Tandem hydroformylation-

The production of alcohols from olefins using hydroformylation technology is now an established procedure. Several strategies have been developed, ranging from separate hydroformylation and hydrogenation steps using different catalysts and reaction vessels to hydroformylation tandem reactions, which proceed in a... 

An interesting one-pot hydroformylation/Fischer indole sequence can be achieved by running the hydroformylation in the presence of a phenylhy-drazine. This protocol gave access to the methyl ester of the plant growth regulator 3-indole butanoic acid (IBA) (Scheme 16) [61-63]. A review on related tandem processes involving the hydroformylation as a key step has appeared recently [9]. 

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]. 

Synthetic Applications of Tandem Reaction Sequences Involving Hydroformylation... 

Homogeneously catalyzed tandem reactions Hydroaminomethylation Hydroformylation... 

Tandem procedures under hydroformylation conditions cannot only make use of the intrinsic reactivity of the aldehyde carbonyl group and its acidic a-position but they also include conversions of the metal alkyl and metal acyl systems which are intermediates in the catalytic cycle of hydroformylation. Metal alkyls can undergo -elimination leading to olefin isomerization, or couplings, respectively, insertion of unsaturated units enlarging the carbon skeleton. Similarly, metal acyls can be trapped by addition of nucleophiles or undergo insertion of unsaturated units to form synthetically useful ketones (Scheme 1). 

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... 

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]. 

Among all tandem hydroformylation sequences the ones involving additional C,C-bond formations are the most synthetically valuable tandem hydroformylation sequences. These C,C-bonds can be formed by adding nucleophiles, which attack the carbonyl carbon, or by adding electrophiles, which attack the a-position. Furthermore, tandem reactions in which the aldehyde or an aldehyde derivative is involved in sigmatropic rearrangement are described. 

In a similar fashion, allylboronates can be used as allylation reagents under hydroformylation conditions. Thus condensed 1,5-oxazadecalin systems are achieved via tandem hydroformylation/allylboration/hydroformylation sequences starting from an N-allyl-y-amidoallylboronate (Scheme 23) [77,78]. The aldehyde obtained from a regioselective hydroformylation undergoes diastereoselective intramolecular allylboration to give an intermediate al-lylic alcohol derivative. The reaction does not stop at this stage, since this... 

In almost the same manner frans-disubstituted hydrooxepans can be obtained from a tandem hydroformylation/allyl boration of (-E)-alkoxyallyl-boronates as a mixture of anomers (Scheme 24) [79]. 

Thus /i-carbolincs can be obtained in a tandem hydroformylation/Pictet-Spengler-type intramolecular electrophilic aromatic substitution of polymer bound olefins (Scheme 26) [80]. 

The aldol reaction is probably one of the most important reactions in organic synthesis. In many industrially important hydroformylation processes selfcondensation of aldehydes is observed. Sometimes this consecutive reaction is favored as in the production of 2-ethyl hexanol. But synthetic applications of tandem hydroformylation/aldol reactions seem to be limited due regiose-lectivity problems of a mixed aldol reaction (Scheme 28). However, various tandem hydroformylation/intramolecular mixed aldol reactions have been described. 

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]. 

Similarly, tandem hydroformylation/aldol sequences can be applied to the formation of bicyclic and spirocyclic compounds. Thus silyl enol ethers of 3-vinyl and 3-allyl cycloalkanones give ring anellated products (Scheme 33) [86,87]. 

Very recently, a tandem sequence consisting of enolboration/hydroform-ylation/aldol reaction has been described [88]. Here configuration of the enol boronate is transferred to the aldol product, allowing good to excellent di-astereoselectivities in the hydroformylation/aldol reaction. With this method, 5-7-membered rings are obtained in excellent yields (Scheme 35). 

A tandem hydroformylation/carbonyl ene reaction can be observed in cases, in which substrates with at least two isolated oleftnic bonds are hydro-formylated at only one double bond selectively. Thus hydroformylation of limonene with PtCkCPPlH /SnCk/PPlH or PtCl2(diphosphine)/SnCl2/PPh3 gives a mixture of two diastereomeric alcohols upon carbonyl ene reaction of the intermediate aldehyde, (Scheme 36). Best results are achieved with a PtC Cdppb) complex. The mechanism of the final intramolecular cycli-zation step resembles an acid catalyzed carbonyl ene reaction [89]. 

With this tandem hydroformylation/hydrazone formation/Fischer indolization 3-substituted indoles such as valuable intermediates for the synthesis of pharmaceuticals as well as pharmaceuticals can be obtained in a very... 

In conclusion, the applicability of the transition metal catalyzed hydroformylation of easily accessible functionalized or non-functionalized unsaturated compounds is expanded by its implementation in reaction sequences, tandem reactions or domino reactions. The hydroformylation can be combined with simple functional group transformations, such as reduction or isomerization, or with C,0-, C,N- and, most importantly, C,C-bond forming reactions. It can be expected that more interesting examples and applications will be presented in the future. 

Eilbracht P, Schmidt AM (2006) Synthetic Applications of Tandem Reaction Sequences Involving Hydroformylation. 18 65-95 Eisen MS, see Lisovskii A (2005) 10 63-105... 

Hydroformylation reactions have been shown to be amenable to use in tandem or domino reaction sequences. In one elegant example, alkene 36 was subjected to rho-dium(I)-catalyzed hydroformylation, and the resulting aldehyde underwent smooth intramolecular allylboration (Scheme 5.14) [19]. This produced a new terminal alkene which underwent a second hydroformylation to provide, after workup,lactols 37 in 80% yield and with excellent diastereoselectivity. 

Wittig yhdes have been shown to be compatible with hydroformylation conditions, and may thus be used in a domino reaction sequence such as from 16a to 38 (Scheme 5.15) [20]. When an a-unsubstituted ylide is employed, the resulting alkene undergoes in-situ rhodium-catalyzed hydrogenation in a triple tandem reaction to convert 10 a to 39. Several other examples were reported establishing the generality of this domino reaction sequence. 

The vast majority of the work described in this chapter was reported since 1995. Rho-dium( I)-catalyzed hydroformylation and silylformylation reactions have only very recently been adapted and developed for use in the efficient synthesis of stereochemi-cally complex natural products. In addition, the recent development of tandem reactions that take advantage of the direct production of aldehydes in these carbonylation reactions have only begun to demonstrate the versatility of this chemistry. Rhodium(I)-catalyzed hydroformylation and silylformylation, venerable reactions that have primarily been associated with organometaUic chemistry, must now be considered important tools for natural product synthesis. The continued development of these methodologies for that purpose may be expected. 

Because of the high and versatile reactivity of aldehyde in the organic transformations, hydroformylation reaction was often combined with other sequential reactions to perform several reactions in one pot. Here, we focus on such tandem reactions containing hydroformylation. 

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. 

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