Pyrazole ring formation

The hydroxymethyl and carboxyl group of Ser can participate in pyrazole-ring formation, as shown in the transformation of A -protected L-Ser with the Mitsunobu reagent into a /3-lactone which afforded the N-protected serine hydrazide upon treatment with methyl hydrazine. Cyclization to 25 was achieved by diisopropyl azodicarboxylate (DIAD) and TPP [90H(31)79]. 

Fused ring systems containing a pyrazole unit can be prepared either from the heterocyclic moiety by formation of a pyrazole ring or from the reaction between a pyrazole derivative and a suitably functionalized reagent. The ring systems thus obtained are discussed in detail in other chapters (Chapters 4.05, 4.35, 4.36) but it is of interest to discuss here those methods which start from a pyrazole derivative as the reactions involved can be considered as examples of the reactivity of pyrazoles. The most widely studied fused ring systems are the [5.6] systems and the examples described in this section will be chosen from this group and, occasionally, from [5.5] and [5.7] systems. 

The different possibilities for the creation of the pyrazole ring according to the bonds formed are shown in Scheme 46. It should be noted that this customary classification lacks mechanistic significance actually, only two procedures have mechanistic implications the formation of one bond, and the simultaneous formation of two bonds in cycloaddition reactions (disregarding the problem of the synchronous vs. non-synchronous mechanism). 

Quaternary salt formation in a 1-substituted pyrazole ring (cf. 23) can occur only at N-2 to give the fully resonance-stabilized symmetrical salt 24. This reaction, which proceeds very readily, has been known for many years and therefore will not be commented on here. 

Such an easy isomerization of acetylenylbenzoic acid amides implies the formation of a five-membered nonaromatic ring condensed with the pyrazole ring. However, the pyrazole analog of o-iodobenzamide (amide of 4-iodo-l-methylpyrazole-3-carboxylic acid) formed under heating with CuC=CPh in pyridine for 9 h only the disubstituted acetylene in 71 % yield is identical in all respects to the compound obtained from the corresponding acid by successive action of SOCI2 and NH3 (90IZV2089) (Scheme 126). 

Reaction of ethyl formate with perhydroisoquinolone 54, in the presence of strong base leads to the (5-foimylketone 55 condensation of that product with hydrazine leads to the formation of a new pyrazole ring. This product, quinpirole (56), is an antihypertensive agent [11]. 

Most ring synthesis methods focus on formation of the five-membered pyrazole through cyclizations involving condensation of hydrazine with carbonyl moieties attached to the [l,2,4]triazine <1996CHEC-II(7)489>. A typical synthesis of the pyrazole ring to give various pyrazolo[4,3-< ][l,2,4]triazines 84 was reported by Rykowski eta/, using a... 

Examples of five-membered heterocyclic systems having more than one heteroatom, the derivatives of which have been selected to illustrate some important methods of ring formation, are pyrazole (36), pyrazolone (37), hydan-toin (38), oxazolone (39), thiazole (40), benzimidazole (41) and benzotriazole (42). 

D Synthesis of Silylated Heterocycles 1 Ring Formations a) Pyrazoles... 

Practically all linear 1,3-diketones13 7-142 give the corresponding pyrazoles with hydrazine104 143 and its derivatives.144-149 The reaction of aliphatic diketones should be moderated by dilution, cooling, or the addition of acid.137 Since pyrazole rings are stable, severe conditions may be used in their preparation where necessary. For details of the hydrazine/acetylacetone reaction see Wiley and Hexner.150 Evidently the reaction proceeds via the formation of the monohydrazone (11)151 which, when aryl-substituted, is less reactive and may be isolated.83,152-159 (However, see reference 159a.) It is not known if the monohydrazones are cyclic (12) or not, but they are... 

The pyrazolo[l, 2-a ]pyrazole ring system is susceptible to thermolysis, photolysis, reduction and hydrogenolysis. Two successive electrocyclic ring opening processes are responsible for the formation of the heteropolyene (66) when (64) is heated the C-vinylazomethine imine (65) is proposed as the intermediate (75TL1125). 

Nitration of l-methyl-4-(2,4-dinitrophenyl)pyrazole (7.47) occurs 25% at the 3-position and 15% at the 5-position of the pyrazole ring, whereas the 2,4,6-trinitro homologue (7.48) nitrates only in the 3-position (70JHC707 71JHC293), probably because of the increased electron withdrawal in 7.48 across the high-order 4,5-bond (cf. the explanation given in the paper that the 5-nitro derivative was formed, but that its rate of decomposition was greater than its rate of formation )... 

Parallel i/wo-ni (ration at position 4 and nitration at position 5 of the pyrazole ring were also observed during the action of the sulfuric-nitric acid mixture on 1,3-dim-ethyl-4-bromopyrazole [369], The released bromine cation partly brominates the initial reagent with the formation of l,3-dimethyl-4,5-dibromopyrazole. The latter is subsequently transformed into l,3-dimethyl-5-bromo-4-nitropyrazole (see the Scheme later). The nitration of l,3-dimethyl-4,5-dibromopyrazole leads to the formation of l,3-dimethyl-5-bromo-4-nitropyrazole and l,3-dimethyl-4-nitropyrazole [369] (Scheme 48). 

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