Iron‐Catalyzed Borrowing Hydrogen C‐Alkylation of Oxindoles with Alcohols

Abstract A general and efficient iron‐catalyzed C‐alkylation of oxindoles has been developed. This borrowing hydrogen approach employing a (cyclopentadienone)iron carbonyl complex (2 mol %) exhibited a broad reaction scope, allowing benzylic and simple primary and secondary aliphatic alcohols to be employed as alkylating agents. A variety of oxindoles underwent selective mono‐C3‐alkylation in good‐to‐excellent isolated yields (28 examples, 50–92 % yield, 79 % average yield).


General information
Unless stated otherwise, all reactions were performed using oven-dried 10 mL microwave vials sealed with an aluminium crimp caps, and were stirred with Teflon-coated magnetic stirrer bars. Dry tetrahydrofuran (THF), toluene, hexanes and diethyl ether were obtained after passing these previously degassed solvents through activated alumina columns (Mbraun, SPS-800). All other solvents and commercial reagents were used as supplied without further purification unless stated otherwise. Room temperature (rt) refers to 20-25 °C. Ice/water and CO2(s)/acetone baths were used to obtain temperatures of 0 °C and -78 °C respectively. All reactions involving heating were carried out using DrySyn blocks and a contact thermometer. In vacuo refers to reduced pressure through the use of a rotary evaporator. [Fe] precatalyst 5 1 6 2 7, 3 8, 4 9, 4 and 10 5 were all prepared according to respective procedures in the literature. Analytical thin layer chromatography was carried out using aluminium plates coated with silica (Kieselgel 60 F254 silica) and visualization was achieved using ultraviolet light (254 nm), followed by staining with a 1% aqueous KMnO4 solution. Flash chromatography used Kieselgel 60 silica in the solvent system stated. Melting points were recorded on a Gallenkamp melting point apparatus, and corrected by linear interpolation of melting point standards benzophenone (47-49 ˚C), and benzoic acid (121-123 ˚C). Infrared spectra were recorded on a Shimadzu IRAffinity-1 Fourier Transform ATIR spectrometer as thin films using a Pike MIRacle ATR accessory. Characteristic peaks are quoted (νmax / cm -1 ). 1 H, 13 C, 19 F NMR spectra were obtained on either a Bruker Avance 400 (400 MHz 1 H, 101 MHz 13 C, 376 MHz 19 F) or a Bruker Avance 500 (500 MHz 1 H, 126 MHz 13 C, 471 MHz 19 F) spectrometer at rt in the solvent stated. Chemical shifts are reported in parts per million (ppm) relative to the residual solvent signal. All coupling constants, J, are quoted in Hz. Multiplicities are reported with the following symbols: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and multiples thereof. The abbreviation Ph to denote phenyl, br to denote broad. High resolution mass spectrometry (HRMS, m/z) data was acquired either at Cardiff University on a Micromass LCT spectrometer or at the EPSRC UK National Mass Spectrometry Facility at Swansea University.

Catalyst synthesis
[Fe] precatalyst 3 was prepared via a 3-step synthesis as stated below:

4-hydroxy-2,5-diphenylcyclopent-4-ene-1,3-dione
Under nitrogen, a flame dried Schlenk tube was charged with ethanol (20 mL) and metal sodium (920 mg, 40 mmol) at 0 °C. After complete dissolution, the solution was charged with 1,3-diphenylacetone (4.20 g, 20.0 mmol) and diethyl oxalate (2.70 mL, 2.92 g, 20 mmol). This was left to react at rt for 48 hours. The mixture was cooled to 0 °C and glacial acetic acid was carefully added dropwise until the colour turned yellow-orange. The reaction mixture was then poured into ice/water (100 mL) and the aqueous layer was acidified to pH 1 by careful dropwise addition of concentrated sulfuric acid (96%

Optimization of Fe-catalyzed oxindole C(3)-benzylation
A 10 mL microwave vial equipped with a stirrer bar was charged with oxindole (133 mg, 1.0 mmol), base (x equiv.), additive (x mol %) and precatalyst (x mol %) The vial was sealed with a cap and was placed under vacuum. After 5 minutes it was flushed with nitrogen and the cycle repeated three times. Under nitrogen the vial was then charged with xylene (2 mL) and benzyl alcohol (124 µL, 130 mg, 1.2 mmol, 1.2 equiv.). The mixture was left to react at 150 °C for 24 hours. It was then cooled, followed by the addition of mesitylene (139 µL, 120 mg, 1.0 mmol), H2O (2 mL) and EtOAc (2 mL). In some cases, brine (1 mL) was added to aid layer separation. The mixture was stirred for 5 min, left to settle for a further 5 min, cap removed and the top layer was sampled and analysed using 1 H NMR.

3-benzylindolin-2-one
The title compound was prepared according to general procedure 1 using benzyl alcohol (

3-methylindolin-2-one
The title compound was prepared according to general procedure 2 using methanol (

3-(sec-butyl)indoline
The title compound was prepared according to general procedure 2 using

Mechanistic probe
A 10 mL microwave vial equipped with a stirrer bar was charged with 3-benzylideneindolin-2-one (221 mg, 1.0 mmol), K2CO3 (69.1 mg, 0.5 mmol, 0.5 equiv.), PPh3 (10.5 mg, 0.04 mmol, 4 mol %) and [Fe] precatalyst 3 (9.1 mg, 0.02 mmol, 2 mol %). The vial was sealed with a cap and was placed under vacuum. After 5 minutes it was flushed with nitrogen and the cycle repeated three times. Under nitrogen the vial was then charged with xylene (2 mL) and benzyl alcohol (124 µL, 130 mg, 1.2 mmol, 1.2 equiv.). The mixture was left to react at 150 °C for 24 hours. It was then cooled, followed by the addition of mesitylene (139 µL, 120 mg, 1.0 mmol), H2O (2 mL) and EtOAc (2 mL). Brine (1 mL) was added to aid layer separation. The mixture was stirred for 5 min, left to settle for a further 5 min, cap removed and the top layer was sampled and analysed using 1 H NMR. The result gave a 71% NMR yield of 3-benzylindolin-2-one.