Bases Potassium amide

Evidence supporting the benzyne mechanism has been obtained by studying the reaction between bromobenzene and the strong base potassium amide (KNH2) in liquid NH , solvent. When bromobenzene labeled with radioactive at the Cl position is used, the substitution product has the label scrambled between Cl and C2. The reaction must therefore proceed through a symmetrical intermediate in which Cl and C2 are equivalent— a requirement that only benzyne can meet. 

Problem 8.20. A representation for a pathway for the conversion of the phenyl diethylphosphate to aminobenzene (aniline, C6H5NH2) is provided in Scheme 8.36. It has been proposed that the strong base (potassium amide) removes a proton ortho to the phosphate linkage of the aromatic bond and that benzyne is formed. Benzyne then reacts with the ammonia solvent to produce the product. An alternative process might involve, for example, direct displacement of the diethylphosphate anion. Write out at least these two suggested processes and propose what you might do to determine which is occurring (if either). 

Very strong bases such as sodium or potassium amide react readily with aryl halides even those without electron withdrawing substituents to give products corresponding to nucleophilic substitution of halide by the base... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

Benzyne is formed as a reactive intermediate in the reaction of aryl halides with very strong bases such as potassium amide... 

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). 

The reaction of 2-methyl-2-phenylisoindolinium iodide (16) with potassium amide as the base, affords both 2-phenyl- (17) and 2-methyl-iso indole (6), together with the azadibenzocycloheptadiene (18). ... 

Formation of the excited amide anion of coelenteramide as the light emitter in the luminescence reaction of coelenterazine was experimentally supported by the experiment of Hori et al. (1973a), in which 2-methyl analogue of coelenterazine was used as the model compound. The summary of their work is as follows In the presence of oxygen, la and lb in DMF emitted bright blue luminescence (Amax 480 and 470 nm, respectively), and produced the reaction products Ha and lib, respectively. The fluorescence emission of lib (Amax 470 nm) and that of the spent chemiluminescence reaction of lb, both in DMF plus a base (potassium r-butoxide), were identical to the chemiluminescence emission of lb in DMF. The fluorescence emission of Ha... 

Kinetic studies of base-catalysed hydrogen exchange have been carried out by Roberts, by Shatenshtein, and by Streitweiser and their coworkers. In earlier work, potassium amide was used as base in liquid ammonia as solvent, whereas later workers used lithium and caesium cyclohexylamides in cyclohexylamine. The reaction can be represented by equilibria (239) and (240)... 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

In the presence of a very strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations.79 For example, reaction of benzoylacetone with sodium amide leads first to the enolate generated by deprotonation at the more acidic methylene group between the two carbonyl groups. A second equivalent of base deprotonates the benzyl methylene group to give a dienediolate. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

WIN 64821 (10) and (—)-ditryptophenaline (11) syntheses [7], not only effectively differentiated the two amide moieties but also most importantly marked the first in a series of stereochemical transfer steps in which the stereochemistry of the constituent L-amino acids was relayed to ultimately define each of the relative and absolute stereochemical configurations at all eight stereogenic centers found in the target compound. Finally, /V-methylation of the base-sensitive amide in 77 % yield using methyl iodide and potassium carbonate in acetone completed the 5-step synthesis of our key tetracyclic bromide monomer starting from commercially available amino acid derivatives. 

As already reported in Section II,A, the amination of 6-bromo-5-deuterio-4-phenylpyrimidine with potassium amide in liquid ammonia provides a produet in which deuterium is no longer present. Based on the work deseribed previously, it seems reasonable to conclude that this easily occurring deuterium-hydrogen exchange takes place in the intermediary imidoyl bromide (17a, X = Br) (Scheme 11.18) and not in the cyanoazadiene (17b). In the strong basie medium a fast equilibrium can be formulated between these open-ehain intermediates (17a, X = Br, 29, and 30) (Scheme 11.18). 

The application of the Chichibabin amination to effect a direct amination of quinazoline has been reported. It gives 4-aminoquinazoline (60MII) as well as 2,4-diaminoquinazoline (59GEP958197). No mechanistic details were discussed, but it can be expected (based on the experience with the amination with 4-phenyl- and 5-phenylpyrimidine) that amination of quinazoline would also involve, at least partly, participation of the Sn(ANRORC) mechanism. Amination with N-labeled potassium amide/liquid ammonia will certainly shed some light on the mechanism operative in this Chichibabin amination. 

Benzyl-6-methylcyclohexanone has been prepared by the hydrogenation of 2-benzylidene-6-methylcyclohexanone over a platinum or nickel catalyst, and by the alkylation of the sodium enolate of 2-formyl-6-methylcyclohexanone with benzyl iodide followed by cleavage of the formyl group with aqueous base. The 2,6-isomer was also obtained as a minor product (about 10% of the monoalkylated product) along with the major product, 2-benzyl-2-methylcyclohexanone by successive treatment of 2-methylcyclohexanone with sodium amide and then with benzyl chloride or benzyl bromide. Reaction of the sodium enolate of 2-formyl-6-methylcyclohexanone with potassium amide in liquid ammonia formed the corresponding dianion which was first treated with 1 equiv. of benzyl chloride and then deformylated with aqueous base to form 2-benzyl-2-methylcyclohexanone.i ... 

Feuer and co-workers ° conducted extensive studies into alkaline nitration with nitrate esters, exploring the effect of base, time, stoichiometry, concentration, solvent, and temperature on yields and purity. Reactions are generally successful when the substrate a-proton acidity is in the 18-25 p A a range. Alkoxide bases derived from simple primary and secondary aliphatic alcohols are generally not considered compatible in reactions using alkyl nitrates. Optimum conditions for many of these reactions use potassium tert-butoxide and amyl nitrate in THF at —30 °C, although in many cases potassium amide in liquid ammonia at —33 °C works equally well. 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

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