4.5- Dihydro-37/-pyrazoles

Attempts to make silyl-substituted cyclopropanes by this route are plagued by alkene-forming reactions, particularly if the intermediate 4,5-dihydro-37/-pyrazole formed has a silyl group at C4. Hence, addition of diazomethane to methyl (Z)-3-trimethylsilylprop-2-enoate gave the methyl 4-trimethylsilyl-4,5-dihydro-3//-pyrazole-3-carboxylate, which eliminated nitrogen... 

A further addition of diazomethane to the strained exocyclic double bond of methylenecyclopropane gave a mixture of 4,5-dihydro-37/-pyrazoles. Separation of the 4-spiro-sub-stituted isomer by preparative GC and pyrolysis gave spiropentane 56.Note the formation of the methylenecyclobutane. In this case, the alkene-forming side reaction is in part driven by the relief of ring strain. Alternatively, spiropentane derivatives were obtained by treating an allene with an excess of diazoalkane and deazetization of the bisadducts 57 formed, e.g. formation of 1,1,4,4-tetramethylspiropentane (58). ... 

These routes are principally valuable for the access they provide to simple alkylated 4,5-dihydro-3//-pyrazoles and other 4,5-dihydro-37/-pyrazoles which are not readily available by the diazoalkane, alkene addition route. For example, 4,5-dihydro-3//-pyrazole, the parent heterocycle, was made by reacting hydrazine with 1,3-dibromopropane and oxidizing the product 1 with copper(II) acetate or mercury(II) oxide. Thermolysis then gave a mixture of cyclopropane and propene. ... 

For the more reactive allylic halides 4 a and 4 b the salt of diethyl hydrazinodicarboxylate was used as the nucleophile in preference to hydrazine.Deazetization of the resultant 4,5-dihydro-37/-pyrazoles 5 gave a mixture of alkylidenecyclopropanes 6 and 7. It should be noted that attempts to make 4-isopropylidene-4,5-dihydro-37/-pyrazole (5 b) by the more obvious route (by the reaction of diazomethane with 3-methylbuta-l,2-diene) failed. This route has been modified for the synthesis of various deuterated derivatives of 5 and used to make optically active (3/ ,57 )-3,5-dimethyl-4-methylene-4,5-dihydro-3/f-pyrazole, but all of the cyclopropanes produced from thermolysis of this compound were racemic. A similar route has also been used in the synthesis of 7,7-dimethyl-6b,7a-dihydro-7//-cycIopropa[fl]acenaph-thylene. ... 

Cyclische N-Acyl-hydrazone mit einer cnr/o-Hydrazinocarbonyl-Gruppe ergeben ahnlich den entsprechenden Carbonsaure-hydraziden keine einheitlichen Reduktions-produkte. Im Gegensatz zu den acyclischen Acyl-hydrazonen werden hauptsachlich cyclische Hydrazone gebildet. 5-Oxo-3,4,4-trimethyl-l-phenyl-4,5-dihydro-pyrazol er-gibt z. B. 50% d.Th. 3,4,4-Trimethyl-l-phenyl-4,5-dihydro-pyrazol und 20% d.Th. 5-Hydroxy-3,4,4-trimethyl-1 -phenyl-4,5-dihydro-pyrazoV ... 

Acyl-4,5-dihydro-pyrazole mit exo-cyclischer Carbonyl-Gruppe werden zu 1 -Alkyl-4,5 -dihydro-pyrazolen reduziert, mit Ausnahme der 1-Formyl-Derivate, die... 

Zu einer Losung von 4,93 g (0,13 Mol) Lithiumalanat in 100 ml abs. Diathylather wird unterRiihren und un-ter Stickstoff vorsichtig eine Losung von 10 g(0,05 Mol) 3,5,5-Trimethyl-1-acetyl-4,5-dihydro-pyrazol in 20 ml abs. Diathylather gegeben. Man kocht 1 Stde. unter RiickfluB, kiihlt ab, versetzt mit Wasser, saugt ab, wascht mit Diathylather, trocknet das Filtrat mit Kaliumcarbonat und engt ein. Der Riickstand wird i. Vak. destilliert Aus-beute 5,2 g (60°/, d.Th.) Kp2li 63-64°. 

