Highly Selective Iridium‐Catalyzed Asymmetric Hydrogenation of Trifluoromethyl Olefins: A New Route to Trifluoromethyl‐ Bearing Stereocenters

Abstract

Fluorine-containing compounds are useful in many applications ranging from pharmaceuticals to ferroelectric crystals. We have developed a new, highly enantioselective synthetic route to trifluoromethyl-bearing stereocenters in up to 96% ee via asymmetric hydrogenation using N,P-ligated iridium catalysts. We also hydrogenated an isomeric mixture of olefins; this reaction gave the hydrogenation product highly enantioselectively (87% ee), and only the E isomer was present after the reaction had reached 56% conversion.Keywords: asymmetric catalysis; fluorine; hydrogenation; iridium; P,N ligands Fluorine-containing compounds are useful in applications ranging from agrochemicals and pharmaceuticals to materials for liquid crystal displays (LCDs). [1] Among the fluoroorganic compounds, trifluoromethyl-substituted molecules have gained much attention, mainly because the electron-withdrawing ability of the trifluoromethyl group can significantly change the physical, chemical and biological properties of a compound. Therefore, much effort has been put towards the synthesis of CF 3 -bearing stereocenters, but their formation is still limited in scope. The existing syntheses of CF 3 -containing chiral centers rely mostly on chemical or biocatalytic resolutions of racemates or on the selective fluorination of chiral, non-fluorinated substrates. [2,3] Chiral Rh and Ru catalysts have been used in the asymmetric hydrogenation of CF 3 -substituted olefins. Because both types of catalysts require a coordinating group near the substrate double bond to obtain high enantioselectivity, all of the trifluoromethyl olefins hydrogenated so far have possessed functionality on or close to the double bond that bears the CF 3 group. In 1980, Koenig et al. reported the first successful asymmetric hydrogenation of a CF 3 -substituted olefin by applying a chiral Rh catalyst in the hydrogenation of 2-acetoxy-3,3,3-trifluoromethyl-1-propene with good enantioselectivity (77%).[4] Ten years later, Burk reported a higher ee (> 95%) for the reduction of the same substrate using Rh catalysts.[5] Kobayashi, Iseki and their co-workers enlarged the scope of functionalized trifluoromethyl olefin hydrogenation using a chiral Ru-(R)-BINAP catalyst.[6] They produced optically active 2-(trifluoromethyl)alkan-1-ols with ee values up to 83% and 2-(trifluoromethyl)propionic acid with 80% ee after derivatization; whereas they hydrogenated an unsaturated CF 3 -substituted ester to an almost racemic product. To the best of our knowledge, there are no routes to obtain simple chiral fluoroalkanes, because all methods give optically active fluoroalkanes with additional functionality.In the past decades, Ir complexes with chiral N,P ligands have proven to be efficient catalysts for the enantioselective hydrogenation of olefins.[7] As these catalysts hydrogenate both unfunctionalized and functionalized olefins, they have an advantage over Rh and Ru catalysts. Since the first chiral mimic of Crabtrees complex was reported by Pfaltz and his coworkers, [8] m...

Iridium catalysis: application of asymmetric reductive hydrogenation

“…32 Similarly, rhodium catalysis was used in conjunction with (R,R)DiPAMP or (S,S) Chiraphos, though results remained capped at 77% ee. 38 As can be seen in Table 4, from the results obtained by the Andersson group, 39 the hydrogenation of these substrates was achieved with very high conversion and ees (up to 96%). Vinyl fluorides have a similarly polarised olefinic bond, but when hydrogenated with similar N,P-ligated iridium catalysts and conditions, the results remained inferior to those in Table 4.…”

Synthesis and Organocatalytic Asymmetric Nitro-aldol Initiated Cascade Reactions of 2-Acylbenzonitriles Leading to 3,3-Disubstituted Isoindolinones

“…Analytical HPLC was performed on HPLC Waters dual 1485 (Waters, Milford, MA, USA). Phosphonium salts were prepared by following a modified reported procedure [45]. 2-Acetylbenzonitriles and racemic isoindolinones obtained from 2-acylbenzonitriles were prepared as described in the literature [8].…”

2-Azanorbornane – a versatile chiral aza-Diels–Alder cycloadduct: preparation, applications in stereoselective synthesis and biological activity

“…Andersson et al undertook asymmetric hydrogenation of various, often demanding, substrates containing double CvC or CvN bonds as a means of introduction of chirality into compounds bearing a variety of functional groups, useful in the synthesis of more complex chiral molecules. [102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118] They selected several chiral ligands which when complexed with iridium(I) led to the optimal results of the catalytic reaction. Among them, (N,P) and (S,P)-donating 2-azanorbornyl derivatives substituted with phosphine and oxazoline or thiazole rings 96, 97 (Fig.…”

“…5 Phosphine-oxazoline and phosphine-thiazole ligands based on a 2-azanorbornane skeleton. [102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118] Organic & Biomolecular Chemistry Review…”