Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

flow synthesis Comments Off

Aug 132016

Abstract Image

Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.

Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material

Michael E. Kopach^*^†, Kevin P. Cole^†, Patrick M. Pollock^†, Martin D. Johnson^†, Timothy M. Braden^†, Luke P. Webster^†, Jennifer McClary Groh^†, Adam D. McFarland^†, John P. Schafer^‡, Jonathan J. Adler^‡, and Morgan Rosemeyer^‡

^† Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

^‡ D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00131, http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00131

*E-mail: kopach_michael@lilly.com.

//////////Flow Grignard, Lithiation, Screening Tools, Development, Continuous Processes, Benzyl Alcohol, Starting Material

Supporting Info

Day 10 of the 2016 Doodle Fruit Games! Find out more at g.co/fruit

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

flow synthesis, SYNTHESIS Comments Off

Aug 112016

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Shing-Hing Lau^†, Samuel L. Bourne^†, Benjamin Martin^‡, Berthold Schenkel^‡, Gerhard Penn^‡, and Steven V. Ley^*^†

^† Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.

^‡ Novartis Pharma AG, Postfach, 4002 Basel, Switzerland

Org. Lett., 2015, 17 (21), pp 5436–5439

DOI: 10.1021/acs.orglett.5b02806, http://pubs.acs.org/doi/10.1021/acs.orglett.5b02806

*E-mail: svl1000@cam.ac.uk.

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

LCZ696 (sacubitril/valsartan) is a first-in-class combination of the angiotensin II receptor-blocker valsartan and the neprilysin inhibitor sacubitril. A recent head-to-head comparison of LCZ696 with enalapril in a double-blind trial was stopped early because the boundary for an overwhelming benefit with LCZ696 was crossed.As a result of this, LCZ696 was reviewed under the FDA’s priority review program and was granted approval on the July 7, 2015 to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II–IV) and reduced ejection fraction.

LCZ696 is a complex aggregate comprised of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively

(2R, 4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoic acid ethyl ester hydrochloride 3

To a stirred solution of (2R, 4S)-5-(4-Biphenylyl)-2-methyl-4-(tert-butylsulfinylamino)valeric acid 14 (50.0 mg, 134 μmol) in absolute ethanol (0.4 mL) at 0 °C was added thionyl chloride (20 μL, 268 μmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed to yield 46.0 mg (99%) of titled compound 3 as a white solid.

1 H NMR (600 MHz, DMSO-d6) δ 8.17 (br. s, 3H), 7.66 (dd, J = 8.0, 7.4 Hz, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (2 H, t, J = 7.4 Hz, H15, 2H), 7.36 (1 H, d, J = 8.0 Hz, H15), 3.99 (q, J = 7.1 Hz, H18), 3.42 – 3.36 (m, H4, 1H), 3.04 (dd, J = 13.8, 5.5 Hz, 1H), 2.81 (dd, J = 13.8, 8.1 Hz, 1H), 2.77 – 2.70 (m, 1H), 1.86 (ddd, J = 14.3, 9.1, 5.0 Hz, 1H), 1.59 (ddd, J = 13.8, 8.1, 5.4 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.1 Hz, 3H).

13C NMR (151 MHz, CDCl3) δ 174.7, 139.7, 138.7, 135.5, 130.0, 129.0, 127.4, 126.8, 126.5, 60.1, 50.4, 38.1, 35.5, 35.0, 17.5, 13.9.

HRMS (ESI+ , m/z [M+H]+ ) Calcd for C20H26NO2 312.1964; found 312.1967;

HPLC. 97:3 d.r. (Daicel Chiralpak AD-H column; isocratic n-hexane/ethanol/methanol/trimethylamine 80/10/10/0.2; 40 o C; flow rate = 0.8 mL min-1 ; λ = 254 nm; run time = 23 mins; tR (2R, 4S) 97.07%; tR (2S,4R) 0.21%; tR (2S, 4S) 2.32%; tR (2R,4R) 0.40%)

13C NMR Ethyl (2R,4S)-5-(4-biphenylyl)-4-amino-2-methylpentanoate hydrochloride 3

////////////Synthesis, Precursor, Sacubitril, Enabling Technologies, flow synthesis, valsartan, LCZ69

Supporting Info

Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

flow synthesis, SYNTHESIS Comments Off

Jun 242016

The synthesis of hydroperoxymethyl oxazoles by oxidation of alkylideneoxazoles with molecular oxygen was implemented in a microstructured reactor for increased safety and larger-scale applications. Elaborate studies on the influence of pressure and temperature were performed, and the apparent activation energy for the oxidation reaction was determined. Elevated temperatures up to 100 °C and pressures up to 18 bar(a) led to a conversion rate of approximately 90% within 4 h of the reaction time, thus displaying the high potential and beneficial effect of using a microreactor setup with liquid recycle loop for this oxidation. The in situ reduction of the generated hydroperoxide functionality shows the capability of this setup for follow-up transformations.

