Cyclopropane derivatives mechanism

An intriguing rearrangement was reported by Yates (72) during an attempt to carry out the Stobbe condensation. It resulted in the formation of a cyclopropane derivative from 4-benzoyloxycyclohexanone by the (proposed) mechanism shown. 

Stabilised sulphur ylides react with alkenylcarbene complexes to form a mixture of different products depending on the reaction conditions. However, at -40 °C the reaction results in the formation of almost equimolecular amounts of vinyl ethers and diastereomeric cyclopropane derivatives. These cyclopropane products are derived from a formal [2C+1S] cycloaddition reaction and the mechanism that explains its formation implies an initial 1,4-addition to form a zwitterionic intermediate followed by cyclisation. Oxidation of the formed complex renders the final products [30] (Scheme 8). 

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

The initial products may be considered to be excited cyclopropane derivatives formed by addition to the double bond and excited olefins formed by insertion into CH bonds. (The detailed reaction mechanisms are discussed in Sec. V.) The isomerization products are expected to be similar to those found in the thermal isomerizations of the corresponding cyclopropane derivative or olefins, the excitation energy being at least 80-85 kcal. in the former case and 85-90 kcal. in the latter (taking AHf° (CH2) 80-85 kcal.). The excitation energy is increased by any excess energy of methylene. 

The mechanism for the formation of this carbenoid and for its reaction with alkenes need not concern us here. Just remember that it reacts as though it is methylene. The Simmons-Smith reaction is an excellent way to prepare cyclopropane derivatives from alkenes, as shown in the following examples. Note the stereochemistry in the second equation. 

The facile formation of cyclopropane derivatives from 1,3-dihalides was originally formulated as a concerted mechanism (109) (Rifi, 1967, 1969). It has been shown more recently, however,... 

The formation of norcaradiene derivatives with naphthalene [reaction (22)] lends some support to this scheme. This mechanism resembles a bimolecular two-step process suggested for the reaction of chloromethyl-aluminum compounds with olefins (199-201). On the other hand, a bimolecular one-step methylene transfer mechanism is generally accepted for the formation of cyclopropane derivatives by the reaction of halo-methylzinc compounds with olefins. This difference between the mechanism proposed for the cyclopropane formation from olefin and that for the ring expansion of aromatic compound may be ascribable to the difference in the stability of intermediates the benzenium ion (XXII) may be more stable than an alkylcarbonium ion (369). 

Enzyme mechanism and inhibition, reactions of cyclopropane derivatives with heterocyclic fragments of enzymes in studies of 88AG(E)537. 

An elegant synthesis of pyrazolo[l,5-a]pyridine (1) in 47% yield is shown in Scheme 35. Sodium methoxide in diglyme at 180 °C catalyzes the rearrangement of the bis-hydrazone (104) and evidence is available for the indicated mechanism. The same technique also allows the preparation of the fused cyclopropane derivative (105) (74HCA1259). 

Formally, the insertion of a carbene(oid) into the 2,3-doubIe bond of the thiophene ring should result in the formation of the 2-thiabicyclo [3.1.0] hex-3-ene ring system. Copper(II)-catalyzed reaction of thiophene with diazomethane results in the formation of 24 (R = H) in modest yield (63TL1047). Analogously, the reaction of thiophene with ethyl diazoacetate yields 24 (R = COjEt) (22LA154). Although these reactions appear to be simple carbene insertion reactions, it is probable that this simple mechanism is not in operation. Rather, the cyclopropane derivatives 24 probably result from the initial formation of the ylid (e.g., 18), which subsequently rearranges. 

Isomerization reactions of ionized cyclopropane derivatives indeed seem to be ubiquitous and many further examples are reported in Refs 49 and 50. However, a careful examination of randomly selected paperindicates that the generality of these processes is not likely to be recognized, because the results and strange interpretations presented in these articles could easily be accounted for by mechanisms described in this chapter instead of the ones originally proposed ... 

Photochemical procedures for the preparation of electrophilic cyclopropanes are relatively important. Appropriately substituted electron-deficient olefins on photolysis undergo a di-7r-methane rearrangement to give the corresponding cyclopropane derivatives. For example, l,l-dicyano-2-methyl-3-arylpropenes (455) provide the dicyanocyclo-propanes (456), presumably via the mechanism of equation 154 . ... 

Strongly basic nucleophiles such as an amide ion allowed a nucleophilic substitution via an elimination-addition mechanism of cyclopropane derivatives possessing an acidic hydrogen atom " ". Aminocyclopropanes 121 and 122 were synthesized in this manner from the corresponding halogenocyclopropanes " (equations 28 and 29). 

The cyclopropanation of )- and (Z)-/S-methylstyrene (393 and 394) led to essentially the same ratio of ( ) and (Z) cyclopropane derivatives 395 and 396, indicating that the reactions proceeded stereospecihcally (81MI4 83BCJ2687). As electron-deficient olefins such as acrylate and acrylonitrile reacted even in the absence of copper(II) bromide, while the reaction of styrenes required the copper salt as catalyst, it was concluded that the reaction mechanism may vary, depending on the nature of the olefin. 

The cyclopropane derivative resulting from a symmetrical intermediate would give the 2-deuterocyclopropanecarboxylic acid 21 [ratio ( -H/a-H) 3], while an unsymmetrical intermediate would give an acid 22 unlabeled on the three-membered ring [ratio (j6-H/a-H) 4]. This ratio was readily determined from NMR spectra, and was consistent with the mechanism via an unsymmetrical intermediate. ... 

A reactive source of cyclopropane derivatives capable of furnishing cyclopropanone acetals is 1-chloro-l-methoxycyclopropane (33), which reacts with methanol in the presence of silver salts to give cyclopropanone dimethyl acetal (34) without rupture of the three-membered ring. It was subsequently shown that methanolysis, which occurs via an S l mechanism, does not require silver salts and occurs in quantitative yield with or without added base. ... 

Optically active l-halo-l-mefhyl-2,2-diphenylcyclopropanes 61 are used as probes to investigate the mechanisms of calcium reduction [39]. Treatment of 61 with calcium biphenyl (Ca(BPh)2) or calcium naphthalene (Ca(NPh)2) then addition of CO2 gives a mixture of cyclopropane derivative 62 and the corresponding carboxylic acid 63 (Scheme 4.17). Walborsky and Hamdouchi have provided evidence showing that these reactions occur by single electron transfer to yield free radicals... 

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