Mol Divers (2015) 19:213–230 DOI 10.1007/s11030-015-9577-3

FULL-LENGTH PAPER

Synthesis and crystal structure of new heterocyles derived from saccharin and uracil carrying 1,2,4-oxadiazolylmethyl group Ya¸sar Dürüst · Besra Özer · Benson M. Cariuki

Received: 8 November 2014 / Accepted: 22 February 2015 / Published online: 10 March 2015 © Springer International Publishing Switzerland 2015

Abstract Saccharin, uracil, and 1,2,4-oxadiazole heterocyles are important in terms of exhibiting various biological acitivities. In this work, four series of 1,2,4-oxadiazolylmethyl-substituted saccharin, and uracil derivatives are synthesized and their structures are identified by means of spectral/physical characteristics. The first series are oxadiazolylmethyl-substituted saccharins. The second one is oxadiazole-substituted uracils which are obtained as a separable mixture of both mono- and bis-substituted end products. Third series is obtained from 5-amino uracil and chloromethyl oxadiazoles. The fourth group is oxadiazolyl methyl-substituted imino uracils. The structures of some title compounds are also confirmed by X-ray diffraction data.

Graphical Abstract

Keywords Saccharin · Uracil · 1, 2, 4-Oxadiazole · N -substitution · X-ray diffraction Introduction Electronic supplementary material The online version of this article (doi:10.1007/s11030-015-9577-3) contains supplementary material, which is available to authorized users. Y. Dürüst (B) · B. Özer Department of Chemistry, Abant ˙Izzet Baysal University, 14280 Bolu, Turkey e-mail: [email protected] B. M. Cariuki School of Chemistry, Cardiff University, Cardiff, UK

Saccharin (2H -1λ6 ,2-benzothiazol-1,1,3-trione) is an artificial sweetener synthesized in 1878 [1,2] that has been found to exhibit significant inhibition towards histone deacetylase (HDAC). In cancer cells, an imbalance of histone acetylation often exists due to the over-expression of HDAC, which leads to silencing of the expression of tumor suppressor genes (such as p21/p53) through hypoacetylation [3]. In addition, some saccharin derivatives were also reported to show in vitro

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Fig. 1 Saccharin and a saccharin derivative as inhibitor of interferonmediated inflammation

Scheme 1 Synthesis of 5-chloromethyl-3- p-substituted phenyl-1,2,4oxadiazoles 2a–k

hGnRH-R

Fig. 2 Uracil, its tautomeric form, and an uracil derivative as a potent human gonadotropin-releasing hormone receptor (hGnRH-R)

inhibition effect on erythrocyte carbonic anhydrase I and II, interferon-mediated inflammation (Fig. 1), human leukocyte elastase, and cathepsin G [4–7]. Naturally occurring pyrimidine derivative uracil (pyrimidine-2,4(1H ,3H )-dione), which was originally discovered in 1900 by Alberto Ascoli, is one of the four nucleobases in the nucleic acid of RNA; it was also found in bovine thymus and spleen, herring sperm, and wheat germ [8–11]. Some uracil derivatives were found to exhibit anticancer and human gonadotropin-releasing hormone receptor antagonist activities (hGnRH-R) (Fig. 2) [12–14]. 1,2,4-Oxadiazole which is a structural portion of the current work and its derivatives can be found in a vast number of compounds exhibiting biological activity, such as ligands of benzodiazepine receptors [15,16], anti-inflammatory agents [17–19], antiviral agents [20], inhibitors of protein tyrosine phosphatases [21], agonists of muscarinic receptors [22,23], and antagonists of histamine HT3 − receptors [24]. Taking into account the above considerations and findings plus our continuous interest in the synthesis of various heterocyclic scaffolds based on the amidoximes, herein we report the synthesis of some saccharin- and uracil-based heterocyles carrying 1,2,4-oxadiazolylmethyl group and their crystal structures. Results and discussion Through this work, the synthesis of 3-aryl- substituted-5chloromethyl-1,2,4-oxadiazoles by starting from monoami-

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doximes (Scheme 1) has primarily been performed. Synthesis of monoamidoximes 1a–k, and 5-chloromethyl-3p-substituted phenyl-1,2,4-oxadiazoles 2a–k has been performed according to previously described methods [25–28]. Both electron-releasing and electron-withdrawing groups on the starting chloromethyl oxadiazoles have been selected. These compounds have been identified based on the physical and spectral data reported in the literature. The reaction of these compounds with saccharin (obenzosulfimide) and uracil (or amino uracil) gave rise to novel N -1,2,4-oxadiazolyl methyl-substituted heterocycles. The structures of the compounds were elucidated by means of spectroscopic and physical methods including X-ray diffraction data. 5-Chloromethyl-3- p-substituted phenyl-1,2,4-oxadiazoles 2a–k reacted with o-benzosulfimide 3 under reflux in DMF to give 2-[(3-( p-substituted phenyl-1,2,4-oxadiazol-5yl)methyl]-1,2-benzisothiazol-3(2H )-one 1,1-dioxides 4a– k (Scheme 2). Primary indication of the new product was the disappearance of NH absorption and sulfone asymmetric and symmetric stretching vibrations originated from saccharin in the IR spectra. Secondly, in the proton NMR of the products, along with aromatic protons arising from both oxadiazole and saccharin itself, oxadiazolyl methylene signals at around 5.20 ppm were confirmative. 13 C NMR signals of methylene carbons have appeared at around 33 ppm, and carbonyl carbon originated from saccharin was observed at around 168 ppm. We were able to obtain an X-ray ORTEP diagram (Fig. 3) from a fine single crystal of 4h which has proven that N substitution occurred even though it was reported that under mild conditions O-alkylation would also occur due to its ambident nucleophilicity [29]. N -substitution of uracil by 5-chloromethyl-1,2, 4-oxadiazoles gave rise a mixture of both N ,N  -disubstituted

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Scheme 2 Synthesis of N oxadiazolylmethyl-substituted saccharins 4a–k

3 Fig. 3 X-ray ORTEP diagram of 4h

and N -monosubstituted products. First ones, which are less polar and eluted first through chromatography column, are the N ,N  -disubstituted products; 1,3-bis[(3-( p-substituted phenyl)-1,2,4-oxadiazol-5-yl)methyl]pyrimidine-2,4(1H, 3 H )-diones (6a–c, 6e–j) and the others, which are more polar due to NH, are 3-[(3-( p-substituted phenyl)-1,2,4-oxadiazol5-yl)methyl]pyrimidine-2,4(1H, 3H )-diones (7a–c and 7e– j) (Scheme 3). N ,N  -disubstituted uracils 6a–j showed no NH absorptions in the IR spectra, but carbonyl bands arising from uracil. N -monosubstituted uracil derivatives 7a–j showed NH absorption at around 3400 cm−1 along with the carbonyl stretching absorptions. We observed carbonyl absorptions in

both compounds between 1730 and 1700 cm−1 . In addition, the C=N absorption originated from oxadiazole moiety appeared at around 1620 cm−1 . In the LC–MS spectra of the uracil-substituted compounds, we see [M+H]+ as base signal. NMR data are in accord with the structures. In this regard, upon examination of 1 H NMR spectra, CH2 protons were observed at around 5.48 and 5.41 ppm as singlets. Alkenic hydrogens of the uracil, one of the CH protons which is closer to nitrogen atom gives doublet at around 8.10 ppm, while the other resonates at 6.10 ppm. In the 13 C NMR spectra, we can see two methylene carbons at around 44 and 36 ppm and carbonyl carbons at around 167 and 150 ppm, respectively. Iminic carbons of the oxadiazole rings resonate at around

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Scheme 3 Synthesis of bis and mono N -substituted 1,2,4-oxadiazolylmethyl uracil derivatives 6 and 7

Fig. 4 X-ray ORTEP diagram of 6b

175, 167, and 161 ppm, more deshielded one is the number 3 carbon (oxadiazole ring numbering) due to being located between two sp2 hybridized nitrogen atoms in comparison with the other iminic carbons. Double-bond carbons of the uracil resonated at around 126 and 102 ppm. We established the exact structure of one of the bis N -substituted uracil derivatives, 6b, by obtaining X-ray diffraction data from a fine single crystal (Fig. 4). Upon investigation of the IR, NMR, and LC–MS spectra for the compound 7a, monosubstituted uracil derivative, as a representative molecule, we observed that NH, carbonyl, and C=N absorptions arose at around 3400, 1720, and 1586 cm−1 , respectively. These structural evidences are also supported by [M+H]+ at 271 m/z in LC–MS spectra. 5-Amino-1,3-bis[(3-( p-substituted phenyl)-1,2,4-oxadiazol-5-yl)methyl]pyrimidine-2,4(1H ,3H )-diones 9a–i were

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obtained by the reaction of 5-chloromethyl-3-( p-substituted phenyl)-1,2,4-oxadiazoles 2a–i and 5-amino uracil 8 at room temperature in dimethyl formamide (Scheme 4). Thus, eight novel compounds are introduced. The structural elucidation of the N , N  -bisoxadiazolylmethyl- substituted 5-amino uracils 9a–i was performed by IR, NMR (1 H, 13 C), and LC–MS spectra. These compounds (8 examples) are quite polar due to NH2 besides carbonyls. Therefore, we were able to record their NMR spectra in DMSO-d6 due to solubility problems in CDCl3 . 1 H NMR spectra showed the typical methylene and amino protons. Particularly, NH2 protons appeared at 4.60 ppm as a broad singlet and methylene protons separately at around 5.40 ppm as singlets. 13 C NMR spectra revealed that most deshielded carbons are number 3 carbons of the oxadiazole ring similar to those in disubstituted cases. From the NMR data, we can conclude that N , N disubstitution occurred solely by the deprotonation of more acidic NHs instead of NH2 since no other product could be detected. Structure elucidation is also supported by LC–MS spectrum at which base peak was observed at m/z 536 for the compound 9i, for example. When we inspect the LC–MS spectra of 9a, 9b, 9c, and 9i, we noticed that along with M+H signals there are signals with the intensities varying from 20 to 90 % that may be attributed to a retro-Diels–Alder type reaction occurred on one of the oxadiazole rings (Scheme 5). In order to perform the synthesis of N -oxadiazolylmethylsubstituted benzylideneamino pyrimidinediones, we prepared imines of uracil 11a–g by condensation with substituted benzaldehydes 10 according to the literature procedure (Scheme 6) [30,31]. The structures of the compounds 11a–g were confirmed based on the spectral/physical data reported (NMR, IR, Mass,

