We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput

Grunenberg, Lars

Labes, Ricardo

Ley, Steven V

Lima, Fabio

Rahman, Husaini BA

Sedelmeier, Joerg

English

Apollo (Cambridge)

5606 | Chem. Commun., 2018, 54, 5606--5609 This journal is©The Royal Society of Chemistry 2018Cite this:Chem. Commun., 2018,54, 5606Organic photocatalysis for the radical couplingsof boronic acid derivatives in batch and flow†Fabio Lima, a Lars Grunenberg, ‡a Husaini B. A. Rahman,‡a Ricardo Labes, aJoerg Sedelmeierb and Steven V. Ley *aWe report an acridium-based organic photocatalyst as an efficientreplacement for iridium-based photocatalysts to oxidise boronicacid derivatives by a single electron process. Furthermore, weapplied the developed catalytic system to the synthesis of fouractive pharmaceutical ingredients (APIs). A straightforward scale upapproach using continuous flow photoreactors is also reportedaffording gram an hour throughput.Visible-light photoredox catalysis has become an important toolfor radical species generation without the need for stoichio-metric reagents.1 Using these methods, a large number ofapplications have emerged for the catalytic generation of carbonradical species via single electron oxidation of charged anionicspecies, such as carboxylates, silicates, and trifluoroborate salts.2We recently developed a photoredox method to generate radicalsfrom neutral boronic acids or esters, making use of an additionalLewis base catalyst (LB) to activate the trivalent boronic speciestowards single-electron oxidation.3 The substantial number ofcompatible substrates, combined with their commercial avail-ability makes it a method of choice to generate carbon radicalscatalytically and engage them in versatile radical-based couplingreactions. However, effective oxidation of these redox-activecomplexes has until now only been realised using costly iridiumbased photoredox catalysts (Ir-1 or Ir-2). Despite the promisesoffered by the photoredox disconnections for pharmaceuticalproducts synthesis,4 industry has to comply with residual transi-tion metal limits in final products (oral permitted daily exposurefor iridiumr100 mg per day).5 To comply with these low residualmetal levels, costly purification protocols have to be carriedout after transformations using transition metal catalysts. Withthe recent development of efficient new generation organicphotocatalysts,5a,6 we sought to identify a suitable organicreplacement to the previously used iridium photosensitisers.7Ideally this protocol could be scaled up using a continuous flowreactor and its utility demonstrated by synthesising pharma-ceutically relevant compounds in an efficient manner.To start this investigation, we chose a model radical conju-gate addition reaction of boronic ester 1 or boronic acid 2 withmethyl vinyl ketone (MVK, 3) as radical acceptor.3b We sub-jected these species to a series of photoredox catalysts in thepresence of catalytic amount of Lewis base (LB = quinuclidin-3-olor DMAP) and under blue LEDs (14W at l = 450 nm) irradiation toproduce the coupled products 4 or 5 (Scheme 1). A wide range ofvisible-light absorbing organic photocatalysts were screened usingthese two model reactions (full table in ESI†).Scheme 1 Selected examples of catalyst performance. See ESI† for fulloptimisation.a Department of Chemistry, University of Cambridge, Lensfield Road,Cambridge CB2 1EW, UK. E-mail: svl1000@cam.ac.uk;Web: http://www.leygroup.ch.cam.ac.ukb Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc02169d‡ These authors contributed equally to the project.Received 19th March 2018,Accepted 12th April 2018DOI: 10.1039/c8cc02169drsc.li/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 16 May 2018. Downloaded on 7/16/2018 2:59:58 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal  | View IssueThis journal is©The Royal Society of