Synthesis of novel 5,6-substituted furo[2,3-d]pyrimidines via Pd-catalyzed cyclization of alkynylpyrimidinols with aryl iodides

Article abstract of DOI:10.1016/j.tet.2006.12.077

A flexible method for the synthesis of 5,6-disubstituted furo[2,3-d]pyrimidine derivatives is described. The key step is a palladium-catalyzed arylative cyclization of alkynylpyrimidinols with various aryl iodides, which gave the title compounds in 36-75% yield.

Full text of DOI:10.1016/j.tet.2006.12.077

Tetrahedron 63 (2007) 1931–1936
Synthesis of novel 5,6-substituted furo[2,3-d]pyrimidines via
Pd-catalyzed cyclization of alkynylpyrimidinols with aryl iodides
*
Zhende Liu, Dewen Li, Shukun Li, Donglu Bai, Xuchang He and Youhong Hu
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
Received 8 October 2006; revised 21 December 2006; accepted 22 December 2006
Available online 28 December 2006
Abstract—A flexible method for the synthesis of 5,6-disubstituted furo[2,3-d]pyrimidine derivatives is described. The key step is a palladium-
catalyzed arylative cyclization of alkynylpyrimidinols with various aryl iodides, which gave the title compounds in 36–75% yield.
Ó 2007 Elsevier Ltd. All rights reserved.
R1
N
OH
R1
N
1. Introduction
O
R3
O
R4I
8
+
N
N
+
Furo[2,3-d]pyrimidines exhibit valuable biological activities
such as antifolate,1 anticancer,2 antiviral,3 and inhibitions of
glycogen synthase kinase-3 (GSK-3)4 and Chk1 kinase.5
Generally, these compounds were synthesized by the conver-
sion of 2-amino-3-cyano-5-substituted furans to 4-amino-
furopyrimidines in several steps.2,4–6 Various benzofurans
have been obtained by palladium-catalyzed cyclization,7–12
but the preparation of heterocycle-fused furan by this method
is rare. In 1981, Robins and Barr reported the first nucleoside
analogues with furopyrimidine ring system, as by-products
in Pd/Cu-catalyzed Sonogashira coupling reactions13 of
terminal alkynes with 5-iodouracil nucleosides.14 Others
reported few examples to synthesize 2,4,6-substituted furo-
[2,3-d]pyrimidine analogues by Sonogashira coupling reac-
tion and direct cyclization from 5-iodopyrimidinones with
acetylene.3,15 So far, the known methods could not be
used to generate diversified multi-substituted furo[2,3-d]-
pyrimidines’ derivatives, which are important for library
generation.
R4
R2
N
R3
R2
9
6
R1
OH
O
R1
R3
+
N
H2N
NH
R2
OEt
I
5
1
2
R2 4
Figure 1. Retrosynthetic analysis of diversified furo[2,3-d]pyrimidines.
2. Results and discussion
To test the feasibility of our method, we first prepared 2-
substituted iodopyrimidinols 4 as important intermediates
by the condensation of ethyl 3-oxobutanoate 2 with methyl
or phenyl amidine 116 followed by iodination of the resulting
pyrimidinols 3.17 The products 4a (R1¼Me) and 4b (R1¼Ph)
were obtained in 49% and 90% yields, respectively (Fig. 2).
Considering the potent bioactivities of the compounds with
the furo[2,3-d]pyrimidine core, developing new strategy
to efficiently synthesize the novel multi-substituted furo-
[2,3-d]pyrimidine derivatives has attracted our attention. To
introduce diversified four substituents of furo[2,3-d]pyrim-
idine derivatives, our retrosynthetic analysis implicated the
use of amidines, b-keto esters, alkynes, and aryl halides as
the starting materials and palladium-catalyzed cascade cross
coupling-cyclization as the key step (Fig. 1).
AccordingtothegeneralSonogashirareactioncondition, iodo-
pyrimidinol 4a was treated with various phenyl acetylenes 5
in the presence of an excess of i-Pr2NEt, catalyzed by PdCl2-
(PPh3)2 and CuI in CH3CN at room temperature overnight to
afford the desired arylethynylpyrimidinols6 in low yields with
the direct cyclized by-products in high yield. To avoid the
R1
O
O
R1
N
OH
I
R1
N
OH
I2, NaOH
NaOEt
EtOH
OEt
+
R2
H2N
NH
N
N
1
2
3
4
R2
R2
Keywords: Furo[2,3-d]pyrimidines; Sonogashira coupling reaction; Palla-
dium-catalyzed cyclization.
