Heck–Matsuda Reaction in Flow

Abstract Image

Product 3 was obtained as a mixture of diastereomers (58:42). The NMR data are consistent with literature precedent.20a

Major diastereomer: 1H NMR (300 MHz, CDCl3) δ (ppm) 7.25-7.28 (m, 2H), 7.14-7.17 (m, 2H), 5.14 (dd, 1H, J = 2.5, 5.8 Hz), 4.29 (t, 1H, J = 8.3 Hz), 3.79 (dd, 1H, J = 6.9, 8.4 Hz), 3.54-3.62 (m, 1H), 3.38 (s, 3H), 2.32 (dd, 1H, J = 7.7, 12.9 Hz), 2.04 (ddd, 1H, J = 5.1, 9.3, 13.1 Hz);

Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ 7.25-7.28 (m, 4H), 5.16 (d, 1H, J = 4.4 Hz), 4.17 (t, 1H, J = 8.1 Hz), 3.72 (dd, 1H, J = 8.5, 9.7 Hz), 3.42 (s, 3H), 3.32-3.36 (m, 1H), 2.59 (ddd, 1H, J = 5.5, 10.3, 13.7 Hz), 1.91 (ddd, 1H, J = 2.4, 7.7, 10.2 Hz);

13C NMR (75 MHz, CDCl3) δ (ppm) 141.4, 140.0, 132.4, 132.3, 129.1, 128.7, 128.7, 128.5, 105.7, 105.4, 73.7, 73.0, 54.9, 54.7, 43.6, 42.1, 41.4, 41.1.

(20) (a) Oliveira, C. C.; Angnes, R. A.; Correia, C. R. D. J. Org. Chem. 2013, 78, 4373. (b) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. Chem. Int. Ed. 2015, 54, 14036.

The optimization of a palladium-catalyzed Heck–Matsuda reaction using an optimization algorithm is presented. We modified and implemented the Nelder–Mead method in order to perform constrained optimizations in a multidimensional space. We illustrated the power of our modified algorithm through the optimization of a multivariable reaction involving the arylation of a deactivated olefin with an arenediazonium salt. The great flexibility of our optimization method allows to fine-tune experimental conditions according to three different objective functions: maximum yield, highest throughput, and lowest production cost. The beneficial properties of flow reactors associated with the power of intelligent algorithms for the fine-tuning of experimental parameters allowed the reaction to proceed in astonishingly simple conditions unable to promote the coupling through traditional batch chemistry.



A Continuous Flow Chemistry Platform for Low Temperature Reactions

A low temperature reactor platform that facilitates metalation followed by electrophilic quenching, and related reactions under continuous flow-through conditions has been developed.

Pre-cooling loops are incorporated for all 3 reactor input streams and gaseous reagent inputs can be easily introduced by attaching a ‘tube-in’tube’ presaturation module.

All of the coil reactors and flow chemistry equipment described are are available from Uniqsis Ltd

Upgrading of glycerol acetals by thermal catalyst-free transesterification of dialkyl carbonates under continuous-flow conditions

GA (1)

Upgrading of glycerol acetals by thermal catalyst-free transesterification of dialkyl carbonates under continuous-flow conditions
Green Chem., 2015, Advance Article
DOI: 10.1039/C4GC01750A, Paper

M. Selva, S. Guidi, M. Noe
At 225-300 [degree]C and 20-70 bar, glycerol acetals are upgraded by a continuous-flow catalyst-free transesterification of dialkyl and alkylene carbonates.

