Friedel-Crafts acylation, route

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

PoIysuIfonyIa.tlon, The polysulfonylation route to aromatic sulfone polymers was developed independendy by Minnesota Mining and Manufacturing (3M) and by Imperial Chemical Industries (ICI) at about the same time (81). In the polymerisation step, sulfone links are formed by reaction of an aromatic sulfonyl chloride with a second aromatic ring. The reaction is similar to the Friedel-Crafts acylation reaction. The key to development of sulfonylation as a polymerisation process was the discovery that, unlike the acylation reaction which requires equimolar amounts of aluminum chloride or other strong Lewis acids, sulfonylation can be accompHshed with only catalytic amounts of certain haUdes, eg, FeCl, SbCl, and InCl. The reaction is a typical electrophilic substitution by an arylsulfonium cation (eq. 13). 

The mechanism for that step is closely related to that of the Friedel-Crafts acylation. Upon subsequent hydrolysis the o-substituted Lewis acid-coordinated phenolate 7 is converted to the free o-acylphenol 2. By an analogous route, involving an electrophilic aromatic substitution para to the phenolate oxygen, the corresponding para-acylphenol is formed. 

Many organic chemical transformations have been carried out in ionic liquids hydrogenation [4, 5], oxidation [6], epoxidation [7], and hydroformylation [8] reactions, for example. In addition to these processes, numerous synthetic routes involve a carbon-carbon (C-C) bond-forming step. As a result, many C-C bondforming procedures have been studied in ambient-temperature ionic liquids. Among those reported are the Friedel-Crafts acylation [9] and allcylation [10] reactions, allylation reactions [11, 12], the Diels-Alder reaction [13], the Heck reaction [14], and the Suzuld [15] and Trost-Tsuji coupling [16] reactions. 

Whereas pyrroles normally undergo substitution at the C-2 position, 1-arylsulfonylpyrroles display a tunable reactivity in Friedel-Crafts acylations, wherein substitution occurs at C-3 in the presence of "hard acids" such as aluminum chloride but mainly at C-2 when catalyzed by weaker acids <81TL4899,81TL4901>. An alternative route to 3-aroylpyrroles 38 has been introduced via irradiation of 1-acetyl- or 1-phenylsulfonylpyrrole (36) with arenethiocarboxamides <96H(43)463>. The proposed mechanism involves formation and scission of a thietane intermediate 37, followed by hydrolysis of the resultant imine. 

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 Friedel-Crafts acylation at the 3-position of the azulene ring was possible due to the effect of the electron-withdrawing 1-methoxycarbonyl group. 183 has been prepared previously in an eight-step synthetic route in an unsatisfactory reaction yield156. 

Recently, the same authors reported a different route for the total synthesis of olivacine (238a) and ellipticine (228) starting from 2,4,6-tiimethoxypyiidine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). Interestingly, this method also uses the same common precursor, N-benzylindole-2,3-dicarboxylic anhydride (852) as shown in Schemes 5.204 and 5.205. Contrary to the earlier route, this sequence involves a Friedel-Crafts acylation of 2,4,6-trimethoxypyridine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). 

As outhned in Scheme 12.2, the process route to fluvastatin (1) commenced with Friedel-Crafts acylation of fluorobenzene (20) with chloroacetyl chloride (21) in the presence of AICI3 to prepare a-chloroketone 22 (Repic et al., 2001). Reaction of 22 with N-i-Pr aniline at elevated temperature generated tertiary amine 23, which was engaged... 

The Friedel-Crafts acylation of aromatic compounds is an important synthesis route to aromatic ketones in the production of fine and specialty chemicals. Industrially this is performed by reaction of an aromatic compound with a carboxylic acid or derivative e.g. acid anhydride in the presence of an acid catalyst. Commonly, either Lewis acids e.g. AICI3, strong mineral acids or solid acids e.g. zeolites, clays are used as catalysts however, in many cases this gives rise to substantial waste and corrosion difficulties. High reaction temperatures are often required which may lead to diminished product yields as a result of byproduct formation. Several studies detail the use of zeolites for this reaction (1). 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

The structure of the pyridazine-based antidepressant agent minaprine (34-6) departs markedly from both the older tricyclic drugs and the more recent selective serotonin re-uptake inhibitors. There is evidence that the compound acts via a dopa-mimetic route. Friedel-Crafts acylation of benzene with itaconic anhydride (34-1) leads to the keto-acid (34-2). Condensation with hydrazine leads to the formation of the hydrazine and hydrazide bonds the double bond shifts into the ring to give the fully unsaturated pyridazinone (34-3) this is then converted to the chloride (34-4) in the usual way. The displacement of halogen by the amine on 3-(A -morpho-lino)propylamine (34-5) affords (34-6) [36]. 

