Rh2(esp)2 Catalyst

Product Manager：Nick Wilde

The Stanford-based Du Bois group has refined the catalytic prowess of Rh in oxidative C-H activation reactions, targeting sulfamate, sulfamide, carbamate, urea, and guanidine substrates. This enhancement stems from their ingenious substitution of tetramethylated m-benzenediproprionic acid 1 through a decarboxylative metathesis process involving Rh2(OAc)4, as outlined in Scheme 1.1-2

Scheme 1. Decarboxylative metathesis of Rh2(OAc)4

Tri- and tetrasubstituted amines were produced in high yields through the employment of PhI(O2CtBu)2 as the oxidant, which was administered via a slow addition process. This oxidant boasts ease of preparation, stability, and superior solubility in non-polar solvents, contrasting favorably with PhI(OAc)2. Its efficacy in promoting C-H amination reactions is noteworthy. The pronounced tendency of unactivated methylene groups to participate in C-H amination stems from the robustness of the catalytic system. Notably, substrates containing 3° C-H bonds underwent complete transformation into the desired heterocycles, even at minimal catalyst loadings of 0.15 mol%. The remarkable enhancement in catalyst turnover is exemplified in Scheme 2, where achieving comparable product yields in the intramolecular transformation of sulfamates to heterocycles necessitated the use of five times the amount of the isosteric Rh2(O2CtBu)4.

Scheme 2.

In addition to its prowess in oxidative cyclization of sulfamide, urea, and guanidine substrates, Du Bois and his team have harnessed the exceptional efficiency of the Rh2(esp)2 catalyst. Notably, Rh2(esp)2 has demonstrated remarkable capability in facilitating intermolecular C-H insertion into a diverse array of benzylic and 3° substrates, utilizing 2,2,2-trichloroethylsulfamate as the N-atom donor (refer to Scheme 3). A distinguishing characteristic of this Rh2(esp)2-mediated process is its operation with limiting quantities of starting materials, setting it apart from other Mn, Fe, Ru, and Cu-catalyzed intermolecular amination techniques. This innovative approach offers a swift route to amino alcohols, amino acids, and diamines, thereby expanding the synthetic toolbox for these valuable compounds.3-4

Scheme 3.

This innovative oxidative strategy showcases a distinctive capability to precisely orchestrate chemo-, regio-, and diastereoselective transformations, enabling the tailored preparation of 1,3-diamines, amino alcohols, and β-amino acids. The Du Bois research team has advanced this C-H amination technique, harnessing it for the total synthesis of (-)-tetrodotoxin (TTX), a potent neurotoxin found in pufferfish.5 The intricate, oxygen-rich cyclohexanone scaffold of TTX underscores the formidable synthetic hurdle it poses, with only two prior successful synthesis routes prior to this groundbreaking work. 6-7 In the pursuit of (-)-TTX, the group leveraged stereospecific C-H bond amination, employing a meticulously designed 1° carbamate to strategically install a C-N bond in an asymmetric manner during the synthesis's advanced stages (Scheme 4).8 These groundbreaking C-H activation methodologies and catalysts developed by the Stanford researchers now constitute a potent arsenal for synthetic chemists, empowering them to construct complex amine frameworks with unparalleled precision and efficiency.

Scheme 4.

References

1. Espino CG, Fiori KW, Kim M, Du Bois J. 2004. Expanding the Scope of C-H Amination through Catalyst Design. J. Am. Chem. Soc.. 126(47):15378-15379. https://doi.org/10.1021/ja0446294

2. Williams Fiori K, Fleming JJ, Du Bois J. 2004. Rh-Catalyzed Amination of Ethereal C-H Bonds: A Versatile Strategy for the Synthesis of Complex Amines. Angew. Chem. Int. Ed.. 43(33):4349-4352. https://doi.org/10.1002/anie.200460791

3. Dauban P, Dodd RH. 2003. Iminoiodanes and C-NBond Formation in Organic Synthesis. Synlett.(11):1571-1586. https://doi.org/10.1055/s-2003-41010

4. Müller P, Fruit C. 2003. Enantioselective Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH Bonds. Chem. Rev.. 103(8):2905-2920. https://doi.org/10.1021/cr020043t

5. Díaz-Requejo MM, Belderraín TR, Nicasio MC, Trofimenko S, Pérez PJ. 2003. Cyclohexane and Benzene Amination by Catalytic Nitrene Insertion into C?H Bonds with the Copper-Homoscorpionate Catalyst TpBr3Cu(NCMe). J. Am. Chem. Soc.. 125(40):12078-12079. https://doi.org/10.1021/ja037072l

6. Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiura S, Kakoi H. 1972. Synthetic studies on tetrodotoxin and related compounds. III. Stereospecific synthesis of an equivalent of acetylated tetrodamine. J. Am. Chem. Soc.. 94(26):9217-9219. https://doi.org/10.1021/ja00781a038

7. Ohyabu N, Nishikawa T, Isobe M. 2003. First Asymmetric Total Synthesis of Tetrodotoxin. J. Am. Chem. Soc.. 125(29):8798-8805. https://doi.org/10.1021/ja0342998

8. Hinman A, Du Bois J. 2003. A Stereoselective Synthesis of (-)-Tetrodotoxin. J. Am. Chem. Soc.. 125(38):11510-11511. https://doi.org/10.1021/ja036830

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