ZHU Xi-FengGUO Yn-Chun②YU Zhi-RnLIAO Xin-ChengZHAO Yu-Fen,(The College of Chemistry nd Moleculr Engineering, The Key Lortory of Chemicl Biology nd Orgnic Chemistry of Henn Province, Zhengzhou University, Zhengzhou 450052, Chin)(Deprtment of Chemistry, College of Chemistry nd Chemicl Engineering, The Key Lortory for Chemicl Biology of Fujin Province, Ximen University, Ximen 361005, Chin)

Syntheses and Crystal Structures of Two New α-Aminophosphonate Derivatives Containing Thieno[2,3-d]pyrimidine①

ZHU Xi-FengaGUO Yan-Chuna②YU Zhi-RanaLIAO Xin-ChengaZHAO Yu-Fena,ba(The College of Chemistry and Molecular Engineering, The Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou 450052, China)b(Department of Chemistry, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen 361005, China)

Two new α-aminophosphonate derivatives containing thieno[2,3-d]pyrimidine, diethyl(((6-ethyl-2-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl)amino)(4-methoxyphenyl)methyl) phosphonate (1) and diethyl((4-bromophenyl)((6-ethyl-2-methyl-4-oxothieno[2,3-d]pyrimidin-3 (4H)-yl)amino)methyl)phosphonate (2), have been synthesized by a facial phosphorylated reaction, and their structures were characterized by NMR, IR, HRMS and X-ray single-crystal diffraction.Compound 1 (C21H28N3O5PS, Mr= 465.49) belongs to the orthorhombic system, space group P212121, with a = 10.83653(16), b = 12.04906(19), c = 18.0061(3) ?, V = 2351.06(6) ?3, Z = 4, Dc= 1.315 g/cm3, μ = 2.177 mm-1, F(000) = 984.0, the final R = 0.0389 and wR = 0.0985 for all data.Compound 2 (C20H25BrN3O4PS, Mr= 514.37) belongs to the orthorhombic system, space group P212121, with a = 10.9187(5), b = 11.9522(4), c = 17.7667(7) ?, V = 2318.60(16) ?3, Z = 4, Dc= 1.474 g/cm3, μ = 4.175 mm-1, F(000) = 1056.0, the final R = 0.0367 and wR = 0.0946 for all data.

thieno[2,3-d]pyrimidine, α-aminophosphonate derivatives, synthesis, crystal structure;

1 INTRODUCTION

The derivatives of thieno[2,3-d]pyrimidine have attracted much interest, which exhibit considerable biological and medical activities including antitumor[1-3], antiviral[4], antimicrobial[5], anti-inflammatory, analgesic[6], antimalarial[7], anti proliferation[8], etc.Meanwhile, as phosphorus analogs of α-amino acids and their esters, α-aminophosphonate derivatives’ significant pharmacyological effects have been found constantly: antitumor[9,10], antibiotics[11], insecticide[12]and antiviral[13].Many efforts have been devoted to the synthesis and rational construction of thieno[2,3-d] pyrimidine in the side chain[14-17].However, little is known about the introduction of aminophosphonate in their structures.Based on the principle of bioactive superposition, in order to obtain an efficient analogue to improve the biological activities of both compounds, the thieno[2,3-d]pyrimidine ring was introduced into the α-aminophosphonate compounds.Two new α-amino phosphonate derivatives containing thieno[2,3-d] pyrimidine were synthesized with a high yield, and their structures were determined by NMR, IR,HRMS and X-ray single-crystal diffraction.

2 EXPERIMENTAL

2.1 General information

All commercial reagents and solvents were used as received without further purification.IR spectra were determined on a Shimadazu IR-408 Fourier spectrometer (KBr pellet).Melting points were measured on an XT-4 micromelting apparatus and uncorrected.High resolution mass spectra (HRMS) were obtained with a Q-Tof mass spectrometer using the ESI technique.NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.1H and13C chemical shifts were quoted in CDCl3with tetramethylsilane (TMS) as the internal standard, and31P chemical shifts were acquired in CDCl3with H3PO4as the internal standard.Column chromatography was performed on silica gel 200～300 mesh.

