Cyclopropanation dichlorocyclopropanation

If dichlorocarbene is generated in the presence of an alkene, addition to the double bond occurs and a dichlorocyclopropane is formed. As the reaction of dichlorocarbene with ds-2-pentene demonstrates, the addition is stereospecific, meaning that only a single stereoisomer is formed as product. Starting from a cis alkene, for instance, only cis-disubstituted cyclopropane is produced starting from a trans alkene, only trans-disubstituted cyclopropane is produced. 

With the exception of the parent compounds, where the Michael adducts are isolated, acrylic esters [see, e.g. 6,7,31,105,111 ] and nitriles [6,7], and vinyl ketones [26, 113, 115] generally yield the cyclopropanes (Table 7.6) under the standard Makosza conditions with chloroform. Mesityl oxide produces a trichlorocyclopropy-lpropyne in low yield (10%) [7]. When there is no substituent, other than the electron-withdrawing group at the a-position of the alkene, further reaction occurs with the trichloromethyl anion to produce spiro systems (35-48%) (Scheme 7.12) [7, 31]. Under analogous conditions, similar spiro systems are formed with a,p-unsaturated steroidal ketones [39]. Generally, bromoform produces cyclo adducts with all alkenes. Vinyl sulphones are converted into the dichlorocyclopropane derivatives either directly or via the base-catalysed cyclization of intermediate trichloromethyl deriva-... 

We admit to presenting no benzene counterpart for gew-disubstituted cyclopropanes. Then again, there are almost no thermochemical data with which to make comparisons save for the three dimethylcyclopropanes. For example, the enthalpy of formation of 1,1-dichlorocyclo-propane is available as are those of the three dichlorobenzenes, but we lack thermochemical data for the monosubstituted cyclopropyl chloride and for both 1,2-dichlorocyclopropanes. 

Other means of improving sulfide yields in the reaction of halides with thiolates are (1) the use of thiols and platinum(II) complex catalysts287, (2) the generation of thiolate anions by electrochemical means288 and (3) the use of phase-transfer conditions237. The first method has been used for the synthesis of thioketals from geminal diiodides and the third has been used for the conversion of gem-dichlorocyclopropanes into cyclopropane thioketals, which are effectively masked cyclopropane moieties. 

Polymerization of 1,1 -Dichlorocyclopropanes. Experiments were first carried out on vinyldichlorocyclopropanes derived from isoprene and butadiene. The polymers obtained were very different from the cyclopropane macromolecular products already described (17), and it was found that cyclopropane participates in polymerization reactions. The study was therefore repeated in the simplest case—i.e., that of saturated cyclopropane monomers. 

Of the cyclopropane systems containing unsaturated groups, it is 2-methyl-2-phenyl-l,l-dichlorocyclopropane IX which gives results identical to those described in Table V the same reactions can be described for IX as for VI. 2-Phenyl-1,1-dichlorocyclopropane X also gives polymers, but of much lower solubility than those from IX, it being noted... 

A novel ring opening reaction of cyclopropanes was discovered in the context of fused pyrrole synthesis <07OL5421>. For example, treatment of 1,1-dichlorocyclopropane 36 with LDA led to the production of fused pyrrole 37. The reaction likely proceeds through the formation of a carbene intermediate. 

The oxirane rings in 3,4-epoxychromanes and 1,2-epoxytetrahydronaphthalenes have been converted into ethoxycarbonylcyclopropanes by reaction with ethyl malonate anion These transformations, however, appear to lack generality, gem-Dichlorocyclopropanes have been obtained from oxiranes under dichlorocarbene-generating PTC conditions Oxiranes can also be transformed into cyclopropanes in their reaction with active methylene compounds (Section III.C.l). 

Cyclopropanation of alkenes carrying electron-withdrawing groups with dihalo-carbenes does not take place under the normal reaction conditions unless the dihalocar-bene is generated from trihalomethylphenylmercury compounds. By this procedure acrylonitrile was converted into l-cyano-2, 2-dichlorocyclopropane in 78% yield and other acrylic derivatives are transformed into dichloromethyl cyclopropane carboxylates (186) (equation 46). Treatment of electron-deficient olefins with dibromomethane in the presence of Ni(0) complex/Zinc/Lewis acid seems to be very effective for cyclopropanation. ... 

