An α‐Cyclopropanation of Carbonyl Derivatives by Oxidative Umpolung

Abstract The reactivity of iodine(III) reagents towards nucleophiles is often associated with umpolung and cationic mechanisms. Herein, we report a general process converting a range of ketone derivatives into α‐cyclopropanated ketones by oxidative umpolung. Mechanistic investigation and careful characterization of side products revealed that the reaction follows an unexpected pathway and suggests the intermediacy of non‐classical carbocations.


1) General
Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon. All solvents were distilled from appropriate drying agents prior to use. All reagents were used as received from commercial suppliers unless otherwise stated.
Trifluoromethane sulfonic anhydride (triflic anhydride) was dried over P2O5 and distill under argon prior use. Iodosobenzene was prepared according to the literature. [1] Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminum plates coated with silica gel F254 with 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck and co.). Neat infrared spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer. Wavenumbers (νmax) are reported in cm -1 . Mass spectra were obtained using a Finnigan MAT 8200 or (70 eV) or an Agilent 5973 (70 eV) spectrometer, using electrospray ionization (ESI).
All 1 H NMR and 13 C NMR spectra were recorded using a Bruker AV-400 or AV-600 spectrometer at 300K.
Chemical shifts were given in parts per million (ppm, δ), referenced to the solvent peak of CDCl3, defined at δ = 7.26 ppm ( 1 H-NMR) and δ = 77. . Coupling constants are quoted in Hz (J). 1 H NMR splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q) as they appeared in the spectrum. Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br).

S9
: EtOAc, 100 : 0 → 80 : 20 v/v%) to give the pure compound [ 13 C]-14a as a colorless liquid (yield 361 mg, >95%). [3] The same procedure was used to synthesize the dideuterated compound [D2]-14a with D3CI. However, the deprotection step of the acetal has to be done as quickly as possible (check conversion by TLC) under more dilute conditions (ca. 2 M), since hydrogen/deuterium exchange can take place.

Scheme S 6
To a flame-dried Schlenk flask with a reflux condenser were added Pd(OAc)2 (2.5 mol%) and norbornene (1.1 eq). The flask was evacuated and backfilled with argon 3 times, then toluene (5 M) was added to the flask. To the mixture, the acid chloride (1.0 eq) and triisopropylsilane (1.1 eq) were added and the mixture was stirred at 50 °C for 18 h. After cooling to room temperature, all volatiles were removed under reduced pressure. The product was isolated by silica gel column chromatography (typical eluent -heptanes : EtOAc, 75 : 25 → 50 : 50 v/v%). [13] Procedure G Scheme S 7 Pyridinium chlorochromate (PCC -1.5 eq) was added to a mixture of norbornane-2-methanol (61, 1.0 eq), SiO 2 (20% w/w), MgSO 4 (20% w/w) in CH 2 Cl 2 (0.1 M) and stirred for 12 h at 25 °C. The mixture was filtered over silica gel and then the volatiles were removed under reduced pressure to afford 62 in quantitative yield.
In a flame dried Schlenk, anhydrous THF (0.3 M) was added to Mg chips (3.0 eq). To the mixture, the corresponding aryl bromide (3.0 eq) was added and stirred until full consumption of the magnesium was observed. The Grignard reagent was then added to a solution of 62 in THF (0.1 M) at -78 °C and stirred for 1 h before the temperature was raised to 25 °C and the mixture stirred for an additional 1 h. The S10 reaction was quenched by the addition of an HCl aqueous solution (1 M). The organic layer was then diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4, filtered ad the volatiles removed under reduced pressure. The product 63 was isolated by column chromatography over silica gel. (typical eluent -heptanes : EtOAc, 20 : 80 → 50 : 50 v/v%).

Scheme S 8
SOCl2 (2.5 eq) was added to a solution of norbornane-2-methanol 65 (1.0 eq.), in CH2Cl2 (0.1 M) at 25 °C and stirred for 1 h. The volatiles were then removed under reduced pressure. The residue was dissolved in CH2Cl2 and slowly added to a solution of MeO(Me)NH•HCl (2.0 eq.) and Et3N (4.0 eq.) in CH2Cl2 (0.3 M) at 0 °C. The solution was then stirred for 1.5 h at 25 °C. The reaction was discontinued by the addition of a saturated aqueous solution of NaHCO3 and the organic phase was then washed with brine, dried over MgSO4, filtered and then the volatiles removed under reduced pressure. The product 66 was isolated by column chromatography over silica gel (eluent -heptanes : EtOAc, 90 : 10 → 60 : 40 v/v%).
In a flame dried Schlenk flask, anhydrous THF (0.3 M) was added to Mg chips (3.0 eq.). To the mixture, the corresponding aryl bromide (3.0 eq.) was added and until most of the magnesium had dissolved. The Grignard reagent was then added to a solution of 66 in THF (0.1 M) at -78 °C and stirred for 1 h before the temperature was raised to 0 °C and the mixture stirred for an additional 1 h. The reaction was discontinued by the addition of an HCl aqueous solution (1 M). The organic layer was then diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4, filtered ad the volatiles removed under reduced pressure. The product 54 was isolated by column chromatography over silica gel (typical eluent -heptanes : EtOAc, 20 : 80 → 50 : 50 v/v%). [2] S11 Procedure J (Substrates 17c-17g) Scheme S 9 To a solution of ketone 54 (1.0 eq.) in CH3CN (0.1 M) were added Et3N (1.6 eq.), chlorotrimethylsilane (1.7 eq.) and sodium iodide (1.6 eq) in this order. The reaction mixture was stirred for 14 h at room temperature, then the mixture was diluted with pentane and the organic phase was washed with a saturated aqueous solution of NaHCO3 and brine (100 ml), dried over anhydrous MgSO4, filtered and all the volatiles were removed under reduced pressure. The crude mixture was purified by flash column chromatography over silica gel eluent affording product 17a -h (typical eluent -pentane : toluene, 67 : 33 → 50 : 50 v/v%). [14] Procedure K (Substrates 17a-b, 17h) Trimethylsilyl trifluoromethanesulfonate (6.5 eq.) was added to a solution of the ketone (1.0 eq.) and Et3N (10.0 eq.) in CH2Cl2 (0.7 M) at 0 °C. The mixture was stirred at 0 °C for 2.5 h and then at 24 °C for 3 h.
The reaction was discontinued by addition of a saturated aqueous solution of NaHCO3 solution. The resultant mixture was diluted with EtOAc to give a biphasic solution. The organic layer was collected, washed with H2O and brine, dried over Na2SO4, and concentrated to crude. The product was isolated by flash column chromatography over silica gel (typical eluent -pentane : toluene, 67 : 33 → 50 : 50 v/v%). [14] 3) Experimental section