R1 = Me, Ph;
R2 = Me
* Corresponding author. Tel.: +86 21 50806600x3518; fax: +86 21
50805896; e-mail: yhhu@mail.shcnc.ac.cn
Figure 2. Preparation of iodopyrimidinols 4.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.077

1932
Z. Liu et al. / Tetrahedron 63 (2007) 1931–1936
direct cyclized by-products, by decreasing the amount of the
base (i-Pr2NEt) to 1.0 equivalence the coupling of iodopyrim-
idinols 4a–b with a series of substituted phenyl acetylenes 5
gave the products 6a–g in good yields (Table 1, Method A).
by acetyl bromide, Sonogashira couplings of compound 7a
with alkyl acetylenes proceeded smoothly to furnish a mix-
ture of compounds 6h–i and the hydroxyl protected coupling
products, which could be transferred to the products 6h–i
by removal of acetyl group using hydrazine at 0 ꢀC in
THF (Table 1, Method B).
Unfortunately, the reaction of iodopyrimidinol 4b with alkyl
acetylene 5e did not proceed to give the corresponding 6h
under the same conditions. By raising reaction temperature
to 60 ꢀC, only the direct cyclized product was obtained. Af-
ter the hydroxyl group of iodopyrimidinol 4b was protected
Alkynylpyrimidinol 6a and iodobenzene (8a) were annu-
lated by palladium-catalyzed cyclization under the reported
conditions.9 The desired product 9a was obtained in 33%
Table 1. Preparation of alkynylpyrimidinols 6 by Sonogashira coupling
R1
N
OH
R1
N
OH
Method A
N
N
R3
I
5
R2
R3
R2
4
6
R1
N
OAc
5
Method B
N
I
R2
7 R1= Ph, 83%
Entry
1
Iodopyrimidinol
Alkyne
Method
Product
OH
Yield (%)
86
N
OH
A
N
N
N
I
5a
4a
6a
OH
F
F
N
2
3
4
4a
A
A
A
83
92
89
N
5b
5c
6b
OH
N
N
OMe
CF3
4a
OMe
CF3
6c
6d
OH
N
N
4a
5d
OH
F
Ph
N
OH
N
5
5b
A
53
N
Ph
I
N
4b
6e
OH
N
6
7
4b
5c
A
A
92
60
OMe
Ph
N
6f
OH
N
N
4b
5d
CF3
CN
Ph
6g
OH
Ph
N
OAc
N
N
CN
8
9
B
B
35
65
N
Ph
I
7a
5e
5f
6h
OH
N
N
Ph
7a
6i

Z. Liu et al. / Tetrahedron 63 (2007) 1931–1936
Table 2. Synthesis of multi-substituted furo[2,3-d]pyrimidines 9
1933
R1
N
R1
N
OH
N
R1
O
O
ArI, cat. Pd2(dba)3
R3
R3
N
N
N
+
bpy, Cs2CO3, MeCN
R3
Ar
6
9
10
Entry
R1
R3
Ar
Phenyl
4-Methoxyphenyl
Thiophen-2-yl
4-Methoxycarbonylphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
Yield of 9 (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Ph
p-Tolyl
p-Tolyl
p-Tolyl
p-Tolyl
2-Fluorophenyl
4-Methoxyphenyl
4-(Trifluoromethyl)phenyl
2-Fluorophenyl
4-Methoxyphenyl
4-(Trifluoromethyl)phenyl
3-Cyanopropyl
9a (57)
9b (70)
9c (55)
9d (36)
9e (75)
9f (43)
9g (48)
9h (75)
9i (49)
9j (68)
9k (38)
9
10
11
Ph
Ph
Ph
yield accompanied with the directly cyclized by-product 10a
(R1¼Me, R3¼p-tolyl). When Cs2CO3 was used as a soft
base, the cyclization yield of 6a with 8a was increased to
57% to give 9a as the major product (Table 2, Entry 1).
chromatography (TLC) on 0.15–0.20 mm precoated Merck
Silica Gel 60 F254, visualizing with ultraviolet light. Flash
column chromatography was performed on silica ZCX-II
(Qingdao Haiyang Chemical Co. Ltd., 200–300 mesh) using
reagent grade petroleum ether, dichloromethane, ethyl
acetate, and methanol. Ethyl acetoacetate, potassium
carbonate, and cesium carbonate were purchased from Sino-
pharm Chemical Reagent Co. Ltd. Acetamidine hydrochlo-
ride, benzamidine hydrochloride hydrate, copper(I) iodide,
and alkynes were purchased from Alfa Aesar GmbH &
Co. KG. Bis(triphenylphosphine) palladium(II) dichloride,
tris(dibenzylideneacetone) dipalladium(0), and aryl iodides
were purchased from Sigma–Aldrich Inc. 2,20-Bipyridine
was purchased from Tokyo Kasei Kogyo Co. Ltd. All other
commercial reagents were used without further purification,
unless otherwise indicated.
