Structure and Reactivity of N‐Heterocyclic Alkynyl Hypervalent Iodine Reagents

Abstract Ethynylbenziodoxol(on)e (EBX) cyclic hypervalent iodine reagents have become popular reagents for the alkynylation of radicals and nucleophiles, but only offer limited possibilities for further structure and reactivity fine‐tuning. Herein, the synthesis of new N‐heterocyclic hypervalent iodine reagents with increased structural flexibility based on amide, amidine and sulfoximine scaffolds is reported. Solid‐state structures of the reagents are reported and the analysis of the I−Calkyne bond lengths allowed assessing the trans‐effect of the different substituents. Molecular electrostatic potential (MEP) maps of the reagents, derived from DFT computations, revealed less pronounced σ‐hole regions for sulfonamide‐based compounds. Most reagents reacted well in the alkynylation of β‐ketoesters. The alkynylation of thiols afforded more variable yields, with compounds with a stronger σ‐hole reacting better. In metal‐mediated transformations, the N‐heterocyclic hypervalent iodine reagents gave inferior results when compared to the O‐based EBX reagents.


General methods
All reactions were carried out in oven dried glassware under an atmosphere of nitrogen, unless for the oxidative decarboxylation and if stated otherwise. For flash chromatography, distilled technical grade solvents were used. THF, CH 3 CN, toluene and CH 2 Cl 2 were dried by passage over activated alumina under nitrogen atmosphere (H 2 O content < 10 ppm, Karl-Fischer titration). All chemicals were purchased from Acros, Aldrich, Fluka, VWR, TCI, Merck or Bachem and used as such unless stated otherwise. All dipeptides starting materials were commercially available and used as received. Chromatographic purification was performed as flash chromatography using Macherey-Nagel silica 40-63, 60 Å, using the solvents indicated as eluent with 0.1-0.5 bar pressure. TLC was performed on Merck silica gel 60 F254 TLC aluminum or glass plates and visualized with UV light and KMnO 4 stain. 1 H-NMR spectra were recorded on a Brucker DPX-400 400 MHz spectrometer in chloroform-d, DMSO-d 6 or acetonitrile-d 3 , all signals are reported in ppm with the internal chloroform signal at 7.26 ppm, the internal DMSO signal at 2.50 ppm or the internal acetonitrile signal at 1.94 ppm as standard. The data is being reported as (s = singlet, d = doublet, t= triplet, q = quadruplet, qi = quintet, m = multiplet or unresolved, br = broad signal, app = apparent, coupling constant(s) in Hz, integration, interpretation). 13 C-NMR spectra were recorded with 1 H-decoupling on a Brucker DPX-400 100 MHz spectrometer in chloroform-d, DMSO-d 6 or acetonitrile-d 3 , all signals are reported in ppm with the internal chloroform signal at 77.0 ppm, the internal DMSO signal at 39.5 ppm or the internal acetonitrile signals at 1.32 and 118.26 ppm as standard. Infrared spectra were recorded on a JASCO FT-IR B4100 spectrophotometer with an ATR PRO410-S and a ZnSe prisma and are reported as cm-1 (w = weak, m = medium, s = strong, br = broad).
High resolution mass spectrometric measurements were performed by the mass spectrometry service of ISIC at the EPFL on a MICROMASS (ESI) Q-TOF Ultima API. MS-MS analyses were performed on a LTQ Orbitrap FTMS instrument (LTQ Orbitrap Elite FTMS, Thermo Scientific, Bremen, Germany) operated in the positive mode coupled with a robotic chip-based nano-ESI source (TriVersa Nanomate, Advion Biosciences, Ithaca, NY, U.S.A.). A standard data acquisition and instrument control system was utilized (Thermo Scientific) whereas the ion source was controlled by Chipsoft 8.3.1 software (Advion BioScience). Samples were loaded onto a 96-well plate (Eppendorf, Hamburg, Germany) within an injection volume of 5µl. The experimental conditions for the ionization voltage was +1.4kV and the gas pressure was set at 0.30 psi. The temperature of ion transfer capillary was 275 °C, tube voltages. FTMS spectra were obtained in the 80-1000 m/z range in the reduce profile mode with a resolution set to 120,000. In all spectra one microscan was acquired with a maximum injection time value of 1000ms. Typical CID experiments were carried out using Normalized collision energy values of 26-28 and 5 Da of isolation width.

