In silico rationalisation of selectivity and reactivity in Pd-catalysed C–H activation reactions
- Liwei Cao,
- Mikhail Kabeshov,
- Steven V. Ley and
- Alexei A. Lapkin
Beilstein J. Org. Chem. 2020, 16, 1465–1475, doi:10.3762/bjoc.16.122
Graphical Abstract
Figure 1: An approximate energy map for the electrophilic aromatic substitution mechanism.
Scheme 1: Schematic representation of the two mechanisms of Pd-catalysed C–H activation reaction considered i...
Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide
- Richard J. Ingham,
- Claudio Battilocchio,
- Joel M. Hawkins and
- Steven V. Ley
Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56
Graphical Abstract
Figure 1: Raspberry Pi® (RPi) computer operating in the laboratory, shown here without its protective case. U...
Figure 2: Two step approach to piperazine-2-carboxamide via hydrolysis followed by reduction. (a) Retrosynthe...
Figure 3: Heterogeneous hydration of pyrazine-2-carbonitrile with hydrous zirconia.
Figure 4: FlowIR™ profile for the reactor output after hydration of pyrazine-2-carbonitrile using hydrous zir...
Figure 5: (a) Fluidic setup for the zirconia catalysed hydration of aromatic nitrile. (b) Raspberry Pi® micro...
Figure 6: Flowchart describing the control sequence for operating and monitoring the hydration reaction. The ...
Figure 7: Profile for a 3 hour reaction simulating a long run. The absorbance shown is that at 1685 cm−1, whi...
Figure 8: Reactor setup for optimisation reactions. A multi-position valve (V2) was used for collecting sampl...
Figure 9: Representation of the control sequence for running experiments under a set of conditions. (See Supporting Information File 3 for...
Figure 10: Reduction products of piperazine-2-carboxamide.
Figure 11: (a) In-line reservoir schematic. The liquid level is measured by observation of a plastic float. (b...
Figure 12: Flow set up for the automated machine assisted synthesis of (R,S)-piperidine-2-carboxamide.
Figure 13: Control sequence for the two-step process.
Figure 14: Chart of monitored parameters over a 15 hour reaction. The output from the hydrolysis step is direc...
The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow
- Kimberley A. Roper,
- Malcolm B. Berry and
- Steven V. Ley
Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207
Graphical Abstract
Scheme 1: Formation of gem-dibromoolefin 3 from the reaction of carbon tetrabromide and triphenylphosphine as...
Scheme 2: Formation of the triphenylphosphine monoliths.
Figure 1: a. An unfunctionalised triphenylphosphine monolith; b. Monolith after functionalisation with carbon...
Scheme 3: Functionalising the triphenylphosphine monolith to give the active Ramirez monolith using carbon te...
Scheme 4: Flow synthesis of gem-dibromoolefins using the functionalised triphenylphosphine monolith.
Scheme 5: Flow synthesis of bromides from the corresponding alcohols using the functionalised triphenylphosph...
Scheme 6: Mechanisms for the Ramirez and Appel reactions [41,59].
Camera-enabled techniques for organic synthesis
- Steven V. Ley,
- Richard J. Ingham,
- Matthew O’Brien and
- Duncan L. Browne
Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118
Graphical Abstract
Figure 1: The evolution of computer-based monitoring and control within the laboratory of the future. (a) In ...
Figure 2: A selection of the wide range of digital camera devices available, focusing on those that can be at...
Figure 3: (a) Network cameras (Linksys WVC54GC) in operation in the Innovative Technology Centre laboratory. ...
Figure 4: Remote transmission of video imagery and reaction monitoring data.
Figure 5: A camera can assist the chemist in a number of ways. Digital video recordings of reactions can be u...
Figure 6: Suzuki–Miyaura reaction performed within a microfluidic system. The product is observed by high-spe...
Figure 7: Friedel–Crafts reactions performed by using solid-acid catalysis at high pressures. A camera allowe...
Figure 8: (a) The video camera setup providing a view of the reaction within the microwave cavity; (b) a pall...
Figure 9: (a) Buchwald–Hartwig coupling within a microchannel reactor. (b) Camera view of aggregate deposits ...
Figure 10: The key diprotected piperazic acid precursor in the synthesis of chloptosin.
Figure 11: (a) Piperazic acid mixture, and (b) apparatus for enantiomeric upgrading by recorded crystallisatio...
