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Article

Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines

by
Jonathan Elie
1,2,
Corinne Fruit
1 and
Thierry Besson
1,*
1
Perha Pharmaceuticals, Perharidy Peninsula, 29680 Roscoff, France
2
Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(12), 3540; https://doi.org/10.3390/molecules26123540
Submission received: 22 April 2021 / Revised: 2 June 2021 / Accepted: 9 June 2021 / Published: 10 June 2021
(This article belongs to the Special Issue The Application of Microwave Technology in Chemistry)
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Versions Notes

Abstract

:
This paper reports a convenient sequential one-pot approach for the synthesis of an array of 14 pyrazolo[1,5-a][1,3,5]triazines, substituted in C8 by halogen (Br), various functions (CN and CO2Et) and alkyl or (het)aryl groups. This study confirms the interest of combining the efficient heating obtained under dielectric microwave heating and the achievement of sequential one-pot reactions, avoiding the tedious work-up and purification of intermediate compounds, achieving sustainable synthesis processes. Considering usual conventional methods, this microwave protocol is featured by advantages in terms of yields, reaction times, and convenient gram scale synthesis.

Graphical Abstract

1. Introduction

The pyrazolo[1,5-a][1,3,5]triazine is a heterocyclic system which has generated considerable interest in the communities of academic and industrial medicinal chemists [1,2]. This nitrogen-rich heterocyclic core was intensively developed as a bioisosteric substitute of biogenic purines (e.g., adenine, guanine, and xanthine in Figure 1) for the conception of potentially bioactive compounds in a wide range of biological applications [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21]. In this context, numerous synthetic routes of various substituted pyrazolo[1,5-a][1,3,5]triazines have been yet reported [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Extending our interest in associating microwave-assisted chemistry with one-pot sequential approaches [38,39,40], we envisioned developing convenient and sustainable access to C8-functionalized 2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazin-4(3H)-ones that are privileged precursors to complex molecules at therapeutic aims (Figure 1).
This paper reports a convenient one-pot process for the synthesis of these 5-aza-9-deazapurines substituted in C8 by various functions (CN and CO2Et) and alkyl or (het)aryl groups.

2. Results and Discussion

Based on literature data, three steps are required for the synthesis of the target heterocyclic systems. The first step started from 5-aminopyrazole or its 4-substituted analogs (1) which were reacted with ethoxycarbonyl isothiocyanate in various solvents (e.g., ethyl acetate, [10], ethyl acetate/benzene [13,21] or dimethylformamide DMF [14]) to give the intermediate N-carbetoxythioureas (2). The latest were heated in basic conditions (e.g., ammonium hydroxide in methanol [10], aqueous sodium hydroxide [13,14,15,21,22,25,29], sodium methoxide [5] and sodium ethoxide in ethanol [7,14,15]) and then cyclized, giving the 2-thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-ones (3). The following S-methylation with methyl iodide (MeI) in the presence of sodium hydroxide (NaOH) gave the corresponding 2-(methylsulfany)lpyrazolo[1,5-a][1,3,5]triazin-4(3H)-one derivatives (4) [10,13,14,15,21,22,23]. In various works, chlorination of compounds 4 with phosphorus oxychloride (POCl3), in the presence of N,N-dimethylaniline [13,14,15] gave 4-chloro-2-methylthio-[1,5-a][1,3,5]triazines (5), highly versatile molecular bricks featuring two main substitution sites (labeled site I and site II in Scheme 1) allowing a wide range of ring extensions in the case of scaffold hopping strategies.
In an initial attempt to perform a microwave-assisted process for the first step, a mixture of 5-aminopyrazole (1a, R = H) and ethoxycarbonylisothiocyanate (1 equiv.) in ethyl acetate (AcOEt) was heated in sealed vial under microwaves at 100 °C for 5 min and afforded the corresponding N-carbetoxythiourea (2a) in a 52% yield (Scheme 2).
Applying conventional heating methods previously described at atmospheric pressure (reflux 77 °C, 1 h in an oil bath), compound 2a was isolated in only 40% yield, while 84% was reported in the literature [17]. The reaction was repeated and the yield remained unchanged. Whatever methods applied it was found that the work-up and isolation of the product was trickier than described, and degradation products (not identified) were found at the end of the process while crude 1H-NMR analysis indicated a complete conversion of the starting pyrazole.
To overcome such low yields and tedious work-up, the synthesis of 2-thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (3a) was envisioned from 1a via a one-pot approach. The development of the experimental conditions confirmed the necessity to add slowly the isothiocyanate derivative at 0 °C (0.2 mL/min) before irradiating the sealed microwave vial [21,22]. After 5 min of heating at 100 °C, EtOAc was evaporated and aqueous NaOH (2N) added. The resulting suspension was then stirred for 3 min at 80 °C under microwave irradiation. After work-up, the expected product 3a was isolated by filtration, in an excellent yield (94%) (Scheme 3). Methylation of the sulfur atom of 3a was realized with iodomethane (MeI) in 30 min at room temperature (r.t.) in basic conditions (NaOH 2N), with ethanol (EtOH) as solvent, affording 2-(methylsulfanyl)[1,3,5]triazin-4(3H)-one derivative (4a) in a 76% yield, and in an overall yield of 71% from 5-aminopyrazole (1a) (Scheme 3).
The preparation of 4a and its derivatives is a crucial step in the synthesis of multi-functionalized compounds that are key precursors for further bioactive compounds. After considering the experimental conditions described above, the whole process was carried out in the same vessel, avoiding intermediate purification of 2a and 3a and introducing the reagents sequentially. In this novel procedure, tetrahydrofuran (THF) replaced ethyl acetate. This solvent is inert to the reaction conditions and improve the solubilization of reaction intermediates.
Specifically, in a microwave vial, ethoxycarbonyl isothiocyanate (1.0 equiv.) was added dropwise to a solution of 5-aminopyrazole (1a) (1.0 equiv.) in dry THF (3 mL) at 0 °C. After complete addition, the mixture was stirred 2 min at room temperature and the vessel was sealed, deposited in a microwave reactor and heated at 100 °C for 5 min. After cooling until 50 °C, NaOH 2N (2.0 equiv.) was added and the vial was sealed again and irradiated at 80 °C for 3 min. After cooling, MeI (1.0 equiv.) was added dropwise and the mixture was stirred for 15 min at room temperature. No flash chromatography on silica gel was required for the purification step and the precipitated product 4a was isolated after acidification, filtration, washing and drying steps, as a pure white solid. With a yield of 77% (Scheme 4), this 2-(methylsulfanyl)triazine derivative was obtained in a slightly higher overall yield than reported above (71%). The scale of the reaction has been successfully enhanced, since starting from 1.0 g or 2.0 g of 5-aminopyrazole (1a) yielded 73% and 72% of the attempted product 4a, respectively.
With optimized conditions in hand, the reaction conditions were applied to a range of 5-aminopyrazoles (1b–n) substituted at C8 by a halogen atom (Br) (1b), functional groups (carbonitrile 1c, ethyl ester 1d), or various alkyl (1e–i) and (het)aryl groups (1j–n). The corresponding 2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-ones (4b–n) were obtained as depicted in Scheme 4. Except for the two electro-withdrawing carbonitrile and ethyl carboxylate substituents for which low yields were observed, the effect of the alkyl and aryl substituents cannot be really evaluated since an average value of around 70% can be observed. It may be noted that when the same sequential one-pot procedures (sealed vessel, quantities of reactants, solvent, base and reaction times) were applied to the synthesis of compounds 4a and 4f, with a traditional oil bath heating system, the overall yields observed were in the 45–50% range.
To complete our study, the synthesis of the polyfunctionalized 8-bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine (6) was investigated. Considering that previous attempts of microwave-assisted chlorination of analogous pyrimidin-4-ones with POCl3 were revealed difficult and sometimes quite hazardous [41], C4-chlorination of compound 4a was performed via conventional operating conditions described in various papers and patents [10,13,14,15,21,22,23]. The reaction was successfully carried out at 110 °C for 3 h in a sealed vessel using a large excess (10 equiv.) of freshly opened commercial POCl3, in the presence of N,N-dimethylaniline (1.0 equiv.). Intermediate 4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine (5) was isolated in 94% yield (Scheme 5). However, the purification phase appeared to be very critical and it was noted that compound 5 may be unstable over time: it is strongly sensitive to moisture and its hydrolysis lead to its oxygenated precursor. Considering these results, synthesis of brominated product 6 was carried out from freshly isolated compound 5, with an excess (1.5 equiv.) of N-bromosuccinimide (NBS). This microwave-assisted process provided 6 with an excellent yield of 95%. A scale-up was successfully achieved in the same yield, starting from 1 g of 4a for the first step and 2 g of 5 for the second one (Scheme 5).

