Carbene or Carbenoid Additions

Cyclopropanation of carbon-carbon double bonds with methylene can be achieved in several ways. Aside from the carbene or carbenoid additions, activated multiple bonds may be cyclopropanated by reaction with ylides or by a synthetic route via 1-pyrazolines (see Sections III. B and III. D in this chapter, and also Chapter 9). Addition of halocarbenes followed by hydrogenolysis provides a further route for the cyclopropanes (Section V.A). 

A. Carbene or Carbenoid Addition to Stereospecifically Deuterated Alkenes... 

The reaction of Michael acceptors with dimethyloxosulfonium methanide has been extensively explored. " In addition to carbene (or carbenoid) additions (Section 1.2.1.) and the Simmons-Smith method, " (see also Section 1.2.1.1.) this is the most widely utilized method for the introduction of a cyclopropane ring, in good to excellent yield, to a,)S-unsaturated... 

The true and the formal cationic cyclopropyl to allyl rearrangements are of utmost synthetic significance. Requisite cyclopropanes of the structural types 1-5 are readily accessible via dihalocarbene, monohalocarbene, or methylene additions (see Section l.A.1.2. and Houben-Weyl, Vol. E19b) to various alkenes. These carbene or carbenoid additions are compatible with a wide range of functional and nonfunctional substituents on the alkenes. 

Those reactions that have found general use for the preparation of aziridines can be grouped into two broad classes addition and cyclization processes, and each of these categories can be further divided. Addition processes can be classified as being C2+N1 reactions (addition of nitrenes, or nitrene equivalents [ nitrenoids ], to alkenes Scheme 4.1) or (J N1+C1 reactions (addition of carbenes or carbenoids to imines Scheme 4.2). 

Which isomer is predominantly formed depends on R, R, and on the method by which the carbene or carbenoid is generated. Most studies have been carried out on monosubstituted species (R = H), and in these studies it is found that aryl groups generally prefer the more substituted side (syn addition) while carbethoxy groups usually show anti stereoselectivity. When R = halogen, free halocarbenes show little or no stereochemical preference, while halocarbenoids exhibit a preference for syn addition. Beyond this, it is difficult to make simple generalizations. 

The earlier examples of [2 + 1] cycloaddition of a carbene (or carbenoid) on the double bond of alkylidenecyelopropanes to yield spiropentane derivatives were observed as undesired side reactions in the synthesis of alkylidenecyelopropanes through the addition of a carbene to a substituted allene [161]. In some cases the spiropentane derivative was obtained as the major product [161a, c] especially when a large excess of the carbene reagent was used. For example, when methyl 3,4-pentadienoate (610) was treated with a ten-fold excess of methylene iodide and zinc-copper couple the two products 611 and 612 were isolated in 1 4.5 ratio (Scheme 86) [161a]. 

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

The discovery of carbene and carbenoid additions to olefins was the major breakthrough that initiated the tapping of this structural resource for synthetic purposes. Even so, designed applications of cyclopropane chemistry in total syntheses remain limited. Most revolve around electrophilic type reactions such as acid induced ring opening or solvolysis of cyclopropyl carbinyl alcohol derivatives. One notable application apart from these electrophilic reactions is the excellent synthesis of allenes from dibromocyclopropanes 2). 

Intramolecular carbene addition reactions have a special importance in the synthesis of strained ring compounds. Because of the high reactivity of carbene or carbenoid species, the formation of highly strained bonds is possible. The strategy for synthesis is to construct a potential carbene precursor, such as diazo compounds or di- or trihalo compounds, which can undergo intramolecular addition to the desired structure. Section E of Scheme 10.5 gives some representative examples. 

All-carbon 2 + 3 cycloadditions 5-49 Dimerization of olefins 5-50 Addition of carbenes or carbenoids to olefins or alkynes 5-51 Tetramerization of alkynes... 

The addition of fluorinated carbenes or carbenoids to alkenes and alkynes... 

