HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 2, 2016, pp. 260-271
Received, 19th November, 2015, Accepted, 16th December, 2015, Published online, 15th January, 2016.

■ Synthesis of 6,7-Dihydropyrido[2,3-d]pyrimidin-5(8H)-one Derivatives Based on the Reaction of 1-(4-Chloropyrimidin-5-yl)alk-2-en-1-one Derivatives with Primary Amines

Kazuhiro Kobayashi,* Ryoga Ono, Kouki Ishitobi, Yuuki Chikazawa, Hidetaka Hiyoshi, and Kazuto Umezu

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A convenient sequence for the synthesis of 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives has been developed. Thus, treatment of 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine with lithium diisopropylamide (LDA) generates 4-chloro-5-lithio-6-methoxy-2- (methylsulfanyl)pyrimidine, which are allowed to react with α,β-unsaturated aldehydes to give the corresponding 1-(4-chloropyrimidin-5-yl)alk-2-en-1-ol derivatives. Oxidation of these alkenols with activated manganese(IV) oxide provides 1-(4-chloropyrimidin-5-yl)alk-2-en-1-one derivatives, of which reaction with a variety of primary amines constitutes tetrahydropyridinone structure to give the desired products.

INTRODUCTION
A number of pyrido[2,3-d]pyrimidin-5(8H)-one derivatives have recently been synthesized1,2 and some of them have been reported to exhibit a variety of biological activities.2 However, only few reports on the synthesis of 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives, which are also of biological importance. As the sole example, to the best of our knowledge, Assy and Moustafa prepared some derivatives by condensation of 1-[4-(alkylamino)pyrimidin-5-yl]ethanones with benzaldehyde.3 On the other hand, we have recently reported methods for the synthesis of several pyrimidine-fused heterocycles utilizing 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine (1), readily available from 4,6-dichloro-2- (methylsulfanyl)pyrimidine (DCSMP).4 In continuation of these studies, we embarked upon development of a facile method for the preparation of 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives from 1. This paper describes that 7,8-disubstituted 4-methoxy-2-(methylsulfanyl)-6,7-dihydropyrido[2,3- d]pyrimidin-5(8H)-ones (4), (5), (7), and (8) can be prepared by an easy three-step sequence from 1.

RESULTS AND DISCUSSION
From the outset, we envisioned that the reaction of 1-(4-chloropyrimidin-5-yl)alk-2-en-1-one derivatives (3) with primary amines would provide the desired 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives (4). First to be carried out was the preparation of 3 by the treatment of 4-chloro-5-lithio-6-methoxy-2-(methylsulfanyl)pyrimidine, generated from 4-chloro-6-methoxy-2- (methylsulfanyl)pyrimidine (1) on treatment with lithium diisopropylamide (LDA) in THF at –78 ˚C,4 with α,β-unsaturated aldehydes, followed by the oxidation of the resulting 1-(4-chloropyrimidin-5-yl)alk- 2-en-1-ol derivatives (2) with activated manganese(IV) oxide (Scheme 1). This sequence could be achieved in uneventful fashion to provide 3 in good yields as compiled in Table 1.

The pyrimidinyl enones (3), thus obtained, were then subjected to the reaction with primary amines in DMF. First, the reactions of 3a (R = Me) with aliphatic primary amines were carried out (Scheme 2). They proceeded quickly even at 0 ˚C and were over in less than 1 h to afford the corresponding desired products (4a-4d) in good yields (Table 2, Entries 1-4). When phenylhydrazine was used, the reaction also proceeded at 0 ˚C. However, it resulted in the formation of a rather complicated mixture of products and only moderate yield of the desired products (4e) was isolated (Entry 5). The treatment of 3a with benzenamine was initially conducted at 0 ˚C. However, no desired product (4f) was formed. When the temperature was raised to 40 ˚C, the reaction proceeded in a satisfactory manner to produce 4f in fair yield (Entry 6). The reaction of 3b (R = Et) with butanamine also proceeded at 0 ˚C. However, it required much longer reaction time and the yield of the corresponding product (4g) was somewhat lower than that of 4a (Entry 7). In the production of 4 from 3, the conjugate addition of primary amine is thought to take place initially, resulting in the formation of the corresponding β-(alkylamino) ketones. This is followed by the SNAr displacement of the chlorine on the pyrimidine ring with the amino nitrogen of the corresponding adducts to give rise to 4.

Next, the reactions of β-aryl enone derivatives (3c-e) with primary amines were examined. They proceeded at room temperature to give the desired pyridopyrimidinone derivatives (5) accompanying the formation of the corresponding 1-[4-(alkylamino)pyrimidin-5-yl]-3-arylprop-2-en-1-ones (6) as shown in Scheme 3. The results are summarized in Table 3, which indicate that the use of a small amine, such as methanamine, and the substitution of the electron-withdrawing group on the benzene ring of the substrate shortened the reaction times and favored the formation of 5. It should be noted that the prolonged time of each reaction did not affect the ratio of the products at all. Moreover, when isolated 6a was subjected to the same reaction conditions, transformation into 5a did not occur. These observations indicate that the production of 5 through the initial formation of 6, followed by intramolecular conjugate addition, is ultimately ruled out.

