Direct Palladium-Catalyzed Arylations of Aryl Bromides. with 2/9-Substituted Pyrimido[5,4-b]indolizines

Direct Palladium-Catalyzed Arylations of Aryl Bromides with 2/9-Substituted Pyrimido[5,4-b]indolizines Min Jiang, Ting Li, Linghua Meng, Chunhao Yang,* Yuyuan Xie*, and Jian Ding State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203 P.R.China Supporting Information Contents General Methods Procedures for the Coupling Reaction Copies of 1 MR and 13 C MR of Compounds

General Methods Reagents (chemicals) were purchased from commercial sources (Alfa and Shanghai Chemical Reagent Company), and used without further purification. All reagents were stored in the presence of CaCl 2 in a desiccator under vacuum at room temperature and protected from light. Analytical thin layer chromatography (TLC) used was HSGF 254 (0.15-0.2 mm thickness, Yantai Huiyou Company, China). All products were characterized by MR and MS. 1 H and 13 C MR spectra were obtained on Varian Mercury-300 and Varian Mercury-400 spectrometers with tetramethylsilane (TMS) as the internal standard (IS). Chemical shifts were reported in parts per million (ppm, δ) downfield from TMS. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Low- and high-resolution mass spectra (LRMS and HRMS) were obtained on a Finnigan MAT 95 spectrometer. Procedures for the Coupling Reaction General Procedure: A solution of 2-substituted pyrimido[5,4-b]indolizine (0.4 mmol), aryl bromide (0.48 mmol), KOAc (0.078g, 0.8 mmol) and Pd (PPh 3 ) 4 (0.023g, 5 mol%, 0.02 mmol) in HMPA (2 ml) was stirred at 100 o C for 10 min under argon atmosphere. To this solution was added water (0.073 g, 0.4 mmol), and the mixture was stirred at 100 o C for 8h. The mixture was poured into water (20 ml) and the organic compound was extracted with ethyl acetate (3 10 ml). The combined organic layers were dried with a 2 SO 4, concentrated and purified by flash column chromatography (petroleum ether/ethyl acetate) to give the desired product. 2

Characterization data: 2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) Yellow solid,mp: 202-204. 1 H MR (300 MHz, CDCl 3 ): δ 9.51 (s, 1H), 8.83-8.80 (d, J =7.2 Hz,1H), 8.62 (d, J = 7.8 Hz, 2H), 7.74-7.68 (m, 3H), 7.57-7.44 (m, 5H), 7.37 (t, J =7.2 Hz, 1H), 7.03(dd, J = 6, 8.7 Hz, 1H), 6.63 (t, J = 6.9 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): δ 155.5, 149.9, 144.7, 138.4, 133.6, 133.4,129.6, 129.2, 128.6 128.5, 127.9, 126.4, 125.8, 123.9, 118.4, 116.0, 110.0, 103.8; MS (EI, m/z): 321 [M] + ; HRMS (EI): Calcd. for C 22 H 15 3 [M] + : 321.1266: Found: 321.1266. 2-Phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3ab) Yellow solid, mp: 186-187. 1 H MR (300 MHz, CDCl 3 ): δ 9.51 (s, 1H), 8.84-8.81 (d, J = 6.9 Hz,1H), 8.63 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 9.6 Hz, 1H), 7.60-7.44(m, 5H), 7.36 (d, J = 7.5, 2H), 7.06 (d, J = 6.9 Hz, 1H), 6.63 (t, J = 6 Hz, 1H), 2.46(s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 155.4, 149.9, 144.6, 138.4, 136.2, 133.2, 130.5, 129.9, 129.6, 129.2, 128.6, 128.5, 127.9, 125.6, 123.9, 118.6, 116.1, 110.0, 103.8, 21.2; MS (EI, m/z): 335 [M] + ; HRMS (EI): Calcd. for C 23 H 17 3 [M] + : 335.1422; Found: 335.1424.. 3

