HETEROCYCLES

Paper | Special issue | Vol. 86, No. 1, 2012, pp. 411-424
Received, 16th June, 2012, Accepted, 27th July, 2012, Published online, 8th August, 2012.
DOI: 10.3987/COM-12-S(N)40

■ Highly Stereoselective Synthesis of anti-Tetrahydropyrimidine Derivatives under Microwave Heating

Qian Wang, An-Xiao Dai, Mian-Shuai Yi, Bo Jiang, Shu-Jiang Tu,* and Guigen Li*

Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

New [3+3] heterocyclization has been established for the synthesis of anti-tetrahydropyrimidine derivatives. The reaction was conducted by reacting readily available and inexpensive starting materials, such as 4-arylidene-2-phenyloxazol-5(4H)-ones, and aryl amidines, under solvent-free condition and microwave irradiation. During the reaction processes, the selective construction of anti-tetrahydropyrimidine skeleton and two amide functions were readily achieved via TEA-catalyzed ring-opening of oxazoles in a one-pot operation; in the meanwhile, lactone was converted into corresponding lactam in an intermolecular manner.

INTRODUCTION
The pyrimidines and their derivatives have been utilized as important heterocyclic building blocks in a wide array of synthetic and industrial applications. They are integral parts of genetic materials of DNA and RNA as nucleotides and nucleosides, but also play critical roles in biomedical and pharmaceutical research.1 Hydropyrimidines belong to pyrimidine family exhibiting a broad range of biological activities, such as anti-viral, anti-tumor, anti-bacterial and anti-inflammatory activities.2 In addition, they are also served as mitotic kinesin Eg5 motor protein inhibitors,3 α-adrenergic antagonists,4 calcium channel blockers,5 as well as potent HIV gp-120-CD4 inhibitors.6 Furthermore, 2-aryl substituted hydropyrimidine scaffold was reported to display a range of interesting pharmacological properties such as anti-hepatitis B replication activity7 and Rho-associated kinase isoform 1 (ROCK1) inhibitor.8 Accordingly, many powerful methodologies for the synthesis of these heterocycles have been developed, and the majority of these methods involve Biginelli reaction of β-keto esters (Figure 1, Type A),9 perhydropyrimidines formation from 1,3-oxazol-5-ones (Figure 1, Type B)10 and palladium-catalyzed cross-coupling (Figure 1, Type C).11 To the best of our knowledge, an efficient construction of anti-tetrahydropyrimidine skeleton of type D substituted at multiple sites with very high stereoselectivities has not been documented so far.

Amidines and related compounds possessing 1,3-binucleophilic centers are versatile synthetic intermediates in organic chemistry.12 They are frequently applied in the preparation of pyrimidine derivatives.12,13 Many pyrimidines have been synthesized by the reactions of amidines, aldehydes, and appropriate ketones via various methods.13 Very recently, our group has developed several reactions that can offer easy access to useful functionalized multiple ring structures of chemical and pharmaceutical interest.14 As part of our continuing interest in the development of new reaction in heterocyclic compounds,14,15 In this paper, we would like to report a new route to a set of anti-tetrahydropyrimidine derivatives with two aryl and one amide groups residing in 2-, 4- and 5-positions, respectively (Figure 1, Type D). This reaction was achieved by using readily available 4-arylidene-2-phenyloxazol-5(4H)-ones 1 and aryl amidines 2 under solvent-free condition and microwave heating shown in Scheme 1.

RESULTS AND DISCUSSION
We have planned to link two biologically important nuclei, tetrahydropyrimidine and amides, to generate a new series of compounds, pyrimidine analogues, using [3+3] heterocyclization of 4-arylidene- 2-phenyloxazol-5(4H)-ones 1 and aryl amidines 2. It should be known that the amido function is synthetically and pharmacologically readily manipulable and important. Tetrahydropyrimidine scaffolds incorporating the amide (–NH-C=O) function is seldom reported and is not accessible through any one of known synthetic routes although they appear as attractive scaffolds to be utilized for exploiting chemical diversity and generating a drug-like library to screen for lead candidates. In addition, 4-arylidene-2-phenyloxazol-5(4H)-ones are versatile and readily obtainable reagents, and their chemistry has received considerable attention in recent years.16
We started this research by subjecting a preformed 4-arylidene-2-phenyloxazol-5(4H)-ones 1a to the reaction with benzimidamide 2a in various solvents at 80 °C under microwave irradiation using triethylamine (TEA) as a base catalyst. The results of extensive solvent screening and optimization are shown in Table 1. Triethylamine (TEA)-catalyzed two-component reaction in organic solvents such as ethanol, CH2Cl2, and glycol gave the desired anti-tetrahydropyrimidine 3a as a single isomer in low yields without observation of syn-tetrahydropyrimidine 3a’ (Table 1, entries 1-4). In another case, when DMF was used as the solvent, the reaction proceeded more efficiently, and anti-product 3a was obtained in 60% chemical yield. To our satisfaction, 73% yield of anti-tetrahydropyrimidine 3a was achieved under solvent-free condition. Subsequently, the reaction catalyzed by TEA was performed and repeated many times at different temperatures in sealed vessels under solvent-free condition and microwave irradiation for 20 min. The highest yield of anti-tetrahydropyrimidine 3a (80%) as a single isomer was obtained when the reaction temperature was increased to 100 °C.
The structural elucidation and the attribution of stereoselectivity were unequivocally determined by NMR spectroscopic analysis. The anti and syn isomers were identified by coupling constants (J) of vicinal protons adjacent to aryl and NH in their 1H-NMR spectra. The coupling constants J of anti isomer is higher than that of corresponding syn one (Scheme 2).17 1H-NMR spectrum of 3a showed a doublet at δ 5.05 due to CH and coupling constant J = 13.6 Hz (Figure 2); it indicated that compounds 3 were in anti-configuration because of steric hindrance between the aryl substituent and vicinal amido group.