Subsequently, in order to demonstrate the present synthesis more efficient, the reactions of β-alkenone derivatives (3a) and (3b) with 2-aminoacetonitrile hydrochloride or glycine ethyl ester hydrochloride in the presence of 2 equivalents of triethylamine were examined. As shown in Scheme 4, they proceeded at room temperature to provide the corresponding pyridopyrimidinone derivatives (7). While the yields of the products (7a) and (7b) from 3a were relatively good, the reaction of 3b with 2-aminoacetonitrile hydrochloride afforded the corresponding product (7c) in a considerably lower yield. Similarly, the reaction of 3a with 3-bromopropanamine hydrobromide in the presence of 2 equivalents of triethylamine at 0 ˚C was carried out. Unfortunately, however, it resulted in the formation of a rather intractable mixture of products, from which only a low yield of the desired product (8) was isolated (Scheme 5). This may be due to the liability of the terminal bromide of the product.

In conclusion, a convenient synthesis of 6,7-dihydropyrido[2,3-d]pyrimidin-5(8H)-one derivatives has been realized. The ready availability of the starting materials as well as the simple operations makes this method attractive. Further experiments aimed at developing methodology for the preparation of other pyrimidine-fused heterocycles utilizing the precursors in this work are currently under active investigation.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum65 FTIR spectrophotometer. 1H NMR and 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 and 125 MHz, respectively. High-resolution MS spectra (ESI, positive) or (EI, TOF; 70eV) were measured by a Thermo Scientific Exactive or a JEOL JMS-T100GCV spectrometer, respectively. Elemental analyses were performed with Elementar Vario EL II instrument. TLC was carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidine (1) was prepared following the reported procedure.4 n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
Pyrimidinyl Alkenols (2). These compounds were prepared according to the procedure previously reported for the preparation of 2c-e.4b The physical, spectral, and analytical data for new compounds follow.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]but-2-en-1-ol (2a): a white solid; mp 63–65 ˚C (hexane); IR (KBr) 3346, 1663 cm–1; 1H NMR δ 1.70 (d, J = 5.4 Hz, 3H), 2.55 (s, 3H), 2.99 (d, J = 10.7 Hz, 1H), 4.07 (s, 3H), 5.45 (dd, J = 10.7, 5.4 Hz, 1H), 5.68–5.79 (m, 2H). Anal. Calcd for C10H13ClN2O2S: C, 46.06; H, 5.03; N, 10.74. Found: C, 46.12; H, 5.23; N, 10.66.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]pent-2-en-1-ol (2b): a colorless oil; Rf 0.33 (AcOEt/hexane 1:5); IR (neat) 3419, 1657 cm–1; 1H NMR δ 0.99 (t, J = 6.9 Hz, 3H), 2.03–2.08 (m, 2H), 2.55 (s, 3H), 3.00 (d, J = 10.3 Hz, 1H), 4.07 (s, 3H), 5.45–5.48 (m, 1H), 5.69–5.78 (m, 2H). Anal. Calcd for C11H15ClN2O2S: C, 48.08; H, 5.50; N, 10.20. Found: C, 48.09; H, 5.53; N, 10.06.
Typical Procedure for the Preparation of Pyrimidinyl Ketones (3). (E)-1-[4-Chloro-6-methoxy-2- (methylsulfanyl)pyrimidin-5-yl]but-2-en-1-one (3a). A mixture of 2a (0.48 g, 1.9 mmol) and activated MnO2 (1.6 g, 19 mmol) in CHCl3 (5 mL) was stirred at rt for 2 h. The mixture was filtered through a Celite® pad under reduced pressure and the filtrate was concentrated by evaporation. The residual solid was recrystallized from hexane/CH2Cl2 to give 3a (0.43 g, 89%); a white solid; mp 99–101 ˚C; IR (KBr) 1652, 1635 cm–1; 1H NMR δ 1.97 (dd, J = 6.9, 1.5 Hz, 3H), 2.57 (s, 3H), 3.99 (s, 3H), 6.33 (dd, J = 16.1, 1.5 Hz, 1H), 6.71 (dq, J = 16.1, 6.9 Hz, 1H). Anal. Calcd for C10H11ClN2O2S: C, 46.42; H, 4.29; N, 10.83. Found: C, 46.38; H, 4.19; N, 10.90.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]pent-2-en-1-one (3b): a white solid; mp 51–52 ˚C (hexane/CH2Cl2); IR (KBr) 1655, 1635 cm–1; 1H NMR δ 1.10 (t, J = 7.4 Hz, 3H), 2.30–2.33 (m, 2H), 2.58 (s, 3H), 3.99 (s, 3H), 6.30 (d, J = 16.0 Hz, 1H), 6.75 (dd, J = 16.0, 6.3 Hz, 1H). Anal. Calcd for C11H13ClN2O2S: C, 48.44; H, 4.80; N, 10.27. Found: C, 48.29; H, 4.86; N, 10.11.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]-3-phenylprop-2-en-1-one (3c): a white solid; mp 120–122 ˚C (hexane/CH2Cl2); IR (KBr) 1653, 1624 cm–1; 1H NMR δ 2.61 (s, 3H), 4.01 (s, 3H), 6.94 (d, J = 16.1 Hz, 1H), 7.39 (d, J = 16.1 Hz, 1H), 7.41–7.43 (m, 3H), 7.56 (dd, J = 7.6, 1.5 Hz, 2H). Anal. Calcd for C15H13ClN2O2S: C, 56.16; H, 4.08; N, 8.73. Found: C, 55.98; H, 4.08; N, 8.74.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]-3-(4-chlorophenyl)prop-2-en-1-one (3d): a white solid; mp 136–138 ˚C (hexane/CH2Cl2); IR (KBr) 1683, 1651, 1607 cm–1; 1H NMR δ 2.60 (s, 3H), 4.01 (s, 3H), 6.90 (d, J = 16.0 Hz, 1H), 7.36 (d, J = 16.0 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H). Anal. Calcd for C15H12Cl2N2O2S: C, 50.72; H, 3.41; N, 7.89. Found: C, 50.53; H, 3.45; N, 7.84.
