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Article

Efficient Synthesis of Novel Triazolo[5,1-b]purines by Diacetoxyiodobenzene-Mediated Oxidative Cyclization of Schiff Bases

by
Artyom O. Neymash
*,
Victor V. Fedotov
,
Evgeny N. Ulomsky
*,
Daniil N. Lyapustin
,
Semen V. Aminov
and
Vladimir L. Rusinov
Chemical Engineering Institute, Ural Federal University, 19 Mira St., 620002 Yekaterinburg, Russia
*
Authors to whom correspondence should be addressed.
Reactions 2024, 5(4), 1089-1100; https://doi.org/10.3390/reactions5040058
Submission received: 8 November 2024 / Revised: 11 December 2024 / Accepted: 16 December 2024 / Published: 18 December 2024
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Abstract

In this work, we have developed a method for synthesizing new 8-substituted triazolo[5,1-b]purines using diacetoxyiodobenzene as an oxidizing agent with good yields (59–67%). The advantages of this approach include mild reaction conditions and removing the need to use transition metals. Based on the results obtained, a plausible reaction pathway was proposed. The developed approach opens new possibilities for the preparation of previously inaccessible condensed purine derivatives, which are of interest for the development of biomolecules with a variety of pharmacological applications. The structures of the compounds were confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and an elemental analysis.

Graphical Abstract

1. Introduction

Natural purines are among the most known and well-studied representatives of nitrogen heterocycles due to their involvement in the regulation of essential biological processes in many living organisms [1,2,3]. The presence of these heterocyclic fragments in the structure of nucleic acids has inspired active research aimed at creating modified nucleosides and peptide nucleic acids, which, in turn, has led to the development of new drugs based on purines [4,5,6,7,8,9,10,11] (Figure 1).
Indeed, drugs based on natural purines are used to treat different types of cancer [12,13,14,15], including leukemia, with medications that have different mechanisms of action [16,17]; they are also included in antiretroviral therapy, one of the few ways to treat HIV [18,19,20]. Originally, such drugs were guanine- and adenine-based nucleosides [21,22], but subsequently, self-modified aglycones were also used. Some of these modified systems include 2-aminopurine derivatives that are not direct analogs of guanine [23,24]. Not only do 2-aminopurines have a wide range of biological activities [25,26,27,28] but they also exhibit fluorescent properties [29,30], which provide possibilities for their use in analyzing the geometry and dynamics of nucleic acids [31,32]. Based on this, it is essential to develop new polycyclic structures based on 2-aminopurine to obtain compounds for the use as potential drugs or organic luminescent materials.
By polycyclic structures, we primarily refer to azoloannelated purines, namely triazolo[5,1-b]purines. In the literature, there are few methods for obtaining such heterocyclic systems, and all involve the sequential annelation of the pyrimidine cycle to the 1,2,4-triazole moiety, followed by the formation of the imidazole ring (Scheme 1). For example, Tenor and Kröger use 2-acetamidocyanoacetic ester for this purpose [33], while in more recent work, the construction is based on the corresponding nitro derivatives [34,35]. Previously, we developed a method for the preparation of 2-aminopurine starting from aminotetrazole [36], and a preparation of 6,7-diaminoazolo [1,5-a]pyrimidines was proposed in Gazizov’s publication [37,38]. Combining the ideas of these works, the present study, proposes a new approach to obtain C-8 modified triazolo[5,1-b]purines, starting from 6,7-diamino-2-thienyl-1,2,4-triazolo[1,5-a]pyrimidine and involving oxidation of the corresponding Schiff bases.

