Gold and BINOL-Phosphoric Acid Catalyzed Enantioselective Hydroamination/N-Sulfonyliminium Cyclization Cascade

A highly enantioselective hydroamination/N-sulfonyliminium cyclization cascade is reported using a combination of gold(I) and chiral phosphoric acid catalysts. An initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalyzed cyclization process provide access to complex sulfonamide scaffolds in excellent yield and high enantiocontrol. The method can be extended to lactam derivatives, with excellent yields and enantiomeric excesses of up to 93% ee.


General Experimental Techniques
For reactions requiring anhydrous conditions, glassware was dried in an oven at 100 °C and reactions were carried out under a nitrogen or argon atmosphere. Room temperature (rt) refers to 20-25 °C. Temperatures of 0 °C were achieved using an ice-bath. All compounds were named using ACD IUPAC name predictor.

Solvents and Reagents
Commercial reagents were used as purchased without any further purification unless otherwise stated. Chiral Brønsted acids (BPA-1A to BPA-1D and BPA-2A) were synthesised by Dr Michael Muratore and Dr Lie Shi following standard literature procedure. 1,2,3 Bulk solutions were concentrated under reduced pressure using a Büchi rotary evaporator.
Anhydrous toluene, tetrahydrofuran and dichloromethane were obtained by filtration through activated alumina (powder ~150 mesh, pore size 58Å, basic, Sigma-Aldrich) columns. Dichloroethane and acetonitrile were distilled over calcium hydride. Petroleum ether (PE) refers to distilled light petroleum with boiling points in the range of 40 °C -60 °C.

Chromatography
All reactions were monitored by thin-layer chromatography (TLC) where appropriate using Merck Kiesel gel 60 F 254 (230-400 mesh) silica plates which were visualised by UV-light (250 nm) or by staining using aqueous potassium permanganate solutions or vanillin, sulphuric acid in ethanol where appropriate. Column chromatography was carried out using Merck Kieselgel 60 silica gel (230-400 mesh). Enantiomeric excesses were determined using high performance liquid chromatography (HPLC) performed on a Hewlett-Packard 1050 Series system or Agilent 1200 Series system (column and solvent conditions are given with the compound).

General procedure A for the preparation of indole carbaldehydes (17)
Phosphorus oxychloride (2.5 eq) was added dropwise to dry dimethyl formamide (5 ml per 1 ml of POCl 3 ) with ice-bath cooling under nitrogen. The mixture was stirred for 5 minutes before the chosen indole (1 equivalent) was added in dimethyl formamide (10 ml per 1 g of indole). The mixture was then allowed to warm to room temperature and stirred for 3 hours. The reaction became a thick suspension that required vigorous stirring. Potassium hydroxide solution (3.8 M, 10 eq) was added via dropping funnel and the mixture was heated at reflux for 14-16h. The solution was cooled to room temperature before adding a saturated sodium hydrogen carbonate solution and ethyl acetate until the mixture became clear and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to furnish the desired aldehyde that required no further purification.

3-formyl-1H-indole-5-carbonitrile
The title compound 17g was synthesised according to general procedure A in 97% yield as an off white solid.

4-chloro-1H-indole-3-carbaldehyde
The title compound 17b was synthesised according to general procedure A in 85% yield as a light brown solid.

General procedure B for the synthesis of nitro-olefins 18
A mixture of the corresponding aldehyde 17 (1 eq), and ammonium acetate (dried under reduced pressure until the crystals became free flowing) (3 eq) in nitromethane (20 ml per 1 g of aldehyde) were heated at reflux under nitrogen for 1 hour (behind a blast shield). The reaction mixture was then allowed to cool to room temperature. Two purification methods: 1) The solvent was removed in vacuo and the residue washed with water and filtered. The filtration cake was pre-absorbed onto silica gel and purified by flash column chromatography (PE:ethyl acetate, 2:1) to furnish the desired nitro-olefin.
2) The reaction was allowed to cool to room temperature and left to crystaillize for 14-16 h. The solid was filtered, washed with water and dried over phosphourous pentoxide in a vacuum dessicator affording the desired nitroolefin 18.

General procedure C for the synthesis of tryptamines 19
A solution nitro olefin 18 (1 equivalent) in tetrahydrofuran (10 ml per 1 mmol of nitro olefin) was added to a stirred slurry of lithium aluminium hydride powder (6 equivalents) in tetrahydrofuran (equal mass to volume, e.g. 1 g (LiAlH 4 ):1ml (tetrahydrofuran)) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 36 hours. The reaction was cooled to 0 °C and was quenched by dropwise addition of water until effervescence ceased. The mixture was then filtered and the solid washed with ethylacetate, the filtrate was concentrated in vacuo to furnish the desired tryptamine 19 which was purified by flash column chromatography or acidic extraction from CH 2 Cl 2 solution followed by addition of solid KOH until the PH measures 14 (by universal indicator paper) and extracted with CH 2 Cl 2 dried over NaSO 4 and concentrated.

General procedure D for preparation of 5
To a stirred solution of sulfonylchloride 9 (1.1 eq) in dichloromethane (5 ml/mmol of tryptamine) under argon at -78 °C was added the desired tryptamine derivative 19 (1 eq) and triethyamine (1.1 eq) in dichloromethane (7 ml/mmol of tryptamine). The mixture was stirred at -78 °C for 5 to 10 mins then concentrated in vacuo (in a room temperature water bath) to give the crude product. The residue was purified by flash column chromatography (CH 2 Cl 2 :Et 2 O, 1:0 to 8:2) to give the desired sulfonamide derivative 5.
Recrystallization from ethanol gives thin white crystalline plates.
Recrystallization from ethanol gives thin white crystalline plates.
Recrystallization from ethanol gives an off white solid.
Recrystallization from ethanol gives an off white solid.
Recrystallization from ethanol gives thin white crystalline plates.
Recrystallization from ethanol gives thin white crystalline plates.
Recrystallization from ethanol gives thin white crystalline plates.
Recrystallization from ethanol gives an off white solid.
Recrystallization from ethanol gives an off white solid.
Recrystallization from ethanol gives an off white solid.
Recrystallization from ethanol gives thin white crystalline plates.

General procedure F for preparation of racemic derivatives 6
To a solution of the desired sulfonamide 5 (1 eq) and diphenylphosphate (0.1 eq) in toluene (14 ml

Racemic-6a
was synthesised according to general procedure F as an off white solid.

General procedure G for the preparation of 9
Hexynoic acid (1 eq) was added in one portion to a suspension of (1.5 eq) and DMAP (0.04 eq) in dichloromethane (3 ml/mmol of hexynoic acid) under argon and the mixture was stirred for 5 mins. A solution of tryptamine 19 (1.4 eq) in dichloromethane (7 ml/mmol of hexynoic acid) was added to the solution. The reaction mixture was stirred at rt for 12 h.
Upon completion hydrochloric acid solution (1M, 10 ml) was added. The layers were separated and the aqueous was extracted with dichloromethane (2 × 20 ml). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (CH 2 Cl 2 :Et 2 O, 1:0 to 7:3).

General procedure H for the racemic preparation of cyclic amides 10
To a foil covered flask [Au(o-biphenylPtBu 2 )(MeCN)]SbF 6 (8) (0.05 eq), diphenylphosphate (0.1 eq) and desired amide derivative (9) (1 eq) were added and placed under nitrogen atmosphere. Toluene (14 ml/1 mmol of 9) was added in one portion and the reaction was heated to 110 °C and left for 48 to 72 hours. The solvent was removed in vacuo and purified by flash column chromatography (CH 2 Cl 2 : Et 2 O, 1 : 0 to 7 : 3).

General procedure I for the Enantioselective preparation of cyclic amides 10
To

2.12.
Optimization, Derivative for X-ray and Control reactions.

Mechanistic evidence for N-sulfonylimminium 13
To a flask containing ketone 14 (0.1 mmol, 1 eq), and BPA-1A (0.01 mmol, 0.1 eq) under nitrogen atmosphere was added toluene at 90 °C rapidly via canula. The reaction mixture was stirred at reflux for 1 hour then cooled to room temperature. Concentration in vacuo and purification by flash column chromatography furnished the title compound (99 % yield, 92 % e.e.).

General proceedure for optimization in the preparation of 10a.
To an aluminium foil covered flask [Au(o-biphenylPtBu 2 )(MeCN)]SbF 6 (8) (0.0015 mmol, 0.01 eq) was added in dichloromethane (1 ml) and the dichloromethane was removed under nitrogen stream. Amide 9 (0.15 mmol, 1 eq) and BPA-1A (0.015 mmol, 0.1 eq) were added and were dissolved in toluene (21 ml/0.15 mmol of 9) under nitrogen. The mixture was then heated to reflux and monitored (by TLC) until the reaction reached completion. The reaction was concentrated in vacuo and purified by FCC.

Optimisation table for the preparation of 10a.
Entry Acid (BPA) Acid (mol %) 6a (0.12 mmol, 1 eq) was dissolved in DMF (1 ml/0.12 mmol of 6a) under argon and added to a dried flask containing sodium hydride (1.6 mmol, 1.3 eq) in an ice bath. The mixture was stirred at 0°C for 10 mins and then allowed to warm to room temperature stirring for a further 10 mins. 3-bromobenzylbromide (0.37 mmol, 3 eq) was added to the mixture in one portion and allowed to stir at room temperature for 3 h. The reaction was diluted with water (5 ml/0.12 mmol of 6a) and extracted with ethyl acetate (3 x 5 ml/0.12 mmol of 6a). The combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by FCC to gave XX as a white solid (68% yield). Recrystallization from ether by slow evaporation gave crystals of high enough quality for single crystal x-ray diffraction (<99% e.e.). Chiralcel AD, 80:20 Hexane/IPA, 1ml/min, 220, major t R = 12.0 min, minor t R = 18.1 min).