4-Methylene-1-pyrazoline

The photolysis of the 4-alkylidene-l-pyrazoline (94) gives rise to two isomeric methylene cyclopropanes (95 and 96).76 The available evidence points to the intermediacy of a trimethylenemethyl species (97) in the triplet state which can cyclize in three ways. The same species is postulated in the photolysis of a series of 4-alkylidene-l-pyrazoline-3-carboxylates.77 This appears to be a general route to derivatives of trimethylenemethyl trimethylenemethyl itself has been generated from 4-methylene-1-pyrazoline and the triplet nature of the intermediate identified by electron spin resonance (ESR) spectroscopy.78... 

Methylene-1 -pyrazoline Secondary deuterium isotope effects on the reaction rate 81CJC2556... 

Like other pyrazolines, 4-methylene-1-pyrazoline (MP) undergoes thermal extrusion of dinitrogen to form methylenecyclopropane (MCP) [35], but it does so much more rapidly the energy of activation is about 9 kcal/mol lower than that of the parent 1-pyrazoline, more than enough to offset a hundredfold reduction in the pre-exponential factor [40, 41]. This kinetic behaviour is prima facie evidence that the reaction proceeds stepwise via a triplet intermediate. The obvious choice was trimethylenemethane (TMM), that had been shown to have a triplet ground-state [36, 37, 38], in confirmation of numerous theoretical predictions [39], [18, pp. 141ff.j. 

They also studied the thermolysis of the compound 41. They found the thermolysis of 41 proceeds at 1/63 the rate of 4-methylene-1-pyrazoline. The 41 is undergoing thermolysis by a mechanism different from that for 4-methylene-1-pyrazoline. The 2,2,3,3-tetramethylmethylenecyclopropane 42 produced rapidly isomerizes under the reaction conditions to 2,2-dimethylisopropylidenecyclopropane 43. The four opposed methyl groups of 42 have created sufficient ground state destabilization as to cause its isomerization to be 147 times faster than the conversion of 2,2-dimethylmethylenecyclopropane 44 to isopropylidenecyclopropane 45. 

In the presence of base, the sulfone 189 rearranges to the methylene-pyrazoline 190, whereas its regioisomer 191 shows no reaction (Scheme 65).57 This is the reverse of the type of thermal rearrangement shown in Scheme 25. 

In variants of the above processes, the bifunctional reactivity of 4-(dialkylamino-methylene)pyrazolin-5-thiones (155) (Scheme 25) and oxazolin-5-thiones (157) (Equation (45)) with a-halocarboxylic acids (or esters) was exploited for the synthesis of thieno[2,3-c]pyrazoles (156)... 

Andrews and Day observed fluorescence from methylene-1-pyrazolines. They also showed that energy transfer from the lowest excited singlet state to dienes (piperylene) occurs with moderate efficiency. The decomposition products from methylene pyrazolines have been postulated to be the resonance stabilized diradicals,... 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Irradiation of 4-hydroxy- and 4-alkoxy-3-pyrazolin-5-one derivatives (163 R = OH, OR) leads to ring cleavage with the formation of /3-diamides (165) 69TL271). The methylene blue sensitized rearrangement of the same pyrazolinone (R = H) to the oxindole (166) also... 

In general, reaction of diazomethane with a, -unsaturated carbonyl compounds affords pyrazolines in which the nucleophilic methylene group is attached to the carbon atom of the carbonyl compound. According to Huisgen, the reactions belong to the general class of 1,3-dipolar cycloadditions. 

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. 

In the 6-chloro-A " series diazomethane addition and pyrazoline cleavage require more strenuous conditions. " An unexpected result is observed with the 4-chloro-A system (15) which adds two equivalents of diazomethane to give the 4-chloro-la,2a 6, 7 -dimethylene compound (16) in 16% yield after cleavage of the labile crude bispyrazoline with a catalytic amount of perchloric acid. The assignment of the -configuration to the 6,7-methylene group is based on the shift of the 19-H NMR resonance to higher field. 

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) ... 

A 50% aqueous solution of potassium hydroxide (160 ml) is added at —5° over a period of 30 min to a mixture consisting of 80 g (0.78 moles) N-nitrosomethylurea, 104 g (0.32 moles) 3 -acetoxy-5a-pregna-9(ll),16-dien-20-one and 1 liter of methylene dichloride. The mixture is allowed to come to room temperature and the reaction is continued for 2 hr. The mixture is stirred for 15 min and 1.5 liters of water is added slowly in order to discharge any excess of diazomethane. The layers are separated and the aqueous phase is extracted with 300 ml of methylene dichloride. The organic phase is washed with water dried and concentrated. The residue is triturated with 750 ml of petroleum (bp 100-120°) and the resulting solid is dried in vacuo at 100° to give 106.5 g (92%) of the pyrazoline mp 158° (dec.) [ah 72° (CHCI3) 2 3, 229 mfi (e 1,167). 