Chemistry 2018 Chem. Commun., 2018, 54, 5606--5609 | 5607Along with rose bengal (RB), two recently developed organicdyes (4CzlPN8 and Mes-Acr-46) emerged from this screening aspotential organic replacement to Ir-1 and Ir-2. While organicdyes degradation upon prolonged irradiation can be a potentialpitfall, no discolouration (or photobleaching) occurred duringthe course of the irradiation with these three photocatalysts. Itwas therefore postulated that these dyes were stable enough tobe used without decline of reactivity. Finally, as Mes-Acr-4 con-sistently led to the highest yields (similar to Ir-1 and Ir-2)with both the boronic ester (1, entry 4) and acid (2, entry 9),it was chosen as a promising replacement to the iridium-basedphotocatalysts.We then further compared the generality ofMes-Acr-4 againstIr-2 with a wider range boronic acid derivatives (Table 1). As faras the cross-coupled product yields are concerned, the perfor-mance of the Mes-Acr-4 dye was often equivalent to the Ir-2photocatalyst.While products 4, 5 and 14 were obtained in the sameisolated yields with both photocatalysts, the organic dye wassuperior to the iridium one for reactions leading to 11, 13 and15. However, in some cases, inferior yields were observed withthe organic dye (see compounds 9, 10 and 12). Although noapparent correlation between the structure of the boronic acidderivative and their reactivity could be drawn, no reactivityshutdown was observed by replacing the iridium-photocatalystby Mes-Acr-4.To more finely compare the two catalysts, a reaction profileof the conjugate addition of the cyclohexyl boronic acid (2) wasrecorded by following the reaction using NMR spectroscopy (Fig. 1).To do this, reagents were dissolved in a deuterated solventmixture and irradiated inside a borosilicate NMR tube. Atdifferent time points, the light was turned off, thereby puttingthe reaction on hold to conduct a 1H-NMRmeasurement. Using1,3,5-trimethoxy benzene as an internal standard, it was possibleto determine the yield in the deuterated product (5d) over time.Using this method, we were able to conveniently monitor thereaction progress with minimal material usage (0.05 mmol of 2).While the two catalysts performed equally after the 24 h ofirradiation (5 in Table 1), we could observe that they do notshare the same reaction profile (Fig. 1). Although the two curvesseem to follow similar initial kinetics, the slope of the Ir-2 curvesuddenly drops after 30min while theMes-Acr-4 one continues tofollow a more regular path. We postulated that this behaviour is asign of a catalyst deactivation pathway.9 Indeed, radical alkylationof the pyridyl ligands has already been observed on similariridium-based photoredox catalysts.9 Also, 2,20-bipyridyl (bpy)ligand substitution (of Ir-2) in acetonitrile solvent was identifiedas another deactivation pathway for these photocatalysts.10 Wetherefore postulated that the strongly nucleophilic DMAP catalystcan result in bpy displacement on the iridium centre of Ir-2 andlead to catalyst deactivation. DiRocco demonstrated that theMes-Acr-4 catalyst was reasonably stable under similar conditions.6From this analysis we discovered that theMes-Acr-4 catalyst bringsfaster kinetics than Ir-2 at the same catalyst loading and istherefore more effective for this reaction.Pleasingly, this reaction monitoring also informed us thatthe reaction can be completed in 70 min, with this new catalyst.This relatively short reaction time, combined with the benefitsof microscale on photoreactions,11 motivated us to study thetransferability of this process in a continuous flow reactor.To facilitate this transfer, we initially compared the reactionprofile observed in the NMR tube (14 W at l = 450 nm) to theyields obtained in a Vapourtec UV-150 reactor equipped with blueLEDs (17 W at l = 420 nm). These reactions were performedindividually