Supporting Information

Table of Contents

1. General directions S2

2. Synthesis of (±)-indolines 5b-f and 5h-q S3-S9

3. Synthesis of sulfonylating agent - 2-Isopropyl-4-nitrobenzenesulfonyl chloride S10-S11

4. Synthesis of (±)-indoline sulfonamides 6-8a, 6b-f and 6i-q S12-S17

5. Synthesis and resolution of catalysts 4a and 4b S18-S24

6. Assignment of the absolute configuration of catalyst 4a enantiomers S25-27

7. KR of (±)-2-methylindoline (5a) – Optimisation using catalyst (-)-4a S28

8. KR of (±)-indolines 5a-5q – Analytical scale resolutions S29-S44

9. KR of (±)-2-methylindoline (5a) – Scale up, deprotection and catalyst recovery S45-S47

10. Conformational analysis on sulfonyloxypyridinium salt intermediate 9 S48

11. References S49

12. Spectra for all new compounds S50-S124

S2

1. General Directions

All reactions were performed under nitrogen using oven-dried glassware unless stated otherwise. Kinetic

resolutions were performed under an atmosphere of argon. Yields refer to chromatographically and

spectroscopically (1H-NMR) homogenous materials, unless otherwise indicated. MeCN, CH2Cl2, THF, Et2O,

DMF, and toluene were dried and deoxygenated with a Grubbs Pure-Solv 400 solvent purification system. The

moisture content of the solvents was monitored by Karl Fischer coloumetric titration (Mettler-Toledo DL39). All

other materials including: (±)-2-methylindoline (5a), (±)-indoline-2-carboxylic acid, 3-methylbut-1-yne, (±)-2-

phenylindoline (5g), 5-chloro-2-methyl-1H-indole, 2,5-dimethyl-1H-indole, 5-methoxy-2-methyl-1H-indole, 2,3-

dimethylindole, 1,2,3,4-tetrahydrocyclopenta[b]indole, 2,3,4,9-tetrahydro-1H-carbazole and 2,3,4,9-Tetrahydro-

1H-pyrido[3,4-b]indole were obtained from commercial suppliers and used without further purification unless

stated otherwise. Flash chromatography (FC) was performed on silica gel (Merck Kieselgel 60 F254 230-400

mesh) unless otherwise stated. Thin Layer Chromatography was performed on Merck aluminium-backed plates

pre-coated with silica (0.2 mm, 60 F254) which were visualized either by quenching of ultraviolet fluorescence

(λmax= 254 and 366 nm) or by charring with 10% KMnO4 in 1 M H2SO4. Melting points were determined on a

Stanford Research System OptiMelt. Optical rotations were measured with a Bellingham Stanley APP440+

Polarimeter. Standard infra-red spectra were recorded on Perkin-Elmer Two Spectrum ATR-IR spectrometer and

Shimadzu IRAffinity-1S. Only selected absorbances are reported. 1H NMR spectra were recorded at 400 MHz on

a Bruker DRX-400 instrument. Chemical shifts (H) are quoted in parts per million (ppm), referenced to the CHCl3

residual solvent peak as an internal standard. Coupling constants (J) are reported to the nearest 0.1 Hz. 13C NMR

spectra were recorded at 100 MHz on Bruker AMX- 400 instrument. Chemical shifts (C) are quoted in ppm,

referenced to the CHCl3 residual solvent peak as an internal standard. High-resolution mass spectra (m/z) were

recorded on Micromass Autospec Premier spectrometer with magnetic sector detector. High Resolution Mass

Spectrometry (HRMS) measurements are valid to ±5ppm. GC analyses were carried out using an Agilent 7890B

Series GC equipped with a Varian GC capillary column (WCOT fused silica 30 m × 0.32 mm; film thickness 0.25

μm), a flame ionization detector, a split/splitless injector and an Agilent Technologies 7683 B Series auto sampler.

Hydrogen gas was employed as the carrier gas with a flow rate of 30 mL/min using a constant flow mode. High-

purity nitrogen gas was used as a make-up gas for the detector at a flow rate of 25 mL/min. Samples were injected

in split-less mode at an oven temperature of 100 °C. The oven temperature was programmed as follows: 100 °C

held for 1 min, then ramped at 30 °C/min to 180 °C. Peaks were quantified with Agilent Technologies ChemStation

software. HPLC analysis was carried out using an Agilent HP Series 1100 HPLC. ECD spectra were run on a

Jasco J 810 spectropolarimeter using a 1 cm path length quartz cuvette with 1 nm bandwidth at 298K. Infra Red

and vibrational circular dichroism (VCD) spectra were recorded on a Bruker PMA 50 accessory coupled to a

Tensor 27 Fourier transform infrared spectrometer. A photoelastic modulator (Hinds PEM 90) set at l/4 retardation

was used to modulate the handedness of the circular polarized light. Demodulation was performed by a lock-in

amplifier (SR830 DSP). An optical low-pass filter (< 1800 cm-1) in front of the photoelastic modulator was used

to enhance the signal/noise ratio. Solutions of ca. 2.1 mg of catalyst 4a in 160 ml CDCl3were prepared and

measured in a cell equipped with CaF2 windows and a 200 mm spacer. The spectrum of the neat solvent served as

the reference and was subtracted from the spectra of the enantiomers. For both the sample and reference 24,000

scans at 4 cm-1 resolution were averaged. All quantum mechanical studies were undertaken using the Gaussian 09

software.[1]

S3

2. Synthesis of (±)-indolines 5b-f and 5h-q

(±)-Indolin-2-ylmethanol[2]

(±)-Indoline-2-carboxylic acid (499 mg, 3.05 mmol, 1 eq.) was dissolved in dry THF (35 mL)

and lithium aluminium hydride (351 mg, 9.25 mmol, 3 eq.) was added at 0 °C while stirring.

The solution was allowed to warm to rt and was stirred for 1.5 h. The reaction was quenched by adding potassium

sodium tartrate (20 mL, 10 % w/v) at 0 °C and filtered. The filtrate was treated with sat. NH4Cl (20 mL), extracted

with EtOAc (3 20 mL) dried over MgSO4 and conc. in vacuo. The crude residue was purified by FC (eluent:

10% MeOH/CH2Cl2) to afford alcohol as a yellow solid (432 mg, 2.9 mmol, 95%). 1H NMR (400 MHz, CDCl3,

ppm): 7.09 (dd, J = 7.3, 1.3 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.73 (td, J = 7.4, 1.0 Hz, 1H), 6.65 (d, J = 7.8 Hz,

1H), 4.11 - 4.00 (m, 1H), 3.73 (dd, J = 10.8, 3.9 Hz, 1H), 3.58 (dd, J = 10.9, 6.4 Hz, 1H), 3.12 (dd, J = 15.8, 9.3

Hz, 1H), 2.84 (dd, J = 15.8, 7.9 Hz, 1H), 2.78 (s, 2H). Spectroscopic data in agreement with literature.[2]

(±)-2-(((Triethylsilyl)oxy)methyl)indoline (5b)

To a well-stirred solution of (±)-indolin-2-ylmethanol (250 mg, 1.68 mmol, 1 eq.), NMI

(15 L, 0.168 mmol, 10 mol%) and DIPEA (0.58 mL, 3.36 mmol, 2 eq.) in CH2Cl2 (17

mL) was added TES-Cl (0.34 mL, 0.201 mmol, 1.2 eq.). The colourless solution was stirred at rt for 21.5 h and

then conc. in vacuo. The crude residue was purified by FC (eluent: 10% EtOAc/hexanes) to yield silylated indoline

product as a colourless liquid (193 mg, 0.74 mmol, 44%). IR (film, cm-1): 3354, 2953, 2911, 2876, 1611, 1485,

1466, 1377, 1342, 1319, 1244, 1016, 974, 912, 800. 1H NMR (400 MHz, CDCl3, ppm): 7.08 (dd, J = 7.2, 1.3

Hz, 1H), 7.02 (td, J = 7.6, 1.3 Hz, 1H), 6.69 (td, J = 7.4, 1.1 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.27 (s, 1H), 3.96

(m, 1H), 3.57 (m, 2H), 3.12 (dd, J = 15.8, 9.1 Hz, 1H), 2.65 (dd, J = 15.8, 5.8 Hz, 1H), 0.98 (td, J = 8.0, 1.8 Hz,

9H), 0.63 (qd, J = 8.0, 1.7 Hz, 6H). 13C NMR (101 MHz, CDCl3): 150.7, 128.3, 127.5, 124.9, 118.6, 109.6,

66.4, 60.6, 32.3, 6.9, 4.5. HRMS (ES+): Found: 264.1796 ([M+H] C15H25NOSi Requires: 264.1784).

(±)-2-(((Triisopropylsilyl)oxy)methyl)indoline (5c)

To a well-stirred solution of (±)-indolin-2-ylmethanol (250 mg, 1.68 mmol, 1 eq.), NMI

(15 L, 0.168 mmol, 10 mol%) and DIPEA (0.58 mL, 3.36 mmol, 2 eq.) in CH2Cl2 (17

mL) was added TIPSCl (0.43 mL, 0.201 mmol, 1.2 eq.). The yellow solution was stirred

at rt for 22.5 h and then conc. in vacuo. The crude residue was purified by FC (eluent: 5% Et2O/hexanes) to afford

silylated indoline product as a colourless oil (250 mg, 0.82 mmol, 49%). IR (film, cm-1): 3387, 2941, 2893, 2864,

1611, 1485, 1466, 1246, 1105, 883, 791, 746, 683. 1H NMR (400 MHz, CDCl3, ppm): 7.06 (d, J = 7.3 Hz, 1H),

7.01 (t, J = 7.5 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 4.28 (s, 1H), 4.02 - 3.91 (m, 1H), 3.70

- 3.55 (m, 2H), 3.11 (dd, J = 15.8, 9.0 Hz, 1H), 2.64 (dd, J = 15.8, 5.5 Hz, 1H), 1.12 - 1.00 (m, 21H). 13C NMR

(101 MHz, CDCl3, ppm): 150.7, 128.3, 127.5, 125.0, 118.5, 109.6, 67.0, 60.7, 32.2, 18.1, 12.1. HRMS (ES+):

Found: 306.2253 ([M+H] C18H32NOSi Requires: 306.2253).

(±)-2-(((tert-Butyldimethylsilyl)oxy)methyl)indoline (5d)[3]

To a well-stirred solution of (±)-indolin-2-ylmethanol (250 mg, 1.68 mmol, 1 eq.),

NMI (15 L, 0.168 mmol, 10 mol%) and DIPEA (0.58 mL, 3.36 mmol, 2 eq.) in

CH2Cl2 (17 mL) was added TBSCl (300 mg, 0.201 mmol, 1.2 eq.). The colourless

solution was stirred at rt for 21.5 h and then conc. in vacuo. The crude residue was purified by FC (eluent: 5%

Et2O/hexanes) to yield indoline product as a colourless liquid (393 mg, 1.50 mmol, 89%). 1H NMR (400 MHz,

S4

CDCl3, ppm): 7.07 (dd, J = 7.3, 1.2 Hz, 1H), 7.01 (t, J = 7.6, 1.0 Hz, 1H), 6.68 (t, J = 7.4, 1.0 Hz, 1H), 6.62 (d,

J = 7.8 Hz, 1H), 4.21 (s, 1H), 3.99 - 3.88 (m, 1H), 3.63 - 3.50 (m, 2H), 3.10 (dd, J = 15.8, 9.0 Hz, 1H), 2.64 (dd,

J = 15.8, 5.8 Hz, 1H), 0.91 (s, 9H), 0.06 (d, J = 0.9 Hz, 6H). HRMS (ES+): Found: 264.1789 ([M+H] C15H26NOSi

Requires: 264.1784). Spectroscopic data in agreement with literature.[3]

General Procedure A - Reduction of indoles

To a flask containing tin-powder (4.5 eq.), HCl (aq. 37% v/v, 3.2 mL/mmol indoline) and EtOH (9.7 mL/mmol

indoline) was added indoline (1 eq.) and the mixture stirred at 70 °C for several hours. Then, KOH (aq., 20% v/w,

23.5 mL/mmol indole) was added and the mixture extracted with Et2O (3 × 35 mL/mmol), filtered through Celite,

dried over MgSO4 and conc. in vacuo. The residue was purified by FC to afford desired indoline product.

2-(2-Methylbutyne)-aniline[4]

3-Methylbut-1-yne (1.79 mL, 17.5 mmol, 1.75 eq.) was added to a well-stirred solution of 2-

iodovanilin (2.19 g, 10 mmol, 1 eq.), CuI (8.6 mg, 0.045 mmol, 0.5 mol%.), Pd(PPh3)2Cl2 (37

mg, 0.0525 mmol, 0.5 mol%) in freshly distilled Et3N (63 mL). The solution was left to stir

under N2 for 72 h. Then, the solution was conc. in vacuo and the residue dissolved in Et2O (150 mL). The solution

was filtered through Celite, dried and conc. in vacuo. The crude residue was purified by FC (eluent: 30% - 40%

CH2Cl2/hexanes) to yield product as a yellow oil (1.16, 7.3 mmol, 73%). 1H NMR (400 MHz, CDCl3, ppm):

7.32 - 7.19 (m, 1H), 7.10 (ddd, J = 8.8, 7.4, 1.5 Hz, 1H), 6.74-6.62 (m, 2H), 4.16 (s, 2H), 2.86 (hept, J = 6.9 Hz,

1H), 1.31 (d, J = 6.9 Hz, 6H). HRMS (CI+): Found: 160.1118 ([M+H] C11H14N Requires: 160.1121).