5-(4-Methoxyphenyl)-2-phenylpyrimido[5,4-b]indolizine (3ac) O Red solid, mp: 166-168. 1 H MR (300 MHz, CDCl 3 ): δ 9.49 (s, 1H), 8.82 (d, J = 6.9 Hz,1H), 8.64-8.61 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 9.6 Hz, 1H), 7.62-7.46(m, 5H), 7.10 (d, J = 8.4, 2H), 7.05-6.99 (m, 1H), 6.63 (t, J = 6.9Hz, 1H), 3.91 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 158.3, 155.3, 149.8, 144.5, 138.4, 133.1, 129.8, 129.7, 128.6, 127.9, 125.8,125.4, 123.9, 118.5, 116.1, 114.7, 109.9, 103.6, 55.4; MS (EI, m/z): 351 [M] + ; HRMS (EI): Calcd. for C 23 H 17 3 O [M] + : 351.1372; Found: 351.1366.. 2-Phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3af) Yellow solid, mp: 238 dec. 1 H MR (300 MHz, CF 3 COOD): δ 9.94 (s, 2H), 9.91 (d, J = 1.2 Hz,1H), 9.79 (s, 1H), 9.22 (d, J = 5.1 Hz, 1H), 8.44 (d, J = 5.7 Hz, 2H), 8.12 (d, J = 6.9 Hz, 1H), 7.83 (t, J = 5.1 Hz, 2H), 7.77 (t, J = 5.1 Hz, 2H), 7.36 (t, J = 4.5 Hz, 1H); 13 C MR (100 MHz, CF 3 COOD): δ 157.5, 152.5, 150.2, 148.5, 143.2, 142.4, 136.1, 135.8, 132.2, 131.4, 130.3, 128.9, 126.4, 115.9, 95.5; MS (EI, m/z): 323 [M] + ; HRMS (EI): Calcd. for C 20 H 13 5 [M] + : 323.1171; Found: 323.1163. 2-Phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3ah) 4

Yellow solid, mp: 192-194. 1 H MR (300 MHz, CDCl 3 ): δ 9.55 (s, 1H), 9.30 (s, 1H), 8.88 (d, J = 7.5 Hz, 1H), 8.62 (d, J = 8.1 Hz, 2H), 8.37 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.79-7.71 (m, 2H), 7.63-7.46 (m, 4H), 7.17-7.12 (m, 1H), 6.72 (t, J = 6.6 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): δ 156.1, 150.8, 149.5, 146.5, 145.1, 138.2, 134.1, 133.9, 129.8, 129.2, 129.1, 128.6, 128.4, 127.9, 127.5, 127.2, 126.9, 124.2, 117.8, 116.1, 110.5, 99.9; MS (EI, m/z): 372 [M] + ; HRMS (EI): Calcd. for C 25 H 16 4 [M] + : 372.1375; Found: 372.1378.. 5-(3-itrophenyl)-2-phenylpyrimido[5,4-b]indolizine (3ai) O 2 Yellow solid, mp: 194-196. 1 H MR (300 MHz, DMSO-d6): 9.63 (s, 1H), 9.03 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 7.2 Hz, 2H), 8.46 (t, J = 1.5 Hz, 1H), 8.24-8.16 (m, 2H), 7.91 (d, J = 9.3 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.59-7.51 (m, 3H), 7.36 (dd, J = 9.3 Hz, 1H), 7.94 (t, J = 6.3 Hz, 1H); 13 C MR (100 MHz, CDCl 3 ): δ 156.1, 149.3, 149.0, 145.0, 138.1, 135.6, 134.1, 134.0, 130.1, 129.9, 128.6, 127.9, 127.4, 124.3, 122.8, 120.8, 117.6, 115.7, 110.6, 101.1; MS (EI, m/z): 366 [M] + ; HRMS (EI): Calcd. for C 22 H 14 4 O 2 [M] + : 366.1117; Found: 366.1119.. 2-Methyl-5-phenylpyrimido[5,4-b]indolizine (3ba) 5

Yellow solid, mp: 150-152. 1 H MR (300 MHz, CDCl 3 ): δ 9.35 (s, 1H), 8.67 (d, J = 6.9 Hz, 1H), 7.71-7.63 (m, 3H), 7.55-7.50 (m, 2H), 7.37-7.32 (m, 1H), 7.02-6.96 (m, 1H), 6.60 (td, J = 0.9, 6.9 Hz, 1H), 2.93 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 158.3, 149.5, 144.5, 133.5, 132.5, 129.2, 128.6, 126.4, 125.4, 123.6, 118.4, 115.3, 110.0, 103.5, 25.7; MS (EI, m/z): 259 [M] + ; HRMS (EI): Calcd. for C 17 H 13 3 [M] + : 259.1109; Found: 259.1114. 2-Methyl-5-p-tolylpyrimido[5,4-b]indolizine (3bb) Yellow solid, mp: 183-185. 1 H MR (300 MHz, CDCl 3 ): δ 9.35 (s, 1H), 8.68 (td, J = 1.2, 7.5 Hz, 1H), 7.71-7.65 (m, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.02-6.96 (m, 1H), 6.60 (td, J = 0.9, 6.3 Hz, 1H), 2.94 (s, 3H), 2.45 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 158.5, 149.9, 144.3, 136.0, 132.1, 130.6, 129.8, 129.1, 128.6, 128.5, 124.9, 123.5, 118.5, 115.3, 109.7, 103.3, 25.9, 21.2; MS (EI, m/z): 273 [M] + ; HRMS (EI): Calcd. for C 18 H 15 3 [M] + : 273.1266; Found: 273.1263.. 5-(4-Methoxyphenyl)-2-methylpyrimido[5,4-b]indolizine (3bc) O 6

