Synthesis of Novel Dipyrimidinone Diphenyl Ethers†

doi:10.7503/cjcu20140434

Abstract

Abstract:

Generally, many diphenyl ethers show good bioactivity, the advances of these kind of compounds in medical area have made the synthesis research becoming a hot topic. In this work, through the Biginelli’s condensation of 4,4'-diformyl diphenylethers, β-ketoesters and urea catalyzed by FeC1₃·6H₂O, 12 novel dipyrimidinone diphenyl ethers were synthesized. The synthesis mechanism of dipyrimidinone was discussed and the reaction conditions were optimized. In the meantime, the synthetic method of 4,4'-diformyl diphenyl ether derivatives was also improved. Due to the appropriate timing of the reactants and catalyst's addition, this method had the advantage of short reaction time and excellent yields(90%). Finally, the preliminary toxicity testing of all the target compounds was investigated.The results showed that EC₉₅of compounds 6d, 6h and 6i were smaller than the comparison compound to Fusarium oxysporium f.s.p. niveum. The compounds containing R²(CF₃) had better biological acitivity than the others.

Key words: Dipyrimidinone diphenyl ether, 4, 4'-Diformyl diphenylether, Biginelli reaction

CLC Number:

O626

TrendMD:

GAO Qi, CHEN Bang, HOU Xiaomeng, BAI Yinjuan, SONG Yang, TANG Xuesong. Synthesis of Novel Dipyrimidinone Diphenyl Ethers^†[J]. Chem. J. Chinese Universities, 2015, 36(1): 93.

Figures/Tables 10

References 28

[1]	Hu L. X., Kully M. L., Boykin D. W., Abood N., Bioorg. Med. Chem. Lett., 2009, 19(16), 4626—4629
[2]	Ali K., Eyada H. A., EI-Rahman M. T. A., Helal M. H., El-Gaby M. S. A. E., Ali G. A. M. E. H., J. Mater. Sci. Eng. B , 2011, 1(4), 461—471
[3]	Kumar N., Singh B., Bhandari P., Gupta A. P., Uniyal S. K., Kaul V. K., Phytochemistry , 2005, 66(23), 2740—2744
[4]	Xu Y. M., Johnson R. K., Hechta S. M., Bioorg. Med. Chem., 2005, 13(3), 657—659
[5]	Fuente J. Á., Manzanaro S., Martín M. J., Quesada T. G., Reymundo I., Luengo S. M., Gago F., J. Med. Chem., 2003, 46(24), 5208—5221
[6]	Segraves E. N., Shah R. R., Segraves N. L., Johnson T. A., Whitman S., Sui J. K., Kenyon V. A., Cichewicz R. H., Crews P., Holman T. R., J. Med. Chem., 2004, 47(16), 4060—4065
[7]	Zhang L., Chang W. Q., Sun B., Groh M., Speicher A., Lou H. X., PLoS One, 2011, 6(12), e28953
[8]	Li Y., Ishibashi M., Chen X., Ohizumi Y., Chem. Pharm. Bull., 2003, 51(7), 872—874
[9]	Chen S., Xin Y., Zhan Y., Hou R. T., Wang Y. L., Chen S. H., Yang Z. R., Chin. J. Org. Chem., 2008, 28(3), 489—493
	(陈鸶, 辛莹, 詹妍, 侯若彤, 王玉良, 陈淑华, 杨志荣. 有机化学, 2008, 28(3), 489—493)
[10]	Jarrahpour A., Ebrahimi E., Clercq E. D., Sinou V., Latour C., Bouktab L. D., Brunel J. M., Tetrahedron , 2011, 67(45), 8699—8704
[11]	Li B., Pai R., Cardinale S. C., Butler M. M., Peet N. P., Moir D. T., Bavari S., Bowlin T. L., J. Med. Chem., 2010, 53(5), 2264—2276
[12]	Li L., Zhong M., Preparation of 5-(Biphenyl-4-yl)imidazole Derivatives as Inhibitors of Protein, WO2010096777 , 2010-08-26
[13]	Mughal U. R., Mehmood R., Malik A., Ali B., Tareen R. B., Helv. Chim. Acta, 2012, 95(1), 100—105
[14]	Kappe C. O., Eur. J. Med. Chem., 2000, 35(12), 1043—1052
[15]	Wang J., Ding L., Xiao D., Xue S. J., Chin. J. Org. Chem., 2012, 32(11), 2187—219
	(王晶, 丁丽, 肖笛, 薛思佳. 有机化学, 2012, 32(11), 2187—2192)
[16]	Kamal A., Malik M. S., BaJee S., Azeeza S., Faazil S., Ramakrishna S., Naidub V. G. M., Vishnuwardhanba M. V. P. S., Eur. J. Med. Chem., 2011, 46(8), 3274—3281
[17]	Borse B. N., Borude V. S., Shukla S. R., Curr. Chem. Lett., 2012, 1(2), 59—68
[18]	Dhankar R. P., Rahatgaonkar A. M., Chorghade M. S., Tiwarid A., Spectrochim. Acta Part A, 2012, 93, 348—353
[19]	Kumar V., Rana H., Sankolli R., Kaushik M. P., Tetrahedron Lett., 2011, 52(46), 6148—6151
[20]	Zink L., Neildé K., Crozet M. D., Vanelle P., Tetrahedron Lett., 2012, 53(40), 5393—5397
[21]	Guilani B., Rasco M. L., Hermann C. F. K., Gibson H. W., J. Heterocycl. Chem., 1990, 27(4), 1007—1009
[22]	Liu S. H., Ling Y., Li H. Y., Xu D., Yang X. L., Chem. J. Chinese Universities, 2014, 35(2), 281—285
	(刘少华, 凌云, 李宏月, 徐丹, 杨新玲. 高等学校化学学报, 2014, 35(2), 281—285)
[23]	Chen Y. W., Wang B. L., Guo Y. J., Zhou Y. Y., Pan L., Xiong L. X., Yu S. J., Li Z. M., Chem. Res. Chinese Universities, 2014, 30(1), 98—102
[24]	Gurung S. K., Kim S. B., Park H., Arch. Pharmacal Res., 2010, 33(12), 1919—1926
[25]	Zhang J., Chen J., Liu M., Zheng X., Ding J., Wu H., Green Chem., 2012, 14(4), 912—916
[26]	Sugimura R., Qiao K., Tomida D., Yokoyama C., Catal. Commun., 2007, 8(5), 770—772
[27]	Kim D. J., Kim S. H., Jin S. H., Park D. K., Cho H. N., Zyung T., Cho I., Choi S. K., Eur. Polym. J., 1999, 35(2), 227—223
[28]	Lu J., Ma H. R., Li W. H., Chin. J. Org. Chem., 2000, 20(5), 815—819(路军, 马怀让, 李万华. 有机化学, 2000, 20(5), 815—819)

