Renat Kadyrov

Rhodium(I) catalyzed asymmetric hydrogenation of enamines

The asymmetric hydrogenation of prochiral electron-rich enamines with rhodium(I) diphosphine and diphosphinite catalysts is described. The reaction is strongly sensitive to the ligand applied. Good results are observed with catalysts based on (R,R)-DIOP, Kβ+-OH, (R,R)-bdpch and other ligands forming seven-membered chelates with the metal. It is shown, that by conversion of a cyclic imine, which could not be hydrogenated, into the corresponding enamine a substrate is formed which is smoothly reduced at 1 bar initial hydrogen pressure by up to 72% ee.

New carbohydrate bisphosphites as chiral ligands

Abstract The synthesis of the 2,3-bisphosphite derivatives of phenyl 4,6- O -benzylidene-β-D-glucopyranoside leads to new chelating ligands. Their rhodium(I) and platinum(II) complexes have been tested as catalysts for the asymmetric hydroformylation of vinyl acetate, allyl acetate and p -methoxystyrene. Good regioselectivity (>90% branched product), but an enantioselectivity of only ≤36% ee were found under mild reaction conditions (25–40°C, 40–70 bar syngas).

Low catalyst loading in ring-closing metathesis reactions.

An efficient procedure is described for ring-closing metathesis reactions. A conversion of 95% for diethyl diallylmalonate in dilute solution could be achieved within a few minutes, reaching TOF = 4173 min(-1), with very low loading of commercially available Ru catalysts that contained unsaturated NHC ligands. In general, only 50 to 250 ppm of the catalyst is required to achieve near-quantitative conversion into a broad variety of 5-16-membered heterocyclic compounds. The practicality of this procedure was illustrated in the synthesis of 5-8-membered N-tert-butoxycarbonyl (N-Boc)- and N-para-toluenesulfonyl (N-Ts)-protected cyclic amines and 9-16-membered lactones. The synthesis of macrocyclic proline-based lactams required slightly higher catalyst loadings. Along with monocyclic products, oligomeric byproducts, mostly cyclodimers, were isolated and characterized.

A Scrutiny on the Reductive Amination of Carbonyl Compounds Catalyzed by Homogeneous Rh(I) Diphosphane Complexes

The reductive amination of a series of aldehydes with secondary amines and H2 in the presence of a homogeneous Rh-diphosphane catalyst was studied in order to establish a general mechanism of this reaction and to identify conditions for the improvement of the amine/alcohol ratio in the product. Several possible intermediates as constitu- ents of changing equilibria like half-aminals, N,O- acetals and aminals were observed in the reaction mixture by means of 1 H NMR spectroscopy. In individual trials, these compounds could be success- fully hydrogenated under the conditions applied for reductive amination (50 bar H2 pressure, MeOH). Some evidence is accumulated that half-aminals and N,O-acetals might be key intermediates of the reductive amination. Moreover, it was found that the formation of the undesired product alcohol is likely based on the reduction of the startingcarbonyl compound. However, due to numerous equilibria consistingof several intermediates, g conclu- sions are hard to be drawn. Proof will be given that, in several cases, the efficiency of the reductive amina- tion of aliphatic aldehydes can be significantly improved by prehydrogenation of the cationic (Rh(dppb)(COD)) complex.

Efficient Enantioselective Synthesis of Optically Active Diols by Asymmetric Hydrogenation with Modular Chiral Metal Catalysts

