Cyclopropane ester enolates

Of interest, with regard to synthetic applications are cyclopropane ester enolates and their reactions. 

Few examples exist for the conjugate addition of ester enolates to a,(3-unsaturated esters typically the incipient enolate undergoes decomposition and secondary reactions. The first examples, described by Schlessinger,144 are the addition of /-butyl lithioacetate and /-butyl a-lithio-a-(methylthio)propionate to butenolide (176 Scheme 69). Similarly, Normant reported that cyclopropanes are obtained from a-ha-loesters (177) and ethyl acrylate or acrylonitrile.145... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

The stereoselectivity of this reaction rises when more bulky nucleophiles are employed (compare entries 7, 3,1, and 5). This is most impressively demonstrated by comparison of the y-lactol reduction with its allylation leading to 205 or 206, respectively (Scheme 10). Formation of tetrahydrofuran derivative 208, dihydrofuran 209, or unsaturated a-methylen-y-butyrolactone 207 illustrate that various modes of straightforward work-up procedures provide two different five membered heterocycles 93 b-96). A second example without the geminal dialkyl substitution at C-3 of the siloxy-cyclopropane depicted in Eq. 86 making available the annulated tetrahydrofuran-3-carboxylate 210 underlines the generality of the C-C-bond forming hydroxyalkylation reaction via ester enolates. 

It seems obvious that the same mechanism could also apply to the cyclopropanation of the fran,s-crotonic ester (Figure 9.3, bottom). A Michael addition of the S ylide would then convert it directly into the ester enolate B. This species would cyclize exclusively to the fratw-disubstituted cyclopropane exactly as when it is produced from the cis-crotonic ester in two steps via the conformer A. 

As with other intramolecular ene reactions, this reaction is best suited to the preparation of cyclopentanes, but can also be used for the preparation of cyclohexanes. The reaction cannot be used for the formation of cyclopropanes or cyclobutanes since the unsaturated carbonyl compound is more stable than the ene adduct. 8,e-Unsaturated ketones (167) do not give cyclobutanes (171) by enolization to give (170) followed by a type I reaction but instead give cyclohexanones (169) by enolization to give (168) followed by a type II reaction. Alkynes can replace alkenes as the enophile. Enols can be prepared from pyrolysis of enol esters, enol ethers and acetals and from -keto esters and 1,3-dicaibonyl compounds. Tlie reaction is well suited to the preparation of fused or bridged bicyclic and spirocyclic compounds. Tandem ene reactions in which two rings are formed in one pot from dienones have also been described. The examples discussed below 2-i63 restricted to those published since Conia and Le Perchec s 1975... 

Dimethyl 3-(2-methyl-l-propenyl)-2,2-dimethylcyclopropane-l,l-dicarboxylate (324) is synthesized by the reaction of (2-halo-2-methylpropylidene)malonate (291) with 2-methyl-l-propenylmagnesium bromide (323). The cyclopropane is accompanied by the malonoester (325) and a butanolide (326) formed by nucleophilic attack of an ester enolate (equation 101) . ... 

Reactions of dimethyl(vinyl)sulphonium salts with some lithium ester enolates and a-lithionitriles give cyclopropanes (382). When the lithium salts are tertiary, the butene derivatives (383) are formed (equation 126). ... 

Piehl and Brownconcluded that a-hydrogens in monofunctional derivatives of cyclopropane are relatively unreactive in accordance with I-strain theory because deprotonation of a to an electron-accepting group should lead to additional strain in exocyclic double-bonded forms , as in the case of the ester enolate of 201. 

In contrast the trans, trans acid (222) was deprotonated at the benzylic position to give the allyl anion (224), which upon protonation gave as expected, 225. It has not been possible to prove the existence of the cyclopropyl anions 219 and 223 (only in the case of the methyl ester enolates the cyclopropyl anion corresponding to 219 has been shown by deuteration to exist at — 78°C). Thus, deprotonation of cyclopropyl carbonyl compounds may be strongly dependent on the structural details of the cyclopropane, as previously demonstrated by the relative acidities of 209 and 210. 

A successful trapping reaction of a cyclopropyl ester enolate with trimethylsilyl chloride (TMSC) was first performed by Ainsworth and coworkers . In the reaction of 232 with lithium diisopropyl amide at — 78°C, followed by addition of TMSC, the ketene acetal 233 was formed in 10% yield as well as the silylated cyclopropane 234 (40%). Ketene acetals other than 233 are formed in yields > 90 %. 