With this result in hand, we studied the scope of this new methodology. Using the optimized reaction conditions, a variety of structurally diverse 4-arylidene-2-phenyloxazol-5(4H)-ones were investigated, and a series of new multi-functionalized anti-tetrahydropyrimidine 3 were afforded in good yields. As shown in Table 2 that we sought for the oxazol-5(4H)-one substrate scope, benzimidamide 2a was then used as model substrates (Table 2). The results indicated that oxazol-5(4H)-one bearing different substituents including electron-withdrawing (such as chloro, bromo or fluoro) and electron-donating groups (such as methyl, or methoxy) on the aromatic rings were suitable for the synthesis of compound 3. Subsequently, the aryl amidine scope of this transformation was next investigated (Table 2). Several different aryl amidines were compared and substituents with 4-bromophenyl 2b, 4-chlorophenyl 2c, pyridin-3-yl 2d, or pyridin-4-yl 2e groups were found to be suitable for this reaction. The results exhibit the scope and generality of the new reaction with respect to a range of oxazol-5(4H)-one and aryl amidine substrates. Furthermore, functional groups like bromide and chloride were well tolerated. These functional groups provide ample opportunity for further functional group manipulations, for example, by modern cross-coupling reactions.
Similar to our previous process,14,15 the present reaction also showed the following attractive characteristics: (1) fast reaction rates which enable the reaction to be completed within 17-28 min; (2) high atom utilization; (3) the convenient work-up which only needs simple filtration since products directly precipitate out when the reaction system is neutralized with diluted hydrochloric acid and then poured into cold water; (4) readily available starting materials of aryl amidines and preformed oxazol-5(4H)-ones. Moreover, during these processes, the selective construction of anti-tetrahydropyrimidine skeleton and two amide functions were readily achieved accompanied by ring-opening of oxazoles via TEA-catalyzed reaction in a one-pot operation, and lactone was converted into corresponding lactam in a one-pot and intermolecular manner.
On the basis of the above results, possible mechanism has been proposed for the formation of anti-tetrahydropyrimidine derivatives 3 as shown in scheme 3. Firstly, Michael addition between 4-arylidene-2-phenyloxazol-5(4H)-ones 1 and benzamidine 2 furnishes the intermediate I, which subsequently isomerizes to form intermediate II. Next, the intermediate II undergoes intramolecular nucleophilic addition (II to III) and elimination (III to 3) to afford the final product 3.

In conclusion, we have developed TEA-catalyzed domino heterocyclization for stereoselective synthesis of anti-tetrahydropyrimidine with concomitant formation of two amide functions in one-pot manner. The reaction proceeds by [3+3] heterocyclization obtaining anti-tetrahydropyrimidines in good yields, showing that the synthetic route allows us to assemble building blocks of tetrahydropyrimidine derivatives with a wide diversity in substituents. The ready accessibility of inexpensive starting materials, the broad compatibility of oxazol-5(4H)-one and aryl-amidine substrates, and the generality of this process make the reaction highly valuable in view of synthetic and medical importance of heterocycles of this type. Features of this strategy include mild condition, convenient one-pot operation, short reaction periods of 17-28 min, and excellent stereoselectivities.

