Bases amide

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

Amide-Based Sulfonic Acids. The most important amide-based sulfonic acids are the alkenylarnidoalkanesulfoiiic acids. These materials have been extensively described ia the Hterature. A variety of examples are given ia Table 5. Acrylarnidoalkanesulfoiiic acids are typically prepared usiag technology originally disclosed by Lubrizol Corporation ia 1970 (80). The chemistry iavolves an initial reaction of an olefin, which contains at least one aHyhc proton, with an acyl hydrogen sulfate source, to produce a sulfonated intermediate. This intermediate subsequendy reacts with water, acrylonitrile, and sulfuric acid. 

Compounds where fluorine is bound directly to silicon may be prepared duectly from sihcon tetrafluonde, obtamed by treatment of sihcon tetrachlonde with antimony tnfluonde and an alkyUithium or hthium amide base [99, 100] (equauon 80)... 

Alkyltrifluorosilanes and disubstituted difluorosilanes are themselves quite reactive with nucleophiles such as lithium amide bases [102, 103 104], alkyl-lithium reagents [1051, Gngnard reagents [105], or alkoxides [105] (equations 82 and 83)... 

Yagci and Deniziigil [44] applied the method of partial decomposition of MAIs introducing styrene and methyl methacrylate blocks into poly(amide)s. The poly-(amide)-based MAI had been prepared by a reaction of AIBN with formaldehyde (see Scheme 10). Evidently, since each unit of the preformed MAI carries one azo group, there are enough azo sites in every MAI molecule for a controlled and adjustable partial decomposition. 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

This fully aromatic amide, based oil the amino acid p-aminobenzoic acid, can be spontaneously synthesized from p-aminobenzoic chloride.7 9 72 To prevent this occurring at an unwanted moment, the amine group is masked by forming the hydrochloric acid salt with hydrochloric acid. 

A recent development in understanding the reactivity of bases has focused on their structures in solution and in the crystalline state. Due to the importance of dialkyl amide bases, there is a significant body of work, led by Williard and Collum , that has attempted to understand the structures of these reactive molecules. It is clear that they are aggregates. Lithium diisopropylamide (LiN/-Pr2) was isolated from a THF solution and X-ray crystallography revealed a dimeric structure (13 R = i-Pr, S = THF) in the... 

Phosphinous amides, based on proline and tetrahydroisoquinoline carboxylic acid, bearing a second donor center (50, Ar=Ph R =H, CH3,Tr, Ph R =H, CH3,Tr, Ph and 51, R =H,Tr R =H,Tr) (Scheme 40) have been developed for use in allylic alkylation and amination of substituted propenyl acetates, yielding the corresponding products in 87-98% (5-94% ee) and 29-97% (14-93% ee) respectively [55, 167]. With bidentate ligands of type 38 where R=(S)-PhMeCH, and with the bis(aminophosphanes) 52 (R=Ph) similar allylic alkylations have been also tested [168,169]. 

A range of amide bases can be employed. Typically LDA is used, but in certain complex cases, LiNEt2 was found to be more effective. One exceptional case involves the ostensibly simple alkylation of a cyanohydrin acetonide with allyl chloride (Eq. 12). Here, use of LDA gave essentially none of the desired product 39, whereas KHMDS or LHMDS gave excellent yields [5]. 

Note also that dialkyl ketones such as acetone and 3-pentanone are slightly more acidic than the simple alcohols in DMSO. Use of alkoxide bases in DMSO favors enolate formation. For the amide bases, -K b-h) << a(c-H)> and complete formation of the enolate occurs. 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

The stereochemistry of the silyl ketene acetal can be controlled by the conditions of preparation. The base that is usually used for enolate formation is lithium diisopropyl-amide (LDA). If the enolate is prepared in pure THF, the F-enolate is generated and this stereochemistry is maintained in the silyl derivative. The preferential formation of the F-enolate can be explained in terms of a cyclic TS in which the proton is abstracted from the stereoelectronically preferred orientation perpendicular to the carbonyl plane. The carboxy substituent is oriented away from the alkyl groups on the amide base. 

These reagents are appropriate even for very sensitive molecules. Their efficacy is presumably due to the Lewis acid effect of the aluminum and magnesium ions. The hindered nature of the amide bases also minimizes competition from nucleophilic ring opening. 

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