HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 12, 2009, pp. 2951-2962
Received, 10th July, 2009, Accepted, 5th October, 2009, Published online, 6th October, 2009.
DOI: 10.3987/COM-09-11794

■ Synthesis of 6-Substituted Purine Derivatives

Amal Al-Azmi* and K. Anita Kumari

Department of Chemistry, Faculty of Science, Kuwait University, Safat 13060, P.O. Box 5969, Kuwait

Abstract

Hydroxylamine hydrochloride reacts readily with (5-amino-1-aryl-1H-imidazol-4-yl)iminoacetonitriles to furnish 5-amino-1-aryl-N-hydroxy-1H-imidazole-4-carboxamidines. When a mixture of 5-amino-1-aryl-N-hydroxy-1H-imidazole-4-carboxamidine and excess of triethyl orthoesters is reacted at room temperature novel purin-6-one oximes are obtained in moderate yields. Further, reaction of formamidines and ethyl acetoacetate with DBU afforded 6-carbamoylpurines. X-Ray analysis carried out on 9-(4-methoxyphenyl)-2-methyl-9H-purine-6-carboxamide monohydrate confirmed its structure. Diazotization of [5-amino-1-(4-methoxyphenyl)-1H-imidazol-4-yl]iminoacetonitrile in the presence of an excess of sodium nitrite and concentrated HCl gave 4-carboxy-5-chloro-1-(4-methoxyphenyl)imidazolidinium chloride via nucleophilic aromatic substitution reaction. However, (1-aryl-5-hydroxy-1H-imidazol-4-yl)imino-acetonitrile is obtained as product when (5-amino-1-aryl-1H-imidazol-4-yl)iminoacetonitriles (Ar = 4-MeC6H4 and Ar = 4-ClC6H4) were the reactants. The structure of 4-carboxy-5-chloro-1-(4-methoxyphenyl)imidazolidinium chloride was also established by X-ray analysis.

Purines are an important class of heterocycles because of their significant role as biologically active compounds.1-12 Generally, their activity depends mainly on the type and position of substituents on the ring, and several reports in the last decade described various methods to synthesize a wide range of purine derivatives.13-23 As a result, the search for new synthetic approaches to prepare purines with a wide variety of substituents on either or both rings is continuing. In our research group, we have been investigating the utility of both formamidines 1 and imidazoles 2 as precursors to find new facile synthetic methods to prepare novel fused nitrogen heterocycles such as imidazole derivatives, purines, 6-carbamoylpurines and pyrimido[5,4-d]pyrimidines. The literature reports describe many synthetic procedures to prepare 6-substituted purines starting from either formamidines 1 or imidazoles 2. The use of both compounds as versatile precursors to 6-substituted purines and other nitrogen heterocycles is increasing.16-21 Conversion of the active cyanoformimidoyl unit in imidazole 2 into a new nucleophilic reactive site could be used for further transformations.

RESULTS AND DISCUSSION
Addition of hydroxylamine hydrochloride (5 equiv.) to a suspension of (5-amino-1-aryl-1H-imidazol-4-yl)iminoacetonitrile 2a (Ar = 4-MeOC6H4) or 2b (Ar = 4-MeC6H4) in ethanol and stirring the mixture overnight at room temperature led to the isolation of white crystalline solids identified as 5-amino-N-hydroxy-1-aryl-1H-imidazole-4-carboxamidine 4a (Ar = 4-MeOC6H4) and 4b (Ar = 4-MeC6H4). Both imidazoles were used as intermediates and reacted with triethyl orthoesters. When a suspension of imidazole 4a and triethyl orthoformate was refluxed, purine 5a was isolated (48%) (Scheme 1). When the same reaction was carried out using triethyl orthoacetate, complete decomposition of the reaction mixture took place. However, stirring the mixture at room temperature for 18 hours afforded the product 5b (45%). When a mixture of imidazole 4a and an excess of triethyl orthoformate was stirred at room temperature for 18-20 hours, the yield of 5a increased (60%).

