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P-Stereogenic Bisphosphines with a Hydrazine Backbone: from N–N Atropoisomerism to Double Cite This: Chem

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P-Stereogenic Bisphosphines with a Hydrazine Backbone: from N–N Atropoisomerism to Double Cite This: Chem ChemComm View Article Online COMMUNICATION View Journal | View Issue P-Stereogenic bisphosphines with a hydrazine backbone: from N–N atropoisomerism to double Cite this: Chem. Commun., 2017, 53,4605 nitrogen inversion† Received 14th March 2017, a a ab Accepted 31st March 2017 Amparo Prades, Samuel Nu´n˜ez-Pertı´n˜ez, Antoni Riera * and Xavier Verdaguer *ab DOI: 10.1039/c7cc01944k rsc.li/chemcomm The synthesis of P-stereogenic bisphosphine ligands starting from a phosphinous acid chiral synthon and hydrazine is reported. The dialkylation of the hydrazine backbone yielded atropo- and nitrogen inversion isomers which are in slow exchange. The crystallization of Creative Commons Attribution 3.0 Unported Licence. one of the isomers allowed us to study the reaction kinetics of the Scheme 1 Strategy developed for the synthesis of P-stereogenic C2 equilibria. The new ligands were tested in the Rh catalysed asymmetric bisphosphines with a hydrazine backbone. hydrogenation of various benchmark substrates attaining up to 99% ee. context, we addressed whether our methodology could also be Developing active and selective chiralcatalystsishighlyrelevant amenable for the rapid and efficient synthesis of ligands with C2 for the chemical and pharmaceutical industries.1 ‘‘Ligand symmetry. We hypothesized that the coupling of hydrazine to the engineering’’ is a key approach to generate new and more activated phosphinous acid 1 could provide nitrogen analogs of efficient catalytic systems. Among the different types of ligand, bis-P* type ligands (Scheme 1).10 Here we report the synthesis of This article is licensed under a chiral phosphines have made a key contribution to asymmetric two borane-protected P-stereogenic hydrazine bisphosphine catalysis, which is one of the most effective synthetic methodo- ligands derived from hydrazine and 1. In solution, these ligands logies by which to obtain optically pure compounds.2 Since are present as a mixture of atropo- and nitrogen inversion isomers 3 Open Access Article. Published on 31 March 2017. Downloaded 20/04/2017 15:24:27. the pioneering work of Kagan with DIOP and Knowles with in slow exchange. These ligands were also tested in the Rh DIPAMP,4 a large number of chiral bisphosphine ligands have catalyzed asymmetric hydrogenation, attaining selectivities up to been reported. Among these, P-stereogenic phosphines have 99% ee. proved to be a privileged class of ligands.5,6 Despite enormous Initially, in order to identify all possible intermediates, advances in this field, P-stereogenic ligands are usually made a sequential synthesis was performed, starting from 1 and through a lengthy multistep synthesis. Thus, the search for cost Boc-hydrazine (Scheme 2). Phosphinous acid 1 was activated 7c efficient synthesis of optically pure P-stereogenic ligands is of with Ms2O following our procedure. The reaction with tert-butyl key importance. carbazate at À20 1C provided hydrazine 2 (58%)inanSN2@P-type Our group has recently reported procedures for the synthesis process. The reaction was stereospecific and occurred with of optically pure P-stereogenic tert-butylmethylphosphinous inversion of configuration at the phosphorus center. The Boc acid borane 1.7 This fragment is highly versatile and has allowed protecting group was removed using anhydrous HCl in MeOH 8 9 access to C1 symmetric MaxPHOS and MaxPHOX ligands. In this to yield phosphino hydrazine 3 in 72% yield. From 3, a second phosphinous acid coupling provided bisphosphine 4 in 56% yield. Satisfactory stereocontrol was observed throughout the a Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, E-08028, Spain. syntheses, and meso-4 was not detected. We next attempted the E-mail: [email protected], [email protected]; one-pot preparation of 4 starting from hydrazine and 2 equiva- Tel: +34 934034813 lents of phosphinous acid 1. We observed that 4 was assembled b Dept. Quı´mica Inorga`nica i Orga`nica, Seccio´ de Quı´mica Orga`nica, efficiently in one step with 82% yield. Universitat de Barcelona, Martı´ iFranque`s 1, E-08028 Barcelona, Spain To improve the stability of the resulting ligands, we derivatized † Electronic supplementary information (ESI) available: Experimental procedures, 11 characterization data and NMR spectra for new compounds; crystallographic data file 4 by alkylation on both nitrogen atoms. The methylation in CIF format. CCDC 1533430–1533432. For ESI and crystallographic data in CIF or of 4 was achieved by deprotonating hydrazine nitrogen atoms other electronic format see DOI: 10.1039/c7cc01944k with sodium hydride and adding an excess of methyl iodide This journal is © The Royal Society of Chemistry 2017 Chem. Commun., 2017, 53, 4605--4608 | 4605 View Article Online Communication ChemComm Scheme 2 Sequential