One‐Pot Two‐Step Synthesis of Optically Active α‐Amino Phosphonates by Palladium‐Catalyzed Hydrogenation/Hydrogenolysis of α‐Hydrazono Phosphonates

Abstract

An efficient and convenient one-pot procedure for the stereoselective catalytic synthesis of ring-substituted [amino(phenyl)methyl]phosphonates has been developed. The enantioselective hydrogenation of easily available diisopropyl (Z)-[aryl(phenylhydrazono)methyl]phosphonates using palladium(II) acetate as a precatalyst, (R)-2,2'-bis (diphenylphosphino)-5,5'-dichloro-6,6'-dimethoxy-1,1'-biphenyl [(R)-Cl-MeO-BIPHEP] as a ligand, and (1S)-(+)-10-camphorsulfonic acid as an activator in a mixture of 2,2,2-trifluoroethanol and methylene chloride at ambient temperature results in the formation of corresponding [aryl(2-phenylhydrazino)methyl]phosphonates. The subsequent cleavage of the NÀN bond has been accomplished with molecular hydrogen after the addition of palladium on carbon and methanol into crude reaction mixture to afford the optically active [amino(aryl)methyl]phosphonates. The method is operationally simple and provides an appreciable enantioselectivity up to 98 % ee.Keywords: a-amino phosphonates; asymmetric catalysis; a-hydrazono phosphonates; hydrogenation; palladium a-Amino phosphonates, particularly nonracemic ones, have been a topic for decades due to a wide spectrum of their possible applications.[1] Nevertheless, the stereocontrolled formation of a-amino phosphonates remains a challenge in chemical synthesis. Among catalytic concepts for the enantioselective synthesis of a-amino phosphonates, two methodologies are leading, namely, asymmetric hydrophosphonylation of aldimines and ketimines and asymmetric reduction of a,b-dehydroaminophosphonates.[2] Several years ago we reported on the feasibility of Rh-catalyzed asymmetric hydrogenation of a-imino phosphonates as a straightforward access to optically active a-amino phosphonates containing the quaternary b-carbon atom.[3] Subsequently, this approach was extended on oxazaborolidine catalyzed reduction of (2,2,2-trifluoro-1-iminoethyl)phosphonates with catecholeborane.[4] Along with all apparent advantages, some pitfalls of this method should be mentioned. First, aimino phosphonates are actually an equilibrium mixture of Z/E-isomers, which may have an adverse effect on the overall stereoselectivity of the process. In addition, these starting substrates are slowly hydrolyzed on storage. Finally, the common synthesis of aimino phosphonates via the Michaelis-Arbuzov rearrangement requires the usage of labile imidoyl chlorides under harsh reaction conditions.[5] When the present paper was in preparation, Zhou et al. communicated on excellent results in Pd-catalyzed asymmetric hydrogenation of a-tosylimino phosphonates. [6] However, the latter precursors cannot be considered the best choice, because they are synthesized from the same racemic a-tosylamino phosphonates by N-chlorination/dehydrochlorination procedure. [7] Readily accessible a-oxo phosphonates [8] are important reagents for the preparation of elaborate phosphonates. Unfortunately, they cannot be used for the synthesis of the corresponding a-imino phosphonates since the interaction of si...

Chirality-Driven Mode of Binding of α-Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS)

“…11 A number of methodologies for their asymmetric synthesis have been previously reported. Recent examples include metal-catalyzed asymmetric hydrogenation of α,βdehydroaminophosphonates, 12 α-iminophosphonates, 13 and αhydrazono phosphates, 14 asymmetric hydrophosphonylation of imines, 15 [3 + 2] cycloaddition of dehydroaminophosphonates and N-tosylhydrazones, 16 and other enantioselective C−C bond forming reactions that can lead to the formation of chiral quaternary Cα centers, as well as the asymmetric three component Kabachnik−Fields condensations. 17 In this study, we adopted the asymmetric 1,4-addition of aryltrifluoroborates to dehydroaminophosphonate catalyzed by a Rh-Difluorphos complex for the preparation of the (R)-α-aminophosphonates with a benzylic side chain as previously reported by Darses (Scheme 1, path A).…”

“…A number of methodologies for their asymmetric synthesis have been previously reported. Recent examples include metal-catalyzed asymmetric hydrogenation of α,β-dehydroaminophosphonates, α-iminophosphonates, and α-hydrazono phosphates, asymmetric hydrophosphonylation of imines, [3 + 2] cycloaddition of dehydroaminophosphonates and N -tosylhydrazones, and other enantioselective C–C bond forming reactions that can lead to the formation of chiral quaternary Cα centers, as well as the asymmetric three component Kabachnik–Fields condensations …”

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

“…Using a combination of Pd and biaryl chiral ligand L17b, the AH of α-hydrazono phosphonates S51 proceeded with high enantiocontrol. 203 Subsequent cleavage of the N−N bond after the addition of Pd/C and methanol into the crude reaction mixture afforded the optically active P51 (Scheme 39).…”

α‐Iminophosphonates: Useful Intermediates for Enantioselective Synthesis of α‐Aminophosphonates

“…Using a similar methodology and bisphosphine ligand IV , the same group extended the reaction to the use of hydrazones 22 (Scheme ). Thus, a two‐step hydrogenation/hydrogenolisis gave access to unprotected α‐aminophosphonates 24 in yields from 57 to 92% and enantioselectivities above 90% …”

“…Thus, a two-step hydrogenation/hydrogenolisis gave access to unprotected α-aminophosphonates 24 in yields from 57 to 92% and enantioselectivities above 90%. [31] Scheme 5. Synthesis of α-ketiminophosphonates by a formal oxidation of αaminophosphonates.…”