Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow

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Palladium-Catalyzed Aerobic Oxidative Coupling of o‑Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling Nico Erdmann, Yuanhai Su, Benjamin Bosmans, Volker Hessel, and Timothy Noel̈ * Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands S Supporting Information *

Recently, Stahl et al. described an innovative approach based on the aerobic cross-dehydrogenative homocoupling of the bulk chemical o-xylene (1) to generate biaryl 2 as outlined in Scheme 1.21 Whereas the cross-dehydrogenative coupling of

ABSTRACT: Herein, the first continuous cross-dehydrogenative homocoupling of an unactivated arene using oxygen as sole oxidant is reported. Employing microreactor technology which enables the use of elevated temperatures and pressures leads to a boost of the catalytic reaction. Hence, a major reduction in reaction time is achieved. Due to the significance as precursor for MOFs as well as high-tech and high-value polymers, the study focused on the production of 3,4,3′,4′-tetramethylbiphenyl.

Scheme 1. Cross-Dehydrogenative Coupling of o-Xylene by Stahl et al.

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INTRODUCTION Biaryls are common and important structural motifs, encountered in a variety of molecules relevant for the pharmaceutical industry and material science. Such compounds are typically prepared via traditional cross-coupling strategies, which require prefunctionalization of the substrates.1−4 More recently, cross-dehydrogenative coupling (CDC) has been developed as an appealing strategy to prepare biaryls.5−9 This synthetic method allows for the connection of two carbon fragments by a double C−H activation event under oxidative conditions. When using O2 as the sole oxidant, theoretically, only water will be produced as a byproduct. However, the use of O2 presents some particular processing challenges to the chemist and chemical engineer. Strict handling procedures are required to ensure safety, especially at a large scale. This includes the use of diluted O2 in N2 to stay below the limiting oxygen concentration, which has a negative impact on the reaction kinetics. In addition, gas-to-liquid mass transfer limitations occur when dealing with multiphase reaction conditions. Continuous-flow chemistry in microchannels grants a number of advantages which should allow to safely carry out and accelerate oxidative CDC chemistry in flow.10−16 The small dimensions of microreactors allow to mitigate potential safety hazards associated with the handling of pure oxygen in combination with flammable solvents.17,18 Further, gas−liquid segmented flow regimes in microchannels are characterized by their high interfacial areas, which eliminate mass transfer limitations.19,20 This is especially important to enable an efficient reoxidation of the palladium catalyst, and thus avoiding catalyst deactivation. The excellent gas−liquid mass transfer in combination with elevated reaction temperatures also intensifies the reaction kinetics and reduces the reaction times significantly. © 2016 American Chemical Society

unactivated and activated arenes is already studied in great detail,8,14,22−−35 Stahl et al. achieved an unprecedented regioselectivity distinguishing between different C−H bonds (Scheme 1). This finding was supported by a thorough mechanistic study.36 However, the main drawback of the procedure is the rather low yield (i.e., 7%) and the long reaction times (several hours). The conversion was kept low to obtain high selectivities, which is most likely due to occurrence of consecutive reactions leading to undesired oligomerization reactions. Biaryl 2 is a high potential intermediate in the synthesis of metal organic frameworks (4) and of the high-performance polyimide resin Upilex (5) (Scheme 2). Various efforts have been undertaken by Ube Industries to prepare biaryl 2 efficiently, to achieve a reduced production cost by applying novel production technologies and synthetic routes. Consequently, an improved, safe, and scalable protocol would be highly desired to make this route commercially feasible. Herein, we describe the development of a fast and efficient CDC continuous-flow protocol of o-xylene to yield biaryl 2. We commenced our investigations with a series of batch experiments (see Supporting Information). Optimal conditions in batch involved the use of Pd(OAc)2 as a catalyst, Cu(OTf)2 Received: February 14, 2016 Published: March 10, 2016 831

DOI: 10.1021/acs.oprd.6b00044 Org. Process Res. Dev. 2016, 20, 831−835

Organic Process Research & Development

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Gratifyingly, the results showed that the CDC reaction was more reproducible and could be accelerated by increasing the gas−liquid interfacial area (Scheme 3).

