Halocyclopropanes, reactions

Halocyclopropanes, reactions of, 13, 2 Halogen-metal interconversion reactions,... 

Bromo- and iodocyclopropanes cannot be prepared by the direct halogenation of cyclopropanes. Substituted chloro- and bromocyclopropanes have been synthesized by the photochemical decomposition of a-halodiazomethanes in the presence of olefins iodocyclopropanes have been prepared from the reaction of an olefin, iodoform and potassium f-butoxide followed by the reduction of diiodocyclopropane formed with tri-w-butyl tin hydride. The method described employs a readily available light source and common laboratory equipment, and is relatively safe to carry out. The method is adaptable for the preparation of bromo- and chlorocyclopropanes as well by using bromodiiodomethane or chlorodiiodomethane instead of iodoform. If the olefin used will give two isomeric halocyclopropanes, the isomers are usually separable by chromatography. ... 

Both phase-transfer and crown ether catalysis have been used to promote a-elimination reactions of chloroform and other haloalkanes.90 The carbene is trapped by alkenes to form halocyclopropanes. 

This chapter focuses on the use of silver(I) salts as Lewis acids in the ring-opening reactions of halocyclopropanes. Both the classical and most recent examples of this type of chemistry are examined with emphasis on the use of this simple transformation to build up complex intermediates that are potentially useful in the construction of natural products. 

While cationic ring opening of halocyclopropanes can be induced under strictly thermal conditions, it is most often performed in the presence of a Lewis acid.8 The Lewis acids commonly used in these reactions are silver(I) salts due the inherent halophilicity of the silver cation. The silver(I)-mediated reactions can be carried out at lower temperatures due to activation of the departing halide by coordination to silver in what has been described as a highly concerted push-pull mechanism.13 Under these conditions the halide-substituted carbon atom bears slightly increased positive character, which enables the cationic ring opening to proceed under mild conditions (Fig. 4.4). 

The construction of complex intermediates from simple and readily available starting materials has been accomplished using the electrocyclic ring-opening reaction of halocyclopropanes. This is typically achieved through interception of the cationic haloallyl intermediate by solvent, the silver(I) counteranion, or some alternate tethered heteroatom or carbon-based nucleophile. Examples of these processes are described below. 

The successful utilization of nitrogen-based nucleophiles in the previously described cascade reactions has allowed for the synthesis of complex polycyclic structures from simple and readily available starting materials. The fact that carbamates can participate as nucleophiles has provided the opportunity for development of diastereoselective ring closures onto the halocyclopropane-derived allyl cation. 

The silver(I)-mediated electrocyclic ring opening of halocyclopropanes has been used to induce extensive skeletal rearrangements in gcm-dibromospiropentanes, providing rapid construction of naphthalenes and/or indenes (Scheme4.21 ).34 A variety of Lewis acids, Brpnsted acids, and solvent effects were carefully examined before optimal conditions were identified. It was found that subjection of spirocycle 60 to silver acetate in trifluoroacetic acid afforded rearrangement products 61 and 62 in moderate to good yields. The proposed mechanism of the reaction is illustrated in Scheme 4.21. 

To further expand the scope of this new silver(I)-mediated reaction sequence, interrupted Nazarov cyclizations were explored using the halocyclopropane chemistry, an investigation that was prompted by the discovery of an intriguing result. It was found that treatment of the phenethyl-substituted compound 76 with 1.5 equiv of silver tetrafluoroborate in dichloromethane provided benzohydrindenone 77 as the sole product, with no apparent formation of the simple a-chlorocyclopentenone (Scheme 4.24). This prompted an examination of appropriately substituted gem-dichlorocyclopropane substrates in analogous interrupted Nazarov processes to ascertain the scope of this new cascade reaction sequence. 

The cascade sequences presented herein demonstrate unprecedented modes of reactivity in Nazarov chemistry that are initiated by the silver(I)-promoted ring opening of halocyclopropanes. The ease with which the gem-dichlorocyclopropanes can be prepared, the relatively mild reaction conditions, and the efficiency of these processes make these substrates attractive intermediates for an application in natural product synthesis. 

However, the ready availability of halocyclopropanes has led to extensive studies of their 1,2-dehydrochlorination, and amines are now rarely used as cyclopropene precursors. Although the reaction of 1,1-dichlorocyclopropanes with strong base does in certain situations lead to cyclopropenes, it is frequently the case that the initially formed 1-halocyclopropene does not survive under the reaction conditions, undergoing either addition of a nucleophile to the alkene bond or prototropic shifts followed by further dehydrohalogenation. Two main variations on this method are available which proceed under conditions where further reaction does not, in general, occur, that is 1,2-dehalogenation and 1,2-dehalosilylation. Each of these three alternatives will be considered in turn. 

Problems with subsequent reaction of a 1-halocyclopropene may be avoided by reduction of the dihalocyclopropane to a monohalocyclopropane prior to dehydrohalogenation. Thus 3,3-dimethylcyclopropene may be obtained in multi-gram quantities by treatment of l-bromo-3,3-dimethylcyclopropane with potassium t-butoxide in DMSO at —78 °C19). Dehydrohalogenation of a series of related 3,3-dialkyl substituted monochloro- or monobromo-cyclopropanes leads to moderate yields of cyclopropenes (11, R = alkyl, alkenyl, aryl, CN, Cl, Rl = H, Ph, t-Bu, R2 = H)20) Indeed, dehydrobromination of (12) leads to either mono- or di-cyclopropenes 2l>. Reaction of a dihalocyclopropane with an alkyl lithium at low temperature followed by carboxylation of the derived 1-lithio-l-halocyclopropane provides a convenient source of 1-halocyclopropane carboxylates dehydrohalogenation leads to cyclo-... 

The reaction can also be used to produce m-2-substituted halocyclopropanes, l-chloro-2-phenylcydopropenes undergoing efficient hydrogenation using palladium on calcium carbonate by cis-addition of hydrogen with no evidence for competing hydrogenolysis of the C—Cl bond 27). 

Reduction of vicinal dihalocyclopropanes has also been used to introduce deuterium labels stereoselectively. The peculiar stereochemistry of this process (all stereoisomers of the original halocyclopropane give the same stereoisomer of the product) suggests that perhaps a cyclopropene might be formed which then undergoes electron transfer reduction under the conditions of the reaction (see Figure 7). 

Tetracyclic compounds 18 were obtained, together with the DBU hydrohalide salt, in the reaction of dimethyl l-halocyclopropane-l,2-dicarboxylates... 

Halocyclopropanes are converted to cyclopropyl acetates under solvolytic conditions in the presence or absence of a silver salt, but the yields are usually moderate " or low, although exceptions are known.However, interesting stereospecific reactions have been observed in a couple of cases. Solvolysis of l-bromo-4,5-benzotricyclo[4.4.1.0]undec-4-en-... 

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