Electrophilic cyclopropanes bases

B. Reaction of Electrophilic Cyclopropanes with Nucleophiles and Bases. 519... 

Reaction of electrophilic cyclopropanes with oxygen nucleophiles and bases. 519... 

Electrophilic cyclopropanes 392, which are useful intermediates in organic syntheses, can be prepared by the cyclopropanation of olefins with diethyl dibromomalonate and its derivatives (81MI4). The reaction is carried out in the presence of 1 mol equiv. of copper(II) bromide and 2-4 mol equiv. of DBU. Alternatively, the reaction can be effected with diethyl bromomalonate (83BCJ2687) in the presence of a catalytic amount of copper(II) bromide and a slight excess of DBU in benzene at ambient temperature. When some other base (e.g., triethylamine, DABCO, pyridine, or sodium hydride) was applied instead of DBU, the yield was lower or no reaction occurred. The use of other copper salts led to a decrease in the yield. When cyclopropanation was carried out in dimethyl sulfoxide, dimethylformamide, or acetonitrile, the yield of product 392 was again lower. 

Structure-Reactivity Relationships Based on a Comprehensive Survey of the Current Literature 333 Table 13.1 Anionic polymerization of electrophilic cyclopropanes. 

When the cis/trans stereoselectivity of cyclopropanation with ethyl diazoacetate in the presence of CuCl P(0-z-Pr)3, Rh6(CO)16 or PdCl2 2 PhCN was plotted against that obtained with Rh2(OAc)4, a linear correlation was observed in every case, with slopes of 1.74,1.04 and 0.59, respectively (based on 22 olefins, T = 298 K) S9). These relationships as well as the results of regioselectivity studies carried out with 1,3-dienes point to the similar nature of the intermediates involved in Cu-, Rh-and Pd-catalyzed cyclopropanation. Furthermore, obvious parallels in reactivity in the transformations of Scheme 45 for a variety of catalysts based on Cu, Rh, Fe, Ru, Re and Mo suggest the conclusion that electrophilic metal carbenes are not only involved in cyclopropanation but also in ylide-forming reactions66. ... 

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. 

The organometallic chemistry of alkynylcyclopropanes involves primarily the formation and reactions of carbon-metal er-bonds. Metals come essentially from the main group elements, with lithium playing a major role. The two metallation sites are the cyclopropyl and the acetylenic positions, which are expected to differ considerably in their acidity values (t-butylacetylene, pKa = 25230, cyclopropane, pKa = 46183) but less in the reactivity of their metal conjugated bases towards electrophiles. 

Enolates with a leaving group in the y position can cyclize to yield cyclopropanes instead of reacting intermolecularly with an electrophile. 3-Halopropy] ketones or 4-halobutyric acid esters, for instance, are readily converted to cyclopropane derivatives when treated with a base (Scheme 5.64 see also Section9.4.1). 

Addition of electrophilic carbenes to enamines usually does not proceed with good efficiency, very likely because of the disturbance by the Lewis basic nitrogen 15). If however the less basic enamide derivatives are used as olefins, high conversions to donor-acceptor cyclopropanes are possible. Thus cyclic carbamate 245, which itself originates from an oxycyclopropane, gives the bicyclic compound 246 almost quantitatively. Its cleavage with aqueous base provides lactone 247 that could be coupled with tryptophyl bromide to afford 248, a direct precursor of the alkaloid eburnamoni-ne 105>. 

Diver has recently reported new entries for the assembly of tetracyclic derivatives [89]. Interestingly, ruthenium metathesis-type catalysts have also given birth to tricyclic derivatives incorporating a cyclopropane from di-enynes [90]. Cationic gold-based catalysts have proven to be even more reactive promotors of various reactions resulting from a preliminary electrophilic activation [91]. They also allow the formation of tetracyclic derivatives 140 from acyclic precursors 139 at low temperature and as single diastereomers. In one case, the minor metathesis diene 141 was isolated. Tetracyclic products... 

Cyclopropanes have also been obtained by reaction of enamines with a-chloro electrophilic alkenes. After Michael addition the chlorine undergoes nucleophilic displacement by the regenerated enamine or enolate anion260,261 (Scheme 112). Bicy-clo[ 1.1.0] butanes may be obtained by cycloaddition of trimethyl ethylenetricarboxylate followed by a base catalysed displacement of the amine moiety262 (Scheme 113). 

The treatment of 4-chlorobutyronitrile, 3-chloropropyl phenyl sulfone, and other related compounds with a base affords 7-halocarbanions which are usually prone to undergo intramolecular substitution to produce substituted cyclopropanes. However, these carbanionic intermediates can be trapped with external electrophilic partners, such as aldehydes, to give alcoholate anions, which then cyclize to produce 2,3-disubstituted tetrahydrofurans in excellent yields (Scheme 78) <2002CEJ4234>. 

Cyclopropane ring scission occurs readily either under reducing conditions or upon the action of electrophilic or nucleophilic agents. These possibilities offer multiple options for the synthetic utilization of the cyclopropane moiety in organic synthesis. One of the most important applications is based upon the use of the cyclopropanation-catalytic hydrogenation sequence as a method for the creation of the gem-dimethyl moiety, a fragment frequently encountered in many naturally occurring compounds. A typical example is shown in Scheme 2.161. 

Rhodium-based catalysis suffers from the high cost of the metal and quite often from a lack of stereoselectivity. This justifies the search for alternative catalysts. In this context, ruthenium-based catalysts look rather attractive nowadays, although still poorly documented. Recently, diruthenium(II,II) tetracarboxylates [42], polymeric and dimeric diruthenium(I,I) dicarboxylates [43], ruthenacarbor-ane clusters [44], and hydride and silyl ruthenium complexes [45 a] and Ru porphyrins [45 b] have been introduced as efficient cyclopropanation catalysts, superior to the Ru(II,III) complex Ru2(OAc)4Cl investigated earlier [7]. In terms of efficiency, electrophilicity, regio- and (partly) stereoselectivity, the most efficient ruthenium-based catalysts compare rather well with the rhodium(II) carboxylates. The ruthenium systems tested so far seem to display a slightly lower level of activity but are somewhat more discriminating in competitive reactions, which apparently could be due to the formation of less electrophilic carbenoid species. This point is probably related to the observation that some ruthenium complexes competitively catalyze both olefin cyclopropanation and olefin metathesis [46], which is at variance with what is observed with the rhodium catalysts. 

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. °... 

A number of cyclopropanes can be obtained by replacing one or several groups attached to a cyclopropane ring with other atoms or substituents. Many of these substitution reactions are two-step or multistep processes, which may involve base-induced generation of cyclopropyl anions that are quenched by an electrophile, formation under basic conditions of cyclopropenes which are trapped by a nucleophile, or generation of a cyclopropyl radical that undergoes subsequent reactions under neutral conditions. Formal substitution also takes place when cyclopropanes are converted to cyclopropylidenes which suffer l,n insertion, n > 3. Substitution reactions therefore cover a variety of compounds and a wide range of reaction conditions. 

Stereochemical investigations of the above mentioned reactions of cyclopentadienyliron complexes have been helpful in understanding the mechanism of [2+1] cyclopropanation of alkenes with cationic cyclopentadienyliron carbene complexes. Based on the results of these investigations, the cyclopropanation is believed to occur due to electrophilic attack by the carbene center of metallacarbenoid 5 at the less substituted position of the alkene to produce cationic complex 6 which undergoes back-side ring closure to alford 7 or front-side ring closure to afford 8 depending on cation stability, lifetime and rotation of the fS-y bond in 6. ... 

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