Cascade and Domino Catalytic Reactions

This chapter has reported various examples to evidence how the new advances in catalyst design allow us to perform selectively in one-pot multistep reactions. These, which apply in particular for fine chemicals production, are often called "cascade" reactions, because they effectively involve the desorption from one site to react on another site physically distant from the first. It is thus a different concept from that shown in Figure 2.66: n-butane to maleic anhydride on (VO)2P2O7 catalysts, where all the reaction pathway proceeds only on the catalyst surface without desorption of reaction intermediates. However, in cascade reactions there is no separation of the products and thus they all occur in the same reactor. This is the reason for the indication "one-pot" reactions.

A further interesting example is the synthesis of nabumetone, an antiinflammatory agent, with a multifunctional base/acid/Pd catalyst through a cascade reaction [341]. The commercial synthesis (Hoechst/Celanese) is based on a two-step process involving either a Heck reaction between 6-bromo-2-methoxy-naphthalene and methyl vinyl ketone or a condensation between 6-methoxy-2-naphthaldehyde and acetone to give an intermediate that is separated, purified and hydrogenated in a second, separate process to give the final product, while producing a large amount of waste products. Corma et al. [341] have reported a residue-free catalytic process for the production of nabumetone in 98% yield and 100% selectivity, achieved through a cascade reaction system involving a multifunctional base/acid/hydrogenation catalyst based on nanocrystalline (3 nm) MgO (Figure 2.67).

Prescribing Cascades Examples
Figure 2.67 Synthesis of nabumetone with a multifunctional base/acid/Pd catalyst through a cascade reaction. Source: adapted from Corma et al. [341].

Another recent example from the Corma group concerns the one-pot synthesis of a topoisomerase-I inhibitor, an agent designed to interfere with the action of topo-isomerase enzymes. The commercial synthesis (Hoechst AG, US Pat 3 538 097) involves a seven-step procedure with a final cumulative yield of about 13%, due to the loss of selectivity in each step. In the one-pot synthesis reported by Corma's group [320], a combination of homogeneous and heterogeneous steps is used to obtain a global yield of 72% (Figure 2.68). This catalytic process has a clear advantage over the commercial organic synthesis procedure (which also produces more waste).

Another concept is that of domino reactions. This concept is known in organic chemistry [342], but less so in catalysis. The usual procedure for the synthesis of

HETEROGENEOUS, p.j HETEROGENEOUS

HETEROGENEOUS, p.j HETEROGENEOUS

Au Au

(Final Yield 72%)

Figure 2.68 One-pot synthesis of a topoisomerase-I inhibitor. Source: adapted from Corma et al. [320].

Figure 2.69 Domino reaction for the synthesis of an ether fragrance. Source: adapted from Corma et al. [320, 343].

organic compounds is the stepwise formation of the individual bonds in the target molecule. However, it would be more efficient if one could form several bonds in one sequence without isolating the intermediates, changing the reaction conditions, or adding reagents. This "domino" type procedure allows the minimization of waste, and the reduced use of solvents, reagents, adsorbents and energy with respect to stepwise reactions. The concept of a domino reaction is thus analogous to that of cascade reactions. It is used when a single catalyst, instead of different catalytic components, can perform the entire sequence of steps necessary, and the sequence of transformations is induced by a modification of the reaction conditions, or stepwise addition of the reagents. This is a unique opportunity for solid heterogeneous catalysts, because homogeneous catalysts are often characterized by a defined single functionality.

An interesting example of catalytic domino reaction is the synthesis of an ether fragrance reported by Corma and Renz [343] using either Sn-beta or Zr-beta, although the latter is preferable, giving at 100 °C (8h) complete conversion with virtually 100% overall selectivity, while the Sn-beta is equally selective but less active. Figure 2.69 reports the scheme of this reaction. In a first step, the alcohol is produced by a Meerwein-Ponndorf-Verley reduction at 100 °C.

A one-pot reaction with cascade catalysis is not only particularly relevant in the case of fine chemistry but also for the new area of bioresource use. Several interesting examples have been discussed recently by Gallezot [344].

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