A practically useful coupling reaction between aromatic halides and redox-active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer-time and larger-scale experiments further demonstrates the robustness of the system

Chen, Yiding

Ley, Steven V

May, Oliver

Watanabe, Eiichi

English

Apollo (Cambridge)

COMMUNICATION              A practical method for continuous production of sp3-rich compounds from (hetero)aryl halides and redox-active esters  Eiichi Watanabe[a]‡, Yiding Chen[b]‡, Oliver May[b] and Steven V. Ley*[b] Abstract: A practically useful coupling reaction between aromatic halides and redox-active esters was realized via nickel catalysis through the use of packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer-time and larger-scale experiments further demonstrates the robustness of the system.   Developing molecular complexity is an important aspect of modern drug discovery programs and has been associated with success in progressing compounds into clinical development[1] by improving target selectivity[2] and safety.[3] Increasing the number of sp3 centers similarly enhances the three-dimensional complexity, again improving success rates.[4] As a consequence，practical and simple methods to construct C(sp3)-C(sp2) bonds are of fundamental importance.[5] A seminal contribution to this field was reported by MacMillan and Doyle who utilized an Ir-photoredox/Ni dual catalyst system to achieve decarboxylative C(sp3)-C(sp2) cross coupling (Figure 1).[6] In this reaction, the synergistic combination of photoredox catalysis and nickel catalysis forges 3D-rich structures from simple and readily available organic molecules. More importantly, carboxylic acid starting materials have a higher accessibility compared to other conventional cross-coupling partners.[7] Following this pioneering report, synthetic methods that enable medicinal chemists to generate C(sp3)-enriched compounds by these decarboxylative pathways have been widely explored.[8] Among these alternative approaches, Weix et. al reported the use of zinc powder as a reducing reagent,[9] therefore avoiding expensive iridium catalysts,[6] or the need for preformed pyrophoric organozinc reagents[10] and photo-/electrochemical reactors.[8c, 8d, 11] More recently, Fier et. al also described a metallic zinc mediated cross-coupling reaction between aryl bromides and redox-active alkyl sulfones.[12] Despite the relevance and the effectiveness of these discoveries, activated zinc powder can be challenging to work with on large scales mainly due to issues of surface variation and safety.[13] Given our expertise in continuous processing methods,[14] and with the availability of newly developed flow columns packed with metallic zinc,[15] we decided to further explore their deployment in cross-coupling sequences. We believe using zinc bed columns to be superior to typical batch procedures for several reasons, especially avoiding excessive use of zinc powder, problems during downstream processing and the difficulty of controlling exothermic reactions. Here, we report a simple, practical improvement to general nickel-catalyzed decarboxylative cross-coupling processes by utilizing a zinc bed column in a continuous flow system. This robust procedure enables access to a wide variety of 3D rich molecules starting from versatile (hetero)aryl halides, and redox-active esters which are themselves easily prepared from corresponding carboxylic acids in flow.    Figure 1. C(sp3)-C(sp2) coupling of redox-active ester and carboxylic acid  Pre-activation of the zinc packed Omnifit® cartridge followed a protocol developed by Alcázar et. al,[15] whereby a solution of TMSCl and 1-bromo-2-chloroethane in THF was flushed through the system (See Supporting Information for detailed procedure). Our initial study utilized similar conditions to the batch procedure reported by Weix et. al for comparison,[9a] where a mixture of 1-chloro-4-iodobenzene 1a, redox-active ester 2a together using NiCl2 glyme complex and di-tert-butyl-2,2-bipyridine ligand in DMAc were passed through a packed zinc (30 mesh) column with a residence time of 40 min led to a modest 49% yield of the coupled product 3a (Table 1, entry1). Subsequent ligand screening highlighted L1 as being superior, giving an improved the yield of 98% (entry 2). Encouraged by this success, attempts were made to shorten the residence time of the reaction in order to achieve a faster overall cross-coupling process. Following on an extensive study of residence time and examining various grades and combinations of zinc powder (see Supporting Information, Table SI1, Figure SI1), using a mixture of 30 and 325 [a] Dr Eiichi Watanabe New Path Molecular Ltd.  