HETEROCYCLES

Paper | Regular issue | Vol. 85, No. 6, 2012, pp. 1405-1416
Received, 16th March, 2012, Accepted, 16th April, 2012, Published online, 19th April, 2012.
DOI: 10.3987/COM-12-12463

■ Synthesis of 5,6-Disubstituted Thieno[2,3-d]pyrimidines from 4-Chloropyrimidines

Kazuhiro Kobayashi,* Teruhiko Suzuki, Taketoshi Kozuki, Naoki Matsumoto, 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

Facile reaction sequences for the preparation of 5,6-disubstituted thieno[2,3-d]pyrimidines starting with 4-chloropyrimidines have been developed. 4-Chloro-6-methoxypyrimidines were aroylated at the 5-positions via lithiation with LDA and subsequent treatment with benzaldehyde or N-methoxy-N-methylbenzamides to give aryl(4-chloro-6-methoxypyrimidin-5-yl)methanones. These pyrimidinyl ketones were transformed in one-pot into 5,6-disubstituted 4-methoxythieno[2,3-d]pyrimidines by a successive treatment with sodium sulfide, BrCH2EWGs, and sodium hydride. Lithiation of 4,6-dichloro-2- (methylsulfanyl)pyrimidine at the 5-position was followed by treatment with tertiary formamides to give 4-chloro-6-(dialkylamino)pyrimidine-5-carboxaldehydes, which could be transformed into 5,6-disubstituted 4-(dialkylamino)thieno[2,3-d]pyrimidines via aryl[4-chloro-6-(dialkylamino)pyrimidin-5-yl]methanones using the same one-pot thiophene ring forming sequence.

INTRODUCTION
We have previously reported that 2,3-disubstituted thieno[2,3-b]pyridines,1 thieno[2,3-c]pyridines,1 thieno[3,2-c]pyridines,1 and 6,7-disubstituted thieno[2,3-b]pyrazines2 can be prepared in one-pot from corresponding aryl(chloropyridinyl)methanones and aryl(2-chloropyrazin-3-yl)methanones by successive treatment with sodium sulfide, BrCH2EWGs, and sodium hydride. As an extension of these syntheses to other thiophene-fused nitrogen heterocycles, we decided to synthesize 5,6-disubstituted thieno[2,3-d]pyrimidines. We now report the results of our investigation, which provide convenient routes to 4-methoxy- (4 and 7) and 4-(dialkylamino)thieno[2,3-d]pyrimidines (12) starting with 4-chloropyrimidines. Thieno[2,3-d]pyrimidines have attracted significant interest from chemical community because of their medicinal and synthetic utilities. A number of compounds having the thieno[2,3-d]pyrimidine structure have been reported to show biological activities.3,4 Thieno[2,3-d]pyrimidine derivatives have been utilized for the preparation of structurally more complex and biologically more useful heterocycles.5 Hitherto many groups have reported efficient methods for the preparation of thieno[2,3-d]pyrimidines derivatives.4,6 However, most of these methods depend on the pyrimidines ring formation starting with appropriately substituted thiophene derivatives.

RESULTS AND DISCUSSION
First, we tried direct 5-benzoylation of 4-chloro-6-methoxypyrimidine (1) providing (4-chloro-6-methoxypyrimidin-5-yl)phenylmethanone (3) in order to prepare 4-methoxy-5- phenylthieno[2,3-d]pyrimidines (4). Treatment of 1 with LDA in THF at –78 °C was followed by the addition of N-methoxy-N-methylbenzamide. However, this attempt resulted in failure; no benzoylation occurred. Compound 3 proved to be obtainable by the following two-step sequence. After treatment of 1 with LDA under the above conditions, benzaldehyde was added to give upon aqueous workup (4-chloro-6-methoxypyrimidin-5-yl)phenylmethanol (2) in good yield. The PCC oxidation of 2 led to rapid and good yield conversion into 3, as shown in Scheme 1. The previously reported one-pot thiophene ring formation was applied to this chloropyrimidinyl ketone (3). Thus, 3 was allowed to react with sodium sulfide in DMF at 60 °C to form reddish brown solutions within 1 h, which were successively treated with BrCH2EWGs and sodium hydride at 0 °C to afford, after aqueous workup followed by recrystallization, 6-substituted 4-methoxy-5-phenylthieno[2,3-d]pyrimidines (4a) and (4b) in good yields.

