Diazomethane 2-pyrazolines

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

The addition of diazomethane to unsaturated esters (1), as ethyl acrylate, methyl crotonate and ethyl cinnamate, was investigated by Auwers who showed that the primary addition product is a A -pyrazoline (2) which rearranges spontaneously to the conjugated A -pyrazoline (3). 

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 addition of diazomethane to a,/l-unsaturated ketones, e.g., benzalace-tone and benzalacetophenone, results in A -pyrazolines (16) which decompose thermally to the conjugated ketones (17). Cyclopropane formation is not observed in this instance. 

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 first addition of diazomethane in the steroid series was carried out with the A -20-keto system (1) leading to a [17a,16a-c]-A -pyrazoline (2). ... 

The addition of diazomethane to 17j -hydroxy-5a-androst-l-en-3-one (7) gives the A -pyrazoline (8) in which the C=N bond is conjugated with the 3-keto group. °°... 

With -3-ketones, i.e., (11), diazomethane addition proceeds with attack at the A -bond leading to stereospecific formation of [2a,la-c]-A -pyrazolines (12). 

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. 

Addition of diazomethane to the A -17-ketone (20) proceeds from the -face of the molecule to give (22) in high yield after cleavage of the intermediate pyrazoline (21). ° ... 

Although A" -3-keto steroids are inert to diazomethane, Fieser ° observed pyrazoline formation (24) with the more reactive cholest-4-ene-3,6-dione (23). 

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). 

Johnson and co-workers also investigated the general acid-catalyzed diazomethane reaction with benzalacetone (20). When treated with 3 mole-equivalents of diazomethane, the latter is converted to the A -pyrazoline... 

Synthesis of pyrazolines in reactions of a,(3-enones with diazomethane and hydrazines 97KGS747. 

The desilylacetylated qrcloadducts, produced from the reactions of trimethylsilyl-diazomethane with 3-crotonoyl-2-oxazolidinone or 3-crotonoyl-4,4-dimethyl-2-oxa-zolidinone, were transformed to methyl traws-l-acetyl-4-methyl-l-pyrazoline-5-car-boxylate through the reactions with dimethoxymagnesium at -20 °C. When the optical rotations and chiral HPLC data were compared between these two esters, it was found that these two products had opposite absolute stereochemistry (Scheme 7.39). The absolute configuration was identified on the basis of the X-ray-determined structure of the major diastereomer of cycloadduct derived from the reaction of trimethylsilyldiazomethane to (S)-3-crotonoyl-4-methyl-2-oxazolidi-none. 

To a solution of 4.76 g of 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-3-pyrazoline-5-one in 200 ml of ether was added an ether solution containing 6 molar equivalents of diazomethane and the reaction mixture was allowed to stand at room temperature for 20 hours. After distilling off the solvent, the residue was dissolved in 160 ml of water, made alkaline (pH 10) with sodium hydroxide solution and extracted three times with 140 ml of benzene. The extract was washed with a small amount of water, dried over sodium sulfate and evaporated to give a crystalline mass. Recrystallization from isopropylether gave 1-(4 -methyl-6 -methoxy-2 -pyrimidinyl)-3-methyl-5-methoxypyrazole (3.96 g, 84%) as colorless prisms, MP 90° to 92°C. 

Diazomethane and 1 -substituted 1 //-azepine-4,5-dicarboxylates 44 yield the C4 — C5 pyrazoline adducts, e. g. 45.234 In contrast, the 1-mesyl and the 1-tosyl derivatives yield only adducts of the benzene imine valence tautomers of the l//-azepines. 

Similar pyrazoline adducts 142 and 143 have also been isolated from the reaction of p-phosphonoacrylate esters 141 with diazomethane (79). 

Isolable pyrazolines (183) are obtained from the (1,3-butadiene)phosphonic acid esters (182 X=S02Me, COOalkyl R "=H or Me R2=Me or Ph) (products from (182 X=CN) are thermo-labile) and diazomethane. Pyrolysis of the phosphorylated pyrazolines affords phosphonopentadienes rather than phosphono-cyclopropanes (contrast (184)) and with NaH give pyrazoles or pyrazolephbsphonic acid esters. 