3. Materials and Methods

Compound 3, and some derivatives of the 4 series (4a–g) were randomly described in academic works and patents cited in this paper. To complete data sometimes uneasy to found in the literature, all compounds 4a–n were fully characterized. Compounds 5 and 6 were briefly described in Refs1–23]. 1H NMR and 13C NMR spectra of these compounds are available in Supplementary Materials (Section S1–S20). General information and procedure for their synthesis are described below.

3.1. General Information

All reagents (1a–n) were purchased from commercial suppliers (Alfa Aesar, Thermo Fisher Scientific Heysham, Lancashire, UK) or Manchester Organics Ltd. (The Heath Business & Technical Park, Runcorn WA7 4QX, UK) or Enamine Ltd. (LV-1035 Riga, Latvia) or Merck KGaA (Darmstadt, Germany), and were used without further purification. All reactions were monitored by thin-layer chromatography with aluminum plates (0.25 mm) precoated with silica gel 60 F254 (Merck KGaA Darmstadt, Germany or Fluorochem, Hadfield, Derbyshire, UK). Visualization was performed with UV light at a wavelength of 254 nm. Melting points of solid compounds were measured with a SMP3 Melting Point instrument (STUART, Bibby Scientific Ltd., Roissy, France) with a precision of 1.5 °C. IR spectra were recorded with a Spectrum 100 Series FTIR spectrometer (PerkinElmer, Villebon S/Yvette, France). Liquids and solids were investigated with a single-reflection attenuated total reflectance (ATR) accessory; the absorption bands are given in cm−1. NMR spectra (1H and 13C) were acquired at 295 K using an AVANCE 300 MHz or AVANCE III 400 MHz spectrometer (Bruker, Wissembourg, France) at 300 or 400 MHz for 1H and 75.4 or 101 MHz for 13C. Coupling constant J was in Hz and chemical shifts were given in ppm. Mass (ESI, EI and field desorption (FD) were recorded with an LCP 1er XR spectrometer (WATERS, Guyancourt, France)). Mass spectrometry was performed by the Mass Spectrometry Laboratory of the University of Rouen. The mass spectra [ESI, EI, and field desorption (FD)] were recorded with an LCP 1er XR spectrometer (WATERS, Guyancourt, France). Microwaves-assisted reactions were carried out in sealed tubes with a Monowave 400 instrument and temperatures were measured by IR-sensor (Anton Paar France S.A.S., les Ulis, France). Time indicated in the various protocols is the time measured when the mixtures were at the programmed temperature.
Regarding the keto-enolic tautomeric forms of these molecules (pyrazolo[1,5-a]-1,3,5-triazin-4(3H)-ones or pyrazolo[1,5-a][1,3,5]triazin-4-ols), complete DEPT135, and two-dimensional NMR experiments (HMBC, HSQC and NOESY) were performed with compounds 4a and 4g (see Supplementary Materials). Analysis of the IR investigations are rather in favor of the pyrazolo[1,5-a]-1,3,5-triazin-4(3H)-one as the privileged shape. This seems confirmed by comparing the 1H NMR spectra in SM Section with data given in [13] (for 4a) and in Ref. [42] (see Supplementary Information).

