Synthesis of poly-functionalized pyrazoles under Vilsmeier-Haack reaction conditions

Synthesis of 1,3-disubstituted 5-chloro-1 H -pyrazole-4-carbaldehydes was achieved by formylation of the corresponding 5-chloro-1 H -pyrazoles under Vilsmeier-Haack conditions.


Introduction
The pyrazole core is a privileged structural motif of the modern drugs and bioactive natural compounds.2][3][4][5][6][7][8][9] In fact, the pyrazole ring ranks 44 th in a frequency among 351 ring systems found in currently marketed drugs. 10The incorporation of functional groups into the pyrazolic architecture attracts considerable interest because this modification opens the possibility for further transformations.These poly-functionalized heterocyclic systems have shown promising applications in the search of new biologically active candidates for drug discovery as well as polydental ligand systems.Among them the pyrazoles bearing a halogen atom and formyl group are of particular interest. 11hus, halopyrazoles show a diverse range of biological activity. 12Moreover, the introduction of a halogen atom into the pyrazole ring represents often a first step in the synthesis of hard-to-reach derivatives.4][15][16] On the other hand, 4-formylpyrazoles are currently used for the preparation of nitronylnitroxyl pyrazole-containing ligands, which are promising building blocks in design of new heterospin magnetics, 17 as well as diverse heteropolycyclic derivatives. 18It is worth mentioning that the poly-condensed heterocyclic ring system, which was synthesized from 5-chloro-1H-pyrazole-4carbaldehyde, exhibited potent anti-inflammatory and analgesic activities.In this case, the incorporation of pyrazole nucleus to quinoxaline moiety caused significant biologically activities. 19enerally, the methods for synthesis of formyl(halo)pyrazoles can be divided into two groups.The first approach presupposes the use of polyfunctional starting materials in cascade assembly of the heterocyclic core.The second one is based on the incorporation of the functional group into previously prepared pyrazoles.The modification of the existing heterocyclic system seems to be a more convenient approach to target compounds.
The methods for preparation of halo-substituted formyl pyrazoles, to the best of our knowledge, have rarely been reported.One of the approaches to 3/5-chloro (or 5-bromo)-4-formyl pyrazole derivatives is based on pyrazolones which undergo haloformylation under Vilsmeier-Haack reaction. 13,20,21Taking into account that pyrazolones are produced by refluxing of hydrazines with 1,3-dicarbonyl compounds, 22 this method was extended only for derivatives obtained from the most available representatives of 1,3-diketones or βketoesters. 13In addition, the pyrazolones were often obtained in low yields. 23,24ther pathways to target compounds are based on the reaction of 3-halo-1H-pyrazoles with organometallics 25 or diazonium derivatives. 26However, low availability of the starting materials as well as high laboriousness are disadvantages of these approaches.Thus, a straightforward approach to functionalized pyrazoles from available initial reagents is of interest.Herein, we report a general and efficient method for the synthesis of halo-substituted formylpyrazoles by simple formylation of corresponding halopyrazoles.
First, we sought the optimal reaction conditions using 1-methyl-3-propyl-5-chloro-1H-pyrazole (1a; R = Pr, R' = Me) (Sheme 1) as a model compound and the results are shown (Table 1).When reaction was carried out at 70°C, no products were observed at all (Entry 1).The best results were obtained when the pyrazole 1a was treated with excess of DMF and POCl3 at 120°C.For instance, using a 5-fold excess of DMF and 2-fold excess of POCl3 at 120°C for 2 h gives carbaldehyde 2a in 55% yield instead of 32% only for 2-fold excess of the same reagents (Entries 2, 3).
The use of excess of POCl3 leads to increasing amounts of chloroiminium ions, the key intermediates of the Vilsmeier-Haack reaction, and therefore favors the formation of target pyrazole.The excess of DMF ensures homogeneity of the process and solvates the released hydrogen chloride.The yield of 2a is not increased when more than 6 and 4 equivalents of DMF and POCl3 are used.At this ratio of reagents, a further increase in the reaction time does not affect the yield of the target product (Entries 7, 8).The use of microwave assistance did not favor the formation of target pyrazole 2a (Entries 4, 5).Thus, the optimum conditions of the process are heating the mixture of 5-chloropyrazole 1a with 6 equivalents of DMF and 4 equivalents of POCl3 at 120°C for 1 h.Under such conditions, yield of the target 1H-pyrazole-4-carbaldehyde 2a reached 67% (Entry 7).
Table 1.Optimization of the reaction conditions (ratio of the 3 reactants, temperature, duration of reaction) for the conversion of 1-methyl-3-propyl-5-chloro-1H-pyrazole (1a; R = Pr, R' = Me) into 1-methyl-3-propyl- Under the selected optimized conditions, the various 5-chloropyrazoles 1b-r were examined (Table 2).The experiments suggested that the reaction result is dependent on the substrate structure.To our delight, like model compound 1a, a total conversion of starting 5-chloro-1,3-dialkyl-substituted pyrazoles 1b,d,e,m,n (Entries 2,4,5,13,14) was achieved after refluxing at 120°C for 1-2.5 h.In contrast, 1-aryl and 3-aryl substituted pyrazoles 1f-1l needed much more time to complete the reaction (Entries 6-12).no target product e a All reactions were carried out on a 2.00 mmol scale.b The time for full conversion of 5-chloro-1H-pyrazole was monitored by TLC.c All yields refer to isolated and purified products.d The starting pyrazoles were isolated in quantitative yield.e Conversion of the starting pyrazole was 100% and 1H-pyrazole-4-carbaldehyde was not formed.
We concluded that the aromatic substituents, being more electron-withdrawing than the alkyl groups, prevent the formylation of 5-chloropyrazoles.This is especially evident for the nitrophenyl-substituted derivative 1l (Entry 12).
It should be noted that only a single example of formylation of 5-chloropyrazole 1g with the POCl3/DMF system was reported. 35Our attempts to reproduce this experiment under the conditions described failed.In contrast, the application of optimal conditions found in our study allowed us to prepare the target formylated pyrazole in moderate yield (Entry 7).
We hypothesized that such yields of pyrazoles 2f,g can be explained by formation of by-products.In fact, when the reaction of substrate 1f with DMF and POCl3 was conducted under optimal conditions, the target pyrazole 2f (52%) was isolated together with a minor amount of heterocycle 3 (6%).Its formation seems to be the result of the reaction of initial substrate 1f with formaldehyde which was generated in situ in small quantity under long heating of DMF (Scheme 3).
An unexpected result was obtained when 5-chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole 1o was treated with DMF and POCl3 under optimal conditions.In this case the formylated pyrazole 2o is a minor product while the pyrazole 5 was isolated in 72% yield.We assumed that the latter compound was formed in one-pot tandem reaction sequence via elimination of the hydrogen chloride 30 and following formylation of vinyl moiety of intermediate A, as we have described in our previous work 36 .The target pyrazole 2o undergoes also dehydrochlorination under reaction conditions to afford 5-chloro-1-methyl-3-vinyl-1H-pyrazole-4carbaldehyde 4 in 7% yield (Scheme 4).The reaction's scope is quite broad but pyrazoles 1p-r bearing strong electron-withdrawing groups on benzene ring or bulky moiety showed a low reactivity.Thus, the conversion of 1p,q achieved only 5% after refluxing of the mixture for a long time (entries 16,17).Finally, with pyrazole 1r the dealkylation reaction was observed: only a mixture of tautomers 6 was isolated (Scheme 5).This heterocycle does not afford formylated pyrazole under selected conditions. 37RKAT USA, Inc Scheme 5. Dealkylation of 1-(tert-butyl)-5-chloro-3-propyl-1H-pyrazole 1p.