Subsequently, it was found that 4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidine (5) performed more capably than 1 to permit direct formation of aryl[4-chloro-6-methoxy-2-(methylsulfanyl)pyrimidin-5- yl]methanones (6) as shown in Scheme 2. Thus, treatment of 5 with LDA in THF at –78 °C followed by the addition of N-methoxy-N-methylbenzamides afforded 6 after aqueous workup in fair yields as summarized in Table 1. When the ketones (6) thus obtained were treated successfully with sodium sulfide, BrCH2EWGs, and sodium hydride under the same conditions as described for the preparation of 4, 5,6-disubstituted 4-methoxy-2-(methylsulfanyl)thieno[2,3-d]pyrimidines (7) were obtained in the yields summarized in Table 2. The yields ranged from moderate to fair depending on the substrates (6).

In order to extend the present method to the synthesis of 5,6-disubstituted 4-(dialkylamino)thieno[2,3-d]pyrimidines (12), we initially attempted 5-benzoylation of 4-chloro-6- dimethylamino-2-(methylsulfanyl)pyrimidine under the same conditions as described for the preparation of 6. Unfortunately, however, this attempt resulted in failure; only a trace amount of the desired product was obtained. Of interest is that when 4,6-dichloro-2-(methylsulfanyl)pyrimidine (8) was lithiated with LDA in THF at –78 °C and the resulting lithium product was treated with tertiary formamides, 4-chloro-6-dialkylamino-2-(methylsulfanyl)pyrimidine-5-carboxaldehydes (9) were obtained in fair to good yields as shown in Scheme 3. Unfortunately, however, simultaneous 5-benzoylation and 4-dimethylamination could not be accomplished using N,N-dimethylbenzamide; the reaction gave an intractable mixture of products. The action of arylmagnesium bromide on these aldehydes (9), followed by PCC oxidation of the resulting alcohols (10), gave aryl(4-chloropyrimidin-5-yl)methanones (11) in generally good yields as summarized in Table 3. These ketones (11) were subjected to the one-pot sequence under the same reaction conditions described for the preparation of 4 and 7. It was found that they behaved similarly to give rise to the desired products (12) as shown in Scheme 3. The yields of 12 are moderate as summarized in Table 4.

In conclusion, we have demonstrated that 5,6-disubstituted 4-methoxy- and 4-(dialkylamino)thieno[2,3-d]pyrimidines could be prepared from 4-chloropyrimidines. The method may be of value in organic synthesis because of the ready availability of the starting materials and the easy experimental operations.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Shimadzu FTIR-8300 spectrophotometer. 1H NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or a JEOL LA400FT NMR spectrometer operating at 400 MHz. 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. 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-methoxypyrimidine (1) was prepared according to the reported method.7 n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
(4-Chloro-6-methoxypyrimidin-5-yl)phenylmethanol (2). To a stirred solution of LDA (1.8 mmol), generated by the standard method from n-BuLi and i-Pr2NH, in THF (2 mL) at –78 °C was added a solution of 1 (0.25 g, 1.8 mmol) in THF (2 mL) dropwise. After 1.5 h, PhCHO (0.19 mg, 1.8 mmol) was added and stirring was continued for an additional 30 min. Saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by evaporation. The residue was purified by column chromatography on silica gel (AcOEt–hexane 1:2) to give 2 (0.33 g, 75%); a white solid; mp 89–91 °C (hexane–CH2Cl2); IR (KBr) 3310 cm–1; 1H NMR (500 MHz) δ 3.55 (d, J = 11.5 Hz, 1H), 4.01 (s, 3H), 6.28 (d, J = 11.5 Hz, 1H), 7.28–7.37 (m, 5H), 8.55 (s, 1H). Anal. Calcd for C12H11ClN2O2: C, 57.49; H, 4.42; N, 11.17. Found: C, 57.19; H, 4.60; N, 11.19.
