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. 2023 Jul 26;145(29):16045-16057.
doi: 10.1021/jacs.3c04376. Epub 2023 Jul 13.

Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives

Yonggang Jiang  1 , Dongxiang Liu  1 , Madeline E Rotella  2 , Guogang Deng  1 , Zhengfen Liu  1 , Wen Chen  1 , Hongbin Zhang  1 , Marisa C Kozlowski  2 , Patrick J Walsh  2 , Xiaodong Yang  1
Affiliations

Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives

Yonggang Jiang et al. J Am Chem Soc. .

Abstract

Hydrogen atom transfer (HAT) processes are among the most useful approaches for the selective construction of C(sp3)-C(sp3) bonds. 1,5-HAT with heteroatom-centered radicals (O•, N•) have been well established and are favored relative to other 1,n-HAT processes. In comparison, net 1,2-HAT processes have been observed infrequently. Herein, the first amidyl radicalls are reported that preferentially undergo a net 1,2-HAT over 1,5-HAT. Beginning with single electron transfer from 2-azaallyl anions to N-alkyl N-aryloxy amides, the latter generate amidyl radicals. The amidyl radical undergoes a net-1,2-HAT to generate a C-centered radical that participates in an intermolecular radical-radical coupling with the 2-azaallyl radical to generate 1,2-diamine derivatives. Mechanistic and EPR experiments point to radical intermediates. Density functional theory calculations provide support for a base-assisted, stepwise-1,2-HAT process. It is proposed that the generation of amidyl radicals under basic conditions can be greatly expanded to access α-amino C-centered radicals that will serve as valuable synthetic intermediates.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Generation of azaallyl radical 8 via deprotonation of 2a followed by SET to 1a. Free energies were computed using UM06/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d). See Figure S7 for energetics with UM06–2X/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d).
Figure 2.
Figure 2.
Generation of radical-radical coupling product 3aa via base-assisted, stepwise 1,2-HAT of 9a. Free energies were computed using UM06/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d). See Figure S12 for energetics with UM06–2X/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d).
Figure 3.
Figure 3.
Generation of amidyl radical 11s via indirect, base-assisted 1,2-HAT of 9s. Direct 1,2-, 1,5-, and 1,6-HAT processes are also shown. Free energies were computed using UM06/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d). See Figure S15 for energetics with UM06–2X/6–311+G(d,p)-CPCM(DMSO)//UB3LYP/6–31G(d).
Scheme 1.
Scheme 1.
Reactions of heteroatom-centered radicals. a. 1,5- vs. 1,2-HAT processes with heteroatom centered radicals (X). b. Transition-metal-catalyzed 1,2-hydrogen atom transfer (1,2-HAT) of heteroatom-centered radicals. c. Net-1,2-HAT of aminyl radicals in biological systems.
Scheme 2.
Scheme 2.
Reaction development. a. SET of 2-azaallyl anions with various electrophiles followed by radical-radical coupling. b. Generation of amidyl radicals, net-1,2-HAT and radical-radical coupling to generate 1,2-diamine derivatives (This work).
Scheme 3.
Scheme 3.
Gram-scale synthesis and hydrolysis reactions. a. Gram-scale sequential one-pot synthesis of 3da and 3oa. b. Hydrolysis of the products to access diamines 4da and 4oa.
Scheme 4.
Scheme 4.
EPR spectrum of the PBN-trapped carbon-centered radical.
Scheme 5.
Scheme 5.
Possible paths. a. Base-promoted elimination mechanism. b. Amidyl radicals α-C(sp3)–H coupling via net-1,2-HAT.
Scheme 6.
Scheme 6.
Control experiments. a. Radical trapping experiment. b. Reaction in the absence of ketimine. c. Less reducing 2-azaallyl anion.
Scheme 7.
Scheme 7.
Reaction of radical clock 1q.
Scheme 8.
Scheme 8.
Cross-over experiments.
Scheme 9.
Scheme 9.
Deprotonation/protonation mechanism to net 1,2-HAT.
Scheme 10.
Scheme 10.
Overview of mechanistic probes. a. 1,2-HAT vs. 1,5-HAT. b. 1,2-HAT against benzylic 1,5-HAT. c. 1,5-HAT.
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