Tandem hydroformylation reaction cyclization

In almost the same manner, tandem hydroformylation/aldol condensation aldol condensation of ketoolefins, such as p,y-unsaturated ketones, gives a single cyclization product under acid catalysis. Similar to the stepwise reaction, the in situ generated aldehyde preferentially acts as the electrophilic carbonyl component, while the ketone acts as the nucleophilic enol to form the five-membered ring product. Subsequent dehydration and hydrogenation of the resulting enone readily occurs under the reductive reaction conditions used (Scheme 30) [84],... 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Spiropyrans (55a and 55b) and other related systems bearing quaternary centers are important synthons in a large class of natural products with bodi biological and pharmaceutical importance. These natural products include several important antibiotics and pheromones. Eilbracht and co-workers developed a tandem hydroformylation/cyclization sequence under relatively mild conditions, which led selectively to several spiropyrans 55a and 55b (Table 2-2) from relatively easy to synthesize homoallylic alcohols 54. Furthermore, little or no purification was required for this tandem series of reactions. 

Scheme 5.122 Synthesis of pseudoconhydrine and its epimer via a tandem hydroformylation-cyclization reaction.

Hydroformylation can be incorporated efficiently into tandem reactions [17]. Various tryptamine-based pharmaceuticals were prepared by hydroformylation carried out in the presence of hydrazine derivatives. The aldehydes were generated in situ from the alkenes and trapped by the hydrazines to form the hydrazones that on cyclization gave the indole products. Application of water-soluble ligands such as TPPTS made it possible to execute hydroformylation and cyclization in one step in aqueous sulfuric acid [18]. 

Scheme 6.27 Tandem hydroformylation-cyclization reaction to bicyclic imidazole-derivatives...

Limonene was reacted with syngas to give a bicyclic alcohol in a hydroformylation-cyclization tandem reaction (Scheme 1.53) [60]. In this approach, there was no need to isolate the intermediate aldehyde. Diastereomers were formed in nearly equal amounts (47 53). 

The group of Taddei added the important observation to the hydroformyla-tion chemistry of formaldehyde that the irradiation with microwaves is of additional value [18]. The scope of the methodology has been broadened to several hydroformylation-cyclization tandem reactions, as exemplarily illustrated with a final Af,0-acetalization step (Scheme 3.7). 

In a patent by Mitsubishi, it is available via hydroformylation of limonene and subsequent acid-catalyzed intramolecular cyclization of the aldehyde [1]. The alcohol can also be produced in one step by Pt/Sn-catalyzed hydroformylation, suggested by a protocol of Gusevskaya and coworkers (Scheme 5.123) [2, 3]. Platinum and tin are essential for the cychzation in the last step. Alternatively, the tandem reaction has been investigated in detail with rhodium complexes based on PPhg, P[0(o-fBu)Ph]3, or PPTS (pyridinium / -toluenesulfonate)... 

Our group has developed a new route towards functionalized bicyclic imidazole derivatives consisting of a one-pot tandem reaction sequence under hydrofor-mylation conditions using the catalyst system Rh/44 [80]. 8-Hydroxy-6-methyl-5,6,7,8-tetrahydroimidazo-[l,2-a]pyridine as a mixture of 2 stereoisomers was formed selectively in high yield by hydroformylation of A -(j8-methallyl)imidazole and subsequent intramolecular cyclization (Scheme 6.27). 

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