2-Methyl-7-Substituted Pyrazolo [ 1 , 5-a ] pyrimidines : Highly Regioselective Synthesis and Bromination

Este trabalho descreve a reação de ciclocondensação de 3-amino-5-metil-1H-pirazol com 1,1,1-tricloro-4-alcóxi-3-alquen-2-onas [CCl 3 C(O)CH=C(R)OR, onde R/R = H/Me, Me/Et, Et/Me, Pr/Et, Bu/Me, iso-Bu/Me] e β-dimetilaminovinil cetonas [RC(O)CH=CHNMe 2 , onde R = Ph, Ph-4-Me, Ph-4-F, Ph-4-Cl, Ph-4-Br, Ph-4-NO 2 , fur-2-il, tien-2-il, pirrol-2-il, pyrid-2-il], em refluxo de ácido acético para a obtenção de uma série de catorze pirazolo[1,5-a]pirimidinas. Os produtos foram obtidos em bons rendimentos (65-98%). Este trabalho apresenta ainda uma metodologia simples e seletiva para a obtenção de 3-bromo-pirazolo[1,5-a]pirimidinas, com rendimentos de 70-98%.


Introduction
Among the broad range of templates, heterocycle scaffolds represent the most promising molecules as lead structures in the discovery of novel synthetic drugs 1 and the revision of synthetic methods for their obtainment are intense. 2In particular, the pyrazolo[1,5-a]pyrimidine heterocyclic can be found in a large number of pharmaceutical agents with a diverse range of activities.Pyrazolo [1,5-a]  pyrimidines are purine analogues and as such have useful properties as antimetabolites in purine biochemical reactions.Compounds of this class have attracted wide pharmaceutical interest because their antitrypanisommal activity, 3 antischistosomal activity, 4 activity as HMG-CoA reductase inhibitors, 5 COX-2 selective inhibitors, 6 AMP phosphodiesterase inhibtors, 7 KDR kinase inhibitors, 8 selective peripheral benzodiazepine receptor ligants 9 and as antianxiety agents. 10Recently other pharmaceutical activity has been reported, for example, as an agent for the treatment of sleep disorders 11 and as an oncological agent. 12The show examples highlight the high level of interest in variously substituted pyrazolo [1,5-a]pyrimidines and their modified analogues there is a wide range of methods available for the synthesis of pyrazolo [1,5-a]pyrimidines. 13However, a facile procedure that can incorporate diversity structural it is high desirable.There are a limitedness number and variety of pyrazolo pyrimidines trifluoromethyl substituted described in literature. 14Conversely, pyrazolo [1,5-a]  pyrimidines trichloromethyl substituted are rare. 15The most convenient method to construct trihalogenated compounds is to use halogen-containing building blocks as starting reagents. 16,17Our research group developed a general procedure for preparing β-alkoxyvinyl trihalomethyl ketones by acylation of enol ethers and acetals using 2-Methyl-7-Substituted Pyrazolo [1,5-a]pyrimidines J. Braz.Chem.Soc.206   functionalized acyl groups CX 3 CO (where X = F and Cl). 16n addition, we have exhaustively studied the versatility of the β-alkoxyvinyl trihalomethyl ketones on heterocyclic synthesis and our research have resulting in outstanding contributions to heterocyclic synthesis. 2,16On the other hand, aminopyrazoles are known to be highly reactive heterocyclic compounds, e.g., the nucleophilic attack of C-4 of the aminopyrazoles on the carbonyl groups, 18 and the N-nucleophilic attack on aromatic aldehydes yielding aldimines, have been extensively reported. 19Aminopyrazoles also react as electron-rich dienophiles in the inverse electron demand Diels-Alder [4+2] cycloaddition reactions. 20he use of 3-and 5-aminopyrazoles as precursors of fused heterocycles, such as pyrazolo[1,5-a]pyrimidines 21 and pyrazolo [3,4-b]pyridines 22 has also been described.Additionally, halogenation of pyrazolo [1,5-a]pyrimidines can be used to obtain key substructures in a large variety of compounds with important biological activities, and the halogenated compounds also can be used as reagents in cross-coupling reactions with terminal acetylenes, organotin aryl derivatives or aryl boronic acids. 23Thus, in the course of our investigations on heterocyclic chemistry and in view of the growing importance of halogenated heterocycles, the aim of this study is to show: (i) the synthesis of halomethyl-containing pyrazolo[1,5-a] pyrimidines (3) from the reaction of 3-amino-5-methyl-1H-pyrazole with 4-alkoxy-1,1,1-trichloro-3-alken-2-ones (1) or β-dimethylaminovinyl ketones (2) (Scheme 1) and (ii) the bromination of the pyrazolo [1,5-a]pyrimidines (3)  with bromine to obtain 3-bromopyrazolo[1,5-a]pyrimidines (4) (Scheme 2).

