A versatile multistep continuous flow setup is reported for the four-step conversion of anilines into

pyrazole products. The synthesis machine incorporates the use of amine-redox chemistry through diazotization and a metal-free vitamin C mediated reduction. The machine can be used for the synthesis of an array of analogues or the scale up of an individual target

Browne, DL

Ley, SV

Poh, J-S

English

UCL Discovery

ReactionChemistry &EngineeringPAPERCite this: React. Chem. Eng., 2016, 1,101Received 23rd November 2015,Accepted 23rd December 2015DOI: 10.1039/c5re00082crsc.li/reaction-engineeringA multistep continuous flow synthesis machine forthe preparation of pyrazoles via a metal-freeamine-redox process†‡Jian-Siang Poh,a Duncan L. Browne*ab and Steven V. LeyaA versatile multistep continuous flow setup is reported for the four-step conversion of anilines intopyrazole products. The synthesis machine incorporates the use of amine-redox chemistry through diazoti-zation and a metal-free vitamin C mediated reduction. The machine can be used for the synthesis of an ar-ray of analogues or the scale up of an individual target.IntroductionThe synthesis of heterocyclic compounds continues to serveas a cornerstone for the preparation of materials necessaryfor our modern society. The way in which such materials areconstructed is therefore an important area of researchwhereby ease of diversity, simplicity of scale up and sustain-ability of the method represent key factors in the future ad-vancement of this established field. In the case of pyrazoles,five-membered heterocycles featuring two adjacent nitrogenatoms, their functionality is characterized by their appearancein materials, agrochemicals and pharmaceuticals, examplesof which are celecoxib (1), crizotinib, sildenafil andpyrazoxyfen (Fig. 1a).1 At scale these compounds are mostcommonly prepared by the cyclo-condensation of hydrazineswith 1,3-dicarbonyl compounds or their equivalents. This canbe achieved by either the cyclo-condensation with simple hy-drazine followed by a non-selective alkylation of a tautomericmixture, or by appropriate substitution of hydrazine followedby an electronically controlled regioselective cyclo-condensation (Fig. 1b). The latter approach is often preferredas it leads to more selective processes. However, both strate-gies require the preparation and storage of hydrazines onscale, a practice which represents a significant safety risk,economic investment and is applicable to a relatively limitedsubstrate scope.Substituted hydrazines are often prepared by nucleophilicaromatic substitution (SNAr) of the appropriately activatedbenzene systems, or more recently, utilising palladium-catalysed cross-coupling methods with hydrazine. In the lat-ter case, the scope has been increased by the development ofimportant ligands that permit a difficult reductive elimina-tion step.2 Although this cross-coupling approach may havesome way to go before its application on scale becomes eco-nomically and environmentally sustainable, some headwayhas been made with the development of a continuous flowapproach.3 An alternative option, which permits access to avast range of substituted hydrazines centres on the use ofamine-redox chemistry. This method consists of oxidationthrough diazotization, followed by reduction of the N–N tri-ple bond, commonly with tinĲII) chloride (Fig. 1b).4However, in recent years there has been an interest inmoving towards more sustainable reductants, those that canbe washed away from the product through simple aqueousextraction where ascorbic acid or sodium sulfite serve as re-ductant, including our own previous mechanistic work andflow proof-of-concept.5 Here we describe the first report of anend-to-end multistep6 continuous flow process7 for theamine-redox cycle followed by hydrolysis of the hydrazinesurrogate and ensuing cyclo-condensation, a processcharacterised by low inventories of both diazonium salt andhydrazine at any one time and the use of vitamin C asreductant.8Results and discussionOur first experiments towards this goal commenced with thedevelopment of compatible flow conditions for the reductionstage followed by hydrolysis and cyclo-condensation (Fig. 2).Aiming for N-arylated pyrazoles, we tested the performance ofthe setup by injecting 0.8 mmol segments of4-trifluoromethylbenzenediazonium tetrafluoroborate (2, 0.2M in MeCN) and L-ascorbic acid (3, 0.2 M in H2O) which wereReact. Chem. Eng., 2016, 1, 101–105 | 101This journal is © The Royal Society of Chemistry 2016aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge,CB2 1EW, UKb School of Chemistry, Cardiff University, Main Building, Park Place, CF10 3AT,UK. E-mail: dlbrowne@cardiff.ac.uk† Raw spectra can be found at https://www.repository.cam.ac.uk/handle/1810/252343.‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c5re00082cOpen Access Article. Published on 07 January 2016. Downloaded on 03/07/2017 13:46:19.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal  | View Issue102 | React. Chem. Eng., 2016, 1, 101–105 This journal is © The Royal Society of Chemistry 2016combined at a T-piece and passed through a preliminary re-actor coil where the reduction stage could take place. This so-lution then passed through an in-line flow IR device whichserved two purposes: (i) to monitor the presence of the de-sired carbonyl stretching frequency resulting from the oxa-mate moiety as well as to monitor levels of diazonium com-pound still on-stream; (ii) to actively control the flow rate of athird pump9 delivering both pentane-2,4-dione and thehydrochloric acid necessary for oxamate cleavage so that stoi-chiometries could be matched with the flowing segment,thus delivering matched concentration profiles.Once combined with the acid and the dione, the streamthen passed through a heated coil before emerging at theoutput through a 100 psi back-pressure regulator. The flowprocedure developed here offers advantages over batch proce-dures, allowing rapid screening of reaction conditions withminimal operator input, as well as the in situ formation ofunstable and/or explosive intermediates (hydrazides and hy-drazines) to minimize operator exposure.With an appropriate apparatus setup to optimize thethree-step reduction/hydrolysis/cyclo-condensation sequenceestablished, various parameters were investigated (Table 1).Notably, it was found that the final yield of pyrazole washighly dependent on the residence time for the reductionstep with tR = 6 min appearing to be optimal; a decreased res-idence time does not allow the reduction to proceed to com-pletion, whereas increased residence times result in greaterdecomposition of hydrazide 4. We are mindful here of recentreports on the catalytic generation of radical intermediatesthrough the action of ascorbic acid on diazonium salts as alikely competing pathway.10 There is also an optimum tem-perature for reactor coil 2 around 140 °C, where higher thanthis seemed to result in reduced yields of pyrazole products.Optimal conditions were found (Table 1, entry 4), providingpyrazole 5 in 69% yield after isolation.Next we sought to assess the scope of the reaction, butwith the following modifications to the flow procedure: (i) itwould be preferable for the diazonium salts to also be pro-duced in situ from their corresponding anilines, thusavoiding the isolation and handling of additional explosivespecies; (ii) a transformation of the procedure from seg-mented flow to continuous flow would allow safe scale-up toprovide gram-quantities of N-arylated pyrazoles. A ‘diazotiza-tion module’ was easily incorporated into the existing flowset-up to replace the diazonium tetrafluoroborate inputstream, resulting in a four-step telescoped flow procedure(Fig. 3a).In order to assess whether the new flow set-up with the insitu generation of diazonium chloride salts (as opposed tothe tetrafluoroborate salts) was compatible with the existingreduction, hydrolysis and condensation steps, we subjected4-trifluoromethylaniline to the fully telescoped process, un-dergoing diazotization with 1 equiv. of t-butyl nitrite, reduc-tion with 1 equiv. of L-ascorbic acid and condensation with1.1 equiv. of pentane-2,4-dione, run under continuous flowconditions for 2 h. Pleasingly, the desired pyrazole 5 was iso-lated in 69% yield over four steps, in good agreement withthe previously optimized results. Scope of the reaction andflow process with respect to anilines was then explored. Ingeneral, most electron-withdrawing substituents on the ani-lines were tolerated (Fig. 3b). Notably, anthranilic acid, whosediazonium derivative is known to decompose (explosively, ifuncontrolled) to benzyne could be effectively employed in theflow process and provided pyrazole 7 in 61% yield.Fig. 1 a Examples of pyrazole scaffolds. b Synthetic approachestowards pyrazole scaffolds.Reaction Chemistry & EngineeringPaperOpen Access Article. Published on 07 January 2016. Downloaded on 03/07/2017 13:46:19.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineReact. Chem. Eng., 2016, 1, 101–105 | 103This journal is © The Royal Society of Chemistry 2016Conversion of the 4-pentafluorosulfanyl amine to pyrazole 12via its corresponding, previously unknown, hydrazineproceeded in a moderate 45% yield. Electron-rich systemssuch as 4-methoxyaniline were not tolerated in the reductionstep, but heteroaromatic ring systems were applicable; both3-amino-2-chloropyridine and 3-aminoquinoline provided thedesired pyrazoles (11 and 13) in good yields.Next, a variety of 1,3-dicarbonyl compounds or equivalentswere examined in the telescoped multistep process (Fig. 3c).The unsymmetrical 1,3,4-tricarbonyl compound 14 providedpyrazoles 15 (ref. 11) and 16 as single regioisomers, in a com-bined yield of 78%. Acetylenic ketone 17 and3-aminocrotononitrile (19) were also converted to pyrazole 18and 20 (ref. 11) respectively as single regioisomers within thestandard operating conditions of this pyrazole synthesisingmachine. Enaminone 21 was also an effective substrate lead-ing to 57% yield of a 3 : 1 mixture of pyrazole regioisomers(22a and 22b).As a further illustration of the utility of the telescoped pro-cedure, perhaps as a machine to aid possible drug discovery,a selection of relevant 1,3-diketones were crossed with anilinestarting materials to yield pyrazole analogues of celecoxib (1)as a product output (Fig. 3d). Furan-bearing, penta-fluorosulfanyl pyrazole 23 was furnished in 46% yield,whereas the N-pyridyl variant (24) was isolated in 48% yield.A scale-up experiment where the machine was running for a12 hour period demonstrated the synthesis of the4-nitrophenyl analogue 25 in 40% yield, affording 3.76 g ofthe isolated pyrazole product. Finally, the appropriate sulfa-nilamide was diazotized, reduced with L-ascorbic acid, hydro-lyzed and condensed with the corresponding dione to providethe COX-2 selective non-steroidal anti-inflammatory drugcelecoxib (1) in 48% yield over four continuous steps.ConclusionsIn summary, we have reported a metal-free continuous flowmethod for the generation of a variety of N-arylated pyrazolesvia amine-redox chemistry. The telescoped flow process of-fers a distinct advantage over corresponding batch proce-dures due to the in situ formation and use of several reactiveintermediates. Critically, this end-to-end style of synthesisavoids the stock-piling and storage of hazardous drug inter-mediates (diazonium salts and hydrazines) by advancingthem to the next step as they are produced. The machine,and conditions/parameters reported here are applicable to arelatively broad range of amine and 1,3-dicarbonyl materials.Further investigations into the handling and use of reactiveintermediates in flow as well as the development of multistepmachines to support the synthesis and discovery process arecurrently ongoing in our laboratories.Fig. 2 Equipment setup for segmented flow reduction/hydrolysis/cyclo-condensation sequence.Table 1 Optimization of conditions for segmented flow reduction/hy-drolysis/cyclo-condensation sequenceEntry Coil 1, tR/min Coil 2, T/°C Equiv. of HCl Yielda (%)1 2.5 100 5.5 212 2.5 140 5.5 463b 2.5 140 5.5 454 6 140 5.5 71 (69)5 10 140 5.5 676 18 140 5.5 627 35 140 5.5 588 6 100 5.5 219 6 120 5.5 5510 6 160 5.5 5311c 6 140 5.5 7012d 6 140 5.5 7113 6 140 0 3514 6 140 2.2 6815 6 140 11 58All entries run on 0.8 mmol scale with respect to diazoniumtetrafluoroborate, with r.t. in coil 1 and a 35 minute residence timein reactor coil 2, 1.1 equivalents of dione and 1 equivalent ofascorbic acid.a Yield determined from quantitative 1H NMR analysiswith DMF as internal standard, yield of isolated product inparentheses. b 63 minute residence time in reactor coil 2. c 2.2equivalents of dione used. d 2 equivalents of ascorbic acid used.Reaction Chemistry & Engineering PaperOpen Access Article. Published on 07 January 2016. Downloaded on 03/07/2017 13:46:19.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online104 | React. Chem. Eng., 2016, 1, 101–105 This journal is © The Royal Society of Chemistry 2016Fig. 3 Equipment setup and scope for the continuous flow diazotization/reduction/hydrolysis/cyclo-condensation sequence. a Entries run on 4.8mmol scale with respect to aniline unless otherwise stated, yields represent isolated product. b Using NaNO2 in H2O as diazotizing agent.c Using a15 mL reaction coil at 30 °C for the reduction module. d Run on 28.8 mmol scale over 12 hours.Reaction Chemistry & EngineeringPaperOpen Access Article. Published on 07 January 2016. Downloaded on 03/07/2017 13:46:19.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineReact. Chem. Eng., 2016, 1, 101–105 | 105This journal is © The Royal Society of Chemistry 2016AcknowledgementsWe thank Prof. Tony Kirby for insightful discussions regard-ing the reaction mechanism. We are also grateful to the Cam-bridge Home and European Scholarship Scheme (JSP) andEPSRC (DLB and SVL, grant numbers EP/K0099494/1 and EP/K039520/1) for financial support.Notes and references1 (a) S. Fustero, M. Sánchez-Roselló, P. Barrio and A. Simón-Fuentes, Chem. Rev., 2011, 111, 6984; (b) Y. L. Janin, Chem.Rev., 2012, 112, 3924; (c) T. Eicher, S. Hauptmann and A.Speicher, The Chemistry of Heterocycles: Structures, Reactions,Synthesis, and Applications, Wiley-VCH, 3rd edn, 2012; (d)J. A. Joule and K. Mills, Heterocyclic Chemistry, Wiley-Blackwell, 5th edn, 2010, For examples of continuous flowapproaches towards pyrazoles see: (e) I. R. Baxendale, S. C.Schou, J. Sedelmeier and S. V. Ley, Chem. – Eur. J., 2010, 16,89; ( f ) C. J. Smith, F. J. Iglesias-Sigüenza, I. R. Baxendaleand S. V. Ley, Org. Biomol. Chem., 2007, 5, 2758; (g) H.Lange, C. F. Carter, M. D. Hopkin, A. Burke, J. G. Goode,I. R. Baxendale and S. V. Ley, Chem. Sci., 2011, 2, 765; (h) D.Obermayer, T. N. Glasnov and C. O. Kappe, J. Org. Chem.,2011, 76, 6657; (i) J. R. Breen, G. Sandford, D. S. Yufit,J. A. K. Howard, J. Fray and B. Patel, Beilstein J. Org. Chem.,2011, 7, 1048; ( j) M. Damm, T. N. Glasnov and C. O. Kappe,Org. Process Res. Dev., 2010, 14, 215; (k) C. Battilocchio, B. J.Deadman, N. Nikbin, M. O. Kitching, I. R. Baxendale andS. V. Ley, Chem. – Eur. J., 2013, 19, 7917.2 R. J. Lundgren and M. Stradiotto, Angew. Chem., Int. Ed.,2010, 49, 8686.3 A. DeAngelis, D.-H. Wang and S. L. Buchwald, Angew. Chem.,Int. Ed., 2013, 52, 3434.4 For a continuous flow process using tinĲII) chloride as areducing agent for diazonium salts, see: (a) B. Li, D. Widlicka,S. Boucher, C. Hayward, J. Lucas, J. C. Murray, B. T. O'Neil, D.Pfisterer, L. Samp, J. VanAlsten, Y. Xiang and J. Young, Org.Process Res. Dev., 2012, 16, 2031, For the use of tinĲII) chlorideas a reducing agent for diazonium salts in patent literature,see: (b) R. Baker, V. G. Matassa and L. J. Street, Merck Sharpand Dohme Ltd., US Pat., 5298520, 29 March 1994.5 For methods utilising sodium sulfite, see: (a) G. H.Coleman, Org. Synth., 1922, 2, 71; (b) J. P. Koilpillai, M.Subramanian, U. Mallela, V. B. Boddu, R. Dandala and S.Meenakshisunderam, Aurobindo Pharma Ltd., WO Pat.,2008/075163, 26 June 2008; (c) Z. Yu, G. Tong, X. Xie, P.Zhou, Y. Lv and W. Su, Org. Process Res. Dev., 2015, 19, 892,For methods utilising L-ascorbic acid, see: (d) M. Marinozzi,G. Marcelli, A. Carotti and B. Natalini, RSC Adv., 2014, 4,7019; (e) C. P. Ashcroft, P. Hellier, A. Pettman and S.Watkinson, Org. Process Res. Dev., 2011, 15, 98; ( f ) T. Norris,C. Bezze, S. Z. Franz and M. Stivanello, Org. Process Res.Dev., 2009, 13, 354; (g) D. L. Browne, I. R. Baxendale andS. V. Ley, Tetrahedron, 2011, 67, 10296.6 For recent reviews on flow chemistry, see: (a) J. C. Pastre,D. L. Browne and S. V. Ley, Chem. Soc. Rev., 2013, 42, 8849;(b) S. V. Ley, D. E. Fitzpatrick, R. Ingham and R. M. Myers,Angew. Chem., Int. Ed., 2015, 54, 3449; (c) S. V. Ley, D. E.Fitzpatrick, R. Myers, C. Battilocchio and R. J. Ingham,Angew. Chem., Int. Ed., 2015, 54, 10122; (d) B. Gutmann, D.Cantillo and C. O. Kappe, Angew. Chem., Int. Ed., 2015, 54,6688; (e) K. F. Jensen, B. J. Reizman and S. G. Newman, LabChip, 2014, 14, 3206; ( f ) N. G. Anderson, Org. Process Res.Dev., 2012, 16, 852; (g) I. R. Baxendale, J. Chem. Technol.Biotechnol., 2013, 88, 519.7 For examples of some recent multistep flow processes, see:(a) J. Hartwig, S. Ceylan, L. Kupracz, L. Coutable and A.Kirschning, Angew. Chem., Int. Ed., 2013, 52, 9813; (b) D.Ghislieri, K. Gilmore and P. H. Seeberger, Angew. Chem., Int.Ed., 2015, 54, 678; (c) S. Newton, C. F. Carter, C. M. Pearson,L. de C. Alves, H. Lange, P. Thansandote and S. V. Ley,Angew. Chem., Int. Ed., 2014, 53, 4915; (d) L. Kupracz and A.Kirschning, Adv. Synth. Catal., 2013, 355, 3375; (e) J. C.Pastre, D. L. Browne, M. O'Brien and S. V. Ley, Org. ProcessRes. Dev., 2013, 17, 1183; ( f ) P. R. D. Murray, D. L. Browne,J. C. Pastre, C. Butters, D. Guthrie and S. V. Ley, Org. ProcessRes. Dev., 2013, 17, 1192; (g) C. Battilocchio, I. R. Baxendale,M. Biava, M. O. Kitching and S. V. Ley, Org. Process Res.Dev., 2012, 16, 798; (h) M. A. Kabeshov, B. Musio, P. R. D.Murray, D. L. Browne and S. V. Ley, Org. Lett., 2014, 16,4618; (i) S.-H. Lau, A. Galván, R. R. Merchant, C.Battilocchio, J. A. Souto, M. B. Berry and S. V. Ley, Org. Lett.,2015, 17, 3218; ( j) M. Chen and S. L. Buchwald, Angew.Chem., Int. Ed., 2013, 52, 4247; (k) C. A. Correia, K. Gilmore,D. T. McQuade and P. H. Seeberger, Angew. Chem., Int. Ed.,2015, 54, 4945; (l) T. Tsubogo, H. Oyamada and S.Kobayashi, Nature, 2015, 520, 329.8 For some recent examples of controlling hazardouschemistry in flow see: (a) S. T. R. Müller, D. Smith, P. Hellierand T. Wirth, Synlett, 2014, 25, 871; (b) J. A. Newby, D. W.Blaylock, P. M. Witt, J. C. Pastre, M. K. Zacharova, S. V. Leyand D. L. Browne, Org. Process Res. Dev., 2014, 18, 1211; (c)J. A. Newby, D. W. Blaylock, P. M. Witt, R. M. Turner, P. L.Heider, B. H. Harji, D. L. Browne and S. V. Ley, Org. ProcessRes. Dev., 2014, 18, 1221; (d) B. Gutmann, P. Elsner, A.O'Kearney-McMullan, W. Goundry, D. M. Roberge and C. O.Kappe, Org. Process Res. Dev., 2015, 19, 1062; (e) A. A.Kulkarni, Beilstein J. Org. Chem., 2014, 10, 405; ( f ) J.-I.Yoshida, Y. Takahashi and A. Nagaki, Chem. Commun.,2013, 49, 9896.9 H. Lange, C. F. Carter, M. D. Hopkin, A. Burke, J. G. Goode,I. R. Baxendale and S. V. Ley, Chem. Sci., 2011, 2, 765.10 (a) B. Majhi, D. Kundu and B. C. Ranu, J. Org. Chem.,2015, 80, 7739; (b) F. P. Crisóstomo, T. Martín and R.Carrillo, Angew. Chem., Int. Ed., 2014, 53, 2181.11 CCDC 1430558 and 1430559 contain the supplementarycrystallographic data for this paper. These data are providedfree of charge by The Cambridge Crystallographic DataCentre.Reaction Chemistry & Engineering PaperOpen Access Article. Published on 07 January 2016. Downloaded on 03/07/2017 13:46:19.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online

A multistep continuous flow synthesis machine for the preparation of pyrazoles via a metal-free amine-redox process

https://discovery.ucl.ac.uk/10114378/1/c5re00082c.pdf

A multistep continuous flow synthesis machine for the preparation of pyrazoles via a metal-free amine-redox process

Abstract

Similar works

Full text

Available Versions

UCL Discovery