Versailles instrumentation
NMR spectra were collected on a Bruker AC-300 spectrometer operating at the denoted spectrometer frequency given in MHz for the specified nucleus. Reported coupling constants and chemicals shifts were based on a first order analysis. CFCl 3 (0.00 ppm) was used as internal reference for 19 F NMR spectra. High resolution mass spectrometry (HRMS) was recorded on a Mass Spectrometer XEVO-QTOF in the Institute Lavoisier of Versailles -University of Versailles Saint Quentin.
Photoredox catalyzed reactions were performed in test tubes (5 and 10 mL), which were hold using a rack for test tubes placed at the center of a crystallization flask. On this flask were attached the blue LEDs (RUBAN LED 5MÈTRES -60LED/M -3528 BLEU -IP65 with Transformateur pour Ruban LED 24W/2A/12V, bought directly on RubanLED.com). The distance between the LEDs and the test tubes was approximatively 2 cm for the test tubes and 5 cm for the Schlenk flasks. Long irradiation resulted in temperature increasing up to 37°C during overnight reactions.
HPLC analysis on chiral stationary phase was performed on a Agilent Acquity instrument using a Daicel CHIRALPAK IA, IB-N5 and IC chiral columns. The exact conditions for the analyses are specified within the characterization section. HPLC traces were compared to racemic samples prepared by running the reactions using racemic substrates. Absolute values of enantiomeric excesses are reported.

Preparation of precursors 2-Iodobenzamidine hydrochloride (31)
Following a reported procedure, 1 an oven-dried 250 mL flask was charged with LiHMDS (22 mL, 22 mmol, 1.1 equiv.) and cooled to 0 °C and a solution of 2-iodobenzonitrile (7) (4.6 g, 20 mmol, 1.0 equiv.) in 2.5 mL of dry THF was added dropwise and the reaction mixture was stirred at this temperature for 15 min. The reaction mixture was then stirred at room temperature for 4h. After cooling the reaction mixture to 0 °C, HCl (5 M in isopropanol, 12 mL, 60 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was stirred at 0 °C and let warm up to rt. The precipitated product was filtered, washed with Et 2 O and dry on the filter for 1 h to afford the title compound (31) as a white solid (5.1 g, 18 mmol, 90% yield). 1

2-Iodo-N,N'-ditosylbenzimidamide (9)
Following a slightly modified procedure, 4 an oven-dried 10 mL microwave vial was charged with 2-iodo-N-tosylbenzimidamide (1.5 g, 3.8 mmol, 1.0 equiv) and triethylamine (0.80 mL, 5.6 mmol, 1.5 equiv) and 1.9 mL of dry DCM. After 10mins a solution of p-toluenesulfonyl chloride (1.1 g, 5.6 mmol, 1.50 equiv) and triethylamine (0.80 mL, 5.6 mmol, 1.5 equiv) in 1.9 mL of dry DCM was added dropwise to the reaction mixture. The reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with DCM (10 mL), and the mixture was washed 1M HCL (3X 10 mL). The organic phase was combined with a dichloromethane extract of the aqueous phase, dried (MgSO4), and concentrated under vacuum. The crude mixture was purified by flash column chromatography using DCM/MeOH 2% as mobile phase to afford the title compound as a yellowish solid (9) (1.7 g, 3.1 mmol, 83% yield).

