From the bottle: simple iron salts for the efficient synthesis of pyrrolidines via catalytic C–H bond amination

Commercially available iron salts FeX2 are remarkably active catalysts for pyrrolidine formation from organic azides via direct C–H bond amination. With FeI2, amination is fast and selective, (<30 min for 80% yield at 2 mol% loading), TONs up to 370 are reached with just 0.1 mol% catalyst, different functional groups are tolerated, and a variety of C–H bonds were activated.

Data reduction was performed using the CrysAlisPro S2 program. The intensities were corrected for Lorentz and polarization effects, and an absorption correction based on the multi-scan method using SCALE3 ABSPACK in CrysAlisPro S2 was applied.
The structure was solved by direct methods using SHELXT, S3 which revealed the positions of all non-hydrogen atoms of the title compounds. All non-hydrogen atoms were refined anisotropically. H-atoms were assigned in geometrically calculated positions and refined using a riding model where each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its parent atom (1.5 Ueq for methyl groups).
Refinement of the structure was carried out on F 2 using full-matrix least-squares procedures, which minimized the function Σw(Fo 2 -Fc 2 ) 2 . The weighting scheme was based on counting statistics and included a factor to downweight the intense reflections. All calculations were performed using the SHELXL-2014/7 S3 program in OLEX2. S4 Further crystallographic details are compiled in table S3. Crystallographic data for the structure of 1b.HBr has been deposited with the Cambridge Crystallographic Data entre (CCDC) as supplementary publication number 2208587. S4

Substrate synthesis
All the syntheses of substrates 1a-13a have been reported previously, S14 and included here for the sake of convenience and completion.
General procedure Synthesized according to a literature procedure. S5 Corresponding carboxylic acid was dissolved in MeOH and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 16 h and concentrated under reduced pressure. Water was added and the emulsion was extracted with Et2O, washed with brine, dried over Na2SO4, filtered and concentrated to obtain the corresponding ester as the product.
Synthesized according to a literature procedure. S5 In an oven dried Schlenk under an argon atmosphere corresponding ester (1.0 eq) was dissolved in anhydrous Et2O and cooled to 0 °C. A solution of 3.0 M MeMgBr (3.0 eq) in Et2O was added dropwise and the obtained white suspension was stirred for 16 h. The mixture was quenched with concentrated aqueous NH4Cl solution and extracted with Et2O, washed with brine, dried over Na2SO4, filtered and concentrated to obtain the corresponding alcohol as the product.
Synthesized according to a literature procedure. S5 In an oven dried Schlenk under an argon atmosphere corresponding alcohol (1.0 eq) and TMSN3 (1.2 eq) was dissolved in anhydrous C6H6. BF3Et2O (1.2 eq) was added dropwise and the solution was stirred for 16 h. The obtained mixture was quenched with water, extracted with Et2O, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography over SiO2 using hexane as eluent.
All azide products were transferred into a J Young Schlenk, degassed by four freeze-pumpthaw cycles and dried over 4 Å molecular sieves for at least one week before use in catalysis.
Substrate 1a S5 Synthesized according to a literature procedure. S6 4-phenylbutanoic acid (50.0 g; 305 mmol; 1.0 eq) was dissolved in MeOH (500 mL) and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 16 h and concentrated under reduced pressure. Water (100 mL) was added and the emulsion was extracted with Et2O (3x 250 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (52.11 g; 292.4 mmol; 96%).
Synthesized according to a literature procedure. S6 In an oven dried Schlenk under an argon atmosphere methyl 4-phenylbutanoate (52.0 g; 292 mmol; 1.0 eq) was dissolved in anhydrous Et2O (300 mL) and cooled to 0 °C. A solution of 3.0 M MeMgBr (292 mL; 875 mmol; 3.0 eq) in Et2O was added dropwise and the obtained white suspension was stirred for 16 h. The mixture was quenched with concentrated aqueous NH4Cl (200 mL) solution and extracted with Et2O (5x 250 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (38.91 g; 218.3 mmol; 75%).