Scheme S 10
Iodosobenzene (1.2 eq., 0.24 mmol, 52.8 mg) was dispersed in CH2Cl2 (2 mL) and methanesulfonic acid was added (1.3 eq., 0.26 mmol, 16.9 µL), forming a clear yellow solution. The mixture was cooled to S12 -78 °C, resulting in a less clear solution (precipitation). BF3•OEt2 (1.5 eq., 0.30 mmol, 37 µL) was added and the solution became clear again with simultaneous intensifying of the yellow color. The mixture was stirred for 15 min at the same temperature before the silyl enol ether (1.0 eq., 2.0 mmol) was added quickly at once. Alternatively, the substrate can be added as a CH2Cl2 solution leading to the same results.
The reaction changed color immediately (usually to brown, depending on the substrate) and a precipitate can be observed. After stirring for further 15 min, the flask was removed from the cooling-bath and reactive species were immediately quenched by the addition of H2O (ca. 4 mL) and diluted with CH2Cl2 (ca. 4 mL). The mixture was transferred to a separatory funnel and the aqueous phase was extracted with CH2Cl2 (3x), and the combined organic layers were dried over Na2SO4 and filtered. After removal of the volatiles under reduced pressure, the crude material was purified by column chromatography (typical eluent -heptanes : EtOAc, 90 : 10 → 50 : 50 v/v%) to give the pure cyclopropane. In most cases, the product was eluted when the eluent was composed as follows: heptanes : EtOAc, 75 : 25 v/v%.
The mixture was cooled to -78 °C. Then, the silyl enol ether (1.0 eq., 2.0 mmol, 46.5 mg) was added quickly at once. Alternatively, the substrate can be added as a CH2Cl2 solution leading to the same results. The reaction changed color immediately (usually to brown, depending on the substrate) and a precipitate can be observed. After stirring for 5 min, the nucleophile was added (see characterization section for more details) and the reaction was stirred for further 10 min at -78 °C. Then the reaction was warmed up to room temperature and stirred for an additional 10 min. Reactive species and excess of Lewis acid were quenched with H2O (ca. 4 mL), the reaction mixture was diluted with CH2Cl2 (ca. 4 mL) and transferred to a separatory funnel. The aqueous phase was extracted with CH2Cl2 (3x), and the combined organic layer was dried over Na2SO4 and filtered. After removal of the volatiles under reduced pressure, the crude material was purified by column chromatography (typical eluent -heptanes : EtOAc, 90 : 10 → 50 : 50 v/v%) to give the pure cyclopropane.
Once all components had gone into solution, the mixture was cooled -78 °C and the corresponding silyl enol ether 17 (1.0 eq., 0.30 mmol) was added. The solution was stirred for 10 min at -78 °C and then 10 min at 25 °C. Reactive species and excess of Lewis acid were quenched by the addition of a saturated aqueous solution of NaHCO3, diluted with EtOAc and the organic phase washed with a saturated aqueous solution of NaCl. The organic phase was then dried over anhydrous MgSO4, filtered and all the volatiles removed under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (typical eluent -heptanes : EtOAc, 83 : 17 → 50 : 50 v/v%) to afford the desired product 19a -h.

Scheme S 13
To a solution of amide 34a -d (1.0 eq.0.25 mmol) and 2-iodopyridine (2.2 eq., 0.55 mmol) in CH2Cl2 (2 mL, 0.1 M) at 0 °C was added trifluoromethanesulfonic anhydride (1.1 eq., 0.27 mmol, 46.3 µL) and the resulting solution was stirred at 0 °C for 15 min. Pyridine N-oxide (1.5 eq., 0.37 mmol) was added in one portion and the reaction solution was stirred at 0 °C for 5 min. The solution was then allowed to warm up to ambient temperature (25 °C) over the course of 2 h, after which time a saturated aqueous solution of NaHCO3 was added. The biphasic mixture was separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (typical eluent -heptanes : EtOAc, 90 : 10 → 50 : 50 v/v%) to afford the desired product.  1446,1334,1302,1279,1251,1117,1074,1040,1020,993,948,900,869,839,754,695,635, 526 cm -1 .

S104
Platon vii for symmetry check. Experimental data and CCDC-Codes Experimental data and CCDC-Code (Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html) can be found in Table   S1. Crystal data, data collection parameters, and structure refinement details are given in Tables S2 to S3. Crystal structure and packing view are visualized in Figure S3 to S4.