Transition Metal Free C–N Bond Forming Dearomatizations and Aryl C–H Aminations by in Situ Release of a Hydroxylamine-Based Aminating Agent

We outline a simple protocol that accesses directly unprotected secondary amines by intramolecular C–N bond forming dearomatization or aryl C–H amination. The method is dependent on the generation of a potent electrophilic aminating agent released by in situ deprotection of O-Ts activated N-Boc hydroxylamines.


General Experimental Details.
Starting materials were purchased from commercial sources (Acros, Aldrich, Alfa Aesar) and used without further purification unless otherwise stated. Anhydrous 2,2,2-trifluoroethanol was obtained by drying over 4Ȧ molecular sieves while other anhydrous solvents were obtained by passage through drying columns supplied by Anhydrous Engineering Ltd. The removal of solvents in vacuo was achieved using both a Büchi rotary evaporator (bath temperatures up to 45 °C) at a pressure of either 15 mmHg (diaphragm pump) or 0.1 mmHg (oil pump), as appropriate, and a high vacuum line at r.t.. Reactions requiring anhydrous conditions were run under a dry atmosphere of nitrogen or argon; glassware was either flame dried immediately prior to use or placed in an oven (200 °C) for at least 2 h and allowed to cool either in a desiccator or under an atmosphere of nitrogen or argon; liquid reagents, solutions or solvents were added via syringe through rubber septa. Flash column chromatography was performed using silica gel (Aldrich 40-63 μm, 230-400 mesh). Thin layer chromatography was performed using aluminium backed 60F254 silica plates. Visualisation was achieved by UV fluorescence or a basic KMnO4 solution and heat. Proton nuclear magnetic resonance were recorded on a Varian or Jeol spectrometer at 400 MHz or 500 MHz while 13 C NMR spectra were recorded at 100 MHz. Chemical shifts (δ) are given in parts per million (ppm) and referenced to the appropriate residual solvent peak. Peaks are described as singlets (s), doublets (d), triplets (t), quartets (q), quintets (qn), sextets (s), multiplets (m) and broad (br.). Coupling constants (J) are quoted to the nearest 0.1 Hz. Assignments of 1 H NMR and 13 C NMR signals were made, where possible, using COSY, HSQC, HMBC, NOE and TOCSY experiments. Mixtures of isomers which could not be separated (e.g. diastereomers and/or rotamers) have been characterized together and are referred to as A and B. Numbering systems for NMR signal assignments are specified on the structure and are not related to those used for the compound names. In situ yields were determined by integration of the 1 H NMR of the crude material employing 1,3,5-trimethoxybenzene or 1,4-dinitrobenzene as internal standard.
Mass spectra were determined by the University of Bristol mass spectrometry service using a Bruker Daltonics FT-ICR-MS Apex 4e 7.0T FT-MS. Infrared spectra were recorded on a Perkin Elmer Spectrum Two FTIR spectrometer as either neat films or solids. Abbreviations used are: w (weak), m (medium), s (strong) and br (broad). Melting points were determined using a Reichert melting point table and temperature controller and are uncorrected.

General procedure A for TBS protection of phenol
To a solution of alcohol (1.0 eq.) in DMF (approx. 2mL/mmol) at 0 o C was added imidazole (3.3 eq.) and tert-butyldimethylsilyl chloride (2.2 eq.). The reaction was stirred at r.t. and monitored by TLC. Upon completion, the reaction was quenched by addition of H2O and the organic phase extracted with hexane, dried over Na2SO4 and concentrated in vacuo. To the crude reaction mixture was added MeOH (1 mL/mmol), THF (1 mL/mmol) and aq. K2CO3 (2.0 eq.) After stirring for 12 h the reaction was quenched with aq. 1 M HCl at 0 o C (until pH approx. 3). The mixture was extracted with Et2O (3 × 20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash column chromatography.

General procedure B for reduction of carboxylic acid/ester to alcohol using LiAlH4
To a solution of carboxylic acid/ester (1.0 eq.) in anhydrous THF or Et2O (approx. 5 mL/mmol) at 0 o C was added LiAlH4 (equivalents specified) dropwise. The reaction was stirred at r.t. and monitored by TLC. Upon completion, the reaction mixture was cooled to 0 o C before addition of water (1 mL/g of LiAlH4), 15% aq. NaOH (1 mL/g LiAlH4) and a final portion of water (3 mL/g of LiAlH4). The mixture was filtered through Celite® and washed with CH2Cl2. The phases were separated and the aqueous phase extracted with CH2Cl2 (2 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was purified by flash column chromatography.

General procedure C for preparation of hydroxylamine derivatives by Mitsunobu reaction 1
Diisopropyl azodicarboxylate (1.2 eq.) was added at 0 o C to a stirring solution of triphenylphosphine (1.2 eq.) in anhydrous THF (approx. 2mL/mmol) under a nitrogen atmosphere. After 30 min stirring at this temperature a solution of alcohol (1.0 eq.) and amine nucleophile (1.2 eq.) in anhydrous THF (approx. 2mL/mmol) were added. The reaction was stirred at 0 o C for 1 h after which it was stirred at r.t. and monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo and purified by flash column chromatography. S4

General procedure D for removal of silyl protecting group with TBAF/AcOH
To a solution of silyl ether (1.0 eq.) in THF (approx. 20mL/mmol) at 0 o C was added a solution of 1:1 TBAF/AcOH (equivalents specified, 0.1 M in THF). The reaction mixture was stirred at r.t. and monitored by TLC. Upon completion, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (2 × 10 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered and the concentrated in vacuo. The crude product was purified by flash column chromatography.
The reaction was stirred at this temperature for 4 h and then warmed to 0 o C and stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (10 mL) and quenched with Rochelle's salt (10 mL). The mixture was filtered through Celite® and washed with EtOAc.
The phases were separated and the aqueous phase extracted with EtOAc (10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo.

1-(Allyloxy)naphthalene 22
The title compound was prepared according to a literature procedure. 22 Spectroscopic properties were consistent with the data available in the literature. 23

2-Allylnaphthalen-1-ol 24
The title compound was prepared according to a literature procedure. 22

S56
Spectroscopic properties were consistent with the data available in the literature. 24

((2-Allylnaphthalen-1-yl)oxy)(tert-butyl)dimethylsilane 24
The title compound was prepared according to a literature procedure. 22 Spectroscopic properties were consistent with the data available in the literature. 24

S61
General procedure D: tert-Butyl (3-(2-((tert-butyldimethylsilyl) The title compound was prepared according to a literature procedure. 25 Spectroscopic properties were consistent with the data available in the literature. 26

2-(Cinnamyloxy)naphthalene 27
The title compound was prepared according to a literature procedure. 27 Spectroscopic properties were consistent with the data available in the literature. 27

1-(1-Phenylallyl)naphthalen-2-ol 28
The title compound was prepared according to a literature procedure. 27 Spectroscopic properties were consistent with the data available in the literature. 28