Aryne-Enabled C-N Arylation of Anilines

Abstract

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C-N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C-N bond.

Keywords: C−N arylation; Smiles rearrangement; aniline; aryne; biaryl synthesis.

Figure 1

(a) Examples of pharmaceutically and industrially important aniline‐containing molecules. (b) Pre‐functionalization strategies for C−N bond functionalization. (c) Prospective in situ arylation of aniline C−N bond. (d) Aryne‐enabled C−N functionalization of electron‐poor anilines. (d) Precedent for four membered transition state in aryne σ‐insertion chemistry.

Figure 2

Scope of the transformation. Reactions performed on a 0.2 mmol scale, using 3.0 equivalents of aniline, isolated yields. NMR yields (nitromethane as internal standard) in parentheses. [a] 0.1 mmol scale, [b] 1.0 eq. aniline, [c] 2.0 eq. aniline. [d] Conditions: Fe_(s), NH₄Cl (aq), MeOH, 50 °C, 16 h.

Figure 3

Scope of the aryne. Reactions performed on a 0.2 mmol scale, using 3 equivalents of aniline, isolated yields. NMR yields in parentheses. Filled circles represent site of substituent in minor regiosiomer. [a] 0.1 mmol scale.

Figure 4

^a Aryne‐enabled ring expansion. ^b C−N arylation of drug derivatives. Reactions performed on a 0.2 mmol scale, using 3 equivalents of aniline, isolated yields. NMR yields (nitromethane as internal standard) in parentheses.

Figure 5

Mechanistic investigations. (a) Probing the protodemethylation pathway. (b) Benzyne precursor alteration (NMR yield, using 1,3,5‐trimethoxybenzene as internal standard). (c) Proposed mechanism.