At 250–300 °C and 30–50 bar, a continuous-flow (CF) transesterification of different dialkyl and alkylene carbonates (dimethyl-, diethyl-, dibenzyl-, and propylene carbonate, respectively) with two glycerol derived acetals (glycerol formal and solketal) was investigated without any catalyst. An unprecedented result was obtained; not only the desired process occurred, but also the formation of the corresponding mono-transesterification products took place with an excellent selectivity (up to 98%) in all cases. Under isothermal conditions, a study on the effect of pressure allowed us to optimize the conversion of acetals (up to 95%) for the reactions of dimethyl- and diethyl-carbonate (DMC and DEC, respectively). This proved that an abrupt progress of the reaction occurred for very small increments of pressure. For example, at 250 °C, the thermal transesterification of DMC with glycerol formal showed a sharp increase of the conversion from 1–2% at 30 bar to [similar]85% at 37 bar. The lower the temperature, the lower the pressure interval at which the onset of the reaction is achieved. The absence of catalysts allowed us to run CF-reactions virtually indefinitely and with a very high productivity (up to 68 mg min−1) compared to the capacity (1 mL) of the used CF-reactor. Products of the transesterification of DMC and DEC were isolated in good-to-almost quantitative yields. In the case of heavier carbonates, steric reasons were responsible for the considerably lower reactivity of propylene carbonate (PC) with respect to DMC and DEC, while the transesterification of dibenzyl carbonate (DBnC, solid at room temperature) with glycerol formal required the presence of acetone as an additional solvent/carrier. Although the reactions of both PC and DBnC were not optimized, results offered a proof-of-concept on the extension of thermal transesterification processes to higher homologues of linear and alkylene carbonates.

Piecing together the puzzle: understanding a mild, metal free reduction method for large scale synthesis of hydrazines



Piecing together the puzzle: understanding a mild, metal free reduction method for large scale synthesis of hydrazines

D.L. Browne,* I.R. Baxendale, S.V. Ley, Tetrahedron 2011, 67, 10296-10303.



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A key intermediate for the synthesis of hydrazines via a mild, metal free reduction of diazonium salts has been isolated and characterized by X-ray analysis. The presence of this intermediate is general, as demonstrated by the preparation of a number of analogues. A discussion of the mechanism and potential benefits of such a process are also described.




Mild and selective heterogeneous catalytic hydration of nitriles to amides by flowing through manganese dioxide


Mild and selective heterogeneous catalytic hydration of nitriles to amides by flowing through manganese dioxide

C. Battilocchio, J.M. Hawkins, S.V. Ley, Org. Lett. 2014, 16, 1060-1063.

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge U.K.
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
Org. Lett., 2014, 16 (4), pp 1060–1063
DOI: 10.1021/ol403591c
A sustainable flow chemistry process for the hydration of nitriles, whereby an aqueous solution of the nitrile is passed through a column containing commercially available amorphous manganese dioxide, has been developed. The product is obtained simply by concentration of the output stream without any other workup steps. The protocol described is rapid, robust, reliable, and scalable, and it has been applied to a broad range of substrates, showing a high level of chemical tolerance.

.Continuous preparation of arylmagnesium reagents in flow with in-line IR monitoring

.Continuous preparation of arylmagnesium reagents in flow with in-line IR monitoring

T. Brodmann, P. Koos, A. Metzger, P. Knochel, S.V. Ley, Org. Proc. Res. Dev. 2012, 16, 1102-1113.


A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.

Rapid Wolff-Kishner reductions in a silicon carbide microreactor

Green Chem., 2013, Advance Article
DOI: 10.1039/C3GC41942H, Paper
Stephen G. Newman, Lei Gu, Christoph Lesniak, Georg Victor, Frank Meschke, Lahbib Abahmane, Klavs F. Jensen
Wolff-Kishner reductions are performed continuously in a silicon carbide microreactor. Short reactions times and safe operation are achieved, giving high yields without reactor corrosion issues using just 1.5 equivalents of hydrazine.

Rapid Wolff-Kishner reductions in a silicon carbide microreactor


Wolff–Kishner reductions are performed in a novel silicon carbide microreactor. Greatly reduced reaction times and safer operation are achieved, giving high yields without requiring a large excess of hydrazine. The corrosion resistance of silicon carbide avoids the problematic reactor compatibility issues that arise when Wolff–Kishner reductions are done in glass or stainless steel reactors. With only nitrogen gas and water as by-products, this opens the possibility of performing selective, large scale ketone reductions without the generation of hazardous waste streams