(4-Chloro-6-methoxypyrimidin-5-yl)phenylmethanone (3). This compounds were prepared by the PCC oxidation of 2 under the conditions reported previously;2 yield: 87%; a white solid; mp 78–80 °C (hexane–CH2Cl2); IR (KBr) 1676 cm–1; 1H NMR (500 MHz) δ 3.98 (s, 3H), 7.51 (dd, J = 7.8, 7.3 Hz, 2H), 7.66 (tt, J = 7.3, 1.4 Hz, 1H), 7.83 (dd, J = 7.8, 1.4 Hz, 2H), 8.69 (s, 1H). Anal. Calcd for C12H9ClN2O2: C, 57.96; H, 3.65; N, 11.27. Found: C, 57.84; H, 3.49; N, 11.22.
4-Chloro-6-methoxy-2-methylsulfanylpyrimidine (5). This compound was prepared from 4,6-dichloro-2-methylsulfanylpyrimidine under the conditions for the preparation of 1 from 4,6-dichloropyrimidine.7 5: a white solid; mp 36–38 °C (hexane); IR (KBr) 1560, 1541 cm–1; 1H NMR (400 MHz) δ 2.56 (s, 3H), 3.98 (s, 3H), 6.42 (s, 1H). Anal. Calcd for C6H7ClN2OS: C, 37.80; H, 3.70; N, 14.69. Found: C, 37.71; H, 3.70; N, 14.68.
Typical Procedure for the Preparation of Aryl(pyrimidin-5-yl)methanones (6). (4-Chloro-6-methoxy-2-methylsulfanylpyrimidin-5-yl)phenylmethanone (6a). To a stirred solution of LDA (0.68 mmol) in THF (3 mL) at –78 °C was added a solution of 5 (0.13 g, 0.68 mmol) in THF (1 mL) dropwise. After 1.5 h, N-methoxy-N-methylbenzamide (0.11 g, 0.68 mmol) was added dropwise and stirring was continued for an additional 30 min at the same temperature. Saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by evaporation. The residue was purified by column chromatography on silica gel (AcOEt–hexane 1:15) to give 6a (0.13 g, 66%); a white solid; mp 143–145 °C (hexane–CH2Cl2); IR (KBr) 1667 cm–1; 1H NMR (500 MHz) δ 2.60 (s, 3H), 3.95 (s, 3H), 7.49 (dd, J = 8.6, 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.84 (dd, J = 8.6, 1.1 Hz, 2H). Anal. Calcd for C13H11ClN2O2S: C, 52.97; H, 3.76; N, 9.50. Found: C, 52.85; H, 3.77; N, 9.42.
(4-Chloro-6-methoxy-2-methylsulfanylpyrimidin-5-yl)(3-methylphenyl)methanone (6b): a white solid; mp 119–121 °C (hexane–CH2Cl2); IR (KBr) 1668 cm–1; 1H NMR (500 MHz) δ 2.41 (s, 3H), 2.61 (s, 3H), 3.95 (s, 3H), 7.37 (dd, J = 8.0, 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H). Anal. Calcd for C14H13ClN2O2S: C, 54.46; H, 4.24; N, 9.07. Found: C, 54.19; H, 4.19; N, 9.05.
(4-Chloro-6-methoxy-2-methylsulfanylpyrimidin-5-yl)(3-chlorophenyl)methanone (6c): a white solid; mp 89–91 °C (hexane–Et2O); IR (KBr) 1677 cm–1; 1H NMR (400 MHz) δ 2.61 (s, 3H), 3.96 (s, 3H), 7.44 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H). Anal. Calcd for C13H10Cl2N2O2S: C, 47.43; H, 3.06; N, 8.51. Found: C, 54.19; H, 4.19; N, 9.05.