Red solid, mp: 170-172. 1 H MR (300 MHz, CDCl 3 ): δ 9.32 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 9 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 7.01-6.96 (m, 1H), 6.60 (t, J = 6.3 Hz, 1H), 3.89 (s, 3H), 2.96 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 158.4, 158.3, 149.8, 144.2, 132.0, 129.7, 125.9, 124.8, 123.5, 118.4, 115.3, 114.6, 109.7, 103.1, 55.3, 25.8; MS (EI, m/z): 289 [M] + ; HRMS (EI): Calcd. for C 18 H 15 3 O [M] + : 289.1215; Found: 289.1207. 2-Methyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3bf) Yellow solid, mp: 280 dec. 1 H MR (300 MHz, CF 3 COOD): δ 9.8 (s, 2H), 9.71 (d, J = 6.9 Hz, 2H), 9.02 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.73-7.69 (m, 1H), 7.23 (d, J = 5.1 Hz, 1H), 3.17 (s, 3H); 13 C MR (100 MHz, CF 3 COOD): 157.7, 154.9, 150.2, 148.2, 142.7, 142.2, 135.8, 132.3, 126.3, 117.1, 116.0, 95.1, 21.9; MS (EI, m/z): 261 [M] + ; HRMS (EI): Calcd. for C 15 H 11 5 [M] + : 261.1014; Found: 261.1012. 2-Methyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3bh) Yellow solid, mp: 184-186. 1 H MR (300 MHz, CDCl 3 ): δ 9.42 (s, 1H), 9.28 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 7.5 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.78-7.71 (m, 2H), 7.62 (td, J = 1.2, 7.8 Hz, 1H), 7.14-7.09 (m, 1H), 6.70 (td, J = 1.2, 7.5 Hz, 1H), 2.96 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 159.2, 150.9, 149.4, 146.5, 144.9, 133.9, 133.3, 129.3, 129.1, 7

128.4, 127.5, 127.2, 126.5, 123.9, 117.7, 115.4, 110.4, 99.6, 25.9; MS (EI, m/z): 310 [M] + ; HRMS (EI): Calcd. for C 20 H 14 4 [M] + : 310.1218; Found: 310.1223. 2-Methyl-5-(3-nitrophenyl)pyrimido[5,4-b]indolizine (3bi) O 2 Yellow solid, mp: 258-260. 1 H MR (300 MHz, CDCl 3 ): 9.37 (s, 1H),8.76 (d, J = 7.8 Hz, 1H), 8.51 (t, J = 1.8 Hz, 1H), 8.20-8.16 (m, 1H), 7.98 (td, J = 1.2, 7.8 Hz, 1H), 7.75-7.68 (m, 2H), 7.18-7.13 (m, 1H), 6.72 (td, J = 1.2, 7.5 Hz, 1H), 2.96 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 159.3, 149.3, 148.9, 144.8, 135.6, 134.1, 133.1, 130.1, 126.9, 123.9, 122.8, 120.7, 117.5, 115.0, 110.4, 100.6, 25.9; MS (EI, m/z): 304 [M] + ; HRMS (EI): Calcd. for C 17 H 12 4 O 2 [M] + : 304.0960; Found: 304.0962. 4-(5-Phenylpyrimido[5,4-b]indolizin-2-yl)morpholine (3ca) O Yellow solid, mp: 192-193. 1 H MR (300 MHz, CDCl 3 ): δ 9.11 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 7.64-7.47 (m, 5H), 7.30 (t, J = 7.2, 1H), 6.80 (dd, J = 6.3, 9.3 Hz, 1H), 6.43 (t, J = 6.3 Hz, 1H), 3.92 (t, J = 4.5 Hz, 4H), 3.84 (t, J = 4.5 Hz, 4H); 13 C MR (100 MHz, CDCl 3 ): 151.2, 145.8, 134.2, 130.5, 129.0, 128.4, 125.9, 123.3, 123.0, 118.6, 110.9, 109.3, 103.5, 66.9, 45.1; MS (EI, m/z): 330 [M] + ; HRMS (EI): Calcd. for C 20 H 18 4 O [M] + : 330.1481; Found: 330.1489. 4-(5-p-Tolylpyrimido[5,4-b]indolizin-2-yl)morpholine (3cb) 8