2.2 Synthesis

The syntheses of compounds 1 and 2 are shown in Scheme 1.

2.2.1 Synthesis of 3-amino-6-ethyl-2-methylthieno[2,3-d]pyrimidin-4(3H)-one

Hydrazine hydrate (0.25 mol) was added to a solution of 2-acetylamino-3-ethoxycarbonyl-5-ethyl thiophene (0.05 mol) dissolved in 30 mL ethanol.The mixture was heated to reflux for 5 h as monitored by silica gel thin layer chromatography (TLC), followed by cooling to room temperature.The crude product was filtered and purified by recrystallization from ethanol to afford a white solid with a yield of 85%, m.p.: 155～157 ℃.

Scheme 1.Syntheses of the title compounds 1 and 2

2.2.2 Syntheses of 6-ethyl-3-((4-methoxybenzylidene)amino)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (m-1) and 3-((4-bromobenzylidene)amino)-6-ethyl-2-methyl thieno[2,3-d]pyrimidin-4(3H)-one (m-2)

A solution of 3-amino-6-ethyl-2-methyl-thieno-[2,3-d]pyrimidin-4(3H)-one (0.03 mol) and 4- methoxybenzaldehyde or 4-bromobenzaldehyde (0.036 mol) in acetic anhydride (40 mL) was heated to reflux for 2 h.Then the mixture was concentrated in vacuum and the residue was further purified by recrystallization from ethanol to obtain m-1 (a white solid, yield 75%, m.p.: 145～146 ) ℃or m-2 (a white solid, yield 90%, m.p.: 142～143 ℃), respectively.

2.2.3 Syntheses of 1 and 2

The mixture of compound m-1 or m-2 (7 mmol) and diethyl phosphonate (20 mL) was heated to 120℃under a nitrogen atmosphere.The progress of the reaction was monitored by TLC.After the reaction was finished, the K2CO3solution (0.1 mol/L) was added dropwise to the solution until pH = 8.0, then the solution was filtered and evaporated to dryness.The product was recrystallized with a mixed solution of dichloromethane and petroleum ether (v/v = 1:3) to give the target compound 1 or 2.Single crystal was obtained by slow crystallization from a mixed solution of dichloromethane and petroleum ether at room temperature.

The title compound 1 was obtained as colourless crystals in 74% yield after recrystallization, m.p.: 145～146 ℃.IR (KBr) ν/cm-1: 3222(NH, s), 2973(CH3, s), 2934(CH2), 1690(C=O, s), 1610, 1562, 1508, 1441, 1251(P=O), 1044(P-O-C);1H NMR (CDCl3) δ: 7.46 (s, 2H, ArH), 7.01 (s, 1H, C4HS), 6.83～6.81 (m, 2H, ArH), 5.74 (s, 1H, NH), 4.85 (dd, JPCH= 13.0, 2.5 Hz, 1H, PCH), 4.01～3.75NMR (CDCl3) δ: 161.92, 160.14, 157.77, 157.21, 144.85, 131.50, 124.10, 122.60, 117.00, 113.93, 63.39, 62.19, 60.42, 58.85, 55.18, 23.89, 22.32, 16.11, 15.12;31P NMR (CDCl3) δ: 21.28.HRMS (ESI): m/z [M+H]+, calculated for C21H29N3O5PS: 466.1566, Found: 466.1563.

The title compound 2 was obtained as colorless crystals in 86% yield after recrystallization, m.p.: 99～101 ℃.IR (KBr) ν/cm-1: 3220(NH, s), 2975 (CH3, s), 2932(CH2), 1691(C=O, s), 1562, 1483, 1433, 1247(P=O), 1045(P-O-C);1H NMR (CDCl3) δ: 7.42 (s, 4H, ArH), 6.97 (s, 1H, C4HS), 5.82 (s, 1H, NH), 4.88～4.84 (dd, JPCH= 13.6, 2.5 Hz, 1H, PCH),NMR (CDCl3) δ: 161.90, 157.72, 156.99, 145.09, 131.74, 123.37, 122.55, 116.93, 63.51, 62.45, 60.49, 58.94, 23.91, 22.33, 16.14, 15.14.31P NMR (CDCl3) δ: 20.23.HRMS(ESI): m/z [M+Na]+, calculated for C20H25BrN3O4PSNa: 536.0384, Found: 536.0380.2.3 Crystal data and structure determination

