Acylation of Aliphatic Compounds

When a nitrile is reacted with an aromatic compound in the presence of HC1, in the additional presence of ZnC or AICI3, a ketimine salt is formed, which after subsequent hydrolysis gives an aromatic ketone  

The reacting species is a rather weak electrophile and, therefore, only particularly reactive aromatics are suitable substrates. Consequently, the reaction is restricted for polyhydric phenols and their ethers, and reactive heterocycles. With strong acidic systems, such as AICI3 in halogenated benzene solvents, alkylben-zenes can react at more elevated temperatures ( 50°C). Trichloroacetonitrile works also well with nonactivated aromatics. The 12 chloroimine, the protonated nitrile (13), or the nitrile coordinated with the Lewis acid are possible involved electrophiles. 

More recent studies with superacidic systems (TfOH, TfOH—SbF5), used also in the Gattermann reaction, indicated that strong acids significantly increase reactivities of benzene with benzonitrile.33 104 It is concluded that the superelectrophilic 14 dication formed as a results of protonation of 13 is the reactive species in the Houben-Hoesch reaction. 

In principle, the acylation of aliphatic compounds is analogous with the Friedel-Crafts acylation of aromatics in the sense that a hydrogen of the reacting alkanes, alkenes, or alkynes is replaced by an acyl group to yield ketones, unsaturated ketones, or conjugated acetylenic ketones, respectively. As discussed subsequently, however, the reactions are more complex. The acylation of aliphatics is an important but less frequently used and studied process.11-13 

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ACYLATION OF ALIPHATIC COMPOUNDS Similar to alkylation, not only aromatic but also aliphatic and cycloaliphatic compounds undergo Friedel-Crafts acylation reactions. 

CoBr2 is a very efficient catalyst for acylation of organozinc compounds with aliphatic and aromatic acid chlorides,... 

Of the acylation of aliphatics, the acylation of alkenes pioneered by Nenitzescu was mainly explored, because the resulting unsaturated ketones are intermediates in synthesis. This acylation of alkenes, however, has its difficulties. First, the product unsaturated ketones, which are reactive compounds themselves, can undergo various further transformations, such as addition, elimination, and isomerization, often resulting in complex product mixtures. The acylation of alkenes, therefore, is less selective and often yields products other than expected by a simple substitution of one of the vinylic hydrogens. 

Regioselective Acylation of Hydroxy Compounds. Aliphatic diols can be selectively acylated at the primary and secondary positions by a number of lipases in nonaqueous solvents... 

Regioselective Acylation of Hydroxy Compounds. Aliphatic diols can be selectively acylated at the primary position by a number of lipases in nonaqueous solvents. For example, PPL suspended in solutions of various diols in ethyl carboxylates catalyzes transesterification in a highly regioselective manner, producing primary monoesters in up to 97% yield (93). Similarly, chloramphenicol [56-75-7] (72) (R = N02) can be acylated by a number of lipases to produce optically pure, water-insoluble 3-O-palmitate in a highly selective manner (94). 

The direct interaction of benzyl carbonyl compounds 38 and 48 with aromatic aldehydes in the presence of PPA or AC2O + HC104(86KGS125 87TH1), or with acetals or acylals of aliphatic or aromatic aldehydes in the presence of triphenylmethyl perchlorate (73KGS881 75ZOR1962), gives rise to benzo[c]pyrylium salts 62 in yields of 15-70 %. 

The conversion of aliphatic and aromatic acyl halides to a keto nitriles has been effected by heating the halides with dry metallic cyanides, of which cuprous cyanide has given the most satisfactory results (60-87%). The acyl bromides rather than the chlorides ate preferred, at least in the formation of aliphatic compounds. Thus, pyruvonitrile is prepared in 77% yield from acetyl bromide and cuprous cyanide whereas no product is obtained if acetyl chloride is employed. Benzoyl cyanide is made in 65% yield by heating the corresponding acyl chloride with cuprous cyanide. "... 

Haworth phenanthrene synthesis. Acylation of aromatic compounds with aliphatic dibasic acid anhydrides to (i-aroylpropionic acids, reduction of the carbonyl group according to Clemmensen or Wolff-Kishner procedures, cyclization of the y-arylbutyric acid with 85% sulfuric acid, and conversion of the cyclic ketone to polycyclic hydroaromatic and subsequently to aromatic compounds. 

Acyl-2-pyrazoIin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-ones and conversion of other heterocycles. As might be expected the reaction of /J-ketoesters with hydrazines has been utilized.124,1124,1532,1533 In this case the /J-ketoester has an a-acyl substituent (eq. 216). Both Borsche and Lewinsohn124 and Vila1533... 

These studies allow the efficient synthesis of anfhraquinones under mild conditions, including anthracyclinones, by direcf ortho-bisacylafion of aromatic compounds with orf/io-phthaloyl dichlorides a few examples are reported in Table 2.6. Similarly, aromatic cycloalkanediones can be easily prepared by bis-acylation of aromafic compounds wifh different aliphatic diacyl chlorides. ... 

More interestingly, carboxylic acids can be employed in the acylation of aromatic compounds. The acylation of toluene and anisole with C2-C42 aliphatic carboxylic acids can be carried out with CsPW, affording the corresponding products in 41%-71% yield. These solid acids are superior in activity to the conventional acid catalysts such as sulfuric acid and zeolites, and can be reused after a simple workup, albeit with reduced activity. 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

When applied to ketones, this is called Norrish Type / cleavage or often just Type I cleavage. In a secondary process, the acyl radical R —CO can then lose CO to give R radicals. Another example of a category 1 process is cleavage of CI2 to give two Cl atoms. Other bonds that are easily cleaved by photolysis are the 0—0 bonds of peroxy compounds and the C—N bonds of aliphatic azo compounds R—N=N—R. The latter is an important source of radicals R , since the other product is the very stable N2. 

Acylation of the nitronate 9-71 leads to the iminium ion 9-72 which, by the addition of an isocyanide, forms the cation 9-73. Following two acyl group migrations, the compound 9-75 is obtained via 9-74. The best results were obtained when allylic nitro derivatives were used, as these can form the corresponding enolate in the presence of NEt3. Aliphatic nitro compounds could also be employed, but in these cases it was necessary to use the more basic DBU. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

One of the most potent, selective inhibitors to date comes from a series of aliphatic sulfides which has been optimized for HDAC6 selectivity over HDACs 1 and 4. The best compound, 18, exhibits an IC50 of 29 nM against HDAC6 and ca. 35-40-fold selectivity, but as with the original thiol compounds, the sulfur atom needs to be acylated to achieve cellular activity [46]. 

As outlined in Section 2, simple aliphatic compounds with short to medium length alkyl chains bind to CDs, and the strength of the binding increases in proportion to the chain length (C2 to C8) and size (Matsui et al., 1985 Tee, 1989 Tee et al., 1990b). Thus, with aryl esters having medium length alkanoate chains it is possible that inclusion of the acyl chain of the ester may become dominant in the initial state, and possibly in the transition state for esterolysis also. Several studies support this expectation. 

Hudson, B. E., and Ch. R. Hauser Condensations. XVI. Various Acylations and Alkylations of the Sodium Enolates of Aliphatic Esters. Methods for the Synthesis of a,a-Disubstituted j -Keto Esters and of Certain Other Compounds. J. Amer. chem. Soc. 63, 3156 (1941). 

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