with different residence times, and the kinetic profileTable 1 Performance ofMes-Acr-4 against Ir-2 for several radical alkylationsof boronic acid derivativesIsolated yields. Reactions carried out with 0.2 mmol of 6 or 7, 0.8 mmolof 3, 2 mol% of Mes-Acr-4 and 20 mol% of the indicated Lewis base(LB). a DMAP was used as a Lewis base. Isolated yield obtained with Ir-2for the same product in parentheses.Fig. 1 Reaction following ofMes-Acr-4 against Ir-2 in NMR tube. Reactionmonitoring using 1H-NMR, comparison between Mes-Ar-4 (dots) and Ir-2(squares). Reactions carried out at 0.05 mmol of 2, 0.2 mmol of 3, 2 mol% ofthe indicated PC and 20 mol% DMAP in deuterated solvents.Communication ChemCommOpen Access Article. Published on 16 May 2018. Downloaded on 7/16/2018 2:59:58 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article Online5608 | Chem. Commun., 2018, 54, 5606--5609 This journal is©The Royal Society of Chemistry 2018proved to be similar (Fig. 2). While observed kinetics for photo-reactions limited by photon-flux are often significantly differentin a large batch vessel than in the small channels of a photo flowreactor,11a we observed similar yields after the same time ofirradiation between the two systems.We hypothesised that the inner diameter (i.d.) of the NMRtube (i.d. = 5.0 mm) was not large enough compared to the FEPtubing of the UV-150 coil (i.d. = 1.3 mm) to observe a significantdifference in terms of light absorption efficiency. With thesereaction conditions and using reported data on similar photo-catalysts,11c approximately 90% of the light is absorbed withinthe first 0.3 mm of the solution. Reaction rate could also bedependent on the mass transfer.11b Nevertheless, as the reactionfollowing curve obtained via NMR matched with the kineticsobserved in the UV-150 photoreactor (10 mL), we decided to usethe NMR reaction monitoring to predict the residence timerequired to reach the full conversion in the flow photoreactor.As every substrate will require a different irradiation time, we willbe able to circumvent the material- and time-consuming residencetime optimisation on the flow equipment by simulating therequired irradiation time with a single batch experiment.12To complete this flow photoreactor investigation, we examinedthismodel reaction in a photoreactor (Photosyn) recently developedby Uniqsis Ltd and that was made available in our lab for a brieftesting period. The powerful LEDs (420 W at l = 450 nm) equippedon this reactor allowed faster rates to be observed in a 5 mLinvestigation coil (PFA, i.d. = 1.0 mm). This massive power increasebrought the irradiation time necessary to reach 80% yield of 5 from70 min in the UV-150 reactor to 30 min in the Photosyn. Thissignificant rate enhancement encouraged us to run a larger scaleexperiment on a 50 mL coil (PFA, i.d. = 2.4 mm) using the sameirradiation system (Scheme 2). Pleasingly the results obtained inthe 5 mL coil translated well in the 50 mL coil in which we couldobtain 3.7 g (24.1 mmol, 81% yield) of 5 in 3 h, corresponding to athroughput of 8.0 mmol h1.With a robust organocatalytic system in hand to activateboronic acid derivatives and transfer the chemistry in a flowphotoreactor, we decided to explore its application for effec-tive active pharmaceutical ingredients synthesis.4a As powerfulapproaches using photogenerated a-amino radicals were reportedfor the concise synthesis of baclofen13 and pregabalin,14 we weretherefore naturally inclined to test the applicability of the recentlydeveloped methodology for the synthesis of active pharmaceuticalingredients (API) from the g-amino butyric acid (GABA) family.This approach uses the Boc-protected amino boronic ester(16) as the a-amino radical source. This substrate would undergoour recently developed Lewis base and photoredox dual catalysedaddition to diethyl malonate-derived