Cyclopropane 1,1-dihalocyclopropane

Treatment of geminal dihalocyclopropyl compounds with a strong base such as butyl lithium has been for several years the most versatile method for cumulenes. The dihalo compounds are easily obtained by addition of dihalocarbenes to double--bond systems If the dihalocyclopropanes are reacted at low temperatures with alkyllithium, a cyclopropane carbenoid is formed, which in general decomposes above -40 to -50°C to afford the cumulene. Although at present a number of alternative methods are available , the above-mentioned synthesis is the only suitable one for cyclic cumulenes [e.g. 1,2-cyclononadiene and 1,2,3-cyclodecatriene] and substituted non-cyclic cumulenes [e.g. (CH3)2C=C=C=C(CH3)2]. 

More useful for synthetic purposes, however, is the combination of the zinc-copper couple with methylene iodide to generate carbene-zinc iodide complex, which undergoes addition to double bonds exclusively to form cyclopropanes (7). The base-catalyzed generation of halocarbenes from haloforms (2) also provides a general route to 1,1-dihalocyclopropanes via carbene addition, as does the nonbasic generation of dihalocarbenes from phenyl(trihalomethyl)mercury compounds. Details of these reactions are given below. 

The reaction between CHCI3 and OH is often carried out under phase-transfer conditions. It has been shown that the reaction between PhCHCl2 and t-BuOK produces a carbenoid, but when the reaction is run in the presence of a crown ether, the free PhCCl is formed instead.Dihalocyclopropanes are very useful compoundsthat can be reduced to cyclopropanes, treated with magnesium or sodium to give allenes (18-3), or converted to a number of other products. 

Gem-Dihalocydopropanes belong to the most readily available cyclopropane derivatives known today. They have been shown to be extremely valuable starting materials for the preparation of cyclopropanes and cyclopropenes, they may be converted to bicyclobutane derivatives and spiropentanes, can lead to allenes and the higher cumulenes, cyclopentenes and cyclopentadienes, and many other classes of compounds, both hydrocarbon systems and derivatives with valuable functional groups. The article summarizes the preparative developments in the area of gem-dihalocyclopropane chemistry during the last decade. 

Phase transfer-catalyzed reactions have recently been employed to dehydro-halogenate gem-dihalocyclopropanes [156, 157]. Thus, 1-methylene-2-vinylcyclo-propane has been prepared from l,l-dichloro-2-ethyl-3-methylcyclopropane in 60 % yield. Under the reactipn conditions (solid KOH, DMSO in the presence of dibenzo-18-crown-6, 100-130 °C) further transformations may take place, however. For example, monoalkylated cyclopropanes have been converted to mixtures of acyclic enynes and conjugated trienes. And 7,7-dichloronorcarane is converted to toluene under these conditions. 

Although the gem-dihalocyclopropanes are fairly stable compounds, they can participate — as has been shown in the above sections — in quite a number of chemical transformations. Several reactions between dihalocarbenes and alkenes have been described in which no dihalocyclopropane formation could be observed that these intermediates might have been produced was only inferred from the type of products finally isolated. A typical process of this type is the e/ufo-addition of dihalocarbenes to norbomene and norbomadiene as discussed above. Comparable rearrangements have been observed, when dichlorocarbene additions either lead to aromatic products or when they cycloadd to rather inert aromatic systems. In the latter case a ring-enlargement takes place. A reaction related to the concerted opening of two cyclopropane rings in a bicyclopropyl system as discussed above takes place when dichlorocarbene is added to spiro[2.4]hepta-4,6-diene [227]. 

To summarize, gwi-dihalocyclopropanes may serve as starting materials for the preparation of cyclopropane and cyclopropene derivatives, they can lead to compounds with bicyclobutane and spiropentane structures, provide allenes and... 

Although many recent improvements in the preparation of the Simmons Smith reagent might be helpful23 24, the authors of this chapter would recommend one to consider an alternative two-step cyclopropanation procedure, which includes cycloaddition of dichloro- or dibromocarbene to methylenecycloalkane25 followed by reductive dehalo-genation (equation l)26. The first reaction is usually carried under phase transfer conditions and presents a very simple and efficient procedure. Reduction of gem-dihalocyclopropanes with lithium in tert-butanol or with sodium in liquid ammonia usually proceeds without complications and with high yield. 

Dihalocyclopropanes containing all possible combinations of halogens have been synthesized. From the vantage point of the synthetic chemist, dibromo- and dichloro-cyclopropanes elicit the most useful and fascinating chemistry, and therefore this discussion will be centered around the formation and transformations of these two groups of compounds. For the sake of completeness, dihalocyclopropenes have been discussed where appropriate. To emphasize the synthetic potential, separate subsections are devoted to certain topics, e.g. formation of heterocycles. 

