Rh-BIPHEPHOS

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. 

A short total synthesis of (-l-)-prosopinine 36 from (R)-serine was achieved via cyclohydrocarbonylation catalyzed by Rh-BIPHEPHOS complex for the construction of the key piperidine ring (2R,33 )-33 (Scheme 6). Compound 33 was converted to (-l-)-prosopinine 36 via the nucleophilic displacement of the ethoxy group with organocopper reagent 34 forming 35, followed by deprotection. A similar procedure has been used for the total synthesis of (—)-deoxoprosophylline 37. 

The Rh-BIPHEPHOS-catalyzed cyclohydrocarbonylation has also been successfully applied to the rapid synthesis of a variety of l-azabicyclo[X.Y.O]alkane amino acids, which serve as conformationally restricted dipeptide surrogates for enzyme inhibitors and receptor antagonists, directly from dehydrodipeptide substrates (Scheme Reaction... 

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... 

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]. 

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

A/ -Allyl-phthalimide has also been employed successfully as a substrate, where with a Rh(BIPHEPHOS) catalyst 95% of the desired aldehyde was generated with an Ub ratio of 18 1 [85]. 

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. 

In 2015, Jorke and colleagues [31] calculated the thermodynamic properties and the resulting equilibrium composition of 1-decene in the presence of a Rh(BIPHEPHOS) catalyst at the temperature interval between 95 and 115 C in Ai M-dimethylformamide (DMF) or toluene, taking the network of all decene isomers into consideration (Scheme 5.5). 

Kragl and colleagues [92] used a Rh(BIPHEPHOS) catalyst in the hydroformy-lation of a mixture of 7Z-2-pentene. At 160 °C and 30 bar syngas pressure, 99%... 

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. 

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. 

Also, 1-dodecene can be selectively reacted with syngas in the presence of a Rh(BIPHEPHOS) catalyst to give n-tridecanal (Table 6.1, entry 5). A related Rh catalyst based on nanoparticles (2.7-4.8 nm) could be three times recycled without loss of activity when the reaction was conducted in a thermomorphic solvent system [61]. Also, under the conditions illustrated in Scheme 6.6 ( = 4), tridecanal is formed, but in comparison to shorter chain olefins the conversion dropped and the aldehyde was obtained only in a moderate Ub ratio [54]. Other attempts have been based on more sophistic ligands such as amphiphilic sulfonated monophosphines [62] and diphosphines [55, 63], phosphine-functionalized phosphonium ionic liquids [64], and MeO-substituted phosphines [65]. Tridecanal has a slightly floral scent reminiscent of citrus and grapefruit peel. 

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)... 

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. 

Scheme 6.14.6 Isomerization/hydroformylation of trans-4-octene using a Rh-BIPHEPHOS catalyst. Adapted from Behr etal. (2003).

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