Deprotonation superbases

The "zip-reaction (U. Kramer, 1978, 1979) leads to giant macrocycles. Potassium 3- ami-nopropyl)amide = KAPA ( superbase ) in 1,3-diaminopropane is used to deprotonate amines. The amide anions are highly nucleophilic and may, for example, be used to transam-idate carboxylic amides. If N- 39-atnino-4,8,12,16,20,24,28,32,36-nonaazanonatriacontyl)do-decanolactam is treated with KAPA, the amino groups may be deprotonated and react with the macrocyclic lactam. The most probable reaction is the intramolecular formation of the six-membered ring intermediate indicated below. This intermediate opens spontaneously to produce the azalactam with seventeen atoms in the cycle. This reaction is repeated nine times in the presence of excess KAPA, and the 53-membered macrocycle is formed in reasonable yield. 

PH3, primary and secondary phosphines can be deprotonated in the superbasic KOH(solid)/DMSO media [15,16,25]. Nucleophilic aromatic substitution of fluorine in substituted fluorobenzenes with the resulting... 

Standard organolithium reagents such as butyllithium, ec-butyllithium or tert-butyllithium deprotonate rapidly, if not instantaneously, the relatively acidic hydrocarbons of the 1,4-diene, diaryhnethane, triarylmethane, fluorene, indene and cyclopentadiene families and all terminal acetylenes (1-alkynes) as well. Butyllithium alone is ineffective toward toluene but its coordination complex with A/ ,A/ ,iV, iV-tetramethylethylenediamine does produce benzyllithium in high yield when heated to 80 To introduce metal into less reactive hydrocarbons one has either to rely on neighboring group-assistance or to employ so-called superbases. 

An olefinic double bond can be conceived as a two-membered ring . The specific geometry at the unsaturated centers makes the latter prone to deprotonation. Nevertheless, superbasic reagents are required for the metalation of heteroatom-free alkenes (see Section... 

Ethyl phenyl sulphide is lithiated mainly in the ortho position, but with significant amounts of meta and para lithiation and substitution products. Superbases, on the other hand, prefer to deprotonate afkylthio benzenes at benzylic or a-positions, rather than on the ring ... 

The trilluoromethyl group behaves in a similar way , but it is now clear that deprotonation of sites ortho to such acidifying but non-coordinating and non-electrophilic substituents is best carried out with BuLi-KOBu-t superbases (see Section VI). A combination of BuLi metallation and superbase metallation of fluoroarenes has been used in the synthesis of components 163 and 164 for fluorinated liquid crystals (Scheme 82). ... 

Toluene itself can be lithiated by w-BuLi-TMEDA at or above room temperature, and deprotonation occurs almost exclusively at the methyl group—about 10% ring metallation (mainly in the meta position) is observed with w-BuLi-TMEDA (Scheme 188) . At lower temperatures deprotonation is very slow , and the best conditions for achieving the metallation of toluene are the Lochmann-Schlosser superbases (see Section VI) °. 

Fluorotoluene can be deprotonated in the benzylic position by the superbases, but the halogen appears to offer little activation to the process. 2-Trifluoromethyltoluene is more readily deprotonated, but decomposes by elimination of fluoride even at — 100°C . 

The combination of an alkyllithium with a metal aUcoxide provides a marked increase in the basicity of the organolithium . The most widely used of these superbases is the one obtained from BnLi and KOBu-t, known as LiCKOR (Li—C + KOR) °. The exact natnre of the prodncts obtained by snperbase deprotonations—whether they are organolithinms, organopotassiums, or a mixtnre of both—is debatable, as is the precise nature of the superbase itself. For example, while prolonged mixing of alkyllithium and... 

KOBu-f in hexane gives a precipitate of butylpotassium" " , the reactivity of a slurry of BuLi—KOBu-f does not match that of BuK. Simplistically, superbases can be considered to be organolithiums solvated by very electron-donating ligands (much more so than THF or TMEDA). As synthetic tools they provide a useful top end to the armoury of bases for regioselective functionalization by deprotonation. 

The violence of superbasic slurries towards functionalized organic molecules means that they are at their most effective with simple hydrocarbons they also tolerate ethers and fluoro substituents. LiCKOR will deprotonate allyUc, benzylic, vinylic, aromatic and cyclopropane C—H bonds with no additional assistance. From benzene, for example, it forms a mixture of mono and dimetallated compounds 617 and 618 (Scheme 241) . ( Li/K indicates metallation with a structurally ill-defined mixture of lithium and potassium.)... 

Deprotonation of 3-fluorotoluene 623 with n-BuLi—KOBu-f or, better, f-BuLi—KOBu-f follows the selectivity expected with these superbases and leads to metallation at the least hindered position ortho to the fluoro substituent. Trapping the metallated intermediate 624... 

