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 3
Chapter 3
Bifunctional Molecular Photoswitches based on
Overcrowded Alkenes for Dynamic Control of
Catalytic Activity in Michael Addition Reactions
The emerging field of artificial photoswitchable catalysis has recently shown striking examples of functional light-responsive systems allowing for dynamic control of activity and selectivity in organocatalysis and metal-catalyzed transformations. While our group has already disclosed systems featuring first generation molecular motors as the switchable central core, a design based on second generation molecular motors is lacking. Herein, the syntheses of two bifunctionalized molecular switches based on a photoresponsive tetrasubstituted alkene core are reported. They feature a thiourea substituent as hydrogen-donor moiety in the upper half and a basic dimethyl amine group in the lower half. This combination of functional groups offers the possibility for application of these molecules in photoswitchable catalytic processes. The light-responsive central cores were synthesized via a Barton-Kellogg coupling of the prefunctionalized upper and lower halves. Derivatization via Buchwald-Hartwig amination and subsequent introduction of the thiourea substituent afforded the target compounds. Control of catalytic activity in the Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione is achieved upon irradiation of stable-(E) and stable-(Z) isomers of the bifunctional catalyst 1. Both isomers display a decrease in catalytic activity upon irradiation to the metastable state, providing systems with the potential to be applied as ON/OFF catalytic photoswitches.
This chapter has been published as: S. F. Pizzolato, B. S. L. Collins, T. van Leeuwen, B. L. Feringa, Chem.
3.1 Introduction
3.1.1 Photocontrol of catalytic functions
External control of catalytic systems by light is a highly challenging and still underdeveloped field of modern organic chemistry. In the quest for responsive catalytic systems, many advantages arise from the use of light as a clean, non-invasive stimulus, where judicious choice of irradiation wavelength may allow precise control over catalyst function, activity and selectivity. A number of photoresponsive catalysts have been developed over the last decade, exploiting the established switching properties of azobenzenes, diarylethenes and overcrowded alkenes.1–5 Promising results in photochemical control of catalyst activity or selectivity have been achieved via different approaches by harnessing cooperative,6–12 steric13–20 and electronic effects21–25 of the photo-accessible isomers.
For instance, Hecht and co-workers developed a series of photoswitchable catalysts, based on a 3,5-disubstituted azobenzene core featuring a piperidine base, in which the modulation of steric shielding was used to control catalytic activity (Scheme 3.1a).16 Upon photoswitching, the basic piperidine nitrogen atom is exposed in the (Z)-isomer, allowing enhancement of rate of the aza-Henry reaction of nitroethane to p-nitroanisaldehyde compared to the (E)-isomer (kZ/kE = 35.5). Rebek and co-workers introduced a
light-responsive cavitand/piperidinium complex that displayed switchable catalytic activity for the Knoevenagel condensation of aromatic aldehydes with malonitrile.17 The cavitand features an azobenzene arm capable of competing with the piperidinium ion for the cavity when irradiated with UV light, allowing reversible control of the guest binding and reactivity. Imahori and co-workers reported a bis(trityl alcohol)-substituted azobenzene as a cooperative bifunctional switchable catalyst capable of reversible activity control when applied to a Morita–Baylis–Hillman reaction of 3-phenylpropanal and 2-cyclopenten-1-one.10 The switchable catalyst was able to increase the yield of the reaction after 2 h (background, 27%) from 37% using the less active state (E)-isomer to 78% yield using the more active (Z)-isomer. Pericás and co-workers developed a switchable azobenzene-thiourea organocatalyst, which was used to achieve control of Michael addition reactions through reversible hydrogen-bond shielding of the catalytic unit, enabled by a nitro group as the blocking moiety.20 The (E)-isomer effectively catalyzes the Michael addition of 2,4-pentanedione to (E)-3-bromo-β-nitrostyrene (full conversion was achieved after 19 h), while the photogenerated (Z)-isomer, in which the nitro group engages in hydrogen bonding interactions with the thiourea moiety, leads to a significantly lower reaction rate (only 23% conversion after 20 h). Chen and co-workers developed a pseudo-enantiomeric pair of optically switchable helicenes containing a catalytic 4-N-methylaminopyridine (MAP).26 Successful application was found in the enantiodivergent Steglich rearrangement of O- to C-carboxylazalactones, with formation of either enantiomer with up to 91% ee (R) and 94% ee (S), respectively. Branda and co-workers developed various systems for exploiting the characteristic switching of structural and electronic properties of diarylethenes to allow for instance for control of Lewis acidity/basicity,27,28 stereoselectivity8 and substrate reactivity,29–33 Other approaches, including the application of photoresponsive systems for controlling the rate of ring-opening polymerizations,24,34–36 are summarized in comprehensive recent reviews.1–5
Our group demonstrated stimuli-responsive control of the activity and enantioselectivity of a catalyst via dynamic conformational changes of a first generation molecular motor equipped with two functional groups able to cooperatively accelerate a reaction (Scheme 3.1b; for the switching process of the main core, see Scheme 3.2a).9 The two pseudo-enantiomeric (Z)-isomers of the molecular motor during its rotary cycle were shown to control the stereochemical outcome of an organocatalytic thiol 1,4-addition, allowing access to both enantiomers of the product depending on the state of the catalyst. This organocatalyst bears a 2-aminopyridine base and a weakly acidic thiourea functionality, which were proposed toengage in bidentate coordination of the substrates, leading to both accelerated reaction rates and high levels of stereocontrol. Subsequently we extended the application of this concept to an organocatalyzed Henry reaction upon structural modification of the chiral catalyst, improving its versatility and efficiency through a more constrained catalytic pocket.12
Scheme 3.1. a) Photoswitchable azobenzene-based piperidine as light- and heat-triggered catalyst to achieve rate control of Henry reaction via reversible steric shielding of basic/nucleophilic site. b) Photoswitchable overcrowded alkene-based light- and heat-triggered thiourea-DMAP bifunctional catalyst to achieve control of rate and enantioselectivity in a Michael addition reaction via reversible E-Z photoisomerization and thermal helix inversion.
Furthermore application of dynamic control of chirality with responsive phosphine ligands for palladium-catalyzed enantioselective allylic substitution was demonstrated.37 A similar chiral first generation molecular motor scaffold was recently exploited in a light- and heat-responsive bis-urea receptor capable of multi-state regulation of dihydrogen phosphate ion binding affinity.38 A major difference in binding affinity of the interchangeable isomers was observed, enabling external control of substrate binding by the dynamic host.
3.1.2 Unique features of molecular motors
Having established the potential of molecular motors39–42 as multiple switching elements in dynamic chemical systems for stereoselective catalysis and anion recognition, we engaged in the challenge of developing a prototype for a responsive bifunctional organocatalyst43–47 based on the second generation molecular motor core. Unlike the first generation molecular motor (Scheme 3.2a),48 the second generation motor structure features non-identical upper and lower halves, in which the upper half contains the sole stereogenic center of the molecule (Scheme 3.2b).49–54 Upon irradiation with UV-light the central stilbene-type alkene can undergo a photochemical E-Z isomerization that yields a metastable (MS) diastereoisomer (top/right structures), which holds the opposite helical chirality to the original stable (St) diastereoisomer (top/left structures). The metastable species can subsequently undergo a thermally activated isomerization in which the upper half moves along the lower half, again resulting in an inversion of helicity, namely thermal helix inversion (THI).50 In the resulting stable isomer (bottom/right structures), the upper half has undergone a 180° rotation with respect to the lower half.
Scheme 3.2. Isomerization processes leading to unidirectional rotation in: (a) first generation molecular motor stage cycle with four distinctive stereoisomers); (b) second generation molecular motor (four-stage cycle with only two distinctive stereoisomers in case of symmetrically substituted lower half). St = stable isomer, MS = metastable isomer.
