Amide “superbase

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of II might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of foimaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aprotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures. The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

Scheme 16.3. The amide superbase mechanism for ECD of peptides. Electron capture in an excited state of a backbone amide group is followed by proton transfer for charge neutralization and subsequent N-Co, bond cleavage. (Reproduced from Ref. 180 with permission from Elsevier Science.)...

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. 

In a deliberate attempt to trap the carbanion/amide intermediates formed en route to the homoamido inverse crown complexes, [ (TMP)(/z-Bu)(/x-TMP)NaMg(TMEDA) ] 432 (Figure 38) was isolated and characterized.440 This complex spans the superbase and inverse crown structural modalities. 

Potassium loaded on a porous silicon nitride has been reported as a superbase catalyst. With appropriate pre-treatment, the catalyst was found to be highly active for 2,3-dimethylbut-l-ene isomerisation yielding 2,3-dimethylbut-2-ene in close to 100% selectivity. In order for high activity to be demonstrated, 30 wt% potassium amide was loaded by impregnation. A trace of Fc203 was also added on impregnation. A silicon nitride synthesised via a silicon diimide precursor which was pre-treated at 1000°C was found to be best and the catalyst was activated by heating in vacuo. The possibility that this resulted in active potassium nitride species via ... 

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... 

Steric hindrance controls a three-way divergence of regioselectivity in the metallation of 530.456 n-BuLi lithiates ortho to OMe at the site where coordination to the secondary amide can also be achieved. r-BuLi prefers to lithiate at the less hindered benzylic site, still presumably benefitting from amide coordination. The superbase, on the other hand, cares nothing for coordination to the amide and metallates at the less hindered site ortho to OMe. 

Another mixed aggregate complex consisting of Bu°Li and r-butoxide was reported in 1990 as the tetramer (45). Hiis complex was first isolated by Lochmann and has been shown to be tetrameric and dimeric in benzene and THF, respectively, by cryoscopic measurements, and it has also been studied by rapid injection NMR techniques. Hiis species has received much attention because it is related to the synthetically useful superbasic or LiKOR reagents prepared by mixing alkali metal alkoxides with lithium alkyls or lithium amides. ... 

T4.5 Start from Section 4.14 Superacids and superbases which covers classical examples of superbases, nitrides, and hydrides of s-block elements. However, there are several groups of superbases that you can look at. For example, amides (diisopropylamide related) are commonly used superbases. More modem are phosphazene bases which are neutral rather bulky compounds containing phosphorus and nitrogen. An interesting topic is a proton sponge (or Alder s base) and its derivatives as well as several theoretical and practical approaches used in rational design of superbases. 

Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. -This route has not received much attention over the past year. A stereoselective synthesis of tris(Z-styryl)phosphine is offered by the addition of phosphine to phenylacetylene in a superbasic system (HMPA-H20-K0H)." In a similar vein, the reaction of phosphine with styrene and a-methylstyrene in a superbasic medium (DMSO-KOH) provides a route to the primary phosphines, (2-phenylethyl)phosphine and (2-methyl-2-phenylethyl)phosphine, respectively. 7 Transition metal phosphine complexes have been shown to catalyse the a-hydroxylation, P-cyanoethylation, and P-alkoxycarbonylethylation of phosphine. 71 Addition of primary phosphines to acrylic esters has been used for the synthesis of the phosphines (80).7 A similar addition of diphenylphosphine to acrylic esters and amides has given a series of hydrophilic phosphines (81). 72 The bis(phosphorinanyl)ethane (82) is formed in the photochemical addition of l,2-bis(phosphino)ethane to 1,4-pentadiene. ... 

The phosphazene bases BTPP and Bu-P2 mediate the rearrangement of unactivated A -alkyl-(9-benzoyl hydroxamic acid derivatives to give 2-benzoyl amides. The rate of reaction was found to be dependent upon the steric nature of the A -alkyl substituent [39a]. Treatment of malonyl derived (9-acyUiydroxamic acid derivatives with the phosphazene superbase Bu-P2 gives 2,3-dihydro-4-isoxazole carboxylic ester derivatives. The rate and yield of the reaction depend upon the (9-acyl substituent [36b] (Scheme 5.21). 

Despite these fascinating properties, there have been very few studies on the development of asymmetric organobase catalysts [31,39,89], compared with the dramatic progress in polymer-supported chiral lithium amide based asymmetric transformations [90]. It can be expected that new effective polymer-supported chiral superbase reagents will be discovered in the near future. 

DIRECTED METALATION OF ARENES WITH ORGANOLITHIUMS, LITHIUM AMIDES, AND SUPERBASES... 

To further examine the nucleophilic side of the CH activation continuum, the our group and the Cundari group undertook a computational study [59] of alkali metal amide and alkaline earth metal amide CH activation reactions with alkanes. This study is directly related to classic superbase chemistry using cesium cyclohexylamide-type reagents to induce CH bond deprotonation of alkanes [60]. 

Chardin, A., Berthelot, M., Laurence, C. and Morris, D.G. (1994) Carbonyl oxygen as a hydrogen-bond superbase the amidates. J. Phys. Org. Chem., 7, 705-711. 

Superbase systems are known to contain a strong base and a solvent or reactant capable of specifically binding the cation baring the conjugated anion [138]. Such systems can be prepared on the basis of linear or cyclic glycol ethers, microcyclic polyethers (crown ethers), highly polar non hydroxylic solvents (sulfoxides, e.g., DMSO), sulfones (sulfolane), amides (N-methylpyrrolidone, dimethylformamide, hexametapol), and phosphine oxides as well as from liquid anunonia, amines, etc. For example, basicity of sodium methylate in 95% DMSO is by seven orders higher than in pure methanol [139]. 

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