Ruoho and Rong have descnbed a shorter route to salmeterol (Scheme 4). Friedel-Crafts acylation of salicylaldehyde (16) with bromoacetyl bromide in the presence of aluminum chloride gave the acetophenone 17. Alkylation of amine 18 with bromoacetyl 17 in refluxing acetonitrile gave the ketone 19. Reduction of 19 with sodium borohydride in methanol followed by catalytic hydrogenolysis of the benzyl group over 10% Pd/C gave salmeterol (2). 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

For the synthesis of isoindoles (benzo[c]pyrroles) by type la cyclization the required intermediate is an o -acylbenzylamine. The only viable route to these substances which has been developed starts with a -bromo-o -toluic acid which is converted first to a phthalimide and then to the acid chloride. The acid chloride is then elaborated to the requisite ketone by Friedel-Crafts acylation. Condensation to the isoindole occurs on liberation of the primary amino group using hydrazine (equation 18) (64JA4152). 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Fig. 1) similar to the original published route of synthesis (6). Friedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone 99-45-6]> which on catalytic reduction yields (+)-epinephrine [329-65-7], Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

Friedel-Crafts acylation of alkenes.9 C2H5A1C12 is an effective catalyst for acylation of alkenes with acyl chlorides or anhydrides in CH2C12. The reaction proceeds in higher yield than that previously reported with other Lewis acid catalysts (such as ZnCl2). The reaction provides a useful route to /J,y-enones. 

The main industrial route to aromatic ketones is via the Friedel-Crafts acylation, nowadays classified as an environmentally hostile process with gaseous effluents and mineral wastes. Typically catalyzed by the Lewis acid A1C13, this is a self-blocking... 

There have been many commercial and laboratory publications on the synthesis of ibuprofen. Two of the most popular ways to obtain ibuprofen are the Boots process and the Hoechst process. The Boots process is an older commercial process developed by the Boots Pure Dmg Company, the discoverers of ibuprofen in the 1960s, and the Hoechst process is a newer process developed by the Hoechst Company. Most of these routes to Ibuprofen begin with isobutylbenzene and use Friedel-Crafts acylation. The Boots process requires six steps, while the Hoechst process, with the assistance of catalysts, is completed in only three steps (Figure 20.2). 

Ionic routes to allylic 4 and benzylic 6 alcohols include reduction of the ketones 3 and 5 as these are easily made by aldol reactions and Friedel-Crafts acylation. The alcohols can be converted into electrophiles by tosylation or conversion into bromides. 

These catalytic reactions provide a unique pathway for addition of aromatic C-H bonds across C=C bonds. In contrast with Friedel-Crafts catalysts for olefin hydroarylation, the Ru-catalyzed hydrophenylation reactions of a-olefins selectively produce linear alkyl arenes rather than branched products. Although the selectivity is mild, the formation of anti-Markovnikov products is a unique feature of the Ru(II) and Ir(III) catalysts discussed herein. Typically, the preferred route for incorporation of long-chain linear alkyl groups into aromatic substrates is Friedel-Crafts acylation then Clemmensen reduction, and the catalysts described herein provide a more direct route to linear alkyl arenes. 

The Friedel-Crafts acylation of aromatics is the main route for the formation of aromatic ketones, intermediates widely used for the production of pharmaceuticals, fragrances, flavours insecticides and other products. 

There are a number of synthetic routes available to access the benzhy-drols needed for this approach. The first published route to SNC80 used a Friedel-Crafts acylation of toluene with m-anisoyl chloride to yield a benzo-phenone, followed by sodium borohydride reduction of the ketone (after the three-step elaboration of the para-methyl group into the diethylcarboxamide, Scheme 3) [23,24],... 

Gutman,50 in his process route, which did not report any yields, hydrogenated the pyridine ring first to access the piperidine moiety and constructed the indanone ring system via an intramolecular Friedel-Crafts acylation (Scheme 5). Hydrogenation of diester 31, obtained from condensation of 4-pyridine carboxaldehyde and dimethyl malonate, followed by benzylation of the piperidine intermediate afforded A-benzylated piperidine 32. Alkylation of 32 with 3,4-dimethoxybenzyl chloride (33) and subsequent hydrolysis gave dicarboxylic acid 34. Subjection of 34 to strong acid resulted in intramolecular Friedel-Crafts acylation and in situ decarboxylation to provide 3. 

---