Ehu Camille Aka

Eric Wimmer

Elvina Barré

Natarajan Vasudevan

Daniel Cortés- Borda

Tchirioua Ekou

Lynda Ekou

Mireia Rodriguez-Zubiri

François-Xavier Felpin

Reconfigurable Flow Platform for Automated Reagent Screening and Autonomous Optimization for Bio-inspired Lignans Synthesis

Naturally occurring benzoxanthenones which belongs to the vast family of lignans, are promising biologically relevant targets. They are biosynthetically produced by the oxidative dimerization of 2-propenyl phenols. In this manuscript, we disclose a powerful automated flow-based strategy for identifying and optimizing a cobalt-catalyzed oxidizing system for the bio-inspired dimerization of 2-propenyl phenols. We designed a reconfigurable flow reactor associating on-line monitoring and process-control instrumentation. Our machine was first configured as an automated screening platform to evaluate a matrix of 4 catalysts (plus the blank) and 5 oxidant (plus the blank) at two different temperatures, resulting in an array of 50 reactions. The automated screening was conducted on micromole scale at a rate of one fully characterized reaction every 26 minutes. After having identified the most promising cobaltcatalyzed oxidizing system, the automated screening platform was straightforwardly reconfigured to an autonomous self-optimizing flow reactor by implementation of an optimization algorithm in the closed-loop system. The optimization campaign allowed the determination of very effective experimental conditions in a limited number of experiments which allowed to prepare natural products carpanone and polemannone B as well as synthetic analogues.

■ INTRODUCTION

Naturally occurring benzoxanthenones constitute a small group of natural products isolated as racemates and belonging to the vast family of lignans. [START_REF] Brophy | Novel lignans from a cinnamomum sp. from bougainville[END_REF] The most representative members of benzoxanthenone-based natural products include carpanone 1, polemannone A-C 2-4 and sauchinone 5 and feature a highly oxygenated polycyclic structure with five contiguous stereogenic centers (Figure 1). They have been identified as biologically relevant targets with anti-inflammatory, [START_REF] Bae | a lignan from Saururus chinensis, reduces tumor necrosis factor-α production through the inhibition of c-raf/MEK1/2/ERK 1/2 pathway activation[END_REF][START_REF] Gao | Sauchinone prevents IL-1β-induced inflammatory response in human chondrocytes[END_REF] hepatoprotective, 4- 5 and antitumor properties. [START_REF] Kim | Sauchinone exerts anticancer effects by targeting AMPK signaling in hepatocellular carcinoma cells[END_REF] Synthetic analogues have also been reported to be potent inhibitors of exocytosis and might be useful for the study of vesicular traffic. [START_REF] Goess | Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors[END_REF][START_REF] Lindsley | Solid-Phase Biomimetic Synthesis of Carpanone-like Molecules[END_REF] Therefore, the significant complexity of the benzoxanthenone skeleton associated to the potential of these structures to interfere with several biological mechanisms, make these structures appealing targets for synthetic chemists.

It has been postulated that the biosynthesis of the benzoxanthenone skeleton occurs through the oxidative dimerization of the corresponding 2-propenyl phenol. [START_REF] Brophy | Novel lignans from a cinnamomum sp. from bougainville[END_REF] This assumption was latter supported by synthetic studies showing that the bio-inspired oxidative dimerization of 2-propenyl phenols using a variety of oxidants such as PdCl 2 , [START_REF] Chapman | Total Synthesis of Carpanone[END_REF][START_REF] Liron | A New Cross-Coupling-Based Synthesis of Carpanone[END_REF] [Co]/O 2 , [START_REF] Matsumoto | Transition Metal(II) Schiff's Base Complexes Catalyzed Oxidation of trans-2-(1-propenyl)-4,5-methylenedioxyphenol to Carpanone by Molecular Oxygen[END_REF][START_REF] Baxendale | A Concise Synthesis of Carpanone Using Solid-Supported Reagents and Scavengers[END_REF] CuCl 2 /()sparteine/O 2 , [START_REF] Daniels | A New Catalytic Cu(II)/Sparteine Oxidant ystem for β,β-Phenolic Couplings of Styrenyl Phenols: Synthesis of Carpanone and Unnatural Analogs[END_REF][START_REF] Fadeyi | Total Synthesis of Polemannones B and C[END_REF] PhI(OAc) 2 [START_REF] Goess | Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic Inhibitors[END_REF][START_REF] Lindsley | Solid-Phase Biomimetic Synthesis of Carpanone-like Molecules[END_REF] and laccase, [START_REF] Constantin | Oxidative Dimerization of (E)-and (Z)-2-Propenylsesamol with O2 in the Presence and Absence of Laccases and Other Catalysts: Selective Formation of Carpanones and Benzopyrans under Different Reaction Conditions[END_REF] indeed furnishes the benzoxanthenone skeleton.

We recently described the multi-step synthesis of carpanone 1 in flow using a modular autonomous flow reactor. [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] Advantages of conducting reactions in flow with respect to traditional batch reactors include higher mass and heat transfers, better reproducibility, improved kinetics, safer experimental conditions and easier automation. [START_REF] Wegner | Ten Key Issues in Modern Flow Chemistry[END_REF][START_REF] Ley | On Being Green: Can Flow Chemistry Help?[END_REF][START_REF] Vaccaro | Flow Approaches Towards Sustainability[END_REF][START_REF] Gutmann | Continuous-Flow Technology-A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients[END_REF][START_REF] Movsisyan | Taming Hazardous Chemistry by Continuous Flow Technology[END_REF][START_REF] Plutschack | he Hitchhiker's Guide to Flow Chemistry[END_REF][START_REF] Oger | Handling Diazonium Salts in Flow for Organic and Material Chemistry[END_REF][START_REF] Oger | Using Aryl Diazonium Salts in Palladium-Catalyzed Reactions under Safer Conditions[END_REF] In our approach, all discrete steps of the flow synthetic route were optimized with the use of a black-box optimization algorithm working without a priori reaction and gradient information. In particular, the oxidative dimerization furnishing carpanone 1 was optimized in 1,2-dichloroethane using molecular oxygen as the oxidant associated to a Co II (salen) complex as the catalyst. While these experimental conditions furnished carpanone 1 in 82% isolated yield, we later faced difficulties to prepare multi-gram amounts of carpanone 1 for two reasons. First, under the optimal conditions, carpanone 1 was prepared with an excellent isolated yield (82%) but with a modest productivity (ca. 17 mg/h) due to the high dilute experimental conditions (ca.

0.015 M) and the modest kinetic (ca. 40 min residence time). Second, the use of a stock solution of 1,2-dichloroethane saturated with pure oxygen posed severe safety concerns for our industrial partner in charge of the scaling-up. [START_REF] Gavriilidis | Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries[END_REF] While the first issue could be addressed with an increase of the initial concentration of starting materials, the second issue required us to reinvestigate the oxidative conditions through the screening of alternative oxidants and catalysts compatible with a flow regime. The experimental flow setup we developed for the synthesis of carpanone in our previous investigations was not adapted for reagents screening as it would require the use of three streams for the starting material, oxidant and catalyst, respectively. This also implies that an automated screening of oxidants and catalysts was not possible as it would require a manual change of the stock solutions. In this manuscript, we report the development of a reconfigurable and intelligent synthesis platform that allows both automated micromole-scale reagent screening and autonomous reaction optimization in flow.

The automated platform includes a number of benefits as it allows very reproducible experiments on a micromole scale due to the use of a liquid handling robot and minimizes the consumption of solvent due to the use of a single stream. Additionally, the use of a liquid handling robot in charge of the reaction mixture preparation prevents issues associated with the reproducibility of the mixing process.

This machine led to the discovery of uncovered oxidative conditions for the construction of the benzoxanthenone skeleton and allowed the synthesis of naturally occurring capanone 1 and polemannone B 3 as well as a synthetic analogue.

■ RESULTS AND DISCUSSION

The bio-inspired oxidative dimerization of 2-propenyl phenols has been reported in batch under a variety of experimental conditions which are, for most of them, unsuitable for flow conditions due to either solubility issues (PdCl 2, laccase) or long reaction times (CuCl 2 /()-sparteine/O 2 , 24 h). We demonstrated that the use of Co II (salen)/O 2 as the oxidizing system could be efficiently transferred from batch to continuous flow conditions; [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] however, the use of molecular oxygen was associated with safety concerns, especially in the industrial environment. Considering that the reasonable price of cobalt-based catalysts was an important asset, we decided to explore the combination of a selection of commercially available Co catalysts with oxidants compatible with flow conditions to properly address safety concerns for scaling-up experiments; keeping in mind that oxidants are, by nature, hazardous compounds requiring careful handling, especially on large scale.

