Pyrazoles from diketones

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

The polymer-assisted solution-phase (PASP) synthesis of a 192-member group of 1,5-biaryl pyrazoles from 1,3-diketones and 4-hydrazinobenzoic acid as precursors has been reported <2004JC0332>. Condensation of aromatic or aliphatic esters with resin-supported sulfonamides 527, followed by cyclization with hydrazines, activation with trimethylsilyldiazomethane, and cleavage using amines, provided highly substituted, isomeric pyrazoles 528 and 529 (Scheme 63) <20000L2789>. 

Celecoxib is prepared in a convergent synthesis by a classical condensation reaction, which gives a pyrazole from the corresponding 1,3-diketone and a hydrazine. [205] The hydrazine is obtained from aniline by sulfonation, diazotisa-tion and reduction. The 1,3-diketone is accessible in one step from 4-methylac-etophenone and ethyl trifluoroacetate. 

Pyrazoles from p-diketones and hydrazines under ultrasonication... 

From Hydrazines and P-Bifunctional Compounds. One of the oldest examples in this class is the reaction of a p-diketone with a substituted hydrazine to give a pyrazole (eq. 1). 

Pyrazoles are formed when the diazo compounds react with alkynes or with functionalized alkenes, viz. the enols of /3-diketones. Pyrazolenines (353 Section 4.04.2.2.1) are isolated from disubstituted diazomethanes. Many pyrazoles, difficult to obtain by other methods, have been prepared by this procedure, for example 3-cyanopyrazole (616) is obtained from cyanoacetylene and diazomethane (7iJCS(C)2i47), 3,4,5-tris(trifiuoromethyl)pyrazole (617) from trifluorodiazoethane and hexafluoro-2-butyne (8lAHC(28)l), and 4-phenyl-3-triflylpyrazole (618 R =H) from phenyltriflylacetylene and diazomethane (82MI40402). An excess of diazomethane causes iV-methylation of the pyrazole (618 R = H) and the two isomers (618 R = Me) and (619) are formed in a ratio of 1 1. 

Hydrazoyl halides are useful reagents for the synthesis of pyrazolines and pyrazoles (80JHC833). The elimination of HX, usually with triethylamine, is now the preferred method for the generation of the nitrilimine (621) in situ. Although in some cases it is not clear if the mechanism involves a nitrilimine (621) (as for example in the Fusco method in which sodium salts of /3-diketones are used), in other reactions it is the most reasonable possibility. For example, the synthesis of pyrazolobenzoxazine (633) from the hydrazoyl halide (631) probably occurs via the nitrilimine (632). Trifluoromethylpyrazoles (634) have been prepared by the reaction of a hydrazoyl halide and an alkynic compound in the presence of triethylamine (82H(19)179). 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

Szczepaikiewicz et al. [85] reported the synthesis of pyrazoles (e.g., 167) from the diketone 168 with hydrazine hydrate, shown in Scheme 43. Nigram et al. executed a similar synthetic sequence [86]. 

Carbon disulphide should not be used as the solvent for alkylation of fS-diketones, as the carbanion reacts preferentially with the solvent to generate the dithiocarboxyl-ate derivative, which undergoes mono- and dialkylation (Scheme 6.9) [95]. Ketene thioacetals have also been isolated from acetophenones (60-80%) and cyclopenta-diene (80%) using an ultrasound technique in carbon disulphide [96] and, in a similar manner, pyrazol-5-ones form pyrazole-4-dithiocarboxylic esters [97]. 

Pyrazoles were obtained from corresponding 2-hydroxy(or aIkoxy-)imino-1,3-diketones or related ketoesters and hydrazine . Thus, reaction of oximes 112 with hydrazine in ethanol afforded aminopyrazoles 113 in 48-95% yields (equation 48) . Interaction of... 

These methods are limited in scope. Direct thiation has been reported for the transformation of vicinal diketones to [3,4]-annelated thiophenes <1996CHEC-II(7)49>. Thionations and selenations of vicinal halomethyl ketones with thioacetamide or iV,iV-diethylselenopropionamide as sulfur and selenium donors, respectively, have also been reported <1996CHEC-II(7)49>. In a recent example, thieno[3,4-f]pyrazoles 160 were readily prepared from aryl 5-bromomethyl-l//-l-phenylpyrazole-4-yl ketones 159 by reaction with thioacetamide (Equation 35) <1998JHC71>. Additionally, an example of an amination cyclization by reaction of 161 with benzylamine to afford pyrrolo[3,4-i/ thiazole 162 has been described (Equation 36) <1998JHC71>. 

The reaction between 1,3-dicarbonyl compounds 1 and hydrazines is the most general method for preparing l//-pyrazoles 2 (Scheme 2).2-4,5 If a 2,2-disubstituted 1,3-diketone is employed (1 R3, R4 H), reaction with hydrazine hydrate gives instead a 4//-pyrazole 3, as was first reported by Knorr.Sa Generally, the reactants are heated under reflux in a solvent such as methanol, ethanol, benzene, or carbon tetrachloride yields range from 50% to quantitative. 

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

One of the most important methods of pyrazole synthesis involves the reaction of 1,3-diketones with hydrazine derivatives. The method has wide scope, especially considering that the diketones may be replaced by acetals, hemiacetals, chlorovinyl ketones, tetrahalides, etc. Most accessible by this path is 3,5-dimethylpyrazole (10), obtained in 85% yield from acetylacetone and hydrazine hydrate.134-138... 

A modified procedure for the preparation of pyrazoles includes the solventless condensation of diketones and hydrazines in the presence of a catalytic amount of sulfuric acid at ambient temperature <2004GC90>. 1,3-Diketones can be synthesized directly from ketones and acid chlorides and then converted in situ into pyrazoles by the addition of hydrazine <2006OL2675>. The possible modifications to the 1,3-dioxo component in the reaction with hydrazines include the use of -ketoesters, -ketonitriles, -halocarbonyl compounds, -hydroxyketones, -sulfonylketones, and 1,3-dihaloalkanes . 

---