N‐Trifluoromethyl Hydrazines, Indoles and Their Derivatives

Abstract Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N‐CF3 hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri‐ and tetra‐substituted N‐CF3 hydrazines, hydrazones, sulfonyl hydrazines, and valuable N‐CF3 indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF3)‐NH2 to function as a directing group in C−H functionalization is also showcased.


Techniques
All reactions were performed without any precaution for moisture and oxygen unless stated otherwise. Silver fluoride was stored and weighed inside a glovebox before being brought outside to set up reactions. Liquid reagents, solutions or solvents were added via syringe. Unless otherwise stated, experiments were carried out at room temperature (23 ± 2 °C). The removal of solvents in vacuo was achieved using a rotary evaporator (bath temperatures up to 40 °C) at a pressure of 20 mmHg (diaphragm pump), or at 0.1 mmHg (oil pump) on a vacuum line at room temperature.

Reagents and solvents
Commercially available solvents and reagents were used directly as supplied without further purification. Acetonitrile was bought from Fischer Scientific. BTC was purchased from TCI, silver fluoride was purchased from Fluorochem [i.e. ChemPUR in Germany]. 3-Iodophenyl isothiocyanate, and all anilines were commercially available and used as received. All anhydrous solvents were either purchased from Aldrich or dried using a solvent purification system (Innovative Technology PS-MD-5).

Note on Silver fluoride
We observed significant variation of the quality of silver fluoride depending on batches. Based on our tests silver fluoride of lower quality will convert isothiocyanates to carbamic fluorides but might require heating at 50°C and may affect the overall yield and quality. While optimum silver fluoride which we used in previous reports [1] and the current, should be bright orange and a loose powder with some aggregates (left). Lower quality silver fluoride shows a rough appearance and various colors including darker orange (right).

Purification
Column chromatography was performed on Merck silica gel 60 (35 to 70 mesh). Thin layer chromatography was performed on Macherey-Nagel ALUGRAM® Xtra SIL G/UV254 plates with unmodified silica and visualized either under UV light or stained with vanillin, PMA, ceric ammonium molybdate or ninhydrin.

Reaction
Microwave reactions were carried in a CEM Discover model 909155 using 10 mL reaction vessels.
Temperature was controlled via infrared probe and the pressure release limit was set to 5 bars. Characterization All compounds were characterized by NMR ( 1 H, 13 C and 19 F when applicable), high resolution mass spectrometry (if susceptible to ionization) and FT-IR. 1 H, 13 C and 19 F NMR spectra were recorded on either a Varian VNMRS 600, Varian VNMRS 400 or Varian Mercury 300 spectrometer. Spectra were recorded at ambient temperature in CDCl3 (unless stated otherwise).
Chemical shifts are reported in ppm, relative to residual solvent peaks and coupling constants J in Hertz (Hz). Signals are described as br = broad, s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, qn = quintet, sext = sextet, sept = septet, dsept = doublet of septets and m = multiplet. High-resolution mass spectrometry was performed on a Thermo Scientific LTQ Orbitrap XL spectrometer or on a Finnigan SSQ 7000, EI: 70 eV (EI). Gas chromatography coupled with mass spectrometry (GC-MS) analyses were performed using an Agilent Technologies 5975 series MSD mass spectrometer coupled with an Agilent Technologies 7820A gas chromatograph (with an Agilent 19091s-433 HP-SMS column (30 m x 0.250 µm x 0.25 µm)). The molecular ion

Experimental section
General procedure for the synthesis of N-CF3 carbamoyl azides A 4 mL vial was charged with the carbamic fluoride (1 mmol, 1 equiv.) THF (1.25 mL) and sodium azide (78 mg, 1.2 mmol, 1.2 equiv.). The suspension was stirred for 16 h at room temperature. The suspension was then filtered over 1 cm of celite in a glass pipette and rinsed with 500 µL of THF. The combined filtrates were concentrated in vacuo to afford the pure carbamoyl azide.   General procedure for the synthesis of N-CF3 hydrazines A 4 mL vial was charged with the carbamic fluoride (1 mmol, 1 equiv.) THF (1.25 mL) and sodium azide (78 mg, 1.2 mmol, 1.2 equiv.). The suspension was stirred for 16 h at room temperature. The suspension was then filtered over 1 cm of celite in a glass pipette and rinsed with 500 µL of THF directly into a 10 mL microwave reaction vessel. To the carbamoyl azide solution was added water (500 µL) and THF (2.5 mL) and the vessel was sealed. This solution was heated under stirring and microwave irradiation at 100 °C for the indicated time. The aqueous phase was then removed and extracted with CH2Cl2. The combined organic phases were adsorbed onto celite and purified by column chromatography on silica gel using the indicated solvent system.

