Complexity from Simplicity: Tricyclic Aziridines from the Rearrangement of Pyrroles by Batch and Flow Photochemistry

Maskill, Katie G.; Knowles, Jonathan P.; Elliott, Luke D.; Alder, Roger W.; Booker‐Milburn, Kevin I.

doi:10.1002/ange.201208892

Cited by 19 publications

(17 citation statements)

References 37 publications

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“…wrapped around a custom quartz tube containing a low pressure 36 W single ended PL-L lamp (254 or 365 nm) cooled by air. [16] Reactor volume: 90 mL (one layer).…”

Section: Methodsmentioning

confidence: 99%

“…This employed a reactor of flexible, UV‐transparent fluorinated ethylene propylene (FEP) tubing wrapped closely around a UV‐emitting source (Figure 1 a). The surface area and proximity of the photolysate to the UV source ensured effective irradiation of large volumes of solution minimizing transmission versus distance constraints, resulting in the production of 20–500 g of photochemical products in 24 h. Precise regulation of flow rate enabled residence time to be controlled in the cases when over‐irradiation of evolving product is a problem 14–16. Recently, a second‐generation reactor has enabled use of air‐cooled low‐pressure 36 W lamps in conjunction with FEP tubing,16–18 with the advantage of allowing controlled irradiation at selected wavelengths centered around 254, 312 and 365 nm by simply exchanging lamps (Figure 1 b).…”

Section: Introductionmentioning

confidence: 99%

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Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

Elliott

Knowles

Koovits

et al. 2014

Chemistry A European J

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The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20% lower than that of batch, whereas three-layer reactors were 20% more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.

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“…wrapped around a custom quartz tube containing a low pressure 36 W single ended PL-L lamp (254 or 365 nm) cooled by air. [16] Reactor volume: 90 mL (one layer).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

Elliott

Knowles

Koovits

et al. 2014

Chemistry A European J

Self Cite

180

120

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“…An intriguing example constitutes the UV photomicroreactor developed by Booker-Milburn that was applied for the synthesis of a variety of complex organic molecules by a photocycloaddition strategy. [47] A first device consisted of three layers of FEP tubing (2.7 mm ID) that was coiled around a Pyrex immersion well containing a 400 W medium-pressure Hg lamp. The larger diameter tubing allowed the generated back pressure at higher flow rates to be minimized, to provide a high throughput and to avoid microreactor clogging.…”

Section: Direct Photochemical Activationmentioning

confidence: 99%

Photochemical Transformations Accelerated in Continuous‐Flow Reactors: Basic Concepts and Applications

Straathof

Hessel

et al. 2014

Chemistry A European J

451

271

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Continuous-flow photochemistry is used increasingly by researchers in academia and industry to facilitate photochemical processes and their subsequent scale-up. However, without detailed knowledge concerning the engineering aspects of photochemistry, it can be quite challenging to develop a suitable photochemical microreactor for a given reaction. In this review, we provide an up-to-date overview of both technological and chemical aspects associated with photochemical processes in microreactors. Important design considerations, such as light sources, material selection, and solvent constraints are discussed. In addition, a detailed description of photon and mass-transfer phenomena in microreactors is made and fundamental principles are deduced for making a judicious choice for a suitable photomicroreactor. The advantages of microreactor technology for photochemistry are described for UV and visible-light driven photochemical processes and are compared with their batch counterparts. In addition, different scale-up strategies and limitations of continuous-flow microreactors are discussed.

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“…[4] We have previously reported the photochemical transformation of simple N-butenyl-substituted pyrroles into complex tricyclic aziridines 2. [5] We recently demonstrated that these strained photochemical products undergo arange of thermal and Pdcatalyzed ring-opening/annulation reactions to produce ab road range of fused polyheterocycles,i nj ust two steps from simple pyrroles (Scheme 1). [6] We were therefore keen to exploit the functionality and inherent strain in these aziridines as part of an alkaloid synthesis,i np articular the aziridine carboxylates 3.H erein we report as hort total synthesis of (AE)-1 utilizing ah ighly unusual and selective, ligand controlled intramolecular Heck-reaction onto one of apair of equilibrating enamine intermediates.…”