EXPERIMENTAL
Microwave irradiation was carried out with Initiator 2.5 Microwave Synthesizers from Biotage, Uppsala, Sweden. Melting points were determined in open capillaries and were uncorrected. IR spectra were taken on a FT-IR-Tensor 27 spectrometer in KBr pellets and reported in cm-1. 1H NMR spectra were measured on a Bruker DPX 400 MHz spectrometer in DMSO-d6 with chemical shift (δ) given in ppm relative to TMS as internal standard [(s = singlet, d = doublet, t = triplet, brs = broad singlet, m = multiplet), coupling constant (Hz)]. HRMS (ESI) was determined by using microTOF-QⅡHRMS/MS instrument (BRUKER).
Synthesis of Products 3 under Microwave Irradiation
In a 10 mL reaction vial, 4-(4-chlorophenyl)-2-phenyloxazol-5(4H)-one (1a, 1 mmol), benzamidine (2a, 1.1 mmol) and triethylamine (1.0 mzL) were mixed and stirred at room temperature for 3 min. Then the mixture was heated for a given min at 100 °C under microwave irradiation. Upon completion, monitored by TLC, the reaction mixture was cooled to room temperature. The resulting suspension was neutralized with diluted hydrochloric acid solution and then poured into cold water (50 mL). The crude solid product was collected by Büchner filtration and washed with H2O and acetone. The solid was purified by recrystallization form acetone to give the pure product 3a.
N-(4-(4-Chlorophenyl)-1,4,5,6-tetrahydro-6-oxo-2-phenylpyrimidin-5-yl)benzamide (3a)
White solid, mp 251-253 °C; IR (KBr): 3280, 1720, 1539, 1490, 1290, 1001, 820 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.14 (s, 1H, NH), 8.72 (d, J = 8.8 Hz, 1H, NH), 7.93 (d, J = 7.2 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.53 (m, 2H, ArH), 7.59-7.45 (m, 6H, ArH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 5.05 (d, J = 13.6 Hz, 1H, CH), 4.68 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 169.8, 166.1, 151.7, 140.7, 133.0, 131.6, 131.4, 131.0, 129.7, 128.2, 127.8, 127.3, 127.1, 60.8, 52.5; HRMS (ESI) m/z: calc. For C23H18ClN3NaO2: 426.0985 [M+Na]+, found: 426.0985.
N-(4-(4-Bromophenyl)-1,4,5,6-tetrahydro-6-oxo-2-phenylpyrimidin-5-yl)benzamide (3b)
White solid, mp 259-261 °C; IR (KBr): 3280, 2913, 1720, 1538, 1365, 1011, 816 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.15 (s, 1H, NH), 8.71 (d, J = 8.8 Hz, 1H, NH), 7.93 (d, J = 7.6 Hz, 2H, ArH), 7.76 (d, J = 1.2 Hz, 1H, ArH), 7.74 (t, J = 2.0 Hz, 1H, ArH), 7.56-7.52 (m, 3H, ArH), 7.51-7.45 (m, 5H, ArH), 7.40 (d, J = 8.4 Hz, 2H, ArH), 5.03 (d, J = 14.0 Hz, 1H, CH), 4.67(dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 133.8, 133.0, 131.4, 131.0, 130.7, 130.1, 128.3, 128.2, 127.3, 127.1, 120.2, 52.4; HRMS (ESI) m/z: calc. For C23H18BrN3NaO2: 472.0457 [M+Na]+, found: 472.0457 [M+Na]+.
N-(4-(4-Fluorophenyl)-1,4,5,6-tetrahydro-6-oxo-2-phenylpyrimidin-5-yl)benzamide (3c)
White solid, mp 255-257 °C; IR (KBr): 3305, 1720, 1509, 1459, 1399, 1222, 831 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.13 (s, 1H, NH), 8.70 (d, J = 8.8 Hz, 1H, NH), 7.93 (d, J = 7.6 Hz, 2H, ArH), 7.75 (s, 1H, ArH), 7.73 (t, J = 1.2 Hz, 1H, ArH), 7.54-7.42 (m, 2H, ArH), 7.48-7.44 (m, 6H, ArH),7.16 (t, J = 8.8 Hz, 2H, ArH), 5.04 (d, J = 14.0 Hz, 1H, CH), 4.68 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 169.9, 166.1, 137.8, 133.0, 131.0, 129.7, 128.2, 127.0, 114.6, 114.4, 60.7, 52.6; HRMS (ESI) m/z: calc. For C23H18FN3NaO2: 410.1281 [M+Na]+, found: 410.1282.
N-(1,4,5,6-Tetrahydro-6-oxo-2,4-diphenylpyrimidin-5-yl)benzamide (3d)
White solid, mp 249-251 °C; IR (KBr): 3286, 1719, 1541, 1312, 1288,1001, 852 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.12 (s, 1H, NH), 8.70 (d, J = 8.8 Hz, 1H, NH), 7.92 (d, J = 7.2 Hz, 2H, ArH), 7.73 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.49 (m, 3H, ArH), 7.45 (t, J = 8.4 Hz, 5H, ArH), 7.29 (t, J = 7.2 Hz, 2H, ArH),7.22 (t, J = 7.2 Hz, 1H, ArH), 5.04 (d, J = 13.6 Hz, 1H, CH), 4.69 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH); HRMS (ESI) m/z: calc. for C23H19N3NaO2: 392.1375[M+Na]+, found: 392.1375.
N-(1,4,5,6-Tetrahydro-4-(4-methoxyphenyl)-6-oxo-2-phenylpyrimidin-5-yl)benzamide (3e)
White solid, mp 277-279 °C; IR (KBr): 3309, 1720, 1541, 1458, 1234, 1038, 825 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.09 (s, 1H, NH), 8.67 (d, J = 8.8 Hz, 1H, NH), 7.92 (d, J = 7.6 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 2H, ArH), 7.54-7.51 (m, 2H, ArH), 7.49-7.44 (m, 4H, ArH), 7.35 (d, J = 7.6 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz ,2H, ArH), 4.98 (d, J = 14.0 Hz, 1H, CH), 4.65 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 3.69 (s, 3H, OCH3); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 170.0, 133.1, 131.3, 128.8, 128.2, 127.2, 127.1, 113.2, 60.8, 54.9; HRMS (ESI) m/z: calc. For C24H21N3NaO3: 422.1481 [M+Na]+, found: 422.1470.
N-(1,4,5,6-Tetrahydro-6-oxo-2-phenyl-4-p-tolylpyrimidin-5-yl)benzamide (3f)
White solid, mp 265-267 °C; IR (KBr): 3287, 3110, 1731, 1542, 1369, 1283, 1283, 1011, 814 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.10 (s, 1H, NH), 8.68 (d, J = 8.8 Hz, 1H, NH), 7.92 (d, J = 7.2 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.51 (m, 2H, ArH), 7.49-7.44 (m, 4H, ArH), 7.31 (d, J = 8.0 Hz, 2H, ArH), 7.09 (d, J = 7.6 Hz, 2H, ArH), 5.01 (d, J = 14.0 Hz, 1H, CH), 4.65 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 2.24 (s, 3H, CH3); HRMS (ESI) m/z: calc. For C24H21N3NaO2: 406.1531 [M+Na]+, found: 406.1531.
N-(2-(4-Bromophenyl)-4-(4-chlorophenyl)-1,4,5,6-tetrahydro-6-oxopyrimidin-5-yl)benzamide (3g)
White solid, mp 257-259 °C; IR (KBr): 3301, 1719, 1542, 1492, 1371, 1011, 834, 820 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.19 (s, 1H, NH), 8.72 (d, J = 8.8 Hz, 1H, NH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 2H, ArH) 7.69 (d, J = 8.4 Hz, 2H, ArH), 7.54(t, J = 7.2 Hz, 1H, ArH), 7.49-7.45 (m, 4H, ArH), 7.36 (d, J = 8.4 Hz, 2H, ArH), 5.04 (d, J = 14.0 Hz, 1H, CH), 4.71 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 133.8, 133.2, 131.4, 131.2, 129.7, 128.3, 127.6, 127.1, 79.1, 52.3; HRMS (ESI) m/z: calc. for C23H17BrClN3NaO2: 506.0064 [M+Na]+, found: 506.0064.

