Acylation direct

There are two approaches to the production of peptide a-oxo derivatives (1) the Dakin-West acylation directly from N-protected peptides (Section 15.1.5.1), and (2) oxidation of N-protected peptidyl a-substituted carboxylic acid derivatives (Section 15.1.5.2), which are prepared from N-protected peptides or nonpeptidyl intermediates. The oxidation approach has a synthetic advantage over the Dakin-West acylation as there can be retention of configuration in the final product, but it can be tedious to perform and, in some cases, it requires particular care. 

The orientation is right attack is para to one of the methoxy groups and ortho to the methyl. The substrate for the Friedel-Crafts acylation reaction, 3,4-dimethoxytoluene, is prepared from compound A by a Clemmensen or Wolff-Kishner reduction. Compound A cannot be acylated directly because it bears a strongly deactivating —CH substituent. 

C-Acylation. Active methylene compounds can be C-acylated directly by carboxylic acids with diethyl phosphorocyanidate (1) in combination with tri-ethylamine. DMF is the preferred solvent TMEDA or DBU can replace tri-ethylamine. ... 

The Fries rearrangement of acyloxybenzene or naphthalene derivatives proceeds smoothly in the presence of a catalytic amount of Sc(OTf)3 (Eq. 6) [19]. It has also been found that the triflate was an efficient catalyst in 2-acylation (direct acylation) reactions of phenol or naphthol derivatives with acid chlorides. Both reactions were successfully conducted by use of a small amount of Sc(OTf)3. 

Many other types of organometallics which are not acylated directly acid chlorides and which do not undergo addition to ketones may still transmetallate into the acylpalladiumfll) complex. Simple alkyl organomercurials have been acylated in this fashion to give moderate to good yields of ketones. " Larock has studied the palladium-catalyzed acylation of vinylmercury(II) compounds with acyl halides (equation 104). The reaction was only modestly productive and could not compare to the yield provided by aluminum chloride catalysis. 

In chapter 16 we shall discover that vinyl-copper reagents can be prepared with stereochemical control over double bond geometry and acylated directly with acid chlorides. We shall also meet vinyl silanes and see how they too can be acylated with acid chlorides. In this chapter we shall consider only the acylation of alkenes themselves with acid chlorides, that is the aliphatic Friedel-Crafts reaction.15 The normal Friedel-Crafts reaction 66 combines an aromatic compound with an acid chloride and a Lewis acid to give a cation 67 which loses a proton to give an aryl ketone 68. 

It has been a widespread assumption that enzymes are fragile molecules that only work in aqueous environments. However, over the last 20 years numerous reports have appeared that feature a wide range of enzymes used for organic synthesis in non-aqueous environments. The discovery that many enzymes retain their catalytic activity in non-aqueous media is often attributed to Klibanov, despite a few much earlier reports [1]. A non-aqueous system may be required for a given transformation due to solubility properties or to drive a reaction equilibrium (such as lipases working in the synthesis/acylation direction) and can even lead to advantages such as enhanced thermostability or altered substrate selectivity. 

The esterases and lipases are members of a still larger group of enzymes that catalyze acyl transfer, either in the direction of solvolysis or by acylation of the substrate. Both types of enzymes are called hydrolases. In water, hydrolysis occurs, but in the presence of alcohols, transesterification can occur. Reactions in the acylation direction are done in the presence of acyl donors. Esters of enols such as vinyl acetate or isopropenyl acetate are often used as sources of the acyl group. These enol esters are more reactive than alkyl esters, and the enol that is displaced on acyl transfer is converted to acetaldehyde or acetone. To avoid side products arising from these carbonyl compounds, one can use 1-ethoxyvinyl esters, which give ethyl acetate as the by-product. ... 

Further, preparation of the carboxylic acid salts is unnecessary if the free acid is acylated directly with the acid chloride. 

In this procedure, a-glycerol phosphate is acylated directly using acyl anhydrides (Lapidot et aL, 1969). The acyl anhydrides are prepared with dicyclohexyl-carbodi-imide (Rosenthal, 1975). Optically active or racemic phosphatidic acids can be prepared and either saturated or unsaturated acyl residues added. The method depends on the ability of the fatty acid salt to suppress the formation of mixed phosphoric-carboxylic anhydrides with the consequent phosphorylation of adjacent hydroxy groups. The use of acyl anhydrides rather then acyl chlorides probably prevents the formation of glycerol chlorhydrin esters (Aneja and Chadha, 1971a). 

