Carbenes, from chloroform

The Ciamician-Dennstedt reaction involves the reaction of a pyrrole (1) with the carbene generated from chloroform and a base to provide a 3-chloropyridine (2, Scheme 8.3.1). 

PTC has been extensively used for making cyclopropyl derivatives. The most common reaction involves generation of dichlorocarbene from chloroform, using NaOH and a quaternary ammonium hydroxide. The carbene subsequently reacts with an alkene in high yield. Hydrolysis of dichlorocarbene, normally rapid in the presence of water, is minimal. An interesting and very efficient example of a Michael addition to produce a cyclopropyl derivative is shown in Scheme 4.26. 

Carbenes from Halides by a-Elimination. The a-elimination of hydrogen halide induced by strong base (Scheme 10.8, Entry 4) is restricted to reactants that do not have (3-hydrogens, because dehydrohalogenation by (3-elimination dominates when it can occur. The classic example of this method of carbene generation is the generation of dichlorocarbene by base-catalyzed decomposition of chloroform.152... 

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. 

Section D illustrates formation of carbenes from halides by a-elimination. The carbene precursors are formed either by deprotonation (Entries 14 and 17) or halogen-metal exchange (Entries 15 and 16). The carbene additions can take place at low temperature. Entry 17 is an example of generation of dichlorocarbene from chloroform under phase transfer conditions. 

From Chapter 7 it is apparent that the trichloromethyl anion is formed under basic conditions from chloroform, as a precursor of the carbene. The anion can also react with Jt-deficient alkenes (see Section 7.3) and participate in nucleophilic substitution reactions, e.g. 1,1-diacyloxy compounds are converted into 1,1,1-trichloroalkan-2-ols [58] (Scheme 6.35). Similarly, benzyl bromides are converted into (2-bromoethynyl)arenes via an initial nucleophilic displacement followed by elimination of hydrogen bromide [59] (Scheme 6.35). 

Compared with primary and secondary amines, tertiary amines are virtually unreac-tive towards carbenes and it has been demonstrated that they behave as phase-transfer catalysts for the generation of dichlorocarbene from chloroform. For example, tri-n-butylamine and its hydrochloride salt have the same catalytic effect as tetra-n-butylammonium chloride in the generation of dichlorocarbene and its subsequent insertion into the C=C bond of cyclohexene [20]. However, tertiary amines are generally insufficiently basic to deprotonate chloroform and the presence of sodium hydroxide is normally required. The initial reaction of the tertiary amine with chloroform, therefore, appears to be the formation of the A -ylid. This species does not partition between the two phases and cannot be responsible for the insertion reaction of the carbene in the C=C bond. Instead, it has been proposed that it acts as a lipophilic base for the deprotonation of chloroform (Scheme 7.26) to form a dichloromethylammonium ion-pair, which transfers into the organic phase where it decomposes to produce the carbene [21]. 

Dichlorocarbene, produced under basic conditions from chloroform (7.1.1) reacts with ri.y,fran.r,fran.y-cyclododeca-l,5,9-triene to produce the mono-, bis- and tris-insertion adducts, depending on the reaction conditions and the catalyst used [65, 67]. Early claims that the carbene is activated by the hydroxyethylammonium... 

Problem 9.24 The carbene iCCl generated from chloroform, CHCI, and KOH in the presence of alkenes gives substituted cyclopropanes. Write the equation for the reaction of CClj and propene. <... 

In the course of a study on organic functionalization of CNTs, Haddon s group discovered in 1998 that dichlorocarbene was covalently bound to soluble SWCNTs (Scheme 1.18) [97]. Originally, the carbene was generated from chloroform with potassium hydroxide [79a] and later from phenyl(bromodichloromethyl)mercury [97]. However, the degree of functionalization was as low as 1.6 at. % of chlorine only, determined by XPS [153],... 

Hydroxide and alkoxide anions are strong enough bases to promote a elimination from chloroform, and from other trihalomethanes. Carbenes can be formed from dihaloalkanes by deprotonation with stronger bases such as LDA, and even from primary alkyl chlorides using the extremely powerful bases phenylsodium or f-BuLi/f-BuOK (weaker bases just cause P elimination). 

