Ethers reaction with amide bases

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

For the synthesis of perfectly dendronized sohd-phase polymers (Fig. 7.4) various dendritic structures were prepared based on amide connections [6]. For example, the naturally occurring amino acid lysine was used as a building block in creating a dendritic scaffold [33]. The synthesis of symmetrical tri-branching den-drimers on aminomethyl polystyrene macrobeads was also described in literature [34]. Recently, aryl ether dendrimers were prepared on hydroxymethyl polystyrene using a Mitsunobu reaction with 3,5-bis(acetoxymethyl)phenol [35]. 

Lactams and some non-cyclic, secondary amides (RCONHR) can be alkylated with high regioselectivity either at nitrogen (Section 6.6) or at oxygen. N-Alkylations are generally conducted under basic reaction conditions whereas O-alkylations are often performed with trialkyloxonium salts, dialkyl sulfates, or alkyl halides/silver salts without addition of bases. Protonated imino ethers are formed these are usually not isolated but are converted into the free imino ethers with aqueous base during the work-up. Scheme 1.8 shows examples of the selective alkylation of lactams and of the formation of 2-pyrrolidinones or 2-iminotetrahydrofurans by cycli-zation of 4-bromobutyramides. 

A solution of 2.5 parts of sodium in n-butylalcohol is boiled with 30 parts of a-chloro-y-quinoline-carboxylic acid diethyl-amino-ethylene-amide in a reflux apparatus, and when the reaction is over the excess of butylalcohol is distilled. The remaining base is taken up with ether the solution is washed with water and dried. The solvent is then distilled. The a-n-butoxy- quinoline-carboxylic acid diethyl-amino-ethylene-amide forms as colorless crystals, after recrystallization from petroleum ether melting point of it 64°C. 

A vigorously stirred suspension of 0.2 to 1 mole of sodium amide in 200 ml of xylene, in which were dissolved 0.1 mole of a,a-diphenyl-7-hexamethyleneimino butyronitrile was boiled for 12 hours. Thereupon the excess of sodium amide was decomposed with water and the xylene layer was separated, washed with water and extracted with hydrochloric acid. This acidic extract was made strongly alkaline with concentrated lye and the separated base was extracted with ether. After drying, the ether was evaporated and the l,l-diphenyl-3-hexamethyleneimino propane distilled in vacuo. The boiling point was 170-174°C/1 mm, the refractive index nD20 = 1.56 36, and the density d420 = 1.009. From the oil obtained several acid additions and quaternary ammonium salts can be obtained by reaction with acids containing a non-toxic anion or esters thereof. The hydrochloric acid salt, for instance, melts at 189-192°C, the methiodide at 174-177°C under decomposition. 

To a suspension of 3.12 g of sodium amide in 50 ml dry toluene was added dropwise 12 g of 2-(dimethylamino)ethylaminopyridine. The mixture was refluxed for 2 hours, cooled to 50°C, and 21 g 3-thenyl bromide was added dropwise. When reaction subsided, the brownish-orange mixture was refluxed for 0.5 hour, cooled, and poured into 150 ml of water. The toluene layer was separated, extracted with 5% hydrochloric acid. This extract was saturated with potassium carbonate. The free base was extracted with ether, dried and fractionated. Yield of N,N-dimethyl-N -2-pyridinyl-N -(3-thienylmethyl)-l,2-ethanediamine 31%, boiling point 169-172°C/1 mm. 

The oxidation of alcohols to aldehydes or ketones by periodane has several advantages over chromium and DMSO-based oxidants because of its shorter reaction times, higher yields and simplified work up. There is very little overoxidation to the carboxylic acid. It is a practical reagent for the facile and efficient oxidation of benzylic and allylic alcohols. Saturated alcohols are slow in their reactions with it. It oxidizes alcohols in the presence of non-hydroxylic functional groups such as sulfides, enols, ethers, furans and 2°-amides. An example of the DMP oxidation is the oxidation of 3,4,5-trimethoxybenzyl alcohol (7.17) with 7.16 in CH2CI2 to give 94% yield of 3,4,5-trimethoxybenzaldehyde (7.18). 

The nucleophilicity of silyl enol ethers has been examined. Base-induced formation of the enolate anion generally leads to a mixture of (E)- and (Z)-isomers, and dialkyl amide bases are used in most cases. The (EjZ ) stereoselectivity depends on the structure of the lithium dialkylamide base, with the highest EjZ) ratios obtained with LiTMP-butyllithium mixed aggregates in THF. ° The use of LiHMDS resulted in a reversal of the (E/Z) selectivity. In general, metallic (Z) enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. 

In the presence of a strong base, the a carbon of a carboxylic ester or other acid derivative can condense with the carbonyl carbon of an aldehyde or ketone to give a p-hydroxy ester, ° amide, and so on., which may or may not be dehydrated to the a,p-unsaturated derivative. This reaction is sometimes called the Claisen reaction an rmfortunate usage since that name is more firmly connected to 16-85. Early reactions used hydroxide or an alkoxide base in water or alcohol solvents, where self-condensation was the major process. Under such conditions, the aldehyde or ketone was usually chosen for its lack of an a-proton. Much better control of the reaction was achieved when amide bases in aprotic solvents, such as ether or THE, were used. The reaction of tert-butyl acetate and in hexane... 

Functionally substituted benzylic, allylic, and vinylic compounds containing alkoxides, esters, ethers, nitriles, or amides can be reacted with halosilanes under Barbier conditions using HMPT to yield C- and O-silylated products, 1,2- or 1,4-addition products, as well as reductive dimers. Radical and anionic intermediates are postulated, based on SET reactions from the metal, and multiple silated species can be obtained. The use of the TMSCl-Mg-HMPT system has been extensively investigated by Galas group [85] at the University of Bordeaux, and their work has greatly advanced the science of the Barbier reaction with silanes. 

Since most of the synthetically useful enolate anions described in the previous section are prepared by the reactions of enolizable substrates with alkali metal amide bases, it is appropriate to note a few structures of these amide bases. The common bases in synthetic organic chemistry include LDA and LHMDS. The structures of both of these bases are known as the THF solvates.Both of these compounds form bis-solvated dimers corresponding to structure (201). The diethyl ether solvate of LHMDS also forms a bis-solvated dimer (202).Sodium hexamethyldisilazide crystallizes as an unaggregated monomer from benzene solution.Two different cryst line forms of KHMDS are known as the polymeric dioxane solvate (203), ° and the unsolvated dimer (204). ... 

The above described acid amide was finely powdered, and shaken continuously with a slight excess of sodium hypochlorite (compare, Trans., 1910, 97,1210) until the whole had passed into solution. The liquid was then heated to 100° for a short time, and, after cooling, thoroughly extracted with ether. The ethereal solution, which contained the J3-3 5-dimethoxyphenylethylaraine formed in the reaction, was agitated with small portions of dilute hydrochloric acid until no further quantity of base was extracted. The, acid extracts were then united, and shaken... 

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