Compd.	Appearance	Yield(%)	m.p./℃	HRMS(ESI) [M+Na]⁺(calcd.), m/z
3a	White solid	93—95	63—64(59.5—64^[21])
3b	Pale yellow viscous liquid	90—91		283.0131(283.0132)
3c	White solid	95—96	79—80	283.0130(283.0132)
3d	White solid	92—94	75—76	317.0383(317.0396)

Compd.	Appearance	Yield(%)	m.p./℃	HRMS(ESI) [M+Na]⁺(calcd.), m/z
3a	White solid	93—95	63—64(59.5—64^[21])
3b	Pale yellow viscous liquid	90—91		283.0131(283.0132)
3c	White solid	95—96	79—80	283.0130(283.0132)
3d	White solid	92—94	75—76	317.0383(317.0396)

Compd.	Appearance	Yield(%)	m.p./℃	HRMS(ESI)[M+Na]⁺ (calcd.), m/z	IR(KBr), /cm^-1
6a	Pale yellow solid	86	182—184	529.1690(529.1694)	3236, 3120, 2949, 1702, 1642, 1602, 1500, 1434,
					1232, 1090, 875, 758, 655
6b	White solid	85	185—187	563.1295(563.1304)	3248, 2950, 1702, 1645, 1604, 1488, 1434, 1384,
					1319, 1231, 1092, 757
6c	White solid	84	189—190	563.1296(563.1304)	3242, 3116, 2950, 1704, 1644, 1593, 1480, 1319,
					1232, 1092, 917, 761, 659
6d	Pale yellow solid	81	171—173	597.1591(597.1568)	3247, 2952, 1705, 1644, 1601, 1497, 1432, 1316,
					1235, 1162, 1093, 923, 763, 662
6e	Pale yellow solid	84	163—164	551.2010(557.2007)	3244, 3115, 2978, 1704, 1642, 1597, 1500, 1448,
					1231, 1089, 876, 758, 656
6f	White solid	87	179—181	591.1608(591.1617)	3245, 3117, 2977, 1704, 1644, 1602, 1487, 1453,
					1375, 1322, 1231, 1091, 763
6g	White solid	86	161—162	591.1603(591.1617)	3243, 3117, 2976, 1703, 1644, 1594, 1479, 1319,
					1231, 1092, 917, 761, 659
6h	Pale yellow solid	83	242—244	625.1904(625.1881)	3247, 3123, 2979, 1705, 1646, 1599, 1498, 1433,
					1316, 1235, 1164, 1093, 1046, 923, 763, 663
6i	Pale yellow solid	83	287—289	497.1811(497.1795)	3228, 3116, 2927, 1692, 1646, 1598, 1499, 1460,
					1230, 871, 790
6j	Pale yellow solid	83	197—199	531.1419(531.1406)	3235, 3231, 2928, 1693, 1642, 1603, 1488, 1432,
					1379, 1327, 1243, 1112, 815
6k	White solid	85	193—195	531.1410(531.1406)	3241, 3234, 2956, 1704, 1644, 1595, 1478, 1320,
					1235, 1109, 918, 766, 659
6l	White solid	80	186—188	565.1689(565.1669)	3238, 3131, 2929, 1704, 1648, 1600, 1497, 1385,
					1316, 1238, 1162, 1120, 1043, 924, 763, 714