Subsequently, various aryl iodides were subjected to the cy-
clization under the improved reaction conditions as shown in
Table 2. It was found that the aryl iodide (1-iodo-4-methoxy-
benzene, 8b) with electron-donating group gave the best
result of 70% yield (Table 2, Entry 2), presumably due to
the favorable stabilization of ligation to palladium(0) com-
plex with triple bond. On the contrary, the methyl 4-iodo-
benzoate (8d) with electron-withdrawing group reacted
with arylethynylpyrimidinol 6a to afford product 9d in
low yield (Entry 4). Cyclization of compound 6a with iodo-
thiophene (8c) furnished the product 9c in 55% yield. Com-
pound 6a with the sterically hindered 2-iodotoluene and
2-iodonaphene, only produced the direct cyclized product
10a and recovered the starting material.
Melting points were determined in a capillary tube and were
uncorrected. 1H NMR and 13C NMR spectra were recorded
with Gemini-300 or Bruker AMX-400 spectrometers using
chloroform-d, DMSO-d6 or CF3COOD as solvents. Chemi-
cal shifts (d) reported in parts per million relative to chloro-
form-d (7.26 ppm 1H, 77.07 ppm 13C), DMSO-d6 (2.50 ppm
Substitution on aryl group of arylethynylpyrimidinols 6
didn’t show significant effects on the cyclization. Most of
the corresponding products 9 were obtained in moderate
yields. Compound 6h was cyclized with 4-methoxyl iodo-
benzene to give the product 9k in low yield. Sterically
hindered 6i gave complicated products.
1
1H, 39.52 ppm 13C), and CF3COOD (11.50 ppm H, 116.6
and 164.2 ppm 13C). Multiplicities are indicated by: s (sin-
glet), d (doublet), t (triplet), q (quartet), m (multiplet), br
s (broad singlet). Coupling constants (J) are reported in
hertz. Mass spectra were recorded with Varian MAT-711
and MAT-95 spectrometers.
3. Conclusion
In summary, we have developed an efficient method via
palladium-catalyzed cyclization to synthesize novel 2,4,5,6-
tetrasubstituted furo[2,3-d]pyrimidines. The method allows
for the generation of libraries of such compounds.
4.2. General procedure of the preparation
of pyrimidinols 3
To a solution of sodium (2.3 g, 0.1 mol) in EtOH (60 mL)
were added ethyl acetoacetate 2 (6.38 mL, 0.05 mol)
and amidine 1 (0.05 mol). The reaction mixture was
refluxed for 18 h and then cooled to room temperature.
The resulting mixture was adjusted to pH¼5.5 using con-
centrated HCl and concentrated. The residue was directly
purified by flash column chromatography to afford the
product 3.
4. Experimental
4.1. General methods
Reaction solvents were purchased from Sinopharm Chemi-
cal Reagent Co. Ltd. and were dried, distilled before use.
Ethanol was distilled over sodium and acetonitrile was dis-
tilled over CaH2. Reaction was monitored by thin layer
4.2.1. 2,6-Dimethylpyrimidin-4-ol (3a, R1¼R2¼Me).
Yield: 85%; white solid; mp 194–195.5 ꢀC (lit.16b 194.5–

1934
Z. Liu et al. / Tetrahedron 63 (2007) 1931–1936
1
3
195 ꢀC); H NMR (300 MHz, CDCl3): d 13.14 (br s, 1H),
6.17 (s, 1H), 2.46 (s, 3H), 2.29 (s, 3H).
1JC–F¼247.7 Hz), 160.9, 158.2, 133.0, 130.8 (d, JC–F
¼
¼
4
2
8.7 Hz), 124.8 (d, JC–F¼3.2 Hz), 115.7 (d, JC–F
3
20.4 Hz), 111.1 (d, JC–F¼15.5 Hz), 106.0, 90.7, 88.7,
22.9, 21.2; LRMS (EI) m/z 243 ([M+1]+), 242 (100, M+),
201; HRMS (EI) calcd for C14H11FN2O (M+): 242.0855,
found 242.0856.
4.2.2. 6-Methyl-2-phenylpyrimidin-4-ol (3b, R1¼Ph;
R2¼Me). Yield: 98%; yellow solid; mp 217–218 ꢀC
(lit.16d 218–219 ꢀC); H NMR (300 MHz, CDCl3): d 12.75
1
(br s, 1H), 8.18–8.15 (m, 2H), 7.57–7.50 (m, 3H), 6.30 (s,
1H), 2.40 (s, 3H).