2. Materials and Methods

Commercial reagents were obtained from Sigma-Aldrich (Burlington, MA, USA), Acros Organics (Antwerpen, Belgium), or Alfa Aesar (Ward Hill, MA, USA), and were used without preprocessing. All workup and purification procedures were performed using analytical-grade solvents. The spectra were acquired using a Bruker DRX-400 (Karlsruhe, Germany) spectrometer at 400 MHz (1H) and 101 MHz (13C), respectively, or a Bruker Avance NEO 600 instrument at 151 MHz (13C), using DMSO-d6 and CF3COOD as solvents and an external reference, respectively. Chemical shifts are expressed in δ (parts per million, ppm) values and coupling constants are expressed in hertz (Hz). The following abbreviations are used for the multiplicity of NMR signals: s, singlet; d, doublet; t, triplet; dd, doublet of doublet; m, multiplet; and AN, anthracene. IR spectra were recorded on a Bruker α spectrometer equipped with a ZnSe ATR accessory. Elemental analysis was performed on a PerkinElmer PE 2400 elemental analyzer (Waltham, MA, USA). Melting points were determined on a Stuart SMP3 (Staffordshire, UK) and are uncorrected. Monitoring the reaction progress was completed using TLC on Sorbfil plates (Imid Ltd., Krasnodar, Russia) (the eluent is EtOAc, visualizing with UV light).
General procedure (1) for the synthesis of 4-(aryl)-amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3a–g).
To a suspension of 2.32 g (0.01 mol) 2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-6,7-diamine 1 in 20 mL DMF, the 0.01 mol of corresponding aldehyde 3a–g and 10% mol (0.06 mL) of MeSO3H were added and the mixture was heated at 120 °C on an oil bath for 12 h. The reaction mixture was cooled to room temperature and the precipitate was filtered. The precipitate was then washed with MeOH and Et2O.
6-((4-(Dimethylamino)benzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3a). The reaction was performed according to the general procedure (1) employing 1.49 g (0.01 mol, 1 equiv.) of 4-(dimethylamino)benzaldehyde 2a. Yellow powder. Yield 86% (3.12 g). mp. 283–285 °C. IR ν, cm−1: 3270, 3233, 1276, 1237. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 8.73 (1H, s, -CH=N), 8.55 (1H, s, H-4), 7.91 (4H, m, H-2″, H-3″, H-5″, H-6″), 7.84 (1H, d, J = 3.6 Hz, H-3′), 7.74 (1H, d, J = 5.0 Hz, H-5′), 7.25 (1H, t, J = 3.5 Hz, H-4′), 6.79 (2H, d, J = 8.5 Hz, NH2), 3.03 (6H, s, (CH3)2). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 160.61, 157.70, 155.01, 152.92, 145.25, 142.55, 134.46 (2C), 131.01 (2C), 129.19, 128.57, 128.11, 124.82, 118.91, 118.87 (2C). Calculated for C18H17N7S: C 59.49, H 4.71, N, 26.98; found: C 59.41, H 4.76, N 27.04.
6-((4-Methoxybenzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3b). The reaction was performed according to the general procedure (1) employing 1.36 g (0.01 mol, 1 equiv.) of 4-methoxybenzaldehyde 2b. Yellow powder. Yield 81% (2.83 g). mp. >300 °C. IR ν, cm−1: 3265, 3235, 1218, 1178. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 8.86 (1H, s, -CH=N), 8.62 (1H, s, H-4), 8.21 (2H, s, NH2), 8.06 (2H, d, J = 8.7, H-2″, H-6″), 7.85 (1H, dd, J = 3.7, 1.3 Hz, H-3′), 7.76 (1H, dd, J = 5.0, 1.3 Hz, H-5′), 7.25 (1H, dd, J = 5.0, 3.6 Hz, H-4′), 7.06 (d, J = 8.7 Hz, 2H, H-3″, H-5″), 3.85 (3H, s, CH3). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 161.77, 160.09, 156.38, 154.75, 145.12, 142.30, 133.79, 130.72 (2C), 129.40, 128.91, 128.20, 127.76, 117.52, 114.06 (2C), 55.40. Calculated for C17H14N6OS: C 58.27, H 4.03, N, 23.98; found: C 58.21, H 4.14, N 23.94.