(E)-1-[4-Chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5-yl]-3-(4-methoxyphenyl)prop-2-en-1-one (3e): a white solid; mp 133–135 ˚C (hexane/CH2Cl2); IR (KBr) 1646 cm–1; 1H NMR δ 2.60 (s, 3H), 3.86 (s, 3H), 4.00 (s, 3H), 6.82 (d, J = 16.1 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 7.33 (d, J = 16.1 Hz, 1H), 7.52 (d, J = 9.2 Hz, 2H). Anal. Calcd for C16H15ClN2O3S: C, 54.78; H, 4.31; N, 7.99. Found: C, 54.49; H, 4.04; N, 8.24.
General Procedure for the Preparation of Pyridopyrimidinones (4) and (5). To a stirred solution of 3 (1.0 mmol) and Et3N (1.0 mmol) in DMF (4 mL) at 0 ˚C was added an amine (1.0 mmol) dropwise. Stirring was continued at the temperature indicated in Table 1 or Scheme 3 until 3 had been consumed completely (TLC, SiO2, AcOEt/hexane 1:1, see Tables 2 and 3). Water (20 mL) was added and the mixture was extracted with AcOEt (3 × 15 mL). The combined extracts were washed with water (3 × 15 mL) and brine (15 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography (AcOEt/hexane 1:1) on SiO2 to afford 4 or 5.
8-Butyl-4-methoxy-7-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4a): a colorless viscous oil; Rf 0.31 (AcOEt/hexane 1:1); IR (neat) 1678 cm–1; 1H NMR δ 0.97 (t, J = 7.6 Hz, 3H), 1.20 (d, J = 6.1 Hz, 3H), 1.35–1.43 (m, 2H), 1.63–1.72 (m, 2H), 2.39 (dd, J = 16.1, 2.3 Hz, 1H), 2.51 (s, 3H), 2.85 (dd, J = 16.1, 6.1 Hz, 1H), 3.02–3.07 (m, 1H), 3.74–3.77 (m, 1H), 4.03 (s, 3H), 4.20–4.26 (m, 1H); 13C NMR δ 13.91, 14.09, 16.23, 20.15, 30.50, 43.79, 47.19, 51.38, 54.52, 93.81, 161.20, 166.90, 175.09, 189.27. HR-MS (ESI). Calcd for C14H22N3O2S (M+H): 296.1432. Found: m/z 296.1424. Anal. Calcd for C14H21N3O2S: C, 56.92; H, 7.17; N, 14.22. Found: C, 56.80; H, 7.25; N, 14.15.
4-Methoxy-7-methyl-2-(methylsulfanyl)-8-(2-phenylmethyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4b): a white solid; mp 96–98 ˚C (hexane/CH2Cl2); IR (KBr) 1678 cm–1; 1H NMR δ 1.18 (d, J = 6.9 Hz, 3H), 2.35 (dd, J = 16.0, 2.3 Hz, 1H), 2.46 (s, 3H), 2.80 (dd, J = 16.0, 6.1 Hz, 1H), 3.70–3.76 (m, 1H), 4.06 (s, 3H), 4.20 (d, J = 15.3 Hz, 1H), 5.68 (d, J = 15.3 Hz, 1H), 7.28–7.31 (m, 3H), 7.35 (t, J = 7.6 Hz, 2H); 13C NMR δ 14.18, 15.83, 43.78, 49.63, 50.35, 54.64, 93.93, 127.49, 127.60, 128.75, 137.60, 161.57, 167.02, 175.45, 189.17. HR-MS (ESI). Calcd for C17H20N3O2S (M+H): 330.1276. Found: m/z 330.1274. Anal. Calcd for C17H19N3O2S: C, 61.98; H, 5.81; N, 12.76. Found: C, 61.91; H, 5.71; N, 12.79.
