Nonclassical Mechanism in the Cyclodehydration of Diols Catalyzed by a Bifunctional Iridium Complex

Abstract 1,4‐ and 1,5‐diols undergo cyclodehydration upon treatment with cationic N‐heterocyclic carbene (NHC)–IrIII complexes to give tetrahydrofurans and tetrahydropyrans, respectively. The mechanism was investigated, and a metal‐hydride‐driven pathway was proposed for all substrates, except for very electron‐rich ones. This contrasts with the well‐established classical pathways that involve nucleophilic substitution.


General
All reactions were carried out under an atmosphere of argon in oven-dried Biotage® microwave vials unless otherwise specified. Reagents were of analytical grade, obtained from commercial suppliers and used as purchased. Anhydrous toluene and dichloromethane were obtained using a VAC solvent purification system. Flash chromatography was carried out on Davisil 60 Å (35-70 µm) silica gel. Analytical TLC was performed on aluminum plates pre-coated (0-25 mm) 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. Nuclear magnetic resonance (NMR) spectra were recorded at 400 or 500 MHz for 1 H NMR, and at 100 or 125 MHz for 13 C NMR, on a Bruker 400 or on a Bruker AV 500 spectrometer, respectively. 1 H and 13 C NMR chemical shifts (δ) are reported in ppm relative to the residual non-deuterated solvent peaks (Chloroform-d1: δH 7.26 (s) ppm, and δC 77.0 (t) ppm. Acetone-d6: δH 2.05 (quint) ppm, and δC 206.3 (m) and 29.9 (sept) ppm.
The resulting diketone 5 (1 equiv) was added to a flask containing ethanol (95%) in an ice bath at 0 °C. NaBH4 (5 equiv) was added and the mixture was kept stirring at 0 °C for 1 h. After that time, the ice bath was removed and the mixture was stirred at room temperature overnight. Water (40 mL) and aqueous HCl (1 M) were added to the mixture until pH 7 was reached. The resulting aqueous phase was washed with ethyl acetate (3 x 100 mL) and the combined organic phases were dried over MgSO4 and filtered off. The organic solvent was removed under vacuum and the residue was purified by column chromatography using petroleum ether and ethyl acetate (9:1 v/v) as eluent. The yields obtained after the reduction were almost quantitative.

S8
6. General procedure (c) for the synthesis of 1,5-diols 1,5-Diketone 5n is commercially available and was used as received. The synthesis of 1,5-diketone 5m was performed in accordance to a reported procedure. [5] A solution of 1-phenyl-1-trimethylsiloxyethylene (12, 1.1 mmol) in acetonitrile was added to a solution of methyl vinyl ketone (10, 1 mmol) and iodine (0.1 mmol) and stirred at room temperature. After completion of the reaction monitored by TLC, methanol and sodium thiosulfate were added consecutively. The mixture was extracted with ethyl acetate, and the crude product was purified by column chromatography. The corresponding diketone 5 (1 equiv) was added to a flask containing ethanol (95%) in an ice bath at 0 °C. NaBH4 (5 equiv) was added and the mixture was kept stirring at (one diast.)), 1.22 (d, 3 H, J = 6.2 Hz, CH3 (one diast.)).

General procedure (d) for the cyclodehydration of 1,4-and 1,5-diols
A microwave vial impregnated with 1a (0.03 mmol) and flushed with a current of argon was loaded with toluene (2.6 mL), tert-butanol (1 mL) and the corresponding diol (2, 1 mmol). The reaction mixture was stirred and refluxed for 24 h. After completion of the reaction time, the mixture was cooled down and the yield was quantified by 1 H NMR or after purification by column chromatography.
9. Spectral data of synthesized products
The spectroscopic data was in accordance with the data reported in the literature. [13] Yield: 24%

Study of the transient products in the cyclodehydration of diols
When the reactions were run at lower temperatures, the amount of these transient intermediates in the crude reaction mixtures increased. Importantly, upon further heating at higher temperature, they were transformed into the desired final cyclic ethers. Table S2. Effect of the temperature in the cyclodehydration of 2j. [a] entry t (h) 3j' (%) [b] 4j (%) [b] 5j (%) [b] 6j (%) [

Hammett studies
Six parallel reactions were carried out with 1,4-diols 2a-2f following the general procedure for mechanistic studies. The tube was transferred to the NMR spectrometer with the probe preheated at 100 ºC. 1 H NMR spectra were recorded every 2 min. Each experiment was done thrice. Changes in the ratio between the integration of the signals from the protons in the carbon atoms in alpha position to the alcohol moieties in substrates 2a-2f and from the protons in positions C2 and C5 in the tetrahydrofuran products 3a-3f were used to monitor the consumption of substrate. Each experiment was done three times. The results are presented in Figure S1. Scheme S8. Non-competition Hammett studies using diols 2a-2f. Figure S1. Average of non-competitive parallel reaction using diols 2a-2f.

Kinetic isotope effect (KIE)
Deuterated 1,4-diols were synthesized following the general procedure for the reduction of diketones to diols (Section S7, vide supra) using NaBD4. (0.375 mmol) in toluene, and tert-butanol (100 µL) were loaded to an NMR tube impregnated with catalyst 1a. The total reaction volume was adjusted to 400 µL by addition of toluene or toluene-d8. The tube was transferred to the NMR spectrometer with the probe preheated at 100 ºC. 1 H NMR spectra were recorded every 2 min.
Changes in the ratio between the integration of the signals from the terminal methyl groups of diols 2 and tetrahydrofurans 3 were used to monitor the consumption of substrate. Each experiment was done thrice.
The initial rate plots for the experiments with alcohols 2a-d0, 2a-d2 are given in Figure S2. The measurement of the kinetic isotope effect for the cyclodehydration of diols 2a-d0/2 resulted in a KIE value of 2.94 ± 0.14.

S31
The initial rate plots for the experiments with alcohols 2b, 2b-d2 are given in Figure   S3. The measurement of the kinetic isotope effect for the cyclodehydration of diols 2a-d0/2 resulted in a KIE value of 1.14 ± 0.08. Figure S3. Kinetic Isotope Effect for diols 2a-d0/2.

Carbocation trapping experiments with nucleophiles
Our first attempt to trap the envisioned intermediate carbocation within the acid mediated mechanism did not afford any clear conclusion. The addition of a nucleophile, i.e. methanol, indole, pyrrole or N,N-dimethylaniline, to the electron-rich 1,4-diol 2b under the general procedure (d) did only yield the corresponding tetrahydrofuran 3b ( Figure S4- Figure S7). [21] In contrast, methanol and indole succeeded in trapping the positively charged intermediate of the oxidative process of 1-(p-methoxyphenyl)-1-pentanol (13b) yielding the corresponding product 14b as the major product of the reaction ( Figure S8 and Figure S9), being further confirmed by LMRS ( Figure S10).
The disparity in products obtained starting from 2b and 13b could appointed to the quick cyclization (See step ii, Scheme 3b) that the former undergoes and the latter, lacking the second alcohol moiety, does not. A reference experiment using 1-phenyl-1-pentanol (13a) only gave the oxidized product 6a (Figure S11), confirming the difference in the reaction mechanism followed by very electron rich substrates, or mild electron rich and electron poor alcohols.