(4-Chloro-6-methoxy-2-methylsulfanylpyrimidin-5-yl)(4-methoxyphenyl)methanone (6d): a white solid; mp 127–128 °C (hexane–Et2O); IR (KBr) 1661, 1600 cm–1; 1H NMR (400 MHz) δ 2.60 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 6.96 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H). Anal. Calcd for C14H13ClN2O3S: C, 51.77; H, 4.03; N, 8.63. Found: C, 51.72; H, 4.01; N, 8.38.
Typical Procedure for the Preparation of 6-(Dialkylamino)pirimidine-5-carboxaldehydes (9). 4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidine-5-carboxaldehyde (9a).8 To a stirred solution of LDA (1.0 mmol) in THF (2.5 mL) at –78 °C was added a solution of 8 (0.20 g, 1.0 mmol) in THF (1.5 mL) dropwise. After 1.5 h, DMF (73 mg, 1.0 mmol) was added dropwise and stirring was continued for an additional 10 min. Water (10 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by evaporation. The residual solid was recrystallized from hexane–CH2Cl2 to give 9a (0.17 g, 75%); a white solid; mp 122–125 °C; IR (KBr) 1664 cm–1; 1H NMR (400 MHz) δ 2.53 (s, 3H), 3.13 (s, 6H), 10.24 (s, 1H).

4-Chloro-2-methylsulfanyl-6-(piperidin-1-yl)pyrimidine-5-carboxaldehyde (9b): a white solid; mp 126–128 °C (hexane–CH2Cl2); IR (KBr) 1664 cm–1; 1H NMR (400 MHz) δ 1.70 (br s, 6H), 2.51 (s, 3H), 3.60 (br s, 4H), 10.17 (s, 1H). Anal. Calcd for C11H14ClN3OS: C, 48.61; H, 5.19; N, 15.46. Found: C, 48.36; H, 5.26; N, 15.40.
Typical Procedure for the Preparation of Aryl[6-(dialkylamino)pirimidin-5-yl]methanols (10). (4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)phenylmethanol (10a). To a stirred solution of 9a (0.23 g, 1.0 mmol) in THF (3 mL) at 0 °C was added dropwise PhMgBr, prepared from PhBr (0.19 g, 1.2 mmol) and Mg (35 mg, 1.4 mmol) in THF (3 mmol). After 10 min, saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated by evaporation. The residual solid was recrystallized from hexane–CH2Cl2 to give 10a (0.28 g, 90%); a pale-yellow solid; mp 152–154 °C (hexane–CH2Cl2); IR (KBr) 3262 cm–1; 1H NMR (400 MHz) δ 2.54 (s, 3H), 2.96 (s, 6H), 3.28 (d, J = 8.8 Hz, 1H), 6.16 (d, J = 8.8 Hz, 1H), 7.26–7.36 (m, 5H). Anal. Calcd for C14H16ClN3OS: C, 54.27; H, 5.21; N, 13.56. Found: C, 54.27; H, 5.45; N, 13.50.
(4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)(4-chlorophenyl)methanol (10b): a white solid; mp 179–181 °C (hexane–CH2Cl2); IR (KBr) 3300 cm–1; 1H NMR (500 MHz) δ 2.53 (s, 3H), 2.95 (s, 6H), 3.21 (d, J = 9.2 Hz, 1H), 6.11 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H). Anal. Calcd for C14H15Cl2N3OS: C, 48.84; H, 4.39; N, 12.21. Found: C, 48.63; H, 4.48; N, 11.94.
(4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)(4-methoxyphenyl)methanol (10c): a white solid; mp 161–163 °C (hexane–CH2Cl2); IR (KBr) 3272, 1610 cm–1; 1H NMR (400 MHz) δ 2.54 (s, 3H), 2.95 (s, 6H), 3.27 (d, J = 9.8 Hz, 1H), 3.82 (s, 3H), 6.08 (d, J = 9.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H). Anal. Calcd for C15H18ClN3O2S: C, 53.01; H, 5.34; N, 12.36. Found: C, 52.90; H, 5.47; N, 12.35.