6-((Anthracen-9-ylmethylene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3c). The reaction was performed according to the general procedure (1) employing 2.06 g (0.01 mol, 1 equiv.) of 9-anthracenecarboxaldehyde 2c. Orange powder. Yield 82% (3.44 g). mp. 270–272 °C. IR ν, cm−1: 3404, 3143, 1278, 1217. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 10.08 (1H, s, -CH=N), 8.62 (1H, s, H-4), (3H, m, 3x HAN), 8.80 (1H, s, H-4), 8.19 (2H, d, J = 8.2 Hz, 2x HAN), 8.15 (2H, s, NH2), 7.89 (1H, dd, J = 3.7, 1.2 Hz, H-3′), 7.79 (1H, dd, J = 5.0, 1.2 Hz, H-5′), 7.63 (4H, m, 4x HAN), 7.27 (1H, dd, J = 5.0, 3.6 Hz, H-4′). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 160.73, 158.08, 155.52, 145.46, 143.85, 134.25, 131.35 (4C), 130.98, 130.70 (4C), 129.50, 129.34, 128.72, 128.36, 127.99, 127.84, 126.09, 125.82, 119.58. Calculated for C24H16N6S: C 68.55, H 3.84, N, 19.99; found: C 68.50, H 3.89, N 19.27.
2-(Thiophen-2-yl)-6-((thiophen-3-ylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3d). The reaction was performed according to the general procedure (1) employing 1.12 g (0.01 mol, 1 equiv.) of thiophene-2-carboxaldehyde 2d. Yellow powder. Yield 68% (2.22 g). mp. >300 °C. IR ν, cm−1: 3407, 3231, 1258. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 9.04 (1H, s, -CH=N), 8.56 (1H, s, H-4), 7.84 (1H, d, J = 3.6 Hz, Hthpen), 7.81 (2H, s, NH2), 7.68 (1H, dd, J = 15.9, 4.3 Hz, Hthpen), 7.66 (1H, dd, J = 13.1, 3.6 Hz, H-5thpen), 7.62 (1H, dd, J = 5.1, 1.6 Hz, Hthpen), 7.19 (q, J = 4.5 Hz, 2H, Hthpen). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 160.64, 155.27, 151.62, 145.23, 143.35, 143.19, 134.20, 133.24, 131.80, 129.46, 128.70, 128.60, 128.30, 117.88. Calculated for C14H10N6S2: C 51.52, H 3.09, N, 25.75; found: C 51.43, H 3.18, N 25.79.
6-((4-Bromobenzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3e). The reaction was performed according to the general procedure (1) employing 1.85 g (0.01 mol, 1 equiv.) of 4-bromobenzaldehyde 2e. Light green crystalline powder. Yield 70% (2.79 g). mp. >300 °C. IR ν, cm−1: 3238, 1258. 1H NMR (600 MHz, DMSO-d6) δ, ppm (J, Hz): 8.99 (1H, s, -CH=N), 8.83 (1H, s, H-4), 8.77 (1H, dd, J = 4.5, 1.3 Hz, Har), 8.62 (2H, s, NH2), 8.57 (1H, dd, J = 8.0, 1.1 Hz, Har), 8.12 (1H, m, H-3′), 7.86 (1H, dd, J = 3.6, 1.3 Hz, Har), 7.78 (1H, dd, J = 4.9, 1.2 Hz, Har), 7.63 (1H, ddd, J = 7.4, 5.0, 1.3 Hz, H-5′), 7.25 (1H, m, H-4′). 13C NMR (151 MHz, DMSO-d6) δ, ppm (J, Hz): 160.30, 155.04, 153.16, 152.74, 147.93, 146.19, 142.75, 133.39 (2C), 129.29, 128.33 (2C), 128.15, 125.77, 123.26, 115.58. Calculated for C16H11BrN6S: C 48.13, H 2.78, N, 21.05; found: C 48.18, H 2.75, N 21.03.
6-((Pyridin-2-ylmethylene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3f). The reaction was performed according to the general procedure (1) employing 1.07 g (0.01 mol, 1 equiv.) of 3-pyridinecarboxaldehyde 2f. Dark yellow powder. Yield 65% (2.08 g). mp. 183–185 °C. IR ν, cm−1: 3449, 3083, 1186. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 8.93 (1H, s, -CH=N), 8.74 (1H, s, H-4), 8.69 (1H, d, J = 4.0 Hz H-3′), 8.60 (1H, d, J = 8.0 Hz, H-6″), 8.30 (2H, s, NH2), 7.93 (1H, td, J = 7.7, 1.8 Hz, H-4″), 7.85 (1H, dd, J = 3.6, 1.2 Hz, H-5′), 7.65 (1H, dd, J = 5.0, 1.2 Hz, H-4′), 7.47 (1H, dd, J = 7.4, 4.8 Hz, H-5″), 7.21 (1H, dd, J = 5.0, 3.6 Hz, H-3″). 13C NMR (151 MHz, DMSO-d6) δ, ppm (J, Hz): 160.29, 155.07, 153.60, 153.09, 148.17, 146.11, 142.80, 138.72, 133.43, 129.25, 128.31, 128.11, 125.66, 123.01, 115.64. Calculated for C15H11N7S: C 56.06, H 3.45, N, 30.51; found: C 56.11, H 3.44, N 30.57.