It is assumed that hydroxylamine initially adds to substrate 2 to yield intermediate 3 which then loses HCN to furnish product 4. Similar elimination has been observed in the reaction of imidazoles 2 with phenylsulfonylacetonitrile and a catalytic amount of DBU21 (Scheme 1).
In the literature, the reaction of formamidines 1 with active methylenes has been described.22 However, to our knowledge their reaction with ethyl acetoacetate has not yet been reported. A mixture of equimolar amounts of ethyl acetoacetate and 1a reacted in the presence of DBU to form a product for which structure 6a was proposed (Scheme 2).

Although the spectroscopic features of the collected needles were very similar to those of 6-carbamoylpurines,17,19,22,23 an X-ray crystal structure analysis was carried out to confirm the structure of the product (Figure 1).

The isolation of 6-purinecarboxamide monohydrate 6a suggests that the first step in the reaction is the conversion of formamidine 1a to imidazole 2a.12 A mechanism of 6-carbamoylpurines 6 formation from imidazoles 2 has been described previously.22,23
Alternatively, the reaction may proceed by a nucleophilic attack of the imino function on the acetyl group. Then, an elimination of water molecule occurs to yield 9 that undergoes a rapid loss of an ethyl acetate molecule, followed by basic hydrolysis of the cyano function to furnish 6 (Scheme 3).

An attempt to diazotize imidazole 2a to form imidazotriazines 11 using previously described procedure, resulted only in recovering the starting material.24 Nevertheless, when a large excess of NaNO2 and concentrated HCl were used, red crystals were isolated. The 1H NMR spectrum of the crystals revealed the presence of a singlet for one proton at δ 4.58 ppm which was D2O exchangeable, a base peak at m/z 252 appeared in the MS, also the IR showed a band at 1712 cm-1 which indicates the presence of a carbonyl group. In order to establish the structure of these crystals, X-ray was carried out and showed the product to be 4-carboxy-5-chloro-1-(4-methoxyphenyl)imidazolidinium chloride 12 which resulted from a nucleophilic aromatic substitution reaction (Figure 2).

Diazotization was also performed on imidazoles 2b,c utilising the same conditions used to diazotize imidazole 2a; small amount of red crystals were collected. The 1H NMR and MS spectra of these crystals, on the other hand, showed a different pattern than expected. Careful examination of the spectroscopic analyses of the obtained crystals enabled us to identify the products to be (1-aryl-5-hydroxy-1H-imidazol-4-yl)iminoacetonitrile 13b (Ar = 4-MeC6H4) and 13c (Ar = 4-ClC6H4) (Scheme 4).

The yields in both reactions were low [12 (40%), 13b (30%) and 13c (40%)], and all attempts to increase the yields were unsuccessful. Although the same conditions were utilised for imidazoles 2a,b and c, it appears that two different SNAr reactions operate. This might be due to the difference in the electronic effect of the methyl, chloro and methoxy substituents (Scheme 5).

CONCLUSION
In conclusion, the reactive unit in (5-amino-1-aryl-1H-imidazol-4-yl)iminoacetonitrile could be converted into another reactive site simply by treating it with hydroxylamine hydrochloride. These imidazoles were shown to be valuable precursors for the synthesis of novel purines when reacted with triethyl orthoesters. In addition, reactions of formamidines with ethyl acetoacetate in the presence of DBU furnishes 6-carbamoylpurines. Also, two different SNAr reactions took place via the diazotization of (5-amino-1-aryl-1H-imidazol-4-yl)iminoacetonitrile.

EXPERIMENTAL
General
Formamidines 1a-c and imidazoles 2a,b were prepared according to literature procedures.12 Percentage yields calculated for (4a,b, 5a-f, 6a,b, 12 and 13b,c) are based on 1.0 g of starting material. 1H NMR spectra were recorded on a Bruker DPX 400 spectrometer at 400 MHz. CDCl3 or DMSO-d6 as a solvent and tetramethylsilane (TMS) as an internal standard; chemical shifts are reported in δ units (ppm). 13C NMR spectra were obtained using a Bruker DPX 400 spectrometer at 100 MHz. Mass spectra were recorded on a VG autospec Q spectrometer with a digital data output. IR was recorded on rt-ir Perkin Elmer System 2000, using KBr disc and (νmax) was recorded in cm-1. Melting points were determined by using a Gallenkamp melting point apparatus and are uncorrected. TLC was performed on a 0.25 mm pre-coated silica gel plates (Merck).

