Aplicación del procedimiento en el proyecto Sistema para el Manejo Integral de la Perforación de

During the last 40 years, homogenous transition metal-catalyzed asymmetric hydrogenation has been used for the synthesis of numerous chiral compounds due to its high efficiency and cost-effectiveness.6-8, 22, 67, 136, 177, 200, 231, 233 A plethora of substrates were hydrogenated asymmetrically by employing catalysts based on precious metals such as rhodium, ruthenium and iridium catalysts (Figure II-34).^108a,

109 Despite the huge progress, the efficiency of AH of the C=C bond by rhodium and ruthenium catalysts is still dictated by the presence of a coordinating functional group, such as amide, ester, alcohol, adjacent to the C=C bond.27, 33, 73, 139, 235

53 Figure II- 34. Catalytic systems for the AH of C=C bonds

Therefore, the application of these catalysts has been largely restricted to limited families of substrates, such as amino acid derivatives or allylic alcohols.

Because unfunctionalized aryl/alkyl tri- or tetra-substituted olefins do not have a directing group (or another coordination site), their asymmetric hydrogenation is much harder to achieve. And for this reason, they constitute the most desirable target for this process.^{28, 62, 69}

The first homogeneous hydrogenation of olefins was discovered by the Nobel Prize Laureate Sir Geoffrey Wilkinson, who showed the utility of RhCl(PPh3)3 as a catalyst.⁵⁵ Wilkinson's catalyst laid the foundation for further development by such scientists as Horner, Knowles, and Kagan. The first introduction of chiral phosphine

54 ligands was done independently by Horner and Knowles;²³⁶ however, the optical purity of hydrogenated olefins was low (3-15% ee). Kagan accomplished a true breakthrough in this area with the design of the DIOP ligand (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane). This new Rh/DIOP system could catalyze the hydrogenation of activated olefins (bearing an adjacent acid or ester group) to obtain products with high enantioselectivity (up to 80 % ee)(Figure II-35).²³⁷ However, these Rh-based systems failed to hydrogenate non-functionalized olefins.

Figure II- 35. Kanga's Rh catalytic system.

In 1993, a chiral titanocene complex, which was the first successful chiral metallocene catalyst for the asymmetric reduction of unfunctionalized tri-substituted olefins, was reported by Buchwald’s group²³⁸ (Figure II-36), using the chiral 1,1'-binaphth-2,2-diolate ligand. The chiral titanocene catalyst gave high enantioselectivities (ee’s ranging from 83% to >99%) in the AH of several trisubstituted olefins, although high catalyst load (6-10 % mol), high pressure of hydrogen (140 bars), elevated temperature (65^oC), and a long reaction time (several days) are required to achieve reasonable yields. Moreover, this chiral titanocene

55 catalyst is highly unstable and needs to be handled under inert atmosphere conditions.

Figure II- 36. Buchwald's titanocene catalysts for AH of olefins

Six years later, based on the idea that cationic metal complexes, due to their high electrophilicity, should be particularly effective at binding highly substituted olefins, Buchwald and co-workers introduced a chiral cationic zirconocene catalyst for the AH of tri- and tetra-substituted olefins.²³⁹ This chiral cationic zirconocene catalyst displayed better catalytic activity than the neutral titanocene analog, resulting in a shorter reaction time (13-21 h), lower temperature (25^oC), and lower pressure of hydrogen (80 bars) (Figure II-37).

56 Figure II- 37. Zirconocene catalyst for AH of olefins

In an early work of Crabtree and coworkers²⁴⁰, the complex [Ir(pyridine)(PCy3)(COD)]PF6 (II-38a) was found to be a very efficient catalyst for the hydrogenation of hindered olefins (Figure II-38). However, a known problem of Crabtree’s catalyst is the deactivation of the active catalyst (II-38b) due to the formation of an inactive trinuclear iridium-hydride cluster (II-38c). In 1997, one of the biggest breakthroughs in the AH of non-functionalized olefins was the report by Pfaltz and coworkers²⁴¹ on the preparation of chiral iridium complexes [Ir(COD)(PHOX)][BAF] (II-38d).²⁴² These complexes, featuring bidentate phosphinooxazoline (PHOX) ligands and the [B[3,5-(CF3)2C6H3]4]⁻ anion, abbreviated as [BAF], can be considered as chiral analogs of the Crabtree’s catalyst.

The borate counter ion was used in place of hexafluorophosphate used in Crabtree’s catalyst. The performance of Pfaltz’s catalysts was much improved compared to the chiral metallocene catalysts discussed above, as they could operate at room temperature, under low hydrogen pressure (50 bars), short reaction time (full conversion in 2h), and gave high ee’s (80-99%). Moreover, the chiral iridium

57 catalysts had further significant advantages as they displayed a good activity at very low catalyst loadings (0.02 mol %) and were also less sensitive to moisture than the parent Crabtree’s catalyst.

