instru-
ment using CDCl3 as solvent and TMS as internal standard. High-
resolution mass spectra (HRMS) were obtained with a Bruker Dal-
tonics APEX II 47e mass spectrometer. Column chromatography
was generally performed on silica gel (200–300 mesh) and TLC
analyses were conducted on silica gel GF254 plates.
conditions, the cross coupling of pyridin-2-yl 4-methylbenz-
ene sulfonate and 1-octyne (4b) also afforded good yield
(Table 3, entry 9). As in the previous case, use of 5-bromo-
substituted pyridin-2-yl sulfonate led to formation of two
cross-coupling products, 5-(oct-1-ynyl)pyridin-2-yl 4-meth-
ylbenzenesulfonate (5j; 84% yield), and a trace amount of
2,5-di(oct-1-ynyl)pyridine (5k) under the optimal condi-
tions. Compound 5j was then coupled with 4b to generate
bialkynyl-substituted pyridine 5k in a yield of 59% by using
[Pd(PP3)4] and copper(I) thiophenecarboxylate (CuTC) as
catalysts, DPE-Phos as ligand, and 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) as base (Scheme 2). When sulfonate 1i
was used as substrate, however, no reaction was detected by
TLC or LC-MS. Use of 1j gave a complex mixture (TLC
General Procedure for the Synthesis of 3a–z: A sealed tube (15 mL),
fitted with a septum, containing Pd(OAc)2 (11.2 mg, 0.05 equiv.)
and PPh3 (52.5 mg, 0.20 equiv.) was evacuated and purged with
nitrogen gas three times. Pyrimidin-2-yl sulfonate (1; 1.0 mmol),
arylboronic acid (2; 1.5 mmol), K3PO4 (2.5 equiv.), and 1.4-dioxane
(4 mL), were added to the system and the reaction mixture was
stirred at 110 °C for 7 h until complete consumption of 1 (based
on TLC analysis). Upon completion of the reaction, the mixture
was cooled to room temp., quenched by addition of satd. aq NH4Cl
(3 mL), and extracted with diethyl ether (2ϫ 10 mL). The organic
solvents were combined and washed with aqueous NaOH (2 mmol/
mL, 2 mL), brine, and dried with MgSO4. Purification by silica gel
column chromatography (petroleum ether/EtOAc, 90:1) gave the
corresponding 2-substituted pyrimidine/pyridine.
1
and H NMR analysis) without formation of the desired
product.
Conclusions
We have developed a general synthetic approach to C-2
substituted pyrimidines/pyridines by using the Suzuki/
Sonogashira cross-coupling of pyrimidin/pyridin-2-yl sulf-
onates. A wide range of C-2 substituted pyrimidines/pyr-
idines were obtained in excellent yields. It is noteworthy that
the approach involves easily prepared pyrimidin/pyridin-2-
yl sulfonates as an attractive reaction partner, and the syn-
thesis of extended π-conjugated systems through
Suzuki/Sonogashira arylation and alkynylation reactions.
Furthermore, the desired compounds contain an alkynyl
group, which increases the diversity of the molecule and
can allow the preparation of other interesting libraries.[18]
Synthesis and screening of compounds based on pyrimidine
scaffolds may lead to the discovery of novel lead com-
pounds with biological activities.
Ethyl 4-Methyl-2,6-diphenylpyrimidine-5-carboxylate (3a):[23] White
1
solid; m.p. 66–67 °C. H NMR (400 MHz, CDCl3): δ = 8.62–8.59
(m, 2 H), 7.81–7.79 (m, 2 H), 7.54–7.52 (m, 6 H), 4.25 (q, J =
7.2 Hz, 2 H), 2.75 (s, 3 H), 1.12 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.5, 165.4, 163.7, 163.7, 138.2, 137.1,
131.1, 130.0, 128.7, 128.6, 128.5, 128.5, 123.4, 61.8, 22.9, 13.7 ppm.
HRMS: calcd. for C20H18N2O2 [M + H]+ 319.1441; found
319.1443.
Ethyl 4-Methyl-6-phenyl-2-p-tolylpyrimidine-5-carboxylate (3b):
White solid; m.p. 61–63 °C. 1H NMR (400 MHz, CDCl3): δ = 8.48
(d, J = 8.2 Hz, 2 H), 7.79–7.77 (m, 2 H), 7.54–7.46 (m, 3 H), 7.32
(d, J = 8.1 Hz, 3 H), 4.23 (q, J = 7.2 Hz, 2 H), 2.72 (s, 3 H), 2.46
(s, 3 H), 1.11 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.5, 165.3, 163.7, 163.6, 141.5, 138.3, 134.4, 130.0,
129.3, 128.7, 128.5, 128.5, 123.1, 61.8, 22.7, 21.6, 13.7 ppm.
