Pyrazoline formylation

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Pyrazoline, l-formyl-3-methyl- H NMR, 5, 188 (70BSF3466, 67MI40402) 2-Pyrazoline, 5-methoxycarbonyl-4,5-diphenyl-X-ray, 5, 191 (76BSB545)... 

The features of the electronic structure of aryl-substituted pyrazolines influence their chemical properties. For example, in the case of 3-substituted 7V-phenyl-pyrazolines 100 reactions of formylation, acylation, nitration, sulfonation, azocoupling and other electrophilic processes involve the para position of the 7V-phenyl ring, with formation of compounds 101 [103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113]. On the other hand, some electrophilic reactions, including nitration, bromination, chlorination, formylation and azocoupling, for 3-unsubstituted pyrazolines 102 occur at position 3, yielding heterocycles 103 and in some cases as a mixture with 104 [108, 114, 115] (Scheme 2.26). This fact provides evidence for orbital control of these reactions. 

Pyrazole (3 chloro,4 carboxy,1 methyl 5 sulfonamide) halosulfuron Pyrazole (1.4 dimethyl,2 chloro, 3 formyl) fenpyroximate Pyrazole (2 methyl, 3 amino, 4 carboxy) pyrazosulfuron Pyrazole (2 methyl,4 carboxy, ethyl ester) pyrazosulfuron Pyrazole (1 methyl,2 ethyl,4 chloro 5 carboxy) tebufenpyrad 5 Pyrazolone (1.3 dimethyl) benzofenap, pyrazolinate, pyrazoxyfen Pyridazine (1 phenyl 3 hydroxy, 6 oxo) pyridafenthion... 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

Chiral electrophilic cyclopropanes (63) are prepared in high enantiomeric excess starting from butadiene-iron tricarbonyl complexes (60) containing a non-complexed double bond. Reaction with diazomethane and decomposition of the resulting pyrazolines (61) in the presence of Ce" gave the corresponding chiral cyclopropanes (62). Breakdown of the dienic substituent of electrophilic cyclopropane (62) by means of ozonization resulted in the formation of formyl-substituted electrophilic cyclopropane (63) still carrying the asymmetric centre (equation 10) " . ... 

Dimers of 3-alkoxycarbonyl-5-formyl-5-methyl-A -pyrazoline 9-Oxo-2a,3,5,6,7,8,8a,9-octahydroindolizino[ 1, 2 5,4]pyrazolo- 75AX(B)548, 76AX(B)2216... 

L-f/ireo-glycerol-l-yl)-pyrazoline-5-one (49) when its solution in alkali was acidified with acetic acid (50). The reaction was further extended to other bis(arylhydrazones) (51), The structure of the phenyl analogue (49) was established by oxidation to the known 3-carboxy-l-phenyl-4-phenylazopyrazolin-5-one (50). Later, on the basis of NMR data (39), the structure of this group of compounds was formulated as the hydra-zones (51). Acylation of 51 aflForded the tri-O-acylated derivatives (51), while periodate oxidation of 51 gave 3-formyl-l-aryl-4,5-pyrazoledione-... 

A number of syntheses of compounds having nitrogen on a carbon attached to 2-pyrazolin-5-one rings have already been mentioned, but several others are known. The most important of these is the reaction of 4-formyl- or 4-acyl-2-pyrazolin-5-ones with hydroxylamine, hydrazines, semicarbazide and similar chemicals.559 1841 These compounds can also be obtained by direct synthesis from an appropriate /3-ketoester or derivative and a hydrazine (eq. 50).138 512-1100 An interesting syn-... 

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with jS-ketoesters forms 2-aryl-3-pyrazolin-5-ones.679,849,984,988,1001 The aeyl group is lost in the cyclization and these products have no N-l substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3-pyrazoIin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus penta-chloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a j8-ketoester to give l,2-disubstituted-3-pyrazolin-5-ones.54,370 The sub-... 

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /9-ketoester with hydrazines according to the classical method for preparation of 2-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /9-substituents whose reaction is equivalent to that of a /9-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,1027 ethyl phenylpenaldate243 and the acetal of an a-amido-/9-formyl ester.59,243 Cornforth has isomerized 2-phenyl-4-hydrazino-methylidyneoxazolidone to 4-benzamido-2-pyrazolin-5-one. The same compound was obtained by treatment of 1-ethoxyvinyl-2-phenyl-oxazolidone with phenylhydrazine.319... 

A large number of 2-pyrazolin-5-one aldehydes and ketones are known. These are listed in Table XXX. It is possible to have both 3-and 4-formyl and acyl substituents and both are known, although only one 5-oxo-2-pyrazoline-3-carboxaldehyde has been reported. There has been very little study of the effect of 4-acyl substituents on the structure of 2-pyrazolin-5-ones, but it seems probable that such compounds would tend to exist to a large extent as the 5-hydroxypyrazoles since they would be 1,3-dicarbonyl compounds. 

The 4-formyl and 4-acyl-3-pyrazolin-5-ones react like normal carbonyl compounds with active methylene groups,898-1190 amines,107,1190 hydroxylamine,196 hydrazines196-201 and semicarba-zide,201 although some fail to react with thiosemicarbazide.799 They... 

C,6H21CIIN5O2 0.5 H2O, lO Chloro-2 [2-(dimethylamino)ethyl]-2,7-dihydro-7-methyl-3H-1,2,4-triazolo[4,3-d][1,4]benzodiazepine-3,6(5H)-dione methiodide hemihydrate, 45B, 297 ClsH2 BrN03, -)-trans-4-Methyl-1Ob-methoxycarbonyl-1,2,3,4,4a,5,6,-1Ob-octahydrobenzo f)quinoline hydrobromide monohydrate, 44B, 259 Cl 6 2 uNftOg, 3-Carboethoxy-5-methyl-5-formyl-A -pyrazoline aminohe-miacetal dimer, 42B, 219... 

Cl6H2 NftOg, 3-Carbomethoxy-5-methyl-5-formyl-A2-pyrazoline dimer, 41B, 348... 

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