1,2-Dihydro-3/7-pyrazol-3-ones, synthesis

Thieno[3,4-d]oxazole-3a(4H)-carboxylic acid, dihydro-2-methyl-synthesis, 6, 1020 Thieno[2,3-d Joxazoles synthesis, 6, 990 Thieno[3,2-g]pteridine structure, 3, 284 lH-Thieno[3,4-c]pyran-2-ones synthesis, 4, 1032 Thienopyrazines synthesis, 4, 1022-1024 Thieno[2,3-6]pyrazines, 4, 1023 electrophilic substitution, 4, 1024 Thieno[3,4-6]pyrazines, 4, 1024 Thieno[3,4-c]pyrazole, 4,6-dihydro-3-hydroxy-carbamates... 

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. 

Imidazo[l,5-a]pyrazin-8(7H)-ones synthesis, 5, 625 lmidazo[4,5-6]pyrazin-2-ones reactions, 5, 626 synthesis, 5, 645, 646 1 H-Imidazo[l,2-fc]pyrazole, 2,3-dihydro-synthesis, 6, 991 Imidazo[4,5-c]pyrazole,... 

One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound -keto esters starting from acid chlorides and Meldrum s acid. One such resin-bound y3-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-ffee N-2-unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-37/-pyrazol-3-ones was reported. 

Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-l 7/-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4-c][l, 2]thiazin-4(37/)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield l-methyl-7-(trifhioromethyl)-l//-pyrido[2,3-c][l,2]thiazin-4(3//)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>. 

In CHEC-II(1996), several applications of dihydro-2//-l,2,3-diazaphospholes, generated in situ from a ketone hydrazone and PC13, as useful intermediates for the synthesis of indoles, pyrroles, pyrrolylacetates, and 1,2-di-hydro-2-alkenyl-37/-pyrazol-3-ones are listed <1996CHEC-II(4)771>. 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

The synthesis as well as the structural and vibrational characterization of the HgL2Cl2 complex (L = 3,5-dimethyl-l-thiocarboxamide) have been reported <2005NJC833>. New metal chelates of Zn(ll) and Cd(n) (ML2) based on (4Z)-3-methyl-l-phenyl-5-thioxo-l,5-dihydro-4//-pyrazol-4-one quinolin-8-ylhydrazone (HL ) and (4Z)-5-methyl-2-phenyM-[(quinolin-8-ylimino)methyl]-2,4-dihydro-3//-pyrazole-3-thione (HL ) were synthesized <2005RCB633>. 

The most common method for the preparation of pyrazoles from other heterocycles is from pyranone-type compounds. Condensation of 2,3-dihydro /7-pyran -ones 787 with various aryl hydrazines in the presence of montmorillonite KSF clay under mild conditions proceeded rapidly to afford enantiomerically pure 5-substituted pyrazoles 788 (Equation 172) <2004TL6033>. Comparable results were obtained when arylhydrazines were reacted with 2-formyl glycals under microwave irradiation <2004TL8587>. Phenylhydrazine and hydrazine were reacted with 3-acetyl-4-hydroxy-6-methyl-2/7-pyran-2-one to afford 4-acetoacetyl-3-methylpyrazolin-5-ones, which were employed in the synthesis of bipyrazoles and pyrazoloisoxazoles <1999JHC1291>. Reaction of 3,3-dialkyl-6-(trifluoromethyl)-2,3-dihy-dro -pyrones with hydrazine hydrate afforded 3-(trifluoromethyl)-5-substituted-pyrazoles <1998RCB1365>. 

In some of these reactions, control of stereochemistry is critical and it is fortunate that for protected amino acid precursors, photochemical deazetization of the 4,5-dihydro-3//-pyrazole proceeds with high retention of stereochemistry. Hence, in the synthesis of the amino acid 12, the initial diazoalkane addition gave only one isomer (probably with the stereochemistry shown) and, although thermolysis gave a mixture of stereoisomers, photolysis gave the cyclopropane with the required trans configuration. 

This actually proves to be the method of choice in the synthesis of cis- and tranx-3,5-diethyl-3,5-dimethyl-4,5-dihydro-3//-pyrazol-4-one (2). Like the ketone 1, ketones 2 are key intermediates in the synthesis of many alkylidenecyclopropanes and of cyclopropimines vide infra). A more general version of this reaction has been reported in the patent literature the reaction... 

The most fruitful group of reactions in this category, however, involves the 4,5-dihydro-3/f-pyrazol-4-ones 15 and 16. These are reluctant azoalkanes and difficult to deazetize under normal conditions, but this chemically robust nature enables them to be used in the synthesis of a wide variety of cyclopropyl derivatives. 

Aldehydes, arylideneanilines, carboxylic acids and orthoesters have been used as one-oarbon units for binding the two amino functions of 4-amino-l-alkyl-3-propylpyrazole-5-oarboxamide to give l,6-dihydro-pyrazolo[4,3-<7]pyrimidin-7-ones <05MC619 05JHC751>. A modified efficient synthesis of variably substituted pyrazolo[4,3-<7]pyrimidm-7-ones has been described using a pyrazole-5-carboxylic acid, which was selectively brominated at position 4 and then converted into the carboxamide. Microwave irradiation gave better yields in the conversion of the carboxamides to pyrazolo[4,3-J]pyrimidinones <05JHC1085>. 

Under these conditions, the expected 1,3,4-thiadiazines 8o, 8p, 8r, and 8s cannot be isolated from the reactions of thiobenzhydrazide or thiophenylacetic acid hydrazide with 2-bromo-l-phenylpropan-l-one and 2-bromo-l-phenylbutan-l-one because partial desulfurization to the pyrazoles occurs. However, the synthesis of these compounds is possible by dehydration of the corresponding 4,5-dihydro-6//-l,3,4-thiadiazin-5-ols. Compounds 8a, h and 8n-s can also be obtained from the respective 4,5-dihydro-6//-l,3,4-thiadiazin-5-ols (Method B). 

The standard synthesis for 2,4-dihydro-3//-pyrazol-3-ones is the cyclocondensation of hydrazine, alkyl-or arylhydrazines with y ketocarboxylic esters Knorr synthesis, 1883), e.g. ... 

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