Friedel-Crafts cyclisation

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

Intramolecular Friedel-Crafts cyclisation of the acid 1 to the 4-position takes place perfectly normally to give the tricyclic ketone. Under almost identical conditions (AlCl3/nitrobenzene/0°C), the acid chloride derived from 2 cyclised smoothly to give a 50% yield of a tricyclic ketone. This however, was shown to be 3, and not the expected product. 

The intramolecular Friedel-Crafts cyclisation of N-2-naphthylalkylalanines proceeds with retention of configuration and subsequent reduction of the resulting isoquinolinone provides a stereospecific synthesis of the diastereoisomeric 1,2,3,4-tetrahydrobenzo[f]isoquinolin-1-ols (93 and 94) (E. Gellert, N. Kumar and D. Tober,... 

Michael addition of acrylic acid to the chloroamine 32 is straightforward and Friedel-Crafts cyclisation of 35 gives only 31, presumably because the position next to the chlorine atom is slightly disfavoured both sterically and electronically. Chlorination and oxidation are conveniently carried out in the same step and the two halves (26 and 28) of this convergent synthesis are combined to give amopyroquine 25. 

Pivaloylindole gives high yields of 6-substituted ketones on reaction with a-halo-acid-chlorides and aluminium chloride simple acid chlorides react only at 0-3. The sequence below shows how a 1-pivaloyl-3-(indol-3-yl)propanoic acid undergoes Friedel-Crafts cyclisation to C-4, away from the deactivated heterocyclic ring. °... 

Many of the homochiral AB synthons described above have been utilised in syntheses of anthracyclinones which are based on Friedel-Crafts cyclisations. As was noted earlier such reactions often require vigorous conditions, and there is some controversy concerning the enantiomeric purity of the products so obtained. While some groups claim that condensation of the hydroxy ketone 174 with phthalic anhydride in an intimate mixture of sodium chloride and aluminium chloride yields optically pure ( —)-4-demethoxy-7-deoxydauno-mycinone [16, 141] others report a considerable degree of racemisation under virtually identical conditions [135, 142], although the problem may be avoided under the somewhat milder conditions employed in a recent condensation of 174 with phthaloyl dichloride [143]. In contrast, stereochemical integrity of the product is assured under the mild conditions employed in Swenton s carbanion based synthesis of (4-)-daunomycinone 5 [53] and in our Diels-Alder based... 

Cyclisation of 3-methyl-5-phenoxy-l-phenylpyrazole-4-carboxylic acid by polyphosphoric acid (PPA) gave 3-methyl-4-oxo-l-phenylbenzo-pyrano[2, 3-c]pyrazole (XI) in 70 per cent yield [8]. It was also obtained in 65 per cent yield from the Friedel-Crafts cyclisation of the acid chloride [8],... 

Olah et al. (1999) have been able to realize selective cyclisation of o-benzoyl benzoic acid to anthraquinone using dichlorobenzene as a solvent and Nafion-H as a catalyst. This may lead to avoidance of the Friedel-Crafts reaction using a stoichiometric amount of aluminium chloride and resulting in a lot of wa,ste. Many other examples of similar reactions have been reported. 

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 aroylation of an aromatic system by reaction with phthalic anhydride under Friedel-Crafts conditions is described in Section 6.11.1, p. 1006. The cyclisation of the derived o-aroylbenzoic acid with polyphosphoric acid is a convenient route to substituted anthraquinones. The reaction is illustrated by the formation of 2-methylanthraquinone from o-(p-toluoyl)benzoic acid (Expt 6.132). 

We should not normally consider the Friedel-Crafts alternative 58a as the intermediate 61 would be unstable. But what that means is that 61 will cyclise rapidly to 58. Indeed it is difficult to isolate13 61 as it gives 58 even at 35 °C. 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

Corey1 wanted to make the ketone 2 as an intermediate in the synthesis of the marine allomone 1 (a substance exuded by an organism and used by a predator). Disconnection 2a (Friedel-Crafts alkylation) would be easy to realise as it occurs para to the powerful o,p-directing OMe group. But disconnection 2b is more difficult as it must occur meta to OMe. So we should make the formation of bond b a cyclisation and disconnect it first. 

Another advantage of this approach is that we can now use electrophilic substitution on the pyrrole to add the rest of the molecule. So the secondary benzylic alcohol 106 might well cyclise to 105 with Lewis acid catalysis as the cation will be reasonably stable and the reaction is intramolecular. But the Friedel-Crafts alkylation to give 107 will not succeed as the cation would be primary. 

Tin (II) triflate gave a quantitative yield of the Friedel-Crafts product 113, emphasising the efficiency of cyclisation, and this compound was hydrogenated over platinum oxide to give... 

This regioselective synthesis of benzannelated rings, which, unlike its Friedel Crafts equivalent, is not perturbed by the nature of other directing groups carried by the ring, has been used in several syntheses. Indanone 76 from cyclisation of 75 is an intermediate in a synthesis of nanaomycin A,44 and tetralone 77 is an intermediate in a synthetic study towards daunomycin 45... 

