Dative Directing Group Effects in Ti-Catalyzed [2+2+1] Pyrrole Synthesis: Chemo- and Regioselective Alkyne Heterocoupling

Abstract

Transient dative substrate-Ti interactions have been found to play a key role in controlling the regioselectivity of alkyne insertion and [2+2] cycloaddition in Ti-catalyzed [2+2+1] pyrrole synthesis and Ti-catalyzed alkyne hydroamination. TMS-protected alkynes with pendent Lewis basic groups can invert the regioselectivity of TMS-protected alkyne insertion, leading to the selective formation of highly substituted 3-TMS pyrroles. The competency of various potential directing groups was investigated, and it was found that the directing-group effect can be tuned by modifying the catalyst Lewis acidity, the directing-group basicity, or the directing-group tether length. Dative directing-group effects are unexplored with Ti catalysts, and this study demonstrates the potential power of dative substrate-Ti interactions in tuning selectivity.

Synthesis of pentasubstituted 2-aryl pyrroles from boryl and stannyl alkynes via one-pot sequential Ti-catalyzed [2 + 2 + 1] pyrrole synthesis/cross coupling reactions

“…This leads us to speculate that oxophilic Ti may be transmetallating or otherwise reacting with the Bpin B-O bonds. 24 Further optimization attempts with Bpin-substituted alkynes were unsuccessful ( Fig. S11 †).…”

Synthesis of Pentasubstituted 2-Aryl Pyrroles from Boryl and Stannyl Alkynes via One-Pot Sequential Ti-Catalyzed [2+2+1] Pyrrole Synthesis/Cross Coupling Reactions

“…Additionally, there was obvious decomposition of the Bpin moiety, leading us to speculate that oxophilic Ti may be transmetallating or otherwise reacting with the Bpin B-O bonds. 19 Further optimization attempts with Bpin-substituted alkynes were unsuccessful ( Figure S11). Thus, we next examined PhCC-BBN×THF (1a-BBN) ( Table 1, entry 2).…”

“…GC chromatographs were collected on Agilent 7890B GC system equipped with the HP-5 column (30 m, 0.32 mm, 0.25 µm, 7 inch cage), an oxidation-methanation reactor (Polyarc ® System, Activated Research Company), and a FID detector for quantitative carbon detection. 7,8 1 H, 11 B, 13 C{ 1 H}, 19 F{ 1 H}, 119 Sn{ 1 H}, 1 H- 13 C and 1 H- 15 N HMBC, NOESY, and No-D 1 H NMR were collected on Bruker Avance III HD NanoBay 400 MHz or Bruker Avance III HD 500 MHz spectrometers. Chemical shifts are reported with respect to residual protio-solvent impurity for 1 H (s, 7.26 ppm for CDCl3; s, 7.16 ppm for C6D6) and 13 C (t, 77.16 ppm for CDCl3; t, 128.06 ppm for C6D6).…”

“…The peak area of selected 1 H NMR peaks were calculated by Gaussian-Lorentzian fitting to omit the influence from minor baseline overlapping. 19 Catalytic Reaction of 1a-BBN Figure S37. 1 Sample yield calculation based on 1 H NMR peak area:…”

“…The peak area of selected 1 H NMR peaks were calculated by Gaussian-Lorentzian fitting to omit the influence from minor baseline overlapping. 19 Precaution: Trialkyltin species are highly toxic. Proper PPE is required.…”