Hydroformylation-cyclization

Garbay reported the chemoselective reduction of a a-dehydrophenylala-nine substrate bearing a p-acrylate moiety [105]. Robinson et al. have also used a tandem, one-pot asymmetric hydrogenation-hydroformylation-cyclization approach to generate six- to eight-membered cyclic a-amino acids [136]. 

Cyclic a-amino acids with an enamine pattern can be obtained upon enantioselective hydrogenation followed by a hydroformylation/cyclization sequence in a single-pot version Rh(I)-DuPHOS acts as a catalyst for both steps, the enantioselective hydrogenation of prochiral dienamides and the hydroformylation of the resulting homoallylic amines (Scheme 13) [52,53]. 

In a similar fashion, hydroformylation of N-allyl-pyrrols leads to 5,6-dihydroindolizines via a one-pot hydroformylation/cyclization/dehydration process (Scheme 27) [81,82]. The cyclization step represents an intramolecular electrophilic aromatic substitution in a-position of the pyrrole ring. This procedure was expanded to various substrates bearing substituents in the al-lyl and in the pyrrole unit. 

Auto-tandem hydroformylation-cyclization, catalyzed by [RhCl(cod)]2, enables expansion of the organic skeleton of unsaturated silyl enol ethers (Scheme 10). Linear aldehydes generated in the hydroformylation step subsequently undergo Rh-catalyzed, intramolecular Mukaiyama aldol addition. Bicyclic ketones are also accessible from cyclic silyl enol ethers. 

Cyclohydrocarbonylation of 1-allylpyrroles 74a-d catalyzed by Rh4(CO)i2 gave the corresponding 5,6-dihydro-indolizines 77a-d in good yield and excellent regioselectivity (Scheme 12)." This reaction proceeded through a cascade hydroformylation-cyclization-dehydration sequence (Scheme 12). Exclusive introduction of a formyl group... 

Conventionally, this reaction is conducted in the presence of a Lewis acid. We had to check that the catalyst used in the hydroformylation was still active in the presence of such an acidic additive. To this point, only catalytic amounts of PPTS (pyridinium p-toluenesulfonate) had been used in CHC reactions. This study was conducted on substrate 21, which was designed to allow only the hydroformylation/cyclization sequence (Scheme 9). It was synthesized by peptide coupling between 0-Me-phenylglycinol and vinyl acetic acid in a yield of 84%. Without an acidic additive, the hydroformylation reaction of this substrate proceeded in 93% yield and produced the linear aldehyde/branched aldehyde in a ratio of 92 8. We obtained the enamide after the CHC reaction in very good yields both in the presence of pTSA and Lewis acids (e.g., BF3-Et20, Zn (OTf)2). In addition, it should be noted that the regioselectivity of the hydroformylation reaction dictated by chelation of the BiPhePhos ligand is not disturbed by the presence of the acidic additive. 

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. 

Table 2-2. Tandem hydroformylation cyclization of homoallyl alcohols.

The hyfroformylation of propargylamines 202 in the presence of the classical catalytic system [Rh(OAc)2]2/PPh3 gives 2,4-disubstituted pyrroles 204 in excellent yields, through consecutive hydroformylation, cyclization and double bond isomerization [116, 117]. 

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). 

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

The group of Lazzaroni reported the synthesis of 5,6-dihydroindolizines from 1-allylpyrroles via a tandem hydroformylation-cyclization-dehydration sequence as shown in Scheme 5.125 [6]. Substituents at the pyrrol ring as well as on the olefin were tolerated. In the best case, 68% yield of the fused bicycles was obtained. 

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

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