General procedure for preparation of Imidazole 2c
A suspension of formamidine 1c (Ar = 4-ClC6H4) (5.00 mmol) and DBU (1 mL, 6.70 mmol) in EtOH was stirred at room temperature for 1 h, the solid obtained was recrystallised from a mixture of hot EtOH/H2O.

[5-Amino-1-(4-chlorophenyl)-1H-imidazol-4-yl]iminoacetonitrile 2c: light yellow powder (0.88 g, 3.58 mmol, 88%), mp > 200 oC (decomp.) [C11H8N5Cl requires: 245.0462; M 245. Found: accurate mass: 245.0462; m/z (EI) M+ 245, 57%, 138, 100%]; δH 400 MHz (DMSO-d6, TMS), 6.76 (s, 2H, NH2), 7.50 (s, 1H, CH), 7.55 (m, 2H, ArH); 7.65 (m, 2H, ArH), 11.16 (s, 1H, NH); δC 100 MHz (DMSO-d6, TMS), 143.91, 143.02, 133.19, 132.72, 130.01, 129.91, 126.94, 116.31, 113.32; νmax: (KBr) 3444, 3298, 2226, 1631, 1580, 1538, 1489, 1393, 1305, 1246, 1172, 1088, 1051, 915, 829 cm−1.

General procedure for preparation of Imidazoles 4a,b
A mixture of hydroxylamine hydrochloride (5.0 equiv.) and sodium acetate (4.0 equiv.) was added to a suspension of imidazole 2 (1.0 equiv.) in EtOH, while stirring. The stirring was continued overnight, and the solids obtained were recrystallised from a mixture of hot EtOH/H2O.

5-Amino-N-hydroxy-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamidine 4a: white crystalline solid (0.49 g, 1.98 mmol, 48%), mp 209-211 oC [C11H13N5O2 requires: 247.1063; M 247. Found: accurate mass: 247.1069; m/z (EI) M+ 247, 100%]; δH 400 MHz (DMSO-d6, TMS), 3.82 (s, 3H, OCH3), 5.23 (s, 2H, NH2), 5.42 (s, 2H, NH2), 7.09 (d, 2H, J 9.2 Hz, ArH), 7.32 (s, 1H, CH), 7.41 (d, 2H, J 9.2 Hz, ArH), 8.97 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 159.24, 150.69, 137.00, 130.00, 128.32, 126.49, 115.24, 112.37, 55.97; νmax: (KBr) 3442, 3335, 1645, 1617, 1516, 1305, 1255, 1181, 1023, 926, 838 cm−1.

5-Amino-N-hydroxy-1-(p-tolyl)-1H-imidazole-4-carboxamidine 4b: white crystalline solid (0.74 g, 3.2 mmol, 60%), mp 225-227oC [C11H13N5O2 requires: 231.1114; M 231. Found: accurate mass: 231.1115; m/z (EI) M+ 231 100%]; δH 400 MHz (DMSO-d6, TMS), 2.38 (s, 3H, CH3), 5.27 (s, 2H, NH2), 5.42 (s, 2H, NH2), 7.35 (m, 5H, ArH & CH), 8.97 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 150.18, 137.36, 136.29, 132.61, 130.14, 129.41, 124.20, 112.21, 20.63; νmax: (KBr) 3434, 3396, 3313, 3180, 2846, 1633, 1581, 1514, 1490, 1447, 1322, 1194, 932 cm−1.

General procedure for preparation of Purines 5a-f
A suspension of imidazoles 4 (1 equiv.), and of triethyl orthoformate/acetate or propionate (12 equiv.) was either refluxed for 2 h (5a), or stirred at room temperature overnight (18-20 h) (5a-f). The solids formed were filtered.

