Linear selective hydroformylation

Recently, a new bidentate hemispherical chelating bisphosphite ligand based on a calixarene backbone has been designed for linear selective hydroformylation of alkenes (Scheme 9) [54], Excellent levels of regioselectivity have been observed, and even the intrinsic branched-selective hydroformylation of styrene could be overruled by this system. However, the system suffers from low catalytic activity. 

More recently, during research aimed at supporting the highly linear selective hydroformylation catalyst [Rh(H)(Xantphos)(CO)2] onto a silica support, the presence of a cationic rhodium precursor in equilibrium with the desired rhodium hydride hydroformylation catalyst was observed. The presence of this complex gave the resulting catalyst considerable hydrogenation activity such that high yields of linear nonanol could be obtained from oct-1-ene by domino hy-droformylation-reduction reaction [75]. 

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. ... 

A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

Fig. 4 Comparison emphasizing the synthetic equivalence of linear-selective hydroformylation...

Fine chemical applications of rhodium-catalyzed hydroformylation have steadily increased over the past 20 years. Use of this chemistry in the fragrance industry appears to be relatively common. Pharmaceutical applications have started to increase as the technology becomes more familiar to process chemists. The commercial availability of ligands for both linear-selective hydroformylation and asymmetric hydroformylation has removed a barrier for screening catalysts by synthetic chemists. As additional large-scale examples of rhodium-catalyzed hydroformylation continue to be published, we expect this technology to be applied even more widely to fine chemical synthesis. 

Figure 2-2. Diphosphine and diphosphite ligands for highly linear selective hydroformylation.

In contrast to the previous examples, the preferred formation of linear aldehydes was the main target in some syntheses to construct a cyclic derivative with an appropriate ring size in the next step or for simply elongating a carbon chain. The linear aldehydes are the proper intermediates for the synthesis of indolizidine alkaloids [11], the tricyclic marine alkaloid lepadiformine [12], ACE inhibitors such as MDL 27210 and its analogues [13,14], and bryostatin, a remarkably potent anticancer agent [15]. Rhodium complexes of bisphosphite ligands provide one of the best known classes of linear-selective hydroformylation catalysts for simple ot-olefins. Except for the lepadiformine intermediate, where hydroformylation was carried out in the presence of the Rh(acac)(CO)2/P(OPh)3 catalyst system, in other... 

FIGURE 14.1. A selection of ligands for linear selective hydroformylation. 

In terms of achieving enantioselectivity, whereas a range of hgands will generally have to be screened, quite a wide range of alkene structures has been hydroformylated with reasonable enantioselectivity in recent years. An exception (at present) is the enantioselective construction of chiral centers 3 to the formyl group by a linear selective hydroformylation of a 1,1 -alkene. 

In a recent example, linear selective hydroformylation was employed in a large-scale synthesis of (5)-allysine ethylene acetal, reported by Chirotech. (5)-Allysine ethylene acetal is a key intermediate for several angiotensin-I converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors (for example, omapatrilat) that are currently in chnical trials (Scheme 14.3.). The inhibition of both these (ACE and NEP) enzymes by a single drug is an approach used for the treatment of cardiovascular diseases such as hypertension and heart failure. The product produced in Scheme 14.3 is also a possible precursor for (3-lactam antibiotics. ... 

In this procedure, a linear selective hydroformylation was carried out as the second of a five step synthesis, which also made use of bioresolution to obtain the high-value chiral product in excellent purity (>99% ee) from the readily available crotonaldehyde starting material (Scheme 14.3.). 

SCHEME 14.3. Linear selective hydroformylation as a key step in the synthesis of a high-value chiral pharma intermediate. 

It can therefore be noted that linear-selective hydroformylation of terminal alkyl-alkenes has been developed to the stage where it can be used as a functional group tolerant C—C bond forming reaction in organic synthesis. 

Given the previous discussion on reductive amination, it is surprising that the potentially more complicated domino hydroformylation-reductive amination reactions have been more thoroughly developed. The first example of hydroaminomethylation was reported as early as 1943 [83]. The most synthetically useful procedures utilize rhodium [84-87], ruthenium [88], or dual-metal (Rh/Ir) catalysts [87, 89, 90]. This area was reviewed extensively by one of the leading research groups in 1999 [91], and so is only briefly outlined here as the second step in the domino process is reductive amination of aldehydes. Eilbrachfs group have shown that linear selective hydroaminomethylation of 1,2-disubstituted alkenes... 

Although early catalysts were based on cobalt, nowadays, rhodium catalysts are preferred because they require lower pressure and afford higher chemo- and regioselectivity [1,2]. In recent years, extensive research into the production of only linear aldehydes has provided impressive results. The application of phosphines with a wide bite angle in the rhodium catalyzed hydroformylation of terminal alkenes enable the regioselectivity to be almost totally controlled [3]. Branched selective hydroformylation, al-... 

Recently, rhodium/poly(enolate-co-vinyl alcohol-co-vinyl acetate) catalysts have been developed for the biphasic hydroformylation of aliphatic alkenes and applied to the selective hydroformylation of functionalized alkenes [16], Although the conversions were low (< 25%), excellent selectivities for the hydroformylation of n-bu-tyl vinyl ether and methyl 3,3-dimethylpenten-4-onate can be achieved with such water-soluble polymer-anchored rhodium catalysts. For instance, the hydroformylation of methyl 3,3-dimethylpenten-4-onate gives only the linear aldehyde. 

The asymmetric hydroformylation of alkenes is an exceptionally atom-efficient method for the synthesis of enantiomerically-pure carbonyl-containing compounds.[1] The hydroformylation of vinylacetate, in particular, represents an excellent method for the preparation of ot-alkoxy aldehydes and, through their reduction, homochiral 1,2-diols. The use of the novel chiral ligand, ESPHOS (1),[2] in a rhodium(I) complex, results in hydroformylation of vinyl acetate in high branched linear selectivity and exceptional ee (Figure 12.1).[3]... 

Ever since transition metal clusters have been discussed as catalysts, [4] there have been many attempts to develop catalytically active polynuclear complexes in which the metal centers interact during the formation of the target molecule ( cooperativity ) to control activity and selectivity of the catalytic process. In this way, a highly selective hydroformylation catalyst for propene was found in the cluster anion [HRu3(CO)n] (linear to branched product ration of butyraldehyde... 

The Rh(II) bidentate ligand hydroformylation catalyst developed by Kuraray has been licensed [7b]. This catalyst gives high linear selectivity and high activity at low pressure for the olefin having a functional group. 

Other alternative reaction pathways to AA or MAA via hydroformylation of 7-octenoic acid or the respective ester and consecutive oxidation of the formed aldehydic group may fail due to the poor accessibility of the C8 compound needed as starting material. This is unfortunate because recent development in the selective hydroformylation to linear aldehydes using sophisticated phosphite ligands [134,135] may enable such reaction sequence. 

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