Phenyl-l-propanoyl-4,5-dihydro-pyrazol liefert 1-Propyl-3-phenyl-4,5-dihydro-pyrazol (68% d.Th. Kp22 163-165°). 

Wahrend 6-Hydroxy-9H-allopurin in 1 n Essigsaure zum 6-Oxo-l, 2,3,6-tetrahydro-9H-allopurin (80% d.Th. F 210°) reduziert werden kann, werden in 2n Schwefelsaure 6-Oxo-perhydro-allopurin neben 3-Amino-4-aminocarbonyl-2,3-dihydro-pyrazol (an Quecksilber beide Produkte isolierbar) erhalten1,s a-2 ... 

An analogous approach has been utilized to generate the central piperazine ring of 337 via dimerization of 5-amino-4-bromo-2-phenyl-2,4-dihydro-pyrazol-3-one 336 under basic conditions in good yield (Equation 91) <2003HAC211>. 

These hydrazino acrylates can then be cydized to the corresponding 1,2-dihydro-pyrazol-3-ones either under the action of irradiation or by heating conventionally. These last compounds have also been prepared directly from the starting acrylates. 

Syntheses in this category consist of intermolecular thioalkylation of 5-oxo+,5-dihydro-pyrazole-l-carbothioic acid phenyl amides 253 followed by intramolecular aldol condensation to give substituted pyrazolothiazole-type compounds 254 (Equation 111) < 1998PS119>. 

The 2,3-dioxo-6-thioxo-2,3,5,6-tetrahydro-l/7-imidazo[l,2-A]pyrazole 393 and 5,6-dioxo-2,3-dihydro-l//-imidazo[l,2- ]-imidazole 395 were synthesized by condensation of the respective 5-amino-3-thioxo-2,3-dihydro-pyrazole 392 and 2-aminoimidazoline 394 compounds with either oxalyl dichloride or diethyl oxalate in moderate to poor yields (Equations 178 and 179) <1995JPR472, 2002EJM845>. These cyclizations can suffer from various side reactions such as expulsion of CO, polymerization, or formation of open-chain products. To solve these problems, reagents such as oxalic acid bis-imidoyl- and bis-hydrazoylchlorides 397 and 400 as well as 2,3-dichloroquinoxalines 403... 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

Dihydro-pyrazol-3-ones, (III), imidazoles, (IY) and pyrazole derivatives, (Y), prepared by Green (4), Sanner (5), and Bebbington (6), respectively, were effective as GSK3 inhibitors and used in treating Type II diabetes. 

Thermal decomposition of diazomethane may produce a less energetic carbene, but it has the disadvantage that other modes of reaction of diazomethane, not involving methylene, become important, e.g. the addition of diazomethane to C-C double bonds to form dihydro-pyrazoles. 

These elimination reactions are acid/base-catalyzed, and in the nitro-substituted 4,5-dihydro-pyrazoles ° it is important that thermolysis is carried out under strictly neutral conditions. As the synthesis of 1-methyl-l-nitro-2-phenylcydopropane (35) illustrates, photochemical deazetization can be accompanied by similar problems. ... 

Der Pyrazol-Kern ist schwer zu reduzieren51. In essigsaurem Medium kann der Ring mit Palladium katalytisch hydriert werdcn, wobei Dihydro-pyrazole cntstehenS2. Die Reduktion zum Dihydro-pyrazol gelingt auch mit Natrium Oder Zink (s. S. 709). 

Chlormethyl-oxiran reagiert mit iiberschussigen Aryl-hydrazinen zu 1-Aryl-1 H-pyrazolen, dabei bewirkt Aryl-hydrazin die Dehydrierung der Dihydro-pyrazol-Zwischenstufe1114,1316 ... 

