Carbanion cyclization

Like the electrohydrodimerization and electrohydrocyclizahon reactions, this process also requires the consumphon of two electrons and two protons. It has been shown to occur via a sequence consisting of electron transfer followed by a ratedetermining protonation of the resulting radical anion, addihon of a second electron to generate a carbanion, cyclization of the carbanion onto the carbonyl acceptor unit and the addition of the second proton [16]. Carbon acids like dimethyl malonate and malononitrile are often used as a proton source. The course of this and other... 

In practice, reduction of 35 (—2.43 V vs SCE) in the presence of 3,5-dimethylphenol as a proton donor, tetra- -butylammonium hexafluorophos-phate as the supporting electrolyte, and DMF as the solvent, led to the y-hydroxy ester 40 and lactone 41 [22]. No sign of any material resulting from cyclization onto the alkene was detected. It was concluded that radical cyclization does not occur in this instance, and that the homogeneous electron transfer rate exceeds that of a 5-exo-trig radical cyclization, thereby implying the operation of either a radical anion or carbanion cyclization pathway. 

Nakai and coworkers90 have demonstrated that the carbanion cyclization of enantio-enriched a-(homoallyloxy)alkyllithiums, prepared from the corresponding stannanes 192, proceeds with complete retention of configuration at the lithium-atom-bearing carbon centre. The obtained tetrahydrofurans 193 are formed with high trans-selectivity and without losing the enantiomeric purity. This means that the lithium might coordinate to the... 

Krief et al. [27-29] have carried out the synthesis of l-arylbicyclo[3.1.0] hexanes and l-arylbicyclo[4.1.0]heptanes via carbanionic cyclization of olefins... 

Previously Arigoni210 had put forward an elegant stereochemical argument for the co-occurrence of (—)-longifolene (432) and (—)-sativene (433) from this fungus, as summarized in Scheme 56. The detection of (431) in the mycelium adds substantial support to this proposal since it is the very ten-membered ring intermediate en route to (—)-sativene. The final verification of the structure of (431) was achieved by carbanionic cyclization of the, cis,trans-fa.mesy sulphide (434) followed by reductive removal of the sulphide group and dehydration of the derived tertiary alcohol. 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

The reduction of o-nitrophenyl acetic acids or esters leads to cyclization to oxindoles. Several routes to o-nitrophenylacetic acid derivatives arc available, including nitroarylation of carbanions with o-nitroaryl halides[2l,22] or trif-late[23] and acylation of o-nitrotoluenes with diethyl oxalate followed by oxidation of the resulting 3-(u-nitrophenyl)pyruvate[24 26]. 

The main Uab synthetic pathway is illustrated in Scheme 6.1 and corresponds to C-acylation of an o-aminobenzyl carbanion equivalent. Acylation is normally followed by in situ cyclization and aromatization. This route is therefore closely related to the cyclizations of o-aminobenzyl ketones described in Section 2.3 but the procedures described here do not involve isolation of the intermediates. 

Carbanions in the form of ylides also add to azirines. For example, treatment of 1-azirine (227) with dimethylsulfonium methylide gives 1-azabicyclobutane (229) in good yield (72JA2758). The addition of the methylene group occurs by initial nucleophilic attack by the ylide to give intermediate (228) which cyclizes with expulsion of dimethyl sulfide. 

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Several years ago, there was much debate concerning the mechanism of the Darzens condensation.2.3 The debate concerned whether the reaction employed an enolate or a carbene intermediate. In recent years, significant evidence that supports the enolate mechanism has been obtained, wherein the stabilized carbanion (11) of the halide (10) is condensed with the electrophile (12) to give diastereomeric aldolate products (13,14), which subsequently cyclize via an internal Sn2 reaction to give the corresponding oxirane (15 or 16). The intermediate aldolates have been isolated for both a-fluoro- and a-chloroesters 10. 

