Chloroform, dichlorocarbene from

During the next fifty years the interest in derivatives of divalent carbon was mainly confined to methylene (CHg) and substituted methylenes obtained by decomposition of the corresponding diazo compounds this phase has been fully reviewed by Huisgen. The first convincing evidence for the formation of dichlorocarbene from chloroform was presented by Hine in 1950. Kinetic studies of the basic hydrolysis of chloroform in aqueous dioxane led to the suggestion that the rate-determining step was loss of chloride ion from the tri-chloromethyl anion which is formed in a rapid pre-equilibrium with hydroxide ions ... 

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. 

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. 

The ultrasonic preparation of thioamides from amides and phosphorus pentasulfide by Raucher(51) and of dichlorocarbene from chloroform and potassium hydroxide by Regen(52) are some of the more recent examples of nonmetallie applications. We were surprised to find that ultrasound greatly accelerates the reduction of haloaroma-tics by lithium aluminum hydride, permitting the reaction to be... 

These polystyrene-based catalysts are effective for the cyanide displacements of 1-bromooctane and 1-chlorooctane, and also for the generation of dichlorocarbene from chloroform and aqueous sodium hydroxide, giving quantitative yields of (2,2-dichlorocyclopropyl)benzene from styrene. The catalysts may be recovered simply by filtering the reaction mixture. Unfunctionalized polystyrene does not catalyse these reactions. As well as improving product purification and catalyst recovery, this approach also avoids... 

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]. 

Some a-eliminations have already been discussed, like the formation of dichlorocarbene from chloroform and base. Others will be presented in certain contexts later. 1,3-Eliminations are mentioned in the preparation of 1,3-dipoles such as diazoalkanes or a-diazoketones and nitrile oxides (Chapter 15). Chapter 4 is limited to a discussion of the most important eliminations, which are the alkene-forming, /3-eliminations. Note that /3-Eliminations in which at least one of the leaving groups is removed from a heteroatom are considered to he oxidations. Eliminations of this type are therefore not treated here hut in the redox chapter (mainly in Section 17.3.1). 

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. 

Tetrachloroethylene, a nonflammable solvent widely used in the dry cleaning industry, boils at 121°C and is relatively inert toward electrophilic dichlorocarbene. On generation of dichlorocarbene from either chloroform or sodium trichloroacetate in the presence of tetrachloroethylene, the yield of hexachlorocyclopropane (mp 104°C) is only 0.2-10% (W. R. Moore, 1963 E. K. Fields, 1963). The first ideafor simplifying the procedure was... 

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. ... 

Isonitrile synthesis from primary amines and dichlorocarbene (from chloroform) or dibromocarbene (see 1st edition). 

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. 

Triphase catalysis. Regen has shown that this insoluble resin (1) can serve as a catalyst for certain aqueous phase-organic phase reactions. When the polymer is suspended in a heterogeneous mixture of 1-bromooctane and aqueous sodium cyanide, which is then heated to 110° for 4 hr., 1-cyanooctane is formed in 92% yield. The alkyl halide is unchanged in the absence of (1). The resin also catalyzes the generation of dichlorocarbene from chloroform solutions placed over aqueous sodium hydroxide. If this mixture with (1) and a-methyl-styrene is heated for 40 hr. at 50°, the adduct (2) is obtained in 99% yield. 

Dichlorocarbene. This base is useful for preparation of dichlorocarbene from chloroform. One advantage is that the reaction can be carried out in a homogeneous system (pentane, hexane, THF). Higher temperatures (65°) are necessary than when potassium f-butoxide is used, and the reaction is some-... 

Under strongly basic conditions (generation of dichlorocarbene from chloroform and potassium hydroxide), electrophilic substitution of pyrrole by dichlorocarbene dominates, leading eventually to pyr-role-2-carbaldehyde. In a weakly basic medium (generation of dichlorocarbene by heating sodium tri-chloroacetate), the [2+1] cycloaddition prevails. The primary product eliminates hydrogen chloride to give 3-chloropyridine. 

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... 

Dichlorocarbene can be generated by heating sodium trichloroacetate. Propose a mechanism for the reaction, and use curved arrows to indicate the movement of electrons in each step. What relationship does your mechanism bear to the base-induced elimination of HC1 from chloroform ... 

Benzodiazepines undergo addition of dichlorocarbene, produced from chloroform and sodium hydroxide under phase-transfer conditions (see Houben-Weyl, Vol. El9b, p 1 523 fif) to give 2H-bisazirino[l,2-a 2, Y-d 1,5]benzodiazepines, e.g. formation of 28.301... 

The present method utilizes dichlorocarbene generated by the phase-transfer method of Makosza4 and Starks.5 The submitters have routinely realized yields of pure distilled isocyanides in excess of 40%.6 With less sterically hindered primary amines a 1 1 ratio of amine to chloroform gives satisfactory results. Furthermore, by modifying the procedure, methyl and ethyl isocyanides may be prepared directly from the corresponding aqueous amine solutions and bromoform.7 These results are summarized in Table I. 

Chloroform is more rapidly hydrolyzed with base than dichloromethane or carbon tetrachloride and gives not only formic acid but also carbon monoxide Hine has shown that the mechanism of chloroform hydrolysis is quite different from that of dichloromethane or carbon tetrachloride, though superficially the three reactions appear similar. The first step is the loss of a proton to give CCla , which then loses Cl to give dichlorocarbene CCI2, which is hydrolyzed to formic acid or carbon monoxide. 

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. 

Dichlorocarbenes can be synthesized by the a elimination of hydrogen chloride from chloroform. 

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