4-Methoxy-8-(2-methoxyethyl)-7-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4c): a white solid; mp 110–112 ˚C (hexane/CH2Cl2); IR (KBr) 1683 cm–1; 1H NMR δ 1.19 (d, J = 6.9 Hz, 3H), 2.36 (dd, J = 15.2, 2.3 Hz, 1H), 2.50 (s, 3H), 2.91 (dd, J = 15.2, 6.1 Hz, 1H), 3.27–3.32 (m, 1H), 3.37 (s, 3H), 3.62–3.64 (m, 2H), 3.88–3.94 (m, 1H), 4.03 (s, 3H), 4.34 (dt, J = 11.6, 4.6 Hz, 1H); 13C NMR δ 14.10, 16.03, 43.61, 47.32, 52.47, 54.54, 59.02, 71.20, 94.00, 161.15, 166.79, 175.07, 189.55. HR-MS (ESI). Calcd for C13H20N3O3S (M+H): 298.1225. Found: m/z 298.1217. Anal. Calcd for C13H19N3O3S: C, 52.51; H, 6.44; N, 14.13. Found: C, 52.58; H, 6.43; N, 14.16.
8-Cyclopropyl-4-methoxy-7-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4d): a white solid; mp 100–102 ˚C (hexane/CH2Cl2); IR (KBr) 1681 cm–1; 1H NMR δ 0.66–0.70 (m, 1H), 0.80–0.83 (m, 2H), 1.07–1.13 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H), 2.41 (dd, J = 16.0, 1.5 Hz, 1H), 2.56 (s, 3H), 2.73–2.78 (m, 1H), 2.81 (dd, J = 16.0, 6.9 Hz, 1H), 3.89–3.91 (m, 1H), 4.04 (s, 3H); 13C NMR δ 6.23, 10.51, 14.18, 15.66, 30.18, 44.46, 52.55, 54.62, 94.66, 163.54, 166.89, 175.10, 189.74. HR-MS (ESI). Calcd for C13H18N3O2S (M+H): 280.1119. Found: m/z 280.1118. Anal. Calcd for C13H17N3O2S: C, 55.89; H, 6.13; N, 15.04. Found: C, 55.97; H, 6.15; N, 15.05.
4-Methoxy-7-methyl-2-(methylsulfanyl)-8-(phenylamino)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)- one (4e): a white solid; mp 176–178 ˚C (hexane/CH2Cl2); IR (KBr) 3290, 1664, 1606 cm–1; 1H NMR δ 1.35 (d, J = 6.1 Hz, 3H), 2.29 (s, 3H), 2.65 (dd, J = 16.0, 4.6 Hz, 1H), 3.12 (d, J = 16.0, 6.1 Hz, 1H), 4.01–4.07 (m, including s at 4.05, 4H), 6.69 (s, 1H), 6.90 (d, J = 7.6 Hz, 2H), 6.95 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 2H); 13C NMR δ 14.14, 16.16, 44.72, 54.93, 55.31, 94.43, 113.62, 121.50, 129.27, 147.75, 153.05, 166.75, 176.24, 188.74. HR-MS (ESI). Calcd for C16H19N4O2S (M+H): 331.1228. Found: m/z 331.1222. Anal. Calcd for C16H18N4O2S: C, 58.16; H, 5.49; N, 16.96. Found: C, 58.04; H, 5.68; N, 16.90.
4-Methoxy-7-methyl-2-(methylsulfanyl)-8-phenyl-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4f): a white solid; mp 161–163 ˚C (hexane/CH2Cl2); IR (KBr) 1686 cm–1; 1H NMR δ 1.26 (d, J = 6.1 Hz, 3H), 2.13 (s, 3H), 2.57 (dd, J = 16.0, 4.6 Hz, 1H), 3.08 (dd, J = 16.0, 6.1 Hz, 1H), 4.05 (s, 3H), 4.13–4.19 (m, 1H), 7.25 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H); 13C NMR δ 13.82, 17.19, 44.57, 54.55, 54.73, 94.25, 127.16, 128.02, 128.95, 142.07, 161.80, 167.01, 175.05, 189.26. HR-MS (ESI). Calcd for C16H18N3O2S (M+H): 316.1119. Found: m/z 316.1114. Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found: C, 60.94; H, 5.50; N, 13.30.
8-Butyl-7-ethyl-4-methoxy-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (4g): a pale-yellow viscous oil; Rf 0.32 (AcOEt/hexane 1:3); IR (neat) 1677 cm–1; 1H NMR δ 0.91 (t, J = 7.4 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H), 1.35–1.42 (m, 2H), 1.62–1.69 (m, 4H), 2.51 (s, 3H), 2.56 (dd, J = 16.0, 1.7 Hz, 1H), 2.79 (dd, J = 16.0, 6.3 Hz, 1H), 2.95–3.00 (m, 1H), 3.45–3.49 (m, 1H), 4.02 (s, 3H), 4.30–4.34 (m, 1H); 13C NMR δ 10.24, 13.93, 14.09, 20.19, 23.12, 30.57, 40.63, 48.03, 54.50, 57.35, 93.98, 161.41, 166.81, 175.03, 189.33. HR-MS (EI). Calcd for C15H23N3O2S (M): 309.1511. Found: m/z 309.1510. Anal. Calcd for C15H23N3O2S: C, 58.23; H, 7.49; N, 13.68; S, 10.36. Found: C, 57.89; H, 7.40; N, 13.66; S, 10.47.