O Yellow solid, mp: 190-192. 1 H MR (300 MHz, CDCl 3 ): δ 9.11 (d, J = 5.1 Hz, 1H), 8.36 (t, J = 6.3 Hz, 1H), 7.64-7.47 (m, 3H), 7.31 (d, J = 8.4 Hz, 2H), 6.79-6.74 (m, 1H), 6.41 (t, J = 6.3 Hz, 1H), 3.90 (t, J = 4.5 Hz, 4H), 3.84 (t, J = 4.5 Hz, 4H), 2.43 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): 157.4, 151.2, 145.7, 135.6, 134.2, 131.1, 130.3, 129.7, 129.0, 128.4, 128.3, 125.9, 123.0, 118.7, 118.6, 110.9, 109.2, 103.5, 66.9, 45.1, 21.1; MS (EI, m/z): 344 [M] + ; HRMS (EI): Calcd. for C 21 H 20 4 O [M] + : 344.1637; Found: 344.1627. 4-(5-(4-Methoxyphenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cc) O O Red solid, mp: 194-196. 1 H MR (300 MHz, CDCl 3 ): δ 9.07 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 7.55-7.50 (m, 3H), 7.04 (dd, J = 3, 11.4 Hz, 2H), 6.74 (dd, J = 6.3, 9.6 Hz, 1H), 6.40 (t, J = 6.9 Hz, 1H), 3.93-3.90 (m, 4H), 3.87 (s, 3H), 3.86-3.83 (m, 4H); 13 C MR (100 MHz, CDCl 3 ): 157.9, 157.5, 151.2, 145.5, 130.0, 129.5, 126.5, 122.9, 122.7, 118.6, 114.5, 111.0, 109.0, 103.1, 66.9, 55.3, 45.1; MS (EI, m/z): 360 [M] + ; HRMS (EI): Calcd. for C 21 H 20 4 O 2 [M] + : 360.1586; Found: 360.1584. 4-(5-(Pyrimidin-5-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cf) 9

O Red solid, mp: 240-242. 1 H MR (300 MHz, CDCl 3 ): δ 9.12 (s, 1H), 9.07 (s, 1H), 9.01 (s, 2H), 8.45 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.6 Hz, 1H), 6.96 (dd, J = 6.6, 9.6 Hz, 1H), 6.56 (t, J = 6.6 Hz, 1H), 3.93 (t, J = 4.8 Hz, 4H), 3.84 (t, J = 4.8 Hz, 4H); 13 C MR (100 MHz, CDCl 3 ): 157.8, 155.6, 155.4, 150.5, 146.5, 131.5, 129.1, 125.3, 123.5, 117.3, 110.1, 109.9, 95.4, 66.8, 44.9; MS (EI, m/z): 332 [M] + ; HRMS (EI): Calcd. for C 18 H 16 6 O [M] + : 332.1386; Found: 332.1389. 4-(5-(Quinolin-3-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ch) O Red solid, mp: 184-186. 1 H MR (300 MHz, CDCl 3 ): δ 9.24 (d, J = 1.8 Hz, 1H), 9.15 (s, 1H), 8.43 (td, J = 0.9, 5.4 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 6.3 Hz, 1H), 7.85 (dd, J = 0.9, 6 Hz, 1H), 7.72-7.68 (m, 1H), 7.65-7.56 (m, 2H), 6.93-6.88 (m, 1H), 6.53-6.50 (m, 1H), 3.93 (t, J = 3.6 Hz, 4H), 3.85 (t, J = 3.6 Hz, 4H); 13 C MR (100 MHz, CDCl 3 ): 157.8, 151.0, 150.9, 146.3, 146.2, 133.2, 131.3, 129.2, 128.7, 128.5, 127.8, 127.4, 127.0, 124.4, 123.3, 117.9, 110.7, 109.7, 99.7, 66.9, 45.0; MS (EI, m/z): 381 [M] + ; HRMS (EI): Calcd. for C 23 H 19 5 O [M] + : 381.1590; Found: 381.1598. 4-(5-(3-itrophenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ci) 10