In our previous study we showed that the combination of a 5-membered ring in the lower half (fluorene) with a sulfur containing 6-membered ring in the upper half (5,8-dimethylthiochromene and benzo[f]thiochromene) resulted in distinctive high energy activation barriers for the thermal relaxation step in the rotary cycle of the second generation molecular motors and consequently long half-lives of the metastable species.50,55 More precisely, the THI energy barrier dramatically increases due to the high conformational constraints, resulting in an alternative and predominant thermal relaxation process, known as thermal E-Z isomerization (TEZI) (for 5,8-dimethylthiochromene: Δ‡G°THI (100 °C, 1 atm) = 138 kJ・ mol−1, Δ‡G°TEZI (100 °C, 1 atm) = 129 kJ・mol−1,t½ (20 °C, 1 atm) = 75 years; for benzo[f]thiochromene: Δ‡G°THI (100 °C, 1 atm) = 140 kJ・mol−1, Δ‡G°TEZI (100 °C, 1 atm) = 129 kJ・mol−1,t½ (20 °C, 1 atm) = 4300 years). We demonstrated that these overcrowded alkene systems could be used as thermally highly stable and selective photoswitchable bistable systems, both important requirements for reliable photoresponsive catalysts, where each state should be selectively addressable with a high photostationary state (PSS) ratio while remaining stable over time.
An interesting aspect of the second generation molecular motor scaffold is the possibility of functionalizing the otherwise symmetrical lower half with two different catalytically active moieties (depicted as A and B in Scheme 3.3), which could dynamically cooperate with the single functionality (C) on the upper half. Through this design two distinct bifunctional catalytic pairs could be accessed. Notably these two pairs of catalytic functional groups would also be addressed with two opposite helical chirality, P or M, upon irradiation and thermal relaxation. We envision such a design as a feasible future route for stimuli-responsive switchable catalysts in multi-tasking systems and one-pot multi-step diastereo- and enantioselective reactions.2–4,9,37,56–60
Scheme 3.3. Proposed design of a trifunctional light- and heat-responsive organocatalyst for diastereo- and enantioselective one-pot multi-step systems. The catalyst is envisioned to be switchable between four different states, each displaying a different combination of active cooperative catalytic pair (AC or BC) and helicity (P or M). In the scheme are displayed only two of the four possible products accessible by combining three starting components (depicted as geoometrical shapes) in a chemo- and enantioselective fashion (suggested handedness of the newly generated stereogenic centers indicated on the connecting bond). By triggering the proper catalyst states, both enantiomers of each diastereoisomer could be accessed.
While the ultimate goal remains the syntheses of tri-functionalized bistable switches and their use as catalysts in one-pot multistep reactions, initial studies have focused on the feasibility of introducing well-established catalytic functional groups onto the overcrowded alkene scaffold found in second generation molecular motors. Herein we report the first syntheses of two bifunctional molecular switches 1 and 2 based on the second generation molecular motor scaffold (Figure 3.1a). Featuring catalytic functions, each switch was obtained both as (E)- and (Z)-stereoisomers (only (E)-isomer shown). Related to analogous examples,9,16 these switches may allow for dynamic control of activity as ON/OFF or OFF/ON catalysts (Figure 3.1b). Moreover, the present preliminary study is a stepping stone for future synthesis of more complex trifunctionalized photoswitchable catalysts for multi-step synthesis (see Scheme 3.3).
3.2 Results and discussion
3.2.1 Design
In order to address high switching performance and thermal stability, the aforementioned bistable switch core was chosen (thiopyran upper half – fluorene lower half, Figure 3.1a).
Figure 3.1. (a) Bifunctional molecular switches 1 and 2 ((Z)-isomers omitted). (b) General scheme for photoswitching of bifunctional catalyst and potential application as an OFF/ON catalyst. c) Retrosynthetic analysis of 1 and 2.
Our prototypes feature a thiourea substituent in the upper half, a well-established hydrogen-donor moiety in organocatalysis,47,61,62 and a basic dimethyl amine group in the lower half. These functionalities were chosen to reflect commonly encountered functional groups within the field of organocatalysis47,62–68 and to avoid synthetic compatibility issues associated with the Barton-Kellogg coupling,69,70 the signature synthetic step for this family of overcrowded alkenes. The reaction conditions required to synthesize the thioketone and diazo coupling partners (Figure 3.1c) impose challenges to the synthetic design. For instance, the established methodology commonly adopted to generate the thioketone includes the use of Lawesson‘s reagent or P4S10 at high temperatures for prolonged reaction times, which may cause problems with other functionalities present in the molecule. In line with these considerations, we chose to install a dimethylamine substituent in the lower half, which is expected to tolerate the conditions for thioketone formation. On the other hand, the more sensitive thiourea motif in the upper half is to be installed after the construction of the tetrasubstituted alkene and amination of the upper half via a Buchwald-Hartwig coupling (Figure 3.1c).71
3.2.2 Synthesis
The synthesis of (E)-1 and (Z)-1 is outlined in Schemes 3.4 and 3.5. The lower half coupling partner was synthesized from commercially available 2-aminofluorene (Scheme 3.4). Methylation of the aniline moiety via reductive amination with formaldehyde and sodium cyanoborohydride provided 3 (89%). Oxidation of
the fluorene was then achieved under an atmosphere of air using the trialkyl ammonium salt Triton B as a catalyst in pyridine (89%). Fluorenone 4 was converted into the reactive thioketone 5 via thionation with P4S10 in moderate yield (33%), where experimental observations indicate a subtle balance between conversion of starting material and decomposition of product in this step, both highly dependent on temperature and reaction time.
Scheme 3.4. Synthesis of lower half of switches 1 and 2.
The synthesis of the upper half started from commercially available 2-bromo-1,4-dimethylbenzene (Scheme 3.5). By reacting with chlorosulfuric acid, the aryl halide was first converted to the corresponding arylsulfonyl chloride 6 (90%). Subsequent reduction with zinc powder and sulfuric acid provided a 1.0:0.6 mixture of 4-bromo-2,5-dimethylbenzenethiol 7 and the corresponding disulfide, respectively (82% overall), which was converted quantitatively to pure 7 by reduction with sodium borohydride. A 1,4-addition reaction with methacrylic acid afforded the sulfide 8 (38%). The thiopyranone ring was finally constructed via a two-step procedure from acid 8 via conversion to the more reactive acyl chloride with oxalyl chloride followed by intramolecular Friedel-Crafts acylation to afford 9 (93%). All steps could be performed on gram-scale with an overall yield of 26% over five steps from commercial starting material.
Scheme 3.6. Synthesis of molecular switches (E)-1 and (Z)-1. Note: (E)-13 and (Z)-13 were assigned via the 1H NMR chemical shifts of the absorption peaks corresponding to the dimethylamine substituent and the protons in position 1 or 8 on the fluorenyl lower half in line with previously reported analogous second generation molecular motor scaffolds (see Experimental section for further details).