Spectroscopic data in agreement with literature.[4]

2-Isopropylindole[5]

2-(2-Methylbutyne)-aniline (1.06 g, 6.7 mmol, 1 eq.) was added to a well-stirred solution of

CuI (4.2 mg, 0.022 mmol, 0.003 eq.) in DMF (30 mL). The yellow solution darkened as it was

heated to reflux for 4 h followed cooling to rt and stirring for a further 16 h. Then it was diluted with Et2O (150

mL), washed with dilute brine (40 mL), dried over MgSO4 and conc. in vacuo. The crude residue was purified by

FC (eluent: 40% CH2Cl2/hexanes) to yield desired indole product as a yellow solid (616 mg, 3.9 mmol, 58%). 1H

NMR (400 MHz, CDCl3, ppm): 7.92 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.21 - 7.02 (m,

2H), 6.30 (s, 1H), 3.11 (hept, J = 6.8 Hz, 1H), 1.39 (d, J = 6.8 Hz, 6H). HRMS (ES+): Found: 160.1131 ([M+H]

C11H14N Requires: 160.1126). Spectroscopic data in agreement with literature.[5]

(±)-2-Isopropylindoline (5e)[4]

Following the General Procedure A, 2-isopropylindole (271 mg, 1.7 mmol) and Sn (914 mg,

7.7 mmol) were reacted for 14.5 h during which the solution went from a grey suspension to a

clear solution. After work-up, the crude residue was purified by FC (eluent: 40% CH2Cl2/hexanes) to yield indoline

product as an oily yellow solid (161 mg, 1.0 mmol, 59%). 1H NMR (400 MHz, CDCl3, ppm): 7.07 (d, J = 8.5

Hz, 1H), 7.00 (td, J = 7.7, 1.0 Hz, 1H), 6.67 (td, J = 7.5, 1.0 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 3.92 (s, 1H), 3.57

(ddd, J = 9.8, 8.7, 7.5 Hz, 1H), 3.07 (dd, J = 15.6, 8.7 Hz, 1H), 2.74 (dd, J = 15.5, 9.9 Hz, 1H), 1.87 - 1.71 (dh, J

S5

= 13.6, 6.8 Hz , 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). Spectroscopic data in agreement with

literature.[4]

2-n-Butyl-1H-indole[6]

An oven-dried Schlenk-flask was charged with indole (117 mg, 1 mmol, 1 eq.), BuBr (0.24

mL, 2.23 mmol, 2.23 eq.), PdCl2(MeCN)2 (26 mg, 0.1 mmol, 10 mol%), K2CO3 (276 mg, 2

mmol, 2 eq.) and DMA (5 mL). The flask was purged with argon and degassed through 3 freeze-pump-thaw cycles.

The reaction reaction was then heated to 70 °C under argon for 20.5 h. The mixture was conc. in vacuo and the

crude residue was purified by FC (eluent: 5% Et2O/hexanes) to afford product as a yellow oil (93 mg, 0.54 mmol,

54%). 1H NMR (400 MHz, CDCl3): 7.78 (s, 1H), 7.62 - 7.54 (m, 1H), 7.35 - 7.27 (m, 1H), 7.21 - 7.09 (m, 2H),

6.33 - 6.25 (m, 1H), 2.77 (t, J = 7.7 Hz, 2H), 1.79 - 1.67 (m, 2H), 1.47 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H).

HRMS (ES+): Found: 174.1277 ([M+H] C12H16N Requires: 174.1283). Spectroscopic data in agreement with

literature.[6]

(±)-2-n-Butylindoline (5f)[7]

Following General Procedure A, 2-n-butylindole (54 mg, 0.31 mmol) and Sn (167 mg) were

reacted for 5.5 h at 90 °C during which the solution went from a grey suspension to a clear

solution. After work-up, the crude residue was purified by FC (eluent: 40% CH2Cl2/hexanes) to afford indoline

product as a yellow oil (42 mg, 0.24 mmol, 77%). 1H NMR (400 MHz, CDCl3, ppm): 7.07 (dd, J = 7.2, 1.4 Hz,

1H), 7.00 (td, J = 7.6, 1.1 Hz, 1H), 6.68 (td, J = 7.5, 1.0 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 4.09 - 3.44 (m, 2H),

3.12 (dd, J = 15.5, 8.6 Hz, 1H), 2.68 (dd, J = 15.5, 8.5 Hz, 1H), 1.60 (ttd, J = 9.0, 6.8, 6.2, 3.9 Hz, 2H), 1.46 - 1.26

(m, 4H), 0.99 - 0.84 (m, 3H). Spectroscopic data in agreement with literature.[7]

(±)-Methyl indoline-2-carboxylate (5h)[8]

Acetyl chloride (3.0 mL, 42 mmol, 14 eq.) and MeOH (30 mL) were stirred for 5 min before

adding (±)-indoline-2-carboxylic acid (490 mg, 3 mmol, 1 eq.). The mixture was refluxed

for 24 h after which the solvent had evaporated. The residue was purified by FC (eluent: 80% - 100%

CH2Cl2/hexanes) to afford esterified product as a yellow oil (508 mg, 2.9 mmol, 97%). 1H NMR (400 MHz,

CDCl3): 7.12 - 7.00 (m, 2H), 6.79 - 6.68 (m, 2H), 4.39 (dd, J = 10.2, 5.5 Hz, 1H), 3.40 (dd, J = 16.1, 10.1 Hz,

1H), 3.32 (dd, J = 16.1, 5.5 Hz, 1H). Spectroscopic data in agreement with literature.[8]

(±)-5-Chloro-2-methylindoline (5i)[9]

Following General Procedure A, 5-chloro-2-methyl-1H-indole (250 mg, 1.5 mmol) and

Sn (797 mg, 6.7 mmol) were reacted for 5 h at 90 °C during which the solution went from

a grey suspension to a clear solution. After work-up, the crude residue was purified by FC

(eluent: 50% CH2Cl2/hexanes) to yield indoline product as a colourless oil (189 mg, 1.13 mmol, 75%). 1H NMR

(400 MHz, CDCl3, ppm): 7.02 (dt, J = 2.2, 1.2 Hz, 1H), 6.95 (ddt, J = 8.2, 1.9, 1.0 Hz, 1H), 6.49 (d, J = 8.2 Hz,

1H), 4.00 (ddq, J = 8.6, 7.7, 6.2 Hz, 1H), 3.75 (s, 1H), 3.12 (dd, J = 15.7, 8.5 Hz, 1H), 2.61 (ddt, J = 15.7, 7.5, 1.0

Hz, 1H), 1.28 (d, J = 6.2 Hz, 3H). Spectroscopic data in agreement with literature.[9]

(±)-2,5-Dimethylindoline (5j)[10]

Following General Procedure A, 2,5-dimethyl-1H-indole (250 mg, 1.7 mmol) and Sn (914

mg, 7.7 mmol) were reacted for 4 h at 90 °C during which the solution went from a grey

S6

suspension to a clear solution. After work-up, the crude residue was purified by FC (eluent: 100% CH2Cl2) to yield

indoline product as a white solid (164 mg, 1.12 mmol, 66%). 1H NMR (400 MHz, CDCl3, ppm): 6.91 (s, 1H),

6.82 (d, J = 7.7 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 3.97 (tq, J = 8.2, 6.3 Hz, 1H), 3.61 (s, 1H), 3.11 (dd, J = 15.4,

8.4 Hz, 1H), 2.61 (dd, J = 15.4, 7.8 Hz, 1H), 2.25 (s, 3H), 1.29 (d, J = 6.3 Hz, 3H). Spectroscopic data in agreement

with literature.[10]

(±)-5-Methoxy-2-methylindoline (5k)[11]

Following General Procedure A, 5-methoxy-2-methyl-1H-indole (30 mg, 0.2 mmol) and

Sn (109 mg, 0.92 mmol) were reacted for 3 h at 90 °C during which the solution went

from a grey suspension to a clear solution. After work-up, the crude residue was purified

by FC (eluent: 10% MeOH/CH2Cl2) to afford indoline product as a orange solid (27 mg, 0.16 mmol, 83%).1H

NMR (400 MHz, CDCl3, ppm): 6.72 (dd, J = 2.4, 1.2 Hz, 1H), 6.59 (ddt, J = 8.5, 2.6, 0.9 Hz, 1H), 6.54 (d, J =

8.4 Hz, 1H), 3.97 (tq, J = 8.1, 6.2 Hz, 1H), 3.74 (s, 3H), 3.38 (s, 1H), 3.11 (m, 1H), 2.62 (ddt, J = 15.5, 7.9, 1.0

Hz, 1H), 1.29 (d, J = 6.2 Hz, 3H). Spectroscopic data in agreement with literature.[11]

(±)-2-Methyl-6-nitroindoline[12]

(±)-2-Methylindoline (1.0 g, 3.8 mmol, 1 eq.) was added dropwise to conc. H2SO4 (8 mL)

at 5°C. Then the temperature was lowered to 0°C and conc. HNO3 (0.37 mL) was added

dropwise after which the solution turned purple. After 100 min, the solution was quenched

with NaOH (10% w/w, 100 mL) and extracted with CH2Cl2 (3 70 mL). The combined organic phase was dried

over MgSO4 and concentrated in vacuo. The crude product was purified by FC (eluent: 10% Et2O/hexanes) to

afford nitrated indoline product as a red solid (582 mg, 3.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, ppm):

7.56 (dd, J = 8.0, 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.12 (dt, J = 8.1, 1.1 Hz, 1H), 4.12 (ddq, J = 8.7, 7.4, 6.2

Hz, 1H), 4.72 (s, 1H), 3.21 (ddd, J = 16.6, 8.8, 1.1 Hz, 1H), 2.69 (ddd, J = 16.6, 7.4, 1.2 Hz, 1H), 1.31 (d, J = 6.2

Hz, 3H). HRMS (ES+): Found: 179.0819 ([M+H] C9H11N2O2 Requires: 179.0821). Spectroscopic data in

agreement with literature.[12]

(±)-2-Methylindolin-6-amine

(±)-2-Methyl-6-nitroindoline (570 mg, 3.2 mmol, 1 eq.) in EtOAc/EtOH (1:1, 26 mL) was

added to Pd/C (10% w/w, 175 mg) and the flask was evacuated and filled with H2 (× 3)

and the resulting black suspension was stirred at rt for 5.5 h under H2 (1 atm.). Then, the

mixture was added to EtOAc (100 mL) and the phases were separated. The organic phase was filtered over Celite,

dried over MgSO4 and conc. in vacuo. The crude residue was purified by FC (Eluent: 2.5 % MeOH/hexanes) to

yield aniline productas a dark red oil (416 mg, 2.8 mmol, 88%). IR (film, cm-1): 3334, 3213, 2959, 1621, 1504,

1464, 1377, 1270, 1178, 963, 838, 804, 622. 1H NMR (400 MHz, CDCl3, ppm): 6.84 (dd, J = 7.6, 1.2 Hz, 1H),

6.10 - 6.02 (m, 1H), 6.01 (d, J = 2.0 Hz, 1H), 4.03 - 3.88 (m, 1H), 3.51 (s, 3H), 3.04 (dd, J = 14.9, 8.4 Hz, 1H),

2.53 (dd, J = 14.9, 7.6 Hz, 1H), 1.27 (d, J = 6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 152.09, 146.15,

125.06, 120.13, 105.43, 97.16, 55.64, 37.03, 22.34. HRMS (ES+): Found: 149.1073 ([M+H] C9H13N2 Requires:

149.1079).

S7

(±)-tert-Butyl 6-amino-2-methylindoline-1-carboxylate

(±)-2-Methylindolin-6-amine (100 mg, 0.67 mmol, 1 eq.) and Boc2O (0.16 mL, 0.67 mmol,

1 eq.) were dissolved in CH2Cl2 (1 mL) and stirred for 20 h at rt. The solution was then

diluted with CH2Cl2 (5 mL), washed with NaHCO3 (2 mL), brine (2 mL), dried over MgSO4

and conc. in vacuo. The resulting crude mixture was purified by FC (eluent: 0.9% MeOH/CH2Cl2) to afford N-

Boc protected indoline as a brown oil (41 mg, 0.16 mmol, 24%). IR (film, cm-1): 3365, 2973, 2929, 2863, 1691

(C=O), 1616, 1530, 1501, 1460, 1394, 1291, 1164, 1042. 1H NMR (400 MHz, CDCl3, ppm): 7.24 (s, 1H), 6.89

(dt, J = 7.7, 1.1 Hz, 1H), 6.28 (dd, J = 7.8, 2.2 Hz, 1H), 4.45 (s, 1H), 3.57 (s, 2H), 3.22 (ddd, J = 15.2, 9.5, 1.3 Hz,

1H), 2.48 (dd, J = 15.2, 2.3 Hz, 1H), 1.55 (s, 9H), 1.26 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm):

152.4, 146.2, 142.8, 125.4, 120.0, 109.1, 103.1, 80.5, 56.1, 35.2, 28.6, 21.3. HRMS (ES+): Found: 249.1601

([M+H] C14H21N2O2 Requires: 249.1598).

(±)-tert-Butyl 6-(dimethylamino)-2-methylindoline-1-carboxylate

To a well-stirred solution of (±)-tert-butyl 6-amino-2-methylindoline-1-carboxylate (25

mg, 0.1 mmol, 1 eq.), TBAI (2.5 mg, 0.007 mmol, 7 mol%) and KOH (14 mg, 0.25 mmol,

2.5 eq.) in benzene:H2O (7:1, 0.8 mL) was added MeI (15 L, 0.25 mmol, 2.5 eq.) dropwise

at rt. The solution was heated at 90°C for 25 h after which the mixture was cooled to rt and extracted with Et2O (3

2 mL). The combined organic phase was washed with brine (2 mL), dried over MgSO4 and conc. in vacuo. The

resulting crude oil was purified by FC (eluent: 0.5% MeOH/CH2Cl2) to afford product as a yellow oil (15 mg,

0.052 mmol, 52%). IR (film, cm-1): 2974, 2932, 2863, 1695, 1617, 1509, 1617, 1509, 1454, 1388, 1288, 1167,

1043, 952, 868, 844, 762. 1H NMR (400 MHz, CDCl3, ppm): 7.53 - 7.20 (m, 1H), 6.98 (dt, J = 8.2, 1.0 Hz, 1H),

6.36 (dd, J = 8.2, 2.4 Hz, 1H), 4.49 (s, 1H), 3.29 - 3.18 (m, 1H), 2.93 (s, 6H), 2.49 (dd, J = 15.3, 2.4 Hz, 1H), 1.47

(s, 9H), 1.32 - 1.22 (m, 3H). 13C NMR (101 MHz, CDCl3, ppm): 152.3, 150.8, 143.0, 125.0, 107.2, 101.1, 100.4,

80.4, 56.0, 41.2, 34.8, 28.5, 21.1. HRMS (ES+): Found: 277.1922 ([M+H] C16H25N2O2 Requires: 277.1916).