Oxazole–hydroperoxide 3as a colorless solid. R_f (PE/EA 3:1 = 0.31).

¹H NMR (30 MHz, CDCl₃) δ = 4.98 (s, 2H), 7.12 (s, 1H), 7.49–7.29 (m, 3H), 7.88–7.75 (m, 2H), 10.16 (s, 1H). GC-MS (EI) m/z = 173.1 (M – OH), 144.1 (M – CH₂OOH), 116.1 (M – C₆H₅ + 2H), 89.1.

Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

Sarah Bay^†, Tobias Baumeister^‡, A. Stephen K. Hashmi^†^§, and Thorsten Röder^*^‡

^† Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,Germany

^‡ Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany

^§ Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00118

*E-mail: t.roeder@hs-mannheim.de. Telephone: +49 621 292 6800.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00118

Organisch-Chemisches Institut
Im Neuenheimer Feld 270
69120 Heidelberg
Germany

Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paul-Wittsack-Str. 10, 68163 Mannheim, Germany

Panorama picture of the Campus in July 2006

Thorsten Röder

Prof. Dr.

Professor (Full)

Hochschule Mannheim, Mannheim · Institute of Chemical Process Engineering

Research experience

Sep 2009–present

Professor (Full)

Hochschule Mannheim · Institute of Chemical Process Engineering

Germany · Mannheim
Sep 2005–Aug 2009

Laboratory Head

Novartis · Chemical and Analytical Process Development

Switzerland · Basel
Sep 1999–Aug 2004

PhD Student

Universität Paderborn · Department of Chemistry · Physical Chemistry Prof. Kitzerow

Germany · Paderborn

Teaching experience

Sep 2009–present

Professor (Full)

Hochschule Mannheim · Institute of Chemical Process Engineering

Germany

Lectures in: Chemical Reaction Engineering Thermodynamic Microreactors & Nanotechnology CFD Practical Course: Chemical Reaction Engineering

Education

Oct 1999–Oct 2004

Universität Paderborn

Physical Chemistry · Dr. rer. nat.

Germany · Paderborn
Sep 1994–Sep 1999

Universität Paderborn

Chemistry · Diplom Chemiker

Germany

Prof. Dr. A. Stephen K. Hashmi

E-Mail hashmi@hashmi.de

/////////Safe and Fast, Flow Synthesis, Functionalized Oxazoles, Molecular Oxygen, Microstructured Reactor

Flow approach towards AZD 6906

flow synthesis, PROCESS Comments Off

May 272016

Scheme 1: Flow approach towards AZD6906 (65).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry, Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

In 2012 researchers from AstraZeneca (Sweden) reported upon a scale-up campaign for their gastroesophageal reflux inhibitor programme. Specifically, flow chemical synthesis was used to efficiently and reliably provide sufficient quantities of the target compound AZD6906 (65), which had been prepared previously in batch. From these earlier batch studies concerns had been raised regarding exothermic reaction profiles as well as product instability which needed to be addressed when moving to larger scale synthesis. Flow was identified as a potential way of circumventing these specific problems and so was extensively investigated. The developed flow route [1 ] started with the reaction of methyl dichlorophosphine (66) and triethyl orthoacetate (67), which in batch could only be performed under careful addition of the reagent and external cooling using dry ice/acetone. Pleasingly, a simple flow setup in which the two streams of neat reagents were mixed in a PTFE T-piece maintained at 25 °C was found effective in order to prepare the desired adduct 68 in high yield and quality showcasing the benefits of superior heat dissipation whilst also safely handling the toxic and pyrophoric methyl dichlorophosphine reagent (Scheme 1).