Figure 12: (a) Crystallisation of a Mn(II) polyoxometalate. (b) A bespoke reactor produced using additive fabr...
Figure 13: Computer processing of digital imagery produces numerical data for later processing.
Figure 14: (a) The Morphologi G3 particle image analyser, which uses images captured with a camera microscope ...
Figure 15: Use of the Python Imaging Library to analyse the proportion of an image consisting of red pixels. A...
Figure 16: (a) Arduino [73,75], a flexible open-source platform for rapidly prototyping electronic applications. (b) ...
Figure 17: Patented device incorporating a standard 96-well plate illuminated by a white-light source. The pla...
Figure 18: Simple colour-change experiments to assess a new AF-2400 gas permeable flow reactor. The reactor co...
Figure 19: (a) Ozonolysis of a series of alkenes using ozone in a bottle-reactor; (b) Glaser–Hay coupling usin...
Figure 20: (a) Camera-assisted titration of ammonia using bromocresol green. NH3 is dissolved in the gas-flow ...
Figure 21: (a) Bubble-counting setup. As the output of the gas-flow reactor (hydrogen dissolved in dichloromet...
Figure 22: Usage of digital cameras to enable remote control of reactions.
Figure 23: In-line solvent switching apparatus. The reactor output is directed into a bottle positioned on a h...
Figure 24: Catch and Release apparatus. (1) The amide intermediate is sequestered onto the central sulfonic ac...
Figure 25: Clips from video footage showing the silica reagent changing appearance; the arrows indicate the ed...
Figure 26: Combination of computer vision and automation to enable machine-assisted synthetic processes.
Figure 27: A coloured float at the interface between heavy and light solvents allows a camera to recognise the...
Figure 28: Graphical demonstration of the image-recognition process. At the start of the experiment, the colou...
Figure 29: Application of the computer-vision-enabled liquid–liquid extractor. The product mixture of a hydraz...
Figure 30: Application of a computer-vision technique to measure the dispersion of a plug of material passing ...
Figure 31: Multiple extractors in series controlled by a single camera.
Figure 32: Two-step synthesis of branched aldehydes from aryl iodides using two reactive gases. A liquid–liqui...
The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors
- Kimberley A. Roper,
- Heiko Lange,
- Anastasios Polyzos,
- Malcolm B. Berry,
- Ian R. Baxendale and
- Steven V. Ley
Beilstein J. Org. Chem. 2011, 7, 1648–1655, doi:10.3762/bjoc.7.194
Graphical Abstract
Scheme 1: The two proposed mechanistic pathways for the Appel reaction.
Scheme 2: Functionalisation of the triphenylphosphine monolith by using carbon tetrabromide in a recycling pr...
Figure 1: a. Unfunctionalised triphenylphosphine monolith; b. Monolith after fuctionalisation with carbon tet...
Scheme 3: Flow synthesis of bromides from alcohols by using the functionalised triphenylphosphine monolith.
Figure 2: Linear decrease of the brown decolourisation.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
- Marcus Baumann,
- Ian R. Baxendale,
- Steven V. Ley and
- Nikzad Nikbin
Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57
Graphical Abstract
Figure 1: Structures of atorvastatin and other commercial statins.
Figure 2: Structure of compactin.
Scheme 1: Synthesis of pentasubstituted pyrroles.
Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
Scheme 6: Convergent synthesis towards atorvastatin.
Figure 3: Binding pocket of sunitinib in the TRK KIT.
Scheme 7: Synthesis of sunitinib.
Scheme 8: Alternative synthesis of sunitinib.
Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
Scheme 13: Alternative introduction of the sulfonamide.
Scheme 14: Negishi-type coupling to benzylic sulfonamides.
Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
Scheme 18: Improved synthesis of rizatriptan.
Scheme 19: Larock-type synthesis of rizatriptan.
Scheme 20: Synthesis of eletriptan.
Scheme 21: Heck coupling for the indole system in eletriptan.
Scheme 22: Attempted Fischer indole synthesis of elatriptan.
Scheme 23: Successful Fischer indole synthesis for eletriptan.
Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
Scheme 26: Palladium-mediated synthesis of ondansetron.
Scheme 27: Fischer indole synthesis of ondansetron.
Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
Figure 4: Structures of carvedilol 136 and propranolol 137.
Scheme 29: Synthesis of the carbazole core of carvedilol.
Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
Scheme 31: Convergent synthesis of etodolac.
