Automated chemical synthesis

Editors: Prof. Ian R. Baxendale, Durham University
Dr. Marcus Baumann, Durham University and
Dr. Richard Bourne, University of Leeds

This Thematic Series presents the latest research results in automated chemical synthesis.

Automated glycan assembly of a S. pneumoniae serotype 3 CPS antigen

Markus W. Weishaupt,
Stefan Matthies,
Mattan Hurevich,
Claney L. Pereira,
Heung Sik Hahm and
Peter H. Seeberger

Full Research Paper
Published 12 Jul 2016

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1. Graphical Abstract
2. Figure 1: Disaccharide repeating unit of the S. pneumoniae serotype 3 CPS.
  
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3. Figure 2: Building blocks and solid support for the automated solid-phase synthesis of S. pneumoniae serotype...
  
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4. Scheme 1: Attempted assembly of SP3 trisaccharide 5 using glycosyl phosphate building blocks 1 and 2. Reagent...
  
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5. Figure 3: HPLC chromatogram of the crude products of the attempted AGA of SP3 trisaccharide 5; conditions: YM...
  
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6. Scheme 2: Attempted AGA of SP3 trisaccharide 9 using glycosyl phosphate building blocks 1 and 3. Reagents and...
  
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7. Figure 4: HPLC chromatogram of the crude products of the attempted AGA of SP3 trisaccharide 9; conditions: YM...
  
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8. Scheme 3: Automated synthesis of linker-bound glucuronic acid 10 using glycosyl phosphate building block 1. R...
  
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9. Scheme 4: Automated synthesis of SP3 trisaccharide 5 using glycosyl phosphate building blocks 1 and 2. Reagen...
  
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10. Figure 5: HPLC chromatogram of the crude products of the automated solid-phase SP3 trisaccharide 5 synthesis;...
  
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11. Scheme 5: Global deprotection of SP3 trisaccharide 5. Reagents and conditions: a) LiOH, H₂O₂, THF, −5 °C to r...
  
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Beilstein J. Org. Chem. 2016, 12, 1440–1446, doi:10.3762/bjoc.12.139

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Flow carbonylation of sterically hindered ortho-substituted iodoarenes

Carl J. Mallia,
Gary C. Walter and
Ian R. Baxendale

Full Research Paper
Published 19 Jul 2016

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1. Graphical Abstract
2. Figure 1: Steric interactions of the carbon monoxide coordination to the aryl complex intermediate.
  
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3. Figure 2: A) molecular structure of complex 1; B) ball and stick representation of X-ray structure; C) ball a...
  
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4. Figure 3: Reverse “tube-in-tube” reactor.
  
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5. Scheme 1: Comparison of plug flow reactor carbonylation (left) and “tube-in-tube” reactor carbonylation (righ...
  
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6. Scheme 2: Schematic diagram of the flow process.
  
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7. Figure 4: Phosphine ligands used for the ortho-carbonylation reaction.
  
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8. Scheme 3: The batch carbonylation of 2-chloro-1-iodobenzene in conventional lab (top) and using a Parr autocl...
  
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9. Scheme 4: Structures of ortho-substituted carboxylic acids prepared via a continuous flow hydroxy-carbonylati...
  
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10. Scheme 5: Flow carbonylation of 2-iodonaphtalene.
  
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11. Figure 5: X-ray structure of substrate 33.
  
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12. Scheme 6: Scale up synthesis of 2-chloro-4-fluorobenzoic acid (20).
  
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Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

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Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

Carl J. Mallia,
Paul M. Burton,
Alexander M. R. Smith,
Gary C. Walter and
Ian R. Baxendale

Full Research Paper
Published 26 Jul 2016

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1. Graphical Abstract
2. Scheme 1: Comparison of early C–N and C–O coupling reactions.
  
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3. Figure 1: General flow scheme for catalytic Chan–Lam reaction.
  