Building 580  Babraham Research Campus, Cambridge (UK) [b] Dr Yiding Chen, Mr Oliver May, Prof Steven V. Ley Department of Chemistry, University of Cambridge Lensfield Road, Cambridge (UK) Email: svl1000@cam.ac.uk ‡ Aurthors contributed equally  Supporting information for this article is given via a link at the end of the document. COMMUNICATION              mesh of zinc powder successfully reduced the residence time (Table 1, entry 3 – 6) to only 10 min. Furthermore, more than 10 times reuse of the zinc column showed no lost in efficiency (entry 7). Control experiments demonstrated that both the nickel catalyst and the ligand were necessary for reaction to occur (entry 8, 9). It is also worth noting that the preparation of reaction mixture does not require the use of a glove box or specially dried solvents. The shorter reaction time in flow (10 min) to a comparable batch (12 h) procedure is noteworthy.   Table 1. Reaction Optimisation  entry ligand mesh tR (min) LC yield (%) 1a 3a 1 Dtbpy 30 40 32 49 2 L1 30 40 0 98 3 L1 30 30 0 100 4 L1 20 20 14 81 5 L1 30/325 (11:2) 20 4 95 6a L1 30/325 (11:2) 10 0 100 7b L1 30/325 (11:2) 10 0 100 8 none 30/325 (11:2) 10 30 0 9c none 30/325 (11:2) 10 28 0 a) After 3 times use. b) 10 times use. c) Without nickel catalyst Under optimized conditions, we then assessed the scope of the reaction with various aryl iodides (Figure 2). Apart from 1-chloro-4-iodobenzene 1a, 1-bromo-4-iodobenzene 1b also acting as suitable reaction partner to afford the corresponding coupled product of 3b nicely illustrating the chemoselectivity of the process. It is also worth noting that 3b and the boronic pinacol ester product 3c, both serve as precursors for future diversification through conventional cross-coupling reactions. Iodonaphthalene 1d and iodophenanthrene 1e also delivered the corresponding products in an excellent 90% and 91% yield respectively (3d and 3e). Electron-donating groups such as 4-iodoanisole 1f and 4-iodothioanisole 1g, which often failed as coupling partners for similar nickel catalyzed reductive cross-coupling reactions, here were able to obtain the desired product 3f and 3g in good yields.[8c, 8d],[16] Trifluoromethoxy 3h and trifluoromethyl product 3i exemplified the tolerance for electron-withdrawing groups. With respect to functional-group compatibility, aryl iodides containing nitrile 1j, ketone 1k, ester 1l, amide 1p and phenol 1q functionality, some of which can sometimes be problematic in Kumada and Negishi type coupling, were all well-tolerated under our cross-coupling conditions.[8b] Variations in the position of substituents on the phenyl ring led to meta-substituted compound 3m with 93% yield, while ortho-coordinating groups, such as ester (3n) and phenyl (3o) led to slightly diminished yield of 85% and 89% respectively.[16] To further illustrate the robustness of the protocol, we found that crude redox-active esters, e.g. 3a, prepared from corresponding carboxylic acids  afforded comparable yields to using the pure isolated active esters.  Figure 2. Scope on aryl iodides Crucial to the success of this method is that heteroaryl halides as coupling substrates, including several reactive substrates, were well tolerated. The resulting coupled products were obtained in good to excellent yields (Figure 3).[17] 4-Iodopyridine derivatives (1r-t) all gave the corresponding products in useful yields. Among these a gram scale synthesis of 4-(4-piperidinyl)-pyridine analogue 3t was achieved, whose structure is frequently found in many functional materials but conventionally requires a 4-step synthetic sequence from commercially available starting materials.[18] The crude product was treated with basic a workup followed by a A-15 resin extraction. The desired product was acquired in 61% yield with high purity without the need for silica gel chromatography. Coupling between 3-iodopyridyl substrates (1u-x) and various redox-active esters were all successful (3u-x), especially using activated 2-bromo-5-iodopyridine (1v). Although in this example a trace of 2-substituted byproduct was detected under the reaction conditions. Lowered yields were noticed when coupling with 2-iodopyridyl substrates (1y-1aa), where dehalogenated pyridines were byproducts. Nonetheless a good COMMUNICATION              chemoselectivity between bromo- and iodo-substitutions was clearly demonstrated (3aa). 5-Substituted quinolines (3ab and 3ac) and 4-substituted pyrimidines (3ad and 3ae) were obtained in good to excellent yields. Particularly worth noting is with aryl bromide 1ae and 1af, the coupling here could be readily achieved with bromide substrates using a higher loading of catalyst and an elongated residence time to give the desired product 3ae and 3af in 80% and 57% yield respectively, while 3af could not be obtained from the corresponding iodide. Several other heteroaromatic coupling partners, for example carbazole 1ag, 5-iodoindole 1ah as well as the more reactive 3-iodoindoles 3ai and 3aj all produced useful results.    