Preparation dihalocyclopropanes

Reaction of dibromocyclopropane (39) with hot quinoline gives 1-ethoxy-cyclohepta-l,3,5-triene (37) in 32% yield. Dihalocyclopropanes prepared from larger ring enol ethers do not react with hot pyridine but afford products with hot quinoline formed by transannular reactions. 

The treatment of 1,1-dihalocyclopropanes by methyllithium appears to be a general route to allenes, providing the product is not highly strained. An example is shown in the reaction (13). The procedure given below employs the reaction for the preparation... 

Cyclopropyl iodides like 70 and bromides are good substrates for the exchange reaction (equation 44)77,82,83 reaction is stereoselective and sufficiently fast at low temperatures, thus allowing the preparation of functionalized compounds. If a coordinating group like an ester is present in a. gem-dihalocyclopropane like 71, the cA-halogen substituent is exchanged selectively in ether (equation 45). ... 

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. 

Novel preparative possibilities arise when cyclopropylidene intermediates are generated from functionalized dihalocyclopropanes. Thus Baird has shown that bicyclic ethers may be formed in high yield by an intramolecular insertion from cyclopropyl alkyl ethers [120],... 

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. 

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... 

It is not unreasonable to expect preparatively useful photoreactions of appropriately functionalized dihalocyclopropanes also. Although the present trend in gew-dihalocyclopropane chemistry clearly favors the use of more highly functionalized substrates, the traditional role — mentioned in the introduction — of employing these strained molecules in hydrocarbon synthesis, is by no means an approach of the past. This point is stressed by the recent synthesis of octavalene... 

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 are generally prepared by the addition of dihalocarbenes to alkenic substrates. As indicated in the introduction, the first synthesis of a dihalocyclopropane was accomplished by Doering and Hoffmann by the addition of dichlorocarbene, generated from chloroform and potassium r-butoxide (Bu OK), to cyclohexene giving dichloronorcarane (1), as shown in equation (l).s... 

The dihalocyclopropanes were prepared either by reaction of PhHgCBr3 with the ethylenic compound by Seyfertss method or by the reaction of sodium tert-amylate with CHC13 or CHBr3. Using an excess of the reagent (2-8 times the stoichiometric amount) the total reaction products are obtained on both models and polyenes with almost quantitative yields. 

Models Ia-Va reacted with dihalocarbenes prepared either by a-elimination (11) or by thermolysis of Ph-Hg-CX2Br (22), giving rise to the corresponding dihalocyclopropane derivatives Ib-Vb (Figure 3). It was possible with these derivatives to characterize B, to study the reduction of B (X = Br) to C, and to characterize C. 

Syntheses of acetals of atropaldehyde have been reported previously, but all required either multistep sequences or difficultly accessible starting materials.5,6 Thus the ethylene glycol acetal has been prepared from 2-phenylpropanal in a three-step procedure.5 Ring openings of dihalocyclopropanes to give acetals are well known.7-10 The reaction of l,l-dichloro-2-phenylcyclopropane with methanolic sodium methoxide has been shown to give 1-phenyl-2,2-dimethoxycyclopropane. u... 

A good deal of the preparative utility of dihalocyclopropanes arises from the easy halogen-metal exchange. The corresponding carbanion (lithium carbenoid , see Section VLE.l) can be trapped at low temperature by a variety of electrophiles, resulting in substituted or functionalized halocyclopropanes (equation 128). 

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... 

In general, allenes are prepared by the same types of reactions which lead to alkenes elimination of hydrogen halides, halogens and water from adjacent carbon atoms. However, some methods are characteristic of allene synthesis, e.g. the dehalogenation of gem-dihalocyclopropanes, rearrangement of alkynes and the 1,4-addition to vinylalkynes. 

The starting materials are best prepared by the method of Makosza U3) (for dihalocyclopropanes) or via halocarbene addition to alkenes 114°. 

