Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

Abstract

Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.

Keywords: flash chemistry; flow chemistry; green chemistry; microreactor technology; sustainable synthesis.

Figure 1

Microreactor technologies and flow chemistry for a sustainable chemistry.

Scheme 1

A flow microreactor system for the generation and trapping of highly unstable carbamoyllithium species.

Scheme 2

Flow synthesis of functionalized α-ketoamides.

Scheme 3

Reactions of benzyllithiums.

Scheme 4

Trapping of benzyllithiums bearing carbonyl groups enabled by a flow microreactor. (Adapted with permission from [18], copyright 2015 The Royal Society of Chemistry).

Scheme 5

External trapping of chloromethyllithium in a flow microreactor system.

Scheme 6

Scope for the direct tert-butoxycarbonylation using a flow microreactor system.

Scheme 7

Control of anionic Fries rearrangement reactions by using submillisecond residence time. (Adapted with permission [43], copyright 2016 American Association for the Advancement of Science).

Figure 2

Chip microreactor (CMR) fabricated with six layers of polyimide films. (Reproduced with permission from [43], copyright 2016 American Association for the Advancement of Science).

Scheme 8

Flow microreactor system for lithiation, borylation, Suzuki–Miyaura coupling and selected examples of products.

Scheme 9

Experimental setup for the flow synthesis of 2-fluorobi(hetero)aryls by directed lithiation, zincation, and Negishi cross-coupling. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

Scheme 10

Experimental setup for the coupling of fluoro-substituted pyridines. (Adapted with permission from [53], copyright 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

Scheme 11

Continuous flow process setup for the preparation of 11 (Reproduced with permission from [54], copyright 2015 American Chemical Society).

Scheme 12

Continuous-flow photocatalytic oxidation of thiols to disulfides.

Scheme 13

Trifluoromethylation by continuous-flow photoredox catalysis.

Scheme 14

Flow photochemical synthesis of 6(5H)-phenanthridiones from 2-chlorobenzamides.

Scheme 15

Synthesis of biaryls 14a–g under photochemical flow conditions.

Scheme 16

Flow oxidation of hydrazones to diazo compounds.

Scheme 17

Synthetic use of flow-generated diazo compounds.

Scheme 18

Ley’s flow approach for the generation of diazo compounds.

Scheme 19

Iterative strategy for the sequential coupling of diazo compounds.

Scheme 20

Integrated synthesis of Bakuchiol precursor via flow-generated diazo compounds.

Scheme 21

Kappe’s continuous-flow reduction of olefines with diimide.

Scheme 22

Multi-injection setup for the reduction of artemisinic acid.

Scheme 23

Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).

Figure 3

Reconfigurable modules and flowcharts for API synthesis. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).

Figure 4

Reconfigurable system for continuous production and formulation of APIs. (Reproduced with permission from [85], copyright 2016 American Association for the Advancement of Science).