Dynamic transfer of chirality in photoresponsive systems
Pizzolato, Stefano Fabrizio
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Pizzolato, S. F. (2017). Dynamic transfer of chirality in photoresponsive systems: Applications of molecular photoswitches in catalysis. University of Groningen.
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Chapter 8
Chapter 8
Study towards a Photoswitchable Chiral Bidentate
Phosphine Ligand based on an Overcrowded Alkene
for Metal-catalyzed Asymmetric Transformations
This chapter describes the study towards the synthesis and application of a photoswitchable chiral bis(diphenylphosphine)-ligand based on a second generation molecular motor core. We envisioned a large variation of axial chiral induction and steric hindrance induced around the coordinated metal center upon photochemical isomerization of the responsive ligand. Derivatization of the 2,2’-bisphenol-functionlized chiral molecular switch described in Chapter 5 provided the bis-triflate-intermediate. Several metal-catalyzed aryl phosphination methodologies previously developed for conventional biaryl scaffold were attempted. However, the target compound was not obtained. Experimental evidence suggests that the highly hindered structure of the designed bidentate ligand may even preclude the proposed synthetic route at all. An alternative proposal to develop a photoswitchable Brønsted acid catalyst based on an analogous diphenylphosphine-hydroxyl derivative is presented.
8.1 Introduction
8.1.1 Design of natural and artificial metal complexes
The ability to reversibly control the shape of structures at the nano-scale is a highly challenging and attractive target of modern molecular design. Indeed, such molecular devices constitute powerful tools for achieving switchable chiral induction. Chiral inversion and asymmetric induction processes play an important role in host-guest chemistry, self-assembly and molecular recognition, as well as in nature.1–4 They are in fact known to affect the properties and functions of DNA5 and proteins.6 Inspired by nature, the dynamic cooperative effects and correlated motions of artificial chiral supramolecular structures held together by weak intermolecular interactions such as hydrogen bonding, metal coordination, π-π interactions, Coulomb forces, dipole-dipole interactions, and van der Waals forces have led to the development of complex molecular assemblies that can be used for switching7–10 and amplification of chirality.11–18 The versatile coordination chemistry and stereo-dynamics of chiral metal complexes that exploit transfer of chirality from ligands to metal centers19 can be used to mimic such processes, to devise chiral switches that respond to external stimuli, and to develop supramolecular architectures exhibiting chiral amplification and memory.20–26
Since the first separation of enantiomeric octahedral cobalt complexes achieved by Werner in 1911,27 chemists have progressively developed deeper knowledge and control of chirality in coordination species.28 A major breakthrough was accomplished with the stereoselective synthesis of metal complexes via introduction of chiral, non-racemic coordinating ligands. Several examples of supramolecular designs29 based on chiral organometallic structures have been crafted in the past decades, ranging from mononuclear complexes to oligo- or polynuclear assemblies, helicates, catenanes, knots, rotaxanes,29,30 and polyhedral three-dimensional structures.31,32 Chiral metal complexes are now extensively used in several enantioselective catalytic synthetic methodologies by the pharmaceutical industry.33 Stereodiscrimination is also an invaluable feature of modern chiral polymerization catalysts, which can give access to polymers with highly controlled tacticity and consequent tailored mechanical properties.34 The ability to exert spatio-temporal control in a polymerization process by means of a responsive stereodynamic catalyst is a concrete example of industrial application of such an underdeveloped concept.2
8.1.2 Asymmetric transformation of stereodynamic biaryls
Biaryls such as BINOL35 and BINAP36 are certainly listed among the most widely recognized atropisomeric inductors and constitute the main scaffold of several families of rigid chiral ligands exploited in asymmetric synthesis. Their C2-symmetric 1,1‘-binaphthyl scaffold lacks of stereogenic centers, however it features an element of axial chirality due to the restricted rotation around the aryl-aryl bond. The dihedral angle between the two naphthyl halves is approximately 90°, which makes such framework capable of providing a strong chiral induction. It is no coincidence that extensive development and application of binaphthyl-based catalyst in asymmetric synthesis was achieved in the past decades.37–39 On the other hand, several stereodynamic bidentate ligands that effectively amplify chirality at a metal center have been reported to improve both selectivity and efficiency of asymmetric catalysts. A small selection of previously reported catalysts based on metal complexes featuring stereolabile ligands is presented in Figure 8.1.40–49
Figure 8.1. Previously reported catalysts based on metal complexes featuring stereolabile ligands.
The rotation energy barrier of biaryls can usually be explained on the basis of steric and electronic substituent effects.50 Their conformational stability mainly depends on the presence of bulky ortho-substituents. Meta-substituents further enhance steric hindrance to rotation through the so-called buttressing effect: they reduce the flexibility of ortho-substituents and therefore enhance steric repulsion during rotation about the chiral axis. The energy barrier to atropisomerization steadily increases with the steric demand of the groups due to both enthalpic and negative entropic contributions. The latter originates from the compromized rotational freedom of ortho-substituents in the crowded transition state. Electronic effects play a secondary role due to enhanced CH/π-interactions, which becomes the predominant effect on the rotational energy barrier upon promoting out-of-plane bending via less sterically hindered transition states. The conformational stability of bridged biaryl units varies significantly with ring size. As a rule of thumb, biaryls that possess one bridging atom are not stable to rotation to room temperature even if the remaining two ortho-positions are occupied by bulky groups.51,52 An increase in bridge length enhances the torsion angle between the two aryl rings and raises the energy barrier to racemization. Nevertheless, with a five- or six-membered ring may still undergo rotation around the chiral axis, unless bulky ortho-substituents are present in the bridged biaryl framework.53–59 Biaryl containing seven-membered or larger rings are generally as stable as their unbridged analogs.60–63 By analogy with the stabilization of interconverting axially chiral ligands by incorporation of a rigid bridge, coordination of a bidentate biaryl to a metal center can significantly enhance the rotational energy barrier. Mikami,40,41,64 Jacobsen45 and Katsuki65 introduced the concept of asymmetric activation of a stereolabile racemic catalysts derived from conformationally unstable ligands with a non-racemic chiral activator. Such concept is based on rapidly interconverting chiral catalysts, for example racemic BIPHEP-derived transition metal complexes, that are converted to a diastereomerically enriched or pure catalytic species through addition of an enantiopure activator. For example, 2,2‘-bis(diarylphosphino)biphenyls such as BIPHEP and DM-BIPHEP undergo rapid rotation about the chiral axis at room temperature.66 However, the conformational stability of these diphosphines increases upon metal complexation. The addition of enantiopure diamines to ruthenium and rhodium
complexes of BIPHEP and DM-BIPHEP has been reported to give diastereoisomers that are stable to isomerization at room temperature. Notably, the rapid racemization of BIPHEP is due to its ortho-disubstituted biphenyl structure, as opposed to the conformationally stable ortho-tetrasubstituted biphenyl ligand MeOBIPHEP (see Scheme 8.49). Achiral ligands can exist as a fluxional mixture of chiral and enantiomeric conformers. Interaction with another chiral compound can render the equienergetic and equally populated chiral conformation diastereomeric. Since diastereoisomers differ in energy, the ligand is likely to preferentially occupy one chiral conformation. The presence of an enantiopure compound can therefore induce a conformational bias in an achiral ligand resulting in amplification of chirality. In contrast, Walsh‘s approach utilises stereolabile achiral activators, such as chiral diamine or diimine, to optimize the performance of a chiral enantiopure BINOL-derived catalyst that is inherently stable to racemization. 46–48 The preferential population of one chiral conformation of the stereolabile achiral activator amplifies the asymmetric environment of the enantiopure catalyst, thus providing and enhancement in asymmetric induction.