Ketone 9 was converted to the corresponding hydrazone 10 (42%) via condensation with hydrazine monohydrate (Scheme 3.6). The hydrazone 10 could be transformed into the required diazo coupling partner 11 for the Barton-Kellogg coupling reaction via rapid in situ oxidation at low temperature with [bis(trifluoroacetoxy)iodo]-benzene. Reaction with thioketone 5 yielded a mixture of episulfides, (E)-12 and (Z)-12, which were readily converted via desulfurization with triphenylphosphine to the overcrowded alkenes (E)-13 and (Z)-13. The two isomers could be separated by flash column chromatography to provide (E)-13 and (Z)-13 in 35% and 21% yield, respectively, starting with hydrazone 10. The geometry of isomers (E)-13 and (Z)-13, obtained in their stable states only, was assigned on the basis of the 1H NMR chemical shifts of the absorptions corresponding to the dimethylamine substituent and the protons in position 1 or 8 on the fluorenyl lower half (highlighted in Scheme 3.6) in line with previously reported analogous second generation molecular motor scaffolds (for example: St-(E)-13, δ (-NMe2) = 3.07 ppm, St-(Z)-13, δ (-NMe2) = 2.69 ppm; St = stable form; see Experimental section for further details). Initial attempts to install the benzophenone imine moiety on bromides 13 via Buchwald-Hartwig amination failed, with no detectable conversion even after prolonged reaction times. A halide exchange to the iodide species before the Buchwald-Hartwig reaction, however, allowed us to successfully continue the synthesis. Bromides (E)-13 and (Z)-13 were converted separately via aromatic Finkelstein reaction to the corresponding iodides (E)-14 and (Z)-14 using a combination of copper iodide and potassium iodide. High
temperatures and long reaction times were required, providing (E)-14 in good yield (90%) and (Z)-14 as a mixture of product and unconverted bromide starting material ((Z)-14:(Z)-13 = 8:1, 48%). The more reactive iodide species were then submitted to the Buchwald-Hartwig amination reaction using a palladium(II) acetate – 1,1‘-bis(diphenylphosphino)ferrocene catalytic system to install the benzophenone imine moiety ((E)-15: 36%, (Z)-15: 63%). After hydrolysis to the free amine 16 ((E)-16: 80%, (Z)-16: 91%), nucleophilic addition to 3,5-bis(trifluoromethyl)phenyl isothiocyanate afforded the target thiourea-functionalized switches ((E)-1: 85%, (Z)-1: 90%).
The related switches (E)-2 and (Z)-2 were synthesized via an analogous route starting from 6-bromo-2-naphthol as shown in Schemes 3.7 and 3.8.
Scheme 3.7. Synthesis of the upper half of molecular switch 2 from commercial starting material in 70% yield over five steps.
Scheme 3.8. Synthesis of molecular switches (E)-2 and (Z)-2. 3.2.3 Photoswitching process
The switching properties of (E)-1, (Z)-1, (E)-2 and (Z)-2 were monitored by UV-vis absorption spectroscopy (Figure 3.2) and 1H NMR spectroscopy (illustrated for (E)-1 in Figure 3.3 and (Z)-1 in Figure 3.4, vide infra). Solutions of stable (E)-1, (Z)-1, (E)-2 and (Z)-2 in tetrahydrofuran (1.0-2.0·10−5 M) in 1 cm quartz cuvettes were irradiated at room temperature under stirring for a few minutes towards the metastable state using UV light ((E)-1 and (Z)-1, 312 nm; (E)-2 and (Z)-2, 365 nm). The photochemical E-Z isomerizations were found to be characterized by clear isosbestic points, indicating the absence of side-reactions. All four switches exhibited a decrease in intensity of the absorption bands at 300–350 nm upon irradiation at 312 nm or 365 nm and the appearance of a new absorption band in the region 350–480 nm, characteristic of the generated metastable isomers. The metastable isomers were shown to be highly thermally stable, exhibiting no degradation or back-isomerization upon standing at room temperature for extended periods of time.
The PSS ratios for all four switches were determined using 1H and 19F NMR spectroscopy. In a general procedure, the compound (approximately 0.5 mg) was dissolved in CD2Cl2 (0.7 mL) and the sample was irradiated in an NMR tube at 312 nm at room temperature. The isomerization process was monitored over time by means of 1H NMR spectroscopy (see Figure 3.3 for St-(E)-1). No further changes were observed after 15 min of irradiation. Both isomers, St-(E)-1 and MS-(Z)-1 were assigned using two dimensional COSY and NOESY NMR experiments (see Experimental section for further details). The relative
integration of the absorptions of the two isomers revealed a PSS ratio (312 nm) in CD2Cl2 of St-(E)-1:MS-(Z)-1 = 18:82.
Figure 3.15 UV-vis spectra of the switching process of 1 and 2. Experimental UV-vis absorption spectra in black of stable forms of (E)-1, (Z)-1, (E)-2, and (Z)-2 (THF, 1.0–2.5·10−5 M). Irradiation of (E)-1 (312 nm), (Z)-1 (312 nm), (E)-2 (365 nm), and (Z)-2 (365 nm) to the metastable isomers affords a PSS shown in darl gray with five intermediate moments in the process (total irradiation time: 5-10 min) shown in light gray (St:MS ratio: (E)-1, 18:82; (Z)-1, 10:90; (E)-2, 20:80; (Z)-2, 16:84, ratios as determined by 1H and 19F NMR spectroscopy in CD2Cl2, vide infra). Similar results were also obtained when CH2Cl2, toluene or acetonitrile were used as solvent.
Figure 3.3. (a) 1H NMR spectra of St-(E)-1 (approximately 0.5 mg in CD2Cl2, 0.7 mL), with magnification of corresponding 19F NMR spectra as inserts. (b) 1H NMR spectra after irradiation with 312 nm light of St-(E)-1 to the metastable state MS-(Z)-1 affords a PSS mixture of St-St-(E)-1:MS-(Z)-1 = 18:82, with magnification of corresponding 19F NMR spectra. Spectral region ofsolvent residual peak (5.30–5.10 ppm) cut for clarity.
An analogous experiment with St-(Z)-1 was performed (Figure 3.4). A PSS ratio of St-(Z)-1:MS-(E)-1 = 10:90 was achieved after irradiation at 312 nm in CD2Cl2 for 15 min.
Figure 3.4. (a) 1H NMR spectra of St-(Z)-1 (approximately 0.5 mg in CD2Cl2, 0.7 mL), with magnification of corresponding 19F NMR spectra as inserts. (b) 1H NMR spectra after irradiation with 312 nm light of (Z)-1 to the metastable state MS-(E)-(Z)-1 affords a PSS mixture of St-(Z)-(Z)-1:MS-(E)-(Z)-1 = (Z)-10:90, with magnification of corresponding 19F NMR spectra. Arrows indicate absorption peaks of corresponding hydrogen atoms in St-(Z)-1 and MS-(E)-1.
Comparable results were obtained for St-(E)-2 and St-(Z)-2, affording, upon irradiation with 365 nm light, a PSS ratio of St-(E)-2:MS-(Z)-2 = 20:80 and St-(Z)-2:MS-(E)-2 = 16:84, respectively (see Experimental section for further details). Interestingly, irradiation at longer wavelength (395 nm for 1 and 420 nm for 2) gave PSS mixtures consisting mostly of the metastable isomer,72 even though this isomer absorbs more strongly at these wavelengths, and led to no, or minimal, change in the UV-vis spectra.73 Similar results were also obtained when dichloromethane, toluene or acetonitrile were used as solvent. Notably, the corresponding unfunctionalized molecular switches constituting the light-responsive core of 1 and 2 have been shown to undergo efficient reversible switching with 312/365 nm and 420/450 nm light over multiple cycles with no evidence of fatigue.55 Moreover, the thiourea moiety was present in our previous successful examples of functionalized molecular motors employed in photoresponsive catalytic and anion binding systems.9,12,38 From a parallel series of irradiation tests performed on compounds 13, 16 and 28 (an analogous compound of 13 lacking the amine moiety in the lower half) (Figure 3.5), the reduced photoswitching behavior appears to arise due to the detrimental influence of the dimethylamine substituent. Compound 28 was in fact the only compound in this study which displayed efficient reversible photo-isomerization (see Experimental section for further details).
Figure 3.5. The different intermediates or substructures of target compound 1 studied to investigate the role of the amine substituents in the reversibility of the photoswitching process.
This lack of reversible switching considerably reduces the possibility of using these switches as efficient reversible ON/OFF catalysts and future studies will aim to discern what functional groups, specifically what functional groups with potentially catalytic capabilities, are compatible with efficient reversible photoisomerization.