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Scheme 4 Synthesis of N ,N  -bisoxadiazolylmethylsubstituted 5-amino uracils (9a–e and 9g–i)

.+

N

O

O

N

O

N

N

O N

+ O

N

R1

9

NH

N

N

N O

NH2 R1

N

O NH2

R1

R1= H, CH3, F, CH3S

Scheme 5 Mass spectral fragmentation of 9a, 9b, 9c, and 9i

Scheme 6 Synthesis of (E)-5-(benzylideneamino)pyrimidine-2,4(1H , 3H )-diones ( 11a–g)

m.p., and Rf values) in the literature [30,31]. Thus, in the IR spectra, the disappearance of the NH2 absorptions at around 3400 and 3375 cm−1 is an important evidence for the structural elucidation supported by NMR. In this regard, 1 H NMR spectrum of compound 11e indicates two NH protons at around 11.50 and 7.50 ppm, respectively; in addi-

tion, the iminic and alkenic protons appeared at around 9.60 and at 7.80 ppm, respectively. 13 C NMR data also supported the structure where carbonyl carbons of uracil resonated at around 155.80 and 150.60 ppm and iminic carbon at around 161.90 ppm. Molecular ion (m/z; 246, base signal) was observed in the LC–MS spectrum. Benzylideneamino pyrimidinediones 11 were then reacted with 3- p-substituted phenyl-5-chloromethyl-1,2,4-oxadiazoles 2a–c in DMF at room temperature overnight to afford the compounds 12a–c (Scheme 7). The structures of 12a–c were confirmed based on the spectral and physical data. Thus, in the 1 H NMR spectrum of the compound 12b where R1 = CH3 S and R2 = CN, iminic and alkenic protons resonated at around 9.53 and 8.52 ppm, respectively. Two aliphatic CH2 and CH3 S protons were observed at around 5.57, 5.48, and 2.52 ppm, respectively, as singlets. 13 C NMR spectra exhibited six different carbons between 150 and 180 ppm. Two of them are assigned to two carbonyls of the uracil part at around 160-158 ppm. The iminic carbon signals originated from imino uracil were observed at around 150 ppm, while those from oxadiazole rings appeared at around 175 and 168 ppm. The cyano carbon of 12b appears at around 113 ppm. The aliphatic carbons, two CH2 , at around 45.9

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Scheme 7 Synthesis of N ,N  -bisoxadiazolylmethyl-substituted benzylideneamino pyrimidinediones (12a–c)

and 37.9 ppm were found to resonate separately and the two CH3 S carbons are at 14.7 ppm. Interestingly, we detected an isomeric mixture of 12a possibly resulted from the E/Z stereochemistry of starting imine 11a .The proton NMR shows, for example, two iminic protons at 9.33 and 9.28 with an integral ratio 1:3. In addition, methyl signals also appeared as 1:3 ratio. Similar integral ratios also were found for doublets of the aromatic protons in methyl-substituted phenyl ring of the imine part. LC–MS data also confirmed the molecular mass of the compounds, m/z at 649 as a base peak for the compound 12b. From these data, we conclude that N ,N  -disubstitution took place on the imino uracil molecule.

Conclusion In this work, we have demonstrated a one-pot and practical synthesis of 11 N -oxadiazolylmethyl-substituted obenzosulfimides, 18 novel N -oxadiazolylmethyl-substituted uracils, and eight novel 1,2,4- oxadiazolylmethyl-substituted 5-aminouracils. In addition, three novel N ,N  -bisoxadiazolylmethyl-substituted benzylideneamino pyrimidinediones have been synthesized. The structures of all new compounds were fully determined using spectral/physical data including X-ray diffraction. All of these 40 compounds are novel, and since they carry oxadiazole, uracil, amino uracil, and benzosulfimide groups, they may be considered as potential bioactive heterocycles. For this reason, in the near future, they will be assayed for a series of biological activities such as anti-tumoral, anti-protozoal, and antimicrobial.

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Experimental section 1H

and 13 CNMR spectra were recorded on VARIAN, BRUKER, and JEOL spectrometers (300 and 400 MHz for 1 H; 75 and 100 MHz for 13 C). IR spectra were recorded on a SHIMADZU FTIR 8400-S instrument (KBr pellet). LC–MS spectra were run on Waters 2695 Alliance Micromass ZQ. High- Resolution Mass Spectra have been obtained from Waters Lct Premier XE oa-TOF Mass Spectrometer (Waters Corporation, Milferd, MA, USA). Melting points were determined on a MELTEMP apparatus and uncorrected. Flash column chromatography was performed on Silica Gel (Merck, 230–400 Mesh ASTM). TLC was done using precoated plates with fluorescent indicator (Merck 5735). The stain solutions of permanganate and iodine were used for visualization of the TLC spots. Starting materials, monoaryl amidoximes, and 5-chloromethyl-3-( p-substituted phenyl)1,2,4-oxadiazoles 2 were synthesized according to the methods described in the literature previously [25–28]. Synthesis of N -oxadiazolylmethyl-substituted o-benzosulfimides (4a-k) 2-((3-Phenyl-1,2,4-oxadiazole-5-yl)methyl) benzo[d]isothiazol-3(2H )-one1,1-dioxide (4a)

N N O

N S O O

O

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General procedure A mixture of 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole 2a (0.034 g, 0.18 mmol) and benzo[d]isothiazol-3(2H )-one 1,1-dioxide 3 (0.033 g, 0.18 mmol) with K2 CO3 (0.0124 g, 0.09 mmol) in DMF (5mL) was heated at 130 ◦ C for 2h and monitored by TLC. The reaction mixture was extracted with (ethyl acetate: cold water 1:1) ×4 and concentrated in vacuo, then the crude residue was purified by flash column chromatography (n-hexane:ethyl acetate; 4:1) to give 4a as a light yellow solid. Yield. 38 mg, 62 %. m.p.: 158–160 ◦ C. Rf : 0.625 (n-hexane:ethyl acetate;1:1). IR (KBr) (νmax , cm−1 ): 3084, 2924, 2864, 1739 (C=O), 1340 (asymm-SO2 -stretch), 1167 (symm-SO2 -stretch), 1649, 1599 (C=N), 1460, 1300, 1062. 1 H NMR (300 MHz, CDCl3 ): δ H = 8.15–7.85 (m, 6 H), 7.49–7.42 (m, 3H), 5.20 (s, 2H). 13 C NMR (100 MHz, CDCl3 ): δC = 172.81 (C=N), 168.50 (C=O), 158.40 (C=N), 137.95, 135.62, 134.93, 131.64, 129.04, 127.84, 127.03, 126.42, 125.96, 121.59, 33.88 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C16 H12 N3 O4 S, 342.0549; found 342.0547. 2-((3-(p-Tolyl)-1,2,4-oxadiazole-5-yl)methyl)benzo[d] isothiazol-3(2H )-one1,1-dioxide (4b) H3C

O

N N O

N S O O

Light white solid. Yield. 35 mg, 41 %. m.p. 143–144 ◦ C. Rf : 0.600 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3101, 2987, 2922, 1741 (C=O), 1338 (asymm-SO2 stretch), 1190 (symm-SO2 -stretch), 1654, 1591 (C=N), 1465, 1298, 1057, 902, 827.1 H NMR (400 MHz, DMSO-d6 ): δH = 8.42 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.13 (dt, J = 7.6 Hz, 1H), 8.06 (dt, J = 7.6 Hz, 1H), 8.07 (dt, J = 7.6 Hz, 2H), 7.87 (d, J = 6.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 2.37 (s, 3H).13 C NMR (100 MHz, DMSO-d6 ): δC = 174.04 (C=N), 167.74 (C=O), 158.20 (C=N), 141.76, 136.70, 136.30, 135.53, 129.80, 126.89, 125.67, 125.45, 122.68, 121.90, 33.49 (CH2 ), 20.98 (CH3 ). HRMS (ESI-TOF, [M+H]): calcd for C17 H14 N3 O6 S, 356.0705; found 356.0697. 2-((3-(4-Fluorophenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d]isothiazol-3(2H )-one1,1-dioxide (4c) F N N O

N O S O

O

Light white solid. Yield. 166 mg, 58 %. m.p. 134 − 135 ◦ C. Rf : 0.484 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3091, 3005, 2940, 1741 (C=O), 1342 (asymm-SO2 stretch), 1190 (symm-SO2 -stretch), 1595, 1579 (C=N), 1483, 1413, 1068, 852. 1 H NMR (300 MHz, CDCl3 ): δH = 8.13 (d, J = 7.6 Hz, 1H), 8.06 (dd, J = 8.4, 6.1 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 5.21 (s, 2H). 13 C NMR (100 MHz, CDCl3 ): δC = 172.75 (C=N), 167.96 (C=O), 164.67 (d, J = 250.5 Hz, C–F), 158.41 (C=N), 137.66, 135.43, 134.74, 129.86, 129.75, 126.75, 125.73, 122.44, 122.40, 121.38, 116.19, 115.89, 33.61 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C16 H11 N3 O4 SF, 360.0454; found 360.0443. 2-((3-(4-Chlorophenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d]isothiazol-3(2H )-one1,1-dioxide (4d) Cl N N O