Thus, simple ketones or aliphatic aldehydes may be successfully used as starting materials in the CSIC (Carbanion mediated Sulfonate Intramolecular Cyclization) reaction. Ai-alkylsulfonamides could be also cyclized under CSIC conditions (99T(55)7625) affording the spiroisothiazoline 79. By treatment with TMSCl, Nal in acetonitrile at r.t., hydrolysis of the enamine and formation of the corresponding keto derivative 80 was obtained. 

Asymmetric induction by sulfoxide is a very attractive feature. Enantiomerically pure cyclic a-sulfonimidoyl carbanions have been prepared (98S919) through base-catalyzed cyclization of the corresponding tosyloxyalkylsulfoximine 87 to 88 followed by deprotonation with BuLi. The alkylation with Mel or BuBr affords the diastereomerically pure sulfoximine 89, showing that the attack of the electrophile at the anionic C-atom occurs, preferentially, from the side of the sulfoximine O-atom independently from the substituent at Ca-carbon. The reaction of cuprates 90 with cyclic a,p-unsaturated ketones 91 was studied but very low asymmetric induction was observed in 92. 

An attempt to cyclize the corresponding fully aromatic system (16) gave instead the indazole (17), Eq. (24), probably because the acidity of the bridging methylene group in (16) enables cyclization to occur on the diazonium ion through the carbanion. ... 

Intramolecular cyclization of 2-phenysulfonylmethyl lactam 3 took place upon reaction with lithium hexamethyldisilazan via generating its a-sulfonyl carbanion to give a cyclized postulated intermediate that can be quenched with trimethylchlorosilane to afford the stable silyl ketal 4. The later ketal was desulfonylated by Raney-Ni and desilylated through treatment with tetrabutyl ammonium fluoride (BU4NF) to afford the carbacephem 5 (94M71) (Scheme 1). 

Carbanions of active methylene compounds also react with aziridine-2-car-boxylic esters to give ring-opened products [129]. The ring-opened intermediates usually cyclize spontaneously to pyrrolidones. Treatment of 190 (Scheme 3.70) with the sodium enolate of dimethyl malonate 191, for example, afforded pyrroli-done 192 in 15% isolated yield, together with 30% of the debenzoylated product 193. 

The cyclization of aryl 3-chloropropyl sulfones by potassium t-butoxide in t-butyl alcohol at 30 °C (equation 20) has a p value of 2.32 for substituents in Ar202. This is considered by Bird and Stirling to indicate the formation of an intermediate carbanion which is essentially in equilibrium with the reactants. A recent review by Stirling203 deals with structure-reactivity aspects of many sulfonyl promoted reactions of this type. 

Russell and coworkers147 had found that treatment of dimsyl anion 88 or of a similar methylsulfonyl carbanion with 1,2-, 1,3- and 1,4-dicarboxylic acid esters can give five- to seven-membered cyclic compounds. By this type of cyclization, they prepared ninhydrin hydrate 106 from diethyl phthalate148,149. 

Treatment of a-lithionitriles with vinylic sulfones resulted in the formation of cyclized products, i.e., 3-oxothian-l, 1-dioxides 346 or cyclopropane derivatives 348. When a-lithiated aliphatic nitriles were used, carbanions 343, formed by the nucleophilic addition,... 

The cyclopropane cyclizations by elimination of triflinic acid (CF3S02H) are readily effected by basic treatment of triflones (trifluoromethyl alkyl sulfones) with activated /-protons (equations 46 and 47)39. The cyclopropane diesters 45 are formed on treatment of 44 with potassium hydride in DMSO or sodium methoxide in methanol (equation 48). In contrast, the monoester 46 failed to give the desired cyclopropane40. Addition of carbanions derived from /f, y-unsaturated phenyl sulfones to a, /i-unsaturated carboxylic esters and subsequent elimination of benzenesulfinate ion give cyclopropanes possessing the unsaturated side chain and the ester function in trans positions (equation 49)41. 

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