Multicatalytic processes

Pd-catalyzed cross-coupling reactions were studied in one-pot multicatalytic processes to synthesize disubstituted alkenes and alkanes from carbonyl derivatives [68]. The use of Cu-catalyzed methylenation reactions was the key starting reaction to produce terminal alkenes that are not isolated but submitted to further structure elongation (hydroboration followed by Suzuki cross-coupling) (Figure 1.13). These processes have been used to synthesize methoxylated ( )-stilbenoids (i.e., ( )-1,3-dimethoxy-5-(4-methoxystyryl)benzene). 

Figure 1.13 One-pot multicatalytic processes. (Reproduced with permission from Ref [68].)...

S. Li, Y. Luo, J. Wu, Org. Lett. 2011, 13, 4312 315. Three-component reaction of N -(2-alkynylbenzylidene)hydrazide, alkyne, with sulfonyl azide via a multicatalytic process a novel and concise approach to 2-amino-H-pyrazolo[5,l-a] isoquinolines. 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

In a different approach, Lebel and co-workers designed a multicatalytic process combining the [(IPr)Pd(OAc)2]-catalyzed alcohol oxidation and their [RhCl(PPh3)3]-catalyzed carbonyl methylenation. They were able to perform both reactions sequentially in one pot, effectively converting alcohols into terminal alkenes (Equation (12.3)). To further highlight this approach, they performed a three-reaction cascade comprised of the two former reactions, which resulted in the formation of a diene, followed by an alkene metathesis in... 

The intramolecular oxidative formylation and ketonyla-tion reactions conceptually related to those described in preceding sections allow for preparation of carbonyl-bearing complex heterocycles from simple ene-ols, however with the use of stoichiometric amount of palladium reagent. Thus, this new oxidative carbonylation method offers intriguing possibilities for incorporation into synthetically productive multicatalytic processes. An example is the transformation shown in Scheme 15.26, a key step in the synthesis of diospongin A. The transformation of diol 96 under Lambert s reaction conditions proceeded smoothly to provide diospongin A with excellent diastereoselectivity (Jr >20 1). 

However, the latter type of metal-catalyzed cascade reactions turns out to be even more challenging since issues of selectivity and efficiency are crucially dependent on the particular catalyst structure. This type can either be performed in a parallel or sequential fashion [16,21], Whereas parallel catalysis is significantly more difficult to develop, sequential catalysis offers the possibility of altering reaction conditions and additives from step to step in the sense of bi- or multicatalytic one-pot processes, assisted tandem catalysis, or auto tandem catalysis [1]. Therefore, a demanding goal is the development of one-catalyst multireaction sequences that set the stage for new reactions in diversity-oriented syntheses of complex molecular structures (for reviews on diversity-oriented syntheses see [27-33]). 

It is probable that the recognition of the existence and role of 19e species in mechanisms will lead in the near future to the finding of new processes that may involve multicatalytic components with sophisticated technological devices. 

Also of interest in this report was Dixon s use of a multicatalytic cascade process whereby the lactone was formed in situ via the gold(I)-catalyzed cycloisomerization of alkynoic acids in the presence of the same chiral phosphoric acid. In this system, ees of up to 95% were obtained. 

Multicatalytic domino processes are synthetic strategies in which two or more catalytic domino reactions are sequentially used in the synthesis of a compound Hbrary [8-10]. The product obtained from the first domino reaction is the substrate for subsequent cascades, which yield products with either a different scaffold or modified functional group formation. 

In terms of relay and sequential metal-organo multicatalytic systems, these catalysts are most commonly used for 1,2 (aldol type) or 1,4 (Michael type) additions to suitable electrophiles. The most pervasive approach takes advantage of some metal-catalyzed process to generate a substrate for the organocatalyst. The examples illustrated in Scheme 26.16 show how chemical [94] or photochemical [95] metal-catalyzed oxidation of amines generates imine species that then undergo organocatalyzed 1,2 addition. 

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

In 2011, Panteleev et al. reported a domino alkyne arylation and N-arylation process by combining rhodium and palladium catalysis [10], Based on a Rh-catalyzed alkyne arylation and subsequent Pd-catalyzed intramolecular N-arylation process, this multicatalytic cascade reaction efficiently incorporated amine-pendant aryl alkynes 25 and aryl boronic acid into functionalized dihydroquinoline derivatives (Scheme 9.7). 

Incorporation of the new catalysis concept and N-heterocyclic carbene catalysis into multicatalytic systems emerged as a new direction to build up a complex scaffold such as those often found in natural products. Liu et al. developed an enantioselective Diels-Alder reaction via trienamine catalysis of indole-2,3-quinodimethane and activated alkenes. More recently, they combined this Diels-Alder process with N-heterocyclic carbene catalysis for the rapid generation of chiral cyclopentanone-fused tetrahydrocarbazoles with diverse substitution [30]. Mechanistically, with the... 

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