Figure II- 38. Crabtree based catalysts

Recently developed iridium catalysts show exceptionally high enantioselectivity toward the hydrogenation of unfunctionalized olefins (including the tri- and even tetra-substituted olefins). Significantly, chiral monofluorides and trifluoromethyl groups were achieved by Anderson's group⁶⁸ with the use of iridium catalysts. However, harsh conditions, with high temperature and pressure, were required for these catalytic systems. Moreover, the occurrence of a dehalogenation by-process brings about another issue for the asymmetric hydrogenation of vinyl fluoride olefins.⁴⁸

In general, iridium-based catalysts have dominated the arena of asymmetric

58 hydrogenation of non-functionalized olefins. An effective and iridium-free process for the AH of non-functionalized olefins has been a target for many synthetic chemists, and the answer for this search may be found in earth abundant transition metal catalysis, or other metal-free methods.

59 II.4.2 Earth-abundant metal catalyzed hydrogenation of olefins

In 2004, Chirik et al.^243a reported a well-defined iron complex (Figure II-39) featuring tridentate pyridinediimine (PDI) ligands for the hydrogenation of simple mono- and di-substituted olefins. This iron catalyst displayed an impressive activity with fast conversion time (12 minutes), low temperature (22^oC), and low hydrogen pressure (4 atm) for the hydrogenation of 1-hexene. Mechanistic studies (Figure II-39, bottom) suggested that the active iron catalyst is formed upon dissociation of both dinitrogen molecules to form an unsaturated iron complex. Afterward, olefin coordination takes place, followed by oxidative addition of hydrogen to form an 18-electron complex. The iron alkyl complex is then formed through the insertion of the olefin into the M-H bond and subsequent reductive elimination to furnish the alkane and regenerate the active complex.

Figure II- 39. Chirik's iron catalyst

60 In the same year, Peters’ group^243b presented another well-defined iron catalyst supported by a tris(phosphino)borate ligand for the hydrogenation of 1-hexene.

Compared to Chirik’s system, this iron catalyst did not show significant improvements. However, a mechanistic study of the catalytic cycle suggested a very interesting cycle which may help chemists to start the development of new generations of iron catalysts for hydrogenation. The common belief in the field had been that the catalytic activity of iron complexes required the Fe(0)/Fe(II) redox pair, involving a low oxidation state Fe(0) species. In contrast, Peters and Daida's group considered the possibility of the Fe(II)/Fe(IV) redox as a feasible pathway, avoiding the low valent Fe(0)/Fe(II) cycle (Figure II-40).

Figure II- 40. Peters and Daida's iron catalytic system for hydrogenation of olefins

61 In 2013, one of the most important breakthroughs in earth-abundant metal catalysis was accomplished by the Chirik group,²⁴⁴ who introduced cobalt-based systems that could catalyze the asymmetric hydrogenation of an activated olefin, methyl 2-acetamidoacrylate (Figure II-41). The best catalytic conditions were 5 mol % of catalyst and 34 atm H2 to completely hydrogenate the above substrate in 12h at room temperature with the enantioselectivity up to 92.7 % ee. Although this efficiency of this catalyst is still lower than with precious metal systems, this reaction was the first example of an earth-abundant metal catalyzing asymmetric hydrogenation of olefins. No doubt, this result will motivate future studies on developing the sustainable catalytic processes.

Figure II- 41. Chirik's cobalt catalytic system

A year later, Wangelin et al. suggested another cobalt complex, which was

62 able to catalyze the hydrogenation of non-activated di-substituted olefins (Figure II-42).²⁴⁵ Furthermore, this system displayed a good activity under milder conditions, such as 1 mol % cat, 1 bar of H2, 20 ^oC, and 3 h to obtain 100% conversion of olefins.

Mechanistic studies suggested that the availability of many π-donor sites (as seen in benzene or anthracene ligands) actually stabilized the intermediate hydrido cobaltate or alkyl cobalt (I) hydride species.

Figure II- 42. Wangelin's cobalt catalytic mechanism

In 2016, Jones' group²²⁸ described pincer iron catalysts which could catalyze the hydrogenation of non-activated olefins under ambient conditions (1 atm of H2, 20 ^oC) at 5 mol % catalyst load to achieve complete conversion of olefins within only 24 h (Figure II-43). The suggested catalytic cycle, supported by DFT calculations, involved a metal−ligand cooperative pathway, similar to what had been observed in nickel and cobalt systems developed by Hanson and co-workers.²⁴⁶

63 Figure II- 43. Jones' iron PNP pincer catalysts