A2-Pyrazoline

Pyrazoles can be synthesized by thermal cycloreversion of adducts formed in the 1,3-dipolar cycloaddition of alkyldiazoacetates with norbornadiene. The rate of the primary process of cycloaddition is accelerated by iron pentacarbonyl (Scheme 88)155 a similar catalytic effect has been observed during the formation of ethyl 5-phenyl-A2-pyrazoline-3-carboxylate from cycloaddition of ethyl diazoacetate and styrene.155 Reactions of this type are catalyzed presumably because of coordination of one or both reactants to the transition metal, and a wider study of the effect of a variety of complexes on 1,3-dipolar cycloaddition processes would be valuable. 

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 . 

Rurack K, Bricks JL, Schulz B et al (2000) Substituted l,5-diphenyl-3-benzothiazol-2-yl-A2-pyrazolines synthesis, X-ray structure, photophysics, and cation complexation properties. J Phys Chem A 104 6171-6188... 

This paper discusses the synthesis and physico-chemical consequences of binding low ionization 17-donors, such as TTF monocarboxylic acid (I) and l,3-di-(p-methoxyphenyl)-5-(p-hydroxyphenyl)-A2-pyrazoline (II) to a poly(vinylbenzylchloride) backbone. 

V-AryIsulfonyI-A2-pyrazolines 68 on heating with base eliminate arylsul-finic acid to yield 3//-pyrazoles 6 (Scheme 24).111 In some examples the... 

All examples of nucleophilic reactions have involved reducing agents A2-pyrazolines are common products. 

The use of 3 also allows for [3 + 2] cycloaddition with enaminoketones (38) (Scheme 8.3). When the morpholine-derived enaminoketon 6 was used, a mixture of A2-pyrazoline 7 and pyrazole 8 was obtained. Complete transformation of 7 into 8 was achieved by treatment with water. In the case of the pyrrolidine-derived enaminoketone 9, pyrazole 11 and diazabicycloheptadiene 10 are formed competitively. In the formation of the latter compound, reaction of a second equivalent of 3 with the carbonyl group of 9 is involved. Reaction of uracil as... 

The (r 4-diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A2-pyrazolines were formed. The enantiomerically pure... 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A2-pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include a-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) 1 -benzopyran-2(//)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

The spiropyrazolines obtained from 51 were converted into enantiopure A2-pyrazoline-3-carboxylates and 1 -(hydroxyethyl)cyclopropane-1 -carboxylates (128). Those obtained from 54 and 55 were transformed into optically active a-spirocyclopropyllactones and 3-amino-3-(hydroxyethyl)pyrrolidin-2-ones (130). The spiropyrazoline obtained from a chiral propylidene-diketopiperazine and diazomethane was converted into (+)-(1 R,2S)-1 -amino-2-ethy((cyclopropane-1 -carboxylic acid (allocoronamic acid) (135). 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and (—)-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A2-pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A2-pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

The cycloaddition of several diazoalkanes with (2-arylvinyl)-[(—)-(8-phenyl-menthyloxy]methylene chromium complexes 72 gave the A2-pyrazolines 73 with high diastereoselectivity. These compounds were converted into pyrazolinecarbox-ylates 74 by /V-protection and metal decomplexation (98) (Scheme 8.17). It is... 

The first effective enantioselective 1,3-dipolar cycloaddition of diazoalkanes catalyzed by chiral Lewis acids was reported in the year 2000 (139). Under catalysis using zinc or magnesium complexes and the chiral ligand (/ ,/ )-DBFOX/Ph, the reaction of diazo(trimethylsilyl)methane with 3-alkenoyl-2-oxazolidin-2-one 75 (R2 = H) gave the desilylated A2-pyrazolines (4S,5R)-76 (R =Me 87% yield, 99% ee at —40°C) (Scheme 8.18). Simple replacement of the oxazolidinone with the 4,4-dimethyloxazolidinone ring resulted in the formation of (4/ ,5S)-77 (R1 = Me 75% yield, 97% ee at -78 °C). 

It should be noted, however, that the 1,3-dipolar cycloaddition chemistry of diazo compounds has been used much less frequently for the synthesis of natural products than that of other 1,3-dipoles. On the other hand, several recent syntheses of complex molecules using diazo substrates have utilized asymmetric induction in the cycloaddition step coupled with some known diazo transformation, such as the photochemical ring contraction of A -pyrazolines into cyclopropanes. This latter process often occurs with high retention of stereochemistry. Another useful transformation involves the conversion of A2-pyrazolines into 1,3-diamines by reductive ring-opening. These and other results show that the 1,3-dipolar cycloaddition chemistry of diazo compounds can be extremely useful for stereoselective target-oriented syntheses and presumably we will see more applications of this type in the near future. 

Many examples of ring closures by oxidation of hydrazone derivatives have been reported. Anodic oxidation of chalcone72 phenylhydrazone (17) performed in CH3CN—LiCI04 at platinum, using controlled potential electrolysis, gave 1,3,5-triphenylpyrazole (15-40% yield) (18), 1,3,5-triphenyl-A2-pyrazoline (19), l,3,5-triphenyl-A2-pyrazolinium perchlorate, 4,4-bis[3,5-diphenyl-A2-pyrazolinyl-(l)]-biphenyl (20), the diperchlorate of 20, and 4,4 -bis-[3,5-diphenylpyrazolyl-(l)]-biphenyl (21) [Eq. (30)]. 

