Hydroformylation-Cyclization Reaction

8-Dimethyl-bicyclo[3.3.1]non-7-en-2-ol is a compound with an interesting odor and therefore ofvalue forthe manufacture of perfumes (see also Section 6.1). 

The Mukayama-aldol reaction, which runs under the severe conditions of hydroformylation, ends up with a complete migration of the silyl group. With this methodology, particularly spirocyclic aldol adducts, hydropentalenes, hydroindanes, or substituted naphthols become available. 

An example with huge economic relevance is the manufacture of 2-propyl-heptanol (2-PH) as a component of plasticizer alcohols and, on a smaller scale, for use in cosmetics [9]. On an industrial scale, the transformation is commonly conducted as a three-step approach starting with the hydroformylation of isomeric butenes, subsequent aldol reaction of formed -valeraldehyde, and, finally, combined hydrogenation of the C-C double bond and aldehyde group [10]. In a similar process, the production of the plasticizer alcohol 2-ethyl-hexanol (2-EH) is carried out [11, 12]. 

5 Hydroformylation Followed by Another C-C-Bond Formation Step 499 

Considering the matched/mismatched problem (see Section 4.3.2), the combination of the (25,45 )-configured ligand for the hydroformylation step and (5)-proline for the aldol condensation resulted in superior diastereo- and enantioselectivities. The results were improved by altering the structure of the organocatalyst (up to 6.6 1 dr). 

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

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

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]. 

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. 

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). 

Hydroformylation of allyl amides catalyzed by Rh(BIPHEPHOS) in acetic acid (reaction in toluene failed) can be utilized as the initial step of a cyclization reaction (Scheme 4.43) [88]. Under the described conditions, the intermediate aldehyde undergoes ring closure with the participation of the aromatic ring. 

The cobalt-catalyzed reaction was studied by isolation of the lactones formed by hydrogenation and lactonization at higher temperatures (73). The hydroformylation was conducted at 140°C and 300 atm, followed by hydrogenation and cyclization at 200°-240°C, Eq. (33). 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

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],... 

Cyclization also accompanies the hydroformylation of unsaturated C4-alcohols catalyzed by a rhodium/PNS (27) complex (Scheme 4.14). Interestingly, an approximately 3-fold increase was observed in the activity of the catalyst upon increasing the pH from 7 to 9.5 [95]. Rhodium could be efficiently recycled in the aqueous phase, but since there was a considerable pH-drop during the reaction (from 9 to 5) the activity of the catalyst had to be regenerated by addition of a base (NaOH). 

Other Cig-fatty acids have also a high potential in hydroformylation, such as ricinoleic acid, which contains an additional hydroxy group at position 12 of the fatty carbon chain and which is not food relevant [26], The hydroformylation of ethyl ricinoleate, derived from castor oil, shows selectivity for cyclization of the carbon chain because of the reaction of the hydroxyl group with the formyl group (Scheme 8). 

The same catalyst precursor, generated from [(EDTA)RuCI] which is also water soluble, was used for the hydroformylation of allylic alcohol under the same reaction conditions (//). At 50 bar and 130°C, in water as solvent, 4-hydroxybutanal was produced [Eq. (5)], together with about 2% of formaldehyde. However, the reaction proceeded further to give butane-1,4-diol by hydrogenation and y-butyrolactone as well as dihydrofuran by cyclization [Eq. (6)]. The same catalytic cycle as that proposed in Scheme 3 can be considered. A kinetic investigation revealed a first-order dependence on the ruthenium complex concentration and on the allyl alcohol... 

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