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
. 2019 Jul 22;58(30):10245-10249.
doi: 10.1002/anie.201905021. Epub 2019 Jun 24.

Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents

Conghui Tang  1 , Mikiko Okumura  1 , Yunbo Zhu  1 , Annie R Hooper  1 , Yu Zhou  1 , Yu-Hsuan Lee  1 , David Sarlah  1
Affiliations

Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents

Conghui Tang et al. Angew Chem Int Ed Engl. .

Abstract

A protocol for palladium-catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

Keywords: arenes; aromaticity; cycloadditions; palladium; photochemistry.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
(A) Transition metal-catalyzed arenophile-mediated dearomative aminofunctionalizations. (B) Examples of bioactive compounds with syn-1,4-carboaminated cyclohexane scaffold.
Figure 2.
Figure 2.
Diversification of product 8f. Reagents and conditions [1] (i) Rh/Al2O3 (cat.), H2, 96%; (ii) α–bromoacetophenone, K2CO3, 56%; (iii) KOH, 95%; [2] Li, NH3, 83%; [3] (i) Rh/Al2O3 (cat.), H2, 96%; (ii) HCl, 59%; [4] (i) Rh/Al2O3 (cat.), H2, 96%; (ii) tBuOCl, AcOH, 73%; [5] (i) Rh/Al2O3 (cat.), H2, 96%; (ii) tBuOCl, 68%.
Figure 3.
Figure 3.
Synthesis of sertraline (2) from naphthalene (7f) and establishment of enantioselectivity of dearomative syn-1,4-carboamination.[a] Reagents and conditions: [1] naphthalene (7f, 1.0 mmol, 2.0 eq.), MTAD (1, 0.5 mmol, 1.0 eq.), CH2Cl2 (0.1 M), visible light, –50 ºC; then addition of PhMgBr (2.0 eq., 2.0 M in THF), Pd2(dba)3·CHCl3/DPEphos (10 mol%/20 mol%) in THF, –50 to 15 ºC, 10 h, 58%. [2] Rh/Al2O3 (cat.), H2, 98%. [3] α-bromoacetophenone, NaOEt, EtOH, then KOH, 51%. [4] LiAl(OMe)3H, 65%.
See this image and copyright information in PMC

References

    1. For recent reviews on synthetic utility of dearomatization chemistry, see: a) Pape AR, Kaliappan KP, Kündig EP, Chem. Rev. 2000, 100, 2917–2940; - PubMed
    2. b) Rosillo M, Dominguez G, Pérez-Castells J, Chem. Soc. Rev. 2007, 36, 1589–1604; - PubMed
    3. c) Zhuo C-X, Zhang W, You S-L, Angew. Chem. Int. Ed. 2012, 51, 12662–12686; Angew. Chem. 2012, 124, 12834–12858; - PubMed
    4. d) Remy R, Bochet CG, Chem. Rev. 2016, 116, 9816–9849; - PubMed
    5. e) Liebov BK, Harman WD, Chem. Rev. 2017, 117, 13721–13755; - PubMed
    6. f) Wertjes WC, Southgate EH, Sarlah D, Chem. Soc. Rev. 2018, 47, 7996–8017. - PubMed
    1. For selected reviews on dearomative reductions, see: a) Rabideau PW, Marcinow Z, Org. React. 1992, 42, 1;
    2. b) Foubelo F, Yus, M. M Reduction/Hydrogenation of Aromatic Rings, In Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, (Ed.: Mortier J), Wiley, Hoboken, 2015, 337–364;
    3. c) Stanislaus A, Cooper BH, Catal. Rev. Sci. Eng. 1994, 36, 75–123;
    4. d) Wang D-S, Chen Q-A, Lu S-M, Zhou Y-G, Chem. Rev. 2012, 112, 2557–2590. - PubMed
    1. L. Pouységu, D. Deffieux, S. Quideau, S. Tetrahedron 2010, 66, 2235–2261. For recent examples: a) M. Uyanik N Sasakura M Mizuno M; Ishihara K ACS Catal. 2017, 7, 872–876;
    2. b) Uyanik M, Mutsuga T, Ishihara K, Angew. Chem. Int. Ed. 2017, 56, 3956–3960; Angew. Chem. 2017, 129, 4014–4018. - PubMed
    1. For recent examples, see: a) Phipps RJ, Toste FD, J. Am. Chem. Soc. 2013, 135, 1268–1271; - PubMed
    2. b) Wiesenfeldt MP, Nairoukh Z, Li W, Glorius F, Science 2017, 357, 908–912; - PubMed
    3. c) Nakayama H, Harada S, Kono M, Nemoto T, J. Am. Chem. Soc. 2017, 139, 10188–10191; - PubMed
    4. d) Farndon JJ, Ma X, Bower JF, J. Am. Chem. Soc. 2017, 139, 14005–14008; - PMC - PubMed
    5. e) Good SN, Sharpe RJ, Johnson JS, J. Am. Chem. Soc. 2017, 139, 12422–12425; - PMC - PubMed
    6. f) James MJ, Schwarz JL, Strieth-Kalthoff F, Wibbeling B, Glorius F, J. Am. Chem. Soc. 2018, 140, 8624–8626. - PubMed
    1. Roche SP, Porco JA Jr., Angew. Chem. Int. Ed. 2011, 50, 4068–4093; Angew. Chem. 2011, 123, 4154–4179; - PMC - PubMed

Publication types