Hydrazines 43-pyrazolines

Curtius, T. Ber. 1890, 23, 3033-3041. Theodor Curtins (1857-1928) was bom in Duisburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music. 

Pyrazolines can be prepared from the reaction between a hydrazine and two carbonyl compounds, one of them having at least one hydrogen atom a to the carbonyl group. Formally, these reactions correspond to the [NN + C + CC] class. However, if one considers the different steps in the ring formation, they more properly belong to the [CNN + CC] (Section 4.04.3.1.2(ii)), the [CCNN + C] (Section 4.04.3.1.2(i)), or the formation of one bond (Section 4.04.3.1.1) classes. 

The synthesis of A -pyrazolines by reaction of a 1,2-disubstituted hydrazine, formalin and a carbonyl compound, known as the Hinman synthesis, probably proceeds by the mechanism shown in Scheme 57 (69BSF3300). 

H) has been isolated (636). With monosubstituted hydrazines and aldehydes, A -pyrazolines (637) are formed (69CHE805). 

Synthesis of pyrazolines in reactions of a,(3-enones with diazomethane and hydrazines 97KGS747. 

Reaction of substituted hydrazine analogue with protected 3-dicarbonyl compound 67 leads to a ring-forming two-site reaction and formation of the pyrazoline diuretic agent, muzolimine (68). ... 

A mixture of 16.3 g of 4-methyl-6-methoxy-2-pyrimidinyl-hydrazine, 13.7 g of ethyl acetoacetate and 16.3 ml of methanol was refluxed 2 hours on a water bath. After a mixture of 4.7 g of sodium hydroxide, 4.7 ml of water and 27 ml of methanol was added dropwise thereto at about 50°C, the reaction mixture was refluxed for 2 hours more, then methanol was distilled off and the residue was dissolved in 130 ml of water. The solution was adjusted to pH 6 with acetic acid. The precipitate was filtered, washed with water and dried to give 24 g (yield 95.3%) of crystals, MP 97° to 98°C. Recrystallization from ligroin gave 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-3-pyrazoline-5-one, MP 102° to 103°C. 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

The general method for the preparation of diphenylpyrazolines is shown in Scheme 11.8, in which X is a suitable leaving group, usually chloro but sometimes dialkylamino. This reaction normally proceeds readily, although pH control may be important. Preparation of the substituted ketone and hydrazine intermediates needed for the synthesis may involve lengthy and complicated sequences. Further reactions are often required to modify the substitution in ring B after formation of the pyrazoline ring. The preparation of compound 11.26 shown in Scheme 11.9 illustrates one of the simpler instances. 

Ketene dithioacetal 130 reacts with 3-amino-2-pyrazolin-5-one 129 to give the highly functionalized pyrazolopyridine 131, which is converted into the bispyrazolopyridine 132 by reaction with hydrazine hydrate (Scheme 9) <1997JCM256>. 

Compounds of this type with an electron-withdrawing substituent at C-a can be easily prepared by condensation of 2-(benzotriazol-l-yl)acetophenone 869 with aldehydes. Exclusively (E) isomers of a,(l-unsaturated ketones 870 are formed. Treatment with hydrazines converts derivatives 870 into pyrazolines 871. Elimination of benzotriazole from 871 in the presence of mild bases furnishes pyrazoles 872. When in these reactions hydroxylamine is used instead of hydrazines, the corresponding isoxazoles are obtained (Scheme 141) <2001JOC6787>. 

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]. 

The reaction of different substituted hydrazines (or hydroxylamines) with the a,/3-unsaturated ketones 210 gives pyrazolines 211 (or isoxazolines 212), as the result of a Michael addition reaction followed by an intramolecular Mannich reaction (Scheme 12) <2001FAR32>. 

Scheme 7 shows formation of a new fused ring described by Mohan and Kataria <1998IJB819>. These authors reported that treatment of the benzylidene compound 19 with hydrazine hydrate in acetic acid in the presence of sodium acetate gave the tricyclic fused pyrazoline derivative 20 in acceptable yield (61%). The two hydrogen atoms at the site of the ring closure were found to be as. 

Diethyl N-phenylaminothiocarbonylmalonate was reacted with hydrazine hydrate in boiling ethanol for 4 hr to give a mixture of 5-phenylamino-2-pyrazolin-5-one and monoethyl ester, a hydrazide of hydrazino(phe-nylamino)methylenepropanedioic acid (77G555). 

Disubstituted hydrazines and semicarbazones react with a-haloacyl halides under two-phase catalytic conditions to produce l,2-diazetidin-3-ones (20-85%) [35], whereas (3-haloacyl halides react with hydrazines to form pyrazolin-3-ones (ca. 30%). 