[4-Chloro-2-methylsulfanyl-6-(piperidin-1-yl)pyrimidin-5-yl]phenylmethanol (10d): a white solid; mp 114–116 °C (hexane–Et2O); IR (KBr) 3313 cm–1; 1H NMR (400 MHz) δ 1.53–1.56 (m, 6H), 2.54 (s, 3H), 3.04–3.28 (m, 4H), 4.08 (d, J = 9.8 Hz, 1H), 6.07 (d, J = 9.8 Hz, 1H), 7.26–7.35 (m, 5H). Anal. Calcd for C17H20ClN3OS: C, 58.36; H, 5.76; N, 12.01. Found: C, 58.32; H, 5.81; N, 11.82.
Aryl[6-(dialkylamino)pirimidin-5-yl]methanones 11. These compounds were prepared by the PCC oxidation of 10 under the conditions reported previously.2
(4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)phenylmethanone (11a): a white solid; mp 122–124 °C (hexane–Et2O); IR (KBr) 1663, 1541 cm–1; 1H NMR (400 MHz) δ 2.55 (s, 3H), 2.98 (s, 6H), 7.50 (dd, J = 8.6, 7.4 Hz, 2H), 7.62 (tt, J = 7.4, 1.1 Hz, 1H), 7.92 (dd, J = 8.6, 1.1 Hz, 2H). Anal. Calcd for C14H14ClN3OS: C, 54.63; H, 4.58; N, 13.65. Found: C, 54.33; H, 4.60; N, 13.57.
(4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)(4-chlorophenyl)methanone (11b): a white solid; mp 135–137 °C (hexane–CH2Cl2); IR (KBr) 1674 cm–1; 1H NMR (500 MHz, CDCl3) δ 2.54 (s, 3H), 2.98 (s, 6H), 7.48 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H). Anal. Calcd for C14H13Cl2N3OS: C, 49.13; H, 3.83; N, 12.28. Found: C, 49.09; H, 3.89; N, 12.13.
(4-Chloro-6-dimethylamino-2-methylsulfanylpyrimidin-5-yl)(4-methoxyphenyl)methanone (11c): a white solid; mp 130–132 °C (hexane–Et2O); IR (KBr) 1657 cm–1; 1H NMR (500 MHz) δ 2.54 (s, 3H), 3.00 (s, 6H), 3.90 (s, 3H), 6.97 (d, J = 9.8 Hz, 2H), 7.89 (d, J = 9.8 Hz, 2H). Anal. Calcd for C15H16ClN3O2S: C, 53.33; H, 4.77; N, 12.44. Found: C, 53.07; H, 4.88; N, 12.19.
[4-Chloro-2-methylsulfanyl-6-(piperidin-1-yl)pyrimidin-5-yl]phenylmethanone (11d): a white solid; mp 120–122 °C (hexane–CH2Cl2); IR (KBr) 1655, 1544 cm–1; 1H NMR (400 MHz) δ 1.38–1.44 (m, 4H), 1.53–1.57 (m, 2H), 2.54 (s, 3H), 3.43–3.46 (m, 4H), 7.50 (dd, J = 8.8, 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H). Anal. Calcd for C17H18ClN3OS: C, 58.70; H, 5.22; N, 12.08. Found: C, 58.66; H, 5.22; N, 12.05.
Typical Procedure for the Preparation of Thienopyrimidines (4), (7), and (12). 4-Methoxy-5-phenylthieno[2,3-d]pyrimidine-6-carbonitrile (4a). A solution of 3 (0.14 g, 0.56 mmol) and Na2S nonahydrate (0.15 g, 0.62 mmol) in DMF (3 mL) was heated at 60 °C for 1 h. After cooling to 0 ˚C, BrCH2CN (74 mg, 0.62 mmol) was added; the mixture was stirred for 15 min. Then NaH (60% in oil; 25 mg, 0.62 mmol) was added and stirring was continued for an additional 10 min before water (20 mL) was added. The precipitate was collected by filtration and recrystallized from hexane–CH2Cl2 to give 4a (0.12 g, 79%); a beige solid; mp 189–190 °C; IR (KBr) 2220 cm–1; 1H NMR (500 MHz) δ 3.96 (s, 3H), 7.51 (br s, 5H), 8.77 (s, 1H); 13C NMR δ 54.35, 104.88, 113.74, 116.52, 128.07, 129.47, 129.58, 132.19, 146.55, 156.17, 165.36, 168.93; MS m/z 267 (M+, 100). Anal. Calcd for C14H9N3OS: C, 62.91; H, 3.39; N, 15.72. Found: C, 62.88; H, 3.29; N, 15.70.