The most generally employed approach for the formation of cyclopropanes is the addition of a carbene or carbenoid to an alkene. In many cases, a free carbene is not involved as an actual intermediate, but instead the net, overall transformation of an alkene to a cyclopropane corresponds, in at least a formal sense, to carbene addition. In turn, the most traditional method for effecting these reactions is to employ diazo compounds, R R2 —N2, as precursors. Thermal, photochemical and metal-catalyzed reactions of these diazo compounds have been studied thoroughly and are treated separately in the discussion below. These reactions have been subjects of several comprehensive reviews,8 to which the reader is referred for further details and literature citations. Emphasis in the present chapter is placed on recent examples. 

When the carbene or carbenoid resulting from a dihalocyclopropane is unable to rearrange to the al-lene due to steric or other factors, insertion or addition reactions characteristic of carbenes take place. Thus dibromonorcarane on reaction with methyllithium gives a bicyclobutane derivative by insertion of the carbene into a 0-C—H bond (equation 57).178 Allene formation is sterically unfavorable in this case. Similarly, dibromotetramethylcyclopropane gives l,2,2-trimethylbicyclo[1.1.0]butane instead of tetra-methylallene (equation 58).179 181 An example involving a tricyclic dibromocyclopropane is given in equation (59).182... 

The availability of phosphaalkenes and phosphaalkynes has led to a further route for the synthesis of phosphiranes and phosphirenes by the formal addition of carbenes or carbenoides to P-C multiple bonds. An example already depicted in Scheme 6 involved in the [2+1] cycloaddition reaction of a stable phosphinotrimethylsilylcarbene to tert-butylphosphaalkyne <1995JA10785, 1999CEJ274>. A carbenoid was also used in the synthesis of an unusual phosphirene from a siloxy-substituted phosphaalkene (Equation 30) <1997JOM(529)127>. 

The most commonly used methods for the synthesis of cyclopropenes fall into three categories. The addition of a carbene (or carbenoid) to an alkyne constructs the ring in a single step by the formation of two [Pg.1226]

A number of 1,1-diheteroatom-substituted cyclopropanes have been prepared by the addition of one-carbon fragments (carbenes or carbenoids) to olefins. Since the geminally... 

In a large number of carbene and carbenoid addition reactions to alkenes the thermodynamically less favored syn-isomers are formed 63). The finding that in the above cyclopropanation reaction the anti-isomer is the only product strongly indicates that the intermediates are organonickel species rather than carbenes or carbenoids. Introduction of alkyl groups in the 3-position of the electron-deficient alkene hampers the codimerization and favors isomerization and/or cyclodimerization of the cyclopropenes. Thus, with methyl crotylate and 3,3-diphenylcyclopropene only 16% of the corresponding vinylcyclopropane derivative has been obtained. 2,2-Dimethyl acrylate does not react at all with 3,3-dimethylcyclopropene to afford frons-chrysanthemic add methyl ester. This is in accordance with chemical expectations 69) since in most cases the tendency of alkenes to coordinate to Ni(0) decreases in the order un-, mono-< di- < tri- < tetrasubstituted olefines. 

Monoaddition of carbenes or carbenoids to allenes (Route d) has also been achieved, but addition of two carbenes to give spiropentane derivatives is difficult to avoid. Examples of successful applications of this approach are dihalocarbene additions to substituted allenes123) (Eq. 62) to give dihalomethylenecyclopropanes in good yields. 

Chloro(cycloalkyl)carbenes (or carbenoids) undergo addition to alkenes to give 1-chloro-l-cycloalkylcyclopropanes. Two methods for the synthesis of these products are known ... 

Reaction of bromofluorophenylmethane (for a preparation see ref 118) and potassium tert-butoxide with an alkene afforded l-fluoro-l-phenylcyclopropanes (Houben-Weyl, Vol.4/3, p233 Vol. E19b, p980). To identify the reacting species, e.g. carbene or carbenoid, the reaction was carried out without and with an equimolar amount of 18-crown-6. ° Alternatively, chlorofluorophenylmethane, in place of the bromo derivative, can be used. Reactions with bromofluorophenylmethane were performed at 25 °C (sealed tube), whilst those with chlorofluorophenylmethane at 60-80 °C. Addition of fluoro(phenyl)carbene to alkenes is at least 98% stereospecific e.g. formation of . ... 

The addition of carbenes or carbenoids to 1,1-dioxygenated alkenes provides access to cyclopropanone acetals or related compounds. ... 

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