2-Iodobenzylamine (32)
Following a slightly modified procedure, 6 in an oven dried round-bottom flask 2-iodobenzonitrile (5.0 g, 22 mmol, 1.0 equiv.) and dry THF (44 mL) were mixed together, then borane-THF complex (41 ml, 41 mmol, 1.9 equiv.) was added dropwise to the solution at 0 °C. The mixture was refluxed under stirring for 5 h, then it was hydrolyzed at 0 °C with HCl 6 N until pH ~ 1; after, it was made basic with KOH until pH ~ 13 and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO 4 and the solvent was removed under vacuum. The crude mixture was purified by flash column chromatography (DCM to DCM/MeOH 20:1) to afford the title compound as green oil (32) (3.1 g, 13 mmol, 61% yield) Rf = 0.36 (DCM/MeOH 9:1). 1  Following a slightly modified procedure, 6 in an oven dried round-bottom flask 2-iodobenzylamine (1.0 g, 4.3 mmol, 1.0 equiv.) triethylamine (3.3 ml, 24 mmol, 5.5 equiv.) and dry THF (14 mL) were mixed together, then p-toluenesulfonyl chloride (1.1 g, 5.6 mmol, 1.3 equiv.) was added to the solution at 0 °C. The solution was left under stirring overnight at room temperature, then it was extracted with EtOAc. The combined organic phases were washed with H 2 O and brine, dried over MgSO 4 and the solvent was removed under vacuum. The crude mixture was purified by flash column chromatography (Pentane/EtOAc 10:1) to afford the title compound as a white solid (10) (1.6 g, 4.2 mmol, 97% yield). 1

((trifluoromethyl)sulfinyl)benzene (33)
A dry 1 L, three-necked, round-bottomed flask equipped with a thermometer and a mechanical stirrer was charged with sodium trifluoromethanesulfinate (90 g, 0.58 mol, 1.0 equiv.) and dried under vacuum for 24 h prior to use. The flask is placed in a cold-water bath and trifluoromethanesulfonic acid (0.32 L, 3.6 mol, 6.2 equiv.) is added, under argon, in three portions with vigorous stirring (around 100 mL each), in order to keep the temperature under 50 °C. After the addition, the reaction is stirred for 20−30 min until the temperature decreases to room temperature. Then, benzene (90 mL, 1.0 mol, 1.7 equiv.) is added in one portion and the solution is stirred at room temperature for 19 h under an inert atmosphere. The reaction is quenched by pouring the reaction medium on ice (900 g), extracted with dichloromethane (3 × 100 mL), and washed with a saturated solution of NaHCO 3 (3 × 60 mL). The organic phase is dried over MgSO 4 , filtered, and concentrated under reduced pressure. The product is purified by distillation under reduced pressure (78−80 °C at 15 mmHg) to afford the title compound as a colorless oil (33) (78 g, 0.40 mol, 69% yield). The characterization data corresponded to the reported values. 8

(S-(trifluoromethyl)sulfonimidoyl)benzene (12)
In a dry 500 mL two-necked round-bottomed flask equipped with a dropping-funnel and a thermometer, a solution of phenyl trifluoromethyl sulfoxide 33 (40.0 g, 206 mmol, 1.00 equiv.) in dry acetonitrile (120 mL, 2.28 mol, 11.0 equiv.) is cooled to −15 °C under argon. Tf 2 O (52.0 mL, 309 mmol, 1.50 equiv.) is introduced into the dropping-funnel and added dropwise to the solution, keeping the temperature around −15 °C. The solution is then left at −15 °C for 18 h under argon in a freezer. The reaction is quenched by pouring the reaction media on ice (400 g), extracted with dichloromethane (3 × 80 mL), and washed with a saturated solution of NaHCO3 (3 × 40 mL). The organic phase is dried over MgSO 4 , filtered, and concentrated under reduced pressure. To a solution of this crude product in acetonitrile (160 mL) and water (40 mL) is added KMnO 4 (32.6 g, 206 mmol, 1.00 equiv.) portionwise. The reaction is stirred at room temperature for 18 h and diluted with H2O (150 mL), and a saturated solution of Na 2 S 2 O 4 is added until complete discoloration of the solution. The product is extracted with dichloromethane (3 × 70 mL), and the organic phase is dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude product is dissolved in acetonitrile (184 mL), and HCl 6 M (67.2 mL) is added. The reaction is stirred at room temperature for 18 h. Then, water (100 mL) is added and the organic phase is extracted with dichloromethane (3 × 50 mL), washed with a solution of saturated NaHCO3 (3 × 20 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The product is filtered on silica (200 g) using petroleum ether/ethyl acetate 8/2 as eluent to afford the title compound as a white solid (12) (32.8 g, 157 mmol, 76%). The characterization data corresponded to the reported values. 8