HRMS: calcd. for C21H20N2O2 [M + H]+ 333.1958; found
333.1601.
Experimental Section
Ethyl 4-Methyl-6-phenyl-2-m-tolylpyrimidine-5-carboxylate (3c):
White solid; m.p. 69–71 °C. 1H NMR (400 MHz, CDCl3): δ = 8.28
(d, J = 7.4 Hz, 2 H), 7.68 (dd, J = 6.5, 3.1 Hz, 2 H), 7.42–7.39 (m,
3 H), 7.31 (t, J = 7.9 Hz, 1 H), 7.24 (t, J = 7.5 Hz, 1 H), 4.13 (q,
J = 7.2 Hz, 2 H), 2.62 (s, 3 H), 2.38 (s, 3 H), 1.01 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.4, 165.3, 163.8,
General Methods: All reactions were conducted under a nitrogen
atmosphere with a dual-manifold Schlenk tube, unless otherwise
mentioned, and in oven-dried glassware. Solvents were purified and
dried by standard methods prior to use. All commercially available
reagents were used without further purification unless otherwise
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163.3, 138.2, 138.1, 137.0, 131.8, 129.9, 129.1, 128.5, 128.4, 125.8,
123.3, 61.7, 22.9, 21.5, 13.6 ppm. HRMS: calcd. for C21H20N2O2
[M + H]+ 333.1958; found 333.1602.
1.06 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.33, 165.46, 165.20, 163.65, 162.71, 162.28, 136.97, 134.28,
131.10, 130.58, 130.50, 128.58, 128.50, 123.16, 115.66, 115.44,
61.84, 22.82, 13.74 ppm. HRMS: calcd. for C20H17FN2O2 [M +
H]+ 337.1347; found 337.1349.
Ethyl 4-Methyl-6-phenyl-2-o-tolylpyrimidine-5-carboxylate (3d):
White solid; m.p. 77–78 °C. 1H NMR (400 MHz, CDCl3): δ = 7.87–
7.79 (m, 1 H), 7.73–7.57 (m, 2 H), 7.46–7.33 (m, 3 H), 7.32–7.19
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxyl-
(m, 3 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.63 (s, 3 H), 2.55 (s, 3 H), ate (3k): White solid; m.p. 83–84 °C. 1H NMR (400 MHz, CDCl3):
1.03 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
δ = 8.52–8.41 (m, 2 H), 7.69–7.59 (m, 2 H), 7.47–7.34 (m, 5 H),
4.16 (q, J = 7.2 Hz, 2 H), 2.62 (s, 3 H), 1.07 (t, J = 7.2 Hz, 3
168.36, 166.75, 165.00, 163.12, 137.93, 137.62,137.45, 131.31,
130.55, 129.97, 129.65, 128.48, 128.39, 125.93, 122.77, 61.86, 22.78, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.15, 165.55, 163.66,
21.32, 13.66 ppm. HRMS: calcd. for C21H20N2O2 [M + H]+
333.1958; found 333.1600.
162.31, 136.81, 136.56, 136.36, 131.20, 129.85, 128.73, 128.63,
128.52, 123.19, 61.92, 22.79, 13.74 ppm. HRMS: calcd. for
C20H17ClN2O2 [M + H]+ 353.1051; found 353.1049.
Ethyl
2-(4-Methoxyphenyl)-4-methyl-6-phenylpyrimidine-5-carb-
oxylate (3e): White solid; m.p. 57–59 °C. 1H NMR (400 MHz,
Ethyl 4-(4-Bromophenyl)-6-methyl-2-phenylpyrimidine-5-carboxyl-
1
CDCl3): δ = 8.49–8.39 (m, 2 H), 7.72–7.60 (m, 2 H), 7.46–7.32 (m, ate (3l): White solid; m.p. 87–89 °C. H NMR (400 MHz, CDCl3):
3 H), 6.95–6.85 (m, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 3.79 (s, 3 H),
δ = 8.50 (m, 2 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.47–7.37 (m, 5 H),
4.19 (q, J = 7.2 Hz, 2 H), 2.63 (s, 3 H), 1.06 (t, J = 7.2 Hz, 3
2.59 (s, 3 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.54, 165.23, 163.53, 163.40, 162.13, 141.51, 138.41, H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.52, 165.39, 163.06,
134.4, 130.34, 129.82, 128.39, 122.57, 113.79, 61.63, 55.33, 22.84, 137.14, 137.00, 131.02, 128.94, 128.87, 128.60, 128.49, 127.78,
13.63 ppm. HRMS: calcd. for C21H20N2O3 [M + H]+ 349.1547;
found 349.1550.
