Abstract
New organic reactivity has often been discovered by happenstance. Several recent research efforts have attempted to leverage this to discover new reactions. In this Review, we attempt to unify reported approaches to reaction discovery on the basis of the practical and strategic principles applied. We concentrate on approaches to reaction discovery as opposed to reaction development, though conceptually groundbreaking approaches to identifying efficient catalyst systems are also considered. Finally, we provide a critical overview of the utility and application of the reported methods from the perspective of a synthetic chemist, and consider the future of high-throughput screening in reaction discovery.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nicolaou, K. C., Hanko, R. & Hartwig, W. Handbook of Combinatorial Chemistry: Drugs, Catalysts, Materials (Wiley-VCH, 2002).
Weber, L., Illgen, K. & Almstetter, M. Discovery of new multi component reactions with combinatorial methods. Synlett 1999, 366–374 (1999).
Reetz, M. T. Combinatorial and evolution-based methods in the creation of enantioselective catalysts. Angew. Chem. Int. Ed. 40, 284–310 (2001).
Tsukamoto, M. & Kagan, H. B. Recent advances in the measurement of enantiomeric excesses. Adv. Synth. Catal. 344, 453–463 (2002).
Leung, D., Kang, S. O. & Anslyn, E. V. Rapid determination of enantiomeric excess: a focus on optical approaches. Chem. Soc. Rev. 41, 448–479 (2012).
Menger, F. M., Eliseev, A. V. & Migulin, V. A. Phosphatase catalysis developed via combinatorial organic chemistry. J. Org. Chem. 60, 6666–6667 (1995).
Liu, G. & Ellman, J. A. A general solid-phase synthesis strategy for the preparation of 2-pyrrolidinemethanol ligands. J. Org. Chem. 60, 7712–7713 (1995).
Burgess, K., Lim, H-J., Porte, A. M. & Sulikowski, G. A. New catalysts and conditions for a C–H insertion reaction identified by high throughput catalyst screening. Angew. Chem. Int. Ed. Engl. 35, 220–222 (1996).
Porte, A. M., Reibenspies, J. & Burgess, K. Design and optimization of new phosphine oxazoline ligands via high-throughput catalyst screening. J. Am. Chem. Soc. 120, 9180–9187 (1998).
Cole, B. M. et al. Discovery of chiral catalysts through ligand diversity: Ti-catalyzed enantioselective addition of TMSCN to meso epoxides. Angew. Chem. Int. Ed. Engl. 35, 1668–1671 (1996).
Gilbertson, S. R. & Wang, X. The combinatorial synthesis of chiral phosphine ligands. Tetrahedron Lett. 37, 6475–6478 (1996).
Sigman, M. S. & Jacobsen, E. N. Schiff base catalysts for the asymmetric Strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 120, 4901–4902 (1998).
Francis, M. B., Finney, N. S. & Jacobsen, E. N. Combinatorial approach to the discovery of novel coordination complexes. J. Am. Chem. Soc. 118, 8983–8984 (1996).
Francis, M. B. & Jacobsen, E. N. Discovery of novel catalysts for alkene epoxidation from metal-binding combinatorial libraries. Angew. Chem. Int. Ed. 38, 937–941 (1999).
Ding, K. Synergistic effect of binary component ligands in chiral catalyst library engineering for enantioselective reactions. Chem. Commun. 909–921 (2008).
Ding, K., Du, H., Yuan, Y. & Long, J. Combinatorial chemistry approach to chiral catalyst engineering and screening: rational design and serendipity. Chem. Eur. J. 10, 2872–2884 (2004).
Reetz, M. T., Sell, T., Meiswinkel, A. & Mehler, G. A new principle in combinatorial asymmetric transition-metal catalysis: mixtures of chiral monodentate P ligands. Angew. Chem. Int. Ed. 42, 790–793 (2003).
Reetz, M. T. & Mehler, G. Mixtures of chiral and achiral monodentate ligands in asymmetric Rh-catalyzed olefin hydrogenation: reversal of enantioselectivity. Tetrahedron Lett. 44, 4593–4596 (2003).