Scheme 2. Synthesis and Application of TetramethylBiphenyl (2)

Scheme 3. Stopped Flow Experiment

Next, a continuous-flow microcapillary system was developed which allowed to perform the CDC reaction to yield biaryl 2 at high temperatures and different oxygen pressures. Details of the setup are given in the Supporting Information. Liquid reactants are pumped into the system with an HPLC pump and are merged in a T-mixer with an oxygen stream delivered from an oxygen cylinder via a mass flow controller. The segmented gas− liquid stream was led into a stainless steel capillary microreactor (750 μm, 29.4 m, 13 mL volume). A back pressure regulator was used to control the pressure in the reactor. This versatile flow system allowed us to screen various reaction parameters up to 70 bar oxygen pressure and temperatures >150 °C. To our delight, a 19% yield of 2 with an overall selectivity of 51% could be achieved within 40 min when an oxygen pressure of 40 bar was applied (Table 1, Entry Table 1. Catalyst Loading in Flowa

as a cocatalyst, 2-F-pyridine as a ligand, trifluoroacetic acid (TFA), and acetic acid as the solvent. In all experiments, the regioselectivity between 3,4,3′,4′-tetramethyl-biphenyl (2) and its main isomer 2,3,3′,4′-tetramethyl-biphenyl (3) stayed consistent in the range of 91−93%. As the major pitfall for this reaction is the occurrence of consecutive C−H activations on the product, in the following, selectivity is defined as the main regioisomer compared to the total conversion. During the course of these investigations, we also found that it was hard to get reproducible results. We attributed this to gas−liquid mass transfer limitations as small changes in stirring rate resulted in large reactivity differences.38 To investigate the feasibility of continuous-flow chemistry, we performed several stopped-flow experiments in which a gas−liquid reaction mixture was introduced into a capillary and subsequently capped. Such experiments are ideal to verify the advantages of a well-defined larger interfacial area without assembling an entire, technologically complex and thus expensive continuous-flow setup.

a b

entry

Pd(OAc)2

Cu(OTf)2

yieldb

selectivityc

1 2 3 4 5 6 7

2% 3% 7.5% 10% 15% 10% 10%

2% 3% 7.5% 10% 15% 20% 5%

19% 22% 25% 34% 33% 32% 23%

51% 79% 54% 52% 49% 46% 75%

All reactions were performed on a 1 mmol scale based on o-xylene. GC-yield using n-decane as internal standard. cOverall selectivity.

1). This represents a substantial reduction in reaction time, which can be attributed to (i) improved gas−liquid mass transfer, (ii) improved mixing efficiency in Taylor flow regimes, and (iii) the use of pure oxygen to reoxidize palladium. To further increase the yield, the catalyst loading was increased (Table 1, Entries 2−5). The best results were obtained with a catalyst loading of 10 mol % Pd (Table 1, Entry 4). A further increase in the amount of cocatalyst Cu(OTf)2 did not lead to any improvement in yield and selectivity (Table 1, Entries 6− 7). Next, the optimal concentration was determined (Table 2). As to be expected in a dimerization reaction, the yield increased with an increase in concentration. A concentration of 2.4 M was 832



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In a next optimization step, the influence of the oxygen to substrate ratio (a) was examined, while keeping the reaction time, flow regime, temperature, and pressure constant. As can be seen from Figure 1, the ratio of oxygen to substrate at 40 bar in the range of a = 1 to a = 10 has nearly no effect on

Table 2. Concentration Study of the CDC Reaction

entry

concentration

yielda

selectivityb

1 2 3 4 5c

0.5 M 1M 1.5 M 2.4 M 4.8 M

19% 22% 25% 34% 33%

51% 79% 54% 52% 49%

a c

GC-yield using n-decane as internal standard. bOverall selectivity. Rapid phase separation was experienced at rt.

determined to optimal (Table 2, Entry 2). More concentrated reaction mixtures led to phase separation and microreactor clogging due to precipitation of the product. With the optimal catalyst loading and concentration in hand, the paradigm introduced by Stahl et al. was studied in more detail. Whereas Stahl et al. reported that 2-fluoropyridine was the only active ligand in this transformation, it was discovered that in flow the use of 1 equiv of other pyridine ligands enabled the reaction as well (Scheme 4).

Figure 1. Influence of oxygen−o-xylene ratio (a). Note that a equals the stoichiometry of oxygen to the starting material o-xylene.

the yield and the selectivity of the reaction. Only in a substoichiometric ratio a dependency is apparently visible. This indicates that at elevated pressure the reaction does not experience any mass transfer limitation in micro flow. As the slug flow regime appeared most stable at a ratio of a = 5, this value was used for the further optimization. Next, a systematic study of the influence of the pressure and temperature on the reaction yield and selectivity was undertaken. Figure 2 shows a contour plot in which the most optimal process regions are visualized. With elevated oxygen pressures from 10 to 40 bar at 110 °C, the yield increases from 25% to 38%. On the other hand, it is apparent from the figure that the increase in temperature has a maximum around 110 °C. Increasing the temperature higher than 130 °C leads to a rapid decrease in selectivity and yield. We believe that this has to do with a degradation of the catalytically active species.39 With the optimized process conditions in hand, a fine-tuning of the reaction conditions was performed leading to a decrease in catalyst loading. By employing just 5 mol % of Pd(OAc)2 as catalyst and 5 mol % Cu(OAc)2, biaryl 2 could be formed in 41% (31% isolated) yield with a overall selectivity of 60% within 40 min (Scheme 5). This achievement represents a major process optimization potentially leading the way for a more cost efficient and atom-economic production of 3,4,3′,4′tetramethyl-biphenyl 2.