Conclusions
An efficient method for the synthesis of previously unknown or hardly accessible 4-formylpyrazoles containing also a chlorine atom in position 5 has been developed.A number of different 5-chloro-4-formylpyrazoles bearing diverse substitution patterns can be synthesized by this method.The simplicity of execution, ready availability of starting materials and importance of the prepared pyrazoles make this procedure attractive for synthetic chemists.The method supplements the known approaches to halo-substituted formylpyrazoles and opens further routes to a variety of pyrazole derivatives, promising for the study of reactivity and possessing numerous valuable properties.

General procedure for the synthesis of 1H-pyrazoles (1).
A triethylamine (2 mmol) was added to a solution of dichlorovinylketone (2 mmol) in diethyl ether (10 mL) under cooling with ice-water bath.After that a hydrazine (2 mmol) was added dropwise for 20 min.In the synthesis of N-methylpyrazole 1k 2 equiv (4 mmol) of dimethylhydrazine was used without using of triethylamine.The reaction mixture was stirred for 1.5 h at room temperature.The reaction mixture was filtered off and diethyl ether was evaporated.Individual pyrazoles usable for further purposes without additional purification were obtained.

General procedure for the synthesis of 1H-pyrazole-4-carbaldehydes (2).
POCl3 (4 equiv.) was added to DMF (6 equiv.) at 0 °C.After 10-15 min, pyrazole (1.0 equiv.) was added to the reaction mixture, which was then stirred at 120°C until the pyrazole was completely consumed (based on TLC analysis).The reaction was quenched with water and was neutralized with a saturated solution of Na2CO3 to pH~7.The mixture was extracted with chloroform (3 times).The combined organic layers were dried with Mg2SO4, and filtered.The solvent was removed under vacuum and the residue was purified by silica gel column chromatography (diethyl ether/hexane) to afford the 1H-pyrazole-4-carbaldehyde.