Keywords

1 Introduction

The hydroformylation of alkenes, which was originally discovered by Otto Roelen in 1938 [1–3], is nowadays one of the most important industrial applications of homogeneous catalysis [4–12]. However, the potential of this process in fine chemicals production is still to be exploited.

From a synthetic point of view, the reaction is a one-carbon chain elongation caused by the addition of carbon monoxide and hydrogen across the π system of a C═C double bond [13, 14 and references therein]. As a pure addition reaction, the hydroformylation reaction meets all the requirements of an atom economic process [15]. Furthermore, the synthetically valuable aldehyde function is introduced, which allows subsequent skeleton expansion that may even be achieved in one-pot sequential transformations [16, 17].

Since early studies, ligand modification of the rhodium catalyst has been the main strategy to influence the catalyst activity and selectivity [18–21 and references therein].

In the asymmetric hydroformylation of alkenes, the first examples of high level of enantioselectivity (ees up to 90%) were achieved by Stille and Consiglio using chiral Pt- diphosphine systems [22–24]. However, these catalysts suffered several disadvantages such as low reaction rates, tendency to hydrogenate the substrates, and low regioselectivity to the branched products.

Rhodium is currently the metal of choice to achieve high enantioselectivities in the hydroformylation of a relatively large variety of alkene substrates. The elucidation of the different steps of the catalytic cycle and the characterization of the resting state, together with the discovery of several types of ligands that are able to provide high enantioselectivities, have made rhodium-catalyzed hydroformylation a synthetically useful tool [25, 26].

In asymmetric hydroformylation of alkenes, the regioselectivity is key to providing chiral products and is a function of many factors. These include inherent substrate preferences, directing effects exerted by functional groups as part of the substrate, as well as catalyst effects. In order to appreciate substrate inherent regioselectivity trends, alkenes have to be classified according to the number and nature of their substituent pattern (Scheme 1) [13, 14 and references therein].

Scheme 1
scheme 04291

Regioselectivity trends in the hydroformylation of various alkenes

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For the terminal alkenes 1 containing electron-withdrawing substituents, the formation of the branched product 2 is favored. The regioselectivity issue usually only arises for terminal and 1,2-disubstituted alkenes 4, where isomerization usually leads to the formation of the linear products. For 1,1-disubstituted 7 and trisubstituted 10 alkenes, only one regioisomer is generally produced (8 and 11, respectively) with the formyl group being usually added so the formation of a quaternary carbon center is avoided [27].

However, recent studies showed that these general trends can sometimes be reversed by appropriate catalyst modifications and choice of reaction conditions, clearly showing that these trends are only indicative and that there are still many challenges to tackle in this area. Among the most significant issues are (1) the low reaction rates at low temperature where good selectivities are usually observed, (2) the difficulty to control simultaneously the regio- and the enantioselectivity, and (3) the limited substrate scope for any single ligand.

2 Rh-Catalyzed Hydroformylation Mechanism

In Scheme 2 the well accepted mechanism of the Rh-catalyzed hydroformylation proposed by Heck is described for bidentate ligands [28]. It corresponds to Wilkinson’s so-called dissociative mechanism [18–20]. The associative mechanism involving 20-electron intermediates for ligand/substrate exchange will not be considered. In this process, a great understanding of the mechanism has been possible due to the observation and structural characterization of the resting state of the catalyst by in situ spectroscopic techniques (HP-IR, HP-NMR) [21 and references therein]. For bidentate ligands (L–L), the common starting complex is the [RhH(L–L)(CO)2] species 13, containing the ligand coordinated in equatorial positions (denoted eq–eq throughout the scheme) or in an apical–equatorial position (complexes denoted eq–ax).

Scheme 2
scheme 04292

Mechanism of the Rh-catalyzed asymmetric hydroformylation in the presence of bidentate ligand (L–L)

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Dissociation of equatorial CO from 13 leads to the square-planar intermediate 14, which associates with alkene to give complexes 15, where the ligand can again be coordinated in two isomeric forms eq–ax and eq–eq, having a hydride in an apical position and alkene coordinated in the equatorial plane. On the basis of experimental results and theoretical calculations, it has been proposed that the regioselectivity is determined by the coordination of the alkene to the square planar intermediate 14 to give the pentacoordinate intermediates 15 [29]. This step is also crucial in determining the enantioselectivity since the enantioface discrimination occurs between 14 and 16, and particularly between 14 and 15. The CO dissociation from 13 was shown to be much faster than the overall hydroformylation process, indicating that the rate of the reaction is dominated by the reaction of 14 with either CO or the alkene to form 13 or 15 [30]. It has not been established experimentally whether alkene complexation is reversible or not, although in Scheme 2 all steps are described as reversible except the final hydrogenolysis. Experiments using deuterated substrates suggest that alkene coordination and insertion into the Rh–H bond can be reversible, certainly when the pressures are low. Complexes 15 undergo migratory insertion to give the square-planar alkyl complex 16. This species can undergo β-hydride elimination, thus leading to isomerization, or can react with CO to form the trigonal bipyramidal (TBP) complexes 17. Thus, under low pressure of CO more isomerization may be expected. At low temperatures (<70°C) and sufficiently high pressure of CO (>10 bar) the insertion reaction is usually irreversible and thus the regioselectivity and the enantioselectivity in the hydroformylation of alkenes are determined at this point. Complexes 17 undergo the second migratory insertion (see Scheme 2) to form the acyl complex 18, which can react with CO to give the saturated acyl intermediates 19 or with H2 to give the aldehyde product and the unsaturated intermediate 14. The reaction with H2 presumably involves oxidative addition and reductive elimination, but for rhodium no trivalent intermediates have been observed [31]. At low hydrogen pressures and high rhodium concentrations, the formation of dirhodium dormant species such as 20 becomes significant [32].

