Activation pyrazolines

Maruoka has documented a Ti-BINOL complex that promotes enantioselective cycloaddition reactions of diazoacetates and unsaturated aldehydes [94, 95]. The bridged structure 111 has been formulated as the active catalyst in this process (Scheme 18.21). A particularly attractive application involves the use of a-substituted acroleins in the reaction. These gave optically active pyrazolines with quaternary stereogenic centers such as 112 (95% ee). The procedure represents a substantive contribution to the area, additionally... 

Aldehydes and ketones react with azolinones. The reaction between aldehydes and 2-phenyl-5-oxazolinone (131 Y = H), formed in situ from PhC0NHCH2C02H and AC2O, gives azlactones (131 Y = RCH). Similar reactions are given by 4-thiazolidinones, e.g. (132) gives (133) (79AHC(25)83), and 4-imidazolinones. In pyrazolin-5-ones the 4-position is sufficiently activated for condensation to occur with ketones in acidic media (Scheme 8) (66AH06)347). 

The stereochemistry of pyrazolines and pyrazolidines has already been discussed (Section 4.04.1.4.3). Optically active A - and A -pyrazolines have seldom been described (77JA2740, 79CJC360), but cis-trans isomeric pairs are common. The C-4 acid-catalyzed epimerization involves the mechanism shown in Scheme 38 (70TL3099), but in spite of some inconclusive arguments the C-5 epimerization has never been established with certainty. 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

Bi-3-pyrazoline-5,5 -dione, 2,2, 3,3 -tetramethyl-l,l -diphenyl-biological activity, 5, 295 Bipyrazolyl, 5, 234 Bipyrazolyl, l,r-dimethyl-... 

Pyrrolidino[l,2-6][l,3,4]oxadiazoline, 5-phenyl-biological activity, 6, 1024 Pyrrolidino[2,1 -6][1,3]oxazolidines synthesis, 5, 137 Pyrrolidino[l,2-6]pyrazolines synthesis, 5, 148... 

A solution of 500 mg 3 -acetoxypregn-5-en-20-one-[17a,16a-c]-A -pyrazoline in 100 ml of anhydrous dioxane is stirred with a magnetic stirrer and irradiated in a water-cooled quartz reactor with a high pressure Biosol Philips 250 W quartz lamp for 1 hr. The solvent is removed at reduced pressure and the residue is chromatographed on alumina (activity III). Elution with petroleum ether-benzene (3 1) gives 0.2 g (42%) of 3 -acetoxy-16a,17a-methylene-pregn-5-en-20-one mp 193-193.5° after two recrystallizations from methylene dichloride-ethyl acetate. 

It was our delight that the reactions catalyzed were activated even at -40 °C in the presence of a catalytic amount of achiral titanium catalysts (10 mol%) to afford the desilylacetylated 2-pyrazoline cycloadduct Na, l-acetyl-4-methyl-5-(2-oxo-3-oxazolidinylcarbonyl)-2-pyrazoline, in high yields as the far major product (Scheme 7.35). Although some chiral titanium TADDOlate catalysts were successfully applied to activate these reactions leading to the moderate enantioselectivities (up to 55% ee), the chemical yields were not satisfactory. 

The photoelimination of nitrogen from 1-pyrazolines is one of the most thoroughly investigated photoreactions and it has been used extensively in the synthesis of cyclopropane derivatives.334 Both stereospecific and non-stereospedfic processes have been observed and these are believed, at least in simple 1-pyrazolines, to correspond to singlet and triplet excited states, respectively. Two reaction pathways have been proposed in the azoalkane 405335 direct excitation via a thermally activated S, state affords the C6H6 isomers 406 to 409, whereas triplet-sensitized excitation results in a tem-... 

Moffett and coworkers203 reported the synthesis of several 4-/3-D-ribofuranosylpyrazoles, such as 284(a-c), by 1,3-dipolar cycloaddition of diazoalkanes to the alkenic C-glycosyl compound 283, followed by dehydrogenation of the resulting pyrazolines. In view of the known biological activities of several nucleosides containing the... 

Although none of the pyrazolines have been tested as tubulin binders Jeong et al. reported the activity of pyrazolines for their lipid peroxidation inhibitory... 

Synthesis and Anticancer Activity of Some Novel 1,3,5-Trisubstituted pyrazolines using MDA-MB-231 and Hep-G2 cancer cell lines... 

These differences in film morphology were also reflected as differences in film formation conditions, film adhesion, and in electrochemical properties. The pyrazoline beads readily formed films from solvents such as benzene. For the phenoxy TTF system, however, only CH2Cl2 was effective in forming films. In general, the TTF cross-linked polymers were found to be less adherent to the metallized substrates than the pyrazoline cross-linked polymers. Electro-chemically, it was found that the pyrazoline films showed complete activity after one potential sweep. The TTF polymer films, on the other hand, required from 5 to 20 cycles to reach full electrochemical activity as evidenced by a constant voltammogram with cycling. Furthermore, it was observed that the TTF polymer films were much less electroactive than the pyrazoline materials as shown by optical densities and total coulombs passed which were several times less for the TTF systems. 

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. 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

Other novel diazo compounds that have been subjected to 1,3-dipolar cycloaddition with activated alkenes, and that give unusually functionalized pyrazolines (Scheme 8.7), include l-diazo-3-trimethylsilylpropan-2-one (20) (49), 2-diazo-methyl-4(57/)-furanones (21) (50), methyl 2-diazo-5-methylanilino-5-oxopentano-ate (22) (51), 2-(acylamino)-2-diazoacetates (23) (51), ethyl 2-diazo-4,4,4-trichloro-3-(ethoxycarbonylamino)butyrate (24) (52), and diazopropyne (53). 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

The spiropyrazohnes obtained from 51 were converted into enantiopure A -pyrazoline-3-carboxylates and 1 -(hydroxyethyl)cyclopropane-1 -carboxylates (128). Those obtained from 54 and 55 were transformed into optically active a-spirocyclopropyllactones and 3-amino-3-(hydroxyethyl)pyrrolidin-2-ones (130). The spiropyrazoline obtained from a chiral propylidene-diketopiperazine and diazomethane was converted into (+)-(lR,25)-l-amino-2-ethyl)cyclopropane-l-carboxylic acid (allocoronamic acid) (135). 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and ( )-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A -pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A -pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

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