Iodopyrazole

With iodine in carbon tetrachloride, 4-methylpyrazole affords a deep-red oil for which the structure (266) has been proposed. Nitric acid, silver nitrate and iodine together convert pyrazole into 1,3,4-triiodopyrazole (267 = R" = I, = H). The fV-iodopyrazoles are... 

Pyrazole does not react with iodine although pyrazolylsilver is converted into 4-iodopyrazole. 3-Iodoindazole can be obtained by the reaction of iodine with the silver salt of indazole. Kinetic studies on pyrazole iodination have been carried out by Vaughan et al. (71PMH(4)55, B-76MI40402). Coordination of pyrazole by nickel(II) in aqueous solution increases the rate of iodination by factors of two at pH 6 and eight at pH 7.2 (72JA2460). 

A number of di- and tri-(3-A-morpholinopropyn-l-yl)-l-methylpyrazoles were prepared by the condensation of corresponding iodopyrazoles with 4-prop-2-ynylmorpholine in presence of Cu(0), K2CO3 in boiling pyridine, but without palladium catalyst. Despite the low activity of this catalytic system and the long condensation time (75-95 h) the yield of 3,4-di-, 4,5-di-, and 3,4,5-tri-(3-A-morpholinopropyn-l-yl)-l-methylpyrazoles reached 70-80% (Schemes 42 and43). 

A similar phenomenon was observed for 3-amino- and5-amino-4-iodopyrazoles. The anomalous reaction in which the products of oxidative coupling of terminal acetylenes (up to 90%) are present along with the products of deiodination (up to 90%) has been described for the first time [99JCS(P1 )3713] and will be considered below in the part related to cross-coupling of 4-iodopyrazoles. 

Note that iodopyrazoles 34 and 35 did not react with p-methoxyphenylacetylene and oct-1 - yn in the presence of Pd(PPh3 )2Cl2 and Cul in boiling triethylamine. Only by using the more reactive p-nitrophenyl- or phenylacetylene, were the desired alkynylpyrazoles obtained in these conditions. 

The reaction time between 4-iodopyrazoles and 1-alkynes varies from 5 to 25 h and the yield of products is 55-95%. It is noteworthy that the nature of the terminal acetylene has a greater effect on the rate of halogen atom substitution for low-reactive 4-iodopyrazoles. Thus, the reaction time for ethynylarenes is 5-6 h, and for less acidic aliphatic 1-alkynes is 10-25 h (Table XTT). 

Amino-4-iodopyrazoles demonstrate the lower reactivity of the iodine atom in halogenopyrazoles. Todopyrazoles 36 and 37 were coupled with p-nitrophenylace-tylene in EtsN in the presence of Pd(PPh3)2Cl2 and Cul at 80°C to give good yields of the A-acetyl 4-alkynylpyrazoles (Scheme 49). 

However, attempts to couple (A-acetyl)-4-iodopyrazole 36 under the same conditions withphenylacetylene,p-methoxyphenylacetylene, andoct-l-yne, once again, were unsuccessful, instead, reductive deiodination to give 5-(iV-acetylamino)-3-methyl-l-ethylpyrazole and homo-coupling of alk-l-yne occurred (Scheme 49). The isomeric 3-(A-acetylamino)pyrazole 37 was somewhat less inclined to deiodination. 

It was found [99JCS(PI )3713] that, in all cases, the formation of the deiodinated products 38 and 39 was accompanied by formation of the diynes 40 which were isolated in 60-90% yield. The authors believed that the mechanism of deiodination may be represented as an interaction ofbis(triphenylphosphine)phenylethynyl-palladium(II) hydride with the 4-iodopyrazole, giving rise to the bisftriphenylphos-phine)phenylethynyl palladium(II) iodide complex which, due to the reductive elimination of 1 -iodoalkyne and subsequent addition of alk-1 -yne, converts into the initial palladium complex. Furthermore, the interaction of 1-iodoalkynes with the initial alkyne in the presence of Cul and EtsN (the Cadiot-Chodkiewicz reaction) results in the formation of the observed disubstituted butadiynes 40 (Scheme 51). 

It should be noted that a considerable acceleration of the reaction for low-reactive 4-iodopyrazoles is observed for substrates in which acceptor substituents at the pyrazole nitrogen atom additionally play the role of protecting group. Thus, it has been shown (88M253) that iV-phenacyl- and iV-p-tosyl-4-iodopyrazoles interact with phenylacetylene, 2-methyl-3-butyn-2-ol, and trimethylsilylacetylene at room temperature for 3-24 h in 70-95% yields (Scheme 56). 

A similar acceleration owing to the influenee of N-eleetron-withdrawing group was observed by other authors (87USP4663334) for A-aeetyl-4-iodopyrazole in the reaetion with alkynes [Pd(PPh3)2Cl2, Cul, triethylamine, THF, room temperature, 1 h, 20°C]. 

The interaction between a 4-iodopyrazole-3-carboxylic acid and copper ace-tylides having both donor and acceptor substituents at the triple bond generated six- rather than five-membered lactones, as in the aromatic series (Scheme 117). 

The isomeric 4-iodopyrazole-5-carboxylic acid is cyclocondensed in a similar way. Introduction of the additional methyl group into the ring has no effect on the direction of cycloaddition 4-iodo-l,3-dimethylpyrazole-5-carboxylic acid forms only 5-lactones (Scheme 118). 

Using the spectral data of Fig. 22, and similar data obtained for the nitrophorins in the absence of NO and in the presence of histamine, imidazole, or 4-iodopyrazole, Nernst plots such as that shown in the insert of Fig. 22 were constructed, and the midpoint potentials of the nitrophorins and their NO and histamine complexes were calculated. The results are summarized in Table IV, where they are compared to those obtained earlier for NPl (49, 50, 55). All potentials are expressed vs NHE (+205 mV with respect to the Ag/AgCl electrode used in the spectroelectrochemical titrations and the Nernst plot shown in the insert of Fig. 22). It can be seen that the reduction potentials of all four nitrophorins in the absence of NO or histamine are within 20-40 mV of each other. The reduction potentials of their NO complexes, however, differ significantly from each other. For example, the reduction potential of NP4-NO is about 350 mV more positive than that of NP4 in the absence of NO, as compared to a 430 mV shift for NPl upon binding NO, and the positive shifts for NP2—NO and NP3—NO are somewhat smaller (318 and 336 mV, respectively, at pH 7.5) 49, 50). These differences relate to the ratios of the dissociation constants for the two oxidation states, as discussed later. 

In pyrazolium salts chlorine can be displaced quite readily by iodide (77BSF171), and Sandmeyer reactions have found application in the preparation of iodopyrazoles from their diazonium salts [90AHC(48)65 90JAP(K)02/304064]. 

Five membered heterocycles, containing more than 1 heteroatom were also used in Sonogashira reactions. 4-Iodopyrazole, protected in the form of its ethyl vinyl ether adduct (6.51.) was reacted with a series of acetylenes and the acidic workup of the crude product led to 4-ethynylpyrazole derivatives in good yield.77... 

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