Reaction of dihalocarbenes with alkenes, [1 +2] cycloaddition, is the method of choice for the preparation of 1,1-dihalocyclopropanes. The reaction proceeds stereospecifically preserving the configuration of the alkene in the products. These observations allow the conclusion to be made that the dihalocarbene reacts in the singlet state with alkenes. Experimental data (relative activities of alkenes, selectivity indices as well as theoretical calculations indicate that dihalocarbenes are electrophilic species. This means that they react readily with electron-rich (nucleophilic) alkenes. Dihalocarbenes may also react with electron-poor alkenes, but at a much slower rate. In the case of alkenes with a fairly unreactive double bond, dihalocarbene may also attack other sites of the alkene molecule, e.g. insert into a C-H bond. The selectivity (reactivity) of dihalocarbenes depends on the temperature at 20 C typical dihalocarbenes can be arranged in the order given, with respect to their selectivities versus reactivities (Houben-Weyl, Vol. El9b, p 1598). 

A reaction of haloforms with a base, which generates dihalocarbenes (a-elimination) and their addition to alkenes is an efficient method for the preparation of 1,1-dihalocyclopropanes, with the exception of 1,1-difluoro derivatives (Houben-Weyl, Vol.E19b, pp 1464-1466). When chlorodifluoromethane and an alkene are treated with methyllithium, potassium tcrt-butox-ide, powdered sodium hydroxide in tetraglyme or a concentrated aqueous solution of alkali metal hydroxide and a phase-transfer catalyst, the expected 1,1-difluorocyclopropanes are formed in low yields. Comparable low yields of these products result, if dichlorodi-fluoromethane and an alkene are treated with methyllithium. " The main products formed are those that result from reaction of difluorocarbene (carbenoid), and its precursor, with the base or the solvent present in the system (for examples, see refs 10-12). Therefore, the reaction of chlorodifluoromethane with base and an alkene lacks preparative value. The difficulties mentioned above are circumvented in the method using chlorodifluoromethane, oxirane (or chloromethyloxirane), with tetraalkylammonium halide as a catalyst and an alkene (Houben-eyl, Vol. 4/3, p 380 and Vol. E19b, pp 1468-1469). 

The dibromochloromethane (for the preparation, see refs 131, 144) must be of high purity, admixtures of other haloforms result in the formation of dihalocyclopropane mixtures. 

Alkenes of low reactivity such as hex-l-ene, hept-l-ene " and oct-l-ene, give 1-bromo-l-chlorocyclopropanes exclusively (selectivity 100%) with dibenzo-18-crown-6 catalyst, yet a mixture of all dihalocyclopropanes was formed in low yield in the case of 3,3-dimethylbut-l-ene. 1-Bromo-l-chlorocyclopropanes 1 were prepared via the reaction of dibromochloromethane with oxirane, a catalytic amount of tetraethylammonium bromide and an alkene. 

A number of 1,1-dihalocyclopropanes have been reduced electrochemically to monohalides using a mercury cathode in an appropriate solvent containing a supporting electrolyte, e.g. reduction of 38 (Table 4)112,130 ggg j.gj-g 128-130, 132, 133, 745, 758), but few reactions have been carried out on a preparative scale. One exception is 9,9-dibromobicyclo[6.1.0]nonane which is converted stereospecifically to exo-9-bromobicyclo[6.1.0]nonane (39) in better than 80% yield at a mercury cathode at 0°C using methanol as solvent and lithium chloride as supporting electrolyte. A reaction resulting in 17% asymmetric yield is described in ref 886. 

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-... 

Another widely used procedure for preparing cycloproparenes involves the double elimination of 1,2-dihalocyclopropanes. The latter are typically prepared by the cycloaddition of 1,2-dihalocyclopropenes to 1,3-dienes. The resulting cycloadduct containing the 1,2-dihalocyclo-propane moiety is then treated with base to give the product cycloproparene. The special case of cycloproparenes formed from the adducts of l-bromo-2-chlorocyclopropene is covered in the next section. 

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