It was hypothesized that the lone pair of the dimethylamine substituent might be responsible for the deactivation of the switching process, originating from a detrimental difference between the absorbances and quantum yields of the stable and metastable isomers. Hence, the addition of a Brønsted acid may result in a recovery of the reversible switching properties, providing the possibility for a pH-gated photo-responsive system. Solutions of St-(E)-1 and St-(Z)-1 (THF, 1.0–2.5·10−5 M) were irradiated with UV-light (365 nm and 395 nm) before and after the addition of excess of acid or base (respectively, aliquots of 2M aq. HCl and 2M aq. NaOH) (see Experimental section for further details). Large changes in the UV-vis spectra profiles and shift of the isosbestic points during irradiation cycles were observed upon addition of aliquots of both base and acid (365 nm in presence of base, 395 nm in presence of acid). This observation could be explained by activation of the backward switching path upon protonation of the dimethylamine substituent. However, degradation could not be excluded as alternative reasoning for the observed change in the UV-vis spectra during the backward irradiation, as the original spectra could not be recovered upon multiple irradiation cycles. Nevertheless, such observation opens new insights for future development of pH-gated photo-responsive systems based on molecular motors/switches.
3.2.4 Catalytic activity
Having investigated the photoresponsive dynamic motion of bifunctionalized switches 1-2, we next studied their ability as photoswitchable cooperative catalysts. Wang and co-workers reported a BINAM-based catalyst bearing a combination of an aromatic dimethylamine substituent as the active nucleophilic group and a thiourea as the H-bond donor moiety displaying promising activity as a catalyst for the Morita-Baylis-Hillman (MBH) reaction.67 Despite the literature claims, our attempts to catalyze the reaction between 2-cyclohexen-1-one and 3-phenylpropionaldehyde by either (E)-1, (Z)-1, (E)-2, (Z)-2 or the original literature catalyst did not lead to any conversion to the desired Michael adduct as determined by 1
H NMR spectroscopy (Scheme 3.9). We postulate that these disappointing results are due to the limited catalytic activity of the dimethylaniline moiety, both in terms of the low nucleophilicity of the aryl amine and the structurally constrained nature of the tertiary amine within the catalyst. Future studies will focus on the introduction of alternative, more nucleophilic, aliphatic amine functionalities (e.g. aliphatic amine) into the lower half, in line with the majority of successful catalysts reported for the asymmetric organocatalyzed MBH reaction.74–78
Scheme 3.9. Attempted catalysis of the Morita-Baylis-Hillman reaction between 2-cyclohexen-1-one and 3-phenylpropionaldehyde using either (E)-1, (Z)-1, (E)-2 or (Z)-2; no conversion to the desired Michael adduct was observed by 1H NMR spectroscopy.
While our initial model of cooperative catalysis induced by photocontrolled geometrical changes appears to be completely unsuccessful, other recent reports led us to reassess the molecular photoswitches (E)-1, (Z)-1, (E)-2 and (Z)-2. Studies by both Hecht and Pericás have addressed the possibility of shielding a catalytic moiety, in one photoaccessible isomer, either by simple steric interactions (Hecht) or through hydrogen bonding interactions (Pericás).16,20 Analysis of the photoswitches (E)-1, (Z)-1, (E)-2 and (Z)-2 suggests that the catalytically active hydrogen bonding thiourea moiety could be analogously deactivated in both the St-(Z) or MS-St-(Z) isomers either through steric shielding of the thiourea moiety by the dimethylamine group or through hydrogen bonding interactions. In order to investigate these ideas further, we tested our system in the Michael addition reaction (as described by Pericás) between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione, in which we postulated that the thiourea moiety in the upper half could engage in hydrogen bonding with the nitro-substituent of the substrate, activating it towards nucleophilic attack. The dimethylaniline moiety in the lower half was anticipated to allow control on the activity of the thiourea moiety by steric hindrance or hydrogen bonding interactions, thus causing a difference in catalytic activity between the more accessible (E)-isomers (either St-(E) or MS-(E)) and the corresponding blocked (Z)-isomers (either MS-(Z) or St-(Z)). Each distinct case could then, respectively, represent a successful example of ON/OFF (St-(E) to MS-(Z)) or OFF/ON (St-(Z) to MS-(E)) catalytic switches. Figure 3.6 illustrates the progress of the conversion, monitored by 1H NMR spectroscopy, of the Michael reaction between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione, mediated by different forms of the thiourea catalysts in combination with trimethylamine. When the reaction was conducted in the absence of catalyst, only 10% conversion was observed after 18 h (v0 = 5.56·10
-4
M h-1), in line with the results reported by Pericás and co-workers. In the presence of 3 mol% of St-(E)-1, a clear acceleration of the reaction was observed, with 60% conversion reached after 18 h (v0 = 5.33·10
-3
M h-1). Interestingly, when the reaction was performed under the same conditions with a PSS mixture (312 nm) of St-(E)-1:MS-(Z)-1 = 20:80 as catalyst, the rate of the reaction was substantially decreased, reaching only 19% conversion after 18 h (v0 = 1.08·10-3 M h-1). These results are highly supportive of a model similar to the one described by Hecht and Pericás, in which shielding in one geometric isomer inhibits the activating abilities of a key catalytic functionality in the molecule. Additionally, the catalyst St-(E)-1 could be switched to the less active state MS-(Z)-1 during the course of the reaction by irradiation of the sample after 4 h. In the presence of 3 mol% of St-(Z)-1, an increase of the reaction rate compared to the blank reaction was observed, with 40% conversion reached after 18 h (v0 = 2.94x10
-3
M h-1). Remarkably, when the reaction was performed under the same conditions with a PSS mixture (312 nm) of St-(Z)-1:MS-(E)-1 = 12:88 as catalyst, the rate of the reaction decreased, reaching less than 16% conversion after 18 h (v0 = 1.02·10
-3
M h-1). Contrary to expectations, the deactivated isomer St-(Z)-1 showed moderate catalytic activity, while the expected active isomer MS-(E)-1 provided only minimal increase in reaction rate beyond the observed background reaction. Similar to St-(E)-1, St-(Z)-1 could also be switched to the less active state during the course of the reaction by irradiation of the sample after 4 h. It should be noted that no degradation of the catalyst occurred during the irradiation process, as well as no thermal decay of the metastable species was detected, as determined by 1H NMR spectroscopy throughout the kinetic experiments.
10% conversion during 18 h (v0 = 5.56·10 -4
M h-1) even in the presence of the catalyst, the sole contribution of the catalysts can then be calculated as follows in terms of conversion ( ., equation 1), initial reaction rate ( , equation 2), and turnover frequency (TOF, equation 3):
(1)
(2)
⁄ (3)
Figure 3.6. (a) Photoswitching of catalytic activity of (E)-1 in Michael addition: background blank reaction - no cat. (black); catalyzed by St-(E)-1 (red); catalyzed by PSS mixture of St-(E)-1:MS-(Z)-1 = 18:82 upon UV irradiation (312 nm) of St-(E)-1 (green); catalyzed by St-(E)-1 upon intermediate irradiation (indicated with orange bar) after 4 h (blue). (b) Photoswitching of catalytic activity of (Z)-1 in Michael addition: background blank reaction - no cat. (black); catalyzed by (Z)-1 (red); catalyzed by PSS mixture of St-(Z)-1:MS-(E)-1 = 10:90 upon UV irradiation (312 nm) of St-(Z)-1 (green); catalyzed by St-(Z)-1 upon intermediate irradiation (indicated with orange bar) after 4 h (blue). (c) Reaction Scheme 3.of Michael addition. (d) Comparison between the net activity (yield (%) indicated above corresponding bar, contribution of background reaction subtracted) of (E)-1 and (Z)-1 as not irradiated (blue) and pre-irradiated mixture (red). For reaction conditions, irradiation and monitoring procedures, see Experimental section.
