An efficient synthesis of functionalized 3-(hetaryl)pyrazoles

An efficient synthesis of novel 3-heteroaryl-pyrazoles, which have not been reported hitherto, is described via reactions of ethyl 3-[( E )-3-( N , N -dimethylamino)acryloyl]-1-(4-chlorophenyl)-5- phenyl-1 H -pyrazole-4-carboxylate with hydrazine hydrate, hydroxylamine, various heterocyclic amines, active methylene compounds and diazotized heterocyclic amines. The structures of the compounds prepared were determined by spectral and elemental analyses and alternative syntheses wherever possible.


Introduction
Pyrazoles are an important class of heterocyclic compounds.Literature reports reveal that many synthetic pyrazole derivatives are used in the pharmaceutical, agrochemical, photographic and other fields.Examples of such synthetic pyrazole derivatives are Sildenafil (Viagra), 1 Ionazlac 2 and Difenamizole. 3In addition, hydrazonoyl halides (RC(X)=NNHR') proved useful precursors for synthesis of numerous biologically active pyrazoles and fused pyrazoles. 4These findings oriented our attention to the synthesis of a new series of functionalized 3-(hetaryl)pyrazoles that might have bioactivity.In connection with our continued studies on such hydrazonoyl halides [4][5][6][7][8][9][10][11][12][13][14] and our recently reported synthesis of 3-[(E)-3-(N,N-dimethylamino)acryloyl]-1-(4chlorophenyl)-5-phenyl-1H-pyrazole-4-carboxylate 3 15 from N-(4-chlorophenyl) 2-oxopropanehydrazonoyl chloride 1 (Scheme 1), we report herein the results of our study of the reactions of 3 with several N-and C-nucleophiles as well as some N-electrophiles namely diazotized heterocyclic amines.The aim of the present paper is to present an efficient synthesis of novel 3-heteroaryl-pyrazoles, which have not been reported hitherto.The results of screening of their biological activity will be reported in due course.

Scheme 1 Scheme 2
The reactivity of the enaminone 3 towards some heterocyclic amines was also examined.Thus, reaction of 3 with 5-amino-1,2,4-triazole 6 in acetic acid under reflux yielded the respective 1,2,4-triazolo [1,5-a]pyrimidine derivative 7 (Scheme 3).Similar treatment of 3 with 2-aminobenzimidazole 8 and 5-amino-3-phenylpyrazole 10 under the same reaction conditions afforded the respective benzimidazo [1,2-a]pyrimidine and pyrazolo [1,5-a]pyrimidine derivatives 9 and 11, respectively (Scheme 3).To account for the formation of the products 7, 9 and 11, it is suggested that the studied reactions started with Michael-type addition of the exocyclic amino group of each the amines used to the activated double bond of 3 followed by in situ tandem elimination of dimethylamine and dehydrative cyclization (Scheme 4).The 1 H NMR spectrum of each of the products 7, 9 and 11 revealed two doublets signals in the regions δ 7.53-7.99and 7.96-8.67with J = 4.5 Hz assignable to the two vicinal protons of the pyrimidine ring residue. 17Next, reactions of the enaminone 3 with some active methylene compounds were examined.Thus, reaction of 3 with acetylacetone 12a, ethyl acetoacetate 12b and ethyl benzoylacetate 12c in acetic acid in the presence of ammonium acetate under reflux yielded products that were identified as 2-(pyrazol-3-yl)pyridine derivatives 13a-c, respectively (Scheme 5).As depicted in the latter Scheme 5, the formation of 13 seems to start with Michael addition of the active methylene compound 12 to the activated double bond of 3 followed by tandem elimination of dimethylamine and condensation with ammonia.The other possible isomeric structure 14 was discarded on the basis of spectral data.For example, each of the products 13a-c exhibits in its 1 H NMR spectrum two doublet signals in the regions δ 7.86-8.07and 8.28-8.34due to pyridine H-3 and H-4, respectively with J = 9 Hz.The latter coupling constant value is characteristic for pyridine H-3 and H-4 and much higher than that for H-2 and H-3 (J = 4-6 Hz). 18

Scheme 5
Reactions of 3 with malononitrile 15a and ethyl cyanoacetate 15b in refluxing ethanol in the presence of sodium ethoxide afforded products that were identified as 16a and 16b, respectively.The assignment of the structures of the latter products was based on their spectral (IR, 1 H NMR and MS) and elemental analyses data (see Experimental).Furthermore, the structure of the product 16a was confirmed by its alternative synthesis by reaction of 3 with cyanoacetamide 17a under the same reaction conditions (Scheme 6).Here also, it is suggested that the formation of 16 seems to start with Michael addition of the active methylene compound 15 to the activated double bond of 3 followed by tandem cyclization, elimination of dimethylamine and Dimroth type rearrangement of the formed pyran intermediate to give 16 as end product.