Peña, D. et al. Improving conversion and enantioselectivity in hydrogenation by combining different monodentate phosphoramidites: a new combinatorial approach in asymmetric catalysis. Org. Biomol. Chem. 1, 1087–1089 (2003).
Minnaard, A. J., Feringa, B. L., Lefort, L. & de Vries, J. G. Asymmetric hydrogenation using monodentate phosphoramidite ligands. Acc. Chem. Res. 40, 1267–1277 (2007).
Furka, Á., Sebestyén, F., Asgedom, M. & Dibó, G. General method for rapid synthesis of multicomponent peptide mixtures. Int. J. Pept. Prot. Res. 37, 487–493 (1991).
Evans, C. A. & Miller, S. J. Proton-activated fluorescence as a tool for simultaneous screening of combinatorial chemical reactions. Curr. Opin. Chem. Biol. 6, 333–338 (2002).
Lichtor, P. A. & Miller, S. J. Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation. Nature Chem. 4, 990–995 (2012).
McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an α-amino C-H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).
Ganem, B. Strategies for innovation in multicomponent reaction design. Acc. Chem. Res. 42, 463–472 (2009).
Beeler, A. B., Su, S., Singleton, C. A. & Porco, J. A. Discovery of chemical reactions through multidimensional screening. J. Am. Chem. Soc. 129, 1413–1419 (2007).
Kinoshita, H., Ingham, O. J., Ong, W. W., Beeler, A. B. & Porco, J. A. Tandem processes identified from reaction screening: nucleophilic addition to aryl N-phosphinylimines employing La(III)-TFAA activation. J. Am. Chem. Soc. 132, 6412–6418 (2010).
Elvira, K. S., Casadevall i Solvas, X., Wootton, R. C. R. & DeMello, A. J. The past, present and potential for microfluidic reactor technology in chemical synthesis. Nature Chem. 5, 905–915 (2013).
Goodell, J. R. et al. Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds. J. Org. Chem. 74, 6169–6180 (2009).
Martin, V. I., Goodell, J. R., Ingham, O. J., Porco, J. A. & Beeler, A. B. Multidimensional reaction screening for photochemical transformations as a tool for discovering new chemotypes. J. Org. Chem. 79, 3838–3846 (2014).
Klán, P. & Wirz, J. Photochemistry of organic compounds: from concepts to practice (Wiley-Blackwell, 2009).
Treece, J. L., Goodell, J. R., Vander Velde, D., Porco, J. A. & Aubé, J. Reaction discovery using microfluidic-based multidimensional screening of polycyclic iminium ethers. J. Org. Chem. 75, 2028–2038 (2010).
Robbins, D. W. & Hartwig, J. F. A simple, multidimensional approach to high-throughput discovery of catalytic reactions. Science 333, 1423–1427 (2011).
Gao, X. & Kagan, H. B. One-pot multi-substrate screening in asymmetric catalysis. Chirality 10, 120–124 (1998).
Gennari, C., Ceccarelli, S., Piarulli, U., Montalbetti, C. A. G. N. & Jackson, R. F. W. Investigation of a new family of chiral ligands for enantioselective catalysis via parallel synthesis and high-throughput screening. J. Org. Chem. 63, 5312–5313 (1998).
Satyanarayana, T. & Kagan, H. B. The multi-substrate screening of asymmetric catalysts. Adv. Synth. Catal. 347, 737–748 (2005).
Duursma, A., Minnaard, A. J. & Feringa, B. L. One-pot multi-substrate enantioselective conjugate addition of diethylzinc to nitroalkenes. Tetrahedron 58, 5773–5778 (2002).
Satyanarayana, T., Abraham, S. & Kagan, H. B. Nonlinear effects in asymmetric catalysis. Angew. Chem. Int. Ed. 48, 456–494 (2009).
an der Heiden, M. R. et al. Insights into Sonogashira cross-coupling by high-throughput kinetics and descriptor modeling. Chem. Eur. J 14, 2857–2866 (2008).
Richter, C., Schaepe, K., Glorius, F. & Ravoo, B. J. Tailor-made N-heterocyclic carbenes for nanoparticle stabilization. Chem. Commun. 50, 3204–3207 (2014).