N-(2-(4-Bromophenyl)-1,4,5,6-tetrahydro-4-(4-methoxyphenyl)-6-oxopyrimidin-5-yl)benzamide (3h)
White solid, mp 260-262 °C; IR (KBr): 3315, 3133, 1718, 1512, 1370, 1288, 1036, 824 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.14 (s, 1H, NH), 8.67 (d, J = 8.8 Hz, 1H, NH), 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.74 (d, J = 7.2 Hz, 2H, ArH), 7.68 (d, J = 8.4 Hz, 2H, ArH), 7.53 (t, J = 7.2 Hz, 1H, ArH), 7.46 (t, J = 7.6 Hz, 2H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 4.97 (d, J = 13.6 Hz, 1H, CH), 4.67 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H, CH), 3.69 (s, 3H, OCH3);HRMS (ESI) m/z: calc. for C24H20BrN3NaO3: 502.0563 [M+Na]+, found: 502.0569.
N-(2-(4-Bromophenyl)-1,4,5,6-tetrahydro-6-oxo-4-p-tolylpyrimidin-5-yl)benzamide (3i)
White solid, mp 260-262 °C; IR (KBr): 3308, 1719, 1542, 1371, 1245, 1073, 835, 814 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.15 (s, 1H, NH), 8.69 (d, J = 9.2 Hz, 1H, NH), 7.87 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 7.2 Hz, 2H, ArH), 7.68 (d, J = 8.4 Hz, 2H, ArH), 7.53 (t, J = 7.2 Hz, 1H, ArH), 7.46 (t, J = 7.2 Hz, 2H, ArH), 7.32 (d, J = 7.6 Hz, 2H, ArH), 7.10 (d, J = 8.0 Hz, 2H, ArH), 5.00 (d, J = 9.6 Hz, 1H, CH), 4.68 (dd, J1 = 13.2 Hz, J2 = 9.2 Hz, 1H, CH), 2.25 (s, 3H, CH3); HRMS (ESI) m/z: calc. for C24H20BrN3NaO2: 486.0614 [M+Na]+, found: 486.0613.
N-(2-(4-Bromophenyl)-1,4,5,6-tetrahydro-4-(3,4,5-trimethoxyphenyl)-6-oxopyrimidin-5-yl)benzamide (3j)
White solid, mp 263-264 °C; IR (KBr): 3262, 2997, 1720, 1551, 1372, 1242, 1133, 1009, 834 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.15 (s, 1H, NH), 8.79 (d, J = 8.8 Hz,1H, NH), 8.87 (d, J = 8.4 Hz, 2H, ArH), 7.77 (d, J = 7.2 Hz, 2H, ArH), 7.69 (d, J = 8.8 Hz, 2H, ArH), 7.54 (t, J = 7.2 Hz, 1H, ArH), 7.46 (t, J = 7.6 Hz, 2H, ArH), 6.74 (s, 2H, ArH), 4.99 (d, J = 14.0 Hz, 1H, CH), 4.68 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 3.66 (s, 6H, OCH3), 3.60 (s, 3H, OCH3); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 169.8, 166.1, 152.3, 150.6, 137.0, 136.4, 133.9, 132.3, 131.4, 131.2, 129.4, 128.2, 127.1, 124.6, 105.2, 61.4, 59.8, 55.6, 52.4; HRMS (ESI) m/z: calc. for C26H24BrN3NaO5: 562.0775 [M+Na]+, found: 562.0774.
N-(4-(4-Bromophenyl)-2-(4-chlorophenyl)-1,4,5,6-tetrahydro-6-oxopyrimidin-5-yl)benzamide (3k)
White solid, mp 293-295 °C; IR (KBr): 3300, 1720, 1542, 1367, 1286, 1073, 838 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.21 (s, 1H, NH), 8.88 (d, J = 8.8 Hz,1H, NH), 7.95 (d, J = 7.6 Hz, 2H, ArH), 7.79 (d, J = 7.2 Hz, 2H, ArH), 7.54 (t, J = 8.4 Hz, 3H, ArH), 7.50-7.42 (m, 6H, ArH), 5.12 (d, J = 13.6 Hz, 1H, CH), 4.68 (dd, J1 = 13.2 Hz, J2 = 8.8 Hz, 1H, CH); HRMS (ESI) m/z: calc. for C23H17BrClN3NaO2: 506.0064 [M+Na]+, found: 506.0064.
N-(2-(4-Chlorophenyl)-1,4,5,6-tetrahydro-6-oxo-4-phenylpyrimidin-5-yl)benzamide (3l)
White solid, mp 261-263 °C; IR (KBr): 3306, 1718, 1541, 1456, 1287, 1015, 840 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.18 (s, 1H, NH), 8.70 (d, J = 8.8 Hz,1H, NH), 7.94 (d, J = 8.4 Hz, 2H, ArH), 7.73 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.51 (m, 3H, ArH), 7.47-7.42 (m, 4H, ArH), 7.29 (t, J = 7.2 Hz, 2H, ArH), 7.23-7.20 (m, 1H. ArH), 5.04 (d, J = 13.6 Hz, 1H, CH), 4.70 (dd, J1 = 13.2 Hz, J2 = 8.8 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 141.4, 133.9, 131.9, 131.3, 129.2, 128.3, 128.2, 127.8, 127.1, 61.4, 52.5; HRMS (ESI) m/z: calc. for C23H18ClN3NaO2: 426.0985 [M+Na]+, found: 426.0986.