Only a limited number of derivatives of this ring system have been reported in literature. The only efficient synthesis utilized azoaroyl-1,2,4-triazines. Thus, condensation of 138 with hydrazines afforded the hydra-zones (139), which give 140 on reflux in acetic acid [85MI2,85PHA(39)504] (Scheme 20). It has been reported that derivatives of 74 were synthesized by cyclization of pyrazoline-4,5-dion-4-isothiosemicarbazones and 4-amidinohydrazones in phenol at 180-200°C (88JPR57). 

The synthesis of isoxazolines and pyrazolines via the Michael addition of hydro-xylamine and phenyl hydrazine to chalcones and related enones was also reported with activated Ba(OH)2 as a basic catalyst (293) (Scheme 45). In both cases, reactions were performed at reflux of ethanol, and excellent yields (65-80%) with 100% selectivity to the heterocyclic compounds were observed. Steric hindrance associated with the carbonyl compound as well as the electronic character of the substituents in the aromatic ring slightly affected the yields of the heterocyclic compounds. 

Reaction of 2-isothiocyanato-/ra/w-cinnamaldehyde (110) with hydrazine gave the pyrazolo[l,5-c]quinazolines (111), presumably via the corresponding hydrazone and conjugate addition to the pyrazoline followed by cyclization [76JCS(P1)653]. 

Reaction of (86) with a hydrazine resulted in the pyrazoline (90). A similar transformation of chromone is described in Section 3.2.1.6.4.iv. 

Azomethine imine cycloadditions provide access to pyrazolidines, pyrazolines and pyrazoles. Intramolecular cyclizations were first reported in 1970.78 The main method for generation of azomethine im-ines involves reaction of a 1,2-disubstituted hydrazine with an aldehyde or an aldehyde precursor. 

Aldehyde (166) reacted with excess hydrazine hydrochloride to afford a pyrazoline in 63% yield a mixture of pyrazoline and pyrazolidine was obtained under an inert atmosphere.83 This reaction presumably involves the hydrazone and protonated azomethine imine as intermediates. Using (166) in excess afforded a bisintramolecular adduct in 87% yield. 

To accelerate the reactions rates and to increase their yields, sometimes microwave-assisted procedures are applied. The first mention of using a solvent-free microwave procedure was in [55]. The authors described the synthesis of 1,3,5-triarylpyrazoline by the cyclization of chalcones with phenylhydrazine on a basic alumina solid support. The target heterocycles were synthesized under microwave irradiation in high yields (up to 85%) in 1-2 min instead of 3 h in the case of thermal activation. Another publication [56] deals with the rapid (2-12 min) solvent-phase cyclization of naphthyl-substituted chalcones 41 and hydrazines 42 in a microwave field yielding the appropriate pyrazolines 43 quantitatively (Scheme 2.10). 

The regioselectivity of pyrazole 55 formation is completely the reverse of that of pyrazoline 57 in the reaction of ketones 54 with hydrazines without DPPH. In addition, heterocycles 56 cannot be obtained from 57 by the action of DPPH. These facts show that the radical-initiated treatment of a, 3-unsaturated ketones with hydrazines does not occur via the initial pyrazoline 57 formation. 

The reaction of arylidenecyclonones with hydrazines proceeds with the formation of regio- and stereoisomers. Thus, treatment of bisbenzylidene-4-thiopyranones 66 with propylhydrazine 67 in boiling methanol yields mixtures of two isomeric pyrazolines 68 and 69, with 68 predominating [90] (Scheme 2.17). The amount of isomer 69 increases when X is S to SO and S02. 

The stereochemistry of the reaction of arylidenecycloalkanones with hydrazines has been discussed in several publications. It is established that in most cases during the formation of /nmv-pyrazolines or their mixtures with cis isomers, the predominant trans form is observed [84, 85, 91, 92, 93, 94], For example, the reaction of 2-benzylidenetetralone 70 with hydrazines in boiling pyridine yields solely trarax-pyrazoline 71 [85] (Scheme 2.18). 

The reaction of arylidenechromanones with hydrazine in methanol also yields only the trans isomer of the appropriate pyrazoline [91]. Cyclization of diarylidenecyclonones 72 with numerous hydrazines in boiling methanol according to [17] yields a mixture of trarax-pyrazoline 73 and its regioisomer 74 (Scheme 2.18). 

Reactions of arylidenecycloalkanones with thiosemicarbazide in contrast to hydrazines usually yield cis isomers of the appropriate 7V-thiocarbamoyl derivatives of pyrazolines. For instance, treatment of 3,5-diarylidene-l-methyl-4-piperidones 80 and some other cyclic unsaturated ketones with thiosemicarbazide 81 under acidic conditions leads to dx-pyrazolines 82 in high yields [65] (Scheme 2.20). 

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