A Base-Catalyzed Cascade Route to Phenolic 6-Cyanopurines via O-Alkylformamidoximes

Abstract

N-[1,2-Dicyano-2-(hydroxyphenylideneamino)vinyl]-O-alkylformamidoximes were prepared from the reaction of N-(2-amino-1,2-dicyanovinyl)-O-alkylformamidoximes with phenolic aldehydes. These compounds generated 2-hydroxyphenyl-4,5-dicyano-N-(N'-alkoxyformimidoyl)imidazoles in the presence of manganese oxide, whereas in triethylamine 6-cyano-8-hydroxy-phenylpurines were isolated. The reaction was followed by ¹H NMR spectroscopy and a plausible mechanism is presented.

Purines are valuable compounds with special impact in the area of medicinal chemistry, with a number of derivatives presenting antifungal,[1] [2] antibacterial,[1,2] antimycobacterial,[2] anticancer,[3] and antiviral[4] activity. The synthesis of substituted purines has been addressed in several review articles, but only a few 8-aryl-6-cyanopurines have been reported from 8-bromo,[5] 8-methyl[6] or 8-carbonyl[7] substitution on the purine scaffold. The cyano group in the 6-position is usually incorporated through cyanide ion substitution of either 6-iodo,[8] 6-chloro,[9] 6-tosyl,[10] 6-methylsulfonyl,[11] or 6-trimethylammonium[12] purine derivatives, and also by dehydration of the 6-oximo derivative.[13]

Phenolic 6-cyanopurines 4 have great potential as new antifungal scaffolds because they are structurally related to 6-substituted aminopurines[1] and also to benzimidazole antifungal agents, which are widely used in crop protection.[14]

The present work describes a convenient and efficient synthesis of 2-hydroxyphenyl-4,5-dicyano-N-(N'-alkoxyformimidoyl)imidazoles and 6-cyano-8-hydroxyphenylpurines. To our knowledge, these compounds have not been previously reported.

Prior studies on the reactivity of amidoximes 1 in our research group, showed that condensation with aromatic aldehydes occurs smoothly at room temperature, leading to good yields of the corresponding imines. In the absence of catalysis, the process was slow (2–20 days at room temperature) but it was observed that traces of carboxylic acid, generated in the reaction mixture from oxidation of the aldehyde, accelerated the reaction rate by promoting the elimination of water from the adduct.[15] Non-phenolic molecules with the core structure 2 (see Table [1]) have been previously prepared and cyclized in an intramolecular manner to substituted 4,5-dicyanoimidazoles in nitromethane and chloroform and in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).[15] Inspired by this synthetic approach, the present work describes the reaction of amidoximes 1 with phenolic aldehydes. The phenolic derivatives of these 4,5-dicyanoimidazoles are biologically promising compounds, and previous work has revealed a synergistic effect of a phenolic compound with the activity of an azole antifungal agent.[16] [17] The process was considerably accelerated by the use of p-toluenesulfonic acid catalysis, being complete after 15 min at room temperature, and the product was isolated as a yellow solid in very good yield (Table [1], entries 1–6). The cyclization of these amidoximes to the corresponding imidazole required the use of an oxidizing agent, and DDQ was initially selected for this purpose; however, this strong oxidizing agent led to extensive over-oxidation of the reaction mixture, probably due to the presence of the phenolic moiety. Instead, heating compounds 2 to reflux in tetrahydrofuran, in the presence of a large excess of manganese oxide (25–50 equiv) resulted in the formation of the substituted imidazoles 3 after 1–7 days (Table [1], entries 7–12). Manganese oxide, a mild oxidizing agent,[18] proved to be the best option for this sensitive process, in which oxidation of the phenolic unit had to be prevented.