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4. Figure 2: Observed trend for the effect of changing oxygen pressure on the NMR yield of 19.
  
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5. Figure 3: Comparison of ¹H NMR spectra of non-purified (top) and QP-DMA purified (bottom) continuous flow syn...
  
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6. Scheme 2: Scope of the catalytic Chan–Lam reaction in continuous flow.
  
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7. Scheme 3: Syntheses of substrate 39.
  
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8. Figure 4: NOESY NMR spectrum for 30 with the characteristic NOESY signal encircled.
  
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9. Figure 5: NOESY NMR spectrum for 33 with the characteristic NOESY signal encircled.
  
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10. Figure 6: NOESY NMR spectrum for 35 with the characteristic NOESY signal encircled.
  
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11. Figure 7: Substrates that gave no products in flow.
  
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12. Scheme 4: Scale-up procedure for 19.
  
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Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

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The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

Faith M. Akwi and
Paul Watts

Full Research Paper
Published 06 Sep 2016

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1. Graphical Abstract
2. Scheme 1: PTSA-catalyzed diazotization and azo coupling reaction.
  
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3. Scheme 2: Ferric hydrogen sulfate (FHS) catalyzed azo compound synthesis.
  
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4. Scheme 3: Synthesis of azo compounds in the presence of silica supported boron trifluoride.
  
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5. Scheme 4: Phase transfer catalyzed azo coupling of 5-methylresorcinol in microreactors.
  
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6. Scheme 5: Synthesis of yellow pigment 12 in a micro-mixer apparatus.
  
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7. Scheme 6: Continuous flow synthesis of Sudan II azo dye in LTF-MS microreactors.
  
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8. Figure 1: pH profile plot at constant flow rate of 0.03 mL/min.
  
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9. Figure 2: pH profile plot at a constant flow rate of 0.7 mL/min.
  
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10. Scheme 7: Azo coupling reaction under acidic conditions.
  
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11. Figure 3: pH profile plot at a constant flow rate of 0.03 mL/min.
  
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12. Figure 4: pH profile plot at constant flow rate of 0.7 mL/min.
  
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13. Figure 5: Temperature profile plot at constant pH 5.66.
  
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14. Figure 6: Schematic representation of the microreactor set up.
  
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15. Figure 7: Schematic representation of the microreactor set up.
  
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16. Figure 8: Scaled up microreactor set up: PTFE tubing i.d. 1.5 mm a) Chemyx Fusion 100 classic syringe pump, b...
  
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Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

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Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

Olga C. Dennehy,
Valérie M. Y. Cacheux,
Benjamin J. Deadman,
Denis Lynch,
Stuart G. Collins,
Humphrey A. Moynihan and
Anita R. Maguire

Full Research Paper
Published 24 Nov 2016

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1. Graphical Abstract
2. Scheme 1: Reaction pathways of α-thio-β-chloroacrylamides.
  
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3. Scheme 2: Typical three-step batch preparation of α-thio-β-chloroacrylamide.
  
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4. Scheme 3: Batch process for preparation of α-chloroamide 1.
  
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5. Scheme 4: Process for the conversion of 2-chloropropionyl chloride and p-toluidine to α-chloroamide 1 under o...
  
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6. Scheme 5: Conversion of 1 to 2 in continuous mode using MeOH as solvent.
  
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7. Scheme 6: Optimized process for the conversion of α-chloroamide 1 to α-thioamide 2 under flow conditions.
  
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8. Scheme 7: Mechanism of the β-chloroacrylamide cascade process [29].
  
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9. Scheme 8: Optimized flow process for conversion of α-thioamide 2 to α-thio-β-chloroacrylamide Z-3.
  
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Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

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The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot

Philip J. Kitson,
Stefan Glatzel and
Leroy Cronin

Full Research Paper
Published 19 Dec 2016

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1. Graphical Abstract
2. Figure 1: Prusa i3 RepRap printer modified for the automated synthesis of ibuprofen. Left: Full view of robot...
  