The colorless single crystals of compounds 1 (0.30mm × 0.25mm × 0.22mm) and 2 (0.35mm × 0.30mm × 0.30mm) were selected for X-ray diffraction analysis.The data were collected on an Agilent Xcalibur Eos-II-CCD diffractometer equipped with a graphite-monochromatic Cu-Kα radiation (λ = 1.5418 ?) using an ω scan mode in the ranges of 4.42<θ<67.07° for 1 and 4.46<θ< 72.28° for 2 at 291.15 K.The unit cell dimensions were obtained with the least-squares refinements.All the structures were solved by direct methods with SHELXS program[18]and refined by full-matrix least-squares method on F2with anisotropic thermal parameters for all non-hydrogen atoms using SHELXL[19].Hydrogen atoms were generated geometrically.For compound 1, a total of 8872 reflections were recorded and 4183 were unique (Rint= 0.0232), among which 3930 (–12≤h≤8, –14≤k≤13, –19≤l≤21) were observed.The final cycle of refinement converged to R = 0.0389, wR = 0.0985= 0.226 and (?ρ)min= –0.216 e/?3.For compound 2, a total of 8957 reflections were recorded and 4476 were unique (Rint= 0.0225), among which 4245 (–13≤h≤13, –9≤k≤14, –19≤l≤21) were observed.The final refinement gave R = 0.0376, wR0.000, (?ρ)max= 0.252 and (?ρ)min= –0.373 e/?3.Molecular illustrations were prepared using the XP package.

3 RESULTS AND DISCUSSION

The selected bond lengths and bond angles of the title compounds are shown in Tables 1～4, respectively.The hydrogen bond data are listed in Tables 5 and 6, respectively.The molecular structures and crystal packing of compounds 1 and 2 are depicted in Figs.1, 2, 3 and 4, respectively.

Table 1.Selected Bond Lengths (?) and Bond Angles (°) for Compound 1

To be continued

Table 2.Selected Torsion Angles (°) for Compound 1

Table 3.Selected Bond Lengths (?) and Bond Angles (°) for Compound 2

Table 4.Selected Torsion Angles (°) for Compound 2

Table 5.Hydrogen Bonding Geometry for Compound 1

Table 6.Hydrogen Bonding Geometry for Compound 2

Fig.1.Molecular structure of compound 1

Fig.2.Molecular arrangement andhydrogen bond in compound 1

Fig.4.Molecular arrangement and hydrogen bond in compound 2

Fig.3.Molecular structure of compound 2

Compound 1 crystallizes in space group P212121with Z = 4, and the molecular structure is shown in Fig.1.For compound 1, the bond length of P=O is 1.460(2) ?, which is close to those found in other related structures[20], and shorter than those of P(1)–O(1) (1.5756(19) ?) and P(1)–O(2) (1.5764(19) ?).The C(1)–O(1)–P(1), C(3)–O(2)–P(1) and N(1)–C(5)–P(1) bond angles are 121.87(19), 120.0(2) and 113.16(15)°, respectively.The torsion angles of S(1)–C(14)–C(15)–C(16), C(12)–N(3)–C(14)–C(15) and S(1)– C(14)–C(15)–C(13) are 0.5(3), 4.4(4) and –178.93(17)°, respectively, which indicate rings S(1)–C(14)–C(15)–C(16)–C(17) and N(3)–C(12)– N(2)–C(13)–C(15)–C(14) are not coplanar.The molecules are linked together by a noticeable intermolecular hydrogen bond, and the nitrogen of pyridine forms an intermolecular hydrogen bond with parahelium of the neighboring molecule: N(1)–H(1)××N(3) (Fig.2).The distances between the donors and acceptors are 3.133(3) ? (N(1)–H(1)××N(3), symmetry code: x?1/2, 1/2?y, 1?z).The parameters of primary hydrogen bonds are listed in Table 5.