3.2. Chemistry

3.2.1. Synthesis of 2-Thioxo-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (3a)

In a microwave vial, ethoxycarbonyl isothiocyanate (1.0 equiv.) was added drop-wise to a solution of 5-aminopyrazole 1a–n (1.0 equiv.) in dry THF (3 mL) at 0 °C. After complete addition, the mixture was stirred 2 min at room temperature and the vial was sealed, deposited in a microwave reactor and heated at 100 °C for 5 min. After cooling, NaOH 2N (2.0 equiv.) was added and the vessel was sealed again and irradiated at 80 °C for 3 min. After cooling, the resulting aqueous solution was acidified (pH < 5) with HCl 2N then the precipitate was filtered off, washed with water up to neutral pH, triturated with Et2O then DCM and dried under vacuum to give 3a (4.601 g, 94%) as a white solid (4.601 g, 94%) from 1a (2.5 g, 29.2); m.p. 197–199 °C; IR (neat) νmax: 3064.70, 2965.10, 2868.85, 2098.89, 1756.33 (CO), 1719.25, 1637.00, 1530.29, 1422.11, 1363.21, 1236.75, 1173.58, 1131.32 (CS), 1087.90, 1038.44, 961.01, 886.45, 773.52, 699.10, 654.80, 540.74 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 5.89 (d, J = 1.9 Hz, 1H, HAr), 7.87 (d, J = 1.8 Hz, 1H, HAr), 12.74 (s, 1H, NH), 13.45 (s, 1H, NH). 13C NMR (75 MHz, DMSO) δ 89.5 (CHAr), 140.6 (Cq), 141.6 (Cq), 145.6 (CHAr), 173.0 (Cq). HRMS (EI-MS): m/z calcd for C5H4N4SO: 169.0184 [M + H]+, found: 169.0190.