In our initial experimental procedure, a stock solution of cobalt catalyst in 1,2dichloroethane was saturated with oxygen gas (O 2 ). [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] While this protocol features an obvious simplicity reaching the main principles of sustainable chemistry, [START_REF] Hone | The Use of Molecular Oxygen for Liquid Phase Aerobic Oxidations in Continuous Flow[END_REF] it suffers from safety concerns upon scaling-up, as the stock solution could represent a highly flammable volume of several liters. [START_REF] Osterberg | Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry[END_REF] The other issue associated with this protocol is related to the difficulty in measuring the exact volume of O 2 dissolved in 1,2dichloroethane so that the amount of oxygen available for the oxidative dimerization could not be precisely determined. This point is particularly relevant upon increasing the concentration of starting material as the amount of oxygen required by unit of volume would substantially increase until reaching a value where oxygen becomes the limiting reagent. The use of a diluted gas mixture (5-10% O 2 in N 2 ) is an alternative strategy which allows users to keep the O 2 concentration in the organic solvent below the explosive limit. However, the low amount of O 2 which can be solubilized with such a strategy could preclude the reaction to reach complete conversion. [START_REF] Ye | Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions[END_REF] With the aim of addressing these limitations we embarked on the search for a new oxidizing system avoiding the use of O 2 . In this frame, we designed a new reconfigurable and fully automated screening platform capable of preparing reaction mixture from specified reagents on the μmol scale (Figure 2, see also Figure S2 in SI for a photograph of the platform). Our one-stream system includes a liquid handling robot in charge of the reaction mixture preparation, a pump, a thermostated reactor coil and a switch valve which samples a small fraction of the crude mixture for the on-line HPLC analysis.

FIGURE 2.

Evaluation of oxidizing systems through a mol scale automated screening platform An automatic data processing integrates the chromatogram and calculates the yield using an internal standard. All modules from the screening platform are connected to a computer through RS-232 ports and controlled with an ad-hoc process-control software.

To start a screening campaign, an operator populates the 56-well plate with vials containing the required reagents (starting material, catalyst, base…). After having fed the process-control software with the concentration of the stock solution-containing vials, the composition of the reaction mixture, the stoichiometry chosen for the screening and the volume injected in the coil reactor, the sampling robot automatically determines the volume of suction in each vial to prepare the reacting mixture injected in the coil reactor. Two different setups were designed depending on the nature of the oxidant. Non-gaseous oxidants were sampled by the liquid handling robot from the stock solutions and the reaction occurred in a PEEK reactor. Gaseous oxidants such as air and oxygen were supplied to the reaction mixture through the use of a gas-permeable coil reactor made from the AF-2400 polymer. [START_REF] O' Rien | Flow Ozonolysis Using a emipermeable Teflon AF-2400 Membrane o Effect Gas-iquid Contact[END_REF][START_REF] Rzozowski | Flow Chemistry: Intelligent Processing of Gas-Liquid Transformations Using a Tube-in-Tube Reactor[END_REF] The search for a new oxidizing system using the screening platform was carried out with the benchmark oxidative dimerization of 2-propenyl phenol 6 to benzoxanthenone 10. We °C. For safety reasons we did not studied gaseous oxidant, and especially oxygen, at 50 °C. In this screening campaign the use of oxygen served as a standard to assess the efficiency of other oxidants screened. To our knowledge, the cobalt-catalyzed oxidative dimerization of 2propenyl phenols had only been investigated with oxygen as oxidant and the potential of alternative oxidants in promoting the expected dimerization remained to be demonstrated.

Reactions explored with the screening platform were arbitrarily conducted using 4 μmol of 6 with 1.5 equivalents of non-gaseous oxidant and 10 mol% of cobalt catalyst at either 25 or 50 °C. By using a high loading of cobalt catalysts and an excess of oxidant, we minimize the risk of missing an effective Co/oxidant combination. 2-Propenyl phenol 6, non-gaseous oxidants and cobalt catalysts were prepared as stock solutions in 1,2-dichloroethane at 0.2, 0.4, and 0.0025 M, respectively and placed in the 56-well plate of the liquid handling robot. For the use of gaseous oxidants, the experimental setup was slightly modified by switching the PEEK reactor for a gas permeable tubing reactor made from AF-2400 polymer that passed through a chamber supplied with a flow of either air or oxygen. [START_REF] O' Rien | Flow Ozonolysis Using a emipermeable Teflon AF-2400 Membrane o Effect Gas-iquid Contact[END_REF] This procedure differs from the one we previously published and addresses the risk of lacking oxidant when using concentrated solution of 2-propenyl phenols. In order to allow the screening at an elevated throughput, all reactions were conducted at a single residence time of 10 minutes. Each fully automated experiment, including the robot-mediated reaction mixture preparation, the reaction time, the on-line HPLC analysis and the data processing (integration and yield calculation) was completed in ca. 26 minutes and the screening campaign was achieved at a rate of 27 experiments every 12 hours; for safety reason the machine was not used overnight. Both oxidants and catalysts were selected

for their (i) potential to promote the oxidative dimerization, (ii) solubility in 1,2dichloroethane, (iii) ease of handling under standard conditions and (iv) commercial availability. Several oxidants were discarded as they were either insoluble in DCE (DDQ and TEMPO) or required aqueous biphasic conditions (H 2 O 2 and Oxone ® ).

The analysis of the 50-reaction screen revealed several interesting features (Figure 3). Having identified [Co]-9a/t-BuOOH 8a as the most promising oxidative system from the screening of 50 reactions, we further optimized experimental conditions using an autonomous self-optimizing flow reactor. This emerging technology combines the power of automated flow devices with an assistive optimization algorithm and integrates a quasi-real time in-line/online monitoring. [START_REF] Rasheed | Intelligent Microflow: Development of Self-Optimizing Reaction Systems[END_REF][START_REF] Fabry | Self-Optimizing Reactor Systems: Algorithms, On-line Analytics, Setups, and Strategies for Accelerating Continuous Flow Process Optimization[END_REF][START_REF] Fabry | Online Monitoring and Analysis for Autonomous Continuous Flow Self-Optimizing Reactor Systems[END_REF][START_REF] Sans | Towards Dial-a-Molecule by Integrating Continuous Flow, Analytics and Self-Optimisation[END_REF][START_REF] Reizman | Feedback in Flow for Accelerated Reaction Development[END_REF] In most chemical laboratories, optimizations are traditionally conducted by modifying one factor at a time until reaching an optimum. While the simplicity of execution is the major asset explaining the popularity of this approach, the data obtained fail to explain interactions between variables, precluding any efficient automation. The automated screening of a set of predetermined experimental conditions generated from design-ofexperiment (DoE) methods partially addresses the issues of one-factor-at-a-time optimizations. However, multi-variable optimizations using DoE methods usually require a high number of experiments to locate a satisfactory optimum.

The use of feedback algorithms working in black box-type systems is a powerful alternative to traditional one-factor-at-a-time and DoE methods for optimizing chemical reactions. [START_REF] Henson | Designing Algorithms To Aid Discovery by Chemical Robots[END_REF][START_REF] Gromski | How to explore chemical space using algorithms and automation[END_REF] Several black box algorithms of different numerical complexity have been reported in the literature for integration in self-optimizing flow devices. [START_REF] Krishnadasan | Intelligent Routes to The Controlled Synthesis of Nanoparticles[END_REF][START_REF] Mcmullen | An Automated Microfluidic System for Online Optimization in Chemical Synthesis[END_REF][START_REF] Parrott | Self-Optimizing Continuous Reactions in Supercritical Carbon Dioxide[END_REF][START_REF] Moore | Automated Multitrajectory Method for Reaction Optimization in a Microfluidic System using Online IR Analysis[END_REF][START_REF] Skilton | Real-Time Feedback Control Using Online Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy for Continuous Flow Optimization and Process Knowledge[END_REF][START_REF] Houben | Closed-Loop Multitarget Optimization for Discovery of New Emulsion Polymerization Recipes[END_REF][START_REF] Holmes | Online Quantitative Mass Spectrometry for the Rapid Adaptive Optimisation of Automated Flow Reactors[END_REF][START_REF] Holmes | Self-Optimisation of the Final Stage in the Synthesis of EGFR Kinase Inhibitor AZD9291 Using an Automated Flow Reactor[END_REF][START_REF] Walker | Tuning Reaction Products by Constrained Optimisation[END_REF][START_REF] Echtermeyer | Self-Optimisation and Model-Based Design of Experiments for Developing a C-H Activation Flow Process[END_REF][START_REF] Jeraal | Enhanced Process Development Using Automated Continuous Reactors by Self-Optimisation Algorithms and Statistical Empirical Modelling[END_REF][START_REF] Cherkasov | OpenFlowChema platform for quick, robust and flexible automation and self-optimisation of flow chemistry[END_REF] From these algorithms, the Nelder-Mead method, 50 also known as the simplex method, has been reported to be one of the simplest for implementation in automated flow reactors. [START_REF] Mcmullen | An Integrated Microreactor System for Self-Optimization of a Heck Reaction: From Micro-to Mesoscale Flow Systems[END_REF][START_REF] Bourne | Adaptive Process Optimization for Continuous Methylation of Alcohols in Supercritical Carbon Dioxide[END_REF][START_REF] Jumbam | The Effect of Self-Optimisation Targets on the Methylation of Alcohols Using Dimethyl Carbonate in Supercritical CO2[END_REF][START_REF] Amara | Automated Serendipity with Self-Optimizing Continuous-Flow Reactors[END_REF][START_REF] Sans | A Self Optimizing Synthetic Organic Reactor System Using Real-Time In-Line NMR Spectroscopy[END_REF][START_REF] Fitzpatrick | A Novel Internet-Based Reaction Monitoring, Control and Autonomous Self-Optimization Platform for Chemical Synthesis[END_REF][START_REF] Poscharny | Machine Assisted Reaction Optimization: A self-Optimizing Reactor System for Continuous-Flow Photochemical Reactions[END_REF][START_REF] Hsieh | Photoredox Iridium-Nickel Dual-Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor[END_REF][START_REF] Wimmer | An autonomous self-optimizing flow machine for the synthesis of pyridine-oxazoline (PyOX) ligands[END_REF][START_REF] Soldatova | Flow Synthesis of Iodonium Trifluoroacetates through Direct Oxidation of Iodoarenes by Oxone®[END_REF] Numerically, it is one of the simplest optimization algorithms and does not require gradient approximation which is a strong asset when working with expensive experiments. However, the Nelder-Mead method suffers from two important drawbacks: (i) it does not converge rapidly when optimizing large multi-variable problems and (ii) it only converges to a local optimum which quality highly depends on the initialization and the studied system. [START_REF] Baumgartner | Optimum catalyst selection over continuous and discrete process variables with a single droplet microfluidic reaction platform[END_REF] We addressed these issues through the development of a profoundly modified version of the Nelder-Mead method that includes (i) the possibility to temporarily modify the dimensionality of the search to explore a subspace, (ii) multiple stopping criteria to lower the number of experiments, (iii) diversification and intensification mechanisms to escape from an unsatisfactory local optimum, (iv) the golden search method for 1-D optimizations which cannot be addressed by the Nelder-Mead method. [START_REF] Cortés-Borda | Optimizing the Heck-Matsuda Reaction in Flow with a Constraint-Adapted Direct Search Algorithm[END_REF] Moreover, in addition to the traditional linear constraints imposed by boundary constraints, our algorithm contains an optional mechanism to restrict the search space through linear constraints in order to exclude experimental conditions considered as unsound (lack of reactivity, poor stability of reagents/products…).

