Dichlorocarbene phase-transfer catalysis

Contents Introduction and Principles. - The Reaction of Dichlorocarbene With Olefins. - Reactions of Dichlorocarbene With Non-Olefinic Substrates. -Dibromocarbene and Other Carbenes. - Synthesis of Ethers. - Synthesis of Esters. - Reactions of Cyanide Ion. - Reactions of Superoxide Ions. - Reactions of Other Nucleophiles. - Alkylation Reactions. - Oxidation Reactions. - Reduction Techniques. - Preparation and Reactions of Sulfur Containing Substrates. -Ylids. - Altered Reactivity. - Addendum Recent Developments in Phase Transfer Catalysis. 

Various synthetic routes to isocyanides have been reported since their identification over 100 years ago.8 Until now, the useful synthetic procedures all required a dehydration reaction8-11 Although the carbylamine reaction involving the dichlorocarbene intermediate is one of the early methods,8 it had not been preparatively useful until the innovation of phase-transfer catalysis (PTC).4 5... 

The phase-transfer catalysis method has also been utilized effectively for addition of dichlorocarbene to olefins,4 as well as for substitution and elimination reactions, oxidations, and reductions.18 The preceding procedure in this volume is another example.13... 

In addition, there are a few examples of heterogeneous nonaqueous sonochemistry, in both liquid-liquid and liquid-solid systems. Two recent reports have utilized ultrasonic agitation in place of or along with phase transfer catalysis for the preparation of dichlorocarbene from aqueous NaOH/CHCl3 (166), and for N-alkylation of amines with alkyl halides (167). Along the same lines, several papers have appeared in which... 

Di Cesare and Gross175 introduced a procedure using phase-transfer catalysis to induce the action of dichlorocarbene on various protected sugars,176 and obtained the chloro derivative 162c from compound 161. Another, similar migration was observed,178 and confirmed,134,174 for the chlorination of methyl 2,3-anhydro-4,6-0-benzylidene-a-D-al-lopyranoside (166) with (chloromethylene)dimethyliminium chloride, which gave the rearranged chloro derivative 167. 

Systematic studies of the dicyclopropanation of olefinic sugars have been published [194], Dichlorocarbene, generated under phase-transfer catalysis reacts with 2,3-unsaturated pyranosides, such as 161 to yield a single isomer of the expected cyclopropane 162 (Scheme 55). A typical procedure is given in Section IE. The reaction is also possible with an enol... 

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). 

Scheme 1.6 Addition of dichlorocarbene to styrene by phase transfer catalysis [16c].

Figure 3.11 illustrates a scenario where OH ions are transported from the aqueous into the chloroform phase by tetraalkylammonium cations. There, the tetraalkylammonium hydroxide is the base and is available for deprotonation in the entire chloroform phase—a process that was previously limited to just the interface. The C13C so formed could undergo fragmentation to dichlorocarbene, which could then add to the alkene to be cyclopropanated. This scenario provides a plausible explanation of the reaction mechanism for dichlorocyclo-propanations, which in practice are usually performed under phase-transfer catalysis (cf. Figure 3.13 for an example). 

Phase Transfer Catalysis—Reaction of Dichlorocarbene with Cyclohexene... 

The reaction involving dichlorocarbene also provides a wide range of epoxides, " including terminal. a.a- and a,p-dialkyl-substituted and tiialkyl-substituted compounds, from a large variety of 3-hy-drcxyalkyl methyl and phenyl selenides (Scheme 162, d). The thallous ethoxide reaction, although it takes place more slowly (especially with phenylseleno derivatives) than under phase transfer catalysis condirions, " has to be in several instances preferred since it avoids the concomitant formation of... 

The preparation of orthoformic acid esters from chloroform and alkali metal alkoxides is a long known procedure, " which can be performed under phase transfer catalysis. If small amounts of alcohol are present in the phase-catalyz process, cyclopropanes (372 Scheme 67) can be produced by aHHifinn of dichlorocarbene to l,2-dialkoxy-l,2-dichloroethylenes, which are thought to be intermediates. " Al-kenes of this kind, e.g. (373 equation 176), have been observed as byproducts in the synthesis of tri-r-butylorthoformate from chlorodifluoromethane or dichlorofluoromethane and potassium r-butoxide. Trimethoxyacetonitrile was prepared from trichloroacetonitrile and sodium methoxide. ... 

Surprisingly, with dichlorocarbene generated by another method (ther-mocatalytic decomposition of sodium trichloroacetate instead of alkaline hydrolysis of chloroform under phase-transfer catalysis conditions) N-(p-R-benzylidene)-feH-butylamines 55 (R = H, Cl) give 3,3-dichloroazetidi-... 

Cycloimmonium ylides, prepared by interaction of a substituted pyridine with dichlorocarbene generated under phase-transfer catalysis condi-... 

Reaction of piperidone 145 with dichlorocarbene under phase-transfer catalysis conditions affords a mixture of 146 and 147 in 85-90% yields (80JOC1513, 80TL119) with the ratio determined by the catalyst (80JOC1513). The reaction presumably occurs via dichlorocarbene addition onto the carbonyl group of 145 followed by rearrangement with ring contraction. 

Chlorofluorocarbene generated under phase-transfer catalysis conditions undergoes addition not only to the double bond of enynes (as dichlorocarbene usually does, see Section 1.2.1.4.2.1.4.) but also to the triple bond chlorofluorocyclopropenes thus formed hydrolyze to the corresponding cyclopropenones. If the double bond is sterically crowded, for example, by the presence of a tert-butyl group, chlorofluorocarbene exclusively attacks the triple bond (see Houben-Weyl, Vol. E19b, p 1495). Typical examples 3-6 are given. 