4.4.3. 5-(2-(4-Methoxyphenyl)ethynyl)-2,6-dimethylpyr-
imidin-4-ol (6c). Yield: 92%; yellow solid; mp 158–159 ꢀC;
1H NMR (300 MHz, CDCl3): d 7.49 (d, J¼8.7 Hz, 2H),
6.88 (d, J¼8.7 Hz, 2H), 3.83 (s, 3H), 2.56 (s, 3H), 2.54 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d 166.6, 161.0,
159.4, 157.3, 132.6, 114.6, 114.4, 107.0, 97.7, 82.0, 55.3,
23.0, 21.2; LRMS (EI) m/z 255 ([M+1]+), 254 (21, M+),
239, 84 (100); HRMS (EI) calcd for C15H14N2O2 (M+):
254.1055, found 254.1065.
4.3. General procedure for the preparation of
iodopyrimidinols 4
To a well-stirred solution of 3 (10 mmol) in 1.25 N NaOH
(18 mL) was added iodine (2.80 g, 11 mmol). The reaction
mixture was refluxed for 2 h and then cooled to room tem-
perature. The mixture was extracted with CHCl3 for three
times. The organic phase was dried over Na2SO4, filtered,
and evaporated. The residue was purified by flash chromato-
graphy to afford the product 4.
4.4.4. 5-(2-(4-(Trifluoromethyl)phenyl)ethynyl)-2,6-di-
methylpyrimidin-4-ol (6d). Yield: 89%; white solid; mp
194–196 ꢀC; 1H NMR (300 MHz, CDCl3): d 7.66–7.59
4.3.1. 5-Iodo-2,6-dimethylpyrimidin-4-ol(4a).Yield: 49%;
(m, 4H), 2.57 (s, 3H), 2.55 (s, 3H); 13C NMR (100 MHz,
1
2
white solid; mp 196–199 ꢀC (lit.17b 198–203 ꢀC); H NMR
(300 MHz, CDCl3): d 2.59 (s, 3H), 2.47 (s, 3H); LRMS
DMSO-d6): d 168.1, 160.8, 158.4, 131.7, 128.6 (q, JC–F
¼
1
31.9 Hz), 126.9, 125.6, 124.0 (d, JC–F¼270.6 Hz), 105.7,
96.1, 86.3, 23.1, 21.2; LRMS (EI) m/z 293 ([M+1]+), 292
(M+), 251, 149 (100); HRMS (EI) calcd for C15H11F3N2O
(M+): 292.0823, found 292.0830.
(EI) m/z 250 (100, M+).
4.3.2. 5-Iodo-6-methyl-2-phenylpyrimidin-4-ol (4b).
Yield: 90%; white solid; mp 239–240 ꢀC (lit.17b 249–
1
251 ꢀC); H NMR (300 MHz, CDCl3): d 12.26 (br s, 1H),
4.4.5. 5-(2-(2-Fluorophenyl)ethynyl)-6-methyl-2-phenyl-
pyrimidin-4-ol (6e). Yield: 53%; yellow solid; mp 205–
8.25–8.22 (m, 2H), 7.60–7.53 (m, 3H), 2.70 (s, 3H); LRMS
(EI) m/z 313 ([M+1]+), 312 (100, M+), 209, 104; HRMS
(EI) calcd for C11H9IN2O (M+): 311.9760, found 311.9757.
1
206 ꢀC; H NMR (300 MHz, CDCl3): d 11.83 (br s, 1H),
8.21–8.18 (m, 2H), 7.60–7.53 (m, 4H), 7.39–7.31 (m, 1H),
7.18–7.11 (m, 2H), 2.70 (s, 3H); 13C NMR (100 MHz,
1
4.4. General procedure for the preparation of alkynyl-
pyrimidinols 6 by Sonogashira reaction
DMSO-d6): d 167.7, 161.7 (d, JC–F¼248.1 Hz), 155.2,
133.1, 132.1, 131.9, 131.1 (d, 3JC–F¼8.2 Hz), 128.8, 128.1,
4
2
124.9 (d, JC–F¼3.2 Hz), 115.8 (d, JC–F¼20.5 Hz), 111.0
3
A
mixture of iodopyrimidinol (1.00 mmol), alkyne
(d, JC–F¼15.4 Hz), 91.7, 88.9, 23.3; LRMS (EI) m/z 305
(1.20 mmol), copper(I) iodide (0.05 mmol), dichlorobis(tri-
phenylphosphine)-palladium (0.05 mmol), and diisopropyl-
ethylamine (1.00 mmol) in dry acetonitrile (10 mL) or DMF
(5 mL) was stirred at 25–40 ꢀC for 24 h under N2 protection.