The transformation of our automated screening platform to an autonomous selfoptimizing flow reactor was straightforward and convenient as the only modification consisted of the integration of our additional optimization algorithm to the processcontrol software. Our approach allows to either screen discrete variables for reaction development or continuous variables for a fine-tuning of experimental conditions (selfoptimization). While the use of automated screening platforms have been described in the literature, [START_REF] Shi | Capillary-Based, Serial-Loading, Parallel Microreactor for Catalyst Screening[END_REF][START_REF] Goodell | Development of an Automated Microfluidic Reaction Platform for Multidimensional Screening: Reaction Discovery Employing Bicyclo[3.2.1octanoid Scaffolds[END_REF][START_REF] Fang | Rapid Catalyst Screening by a Continuous-Flow Microreactor Interfaced with Ultra-High-Pressure Liquid Chromatography[END_REF][START_REF] Treece | Reaction Discovery Using Microfluidic-Based Multidimensional Screening of Polycyclic Iminium Ethers[END_REF][START_REF] Moore | Kinetics analysis and automated online screening of aminocarbonylation of aryl halides in flow[END_REF][68] the use of a reconfigurable platform for either screening or selfoptimization offers a much higher flexibility. The optimization was conducted at higher concentrations with stock solutions of 2-propenyl phenol 6, [Co]-9a and t-BuOOH 8a at concentration of 1 M, 0.03 M and 2 M, respectively, in order to assure an elevated throughput.

The reaction yield was optimized in a 4-dimension space where the residence time, temperature, equivalent of t-BuOOH 8a and loading of [Co]-9a were selected as input variables in the range of 5-60 minutes, 25-50 °C, 1-2 equivalents, 1-10 mol%, respectively. In addition to the bounded search space, we also fixed the initial point X 0 at 5 minutes of residence time, 25 °C, 1 equivalent of t-BuOOH 8a and 5 mol% of [Co]-9a with d values of 10 min, 5 °C, 0.2 equivalent and 2 mol%, respectively. While we preferred to focus on the reaction yield optimization, we were also interested in developing experimental conditions allowing decent productivity. Therefore, for experimental conditions displaying the highest yields, the associated productivity have been considered as well. respectively. The calculated productivity for each experiment can be found in Table S1.

Unfortunately, upon purification by flash chromatography, benzoxanthenone 10 turned to be extremely instable in our hand, leading to a modest isolated yield (55%).

We further pursued our efforts toward the synthesis of natural lignans carpanone 1

and polemannone B 3 using the optimized conditions from experiment 16.

Desmethoxycarpacine 12, obtained in three steps from sesamol 11 following our previously published flow procedure, was dimerized to carpanone 1 in 85% isolated yield (Scheme 1). [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] A minor isomer, identified on the crude mixture (ca. 3%), was lost during the purification step and carpanone 1 was isolated as a single isomer. In such experimental conditions the productivity spectacularly increased from ca. 17 mg/h using our previous setup to ca. 263 mg/h in this work. The reproducibility of our automated screening platform machine was also assessed with the oxidative dimerization of desmethoxycarpacine 12 to carpanone 1 on 6 consecutive runs in the optimal conditions of experiment 16. The reaction yields calculated by the online HPLC system were 85, 86, 86, 86, 86 and 87%, respectively, corresponding to an average HPLC yield of 86% (vs 85% for the isolated yield) and a standard deviation of only 0.63. In all our tests, regardless of the oxidant used, we never observed the formation of benzopyrane-type structures. In a previous report we proposed an initial para-quinol-type coupling followed by an endo-[4+2] cycloaddition (Scheme 5, top). [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] While this mechanism properly explains the anti-selectivity at the methyl group, we did not have any experimental evidence at that time to support this proposal. We have reinvestigated this mechanism, and we are now able to confirm our proposal when using [Co]-9a/t-BuOOH 8a as oxidizing system.

The oxidation of [Co]-9a by t-BuOOH 8a produces the corresponding Co III (salen)(OH) complex 19 along with the tert-butoxy radical (Scheme 5, bottom). [START_REF] Forster | Cobalt Schiff base complex-catalyzed oxidation of anilines with tert-butyl hydroperoxide[END_REF]

■ CONCLUSION

In this work we designed a reconfigurable flow reactor which could be used either as an automated screening platform or as an autonomous self-optimizing reactor for natural product synthesis. The capability of our automated screening platform to screen discrete variables on the micromole scale and analyze the crude content through an online monitoring in a short time frame is a strong asset in reaction discovery. By associating process control instrumentation and online analysis to an optimization algorithm in a closed-loop system, the screening platform can be easily transformed to a powerful autonomous self-optimizing flow reactor for the optimization of continuous variables. The automated screening platform identified a new cobalt-catalyzed oxidative system for the dimerization of 2-propenyl phenols to benzoxanthenone skeletons from an array of 50 reactions which represent a total of only 200 μmol (0.66 mg per reaction) of starting material. The cobalt-catalyzed oxidative system identified with the screening platform was further optimized in a 4-dimension space using an autonomous closed-loop system. A very satisfactory optimum was located after only 16 experiments and the system reached a stopping criterion after only 24 experiments.

This cobalt-catalyzed oxidizing proved to be particularly efficient to prepare natural products carpanone and polemannone B as well as a synthetic analogue.

Through this work, we demonstrated that while essentially used for preparative procedures, flow reactors are also particularly well suited for automated reagent screening and autonomous reaction optimization. While the development of automation in chemistry is a modern preoccupation, [START_REF] Skilton | Remote-Controlled Experiments with Cloud Chemistry[END_REF][START_REF] Bédard | Reconfigurable system for automated optimization of diverse chemical reactions[END_REF][START_REF] Ingham | Camera-Enabled Techniques for Organic Synthesis[END_REF][START_REF] Ley | Organic Synthesis: March of the Machines[END_REF][START_REF] Fitzpatrick | Engineering Chemistry for the Future of Chemical Synthesis[END_REF][START_REF] Ley | The Engineering of Chemical Synthesis: Humans and Machines Working in Harmony[END_REF] the results described in this work shows that process control instrumentation associated to menial and assistive algorithms assist chemists and improve their intellectual productivity.

■ EXPERIMENTAL SECTION

General information. All commercially available chemicals were used as received unless otherwise noted. [START_REF] Brophy | Novel lignans from a cinnamomum sp. from bougainville[END_REF] H and [START_REF] Daniels | A New Catalytic Cu(II)/Sparteine Oxidant ystem for β,β-Phenolic Couplings of Styrenyl Phenols: Synthesis of Carpanone and Unnatural Analogs[END_REF] C NMR spectra were recorded at 300 or 400 and 75 MHz or 100 MHz, respectively. 1 H and [START_REF] Daniels | A New Catalytic Cu(II)/Sparteine Oxidant ystem for β,β-Phenolic Couplings of Styrenyl Phenols: Synthesis of Carpanone and Unnatural Analogs[END_REF] C NMR spectra were referenced to the internal deuterated solvent (CDCl 3 ) at 7.26 and 77.16 ppm, respectively. FT-IR spectra were recorded in the ATR mode. Wavelengths of maximum absorbance (ν max ) are quoted in wave numbers (cm -1 ). High resolution mass spectrometry (HRMS) was recorded on a microTOF spectrometer equipped with orthogonal electrospray interface (ESI). Analytical thin-layer chromatography (TLC) was carried out on silica gel 60 F 254 plates and visualized with a UV lamp at 254 nm or stained with a basic potassium permanganate solution. Flash column chromatography was performed using silica gel 60 (40-63 µm).

Details of the experimental setup. HPLC pumps (JASCO PU2080

) equipped with a RS-232 port were employed to flow the solution through the system. A sampler handler (JASCO AS 2055) equipped with a RS-232 port was used to inject the reagents in the line. The reactor coil was heated with a heating plate (Heidolph, MR Hei-Connect) equipped with a RS-232 port. A 2-way 6-port valve (VICI, Cheminert C2-3006D) equipped with a RS-232 port was used to inject an aliquot of the crude mixture within the on-line HPLC unit. The HPLC column outlet was connected to a UV detector (JASCO, UV 2075) equipped with a RS-232 port. The flow outlet was connected to a programmable fraction collector (Advantec, CHF 1225C). All units equipped with a RS-232 port were autonomously controlled with MATLAB ® through the use of communication protocols provided by the manufacturers.