The (5 5 5) fused heterocycles have also been synthesized from enedione 88 by utilizing its susceptibility to the nucleophilic attack. The enedione 88 was accordingly treated with excess of ethereal diazomethane in methanol at 4°C to afford the 7 -methyl derivative 31 presumably via 374 which was not isolated. 2-Pyrazoline derivative 31 was isolated in 46% yield under the same reaction conditions at room temperature (Scheme 80) <2002OL4387>. 

Diazomethane is also decomposed by N O)40 -43 and Pd(0) complexes43 . Electron-poor alkenes such as methyl acrylate are cyclopropanated efficiently with Ni(0) catalysts, whereas with Pd(0) yields were much lower (Scheme 1)43). Cyclopropanes derived from styrene, cyclohexene or 1-hexene were formed only in trace yields. In the uncatalyzed reaction between diazomethane and methyl acrylate, methyl 2-pyrazoline-3-carboxylate and methyl crotonate are formed competitively, but the yield of the latter can be largely reduced by adding an appropriate amount of catalyst. It has been verified that cyclopropane formation does not result from metal-catalyzed ring contraction of the 2-pyrazoline, Instead, a nickel(0)-carbene complex is assumed to be involved in the direct cyclopropanation of the olefin. The preference of such an intermediate for an electron-poor alkene is in agreement with the view that nickel carbenoids are nucleophilic 44). 

In a study aimed at elucidating the mechanism of the thermal decomposition of spiropentane 229, the two regioisomeric pyrazolines 227 and 228 were obtained in high yield by allowing a solution of MCP (1) and diazomethane (226) (or diazomethane-d2) in diethylether to stand at 3 °C for three weeks (Scheme 37) [59]. 

Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of P-nitro-meso-tetraphenylporphyrin le with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) <02S 1155>. The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. 

Diphenylcyclopropane has been prepared in 24% yield by the Simmons-Smith reaction,2 in 78% yield by treatment of 3,3-diphenylpropyltrimethylammonium iodide with sodium or potassium amide,3 in 61% yield by reaction of 1,1-diphenyl-ethylene with dimethylsulfonium methylide,4 and in unspecified yields from 1,1-diphenylethylene by reaction with diazomethane followed by pyrolysis of the resulting pyrazoline or by reaction with ethyl diazoacetate followed by distillation of the corresponding acid over calcium oxide.5... 

The pyrazoline derivative 260 was also the precursor for the synthesis (252) of the naturally occurring umbelactone. Reaction of butenolide 159c with diazomethane gave the pyrazoline 260, which was subjected to pyrolysis to give (—)-(5 )-umbelactone (261). As the natural umbelactone was described as being dextrorotatory, the synthesis of (+)-(R)-umbelactone from 159c was also performed. 

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

A reaction of 3-(phenylsulfonyl)-l,2-butadiene and diazomethane gave pyrazoline 83 in good yield. Upon irradiation, a 1,3-sulfonyl shift occurred to provide the disub-stituted pyrazole 84 [82]. 

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. 

Further studies on 1,3-dipolar addition reactions of diazophosphonates have been recorded,122 and work on 2-diazo-l-hydroxyalkylphosphonates also continues.123 The ester (155 R = H) reacts with esters of acetylenedicarboxylic acid without liberation of nitrogen to give stereoisomeric C-phosphorylated pyrazolines, which can be decomposed with both phosphorus-carbon and carbon-carbon bond fission, affording mixtures containing dimethyl acetylphosphonate, dimethyl hydrogen phosphonate, and tri(alkoxycarbonyl)pyrazolines. In the reaction between the same diazophosphonate and diazomethane, the latter conceivably acts as a basic catalyst for proton transfer in a series of steps which includes phosphonate-phosphate isomerization. The importance of a labile proton is demonstrated by the fact that the ester (155 R = Me) does not react in the manner described above. 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

Diazomethane is capable of addition reactions with double bonds. Pyrazoline rings are formed. Studebaker et al. (38) saw in this reaction an indication of quinone groups ... 

When l,4-dihydronaphthalen-l,4-imine (2) was first obtained via the hydrobromide (113), it was shown to react with phenyl azide to give an adduct (127). The analogous phenyl azide adduct (128) from compound 103 has been better characterized. Naphthalen-l,4-imines also add diazomethane across the 2,3-double bond, forming pyrazolines, e.g., 104 -> 129, two of which have been photolyzed to give the corresponding cyclopropane derivatives (130) with extrusion of nitrogen. ... 

Figure 9. Preparation of some carbohydrate pyrazolines by cycloaddition of diazomethane to nitroalkenic sugars.

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