As the subsequent Claisen condensation step was also known to generate a considerable exotherm, a similar flow setup was used in order to allow the reaction heat to dissipate. The superiority of the heat transfer process even allowed this step to be performed on kilogram quantities of both starting materials (68, 69) at a reactor temperature of 35 °C giving the desired product 72 within a residence time of only 90 seconds. Vital to the successful outcome was the efficient in situ generation of LDA from n-BuLi and diisopropylamine as well as the rapid quenching of the reaction mixture prior to collection of the crude product. Furthermore, flow processing allowed for the reaction of both substrates in a 1:1 ratio (rather than 2:1 as was required in batch) as the immediate quenching step prevented side reactions taking place under the strongly basic conditions. Having succeeded in safely preparing compound 72 on kilogram scale, the target compound 65 was then generated by global deprotection and subsequent recrystallisation where batch was reverted to as the conditions had been previously devised and worked well.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry

Telephone: +44 (0) 191 33 42185

Member in the Centre for Sustainable Chemical Processes

(email at i.r.baxendale@durham.ac.uk)

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.

Gustafsson, T.; Sörensen, H.; Pontén, F. Org. Process Res. Dev. 2012, 16, 925–929. doi:10.1021/op200340c

Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906

Tomas Gustafsson, Henrik Sörensen, and Fritiof Pontén*

Medicinal Chemistry, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden

Org. Process Res. Dev., 2012, 16 (5), pp 925–929

DOI: 10.1021/op200340c

Publication Date (Web): February 21, 2012

*Telephone: +46 31 776 16 65. Email: fritiof.ponten@astrazeneca.com.

This article is part of the Continuous Processes 2012 special issue.

One benefit of flow reactors is improved control over reaction temperature, due to reduced reaction volume at a given time, higher surface area, and the movement of the reaction mixture. This is particularly helpful for very exothermic reactions, which often require cryogenic cooling to prevent runaway reactions – this type of cooling is very expensive and resource-intensive on a large scale. One such reaction is described in a recent paper from AstraZeneca, in which a phosphinate anion adds into a glycine derivative. The product of this reaction is an intermediate in the synthesis of a gastroesophageal reflux inhibitor drug candidate called AZD6906.

////Flow synthesis, AZD 6906

Flow synthesis of Fluoxetine

Uncategorized Comments Off

May 272016

Scheme 1: Flow synthesis of fluoxetine (46).

One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac[1]. In this account each step was performed and optimised individually in flow, with analysis and purification being accomplished off-line. The synthesis commences with the reduction of the advanced intermediate ketone 47 using a solution of pre-chilled borane–THF complex (48) to yield alcohol 49 (Scheme 1).

Conversion of the pendant chloride into iodide 51 was attempted via Finckelstein conditions, however, even when utilising phase-transfer conditions in order to maintain a homogeneous flow regime the outcome was not satisfactory giving only low conversions. Alternatively direct amination of chloride 49 utilising high temperature flow conditions (140 °C) allowed the direct preparation of amine 50 in excellent yield.

Flow processing using a short residence time (10 min) at the elevated temperature allowed for a good throughput; in addition, the handling of the volatile methylamine within the confines of the flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up.

The final arylation of 50 was intended to be performed as a S_NAr reaction, however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents 52 and 53) was developed and successfully applied to deliver fluoxetine (46) in high yield.

Overall, this study is a good example detailing the intricacies faced when translating an initial batch synthesis into a sequence of flow steps for which several adaptations regarding choice of reagents and reaction conditions are mandatory in order to succeed.

Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854–3862. doi:10.1039/C0OB00906G
Paper

Preparation of fluoxetine by multiple flow processing steps

Batoul Ahmed-Omer^a and Adam J. Sanderson*^a

*Corresponding authors

^aEli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK

Org. Biomol. Chem., 2011,9, 3854-3862

DOI: 10.1039/C0OB00906G

http://pubs.rsc.org/en/Content/ArticleLanding/2011/OB/c0ob00906g#!divAbstract

Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

Graphical abstract: Preparation of fluoxetine by multiple flow processing steps

1 The general method set-up of flow process used for the synthesis of (±)- fluoxetine.

Scheme 1 Synthesis of (±)-fluoxetine in flow: (i) BH3·THF, r.t., 5 min (77%); (ii) NaI, toluene: water, 100 °C, 20 min (43%); (iii); MeNH2 (aq), …

//////////Flow synthesis, fluoxetine

Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl⋅LiCl†

SYNTHESIS Comments Off

May 072016

Knochel’s group in Munich have recently disclosed how a variety of functionalised heterocycles and sensitive acrylates can be rapidly magnesiated and subsequently quenched with an electrophile under continuous flow-through;conditions using a Uniqsis static mixer/reactor chip.

