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. 2019 May 6;58(19):6385-6390.
doi: 10.1002/anie.201813960. Epub 2019 Mar 14.

Merging Photochemistry with Electrochemistry: Functional-Group Tolerant Electrochemical Amination of C(sp3 )-H Bonds

Fei Wang  1 , Shannon S Stahl  1
Affiliations

Merging Photochemistry with Electrochemistry: Functional-Group Tolerant Electrochemical Amination of C(sp3 )-H Bonds

Fei Wang et al. Angew Chem Int Ed Engl. .

Abstract

Direct amination of C(sp3 )-H bonds is of broad interest in the realm of C-H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp3 )-H/N-H coupling that exhibits good reactivity with both sp2 and sp3 N-H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light-induced cleavage of intermediate N-I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional-group compatibility of electrochemical C-H amination, for example, tolerating electron-rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.

Keywords: C−H functionalization; amination; electrochemistry; iodine; photochemistry.

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Conflict of interest statement

Conflict of interest:

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Electrochemical strategies for dehydrogenative amination of sp3 C–H bonds (A) and the associated anodic potentials required for each approach (B). ET = electron transfer, PT = proton transfer, PCET = proton-coupled electron transfer.
Scheme 1.
Scheme 1.
Comparison of previous electrochemical methods for sp3 C–H amination. For detail procedures, see refs. – and Supporting Information. Yields were determined by 1H NMR with m-xylene as internal standard, conversion is shown in parenthesis. [a] Conditions: 1a or 1b (0.2 mmol) and nBu4NPF6 (0.1 M) in HFIP (10 mL), 2.5 mA, RT. [b] Conditions: 1a or 1b (0.2 mmol), NaOAc (0.2 mmol) and nBu4NBF4 (0.2 mmol) in DCE/HFIP (6 mL, 2:1), 7.5 mA, RT. [c] 1a or 1b (0.4 mmol), NaOMe (0.2 mmol) and KBr (0.2 mmol) in methanol (6 mL) at 65 °C, 100 mA, DCE = 1,2-dichloroethane. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol. n.d. = not detected.
Scheme 2.
Scheme 2.
Substrate scope of iodide-mediated dehydrogenative amination. The reaction was conducted on a 0.5 mmol scale, see Supporting Information for details. All yields are isolated yield. [a] 2a has also been produced under conditions with stoichiometric chemical oxidants: PhI(OAc)2/cat. I2, 90%; PhI(OAc)2/I3−, 93%; mCPBA/cat. I2, 54%; [b] dr = 1:1. [c] dr = 1.8:1. [d] dr = 1.2 :1. [e] With 2,6-lutidine instead of pyridine as additive. TsOH = p-toluenesulfonic acid.
Scheme 3.
Scheme 3.
Simplified mechanism for photo/electrochemical iodide-mediated dehydrogenative C–H/N–H coupling.
Scheme 4.
Scheme 4.
CVs of iodide and representative substrates. Conditions: 5 mM substate in acetonitrile with KPF6 (0.1 M) as supporting electrolyte, glassy carbon as working electrode (~ 7.0 mm2) and a platinum wire counter electrode, scan rate = 100 mV/s.
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