8.1.3 Photoswitchable metal complexes for asymmetric catalysis
The attractive prospects on the development and applications of stimuli-responsive catalysts have been extensively explained throughout this thesis. Initial efforts were mainly devoted to the ON–OFF switching of catalytic activity.67–69 Later, remarkable reversal of enantioselectivity in asymmetric catalysis has been achieved using solvent responsive helical polymers,70 light-triggered organocatalysts71,72 and redox sensitive metal complexes.73 As previously remarked in Chapter 6, a highly desirable feature of an ideal responsive stereoselective catalyst is the ability to readily modify the chiral configuration of its active form. In the case of homogenous catalysts based on metal complexes, some of the previously described systems rely on the isomerization of photoresponsive coordination ligands before the addition of the metal source.74,75 Such an approach is exploited because the formation of the active catalyst might impede the efficient reconfiguration, either due to slow metal-ligand dissociation processes in multi-dentate complexes76 or quenching of the photo-generated excited state via internal energy transfer influenced by the metal center.77 Moreover, the use of multi-dentate responsive ligands characterized by a large variation in geometry and distance of coordination sites between the interchangeable states, may lead to the reconfiguration among mono- and oligomeric structures with divergent catalytic performances.74,75 On the other hand, the optimal stereoselective metal-based catalyst should feature a limited number (ideally two) of enantiomeric or pseudoenantiomeric active forms. The latter should also be interchangeable in their coordinated states, providing access to chiral catalysts that could perform multiple enantioselective transformation in a sequential manner without the need of an intermediate metal-decomplexation step. Although it is difficult to switch the chirality of conventional ligands, artificial light-driven molecular switches and motors provide a unique platform to achieve this goal.78–80 Branda and co-workers reported a dithienylethene-based switch in asymmetric catalysis, which represents the first reported example of modulation of stereoselectivity of a copper-catalyzed reaction by light (Scheme 8.1).81 They designed a chiral bis(oxazoline) ligand with a switchable dithienylethene bridge unit, which allowed the selectivity of a cyclopropanation reaction to be controlled with light. The approach exploited the differences in steric interactions between the open and closed forms. In the open form o-L1, the two oxazoline moieties of the ligand can bind copper(I) providing moderate enantioselectivities in the cyclopropanation of styrene (30– 50% ee). In the closed form c-L1, the two oxazolines are far apart, in an anti orientation, and cannot provide bidentate coordination for the copper(I) atom. On using the ring-closed form, a significant drop in enantioselectivity (5% ee) for the same catalyzed reaction was observed, although when a PSS mixture consisting of 23% of the closed form was used, no significant drop in enantioselectivity was observed. Unfortunately, this system is not effective in switching the selectivity in situ due to the low PSS. The same group also developed a dithienylethene photoswitch bearing phosphine groups, displaying steric and electronic differences between two photogenerated isomers.82 The coordination chemistry of this ligand
was demonstrated by preparing a gold(I) complex and a phosphine selenide. However, no catalytic application was presented in the study.
Scheme 8.1. Photoswitching of a dithienylethane-based oxazoline ligand L1 that shows different
stereoselectivities in the copper-catalyzed asymmetric cyclopropanation of styrene developed by Branda and co-workers.81
Craig and co-workers presented the first application of a photoswitchable bis-phosphine ligand in enantioselective catalysis.83 Ligand L2 couples an achiral stilbene molecular photoswitch to the biaryl backbone of a tetrasubstituted chiral bis-phosphine ligand analogous to MeOBiphep (Scheme 8.2). Photochemical manipulation of ligand geometry is allowed without perturbing its electronic structure and coordinating abilities. (E)-L2 and (Z)-L2 were isolated from the irradiated ligand mixture using column chromatography. The changes in catalyst activity and selectivity displayed in palladium-catalyzed Heck arylations and Trost allylic alkylations upon switching were attributed to intramolecular mechanical forces, which varied the dihedral angle of the biaryl motif and consequently the catalyst performance. Although, in all cases, the Z-isomer demonstrated higher selectivity than the E-isomer, reaction with either isomer resulted in the same major enantiomer of the product (despite differing degrees of enantioselectivity). No inversion of axial chirality of the biaryl bis-phosphine catalytic module was achieved upon switching of such a stilbene actuator design, which resulted in the lack of stereoinversion when applied to the asymmetrically catalyzed transformation.
Scheme 8.2. Photoswitchable stilbene-derived biaryl bis-phosphine ligand L2 developed by Craig and
co-workers.83
Unidirectional rotary molecular motors based on overcrowded alkenes can intrinsically act as multistage chiral switches as we have recently shown in the design of three-stage organocatalysts71,72 and bis-phosphine ligands for metal catalysts.75 The design used to date is based on first generation molecular motors,84 of which core is composed of two identical halves each bearing one functional group of the catalytic pair. The photochemical and thermal isomerizations resulting in unidirectional rotation around the central overcrowded alkene bond provide stepwise control over the helicity of the bifunctional bidentate ligand L3 and spatial distance between the coordinating phosphine substituents. As the photochemically-generated isomer (P,P)-(Z)-L3 and subsequent thermally-triggered isomer (M,M)-(Z)-L3 are pseudo enantiomers, chiral products (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone with opposite absolute configuration are obtained when these isomers are used in a palladium-catalyzed enantioselective allylic substitution (Scheme 8.3).75 However, the thermally induced process of helix inversion between the pseudoenantiomeric forms (P,P)-(Z)-L3 and (M,M)-(Z)-L3 is not per se reversible. Indeed, starting from the isomer (P,P)-(Z)-L3, three consequent isomerization (light-heat-light) are required to recover the initial isomer (M,M)-(Z)-L3.84 Hence, fully reversible handedness switching of chiral inductors remains highly challenging so far. In case of non-labile coordination complexes, bridging the two halves to construct a stable cyclic structure via metal complexation would also impede the characteristic isomerization cycle. Further reversal of ligand chirality would require decomplexation of the active catalyst, for example upon addition of a sequestering agent.
Scheme 8.3. Stereodivergent synthesis of (3S,4R)-and (3R,4S)-toluensulfonyloxazolidinone via
palladium-catalyzed enantioselective allylic substitution by switching the chirality of bis-phosphine ligand based on a first generation molecular motor (Z)-L3 developed by Feringa and co-workers.75
In recognizing this, we decided to develop novel switchable bidentate bis-phosphine ligand based on the scaffold of second generation molecular motors. Such a new design would feature a symmetrical fluorenyl half, which would provide access to only two possible diastereoisomeric interconvertible forms and consequently simplify the switching process. Light should allow non-invasive and dynamic control of multistage ligand chirality, introducing simple yet efficient designs of programmable coordination complexes.85 Fascinating prospects in the control of functions would arise from such a strategy (note that dynamic chiral metal complexes were recently used in chiral recognition,86,87 transmission of chirality,88 chiral amplification89 and asymmetric catalysis73–75).