Compd.	Appearance	Yield(%)	m.p./℃	HRMS(ESI)[M+Na]⁺ (calcd.), m/z	IR(KBr), /cm^-1
6a	Pale yellow solid	86	182—184	529.1690(529.1694)	3236, 3120, 2949, 1702, 1642, 1602, 1500, 1434,
					1232, 1090, 875, 758, 655
6b	White solid	85	185—187	563.1295(563.1304)	3248, 2950, 1702, 1645, 1604, 1488, 1434, 1384,
					1319, 1231, 1092, 757
6c	White solid	84	189—190	563.1296(563.1304)	3242, 3116, 2950, 1704, 1644, 1593, 1480, 1319,
					1232, 1092, 917, 761, 659
6d	Pale yellow solid	81	171—173	597.1591(597.1568)	3247, 2952, 1705, 1644, 1601, 1497, 1432, 1316,
					1235, 1162, 1093, 923, 763, 662
6e	Pale yellow solid	84	163—164	551.2010(557.2007)	3244, 3115, 2978, 1704, 1642, 1597, 1500, 1448,
					1231, 1089, 876, 758, 656
6f	White solid	87	179—181	591.1608(591.1617)	3245, 3117, 2977, 1704, 1644, 1602, 1487, 1453,
					1375, 1322, 1231, 1091, 763
6g	White solid	86	161—162	591.1603(591.1617)	3243, 3117, 2976, 1703, 1644, 1594, 1479, 1319,
					1231, 1092, 917, 761, 659
6h	Pale yellow solid	83	242—244	625.1904(625.1881)	3247, 3123, 2979, 1705, 1646, 1599, 1498, 1433,
					1316, 1235, 1164, 1093, 1046, 923, 763, 663
6i	Pale yellow solid	83	287—289	497.1811(497.1795)	3228, 3116, 2927, 1692, 1646, 1598, 1499, 1460,
					1230, 871, 790
6j	Pale yellow solid	83	197—199	531.1419(531.1406)	3235, 3231, 2928, 1693, 1642, 1603, 1488, 1432,
					1379, 1327, 1243, 1112, 815
6k	White solid	85	193—195	531.1410(531.1406)	3241, 3234, 2956, 1704, 1644, 1595, 1478, 1320,
					1235, 1109, 918, 766, 659
6l	White solid	80	186—188	565.1689(565.1669)	3238, 3131, 2929, 1704, 1648, 1600, 1497, 1385,
					1316, 1238, 1162, 1120, 1043, 924, 763, 714