N-(2-(4-Chlorophenyl)-1,4,5,6-tetrahydro-4-(4-methoxyphenyl)-6-oxopyrimidin-5-yl)benzamide
(3m)
White solid, mp 277-279 °C; IR (KBr): 3313, 2932, 1718, 1512, 1464, 1370, 1038, 824 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.14 (s, 1H, NH), 8.67 (d, J = 8.8 Hz,1H, NH), 7.86 (d, J = 8.8 Hz, 2H, ArH), 7.74 (d, J = 7.2 Hz, 2H, ArH), 768 (d, J = 8.4 Hz, 2H, ArH), 7.55-7.51 (m, 1H, ArH), 7.46 (t, J = 7.6 Hz, 2H, ArH), 7.34 (d, J = 8.8 Hz, 2H, ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 4.97 (d, J = 13.6 Hz, 1H, CH), 4.66 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 3.69 (s, 3H, ArH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 133.9, 132.3, 131.3, 131.2, 129.4, 128.8, 128.2, 127.1, 113.2, 54.9, 52.6; HRMS (ESI) m/z: calc. for C24H20ClN3NaO3: 456.1091 [M+Na]+, found: 456.1089.
N-(2-(4-Chlorophenyl)-1,4,5,6-tetrahydro-4-(3,4,5-trimethoxyphenyl)-6-oxopyrimidin-5-yl)benzamide (3n)
White solid, mp 253-254 °C; IR (KBr): 3263, 2997, 1721, 1551, 1372, 1132, 1004, 834 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.16 (s, 1H, NH), 8.86 (d, J = 8.4 Hz, 1H, NH), 7.96 (d, J = 8.0 Hz, 2H, ArH), 7.83 (d, J = 7.6 Hz, 2H, ArH), 7.56-7.52 (m, 3H, ArH), 7.46 (t, J = 7.6 Hz, 2H, ArH), 6.79 (s, 2H, ArH), 5.08 (d,J = 13.6 Hz, 1H, CH), 4.68 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H, CH), 3.67 (s, 6H, OCH3), 3.59 (s, 3H, OCH3); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 152.2, 133.9, 131.3, 129.2, 128.3, 128.2, 127.1, 105.2, 99.4, 59.8, 55.8, 55.2; HRMS (ESI) m/z: calc. for C26H24ClN3NaO5: 516.1302 [M+Na]+, found: 516.1302.
N-(4-(4-Chlorophenyl)-1,4,5,6-tetrahydro-6-oxo-2-(pyridin-3-yl)pyrimidin-5-yl)benzamide (3o)
White soild mp 269-270 °C; IR (KBr): 3281, 1720, 1647, 1543, 1489, 1292, 820 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.31 (s, 1H, NH), 9.07 (s, 1H, ArH), 8.74 (d, J = 11.6 Hz, 2H, ArH), 8.26 (d, J = 7.6 Hz, 1H, NH), 7.76 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.47 (m, 6H, ArH), 7.37 (d, J = 8.8 Hz, 2H, ArH), 5.08 (d, J = 13.6 Hz, 1H, CH), 4.75 (dd, J1 = 13.2 Hz, J2 = 9.6 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 169.7, 166.2, 151.5, 150.3, 148.3, 140.5, 129.7, 128.9, 128.3, 127.8, 127.1, 123.2, 60.9, 52.4; HRMS (ESI) m/z: calc. for C22H17ClN4O2: 403.0961 [M-H]+, found: 403.0960.
N-(4-(4-Fluorophenyl)-1,4,5,6-tetrahydro-6-oxo-2-(pyridin-3-yl)pyrimidin-5-yl)benzamide (3p)
White soild mp 270-271 °C; IR (KBr): 3280, 3073, 2898, 2778, 1736, 1648, 1543, 1222, 857, 823 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.25 (s, 1H, NH), 9.07 (s, 1H, ArH), 8.71 (d, J = 4.0 Hz, 2H, ArH), 8.26 (d, J = 7.6 Hz, 1H, NH), 7.74 (d, J = 7.2 Hz, 2H, ArH), 7.55-7.45 (m, 6H, ArH), 7.12 (t, J = 8.8 Hz, 2H, ArH), 5.07 (d, J = 14.0 Hz, 1H, CH), 4.74 (dd, J1 = 13.2 Hz, J2 = 9.2 Hz, 1H, CH); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 151.5, 148.3, 131.4, 129.8, 129.7, 128.9, 128.3, 127.1, 123.2, 114.7, 114.4, 52.5; HRMS (ESI) m/z: calc. for C22H16FN4O2: 387.1257 [M-H]+, found: 387.1269.
N-(1,4,5,6-Tetrahydro-4-(4-methoxyphenyl)-6-oxo-2-(pyridin-3-yl)pyrimidin-5-yl)benzamide (3q)