9-(4-Methoxyphenyl)-1,9-dihydropurin-6-one oxime 5a (recrystallised from a mixture of hot EtOH/H2O): white powder (0.50 g, 1.94 mmol, 48%), rt (0.62 g, 2.40 mmol, 60%), mp 274-276 oC (decomp.) [C12H11N5O2 requires: 257.0907; M 257. Found: accurate mass: 257.0907; m/z (EI) M+ 257, 100%]; δH 400 MHz (DMSO-d6, TMS), 3.84 (s, 3H, OCH3), 7.16 (d, 2H, J 6.8 Hz, ArH), 7.67 (d, 2H, J 6.8 Hz, ArH), 8.78 (s, 1H, CH), 8.81 (s, 1H, CH), 8.94 (s, 1H, NH), 9.70 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 159.26, 148.77, 144.70, 144.14, 143.80, 126.57, 125.52, 119.15, 114.80, 55.64; νmax: (KBr) 3423, 3279, 3075, 1703, 1520, 1260, 1192, 1177, 1031, 972, 827 cm−1.

9-(4-Methoxyphenyl)-2-methyl-1,9-dihydropurin-6-one oxime 5b (recrystallised from a mixture of hot EtOH/H2O): white powder (0.49 g, 1.80 mmol, 45%), mp 275 oC [C13H13N5O2 requires: 271.1064; M 271. Found: accurate mass: 271.1063; m/z (EI) M+ 271, 20%, 255, 100%]; δH 400 MHz (DMSO-d6, TMS), 2.70 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.17 (d, 2H, J 6.8 Hz, ArH), 7.67 (d, 2H, J 6.8 Hz, ArH), 8.72 (s, 1H, CH), 9.31 (s, 1H, NH), 9.91 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 159.55, 154.20, 149.27, 143.38, 143.20, 127.27, 125.94, 118.39, 115.22, 56.04, 20.97; νmax: (KBr) 3372, 3078, 3062, 1690, 1519, 1444, 1430, 1304, 1257, 1199, 1180, 1090, 1023, 840 cm−1.

2-Ethyl-9-(4-methoxyphenyl)-1,9-dihydropurin-6-one oxime 5c (recrystallised from mixture of EtOH/H2O/acetone): white powder (0.57 g, 2.0 mmol, 50%), mp 260 oC (decomp.) [C14H15N5O2 requires: 285.1220; M 285. Found: accurate mass: 285.1220; m/z (EI) M+ 285, 10%, 269, 100%]; δH 400 MHz (DMSO-d6, TMS) 1.23 (t, 3H, J 7.2 Hz, -CH2CH3), 3.07 (q, 2H, J 7.2 Hz, -CH2CH3), 3.85 (s, 3H, OCH3), 7.17 (d, 2H, J 8.8 Hz, ArH), 7.73 (d, 2H, J 9.2 Hz, ArH), 8.77 (s, 1H, CH), 9.31 (s, 1H, NH), 9.91 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 159.62, 158.54, 149.90, 144.72, 143.82, 127.02, 125.77, 118.30, 115.22, 56.06, 26.19, 10.23; νmax: (KBr) 3423, 2975, 1688, 1574, 1523, 1456, 1405, 1304, 1260, 1181, 1050, 1027, 926 cm−1.

9-(p-Tolyl)-1,9-dihydropurin-6-one oxime 5d (recrystallised from mixture of EtOH/H2O/acetone): white powder (0.52 g, 2.15 mmol, 50%), mp 315 oC [C12H12N5O requires: 241.0958; M 241. Found: accurate mass: 241.0959; m/z (EI) M+ 241, 100%]; δH 400 MHz (DMSO-d6, TMS), 2.39 (s, 3H, CH3), 7.40 (d, 2H, J 7.6 Hz, ArH), 7.71 (d, 2H, J 8.0 Hz, ArH), 8.31 (br.s, 1H, NH), 8.72 (s, 1H, CH), 8.76 (s, 1H, CH), 9.20 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS) 148.67, 144.53, 143.51, 138.11, 131.42, 130.06, 123.54, 119.26, 56.00, 20.68, 18.59; νmax: (KBr) 3327, 3209, 3113, 1696, 1520, 1494, 1391, 1345, 1245, 1193, 1092, 812 cm−1.