Synthesis of (E)-4-methoxy-2-(prop-1-en-1-yl)phenol (6)

. [START_REF] Daniels | A New Catalytic Cu(II)/Sparteine Oxidant ystem for β,β-Phenolic Couplings of Styrenyl Phenols: Synthesis of Carpanone and Unnatural Analogs[END_REF] To a solution n-BuLi ( The reaction mixture was injected in a stream of C 2 H 4 Cl 2 pumped at 0.5 mL/min as depicted in Figure 2. The oxidative dimerization occurred either in a PEEK reactor coil (5 mL, 0.75 mm id) heated at the required temperature (25 or 50 °C) for oxidants 8a-c or in a AF-2400 reactor coil that passed through a glass bottle closed with a GL-45 cap and supplied with a flow of either air or oxygen. [START_REF] O' Rien | Flow Ozonolysis Using a emipermeable Teflon AF-2400 Membrane o Effect Gas-iquid Contact[END_REF] The reactor outlet was connected to an automatic 2-way 6-port switch valve which injected 0.2 µL of the crude mixture in the HPLC unit while the remaining stream was collected in a fraction collector. A mixture of MeOH/H 2 O (70/30, v/v) was used as mobile phase for the HPLC analysis at a flowrate of 0.4 mL/min. A UV detector was connected to the outlet of the HPLC column (Agela Promosil C18, 3.5 mm × 150 mm, 5 µm) to follow the absorbance at a wavelength of 270 nm. Peak integration and yield calculation were under full MATLAB automation.

Experimental setup of the autonomous self-optimizing flow reactor. Synthesis of benzoxanthenone (10).

Synthesis of Carpanone (1).

An automatic sample handler prepared 200 µL of the reaction mixture from stock solutions of (E)-6-(prop-1-enyl)-1,3-benzodioxol-5-ol 12 [START_REF] Cortés-Borda | An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone[END_REF] (0.25 M, 1 equiv), t-BuOOH 8a (0.5 M, 1.09 equiv) and [Co]-9a (0.03 M, 1 mol%). The reaction mixture was injected in a stream of C 2 H 4 Cl 2 pumped at 0.19 mL/min as depicted in Scheme 1. The oxidative dimerization occurred in a PEEK reactor coil (5 mL, 0.75 mm id) heated at 32 °C.

The reactor outlet was connected to an automatic 2-way 6-port switch valve which injected 0.2 µL of the crude mixture in the HPLC unit while the remaining stream was collected in a fraction collector. A mixture of MeOH/H 2 O (70/30, v/v) was used as mobile phase for the HPLC analysis at a flowrate of 0.4 mL/min. A UV detector was connected to the outlet of the HPLC column (Agela Promosil C18, 3.5 mm × 150 mm, 5 µm) to follow the absorbance at a wavelength of 270 nm. Peak integration and yield calculation were under full MATLAB

automation. An analytical sample of carpanone 1 was obtained by flash chromatography (10% (34 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 24 h. After completion, the mixture was diluted with chloroform (50 mL) and was successively washed with saturated aqueous Na 2 SO 3 solution (50 mL), saturated aqueous Na 2 CO 3 solution (50 mL), brine (50 mL) and water (50 mL). The organic phase was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The crude formate was obtained as a yellow oil (1.82 g, 80%) and directly used in the next step without further purification.

5-Allyloxy-4-hydroxy-1,3-benzodioxole (15). [START_REF] Majerus | New syntheses of dillapiol [4,5dimethoxy-6-(2-propenyl)-1,3-benzodioxole], its 4-methylthio and other analogs[END_REF]

FIGURE 1 .

 1 FIGURE 1. Naturally occurring benzoxanthenones lignans. Oxidative dimerization of 2propenyl phenols as inset.

prepared a 40 -

 40 member 3-dimensional array from a selection of 3 non-gaseous oxidants 8a-c (plus one blank) and 4 cobalt catalysts 9a-d (plus one blank). The array was split in two runs of 20 experiments carried out at 25 and 50 °C. An additional 10-member 2D array from a selection of catalysts 9a-d (plus one blank) and 2 gaseous oxidants 8d-e were conducted at 25

First, reaction conducted at 50 FIGURE 3 .

 503 FIGURE 3. Heatmap visualization of the automated micromole-scale screen across a 50member array.

FIGURE 4 .

 4 FIGURE 4. (a) Maximization of the yield of benzoxanthenone 10. (b) Representation of the four-dimensional experimental conditions for the maximization of the yield for benzoxanthenone 10.

SCHEME 1 .

 1 SCHEME 1. Improved flow synthesis of carpanone 1 in flow.

SCHEME 2 .SCHEME 3 . 15 SCHEME 4 .

 23154 SCHEME 2. Total synthesis of Polemannone B 3 under mixed batch/flow modes.

SCHEME 5 .

 5 SCHEME 5. Mechanistic proposal for the bio-inspired formation of benzoxanthenones lignans through Co(II)/t-BuOOH oxidative dimerization of 2-propenyl phenols.

Found 165. 0920

 0920 Experimental setup of the automated screening platform. An automatic sample handler prepared 200 µL of the reaction mixture from stock solutions of 2-propenyl phenol 6 (0.2 M plus xylene as the internal standard at 0.5 M), oxidants (0.4 M) and catalysts (2.5 × 10 3 M).

  An automatic sample handler prepared 200 µL of the reaction mixture from stock solutions of 2-propenyl phenol 6 (1 M plus xylene as the internal standard at 2.5 M), t-BuOOH 8a (2 M) and [Co]-9a (0.03 M). The reaction mixture was injected in a stream of C 2 H 4 Cl 2 pumped at the required flow. The oxidative dimerization occurred in a PEEK reactor coil (5 mL, 0.75 mm id) heated at the required temperature. The reactor outlet was connected to an automatic 2-way 6-port switch valve which injected 0.2 µL of the crude mixture in the HPLC unit while the remaining stream was collected in a fraction collector. A mixture of MeOH/H 2 O (70/30, v/v) was used as mobile phase for the HPLC analysis at a flowrate of 0.4 mL/min. A UV detector was connected to the outlet of the HPLC column (Agela Promosil C18, 3.5 mm × 150 mm, 5 µm) to follow the absorbance at a wavelength of 270 nm. Peak integration and yield calculation were under full MATLAB automation. The calculated yield was automatically sent to the algorithm which set new experimental conditions to the units via RS-232 ports. A 4-D optimization of the reaction yield was conducted using the temperature, residence time, loading of [Co]-9a and equivalents of t-BuOOH 8a as the input variables. The initial experiment of the simplex was: 25 °C, 5 min of residence time, 5 mol% of [Co]-9a and 1 equivalent of t-BuOOH 8a with d values of 5 °C, 10 min, 2 mol% and 0.2 equivalent, respectively. The lower and upper boundaries of the research space were the following: 25-50 °C, 5-60 min, 1-10 mol% and 1-2 equiv. for the temperature, residence time, catalyst loading and equivalents of oxidant, respectively. An optimum giving 92% HPLC yield was found in experiment 16 at 32 °C, 27 min of residence time, 1 mol% of [Co]-9a and 1.09 equivalents of t-BuOOH 8a (see

5 -

 5 Allyloxy-1,3-benzodioxole(13).The experimental setup consisted in two streams as depicted in Scheme 2. The first stream contained a solution of sesamol 11 (0.4 M) and KOH (0.6 M) in MeOH/H 2 O (95/5, v/v) while the second stream contained a solution of alkyl iodide (0.8 M) in MeOH/H 2 O (95/5, v/v). Each solution was continuously pumped with two independent pumps at 32 µL/min for the first stream and 29 µL/min for the second stream. The two streams met in a stainless steel T-shaped piece (internal volume: 0.57 μL). The resulting mixture was introduced in a stainless steel reactor coil (2 mL, 0.75 mm id) heated at 75 °C. The reactor outlet was connected to a back pressure regulator (BPR) to maintain the internal pressure at ca. 15 bar. An analytical sample of 5-allyloxy-1,3-benzodioxole 7 was obtained by flash chromatography (10% AcOEt-petroleum ether) as a colourless oil (1.04 g, 76%). IR (ATR) ν 2283, 1629, 1483, 1178, 1035, 923, 780 cm -1 . 1 H NMR (300 MHz, CDCl 3 ,) δ 6.70 (d, 1H, J = 8.5 Hz), 6.52 (d, 1H, J = 2.5 Hz), 6.34 (dd, 1H, J = 2.5, 8.5 Hz), 6.03 (ddt, 1H, J = 5.3, 10.6, 17.2 Hz), 5.91 (s, 2H), 5.39 (dq, 1H, J = 1.6, 17.3 Hz), 5.28 (dq, 1H, J = 1.4, 10.5 Hz), 4.46 (dt, 2H, J = 1.5, 5.3 Hz).

