Unraveling the Mechanism of the IrIII‐Catalyzed Regiospecific Synthesis of α‐Chlorocarbonyl Compounds from Allylic Alcohols

Abstract We have used experimental studies and DFT calculations to investigate the IrIII‐catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization–chlorination of allylic alcohols into α‐chlorinated carbonyl compounds. The mechanism involves a hydride elimination followed by a migratory insertion step that may take place at Cβ but also at Cα with a small energy‐barrier difference of 1.8 kcal mol−1. After a protonation step, calculations show that the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization–chlorination reaction, calculations show that the chlorination step takes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations.


General information
All reagents were used as obtained from commercial sources without further purification. Flash chromatography was performed with 60 Å (35-70 µm) silica gel (GC 60A 35-70 Micron, DAVISIL) using mixtures pentane / EtOAc as eluent. Analytical TLC was performed on aluminum plates precoated with silica gel (Merck, Silica Gel 60 F254). Compounds were detected by exposure to UV light or by revealing the plates in a solution of 5% KMnO4 in water. 1 H and 13 C NMR spectra were recorded at 400 or 500 MHz and 100 or 125 MHz respectively on Bruker Advance spectrometers. Chemical shifts (δ) are shown in ppm, using the residual peaks of CH(D)Cl3 (δH 7.26 and δC 77.00) as reference. Coupling constants (J) are given in Hz. High-resolution mass spectra (HRMS) were recorded on Bruker microTOF ESI-TOF mass spectrometer.

General procedure for the isomerization of allylic alcohols
To a solution of the allylic alcohol 1 (0.2 mmol, 1 equiv.) in a mixture of acetone and H2O (2:1, 0.1 M), [Cp*IrCl2]2 (4 mg, 2.5 mol%) was added. The resulting mixture was stirred at room temperature and monitored by TLC. When the reaction was completed, EtOAc (10 mL) and H2O (10 mL) were added to the mixture and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduce pressure. The crude was purified by flash chromatography affording the corresponding carbonyl compound 2.

General procedure for the isomerization / chlorination of allylic alcohols
To a solution of the allylic alcohol 1 (0.2 mmol, 1 equiv.) and N-chlorosuccinimide (32 mg, 0.24 mmol, 1.2 equiv.) in a mixture of acetone and H2O (2:1, 0.1 M), [Cp*IrCl2]2 (4 mg, 2.5 mol%) was added. The resulting mixture was stirred at room temperature and monitored by TLC. When the reaction was completed, EtOAc (10 mL) and H2O (10 mL) were added to the mixture and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduce pressure. The crude was purified by flash chromatography affording the corresponding a-chlorocarbonyl compound.

Reaction profile of the Ir(III) catalyzed isomerization and isomerization-chlorination of allylic alcohol 1b
The mechanism of the Ir-catalyzed isomerization and isomerization-chlorination of 1,2-disubstituted allylic alcohol 1b was also investigated by DFT calculations. The calculated Gibbs energy profile is depicted in Figure S5 and the corresponding optimized structures are given in Figure S6.

Reaction profile of the Ir(III) catalyzed isomerization and isomerization-chlorination of allylic alcohol 1e in acetone
The iridium-catalyzed isomerization and isomerization-chlorination of 1e were also investigated in pure acetone solvent. The obtained mechanism is summarized in Scheme S4 and the calculated Gibbs energy profile is given in Figure S7. Additional results are shown in Figures S8.

Scheme S4.
Catalytic cycle for iridium-catalyzed isomerization and isomerization-chlorination of 1e in acetone. Figure S7. Calculated Gibbs energy profile (kcal/mol) for the iridium-catalyzed isomerization and isomerization-chlorination of 1e in acetone.     Note that 1b-TS6a, TS7-ClPA,and TS7-2 are marked with an asterisk (*) in Figures S5, S8, and S10. These geometries have one additional imaginary frequency each (<11 cm -1 ). Many attempts were made to eliminate these frequencies without success. It was therefore replaced by a real frequency of the same magnitude in the RRHO calculations. Experience of similar cases shows that the error bar of this treatment rather small.

S30
Calculated absolute energies and energy corrections.