The ¹H and ¹³C NMR spectra of the 4,5-dicyanoimidazoles 3 in DMSO-d ₆ are characterized by the presence of two sets of signals. This doubling of signals, which did not affect the aromatic ring on C-2 of the imidazole ring, could be brought about by an inversion barrier for the imine substituent on N-1. The presence of the hydroxyl group in the 2-position of the aromatic group (compounds 3a and 3d), resulted in a single set of signals in the ¹H and ¹³C NMR spectra, and the absence of signals for C-4 and C-5 of the imidazole core. The high chemical shift of the OH proton (δ = 12–15 ppm) indicated strong intramolecular H-bonding with the neighboring imidazole nitrogen, and is probably responsible for lowering the inversion barrier of the imine substituent.

Amidoximes 1 have previously been cyclized in the presence of base, leading to substituted imidazoles (in aqueous NaOH) or pyrimidines (in EtOAc and DBU).[19] The cyclization of 2 was performed in acetonitrile and triethylamine under reflux conditions (Table [1], entries 13 and 15) or in DMSO and triethylamine at room temperature (Table [1], entry 14).

Table 1 Reaction Conditions for the Synthesis of Compounds 2–4

Entry	Compound	R	OH position	Reaction conditions	Yield (%)a
1	2a	Bn	R1	MeOH, TsOH, r.t., 15 min	97
2	2b	Bn	R2	EtOH, TsOH, r.t., 20 min	65
3	2c	Bn	R3	EtOH, TsOH, r.t., 15 min	93
4	2d	Me	R1	EtOH, TsOH, r.t., 15 min	84
5	2e	Me	R2	CH2Cl2–EtOH (10:1), r.t., TsOH, 15 min	88
6	2f	Me	R3	EtOH, TsOH, r.t., 15 min	95
7	3a	Bn	R1	THF, MnO2, reflux, 7 d	64
8	3b	Bn	R2	THF, MnO2, reflux, 2 d	59
9	3c	Bn	R3	THF, MnO2, reflux, 29 d	77
10	3d	Me	R1	THF, MnO2, reflux, 7 d	40
11	3e	Me	R2	THF, MnO2, reflux, 2 d	81
12	3f	Me	R3	THF, MnO2, reflux, 25 h	66
13	4a	–	R1	MeCN, Et3N, reflux, 3 h	58
14	4b	–	R2	DMSO, Et3N, r.t., 4 d	72
15	4c	–	R3	MeCN, Et3N, reflux, 3 h	67

^a Isolated yield.

A cascade sequence can generate the 6-cyano-8-hydroxyphenylpurines 4 through an unusual reaction pathway. The synthesis of these compounds by direct cyclization methods is an unprecedented and very useful synthetic approach. These products were fully characterized and the ¹H NMR spectrum showed the C-2 proton at δ = 8.8–9.0 ppm and a very broad and acidic N–H signal (δ = 10.0–15.0 ppm). The presence of the cyano group was confirmed by ¹³C NMR (δ = 114.7–115.0 ppm) and infrared spectroscopy (a medium intensity signal around 2240 cm^–1).

The less expensive precursor O-benzylformamidoxime 1a was used in the synthesis of the 6-cyanopurine 4a. However, benzyl alcohol is produced in the process and the high boiling point of this side product prevented its elimination from the reaction medium and interfered with the isolation of the purine. Purines 4b and 4c were initially synthesized from O-benzylformamidoxime 1a and they could not be precipitated from the reaction medium. ­However, when these compounds were synthesized from O-methylformamidoxime 1b, elimination of methanol ­resulted in a simpler isolation process.

The synthesis of such imidazoles and purines with a phenolic unit is sensitive because the phenol ring can be oxidized during the synthesis and because these molecules, incorporating both acidic (phenol) and basic (amidoxime, imidazole and purine) groups are difficult to isolate.

A mechanistic study of the formation of purine 4a by intramolecular cyclization of amidoxime 2d was performed by ¹H NMR spectroscopic analysis in DMSO-d ₆. In this experiment, amidoxime 2d (3 mg) was dissolved in DMSO-d ₆ (750 μL) and the mixture was kept at room temperature. A slow evolution was detected by recording ¹H NMR spectra at regular intervals over a period of 6 months. Traces of purine 4a were already detected in the reaction mixture after 18 days and the starting material 2d was completely consumed after approximately 90 days.