N S O O

O

Light yellow solid.Yield.130 mg, 99 %. m.p.: 142–143 ◦ C. Rf : 0.571 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3091, 3009, 2943, 2918, 1739 (C=O), 1342 (asymm1192 (symm-SO2 -stretch), 1664, SO2 -stretch), 1595 (C=N), 1568, 1467,1410, 1271,1165, 1066. 1 H NMR (300 MHz, CDCl3 ): δH = 8.18 (m, 1H), 8.02-7.80 (m, 4H), 7.43 (m, 3H), 5.20 (s, 2H). 13 C NMR (100 MHz, DMSOd6 ): δC = 173.14 (C=N), 168.20 (C=O), 158.65 (C=N), 137.81, 135.71, 135.01, 129.39, 129.13, 126.92, 125.96, 124.87, 121.63, 33.83 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C16 H11 N3 O4 SCl, 376.0159; found 376.0151. 2-((3-(4-Iodophenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d]isothiazol-3(2H )-one1,1-dioxide (4e) I N N O

N O S O

O

Light yellow solid. Yield. 74 mg, 54 %. m.p.: 161–162 ◦ C. Rf : 0.500 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3088, 2943, 1922, 1739 (C=O), 1342 (asymmSO2 -stretch), 1190 (symm-SO2 -stretch), 1593, 1552 (C=N), 1467, 1404, 1315, 1057. 1 H NMR (400 MHz, CDCl3 ): δH = 8.43 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 7.2Hz, 1H), 8.13 (td, J = 7.6, 1.2 Hz, 1H), 8.06 (td, J = 7.6, 0.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.75 (d, J =8.4 Hz, 2H), 5.51 (s, 2H). 13 C NMR (100 MHz, DMSO-d6 ): δC = 173.08 (C= N),168.48 (C=O), 158.64 (C=N), 138.32, 137.88, 135.68, 135.00, 129.31, 126.97, 125.99, 125.90, 121.64, 98.49

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(C–I), 33.84 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C16 H11 N3 O4 SI, 467.9515; found 467.9522. 2-((3-(4-Bromophenyl)-1,2,4-oxadiazole-5-yl) methylbenzo[d]isothiazol-3 (2H )-one1,1-dioxide (4f) Br N N O

N O S O

O

Light white solid. Yield. 74 mg, 78 %. m.p.: 163–164 ◦ C. Rf : 0.606 (n-hexane:ethyl acetate; 1:1). IR (KBr, v:cm−1 ): 3090, 3007, 2943, 2918, 1739 (C=O), 1342 (asymm-SO2 stretch),1192 (symm-SO2 -stretch), 1595, 1566 (C=N), 1469, 1408, 1271, 1165, 1066. 1 H NMR (300 MHz, CDCl3 ): δH = 8.13 (d, J = 7.5 Hz, 1H), 7.99–7.86 (m, 5H), 7.58 (d, J = 8.4 Hz, 2H), 5.20 (s, 2H). 13 C NMR (75 MHz, CDCl3 ): δC, = 172.87 (C=N), 168.07 (C=O), 158.39 (C=N), 137.61, 135.44, 134.75, 132.11, 129.07, 126.71, 126.02, 125.73, 125.09, 121.39, 33.58 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C16 H11 N3 O4 SBr, 419.9654; found 419.9660. 2-((3-(4-Nitrophenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d]isothiazol-3(2H )-one1,1-dioxide (4g) O2N N N O

N O S O

O

Light white solid. Yield. 74 mg, 44 %. m.p.: 223 ◦ C (dec.). Rf : 0.606 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3095, 3005, 2945, 2850, 1739 (C=O), 1338 (asymmSO2 -stretch), 1190 (symm-SO2 -stretch), 1585, 1566 (C=N), 1465, 1413, 1271, 1105, 1068. 1 H NMR (400 MHz, CDCl3 ): δH = 8.16 (t, J = 11.6 Hz, 2H), 8.04–7.87 (m, 4H), 7.77 (t, J = 11.2 Hz, 2H), 5.24 (s, 2H). 13 C NMR (100 MHz, CDCl3 ): δC = 173.53 (C=N), 167.28 (C=O), 158.41 (C=N), 149.59, 137.65, 135.54, 134.84, 132.01, 128.64, 126.70, 125.82, 124.08, 121.45, 33.56 (CH2 ). HRMS (ESITOF, [M+H]): calcd for C17 H11 N4 O6 S, 367.0501; found 367.0497. 2-((3-(4-Trifluoromethylphenyl)-1,2,4-oxadiazole-5-yl) methyl) benzo [d] isothiazol-3(2H )-one1,1-dioxide (4h) F3C N N O

123

N O S O

O

Light yellow solid. Yield. 219 mg, 93 %. m.p.: 166–167 ◦ C. Rf : 0.697 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3093, 3005, 2945, 2850, 1737 (C=O), 1338 (asymmSO2 -stretch), 1190 (symm-SO2 -stretch), 1585, 1566 (C=N), 1487, 1417, 1273, 1170, 1114. 1 HNMR (300 MHz, CDCl3 ): δH = 8.16 (t, J = 8.7 Hz, 3H), 8.01–7.87 (m, 3H), 7.70 (d, J = 8.1 Hz, 2H), 5.21 (s, 2H). 13 C NMR (75 MHz, CDCl3 ): δC = 173.44 (C=N), 168.03 (C=O), 158.65 (C=N), 137.90, 135.71, 135.01, 133.53, 129.81, 129.34, 128.21, 126.96, 126.07, 126.02, 123.87 (q, J = 290.7 Hz, CF3 ), 33.82 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C17 H11 N3 O4 SF3 , 410.0422; found 410.0417. 2-((3-(4-(Methylthio)phenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d] isothiazol-3(2H )-one1,1-dioxide (4i) H3C

S N N O

N O S O

O

Light yellow solid. Yield. 105 mg, 66 %. m.p.: 153–154 ◦ C. Rf : 0.471 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3176, 3086, 2916, 2868, 1747 (C=O), 1329 (asymmSO2 -stretch), 1186 (symm-SO2 -stretch), 1658, 1595 (C=N), 1467, 1294,1126,970. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.16−8.10 (m, 1H), 8.02–7.84 (m, 5H), 7.27 (d, J = 11.6 Hz, 2H), 5.21 (s, 2H), 2.51 (s, 3H). 13 C NMR (100 MHz, DMSO-d6 ): δC = 173.15 (C=N), 171.11 (C=O), 159.57 (C=N), 157.25, 143.70, 137.87, 135.66, 134.96, 128.04, 126.92, 125.93, 122.61, 121.60, 33.86 (CH2 ), 15.24 (S– CH3 ). HRMS (ESI-TOF, [M+H]): calcd for C17 H14 N3 O4 S2 , 388.0426; found 388.0412. 2-((3-(4-(Methoxy)phenyl)-1,2,4-oxadiazole-5-yl)methyl) benzo[d] isothiazol-3(2H )-one1,1-dioxide (4j)

H3C

O N N O

N

O

O S O

Light white solid. Yield. 57 mg, 43 %. m.p.: 154–155 ◦ C. Rf : 0.457 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3090, 2997, 2916, 1753 (C=O), 1329 (asymmSO2 -stretch), 1188 (symm-SO2 -stretch), 1602, 1572 (C=N), 1483, 1425, 1305, 1255, 1172, 1105, 1064. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.38 (d, J = 7.6Hz, 1H), 8.16 (d,

Mol Divers (2015) 19:213–230

221

J = 7.6Hz, 1H), 8.10 (td, J = 7.6, 1.2 Hz, 1H), 8.03 (td, J = 8.0, 1.2 Hz, 1H), 7.88 (dt, J = 8.8, 4.8 Hz, 2.8 Hz, 2H), 7.06 (d, J = 7.2Hz, 2H), 5.43 (s, 2H), 3.79 (s, 3H). 13 C NMR (75 MHz, CDCl ): δ 3 C, = 172.55 (C=N), 168.10 (C=O), 161.20 (C–OCH3 ), 138.10, 135.61, 134.93 129.47, 125.95, 121.58, 118.84, 114.44, 55.62 (OCH3 ). HRMS (ESITOF, [M+H]): calcd for C17 H14 N3 O5 S, 372.0654; found 372.0642. 4-(5-((1,1-Dioxido-3-oxobenzo[d]isothiazol-2(3H )-yl) methyl)-1,2,4-oxadiazol-3-yl)benzonitrile (4k) NC

N N

O

O N O

S

O

Light yellow solid. Yield. 0.040 mg, 62 %. m.p.: 154–155 ◦ C. Rf : 0.457 (n-hexane:ethyl acetate; 1:1). IR (KBr) (νmax , cm−1 ): 3074, 2956, 2924, 2231 (C≡N), 1735 (C=O), 1664, 1597 (C=N), 1467, 1413, 1342 (asymm-SO2 -stretch), 1186 (symm-SO2 -stretch), 1062, 854. 1 H NMR (300 MHz, CDCl3 ): δH = 8.17 (t, J = 10.4 Hz, 3H), 8.04–7.87 (m, 3H), 7.77 (t, J = 11.2 Hz, 2H), 5.24 (s, 2H).13 C NMR (100 MHz, CDCl3 ): δC = 173.66 (C=N), 167.74 (C=O), 158.63 (C=N), 137.87, 135.77, 135.06, 132.85, 130.55, 128.39, 126.90, 126.01, 121.67, 118.34, 115.20 (C≡N), 33.80 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C17 H11 N4 O4 S, 367.0501; found 367.0497. Synthesis of N ,N  -oxadiazolylmethyl and N-substituted uracil derivatives (6a-c and 6e-j) and (7a-c and 7e-j) general procedure

