Dianions with epoxides

Treatment of aminophenols with alkylating agents can yield either O- or N-alky-lated products, depending on the type of electrophile used and on the reaction conditions. If weak bases and hard electrophiles are used, either clean O-alkylation or mixtures of products can result (Scheme 6.20). Acid-catalyzed alkylation of aminophenols with epoxides usually yields N-alkylated products [47] (Scheme 6.12). Selective N-alkylation of aminophenols can also be achieved by using softer electrophiles or by conversion of the aminophenol into a dianion, followed by treatment with one... 

TABLE 3. Reaction of ketone a,a -dianions with carbonyl and epoxide derivatives... 

On the other hand, doubly metallated 2-propanethiol (thioacrolein dianion) reacts preferentially (7 0 ratio = 70 30, Scheme 16, entries b and d) at its -position - with alkyl and benzyl chlorides and bromides and with epoxides. The cis stereochemistry found in the 7-adduct suggests that the organometallic is internally chelated as shown in Scheme 16. The nature of the metal (Li or K) does not affect the percentages of the alkylated vinyl sulfides,whereas addition of HMPA to the dilithio derivative inverts the regioisomeric ratio obtained (Scheme 16, entry c, compare to entries b and d). ... 

Epoxides - The first indication of the synthetic utility of metalated carboxylic acids resulted from efforts to prepare steroidal aldosterone inhibitors from spiroepoxides.39 Model studies indicated that the reaction fails as a result of severe steric hindrance in either the epoxide or carboxylic acid and that monosubstitution occurs for the same reason.39 The reaction has been used in a key step of an elegant synthesis of vernolepin, 5. 40 Forcing conditions are required, and, in contrast to acid dianions, anions of unactivated esters fail to react with epoxides.39 41... 

Reactions alkylations, reactions with epoxides and aldehydes, conjugate additions Heterocyclic synthesis with allyl silanes Reactions with Co-stabilised cations An Allyl Dianion The Role of Tin in Anion Formation Halide Exchange with Chelation Indium Allyls Allyl Anions by Deprotonation The synthesis ofall-trans dienes The synthesis ofall-trans retinol... 

Deprotonation of allyl tetramethylphosphorodiamidate, readily prepared from allyl alcohol, induces the migration of phosphorus from oxygen to carbon. A second deprotonation then occurs to give the dianion (33 Scheme 16). Alkylation with 1-iodopropane takes place at the 7-position to give hexanoic acid after hydrolysis. Reaction of (33) with aldehydes and ketones followed by hydrolysis gives 7-lac-tones, and a similar sequence with epoxides produces 6-lactones. 

Deprotonation of unusual carbon acids. Lithiation of epoxides as well as of chromium-carbene complexes is a prelude to C-C bond formation. a-Keto acids are converted to a-alkoxyacrylic acids on quenching the dianions with hard carbon electrophiles." ... 

Hydroxyacetylenic acids. The dianion of propiolic acid (1) can be generated at -45° with LDA in 1 1 THF—HMPT solution. The dianion reacts with epoxides to form 5-hydroxyacetylenic acids (2) in moderate yields. The products can be converted into substituted 5,6-dihydro-2H-pyrane-2-ones, a ring... 

The dianion reacts with epoxides to form y-hydroxy acid s, which can be dehydrated to trimethylsilyl-7-butyrolactones ... 

Trimethylsilyl triflate catalyses the condensation of enol silyl ethers (e.g., PhC(OSiMe3)=CHMe) with 2-acetoxytetrahydropyran to give a 62 38 mixture of erythroithreo pyrans (2).23 Cyclization of 7-hydroxyketones [such as (3)] (which are obtained by the action of dianions on epoxides) by bases gives on prolonged reaction the cis-tetrahydropyran (4) whilst shorter reaction times lead to a cis-trans mixture.21 ... 

Valerolactones. - Dianions (441), derived from the parent acrylic acids using t-butyl lithium, condense smoothly with epoxides in the presence of BF2-OEt2 to give generally excellent yields of the unsaturated lactones (442), useful as precursors to a wide range of valerolactones... 

Enaminones 93 can be regioselectively dimetallated to give the kinetic dianion 94 or the thermodynamic dianion 95. Treatment of 94 and 95 with epoxides 96 gives isomeric hydroxy enaminones 97 and 98, which cy-clize under acidic conditions to give a-tetrahydrofurylidene ketones 99 [92JCS(P1)2095]. (See Scheme 27 on facing page.)... 

The dianion was also shown to undergo ring-opening reactions with epoxides and aziridines (eq 11). 

The substituted ketene S,S-dithioacetal (76) has been developed as a P-lithioacrylate equivalent (Scheme 22). Deprotonation of (76) leads to an allylic anion (77) that reacts with a wide range of electophiles to give the T-substituted adduct (78), as the only observed product. Hydrolysis of the ketene thioacetal then releases the carboxyl residue, and this activates the system towards elimination of thiophenol, thereby unmasking the acrylate unit. Dianion (79) may also be regarded as a modified B-lithio-acrylate equivalent, but the chemistry of this species is diverse. Not only have B-substituted a, B-unsaturated amides been synthesized, but the same reagent reacts, for example, with epoxides to give ultimately dihydropyrans the species (79) is therefore perhaps more accurately represented as equivalent to the dipolar... 

