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. 2019 Jun 7;21(11):4370-4373.
doi: 10.1021/acs.orglett.9b01592. Epub 2019 May 17.

Regio- and Enantioselective Synthesis of 1,2-Diamine Derivatives by Copper-Catalyzed Hydroamination

Saki Ichikawa  1 , Xi-Jie Dai  1 , Stephen L Buchwald  1
Affiliations

Regio- and Enantioselective Synthesis of 1,2-Diamine Derivatives by Copper-Catalyzed Hydroamination

Saki Ichikawa et al. Org Lett. .

Abstract

A highly regio- and enantioselective synthesis of 1,2-diamine derivatives from γ-substituted allylic pivalamides using copper-catalyzed hydroamination is reported. The N-pivaloyl group is essential, in both facilitating the hydrocupration step and suppressing an unproductive β-elimination from the alkylcopper intermediate. This approach enables an efficient construction of chiral differentially protected vicinal diamines under mild conditions with broad functional group tolerance.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Strategies for the Asymmetric Synthesis of 1,2-Diamine Derivatives.
Figure 2.
Figure 2.
Possible Catalytic Cycle and Unproductive β-Elimination. R1 = alkyl groups.
Scheme 1.
Scheme 1.
Protecting Group Screening to Facilitate Hydrocupration and Suppress β-Elimination.[a, b, c] [a] Reaction conditions: 0.1 mmol 1 (1.0 equiv), 2a (1.2 equiv), (R)-CuCatMix* (Cu(OAc)2/(R)-DTBM-SEGPHOS/PPh3 = 1/1.1/1.1, 5.0 mol % [Cu]), (MeO)2MeSiH (4.0 equiv) in THF (0.25 mL, 0.4 M) at 40 °C; see the Supporting Information for details. [b] The yield was determined by 1H NMR spectroscopy of the crude reaction mixture, using 1,1,2,2-tetrachloroethane as an internal standard. [c] The enantiomeric ratio was determined by chiral SFC analysis on commercial chiral columns.
Scheme 2.
Scheme 2.
Scope of γ-Substituted Allylic Amines.[a, b, c] [a] Reaction conditions: 0.5 mmol 1a–1e (1.0 equiv), 2a (1.2 equiv), (R)-CuCatMix* (Cu(OAc)2/(R)-DTBM-SEGPHOS/PPh3 = 1/1.1/1.1, 5.0 mol % [Cu]), (MeO)2MeSiH (4.0 equiv) in THF (1.25 mL, 0.4 M) at 40 °C; see the Supporting Information for details. [b] The regioisomeric ratio of 3a was determined by GC analysis of the crude reaction mixture, using n-dodecane as an internal standard. The regioisomeric ratios of 3b–3e were determined by 1H NMR spectroscopy of the crude reaction mixture, using 1,1,2,2-tetrachloroethane as an internal standard. [c] 10 mol % of (R)-CuCatMix* was used.
Scheme 3.
Scheme 3.
Scope of Amine Electrophiles.[a, b, c] [a] Reaction conditions: 0.5 mmol 1 (1.0 equiv), 2b–2g (1.2 equiv), (R)-CuCatMix* (Cu(OAc)2/(R)-DTBM-SEGPHOS/PPh3 = 1/1.1/1.1, 5.0 mol % [Cu]), (MeO)2MeSiH (4.0 equiv) in THF (1.25 mL, 0.4 M) at 40 °C; see the Supporting Information for details. [b] The regioisomeric ratio was determined by 1H NMR spectroscopy of the crude mixture, using 1,1,2,2-tetrachloroethane as an internal standard. [c] 10 mol % of (R)-CuCatMix* was used.
Scheme 4.
Scheme 4.
Gram-Scale Reaction.
See this image and copyright information in PMC

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