6-((4-(Diphenylamino)benzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (3g). The reaction was performed according to the general procedure (1) employing 2.73 g (0.01 mol, 1 equiv.) of 4-(diphenylamino)benzaldehyde 2g. Yellow powder. Yield 61% (2.97 g). mp. 265–267 °C. IR ν, cm−1: 3444, 3057, 1274. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 8.81 (1H, s, -CH=N), 8.60 (1H, s, H-4), 8.16 (2H, s, NH2), 7.95 (2H, d, J = 8.4 Hz, HC6H4), 7.83 (H, m, HPh), 7.75 (H, m, HPh), 7.37 (4H, t, J = 7.7 Hz, HPh), 7.23 (H, dd, J = 5.0, 3.6 Hz, HPh), 7.13 (6H, m, HPh), 6.96 (2H, d, J = 8.3 Hz, HC6H4). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 160.07, 156.06, 154.71, 149.93, 146.38 (2C), 145.05, 142.24, 133.79, 130.22 (2C), 129.74 (4C), 128.88, 128.17, 127.72, 125.19 (4C), 124.25 (2C), 120.57 (2C), 117.65 (2C). Calculated for C28H21N7S: C 68.97, H 4.34, N, 20.11; found: C 69.04, H 4.29, N 20.17.
General procedure (2) for the synthesis of aryl-4-(2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purin-7-yl)aniline (4a–g) is as follows:
To a solution of the corresponding Schiff base (0.001 mol), 3a–g in 5 mL CF3COOH and 0.40 g (0.00125 mol, 1.25 equiv.) of PhI(OAc)2 were added. The reaction mixture was stirred at room temperature for 4 h. Then, 5 mL MeOH was added to the reaction mixture. The resulting solution was stirred for another 15 min and then evaporated. The residue was purified by flash chromatography; eluent—CHCl3/MeOH (9/1).
N,N-Dimethyl-4-(2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purin-7-yl)aniline (4a). The reaction was performed according to the general procedure (2) employing 0.45 g (0.00125 mol, 1 equiv.) of ((4-(dimethylamino)benzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3a. Yellow powder. Yield 60% (0.27 g). mp. 275-277 °C. IR ν, cm−1: 3088, 3059, 1133, 1094. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 13.71 (1H, s, NH), 8.94 (1H, s, H-4), 8.10 (2H, d, J = 8.8 Hz, H-2″, H-6″), 7.87 (1H, dd, J = 3.6, 1.2 Hz, H-3′), 7.61 (1H, dd, J = 5.0, 1.2 Hz, H-5′), 7.21 (1H, dd, J = 5.0, 3.6 Hz, H-4′), 6.83 (2H, d, J = 8.8 Hz, H-3″, H-5″), 3.10 (6H, s, (CH3)2). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 159.24, 154.93, 153.95, 152.14, 144.88, 139.03, 133.84, 128.45 (2C), 128.31, 127.99, 127.18, 120.37, 114.47, 111.62 (2C), 40.3 (2C). Calculated for C18H15N7S: C 59.82, H 4.18, N, 27.13; found: C 59.78, H 4.23, N 27.04.
7-(4-Methoxyphenyl)-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (4b). The reaction was performed according to the general procedure (2) employing 0.44 g (0.00125 mol, 1 equiv.) of ((4-methoxybenzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3b. White powder. Yield 66% (0.28 g). mp. >300 °C. IR ν, cm−1: 3061, 2839, 1438, 1177. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 13.99 (1H, s, NH), 9.03 (1H, s, H-4), 8.24 (2H, d, J = 8.8 Hz, H-2″, H-6″), 7.88 (1H, dd, J = 3.6, 1.2 Hz, 1H, H-3′), 7.62 (1H, d, J = 5.0 Hz, 1H, H-5′), 7.21 (1H, dd, J = 5.0, 3.6 Hz, H-4′), 7.12 (2H, d, J = 8.6 Hz, H-3″, H-5″), 4.04 (3H, s, CH3). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 161.92, 159.46, 154.14, 153.78, 144.57, 140.30, 133.84, 129.05 (2C), 128.69, 128.29, 127.48, 120.65, 120.49, 114.77 (2C), 55.52. Calculated for C17H12N7OS: C 58.61, H 3.47, N, 24.12; found: C 58.52, H 3.55, N 24.08.