In the case of St-(E)-1, by subtracting the contribution of the background reaction, a 50% conversion (v0 = 5.33·10-3 M h-1 - 0.56·10-3 M h-1 = 4.77·10-3 M h-1, TOF = 1.59h-1) can be attributed to the sole catalyst
action. In the case of the corresponding PSS mixture of St-(E)-1:MS-(Z)-1 = 20:80, a mere 9% conversion (v0 = 1.08·10
-3
M h-1 - 0.56·10-3 M h-1 = 0.52·10-3 M h-1, TOF = 0.173 h-1) can be attributed to the catalyst mixture. Notably, this value appears to be proportional to the fraction of St-(E)-1 present in the catalyst mixture (stable-(E)-1 = 20%), if compared to the former not-irradiated sample (i.e. St-(E)-1 = 100%). Similar behavior is encountered in the second set of experiments involving St-(Z)-1 and MS-(E)-1. By subtracting the background reaction contribution, pure St-(Z)-1 appears to give 30% conversion after 18 h (v0 = 2.94·10
-3
M h-1 - 0.56·10-3 M h-1 = 2.38·10-3 M h-1, TOF = 0.793h-1), while the PSS mixture of St-(Z)-1:MS-(E)-1 = 12:88, afforded only 6% conversion (v0 = 1.02·10
-3
M h-1 - 0.56·10-3 M h-1 = 0.46·10-3 M h-1, TOF = 0.153h-1).
As shown by the experimental results, both stable isomers displayed significant loss of catalytic activity upon irradiation to the metastable state. As opposed to our assumption, this behavior does not seem predominantly regulated by shielding of the thiourea moiety by the amine substituent, either through steric or hydrogen bonding interactions (vide infra, Computational study), but apparently other parameters play a key role.
3.2.5 Computational study
Although the exact reason for the observed decrease in catalytic activity upon irradiation remains elusive, DFT calculations on various conformations of all four isomers, St-(E)-1, MS-(Z)-1, St-(Z)-1 and MS-(E)-1, have allowed us to gather further information to help interpret the results. Conformational analysis on all four isomers allowed us to identify the most stable cis and trans conformations of all the possible ground state isomers of 1 (Figure 3.7), where cis and trans describes the conformation of the thiourea motif. It was found in accordance with a previous study that the presumably less catalytically active anti conformation of the thiourea unit for each stable and metastable isomers of 1 lies lower in energy. 79 However the Gibbs free energy difference (ΔG ≈ 4 kcal mol-1
) is the same for all isomers of 1. The calculations also allow us to rule out the possibility of intramolecular hydrogen bonding interactions between the thiourea and dimethylaniline moieties, where the distances are too large in all four isomers for hydrogen bonding. Future research will focus on the investigation of a possible substantial alteration of the electronic properties upon switching to the metastable states, which could provide a plausible explanation for the detrimental impact on the catalytic activity.
Figure 3.7. DFT optimized structures of the cis (top) and trans (bottom) conformations adopted by the thiourea substituent for each stable and metastable isomer of 1 (from left to right, the order follows the switching cycle for second generation molecular motor as depicted in Scheme 3.2b: (E)-1, MS-(Z)-1,
St-3.3 Conclusions
We have described the design and synthesis of two photoresponsive bifunctionalized catalysts based on an overcrowded alkene core. Each motor half is equipped with a catalytically active "arm", with the aim of obtaining bifunctional switches whose catalytic activity could be turned ON and OFF by light-induced configurational isomerization. The compounds show switching upon irradiation with 312 nm light, forming the corresponding metastable states with good photostationary states. Interestingly, they do not exhibit reversible switching and further investigations are required to determine the influence of the dimethylamine group on the reversibility of the switching processes of bistable switches based on overcrowded alkenes. Switches St-(E)-1 and St-(Z)-1 display properties of photoswitchable catalytic activity control in the Michael addition reaction between (E)-3-bromo-β-nitrostyrene and 2,4-pentanedione. From the experimental results, both isomers displayed a decrease in catalytic activity upon irradiation to the metastable state, which could not be accredited to any detectable decomposition of the catalysts. As opposed to our initial assumption of controlling the activity of the thiourea moiety by steric hindrance or hydrogen bonding interactions, both E- and Z-isomers behave comparably as ON/OFF catalytic switches upon photoisomerization with clear changes in reaction rate and turnover frequency, regardless of the catalyst geometry. Therefore such behavior does not seem predominantly regulated by the steric hindrance exerted by the amine substituent around the thiourea moiety. As demonstrated in this work, an aromatic amine substituent was shown to be detrimental for the photochemical reversibility of the switching process and to be a poorly active catalytic moiety. These studies provide valuable insight into the requirements for the design of more effective and complex trifunctionalized molecular switches, 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 effect of ancillary functional groups on reversible photoswitching and the introduction of more active catalytic groups to ensure higher catalyst performance.
3.4 Acknowledgements
The author would like to thank Dr. B. S. L. Collins and T. van Leeuwen for their fundamental contribution to this work. Synthesis and characterization of catalysts (E)/(Z)-1 was performed by Dr. B. S. L. Collins. Computational study was performed by T. van Leeuwen. The authors would like to thank Ing. P. van der Meulen for the technical support during the kinetic NMR spectroscopy experiments.
3.5 Experimental section
3.5.1 General methods
Chemicals were purchased from Sigma Aldrich, Acros or TCI Europe N.V. Solvents were reagent grade and distilled and dried before use according to standard procedures. Dichloromethane and toluene were used from the solvent purification system using a MBraun SPS-800 column. THF was distilled over sodium under nitrogen atmosphere prior to use. Column chromatography was performed on silica gel (Silica Flash P60, 230–400 mesh).NMR spectra were recorded on a Varian Gemini-200 (50 MHz), a Varian Oxford NMR 300 (75 MHz), an Agilent Technologies 400-MR (100 MHz) or on a Varian Unity Plus 500 (125 MHz) spectrometer in the reported solvent. Chemical shifts are denoted in δ values (ppm) relative to CDCl3 (1H: δ = 7.26 and 13C: δ = 77.00), to CD2Cl2 ( 1 H: δ = 5.32 and 13 C: δ = 54.0), d6-acetone ( 1 H: δ = 2.05 and 13 C: δ = 29.84 and 206.26) or d8-toluene ( 1 H: δ = 2.09). For 1
H and 19F NMR, the splitting parameters are designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sext (sextet), m (multiplet), b (broad) and app. (apparent). MS (EI) and HRMS (EI) spectra were obtained with a AEI MS-902 or with a LTQ Orbitrap XL. Melting points were measured on a Büchi Melting Point B-545 apparatus. Irradiation was performed using a Spectroline ENB-280C/FE lamp (312 nm), a Thorlabs M365F1 (365 nm), M395F1 (395 nm) and M420F2 (420 nm) fiber-coupled coupled high power LEDs. UV-vis absorption spectra were measured on a Analityk Jena SPECORD S600 spectrophotometer. All spectra were recorded at 20 °C using Uvasol-grade THF (Merck) as solvent. Room temperature (rt) as mentioned in the experimental procedures, characterization and photoisomerization experiments is to be considered equal to 20 °C.
3.5.2 Computational Details
Density functional theory (DFT) calculations were carried out with the Gaussian 09 program (rev. D.01) program package.80 All of the calculations were performed on systems in the gas phase using the Becke‘s three parameter hybrid functional81 with the LYP correlation functionals82,83 (DFT B3LYP/6-31G(d,p)). Each geometry optimization was followed by a vibrational analysis to determine that a minimum or saddle point on the potential energy surface was found. For compounds with more than one minimum energy or saddle point conformation, the conformation with the lowest energy was chosen.