White soild mp 268-269 °C; IR (KBr): 3278, 1721, 1650, 1515, 1473, 1241, 1180, 829 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.26(s, 1H, NH), 9.05 (s, 1H, ArH), 8.70 (d, J = 9.2 Hz, 2H, ArH), 8.25 (d, J = 7.6 Hz, 1H, NH), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.55-7.45 (m, 4H, ArH), 7.35 (d, J = 8.4 Hz, 2H,ArH), 6.85 (d, J = 8.8 Hz, 2H, ArH), 5.01 (d, J = 13.6 Hz, 1H, CH), 4.70 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H, CH), 3.69 (s, 3H, OCH3); HRMS (ESI) m/z: calc. for C23H19N4O3: 399.1456 [M-H]+, found: 399.1456.
N-(1,4,5,6-Tetrahydro-6-oxo-2-(pyridin-3-yl)-4-p-tolylpyrimidin-5-yl)benzamide (3r)
White soild mp 260-261 °C; IR (KBr): 3277, 3066. 2091, 1733, 1648, 1543, 1292, 1102, 813 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.24 (s, 1H, NH), 9.07 (s, 1H, ArH), 8.71 (d, J = 5.6 Hz, 2H, ArH), 8.26 (d, J = 7.6 Hz, 1H, NH), 7.76 (d, J = 7.2 Hz, 2H, ArH), 7.55-7.44 (m, 4H, ArH), 7.33 (d, J = 7.6 Hz, 2H,ArH), 7.10 (d, J = 7.6 Hz, 2H, ArH), 5.04 (d, J = 13.6 Hz, 1H, CH), 4.73 (dd, J1 = 13.2 Hz, J2 = 9.2 Hz, 1H, CH), 2.24 (s, 3H, CH3); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 151.5, 148.3, 131.3, 128.9, 128.4, 128.2, 127.7, 127.1, 123.2, 52.5, 20.6; HRMS (ESI) m/z: calc. for C22H17N4NaO2: 369.1351 [M-H]+, found: 369.1350.
N-(1,4,5,6-Tetrahydro-4-(3,4,5-trimethoxyphenyl)-6-oxo-2-(pyridin-3-yl)pyrimidin-5-yl)benzamide (3s)
White soild mp 264-265 °C; IR (KBr): 3277, 2899, 1723, 1650, 1311, 1278, 843 cm-1; 1H NMR (400MHz, DMSO-d6) (δ, ppm): 11.24 (s, 1H, NH), 9.08 (s, 1H, ArH), 8.70 (d, J = 9.2 Hz, 2H, ArH), 8.27 (d, J = 7.6 Hz, 1H, NH), 7.77 (d, J = 7.2 Hz, 2H, ArH), 7.56-7.46 (m, 4H, ArH), 6.75 (s, 2H, ArH), 5.04 (d, J = 14.0 Hz, 1H, CH), 4.71 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H, CH), 3.67 (s, 6H, OCH3), 3.60 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) (δ, ppm): 169.9, 166.2, 152.3, 151.5, 149.9, 148.4, 136.4, 135.0, 133.9, 131.4, 128.9, 128.2, 127.1, 123.3, 105.2, 61.4, 59.8, 55.6, 52.5; HRMS (ESI) m/z: calc. for C25H23N4O5: 459.1668 [M-H]+, found: 459.1648.
N-(1,4,5,6-Tetrahydro-4-(4-methoxyphenyl)-6-oxo-2-(pyridin-4-yl)pyrimidin-5-yl)benzamide (3t)
White soild mp 262-263 °C; IR (KBr): 3312, 3153, 2840, 1721, 1649, 1510, 1241, 815 cm-1; 1H NMR (400 MHz, DMSO-d6) (δ, ppm): 11.28 (s, 1H, NH), 8.71 (s, 2H, ArH), 8.69 (d, J = 5.2 Hz, 1H, NH), 7.86 (d, J = 5.2 Hz, 2H, ArH), 7.75 (d, J = 7.6 Hz, 2H, ArH), 7.53 (t, J = 7.2 Hz, 1H, ArH), 7.46 (t, J = 7.2 Hz, 2H, ArH), 7.34 (d, J = 7.6 Hz, 2H, ArH), 6.85 (d, J = 8.4 Hz, 2H, ArH), 5.03 (d, J = 13.6 Hz, 1H, CH), 4.69 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 3.69 (s, 3H, OCH3); HRMS (ESI) m/z: calc. for C23H19N4O3: 399.1456 [M-H]+, found: 399.1456.
N-(1,4,5,6-Tetrahydro-6-oxo-2-(pyridin-4-yl)-4-p-tolylpyrimidin-5-yl)benzamide (3u)
White soild mp 272-273 °C; IR (KBr): 3276, 3113, 1731, 1653, 1542, 1287, 1066, 816 cm-1; 1H NMR (400MHz, DMSO) (δ, ppm): 11.28 (s, 1H, NH), 8.72 (s, 2H, ArH), 8.70 (d, J = 5.2 Hz, 1H, NH), 7.86 (d, J = 4.4 Hz, 2H, ArH), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.53 (t, J = 7.6 Hz, 1H, ArH), 7.46 (t, J = 7.2 Hz, 2H, ArH), 7.32 (d, J = 7.6 Hz, 2H, ArH), 7.10 (d, J = 7.6 Hz, 2H, ArH), 5.05 (d, J = 13.6 Hz, 1H, CH), 4.71 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H, CH), 2.24 (s, 3H, CH3); 13C NMR (100MHz, DMSO-d6) (δ, ppm): 166.1, 149.9, 140.3, 138.3, 131.3, 128.2, 127.1, 121.3, 61.3, 52.4, 20.6; HRMS (ESI) m/z: calc. for C23H19N4O2: 383.1507 [M-H]+, found: 383.1506.

