Hydroformylation of functionalized alkenes

The formyl group generated by rhodium (I) catalyzed hydroformylation is generally incorporated at the carbon atom contiguous to the heteroatom. This is die case of 1-monosubstituted and 1,2-disubstimted alkenes. 

Usually unsaturated functionalized cyclic alkenes such as dihydrofurans [27] and N-acyl-2-pyrrolines [23] are also very reactive towards rhodium-catalyzed hydroformylation. They principally give the expected a-formyl 

The evolution of the reaction shows that 23 is isomerized into 22 before the hydroformylation reaction starts, because the M-P-alkyl intermediate is b-ehminated faster than CO is inserted. However, if the reaction is started from 23 and the ligands have small cone angles, such as P(OMe)3, practically the only aldehyde detected is the 3-formyl derivative (entry 3). If it is started from 22, the 3-formyl derivative is the main aldehyde detected (entry 1). This suggests that under these conditions there is no P-elimination process or that it is very slow. 

These results show that the regioselectivity of the process can be controlled if the ligand and reaction conditions are selected. Thus, PPhs can be used to quantitatively convert 23 into 25. The results are similar to when P(OMe)3 is used in a high P/Rh ratio, at moderate temperatures and high CO pressures but the catalyst is more active using PPhs. When P(0-o- BuC6H4)3 is used at high temperatures and low CO pressure, however, the main aldehyde 24 is obtained. 

However, 3,4-di hydro-2H-pyran and 5,6-dihydro-2H-pyran required more drastic conditions to be hydroformylated and when only P(0-o- BuC6H4)3 was used as the ligand conversions were as high as 80% and the selectivity in 2-/3-formyl derivatives was 68/32 [27]. 

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Functionalized Alkenes Asymmetric hydroformylation of functionalized alkenes can serve as a useful method for the syntheses of polyfunctionalized intermediates to biologically... 

Although the broad applicability of the hydroformylation in homogeneous medium has been demonstrated without ambiguity, the scope of biphasic catalysis for the hydroformylation of functionalized alkenes remains to be investigated. Indeed, there are relatively few examples in the literature related to hydroformylation of such substrates. Furthermore, most of the work described so far has been devoted to the hydroformylation of d-functionalized alkenes (the functional group is not di-... 

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. 

Functionalized alkenes. Regioselective hydroformylation of functionalized alkenes has been extensively studied. The rhodium complex with... 

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). ... 

X = MeC(O), MeOC(O), BzOC(O), Et2NC(0), (EtO)2CH. (CH2CO)2N n = Oto8 Scheme 2-3. Highly regioselective hydroformylation of functionalized alkenes. 

Table 2 Results of room-temperature/ambient-pressure hydroformylation of functionalized terminal alkenes with the rhodium/6-DPPon (10) catalyst...

The asymmetric hydroformylation of functionalized aliphatic alkenes is generally more difficult than the hydroformylation of vinyl arenes. The rhodium-catalyzed hydroformylation of vinyl acetate (36) yields 2- and 3-acetoxypropanals, 37 and 38, with high chemoselectivity. Ethyl acetate and acetic acid can also be found as by-products. One of the potential applications of vinyl acetate hydroformylation is the production of enantiopure propane 1,2-diol (Scheme 6). 

The same authors recently described the synthesis of similar rhodium-complexed dendrimers supported on a resin having both interior and exterior functional groups. These were tested as catalysts for the hydroformylation of aryl alkenes and vinyl esters (52). The results show that the reactions proceeded with high selectivity for the branched aldehydes, with excellent yields, even up to the tenth cycle. The hydroformylation experiments were carried out with first- and a second-generation rhodium-complexed dendrimers as catalysts, with a mixture of 34.5 bar of CO and 34.5 bar of H2 in dichloromethane at room temperature. Each catalyst was easily recovered by simple filtration and was reusable for at least six more cycles without... 

A rhodium catalyst derived from the 6-DPPon ligand 1 displayed behavior typical of a bidentate ligand upon hydroformylation of terminal alkenes [9]. Thus, excellent regioselectivity in favor ofthe linear aldehyde isomer was noted for hydroformylation of a range of functionalized terminal alkenes (Table 2.1). Among them even those... 

Table 2.2 Room temperature/ambient pressure regioselective hydroformylation of functionalized terminal alkenes - substrate scope, a selection from 31 examples.