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3. Scheme 1: Synthetic route chosen for automated synthesis robot.
  
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4. Figure 2: Top: The three reaction vessels printed for ibuprofen synthesis on different scales; bottom left: i...
  
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5. Scheme 2: The digitisation of the synthesis of ibuprofen. This flow diagram shows the individual steps of the...
  
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Beilstein J. Org. Chem. 2016, 12, 2776–2783, doi:10.3762/bjoc.12.276

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Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

Deborah E. Crawford

Review
Published 11 Jan 2017

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1. Graphical Abstract
2. Figure 1: Typical pilot scale single screw extruder (left) and a laboratory scale twin screw extruder (right)....
  
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3. Figure 2: PTFE screw employed in single screw extrusion, with increasing root diameter (RD) from 45 mm to 95 ...
  
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4. Figure 3: Modulated stainless steel intermeshing co-rotating screws employed typically in twin screw extrusio...
  
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5. Scheme 1: Polymerisation of styrene using s-BuLi as an initiator.
  
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6. Scheme 2: Telescoping process of the formation of polystyrene, followed by post polymerisation functionalisat...
  
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7. Scheme 3: Proposed mechanism for the branching of polylactide. Adapted from [23].
  
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8. Scheme 4: Chemical reaction between isocyanate and an alcohol to form polyurethane.
  
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9. Figure 4: Representative diagram explaining the process involved in step growth polymerisation, which involve...
  
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10. Scheme 5: Generic polycondensation reaction to produce polyamides.
  
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11. Figure 5: Comparison of choline chloride/D-fructose DES prepared via twin screw extrusion (left) and conventi...
  
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12. Scheme 6: Synthesis of HKUST-1, ZIF-8 and Al(fumarate)OH by twin screw extrusion. Adapted from [2].
  
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13. Figure 6: Synthesis of Ni(NCS)₂(PPh₃)₂ and [Ni(salen)] by twin screw extrusion. Adapted from [2].
  
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Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

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Solution-phase automated synthesis of an α-amino aldehyde as a versatile intermediate

Hisashi Masui,
Sae Yosugi,
Shinichiro Fuse and
Takashi Takahashi

Letter
Published 17 Jan 2017

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1. Graphical Abstract
2. Scheme 1: Automated synthesis of 4a.
  
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3. Figure 1: Full picture of ChemKonzert, showing two reaction vessels (RF1 and RF2), a centrifugal separator (S...
  
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Beilstein J. Org. Chem. 2017, 13, 106–110, doi:10.3762/bjoc.13.13

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3D printed fluidics with embedded analytic functionality for automated reaction optimisation

Andrew J. Capel,
Andrew Wright,
Matthew J. Harding,
George W. Weaver,
Yuqi Li,
Russell A. Harris,
Steve Edmondson,
Ruth D. Goodridge and
Steven D. R. Christie

Full Research Paper
Published 18 Jan 2017

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1. Graphical Abstract
2. Scheme 1: The reaction of (R)-(−)-carvone (1) with semicarbazide to form the corresponding semicarbazone 2.
  
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3. Figure 1: CAD model of SL reactor design RD1 (left), RD1 with attached sprung clip (centre), commercially ava...
  
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4. Figure 2: Energy versus wavelength spectra comparing the amount of stray light being picked up by the detecto...
  
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5. Figure 3: Reactor set-up for carvone optimisation using RD1 as an inline spectroscopic flow cell. Reagents we...
  
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6. Figure 4: RD1 held in place within the DAD compartment of an Agilent 1100 HPLC.
  
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7. Figure 5: Optimisation plot for the SIMPLEX optimisation of semicarbazone 2. Optimum reaction conditions with...
  
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8. Figure 6: SLM reactor RD2 (left), CAD model of RD2 (right). External dimensions of RD2 are 100 (length) × 20 ...
  