(±)-N,N-2-Trimethylindolin-6-amine (5l)

To a well-stirred solution of (±)-tert-butyl 6-(dimethylamino)-2-methylindoline-1-

carboxylate (40.3 mg, 0.15 mmol, 1 eq.) in CH2Cl2 (2 mL), trifluoroacetic acid (0.8 mL)

was added dropwise at rt. The dark solution was stirred for 3 h and was then conc. in vacuo.

The residue was taken up in CH2Cl2 washed with sat. NaHCO3 (5 mL), dried of MgSO4 and conc. in vacuo. The

crude residue was purified by FC (eluent: 1% MeOH/0.1% Et3N/CH2Cl2) to afford deprotected indoline product

as a colourless oil (26 mg, 0.15 mmol, 99%). IR (film, cm-1): 3360, 2957, 2841, 1620, 1582, 1510, 1448, 1354,

1239, 1099, 974, 815. 1H NMR (400 MHz, CDCl3, ppm): 6.94 (d, J = 8.0 Hz, 1H), 6.17 - 6.09 (m, 2H), 4.02 -

3.91 (m, 1H), 3.60 (s, 1H), 3.06 (dd, J = 14.9, 8.3 Hz, 1H), 2.88 (s, 6H), 2.55 (ddd, J = 14.9, 7.5, 1.1 Hz, 1H), 1.27

(dd, J = 6.2, 2.4 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 152.0, 151.2, 124.8, 117.8, 103.7, 95.3, 55.6, 41.3,

37.0, 22.4. HRMS (ES+): Found: 177.1383 ([M+H] C11H17N2 Requires: 177.1392).

(±)-cis and (±)-trans-2,3-Dimethylindolines (5m and 5n)

Sodium cyanoborohydride (3.0 g, 3 eq.) was dissolved in glacial acetic acid (20

mL) and the resulting solution carefully transferred by canula to a solution of

2,3-dimethylindole (2.28 g, 15.7 mmol) in glacial acetic acid (130 mL). The

resulting solution was stirred in an open flask for 12 h at room temperature. Sat. K2CO3 (aq.) was added until the

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reaction mixture had become basic. Extraction with Et2O (3 × 100 mL) followed by drying of the combined organic

phases over MgSO4 and rotary evaporation afforded crude product which was purified by FC (eluent: 3%

EtOAc/hexanes) to afford:

(±)-cis-2,3-dimethylindoline (5m)[3] (211 mg, 1.43 mmol, 9%). 1H NMR (400 MHz, CDCl3, ppm): δ 7.11-7.03

(m, 2H), 6.78-6,74 (m, 1H), 6.64 (d, J = 7.7 Hz, 1H), 4.01-3.94 (m, 1H), 3.57 (br s, 1H), 3.33-3.26 (m, 1H), 1.21

(d, J = 7.2 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H). LRMS (m/z +ES): Found: 148.6 (M+H C10H14N Requires: 148.1).

Spectroscopic data in agreement with literature.[3]

(±)-trans-2,3-dimethylindoline (5n)[3] (502 mg, 3.41 mmol, 22%). 1H NMR (400 MHz, CDCl3, ppm): δ 7.08-

7.01 (m, 2H), 6.78-6.74 (m, 1H), 6.65-6.63 (m, 1H), 3.88 (br s, 1H), 3.53-3.46 (m 1H), 2.89-2.81 (m, 1H), 1.36-

1.33 (m, 6H). LRMS (m/z +ES): Found: 148.3 (M+H C10H14N Requires: 148.1). Spectroscopic data in agreement

with literature.[3]

(±)-cis-1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole (5o)[13]

Following General Procedure A, 1,2,3,4-tetrahydrocyclopenta[b]indole (236 mg, 1.5 mmol) and

Sn (797 mg, 6.7 mmol) were reacted for 4 h during which the solution went from a red suspension

to a clear yellow solution. After work-up, the crude residue was purified by FC (eluent: 25 - 50%

CH2Cl2/hexanes) to yield indoline product as a yellow oil (81 mg, 0.51 mmol, 34%). 1H NMR (400 MHz, CDCl3,

ppm): 7.10 - 6.95 (m, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 4.37 (ddd, J = 8.6, 6.0, 2.3 Hz, 1H),

4.12 - 3.15 (m, 2H), 1.96 (dddd, J = 12.5, 10.6, 8.8, 6.5 Hz, 1H), 1.85 - 1.49 (m, 5H). Spectroscopic data in

agreement with literature.[13]

(±)-cis-2,3,4,4a,9,9a-Hexahydro-1H-carbazole (5p)[3]

Following General Procedure A, 2,3,4,9-tetrahydro-1H-carbazole (499 mg, 2.91 mmol) and Sn

(1.59 g, 13.4 mmol) were reacted for 4 h during which the solution went from a red suspension to

a clear yellow solution. After work up, the crude residue was purified by FC (eluent: 5%

EtOAc/hexanes) to afford product as a beige solid (375 mg, 2.18 mmol, 75%). 1H NMR (400 MHz, CDCl3, ppm):

7.09 (d, J = 7.4 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.75 (td, J = 7.4, 1.0 Hz, 1H), 6.68 (d, J = 7.4 Hz, 1H), 3.73

(td, J = 6.7, 5.1 Hz, 1H), 3.10 (q, J = 6.7 Hz, 1H), 1.82 – 1.72 (m, 2H), 1.72 – 1.62 (m, 1H), 1.61 – 1.49 (m, 2H),

1.48 – 1.25 (m, 3H). HRMS (m/z +ES): Found: 174.1282 (M+H C12H16N Requires: 174.1283). Spectrscopic data

in agreement with literature.[3]

tert-Butyl 3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate[14]

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole (0.50 g, 2.9 mmol, 1 eq.), Boc2O (0.75 mL, 3.25

mmol, 1.13 eq.) and K2CO3 (454 mg, 3.25 mmol, 1.13 eq.) was suspended in i-PrOH (5 mL)

and H2O (6 mL) and stirred at rt for 21 h. The mixture was diluted with EtOAc (50 mL), washed

with brine (20 mL), dried of MgSO4 and conc. in vacuo. The crude mixture was purified by FC (eluent: 25%

EtOAc/hexanes) to afford protected carboline product as a white oily solid (610 mg, 2.24 mmol, 77%). 1H NMR

(400 MHz, CDCl3, ppm): 8.10 – 7.80 (m, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.22 - 7.01 (m,

2H), 4.65 (s, 2H), 3.77 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 1.51 (s). HRMS (CI+): Found: 273.1589 ([M+H]

C16H21N2O2 Requires: 273.1598). Spectroscopic data in agreement with literature.[14]

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(±)-cis-tert-Butyl 4,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole-2(3H)-carboxylate (5q)

To a well stirred solution of tert-butyl 3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

(25 mg, 0.092 mmol, 1 eq.) in glacial AcOH (1.5 mL) was added NaBH3CN (23 mg, 0.37 mmol,

3 eq.). The solution was stirred at rt for 16 h. Then NaOH (10% w/v, 8 mL) was added and the

solution was extracted with CH2Cl2 (3 × 5 mL), dried over MgSO4 and conc. in vacuo. The crude residue was

purified by FC (eluent: 25% - 50% CH2Cl2/hexanes) to afford product as a colourless oil (17 mg, 0.063 mmol,

68%). IR (film, cm-1): 3332, 2975, 2928, 1686 (C=O), 1610, 1478, 1415, 1365, 1246, 1168, 1019, 868, 743. 1H

NMR (400 MHz, DMSO-d6, ppm): 6.99 (d, J = 7.2 Hz, 1H), 6.89 (td, J = 7.6, 1.3 Hz, 1H), 6.53 (t, J = 7.3 Hz,

1H), 6.46 (d, J = 7.7 Hz, 1H), 5.59 (s, 1H), 3.74 (s, 1H), 3.41 (dd, J = 13.6, 4.2 Hz, 1H), 3.27 - 3.08 (m, 3H), 2.49

(p, J = 1.7 Hz, 1H), 1.97 - 1.79 (m, 1H), 1.67 (m , 1H), 1.37 (s, 9H). 13C NMR (101 MHz, DMSO-d6, ppm):

154.5, 151.4, 131.1, 127.3, 123.4, 117.1, 108.5, 78.4, 56.8, 44.4, 40.3, 38.5, 28.11, 25.9. HRMS (ES+): Found:

275.1764 ([M+H] C16H23N2O2 Requires: 275.1760).

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3. Synthesis of sulfonylating agent - 2-Isopropyl-4-nitrobenzenesulfonyl chloride

2-Isopropyl-4-nitrophenol[15]

2-isoPropylphenol (6.1 mL, 45 mmol, 1 eq.) was dissolved in EtOAc (200 mL) and the solution

was cooled to 0 °C before conc. HNO3 (68% w/v, 2.95 mL, 45 mmol) was added. The cold

solution was then transferred to an ultrasonication bath and sonication was started. ZnCl2 (6.1 g, 45 mmol) was

added and the dark red solution was sonicated for 1 h. Then the solution was washed with H2O (2 100 mL), brine

(100 mL) and dried over MgSO4. The solution was conc. in vacuo to yield a dark red oil that was purified by FC

(eluent: 20% EtOAc/hexanes) to afford nitrated product as a red, oily solid (3.1 g, 17.1 mmol, 38%). 1H NMR

(400 MHz, CDCl3, ppm): 8.13 (d, J = 2.7 Hz, 1H), 8.01 (dd, J = 8.8, 2.7 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.47

(s, 1H), 3.29 (hept, J = 6.9 Hz, 1H), 1.34 - 1.25 (m, 6H). HRMS (ES+): Found: 182.0811 ([M+H] C9H12O3N

Requires: 182.0812). Spectroscopic data in agreement with literature.[15]

O-(2-Isopropyl-4-nitrophenyl) dimethylcarbamothioate

To a well stirred solution of 2-isopropyl-4-nitrophenol (3.0 g, 16.6 mmol, 1 eq.) in dry DMF

(100 mL) was added DABCO (3.71 g, 33.1 mmol, 2 eq.) and dimethylthiocarbomyl chloride

(3.07 g, 24.8 mmol, 1.5 eq.) at rt. The solution was heated to 50 °C left to stir for 5 days. The

reaction mixture was cooled down to room temperature and diluted with water (50 mL). The solution was extracted

with CH2Cl2 (3 75 mL) and the combined organic phase was washed with HCl (5% w/v, 50 mL), NaOH (1 M,

50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The

crude was purified by FC (eluent: 40% CH2Cl2/hexanes) to afford product as a yellow crystalline solid (2.72 g,

10.1 mmol, 62%). M.p 90-92 °C. IR (film, cm-1): 2965, 2871, 1523, 1481, 1395, 1346, 1287, 1226, 1184, 1121,

1073, 904, 733. 1H NMR (400 MHz, CDCl3, ppm): 8.22 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 8.8, 2.8 Hz, 1H), 7.15

(d, J = 8.8 Hz, 1H), 3.47 (s, 3H), 3.39 (s, 3H), 3.09 (hept, J = 7.0 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (101

MHz, CDCl3, ppm): 186.5, 156.0, 146.0, 142.9, 124.8, 122.6, 122.0, 43.6, 39.0, 27.7, 22.9. HRMS (CI+): Found:

269.0949 ([M+H] C12H17N3O232S2 Requires: 269.0954).

(S)-(2-Isopropyl-4-nitrophenyl) dimethylcarbamothioate

O-(2-isopropyl-4-nitrophenyl) dimethylcarbamothioate (834 mg, 3.1 mmol, 1 eq.) was

dissolved in DMA (10 mL) and heated to 180 °C in a microwave for 100 min. The solution

was conc. over a stream of N2 and the resulting residue was purified by FC (eluent: 10 %

EtOAc/hexanes) to afford product as an off-white solid (712 mg, 2.7 mmol, 85%). M.p 132-133 °C. IR (film, cm-

1): 3078, 2965, 2870, 1661, 1516, 1341, 1261, 1101, 1043, 905, 783, 748, 692, 656. 1H NMR (400 MHz, CDCl3,

ppm): 8.20 (d, J = 2.6 Hz, 1H), 8.02 (dd, J = 8.5, 2.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 3.53 (hept, J = 6.9 Hz,

1H), 3.15 (s, 3H), 3.04 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3, ppm): 165.0, 154.3, 149.0,

138.4, 135.7, 121.0, 120.8, 37.3, 31.6, 23.5. HRMS (ES+): Found: 269.0972 ([M+H] C12H17N2O332S Requires:

269.0960).

2-Isopropyl-4-nitrobenzenesulfonyl chloride

A solution of NCS (3.65 g, 27.3 mmol, 4 eq.) in MeCN (55 mL) was added dropwise to a well-

stirred suspension of S-(2-isopropyl-4-nitrophenyl) dimethylcarbamothioate (1.8 g, 6.8 mmol,

1 eq.) in MeCN (45 mL) and HCl (2 M, 9 mL) at 0 °C. The solution was stirred at 0 °C for 6 h

S11

before being diluted with iPr2O (45 mL), washed with H2O (45 mL) and brine (45 mL), dried over MgSO4 and

conc. in vacuo. The crude residue was purified by FC (eluent: 30% CH2Cl2/hexanes) to afford sulfonyl chloride 5

as a white solid (1.35 g, 5.1 mmol, 75% yield). M.p = 110-111 °C. IR (film, cm-1): 3100, 2972, 1541, 1531, 1373,

1352, 1179, 928, 787, 698, 615. 1H NMR (400 MHz, CDCl3): 8.43 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H),

8.20 (dd, J = 8.9, 2.3 Hz, 1H), 4.13 (hept, J = 6.8 Hz, 1H), 1.42 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3):

152.0, 151.8, 146.5, 130.2, 124.3, 121.5, 29.9, 23.8. HRMS (CI-): Found: 244.0287 ([M+Cl+O] C9H10NO532S

Requires: 244.0274).