ether:cold water; 1:1) ×4 and washed with brine solution (15 mL). The organic layer was dried over Na2 SO4 . Reaction mixture was concentrated in vacuo, and the crude residue was purified by flash column chromatography (n-hexane:ethyl acetate; 6:1) to give 6a as a yellow oil and 7a as a white solid. 6a: Yield. 30 mg, 39 %. Rf : 0.428, (n-hexane:ethyl acetate; 1:3). IR (KBr) (νmax , cm−1 ) : 3070, 2997, 2960, 2924, 2857, 1718 (C=O), 1676, 1597 (C=N), 1446, 1483, 1425, 1305, 1255, 1172, 1105, 1064. 1 H NMR (400 MHz, DMSOd6 ): δH = 8.06 (d, J = 7.6 Hz, 1H), 7.98-7.93 (m, 4H), 7.82 (s, 1H), 7.61–7.52 (m, 5H), 6.05 (d, J = 8.4 Hz, 1H), 5.49 (s, 2H), 5.41 (s, 2H). 13 C NMR (100 MHz, DMSOd6 ): δC = 175.55 (C=N), 175.39 (C=N), 167.65 (C=N), 167.59 (C=N), 161.59 (C=O), 150.68 (C=O), 145.07, 134.03, 132.56, 131.71, 131.61, 129.22, 129.16, 126.95, 126.91, 125.64, 40010125.53, 100.83, 44.79 (CH2) , 36.57 (CH2 ). LC–MS (80 eV) (m/z, %): 429 (100) [M+H]+ , 285 (9), 270 (5). HRMS (ESI-TOF, [M+H]): calcd for C22 H17 N6 O4 , 429.1311; found 429.1307. 7a: Yield.12 mg, 24 %. m.p.: 193–195 ◦ C. Rf : 0.171 (n-hexane:ethyl acetate; 1:3). IR (KBr) (νmax , cm−1 ): 3527 (N–H), 3149, 3095, 2823, 2872, 1728, 1714 (C=O), 1693, 1597 (C=N), 1460, 1386, 1357, 1253, 1197, 1101, 941, 904. 1 H NMR (400 MHz, DMSO-d ): δ 6 H = 11.56 (s, NH), 7.99 (d, J = 6.8Hz, 2H), 7.84 (d, J = 8,1 Hz, 1H), 7.58 (q, J = 8.5 Hz, 3H), 5.74 (s, 1H), 5.34 (s, 2H). 13 C NMR (100 MHz, DMSO-d ): δ 6 C = 176.52 (C=N), 168.41 (C=N), 164.33 (C=O), 151.51 (C=O), 146.21, 132.49, 130.03, 127.74, 126.32, 102.52, 44.42 (CH2) . LC–MS (80 eV) (m/z, %): 271 (64) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C13 H11 N4 O3 , 271.0831; found 271.0838. 1,3-Bis((5-(p-tolyl)-1,2,4-oxadiazol-3-yl)methyl)pyrimidine -2,4(1H ,3H )-dione (6b) and 3-((3-(p-tolyl)-1,2,4oxadiazol-5-yl)methyl)pyrimidine-2,4(1H ,3H )-dione (7b)

1,3-Bis((5-phenyl-1,2,4-oxadiazol-3-yl)methyl)pyrimidine2,4(1H ,3H ) dione (6a) and 3-((5-phenyl-1,2,4-oxadiazol3-yl)methyl)pyrimidine-2,4(1H,3H)-dione (7a)

N

O

O

O

N

N N

O N

6a

N

O

O

N

O

N

N

O HN

N

O N

O

N

N O N

O N

HN

O

N O N

N

7a

A mixture of uracil 5 (0.020 g, 0.179 mmol) and 5(chloromethyl)-3-phenyl-1,2,4-oxadiazole 2a (0.070 g, 0.358 mmol) with K2 CO3 (0.025 g, 0.179 mmol) in DMF (5mL) was mixed at room temperature for 5h and monitored by TLC. The reaction mixture was then extracted with (diethyl

H3C

6b

CH3

7b

CH3

6b: White solid. Yield. 38 mg, 35 %. Rf : 0.486 (n-hexane: ethyl acetate; 1:3). m.p.: 133–134 ◦ C. IR (KBr) (νmax , cm−1 ): 3078, 3034, 2985, 2949, 2922, 2854, 2815, 1730 (C=O), 1672, 1597 (C=N), 1535, 1481, 1454, 1411, 1361, 1340, 1242, 943, 891, 746. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.04 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 14.0, 8.0 Hz, 4H), 7.31 (t, J = 7.6 Hz, 4H), 6.04 (d, J = 8.0 Hz, 1H), 5.46 (s, 2H, CH2 ), 5.38 (s, 2H, CH2 ), 2.378 (s, 3H, CH3 ), 2.370

123

222

Mol Divers (2015) 19:213–230

(s, 3H, CH3 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.12 (C=N), 175.96 (C=N), 168.37 (C=N), 168.30 (C=N), 162.35 (C=O), 151.42 (C=O), 145.83, 142.43, 142.30, 130.52, 130.46, 127.66, 127.62, 123.64, 123.53, 101.58, 45.53 (CH2 ), 37.29 (CH2 ), 21.75 (2XCH3 ). LC–MS (80 eV) (m/z, %): 457 (100) [M+H]+ , 154 (6). HRMS (ESI-TOF, [M+H]): calcd for C24 H21 N6 O4 , 457.1624; found 457.1627. 7b: White solid. Yield. 24 mg, 35 %. Rf : 0.273 (nhexane:ethyl acetate; 1:3). m.p.: 201–202 ◦ C. IR (KBr) (νmax , cm−1 ): 3446 (N–H), 2982, 2941, 2922, 1735 (C=O), 1678, 1595 (C=N), 1485, 1344, 1107, 895, 736. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.54 (s, 1H, NH), 7.98 (dd, J = 16.0, 8.4 Hz, 3H), 7.37 (d, J = 8.0 Hz, 2H), 5.73 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H, CH2 ), 2.38 (s, 3H, CH3 ). 13 C NMR (100 MHz, DMSO-d ): δ 6 C = 175.33 (C=N), 168.37 (C=N), 164.32 (C=O), 151.51 (C=O), 146.21, 142.47, 130.56, 127.69, 123.56, 102.51, 44.39 (CH2 ), 21.76 (CH3 ). HRMS (ESI-TOF, [M+H]): calcd for C14 H18 N7 O4 , 285.0988; found 285.0983.

1348, 1242, 1165, 943, 844,817. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.55 (s, 1H, NH), 8.06-8.02 (m, 2H), 7.84 (d, J = 8.0Hz, 1H), 7.41 (t, J = 8.8 Hz, 2H), 5.73 (d, J = 7.6 Hz, 1H), 5.34 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 175.88 (C=N), 166.85 (C=N), 163.96 (d, J = 247.7 Hz, C–F), 163.54 (C=O), 150.74 (C=O), 145.41, 129.64, 129.55, 122.15, 116.55, 116.33, 101.76, 43.61 (CH2 ). LC–MS (80 eV) (m/z, %): 289(100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C13 H10 FN4 O3 , 289.0737; found 289.0735. 1,3-Bis((3-(4-iodophenyl)-1,2,4-oxadiazol-5yl)methyl)pyrimidine 2,4 (1H,3H)-dione (6e) and 3-((5-(4-iodophenyl)-1,2,4-oxadiazol-3yl)methyl)pyrimidine-2,4 (1H,3H)-dione (7e)

N

1,3-Bis((3-(4-fluorophenyl)-1,2,4-oxadiazol-5ylmethyl) pyrimidine-2,4 (1H,3H)-dione (6c) and 3-((5-(4-fluoro phenyl)-1,2,4-oxadiazol-3-yl)methyl)pyrimidine-2,4(1H, 3H)-dione (7c)

N

O

O

O

N

O

N

N

F

I

HN

N

O N

6c

O

N

N O N

F

7c F

6c: White solid. Yield. 38 mg, 31 %. Rf : 0.555 (n-hexane:ethyl acetate; 1:3). m.p.: 123–124 ◦ C. IR (KBr) (νmax , cm−1 ): 3080, 3018, 2951, 2924, 2850, 2762, 1730 (C=O), 1604, 1581 (C=N), 1672, 1483, 1450, 1419, 1359, 1342, 1240, 893. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.06– 7.98 (m, 5H), 7.41–7.34 (m, 4H), 6.05 (d, J =8.4 Hz, 1H), 5.48 (s, 2H, CH2 ), 5.40 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.42 (C=N), 176.25 (C=N), 167.63 (C =N), 167.56 (C=N), 164.73 (d, J = 248.4 Hz, C–F), 164.67 (d, J = 248.4 Hz, C–F), 162.34 (C=O), 151.4 (C=O), 145.81, 130.36, 130.30, 130.27, 130.21, 122.98, 122.95, 122.88, 122.84, 117.28, 117.20, 117.06, 116.98, 101.61, 45.53 (CH2 ), 37.31 (CH2 ). LC–MS (80 eV) (m/z, %): 465 (100)[M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C22 H15 F2 N6 O4 , 464.1123; found 465.1130. 7c: White solid. Yield.24 mg, 32 %. Rf : 0.444 (nhexane:ethyl acetate; 1:3). m.p.: 226–1227 ◦ C (dec). IR (KBr) (νmax , cm−1 ): 3537 (N–H), 3109, 3016, 2999, 2926, 2872, 1712 (C=O), 1664, 1608 (C=N), 1483, 1460, 1417,

123

O

O

O

N

N N

O HN

N

O N

6e

O

N

N O N

I

7e

I

6e: White solid. Yield. 74 mg, 70 %. Rf : 0.645 (n-hexane:ethyl acetate; 1:3). m.p.: 82–83 ◦ C. IR (KBr) (νmax , cm−1 ): 3091, 2956, 2852, 2802, 2754, 1757, 1701 (C=O), 16647.70 (C=N), 1591, 1558 (C=N), 1452, 1400, 1329, 1298, 1247, 1180, 1107, 1057, 833, 786. 1 H NMR (400 MHz, DMSO-d6 ): δH = 7.99 (d, J = 8.4 Hz, 1H), 7.86 (t, J =8.2 Hz, 4H), 7.70–7.47 (m, 4H), 6.00 (d, J = 8.4 Hz, 1H), 5.43 (s, 2H, CH2 ), 5.35 (s, 2H, CH2 ). 13 CNMR (100 MHz, DMSO-d6 ): δC = 176.57 (C=N), 176.41 (C=N), 167.93 (C =N), 167.87 (C=N), 162.32 (C=O), 151.40 (C=O), 145.82, 138.94, 138.87, 129.43, 129.40, 125.83, 125.72, 101.61, 100.03 (C–I), 99.89 (C–I), 45.51 (CH2 ), 37.27 (CH2 ). LC– MS (80 eV) (m/z, %): 681(35) [M+H]+ , 441(21). HRMS (ESI-TOF, [M+H]): calcd for C22 H15 N6 O4 I2 , 680.9244; found 680.9247. 7e: White solid. Yield. 25 mg, 41 %. Rf : 0.290 (nhexane:ethyl acetate; 1:3). m.p.: 210–211 ◦ C. IR (KBr) (νmax , cm−1 ): 3441 (N–H), 3090, 2956, 2920, 1722 (C=O), 1666, 1591 (C=N), 1562, 1450, 1402, 1336, 1273, 1234, 1180, 1107, 1006, 808, 740. 1 H NMR (400 MHz, DMSOd6 ): δH = 11.54 (s, 1H), 7.95 (d, J =8.4 Hz, 2H), 7.83 (dd, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 5.73 (d, J = 7.6 Hz, 1H), 5.34 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSOd6 ): δC = 176.75 (C=N), 167.95 (C=N), 164.30 (C=O), 151.49 (C=O), 146.18, 138.94, 129.50, 125.77, 102.54, 100.00 (C–I), 44.37 (CH2) . HRMS (ESI-TOF, [M+H]): calcd for C13 H9 N4 O3 I, 395.9720; found 395.9718.