1,1-Dimethylethyl 4-Methoxy-5-phenylthieno[2,3-d]pyrimidine-6-carboxylate (4b): a white solid; mp 115–117 °C (hexane); IR (KBr) 1684 cm–1; 1H NMR (500 MHz) δ 1.31 (s, 9H), 3.80 (s, 3H), 7.27–7.30 (m, 2H), 7.38–7.40 (m, 3H), 8.69 (s, 1H); 13C NMR δ 27.71, 53.89, 82.69, 119.37, 127.21, 127.62, 129.15, 129.70, 135.48, 139.76, 155.01, 161.33, 165.58, 167.64; MS m/z 342 (M+, 61), 286 (100). Anal. Calcd for C18H18N2O3S: C, 63.14; H, 5.30; N, 8.18. Found: C, 63.09; H, 5.47; N, 8.19.
4-Methoxy-2-methylsulfanyl-5-phenylthieno[2,3-d]pyrimidine-6-carbonitrile (7a): a pale-yellow solid; mp 200–203 °C (hexane–CH2Cl2); IR (KBr) 2222 cm–1; 1H NMR (500 MHz) δ 2.63 (s, 3H), 3.91 (s, 3H), 7.48–7.50 (m, 5H); 13C NMR δ 14.38, 54.30, 101.88, 112.98, 114.12, 128.02, 129.35, 129.52, 132.35, 146.74, 150.07, 169.80, 171.42; MS m/z 313 (M+, 100). Anal. Calcd for C15H11N3OS2: C, 57.49; H, 3.54; N, 13.41. Found: C, 57.49; H, 3.71; N, 13.20.
1,1-Dimethylethyl 4-Methoxy-2-methylsulfanyl-5-phenylthieno[2,3-d]pyrimidine-6-carboxylate (7b): a white solid; mp 154–156 °C (hexane–Et2O); IR (KBr) 1688 cm–1; 1H NMR (500 MHz) δ 1.29 (s, 9H), 2.62 (s, 3H), 3.77 (s, 3H), 7.26–7.38 (m, 5H); 13C NMR δ 14.33, 27.75, 53.89, 82.37, 115.96, 126.99, 127.15, 127.51, 129.13, 135.64, 140.08, 161.59, 164.44, 168.60, 169.44; MS m/z 388 (M+, 50), 332 (100). Anal. Calcd for C19H20N2O3S2: C, 58.74; H, 5.19; N, 7.21. Found: C, 58.63; H, 5.27; N, 7.18.

1,1-Dimethylethyl 4-Methoxy-5-(3-methylphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6- carboxylate (7c): a white solid; mp 136–138 °C (hexane–CH2Cl2); IR (KBr) 1691 cm–1; 1H NMR (400 MHz) δ 1.23 (s, 9H), 2.39 (s, 3H), 2.62 (s, 3H), 3.79 (s, 3H), 7.05–7.07 (m, 2H), 7.18 (d, J = 7.8 Hz, 1H), 7.26 (dd, J = 7.8, 7.3 Hz, 1H); 13C NMR δ 14.34, 21.38, 27.75, 53.93, 82.27, 115.94, 126.22, 126.89, 127.03, 128.23, 129.91, 135.41, 136.45, 140.28, 161.68, 164.45, 168.59, 169.33; MS m/z 402 (M+, 69), 346 (100). Anal. Calcd for C20H22N2O3S2: C, 59.68; H, 5.51; N, 6.96. Found: C, 59.40; H, 5.81; N, 6.82.
