Mild Nitration of Pyrazolin‐5‐ones by a Combination of Fe(NO₃)₃ and NaNO₂: Discovery of a New Readily Available Class of Fungicides, 4‐Nitropyrazolin‐5‐ones

Abstract

4‐Nitropyrazolin‐5‐ones have been synthesized by the nitration of pyrazolin‐5‐ones at room temperature by employing the Fe(NO3)3/NaNO2 system. The method demonstrated selectivity towards the 4‐position of pyrazolin‐5‐ones even in the presence of NPh and allyl substituents, which are sensitive to nitration. It was shown that other systems containing FeIII and nitrites, namely Fe(NO3)3/tBuONO, Fe(ClO4)3/NaNO2, and Fe(ClO4)3/tBuONO, were also effective. Presumably, FeIII oxidizes the nitrite (NaNO2 or tBuONO) to form the NO2 free radical, which serves as the nitrating agent for pyrazolin‐5‐ones. The synthesized 4‐nitropyrazolin‐5‐ones were discovered to be a new class of fungicides. Their in vitro activities against phytopathogenic fungi were found comparable or even superior to those of commercial fungicides (fluconazole, clotrimazole, triadimefon, and kresoxim‐methyl). These results represent a promising starting point for the development of a new type of plant protection agents that can be easily synthesized from widely available reagents.

Synthetic Routes to Bioactive Bipyrazole Derivatives

“…Treatment of the pyrazolin‐5‐one 222 with Fe(ClO 4 ) 3 at room temperature resulted in its oxidative dimerization and formation of the diastereomeric mixture of 4,4′,5,5′‐tetramethyl‐2,2′‐diphenyl‐2,2′,4,4′‐tetrahydro‐3H,3′H‐[4,4′‐bipyrazole]‐3,3′‐dione 223 in 44 % meso and 32 % racemic (Scheme 57). [108] …”

4-Nitropyrazolin-5-ones as Readily Available Fungicides of the Novel Structural Type for Crop Protection: Atom-Efficient Scalable Synthesis and Key Structural Features Responsible for Activity

“…20−22 Thus, the discovery of new classes of fungicides with novel MoA is very important for both medicine and crop protection. 23−28 In our previous work, 29 nitropyrazolones were discovered as a novel class of highly potent fungicides, but a practical approach for their synthesis was not proposed, which limited their potential for crop protection. Namely, the previously developed method 29 was not effective for the synthesis of N1substituted nitropyrazolones, whereas a substituent at N1 was essential for fungicidal activity.…”

Facile and Efficient Nitration of 4‐Aryl‐1(2H)‐Phthalazinone Derivatives Using Different Catalysts

“…[13,14] Moreover, nitro-aromatic compounds consider a key intermediate for the construction of a great variety of valuable products such as drugs, [15][16][17] dyes, [18] explosives and energetic materials. [19,20] Many methods for the nitration of aromatic compounds have been developed using different nitrating agents including HNO 3 , metal nitrates (Fe(NO 3 ) 3 , [21,22] Zr(NO 3 ) 4 , LiNO 3 , Mg(NO 3 ) 2 , Pb(NO 3 ) 2, Cr(NO 3 ) 3 , [23] sodium nitrites (NaNO 2 ), [24,25] KNO 2 , [26] NO 2 BF 4 [27] and N 2 O 5 [28,29] using different nitrating catalysts such as Lewis acids, [30] Bronsted acids (H 2 SO 4 , H 3 PO 4 , CH 3 COOH), ptoluene sulfuric acid (PTSA), [31] iodine(III)-catalyzed electrophilic nitration, [32] diaryliodonium salts, [33] Alumina sulfuric acid (ASA), [34] silica sulfuric acid, [35] dehydrating agents, [36] oxidizing agent catalysts (P 2 O 5 and Cerium Ammonium Nitrate (CAN)), [37] different organic solvents, [38] and may use solid support materials such as (silica contain zeolites), [39] and also some researchers studied nitration reactions under microwave [40] and ultrasound [41] irradiation. However, many problems have been observed, which result from introducing a nitro group into organic compounds particularly, over nitration, regioselectivity, [42] competitive oxidation and hydrolysis of sensitive compounds.…”