127.18, 127.16, 123.22, 61.82, 22.88, 13.72 ppm. HRMS: calcd. for
C20H17BrN2O2 [M + H]+ 397.0546; found 397.0548.
Ethyl 2-(4-Fluorophenyl)-4-methyl-6-phenylpyrimidine-5-carboxylate Ethyl 4-Methyl-2-phenyl-6-p-tolylpyrimidine-5-carboxylate (3m):
(3f): White solid; m.p. 94–96 °C. 1H NMR (400 MHz, CDCl3): δ =
8.54–8.42 (m, 2 H), 7.75–7.57 (m, 2 H), 7.49–7.28 (m, 3 H), 7.07
White solid; m.p. 66–67 °C. 1H NMR (400 MHz, CDCl3): δ = 8.60–
8.38 (m, 2 H), 7.60 (d, J = 8.1 Hz, 2 H), 7.46–7.35 (m, 3 H), 7.23–
(t, J = 8.7 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 2.60 (s, 3 H), 1.00 7.17 (m, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.60 (s, 3 H), 2.34 (s, 3
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.32,
166.13, 165.42, 163.59, 162.68, 138.12, 133.32, 130.82, 130.73,
129.98, 128.45, 128.35, 123.24, 115.52, 115.31, 61.75, 22.80,
13.62 ppm. HRMS: calcd. for C20H17FN2O2 [M + H]+ 337.1347;
found 337.1345.
H), 1.06 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 168.63, 165.14, 163.59, 163.34, 140.23, 137.23, 135.30, 130.91,
129.17, 128.58, 128.44, 128.41, 123.14, 61.72, 22.81, 21.38,
13.73 ppm. HRMS: calcd. for C21H20N2O2 [M + H]+ 333.1598;
found 333.1600.
Ethyl 2-(4-Chlorophenyl)-4-methyl-6-phenylpyrimidine-5-carboxyl-
Ethyl
4-(4-Methoxyphenyl)-6-methyl-2-phenylpyrimidine-5-carb-
ate (3g): White solid; m.p. 84–86 °C. 1H NMR (400 MHz, CDCl3):
oxylate (3n): Colorless oil. 1H NMR (400 MHz, CDCl3): δ = 8.54–
δ = 8.51–8.36 (m, 2 H), 7.80–7.56 (m, 2 H), 7.52–7.29 (m, 5 H), 8.43 (m, 2 H), 7.77–7.62 (m, 2 H), 7.45–7.36 (m, 3 H), 6.88 (d, J
4.13 (q, J = 7.2 Hz, 2 H), 2.61 (s, 3 H), 1.01 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.25, 165.48, 163.63,
162.64, 138.04, 137.29, 135.59, 130.00, 129.96, 128.70, 128.44,
128.41, 123.52, 61.80, 22.80, 13.64 ppm. HRMS: calcd. for
C20H17ClN2O2 [M + H]+ 353.1051; found 353.1053.
= 8.8 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 3.72 (s, 3 H), 2.56 (s, 3
H), 1.05 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 168.72, 164.98, 163.36, 162.53, 161.17, 137.14, 130.82, 130.32,
130.01, 128.44, 128.36, 122.68, 113.80, 61.66, 55.24, 22.71,
13.73 ppm. HRMS: calcd. for C21H20N2O3 [M + H]+ 349.1547;
found 349.1548.