7-(Anthracen-9-yl)-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (4c). The reaction was performed according to the general procedure (2) employing 0.52 g (0.00125 mol, 1 equiv.) of (anthracen-9-ylmethylene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3c. Orange powder. Yield 59% (0.31 g). mp. >300 °C °C. IR ν, cm−1: 3378, 3363, 1057. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 14.59 (1H, s, NH), 9.29 (1H, s, H-4), 8.95 (1H, s, HAN), 8.27 (2H, d, J = 8.3 Hz, 2H, HAN), 7.93 (1H, dd, J = 3.7, 1.2 Hz, H-3′), 7.84 (2H, d, J = 8.6 Hz, HAN), 7.78 (1H, d, J = 5.0, H-5′), 7.60 (5H, m, H-5′, HAN), 7.22 (1H, dd, J = 5.0, 3.6 Hz, H-4′). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 159.56, 154.22, 152.17, 144.46, 133.78 (2C), 130.61 (2C), 130.55 (2C), 130.18, 128.75 (2C), 128.66, 128.33 (2C), 127.55, 127.48, 125.87 (2C), 125.27 (2C), 123.16, 120.64. Calculated for C24H14N6S: C 68.88, H 3.37, N, 20.08; found: C 68.80, H 3.35, N 20.03.
2,7-Di(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (4d). The reaction was performed according to the general procedure (2) employing 0.41 g (0.00125 mol, 1 equiv.) of 2-(thiophen-2-yl)-6-((thiophen-2-ylmethylene)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3d. Gray powder. Yield 62% (0.25 g). mp. 254–256 °C. IR ν, cm−1: 3082, 1281, 1189. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 14.46 (1H, s, NH), 9.10 (1H, s, H-4), 8.06 (1H, d, J = 3.8 Hz, H-3″), 7.95 (1H, d, J = 5.0 Hz, H-5″), 7.90 (1H, dd, J = 3.6, 1.2 Hz, H-3′), 7.77 (1H, d, J = 5.0 Hz, H-5′), 7.33 (1H, dd, J = 5.0, 3.7 Hz, H-4″), 7.25 (1H, dd, J = 5.1, 3.6 Hz, H-4′). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 159.56, 154.18, 149.12, 133.73 (2C), 131.73 (2C), 131.32 (2C), 129.38, 128.97, 128.78, 128.31, 127.54. Calculated for C14H8N6S2: C 51.84, H 2.49, N, 25.91; found: C 51.79, H 2.45, N 25.90.
7-(4-Bromophenyl)-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (4e). The reaction was performed according to the general procedure (2) employing 0.49 g (0.00125 mol, 1 equiv.) of ((4-bromobenzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3e. Yellow powder. Yield 66% (0.33 g). mp. >300 °C. IR ν, cm−1: 3081, 1087, 1044. 1H NMR (600 MHz, DMSO-d6) δ, ppm (J, Hz): 14.52 (1H, s, NH), 9.16 (1H, s, H-4), 8.24 (2H, m, H-2″, H-6″), 7.90 (1H, dd, J = 3.5, 1.2 Hz, H-3′), 7.86 (2H, m, H-3″, H-5″), 7.77 (1H, dd, J = 5.0, 1.2 Hz, H-5′), 7.25 (1H, dd, J = 5.0, 3.6 Hz, H-4′). 13C NMR (151 MHz, DMSO-d6 + CF3COOD) δ, ppm (J, Hz): 159.56, 154.22, 152.41 (2C), 144.23, 141.17, 133.71, 132.43 (2C), 129.13 (2C), 128.82, 128.35, 127.58, 127.46, 125.23. Calculated for C16H9BrN6S: C 48.38, H 2.28, N, 21.16; found: C 48.43, H 2.26, N 21.21.
7-(Pyridin-2-yl)-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (4f). The reaction was performed according to the general procedure (2) employing 0.40 g (0.00125 mol, 1 equiv.) of ((pyridin-2-ylmethylene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3f. Beige powder. Yield 64% (0.25 g). mp. >300 °C. IR ν, cm−1: 3084, 3029, 1140. 1H NMR (600 MHz, DMSO-d6+CF3COOD) δ, ppm (J, Hz): 9.03 (1H, s, H-4), 8.75 (1H, d, J = 4.8 Hz, H-2″), 8.41 (1H, d, J = 7.8 Hz, H-5″), 8.04 (1H, td, J = 7.7, 1.7 Hz, H-4″), 7.88 (1H, dd, J = 3.5, 1.2 Hz, H-3′), 7.68 (1H, d, J = 5.0 Hz, H-5′), 7.57 (1H, dd, J = 7.6, 4.8 Hz, H-3″), 7.19 (1H, dd, J = 5.0, 3.5 Hz, H-4′). 13C NMR (151 MHz, DMSO-d6+CF3COOD) δ, ppm (J, Hz): 159.36, 154.12, 152.82, 150.08, 146.73, 144.97, 142.44, 138.96, 133.56, 129.50, 128.82, 128.60, 126.72, 123.52, 121.66. Calculated for C15H9N7S: C 56.42, H 2.84, N, 30.70; found: C 56.51, H 2.91, N 30.65.