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4. Synthesis of (±)-indoline sulfonamides 6-8a, 6b-f and 6i-q

General Procedure B – Indoline sulfonylation

To a well-stirred solution of (±)-indoline (1.0 eq.), arylsulfonyl chloride (1.0 eq.) and 4-DMAP-N-oxide (10-20

mol%) or N-methylimidazole (5-20 mol%) in CH2Cl2 under argon was added DIPEA (2 eq.). The solution was

stirred for several hours at room temperature. The solution was conc. in vacuo and the crude residue was purified

by FC to afford sulfonylated indolines.

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-methylindoline (6a)

Following General Procedure B, (±)-2-methylindoline (5a, 130.2 mg, 1.0 mmol), 2-

isopropyl-4-nitrobenzenesulfonyl chloride (264 mg, 1.0 mmol), 4-DMAP-N-oxide (14 mg,

0.1 mmol) and DIPEA (0.34 mL, 2 mmol) were reacted for 21 h. The resulting yellow

solution was conc. in vacuo and the crude residue purified by FC (eluent: 30% CH2Cl2/hexanes) to afford

sulfonamide product as a white solid (298 mg, 0.83 mmol, 83%). M.p 140-141 °C. IR (film, cm-1): 2964, 1530,

1478, 1348, 1165, 1107, 908, 785, 734, 649. 1H NMR (400 MHz, CDCl3, ppm): 8.27 (d, J = 2.2 Hz, 1H), 8.08 -

7.96 (m, 2H), 7.40 (dd, J = 7.7, 1.6 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.06 (td, J = 7.3, 6.8, 1.0 Hz, 1H), 4.48 (dqd, J

= 8.6, 6.4, 2.1 Hz, 1H), 3.87 (hept, J = 6.8 Hz, 1H), 3.26 - 3.13 (m, 1H), 2.61 (dd, J = 16.0, 2.1 Hz, 1H), 1.43 (d,

J = 6.4 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 151.8,

150.3, 143.0, 140.3, 130.6, 130.1, 128.0, 125.8, 124.6, 123.4, 120.7, 116.0, 59.0, 36.3, 30.2, 24.1, 23.5, 22.8.

HRMS (CI+): Found: 361.1219 ([M+H] C18H21N2O432S Requires: 361.1217).

(±)-2-Methyl-1-((4-nitrophenyl)sulfonyl)indoline (7a)[16–18]

Following General Procedure B, (±)-2-methylindoline (5a, 52 mg, 0.39 mmol), 4-

nitrobenzenesulfonyl chloride (103 mg, 0.47 mmol), 4-DMAP-N-oxide (5 mg, 0.039

mmol) and DIPEA (0.14 mL, 0.78 mmol) were reacted for 21 h. The resulting yellow

solution was conc. in vacuo and the crude residue purified by FC (eluent: 10% EtOAc2/hexanes) to afford

sulfonamide product as an off white solid (114 mg, 0.36 mmol, 92%). 1H NMR (400 MHz, CDCl3, ppm): 8.25

(d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 6.9 Hz, 1H) 7.07-7.13 (m 2H),

4.42 (ddq, J = 9.6, 6.7, 2.8 Hz, 1H), 2.95 (dd, J = 16.7, 9.6 Hz, 1H), 2.51 (dd, J = 16.7, 2.8 Hz, 1H), 1.47 (d, J =

6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 150.7, 144.3, 140.2, 131.8, 128.5, 128.3, 125.8, 125.6, 124.4,

117.3, 59.3, 36.0, 23.8. LRMS (m/z +ES): Found: 319.3 (M+H C15H15N2O432S Requires: 319.1). Spectroscopic

data in agreement with literature.[16–18]

(±)-2-Methyl-1-((2-nitrophenyl)sulfonyl)indoline (8a)[16,17]

Following General Procedure B, (±)-2-methylindoline (5a, 130.2 mg, 1 mmol), 2-

nitrobenzenesulfonyl chloride (220 mg, 1.0 mmol), 4-DMAP-N-oxide (14 mg, 0.1 mmol) and

DIPEA (0.34 mL, 2 mmol) were reacted for 21 h. The resulting yellow solution was conc. in

vacuo and the crude residue purified by FC (eluent: 25% CH2Cl2/hexanes) to afford sulfonamide

product as a dark red oil (238 mg, 0.75 mmol, 75%). IR (film, cm-1): 3023, 2983, 1542, 1513, 1210, 1109, 987. 1H

S13

NMR (400 MHz, CDCl3, ppm): 7.87 (dd, J = 7.9, 1.2 Hz, 1H), 7.67 (td, J = 7.9, 1.2 Hz, 1H), 7.65-7.61 (m, 3H),

7.25-7.18 (m, 2H), 7.08 (t, J = 7.9 Hz, 1H), 4.82-4.63 (m, 1H), 3.32 (dd, J = 15.9, 9.1 Hz, 1H), 2.61 (dd, 15.9, 2.0

Hz, 1H), 1.44 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, Toluene-d7, ppm): 148.6, 140.4, 133.2, 132.2, 131.6,

130.6, 130.5, 125.9, 124.5, 123.7, 116.0, 59.5, 36.0, 22.9. HRMS (m/z +ES): Found: 319.0762 (M+H

C15H15N2O432S Requires: 319.0753). Spectroscopic data in agreement with literature.[16,17]

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-(((triethylsilyl)oxy) methyl)indoline (6b)

Following General Procedure B, (±)-2-(((triethylsilyl)oxy)methyl) indoline (5b, 26.3 mg,

0.1 mmol), 2-isopropyl-4-nitrobenzene-sulfonyl chloride (26.4 mg, 0.1 mmol), NMI (0.4

L, 0.005 mmol, 5 mol%) and DIPEA (20 L, 0.2 mmol) were stirred for 27 h. The resulting

yellow solution was conc. in vacuo and the crude residue was purified by FC (eluent: 5% EtOAc/hexanes) to afford

the sulfonamide product as a yellow oil (27 mg, 0.055 mmol, 55%). IR (film, cm-1): 2957, 2875, 1531, 1478, 1461,

1407, 1348, 1240, 1165, 1108, 784, 749, 731. 1H NMR (400 MHz, CDCl3, ppm): 8.29 (dd, J = 2.0, 0.8 Hz, 1H),

8.10 – 8.00 (m, 2H), 7.40 (dd, J = 8.4, 1.1 Hz, 1H), 7.23 – 7.14 (m, 2H), 7.06 (td, J = 7.4, 1.1 Hz, 1H), 4.38 (dtd,

J = 7.7, 5.6, 4.1 Hz, 1H), 3.95 – 3.80 (m, 2H), 3.66 (dd, J = 10.1, 7.8 Hz, 1H), 3.07 (d, J = 5.6 Hz, 2H), 1.27 (d, J

= 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.9 Hz, 9H), 0.65 – 0.49 (m, 6H. 13C NMR (101 MHz, CDCl3,

ppm): 151.9, 150.4, 142.9, 141.3, 131.3, 130.2, 127.8, 125.7, 124.9, 123.6, 120.8, 116.0, 64.7, 63.4, 31.3, 30.5,

24.3, 23.6, 6.8, 4.4. HRMS (ES+): Found: 491.2045 ([M+H] C15H25NOSi Requires: 491.2036).

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-(((triisopropylsilyl) oxy)methyl)indoline (6c)

Following General Procedure B, (±)-2-(((triisopropylsilyl)oxy)methyl)indoline (5c, 30

mg, 0.1 mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (26.4 mg, 0.1 mmol), NMI (2

L, 0.02 mmol) and DIPEA (34 L, 0.2 mmol) were reacted for 20 h. The resulting yellow

solution was conc. in vacuo and the crude residue was purified by FC (eluent: 5% Et2O/hexanes) to afford the

sulfonamide product as a colourless oil (49 mg, 0.92 mmol, 92%). IR (film, cm-1): 2943, 2866, 1531, 1479, 1462,

1348, 1165, 1109, 988, 881, 785, 623, 575; 1H NMR (400 MHz, CDCl3, ppm): 8.26 (d, J = 2.3 Hz, 1H), 8.06 -

7.94 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 4.35 (tt, J = 7.1, 3.2 Hz,

1H), 3.97 (dd, J = 9.9, 4.0 Hz, 1H), 3.86 (p, J = 6.8 Hz, 1H), 3.77 (dd, J = 9.9, 7.5 Hz, 1H), 3.17 - 2.96 (m, 2H),

1.31 - 1.21 (m, 6H), 1.11 - 0.93 (m, 21H). 13C NMR (101 MHz, CDCl3, ppm): 151.8, 150.2, 142.7, 141.3, 131.3,

130.0, 127.7, 125.5, 124.8, 123.5, 120.7, 115.9, 65.4, 63.3, 31.1, 30.3, 24.2, 23.5, 17.9, 11.89. HRMS (ES-): Found:

531.2356 ([M-H] C27H39N2O5Si32S Requires: 531.2349).

(±)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((2-ethyl-4-nitrophenyl)sulfonyl)indoline (6d)

Following General Procedure B, (±)-2-(((tert-butyldimethylsilyl)oxy)methyl)indoline

(5d, 26 mg, 0.1 mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (26.4 mg, 0.1 mmol),

NMI (2 L, 0.02 mmol) and DIPEA (34 L, 0.2 mmol) were reacted for 20 h. The resulting

yellow solution was conc. in vacuo and the crude residue was purified by FC (eluent: 5% Et2O/hexanes) to afford

the sulfonamide product as a colourless oil (37 mg, 0.76 mmol, 76%). IR (film, cm-1): 2955, 2930, 2857, 1531,

1256, 1348, 1165, 1107, 837, 783, 644, 623, 573; 1H NMR (400 MHz, CDCl3, ppm): 8.27 (d, J = 2.1 Hz, 1H),

8.06 - 7.96 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.21 - 7.10 (m , 2H), 7.03 (t, J = 7.4 Hz, 1H), 4.37 (hept, J = 6.8 Hz,

1H), 3.93 - 3.81 (m, 2H), 3.69 (dd, J = 10.3, 6.9 Hz, 1H), 3.15 - 2.97 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H), 1.03 (d, J

= 6.7 Hz, 3H), 0.78 (s, 9H), 0.01 (d, J = 17.2 Hz, 6H); 13C NMR (101 MHz, CDCl3, ppm): 151.7, 150.2, 142.9,

S14

141.3, 131.3, 129.9, 127.7, 125.5, 124.7, 123.5, 120.7, 115.7, 65.1, 63.3, 31.2, 30.3, 25.7, 24.2, 23.5, 18.1, -5.5.

HRMS (CI+): Found: 491.2025 ([M+H] C24H35N2O532SSi Requires: 491.2030).

(±)-2-Isopropyl-1-((2-isopropyl-4-nitrophenyl)sulfonyl)indoline (6e)

Following General Procedure B, (±)-2-isopropylindoline (5e, 14.5 mg, 0.09 mmol), 2-

isopropyl-4-nitrobenzenesulfonyl chloride (23.6 mg, 0.09 mmol), 4-DMAP-N-oxide (2.5

mg, 0.02 mmol 20 mol%) and DIPEA (34 L, 0.2 mmol) were reacted for 16.5h. The

resulting yellow solution was conc. in vacuo and the crude residue purified by FC (eluent:

20% EtOAc/hexanes) to afford sulfonamide product as a yellow oil (24 mg, 0.061 mmol, 68%). IR (film, cm-1):

3101, 3046, 2965, 2936, 2874, 1530, 1479, 1462, 1348, 1167, 1096, 785, 698. 1H NMR (400 MHz, CDCl3, ppm):

8.23 (d, J = 1.8 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 7.6

Hz, 1H), 7.04 (td, J = 7.4, 1.0 Hz, 1H), 4.15 (ddd, J = 9.1, 5.1, 2.4 Hz, 1H), 3.82 (hept, J = 6.8 Hz, 1H), 2.83 (m,

1H), 2.73 (dd, J = 16.6, 2.5 Hz, 1H), 2.15 (hept, J = 6.8, 1H), 1.21 (d, J = 6.8 Hz, 3H), 0.95 (m, 6H), 0.83 (d, J =

6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 152.0, 150.4, 142.4, 141.6, 132.6, 130.9, 127.9, 125.3, 125.1,

123.5, 120.7, 117.0, 68.1, 33.3, 30.4, 30.2, 24.4, 23.5, 18.7, 16.4. HRMS (CI+): Found: 389.1530 ([M+H]

C20H25N2O432S Requires: 389.1530).

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-n-butylindoline (6f)

Following General Procedure B, (±)-2-n-butylindoline (5f, 15.7 mg, 0.09 mmol), 2-

isopropyl-4-nitrobenzenesulfonyl chloride (23.6 mg, 0.09 mmol), 4-DMAP-N-oxide (2.5

mg, 0.018 mmol, 20 mol%) and DIPEA (31 L, 0.18 mmol) were reacted for 24 h. The

resulting yellow solution was conc. in vacuo and the crude residue purified by FC (eluent: 30% CH2Cl2/hexanes)

to afford sulfonamide product as a yellow oil (28 mg, 0.07 mmol, 76%). IR (film, cm-1): 2959, 2932, 2872, 1530,

1462, 1348, 1165, 785, 696, 623, 577. 1H NMR (400 MHz, CDCl3, ppm): 8.24 (d, J = 2.1 Hz, 1H), 8.08 - 7.96

(m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.23 - 7.10 (m, 2H), 7.05 (td, J = 7.4, 1.0 Hz, 1H), 4.31 (tdd, J = 8.8, 5.1, 1.9

Hz, 1H), 3.83 (hept, J = 6.9 Hz, 1H), 3.00 (ddt, J = 16.0, 9.1, 1.2 Hz, 1H), 2.67 (dd, J = 16.0, 1.7 Hz, 1H), 1.81

(dtd, J = 13.1, 7.8, 7.2, 5.1 Hz, 1H), 1.72 - 1.58 (m, 1H), 1.43 - 1.27 (m, 4H), 1.23 (d, J = 6.7 Hz, 3H), 0.98 (d, J

= 6.8 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 151.9, 150.4, 142.9, 140.8, 131.8,

130.6, 128.0, 125.7, 125.1, 123.5, 120.8, 116.9, 63.4, 36.0, 34.1, 30.4, 27.2, 24.4, 23.6, 22.6, 14.1. HRMS (ES-):

Found: 401.1542 ([M-H] C21H25N2O432S Requires: 401.1535).

