5-Acylation reaction scheme

BF3 is an effective reagent for various kinds of reaction such as Friedel-Crafts alkylation and acylation reactions (Scheme 63),291 cyclization reactions, rearrangement,292 Diels-Alder reactions,293 and aldol reactions. 

In a similar manner, acyl carbocations formed from acyl halides act as an electrophile in Friedel-Crafts acylation reactions (Scheme 2.3). 

Chloro-6-pyridazinecarboxylic acid chloride was prepared from the acid in thionyl chloride. The acid chloride is unstable, but direct reaction of the unpurified material in Friedel-Crafts acylation reactions (Scheme 51) gave moderate to excellent yields of aroylpyridazines <92JHC1583>. 

Verdini and coworkers [122] have introduced the 2-methyl-2-(2 -ni-tro)phenoxy-propionyl (Mnp) group for the preparation of stable monopro-tected gem-diamino alkyl residues 27 via IBTFA treatment of the carboxamide precursor 26. The precursor 26 is prepared by coupling amino a-carboxamide and 2-methyl-2-(2 -nitro)phenoxy-propionic acid as its O-succinimidyl ester 25. Hydrochloride salts, such as 27, are generally stable, crystalline compounds that can be stored at room temperature for several months. Once deprotonated, 27 is stable enough for acylation reactions (Scheme 9) [122]. 

A report of Shioji and co-workers studied the kinetic resolution of hydroxymethylphosphine boranes 147 by lipase-catalysed acylation reactions (Scheme 6.57). 

High yields of coumarin derivatives can be achieved when o-iodo phenolic compounds react with alkynes via domino alkyne addition-CO insertion-nucleophilic acylation reaction (Scheme 64) (130L4834). 

Carbocations are formed by several reactions. One example has been discussed already in the context of the SnI reaction (Scheme 2.2.8a). Other important options include the addition of protons to double bonds, for example, the addition of a Br0nsted acid to an alkene or ketone (Scheme 2.2.8b and c, respectively). The addition of a Lewis acid to a carbonyl group can also lead to a type of carbocation, an effect that is exploited in all kinds of technical Friedel-Crafts acylation reactions (Scheme 2.2.8d). Finally, in high-temperature refinery processes, the formation of carbocations from alkanes is of highest relevance. Here acidic catalysts are usually applied that abstract a hydride from the alkane to form hydrogen and a carbocation at the alkane substrate (Scheme 2.2.8e). 

Papyracillic acid B (203), isolated from an endophytic fungus Microsphaeropsis sp., is a penicillic acid analog containing a spirofused cyclic ketal core appended with an exocychc aUcene [111]. Very recently, its racemic synthesis has been achieved by Zercher et al. [112] via a Zn-carbenoid-mediated chain extension-acylation reaction (Scheme 1.32). At the last step of Zercher s synthesis, paparyciUic acid is obtained as 1 1 epimeric mixture with its C4 epimer, probably through an epimerization facilitated by exocyclic methylene group. 

Small amounts of salt-like addition products (85) formed by reaction on the ring nitrogen may be present in the medium. (Scheme 60) but. as the equilibrium is shifted by further reaction on the exocyclic nitrogen, the only observed products are exocyclic acylation products (87) (130. 243. 244). Challis (245) reviewed the general features of acylation reactions these are intervention of tetrahedral intermediates, general base catalysis, nucleophilic catalysis. Each of these features should operate in aminothiazoles reactivity. 

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

Interesting results have been obtained in intramolecular acylation reactions involving pyrrole and thiophene derivatives. A muscone synthesis involves selective intramolecular acylation at a vacant a-position (Scheme 18) (80JOC1906). In attempts to prepare 5,5-fused systems via intramolecular acylation reactions on to a jS-position of a thiophene or a pyrrole, in some cases ipso substitution occurs with the result that rearranged products are formed (Scheme 19) (82TH30200). 

TBAF has been used as a source of fluoride ions in a number of substitution reactions studied by Cox et al. [23]. Allcyl and acyl halides react with TBAF to give the corresponding allcyl or acyl fluoride in good yield. In the reaction between (R)-2-tosyloctane and TBAF, the product was (S)-2-fluorooctane, confirming an Sn2 mechanism for the reaction (Scheme 5.1-5) [18, 23]. 