8.2 Results and discussion
8.2.1 Design
Chapter 5 describes the development of a photoresponsive molecular switch 1 featuring a versatile 2,2‘-bisphenol motif in which chirality is transferred across three stereochemical elements (Scheme 8.4a). Starting from the isomer (S,M=,Ma)-1, the photochemical E-Z isomerization (PEZI) of the helical-shaped
central alkene bond towards the isomer (S,P=,Pa)-1 allows via coupled motion the reversible control of the
helical and axial chirality of the biaryl motif. Successful application as stereodynamic chiral ligand in a catalyzed asymmetric 1,2-addition of diethylzinc to benzaldehydes was demonstrated. Furthermore we
previously proposed that such dynamic chiral selector could be derivatized to extend its applications into more sophisticated catalytic systems. Indeed, in Chapter 6 we described the development of five chiral photoresponsive phosphoramidite ligands derived from 1. The latter were successfully applied as tunable ligands for copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexen-1-one. Control over catalytic activity and stereoselectivity was achieved upon photo-induced isomerization using variable diastereoisomeric mixtures of phosphoramidite-switch derivatives. Analogously, an attempt to develop a switchable chiral phosphoric acid based on the same scaffold for application in photoswitchable organocatalysis is presented in Chapter 7. Parallel to the last project, we envisioned such a biaryl-functionalized core to be a promising candidate for developing the first bis-phosphine ligand based on a second generation molecular switch 2, capable of providing light-triggered stereodynamic control in a catalytic transformation upon metal complexation (Scheme 8.4b-c).
Scheme 8.4. Design of chiral photoresponsive bis-phosphine ligand 2. a) Previously described chiral
bisphenol -susbtituted switch 1. b) Front structural view of metal complex with photoswitchable 2,2‘-bis(phosphine) biphenyl-substituted overcrowded alkene-derivative 2 with axial helicity and chirality (black) of the 2,2‘-biphenyl core coupled to helicity (blue) and point chirality (red) of the molecular switch scaffold. Descriptors are based on the structure of compound (S)-2 (for explanation of the chiral descriptors, vide infra). c) Schematic top-down view of metal complexes MLn-(S)-2: two metal-ligand complexes with opposite coupled helicity (M or P) can be selectively addressed by irradiation with UV-light: MLn-(S,M,Ra)-2 and MLn-(S,P,Sa)-2.
In the photoresponsive bis-phosphine catalyst previously developed by our group,75 the cooperative catalytic action was achieved by interaction of two ligating groups each attached to one half of a light-driven unidirectional four-stage cycle first generation molecular motor.71,72,75 Such a design is limited to the effective cooperative catalytic activity between two groups located on structurally distant points of the photoresponsive scaffold only in the corresponding Z-isomers. Moreover, the four-stage cycle leads to a complex mixture of four isomers upon multiple irradiation cycles, due to the incomplete conversion toward
the metastable isomer during each photochemical isomerization process. In comparison, we envisioned metal complex of compound 2 to be switchable between only two possible forms displaying coupled alkene and biaryl helicities (M and P, Scheme 8.4c). Due to the symmetric fluorenyl substituent, the design described herein would display a strong reversible transfer of helicity to the biaryl motif with limited variation in morphology of the switch unit. Consequently, we envisioned a sharp reversal of stereoselectivity while retaining high catalytic activity, as opposed to previous switchable catalyst designs based on first generation molecular motors featuring Z and E isomers with large differences in shape and catalytic efficiency.
The system described herein features four stereochemical elements.90,91 The first element is the fixed stereogenic center (R or S) of the switch unit (highlighted in red). The second element is the helicity of the overcrowded alkene (highlighted in blue), which is under thermal control by the configuration at the stereogenic center but can be inverted between right-handed (P=) or left-handed (M=) upon photoisomerization. More precisely, the more stable diastereoisomer of the R enantiomer will adopt a P helicity, while the photo-generated diastereoisomer with higher energy will adopt an M helicity. The third and fourth elements are, respectively, the helical geometry (Pa or Ma) and axial chirality (Ra or Sa) of the biaryl unit (black), which are dictated via steric repulsion by the helicity of the alkene. In Chapter 5 we showed that amongst the four theoretically possible conformations of a biaryl unit, only conformations in which the non-annulated aryl group was parallel to the fluorenyl lower half were adopted. The other conformations, with the aryl orientated perpendicular with respect to the lower half, were expected to induce significant steric strain (see Scheme 8.5). Similar to the previously described coupled transfer of dynamic chirality displayed by 1, the true helicity of the biaryl is inextricably connected to the helicity of the overcrowded alkene chromophore, and is identical to it in each of the isomers. Analogously, two atropisomers of 2 having identical alkene and biaryl helicity but opposite biaryl axial chirality are expected. Therefore, three stereodescriptors (R/S, P/M and Ra/Sa) will be sufficient for the description of any expected
isomer reported in this work (unless indicated otherwise for more clear description). So for isomer
(R,P,Sa)-2: R = configuration of stereogenic center, P = helicity of alkene and biaryl, Sa = axial chirality of biaryl (Scheme 8.4c). The doubly expressed axial stereodescriptor (Ra/Sa) throughout the text denotes a mixture of rotamers with identical absolute stereochemistry at the stereocenter and configurational helicity (S,M,Ra/Sa means a mixture of atropisomers S,M,Ra and S,M,Sa). Similarly to the phosphoramidite-switch derivatives previously described in Chapter 6, our goal was to achieve reversible external control of chirality in a chiral metal complex. We proposed that the tunable helicity (P or M) of the switch core in turn would dictate the preferential axial configuration (Ra or Sa) of the desirable syn conformation of the biaryl moiety and eventually, for instance, the configuration (R or S) of a newly formed stereogenic center when applied to an enantioselective catalytic event.
Scheme 8.5 illustrates the envisioned interplay of dynamic stereochemical elements of bis-phosphine ligand (S)-2 before and after metal complexation and the light-triggered switching process between the two proposed diasteroisomeric species. Two rotamers, displaying syn or anti conformation of the biphenyl, are expected for each helical diastereoisomer (S,M) and (S,P), respectively. Due to the steric hindrance caused by the phosphine substituents, high energy barrier for biaryl axial inversion is envisioned in the free ligand
2. Thus no inversion of axial chirality is expected upon light-triggered inversion of helicity, namely M,S a-anti ⇄ P,Sa-syn and P,Ra-syn ⇄ P,Ra-anti. However, the helicity of the alkene and biaryl units are still expected to convert through a coupled motion to accommodate the alkene bond isomerization (Scheme 8.5a). On the other hand, the bidentate metal complex is envisioned to permit the axial inversion of the biaryl unit between the parallel and perpendicular conformations, respectively, for instance, between M=,Ma,Ra-syn and M=,Pa,Sa-syn (Scheme 8.5b). If compared to monodentate anti-isomers, bidentate
coordination species are envisioned to have access to transition states with lower energy barrier for biaryl axial inversion. Notably, both mono- and bidentate coordination species MLn-2 are possible. However, only the isomers with syn conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal center and successfully transfer the chirality within a catalytically active complex. Therefore, we
envisioned that the parallel syn-conformer of the bidentate complex M=,Ma,Ra-syn would be largely
thermodynamically favored and be present as the major species at the equilibrium. In summary, isomers with syn conformation and coupled helicity are expected to interconvert upon irradiation, while isomers with anti conformation would either isomerize to corresponding energetically favored syn isomers or spectate as catalytically inactive monodentate complexes (Scheme 8.5c). Overall, two main syn conformers with opposite axial chirality would be selectively addressable by means of light-irradiation with appropriate wavelength, giving access to a reversibly switchable chiral metal complex for catalytic applications.