General procedure for C-H activation using N-CF3 hydrazine as a directing group
In an argon-filled glovebox a vial was loaded with [RhCp*Cl2]2 (2.4 mg, 2 mol%) and AgSbF6 (5.6 mg, 8 mol%). It was brought outside and a solution of the hydrazine (0.2 mmol, 1 equiv.) in MeOH (600 L) was added followed by acetic acid (14 μL, 1.2 equiv.) and the electrophile (2 equiv.). The reaction mixture was sealed and stirred under the exclusion of light (vial was wrapped in aluminum foil) for 36 h at room temperature. The reaction was then diluted with CH2Cl2 and filtered through silica. The filtrate was concentrated in vacuo before being purified by column chromatography on silica gel using the indicated solvent system. [4] (

9-(Trifluoromethyl)-6-((trimethylsilyl)methyl)-2,3,4,9-tetrahydro-1H-
carbazole 24: Under inert atmosphere bromo-9-(trifluoromethyl)-2,3,4,9tetrahydro-1H-carbazole (63 mg, 0.2 mmol, 1 equiv.) and Pd I iodo-dimer [6] (5 mg, 0.005 mmol, 2.5 mol%) were dissolved in toluene (3 mL) and ((trimethylsilyl)methyl)magnesium bromide solution (600 L, 0.3 mmol, 1.5 equiv.) was added. The reaction was stirred for 10 min and then exposed to air for 5 min.            (methylsulfonyl)phenyl)(trifluoromethyl)carbamic fluoride were prepared using previously reported procedure and analyses matched previously reported data. The same procedure was used to prepare all new carbamic fluorides without any changes and all compounds were fully characterized. [1] A 20 mL vial was charged with the isothiocyanate (2 mmol, 1 equiv.), silver fluoride (10 mmol, 5 equiv.) and bis(trichloromethyl) carbonate (BTC) (237 mg, 0.8 mmol, 0.4 equiv.). Acetonitrile (10 mL) was added quickly and the vial was sealed (if the isothiocyanate was a liquid or an oil it was added as a solution in acetonitrile). The mixture was stirred at room temperature. After the indicated time, the crude mixture was added at once to Et2O (40 mL) and stirred for 10 minutes. The obtained mixture was filtered through celite and the solvents were then evaporated. The crude material was redissolved in Et2O and was filtered once more through a pad of celite to remove the last traces of salt byproducts. The N-trifluoromethylcarbamic fluoride was then obtained in a technical grade purity ranging from 90 to 99%.

General procedure for the synthesis of isothiocyanates
A 100 mL round-bottom flask was charged with the aniline (5 mmol, 1 equiv.), CH2Cl2 (25 mL) and saturated aqueous NaHCO3 (25 mL). Under strong stirring thiophosgene (460 L, 6 mmol, 1.2 equiv.) was slowly added to the biphasic system at room temperature. After 1 h, the two phases were separated and the aqueous phase was extracted with CH2Cl2 (2x). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The product was then used without further purification.

1-Bromo-2-chloro-4-isothiocyanatobenzene :
The title compound was obtained as a brown liquid in 92% yield (1.14 g) using 4-bromo-3-chloroaniline (1.03 g) following the general procedure for isothiocyanates. 1   Suitable crystals for X-ray diffraction analysis were selected and mounted on a glass fiber with grease on a Bruker APEX-II CCD diffractometer. The crystals were kept at T = 296 K during data collection. The structures were solved with the ShelXT [8] structure solution program using the direct solution method and by using Olex2 [9] as the graphical interface. The model was refined with ShelXL [10] using least squares minimization.

General Computational details
Available X-ray structures were imported from the CCDC and reoptimized using DFT. Calculations were performed using Gaussian 09, Revision D.01. [11] Geometry optimization was conducted in the gas-phase at the ωB97XD/6-31G(d) level of theory. Frequencies were calculated at the same level of theory and used to verify the nature of all stationary points as minima (no imaginary frequencies).
Images were created using the CYLview software. [12] GAZXIR ICOPAU INUXIA SEFTOM 28 3-Methylindole HOMBAP   Table S1 and chart S1 display the correlation between bond length and dihedral angle in various N-CH3 indoles and their N-CF3 counterpart. Two distinct groups arise as replacing the CH3 moiety with a CF3 consistently shorten the C-N bond and pyramidalize the nitrogen within the indole. Chart S1. Correlation between N-CR3 bond length and dihedral angle; Orange: N-CF3, Blue: N-CH3.
Chart S2. Correlation between N-CH3 and N-CF3 difference in bond length and dihedral angle.