(±)-5-Chloro-1-((2-isopropyl-4-nitrophenyl)sulfonyl)-2-methylindoline (6i)

Following General Procedure B, (±)-5-chloro-2-methylindoline (5i, 20 mg, 0.12

mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (31 mg, 0.12 mmol) and NMI (1.5

L, 0.012 mmol, 10 mol%) and DIPEA (44 L, 0.24 mmol) were reacted for 16 h. The

resulting yellow solution was conc. in vacuo and the crude residue was purified by FC (eluent: 30%

EtOAc/hexanes) to afford the sulfonamide product as a white oily solid (24 mg, 0.063 mmol, 32%). IR (film, cm-

1): 2965, 2932, 2870, 1531, 1474, 1348, 1165, 785, 733, 698, 631, 583; 1H NMR (400 MHz, CDCl3, ppm): 8.28

(d, J = 2.3 Hz, 1H), 8.06 (dd, J = 8.8, 2.3 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.19 - 7.10

(m, 2H), 4.48 (dqd, J = 8.8, 6.4, 2.2 Hz, 1H), 3.83 (hept, J = 6.8 Hz, 1H), 3.19 (dd, J = 16.3, 9.2 Hz, 1H), 2.60 (dd,

J = 16.4, 2.2 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.25 (d, J = 6.8 Hz, 1H), 1.08 (d, J = 6.7 Hz, 1H). 13C NMR (101

S15

MHz, CDCl3, ppm): 151.9, 150.5, 142.8, 139.2, 132.7, 130.2, 130.0, 128.2, 126.1, 123.7, 120.9, 117.0, 59.5,

36.2, 30.3, 24.2, 23.7, 22.9. HRMS (ES+): Found: 395.0759 ([M+H] C18H2035ClO4N232S Requires: 395.0754.

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2,5-methylindoline (6j)

Following General Procedure B: (±)-2,5-dimethylindoline (5j, 25 mg, 0.17 mmol), 2-

isopropyl-4-nitrobenzenesulfonyl chloride (45 mg, 0.17 mmol) and NMI (1.5 L, 0.012

mmol, 7 mol%) and DIPEA (59 L, 0.34 mmol) were stirred for 21.5 h. The resulting

yellow solution was conc. in vacuo and the crude residue was purified by FC (eluent: 50% CH2Cl2/hexanes) to

afford the sulfonamide product as a white solid (53 mg, 0.15 mmol, 87%). M.p 154-155 °C. IR (film, cm-1): 3100,

2967, 2930, 2870, 1530, 1487, 1346, 1163, 785, 733, 637, 584. 1H NMR (400 MHz, CDCl3, ppm): 8.26 (d, J =

2.3 Hz, 1H), 8.03 (dd, J = 8.7, 2.3 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.02-6.94 (m, 2H),

4.46 (dqd, J = 8.8, 6.5, 2.1 Hz, 1H), 3.88 (hept, J = 6.8 Hz, 1H), 3.14 (dd, J = 16.1, 9.1 Hz, 1H), 2.55 (dd, J = 15.9,

2.0 Hz, 1H), 2.29 (s, 3H), 1.41 (d, J = 6.5 Hz, 3H), 1.24 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H); 13C NMR

(101 MHz, CDCl3, ppm): 151.9, 150.4, 143.2, 138.0, 134.7, 131.0, 130.2, 128.6, 126.5, 123.5, 120.8, 116.1,

59.2, 36.4, 30.3, 24.3, 23.6, 22.9, 21.1. HRMS (CI+): Found: 375.1383 ([M+H] C19H23O4N232S Requires:

375.1373.

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-5-methoxy-2-methylindoline (6k)

Following General Procedure B, (±)-5-methoxy-2-methylindoline (5k, 16 mg, 0.1

mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (26.4 mg, 0.1 mmol), NMI (2 L,

0.02 mmol) and DIPEA (34 L, 0.2 mmol) were reacted for 14 h. The resulting yellow

solution was conc. in vacuo and the crude residue was purified by FC (eluent: 50% - 100% CH2Cl2/hexanes) to

afford the sulfonamide product as a yellow oil (31 mg, 0.079 mmol, 79%). IR (film, cm-1): 2966, 1596, 1529,

1486, 1347, 1262, 1164, 1033, 904, 811, 784, 636. 1H NMR (400 MHz, CDCl3, ppm): 8.25 (d, J = 2.2 Hz, 1H),

8.09 - 7.90 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.9 Hz, 2H), 4.42 (dtt, J = 8.6, 6.6, 3.3 Hz, 1H), 3.86

(hept, J = 6.9 Hz, 1H), 3.77 (s, 3H), 3.08 (dd, J = 16.1, 9.0 Hz, 1H), 2.51 (dd, J = 16.1, 2.0 Hz, 1H), 1.39 (d, J =

6.5 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3): 157.5, 151.8,

150.2, 142.8, 133.5, 132.8, 130.3, 123.4, 120.7, 117.6, 113.0, 111.6, 59.2, 55.7, 36.4, 30.3, 24.3, 23.4, 22.7. HRMS

(ES+): Found: 391.1250 ([M+H] C19H23O5N232S Requires: 391.1249.

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-N,N,2-trimethylindolin-6-amine (6l)

Following General Procedure B, (±)-N,N-2-trimethylindolin-6-amine (5l, 15 mg,

0.085 mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (34 mg, 0.128 mmol, 1.5

eq.) and 4-DMAP-N-oxide (2.4 mg, 0.2 mmol) and DIPEA (30 L, 0.17 mmol) were

reacted for 4.5 h. The resulting yellow solution was conc. in vacuo and the crude residue purified by FC (eluent:

50% CH2Cl2/0.1% Et3N/hexanes) to afford sulfonamide product as an orange solid (24 mg, 0.058 mmol, 69%).

M.p 136-137 °C. IR (film, cm-1): 2964, 1619, 1530, 1461, 1347, 1164, 1109, 784, 630. 1H NMR (400 MHz, CDCl3,

ppm): 8.26 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 8.7, 2.2 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H),

6.83 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 8.3, 2.4 Hz, 1H), 4.47 (dqd, J = 8.6, 6.5, 2.0 Hz, 1H), 3.93 (h, J = 6.8 Hz,

1H), 3.09 (ddd, J = 15.4, 9.1, 1.3 Hz, 1H), 2.91 (s, 6H), 2.49 (dd, J = 15.4, 2.0 Hz, 1H), 1.43 (d, J = 6.4 Hz, 3H),

1.24 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3, ppm): 151.8, 151.0, 150.2, 143.4,

S16

141.3, 130.0, 125.8, 123.3, 120.6, 118.0, 109.1, 100.8, 59.9, 40.9, 35.3, 30.1, 24.1, 23.5, 23.0. HRMS (ES+):

Found: 404.1655 ([M+H] C20H26N3O432S Requires: 404.1644).

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-cis-2,3-dimethylindoline (6m)

Following General Procedure B, (±)-cis-2,3-dimethylindoline (5m, 15 mg, 0.1 mmol), 2-

isopropyl-4-nitrobenzenesulfonyl chloride (40 mg, 0.15 mmol, 1.5 eq.), 4-DMAP-N-oxide

(1.5 mg, 0.1 mmol, 10 mol%) and NEt3 (28 L, 0.20 mmol) were reacted for 4.5 h. The

resulting yellow solution was conc. in vacuo and the crude residue was purified by FC

(eluent: 25% CH2Cl2/hexanes) to afford sulfonamide product as a yellow oil (29 mg, 0.078 mmol, 76%). IR (film,

cm-1): 3107, 3095, 2922, 1660, 1609, 912, 892. 1H NMR (400 MHz, CDCl3, ppm): δ 8.28 (d, J = 2.2 Hz, 1H),

8.15-8.07 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.25-7.20 (m, 1H), 7.13-7.09 (m, 2H), 4.49 (dq, J = 8.6, 6.7 Hz, 1H),

3.86 (p, J = 6.7 Hz, 1H), 3.28 (qd, J = 7.8, 6.4 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.26 (dd, J = 7.0, 3.1 Hz, 6H),

1.00 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3, ppm): δ 151.7, 150.3, 143.2, 139.8, 136.1, 130.4, 128.0,

124.9, 124.0, 123.4, 120.7, 116.3, 63.7, 38.5, 30.3, 24.6, 23.4, 15.9, 12.0. HRMS (m/z +ES): Found: 375.1369

(M+H C19H23N2O432S Requires: 375.1379).

(±)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-trans-2,3-dimethylindoline (6n)

Following General Procedure A, (±)-trans-2,3-dimethylindoline (5n, 15 mg, 0.1 mmol),

2-isopropyl-4-nitrobenzenesulfonyl chloride (40 mg, 0.15 mmol, 1.5 eq.), 4-DMAP-N-

oxide (1.5 mg, 0.1 mmol, 10 mol%) and NEt3 (28 L, 0.20 mmol) were reacted for 4.5 h.

The resulting yellow solution was conc. in vacuo and the crude residue was purified by FC

(eluent: 25% CH2Cl2/hexanes) to afford sulfonamide product as a yellow oil (21 mg, 0.056 mmol, 55%). IR (film,

cm-1): 3013, 3007, 2893, 1609, 1577, 1483, 928, 837, 716. 1H NMR (400 MHz, CDCl3, ppm): δ 8.30 (d, J = 2.0

Hz, 1H), 8.13-8.07 (m, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.27-7.22 (m, 1H), 7.1 (d, J = 7.4 Hz, 1H), 7.10 (td, J = 7.4,

1.0 Hz, 1H), 4.01-3.89 (m, 2H), 2.84 (qd, J = 7.1, 2.4 Hz, 1H), 1.44 (d, J = 6.5 Hz, 3H), 1.30 (d, J = 6.5 Hz, 3H),

0.98 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 7.1 Hz, 3H).13C NMR (100 MHz, CDCl3, ppm): δ 151.8, 150.2, 142.5, 139.6,

136.1, 130.7, 128.1, 125.0, 124.7, 124.3, 123.4, 120.6, 116.1, 66.5, 43.7, 30.2, 24.3, 23.4, 22.2, 21.6. HRMS (m/z

+ES): Found: 375.1372 (M+H C19H23N2O432SRequires: 375.1379).

(±)-cis-4-((2-Isopropyl-4-nitrophenyl)sulfonyl)-1,2,3,3a,4,8b-hexahydr-ocyclopenta[b]indole (6o)

Following General Procedure B, (±)-cis-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (5o,

15.9 mg, 0.1 mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (26.0 mg, 0.1 mmol) and

4-DMAP-N-oxide (1.4 mg, 0.01 mmol) and DIPEA (34 L, 0.2 mmol) were reacted for 26

h. The resulting yellow solution was conc. in vacuo and the crude residue purified by FC

(eluent: 30% CH2Cl2/hexanes) to afford sulfonamide product as a yellow solid (28 mg, 0.072 mmol, 72%). IR

(film, cm-1): 3107, 2961, 2870, 1530, 1477, 1460, 1348, 1163, 839, 785, 746, 623. 1H NMR (400 MHz, CDCl3,

ppm): 8.29 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H),

7.17 – 7.11 (m, 2H), 7.04 (td, J = 7.4, 1.1 Hz, 1H), 4.66 (ddd, J = 9.6, 7.2, 2.9 Hz, 1H), 3.94 (h, J = 6.8 Hz, 1H),

3.84 (td, J = 8.4, 2.4 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.06 - 1.92 (m, 2H), 1.91 - 1.82 (m, 1H), 1.66 (dtt, J = 12.6,

6.3, 3.8 Hz, 1H), 1.46 (dtt, J = 12.7, 10.2, 6.4 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.7 Hz, 3H). 13C NMR

(101 MHz, CDCl3, ppm): 152.0, 150.3, 143.1, 142.0, 134.8, 129.5, 128.1, 125.2, 124.6, 123.7, 120.8, 114.3,

S17

68.0, 45.7, 36.2, 34.3, 30.2, 24.1, 24.0, 23.9. HRMS (CI+): Found: 387.1373 ([M+H] C20H23O4N232S Requires:

387.1373).

(±)-cis-9-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazole (6p)

Following General Procedure B, (±)-cis-2,3,4,4a,9,9a-hexahydro-1H-carbazole (5p, 13

mg, 0.075 mmol), 2-isopropyl-4-nitrobenzenesulfonyl chloride (28 mg, 0.11 mmol, 1.5 eq.),

4-4-DMAP-N-oxide (1.0 mg, 0.1 mmol, 15 mol%) and DIPEA (30 L, 0.17 mmol) were

reacted for 4.5 h. The resulting yellow solution was conc. in vacuo and the crude residue

was purified by FC (20% CH2Cl2:hexanes) to afford product as an oily solid (20 mg, 0.05 mmol, 68%). IR (film,

cm-1): 3013, 3007, 2988, 1657, 1438, 1232, 932, 889. 1H NMR (400 MHz, CDCl3): 8.25 (d, J = 2.3 Hz, 1H),

8.17 (d, J = 8.7 Hz, 1H), 8.07 (dd, J = 8.7, 2.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.23 – 7.16 (m, 1H), 7.15 – 7.04

(m, 2H), 4.32 (ddd, J = 10.6, 7.4, 6.1 Hz, 1H), 3.86 (hept, J = 6.8 Hz, 1H), 3.25 – 3.12 (m, 1H), 2.25 – 2.16 (m,

1H), 2.15 – 2.06 (m, 1H), 1.79 – 1.57 (m, 2H), 1.56 – 1.39 (m, 2H), 1.31 – 1.07 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H),

0.99 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3): 151.83, 150.46, 143.56, 140.91, 134.96, 130.68, 127.90,

124.95, 123.57, 123.51, 120.87, 116.90, 64.56, 40.36, 30.30, 29.11, 24.43, 24.31, 23.55, 22.75, 20.71. HRMS

(ES+): Found: 401.1461 ([M+H] C21H25N2O432S Requires: 401.1457).