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
6a	9.28(s, 2H, NH), 7.81(s, 2H, NH), 7.25(d, J=7.2 Hz, 4H, ArH), 6.96(d, J=7.2 Hz, 4H, ArH), 5.17(s, 2H), 3.54(s, 6H), 2.28(s, 6H)	165.85, 155.76, 152.24, 148.69, 139.82, 127.93, 118.52, 99.08, 53.29, 50.84, 17.90
6b	9.33(s, 1H, NH), 9.25(s, 1H, NH), 7.84(s, 1H, NH), 7.77(s, 1H, NH), 7.39(d, J=1.6 Hz, 1H, ArH), 7.23(d, J=8.4 Hz, 2H ArH), 7.20(dd, J=1.6, 8.4 Hz, 1H, ArH), 7.06(d, J=8.0 Hz, 1H, ArH), 6.90(d, J=8.0 Hz, 2H, ArH), 5.17(d, J=3.2 Hz, 1H), 5.13(d, J=3.2 Hz, 1H), 3.56(s, 3H), 3.54(s, 3H), 2.27(s, 3H), 2.25(s, 3H)	165.76, 165.68, 155.53, 152.08, 151.92, 150.46, 149.28, 148.69, 141.97, 139.84, 128.32, 127.93, 126.51, 124.32, 121.18, 117.28, 98.93, 98.32, 53.16, 52.91, 50.92, 50.81, 17.90, 17.83
6c	9.35(s, 1H, NH), 9.29(s, 1H, NH), 7.82(s, 1H, NH), 7.74(s, 1H, NH), 7.03(d, J=6.8 Hz, 2H, ArH), 6.99(s, 1H, ArH), 6.95(d, J=7.6 Hz, 1H, ArH), 6.90—7.20(m, 3H, ArH), 5.59(s, 1H), 5.18(s, 1H), 3.55(s, 3H), 3.48(s, 3H), 2.30(s, 3H), 2.27(s, 3H)	165.83, 165.50, 156.71, 154.76, 152.22, 151.57, 149.45, 148.75, 140.71, 136.39, 132.49, 130.00, 128.12, 119.28, 118.51, 117.46, 99.01, 97.79, 53.33, 50.96, 50.83, 50.78, 17.91, 17.80
6d	9.40(s, 1H, NH), 9.28(s, 1H, NH), 7.81(s, 1H, NH), 7.51(s, 1H, NH), 7.22—7.44(m, 5H, ArH), 7.06(d, J=6.0 Hz, 2H, ArH), 5.53(s, 1H), 5.18(s, 1H), 3.55(s, 3H), 3.44(s, 3H), 2.33(s, 3H), 2.27(s, 3H)	165.98, 165.41, 156.34, 154.70, 152.32, 151.36, 149.90, 148.97, 141.06, 137.96, 131.13, 128.35, 127.43(q, ²J_CCF=29 Hz), 125.53, 122.42, 115.05, 120.92(q, ¹J_CF=263 Hz), 99.11, 98.33, 53.45, 51.00, 50.80, 50.18, 18.06, 17.93
6e	9.28(s, 2H, NH), 7.80(s, 2H, NH), 7.28(d, J=8.4 Hz, 4H, ArH), 6.97(d, J=8.3 Hz, 4H, ArH), 5.20(s, 2H), 4.00(m, 4H), 2.29(s, 6H), 1.10(t, J=8.0 Hz, 6H)	165.36, 155.81, 152.26, 148.37, 140.06, 128.04, 118.47, 99.37, 59.28, 53.53, 17.86, 14.10
6f	9.29(s, 1H, NH), 9.21(s, 1H, NH), 7.81(s, 1H, NH), 7.74(s, 1H, NH), 7.39(s, 1H, ArH), 7.18—7.30(m, 3H, ArH), 7.07(d, J=8.4 Hz, 1H, ArH), 6.90(d, J=8.4 Hz, 2H, ArH), 5.17(d, J=3.2 Hz, 1H), 5.14(d, J =3.2 Hz, 1H), 4.01(m, 4H), 2.27(s, 3H), 2.25(s, 3H), 1.10(t, J=6.4 Hz, 3H), 1.09(t, J=6.8 Hz, 3H)	165.26, 165.14, 155.54, 152.02, 151.85, 150.40, 148.95, 148.36, 142.25, 140.03, 128.47, 128.00, 126.58, 124.23, 121.19, 117.16, 99.17, 98.55, 59.29, 59.19, 53.35, 53.14, 17.83, 17.77, 14.05, 13.92