Ethyl 4-Methyl-6-phenyl-2-(thiophen-2-yl)pyrimidine-5-carboxylate
(3h): White solid; m.p. 89–91 °C. 1H NMR (400 MHz, CDCl3): δ
= 8.03 (dd, J = 3.7, 1.1 Hz, 1 H), 7.71–7.56 (m, 2 H), 7.51–7.28
(m, 4 H), 7.07 (dd, J = 4.9, 3.8 Hz, 1 H), 4.11 (q, J = 7.2 Hz, 2 H),
2.57 (s, 3 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
Ethyl
4-(4-Chlorophenyl)-6-methyl-2-(thiophen-2-yl)pyrimidine-5-
1
carboxylate (3o): White solid; m.p. 83–84 °C. H NMR (400 MHz,
CDCl3): δ = 8.02 (dd, J = 3.7, 1.2 Hz, 1 H), 7.74–7.52 (m, 2 H),
7.44 (dd, J = 5.0, 1.2 Hz, 1 H), 7.41–7.31 (m, 2 H), 7.08 (dd, J =
CDCl3): δ = 168.20, 165.54, 163.67, 160.49, 142.96, 137.88, 130.54, 5.0, 3.7 Hz, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 2.57 (s, 3 H), 1.06 (t,
130.00, 129.82, 128.42, 128.29, 128.21, 122.77, 61.71, 22.70,
13.61 ppm. HRMS: calcd. for C18H16N2O2S [M + H]+ 325.1005,
found; 325.1008.
J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.01,
165.79, 162.37, 160.55, 142.75, 136.39, 136.27, 130.75, 129.97,
129.81, 128.71, 128.28, 122.59, 61.88, 22.73, 13.73 ppm. HRMS:
calcd. for C18H15ClN2O2S [M + H]+ 359.0616; found 359.0615.
Ethyl 4-Methyl-2-(naphthalen-1-yl)-6-phenylpyrimidine-5-carboxyl-
1
ate (3i): White solid; m.p. 83–85 °C. H NMR (400 MHz, CDCl3): Ethyl 4-(4-Chlorophenyl)-6-methyl-2-(naphthalen-1-yl)pyrimidine-5-
1
δ = 8.62–8.60 (m, 1 H), 8.06 (dd, J = 7.2, 1.2 Hz, 1 H), 7.89 (d, J
carboxylate (3p): Colorless oil. H NMR (400 MHz, CDCl3): δ =
= 8.2 Hz, 1 H), 7.87–7.80 (m, 1 H), 7.77–7.65 (m, 2 H), 7.59–7.31 8.59 (dd, J = 8.3, 0.7 Hz, 1 H), 8.03 (dd, J = 7.2, 1.2 Hz, 1 H), 7.84
(m, 6 H), 4.18 (q, J = 7.2 Hz, 2 H), 2.69 (s, 3 H), 1.05 (t, J = (d, J = 8.2 Hz, 1 H), 7.78 (dd, J = 8.1, 1.0 Hz, 1 H), 7.72–7.61 (m,
7.2 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.26, 2 H), 7.49–7.31 (m, 5 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.65 (s, 3 H),
166.35, 165.29, 163.53, 137.85, 135.41, 134.05, 130.96, 130.73,
130.06, 129.58, 128.55, 128.42, 126.85, 125.85, 125.70, 125.16,
123.18, 109.69, 61.93, 22.86, 13.67 ppm. HRMS: calcd. for
C24H20N2O2 [M + H]+ 369.1598; found 369.1560.
1.05 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.00, 166.34, 165.44, 162.07, 136.34, 136.20, 135.13, 133.98,
130.86, 130.82, 129.79, 129.61, 128.74, 128.42, 126.82, 125.82,
125.59, 125.07, 122.92, 61.99, 22.84, 13.70 ppm. HRMS: calcd. for
C24H19ClN2O2 [M + H]+ 403.1208; found 403.1210.
2-Phenylpyridine (3q):[24] Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 8.95–8.89 (m, 1 H), 8.62 (d, J = 4.6 Hz, 1 H), 7.98–
7.87 (m, 2 H), 7.72–7.59 (m, 2 H), 7.37 (m, 3 H), 7.24–7.12 (m, 1
Ethyl 4-(4-Fluorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate
(3j): White solid; m.p. 85–86 °C. 1H NMR (400 MHz, CDCl3): δ =
8.46 (dd, J = 6.8, 3.0 Hz, 2 H), 7.77–7.62 (m, 2 H), 7.48–7.33 (m,
3 H), 7.11–7.06 (m, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.61 (s, 3 H),
7180
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7175–7183

C2-Functionalized Pyrimidines and Pyridines
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.33, 149.50, 139.17,
136.85, 128.97, 128.72, 126.88, 122.08, 120.59 ppm. HRMS: calcd.
for C11H9N [M + H]+ 156.0808; found 156.0809.
