Hydroformylation BIPHEPHOS

Much progress has been made on regioselective hydroformylation of terminal alkenes in favor of the linear product. In particular bidentate phosphine or phosphite ligands, which have a natural bite angle 9 of about 110°, will favor the linear product. The most successful ligand types are BISBI [49, 50], BIPHEPHOS [51,52], and XANTPHOS systems (Scheme 8) [53]. 

As demonstrated by Hoffmann and coworkers, hydroformylation can also be combined with an allylboration and a second hydroformylation, which allows the formation of carbocycles and also heterocycles [213]. A good regioselectivity in favor of the linear aldehyde was obtained by use of the biphephos ligand [214]. Reaction of the allylboronate 6/2-76 having an B-configuration with CO/H2 in the presence of catalytic amounts of Rh(CO)2(acac) and biphephos led to the lactol 6/2-80 via 6/2-77-79 (Scheme 6/2.17). In a separate operation, 6/2-80 was oxidized to give the lactone 6/2-81 using tetrabutyl ammonium perruthenate/N-methylmorpholine N-oxide. 

The unsubstituted quinazolidine system 5 was constructed from mesylate 173. The key feature in this synthesis is based on a cyclohydrocarbonylation of the protected 4-amino-l,6-heptadiene 169 catalyzed by Rh(acac)(CO)2-BIPHEPHOS. Formation of the hemiamidal-aldehyde 171 took place by hydroformylation of the two olefin moieties and cyclization. Elimination of water gave 172, which, after treatment with NaBFE, subsequent mesylation to 173, and catalytic hydrogenation, afforded 5 (Scheme 29) <1998TL4599>. 

General Procedure for the Hydroformylation/N,N-acetal Formation. Synthesis of Biaza-cycloalkanes. The unsaturated diamine (leq), [Rh(OAc)2h (0.5 mol % Rh atoms) and BIPHEPHOS (2 mol %) were placed in an autoclave under N2 followed by deoxygenated benzene The vessel was flushed and evacuated three times with CO/H2 (1 1,13 bar) and then pressurized to 28 bar. The reaction was kept at 40-80 °C for 20h. The autoclave was cooled and the gases were released followed by selective extraction of the total product with light petroleum. Concentration of the solvent gave in most cases NMR pure material of the title compounds. 

Recently, we reported that the rhodium/BIPHEPHOS-catalyzed hydroformylation of trans-4-octene (Scheme 6) provides an interesting approach for the synthesis of n-nonanal [23]. In this context trans-4-octene can also be seen as a model substance for hydroformylation of internally unsaturated fatty acid esters. This could open up access to the use of renewable resources for the synthesis of valuable n-aldehydes. 

Propylene carbonate is a good solvent of the rhodium precursor [Rh(acac) (00)2] and the phosphite ligand BIPHEPHOS and can thus be used as the catalyst phase in the investigation of the isomerizing hydroformylation of trans-4-octene to n-nonanal in a biphasic system [24]. As already mentioned, the reaction products can be extracted with the hydrocarbon dodecane. Instead of an additional extraction after the catalytic reaction, we carried out in-situ extraction experiments, where the products are separated from the catalytic propylene carbonate phase while the reaction is still in progress. Conversion of 96% and selectivity of 72% was achieved under comparably mild conditions (p(CO/H2) = 10 bar, T = 125 °C, 4 h, substrate/Rh = 200 1). 

Table 10 Hydroformylation of trans-4-octene in cyclic carbonate/N-octyl-2-pyrrolidone/ extraction agent, T = 125 °C, p(syngas, 1 1) = 10bar, t(reaction) = 4h, m(solvents) = 30 g, n([Rh(acac)(CO)2]) = lO- mol, n(BIPHEPHOS) = 5 x mol...

The combination of rhodium dicarbonyl acetylacetonate complex (Rh(acac)(CO)2) and a diphosphite ligand, (2,2 -bis[(biphenyl-2,2 -dioxy)phosphinoxy]-3,3 -di-/i t/-butyl-5,5 -dimethoxy-l,T-biphenyl (BIPHEPHOS), is an excellent catalyst system for the linear-selective hydroformylation of a wide range of alkenes. This catalyst system has been successfully applied to the cyclohydrocarbonylation reactions of alkenamides and alkenylamines, which are employed as key steps for the syntheses of piperidine,indolizidine, and pyrrolizidine alkaloids. ... 

Cyclohydrocarbonylation of unsymmetrical amidodiene 29 catalyzed by Rh-BIPHEPHOS complex yielded dehydropiperidine aldehyde 31 as the sole product (Scheme S). The fact that no pyrroline was formed indicates that this reaction was extremely chemo- and regioselective so that the hydroformylation took place at the homoallylic olefin moiety exclusively, yielding the linear aldehyde intermediate 30. 

The cascade hydroformylation-allylboration-hydroformylation of ( )-aminoallylborate 85 catalyzed by Rh(acac)(CO)2-BIPHEPHOS afforded oxazabicyclic lactol 87 via linear aldehyde 86 in 83% yield (Scheme 14)." The regioselective hydroformylation of 7-amidoallylboronate 88 gave linear aldehyde 89 which was in equilibrium with lactol 90. Removal of the benzyloxycarbonyl (Cbz) group by hydrogenolysis initiated another cascade process, that is, amination-hydro-genation, affording indolizidine 91 in 60% overall yield." ... 

Clean hydroformylation of the internal alkynes 58 to give the a,/ -unsaturated aldehydes 59 was achieved using the Rh catalyst coordinated by BIPHEPHOS (L) under 1 atm of CO/H2 at room temperature in CH2CI2 as a solvent [35],... 

