Bicyclic Phosphine Research Articles

Palladium-catalyzed Heck reactions promoted by limonene-derived bicyclic phosphines

Tertiary bicyclic phosphines derived from (R)-(+)-limonene provided efficient palladium catalysts for Heck cross-coupling reactions. Overall, high yields of the desired aryl alkenes products were obtained for cross-coupling of sterically and electronically diverse substrates. The efficiency of the catalysts was further demonstrated in the synthesis of commercial ketones, such as raspberry ketone and its derivatives.

Chiral phosphine-catalyzed asymmetric [4 + 1] annulation of polar dienes with allylic derivatives: Enantioselective synthesis of substituted cyclopentenes

A chiral phosphine-catalyzed asymmetric [4 + 1] annulation reaction of polar 1,3-dienes and allylic derivatives is reported. Under the catalysis of P-chiral bicyclic phosphine (15 mol%), a series of 1,1-dicyano-2,4-diaryl-1,3-dienes (21 examples) readily undergo stereoselective [4 + 1] annulation reactions with allylic acetate under mild conditions, delivering enantio-enriched polysubstituted cyclopentenes in 49–89% yields and 51–98% ee. A plausible mechanism for the reaction is also discussed.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Sterically Constrained Bicyclic Phosphines: A Class of Fascinating Compounds Suitable for Application in Small Molecule Activation and Coordination Chemistry.

Bicyclic phosphines with two annulated, electronically unsaturated five-membered heterocycles are available through facile routes. In most cases, their phosphorus atoms are bound to heteroatoms such as oxygen or nitrogen (PN3 or PN2 O), whereas homoleptic coordination by three sp2 -hybridized carbon atoms has been reported only recently. Steric strain causes unique reactivity. Oxidative addition of halogens, N-H or O-H bonds have afforded phosphoranes as valuable materials for secondary processes. Ring opening was identified as an important step for the understanding of these reactions and has been observed experimentally with a diphosphorus-based ring system. A PH2 derivative has been considered as a model system for small molecule activation, and hydrogen transfer to a diazo compound was observed experimentally. Several of these phosphines are excellent ligands for the coordination of transition-metal atoms. The very bulky PC3 compound has a basicity similar to that of PPh3 and may allow the synthesis of complexes with unusually low coordination numbers at the metal atoms. These phosphines found recently renewed interest as promising reagents in various secondary transformations such as the activation of σ-bonds or in coordination chemistry.

Catalytic Enantioselective Synthesis of Guvacine Derivatives through [4 + 2] Annulations of Imines with α-Methylallenoates.

P-Chiral [2.2.1] bicyclic phosphines (HypPhos catalysts) have been applied to reactions between α-alkylallenoates and imines, producing guvacine derivatives. These HypPhos catalysts were assembled from trans-4-hydroxyproline, with the modular nature of the synthesis allowing variations of the exocyclic P and N substituents. Among them, exo-( p-anisyl)-HypPhos was most efficacious for [4 + 2] annulations between ethyl α-methylallenoate and imines. Through this method, ( R)-aplexone was identified as being responsible for the decrease in the cellular levels of cholesterol.

Bridged [2.2.1] bicyclic phosphine oxide facilitates catalytic γ-umpolung addition-Wittig olefination.

A novel bridged [2.2.1] bicyclic phosphine oxide, devised to circumvent the waste generation and burdens of purification that are typical of reactions driven by the generation of phosphine oxides, has been prepared in three steps from commercially available cyclopent-3-ene-1-carboxylic acid. The performance of this novel phosphine oxide was superior to those of current best-in-class counterparts, as verified experimentally through kinetic analysis of its silane-mediated reduction. It has been applied successfully in halide-/base-free catalytic γ-umpolung addition-Wittig olefinations of allenoates and 2-amidobenzaldehydes to produce 1,2-dihydroquinolines with good efficiency. One of the 1,2-dihydroquinoline products was converted to known antitubercular furanoquinolines.

Asymmetric Synthesis of Pyrrolines Using Bicyclic Phosphine Catalysts

Asymmetric Synthesis of Pyrrolines Using Bicyclic Phosphine Catalysts

Hydroxyproline-derived pseudoenantiomeric [2.2.1] bicyclic phosphines: asymmetric synthesis of (+)- and (-)-pyrrolines.