In contrast with the first class of functionalized alkenes, immobilization of the catalyst in aqueous phase results in an enhancement of the catalytic activity [19]. Indeed, it has been observed that the hydroformylation rates of arylic esters having high solubility in water were much higher in biphasic systems than those observed under comparable homogeneous conditions. Except for 2-ethylhexyl acrylate, the initial rate was increased by a factor of 2.4, 12, 2.8, and 14 for methyl, ethyl, butyl, and 2-ethoxyethyl acrylate, respectively (see Figure 1) [20]. One of the most intriguing features is that the hydroformylation rates for ethyl and butyl acrylates in biphasic medium were respectively higher than and comparable with those observed with methyl acrylate. Actually, the water-solubilities of ethyl and butyl acrylates (18.3 and 2.0 g L-1 at 20 °C, respectively) are lower than that of methyl acrylate (59.3 g L-1 at 20°C). 

The behavior of functionalized alkenes depends strongly on the proximity of the functional group relative to the double bond to be hydroformylated. The few examples described so far reveal that most of the principles used for the hydroformylation of unfunctionalized alkenes can be applied. However, unusual results can be observed with a-functionalized alkenes, i.e., with acrylates. The formation of reactive nonchelated species has been suggested as an explanation of this behavior. Such a phenomenon should probably be generalized to other alkenes bearing functional groups in a suitable position, but experiments still remain to be done under biphasic conditions to confirm this hypothesis. 

BIPHEPHOS (25) is an excellent catalyst for regioselective hydroformylation of functionalized terminal alkenes to give aldehydes (Eq. 15).A zwittcrionic... 

Bulky monophosphite hgands proved to be very useful for the functionalization of very unreactive substrates. Already in their first study van Leeuwen and Roobeek obtained relatively high rates for the hydroformylation of substrates such as cyclohexene and limonene. [8]. Van Rooy performed a systematic study to the rhodium catalyzed hydroformylation of substituted alkenes and compared the reaction rates with the triphenylphosphine system [42]. The bulky monophosphite derived catalyst was up to two orders of magnitude faster and gave acceptable rates using substrates for which the Wilkinson hydrofomylation catalyst gave hardly any activity. 

In 2012, the scope of substrates was extended to a series of functionalized alkenes [20]. Allyl alcohol produced only 31% of the desired alcohol, but a significant reduction of the olefin was complained about. The formation of y-isobutyrolactone was also observed. In contrast, longer alkenyl alcohols produced up to 95% (e.g., 1,6-hexanediol) of the desired diols. Protection of the alcoholic group (THP, Ac, Bn) had only a sUght effect. The contribution of the individual metal complexes to the single steps (olefin isomerization, hydroformylation, and hydrogenation) was clarified in a kinetic study. 

We envisaged the hydroformylation of the alkene 52 to give the desired aldehyde 53 which would directly cyclize to 54. In this case the reaction would not stop at this stage, because in the allylboration reaction another terminal olefin function is generated, which would undergo a second... 

Efficient chemoselective hydroformylation of monosubstituted alkenes was observed at room temperature under atmospheric pressure of CO H2 = 1 1, without affecting functional groups such as disubstituted alkene moieties, aryl and alkenyl iodide moieties, and hydroxy and carboxy groups (Equations 7.9 and 7.10) [78[. 

The regioselectivity of the hydroformylation of alkenes 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 substitution pattern (Scheme 3) [4]. 

Most recently new applications for substrate-controlled branched-selective hydroformylation of alkenes substituted with inductively electron-with drawing substituents have emerged. A recent example is the hydroformylation of acrylamide with a standard rhodium/triphenylphosphine catalyst, which yields the branched aldehyde exclusively (Scheme 4) [40]. Reduction of the aldehyde function furnishes 3-hydroxy-2-methylpropionamide, which is an intermediate en route to methyl methacrylate. 

Hydroformylation of a range of 1,1-di- and 1,1,2-trisubstituted unsatur-ated esters yields quaternary aldehydes (Table 1, entries 1-8). Hence, the regiochemistry-directing influence of the electron-withdrawing ester function overcompensates Keuleman s rifle. Furthermore, hydroformylation of 1,2-disubstituted unsaturated esters occurred with high a-selectivity and chemoselectivity (Table 1, entries 9 and 10). As a side reaction hydrogenation of the alkene has been observed [41]. 

Many chiral diphosphine ligands have been evaluated with regard to inducing enantioselectivity in the course of the hydroformylation reaction [25,26]. However, a real breakthrough occurred in 1993 with the discovery of the BI-NAPHOS ligand by Takaya and Nozaki [65]. This was the first efficient and rather general catalyst for the enantioselective hydroformylation of several classes of alkenes, such as aryl alkenes, 1-heteroatom-functionalized alkenes, and substituted 1,3-dienes, and is still a benchmark in this area [66,67]. But still a major problem in this field is the simultaneous control of enantio-... 

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