We discovered that aza-DA reactions could be effectively catalyzed by lanthanide triflates in water (17). The catalytic process greatly reduces the limitations mentioned earlier. Aldehydes other than formaldehyde and glyoxylate work well to provide the DA adducts in good yields. The reactions of various dienes other than cyclopentadiene also give excellent yields (Figure 1). Moreover, the lanthanide triflates can be recovered easily and reused after the product is extracted with methylene dichloride. In fact, the lanthanide(III) catalysts described in this article are reusable in most cases.

We expect that the lanthanide-catalyzed aza-DA reactions will be used in organic synthesis. We have successfully applied this method to synthesizing aza-sugars and their analogues, which are potential inhibitors of glycoprocessing enzymes (18) (Figure 2). For example, by starting from a D-mannose derivative, the reaction of glyceraldehyde acetonide 1 (boldface numbers appear on Figure 2) with benzylamine hydrochloride and cyclopentadiene in water proceeded readily in the presence of lanthanide triflates to afford three adducts; 4 was the main product. The corresponding reaction of another chiral aldehyde 6, prepared via diazotization of D-glucosamine hydrochloride, stereoselectively yielded 7 as the major product. As is often observed, the radii of the lanthanide ions played an important role in the catalytic process. The medium-size lanthanides gave better results than smaller or larger ones. The diastereoselectivities can be rationalized by proposed lanthanide-coordinated intermediates. Products 4 and 7 were subsequently converted into aza-sugar analogues after several steps.

The use of aqueous media allows the use of unprotected carbohydrates or their derivatives as one of the components in the aza-DA reaction. Application of the lanthanide-promoted aqueous aza-DA reaction in carbohydrate chemistry promises to provide a novel entry to numerous carbohydrate-derived nitrogen-containing heterocycles.

Synthesizing pyridine and its derivatives
The pyridine family and its derivatives are important in biological functions; they also are versatile intermediates for the synthesis of natural products such as alkaloids. Considerable research has focused on synthesizing these compounds from acyclic starting materials.

In our recent exploration of lanthanides as stable Lewis acids in aqueous solutions, we found that lanthanide triflates effectively promote reactions of aldehydes with amine hydrochlorides to afford 2,3-dihydropyridiniums and pyridinium derivatives (19). The reactions proceed readily in water at room temperature. For example, hexanal reacts with benzylamine hydrochloride in aqueous solutions of lanthanide triflates to give 3,5-dibutyl-2-pentyl-N-benzyl-2,3-dihydropyridinium and 3,5-dibutyl-2-pentyl-N-benzylpyridinium in a combined yield of 82%. The counterions in the products could be OTf^- or Cl^-, depending on workup conditions. The dihydropyridinium then can be converted to the corresponding pyridinium by dehydrogenation in the presence of triethylamine in refluxing toluene. The latter can be debenzylated to produce the pyridine compound (Figure 3).

We found that other aldehydes and amine hydrochlorides react similarly. However, one of the two products could be absent, depending on the aldehyde used. For example, the reaction of propionaldehyde or butanal with benzylamine hydrochloride gave only 2,3-dihydropyridiniums; no corresponding pyridiniums were isolated. In contrast, the reactions of phenylacetaldehyde and 4-decenal gave only pyridinium products.

We believe that the reactions proceed through sequential condensations of three molecules of the Schiff base formed between the aldehyde and the amine. The pyridinium products result from oxidation of the corresponding 2,3-dihydropyridiniums (Figure 4). This method of Ln(OTf)₃-catalyzed reactions in water is a novel extension of pyridine synthesis via the condensation of aldehydes and amines (the Chichibabin reaction). The Chichibabin reaction normally requires high temperatures, high pressures, or vapor-phase reaction conditions, whereas the Ln(OTf)₃-catalyzed reactions proceed under mild conditions.

Reactions of indoles with aldehydes
Protic acids and Lewis acids promote reactions of indole with aromatic and aliphatic aldehydes and ketones. The reactions produce azafulvenium salts, which then react further with a second indole molecule to form bisindolyl-methanes (20-22). By using lanthanide triflates as catalysts, we recently realized this reaction in aqueous media (Figure 5) (23). Ethanol-water was the best solvent system for yield and product isolation. Although all the lanthanides showed good catalytic effects, dysprosium triflate gave the best result.

Aromatic aldehydes with either electron-donating or electron-withdrawing substituents also reacted well to give excellent yields. The reactions of ketones took longer but still produced moderate-to-excellent yields. In contrast, the corresponding reactions using trifluoroboron etherate or aluminum chloride generated several unexpected products (24, 25). In the case of the 3-substituted indoles, the most active site (C-3) was blocked, so that both ketones and aromatic aldehydes failed to react, whereas the corresponding reaction of hexanal afforded a [1+1] ethanolysis product other than the normal [2+1] adduct.

Imines, like the carbonyl compounds we have been working with, are electrophilic and can be effectively activated by Ln(OTf)₃. As an extension of the above work, we recently examined the corresponding reaction of indole with a variety of imines. The reaction proceeded in a manner similar to that shown in Figure 5, producing secondary indolyl amines as well as bisindolyl-methanes as the byproducts. This is a convenient alternative for performing the conventional Mannich reaction of indole with primary amines, which usually gives a low yield because of various side reactions.

Aziridine synthesis
Aziridines are versatile building blocks for synthesizing various biologically important molecules (26, 27). Adding a carbene moiety to an imine is one of the simplest approaches to aziridine synthesis. Templeton and co-workers have shown that Lewis acids such as BF₃·O(C₂H₅)₂, AlCl₃, and TiCl₄ are efficient catalysts in the aziridination reaction of ethyl diazoacetate (EDA) with imines (28). The aziridination is effected by activating the imines followed by a nucleophilic addition of EDA. Just recently, by using lanthanide triflates, we accomplished this aziridination reaction in protic media that included the CH₃CN-H₂O system.