Hydroformylation BIPHEPHOS ligand

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. 

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. 

We subjected this compound to rhodium catalyzed hydroformylation using the BIPHEPHOS ligand, which guarantees the predominant formation of the unbranched aldehyde. (28, 29) Hydroformylation, allylboration and the second hydroformylation proceeded cleanly to furnish the piperidinol derivative 57 in 73% yield. The latter compound was found to exist as a mixture of the lactoi and the aldehyde form. (25)... 

Hydroformylation with the BIPHEPHOS ligand is a slow process reqiiireing 5 days at 65°C to proceed. The domino hydroformylation allylboration hydroformylation sequence resulted in a mixture of anomeric lactols (48%). In order to facilitate product analysis this mixture was directly oxidized to the corresponding lactones 62 and 63 (63%). The diastereomeric lactones were obtained in a 1 1 ratio, (18) indicating that the asymmetric induction from the resident stereocenter is low. 

A famous example of a ligand structure that promotes the isomeriza-tion-hydroformylation reaction sequence in a highly selective manner is the BIPHEPHOS ligand (Scheme 6.14.6). BIPHEPHOS has been demonstrated to convert trans-4-octene into 1-nonanal with a remarkably high selectivity of 89% (given the complex reaction scheme) (Behr et al., 2003). However, the Rh-BIPHEPHOS hydroformylation system for trans-4-octene is relatively slow (TOF = 46h ), leaving room for further ligand optimization to make combined isomerization/hydroformylation processes more efficient. 

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]. 

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). 

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. ... 

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... 

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... 

Dr Reddy s Laboratories claimed the diastereoselective hydroformylation of an enantiopure bicyclic lactam by means of a Rh[(/ ,/ )-Kelliphite] catalyst (Scheme 4.59) [18]. The olefinic substrate that is produced on a multi-ton scale by Chirotech gives after hydroformylation and a single crystallization step the almost pure aldehyde. Noteworthy, (S,S)-Kelliphite or other ligands, such as (/J,/ ,S)-Bisdiazaphos or (achiral) BIPHEPHOS, induced mainly the formation of the undesired regioisomeric aldehyde. The reaction has been upscaled to 15 g of substrate and used eventually for the production of multifunctionalized... 

Currently, the workhorse in hydroformylation that converts a range of terminal long-chain olefins with high activity and w-regioselectivity into the corresponding n-aldehydes is a Rh catalyst modified with the commercially available and cheap diphosphite ligand BIPHEPHOS [48] (used for inexpensive floral notes) [49]. 

The double bond in methyl oleate can migrate to the terminus under the effect of Rh catalysts containing a sterically demanding diphosphite ligand, as shown by Behr et al. [26] with BIPHEPHOS (Scheme 6.81, lower part). The subsequent hydroformylation achieved 65% conversion of the substrate and produced methyl 19-oxononadecanoate in 26% yield within 17 h. Approximately 12% of the olefin hydrogenation product was simultaneously observed. 

In a subsequent study in the year 2015, the effect of different metals with BIPHEPHOS as a ligand on the same transformation was investigated [59]. Unexpectedly, under nonoptimized hydroformylation conditions, the relevant iridium catalyst exhibited only 5 times lower reactivity than the rhodium system. But the latter allowed slightly better control of the distribution of internal olefins. Ruthenium and palladium catalysts performed significantly worse. 

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