Additional evidence for the presence of cyclopropene intermediates in the interconversion of aryl and aromatic carbenes comes from the products of dehydrohalogenation of gem-dichlorocyclopropanes For example, treatment of cyclopropane 229 with base gives a ca. 1 2 mixture of the ethers 231 and 233, products which are easily rationalized by the pathways shown in equation 76. Of particular significance here is the observation that products derived from both 230 and 232 are obtained. This represents the first definite evidence that bicycloheptatrienes open to both cycloheptatrienylidenes and arylcarbenes under mild conditions, i.e. at ambient temperatures. 

Complementing cyclopropanation reactions, the dichlorocyclopropanation of glycals has also been used as a means to introduce methyl groups at sugar C2 positions. An excellent illustration of this strategy was reported in connection with a synthesis of the C29 to C51 fragment of altohyrtin A [64]. 

A carbene, RjC , is a neutral molecule containing a divalent carbon with only six valence electrons. Carbenes are highly reactive toward alkenes, adding to give cyclopropanes, Dichlorocarbene adds to alkenes to give 1,1- dichlorocyclopropanes, Nonhalogenated cyclopropanes are best prepared by treatment of the alkene with CH l2 and zinc-copper alloy—the Simmons-Smith reaction. 

Cyclopropane can be drawn as in 1 to show perspective, or as in 2-5 (for its derivatives), in which the cyclopropane ring is in the plane of the paper. Monosubstituted cyclopropanes, such as 2, are not chiral. The disubstituted cyclopropane 3 is also not chiral it has two stereogenic centres with identical substituents and of opposite configuration, and is therefore meso. Compound 3, which has a plane of symmetry through the mid-point of the C(l)-C(2) bond, is cw-l,2-dichlorocyclopropane. 

Cyclopropane has a very large heat of combustion because it is highly strained. Compounds such as trans-, 2-dichlorocyclopropane are chiral. 

Many hundreds of examples of 1,1-dichlorocyclopropanes prepared by the addition of dichloro-carbene to alkenes are known. Exhaustive collections of these compounds are reported in refs 28 30. The key problems connected with the cyclopropanation of alkenes are discussed in Houben-Weyl, Vol. E19b, pp 1538-1541, for examples of the formation of 1,1-dichlorocyclo-propanes, see Houben-Weyl, Vol. 4/3, pp 163-165,179,376-379 and Vol. E19b, pp 1528-1529, 1534. 

Alkenes with a halogen more remote from the double bond yield 1,1-dichlorocyclopropanes usually without difficulties. Some typical examples of these cyclopropanes are collated in Table 12. 

Preparation of 2-acyloxy-l,l-dichlorocyclopropanes via the addition of dichlorocarbene to acyloxyalkenes depends on the structure of the alkene and on the mode of generation of the carbene. Thus, ketone enol esters give cyclopropanes irrespective of the method used for the generation of dichlorocarbene. 

Using bromodichloromethyl(phenyl)mercury, vinyl acetate afforded 2-acetoxy-l,l-dichlo-rocyclopropane (1, 85%), dichlorocyclopropanation of other aldehyde enol esters would also be expected. The cyclopropane 1 ( 10%) together with 2-acetoxy-l,l,l-trichloropropane (2,10%) were formed when the dichlorocarbene was generated from sodium trichloroacetate, the chain product 2 results from the reaction of the trichloromethyl anion (for the mechanism, see ref 197). These reactions are described in Houben-Weyl, Vol. 4/3, pp 177-178. Under phase-transfer catalytic conditions (CHClj/base/PTC), with a typical catalyst such as benzyl-triethylammonium chloride, vinyl acetate gave 2 (65%) only (Houben-Weyl, Vol.E19b, ppl550-1551). 