Wliile the earliest TR-CIDNP work focused on radical pairs, biradicals soon became a focus of study. Biradicals are of interest because the exchange interaction between the unpaired electrons is present tliroiighoiit the biradical lifetime and, consequently, the spin physics and chemical reactivity of biradicals are markedly different from radical pairs. Work by Morozova et al [28] on polymethylene biradicals is a fiirther example of how this method can be used to separate net and multiplet effects based on time scale [28]. Figure Bl.16.11 shows how the cyclic precursor, 2,12-dihydroxy-2,12-dimethylcyclododecanone, cleaves upon 308 mn irradiation to fonn an acyl-ketyl biradical, which will be referred to as the primary biradical since it is fonned directly from the cyclic precursor. The acyl-ketyl primary biradical decarbonylates rapidly k Q > 5 x... 

The mechanism of the Fries reaction is not known with certainty. One mechanism regards it as a true intramolecular rearrangement in which the acyl group migrates directly from the oxygen atom to the carbon atoms of the ring. Another scheme postulates that the ester is cleaved by the reagent... 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

Substituted 5-hydroxythiazoles (267b), Rj = alkylmercapto, acyl-amino, and sec-amino, are prepared by cydization of N-thioacyl-amino acids (266) with phosphorus tribromide or acetic anhydride (Scheme 137) (317, 350). i en the cydization of 266, R2 = H, is carried out with acetic anhydride in the presence of benzaldehyde (317, 325) or ethylformate (317), the benzylidene (268), R2=Ph, Rj = SR or CH2Ph, or 4-ethoxymethylene (268), Rj = SR and R2 = OEt, derivative is obtained directly (Scheme 138). 

Very strongly deactivating 0 II —CCI —C=N —SO3H -CF3 —NO2 (acyl chloride) (cyano) (sulfonic acid) (trifluoromethyl) (nitro) Meta directing... 

Because the position of electrophilic attack on an aromatic nng is controlled by the direct ing effects of substituents already present the preparation of disubstituted aromatic com pounds requires that careful thought be given to the order of introduction of the two groups Compare the independent preparations of m bromoacetophenone and p bromoace tophenone from benzene Both syntheses require a Friedel-Crafts acylation step and a bromination step but the major product is determined by the order m which the two steps are carried out When the meta directing acetyl group is introduced first the final product IS m bromoacetophenone... 

A less obvious example of a situation in which the success of a synthesis depends on the order of introduction of substituents is illustrated by the preparation of m nitroace tophenone Here even though both substituents are meta directing the only practical synthesis is the one in which Friedel-Crafts acylation is carried out first... 

The key here is to recognize that an ethyl substituent can be introduced by Fnedel-Crafts acylation followed by a Clemmensen or Wolff-Kishner reduction step later in the syn thesis If the chlorine is introduced prior to reduction it will be directed meta to the acetyl group giving the correct substitution pattern... 

Direct nitration of aniline and other arylamines fails because oxidation leads to the formation of dark colored tars As a solution to this problem it is standaid practice to first protect the ammo group by acylation with either acetyl chloride or acetic anhydride... 

Perfluoropolyethers with the linear perfluoropropoxy repeat unit have been commercialized (28). They are prepared by the anionic oligomerization of tetrafluorooxetane followed by direct fluorination to remove the acyl fluoride end group as well as to fluorinate the remaining CH2 groups n can vary widely. 

Ketone formation can also be avoided if one of the functional acyl halogens ia phosgene is blocked. Carbamyl chlorides, readily obtained by the reaction of phosgene with ammonia or amines, are suitable reagents for the preparation of amides ia direct Friedel-Crafts acylation of aromatics. The resulting amides can be hydroly2ed to the corresponding acids (134) ... 

When aiomatics aie present, they can capture the intermediate vinyl cation to give P-aryl-a,P-unsatutated ketones (182). Thus acylation of alkyl or aryl acetylenes with acyhum salts in the presence of aromatics gives a,P-unsaturated ketones with a trisubstituted double bond. The mild reaction conditions employed do not cause direct acylation of aromatics. 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

Liquid crystal polyesters are made by a different route. Because they are phenoHc esters, they cannot be made by direct ester exchange between a diphenol and a lower dialkyl ester due to unfavorable reactivities. The usual method is the so-called reverse ester exchange or acidolysis reaction (96) where the phenoHc hydroxyl groups are acylated with a lower aHphatic acid anhydride, eg, acetic or propionic anhydride, and the acetate or propionate ester is heated with an aromatic dicarboxyHc acid, sometimes in the presence of a catalyst. The phenoHc polyester forms readily as the volatile lower acid distills from the reaction mixture. Many Hquid crystal polymers are derived formally from hydroxyacids (97,98) and thein acetates readily undergo self-condensation in the melt, stoichiometric balance being automatically obtained. 

Direct alkylation or acylation of the oxygen of THF by exchange or addition occurs with the use of trialkyl oxonium salts, carboxonium salts, super-acid esters or anhydrides, acyhum salts, and sometimes carbenium salts. 

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