olefins (17).3b The resultingcoupled product (18) could then be deprotected, hydrolysed anddecarboxylated using aqueous HCl (6 M) and heating to revealthe amino acid hydrochlorides (19).13 We initially studied thefeasibility of this transformation in batch (Table 2). After a briefoptimisation of the reaction conditions, we could couple themethyl-amino building block (16) to malonate derived trisubsti-tuted olefins in high yields (20 to 22). A further excess of 16 andlonger irradiation time (48 h instead of 18 h) was required tocouple the tetra-substituted olefin in acceptable yield (23).The isolated drug precursors were then subjected to one potdeprotection, hydrolysis, and decarboxylation using aqueousHCl. While phenibut was obtained without residual lactamformation after only 1 h of reflux, the other precursors requiredprolonged heating (24 h) to fully hydrolyse their correspondingFig. 2 Yield comparison between NMR tube and flow irradiation. Com-parison between batch (black) and flow (grey) modes. UV-150 (10 mL FEPcoil) and Photosyn (5 mL PFA coil).Scheme 2 Larger scale reaction in photosyn (420 W at l = 450 nm).Reaction carried out at 0.1 M concentration of 2 in acetone :methanol(1 : 1) using 2 mol% of Mes-Acr-4 and 20 mol% of DMAP.Table 2 Application to g-amino butyric acids analogues synthesis inbatchIsolated yields. Step 1 carried out at 0.1 M concentration of 17 inacetone :methanol (1 : 1). a Step 1 deviating from standard conditions,0.60 mmol of 16 and 48 h of irradiation. b Step 2 deviating fromstandard conditions, only 1 h of refluxing is necessary.ChemComm CommunicationOpen Access Article. Published on 16 May 2018. Downloaded on 7/16/2018 2:59:58 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineThis journal is©The Royal Society of Chemistry 2018 Chem. Commun., 2018, 54, 5606--5609 | 5609g-lactams to the final crystalline APIs as hydrochloride salts inhigh yields. With these encouraging results, we decided toapply this method in the flow synthesis of these active pharma-ceutical ingredients. Tests on telescoping the hydrolysis of 18revealed that the impurity profile carried out from step 1 wouldmake the purity of the final APIs insufficient to crystallise.15Therefore, only the photoredox coupling step was investigatedin a flow reactor.16 As observed during the optimisation study,the long irradiation time required for the synthesis of thegabapentin precursor (23) prevented us from transferring thisreaction to flow (t = 100 min limit).Therefore, we investigated only the reaction profile of thethree other precursors (20 to 22) using the NMR methodpreviously described (see ESI†). These profiles allowed us toidentify the residence time needed for each partner. While thedeuterated phenibut precursor required 80 min of irradiation,the baclofen and pregabalin ones could be prepared efficientlyin 60 min and 40 min respectively.Using these ‘‘predicted’’ residence times in the UV-150 setupresulted in finely tuned conditions for these APIs precursorscoupling reactions (Table 3). Pleasingly, all the targeted com-pounds were successfully obtained in high yields after purifica-tion (20 to 22). These experiments confirm the feasibility of thephotoredox coupling step in a flow reactor for potential scale upin a larger photoreactor.As a summary, we identified the organic dyeMes-Acr-4 as analternative to iridium photocatalysts for the photoredox activa-tion of boronic acid derivatives. This organic photocatalyst haveshown similar to better activity than Ir-2 in photoredox couplingswith methyl vinyl ketone as well as enhanced stability under thereaction conditions. NMR reaction monitoring allowed us torapidly predict the necessary residence time to transfer thesereactions in flow. Gram per hour throughput could be obtainedusing a recently developed larger (50 mL) visible light photo-reactor. The