Results and Discussion
The 4-alkoxy-1,1,1-trichloro-3-alken-2-ones 1a-f, were synthesized from the reaction of trichloroacetyl chloride with enol ether or acetal, in accordance with the methodology developed in our laboratory. 16The β-dimethylaminovinyl ketones 2g-p were prepared from the reaction of N,N-dimethylformamide dimethylacetal with methyl ketones, using the procedure described in the literature. 24The 3-amino-5-methyl-1H-pyrazole used is commercially available.
The general methodology used in this work for preparing the halomethylated-(3a-f) and aryl-pyrazolo [1,5-a]  pyrimidines (3g-p) was similar to the methodology described in the literature for the cyclocondensation reaction of a β-dicarbonyl compounds with 3-amino-pyrazole. 25The reaction was carried out from the cyclocondensation reaction of the 3-amino-5-methyl-1H-pyrazole with 4-alkoxy-1,1,1trichloro-3-alken-2-ones (1a-f), or β-dimethylaminovinyl ketones (2g-p), in reflux of acetic acid for 16 hours.The crude compounds 3 were purified by recrystallization from hexane, and the pure products were obtained in moderate to high yields (65-98%).The structure of compounds 3 was confirmed by 1 H/ 13  C NMR signal at 157.5 ppm (pyrimidine C5) and another one between the 1 H NMR signal at 7.28 ppm (pyrimidine C6-H) and the 13 C NMR signal at 148.9 ppm (pyrimidine C6).This information is in agreement with the proposed structure, and this structure was confirmed by X-ray diffraction for compound 3g (Figure 1). 26A mechanism to reaction is suggest in Scheme 2, the reaction probably involved an initial C-N bond formation, from the attack of the nitrogen atom of the NH 2 group on the β-carbon of the enone 1,2, with subsequent substitution of the alkoxy or N,N,-dimethylamino group, to furnish the enamino ketone intermediates.In a second moment, there was an intramolecular nucleophilic addition of the pyrazole ring nitrogen atom to the carbonyl carbon of the enone 1,2, with subsequent elimination of one molecule of water. 27 contrast with previous studies, 28,29 the reaction was highly regioselective and only the pyrazolo[1,5-a] pyrimidine isomer was obtained, where R 2 was attached to C7 and R 1 was attached to C5 of the pyrimidine ring.The high regiosselectively of the reaction could be rationalized in terms of the difference of the nucleophilicity of the nitrogen atoms of the NH 2 group (soft) and N1/N2 of the pyrazole ring (hard), together with the difference of the electrophilicity of the β-carbon atom (soft) and carbonylic carbon (hard) of the enone 1,2.In addition, semi-empirical quantum chemical calculations were used to compare the stability of the possible intermediates formed before the pyrimidine ring closure.The analyzes of the stability of these intermediates showed that the enaminone formed by the addition of the NH 2 group of the aminopyrazole on the C-β possesses the higher stability (>10 kcal mol -1 ) than the enaminone formed by the addition of the nitrogen ring pyrazole on the C-β.For this study, the semi-empirical AM1 (Austin Model 1) method incorporated in the Hyperchem software 30,31 was implemented.
In a second step of this study, we reacted the pyrazolo [1,5-a] Considering the reaction conditions used for an electrophilic aromatic substitution, the selectivity of the bromination reaction of the pyrazolo[1,5-a]pyrimidines described in the present work can be understood from the resonance structures of the arenium-like intermediates (Scheme 4).When electrophilic bromine reacted in the C-3, four resonance structures of the intermediate were originated, whereas when the same eletrophile reacted in J. Braz.Chem.Soc.208 C-6, only two resonance structures of the intermediate were generated.In addition, it is well-known that pyrazoles are π-exceeding rings and pyrimidines are π-deficient rings.Thus, the pyrazole ring, as expected, is more reactive than the pyridines in this bromination reaction. 32Finally, although the reaction conditions could be used for side chain bromination reaction of methyl aromatics, such as pyridines and benzoderivatives, 33 in the case of methyl pyrazoles there are no reports in the literature about side chain bromination reactions. 23Our results of the bromination reaction are in accordance with those described in the literature.

Conclusions
In summary, the synthesis described in this paper is a highly regioselective, practical and simple method for the preparation of halomethyl-containing pyrazolo[1,5-a] pyrimidines from 3-amino-5-methyl-1H-pyrazole and 1,3-dieletrophilic compounds.In addition, we reported a mild and convenient protocol for 3-halogenation of pyrazolo[1,5-a]pyrimidines with NBS and showed that the present procedure gave the products in good yields.

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial suppliers without further purification.Yields listed in Schemes 1 and 2. All melting points were determined on a Reichert Thermovar apparatus.The 1 H/ 13 C NMR and 2D NMR spectra were recorded on a Bruker DPX 400 spectrometer ( 1 H at 400.13 MHz and 13 C at 100.61 MHz) 298 K, digital resolution of ± 0.01 ppm, with 0.1 mol L -1 solution in CDCl 3 as solvent or Acetone-d 6 containing TMS as internal standard.All spectra were registred in a 5 mm tube, at a natural abundance.Mass spectra were registered in a HP 5973 MSD connected to a HP 6890 GC and interfaced by a Pentium PC.The GC was equipped with a split-splitless, injector, autosampler, cross-linked HP-5 capillary column (30 m 0.32 mm of internal diameter), and helium was used as the carrier gas.

General procedure for the preparation of pyrazolo[1,5-a] pyrimidines 3a-p
A solution of 3-amino-5-methyl-1H-pyrazole (1.0 mmol) in acetic acid (5 mL) was added to a stirred precursor 1 or 2 (1.0 mmol) in acetic acid (5 mL).The mixture was stirred for 16 h and after the reaction time, the products were extracted with chloroform (3 × 10 mL), washed with distiled water (3 × 10 mL) and dried on magnesium sulfate.The solvent was removed in a rotary evaporator and the products 3 were purified by recrystallization from hexane.
General procedure for the preparation of 3-bromopyrazolo [1,5-a] pyrimidines 4a,b,d,g,i-n A mixture of pyrazolo[1,5-a]pyrimidine 3 (1.0 mmol), N-bromocuccinimide (1.0 mmol) and THF (5 mL) was stirred for 20 h under reflux temperature.After the reaction time, the solution was extracted with chloroform (3 × 10 mL), washed with distilled water (3 × 10 mL) and dried on magnesium sulfate.The solvent was removed in a rotary evaporator and the products 4 were purified by recrystallization from hexane.