Pyrazoles, nitro-, synthesis

The creation of the N—N bond as the last step of the ring synthesis is common in indazoles and very rare in pyrazoles. In indazoles this method is well known (type B synthesis (67HC(22)l), for example, the dehydration of oximes (570) with acetic anhydride yields 1-acetylindazoles (571), and in basic medium the indazole 1-oxides (573) are formed from the nitro derivatives (572). 

Pyrazole, 1 -(2-methylaminophenyl)-synthesis, 5, 283 Pyrazole, l-methyl-5-nitro-2-oxide... 

Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of P-nitro-meso-tetraphenylporphyrin le with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) <02S 1155>. The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

Panke et al. (2003) also demonstrated enhanced reaction control, with respect to the temperature-sensitive synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219, a key intermediate in the synthesis of the lifestyle drug Sildenafil (220) (Scheme 64). When performing the nitration of 2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid 219 under adiabatic conditions, with a dilution of 6.01kg 1), Dale et al. (2000) observed a temperature rise of 42 °C (from 50 to 92 °C) upon addition of the nitrating solution. As Scheme 63 illustrates, this proved problematic as at 100 °C decomposition of the product 219 was observed and in order to reduce thermal decomposition of pyrazole 219, and increase process safety, the authors investigated addition of the nitrating solution in three aliquots, which resulted in a reduced reaction temperature of 71 °C and an increase in chemoselectivity unfortunately, the reaction time was increased from 8 to 10 h. 

Scheme 64 An illustration of the temperature-sensitive synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219, a key intermediate of Sildenafil (220).

By conducting the reaction in a flow reactor, where the heat of reaction can be rapidly dissipated, the authors were able to maintain a reaction temperature of 90 °C as a result of adding the nitrating mixture continuously. Coupled with a residence time of 35 min, the authors were able to attain a throughput of 5.5 gh 1 with an overall yield of 73% 219. In addition to the dramatic reduction in residence time (10h-35min) and the increased process safety, the continuous flow methodology afforded a facile route to the chemoselective synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219. 

The construction of a heterocyclic ring from two reagents, one of which contains a nitro group, is widely used in the synthesis of the nitro derivatives of pyrazole, isoxazole, and 1,2,3-triazole. Thus, for example, the reaction of sodionitromalonal-dehyde with substituted hydrazines leads to the corresponding derivatives of 4-nitropyrazole [33, 61, 471 173] (Scheme 63). 

In view of the importance of 2-nitroimidazoles as antibiotics e.g. 2-nitroimidazoIe azomycin ) and the problems involved in their synthesis (usually via the 2-aminoimidazole) it seemed worthwhile to attempt to prepare these compounds by thermal rearrangement of the (V-nitro compounds (by analogy with the well-known reactions of 1-nitro-pyrazoles and -indazoles) (Chapter 4.04). Thus, when 1,4-dinitroimidazole (16) is heated at 140 °C in chlorobenzene, benzonitrile or anisole there is conversion into 2,4- and 4,5-dinitroimidazoles, but considerable denitration can also occur, giving 4-nitroimidazole (Scheme 6). 2-Methyl-l,4-dinitroimidazole rearranges smoothly to 2-methyl-4,5-dinitroimidazole, but 5-methyl-l,4-dinitroimidazole appears to denitrate in preference to any other reaction. Further study of these reactions is indicated. 

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