Sulfoximines 15, 17a, 17b and 17c
Following a reported procedure, 11 a round bottom flask was charged with sulfide (1.0 equiv.) and MeOH (1 M). PIDA (2.5 equiv.) and ammonium carbamate (2.0 equiv.) were successively added, the flask well closed to maintain an ammoniac atmosphere and the reaction mixture stirred at room temperature for 3h (only 30 min were necessary for the transformation of 14 in 15, and quantity of PIDA and ammonium carbamate could be reduced respectively to 1.5 equiv. and 2.1 equiv. in this case). Chromatography on silica gel (P/EtOAc 1/1) afforded the desired ortho-iodinated sulfoximine as solid. 15, 17a, 17b and 17c were respectively obtained in 60%, 70%, 63% and 60 yield starting from 14, 16a, 16b and 16c respectively.

-benzenesulfonamide (Cl-Ts-BZI, 19)
Following a reported procedure, 13 an oven-dried round-bottom flask equipped with magnetic stirring bar was charged under Ar with solid 2-iodo-N,N'-ditosylbenzimidamide (9) (1.1 g, 2.0 mmol, 1.0 equiv.) and anhydrous MeCN (7.0 mL) was added. The resulting stirred suspension was heated to 75 °C. A solution of trichloroisocyanuric acid (0.19 g, 0.80 mmol, 0.40 equiv, 1.2 equiv. in "Cl") in 1.0 mL of anhydrous MeCN was added dropwise. After addition was complete, the reaction mixture was refluxed for an additional 15 min. The reaction mixture was vacuumfiltered over a sintered-glass funnel and the precipitate was rinsed with additional hot MeCN (10−20 mL), the precipitate was air-dried. . Despite many attempts, the mass of the compound was not found by HRMS.

Reactivity investigation Alkynylation of β-ketoesters
Following a reported procedure, 17 a solution of methyl 1-oxo-2,3-dihydro-1H-indene-2carboxylate (20 mg, 0.10 mmol, 1.0 equiv.) and hypervalent iodine reagent (0.13 mmol, 1.30 equiv.) in dry THF (1.7 mL) was stirred at -78 °C for 5 min under nitrogen. After this period of time, TBAF (0.13 mL, 0.13 mmol, 1.3 equiv.) was added and the mixture was vigorously stirred at -78 °C. The reaction was monitored by TLC analysis (Pentane/EtOAc, 4:1, UV and p-anisaldehyde) and was complete at -78 °C in 1 hour. The reaction was quenched by addition of water at rt and aqueous layer was extracted with DCM. The combined layer were dried over MgSO4 and concentrated under vacuum. The crude mixture was purified by PrepTLC (Pentane/EtOAc 5/1) to afford the title 24 as a yellow oil.

Alkynylation of thiol
Following a reported procedure, 18 a 5 mL microwave vial was charged with a magnetic stir bar, 2-bromobenzenethiol (12 μL, 0.10 mmol, 1.0 equiv.), 1,1,3,3-tetramethylguanidine (13 μL, 0.10 mmol, 1.0 equiv.) and THF (1.0 mL). After stirring the resulting solution for 5 minutes at room temperature, hypervalent iodine reagent (0.10 mmol, 1.0 equiv.) was added as a solid in one portion. The resulting reaction mixture was stirred with an open flask for 5 minutes at room temperature. Next, the mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo. The reaction mixture was purified by PrepTLC using pentane as mobile phase affording 26 as a clear colourless oil.
The 1 H NMR data corresponds to literature data. 18

Single Crystal X-Ray Diffraction for the compound 3
Crystals of the compound 3 were obtained from slow evaporation of a DCM solution.

Single Crystal X-Ray Diffraction for the compound 4
Crystals of the compound 4 were obtained from slow evaporation of a DCM solution.

Single Crystal X-Ray Diffraction for the compound 5
Crystals of the compound 5 were obtained from slow evaporation of a DCM solution.