An efficient oxidation reaction method for the continuous flow synthesis of aryl acetaldehyde was reported, which was used by gas chromatography to control and reduce the excessive oxidation of sensitive products. This reaction is universal to a wide range of functionalized styrene and can be scaled up to the multi-gram scale.
1. Introduction:
Molecular oxygen as a reagent for the synthesis of organic compounds has an attractive research topic, especially attracting attention from industry. Molecular oxygen** is inexpensive and easy to obtain, and is a green substitute for many oxidants in the current synthesis. The use of oxygen typically requires transition metal catalysts to facilitate the reaction rate, and in most cases, the desired conversion with high conversion rates can be achieved. However, in cases where partially oxidizing compounds are required, excessive oxidation can be an important problem and can be more easily controlled through the use of alternative oxidants.
Grubbs and collaborators proposed a method of interest in which the anti-Markovnikov Wacker oxidation of styrene yields an environmentally sensitive aryl acetaldehyde product, in which excellent aldehyde selectivity can be obtained using sterically hindered tert-butanol as the reaction solvent. In order to prevent excessive oxidation of the desired product at the benzyl position, which eventually leads to the cleavage of olefin bonds to form benzaldehyde, the copper and oxygen traditionally used in wacker oxidation are replaced by hydroquinone (BQ) because their stoichiometric ratios can be more easily controlled.
Several methods for achieving anti-Markovnikov Wacker oxidation have been previously studied. Reactions using guide groups have been used, but the range of substrates is somewhat limited. Spencer et al.'s results suggest that the increase from catalytic PDCL2 to stoichiometric PDCL2 can lead to selective bias towards aldehyde products. In addition, Feringa and collaborators demonstrated for the first time the use of (MeCN)2PDCL2 and CuCl2 with O2 catalysts as well as the anti-Markovnikov product required for the implementation of T-Buoh. However, they reported that the yield of styrene oxidation to phenylacetaldehyde was less than 10%.
Given our group's experience in flow chemistry techniques, especially in gas flow equipment, we envisage the development of a highly efficient aerobic anti-Markovnikov wacker oxidation. With the proper application of microreactors and more precise control of reaction parameters such as oxygen pressure, reaction time, and temperature, it is conceivable that any degree of excessive oxidation may be sufficiently mitigated when using CuCl2 and O2, a problem that has so far hindered the development of this aerobic process.
We compared BQ and CuCl2 with O2 in batch mode (Table 1). When using BQ as an oxidizing agent, 4-chlorostyrene was almost completely converted and had good selectivity, as previously reported, although some excessive oxidation was also observed (Experiment 1). More electron-enriched 4-methoxystyrene gave lower conversion and poorer aryl acetaldehyde selectivity (Experiment 2). Again, some excessive oxidation was observed, but to a lesser extent for this electron-enrichment derivative. Replacing Bq with CuCl2 (5mol) and O2 (10 Bar) can lead to a complete transformation of two examples of electron changes. However, as expected, significant excessive oxidation of the desired product to the corresponding benzaldehyde was observed. Reducing the oxygen pressure (5 bar) results in incomplete conversion and continued formation of the corresponding benzaldehyde, probably due to oxygen depletion due to the competitive rate of over-oxidation in the autoclave. However, the degree of over-oxidation can be reduced by reducing the cocatalyst loading by a factor of five to 1mol (Experiment 5, Table 1). Further reducing the cocatalyst loading results in longer reaction times.
Table 1Anti-markovnikov wacker oxidation of various functionalized styrene (batch mode).
It is important to note that the stirred autoclaves present in the pharmaceutical industry can be used for aerobic oxidation reactions using a diluted air mixture (5-8% O2 in N2), which requires continuous ventilation through the reactor to prevent oxygen depletion. Therefore, despite the improvements in the aerobic batch process, further batch optimization was of little significance to the flow mode process and was quickly pursued.
