Synthesis and catalytic application of novel binaphthyl-derived phosphorous ligands

We describe our recent achievements in the synthesis of chiral phosphorous ligands and their application in catalytic asymmetric hydrogenation reactions. Special attention is given to the development of novel binaphthophosphepine ligands. Starting from enantiomerically pure 1,1’-binaphthol or 2,2’-dimethyl-1,1’-binaphthyl and the building blocks A or B, new chelating P-ligands have been synthesized in one step in good to excellent yields (68–95%). The resulting chiral bidentate phosphines, phosphites and phosphonites were tested in various asymmetric hydrogenation benchmark reactions. Interestingly, small structural changes within the ligands exhibit a significant influence on the enantioselectivity of the hydrogenation reactions.


Introduction
Catalysis, which is the science of accelerating chemical transformations, enables the chemical and pharmaceutical industry to offer a wide range of products for our health, environment, and nutrition.This makes catalysts indispensable for the needs of today's society and important tools for increasing sustainability.Catalysts are mainly used for environmental protection, the production of bulk and fine chemicals, oil processing in refineries, and polymer synthesis.
For some years our main area of scientific interest has been applied homogeneous catalysis with organometallic complexes.A key issue for controlling the activity, productivity, and selectivity of a given transition metal complex is the synthesis of molecularly defined catalytic centers.In other words, the electronic and steric properties of each active center can be controlled by using organic ligands, which coordinate to the metal center.Thus, "ligandtailoring" constitutes an extremely powerful tool to control all kinds of selectivity for a desired catalytic reaction and to influence catalyst stability and activity.Due to the advancements in organometallic chemistry and organic ligand synthesis, nowadays a plethora of ligands [P-, N-, and recently C-based ligands) is theoretically available (>>100.000).A selection of ligands recently developed in our laboratory is shown in Scheme 1. Apart from new aryl and alkyl phosphines 1-4, 1 tridentate nitrogen ligands 2 5 and carbenes have been synthesized in recent years.In particular the importance of carbenes 3 is underlined by the fact that in 2005 the Nobel Prize in chemistry was awarded to Y. Chauvin, R. H. Grubbs and R. R. Schrock for the development of metathesis.For more than a decade the development of synthetic methods and the application of catalysis for the preparation of biologically active compounds have attracted our interest (Figure 1).In this respect palladium-catalysis 4 and amination reactions 5 have been particularly investigated over the years.Since 1998 catalysis with carbon monoxide 6 and oxidation catalysis 7 using molecular oxygen or hydrogen peroxide became prominent areas.Most recently, we initiated a program on the use of homogeneous catalysis for hydrogen generation and biomimetic catalysis, which is based on Fe-catalysis.An important goal of all our work is the facilitation of innovative processes by transfer of basic research to an industrially useful level.

Synthesis of novel binaphthophosphepines
Clearly, transition metal-catalyzed asymmetric reactions offer efficient and elegant possibilities for the synthesis of enantiomerically pure compounds. 8Among the different transition metalcatalyzed asymmetric reactions, hydrogenations of olefins, imines and ketones have been used extensively in the last two decades and are likely to provide the most important access to chiral pharmaceutical intermediates. 9In general, optically active phosphine ligands have been viewed as essential in order to achieve high enantioselectivity in asymmetric hydrogenation reactions. 8nspired by the seminal work of Reetz et al., 10 Feringa and de Vries et al., 11 as well as Pringle and Claver et al., 12 we became interested in the synthesis and catalytic application of chiral monodentate phosphines with a 4,5-dihydro-3H-dinaphtho[2,1-c;1',2'-e]phosphepine motif 6 (Scheme 2). 13The first example of this class of ligands has been prepared by Gladiali et al. 14 in the mid 90's.Parallel to the work of Zhang 15 we established the use of 6 as enantioselective ligands for asymmetric hydrogenation of α-amino acid precursors, itaconic esters, 16 enamides, 17 and β-ketoesters. 18Since our start we have prepared a variety of monodentate ligands, which are prepared in either 1 or 2 steps from optically pure 2,2'-dimethylbinaphthyl (ee >99%).This building block is accessible on a 20g scale from 2,2'-binaphthol via esterification with trifluoromethanesulfonic acid anhydride in the presence of pyridine (99% yield) and subsequent nickel-catalyzed Kumada coupling with methylmagnesium bromide in diethyl ether (95% yield).
][22] The diphosphonites 8 were obtained in good yield by reaction of the building block S-B with Sor R-binaphthol in the presence of 1.1 equiv. of triethylamine.The crude product was purified by recrystallization as the rhodium complex [Rh(cod)8]BF 4 .For the synthesis of the corresponding phosphonites 9 and phosphines 10 the two methyl groups of 2,2'-dimethyl-1,1'-binaphthyl were lithiated selectively to form dark violet crystals. 21Subsequently, chlorides A or B are quenched with the dilithium salt to produce the corresponding chelating ligands in high yield.In summary, we have synthesized a small pool of chelating ligands by replacing oxygen against carbon, step by step, allowing us a systematic investigation of the structural influence on the catalytic behaviour.Prior to our work ligands 8-9 had not been prepared, while 7 and 10 had not been used for asymmetric hydrogenation reactions.The diphosphite (S,S,S)-7 was first disclosed by Pringle and co-workers, 22 who used a Ni(0) complex of 7 for the hydrocyanation of norbornene with acetone cyanohydrine, giving the corresponding product in up to 38% ee.Another application of (S,S,S)-7-Cu(OTf) 2 was reported by Chan et al. 20 for the conjugate addition of diethylzinc to enones, where enantioselectivities up to 90% were achieved.In addition, Bakos 23 and Chan 24 tested the diphosphites 7 in the asymmetric hydroformylation of styrene and vinyl acetate, respectively.Buchwald et al. used a cobalt complex in combination with 7 as catalyst for intramolecular asymmetric Pauson-Khand reactions to obtain cyclopentenones in up to 75% enantiomeric excess. 25The conjugate addition of arylboronic acids to dehydroalanine derivatives has been successfully carried out (up to 72% ee) in the presence of (R,R,R)-7. 26The synthesis of diphosphine 10 as a diastereomeric mixture is also known in the literature. 27Further bidentate ligands bearing the phosphepine unit A connected by phenyl or ferrocenyl bridges are known from the elegant work of Zhang et al. as binaphane and f-binaphane. 19ur initial catalytic studies focused on the asymmetric hydrogenation of α-aminoacid derivatives and itaconic acid dimethyl ester.Typically, catalytic experiments were carried out with 1 mol% of the catalyst [Rh(cod)L]BF 4 which was prepared in situ from 0.01 mmol [Rh(cod) 2 ]BF 4 and 1.1 equiv. of ligands 7-10.Table 1 summarizes the results for the asymmetric hydrogenation of methyl α-acetamidocinnamate 11 in toluene and ethyl acetate.In general, the S,S,Sconfigured ligands produce higher enantioselectivity than the S,R,Sconfigured ones.This trend dramatically finds its expression for the phosphonites 8 (Table 1, entries 5 and 6) where (S,S,S)-8 gave 95% ee and (S,R,S)-8 led to the racemic mixture.Obviously the S,S,S-form of the ligand constitutes the matched-and the S,R,S-form the mis-matched case.However, both combinations of phosphepine 10 (S,S,S and S,R,S) hydrogenated methyl α-acetamidocinnamate 11 with moderate enantioselectivity (between 38% and 47%, Table 1, entries 11-14).Regarding