4-Methoxy-2-(methylsulfanyl)-7-phenyl-8-(2-phenylethyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)- one (5a). This compound was obtained accompanying 6a. A white solid; mp 110–112 ˚C (hexane/CH2Cl2); IR (KBr) 1678 cm–1; 1H NMR δ 2.60 (s, 3H), 2.63 (dd, J = 16.0, 3.1 Hz, 1H), 2.87–2.95 (m, 2H), 3.02–3.08 (m, 1H), 3.10–3.16 (m, 1H), 4.03 (s, 3H), 4.39 (dd, J = 6.9, 3.1 Hz, 1H), 4.51–4.56 (m, 1H), 7.02 (dd, J = 7.6, 1.5 Hz, 2H), 7.17 (d, J = 6.9 Hz, 2H), 7.23–7.28 (m, 4H), 7.30 (dd, J = 7.6, 6.9 Hz, 2H); 13C NMR δ 14.24, 34.40, 44.36, 50.54, 54.59, 60.17, 94.87, 126.07, 126.64, 128.11, 128.60, 128.83, 129.01, 138.36, 138.89, 162.70, 166.71, 175.57, 183.04. HR-MS (ESI). Calcd for C23H24N3O2S (M+H): 406.1589. Found: m/z 406.1584. Anal. Calcd for C23H23N3O2S: C, 68.12; H, 5.72; N, 10.36; S, 7.91. Found: C, 67.96; H, 5.65; N, 10.34; S, 7.92.
1-[3-Methoxy-2-(methylsulfanyl)-5-[(2-phenylethyl)amino]pyrimidin-4-yl]-3-phenylprop-2-en-1-one (6a): a yellow solid; mp 152–154 ˚C (hexane/CH2Cl2); IR (KBr) 3222, 1636 cm–1; 1H NMR δ 2.56 (s, 3H), 2.95 (t, J = 7.6 Hz, 2H), 3.81 (q, J = 7.6 Hz, 2H), 4.07 (s, 3H), 7.23–7.26 (m, 3H), 7.32 (t, J = 7.6 Hz, 2H), 7.37–7.42 (m, 3H), 7.58 (dd, J = 7.6, 1.5 Hz, 2H), 7.62 (d, J = 15.3 Hz, 1H), 7.73 (d, J = 15.3 Hz, 1H), 10.04 (br s, 1H). Anal. Calcd for C23H23N3O2S: C, 68.12; H, 5.72; N, 10.36. Found: C, 68.14; H, 6.01; N, 10.22.
4-Methoxy-8-methyl-2-(methylsulfanyl)-7-phenyl-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (5b). This compound was obtained accompanying 6b. A white solid; mp 164–165 ˚C (hexane/CH2Cl2); IR (KBr) 1668 cm–1; 1H NMR δ 2.56 (s, 3H), 2.78 (dd, J = 16.0, 3.4 Hz, 1H), 3.11 (dd, J = 16.0, 6.9 Hz, 1H), 3.21 (s, 3H), 4.07 (s, 3H), 4.72 (dd, J = 6.9, 3.4 Hz, 1H), 7.11 (dd, J = 8.0, 1.7 Hz, 2H), 7.25–7.32 (m, 3H); 13C NMR δ 14.19, 35.97, 44.69, 54.59, 61.48, 94.89, 126.02, 128.13, 129.09, 138.30, 163.19, 166.68, 175.56, 188.17. HR-MS (EI). Calcd for C16H17N3O2S (M): 315.1041. Found: m/z 315.1053. Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found: C, 60.86; H, 5.49; N, 13.17.
1-[3-Methoxy-5-(methylamino)-2-(methylsulfanyl)]pyrimidin-4-yl]-3-phenylprop-2-en-1-one (6b): a yellow solid; mp 128–130 ˚C (hexane/CH2Cl2); IR (KBr) 3226, 1638 cm–1; 1H NMR δ 2.56 (s, 3H), 3.10 (d, J = 4.6 Hz, 3H), 4.07 (s, 3H), 7.26 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.41 (br, 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.63 (d, J = 14.9 Hz, 1H), 7.75 (d, J = 14.9 Hz, 1H). HR-MS (EI). Calcd for C16H17N3O2S (M): 315.1041. Found: m/z 315.1045. Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32. Found: C, 60.83; H, 5.41; N, 13.31.
