Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

Motiwala, Hashim F.; Charaschanya, Manwika; Day, Victor W.; Aubé, Jeffrey

doi:10.1021/acs.joc.5b02764

Cited by 67 publications

(30 citation statements)

References 63 publications

(91 reference statements)

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“…Analogous hydrogen bonding has been observed numerous times, for example between HFIP and amino acids. [98][99][100][101] In accordance with this proposal, the MW calculated for mononuclear complexes diffusing alongside one molecule of HFIP (1:1:2•HFIP) lies well within the measured range of diffusion constants.…”

Section: Scheme 5 Proposed Active Species and Resting Statesupporting

confidence: 68%

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium: A Combined Experimental and Theoretical Study

Wedi¹,

Bergander²,

Mück‐Lichtenfeld³

et al. 2019

Preprint

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Recently, synthetic methods have been discovered which enable the directing group-free C–H activation of arenes with palladium-catalysts and do not require an excess of the arene substrate. By overcoming this long standing challenge, such methods have now become suitable for the functionalization of complex organic molecules. The key to success in several of these transformations has been the use of two complementary ligands, an N-acyl amino acid and an Nheterocycle. Further applications of this design principle will likely require the guidance by a profound mechanistic understanding. This prompted us to engage in a detailed experimental and computational mechanistic study of the dual ligand enabled C–H activation of arenes. Based on comprehensive kinetic experiments, (CID-)MS, (DOSY-)NMR, and DFT calculations we find that a 1:1:1 complex of palladium and the two ligands is indeed the active species that enables a partially rate-limiting concerted C–H activation as part of a Pd<sup>0</sup>/Pd<sup>II</sup>-cycle. Our study highlights the importance of catalyst speciation and allows us to rationalize the role of each ligand as well as the observed regioselectivities. These findings are expected to be highly useful for further method development using this powerful class of catalysts.

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Section: Scheme 5 Proposed Active Species and Resting Statesupporting

confidence: 68%

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium: A Combined Experimental and Theoretical Study

Wedi¹,

Bergander²,

Mück‐Lichtenfeld³

et al. 2019

Preprint

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show abstract

“…More recently, this methodology has been extended to an intermolecular Schmidt reaction with triflic acid employed as the optimal catalyst. 29 The same group has also reported the HFIP promoted intramolecular Friedel-Crafts reaction of acyl chlorides 18 requiring no additional catalyst (Figure 2a). 26 Mechanistic experiments supported acyl chloride activation promoted via hydrogen bonding to HFIP.…”

Section: A) Carbonyl and Acetal Activationmentioning

confidence: 94%

Hexafluoroisopropanol as a highly versatile solvent

et al. 2017

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Hexafluoroisopropanol (HFIP) has recently become a very popular solvent with uses in many different applications; analysis shows that it possesses a wide range of interesting and unique properties. In this Perspective we detail the main uses of HFIP in the natural sciences and disclose the underlying principles that give it such wide appeal. Accordingly, we will show the broad usage and beneficial effects of HFIP in different fields such as organic, inorganic or physical chemistry, chemical biology and polymer science.

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“…3c ). Owing to the relatively hindered nature of the D-ring ketones, a survey of conditions was first carried out; the best results were obtained by carrying out the reaction in hexafluoroisopropanol 36 (optimization of reaction conditions shown in Supplementary Table 3 ). Analysis of the two possible 1,3-oxazinane intermediates suggests that the quaternary C-13 serves as a large substituent while the C-16 methylene is relatively small (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reagent-controlled regiodivergent ring expansions of steroids

Charaschanya

Aubé

2018

Nat Commun

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Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.

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Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

Cited by 67 publications

References 63 publications

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium: A Combined Experimental and Theoretical Study

Mechanism of the Arene-Limited Nondirected C–H Activation of Arenes with Palladium: A Combined Experimental and Theoretical Study

Hexafluoroisopropanol as a highly versatile solvent

Reagent-controlled regiodivergent ring expansions of steroids

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