Polyphosphoric acid Friedel-Crafts reaction

Whereas the above reactions are appHcable to activated aromatics, deactivated aromatics can be formylated by reaction with hexamethylenetetramine in strong acids such as 75% polyphosphoric acid, methanesulfonic acid, or trifluoroacetic acid to give saUcylaldehyde derivatives (117). Formyl fluoride (HCOF) has also been used as formyl a ting agent in the Friedel-Crafts reaction of aromatics (118). Formyl fluoride [1493-02-3] in the presence of BF was found to be an efficient electrophilic formyl a ting agent, giving 53% para-, 43% ortho- and 3.5% meta-tolualdehydes upon formylation of toluene (110). 

Methods were developed for the preparation of thienoindolizines 254 and thienoquinolizines 255 from derivatives of proline and pipecolinic acid (1993H2303, 1994JHC495, 1996JHC873, 1996PS169, 1999H445). Polyphosphoric acid (PPA) can be used as a cyclizing agent. The reaction can also be performed by the transformation of pipecolinic acids into acid chlorides followed by the intramolecular Friedel-Crafts reaction without isolation of the intermediate. 

The conventional method for preparation of these aromatic ketones involves reaction of the aromatic hydrocarbon with a carboxylic acid derivatives using a Lewis acid (AICI3, FeCb, BF3, ZnCb, TiCl4) or Bronsted acids (polyphosphoric acid, HF). The major drawback of the Friedel-Crafts reaction is the need to use a stoicheiometrical quantity of Lewis acid relative to the formed ketone. This quantity is required due to the fact that the... 

PPA = polyphosphoric acid al = alkylation ac = acylation chlor = chlorination iso = isomerization halo = halogenation cycl = cyclization poly = polymerization for = formylation dehydr = dehydration nitr - nitration general = active in most Friedel-Crafts reactions deal = dealkylation rearr = rearrangement. 

A number of variations of the Friedel-Crafts reaction conditions are possible. Acid anhydrides can serve as the acylating agent in place of acid chlorides. Also, the carboxylic acid can be used directly, particularly in combination with strong acids. For example, mixtures of carboxylic acids with polyphosphoric acid, in which a mixed anhydride is presumably formed in situ, are reactive acylating agents. Similarly, carboxylic acids dissolved in trifluoromethanesulfonic acid can carry out Friedel-Crafts acylation. The reactive electrophile under these conditions is believed to be the protonated mixed anhydride. In these procedures, the leaving group... 

Alkylation of Aromatics. Aromatic hydrocarbons containing a replaceable hydrogen can be alkylated unless steric effects prevent introduction of the alkyl group (61,78-82). The reaction is called the Friedel-Crafts alkylation, first realized in the presence of aluminum chloride, which is the catalyst still the most frequently used and studied in Friedel-Crafts reactions. In addition, many other acid catalysts are effective (80,82-84). These include other Lewis acids (other aluminum halides, gallium chloride, boron trifluoride, ferric chloride, zinc chloride, stannous and stannic chloride, antimony chloride) and protic acids (hydrogen fluoride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, trifluo-romethanesulfonic acid, and alkane- and arenesulfonic acids). 

This principal reaction mechanism is widely believed to apply to most S Ar reactions irrespective of the electrophilic reagent. There are however a number of experimental observations that indicate exceptions to this mechanism. There are examples of thermodynamically controlled Friedel-Crafts reactions, when using reaction conditions like polyphosphoric acid and elevated temperatures [27,28]. In iodination and some cases of Friedel-Crafts acylation, the last step of the reaction, the proton abstraction, has been shown to have a substantial kinetic isotope effect, which indicates that this step is at least partially rate limiting [29-31]. There are also still open questions regarding the exact nature of the reaction intermediates, and we will focus on these issues in the remaining part of the chapter. 

Lastly, acetic anhydride participates in the Friedel-Crafts reaction. Polyphosphoric acid is both reagent and solvent in these reactions (eq 69). 

Friedel-Crafts reactions, the Fischer indole synthesis, the Beckmann rearrangement, and other dehydrations an alternative to polyphosphoric acid )... 

Substituted 2-phenoxyphenylacetic acids readily cyclize under Friedel-Crafts conditions or acid catalysis to give dibenz[Z>,/]oxepin-10(l l//)-ones.71 85,104- 108 When this reaction is carried out in methanolic hydrochloric acid the 10-methoxy-substituted dibenz[6,/]oxepin system 9a can be isolated.109 5-(Nitro-2-phenoxyphenyl)-2-oxopropanoic acid undergoes cyclization in the presence of polyphosphoric acid yielding the carboxylated dibenzoxepin 9b.107... 

