Pyrazolines, preparation

Chemical shifts for some representatives of the less common class of A -pyrazolines are shown in Table 13. These cyclic enehydrazines are also probably puckered (69) however, no X-ray determination nor conformational study has been carried out to solve this problem. Compound (70) is representative of the rare N(l)-unsubstituted A -pyrazolines prepared by Burger et al. (79T389). 

The reaction is very common in pyrazolone chemistry. Since alkoxypyrazoles and tautomerizable pyrazolones undergo this reaction and 3-pyrazolin-5-ones, like antipyrine, do not, it is assumed that the reaction takes place at C-4 of the OH tautomer. Pyrazolone diazo coupling is an important industrial reaction since the resulting azo derivatives are used as dyestuffs. For instance, tartrazine (Section 4.04.4.1.3) has been prepared this way. 3,5-Pyrazolidinediones react with aryldiazonium salts resulting in the introduction of a 4-arylazo group. As has been described in Section 4.04.2.1.4(v), diazonium salts couple in the 3-position with indazole to give azo compounds. 

Nitrilimines (621) are another class of 1,3-dipoles which provide a useful entry into the pyrazole ring. They are often generated by cycloreversion (79AG(E)72l) of tetrazoles, triazolopyridines and oxadiazolones (79JOC2957) (Scheme 55). Pyrazolines of known stereochemistry, pyrazoles and indazoles (Section 4.04.3.1.1(iii)) have all been prepared from nitrilimines. 

Hydrazoyl halides are useful reagents for the synthesis of pyrazolines and pyrazoles (80JHC833). The elimination of HX, usually with triethylamine, is now the preferred method for the generation of the nitrilimine (621) in situ. Although in some cases it is not clear if the mechanism involves a nitrilimine (621) (as for example in the Fusco method in which sodium salts of /3-diketones are used), in other reactions it is the most reasonable possibility. For example, the synthesis of pyrazolobenzoxazine (633) from the hydrazoyl halide (631) probably occurs via the nitrilimine (632). Trifluoromethylpyrazoles (634) have been prepared by the reaction of a hydrazoyl halide and an alkynic compound in the presence of triethylamine (82H(19)179). 

Pyrazolines can be prepared from the reaction between a hydrazine and two carbonyl compounds, one of them having at least one hydrogen atom a to the carbonyl group. Formally, these reactions correspond to the [NN + C + CC] class. However, if one considers the different steps in the ring formation, they more properly belong to the [CNN + CC] (Section 4.04.3.1.2(ii)), the [CCNN + C] (Section 4.04.3.1.2(i)), or the formation of one bond (Section 4.04.3.1.1) classes. 

The preparation of 16a,17a-methylene steroids (4) is best carried out by treatment of (2) with perchloric acid or boron trifluoride etherate. °° ° In this process the pyrazoline is introduced as a solid at room temperature into a solution of acetone containing a catalytic amount of the acid. The reaction requires 5 to 30 minutes for completion. 

A solution of diazomethane in 2.4 liters ether, prepared from 177 g (1.71 moles) of A-nitrosomethylurea and 530 ml of 40% aqueous potassium hydroxide, is added to 26.4 g (0.81 moles) 17 -acetoxyandrosta-1,4,6-triene-3-one in 250 ml ether. After 6 days at room temperature the ether is removed by distillation at reduced pressure and the residue is chromatographed on 1.5 kg of silica gel (deactivated with water 10% v/w). The product is eluted with methylene dichloride and recrystallized from diisopropyl ether-methylene dichloride to give 11 g (37 %) 17 -acetoxyandrosta-4,6-dien-3-one-[2a,la-c]-A -pyrazoline mp 161° (dec.) —91° (CHCI3) ... 

For a convenient photochemical preparation of steroidal a-cyclopropyl ketones from the A -pyrazoline derivatives of the corresponding a, -unsaturated ketones, cf. ref. 50. 

A simple preparative route to the previously unknown lH-3-pyrazolines via azomethine imines was developed. Olefins of the type R cH=CHR react with hexafiuoroacetone azine to give azomethine mines, which undergo a sequence of prototropic shifts to form 17/-3-pyrazolines [196, 202], On heating, the latter are transformed into 3-trifluoromethylpyrazoles [196, 206] and, on treatment with bases, into 1,2,5,6-tetrahydropynmidines [206] (equation 45)... 

