Tandem hydroformylation-acetalization

Very recently the tandem hydroformylation/acetalization has been used for the synthesis of new synthetically valuable chiral auxiliary derived from camphor. Stereoselective allylation of camphor and subsequent terminal hydroformylation of the resulting homoallylic alcohol affords the 5-lactol auxiliary (camTHP OH) in multigram scale (Scheme 8) [41]. 

Rhodium-catalyzed tandem hydroformylation-acetalization of a,co-alkenediols is a facile entry to perhydrofuro[2,3-6]furans. A benzoannulated tetrahydrofuro[2,3-fc]furan was obtained in this manner <02OL289>. A mixture of trisubstituted tetrahydrofurans was obtained from a n-allylmolybdenum complex and this is depicted in the following scheme <020L2001>. 

Eilbracht et al. by means of rhodium-catalyzed tandem hydroformylation/acetalization of cccw-alkenediols [20]. It had been previously reported that hydroformylation of alkenol resulted in cyclic hemiacetal [21]. Starting from enediols, the authors paved the way for subsequent acetalization, leading to fused bicyclic compounds in a one-pot cascade. As expected, exclusive formation of czs-fused perhydrofuro[2,3fr]furan 6 occurred when applying 60 bar of syngas (CO H2 = 3 1) at 120 °C in dichloromethane to diol 5 in the presence of a [Rh(cod)Cl]2/PPh3 catalytic system (Scheme 4). 

A tandem hydroformylation/acetalization reaction of/r-menthenic terpenes in the absence of an acid co-catalyst was reported by Vieira et The reaction took place in ethanol solution in the presence of PPhsor P(0-o-BuPh)3. 

Typical procedure forthe tandem hydroformylation-acetalization reaction of terpene ... 

Scheme 6.109 Tandem hydroformylation-acetalization of cyclohexene oxide.

Scheme 6.110 Tandem hydroformylation-acetalization of enantiopure epoxides and pharmaceutically interesting targets.

In this survey, selected synthetic applications of tandem hydroformylation sequences are described and complementing the more comprehensive reviews covering the literature up to 1998/99 [27], and up to 2003 [28,29]. The material is ordered according to the type of the additional transformation involving heterofunctionalization of the aldehyde group to form acetals, aminals, imines and enamines, as well as reduction of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C,C-bond formation at the carbonyl group or at the acidic... 

On the other hand, if an amine, protected by an electron-withdrawing group, is suitably placed within the molecule, tandem hydroformylation-condensation occurs without alkene reduction. Depending on the reaction conditions, either an A, 0-acetal 4.145 (Scheme 4.55) or an enamide 4.148 (Scheme 4.56) derivative may be obtained. Each of these can be useful synthetic intermediates for the stereocontrolled formation of piperidines. Dihydroxylation of enamide 4.148 lead to a short synthesis as ej /-pseudoconhydrine 4.151. ... 

The same catalytic system proved to be advantageous for the tandem hydroformylation (Wittig olefination) reaction of a more sophisticated vinyl acetate as substrate at about 10bar (Scheme 4.68) [41]. (-p)-Patulohde C, a compound exhibiting both antifungal and antibacterial activity, was obtained with 93% de (for more details and examples of stereoselective tandem reactions, see Section 5.5). 

Consecutive hydroformylation-acetalization reaction can be achieved either by the proper choice of a single catalyst, which assists in both reactions (1), or by the utilization of two different catalysts (2), the first for the hydroformylation and the second for the acetalization (Scheme 5.69). Because of the taxonomy of Fogg and dos Santos [4], the first approach can also be termed auto-tandem catalysis. 

Scheme 5.69 Types of hydroformylation-acetalization tandem reactions.

Application of the Hydroformylation-Acetalization Tandem Reaction in Practice... 

More interesting seems to be the hydroformylation-acetalization in one pot under the same conditions as a tandem reaction. In this regard, two aspects must be differentiated undesired and desired acetalization after the hydroformylation step. 

During hydroformylation, acetalization of aldehydes can take place as an undesired side reaction when the hydroformylation is conducted in alcohols as solvent and under the influence of a hydroformylation catalyst with acidic properties. Moreover, when alcohols result in a hydroformylation-hydrogenation tandem reaction (see Section 5.2), acetalization has always been taken into consideration. 

Beginning with the only occasionally observed formation of acetals as final products of hydroformylation reactions, the hydroformylation-acetalization tandem reaction is nowadays one of the most important reactions in the framework of hydroformylation. Today, the undesired formation of acetals can be avoided by special setup of the reaction conditions. On the other hand, the tandem reaction is an important protocol for the protection of the carbonyl groups toward several... 

Special hydroformylation protocols allow the one-step production of alcohols (hydroformylation-hydrogenation tandem reaction, see also Section 5.2), which are also of crucial importance as aroma compounds. Acetals, which have similar odors like their aldehydic precursors, maybe produced in the hydroformylation in alcohols as solvent under acidic conditions (hydroformylation-acetalization tandem reaction, see also Section 5.3) [15]. The acetal formed protects the aldehyde toward oxidations, reactions with amines, or aldol condensations. Especially in demanding fragrances, these modifications that may affect the scent impression are not desired. 

The intermediary aldehydes derived from the Ru-catalyzed hydroformylation can be trapped as acetals, as shown by Borner and colleagues (Scheme 1.40) [45]. Only traces of alcohols or aldehydes could be detected. The tandem reaction proceeded exclusively with diols that formed thermodynamically stable 1,3-dioxolane and 1,3-dioxane rings. Methanol as the acetalization reagent failed. As olefins, terminal aliphatic olefins as well as styrene derivatives reacted. The catalyst could be recycled and reused at least twice. 

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