Alkenes dichlorocyclopropanation

If dichlorocarbene is generated in the presence of an alkene, addition to the double bond occurs and a dichlorocyclopropane is formed. As the reaction of dichlorocarbene with ds-2-pentene demonstrates, the addition is stereospecific, meaning that only a single stereoisomer is formed as product. Starting from a cis alkene, for instance, only cis-disubstituted cyclopropane is produced starting from a trans alkene, only trans-disubstituted cyclopropane is produced. 

The catalytic conditions (aqueous concentrated sodium hydroxide and tetraalkylammonium catalyst) are very useful in generating dihalo-carbenes from the corresponding haloforms. Dichlorocarbene thus generated reacts with alkenes to give high yields of dichlorocyclopropane derivatives,16 even in cases where other methods have failed,17 and with some hydrocarbons to yield dicholromethyl derivatives.18 Similar conditions are suited for the formation and reactions of dibromocar-benc,19 bromofluoro- and chlorofluorocarbene,20 and chlorothiophenoxy carbene,21 as well as the Michael addition of trichloromethyl carbanion to unsaturated nitriles, esters, and sulfones.22... 

Both phase transfer and crown ether catalysis have been used to promote a-elimination reactions of chloroform and other haloalkanes.153 The carbene can be trapped by alkenes to form dichlorocyclopropanes. 

The addition of dichlorocarbene, generated from chloroform, to alkenes gives dichlorocyclopropanes. The procedures based on lithiated halogen compounds have been less generally used in synthesis. Section D of Scheme 10.9 gives a few examples of addition reactions of carbenes generated by a-elimination. 

Compared with the classical procedures, which employ chloroform and dry potassium /ert-butoxide, Makosza s method is several magnitudes superior, in spite of the normally recognized requirements that the dichlorocarbene should be produced under totally anhydrous conditions. Several early reports of the reactions of dichlorocarbene, generated by Makosza s procedure, led to suggestions that the activity of the carbene was considerably greater than that of the classically produced carbenes. This assumption was based on the overall higher yields of dichlorocyclopropanes derived from the reaction with alkenes, and upon the observation that weakly activated alkenes reacted with Makosza carbenes, but not with the classically produced carbenes. A consideration of the mechanism of formation of the carbenes under phase-transfer catalytic conditions exposes the fallacies in the assumptions. 

Alkynes tend to be much less reactive than alkenes. For example, 1,2-diphenylethyne produces only 23% of the dichlorocyclopropene from its reaction with dichlorocarbene, compared with 96% of the dichlorocyclopropane obtained from rrans-stilbene under analogous conditions [4]. Conjugated eneynes react preferentially at the C=C bond with dihalocarbenes [18-20, 22, 38] and with dimethylvinylidene carbene [158],... 

With the exception of the parent compounds, where the Michael adducts are isolated, acrylic esters [see, e.g. 6,7,31,105,111 ] and nitriles [6,7], and vinyl ketones [26, 113, 115] generally yield the cyclopropanes (Table 7.6) under the standard Makosza conditions with chloroform. Mesityl oxide produces a trichlorocyclopropy-lpropyne in low yield (10%) [7]. When there is no substituent, other than the electron-withdrawing group at the a-position of the alkene, further reaction occurs with the trichloromethyl anion to produce spiro systems (35-48%) (Scheme 7.12) [7, 31]. Under analogous conditions, similar spiro systems are formed with a,p-unsaturated steroidal ketones [39]. Generally, bromoform produces cyclo adducts with all alkenes. Vinyl sulphones are converted into the dichlorocyclopropane derivatives either directly or via the base-catalysed cyclization of intermediate trichloromethyl deriva-... 

When no electrophile is present, reduction of carbon tetrachloride leads to di-chlorocarbene by elimination of chloride ion from the trichloromethyl carbanion intermediate. Dichloromethane is the best solvent for this process [79], The car-bene is trapped by reaction with an alkene to form a dichlorocyclopropane (Table... 

In contrast to the bromo and iodo analogs, organic chloro compounds are relatively inert toward organolithium reagents. There are only a few classes of chlorinated substrates, notably gm-dichlorocyclopropanes , l,l-dichloro-l-alkenes ° and doubly vicinal oligochlorobenzenes (1,2,3-trichlorobenzene , 1,2,3,4-tetrachlorobenzene , hexachlorobenzene etc.) that are capable of sustaining the halogen/lithium permutation mode. 

Fig. 3.11. Plausible, but incorrect mechanism of the phase-transfer catalyzed dichlorocyclopropanation of alkenes as often encountered in (close ) analogy to the Bu4N Cl catalyzed Kolbe nitrile synthesis in the two-phase system CH /aqueous solution of NaCN.

Fig. 3.12. Correct mechanism of the phase-transfer catalyzed dichlorocyclopropanation of alkenes.

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. 

Reacts with chloroform in the presence of an alkene to yield a dichlorocyclopropane (Section 7.6). 

Cyclopropanation of alkenes carrying electron-withdrawing groups with dihalo-carbenes does not take place under the normal reaction conditions unless the dihalocar-bene is generated from trihalomethylphenylmercury compounds. By this procedure acrylonitrile was converted into l-cyano-2, 2-dichlorocyclopropane in 78% yield and other acrylic derivatives are transformed into dichloromethyl cyclopropane carboxylates (186) (equation 46). Treatment of electron-deficient olefins with dibromomethane in the presence of Ni(0) complex/Zinc/Lewis acid seems to be very effective for cyclopropanation. ... 