The primarily formed radical-cation dimerizes at C-3 to bis(l-phenyl-A2-pyrazolin-3-yl) if C-3 is unsubstituted.281 By-products include biphenyl derivatives formed by an alternative dimerization of the parent radical-cation. The major product is further oxidized under the reaction conditions to stable cations. By blocking the para position of the phenyl ring in the 1-position, a persistent radical would be expected, and in the presence of a base, e.g., pyridine, the corresponding pyrazole was obtained.284,285 The anodic oxidation of 1,5-diphenyl-3-(4-hydroxycoumarinyl)-A2-pyrazoline in CH3CN-Et4NC104 solution, containing pyridine, resulted in the isolation of l,5-diphenyl-3-(4-hydroxycoumarinyl)pyrazole in 95% yield when the para position was not blocked.290... 

Anodic oxidation of l,3-diaryl-5-methyl-A2-pyrazoline-5-carboxylic acids in CH3CN-Et4NBF4 proceeded with decarboxylation to the aromatized pyrazoles in high yield.414 Similarly, electrochemical oxidation of N-acetyl-2,3-substituted A4-pyrroline-2-carboxylic acids in water-tetrahydrofuran (3 1) containing KOH forms the corresponding pyrroles (80-98%).415... 

C3N2 N N — — — Pyrazole b substituted pyrazoles A1- and A2-pyrazolines pyrazolinones pyrazolidines pyrazolidinones... 

Some other examples of application of 15N NMR spectroscopy include establishing the protonation site of A2-pyrazolines (87MI301-01) and assigning the structures to isomeric N-7 and N-9 substituted purines (86T5073). 

A2-Pyrazolines are converted into pyrazoles by oxidation with bromine or Pb(OAc)4 and they can also be dehydrogenated with sulfur. 3,5-Diphenylpyrazoline (419) on heating with platinum disproportionates to the pyrazole (420) and the pyrazolidine (421) (66AHC(6)347). 

A2-Pyrazolines and A2-isoxazolines (432 Z = NH, O) are cyclic hydrazones and oximes, respectively. 2-Pyrazolines are quatemized at the 1-position (444—>445) (64AHC(3)i). 1,3,4-Oxadiazo-lines (e.g. 446) are very easily ring-opened (66AHC(7)183). 

The addition of diazomethane to a,/ -unsaturated esters (1), as ethyl acrylate, methyl crotonate and ethyl cinnamate, was investigated by Auwers181 who showed that the primary addition product is a A pyrazoline (2) which rearranges spontaneously to the conjugated A2-pyrazoline (3). 

However, in the case of a-substituted unsaturated esters (4), as for example methacrylic or tiglic acid esters, diazomethane addition results in the formation of stable A pyrazolines (5). The latter products require halogen acids for conversion to the isomeric nonconjugated A2-pyrazolines (6). 

Johnson and co-workers9b also investigated the general acid-catalyzed diazomethane reaction with benzalacetone (20). When treated with 3 mole-equivalents of diazomethane, the latter is converted to the A2-pyrazoline... 

Pyrolysis at 190° of the resulting diastereomeric Al-pyrazolines (8) and (11) leads to elimination of nitrogen and formation of the cis- and trans-cyclo-propanecarboxylates (9) and (12), respectively. Thermal decomposition of the A -pyrazoline (13) affords methyl tiglate (14) in addition to the cyclopropane derivative (15) in a ratio 2 1, while A2-pyrazolines such as (3) give only a,ft- or / ,y-unsaturated esters, and no cyclopropane derivatives. 

The addition of diazomethane to a,/ -unsaturated ketones, e.g., benzalace-tone and benzalacetophenone, results in A2-pyrazolines (16) which decompose thermally to the conjugated ketones (17). Cyclopropane formation is not observed in this instance.184,185... 

The addition of diazomethane to 17/Miydroxy-5a-androst-l-en-3-one (7) gives the A2 -pyrazoline (8) in which the C=N bond is conjugated with the 3-keto group.200... 

A2-pyrazolines from, 5, 250 structure, 5, 169 Isoquinoline, 4-acetamido-reduction, 2, 327... 

The 3 + 2-cycloaddition of commercially available Me3SiCHN2 with camphor sultam-derived dipolarophiles produces 3-trimethylsilyl-substitutcd-A1 -pyrazolincs which on acid treatment convert into optically active A2-pyrazolines.60 The nucleophilic addition of ethyl diazoacetate with /V-cthoxycarbonyl-/V-(2,2,2-trichlorocthylidcne)a-mine produces a new diazo intermediate (35), which by 1,3-dipolar cycloaddition followed by a sigmatropic rearrangement of the cycloadduct (36) furnishes a substituted pyrazole (37) (Scheme 13).61. 

Some aryl halide derivatives of pyrazoline can undergo photocyclization. Thus, 5-(2-halogenphenyl)-l,3-diphenyl-A2-pyrazoline 120 proceeds by a simple bond homolysis from the Si state to give 2-phenylpyrazolo[l,5-/Iphenathridine 121 [171] (Scheme 2.33). 

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