N,N-Diphenyl-4-(2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purin-7-yl)aniline (4g). The reaction was performed according to the general procedure (2) employing 0.61 g (0.00125 mol, 1 equiv.) of ((4-(diphenylamino)benzylidene)amino)-2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 3g. Yellow powder. Yield 67% (0.41 g). mp. >300 °C. IR ν, cm−1: 1453, 1315, 1272. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 14.13 (1H, s, NH), 9.06 (1H, s, H-4), 8.16 (2H, d, J = 8.5 Hz, HC6H4), 7.91 (1H, d, J = 4.0 Hz, H-3′), 7.76 (1H, d, J = 5.0 Hz, H-5′), 7.42 (4H, t, J = 7.7 Hz, HPh), 7.26 (1H, t, J = 4.3 Hz, H-4′), 7.20 (6H, m, HPh), 7.06 (2H, d, J = 8.5 Hz, HC6H4).13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 160.07, 154.75, 154.28, 150.87, 146.66 (4C), 134.44 (2C), 130.36 (4C), 129.12 (2C), 128.69, 127.91, 126.18 (4C), 125.20 (3C), 120.77 (3C). Calculated for C28H19N7S: C 69.26, H 3.94, N, 20.19; found: C 69.34, H 3.88, N 20.22.
The procedure for the synthesis of 7-(thiophen-2-yl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[1,5-a]pyrimidine (5) is as follows:
To a mixture of 5.0 mL acetic acid and 0.350 mL of isoamyl nitrite (0.0026 mol), 0.3 g (0.0013 mol) of 2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-diamine was added, 1 and the mixture was heated at 60 °C on an oil bath for 5 h. The resulting suspension was cooled to room temperature and the precipitate was filtered out to give the pure product.
7-(Thiophen-2-yl)-3H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[1,5-a]pyrimidine (5). Yellow powder. Yield 58% (0.18 g). mp. >300 °C. IR ν, cm−1: 3082, 1513. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 9.66 (1H, s, H-4), 7.90 (1H, dd, J = 3.6, 1.3 Hz, H-3′), 7.79 (1H, dd, J = 5.0, 1.3 Hz, H-5′), 7.26 (1H, dd, J = 5.0, 3.6 Hz, H-4′). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 159.86, 154.79, 149.00, 143.15, 132.90, 129.42, 129.16, 128.42, 127.94. Calculated for C9H5N7S: C 44.44, H 2.07, N, 40.31; found: C 44.37, H 2.12, N 40.33.
The procedure for the synthesis of 7-methyl-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (6) is as follows:
To a mixture of 3.0 mL (0.018 mol) of triethylorthoacetate and 1.0 mL (0.01 mol) of acetic anhydride, 0.3 g (0.0013 mol) of 2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6,7-diamine was added 1 and the mixture was heated at 145 °C on an oil bath for 4 h. The resulting solution was evaporated and 5.0 mL acetone was added. The precipitate was filtered out to provide the pure product.
7-Methyl-2-(thiophen-2-yl)-6H-[1,2,4]triazolo[5,1-b]purine (6). Brown powder. Yield 62% (0.21 g). mp. >300 °C. IR ν, cm−1: 3334, 1284. 1H NMR (400 MHz, DMSO-d6) δ, ppm (J, Hz): 13.69 (1H, s, NH), 9.03 (1H, s, H-4), 7.85 (1H, dd, J = 3.7, 1.2 Hz, H-3′), 7.74 (1H, dd, J = 5.0, 1.2 Hz, H-5′), 7.24 (1H, dd, J = 5.0, 3.6 Hz, H-4′), 2.65 (3H, s, CH3). 13C NMR (101 MHz, DMSO-d6) δ, ppm (J, Hz): 159.37, 155.36, 153.90, 144.15, 140.33, 133.84, 128.63, 128.25, 127.39, 119.61, 14.97. Calculated for C11H8N6S: C 51.55, H 3.15, N, 32.79; found: C 51.50, H 3.19, N 32.70.

