Pyrazolines, conversion

Cyclopropane derivatives are the major products of photoelimination of nitrogen from 1-pyrazolines. Conversion of the fused pyrazoline (10) into the cyclopropane (11) was achieved in this way in 85% yield by irradiation in the presence of acetophenone and constitutes a valuable step in a synthesis of a diquinane alcohol. The short-lived triplet 1,3-cyclopentadiyl biradical, generated by benzophenone-sensitised irradiation of diazabicyclo-(2.2.1]hept-2-ene, has been trapped as a Jbis-alkoxyamine by a nitroxide. The diazabicycloheptenes (12) gave in a similar fashion the bicydo[2.1.0]pentanes (13) on triplet-sensitised photolysis, whereas laser/liquid jet excitation of the same compounds gave in addition the cyclopentenes (14), derived by 1,2-hydrogen shift evidence for a two-photon process is described. The results of a time-resolved spectroscopic study of the photodecomposition of 2,3-diazabicyclo[2.2.l]hept-2-ene in the vapour phase have also been reported.Photolysis of 2,3-diaza-5-methylenebicyclo[2.2.l]hept-2-ene affords the semi-localised... 

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 A -pyrazolines (6). 

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. 

Oxidation of chalcone phenylhydrazone 13 leads to a pyrazole and the expelled proton catalyses formation of a pyrazoline from the chalcone phenyl-hydrazone [43]. The latter undergoes further anodic oxidation (p. 308). In the presence of pyridine as a proton acceptor, the pyrazole becomes the major product. A further example of oxidative cyclization is the conversion of a-oximino phenylhydrazones to 1,2,3-triazole-l-oxides 14 [44]. 

Cyclic diazoalkanes have been used to generate spirocyclopropanes via ring contraction of pyrazolines formed in the initial cycloaddition step. Two novel examples are the transformation of 3-diazo-2-nitromethylenepiperidine (16) into 5-aza-spiro[2.5]octane 17 (45) and the conversion of 1-diazo-2-methylenecyclo-propane (18) into methylene-spiro[2.2]pentane 19 (46) (Scheme 8.6). Related reactions have also been reported for diazocyclopropane (47) and diazospiropen-tane (48). 

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 A -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. 

In the conversion of the pyrazoline 33, formed from the / -nitrostyrene 32 and DPD, to the l//-pyrazole 34 with HCI, migration of the phenyl group was believed to be concerted with loss of N02. 87 It is, however, possible that the reaction proceeds via rearrangement of an intermediate 3//-pyrazoIe 35 (Scheme 11). 

Diazomethane yields the isomeric pyrazolines 40 and 41, respectively, from the bromo esters 38 and 39. These undergo an autocatalytic exothermic conversion to the same 1 //-pyrazole 42 on heating, or on standing in solution (Scheme 13). This is taken as evidence that 25 is an intermediate, because if group migration was concerted with loss of Br , 40 and 41 should give different products.89... 

Camera and co-workers (287) described the 1,3-dipolar cycloaddition of trimethylsilyldiazomethane 171 with 165 (Note Opposite enantiomers are shown here). The intermediate 1-pyrazoline obtained from this reaction rearranged after acidic work up to furnish the 2-pyrazolines 172 with 80-88% de (Scheme 12.52). By further conversion of these products, optically active azaprolines were synthesized. 

Diazomethane and its simple analogs undergo cycloaddition to unsaturated compounds both directly and after conversion to carbenes. The direct cycloadditions are 1,3-dipolar for the most part and provide access to pyrazolines and pyrazoles. Intramolecular cyclizations were recognized as early as 1965 95 The two main methods used in generation of diazo compounds for subsequent intramolecular cycloaddition include thermolysis of tosylhydrazone salts and thermolysis of iminoaziridines. Decomposition of nitros-amines has also been employed. 

Pyrazolines may be obtained readily from a,j3-unsaturated aldehydes or ketones and aliphatic diazo compounds.44,349 Convenient syntheses have been worked out using Mannich bases,488-494 by the cyclization of aldehydo- and keto-azines.495-499 The conversion of a number of 4- and 5-substituted pyrazolines to the corresponding pyrazoles by frams-elimination was noted above. The 4-amino-pyrazolines with the appropriate configuration (41) readily eliminate... 

The conversion of pyrazolines to pyrazoles has been accomplished successfully in a number of cases by using potassium permanganate.64, 507, 514 Side-chain double bonds are oxidized to carboxylic acids by this treatment.515-519 Amino groups should be protected.620... 

The generation from furoxans of other heterocyclic systems, some of which show useful biological activity (see Section 4.22.5), has been the subject of intensive investigation. The following subsections summarize the conversion of benzofuroxans into quinoxaline and benzimidazole oxides, the rearrangement of 4-substituted benzofuroxans, and the transformation of monocyclic furoxans into isoxazoles and isoxazolines, furazans, and pyrazolines. More detailed discussion is to be found in recent comprehensive reviews (75S415, 76H(4)767, 81AHC(29)251>. 

Amino polystyrene pyrazolone linker resin 58 provided various amide products 59 with a high conversion rate and good purity under mild conditions the resin linker was stable under the reaction conditions, resistant to hydrolysis, and reused repeatedly without loss of activity <03TL8063>. The preparation of pyrazoline derivatives 61 was accomplished with traceless solid-phase sulfone linker 60 with phenylhydrazine <030L1067>. Aniline cellulose-bound enaminones 62 reacted with phenylhydrazine under microwave irradiation to produce pyrazolocarboxylic acid derivatives 63 in high yields <03JCO465>. 

Several unique heterocyclic fused-1,2,4-triazole structures have been published. Pyridine amination of 216 with O-mesitylenesulfonylhydroxylamine followed by condensation with various aryl and heterocyclic aldehydes and subsequent cyclization and oxidation gave triazolopyridines 217 <03TL1675>. Triazolopyridines 217 were utilized in the direct conversion to the triazolopyridine amides 218 with methylaluminoxane premixed with amines in a combinatorial library synthesis. A convenient synthesis of novel 4-(l,2,4-triazol-l-yl)-2-pyrazolines and their derivatives has been reported <03SC1449>. A novel triheterocyclic ring system, thieno[2,3-y][l,2,4]triazolo[l,5-a]azepines, has been published <03S1231>. 

Several aromatization methods have been published for the conversion of pyrazolines 226 into pyrazoles 227 and conditions are presented in Table 6. 

The photoelimination of nitrogen from 1-pyrazolines provides a valuable route to 1, 3-biradicals and products derived therefrom. The high yield conversion of the pyrazoline (7) into... 

An example of a y-elimination reaction is the formation of a cyclopropane from 1-pyrazoline initiated either by heat or light. The initial biradical, which is formed by the loss of the nitrogen molecule, then closes the ring to give the cyclic product. The conversion of R-CO-R to R-R and C=0 is called a Norrish Type I reaction. In this case, the C C bonds on each side of the carbonyl group cleave, and the resultant radicals then combine and so effect the extrusion of the CO molecule. 

Bodendorf and Ziegler113 have reported the conversion of a 4-(l-hydroxy-2-methylaminopropyl)-3-pyrazolin-5-one into a 4-(2-oxopropyl)-3-pyrazolin-5-one in the presence of acid (eq. 136). 

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