As mentioned above, the catalytic hydroformylation of alkenes is one of the largest applications of homogeneous organotransition metal catalysis today. Due to the robustness of the process and the wide availability of alkene substrates, enantioselective hydroformylation provides high possibilities to obtain a great variety of enantiomerically pure aldehydes. The first Rh-based systems that were reported in the asymmetric hydroformylation contained diphosphine ligands that provided low to moderate enantioselectivities [25, 26]. With this type of ligand, the highest ee value was reported using styrene as substrate and bdpp (bis-diphenylphosphino pentane) as ligand (ees up to 64%) [33]. Later, higher enantioselectivities were achieved using more sophisticated diphosphite and phosphine–phosphite ligands [6–14 and references therein; 18–20].

In the following sections, the most relevant results reported in the asymmetric Rh-catalyzed hydroformylation of alkenes are described. The reactions are classified by degree of substitution of the substrates in order to highlight the issue of the substrate/ligand compatibility in this process. Advances in supported chiral catalysts in this process are also described.

3 Rh-Catalyzed Asymmetric Hydroformylation of Monosubstituted Alkenes

The hydroformylation of monosubstituted alkenes (Scheme 3) was extensively studied due to the interest in the synthesis of linear aldehydes (non-chiral) or the enantioselective synthesis of 2-substituted branched aldehydes using chiral hydroformylation catalysts [4–14 and references therein].

Scheme 3
scheme 04293

Asymmetric hydroformylation of monosubstituted alkenes

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For example, the hydroformylation of vinyl arenes (R = aryl) is used as a model for the synthesis of 2-aryl propionaldehydes, which are intermediates in the synthesis of 2-aryl propionic acids, the profen class of non-steroidal drugs. The Rh-catalyzed asymmetric hydroformylation of several other monosubstituted alkenes, such as allyl cyanide and vinyl acetate, was successfully carried out [6–14 and references therein]. In general, 1,3-diphosphite and phosphine–phosphite ligands provided the best results in these processes [18–20]. However, the use of bisphosphacyclic ligands has recently emerged as an efficient alternative [6–14 and references therein].

3.1 1,3-Diphosphite Ligands

The use of diphosphite ligands was intensively studied in this process as they provide high levels of selectivity with these substrates [34]. The initial success in the rhodium-catalyzed asymmetric hydroformylation of vinyl arenes came from Union Carbide with the discovery of the diphosphite ligand (2R, 4R)-pentane-2,4-diol 21 (Scheme 4) [35, 36].

Scheme 4
scheme 04294

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligands 21–25

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Good chemo-, regio-, and enantioselectivities (ee up to 90%) were obtained with (2R, 4R)-pentane-2,4-diol diphosphite derivatives (21a–c) but only when the reaction was performed around room temperature. Inspired by these excellent results, other research groups synthesized the series of diphosphite ligands 22–25 in order to study the effect of structural modifications on the Rh-catalyzed asymmetric hydroformylation of vinyl arenes (Scheme 4) [37–41].

The influence of the bite angle of these ligands was studied with diphosphite ligands (2R, 4R)-pentane-2,4-diol 21, (2R, 4R)-butane-2,4-diol 22, and (2R, 4R)-hexane-2,4-diol 23 [38]. In general, the ligand 21, which contains a three-carbon-atoms bridge, provided higher enantioselectivities than ligands 22 and 23, which have a two and four-carbon-atoms bridge, respectively.

The effect of different phosphite moieties was studied with ligands 21a–g [37–39]. In general, sterically hindered phosphite moieties are necessary to achieve high enantioselectivities. The results indicated that varying the ortho and para substituents on the biphenyl and binaphthyl moieties also has a great effect on the asymmetric induction. The highest enantioselectivity (ee up to 90% at 20 bar of syngas and 25°C) in the Rh-catalyzed asymmetric hydroformylation of styrene was obtained by using ligands 21a and 21d.

The influence of the backbone was studied comparing the results obtained with the ligands 21 and 24 [37–39]. Surprisingly, ligand 24, which contains a more sterically hindered phenyl group, provided lower enantioselectivity than ligand 21.

A cooperative effect between the different chiral centers of the phosphite ligands 21f–i and 25f–i was demonstrated. Initially, van Leeuwen and co-workers studied the cooperative effect between the chiral ligand bridge and the axially chiral binaphthyl phosphite moieties by comparing ligands 21f, g and 25f, g. The hydroformylation results indicated a suitable combination for ligand 21g (ees up to 86%) [37–39]. Later, Bakos and co-workers found a similar matched–mismatched effect between the chiral ligand bridge and the chiral phosphite moiety of the ligands 21h, i and 25h, i [40]. Interestingly, the hydroformylation results obtained with ligands 21a and 21d, which are conformationally flexible and contain axially chiral biphenyl moieties, are similar to those obtained with ligand 21g. This indicated that diphosphite ligands containing these biphenyl moieties predominantly exist as a single atropoisomer in the hydridorhodium complexes [RhH(CO)2(diphosphite)] when bulky substituents are present in ortho positions [37–39]. It is therefore not necessary to use expensive conformationally rigid binaphthyl moieties.