The reaction mixture was filtered and the solid phase was
washed with methanol (10 mL). The filtrate was concen-
trated, and the residue was purified by flash column chroma-
tography to afford the coupling products 6a–g (Method A).
For compounds 6h and 6i, the reactant was changed
into the corresponding hydroxyl protected iodopyrimidinol
(Method B).
([M+1]+), 304 (M+), 277, 201, 149 (100); HRMS (EI) calcd
for C19H13FN2O (M+): 304.1012, found 304.1019.
4.4.6. 5-(2-(4-Methoxyphenyl)ethynyl)-6-methyl-2-phe-
nylpyrimidin-4-ol (6f). Yield: 92%; yellow solid; mp
157–160 ꢀC; 1H NMR (300 MHz, CDCl3): d 8.23–8.20
(m, 2H), 7.56–7.51 (m, 5H), 6.91 (d, J¼8.7 Hz, 2H), 3.86
(s, 3H), 2.66 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 166.4, 159.6, 154.5, 132.7, 131.9, 128.7, 127.9, 114.6,
114.4, 98.9, 82.3, 55.3, 23.3; LRMS (EI) m/z 317
([M+1]+), 316 (100, M+), 301, 277, 149; HRMS (EI) calcd
for C20H16N2O2 (M+): 316.1212, found 316.1212.
4.4.1. 2,6-Dimethyl-5-(2-p-tolylethynyl)pyrimidin-4-ol
1
(6a). Yield: 86%; white solid; mp 151–153 ꢀC; H NMR
4.4.7. 5-(2-(4-(Trifluoromethyl)phenyl)ethynyl)-6-
methyl-2-phenylpyrimidin-4-ol (6g). Yield: 60%; yellow
(300 MHz, CDCl3): d 12.73 (br s, 1H), 7.45 (d, J¼8.4 Hz,
2H), 7.15 (d, J¼8.4 Hz, 2H), 2.56 (s, 3H), 2.54 (s, 3H),
2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 166.9,
161.0, 157.6, 138.4, 131.0, 129.4, 119.7, 106.5, 97.8, 82.9,
23.1, 21.2, 21.0; LRMS (EI) m/z 239 ([M+1]+), 238 (100,
M+), 197; HRMS (EI) calcd for C15H14N2O (M+):
238.1106, found 238.1115.
1
solid; mp 204–207 ꢀC; H NMR (300 MHz, CF3COOD):
d 7.91 (d, J¼8.1 Hz, 2H), 7.81 (t, J¼7.5 Hz, 1H), 7.65–
7.53 (m, 6H), 2.77 (s, 3H); 13C NMR (75 MHz, CF3COOD):
2
d 160.9, 159.9, 139.8, 134.88 (q, JC–F¼32.2 Hz), 134.3,
132.8, 130.6, 127.6, 127.5, 126.4, 124.9, 124.1, 113.6,
106.5, 79.4, 19.9; LRMS (EI) m/z 354 (M+), 277 (100);
HRMS (EI) calcd for C20H13F3N2O (M+): 354.0980, found
354.0976.
4.4.2. 5-(2-(2-Fluorophenyl)ethynyl)-2,6-dimethylpyr-
imidin-4-ol (6b). Yield: 83%; white solid; mp 117–119 ꢀC;
1H NMR (300 MHz, CDCl3): d 7.57–7.52 (m, 1H), 7.37–
7.29 (m, 1H), 7.16–7.07 (m, 2H), 2.58 (s, 3H), 2.54 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d 167.7, 161.6 (d,
4.4.8. 6-(4-Hydroxy-6-methyl-2-phenylpyrimidin-5-yl)-
hex-5-ynonitrile (6h). Yield: 35%; white solid; mp 145–
1
148 ꢀC; H NMR (300 MHz, CDCl3): d 11.95 (br s, 1H),

Z. Liu et al. / Tetrahedron 63 (2007) 1931–1936
1935
1
8.14–8.12 (m, 2H), 7.56–7.53 (m, 3H), 2.74 (t, J¼6.9 Hz,
2H), 2.57 (t, J¼7.2 Hz, 2H), 2.56 (s, 3H), 2.05–1.96 (m,
2H); 13C NMR (100 MHz, CDCl3): d 168.5, 164.4, 154.1,
132.2, 131.6, 128.8, 128.0, 119.1, 108.1, 97.9, 75.3, 24.7,
23.7, 19.0, 16.2; LRMS (EI) m/z 278 ([M+1]+), 277 (100,
M+), 223; HRMS (EI) calcd for C17H15N3O (M+):
277.1215, found 277.1211.