mentioning

confidence: 99%

“…60 mg quantities of (AE)-8 at at ime using a6 Wb atch reactor. [5] Fortunately,w ef ound that using our three-lamp FEP-flow reactor gave routine access to 1.91 go fa ziridine (AE)-8 in as ingle 373 min run (productivity of 7.37 g/24 h). This highlights once again the value of flow photochemistry for scaling-up high dilution/low quantum yield reactions-this would simply not be possible on laboratory batch scale.…”

mentioning

confidence: 99%

A Short Synthesis of (±)‐3‐Demethoxyerythratidinone by Ligand‐Controlled Selective Heck Cyclization of Equilibrating Enamines

Blackham

Booker‐Milburn

2017

Angewandte Chemie

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As hort, 5-step total synthesis of (AE)-3-demethoxyerythratidinone from as imple pyrrole derivative is described. Features include the formation of gram quantities of ak ey tricylic aziridine from ac hallenging photochemical cascade reaction through the use of flowphotochemistry.The final step involved ah ighly unusual Heckc yclization whereby ligand control enabled efficient formation of the natural product in 69 %y ield from the minor isomer present in an equilibrating mixture of labile enamines.The alkaloid (+ +)-3-demethoxyerythratidinone 1 is one of over 100 natural products produced by the Erythrina genus of flowering plants. [1] The Erythrina alkaloids display ab road range of pharmacological activities including hypotensive, sedative,n euromuscular blocking,C NS depressing and curare-like activities.T he key structural feature of this family is the tetracyclic tetrahydroisoquinoline core.S ince the first total synthesis of 1 by Tsuda in 1984, [2] this tetracyclic alkaloid has been used by others in order to demonstrate the utility of various synthetic methodologies.[3] Av ery elegant synthesis was recently reported by Reisman, where chiral sulfinyl imine chemistry was used to control the stereochemistry of the key quaternary center, [3d] giving (À)-3-demethoxyerythratidinone in just six steps overall (Figure 1).Individually both photochemical and Pd-catalyzed crosscoupling methodologies have been shown to be powerful techniques in organic synthesis as well as valuable tools in the synthesis of complex molecular architectures.[4] We have previously reported the photochemical transformation of simple N-butenyl-substituted pyrroles into complex tricyclic aziridines 2.[5] We recently demonstrated that these strained photochemical products undergo arange of thermal and Pdcatalyzed ring-opening/annulation reactions to produce ab road range of fused polyheterocycles,i nj ust two steps from simple pyrroles (Scheme 1).[6] We were therefore keen to exploit the functionality and inherent strain in these aziridines as part of an alkaloid synthesis,i np articular the aziridine carboxylates 3.H erein we report as hort total synthesis of (AE)-1 utilizing ah ighly unusual and selective, ligand controlled intramolecular Heck-reaction onto one of apair of equilibrating enamine intermediates. Our initial strategy to 1 (Scheme 1) involved aryl cyclization onto the iminium ion 4 which itself would be generated by in situ decarboxylation of the amino acid 5.[7] Although iminium ion cyclizations are one of the most frequently used approaches to such alkaloids, [8] these have usually involved the intermediary of N-acyliminium ions.[9] Ther equisite amino-acid 5 should be obtained by Pd 0 -catalyzed acetate ring-opening of the aziridine 3 followed by N-alkylation with the iodide 6.Irradiation of pyrrole 7 (254 nm) gave the aziridine (AE)-8 in a39% yield (Scheme 2). As before,wefound that this two- photon process suffers from low productivity due to al ikely low overall quantum yield and as such was limited to ca. 60 ...

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Complexity from Simplicity: Tricyclic Aziridines from the Rearrangement of Pyrroles by Batch and Flow Photochemistry

Cited by 19 publications

References 37 publications

Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

Photochemical Transformations Accelerated in Continuous‐Flow Reactors: Basic Concepts and Applications

A Short Synthesis of (±)‐3‐Demethoxyerythratidinone by Ligand‐Controlled Selective Heck Cyclization of Equilibrating Enamines

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