Stereoselectivity in hydroformylation reactions, as a result of the supporting ligand set (e.g. large bite angle diphosphines or chiral diphosphines) or by stereocontrol of the substrate has also been discussed by Breit. Rhodium complexes supported by large bite angle diphosphines such as bisbi, biphephos and xantphos, shown in Scheme 10, are now well-established... 

The first investigations concerning the hydroformylation of fatty compounds were accomplished by Ucciani and co-workers with cobalt catalysts such as cobalt bislaurate and dicobalt octacarbonyl [29]. Later, Frankel and co-workers found that the cobalt-catalyzed hydroformylation of methyl oleate also leads to the corresponding fatty alcohols [30]. In recent investigations on the hydroformylation of fatty compounds, the preferred catalyst is based on rhodium. For instance, the hydroformylation of methyl oleate catalyzed by [Rh(acac)(CO)2]/biphephos yields an isomeric mixture of formylstearic add methyl esters [31]. 

BIPHEPHOS (25) is an excellent catalyst for regioselective hydroformylation of functionalized terminal alkenes to give aldehydes (Eq. 15).A zwittcrionic... 

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. 

Several pharmaceutically relevant examples are found in the patent literature where hydroformylation reactions are performed on significant scale (>100 g substrate). For example, researchers at Pharmacia (now Pfizer) reported the hydroformylation of A-Boc-(S)-7-allylcaprolactam on 250-g scale using Rh-biphephos to give aldehyde 9 (Fig. 4) with 96% linear selectivity [9]. Ozonolysis of the 7-pentenylcaprolactam derivative was used for smaller scale preparation of 9. Hydroformylation is a safer process equivalent to ozonolysis which is more amenable to scale-up. 

Hydroformylation of A-allyl phthalimide on 200-g scale was described in a recent patent by Dow [10]. Using the Rh-biphephos catalyst, the desired linear aldehyde (10) was produced in 11.5 1 linear/branched ratio. Acetal protection of the aldehyde and cleavage of the phthalimide gave the protected amino aldehyde (11), useful as a pharmaceutical intermediate. 

There are numerous reports of hydrofonnylation reactions where an amine substituent in the substrate condenses with the aldehyde product to form a heterocyclic ring (Fig. 6). Intramolecular hydroaminomethylation reactions are often referred to as cyclohydrocarbonylation reactimis. A Cbz-protected homoallylic amine underwent cyclohydrocarbonylatiOTi with Rh-biphephos to form the natural product, ( )-coniine (Fig. 6, 13) [25]. Alper recently reported the formation the seven-membered ring of 2-benzazepines (Fig. 6, 14) by hydroformylation of 2-isopropenylbenzaldehydes in the presence of anilines [26]. Intramolecular hydroaminomethylation of 2-isopropenylanilines produces 1,2,3,4-tetrahydroquinolines (Fig. 6, 15) [27]. In some instances, the enamine derived from intramolecular condensation of the resulting aldehyde is desired. For example, the synthesis of a key intermediate (Fig. 6,16) in the synthesis of a series of ACE inhibitors was... 

Highly regioselective hydroformylation of functionalized alkenes has been studied. The rhodium complex with BIPHEPHOS efficiently catalyzes the regioselective hydroformylation of a variety of functionalized terminal alkenes, giving the corresponding aldehydes (Scheme 2-3). ... 

Treating the protected amine 141 in the presence of the Rh-BIPHEPHOS catalyst (see Figure 3) under hydroformylation conditions, leads to enamide 142. The consecutive reactions are hydroformylation to give the linear aldehyde, cyclization to give aminoacetal and the elimination of water. Compound 142 is a key intermediate in the synthesis o rosopinine 143 [86]. 

Using CO/H2. Internal alkynes 197 are hydroformylated at room temperature and 1 bar CO/H2 with the catal5ftic system [Rh]/BIPHEPHOS to give excellent yields of a,P-unsaturated aldehydes 198 [ 113]. 

Sometimes, also polynuclear clusters such as Rh4(CO)j2 or Rh6(CO)26 were submitted to the formation of rhodium catalysts [18]. Metallic rhodium embedded in inorganic materials (carbon, AI2O3) was tested for mini-plant manufacturing. In this context, the frequently phosphorus ligands [PPhj, P(OPh)3] were added with the intention to detach rhodium from the heterogeneous layer (activated rhodium catalyst = ARC) [19, 20] More recently, ligand (Xantphos, PPhj, BIPHEPHOS)-modified or unmodified rhodium(O) nanoparticles were used as catalyst precursors for solventless hydroformylation [21]. It is assumed that under the reaction conditions these metal nanoparticles decompose and merge into soluble mononuclear Rh species, which in turn catalyze the hydroformylation. 

A comparison in the literature of arylphosphites with a MeO or tert-Bu group shows rather disparate results. In the hydroformylation of octenes with BIPHEPHOS-type ligands, the tert-Bu ligand induced in the corresponding Rh catalyst a TOF (turnover frequency) of approximately twice as high as the MeO... 

Isomeric pentenes, hexenes, and octenes have been used frequently in academic research to study the properties of new catalytic systems [38, 39]. Kragl and coworkers [40] have screened the hydroformylation of a series of terminal olefins (1-pentene until 1-dodecene) with a rhodium catalyst based on BIPHEPHOS and achieved excellent n-regioselectivities and TOFs (turnover frequencies) between 1895 and 8200 h (Scheme 4.7). 

Scheme 4.7 n-Regioselective hydroformylation of various terminal olefins with Rh(BIPHEPHOS). 

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. 

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