3.2.2. General Procedure for the Synthesis of 2-(Methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-ones (4a–n)

In a microwave vial, ethoxycarbonyl isothiocyanate (1.0 equiv.) was added drop-wise to a solution of 5-aminopyrazole 1a–n (1.0 equiv.) in dry THF (3 mL) at 0 °C. After complete addition, the mixture was stirred 2 min at room temperature and the vial was sealed, deposited in a microwave reactor and heated at 100 °C for 5 min. After cooling, NaOH 2N (2.0 equiv.) was added and the vessel was sealed again and irradiated at 80 °C for 3 min. After cooling, MeI (1.0 equiv.) was added dropwise and the mixture stirred at room temperature for 15 min. The solvent was partially concentrated and the resulting aqueous solution was acidified (pH < 5) with HCl 2N or acetic acid (for 4n only) and poured in cold water (10 mL). The precipitate was filtered off, washed with water up to neutral pH and the resulting solid was dried under vacuum (4a–n).
2-(Methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4a). White solid (0.325 g, 74%) from 1a (0.2 g, 2.41 mmol) according to the general procedure; m.p. 244–246 °C; IR (neat) νmax: 3097, 3017, 2933, 2904, 2817, 1715 (CO), 1592, 1426, 1337, 1228, 1186, 1156, 1117, 969, 904, 813, 744, 669, 629, 600, 543 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.53 (s, 3H, CH3), 6.35 (d, J = 1.9 Hz, 1H, HAr), 7.97 (d, J = 1.9 Hz, 1H, HAr), 12.89 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 13.1 (CH3), 97.1 (CHAr), 143.5 (Cq), 145.7 (CHAr), 148.4 (Cq), 157.0 (Cq); HRMS (EI-MS): m/z calcd for C6H6N4OS: 183.0335 [M + H]+, found: 183.0333.
8-Bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4b). Beige solid (0.530 g, 69%) from 1b (0.5 g, 2.93 mmol) according to the general procedure; m.p. 268–270 °C; IR (neat) νmax: 3123, 3065, 2889, 2824, 1847, 1790 (CO), 1587, 1552, 1480, 1424, 1357, 1317, 1232, 1162, 1000, 898, 768, 736, 672, 651, 625, 543 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H, CH3), 8.11 (s, 1H, HAr), 13.07 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6) δ 13.1 (CH3), 83.8 (Cq), 143.0 (Cq), 145.5 (CHAr), 145.7 (Cq), 158.7 (Cq); HRMS (EI-MS): m/z calcd for C6H5BrN4OS: 260.9440 [M + H]+, found: 260.9453.
2-(Methylsulfanyl)-4-oxo-3,4-dihydropyrazolo[1,5-a][1,3,5]triazine-8-carbonitrile (4c). White solid (0.090 g, 23%) from 1c (0.2 g, 1.85 mmol) according to the general procedure; m.p. 254–256 °C; IR (neat) νmax: 3128, 3082, 2936, 2235 (CN), 1765 (CO), 1584, 1545, 1485, 1455, 1344, 1226, 1168, 1044, 897, 743, 703, 667, 629, 557 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.60 (s, 3H, SCH3), 8.43 (s, 1H, HAr), 13.16 (br, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 13.2 (CH3), 81.5 (Cq), 112.8 (Cq), 142.8 (Cq), 146.0 (CHAr), 152.6 (Cq), 163.3 (Cq). HRMS (EI-MS): m/z calcd for C7H5N5OS: 208.0288 [M + H]+, found: 208.0290.
Ethyl 2-(methylsulfanyl)-4-oxo-3,4-dihydropyrazolo[1,5-a][1,3,5]triazine-8-carboxylate (4d). White solid (0.110 g, 34%) from 1d (0.2 g, 1.29 mmol) according to the general procedure; m.p. 220–222 °C; IR (neat) νmax: 3668, 2986, 2901, 1802 (COamide), 1745, 1693 (COester), 1574, 1537, 1465, 1408, 1382, 1255, 1224, 1173, 1118, 1038, 840, 775, 690, 666, 632, 556 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J = 7.0 Hz, 3H, CH2-CH3), 2.61 (s, 3H, SCH3), 4.23 (q, J = 7.0 Hz, 2H, CH2-CH3), 8.26 (s, 1H, HAr), 13.09 (br, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 13.0 (SCH3), 14.2 (CH2-CH3), 59.7 (CH2-CH3), 102.6 (Cq), 143.2 (Cq), 146.0 (CHAr), 148.9 (Cq), 161.4 (Cq), 161.4 (Cq). HRMS (EI-MS): m/z calcd for C9H10N4O3S: 255.0546 [M + H]+, found: 255.0540.
8-Methyl-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4e). Black solid (0.510 g, 52%) obtained from 1e (0.5 g, 5.04 mmol) according to the general procedure, m.p. 186–188 °C; IR (neat) νmax: 3674, 2987, 2900, 1758 (CO), 1606, 1558, 1487, 1439, 1347, 1239, 1173, 1053, 981, 899, 821, 738, 724, 661, 628, 519 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H, CH3), 2.56 (s, 3H, SCH3), 7.86 (s, 1H, HAr), 12.70 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 7.1 (CH3), 12.9 (SCH3), 105.5 (Cq), 143.6 (Cq), 145.2 (Cq), 146.6 (CHAr), 155.3 (Cq). HRMS (EI-MS): m/z calcd for C7H8N4OS: 197.0419 [M + H]+, found: 197.0496.
8-Ethyl-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4f). White solid (0.655 g, 65%) obtained from 1f (0.5 g, 4.41 mmol) according to the general procedure; m.p. 188–190 °C; IR (neat) νmax: 3498, 3080, 2961, 2873, 2634, 1993, 1761 (CO), 1598, 1563, 1497, 1450, 1353, 1238, 1171, 1065, 1033, 960, 908, 823, 740, 703, 663, 630, 547 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J = 7.6 Hz, 3H, CH2-CH3), 2.52–2.60 (m, 5H, CH2-CH3 and SCH3), 7.91 (s, 1H, HAr), 12.73 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6) δ 12.9 (SCH3), 14.4 (CH2-CH3), 15.5 (CH2-CH3), 112.0 (Cq), 143.7 (Cq), 144.7 (Cq), 145.5 (CHAr), 155.3 (Cq); HRMS (EI-MS): m/z calcd for C8H10N4OS: 211.0648 [M + H]+, found: 211.0655.
8-Isopropyl-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4g). Pale yellow solid (0.964 g, 75%) obtained from 1g (0.750 g, 5.69 mmol) according to the general procedure; m.p. 203–205 °C; IR (neat) νmax: 3079, 2953, 2925, 2865, 2798, 2634, 1759 (CO), 1595, 1572, 1554, 1492, 1448, 1359, 1312, 1242, 1175, 1030, 908, 826, 741, 701, 665, 629, 553 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, J = 7.0 Hz, 6H, 2 × CH3-iPr), 2.54 (s, 3H, SCH3), 3.01 (hept, J = 7.0 Hz, 1H, HiPr), 7.91 (s, 1H), 12.73 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 12.9 (SCH3), 22.9 (2 × CH3-iPr), 23.1 (CHiPr), 116.9 (Cq), 143.6 (Cq), 144.1 (Cq), 144.2 (CHAr), 155.0 (Cq). HRMS (EI-MS): m/z calcd for C9H12N4OS: 225.0805 [M + H]+, found: 225.0806.
8-Cyclopropyl-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4h). Beige solid (0.410 g, 60%) obtained from 1h (0.380 g, 3.08 mmol) according to the general procedure; m.p. 225–227 °C; IR (neat) νmax: 3079, 2995, 2883, 2635, 1758 (CO), 1606, 1561, 1504, 1449, 1349, 1313, 1238, 1207, 1167, 1030, 906, 876, 813, 739, 696, 660, 627, 548 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 0.77–0.93 (m, 4H, 2 × CH2-cPr), 1.83 (ddd, J = 16.8, 8.3, 5.2 Hz, 1H, CHcPr), 2.54 (s, 3H, CH3), 7.79 (s, 1H, HAr), 12.70 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6) δ 4.8 (CHcPr), 7.2 (2 × CH2-cPr), 12.9 (CH3), 112.7 (Cq), 143.5 (Cq), 144.1 (CHAr), 144.6 (Cq), 155.1 (Cq). HRMS (EI-MS): m/z calcd for C9H10N4OS: 223.0348 [M + H]+, found: 223.0661.
8-Cyclobutyl-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4i). White solid (0.190 g, 55%) obtained from 1i (0.2 g, 1.46 mmol) according to the general procedure; m.p. 222–224 °C; IR (neat) νmax: 3667, 3080, 2969, 2900, 2634, 2119, 1759 (CO), 1596, 1567, 1497, 1454, 1348, 1240, 1197, 1163, 1053, 988, 906, 822, 739, 665, 629, 546 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 1.81–2.03 (m, 4H, CH2-CH2-CH), 2.25 (qd, J = 8.5, 2.7 Hz, 4H, CH2-CH2-CH), 2.55 (s, 3H, SCH3), 3.54 (p, J = 8.7 Hz, 1H, HcBut), 8.00 (s, 1H, HAr), 12.72 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 12.9 (SCH3), 18.4 (2 × CH2-CH2-CH), 29.0 (CHcBut), 29.5 (2 × CH2-CH2-CH), 114.8 (Cq), 143.6 (Cq), 144.2 (Cq), 144.9 (CHAr), 155.3 (Cq). HRMS (EI-MS): m/z calcd for C10H12N4OS: 237.0805 [M + H]+, found: 237.0809.
2-(Methylsulfanyl)-8-phenyl-pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4j). White solid (0.500 g, 65%) obtained from 1j (0.5 g, 2.98 mmol) according to the general procedure; m.p. 277–279 °C; IR (neat) νmax: 3491, 3065, 2890, 2824, 1944, 1756 (CO), 1594, 1559, 1460, 1432, 1356, 1228, 1173, 1145, 1094, 981, 934, 904, 795, 755, 713, 687, 670, 628, 550, 511 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, SCH3), 7.25 (t, J = 7.4 Hz, 1H, HAr), 7.42 (t, J = 7.6 Hz, 2H, 2 × HAr), 8.03 (d, J = 7.7 Hz, 2H, 2 × HAr), 8.53 (s, 1H, HAr), 12.98 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 13.2 (SCH3), 109.8 (Cq), 125.7 (2 × CHAr), 126.4 (CHAr), 128.7 (2 × CHAr), 131.2 (Cq), 143.5 (Cq), 143.8 (CHAr), 144.1 (Cq), 157.6 (Cq). HRMS (EI-MS): m/z calcd for C12H10N4OS: 259.0648 [M + H]+, found: 259.0657.
2-(Methylsulfanyl)-8-(p-tolyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4k). White solid (0.560 g, 68%) obtained from 1k (0.550 g, 3.02 mmol) according to the general procedure; m.p. > 290 °C; IR (neat) νmax: 3486, 3064, 3007, 2884, 1759 (CO), 1595, 1561, 1511, 1455, 1407, 1352, 1316, 1255, 1228, 1172, 1144, 982, 907, 809, 741, 695, 671, 626, 550, 514 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H, SCH3), 2.63 (s, 3H, CH3-Ph), 7.23 (d, J = 7.8 Hz, 2H, 2 × HAr), 7.91 (d, J = 8.0 Hz, 2H, 2 × HAr), 8.48 (s, 1H, HAr), 12.95 (s, 1H, OH). 13C NMR (75 MHz, DMSO-d6) δ 13.2 (SCH3), 20.8 (CH3-Ph), 109.9 (Cq), 125.6 (2 × CHAr), 128.2 (Cq), 129.3 (2 × CHAr), 135.5 (Cq), 143.5 (Cq), 143.7 (CHAr), 143.8 (Cq), 157.2 (Cq). HRMS (EI-MS): m/z calcd for C13H12N4OS: 273.0805 [M + H]+, found: 273.0810.
8-(4-Chlorophenyl)-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4l). White solid (0.255 g, 84%) obtained from 1l (0.2 g, 1.03 mmol) according to the general procedure; m.p. > 290 °C; IR (neat) νmax: 3674, 2987, 2900, 2123, 1753 (CO), 1595, 1560, 1511, 1453, 1352, 1303, 1247, 1173, 1038, 979, 906, 815, 742, 694, 671, 625, 589, 551, 522 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, SCH3), 7.48 (d, J = 8.3 Hz, 2H, 2 × HAr), 8.06 (d, J = 8.4 Hz, 2H, 2 × HAr), 8.54 (s, 1H, HAr), 13.05 (s, 1H, OH) 13C NMR (101 MHz, DMSO-d6) δ 13.3 (SCH3), 108.6 (Cq), 127.2 (2 × CHAr), 128.7 (2 × CHAr), 130.2 (Cq), 130.7 (Cq), 143.4 (Cq), 143.6 (CHAr), 144.3 (Cq), 158.1 (Cq). HRMS (EI-MS): m/z calcd for C12H9ClN4OS: 293.0258 [M + H]+, found: 293.0263.
8-(4-Methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4m). White solid (0.510 g, 64%) obtained from 1m (0.525 g, 2.77 mmol) according to the general procedure; m.p. > 290 °C; IR (neat) νmax: 3062, 2883, 1759 (CO), 1587, 1553, 1487, 1454, 1401, 1351, 1224, 1174, 1086, 983, 906, 808, 740, 676, 663, 627, 552, 511 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3H, SCH3), 3.78 (s, 3H, OCH3), 6.84–7.17 (m, 2H, 2 × HAr), 7.88–8.12 (m, 2H, 2 × HAr), 8.46 (s, 1H, HAr), 12.92 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 13.2 (SCH3), 55.1 (OCH3), 109.7 (Cq), 114.2 (2 × CHAr), 123.6 (Cq), 126.9 (2 × CHAr), 143.3 (Cq), 143.5 (CHAr), 143.5 (Cq), 156.9 (Cq), 157.9 (Cq). HRMS (EI-MS): m/z calcd for C13H12N4O2S: 289.0754 [M + H]+, found: 289.0752.
2-(Methylsulfanyl)-8-(2-pyridyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (4n). White solid (0.280 g, 86%) obtained from 1n (0.2 g, 1.25 mmol) according to the general procedure; m.p. 271–273 °C; IR (neat) νmax: 3662, 3395, 3098, 2987, 1631 (CO), 1573, 1474, 1454, 1425, 1368, 1289, 1253, 1196, 1144, 1048, 991, 932, 776, 642, 515 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.66 (s, 3H, SCH3), 7.24 (dd, J = 7.5, 4.9 Hz, 1H, HAr), 7.86 (t, J = 7.9 Hz, 1H, HAr), 8.28 (d, J = 8.0 Hz, 1H, HAr), 8.51 (s, 1H, HAr), 8.57 (d, J = 4.9 Hz, 1H, HAr), 13.11 (s, 1H, OH). 13C NMR (101 MHz, DMSO-d6) δ 13.4 (SCH3), 110.3 (Cq), 120.5 (CHAr), 121.4 (CHAr), 137.0 (CHAr), 143.5 (Cq), 144.2 (CHAr), 145.4 (Cq), 149.1 (Cq), 150.2 (Cq), 159.3 (Cq). HRMS (EI-MS): m/z calcd for C11H9N5OS: 260.0601 [M + H]+, found: 260.0603.