2-Methyl-9-(p-tolyl)-1,9-dihydropurin-6-one oxime 5e (recrystallised from mixture of EtOH/H2O/acetone): white powder (0.51 g, 2.0 mmol, 50%), mp 275 oC (decomp.) [C13H13N5O requires: 255.1114; M 255. Found: accurate mass: 255.1114; m/z (EI) M+ 255, 25%, 239, 100%]; δH 400 MHz (DMSO-d6, TMS) 2.41 (s, 3H, CH3), 2.70 (s, 3H, CH3), 7.44 (d, 2H, J 8 Hz, ArH), 7.67 (d, 2H, J 8.4 Hz, ArH), 8.78 (s, 1H, CH), 9.35 (s, 1H, NH), 9.95 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 154.40, 149.23, 143.55, 143.10, 138.33, 131.41, 130.14, 123.92, 118.23, 20.73, 20.68; νmax: (KBr) 3384, 3262, 3100, 1673, 1521, 1396, 1317, 1244, 1207, 1188, 1145, 971, 814 cm−1.

2-Ethyl-9-(p-tolyl)-1,9-dihydropurin-6-one oxime 5f (recrystallised from a mixture of hot EtOH/H2O): white powder (0.52 g, 1.93 mmol, 45%), mp 270 oC (decomp.) [C14H15N5O requires: 269.1271; M 269. Found: accurate mass: 269.1273; m/z (EI) M+ 269, 12%, 252, 100%]; δH 400 MHz (DMSO-d6, TMS), 1.24 (t, 3H, J 7.2 Hz, -CH2CH3), 2.40 (s, 3H, CH3), 2.99 (q, 2H, J 7.2 Hz, -CH2CH3), 3.85 (s, 3H, OCH3), 7.42 (d, 2H, J 8.4 Hz, ArH), 7.76 (d, 2H, J 8.4 Hz, ArH), 8.82 (s, 1H, CH), 9.33 (s, 1H, NH), 9.94 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS), 157.46, 149.14, 142.93, 138.04, 131.66, 130.15, 123.38, 116.11, 79.26, 25.71, 20.71, 9.88; νmax: (KBr) 3382, 3108, 1672, 1594, 1523, 1399, 1341, 1208, 1188, 1142, 968, 869, 812 cm−1.

General procedure for preparation of Purines 6a,b
A mixture ethyl acetoacetate (5 equiv.) and DBU (1.6 equiv.) was stirred in an ice bath. To this, a suspension of formamidines 1a (1.00 g, 4.14 mmol), 1b (1.00 g, 4.44 mmol) in EtOH (8 mL) was added. The stirring was continued for 2 h in an ice bath, and 18 h at room temperature. The formed precipitates were filtered off, and recrystallised from EtOH (6a) and a mixture of EtOH/H2O (6b).

9-(4-Methoxyphenyl)-2-methyl-9H-purine-6-carboxamide monohydrate 6a: colourless needles (0.81 g, 2.65 mmol, 65%), mp 270-273 oC [C14H15N5O3. Anal. Calcd for CHN: C, 55.81; H, 4.98; N, 23.25. Found: C, 55.85; H, 5.01; N, 23.11; m/z (EI) (M-H2O)+ 283, 100%; M 301]; δH 400 MHz (DMSO-d6, TMS), 2.74 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.16 (d, 2H, J 9.8 Hz, ArH), 7.74 (d, 2H, J 9.8 Hz, ArH), 8.09 (s, 1H, NH), 8.38 (s, 1H, NH), 8.94 (s, 1H, CH); δC 100 MHz (DMSO-d6, TMS) 164.88, 161.84, 159.49, 154.05, 148.35, 147.01, 129.54, 127.41, 126.03, 115.19, 56.04, 26.09; νmax: (KBr) 3461, 3394, 3121, 1699, 1671, 1650, 1579, 1519, 1408, 1388, 1254, 1229, 1182, 1028, 956, 836 cm−1.

2-Methyl-9-(p-tolyl)-9H-purine-6-carboxamide monohydrate 6b: white solid (0.96 g, 3.36 mmol, 76%), mp 275-277 oC [C14H15N5O2 requires: accurate mass 267.1114; M 285. Found: accurate mass (M-H2O): 267.1116; m/z (EI) (M-H2O)+ 267, 45%, 224, 100%]; δH 400 MHz (DMSO-d6, TMS) 2.42 (s, 3H, CH3), 2.75 (s, 3H, CH3), 7.44 (d, 2H, J 8 Hz, ArH), 7.46 (d, 2H, J 8.4 Hz, ArH), 8.10 (s, 1H, NH), 8.38 (s, 1H, NH), 9.01 (s, 1H, CH); δC 100 MHz (DMSO-d6, TMS), 164.89, 161.89, 153.93, 148.54, 146.81, 138.35, 132.17, 130.48, 129.67, 124.19, 26.13, 21.14; νmax: (KBr) 3452, 1710, 1574, 1521, 1398, 1336, 1290, 1228, 1203, 957 cm−1.

