Dichlorocyclopropanes, synthesis

Synthesis From Other Ring Systems. These syntheses are further classified based on the number of atoms in the starting ring. Ring expansion of dichlorocyclopropane carbaldimine (53), where R = H and R = ryl, on pyrolysis gives 2-arylpyridines. Thermal rearrangement to substituted pyridines occurs in the presence of tungsten(VI) oxide. In most instances the nonchlorinated product is the primary product obtained (63). 

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. 

The treatment of the bromoacetal (255) with catalytic amounts ( 10%) of a Co(I) species, generated by the electroreduction of cobaloxime (232) in an Me0H-LiCl04 system at —1.8 V, produces the cis-fused adduct (256) in 60 70% yield (Scheme 96) [392]. Cathodic reduction is used for the synthesis of a [Co(CO)3PBu3] complex in a methanol-methyl formate medium, which catalyzes the alkoxycarbonylation of dichloromethane to dimethyl mal-onate in up to 75% yield [393]. The Co(II) complexes are found to be effective for the homogeneous reduction of gem-dichlorocyclopropanes in the presence of anthracene [394]. The formation of the C—C double bond of (258) may be ascribed to the a-elimination of the Co-H species. Thus, benzalchloride (257) can be converted to a mixture consisting primarily of ds- and trans-stilbenes (258) by the action of electrogenerated Co(I)(salen) (Scheme 97) [395-398]. 

The c-ring expansion of aporphines via the dichlorocyclopropane ring opening238 induced by LAH has been utilized in a synthesis of homoaporphine alkaloids (equation 93). Reductive cleavage of 2-silyloxy-dibromocyclopropanes gives a,(3-unsaturated ketones directly (equation 96).239... 

An elegant synthesis of the neurotoxic alkaloid anatoxin has exploited the electrocyclic opening of the dibromobicyclo[5.1.0]octane followed by transannular cyclization (Scheme 13).238 Similarly, the thermal electrocyclic opening of the dichlorocyclopropane followed by intramolecular trapping of the developing allylic cation by a suitably positioned amine has been used in a homoaporphine synthesis.238... 

The intramolecular nitrogen-trapping protocol used by Banwell has also been successfully exploited in the assembly of spirocyclic frameworks relating to the aromatic erythrina alkaloids.24 However, when it was applied to the synthesis of nonaromatic spirocycles, as found in histrionicotoxin, the flexible alkyl tether proved to be problematic.25 In this study, gem-dichlorocyclopropane substrate 37 was initially subjected to silver(I) salts under a variety of conditions only to provide solvolysis and elimination products without any indication of trapping by the pendent... 

The cascade sequences presented herein demonstrate unprecedented modes of reactivity in Nazarov chemistry that are initiated by the silver(I)-promoted ring opening of halocyclopropanes. The ease with which the gem-dichlorocyclopropanes can be prepared, the relatively mild reaction conditions, and the efficiency of these processes make these substrates attractive intermediates for an application in natural product synthesis. 

Fig. 3.11. Plausible, but incorrect mechanism of the phase-transfer catalyzed dichlorocyclopropanation of alkenes as often encountered in (close ) analogy to the Bu4N Cl catalyzed Kolbe nitrile synthesis in the two-phase system CH /aqueous solution of NaCN.

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. 

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. 

Despite intense theoretical interest, surprisingly few attempts to prepare the parent hydrocarbon were reported prior to its synthesis in 1984 however, evidence for simple alkyl methylenecyclopropenes can be found in the base-induced elimination-isomerization reactions of gem-dichlorocyclopropanes " " . 

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]. 

The above conditions allow the synthesis of a large variety of a,a-dialkyl substituted ketones including spiro derivatives and cyclopentanones, cyclohexanones, cycloheptanones and cyclododecanones bearing two alkyl groups at die a-posidon (Scheme 162, e Scheme 165, c Scheme 166, e Scheme 186, a and b Scheme 187 Scheme 188, a Scheme 189, a and The reactions are less selective when the dichlorocarbene is generated from bromodichloromethane and lead to gem-dichlorocyclopropanes if the dichlorocarbene is produced from chloroform and potassium r-butoxide (Scheme 162, f Scheme 188, b Scheme 189, c). ... 