Scheme 8.5. a) Schematic representation of switching process between the rotamers of free ligand (S)-2. b)
Depiction of the possible mono- and bidentate coordination species MLn-(S)-2. Only the isomer with syn conformation (torsion angle = 0°–±90°) were expected to efficiently bind a metal center and successfully transfer the chirality within a catalytically active complex. c) Schematic representation of switching process between the rotamers of metal complexes MLn-(S)-2. Note: for monodentate coordination species, the proposed metal coordination position at the upper phosphine moiety of the biaryl was arbitrary chosen.
8.2.2 Retrosynthetic analysis
The proposed retrosynthetic analysis of switchable metal complex with bis-phosphine ligand 2 from bisphenol -derived switch 1 is presented in Scheme 8.6.
Scheme 8.6. Proposed retrosynthetic analysis of switchable bis-phosphine ligand 2 from bisphenol -derived
switch 1.
Metal complex MLn-2 could be obtained from free ligand 2 upon metal complexation. The target photoresponsive ligand 2 was envisioned to be accessible via metal-catalyzed phosphination of bis-triflate
derivative with diphenylphosphine.92 Similarly, bis-triflate 3 can be obtained from 1 upon reaction with triflic anhydride.
8.2.3 Derivatization of resolved bisphenol derivative
The synthesis of bis-triflate switch derivative 3 starting from 2,2‘-bisphenol -derived molecular switch 1 is illustrated in Scheme 8.7. A previously described, (S)-1 is obtained after resolution as a mixture of interconverting conformers, i.e. (S,M,Ra)-1 and (S,M,Sa)-1 (hence, indicated as (S,M,Ra/Sa)-1; for synthesis and chiral resolution of 1, see Chapter 5). Optically enriched (S,M,Ra/Sa)-1 (99% ee) was reacted with triflic anhydride and pyridine in dichloromethane to yield a mixture of Ra-syn conformer (S,M,Ra)-3 and Ma-anti
conformer (S,M,Sa)-3 in a ratio of Ra-syn:Ma-anti = 40:60, as determined via
1
H NMR analysis of the crude mixture.
Scheme 8.7. Synthesis of conformers of bis-triflate switch derivative 3.
Chapter 5 describes the assignment of conformers (R,P,Sa)-1 and (R,P,Ra)-1 based on experimental and calculated chemical shifts of the corresponding 1H NMR spectra. Despite the difference in absolute chemical shift value, the relative position of the experimentally assigned absorptions peaks for the atropisomer in the experimental 1H NMR spectra are in full agreement with the corresponding calculated absorption peaks. Notably, almost every resonance absorption of the syn isomer (R,P,Sa)-1 resonates at higher frequency than the minor anti isomer (R,P,Ra)-1. By comparison with experimental 1H NMR spectra of (S,M,Ra/Sa)-1 (Figure 8.2a), the isolated early (Figure 8.2b) and later fraction (Figure 8.2c) obtained after flash column chromatography of the mixture were similarly assigned to the Ra-syn and Ma-anti conformers
of 3, (S,M,Sa)-3 and (S,M,Ra)-3, respectively, based on the relative position of each distinctive resonance absorptions. Each single atropisomer was analyzed via 1H NMR spectroscopy before and after prolonged heating (solution in toluene, 110 °C for 6 h). No isomerization towards the other conformer was observed. Compared with bisphenol 1, bis-triflate 3 displayed a much higher thermal stability for the biaryl axial isomerization, as no internal hydrogen bonding can take place between the two protected phenolic moieties of the biaryl unit. This behavior is indicative of the importance of a cyclized intermediate which can give access to a transition state with a low energy barrier for biaryl isomerization in order to achieve an efficient coupled transfer of helicity within a reversible bidentate coordinating species.
Figure 8.2. Comparison of 1H NMR spectra (CDCl3) of: a) interconverting atropisomers (S,M,Ra/Sa)-1 (see Chapter 5 for full assignment); b) isolated atropisomer (S,M,Sa)-3; c) isolated atropisomer (S,M,Ra)-3.
8.2.4 Metal-catalyzed phosphorylation
Initial investigation of NiCl2(dppe)-catalyzed double phosphination or phosphorylation reactions with either diphenylphosphine (Scheme 8.8a),92 diphenylphosphine-borane complex (Scheme 8.8a)93 or diphenylphosphine oxide (Scheme 8.8b)94 were conducted on (S,M,Ra)-3 by modified procedures previously reported for bis-triflate derivatives of BINOL. However, the tested conditions resulted in no conversion towards either bis-diphenylphosphine derivative 2 or bis-diphenylphosphineoxide derivative 4. Notably, substrate 3 was recovered in approximately 90% in all cases.
Scheme 8.8. Attempted NiCl2(dppe)-catalyzed phosphination and phosphorylation reactions of bis-triflate derivative (S,M,Ra)-3.
Our experiments suggest that the procedure successfully implemented on naphthalene derivatives cannot be extended to this less activated biphenyl substrate. We continued our endeavor by exploring the palladium-catalyzed phosphorylation of aryl triflates in combination with phosphine oxide reduction. Previously reported substituted BINAP and BIPHEP derivatives were synthesized via a four-step sequence of phosphorylation (1) - phosphine oxide reduction (2) - phosphorylation (1) - phosphine oxide reduction (2) (Scheme 8.9).38,95–97 As opposed to the Nickel-catalyzed processes, it appears that the first phosphine oxide group deactivates the single substituted intermediate towards a second phosphorylation step. Upon reduction of the phosphine oxide substituent, a second one can be subsequently installed. However, such alternative route via a four-step sequence would be detrimental for the final yield of target compound 2.
Scheme 8.9. Retrosynthetic analysis of bis(diphenylphosphine) derivatives via four-step sequence of
palladium-catalyzed phosphorylation (1) of aryl triflates and phosphine oxide reduction (2).
Each conformer of bis-triflate 3 was successfully submitted to palladium-catalyzed phosphorylation with diphenylphosphine oxide. Reactions were successfully conducted in presence of PdCl2(dppp) (dppp = bis(diphenylphosphino)propane) (Scheme 8.10a-b) or PdOAc2 and dppb (dppb = bis(diphenylphosphino)butane) (Scheme 8.10c) to yield the diphenylphosphino-triflate derivative 5 with
moderate to good yield.98 Theoretically, substitution of a single triflate substituent could provide two distinct regioisomers of the monophosphorylated biaryl derivative 5 (phosphine oxide on the upper ring and triflate on the lower, and vice versa), each as a mixture of two conformers (syn and anti). Notably, a common single isomer of the monosubstituted diphenylphosphine oxide-triflate product was obtained, regardless of the starting bis-triflate conformer. By comparison with the 1H NMR spectra of the starting materials, conformer (S,M,Ra)-5 was proposed as the obtained species. We hypothesized the opposite conformer to be much more sterically hindered. Therefore, upon prolonged heating necessary to achieve full conversion in the phosphorylation reaction, both conformers of 3 are transformed upon biaryl inversion into the same most stable isomer of product (S,M,Ra)-5, either during or after the palladium-catalyzed substitution. However, analysis with 2D-NMR techniques did not help to achieve full certainty about the actual substitution pattern and conformation of the analyzed isomer among the four possible species. Further investigation was not conducted due to interruption of the project (vide infra). On the other hand, the proposed structure of 5 is consistent with the mechanism of base-promoted degradation of triflate shown in Scheme 8.15 (vide infra).