O O 2 Red solid, mp: 260-262. 1 H MR (300 MHz, CDCl 3 ): δ 9.10 (s, 1H), 8.45-8.41 (m, 2H), 8.10 (dd, J = 0.9, 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 8.1, 16.2 Hz, 2H), 6.93 (dd, J = 6.3, 9.6 Hz, 1H), 6.52 (t, J = 6.3 Hz,1H), 3.92 (t, J = 4.5 Hz, 4H), 3.84 (t, J = 4.5 Hz, 4H); 13 C MR (100 MHz, CDCl 3 ): 157.7, 150.7, 148.9, 146.2, 136.2, 133.8, 131.2, 129.9, 124.9, 123.4, 122.5, 120.2, 117.7, 110.4, 109.8, 100.8, 66.8, 44.9; MS (EI, m/z): 375 [M] + ; HRMS (EI): Calcd. for C 20 H 17 5 O 3 [M] + : 375.1331; Found: 375.1332. 9-Methyl-2,5-diphenylpyrimido[5,4-b]indolizine (3da) Yellow solid, mp: 220-222. 1 H MR (300 MHz, CDCl 3 ): δ 9.48 (s, 1H), 8.55 (d, J = 7.5 Hz, 2H), 7.69-7.63 (m, 3H), 7.57-7.43 (m, 5H), 7.37 (t, J =7.2 Hz, 1H), 6.95 (dd, J = 6.6, 9.3 Hz, 1H), 6.37 (d, J = 6.0 Hz, 1H), 3.31 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): 154.5, 149.2,146.9, 139.2, 138.7, 134.9, 133.6, 129.2, 129.0, 128.9, 128.4, 127.5, 126.3, 125.2, 116.3, 115.6, 110.9, 103.8, 22.3; MS (EI, m/z): 335 [M] + ; HRMS (EI): Calcd. For C 23 H 17 3 [M] + : 335.1422; Found: 335.1431. 9-Methyl-2-phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3db) 11

Yellow solid, mp: 202-204. 1 H MR (300 MHz, CDCl 3 ): δ 9.47 (s, 1H), 8.56 (d, J = 7.2 Hz, 2H), 7.66-7.61 (m, 1H), 7.58-7.41 (m, 5H), 7.35 (d, J = 7.8, 2H), 6.93 (dd, J = 6.3, 9.6Hz, 1H), 6.36 (d, J = 6.9 Hz, 1H), 3.30 (s, 3H), 2.46 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 154.5, 149.3, 146.9, 139.1, 138.8, 136.1, 134.9, 130.5, 129.8, 129.2, 128.9, 128.4, 127.6, 125.0, 116.4, 115.8, 110.8, 103.9, 22.3, 21.2; MS (EI, m/z): 349 [M] + ; HRMS (EI): Calcd. For C 24 H 19 3 [M] + : 349.1579; Found: 349.1582. 9-Methyl-2-phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3dd) Yellow solid, mp: 214-216. 1 H MR (300 MHz, CDCl 3 ): δ 9.54 (s, 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 6.6 Hz, 2H), 8.37 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.77-7.69 (m, 2H), 7.63-7.45 (m, 4H), 7.08 (dd, J =6.3, 9.6 Hz, 1H), 6.49 (t, J = 6.6 Hz, 1H), 3.79 (s, 3H); 13 C MR (100 MHz, CDCl 3 ): δ 154.8, 151.0, 148.5, 147.1, 146.4, 139.5, 139.5, 138.3, 135.6, 133.9, 129.4, 129.2, 128.9, 128.3, 128.2, 127.5, 127.4, 127.0, 126.3, 116.2, 114.8, 111.4, 99.8, 22.2; MS (EI, m/z): 386 [M] + ; HRMS (EI): Calcd. for C 26 H 18 4 [M] + : 386.1531; Found: 386.1550. 9-Methyl-2-phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3de) 12

Yellow solid, mp: 280-282. 1 H MR (300 MHz, CF 3 COOD): δ 9.76 (s, 2H), 9.69 (s, 1H), 9.63 (s, 1H), 8.22 (d, J = 5.4 Hz, 2H), 7.85 (d, J = 6.9 Hz, 1H), 7.67-7.56 (m, 4H), 6.98 (d, J = 5.4 Hz, 1H), 3.38 (s, 3H); 13 C MR (100 MHz, CF 3 COOD): δ 159.5, 152.4, 152.1, 151.8, 146.6, 145.1, 142.6, 137.2, 137.0, 133.8, 133.0, 132.2, 130.2, 119.7, 118.7, 118.0, 116.8, 116.2, 97.1, 23.9; MS (EI, m/z): 337 [M] + ; HRMS (EI): Calcd. for C 21 H 15 5 [M] + : 337.1327 ; Found: 337.1318. 13