(±)-cis-tert-Butyl-9-((2-isopropyl-4-nitrophenyl)sulfonyl)-4,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole-

2(3H)-carboxylate (6q)

Following General Procedure B, (±)-cis-tert-butyl 4,4a,9,9a-tetrahydro-1H-pyrido[3,4-

b]indole-2(3H)-carboxylate (5q, 20 mg, 0.072 mmol), 2-isopropyl-4-nitrobenzenesulfonyl

chloride (28 mg, 0.11 mmol, 1.5 eq.), 4-DMAP-N-oxide (1.0 mg, 0.1 mmol, 15 mol%) and

DIPEA (30 L, 0.17 mmol) were reacted for 4.5 h. The resulting yellow solution was conc.

in vacuo and the crude residue was purified by FC (eluent: 0 - 20% EtOAc/hexanes) to afford sulfonamide product

as a yellow oil (31 mg, 0.062 mmol, 87%). IR (film, cm-1): 2972, 1691, 1602, 1530, 1476, 1460, 1408, 1279, 1165,

1113, 1055, 982, 784. 1H NMR (400 MHz, CDCl3): 8.27 (d, J = 2.3 Hz, 1H), 8.08 - 7.96 (m, 2H), 7.36 (d, J =

8.1 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.16 - 7.05 (m, 2H), 4.45 (s, 1H), 4.04 - 3.79 (m, 2H), 3.63 - 3.19 (m, 3H),

2.96 (ddd, J = 12.9, 10.6, 4.6 Hz, 1H), 2.19 – 2.03 (m, 2H), 1.38 (s, 9H), 1.26 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.7

Hz, 3H). 13C NMR (101 MHz, CDCl3): 155.0, 151.9, 150.5, 142.9, 141.4, 132.8, 130.1, 128.6, 125.2, 124.3,

123.6, 121.0, 116.0, 80.2, 61.4, 60.5, 39.5, 38.4, 30.3, 28.5, 24.2, 23.9, 23.7. HRMS (ES+): Found: 502.2037

([M+H] C25H32N3O632S Requires: 502.2012).

S18

5. Synthesis and resolution of catalysts 4a and 4b

CATALYST 4a

2-(2,4-Bis(trifluoromethyl)phenyl)-4-chloropyridine

2,4-Bis(trifluoromethyl)benzeneboronic acid (2.54 g, 10.14 mmol, 1.5 eq.), potassium

phosphate (2.86 g, 13.52 mmol, 2 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.20 g,

0.20 mmol, 3 mol%) were dissolved in a degassed 1:3 H2O:THF solvent system. After the

addition of 2,4-dichloropyridine (1.00 g, 6.76 mmol) the orange solution was heated under

reflux (90 °C) for 16 h. The reaction mixture was then allowed to cool to room temperature and EtOAc (10 mL)

was added. The resulting organic layer was washed with brine solution (2 × 20 mL), separated, dried over MgSO4

and conc. in vacuo. The resulting residue was purified by FC (0-20% EtOAc:hexanes) to afford product as an off-

white powder (1.78 g, 5.48 mmol, 81%). 1H NMR (400 MHz, CDCl3, ppm): δ 8.67 (d, J = 5.5 Hz, 1H), 8.07 (s,

1H), 7.92 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 5.6, 2.0 Hz, 1H).

Spectroscopic data in agreement with literature.[19]

2-(2-Bromo-4,6-bis(trifluoromethyl)phenyl)-4-chloropyridine

2-(2,4-Bis(trifluoromethyl)phenyl)-4-chloropyridine (0.76 g, 2.49 mmol), N-bromosuccinimide

(0.89 g, 4.98 mmol, 2 eq.) and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol, 5

mol%) were added to a microwave vial. After acetonitrile (14 mL) was added, the reaction

mixture was heated to 180 °C for 20 min in a microwave. The resulting brown solution was

purified by FC (0-15% EtOAc:hexanes) to provide 2-(2-bromo-4,6-bis(trifluoromethyl)phenyl)-4-chloropyridine

as a white crystalline solid (0.75 g, 1.87 mmol, 38%). M.p. = 137-139 oC. IR (film, cm-1): 3097, 3033, 2932, 2837,

1517, 1433, 984, 837. 1H NMR (400 MHz, CDCl3, ppm): δ 8.67 (d, J = 5.4 Hz, 1H), 8.18-8.17 (m, 1H), 8.03 (d, J

= 1.2 Hz, 1H), 7.45 (dd, J = 5.4, 2.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H). 13C (100 MHz, CDCl3): δ 122.5, 124.1,

124.9, 126.2, 126.4, 133.3, 139.8, 144.4, 150.4, 156.4. 19F (377 MHz, CDCl3): δ -58.3, 63.1. HRMS (ES+): Found:

403.9201 ([M+H] C13H679Br35ClF6N Requires: 403.9198).

2-(2-Bromo-4,6-bis(trifluoromethyl)phenyl)-4-chloropyridine-N-oxide

2-(2-bromo-4,6-bis(trifluoromethyl)phenyl)-4-chloropyridine (0.250 g, 0.649 mmol) was

dissolved in a solution of dichloromethane (5 mL) and distilled water (2 mL) and cooled to 0

°C. Sodium bicarbonate (0.109 g, 1.30 mmol, 2 eq.) was added and a large fraction of m-CPBA

(0.224 g, 1.30 mmol, 2 eq.). Once the reaction mixture was warmed to room temperature, the

rest of the m-CPBA was added and the solution was heated to reflux for 16 h. The reaction was then quenched

with 10 mL of Na2SO4 solution and the organic phase was washed with NaHCO3 (10 mL) and brine solution (20

mL) adding CH2Cl2 (3 × 15 mL) before each wash. The resulting solution was dried over magnesium sulfate,

concentrated by rotary evaporation and purified by FC (65% EtOAc:hexanes) to afford product as an off-white

oil, which solidified upon drying in vacuo (0.210 g, 0.501 mmol, 77%). M.p. = 81-83 oC. IR (film, cm-1): 2932,

1450, 1404, 1335, 1265. 1H NMR (400 MHz, CDCl3, ppm): δ 8.29 (d, J = 7.0 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H),

7.42 (dd, J = 7.0, 3.0 Hz, 1H), 7.29 (s, 1H). 13C (100 MHz, CDCl3, ppm): δ 146.2, 140.6, 135.2, 133.8, 133.4,

133.3, 131.0, 129.6, 127.5, 127.1, 122.8. 19F (377 MHz, CDCl3, ppm): δ -60.6, -63.1. HRMS (ES+): Found:

419.9151 ([M+H] C13H6779Br35ClF6NO Requires: 419.9147).

S19

2-(2-Bromo-4,6-bis(trifluoromethyl)phenyl)-4-(dimethylamino)pyridine-N-oxide

2-(2-Bromo-4,6-bis(trifluoromethyl)phenyl)-4-chloropyridine-N-oxide (0.111 g, 0.264 mmol)

was dissolved in MeCN (1 mL) in a microwave vial. Dimethylamine (60% w.t. in water, 1.2

mL) was added before the reaction mixture was heated to 100 °C for 30 min in a microwave.

The resulting pale yellow solution was concentrated by rotary evaporation and purified by FC

(50% i-PrOH /EtOAc) to provide a yellow solid (0.104 g, 0.24 mmol, 92%). M.p = 67-68 oC. IR (film, cm-1): 2932,

1450, 1404, 1335, 1265. 1H NMR (400 MHz, CDCl3, ppm): δ 8.17 (m, 2H), 8.02 (s, 1H), 6.64 (dd, J = 7.5, 3.6

Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 3.08 (s, 6H). 13C (100 MHz, CDCl3) 147.9, 144.7, 139.8, 137.0, 133.2, 132.8

(q, 2JC-F = 34.6 Hz), 132.0 (q, 2JC-F = 32.4 Hz), 127.3, 123.6, 122.5, 120.9, 108.7, 39.9. 19F (376.7 MHz, CDCl3) -

60.1 (s), -63.2 (s). HRMS (ES+): Found: 428.9961 ([M+H] C15H1179BrF6NO Requires: 428.9959).

(±)-4-(Dimethylamino)-2-(5’-phenyl-3,5-bis(trifluoromethyl)-[1,1':3',1''-terphenyl]-2-yl)pyridine-N-oxide

(4a)

2-(2-Bromo-4,6-bis(trifluoromethyl)phenyl)-4-(dimethylamino)pyridine-N-oxide (0.500 g,

1.17 mmol) was dissolved in n-butanol (5 mL) and degassed overnight. It was then added to a

vacuum dried mixture of tris(dibenzylideneacetone)dipalladium (0.080 g, 0.087 mmol, 7.5

mol%), SPhos (0.072 g, 0.75 mmol, 0.15 eq.), anhydrous tripotassium phosphate (0.742 g,

3.50 mmol, 3 eq.) and 5’-m-terphenylboronic acid (0.639 g, 2.33 mmol, 2 eq.) under a nitrogen atmosphere. The

reaction mixture was heated to 90 °C for 72 h, then quenched by the addition of H2O (10 mL) and extracted from

H2O (10 mL) with CH2Cl2 (3 × 15 mL). The organic layer was dried over MgSO4, concentrated by rotary

evaporation and purified by flash FC (0-20% i-PrOH:EtOAc) to obtain product as a yellow solid (339 mg, 0.59

mmol, 50%). M.p = 87-95 oC. 1H NMR (400 MHz, CDCl3, ppm): δ 8.10 (s, 1H), 8.04-8.02 (m, 2H), 7.79-7.77 (m,

3H), 7.64-7.62 (m, 4H), 7.49-7.45 (m, 4H), 7.41-7.37 (m, 2H), 6.43 (dd, J = 7.5, 3.5 Hz, 1H), 6.29 (d, J = 3.5 Hz,

1H). 13C NMR (100 MHz, CDCl3, ppm): δ 145.1, 141.6 (2s), 140.2, 139.3, 139.2, 131.8 (2JC-F = 34 Hz), 130.4,

128.9, 127.7, 127.1, 126.1, 125.1, 122.3, 123.4 (2JC-F = 271 Hz), 123.0 (2JC-F = 269 Hz), 118.9, 118.7, 109.6, 108.4,

39.7. HRMS (ES+): Found: 579.1869 ([M+H] C33H25N2OF6 Requires: 579.1871).

The racemic catalyst (±)-4a was resolved using semi-prep HPLC (OD-H, 1 × 25 cm I.D., 3.3 mL/min, i-

PrOH:EtOAc:hexanes 92:4:4, 25 °C) and the enantiomers collected: (-)-4a: Rt = 46.2 min. (+)-4a: Rt = 52.2 min.

Each of the collected enantiomers were analysed using analytical HPLC (OD-H, 0.46 × 25 cm, 0.7 mL/min, i-

PrOH: EtOAc:hexanes 92:4:4, 20 oC):

(-)-4a: Rt = 49.0 min; >99% ee.

S20

(+)-4a: Rt = 55.2 min; >99% ee; []D27 +49.5 (c = 0.2, CHCl3).

CATALYST 4b

2,4-Diiodoaniline[20]

Aniline (1.82 mL, 20 mmol, 1 eq.) in MeOH (1 L) was added to a well stirred solution of NaI (11.99

g, 80 mmol, 4 eq.) and NaClO2 (3.62 g, 40 mmol, 2 eq.) in H2O (1 L). Then, HCl (aq. 12 M, 5 mL,

60 mmol, 3 eq.) was added. After 6.5 h, H2O (1 L) was added and the solution was extracted with

EtOAc (250 mL 10). The combined organic phase was stirred with a brine solution (1 L) with added Na2S2O5

(10 g) to remove iodine. The phases were separated and the organic phase dried over MgSO4 and conc. in vacuo.

The crude residue was purified by FC (eluent: 10% EtOAc/hexanes) to afford 2,4-diiodoaniline as a red solid (2.98

g, 8.6 mmol, 43%).1H NMR (400 MHz, CDCl3, ppm): 7.89 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H),

6.52 (d, J = 8.5 Hz, 1H), 4.13 (s, 2H). 13C NMR (101 MHz, CDCl3, ppm): 146.5, 145.8, 137.9, 116.2, 84.8, 78.9.

S21

HRMS (CI+): Found: 345.8572 ([M+H] C6H6NI2 Requires: 345.8584). Spectroscopic data in agreement with

literature.[20]

2,4-Bis(perfluorobutyl)aniline[20]

Perfluorobutyl iodide (9.5 mL, 55 mmol, 1 eq.) was added dropwise to a well stirred mixture of

2,4-diiodoaniline (10 g, 29 mmol, 1.05 eq.) and bronze (9.4 g, 148 mmol, 5.4 eq.) in DMSO (145

mL) at room temperature. The reaction mixture was then heated at 125 °C for 16 h. The resulting

suspension was concentrated over a stream of nitrogen and the crude reaction mixture purified by FC (eluent: 10%

EtOAc/hexanes) to afford product (6.46 g, 12.2 mmol, 44%) as a red liquid. 1H NMR (400 MHz, CDCl3, ppm):

7.51 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.6, 2.1 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 4.61 (s, 2H). 13C NMR (101

MHz, CDCl3, ppm): 148.8, 131.3, 130.8, 128.5, 127.5, 118.0, 117.8, 117.7 (C6), 116.6, 116.5, 113.2, 110.6,

110.3, 110.0. 19F NMR (377 MHz, CDCl3, ppm): -80.9, -81.2 (m), -108.3, -108.7 (m), -109.2, -109.6 (m), -110.3,

-110.7 (m), -111.0, -111.5 (m), -125.3, -126.0 (m). HRMS (ES-): Found: 528.0069 ([M-H] C14H4NF18 Requires:

528.0056). Spectroscopic data in agreement with literature.[20]

2,4-Bis(perfluorobutyl)-1-bromobenzene[20]

2,4-Bis(perfluorobutyl)aniline (98 mg, 0.19 mmol, 1 eq.) in MeCN (1 mL) was added dropwise

to a stirring mixture of CuBr2 (51 mg, 0.23 mmol, 1.2 eq.) and tert-butyl nitrite (38 L, 0.28 mmol,

1.5 eq.) in MeCN (2 mL) at 65°C. The resulting dark green solution was stirred for 24 h before

being quenched with HCl (20% v/w, 1 mL). The crude mixture was extracted with EtOAc (3 2 mL), dried over

MgSO4 and concentrated in vacuo. The crude product was purified by FC (eluent: 10% EtOAc/hexanes) to afford

aryl bromide product as a red oil (87 mg, 0.15 mmol, 79%). IR (film, cm-1): 2964, 2918, 2849, 1610, 1479, 1223,

1198, 1131, 1100, 865, 841, 740, 731. 1H NMR (400 MHz, CDCl3): 7.93 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 2.1

Hz, 1H), 7.62 (dd, J = 8.5, 2.1 Hz, 1H). HRMS (ES+): Found: 591.9145 ([M+H] C14H379BrF18 Requires: 591.9131).