The relative amount of amidoxime 2d was assessed by using signals at δ = 8.8 and 8.7 ppm corresponding to the imine proton and C7-H in both isomeric structures, and a clean evolution to dihydropyrimidine 5 was detected. This compound shows the imine proton C(9)-H at δ = 9.3 ppm and the dihydropyrimidine C-2 proton at δ = 7.5 ppm. The N(7)-H signal (δ = 9.7 ppm) and the methoxyl group (δ = 4.0 ppm) could also be identified. The integration of the imine C-9 proton was again used to quantify this compound in the mixture.

Intramolecular cyclization in compound 5 leads to dihydropurine 6, which was identified by the signals at δ = 6.3 (exchanges with D₂O and was assigned to the N-9 proton) and 5.7 ppm, assigned to the C-8 proton. As soon as compound 6 was detected in the NMR spectrum, methanol could be detected (δ = 3.2 ppm) and the signals for purine 4a were also simultaneously formed. This compound was quantified by the singlet δ = 9.0 ppm, corresponding to the C-2 proton. The ratios of compounds 2d, 5, 6, and 4a were measured over 180 days, and the results are combined in Figure [1]. Dihydropyrimidine 5 is particularly stable and constituted more than 60% of reaction mixture after approximately 40 days.

This ¹H NMR study supports the mechanistic proposal for the one-pot formation of purines 4 from amidoximes 2 shown in Scheme [1]. The formation of dihydropyrimidine 5 from amidoxime 2d is a process similar to that previously described by our group for amidoxime 1b, which promptly cyclizes to 5-amino-4-cyano-6-imino-1-methoxy-1,6-dihydropyrimidine by nucleophilic attack of the amidoxime group nitrogen onto the cyano group at the 2-position in the presence of DBU.[19] Intramolecular cyclization with the imine function to generate the dihydropurine 6 was observed for the first time, and the same applies to the elimination of methanol to allow for the formation of an 8-phenyl-6-cyanopurine 4a.

The synthesis of purines 4 was performed in the presence of triethylamine and the process was accelerated considerably by the inclusion of a base. This probably results from a ring-chain tautomeric equilibrium involving intermediates 5 and 6, gradually being displaced due to the elimination of methanol from dihydropurine 6. This process can be assisted by a mild base, by capturing the acidic proton on N-9.

In conclusion, an efficient synthesis of phenolic 4,5-di­cyanoimidazoles 3 and 6-cyanopurines 4 from amidoximes 2 under simple and mild reaction conditions has been developed.[20] A mechanistic study of the formation of purine 4 by intramolecular cyclization of amidoxime 2d was performed by ¹H NMR spectroscopy and allowed us to clarify the mechanism of reaction.

Acknowledgment

This research was funded by the Portuguese Fundação para a Ciência e Tecnologia (PPCDT/QUI/59356/2004). F.M.A. gratefully acknowledges a postdoctoral grant from the Portuguese FCT (SFRH/BPD/26106/2005).