Other methods are also available for the generation of dichlorocarbene which, in the presence of alkenes, forms 1,1-dichlorocyclopropanes, e.g. reaction of chloroform with oxirane, using a quaternary ammonium salt as the catalyst and an alkene (Houben-Weyl, Vol. 4/3, pp 374-381 and Vol. E19b, p 1530).The discovery of new, more convenient and equally efficient methods (especially phase-transfer catalysis) means that older approaches are unused at present. 

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." ... 

It is often difficult to make a comparison between the various results obtained for the same polyenes as different reaction conditions (ratio of reactants, temperature, time) were used in each case. The addition of dichlorocarbene (chloroform/base/phase-transfer catalysis) to straight chain and cyclic unconjugated di- and trienes, carried out under identical conditions but varying the catalysts, showed the peculiar properties of tetramethylammonium chloride. Under precisely tailored conditions, either highly selective mono- or polyaddition of dichlorocarbene to the polyenes is possible tetramethylammonium chloride was the most efficient catalyst for monocyclopropanation. (For the unusual properties of tetramethylammonium salts on the phase-transfer catalyzed reaction of chloroform with electrophilic alkenes see Section 1.2.1.4.2.1.8.2. and likewise for the reaction of bromoform with allylic halides, see Section 1.2.1.4.3.1.5.1.). For example, cyclopropanation of 2 with various phase-transfer catalysts to give mixtures of 3, 4, and 5, ° of 6 to give 7 and 8, ° and of 9 to give 10 and 11. °... 

Attempted 1,4-cycloaddition of dichlorocarbene with 1,3-diphenylisobenzofuran was unsuccessful (Houben-Weyl, Vol.E19b, pi562). The formation of 8,8-dichloro-2-(2-phenylethyl)-2,3-dihydro-l,3-methano-l//-isoindole-l-carbonit ile (31) by the reaction of chloroform with isoindole derivative 30 under phase-transfer catalysis conditions has probably been misinterpreted as 1,4-addition of dichlorocarbene.This reaction may involve the Michael addition of trichloromethyl anion to isoindole followed by the cyclization of the adduct. 

Competitive addition of dichlorocarbene to various alkenes indicates that vinyl ethers are more reactive than I-alkenes.Hence, 2-alkoxy-l,l-dichlorocyclopropanes are usually prepared in good yield. The chloroform/base/phase-transfer catalyst method is the most often used. Substrates very sensitive to aqueous conditions, such as trimethylsilyl vinyl ethers will not, with a high degree of certainty, survive the phase-transfer catalysis conditions, thus other methods are used. ... 

Dichlorocarbene reacts with tetrakis(vinyloxymethyl)methane to form all four possible adducts using the chloroform/potassium tert-butoxide method the monoadduct 12 was the predominant product, while with a large excess of chloroform under the conditions of phase-transfer catalysis, the tetraadduct 13 predominated. 

Cyclic allylic alcohols fairly easily cycloadd dichlorocarbene, particularly if generated under chloroform/base/phase-transfer catalyst conditions. Five- and six-membered-ring allylic alcohols form a mixture of cis- and fran.v-isomers, while those of larger rings form only the trans-isomer. In contrast with the phase-transfer catalysis method, dichlorocarbene generated from bromodichloromethyl(phenyl)mercury did not add to cyclohex-3-en-1 -ol, while cyclonon-3-en-l-ol yielded exo-10,10-dichlorobicyclo[7.1.0]decan-2-ol (28 /o), which could not be purified. Examples of dichlorocarbene adducts to cyclic allylic alcohols are presented in Table 19. 

Thus, diallylamine was A-formylated giving 20 when reacted with chloroform under phase-transfer catalysis conditions addition of dichlorocarbene to the double bond(s) was not observed. ... 

In the case of acrylates mono- or disubstituted at C3, the adducts of dichlorocarbene, formed under phase-transfer catalysis conditions, react further to give the esters of 1,1,2,2-tetrachloro-spiro[2.2]pentanecarboxylic acid as the major products (Houben-Weyl, Vol. E19b, pp 1548-1549). Therefore, the catalyst(s) used for the selective cyclopropanation by phase-transfer catalysis of various acrylates vide supra) were examined. Dichlorocyclopropane 1 was formed from tert-butyl 3-methylbut-2-enoate and chloroform in the presence of 55% aqueous potassium hydroxide and a mixed catalyst polyethylene glycol ( Triton-N-lOl ) and tricapryl-methylammonium chloride ( Aliquat 336 ). The same reaction carried out in the presence of 18-crown-6 as a catalyst afforded three products, the cyclopropane as a minor product. 

Methyl-2,5-dihydro-lH-phosphole 1-oxides underwent addition of dichlorocarbene, generated from chloroform, under conditions of phase-transfer catalysis (24-32 mol percent of catalyst, reflux) to form one diastereomer of the adduct 6 in low yield, yet configurational assignment is not possible. 

Determination of the optimal conditions for the reaction of dibromocarbene with alkenes is more difficult than for the corresponding reaction of dichlorocarbene. This is due to the high reactivity of dibromocarbene which enters into other competitive reactions, particularly hydrolysis under the conditions of phase-transfer catalysis and, in the case of alkenes of low reactivity, its precursor bromoform forms products of free radical reactions if the reaction system is not protected from air and oxygen and from light. These processes have been studied and are described in detail in Houben-Weyl, Vol.E19b, pp 1609-1612. 

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