Scheme 8.10. PdCl2(dppp)- and PdOAc2(dppb)-catalyzed phosphorylation reaction of bis-triflate 3 to diphenylphosphine oxide-triflate 5.
8.2.5 Phosphine oxide reduction
Following the precedent literature, we proceeded with the reduction of the mono-substituted phosphine oxide 5. Various conditions for phosphine oxide reduction of 5 were tested by modified procedures previously reported.99 We suspected an inconvenient sensitivity of the overcrowded alkene functionality of
5 towards harsh reductive conditions. Hence, we initially opted for a highly selective and mild phosphine
oxide reduction methodology previously tested in our group for an analogous phosphine derivative based on a first generation molecular motor.100 Beller and co-workers developed a highly chemoselective metal-free reduction of phosphine oxides to phosphines in the presence of catalytic amounts of specific
phosphoric acid esters and methyldiethoxylsilane HSiMe(OEt)2.101
Scheme 8.11. Tested conditions for the phosphine oxide reduction of (S,M,Ra)-5 to (S,M,Ra)-6.
Other reducible functional groups such as ketones, aldehydes, olefins, nitriles, and esters are well-tolerated under the reported optimized conditions. Basic workup with methanolic KOH was required to cleave the P-Si bond of the phosphonium cation after reduction with silane species to isolate the phosphine products. When such conditions were tested on 5 (Scheme 8.11a, Figure 8.3a), we observed major decomposition of the overcrowded alkene functionality (see also Chapter 7). Analysis of the crude before basic workup via 1
H/31P NMR spectroscopy (Figure 8.3a-b, Figure 8.4) showed 45% conversion of 5 (δP = 27.8 ppm) (Figure 8.3a and Figure 8.4a) to a different unidentified species (δP = 19.0 ppm) (Figure 8.3b and Figure 8.4b), which displayed phosphorus chemical shift not consistent with conventional phosphine ligands (0 ppm > δP > -20 ppm). We supposed this observed new species to be a phosphorus-silane adduct, which was also analyzed via 1H/31P NMR spectroscopy (Figure 8.3c and Figure 8.4c) after purification. The target reduced product diphenylphosphine-triflate 6 (δP = -12.9 ppm) was observed in the crude mixture only as minor component (Figure 8.3b-c and Figure 8.4b-c). We continued our screening by testing the conditions for deoxygenation of phosphine oxides using triphenylphosphine or triethylphosphite as an oxygen acceptor in presence of large excess of trichlorosilane, as reported by Spencer and co-workers.102 Reaction of 5 with triphenylphosphine resulted in no conversion of the substrate (Scheme 8.11b). On the other hand, reaction of 5 with triethylphosphite afforded product 6 in moderate yield (30%) together with an inseparable side-product (Scheme 8.11c), which appeared consistent with a by-side-product of tetrahydrofuranas suggested by 1H NMR analysis of the isolated fraction (not shown). Another methodology for reduction of phosphine oxides to phosphines uses a combination of titanium(IV) isopropylate and triethoxysilane, as reported by Lin and
co-workers in the synthesis of 4,4′-substituted-xylBINAP ligands.38 No basic workup was reported for such procedure, which was considered a promising approach to tackle the sensitivity to strong bases of the switch scaffold described hereto. However, we observed no conversion of the substrate when applied to 5 (Scheme 8.11d). Eventually, we tested a conventional reduction methodology with diisopropylethylamine and trichlorosilane in large excess.96 To our delight, very good selectivity was observed by analysis of the crude with 1H/31P NMR spectroscopy (Figure 8.3d and Figure 8.4d), which displayed high conversion (> 90%) of (S,M,Ra)-5 to (S,M,Ra)-6. The desired product was also obtained in good isolated yield (75%).
Figure 8.3. Comparison of 1H NMR spectra (CDC3) of: a) (S,M,Ra)-5; b) crude reaction mixture obtained after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing reduced phosphine components from previous mixture; d) isolated (S,M,Ra)-6 obtained after conditions indicated in Scheme 8.11e.
Figure 8.4. Comparison of 31P NMR spectra (CDCl3) of: a) (S,M,Ra)-5 (δP = 27.8 ppm); b) crude reaction mixture obtained after reduction conditions indicated in Scheme 8.11a; c) columned fraction containing reduced phosphine components (δP = 19.0 ppm and δP = -12.9 ppm) from previous mixture; d) isolated (S,M,Ra)-6 (δP = -12.9 ppm) obtained after reduction conditions indicated in Scheme 8.11e (with phosphoric acid as internal reference, δP = 0 ppm).
8.2.6 Attempted second metal-catalyzed phosphorylation
(S,M,Ra)-6 was subjected to the same conditions for palladium-catalyzed phosphorylation previously described for 3 (Scheme 8.12).98 Unfortunately, the reaction yielded the oxidized substrate diphenylphosphine oxide-triflate (S,M,Ra)-6 as major component. Oxidation of the substrate may have occurred due to the oxidative properties of DMSO or via oxygen exchange with diphenylphosphine oxide at high temperature. However, Spencer and co-workers reported that the latter pathway requires the presence of trichlorosilane, as employed in their phosphine oxide reduction methodology.102 The detrimental contamination of the reaction mixture with oxygen cannot be excluded either. Notably, no trace of the expected diphenylphosphine-diphenylphosphine oxide 7 was detected by 1H/31P NMR analysis. Such phenomenon suggests that the highly hindered structure of the designed bidentate ligand and the low reactivity of aryl triflate in metal-catalyzed substitution reactions may preclude the proposed synthetic route employed so far.
Scheme 8.12. Attempted conditions for PdOAc2(dppb)-catalyzed phosphorylation reaction of diphenylphosphino-triflate 6 to diphenylphosphino-diphenylphosphine oxide 7.
In Chapter 3 we demonstrated how even the switch central scaffold (e.g. 5,8-dimethylthiochromene upper half – fluorenyl lower half) plays an important role in the reactivity of their substituents. In the case described in fact, the copper-catalyzed aromatic Finkelstein reaction allowed to exchange a bromine atom for an iodine atom, incrementing significantly the conversion of the halogenated switch derivative in the palladium-catalyzed Buchwald-Hartwig coupling. Therefore, in an attempt to exclude the low reactivity of the triflate substituent of compound 6 towards the phosphorylation step among the plausible causes of its failed conversion to 7, a triflate-halogen exchange step was considered. Indeed, metal-catalyzed phosphorylation of aryl bromides and iodides is widely applied alternative methodology to synthesize phosphine-based ligands.103,104 Hayashi and co-workers reported a solid methodology for transformation of aryl triflates, alkenyl sulfonates and phosphates to aryl halides and alkenyl halides, respectively, by treating them with LiBr/NaI and [Cp*Ru(MeCN)3]OTf in dimethylimidazolinone (DMI). Aryl triflates undergo oxidative addition to a ruthenium(II) complex to form η1-arylruthenium intermediates, which are subsequently transformed to the corresponding halides. For comparison, bis-triflate 3, diphenylphosphine oxide-triflate 5, and diphenylphosphine-triflate 6 were treated according to the reported procedures. Bis-triflate (S,M,Ra)-3 was successfully converted to what was assigned as the bromide-Bis-triflate (S,M,Ra)-8 (full conversion, yield not determined, Scheme 8.13a), obtained by flash column chromatography together with large amount of not removable DMI. It should be noted how only the triflate group on the upper phenyl ring of the biaryl motif reacted to the tested conditions. On the other hand, diphenylphosphine oxide-triflate (S,M,Ra)-5 gave no conversion towards either the corresponding diphenylphosphine oxide-bromide (S,M,Ra)-9 or diphenylphosphine oxide-iodide (S,M,Ra)-10 (Scheme 8.13b). Lastly, diphenylphosphine-triflate 6 also gave no conversion towards the corresponding diphenylphosphine-iodide
(S,M,Ra)-11 (Scheme 8.13c). From the performed experiments, it appears that the triflate group on the lower phenyl
ring of the biaryl motif suffers from a general low reactivity towards metal-complex catalyzed substitution. This could be due to its hindered position, almost sandwiched between the upper biaryl substituent and the fluorenyl lower half of the switch module. The limited space may in fact not allow the catalyst to successfully approach the aryl-triflate bond, thus preventing the oxidative addition and eventually any sort of subsequent substituent exchange.
