Chloropyrazoles

Sometimes compounds which exist predominantly in the hydroxyl form give products of N-methylation with diazomethane, for example 3-hydroxy-5-phenylisothiazole (63AHCi2)245) of course, the ambident anion (493) is an intermediate. 3-Hydroxypyrazoles, under rather severe conditions, can be converted into 3-chloropyrazoles with POCI3 <66AHQ6)347). 

Nitration of 3-chloropyrazole 1-oxide 119 (R=CH2Ph, Hal=Cl) gave the 4-nitro derivative, which was unstable, rearranging to l-benzyl-3-hy-droxy-4-nitro-5-chloropyrazole apparently via an intermolecular reaction (1992ACSA972). 

From the results quoted in Section 4.04.2.1.3(x) the stability of acetyl derivatives of indazolone decreases in the order A/ (l)-acetyl>A/ (2)-acetyl > 0(3)-acetyl. The reactivity of 3-hydroxypyrazoles is covered by Dorn s comprehensive review (80CHE1). Amongst the results reported there are the Claisen rearrangement of allyloxypyrazoles (475a) -> (475b) and a method for transforming 3-hydroxy- into 3-chloro-pyrazoles via the pyrazolone (476) and the chloropyrazolium chloride (477). Methylation of 3-hydroxypyrazole (478 X = OH) affords the pyrazolone (476), which in turn is transformed into the salt (477) by reaction with phosphorus oxychloride. The final step is the thermolysis of (477) that yields the 3-chloropyrazole (478 X = C1)... 

The second problem is the relationship between the position of the substituent in the pyrazole nucleus and its mobility. In the 1-phenylpyrazole series in their reactions with Grignard reagents, the bromine reactivity decreases in the order 5-Br>4-Br>3-Br (B-76MI40402). When an electron-withdrawing group is present at the 4-position, the 5-chloropyrazole is more reactive than 3-chloropyrazole, but this has been attributed to bond fixation (Section 4.02.3.9). Thus, this problem needs further clarification. 

Under low temperature Vilsmeier conditions 4,4 -bipyrazol-3,3 -dione 86 was diformylated at the methyl group of one of the pyrazol-3-one rings that was converted into 3-chloropyrazole. The product 87 remained with one pyrazol-3-one ring intact. When the temperature was increased to 75 °C a furo[2,3-f 5,4-c]dipyrazole derivative was obtained (92BCJ1652) (Scheme 22). 

The title compounds also undergo the Claisen rarrangement (5-allyloxypyrazoles 4-allyl-5-pyrazolones) and are readily transformed into 5-chloropyrazoles by means of phosphorus oxychloride (8OCHE1). In the presence of aluminum chloride 5-acyloxypyrazoles (481) undergo the Fries rearrangement affording 4-acyl-5-hydroxypyrazoles (482). 

A somewhat different strategy is employed for preparation of the desoxy analogue containing the reversed pyrazole. Acylation of chloropyrazole with jfl-chloro-benzoyl chloride affords the ketone Reaction of that... 

Chloro-3-(5-chloropyrazol-3-yl)quinoxalme (137, R = H) gave mainly 2-(2-acetyl-5-chloropyrazol-3-yl)-3-chloroquinoxaline (137, R = Ac) [neat AC2O, reflux, 7 min, then 20°C, 30 min 86% (after separation from a little of the 1-acetyl isomer) stmcture confirmed by X-ray analysis] or mainly 2-(l-acetyl-5-chloropyrazol-3-yl)-3-chloroquinoxaline [neat AC2O, 80°C, 2 min ( ), then 20°C, 12 h 70% (after separation from the 2-acetyl isomer)] an extraordi-... 

Base-mediated intramolecular cyclization of an amino-substituted triazole onto the chloropyrazole of compound 257 with loss of HG1 generates the central pyrimidine ring of 258 (Equation 70) <2004JCM50, 2004SC151>. 

Reaction of the azophosphoranes (Scheme 7.32) with dichlorocarbene follows an interesting pathway to produce l-aryl-5-chloropyrazole-3-carboxylic esters. The initial displacement of the phosphine (probably as the oxide) has been confirmed by the isolation of the 3,3-dichloropropenic ester under mild conditions. Subsequent conversion into the pyrazole appears to involve reaction with a trichloromethyl anion followed by attack by a second dichlorocarbene, although evidence for the mechanism of these steps is circumstantial [40],... 

Similarly l-phenyl-3-methyl-4-formyl-5-chloropyrazole reacts with thioglycollic acid in the presence of alkali to yield a mercaptopyrazole derivative that could be cyclized to thieno[2,3-c]pyrazole in the presence of alkali (69KGS760, 69ZOR1498). Similar to this is the reported formation, via 311, of 312 from 310 and mercaptoacetanilide (73ZOR2416). 

Conversion of ethyl 5-chloropyrazole-4-carboxylate into 4-hydroxy-thieno[2,3-c] pyrazoles, via ethyl 5-(phenylcarbomoylmethylthio)-4-pyrazole carboxylate intermediates, has also been reported (72USP3649641). The reaction of disulfide 313 with nitromethane gives 314 (74TL4069). 

Pyrazole 174 has been formed by electrocyclization of transient azido-substituted pyrazole 193 generated from chloropyrazoles upon treatment with sodium azide in refluxing aqueous DMF, but yields of isolated bicycles are moderate (Equation 21) <1995M1265>. 

Tautomerism of 3,5-bis(4-methylpyrazol-l-yl)-4-methylpyrazole (202) also involves the simultaneous rotation of the two lateral rings and has a value of 12 kcal mol-1 (in methanol), almost the same as 3,5-dimethyl-4-chloropyrazole and 3,5-dimethyl-4-nitropyrazole (93CJC1443). 

Dziomko and coworkers have utilized the nucleophilic aromatic substitution of aryl amines to chloropyrazoles or chloropyridines in the template step of their macrocycle syntheses.174 175 The nature of the template process is unclear and it could simply be thermodynamic. However, a kinetic effect is a distinct possibility and would require attack of a coordinated aryl amine (Scheme 52). 

Potassium hydroselenide is allowed to act upon the methiodide of l-phenyl-3 4-dimethyl-5-chloropyrazole, when long, thin, yellow... 

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