Pyrazoline acylation

Acyl-, 4-alkoxycarbonyl- and 4-phenylazo-pyrazolin-5-ones present the possibility of a fourth tautomer with an exocyclic double bond and a chelated structure. The molecular structure of (138) has been determined by X-ray crystallography (Table 5). It was shown that the hydroxy group participates in an intramolecular hydrogen bond with the carbonyl oxygen atom of the ethoxycarbonyl group at position 4 (8OCSCII21). On the other hand, the fourth isomer is the most stable in 4-phenylazopyrazolones (139), a chelated phenyl-hydrazone structure. 

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. 

Diazoalkanes add readily to the double bond of esters of vinylphosphonic acid, giving the pyrazoline derivatives (100), which can lose nitrogen to give esters of cyclopropylphosphonic acids. In a similar reaction, acyl-phosphonic acid esters (101) were converted to epoxy-derivatives (102). A -Phenylsydnone adds to diethyl prop-l-ynephosphonate, giving the pyra-zole (103). The addition of cyclopentadiene to dimethyl vinyl phosphate leads to an exojendo quotient of 1.2, but with hexachlorocyclopentadiene only e/ii/o-isomer is formed. ... 

Similar to their reaction with phosphaalkenes, l-diazo-2-(oxoalkyl)silanes 29 react with various heterophospholes by [3 + 2] cycloaddition of the diazocumulene system 30 (which is in equilibrium with 29) across the P=C bond. With 2-acyl-1,2,3-diazaphospholes 119 (R = Ac, Bz no reaction with R = Me, Ph up to 60 °C), the expected cycloaddition products 120 (Scheme 8.27) could be isolated (186). Elimination of N2 from these bicyclic A -pyrazolines occurred upon heating at 100 °C and furnished the tricyclic systems 122 when SiRs was a trialkylsilyl group. Apparently, the thermolysis of 120 generates the 5-aIkenylidene-l,2,5-diazaphosphole 121 (by N2 extrusion) as well as diazaphosphole 119 (by a [3 + 2] cycloreversion process), which recombine in an intermolecular cycloaddition to furnish 122. When SiRa = SiPhaf-Bu, a formal intramolecular [3 + 2] cycloaddition of the C=P=C unit with an aromatic C=C bond occurs and the polycyclic compound 123 is obtained (187). 

N-Acyl derivatives of 2-pyrazoline (104) have nonplanar heterocyclic rings (74MI1). Only the E conformer, with N, 0-trans orientation, has been observed (70BSF3466 74BSF1137) for these compounds no matter which substituent is present in the heterocyclic ring, and destabilization of the Z-form should be attributed to electrostatic effects. 

The first a-cyclopropyl acyl silanes to be isolated were generated by treatment of a,f-unsaturated acyl silanes with diazomethane, followed by vapour-phase pyrolysis of the intermediate pyrazoline derivatives (vide infra, Section IV.D)141. They suffer acid-induced cleavage or rearrangement under more mild conditions than do their carbon analogues146. 

The first recorded cyclopropyl acyl silane (69) was generated by vapour phase pyrolysis of a pyrazoline derived from a,/)-unsaturated acyl silane by 1,3-dipolar cycloaddition of diazomethane (vide supra, Section DTE)141. Exposure of 69 to titanium tetrachloride induced ring expansion to give the cyclobutanone in 75% yield (Scheme 113). 

The features of the electronic structure of aryl-substituted pyrazolines influence their chemical properties. For example, in the case of 3-substituted 7V-phenyl-pyrazolines 100 reactions of formylation, acylation, nitration, sulfonation, azocoupling and other electrophilic processes involve the para position of the 7V-phenyl ring, with formation of compounds 101 [103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113]. On the other hand, some electrophilic reactions, including nitration, bromination, chlorination, formylation and azocoupling, for 3-unsubstituted pyrazolines 102 occur at position 3, yielding heterocycles 103 and in some cases as a mixture with 104 [108, 114, 115] (Scheme 2.26). This fact provides evidence for orbital control of these reactions. 

However, acylation reactions of N-unsubstituted pyrazolines with halogen anhydrides of acids are very often followed by the destruction of the heterocyclic ring owing to the ease of breaking the C(5)—Nq) bond located at the (3-position of the azomethine group [140, 141, 142, 166]. For example, pyrazoline 108 treated with halogen anhydrides of acids yields a,(3-unsaturated ketone 109 and diacyl-hydrazine 110 [166] (Scheme 2.29). 

