Amide arylation alkylation

Action of alkali amides and alkyl- and aryl-lithiums on mono-halogeno aromatic compounds,... 

An aryl alkyl ketone 1 can be converted into an tn-arylalkane carboxylic amide 2 by employing the Willgerodt reaction The number of carbon centers is retained. The reaction is carried out by treating the ketone with an aqueous solution of ammonium polysulfide. A variant that has been developed by Kindler, and which is called the Willgerodt-Kindler reaction, uses a mixture of sulfur and a secondary amine instead of the ammonium polysulfide. 

In general, the rate of syn/anti equilibration increases with decreasing basicity of the enolate and with increasing steric repulsion in the enolate. The first point is illustrated by the fact that aldolates derived from ketones (X = aryl, alkyl) undergo syn/anti equilibration more readily than those derived from amides or carboxylates (X = NR2,0-). It appears that the rate of the retro-aldol addition is higher when the enolate thereby generated is more stable. 

Fagnou and co-workers reported on the use of a palladium source in the presence of different phosphine ligands for the intramolecular direct arylation reaction of arenes with bromides [56]. Later, they discovered that new conditions employing palladium complex 27 promoted the direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls including different functionalities as ether, amine, amide and alkyl (Scheme 7.11) [57]. 

R1 = H, alkyl, aryl R4 = aryl, alkyl, heterocycle E = ester, acyl, amide nitro... 

The reaction described is of considerable general utility for the preparation of benzoyloxy derivatives of unsaturated hydrocarbons.2"8 Reactions of 2-butyl perbenzoate with various other classes of compounds in the presence of catalytic amounts of copper ions produce benzoyloxy derivatives. Thus this reaction can also be used to effect one-step oxidation of saturated hydrocarbons,9, 10 esters,6,11 dialkyl and aryl alkyl ethers,12 14 benzylic ethers,11,15 cyclic ethers,13,16 straight-chain and benzylic sulfides,12, 17-19 cyclic sulfides,11,19 amides,11 and certain organo-silicon compounds.20... 

The PFR also takes place with aryl alkyl carbonates [125]. Methoxy-substi-tuted dervatives can undergo substitution of MeO by the acyl moiety, as has been reported for esters and amides. This is shown in Scheme 47 for 2-methoxyphenyl ethyl carbonate (168) [126]. On the other hand, the overall quantum yield of photoproducts is 10-fold lower in the para-than in the ortho- or (meta- me-thoxyphenyl. Chlorophenyl ethyl carbonates do not rearrange, but undergo C—Cl homolysis. The efficency of photodechlorination follows the order para < meta < ortho [127],... 

N-(a-Benzotriazolylalkyl)amides (487, = alkyl, aryl, and H) are very efficient amidoalkylating... 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

Amidation of alkyl aryl ethers.2 Either anisole or phenetole undergoes para-amidation exclusively on reaction with acetohydroxamic acid in polyphosphoric acid (yields 50-60%). Thus phenetole is converted into the drug phenacetin in -50% yield (equation I). 

This tripeptide provided moderate levels of selectivity (s < 12.6) for the KR of certain amide-containing sec-alcohols (see Section 8.2.1.4), but displayed essentially no selectivity for KR of aryl alkyl sec-alcohols. However, Miller subsequently devised an elegant fluorescent chemosensor-based screening protocol to assay for acylation [111, 115, 117, 119], and this facilitated the identification of octapeptide 28 as a much more efficient catalyst for KR of sec-alcohols via acylation [115]. The substrate scope includes not only aryl alkyl sec-alcohols but also alkyl alkyl sec-alcohols for which lipases and other organocatalysts invariably perform poorly (Scheme 8.7). 

In intermolecular cyclopropanations [100], it was found better to use a-bromoesters and amides as ylide precursors and a,/ -unsaturated ketones and esters as electron-deficient alkenes - rather than using a-haloketones as the ylide precursor. (For experimental details see Chapter 14.11.4). The reaction gives access to a range of 1,2-dicarbonyl-substituted cyclopropanes (see Fig. 10.5). The al-kene could have an aryl-, alkyl- or indole-substituted ketone, and a-substitution was also tolerated. Notably, Weinreb amides could be used as the ylide precursor and the product subsequently transformed into a diketocyclopropane. Both enan-... 

Selective fluorination of a wide variety of carbanions has been carried out very effectively with iV-fluoro-Y-alkyl sulfonamides by Barnette63. Treatment of carbanions of malonates, enolates of ketones, acids and amides, and alkyl and aryl organometallics results in the transfer of fluorine from nitrogen to carbon (equation 43). Yields are fair to... 

SECTION 80 Amides from Alkyl, Methylenes, and Aryls... 

Ma—Bae may be a covalent or ionic metal amide, alkoxide, alkyl or aryl, or hydroxide depending on the nature of the monomer. M° in equation (4) generally represents an alkali metal which may give up... 

In the WiUgerodt reaction, aryl alkyl ketones react with sulfur and ammonium hydroxide to give amides with the same number of carbon atoms (equation 36). In an extension, aliphatic ketones, aldehydes and unsaturated hydrocarbons also can be used as starting materials. 

Willgerodt reaction. In its original form this reaction involved heating an aryl alkyl ketone in a sealed tube at 210-230° with an aqueous solution of yellow ammonium polysulfide, prepared by dissolving sulfur in ammonium sulfide solution. The product is an aryl substituted aliphatic aciil amide, together with some of the corresponding carboxylic acid and often the hydrocarbon. An example is the... 

Fluorenone oxime was recovered unchanged after being heated with PPA at 120°, but at 180° it was rearranged in almost quantitative yield (Conley )- Conley found PPA to be a superior solvent-catalyst for the Schmidt rearrangement. He added sodium azide in portions to a mixture of a diaryl, aryl-alkyl, symmetrical or unsymmetrical ketones with 15-20 parts of PPA at a temperature in the range 25-75° until evolution of nitrogen ceased, and obtained amides in yields mainly of 80-90%. Doorenbos and Wu studied the conversion of cholestanone and... 

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