  Scheme 2. The oxidative dimerization occurred in a PEEK reactor coil (5 mL, 0.75 mm id) heated at 32 °C. The reactor outlet was connected to an automatic 2-way 6-port switch valve which injected 0.2 µL of the crude mixture in the HPLC unit while the remaining stream was collected in a fraction collector. A mixture of MeOH/H 2 O (70/30, v/v) was used as mobile phase for the HPLC analysis at a flowrate of 0.4 mL/min. A UV detector was connected to the outlet of the HPLC column (Agela Promosil C18, 3.5 mm × 150 mm, 5 µm) to follow the absorbance at a wavelength of 270 nm. Peak integration and yield calculation were under full MATLAB automation. An analytical sample of polemannone B 3 was obtained by flash chromatography (20% Et 2 O-cyclohexane) as a white solid (25.2 mg, 84%). mp 160-161°C

  TableS1in SI for details). In the subsequent experiments, the algorithm rapidly decreased the loading of [Co]-9a until reaching the lower bound at 1 mol%, while in the same time the residence time progressively increased to ca. 30 minutes. On the other hand, both the equivalents of t-BuOOH 8a and the temperature were set to ca. 1.00-1.10 equivalents and 27-33 °C, respectively. The algorithm reduced the dimension From the 24 experiments conducted through this optimization campaign, we observed two appealing solutions corresponding to experiments 16 and 17 which led to benzoxanthenone 10 as a single diastereoisomer with 92 and 95% yield, respectively. A closer look on the experimental conditions revealed that experiment 16 (27 minutes, 32 °C, 1.09 equiv 8a and 1 mol% 9a) provided a better productivity than experiment 17 (31 minutes, 29 °C, 1.08 equiv 8a, and 1 mol% 9a) with values of 887 and 800 mg.h -1 ,

of the search from experiment 17 by fixing the catalyst loading to its lower bound, reaching an optimum corresponding to 95% yield. After 5 consecutive simplexes which did not improve the reaction yield, the algorithm reached a stopping criterion and the optimization stopped after experiment 24.

Table S1

 S1

	for details). An analytical sample
	of benzoxanthenone 10 was obtained by flash chromatography (10% Et 2 O-cyclohexane) as a
	white solid (23.8 mg, 55%). mp 88.5-89.5 °C. IR (ATR) ν 2958, 2929, 2873, 2835, 1678,
	1617, 1492, 1268, 1199, 1115, 1035 cm -1 . 1 H NMR (300 MHz, CDCl 3 ) δ 7.24 (d, 1H, J = 10.2
	Hz), 7.01-7.03 (m, 1H), 6.89-6.90 (m, 1H), 6.75 (d, 1H, J = 8.7 Hz), 6.66 (dd, 1H, J = 2.8, 8.8
	Hz), 6.31 (d, 1H, J = 10.2 Hz), 3.76 (s, 3H), 3.31-3.33 (m, 1H), 3.31 (s, 3H), 3.12-3.16 (m,
	1H), 2.59-2.66 (m, 1H), 2.17-2.23 (m, 1H), 1.15 (d, 3H, J = 7.2 Hz), 0.67 (d, 3H, J = 7.5 Hz).
	13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 186.8, 154.4, 145.1, 143.7, 142.7, 131.8, 128.1, 125.6,
	118.0, 113.6, 113.3, 55.8, 49.3, 37.1, 36.8, 35.2, 34.0, 21.8, 21.4. HRMS (ESI) m/z [M + Na] +
	Calcd for C 20 H 22 NaO 4 349.1416; Found 349.1407.

  78 °C. The resulting yellow solution was stirred for 45 min and then dry DMF (1.25 mL, 15.8 mmol) was added. After 30 min at 78 °C, the reaction mixture was hydrolyzed with saturated NH 4 Cl solution and extracted with Et 2 O (3 × 20 mL). The collected organic fractions were dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. Purification by flash chromatography (60% CH 2 Cl 2 -petroleum ether) furnished the

	13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 154.2, 148.3, 141.8, 133.5, 117.7, 108.0, 106.1, 101.2, 98.4, 69.9. HRMS (ASAP+) m/z [M] + Calcd for C 10 H 10 O 3 178.0630; Found 178.0631. 5-Allyloxy-4-formyl-1,3-benzodioxole (14). 80 A solution of n-BuLi (6 mL, 1.6 M) was added dropwise to a solution of 5-allyloxy-1,3-benzodioxole 13 (1.41 g, 7.91 mmol) in dry IR (ATR) ν 2881, 1675, 1630, 1455, 1234, 1075, 913, 745 cm -1 . 1 H NMR (300 MHz, CDCl 3 ) δ 10.42 (s, 1H), 6.89 (d, 1H, J = 8.6 Hz), 6.33 (d, 1H, J = 8.6Hz), 6.09 (s, 2H), 5.98-6.12 (m, 1H), 5.42 (dq, 1H, J = 1.6, 17.2 Hz), 5.31 (dq, 1H, J = 1.4, 10.5 Hz), 4.56 (dt, 2H, J = 1.5, 5.2 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 188.3, 155.3, 148.5, 142.8, 132.6, 118.1, 113.1, 111.3, 103.8, 103.1, 70.2. HRMS (ESI) m/z [M + Na] + Calcd for C 11 H 10 O 4 Na 229.0477; Found : 229.0485. 5-Allyloxy-4-formate-1,3-benzodioxole. m-CPBA (5.62 g, 19.5 mmol, 60% in water) was THF (20 mL) at corresponding aldehyde 14 (823 mg, 51%) as a yellow solid. mp 98-99 °C [Lit. 80 98-100 °C]. added to a solution of 4-formyl-5-allyloxy-1,3-benzodioxole (2.12 g, 10.3 mmol) in CHCl 3

  2 CO 3(2.40 g, 17.39 mmol) and CH 3 I (2.70 ml, 43.48 mmol, 5 equiv). The resulting reaction mixture was stirred at 25 °C for 72 h and then evaporated to dryness under reduced pressure. Inorganic residues were dissolved in water (15 mL) and the aqueous phase was extracted with Et 2 O (3 × 15 mL). The collected organic extracts were dried over anhydrous MgSO 4 and concentrated under reduced pressure and the resulting residue was purified by flash chromatography (from 30% CH 2 Cl 2 -petroleum ether to 50% CH 2 Cl 2 -petroleum ether) to give 17 as a white solid (791 mg, 89%). mp 31.5-32 °C. IR (ATR) ν 3503, 2885, 1637, 1432, 1176, 1045, 981, 915, 645 cm -1 . 1 H NMR (300 MHz, CDCl 3 ) δ 6.33 (s, 1H), 5.88-6.02 (m, 1H), 5.85 (s, 2H), 5.40 (br s, 1H), 5.02-5.09 (m, 2H), 4.04 (s, 3H), 3.31 (dt, 2H, J = 1.2, 6.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 141.8, 140.0, 136.9, 134.4, 131.2, 117.7, 115.5, 103.0, 101.0, 60.0, 33.9. HRMS (ASAP+) m/z [M] + Calcd for C 11 H 12 O 4 208.0736; Found : 208.0736. (E)-5-hydroxy-4-methoxy-6-(prop-1-enyl)-1,3-benzodioxole (18). A solution of t-BuOK in THF (3.5 mL, 3.47 mmol, 1 M, 1.2 equiv) was added to a solution of 5-hydroxy-4-methoxy-6-(2-propenyl)-1,3-benzodioxole 17 (603 mg, 2.90 mmol, 1 equiv) in THF (3 mL) under argon. The resulting mixture was stirred at 70 °C for 90 min and then quenched with water (50 mL) and 5% HCl (10 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). The collected organic extracts were dried over anhydrous MgSO 4 and concentrated under reduced pressure. Purification by flash chromatography (30% CH 2 Cl 2 -petroleum ether) furnished 18 as a white solid (295 mg, 49%). mp 66-67 °C. IR (ATR) ν 3382, 2886, 1622, 1422, 1178, 1046, 977, 927, 803 cm -1 . 1 H NMR (400 MHz, CDCl 3 ) δ 6.61 (dq, 1H, J = 1.5, 15.8 Hz), 6.58 (s, 1H), 6.08 (dq, 1H, J = 6.6, 15.8 Hz), 5.56 (s, 2H), 5.54 (s, 1H), 4.04 (s, 3H), 1.87 (dd, 3H, J = 1.7, 6.6 Hz). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 142.3, 139.7, 134.9, 131.2, 124.9, 124.8, 116.9, 101.1, 99.0, 60.1, 18.8. HRMS (ESI) m/z [M + H] + Calcd for C 11 H 13 O 4 209.0814; Found 209.0806.