[4-Methoxy-5-(3-methylphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidin-6-yl]phenylmethanone (7d): a pale-yellow solid; mp 118–120 °C (hexane–CH2Cl2); IR (KBr) 1625 cm–1; 1H NMR (400 MHz) δ 2.15 (s, 3H), 2.66 (s, 3H), 3.89 (s, 3H), 6.90–6.93 (m, 2H), 6.99–7.05 (m, 2H), 7.13 (dd, J = 7.8, 7.3 Hz, 2H), 7.22–7.31 (m, 1H), 7.50 (dd, J = 7.8, 2.0 Hz, 2H); 13C NMR δ 14.38, 21.02, 54.00, 114.94, 127.02, 127.61, 127.64, 128.63, 128.72, 129.08, 131.56, 132.13, 133.61, 133.91, 136.62, 137.40, 139.48, 164.64, 169.51, 191.24; MS m/z 406 (M+, 100). Anal. Calcd for C22H18N2O2S2: C, 65.00; H, 4.46; N, 6.89. Found: C, 64.90; H, 4.38; N, 6.80.
5-(3-Chlorophenyl)-4-methoxy-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carbonitrile (7e): a beige solid; mp 199–200 °C (hexane–CH2Cl2); IR (KBr) 2214 cm–1; 1H NMR (400 MHz) δ 2.70 (s, 3H), 3.57 (s, 3H), 7.35 (d, J = 6.8 Hz, 1H), 7.43 (s, 1H), 7.58 (dd, J = 8.8, 6.9 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H); 13C NMR δ 14.64, 52.28, 107.59, 112.62, 113.98, 127.26, 129.08, 130.98, 131.01, 133.45, 135.72, 143.68, 155.38, 169.91, 172.17; MS m/z 347 (M+, 100). Anal. Calcd for C15H10ClN3OS2: C, 51.79; H, 2.90; N, 12.08. Found: C, 51.75; H, 2.76; N, 12.02.
4-Methoxy-5-(4-methoxyphenyl)-2-methylsulfanylthieno[2,3-d]pyrimidine-6-carbonitrile (7f): a white solid; mp 200–202 °C (hexane–CH2Cl2); IR (KBr) 2215, 1609 cm–1; 1H NMR (400 MHz) δ 2.63 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 6.99 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H); 13C NMR δ 14.40, 54.34, 55.32, 101.02, 112.94, 113.45, 114.49, 124.58, 131.02, 146.68, 160.42, 164.02, 169.81, 171.26; MS m/z 343 (M+, 100). Anal. Calcd for C16H13N3O2S2: C, 55.96; H, 3.82; N, 12.24. Found: C, 55.74; H, 4.12; N, 12.24.
4-Dimethylamino-2-methylsulfanyl-5-phenylthieno[2,3-d]pyrimidine-6-carbonitrile (12a): a beige solid; mp 192–194 °C (hexane–CH2Cl2); IR (KBr) 2207 cm–1; 1H NMR (400 MHz) δ 2.61 (s, 3H), 2.63 (s, 6H), 7.45–7.50 (m, 5H); 13C NMR δ 14.31, 40.49, 99.05, 110.31, 114.93, 128.45, 128.97, 129.35, 134.11, 146.98, 160.43, 168.97, 171.22; MS m/z 326 (M+, 100). Anal. Calcd for C16H14N4S2: C, 58.87; H, 4.32; N, 17.16. Found: C, 58.60; H, 4.36; N, 17.10.
1,1-Dimethylethyl 5-(4-Chlorophenyl)-4-dimethylamino-2-methylsulfanyl[2,3-d]pyrimidine-6- carboxylate (12b): colorless crystals; mp 175–177 °C (hexane–CH2Cl2); IR (KBr) 1686 cm–1; 1H NMR (400 MHz,) δ 1.44 (s, 9H), 2.54 (s, 6H), 2.60 (s, 3H), 7.29 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H); 13C NMR δ 14.32, 28.01, 40.61, 82.64, 113.53, 123.82, 127.85, 131.53, 133.87, 134.05, 139.21, 161.20, 161.48, 167.41, 170.03; MS m/z 435 (M+, 69), 379 (100). Anal. Calcd for C20H22ClN3O2S2: C, 55.10; H, 5.09; N, 9.64. Found: C, 55.02; H, 5.18; N, 9.39.