It was found that when using CuCl2 and O2 for the reaction, the reaction time was about 15 minutes and the catalyst loading was 5 mol%, which allowed for extensive reaction optimization in a short period of time. We first determine which co-solvent is suitable to prevent T-Buoh from icing in the flow tube and pump. Mixtures of Phme T-Buoh (1:6) work best compared to other co-solvents, which lead to the formation of other by-products. Following this, the catalyst loading of palladium and copper was briefly investigated and it was found that the catalyst loading of [PD] [Cu] (5 mol% 5 mol%) achieved good conversion and selectivity over a range of reaction time and oxygen pressure variations to obtain the best results for a specific substrate.
The flow settings used to optimize the experiment are shown in Figure 1. Will contain 4-methoxystyrene 1a (0.).4 mmol，0.2M) into injection loop A, and catalyst solutions containing (mE)2PDCl2, CuCl2, and H2O were loaded into injection loop B. The reagents are pumped into a tubular gas reactor with an inner tube, which is pressurized with pure oxygen, using a Uniqsis Flowsyn reactor. The reaction then flows through a 30 ml stainless steel reaction coil that is maintained at a constant temperature, followed by a 25 bar back pressure regulator (BPR). This is to maintain a homogeneous solution by preventing oxygen swelling at pressures up to 25 bar. Finally, the production stream is collected in a vial through a constant flow of nitrogen to remove excess oxygen.
Figure 1Effect of different parameter changes on selectivity and by-product formation. (a) Temperature: H2O (2 equivalent), O2 (10 bar). (B) H2O equivalent: t = 80 °C, O2 (10 bar). (c) Oxygen pressure: H2O (1.)4 equivalents), t = 60. General reaction conditions: phme T-buoh (1:6), flow rate (0.).25+0.25 mlmin (-1)), reaction coil (stainless steel, v=30 ml), gas reactor (v=0.).7 ml）af2400（l=1.5 m）。Injection loop A (2 ml): 4-vinylanisole 1a (0.)4 mmol）。Inject ring B (2 mL) :(meCN) 2PDCl2 (5mol), CuCl2 (5mol), H2O (X equivalent).
The conditions for the trans-Markovnikov Wacker oxidation reaction of 4-methoxystyrene 1A were varied in terms of temperature (Fig. 1, a), water equivalent (Fig. 1, b), and pure oxygen pressure (Fig. 1, c). In these optimizations, the catalyst load, solvent mixture, and residence time (through the flow rate) remain constant.
The reaction temperature was first studied (Figure 1, a). The relatively low temperature (50) within the desired 1 h residence time range yields better selectivity and less by-product formation prior to complete transformation. The gradual increase in temperature resulted in an increase in the reaction rate and a complete transformation was achieved at an optimal temperature of 60 with good selectivity and minimal by-product formation. Thereafter, above 80, the reaction rate and selectivity decrease. The effects of water equivalence were then investigated (Figure 1, b). Since the t-buoh used in these reactions may contain trace amounts of water, the substoichiometric amount of water has also been studied. Incomplete transformation of the initiator is observed during the 1 h residence time frame until the addition of 12 equivalent amounts of water. However, considering the convenience of using flow to control the dwell time, we believe that 14 Equivalence is best for the overall reaction rate and to avoid incomplete transformation when changing the substrate. Next, the effect of oxygen pressure on the reaction was investigated (Figure 1, c). At a constant gas reactor flux (05 ml min), complete transformation was not observed until an oxygen pressure of 8 bar was applied. Further increasing oxygen pressure can lead to over-oxidation and reaction-selective degradation. By gas titration measurements, an oxygen concentration of 0 at 8 bar was determined097m, unsurprisingly close to 0Reaction concentration of 1m. This is a good demonstration of the ease and accuracy of using flow technology to control oxygen concentrations, making it easy to perform reactions that may be challenging in batch mode.
To isolate and purify the arylacetaldehyde product, we chose to crystallize it as a bisulfite adduct. This is only possible due to the relatively pure production flow. The product components are collected directly from the reactor into an Etoh H2O stirred beaker containing sodium bisulfite, resulting in preferential crystallization of the arylacetaldehyde sulfite adduct.