	under reduced pressure. Purification by flash chromatography (30% CH 2 Cl 2 -petroleum ether)
	furnished 5-Allyloxy-4-methoxy-1,3-benzodioxole 16 as a colorless oil (1.52 g, 84%). IR
	(ATR) ν 2886, 1630, 1459, 1231, 1049, 923, 778 cm -1 . 1 H NMR (300 MHz, CDCl 3 ) δ 6.42 (d,
	1H, J = 8.5 Hz), 6.35 (d, 1H, J = 8.5 Hz), 5.99-6.12 (m, 1H), 5.90 (s, 2H), 5.37 (dq, 1H, J =
	1.5, 17.2 Hz), 5.25 (dq, 1H, J = 1.3, 10.5 Hz), 4.50 (dt, 2H, J = 1.4, 5.4 Hz), 4.00 (s, 3H).
	13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 146.3, 143.5, 138.2, 135.0, 133.7, 117.7, 107.3, 101.4,
	101.3, 71.4, 60.4. HRMS (ESI) m/z [M + H] + Calcd for C 11 H 13 O 4 209.0814; Found :
	209.0806.
	5-hydroxy-4-methoxy-6-(2-propenyl)-1,3-benzodioxole (17). A solution of 5-Allyloxy-4-
	5-Allyloxy-4-formate-1,3-benzodioxole
	(1.82 g, 8.2 mmol) in solution in THF (30 mL) was hydrolyzed by 3N NaOH (9 mL). After
	being stirred for 1 h at 25 °C, the reaction mixture was diluted with CH 2 Cl 2 (50 mL). The
	organic phase was extracted with water (4 × 30 mL). The aqueous phase was acidified with 2
	N HCl and extracted with CH 2 Cl 2 (3 × 50 mL). The organic phases were dried over
	anhydrous MgSO 4 and concentrated under reduced pressure. Purification by flash
	chromatography (30% CH 2 Cl 2 -petroleum ether) furnished 5-allyloxy-4-hydroxy-1,3-
	benzodioxole 15 (964 mg, 61%) as a white solid. mp 51-52 °C. IR (ATR) ν 3301, 2902, 1656,
	1471, 1244, 1053, 913, 767 cm -1 . 1 H NMR (300 MHz, CDCl 3 ) δ 6.33 (s, 1H), 6.33 (s, 1H),
	5.98-6.11 (m, 1H), 5.94 (s, 2H), 5.47 (s, 1H), 5.39 (dq, 1H, J = 1.5, 17.2 Hz), 5.31 (dq, 1H, J
	= 1.3, 10.4 Hz), 4.53 (dt, 2H, J = 1.4, 5.5 Hz). 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 143.6,
	142.4, 134.1, 133.1, 131.1, 118.6, 104.8, 101.8, 98.9, 71.2. HRMS (ESI) m/z [M + Na] + Calcd
	for C 10 H 10 O 4 Na 217.0477; Found : 217.0470.

5-Allyloxy-4-methoxy-1,3-benzodioxole

(16)

. To a solution of 5-allyloxy-4-hydroxy-1,3benzodioxole (1.69 g, 8.70 mmol) in acetone (9 mL) was added sequentially K methoxy-1,3-benzodioxole 16 in acetone (1.5 M) was loaded in a PEEK injection loop (2 mL) connected to a stream of acetone pumped at a flow rate of 2 mL/min as depicted in Scheme 2.

The

[3,3]

-Claisen rearrangement occurred in a stainless steel reactor coil (5 mL, 0.75 mm id) heated at 250 °C. The line was constantly pressurized at 70 bar with an electronic back pressure regulator (BPR) to prevent the vaporization of acetone. The product collected in a flask was concentrated

  ). mp 160-161°C [Lit. 81 170 °C]. IR (ATR) ν 2899, 1666, 1618, 1429, 1284, 1097, 1044, 888, 758 cm -1 . 1 H NMR (400 MHz, CDCl 3 ) δ 7.03-7.08 (m, 1H), 6.52 (s, 1H), 5.87 (dd, 2H, J = 1.3, 14.9 Hz), 5.65 (d, 2H, J = 8.5 Hz), 3.96 (s, 3H), 3.93(s, 3H), 3.26 (dd, 1H, J = 2.6, 7.6 Hz), 3.17 (dt, 1H, J = 2.3, 7.5 Hz) 2.45-2.52 (m, 1H), 2.17-2.26 (m, 1H), 1.13 (d, 3H, J = 7.1 Hz), 0.70 (d, 3H, J = 7.6 Hz). 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 183.3, 151.7, 143.9, 143.2, 138.1, 136.0, 133.8, 131.7, 126.6, 117.0, 101.5, 101.3, 100.8, 98.9, 60.4, 59.9, 36.5, 35.8, 35.3, 34.3, 21.6, 21.2. HRMS (ESI) m/z [M + Na] + Calcd for C 22 H 22 O 8 Na 437.1212; Found : 437.1205. The supporting information is available free of charge on the ACS Publication website at DOI: 10.1021/acs.joc.xxxxxxx

	■ ASSOCIATED CONTENT

Table S1 and NMR spectra of purified products: 1, 3, 6, 10, 12, 13, 14, 15, 16, 17, 18 (PDF)

■ ACKNOWLEDGEMENTS his work was supported by the gion des ays de la oire in the framework of the ari cientifique gional martCat and the INCa Institut National du Cancer . E. C. Aka and M. C. Nongbe thank the "Ministère de l'Enseignement up rieur et de la echerche cientifique de Côte d'Ivoire" for a grant. E.W. gratefully acknowledges the INCa for a grant. .C. . gratefully acknowledges the gion des ays de la oire for a grant. We acknowledge Julie Hémez (CEISAM, University of Nantes) for HRMS analyses.

■ AUTHOR INFORMATION

Corresponding author

*E-mail: fx.felpin@univ-nantes.fr ORCID François-Xavier Felpin: 0000-0002-8851-246X

Notes

The authors declare no competing financial interest.


André Nel
email: anel@mnhn.fr

Markus J Poschmann
email: markus.poschmann@gdke.rlp.de

A new stem Orthoptera (Archaeorthoptera: Oedischioidea) from the Early Permian of the Saar-Nahe basin, southwest Germany

Keywords: Insecta, Oedischiidae, Palatinoedischia elongata gen. et sp. nov., Lower Rotliegend, Saar-Nahe basin

The new oedischiine Palatinoedischia elongata nov. gen., nov. sp. is described from the Early Permian of Germany. It is characterized by a very particular broad area between R+M+CuA and CuP of the tegmen. The possible closest relative is the genus Plesioidischia, also from the Early Permian of Germany. They possibly constitute their own clade, but a phylogenetic analysis is needed to clarify the whole superfamily Oedischioidea.

Introduction

The Oedischioidea Handlirsch 1906 is a rather diverse group of Orthoptera, currently known from the Late Carboniferous to the Early Jurassic. Its monophyly and limits, and the composition of the different included families are questionable (Béthoux and Nel, 2002b: 224).

A new phylogenetic analysis is needed to solve these important questions, crucial to clarify the phylogeny of the Orthoptera, because, depending on the authors, this superfamily is considered as belonging to the stem group of the Orthoptera or of the Ensifera. Also, depending on the authors (see fossilworks database), the Oedischioidea would comprise the Oedischiinae Handlirsch, 1906, Elcanoedischiinae Gorochov, 1987a, Mezenoedischiinae Gorochov, 1987a, Mesoedischiidae Gorochov, 1987b, Bintoniellidae Handlirsch, 1939, Proparagryllacrididae Riek, 1956, Pruvostitidae Zalessky, 1928(= Pruvostitinae Zalessky, 1928, Sylvoedischiinae Gorochov, 1987a, Kamiinae Sharov, 1968, Kargalariinae Gorochov, 1995, Maculoedischiinae Gorochov, 1987a, Tettavinae Sharov, 1968), and the Tcholmanvissiidae [START_REF] Zalessky | Sur deux représentants permiens nouveaux de l'ordre des Protorthoptères[END_REF](= Tcholmanvissiinae Zalessky, 1934, Tettoedischiinae Gorochov 1987a).

The Late Carboniferous oldest fossil Orthoptera are attributed to this superfamily. It greatly diversified during the Permian. Depending of the confirmation of its monophyly, this superfamily survived the Permian-Triassic mass extinction.

It is also important to better define the limits and Permian diversity of this group through a phylogenetic analysis, in order to estimate the evolutionary changes that could have occurred during the Carboniferous, Permian, and Triassic.

Here we describe a new Early Permian fossil from the Saar-Nahe basin in southwest Germany that belongs to this group but shows some very particular forewing venational structures.

Material and methods

The specimen has been found by one of us (MJP) at a locality situated between the villages of Sitters and Schiersfeld in the Moschelbach valley/Rhineland-Palatinate (Fig. 1). [START_REF] Poschmann | Sitters and Grügelborn, two important Fossil-Lagerstaetten in the Rotliegend (?Late Carboniferous -Early Permian) of the Saar-Nahe Basin (SW-Germany), with the description of a new palaeoniscoid (Osteichthyes, Actinopterygii)[END_REF] described a nearby situated locality "Sitters", which is slightly older than the one that yielded the present specimen. The fossil described here originates from the younger "Niedermoschel black shale" sensu [START_REF] Schindler | Neue lithostratigraphische Leithorizonte im unteren Rotliegend des Saar-Nahe-Beckens (U. Perm, SW-Deutschland). 1. Leithorizonte der lithostratigraphischen Einheit Lauterecken-bis Odernheim-Schichten L-O 5 (Boy and Fichter)[END_REF], stratigraphically belonging to the informal unit M5 of the Jeckenbach Subformation, Meisenheim Formation, Glan Subgroup of the Lower Rotliegend (Boy et al., 2012, Fig. 1).

