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. 2022 Jul 11;61(28):e202200665.
doi: 10.1002/anie.202200665. Epub 2022 May 20.

Traceless Benzylic C-H Amination via Bifunctional N-Aminopyridinium Intermediates

Pritam Roychowdhury  1 , Roberto G Herrera  1 , Hao Tan  1 , David C Powers  1
Affiliations

Traceless Benzylic C-H Amination via Bifunctional N-Aminopyridinium Intermediates

Pritam Roychowdhury et al. Angew Chem Int Ed Engl. .

Abstract

C-H amination reactions provide the opportunity to streamline the synthesis of nitrogen-containing organic small molecules. The impact of intermolecular C-H amination methods, however, is currently limited the frequent requirement for the amine precursors to bear activating groups, such as N-sulfonyl substituents, that are both challenging to remove and not useful synthetic handles for subsequent derivatization. Here, we introduce traceless nitrogen activation for C-H amination-which enables application of selective C-H amination chemistry to the preparation of diverse N-functionalized products-via sequential benzylic C-H N-aminopyridylation followed by Ni-catalyzed C-N cross-coupling with aryl boronic acids. Unlike many C-H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for C-H amination, deaminative N-N functionalization sequences.

Keywords: Amination; Cross-Coupling; Nickel; Nitrene Transfer; Synthetic Methods.

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Figures

Figure 1.
Figure 1.
Current C–H amination methods with nucleophilic (a) and electrophilic (b) amine precursors provide access to protected nitrogen-containing products. (c) Here we describe benzylic C–H amination with bifunctional N-aminopyridinium reagents that enable sequential nucleophilic amination and electrophilic N–N functionalization to access the products of formal aryl nitrene insertion into benzylic C–H bonds.
Figure 2.
Figure 2.
Summary of the scope and limitations of benzylic C–H aminopyridylation reactions to access N-benzylaminopyridiniums 2. Conditions: (a) 1 (1.3 equiv), N-aminopyridinium triflate (1.0 equiv), DDQ (2.3 equiv), CH2Cl2, 110 °C, 40 h; (b), 1 (1.3 equiv), N-aminopyridinium triflate (1.0 equiv), NIS (2.2 equiv), CH2Cl2, 23 °C, 30 h, blue LEDs. * 1 (5.0 equiv), N-aminopyridinium triflate (1.0 equiv), NIS (2.2 equiv), CH3NO2, 23 °C, 30 h, blue LEDs; yields are isolated.
Figure 3.
Figure 3.
Summary of the scope and limitations of Ni-catalyzed cross-coupling of N-alkylaminopyridinium electrophiles 2 with aryl boronic acids 3 to generate secondary and tertiary amines 4. Conditions: 2 (1.0 equiv), 3 (1.5 equiv), NiBr2(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K3PO4 (2.5 equiv), CH3CN, 65 °C, 16 h; yields are isolated.
Figure 4.
Figure 4.
Ni-catalyzed cross-coupling of N-pyridinium allyl amines affords N-aryl allyl amines. Conditions: 2 (1.0 equiv), PhB(OH)2 (1.5 equiv), NiBr2(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K3PO4 (2.5 equiv), CH3CN, 65 °C, 16 h; yields are isolated.
Figure 5.
Figure 5.
Application of deaminative C–N cross-coupling in complex molecules. Conditions: N-aminopyridinium derivative (1.0 equiv), 7 (1.5 equiv), NiBr2(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K3PO4 (2.5 equiv), CH3CN, 65 °C, 16 h; *N-aminopyridinium derivative (1.5 equiv), 7 (1.0 equiv), NiBr2(dme) (0.10 equiv), 1,10-phenanthroline (0.13 equiv), K3PO4 (2.5 equiv), CH3CN, 65 °C, 16 h; yields are isolated.
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