186 ꢀC; H NMR (300 MHz, CDCl3): d 8.17 (d, J¼8.4 Hz,
2H), 7.52 (d, J¼8.4 Hz, 2H), 7.39 (d, J¼8.4 Hz, 2H), 7.09
(d, J¼8.4 Hz, 2H), 3.97 (s, 3H), 2.81 (s, 3H), 2.32 (s, 3H),
2.28 (s, 3H); 13C NMR (100 MHz, CDCl3): d 166.6, 165.6,
163.0, 160.8, 149.7, 139.5, 137.7, 130.5, 130.3, 129.3,
126.8, 126.0, 116.1, 113.9, 52.3, 25.7, 21.8, 21.3; LRMS
(EI) m/z 373 ([M+1]+), 372 (100, M+), 238, 119; HRMS
(EI) calcd for C23H20N2O3 (M+): 372.1474, found 372.1475.
4.4.9. 6-Methyl-5-(3,3-dimethylbut-1-ynyl)-2-phenylpyr-
imidin-4-ol (6i). Yield: 65%; white solid; mp 199–201 ꢀC;
1H NMR (300 MHz, CDCl3): d 8.27–8.24 (m, 2H), 7.55–
7.52 (m, 3H), 2.56 (s, 3H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 168.0, 164.5, 153.7, 131.8, 128.7,
128.0, 109.5, 108.7, 71.9, 31.1, 28.6, 23.6; LRMS (EI) m/z
266 (50, M+), 251 (100); HRMS (EI) calcd for C17H18N2O
(M+): 266.1419, found 266.1423.
4.5.5. 6-(2-Fluorophenyl)-5-(4-methoxyphenyl)-2,4-di-
methylfuro[2,3-d]pyrimidine (9e). Yield: 75%; colorless
oil; H NMR (300 MHz, CDCl3): d 7.51–7.45 (m, 1H),
1
7.41–7.33 (m, 1H), 7.29–7.27 (m, 2H), 7.17–7.08 (m, 2H),
6.95 (d, J¼6.9 Hz, 2H), 3.88 (s, 3H), 2.83 (s, 3H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3): d 166.3, 163.1, 161.6,
1
159.7 (d, JC–F¼252.8 Hz), 159.5, 145.4, 131.2, 131.1 (d,
4JC–F¼3.6 Hz), 131.0, 124.0, 123.8, 118.4, 117.5 (d, 3JC–F
¼
2
4.5. General procedure for the synthesis of furo[2,3-d]-
pyrimidines 9
16.6 Hz), 116.3 (d, JC–F¼21.4 Hz), 115.5, 114.0, 55.2,
25.8, 22.1; LRMS (EI) m/z 348 (14, M+), 156, 86, 84
(100); HRMS (EI) calcd for C21H17FN2O2 (M+):
348.1274, found 348.1269.
To a solution of alkynylpyrimidinol (0.500 mmol), ArI
(1.00 mmol), bpy (0.100 mmol), Cs2CO3 (1.00 mmol), and
acetonitrile (20 mL) was added Pd2(dba)3 (0.025 mmol)
under N2 atmosphere. The reaction was stirred at 50 ꢀC for
24 h. The mixture was filtered and the solid phase was
washed with methanol (10 mL). The filtrate was concen-
trated and the residue was purified by flash column chroma-
tography to afford the corresponding product.
4.5.6. 5,6-Bis(4-methoxyphenyl)-2,4-dimethylfuro-
[2,3-d]pyrimidine (9f). Yield: 43%; white solid; mp 138–
141 ꢀC; 1H NMR (300 MHz, CDCl3): d 7.50 (d, J¼9.0 Hz,
2H), 7.32 (d, J¼9.0 Hz, 2H), 7.02 (d, J¼9.0 Hz, 2H), 6.81
(d, J¼9.0 Hz, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 2.78 (s, 3H),
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3): d 165.8, 162.3,
160.6, 160.0, 159.6, 149.4, 131.5, 128.2, 124.5, 122.0,
116.7, 114.5, 114.0, 113.5, 55.3, 55.2, 25.7, 21.6; LRMS
(EI) m/z 360 (40, M+), 254 (100), 239, 156, 84; HRMS
(EI) calcd for C22H20N2O3 (M+): 360.1474, found 360.1467.
4.5.1. 2,4-Dimethyl-5-phenyl-6-p-tolylfuro[2,3-d]pyrimi-
1
dine (9a). Yield: 57%; white solid; mp 103–106 ꢀC; H
NMR (300 MHz, CDCl3): d 7.51–7.48 (m, 3H), 7.45–7.40
(m, 4H), 7.09 (d, J¼8.4 Hz, 2H), 2.79 (s, 3H), 2.32 (s,
3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3): d 165.5,
162.6, 160.9, 149.3, 139.0, 132.6, 130.3, 129.2, 129.1,
128.4, 126.6, 126.4, 116.4, 114.8, 25.8, 21.7, 21.3; LRMS
(EI) m/z 315 ([M+1]+), 314 (100, M+), 173; HRMS (EI)
calcd for C21H18N2O (M+): 314.1419, found 314.1423.