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9. Figure 7: RD2 held in place within the thermostatted Agilent 1100 series column department.
  
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10. Figure 8: Optimisation plot for the SIMPLEX optimisation of semicarbazone 1. Optimum reaction conditions were...
  
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11. Scheme 2: The reaction of pentafluoropyridine (3) with 2-(methylamino)phenol (4) to form the corresponding fu...
  
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12. Figure 9: Optimisation plot for the SIMPLEX optimisation of the fused polycyclic heterocycle 5. Two optimal d...
  
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13. Figure 10: SLM reactor design RD3 (left), CAD model of RD3 (right). External dimensions of RD3 are 89 (length)...
  
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14. Figure 11: Optimisation plot for the SIMPLEX optimisation of semicarbazone 2. Optimum reaction conditions were...
  
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Beilstein J. Org. Chem. 2017, 13, 111–119, doi:10.3762/bjoc.13.14

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Diels–Alder reactions of myrcene using intensified continuous-flow reactors

Christian H. Hornung,
Miguel Á. Álvarez-Diéguez,
Thomas M. Kohl and
John Tsanaktsidis

Full Research Paper
Published 19 Jan 2017

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1. Graphical Abstract
2. Scheme 1: Diels–Alder reaction of myrcene (1), with various dienophiles 2.
  
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3. Figure 1: Kinetic studies of the Diels–Alder reaction between myrcene (1) and acrylic acid (2b); a) for diffe...
  
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4. Figure 2: Comparison of conversions in three different reactors for the Diels–Alder reaction of myrcene (1) w...
  
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Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

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Self-optimisation and model-based design of experiments for developing a C–H activation flow process

Alexander Echtermeyer,
Yehia Amar,
Jacek Zakrzewski and
Alexei Lapkin

Full Research Paper
Published 24 Jan 2017

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1. Graphical Abstract
2. Figure 1: A framework of closed-loop or self-optimisation combining smart DoE algorithms, process analytics, ...
  
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3. Scheme 1: Catalytic reaction scheme showing C–H activation of an aliphatic secondary amine 1 to form the azir...
  
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4. Scheme 2: A simplified reaction mechanism based on literature [21], showing intermediate B and the side reaction ...
  
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5. Figure 2: Schematics of the automated continuous-flow system used for model development and ‘black-box’ seque...
  
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6. Figure 3: Results of experiments from the MBDoE in Table 2, conducted for parameter estimation, and their correspond...
  
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7. Figure 4: Results of in silico iterations of the multi-objective active learner (MOAL) algorithm [26]. Each itera...
  
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8. Figure 5: Results of the optimisation driven by a statistical algorithm and in the absence of a physical proc...
  
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Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

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Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

Ananda Herath and
Nicholas D. P. Cosford

Full Research Paper
Published 07 Feb 2017

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1. Graphical Abstract
2. Scheme 1: In-flask (batch) preparation of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles (S1P₁ agonists) [27].
  
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3. Scheme 2: Gram-scale synthesis of mGlu₅ NAM by continuous flow in combination with microfluidic extraction.
  
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4. Scheme 3: Gram-scale synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole S1P₁ agonist scaffold by contin...
  
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Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

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NMR reaction monitoring in flow synthesis

M. Victoria Gomez and
Antonio de la Hoz

Review
Published 14 Feb 2017

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1. Graphical Abstract
2. Figure 1: Graphical representation of (a) conventional flow cell with a saddle-shaped RF coil and (b) flow ca...
  
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3. Figure 2: Possible geometries of NMR coils.
  
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4. Figure 3: The NMR pulse sequence used for NOESY with WET solvent suppression [28].
  
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5. Figure 4: Reaction of p-phenylenediamine with isobutyraldehyde. (a) Flow tube and (b) ¹H NMR stacked plot (40...
  