General procedure for the Synthesis of imidazolidinium chloride 12 and imidazoles 13b and 13c
A suspension of imidazoles 2 (0.50 g, 2.1 mmol) and 4 N HCl (20 mL) was heated gently, and then cooled in an ice bath. A cold solution of NaNO2 (2.5 g, 36.0 mmol) was then added dropwise to the imidazole suspension. After the addition, stirring was continued in an ice bath for 30-45 min. The solution was warmed up for 15 min and stirred at room temperature overnight. The solid obtained was filtered and crystallised using a mixture of (acetone/hexane) for 12 using Vapour Diffusion Technique (VDT) and acetone for 13b,c.

4-Carboxy-5-chloro-1-(4-methoxyphenyl)imidazolidinium chloride 12: red crystals (0.47 g, 1.60 mmol,
40%), mp 230-232 oC [C11H10N2O3Cl2 (M-HCl). Anal. Calcd for CHN: C, 52.27; H, 3.56; N, 11.08.
Found: C, 52.34; H, 3.70; N, 11.16; requires accurate mass 252.0296, Found accurate mass (M-HCl):
252.0293; m/z (EI) (M-HCl)+ 252, 100%, M 289]; δH 400 MHz (DMSO-d6, TMS), 3.84 (s, 3H, OCH3), 4.58 (s, 1H, NH), 7.13 (d, 2H, J 8.8 Hz, ArH), 7.46 (d, 2H, J 8.8 Hz, ArH), 8.25 (s, 1H, CH); δC 100 MHz (DMSO-d6, TMS) 162.42, 160.50, 138.52, 128.39, 127.43, 126.57, 124.36, 115.18, 56.06; νmax: (KBr), 3423, 3117, 1712, 1607, 1535, 1510, 1437, 1384, 1304, 1256, 1175, 1021, 956, 848 cm−1.

[5-Hydroxy-1-(p-tolyl)-1H-imidazol-4-yl]iminoacetonitrile 13b: red crystals (0.30 g, 1.32 mmol, 30%), mp 220 oC (decomp.) [C12H10N4O Anal. Calcd for CHN: C, 63.71; H, 4.42; N, 24.77; M 226. Found: C, 63.79; H, 4.56; N, 24.48; m/z (EI) (M)+ 226, 100%]; δH 400 MHz (DMSO-d6, TMS), 2.40 (s, 3H, CH3), 4.58 (s, 1H, NH), 7.73 (s, 4H, Hz, ArH), 7.54 (s, 1H, CH), 7.56 (s, 1H, NH), 8.33 (s, 1H, OH); δC 100 MHz (DMSO-d6, TMS) 155.47, 150.27, 138.99, 136.01, 130.39, 130.13, 125.43, 121.35, 114.82, 20.66; νmax: (KBr) 3445, 3286, 1636, 1624, 1546, 1514, 1503, 1471, 1395, 1284, 1168, 922 cm−1.

[1-(4-Chlorophenyl)-5-hydroxy-1H-imidazol-4-yl]iminoacetonitrile 13c: red crystals (0.40 g, 1.62 mmol, 40%), mp > 200 oC (decomp.) [C11H7N4OCl. Anal. Calcd for CHN: C, 53.54; H, 2.83; N, 22.71; M 246. Found: C, 53.30; H, 2.83; N, 22.56; m/z (EI) (M)+ 246, 100%]; δH 400 MHz (DMSO-d6, TMS), 7.55 (m, 3H, ArH and NH), 7.65 (m, 4H, ArH, CH & OH); δC 100 MHz (DMSO-d6, TMS), 155.50, 150.39, 135.80, 133.97, 131.65, 129.97, 127.94, 121.27, 114.88; νmax: (KBr) 3431, 3145, 2363, 1634, 1553, 1494, 1391, 1172, 1097m, 923 cm−1.