The Niedermoschel black shale is known since the early 20 th century [START_REF] Reis | Über einige im Unter-und Oberrotliegenden des östlichen Pfälzer Sattels gefundene Tierreste[END_REF]. [START_REF] Schindler | Neue lithostratigraphische Leithorizonte im unteren Rotliegend des Saar-Nahe-Beckens (U. Perm, SW-Deutschland). 1. Leithorizonte der lithostratigraphischen Einheit Lauterecken-bis Odernheim-Schichten L-O 5 (Boy and Fichter)[END_REF] characterized it in a stratigraphical context [START_REF] Poschmann | Ein Neufund von Fayolia sp. (Chondrichthyes: Hai-Eikapsel) mit paläoökologischen Anmerkungen zum Fundhorizont (Niedermoschel-Bank, Unteres Rotliegend; Saar-Nahe-Becken)[END_REF] described this unit in terms of lithology and palaeoecology. The type locality yielded plant remains [START_REF] Uhl | Die Paläoflora aus dem Rotliegend (Oberkarbon -Unterperm; Meisenheim Formation; M5) von Niedermoschel (Saar-Nahe-Becken, SW-Deutschland)[END_REF], a variety of vertebrates (e.g., Hampe, 1996, Poschmann and[START_REF] Schindler | Neue lithostratigraphische Leithorizonte im unteren Rotliegend des Saar-Nahe-Beckens (U. Perm, SW-Deutschland). 1. Leithorizonte der lithostratigraphischen Einheit Lauterecken-bis Odernheim-Schichten L-O 5 (Boy and Fichter)[END_REF] such as fishes and rare branchiosaurs. It is extraordinary for the rich occurrence of arthropods such as ostracods, spinicaudatans, syncarid crustaceans [START_REF] Uhl | Syncarids (Crustacea, Malacostraca) from the Stephanian D (Upper Carboniferous) of the Saar-Nahe-Basin (SW-Germany)[END_REF], xiphosurids [START_REF] Malz | Erste Süßwasser-Limuliden (Arthropoda, Chelicerata) aus dem Rotliegenden der Saar-Nahe-Senke[END_REF], and insects [START_REF] Hörnschemeyer | Fossil insects from the Lower Permian of Nierdermoschel (Germany). AMBA projects AM/PFICM98/1[END_REF]. The terrestrial insect remains were introduced into a lacustrine environment influenced by deltaic input and comprise a large number of lemmatophorids, Blattinopsidae [START_REF] Hörnschemeyer | Review of Blattinopsidae (Protorthoptera) with description of new species from the Lower Permian of Niedermoschel (Germany)[END_REF], and Miomoptera [START_REF] Hörnschemeyer | Fossil insects from the Lower Permian of Nierdermoschel (Germany). AMBA projects AM/PFICM98/1[END_REF][START_REF] Brauckmann | Kohlesümpfe, Seen und Halbwüsten. Dokumente einer rund 300 Millionen Jahre alten Lebewelt zwischen Saarbrücken und Mainz[END_REF]. Most of the insect fossils are wings less than two centimeters long. An exceptionally preserved stem orthopteran, Nosipteron niedermoschelensis [START_REF] Béthoux | A new lobeattid insect from the Permo-Carboniferous of Niedermoschel, southwestern Germany (Archaeorthoptera)[END_REF], has also been described from there. The new locality near Sitters, which yielded the stem orthopteran described herein, shows essentially the same suite of fossils encompassing plant remains, fishes, conchostracans, xiphosurids, and insects. No detailed scientific exploration is available as yet. The sediments at both localities show contact-metamorphism, which greatly enhanced the recognizability of the insect remains as they appear as shiny, silvery fossils on the dark, gray-bluish matrix (Montenary and Uhl, 2005 concerning preservation).

In fact, the Early Permian insects from "Odernheim town site" described by [START_REF] Prokop | Early Permian insects from Saar-Nahe Basin of Odernheim town site, Rheinland-Pfalz in Germany (Insecta, Grylloblattida, Blattinopseida)[END_REF] originate from various localities in the Rotliegend of the Saar-Nahe basin (K.-D. Weiß, pers. comm.). Some of these may originate from the Niedermoschel black shale as well.

The specimen was prepared using pneumatic chisels and studied under a Leica MZ 7.5 binocular microscope. It was coated with MgO, photographed using a Canon 600D digital camera equipped with a canon EFS 60mm macro lens and drawn using a Leica drawing tube attached to the microscope. Photographs with differing planes of focus were stacked into a composite with enhanced depth of field using the free software CombineZP by Alan Hadley.

We follow the classification and wing venation terminology of Béthoux and Nel (2002a) urn:lsid:zoobank.org:pub:F2195993-BA7A-4BC3-8342-EF6E6AEEB13E

Systematic palaeontology

Clade Archaeorthoptera Béthoux and Nel, 2002Order Orthoptera Olivier, 1789Superfamily Oedischioidea Handlirsch, 1906Family Oedischiidae Handlirsch, 1906Subfamily Oedischiinae Handlirsch, 1906 Genus Palatinoedischia nov. Type horizon and locality: Early Permian, Lower Rotliegend, Meisenheim Formation, Jeckenbach Subformation, Niedermoschel black shale (sensu [START_REF] Schindler | Neue lithostratigraphische Leithorizonte im unteren Rotliegend des Saar-Nahe-Beckens (U. Perm, SW-Deutschland). 1. Leithorizonte der lithostratigraphischen Einheit Lauterecken-bis Odernheim-Schichten L-O 5 (Boy and Fichter)[END_REF], probably Asselian-?Sakmarian (Schneider andWerneburg, 2012, Schneider et al., 2020); Saar-Nahe Basin south of Sitters, Germany.

Diagnosis:

As for the genus by monotypy.

Description: Tegmen 62.3 mm long, 10.7 mm wide, rather narrow elongate and slightly falcate; a well-defined ScA, 10.6 mm long; area between C and ScA poorly preserved, ca. 1.4 mm wide; crossveins between ScA and ScP simple, straight and short, perpendicular to ScP and ScA, those between ScP and C poorly preserved, but apparently also short; area between costal margin and ScP ca. 1.7 mm wide; base of RP 27.0 mm distal of wing base; ScP and R+(M+CuA) well separated, 1.2 mm apart with numerous straight crossveins in between; ScP probably ending in C; presence of a basal common stem R+M+CuA but R and M+CuA separating close to wing base, with a 0.7 mm wide area in-between at level of separation of M with CuA; RA convex, simple, with a narrow distal area with short veinlets between it and C; broad area between RA and RP with strongly curved crossveins, 2.6 mm wide; RP rather concave; distance between its base and point of fusion with MA1 7.3 mm; RP+MA1 0.8 mm long; MA1 long and straight, with an apical fork; RP with five branches; CuA separated from M in basal third of wing, at 13.8 mm from wing base; basal stem of M very short, 0.6 mm long; neutral MA with three distal branches, most basal one simple, second forked; and third (MA1 ending into RP and separating again distally; concave MP simple; CuA fused with CuPaα 2.5 mm of its base; CuA+CuPaα posteriorly pectinate, with three visible branches; CuPa long basal of its fusion with CuA, 4.7 mm long; CuPaβ simple, well discernible as a vein distinctly wider than crossveins at its base, but poorly defined distally and partly lost in an irregular net of cells in a broad area between CuA+CuPaα and CuPb; division of CuP into CuPa and CuPb 10.6 mm from wing base; CuPb simple; PCu and two anal veins, all simple; area between R+M+CuA and CuP very broad, 2.9 mm wide, with a net of 3-4 rows of irregular cells in-between.

Discussion

This forewing corresponds to that of a clade Panorthoptera Crampton, 1928 sensu Béthoux and Nel (2002a: 27) Nevertheless, the vein CuPaβ is 'rudimentary' near its base, partly 'lost' in a net of irregular cells. Similar 'aberrant' situations can occur for some other Permian Orthoptera, e.g., 'Tettoedischia minuta [START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF], undoubtedly closely related to Macroedischia within Tettoedischiinae, has a free and simple CuPaα, without any clear anterior branch reaching CuA'; Béthoux and Nel, 2002b: 224). A similar situation occurs in the panorthopteran family Geraridae Scudder, 1885 [START_REF] Béthoux | Wing venation morphology and variability of Gerarus fischeri (Brongniart, 1885) sensu Burnham (Panorthoptera; Upper Carboniferous, Commentry, France), with inferences on flight performance[END_REF]. The pattern of venation fits quite well with those of the Oedischiinae, in the presence of a well-defined vein ScA, a series of regular crossveins in subcostal area and area between ScP and R/RA, ScP and RA well separated, broad areas between RA and RP and between R/RP and MA, and basal fork of M very close to point of separation between M and CuA. We consider that the venation of Palatinoedischia nov. gen.

is compatible with an attribution to the Orthoptera.

Palatinoedischia nov. gen. has two to four rows of irregular cells in the area between R+M+CuA and CuP, while nearly all the described Oedischioidea have a distinctly narrower area with one row of cells. A similar situation occurs in Gerarus Scudder, 1885.

Palatinoedischia nov. gen. strongly differs from the Geraridae in the simple MP and CuPb, narrow elongate tegmen, and very short stem of M [START_REF] Béthoux | Wing venation morphology and variability of Gerarus fischeri (Brongniart, 1885) sensu Burnham (Panorthoptera; Upper Carboniferous, Commentry, France), with inferences on flight performance[END_REF]. Also, affinities with the Tcholmanvissiidae sensu Béthoux and Nel (2002b) are excluded because Palatinoedischia nov. gen. has an anterior branch of MA ending into RP, and no supplementary independent branch basal to fusion of CuPaα with CuA. The Bintoniellidae and the Proparagryllacrididae also have no anterior branch of MA ending into RP (Riek, 1955[START_REF] Riek | A re-examination of the mecopteroid and orthopteroid fossils (Insecta) from the Triassic beds at Denmark Hill, Queensland, with descriptions of further specimens[END_REF](Riek, , 1976;;[START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF]Gorochov, 1987b[START_REF] Gorochov | New taxa of the orthopteran families Bintoniellidae, Xenopteridae, Permelcanidae, Elcanidae and Vitimiidae (Orthoptera, Ensifera)[END_REF][START_REF] Gorochov | New taxa of the superorder Orthopteroidea from the latter half of the Permian of European Russia[END_REF][START_REF] Béthoux | New and rare insect species from the Wellington Formation (Orthoptera, Grylloblattodea; Lower Permian, USA)[END_REF].