Seebach has demonstrated the synthetic utility of the highly nucleophilic doubly reduced diene systems (23) and (24) as d reagents. The lithium-potassium dianion (23) condenses at the 5-carbon with carbonyl compounds, and the dianion (24) is alkylated at this position with epoxides (Scheme 20). ... 

Keto-acids.—The generation and reactions of dianions (7) have been reported. These react very efficiently with alkylating agents (even cyclohexyl tosylate affords a 64% yield of the expected adduct) to give a-keto-acid derivatives. Treatment of (7) with epoxides leads to butyrolactones and with aziridines to y-amino-a-keto-acid derivatives (see also ref. 77a). A simple looking route to /8-keto-acids (9) is by condensation between an acid chloride and the enolate of... 

A full report has been published on the generation of the dianionic species (14) by halogen/metal exchange with 2-bromo-3-phenylcinnamic acid (Bu"Li, -100 C). Subsequent trapping with electrophiles leads to 2-substituted-3-phenylcinnamic acids in 47—74% yield (six examples) reactions with epoxides. 

The dianion of acid (1) also reacts with alkyl halides to afford substituted a-trimethylsilylcarboxylic acids. With epoxides, the dianion provides )/-hydroxy acids that cyclize to a-silylbutyrolactones (eq 2) The resultant a-silyl lactones (2) are precursors to a wide variety of functionalized derivatives. The direct conversion of a butyrolactone to its a-sUyl analog is complicated by the competition of the 0-silylation pathway. 

Despite its own valuable synthetic potential, the use of [ C2]acetylene as a starting material for various building blocks is of much higher relevance. Mercury(II)-catalyzed hydration, for example, gives [ C2]acetaldehyde (Figure 8.5, Route 1) The same reaction carried out in the presence of ammonium persulfate furnishes [ 2] acetic acid (Route 2). Trapping of its mono- or dianion with formaldehyde or carbon dioxide affords [2,3- C2]propynol, [2,3- C2]butyne-l,4-diol, [2,3- C2]propiolic acid " and [2,3- C2]acetylenedicarboxylic acid, respectively (Routes 3-6). UV irradiation of a mixture of HBr and [ C2]acetylene produces l,2-dibromo[ C2]ethane (Route 8) . Reduction with chromium(II) chloride followed by a two-step epoxidation of the initially formed [ C2]ethylene converts [ 2]acetylene into [ C2]ethylene oxide (Route 7) . Finally, catalytic homotrimerization or co-trimerization with other alkynes provides [ " C ]benzene or substituted [ " C ]benzenes, respectively, the central starting materials for the vast majority of substituted benzenoid aromatic compounds (Route 9). 

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

The dianions derived from furan- and thiophene-carboxylic acids by deprotonation with LDA have been reacted with various electrophiles (Scheme 64). The oxygen dianions reacted efficiently with aldehydes and ketones but not so efficiently with alkyl halides or epoxides. The sulfur dianions reacted with allyl bromide, a reaction which failed in the case of the dianions derived from furancarboxylic acids, and are therefore judged to be the softer nucleophiles (81JCS(Pl)1125,80TL505l). 

Metalated epoxides can react with organometallics to give olefins after elimination of dimetal oxide, a process often referred to as reductive alkylation (Path B, Scheme 5.2). Crandall and Lin first described this reaction in their seminal paper in 1967 treatment of tert-butyloxirane 106 with 3 equiv. of tert-butyllithium, for example, gave trans-di-tert-butylethylene 110 in 64% yield (Scheme 5.23), Stating that this reaction should have some synthetic potential , [36] they proposed a reaction pathway in which tert-butyllithium reacted with a-lithiooxycarbene 108 to generate dianion 109 and thence olefin 110 upon elimination of dilithium oxide. The epoxide has, in effect, acted as a vinyl cation equivalent. 

The reductive elimination of a variety of )3-substituted sulfones for the preparation of di-and tri-substituted olefins (e.g. 75 to 76) and the use of allyl sulfones as synthetic equivalents of the allyl dianion CH=CH—CHj , has prompted considerable interest in the [1,3]rearrangements of allylic sulfones ". Kocienski has thus reported that while epoxidation of allylic sulfone 74 with MCPBA in CH2CI2 at room temperature afforded the expected product 75, epoxidation in the presence of two equivalents of NaHCOj afforded the isomeric j ,y-epoxysulfone 77. Similar results were obtained with other a-mono- or di-substituted sulfones. On the other hand, the reaction of y-substituted allylic sulfones results in the isomerization of the double bond, only. The following addition-elimination free radical chain mechanism has been suggested (equations 45, 46). In a closely related and simultaneously published investigation, Whitham and coworkers reported the 1,3-rearrangement of a number of acyclic and cyclic allylic p-tolyl sulfones on treatment with either benzoyl peroxide in CCI4 under reflux or with... 

Scheme 2.52. Reactions of epoxide 2-221 with 1,3-dicarbonyl dianions.

Salen stands for the tetradentate, dianionic ligands bis(salicylidene)-ethylenediamines (not the formal name either ), which form extremely stable complexes with a large variety of metals. Their basic structure and the simplified reaction equation for epoxidation is given in Figure 14.9. 

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