To investigate whether a relationship exists between the solution structures of the [RhH(CO)2(diphosphite)] species and catalytic performance, van Leeuwen and co-workers extensively studied the [RhH(CO)2(diphosphite)] (diphosphite = 21, 25) species formed under hydroformylation conditions by high pressure NMR techniques (HP-NMR) [14 and references therein; 18–20]. From these TBP complexes, two isomeric structures are possible, one containing the diphosphite coordinated in a bis-equatorial (eq–eq) fashion and one in an equatorial–axial (eq–ax) fashion (Scheme 3). The results indicated that the stability and catalytic performance of the [RhH(CO)2(diphosphite)] (diphosphite = 21, 25) species strongly depend on the configuration of the pentane-2,4-diol ligand backbone and on the chiral biaryl phosphite moieties. Thus, ligands 21a, 21d, and 21g, which form well-defined stable bis-equatorial (eq–eq) complexes, lead to good enantiomeric excesses. In contrast, ligands 21i and 25g, which form mixtures of complexes, lead to low enantioselectivities [37–39, 42]. The ligand 21a was also evaluated in the Rh-catalyzed asymmetric hydroformylation of allyl cyanide 1b and vinyl acetate 1c but low to moderate enantioselectivities (13% and 58%, respectively) were obtained with these substrates [6].

1,3-Diphosphite ligands derived from 1,2-O-isopropyliden-α-d-xylofuranose (26, 29) and 6-deoxy-1,2-O-isopropyliden-α-d-glucofuranose (27, 28, 30, 31) were successfully applied in the Rh-catalyzed asymmetric hydroformylation of vinyl arenes (Scheme 5) [43–46].

Scheme 5
scheme 04295

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligands 26–38

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The use of diphosphite ligands 27a, d and 31a, d in the Rh-catalyzed asymmetric hydroformylation of styrene provided the S- and R-enantiomers of the product with high enantioselectivities (ee up to 93%) and excellent regioselectivity (Scheme 5) [45, 46]. The ligand 27b was also tested in the hydroformylation of vinyl acetate, obtaining excellent regioselectivity (99%) with an enantioselectivity of 73% [47].

Recently, related C1-symmetry diphosphite ligands conformationally more flexible (32–35) or incorporating an increase in steric hindrance at the C-6 position (36–39) were synthesized (Scheme 5) [47, 48]. These ligands were probed in the hydroformylation of styrene 1a and vinyl acetate 1c with good regio- and enantioselectivity (up to 81% and 68%, respectively), but these selectivities turned out to be lower than with the ligand 27. Therefore, the bicycle structure and the methyl substituent at C-5 position seem to be required to achieve high enantioselectivity in the hydroformylation of styrene and vinyl acetate when using 1,3-diphosphites derived from carbohydrates.

In summary, the results obtained in the Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes indicate that (1) the absolute configuration of the product is governed by the configuration at the stereogenic centre C-3, (2) the level of enantioselectivity is influenced by the presence of stereocenters at C-3 and C-5 positions, where the phosphorus atoms are attached, (3) bulky substituents in ortho positions of the biaryl phosphite moieties are necessary to achieve high levels of enantioselectivity, and (4) pseudo-enantiomer ligands such as 27 and 31 afford the same level of enantioselectivity for both product enantiomers.

Interestingly, the ligands 27 and 31, for which only [RhH(CO)2(L-L)] species with eq–eq coordination were observed by HP-NMR techniques, provided higher enantioselectivity (ee up to 93%) than the related ligands 28 and 30 (ee up to 64%), for which an equilibrium between the isomeric eq–eq and eq–ax [RhH(CO)2(L)] species was observed by HP-NMR and HP-IR techniques. Therefore, the presence of a single coordination isomer, in this case with ligand coordinated in an equatorial–equatorial (eq–eq) mode, was observed to produce high levels of enantioselectivity in the Rh-catalyzed asymmetric hydroformylation of styrene, as previously mentioned [45–48].

In contrast with the diphosphites previously mentioned, the KELLIPHITE ligand (39), which was developed by Dow Chemical Company, incorporates the chirality in the bisphenol unit, while the backbone is achiral (Scheme 6). The catalytic system containing this ligand afforded very good enantioselectivity in the rhodium-catalyzed hydroformylation of vinyl acetate and allyl cyanide, although low selectivities were obtained in the hydroformylation of styrene [49, 50].

Scheme 6
scheme 04296

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligand KELLIPHITE (39)

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3.2 Phosphine–Phosphite Ligands

The discovery of the (R,S)-BINAPHOS (40) and (S,R)-BINAPHOS (41) ligands in 1993 by Takaya and Nozaki produced a real breakthrough in the Rh-catalyzed asymmetric hydroformylation reaction (Scheme 7) [51].

Scheme 7
scheme 04297

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using (R,S)- and (S,R)-BINAPHOS (40) and (41)

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These ligands allowed, for the first time, an increase in the scope of this process since they provided high enantioselectivity in the Rh-catalyzed asymmetric hydroformylation of several classes of monosubstituted alkenes such as vinyl arenes, 1-heteroatom-functionalised alkenes, and disubstituted 1,3-dienes (Scheme 7), and are still currently references in this area [52 and references therein; 53–63]. Excellent regio- and enantioselectivity were achieved with most of these substrates, although the formation of the branched product (21%) was disfavored when but-1-ene was the substrate. In 2003, De Vries and co-workers reported the first Rh-catalyzed asymmetric hydroformylation of allyl cyanide and, although moderate regioselectivity was obtained (72%), the highest enantioselectivity (66%) by far was achieved using the ligand 40 [64]. As a general rule, the presence of electron-withdrawing substituents such as phenyl or heteroatoms in the alkene substrate leads to a control the regioselectivity in favor of the branched product, independently of the ligand used [6].

It is noteworthy that (R,S)-BINAPHOS (40) or the (S,R)-BINAPHOS (41) ligands yield the two enantiomers of the product with high enantioselectivity [65, 66]; however, the (R,R)- and (S,S)-BINAPHOS, diastereoisomers of ligands 40 and 41, yielded much lower enantioselectivity in this process, thus demonstrating the importance of the combination of opposite configurations at the phosphine and phosphite moieties.