2-p-Tolylpyridine (3r):[19,24] Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 8.57 (d, J = 4.9 Hz, 1 H), 7.80 (d, J = 8.1 Hz, 2 H),
7.65–7.56 (m, 2 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.07 (td, J = 5.0,
3.2 Hz, 1 H), 2.30 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 157.30, 149.45, 138.80, 136.55, 136.45, 129.36, 126.64, 121.67,
120.11, 21.16 ppm. HRMS: calcd. for C12H11N [M + H]+ 170.0964;
found 170.0966.
2-o-Tolylpyridine (3s):[24] Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 8.65–8.59 (m, 1 H), 7.66 (m, 1 H), 7.38–7.27 (m, 2 H),
7.27–7.12 (m, 4 H), 2.29 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.91, 149.11, 140.31, 136.07, 135.65, 130.66, 129.55,
128.20, 125.80, 124.04, 121.56, 77.31, 76.99, 76.67, 20.2 ppm.
HRMS: calcd. for C12H11N [M + H]+ 170.0964; found 170.0963.
2-(4-Methoxyphenyl)-5-nitropyridine (3z): White solid; m.p. 125–
128 °C. 1H NMR (400 MHz, CDCl3): δ = 9.41 (d, J = 2.3 Hz, 1
H), 8.43 (dd, J = 8.8, 2.7 Hz, 1 H), 8.05 (d, J = 8.9 Hz, 2 H), 7.79
(d, J = 8.8 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 2 H), 3.88 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 161.88, 145.25, 142.19, 131.90,
131.64, 129.40, 129.11, 118.76, 114.63, 55.30 ppm. HRMS: calcd.
for C12H10N2O3 [M + H]+ 231.0770; found 231.0772.
General Procedure for the Synthesis of 5a–k: A sealed tube (15 mL),
fitted with a septum, containing Pd(OAc)2 (11.2 mg, 0.05 equiv.)
and DPE-Phos (32.3 mg, 0.06 equiv.) was evacuated and purged
with nitrogen gas three times. Pyrimidin-2-yl sulfonate (1;
1.0 mmol), terminal alkyne (4; 1.5 mmol), CuI (0.10 equiv.), Et3N
(1 mL), and 1.4-dioxane (4 mL) were added to the system and the
reaction mixture was stirred at 110 °C for 48 h until complete con-
sumption of 1 (based on TLC analysis). Upon completion of the
reaction, the mixture was cooled to room temp. and quenched by
the addition of saturated aqueous NH4Cl (3 mL) and extracted
with diethyl ether (2ϫ 10 mL). The organic solvents were com-
bined and washed with aqueous NaOH (2 mmol/mL, 2 mL), brine,
and dried with MgSO4. Purification by silica gel column
chromatography (petroleum ether/EtOAc, 30:1) gave the corre-
sponding 2-substituted pyrimidine.
2-(4-Methoxyphenyl)pyridine (3t):[24] White solid; m.p. 52–53 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.60–8.50 (m, 1 H), 7.91–7.81 (m, 2
H), 7.65–7.51 (m, 2 H), 7.08–7.05 (m, 1 H), 6.93–6.90 (m, 1 H),
6.90–6.88 (m, 1 H), 3.76 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 160.48, 157.12, 149.55, 136.65, 132.05, 128.16, 121.40,
119.78, 114.13, 55.34 ppm. HRMS: calcd. for C12H11NO [M + H]
+
Ethyl 4-Methyl-6-phenyl-2-(phenylethynyl)pyrimidine-5-carboxylate
186.0919; found 186.0921.
1
(5a): White solid; m.p. 161–162 °C. H NMR (400 MHz, CDCl3):
2,5-Diphenylpyridine (3u):[25] White solid; m.p. 163–165 °C. 1H
NMR (400 MHz, CDCl3): δ = 9.01 (d, J = 1.9 Hz, 1 H), 8.11 (d,
J = 7.3 Hz, 2 H), 7.96 (dd, J = 8.2, 2.3 Hz, 1 H), 7.82 (d, J =
8.2 Hz, 1 H), 7.68 (d, J = 7.4 Hz, 2 H), 7.59–7.44 (m, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 156.16, 148.25, 147.99, 139.03,
137.66, 135.18, 134.99, 134.91, 129.15, 128.84, 126.99, 126.77,
120.42 ppm. HRMS: calcd. for C17H13N [M + H]+ 231.1048; found
231.1050.