A trimethylsilyl group facilitates the Friedel-Crafts intramolecular cyclisation of 2-O-benzyl ethers to isochromans. The bulk of the TMS function may force the molecule into an alignment suitable for cyclisation <02OL3797>. 

The synthesis of 2,4-diarylchromen-2-ols through the reaction of phenols with an excess of a chalcone in TFA involves sequential Friedel-Crafts alkylation, cyclisation to a 4/7-1-benzo-pyran, an intermolecular hydrogen transfer generates the 4-arylflavylium ion which is hydrated to give the final product (Scheme 12) <07JOC9383>. 

The Claisen rearrangement is normally performed without a catalyst, however, the use of certain catalysts can increase the rate of the reaction, e.g. BF3, AICI3 and CF3COOH [1,3]. In this case the mechanism is often no longer cyclic, but may become a Friedel-Crafts type reaction, which can result in side products. Furthermore, the Claisen rearrangement in the presence of acids is often accompanied by the cyclisation of the initial rearrangement product [2,3]. 

Haworth reaction A reaction in which an aryl compound is treated with a cyclic anhydride, such as succinic anhydride, and the intermediate Friedel-Crafts product is reduced and then cyclised via an internal Friedel-Crafts reaction to give a 1,2-disubstituted aromatic compound with a carbonyl group in the new ring. The whole sequence is called the Haworth reaction. 

Oppolzer,18 who wanted this cyclopentenone for the synthesis of modhephene 75 followed this strategy and found that the Friedel-Crafts went well with A1C13 as catalyst and the Nazarov cyclisation with another Lewis acid, SnCl4. You will notice the position of the double bond in the final product there are no protons on one side of the cation 73 so one must be lost from the other side. In cases where there is a choice, the more substituted alkene results, as here. The product is ideally functionalised for development into modhephene 75. 

The main synthesis of oxindoles is simple and direct and involves an intramolecular Friedel-Crafts alkylation reaction as the cyclising step. Also straightforward in concept is the displacement of halogen from an ort/to-halo-nitroarene with malonate, this leading to an oxindole after decarboxylation and reduction of the nitro group with spontaneous lactamisation. ... 

Indoxyls are normally prepared from anthranilic acids via alkylation with a haloacetic acid followed by a cyclising condensation with loss of carbon dioxide. " Indoxyl itself is best prepared by Friedel-Crafts type ring closure of iV-phenylglycine activated with triphenylphosphine oxide/triflic anhydride in the presence of triethylamine at room temperature. " ... 

The alternative Friedel-Crafts disconnection requires (18)—a rather unstable compound. This is hardly a problem as (18) is unstable because it cyclises readily to (17). The reaction occurs at 35 C and (18) need not be... 

There are no problems of orientation in the Friedel-Crafts reaction as all positions in the aromatic ring are the same. Reformatsky (Chapter 20) is usually the best method of control for /3-hydroxy esters (12) so we shall need to protect the COjH group as an ester (15). The final cyclisation occurs during ork-up. 

The aliphatic version of the classical aromatic Friedel-Crafts acylation produces, by loss of proton, a non-conjugated enone which can then undergo a second acylation thus generating an unsaturated 1,5-diketone. Clearly, if the alkene is not symmetrical, two isomeric diketones are formed. Under the conditions of these acylations, the unsaturated diketone cyclises, loses water and forms a pyrylium salt. The formation of 2,4,6-trimethylpyrylium, best as its much more stable and non-hygroscopic carboxymethanesulfonate, illustrates the process. 

No simple examples are known of electrophilic or radical substitution of either heterocyclic or homocyclic rings of benzopyrylium salts flavylium and l-phenyl-2-benzopyrylium salts nitrate in the substituent benzene ring. Having said this, the cyclisation of coumarin-4-propanoic acid may represent Friedel-Crafts type intramolecular attack on the carbonyl-O-protonated form i.e. on a 2-hydroxy-1-... 

Searchable data bases have for some time now simplified the search for the more routine methods of 7-membered ring synthesis. For this reason it seems reasonable to omit yet further examples of cyclisation by cyclocondensation or intramolecular Friedel-Crafts reaction, as well as new examples Schmidt and Beckmann ring expansion reactions, unless specific mechanistic or stereochemical features are of interest. 

Fluoroalkyl chromone derivatives can be obtained from the base catalysed reaetion between 2,2-dihydropolyfluoroalkanoates and phenols. Initial loss of HF allows Michael addition of the phenol and subsequent cyclisation of the enol ether yields the heterocycle. m-Substituted phenols give the expected mixture of 5- and 7-substituted chromones, whilst dihydroxy aromatic compounds give polycyclic materials (94JFC263). In a more conventional approach Z-3-(aryloxy)-polyfluoroalkenoic adds, derived from Michael addition of phenols to polyfluoro-2-alkynoic acids, undergo intramolecular Friedel-Crafts acylation to 2-polyfluoro-alkylchromones (94JFC25). 

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