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6. Figure 5: Scheme and experimental setup of the flow system.
  
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7. Figure 6: (a) Microfluidic probe. (b) Microreactor holder. (c) Stripline NMR chip holder. (d) Arrangement of ...
  
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8. Figure 7: Acetylation of benzyl alcohol. Spectra at (a) 9 s and (b) 3 min. Stoichiometry: benzyl alcohol/DIPE...
  
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9. Figure 8: a) Design of MICCS and b) schematic diagram of MICCS–NMR [45]. CH₂Cl₂ solutions of oxime ether and trie...
  
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10. Scheme 1: Proposed reaction mechanism.
  
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11. Figure 9: Flowsheet of the experimental setup used to study the reaction kinetics of the oligomer formation i...
  
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12. Figure 10: Design of the experimental setup used to combine on-line NMR spectroscopy and a batch reactor. Repr...
  
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13. Figure 11: Reaction system 1,3-dimethylurea/formaldehyde. Main reaction pathway and side reactions [47].
  
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14. Figure 12: (a) Experimental setup for the reaction. (b) Reaction samples analyzed independently by NMR. (c) Pl...
  
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15. Figure 13: (a) Schematics of two microreactor cohorts of sample fractions. (b) Reaction product concentration ...
  
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16. Figure 14: NMR analysis of the reaction of benzaldehyde (2 M in CH₃CN) and benzylamine (2 M in CH₃CN) (1:1), r...
  
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17. Figure 15: Flow diagram showing the self-optimizing reactor system. Reproduced with permission from reference [50]...
  
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Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

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A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

Arno Verlee,
Thomas Heugebaert,
Tom van der Meer,
Pavel I. Kerchev,
Frank Van Breusegem and
Christian V. Stevens

Full Research Paper
Published 16 Feb 2017

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1. Graphical Abstract
2. Figure 1: m-Sulfamoylbenzamides as Sirtuin 2 inhibitors (SIRT2) or suppressor of polyglutamine aggregation (p...
  
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3. Figure 2: Syrris AFRICA system.
  
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Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

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Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

Emilia S. Streng,
Darren S. Lee,
Michael W. George and
Martyn Poliakoff

Full Research Paper
Published 21 Feb 2017

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1. Graphical Abstract
2. Scheme 1: Target reaction – intramolecular cyclisation of 1 followed by N-methylation with methanol to yield ...
  
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3. Figure 1: Simplified schematic demonstrating a self-optimising reactor [34,35,37,44]. The reagents are pumped into the sys...
  
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4. Figure 2: Result of the SNOBFIT optimisation for N-methylpiperidine (2b) with and without CO₂ showing yields ...
  
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5. Scheme 2: Cyclisation and N-alkylation of 1,4- and 1,6-amino alcohols.
  
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6. Scheme 3: a) Reactions highlighting the incorporation of CO₂ in to 16. b) High temperature reaction of 15 yie...
  
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7. Scheme 4: Summary of products obtained from the reactions of amino alcohols over γ-Al₂O₃ in scCO₂.
  
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8. Figure 3: Diagram of the high pressure equipment used in the experiments.
  
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Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

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Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

Carmen Moreno-Marrodan,
Francesca Liguori and
Pierluigi Barbaro

Review
Published 20 Apr 2017

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1. Graphical Abstract
2. Scheme 1: Common reaction pathways for alkyne hydrogenation reactions.
  
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3. Figure 1: Schematic representation of most common reactor types for batch and continuous-flow partial hydroge...
  
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4. Figure 2: Schematic representation of flow regimes in microchannels; (a) bubbly flow, (b) slug/Taylor or segm...
  
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5. Figure 3: Sketch of typical continuous flow apparatus for liquid-phase catalytic alkynes hydrogenation reacti...
  
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6. Scheme 2: Hydrogenation reactions of terminal alkynes with potential products and labelling scheme.
  
