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

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.

Figure 1

The amino acid phenylglycine (PhG) and some derivatives of interest that contain it.

Figure 2

Pd precursors that have been tested in the halogenation reaction.

Scheme 1

Two-step synthesis of ortho-halogenated phenylglycines (3aa)–(3gc).

Figure 3

Scope of the halogenation reaction.

Scheme 2

Two-step synthesis of ortho-alkoxylated phenylglycines (5aa)–(5ai).

Figure 4

Pd-mediated ortho-alkoxylation of phenylglycines: reaction scope.

Figure 5

Proposed degradation of the methyl ester of phenylglycine.

Figure 6

Structure of the derivative 6. Ellipsoids of non-hydrogen atoms have been drawn at 50% probability.

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

Structure of derivative 7. Ellipsoids of non-hydrogen atoms have been drawn at 50% probability.