Polyphosphoric acid is a commonly used catalyst for this reaction however, in some cases a mixture of hydrogen bromide/acetic acid gives better results. Acylation of the S-phenyl-, V-(4-tolyl)- or S-(l-naphthyl)-substituted thiobenzenepyruvic acids 3a-c affords the corresponding dibenzo[A,/]thiepins in satisfactory yields, while reaction of the S-(4-methoxyphenyl) or S-(2-naphthyl) derivatives fails to provide any thiepin.60 The intramolecular Friedel-Crafts acylation of 2-(arylsulfanyl)benzeneacetic acids also yields the corrresponding dibenzothiepins in this case the use of hydrogen fluoride sometimes results in purer products.38 The applicability of this method is restricted to the synthesis of stable bisannulated thiepins. 

Dibenzo[/>,/]thiepin derivative (39) has been obtained by cyclization of 2-arylthio-5-nitrophenylpyruvic acid (38) in the presence of polyphosphoric acid 33>. The use of this Friedel-Crafts type reaction is restricted to the synthesis of the stable di- and tri-annelated thiepins such as 40 33), 41 7), and 42 34). 

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst.167 This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (1-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P205 in polyphosphoric acid.168 Still another method uses an arylsulfonic trifiuoromethanesulfonic anhydride ArS020S02CF3 (generated in situ from ArS02Br and CF3S03Ag) without a catalyst.169... 

Alkylation. Friedel-Crafts alkylation (qv) of benzene with ethylene or propylene to produce ethylbenzene [100-41 -4], CgH10, or isopropylbenzene [98-82-8], C9H12 (cumene) is readily accomplished in the liquid or vapor phase with various catalysts such as BF3 (22), aluminum chloride, or supported polyphosphoric acid. The oldest method of alkylation employs the liquid-phase reaction of benzene with anhydrous aluminum chloride and ethylene (23). Ethylbenzene is produced commercially almost entirely for styrene manufacture. Cumene [98-82-8] is catalytically oxidized to cumene hydroperoxide, which is used to manufacture phenol and acetone. Benzene is also alkylated with C1Q—C20 linear alkenes to produce linear alkyl aromatics. Sulfonation of these compounds produces linear alkane sulfonates (LAS) which are used as biodegradable deteigents. 

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). 

You might think of using the acid chloride 16 X = Cl with a Lewis acid and that might well be successful, but it turns out that reaction of the acid 16 X = OH with the ether 15 using polyphosphoric acid as catalyst does both the Friedel-Crafts and the Nazarov in one step. The yield is only 70% but it is a very short synthesis.4... 

The Friedel-Crafts cyclization of the acid chloride (19a) occurs normally at — 70°, with the formation of the azacycloheptenone (20), but the sole product at 5° is 5,6-dihydro-5-tolylsulfonylphenanthridine (21). Similarly, the related acid (19b) gives phenanthridine when heated with polyphosphoric acid at 60°.53 Presumably a 5,6-dihydro-phenanthridine is formed which undergoes dehydrogenation in the reaction medium (cf. Das Gupta et aZ.48). 

There are two main synthetic routes to naphthalene the Haworth synthesis and a Diels-Alder approach. In the Haworth synthesis (Scheme 12.1), benzene is reacted under Friedel-Crafts conditions with succinic anhydride (butanedioic anhydride) to produce 4-oxo-4-phenylbutanoic acid, which is reduced with either amalgamated zinc and HCl (the Clemmensen reduction) or hydrazine, ethane-1,2-diol and potassium hydroxide (the Wolff-Kischner reaction) to 4-phenylbutanoic acid. Ring closure is achieved by heating in polyphosphoric acid (PPA). The product is 1-tetraione and reduction of the carbonyl group then gives 1,2,3,4-tetrahydronaphthalene (tetralin). Aromatization is achieved by dehydrogenation over a palladium catalyst. 

Benzothiazolones (121) undergo Friedel-Crafts acylation through the reaction with acyl chlorides or anhydrides in the presence of a large excess (7-11 equivalents) of the AICI3-DMF reagent (Equation (21)). The same 6-acyl-2-(3//)-benzothiazolones (122) are obtained from (121) and anhydrides in the presence of polyphosphoric acid <94J0C1574>. 

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