Substrate 2a
Adjusted from a literature procedure. S7 (4-bromobutyl)benzene (15.00 g; 12.1 mL; 70.4 mmol; 1.0 eq) and NaN3 (13.73 g; 211.2 mmol; 3.0 eq) were dissolved in DMF (250 mL) and stirred for 16 hours at 80 °C. The reaction was allowed to cool to room temperature and H2O (200 mL) was added. The mixture was extracted with Et2O (3x 150 mL), dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash column chromatography over SiO2 using hexane as eluent. The product was obtained as a colorless oil (11.39 g; 65.0 mmol; 92%).

Substrate 3a
Synthesized according to a literature procedure. S8 4-(p-tolyl)butanoic acid (8.00 g; 44.9 mmol; 1.0 eq) was dissolved in MeOH (100 mL) and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 16 h and concentrated under reduced pressure. Water (100 mL) was added and the emulsion was extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (7.80 g; 40.6 mmol; 90%).

Substrate 7a
Synthesized according to a literature procedure. S10 2-methylbenzoic acid (8.00 g; 58.8 mmol; 1.0 eq) was dissolved in MeOH (100 mL) and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 72 h at 60 °C and concentrated under reduced pressure. Water (100 mL) was added and the emulsion was extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (8.14 g; 54.2 mmol; 92%).
Synthesized according to a literature procedure. S10 In an oven dried Schlenk under an argon atmosphere methyl 2-methylbenzoate (8.14 g; 54.2 mmol; 1.0 eq) was dissolved in anhydrous Et2O (200 mL) and cooled to 0 °C. A solution of 3.0 M MeMgBr (54.2 mL; 163 mmol; 3.0 eq) in Et2O was added dropwise and the obtained white suspension was stirred for 16 h. The mixture was quenched with concentrated aqueous NH4Cl (50 mL) solution and extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (7.28 g; 48.5 mmol; 89%).

Substrate 8a
Synthesized according to a literature procedure. S12 5-phenylpentanoic acid (8.00 g; 44.9 mmol; 1.0 eq) was dissolved in MeOH (100 mL) and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 16 h and concentrated under reduced pressure. Water (100 mL) was added and the emulsion was extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (7.92 g; 41.2 mmol; 92%).
Spectral data were consistent with previously reported characterization of the product. S5
Spectral data were consistent with previously reported characterization of the product. S5

Substrate 13a
Synthesized according to a literature procedure. S16 3-cyclohexylpropanoic acid (8.06 g; 51.6 mmol; 1.0 eq) was dissolved in MeOH (100 mL) and 10 drops of concentrated sulphuric acid were added. The solution was stirred for 72 h at 60 °C and concentrated under reduced pressure. Water (100 mL) was added and the emulsion was extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (8.22 g; 48.3 mmol; 94%).
Synthesized according to a literature procedure. S17 In an oven dried Schlenk under an argon atmosphere methyl 3-cyclohexylpropanoate (8.08 g; 47.5 mmol; 1.0 eq) was dissolved in anhydrous Et2O (200 mL) and cooled to 0 °C. A solution of 3.0 M MeMgBr (47.5 mL; 122 mmol; 3.0 eq) in Et2O was added dropwise and the obtained white suspension was stirred for 16 h. The mixture was quenched with concentrated aqueous NH4Cl (50 mL) solution and extracted with Et2O (3x 100 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The product was obtained as a colorless oil (5.67 g; 33.3 mmol; 70%).

General procedure
Inside an argon filled glovebox, the iron catalyst was weighed into a J Young NMR tube. A stock solution of internal standard was made by dissolving 1,3,5-trimethoxybenzene (45.5 mg; 0.0271 mmol) in 1 mL of deuterated solvent. The corresponding azide (25 mmol) was weighed into a vial, to which internal standard stock solution (0.1 mL) and deuterated solvent (0.4 mL) were added. The contents of the vial were transferred into a J Young NMR tube containing the iron catalyst. The NMR tube was taken outside the glovebox and heated in an oil bath ( Figure S1). For analysis, the reaction was exposed to air, by transferring the contents of the NMR tube in a vial and adding pentane (5 mL). This mixture was left for 16 hours after which small amounts of precipitate formed. Part of the solution was decanted and concentrated to dryness to determine the yields by 1 H NMR spectroscopy.