Mol Divers (2015) 19:213–230

223

1,3-Bis((3-(4-bromophenyl)-1,2,4-oxadiazol-5yl)methyl) pyrimidine-2,4 (1H,3H)-dione (6f) and 3-((5-(4bromophenyl)-1,2,4-oxadiazol-3-yl)methyl)pyrimidine-2,4 (1H,3H)-dione (7f)

N

O

O N

O

O

N

N

O

N

HN

N O N

N O N

Br

Br 6f

Br

7f

6f: White solid. Yield. 45 mg, 46 %. Rf : 0.633 (n-hexane: ethyl acetate; 1:3). m.p.: 151–152 ◦ C. IR (KBr) (νmax , cm−1 ): 3095, 3057, 2985, 2929, 1722 (C=O), 1672, 1649 (C=N), 1597, 1566, 1471, 1448, 1406, 1359, 1342, 1265, 1109, 1012, 808, 740. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.05 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 14.0, 8.4 Hz, 4H), 7.72 (t, J = 8.0 Hz, 4H), 6.05 (d, J = 8.0 Hz, 1H), 5.49 (s, 2H, CH2 ), 5.41 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSOd6 ): δC = 176.60 (C=N), 176.43 (C=N), 167.72 (C=N), 167.66 (C=N), 162.32 (C=O), 151.41 (C=O), 145.81, 133.09, 133.02, 129.64, 129.60, 126.11, 125.99, 125.57, 125.46, 101.61, 45.52 (CH2 ), 37.28(CH2 ). LC–MS:(80 eV): (m/z, %): 587 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C22 H15 N6 O79 4 Br2 , 584.9522; found 584.9526. 7f: White solid. Yield.10 mg, 18 %. Rf : 0.466 (nhexane:ethyl acetate; 1:3). m.p.: 255–256 ◦ C. (dec.). IR (KBr) (νmax , cm−1 ): 3423 (N–H), 3090, 3039, 3016, 2980, 2924, 1703, 1664 (C=O), 1602, 1552 (C=N), 1465, 1421, 1334, 1249, 1199, 1114, 1008, 949, 732. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.55 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 5.73 (d, J = 7.6 Hz, 1H), 5.34 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.82 (C=N), 167.74 (C=N), 164.30 (C=O), 151.50 (C=O), 146.18, 133.15, 129.73, 126.09, 125.53, 102.54, 44.38 (CH2 ). LC–MS: (80 eV): (m/z, %): 351 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C13 H10 BrN4 O3 , 348.9931; found 348.9936. 1,3-Bis((3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl)methyl) pyrimidine-2,4 (1H,3H)-dione (6g) and 3-((5-(4nitrophenyl)-1,2,4-oxadiazol-3-yl)methyl)pyrimidine2,4(1H,3H)-dione (7g)

N

O2N

O

O

N

O

N

N

O HN

N

O N

6g

O

N

N O N

NO2

7g

NO2

6g: White solid. Yield. 40 mg, 37 %. Rf : 0.300 (n-hexane: ethyl acetate; 1:3). m.p.: 192–193 ◦ C. IR (KBr) (νmax , cm−1 ): 3099, 3053, 3009, 2958, 2808, 2789, 1720 (C=O), 1672, 1583 (C=N), 1516, 1417, 1388, 1336, 1313, 1292, 1103, 966, 794, 707. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.40–8.32 (m, 4H), 8.26–8.17 (m, 4H), 8.06 (d, J = 8.0 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H), 5.52 (s, 2H, CH2 ), 5.44 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 177.18 (C=N), 176.97 (C=N), 167.12 (C=N), 167.07 (C=N), 162.28 (C=O), 156.19 (C=O), 151.42, 149.93, 149.87, 145.81, 132.11, 131.99, 129.13, 129.10, 125.16, 125.10, 101.65, 45.54 (CH2 ), 37.30 (CH2 ). HRMS (ESI-TOF, [M+H]): calcd for C22 H15 N8 O8 , 519.1007; found 519.1003. 7g: White solid. Yield. 10 mg, 15 %. Rf : 0.166 (n-hexane: ethyl acetate; 1:3). m.p.: 277–278 ◦ C (dec.). IR (KBr) (νmax , cm−1 ): 3456 (N–H), 3155, 3124, 3097, 3051, 2958, 2854, 1707 (C=O), 1680, 1579 (C=N), 1514, 1462, 1404, 1338, 1278, 1103, 1008, 935, 869, 771. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.56 (s, 1H, NH), 8.40 (d, J =8.4 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 5.75 (dd, J = 8.0, 2.0 Hz, 1H), 5.38 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.58 (C=N), 166.38 (C=N), 163.52 (C=O), 150.74 (C=O), 149.22, 145.38, 131.30, 128.46, 124.47, 101.81, 43.62 (CH2 ). LC–MS (80 eV) (m/z, %): 315 (20) [M]+ , 271 (100) [M–NO2 ]. HRMS (ESI-TOF, [M+H]): calcd for C13 H10 N5 O5 , 316.0676; found 316.0680. 1,3-Bis((3-(4-(trifluoromethyl)phenyl)1,2,4oxadiazolyl) methyl) pyrimidine -2,4(1H,3H)-dione (6h) and 3-((5-(4(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl) pyrimidine-2,4 (1H,3H)-dione (7h)

N

F3C

O

O

O

N

N N

O HN

N

O N

6h

O

N

N O N

CF3

7h

CF3

6h: White solid. Yield. 61 mg, 57 %. Rf : 0.625 (n-hexane: ethyl acetate; 1:3). m.p.: 190–191 ◦ C. IR (KBr) (νmax , cm−1 ): 3095, 3064, 3001, 2968, 2928, 2852, 1726, 1680 (C=O), 1604, 1579 (C=N), 1535, 1446, 1419, 1327, 1157, 1103, 962, 815, 758. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.16 (dd, J = 14.8, 8.0 Hz, 3H), 8.08 (d, J = 8.0 Hz, 2H), 7.86 (t, J = 8.8 Hz, 4H), 6.08 (d, J = 8.4 Hz, 1H), 5.53 (s, 2H, CH2 ), 5.45 (s, 2H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.27 (C=N), 176.10 (C=N), 166.75 (C=N), 166.69 (C=N), 161.64 (C=O), 150.75 (C=O), 145.14, 132.08, 131.98, 131.76, 131.66, 131.44, 131.34, 131.12, 131.02, 129.53, 129.43, 127.86, 127.82, 126.18 (q, J =

123

224

Mol Divers (2015) 19:213–230

7.6Hz, CF3 ), 123.70 (q, J = 270.5 Hz, CF3 ), 100.96, 44.86 (CH2 ), 36.59 (CH2 ). LC–MS: (80 eV): (m/z, %): 565 (50) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C24 H15 F6 N6 O4 , 565.1059; found 565.1053. 7h: White solid. Yield. 10 mg, 15 %. Rf : 0.406 (nhexane:ethyl acetate; 1:3). m.p.247 ◦ C (dec.). IR (KBr) (νmax , cm−1 ): 3410 (N–H), 3097, 3007, 2956, 2854, 2808, 1737 (C=O), 1695, 1656 (C=N), 1514, 1462, 1417, 1329, 1259, 1180, 1010, 941, 850, 758. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.55 (s, 1H, NH), 8.21 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 5.74 (d, J = 7.6 Hz, 1H), 5.36 (s, 1H, CH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.36 (C=N), 166.71 (C=N), 163.53 (C=O), 150.74 (C=O), 145.40, 129.42, 128.02, 127.91, 127.85, 127.80, 123.72 (q, J = 270.5 Hz, CF3 )„ 101.79, 43.63 (CH2 ). LC–MS: (80 eV): (m/z, %): 339 (100) [M+H], 223(45). HRMS (ESI-TOF, [M+H]): calcd for C14 H10 F3 N4 O3 , 339.0705; found 339.0709.