The enantioselective hydrogenation of prochiral ketones is one of the most elegant and effective methods for the preparation of optically active secondary alcohols. With regard to the environment, asymmetric hydrogenations represent a highly efficient and atom-economical process. Multiple applications have been developed using chiral ruthenium complexes with atropisomeric ligands for the synthesis of optically active primary and secondary alcohols. The latter are important building blocks for the synthesis of natural products, pharmaceuticals and, agrochemicals. The development of a general and efficient enantioselective route to terminal, vicinal 1,2-diols still presents a great challenge. These compounds are important chiral building blocks for the synthesis of natural products such as macrodiolides, insect pheromones, b-lactone esterase inhibitors, d-lactones, and many other biologically active substances. 5] In the synthesis of the anti-HIV pharmaceutical Tenofovir and related pharmaceuticals the application of enantiomerically pure (R)-propane-1,2-diol is of critical importance. A further application of terminal optically active 1,2-diols is the resolution of atropisomeric compounds. The asymmetric dihydroxylation of terminal alkenes is the most common method for the preparation for this class of compounds. However, small sterically less demanding alkyl derivatives, such as propene, cannot be enantioselectively oxidized to the diol by asymmetric dihydroxylation, nor to the epoxide by asymmetric epoxidation. The difficulty in the highly enantioselective transformation of small alkyl derivatives arises from the similar steric demands of the two groups adjacent to the carbonyl functionality. The result is poor Re and Si face differentiation for the sterically less demanding alkyl derivatives; in contrast, the sterically more demanding aryl ketones can be readily differentiated (Figure 1). The hydrogenation of a-hydroxy ketones is one alternative for the generation of valuable optically active, terminal 1,2-diols. Good progress has been made in the hydrogenation of the sterically demanding a-hydroxy acetophenones using various ruthenium and iridium catalysts. Rhodium and ruthenium complexes were also successfully applied in asymmetric transfer hydrogenations. Further work concentrated on asymmetric enzymatic reductions. A general, reductive, and highly enantioselective synthesis of aliphatic 1,2-diols has not been reported previously. Therefore, we began our examination of the enantioselective synthesis of optically active diols with the application of a new class of modular diphosphane ligands 1. Particular attention was given to nonsymmetric ligands as these were considered more suitable for the enantioface differentiation of the alkyl hydroxy ketones, which are more challenging substrates. Ligands 1 can be prepared simply in two steps on a large scale and are based on a 2,5-disubstituted thiophene core structure, a chiral phospholane unit, 13] and a readily variable diarylphosphino group (Scheme 1).

Economic preparation of 1,3-diphenyl-1,3-bis(diphenylphosphino)propane: a versatile chiral diphosphine ligand for enantioselective hydrogenations

Abstract The enantioselective hydrogenation of 1,3-diarylpropane-1,3-diones with chiral Ru(II)-diphosphine catalyst has been studied. In a first approach it was found, that Tol-BINAP together with Ru(COD)methallyl 2 formed the most selective catalyst. One of the C 2 -symmetric enantiopure 1,3-diols obtained in turn was transformed via its 1,3-di- O -mesylate into 1,3-bisdiarylphosphines. One of them, 1,3-diphenyl-1,3-bis(diphenylphosphino)propane, could be advantageously utilized as a ligand for the efficient enantioselective Ru-catalyzed hydrogenation of its own 1,3-diketone precursor. Thus, the condition for a ‘cross self-breeding’ catalytic system is fulfilled. A further reduction of the preparation costs could be achived by application of RuCl 3 ·H 2 O instead of other more expensive precatalyst precursors without compromosing the enantioselectivity. The ligand was used in the Rh(I)-catalyzed asymmetric hydrogenation of model substrates and β-amino acid precursors where up to 97% ee could be achieved.

Palladium‐Catalyzed Reductive Carbonylation of Aryl Bromides with Phosphinite Ligands

Aromatic aldehydes are an important class of compounds, that are widely used as building blocks in all areas of chemistry. Traditionally, aromatic aldehydes were synthesized by Vielsmeier–Haag, Gattermann–Koch, Reimer–Tiemann, and Duff reactions. However, these reactions use high amounts of reagents and generate waste and side products. Other synthetic strategies include the reduction of acid chlorides under an atmosphere of hydrogen and the direct formylation of aryl bromides, which involves a halogen/metal exchange with nBuLi and a formylation agent added at low temperatures. However, this approach is limited to aldehydes that bear stable functional groups. Another route is the palladium-catalyzed carbonylation of aryl halides using expensive silylor tin hydrides as the hydrogen source. In 1974, Heck reported a reductive carbonylation of aryl halides using synthesis gas, but relatively high palladium loadings, elevated pressures and temperatures were necessary. In the course of our ongoing investigation of ligand synthesis, we found that di-1-adamantyl-n-butylphosphine (BuPAd2) is an outstanding efficient ligand for the palladium-catalyzed reductive carbonylation. By using BuPAd2 as a ligand, various aldehydes were prepared in good yields from the corresponding aryl bromides under mild reaction conditions. This methodology has been realized on an industrial 100 kg scale. Further studies showed that the topology of the BuPAd2, comprising of two large and one small fragment, plays an important role in this reaction. When the two adamantyl groups were substituted by tert-butyl groups, the activity did not change, but using tri-tert-butylphosphine with three bulky groups resulted in a complete loss of activity. Thus, ligands that are designed to have two bulky groups and one small fragment are potentially suitable for reductive carbonylation reactions. As BuPAd2 is not easy to synthesize and expensive, we believe there is a high demand to find alternative ligands. Herein, we report the synthesis of phophinite ligands for reductive carbonylations; these ligands can be prepared in one step and easily modified. The simplest variant of BuPAd2 is obtained by substituting the butyl group with npropanolate. Here the resulting scaffold is identical, but the electronic properties are different. Following the synthesis of phosphinites, propyl diadamantylphosphinite (ligand A) was easily obtained by adding Ad2PCl to in situ formed sodium propionate in n-propanol (Scheme 1).

