C–H Amination

Product Manager：Nick Wilde

The Du Bois group at Stanford University has achieved significant advancements in Rh-catalyzed C–H amination through oxidative cyclization of carbamate, sulfamate, sulfamide, urea, and guanidine substrates. This methodology produces 1,2- and 1,3-heteroatom motifs masked within 5- and 6-membered ring heterocycles (Scheme 1). 1-8 The cyclization exhibits high stereospecificity, particularly beneficial for optically active substrates.

Scheme 1

Moreover, heterocyclic ureas and guanidines are present as structural components in pharmacologically significant compounds, including NK1 receptor antagonists, various toxins, and bromopyrrole metabolites (Figure 1).3,8

Figure 1

Various Rh-carboxylate catalysts demonstrate at least some degree of effectiveness in promoting the cyclization of ureas and guanidines. However, the most notable results are obtained using catalytic Rh2(esp)2 in conjunction with substrates that possess 2,2,2-trichloroethoxysulfonyl (Tces) protection on the nitrogen. The incorporation of the urea or guanidine group, followed by cyclization, can be achieved using several different reagents as depicted in Schemes 2-6.3 The Mitsunobu reaction between an alcohol and Tces-protected urea generates the cyclization precursor with high efficiency (Scheme 2). Treating this precursor with Rh2(esp)2, in the presence of PhI(OAc)2 and MgO, yields the cyclized product in good to excellent yields, especially for substrates with tertiary or benzylic β-C-H centers (Scheme 3).

Scheme 2

Scheme 3

Tces-protected guanidines can be conveniently synthesized by reacting an amine with either of two reagents derived from S,S-dimethyl-N-(2,2,2-trichloroethoxysulfonyl)carbonimidodithionate (Scheme 4).

Scheme 4

The isothiourea reacts with most primary amines in water at 100°C to produce the Tces-protected guanidine derivative (Scheme 5). Alternatively, more functionalized amines can be reacted with the carbonchloroimidodithioate reagent to form an intermediate pseudothiourea, which can then be converted into the desired guanidine using HMDS as the ammonia source.

Scheme 5

When subjected to standard oxidative cyclization conditions, these Tces-protected guanidines yield the cyclized products in good yield (Scheme 6). Similar to the urea cyclizations, this reaction is particularly effective for substrates with tertiary or benzylic β-C-H centers. The protecting group can be efficiently removed using zinc metal and methanolic acetic acid, resulting in high yields.

Scheme 6

References

1.2006. A Synthesis of (+)-Saxitoxin. J. Am. Chem. Soc.. 128(12):3926-3927. https://doi.org/10.1021/ja0608545

2.Fleming JJ, Du Bois J. 2006. A Synthesis of (+)-Saxitoxin. J. Am. Chem. Soc.. 128(12):3926-3927. https://doi.org/10.1021/ja0608545

3.Kim M, Mulcahy JV, Espino CG, Du Bois J. 2006. Expanding the Substrate Scope for C-H Amination Reactions: Oxidative Cyclization of Urea and Guanidine Derivatives. Org. Lett.. 8(6):1073-1076. https://doi.org/10.1021/ol052920y

4.Wehn PM, Du Bois J. 2005. Exploring New Uses for C-H Amination: Ni-Catalyzed Cross-Coupling of Cyclic Sulfamates. Org. Lett.. 7(21):4685-4688. https://doi.org/10.1021/ol051896l

5.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

6.Williams Fiori K, Fleming JJ, Du Bois J. 2004. Rh-Catalyzed Amination of Ethereal Cα-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

7.Wehn PM, Lee J, Du Bois J. 2003. Stereochemical Models for Rh-Catalyzed Amination Reactions of Chiral Sulfamates. Org. Lett.. 5(25):4823-4826. https://doi.org/10.1021/ol035776u

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/ja0368305

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