7-(4-Chlorophenyl)-4-methoxy-8-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (5c). This compound was obtained accompanying 6c. A pale-yellow solid; mp 166–168 ˚C (hexane/CH2Cl2); IR (KBr) 1674 cm–1; 1H NMR δ 2.56 (s, 3H), 2.73 (dd, J = 15.5, 3.4 Hz, 1H), 3.17 (dd, J = 15.5, 6.9 Hz, 1H), 3.20 (s, 3H), 4.03 (s, 3H), 4.70 (dd, J = 6.9, 3.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H); 13C NMR δ 14.20, 35.96, 44.53, 54.63, 60.94, 94.89, 127.45, 129.31, 134.04, 136.84, 163.09, 166.68, 175.80, 187.75. HR-MS (EI). Calcd for C16H16ClN3O2S2 (M): 349.0652. Found: m/z 349.0668. Anal. Calcd for C16H16ClN3O2S2: C, 54.93; H, 4.61; N, 12.01. Found: C, 54.96; H, 4.63; N, 11.97.
3-(4-Chlorophenyl)-1-[3-methoxy-5-(methylamino)-2-(methylsulfanyl)]pyrimidin-4-yl]prop-2-en-1- one (6c): a pale-yellow solid; mp 124–126 ˚C (hexane/CH2Cl2); IR (KBr) 3194, 1638 cm–1; 1H NMR δ 2.55 (s, 3H), 3.09 (d, J = 4.6 Hz, 3H), 4.06 (s, 3H), 7.36 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 15.5 Hz, 1H), 7.70 (d, J = 15.5 Hz, 1H), 9.86 (br s, 1H). HR-MS (EI). Calcd for C16H16ClN3O2S2 (M): 349.0652. Found: m/z 349.0660. Anal. Calcd for C16H16ClN3O2S2: C, 54.93; H, 4.61; N, 12.01. Found: C, 54.96; H, 4.63; N, 11.97.
4-Methoxy-7-(4-methoxyphenyl)-2-(methylsulfanyl)-8-(2-phenylethyl)-6,7-dihydropyrido[2.3- d]pyridin-5(8H)-one (5d). This compound was obtained accompanying 6d. A white solid; mp 152–154 ˚C (hexane/CH2Cl2); IR (KBr) 1677, 1636 cm–1; 1H NMR δ 2.57–2.61 (m, including s at 2.59, combined 4H), 2.85–2.94 (m, 2H), 3.02–3.05 (m, 1H), 3.11–3.15 (m, 1H), 3.75 (s, 3H), 4.04 (s, 3H), 4.33–4.35 (m, 1H), 4.47–4.52 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.16–7.31 (m, 5H); 13C NMR δ 14.26, 34.35, 44.54, 50.38, 54.63, 55.26, 59.62, 94.77, 114.32, 126.61, 127.30, 128.58, 128.82, 130.24, 138.89, 159.31, 162.52, 166.66, 175.46, 188.39. HR-MS (ESI, positive). Calcd for C24H26N3O3S (M+H): 436.1695. Found: m/z 436.1682. Anal. Calcd for C24H25N3O3S: C, 66.18; H, 5.79; N, 9.65; S, 7.36. Found: C, 66.25; H, 5.60; N, 9.30; S, 7.42.
1-[3-Methoxy-2-(methylsulfanyl)-5-[(2-phenylethyl)amino]pyrimidin-4-yl]-3-(4-methoxyphenyl)-
prop-2-en-1-one (6d): a yellow solid; mp 106–108 ˚C (hexane/CH2Cl2); IR (neat) 3227, 1634 cm–1; 1H NMR δ 2.56 (s, 3H), 2.95 (t, J = 7.6 Hz, 2H), 3.79 (q, J = 7.6 Hz, 2H), 3.85 (s, 3H), 4.06 (s, 3H), 6.92 (d, J = 8.4 Hz, 2H), 7.21–7.26 (m, 3H), 7.32 (dd, J = 7.6, 6.9 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.62 (s, 2H), 10.05 (br s, 1H); 13C NMR δ 14.18, 35.89, 42.83, 54.27, 55.33, 95.40, 114.22, 125.72, 126.36, 128.27, 128.51, 128.73, 129.81, 139.16, 140.67, 161.01, 162.64, 168.29, 173.59, 189.37. HR-MS (ESI). Calcd for C24H26N3O3S (M+H): 436.1695. Found: m/z 436.1684. Anal. Calcd for C24H25N3O3S: C, 66.18; H, 5.79; N, 9.65; S, 7.36. Found: C, 66.02; H, 5.56; N, 9.63; S, 7.64.
4-Methoxy-7-(4-methoxyphenyl)-8-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin- 5(8H)-one (5e). This compound was obtained accompanying 6e. A white solid; mp 120–122 ˚C (hexane/CH2Cl2); IR (KBr) 1674, 1611 cm–1; 1H NMR δ 2.56 (s, 3H), 2.75 (dd, J = 15.3, 3.8 Hz, 1H), 3.14 (dd, J = 15.3, 6.9 Hz, 1H), 3.19 (s, 3H), 3.77 (s, 3H), 4.03 (s, 3H), 4.67 (dd, J = 6.9, 3.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H); 13C NMR δ 14.20, 35.82, 44.86, 54.60, 55.27, 60.96, 94.81, 114.41, 127.28, 130.26, 159.34, 163.05, 166.66, 175.47, 188.49. HR-MS (EI). Calcd for C17H19N3O3S (M): 345.1147. Found: m/z 345.1143. Anal. Calcd for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.17; S, 9.28. Found: C, 58.95; H, 5.26; N, 12.29; S, 9.39.