• References and Notes

• 1 Tunçbilek M, Ateş-Alagöz Z, Altanlar N, Karayel A, Özbey S. Bioorg. Med. Chem. 2009; 17: 1693
  CrossrefSearch in Google Scholar
• 2 Roggen H, Charnock C, Burman R, Felth J, Larsson R, Bohlin L, Gundersen L. Arch. Pharm. Chem. Life Sci. 2011; 344: 50
  CrossrefSearch in Google Scholar
• 3 Rida S, Ashour F, El-Hawash S, El-Semary M, Badr M. Arch. Pharm. Chem. Life Sci. 2007; 340: 185
  CrossrefSearch in Google Scholar
• 4 Narayanasamy J, Pullagurla M, Sharon A, Wang J, Schinazi R, Chu C. Antiviral Res. 2007; 75: 198
  CrossrefSearch in Google Scholar
• 5 Chih Y, Kukla J. Bioorg. Med. Chem. Lett. 1991; 1: 531
  CrossrefSearch in Google Scholar
• 6 Booth B, Coster D, Proenca M. Synthesis 1988; 389
  Thieme Connect
• 7 Booth L, Dias M, Proenca M, Zaki M. J. Org. Chem. 2001; 66: 8436
  CrossrefSearch in Google Scholar
• 8 Mackay L, Hitchings G. J. Am. Chem. Soc. 1956; 78: 3511
  CrossrefSearch in Google Scholar
• 9 Miyashita A, Susuki Y, Ohta K, Higashino T. Heterocycles 1994; 39: 345
  CrossrefSearch in Google Scholar
• 10 Hayashi E, Shimida N, Miyashita A. Yakugaku Zasshi 1976; 96: 1370 ; Chem. Abstr. 1977, 86, 121295
  Search in Google Scholar
• 11 Yamane A, Matsuda M, Ueda T. Chem. Pharm. Bull. 1980; 28: 150
  CrossrefSearch in Google Scholar
• 12 Barlin G, Young A. J. Chem. Soc., Perkin Trans. 1 1972; 1269
  Crossref
• 13 Giner-Sorolla A. Chem. Ber. 1968; 101: 611
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• 14 Schirra M, D’Aquino S, Cabras P, Angioni A. J. Agric. Food Chem. 2011; 59: 8531
  CrossrefSearch in Google Scholar
• 15 Booth B, Costa F, Pritchard R, Proença M. Synthesis 2000; 1269
  Thieme Connect
• 16 Sun S, Lou H, Gao Y, Fan P, Ma B, Ge W, Wang X. J. Pharm. Biomed. Anal. 2004; 34: 1117
  CrossrefSearch in Google Scholar
• 17 Sun S, Gao Y, Ling X, Lou H. Anal. Biochem. 2005; 336: 39
  CrossrefSearch in Google Scholar
• 18 Hamada Y, Shibata M, Sugiura T, Kato S, Shioiri T. J. Org. Chem. 1987; 52: 1252
  CrossrefSearch in Google Scholar
• 19 Booth B, Costa F, Mahmood Z, Pritchard R, Proença M. J. Chem. Soc., Perkin Trans. 1 1999; 1853
• 20 Synthesis of (Z)-N-[1,2-Dicyano-2-(arylideneamino)-vinyl]-O-alkylformamidoximes (2); General Procedure: Toluenesulfonic acid (cat.) was added to a suspension of either 1a (3.31 mmol) or 1b (1.23–2.45 mmol) and the phenolic aldehyde (1.23–3.31 mmol, 1 equiv) in either MeOH, CH₂Cl₂–EtOH (10:1), or EtOH (2–7 mL). The reaction was complete after 15 min stirring on an ice bath, and the yellow solid was collected by filtration and washed with cold Et₂O to afford products 2a–f. (Z)-N-[1,2-Dicyano-2-(2'-hydroxybenzylidenamino)-vinyl]-O-benzylformamidoxime (2a): Yield: 1.11 g (3.20 mmol, 97%); mp 183–185 °C. IR (NaCl): 3407, 3280, 2234, 2222, 1646, 1623, 1606, 1560, 1494, 1459, 1403 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 10.75 (s, 1 H), 9.33 (s, 1 H), 8.77 (s, 1 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.64 (s, 1 H), 7.30–7.45 (m, 6 H), 6.98 (d, J = 8.40 Hz, 1 H), 6.83 (t, J = 7.80 Hz, 1 H), 5.08 (s, 2 H); δ (minor tautomer: m) = 10.58 (s, 1 H), 8.73 (s, 1 H), 8.24 (s, 1 H), 4.98 (s, 2 H); Ratio M/m = 7:1. ¹³C NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 159.53, 157.63, 137.25, 136.94, 135.06, 128.34, 128.12, 127.95, 127.72, 120.58, 119.72, 117.89, 116.86, 113.23, 112.49, 112.31, 75.48; δ (minor tautomer: m) = 159.06, 156.70, 134.50, 129.24, 128.29, 128.21, 127.79, 121.00, 119.44, 116.56, 75.29. Anal. Calcd for C₁₉H₁₅N₅O₂: C, 66.1; H, 4.4; N, 20.3. Found: C, 66.2; H, 4.4; N, 20.1. Synthesis of 2-Aryl-4,5-dicyano-N-(N'-alkoxyformi-midoyl)imidazoles (3); General Procedure: A solution of 2 (0.25 g, 0.72 mmol) in THF was combined with MnO₂ (25–50 equiv). The reaction was complete after 1–29 days heating at reflux and the mixture was filtered through glass fiber paper. The solvent was concentrated under reduced pressure and a yellow solid precipitated by addition of chloroform and n-hexane. The solid was filtered to afford products 3a–f. 4,5-Dicyano-2-(2′-hydroxyphenyl)-N-(N′-benzyloxifor-mimidoyl)imidazole (3a): Yield: 0.16 g (0.46 mmol, 64%); mp 171–174 °C. IR (NaCl): 3195, 3089, 3035, 2248, 2237, 1631, 1605, 1581, 1550, 1518, 1483, 1392 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.00–15.00 (s, <1 H), 7.95 (d, J = 7.50 Hz, 1 H), 7.46 (s, 1 H), 7.24–7.42 (m, 6 H), 7.00 (d, J = 8.40 Hz, 1 H), 6.94 (t, J = 8.10 Hz, 1 H), 5.02 (s, 2 H). 13C NMR (300 MHz, DMSO-d6): δ = 155.51, 151.49, 142.72, 137.61, 131.73, 128.65, 128.33, 128.24, 127.87, 119.53, 116.43, 114.29, 112.12, 109.26, 75.42. Anal. Calcd for C19H13N5O2·0.1H2O: C, 66.0; H, 3,9; N, 20.3. Found: C, 66.0; H, 3.9; N, 20.1. 6-Cyano-8-(2'-hydroxyphenyl)purine (4a): Et₃N (1.0 mL) was added to a suspension of 2a (0.10 g, 0.29 mmol) in MeCN (25 mL) leading to a red solution. The mixture was heated to reflux for 3 h, then the solvent was concentrated on a rotary evaporator. Addition of CH₂Cl₂ and n-hexane led to the formation of a yellow solid that was filtered to give 4a. Yield: 0.04 g (0.17 mmol, 58%); mp >300 °C (dec.). IR (NaCl): 3532, 3280, 2244, 1665, 1625, 1604, 1585, 1514, 1398 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10–15 (s, 2 H), 9.00 (s, 1 H), 8.12 (dd, J = 7.80, 1.50 Hz, 1 H), 7.45 (dt, J = 7.80, 1.50 Hz, 1 H), 7.06 (d, J = 7.80 Hz, 1 H), 7.01 (dt, J = 7.80, 0.90 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.57, 158.40, 155.91, 151.93, 134.08, 133.64, 128.63, 125.20, 119.74, 117.40, 114.70, 112.24. Anal. Calcd for C₁₂H₇N₅O·0.9H₂O: C, 56.9; H, 3.5; N, 27.6. Found: C, 57.2; H, 3.5; N, 27.3. 6-Cyano-8-(3′-hydroxyphenyl)purine (4b): Et₃N (0.52 mL) was added to a solution of 2e (0.10 g, 0.37 mmol) in DMSO (0.5 mL) and the mixture was stirred at r.t. for 4 days. A white solid was formed after addition of CHCl₃ and n-hexane. The product was filtered and washed with n-hexane to give 4b. Yield: 0.06 g (0.27 mmol, 72%); mp >300 °C (dec.). IR (NaCl): 3404, 3153, 2243, 1625, 1613, 1598, 1583, 1527, 1406 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.91 (s, >1 H, NH), 8.98 (s, 1H), 7.75 (d, J = 1.20 Hz, 1 H), 7.74 (d, J = 7.80 Hz, 1 H), 7.41 (t, J = 7.80 Hz, 1 H), 7.01 (dt, J = 8.10, 1.80 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.45, 157.94, 156.78, 151.77, 135.49, 130.39, 129.38, 126.03, 119.41, 118.67, 114.88, 114.41. Anal. Calcd for C₁₂H₇N₅O·0.6H₂O: C, 58.0; H, 3.4; N, 28.2. Found: C, 58.3; H, 3.7; N, 28.0. 6-Cyano-8-(4′-hydroxyphenyl)purine (4c): Et₃N (1.50 mL) was added to a suspension of 2f (0.10 g, 0.37 mmol) in MeCN (9 mL), leading to an orange solution. After 3 h heating to reflux, the solvent was concentrated on a rotary evaporator to give a yellow solid that was filtered and washed with Et₂O to give 4c. Yield: 0.06 g (0.25 mmol, 67%); mp >300 °C (dec.). IR (NaCl): 3454, 3379, 3144, 2236, 1656, 1615, 1592, 1563, 1481, 1437 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 13.50–15.00 (s, 1 H), 10.45 (s, 1 H), 8.93 (s, 1 H), 8.17 (d, J = 8.70 Hz, 2 H), 6.97 (d, 2 H, J = 8.70 Hz). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 161.60, 158.35, 156.69, 151.46, 144.83, 130.12, 124.93, 118.52, 116.18, 115.01. HRMS: m/z [M + H]⁺ calcd for C₁₂H₇N₅O: 238.0684; found: 238.0732.