Copies of spectrum of Compounds: 2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) 9.517 8.830 8.807 8.640 8.614 7.745 7.710 7.707 7.680 7.573 7.548 7.535 7.523 7.509 7.485 7.462 7.396 7.371 7.258 7.057 7.037 7.027 7.005 6.657 6.635 6.612 0.010 5.00 3.10 1.92 1.01 0.93 1.00 0.95 0.96 10 8 6 4 2 0 PPM 14

2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) 15

2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) 16

2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) 17

2,5-Diphenylpyrimido[5,4-b]indolizine (3aa) 18

2-Phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3ab) 9.515 8.839 8.816 8.640 8.616 7.738 7.706 7.606 7.580 7.557 7.535 7.509 7.484 7.460 7.377 7.352 7.258 7.057 7.032 7.005 6.662 6.640 6.618 2.458 0.003 5.43 3.00 2.21 2.02 1.03 1.07 1.25 1.13 1.06 10 8 6 4 2 0 PPM 19

2-Phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3ab) 20

5-(4-Methoxyphenyl)-2-phenylpyrimido[5,4-b]indolizine (3ac) 9.492 8.838 8.836 8.814 8.641 8.615 7.706 7.703 7.673 7.672 7.627 7.599 7.557 7.535 7.507 7.483 7.480 7.460 7.264 7.258 7.113 7.086 7.049 7.028 7.022 7.019 6.997 6.660 6.637 6.615 3.907-0.001 O 4.92 3.00 1.79 1.97 0.73 1.01 1.17 1.19 0.99 10 8 6 4 2 0 PPM 21

5-(4-Methoxyphenyl)-2-phenylpyrimido[5,4-b]indolizine (3ac) 22

2-Phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3af) 9.944 9.943 9.908 9.904 9.790 9.236 9.220 8.452 8.434 8.138 8.115 7.856 7.838 7.821 7.792 7.776 7.759 7.380 7.365 7.350 2.02 2.06 2.28 2.04 1.08 1.13 0.91 1.00 0.86 10 8 6 4 2 0 PPM 23

2-Phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3af) 24

2-Phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3ah) 8.894 8.869 8.637 8.610 9.553 9.305 8.367 8.196 8.167 7.899 7.872 7.790 7.758 7.745 7.717 7.636 7.610 7.584 7.555 7.530 7.505 7.489 7.484 7.464 7.256 7.254 7.172 7.152 7.146 7.143 7.122 6.748 6.725 6.703-0.004 2.20 3.00 1.01 1.03 1.07 2.03 1.12 1.21 1.23 1.22 1.04 1.15 10 8 6 4 2 PPM 25

2-Phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3ah) 26

5-(3-itrophenyl)-2-phenylpyrimido[5,4-b]indolizine (3ai) 9.628 9.045 9.021 8.613 8.607 8.586 8.455 8.449 8.240 8.212 8.196 8.191 8.169 8.163 8.160 7.932 7.901 7.848 7.822 7.796 7.594 7.587 7.565 7.540 7.531 7.508 7.394 7.372 7.362 7.343 7.341 6.969 6.948 6.926 5.098 2.506 2.500 2.494-0.008 O 2 3.12 2.10 2.13 1.02 1.00 1.00 1.191.09 1.02 0.95 10 8 6 4 2 0 PPM 27

5-(3-itrophenyl)-2-phenylpyrimido[5,4-b]indolizine (3ai) 28

2-Methyl-5-phenylpyrimido[5,4-b]indolizine (3ba) 9.354 8.688 8.664 7.719 7.688 7.668 7.663 7.640 7.637 7.551 7.544 7.526 7.499 7.376 7.371 7.367 7.347 7.323 7.256 7.019 7.016 6.997 6.996 6.988 6.984 6.967 6.964 6.613 6.609 6.589 6.568 6.564 2.930-0.004 3.00 3.00 1.91 0.83 0.85 0.95 1.00 0.96 10 8 6 4 2 0 PPM 29