3. Results and Discussion

To obtain 8-substituted triazolo[5,1-b]purines, we selected 2-(thiophen-2-yl)-6,7-diamino-1,2,4-triazolo[1,5-a]pyrimidine 1 as an initial substrate since it is fairly easy to synthesize according to the method [14] and it has an additional conjugated heterocyclic ring, allowing us to obtain a polycyclic purine structure. First, we optimized the reaction of diamine 1 with 4-(N,N-dimethylamino)benzaldehyde 2a (Scheme 2) under various conditions as shown in Table 1.
It was found that boiling the starting reagents in MeOH, EtOH, MeCN, and DMF without a catalyst for 12 h allowed us to obtain the desired product 3a with low yields (Table 1, entry 1-4). At the same time, boiling compounds 1 and 2a in DMF in the presence of methanesulfonic acid led to a significant increase in the conversion of the reaction and easier purification of the product.
With the optimized condition in hand, we carried out the reaction of triazolo[1,5-a]pyrimidine-6,7-diamine 1 with various aromatic aldehydes (Scheme 3). Moreover, products 3a–g have been isolated as pure solids by simple filtration of the reaction mixture, which is a significant advantage of the synthetic procedure.
All synthesized compounds were fully characterized using 1H-NMR, 13C-NMR, IR-spectroscopy, and elemental analysis. In addition, based on the 1H-13C HMBC correlation data of compound 3b, it was established that the condensation reaction involves exclusively the amino group in position 6 of the azolopyrimidine system (Figure 2), since the -CH=N group proton (8.85 ppm) has cross-peaks with C-5 (142.77 ppm) C-2′, C-6′ (131.15 ppm) and C-1′ (129.39 ppm) carbon atoms.
The experimental data obtained correlate with the results from the literature [39,40,41]. It can be assumed that the increased nucleophilicity of the amino group at position 6 of 6,7-diamino-1,2,4-triazolo[1,5-a]pyrimidine 1 is caused by the rapid establishment of equilibrium between amine and imine forms [42], as shown in Scheme 4.
The next step was the oxidation of the obtained imines 3a–g into the corresponding azolopurines. As in the previous step, we conducted an optimization of oxidation reaction conditions using different oxidizing agents. The results are summarized in Table 2.
Interestingly, the oxidation of Schiff base 3a turned out to be a non-trivial process. We determined that literature methods for similar processes were not applicable to this compound. For example, the reaction did not proceed with red lead (Table 2, entry 1) and DDQ (Table 2, entry 2), which are often used in the formation of heterocyclic C-N bonds [43]. Copper (II) salts (Table 2, entry 3, 4) [44] as well as such inorganic oxidizing agents, such as hydrogen peroxide (Table 2, entry 5) and manganese (IV) oxide (Table 2, entry 6), did not show any effect [35]. Interestingly, oxidation occurred with a low yield when using PCC in dimethylformamide upon heating (Table 2, entry 8), while it did not occur when heated in acetic acid (Table 2, entry 7). Finally, using the derivative of hypervalent iodine, namely (diacetoxyiodo)benzene, was successful. It was found that oxidation proceeded by heating in formic acid, but the conversion was low (Table 2, entry 8), however, carrying out the reaction in trifluoroacetic acid at room temperature resulted in product 4a with 60% yield (Table 2, entry 9).
Thus, using the optimized reaction conditions we performed the oxidation of the obtained Schiff bases 3a–g into the corresponding azolopurines 4a–g with yields from 59 to 67%. It should be noted that all derivatives 4a–g were obtained with comparable yields, which indicates an insignificant influence of the nature of the substituents on the oxidation process (Scheme 5). All the synthesized compounds were fully characterized using 1H-NMR, 13C-NMR, IR-spectroscopy, and elemental analysis (Supplementary Materials).
In addition, we studied the possibility of obtaining purines based on 2-(thiophen-2-yl)-6,7-diamino-1,2,4-triazolo[1,5-a]pyrimidine 1 by other methods. Thus, with the action of isoamyl nitrite on diamine 1 in acetic acid upon heating, 7-(thiophen-2-yl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[1,5-a]pyrimidine 6 was obtained with a 58% yield, and boiling 1 with triethylorthoacetate in acetic anhydride created 7-methyl-2-(thiophen-2-yl)-8H-[1,2,4]triazolo[5,1-b]purine in 62% yield (Scheme 6).
Based on the experimental data obtained and previously published studies on the use of (diacetoxyiodo)benzene as an oxidizing agent for the synthesis of condensed systems [45,46], a plausible reaction pathway was proposed (Scheme 7). The first step involves nucleophilic substitution of the acetoxy group of (diacetoxyiodo)benzene to form an intermediate 8. In the next step, the amino cation is formed by eliminating iodobenzene. Subsequent intramolecular cyclization and aromatization lead to the formation of triazolo[5,1-b]purine.

4. Conclusions

Therefore, we have developed a method for the synthesis of novel 8-substituted triazolo[5,1-b]purines using (diacetoxyiodo)benzene as an oxidizing agent by intramolecular C-N bond formation with good yields (59–67%). The advantages of this approach include mild cyclization conditions and good yields of the reaction products. In addition, alternative methods for cyclization of the selected diamine have been proposed to obtain other azolopurine derivatives. The developed approach opens the possibility of obtaining previously inaccessible condensed purine derivatives, which are of interest for creating molecules with varied useful biological and photophysical properties.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions5040058/s1, Figures S1–S33: 1H-, 13C-NMR and IR spectra of compounds 3a–g, 4a–g, 5, 6.

Author Contributions

Synthesis, A.O.N. and V.V.F.; methodology, V.V.F., E.N.U., D.N.L. and V.L.R.; writing—original draft preparation, A.O.N., V.V.F. and D.N.L.; writing—review and editing, A.O.N., V.V.F., S.V.A. and D.N.L.; visualization, V.V.F. and D.N.L.; supervision, E.N.U., V.V.F. and V.L.R.; project administration, V.L.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, Project № 23-23-00642, https://rscf.ru/project/23-23-00642/. Accessed on 1 January 2023.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Acknowledgments

The team of authors would like to thank the Laboratory for Comprehensive Research and Expert Evaluation of Organic Materials under the direction of O.S. Eltsov.

Conflicts of Interest

The authors declare no conflicts of interest.