• References and Notes

• 1 Tunçbilek M, Ateş-Alagöz Z, Altanlar N, Karayel A, Özbey S. Bioorg. Med. Chem. 2009; 17: 1693
  CrossrefSearch in Google Scholar
• 2 Roggen H, Charnock C, Burman R, Felth J, Larsson R, Bohlin L, Gundersen L. Arch. Pharm. Chem. Life Sci. 2011; 344: 50
  CrossrefSearch in Google Scholar
• 3 Rida S, Ashour F, El-Hawash S, El-Semary M, Badr M. Arch. Pharm. Chem. Life Sci. 2007; 340: 185
  CrossrefSearch in Google Scholar
• 4 Narayanasamy J, Pullagurla M, Sharon A, Wang J, Schinazi R, Chu C. Antiviral Res. 2007; 75: 198
  CrossrefSearch in Google Scholar
• 5 Chih Y, Kukla J. Bioorg. Med. Chem. Lett. 1991; 1: 531
  CrossrefSearch in Google Scholar
• 6 Booth B, Coster D, Proenca M. Synthesis 1988; 389
  Thieme Connect
• 7 Booth L, Dias M, Proenca M, Zaki M. J. Org. Chem. 2001; 66: 8436
  CrossrefSearch in Google Scholar
• 8 Mackay L, Hitchings G. J. Am. Chem. Soc. 1956; 78: 3511
  CrossrefSearch in Google Scholar
• 9 Miyashita A, Susuki Y, Ohta K, Higashino T. Heterocycles 1994; 39: 345
  CrossrefSearch in Google Scholar
• 10 Hayashi E, Shimida N, Miyashita A. Yakugaku Zasshi 1976; 96: 1370 ; Chem. Abstr. 1977, 86, 121295
  Search in Google Scholar
• 11 Yamane A, Matsuda M, Ueda T. Chem. Pharm. Bull. 1980; 28: 150
  CrossrefSearch in Google Scholar
• 12 Barlin G, Young A. J. Chem. Soc., Perkin Trans. 1 1972; 1269
  Crossref
• 13 Giner-Sorolla A. Chem. Ber. 1968; 101: 611
  CrossrefSearch in Google Scholar
• 14 Schirra M, D’Aquino S, Cabras P, Angioni A. J. Agric. Food Chem. 2011; 59: 8531
  CrossrefSearch in Google Scholar
• 15 Booth B, Costa F, Pritchard R, Proença M. Synthesis 2000; 1269
  Thieme Connect
• 16 Sun S, Lou H, Gao Y, Fan P, Ma B, Ge W, Wang X. J. Pharm. Biomed. Anal. 2004; 34: 1117
  CrossrefSearch in Google Scholar
• 17 Sun S, Gao Y, Ling X, Lou H. Anal. Biochem. 2005; 336: 39
  CrossrefSearch in Google Scholar
• 18 Hamada Y, Shibata M, Sugiura T, Kato S, Shioiri T. J. Org. Chem. 1987; 52: 1252
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• 19 Booth B, Costa F, Mahmood Z, Pritchard R, Proença M. J. Chem. Soc., Perkin Trans. 1 1999; 1853