Spectroscopic data in agreement with literature.[20]

2-(2,4-Bis(perfluorobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 2,4-bis(perfluorobutyl)-1-bromobenzene (2.9 g, 4.9 mmols, 1 eq.) in Et2O

(14.5 mL) at -78 °C was added t-BuLi (1.7 M in pentane, 5.75 mL, 9.8 mmols, 2 eq.). The

solution was then allowed to warm to rt for 5 min before being cooled to -78 °C and stirred

for a further 30 min. Then, MeOB(pin) (1.54 mL, 9.8 mmols, 2 eq.) was added and the solution was allowed to

warm to rt and stirred for 1.5 h. The reaction mixture was quenched by addition of sat. NH4Cl (14.5 mL), diluted

with EtOAc (14.5 mL) and washed with brine (7 mL). The phases were separated and the aqueous phase was

extracted with EtOAc (3 7 mL). The combined organic phases where dried over MgSO4 and conc. in vacuo. The

crude mixture was purified by FC (eluent: 100% hexanes) to afford boronic ester product as a colourless oil (2.38

g, 3.7 mmols, 76%). IR (film, cm-1): 2984, 2508, 1350, 1232, 1200, 1134, 1066, 806, 733. 1H NMR (400 MHz,

CDCl3, ppm): 7.83 - 7.72 (m, 3H), 1.38 (s, 12H). 13C NMR (101 MHz, CDCl3, ppm): 134.5, 132.8 (t, J = 24

Hz), 130.6 (t, J = 26 Hz), 129.2, 126.0, 119.0, 118.7, 116.4, 116.2, 116.1, 115.3, 110.3, 110.2, 85.2, 24.7. 19F NMR

(377 MHz, CDCl3, ppm): -81.1 (q, J = 21, 11 Hz), -106.5 (t, J = 15 Hz), -111.8 (t, J = 14 Hz), -120.8 (m), -122.9

(q, J = 22, 11 Hz), -125.6 (m), -125.8 (m). 11B NMR (128 MHz, CDCl3): 31.1 (s). HRMS (ES+): Found: 657.0889

([M+H] C20H16BO3F18 Requires: 657.0905).

S22

2-(2,4-Bis(perfluorobutyl)phenyl)-4-chloropyridine

Pd(PPh3)4 (211 mg, 0.18 mmol, 20 mol%) was added to a two-neck flask and evacuated and

refilled with N2 (× 3) before adding degassed THF (19 mL). 2-(2,4-bis(perfluorobutyl)phenyl)-

4,4,5,5-tetra-methyl-1,3,2-dioxaborolane (587 mg, 0.92 mmol, 1 eq.) and 2,4-dichloropyridine

(163 mg, 1.1 mmol, 1.2 eq.) were dissolved separately in THF (2 × 5 mL) and added to the

two-neck flask. K2CO3 (317 mg, 2.29 mmol, 2.5 eq.) in H2O (15 mL) was added and the biphasic mixture was

heated at 80 °C for 20 h. The organic phase was evaporated and the aqueous solution was diluted with EtOAc (75

mL) and H2O (50 mL), the phases were separated and the aqueous phase was extracted with EtOAc (3 × 50 mL).

The combined organic phase was dried over MgSO4, conc. in vacuo and the resulting residue purified by FC

(eluent: 5% Et2O/hexanes) to afford biaryl compound product as a colourless oil (430 mg, 0.69 mmol, 75%). IR

(film, cm-1): 3051, 1574, 1461, 1352, 1229, 1133, 1006, 882, 833, 799, 728. 1H NMR (400 MHz, CDCl3, ppm):

8.56 (dd, J = 4.7, 1.3 Hz, 1H), 7.89 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.38 (m, 2H). 13C

NMR (101 MHz, CDCl3, ppm): 158.3, 149.9, 144.1, 144.0, 132.7, 130.3, 127.5, 124.4, 123.6, 118.9 (t, 33 Hz),

116.4, 116.3, 116.1, 116.0, 115.2 (t, 32 Hz), 113.0, 112.7, 110.3, 109.2. 19F NMR (377 MHz, CDCl3, ppm): -

81.1 (q, J = 19, 10 Hz), -103.9 (t, J = 15 Hz), -111.6 (t, J = 14 Hz), -120.5 (q, J = 21, 11 Hz), -122.7 (q, J = 21, 11

Hz), -125.5, -125.7 (m), -125.8, -126.0 (m). HRMS (ES+): Found: 625.9982 ([M+H] C19H7N35ClF18 Requires:

625.9980).

2-(2-Bromo-4,6-bis(perfluorobutyl)phenyl)-4-chloropyridine

A 5-mL microwave vial was charged with recrystallized NBS (99.7 mg, 0.56 mmol, 2 eq.)

and freshly prepared Pd(PPh3)4 (16 mg, 0.014 mmol, 5 mol%). The vial was evacuated and

refilled with N2 (× 3) and then a solution of 2-(2,4-bis(perfluorobutyl)phenyl)-4-

chloropyridine (175 mg, 0.28 mmol, 1 eq.) in MeCN (1.4 mL) added. The yellow mixture was

heated in a microwave at 180 °C for 20 min to afford a brown solution which was conc. in vacuo and purified by

FC (eluent: 15-30% CH2Cl2/5% PhCH3/hexanes) to afford aryl bromide product as a yellow oil (33 mg, 0.045

mmol, 16%). IR (film, cm-1): 3063, 1576, 1555, 1352, 1230, 1200, 1133, 1008, 880, 804, 730. 1H NMR (400 MHz,

CDCl3, ppm): 8.61 (d, J = 5.4 Hz, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.41 (dd, J = 5.3, 1.9 Hz, 1H), 7.30 (s, 1H).

13C NMR (101 MHz, CDCl3, ppm): 157.1, 150.2, 144.3, 143.7, 135.0, 131.2 (t, J = 24 Hz), 129.8 (t, J = 24 Hz),

127.8, 126.6, 124.8, 124.0, 118.9, 118.6, 116.0, 115.7, 110.5, 110.2, 110.1, 109.2. 19F NMR (377 MHz, CDCl3,

ppm): -81.0 (q, J = 19, 10 Hz), -103.2, -105.5 (m), -111.6 (t, J = 14), -120.4 (q, J = 24, 12 Hz), -122.4 (q, J = 22,

11 Hz), -125.4, -125.6 (m), -125.8 (q, J = 29, 15 Hz). HRMS (ES+): Found: 703.9065 ([M+H] C19H6N35ClBrF18

Requires: 703.9085).

2-(2-Bromo-4,6-bis(perfluorobutyl)phenyl)-4-chloropyridine-N-oxide

2-(2-Bromo-4,6-bis(perfluorobutyl)phenyl)-4-chloropyridine (27.5 mg, 0.040 mmol, 1 eq.)

was dissolved in CH2Cl2 (0.3 mL) at 0°C. To the solution was added H2O (0.1 mL), NaHCO3

(7 mg, 0.080 mmol, 2 eq.) and m-CPBA (11 mg, 0.060 mmol, 1.5 eq.) and the mixture was

allowed to warm to rt. Then a second batch of m-CPBA (4 mg, 0.020 mmol, 0.5 eq.) was added and the mixture

was heated at 40 °C in a sealed tube for 20 h. The resulting mixture was diluted with CH2Cl2 (1 mL), the phases

were separated and the organic phase was washed with Na2SO4 (sat, 1 mL), NaHCO3 (sat, 1 mL) and brine (1 mL).

The combined aqueous phase was extracted with CH2Cl2 (3 1 mL) and the organic phases were conc. in vacuo.

S23

The crude residue was purified by FC (eluent: 20% EtOAc/hexanes) to afford N-oxide product as a colourless oil

(26 mg, 0.035 mmol, 88%). IR (film, cm-1): 3079, 1448, 1402, 1352, 1233, 1201, 1135, 1010, 884, 827, 787, 725.

1H NMR (400 MHz, CDCl3, ppm): 8.25 (d, J = 7.0 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.38 (dd, J = 7.1, 2.9 Hz,

1H), 7.23 (t, J = 3.1 Hz, 1H). 13C NMR (101 MHz, CDCl3, ppm): 146.9, 140.5, 136.4, 135.2, 133.1, 132.13 (t, J

= 26 Hz), 130.7 (t, J = 23 Hz), 127.4, 127.2, 126.8, 117.5, 115.9, 115.5, 115.4, 115.1, 114.3, 112.6, 110.4, 110.0.

19F NMR (377 MHz, CDCl3, ppm): -81.0 (q, J = 18, 9 Hz), -101.7, -101.8 (m), -102.3, -102.6 (m), -111.6, -111.7

(m), 122.2, -122.3 (m), 125.5, -125.7 (m). HRMS (ES+): Found: 721.9005 ([M+H] C19H6NOF1835Cl79Br Requires:

721.9004).

2-(2-Bromo-4,6-bis(perfluorobutyl)phenyl)-4-(dimethylamino) pyridine-N-oxide

To a solution of (2-Bromo-4,6-bis(perfluorobutyl)phenyl)-4-chloropyridine-N-oxide (38

mg, 0.053 mmol, 1 eq.) in MeCN (0.6 mL) in a microwave vial was added HNMe2 (60% in

H2O, 0.23 mL, 2.63 mmol, 50 eq.). The solution was heated in a microwave for 135 min at

100 °C and the resulting mixture was conc. in vacuo. The crude residue was purified by FC

(eluent: 30-50% i-PrOH/EtOAc) to afford desired product as a yellow oil (17 mg, 0.023 mmol, 44%). IR (film,

cm-1): 2961, 2925, 1636, 1506, 1429, 1352, 1259, 1230, 1095, 1020, 798. 1H NMR (400 MHz, CDCl3): 8.22 –

8.05 (m, 2H), 7.84 (s, 1H), 6.63 (dd, J = 7.5, 3.5 Hz, 1H), 6.36 (t, J = 3.6 Hz, 1H), 3.04 (s, 6H). 13C NMR (101

MHz, CDCl3): 147.5, 145.5, 139.8, 138.6, 135.2, 131.5, 130.5, 126.8, 122.5, 117.1, 116.0, 114.9, 114.2, 110.7,

110.1, 110.0, 109.9, 108.8, 108.5, 39.9. 19F NMR (377 MHz, CDCl3): -80.9 (t, J = 10 Hz), -111.44, -111.7 (m),

-122.23 (q, J = 10 Hz), -125.4, -125.8 (m). HRMS (ES+): Found: 728.9848 ([M+H] C21H12N2O79BrF18 Requires:

728.9846).

2-(3,5-Bis(perfluorobutyl)-5'-phenyl-[1,1':3',1''-terphenyl]-2-yl)-4-(dimethylamino)pyridine-N-oxide (4b)

A sealed vial with 5’-m-terphenyl boronic acid (16 mg, 0.058 mmol, 2 eq.), Pd2(dba)3 (2 mg,

0.0021 mmol, 7.5 mol%), SPhos (2 mg, 0.0042 mmol, 0.15 eq.) and K3PO4 (18 mg, 0.086

mmol, 3 eq.) was evacuated for 1 h and refilled with argon. To the vial was then added a

solution of 2-(2-bromo-4,6-bis(perfluorobutyl)phenyl)-4-(dimethyl-amino) pyridine 1-oxide

(21 mg, 0.029 mmol, 1 eq.) in degassed n-butanol (0.2 mL). The reaction mixture was heated at 90 °C for 72 h

before being conc. in vacuo. The crude residue was purified by FC (eluent: 10% EtOAc/Hexanes to 80% i-

PrOH/EtOAc) to afford desired as a yellow oil (11 mg, 0.012 mmol, 44%). IR (film, cm-1): 3040, 2923, 2853,

1730, 1634, 1506, 1430, 1350, 1232, 1134, 1094, 1027, 909, 849, 803, 849, 803, 734, 698. 1H NMR (400 MHz,

CDCl3): 8.09 – 7.93 (m, 3H), 7.84 – 7.70 (m), 7.68 – 7.59 (m), 7.52 – 7.43 (m), 7.43 – 7.35 (m), 6.38 (dd, J =

7.5, 3.5 Hz, 1H), 6.18 (t, J = 3.5 Hz, 1H), 2.86 (s, 6H). 13C NMR (101 MHz, CDCl3): 141.7, 140.3, 139.1, 137.0,

132.4, 129.0, 127.9, 127.2, 126.2, 125.7, 109.4, 108.4, 39.77. 19F NMR (377 MHz, CDCl3): -80.8, -81.0 (m), -

111.2, -111.6 (m), -125.3, -125.8 (m). HRMS (ES+): Found: 879.1714 ([M+H] C39H25N2OF18 Requires:

879.1679).

The racemic catalyst (±)-4b was resolved using preparative SFC [BzS column (benzene sulphonamide), 21.2 ×

250 mm, 70 mL/min, 100 bar, 20% MeOH (+ 0.2% dimethylethylamine), 35 °C] and the enantiomers collected.

Analytical conditions: [BzS column (benzene sulphonamide), 4.6 × 150 mm, 3 mL/min, 150 bar, 5-55% MeOH

(+ 0.2% dimethylethylamine), 40 °C] afforded (-)-4b: Rt = 1.97 min. (+)-4b: Rt = 2.79 min.

S24

(+)-4b: Rt = 2.79 min

S25

6. Assignment of the absolute configuration of catalyst 4a enantiomers

All managed data is located in a data repository,[21] assigned a collection DOI: 10.14469/hpc/1774

Geometry optimisation

Geometry optimisations were performed at the B3LYP /6-311g(2df,p) level including a Grimme D3 dispersion

correction using Becke-Johnson damping[22] for the (Sa) configured enantiomer of 4a. The effect of chloroform

solvent was modelled as a continuum (CPCM model). With three rotatable bonds, eight conformations for the (Sa)

atropisomer were computed and each was verified as a minimum by vibrational analysis.