Catalysis with low catalyst loadings
Due to practical reason, it was impossible to weigh the catalyst directly in the NMR tube for 0.5 and 0.1% mol% catalyst loadings. For these experiments, a known amount of FeI2 was mixed in 1.00 g of 1,3,5-trimethoxybenzene and ground with a pestle and mortal until a homogeneous powder was obtained. This stock ''solid'' was used to weigh out small amounts of FeI2 in the NMR tube for catalysis. S18 Figure S2. Evolution of yield over time of the cyclic amine 1b using 5 mol% FeI2 in toluene-d8 at 120 °C.
Yields are most likely underestimated as some of the cyclic amine product binds to the iron complex, making it undetectable in 1 H NMR spectroscopy due to its paramagnetic nature. This caused the highest measured TOF of 60 h -1 to be underestimated as well.

Solvent scope
Since FeI2 dissolves only poorly in toluene, S18 more polar solvents were tested for this transformation. However, either using DMF-d7 or DMSO-d6 at 120 °C fully inhibited C-H amination ( Table S1, entries 1-2), presumably because of the coordinating ability of these solvents, which prevents any substrate binding. On the other hand, using THF-d8 at 100 °C resulted in a modest 10% yield after 30 min, despite its coordinating ability (entry 3). In comparison, using toluene-d8 at 100 °C gave 40% yield after 30 min (entry 4), and 72% at 120 °C (entry 5). A similar drop in activity in THF-d8 was observed in previous work using Fe(HMDS)2. These data therefore indicate a strong preference for non-coordinating solvents, when performing C-H amination with FeI2 or other iron catalysts that lack a sophisticated ligand stabilization.

Effect of additives
Introduction of potential ligands as additives to FeI2 was investigated. Addition of 1 equiv PPh3, under otherwise identical conditions using the model substrate, resulted in a 74% yield of cyclic amine 1b, identical to runs in the absence of additive (Table S2, entries 1-2). Similarly, pyridine exerted no significant influence on the catalytic activity (entry 3). Contrastingly, multidentate ligands such as 2,2'-bipyridine or 2,2';6',2"-terpyridine fully inhibited catalytic activity (entries 4-5). This catalyst poisoning further suggests a homogeneous mode of operation of this catalyst. Performing the catalytic runs with substrate 9a, which only gave trace amounts of 9b in absence of additives, did not show any product formation using PPh3 or pyridine as additive. This shows that addition of simple ligands does not suppress the tentative product inhibition.

Radical trapping
A standard catalytic run was performed using 5 mol% of FeI2 catalyst. After 2 min at 120 °C 50 mol% of (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) was added. The reaction was heated for another 28 min and quenched afterwards. This resulted in a conversion of 14%, significantly lower than without addition of TEMPO ( Figure S2). This indicates a radical type mechanism, as TEMPO inhibits further conversion upon its addition.

Characterization of C-H aminated products
All products were characterized as crude mixtures after catalysis was completed, unless stated otherwise.

Product 1b
Spectral data were consistent with previously reported characterization of the product. S14

Product 8b
Due to low yields and overlapping signals with starting material and side products, not all signals of 8b could be labelled. However, the formation of 8b was confirmed by characteristic signals consistent with previously reported characterization of the product. S14 Due to low yields and overlapping signals with starting material and side products, not all signals of 12b could be labelled. However, the formation of 12b was confirmed by characteristic signals consistent with previously reported characterization of the product. S14

Product 13b
Due to low yields and overlapping signals with starting material and side products, not all signals of 13b could be labelled. However, the formation of 13b was confirmed by characteristic signals consistent with previously reported characterization of the product. S14