A number of methods for the generation of dichlorocarbene (see Houben-Weyl, Vol. 4/3, pp 150-159, 374-375 and Vol. E19b, pp 1521-1537) are known, but only a few are important for the preparative synthesis of 1,1-dichlorocyclopropanes. The following methods must be considered significant. 

As the alcohol is not formed, there is no need to use sterically hindered alkoxides. This reaction is usually carried out in pentane or in an excess of alkene at 0 to 10 °C and is recommended for the preparation of thermally unstable 1,1-dichlorocyclopropanes. An interesting modification for the synthesis of 1,1-dichlorocyclopropanes which eliminates strongly alkaline medium, utilizes trimethylsilyl trichloroacetate and potassium fluoride in the presence of a catalyst (a quaternary ammonium salt or a crown ether),... 

However, a new, efficient synthesis of 1,1-dichlorocyclopropanes, e.g. 4, via the reaction of chloroform and magnesium with alkenes has been described. ... 

The type of phase-transfer catalyst plays a key role in the phase-transfer catalytic synthesis of l-bromo-1-chlorocyclopropanes, which are formed in good yields and with high selectivity if the reaction of dibromochloromethane with an alkene is performed using a crown ether (dibenzo-18-crown-6, " 3,5-di-fer/-butylbenzo-15-crown-5, " " 3,3, 5,5 -tetra-tert-butyldiben-zo-lS-crown-b ) or tetramethylammonium chloride.For the specific effect of the tetra-methylammonium chloride on the dichlorocyclopropanation of unconjugated dienes, see Section I.2.I.4.2.I.2., and some electrophilic alkenes, see Section I.2.I.4.2.I.8.2. The reason why these catalysts exhibit peculiar properties is not clear,other crown ethers behave like typical phase-transfer catalysts (Table 25). " ... 

As the bromines in 1,1-dibromocyclopropanes are more reactive than the chlorines in the corresponding 1,1-dichloro derivatives, 1,1-dibromocyclopropanes are attractive intermediates in organic synthesis. The most convenient method for the preparation of 1,1-dibromocyclopropanes consists of the addition of dibromocarbene (carbenoid) to an alkene. The mechanistic details of this process have been less thoroughly investigated than dichlorocyclopropanation of alkenes, but both reactions are similar in many respects. 

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... 

A number of dicycloproparenes have been prepared by way of the l-bromo-2-chlorocyclo-propene adducts in moderate to very good yields (Table 10). A special example of this procedure is the synthesis of li/,4/f-dicyclopropa[A,g]naphthalene (18) in 52% yield from the cycloadduct 17 of 1-bromo-2-chlorocyclopropene with 7,7-dichloro-3,4-bis(methylene)bi-cyclo[4.1.0]heptane (16), in which the elimination described in this section is combined with the double elimination of a 1,1-dichlorocyclopropane vide supra). 

Benzoyl-2,2-dichlorocyclopropanes were transformed to 2-amino-5-benzoylfurans when heated with secondary amines, e.g. 80 81.The synthesis of this air-sensitive class of com-... 

A synthesis of substituted buta-l,2,3-trienes 168 from the double dehydrohalogenation of gem-dichlorocyclopropanes 167 has been described. This reaction does not involve cyclopropylidene but likely proceeds through the chlorocyclopropene-vinylcarbene-l-chlorobuta-... 

Metacyclophane synthesis. Parham and Rinehart14 synthesized a new elass of metacyclophanes by reaction of (1) with 2 equiv. of phenyl(triehloromethyl)mercury in boiling benzene the intermediate dichlorocyclopropane (2) suffers spontaneous ring opening to give the cyclophane (3) in 73% yield (pure). 

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