DMSO-d6 ): δH = 11.54 (s, 1H, NH), 7.86 (dd, J = 6.4, 1.6 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 5.73 (d, J = 7.6Hz, 1H), 5.32 (s, 2H, CH2 ), 2.52 (s, 3H, SCH3 ).13 C NMR (100 MHz, DMSO-d6 ): δC = 175.59 (C=N), 167.31 (C=N), 163.52 (C=O), 150.72 (C=O), 145.41, 143.20, 127.29, 125.68, 121.53, 101.73, 43.61 (CH2 ), 13.92 (SCH3 ). LC–MS:(80 eV):(m/z, %): 317 (100) [M+H], 194.1(30). HRMS (ESI-TOF, [M+H]): calcd for C14 H13 N4 O3 S, 317.0708; found 317.0700. 1-((3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)-3((3-(4-(methylthio)phenyl)-1,2,4-oxadiazol-5-yl)methyl) pyrimidine-2,4(1H,3H)-dione (6j) and 3-((5-(4methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)pyrimidine2,4(1H,3H)-dione (7j)

N

1,3-Bis((3-(4-(methylthio)phenyl)-1,2,4-oxadiazol-5-yl) methyl) pyrimidine -2,4(1H,3H)-dione (6i) and 3-((5-(4-(methylthio)phenyl)-1,2,4-oxadiazol-3yl)methyl)pyrimidine-2,4(1H,3H)-dione (7i)

N

S

O

O N

CH3

O

N

N

O HN

N

O N

6i

O

N

N O N

S H3C

7i

S H3C

6i: Yellow oil. Yield. 40 mg, 37 %. Rf : 0.625 (n-hexane: ethyl acetate; 1:3). IR (KBr) (νmax , cm−1 ): 3091, 3055, 2989, 2924, 1718 (C=O), 1668, 1595 (C=N), 1558, 1473, 1408, 1344, 1240, 1186, 1089, 962, 808, 786. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.08 (d, J = 8.0 Hz, 1H), 7.90 (dd, J =14.4, 8.4 Hz, 4H), 7.40 (t, J = 8.4 Hz, 4H), 6.08 (d, J = 8.4 Hz, 1H), 5.50 (s, 2H, CH2 ), 5.42 (s, 2H, CH2 ), 2.57 (s, 6H, 2XSCH3 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.16 (C=N), 176.01 (C=N), 168.07 (C=N), 168.01 (C=N), 162.33 (C=O), 151.40 (C=O), 145.81, 144.01, 143.86, 128.02, 127.98, 126.39, 126.36, 122.29, 122.26, 101.57, 45.51 (CH2 ), 37.28 (CH2 ), 14.70 (SCH3 ). LC–MS: (80 eV): (m/z, %): 521 (100) [M+H]+ , 276 (20), 194 (41), 611 (45). HRMS (ESI-TOF, [M+H]): calcd for C24 H21 N6 O4 S2 , 521.1066; found 521.1060. 7i: White solid. Yield. 27 mg, 41 %. Rf : 0.531 (nhexane:ethyl acetate; 1:3). m.p. 228–229 ◦ C. IR (KBr) (νmax , cm−1 ): 3425 (N–H), 3136, 3113, 2958, 2924, 2872, 2806, 1703 (C=O), 1656, 1597 (C=N), 1558, 1467, 1383, 1298, 1251, 1199, 1085, 900, 827, 738. 1 H NMR (400 MHz,

123

O

O

O CH3

O

N

N N

O HN

N

O N

6j

O

N

N O N

O H3C

7j

O H3C

6j: White solid.Yield. 35 mg, 32 %. Rf : 0.482 (n-hexane: ethyl acetate; 1:3). m.p.: 137–138 ◦ C. IR (KBr) (νmax , cm−1 ): 3055, 2982, 2941, 2839, 1735 (C=O), 1573, 1678 (C=N), 1485, 1446, 1357, 1303, 1255, 1089, 945, 898, 777. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.03 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 14.8, 8.8 Hz, 4H), 7.05 (t, J = 8.8 Hz, 4H), 6.03 (d, J = 7.6 Hz, 1H), 5.44 (s, 2H, CH2 ), 5.36 (s, 2H, CH2 ), 3.82 (s, 3H, OCH3 ), 3.81 (s, 3H, OCH3 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 175.93 (C=N), 175.78 (C=N), 168.10 (C=N), 168.03 (C=N), 162.53 (C=N), 162.45 (C=O), 162.35 (C–OCH3 ) 151.41 (C=O), 145.83, 129.44, 129.39, 118.67 118.55, 115.38, 115.31, 101.57, 56.08 (OCH3 ), 56.05 (OCH3 ), 45.52 (CH2 ), 37.29 (CH2 ). LC–MS: (80 eV):(m/z, %):489 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C24 H21 N6 O6 , 489.1523; found 489.1521. 7j: White solid.Yield. 55 mg 83 %. Rf : 0.241 (nhexane:ethyl acetate; 1:3). m.p.: 174–175 ◦ C. IR (KBr) (νmax , cm−1 ): 3448 (N–H), 3174, 3080, 2958, 2924, 2852, 1734 (C=O), 1689, 1612 (C=N), 1579, 1483, 1431, 1383, 1344, 1257, 1174, 1030, 895, 839. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.54 (s, 1H, NH), 7.91 (t, J =8.8 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.12-7.07 (m, 2H), 5.74 (dd, J = 7.2, 1.2 Hz, 1H), 5.30 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H, OCH3 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 175.50 (C=N), 175.35 (C=N), 168.77 (C=N), 167.33 (C=N), 163.52 (C=O), 161.75 (C–OCH3 ), 150.72 (C=O), 145.43, 128.69, 117.80, 114.63, 101.72, 55.31 (CH3 ), 43.60 (CH2 ). LC– MS: (80 eV): (m/z, %): 301 (60) [M+H], 208 (60),193

Mol Divers (2015) 19:213–230

225

(45). HRMS (ESI-TOF, [M+H]): calcd for C14 H13 N4 O4 , 301.0937; found 301.0928. Synthesis of N-oxadiazolylmethyl-substituted 5-aminouracil derivatives (9a–e, 9g–i) general procedure 5-Amino-1,3-bis((3-phenyl-1,2,4-oxadiazol-5yl)methyl)pyrimidine-2,4(1H,3H)-dione (9a) O N

N

N

N

N O

O

O N

NH2

A mixture of 5-aminouracil 8 (0.181 g, 1.43 mmol) and K2 CO3 (0.203 g, 1.47 mmol) in DMF (5mL) was mixed at room temperature for 2h till a change of color was observed, 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole 2a (0.291 g, 1.50 mmol) was added in one portion, and stirring was continued overnight and monitored by TLC. The reaction mixture was extracted with (diethyl ether:cold water; 1:1) × 4 and washed with brine solution (15 mL). The organic layer was dried with Na2 SO4 . Reaction mixture was concentrated in vacuo, and the crude residue was purified by flash column chromatography (n-hexane:ethyl acetate; 6:1) to give 9a as a white solid.Yield. 73 mg, 11 %. m.p.: 181–182 ◦ C. Rf : 0.625 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3396, 3315, 3265 (NH2 ), 3192, 3072, 2995, 2941, 1718 (C=O), 1662, 1597, 1535 (C=N), 1481, 1444, 1392, 1309, 1224, 1116, 1072, 962, 893, 717, 557. 1 H NMR (400 MHz, DMSOd6 ): δH = 7.99 (t, J = 1.2 Hz, 1H), 7.97 (t, J = 1.2 Hz, 1H), 7.95 (t, J = 1.2 Hz, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.63–7.50 (m, 6H), 7.18 (s, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 4.65 (br s, 2H, NH2 ). 13 C NMR (100 MHz, DMSOd6 ): δC = 176.47 (C=N), 176.44 (C=N), 168.43 (C=N), 168.36 (C=N), 160.36 (C=O), 149.59 (C=O), 132.45, 132.38, 129.99, 129.94, 127.72, 127.69, 126.42, 126.36, 123.32, 120.00, 45.23 (CH2 ), 37.88(CH2 ). LC–MS: (80 eV): (m/z, %): 444 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C22 H18 N7 O4 , 444.1420; found 444.1424. 5-Amino-1,3-bis((3-(p-tolyl)-1,2,4-oxadiazol-5-yl) methyl)pyrimidine 2,4 (1H,3H)-dione (9b)

1612 (C=N), 1597, 1477, 1410, 1359, 1220, 1018, 954, 895, 779, 677. 1 H NMR (400 MHz, DMSO-d6 ): δH = 7.84 (q, J = 7.9 Hz, 4H), 7.33 (t, J = 16.8 Hz, 4H), 7.16 (s, 1H), 5.42 (s, 2H), 5.38 (s, 2H), 4.56 (s, 2H), 2.38 (s, 3H), 2.35 (s, 3H). 13 C NMR (100 MHz, DMSO-d6 ): δC = 177.51 (C=N), 175.38 (C=N), 175.27 (C=N), 167.53 (C=N), 167.36 (C=N), 159.09 (C=O), 148.51 (C=O), 141.52, 141.29, 129.70, 129.62, 126.86, 126.81, 126.79, 123.20, 123.05, 122.83, 122.75, 119.8, 44.52 (CH2 ), 37.11 (CH2 ), 20.97 (CH3 ), 20.94 (CH3 ). LC–MS: (80 eV): (m/z, %): 472 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C24 H22 N7 O4 , 472.1733; found 472.1730. 5-Amino-1,3-bis((3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl) methyl) pyrimidine-2,4(1H,3H)-dione (9c) O F

N

N

N

NH2

White solid. Yield. 35 mg, 10 %. m.p.: 199–200 ◦ C (dec.). Rf : 0.593 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3433, 3342 (NH2 ), 3192, 3088, 3022, 2989, 2881, 1708 (C=O), 1647, 1639 (C=N), 1606, 1581,1481, 1417,1352, 1234, 1157, 1095, 910, 750. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.06 − 7.97 (m, 4H), 7.38 (dd, J = 17.2, 8.8 Hz, 4H), 7.16 (s, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 4.55 (br s, 2H, NH2 ). 13 C NMR (100 MHz, DMSO-d ): δ 6 C = 176.60 (C=N), 176.58 (C=N), 167.63 (C=N), 167.57 (C=N), 165.96 (C=N), 165.90 (C=O), 164.72 (d, J = 248.4 Hz, C–F), 164.67 (d, J = 247.6 Hz, C–F), 149.57 (C=O), 130.31 (q, J = 3.8 Hz, C–F), 123.51, 123.00, 122.97, 122.95, 122.92, 119.71, 117.29, 117.23, 117.07, 116.01, 45.20 (CH2 ), 37.86 (CH2 ). LC–MS: (80 eV): (m/z, %):480 (100) [M+H]+ . HRMS (ESITOF, [M+H]): calcd for C22 H16 N7 O4 F2 , 480.1232; found 480.1222. 5-Amino-1,3-bis((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl) methyl) pyrimidine-2,4(1H,3H)-dione (9d) O Cl