We have prepared two new diastereoisomeric 2-aza-5-phosphabicyclo[2.2.1]heptanes from naturally occurring trans-4-hydroxy-l-proline in six chemical operations. These syntheses are concise and highly efficient, with straightforward purification. When we used these chiral phosphines as catalysts for reactions of γ-substituted allenoates with imines, we obtained enantiomerically enriched pyrrolines in good yields with excellent enantioselectivities. These two diastereoisomeric phosphines functioned as pseudoenantiomers, providing their chiral pyrrolines with opposite absolute configurations.

Versatile Cycloaddition Reactions of 1-Alkyl-1,2-Diphospholes

The reactivity of 1-alkyl-1,2-diphospholes in cycloaddition reactions with dienes, dienophiles or 1,3-dipoles was examined. 1-Alkyl-1,2-diphospholes (2 ) exhibit dual reactivity and act as diene toward maleic acid derivatives or as dienophiles with 2,3-dimethyl-1,3-butadiene. The 1-alkenyl-1,2-diphospholes (4 ) are readily involved in intramolecular [4 + 2] cycloaddition reactions leading to cage phosphines (5 ). Interaction of 1-alkyl-1,2-diphospholes (2) with 1,3-dipolar reagents (diphenyldiazomethane and nitrones) results in formation of the bicyclic phosphiranes (8) and dimers of 1-alkyl-1,2-diphosphole oxides (9) or bicyclic phosphine oxides (10) with a β-lactam moiety depending on temperature.

Lipase-mediated stereoselective transformations of chiral organophosphorus P-boranes revisited: revision of the absolute configuration of alkoxy(hydroxymethyl)phenylphosphine P-boranes

The lipase-promoted kinetic resolution of a series of alkoxy(hydroxymethyl)phenylphosphine P-boranes proceeded with moderate stereoselectivity to give both the unreacted substrates and their O-acetyl derivatives. The absolute configurations of the products, which were earlier ascribed on the basis of the stereoselective reduction of the corresponding phosphine oxides with borane and comparison with the literature data concerning bicyclic phosphine oxides, were disputed by theoretical calculation. Some additional studies were carried out, including theoretical calculations and more accurate chemical correlation, which proved that the borane reduction of acyclic phosphine oxides proceeded with inversion of configuration at the phosphorus center and, therefore, the former assignment of the absolute configurations was incorrect. On this basis, the stereochemistry of the enzymatic reaction was ultimately determined. A mechanism of the borane reduction of acyclic phosphine oxides explaining inversion of configuration at phosphorus is proposed.

Steric and electronic properties in bicyclic phosphines. Crystal and molecular structures of Se = Phoban-Q (Q = C 2, C 3Ph, Cy and Ph)

Reacting a series of the bicylic Phoban-Q (9-Q-9-phosphabicyclo[3.3.1]nonane and 9-Q-9-phosphabicyclo[4.2.1]nonane) derivatives (Q = alkyl, cyclo alkyl, aryl) with KSeCN results in the formation of the corresponding phosphine selenides. The first order phosphorus–selenium coupling constants, 1 J P–Se, ranges from 682 to 689 Hz for the [3.3.1] isomers and from 703 to 717 Hz for the [4.2.1] isomers indicating the former to be significantly more electron rich. The crystal structures of Se = Phoban[3.3.1]-Q (Q = CH 2CH 3, C 3H 6Ph, Cy, and Ph) and Se = Phoban[4.2.1]-Q (Q = Cy and Ph) are reported and reveal P Se bond distances ranging from 2.1090(9) to 2.1245(7) Å. For Q = Cy and Ph the two isomers ([3.3.1] and [4.2.1]) co-crystallise in the same crystal enabling the determination of the molecular structures for both from the same data collection. The cone angles for all ligand derivatives were determined according to the Tolman model but by using the actual P–Se bond distances and were found to be virtually identical ranging from 165° to 175°. Changes in the Q substituent have a minor effect on the overall steric and electronic properties of the Phoban family of ligands and can be used to manipulate physical properties without changing the chemical properties significantly.

Bicyclic phosphines as ligands for cobalt catalysed hydroformylation. Crystal structures of [Co(Phoban[3.3.1]-Q)(CO)3]2 (Q = C2H5, C5H11, C3H6NMe2, C6H11)

A range of tertiary bicyclic phosphine ligands derived from cis, cis-1,5-cyclooctadiene (Phoban family) was studied by batch autoclave reactions during the hydroformylation of a mixture of linear internal decenes using a cobalt catalyst system. Comparative runs were performed with PBu(3) as representative of standard trialkyl phosphine behaviour. The Phoban ligands comprise of a cyclooctyl bicycle with a mixture of the [3.3.1] and [4.2.1] isomers where the third substituent was systematically varied, Phoban-Q (Q = CH(2)CH(3), (CH(2))(4)CH(3), (CH(2))(9)CH(3), (CH(2))(19)CH(3), (CH(2))(3)N(CH(3))(2), C(6)H(11) and C(6)H(5)). An increase in ligand concentration resulted in a decrease in the reaction rate while the selectivity towards the n-alcohol product increased in accordance with a move from more unmodified catalysis to more modified catalysis. Alcohol yields of 77-85% were obtained at rates of 1.8-2.4 h(-1) for highly modified catalysis. Under highly modified conditions the linearity of the alcohol ranges in a narrow band from approximately 85-90% from Phoban-Ph to Phoban-Cy respectively. Hydrogenation of the alkene substrate varied from approximately 9-15% for Phoban-Ph and Phoban-Cy respectively the least and most electron donating derivatives. The two phosphine isomers were separated for Phoban-C(2) and the hydroformylation activity were re-evaluated for each isomer. The less electron donating [4.2.1] isomer required slightly higher ligand concentrations to achieve fully modified catalysis and gave rates and linearities comparable to the [3.3.1] isomer but giving slightly higher yields due to less hydrogenation of the olefin. In comparison, at fully modified conditions, PBu(3) gave a rate of 0.6 h(-1), alcohol yield of 77%, linearity of 81% and 17% hydrogenation. The crystal structures of the cobalt dimers [Co(CO)(3)(Phoban[3.3.1]-C(2))](2), [Co(CO)(3)(Phoban[3.3.1]-C(5))](2), [Co(CO)(3)(Phoban[3.3.1]-C(3)NMe(2))](2), and [Co(CO)(3)(Phoban[3.3.1]-Cy)](2) have been determined and indicated very similar geometries with Co-Co and Co-P bond distances ranging from 2.6526(10)-2.707(3) and 2.1963(8)-2.2074(9) A respectively. The cone angles of the Phoban ligands were calculated from the crystallographic data, according to the Tolman model, and ranges from 159-165 degrees.

Rotational Isomerism of a Phoban-Derived First-Generation Grubbs Catalyst

A ruthenium carbene complex bearing a bicyclic phosphine ligand instead of tricyclohexylphosphine of the otherwise identical first-generation Grubbs catalyst exhibits only a very broad singlet in the 31P NMR at room temperature instead of the expected sharp signal. For this complex as well as for similar derivatives, low-temperature NMR experiments and DFT calculations proved the existence of rotational isomers with the employed unsymmetrical bicyclic phosphine ligand. Such rotational isomers cannot be observed for the first- and second-generation Grubbs catalysts, due to the symmetrical nature of their ligands.

Rhodium-Catalyzed Direct C−H Addition of 3,4-Dihydroquinazolines to Alkenes and Their Use in the Total Synthesis of Vasicoline

The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I) catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur consecutively with heterocycle dehydrogenation in the presence of a Rh(I)/PCy3/HCl catalyst. The reaction was used to develop an effective method for the synthesis of 2-substituted quinazolines through an oxidative workup step. The regiocontrolled synthesis and Rh-catalyzed cyclization of alkene-tethered 3,4-dihydroquinazolines are also described. Applying this method, the second total synthesis of vasicoline was achieved. The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-substituted aryl chloride.

A Stable Ruthenium Catalyst for Productive Olefin Metathesis

New ruthenium carbene complexes 5 and 6, containing a rigid bicyclic phosphine moiety, have been prepared, and the structure of 5 has been unambiguously established by single-crystal X-ray diffraction studies. These ruthenium-based complexes show excellent stability to air and moisture, can be recycled by chromatography, and are available from simple precursors. They are efficient catalysts for various metathesis reactions, particularly for applications where high selectivity is required.

Desymmetrization of meso-hydrobenzoin using chiral, nucleophilic phosphine catalysts.

The desymmetrization of meso-hydrobenzoin is described using chiral phosphine catalysts 8b-d and 9-11. The best enantioselectivity at room temperature was obtained with the newly synthesized phospholane 8c and benzoic anhydride, but the reaction is very slow. Much faster reactions, but somewhat lower enantioselectivities were observed using the bicyclic phosphine catalyst 9. To obtain product 5a with >90% ee required conditions where the ee is upgraded due to the formation of the dibenzoate 6a. Among the new phospholane catalysts, 8b has the best selectivity in the kinetic resolution of benzylic alcohols, but not at the level observed previously with catalyst 11.

Cyclopentannulation on 3-phospholenes: an expedient route to the 2-phosphabicyclo[3.3.0]octene ring system

Treatment of 1-phenyl-3-phospholene derivatives with 2 equiv. of LDA followed by quenching the metallated intermediates with 1,3-dihaloalkanes affords 2-phosphabicyclo[3.3.0]oct-3-ene derivatives in good yield. The annulation reactions are highly regio- and stereoselective and lead to the formation of exo-Ph-P substituted products exclusively. Reduction of the resulting bicyclic phosphine oxides by phenylsilane gives the corresponding phosphines with complete retention of configuration at P. Application of this annulation procedure to acyclic allylic substrates leads to the corresponding monocyclic annulation products.

Bicyclic phosphines as ligands for cobalt-catalysed hydroformylation

A range of tertiary phosphine ligands derived from (R)-(+)-limonene was studied by HP-31P NMR, HP-IR, batch autoclave reactions and molecular modelling during the hydroformylation of 1-dodecene using a cobalt catalyst system and a metal ∶ ligand ratio of 1 ∶ 2. The phosphorus atom was incorporated in a limonene bicycle where the third substituent was systematically varied, Lim-R (R = (CH2)17CH3, (CH2)9CH3, (CH2)4CH3, (CH2)3CH3, (CH2)3C6H5, (CH2)3CN, (CH2)3OCH2C6H5, (CH2)2OCH2CH3). The activity and selectivity was, to a large extent, governed by the equilibria between the modified and unmodified cobalt catalytic species in the reaction. Linearity ranged from 54 to 71% with Lim-(CH2)3CN yielding the most branched product and Lim-(CH2)4CH3 the most linear product. The n ∶ iso ratio (ratio of linear to 2-methyl branched alcohol) also followed the same trend with a ratio of 2.6 for Lim-(CH2)3CN and 4.9 for Lim-(CH2)4CH3. The rate decreased as the linearity increased with pseudo k values of 0.5 to 1.1. Hydrogenation of the alkene varied within a narrow band from 5–6%.

Intrinsic Basicities of Phosphorus Imines and Ylides: A Theoretical Study

A density functional theory (B3LYP/6-311+G**), ab initio (HF/3-21G*), and semiempirical (PM3) study of intrinsic basicities, protonation energies, or protonation enthalpies of organic phosphorus imine (iminophosphorane) including phosphazene, phosphorus ylide (phosphorane), and phosphine superbases has been performed. The study shows that representatives of the first two classes of the above-mentioned organic superbases can reach the basicity level of the strongest inorganic superbases such as alkali-metal hydroxides, hydrides, and oxides. The strongest organic phosphazene imine superbases are predicted to reach the gas-phase basicity level of ca. 300 kcal/mol (number of phosphorus atoms in the system n ≥ 7), whereas the strongest organic phosphazene ylide superbases are estimated to have (at n ≥ 5) gas-phase basicities around or beyond 310−320 kcal/mol. The phosphine superbases, including the Verkade's bicyclic phosphines (proazaphosphatranes) are predicted to have a basicity comparable to P2 phosphazene...

Correlated proton affinities of arylphosphines

Theoretical gas phase proton affinities are presented at the MP2 level for phenylphosphine, dimethylphenylphosphine and the bicyclic phosphines phenylphosphabicyclo(3,3,1) nonane and 1H,5H-benzo(ij)-5-phosphadecalin. The latter two species have proton affinities larger than triphenylphosphine.