[5-(4-Chlorophenyl)-4-dimethylamino-2-methylsulfanyl[2,3-d]pyrimidin-6-yl]phenylmethanone (12c): a pale-yellow solid; mp 206–208 °C (hexane–CH2Cl2); IR (KBr) 1627 cm–1; 1H NMR (500 MHz) δ 2.59 (s, 6H), 2.63 (s, 3H), 7.11 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.20 (dd, J = 8.0, 7.4 Hz, 2H), 7.39 (tt, J = 7.4, 1.1 Hz, 1H), 7.50 (dd, J = 8.0, 1.1 Hz, 2H); 13C NMR δ 14.33, 40.68, 112.52, 127.99, 128.18, 129.48, 130.94, 131.01, 132.64, 133.78, 134.15, 137.34, 137.43, 161.32, 167.52, 170.61, 191.36; MS m/z 439 (M+, 100). Anal. Calcd for C22H18ClN3OS2: C, 60.06; H, 4.12; N, 9.55. Found: C, 59.94; H, 4.34; N, 9.58.
4-Dimethylamino-5-(4-methoxyphenyl)-2-methylsulfanyl[2,3-d]pyrimidine-6-carbonitrile (12d): a white solid; mp 170–173 °C (hexane–CH2Cl2); IR (KBr) 2202, 1608 cm–1; 1H NMR (500 MHz) δ 2.60 (s, 3H), 2.66 (s, 6H), 3.89 (s, 3H), 7.01 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H); 13C NMR δ 14.34, 40.55, 55.42, 98.31, 110.39, 114.36, 115.26, 126.50, 129.80, 146.92, 160.36, 160.61, 168.85, 171.11; MS m/z 356 (M+, 100). Anal. Calcd for C17H16N4OS2: C, 57.28; H, 4.52; N, 15.72. Found: C, 57.20; H, 4.60; N, 15.68.
1,1-Dimethylethyl 4-Dimethylamino-5-(4-methoxyphenyl)-2-methylsulfanyl[2,3-d]pyrimidine-6- carboxylate (12e): colorless crystals; mp 136–138 ˚C (hexane–CH2Cl2); IR (KBr) 1679, 1611 cm–1; 1H NMR (500 MHz) δ 1.44 (s, 9H), 2.54 (s, 6H), 2.60 (s, 3H), 3.87 (s, 3H), 6.93 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H); 13C NMR δ 14.28, 28.04, 40.43, 55.26, 82.22, 113.02, 113.74, 122.87, 127.76, 131.35, 140.65, 159.35, 161.27, 161.75, 167.03, 169.92; MS m/z 431 (M+, 61), 375 (100). Anal. Calcd for C21H25N3O3S2: C, 58.44; H, 5.84; N, 9.74. Found: C, 58.31; H, 5.84; N, 9.51.
1,1-Dimethylethyl 2-Methylsulfanyl-5-phenyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine-6- carboxylate (12f): colorless crystals; mp 155–157 ˚C (hexane–CH2Cl2); IR (KBr) 1710 cm–1; 1H NMR (400 MHz) δ 1.02–1.08 (m, 4H), 1.28–1.34 (m, 2H), 1.38 (s, 9H), 2.60 (s, 3H), 3.04–3.07 (m, 4H), 7.33–7.42 (m, 5H); 13C NMR δ 14.32, 23.92, 24.71, 27.92, 50.44, 82.36, 114.41, 124.66, 127.57, 127.94, 130.17, 135.00, 140.14, 161.66, 161.79, 167.32, 169.98; MS m/z 441 (M+, 52), 385 (100). Anal. Calcd for C23H27N3O2S2: C, 62.55; H, 6.16; N, 9.52. Found: C, 62.50; H, 6.20; N, 9.30.

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