δ = 7.70–7.66 (m, 4 H), 7.48–7.39 (m, 3 H), 7.38–7.27 (m, 3 H),
4.23 (q, J = 8.0 Hz, 2 H), 2.67 (s, 3 H), 1.06 (t, J = 8.0 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.53, 165.59, 164.08,
152.38, 137.19, 132.85, 132.54, 130.40, 130.01, 129.91, 129.52,
128.75, 126.53, 128.38, 128.17, 124.19, 121.25, 88.53, 88.09, 61.98,
22.47, 13.48 ppm. HRMS: calcd. for C22H18N2O2 [M + H]+
343.1441; found 343.1442.
Ethyl
4-Methyl-2-(oct-1-ynyl)-6-phenylpyrimidine-5-carboxylate
5-Phenylpyridin-2-yl 4-Methylbenzenesulfonate (3v): White solid;
m.p. 87–88 °C. 1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J =
2.3 Hz, 1 H), 7.95 (dd, J = 8.3, 3.1 Hz, 3 H), 7.55–7.51 (m, 2 H),
7.48 (t, J = 7.3 Hz, 2 H), 7.43 (d, J = 7.1 Hz, 1 H), 7.37 (d, J =
8.1 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 1 H), 2.47 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.17, 146.60, 146.27, 145.41,
138.54, 136.42, 136.00, 133.68, 128.71, 128.52, 127.07, 116.04,
115.51, 21.83 ppm. HRMS: calcd. for C18H15NO3S [M + H]+
326.0851; found 326.0853.
1
(5b): Yellow oil. H NMR (400 MHz, CDCl3): δ = 7.63–7.49 (m, 2
H), 7.47–7.28 (m, 3 H), 4.10 (q, J = 7.2 Hz, 2 H), 2.54 (s, 3 H),
2.40 (t, J = 7.3 Hz, 2 H), 1.65–1.53 (m, 2 H), 1.43–1.33 (m, 2 H),
1.28–1.19 (m, 4 H), 0.97 (t, J = 7.2 Hz, 3 H), 0.81 (t, J = 6.7 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.58, 165.39, 163.91,
152.27, 137.18, 130.06, 128.44, 128.25, 123.95, 91.65, 79.93, 61.87,
31.25, 28.70, 27.89, 22.52, 22.43, 19.41, 13.99, 13.53 ppm. HRMS:
calcd. for C22H26N2O2 [M + H]+ 351.2067; found 351.2069.
5-Methyl-2-phenylpyridine (3w):[26] Colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 8.55 (dd, J = 1.4, 0.6 Hz, 1 H), 8.01 (dd,
J = 5.3, 3.3 Hz, 2 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.58–7.46 (m, 3
H), 7.45–7.37 (m, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.78, 150.09, 139.44, 137.29, 131.58, 128.71, 128.60,
126.70, 120.01, 18.16 ppm. HRMS: calcd. for C12H11N [M + H]+
170.0964; found 170.0962.
Ethyl
2-(3,3-Dimethylbut-1-ynyl)-4-methyl-6-phenylpyrimidine-5-
1
carboxylate (5c): White solid; m.p. 98–99 °C. H NMR (400 MHz,
CDCl3): δ = 7.57–7.36 (m, 2 H), 7.46–7.25 (m, 3 H), 4.10 (q, J =
7.2 Hz, 2 H), 2.54 (s, 3 H), 1.30 (s, 9 H), 0.97 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.61, 165.29, 163.90,
152.51, 137.33, 129.99, 128.43, 128.29, 123.94, 98.45, 78.87, 61.82,
30.38, 27.90, 22.52, 13.54 ppm. HRMS: calcd. for C22H22N2O2 [M
+ H]+ 323.1754; found 323.1755.
2-(4-Methoxyphenyl)-5-methylpyridine (3x): White solid; m.p. 51–
53 °C. 1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.92 (d, J =
8.8 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 7.9 Hz, 1 H),
6.96 (d, J = 8.8 Hz, 2 H), 3.78 (d, J = 1.4 Hz, 3 H), 2.28 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.17, 154.36, 149.70,
137.20, 132.01, 130.74, 127.72, 119.11, 114.22, 54.97, 17.88 ppm.
HRMS: calcd. for C13H13NO [M + H]+ 200.1075; found 200.1073.
