Benzene, acylation reaction with

Sequential functionalization of pyrazole-l-oxides via regioselective metallation led to the synthesis of 3,4,5-trisub-stituted-l-hydroxypyrazoles <2002JOC3904>. 3-Acylated-2-(4-methoxybenzyl)-2//-pyrazole 1-oxides were formed by the reaction between a 3-magnesium 2//-pyrazole-l-oxide and acid chlorides <2002J(P1)428>. 3-Arylated-l-hydroxypyrazoles were synthesized from 3-metallated-pyrazole 1-oxides <2001JOC8654>. The reaction between hexafluorobenzene and the anion of 1-hydroxypyrazole affords a mixture of the products of bis-, tetrakis-, and hexakis-substitution <2004ARK100>. In the case of hexakis(bromomethyl)benzene, its reaction with 1-hydroxy-pyrazole leads to the hexakis-substituted product. 

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

The aromatic sulfonyl chlorides which have no a-hydrogen and thus cannot form sulfenes give acylic sulfones. Thus 1-piperidinopropene on reaction with benzene sulfonyl chloride (9J) gave 2-benzenesulfonyl-l-piperidinopropene (153). Similarly the enamine (28) reacts with p-toluene-sulfonyl chloride to give the 2-p-toluenesulfonylcyclohexanone (154) on hydrolysis (/OS). 

Depending on the specific reaction conditions, complex 4 as well as acylium ion 5 have been identified as intermediates with a sterically demanding substituent R, and in polar solvents the acylium ion species 5 is formed preferentially. The electrophilic agent 5 reacts with the aromatic substrate, e.g. benzene 1, to give an intermediate cr-complex—the cyclohexadienyl cation 6. By loss of a proton from intermediate 6 the aromatic system is restored, and an arylketone is formed that is coordinated with the carbonyl oxygen to the Lewis acid. Since a Lewis-acid molecule that is coordinated to a product molecule is no longer available to catalyze the acylation reaction, the catalyst has to be employed in equimolar quantity. The product-Lewis acid complex 7 has to be cleaved by a hydrolytic workup in order to isolate the pure aryl ketone 3. 

The Friedel-Crafts acylation reaction has also been performed in iron(III) chloride ionic liquids, by Seddon and co-workers [96]. An example is the acetylation of benzene (Scheme 5.1-66). Ionic liquids of the type [EMIM]Cl/FeCl3 (0.50 < X(FeCl3) < 0.62) are good acylation catalysts, with the added benefit that the ketone product of the reaction can be separated from the ionic liquid by solvent extraction, provided that X(FeCl3) is in the range 0.51-0.55. 

Just as an aromatic ring is alkylated by reaction with an alkyl chloride, it is acylated by reaction with a carboxylic acid chloride, RCOC1, in the presence of AICI3. That is, an acyl group (-COR pronounced a-sil) is substituted onto the aromatic ring. For example, reaction of benzene with acetyl chloride yields the ketone, acetophenone. 

The iron complex 16 in anhyd benzene was treated with an alkyl halide (excess) and anhyd NaHC03 (1 mol equiv) and the mixture was stirred at 20 "C for 20 h. For acylation, an acyl chloride (1 mol equiv) and anhyd NaHCO, were employed and the mixture was stirred at 20CC for 1-2 h. For decomplexation, the TV-substituted iron complex 17 and a 20-fold molar excess of freshly sublimed Me3NO in acetone were stirred for 20 h at 20 C and the reaction mixture was worked up by chromatography to give 18. 

An alternative route to anthraquinone, which involves Friedel-Crafts acylation, is illustrated in Scheme 4.3. This route uses benzene and phthalic anhydride as starting materials. In the presence of aluminium(m) chloride, a Lewis acid catalyst, these compounds react to form 2-benzoyl-benzene-1-carboxylic acid, 74. The intermediate 74 is then heated with concentrated sulfuric acid under which conditions cyclisation to anthraquinone 52 takes place. Both stages of this reaction sequence involve Friedel-Crafts acylation reactions. In the first stage the reaction is inter-molecular, while the second step in which cyclisation takes place, involves an intramolecular reaction. In contrast to the oxidation route, the Friedel-Crafts route offers considerable versatility. A range of substituted... 

The acylation of 6-indazolylaminomethylenemalonate (1470) by reaction with acetic anhydride in the presence of pyridine for 45 min, or with benzoyl chloride in a mixture of DMF and benzene in the presence of sodium ethylate for 75 min, gave 1-acyl derivatives (1504) in 72% and 58% yields, respectively (78YZ1158). 

When benzene or substituted benzene is treated with aeid ehloride in the presenee of anhydrous aluminium ehloride, it affords the eorresponding ketone. This reaetion is known as Friedel-Crafts acylation reaction. 

In-situ IR-spectroscopic characterization of the Friedel-Crafts acylation of benzene in ionic liquids derived from AICI3 and FeCl3 showed that the mechanism of the reaction in ionic liquids was the same as that in 1,2-dichloroethane (128). The immobilization of ferric chloride-containing ionic liquid onto solid supports (e.g., silica and carbon) however failed to catalyze the acylation reaction, because leaching was a serious problem. When the reaction was carried out with gas-phase reactants, catalyst deactivation was observed. 

Salicylic acid can be converted to salicyloyl chloride [1441-87-8] by reaction with thionyl chloride in boiling benzene. The formation of acyl halide may also extend to reaction with the phenolic hydroxyl. The reaction with phosphoms tri- and pentachlorides is not restricted to the formation of the acid chloride. Further interaction of the phosphoms halide and the phenolic hydroxyl results in the formation of the phosphoric or phosphorous esters. 

The use of acyl chlorides in Friedel-Craft acylations of benzene rings, as well as their reactions with organometallics and reductions to aldehydes, has been discussed in Section 15.2. 

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