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
. 2025 Jan 9;30(2):236.
doi: 10.3390/molecules30020236.

o-Halogenation and -Alkoxylation of Phenylglycine Derivatives by Pd-Mediated C-H Functionalization: Scope and Limitations

Eduardo Laga  1 , Sonia Nieto  1 , Carlos Cativiela  1 , Esteban P Urriolabeitia  1
Affiliations

o-Halogenation and -Alkoxylation of Phenylglycine Derivatives by Pd-Mediated C-H Functionalization: Scope and Limitations

Eduardo Laga et al. Molecules. .

Abstract

Orthopalladated derivatives from substituted phenylglycines [Pd(μ-Cl)(C6H3R1C(R2)(R3)N(R4)2]2 (1) react with halogenating reagents (PhICl2, Br2, I2) (2) to give the corresponding o-halogenated amino acids C6H3(X)R1C(R2)(R3)N(R4)2 (3). The reaction is general and tolerates a variety of functional groups (R1 to R4) at the aryl ring, the Cα, and the N atom. On the other hand, the reaction of [Pd(μ-Cl)(C6H3R1C(R2)(R3)N(R4)2]2 (1) with PhI(OAc)2 in the presence of a variety of alcohols R5OH (4) gives the o-alkoxylated phenylglycines C6H3(OR5)R1C(R2)(R3)N(R4)2 (5), also as a general process. A partial loss of the enantiomeric excess is observed when the starting phenylglycine is enantiomerically pure, this arising from the formation of bridging azavinylidene (6) and imine intermediate species (7), which were characterized by X-ray diffraction methods.

Keywords: C-H bond activation; alkoxylation; amino acids; halogenation; palladium.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The amino acid phenylglycine (PhG) and some derivatives of interest that contain it.
Figure 2
Figure 2
Pd precursors that have been tested in the halogenation reaction.
Scheme 1
Scheme 1
Two-step synthesis of ortho-halogenated phenylglycines (3aa)–(3gc).
Figure 3
Figure 3
Scope of the halogenation reaction.
Scheme 2
Scheme 2
Two-step synthesis of ortho-alkoxylated phenylglycines (5aa)–(5ai).
Figure 4
Figure 4
Pd-mediated ortho-alkoxylation of phenylglycines: reaction scope.
Figure 5
Figure 5
Proposed degradation of the methyl ester of phenylglycine.
Figure 6
Figure 6
Structure of the derivative 6. Ellipsoids of non-hydrogen atoms have been drawn at 50% probability.
Figure 7
Figure 7
Synthesis of 7: stabilization of the imine ligand formed from degradation of ortho-metalated phenylglycine 1a by the chelating acetylacetonate ligand.
Figure 8
Figure 8
Structure of derivative 7. Ellipsoids of non-hydrogen atoms have been drawn at 50% probability.
See this image and copyright information in PMC

References

    1. Guillemard L., Kaplaneris N., Ackermann L., Johansson M.J. Late-stage C–H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 2021;5:522–545. doi: 10.1038/s41570-021-00300-6. - DOI - PubMed
    1. Rogge T., Kaplaneris N., Chatani N., Kim J., Chang S., Punji B., Schafer L.L., Musaev D.G., Wencel-Delord J., Roberts C.A., et al. C–H activation. Nat. Rev. Methods Primers. 2021;1:43. doi: 10.1038/s43586-021-00041-2. - DOI
    1. Dutta U., Maiti S., Bhattacharya T., Maiti D. Arene diversification through distal C(sp2)–H functionalization. Science. 2021;372:eabd5992. doi: 10.1126/science.abd5992. - DOI - PubMed
    1. Lam N.Y.S., Wu K., Yu J.Q. Advancing the Logic of Chemical Synthesis: C–H Activation as Strategic and Tactical Disconnections for C–C Bond Construction. Angew. Chem. Int. Ed. 2021;60:15767–15790. doi: 10.1002/anie.202011901. - DOI - PMC - PubMed
    1. Rej S., Das A., Chatani N. Strategic evolution in transition metal-catalyzed directed C–H bond activation and future directions. Coord. Chem. Rev. 2021;431:213683. doi: 10.1016/j.ccr.2020.213683. - DOI

LinkOut - more resources