• 20 Synthesis of (Z)-N-[1,2-Dicyano-2-(arylideneamino)-vinyl]-O-alkylformamidoximes (2); General Procedure: Toluenesulfonic acid (cat.) was added to a suspension of either 1a (3.31 mmol) or 1b (1.23–2.45 mmol) and the phenolic aldehyde (1.23–3.31 mmol, 1 equiv) in either MeOH, CH₂Cl₂–EtOH (10:1), or EtOH (2–7 mL). The reaction was complete after 15 min stirring on an ice bath, and the yellow solid was collected by filtration and washed with cold Et₂O to afford products 2a–f. (Z)-N-[1,2-Dicyano-2-(2'-hydroxybenzylidenamino)-vinyl]-O-benzylformamidoxime (2a): Yield: 1.11 g (3.20 mmol, 97%); mp 183–185 °C. IR (NaCl): 3407, 3280, 2234, 2222, 1646, 1623, 1606, 1560, 1494, 1459, 1403 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 10.75 (s, 1 H), 9.33 (s, 1 H), 8.77 (s, 1 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.64 (s, 1 H), 7.30–7.45 (m, 6 H), 6.98 (d, J = 8.40 Hz, 1 H), 6.83 (t, J = 7.80 Hz, 1 H), 5.08 (s, 2 H); δ (minor tautomer: m) = 10.58 (s, 1 H), 8.73 (s, 1 H), 8.24 (s, 1 H), 4.98 (s, 2 H); Ratio M/m = 7:1. ¹³C NMR (300 MHz, DMSO-d ₆): δ (major tautomer: M) = 159.53, 157.63, 137.25, 136.94, 135.06, 128.34, 128.12, 127.95, 127.72, 120.58, 119.72, 117.89, 116.86, 113.23, 112.49, 112.31, 75.48; δ (minor tautomer: m) = 159.06, 156.70, 134.50, 129.24, 128.29, 128.21, 127.79, 121.00, 119.44, 116.56, 75.29. Anal. Calcd for C₁₉H₁₅N₅O₂: C, 66.1; H, 4.4; N, 20.3. Found: C, 66.2; H, 4.4; N, 20.1. Synthesis of 2-Aryl-4,5-dicyano-N-(N'-alkoxyformi-midoyl)imidazoles (3); General Procedure: A solution of 2 (0.25 g, 0.72 mmol) in THF was combined with MnO₂ (25–50 equiv). The reaction was complete after 1–29 days heating at reflux and the mixture was filtered through glass fiber paper. The solvent was concentrated under reduced pressure and a yellow solid precipitated by addition of chloroform and n-hexane. The solid was filtered to afford products 3a–f. 4,5-Dicyano-2-(2′-hydroxyphenyl)-N-(N′-benzyloxifor-mimidoyl)imidazole (3a): Yield: 0.16 g (0.46 mmol, 64%); mp 171–174 °C. IR (NaCl): 3195, 3089, 3035, 2248, 2237, 1631, 1605, 1581, 1550, 1518, 1483, 1392 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.00–15.00 (s, <1 H), 7.95 (d, J = 7.50 Hz, 1 H), 7.46 (s, 1 H), 7.24–7.42 (m, 6 H), 7.00 (d, J = 8.40 Hz, 1 H), 6.94 (t, J = 8.10 Hz, 1 H), 5.02 (s, 2 H). 13C NMR (300 MHz, DMSO-d6): δ = 155.51, 151.49, 142.72, 137.61, 131.73, 128.65, 128.33, 128.24, 127.87, 119.53, 116.43, 114.29, 112.12, 109.26, 75.42. Anal. Calcd for C19H13N5O2·0.1H2O: C, 66.0; H, 3,9; N, 20.3. Found: C, 66.0; H, 3.9; N, 20.1. 