For compound 2, the spatial structure is similar to compound 1.Compound 2 crystallizes in space group P212121with Z = 4, too.The molecular structure is shown in Fig.3 and one part of the crystal structure containing H-bonds is shown in Fig.4.The bond length of P=O is 1.463(2) ?, very close to the normal value.The distances of P(1)–O(1) and P(1)–O(2) are 1.579(2) and 1.575(2) ?, respectively, a little longer than the typical P–O bond (NaHPO3NH2, 1.51 ?[21]).The C(1)–O(1)–P(1), C(3)–O(2)–P(1) and N(1)–C(5)– P(1) bond angles are 122.0(2), 119.0(3) and 113.62(17)°, respectively.The torsion angles of C(13)–C(17)–C(18)–S(1), N(2)–C(12)–C(13)–C(14) and C(17)–C(13)–C(14)–N(3) are –1.5(3), –4.2(3), 177.8(3)°, respectively.Consequently, rings S(1)–C(14)–C(13)–C(17)–C(18) and N(3)–C(15)– N(2)–C(12)–C(13)–C(14) are still not absolutely coplanar.The crystal packing of the compound is stabilized by a classical intermolecular N(1)?H(1)××N(3) (x?1/2, 1/2?y, 1?z) hydrogen bond with the distance between the donor and acceptor to 3.122(3) ? (Table 6).

REFERENCES

(1) Folkes, A.J.; Ahmadi, K.; Alderton, W.K.; Alix, S.; Baker, S.J.; Box, G.; Chuckowree, I.S.; Clarke, P.A.; Depledge, P.; Eccles, S.A.The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer.J.Med.Chem.2008, 51, 5522–5532.

(2) Jennings, L.D.; Kincaid, S.L.; Wang, Y.D.; Krishnamurthy, G.; Beyer, C.F.; McGinnis, J.P.; Miranda, M.; Discafani, C.M.; Rabindran, S.K.Parallel synthesis and biological evaluation of 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one cytotoxic agents selective for p21-deficient cells.Bioorg.Med.Chem.Lett.2005, 15, 4731–4735.

(3) Horiuchi, T.; Chiba, J.; Uoto, K.; Soga, T.Discovery of novel thieno[2,3-d]pyrimidin-4-ylhydrazone-based inhibitors of Cyclin D1-CDK4: synthesis, biological evaluation, and structure-activity relationships.Bioorg.Med.Chem.Lett.2009, 19, 305–308.

(4) Rashad, A.E.; Shamroukh, A.H.; Abdel-Megeid, R.E.; Mostafa, A.; el-Shesheny, R.; Kandeil, A.; Ali, M.A.; Banert, K.Synthesis and screening of some novel fused thiophene and thienopyrimidine derivatives for anti-avian inf l uenza virus (H5N1) activity.Eur.J.Med.Chem.2010, 45, 5251–5257.

(5) Gaber, H.M.; Bagley, M.C.; Sherif, S.M.Antimicrobial investigations on synthetic p-tolylazo derivatives of thienopyrimidinone based on an ortho-functionalized thiophene nucleus.Eur.J.Med.Chem.2010, 1, 115–123.

(6) Alagarsamy, V.; Meena, S.; Ramseshu, K.V.; Solomon, V.R.; Thirumurugan, K.; Dhanabal, K.; Murugan, M.Synthesis, analgesic, antiinflammatory, ulcerogenic index and antibacterial activities of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin 4(3H)-ones.Eur.J.Med.Chem.2006, 41, 1293–1300.

(7) Edlin, C.D.; Morgans, G.; Winks, S.; Duffy, S.; Avery, V.M.; Wittlin, S.; Waterson, D.; Burrows, J.; Bryans, J.Identification and in-vitro ADME assessment of a series of novel anti-malarial agents suitable for hit-to-lead chemistry.ACS Med.Chem.Lett.2012, 3, 570–573.

(8) Donkor, I.O.; Li, H.; Queener, S.F.Synthesis and DHFR inhibitory activity of a series of 6-substituted-2,4-diaminothieno[2,3-d]pyrimidines.Eur.J.Med.Chem.2003, 38, 605–611.