4.5.7. 6-(4-(Trifluoromethyl)phenyl)-5-(4-methoxy-
phenyl)-2,4-dimethylfuro[2,3-d]pyrimidine (9g). Yield:
48%; white solid; mp 47–49 ꢀC; 1H NMR (300 MHz,
CDCl3): d 7.67 (d, J¼8.4 Hz, 2H), 7.54 (d, J¼8.7 Hz, 2H),
7.34 (d, J¼8.4 Hz, 2H), 7.05 (d, J¼8.7 Hz, 2H), 3.91 (s,
3H), 2.80 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz,
CDCl3): d 166.1, 164.0, 162.4, 160.4, 147.9, 133.1, 131.5,
4.5.2. 5-(4-Methoxyphenyl)-2,4-dimethyl-6-p-tolyl-
furo[2,3-d]pyrimidine (9b). Yield: 70%; white solid; mp
133–136 ꢀC; 1H NMR (300 MHz, CDCl3): d 7.46 (d,
J¼8.1 Hz, 2H), 7.32 (d, J¼6.6 Hz, 2H), 7.09 (d, J¼8.1 Hz,
2H), 7.02 (d, J¼6.6 Hz, 2H), 3.90 (s, 3H), 2.79 (s, 3H),
2.32 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 165.5, 162.6, 161.0, 159.7, 158.4, 149.5, 139.0, 131.4,
129.2, 126.6, 124.4, 116.7, 114.5, 55.3, 25.7, 21.6, 21.3;
LRMS (EI) m/z 345 ([M+1]+), 344 (100, M+), 119; HRMS
(EI) calcd for C22H20N2O2 (M+): 344.1525, found 344.1531.
2
1
130.6 (q, JC–F¼32.8 Hz), 127.0, 125.8, 124.1 (q, JC–F
¼
270.5 Hz), 123.9, 117.8, 116.7, 115.2, 55.6, 26.2, 22.0;
LRMS (EI) m/z 399 ([M+1]+), 398 (100, M+), 173; HRMS
(EI) calcd for C22H17F3N2O2 (M+): 398.1242, found
398.1243.
4.5.8. 6-(2-Fluorophenyl)-5-(4-methoxyphenyl)-4-
methyl-2-phenylfuro[2,3-d]pyrimidine (9h). Yield: 75%;
white solid; mp 130–132 ꢀC; 1H NMR (300 MHz, CDCl3):
d 8.57–8.54 (m, 2H), 7.52–7.48 (m, 3H), 7.39–7.26 (m,
4H), 7.15–7.03 (m, 2H), 6.95 (d, J¼8.7 Hz, 2H), 3.86 (s,
3H), 2.51 (s, 3H); 13C NMR (100 MHz, CDCl3): d 166.6,
4.5.3. 2,4-Dimethyl-5-(thiophen-2-yl)-6-p-tolylfuro[2,3-d]-
pyrimidine (9c). Yield: 55%; white solid; mp 126–130 ꢀC;
1H NMR (300 MHz, CDCl3): d 7.55–7.52 (m, 3H),
7.21–7.18 (m, 1H), 7.16–7.14 (m, 2H), 7.13–7.12 (m, 1H),
2.80 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 165.6, 163.2, 161.4, 151.6, 139.8,
132.6, 129.5, 129.4, 128.0, 127.9, 126.9, 126.1, 116.8,
107.3, 25.6, 21.2, 21.0; LRMS (EI) m/z 321 ([M+1]+), 320
(100, M+), 119, 91; HRMS (EI) calcd for C19H16N2OS
(M+): 320.0983, found 320.0990.
1
161.9, 159.9, 159.8 (d, JC–F¼253.2 Hz), 159.5, 146.2,
137.6, 131.2, 131.1, 131.0, 130.3, 128.5, 128.3, 124.0,
3
123.9, 118.8, 117.6 (d, JC–F¼13.6 Hz), 116.44, 116.39 (d,
2JC–F¼21.4 Hz), 114.0, 55.2, 22.5; LRMS (EI) m/z 411
([M+1]+), 410 (100, M+), 233, 123; HRMS (EI) calcd for
C26H19FN2O2 (M+): 410.1431, found 410.1388.
