Intermolecular phthalides

The preparation of lactones via intramolecular catalytic esterification can be carried out by the Tishchenko reaction of dialdehydes. Alkaline earth metal oxides have been shown to be active not only for the intermolecular Tishchenko reaction, but also for the intramolecular Tishchenko lactonization. Thus, these solid catalysts have been applied for the Tishchenko reaction of o-phthalaldehyde to phthalide 182) (Scheme 34). 

Y. Yamamoto, J.-I. Ishii, H. Nishiyama, K. Itoh, J. Am. Chem. Soc. 2005, 127, 9625-9631. Cp RuCl-catalyzed formal intermolecular cyclotiimerization of three unsymmetrical alkynes through a boron temporary tether regioselective four-component couphng synthesis of phthalides. 

However, this is not what happened. HPLC/MS reveals that only 2-(hydroxymethyl)benzoic acid, 14, is formed when the product is not acidified (electron spray, negative mode), or phthalide, 15, is formed when the product is acidified or when the pH is adjusted to neutral (electron spray, positive mode). This is a desired result since 2-hydroxymethylbenzaldehyde, 21, as discussed above, was not a preferred by-product. Thus Route I in Fig. 6 was confirmed to be the actual neutralization path. The corresponding stepwise mechanism was proposed as follows (Fig. 8). Thus, the intramolecular hydride transfer of 22 as shown in Fig. 8 is more favorable than that of an intermolecular process shown in Fig. 7. 

Intermolecular cross-[2 + 2 + 2] cycloaddition of two different alkynes is important from a synthetic point of view. An (Tf-indenyl)rhodium(I) complex catalyzed the reactions of 2-methyl-3-butyn-2-ol and two molecules of acetylenecarboxylates, which furnish phthalides through sequential [2 + 2 + 2] cycloaddition and transesterification (Scheme 4.6) [9]. 

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