Phenvl-acryloylamino)- 878 2-(4-Phenyl-butadiinyl)- 969 2-(l-Phenyl-5-subst.-4,5-dihydro-pyrazol-3-yl)-987... 

Oxi-2,4-diphenyl-1,3,4-oxadiazolium zerfallt in undeflnierte Produkte, dagegcn erhalt man in Gegenwart, verschiedener Abfangcr Pyrazole, 4,5-Dihydro-pyrazole und... 

Methyl-2-pyridin-2-yl-2,4-dihydro-pyrazol-3-one 40 was synthesized by heating ethyl 3-oxobutanoate 5 and (lH-pyridin-2-ylidene)-hydrazine 39 in methanol containing potassium hydroxide (04IC4387) (Scheme 9). Compound 40 was used to synthesize, among others, silver complexes. 

Dihydro-pyrazol und seine 3- und 4-Alkyl-Derivate werden mit Platin(TV)-oxid in Methanol zu Pyrazoli-dinen reduziert die Rohprodukte (50-75% d.Th.) enthalten 10-20% durch Hydrogenolyse gebildete 1,3-Diamine2. 

Since 1964 a large number of reports describe the condensation of 2,4-dihydro-pyrazol-3-ones with aryl aldehydes. In contrast condensation of 1,2-dihydropyrazol-... 

Since Huisgen et al. first demonstrated the 1,3-dipolar character of pyridine N-imine in 1962,182 the 1,3-dipolar cycloaddition reactions of the heteroaromatic JV-imines have been explored extensively. The reactivity stems from the azomethine structure of the JV-imines.183 The cycloaddition of a variety of activated alkynes and alkenes to the JV-imines yields fused dihydro-pyrazoles and tetrahydropyrazoles, respectively. However, the aromaticity of the heteroaromatic ring is destroyed at this stage, so that such primary cycloadducts usually undergo further reaction to achieve stabilization in various ways as shown in Scheme 4 (i) aromatization, (ii) hydrogen transfer, (iii) rearomatization by rearrangement, and (iv) rearomatization by N—N... 

Die aus 3-Oxo-carbonsaureestern mit Hydrazin leicht zuganglichen 5-Oxo-4,5-dihydro-pyrazole liefern bei der direkten Chlorierung die entsprechenden 4-Chlor- bzw. 4,4-Di-... 

Mit Thallium(III)-nitrat in Methanol werden 5-Oxo-4,5-dihydro-pyrazole bei 25° direkt in 2-Alkinsau-reester oder 2,3-Alkadiensaureester iibergefuhrt493. 

Die aus 3-Oxo-alkansaure-estem mit Hydrazin leicht zuganglichen 3-Alkyl-5-oxo-4,5-dihydro-pyrazole werden in methanolischer Losung durch Thallium(III)-nitrat zu 2-A1-kinsaure-estern oxidiert303 ... 

Mit Hydrazin-Hydrat werden aus Thiocarbonsaure-O-estern Carbonsaure-ester-hy-drazonide bzw. Bis-[l-alkoxy-alkyliden]-hydrazine erhalten (naheres s.S. 830f.). Mit Thiomalonsaure-0,0 -diethylester wird mit Hydrazin 3-Ethoxy-5-oxo-4,5-dihydro--pyrazol gebildet157 ... 

Diazomethane reacts with acetylene in a concerted [3+2] cycloaddition to give 3//-pyrazole which rapidly isomerizes to pyrazole. The 1,3-dipolar cycloaddition of diazoalkanes to alkenes yields dihydro-pyrazoles. 

In general, photolytic azo-extrusion from 4,5-dihydro-3/f-pyrazoles is superior to thermolysis. Photolysis was introduced as a method for synthesis by Jeger s group (Kocsis et al., 1960). The configurations of the products in the thermolysis, in the direct photolysis, and in the sensitized photolysis are often quite different. Cyclopropanation for the synthesis of alkyl cyclopropanes via dihydropyrazoles is preferred to the direct route via carbenes, because, in the latter, the C - H insertion of the carbene into the alkyl group is faster than the cyclopropanation. The dihydro-pyrazole pathway was used in particular for the formation of highly strained bicyclo[1.1.0]butanes (Franck-Neumann, 1967 Komendantov and Bekmukhametov, 1971 6.89) and bicyclo[2.1.0]pentanes (Vogelbacher et al., 1984 6.90). 