2-Methyl-5-phenylpyrimido[5,4-b]indolizine (3ba) 30

2-Methyl-5-p-tolylpyrimido[5,4-b]indolizine (3bb) 9.355 8.696 8.692 8.688 8.672 8.669 8.665 7.719 7.715 7.684 7.658 7.654 7.572 7.552 7.546 7.518 7.368 7.343 7.266 7.022 7.019 7.002 6.998 6.991 6.987 6.970 6.967 6.623 6.620 6.599 6.578 6.575 2.19 2.02 3.35 3.00 0.73 0.70 1.24 1.03 1.00 10 8 6 4 2 PPM 31

2-Methyl-5-p-tolylpyrimido[5,4-b]indolizine (3bb) 32

5-(4-Methoxyphenyl)-2-methylpyrimido[5,4-b]indolizine (3bc) 9.326 8.682 8.658 7.676 7.646 7.577 7.551 7.257 7.098 7.070 7.015 6.993 6.985 6.965 6.624 6.602 6.579 3.894 2.957 O 1.97 1.93 3.00 3.00 0.89 0.84 0.99 1.02 0.95 8 6 4 2 PPM 33

5-(4-Methoxyphenyl)-2-methylpyrimido[5,4-b]indolizine (3bc) 34

2-Methyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3bf) 11.522 9.808 9.720 9.699 9.036 9.019 8.011 7.987 7.736 7.719 7.713 7.696 7.256 7.238 7.222 3.177 3.24 2.06 2.11 1.03 1.02 1.04 1.00 12 10 8 6 4 2 0 PPM 35

2-Methyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3bf) 36

2-Methyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3bh) 9.423 9.279 9.272 8.779 8.776 8.771 8.751 8.358 8.352 8.187 8.158 7.906 7.879 7.784 7.768 7.763 7.751 7.745 7.739 7.717 7.711 7.637 7.634 7.611 7.587 7.583 7.258 7.149 7.130 7.127 7.121 7.118 7.099 7.095 6.719 6.717 6.696 6.692 6.674 6.670 2.961 3.00 1.97 0.85 0.97 0.86 0.95 0.96 1.00 1.04 1.00 0.98 10 8 6 4 2 0 PPM 37

2-Methyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3bh) 38

2-Methyl-5-(3-nitrophenyl)pyrimido[5,4-b]indolizine (3bi) 9.377 8.779 8.758 8.753 8.751 8.521 8.515 8.509 8.205 8.202 8.197 8.195 8.178 8.174 8.170 8.168 8.005 8.001 7.979 7.975 7.971 7.755 7.732 7.724 7.707 7.680 7.265 7.189 7.184 7.168 7.164 7.156 7.153 7.136 7.132 6.741 6.737 6.716 6.696 6.692 2.958-0.000 O 2 3.00 1.91 0.84 0.91 0.97 0.85 0.83 0.83 0.81 12 10 8 6 4 2 0 PPM 39

2-Methyl-5-(3-nitrophenyl)pyrimido[5,4-b]indolizine (3bi) 40

4-(5-Phenylpyrimido[5,4-b]indolizin-2-yl)morpholine (3ca) 9.119 8.392 8.367 7.639 7.612 7.577 7.522 7.498 7.471 7.335 7.310 7.286 7.258 6.826 6.805 6.794 6.773 6.460 6.439 6.416 3.936 3.923 3.906 3.865 3.849 3.837-0.002 O 4.22 4.36 3.24 1.96 1.00 1.03 1.00 0.95 0.93 8 6 4 2 0 PPM 41

4-(5-Phenylpyrimido[5,4-b]indolizin-2-yl)morpholine (3ca) 42

4-(5-p-Tolylpyrimido[5,4-b]indolizin-2-yl)morpholine (3cb) 9.117 9.100 8.390 8.371 8.348 7.640 7.615 7.574 7.543 7.533 7.506 7.472 7.324 7.296 7.257 6.792 6.771 6.741 6.435 6.413 6.391 3.918 3.904 3.863 3.848 3.835 2.428 O 4.35 3.68 4.67 1.95 2.74 1.02 1.00 1.01 0.97 8 6 4 2 0 PPM 43

4-(5-p-Tolylpyrimido[5,4-b]indolizin-2-yl)morpholine (3cb) 44

4-(5-(4-Methoxyphenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cc) 9.070 8.359 8.336 7.559 7.549 7.543 7.533 7.528 7.521 7.502 7.257 7.072 7.062 7.033 7.024 6.781 6.760 6.749 6.728 6.428 6.403 6.383 3.930 3.918 3.901 3.879 3.863 3.846 3.832 O O 4.07 3.79 3.02 2.96 2.03 0.86 0.87 1.01 0.96 10 8 6 4 2 0 PPM 45