In contrast with the previously mentioned diphosphite ligands which coordinate to the Rh centre in an eq–eq fashion, the BINAPHOS ligand was found to coordinate to Rh in an eq–ax mode as a single isomer in the resting state [RhH(CO)2(L–L)] of the process [65, 66].

The second generation of BINAPHOS-type ligands (Scheme 8) was recently developed by the introduction of 3-methoxy substituents on the aryl phosphine units 42 [53, 54], and by replacement of the phosphite group by a phosphoramidite function, yielding the YANPHOS ligand (43) (Scheme 8) [67]. The Rh/42 increased the regio- and enantioselectivity in the asymmetric hydroformylation of styrene, vinylfurans, and thiophenes (Scheme 8).

Scheme 8
scheme 04298

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using the ligands 42 and 43

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YANPHOS (43) (Scheme 8) provided higher enantioselectivity than the BINAPHOS ligand 40 without altering the regioselectivity in the Rh-catalyzed asymmetric hydroformylation of styrene and vinyl acetate (ee up to 99% and 96%, respectively). Additionally, the ligand 43 provided higher enantioselectivity than KELLIPHITE (39) (Scheme 6), although a slight decrease in regioselectivity (80% vs 94%) was observed in the hydroformylation of allyl cyanide (ee up to 96% vs 78%) [68].

Recently, the efficiency of YANPHOS ligand 43 was again demonstrated in the Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with N-allyl amides, N-allyl phthalamides, and N-allyl sulfonamides substituents with excellent ees (up to 96%), good regioselectivities (up to 84%), and a turn over number (TON) up to 9,700.

Inspired by the excellent results obtained using 40 and 41, several new phosphine–phosphite ligands with different backbones have been developed over the last few years but the catalytic results using these ligands provided lower enantioselectivity (from 20% to 85%) than those previously achieved with the original BINAPHOS ligand [69–74]. Some of these ligands help to elucidate the correlation between the ee and the electron-withdrawing properties of the substitution in the alkene [75].

Based on the BINAPHOS structure, a new family of phosphine–phosphite and phosphine–phosphoramidite ligands was constituted using a Taddol-based backbone in the phosphite or phosphoramidite moiety, respectively (Scheme 9) [76, 77]. These ligands were applied in the Rh-catalyzed asymmetric hydroformylation of styrene, allyl cyanide, and vinyl acetate with excellent regioselectivities (up to 98%) and good ees (up to 85%).

Scheme 9
scheme 04299

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using Taddol-based ligands (44 and 45)

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3.3 Bisphospholane Ligands

Several bisphospholane chiral ligands known as efficient ligands for asymmetric hydrogenation were recently evaluated in asymmetric hydroformylation (Scheme 10) [78].

Scheme 10
scheme 042910

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using the diphosphine ligands 46–50

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Two ligands, namely (S)-BINAPINE (46) and (S,S,R,R)-TANGPHOS (47), were found to give excellent enantioselectivities in the asymmetric hydroformylation of styrene, allyl cyanide, and vinyl acetate (Scheme 10) [79]. It is noteworthy that the enantioselectivities achieved for product 2b with these ligands are the highest ever reported for the allyl cyanide substrate.

The discovery of the biphospholane scaffold as a new privileged structure for asymmetric alkene hydroformylation has triggered new research efforts for novel and improved bisphospholane-type ligands. In this context, the (R,R)-Ph-BPE ligand (48) (Scheme 10), derivative of DuPhos, was identified as an outstanding ligand for asymmetric hydroformylation since excellent regio- and enantioselectivities were achieved for styrene, allyl cyanide, and vinyl acetate as substrates with this ligand [80]. Several spacers between the two phosphorus donor atoms were evaluated and the two-carbon bridge of 48 provided the highest selectivity for all three substrates [79].

A series of bis-2,5-diazaphospholane ligands was also probed in this process and the ESPHOS (49) proved to be optimal, with the best results being obtained in the hydroformylation of vinyl acetate (ee up to 89%) (Scheme 10) [81]. The bis-3,4-diazaphospholane ligand 50 also provided excellent regio- and enantioselectivity (ee up to 96%) in this reaction (Scheme 10) [82].

3.4 Bis-Phosphonite Ligands

The bis-phosphonite ligand 51 provided moderate selectivities in the hydroformylation of styrene and allyl cyanide (Scheme 11). However, this ligand provided an excellent 91% ee in the hydroformylation of vinyl acetate [83]. The related diphosphinite ligand derived from ferrocene 52 was also recently reported by Ding and co-workers and its application in the Rh-catalyzed asymmetric hydroformylation of styrene and vinyl acetate provided good conversion but lower enantioselectivities in the hydroformylation of styrene and vinyl acetate (up to 55% and 83%, respectively) [84].

Scheme 11
scheme 042911

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with ligands 51 and 52

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3.5 Phosphite–Phospholane Ligands

Very recently it was demonstrated that branched aldehydes can be produced by hydroformylation of terminal alkenes of formula RCH2CH═CH2 using a new hybrid ligand called “bobphos” (53) (Scheme 12) [85]. This ligand, result of the combination of KELLIPHITE and Ph-bpe, provided good to excellent conversions (between 64% and 99%), very good regioselectivities (between 71% and 91%), and excellent ees (up to 93%) for a series of terminal alkenes (Scheme 12).

Scheme 12
scheme 042912

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with ligand 53

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3.6 Monodentate Phosphorus-Based Ligands

Nowadays, despite the successful use of monodentate ligands in many transition metal catalyzed processes, there are only a few reports concerning their use in asymmetric hydroformylation. Achieving high enantioselectivities in this process using those ligands remains a challenge.