Ethyl 4-Methyl-6-phenyl-2-(p-tolylethynyl)pyrimidine-5-carboxylate
(5d): Yellow oil. H NMR (400 MHz, CDCl3): δ = 7.65–7.56 (m, 2
1
H), 7.51 (d, J = 8.0 Hz, 2 H), 7.45–7.33 (m, 3 H), 7.10 (d, J =
7.9 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 2.58 (s, 3 H), 2.30 (s, 3 H),
0.99 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
167.57, 165.54, 164.05, 152.47, 140.17, 137.20, 132.65, 130.16,
129.13, 128.54, 128.29, 124.00, 118.09, 89.07, 87.66, 61.96, 22.61,
21.63, 13.58 ppm. HRMS: calcd. for C23H20N2O2 [M + H]+
357.1598; found 357.1600.
5-Nitro-2-phenylpyridine (3y): White solid; m.p. 121–122 °C. 1H
NMR (400 MHz, CDCl3): δ = 9.45 (d, J = 2.4 Hz, 1 H), 8.47 (dd,
J = 8.8, 2.7 Hz, 1 H), 8.12–8.02 (m, 2 H), 7.87 (d, J = 8.8 Hz, 1
H), 7.57–7.46 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = Ethyl
4-Methyl-2-(oct-1-ynyl)-6-p-tolylpyrimidine-5-carboxylate
(5e): Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.48 (dd, J =
120.00 ppm. HRMS: calcd. for C11H8N2O2 [M + H]+ 200.0586; 8.2, 2.0 Hz, 2 H), 7.18–7.14 (m, 2 H), 4.13 (dd, J = 7.2, 2.9 Hz, 2
162.29, 145.16, 142.82, 136.98, 131.90, 130.88, 129.10, 127.66,
found 200.0588.
H), 2.52 (d, J = 2.5 Hz, 3 H), 2.42–2.37 (m, 2 H), 2.31 (d, J =
Eur. J. Org. Chem. 2013, 7175–7183
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7181

Z.-J. Quan, F.-Q. Jing, Z. Zhang, Y.-X. Da, X.-C. Wang
FULL PAPER
2.6 Hz, 3 H), 1.64–1.54 (m, 2 H), 1.38 (dd, J = 13.1, 6.4 Hz, 2 H), Supporting Information (see footnote on the first page of this arti-
1.28–1.16 (m, 4 H), 1.05–1.01 (m, 3 H), 0.82–0.79 (m, 3 H) ppm. cle): Full experimental details, characterization data, and 1H NMR
13C NMR (100 MHz, CDCl3): δ = 167.83, 165.15, 163.72, 152.25,
140.42, 134.27, 129.17, 128.28, 123.80, 91.41, 80.03, 61.86, 31.27,
28.71, 27.92, 22.50, 22.45, 21.35, 19.43, 14.00, 13.64 ppm. HRMS:
calcd. for C23H28N2O2 [M + H]+ 365.2224; found 365.2222.
and 13C NMR spectra for all products.
Acknowledgments
Ethyl 4-(4-Chlorophenyl)-6-methyl-2-(oct-1-ynyl)pyrimidine-5-carb-
oxylate (5f): Brown oil. 1H NMR (400 MHz, CDCl3): δ = 7.58–
7.45 (m, 2 H), 7.42–7.31 (m, 2 H), 4.11–4.17 (m, 2 H), 2.54 (d, J
= 1.2 Hz, 3 H), 2.40 (t, J = 7.3 Hz, 2 H), 1.65–1.54 (m, 2 H), 1.43–
1.34 (m, 2 H), 1.28–1.19 (m, 4 H), 1.07–1.03 (m, 3 H), 0.85–0.76
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.43, 165.64,
162.59, 152.33, 136.52, 135.59, 129.73, 128.75, 123.84, 92.04, 79.86,
62.07, 31.27, 29.65, 28.72, 27.90, 22.56, 22.45, 19.44, 14.01,
13.67 ppm. HRMS: calcd. for C22H25ClN2O2 [M + H]+ 385.1677;
found 385.1680.
The authors are thankful for financial support from the National
Nature Science Foundation of China (NSFC) (grant numbers
20902073 and 21062017), the Natural Science Foundation of
Gansu Province (grant numbers 1208RJYA083), and the Scientific
and Technological Innovation Engineering program of Northwest
Normal University (grant numbers nwnu-kjcxgc-03-64, nwnu-lkqn-
10-15).