3.5.3 Synthetic procedures
N,N-dimethyl-9H-fluoren-2-amine (3)
To a solution of commercially available 2-aminofluorene (6.0 g, 33.11 mmol) in an acetonitrile : THF solvent mixture (2:1, 150 mL) was added formaldehyde (37% aq., 25 mL, 331 mmol) followed by sodium cyanoborohydride (6.44 g, 102 mmol). After stirring at rt for 10 min acetic acid (6.63 mL, 116 mmol) was added via syringe. The reaction mixture was then allowed to stir for a further 3 h at rt. The reaction mixture was then cooled with the aid of an ice bath, followed by neutralization via the cautious addition of NaOH (1N aq., 100 mL). The aqueous phase was then extracted into EtOAc (2 x 50 mL) and the combined organic phases were washed with sat. aq. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The crude reaction mixture was then purified by recrystallization from EtOH to provide the title compound N,N-dimethyl-9H-fluoren-2-amine 3 (6.15 g, 29.39 mmol, 89%) as a white solid. Characterization data was according to the literature.84 m.p. 179.7-181.3 °C. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.17 (td, J = 7.4, 1.1 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 3.85 (s, 2H), 3.02 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 150.2, 144.9, 142.3, 142.2, 131.0, 126.5, 124.7, 124.6, 120.3, 118.4, 111.6, 109.2, 41.0, 37.0; HRMS (ESI, m/z): calcd for C15H16N [M+H]+: 210.1277, found: 210.1277.
2-(dimethylamino)-9H-fluoren-9-one (4)
A 250 mL two-necked round bottom flask fitted with a reflux condenser was charged successively with N,N-dimethyl-9H-fluoren-2-amine 3 (1.96 g, 9.35 mmol), pyridine (50 mL) and benzyltrimethylammonium hydroxide (40 wt% solution in EtOH, 0.3 mL, 0.1 equiv). An air inlet was then introduced through the septum and a stream of air was allowed to pass through the reaction mixture. The reaction mixture was then allowed to stir at rt for 18 h under this set-up. After this time the pyridine was removed under reduced pressure. The residue was then dissolved in CH2Cl2 (30 mL) and washed with water (3 x 30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Successive recrystallizations from hot toluene, followed by washing with pentane provided the title compound 2-(dimethylamino)-9H-fluoren-9-one 4 (1.86 g, 8.34 mmol, 89%) as dark purple crystals. m.p. 165.1-166.9 °C; 1H NMR (200 MHz, CDCl3) δ 7.56 (d, J = 7.3, 1H), 7.44–7.27 (m, 3H), 7.11 (td, J = 7.2, 1.7 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 8.3, 2.6 Hz, 1H), 3.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 195.0, 151.2, 145.9, 135.7, 134.8, 134.2, 126.8, 124.1, 121.2, 118.9, 116.6, 108.4, 40.7; HRMS (ESI, m/z): calcd for C15H14NO [M+H]
+
: 224.1070, found: 224.1069.
2-(Dimethylamino)-9H-fluorene-9-thione (5)
A 50 mL two-necked round bottom flask fitted with a reflux condenser and nitrogen inlet was charged with 2-(dimethylamino)-9H-fluoren-9-one 4 (0.630 g, 2.82 mmol), dry toluene (8 mL) and phosphorus pentasulfide (0.94 g, 4.20 mmol, 1.5 equiv) under nitrogen. The reaction mixture was then stirred at 100 °C for approximately 2 h, while the conversion was monitored by TLC (CH2Cl2 in pentane, 30%). The mixture was concentrated under reduced pressure and the residue was purified by quick column chromatography (SiO2, CH2Cl2 in pentane, 30%). The blue fraction was concentrated under reduced pressure to yield the title compound 2-(dimethylamino)-9H-fluorene-9-thione 5 (0.85 g, 2.77 mmol, 33%) as dark blue crystals. Rf (CH2Cl2 in pentane, 30%): 0.65; m.p. 75.7–76.5 °C;
1
H NMR (200 MHz, CDCl3) δ 7.63 (dt, J = 7.3, 1.0 Hz, 1H), 7.36 (td, J = 7.4, 1.2 Hz, 1H), 7.31–7.14 (m, 2H), 7.14 (d, J = 2.6 Hz, 1H), 7.01 (td, J = 7.5, 1.2 Hz, 1H), 6.70 (dd, J = 8.3, 2.6 Hz, 1H), 3.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 229.4, 151.2, 145.4, 142.3, 141.4, 134.4, 131.8, 126.7, 123.9, 120.6, 118.4, 116.3, 108.1, 40.7; HRMS (ESI, m/z): calcd for C15H14NS [M+H]
+
: 240.0842, found: 240.0841.
4-bromo-2,5-dimethylbenzenesulfonyl chloride (6)
A 500 mL round bottom flask was charged with a solution of 2-bromo-1,4-dimethylbenzene (13.8 mL, 100 mmol) in CHCl3 (150 mL). The flask was fitted with a dropping funnel and cooled in an ice bath. Chlorosulfuric acid (26.6 mL, 400 mmol, 4 equiv) was then added dropwise with stirring. The reaction mixture was stirred for 30 min at this temperature and then warmed to rt and allowed to stir for a further 4 h. After this time the reaction mixture was carefully poured onto a crushed ice/water mixture (500 mL). The CHCl3 layer was separated and the aqueous layer was extracted into CHCl3 (2 x 200 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, filtered and concentrated to provide the title compound 4-bromo-2,5-dimethylbenzenesulfonyl chloride 6 (25.6 g, 90.4 mmol, 90%) as a white solid which was used in the next step without further purification. Rf (CH2Cl2 in pentane, 5%): 0.47; m.p. 53.4– 55.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.61 (s, 1H), 2.71 (s, 3H), 2.46 (s, 3H);
13
C NMR (100 MHz, CDCl3) δ 141.8, 137.4, 137.0, 136.7, 133.0, 130.3, 22.6, 19.7; LRMS (EI) m/z (abundance%, ion label): 50(50), 51(100), 64(51), 65(58), 77(88), 78(56), 61 (33), 103(90), 104(87), 105(50), 122(12), 137(16), 182(16), 183(51), 184(35), 185(61), 186(16), 216(22), 218(22), 229(12), 231(12), 247(50), 219(50), 282(35, M+), 284(52), 286(13); elem. anal. calcd for C8H8BrClO2S: C 33.88%, H 2.84%, S 11.31%, found: C 33.89%, H 2.84%, S 11.45%.
4-bromo-2,5-dimethylbenzenethiol (7)
A 500 mL round bottom flask was charged with a suspension of 4-bromo-2,5-dimethylbenzenesulfonyl chloride 6 (14.18 g, 50 mmol) in water (150 mL) and cooled to 0 °C. Concentrated H2SO4 (18.7 mL, 350 mmol, 7 equiv) was then added dropwise via a dropping funnel followed by the addition of zinc powder (16.35 g, 250 mmol, 5 equiv) in small portions and the reaction mixture was stirred at low temperature for a further 30 min. The dropping funnel was then exchanged for a reflux condenser and the reaction mixture was heated to reflux for 4 h. After this time the reaction mixture was cooled to rt and extracted into CHCl3 (2 x 50 mL) and CH2Cl2 (50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide a mixture of the title compound 4-bromo-2,5-dimethylbenzenethiol 7 and the corresponding disulfide 1,2-bis(4-bromo-2,5-dimethylphenyl)disulfane (as deduced by 1H NMR spectroscopy) (8.90 g, 1.00 : 1.18 ratio, approximately 82%) as a pale yellow solid. 1
H NMR (400 MHz, CDCl3) δ 7.35 (s, 1.18 H), 7.32 (s, 1H), 7.29 (s, 1.18 H), 7.14 (s, 1H), 3.23 (s, 1H), 2.35 (s, 4H), 2.30 (s, 7.4 H), 2.27 (s, 3H). A solution of the above mixture (1.0 g, approximately 4.6 mmol) in THF (20 mL) was treated with NaBH4 (0.87 g, 23.0 mmol) in small portions. The resultant suspension was allowed to stir at rt for 3 h, after which time the reaction was quenched via the cautious addition of ice cold water (10 mL) followed by aq. 1M HCl (10 mL) until cessation of gas formation. The aqueous layer was then extracted into EtOAc (50 mL) and the organic extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound 4-bromo-2,5-dimethylbenzenethiol 7 as a white solid (1.0 g, 4.6 mmol, quantitative). The product contained some minor impurities as determined by 1H NMR spectroscopy but was used in the subsequent reaction without further purification. Rf (pentane, 100%): 0.70; m.p. 91.6–94.8 °C;
1
H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.14 (s, 1H), 3.23 (s, 1H), 2.30 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.0, 135.4, 133.7, 131.9, 130.1, 121.9, 22.3, 20.4; HRMS (ESI): calcd. for C8H8BrS [M-H]
+
: 214.9525, found 214.9538.
