Friedel-Crafts reactions pyrrole

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

The reaction of indole and /V-mcthylpyrrole via Friedel-Crafts reactions with 0CHC02Et in various aqueous solutions generated substituted indoles and pyrroles without using any metal catalyst (Eq. 7.8).18... 

The monosubstitution products of the Friedel-Crafts reaction and of the nitration reaction have been interrelated to show that the substituent group is introduced at the same position in each case. A further correlation with the adduct (Id) from indolizine and methyl propiolate provides evidence that this is the 1-position as predicted.56 Acylation of 2-methoxycarbonyl-3-phenylcycl[3,2,2]azine (Is) takes place in the pyrrole part of the molecule.51... 

More recently, MacMillan has introduced the amine catalysts 42 and 45, readily available from L-phenylalanine, methylamine, and acetone or pivalaldehyde, respectively (Schemes 4.15 and 4.16). The broad potential of these materials in enan-tioselective organocatalysis was first proven in Diels-Alder reactions [28] and nitrone cydoadditions [29]. In 1,4-addition of C-nudeophiles MacMillan et al. later showed that Friedel-Crafts reactions of pyrroles with enals can be made highly enantioselective (Scheme 4.15) [30]. 

These five-membered rings have lone pair(s) delocalised from the heteroatom round the ring and are electron-rich . They react all too easily with electrophiles and are unstable in acid whether protic or Lewis. We have to find reactions that can be used in neutral or only weakly acidic solution. The synthesis of tolmetin 99 illustrates the two most important reactions.14 The disconnection of the ketone would lead naturally to an AICI3-catalysed Friedel-Crafts reaction between the acid chloride 100 and the pyrrole 101. 

The pyrrole 19 was made by a Friedel-Crafts reaction on the known and deactivated pyrrole 25. The COiEt group deactivates C-3 and C-5 so reaction occurs at the only unaffected position. The electron-withdrawing CC Et group also makes the pyrrole less susceptible to Lewis acid degradation (chapter 39). The Wittig reaction with the ylid from 20 went in excellent yield but... 

So the decision was taken to use succinic anhydride as the electrophile (chapter 5). Pyrroles prefer to react next to nitrogen with electrophiles (chapter 39), but with a large group on nitrogen 108 (j-P Si), Friedel-Crafts reaction occurred at the other position to give the keto-acid 109. Reduction to the benzylic alcohol and catalytic hydrogenation gave 110 in excellent yield. 

There are few studies on the metal triflate-catalyzed addition of pyrroles to a, 1-unsaturated compounds <2001 AGE 160, 2001TL8063>. The Friedel-Crafts reaction of homochiral pyrrole derivatives 450 with a,P-unsatu-rated esters catalyzed by metal triflates furnished conjugated addition products 451 in good yields without racemiza-tion (Equation 107) <2004S2574>. The addition worked regioselectively at C-5 of pyrrole. The best yields were obtained by using yttrium triflate and methyl 4-phenyl-2-oxobut-3-enoate. The diastereoisomers were separated by column chromatography. 

Pyrrolo[l,2-a]indolequinones were prepared also by cyclization reactions. One of them involves copper-catalyzed pyrolysis of 2-azido-5-methoxy-6-methyl-3-(2,4-pentadienyl)-l,4-benzoquinone to give compound 45 (87JOC3956). The second pyrrole ring was also formed from a 2-hydroxy-propyl side chain of an indolo-4,7-dione (80JOC5057). Benzo analogs were prepared in a Friedel-Crafts reaction from either phthalic anhydride (67TL765) or 2-pyrrolidinylcarbonyl chloride (86H2797). 

The relative reactivities of the five-membered-ring heterocycles are reflected in the Lewis acid required to catalyze a Friedel-Crafts acylation reaction (Section 15.13). Benzene requires AICI3, a relatively strong Lewis acid. Thiophene is more reactive than benzene, so it can undergo a Friedel-Crafts reaction using SnCl4, a weaker Lewis acid. An even weaker Lewis acid, BF3, can be used when the substrate is furan. Pyrrole is so reactive that an anhydride is used instead of a more reactive acyl chloride, and no catalyst is necessary. 

The methodology for synthesis of isoindoles is not as thoroughly explored as that of pyrroles and indoles and there is less information about the generality of specific methods. Nevertheless, reaction patterns for cyclizative condensation are similar to those for pyrroles and indoles. Generation of o-acylbenzylamines generates isoindoles. Several l-arylisoindoles were prepared in two steps from (7) by a Friedel-Crafts reaction followed by release of the amino group from the phthalimide by hydrazinolysis (Scheme 24) <64JA4152>. 

The first three reactions are all electrophilic substitutions a bromination of a pyrrole, the nitration of quinoline, and a Friedel-Crafts reaction of thiophene. Bromination of the pyrrole occurs at the only remaining site. Nitration of quinoline occurs on the benzene rather than the pyridine ring (actually giving a mixture of 5- and 8-nitroquinolines) and the acylation occurs next to sulfur. 

Acylation. It is not necessary to employ AICI3 as a catalyst, as in the Friedel-Crafts reaction of benzene chemistry, for acid chlorides to effect acylation of the pyrrole ring. The reaction (Scheme 7.4) occurs at mild temperatures, and it makes ketones readily available. Although pyrrole is formally a secondary amine, the reduced nucleophilicity of nitrogen does not allow acylation to take place at this site. 

Like benzene derivatives, porphyrins will undergo Friedel-Crafts reactions. Thus, deuterohemin dimethyl ester acylates at its 3- and 8-pyrrole positions [Figure 3.17(a)]. Nitration [Figure 3.17(b)] occurs, unexpectedly, only at the meso-carbons, even when the less electrophilic 3-pyrrole positions are vacant. 

The enantioselective Friedel-Crafts reaction of a. unsaturated 2-acyl iV-methylimidazoles with electron-rich heterocycles, such as indole derivatives, 2-methoxyfuran, and pyrrole, was catalyzed by Sc(OTf)3 conjointly used with a chiral bis(oxazolinyl)pytidine ligand (eq 31). The reaction afforded good enantioselectivities (>90% ee) for a broad range of substrates. 

The product from this first step is an iminium cation that reacts with pyrrole to give a more stable iminium salt. The extra stability comes from the conjugation between the pyrrole nitrogen and the iminium group. The work-up with aqueous Na2C03 hydrolyses the imine salt and removes any acid formed. This method is particularly useful because it works well with Me2NCHO (DMF) to add a formyl (CHO) group. This is difficult to do with a conventional Friedel-Crafts reaction. 

The decarboxylation is a general reaction of pyrroles it s a kind of reverse Friedel—Crafts reaction in which the electrophile is a proton (provided by the carboxylic add itself) and the leaving group is carbon dioxide. The protonation may occur anywhere but it leads to reaction only if it occurs where there is a COjH group. 

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