That it is indeed the planarity of cyclopropyl (ester) enolates that causes extra strain and thus instability and high reactivity of such anions, as well as low acidity of the corresponding C(0)-substituted cyclopropanes, has been firmly established . It was shown that treatment of ( —)-(R)-l-benzoyl-2,2-diphenylcyclopropane... 

An additional example (Figure 4) of stereochemical control was observed by workers at BMC in cyclization of ester enolates (6). Cyclization of the ethyl ester initiated by sodium t-butoxide in hexane produced a 12 88 ratio of cis traps cyclopropanes. 

The ratio of cis trans isomers was 74 26. One obvious interpretation of these results can be derived from observations of Ireland regarding the influence of HMPA on the stereoselection in the formation of ester enolates (7). Based an Ireland s work, in hexane the E-enolate would be formed preferentially and in the presence of HMPA the Z-enolate would be the major diastereomeric intermediate. It follows that E-enolates cyclize selectively to form trans cyclopropanes, and Z-enolates selectively produce cis products (Figure 5). 

Cyclopropane formation was observed with other branched ester enolates but not with malonate and other enolates. Methyl and alkoxycarbonyl groups are found to be tolerable in the terminal position of the allyl ligand for reaction to occur but not a phenyl group. ... 

Rhodium-catalyzed cyclopentene formation has been observed in cyclopropanations of enol ethers 8 and found to depend on the nature of the ligand and the ester of the diazo compound 9 42,43 Cyclopentenes 10 were isolated exclusively with 2,6-di-ter -butyl-4-methylphenyl esters. 

An interesting and highly stereoselective reaction of dimethoxy cyclopropane derivative 81 with some aromatic N-tosyl imines was recently described by Saigo and coworkers [41] (Scheme 16). In the presence of TiCl4, compound 81 condenses with N-sulfonyl imines to stereoselectively produce lactams 84 and 85, with the cis isomer being the predominant product. It is likely that the dimethoxy cyclopropane initially opens to zwitterionic ester enolate 82, which adds to the imine to yield intermediate 83. The rationale presented for the stereoselectivity in condensation of enolate 82 with the imines is similar to that described for the reactions in Schemes 14 and 15, cf. Fig. (1). 

Recently, the limitation to ester enolates has been overcome, and a range of sterically hindered nucleophiles with pKa =2 20 is now known to form cyclopropanes with 7r-allylpalladium complexes2 X A palladiacyclobutane intermediate has been isolated and characterized by X-ray diffraction analysis26. 

Cyclopropanation. Sodium enolates of /3-ketophosphonate esters react with ethylene oxide in a sealed tube to form spiroannulated cyclopropyl ketones in moderate yields. Other epoxides give substituted cyclopropane derivatives. 

Reaction with enoi ethers. Wenkert and co-workers have examined the copper-catalyzed decomposition of this -diazo compound in the presence of an enol ether of an aldehyde (1) and a ketone (5). In the first case, the expected cyclopropane ester (2) was obtained. This was reduced by lithium aluminum hydride to the diol, which cyclized to the hemiaceta (3) on exposure to acid. Collins oxidation of 3 gave the spiro- 3-methylene-y-lactone 4. 

The following example involves the interaction between dithiocarboxylate sulfur and cyclopropane ring. Thus, treatment of the ester enolate, generated from (29), with carbon disulfide and... 

Diesters.—Michael addition of malonic ester enolates to chiral a/3-unsaturated aldimines (obtained from optically pure a-amino-acids) gives, after hydrolysis, aldehyde-diesters (125) in variable chemical (26—54%) and optical (36—86%) yields. The amino-acid components are recovered optically pure. Attack of simple nucleophiles on the bromoalkylidene malonate (126) gives cyclopropane diesters (127) in good yields. A ready, five-step route to the bicyclo[l,l,0]butane triester (128) has been described. ... 

The ester enolate displaces inh-amolecularly the chlorine atom, producing a cyclopropane. 

The use of hexamethylphosphoric triamide and triethylamine as ligands in place of the usual phosphines in the addition of ester enolates to 1 results in the formation of cyclopropanes via the unusual initial attack at the central carhon atom (eq 6). The process is very limited with respect to nucleophile, however, as only branched ester enolates produce a cyclopropane. N,NJ 1, N -tetramethylethylenediamine and carbon monoxide as hgands also promote central carbon attack by ester enolates. ... 

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). 

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