1-[3-Methoxy-5-(methylamino)-2-(methylsulfanyl)]pyrimidin-4-yl]-3-(4-methoxyphenyl)prop-2-en- 1-one (6e): a yellow solid; mp 137–139 ˚C (hexane/CH2Cl2); IR (KBr) 3237, 1634 cm–1; 1H NMR δ 2.55 (s, 3H), 3.08 (d, J = 5.4 Hz, 3H), 3.84 (s, 3H), 4.06 (s, 3H), 6.92 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 16.1 Hz, 1H), 7.65 (d, J = 16.1 Hz, 1H), 9.86 (br s, 1H). HR-MS (EI). Calcd for C17H19N3O3S (M): 345.1147. Found: m/z 345.1151. Anal. Calcd for C17H19N3O3S: C, 59.11; H, 5.54; N, 12.17; S, 9.28. Found: C, 58.98; H, 5.25; N, 12.22; S, 9.34.
Typical Procedure for the Preparation of Pyridopyrimidinones 7. 2-[4-Methoxy-7-methyl-2- (methylsulfanyl)-5-oxo-5,6,7,8-tetrahydropyrido[2.3-d]pyridin-8-yl]acetonitrile (7a). A solution of 2a (0.13 g, 0.50 mmol) and NCCH2NH3+Cl– (46 mg, 0.50 mmol) in DMF (3 mL) containing Et3N (0.10 g, 1.0 mmol) was stirred at room temperature for 7 h. The mixture was worked up as described for the preparation of 4a and the crude product was purified by recrystallization from hexane/CH2Cl2 to afford 7a (0.10 g, 74%); a white solid; mp 137–139 ˚C; IR (KBr) 2249, 1685 cm–1; 1H NMR δ 1.35 (d, J = 6.9 Hz, 3H), 2.50 (dd, J = 16.0, 3.8 Hz, 1H), 2.57 (s, 3H), 2.97 (dd, J = 16.0, 6.1 Hz, 1H), 3.95–3.99 (m, 1H), 4.07 (s, 3H), 4.45 (d, J = 16.8 Hz, 1H), 5.74 (d, J = 16.8 Hz, 1H); 13C NMR δ 14.24, 16.45, 35.27, 44.31, 53.12, 54.97, 95.10, 115.64, 161.19, 166.78, 176.11, 188.33. HR-MS (ESI). Calcd for C12H15N4O2S (M+H): 279.0915. Found: m/z 279.0910. Anal. Calcd for C12H14N3O2S: C, 51.78; H, 5.07; N, 20.13. Found: C, 51.40; H, 5.07; N, 19.75.
Ethyl 2-[4-Methoxy-7-methyl-2-(methylsulfanyl)-5-oxo-5,6,7,8-tetrahydropyrido[2.3-d]pyridin-8- yl]acetate (7b): a white solid; mp 137–139 ˚C (hexane/CH2Cl2); IR (KBr) 1749, 1668 cm–1; 1H NMR δ 1.25 (d, J = 6.1 Hz, 3H), 1.29 (t, J = 7.6 Hz, 3H), 2.45 (dd, J = 15.3, 3.1 Hz, 1H), 2.46 (s, 3H), 3.02 (dd, J = 15.3, 6.1 Hz, 1H), 3.80–3.86 (m, 1H), 3.97 (d, J = 17.6 Hz, 1H), 4.04 (s, 3H), 4.22 (q, J = 7.6 Hz, 2H), 4.78 (d, J = 17.6 Hz, 1H); 13C NMR δ 14.03, 14.18, 16.81, 43.95, 49.01, 52.73, 54.70, 61.34, 94.29, 161.58, 166.69, 169.39, 175.30, 189.27. HR-MS (EI). Calcd for C14H19N3O4S: 325.1096. Found: m/z 325.1100. Anal. Calcd for C14H19N3O4S: C, 51.68; H, 5.89; N, 12.91. Found: C, 51.73; H, 5.67; N, 13.17.
2-[7-Ethyl-4-methoxy-2-(methylsulfanyl)-5-oxo-5,6,7,8-tetrahydropyrido[2.3-d]pyridin-8-yl]aceto-nitrile (7c): a yellow solid; mp 183–185 ˚C (hexane/CH2Cl2); IR (KBr) 2350, 1677 cm–1; 1H NMR δ 0.96 (t, J = 7.4 Hz, 3H), 1.66–1.73 (m, 1H), 1.77–1.82 (m, 1H), 2.57 (s, 3H), 2.65 (dd, J = 16.0, 2.9 Hz, 1H), 2.92 (dd, J = 16.0, 6.3 Hz, 1H), 3.69–3.70 (m, 1H), 4.06 (s, 3H), 4.37 (d, J = 17.2 Hz, 1H), 4.81 (d, J = 17.2 Hz, 1H); 13C NMR δ 9.87, 14.24, 23.39, 35.96, 40.85, 54.92, 58.83, 95.21, 115.62, 161.37, 166.70, 176.08, 188.28. HR-MS (EI). Calcd for C13H16N4O2S: 292.0994. Found: m/z 292.1005. Anal. Calcd for C13H16N3O2S: C, 53.41; H, 5.52; N, 19.16. Found: C, 53.34; H, 5.60; N, 19.17.