Although the use of monodentate phosphorus donor ligands usually provides higher catalytic activity than their bidentate counterparts, only moderate to good enantioselectivities have been reported in asymmetric hydroformylation processes so far. For instance, the ligand 57 was tested in the Rh-catalyzed asymmetric hydroformylation of styrene and allyl cyanide and provided moderate enantioselectivities (Scheme 13). When vinyl acetate was the substrate, very poor ees were obtained (Scheme 13) [49, 50]. However, in 2004, Ojima and co-workers reported the use of the phosphoramidite ligand 55 (Scheme 13), related to monophosphite 54, in the Rh-catalyzed asymmetric hydroformylation of allyl cyanide and achieved excellent regioselectivities together with the highest enantiomeric excess (80%) ever reported for this reaction with a monodentate ligand [86]. These results, although still far from those obtained with bidentate ligands, clearly indicated that achieving high ees using monodentate ligands is possible.

Scheme 13
scheme 042913

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligands 54 and 55

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In 2005, Breit report an alternative approach to the classical synthesis of bidentate ligands for hydroformylation by using the self-assembly of bidentate ligands based on an A-T base-pair model [87]. This method presents the advantage of allowing the rapid screening of various pairs of available monodentate ligands to obtain the most suitable combination for each substrate, overcoming the typical synthetic limitations for new bidentate ligands. Later, van Leeuwen and Reek reported the template-induced formation of chelating heterobidentate ligands by the self-assembly of two distinct monodentate ligands on a rigid bis-zinc(II)-salphen template with two identical binding sites (Scheme 14) [88, 89]. The templated heterobidentate ligand 56 induced much higher enantioselectivities (ee up to 72%) than any of the corresponding homobidentate ligands or non-templated mixed ligand combinations (ee up to 13%) in the Rh-catalyzed asymmetric hydroformylation of styrene.

Scheme 14
scheme 042914

Rh-catalyzed asymmetric hydroformylation of styrene using the templated ligand 56

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4 Rh-Catalyzed Asymmetric Hydroformylation of Disubstituted Alkenes

The Rh-catalyzed asymmetric hydroformylation of disubstituted alkenes has received much less attention than that of their monosubstituted counterparts. To the best of our knowledge, only a few examples of asymmetric Rh-catalyzed hydroformylation of 1,2-disubstituted and 1,1-disubstituted alkenes have been reported so far (Scheme 1) [25, 47, 90–110].

4.1 Linear 1,2-Disubstituted Alkenes

The asymmetric hydroformylation of propenylbenzenes was originally studied by Kollár using PtCl2(bdpp)/SnCl2 as catalyst [90]. The reaction was performed using trans-anethole and estragole as substrate in order to synthesize the branched chiral aldehydes 5a and 6a (Scheme 15). However, the formation of the linear aldehyde was observed due to trans-anethole isomerization into terminal monosubstituted estragole. Furthermore, moderate to low enantioselectivities were obtained (ee up to 27%). The 1,3-diphosphite ligand 26 was used in the Rh-catalyzed asymmetric hydroformylation of trans-anethole 4a and estragole 4b (Scheme 15) but moderate to low enantioselectivities were achieved (ee up to 15%) [91].

Scheme 15
scheme 042915

Isomerization processes and asymmetric hydroformylation of trans-anethole and estragole

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Nozaki et al. reported the asymmetric Rh-catalyzed hydroformylation of trans-anethole 4a into 5a using the BINAPHOS ligand 40 with excellent regioselectivity (98%) and a remarkable 80% ee [92, 93].

In the Rh-catalyzed asymmetric hydroformylation of 1,2-alkyl-disubstituted alkenes (Scheme 16) as substrates, the BINAPHOS ligand 40 provided the highest ee values [92, 93]. Interestingly, it was reported that the E-isomers 4d and 4f yielded lower enantioselectivity than their Z-counterparts 4c and 4e.

Scheme 16
scheme 042916

Rh-catalyzed asymmetric hydroformylation of disubstituted alkenes

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A monodentate phosphoramidite template ligand was developed by Reek et al. and used in the asymmetric Rh-catalyzed hydroformylation of E-2-octene (5i) (Scheme 17). This ligand (57) exhibits a supramolecular control over the Rh center, due to the presence of two pyridine functions in the bis(naphthol) skeleton that are bound to zinc(II) porphyrins. With this ligand, useful conversions (up to 56%) with moderate ees (up to 45%) were achieved. When the BINAPHOS ligand 40 was used in the same reaction, similar conversion (55%) was obtained although without significant enantioselective induction [94].

Scheme 17
scheme 042917

Rh-catalyzed asymmetric hydroformylation of disubstituted alkenes with ligands (40) and (57)

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Very recently the same author described the use of this ligand (57) in the asymmetric Rh-catalyzed hydroformylation of internal alkenes like E-2-hexene (4g), E-2-heptene (4h), and E-2-nonene (4j), achieving conversions up to 65% and moderate ees (up to 47%) [95].

The same research group formerly reported the use of encapsulated catalysts for the selective hydroformylation of unfunctionalized alkenes [96]. The ligand (58) (Scheme 18) acts as a supramolecular “box” with the bis-[Zn(salphen)] moiety as a template and two chiral phosphoramidite ligands as the pillars. In the asymmetric Rh-catalyzed hydroformylation of internal alkenes, the inner aldehydes with R configuration were preferably formed (with the exception of 3-hexene for which the S-aldehyde was produced).