N

N

N

N

N

Cl

O N O NH2

O H3C

F

O N O

N O

N O N

N

N

N

CH3

O N O

N O NH2

White solid. Yield. 50 mg 11 %. m.p.: 194–195 ◦ C.Rf : 0.531 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3385, 3311, 3257 (NH2 ), 3194, 3153, 2953, 2852, 1720 (C=O), 1664,

White solid. Yield. 50 mg 10 %. m.p.: 199–200 ◦ C. Rf : 0.628 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3429, 3340 (NH2 ), 3194, 3082, 3026, 2989, 2958, 2929, 1701 (C=O), 1604, 1593 (C=N), 1568, 1473, 1408, 1350, 1311, 1276, 1213, 1091, 954, 746. 1 H NMR (400 MHz, DMSO-d6 ): δH = 7.96 (dd, J = 14.4, 8.4 Hz, 4H), 7.59 (t, J = 8.8 Hz, 4H), 7.16

123

226

Mol Divers (2015) 19:213–230

(s, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 4.53 (br s, 2H, NH2 ). 13 C NMR (100 MHz, DMSO-d ): δ = 176.75 (C = N), 6 C 167.63 (C=N), 167.57 (C=N), 160.34 (C=O), 149.56 (C=O), 137.20, 137.11, 130.17, 130.11, 129.53, 129.50, 125.26, 125.20, 123.51, 119.73, 45.20 (CH2 ), 37.83 (CH2 ). LC– MS (80 eV) (m/z, %): 512 (100) [M+H]+ . HRMS (ESITOF, [M+H]): calcd for C22 H16 N7 O4 Cl2 , 512.0641; found 512.0624. 5-Amino-1,3-bis((3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl) methyl) pyrimidine-2,4(1H,3H)-dione (9e) O I

N

N

N

N

N O

O

I

O N

NH2

White solid. Yield. 76 mg, 10 %. m.p.: 224–225 ◦ C (dec.). Rf : 0.667 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3431, 3340 (NH2 ), 3194, 3086, 2989, 2958, 2852, 1708 (C=O), 1672, 1643 (C=N), 1589, 1467, 1402, 1344, 1269, 1168, 1105, 910, 742. 1 H NMR (400 MHz, DMSO-d6 ): δH = 7.88 (t, J = 8.4 Hz, 4H), 7.70 (dd, J = 14.8, 8.8, Hz, 4H), 7.12 (s, 1H), 5.41 (s, 2H), 5.37 (s, 2H), 4.52 (br s, 2H, NH2 ).13 C NMR (100 MHz, DMSO-d6 ): δC = 176.55 (C=N), 176.38 (C=N), 167.92 (C=N), 167.86 (C=N), 162.29 (C=O), 151.38 (C=O), 145.79 (C=N), 138.92, 138.85, 129.41, 125.82, 125.71, 101.59, 100.00, 99.85 (C–I), 45.50 (CH2 ), 37.26 (CH2 ). LC–MS: (80 eV): (m/z, %): 696 (20) [M+H]+ 695 (62). HRMS (ESI-TOF, [M+H]): calcd for C22 H16 N7 O4 I2 , 695.9353; found 695.9351.

%): 534 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C22 H16 N9 O8 , 534.1122; found 534.1114. 5-Amino-1,3-bis((3-(4-(trifluoromethyl)phenyl)-1,2,4oxadiazol-5-yl)methyl)pyrimidine-2,4(1H,3H)-dione (9h) O F3C

N

N

N

N

CF3

O N O

N O NH2

White solid. Yield. 70 mg, 11 %. m.p.: 221–222 ◦ C.Rf : 0.457 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3435, 3344 (NH2 ), 3192, 3090, 2987, 2943, 1710 (C=O), 1647, 1599 (C=N) 1483, 1431, 1136, 1332, 1018, 866, 759. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.17 (dd, J =15.2, 8.4 Hz, 4H), 7.88 (dd, J = 10.4, 8.4 Hz, 4H), 7.18 (s, 1H), 5.47 (s, 2H, CH2 ), 5.43 (s, 2H, CH2 ), 4.58 (br s, 2H, NH2 ). 13 C NMR (100 MHz, DMSO-d6 ): δC = 177.11 (C=N), 177.10 (C=N), 167.43 (C=N), 167.37 (C=O), 160.34 (C=O), 149.55 (C=N), 132.38, 132.31, 132.06, 130.22, 130.17, 128.57, 128.54, 126.95, 126.91, 126.88, 126.84, 125.75, 123.53, 123.04, 119.74, 45.25 (CH2 ), 37.81 (CH2 ). LC–MS:(80 eV): (m/z, %): 580 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C24 H16 N7 O4 F6 , 580.1168; found 580.1153. 5-Amino-1,3-bis((3-(4-(methylthio)phenyl)-1,2,4oxadiazol-5-yl)methyl) pyrimidine-2,4(1H,3H)-dione (9i) O

5-Amino-1,3-bis((3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl) methyl) pyrimidine-2,4(1H,3H)-dione (9g)

H3C

S

N

N

N

N O N O

N O

S

CH3

NH2 O O2N

N

N

N

N

NO2

O N O

N O NH2

Orange solid. Yield. 80 mg, 12 %. m.p.: 113–114 ◦ C.Rf : 0.589 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3454, 3362 (NH2 ), 3090, 3036, 2953, 1708 (C=O), 1649, 1591 (C=N), 1521, 1415, 1342, 1301, 1220, 1103, 1014, 854, 725. 1 H NMR (400 MHz, DMSO-d6 ): δH = 8.35 (t, J = 8.8, Hz, 4H), 8.21 (dd, J = 13.2, 8.4, Hz, 4H), 7.17 (s, 1H), 5.76 (s, 1H), 5.48 (s, 2H), 5.44 (s, 2H), 4.56 (br s, 2H, NH2 ).13 C NMR (100 MHz, DMSO-d6 ): δC = 177.33 (C=N), 177.31 (C=N), 167.14 (C=N), 160.33 (C=O), 149.92 (C=O), 149.51 (C=N), 132.13, 132.06, 129.15, 129.12, 125.17, 125.11, 123.56, 119.70, 45.25 (CH2 ), 37.84 (CH2 ). LC–MS: (80 eV): (m/z,

123

White solid. Yield. 45 mg, 10 %. m.p.: 187–188 ◦ C.Rf : 0.705 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3389, 3313 (NH2 ), 3194, 3072, 2949, 2866, 2835, 1716 (C=O), 1662, 1593 (C=N), 1473, 1408, 1359, 1230, 1217, 1089, 1016, 885, 788. 1 H NMR (400 MHz, DMSO-d6 ): δH = 7.88 (d, J =8.4 Hz, 2H), 7.84 (d, J =8.4 Hz, 2H), 7.36 (t, J = 9.0 Hz, 4H), 7.15 (s, 1H), 5.42 (s, 2H), 5.38 (s, 2H), 4.55 (s, 2H), 2.535 (s, 3H), 2.530 (s, 3H). 13 C NMR (400 MHz, DMSO-d6 ): δC = 176.33 (C=N), 176.30 (C=N), 168.08 (C=N), 168.01 (C=O), 160.35 (C=N), 149.55 (C=O), 143.96, 143.84, 128.04, 128.01, 126.41, 126.36, 123.48, 122.40, 122.33, 119.76, 45.20 (CH2 ), 37.83 (CH2 ), 14.70 (SCH3 ). LC–MS: (80 eV) :(m/z, %):536 (100) [M+H]+ . HRMS (ESITOF, [M+H]): calcd for C24 H22 N7 O4 S2 , 536.1125; found 536.1163.

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227

Synthesis of aryl-substituted 5-(benzylideneamino) pyrimidine-2,4-diones (11a-g) as described in the literature [26, 27] general procedure (E)-5-((4-Methylbenzylidene)amino) pyrimidine-2, 4(1H,3H)-dione (11a) O

HN

O

N

HN

(E)-4-(((2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5yl)imino) methyl) benzonitrile (11b)

Yellow solid. Yield. 322 mg 30 %. m.p.: 331–332 ◦ C. Rf : 0.542 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3198, 3169 (N– H), 3072, 3037, 2985, 2960, 2825, 1716 (C=O), 1666 (C=N), 1552, 1489, 1440, 1330, 1276, 817, 763, 538, 466. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.45 (s, 1H, NH), 9.59 (s, 1H), 7.90–7.72 (m, 3H). 13 C NMR (100 MHz, DMSO-d6 ): δC = 161.8 (C = O), 155.9 (C=O), 150.7 (C=N), 148.9, 143.5, 141.9, 129.3, 129.0, 125.7, 124.7, 121.9. LC–MS:(80 eV): (m/z, %) 261(49) [M+H]+ . (E)-5-((4-(Methylthio)benzylidene)amino)pyrimidine2,4(1H,3H)-dione (11f)

(E)-5-((5-Bromo-2-hydroxybenzylidene)amino)pyrimidine2,4(1H,3H)-dione (11c) HO N

SCH3 N

HN

White solid. Yield. 200 mg, 31 %. m.p.: 334–335 ◦ C. Rf : 0.500 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3198 (N–H), 3163, 3068, 3018, 2918, 2823, 2229 (C≡N), 1708 (C=O), 1666 (C=N), 1587, 1444, 1421, 1292, 1199, 877, 761.

O

N H

O

N H

HN

N

HN O

N

HN

NO2

O

CN

O

O

White solid. Yield. 496 mg, 28 %. m.p.: 306–307 ◦ C. Rf : 0.500 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3373, 3215 (N–H), 3165, 3099, 3024, 2966, 2837, 2017, 1774 (C=O), 1651 (C=N), 1512, 1247, 1172, 1030, 877, 752. (E)-5-((4-Nitrobenzylidene)amino)pyrimidine-2,4(1H,3H)dione (11e)

CH3

5-Aminouracil 8 (0.381 g, 3 mmol) was dissolved in water with heating until the complete dissolution. Then a solution of p-tolylbenzaldehyde 10a (0.318 g, 3 mmol) in ethanol (15mL) was added dropwise. An instant white precipitate occurred. After 5 min, the reaction mixture was refluxed for 1h. Then reaction mixture was left overnight. The light yellow precipitate was filtered off and washed with warm water and ethanol to give 11a as a white solid. Yield. 200 mg, 31 %. m.p.334 − 335 ◦ C. Rf : 0.613 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3215 (N–H), 3161, 3066, 3022, 2956, 2918, 2814, 1712 (C=O), 1666 (C=N), 1597, 1492,1444, 1421, 1329, 1172, 875, 813, 765.

