Branched-Selective Cross-Electrophile Coupling of 2-Alkyl Aziridines and (Hetero)aryl Iodides Using Ti/Ni Catalysis

Abstract

The arylation of 2-alkyl aziridines by nucleophilic ring-opening or transition-metal-catalyzed cross-coupling enables facile access to biologically relevant β-phenethylamine derivatives. However, both approaches largely favor C-C bond formation at the less-substituted carbon of the aziridine, thus enabling access to only linear products. Consequently, despite the attractive bond disconnection that it poses, the synthesis of branched arylated products from 2-alkyl aziridines has remained inaccessible. Herein, we address this long-standing challenge and report the first branched-selective cross-coupling of 2-alkyl aziridines with aryl iodides. This unique selectivity is enabled by a Ti/Ni dual-catalytic system. We demonstrate the robustness of the method by a twofold approach: an additive screening campaign to probe functional group tolerance and a feature-driven substrate scope to study the effect of the local steric and electronic profile of each coupling partner on reactivity. Furthermore, the diversity of this feature-driven substrate scope enabled the generation of predictive reactivity models that guided mechanistic understanding. Mechanistic studies demonstrated that the branched selectivity arises from a Ti^III-induced radical ring-opening of the aziridine.

Figure 1.

Strategies for the arylation of 2-alkyl aziridines.

Figure 2.

Strategies for substrate scope design. DoE = design of experiments.

Figure 3.

Additive screening to probe functional group tolerance. Groupings were determined by the lower value of the yield or additive recovery. Reactions run on 0.075 mmol scale. Yield and additive recovery were determined by GC-FID with dodecane as an internal standard.

Figure 4.

(Hetero)aryl iodide scope (0.4 mmol scale). Unless otherwise noted, isolated yields of the mixture of isomers are reported and are the average of two runs. Aryl iodides are labeled based on clusters A–P in chemical space. Cross-coupled products are labeled based on their cluster or class in chemical space (A-1–P-1, het1–het4). ^a19F NMR yield with an external standard.

Figure 5.

Predicted cross-coupled yields of validation aryl iodides with 1a.

Figure 6.

Alkyl aziridine substrate scope (0.4 mmol scale). Unless otherwise noted, isolated yields of the mixture of isomers are reported and are the average of two runs. ^a1H NMR yield with an external standard. ^bBranched isomer isolated in 67% yield (>20:1). ^cBranched isomer isolated in 74% yield (>20:1). ^dpyridine•HBr (1.0 equiv) used instead of NEt₃•HBr (2 equiv), 3 hours.

Figure 7.

Mechanistic possibilities.

Figure 8.

Mechanistic studies into a Ti^III catalyzed radical ring-opening. Reactions run on 0.1 mmol scale. ^aDetermined by GC-FID with an external standard. ^bDetermined by ¹H NMR with an external standard. All free energy calculations are in kcal/mol, and were calculated at the UM06/Def2TZVP//UM06/6– 31G(d,p) [LanL2DZ] level of theory with an SMD solvation model (THF).

Figure 9.

Proposed mechanism.