Pyrazole iodination

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). 

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... 

Halogenation is one of the most studied electrophilic substitutions in the pyrazole series (67HC(22)1, B-76MI40402). The results concern chlorination, bromination and iodination since there is no report on direct fiuorination of pyrazoles (fiuoropyrazoles are prepared by other... 

A -Pyrazolines such as (410) are oxidized by iodine, mercury(II) acetate and trityl chloride to pyrazolium salts (411), and compound (410) even reduces silver nitrate to Ag° (69JOU1480). Electrochemical oxidation of l,3,5-triaryl-2-pyrazolines has been studied in detail (74BSF768, 79CHE115). They Undergo oxidative dimerization and subsequent transformation into the pyrazole derivative (412). 

The 3,5-bis(trifluoromethyl)pyrazolate analog [Ir(cod)(/x-3,5-(CF3)2pz)]2 does not enter into oxidative addition with iodine, methyl iodide, or acetylenes. The mixture of pyrazolate and 3,5-bis(trifluoromethyl)pyrazolate gives [(rj -codllrf/x-pz)(/L-3,5-(CF3)2pz)Ir(rj -cod)], which reacts with bis(trifluoromethyl)acetylene in a peculiar manner [83JCS(CC)580], producing 145, where 3,5-bis(trifluoromethyl) pyrazolate is replaced by the ethylene bridge and the rj -coordination mode of one of the cod ligands is converted into the rj -allylic mode. 

To ascertain the possibility of inserting more than one acetylenic moiety into the pyrazole ring, the replacement of two and three iodine atoms in the appropriate halides by different alk-l-ynes was carried out. To increase the total rate, the cross-coupling of diiodopyrazoles and triiodopyrazole was performed with higher initial concentrations of the reactants than for the monoiodides. The reaction of diiodopyrazoles with the acetal was completed for the most part in 40 h, and in 64 h in the case of triiodopyrazole. The yields of the di- and triacetals reached 70-90% (Table XTTT). 

Conjugated oximes were converted to pyrazoles in a one-pot reaction by refluxing with hydrazine and iodine in ethanol. The process proceeds via an inverse electron-demand Diels-Alder reaction involving electron-deficient heterodienes and diimide species as dipolarophiles . ... 

Reaction with one equivalent of iodine transformed 1-hydroxypyrazoles and their 2-oxides into 4-iodo products (80JOC76). The iodative oxidation of pyrazolones has been discussed (87CC711). A 95% yield of 5-iodo-l-(p-tolylsulfonyl)pyrazole was made from the 5-lithium derivative (92PC1). 

In the copper catalyzed aromatic nucleophilic substitution of aryl halides bromoindole derivatives were converted to the appropriate cyanoindoles. Both 5-bromoindole and its 7V-tosyl derivative gave excellent yields, when a substoichiometric amount potassium iodide was added to the reaction mixture (6.80.), Pyrazole and benzothiophene showed a similar reactivity. The role of the added iodide is to activate the aromatic system through a bromine-iodine exchange.111... 

Another situation is observed in the case of oxidative cyclization of unsaturated ketones 58 with phenylhydrazine 33 in the presence of iodine [61]. The reaction passes through the initial formation of pyrazoline 59, which is oxidized in the presence of iodine to pyrazole 60 (Scheme 2.14). 

Rate data for the iodination of pyrazole in aqueous solution showed the reaction to be first-order in both iodine and heterocycle and an inverse first-order [H+] dependence was found over the pH range 5.96-6.74 (64JA2857). A kinetic study of the aqueous iodination of pyrazole coordinated to Ni2+ showed the coordinated ligand to react more rapidly, and a [H+] dependence that differed from that of the free ligand (82JA2460). However, the results of this study should be viewed with caution, as the presence of several nickel-pyrazole complexes in solution necessarily leads to uncertainties about the exact nature of the reactive species. 

Chromene[4,3-c]pyrazoles 34 are synthesized from l-(benzyloxy)-5-(2-fluorophenyl)-4-iodo-l//-pyrazole by iodine-lithium exchange using -BuLi, followed by addition of an aldehyde. Ring closure of the resulting lithium alkoxides, via an S Ar reaction, is effected using sodium hydride in THF under reflux (Scheme 11) <2001JOC4214>. 

Vaughan and co-workers104 have studied the iodination of pyrazole. The kinetic features are similar to those of the iodination of imidazole. Also in this case, the rate could be separated into parallel uncatalyzed and base-catalyzed reactions and the mechanism proposed... 

The reactivities of 1-methyl-, 1-ethyl-, and 1-isopropylpyrazoles follow the inductive order of the alkyl group. The rate of iodination of the pyrazole neutral molecule was estimated from those of the 1-alkyl derivatives and the relative rate kP lkP for the uncatalyzed reaction was estimated to be in the range 3 x 109 to 7 x 1012, or even larger if it is assumed that the anionic substrate undergoes attack by molecular iodine (the probability of encounter between the anion and IOH2+ is very small) and the neutral substrate by either I, or IOHo+. 

On the other hand, the reactivity of the anions (obtained in the acid dissociations of imidazole and pyrazole) is, of course, very much higher. On iodination in water, the reactivity of the pyrazole anion C3H3N2- has been estimated to be greater than that of the neutral molecule by a factor in the range of 3 x 109 to 7 x 1012, or perhaps even larger.105... 

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