3.2.3. Synthesis of Pyrazolo[1,5-a][1,3,5]triazines 5 and 6

4-Chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine (5) in a 250 mL sealed flask with a stir bar were charged, 4a (6.0 g, 32.9 mmol, 1.0 eq.), POCl3 (31.10 mL, 329.3 mmol, 10.0 eq.) and N,N-dimethylaniline (4.22 mL, 32.9 mmol, 1.0 eq.). The vessel was sealed and heated at 110 °C (heating block) for 3 h. After cooling, the mixture was concentrated and the resulting residue was taken up in dichloromethane (100 mL, DCM). The organic solution was washed with saturated NaHCO3 (3 × 100 mL) The aqueous layer (pH > 7) was extracted twice with DCM (3 × 30 mL) and the resulting organic solution was dried over MgSO4, filtered and concentrated. Purification by flash chromatography with DCM/petroleum ether (5/5 to 7/3) as eluent gave 5 (6.20 g, 94%) as a yellow solid; m.p. 143–145 °C; IR (neat) νmax: 3675, 3140, 2987, 2912, 2901, 2114, 1991, 1822, 1732, 1650, 1595, 1512, 1464, 1418, 1359, 1315, 1223, 1185, 1124, 1005, 896, 862, 773, 654, 630, 601, 535 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.60 (s, 3H, SCH3), 6.50 (d, J = 2.2 Hz, 1H, HAr), 8.15 (d, J = 2.2 Hz, 1H, HAr). HRMS (EI-MS): m/z calcd for C6H5ClN4S: 200.9996 [M + H]+, found: 201.0002.
4-Chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine (6): a microwave vial (10–20 mL) was charged with a stir bar, 5 (2.0 g, 9.97 mmol, 1.0 eq.) and CHCl3 (17 mL) and NBS (2.307 g, 12.96 mmol, 1.3 eq.). The vial was sealed and the resulting mixture was heated at 80 °C for 8 min under microwave irradiation. After cooling, celite was added and the solvent removed for a solid deposit on a flash chromatography, with DCM/petroleum ether (4/6) as eluent. Product 6 (2.641 g, 95%) was obtained as a pale yellow solid; m.p. 150–152 °C; IR (neat) νmax: 3674, 2987, 2900, 2123, 1847, 1792, 1768, 1587, 1549, 1529, 1467, 1417, 1357, 1316, 1232, 1157, 1067, 1001, 927, 768, 735, 673, 650, 625, 543 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 2.66 (s, 3H, SCH3), 8.13 (s, 1H, HAr).
The instability of 6 and 5 in solution do not allowed more complete analysis (e.g., 13C NMR, HRMS in the case of 6) and yield to the starting triazine-4-one 4a, suggesting fast hydrolysis.

