On the Role of Pre- and Post-Electron-Transfer Steps in the SmI2/Amine/H2O-Mediated Reduction of Esters: New Mechanistic Insights and Kinetic Studies

The mechanism of the SmI2-mediated reduction of unactivated esters has been studied using a combination of kinetic, radical clocks and reactivity experiments. The kinetic data indicate that all reaction components (SmI2, amine, H2O) are involved in the rate equation and that electron transfer is facilitated by Brønsted base assisted deprotonation of water in the transition state. The use of validated cyclopropyl-containing radical clocks demonstrates that the reaction occurs via fast, reversible first electron transfer, and that the electron transfer from simple Sm(II) complexes to aliphatic esters is rapid. Notably, the mechanistic details presented herein indicate that complexation between SmI2, H2O and amines affords a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride-mediated reductions and as a source of acyl-radical equivalents for C=C bond forming processes.


General Methods/List of Known Compounds
All compounds reported in the manuscript study have been described in literature or are commercially available. Esters were purchased from commercial suppliers or prepared by standard methods. [1][2][3][4][5][6][7][8][9] All experiments involving SmI 2 were performed using standard Schlenk or glovebox techniques under argon or nitrogen atmosphere unless stated otherwise. All solvents were purchased at the highest commercial grade and used as received or after purification by passing through activated alumina columns or distillation from sodium/benzophenone under nitrogen. All solvents were deoxygenated prior to use. All other chemicals were purchased at the highest commercial grade and used as received. Reaction glassware was oven-dried at 140 °C for at least 24 h or flame-dried prior to use, allowed to cool under vacuum and purged with argon (three cycles). Samarium(II) iodide was prepared by standard methods and titrated prior to use. 10-14 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 on Bruker spectrometers at 300, 400 and 500 MHz ( 1 H NMR) and 75, 100 and 125 MHz ( 13 C NMR). All shifts are reported in parts per million (ppm) relative to residual CHCl 3 peak (7.27 and 77.2 ppm, 1 H NMR and 13 C NMR, respectively). All coupling constants (J) are reported in hertz (Hz). Abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad singlet. All flash chromatography was performed using silica gel, 60 Å, 230−400 mesh. TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness. The plates were visualized using a 254 nm ultraviolet lamp or aqueous potassium permanganate solutions. 1 H NMR and 13 C NMR data are given for all compounds in the Supporting Experimental for characterization purposes. 1 H NMR, 13 C NMR, IR and HRMS data are reported for all new compounds.

Intermolecular Competition Experiments
General Procedure. An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide (THF solution, typically 0.20 mmol, 2.0 equiv, 0.10 M) was added followed by Et 3 N (0.33 mL, 24 equiv) and H 2 O (0.043 mL, 24 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown color of the SmI 2 -Et 3 N-H 2 O complex. A preformed solution of two substrates (each 0.10 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred until decolorization to white had occurred. The reaction mixture was diluted with CH 2 Cl 2 (30 mL) and HCl (1 N, 30 mL).

SI-3
The aqueous layer was extracted with CH 2 Cl 2 (3 x 30 mL), the organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated. The sample was analyzed by 1 H NMR (CDCl 3 , 500 MHz) and GC-MS to obtain conversion and yield using internal standard and comparison with authentic samples.

Hammett and Taft Studies
General Procedure. An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.
Samarium(II) iodide (THF solution, typically 0.20 mmol, 2.0 equiv, 0.10 M) was added followed by Et 3 N (0.33 mL, 24 equiv) and H 2 O (0.043 mL, 24 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown color of the SmI 2 -Et 3 N-H 2 O complex. A preformed solution of two substrates (each 0.10 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred until decolorization to white had occurred. The reaction mixture was diluted with CH 2 Cl 2 (30 mL) and HCl (1 N, 30 mL).
The aqueous layer was extracted with CH 2 Cl 2 (3 x 30 mL), the organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated. The sample was analyzed by 1 H NMR (CDCl 3 , 500 MHz) and GC-MS to obtain conversion and yield using internal standard and comparison with authentic samples.           All reactions carried out using standard Schlenk techniques. a Quenched with air after the indicated time. b Determined by 1 H NMR and/or GC-MS of crude reaction mixtures and comparison with authentic samples. c Combined yield of 8-SI and 9-SI. In all entries, 10-SI was not detected (<2.0%). Entry 2, 9-SI, dr = 41:33:15:11; entry 3, 9-SI, dr = 39:32:18:11. 10-SI was not detected in the reaction of 7-SI with limiting Sm(II) (SmI 2 -Et 3 N-H 2 O, 2-24-24 equiv). Standard procedure for reductions using SmI 2 -amine-H 2 O was followed. 1 48 (m, 1 H), 1.66-1.73 (m, 1 H), 1.90-1.97 (m, 1 H) Table SI-7). 1 (Table 7-SI) (k 5-exo = ca. 2.3 x 10 5 s -1 at 25 °C). 15 The relative product distribution obtained in these experiments allows to approximate a bimolecular rate constant for the reduction of acyl-type radicals using Sm(II). [15][16][17][18] The rate constant k SmI2 was estimated as follows: k SmI2 = (red/cycl) x k 5-exo x [SmI 2 ] -1 . [15][16][17][18] In all cases the concentration of SmI 2 was corrected for changing the reaction volumes as indicated in Tables 4-SI to 7-SI. The product distribution was quantified by 1 H NMR and GC-MS analysis of the crude reaction mixtures and comparison with authentic samples. The approximated k SmI2 rate constant as estimated from the results obtained in Table 6-SI using  SI-17 cyclopropyl-containing radical clock 3-SI indicates that the reduction of acyl-type radicals under these reaction conditions is comparable to a unimolecular reaction with k of about 10 8 s -1 . The approximated k SmI2 rate constant as estimated from the results obtained in Table 7-SI using the substituted analogue of 5-exo-cyclohexenyl radical clock 7-SI indicates that the reduction of acyl-type radicals is comparable to a unimolecular reaction with k of about 10 7 s -1 . Overall, these results demonstrate that the reduction of acyl-type radicals with SmI 2amine-H 2 O is remarkably fast (previously, the rate constant of 7 x 10 6 M -1 s -1 was determined for the reduction of primary alkyl iodides with SmI 2 -HMPA complexes, which is a benchmark reaction in this field). [16][17][18] Equally importantly, these results indicate that acyltype radicals generated using SmI 2 -amine-H 2 O can participate in a wide range of crosscoupling reactions with unactivated radical acceptors. 19 Studies in this direction are a subject of current research in our laboratory and these results will be reported shortly.

Reagent Stoichiometry Studies
General Procedure. An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide (THF solution, 0.45 mmol, 4.5 equiv, 0.10 M) was added followed by

SI-22
To determine whether ester hydrolysis contributes to the mechanism of ester reduction using SmI 2 -NaOH-H 2 O under these reaction conditions, the reduction was carried out in the presence of H 2 18 O (Scheme SI-3, see also