Ring transformations in the reactions of 1,4-dinitropyrazole with N -nucleophiles

The reactions of 1,4-dinitropyrazole with primary amines, hydrazines, hydroxylamine and amidines were studied. 1,4-Dinitropyrazole in these reactions served as the synthetic equivalent of nitromalonaldehyde. The reaction of dinitropyrazole with primary arylhydrazines proved to be a convenient approach to the synthesis of 1-aryl-4-nitropyrazoles.


Introduction
Recently Nishiwaki et al. have shown 1 that β-formyl-β-nitroenamines behave as the synthetic equivalents of unstable nitromalonoaldehyde.We communicated 2 that 1,4-dinitropyrazole, even more readily available than β-formyl-β-nitroenamines, can be used in some syntheses instead of nitromalonaldehyde or its stable but poorly soluble sodium salt.This can be easily understood by looking at structures disclosed below.
1,4-Dinitropyrazoles reacting with nucleophiles often afford 5-substituted-4-nitropyrazoles in cine nucleophilic substitution reactions.These reactions have been widely studied. 3In contrast; the ring transformation reactions of 1,4-dinitropyrazoles have not been reported 4 , besides our recent preliminary communication.For several years, we have been studying the reactions of 1,4-dinitroimidazoles with Nnucleophiles.The reactions with compounds containing primary amino groups, when performed in polar protic solvents, have afforded high yields of the respectively 1-substituted 4nitroimidazoles via a degenerated ring transformation reaction.An anrorc 4 mechanism of the reaction involves: i) the addition of the amine with the formation of a respective σ H complex, ii) proton transfer, iii) the ring opening, and iv) the ring closure reaction followed by v) the elimination of nitroamide and rearomatization of the ring.The mechanism has been proved by us using spectroscopy, kinetic measurements, labeled and chiral nucleophiles. 5We assumed that the reactions of 1,4-dinitropyrazole with some amino compounds would occur according to a similar mechanism.It was rather obvious that 1,4-dinitropyrazole would not undergo ring transformation reactions with mononucleophilic primary amines.In this case the reaction should afford only ring opening products since ring closure reactions would lead to unstable four member azacyclobutene derivatives.For 1,4-dinitropyrazole ring transformation reactions, dinucleophilic reagents would be necessary.

Results and Discussion
One-or two-step nitration of commercially available pyrazole affords good yields of 1,4dinitropyrazole (1). 6Compound 1 is a reasonably stable and well soluble in many common organic solvents.The reactions of dinitropyrazole 1 (Scheme 1) with two equivalents of primary aromatic amines 2, performed in aqueous methanol at ambient temperature, led to the pyrazole ring opening with the formation of known stereoisomeric 1,5-bis(aryl)-3-nitro-1,5-diaza-1,4pentadienes (4). 7The structures of products 4 were confirmed by a comparison of data obtained by us with those described in the chemical literature. 7When similar reactions were carried out with aliphatic amines 3 only small amounts of linear compounds 5 8 were present in the reaction solution together with mixtures of stereoisomeric 3-alkylamino-2-nitropropenals 6 (β-formyl-βnitroenamines) 1,8 .The stuctures of the later compounds were deduced from 1 H NMR and MS spectra of the mixtures.
We also performed the reactions of dinitropyrazole 1 with amidines 13, supposing that in this case they would lead to the pyrazole ring expansion with the formation of respective 5nitropyrimidines (14, Scheme 4). 1 H NMR and MS spectra of the crude products revealed only very small amounts of compounds 14 11 accompanied by mixtures of oligo(nitropyrazole) derivatives.We think that oligo(nitropyrazoles) are formed in the cascades of cine nucleophilic substitution reactions from compound 1, methanol and methoxynitropyrazole 12, the latter two compounds being partly deprotonated in the presence of amidines 13, which are strong bases.An exchange of methanol by DMSO or sulfolane in the reactions of azole 1 with amidines 13 led again to the formation of oligo(nitropyrazoles) following 1-denitration of the starting azole.Performing a two-step one-pot reaction (Scheme 5) allowed us to avoid unwanted cine nucleophilic substitution reactions.Initially, compound 1 was dissolved in methanol and then treated with two equivalents of butylamine (3, R = Bu) until the complete decay of the starting material.Later (without the isolation of intermediate 5, R = Bu), amidine 13a or 13b was added and the resulting mixture was refluxed for a few hours.This one-pot procedure led to the formation of pyrimidines 14a or 14b in more acceptable yields.

Conclusions
The studied reactions of 1,4-dinitropyrazole with N-nucleophiles performed under very mild conditions probably involve the initial formation of the respective σ H complexes derived from attacks of the nucleophiles on 5-th carbon atom of the pyrazole ring.Possible ways of further conversions of the σ H complexes mainly depend on the type of the nucleophile.In general, the reactions of 1,4-dinitropyrazole with mononucleophilic primary amines give ring opening products, and the reactions with 1,2-dinucleophilic hydrazines and hydroxylamine or 1,3dinucleophilic amidines lead to the formation of ring transformation products.1,4-Dinitropyrazole reacting with easily deprotonated mononucleophiles affords cine nucleophilic substitution products.
Examples of 1,4-dinitropyrazole reactions performed by us with dinucleophilic aminocompounds represent three types of ring transformation reactions: i) transformation without a change of the ring size but with a change of the ring heteroatoms, ii) degenerated transformation without a change of the ring size and heteroatoms, iii) transformation with the ring expansion.

Experimental Section
General Procedures.Melting points were determined either in open capillary tubes or using a Boetius apparatus and were uncorrected. 1H NMR spectra (300 MHz) and 13 C-NMR spectra (75.5 MHz) were recorded on a Varian XL-300 spectrometer.Chemical shifts (δ) were given from TMS (0 ppm) as internal standard for 1 H and 13 C NMR.Some mixtures of products were analyzed using Waters HPLC Integrity Systems with a Termabeam Mass Detector (EI, 70 eV), using a direct inlet.Plastic plates (Kieselgel HF 254 type 60(Merck) were used in TLC analysis with UV/VIS (λ=254, 366 nm) CAMAG lamp for spots visualization.Starting materials, besides 1,4-dinitropyrazole (1), were commercially purchased.Known compounds were identified by 1 H NMR and a comparison of their properties with the literature data.The structures of new 1-aryl-4-nitropyrazoles (8) were proposed by analyzing EA, 1 H and 13 C NMR data obtained by us.The MS spectra of compounds 8 and their fragmentation pattern will be published elsewhere.1,4-Dinitropyrazole (1).Yield 59%, m. p. 53-54 °C (lit. 354 °C) was obtained according to the procedure given by Hüttel et al. 6 and then improved by Habraken et al. 3 The general procedure for the reaction 1,4-dinitropyrazole (1) and aromatic primary amines (2).The formation of 1,5-bis(aryl)-3-nitro-1,5-diaza-1,3-pentadiens (4).Aniline derivative 2 (4 mmole) was added to a stirred, ice-cooled solution of 1 (2 mmole) in methanol (10 mL).The forming solutions turned orange.The stirring was continued for 30 minutes and then yellow needles precipitated.The precipitations were collected by filtration and grinded with acetone (50 mL).Insolubilities were discarded and the solutions evaporated to dryness leaving crude products.Crystallization of the products from methanol gave 4 7 .