A general, electrocatalytic approach to the synthesis of vicinal diamines

Abstract

This protocol describes an electrochemical synthesis of 1,2-diazides from alkenes. Organic azides are highly versatile intermediates for synthetic chemistry, materials, and biological applications. 1,2-Diazides are commonly reduced to form 1,2-diamines, which are prevalent structural motifs in bioactive natural products, therapeutic agents, and molecular catalysts. The electrochemical formation of 1,2-diazides involves the anodic generation of an azidyl radical from sodium azide, followed by two successive additions of this N-centered radical to the alkene, and is assisted by a Mn catalyst. The electrosynthesis of 1,2-diazides can be carried out using various experimental setups comprising custom-made or commercially available reaction vessels and a direct-current power supply. Readily accessible electrode materials can be used, including carbon (made from reticulated vitreous carbon and pencil lead), nickel foam, and platinum foil. This protocol is also demonstrated using ElectraSyn, a standardized electrochemistry kit. Compared with conventional synthetic approaches, electrochemistry allows for the precise control of the anodic potential input, eliminates the need for stoichiometric and often indiscriminate oxidants, and minimizes the generation of wasteful byproducts. As such, our electrocatalytic synthesis exhibits various advantages over existing methods for alkene diamination, including sustainability, operational simplicity, substrate generality, and exceptional functional-group compatibility. The resultant 1,2-diazides can be smoothly reduced to 1,2-diamines in a single step with high chemoselectivity. To exemplify this, we include a procedure for catalytic hydrogenation using palladium on carbon. This protocol, therefore, constitutes a general approach to accessing 1,2-diazides and 1,2-diamines from alkenes.

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Fig. 1: Importance of 1,2-diamines in synthetic and medicinal chemistry
Fig. 2: Electrocatalytic diazidation of alkenes.
Fig. 3: Electrolysis setup for 0.2 mmol scale reactions.
Fig. 4: Electrolysis setup for 3 mmol scale reactions.
Fig. 5
Fig. 6

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Acknowledgements

Financial support was provided by Cornell University and the Atkinson Center for a Sustainable Future. S.L. is thankful to the National Science Foundation (NSF) for a CAREER Award (CHE-1751839). This study made use of the Cornell Center for Materials Research Shared Facilities supported by NSF MRSEC (DMR-1719875) and an NMR facility supported by the NSF (CHE-1531632). G.S.S. is grateful for an NSF Graduate Fellowship (DGE-1650441). We thank P. Baran and IKA for their generous gift of ElectraSyn.

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Authors

Contributions

N.F. and S.L. designed the experiments. N.F. and G.S.S. carried out the experiments. N.F., G.S.S., and S.L. wrote the manuscript.

Corresponding author

Correspondence to Song Lin.

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The authors declare no competing interests.

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Key references using this protocol

1. Fu, N., Sauer, G.S., Saha, A., Loo, A. & Lin, S. Science, 357, 575–579 (2017). https://doi.org/10.1126/science.aan6206

2. Fu, N., Sauer, G.S. & Lin, S. J. Am. Chem. Soc. 139, 15548–15553 (2017). https://doi.org/10.1021/jacs.7b09388

3. Ye, K.-Y., Pombar, G., Fu, N., Sauer, G.S., Keresztes, I. & Lin, S. J. Am. Chem. Soc. 140, 2438–2441 (2018). https://doi.org/10.1021/jacs.7b13387

Integrated supplementary information

Supplementary Figure 1.

Preparation of the nickel cathode and carbon anode for electrocatalytic diazidation of alkenes

Supplementary Figure 2. IKA EletraSyn setup: electrode assemblies.

Left: Ni foam and RVC electrodes and the electrode holders; Right: Ni foam and RVC electrode assemblies as described in Box 1

Supplementary Figure 3. IKA EletraSyn setup: parts for vial assembly.

Top: ElectraSyn vial cap; Bottom left: ElectraSyn vial (10 mL) with Teflon tape wrapped around the thread. Bottom middle: RVC electrode assembly. Bottom right: Ni foam electrode assembly

Supplementary Figure 4.

IKA EletraSyn setup: vial assembly

Supplementary Figure 5.

IKA EletraSyn setup: reactor assembly

Supplementary Figure 6.

Custom two-neck glass tube for small-scale electrolysis with standard no. 15 internal thread and 14/20 joint

Supplementary Figure 7. Custom Teflon cap components.

Left: Electrical feedthrough with 2 mm sockets created as described in Box 2. Right: Teflon cap as created in Box 2, including a #15 Teflon bushing, two electrical feedthroughs, and an O-ring; viewed from the side

Supplementary Figure 8. Custom Teflon cap components.

Left: Electrical feedthrough created as described in Box 2. Right: Teflon cap as created in Box 2; viewed from the bottom

Supplementary Figure 9. Custom Teflon cap components.

Left: Disassembled Teflon cap showing the hole drilled in the Teflon. Right: Electrical feedthrough created as described in Box 2

Supplementary Figure 10.

TGA data for (3,4-diazidobutyl)benzene (3)

Supplementary Figure 11.

TGA data for trans-2,3-diazido-1-tosylindoline (4)

Supplementary Figure 12.

TGA data for methyl 2,3-diazido-3-methyl-2-phenylbutanoate (7)

Supplementary Figure 13.

TGA data for 4-(1,2-diazidoethyl)benzaldehyde (9)

Supplementary Figure 14.

TGA data for 1,2-diazidoethyl ferrocene (13)

Supplementary Figure 15.

TGA data for sodium azide

Supplementary Figure 16.

1H NMR spectrum for a mixture of (2,3-diazidopropyl)benzene (16) and (1,2,3-triazidopropyl)benzene (17)

Supplementary Figure 17.

13C NMR spectrum for a mixture of (2,3-diazidopropyl)benzene (16) and (1,2,3-triazidopropyl)benzene (17)

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–17 and Supplementary Methods

Reporting Summary

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Fu, N., Sauer, G.S. & Lin, S. A general, electrocatalytic approach to the synthesis of vicinal diamines. Nat Protoc 13, 1725–1743 (2018). https://doi.org/10.1038/s41596-018-0010-0

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