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7. Figure 4: Structure of Pd@mpg-C3N4 (a), Pd(HHDMA)@C (b), Pd(Pb)@CaCO₃ (c) and Pd@Al₂O₃ (d) catalysts. The str...
  
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8. Figure 5: Sketch of composition (left) and optical image of Pd@MonoBor monolithic reactor (right). Adapted wi...
  
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9. Figure 6: X-ray tomography 3D-reconstruction image of MonoBor [133]. Unpublished image from the authors.
  
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10. Figure 7: Representative TEM image of titanate nanotubes with immobilized PdNP (arrows). Adapted with permiss...
  
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11. Figure 8: Conversion and selectivity vs. time-on-stream for the continuous-flow hydrogenation of 6 over Pd@Mo...
  
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12. Figure 9: Continuous-flow hydrogenation of 3, 6 and 7 over different catalytic reactor systems. Data from ref...
  
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13. Scheme 3: Hydrogenation reactions of internal alkynes with potential products and labelling scheme.
  
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14. Figure 10: Continuous-flow hydrogenation of 11 over Pd@MonoBor catalyst. a) Conversion and selectivity as a fu...
  
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15. Figure 11: Conversion and selectivity vs time-on-stream for the continuous-flow hydrogenation of 11 over Pd@Mo...
  
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16. Figure 12: Continuous-flow hydrogenation reaction of 11 over packed-bed catalysts. Adapted with permission fro...
  
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17. Figure 13: Images of the bimodal TiO₂ monolith with well-defined macroporosity: (a, b) optical; (c) X-ray tomo...
  
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18. Figure 14: Selectivity of the continuous-flow partial hydrogenation reaction of 3 and 4 over packed-bed Pd cat...
  
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Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

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Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

Chinmay A. Shukla and
Amol A. Kulkarni

Review
Published 19 May 2017

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1. Graphical Abstract
2. Figure 1: A number of experiments for various optimization algorithms [46].
  
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3. Figure 2: Symbols used for block and P&ID diagrams.
  
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4. Scheme 1: Multistep synthesis of olanzapine (Hartwig et al. [10])
  
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5. Figure 3: (A) Block diagram representation of the process shown in Scheme 1, (B) piping and instrumentation diagram o...
  
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6. Scheme 2: Multistep flow synthesis for tamoxifen (Murray et al. [11]).
  
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7. Figure 4: (A) Block diagram representation of the process shown in Scheme 2, (B) piping and instrumentation diagram o...
  
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8. Figure 5: (A) Block diagram representation of the process shown in Scheme 3, (B) piping and instrumentation diagram o...
  
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9. Scheme 3: Multistep flow synthesis of rufinamide (Zhang et al. [14]).
  
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10. Figure 6: (A) Block diagram representation of the process shown in Scheme 4, (B) piping and instrumentation diagram o...
  
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11. Scheme 4: Multistep synthesis for (±)-Oxomaritidine (Baxendale et al. [9]).
  
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12. Figure 7: (A) Block diagram representation of the process shown in Scheme 5, (B) piping and instrumentation diagram o...
  
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13. Scheme 5: Multistep synthesis for ibuprofen (Snead and Jamison [60]).
  
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14. Scheme 6: Multistep synthesis for cinnarizine and buclizine derivatives (Borukhova et al. [23])
  
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15. Figure 8: (A) Block diagram representation of the process shown in Scheme 6, (B) piping and instrumentation diagram o...
  
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16. Scheme 7: Multistep synthesis for (S)-rolipram (Tsubogo et al. [4])
  
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17. Figure 9: (A) Block diagram representation of the process shown in Scheme 7 (colours for each reactor shows different...
  
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18. Figure 10: (A) Block diagram representation of the process shown in Scheme 8, (B) piping and instrumentation diagram o...
  
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19. Scheme 8: Multistep synthesis for amitriptyline (Kupracz and Kirschning [7]).
  
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Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

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