(9) Kafarski, P.; Lejczak, B.Aminophosphonic acids of potential medical importance.Curr.Med.Chem.Anti-cancer Agents 2001, 1, 301–312.

(10) Jin, L.H.; Song, B.A.; Zhang, G.P.; Xu, R.Q.; Zhang, S.M.; Gao, X.W.; Hu, D.Y.; Yang, S.Synthesis, X-ray crystallographic analysis, and antitumor activity of N-(benzothiazole-2-yl)-1-(fluorophenyl)-O,O-dialkyl-α-aminophos-phonates.Bioorg.Med.Chem.Lett.2006, 16, 1537–1543.

(11) Arigala, U.R.S.; Matcha, C.; Yoon, K.R.Zn(OAc)2·2H2O-catalyzed synthesis of α-aminophosphonates under neat reaction.Hetero.Chem.2012, 23, 160–165.

(12) Reddy, M.V.N.; Balakrishna, A.; Kumar, M.A.; Reddy, G.C.S.; Sankar, A.U.R.; Reddy, C.S.; Krishna, T.M.One-step synthesis and bioassay of N-phosphoramidophosphonates.Chem.Pharm.Bull.2009, 57, 1391–1395.

(13) Yang, J.Q.; Song, B.A.; Bhadury, P.S.; Chen, Z.; Yang, S.; Cai, X.J.; Hu, D.Y.; Xue, W.Synthesis and antiviral bioactivities of 2-cyano-3-substituted-amino (phenyl) methylphosphonylacrylates (acrylamides) containing alkoxyethyl moieties.J.Agric.Food Chem.2010, 58, 2730–2735.

(14) Wang, Y.D.; Johnson, S.; Powell, D.; McGinnis, J.P.; Miranda, M.; Rabindran, S.K.Inhibition of tumor cell proliferation by thieno [2,3-d]pyrimidin-4(1H)-one-based analogs.Bioorg.Med.Chem.Lett.2005, 15, 3763–3766.

(15) Prasad, M.R.; Prashanth, J.; Shilpa, K.; Kishore, D.P.Synthesis and antibacterial activity of some novel triazolothienopyrimidines.Chem.Pharm.Bull.2007, 55, 557–560.

(16) Fayed, A.A.; Hosni, H.M.; Flefel, E.M.; Amr, Abd El-Galil E.Synthesis and pharmacological activity of some new thieno[2,3-d]pyrimidine and pyrimidopyrazolotheienopyrimidine derivatives.World J.Chemistry 2009, 4, 58–65.

(17) Kikuchi, H.; Yamamoto, K.; Horoiwa, S.; Hirai, S.; Kasahara, R.; Hariguchi, N.; Matsumoto, M.; Oshima, Y.Exploration of a new type of antimalarial compounds based on febrifugine.J.Med.Chem.2006, 49, 4698–4706.

(18) Sheldrick, G.M.SHELXS, Acta Cryst.2008, A64, 112–122.

(19) Sheldrick, G.M.SHELXL, Acta Cryst.2008, A64, 112–122.

(20) Yuan, J.W.; Chen, X.L.; Qu, L.B.; Zhu, Y.; Huang, X.Y.; Zhao, Y.F.Synthesis and crystal structure of 5,7-dimethoxy-2-phenylquinolin-4-yl phenyloxy (N-L-alanine ethyl ester) phosphoramidata.Chin.J.Struct.Chem.2009, 28, 498–502.

(21) Hobbs, E.; Corbridge, D.E.C.; Raistrick, B.The crystal structure of monosodium phosphoramidata, NaHPO3NH2.Acta Cryst.1953, 6, 621–626.

12 January 2015; accepted 25 March 2015 (CCDC 1033371 for 1 and 1033370 for 2)

① This work was supported by the National Natural Science Foundation of China (Nos.21105091 and 21171149)

② Corresponding author.Tel: 0371-67767051, E-mail: ycguo@zzu.edu.cn

10.14102/j.cnki.0254-5861.2011-0630