synthetic utility of this methodology could be furtherdemonstrated by the two-step syntheses of four approvedcentral nervous system drugs from the GABA family in batchand flow modes.We are grateful to Novartis Pharma AG (F. L.), ErasmusScholarship Scheme (L. G.) and the EPSRC (S. V. L., GrantNo. EP/K009494/1, EP/K039520/1 and EP/M004120/1) for financialsupport. We thank Dr Berthold Schenkel and Dr GottfriedSedelmeier form Novartis for insightful discussions. We thankDr Mark Ladlow (UNIQSIS Ltd, UK) for the loan of the largescale Photosyn reactor.Conflicts of interestThere are no conflicts to declare.Notes and references1 J.-P. Goddard, C. Ollivier and L. Fensterbank, Acc. Chem. Res., 2016,49, 1924–1936.2 (a) J. Xuan, Z. G. Zhang and W. J. Xiao, Angew. Chem., Int. Ed., 2015,54, 15632–15641; (b) V. Corce´, L. Chamoreau, E. Derat, J. Goddard,C. Ollivier and L. Fensterbank, Angew. Chem., Int. Ed., 2015, 54,11414–11418; (c) Y. Yasu, T. Koike and M. Akita, Adv. Synth. Catal.,2012, 354, 3414–3420.3 (a) F. Lima, M. A. Kabeshov, D. N. Tran, C. Battilocchio, J. Sedelmeier,G. Sedelmeier, B. Schenkel and S. V. Ley, Angew. Chem., Int. Ed., 2016,55, 14085–14089; (b) F. Lima, U. K. Sharma, L. Grunenberg, D. Saha,S. Johannsen, J. Sedelmeier, E. V. Van der Eycken and S. V. Ley, Angew.Chem., Int. Ed., 2017, 56, 15136–15140.4 (a) J. J. Douglas, M. J. Sevrin and C. R. J. Stephenson, Org. ProcessRes. Dev., 2016, 20, 1134–1147; (b) J. J. Douglas, K. P. Cole andC. R. J. Stephenson, J. Org. Chem., 2014, 79, 11631–11643.5 (a) M. Majek and A. Jacobi von Wangelin, Angew. Chem., Int. Ed.,2015, 54, 2270–2274; (b) N. A. Romero and D. A. Nicewicz, Chem.Rev., 2016, 116, 10075–10166; (c) N. G. Anderson, Practical ProcessResearch and Development: A Guide for Organic Chemists, AcademicPress, Oxford, 2012.6 A. Joshi-Pangu, F. Le´vesque, H. G. Roth, S. F. Oliver, L. C. Campeau,D. Nicewicz and D. A. DiRocco, J. Org. Chem., 2016, 81, 7244–7249.7 K. Teegardin, J. I. Day, J. Chan and J. Weaver, Org. Process Res. Dev.,2016, 20, 1156–1163.8 (a) C. Le´veˆque, L. Chenneberg, V. Corce´, C. Ollivier and L. Fensterbank,Chem. Commun., 2016, 52, 9877–9880; (b) J. Luo and J. Zhang, ACSCatal., 2016, 6, 873–877.9 J. J. Devery III, J. J. Douglas, J. D. Nguyen, K. P. Cole, R. A. Flowers IIand C. R. J. Stephenson, Chem. Sci., 2015, 6, 537–541.10 I. N. Mills, J. A. Porras and S. Bernhard, Acc. Chem. Res., 2018, 51,352–364.11 (a) D. Cambie´, C. Bottecchia, N. J. W. Straathof, V. Hessel andT. Noe¨l, Chem. Rev., 2016, 116, 10276–10341; (b) K. Loubie`re,M. Oelgemo¨ller, T. Aillet, O. Dechy-Cabaret and L. Prat, Chem.Eng. Process., 2016, 104, 120–132; (c) Y. Su, N. J. W. Straathof,V. Hessel and T. Noe¨l, Chem. – Eur. J., 2014, 20, 10562–10589.12 L. D. Elliott, J. P. Knowles, C. S. Stacey, D. J. Klauber and K. I. Booker-Milburn, React. Chem. Eng., 2018, 3, 86–93.13 K. Miyazawa, T. Koike and M. Akita, Adv. Synth. Catal., 2014, 356,2749–2755.14 L. Chu, C. Ohta, Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc.,2014, 136, 10886–10889.15 H. Ishitani, K. Kanai, Y. Saito, T. Tsubogo and S. Kobayashi, Eur.J. Org. Chem., 2017, 6491–6494.16 D. Ghislieri, K. Gilmore and P. H. Seeberger, Angew. Chem., Int. Ed.,2015, 54, 678–682.Table 3 Application to g-amino butyric acids precursors synthesis in flowIsolated yields. 0.5 mmol scale reaction in UV-150 (17 W at l = 420 nm).Reaction carried out at 0.1 M concentration of 17 in acetone :methanol(1 : 1) using 2 mol% of Mes-Acr-4 and 20 mol% of DMAP.Communication ChemCommOpen Access Article. Published on 16 May 2018. Downloaded on 7/16/2018 2:59:58 PM.  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Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow.

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Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow.

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