Automated iterative Csp3–C bond formation

Blair, Daniel J.; Chitti, Sriyankari; Trobe, Melanie; Kostyra, David M.; Haley, Hannah M. S.; Hansen, Richard L.; Ballmer, Steve G.; Woods, Toby J.; Wang, Wesley; Mubayi, Vikram; Schmidt, Michael; Pipal, Robert W.; Morehouse, Gregory F.; Ray, Andrea M. E. Palazzolo; Gray, Danielle L.; Gill, Adrian L.; Burke, Martin D.

doi:10.1038/s41586-022-04491-w

“…The Kumada cross-coupling reaction between PhBr or PhI and a secondary alkyl nucleophile, cyclohexylMgCl, was employed, since these types of Csp 3 -Csp 2 cross-coupling reactions catalyzed by Pd are uncommon. 16,[44][45][46][47][48][49][50][51][52] PhBr showed superior yields to PhI (see below) and so PhBr was chosen as the coupling partner for reaction optimization. The Pd-2 complex, either generated in situ or used as isolated, shows very good catalytic activity (86% by GC-FID) under mild conditions (Table 2, entries 1 and 2, respectively), and a gram-scale reaction reveals a similar yield (Figure S40).…”

Section: Resultsmentioning

confidence: 99%

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

Tran¹,

Bouley²,

Mirica

³

2022

Preprint

0

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Palladium complexes are among the most commonly used transition metal catalysts for different organic transformations with wide applications in the chemical synthesis. Currently, catalytic transformations involving Pd(0)/Pd(II) catalytic cycles are very well-known, and processes involving Pd(II)/Pd(III)/Pd(IV) intermediates are also gaining interest in recent years due to the increasing relevance of high-valent Pd species. By contrast, isolated low-valent Pd(I) complexes, especially mononuclear Pd(I) species, are very rare. Herein, we report the isolation of two heteroleptic Pd(I) complexes stabilized by dithiapyridinophane ligands that were fully characterized by single-crystal X-ray diffraction, EPR, IR, and UV-Vis spectroscopies, and computational studies. Excitingly, these Pd(I) complexes are shown to be superior catalysts for the Csp2-Csp3 Kumada cross-coupling reaction vs. their Pd(0) or Pd(II) analogs.

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“…In order to analyze the catalytic competency of the isolated Pd I complexes, the Kumada crosscoupling reaction between bromobenzene and a secondary alkyl nucleophile, cyclohexylMgCl, was employed, since such Csp 3 -Csp 2 cross-coupling reactions catalyzed by Pd are rare. 16,[35][36][37][38] The Pd-2 complex, either generated in situ or used as isolated, shows very good catalytic activity (86% by GC-FID) under mild conditions (Table 2, entries 1 and 2, respectively), and a gram-scale reaction reveals a similar yield (Fig. S38).…”

Section: Main Textmentioning

confidence: 98%

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

Tran¹,

Bouley²,

Mirica

³

2022

Preprint

1

0

View full text Add to dashboard Cite

Palladium complexes are among the most commonly used transition metal catalysts for different organic transformations with wide applications in the chemical synthesis. Currently, catalytic transformations involving Pd(0)/Pd(II) catalytic cycles are very well-known, and processes involving Pd(II)/Pd(III)/Pd(IV) intermediates are also gaining interest in recent years due to the increasing relevance of high-valent Pd species. By contrast, isolated low-valent Pd(I) complexes, especially mononuclear Pd(I) species, are very rare. Herein, we report the isolation of two heteroleptic Pd(I) complexes stabilized by dithiapyridinophane ligands that were fully characterized by single-crystal X-ray diffraction, EPR, IR, and UV-Vis spectroscopies, and computational studies. Excitingly, these Pd(I) complexes are shown to be superior catalysts for the Csp2-Csp3 Kumada cross-coupling reaction vs. their Pd(0) or Pd(II) analogs.

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“…Methyliminodiacetic acid (MIDA) boronates represent bench stable modular building blocks that are compatible with iterative automated synthesis [17a] of increasing generality. [18] However, despite their utility, many boronic acids are not yet commercially available in a stable MIDA boronate form. We thus focused on digitizing the recently reported method for the direct generation of MIDA boronates from boronic acids.…”

Section: Mida Boronate Ester Synthesismentioning

confidence: 99%

“…[17] While MIDA based synthesis platforms have limitations, they can access a wide range of chemical space and the technology continues to advance leading to increasingly expanded reach of chemical space. [18] However, unlike peptides the requisite building blocks cannot be obtained from natural sources and are therefore not yet as widely commercially available. Thus, the power of chemical synthesis is still limited to those who have access to laboratories and relevant expertise.…”

Section: Introductionmentioning

confidence: 99%

Digitizing Chemical Synthesis in 3D Printed Reactionware

Bubliauskas

¹

,

Blair

²

,

Powell-Davies

³

et al. 2022

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Chemistry digitization requires an unambiguous link between experiments and the code used to generate the experimental conditions and outcomes, yet this process is not standardized, limiting the portability of any chemical code. What is needed is a universal approach to aid this process using a well‐defined standard that is composed of syntheses that are employed in modular hardware. Herein we present a new approach to the digitization of organic synthesis that combines process chemistry principles with 3D printed reactionware. This approach outlines the process for transforming unit operations into digitized hardware and well‐defined instructions that ensure effective synthesis. To demonstrate this, we outline the process for digitizing 3 MIDA boronate building blocks, an ester hydrolysis, a Wittig olefination, a Suzuki–Miyaura coupling reaction, and synthesis of the drug sulfanilamide.

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Automated iterative Csp3–C bond formation

Cited by 69 publications

References 60 publications

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

Digitizing Chemical Synthesis in 3D Printed Reactionware

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