Halides cyclopropane

The last group of reactions uses ring opening of carbonyl or 1-hydroxyalkyl substituted cyclopropanes, which operate as a -synthons. d -Synthons, e.g. hydroxide or halides, yield 1,4-disubstituted products (E. Wenkert, 1970 A). (1-Hydroxyalkyl)- and (1-haloalkyl)-cyclopropanes are rearranged to homoallylic halides, e.g. in Julia s method of terpene synthesis (M. Julia, 1961, 1974 S.F. Brady, I968 J.P. McCormick, 1975). 

The majority of preparative methods which have been used for obtaining cyclopropane derivatives involve carbene addition to an olefmic bond, if acetylenes are used in the reaction, cyclopropenes are obtained. Heteroatom-substituted or vinyl cydopropanes come from alkenyl bromides or enol acetates (A. de Meijere, 1979 E. J. Corey, 1975 B E. Wenkert, 1970 A). The carbenes needed for cyclopropane syntheses can be obtained in situ by a-elimination of hydrogen halides with strong bases (R. Kdstcr, 1971 E.J. Corey, 1975 B), by copper catalyzed decomposition of diazo compounds (E. Wenkert, 1970 A S.D. Burke, 1979 N.J. Turro, 1966), or by reductive elimination of iodine from gem-diiodides (J. Nishimura, 1969 D. Wen-disch, 1971 J.M. Denis, 1972 H.E. Simmons, 1973 C. Girard, 1974),... 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

The reaction of benzoyl chloride with (Me3Si)2 affords benzoyltrimethylsi-lane (878)[626,749,750]. Hexamethyldigermane behaves similarly. The siloxy-cyclopropane 879 forms the Pd homoenolate of a ketone and reacts with an acyl halide to form,880. The 1,4-diketone 881 is obtained by reductive elimination of 880 without undergoing elimination of /7-hydrogen[751]. 

This study suggests a radically new explanation for the nature of Lewis acid activation in the Simmons-Smith cyclopropanation. The five-centered migration of the halide ion from the chloromethylzinc group to zinc chloride as shown in TS2 and TS4 has never been considered in the discussion of a mechanism for this reaction. It remains to be seen if some experimental support can be found for this unconventional hypothesis. The small energy differences between all these competing transition states demand caution in declaring any concrete conclusions. 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

Attempts to exploit the reaction of the dianion with alkyl halides to produce a c/.v-dialkyl complex by using 1,2- or 1,3-dihaloalkanes did not indeed give this result. The reaction of Ru(Por) " with 1,2-dibromoethane was sucessful, but the resulting metallacyclopropane product is better formulated as a /r-complex of ethene, and will be discussed below in the section on alkenc and alkyne complexes. The corresponding reaction of the diiinion with 1,3-dichloropropane gave no evidence for a metallacyclobutane. but instead free cyclopropane was detected by GC analysis and the porphyrin product was Ru(TTP)(THF)2. ... 

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

Some years ago we began a program to explore the scope of the palladium-catalyzed annulation of alkenes, dienes and alkynes by functionally-substituted aryl and vinylic halides or triflates as a convenient approach to a wide variety of heterocycles and carbocycles. We subsequently reported annulations involving 1,2-, 1,3- and 1,4-dienes unsaturated cyclopropanes and cyclobutanes cyclic and bicyclic alkenes and alkynes, much of which was reviewed in 1999 (Scheme l).1 In recent days our work has concentrated on the annulation of alkynes. Recent developments in this area will be reviewed and some novel palladium migration processes that have been discovered during the course of this work will be discussed. 

Similarly, the Pd-catalyzed arylation of l,3-dicyclopropyl-l,2-propadiene 6/1-122 with iodobenzene in the presence of dimethyl maleate led to the diastereomeric cyclopropane derivatives 6/1-124 and 6/1-125 via 6/1-123 in 86% yield as a 4 l-mix-ture [65] (Scheme 6/1.33). Several other aryl halides and dienophiles have been used in this reaction. 

The limitation to electron-rich alkenes in Rh(II)-catalyzed cyclopropanation with phenyldiazomethane leaves untouched the great versatility of zinc halides for this purpose with this, catalyst, efficient and very mild cyclopropanation of 1,3-dienes and unactivated alkenes has been reported 46). 

