Pyrazoles, sterically hindered

Treatment of dibromo or dichloroacetic acid with two equivalents of 3,5-dimethylpyrazole and excess of potassium hydroxide, potassium carbonate and a small portion of TEBA phase-transfer catalyst gives Hbdmpza (3b) in reasonable yield after acidification and extraction with diethylether. This synthesis can also be applied for the unsubstituted pyrazole but not for sterically hindered pyrazoles (40). 

The fixed geometry of a, 3-unsaturated ketones in the S-cis form, as observed in arylidene alkanones, influences their reactivity. For example, the reaction of arylhydrazines with 3,5-diarylidene-4-piperidones, 2-arylidene-l-tetralones, 2,6-diarylidenecyclohexanones and 2-arylideneindan-l,3-diones requires stronger conditions than for the case of their noncyclic analogues [76, 77, 78, 79, 80, 81, 82, 83, 84]. However, arylidene derivatives of cyclohexanone, 1-indanone, 4-chromanone, 4-thiochromanone and TV-methyl-4-piperidone hydrochloride react with hydrazines more easily [85,86,87,88], It is interesting to note that the more complicated and sterically hindered unsaturated ketones of the spiro type 64 react with hydrazine and phenylhydrazine very easily in the presence of piperidine, leading to pyrazoles 65 in high yields [89] (Scheme 2.16). 

Several d and / transition metals have been found to yield polymeric complexes with pyrazoles 14, 178). Reactions of these polymers with HFA produce monomeric species, HFA adding to the free nitrogen atom and the metal. Substitution of one carbon atom adjacent to nitrogen also results in degradation of the polymers. However, no reaction has been found when both a carbon atoms are sterically hindered 14). 

When K[BHJ is heated in an even more sterically hindered pyrazole, i.e., 3,5-bis(t-butyl)pyrazole, up to its boiling point, no reaction occurs at all. 

M M distance can be closely controlled. Note, however, that pyrazole (91) and imidazole (92) can only bridge after deprotonation (100-102), and in highly substituted ligands, coordination usually takes place at the least sterically hindered nitrogen atom. 

More recently, a phosphine ligand-free ruthenium-catalyzed direct arylation with aryl bromides as electrophiles was disclosed. Notably, the use of inexpensive RuCl3(H20)n as catalyst in NMP as solvent allowed for economically attractive C-H bond functionalizations of pyridine, oxazoline and pyrazole derivatives, also with more sterically hindered orfftosubstituted aryl bromides as electrophiles (Scheme 21) [79, 80],... 

When FeCl2(TlTF)i 5 reacts with the sterically hindered thallium salt of ( BuTp,Bu), the complex tra s-FeCl2(Hpz/Bu)4 is formed, the only isolable product appearing to be the first example of a trans-dichloro pseudo-octahedral iron (II) complex bearing four neutral pyrazole ligands.189... 

V-Imidyliminophosphoranes (227) with DMAD gave phosphoranes (228) which spontaneously underwent ring closure with the least sterically hindered imidyl carbonyl group to give pyrrolo[ 1,2-6 ]pyrazole derivatives (229) (81T2595). 

Octahedral complexes of the form ML2X2 (M = Co" or Ni") are known with /ru -(2-ethyl-thio)cyclopentylamme," with 2-(methylthiomethylpyridine (31 R = Me)" and with 2-methyl-8-mercaptoquinoline (29 R = Me, R = H)." With the latter sterically hindered ligand only the thiocyanate complexes are octahedral, the halide complexes being tetrahedral. Complexes of this ligand with Cu" and Cu also were investigated. A number of complexes of 1-thiocarbamylpyrazole (32), and substituted forms, are known. These were discussed by Trofimenko in a review of pyrazole-derived ligands." ... 

In 2009, Lin et al. reported an enantioselective synthesis of an important Janus kinase inhibitor, INCBO18424, the key step of which was an asymmetric aza-Michael addition of pyrazoles to an a,p-unsaturated aldehyde catalysed by a chiral diarylprolinol silyl ether. The use of benzoic acid or 4-nitrobenzoic acid as an additive was shown to increase the reaction rate. The highest enantioselectivities of up to 93% ee were observed for the reactions using the more sterically hindered organocatalysts (Scheme 1.68). 

The desired 5-amino-l-(substituted-thiocarbamoyl)pyrazoles 7 were finally liberated firom resin 44 using various amines (see Table 10.6) by thermal cleavage reaction in toluene at 60 °C. Various types of amine (R R N diversity elements) afforded the 5-amino-1-(substituted-thiocarbamoyl)pyrazole derivatives 7 in good four-step overall yields (22 examples, 33-17% yields, 99-67% purities. Table 10.6) from Merrifield resin 1 with high purities, except for sterically hindered secondary amines, such as diisopropylamine and diisobutylamine. 

Pyrazole and its C-methyl derivatives acting as 2-monohaptopyrazoles in a neutral or slightly acidic medium give M(HPz) X, complexes where M is a transition metal, X is the counterion and m is the valence of the transition metal, usually 2. The number of pyrazole molecules, n, for a given metal depends on the nature of X and on the steric effects of the pyrazole substituents, especially those at position 3. Complexes of 3(5)-methylpyrazole with salts of a number of divalent metals involve the less hindered tautomer, the 5-methylpyrazole (209). With pyrazole and 4- or 5-monosubstituted pyrazoles M(HPz)6X2... 

If competitive aldehydes or ketones are used, preferred or exclusive formation of the sterically least hindered alkylidene dipyrazole is observed.[32] If A -carbonyldipyrazole is heated at 190 °C a pyrazole-transfer reaction also occurs to give tetrapyrazole-l-yl-methane in 50% yield.[33]... 

It has to be emphasized that the resulting bis(pyrazoI-l-yI)acetic acid Hbpza (3a) (Fig. 4) would not be available via the Otero route, since his synthesis is restricted to pyrazoles with substituents in 5-position of the p5rrazoIes. Other bis(pyrazoI-l-yI)methanes would be deprotonated at the CH2 bridge but also in position five of the pyrazole, due to ortho metallation. For the sterically more hindered bis(3,5-di-fert-butylpyrazole)acetic acid (3c) we followed Otero s synthetic pathway. In analogy to the synthesis of bis(3, 5-dimethylpyrazoI-l-yI)methane (2b) (72) 3,5-tert-butyIpyrazoIe... 

As mentioned above, the sterically less hindered bis(3,5-dimethyl-pyrazol-l-yl)acetic acid 3b forms with FeCl2 in a similar reaction a 2 1 complex [Fe(bdmpza)2] (4b) (41). We found a similar behavior for the even less hindered Hbpza (3a). The potassium salt of 3a reacts with FeCU to a bisligand complex [Fe(bpza)2l (4a) (Scheme 9, Fig. 5b). 

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