Synthesis of Pyrazolines and Pyrazoles

RECENT ADVANCES IN SOLID-PHASE 1,3-DIPOLAR CYCLOADDITION REACTIONS 

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The synthesis of pyrazolines and pyrazoles of the [CCNN + C] type with the creation of two bonds, N(2)-C(3) + C(3)-C(4) (or N(l)-C(5) + C(5)-C(4)), has been studied by several groups. Beam and coworkers have published a series of papers on the synthetic utility of lithiated hydrazones. Thus, the methylhydrazone of acetophenone (598) is converted by butyllithium into the dianion (599), which in turn reacts with methyl benzoate to afford the pyrazole (600) (76SC5). In earlier publications Beam et al. have used aldehydes and acyl chlorides to obtain pyrazolines and pyrazoles by the same method. 

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). 

The synthesis of pyrazolines and pyrazoles by a [CCNN + C] process has not made significant advances since <84CHEC-I(5)167>. A new method to prepare 1-hydroxypyrazole 2-oxides by nitro-sation of acrylophenone oxime, [CCCN + A] has been reported <93JHCl 163>. 

Owing to their particular interest two individual reactions will now be discussed separately. The reaction of methoxycarbonylhydrazine and 3-bromo-2,4-pentanedione affords, in addition to the expected pyrazole (608), a pyrazolium salt (609), the structure of which was established by X-ray crystallography (74TL1987). Aryldiazonium salts have been used instead of arylhydrazines in the synthesis of pyrazolines (610) and pyrazoles (611) (82JOC81). These compounds are formed by free radical decomposition of diazonium salts by titanium(n) chloride in the presence of a,/3-ethylenic ketones. 

On the other hand, pyrazoline and pyrazole derivatives are successfully used for material science tasks. For example, triarylpyrazolines are used in the synthesis of green electroluminescent polymers for light-emitting diodes [18], Some aromatic substituted 2-pyrazolines are effective organic luminophores [19,20], fluorophores [21] and scintillating materials [20, 22]. 

Oxidative processes are very characteristic for pyrazoline derivatives such as dihydroheteroaromatic compounds. However, oxidation of pyrazolines is not a widely used preparative method for the synthesis of the appropriate pyrazoles owing to numerous side reactions following heteroaromatization, and other pathways are usually applied to obtain pyrazoles [66]. It should be noted that pyrazolines unsubstituted at positions 1 and 3 are very unstable compounds and easily decompose in air, with nitrogen elimination. Introducing alkyls or aryls in these positions leads to an increase of their stability but oxidative destruction is also possible, for example, under the action of nitrous acid [116, 117]. 

Hassan SY (2013) Synthesis, antibacterial and antifungal activity of some new pyrazoline and pyrazole derivatives. Molecules 18 2683-2711. doi 10.3390/molecules 18032683... 

Pyrazolines substituted at position 4 or 5 with hydroxy or amino groups readily eliminate a molecule of water or amine yielding pyrazoles. The 4-substituted derivatives are relatively more stable than the 5-substituted ones, because for the last group the lone pair at N-1 assists the elimination (407) -> (408) -> (409). The sulfonyl group at position 1 is also easily eliminated and this property is taken advantage of in Dorn s elegant synthesis of 3-aminopyrazole (Section 4.04.3.3.1). 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of P-nitro-meso-tetraphenylporphyrin le with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) <02S 1155>. The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. 

Acid- and base-promoted methods have also been used in the syntheses of pyrazoles. Hydrogenation of methyl 2-Cbz(hydrazine)-3-hydroxy-4,4-dimethoxybutanoate 11 followed by cyclization in the presence of trifluoroacetic acid afforded the first asymmetric synthesis of the (4S,5.R)-5-carbomethoxy-4-hydroxy-A2-pyrazoline 12 <00TL8795>. Reaction of 2-nitrobenzyl triphenylphosphonium ylide (13) with aiyl isocyanates afforded 2-aryl-2H-indazoles 14 <00TL9893>. Base-promoted reaction of nitrobenzenes 15 with aryl imines 16 afforded aryl pyrazoles 17 . 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Pyrazoline compounds are partially unsaturated pyrazoles. Jeong et al. [95, 96] and Moustafa and Ahmad [92] described the formation of these compounds from chalcones (e.g., 196) using hydrazine hydrate to form the pyra-zolines (e.g., 197, Scheme 53 [95]). Chimenti et al. also described the synthesis of the pyrazolines from reaction of hydrazine with chalcones but included acetic acid in the reaction mixture [97]. 

Due to space limitations, it is not possible to provide a comprehensive coverage of all 1,3-dipolar cycloaddition chemistry carried out using diazo compounds over the past two decades. Rather, attention will be given to the most significant developments, including the synthesis of novel heterocyclic systems, the preparation of well-established heterocycles (such as pyrazoles and pyrazolines) with novel functionalities, as well as stereoselective cycloadditions. A discussion of the theoretical, mechanistic, and kinetic aspects of these 1,3-dipolar cycloaddition reactions will be kept to a minimum, but references to important work in these areas will be given at appropriate places. Authoritative reviews dealing with the... 

The most important method for the synthesis of 3i/-pyrazoles is by 1,3-dipoIar cycloaddition between a diazo compound and an alkyne, although alkenes bearing suitable leaving groups have also been used. Other methods include the cyclization of vinyldiazo compounds, and the oxidation of pyrazolines. 

Diazo compounds have been extensively used in the preparation of three-membered carbocycles either as carbene sources or as precursors for 1-pyrazolines or 3//-pyrazoles. Nitrogen extrusion from pyrazolines is particularly valuable for the synthesis of alkylcy-clopropanes, since the direct carbene route is impractical, as a matter of fact, owing to rapid intramolecular processes in alkylcarbenes. The cycloaddition of diazo compounds to unsaturated bonds to give 1-pyrazolines and 3/f-pyrazoles usually proceed in a concerted manner, and hence is stereospecific. In the subsequent nitrogen extrusion from the adducts,... 

In the last 20 years the pyrazole ring has attracted much attention, as it has become fairly accessible and shows diverse properties. Besides the traditional interest in pyrazole derivatives which have been the basis of numerous dyes and drugs, a number of pyrazole anesthetics have appeared.12 Recently it was established that pyrazolines are not only of interest as intermediates in the synthesis of cyclopropanes, but also as effective chemical bleaching agents, and as luminescent and fluorescent substances.3-8 The ease with which... 

In variants of the above processes, the bifunctional reactivity of 4-(dialkylamino-methylene)pyrazolin-5-thiones (155) (Scheme 25) and oxazolin-5-thiones (157) (Equation (45)) with a-halocarboxylic acids (or esters) was exploited for the synthesis of thieno[2,3-c]pyrazoles (156)... 

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