Zelenin and co-workers have shown (85KGS854, 85KGS1000 86KGS128 87KGS1210 88ZOR426) that the reaction products of 1,3-diketones with hydrazides in a molar ratio of 1 2 most frequently possess the cyclic structure of the corresponding 5-hydrazino-2-pyrazolines (such as 76B). They can also be produced in the reactions between the corresponding hydrazine derivatives and l-acyl-5-hydroxy-2-pyrazolines or 1-acyl-5-methylene-2-pyrazolines. 

IV-Alkyl-substituted phthalimides 9 were easily transformed into mono-, di- or trisubslituted pyrazoles 10 via a one-pot addition/decyclization/cyclocondensation sequence <02JCS(P1)207>. 5-Silylpyrazoles can be prepared from condensation of silylalkynones with hydrazines <02T4975>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted pyrazolin-5-ones <02T3639>. 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

Pyrazol-5-ones are widely used in medicine, color photography, analytical chemistry, and agriculture. The tautomeric equilibria between the CFI, OH, and NH forms in a series of 4-substituted-l-phenyl-3-methyl-pyrazolin-5-ones 100-102 have been studied using ab initio calculations at various levels of theory and comparison made with the experimental results obtained from C NMR measurements <2001JP0566>. The tautomerism of 4-acyl-2-phenyl-2-pyrazolidin-3-ones 103 and 104 was studied by C NMR spectroscopy <1999CHE748>. The tautomerism of... 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Dihydropyrazoles can be prepared under microwave irradiation conditions. /3-Alkyl chalcones 649 reacted with hydrazines under microwave conditions followed by addition of acid chlorides to yield 1-acyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazoles 650 (Scheme 82) <2004TL1489>. l,3,5-Trisubstituted-2-pyrazolines 652 were obtained from chalcones 651 and phenylhydrazine on silica gel and with microwave irradiation (Equation 135) <2005JHC157>. 

The synthesis and relative stability of 3,5-diacyl-4,5-dihydro-l//-pyrazoles prepared by dipolar cycloaddition of enones and a-diazoketones has been published <2004JOC9085>. 3-Acyl-4-aryl-2-pyrazolines have been synthesized by the reaction of a,/3-unsaturated ketones with diazomethane <1996IJB1091>. Ethyl diazoacetate added to 1,3-diarylpropenones in a regioselective fashion to give the intermediate 4,5-dihydto-3//-pyrazole derivative 1,3-hydride shift in the latter led to the formation of the isomeric ethyl 4-aryl-5-aroyl-4,5-dihydro-l//-pyrazole-3-carboxylate and ethyl 4-aryl-3-aroyl-4,5-dihydro-l/7-pyrazole-5-carboxylate in a ratio of 5 1 <2001RJ01517>. 1,3-Dipolar cycloaddition of 2-diazopropane with diarylideneacetones afforded diastereomeric bis-A -pyrazolines <1999T449>. 

The nitrogen extrusion from 1-pyrazolines and 3H-pyrazoles giving cyclopropanes and cyclopropenes, respectively, has been extensively reviewed The cyclopropane synthesis from 1-pyrazolines can be executed thermally as well as photochemically, but the latter method generally gives substantially better results than the former. The major side reaction observed in the thermal process is the production of olefins, which arise in the migration of a substituent from the C(4) to C(3) position. A retro-1,3-dipolar addition producing a diazoalkane and an olefin has been observed in certain cases. The decomposition of 3-acyl- or 3-alkoxycarbonyl-1-pyrazolines is catalyzed by acids, such as perchloric acid and boron trifluoride and by Ce The stereochemical course... 

L-f/ireo-glycerol-l-yl)-pyrazoline-5-one (49) when its solution in alkali was acidified with acetic acid (50). The reaction was further extended to other bis(arylhydrazones) (51), The structure of the phenyl analogue (49) was established by oxidation to the known 3-carboxy-l-phenyl-4-phenylazopyrazolin-5-one (50). Later, on the basis of NMR data (39), the structure of this group of compounds was formulated as the hydra-zones (51). Acylation of 51 aflForded the tri-O-acylated derivatives (51), while periodate oxidation of 51 gave 3-formyl-l-aryl-4,5-pyrazoledione-... 

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