A key advantage is that, in contrast to typical batch procedures, these reactions required non-cryogenic conditions (typically 25C); moreover the procedure could be quickly scaled to 45 mmol without modification of the reaction conditions.

Metalations under flow-through conditions permited magnesiations that did not afford the desired product under batch conditions and acylates could be magnesiated and quenched to afford products with high stereoselectivities without concomitant polymerisation.

Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl⋅LiCl^†

T. P. Petersen, M. R. Becker, P. Knochel, Angew. Chem. Int. Ed, 2014, 53, 7933.

A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl⋅LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities.

see

http://onlinelibrary.wiley.com/doi/10.1002/anie.201404221/full

/////Continuous Flow Magnesiation, Functionalized Heterocycles, Acrylates , TMPMgCl⋅LiCl

Continuous-Flow Process for the Synthesis of m-Nitrothioanisole

Uncategorized Comments Off

Apr 062016

Abstract Image

A continuous-flow process for the preparation of m-nitrothioanisole has been set up. The starting material m-nitroaniline was diazotized to give diazonium chloride, followed by azo-coupling with sodium thiomethoxide to give 1-(methylthio)-2-(3-nitrophenyl)diazene, then dediazoniated to gain m-nitrothioanisole in high yield. The continuous-flow process minimized accumulation of the energetic intermediate diazonium salt and has a better capacity for adapting large-scale production. A solvent was introduced in the azo-coupling section to create a biphasic flow system. Side products were inhibited eminently in this flow process.

Continuous-Flow Process for the Synthesis of m-Nitrothioanisole

Zhiqun Yu^†, Xiaoxuan Xie^†, Hei Dong^†, Jiming Liu^‡, and Weike Su^*^†^‡

^† National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China

^‡ Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00023

Publication Date (Web): March 24, 2016

*Tel.: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00023

////////

Palladium-Catalyzed Aerobic Oxidative Coupling of o-Xylene in Flow: A Safe and Scalable Protocol for Cross-Dehydrogenative Coupling

PROCESS, SYNTHESIS Comments Off

Mar 232016

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′-tetramethyl-biphenyl.

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 Noël^*

Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00044

Publication Date (Web): March 10, 2016

*E-mail: t.noel@tue.nl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00044

Supporting Info SEEEEEEEEEEEEE

////Palladium-Catalyzed Aerobic Oxidative Coupling, o-Xylene, Flow, Safe and Scalable Protocol, Cross-Dehydrogenative Coupling

PICS

Cross-dehydrogenative coupling reactions. : The electron is a …

www.nature.com

Cross-dehydrogenative coupling reactions.

Enhancing the usefulness of cross dehydrogenative coupling …

pubs.rsc.org

Cross dehydrogenative coupling (CDC) reactions with different protecting group strategies.

Investigating Scale-Up and Further Applications of DABAL-Me3 Promoted Amide Synthesis

PROCESS Comments Off

Aug 112015

Amides, amidines and amidrazones have been prepared on up to 100g scale from the corresponding esters using DABAL-Me₃.A derivative of Imatinib (Gleevec) was prepared on a 26g scale.

Continuous flow methodology was shown to provide a useful method for larger scales (productivities of >50 g h–1) and could be performed successfully on a smaller laboratory scale using a FlowSyn flow synthesiser.

D. S. Lee, Z. Amara, M. Poliakoff, T. Harman, G. Reid, B. Rhodes, S. Brough, T. McInally, S. Woodward, Org. Process Res. Dev., 2015: DOI: 10.1021/acs.oprd.5b00101

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

SYNTHESIS Comments Off

Jun 162015

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley DOI: 10.1039/C4OB02105C, Paper From themed collection Recent Advances in Flow Synthesis and Continuous Processing

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

Steffen Glöckner,^a Duc N. Tran,^a Richard J. Ingham,^a Sabine Fenner,^a Zoe E. Wilson,^a Claudio Battilocchio^a and Steven V. Ley*^a

*Corresponding authors

^aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

E-mail: svl1000@cam.ac.uk Web: http://www.leygroup.ch.cam.ac.uk/

Org. Biomol. Chem., 2015,13, 207-214

DOI: 10.1039/C4OB02105C

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide


	Fig. 1 Oxazoline- and oxazole-containing natural products.