Engvall, E. & Perlmann, P. Enzyme-linked immunosorbent assay (ELISA) quantitative assay of immunoglobulin G. Immunochemistry 8, 871–874 (1971).
Van Weemen, B. K. & Schuurs, A. H. W. M. Immunoassay using antigen–enzyme conjugates. FEBS Lett. 15, 232–236 (1971).
Taran, F. et al. High-throughput screening of enantioselective catalysts by immunoassay. Angew. Chem. Int. Ed. 41, 124–127 (2002).
Quinton, J. et al. Toward the limits of sandwich immunoassay of very low molecular weight molecules. Anal. Chem. 82, 2536–2540 (2010).
Vicennati, P., Bensel, N., Wagner, A., Créminon, C. & Taran, F. Sandwich immunoassay as a high-throughput screening method for cross-coupling reactions. Angew. Chem. Int. Ed. 44, 6863–6866 (2005).
Quinton, J. et al. Reaction discovery by using a sandwich immunoassay. Angew. Chem. Int. Ed. 51, 6144–6148 (2012).
Kolodych, S. et al. Discovery of chemoselective and biocompatible reactions using a high-throughput immunoassay screening. Angew. Chem. Int. Ed. 52, 12056–12060 (2013).
Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).
Gartner, Z. J. & Liu, D. R. The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. J. Am. Chem. Soc. 123, 6961–6963 (2001).
Kanan, M. W., Rozenman, M. M., Sakurai, K., Snyder, T. M. & Liu, D. R. Reaction discovery enabled by DNA-templated synthesis and in vitro selection. Nature 431, 545–549 (2004).
Momiyama, N., Kanan, M. W. & Liu, D. R. Synthesis of acyclic alpha, beta-unsaturated ketones via Pd(II)-catalyzed intermolecular reaction of alkynamides and alkenes. J. Am. Chem. Soc. 129, 2230–2231 (2007).
Gorin, D. J., Kamlet, A. S. & Liu, D. R. Reactivity-dependent PCR: direct, solution-phase in vitro selection for bond formation. J. Am. Chem. Soc. 131, 9189–9191 (2009).
Rozenman, M. M., Kanan, M. W. & Liu, D. R. Development and initial application of a hybridization-independent, DNA-encoded reaction discovery system compatible with organic solvents. J. Am. Chem. Soc. 129, 14933–14938 (2007).
Chen, Y., Kamlet, A. S., Steinman, J. B. & Liu, D. R. A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system. Nature Chem. 3, 146–153 (2011).
Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).
Cabrera-Pardo, J. R., Chai, D. I., Liu, S., Mrksich, M. & Kozmin, S. A. Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization. Nature Chem. 5, 423–427 (2013).
Montavon, T. J., Li, J., Cabrera-Pardo, J. R., Mrksich, M. & Kozmin, S. A. Three-component reaction discovery enabled by mass spectrometry of self-assembled monolayers. Nature Chem. 4, 45–51 (2012).
Cooper, A. C., McAlexander, L. H., Lee, D-H., Torres, M. T. & Crabtree, R. H. Reactive dyes as a method for rapid screening of homogeneous catalysts. J. Am. Chem. Soc. 120, 9971–9972 (1998).
Moreira, R., Havranek, M. & Sames, D. New fluorogenic probes for oxygen and carbene transfer: a sensitive assay for single bead-supported catalysts. J. Am. Chem. Soc. 123, 3927–3931 (2001).
Shaughnessy, K. H., Kim, P. & Hartwig, J. F. A fluorescence-based assay for high-throughput screening of coupling reactions. Application to Heck chemistry. J. Am. Chem. Soc. 121, 2123–2132 (1999).
Copeland, G. T. & Miller, S. J. A chemosensor-based approach to catalyst discovery in solution and on solid support. J. Am. Chem. Soc. 121, 4306–4307 (1999).
Jarvo, E. R., Evans, C. A., Copeland, G. T. & Miller, S. J. Fluorescence-based screening of asymmetric acylation catalysts through parallel enantiomer analysis. Identification of a catalyst for tertiary alcohol resolution. J. Org. Chem. 66, 5522–5527 (2001).
