Generation of Dichlorocarbene

N-Ethylpiperidine, 43,45 Ethyl-o-toluidine, 43,47 Ethyl trichloroacetate for generation of dichlorocarbene, 41, 76... 

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... 

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. 

Sodium iodide, in conversion of 2,4-di-nitrochlorobenzene to 2,4-dinitro-iodobenzene, 40, 34 reduction of peroxide with, 41, 41 Sodium methoxide, 41, 85 for generation of dichlorocarbene, 41 76... 

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... 

Alternative procedures for the generation of dichlorocarbene and dibromocarbene under phase-transfer catalysed conditions are also available. Where the reactive substrate is labile under basic conditions, the thermal decomposition of solid sodium trichloroacetate or bromoacetate under neutral conditions in an organic solvent is a valuable procedure [10-12], The decarboxylation is aided by the addition of a quaternary ammonium salt, which not only promotes dissolution of the trihaloacetate anion in the organic solvent, but also stabilizes the trihalomethyl anion. Under optimum reaction conditions, only a catalytic amount of the quaternary ammonium salt is required, as a large amount of the catalyst causes the rapid generation of the dichlorocarbene with resultant side reactions. 

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]. 

The generation of dichlorocarbene for addition to olefins has been realized by the use of chloroform and alkali metal alk-oxides4 6 (preferably potassium feri-butoxide), sodium trichloro-acetate,6 butyllithium and bromotrichloromethane,7 and the reaction of an ester of trichloracetic acid with an alkali metal alkoxide.2,8 The latter method, which is here illustrated by the preparation of 2-oxa-7,7-dichloronorcarane, generally gives higher yields of adducts. 

The dichloromethyl derivative 20 is isolated (10%) from 3,4,5-trimethyI-pyrazole and chloroform in the presence of sodium ethoxide generation of dichlorocarbene by thermolysis of sodium trichloroacetate does not give any 4/Z-pyrazole.30 The same product is formed, in lower yield, using chloroform and base with a phase-transfer catalyst.31... 

Generation of dichlorocarbene and its addition to an alkene in a two-phase system proceeds somewhat differently. Here a solution of an alkene in chloroform forms the organic phase the other is concentrated aqueous NaOH. The first step, deprotonation of chloroform, occurs at the phase boundary then the trichloromethyl anion formed at the phase boundary enters the organic phase in the form of ion pairs with Q+. Inside the organic phase the anions dissociate reversibly to dichlorocarbene and Q+C1 exchanges anions at the phase boundary so that Cl passes into the aqueous phase and another trichloromethyl anion into the organic phase. Anions are transferred to the organic phase not from the aqueous phase but from the phase boundary. Reference 5 contains additional details. 

Undoubtedly the most important and widely used procedure for the generation of dichlorocarbene involves the reaction of chloroform with aqueous sodium hydroxide under the conditions of phase transfer catalysis (PTC), introduced by Makosza.20-22 Under these conditions chloroform reacts with sodium hydroxide to form sodium trichloromethylide which on exchange with a quaternary ammonium salt, usually benzyltriethylammonium chloride, is converted to the unstable quaternary ammonium methylide which dissociates in the organic phase to give dichlorocarbene. The dichlorocarbene irreversibly adds to the alkene (Scheme 1). 

Dichlorocarbene is the reactive intermediate formed by the reaction of alkali on chloroform, and typically it adds to olefins to give 1,1-dichlorocyclo-propanes. The PTC procedure for the generation of dichlorocarbene is particularly useful and is illustrated by its reaction with cyclohexene to form (38) (Expt 7.15). The mechanism is formulated below and probably involves the reaction of the quaternary ammonium hydroxide with chloroform at the phase boundary, and dissolution into the organic phase of the quaternary ammonium derivative of the trichloromethyl anion (41). This species breaks down to form dichlorocarbene and the quaternary ammonium chloride. The latter returns to the aqueous phase to maintain the cycle of events, while the dichlorocarbene reacts rapidly with the cyclohexene in the organic phase. 

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. 

Dichlorocarbene addition to aikenes. Dehmiow and LisseP have examined the reaction variables in the generation of dichlorocarbene by PTC. Optimal conditions include use of 4 molar excess each of CHCI3 and 50% aqueous NaOH, 1 mole % of catalyst, and efficient stirring. The reaction should be conducted initially at 0-5°, then at 20° for 1-2 hours, and finally at 50° for 2-4 hours. Most quaternary ammonium salts are suitable as catalysts the anions should be chloride or hydrogen sulfate. From the point of cost/efficiency, the most useful are benzyltriethylammonium chloride, tetra-n-butylammonium chloride, Aliquat 336, and tri-n-propylamine. The reaction rate is strongly dependent on the nucleophilicity of the alkene. 

While some of the aforementioned transformations of 3 and its derivatives are in a way similar to those described earlier e.g. in the adamantane series), a number of reactions of 3 have little precedence. For example, it was truly surprising to discover that 3 turned out to be very reactive towards dichlorocarbene. As a result, the respective dichloromethyl derivative 29 can be formed in a very good yield under conventional conditions of phase transfer generation of dichlorocarbenes. Subsequent treatment of adduct 29 with tert-butyllithium leads to cyclopropadodecahedrane 30. Thus, the formation of 30 from 3 implies the sequence of two consecutive C-H insertions of carbene-like species (Scheme 4.7). 

The method was used by Japanese chemists for generation of dichlorocarbene for reaction with adamantane (I) to give 1-dichloromcthyladamantane (2) yield 54%,... 

Indian chem ists report that other cationic agents are even more eflicient for generation of dichlorocarbene, for example, cetyltrimethylammonium chloride and an Indian detergent sold under the trademark Cetrimide. Starks" has used in the same way a tricaprylylmethylammonium chloride, " in which the alkyl groups are a mixture of Cs"C,2 straight chains. 

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... 

An interesting reaction was observed on phase-transfer generation of dichlorocarbene in the presence of mono- and 1,2-disubstituted hydrazines and dimethyl maleate. In this case the initially formed ammonium ylide 511 transforms to azomethine imine 512 followed by 1,3-dipolar cycloaddition to an olefin providing pyrazolines 513 96ISV(ip). 

Dichlorocarbene. Polish chemists have reported a new method for generation of dichlorocarbene (or a carbenoid species) it involves the reaction of an olefin with chloroform in the presence of a 50 % aqueous NaOH solution and a catalytic amount of benzyl-triethylammonium chloride. For example, dichloronorcarane was obtained from cyclohexene in this way in 72% yield. In the absence of the catalyst, a yield of only 0.5% has been reported.2... 

---