ACKNOWLEDGEMENTS
We are grateful for financial support from the National Science Foundation of China (21072163, 21002083, and 21102124), the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, and the NSF of Jiangsu Education Committee (11KJB150016), Jiangsu Science and Technology Support Program (No. BE2011045), Robert A. Welch Foundation (D-1361) and NIH (R21 DA031860-01).

References

1. (a) J. Monika, M. Tracey, Y. K. Dennis, and K. Rakesh, Bioorg. Med. Chem., 2005, 13, 6663; CrossRef (b) J. Zlatko, B. Jan, A. Graciela, E. D. C. Robert, and J. R. Morris, J. Med. Chem., 2005, 48, 4690. CrossRef
2. (a) C. O. Kappe, Tetrahedron, 1993, 49, 6937; CrossRef (b) C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043. CrossRef
3. (a) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber, and T. J. Mitchison, Science, 1999, 286, 971; CrossRef (b) S. J. Haggarty, T. U. Mayer, D. T. Miyamoto, R. Fathi, R. W. King, T. J. Mitchison, and S. L. Schreiber, Chem. Biol., 2000, 7, 275. CrossRef
4. (a) D. Nagarathnam, W. C. Wong, S. W. Miao, M. A. Patance, and C. Gluchowski, PCT Int. Appl. WO 97 17, 969, 1997; (b) D. R. Sidler, R. D. Larsen, M. Chartrain, N. Ikemoto, C. M. Roberg, C. S. Taylor, W. Li, and G. F. Bills, PCT Int. WO 99 07, 695, 1999; (c) D. Nagarathnam, S. W. Miao, B. Lagu, G. Chiu, J. Fang, T. G. M. Dhar, J. Zhang, S. Tyagarajan, M. R. Marzabadi, F. Q. Zhang, W. C. Wong, W. Y. Sun, D. Tian, J. M. Wetzel, C. Forray, R. S. L. Chang, T. P. Broten, R. W. Ransom, T. W. Schorn, T. B. Chen, S. O’Malley, P. Kling, K. Schneck, R. Benedesky, C. M. Harrell, K. P. Vyas, and C. Gluchowski, J. Med. Chem., 1999, 42, 4764; CrossRef (d) J. C. Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass, K. E. Rittle, K. F. Gilbert, T. G. Steele, C. F. Homnick, R. M. Freidinger, R. W. Ransom, P. Kling, D. Reiss, T. P. Broten, T. W. Schorn, R. S. L. Chang, S. S. O’Malley, T. V. Olah, J. D. Ellis, A. Barrish, K. Kassahun, P. Leppert, D. Nagarathnam, and C. Forray, J. Med. Chem., 2000, 43, 2703. CrossRef
5. H. Cho, M. Ueda, K. Shima, A. Mizuno, M. Hayashimatsu, Y. Ohnaka, Y. Takeuchi, M. Hamaguchi, and K. Aisaka, J. Med. Chem., 1989, 32, 2399. CrossRef
6. A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer, C. De Brosse, S. Mai, A. Truneh, D. J. Faulkner, B. Carte, A. L. Breen, R. P. Hertzberg, R. K. Johnson, J. W. Westley, and B. C. M. Ports, J. Org. Chem., 1995, 60, 1182. CrossRef
7. K. Deres, C. H. Schroer, A. Paessens, S. Goldmann, H. J. Hacker, O. Weber, T. Kraemer, U. Niewoehner, U. Pleiss, J. Stoltefuss, E. Graef, D. Koletzki, R. N. A. Masantschek, A. Reimann, R. Jaeger, R. Grob, B. Beckermann, K.-H. Schlemmer, D. Haebich, and H. Rübsamen-Waigmann, Science, 2003, 299, 893. CrossRef
8. C. A. Sehon, G. Z. Wang, A. Q. Viet, K. B. Goodman, S. E. Dowdell, P. A. Elkins, S. F. Semus, C. Evans, L. J. Jolivette, R. B. Kirkpatrick, E. Dul, S. S. Khandekar, T. Yi, L. L. Wright, G. K. Smith, D. J. Behm, R. Bentley, C. P. Doe, E. Hu, and D. Lee, J. Med. Chem., 2008, 51, 6631. CrossRef