Scheme 18
scheme 042918

Rh-catalyzed asymmetric hydroformylation of internal alkenes with the ligand 58

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4.2 Monocyclic 1,2-Disubstituted Alkenes

Among monocyclic 1,2-disubstituted alkene substrates, five-membered ring heterocycles such as dihydrofurans and dihydropyrroles have been the most studied. With these substrates, the simultaneous control of the chemo-, regio-, and enantioselectivity is a key issue since the presence of a heteroatom in the cycle favors in some cases an isomerization process in the presence of a metal-hydride species. Previous studies using achiral ligands demonstrated that the reaction conditions greatly affected the chemo- and regioselectivity of this reaction [97, 98]. Indeed, allyl ethers were shown to isomerize rapidly into their vinyl analogues under hydroformylation conditions (Scheme 19). This isomerization process is of critical importance since it has a direct influence on the regioselectivity of the reaction, but also on the enantioselectivity since the opposite enantiomers of tetrahydro-3-carbaldehyde are formed from the allylic 4k–m and vinylic 4n–p isomers of the substrate [99]. It is therefore required to limit the isomerization in order to obtain high selectivities. In the Rh-catalyzed asymmetric hydroformylation of 2,5-dihydrofuran 4k, Nozaki et al. reported the first successful results using the BINAPHOS ligand 40 which yielded total regioselectivity to the tetrahydro-3-carbaldehyde 5k with 68% ee (R) (Scheme 21) [92, 93, 100]. However, when the 2,3-dihydrofuran 4n was tested with the same catalyst, no regioselectivity was observed and the ee obtained for the aldehyde 5k decreased to 38% with S configuration. This catalytic system was thus suitable to avoid isomerization of 4k into 4n but not selective for the hydroformylation of 4n. In the same study, the amine analogues 4l, 4m, and 4o were also tested as substrates using the same catalytic system (Scheme 19) and similar results were obtained.

Scheme 19
scheme 042919

Isomerization processes observed during the Rh-asymmetric hydroformylation of five-membered heterocyclic alkenes

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The previously mentioned 1,3-diphosphites 27–38 derived from carbohydrates were successfully applied in the Rh-catalyzed hydroformylation of these substrates [47, 101, 102]. The results indicated that ligands 27, 35–38, which have a glucose configuration, are the most appropriate to obtain high enantioselective induction in the hydroformylation of these substrates. In the case of the 2,5-dihydrofuran 4k, the highest enantioselectivity in the aldehyde 5k was obtained using ligand 35b (88% S). Using this ligand, no isomerization was observed under hydroformylation conditions. Interestingly, the presence of bulky substituents at C-5, such as in ligands 36b–38b, was shown to increase the degree of isomerization. When the 2,3-dihydrofuran (4n) was used as substrate, ees up to 84% (R) in aldehyde 5k were achieved using ligands 36b–37b, together with a regioselectivity of 80%. The 2,5-dihydropyrrole 4l was also tested with the Rh/27b system, achieving comparable results to those previously reported using ligand 40 (71% and 66%, respectively).

Formerly, Reek and co-workers described the synthesis and application of the ligand 59 in the Rh-catalyzed asymmetric hydroformylation of the cyclic olefins 4k–o (Scheme 20). This system provided regioselectivities up to 99% and excellent ees (up to 91%). It should be noted that the highest enantioselectivities (91%) reported to date for the substrates 4k and 4n were achieved with this ligand [96, 103].

Scheme 20
scheme 042920

Rh-catalyzed asymmetric hydroformylation of five-membered heterocyclic alkenes 4k–o

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Interestingly, in the Rh-catalyzed asymmetric hydroformylation of the cyclic alkene 4n (Scheme 20), which usually selectively produces the aldehyde 5n, high regioselectivity (68%) to the aldehyde 6n was recently reported, together with good ees (62%) using the ligand 60 (the highest reported to date) [96].

The asymmetric Rh-catalyzed hydroformylation of dioxapines 4q, r was reported using the BINAPHOS ligand 40 and 1,3-diphosphite ligands derived from carbohydrates 61b (Scheme 21) [92–100, 102]. Using the ligand 40, total regioselectivity to 5q, r was achieved, together with ees up to 76%. Among the carbohydrate derived ligands that were tested, the ligand 61b provided the best results (Scheme 21), affording total regioselectivity to 5q, r and up to 68% ee, thus indicating that no isomerization of 4q, r had occurred.

Scheme 21
scheme 042921

Rh-catalyzed asymmetric hydroformylation of 4q, r

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4.3 Bicyclic 1,2-Disubstituted Alkenes

The Rh-catalyzed asymmetric hydroformylation of substrates 4u and 4v was reported by Nozaki et al. using the ligand 40 (Scheme 22) [92, 93]. The results are really remarkable, in particular with substrate 4v, for which compound 5v was obtained with practically total regio and enantioselectivity (Scheme 22). The corresponding products 5u and 5v are of interest since the aldehyde 5u can be converted in a single step into the corresponding amine which exhibits hypotensive activity and the product 5v is a synthetic intermediate to produce a vasoconstrictor tetrahydrozoline [104].

Scheme 22
scheme 042922

Rh-catalyzed asymmetric hydroformylation of bicyclic alkenes using (R,S)-BINAPHOS ligand 40

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Another bicyclic alkene substrate of interest for carbonylation reactions is the norbornene 4w and its derivatives. The first reports on the asymmetric Rh-catalyzed hydroformylation of norbornene afforded low enantiomeric induction with ees below 25% [105, 106]. In 2005, Bunel and co-workers reported the first highly enantioselective Rh-catalyzed hydroformylation of norbornene into the exo aldehyde with ees up to 92% using the diphospholane ligands 47 and 48 [107]. Using these ligands, they also reported the hydroformylation of several derivatives of this substrate with similar enantioselectivities (Scheme 23).

Scheme 23
scheme 042923

Rh-catalyzed asymmetric hydroformylation of norbornene derivatives using the diphospholane ligand 47

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Recently, the hemispherical diphosphite ligands 62 (Fig. 1) with a conical calixarene skeleton was used in the asymmetric Rh-catalyzed hydroformylation of norbornene, achieving enantioselectivities up to 61% with the exo aldehyde being the major product [108].

