Hydroformylation with BIPHEPHOS

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). ... 

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... 

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. 

The application of the TMS method was pioneered by the Behr group [114, 117], who investigated a broad range of solvent systems and showed its advantages and peculiarities. In a typical approach, 1-dodecene was hydroformylated with a Rh(BIPHEPHOS) catalyst in a mixture of DMF and decane (Scheme 7.18)... 

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. 

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. 

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 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." ... 

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]. 

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. 

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... 

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. 

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. 

On a large-scale route to the noncanonical a-amino acid (5)-allysine, Cobley and Lloyd [106] employed isomerization-hydroformylation of crotonaldehyde acetal as central step (Scheme 5.20). With a Rh(BIPHEPHOS) catalyst at a sub-strate/catalyst ratio of 4000, glutaraldehyde monoethylene acetal was obtained with an Hb selectivity of 15 1. 

The final dehydration step was dependent on the solvent used. Thus, the hydroformylation-acetalization ofAf-protected homoallylamine derivatives with a BIPHEPHOS catalyst in THF (tetrahydrofuran) in the presence of an acid led to cyclic six-membered enamides (Scheme 5.87) [79]. In contrast, the reaction in... 

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]. 

Table 6.1 Hydroformylation of linear aliphatic monooiefins with Rh(BIPHEPHOS).

Since the hydroformylation of 1-octene under the formation of -nonanal (pelargonaldehyde) is a model reaction in academia for testing new reaction conditions in hydroformylation, several efficient methods have been developed. The reaction works well with a Rh(BIPHEPHOS) catalyst (compare Table 6.1, entry 3). Alternatively, internal octenes can be used under the conditions of isomerizing hydroformylation [53]. The aldehyde is naturally occurring in citrus and rose oils. It has a fatty-rose-like odor and confers floral perfumes a typical rose nuance. 

---