Cyclopropanes pyrazolines

Finally, A -pyrazolines lose N2 (73KGS64) but it is possible that this takes place thermally before ionization, since thermolysis of A -pyrazolines usually gives cyclopropanes (Section 4.04.2.2.2(iv)). 

The fundamental subject of this section is the transformation of A -pyrazolines into cyclopropanes (Buchner-Curtius and Kishner cyclopropane syntheses). The cyclopropane is often accompanied by alkenes (67HC(22)l). When applied to A -pyrazolines the reaction occurs via the A isomers (Scheme 37). 

Ethyl-5-methyl (3R, 5R) and (3R, 55) derivatives Elucidation of the stereochemistry of the pyrazoline-> cyclopropane reaction 77JA2740... 

Pyrolysis at 190° of the resulting diastereomeric A -pyrazolines (8) and (11) leads to elimination of nitrogen and formation of the cis- and tmns-cydo-propanecarboxylates (9) and (12), respectively. Thermal decomposition of the A -pyrazoline (13) affords methyl tiglate (14) in addition to the cyclopropane derivative (15) in a ratio 2 1, while A -pyrazolines such as (3) give only 0L,[i- or, y-unsaturated esters, and no cyclopropane derivatives. 

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. 

High vacuum pyrolysis, heating in organic bases, contact with acidic adsorbents and reaction at room temperature with perchloric acid or boron trifluoride etherate cleaves the pyrazoline to give a 45-60% yield of the cyclopropane derivative (13) as well as 9 % of the unsaturated methyl compound (14). ° ... 

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. 

Pyrazolines (51) can be converted to cyclopropane and N2 on photolysis""" or pyroiysis. The tautomeric 2-pyrazolines (52), which are more stable than 51 also give the reaction, but in this case an acidic or basic catalyst is required, the function of which is to convert 52 to 51." In the absence of such catalysts, 52 do not react/ In a similar manner, triazolines (53) are converted to aziridines." Side reactions are frequent with both 51 and 53, and some substrates do not give the reaction at all. However, the reaction has proved synthetically useful in many cases. In general, photolysis gives better yields and fewer side reactions than pyrolysis with both 51 and 53. S/Z-Pyrazoles" " (54) are stable to heat, but in some cases can be converted to... 

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. 

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. 

Allyloxysilyl)diazoacetic esters 6 and the homologous butenyloxy derivative 9 undergo intramolecular cyclopropanation to form 7 and 10, respectively, when decomposed photochemically or by transition metal catalysis. The thermal reaction of 9 produces the same result, whereas the l-oxa-2-sila-3-cyclopentene 8 is formed from 6, presumably via a pyrazoline intermediate. 

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). 

Diazocarbonyl compounds readily undergo [3 + 2] cycloaddition to electron-poor alkenes 139). The 1-pyrazolines thus formed usually tautomerize to 2-pyrazolines if there is a hydrogen in an a-position to one of the nitrogen atoms otherwise, thermally induced ring contraction with evolution of nitrogen to give cyclopropanes can occur (Scheme 18). 

As it is known from experience that the metal carbenes operating in most catalyzed reactions of diazo compounds are electrophilic species, it comes as no surprise that only a few examples of efficient catalyzed cyclopropanation of electron-poor alkeiies exist. One of those examples is the copper-catalyzed cyclopropanation of methyl vinyl ketone with ethyl diazoacetate 140), contrasting with the 2-pyrazoline formation in the purely thermal reaction (for failures to obtain cyclopropanes by copper-catalyzed decomposition of diazoesters, see Table VIII in Ref. 6). 

Simultaneous occurence of the pyrazoline and carbenoid route is observed in the presence of bis(campherquinone-a-dioximato)cobalt(II) 95), but the cyclopropanes derived from ethyl diazoacetate and H2C=CHX (X = COOMe, CN) were obtained only in low yield. 

EvenPd(OAc)2 is not effective in catalyzing the cyclopropanation of a,P-unsaturated nitriles by ethyl diazoacetate. Instead, vinyloxazoles 92 are formed from acrylonitrile or methacrylonitrile by carbenoid addition to the CsN bond 143 Diethyl maleate and diethyl fumarate as well as polyketocarbenes are by-products in these reactions the 2-pyrazoline which would result from initial [3 + 2] cycloaddition at the C=C bond and which is the sole product of the uncatalyzed reaction at room temperature, can be avoided completely by very slow addition of the diazoester... 

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. 

The photoelimination of nitrogen from 1-pyrazolines is one of the most thoroughly investigated photoreactions and it has been used extensively in the synthesis of cyclopropane derivatives.334 Both stereospecific and non-stereospedfic processes have been observed and these are believed, at least in simple 1-pyrazolines, to correspond to singlet and triplet excited states, respectively. Two reaction pathways have been proposed in the azoalkane 405335 direct excitation via a thermally activated S, state affords the C6H6 isomers 406 to 409, whereas triplet-sensitized excitation results in a tem-... 

It was demonstrated (83) that the reaction of dinitrostyrenes (28) with aryl diazo compounds RR CN2 afford nitronates (24 g) in good yields. These products contain the nitro group at the C-4 atom in the trans position with respect to the substituent at C-5 (if R =H). Since the reaction mechanism remains unknown, the direct formation of cyclic nitronates (24 g) from pyrazolines A without the intermediate formation of cyclopropanes also cannot be ruled out. 

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... 

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. 

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. ... 

Reduction of unsaturated aromatic aldehydes to unsaturated hydrocarbons poses a serious problem, especially if the double bond is conjugated with the benzene ring or the carbonyl or both. In Clemmensen reduction the a,)8-unsaturated double bond is usually reduced [160], and in Wolff-Kizhner reduction a cyclopropane derivative may be formed as a result of decomposition of pyrazolines formed by intramolecular addition of the intermediate hydrazones across the double bonds [280]. The only way of converting unsaturated aromatic aldehydes to unsaturated hydrocarbons is the reaction of... 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

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 spiropyrazohnes obtained from 51 were converted into enantiopure A -pyrazoline-3-carboxylates and 1 -(hydroxyethyl)cyclopropane-1 -carboxylates (128). Those obtained from 54 and 55 were transformed into optically active a-spirocyclopropyllactones and 3-amino-3-(hydroxyethyl)pyrrolidin-2-ones (130). The spiropyrazoline obtained from a chiral propylidene-diketopiperazine and diazomethane was converted into (+)-(lR,25)-l-amino-2-ethyl)cyclopropane-l-carboxylic acid (allocoronamic acid) (135). 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

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