Fig. 1
figure 04291

Hemispherical diphosphite ligands 62 with a conical calixarene skeleton

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More recently, the KELLIPHITE ligand (39) was employed in the Rh-catalyzed asymmetric hydroformylation of the bicyclic lactam azababicyclo-[2.2.1]hept-5-en-3-one with very good results. The reaction was completely exo-selective, yielding total conversions and excellent regioselectivities (up to 91%) [109].

4.4 1,1′-Disubstituted Alkenes

The asymmetric hydroformylation of 1,1′-disubstituted alkenes differs from the classical asymmetric hydroformylation of monosubstituted terminal alkenes since the desired product is the linear aldehyde (Scheme 1).

Indeed, the Rh-catalyzed asymmetric hydroformylation of 1,1-methyl styrene (7a) using diphosphite ligand 63 (Scheme 24) to form the linear product 9a was recently patented. The enantioselectivity was, however, moderate (ee up to 46%) [110].

Scheme 24
scheme 042924

Rh-catalyzed asymmetric hydroformylation of 1,1′-disubstituted alkenes

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Interestingly, however, when dehydro amino acid derivatives 7b and dimethyl itaconate 7c were used as substrates (Scheme 24) in the presence of [RhH(CO)(PPh3)3] and 1–6 equiv. of the (R,R)-DIOP ligand 64, the formation of the branched products was largely favored with moderate enantioselectivity (ees up to 59%). In this process highly functionalized quaternary carbons are easily obtained from common products. This interesting reaction deserves more attention by researchers in the field. It should be noted that when the α,β-unsaturated carboxylic compounds such as 7c are hydroformylated in the presence of the [PtCl(SnCl3)], the only hydroformylation product obtained was the linear aldehyde with ees up to 82% [25].

Very recently, Buchwald et al. reported the Rh-catalyzed asymmetric hydroformylation of 1,1-disubstituted alkenes (α-alkyl acrylates) using the 1,3-diphosphine ligand BenzP (65). With this ligand, good regio- (up to 91%) and enantioselectivities (up to 94%) were achieved (Scheme 25) [111]. The fine tuning of the partial pressures of CO/H2 minimizes the problem of the side reactions; in fact, the mild reaction conditions make it safe for general laboratory use (10 bar 1:5 CO/H2, 100°C).

Scheme 25
scheme 042925

Rh-catalyzed asymmetric hydroformylation of α-alkyl acrylates

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4.5 Other Substrates

In this section, recent reports on the Rh-catalyzed asymmetric hydroformylation of “non common” alkene substrates using chiral phosphorus donor ligands and scaffolding [112] ligands (metal-organic cooperative catalysts) are presented.

4.5.1 α,β-Unsaturated Amides, 1,3-Dienes, N-Vinyl Carboxamides, Allyl Carbamates, and Allyl Ethers

The substrate scope for the hydroformylation of dialkyl acrylamides 1x 1–4 has so far been limited to methacrylamide, acrylamide or N-benzyl acrylamide, with low enantioselective induction (20–50% ees) [113, 114].

However, the use of a bis-diazaphospholane ligand (66a) in the Rh-catalyzed asymmetric hydroformylation of N,N-dialkyl acrylamides was recently described, achieving nearly total regioselectivity and ees up to 82% (Scheme 26) [115].

Scheme 26
scheme 042926

Rh-catalyzed asymmetric hydroformylation of N,N-dialkyl acrylamides

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The use of the bis-3,4-diazaphospholane type ligands (66) has also been reported in the rhodium catalyzed hydroformylation of several 1,3-diene substrates (1,3-dienes, N-vinyl carboxamides, allyl carbamates, and allyl ethers) with excellent regio- and enantioselectivities by Landis et al. [116, 117]. Total conversions with good regioselectivities (>88%) and excellent enantioselectivities (91–97%) were achieved (Scheme 27).

Scheme 27
scheme 042927

Rh-catalyzed asymmetric hydroformylation of 1,3-dienes with ligands 66a and 66b

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The ligand 66a was also successfully employed in the Rh-catalyzed asymmetric hydroformylation of other alkene substrates containing amide (1z 1 –z 3 ) and ether (1z 4 –1z 6 ) substituents, with ees up to 99% and 82%, respectively (Schemes 26 and 28) [117].

Scheme 28
scheme 042928

Rh-catalyzed asymmetric hydroformylation of monosubstituted enamides and other allylic substrates with the ligand 66a

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4.5.2 Scaffolding Ligands

The term “catalyst-directing groups” was defined for organocatalysts that are able to form simultaneously covalent bonds with a substrate and dative bonds with a metal catalyst, which allow them to direct metal-catalyzed transformations [118]. In general, these “scaffolding ligands” were named by analogy with scaffolding proteins, which promote biological processes [119].

Using such methodology, the groups of Tan and Breit reported the highly regioselective Rh-catalyzed hydroformylation of homoallylic alcohols [118, 120]. Tan et al. designed the alkoxy benzoazaphosphole ligand 67 derived from N-methyl aniline that undergoes facile exchange with other alcohols or secondary amines (Scheme 29) [120].

Scheme 29
scheme 042929

Alkoxy benzoazaphosphole catalytic directing group

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The asymmetric hydroformylation of several alkene substrates was performed by Tan and co-workers using scaffolding ligands containing a tetrahydroisoquinoline group on the alkoxy benzoazaphosphole yielding the scaffolding ligand 69 (Scheme 30).

Scheme 30
scheme 042930

Tetrahydroisoquinoline alkoxy benzoazaphosphole scaffolding ligand

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The Breit research group demonstrated that Ph2POMe was a suitable catalytic directing group for hydroformylation [118]. Notably, the functionalization of 1,2-disubstituted olefins and other substrates containing stereocenters proceeded with excellent regio- and stereo- selectivity. Additionally, the chemoselective hydroformylation of homoallylic alcohols over unactivated alkenes was observed.