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. 

Atotalof 6.2gof 17 -acetoxyandrosta-4,6-dien-3-one-[2a,la-c]-A -pyrazoline is added portionwise to a solution consisting of 2.4 ml of perchloric acid (70%) in 240 ml acetone. The reaction mixture is then poured into ice water and extracted with methylene dichloride. The organic layer is washed to neutrality with water, dried over anhydrous sodium sulfate and taken to dryness. The residue is chromatographed on 300 g silica gel (deactivated with water 10% v/w) and eluted with methylene dichloride to yield 3.32 g (58%) of 17 -acetoxy-la,2cc-methyleneandrosta-4,6-dien-3-one mp 178-179° (from diisopropyl ether) [aj 188°(CHCl3) 281 mfi (e20,700). Further... 

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. 

The addition of allene to an ethereal solution of diazomethane gave 4-methylene-l-pyrazoline [81]. 

The 1,3-dipolar cycloaddition of diazomethane to MFA (24) occurred exclusively at the C2-C3 Jt-bond to give 4-(fluoromethylene)pyrazolines. The methylene group of diazomethane was regioselectively attached to the C2 carbon atom of 24 with a syw.anti ratio of 88 12 [72b], DFA (25) similarly reacted with diazomethane to give 4-(difluoromethylene)pyrazoline 89 selectively [72b, 86], The cycloaddition reaction of bulkier 2-diazopropane with DFA was less regioselective. 

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). 

The cycloaddition of several diazoalkanes with (2-arylvinyl)-[(—)-(8-phenyl-menthyloxy] methylene chromium complexes 72 gave the A -pyrazolines 73 with high diastereoselectivity. These compounds were converted into pyrazolinecarbox-ylates 74 by A-protection and metal decomplexation (98) (Scheme 8.17). It is... 

Zelenin and co-workers have shown (85KGS854, 85KGS1000 86KGS128 87KGS1210 88ZOR426) that the reaction products of 1,3-diketones with hydrazides in a molar ratio of 1 2 most frequently possess the cyclic structure of the corresponding 5-hydrazino-2-pyrazolines (such as 76B). They can also be produced in the reactions between the corresponding hydrazine derivatives and l-acyl-5-hydroxy-2-pyrazolines or 1-acyl-5-methylene-2-pyrazolines. 

The trienone (74), either by reaction with diazomethane and pyrolysis of the derived pyrazoline or by treatment with dimethylsulphoxonium methylide anion, yielded28 the 1 a,2 -methylene derivative (75). Epoxidation followed by the action of hydrogen chloride gave (77). The methylene bridge was re-formed by the reaction of collidine, the product being (76). Halogenated steroids of use in determining the metabolic fate of 16-chloro-oestrone methyl ethers and of chlormadinone acetate have been synthesized.29... 

Cycloaddition of diazoalkanes to 6-6 bonds was among the first reactions tested on the carbon cages41 and affords isolable fullerene-fused pyrazolines as primary adducts. Photochemically induced extrusion of N2 from the latter yields 6-6-closed methanofullerenes having the functionalized bond embedded in a cyclopropane substructure, whereas the thermal process affords 6-5 open homofullerenes in which a methylene group is bridging the open junction between a six- and a five-membered ring.15-17... 

Ground-state triplet dicarbenes in photochemical systems have also been extensively studied by ESR. Dowd and coworkers (304) examined the interesting, frequently postulated ground triplet trimethylenemethane obtained by photolysis of either 4-methylene-A -pyrazoline or a single crystal of 3-methylene-cyclobutanone. This triplet molecule is axially symmetrical and the proton hyperfine splittings of 8.9 gauss observed in single-crystal experiments indicate that all protons in the molecule are equivalent when the axis perpendicular to the plane... 

VI is that of II minus an HCN fragment. It is also of importance to recognize that cyclopropanation is indeed an excellent method to incorporate a methylene unit into I. Then, one is led to believe that II ought to be the cyclopropane derivative VIII, produced in all probability from pyrazoline intermediate VII (see Scheme 45.2). 

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