Five-membered rings Friedel-Crafts reaction

Friedel-Crafts alkylation can occur intramolecularly to form a fused ring. Intramolecular Friedel-Crafts reactions provide an important method for constructing polycyclic hydrocarbon frameworks. It is somewhat easier to form six-membered than five-membered rings in such reactions. Thus, whereas 4-phenyl-1-butanol gives a 50% yield of a cyclized product in phosphoric acid, 3-phenyl-1-propanol is mainly dehydrated to alkenes.43... 

An important application of the Friedel-Crafts acylation is the intramolecular reaction, leading to ring closure. This variant is especially useful for the closure of six-membered rings, but five-membered ring products and larger rings, as well as heterocycles, are also accessible ... 

This reflects a rather general tendency for the formation of six-membered rings in preference to five- and seven-membered rings in ring closure by intramolecular Friedel-Crafts reactions.38,39 Intramolecular Friedel-Crafts reactions provide an important method for constructing polycyclic hydrocarbon frameworks. Entries 5-7 in Scheme 11.3 are examples of this type of reaction. 

By in situ MAS NMR spectroscopy, the Koch reaction was also observed upon co-adsorption of butyl alcohols (tert-butyl, isobutyl, and -butyl) and carbon monoxide or of olefins (Ao-butylene and 1-octene), carbon monoxide, and water on HZSM-5 (Ksi/ Ai — 49) under mild conditions (87,88). Under the same conditions, but in the absence of water (89), it was shown that ethylene, isobutylene, and 1-octene undergo the Friedel-Crafts acylation (90) to form unsaturated ketones and stable cyclic five-membered ring carboxonium ions instead of carboxylic acids. Carbonylation of benzene by the direct reaction of benzene and carbon monoxide on solid catalysts was reported by Clingenpeel et al. (91,92). By C MAS NMR spectroscopy, the formation of benzoic acid (178 ppm) and benzaldehyde (206 ppm) was observed on zeolite HY (91), AlC -doped HY (91), and sulfated zirconia (SZA) (92). 

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. 

If the 3-position is blocked, reaction occurs at the 2-position and this at first seems to suggest that it is aU right after all to take the electrons the wrong way round the five-membered ring. This intramolecular Friedel-Crafts alkylation is an example. 

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. 

These reactions are most successful for the preparation of six-membered rings, though five- and seven-membered rings have also been closed in this manner. For other Friedel-Crafts ring-closure reactions, see 11-13, 11-14, and 11-23. 

A useful extension of Friedel-Crafts acylation is an intramolecular reaction leading to cyclic products. Thus, five- and six-membered rings are readily and efficiently created by use of an appropriate aryl acyl chloride, as shown below. 

Intramolecular Friedel-Crafts acylation reactions that produce five-membered or six-membered rings occur readily. Cyclization must take place at the position ortho to the reacting side chain. 

In Scheme 10, examples of eaiantioseleetive cycloadditions with formation of three-, four-, five-, and six-membered carbocyclic or heterocyclic rings are presented, to demonstrate the use of Ti-TADDOLates as Lewis acids. The Diels-Alder reaction has, so far, been studied most extensively, and many protocols have been proposed for the preparation of the Ti catalyst, of which as little as 5 mol-% and as much as several equivalents were employed (more often than not, Lewis acids bind strongly to the products of reactions they have mediated cf. the classical Friedel-Crafts acylation with AICI3 ). 

---