5 Heterogenized Catalytic Systems for Asymmetric Hydroformylation of Alkenes

The development of supported chiral catalysts to facilitate its separation from the products and its recycling or its integration into continuous flow systems, is still a challenge in the field of asymmetric catalysis.

In the field of asymmetric hydroformylation, most of the results with heterogenized catalytic systems were reported by the group of Nozaki et al. using BINAPHOS derived systems.

In the late 1990s, the (R,S)-BINAPHOS ligand (71) was immobilized by covalent bonding to a high cross-linked polystyrene and studied the Rh-catalyzed asymmetric hydroformylation of styrene and vinyl acetate [121]. This catalytic system provided good conversions (up to 83%), excellent regioselectivities (up to 90%), and ees up to 93% (Scheme 31).

Scheme 31
scheme 042931

Rh-catalyzed asymmetric hydroformylation of styrene and vinylacetate catalyzed with the ligand (R,S)-BINAPHOS (40) and the polystyrene supported ligand (71)

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A few years later, the new class of polymer-supported (R,S)-BINAPHOS (72) was reported in the asymmetric hydroformylation of styrene and vinyl acetate under batch conditions and in the transformation of Z-2-butene under continuous-flow conditions [57]. The results obtained in the hydroformylation of styrene and vinyl acetate were similar to those previously reported, but the most remarkable results were achieved in the continuous-flow asymmetric hydroformylation of Z-2-butene for which a TOF value of 27 h−1 and ee of 80% were obtained (Scheme 32).

Scheme 32
scheme 042932

Rh-catalyzed asymmetric hydroformylation with the polystyrene supported ligand (R,S)-BINAPHOS (72)

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In 2003, the use of the (R,S)-BINAPHOS-Rh(I) catalyst (73) (Scheme 33), which is covalently anchored to a highly cross-linked polystyrene support, was reported in the asymmetric hydroformylation of several alkenes in the absence of organic solvents [55]. In the hydroformylation of Z-2-butene this system provided total regioselectivity with ees up to 82%. The heterogenized catalysts were also employed in a continuous vapor-flow column reactor to transform 3,3,3-trifluoropropene to the corresponding branched aldehyde with regioselectivity up to 95% and ee of 90%. Less volatile olefins such as 1-hexene, 1-octene, and pentafluoro styrene were successfully converted into the corresponding branched aldehydes with high ee through a flow column reactor with supercritical CO2 as the mobile phase (Scheme 33). Under these conditions sequential injection of styrene (2a) into the scCO2 flow reactor was analyzed, and the authors reported that even after 7 cycles, no loss of activity nor selectivity was observed.

Scheme 33
scheme 042933

Rh-catalyzed asymmetric hydroformylation with the polystyrene supported catalyst 73

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Additionally, the sequential injections of various olefins were analyzed under scCO2 flow and the results are summarized in Table 1. The alkenes studied were styrene (1a), vinyl acetate (1c), 1-octene (1w), 1-hexene (1u), 2,3,4,5,6-pentaflourostyrene (1d 1 ), and CF3(CF2)5CH═CH2 (1d 2 ) and all of them were successfully hydroformylated with high ees (Table 1).

Table 1 Sequential conversion of various olefins using a continuous scCO2 flow system
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6 Conclusions

Rhodium is currently the metal of choice to achieve high enantioselectivities in the hydroformylation of a relatively large variety of alkene substrates. Several breakthroughs in this field led to the discovery of several catalytic systems that can nowadays provide high levels of regio- and enantioselectivity for benchmark substrates such as styrene, vinyl acetate, and allyl cyanide.

Furthermore, recent advances have shown that challenging substrates such as alkyl alkenes and internal alkenes can also be converted into the corresponding branched aldehydes with high enantioselectivity by the appropriate choice of catalysts and reaction conditions. However, higher regio- and enantioselectivity can still be achieved when one of the substituents direct the regioselectivity, as is the case of 2,3-dihydrofuran, dihydropyrrol, indene, or 1,2-dihydronaphthalene (Schemes 20 and 22). In the case of symmetrically substituted alkenes such as 2,5-dihydrofuran and norbornene 4o, p, no regiocontrol is required and high activities and enantioselectivities have been achieved in asymmetric hydroformylation (Schemes 20, 21, 23).

1,1-Disubstituted or 1,1,2-trisubstituted substrates are more challenging. The general trend is the introduction of the formyl group onto the less substituted carbon, thus creating the chiral center at the more substituted carbon atom. However, both types of products were formed by Rh-catalyzed hydroformylation with high enantioselectivity and there is still much to learn on the parameters that favor the formation of one regioisomer over another.

In terms of ligands, compounds containing phosphite moieties such as diphosphites and phosphine–phosphites were considered for many years as the most successful ligands to achieve high enantioselectivities. For instance, the phosphite–phosphine BINAPHOS (40) or its derivatives 42 and 43 are still today the most successful ligands in terms of selectivity and scope. Recently, however, diphosphines in which the P atoms are incorporated into a ring (42–46) were also shown to induce high levels of enantioselectivity in this process. It can consequently be concluded that the key to achieve high enantioselectivities is not the type of phosphorus function involved in the coordination to the metal but the particular spatial arrangement of the coordinated ligand.

A variety of chiral products incorporating a formyl unit can be enantioselectively prepared by Rh-catalyzed asymmetric hydroformylation and this process is nowadays considered a powerful tool in organic synthesis and is still a growing area of research. There are still many challenges to be tackled in this area and, for instance, only a few studies including the recovery and recycling of the chiral catalyst have been reported, which could further improve the sustainability of this process and lead to new applications.