3-((4-bromo-2,5-dimethylphenyl)thio)-2-methylpropanoic acid (8)
A solution of 4-bromo-2,5-dimethylbenzenethiol 7 (8.81 g, 40.6 mmol) in THF (150 mL) cooled in an ice bath was treated with triethylamine (8.48 mL, 60.8 mmol, 1.5 equiv) followed by methacrylic acid (5.16 mL, 60.8 mmol, 1.5 equiv). The reaction mixture was then warmed to rt and further heated to reflux and stirred at this temperature for 6 h. After this time the reaction mixture was cooled to rt and treated with aq. 1M HCl (70 mL). The aqueous layer was extracted into EtOAc (2 x 50 mL) and the combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resultant white solid was subjected to flash column chromatography (SiO2, MeOH in CH2Cl2, gradient 0–2%) to provide the title compound 3-((4-bromo-2,5-dimethylphenyl)thio)-2-methylpropanoic acid 8 (4.63 g, 15.3 mmol, 38%) as a white solid. Rf (EtOAc in
CH2Cl2, 10%): 0.44; m.p. 99.9–101.2 °C; 1
H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 7.25 (s, 1H), 4.85 (br s, 1H), 3.18 (dd, J = 7.4, 13.0 Hz, 1H), 2.92 (dd, J = 6.4, 13.0 Hz, 1H), 2.60 (h, J = 6.9 Hz, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 178.5, 138.8, 136.9, 135.9, 134.5, 132.4, 123.3, 40.9, 37.7, 22.4, 19.8, 17.3; HRMS (ESI): calcd. for C12H14BrO2S [M-H]
+
: 300.9982, found 300.9904.
6-bromo-3,5,8-trimethylthiochroman-4-one (9)
A solution of 3-((4-bromo-2,5-dimethylphenyl)thio)-2-methylpropanoic acid 8 (4.54 g, 15.0 mmol) in CH2Cl2 (100 mL) was cooled in an ice bath and treated with a few drops of N,N-dimethylformamide followed by the dropwise addition of oxalyl chloride (1.90 mL, 22.48 mmol, 1.5 equiv). The reaction mixture was then allowed to warm to rt and was stirred at this temperature for 1 h. After this time the reaction
dimethylphenyl)thio)-2-methylpropanoyl chloride as confirmed by 1H NMR spectroscopy. The acyl chloride was used directly in the following step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.20 (s, 1H), 3.35–3.23 (m, 1H), 3.15–2.95 (m, 1H), 2.90–2.80 (m, 2H), 1.40 (d, J = 6.9 Hz, 2H). The residue was re-dissolved in CH2Cl2 (100 mL) and the solution was cooled in an ice bath. Under a stream of nitrogen AlCl3 (3.0 g, 22.48 mmol, 1.5 equiv) was added in small portions. The reaction mixture was then allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was then cooled in an ice bath and quenched via the cautious addition of water. The aqueous layer was separated and extracted into CH2Cl2 (2 x 50 mL) and the combined organic extracts were washed with sat. aq. NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The 1H NMR spectrum of the crude reaction mixture indicated the presence of the title compound 6-bromo-3,5,8-trimethylthiochroman-4-one 9 and some minor quantities of the corresponding de-brominated ketone (20 : 1.0). The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 0–2%) to provide the title compound 6-bromo-3,5,8-trimethylthiochroman-4-one 9 (3.98 g, 14.02 mmol, 93%, contaminated with small quantities of the de-brominated ketone which was carried through into the subsequent reaction) as a pale pink solid. Rf (EtOAc
in pentane, 2%): 0.56; m.p. 43.1–45.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 3.19–3.11 (m, 1H), 3.03–2.97 (m, 2H), 2.54 (s, 3H), 2.24 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 200.4, 140.8, 137.8, 136.5, 134.2, 133.1, 123.2, 43.3, 32.9, 21.7, 19.7, 15.4; HRMS (ESI): calcd. for C12H14BrOS [M+H]
+
: 284.9943, found 284.9947.
(E)-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)hydrazone (10)
A 100 mL round bottom flask was charged with 6-bromo-3,5,8-trimethylthiochroman-4-one 9 (2.73 g, 9.59 mmol), EtOH (22 mL) and hydrazine monohydrate (9.3 mL, 190 mmol, 20 equiv). The reaction mixture was heated to reflux and allowed to stir at this temperature for 20 h. After this time the reaction mixture was cooled to rt and concentrated under reduced pressure to remove the majority of the EtOH. The residue was then diluted with CH2Cl2 (10 mL) and washed with water (2 x 10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 5–30%) followed by recrystallization from hot EtOH to provide the title compound (E)-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)hydrazone 10 (1.20 g, 3.99 mmol, 42%) as an off-white solid. Rf (EtOAc in pentane, 10%): 0.64 (with considerable tailing); m.p. 107–109 °C; 1H NMR (400 MHz,
CD2Cl2) δ 7.30 (s, 1H), 5.49 (br s, 2H), 3.38 (app. dp, J = 10.7, 6.8 Hz, 1H), 3.07 (dd, J = 12.9, 6.6 Hz, 1H), 2.48 (dd, J = 12.9, 10.8 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 1.18 (d, J = 6.8 Hz, 3H); minor AB quartet observed at 6.95 ppm identified as small quantity of de-brominated hydrazone by comparison with an authentic sample (vide infra); 13C NMR (100 MHz, CD2Cl2) δ 150.1, 138.4, 137.3, 135.3, 135.2, 132.3, 124.1, 37.0, 35.4, 21.6, 19.7, 15.0; two minor signals at 128.9 ppm and 128.5 ppm identified as small quantity of de-brominated hydrazone by comparison with an authentic sample (vide infra); HRMS (ESI): calcd. for C12H16BrN2S: 299.0212, found 299.0215.
(E)-(3,5,8-trimethylthiochroman-4-ylidene)hydrazone
See reference for full experimental details and further characterization.55 1
H NMR (400 MHz, CD2Cl2) δ 7.04–6.90 (m, 2H), 5.42 (br s, 2H), 3.37 (app. dp, J = 10.4, 6.7 Hz, 1H), 3.07 (dd, J = 12.9, 6.5 Hz, 1H), 2.50 (dd, J = 12.9, 10.4 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H), 1.19 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) δ 150.6, 138.4, 135.8, 135.2, 133.6, 128.9, 128.5, 36.9, 34.8, 21.2, 20.0, 15.1.
