Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Dec 17;23(24):9597-9601.
doi: 10.1021/acs.orglett.1c03807. Epub 2021 Dec 9.

Synthesis of α-Branched Amines by Three- and Four-Component C-H Functionalization Employing a Readily Diversifiable Hydrazone Directing Group

Daniel S Brandes  1 , Alex D Muma  1 , Jonathan A Ellman  1
Affiliations

Synthesis of α-Branched Amines by Three- and Four-Component C-H Functionalization Employing a Readily Diversifiable Hydrazone Directing Group

Daniel S Brandes et al. Org Lett. .

Abstract

Efficient syntheses of α-branched amines by three- and four-component C-H functionalization employing a diversifiable hydrazone directing group have been developed. The hydrazone in the α-branched amine products has been readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study represents the first example of a four-component C-H functionalization reaction.

PubMed Disclaimer

Figures

Scheme 1.
Scheme 1.
Multicomponent C–H Functionalization
Scheme 2.
Scheme 2.. Three-Component Reaction Alkene Scope.
aConditions: 0.20 mmol of 1a, 0.40 mmol of 2, 0.22 mmol of 3a. Isolated yields of products after purification by chromatography are reported. b0.80 mmol of 2e.
Scheme 3.
Scheme 3.. Three-Component Reaction Dioxazolone and Hydrazone Scope.
aConditions: 0.20 mmol of 1, 0.40 mmol of 2a, 0.22 mmol of 3. Isolated yields of products after purification by chromatography are reported. bReaction performed on a 1.0 mmol scale in the hydrazone with 2.5 mol % of catalyst. c0.80 mmol of 2a.dReaction performed with 0.40 mmol of 1d, 0.40 mmol of 2a, and 0.20 mmol of 3a at 20 °C for 40 h.
Scheme 4.
Scheme 4.. Four-Component Reaction Scope.
aConditions: 0.20 mmol of 5, 0.24 mmol of 6, 0.60 mmol of 2, 0.30 mmol of 3. Isolated yields of products after purification by chromatography are reported. bReaction performed with 0.44 mmol of 5c, 0.52 mmol of 6a, 0.65 mmol of 2a, 0.22 mmol of 3a at 20 °C for 40 h.
Scheme 5.
Scheme 5.. Diversification of Multicomponent Product 4l.
aMMPP, MeOH. bO3, NaClO2, MeCN/H2O. cO3/DMS, EtOH, then ethyl 2-(triphenyl-λ5-phosphaneylidene)acetate. dO3/DMS, CH2Cl2, then KHMDS, methyltriphenylphosphonium bromide. eO3/DMS, MeOH, then BF3•OEt2, triethylsilane. fO3/DMS, MeOH, then BF3•OEt2, allyl(trimethyl)silane. gTMSN3, PhI(OAc)2, Cu(OAc)2, K2CO3, MeCN. hDiethyl bromomalonate, NaHCO3, [Ir(ppy)2(dtbbpy)][PF6], MeCN, Blue LED.
Scheme 6.
Scheme 6.
Proposed Mechanism for the Four-Component Transformation.
See this image and copyright information in PMC