6g	9.31(s, 1H, NH), 9.26(s, 1H, NH), 7.79(s, 1H, NH), 7.73(s, 1H, NH), 7.24—7.40(m, 3H, ArH), 6.90—7.08(m, 4H, ArH), 5.61(s, 1H), 5.19(s, 1H), 4.00(q, J=7.6 Hz, 2H), 3.94(q, J=6.8 Hz, 2H), 2.32(s, 3H), 2.25(s, 3H), 1.09(t, J=6.8 Hz, 3H), 1.02(t, J=6.8 Hz, 3H)	165.32, 164.98, 156.72, 154.79, 152.13, 151.47, 149.25, 148.46, 140.94, 136.61, 132.51, 130.13, 128.23, 119.19, 118.35, 117.51, 99.22, 97.94, 59.25, 59.16, 53.54, 51.07, 17.83, 17.71, 14.09, 13.96
6h	9.36(s, 1H, NH), 9.23(s, 1H, NH), 7.77(s, 1H, NH), 7.70(s, 1H, NH), 7.49(d, J=8.4 Hz, 1H, ArH), 7.30(m, 4H, ArH), 7.19(s, 1H, ArH), 7.04(d, J=8.4 Hz, 1H, ArH), 5.53(s, 1H), 5.16(s, 1H), 3.99(q, J=7.2 Hz, 2H), 3.88(q, J=6.8 Hz, 2H), 2.31(s, 3H), 2.28(s, 3H), 1.09(t, J=6.8 Hz, 3H), 0.92(t, J=6.8 Hz, 3H)	165.46, 164.92, 156.41, 154.74, 152.27, 151.36, 149.86, 148.67, 141.29, 137.83, 131.08, 128.48, 127.56(q, ²J_CCF=31 Hz), 125.18, 122.67, 121.09(q, ¹J_CF=273 Hz), 114.95, 99.32, 98.31, 59.38, 59.31, 53.72, 50.23, 17.98, 17.91, 14.20, 13.95
6i	9.21(s, 2H, NH), 7.84(s, 2H, NH), 7.25(d, J=7.2 Hz, 4H, ArH), 6.96(d, J=7.2 Hz, 4H, ArH), 5.25(s, 2H), 2.29(s, 6H), 2.11(s, 6H)	194.21, 155.71, 152.03, 148.11, 139.32, 128.11, 118.50, 109.52, 53.18, 30.31, 18.90
6j	9.28(s,1H, NH), 9.21(s, 1H, NH), 7.90(s, 1H, NH), 7.84(s, 1H, NH), 7.41(s, 1H, ArH), 7.24(d, J=8.4 Hz, 2H, ArH), 7.19(dd, J=1.6, 8.4 Hz, 1H, ArH), 7.05(d, J=8.4 Hz, 1H, ArH), 6.90(d, J=8.4 Hz, 2H), 5.27(d, J=3.2 Hz, 1H), 5.24(d, J=3.2 Hz, 1H), 2.34(s, 3H), 2.29(s, 3H), 2.12(s, 3H), 2.07(s, 3H)	194.17, 194.10, 155.57, 152.00, 151.96, 150.43, 148.72, 148.12, 141.61, 139.36, 128.54, 128.16, 126.62, 124.36, 121.18, 117.29, 109.51, 109.26, 53.13, 52.70, 30.48, 30.31, 18.99, 18.88
6k	9.28(s, 1H, NH), 9.22(s, 1H, NH), 7.85(s, 1H, NH), 7.74(s, 1H, NH), 7.28(d, J=8.4 Hz, 2H, ArH), 7.24(d, J=8.4 Hz, 1H, ArH), 7.04(s, 1H, ArH), 7.02(d, J=2.8 Hz, 2H, ArH), 6.93(dd, J=1.6, 8.4 Hz, 1H, ArH), 5.61(d, J=3.2 Hz, 1H), 5.26(d, J=3.2Hz, 1H), 2.34(s, 3H), 2.29(s, 3H), 2.12(s, 3H), 2.07(s, 3H)	194.15, 193.86, 156.78, 154.64, 151.98, 151.43, 148.72, 148.15, 140.23, 135.58, 132.51, 129.75, 128.25, 119.27, 118.52, 117.38, 109.51, 108.34, 53.13, 50.92, 30.31, 30.07, 18.88, 18.80
6l	9.34(s, 1H, NH), 9.22(s, 1H, NH), 7.87(s, 1H, NH), 7.73(s, 1H, NH), 7.42(d, J=8 Hz, 1H, ArH), 7.20—7.32(m, 4H, ArH), 7.06(d, J=8.8 Hz, 2H, ArH), 5.57(d, J=2.8 Hz, 1H), 5.27(d, J=3.2 Hz, 1H), 2.34(s, 3H), 2.29(s, 3H), 2.12(s, 3H), 2.07(s, 3H)	194.30, 193.88, 156.36, 154.55, 152.16, 151.36, 148.86, 148.35, 140.51, 136.88, 130.82, 128.46, 127.62(q, ²J_CCF=31 Hz), 125.09, 120.83(q, ¹J_CF=277 Hz), 120.56, 115.28, 109.09, 108.72, 53.38, 50.38, 30.56, 30.42, 19.05, 19.01