Eight conformers were located, with the lowest energy one (conformer 2) and the highest energy one (conformer

5) differing by 2.39 in G298 (kcal/mol, see Optical Rotation table, below). The conformers cluster into two

groups: conformers 1-4 have the ter-phenyl and (CF3)2C6H2 rings ~coplanar, whereas conformers 5-8 have the ter-

phenyl and (CF3)2C6H2 rings ~perpendicular. e.g.

Conformer 1 Conformer 5

Optical Rotation (OR) prediction

The experimental OR value for enantiomer (+)-4a (AT1), which elutes second on the OD-H chiral HPLC column

with Rt = 55.2 min (>99% ee), was measured as: []D27 +49.5 (c = 0.2, CHCl3).

The OR values for each of the eight conformers of (Sa)-4a, for the measured wavelength of 589nm as well as at

800, 535.8 and 366nm, were calculated using the TPSSh/6-311++G(d,p) combination with geometries at the

previously optimized B3LYP+gd3bj/6-311g(2df,p)/SCRF=chloroform level. The conformers cluster into two

groups: 1-4 have predicted positive OR589 values whereas conformers 5-8 have negative OR values. Following

Boltzmann weighting, this predicts an overall OR value of []589 +94.2 (CHCl3).

This analysis suggests that enantiomer (+)-4a has the (Sa)-configuration, but the assignment is critically dependent

on high accuracy for the computed energies used in the Boltzmann weighting and further corroboration is essential.

Electronic Circular Dichroism (ECD):

The experimental UV and ECD spectra were recorded for both enantiomers of catalyst 4a. Both enantiomers gave

identical IR spectra as expected and the VCD traces were mirror images of each other as expected. Enantiomer

(+)-4a has a positive Cotton effect at ~290 nm (blue) whereas enantiomer (-)-4a has a negative Cotton effect at

this wavelength (red).

conformer E(Hartree) E(kcal/mol) dE(kcal/mol) exp(-E/RT) population OR (589 nm) weighted OR

1 -2056.114931 -1295352.41 0.3843 0.522538081 0.173125554 48.6 8.4

2 -2056.115541 -1295352.79 0 1 0.331316625 166.5 55.2

3 -2056.115297 -1295352.64 0.15372 0.771342353 0.255558545 61.3 15.7

4 -2056.114419 -1295352.08 0.70686 0.303055285 0.100407254 217.3 21.8

5 -2056.11175 -1295350.4 2.38833 0.017708116 0.005866993 -44.8 -0.3

6 -2056.113168 -1295351.3 1.49499 0.080063137 0.026526248 -58.9 -1.6

7 -2056.112772 -1295351.05 1.74447 0.052533982 0.017405381 -76.8 -1.3

8 -2056.114314 -1295352.02 0.77301 0.2710199 0.089793399 -41.4 -3.7

1 94.2

https://data.hpc.imperial.ac.uk/resolve?doi=1774

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UV ECD

The ECD spectra for each of the eight conformers of (Sa)-4a were calculated using time-dependent DFT at the

TPSSh/6-311++G(2df,p)/SCRF=chloroform level of theory. All the wavelengths were subsequently corrected by

a +10 nm shift for optimal fit with the experiment. The conformers cluster into two groups: 1-4 have positive

Cotton effects at ~290 nm whereas conformers 2-8 have negative Cotton effects at this wavelength. e.g.

Conformer 2 Conformer 7

A Boltzmann averaged ECD curve based on the B3LYP+D3BJ/6-311g(2df,p) relative free energies (G298) was

then constructed and found to overlay well with the experimental curve corresponding to (+)-4a.

This analysis also suggests that enantiomer (+)-4a has the (Sa)-configuration. Again the assignment is critically

dependent on the computed free energies used in the Boltzmann weighting.

Vibrational Circular Dichroism (VCD):

The experimental IR and VCD spectra were recorded for both enantiomers of catalyst 4a. Both enantiomers gave

identical IR spectra as expected and the VCD traces were mirror images of each other as expected: (+)-4a (green)

vs. (-)-4a (red). The strongest peaks are in the region 1000-1250 cm-1.

IR VCD

The VCD spectra for each of the eight conformers of (Sa)-4a were calculated at the B97XD/Def2-

TZVPP/SCRF=chloroform level, including one explicit chloroform strongly hydrogen bonded to the N-oxide

oxygen atom. An atomic mass of 2.0 corresponding to CDCl3 was used to obtain normal mode wavenumbers, to

which a scaling factor of 0.98 was applied to allow comparison with the experimental data for (+)-4a (AT 1). All

eight conformers displayed similar spectra in the 1000-1250 cm-1 region (see below) with a pattern negative –

positive – negative –positive (going from low to high wavenumbers) which fits with the experimental spectrum of

(+)-4a. The higher wavenumber region is less well reproduced by the simulated spectrum. In this region the

weighting factors matter because the conformers have different spectra.

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A Boltzmann averaged VCD curve based on the B3LYP+D3BJ/6-311g(2df,p) relative free energies was then

constructed and found to overlay well with the experimental curve corresponding to (+)-4a.

This analysis (supported by the OR and ECD results) confirms that (+)-4a has the (Sa)-configuration, as this

VCD assignment is essentially independent of the computed free energies used in the Boltzmann weighting.

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7. N-Sulfonylative KR of (±)-2-Methylindoline (5a) – Optimisation with catalyst (-)-4a

Entry R

Temp. (oC)

Solvent Base Time (h)

Additive (1 eq.)

Conv (%)[a]

s[b]

1 4-NO2 0 PhCH3 DIPEA 3 - 100 N.D.

2 2-NO2 0 PhCH3 DIPEA 3 - 60 1.3

3 2-NO2 -40 PhCH3 DIPEA 4 - 53 1.4

4 2-NO2 -40 THF DIPEA 3 - 10 1.9

5 2-NO2 -40 CH2Cl2 DIPEA 3 - 100 N.D.

6 2-NO2 -60 PhCH3 DIPEA 3 - 23 1.9

7 2-NO2 -60 PhCH3 DIPEA 3 NBu4Br 46[c] 4.7

8 2-NO2 -78 PhCH3 DIPEA 3 - 15 4.5

9 2-NO2 -78 PhCH3 DIPEA 3 NBu4Br 20 2.6

10 2-i-Pr, 4-NO2 -60 PhCH3 DIPEA 3 - 54 8.9

11 2-i-Pr, 4-NO2 -60 PhCH3 DIPEA 3 NBu4Br 60 7.8

12 2-i-Pr, 4-NO2 -78 PhCH3 DIPEA 2 - 52 13.8

13 2-i-Pr, 4-NO2 -78 THF DIPEA 4 - 65 7.4

14 2-i-Pr, 4-NO2 -78 PhCH3 PMP 2 -

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8. KR of (±)-indolines 5a-5q – Analytical scale resolutions with catalyst (-)-4a

General Procedure C – Kinetic resolution

An oven-dried microwave vial was flushed with argon and sealed. Using syringes, DIPEA (50 L, 0.3 M solution

in toluene, 1 eq.), (±)-indoline (50 L, 0.3 M solution in toluene, 1 eq.), appropriate enantiomer of catalyst 4a (339

L, 4.4 mM solution in toluene, 10 mol%) and dry toluene (10 L) were added. The vial was then cooled to -78

°C. Separately, a solution of 2-isopropyl-4-nitrosulfonyl chloride (150 L, 0.1 M in toluene, 1 eq.) was frozen in

N2 (l). Immediately upon melting, the solution was transferred to the microwave vial at -78 °C and stirred for

several hours. The reaction was quenched with a solution of propylamine (100 L, 1.5 M in toluene, 10 eq.) which

was frozen in liquid N2 and added to the reaction mixture immediately upon melting the solution. After stirring

for 20 min, the mixture was taken up in a syringe and analysed by HPLC.

(R)-2-Methylindoline (5a) and (S)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-methylindoline (6a) using

catalyst (-)-4a (Table 1, Entry 7 and Table 2, Entry 1).

Following General Procedure C, (±)-2-methylindoline (5a, 2.0 mg, 0.015 mmol) was resolved for 3 h using

catalyst (-)-4a. The ee of the starting material and the product were determined by HPLC using a Daicel Chiralpak

OD-H column (eluent: 1% i-PrOH:hexanes; flow rate 0.7 mL/min).

Retention times of starting material 5a: 18.3 min (Major) and 21.9 min (Minor). 76.3% ee. Major

enantiomer assigned as (+)-(R)-5a by comparison of elution times and optical rotation with literature

values.[23–25]

Retention times of product 6a: 23.7 min (Major) and 27.6 min (Minor). 71.8% ee.

Conversion = 51%; selectivity = 13.8.

HPLC analysis of crude reaction mixture after quench:

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HPLC analysis of starting material 5a:

(S)-2-Methylindoline (5a) and (R)-1-((2-Isopropyl-4-nitrophenyl)sulfonyl)-2-methylindoline (6a) using

catalyst (+)-4b (Table 1, Entry 9).

Following General Procedure C, (±)-2-methylindoline (5a, 2.0 mg, 0.015 mmol) was resolved for 24 h using

catalyst (+)-4b. The ee of the starting material and the product were determined by HPLC using a Daicel Chiralpak

OD-H column (eluent: 1% i-PrOH:hexanes; flow rate 0.7 mL/min).

Retention times of starting material 5a: 10.4 min (Minor) and 12.0 min (Major).* 79.3% ee. Major

enantiomer assigned as (-)-(S)-5a by comparison of elution times and optical rotation with literature

values.[23–25]

Retention times of product 6a: 13.2 min (Minor) and 14.1 min (Major). 82.1% ee.

Conversion = 48%; selectivity = 8.2.

HPLC analysis of crude reaction mixture after quench:

* NB. The HPLC retention times for starting material 5a and product 6a in this analysis were significantly shorter than for the

same compounds previously under the same elution conditions (when using the (-)-4b catalyst), but the identity of the

products was confirmed by co-injected with authentic standards and by 1H NMR.

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(R)-2-(((Triethylsilyl)oxy)methyl)indoline (5b) and (S)-1-((2-isopropyl-4-nitrophenyl)sulfonyl)-2-

(((triethylsilyl)oxy)methyl)indoline (6b) using catalyst (+)-4a (Table 2, Entry 2).

Following General Procedure C, (±)-2-(((triethylsilyl)oxy)methyl)indoline (5b, 2.2 mg, 0.015 mmol) was

resolved for 6 h using catalyst (+)-4a. The ee of the starting material and the product were determined by HPLC

using a Daicel Chiralpak IA column (eluent: 1% i-PrOH:hexanes; flow rate 0.7 mL/min).

Retention times of starting material 5b: 4.5 min (Major) and 4.4 min (Minor). 68.5% ee. Major

enantiomer assumed to be of (R) configuration by analogy with 5d.

Retention times of product 6b: 12.5 min (Major) and 14.1 min (Minor). 91.1% ee

Conversion = 34%; selectivity = 14.8.

HPLC analysis of crude reaction mixture after quench:

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HPLC analysis of racemic starting material:

(S)-2-(((Triisopropylsilyl)oxy)methyl)indoline (5c) and (R)-1-((2-isopropyl-4-nitrophenyl)sulfonyl)-2-

(((triisopropylsilyl)oxy)methyl)indoline (6c) using catalyst (-)-4a (Table 2, Entry 3).

Following General procedure C, (±)-2-(((triisopropylsilyl)oxy)methyl)indoline (5c, 4.6 mg, 0.015 mmol) was

resolved for 5 h using catalyst (-)-4a. The ee of the product was determined by HPLC using a Daicel Chiralpak IC

column (eluent: 1% i-PrOH:hexanes; flow rate 1.0 mL/min).

Retention times of starting material 5c: 4.5 min (Major) and 4.8 (Minor); poorly resolved. Major

enantiomer assumed to be of (S) configuration by analogy with 5d.

Retention times of product 6c: 9.7 min (Minor) and 13.0 min (Major). 87.9% ee.

Conversion = 33% [determined by 1H-NMR - comparison of peaks at H 8.11 ppm (6c) and H 6.41 ppm

(5c)]; selectivity = 10.1.

HPLC analysis of crude reaction mixture after quench:

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HPLC analysis of racemic product:

(S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)indoline (5d) and (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-

((2-ethyl-4-nitrophenyl)sulfonyl)indoline (6d) using catalyst (-)-4a (Table 2, Entry 4).

Following General Procedure C, (±)-2-(((tert-butyldimethylsilyl)oxy)methyl)indoline (5d, 3.9 mg, 0.015 mmol)

was resolved for 5 h using catalyst (-)-4a. The ee of the product was determined by HPLC using a Daicel Chiralpak

IC column (eluent: 1% i-PrOH:hexanes; flow rate 1.0 mL/min).

Retention times of starting material 5d: 4.6 min (Major) and 5.1 (Minor); poorly resolved. Major

enantiomer assigned as (+)-(S)-5d by comparison of elution times and optical rotation with literature

values.[3]

Retention times of product 6d: 10.2 min (Minor) and 12.8 min (Major). 89.2% ee.

Conversion = 47% [determined by 1H-NMR - comparison of peaks at H 7.74 ppm (6d) and H 6.39 ppm

(5d)]; selectivity = 17.2.

HPLC analysis of crude reaction mixture after quench:

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HPLC analysis of racemic product:

(R)-2-Isopropylindoline (5e) and (S)-2-isopropyl-1-((2-isopropyl-4-nitrophenyl)sulfonyl)indoline (6e) using

catalyst (+)-4a (Table 2, Entry 5).

Following General Procedure C, (±)-2-isopropylindoline (5e, 2.4 mg, 0.015 mmol) was resolved for 6 h using

catalyst (+)-4a. The ee of the starting material and product was determined by HPLC using a Daicel Chiralpak IC

column (eluent: 1% i-PrOH:hexanes; flow rate 1.0 mL/min).

Retention times of starting material 5e: 8.2 min (Major) and 13.4 min (Minor). 76.7% ee. Major

enantiomer assigned as (+)-(R)-5a by comparison of elution times with literature values.[4]

Retention times of product 6e: 14.3 min (Major) and 18.2 min (Minor). 90.5% ee.

Conversion = 40%; selectivity = 16.2.

HPLC analysis of crude reaction mixture after quench: