Focused microwave-assisted efficient and convenient synthesis of new pyrido[2,3-d] pyrimidinone derivatives

Article abstract of DOI:10.1515/hc-2012-0131

A rapid and efficient method for the preparation of new pyrido[2,3-d]pyrimidinone derivatives by the condensation of 2-amino-4-aryl-6-arylnicotinamides with carbon disulfide or cycloalkanones under focused microwave irradiation is described.

Full text of DOI:10.1515/hc-2012-0131

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0131ꢀ ꢀHeterocycl. Commun. 2012; 18(5-6): 257–261
Zheng-Jun Quan*, Jun-Ling Liang, Lin Bai, Zhang Zhang, Yu-Xia Da and Xi-Cun Wang*
Focused microwave-assisted efficient and
convenient synthesis of new pyrido[2,3-d ]
pyrimidinone derivatives
Abstract: A rapid and efficient method for the preparation methods for the synthesis of heterocyclic compounds has
of new pyrido[2,3-d]pyrimidinone derivatives by the con- been posing a real challenge to organic chemists for over
densation of 2-amino-4-aryl-6-arylnicotinamides with car- a century. For example, the 4(3H)-quinazolinone moiety
bon disulfide or cycloalkanones under focused microwave has been found in several bioactive natural products
irradiation is described.
(Welch et al., 2001; Saleh et al., 2004). Many different
classes of ligands have been designed, synthesized, and
Keywords: cyclization; microwave; pyrido[2,3-d]pyrimidi- tested at the A1 receptor as antagonists, and these encom-
none; synthesis.
pass all kinds of different mono-, bi-, tri-, and even quad-
ricyclic mostly nitrogen-containing aromatic compounds
(Chang et al., 2004). In addition, 2-spiroquinazolinones
are an important class of fused heterocycles that have
attracted significant interest in medicinal chemistry, in
view of their great variety of biological and pharmaceuti-
cal activities (Hirose et al., 1973; Tinker et al., 2003; Birch
et al., 2005; Mustazza et al., 2006). Quinazolinones are
also useful synthetic materials in heterocyclic chemis-
try (Hsu et al., 2008). There are a number of synthetic
methods available for the preparation of quinazolinones
using N-(2-cyanoaryl)amides (Kim et al., 2010), 2-ami-
nobenzonitrile (Kabri et al., 2009), 2-aminobenzamide
(Bakavoli et al., 2007a), and isatoic anhydride (Baka-
voli et al., 2007b) as common starting materials. New
synthesis of pyrazolo[3,4-d]pyrimidine derivatives by
the reaction of 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyra-
zolcarboxamides with aromatic aldehydes has been
described (Bakavoli et al., 2010). The preparation of
* Corresponding authors: Zheng-Jun Quan and Xi-Cun Wang, K e y
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, China,
e-mail: quanzhengjun@hotmail.com; wangxicun@nwnu.edu.cn
Jun-Ling Liang, Zhang Zhang and Yu-Xia Da: Key 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, China
Lin Bai: Institute of Green Chemistry Experiment and Teaching,
Lanzhou City University, Lanzhou 730070, China
Introduction
Microwave irradiation (MWI) has been utilized extensively spiro[cyclohexane-1,2′(1′H)-quinazolin]-4′(3′H)-one has
as a clean source of energy for the synthesis of organic also been reported (Miklós and Fülöp, 2010). However,
compounds (Galema, 1997; Van Eldik and Hubbard, the preparation of pyrido[2,3-d]pyrimidinone derivatives
1997; Varma, 1999). Some important reviews have been by using the MWI method has not been reported previ-
published in recent years, covering a large number of ously. Herein, we report a rapid and efficient procedure
microwave induced reactions (Dallinger and Kappe, 2007; to synthesize pyrido[2,3-d]pyrimidinone derivatives by
Polshettiwar and Varma, 2008). We have reported the PS- condensation of 2-amino-4-aryl-6-arylnicotinamides with
supported, Pd(II)-catalyzed coupling reaction which was carbon disulfide or cycloalkanones using a focused MWI
performed in a focused microwave synthesis system so method (Scheme 1).
that it is possible to control the temperature, pressure,
microwave power, and reaction time very easily and with
a high degree of reproducibility (Bai et al., 2004; Bai and
Wang, 2008).
Results and discussion
Heterocyclic systems are common structural elements
in many natural products and pharmacologically active To synthesize pyrido[2,3-d]pyrimidinone derivatives
substances. Accordingly, the development of efficient 2 and 3, various 2-amino-4-aryl-6-arylnicotinamides 1
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ꢀZ.-J. Quan et al.: Synthesis of new pyrido[2,3-d]pyrimidinone derivatives
R1
R1
R1
O
O
O
O
n
CS2, KOH
DMF, MW
NH2
NH2
NH
SH
NH
CuCl2, DMF, MW
N
N
N
N
N
H
n
R2
R2
R2
2a-m
1
3a-j
2a: R1 = R2 = H; 2b: R1 = 4-Cl, R2 = H; 2c: R1 = 4-Me, R2 = H; 2d: R1 = 4-MeO, R2 = H; 2e: R1 = 4-F, R2 = H
2f: R1 = 2-MeO, R2 = H; 2g: R1 = 4-Br, R2 = H; 2h: R1 = H, R2 = 4-Br; 2i: R1 = 4-Me, R2 = 4-Br
2j: R1 = 4-Cl, R2 = 4-Br; 2k: R1 = 4-F, R2 = 4-Br; 2l: R1 = 4-Br, R2 = 4-Br; 2m: R1 = 4-MeO, R2 = 4-Br;
3a: R1 = R2 = H, n = 1; 3b: R1 = R2 = H, n = 2; 3c: R1 = 4-Cl, R2 = H, n = 1; 3d: R1 = 4-Cl, R1 = H, n = 2
3e: R1 = 4-Me, R2 = H, n = 1; 3f: R1 = 4-Me, R2 = H, n = 2; 3g: R1 = 4-F, R2 = H, n = 1; 3h: R1 = 4-F, R2 = H, n = 2
3i: R1 = 4-Br, R2 = 4-Br, n = 2; 3j: R1 = 4-Me, R2 = 4-Br, n = 1;
Scheme 1ꢀSynthesis of pyrido[2,3-d]pyrimidinone derivatives.
were employed as starting materials to develop a cluster electron-donating, electron-neutral, and electron-with-
of new compounds and corresponding key intermediates drawing substituents on the benzene ring. The formation
according to a known procedure (Kambe et al., 1980; of six-membered spiro products (n=2) is more efficient
Chang et al., 2007). Initially, our study was performed (Scheme 1).
by the focused microwave-promoted model reaction of
In the absence of focused MWI the reaction times
1a with carbon disulfide which furnished the expected are long and the yields are quite low. The results of many
compound 2a (Scheme 1). The best yield (81%) of 2a was experiments under different conditions show that the syn-
obtained by carrying out the reaction in DMF at 155°C, thesis of compounds 2 and 3 under focused MWI is 24–45
with MW energy of 10 W for 15 min using substrate 1a times faster in comparison to the classical heating method
(1 mmol), CS2 (2 mmol), and KOH (3 mmol). Other bases and the yields (>80%) are higher than in the conventional
including K2CO3, NaOH or K3PO4 could also be used, heating method (<30%). Although the beneficial MWI in
although the yields of 2a were lower. The use of NaOH organic synthesis has been in use in varied research fields
was especially disadvantageous to give product 2a in a for many years, the mode of action is not yet fully under-
low yield of 40%. Product 2a could not be obtained in the stood (Herrero et al., 2008; Kappe, 2008).
absence of base. After experimenting with various bases,
base quantity, reaction time, and reaction temperature,
the optimized conditions for the preparation of 2a are as
follows: 1a (1 mmol), CS2 (2 mmol), KOH (3 mmol), and
Conclusions
DMF (2 mL), focused MWI at 10 W. Under these optimal
A simple and efficient practical method for heterocycliza-
conditions, we used various 2-amino-4-aryl-6-arylnico-
tion of 2-amino-4-aryl-6-arylnicotinamides 1 to products
tinamides 1 to test the reaction scope. A wide array of
2a–m and 3a–j has been developed. The salient features
substrates 1 containing an electron-withdrawing group
include high yields and ease of work-up.
and/or an electron-donating group were efficiently
reacted with CS2 giving the corresponding pyrido[2,3-d]
pyrimidinones 2a–m in good to excellent isolated yields
(74–95%).
Experimental
After successful preparation of compounds 2a–m,
another synthetic method was examined by the cycliza-
IR spectra were measured using KBr pellets on a Digilab Merlin FT-IR
spectrophotometer. H NMR spectra (400 MHz) and 13C NMR spectra
tion of 2-amino-4-aryl-6-arylnicotinamides 1 with cycloal-
kanones, including cyclopentanone and cyclohexanone,
in the presence of CuCl2 and using DMF as the solvent
under focused MWI at 200°C, 10 W (Scheme 1). The cor-
responding products spiro[cycloalkane-1,2′-(1′H)-5-aryl-
7-arylpyrido[2,3-d]pyrimidin]-4′(3′H)-ones 3a–j were
obtained in moderate to good yields (70–95%) within
8 min. The yields are good for the reactions of 1 bearing
1
(100 MHz) were recorded on a Mercury plus 400 MHz spectrometer
in DMSO-d6 with TMS as an internal standard. Melting points were
determined on an XT-4 electrothermal micromelting point apparatus
and are uncorrected. Mass spectra were obtained on a Bruker Dal-
tonics APEXII 47e FT-ICR spectrometer. Elemental analyses were per-
formed on a Carlo-Erba 1106 Elemental Analysis instrument. Micro-
wave reactions were conducted using a CEM Focused Microwave™
Synthesis System (CEM Corp., Matthews, NC, USA). All experiments
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ꢀ259
were performed using a stirring option whereby the contents of the 105.6; MS (EI) m/z 349 (M+). Anal. Calcd for C19H12FN3OS: C, 65.32; H,
vessel are stirred by means of a rotating magnetic plate located below 3.46; N, 12.03. Found: C, 65.44; H, 3.59; N, 11.95.
the floor of the microwave cavity and a Teflon coated magnetic stir
bar in the vessel.
2-Mercapto-5-(2-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimi-
din-4(3H)-one (2f)ꢀMp > 250°C; yield; 83%; IR: 3163, 3061, 2930,
2860, 1669, 1588, 1548, 1496, 1364, 1173, 753 cm-1; 1H NMR: δ 13.16 (br,
1H), 12.38 (br, 1H), 8.24 (m, 2H), 7.70–6.81 (m, 8H), 3.82 (s, 3H); 13C
NMR: δ 174.3, 160.5, 148.8, 142.7, 142.0, 127.2, 126.5, 123.2, 121.0, 120.7,
119.0, 117.7, 117.5, 109.0, 100.1, 57.7; MS (EI) m/z 361 (M+). Anal. Calcd
for C20H15N3O2S: C, 66.46; H, 4.18; N, 11.63. Found: C, 66.23; H, 4.42;
N, 11.67.
General procedure for the synthesis of
5-aryl-2-mercapto-7-arylpyrido[2,3-d]-
pyrimidin-4(3H)-ones 2a–m
In a 10-mL glass tube were placed 2-amino-4-aryl-6-arylnicotinamide
1 (1 mmol), CS2 (2 mmol), KOH (3 mmol), DMF (2 mL), and a mag-
netic stir bar. The vessel was sealed with a septum and placed in
the microwave cavity. Microwave irradiation of 10 W was used; the
temperature ramped from room temperature to 155°C. Once 155°C
was reached, the reaction mixture was held at this temperature for
15 min. Afer cooling, the tube was opened and the contents poured
into a flask. Then water was added and the resultant precipitate was
filtered and crystallized from DMF/ethanol.
5-(4-Bromophenyl)-2-mercapto-7-phenylpyrido[2,3-d]pyrimi-
din-4(3H)-one (2g)ꢀMp > 250°C; yield 78%; IR: 3128, 3063, 2903,
1
2541, 1677, 1595, 1553, 1492, 1406, 1176, 772 cm-1; H NMR: δ 13.27 (br,
1H), 12.56 (br, 1H), 8.25 (m, 2H), 7.68–7.42 (m, 8H); 13C NMR: δ 175.3,
159.6, 158.8, 152.6, 152.4, 137.6, 136.5, 133.2, 131.0, 130.5, 129.1, 127.7,
121.9, 119.0, 108.0; MS (EI) m/z 409 (M+). Anal. Calcd for C19H12BrN3OS:
C, 55.62; H, 2.95; N, 10.24. Found: C, 55.46; H, 3.20; N, 10.27.
7-(4-Bromophenyl)-2-mercapto-5-phenylpyrido[2,3-d]pyrimi-
din-4(3H)-one (2h)ꢀMp > 250°C; yield 83%; IR: 3092, 3058, 2868,
2541, 1705, 1647, 1595, 1566, 1402, 1185, 765 cm-1; 1H NMR: δ 13.15
(br, 1H), 12.46 (br, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.95–7.44 (m, 8H); 13C
NMR: δ 175.2, 158.6, 158.2, 154.0, 152.6, 138.3, 135.7, 132.0, 129.7, 128.8,
128.3, 127.6, 124.8, 119.2, 108.3; MS (EI) m/z 409 (M+). Anal. Calcd for
C19H12BrN3OS: C, 55.62; H, 2.95; N, 10.24. Found: C, 55.77; H, 3.07; N,
10.17.
2-Mercapto-5,7-diphenylpyrido[2,3-d]pyrimidin-4(3H)-oneꢀ(2)ꢀ
Mp > 250°C; yield 81%; IR: 3107, 3051, 2892, 1682, 1597, 1555, 1496,
1406, 1177, 766 cm-1;1H NMR: δ 13.20 (br, 1H), 12.40 (br, 1H), 8.24 (d, J =
6.4 Hz, 2H), 7.65–7.43 (m, 9H); 13C NMR: δ 175.5, 159.3, 159.1, 154.1, 153.5,
138.7, 136.8, 130.8, 129.0, 128.7, 128.1, 127.6, 127.5, 118.7, 108.2; MS (EI)
m/z 331 (M+). Anal. Calcd for C19H13N3OS: C, 68.86; H, 3.95; N, 12.68.
Found: C, 68.98; H, 4.08; N, 12.60.
7-(4-Bromophenyl)-2-mercapto-5-(p-tolyl)pyrido[2,3-d]pyrimi-
din-4(3H)-one (2i)ꢀMp > 250°C; yield 95%; IR: 3042, 2911, 2482, 1590,
1553, 1510, 1493, 1152, 812, 712 cm-1; 1H NMR: δ 13.18 (br, 1H), 12.47 (br,
1H), 8.24 (m, 2H), 7.65–7.33 (m, 7H), 2.40 (s, 3H); 13C NMR: δ 174.1, 158.5,
157.7, 152.8, 151.7, 136.8, 135.6, 134.5, 129.9, 128.0, 127.9, 126.4, 125.7, 118.3,
108.0, 19.7; MS (EI) m/z 423 (M+). Anal. Calcd for C20H14BrN3OS: C, 56.61;
H, 3.33; N, 9.90. Found: C, 56.81; H, 3.41; N, 9.87.
5-(4-Chlorophenyl)-2-mercapto-7-phenylpyrido[2,3-d]pyrimi-
din-4(3H)-one (2b)ꢀMp > 250°C; yield 88%; IR: 3125, 3047, 2899,
1
2539, 1676, 1597, 1555, 1494, 1176, 772 cm-1; H NMR: δ 13.14 (br, 1H),
12.43 (br, 1H), 8.24 (m, 2H), 7.66–7.49 (m, 8H); 13C NMR: δ 175.3, 159.5,
158.8, 152.7, 152.3, 137.2, 136.5, 133.2, 131.0, 130.7, 129.0, 127.7, 127.5, 119.0,
108.1; MS (EI) m/z 365 (M+). Anal. Calcd for C19H12ClN3OS: C, 62.38; H,
3.31; N, 11.49. Found: C, 62.12; H, 3.37; N, 11.40.
7-(4-Bromophenyl)-5-(4-chlorophenyl)-2-mercaptopyrido[2,3-d]
pyrimidin-4(3H)-one (2j)ꢀMp > 250°C; yield 90%; IR: 3125, 3047,
2899, 2539, 1631, 1597, 1574, 1491, 1012, 824, 667 cm-1; 1H NMR: δ 13.13
(br, 1H), 12.45 (br, 1H), 8.23 (d, J = 7.0 Hz, 2H), 7.81–7.47 (m, 7H); 13C
NMR: δ 173.4, 157.4, 156.8, 150.7, 150.3, 135.2, 134.5, 131.2, 129.0, 128.7,
127.0, 125.7, 125.5, 117.0, 106.1; MS (EI) m/z 443 (M+). Anal. Calcd for
C19H11BrClN3OS: C, 51.31; H, 2.49; N, 9.45. Found: C, 51.26; H, 2.56; N,
9.33.
2-Mercapto-7-phenyl-5-(p-tolyl)pyrido[2,3-d]pyrimidin-4(3H)-
one (2c)ꢀMp > 250°C; yield 93%; IR: 3055, 2910, 1701, 1601, 1555, 1170,
776 cm-1; 1H NMR: δ 13.09 (br, 1H), 12.38 (br, 1H), 8.23 (m, 2H), 7.61–7.23
(m, 8H), 2.38 (s, 3H); 13C NMR: δ 175.2, 159.3, 158.7, 153.9, 152.7, 137.8,
136.6, 135.4, 130.9, 129.0, 128.9, 128.2, 127.7, 119.3, 108.0, 21.0; MS (EI)
m/z 345 (M+). Anal. Calcd for C20H15N3OS: C, 69.54; H, 4.38; N, 12.17.
Found: C, 69.67; H, 4.51; N, 12.10.
2-Mercapto-5-(4-methoxyphenyl)-7-phenylpyrido[2,3-d]pyrimi-
din-4(3H)-one (2d)ꢀMp > 250°C; yield 80%; IR: 3120, 3050, 2900,
7-(4-Bromophenyl)-5-(4-fluorophenyl)-2-mercaptopyrido[2,3-d]
pyrimidin-4(3H)-one (2k)ꢀMp > 250°C; yield 80%; IR: 3067, 2928,
1
2538, 1676, 1600, 1492, 1495, 1176, 778 cm-1; H NMR: δ 14.49 (br, 1H),
1
1701, 1668, 1634, 1557, 1509, 1452, 1173, 774 cm-1; H NMR: δ 13.02 (br,
13.32 (br, 1H), 8.29 (m, 2H), 7.80–6.91 (m, 8H), 3.81 (s, 3H); 13C NMR:
δ 175.4, 159.5, 158.6, 152.6, 151.4, 137.6, 135.5, 133.0, 130.0, 129.5, 128.1,
127.7, 127.9, 119.2, 108.0, 58.9; MS (EI) m/z 361 (M+). Anal. Calcd for
C20H15N3O2S: C, 66.46; H, 4.18; N, 11.63. Found: C, 66.65; H, 4.27; N,
11.52.
1H), 12.37 (br, 1H), 8.16 (d, J = 7.0 Hz, 2H), 7.73–7.43 (m, 7H); 13C NMR:
δ 169.5, 153.0, 152.0, 147.2, 146.8, 131.7, 131.0, 127.0, 125.5, 125.2, 123.5,
122.0, 121.0, 113.5, 102.6; MS (EI) m/z 427 (M+). Anal. Calcd for C19H11Br-
FN3OS: C, 53.28; H, 2.59; N, 9.81. Found: C, 53.01; H, 2.66; N, 9.72.
5-(4-Fluorophenyl)-2-mercapto-7-phenylpyrido[2,3-d]pyrimi- 5,7-Bis(4-bromophenyl)-2-mercaptopyrido[2,3-d]pyrimidin-
din-4(3H)-one (2e)ꢀMp > 250°C; yield 74%; IR: 3067, 2917, 1701, 1668, 4(3H)-one (2l)ꢀMp > 250°C; yield 92%; IR: 3128, 3060, 2903, 2545,
1
1
1603, 1557, 1508, 1410, 1173, 774 cm-1; H NMR: δ 12.89 (br, 1H), 12.28 1678, 1595, 1553, 1492, 1406, 1176, 778 cm-1; H NMR: δ 13.21 (br, 1H),
(br, 1H), 8.09 (m, 2H), 7.51–7.40 (m, 8H); 13C NMR: δ 172.8, 157.0, 156.3, 12.51 (br, 1H), 8.24 (d, J = 7.0 Hz, 2H), 7.82–7.43 (m, 7H); 13C NMR: δ 173.1,
150.2, 149.8, 134.7, 134.0, 130.0, 128.5, 128.2, 126.5, 125.0, 125.0, 116.5, 158.5, 157.6, 151.6, 151.3, 136.2, 135.5, 132.0, 130.0, 129.4, 128.1, 126.3,
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120.9, 118.4, 107.2; MS (EI) m/z 489 (M+). Anal. Calcd for C19H11Br2N3OS:
1H NMR: δ 8.07 (m, 2H), 7.44–7.02 (m, 8H), 1.80 (m, 4H), 1.60 (m, 4H),
1.37 (m, 2H); 13C NMR: δ 162.8, 161.5, 159.7, 157.4, 156.7, 150.3, 136.1,
135.4, 129.2, 129.0, 128.7, 127.6, 126.0, 113.5, 113.3, 112.5, 104.5, 65.6, 35.7,
23.6, 20.0; MS (EI) m/z 403 (M+). Anal. Calcd for C24H22ClN3O: C, 71.37;
H, 5.49; N, 10.40. Found: C, 71.11; H, 5.56; N, 10.49.
C, 46.65; H, 2.27; N, 8.59. Found: C, 46.29; H, 2.38; N, 8.65.
7-(4-Bromophenyl)-2-mercapto-5-(4-methoxyphenyl)
pyrido[2,3-d]pyrimidin-4(3H)-one (2m)ꢀMp > 250°C; yield 86%;
1
IR: 3165, 3055, 2948, 2838, 1701, 1591, 1555, 1512, 1169, 829 cm-1; H
NMR: δ 13.82 (br, 1H), 12.89 (br, 1H), 8.26 (d, J = 7.0 Hz, 2H), 7.88–7.18
(m, 7H), 3.79 (s, 3H); 13C NMR: δ 171.4, 155.5, 154.6, 148.6, 147.4, 133.6,
131.5, 129.0, 126.0, 125.5, 124.1, 123.7, 122.9, 115.2, 104.0, 54.5; MS (EI)
m/z 439 (M+). Anal. Calcd for C20H14BrN3O2S: C, 54.56; H, 3.20; N, 9.54.
Found: C, 54.75; H, 3.26; N, 9.45.
7′-Phenyl-5′-(p-tolyl)-1′H-spiro[cyclopentane-1,2′-pyrido[2,3-d]
pyrimidin]-4′(3′H)-one (3e)ꢀMp > 250°C; yield; 70%; IR: 3259, 3155,
2910, 2810, 1701, 1653, 1541, 1170, 796 cm-1; 1H NMR: δ 8.21 (br, 1H), 8.19
(m, 2H), 7.87 (br, 1H), 7.57–7.19 (m, 8H), 2.40 (s, 3H), 1.97 (m, 4H), 1.74
(m, 4H); 13C NMR: δ 159.2, 158.3, 156.8, 155.0, 153.8, 147.8, 134.0, 132.5,
126.7, 126.6, 125.7, 124.7, 123.0, 110.5, 110.3, 109.0, 101.7, 73.5, 21.2, 20.0;
MS (EI) m/z 369 (M+). Anal. Calcd for C24H23N3O: C, 78.02; H, 6.27; N,
11.37. Found: C, 77.68; H, 6.39; N, 11.44.
General procedure for the synthesis of
spiro[cycloalkane-1,2′-(1′H)-5-aryl-7-
arylpyrido[2,3-d]pyrimidin]-4′(3′H)-ones
3a–j
In a 10-mL glass tube were placed 2-amino-4-aryl-6-arylnicotinamide
1 (1 mmol), cycloalkanones (1 mmol), CuCl2 (0.1 mmol), DMF (2 mL),
and a magnetic stir bar. The vessel was sealed with a septum and
placed into the microwave cavity. MWI of 10 W was used, the tempe-
rature being increased from room temperature to 200°C. Once 200°C
was reached, the mixture was held at this temperature for 8 min.
Afer cooling the tube was opened and the contents poured into a
flask. Then water was added and the resultant precipitate was filtered
and crystallized from DMF/ethanol.
7′-Phenyl-5′-(p-tolyl)-1′H-spiro[cyclohexane-1,2′-pyrido[2,3-d]
pyrimidin]-4′(3′H)-one (3f)ꢀMp > 250°C; yield 90%; IR: 3229, 3155,
2925, 2832, 1660, 1581, 1533, 1059, 773 cm-1; 1H NMR: δ = 8.22 (m, 2H),
7.59–7.21 (m, 8H), 1.80 (m, 4H), 1.61 (m, 4H), 1.36 (m, 2H), 2.36 (s, 3H);
13C NMR: δ 160.0, 159.1, 157.7, 155.2, 154.9, 147.6, 134.9, 133.4, 127.6, 127.4,
126.7, 125.6, 124.0, 111.5, 111.3, 110.0, 102.5, 63.5, 33.8, 21.6, 21.0, 18.0;
MS (EI) m/z 383 (M+). Anal. Calcd for C25H25N3O: C, 78.30; H, 6.57; N,
10.96. Found: C, 78.43; H, 6.70; N, 10.88.
5′-(4-Fluorophenyl)-7′-phenyl-1′H-spiro[cyclopentane-1,2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-one (3g)ꢀMp > 250°C; yield 90%;
IR: 3426, 3174, 3058, 2962, 2931, 1668, 1599, 1561, 1508, 1442, 1214,
1
774 cm-1; H NMR: δ 8.12 (br, 1H), 8.07 (m, 2H), 7.78 (br, 1H), 7.46–7.05
(m, 8H), 1.94 (m, 4H), 1.70 (m, 4H); 13C NMR: δ 163.2, 162.3, 160.8,
159.0, 157.8, 151.8, 138.0, 136.5, 130.7, 130.6, 129.7, 128.7, 127.0, 114.5,
114.3, 113.0, 105.7, 75.5, 22.2; MS (EI) m/z 373 (M+). Anal. Calcd for
C23H20FN3O: C, 73.98; H, 5.40; N, 11.25. Found: C, 74.16; H, 5.49; N, 11.27.
5′,7′-Diphenyl-1′H-spiro[cyclopentane-1,2′-pyrido[2,3-d]
pyrimidin]-4′(3′H)-one (3a)ꢀMp > 250°C; yield; 84%; IR: 3254, 3193,
3057, 2960, 2868, 1669, 1562, 1496, 1232, 761, 701 cm-1; 1H NMR: δ 8.27
(d, J = 6.4 Hz, 2H), 8.23 (br, 1H), 7.89 (br, 1H), 7.68–7.46 (m, 9H), 1.92
(m, 4H), 1.71 (m, 4H); 13C NMR: δ 159.3, 159.2, 157.8, 156.0, 154.8, 148.8,
135.0, 133.5, 127.7, 127.6, 126.7, 125.7, 124.0, 111.5, 111.3, 110.0, 102.7, 72.5,
19.2; MS (EI) m/z 355 (M+). Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96;
N, 11.82. Found: C, 77.68; H, 6.03; N, 11.93.
5′-(4-Fluorophenyl)-7′-phenyl-1′H-spiro[cyclohexane-1,2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-oneꢀ(3h)ꢀMp >250°C; yield 95%;
IR: 3267, 3194, 3066, 2931, 2857, 1672, 1564, 1510, 1452, 1223, 697 cm-1;
1H NMR: δ 8.08 (m, 2H), 7.47–7.05 (m, 8H), 1.82 (m, 4H), 1.62 (m, 4H),
1.38 (m, 2H); 13C NMR: δ 163.1, 162.1, 160.7, 158.2, 157.9, 151.6, 137.9,
136.4, 130.6, 130.5, 129.7, 128.6, 127.0, 114.5, 114.3, 113.0, 105.5, 66.5,
36.8, 24.6, 21.0; MS (EI) m/z 387 (M+). Anal. Calcd for C24H22FN3O: C,
74.40; H, 5.72; N, 10.85. Found: C, 74.68; H, 5.80; N, 10.94.
5′,7′-Diphenyl-1′H-spiro[cyclohexane-1,2′-pyrido[2,3-d]
pyrimidin]-4′(3′H)-one (3b)ꢀMp > 250°C; yield; 85%; IR: 3254, 3107,
3051, 2950, 2930, 2801, 1682, 1597, 1555, 1496, 1406, 1177, 704 cm-1; 1H
NMR: δ 8.25 (m, 2H), 7.66–7.44 (m, 9H), 1.83 (m, 4H), 1.61 (m, 4H), 1.39
(m, 2H); 13C NMR: δ 159.9, 159.1, 156.7, 154.1, 153.3, 147.6, 133.9, 132.4,
126.6, 126.5, 125.6, 124.6, 123.0, 110.5, 110.3, 109.0, 101.5, 62.3, 32.4,
20.6, 17.0; MS (EI) m/z 369 (M+). Anal. Calcd for C24H23N3O: C, 78.02; H,
6.27; N, 11.37. Found: C, 77.78; H, 6.33; N, 11.28.
5′,7′-Bis(4-bromophenyl)-1′H-spiro[cyclohexane-1, 2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-one (3i)ꢀMp > 250°C; yield 85%;
IR: 3383, 3164, 2933, 2811, 1678, 1589, 1527, 1487, 1404, 1009, 719 cm-1;
1H NMR: δ 8.23 (m, 2H), 7.81–7.42 (m, 7H), 1.81 (m, 4H), 1.61 (m, 4H),
1.37 (m, 2H); 13C NMR: δ 161.2, 160.1, 158.7, 156.2, 155.9, 149.6, 135.9,
134.4, 128.6, 128.5, 127.7, 126.6, 125.0, 112.5, 112.3, 111.0, 103.5, 64.5,
34.8, 22.6, 19.0; MS (EI) m/z 527 (M+). Anal. Calcd for C24H21Br2N3O: C,
54.67; H, 4.01; N, 7.97. Found: C, 54.82; H, 4.15; N, 7.86.
5′-(4-Chlorophenyl)-7′-phenyl-1′H-spiro[cyclopentane-1,2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-one (3c)ꢀMp > 250°C; yield; 80%;
IR: 3226, 3125, 3047, 2920, 2899, 2539, 1676, 1598, 1573, 1493, 1176, 773
1
cm-1; H NMR: δ 8.17 (m, 2H), 8.13 (br, 1H), 7.79 (br, 1H), 7.56–7.15 (m,
8H), 1.96 (m, 4H), 1.72 (m, 4H); 13C NMR: δ 162.2, 161.3, 159.8, 158.0,
156.8, 150.8, 137.0, 135.5, 129.7, 129.6, 128.7, 127.7, 126.0, 113.5, 113.3, 112.0,
104.7, 74.5, 21.2; MS (EI) m/z 389 (M+). Anal. Calcd for C23H20ClN3O: C,
70.85; H, 5.17; N, 10.78. Found: C, 70.50; H, 5.27; N, 10.83.
7′-(4-Bromophenyl)-5′-(p-tolyl)-1′H-spiro[cyclopentane-1,2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-one (3j)ꢀMp > 250°C; yield 80%;
IR: 3385, 3188, 2920, 2809, 1610, 1584, 1544, 1490, 1008, 816, 775 cm-1;
1H NMR: δ 8.26 (m, 2H), 8.24 (br, 1H), 7.80 (br, 1H), 7.67–7.35 (m, 7H),
2.41 (s, 3H), 1.95 (m, 4H), 1.72 (m, 4H); 13C NMR: δ = 158.2, 157.3, 155.8,
154.0, 152.8, 146.8, 133.0, 131.5, 125.7, 125.6, 124.7, 123.7, 122.0, 109.5,
109.3, 108.0, 100.7, 75.0, 21.2, 19.5; MS (EI) m/z 447 (M+). Anal. Calcd for
C24H22BrN3O: C, 64.29; H, 4.95; N, 9.37. Found: C, 64.11; H, 4.87; N, 9.29.
5′-(4-Chlorophenyl)-7′-phenyl-1′H-spiro[cyclohexane-1,2′-
pyrido[2,3-d]pyrimidin]-4′(3′H)-one (3d)ꢀMp > 250°C; yield 95%;
IR: 3292, 3190, 2932, 2899, 2539, 1623, 1601, 1573, 1492, 1089, 772 cm-1;
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ꢂꢁꢁꢁ
Z.-J. Quan et al.: Synthesis of new pyrido[2,3-d]pyrimidinone derivativesꢀ
ꢀ261
Acknowledgments: We are thankful for the financial neering Program of Northwest Normal University (nwnu-
support from the National Nature Science Foundation of kjcxgc-03–64, nwnu-lkqn-10–15).
China (No. 20902073 and No. 21062017), the Natural Sci-
ence Foundation of Gansu Province (No. 096RJZA116),
and the Scientific and Technological Innovation Engi-
Received August 30, 2012; accepted October 13, 2012
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