Chiral phosphinephosphites having axial and central chirality in asymmetric hydroformylations

Abstract Chiral phosphinephosphites were prepared by the reaction of enantiomerically pure cis - or trans -3-diphenylphosphinotetrahydrofuran-4-ol with atropisomeric chlorophosphites. These ligands were tested in the rhodium catalyzed hydroformylation of allyl acetate. Selectivities up to 44% ee were observed in dependence on the configuration of the applied phosphinephosphites and the bulk of the aromatic groups bound to the phosphorus. The results clearly show that both, central and axial chirality are responsible for the stereochemical outcome of this reaction.

P/O ligand systems: Synthesis and reactivity of primary and secondary o-phosphinophenols

Several organometallic reagents such as lithium 2-lithio 4-methylphenolate 1 intermediates formed by orthometallation of o-bromoaryloxy-phosphorus(V)- 2 or -phosphorus(III)-derivatives 3 with magnesium and sodium, respectively, as well as O-methoxymethyl-protected o-lithio-4-methylphenol 4 were used to synthesize suitable precursors 5,6,9,10 of primary and secondary o-phosphinophenols. The P–C bond formation involved coupling with ClPR(NMe2), CIPR(O)(OEt) or an intramolecular carbanionic O C shift of the P-substituent. Reduction with LiAlH4, in the cases of phosphonous or phosphinous acid amides after alcoholysis (to 7,8,11), produced primary and secondary o-phosphinophenols 12, respectively, or O-protected derivatives 13. o-Phosphinophenols 12 are easily protonated at the phosphorus atom, supported by a P+-H … O hydrogen bridge. Metallation (14), acylation, and silylation (16,17) take place preferably at the hyxdroxy group and alkylation at the phosphorus atom. Alkylation of 12 and 14 was found to be slow, but C,O-dilithiated species 15 react to give P-secondary (12b,d,e,) or P-tertiary products (20,21). Cyclization of 15a with Me2SiCl2 affords the 2,3-dihydro-1,3,2-benzoxaphosphasilol 22, cyclocondensation of 12c with RP(NMe2)2 or ClP(NMe2)2 furnishes 2,3-dihydro-1,2,3- benzodiphospholes 23 and 24. A phosphiniden-phosphoran 25 is detected in the reaction between 12a and P(NMe2)3.

o-Hydroxyarylphosphines and diphosphines: metallation-rearrangement versus PO reduction of o-halogenoaryloxyphosphines by sodium☆

Abstract o-Bromo- and o-chloroaryloxyphosphines 1 may react with sodium in two competing ways: (i) metal halogen exchange followed by rapid intramolecular 1,3-rearrangement to give sodium o-hydroxylato-arylphosphines 2, later converted to their OSiMe3 derivatives 3, and (ii) reductive cleavage of the PO bond to give diphosphines 4 or phosphides. The o-metallation is preferred with the more reactive bromides and bulky phosphino substituents or screened PO bonds by substituents at 6-position. The reduction is favoured in the case of the less reactive aryl chlorides, small alkyl and flat phenyl substituents at phosphorus. Mixtures of meso- and rac-diphosphines are formed from asymmetric derivatives ArOPRR′. The meso-isomer of 1,2-di(tert-butyl)-1,2-diphenyldiphosphine is preferred.