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

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.

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 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.
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).
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 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 1 H-NMR analysis indicated a complete conversion of the starting pyrazole.
To overcome such low yields and tedious work-up, the synthesis of 2-thioxo-1Hpyrazolo[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). found at the end of the process while crude 1 H-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 multifunctionalized 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. Scheme 3. MW-assisted sequential one-pot synthesis of 3a and its S-methylation into 4a.
The preparation of 4a and its derivatives is a crucial step in the synthesis of multifunctionalized 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. 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). 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 POCl 3 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 POCl 3 , 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).

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 com-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).

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]. 1 H NMR and 13 C NMR spectra of these compounds are available in Supplementary Materials (Section S1-S20). General information and procedure for their synthesis are described below.

General Information
All reagents (1a-n) were purchased from commercial suppliers (Alfa Aesar, Thermo 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 ( 1 H and 13 C) 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 1 H and 75.4 or 101 MHz for 13 C. 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.

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.