Scheme 8.13. Attempted conditions for [Cp*Ru(MeCN)3]OTf-catalyzed triflate-halogen exchange of bis-triflate 3, diphenylphosphine oxide-bis-triflate 5, and diphenylphosphino-bis-triflate 6 to their corresponding halogenated derivatives 8,9-10 and 11.
The synthesis of bis-diphenylphosphine ligand 2 was not accomplished according to the proposed synthetic route (Scheme 8.6). A different approach could have been considered, possibly installing the phosphine substituents on the biaryl unit before the creation of the overcrowded alkene function required for the photoresponsive properties. However, such approach would need a totally different synthetic sequence and would not exploit the already developed synthesis and chiral resolution of 2,2‘-bisphenol switch derivative
1 presented in Chapter 5. An alternative resolution strategy must be considered beforehand, for example via
formation of diastereoisomeric metal complexes of the target bisphosphine ligand with enantiopure reusable resolving reagent as very last step (Scheme 8.14).105–107
Scheme 8.14. Proposed resolution of 2 with stoichiometric formation of diastereoisomeric
8.2.7 Development of photoswitchable chiral Brønsted acid
At this phase of the research project, a very small timeframe was left. Among the limited amount of feasible options, we proposed to redirect the project goal to the development of a 2-diphenylphosphino-2‘-hydroxy-1,1‘-biphenyl-derived overcrowded alkene 12 as a switchable chiral Brønsted acid (Figure 8.5). Chiral Brønsted acid catalysis has been one of the growing fields in modern organic synthesis.108 Urea/thioureas,109TADDOL,110 and phosphoric acids111,112 have been widely used as catalysts in various asymmetric syntheses. Therefore, it would be interesting to extend the area of application of photoswitchable chiral catalyst to the field of Brønsted acid catalysis. Our design was inspired by the previously reported optically active (S)-2-hydroxy-2‘-diphenylphosphino-1,1‘-binaphthyl ((S)-HOP) and its derivatives, which were successfully applied in asymmetric catalysis either as free organocatalysts or as Lewis acid-assisted Brønsted acids (LBAs). Chen and co-workers described the application of 2-diphenylphosphino-2‘-hydroxy-1,1‘-biphenyl as bifunctional organocatalyst for aza-Morita-Baylis-Hillman (aza-MBH) reaction and domino reaction (aza-MBH followed by a Michael addition and aldol/dehydration reaction) between N-sulfonated imines and acrolein.113 Shi and co-workers reported the use of (S)-HOP and few of its functionalized derivatives as chiral phosphine Lewis bases in the catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins.114 The study revealed that the phosphine atom acted as a Lewis base to activate the Micheal acceptor, and the phenolic OH acted as a Lewis acid (BA) through intramolecular hydrogen bonding with the oxygen atom of carbonyl group to stabilize the in situ formed key enolate intermediate. In addition, the intramolecular hydrogen bonding between the phenolic OH and the nitrogen anion stabilized by the sulfonyl group can give a relatively stable or rigid transition state for achieving high enantioselectivity in the aza-Baylis-Hillman reaction. The same group later extended the catalytic methodology to a selection of chiral phosphine Lewis bases bearing multiple phenol groups and closely related to HOP.115 Yamamoto and co-workers developed a LBA derived from (S)-HOP with La(OTf)3 as a Lewis acid activator, which was applied to the catalytic enantioselective protonation reaction of silyl enol ether of 2-aryl cyclic ketones in the presence of methanol.116
Figure 8.5. Proposed design of photoswitchable chiral Brønsted acid 12, inspired by
phosphine-hydroxyl-biaryl Brønsted acid catalysts previously reported.
An alternative approach would be the synthesis of an analogue of the 2-(diphenylphosphino)-2‘-methoxy-1,1‘-binaphthyl ligand (MOP) developed by Hayashi and co-workers upon methylation of (S)-12.117
Having already developed a synthetic route to phosphorylated intermediate 5, we hypothesized to prepare
12 via hydrolysis of the unreacted triflate substituent and subsequent reduction of the phosphine oxide
group. The hydrolysis of 5 was attempted using sodium hydroxide, a strong inorganic base, according a modified procedure previously reported (Scheme 8.15).37
Scheme 8.15. Attempted conditions for hydrolysis of triflate substituent of 5 towards diphenylphosphine
oxide-hydroxyl derivative 15, which instead yielded the hypothesized by-products 16 and 16’ upon addition of generated phenolate anion to the overcrowded alkene bond, according to the illustrated proposed mechanism.
No conversion to the desired product 15 was observed as determined by NMR analysis of crude. Major decomposition of the switch functionality occurred as determined by 1H NMR spectroscopy (Figure 8.6). Complete hydrolysis of the triflate substituent was determined as observed by lack of any resonance peak in the 19F NMR spectrum. Notably, two sets of resonances with an approximate ratio of 70:30 were observed in the 1H/31P NMR spectra (Figure 8.6 and insert).
Figure 8.6. 1H NMR and 31P NMR (insert) spectra (CDCl3) of proposed atropisomers 16 and 16’ obtained after hydrolysis of 5.
We proposed a mechanism involving initial hydrolysis of the triflate group to the corresponding phenolate anion 13, followed by biaryl axial inversion and addition of the hydroxyl substituent to the upper carbon atom of the overcrowded alkene bond to afford a tetracyclic anion intermediate 14 with a fluorenyl substituent on the tetrasubstituted carbon of the newly formed pyranyl ring. Upon acid workup, the
carbanion located on the position 9 of the fluorenyl substituent is then protonated to give a mixture of two atropisomeric by-products 16 and 16’ (the sets of NMR resonances were not assigned to the corresponding isomers). The driving force of such an unexpected decomposition mechanism is proposed to be the decrease of steric hindrance and loss of torsion strain experienced by the overcrowded alkene bond, which is consequently transmitted to the whole structure via tight coupled transfer of helicity. Moreover, the fluorenyl anion substituent of 18 is expected to be highly energetically favored due to the aromatic electronic configuration (14 electrons). In a comparative experiment, the same procedure described for the attempted hydrolysis of 5 to 15 was applied to the deprotonation of bisphenol 1 and hydrolysis of bis-triflate 3, respectively, affording in either case 19 upon reaction with sodium hydroxide (Scheme 8.16) or potassium hydroxide.