	Scheme 1 Optimised conditions for the flow synthesis of oxazolines.


	Scheme 2 Microchip reaction for the preparation of oxazolines.


	Scheme 3 Platform set up for the scale up experiment.


	Scheme 4 Flow oxidation of aryl-oxazolines using activated MnO₂.


	Scheme 5 Flow oxidation of 2-alkyl-oxazolines using amorphous MnO₂. ^aDeprotection was observed.


	Scheme 6 Automated oxidation of oxazolines using a Raspberry Pi® computer and a multiple position valve.

Table 1 Flow cyclodehydration of β-hydroxy amides using Deoxo-Fluor®

Entry^a			Isolated yield^b
a Reactions were run on a 2 mmol scale. b Compounds were isolated without purification. c The crude material was passed through a plug of calcium carbonate/silica in place of an aqueous work up. d Total flow rate = 10 mL min⁻¹ with 2.6 eq. of Deoxo-Fluor®.
1	1a	2a	98%
2	1b	2b	98%
3	1c	2c	79%^c
4	1d	2d	98%
5	1e	2e	99%
6	1f	2f	95%
7	1g	2g	98%
8	1h	2h	92%
9	1i	2i	95%
10	1j	2j	60%
11	1k	2k	85%^d
12	1l	2l	92%^d

……………………………………… 2a

General protocol for the preparation of oxazoline in flow

A solution of Deoxo-Fluor® (1 mL, 50% in toluene) in CH₂Cl₂ (7.0 mL) and a solution of β-hydroxy amide (2 mmol) in CH₂Cl₂ (8 mL) were combined at a T-piece (each stream run at 3.0 mL min⁻¹) and reacted at rt in a 10 mL PFA reactor coil. The combined stream was then directed to an aqueous quenching stream (9 mL min⁻¹) and the solution directed to a liquid/liquid separator.²²

(4S,5S)-5-Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2a).

¹H-NMR (600 MHz, CDCl₃) δ = 7.98–7.96 (m, 2H), 7.49–7.46 (m, 1H), 7.40–7.38 (m, 2H), 5.05 (dq, 1H, J= 10.2, 6.4 Hz), 4.97 (d, 1H, J = 10.2 Hz), 3.76 (s, 3H), 1.37 (d, 3H, J = 6.5 Hz);

¹³C-NMR (151 MHz, CDCl₃) δ = 170.5, 166.2, 131.9, 128.6, 128.4, 127.3, 77.7, 71.8, 52.2, 16.3;

HR-MS (ESI+) for C₁₂H₁₄NO₃⁺ [M + H]⁺ calc.: 220.0974, found: 220.0981;

FT-IR neat, [small nu, Greek, tilde]

(cm⁻¹) = 2953, 1736, 1645, 1603, 1580, 1496, 1450, 1384, 1349, 1244, 1197, 1174, 1067, 1045, 1001, 973, 934, 904, 886, 851, 778, 695;

specific rotation: [α]^24.1_D = +58.58° cm³ g⁻¹ dm⁻¹ (c = 8.5 in ethanol). Lit.: [α]²⁰_D = +69.4° cm³ g⁻¹ dm⁻¹ (c = 8.5 in EtOH).³⁹

39…………H. Aït-Haddou, O. Hoarau, D. Cramailére, F. Pezet, J.-C. Daran and G. G. A. Balavoine, Chem. – Eur. J., 2004, 10, 699–707

Dr Zoe Wilson

Post Doctoral Research Associate in the group of Professor Steven V. Ley working on the synthesis of complex natural products and synthetic methodology.

College Lecturer and Fellow at Murray Edwards College.