The Mezenoedischiinae have a narrow area between MP and the anterior stem of CuA + CuPaα, and the presence of only one branch of MA posterior to base of MA1, unlike two in Palatinoedischia nov. gen. [START_REF] Carpenter | The Lower Permian insects of Kansas. Part 11. The orders Protorthoptera and Orthoptera[END_REF][START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF]Gorochov, 1987a;Béthoux et al., 2002;[START_REF] Béthoux | New and rare insect species from the Wellington Formation (Orthoptera, Grylloblattodea; Lower Permian, USA)[END_REF]. The Elcanoedischiinae (Kansasoedischia Gorochov 1987a, Elcanoedischia Gorochov 1987a, Metoedischia Martynov 1928); and the Sylvoedischiinae (Stenoedischia Gorochov 1987a, Sylvoedischia Sharov 1968) differ from Palatinoedischia nov. gen. in the presence of only one branch of MA posterior to base of MA1 [START_REF] Martynov | Permian fossil insects of North-East Europe. Trudy Geologicheskogo Muzeya[END_REF][START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF]Gorochov, 1987a). The Sylvoedischiinae also have broader tegmina compared to their length. The Pruvostitidae have ScP with longer branches than in Palatinoedischia nov. gen., and either only one branch of MA posterior to base of MA1 and/or a long basal stem of M before its separation into MA and MP, and/or no fusion between anterior branch of MA and RP, unlike Palatinoedischia nov. gen. [START_REF] Zalessky | On the new insects from the Permian basins of Kama, Viatka and Belaia rivers[END_REF]Gorochov, 1987aGorochov, ,c, 2013)). The Mesoedischiidae also have a long stem of M [START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF][START_REF] Gorochov | Review of Triassic Orthoptera with descriptions of new and little known taxa: part 1[END_REF].

The Oedischiinae Handlirsch, 1906 have a short stem of M as in Palatinoedischia nov.

gen. Oedischia Handlirsch, 1906 has only one branch of MA posterior to base of MA1 [START_REF] Sharov | Filogeniya ortopteroidnykh nasekomykh. Trudy Paleontologicheskogo Instituta[END_REF]. Sinoedischia Hong, 1985 has such two branches, but the basal half of the tegmen is not preserved, so that the length of basal part of M and the pattern of the cubital veins are unknown, rendering the position of this taxon uncertain (Hong, 1985: figs 29-30). Anhomalophlebia

Handlirsch, 1919 has a basal stem of M longer than in Palatinoedischia nov. gen. and no fusion of a branch of MA with RP (see figure in the internet site http://mediaphoto.mnhn.fr/media/14986360852690vFhvxWDuH8srHmM).

Afroedischia Geertsema and van Dijk, 1999 has a very long stem of M, and no fusion of a branch of MA with RP [START_REF] Geertsema | The earliest known Palaeozoic ensiferan insect from Africa, Afroedischia oosthuizeni gen. et sp. n. (Orthoptera: Oedischiidae)[END_REF]: figs 1-2). Anelcana [START_REF] Carpenter | Substitute names for the extinct genera Cycloptera Martynova (Mecoptera) and Parelcana Carpenter (Orthoptera)[END_REF] (replacement name for Parelcana [START_REF] Carpenter | The Lower Permian insects of Kansas. Part 11. The orders Protorthoptera and Orthoptera[END_REF] differs from Palatinoedischia nov. gen. in the area between ScA and ScP quite narrow, a very short basal part of CuA and a short CuPaβ (Carpenter, 1966: fig. 19). Kamaites Zalessky, 1929 is based on a very incomplete wing not showing the essential structures to be compared to the other Orthoptera (Zallesky, 1929: fig. 9). Nobloedischia Beckemeyer, 2011a differs from Palatinoedischia nov. gen. in the presence of only one branch of MA posterior of MA1, presence of long anterior branches of RA, narrower areas between R+M+CuA and CuP and between CuPa and CuPb (Beckemeyer, 2011a: figs 1-3). Scalaeoptera [START_REF] Bolton | A monograph of the fossil insects of the British coal measures[END_REF] is based on a very fragmentary tegmen, impossible to compare to the other Paleozoic Orthoptera (Bolton, 1922: fig. 27). Xeroptera [START_REF] Bolton | A monograph of the fossil insects of the British coal measures[END_REF] is also based on an incomplete tegmen; it possibly does not belong to the Archaeorthoptera but to a very different group, the Paoliida (sensu [START_REF] Prokop | Late Palaeozoic Paoliida is the sister group of Dictyoptera (Insecta: Neoptera)[END_REF], because it has a series of anterior branches of CuA, a rather broad area between CuA and CuP, and apparently no branches of CuP ending into CuA (Bolton, 1922: fig. 26). This taxon needs to be revised.

Loxoedischia Beckemeyer, 2011b shares many characters with Palatinoedischia nov. gen. in the pattern of the veins Cu and M, ScP and ScA. Nevertheless, it has anterior branches of RP, no branch of MA ending into RP (Beckemeyer, 2011b: fig. 1).

The tegmen of Plesioidischia baentschi Schlechtendal, 1906(in Handlirsch, 1906) from the upper Meisenheim or Disibodenberg Formation of Nonnweiler near Birkenfeld/Nahe, revised by Guthörl (1934: fig. 58), greatly resembles that of Palatinoedischia nov. gen., with only the following differences: the area between R+M+CuA and CuP is only slightly wider than that between M and CuA+CuPaα, the veins in area between ScA and ScP are clearly irregular while they are all simple and straight in Palatinoedischia nov. gen. Bolton (1922: 92-93, text-fig. 29, pl. 6, fig. 3) described and figured a Plesioidischia sp. from the 'Middle Coal Measures (binds between 'Brooch' and 'Thick' coals); Tipton, Staffs' in UK. This fossil is the basal third of a tegmen, but it does not show the broadened area between R+M+CuA and CuP of Plesioidischia baentschi. It probably corresponds to a different genus; we consider it as an Oedischioidea incertae sedis.

Conclusion

Palatinoedischia nov. gen. does not fit with any of the described Oedischioidea. It seems to be close to Plesioidischia baentschi because of the great similarities in the wing venations.

Plesioidischia is also known from the early Permian of Germany, but the new fossil clearly corresponds to a different genus and species. Both could belong to the same clade, characterized by the broadened area between R+M+CuA and CuP. We provisionally attribute it to the Oedischiinae, but a phylogenetic analysis of the whole Oedischioidea is necessary to clarify the relationships and definitions of its different components. The monophyly of the whole group and its components are questionable. Thus the comparison of any new taxon to the different families and genera can only be based on similarities and not on well-defined synapomorphies.

  and Schubnel et al. (2020) for the Archaeorthoptera. Abbreviations: C costa; ScA subcosta anterior; ScP subcosta posterior; RA radius anterior; RP radius posterior; MA median anterior; MP median posterior; CuA cubitus anterior; CuP cubitus posterior; PCu postcubital vein; AA anal veins.

  Figs 2, 3 urn:lsid:zoobank.org:act:A73201ED-ADFC-418D-A64E-DE1ACD0E2C7F Derivation of the name: Named 'elongata' after the narrow elongate tegmen. Holotype: PE 2018/5000-LS, State Collection of Natural History of Rhineland-Palatinate, Mainz (original collector's number 751-P; see Brauckmann, 2007). Part and counterpart of a nearly complete forewing, very well-preserved with only extreme base and parts of costal and posterior margins missing.

  because of the following synapomorphies: CuPa differentiated into two branches (CuPaα and CuPaβ) just basal of the fusion of the anterior one (CuPaα) with CuA (synapomorphy of Panorthoptera); ScP probably reaching anterior wing margin and not RA; MA1 and MA2 can be differentiated; CuA+CuPaα with at least two posterior branches; CuPb simple. Palatinoedischia nov. gen. shares with the Orthoptera (sensu Béthoux and Nel, 2002a: 38-39) the MA forked; MP, CuPaβ, CuPb, and PCu simple.

Figure captions : Fig. 1 .

 :1 Figure captions:

Fig. 2 .

 2 Fig. 2. Palatinoedischia elongata nov. gen., nov. sp., holotype PE 2018/5000-LS. Photographs of forewing, whitened with MgO. A. Part PE 2018/5000-LSa. B. Counterpart PE 2018/5000-LSb. C. Basal portion of part. D. Middle portion. E. Apical portion, rotated 90° counterclockwise. Scale bars: 10 mm.

Fig. 3 .

 3 Fig. 3. Palatinoedischia elongata nov. gen., nov. sp., holotype PE 2018/5000-LS. Drawings. A. Part PE 2018/5000-LSa. B. Counterpart PE 2018/5000-LSb. C. Interpretative drawing of wing venation combined from part and counterpart. Scale bar: 10 mm.

B

Acknowledgements

We sincerely thank two anonymous referees for the useful comments on the first version of the paper. MJP thanks Dr. Thomas Schindler (Spabrücken) for joint fieldwork, Sabine Treptow (Waldesch) for help with graphics, and Klaus-Dieter Weiß (Fischbach) for useful hints.