Crystal data and structure refinement for 6a.25
Chemical formula (moiety) C14H15N5O3, chemical formula (total) C14H15N5O3, formula weight 301.31, temperature 150(2) K, radiation, wavelength MoKα, 0.71073 Å, crystal system, space group monoclinic, P21/c, unit cell parameters a = 13.238(3) Å, α = 90°, b = 10.059(2) Å, β = 107.757(16)°, c = 10.7144(8) Å, γ = 90°, cell volume 1358.7(4) Å3, Z 4, calculated density 1.473 g/cm3, absorption coefficient µ 0.108 mm−1, F(000) 632, crystal colour and size colourless, 0.45 × 0.40 × 0.40 mm3, reflections for cell refinement 285 (θ range 2.5 to 27.5°), data collection method, Nonius KappaCCD diffractometer φ and ω scans, θ range for data collection 4.0 to 27.5°, index ranges h −17 to 17, k −13 to 12, l −13 to 13, completeness to θ = 26.0°, 99.4%, reflections collected 12996, independent reflections 3087 (Rint = 0.0234), reflections with F2>2σ 2608, absorption correction semi-empirical from equivalents, min. and max. transmission, 0.953 and 0.958, structure solution direct methods, refinement method full-matrix least-squares on F2, weighting parameters a, b 0.0372, 0.7683, data/restraints/parameters 3087/0/ 217, final R indices [F2>2σ] R1 = 0.0355, wR2 = 0.0840, R indices (all data) R1 = 0.0465, wR2 = 0.0910, goodness-of-fit on F2 1.034, largest and mean shift/su 0.000 and 0.000, largest diff. peak and hole 0.31 and −0.22 e Å−3.

Crystal data and structure refinement for 12.26
Chemical formula (moiety) C11H10ClN2O3+·Cl−, chemical formula (total) C11H10Cl2N2O3, formula weight 289.11, temperature 150(2) K, radiation, wavelength MoKα, 0.71073 Å, crystal system, space group monoclinic, P21/c, unit cell parameters a = 12.3041(18) Å, α = 90°, b = 7.3244(18) Å, β = 94.266(10)°, c = 13.4882(10) Å, γ = 90°, cell volume 1212.2(4) Å3, Z 4, calculated density 1.584 g/cm3, absorption coefficient µ 0.536 mm−1, F(000) 592, crystal colour and size red, 0.45 × 0.30 × 0.30 mm3, reflections for cell refinement 180 (θ range 2.5 to 27.5°), data collection method Nonius KappaCCD diffractometer φ and ω scans, θ range for data collection 4.1 to 27.5°, index ranges h −15 to 15, k −9 to 9, l −17 to 17, completeness to θ = 26.0° 99.5% , reflections collected 13774, independent reflections 2776 (Rint = 0.0278), reflections with F2>2σ 2340, absorption correction semi-empirical from equivalents, min. and max. transmission 0.795 and 0.855, structure solution direct methods, refinement method Full-matrix least-squares on F2, weighting parameters a, b 0.0388, 1.1248, data/restraints/parameters 2776/0/172, final R indices [F2>2σ] R1 = 0.0313, wR2 = 0.0861, R indices (all data) R1 = 0.0415, wR2 = 0.0929, goodness-of-fit on F2 1.128, extinction coefficient 0.0000(12), largest and mean shift/su 0.001 and 0.000, largest diff. peak and hole 0.50 and −0.30 e Å−3.

ACKNOWLEDGMENTS
The financial support of Kuwait University received through research grant SC 01/07 and SAF facilities through projects GS 01/01 and GS 03/01 are gratefully acknowledged. Thanks are due to Professor W. Clegg at the University of Newcastle upon Tyne, UK, for providing X-ray crystallographic results.