Research Group

Ley Group Website

Telephone number

01223 336698 (shared)

Email address

zw261@cam.ac.uk

College

Murray Edwards College

Email: zw261@cam.ac.uk LinkedIn Profile

Zoe grew up on a farm in the small town of Warkworth, New Zealand. After completing her studies she moved to Auckland, New Zealand to attend the University of Auckland where she completed a Bachelor of Science in Medicinal Chemistry then a BSc (Hons) in Medicinal Chemistry under the supervision of Professor Margaret Brimble, working on the synthesis of anti-Helicobacter pylori compounds. She was then funded by a University of Auckland scholarship to carry out Ph.D. research with Professor Brimble into the synthesis of the extremophile natural product berkelic acid. Upon completion of her Ph.D. she was awarded a Newton International Fellowship from the Royal Society to move to the United Kingdom and join the research group of Professor Steven V. Ley in the Department of Chemistry, University of Cambridge. Upon completion of the two year Newton Fellowship, she was then employed as a Post-Doctoral Research Associate to continue working in the Ley group. While in Cambridge, she has been working on the total synthesis of the complex natural products azadirachtin and plantazolicins A and B, in the process developing novel chemistry. In October 2013 Zoe was appointed as a College Lecturer and Fellow at Murray Edwards College.

Teaching

Graduate Lecture Series – Reduction in Organic Chemistry (2 lectures) (2014, 2013)

Senior demonstrator Chemistry II laboratories (2014/2015)

Senior demonstrator Chemistry IB laboratories (2012/2013, 2013/2014)

College Lecturer at Murray Edwards College

Publications

12. Zoe E. Wilson, Sabine Fenner and Steven V. Ley, “Total syntheses of linear poly-thiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B”, Angew. Chem. Int. Ed., 2015, 54, 1284 – 1288 DOI: 10.1002/anie.201410063R1

11. Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley, “The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions”, Org. Biomol. Chem.,2015, 13, 207–214, DOI: 10.1039/c4ob02105c

10. Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “Formal synthesis of berkelic acid: a lesson in α-alkylation chemistry”, J. Org. Chem., 2012, 77, 1, 400–416, DOI: 10.1021/jo201988m

9. Michael C. McLeod, Margaret A. Brimble, Dominea C. K. Rathwell, Zoe E. Wilsonand Tsz-Ying Yuen, “Synthetic approaches to [5,6]-benzannulated spiroketal natural products”, Pure Appl. Chem., 2012, 84, 6, 1379-1390, DOI: 10.1351/PAC-CON-11-08-06

8. Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “An enantioselective formal synthesis of berkelic acid”, Org. Lett., 2011, 13, 19, 5382 – 5385, DOI: 10.1021/ol202265g

7. Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “A flexible approach to 6,5-benzannulated spiroketals”, Eur. J. Org. Chem., 2011, 3938-3945, DOI: 10.1002/ejoc.201100345

6. Jonathan Sperry, Yen-Cheng (William) Liu, Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “Synthesis of benzannulated spiroketals using an oxidative radical cyclization”, Synthesis, 2011, 9, 1383-1398, DOI: 10.1055/s-003001259981

5. Jonathan Sperry, Zoe E. Wilson, Dominea C. K. Rathwell and Margaret A. Brimble, “Isolation, biological activity and synthesis of benzannulated spiroketal natural products”, Nat. Prod. Rep., 2010, 27, 1117-1137, DOI: 10.1039/b911514p

4. Zoe E. Wilson and Margaret A. Brimble, “A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a novel Horner-Wadsworth-Emmons/oxa-Michael cascade”, Org. Biomol. Chem., 2010, 8, 1284-1286, DOI: 10.1039/B927219B

3. Zoe E. Wilson and Margaret A. Brimble, “Molecules derived from the extremes of life”, Nat. Prod. Rep., 2009, 26, 44–71, DOI: 10.1039/b800164m

Featured as an Instant insight article in Chemical Biology (“Life at the extremes”,Chemical Biology, 2008, 3, B95) and featured on the cover of the issue (Nat. Prod. Rep.,2009, 26, 1-2, DOI: 10.1039/B821737H)

2. Fiona J. Radcliff, John D. Fraser, Zoe E. Wilson, Amanda M. Heapy, James E. Robinson, Christina J. Bryant, Christopher L. Flowers, and Margaret A. Brimble, “Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015”, Bioorg. Med. Chem., 2008, 16, 6179–6185, DOI: 10.1016/j.bmc.2008.04.037

1. Zoe E. Wilson, Amanda M. Heapy and Margaret A. Brimble, “Synthesis of indole analogues of the anti-Helicobacter pylori compounds CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108”, Tetrahedron, 2007, 63, 5379–5385, DOI: 10.1016/j.tet.2007.04.067