4. Conclusions

The innovative conditions described in this work are combining the efficient heating obtained under microwave irradiation and the interest to perform sequential one-pot reactions, discarding the tedious work-up and purification processes of intermediates compounds, saving energy, time and minimizing wastes.
The process described in this study allows reproducible and safe operating conditions for convenient and rapid access to valuable C8-substituted 2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-ones (4a–n). In addition, multi-gram scale reactions were also successfully performed, confirming the interest of this procedure.

Supplementary Materials

The following are available online, 1H NMR and 13C NMR spectra of compounds 4a–n and 1H NMR of compounds 5 and 6.

Author Contributions

Conceptualization, T.B.; methodology, J.E., C.F. and T.B.; investigations, J.E.; writing—original draft preparation, T.B.; writing—review and editing, J.E., C.F. and T.B.; supervision, C.F. and T.B.; funding acquisition, C.F. and T.B. All authors have read and agreed to the published version of the manuscript.

Funding

C.F. and T.B. thank the LABEX SynOrg (ANR-11-LABX-0029) for financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in supplementary material.

Acknowledgments

J.E., C.F. and T.B. thank Laurent Meijer (CEO Perha Pharmaceuticlas, Roscoff, France) for helpful discussion and multiform support. They also thank the Université de Rouen-Normandie (UNIROUEN) for its support and Carole Dubouilh-Benard for technical assistance on chemistry work.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Sample Availability

Not available.

