Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Oct 11;60(42):22948-22955.
doi: 10.1002/anie.202110019. Epub 2021 Sep 8.

A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3 )-H Amidation

Kevin Antien  1 , Andrea Geraci  1 , Michael Parmentier  2 , Olivier Baudoin  1
Affiliations

A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3 )-H Amidation

Kevin Antien et al. Angew Chem Int Ed Engl. .

Abstract

Vicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p-nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high reactivity in the oxime-directed iridium(III)-catalyzed amidation of unactivated C(sp3 )-H bonds; 3. leads to amide products which can be hydrolyzed under mild conditions. The amidation reaction is mild, general and compatible with both primary C-H bonds of tertiary and secondary alcohols, as well as secondary C-H bonds of cyclic secondary alcohols. This method provides an easy access to free 1,2-aminoalcohols after efficient and mild cleavage of the oxime directing group and activated amide.

Keywords: 1,2-amino alcohol; C−H activation; amidation; dioxazolone; iridium.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of active pharmaceutical ingredients displaying the 1,2‐aminoalcohol motif.
Scheme 1
Scheme 1
Literature precedents on oxime‐directed C(sp3)−H (sulfon)amidation and current work.
Scheme 2
Scheme 2
Preliminary results.
Scheme 3
Scheme 3
Development and synthesis of a new dioxazolone reagent: K‐diox.
Scheme 4
Scheme 4
Reaction scope for tertiary alcohols. [a] Reaction time: 5 min. [b] PivOH (15 mol %), DCE, 60 °C, 14 h. [c] Reaction time: 72 h. [d] d.r. 1:1. Reactions were run on a 0.4 mmol scale at a concentration of 0.25 M.
Scheme 5
Scheme 5
Reaction scope for secondary alcohols. [a] Reaction time: 72 h. [b] Temperature: 40 °C, reaction time: 96 h. [c] [IrCp*(MeCN)3](SbF6)2 (10 mol %), PivOH (30 mol %), microwave, 100 °C, 1 h. [d] The starting material was engaged as a mixture of anti/syn diastereoisomers (d.r. 75:25). Reactions were run on a 0.4 mmol scale at a concentration of 0.25 M.
Scheme 6
Scheme 6
Reaction scope for methylene bonds. Reactions were run on a 0.4 mmol scale at a concentration of 0.25 M.
Figure 2
Figure 2
Initial reaction rate comparison for the protiated (49) and deuterated (49‐d 3 ) substrates. Reactions were performed in parallel.
Scheme 7
Scheme 7
Tenfold scale‐up of the reaction and subsequent deprotection.
Scheme 8
Scheme 8
Applicability of K‐diox to the directed amidation of other systems.
See this image and copyright information in PMC

References

    1. None
    1. Ager D. J., Prakash I., Schaad D. R., Chem. Rev. 1996, 96, 835–876; - PubMed
    1. O'Brien P., Angew. Chem. Int. Ed. 1999, 38, 326–329; - PubMed
    2. Angew. Chem. 1999, 111, 339–342;
    1. Bergmeier S. C., Tetrahedron 2000, 56, 2561–2576;
    1. Sweeney J. B., Chem. Soc. Rev. 2002, 31, 247–258; - PubMed

Publication types

LinkOut - more resources