(E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((E)-13) and (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine
((Z)-13)
A 100 mL round bottom flask was charged with a solution of (E)-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)hydrazone 10 (915 mg, 3.05 mmol) in N,N-dimethylformamide (25 mL) under nitrogen and cooled to – 30 °C. A solution of [bis(trifluoroacetoxy)iodo]benzene (1.33 g, 3.05 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was then added at this temperature via syringe. The resulting solution was stirred for approximately 1 min followed by the addition of a solution of 2-(dimethylamino)-9H-fluorene-9-thione 5 (1.09 g, 4.57 mmol, 1.5 equiv) in N,N-dimethylformamide (30 mL) via syringe. The resulting solution was stirred at this temperature for 1 h and then allowed to warm slowly to rt and stirred at this temperature for a further 16 h. After this time the reaction mixture was diluted with EtOAc and washed sequentially with sat. aq. NH4Cl (30 mL), water (2 x 30 mL) and brine (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in p-xylene (100 mL) and treated with triphenyl phosphine (1.60 g, 6.09 mmol, 2.0 equiv). The resulting solution was heated to reflux and allowed to stir at this temperature for 22 h. After this time the reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The crude residue was then analyzed by 1H NMR spectroscopy, indicating the presence of the title compounds (E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-13 and (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 in a 1.0 : 0.79 ratio. The crude reaction mixture was then purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 1–3%). The early fractions were concentrated and dissolved in EtOAc leaving a white precipitate that was discarded. The mother liquor was concentrated to give a red solid that was washed with hot EtOH to provide the title compound (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (144 mg). The EtOH washings were then concentrated and submitted to further flash column chromatography (SiO2, aluminium oxide, CH2Cl2 in pentane, gradient 10–20%) to provide a red solid which was further washed with hot EtOH to provide additional trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (163 mg). Combining these solid provided (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (307 mg, 0.64 mmol, 21%). The later fractions were combined and re-submitted to flash column chromatography twice: (toluene, isocratic 100%) followed by (EtOAc in pentane, gradient 1–10%). The resultant yellow solid was then washed with EtOH to provide the title compound
(E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-13 (508 mg, 1.07 mmol, 35%) as a bright yellow solid.
(E)-13: Rf (EtOAc in pentane, 5%): 0.47; m.p. 149–151 °C;
1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.77 (t, J = 8.1 Hz, 1H), 6.08 (d, J = 8.1 Hz, 1H), 4.55 (m, 1H), 3.23 (dd, J = 12.6, 7.8 Hz, 1H), 3.07 (s, 6H), 2.40 (s, 3H), 2.32 (dd, J = 12.5, 9.0 Hz, 1H), 2.23 (s, 3H), 1.38 (d, J = 6.7 Hz, 3H); 1H NMR (400 MHz, CD2Cl2) δ 7.59 (d, J = 8.3 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.06 (d, J = 7.9 Hz, 1H), 4.55 (m, 1H), 3.26 (dd, J = 12.5, 7.9 Hz, 1H), 3.07 (s, 6H), 2.40 (s, 3H), 2.32 (dd, J = 12.5, 9.0 Hz, 1H), 2.22 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CD2Cl2) δ 151.1, 143.6, 141.1, 140.1, 139.3, 139.2, 137.8, 137.3, 136.1, 134.7, 133.0, 130.6, 128.1, 125.6, 123.7, 123.5, 120.5, 118.2, 113.0, 110.3, 41.3, 41.0, 37.9, 20.3, 19.9, 18.4; note: minor signal observed at 105.4 ppm that cannot be accounted for; HRMS (ESI): calcd. for C27H27BrNS [M+H]
+ : 476.1042, found 476.1042. (Z)-13: Rf (EtOAc in pentane, 5%): 0.57; m.p. 212.3–214.9 °C; 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.21
Hz, 1H), 2.71 (s, 6H), 2.40 (s, 3H), 2.35–2.30 (m, 1H), 2.33 (s, 3H), 1.37 (d, J = 7.8 Hz, 3H); some broadened signals observed in 13C NMR spectrum, which were postulated to be due to trace of acid in the sample – the sample was washed sequentially with sat. aq. NaHCO3 and brine, followed by drying over MgSO4 – the subsequent
13
C spectrum recorded in CD2Cl2 shows sharp signals: 1 H NMR (400 MHz, CD2Cl2) δ 7.86 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.61 (dd, J = 8.3, 2.2 Hz, 1H), 5.76 (d, J = 2.3 Hz, 1H), 4.59–4.50 (m, 1H), 3.23 (dd, J = 12.2, 7.9 Hz, 1H), 2.69 (s, 6H), 2.39 (s, 3H), 2.31 (stack of s and dd, 4H), 1.35 (d, J = 6.7 Hz, 3H); (100 MHz, CD2Cl2) δ 150.9,143.9, 142.4, 140.0, 139.52, 139.46, 137.6, 137.4, 136.2, 134.2, 132.8, 129.4, 128.4, 125.5, 125.4, 123.7, 120.0, 118.6, 112.7, 108.0, 40.9*, 37.8, 20.3, 19.8, 18.9 – one 13C signal missing in aliphatic region, but an HSQC NMR experiment confirmed the overlay of the carbon atoms marked ― * ‖ at 40.9 ppm (see attached spectra in Experimental section, NMR Spectra section); HRMS (ESI): calcd. for C27H27BrNS [M+H]
+
: 476.1042, found 476.1044.
(E)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((E)-14) A 50 mL pressure flask with stirring bar was charged successively with potassium iodide (5.57 g, 33.56 mmol, 40 equiv), copper iodide (2.40 g, 12.59 mmol, 15 equiv), (E)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-13 (0.40 g, 0.84 mmol) and
N,N-dimethylformamide (10 mL). The septum was then exchanged for a
Teflon screw cap and the reaction mixture was heated to 140 °C and allowed to stir at this temperature for 48 h. After this time the reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed sequentially with sat. aq. NH4Cl (20 mL), water (2 x 20 mL) and brine (20 mL). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography (SiO2, EtOAc in pentane, gradient 2.5–5%) to provide the title compound (E)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (E)-14 (394 mg, 0.75 mmol, 90%) as a yellow solid. Rf (EtOAc
in pentane, 5%): 0.30; m.p. 173–175 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (s, 1H), 7.13 (t, J = 7.1 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.04 (d, J = 7.9 Hz, 1H), 4.54 (app. sext, J = 7.7 Hz, 1H), 3.23 (dd, J = 7.0, 12.3 Hz, 1H), 3.07 (s, 6H), 2.38 (s, 3H), 2.34 (dd, J = 9.1, 12.5 Hz, 1H), 2.28 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H); 1H NMR (400 MHz, CD2Cl2) δ 7.82 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 7.14 (t, J = 7.2 Hz, 1H), 6.82 (dd, J = 8.0, 2.3 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 4.60–4.51 (m, 1H), 3.26 (dd, J = 12.3, 8.2 Hz, 1H), 3.08 (s, 6H), 2.38 (s, 3H), 2.34 (dd, J = 12.0, 8.9 Hz, 1H), 2.28 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H); 13C NMR spectra in CDCl3, CD2Cl2 and d6-acetone all miss at least one
13 C signal – extensive analysis using 2D NMR experiments COSY, HSQC and gHMBC (see attached spectra in Experimental section, NMR Spectra section) suggest that two of the carbon atoms marked as ― * ‖ overlay at the signal at 139.22 ppm (and the third is at 139.20 ppm): 13C NMR (100 MHz, CD2Cl2) δ 151.1, 144.0, 141.1, 140.5, 139.6, 139.22*, 139.20*, 137.8, 137.4, 134.6, 130.6, 128.1, 125.6, 123.5, 120.5, 118.2, 112.9, 110.3, 99.8, 41.3, 41.1, 37.8, 25.9, 19.6, 18.4; HRMS (ESI): calcd. for C27H27INS: 524.0903, found 524.0893.
(Z)-9-(6-iodo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine ((Z)-14) A 50 mL pressure flask with stirring bar was charged successively with potassium iodide (3.57 g, 21.49 mmol, 40 equiv), copper iodide (1.55 g, 8.06 mmol, 15 equiv), (Z)-9-(6-bromo-3,5,8-trimethylthiochroman-4-ylidene)-N,N-dimethyl-9H-fluoren-2-amine (Z)-13 (256 mg, 0.54 mmol) and N,N-dimethylformamide (7 mL). The septum was then exchanged for a Teflon screw cap and the reaction mixture was heated to 140 °C and allowed to stir at this temperature for 48 h. After this time the reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed
