Pyrrolidines and Piperidines by Ligand‐Enabled Aza‐Heck Cyclizations and Cascades of N‐(Pentafluorobenzoyloxy)carbamates

Abstract Ligand‐enabled aza‐Heck cyclizations and cascades of N‐(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non‐biased 6‐exo aza‐Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines.


General experimental details
Unless stated, all materials were purchased from commercial sources (Acros, Aldrich, Alfa Aesar, Fluorochem and Strem) and used without any further treatment. Reagents requiring purification were purified using standard laboratory techniques according to methods published by Perrin, Armarego, and Perrin (Pergamon Press, 1966). Catalytic reactions were carried out in Young-type re-sealable tubes.
Anhydrous solvents were obtained by distillation using standard procedures or by passage through drying columns supplied by Anhydrous Engineering Ltd. High-boiling solvents were removed from the reaction crudes employing rotary evaporators connected with high-vacuum pumps. Flash column chromatography (FCC) was performed using silica gel (Aldrich 40-63 µm, 230-400 mesh). Thin layer chromatography was performed using aluminium backed 60F254 silica plates. Visualization was achieved by UV fluorescence or a basic KMnO4 solution and heat. Proton nuclear magnetic resonance spectra (NMR) were recorded at 400 MHz or 500 MHz as stated. 13 C NMR spectra were recorded at 100 MHz or 125 MHz as stated. 19 F NMR spectra were recorded at 283 MHz. Chemical shifts (δ) are given in parts per million (ppm). Peaks are described as singlets (s), doublets (d), triplets (t), quartets (q), multiplets (m) and broad (br). Coupling constants (J) are quoted to the nearest 0.5 Hz. All assignments of NMR spectra were based on 2D NMR data (COSY, HSQC and HMBC). In situ yields were determined by employing 1,3,5-trimethoxybenzene as internal standard. Mass spectra were recorded using a Brüker Daltonics FT-ICR-MS Apex 4e 7.0T FT-MS (ESI + mode) and a Shimadzu GCMS QP2010+ (EI + mode). Infrared spectra were recorded on a Perkin Elmer Spectrum Two FTIR spectrometer as thin films or solids compressed on a diamond plate. Melting points were determined using Stuart SMP30 melting point apparatus and are reported uncorrected. Enantiomeric excess was determined by integration of chromatogram peaks. Chiral SFC was performed on an Agilent 1260 Infinity SFC Control Module system equipped with a quaternary pump, diode array detector and column thermostat under the conditions specified. The numbering of compound structures does not necessarily reflect the numbering contained in the systematic names.

General procedures General procedure A: Pentafluorobenzoylation of N-hydroxycarbamates
To a suspension of N-hydroxycarbamate (1.0 eq.) and pentafluorobenzoic acid (1.0 eq.) in CH2Cl2 (10 mL/mmol) at 0 °C was added a solution of N-N'-dicyclohexylcarbodiimide (1.1 eq.) in CH2Cl2 (5 mL/mmol) dropwise. The resulting mixture was stirred at 0 °C for the time noted before filtration to remove the colorless precipitate. The filtrate was concentrated in vacuo and the crude product was purified by FCC.

General procedure B: Johnson-Claisen rearrangement
A solution of propionic acid (0.20 eq.) in triethyl orthoacetate (10 eq.) was heated at 110 °C for 1 hour, after this time allylic alcohol (1.0 eq.) was added and the reaction mixture heated at reflux for the time noted. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford the crude product which was purified by FCC.

General procedure C: Reduction of carboxylic acids or esters
To a solution of carboxylic acid/ester (1.0 eq.) in anhydrous THF or Et2O (approx. 2.5 mL/mmol) at 0 °C was added LiAlH4 (equivalents specified) dropwise. The reaction mixture was warmed to room temperature and monitored by TLC. Upon completion, the reaction mixture was cooled to 0 °C before addition of water (1 mL/g of LiAlH4), 15 % aqueous NaOH (1 mL/g of LiAlH4) and a final portion of water (3 mL/g of LiAlH4). The reaction mixture was stirred at room temperature for around 15 minutes before being dried over Na2SO4 and concentrated in vacuo to afford the product.

General procedure D: Mitsunobu reaction employing diisopropyl azodicarboxylate
To a solution of alcohol (1.0 eq.), hydroxylamine-derived pronucleophile (1.3 eq.) and PPh3 (1.5 eq.) in anhydrous THF:PhMe (3:1, 8 mL/mmol) at 0 °C was added a solution of DIAD (1.5 eq.) in anhydrous PhMe (2 mL/mmol) dropwise. The reaction mixture was stirred at room temperature for the time noted before being concentrated in vacuo and loaded directly onto silica gel for purification by FCC.

General procedure E: Palladium-catalyzed cyclization
A flame-dried re-sealable tube, fitted with a magnetic stirrer, was charged with cyclization substrate, Pd2(dba)3 and phosphine ligand. The tube was fitted with a rubber septum and purged with nitrogen before solvent and Et3N were added via syringe. The tube was sealed and heated at the specified temperature for 24 hours unless otherwise noted. The reaction mixture was cooled to room temperature, concentrated in vacuo and the crude product was purified by FCC.

General procedure F: N-Boc deprotection
A solution of carbamate in TFA (2 mL) and CH2Cl2 (2 mL) was stirred at room temperature for 1 hour before being concentrated in vacuo to afford the product.

General procedure G: Alkylation and decarboxylation of diethyl malonate
To a suspension of NaH (60% weight in mineral oil, 2.0 eq.) in anhydrous THF (approx. 3 mL/mmol) at 0 °C was added diethyl malonate (2.0 eq.) dropwise. The reaction mixture was stirred at 0 °C for 1 hour before dropwise addition of allylic bromide (1.0 eq.). The reaction mixture was warmed to room temperature and monitored by TLC. Upon completion, the reaction mixture was poured into a solution of KOH (12 eq.) in water:MeOH (1:1) and stirred for 30 minutes at room temperature. The reaction mixture was acidified with 10 M aqueous HCl (20 eq.), concentrated to an aqueous solution and extracted with EtOAc (approx. 3 × 5 mL/mmol). The crude mixture of malonic acids was dissolved in DMF (approx. 2 mL/mmol) and heated at reflux for 3 hours before being concentrated in vacuo to afford the crude decarboxylated product.

General procedure E: Palladium-catalyzed cascade reaction
A flame-dried re-sealable tube, fitted with a magnetic stirrer, was charged with cyclization substrate, Pd2(dba)3, phosphine ligand and aryl boronic acid pinacol ester. The tube was fitted with a rubber septum and purged with nitrogen before solvent and Et3N were added via syringe. The tube was sealed and heated at the specified temperature for 48 hours. The reaction mixture was cooled to room temperature, filtered through a pad of silica, eluted with EtOAc and concentrated in vacuo. The crude product was purified by FCC.

Preactivated reagents for Mitsunobu reactions tert-Butyl ((pentafluorobenzoyl)oxy)carbamate (1a)
This compound was prepared according to a literature procedure. 1 To a solution of tert-butyl N-hydroxycarbamate (6.66 g, 50.0 mmol) in CH2Cl2 (150 mL) at 0 °C was added pentafluorobenzoyl chloride (6.90 mL, 50.0 mmol) followed by Et3N (7.00 mL, 50.0 mmol). The reaction mixture was stirred at room temperature for 3 hours before addition of water (100 mmol). The resulting phases were separated and the aqueous phase was extracted with CH2Cl2 (70 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by FCC (eluent: 9:1 hexane:EtOAc) to afford 1a (14.7 g, 90 %)  The spectroscopic properties were consistent with the data available in the literature. 1

Isopropyl N-hydroxycarbamate
To a suspension of NH2OH·HCl (5.00 g, 72.0 mmol) and K2CO3 (8.29 g, 60.0 mmol) in THF (120 mL) at 0 °C was added a solution of isopropyl chloroformate (1.0 M in PhMe, 60 mL, 60 mmol) dropwise over around 30 minutes. The reaction mixture was stirred at room temperature for 48 hours before being filtered. The filtrate was concentrated in vacuo and the crude product was purified by FCC (eluent: 1:1 hexane:EtOAc) to afford the title compound (2.18 g, 31 %) as a colorless crystalline solid.
The reaction mixture was stirred at 0 o C for 30 minutes before being warmed to room temperature and stirred for 16 hours. The reaction mixture was filtered, rinsed with Et2O (100 mL) and the filtrate was concentrated in vacuo. The crude product was crystallized from Et2O to afford the title compound (12.4 g, 56%) as a colorless crystalline solid.
The spectroscopic properties were consistent with the data available in the literature. 2

1,1,1-Trifluoro-2-methylpropan-2-yl hydroxycarbamate
A solution of NH2OH·HCl (3.00 g, 43.2 mmol) and NaHCO3 (5.44 g, 64.8 mmol) in THF (60 mL) and water (60 mL) was stirred at room temperature for 30 minutes before addition of the preceding compound (4.80 g, 21.6 mmol). The reaction mixture was stirred for 20 hours before being partitioned between EtOAc (100 mL) and brine (100 mL). The phases were separated and the organic phase was concentrated in vacuo. The crude material was redissolved in EtOAc (100 mL) and washed with water (3 × 40 mL) before being dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.77
The signal corresponding to the trifluoromethyl group could not be resolved due to its weak intensity.
The spectroscopic properties were consistent with the data available in the literature. 5
The signals corresponding to the pentafluorobenzoyl group could not be resolved due to their weak intensity.
The major product was assigned as the cis diastereomer based on the observed NOE correlation between the C1 and the C4 protons.
The major product was assigned as the cis diastereomer based on the observed NOE correlation between the C2 and the C4 protons.
The spectroscopic properties were consistent with the data available in the literature. 13
The spectroscopic properties were consistent with the data available in the literature. 14
The spectroscopic properties were consistent with the data available in the literature. 16
The reaction mixture was stirred for 1 hour at room temperature before addition of saturated aqueous NH4Cl (50 mL). The resulting phases were separated and the aqueous phase was extracted with Et2O (2 × 50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to afford the title compound (2.67 g, 96 %) as a pale yellow oil.
The product was assigned as the Z isomer based on the observed NOE correlation between the C6 and the C7 protons.

When the reaction was performed using PA-Ph (L-1) under analogous conditions the yield was 70 %.
The Boc group of 4m was removed to confirm that the presence of two sets of signals are due to the presence of two rotamers rather than two alkene isomers, details of this are given below.
The spectroscopic properties were consistent with the data available in the literature. 25

2-(2-(Prop-1-en-1-yl)phenyl)ethan-1-ol
To a solution of the preceding bromide (2.96 g, 15.0 mmol) in anhydrous THF (40 mL) at -78 °C was added n-BuLi (1.55 M in hexane, 10.6 mL, 16.5 mmol). The reaction mixture was stirred at -78 °C for 2 hours before addition ethylene oxide (approx. 3 M in THF,7.5 mL,22.5 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 hours before addition of saturated aqueous NH4Cl (30 mL). The resulting phases were separated and the aqueous phase was extracted with Et2O
The spectroscopic properties were consistent with the data available in the literature. 31
The spectroscopic properties were consistent with the data available in the literature. 35
The spectroscopic properties were consistent with the data available in the literature. 35  Characteristic signals for the minor Z isomer:

2-enoate (2t)
General procedure D: The preceding alcohol (531 mg, 2.50 mmol) was employed with 1a. The signals corresponding to the pentafluorobenzoyl group could not be resolved due to their weak intensity.

The product was assigned as the Z isomer based on the observed NOE correlation between the Me and the t-Bu protons.
When the reaction is run to partial completion: General procedure E: Conditions: 2.5 mol% Pd2 (
The spectroscopic properties were consistent with the data available in the literature. 37
The spectroscopic properties were consistent with the data available in the literature. 38
The spectroscopic properties were consistent with the data available in the literature. 37
The spectroscopic properties were consistent with the data available in the literature. 39
The spectroscopic properties were consistent with the data available in the literature. 40,41

tert-Butyl (E)-non-4-en-1-ylcarbamate (5)
A solution of the preceding pthalimide (505 mg, 1.86 mmol) and hydrazine (55 % aqueous solution, 0.31 mL, 5.58 mmol) in EtOH (10 mL) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and redissolved in CH2Cl2 (15 mL From the 1 H NMR spectrum the yield of 4k was determined to be 79 % and no aza-Wacker product (4a) was observed.
The spectroscopic properties were consistent with the data available in the literature. 42,43 Ethyl 4
The minor diastereomer exists as an approximately 1:1 mixture of rotamers. 1