Figure 3. Scope on heteroaryl halides To further exemplify the potential of the reaction, we expanded the scope with respect to redox-active ester coupling partners using a few different (hetero)aryl iodides (Figure 4). In addition to tetrahydropyranyl 2a substrate, other saturated heterocyclic examples were also viable coupling partners, including N-boc piperidine 1ak and N-cbz piperidine 1al, providing excellent yields for the desired C(sp3)-C(sp2) cross-coupling products (3ak and 3al). Comparable reaction efficiency was also observed with carbocyclic examples 3am and 3an. Primary substituted redox-active esters underwent successful coupling in high yield despite the inherent reluctance to generate primary alkyl radicals via single-electron-transfer process SET.[19] A series of related compounds were generated, including long-chain alkyl chloride 3ap, mono-(methylacryloylxy)ethyl succinate derivative 3aq, pyrene containing  3ar, simple alkene 3as, furan 3at, and amino acids 3au and 3av. α-Amino phthalimide esters 1aw-ay that generate reactive α-amino C(sp2) species, coupled without incident, resulting in high yields of 3aw-ay. Of particular note also was that some active pharmaceutical ingredients (APIs) and natural products are compatible with the reaction conditions affording the anticipated cross-coupled product in good yields (3az-bd). Interestingly, the reaction of redox-active ester 2bd obtained from gabapentin, provided an unusual product which was thought to be generated via a 1,5-hydrogen atom transfer (1,5-HAT) prior to nickel mediated cross-coupling (Figure 4a). As noted by others,[8d, 9a] the limitation of this procedure was the lack of reactivity towards tertiary redox-active esters.[20] Adamantane carboxylic acid and tert-butyl carboxylic acid phthalimide ester both failed to deliver desired product under our standard conditions.    Figure 4. Scope on redox-active esters To best demonstrate the advantage of this method was its ability to transfer to a larger-scale experiment. Equipped with a longer column (i.d.=10.0 mm, length = 120 mm), the reaction set-up was kept operating for 31 hours to deliver a 11.77 g target product. After the reaction, the remaining zinc was still functional without noticeable decline of efficacy. It was also noticed that a small amount of bicyclohexyl byproduct was produced, presumably from the radical dimerization of redox-active ester.   COMMUNICATION              Scheme 1. 10 g-scale synthesis In summary, we have identified a procedurally simple use of a zinc packed column as an alternative reductant to photo- or electrochemical reactor or organometallic reagents for forging C(sp3)-C(sp2) bonds starting from aryl halides and redox-active esters. The method is practical and robust, and provides enhanced substrate compatibility over previously reported examples. Furthermore, the use of crude redox-active esters accelerated the synthesis of highly 3D-rich structures from carboxylic acids and (hetero)aryl halides. Notably, the work features the ease of scale up by harnessing continuous flow conditions.  Acknowledgements  Y. C. thanks Pfizer for funding the postdoctoral fellowship. The authors also gratefully acknowledge financial support from H2020-FETOPEN-2016-2017 programme of European commission (SVL; grant agreement number: 737266-ONE FLOW).  Keywords: Continuous flow, redox-active ester, cross-coupling, packed-column  References:  [1] a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756; b) Y. A. Ivanenkov, B. A. Zagribelnyy, V. A. Aladinskiy, J. Med. Chem. 2019. [2] a) F. Lovering, MedChemComm 2013, 4, 515-519; b) P. A. Clemons, N. E. Bodycombe, H. A. Carrinski, J. A. Wilson, A. F. Shamji, B. K. Wagner, A. N. Koehler, S. L. Schreiber, P. Natl. Acad. 2010, 107, 18787-18792. [3] M. González-Medina, F. D. Prieto-Martínez, J. J. Naveja, O. Méndez-Lucio, T. El-Elimat, C. J. Pearce, N. H. Oberlies, M. Figueroa, J. L. Medina-Franco, Future Med Chem 2016, 8, 1399-1412. [4] a) D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D. M. Wilson, A. Wood, Nat. Chem. 2018, 10, 383-394; b) P. Morgan, D. G. Brown, S. Lennard, M. J. 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Decker, H. A. Navarro, F. I. Carroll, Bioorgan. Med. Chem. 2016, 24, 3842-3848. [19] R. Martin-Montero, V. R. Yatham, H. Yin, J. Davies, R. Martin, Org. Lett. 2019, 21, 2947-2951. [20] T. G. Chen, H. Zhang, P. K. Mykhailiuk, R. R. Merchant, C. A. Smith, T. Qin, P. S. Baran, Angew. Chem. Int. Ed. 2019, 58, 2454-2458.    COMMUNICATION               Entry for the Table of Contents (Please choose one layout)  Layout 2: COMMUNICATION Text for Table of Contents     Eiichi Watanabe[a]‡, Yiding Chen[b]‡, Oliver May[b] and Steven V. Ley*[b] Page No. – Page No. A practical method for continuous production of sp3-rich compounds from (hetero)aryl halides and redox-active esters       

A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters.

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A Practical Method for Continuous Production of sp3‐Rich Compounds from (Hetero)Aryl Halides and Redox‐Active Esters

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A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters.

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