As a demonstration of the complete synthesis of a pharmaceutical in an ionic liquid, Pravadoline was selected, as the synthesis combines a Friedel-Crafts reaction and a nucleophilic displacement reaction (Scheme 5.1-24) [53]. The allcylation of 2-methylindole with l-(N-morpholino)-2-chloroethane occurs readily in [BMIM][PF6] and [BMMIM][PF6] (BMMIM = l-butyl-2,3-dimethylimida2olium), in 95-99 % yields, with potassium hydroxide as the base. The Friedel-Crafts acylation step in [BMIM][PF6] at 150 °C occurs in 95 % yield and requires no catalyst. 

The first example of a Friedel-Crafts acylation reaction in a molten salt was carried out by Raudnitz and Laube [90]. It involved the reaction between phthalic anhydride and hydroquinone at 200 °C in NaCl/AlCl3 (X(A1C13) = 0.69) (Scheme 5.1-58). 

The Fries rearrangement can be viewed as a type of Friedel-Crafts acylation reaction. Two examples of this reaction are given in Scheme 5.1-61. The first is the rearrangement of 4,4 -diacetoxybiphenyl to 4,4 -dihydroxy-3,3 -diacetoxybiphenyl in a NaCl/AlCl3 (X(A1C13) = 0.69) molten salt [93]. The second example is the rearrangement of phenyl 3-chloropropionate to 2 -hydroxy-3-chloropropiophenone, followed by cyclization to an indanone [94]. 

A number of commercially important fragrance molecules have been synthesized by Friedel-Crafts acylation reactions in these ionic liquids. Traseolide (5-acetyl-l,l,2,6-tetramethyl-3-isopropylindane) (Scheme 5.1-63) has been made in high yield in the ionic liquid [EMIM]C1/A1C13 (X(A1C13) = 0.67) [95]. 

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. 

The ability of iron(III) chloride genuinely to catalyze Friedel-Crafts acylation reactions has also been recognized by Holderich and co-workers [97]. By immobilizing the ionic liquid [BMIM]Cl/FeCl3 on a solid support, Holderich was able to acetylate mesitylene, anisole, and m-xylene with acetyl chloride in excellent yield. The performance of the iron-based ionic liquid was then compared with that of the corresponding chlorostannate(II) and chloroaluminate(III) ionic liquids. The results are given in Scheme 5.1-67 and Table 5.1-5. As can be seen, the iron catalyst gave superior results to the aluminium- or tin-based catalysts. The reactions were also carried out in the gas phase at between 200 and 300 °C. The acetylation reac-... 

Singer and co-workers have investigated the acylation reactions of ferrocene in ionic liquids made from mixtures of [EMIMJI and aluminium(III) chloride (Scheme 6.1-5) [9, 10]. The ionic liquid acts both as solvent and as source of the Friedel-Crafts catalyst. In mildly acidic (X(A1C13) > 0.5 [EMIM]I/A1C13, the monoacetylated ferrocene was obtained as the major product. In strongly acidic [EMIM]I/AlCl3 X(A1C13) = 0.67 the diacylated ferrocene was the major product. Also, when R = alkyl, the diacetylated product was usually the major product, but for R = Ph, the monoacetylated product was favored. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

Scheme 7.8 Microwave assisted N-alkylation and acylation reactions...

The results presented in Tables 3 and 4 deserve some comments. First, a variety of enzymes, including whole-cell preparations, proved suitable for the resolution of different hydroxyalkanephosphorus compounds, giving both unreacted substrates and the products of the enzymatic transformation in good yields and, in some cases, even with full stereoselectivity. Application of both methodologies, acylation of hydroxy substrates rac-41 and rac-43 or the reverse (hydrolysis of the acylated substrates rac-42 and rac-44), enables one to obtain each desired enantiomer of the product. This turned out to be particularly important in those cases when a chemical transformation OH OAc or reverse was difficult to perform. As an example, our work is shown in Scheme 3. In this case, chemical hydrolysis of the acetyl derivative 46 proved difficult due to some side reactions and therefore an enzymatic hydrolysis, using the same enzyme as that in the acylation reaction, was applied. Not only did this provide access to the desired hydroxy derivative 45 but it also allowed to improve its enantiomeric excess. In this way. 

Scheme 11.4 shows some other representative Friedel-Crafts acylation reactions. Entries 1 and 2 show typical Friedel-Crafts acylation reactions using A1C13. Entries 3 and 4 are similar, but include some functionality in the acylating reagents. Entry 5 involves formation of a mixed trifluoroacetic anhydride, followed by acylation in 85% H3PO4. The reaction was conducted on a kilogram scale and provides a starting material for the synthesis of tamoxifen. Entry 6 illustrates the use of bismuth triflate as... 

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