4-(5-(4-Methoxyphenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cc) 46

4-(5-(Pyrimidin-5-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cf) 9.129 9.075 9.009 8.465 8.442 7.570 7.538 7.267 7.256 6.992 6.971 6.961 6.940 6.580 6.557 6.535 3.951 3.936 3.919 3.860 3.844 3.830 0.002-0.008 O 4.19 4.00 1.93 0.87 1.05 0.90 0.99 0.98 0.96 8 6 4 2 0 PPM 47

4-(5-(Pyrimidin-5-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3cf) 48

4-(5-(Quinolin-3-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ch) 8.429 8.292 8.287 8.154 8.133 7.861 7.858 7.841 7.838 7.728 7.724 7.711 7.707 7.703 7.690 7.686 7.654 7.651 7.648 7.630 7.627 7.625 7.604 7.601 7.587 7.583 7.581 7.566 7.563 7.258 6.930 6.928 6.914 6.912 6.906 6.903 6.891 6.888 6.537 6.535 6.521 6.519 6.517 6.504 6.501 3.947 3.937 3.932 3.924 3.916 3.875 3.868 3.856 3.845 O 4.54 4.33 2.29 0.94 1.01 0.91 1.000.97 1.01 1.04 0.95 0.87 10 8 6 4 2 0 PPM 49

4-(5-(Quinolin-3-yl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ch) 50

4-(5-(3-itrophenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ci) 9.102 8.454 8.448 8.441 8.417 8.122 8.120 8.096 8.092 7.928 7.902 7.658 7.631 7.604 7.572 7.256 6.955 6.934 6.923 6.903 6.547 6.523 6.502 3.942 3.929 3.912 3.863 3.847 3.833-0.007 O O 2 4.16 4.13 1.00 2.00 0.99 1.02 1.96 0.92 0.88 0.60 10 8 6 4 2 0 PPM 51

4-(5-(3-itrophenyl)pyrimido[5,4-b]indolizin-2-yl)morpholine (3ci) 52

9-Methyl-2,5-diphenylpyrimido[5,4-b]indolizine (3da) 9.489 8.573 8.568 8.544 7.690 7.666 7.639 7.570 7.545 7.517 7.491 7.461 7.438 7.399 7.375 7.258 6.983 6.960 6.950 6.929 6.390 6.369 3.314 0.012 4.09 3.05 3.00 1.92 1.10 0.89 0.94 0.99 0.98 10 8 6 4 2 PPM 53

9-Methyl-2,5-diphenylpyrimido[5,4-b]indolizine (3da) 54

9-Methyl-2-phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3db) 9.490 9.477 8.573 8.569 8.545 7.691 7.668 7.649 7.617 7.583 7.556 7.544 7.541 7.517 7.492 7.460 7.437 7.413 7.371 7.345 7.258 6.979 6.961 6.940 6.929 6.909 6.375 6.352 3.309 3.282 2.465 1.723 1.717 1.703 5.48 3.26 2.99 0.95 2.19 1.24 2.04 1.09 1.08 12 10 8 6 4 2 PPM 55

9-Methyl-2-phenyl-5-p-tolylpyrimido[5,4-b]indolizine (3db) 56

9-Methyl-2-phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3dd) 9.546 9.296 9.288 8.585 8.563 8.374 8.366 8.192 8.164 7.899 7.872 7.770 7.747 7.723 7.693 7.635 7.610 7.586 7.551 7.528 7.504 7.477 7.454 7.258 7.111 7.090 7.079 7.058 6.505 6.483 3.379 1.691-0.002 2.97 1.98 2.98 1.89 0.98 1.00 0.81 0.88 0.96 0.92 0.95 0.92 12 10 8 6 4 2 0PPM 57

9-Methyl-2-phenyl-5-(quinolin-3-yl)pyrimido[5,4-b]indolizine (3dd) 58

9-Methyl-2-phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3de) 9.765 9.692 9.634 8.230 8.212 7.865 7.842 7.670 7.654 7.637 7.619 7.602 7.584 7.564 6.995 6.977 3.381 3.93 3.00 2.03 2.01 0.98 0.91 1.06 0.73 12 10 8 6 4 2 PPM 59

9-Methyl-2-phenyl-5-(pyrimidin-5-yl)pyrimido[5,4-b]indolizine (3de) 60