Scheme 8.16. Decomposition of compounds 1 and 3 towards 19 upon reaction with sodium hydroxide.
Side: structural view of proposed most stable conformer of 19.
The same single set of absorptions was observed in the 1H NMR spectrum. No resonance was observed in the 19F NMR spectra of the crude obtained from reaction with 3. A common product as assigned to structure 19 was suggested to be similarly obtained, after hydrolysis of triflate groups in case of 3, via addition of phenolate anion to the alkene bond according to an analogous mechanism. Notably, unlike the decomposition of 5, a single species was observed by 1H NMR analysis after reaction of 1 or 3 (Figure 8.7).
Figure 8.7. 1H NMR spectra (CDCl3)of product of obtained after treatment of 1 or 3 with strong inorganic bases.
The characteristic resonances that support the proposed structure of 19 are the singlet at δ = 3.70 ppm, assigned to the dibenzylic proton (Ha) in position 9 of the fluorenyl substituent, and the singlet at δ = 4.67 ppm, assigned to the single phenolic proton (Hb). Notably, the doublets at δ = 8.03 ppm and δ = 5.86 ppm were assigned, respectively, to the aromatic protons in the positions 1 (Hc) and 8 (Hd) of the fluorenyl substituent. The chemical shift of their absorption resonances were justified according to their distinctive position relative to the central tetracyclic unit and consequent unusual magnetic environment. In particular, it should be noted how the proton Hd is nearly facing the delocalized electronic orbital of the lower phenol ring of the biaryl unit, thus experiencing a strongly shielding effect which lowers its chemical shift below the expected range of common aromatic protons.
We proposed to circumvent issue of the instability of such phenol derivatives to strong bases by avoiding the need of hydrolysing the unreacted triflate group. Upon careful dosage of triflic anhydride, we proposed to convert bisphenol derivative 1 to a singly substituted triflate-hydroxyl derivative, which could be singly phosphorylated without need of protecting the second phenol functionality. However, the reaction of (R,P,Sa/Ra)-1 in such conditions (Scheme 8.17) yielded a mixture of two proposed rotamers of the product in a ratio of 65:35, as analyzed by 1H/19F NMR spectroscopy.
Scheme 8.17. Synthesis of conformers of triflate-hydroxyl derivative 20 from 1 (or proposed alternatively
substituted derivatives 21).
The structure of the observed species were assigned to conformers (R,P,Sa)-20 and (R,P,Ra)-20, respectively, which feature the same substitution pattern of the biaryl unit but opposite biaryl axial chirality. Such assignment was proposed by comparison of the 1H NMR spectra of substrate 1 (Figure 8.8a) with the singly triflate-substituted products 20 (Figure 8.8b) and the corresponding isolated bis-triflate conformers 3 (Figure 8.8c-d), similarly to the previous cases (vide supra). However, a different regioisomeric structure
21 featuring opposite substituent position on the biaryl unit could also be consistently proposed. Notably,
the same ratio of conformers was observed in the starting material 1 and in the obtained product 20. This could suggest that species 1 and 20 feature an equal difference in free energy between the corresponding conformers (R,P,Sa) and (R,P,Ra). On the other hand, the substitution of the hydroxyl groups with non-coordinating substituents (e.g. via hydrogen bonding) could in fact quench the biaryl axial isomerization, thus fixing the ratio of the conformers displayed in 1 up to the derivatives 20 and 3. Interestingly, CSP-HPLC analysis of the atropisomeric mixture of 20 displayed two sharp elution peaks, which may suggest that no interconversion occurs between the two isomers at the tested analytical conditions. Moreover, when a sample of the latter was subjected to EXSY experiment at 60 °C in CDCl3 to possibly observe a rapid interconversion of the two coexisting species of 20, no exchange of excited resonance peaks was observed,
which corroborates the lack of exchange between the two proposed atropisomeric structures even at slightly higher than ambient temperatures. Such behavior is very different from what was observed for 1 (see Chapter 5). This phenomenon could be explained via two hypotheses: 1) the energy barrier for biaryl axial inversion of conformers 20 is higher than for 1 (see Chapter 5 for details) and could not be observed at the applied conditions, as it would require higher temperatures; 2) the obtained product is a mixture of a single conformer of 20 and 21, respectively, which are coincidentally also stable to biaryl axial inversion at such conditions. However, the latter hypothesis seemed less likely. Regardless, no further investigation was conducted to elucidate such point as it was not the main goal of the project.
Figure 8.8. Comparison of 1H NMR spectra (CDC3) of: a) (R,P,Sa/Ra)-1; b) mixture of conformers (R,P,Sa
)-20 and (R,P,Ra)-1; c) (S,M,Sa)-3; d) (S,M,Ra)-3.
The isolated mixture of conformers of 20 was submitted to the same conditions for palladium-catalyzed phosphorylation previously described for 5 (Scheme 8.18). Unfortunately, the expected diphenylphosphine-hydroxyl derivative 15 was not observed, while substrate 20 was not recovered. In fact, the reaction yielded a complex mixture of by-products that could not be clearly identified even after 1H/19F/31P NMR analysis of the various fractions obtained after column chromatography. Two early fractions displaying a single 19F NMR resonance absorption were lacking of the overcrowded alkene functionality resonances in the 1H NMR spectra and of any 31P NMR resonance absorption. The middle fraction, which displayed the
distinctive overcrowded alkene functionality resonances in the 1H NMR spectra and a single 19F NMR resonance absorption was lacking of any 31P NMR resonance absorption. The latter fraction, which displayed five distinct 31P NMR resonance absorptions and a single 19F NMR resonance absorptions was lacking of any overcrowded alkene functionality resonances as observed in the 1H NMR spectra. In conclusion, the synthetic route towards the Brønsted acid 12 was not completed.
Scheme 8.18. Attempted synthesis of photoswitchable chiral Brønsted acid 12 via phosphorylation of 20
and consequent not tested phosphine oxide reduction of 15.
Due to the insurmountable complications encountered during the development of an effective switchable bisphosphine ligand or Brønsted acid catalyst based on a reversibly photo-responsive bifunctional overcrowded alkene, the venture of designing a novel phosphine-based catalyst for dynamic control of light-assisted synthetic transformations was interrupted.
