Palladium Catalyzed Carbonylation and Related Reactions 

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Retrosyntheses of the Introduction of the Phosphines 2-by-2 (stepwise)

A different generalized retrosynthetic pathway in molecule 5 involves the stepwise introduction of the different pairs of phosphines that form the chelate rings. In Scheme 14 the first retrosynthetic step is a substitution involving a nucleophilic backbone (6) and electrophilic phosphines (17). Methods for achieving this, such as the use of bulky R-groups or phosphorus electrophiles having the general formulation PRXY where X and Y are leaving groups of different basicity, will be described in the section that treats experimental detail. Chiral phosphines are generated in this step. If we take a closer look into the possible disconnection points of molecule 5 and its retrosynthetic approaches, we will see that there are different possibilities (Scheme 15). Method C constitutes a simple nucleophilic substitution between nucleophilic phosphides (21) on the backbone and electrophiles having the desired carbon chain length and bearing terminal phosphines (20). The corresponding synthetic routes can be expected to be very efficient under well-chosen conditions.
Retrosynthetic approach D involves the attachment of preelaborated phosphines (20), with the desired carbon chain length and bearing a leaving group. These electrophiles undergo with the nucleophilic backbone-bis-(sec-phosphine) (21) a simple SN2 substitution reaction. A related approach employs cyclic sulfates in the first step: an initial ring opening with the metallated backbone-bis-(sec-phosphine) gives the corresponding sulfate-anion (24), whose sulfate group can act as a leaving group and gives rise to the target molecule upon reaction with lithiated phosphines (25). Cyclic sulfates have the great advantage of being available in a variety of different ring-sizes144–146; consequently a number of different ligands could be obtained in a short time using simple readily available starting material.

Protection of Phosphines

In many of the retrosyntheses described above, there are inherent incompatibilities between nucleophilic σ3λ3-phosphorus centers and a variety of electrophilic functionalities, which often need to be present on the same molecular fragment. These incompatibilities obviously mean  that some sort of reversible protection will have to be brought to the system. Because many σ3λ3phosphorus centers are inherently difficult and unpleasant to handle, (malodorousness, oxidation sensitivity, potential pyrophoricity, toxicity) it is usually the phosphorus lone pair that receives the protection. The most common “protecting groups” are oxides, sulfides and boranes (Figure 21). Their individual advantages and disadvantages are treated briefly here.
Figure 21: Free and protected phosphines. P-X (X = O, S, Se) and P-BH3 are displayed. Phosphine boranes: in these compounds, boron is connected to phosphorus through a dative bond. R3B•PR3 complexes generally exhibit high thermal stability70 and, due to the low polarity of the P–B and B–H bonds, they are normally stable and rather unreactive. Their stability towards hydrolysis and oxidation, for instance, reflects the basicity of the phosphine, and falls as a function of R in the order R= alkyl > aryl >> H and this stability enormously simplifies the purification of key tertiary phosphine intermediates. Another useful feature in synthetic terms is that hydrogen atoms or methyl groups adjacent to the phosphorus atom are activated; the first of these is especially useful for the functionalization of our backbone secondary phosphines, as well as in our diphosphine chain synthesis. One problem with phosphine boranes in synthetic terms relates to their observation by 31P– NMR. The 31P isotope has a natural abundance of 100 %, a spin of ½, and very high sensitivity, 377 times that of 13C147, all of which facilitate the interpretation of ongoing reactions by in situ NMR studies.148 Phosphine boranes negate many of these advantages, because 10B and 11B have both quadrupolar relaxation that broadens the NMR signal.59 This may cause a problems in detecting individual resonances which lie close to each other in the PNMR spectrum (such as diastereomers; Figure 22, 39c vs 38c) and the very broad signals that they generate obviously reduce the sensitivity of any measurement. The cleavage of the P–B bond is uncomplicated and can be achieved using amines (classically NHEt2, DABCO, etc.) in straightforward SN2 reactions at boron which require moderate to high temperatures (40- >100°C as a function of the substituents). These temperatures may become high enough to cause racemization of enantiopure phosphines during the deboronation step when all substituents are alkyl.77 In such cases, acids (HBF4·Et2O), group76 can be used to provide fast deboronation at low temperatures. Both methods proceed under retention of configuration at phosphorus.56,69,71–77 Another advantage of acid- induced deboronation is the short reaction time of 1-2 h, whereas deprotection using amines can take more than 12 h.

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Synthetic Methods

In the following sections the synthetic routes applied to our target systems will be described in detail. The synthesis of the activated aromatic backbones (DBDOC, BFBF) for functionalization is the starting point for all approaches; hence it will be explained separately.

Synthesis of the DBDOC-H2 Ligand Precursor

Banihashemi and Rahmatpour reported the synthesis of 2,10-dimethyl-12H-6,12-methanodibenzo[ d,g][1,3]dioxocine (DBDOC) skeleton obtaining a yield of 91 %, from an acid catalyzed condensation reaction between two moles of p-cresol (26) and malonaldehyde tetramethyl acetal (27). Various acids were tested, and their optimal procedure employs trifluoroacetic acid (TFA) acting as solvent and catalyst. Their proposed mechanism has a proton-induced Friedel Crafts reaction to give 28 as the first step, followed by entropically favored intramolecular acetalization (Scheme 16).132,159.

Table of contents :

Chapter 1 Introduction
1.1 Phosphine Ligands in Homogeneous Catalysis
1.1.1 Ligand Effects of Phosphines
Electronic and Steric Parameters of Monophosphines
1.1.2 Describing Diphosphines
1.2 Bimetallic Catalysts
1.2.1 Enzyme catalysis
1.2.2 Synthetic bimetallic catalysts
Synthesis and Characterization
1.2.3 Homobimetallic Catalysts
1.2.4 Heterobimetallic Catalyst
1.2.5 Bimetallic Catalysts developed by van Leeuwen and Co-Workers
Chapter 2 Design and Synthesis of Tetraphosphine Ligands
2.1 Introduction
2.2 Symmetry of the Target Ligands
2.3 Retrosynthetic Analyses of the Designed Ligand system
2.3.1 Retrosyntheses of the Introduction of Two Diphosphine Chains
2.3.2 Retrosyntheses of the Introduction of the Phosphines 2-by-2 (stepwise)
2.3.3 Protection of Phosphines
2.4 Synthetic Methods
2.4.1 Synthesis of the DBDOC-H2 Ligand Precursor
2.4.2 Synthesis of the BFBF-H2 Ligand Precursor
2.4.3 Bromination of the DBDOC Backbone
2.5 Introduction of the Phosphines 2-by-2
2.5.1 Phosphination of the Backbone
2.5.2 Generating Secondary Phosphines on the Backbones
2.5.3 Backbone flexibility and Steric Interactions in DBDOC derivatives
2.5.4 Alternative Routes to Generate Secondary Phosphines on the Backbone
Palladium-Catalyzed Cross-Coupling of H-Phosphinates
2.5.5 Conclusion
2.6 Electrophiles suitable for the introduction of chelating sidearms
2.6.1 Preparation of the Electrophilic Phosphine Precursors
2.6.2 Synthesis of a ‘Side-Arm’ Electrophile bearing Phosphine Borane groups
Syntheses of Alternative ‘Side-Arm’ Electrophiles
2.7 Synthesis of Tetraphosphines
2.7.1 Synthesis of Tetraphosphines Using Cyclic Sulfates
2.8 Synthesis of Tetraphosphines: A Comparison of Stepwise Synthetic
2.8.1 Removal of the Borane-Groups from Compound
2.9 Conclusion
Chapter 3 Introduction of Diphosphine Chains directly onto the DBDOC backbone
3.1 Analysis and Synthesis of Unsymmetric Bisphosphines
3.1.1 Reductive Cleavage of a P–Ar bond in bis(diphenylphosphanyl)alkanes
3.1.2 Synthesis of the Unsymmetric Bis(phosphine)s from two different Pfragments
3.1.3 Chlorination of Unsymmetric Bisphosphines
3.2 Coupling Reactions
3.2.1 Copper Induced P–C Bond Formation
3.2.2 Palladium Catalyzed Cross-Coupling
3.3 Conclusion
Chapter 4 Coordination Chemistry
1.1 Coordination Chemistry with DBDOCphos at Pd(II) and Pt(II) centers
1.1.1 Conclusion
1.2 Coordination Chemistry of Tetraphosphines at Pd(II) and Pt(II) centers
1.3 Conclusion
Chapter 5 Palladium Catalyzed Carbonylation and Related Reactions 
5.1 General Introduction
5.2 Hydroformylation
5.3 Palladium Catalyzed Hydroformylation
5.4 Palladium-Catalyzed Hydroformylation of α-Olefins
5.5 DBDOCphos System in Palladium-Catalyzed Hydroformylation
5.6 Tetraphosphine Systems in Pd-catalyzed Hydroformylation
5.6.1 The Effect of Anions on Palladium-catalyzed Hydroformylation
5.6.2 Acid Affecting the Ligand and Hydroformylation
5.6.3 Influence of the Metal-to-Ligand Ratio on Hydroformylation
5.6.4 Rhodium catalyzed hydroformylation1,324
5.7 Conclusion
Chapter 6 Experimental Section
6.1 General procedures
6.1.1 Solvents and Reagents
6.2 Experiments conducted inTarragona
6.3 Experiments conducted in Palaiseau
6.4 Experiments conducted in Saint Andrews
6.5 Syntheses
6.6 Coordination Chemistry
6.7 Batch Autoclave Procedure
6.7.1 Palladium
6.7.2 Rhodium as catalyst
Appendix I: Crystallographic Data
Appendix II : Abstract
References .


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