Addition of Carbenes to Alkenes Cyclopropane Synthesis

Thomson iOW Click Organic Interactive to use a web-based palette to predict products of the addition of various carbenes to alkenes. 

Yet another kind of alkene addition is the reaction of a carbene with an alkene to yield a cyclopropane. A carbene, R2C , is a neutral molecule containing a divalent carbon with only six electrons in its valence shell. It is therefore highly reactive and is generated only as a reaction intermediate, rather than as an isolable molecule. Because they re electron-deficient, carbenes behave as electrophiles and react with nucleophilic C=C bonds. The reaction occurs in a single step without intermediates. 

Mechanism of the formation of dichlorocarbene by reaction of chloroform with strong base. 

ThomsonNOW Click Organic Process to view an animation of the mechanism for the addition of dichlorocarbene to alkenes. 

O Base abstracts the hydrogen from chloroform, leaving behind the electron pair from the C-H bond and forming the trichloromethanide anion. 

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. 

I Spontaneous loss of chloride ion then yields the neutral dichlorocarbene. 

Mechanism of the formation of dichlorocarbene by reaction of chloroform with strong base. Deprotonation of CHCI3 gives the trichloromethanide anion, CCl3, which spontaneously expels a Cl ion. 

FIGURE 8.10 The structure of dichlorocarbene. Electrostatic potential maps show howthe positive region (blue) coincides with the empty p orbital in both dichlorocarbene and a carbocation (GHj ). The negative region (red) in the dichlorocarbene map coincides with the lone-pair electrons. 

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Addition of Water to Alkenes Oxymercuration 239 Addition of Water to Alkenes Hydroboration 242 Addition of Carbenes to Alkenes Cyclopropane Synthesis Reduction of Alkenes Hydrogenation 249... 

Reactions involving free carbenes are very exothermic since two new theoretical treatment of the addition of singlet methylene to ethylene suggests that there is no activation barrier.168 The addition of carbenes to alkenes is an important method for synthesis of many types of cyclopropanes and several of the methods for carbene generation listed in Scheme 10.8 have been adapted for use in synthesis. Scheme 10.9, at the end of this section, gives a number of specific examples. 

The formation of cyclopropanes by the addition of carbenes to alkenes was first reported by Doering and Hoffmann in 1954/ Since then, this most characteristic reaction of carbenes has been successfully exploited for the synthesis of cyclopropanes. The cyclopropane ring system is not only found as a structural element in a wide range of natural products, but is also a very useful synthetic intermediate leading to a variety of cyclic and acyclic compounds. ... 

The addition of carbenes to alkenes is an important method for synthesis of many types of cyclopropanes and several of the methods for carbene generation listed in Scheme 9.1 have been adopted for use in synthesis. A number of specific synthetic examples are given in Scheme 9.2. 

The most common application of carbenes in synthesis is in the formation of three-membered rings by addition to multiple bonds. This is a typical reaction of all carbenes that do not undergo intramolecular insertion. Generation of the carbene in the presence of an alkene gives a cyclopropane product. Addition of halocarbenes to alkenes is a stereospecific cis reaction, but this is not necessarily the case with all carbenes. Hence Z-2-butene 109 gives the cyclopropane 110, in which the two methyl groups remain cis to one another (4.86). The stereospecificity... 

The synthesis of fluorinated cyclopropanes has been achieved via the addition of fluorinated carbenes to alkenes and via the addition of nonfluorinated carbenes to fluorinated alkenes. 

Due to a growing interest in poly-spirocyclopropanes (triangulanes), a general approach to their synthesis has been developed. It consists of the addition of chlorofmethyl)-carbene to an alkene, the dehydrochlorination of the product 1-chloro-l-methylcyclopropane to a methylenecyclopropane, which is then submitted to cyclopropanation. The chloro(methyl)spiroalkanes 2 have been prepared utilizing this approach. 

As with other diazoalkanes, diazomethane reacts with alkenes to form cyclopropane derivatives (sec. 13.9.C.i).272 Reaction with aromatic derivatives leads to ring expansion to cycloheptatriene derivatives.223 Both of these reactions (addition to an alkene or arene insertion) involve generation of an intermediate carbene and addition to a jt bond they will be discussed below. Many of the reactions of diazomethane tend to be ionic in nature and are, therefore, set aside from the other diazoalkane chemistry in this section. One of the commonest uses of diazomethane itself is esterification of small quantities of acids, especially acids that are precious for one reason or another. The reaction is quantitative and gives good yields of a single product, as in Tadano s conversion of 338 to the methyl ester of 339224 in a synthesis of (-)-verrucarol. 

The addition to alkenes is the most important reaction of carbenes first, because it is the simplest synthesis of cyclopropanes (particularly if carbenoids are used, see Sect. 8.7), and, second, it has been very well studied mechanistically. 

Although the Simmons-Smith reaction has found considerable use in organic synthesis, it is not readily applicable to the formation of highly substituted cyclopropanes, since 1,1 -diiodoalkanes (other than diiodomethane) are not readily available. Substituted zinc carbenoids can be prepared from aryl or a,p-unsaturated aldehydes (or ketones) with zinc metal, and these species can be trapped with an alkene to give substituted cyclopropanes.The addition of chromium carbenes (see Section 1.2.2) to alkenes can be used to effect cyclopropanation to give substituted cyclopropanes. Thus, addition of excess 1-hexene to the chromium carbene 113 gave the cyclopropane 114 as a mixture of diastereomers, with the isomer 114 predominating (4.92). ... 

Cyclopropanations of alkenes with alkyl diazoacetates are catalysed by rhodium(ii) carboxylates, and Sasaki et al have shown that crown ethers have several advantages over quaternary ammoniurq ions for the catalytic synthesis of allene-cyclopropanes from addition of allene-carbenes to olehnic substrates. 

The addition of dichlorocarbene, generated from chloroform, to alkenes is a useful synthesis of cyclopropanes. The procedures based on lithiated halogen compounds have been less generally used in synthesis. Section D of Scheme 10.6 gives a few examples of addition reactions of carbenes generated by a elimination. 

The carbene derived by metal-catalysed decomposition of ethyl diazoacetate attacks alkenes to introduce a two-carbon fragment into a cyclopropane—an industrial synthesis of ethyl chrysanthe-mate, a precursor to the pyrethrin insecticides (see p. 000), uses this reaction. The diene in the starting material is more nucleophilic (higher-energy HOMO see Chapter 20) than the single alkene in the product, so the reaction can be stopped after one carbene addition. 

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