8-(3-Bromopropyl)-4-methoxy-7-methyl-2-(methylsulfanyl)-6,7-dihydropyrido[2.3-d]pyridin-5(8H)-one (8). A solution of 2a (0.13 g, 0.50 mmol) and Br(CH2)3NH3+Br– (0.11g, 0.50 mmol) in DMF (4 mL) containing Et3N (0.10 g, 1.0 mmol) was stirred at 0 ˚C for 30 min. The mixture was worked up as described for the preparation of 4a and the crude product was purified by column chromatography on SiO2 (AcOEt/hexane 2:1) to afford 8 (44 mg, 25%); a white solid; mp 144–146 ˚C (hexane/CH2Cl2); IR (KBr) 1686 cm–1; 1H NMR δ 1.36 (d, J = 6.9 Hz, 3H), 2.32–2.36 (m, 1H), 2.47 (dd, J = 16.1, 2.3 Hz, 1H), 2.56–2.63 (m, 1H), 2.73 (s, 3H), 3.50 (dd, J = 16.1, 6.9 Hz, 1H), 3.88–3.92 (m, 1H), 4.09–4.15 (m, 1H), 4.19 (s, 3H), 4.22–4.27 (m, 1H), 4.40–4.45 (m, 1H), 4.53–4.58 (m, 1H); 13C NMR δ 16.13, 16.36, 18.92, 42.32, 45.91, 46.57, 56.18, 56.54, 93.54, 153.64, 163.42, 170.28, 186.78. HR-MS (DART). Calcd for C13H17N3O2S [(M–HBr)+H]: 280.1118. Found: m/z 280.1118. Anal. Calcd for C13H18BrN3O2S: C, 43.34; H, 5.04; N, 11.66. Found: C, 43.57; H, 5.12; N, 11.64.

ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of our university for recording the mass spectra and performing combustion analyses.

References

1. T. Sasada, Y. Aoki, R. Ikeda, N. Sakai, and T. Konakahara, Chem. Eur. J., 2011, 17, 9385. CrossRef
2. (a) G. Hölzemann, H. Crassier, K.-G. Ackermann, W. Stähle, A. Jonczyk, W. Rautenberg, F. Mitjans, E. Rosell-Vives, J. Adan, and M. Riera, PCT Int. Appl., 2005, WO 2005047283 (Chem. Abstr., 2005, 142, 482058); (b) H. Huang, D. A. Hutta, H. Hu, R. L. Desjarlais, C. Schubert, I. P. Petrounia, M. A. Chakin, C. L. Manthey, and M. R. Player, Bioorg. Med. Chem. Lett., 2008, 18, 2355; CrossRef (c) H. Huang, D. A. Hutta, J. M. Rinker, H. Hu, W, H, Parsons, C. Schubert, R. L. DesJalais, C. S. Crysler, M. A. Chaikin, R. R. Donattelli, Y. Chen, D. Cheng, Z. Zhou, E. Yurkov, C. L. Manthey, and M. R. Player, J. Med. Chem., 2009, 52, 1081; CrossRef (d) T. Wang, L. Duncan, W. Gu, H. O’Dowd, Y. Wei, E. Perola, J. Parsons, C. H. Gross, C. S. Moody, S. J. R. Arends, and P. S. Charifson, Bioorg. Med. Chem. Lett., 2012, 22, 3699; (e) A. Mastracchio, C. Lai, and T. D. Penning, PCT Int. Appl., 2013, WO 2013059485 (Chem. Abstr., 2013, 158, 606036); (f) J. S. S. Rountree, C. R. O’Dowd, F. Burkamp, and P. Mark, PCT Int. Appl., 2015, WO 2015019037 (Chem. Abstr., 2015, 162, 300245).
3. M. G. Assy and H. Y. Moustafa, Pol. J. Chem., 1997, 71, 1232.
4. (a) K. Kobayashi, T. Suzuki, T. Kozuki, N. Matsumoto, H. Hiyoshi, and K. Umezu, Heterocycles, 2012, 85, 1405; CrossRef (b) K. Kobayashi, T. Suzuki, A. Imaoka, H. Hiyoshi, and K. Umezu, Heterocycles, 2013, 87, 885; CrossRef (c) K. Kobayashi, M. Kuroda, N. Tanaka, Y. Yokoi, A. Kobayashi, H. Hiyoshi, and K. Umezu, Heterocycles, 2014, 89, 1933; CrossRef (d) K. Kobayashi, S. Yuba, A. Taniguchi, H. Inouchi, H. Hiyoshi, and K. Umezu, Heterocycles, 2014, 89, 2611; CrossRef (e) K. Kobayashi, K. Nakazawa, S. Yuba, H. Hiyoshi, and K. Umezu, Heterocycles, 2015, 90, 216. CrossRef