the catalyst activity, the (S,S,S)-ligands 8 and 10 gave full conversion for this substrate within less than 1 h.On the other hand, especially ligand 7 and 9 hydrogenate so slowly that the reaction was stopped after 24 hours.The best enantioselectivity (96% ee) was achieved in ethyl acetate by applying (S,S,S)-8 (Table 1, entry 7) which bears P-O bonds in the two sevenmembered rings, and P-C bonds in the bridge.Next, we investigated our ligand pool in the asymmetric hydrogenation of methyl αacetamidoacrylate 13.Based on previous solvent optimization studies the reaction was carried out in toluene, toluene+SDS (sodium dodecylsulfonate), THF, and ethyl acetate.Selected results for compounds 7-10 are given in Table 2.In agreement with the hydrogenation of methyl αacetamidocinnamate 11 ligand (S,S,S)-8 led to the best result.Enantioselectivities between 97% and 98% respectively (Table 2, entries 5 and 7) are obtained, while the isomeric (S,R,S)-8 gave only the racemic product!These results clearly show the importance of the right combination of the different chiral elements within the ligand.With respect to activity, in most cases complete conversion was observed in reasonable times.It is noteworthy that, with the exception of ligands 8, the general predefinition of the matched and the mismatched combination of the Rand S-configured building blocks is not clear for the hydrogenation of methyl α-acetamidoacrylate 13.In the asymmetric hydrogenation of dimethyl itaconate only moderate enantioselectivities were achieved with all ligands.For example (S,S,S)-7 and (S,S,S)-8 gave 32% and 39% ee, respectively.
After exploring the catalytic potential of the ligands in the hydrogenation of amino-acid precursors we were interested in the behaviour of (S,S,S)-8 under different reaction conditions.Table 3 shows a comparison of the in situ catalyst and the isolated complex [Rh(cod)(S,S,S)-8]BF 4 .Both α-amino acid derivatives were hydrogenated in up to 98% ee within short time.Using the isolated complex the catalyst activity is improved.Especially for the in situ catalytic system the hydrogenations run slowly in the non-polar solvent toluene (Table 3, entries 4 and 6).Contrary to our previous experience for asymmetric hydrogenation with monodentate ligands 16 the addition of SDS to toluene has no significant influence.
Finally, the bidentate phosphepine 10 was also tested in the ruthenium-catalyzed asymmetric hydrogenation of various β-ketoesters.Other ligands were not included in this study because of the hydrolysis of the P-O bonds under the reaction conditions.All catalytic experiments were performed with 1 mol% catalyst formed in situ from [Ru(cod)methylallyl 2 ]/HBr and 1 equiv. of ligand 10 in ethanol or methanol.The results obtained for the hydrogenation of different 1,3diketoesters are summarized in Table 4.In general, the β-hydroxyesters were obtained in good yield, although with low to mediocre enantioselectivity.The best result (78% ee) is observed for the phenyl-substituted ketoester (Table 4, entry 8) using the phosphepine 10 in the S,R,Sconfiguration.
General procedure for ligand synthesis General procedure for the synthesis of 7 and 8 To 1 equiv. of 2,2'-binaphthol and 2 equiv. of NEt 3 in toluene were added 2 equiv. of building block A or B at 0°C.After stirring the mixture for 2 h at room temperature and filtration of the precipitate the solvent is evaporated.The crude product is crystallized from ethanol/hexane (1) or THF/hexane (2).General procedure for the synthesis of 9 and 10 A suspension of 1 equiv. of the dilithium salt of 2,2'-dimethyl-1,1'-binaphthyl in toluene is added through a tube to 2 equiv. of building block A or B dissolved in toluene, over a period of 30-45 min.The color of the reaction mixture turned from dark violet to yellow.After stirring for 10 h, LiCl was filtered off under inert conditions and washed with toluene.The solvent was evaporated and the crude product purified by flash column chromatography in dry toluene.(10); 592 (100); 529 (5); 413 (7).Mp 228°C.Optical Rotation: [α] 23 = 100 (c = 0.33; toluene).Preparation of the Rh(II) complex of (S,S,S)-8.A solution of ligand (S,S,S)-2 (1.2 mmol) in THF (7 mL) was added dropwise to a stirred solution of Rh(cod)acac (1.2 mmol) in the same solvent (5 mL).After 1 h at 20°C, ethereal HBF 4 (

5 Scheme 1 .
Scheme 1.A selection of ligands developed in our laboratory.

Figure 1 .
Figure 1.Our research areas of interest.
1.2 mmol) is added and the solution stirred for an additional hour.The solvent was removed and the residue crystallized in acetone/methanol to give red-brown solid.Calc.for C 72 H 56 O 2 P 2 RhBF 4 : C, 71.71; H, 4.65%.Found: C, 71.67; H, 4.89%.