Harris, R. F., Nation, A. J., Copeland, G. T. & Miller, S. J. A polymeric and fluorescent gel for combinatorial screening of catalysts. J. Am. Chem. Soc. 122, 11270–11271 (2000).
Stauffer, S. R., Beare, N. A., Stambuli, J. P. & Hartwig, J. F. Palladium-catalyzed arylation of ethyl cyanoacetate. Fluorescence resonance energy transfer as a tool for reaction discovery. J. Am. Chem. Soc. 123, 4641–4642 (2001).
Stambuli, J. P., Stauffer, S. R., Shaughnessy, K. H. & Hartwig, J. F. Screening of homogeneous catalysts by fluorescence resonance energy transfer. Identification of catalysts for room-temperature Heck reactions. J. Am. Chem. Soc. 123, 2677–2678 (2001).
Stauffer, S. R. & Hartwig, J. F. Fluorescence resonance energy transfer (FRET) as a high-throughput assay for coupling reactions. Arylation of amines as a case study. J. Am. Chem. Soc. 125, 6977–6985 (2003).
Lewis, W. G., Magallon, F. G., Fokin, V. V & Finn, M. G. Discovery and characterization of catalysts for azide–alkyne cycloaddition by fluorescence quenching. J. Am. Chem. Soc. 126, 9152–9153 (2004).
Xia, B. et al. ESIPT-mediated photocycloadditions of 3-hydroxyquinolinones: development of a fluorescence quenching assay for reaction screening. Org. Lett. 13, 1346–1349 (2011).
Rozhkov, R. V., Davisson, V. J. & Bergstrom, D. E. Fluorogenic transformations based on formation of C–C bonds catalyzed by palladium: an efficient approach for high throughput optimizations and kinetic studies. Adv. Synth. Catal. 350, 71–75 (2008).
Sashuk, V., Schoeps, D. & Plenio, H. Fluorophore tagged cross-coupling catalysts. Chem. Commun. 770–772 (2009).
Barder, T. E. & Buchwald, S. L. Benchtop monitoring of reaction progress via visual recognition with a handheld UV lamp: in situ monitoring of boronic acids in the Suzuki–Miyaura reaction. Org. Lett. 9, 137–139 (2007).
Lavastre, O. & Morken, J. P. Discovery of novel catalysts for allylic alkylation with a visual colorimetric assay. Angew. Chem. Int. Ed. 38, 3163–3165 (1999).
Shabbir, S. H., Regan, C. J. & Anslyn, E. V. Molecular recognition and self-assembly special feature: a general protocol for creating high-throughput screening assays for reaction yield and enantiomeric excess applied to hydrobenzoin. Proc. Natl Acad. Sci. USA 106, 10487–10492 (2009).
Löber, O., Kawatsura, M. & Hartwig, J. F. Palladium-catalyzed hydroamination of 1,3-Dienes: A colorimetric assay and enantioselective additions. J. Am. Chem. Soc. 123, 4366–4367 (2001).
Kawatsura, M. & Hartwig, J. F. Transition metal-catalyzed addition of amines to acrylic acid derivatives. A high-throughput method for evaluating hydroamination of primary and secondary alkylamines. Organometallics 20, 1960–1964 (2001).
Kim, S. et al. A simple, fast, and easy assay for transition metal-catalyzed coupling reactions using a paper-based colorimetric iodide sensor. Chem. Commun. 48, 8751–8753 (2012).
Jung, E. et al. A colorimetric high-throughput screening method for palladium-catalyzed coupling reactions of aryl iodides using a gold nanoparticle-based iodide-selective probe. Angew. Chem. Int. Ed. 50, 4386–4389 (2011).
Taylor, S. J. & Morken, J. P. Thermographic selection of effective catalysts from an encoded polymer-bound library. Science 280, 267–270 (1998).
Reetz, M., Becker, M. M., Liebl, M. & Fürstner, A. IR-thermographic screening of thermoneutral or endothermic transformations: the ring-closing olefin metathesis reaction. Angew. Chem. Int. Ed. 39, 1236–1239 (2000).