Scheme 6
Finally, reactions of the enaminone 3 with diazotized heterocyclic amines were examined.Thus, reaction of 3 with diazotized 3-amino-1,2,4-triazole 18 and 2-aminobenzimidazole 19 in pyridine at 0- ]triazine derivatives 20 and 21, respectively (Scheme 7).The formation of such products seems to result via initial substitution of the α-hydrogen in the enaminone 3 to form the respective azo coupling intermediate 22 which then undergoes intramolecular Michael addition followed by elimination of dimethylamine.Although the reverse sequence of these steps is also possible and will lead to the same products via the intermediate 23, it seems that the former sequence is more plausible as it involves the formation of the intermediate 22 which is more stable than the intermediate 23.
The structures of both products 20 and 21 were consistent with their elemental and spectral (MS, IR and 1 H NMR) analyses (see Experimental).

Conclusions
The results of the present study indicate that the hydrazonoyl halides and enaminones are useful precursors for the synthesis of different functionalized 3-hetarylpyrazoles.In addition, they indicate that reactions of the studied enaminone are regiospecific as they yielded, in each case, one product in good yield.The compounds prepared are expected to be of pharmacological interest.

Experimental Section
General.All melting points were determined on an electrothermal Gallenkamp apparatus.Solvents were generally distilled and dried by standard literature procedures prior to use.The IR spectra were measured on a Pye-Unicam SP300 instrument in potassium bromide discs.and 13 C NMR spectra were recorded in DMSO-d6 on a Varian Mercury VXR spectrometer (300 MHz for 1 H NMR and 75 MHz for 13 C NMR) and the chemical shifts  downfield from tetramethylsilane (TMS) as an internal standerd.The mass spectra were recorded on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the ionizing voltage was 70 eV.Elemental analyses were carried out by the Microanalytical Center of Cairo University, Giza, Egypt.Both compounds 2 16 and 3 15 were prepared as previously described.Reaction of enaminone 3 with heterocyclic amines.To a solution of 3 (2.11g, 0.005 mole) in acetic acid (20 ml) was added the appropriate heterocyclic amine (6, 8 or 10) (0.005 mole).The mixture was refluxed for 6 h then cooled.The solid that deposited after cooling was filtered off and crystallized from ethanol-dioxane mixture.The physical constants together with the spectral data of the products 7, 9 and 11 prepared are depicted below.

Preparation of compounds 13a-c
To a solution of 3 (2.11g, 5 mmole) in glacial acetic acid (20 mL) was added the appropriate active methylene compound (acetylacetone 12a or ethyl acetoacetate 12b or ethyl benzoylacetate 12c) (0.005 mole) and ammonium acetate (0.5 g, 6 mmole).The reaction mixture was heated under reflux for 20-30 hours.The reaction was followed by TLC.The reaction mixture poured into cold water, the solid product that precipitated was filtered off and crystallized from ethanol to give the respective product 13.The compounds 13a-c prepared together with their physical constant are given bellow.Alternative synthesis of compound 16a.To a solution of 3 (2.11g, 5 mmole) in ethanolic sodium ethoxide solution (0.12 g. 5 mmole of sodium metal in 20 ml absolute ethanol) was added cyanoacetamide 17a (0.42 g, 5 mmole).The reaction mixture was refluxed for 20 h., and the solid that precipitated was filtered off and washed with water then crystallized from ethanol to give compound 16a which was found identical in all respects with that compound produced from reaction of compound 3 with malononitrile.

Coupling of enaminone 3 with diazonium salts of heteroamines
A solution of enaminone 3 (2.11g, 0.005 mole) in pyridine (20 mL) was cooled in an ice bath at 0-5°C while being stirred.To the resulting cold solution was added portionwise a cold solution (0-5°C) of the appropriate diazonium salt of 3-amino-1,2,4-triazole 18 or 2-aminobenzoimidazole 19 prepared as usual by diazotizing the corresponding heterocyclic amine (5 mmole) in nitric acid (6M, 3ml) with sodium nitrite (0.35g, 5mmole) in water (5ml).After all the diazonium salt solution was added, the mixture was stirred for further 30 min.while cooling in an ice-bath.The reaction mixture was then left in a refrigerator for three days.The solid that precipitated was filtered off, washed with water, dried and finally crystallized from ethanol to give product 20 or 21 respectively.