Thorough investigations with dimethyl diazomalonate and catalysts of the type (RO)3P CuX have revealed that the efficiency of competing reaction paths, the synjanti or EjZ selectivity in cyclopropane formation as well as the cis/trans ratio of carbene dimers depend not only on catalyst concentration and temperature but also on the nature of R58) and of the halide anion X 57 6". Furthermore, the cyclopropane yield can be augmented in many cases at the expense of carbene dimer... 

Rhodium(II) pivalate has also been recommended for the cyclopropanation of vinyl halides with ethyl diazoacetate 78). As Table 8 shows, yields with this catalyst are far higher and reaction conditions milder than with copper. Failures are noted,... 

Table 8. Cyclopropanation of vinyl halides with ethyl diazoacetate in the presence of rhodium(Il) pivalate (Rhpiv) or copper...

A striking example for the preferred formation of the thermodynamically less stable cyclopropane is furnished by the homoallylie halides 37, which are cyclopro-panated with high c/s-selectivity in the presence of copper chelate 3891 The cyclopropane can easily be converted into cw-permethric acid. In contrast, the direct synthesis of permethric esters by cyclopropanation of l,l-dichloro-4-methyl-l,3-pentadiene using the same catalyst produces the frans-permethric ester (trans-39) preferentially in a similar fashion, mainly trans-chrysanthemic ester (trans-40) was obtained when starting with 2,5-dimethyl-2,4-hexadiene 92). 

Most remarkably, the homoallylic halides 214 not only yield the thermodynamically unfavored ris-cyclopropanes 215 preferentially (see Sect. 2.2.3), but also give rise to enantioselective formation of the (1/ ) configuration, in contrast to the cyclopropanation of 1,3-butadienes with the same catalysts (see Table 15). Only in the case of olefin 214 (X = CF3, Y = Cl), may the (1 S)-trans isomer be obtained enantioselecti-vely, depending on the catalyst (Table 16, entries 8-11). In these few cases, optical induction occurs at C(3) of the cyclopropane rather than at C(l). 

Katsuki et al. have reported that the CoIII(salen) ((98) X = I, Y = t-Bu) bearing an apical halide ligand shows high trara-selectivity in the cyclopropanation of styrene and its derivatives, albeit with moderate enantioselectivity (Scheme 71).267 The enantioselectivity is influenced, however, by the natures of the apical ligand and the 5,5 -substituents, and high enantio- and traMs-selectivity has been realized by their appropriate tuning ((98) X = Br, Y = OMe).268 It is noteworthy that the CoIII(salen) complex bearing substituents at C3 and C3 shows no catalytic activity. 

Here, we have already noted that cyclopropanes (23) are structural isomers of five-membered cyclic nitronates (24). There was evidence that functionalized cyclopropane (23b) can be isomerized to give the corresponding five-membered cyclic nitronate (24b) under the action of halide anions (82) (Scheme 3.28, Eq. 1). Moreover, the in-depth study (79) demonstrated that the above mentioned... 

The versatile Ti(II) chemistry available using preformed (alkene)Ti(OiPr)2 species was opened up by the discovery of the Kulinkovich cyclopropanation reaction [55]. Since 1995, Sato and collaborators have developed a wide range of elegant and synthetically useful reactions based on the Ti(OiPr)4/iPrMgCl reagent [56]. In particular, it was reported that the Ti(II) complex (q2-propene)Ti(OiPr)2, preformed from Ti(OiPr)4 and 2 equivalents of iPrMgCl, reacts with allylic compounds, such as halide, acetate, carbonate, phosphate, sulfonate, and aryl ether derivatives, to afford allyltitanium compounds as depicted in Scheme 13.27 [57]. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

While a large number of studies have been reported for conjugate addition and Sn2 alkylation reactions, the mechanisms of many important organocopper-promoted reactions have not been discussed. These include substitution on sp carbons, acylation with acyl halides [168], additions to carbonyl compounds, oxidative couplings [169], nucleophilic opening of electrophilic cyclopropanes [170], and the Kocienski reaction [171]. The chemistry of organocopper(II) species has rarely been studied experimentally [172-174], nor theoretically, save for some trapping experiments on the reaction of alkyl radicals with Cu(I) species in aqueous solution [175]. 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

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