The silver ion assisted carbon-halogen bond cleavage and the unraveling of the cyclopropane ring by the cyclopropyl-allyl rearrangement was first noted in the formation of 2-bromocyclohexen-l-ol from dibromobicyclo[3.l.0]hexane under solvolytic conditions (equation 86).220 The silver ion assisted solvolysis of the dihalocyclopropane adduct (43), derived from a Birch reduction product, smoothly rearranges to the tropone (equation 87).221 A number of other synthetic applications222-226 have beien reported... 

Not much is known about the opening of dihalocyclopropanes by Lewis acids beyond reports on the reaction of dibromo- and dichloro-cyclopropanes with aromatic hydrocarbons under the influence of AlCb or FeCb leading to indenes.229"231... 

It is abundantly clear from the preceding discussion that dihalocyclopropanes are versatile intermediates in organic synthesis. Although a wealth of chemistry has already been uncovered, prospects remain bright for interesting developments in the future. Areas such as the application of dihalocyclopropanes in heterocyclic synthesis via carbene insertion into C—H bonds adjacent to heteroatoms, reactions of dihalocyclopropanes with organometallics and the synthetic applications of metallated derivatives deserve further exploration. The chemistry of difluoro-, diiodo- and mixed dihalo-cyclopropanes can be expected to attract some attention. Finally, other heteroatom-substituted cyclopropanes derived ftom dihalocyclopropanes will also invoke further investigation. 

However, a respectable alternative to the direct [2 + l]-routes (a)-(c) is the variant using halo- or dihalocyclopropanes as precursors for the desired target molecules (path d). The cyclopropane ring is formed by addition of halocarbenes to the olefin and subsequent change of functionalities is achieved by treatment with nucleophiles. It is very unlikely that a direct substitution incorporates the donor-substituent. Instead an elimination/addition sequence with the intermediacy of a cyclopropene has to be assumed. 

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-... 

Shortly after discovery of a convenient dihalocyclopropane synthesis their conversion to allenes was effected This area has been reviewed very recently ", and therefore only some very new examples will be mentioned Employing a repetitive cyclopropanation/allene formation sequence, 1,2,3-cyclononatriene—presumably the smallest isolable cyclic butatriene—has become available (equation 120). ... 

The chemistry of dihalocyclopropanes has been reviewed in several places the most recent being in 1983 in an earlier volume of this series. The principles involved in explaining the rate and product behaviors observed with the dihalocyclopropanes follow from those described previously for the reactions of monohalo- or sulfonate ester-substituted cyclopropanes and thus will not be repeated here. In most of these studies the solvolytic reactions were silver ion assisted and only qualitative rate data were presented. The major emphasis was on determining by means of product studies whether the endo or exo halogen was the most reactive in the various systems and thus whether the product was a CIS- or trans-cycloalkene derivative. 

Gem-dihalocyclopropanes are readily prepared from the corresponding dihalocarbenes or dihalocarbenoids. Conversion of these compounds to cyclopropanes containing a deuterium label at a stereochemically defined site is relatively straightforward. Both... 

The cyclopropyl group has enough special characteristics to distinguish it from other alkyl and cycloalkyl groups and we believe it deserves a special volume dealing with its chemistry. Two chapters related to this group appeared in previous volumes of the series. The similarities between cyclopropanes and olefins were discussed in a chapter on the Olefinic properties of Cyclopropanes in The Chemistry of Alkenes, Vol. 2 (1970) and Dihalocyclopropanes were described in Supplement D (1983) which deals with the carbon-halogen bond. 

Red-Al, usually 10% molar excess, was added as a 70% solution in benzene (commercially available) to a vigorously stirred solution of 1,1-dihalocyclopropane in benzene (2-4mL of benzene/0.01 mol of cyclopropane) kept at 88 "C. The white mixture was stirred at bath temperature for 2-5 h and was then hydrolyzed with 10% HCl. The products were extracted with benzene and Et O the combined organic fractions were washed with water and dried (MgSOj,). Evaporation of the solvent left a residue which was analyzed by GC prior to distillation. 

Cyclopropyl halides are versatile starting materials for the preparation of a wide range of cyelopropanes with an additional substituent, which is attached to the ring by a C-C bond. The majority of the reactions has been carried out with monohalocyclopropanes, but there is also a significant body of work dealing with conversions of 1,1-dihalocyclopropanes to 1-substituted 1-halocyclopropanes. Almost without exception the transformations involve ionic intermediates which in most cases include a nucleophilic cyclopropane species. 

When the 1,1-dihalocyclopropane contains an additional functional group, lithiation followed by carboxylation and acid treatment can lead to products other than the corresponding acids. This was observed when this reaction sequence was applied to the diepoxide 4 which gave the monoepoxide lactone 5 in 10% yield by nucleophilic attack of the epoxide.Advantage has been taken of the same principle in the preparation of a number of di- and oligocyclic lactones with a cyclopropane ring incorporated.Thus, when rra s-2,2-dichloro-l,3-dimethyl-... 

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