Scheme 4. Effect of Pyridine Ligands

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However, it was confirmed that 2 equiv of ligand completely shut down the reaction. It is hypothesized that palladium is forming a catalytically inactive Pd(py)2X2 complex. When only 1 equiv of pyridine ligand is used, a free coordination site for the substrate is available which allows for efficient C−H activation. Surprisingly, when 2-fluoropyridine was used as a ligand, we discovered an increase in yield when two equivalents were used. We surmise that 2-fluoropyridine is unable to bind strongly to the palladium thereby allowing the coordination of the substrate. Although the use of pyridine would be of great benefit due to the much lower price compared to 2fluoropyridine, 2-fluoropyridine was used for the further study as it led to higher yields and slightly better regioselectivity than pyridine.

CONCLUSIONS In conclusion, the first CDC coupling of unactivated arenes in flow was developed. The valuable intermediate 3,4,3′,4′tetramethyl-biphenyl 2 could be formed in 41% yield with an overall selectivity of 60%. This demonstrates a significant improvement to other literature reports. It was shown that the use of elevated temperature in the microreactor led to a significant shortening of the reaction time, whereas the elevated oxygen pressure and the higher interfacial area eliminated mass transfer limitations completely. Furthermore, various ligands were used successfully for this CDC reaction. However, 2fluoropyridine achieved the highest regioselectivity, which 833



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Figure 2. Yield (left) and selectivity (right) dependence on temperature and pressure.

3,4,3′,4′-tetramethyl-biphenyl. White solid; 1H-NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 2.35 (s, 6H), 2.32 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ 139.0 (2C), 136.9 (2C), 135.4 (2C), 130.1 (2C), 128.7 (2C), 124.5 (2C), 20.1 (2C), 19.6 (2C).

Scheme 5. Optimized Reaction Conditions

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00044. Experimental procedures along with a more detailed description of the operating platform (PDF)

appears to be independent of the temperature. Through the current study an important milestone in the development of an alternative process for the production of a valuable compound for material science was achieved.

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AUTHOR INFORMATION

Corresponding Author

EXPERIMENTAL DETAILS General Flow Procedure for the Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene. The first 4 mL vial was charged with 22.5 mg (5 mol%, 0.1 mmol) of Pd(OAc)2. 400 μL of acetic acid, 15.5 μL of (10 mol%, 0.2 mmol) trifluoroacetic acid, 17 μL of (10 mol%, 0.2 mmol) 2fluoropyridine, and 39 μL (10 mol%, 0.2 mmol as Internal Standard) of n-decane were added consecutively to the vial. After each addition, the vial was sealed and sonicated for 1 min. Under argon, 241 μL (2 mmol) of o-xylene was added. A second 4 mL vial was charged with 73 mg (20 mol%, 0.4 mmol) of Cu(OAc)2. Under argon, 300 μL of acetic acid was added, and the vial was sonicated until a blue suspension was formed. 71 μL (40 mol%, 0.8 mmol) of trifluoromethanesulfonic acid was added, providing a clear blue solution under sonication. The content of the second vial was added to the first vial under sonication and washed with additional 140 μL of acetic acid forming a 2.4 M reaction mixture based on o-xylene in acetic acid. The reaction mixture was introduced to the reactor via a 1 mL sample loop. The reaction mixture was pumped with a flow of 75 μL/min and mixed with 2 equiv (a = 2) of pure oxygen (7.644 mL/min) under 40 bar achieving a reaction time of 40 min at 110 °C in the oil bath. After the gas−liquid separation, the reaction mixture was extracted with saturated NaHCO3 solution and adsorbed on silica. The crude reaction mixture was purified by flash chromatography in pure petroleum ether affording 65.2 mg (0.31 mmol, 31%) of

*E-mail: [email protected]. Funding

We gratefully acknowledge the CatchBio Project (Project No. 053.70.376) for the funding of N.E. and Y.S. as well as the Marie S. Curie foundation for a Marie CurieIntra-European Fellowship (No. 622415) for Y.S. Financial support is provided by the Dutch Science Foundation (NWO) via an ECHO grant (Grant No. 713.013.001) and a VIDI grant for T.N. (Grant No. 14150). We also acknowledge the European Union for a Marie Curie CIG grant for T.N. (Grant No. 333659) and an ERC Advanced Grant for V.H. (Grant No. 267443). Notes

The authors declare no competing financial interest.

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REFERENCES

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Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow

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