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Ethyl 4-(4-Fluorophenyl)-6-methyl-2-(oct-1-ynyl)pyrimidine-5-carb-
oxylate (5g): Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.64–
7.51 (m, 2 H), 7.04 (dd, J = 11.9, 5.3 Hz, 2 H), 3.71–3.55 (m, 3 H),
2.39 (t, J = 7.3 Hz, 2 H), 1.67–1.50 (m, 2 H), 1.41–1.32 (m, 2 H),
1.23 (t, J = 6.9 Hz, 9 H), 0.80 (d, J = 1.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.16, 168.23, 165.03, 162.54, 162.20,
152.74, 133.33, 130.29, 130.21, 122.79, 115.67, 115.66, 115.44,
90.99, 80.23, 52.56, 33.35, 31.14, 28.60, 27.83, 22.33, 21.45, 19.37,
13.86 ppm. HRMS: calcd. for C22H25FN2O2 [M + H]+ 369.1973;
found 369.1974.
Ethyl
4-(4-Methoxyphenyl)-6-methyl-2-(oct-1-ynyl)pyrimidine-5-
1
carboxylate (5h): Colorless oil. H NMR (400 MHz, CDCl3): δ =
7.56 (d, J = 8.2 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 4.15 (q, J =
7.2 Hz, 2 H), 3.75 (s, 3 H), 2.50 (s, 3 H), 2.39 (t, J = 7.2 Hz, 2 H),
1.65–1.52 (m, 2 H), 1.36 (m, 2 H), 1.28–1.16 (m, 4 H), 1.06 (t, J =
7.2 Hz, 3 H), 0.80 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.90, 164.95, 162.91, 161.24, 152.07, 129.92, 129.32,
123.32, 113.79, 91.09, 79.95, 61.75, 55.18, 31.15, 28.59, 27.81,
22.33, 19.29, 13.88, 13.62 ppm. HRMS: calcd. for C23H28N2O3 [M
+ H]+ 381.2173; found 381.2175.
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2-(Oct-1-ynyl)pyridine (5i):[20c] Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 8.45 (d, J = 4.4 Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H),
7.27 (d, J = 7.8 Hz, 1 H), 7.13–7.03 (m, 1 H), 2.35 (t, J = 7.2 Hz,
2 H), 1.60–1.49 (m, 2 H), 1.37 (m, 2 H), 1.26–1.16 (m, 4 H), 0.81
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.55, 143.77,
135.77, 126.53, 121.98, 90.92, 80.15, 31.14, 28.45, 28.15, 22.33,
19.13, 13.85 ppm. HRMS: calcd. for C13H17N [M + H]+ 188.1434;
found 188.1436.
5-(Oct-1-ynyl)pyridin-2-yl 4-Methylbenzenesulfonate (5j): Brown
oil. 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 2.0 Hz, 1 H),
7.83 (d, J = 8.3 Hz, 2 H), 7.69 (dd, J = 8.4, 2.2 Hz, 1 H), 7.29 (d,
J = 8.0 Hz, 2 H), 6.99 (d, J = 8.4 Hz, 1 H), 2.40–2.33 (m, 5 H),
1.60–1.50 (m, 2 H), 1.43–1.36 (m, 2 H), 1.33–1.21 (m, 4 H), 0.86
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 155.19,
150.79, 145.43, 133.44, 129.92, 128.43, 120.42, 120.39, 114.90,
95.06, 76.10, 31.26, 28.36, 22.50, 21.72, 21.53, 19.36, 14.23 ppm.
HRMS: calcd. for C20H23NO3S [M + H]+ 358.1477; found
358.1475.
2,5-Di(oct-1-ynyl)pyridine (5k): Yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 8.54 (d, J = 1.4 Hz, 1 H), 7.57 (dd, J = 8.1, 2.1 Hz, 1
H), 7.27 (d, J = 8.2 Hz, 1 H), 2.42 (q, J = 7.1 Hz, 4 H), 1.70–1.55
(m, 4 H), 1.51–1.38 (m, 4 H), 1.38–1.23 (m, 8 H), 0.98–0.82 (m, 6
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 152.39, 141.87, 138.39,
125.90, 119.65, 95.40, 92.64, 80.26, 31.81, 31.32, 28.58, 28.47,
28.31, 23.02, 22.51, 19.59,19.51, 19.41, 19.13, 14.09 ppm. HRMS:
calcd. for C21H29N [M + H]+ 296.2378; found 296.2380.
7182
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Eur. J. Org. Chem. 2013, 7175–7183

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Received: April 24, 2013
Published Online: September 19, 2013
Eur. J. Org. Chem. 2013, 7175–7183
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7183