Scheme 32: Alternative synthesis of etodolac.
Figure 5: Structures of imidazole-containing drugs.
Scheme 33: Synthesis of functionalised imidazoles towards losartan.
Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
Scheme 35: Synthesis of trisubstituted imidazoles.
Scheme 36: Preparation of the imidazole ring in olmesartan.
Scheme 37: Synthesis of ondansetron.
Scheme 38: Alternative route to ondansetron and its analogues.
Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
Scheme 40: Synthesis of benzimidazole core pantoprazole.
Figure 6: Structure of rabeprazole 194.
Scheme 41: Synthesis of candesartan.
Scheme 42: Alternative access to the candesartan key intermediate 216.
Scheme 43: .Medicinal chemistry route to telmisartan.
Scheme 44: Improved synthesis of telmisartan.
Scheme 45: Synthesis of zolpidem.
Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
Figure 7: Structure of celecoxib.
Scheme 47: Preparation of celecoxib.
Scheme 48: Alternative synthesis of celecoxib.
Scheme 49: Regioselective access to celecoxib.
Scheme 50: Synthesis of pazopanib.
Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
Scheme 52: Regioselective synthesis of anastrozole.
Scheme 53: Triazine-mediated triazole formation towards anastrozole.
Scheme 54: Alternative routes to 1,2,4-triazoles.
Scheme 55: Initial synthetic route to sitagliptin.
Figure 8: Binding of sitagliptin within DPP-IV.
Scheme 56: The process route to sitagliptin key intermediate 280.
Scheme 57: Synthesis of maraviroc.
Scheme 58: Synthesis of alprazolam.
Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
Scheme 60: Synthesis of itraconazole.
Scheme 61: Synthesis of rufinamide.
Scheme 62: Representative tetrazole formation in valsartan.
Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
Scheme 63: Early stage introduction of the tetrazole in losartan.
Scheme 64: Synthesis of cilostazol.
Figure 11: Structure of cefdinir.
Scheme 65: Semi-synthesis of cefdinir.
Scheme 66: Thiazole syntheses towards ritonavir.
Scheme 67: Synthesis towards pramipexole.
Scheme 68: Alternative route to pramipexole.
Scheme 69: Synthesis of famotidine.
Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
Scheme 71: Synthesis of ziprasidone.
Figure 12: Structure of mometasone.
Scheme 72: Industrial access to 2-furoic acid present in mometasone.
Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
Scheme 74: Synthesis of nitrofurantoin.
Scheme 75: Synthesis of benzofuran.
Scheme 76: Synthesis of amiodarone.
Scheme 77: Synthesis of raloxifene.
Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
Scheme 79: Gewald reaction in the synthesis of olanzapine.
Scheme 80: Alternative synthesis of olanzapine.
Figure 13: Access to simple thiophene-containing drugs.
Scheme 81: Synthesis of clopidogrel.
Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
Scheme 83: Alternative synthesis of key intermediate 422.
Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
Scheme 84: Synthesis of timolol.
Scheme 85: Synthesis of tizanidine 440.
Scheme 86: Synthesis of leflunomide.
Scheme 87: Synthesis of sulfamethoxazole.
Scheme 88: Synthesis of risperidone.
Figure 15: Relative abundance of selected transformations.
Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
Continuous flow based catch and release protocol for the synthesis of α-ketoesters
- Alessandro Palmieri,
- Steven V. Ley,
- Anastasios Polyzos,
- Mark Ladlow and
- Ian R. Baxendale
Beilstein J. Org. Chem. 2009, 5, No. 23, doi:10.3762/bjoc.5.23
Graphical Abstract
Figure 1: The Uniqsis FlowSyn™ continuous flow reactor comprising of a column holder and heating unit (A) and...
Scheme 1: General procedure for the flow synthesis of α-ketoester products 4a–j.
Scheme 2: General procedure for the batch synthesis of nitroolefinic esters 1a–j.
Scheme 3: General procedure for the flow synthesis of nitroolefinic esters 1a,c.
Figure 2: α-Ketoesters prepared and isolated yields.
Hydrogenation of aromatic ketones, aldehydes, and epoxides with hydrogen and Pd(0)EnCat™ 30NP
- Steven V. Ley,
- Angus J. P. Stewart-Liddon,
- David Pears,
- Remedios H. Perni and
- Kevin Treacher
Beilstein J. Org. Chem. 2006, 2, No. 15, doi:10.1186/1860-5397-2-15
