Pyrazolines from alkenes

DCA reactions are an important means of synthesis of a wide variety of heterocyclic molecules, some of which are useful intermediates in multistage syntheses. Pyrazolines, which are formed from alkenes and diazo compounds, for example, can be pyrolyzed or photolyzed to give cyclopropanes. 

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). 

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). 

Based on a detailed investigation, it was concluded that the exceptional ability of the molybdenum compounds to promote cyclopropanation of electron-poor alkenes is not caused by intermediate nucleophilic metal carbenes, as one might assume at first glance. Rather, they seem to interfere with the reaction sequence of the uncatalyzed formation of 2-pyrazolines (Scheme 18) by preventing the 1-pyrazoline - 2-pyrazoline tautomerization from occurring. Thereby, the 1-pyrazoline has the opportunity to decompose purely thermally to cyclopropanes and formal vinylic C—H insertion products. This assumption is supported by the following facts a) Neither Mo(CO)6 nor Mo2(OAc)4 influence the rate of [3 + 2] cycloaddition of the diazocarbonyl compound to the alkene. b) Decomposition of ethyl diazoacetate is only weakly accelerated by the molybdenum compounds, c) The latter do not affect the decomposition rate of and product distribution from independently synthesized, representative 1-pyrazolines, and 2-pyrazolines are not at all decomposed in their presence at the given reaction temperature. 

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... 

Not much is known about the reactivity of the phosphinocarbene 2i. Problems arise, at least in part, from the high 1,3-dipolar reactivity of the diazo precursor li, which hides any carbene reactivity. Indeed, although li is stable in a toluene solution at 60°C for hours, the addition of an electron-poor olefin, such as a perfluoroalkyl-monosubstituted alkene, induces the exclusive formation of the thermodynamically more stable anti-isomer of the cyclopropane 14 (see Section V,B,3,a).36 This clearly demonstrates that the cyclopropanation reaction does not involve the carbene 2i, but that an initial [2 + 3]-cycloaddition occurs leading to the pyrazoline 13, which subsequently undergoes a classical N2 elimination.37... 

Of the many substituted and functionalized alkenes that have been combined with diazo dipoles to give A -pyrazolines or products derived from them (i.e., A -pyrazolines, pyrazoles, cyclopropanes), only a selection will be mentioned. These include ot-alkylidene-cycloalkanones (62), -flavanones, -thioflavanones, -chroma-nones, and thiochromanones (63,64) a-arylidene-indanones and -indolones (65) diarylideneacetones (66) l-benzopyran-2(77)-ones (coumarins) (67,68) 4-nitro-1,2-oxazoles (69) 2-alkylidene-2-cyanoacetates (70) dimethyl 2,3-dicyanofuma-rate (71) tetracyanoethylene (72) tetraethyl ethylenetetracarboxylate (72) 1,4-quinones (35,73-75) 2-X-l,l,l-trifluoro-2-propene [X = Br, (76), SPh, SOPh, S02Ph (77)] nitroalkenes (78) including sugar nitroalkenes (79) 1-diethoxyphos-phoryl-1-alkenyl-sulfoxides (80) methyl 2-(acetylamino)cinnamate and -acrylate... 

The reactions between sydnones (e.g. 26) and unsaturated compounds frequently yield pyrazoles. Pyrazolines are produced by 1,3-dipolar addition to alkenes, and pyrazoles from alkynes.372-374 The cyanopyrazolines formed from a,/3-unsaturated nitriles are immediately converted to pyrazoles.373... 

The reactions of diazomethane with C- and X-substituted alkenes are much slower, and consequently there are fewer known examples. The slower rate of reaction is explained easily by the larger energy separation in the frontier orbitals (10 and 9.8 eV, respectively, in Fig. 6.34). The regioselectivity, however, is the same A -pyrazolines like 6.225 and 6.227 with the substituent at C-3 are obtained with both C- and X-substituted dipolarophiles. This at first sight surprising observation can be explained by the change from dipole-HO-control in the cases of the Z- and C-substituted alkenes 6.223 and 6.224 to dipole-LU-control 6.226 in the case of the X-substituted alkene ethyl vinyl ether. 

Alkenes conjugated with are electron-deficient and hence do not react readily with organic peroxy acids. The observation that the stereochemistry of the pyrazolinone (109) is not retained in the epoxidadon product (110) is interesting (equation 38). The epoxide (110) is not fomaed directly fiom (109). Since the double brad in (109) is electron-deficient its peroxy acid epoxidadon to furnish (111) is a slow process. The isomerizadon the (Z)-pyrazolinfast process. MCPBA epoxidadon of the ( )-isomer derived from (109) Amishes (110). 

Due to the electrophilic character of carbenes. they are not expected to easily react with electron-poor alkenes, and the only reported examples concern reactions with diazo compounds (i.e., diazomethane, diazofluorcnc. ethyl diazoacetate. and phenyldiazoniethane ). However, depending on the reaction conditions, carbenes arc not always the reactive species. Cyclopropanes are often obtained by decomposition of pyrazolines which arise from 1,3-dipolar cycloaddilion reactions (see Section 2.1.1.6.2.3.1.). Even when reactions are performed under irradiation, pyrazolines can be obtained as the result of a diradical addition. ... 

Thermal deazetization of pyrazolines results in the formation of cyclopropanes and alkenes, illustrated in Figure 44 for the parent compound (18). This reaction is of interest in that one could imagine that it would involve the same trimethylene biradical (19) proposed to be an intermediate in cyclopropane stereomutation (Section III.A). Supporting this notion is the observation that the parent pyrazoline gives 89% cyclopropane and 11 % propylene at 250° C. If one took this product ratio as a reflection of the branching ratio from a common trimethylene intermediate, it should then be possible to compare these figures with the relative rates of stereomutation and propylene formation from cyclopropane-d2 . Interestingly, they are identical. 

Thermolysis of pyrazolines was also used for aminocyclopropane synthesis. The corresponding starting materials were obtained from diazomethane and an alkene bearing a suitable nitrogen functional group, e.g. an amido or azido moiety. 

Unfortunately, 4,5-dihydro-32/-pyrazoles can not only produce cyclopropanes but also tautomeric 4,5-dihydro-l//-pyrazoles (d -pyrazolines) and acyclic constitutional isomers of the cyclopropanes. This is illustrated for the 4,5-dihydro-3//-pyrazoles 11 which result from [3-1-2] cycloaddition of a-diazo esters to electron-deficient alkenes. If = H, they undergo rapid tautomerism to form 4,5-dihydro-l//-pyrazoles 12 or 13, both of which are not subsequently... 

The thermally induced cyclopropanation of alkenes with silyldiazoacetates is virtually unknown. Silylated diazo esters are thermally rather stable and do not readily decompose to give a carbene under standard laboratory conditions. The only known cyclopropanation of this type, i.e. synthesis of 2 from ethyl diazo(trimethylsilyl)acetate and ethyl acrylate (formation of E- and Z-isomers, no yield given), probably occurs via a pyrazoline intermediate. 

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