References

  1. Dolzhenko, A.V.; Chu, W.-K. 1,2,4-Triazolo[1,5-a][1,3,5]triazines (5-azapurines): Synthesis and biological activity. Heterocycles 2006, 68, 1723–1759. [Google Scholar] [CrossRef]
  2. Dolzhenko, A.V.; Chu, W.-K. Pyrazolo[1,5-a][1,3,5]triazines(5-Aza-9-deazapurines): Synthesis and biological activity. Heterocycles 2008, 75, 1575–1622. [Google Scholar] [CrossRef] [Green Version]
  3. Senga, K.; O’Brien, D.E.; Scholten, M.B.; Novinson, T.; Miller, J.P.; Robins, R.K. Synthesis and enzymic activity of various substituted pyrazolo[1,5-a]-1,3,5-triazines as adenosine cyclic 3′,5′-phosphate phosphodiesterase inhibitors. J. Med. Chem. 1982, 25, 243–249. [Google Scholar] [CrossRef] [PubMed]
  4. Fujii, S.; Kawamura, H.; Kiyokawa, H.; Yamada, S. Pyrazolotriazines Compounds. U.S. Patent 4,824,834, 25 April 1989. [Google Scholar]
  5. Lübbers, T.; Angehrn, P.; Gmünder, H.; Herzig, S.; Kulhanek, J. Design, synthesis, and structure–activity relationship studies of ATP analogues as DNA gyrase inhibitors. Bioorg. Med. Chem. Lett. 2000, 10, 821–826. [Google Scholar] [CrossRef]
  6. Raboisson, P.; Baurand, A.; Cazenave, J.-P.; Gachet, C.; Schultz, D.; Spiess, B.; Bourguignon, J.-J. A general approach toward the synthesis of C-nucleoside Pyrazolo[1,5-a]-1,3,5-triazines and their 3′,5′-bisphosphate C-nucleotide analogues as the first reported in vivo stable P2Y1-receptor antagonists. J. Org. Chem. 2002, 67, 8063–8071. [Google Scholar] [CrossRef]
  7. Bernard, P.; Raboisson, P.; Joseph, B. Novel Substituted Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives and Their Analogs, Pharmaceutical Compositions Containing Same, Use Thereof as Medicine and Methods for Preparing Same. WO 2004/011464, 5 February 2004. [Google Scholar]
  8. Guzi, T.J.; Paruch, K. Pyrazolotrazines as Kinase Inhibitors. U.S. Patent 0,187,219, 23 February 2005. [Google Scholar]
  9. Insuasty, H.; Estrada, M.; Cortés, E.; Quiroga, J.; Insuasty, B.; Abonía, R.; Nogueras, M.; Cobo, J. Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl pyrazolo[1,5-a]-[1,3,5]-triazines. Tetrahedron Lett. 2006, 47, 5441–5443. [Google Scholar] [CrossRef]
  10. Nie, Z.; Perretta, C.; Erickson, P.; Margosiak, S.; Almassy, R.; Lu, J.; Averill, A.; Yager, K.M.; Chu, S. Structure-based design, synthesis, and study of pyrazolo[1,5-a][1,3,5]triazine derivatives as potent inhibitors of protein kinase CK2. Bioorg. Med. Chem. Lett. 2007, 17, 4191–4195. [Google Scholar] [CrossRef]
  11. Raboisson, P.; Schultz, D.; Muller, C.; Reimund, J.-M.; Pinna, G.; Mathieu, R.; Bernard, P.; Do, Q.-T.; DesJarlais, R.L.; Justiano, H.; et al. Cyclic nucleotide phosphodiesterase type 4 inhibitors: Evaluation of pyrazolo[1,5-a]-1,3,5-triazine ring system as an adenine bioisostere. Eur. J. Med. Chem. 2008, 43, 816–829. [Google Scholar] [CrossRef]
  12. Popowycz, F.; Fournet, G.; Schneider, C.; Bettayeb, K.; Ferandin, Y.; Lamigeon, C.; Tirado, O.M.; Mateo-Lozano, S.; Notario, V.; Colas, P.; et al. Pyrazolo [1, 5-a]-1, 3, 5-triazine as a purine bioisostere: Access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue. J. Med. Chem. 2009, 52, 655–663. [Google Scholar] [CrossRef] [Green Version]
  13. Saito, T.; Obitsu, T.; Minamoto, C.; Sugiura, T.; Matsumura, N.; Ueno, S.; Kishi, A.; Katsumata, S.; Nakai, H.; Toda, M. Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF1) receptor antagonists. Bioorg. Med. Chem. 2011, 19, 5955–5966. [Google Scholar] [CrossRef]
  14. Sun, L.; Bera, H.; Chui, W.K. Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase. Eur. J. Med. Chem. 2013, 65, 1–11. [Google Scholar] [CrossRef] [PubMed]
  15. Sun, L.; Li, J.; Bera, H.; Dolzhenko, A.V.; Chiu, G.N.C.; Chui, W.K. Fragment-based approach to the design of 5-chlorouracil-linked-pyrazolo[1,5-a][1,3,5]triazines as thymidine phosphorylase inhibitors. Eur. J. Med. Chem. 2013, 70, 400–410. [Google Scholar] [CrossRef] [PubMed]
  16. Bera, H.; Lee, M.H.; Sun, L.; Dolzhenko, A.V.; Chui, W.K. Synthesis, anti-thymidine phosphorylase activity and molecular docking of 5-thioxo-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ones. Bioorg. Chem. 2013, 50, 34–40. [Google Scholar] [CrossRef]
  17. Horsley, H.T.; Huang, Q.; Neuss, J.C.; Reuberson, J.T.; Vanderhoydonck, B. Fused Bicyclic Heteroaromatic Derivatives as Kinase Inhibitors and Their Preparation. WO 2015/193169, 12 December 2015. [Google Scholar]
  18. Webber, S.E.; Tao, X.; Brin, E. CK2 Inhibitors, Compositions and Methods Thereof. WO 2017/223432, 28 December 2017. [Google Scholar]
  19. Khulood, H.O.; Mazin, A.A.N.; Nermin, S.; Rabah, A.T.S.; Khaled, A.M.A. Design, synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors. Bioorg. Chem. 2019, 92, 103239. [Google Scholar] [CrossRef]
  20. Bongard, J.; Schmitz, A.L.; Wolf, A.; Zischinsky, G.; Pieren, M.; Schellhorn, B.; Bravo-Rodriguez, K.; Schillinger, J.; Koch, U.; Nussbaumer, P.; et al. Chemical validation of DegS as a target for the development of antibiotics with a novel mode of action. ChemMedChem 2019, 14, 1074–1078. [Google Scholar] [CrossRef]
  21. Kobe, J.; O’rien, D.E.; Robins, R.K.; Novinson, T. The chemistry of 4-hydrazino-7-phenylpyrazolo[1,5-a]-1,3,5-triazines. J. Heterocycl. Chem. 1974, 11, 991–996. [Google Scholar] [CrossRef]
  22. Kobe, J.; Springer, R.H.; O’Brien, D.E. Pyrazolo [1,5-a] 1,3,5-Triazines. U.S. Patent 3,846,423, 5 November 1974. [Google Scholar]
  23. Kobe, J.; O’Brien, D.E.; Robins, R.K. 2-Aryl-7-Substituted Pyrazolo [1,5-a] 1,3,5-Triazines. U.S. Patent 3,865,824, 11 February 1975. [Google Scholar]
  24. Vogel, A.; Troxler, F. Neue Synthesen von Pyrazolo[1,5-a]-s-triazinen. Helv. Chim. Acta 1975, 58, 761–771. [Google Scholar] [CrossRef]
  25. Senga, K.; Kobe, J.; Robins, R.K.; O’Brien, D.E. Synthesis of 1,3-dialkylpyrazolo [1,5-a]-1,3,5-triazine-2,4-diones isomers of 1,3-dialkylxanthines. J. Heterocycl. Chem. 1975, 12, 893–898. [Google Scholar] [CrossRef]
  26. Tam, S.Y.K.; Klein, R.S.; Wempen, I.; Fox, J.J. Nucleosides. 112. Synthesis of some new pyrazolo[1,5-a]-1,3,5-triazines and their C-nucleosides. J. Org. Chem. 1979, 44, 4547–4553. [Google Scholar] [CrossRef]
  27. Chu, C.K.; Watanabe, K.A.; Fox, J.J. Nucleosides. 117. Synthesis of 4-oxo-8-(β-D-ribofuranosyl)-3H-pyrazolo[1,5-a]-1,3,5-triazine (OPTR) via 3-amino-2N-carbamoyl-4-(β-D-ribofuranosyl)pyrazole (ACPR) derivatives. J. Heterocycl. Chem. 1980, 17, 1435–1439. [Google Scholar] [CrossRef]