and direct synthesis of the C2 bisphosphine hydrazine 4. at 55 1C (Scheme 3). The dimethyl derivative 5 was isolated in Fig. 1 X-Ray structure of (RP,RP,Sa)-5. (a) Perspective and (b) Newman 90% yield. When allyl bromide was used as the alkylating agent, projection through the N–N axis. ORTEP drawing showing thermal only monoalkylated product 6 was obtained in moderate yield ellipsoids at 50% probability. (c) Newman projections for the equilibrium of compound 5. In solution, 5 is present as a mixture of diastereomeric (49%). The dialkylated product was not observed, even when N–N atropoisomers. In the solid state, only the (RP,RP,Sa) atropoisomer is the reaction temperature was increased and the solvent changed. observed. At this stage, a large number of electrophiles were also tested; however, dialkylation products were not detected. A cyclization reaction was attempted with 1,3-dibromopropane as the alkylating corresponding to the protons of the NCH3 groups of the two agent. However, the reaction did not afford the expected pyrazo- species got closer, but total coalescence was not observed, and at lidine ring. The NMR spectra were in concordance with the 1 Creative Commons Attribution 3.0 Unported Licence. 100 Cthesampledecomposed. formation of 6, which results from the monoalkylation of 4 The X-ray structure of 5 is depicted in Fig. 1.12 The sum of followed by base-promoted elimination of HBr. Finally, we the angles around the trisubstituted nitrogen atoms added up deduced that, by using 3-bromo-2-bromomethyl-1-propene, we to 360.0 and 359.91, which indicates that the N atoms were could avoid the undesired E2 type reaction. Indeed, using this completely planar. The view through the N–N axis shows how electrophile, the cyclization occurred swiftly, providing the the two N planes are almost perpendicular, the P–N–N–P corresponding pyrazolidine 7 in 77% yield. torsion angle being 98.01. All these findings sustain that the 1 H NMR showed that crystalline 5 was present as a single two species observed in solution are atropoisomers that arise compound;however,upondissolution,itrapidlyequilibratedtoa from the hampered rotation around the N–N bond caused by This article is licensed under a 1 : 1 mixture of isomers. Analysis of 5 by thin-layer chromato- the increased steric hindrance of the phosphorus groups graphy (TLC) on silica provided two spots with retention factors of (Fig. 1c).13 Because of the presence of P-stereogenic centers, 0.3 and 0.5 (hexane : AcOEt 8 : 2). However, when the reaction the new axial chirality leads to two distinct diastereoisomers Open Access Article. Published on 31 March 2017. Downloaded 20/04/2017 15:24:27. crude product was eluted through a SiO2 flash column, the two (RP,RP,Ra)-5 and (RP,RP,Sa)-5, which can be observed as two sets substances were equally presentinallthefractions.2D-TLC 1 of signals in the H NMR spectrum. As (RP,RP,Sa)-5 was the only analysis showed that, even in a quick elution, the two products atropoisomer present in the solid state, a kinetics study was could not be isolated. The system re-equilibrated a second time, performed to determine the activation energy of the equili- with a new set of spots on the TLC appearing for every single spot 14 brium between the two atropoisomers. Crystals of (RP,RP,Sa)-5 in the first elution. This observation suggested that 5 was present were dissolved in deuterated chloroform in a NMR tube, and as a mixture of two isomers in slow exchange. A variable tem- successive 1H-NMR spectra were collected at specific times.15 1 perature H-NMR experiment of a solution of 5 in DMSO-d6 was After approximately 30 min, the concentrations of the two performed at 25, 40 and 70 1C. During the experiment, the signals atropoisomers were the same. The kinetic data followed a first order profile for the Sa/Ra equilibrium with kinetic constant k1=k À 1 = 1.47 Â 10À3 sÀ1, and a DG‡ of 21 kcal molÀ1 = 88 kJ molÀ1. It is commonly assumed that the free energy barrier between conformational and configurational isomers is 100 kJ molÀ1, which means that if the interconversion barrier is higher than 100 kJ molÀ1, isomers can be isolated. This finding is in agreement with the observation that atropoisomers (RP,RP,Sa)-5 and (RP,RP,Ra)-5 can be detected by TLC and NMR but cannot be isolated using chromatographic techniques at room temperature. Similar behavior was observed for pyrazolidine 7. When the crude product was eluted through a SiO2 flash column, two Scheme 3 N-Alkylation of the hydrazine backbone. isomers in a 1 : 1 ratio could be clearly separated and isolated, 4606 | Chem. Commun., 2017, 53, 4605--4608 This journal is © The Royal Society of Chemistry 2017 View Article Online ChemComm Communication Scheme 4 Borane removal and complexation to Rh(I). furnish the desired cationic complexes 8 and 9 (Scheme 4).12,19,20 Asymmetric hydrogenation with catalysts 8 and 9 at 3 bar of H2 and 1 mol% of catalyst loading took place with complete conver- sions(Table1).Inthereductionofmethyla-acetamidoacrylate Fig.
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