The preparation of cyclopropane derivatives has been greatly facilitated by the development of carbene-type intermediates (see Chapter 13) and their ready reaction with olefins. The preparation of phenylcyclopropane from styrene and the methylene iodide-zinc reagent proceeds in only modest yield, however, and the classical preparation of cyclopropane derivatives by the decomposition of pyrazolines (first employed by Buchner in 1890) is therefore presented in the procedure as a convenient alternative. 

Addition of 2-pyrazolines to tetrazines gave 330 (84AP237 88CZ17). The pyrazolotriazine derivative 331 was prepared (76MI6) by treating diamino guanidine with acetyl pyruvic acid ethyl ester in either acid or neutral aqueous solution (Scheme 70). 

In order to synthesize 1,3-diphenyl-l, 3-diamines 3 containing a C2 axis of symmetry, which can be employed as auxiliaries and controller groups in asymmetric syntheses, the diastereoselective addition of organometallic reagents to racemic pyrazolines 2, prepared from cinnamaldehyde (l)23, was investigated. 

The present method9 affords the methyl ester directly in high yields from 2-pyrazolin-5-ones, which are readily prepared in nearly quantitative yields from readily accessible, /3-keto-esters. In addition, the reaction is simple to carry out, conditions are mild, and the product is easily isolated in a high state of purity. A limitation of the reaction is that only the methyl ester can be made, as other alcohols have been found to give poor yields and undesirable mixtures of products. Table I illustrates other examples of the reaction.10... 

The pyrazole analog 140 has been prepared from the reaction of the alkynyl phosphonate with ethyl diazoacetate, whereas the pyrazoline 139 was obtained under similar conditions with diediyl vinylphosphonate (78). 

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. 

Cellulose acetate and triacetate fibres are brightened with disperse-type FBAs, including derivatives of 1,3-diphenylpyrazoline (11.19). These form a commercially important group of FBAs. If suitably substituted they can be applied to substrates other than acetate and triacetate. The commercially more important products of this type are used to brighten nylon and acrylic fibres. Their preparation and other aspects of pyrazoline chemistry are discussed in section 11.8. Examples of pyrazolines used to brighten acetate and triacetate... 

The general method for the preparation of diphenylpyrazolines is shown in Scheme 11.8, in which X is a suitable leaving group, usually chloro but sometimes dialkylamino. This reaction normally proceeds readily, although pH control may be important. Preparation of the substituted ketone and hydrazine intermediates needed for the synthesis may involve lengthy and complicated sequences. Further reactions are often required to modify the substitution in ring B after formation of the pyrazoline ring. The preparation of compound 11.26 shown in Scheme 11.9 illustrates one of the simpler instances. 

Photoelimination of nitrogen from 1-pyrazolines has also been employed in the synthesis of tricyclo[3.2.1.02,4]oct-6-ene,338 prismane,339 quadri-cyclane,340 snoutene ,341 and marasmic acid.342 The trimethylenemethanes 414 have been prepared by photolysis of azoalkanes 415 and characterized spectroscopically.343 Dimerization and cycloaddition to alkenes of these biradicals have been reported.344... 

The same approach was subsequently used by Dolphin and co-workers <02CC2622> and also by Robinson and co-workers <03T499> to prepare pyrazoline cycloadducts from porphyrins and chlorins. Scheme 28 shows new chlorin derivatives (81 and 82) which have been obtained in this way. 

Compounds of this type with an electron-withdrawing substituent at C-a can be easily prepared by condensation of 2-(benzotriazol-l-yl)acetophenone 869 with aldehydes. Exclusively (E) isomers of a,(l-unsaturated ketones 870 are formed. Treatment with hydrazines converts derivatives 870 into pyrazolines 871. Elimination of benzotriazole from 871 in the presence of mild bases furnishes pyrazoles 872. When in these reactions hydroxylamine is used instead of hydrazines, the corresponding isoxazoles are obtained (Scheme 141) <2001JOC6787>. 

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