4.5.9. 5,6-Bis(4-methoxyphenyl)-4-methyl-2-phenyl-
furo[2,3-d]pyrimidine (9i). Yield: 49%; yellow solid; mp
145–146 ꢀC; 1H NMR (300 MHz, CDCl3): d 8.55–8.51
(m, 2H), 7.55 (d, J¼8.7 Hz, 2H), 7.50–7.48 (m, 3H), 7.37
4.5.4. Methyl 4-(2,4-dimethyl-6-p-tolylfuro[2,3-d]pyrim-
idin-5-yl)benzoate (9d). Yield: 36%; white solid; mp 184–

1936
Z. Liu et al. / Tetrahedron 63 (2007) 1931–1936
3. (a) Balzarini, J.; McGuigan, C. J. Antimicrob. Chemother.
2002, 50, 5–9; (b) Janeba, Z.; Maklad, N.; Robins, M. J.
Nucleosides Nucleotides Nucleic Acids 2005, 24, 1729–1743;
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Andrei, G.; Snoeck, R.; De Clercq, E.; Robins, M. J. J. Med.
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Sergeant, C.; Dembinski, R. J. Org. Chem. 2003, 68, 6788–
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4. Maeda, Y.; Nakano, M.; Sato, H.; Miyazaki, Y.; Schweiker,
S. L.; Smith, J. L.; Truesdale, A. T. Bioorg. Med. Chem. Lett.
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(d, J¼8.4 Hz, 2H), 7.05 (d, J¼8.4 Hz, 2H), 6.83 (d,
J¼8.7 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3): d 165.9, 160.9, 160.1,
159.7, 159.3, 150.2, 137.8, 131.5, 130.1, 128.5, 128.3,
128.2, 124.6, 122.1, 117.7, 114.6, 114.0, 113.9, 55.30,
55.27, 22.03; LRMS (EI) m/z 423 ([M+1]+), 422 (100,
M+), 407, 316, 149; HRMS (EI) calcd for C27H22N2O3
(M+): 422.1630, found 422.1615.
4.5.10. 6-(4-(Trifluoromethyl)phenyl)-5-(4-methoxy-
phenyl)-4-methyl-2-phenylfuro[2,3-d]pyrimidine (9j).
Yield: 68%; yellow solid; mp 188–192 ꢀC; 1H NMR
(300 MHz, CDCl3): d 8.55–8.52 (m, 2H), 7.71 (d,
J¼8.4 Hz, 2H), 7.55 (d, J¼9.0 Hz, 2H), 7.50–7.48 (m,
3H), 7.36 (d, J¼8.4 Hz, 2H), 7.07 (d, J¼8.4 Hz, 2H), 3.91
(s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 166.0, 162.3, 160.5, 160.1, 148.2, 137.5, 132.8, 131.2,
130.5, 128.6, 128.4, 126.8, 125.5, 123.8, 117.9 117.2,
114.9, 55.4, 22.1; LRMS (EI) m/z 461 ([M+1]+), 460 (100,
M+), 173; HRMS (EI) calcd for C27H19F3N2O2 (M+):
460.1399, found 460.1398.
6. Lockhart, C. C.; Sowell, J. W. J. Heterocycl. Chem. 1996, 33,
659–661.
7. Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem.
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4.5.11. 4-(5-(4-Methoxyphenyl)-4-methyl-2-phenyl-
furo[2,3-d]pyrimidin-6-yl)butanonitrile (9k). Yield:
1
38%; white solid; mp 114–116 ꢀC; H NMR (300 MHz,
10. Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron
Lett. 2004, 45, 1861–1864.
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CDCl3): d 8.54–8.50 (m, 2H), 7.51–7.48 (m, 3H), 7.30 (d,
J¼8.7 Hz, 2H), 7.05 (d, J¼8.7 Hz, 2H), 3.90 (s, 3H), 2.92
(t, J¼7.5 Hz, 2H), 2.46 (s, 3H), 2.42 (t, J¼6.9 Hz, 2H),
2.19–2.09 (m, 2H); 13C NMR (100 MHz, CDCl3): d 166.4,
161.0, 159.7, 159.5, 151.9, 137.6, 131.2, 130.3, 128.5,
128.2, 123.0, 118.8, 117.2, 115.9, 114.2, 55.3, 25.1, 23.7,
22.2, 16.6; LRMS (EI) m/z 384 ([M+1]+), 383 (70, M+),
329, 277, 223 (100); HRMS (EI) calcd for C24H21N3O2
(M+): 383.1634, found 383.1639.
14. Robins, M. J.; Barr, P. J. Tetrahedron Lett. 1981, 22, 421–424.
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Acknowledgements
This work was supported by the Hundred Talent Project of
the Chinese Academy of Sciences.
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