The superbases are similar in that they avoid hindered positions next to coordinating groups, and prefer to deprotonate ortho to small, powerfully inductively withdrawing OMe, or even at benzylic positions. Superbases prefer to deprotonate both 647 and 648 ortho to OMe rather than the usually more powerfully directing anilide group (Scheme 251) . ... 

Although there is a kinetic barrier to the direct deprotonation of tertiary amines, Ahlbrecht and Dollinger showed in 1984 that the Schlosser superbase, i c-BuLi/f-BuOK, can deprotonate A-methylpiperidine selectively on the methyl group (Scheme 3). This superbase probably yields an a-amino-organopotassium species (and f-BuOLi), but treatment with LiBr effects transmetalation to the more nucleophilic, and less basic, a-amino-organolithium species. Electrophilic quench with several aldehydes and ketones gives substitution products in good yields as typified by the example in Scheme 3. Similarly,... 

The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase. 

The elimination of ethanol seems to start with deprotonation of the a-position of the pyrrole 54 under the action of superbase. The carbenoid intermediate 62 formed is then reduced (Scheme 32). The reducing properties of the KOH/DMSO system have been observed (88KGS350). 

Two general procedures are used to perform LICKOR deprotonations. Alkyllithium and potassium alkoxide can be combined to form the superbase before alkene addition, or the substrate mixed with one component of the superbase before addition of the other component. For LiC, w-BuLi, s-BuLi, and t-BuLi have all been used, whereas the hindered KOR component is most commonly KOt-Bu or sometimes potassium t-pentoxide. Although LICKOR generation is rapid even at low temperatures, substrate deprotonation can be sluggish. For this reason, an incubation period with the substrate at 0 °C or room temperature is often part of a LICKOR procedure. Such extended reaction times are also useful when torsional equilibration of the allylic carbanion is intended. Afterwards, the reaction mixture is cooled back to low temperature before addition of the electrophile. This is typically accompanied by a distinct color change from the vivid red of the allylic carbanion to yellow or decolorized reaction mixtures. 

Solid superbases can deprotonate alkenes in the allylic position and alkyl benzenes (toluene) in the benzylic position. Typical pK, values of some organic molecules are given in Scheme 1 [11], However, these values are only approximations, because plQ values of such highly basic compounds are indirectly adapted to the... 

In isomerization reactions, an alkene is deprotonated to form an allyl anion, which is reprotonated to give the more stable alkene (double-bond migration). The most simple example is the isomerization of 1-butene producing a mixture of cis- and trans-2-butene (Scheme 3). Because the stability of the cis-allyl anion formed as an intermediate is greater than for the trans form, a high cis/trans ratio is observed for base-catalyzed reactions whereas for acid-catalyzed reactions the ratio is close to unity. Thus, the cis/trans ratio of the products has frequently been used as an indication of base-catalyzed reaction mechanisms. The carbanions formed in the course of such superbase reactions are not freely mobile in solution,... 

Although allylic lithiation by deprotonation of non-heterosubstituted compounds is possible using superbases (see section 2.6), in most cases allylic lithiation requires a directing heteroatom. (Non-heterosubstituted allyllithiums are best produced by reductive lithiation of allyl ethers or allyl sulfides - see section 4.4.) One of the few cases where this heteroatom is not a to the new organolithium is shown below the p-lithiation of a homoallylic amide 137. The reaction is particularly remarkable because of the possibility of competing deprotonation... 

Extended allylic systems can be formed by deprotonation of dienes such as 142,144 and 147 with s-BuLi. The dienyllithiums 143, 146 and 148 adopt an extended W conformation, and react to give 1,3-butadienes 146 and 149 with retention of double bond geometry.19 The equivalent species 150 formed by deprotonation with LiCKOR superbases (see section 2.6) adopt a U -shaped configuration. 

Methylbenzyl alcohol 440 can just about be lithiated by treatment with BuLi in E O at room temperature, but the activation of the methyl group is very weak.401 Lateral lithiation of cresol 441 is even harder to achieve, and the superbase conditions required are similar to those used to deprotonate toluene.402 The coordinating effect of the oxyanion is more than outweighed by electron-donation into the ring. 

The BuLw-BuOK superbase will also deprotonate a to nitrogen31 or halogens. The latter leads to carbenoids such as 508, 510 and 512, which either decompose to carbenes (509, 511) or, if an appropriately placed silicon substituent is available, undergo Brook rearrangement (513).445... 

Flurbiprofen 52 (Froben , Cebutid ) is a non-steroidal anti-inflammatory whose structure makes it an ideal target for synthesis using a combination of the powerful deprotonating ability of the superbases and the weakly directing effects of a fluoro or an aryl substituent.5... 

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