When sodium trichloroacetate is heated in diglyme solution with alkenes, there are formed 1,1-dichlorocyclopropanes. How do you account for this ... 

A carbene, RjC , is a neutral molecule containing a divalent carbon with only six valence electrons. Carbenes are highly reactive toward alkenes, adding to give cyclopropanes, Dichlorocarbene adds to alkenes to give 1,1- dichlorocyclopropanes, Nonhalogenated cyclopropanes are best prepared by treatment of the alkene with CH l2 and zinc-copper alloy—the Simmons-Smith reaction. 

Carbenes, a class of transient organic species, are formally both nucleophilic and electrophilic, although their electrophilicity dominates their reactivity. Carbenes are divalent, six-electron carbon compounds (CR2) with one unshared pair of electrons. You can think of them as CR2 or CR2. (No formal charge is implied by the symbol ) The best-known carbene is CCI2, which is generated from CHCI3 and strong base and is used to make dichlorocyclopropanes from alkenes. Carbon monoxide ( 0=C <—> 0=C ) and isocyanides (R-N=C f—> R-N=C ) can be described as especially stabilized carbenes. Carbenes are discussed in more detail in Chapters 2 and 5. 

As the alcohol is not formed, there is no need to use sterically hindered alkoxides. This reaction is usually carried out in pentane or in an excess of alkene at 0 to 10 °C and is recommended for the preparation of thermally unstable 1,1-dichlorocyclopropanes. An interesting modification for the synthesis of 1,1-dichlorocyclopropanes which eliminates strongly alkaline medium, utilizes trimethylsilyl trichloroacetate and potassium fluoride in the presence of a catalyst (a quaternary ammonium salt or a crown ether),... 

Other methods are also available for the generation of dichlorocarbene which, in the presence of alkenes, forms 1,1-dichlorocyclopropanes, e.g. reaction of chloroform with oxirane, using a quaternary ammonium salt as the catalyst and an alkene (Houben-Weyl, Vol. 4/3, pp 374-381 and Vol. E19b, p 1530).The discovery of new, more convenient and equally efficient methods (especially phase-transfer catalysis) means that older approaches are unused at present. 

However, a new, efficient synthesis of 1,1-dichlorocyclopropanes, e.g. 4, via the reaction of chloroform and magnesium with alkenes has been described. ... 

Many hundreds of examples of 1,1-dichlorocyclopropanes prepared by the addition of dichloro-carbene to alkenes are known. Exhaustive collections of these compounds are reported in refs 28 30. The key problems connected with the cyclopropanation of alkenes are discussed in Houben-Weyl, Vol. E19b, pp 1538-1541, for examples of the formation of 1,1-dichlorocyclo-propanes, see Houben-Weyl, Vol. 4/3, pp 163-165,179,376-379 and Vol. E19b, pp 1528-1529, 1534. 

Of the many methods used for dichlorocyclopropanation of alkenes, the formation of dichlorocarbene from chloroform and base/phase-transfer catalyst and its subsequent reaction with an alkene is strongly recommended. In fact, since inception this method has been the most frequently used for the preparation of 1,1-dichlorocyclopropanes. ... 

Alkenes with a halogen more remote from the double bond yield 1,1-dichlorocyclopropanes usually without difficulties. Some typical examples of these cyclopropanes are collated in Table 12. 

Competitive addition of dichlorocarbene to various alkenes indicates that vinyl ethers are more reactive than I-alkenes.Hence, 2-alkoxy-l,l-dichlorocyclopropanes are usually prepared in good yield. The chloroform/base/phase-transfer catalyst method is the most often used. Substrates very sensitive to aqueous conditions, such as trimethylsilyl vinyl ethers will not, with a high degree of certainty, survive the phase-transfer catalysis conditions, thus other methods are used. ... 

Some examples of the 1,1-dichlorocyclopropanes formed from -alkoxy(or siloxy)alkenes are collected in Table 14. 

Table 14. 1,1 -Dichlorocyclopropanes from co-Alkoxy(or siloxy)alkenes and Dichlorocarbene...

Preparation of 2-acyloxy-l,l-dichlorocyclopropanes via the addition of dichlorocarbene to acyloxyalkenes depends on the structure of the alkene and on the mode of generation of the carbene. Thus, ketone enol esters give cyclopropanes irrespective of the method used for the generation of dichlorocarbene. 

This is rather an unexpected result, since sulfur is a weaker electron donor than oxygen and consequently vinyl sulfides should react slower compared to vinyl ethers if cyclopropanation is considered as a straightforward reaction of dichlorocarbene with an alkene double bond. Therefore, the formation of 2-alkyl(or aryl)sulfanyl-l,l-dichlorocyclopropanes is a multistep process, which starts with the generation of sulfonium ylides via the attack of carbene on the sulfur atom of the vinyl sulfide. The ylide thus formed undergoes 1,3-rearrangement and cyclization or reacts with another molecule of vinyl sulfide and then cyclizes. ... 

The formation of 1,1-dichlorocyclopropanes via cycloaddition of dichlorocarbene to alkenes bearing electron-withdrawing groups depends on ... 

Examples of 1,1-dichlorocyclopropanes (largely selected from the more recent literature) prepared from the alkenes substituted by at least two different substituents, are collected in Table 24. These substituents are joined to vinylic carbons or to carbon atoms more distant from the double bond. These compounds usually form 1,1-dichlorocyclopropane derivatives in good yield, yet some substituted alkenes are known to react in a different, difficult-to-predict manner two examples are described below. 

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