References

    1. For examples of three-component C–H functionalization reactions employing Rh(III) catalysis, see: (a) Boerth JA; Ellman JA. Rh(III)-Catalyzed Diastereoselective C–H Bond Addition/Cyclization Cascade of Enone Tethered Aldehydes. Chem. Sci. 2016, 7, 1474–1479. - PMC - PubMed
    2. Zhang S-S; Xia J; Wu J-Q; Liu X-G; Zhou C-J; Lin E; Li Q; Huang S-L; Wang H. Three-Component Catalytic Carboxygenation of Activated Alkenes Enabled by Bimetallic Rh(III)/Cu(II) Catalysis. Org. Lett. 2017, 19, 5868–5871. - PMC - PubMed
    3. Tang M; Li Y; Han S; Liu L; Ackermann L; Li J. Rhodium(III)-Catalyzed C–H Alkylation/Nucleophilic Addition Domino Reaction. Eur. J. Org. Chem. 2019, 660–664. - PMC - PubMed
    4. Li R; Ju C-W; Zhao D. Rhodium(III) vs. Cobalt(III): A Mechanistically Distinct Three-Component C–H Bond Addition Cascade Using a Cp*RhIII Catalyst. Chem. Commun. 2019, 55, 695–698. - PMC - PubMed
    5. Maity S; Potter TJ; Ellman JA α-Branched Amines by Catalytic 1,1-Addition of C–H Bonds and Aminating Agents to Terminal Alkenes. Nat. Catal. 2019, 2, 756–762. - PMC - PubMed
    6. Pinkert T; Wegner T; Mondal S; Glorius F. Intermolecular 1,4-Carboamination of Conjugated Dienes Enabled by Cp*RhIII-Catalyzed C−H Activation. Angew. Chem., Int. Ed. 2019, 58, 15041–15045. - PMC - PubMed
    7. Brandes DS; Sirvent A; Mercado BQ; Ellman JA Three-Component 1,2-Carboamidation of Bridged Bicyclic Alkenes via RhIII-Catalyzed Addition of C–H Bonds and Amidating Reagents. Org. Lett. 2021, 23, 2836–2840. - PMC - PubMed
    8. Mi R; Zhang X; Wang J; Chen H; Lan Y; Wang F; Li X. Rhodium-Catalyzed Regio-, Diastereo-, and Enantioselective Three-Component Carboamination of Dienes via C–H Activation. ACS Catal. 2021, 11, 6692–6697. - PMC - PubMed
    9. Pinkert T; Das M; Schrader ML; Glorius F. Use of Strain-Release for the Diastereoselective Construction of Quaternary Carbon Centers. J. Am. Chem. Soc. 2021, 143, 7648–7654. - PMC - PubMed
    1. For examples of three-component C–H functionalization reactions employing Co(III) catalysis, see: (a) Boerth JA; Hummel JR; Ellman JA. Highly Stereoselective Cobalt(III)-Catalyzed Three-Component C−H Bond Addition Cascade. Angew. Chem., Int. Ed. 2016, 55, 12650–12654. - PMC - PubMed
    2. Boerth JA; Ellman JA A Convergent Synthesis of Functionalized Alkenyl Halides through Cobalt(III)-Catalyzed Three-Component C−H Bond Addition. Angew. Chem., Int. Ed. 2017, 56, 9976–9980. - PMC - PubMed
    3. Boerth JA; Maity S; Williams SK; Mercado BQ; Ellman JA Selective and Synergistic Cobalt(III)-Catalysed Three-Component C–H Bond Addition to Dienes and Aldehydes. Nat. Catal. 2018, 1, 673–679. - PMC - PubMed
    4. Dongbang S; Shen Z; Ellman JA Synthesis of Homoallylic Alcohols with Acyclic Quaternary Centers through CoIII-Catalyzed Three-Component C−H Bond Addition to Internally Substituted Dienes and Carbonyls. Angew. Chem., Int. Ed. 2019, 58, 12590–12594. - PMC - PubMed
    5. Yang J; Ji D-W; Hu Y-C; Min X-T; Zhou X; Chen Q-A Cobalt-Catalyzed Hydroxymethylarylation of Terpenes with Formaldehyde and Arenes. Chem. Sci. 2019, 10, 9560–9564. - PMC - PubMed
    6. Shen Z; Li C; Mercado BQ; Ellman JA Cobalt(III)-Catalyzed Diastereoselective Three-Component C–H Bond Addition to Butadiene and Activated Ketones. Synthesis 2020, 52, 1239–1246. - PMC - PubMed
    7. Dongbang S; Ellman JA Synthesis of Nitrile Bearing Acyclic Quaternary Centers through Co(III)-Catalyzed Sequential C−H Bond Addition to Dienes and N-Cyanosuccinimide. Angew. Chem., Int. Ed. 2021, 60, 2135–2139. - PMC - PubMed
    8. Herraiz AG; Cramer N. Cobalt(III)-Catalyzed Diastereo- and Enantioselective Three-Component C–H Functionalization. ACS Catal. 2021, 11, 11938–11944. - PMC - PubMed
    1. For an example of three-component C–H functionalization reactions employing Ru(II) catalysis, see: Wang X-G; Li Y; Liu H-C; Zhang B-S; Gou X-Y; Wang Q; Ma J-W; Liang Y-M. Three-Component Ruthenium-Catalyzed Direct Meta-Selective C–H Activation of Arenes: A New Approach to the Alkylarylation of Al-kenes. J. Am. Chem. Soc. 2019, 141, 13914–13922. - PubMed
    1. Nugent TC Chiral Amine Synthesis: Methods, Developments and Applications, Wiley-VCH GmbH & Co., Weinheim, 2010.
    1. Seo S; Gao M; Paffenholz E; Willis MC Sequential Catalytic Functionalization of Aryltriazenyl Aldehydes for the Synthesis of Complex Benzenes. ACS Catal. 2021, 11, 6091–6098. - PMC - PubMed