Catalytic α-Arylation of Imines Leading to N-Unprotected Indoles and Azaindoles

Abstract

A palladium N-heterocyclic carbene catalyzed methodology for the synthesis of substituted, N-unprotected indoles and azaindoles is reported. The protocol permits access to various, highly substituted members of these classes of compounds. Although two possible reaction pathways (deprotonative and Heck-like) can be proposed, control experiments, supported by computational studies, point toward a deprotonative mechanism being operative.

Scheme 1. Selected Synthetic Approaches Leading to Highly Substituted Heterocycles by α-Arylation or Vinylation Reactions

Figure 1

Intramolecular approach toward the unprotected N-indole scaffold.

Scheme 2. Selection of the Precatalyst

Catalyst loading 5 mol %. Conversion determined by GC analysis. Conditions unless specified otherwise: 0.25 mmol of 1a, 1.1 equiv of NaOtBu, 0.5 mol % of catalyst, 0.125 M in toluene, 110 °C, 16 h.

Scheme 3. Scope of the Reaction: Synthesis of Indoles

Reaction performed on a 10 mmol scale: 10 mmol of 1c, 1.2 equiv of NaOtBu, 0.5 mol % of 3b, 0.125 M in dioxane, 110 °C, 24 h. Conditions unless specified otherwise: 0.25 mmol of 1, 1.1 equiv of NaOtBu, 0.5 mol % or 2.0% of 3b, 0.125 M in dioxane, 110 °C, 4–24 h. Yields are the average of two runs.

Scheme 4. Synthesis of Azaindoles

Conditions: 0.25 mmol of 1a, 1.1 equiv of NaOtBu, 0.5 or 2.0 mol % of 3b, 0.125 M in dioxane, 110 °C, 16–24 h. Yields are the average of two runs.

Scheme 5. (1) Possible Reaction Pathways Involved in This Approach and (2) Their Representation on the Reaction Coordinates

Scheme 6. Further Mechanistic Studies

Scheme 7. Three Additional Reactions Used To Discriminate between Paths A and B