O

(E)-5-((4-Methoxybenzylidene)amino)pyrimidine2,4(1H,3H)-dione (11d)

O

N H

White solid. Yield. 932 mg, 89 %. m.p.: 337–340 ◦ C. Rf : 0.502 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3514, 3292 (N–H), 3095, 2972, 2831, 1720 (C=O), 1672 (C=N), 1342, 1213, 852, 752. 1 H NMR (400 MHz, DMSO-d6 ): δH = 11.37 (s, 1H, NH), 9.30 (d, J=12.8 Hz, 1H), 8.35 (s, 1H), 7.9077.27 (m, 3H), 7.59 (s, 1H, NH), 2.51 (s, 3H). 13 C NMR (100 MHz, DMSO-d6 ): δC = 176.1, 176.9 (C=O), 168.1, 168.1 (C=O), 162.1 (C=N), 158.3, 144.0, 143.9, 129.9, 128.9, 122.2, 14.8, 14.7 (CH3 ).LC–MS:(80 eV): (m/z, %) 262 (100) [M+H]+ .

Br

N H

Yellow solid. Yield. 1.0g, 80 %. Rf : 0.567 (ethyl acetate). m.p.: 345–346 ◦ C. IR (KBr) (νmax , cm−1 ): 3427 (OH), 3178 (N–H), 3057, 2958, 2739, 2806, 1705 (C=O), 1651 (C=N), 1473, 1242, 860, 765, 553.

(E)-5-(Benzylideneamino)pyrimidine-2,4(1H,3H)-dione (11g) O N

HN O

N H

123

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Mol Divers (2015) 19:213–230

White solid. Yield. 200 mg, 31 %. m.p.: 334–337 ◦ C.Rf : 0.393 (ethyl acetate). IR (KBr) (νmax , cm−1 ): 3215, 3165 (N–H), 3068, 3022, 2956, 2902, 2868, 1712 (C=O), 1678 (C=N), 1573, 1485, 1143, 1070, 831, 748, 653. LC–MS: (80 eV): (m/z, %) 216 (100) [M+H]+ . Synthesis of N-oxadiazolylmethyl-substituted 5-(benzylideneamino)pyrimidine-2,4-diones(12a-c) general procedure (E)-5-((4-Methylbenzylidene)amino)-1,3-bis( (3-phenyl1,2,4-oxadiazol-5-yl)methyl)pyrimidine-2,4(1H,3H)-dione (12a)

127.69, 126.39, 126.30, 123.57, 122.91 (other isomer), 45.73 (CH2 ), 37.94 (CH2 ), 21.83 (CH3 ). LC–MS: (80 eV):(m/z, %) 546 (100) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C30 H24 N7 O4 , 546.1890; found 546.1895. (E)-4-(((1,3-Bis((3-(4-(methylthio)phenyl)-1,2,4-oxadiazol5-yl)methyl)2,4-dioxo- 1,2,3,4-tetrahydropyrimidin-5-yl) imino)methyl)benzonitrile (12b)

H3CS

N

N O N

SCH3

N

A mixture of (E)-5-((4-methylbenzylidene)amino)pyrimidine-2,4(1H, 3H )-dione 11a (0.131 g, 0.57 mmol) and K2 CO3 (0.86 g, 0.62 mmol) was mixed in DMF (5mL) at room temperature for 3h until a change of color was observed, 5(chloromethyl)-3-phenyl-1,2,4-oxadiazole 2a (0.132 g, 0.68 mmol) was added in one portion, and stirring was continued overnight and monitored by TLC. The crude reaction mixture was extracted with (DCM:H2 O; 1:1) × 3. The combined organic layers were dried over Na2 SO4 . Solvent was removed under the reduced pressure, and after the addition of a small amount of MeOH, a white precipitate occurred which upon filtration and recrystallization from methanol gave 12a. Yield. 96 mg, 31 %. m.p.: 168–169 ◦ C.Rf : 0.750 (ethyl acetate:n-hexane,1:1). IR (KBr) (νmax , cm−1 ): 3173, 3066, 2920, 2856, 2820, 1716 (C=O), 1662, 1645, 1597, 1527 (C=N), 1477, 1390, 1105, 1010, 781, 719. 1 H NMR (400 MHz, DMSO-d6 ): δH = 9.33 (s, 1H, CH=N, isomer), 9.28 (s, 1H, CH=N, isomer), 8.36 (s, 1H), 8.00 (t, J = 1.2 Hz, 1H), 7.98 (t, J = 2.0 Hz, 1H), 7.96 (t, J = 1.2 Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H, of one isomer), 7.70 (d, J = 8.0Hz, 2H, of other isomer) 7.62-7.50 (m, 6H), 7.31 (d, J = 8.0Hz, 2H, of one isomer), 7.27 (d, J = 8.0Hz, 2H, of other isomer), 5.57 (s, 2H, CH2 ), 5.49 (s, 2H, CH2 ), 2.36 (s, 3H, one isomer), 2.35 (s, 3H, other isomer). 13 C NMR (400 MHz, DMSO-d6 ): δC = 176.25 (C = N), 176.01 (C=N), 168.44 (C=N), 168.38 (C=N), 162.12 (C=N, other isomer), 161.05 (C=N), 159.92 (C=O), 158.68 (C=O, other isomer), 151.05 (C=N, other isomer), 150.20 (C=N), 142.18, 141.29, 140.23, 138.87, 135.04 (other isomer), 134.45, 132.50, 132.41, 130.18, 129.99, 128.88, 128.49, 127.74,

123

O N

N

N O

H

N

CH3

O

N O

N

N

N O O

N

CN

O

N

12b. White solid. Yield. 80 mg, 24 %. m.p.: 208–209 ◦ C. Rf : 0.450 (ethyl acetate:n-hexane;1:1). IR (KBr) (νmax , cm−1 ): 3080, 3178, 2999, 2924, 2831, 2222 (C≡N), 1712 (C=O), 1672, 1593 (C=N), 1410, 1346, 1220, 1114, 1089, 833, 744, 555. 1 H NMR (400 MHz, DMSO-d6 ): δH = 9.53 (s, 1H, CH=N), 8.52 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.85 (dd, J =14.8, 8.8 Hz, 4H), 7.36 (dd, J = 8.4, 5.6 Hz, 4H), 5.57 (s, 2H, CH2 ), 5.48 (s, 2H, CH2 ), 2.52 (s, 3H, SCH3 ). 13 C NMR (400 MHz, DMSOd6 ): δC = 176.02 (C = N), 175.77 (C=N), 168.11 (C=N), 168.05 (C=N)), 159.66 C=N, 158.80 (C=O), 150.04 (C=O), 144.06, 143.93, 143.39, 141.15, 133.50, 129.22, 128.89, 128.00, 126.37, 126.34, 122.33, 122.23, 119.27, 113.73 (C≡N), 45.84 (CH2 ), 37.90 (CH2 ), 14.69 (SCH3 ). LC– MS:(80 eV): (m/z, %) 649 (34) [M+H]+ 559(13). HRMS (ESI-TOF, [M+H]): calcd for C32 H25 N8 O4 S2 , 649.1440; found 649.1437. (E)-1,3-Bis((3-(4-bromophenyl)-1,2,4-oxadiazol-5yl)methyl)-5-((4-methoxybenzylidene)amino) pyrimidine-2,4(1H,3H)-dione(12c) Br OCH3

O

N N O

N

N O

H

N

O N

N

Br

Mol Divers (2015) 19:213–230

12c. White solid. Yield. 67 mg, 23 %. m.p.: 221–222 ◦ C. Rf : 0.530 (ethyl acetate:n-hexane; 1:1). IR (KBr) (νmax , cm−1 ): 3076, 3010, 2916, 2839, 1763 (C=O), 1712 (C=O), 1658, 1595, 1573 C=N, 1442, 1342, 1246, 1170, 1112, 904, 835, 744. 1 H NMR (400 MHz, DMSO-d6 ): δH = 9.16 (s, 1H, CH=N), 8.24 (s, 1H, C=CH), 7.85 (dd, J = 14.4, 8.8 Hz, 4H), 7.78 (d, J = 9.2 Hz, 2H), 7.68 (dd, J = 8.8, 6.8 Hz, 4H), 7.02 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H, CH2 ), 5.44 (s, 2H, CH2 ), 3.79 (s, 3H, OCH3 ).13 C NMR (100 MHz, DMSO-d6 ): δC = 176.53 (C=N), 176.28 (C=N), 167.80 (C=N), 167.75 (C=N), 162.65 (C=N), 160.76 (C–OCH3 ), 159.95 (C=O), 150.21 (C=O), 124.0, 139.22, 133.08, 133.02, 130.68, 129.83, 129.69, 129.65, 126.09, 125.99, 125.62, 125.53, 124.04, 115.05, 56.08 (OCH3 ), 45.63 (CH2 ), 37.87 (CH2 ). LC–MS (80 eV): (m/z, %) 719 (64) [M+H]+ . HRMS (ESI-TOF, [M+H]): calcd for C30 H22 N7 O5 Br2 , 718.0049; found 718.0055.

Supporting information X-ray diffraction data of the compounds 4h and 6b have been deposited at the Cambridge Crystallographic Data Center and allocated deposition numbers are CCDC 1005652, 1024965, respectively. It can be obtained free of charge from http:// www.ccdc.cam.ac.uk/data_request/cif. Acknowledgments Abant ˙Izzet Baysal University, Directorate of Research Projects Commission (BAP Grant No. 2013.03.03.665), is gratefully acknowledged for financial support.

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