The nature of the cyclopropane-forming reaction is still controversial in the sense of a differentiation between a two-step cleavage of the two CN bonds and a concerted formation of a biradical in the azo-extrusion part of the reaction (for a review of the older literature, see Mackenzie, 1975, p. 354, and Engel, 1980, p. 118). This reaction does not strictly belong to the scope of this book. Therefore, we will not discuss it further except to refer to an investigation of Reedich and Sheridan (1988) who reported that, in contrast to earlier results (see, e. g., Cichra et al., 1980, and other references there), both thermal and photochemical processes take place by stepwise cleavage in a pair of isomeric dihydro-pyrazoles. 

Cyclopropanations by azo-extrusion of dihydro-pyrazoles may be accompanied by rearrangement of substituents. For instance, Hamaguchi and Nagai (1989) showed that, in 4-(arylseleno)- and 4-(arylthio)-4,5-dihydro-pyrazoles, these heteroaryl groups migrate into the 5-position with formation of cyclopropanes or ring opening to ethene derivatives. 

Double bonds of benzene and related aromatic compounds do not react with diazoalkanes in 1,3-cycloadditions. The corresponding benzo-annellated dihydro-pyrazoles such as (1 a,6a)-6,9,9-trimethyl-7,8-diazabicyclo[4.3.0]nona-2,5,7-triene (6.98, R = H) can be synthesized, however, from methyl cyclohexa-l,4-dienecarboxy-late (6.97, R = H), as shown by Klarner et al. (1990). The reduction of the ester group to a methyl group was carried out with di-isobutylaluminum hydride (DIBAL-H), esterification of the OH group with methanesulfonyl chloride and reduction with lithium triethyl borohydride. The second double bond was introduced by bromina-tion with Br2 on a polymeric carrier after Bongini et al. (1980). Cycloaddition with 2-diazopropane in ether at -- 5 °C and the following steps gave 6.98 in a yield of 58%. 

Very active interest in a new addition reaction of aliphatic diazo compounds started in 1991 when WudPs group reported that diphenyldiazomethane forms diphenylmethanofullerene with buckminsterfullerene (C o Suzuki et al., 1991). Although this investigation showed that the reaction proceeds via the formation of a dihydro-pyrazole, i.e., in the mode of a 1,3-dipolar cycloaddition followed by an azo-extrusion, we shall discuss the syntheses of methanofullerenes in its entirety in the chapter on carbenes (Sect. 8.4) because Diederich s recent work (see review of Diederich et al., 1994b) shows that the methano bridge can also be obtained from a carbene. The question whether the dihydro-pyrazoles are intermediates or side-equilibrium products (see earlier in this section) is also open for the reaction of with diazoalkanes. 

An instructive example was provided by Schneider and Goldbach (1980), who obtained the dihydro-pyrazole 6.107 in the reaction of 3-diazoprop-l-ene with (E, Z l,3,5-octatriene by attack on the terminal double bond. Photolysis of 6.107 (>310 nm) at — 10°C provided dictyopterene B (6.109) together with the cw-isomer 6.108, which gave ectocarpene (6.110) in a Cope rearrangement. Both these natural products are constituents of Pacific brown algae found in the waters around Hawaii. 

The synthesis of optically active cyclopropanes via formation of dihydro-pyrazoles by 1,3-cycloaddition and azo-extrusion has been studied since the late 1950 s. Modest success (10% ee) was achieved by cycloaddition of diazoalkanes to acrylic acid, esterified with ( —)-menthol, as studied by Walborsky s group (Impastato et al., 1959). Today, the use of chiral metal complexes as catalysts for the synthesis of chiral... 

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