This is rather an unexpected result, since sulfur is a weaker electron donor than oxygen and consequently vinyl sulfides should react slower compared to vinyl ethers if cyclopropanation is considered as a straightforward reaction of dichlorocarbene with an alkene double bond. Therefore, the formation of 2-alkyl(or aryl)sulfanyl-l,l-dichlorocyclopropanes is a multistep process, which starts with the generation of sulfonium ylides via the attack of carbene on the sulfur atom of the vinyl sulfide. The ylide thus formed undergoes 1,3-rearrangement and cyclization or reacts with another molecule of vinyl sulfide and then cyclizes. ... 

The chloroform/base/phase-transfer catalyst method is generally used for the preparation of 2-amino-l,l-dichlorocyclopropanes 1 from enamines. Morpholine enamines form stable products, often with high yields. 1,1-Dichlorocyclopropanes derived from other enamines are less stable, nevertheless they are conveniently isolated in the form of stable hydrochlorides. Typical examples of these cyclopropanes are collected in Table 21. 

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. 

Stereospecific addition of dichlorocarbene, generated from chloroform/base/phase-trans-fer catalyst, with tetramethylammonium chloride as a catalyst, to tm-butyl (Z)- and (i )-but-2-enoate giving cyclopropanes 4 has been observed additionally, the product 5 of further transformation of 1,1-dichlorocyclopropanes was formed. These results confirm a simple singlet dichlorocarbene cycloaddition. 

Cyclopropyl thioacetals are conveniently prepared by treating 1,1-dichlorocyclopropanes with a thiol under basic conditions using methanol, ethanol or dimethyl sulfoxide as solvent. Almost all the thioacetals synthesized this way are l,l-bis(phenylsulfanyl)cyclopropanes. The reaction... 

Dichlorocyclopropanes have been converted to l,l-bis(phenylsulfanyl)cyclopropanes in good yield under phase-transfer conditions using sodium hydroxide as base, benzene as organic solvent, and tetrabutylammonium bromide or benzyltriethylammonium chloride as catalyst. Typically, ler/-butyl 2,2-bis(phenylsulfanyl)cyclopropanecarboxylate (3) was obtained in 71 /o yield from tert-butyl 2,2-dichlorocyclopropanecarboxylate by this method. ... 

One of the earliest useful applications of eliminations in the cyclopropane series is the two-step synthesis of l-alkenyl-2-alkylidenecyclopropanes from simple alkenes. The first step consists of addition of dichlorocarbene to the alkene to give a 1,1-dichlorocyclopropane. This is then followed by double dehydrochlorination with potassium /ert-butoxide in dimethyl sulfoxide at room temperature (Table 6). The product diene contains one double bond exo to the cyclopropane ring and the other in the vinyl position, presumably through the intermediacy of an undetected, highly strained methylenecyclopropene. The method is illustrated by the synthesis of l-methylene-2-vinylcyclopropane (3) starting from pent-2-ene (1). ... 

The double elimination of 1,1-dichlorocyclopropanes with potassium tert-butoxide to give cycloproparenes is an important variant of the reaction discussed in Section 5.2.2.1.2.3. When a six-membered ring fused to the cyclopropane contains a double bond, the elimination is accompanied by isomerization of the new double bonds to give an aromatic ring (Table 7). The reaction is illustrated by the synthesis of bicyclo[4.1.0]hepta-l,3,5-triene (l//-cyclo-propabenzene, 3) in two steps from cyclohexa-1,4-diene (1), the first step being dichlorocarbene addition to the diene to give 7,7-dichlorobicyclo[4.1.0]hept-3-ene... 

While the double dehydrochlorination of 1,1-dichlorocyclopropane derivatives has proved successful in the preparation of a variety of cyclopropabenzenes and cyclopropa[6]naphthalenes (Table 7), the reaction fails to provide cyclopropa[a]naphthalenes, cyclopropanthracenes or higher derivatives. In these cases only substituted arenes arising from the opening of the cyclopropane ring were obtained. For the preparation of lFf-cyclopropa[<2]naphthalene a retro-Diels-Alder reaction was used (see Section 5.2.2.6.). 

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