Reetz, M. T., Becker, M. H., Kühling, K. M. & Holzwarth, A. Time-resolved IR-thermographic detection and screening of enantioselectivity in catalytic reactions. Angew. Chem. Int. Ed. 37, 2647–2650 (1998).
Fürstner, A. et al. Comparative investigation of ruthenium-based metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands. Chem. Eur. J. 7, 3236–3253 (2001).
Connolly, A. R. & Sutherland, J. D. Catalyst screening using an array of thermistors. Angew. Chem. Int. Ed. 39, 4268–4271 (2000).
Berkowitz, D. B., Bose, M. & Choi, S. In situ enzymatic screening (ISES): a tool for catalyst discovery and reaction development. Angew. Chem. Int. Ed. 41, 1603–1607 (2002).
Berkowitz, D. B. & Maiti, G. Following an ISES lead: the first examples of asymmetric Ni(0)-mediated allylic amination. Org. Lett. 6, 2661–2664 (2004).
Dey, S., Karukurichi, K. R., Shen, W. & Berkowitz, D. B. Double-cuvette ISES: in situ estimation of enantioselectivity and relative rate for catalyst screening. J. Am. Chem. Soc. 127, 8610–8611 (2005).
Dey, S., Powell, D. R., Hu, C. & Berkowitz, D. B. “Cassette” in situ enzymatic screening identifies complementary chiral scaffolds for hydrolytic kinetic resolution across a range of epoxides. Angew. Chem. Int. Ed. 46, 7010–7014 (2007).
Friest, J. A., Broussy, S., Chung, W. J. & Berkowitz, D. B. Combinatorial catalysis employing a visible enzymatic beacon in real time: synthetically versatile (pseudo)halometalation/carbocyclizations. Angew. Chem. Int. Ed. 50, 8895–8899 (2011).
Ginotra, S. K., Friest, J. A. & Berkowitz, D. B. Halocarbocyclization entry into the oxabicyclo[4.3.1]decyl exomethylene-δ-lactone cores of linearifolin and zaluzanin A: exploiting combinatorial catalysis. Org. Lett. 14, 968–971 (2012).
Markert, C. & Pfaltz, A. Screening of chiral catalysts and catalyst mixtures by mass spectrometric monitoring of catalytic intermediates. Angew. Chem. Int. Ed. 43, 2498–2500 (2004).
Hinderling, C. & Chen, P. Rapid screening of olefin polymerization catalyst libraries by electrospray ionization tandem mass spectrometry. Angew. Chem. Int. Ed. 38, 2253–2256 (1999).
Markert, C., Rösel, P. & Pfaltz, A. Combinatorial ligand development based on mass spectrometric screening and a double mass-labeling strategy. J. Am. Chem. Soc. 130, 3234–3235 (2008).
Müller, C. A. & Pfaltz, A. Mass spectrometric screening of chiral catalysts by monitoring the back reaction of quasienantiomeric products: palladium-catalyzed allylic substitution. Angew. Chem. Int. Ed. 47, 3363–3366 (2008).
Teichert, A. & Pfaltz, A. Mass spectrometric screening of enantioselective Diels-Alder reactions. Angew. Chem. Int. Ed. 47, 3360–3362 (2008).
Fleischer, I. & Pfaltz, A. Enantioselective Michael addition to alpha, beta-unsaturated aldehydes: combinatorial catalyst preparation and screening, reaction optimization, and mechanistic studies. Chem. Eur. J. 16, 95–99 (2010).
Bächle, F., Duschmalé, J., Ebner, C., Pfaltz, A. & Wennemers, H. Organocatalytic asymmetric conjugate addition of aldehydes to nitroolefins: identification of catalytic intermediates and the stereoselectivity-determining step by ESI-MS. Angew. Chem. Int. Ed. 52, 12619–12623 (2013).
Dominguez, B., Hodnett, N. S. & Lloyd-Jones, G. C. Testing racemic chiral catalysts for kinetic resolution potential. Angew. Chem. Int. Ed. 40, 4289–4291 (2001).