  28. Chu, C.K. A facile synthesis of 8-(β-D-ribofuranosyl)-4-thioxo-3H-pyrazolo[1,5-a]-1,3,5-triazine and its α-anomer. J. Heterocycl. Chem. 1984, 21, 389–392. [Google Scholar] [CrossRef]
  29. Robins, R.K.; Revankar, G.R.; O’Brien, D.E.; Springer, R.H.; Albert, T.N.A.; Senga, K.; Miller, J.P.; Streeter, D.G. Purine analog inhibitors of xanthine oxidase—Structure activity relationships and proposed binding of the molybdenum cofactor. J. Heterocycl. Chem. 1985, 22, 601–634. [Google Scholar] [CrossRef]
  30. Raboisson, P.; Schultz, D.; Lugnier, C.; Bourguignon, J.-J. Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines by regioselective acylation. Tetrahedron Lett. 2002, 43, 9501–9503. [Google Scholar] [CrossRef]
  31. Raboisson, P.; Schultz, D.; Lugnier, C.; Mathieu, R.; Bourguignon, J.-J. A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines. Tetrahedron Lett. 2003, 44, 703–705. [Google Scholar] [CrossRef]
  32. Popowycz, F.; Bernard, P.; Raboisson, P.; Joseph, B. Synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazine derivatives by palladium-catalyzed cross-coupling reactions. Synthesis 2007, 367–374. [Google Scholar] [CrossRef]
  33. Bondock, S.; Tarhoni, A.G.; Fadda, A. heterocyclic synthesis with 4-benzoyl-1-cyanoacetylthiosemicarbazide: Selective synthesis of some thiazole, triazole, thiadiazine, pyrrylthiazole, and pyrazolo[1,5-a]triazine derivatives. Monatsh. Chem. 2008, 139, 153–159. [Google Scholar] [CrossRef]
  34. El-Mekabaty, A.; Habib, O.M.O.; Moawad, E.B.; Hasel, A.M. Reactivity of 2-thiazolylhydrazonomalononitrile toward carbon and nitrogen nucleophilic reagents: Applications to the synthesis of new heterocycles. J. Heterocycl. Chem. 2016, 53, 1214–1221. [Google Scholar] [CrossRef]
  35. Lim, F.P.L.; Halcovitch, N.R.; Tiekink, E.R.T.; Dolzhenko, A.V. A new microwave-assisted, three-component reaction of 5-aminopyrazole-4-carboxylates: Selective synthesis of substituted 5-aza-9-deaza-adenines. Tetrahedron 2018, 74, 1868–1879. [Google Scholar] [CrossRef]
  36. Aggarwal, R.; Kumar, S. 5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines. Beilstein J. Org. Chem. 2018, 14, 203–242. [Google Scholar] [CrossRef] [Green Version]
  37. Lim, F.P.L.; Luna, G.; Tan, K.C.; Tiekink, E.R.T.; Dolzhenko, A.V. A synthesis of new 7-amino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazines via a selective three-component triazine ring annulation. Tetrahedron 2019, 75, 2322–2329. [Google Scholar] [CrossRef]
  38. Hédou, D.; Deau, E.; Dubouilh-Benard, C.; Sanselme, M.; Martinet, A.; Chosson, E.; Levacher, V.; Besson, T. Microwave-assisted (3+2) cycloaddition and Suzuki-Miyaura cross-coupling for a concise access to novel polyaromatic scaffolds. Eur. J. Org. Chem. 2013, 7533–7545. [Google Scholar] [CrossRef]
  39. Deau, E.; Hédou, D.; Chosson, E.; Levacher, V.; Besson, T. Convenient one-pot synthesis of N3-substituted pyrido[2,3-d]-, pyrido[3,4-d]-, pyrido[4,3-d]-pyrimidin-4(3H)-ones, and quinazolin-4(3H)-ones analogs. Tetrahedron Lett. 2013, 54, 3518–3521. [Google Scholar] [CrossRef]
  40. Harari, M.; Couly, F.; Fruit, C.; Besson, T. Pd-catalyzed and copper assisted regioselective sequential C2 and C7 arylation of thiazolo[5,4-f]quinazolin-9(8H)-one with aryl halides. Org. Lett. 2016, 18, 3282–3285. [Google Scholar] [CrossRef] [PubMed]
  41. Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.; Corbière, C.; Buquet, C.; Iannelli, M.; Leblond, B.; Marsais, F.; Besson, T. Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent. Tetrahedron 2010, 66, 4495–4502. [Google Scholar] [CrossRef]
  42. Lefoix, M.; Mathis, G.; Kleinmann, T.; Truffert, J.-C.; Asseline, U. Pyrazolo[1,5-a]-1,3,5-triazine C-nucleoside as deoxyadenosine analogue: Synthesis, pairing, and resistance to hydrolysis. J. Org. Chem. 2014, 79, 3221–3227. [Google Scholar] [CrossRef] [PubMed]
Molecules 26 03540 g001 550
Figure 1. Structures of biogenic purines (adenosine, guanine, xanthine) and C8-functionalized 2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazin-4(3H)-ones targeted in this study.
Figure 1. Structures of biogenic purines (adenosine, guanine, xanthine) and C8-functionalized 2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazin-4(3H)-ones targeted in this study.
Molecules 26 03540 g001
Molecules 26 03540 sch001 550
Scheme 1. Usual synthetic routes of the target heterocyclic systems (4). The range of yields described for steps 1, 2 and 3, can vary according to the various protocols.
Scheme 1. Usual synthetic routes of the target heterocyclic systems (4). The range of yields described for steps 1, 2 and 3, can vary according to the various protocols.
Molecules 26 03540 sch001
Molecules 26 03540 sch002 550
Scheme 2. Comparison of MW-assisted vs. conventional thermal heating for the synthesis of N-carbetoxythiourea (2a).
Scheme 2. Comparison of MW-assisted vs. conventional thermal heating for the synthesis of N-carbetoxythiourea (2a).
Molecules 26 03540 sch002
Molecules 26 03540 sch003 550
Scheme 3. MW-assisted sequential one-pot synthesis of 3a and its S-methylation into 4a.
Scheme 3. MW-assisted sequential one-pot synthesis of 3a and its S-methylation into 4a.
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Molecules 26 03540 sch004 550
Scheme 4. Scope of the MW-assisted sequential process giving 2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-ones (4a–n) from 5-aminopyrazoles (1a–n).
Scheme 4. Scope of the MW-assisted sequential process giving 2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-ones (4a–n) from 5-aminopyrazoles (1a–n).
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Scheme 5. Synthesis of pyrazolo[1,5-a][1,3,5]triazine 6 from 4a. In the first step, the reaction mixture was heated in conventional heating conditions (oil bath).
Scheme 5. Synthesis of pyrazolo[1,5-a][1,3,5]triazine 6 from 4a. In the first step, the reaction mixture was heated in conventional heating conditions (oil bath).
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Elie, J.; Fruit, C.; Besson, T. Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines. Molecules 2021, 26, 3540. https://doi.org/10.3390/molecules26123540

AMA Style

Elie J, Fruit C, Besson T. Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines. Molecules. 2021; 26(12):3540. https://doi.org/10.3390/molecules26123540

Chicago/Turabian Style

Elie, Jonathan, Corinne Fruit, and Thierry Besson. 2021. "Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines" Molecules 26, no. 12: 3540. https://doi.org/10.3390/molecules26123540

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