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

Overview

Journal Molecules

Publisher MDPI

Date 2025 Jan 25

PMID 39860106

Authors

Eduardo Laga

Sonia Nieto

Carlos Cativiela

Esteban P Urriolabeitia

Affiliations

Soon will be listed here.

Abstract

Orthopalladated derivatives from substituted phenylglycines [Pd(μ-Cl)(CHRC(R)(R)N(R)] () react with halogenating reagents (PhICl, Br, I) () to give the corresponding o-halogenated amino acids CH(X)RC(R)(R)N(R) (). The reaction is general and tolerates a variety of functional groups (R to R) at the aryl ring, the Cα, and the N atom. On the other hand, the reaction of [Pd(μ-Cl)(CHRC(R)(R)N(R)] () with PhI(OAc) in the presence of a variety of alcohols ROH () gives the o-alkoxylated phenylglycines CH(OR)RC(R)(R)N(R) (), 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 () and imine intermediate species (), which were characterized by X-ray diffraction methods.

References

Liu B, Romine A, Rubel C, Engle K, Shi B . Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp)-H Bonds. Chem Rev. 2021; 121(24):14957-15074. PMC: 8968411. DOI: 10.1021/acs.chemrev.1c00519. View

Laga E, Garcia-Montero A, Sayago F, Soler T, Moncho S, Cativiela C . Cyclopalladation and reactivity of amino esters through C-H bond activation: experimental, kinetic, and density functional theory mechanistic studies. Chemistry. 2013; 19(51):17398-412. DOI: 10.1002/chem.201302693. View

Higham J, Ma T, Bull J . When is an Imine Directing Group a Transient Imine Directing Group in C-H Functionalization?. Chemistry. 2024; 30(25):e202400345. DOI: 10.1002/chem.202400345. View

Holmberg-Douglas N, Nicewicz D . Photoredox-Catalyzed C-H Functionalization Reactions. Chem Rev. 2021; 122(2):1925-2016. PMC: 8939264. DOI: 10.1021/acs.chemrev.1c00311. View

Albert J, Cadena J, Gonzalez A, Granell J, Solans X, Font-Bardia M . The first NH aldimine organometallic compound. Isolation and crystal structure. Chem Commun (Camb). 2003; (4):528-9. DOI: 10.1039/b211808d. View

Mortell K, Anderson D, Lynch 3rd J, Nelson S, Sarris K, McDonald H . Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels. Bioorg Med Chem Lett. 2005; 16(5):1138-41. DOI: 10.1016/j.bmcl.2005.11.108. View

Albert J, Cadena J, Gonzalez A, Granell J, Solans X, Font-Bardia M . Deamination of the amino acid fragment in imine metallacycles: unexpected synthesis of an NH-aldimine organometallic compound. Chemistry. 2005; 12(3):887-94. DOI: 10.1002/chem.200500099. View

Sheldrick G . Crystal structure refinement with SHELXL. Acta Crystallogr C Struct Chem. 2015; 71(Pt 1):3-8. PMC: 4294323. DOI: 10.1107/S2053229614024218. View

He G, Wang B, Nack W, Chen G . Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp(3) C-H Functionalization. Acc Chem Res. 2016; 49(4):635-45. DOI: 10.1021/acs.accounts.6b00022. View

10.

Organ M, Ghasemi H . Metal-catalyzed coupling reactions on an olefin template: the total synthesis of (13E,15E,18Z,20Z)-1-hydroxypentacosa- 13,15,18,20-tetraen-11-yn-4-one 1-acetate. J Org Chem. 2004; 69(3):695-700. DOI: 10.1021/jo035376k. View

11.

Sheldrick G . A short history of SHELX. Acta Crystallogr A. 2007; 64(Pt 1):112-22. DOI: 10.1107/S0108767307043930. View

12.

Terrey M, Holmes A, Perry C, Cross W . C-H Olefination of Tryptophan Residues in Peptides: Control of Residue Selectivity and Peptide-Amino Acid Cross-linking. Org Lett. 2019; 21(19):7902-7907. DOI: 10.1021/acs.orglett.9b02894. View

13.

Wu K, Lam N, Strassfeld D, Fan Z, Qiao J, Liu T . Palladium (II)-Catalyzed C-H Activation with Bifunctional Ligands: From Curiosity to Industrialization. Angew Chem Int Ed Engl. 2024; 63(19):e202400509. PMC: 11216193. DOI: 10.1002/anie.202400509. View

14.

Kinsinger T, Kazmaier U . C-H Functionalization of N-Methylated Amino Acids and Peptides as Tool in Natural Product Synthesis: Synthesis of Abyssenine A and Mucronine E. Org Lett. 2018; 20(23):7726-7730. DOI: 10.1021/acs.orglett.8b03475. View

15.

Wang Y, Dana S, Long H, Xu Y, Li Y, Kaplaneris N . Electrochemical Late-Stage Functionalization. Chem Rev. 2023; 123(19):11269-11335. PMC: 10571048. DOI: 10.1021/acs.chemrev.3c00158. View

16.

Bellotti P, Huang H, Faber T, Glorius F . Photocatalytic Late-Stage C-H Functionalization. Chem Rev. 2023; 123(8):4237-4352. DOI: 10.1021/acs.chemrev.2c00478. View

17.

Xiao K, Chu L, Yu J . Enantioselective C-H Olefination of α-Hydroxy and α-Amino Phenylacetic Acids by Kinetic Resolution. Angew Chem Int Ed Engl. 2016; 55(8):2856-60. PMC: 4899946. DOI: 10.1002/anie.201510808. View

18.

Lam N, Wu K, Yu J . Advancing the Logic of Chemical Synthesis: C-H Activation as Strategic and Tactical Disconnections for C-C Bond Construction. Angew Chem Int Ed Engl. 2020; 60(29):15767-15790. PMC: 8177825. DOI: 10.1002/anie.202011901. View

19.

Zhu C, Ang N, Meyer T, Qiu Y, Ackermann L . Organic Electrochemistry: Molecular Syntheses with Potential. ACS Cent Sci. 2021; 7(3):415-431. PMC: 8006177. DOI: 10.1021/acscentsci.0c01532. View

20.

Hernandez J . C-H Bond Functionalization by Mechanochemistry. Chemistry. 2017; 23(68):17157-17165. DOI: 10.1002/chem.201703605. View