References

1. J. H. Lister, in The Chemistry of Heterocyclic Compounds, vol. 24 (II); Fused Pyrimidines, Part II, Purines,; ed. by E. C. Taylor and A. Weissberger, Wiley-Interscience, New York, 1971, 380-382.
2. K. T. Potts, in Comprehensive Heterocyclic Chemistry, ed. by A. R. Katritzky and C. W. Rees, Pergamon Press, 1984, 5, 548-549.
3. C. A. Ramsden, in Comprehensive Heterocyclic Chemistry II, ed. by A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Pergamon, 1996, 7, 414.
4. A. Al-Azmi, B. L. Booth, R. A. Carpenter, A. Carvalho, E. Marrelec, R. G. Pritchard, and F. J. R. P. Proença, J. Chem. Soc., Perkin Trans. 1, 2001, 2532. CrossRef
5. M. A. Carvalho, T. M. Esteves, M. F. Proença, and B. L. Booth, Org. Biorg. Chem., 2004, 2, 1019. CrossRef
6. a) M. A. Carvalho, S. Esperança, T. M. Esteves, and M. F. Proença, Eur. J. Org. Chem., 2007, 1324; CrossRef b) M. J. Alves, B. L. Booth, M. A. Carvalho, R. G. Pritchard, and F. J. R. P. Proença , J. Heterocycl. Chem., 1997, 34, 913. CrossRef
7. M. Hocek, M. Masojidkova, A. Holy, A. Graciela, R. Snoeck, J. Balzarini, and E. DeClerq, Collect. Czech. Chem. Commun., 1996, 61, 1525. CrossRef
8. T. E. Mabry, C. D. Jones, T. S. Chou, J. M. Colacino, G. B. Grindey, J. F. Worzalla, and H. L. Pearce, Nucleosides Nucleotides, 1994, 13, 1125. CrossRef
9. J. L. Kelley, D. C. Wilson, V. L. Styles, F. S. Soroko, and B. R. Cooper, J. Heterocycl. Chem., 1995, 32, 1417. CrossRef
10. A. Al-Azmi, P. George, and O. M. E. El-Dusouqui, J. Heterocycl. Chem., 2007, 44, 515. CrossRef
11. W. Pendergast and W. R. Hall, J. Heterocycl. Chem., 1989, 26, 1863. CrossRef
12. A. Al-Azmi, A. Elassar, and B. L. Booth, Tetrahedron, 2003, 59, 2749. CrossRef
13. Al-Azmi, J. Chem. Res., 2005, 8, 530. CrossRef
14. Al-Azmi, B. L. Booth, R. G. Pritchard, and F. J. R. P. Proença, J. Chem. Soc., Perkin Trans.1, 2001, 485. CrossRef
15. M. J. Alves, B. L. Booth, M. A. Carvalho, R. G. Pritchard, and F. J. R. P. Proença, J. Heterocycl. Chem., 1997, 34, 739. CrossRef
16. M. J. Alves, B. L. Booth, M. A. Carvalho, A. M. Dias, and M. F. Proença, J. Chem. Res. (S), 1996, 212; J. Chem. Res. (M), 1996, 1101.
17. B. L. Booth, A. M. Dias, and M. F. Proença, J. Chem. Soc., Perkin Trans. 1, 1992, 2119. CrossRef
18. M. J. Alves, B. L. Booth, and M. F. Proença, J. Chem. Soc., Perkin Trans.1, 1990, 1705. CrossRef
19. M. J. Alves, B. L. Booth, A. P. Freitas, and M. F. Proença, J. Chem. Soc., Perkin Trans.1, 1992, 913. CrossRef
20. A. P. Freitas, M. F. Proença, and B. L. Booth, J. Heterocycl. Chem., 1995, 32, 457. CrossRef
21. M. E. A. Zaki and M. F. Proença, Tetrahedron, 2007, 63, 3745. CrossRef
22. M. E. A. Zaki, M. F. Proença, and B. L. Booth, J. Org. Chem., 2003, 6, 276. CrossRef
23. M. E. A. Zaki, M. F. Proença, and B. L. Booth, Synlett, 2005, 16, 2429. CrossRef
24. A. Al-Azmi, P. George, and O. M. E. El-Dusouqui, Heterocycles, 2007, 71, 2183. CrossRef
25. Crystal data for compound 6a: (ref. CCDC 695454) can be obtained on request from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EW, UK. CCDC.
26. Crystal data for compound 12: (ref. CCDC 695453) can be obtained on request from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EW, UK. CCDC.