8.3 Conclusions
This chapter describes the study towards a bidentate biaryl bis(diphenylphosphine) ligand based on an overcrowded alkene for photoswitchable asymmetric homogeneous metal-catalyzed transformation. The design of the system implies a reversible change of helicity of the overcrowded alkene central scaffold which produces a consequent inversion of helical and axial chirality of the biaryl unit. The absolute stereochemistry is overall governed by the fixed point chirality sited in the stereocenter of the molecular switch. An efficient coupled motion with effective inversion of the local chirality surrounding the coordinated metal center is envisioned to occur only in the bidentate metal-ligand complex. The formation of a seven-membered ring metallacyclic structure is key for lowering of the energy barrier for biaryl axial inversion, as such species was expected to have access to a transition state characterized by a lower energy if compared with the free ligand. We proposed a synthetic route of bisphosphine ligand 2 starting from 2,2‘-bisphenol functionalized molecular switch 1 previously described in Chapter 5. Derivatization of the bisphenol moiety to the corresponding bis-triflate 3 yielded a mixture of separable non-interconverting atropisomers. Initial unsuccessful tests were conducted according to nickel-catalyzed phosphination or phosphorylation methodologies previously reported for conventional binaphthyl-based scaffolds. The lower reactivity of the biphenyl bis-trilate unit of 3 required a more robust yet laborious multi-step approach comprising sequences of palladium-dppp/dppb-catalyzed phosphorylation and consequent phosphine oxide reduction. Both atropisomers of 3 yielded a single isomer of singly phosphorylated derivative 5, which was reduced to the corresponding diphenylphosphine-triflate 7 with trichlorosilane and ethyldiisopropylamine. No substitution of the second triflate moiety was achieved by following the conditions of the previously successful phosphorylation step. We attempted to enhance the reactivity of the lower leaving group via ruthenium-catalyzed triflate-bromide/iodide exchange. Unfortunately, no conversion of 7 was observed. We hypothesized that the steric hindrance around the lower triflate group caused by the molecular switch core interferes with the catalytic system, thus precluding any further transformation via metal-catalyzed substitution. The synthesis of the target bidentate ligand 2 was not accomplished. We proposed to redirect the goal of the project to the development of a chiral photoswitchable Brønsted acid catalyst 12 featuring diphenylphosphine and phenol functionalities on the biphenyl unit. Hydrolysis of the triflate group of 5
with strong inorganic bases resulted in loss of the overcrowded alkene motif, possibly via addition of the generated phenolate anion to the alkene bond to generate a tetracyclic structure. The same reactivity was observed for bisphenol 1 and bis-triflate 3. Our hypothesis implies an energetically favorable loss of steric strain and bond torsion that, unexpectedly, drives the addition of a phenolate to an alkene bond. Finally, we also proposed to synthesize 12 via palladium-catalyzed phosphorylation of the monotriflate derivative 20. However, this approach was found not fruitful, indicating a detrimental sensitivity of the phenol to tested conditions. This study describes a novel approach to a truly reversible photoswitchable chiral bidentate metal-complex. Notably, application of an externally triggered multistate chiral catalyst in tandem catalysis is still an undisclosed achievement. Our investigation provides valuable insight into the requirements for the design of more effective and complex responsive systems, which may allow the photocontrol of catalyst activity and selectivity in multicomponent reactions. Key to the successful development of these future catalysts will be a deeper understanding of the compatibility of ancillary functional groups with the stability of the overcrowded alkene functionality and the introduction of more reactive substituent to ensure higher versatility during the catalyst development and synthesis.
8.4 Experimental section
8.4.1 General methods
General experimental details can be found in Chapters 5 and 6.
8.4.2 Synthetic procedures
(1R,7S)-8-(9H-fluoren-9-ylidene)-7-methyl-1-(2-(((trifluoromethyl)sulfonyl)oxy)phenyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (3).
A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. A solution of 2,2‘-bisphenol derived switch (S,M)-1 (400 mg, 0.96 mmol) in dry CH2Cl2 (4 mL) was injected under nitrogen. To this solution was added dry pyridine (0.21 mL, 2.60 mmol, 2.7 equiv), followed by triflic anhydride (0.34 mL, 2.02 mmol, 2.1 equiv) slowly at 0 °C . The reaction mixture was stirred at 0 °C for 3 h, at which time TLC indicated that the reaction was completed. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed subsequently with aq. 1 M HCl (10 mL), aq. 1 M NaHCO3 (10 mL), and brine (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The product was purified by column chromatography (SiO2, pentane:CH2Cl2 = 5:1 to 1:1) to yield bis-triflate 3 (570 mg, 0.83 mmol, 86%) as a 40:60 mixture of stable atropisomers as a yellow foam. The isolated early fractions were assigned to pure (S,M,Ra)-3 (190 mg, 0.28 mmol, 29%). The middle fractions were assigned to a mixture of (S,M,Ra)-3 and (S,M,Sa)-3. The isolated later fractions were assigned to pure (S,M,Sa)-3 (300 mg, 0.44 mmol, 46%). (S,M,Ra)-3 (early fraction): Rf: 0.82, pentane:CH2Cl2 = 5:1. m.p. 171.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.73–7.57 (m, 3H), 7.55 – 7.44 (m, 2H), 7.34–6.99 (m, 8H), 6.83 (ddd, J = 8.2, 6.5, 2.1 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 3.96 (h, J = 7.3 Hz, 1H), 2.76 (dt, J = 15.8, 4.2 Hz, 1H), 2.51–2.32 (m, 2H), 1.36–1.18 (m, 1H), 1.27 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 146.6, 146.5, 142.9, 142.9, 140.7, 140.6, 139.8, 138.7, 137.8, 136.4, 133.2, 130.4, 129.3, 128.4, 128.0, 127.9, 127.2, 127.0, 126.7, 126.6, 124.9, 124.5, 121.3, 120.1, 119.7, 119.5, 118.4 (q, J = 319.9 Hz), 118.3 (q, J = 319.9 Hz), 35.3, 31.8, 29.2, 20.3. 19F NMR (282 MHz, CDCl3) δ -74.15, -74.58. HRMS (ESI, m/z): calcd for C32H23F6O6S2 [M+H]+
: 681.0835, found: 681.0830. (S,M,Sa)-3 (later fraction): Rf: 0.65, pentane:CH2Cl2 = 5:1. m.p. 174.8 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 6.7, 1.9 Hz, 1H), 7.56 (dd, J = 6.7, 1.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 8.1, 1.9 Hz, 1H), 7.30–7.22 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.08–7.03 (m, 1H), 7.00–6.90 (m, 3H), 6.67 (d, J = 7.9 Hz, 1H), 4.16 (h, J = 7.2 Hz, 1H), 2.82–2.72 (m, 1H), 2.53–2.40 (m, 2H), 1.43 (d, J = 6.9 Hz, 3H), 1.31–1.19 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 148.7, 146.4, 143.1, 140.9, 140.5, 139.9, 139.2, 137.8, 137.2, 136.4, 133.2, 130.2, 129.6, 128.9, 128.0, 127.7, 127.2, 127.0, 126.0, 125.4, 124.6, 123.9, 121.7, 119.7, 119.1, 119.0, 118.4 (q, J = 319.9 Hz), 118.4 (q, J = 319.9 Hz), 34.4, 30.8, 29.2, 21.9. 19F NMR (376 MHz, CDCl3) δ -74.08, -74.23. HRMS (ESI, m/z): calcd for C32H23F6O6S2 [M+H]+: 681.0835, found: 681.0830.
2-((1R,7S)-2-(diphenylphosphoryl)-8-(9H-fluoren-9-ylidene)-7-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)phenyl trifluoromethanesulfonate (5).
Diphenylphosphine oxide-triflate 5 was prepared from 3 by a modified procedure previously reported.98 A flame-dried Schlenk tube was equipped with vacuum/nitrogen stopcock and a magnetic stirring bar. In a glovebox, the Schlenk tube was charged with bis-triflate (S,M,Ra)-3 (90 mg, 0.132 mmol), diphenylphosphine oxide (110 mg, 0.530 mmol, 4 equiv) and dichloro[1,3-bis(diphenylphosphino)propane]palladium(II) [PdCl2(dppp)] (15.6 mg, 0.026 mmol, 0.2 equiv). The Schlenk tube was removed from the glovebox and attached to a nitrogen line. Dry dimethyl sulfoxide (1 mL) and diisopropylethylamine (0.122 mL, 0.793 mmol, 6 equiv) were added by syringe. The mixture was heated with stirring at 110 °C for 24 h. After being cooled to room temperature,