Ebner, C., Müller, C. A., Markert, C. & Pfaltz, A. Determining the enantioselectivity of chiral catalysts by mass spectrometric screening of their racemic forms. J. Am. Chem. Soc. 133, 4710–4713 (2011).
Wassenaar, J. et al. Catalyst selection based on intermediate stability measured by mass spectrometry. Nature Chem. 2, 417–421 (2010).
Mader, M. M. & Bartlett, P. A. Binding energy and catalysis: the implications for transition-state analogs and catalytic antibodies. Chem. Rev. 97, 1281–1302 (1997).
Wulff, G. Enzyme-like catalysis by molecularly imprinted polymers. Chem. Rev. 102, 1–28 (2002).
Brisig, B., Sanders, J. K. M. & Otto, S. Selection and amplification of a catalyst from a dynamic combinatorial library. Angew. Chem. Int. Ed. 42, 1270–1273 (2003).
Vial, L., Sanders, J. K. M. & Otto, S. A catalyst for an acetal hydrolysis reaction from a dynamic combinatorial library. New J. Chem. 29, 1001–1003 (2005).
Gasparini, G., Prins, L. J. & Scrimin, P. Exploiting neighboring-group interactions for the self-selection of a catalytic unit. Angew. Chem. Int. Ed. 47, 2475–2479 (2008).
Matsumoto, M., Estes, D. & Nicholas, K. M. Evolution of metal complex-catalysts by dynamic templating with transition state analogs. Eur. J. Inorg. Chem. 2010, 1847–1852 (2010).
Kannappan, R. & Nicholas, K. M. Selection of chiral zinc catalysts for the kinetic resolution of esters via dynamic templating. ACS Comb. Sci. 15, 90–100 (2013).
Schmink, J. R., Bellomo, A. & Berritt, S. Scientist-led high-throughput experimentation (HTE) and its utility in academia and industry. Aldrichim. Acta 46, 71–80 (2013).
Molander, G. A., Trice, S. L. J. & Dreher, S. D. Palladium-catalyzed, direct boronic acid synthesis from aryl chlorides: a simplified route to diverse boronate ester derivatives. J. Am. Chem. Soc. 132, 17701–17703 (2010).
Collins, K. D., Ru¨hling, A. & Glorius, F. Application of a robustness screen for the evaluation of synthetic organic methodology. Nature Protoc. 9, 1348–1353 (2014).
Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nature Chem. 5, 597–601 (2013).
Collins, K. D. & Glorius, F. Employing a robustness screen: rapid assessment of rhodium(III)-catalysed C–H activation reactions. Tetrahedron 69, 7817–7825 (2013).
Friedfeld, M. R. et al. Cobalt precursors for high-throughput discovery of base metal asymmetric alkene hydrogenation catalysts. Science 342, 1076–1080 (2013).
DiRocco, D. A. et al. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Ed. 53, 4802–4806 (2014).
Zhao, W., Huang, L., Guan, Y. & Wulff, W. D. Three-component asymmetric catalytic Ugi reaction — concinnity from diversity by substrate-mediated catalyst assembly. Angew. Chem. Int. Ed. 53, 3436–3441 (2014).
Acknowledgements
We are grateful to the European Research Council (ERC) under the European Community's Seventh Framework Program (FP7 2007-2013)/ERC grant agreement no 25936, and the DFG (Leibniz award) for generous financial support.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Collins, K., Gensch, T. & Glorius, F. Contemporary screening approaches to reaction discovery and development. Nature Chem 6, 859–871 (2014). https://doi.org/10.1038/nchem.2062
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchem.2062
This article is cited by
-
Bridging the information gap in organic chemical reactions
Nature Chemistry (2024)
-
Ultra-high-throughput mapping of the chemical space of asymmetric catalysis enables accelerated reaction discovery
Nature Communications (2023)
-
Ni-catalyzed mild hydrogenolysis and oxidations of C–O bonds via carbonate redox tags
Nature Communications (2023)
-
Non-innocent electrophiles unlock exogenous base-free coupling reactions
Nature Catalysis (2022)
-
In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines
Nature Synthesis (2022)