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Reactions 05 00058 g001
Figure 1. Examples of purine-based drugs.
Figure 1. Examples of purine-based drugs.
Reactions 05 00058 g001
Reactions 05 00058 sch001
Scheme 1. State-of-the-art and current work [33,34,35,36,38].
Scheme 1. State-of-the-art and current work [33,34,35,36,38].
Reactions 05 00058 sch001
Reactions 05 00058 sch002
Scheme 2. Preparation of the Schiff base 3a.
Scheme 2. Preparation of the Schiff base 3a.
Reactions 05 00058 sch002
Reactions 05 00058 sch003
Scheme 3. Preparation of the Schiff bases 3a–g.
Scheme 3. Preparation of the Schiff bases 3a–g.
Reactions 05 00058 sch003
Reactions 05 00058 g002
Figure 2. Key interactions of the proton of the methylene fragment in compound 3b.
Figure 2. Key interactions of the proton of the methylene fragment in compound 3b.
Reactions 05 00058 g002
Reactions 05 00058 sch004
Scheme 4. Amine–Imine equilibrium.
Scheme 4. Amine–Imine equilibrium.
Reactions 05 00058 sch004
Reactions 05 00058 sch005
Scheme 5. Preparation of Schiff 4a–g bases.
Scheme 5. Preparation of Schiff 4a–g bases.
Reactions 05 00058 sch005
Reactions 05 00058 sch006
Scheme 6. Preparation of azolopurines 5,6.
Scheme 6. Preparation of azolopurines 5,6.
Reactions 05 00058 sch006
Reactions 05 00058 sch007
Scheme 7. Plausible pathway of oxidation by PIDA.
Scheme 7. Plausible pathway of oxidation by PIDA.
Reactions 05 00058 sch007
Table 1. Optimization of condensation reaction 1.
Table 1. Optimization of condensation reaction 1.
EntrySolvent 2CatalystTemp (°C)Yield (%) 3
entry 1MeOH-reflux45
entry 2EtOH-reflux39
entry 3MeCN-reflux33
entry 4DMF-12048
entry 5MeOHMeSO3H (10% mol)reflux62
entry 6 EtOHMeSO3H (10% mol)reflux47
entry 7DMFMeSO3H (10% mol)12086
entry 8DMFMeSO3H (15% mol)12086
1 Reaction conditions: 1 (0.10 mol), 2 amount of solvent—20 mL, reflux, 12 h, conventional heating with an oil bath, and 3 isolated yields.
Table 2. Optimization of oxidation reaction 1.
Table 2. Optimization of oxidation reaction 1.
EntryOxidantSolvent 2Temp (°C)t (h)Yield (%) 3
entry 1Pb3O4MeOH-3-
entry 2DDQEtOH-12-
entry 3CuCl2MeCN-4-
entry 4Cu(CH3COO)2DMF-4-
entry 5H2O2-905-
entry 6MnO2DMF1003-
entry 7PCCAcOH1006-
entry 8PCCDMF100427
entry 9PhI(OAc)2HCOOH100623
entry 10PhI(OAc)2TFAr.t660
1 Reaction conditions: 3a (0.10 mol), 2 amount of solvent—3 mL, conventional heating with an oil bath, and 3 isolated yields.
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MDPI and ACS Style

Neymash, A.O.; Fedotov, V.V.; Ulomsky, E.N.; Lyapustin, D.N.; Aminov, S.V.; Rusinov, V.L. Efficient Synthesis of Novel Triazolo[5,1-b]purines by Diacetoxyiodobenzene-Mediated Oxidative Cyclization of Schiff Bases. Reactions 2024, 5, 1089-1100. https://doi.org/10.3390/reactions5040058

AMA Style

Neymash AO, Fedotov VV, Ulomsky EN, Lyapustin DN, Aminov SV, Rusinov VL. Efficient Synthesis of Novel Triazolo[5,1-b]purines by Diacetoxyiodobenzene-Mediated Oxidative Cyclization of Schiff Bases. Reactions. 2024; 5(4):1089-1100. https://doi.org/10.3390/reactions5040058

Chicago/Turabian Style

Neymash, Artyom O., Victor V. Fedotov, Evgeny N. Ulomsky, Daniil N. Lyapustin, Semen V. Aminov, and Vladimir L. Rusinov. 2024. "Efficient Synthesis of Novel Triazolo[5,1-b]purines by Diacetoxyiodobenzene-Mediated Oxidative Cyclization of Schiff Bases" Reactions 5, no. 4: 1089-1100. https://doi.org/10.3390/reactions5040058

APA Style

Neymash, A. O., Fedotov, V. V., Ulomsky, E. N., Lyapustin, D. N., Aminov, S. V., & Rusinov, V. L. (2024). Efficient Synthesis of Novel Triazolo[5,1-b]purines by Diacetoxyiodobenzene-Mediated Oxidative Cyclization of Schiff Bases. Reactions, 5(4), 1089-1100. https://doi.org/10.3390/reactions5040058

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