The two classical methods used for generating carbenes are the a-eliminatiun reactions of halogen compounds and the decomposition of diazo compounds. The generation of dichlorocarbene from chloroform under basic conditiorts or from HgCCl2Br by thermal decomposition is a classical example of the first method. 

German chemists have used the method successfully for preparation of dichloro-cyclopropanes from olefins which yield little or no products when the dichlorocarbene is generaied from chloroform and potassium /-bntoxide. TTiey also generated dibromo-carbene in the same way. Cyclopropcnes are obtained in only low yields from acetylenes owing to side reactions. 

The base removes the acidic proton from chloroform. The resulting anion then loses chloride ion, giving a divalent carbon with two unshared electrons. In this case, the unshared electrons are paired (occupy the same orbital), i.e., dichlorocarbene is a singlet. The carbon of the carbene has no charge. 

Unsaturated compounds possessing an allylic C-H bond(s) are prone to insertion of dichlorocarbene, aside from the addition of dichlorocarbene to the double bond. This reaction occurs, in particular, more frequently if the dichlorocarbene is generated from chloroform by phase-transfer catalysis or from dichlorohalomethyl(phenyl)mercury. Thus, careful investigation reveals that, in contrast to earlier findings, 9,10-octalin forms both carbene addition 1 and insertion 2 products in comparable yields." ... 

Furthermore, /8-cyclodextrin shows superb selectivity in the syntheses of 2.5-cyclohexadienones (12), which are important starting materials for the syntheses of physiologically active compounds, from / -substituted phenols, chloroform, and sodium hydroxide (Scheme 7) [25]. The selectivity of the production of 12 in the presence of /8-cyclodextrin is virtually 100%, in contrast to the formation of large amounts (about 4-8 times as large as 12) of ori/jo-formulated compound 13 in its absence. The remarkable selectivity in the present reaction is probably due to the formation of dichlorocarbene from chloroform and hydroxide ion in the cavity of /8-cyclodextrin. The / ara-substituted phenol should approach the cavity (and thus the carbene) from the side involving the para-ca.rhon, resulting in a selective reaction. The penetration of this apolar side in the apolar cavity should be more favorable than the penetration of the polar side by the phenoxide atom. 

No matter how they are generated, carbenes and carbenoids undergo four typical reactions. The most widely used reaction is cyclopropanation, or addition to a TT bond. The mechanism is a concerted [2 + 1] cycloaddition (see Chapter 4). The carbenes derived from chloroform and bromoform can be used to add CX2 to a 7T bond to give a dihalocyclopropane, while the Simmons-Smith reagent adds CH2. Carbenoids generated from diazoalkanes with catalytic Rh(II) or Cu(II) also undergo cyclopropanations. 

Carbene reaction under PTC conditions. Reaction of dichlorocarbene generated from chloroform and alkali with benzaldehyde to yield mandelic acid. Subsequent hypochlorite oxidation of methyl mandelate and esterification to form metamitron. 

There are also elimination reactions in which the two departing groups are not located on adjacent atoms. In a 1,1-elimination (a-elimination), the two leaving groups are bonded to the same atom, so a carbene is produced (Figure 10.3). A specific example is the base-promoted S5mthesis of dichlor-ocarbene from chloroform (equation 10.1). 

Method using Base and a Substituted Halogenomethane. The influence of catalyst anions (as their tetrabutylammonium salts) and cations (as chlorides or bromides) on the generation of dichlorocarbene from chloroform-sodium hydroxide has been studied under standard conditions by determining the yield of dichloronorcarane produced from the addition of the carbene to cyclohexene. The presence of olefin appears to be necessary since in its absence only very slow decomposition of the trichloromethyl anion occurs. Dehmlow has also devised a new procedure for phase-transfer-catalysed cyclopropanation. Treatment of an alkene (or cycloalkene) with sodium trichloroacetate and a tetra-alkylammonium salt in chloroform without... 

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