9. (a) S. J. Tu, F. Fang, S. L. Zhu, T. J. Li, X. J. Zhang, and Q. Y. Zhuang, Synlett, 2004, 537; CrossRef (b) D. S. Bose, L. Fatima, and H. B. Mereyala, J. Org. Chem., 2003, 68, 587; CrossRef (c) Y. Ma, C. Qian, L. Wang, and M. Yang, J. Org. Chem., 2000, 65, 3864; CrossRef (d) M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol, and P. Machado, Chem. Rev., 2009, 109, 4140; CrossRef (e) S. Kobayashi, M. Sugiura, H. Kitagawa, and W. W. L. Lam, Chem. Rev., 2002, 102, 2227; CrossRef (f) A. Stadler and C. O. Kappe, J. Comb. Chem., 2001, 3, 624; CrossRef (g) L. Pisani, H. Prokopcova, J. M. Kremsner, and C. O. Kappe, J. Comb. Chem., 2007, 9, 415; CrossRef (h) Y. Huang, F. Yang, and C. Zhu, J. Am. Chem. Soc., 2005, 127, 16386; CrossRef (i) X. H. Chen, X. Y. Xu, H. Liu, L. F. Cun, and L. Z. Gong, J. Am. Chem. Soc., 2006, 128, 14802; CrossRef (j) N. Li, X. H. Chen, J. Song, S. W. Luo, W. Fan, and L. Z. Gong, J. Am. Chem. Soc., 2009, 131, 15301. CrossRef
10. L. D. S. Yadav, A. Rai, V. K. Rai, and C. Awasthi, Tetrahedron, 2008, 64 1420. CrossRef
11. Q. Sun, F. Suzenet, and G. Guillaumet, Tetrahedron Lett., 2012, 53, 2694. CrossRef
12. (a) P. Perjesi, A. Foldesi, and J. Tamas, Monatsh. Chem., 1993, 124, 167; CrossRef (b) N. R. El-Rayyes, B. Al-Saleh, and F. J. Al-Omran, Chem. Eng. Data, 1987, 32, 280. CrossRef
13. (a) X. Zhu, G. Zhao, X. Zhou, X. Xu, G. Xia, Z. Zheng, L. Wang, X. Yang, and S. Li, Bioorg. Med. Chem. Lett., 2010, 20, 299; CrossRef (b) V. K. Ahluwalia, C. Gupta, and C. H. Khanduri, Indian J. Chem., Sect. B, 1992, 31B, 355; (c) A. L. Weis and F. Frolow, J. Chem. Soc., Perkin Trans. 1, 1986, 83; CrossRef (d) A. L. Weis, Synthesis, 1985, 528; CrossRef (e) A. Kuno, Y. Sugiyama, K. Katsuta, T. Kamitani, and H. Takasugi, Chem. Pharm. Bull., 1992, 40, 1452. CrossRef
14. (a) B. Jiang, M.-S. Yi, F. Shi, S.-J. Tu, S. Pindi, P. McDowell, and G. Li, Chem. Commun., 2012, 48, 808; CrossRef (b) B. Jiang, Q.-Y. Li, H. Zhang, S.-J. Tu, S. Pindi, and G. Li, Org. Lett., 2012, 14, 700; CrossRef (c) B. Jiang, C. Li, F. Shi, S.-J. Tu, P. Kaur, W. Wever, and G. Li, J. Org. Chem., 2010, 75, 2962; CrossRef (d) B. Jiang, S.-J. Tu, P. Kaur, W. Wever, and G. Li, J. Am. Chem. Soc., 2009, 131, 11660; CrossRef (e) C. Cheng, B. Jiang, S.-J. Tu, and G. Li, Green Chem., 2011, 13, 2107. CrossRef
15. (a) B. Jiang, G. Zhang, N. Ma, F. Shi, S.-J. Tu, P. Kaur, and G. Li, Org. Biomol. Chem., 2011, 9, 3834; CrossRef (b) B. Jiang, X. Wang, F. Shi, S.-J. Tu, and G. Li, Org. Biomol. Chem., 2011, 9, 4205; CrossRef (c) B. Jiang, W.-J. Hao, J.-P. Zhang, S.-J. Tu, and F. Shi, Org. Biomol. Chem., 2009, 7, 1171; CrossRef (d) B. Jiang, F. Shi, and S.-J. Tu, Curr. Org. Chem., 2010, 14, 357; CrossRef (e) B. Jiang, Y.-P. Liu, and S.-J. Tu, Eur. J. Org. Chem., 2011, 3026; CrossRef (f) S.-L. Wang, F.-Y. Wu, C. Cheng, G. Zhang, Y.-P. Liu, B. Jiang, F. Shi, and S.-J. Tu, ACS Comb. Sci., 2011, 13, 135.
16. (a) S. Tu, J. Zhang, R. Jia, B. Jiang, Y. Zhang, and H. Jiang, Org. Biomol. Chem., 2007, 5, 1450; CrossRef (b) S. Tu, J. Zhang, R. Jia, B. Jiang, Y. Zhang, C. Yao, and H. Jiang, Chem. Lett., 2007, 222; CrossRef (c) S. Tu, J. Zhang, R. Jia, Y. Zhang, B. Jiang, and F. Shi, Synthesis, 2007, 558; CrossRef (d) F. Shi, A.-X. Dai, X.-H. Zhang, B. Jiang, and S.-J. Tu, ACS Comb. Sci., 2011, 13, 147. CrossRef
17. (a) T. P. Loh, S. B. K. W. Liung, K. L. Tan, and L. L. Wei, Tetrahedron, 2000, 56, 3227; CrossRef (b) C. Gennari, I. Venturini, G. Gislon, and G. Schimperma, Tetrahedron Lett., 1987, 28, 227; CrossRef (c) G. Guanti, E. Narisano, and L. Banfi, Tetrahedron Lett., 1987, 28, 4331; CrossRef (d) H. Wu, Y. Shen, L.-Y. Fan, Y. Wan, P. Zhang, C.-F. Chen, and W.-X. Wang, Tetrahedron, 2007, 63, 2404. CrossRef