6-Cyano-8-(2'-hydroxyphenyl)purine (4a): Et₃N (1.0 mL) was added to a suspension of 2a (0.10 g, 0.29 mmol) in MeCN (25 mL) leading to a red solution. The mixture was heated to reflux for 3 h, then the solvent was concentrated on a rotary evaporator. Addition of CH₂Cl₂ and n-hexane led to the formation of a yellow solid that was filtered to give 4a. Yield: 0.04 g (0.17 mmol, 58%); mp >300 °C (dec.). IR (NaCl): 3532, 3280, 2244, 1665, 1625, 1604, 1585, 1514, 1398 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 10–15 (s, 2 H), 9.00 (s, 1 H), 8.12 (dd, J = 7.80, 1.50 Hz, 1 H), 7.45 (dt, J = 7.80, 1.50 Hz, 1 H), 7.06 (d, J = 7.80 Hz, 1 H), 7.01 (dt, J = 7.80, 0.90 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.57, 158.40, 155.91, 151.93, 134.08, 133.64, 128.63, 125.20, 119.74, 117.40, 114.70, 112.24. Anal. Calcd for C₁₂H₇N₅O·0.9H₂O: C, 56.9; H, 3.5; N, 27.6. Found: C, 57.2; H, 3.5; N, 27.3. 6-Cyano-8-(3′-hydroxyphenyl)purine (4b): Et₃N (0.52 mL) was added to a solution of 2e (0.10 g, 0.37 mmol) in DMSO (0.5 mL) and the mixture was stirred at r.t. for 4 days. A white solid was formed after addition of CHCl₃ and n-hexane. The product was filtered and washed with n-hexane to give 4b. Yield: 0.06 g (0.27 mmol, 72%); mp >300 °C (dec.). IR (NaCl): 3404, 3153, 2243, 1625, 1613, 1598, 1583, 1527, 1406 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 9.91 (s, >1 H, NH), 8.98 (s, 1H), 7.75 (d, J = 1.20 Hz, 1 H), 7.74 (d, J = 7.80 Hz, 1 H), 7.41 (t, J = 7.80 Hz, 1 H), 7.01 (dt, J = 8.10, 1.80 Hz, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 158.45, 157.94, 156.78, 151.77, 135.49, 130.39, 129.38, 126.03, 119.41, 118.67, 114.88, 114.41. Anal. Calcd for C₁₂H₇N₅O·0.6H₂O: C, 58.0; H, 3.4; N, 28.2. Found: C, 58.3; H, 3.7; N, 28.0. 6-Cyano-8-(4′-hydroxyphenyl)purine (4c): Et₃N (1.50 mL) was added to a suspension of 2f (0.10 g, 0.37 mmol) in MeCN (9 mL), leading to an orange solution. After 3 h heating to reflux, the solvent was concentrated on a rotary evaporator to give a yellow solid that was filtered and washed with Et₂O to give 4c. Yield: 0.06 g (0.25 mmol, 67%); mp >300 °C (dec.). IR (NaCl): 3454, 3379, 3144, 2236, 1656, 1615, 1592, 1563, 1481, 1437 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 13.50–15.00 (s, 1 H), 10.45 (s, 1 H), 8.93 (s, 1 H), 8.17 (d, J = 8.70 Hz, 2 H), 6.97 (d, 2 H, J = 8.70 Hz). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 161.60, 158.35, 156.69, 151.46, 144.83, 130.12, 124.93, 118.52, 116.18, 115.01. HRMS: m/z [M + H]⁺ calcd for C₁₂H₇N₅O: 238.0684; found: 238.0732.

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