The separation yields reported in Table 2 are calculated based on vacuum filtration of **arylacetaldehyde sulfite adduct crystals. Free aldehydes can be regenerated from sulfite adducts by the addition of hydrated sodium carbonate or, under non-aqueous conditions, by the addition of chlorotrimethylsilane.
Table 2Anti-markovnikov wacker oxidation of various functionalized styrene.
Aldehyde-selective trans-Markov Wacker oxidation of 1A was studied with optimal reaction conditions at hand, and a range of functionalized styrene was studied using the same flow settings as in Scheme 1, as shown in Table 2. Not surprisingly, the electronic properties of aryl substituents significantly influence selectivity and propensity for excessive oxidation. Electron-rich styrenes are slightly less selective and produce more methyl ketones, while substrates with halogen substituents are more inclined to generate the desired arylacetaldehyde product. However, electron-rich species are less susceptible to over-oxidation before reaching complete transformation. For example, the reaction of 4-(trifluoromethyl)styrene 1k forms a large number of by-products before all the initiators have been consumed. As a result, reduced residence time leads to lower conversion rates and lower by-product formation, resulting in higher overall yields. Both substrates 1e and 1j with ortho-substituents have good selectivity and less by-product formation. However, despite the high conversion rate of the resulting product for this process, the crystallization of some products proves more difficult, especially due to the small scale of the crystallization process. Examples with ortho-substituents prove to be particularly difficult to recover using this technique.
Scenario 1Reaction conditions: phme T-buoh (1:6), flow rate (0.)25+0.25 mlmin (-1)), reaction tube ring (v=30 ml), gas reactor (v=0.).7 ml）af2400（l=1.5 m）。Injection loop A (2 ml): Substrate 1A (0.)4 mmol，0.2m）。Injection ring B (2 ml) :(meCN)2PDCL2, CuCl2, H2O.
Using the reaction concentrations and conditions studied so far, 0A 4 mmol substrate uses an injection loop system. To demonstrate the scalability of the process, we plan to increase throughput and run the reaction continuously for several hours. A second optimization of the conditions is necessary to find the optimal oxygen pressure at higher substrate concentrations (see Table 3). Increase the reaction concentration to 0An initial attempt of 5m resulted in palladium-black precipitation (Experiment 1). This did not lead to a blockage of the reactor, but the concentration was subsequently reduced to 03m conducted the following experiments.
Table 3Optimize experimental options at scale.
Somewhat surprisingly, a large number of unreacted initiates were observed along with the by-products of excessive oxidation, similar to what was observed when the oxygen pressure in the batch pressure kettle was reduced. Reducing the cocatalyst load to 1 mol (Experiment 3) reduces the rate of competitive over-oxidation and achieves almost complete conversion.
When increasing the reaction concentration back to 0At 5m, palladium black formation is no longer an issue, but oxygen depletion continues to prevent full conversion from being achieved. A similar problem encountered by our group was solved by the introduction of a second gas reactor. As a result, we decided to look into a similar setup along the way.
The effect of doubling the oxygen addition to the reacting stream (Scheme 2) has been shown to favor an improvement in the yield of the desired product (Experiment 6). Oxygen depletion at high concentrations continues to hinder the progress of the reaction (Experiment 7), and further increases in oxygen pressure will only lead to unacceptable over-oxidation. Use 0A reaction concentration of 3M can achieve a conversion rate of 99 and increase the combined flow rate to 12 mlmin (-1) (40 min dwell time) finally provided acceptable amplification conditions (Experiment 9).
Scenario 2Flow diagram of multi-gram preparation using a second gas reactor for 2 h to provide sufficient oxygen**. A 5 ml injection loop was used during the optimization process, but was not used during the scale-up process, and the reagent was continuously introduced through the pump.
The total continuous yield from 3 mmol H (-1) used in Scheme 1 was increased to 21 by Scheme 2 and optimized scale-up conditions (Experiment 9, Table 3).6 mmol h^(-1)。A total of 96 mmol of substrate was processed for 1 h during the 6-hour run (taking into account all species in the reactor and dispersion effects). The export stream was collected into a large stirred beaker containing sodium bisulfite, and at the end of the experiment the crystals formed were filtered by vacuum filtration**. For 2 h of pure crystalline 4-chlorophenylacetaldehyde sulfite adducts, a total yield of 71 (1762 g, 68 mmol), and the selectivity of the crude product mixture was 76:4 (2h 3h).
Taken together, we have developed an efficient, reproducible, aluminate flow synthesis method for aryl acetaldehyde. It is only through flow technology such as an in-tube gas reactor that a molar ratio of oxygen can be precisely added to the reaction stream. In addition, the relatively pure flow of the product makes it possible to obtain the desired product by simple, selective crystallization of the formation of sulfite adducts. This air oxidation is suitable for electron enrichment and electron depletion of styrene. In addition, there is no need to use expensive separation technologies to remove spent oxidants, such as hydroquinone or metal-based oxidants. In addition, the use of an in-tube gas reactor to add only the necessary amount of pure oxygen to the pressurized reaction stream can increase the safety of such a process. There is no effective reactor headspace, which prevents solvent and oxygen from combining in the gas phase to form explosive mixtures and reduces the possibility of spontaneous ignition. In addition, there is no incentive to use a diluted oxygen mixture, and a lower, safer reactor pressure can be used to obtain the same oxygen concentration in the solution.
When oxygen depletion at high reaction concentrations became a problem, the scalability of the process was tested. However, rapid optimization and the use of a two-gas reactor setup allowed us to achieve similar reaction selectivity and increase the initial yield by a factor of 7, with the subsequent successful synthesis of the product on multiple restraints.
Second, the experimental part
Batch mode synthesis of styrene for aryl acetaldehyde will oxidize the hydroquinone (1.)15 equivalent) and catalyst (MECN) 2PDCl2 (25 mol%) was added to tert-butanol (10 ml) heated to 85. The olefins (125 mmol) and H2O (11 equivalent) to the reaction mixture (0125 m) and stir at 85 for 60 minutes. Alternatively, replace hydroquinone with CuCl2 (5 mol%) and pressurize the reaction vessel with pure O2 (10 bar). After 60 min, the reaction vessel is rapidly cooled to ice water and depressurized. Samples are taken immediately for gas chromatography analysis.
Flow mode synthesis of styrene for aryl acetaldehyde synthesis of alkenes (04 mmol) dissolved in Phme T-Buoh (1:6, 2 ml, 0.).2 M) and load injection loop A (2 ml). (meCN)2PDCl2 (5 mol%), CuCl2 (5 mol%), and H2O (1.)4 equivalent) dissolved in Phme T-Buoh (1:6, 2 mL) and loaded into injection loop B (2 mL). Use the Uniqsis FlowSyn reactor through two 2 ml PEEK injection loops A and B at 025+0.The reagent was pumped at a flow rate of 25 mlmin (-1) using Phme T-Buoh (1:6) as the storage solvent) and the two streams were combined through a T-mixer. The reaction mixture is then passed through a tubular gas reactor (v=0.) with a pressure of pure O2 (8 bar).7 ml）af2400（l=1.5 m) followed by a 30 ml stainless steel reaction coil at 60 8C (residence time: 60 min). The export stream passes through BPR (15 bar) and collects a 6 mL fraction (flushed with nitrogen) containing the reaction column and any dispersions and fills a 6 mL fraction containing NaHSO3 (04 mmol) dissolved in a bottle of H2O Etoh (1:1, 1 ml). Crystallization of aryl acetaldehyde sulfite adducts proceeds slowly (12 min) during the time of collection of the fraction. If desired, crystallization can be facilitated by further diluting the product fraction with ETOH. Collect adduct crystals by filtration with a Brinell funnel, wash with EToh and ET2O, and finally dry under vacuum. A small fraction of the sample can be taken for gas chromatography analysis to determine conversion and selectivity and then added to the sodium sulfite solution.
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