SI-1

Synthesis of Benzofuro[3,2-b]indoline Amines by a Deamination-Interrupted Fischer Indolization and their

Unexpected Reactivity Towards Nucleophiles.

Terry Tomakinian, Régis Guillot, Cyrille Kouklovsky and Guillaume Vincent*

Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO) Equipe Méthodologie, Synthèse et Molécules Thérapeutiques Univ Paris Sud, CNRS and Université Paris-Saclay Bat. 410, 91405 Orsay, France guillaume.vincent@u-psud.fr

Supporting Information

Table of Content

General informations SI-2

Experimental details and descriptions of compounds SI-3

NMR spectra of compounds SI-23

Absorbance and Fluorescence spectra of 11a-I SI-59

X-Ray Crystallography SI-61

Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2016

SI-2

General Informations

Unless otherwise stated, all reactions were carried out under air atmosphere. Tetrahydrofuran

was distilled under argon over sodium-benzophenone. Dichloromethane was distilled under

argon over CaH2. Unless otherwise noted, all reagent-grade chemicals and other solvents were

obtained from commercial suppliers and were used as received. Reactions were monitored with

analytical thin-layer chromatography (TLC) on silica gel 60 F254 plates and visualized under

UV (254 nm) and/or by staining with vanillin (1%) + sulfuric acid (5%) in EtOH or KMnO4

solution followed by heating. Flash chromatography were performed on silica gel (Chromagel

Si60ACC [70-200 µm]) as stationary phase. 1H NMR spectra were recorded on Bruker AC250

(250 MHz), Bruker DRX300 (300 MHz) and Bruker AM360 (360 MHz) instruments; chemical

shifts (δ) are given in parts per million with respect to the residual protonated solvent (δ = 7.26

ppm for CDCl3, 2.50 ppm for DMSO-d6 and 5.32 for CD2Cl2), which served as an internal

standard. 13C NMR spectra were recorded on Bruker AC250 (63 MHz), DRX300 (75 MHz),

AM360 (90 MHz) and Bruker 400 (100 MHz) instruments; chemical shifts are expressed with

respect to the deuterated solvent (δ = 77.16 ppm for CDCl3, 39.52 ppm for DMSO-d6).

Coupling constant(s) in hertz (Hz) were measured from one-dimensional spectra and

multiplicities were abbreviated as following: br (broad), s (singlet), d (doublet), t (triplet), q

(quadruplet), m (multiplet). Melting points were measured with a Reichert Austria microscope.

Infrared spectra were recorded as thin films on NaCl plates. High resolution mass spectra

(HRMS) were recorded using Electrospray Ionization (ESI) method with a Bruker Daltonics

MicrOTOF-Q instrument. UV Absorption spectra were recorded with a Cary 5000 Varian

spectrophotometer and fluorescence spectra were recorded on a FluoroMax-4 Horiba Jobin

Yvon spectrofluorometer.

SI-3

Experimental details and descriptions of compounds

Synthesis of starting materials

a. Arylhydrazine free bases

Phenyl hydrazine 1a, 4-trifluorophenyl hydrazine 1e were commercially available as their free

base.

The other aryl hydrazine free bases 1b-d, 1f-h were prepared by neutralization of the

corresponding commercially available hydrochloride salts according to the following

procedure:

To a solution of arylhydrazine hydrochloride in water (0.5 M), K2CO3 (1.5 equiv.) was added

and the mixture was stirred for 15 min at room temperature. The aqueous layer was extracted

with dichloromethane and the organic layer was dried over MgSO4 and concentrated under

reduced pressure to afford arylhydrazine 1 as a white solid (around 90%).

b. Benzofuran-3(2H)-ones 2a-f

2a, 2b, 2e, 2f were prepared from Farran, D.; Bertrand, P. Synth. Commun. 2012, 42, 989–1001.

2c was prepared from Clark, J. S.; Hansen, K. E. Chem. Eur. J. 2014, 20, 5454-5459.

2d was prepared from Diedrichs, N.; Ragot, J. P.; Thede, K. Eur. J. Org. Chem., 2005, 1731-

1735.

Fischer synthesis of benzofuro[3,2-b]indoline amines 4a-r

General procedure A: A solution of benzofuran-3(2H)-one 2 in a 0.7:1 mixture of acetic acid

and water was stirred for 30 min at RT or 40°C. Aryllhydrazine free base 1 was then added,

and the resulting reaction mixture was stirred for 1h at RT or 40°C. The reaction was quenched

at RT with saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc. The combined

SI-4

organic layers were washed with brine, dried over MgSO4 and concentrated under reduced

pressure. After this aqueous work-up, the crude was purified either by preparative TLC

(Cyclohexane/EtOAc) either by washing the crude solid with petroleum ether/AcOEt (95/5) in

order to obtain benzofuro[3,2-b]indoline amine 4.

(4b,9b)-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine and (4a)2-(2-

aminophenyl)-2-methylbenzofuran-3(2H)-one (7a)

4a was prepared from phenylhydrazine 1a (0.050 mL, 0.508 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (100 mg, 0.676 mmol) in a mixture of

acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred for 1h at

40°C. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20)

led to 4b-methyl-benzofuro[3,2-b]indoline amine 4a as a brown solid (107 mg, 0.448 mmol,

88%) and 2-(2-aminophenyl)-2-methylbenzofuran-3(2H)-one 7a as a yellow oil (10 mg, 0.045

mmol, 9%).

Data for 4a:

Rf: 0.20 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.43 (dd, J = 7.5, 1.5 Hz, 1H), 7.34 (dd, J =

7.2, 0.9 Hz, 1H), 7.17 (td, J = 7.8, 1.2 Hz, 1H), 7.10 (td, J = 7.5, 1.2 Hz, 1H), 6.91 (t, J = 7.2

Hz, 1H), 6.81-6.75 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H), 3.10 (bs, NH2), 1.68 (s, 3H).

13C NMR (100 MHz, CDCl3, 300 K) δ (ppm): 158.7, 147.8, 131.0, 130.3(2C), 129.9, 124.9,

123.7, 121.3, 119.6, 110.9, 110.0, 96.0, 86.6, 20.1.

IR (NaCl), v (cm-1): 3233, 2950, 1611, 1490, 1328, 1260, 1186, 1069, 857, 746.

HRMS (ESI+): calculated: 222.0913 ([C15H12NO]+; [M-NH3+H]+); found: 222.0906.

calculated: 239.1184 ([C15H15N2O]+; [M+H]+); found: 239.1171.

Data for 7a:

Rf: 0.30 (Cyclohexane/EtOAc: 70/30)

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm): 7.67-7.61 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H),

7.16 (d, J = 8.6 Hz, 1H), 7.10-7.05 (m, 2H), 6.72-6.66 (m, 2H), 1.92 (s, 3H).

13C NMR (100 MHz, CDCl3, 300 K) δ (ppm): 203.1, 170.2, 145.5, 138.4, 129.4, 125.8, 125.1,

122.3, 121.8, 119.9, 118.2, 115.3, 113.4, 90.8, 20.7.

IR (NaCl), v (cm-1): 3353, 2927, 2854, 1707, 1610, 1486, 1477, 1465, 1311, 1252, 1096, 899,

749.

HRMS (ESI+): calculated: 222.0913 ([C15H12NO]+; [M-H2O+H]+); found: 222.0913.

SI-5

calculated: 240.1019 ([C15H14N2O]+; [M+H]+); found: 240.1020.

calculated: 262.0835 ([C15H14NaN2O]+; [M+Na]+); found: 262.0838.

(4b,9b)-3-bromo-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4b)

4b was prepared from 4-bromophenylhydrazine (100 mg, 0.535 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (100 mg, 0.676 mmol) in a mixture of

acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred for 12 h at

RT. After the aqueous work-up, the crude solid was washed with petroleum ether/EtOAc 95/5

which led to 3-bromo-4b-methyl-benzofuro[3,2-b]indoline amine 4b as a yellow solid (115 mg,

0.362 mmol, 68%).

Data for 4b:

Rf : 0.23 (Cyclohexane/EtOAc: 80/20).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.42-7.37 (m, 2H), 7.21-7.16 (m, 2H), 6.91 (t,

J = 8.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 4.59 (bs, NH), 1.81 (bs,

NH2), 1.66 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.6, 146.7, 133.0, 132.4, 132.2, 130.7, 128.1,

123.6, 121.5, 115.5, 111.5, 111.0, 95.4, 87.2, 20.1.

IR (NaCl), v (cm-1): 3244, 2926, 1604, 1484, 1464, 1255, 1240, 1154, 1096, 856, 802, 757.

HRMS (ESI+): calculated: 300.0019 ([C15H1179BrNO]+; [M-NH3+H+]); found: 300.0015.

calculated: 317.0284 ([C15H1479Br2NO]+; [M+H+]); found: 317.0278.

(4b,9b)-3-chloro-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4c)

4c was prepared from 4-chlorophenylhydrazine 1c (111 mg, 0.778 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (138 mg, 0.934 mmol) in a mixture of

acetic acid (1.4 mL) and water (1.8 mL). The resulting reaction mixture was stirred for 12 h at

RT. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led

to 3-chloro-4b-methyl-benzofuro[3,2-b]indoline amine 4c as a red solid (113 mg, 0.414 mmol,

53%).

Data for 4c:

Rf : 0.20 (Cyclohexane/EtOAc: 70/30).

SI-6

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm): 7.39 (dd, J = 8.2, 1.2 Hz, 1H), 7.28 (d, J = 2.2

Hz, 1H), 7.18 (td, J = 7.8, 1.2 Hz, 1H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.81 (t, J = 8.2 Hz, 1H),

6.76 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.60 (bs, NH), 2.05 (bs, NH2), 1.67 (s, 3H).

13C NMR (63 MHz, CDCl3, 300 K) δ (ppm): 158.7, 146.3, 131.9, 130.7, 130.2, 129.3, 125.2,

124.2, 123.6, 121.5, 114.3, 111.1, 95.5, 87.4, 20.1.

IR (NaCl), v (cm-1): 3219, 2957, 2924, 2850, 1609, 1487, 1257, 1186, 1069, 865, 804, 754,

641.

HRMS (ESI+): calculated: 256.0524 ([C15H11ClNO]+; [M-NH3+H+]); found: 256.0525.

calculated: 273.0795 ([C15H14ClN2O]+; [M+H+]); found: 273.0786.

(4b,9b)-3-fluoro-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4d)

4d was prepared from 4-fluorophenylhydrazine (64 mg, 0.508 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (100 mg, 0.676 mmol) in a mixture of

acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred for 1 h at

40°C. After the aqueous work-up, flash column chromatography purification

(Cyclohexane/EtOAc: 70/30) led to 3-fluoro-4b-methyl-benzofuro[3,2-b]indoline-amine 4d as

a yellow solid (53 mg, 0.207 mmol, 49%).

Data for 4d:

Rf : 0.17 (Cyclohexane/EtOAc: 70/30).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm) : 7.40 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.2 Hz,

1H), 7.03 (dd, JH-H = 8.2 Hz; JH-F = 2.9 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.82-6.76 (m, 2H),

6.48 (dd, JH-F = 8.6 Hz; JH-H = 4.0 Hz, 1H), 1.66 (s, 3H).

13C NMR (91 MHz, CDCl3, 300 K) δ (ppm): 158.7, 157.3 (d, J = 240 Hz), 143.7, 131.6 (d, J

= 7 Hz), 131.0, 130.6, 123.6, 121.5, 116.8 (d, J = 24 Hz), 111.8 (d, J = 23 Hz), 111.0, 110.9 (d,

J = 7 Hz), 95.7, 87.4, 20.1.

IR (NaCl), v (cm-1): 3325, 2930, 2859, 1610, 1490, 1261, 1073, 814, 754, 737.

HRMS (ESI+): calculated: 240.0819 ([C15H11FNO]+; [M-NH3+H+]); found: 240.0824.

calculated: 257.1090 ([C15H14FN2O]+; [M+H+]); found: 257.1086.

SI-7

(4b,9b)-3-trifluoromethyl-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-

amine (4e)

4e was prepared from 4-trifluoromethylphenylhydrazine 1e (95 mg, 0.539 mmol) following

general procedure A using 2-methylbenzofuran-3(2H)-one 2a (100 mg, 0.676 mmol) in a

mixture of acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred

for 1 h at 40°C. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc:

80/20) led to 3-trifluoromethyl-4b-methyl-benzofuro[3,2-b]indoline amine 4e as a yellow solid

(77 mg, 0.251 mmol, 47%).

Data for 4e:

Rf : 0.16 (Cyclohexane/EtOAc: 70/30).

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm) : 7.56 (s, 1H), 7.40 (dd, J = 8.0, 1.2 Hz, 1H),

7.34 (dd, J = 8.5, 1.2 Hz, 1H), 7.19 (td, J = 8.0, 1.5 Hz, 1H), 6.92 (t, J = 8.2 Hz, 1H), 6.77 (d,

J = 8.2 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 4.09 (bs, NH), 2.03 (bs, NH2), 1.69 (s, 3H).

13C NMR (63 MHz, CDCl3, 300 K) δ (ppm): 158.7, 150.5, 130.8, 130.3 (d, J = 18 Hz), 128.1,

126.9, 123.7, 122.6, 121.6, 121.1, 111.1, 109.1, 95.2, 87.4, 20.1.

IR (NaCl), v (cm-1): 3218, 2950, 1623, 1331, 1187, 1104, 759.

HRMS (ESI+): calculated: 290.0787 ([C16H11F3NO]+; [M-NH3+H+]); found: 290.0791.

calculated: 307.1058 ([C16H14F3N2O]+; [M+H+]); found: 307.1052.

(4b,9b)-3-isopropyl-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4f)

4f was prepared from 4-isopropylphenylhydrazine 1f (71 mg, 0.526 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (109 mg, 0.736 mmol) in a mixture of

acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred for 1 h at

40°C. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20)

led to 3-isopropyl-4b-methyl-benzofuro[3,2-b]indoline amine 4f as a yellow solid (100 mg,

0.357 mmol, 68%).

Data for 4f:

Rf: 0.23 (Cyclohexane/EtOAc: 70/30).

SI-8

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm) : 7.41 (dd, J = 7.2, 1.5 Hz, 1H), 7.21 (d, J = 1.7

Hz, 1H), 7.16 (td, J = 7.5, 1.2 Hz, 1H), 6.98 (dd, J = 8.2, 1.7 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H),

6.78-6.73 (m, 1H), 6.51 (d, J = 8.3 Hz, 1H), 2.88-2.77 (m, 1H), 1.69 (s, 3H), 1.20 (d, J = 7.0

Hz, 6H).

13C NMR (63 MHz, CDCl3, 300 K) δ (ppm) : 158.8, 145.9, 140.7, 131.4, 130.4, 130.0, 128.5,

123.6, 122.8, 121.2, 111.0, 110.0, 96.4, 86.9, 33.8, 24.5, 24.4, 20.2.

IR (NaCl), v (cm-1): 3293, 3223, 2956, 2929, 1622, 1493, 1463, 1234, 1186, 1059, 863, 744,

639.

HRMS (ESI+): calculated: 264.1383 ([C18H18NO]+; [M-NH3+H+]); found: 264.1382.

calculated: 281.1654 ([C18H21N2O]+; [M+H+]); found: 281.1644.

(4b,9b)-3-methyl-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4g)

4g was prepared from 4-methylphenylhydrazine 1g (67 mg, 0.549 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (108 mg, 0.730 mmol) in a mixture of

acetic acid (1.3 mL) and water (1.7 mL). The resulting reaction mixture was stirred for 1 h at

40°C. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20)

led to 3-methyl-4b-methyl-benzofuro[3,2-b]indoline amine 4g as a yellow solid (24 mg, 0.095

mmol, 17%).

Data for 4g:

Rf: 0.17 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.43 (d, J = 7.5 Hz, 1H), 7.24-7.13 (m, 2H),

6.93-6.89 (m, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 2.25 (s, 3H), 1.68 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.7, 145.6, 131.3, 131.0, 130.4, 130.3, 129.2,

125.4, 123.6, 121.3, 111.0, 110.2, 96.2, 86.9, 21.0, 20.1.

IR (NaCl), v (cm-1): 3235, 2950, 1676, 1544, 1499, 1321, 1283, 1181, 1064, 860, 754, 735.

HRMS (ESI+): calculated: 236.1070 ([C16H14NO]+; [M-NH3+H+]); found: 236.1073.

calculated: 253.1341 ([C16H17N2O]+; [M+H+]); found: 253.1334.

(4b,9b)-3-methoxy-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4h)

SI-9

4h was prepared from 4-methoxyphenylhydrazine 1h (121 mg, 0.877 mmol) following general

procedure A using 2-methylbenzofuran-3(2H)-one 2a (155 mg, 1.05 mmol) in a mixture of

acetic acid (0.8 mL) and water (1.3 mL). The resulting reaction mixture was stirred for 12 h at

RT. After the aqueous work-up, the crude solid was washed with petroleum ether/EtOAc 95/5

which led to 3-methoxy-4b-methyl-benzofuro[3,2-b]indoline amine 4h as a brown solid (76

mg, 0.283 mmol, 32%).

Data for 4h:

Rf: 0.21 (Cyclohexane/EtOAc: 80/20).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm) : 7.39 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.5 Hz,

1H), 6.93-6.88 (m, 2H), 6.75 (d, J = 7.2 Hz, 1H), 6.69 (dd, J = 8.6, 2.9 Hz, 1H), 6.51 (d, J =

8.3 Hz, 1H), 3.74 (s, 3H), 1.68 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.6, 154.2, 141.5, 131.5, 131.4, 130.4, 123.4,

121.3, 116.6, 111.2, 110.9, 110.3, 96.1, 87.1, 56.1, 20.1.

IR (NaCl), v (cm-1): 3235, 2950, 1676, 1544, 1499, 1321, 1283, 1202, 1064, 860, 754, 735.

HRMS (ESI+): calculated: 252.1019 ([C16H14NO2]+; [M-NH3+H+]); found: 252.1018.

calculated: 269.1290 ([C16H17N2O2]+; [M+H+]); found: 269.1280.

(4b,9b)-4b-ethyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4i)

4i was prepared from phenylhydrazine 1a (0.040 mL, 0.406 mmol) following general procedure

A using 2-ethylbenzofuran-3(2H)-one 2a (80 mg, 0.493 mmol) in a mixture of acetic acid (0.6

mL) and water (1.0 mL). The resulting reaction mixture was stirred for 5 h at RT. After the

aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led to 4b-ethyl-

benzofuro[3,2-b]indoline amine 4i as an orange solid (78 mg, 0.310 mmol, 76%).

Data for 4i:

Rf: 0.20 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm) : 7.38 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz,

1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.78-6.75 (m,

2H), 6.57 (d, J = 7.5 Hz, 1H), 4.61 (bs, NH), 2.18-2.04 (m, 2H), 2.03 (bs, NH2), 1.08 (t, J = 7.9

Hz, 3H).

13C NMR (90 MHz, CDCl3, 300 K) δ (ppm): 159.0, 148.2, 132.0, 130.4, 130.0, 129.2, 125.7,

123.2, 121.2, 119.6, 110.9, 110.1, 97.2, 87.2, 26.8, 8.4.

IR (NaCl), v (cm-1): 3320, 2970, 2924, 1612, 1484, 1382, 1096, 747.

SI-10

HRMS (ESI+): calculated: 236.1070 ([C16H14NO]+; [M-NH3+H+]); found: 236.1074.

calculated: 253.1341 ([C16H17N2O]+; [M+H+]); found: 253.1338.

(4b,9b)-3-bromo-4b-ethyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4j) and

2-(2-amino-5-bromophenyl)-2-ethylbenzofuran-3(2H)-one (7j)

4j was prepared from 4-bromophenylhydrazine 1b (57 mg, 0.304 mmol) following general

procedure A using 2-ethylbenzofuran-3(2H)-one 2a (60 mg, 0.370 mmol) in a mixture of acetic

acid (0.6 mL) and water (0.9 mL). The resulting reaction mixture was stirred for 12 h at RT.

After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led to

3-bromo-4b-ethyl-benzofuro[3,2-b]indoline amine (4j) as a brown oil (46 mg, 0.139 mmol,

45%).

Data for 4j:

Rf : 0.14 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm) : 7.41 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 7.5 Hz,

1H), 7.20-7.14 (m, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 7.5 Hz,

1H), 4.60 (bs, NH), 2.16-1.99 (m, 2H), 2.00 (bs, NH2), 1.06 (t, J = 7.5 Hz, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.8, 147.2, 132.8, 132.2, 131.6, 130.7, 128.7,

123.2, 121.5, 111.5, 111.1, 111.0, 96.7, 87.8, 26.7, 8.2.

IR (NaCl), v (cm-1): 3301, 2927, 1607, 1481, 1383, 1262, 859, 752, 704.

HRMS (ESI+): calculated: 314.0175 ([C16H1379BrNO]+; [M-NH3+H+]); found: 314.0169

calculated: 333.0426 ([C16H1681BrN2O]+; [M+H+]); found: 333.0412

(4b,9b)-4b-ethyl-3-isopropyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4k)

4j was prepared from 4-isopropylphenylhydrazine 1f (65 mg, 0.456 mmol) following general

procedure A using 2-ethylbenzofuran-3(2H)-one 2b (88 mg, 0.543 mmol) in a mixture of acetic

acid (0.6 mL) and water (1.0 mL). The resulting reaction mixture was stirred for 5h at RT. After

the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led to 4b-

ethyl-3-isopropyl- benzofuro[3,2-b]indoline amine 4k as an orange solid (45 mg, 0.148 mmol,

33%).

SI-11

Data for 4k:

Rf: 0.18 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.38 (d, J = 7.5 Hz, 1H), 7.21 (s, 1H), 7.13 (t,

J = 8.5 H, 1H), 6.97 (t, J = 8.5 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.51

(d, J = 7.5 Hz, 1H), 2.88-2.75 (m, 1H), 2.17-2.07 (m, 2H), 1.20 (d, J = 9.6 Hz, 6H), 1.07 (t, J

= 7.5 Hz, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 159.0, 146.2, 140.4, 132.2, 130.3, 129.2, 128.1,

123.5, 123.2, 121.2, 110.9, 110.0, 97.5, 87.4, 33.8, 26.9, 24.5, 24.4, 8.5.

IR (NaCl), v (cm-1): 3310, 3002, 2959, 1618, 1495, 1476, 1463, 1382, 1240, 862, 751.

HRMS (ESI+): calculated: 278.1539 ([C19H20NO]+; [M-NH3+H+]); found: 278.1535.

calculated: 295.1810 ([C19H23N2O]+; [M+H+]); found: 295.1800.

(4b,9b)-4b-allyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4l)

4l was prepared from phenylhydrazine 1a (0.04 mL, 0.406 mmol) following general procedure

A using 2-allylbenzofuran-3(2H)-one 2c (90 mg, 0.517 mmol) in a mixture of acetic acid (0.8

mL) and water (1.1 mL). The resulting reaction mixture was stirred for 5h at RT. After the

aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led to 4b-allyl-

benzofuro[3,2-b]indoline amine 4l as an orange solid (76 mg, 0.287 mmol, 71%).

Data for 4l:

Rf : 0.26 (Cyclohexane/EtOAc: 80/20).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm) : 7.45-7.40 (m, 2H), 7.23-7.13 (m, 2H), 6.95 (t,

J = 7.2 Hz, 1H), 6.85-6.80 (m, 2H), 6.61 (d, J = 7.9 Hz, 1H), 5.96-5.84 (m, 1H), 5.29-5.18 (m,

2H), 4.73 (bs, NH), 3.04-2.89 (m, 2H), 2.02 (bs, NH2).

13C NMR (63 MHz, CDCl3, 300 K) δ (ppm): 158.7, 148.2, 133.0, 131.8, 130.4, 130.3, 128.7,

125.7, 123.3, 121.3, 119.5, 119.2, 110.9, 110.0, 95.9, 87.3, 38.9.

IR (NaCl), v (cm-1): 3053, 2984, 1612, 1482, 1265, 1094, 923, 736.

HRMS (ESI+): calculated: 248.1070 ([C17H14NO]+; [M-NH3+H+]); found: 248.1062

calculated: 265.1341 ([C17H17N2O]+; [M+H+]); found: 265.1330.

SI-12

(4b,9b)-8-bromo-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4m)

4m was prepared from phenylhydrazine 1a (0.05 mL, 0.508 mmol) following general procedure

A using 5-bromo-2-methylbenzofuran-3(2H)-one 2d (150 mg, 0.66 mmol) in a mixture of

acetic acid (0.5 mL) and water (0.9 mL). The resulting reaction mixture was stirred for 12 h at

RT. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led

to 8-bromo-4b-methyl-benzofuro[3,2-b]indoline amine (4m) as a brown oil (105 mg, 0.332

mmol, 65%).

Data for 4m:

Rf: 0.25 (Cyclohexane/EtOAc: 80/20).

1H NMR (300 MHz, DMSO, 300 K) δ (ppm): 8.03 (s, NH), 7.42-7.34 (m, 3H), 7.14 (t, J =

7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 1.82

(s, 3H).

13C NMR (75 MHz, DMSO, 300 K) δ (ppm): 157.4, 148.2, 133.3, 130.6, 129.8, 128.4, 128.2,

124.3, 118.8, 112.5, 111.5, 110.2, 97.7, 83.9, 19.6.

IR (NaCl), v (cm-1): 3364, 3003, 2950, 1612, 1480, 1472, 1258, 1104, 1070, 903, 867, 518.

HRMS (ESI+): calculated: 300.0024 ([C15H1179BrNO]+; [M-NH3+H+]); found: 300.0015.

calculated: 317.0284 ([C15H1479BrN2O]+; [M+H+]); found: 317.0275.

(4b,9b)-8-bromo-3-isopropyl-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-

amine (4n)

4n was prepared from 4-isopropylphenylhydrazine 1f (138 mg, 0.921 mmol) following general

procedure A using 5-bromo-2-methylbenzofuran-3(2H)-one 2d (261 mg, 1.11 mmol) in a

mixture of acetic acid (0.8 mL) and water (1.4 mL). The resulting reaction mixture was stirred

for 12 h at RT. After the aqueous work-up, the crude solid was washed with petroleum

ether/ethyl acetate (95/5) and 8-bromo-3-isopropyl-4b-methyl-benzofuro[3,2-b]indoline amine

(4n) was obtained as a white solid (222 mg, 0.617 mmol, 67%).

Data for 4n:

Rf: 0.65 (Cyclohexane/EtOAc: 80/20).

SI-13

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm) : 7.53 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.5, 2.2

Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.2, 1.5 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 6.55

(d, J = 8.2 Hz, 1H), 2.90-2.79 (m, 1H), 1.70 (s, 3H), 1.22 (d, J = 7.0 Hz, 6H).

13C NMR (90 MHz, CDCl3, 300 K) δ (ppm): 157.9, 145.7, 140.9, 133.8, 133.0, 129.5, 128.7,

126.8, 122.8, 112.7, 112.6, 110.0, 97.4, 86.8, 33.8, 24.5, 24.4, 20.0.

IR (NaCl), v (cm-1): 3293, 3222, 3032, 2826, 1623, 1590, 1495, 1465, 1362, 991, 885, 657,

623.

HRMS (ESI+): calculated: 344.0473 ([C18H1781BrNO]+; [M-NH3+H+]); found: 344.0466.

calculated: 359.0754 ([C18H2079BrN2O]+; [M+H+]); found: 359.0746.

(4b,9b)-4b,7-dimethyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4o)

4o was prepared from phenylhydrazine 1a (0.03 mL, 0.305 mmol) following general procedure

A using 6-methyl-2-methylbenzofuran-3(2H)-one 2e (50 mg, 0.309 mmol) in a mixture of

acetic acid (0.5 mL) and water (0.9 mL). The resulting reaction mixture was stirred for 12 h at

RT. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led

to 4b,7-dimethyl-benzofuro[3,2-b]indoline amine 4o as a yellow solid (47 mg, 0.186 mmol,

61%).

Data for 4o:

Rf: 0.20 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.33 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz,

1H), 7.09 (td, J = 7.5, 1.2 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 7.5 Hz, 1H), 6.58 (s,

1H), 6.55 (d, J = 7.5 Hz, 1H), 4.60 (bs, NH) 2.26 (s, 3H), 1.68 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.9, 147.9, 140.8, 130.3, 128.4, 125.0, 123.2,

122.1, 120.1, 119.6, 111.4, 110.0, 96.2, 86.6, 21.8, 20.2.

IR (NaCl), v (cm-1): 3216, 2922, 2845, 1609, 1496, 1473, 1284, 1187, 1155, 1068, 948, 745.

HRMS (ESI+): calculated: 236.1070 ([C16H14NO]+; [M-NH3+H+]); found: 236.1071.

calculated: 253.1341 ([C16H17N2O]+; [M+H+]); found: 253.1334.

SI-14

(4b,9b)-3-bromo-4b,7-dimethyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4p)

4p was prepared from 4-bromophenylhydrazine 1b (47 mg, 0.251 mmol) following general

procedure A using 6-methyl-2-methylbenzofuran-3(2H)-one 2e (50 mg, 0.308 mmol) in a

mixture of acetic acid (0.4 mL) and water (0.6 mL). The resulting reaction mixture was stirred

for 5 h at RT. After the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc:

80/20) led to 3-bromo-4b,7-dimethyl-benzofuro[3,2-b]indoline amine 4p as an orange solid (31

mg, 0.093 mmol, 37%).

Data for 4p:

Rf: 0.10 (Cyclohexane/EtOAc: 80/20).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.44 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 7.5 Hz,

1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.62 (s, 1H), 6.45 (d, J = 8.5 Hz,

1H), 4.64 (bs, NH), 2.30 (s, 3H), 1.92 (bs, NH2), 1.68 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 158.8, 146.7, 141.2, 133.0, 132.6, 128.0, 123.2,

122.4, 111.5, 111.5, 111.0, 95.5, 87.8, 21.8, 20.1.

IR (NaCl), v (cm-1): 3300, 2926, 1606, 1478, 1262, 1189, 1155, 1062, 947, 858, 807, 545.

HRMS (ESI+): calculated: 314.0175 ([C16H1379BrNO]+; [M-NH3+H+]); found: 314.0170.

calculated: 331.0436 ([C16H1679BrN2O]+; [M +H+]); found: 331.0439.

(4b,9b)-7-methoxy-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-amine (4q)

4r was prepared from phenylhydrazine (0.04 mL, 0.406 mmol) following general procedure A

using 6-methoxy-2-methylbenzofuran-3(2H)-one 2f (87 mg, 0.489 mmol) in a mixture of acetic

acid (0.6 mL) and water (1.0 mL). The resulting reaction mixture was stirred for 5h at RT. After

the aqueous work-up, preparative TLC purification (Cyclohexane/EtOAc: 80/20) led to 7-

methoxy-4b-methyl-benzofuro[3,2-b]indoline amine 4r as an orange solid (58 mg, 0.216 mmol,

53%).

Data for 4q:

Rf: 0.14 (Cyclohexane/EtOAc: 70/30).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm): 7.32 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 8.3 Hz,

1H), 7.09 (t, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.45 (dd, J =

8.3, 2.2 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), 3.71 (s, 3H), 1.67 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 162.0, 160.1, 147.9, 130.4, 129.4, 124.9, 123.9,

123.4, 119.6, 110.1, 107.8, 96.8, 96.5, 86.5, 55.6, 20.2.

SI-15

IR (NaCl), v (cm-1): 3367, 2967, 2927, 2837, 1612, 1497, 1485, 1444, 1195, 1158, 1069, 956,

749.

HRMS (ESI+): calculated: 252.1019 ([C16H14NO2]+; [M-NH3+H+]); found: 252.1014.

calculated: 269.1290 ([C16H17N2O2]+; [M+H+]); found: 269.1277.

N-((4bS,9bR)-4b-methyl-9b,10-dihydro-4bH-benzofuro[3,2-b]indol-9b-yl)-1-

(methylsulfonyl)methanesulfonamide (10)

To 50 mg (0.209 mmol) of 4a in 2 mL of nitromethane at 0°C was added Et3N (0.06 mL, 0.418

mmol) and then MsCl ( 0.03 mL, 0.418 mmol). The reaction was then stirred 12 h at RT; The

reaction was quenched with saturated aq. NaHCO3. The aqueous layer was extracted with

dichloromethane. The combined organic layers were dried over MgSO4 and concentrated under

reduced pressure. Preparative TLC purification (Cyclohexane/EtOAc: 70/30) led to a yellow

solid (6 mg, 0.0152 mmol, 7%) with several other products.

Data for 10:

Rf: 0.4 (Cyclohexane/EtOAc: 70/30).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm): 7.74 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz,

1H), 7.28-7.20 (m, 2H), 7.00-6.95 (m, 2H), 6.80 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H),

5.98 (s, NH), 5.15 (d, J = 15.0 Hz, 1H), 4.77 (s, NH), 4.70 (d, J = 15.0 Hz, 1H), 3.26 (s, 3H),

1.98 (s, 3H).

HRMS (ESI+): calculated: 417.0549 ([C17H18N2NaO5S2]+; [M+Na+]); found: 417.0550.

Synthesis of 3,3-disubstituted indolenines 11a-h from

benzofuro[3,2-b]indoline amines 4.

General procedure B: To a solution of a benzofuro[3,2-b]indoline amine 4 in dichloromethane

at RT was added BF3.Et2O. After 5 min of stirring at RT, allylTMS or AllylMgBr (1M in Et2O)

was added to the reaction mixture which was stirred for 3 to 12 h at RT or 36°C. The reaction

was quenched with saturated aq. NaHCO3. The aqueous layer was extracted with

dichloromethane. The combined organic layers were dried over MgSO4 and concentrated under

reduced pressure. Flash column chromatography or preparative TLC purification

(Cyclohexane/EtOAc) led to indolenine 11.

12-allyl-6,6-difluoro-12-methyl-6,12-dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-

7-ium-6-uide (11a)

11a was prepared from benzofuroindoline amine 4a (40 mg, 0.167 mmol) following general

procedure B using BF3.Et2O (0.03 mL, 0.243 mmol), allylTMS (0.08 mL, 0.504 mmol) in

SI-16

dichloromethane (1.6 mL) during 12 h at RT. Flash column chromatography purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11a as a yellow solid (36 mg, 0.116 mmol,

70%).

Alternatively

11a was prepared from benzofuroindoline amine 4a (60 mg, 0.251 mmol) following general

procedure B using BF3.Et2O (0.04 mL, 0.315 mmol), allylMgBr (0.627 mL of a 1M solution

in Et2O, 0.627 mmol) in dichloromethane (2.1 mL) during 12 h at RT. Preparative TLC

purification (Cyclohexane/EtOAc: 80/20) led to indolenine 11a as a yellow solid (65 mg, 0.209

mmol, 83%).

Data for 11a:

Rf: 0.52 (Cyclohexane/EtOAc: 70/30).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.95 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 9.0 Hz,

1H), 7.60 (t, J = 7.5 Hz, 1H), 7.47-7.41 (m, 3H), 7.22 (d, J= 9.0 Hz, 1H), 7.06 (t, J = 7.5 Hz,

1H), 5.13-5.01 (m, 1H), 4.81-4.74 (m, 2H), 3.01 (d, J= 7.2 Hz, 2H), 1.79 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 179.0, 160.1, 143.2, 141.7, 137.9, 130.1, 129.4,

128.0, 127.9, 122.0, 121.3, 120.4, 120.1, 118.9, 113.0, 56.9, 44.2, 24.4.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.88 (t, J = 16 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.52 - (–)135.78 (m, 2F).

IR (NaCl), v (cm-1): 3385, 2924, 1610, 1535, 1485, 1328, 1260, 1158, 1069, 757.

HRMS (ESI+): calculated: 334.1188 ([C18H16BF2NNaO]+; [M+Na+]); found: 334.1193.

12-allyl-10-bromo-6,6-difluoro-12-methyl-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11b)

11b was prepared from benzofuroindoline amine 4b (34 mg, 0.107 mmol) following general

procedure B using BF3.Et2O (0.02 mL, 0.162 mmol), allylTMS (0.05 mL, 0.314 mmol) in

dichloromethane (1.0 mL) during 3 h at 36°C. Flash column chromatography purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11b as a yellow solid as a yellow solid (31 mg,

0.794 mmol, 74%).

Data for 11b:

Rf: 0.42 (Cyclohexane/EtOAc: 8/2)

SI-17

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm) : 7.85 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 8.4 Hz,

1H), 7.64-7.60 (m, 2H), 7.57 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.13-

5.04 (m, 1H), 4.86-4.77 (m, 2H), 3.00 (d, J = 7.2 Hz, 2H), 1.78 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 179.1, 160.3, 143.8, 142.2, 138.3, 132.6, 129.6,

127.8, 125.6, 122.0, 121.4, 120.9, 120.3, 120.2, 112.8, 57.1, 44.1, 24.3.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.797 (t, J = 14 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.49 - (–)135.76 (m, 2F)

IR (NaCl), v (cm-1): 3280, 2928, 1618, 1603, 1531, 1483, 1444, 1286, 1262, 1066, 914, 840,

758, 503.

HRMS (ESI+): calculated: 412.0294 ([C18H15B79BrF2NNaO]+; [M+Na+]); found: 412.0283.

calculated: 414.0272 ([C18H15B81BrF2NNaO]+; [M+Na+]); found: 414.0266.

12-allyl-10-chloro-6,6-difluoro-12-methyl-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11c)

11c was prepared from benzofuroindoline amine 4c (42 mg, 0.154 mmol) following general

procedure B using BF3.Et2O (0.05 mL, 0.4050 mmol), allylTMS (0.07 mL, 0.440 mmol) in

dichloromethane (1.5 mL) during 3 h at 36°C. Flash column chromatography purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11c as a yellow solid (40 mg, 0.116 mmol,

75%).

Data for 11c:

Rf: 0.54 (Cyclohexane/EtOAc: 7/3).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.87-7.84 (m, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.44

(d, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.16-5.01

(m, 1H), 4.85-4.76 (m, 2H), 3.00 (d, J = 7.2 Hz, 2H), 1.78 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 179.2, 160.3, 143.5, 141.7, 138.3, 134.2, 129.7,

129.6, 127.8, 122.7, 121.3, 120.9, 120.3, 119.8, 112.8, 57.1, 44.1, 24.3.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.809 (t, J = 14 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.58 - (–)135.64 (m, 2F)

IR (NaCl), v (cm-1): 3385, 2924, 1619, 1606, 1532, 1445, 1287, 1263, 1069, 922, 847, 737.

HRMS (ESI+): calculated: 368.0799 ([C18H15BClF2NNaO]+; [M+Na+]); found: 368.0796.

SI-18

12-allyl-6,6-trifluoro-12-methyl-6,12-dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-

7-ium-6-uide (11d)

11d was prepared from benzofuroindoline amine 4d (20 mg, 0.0781 mmol) following general

procedure B using BF3.Et2O (0.03 mL, 0.243 mmol), allylTMS (0.06 mL, 0.377 mmol) in

dichloromethane (0.9 mL) during 3 h at 36°C. Flash column chromatography purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11d as a yellow solid (16 mg, 0.0486 mmol,

62%).

Data for 11d:

Rf: 0.62 (Cyclohexane/EtOAc: 8/2)

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm) : 7.92-7.83 (m, 2H), 7.60 (t, J = 7.5 Hz, 1H),

7.23-7.13 (m, 3H), 7.04 (t, J = 7.5 Hz, 1H), 5.10-5.05 (m, 1H), 4.85-4.76 (m, 2H), 3.00 (dd, J=

6.9, 3.0 Hz, 2H), 1.78 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 179.0, 162.6 (d, J = 245 Hz), 160.0, 144.1 (d, J

= 9 Hz), 139.2, 138.0, 129.7, 127.8, 121.3, 120.9, 120.3, 120.1, 116.6 (d, J = 24 Hz), 113.0,

110.0 (d, J = 24 Hz), 57.2, 44.1, 24.3.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.80 (t, J = 16 Hz, 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)111.72 (s, 1F), (–)135.66 - (–)135.94 (m,

2F)

IR (NaCl), v (cm-1): 3230, 3050, 2982, 1612, 1574, 1536, 1475, 1450, 1269, 1067, 928, 757.

HRMS (ESI+): calculated: 352.1094 ([C18H15BF3NNaO]+; [M+Na+]); found: 352.1085

12-allyl-6,6-difluoro-12-methyl-10-(trifluoromethyl)-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11e)

11e was prepared from benzofuroindoline amine 4e (90 mg, 0.294 mmol) following general

procedure B using BF3.Et2O (0.05 mL, 0.405 mmol), allylTMS (0.15 mL, 0.944 mmol) in

dichloromethane (2.5 mL) during 12 h at RT. Preparative TLC purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11e as a yellow oil (57 mg, 0.150 mmol, 51%).

Data for 11e:

SI-19

Rf: 0.33 (Cyclohexane/EtOAc: 8/2).

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm): 8.05 (d, J = 8.2 Hz, 1H), 7.89 (dd, J = 8.2, 1.5

Hz, 1H), 7.77-7.63 (m, 3H), 7.26-7.22 (m, 1H), 7.07 (t, J = 8.2 Hz, 1H), 5.18-5.08 (m, 1H),

4.92-4.79 (m, 2H), 3.10 (d, J = 7.2 Hz, 2H), 1.88 (s, 3H).

13C NMR (90 MHz, CDCl3, 300 K) δ (ppm): 181.0, 160.7, 145.9, 142.3, 138.9, 130.0 (d, J =

30 Hz), 129.4, 128.1, 127.0, 121.5, 121.1, 120.8 (q, J = 275 Hz), 120.5, 119.4, 119.1, 112.7,

57.3, 44.1, 24.2.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.83 (t, J = 15 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)61.86 (s, 3F), (–)0135.07 - (–)136.36 (m,

2F).

IR (NaCl), v (cm-1): 3397, 3084, 2983, 2927, 1613, 1532, 1485, 1448, 1432, 1328, 1278, 1266,

1171, 1126, 1065, 922, 849, 757.

HRMS (ESI+): calculated: 402.1062 ([C19H15BF5NNaO]+; [M+Na+]); found: 402.1055

12-allyl-6,6-difluoro-10-isopropyl-12-methyl-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11f)

11f was prepared from benzofuroindoline amine 4f (45 mg, 0.161 mmol) following general

procedure B using BF3.Et2O (0.04 mL, 0.324 mmol), allylTMS (0.08 mL, 0.503 mmol) in

dichloromethane (1.7 mL) during 12 h at RT. Preparative TLC purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11e as a yellow oil (23 mg, 0.0652 mmol, 40%).

Data for 11f:

Rf: 0.50 (Cyclohexane/EtOAc: 8/2).

1H NMR (300 MHz, CDCl3, 300 K) δ (ppm): 7.89-7.83 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.31

(d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 5.10-5.01

(m, 1H), 4.81-4.72 (m, 2H), 3.08-2.94 (m, 1H), 3.00 (d, J = 7.2 Hz, 2H), 1.77 (s, 3H), 1.28 (d,

J = 7.2 Hz, 6H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 178.3, 159.9, 149.7, 141.9, 141.2, 137.5, 130.3,

127.8, 127.6, 121.0, 120.2, 120.1, 120.0, 118.5, 113.1, 56.8, 44.2, 34.6, 24.4, 24.2, 24.2.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.85 (t, J = 14 Hz, 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.29 - (–)136.33 (m, 2F)

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IR (NaCl), v (cm-1): 3377, 2961, 1613, 1607, 1573, 1535, 1480, 1449, 1286, 1267, 1100, 1065,

925, 829, 756.

HRMS (ESI+): calculated: 376.1658 ([C21H22BF2NNaO]+; [M+Na+]); found: 376.1655.

12-allyl-6,6-difluoro-10,12-dimethyl-6,12-dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-

a]indol-7-ium-6-uide (11g)

11g was prepared from benzofuroindoline amine 4g (70 mg, 0.277 mmol) following general

procedure B using BF3.Et2O (0.05 mL, 0.405 mmol), allylTMS (0.14 mL, 0.884 mmol) in

dichloromethane (2.7 mL) during 12 h at RT. Preparative TLC purification

(Cyclohexane/EtOAc: 80/20) led to indolenine 11g as a yellow oil (33 mg, 0.102 mmol, 37%).

Data for 11g:

Rf: 0.31 (Cyclohexane/EtOAc: 8/2).

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm) : 7.85 (dd, J = 8.0, 1.4 Hz, 1H), 7.81 (d, J = 8.0

Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.27-7.19 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 5.10-5.03 (m,

1H), 4.80-4.74 (m, 2H), 2.99 (d, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.76 (s, 3H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 178.2, 159.9, 142.0, 141.1, 138.5, 137.6, 130.2,

130.1, 127.7, 122.6, 121.2, 120.3, 120.0, 118.5, 113.1, 56.8, 44.2, 24.5, 21.9.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.86 (t, J = 15 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm) : (–)135.44 - (–)136.47 (m, 2F).

IR (NaCl), v (cm-1): 3389, 2929, 1608, 1535, 1479, 1448, 1279, 1268, 1095, 1059, 926, 820,

756.

HRMS (ESI+): calculated: 348.1345 ([C19H18BF2NNaO]+; [M+Na+]); found: 348.1339.

12-allyl-6,6-difluoro-10-methoxy-12-methyl-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11h)

11h was prepared from benzofuroindoline amine 4h (70 mg, 0.2609 mmol) following general

procedure B using BF3.Et2O (0.05 mL, 0.406 mmol), allylTMS (0.14 mL, 0.884 mmol) in

dichloromethane (2.7 mL) during 12 h at RT. Preparative TLC purification

SI-21

(Cyclohexane/EtOAc: 80/20) led to indolenine 11g as a yellow solid (41 mg, 0.120 mmol,

46%).

Data for 11h:

Rf: 0.22 (Cyclohexane/EtOAc: 8/2)

1H NMR (360 MHz, CDCl3, 300 K) δ (ppm): 7.85-7.82 (m, 2H), 7.56 (t, J = 8.6 Hz, 1H), 7.18

(d, J = 8.6 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.97-6.93 (m, 2H), 5.14-5.02 (m, 1H), 4.81-4.75

(m, 2H), 3.86 (s, 3H), 3.00-2.97 (m, 2H), 1.75 (s, 3H).

13C NMR (90 MHz, CDCl3, 300 K) δ (ppm): 177.1, 160.1, 159.5, 143.8, 137.2, 136.6, 130.1,

127.4, 121.0, 120.3, 120.0, 119.6, 114.1, 113.2, 108.6, 56.8, 56.1, 44.2, 24.5.

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.85 (t, J = 15 Hz , 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.68 - (–)136.73 (m, 2F)

IR (NaCl), v (cm-1): 3380, 2985, 2839, 1609, 1535, 1481, 1448, 1278, 1097, 1066, 925, 865,

757.

HRMS (ESI+): calculated: 364.1294 ([C19H18BF2NNaO2]+; [M+Na+]); found: 364.1285

12-allyl-2-bromo-6,6-difluoro-10-isopropyl-12-methyl-6,12-

dihydrobenzo[5,6][1,3,2]oxazaborinino[3,4-a]indol-7-ium-6-uide (11i)

11i was prepared from benzofuroindoline amine 4n (70 mg, 0.195 mmol) following general

procedure B using BF3.Et2O (0.04 mL, 0.324 mmol), allylTMS (0.11 mL, 0.692 mmol) in

dichloromethane (1.9 mL) during 12 h at RT. Preparative TLC purification

(Cyclohexane/EtOAc: 90/10) led to indolenine 11i as a yellow solid solid (57 mg, 0.132 mmol,

68%).

Data for 11i:

Rf: 0.69 (Cyclohexane/EtOAc: 8/2).

1H NMR (250 MHz, CDCl3, 300 K) δ (ppm) : 7.93 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 8.2 Hz,

1H), 7.63 (dd, J = 9.0, 2.5 Hz, 1H), 7.35-7.29 (m, 2H), 7.10 (d, J = 9.0 Hz, 1H), 5.14-4.98 (m,

1H), 4.82-4.74 (m, 2H), 3.06-2.90 (m, 3H), 1.77 (s, 3H), 1.27 (d, J = 6.7 Hz, 6H).

13C NMR (75 MHz, CDCl3, 300 K) δ (ppm): 177.2, 158.8, 150.2, 142.0, 140.9, 140.0, 129.9,

129.5, 127.7, 123.0, 120.5, 120.0, 118.8, 114.5, 111.6, 57.0, 44.1, 34.6, 24.4, 24.3, 24.3.

SI-22

11B NMR (96 MHz, CDCl3, 300 K) δ (ppm): 0.79 (t, J = 15 Hz, 1B).

19F NMR (235 MHz, CDCl3, 300 K) δ (ppm): (–)135.32 - (–)136.32 (m, 2F)

IR (NaCl), v (cm-1): 3078, 2964, 2873, 1604, 1566, 1528, 1474, 1323, 1259, 1058, 927, 915,

830.

HRMS (ESI+): calculated: 454.0764 ([C21H21B79BrF2NNaO]+; [M+Na+]); found: 454.0758.

calculated: 456.0741 ([C21H21B81BrF2NNaO]+; [M+Na+]); found: 456.0737.

SI-23

NMR spectra of compounds 4, 7a and 11

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DMSO

DMSO

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11B

19F

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11B

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19F

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11B

19F

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19F

11B

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11B

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19F

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11B

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19F

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11B

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19F

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11B

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19F

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11B

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19F

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UV absorption and fluorescence

Absorption and fluorescence of 11a-i were recorded in dilute solutions of CH2Cl2. The

fluorescence was measured upon photoexcitation at 390 nm (fence: 2 nm; increment: 0.5).

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SI-61

X-Ray Crystallography

X-ray diffraction data of compound 4a and 10 were collected by using a Kappa X8 APEX II

Bruker diffractometer with graphite-monochromated MoK radiation ( = 0.71073 Å). X-ray

diffraction data of compound 11a was collected by using a Kappa VENTURE PHOTON 100

Bruker diffractometer with IµS microfocus graphite-monochromated MoK radiation ( =

0.71073 Å). Crystals were mounted on a CryoLoop (Hampton Research) with Paratone-N

(Hampton Research) as cryoprotectant and then flashfrozen in a nitrogen-gas stream at 100 K.

The temperature of the crystal was maintained at the selected value (100 K) by means of a 700

series Cryostream cooling device to within an accuracy of ±1 K. The data were corrected for

Lorentz polarization, and absorption effects. The structures were solved by direct methods using

SIR-97[1] and refined against F2 by full-matrix least-squares techniques using SHELXL-2013[2]

with anisotropic displacement parameters for all non-hydrogen atoms. All calculations were

performed by using the Crystal Structure crystallographic software package WINGX [3].

The crystal data collection and refinement parameters are given in Table S1.

CCDC 1440630-1440632 contains the supplementary crystallographic data for this paper.

These data can be obtained free of charge from the Cambridge Crystallographic Data Centre

via http://www.ccdc.cam.ac.uk/Community/Requestastructure.

Table S1. Crystallographic data and structure refinement details for compounds.

Compound 4e 10 11a

CCDC 1440630 CCDC 1440631 CCDC 1440632

Empirical Formula C16 H13 F3 N2 O C17 H18 N2 O5 S2 C18 H16 B F2 N O

Mr 306.28 394.45 311.13

Crystal size, mm3 0.29 x 0.21 x 0.08 0.31 x 0.14 x 0.04 0.13 x 0.12 x 0.09

Crystal system triclinic triclinic orthorhombic

Space group P -1 P -1 P b c a

a, Å 5.4475(4) 9.2208(2) 13.5204(7)

b, Å 12.1951(11) 9.2881(2) 12.9163(7)

c, Å 12.2971(10 11.3189(3) 17.2730(8)

α, ° 114.682(2) 92.7550(10) 90

β, ° 98.556(2) 103.352(2) 90

γ, ° 98.672(2) 106.5060(10) 90

Cell volume, Å3 713.13(10) 878.64(4) 3016.4(3)

Z 2 2 8

T, K 100(1) 100(1) 100(1)

SI-62

F000 316 412 1296

µ, mm–1 0.117 0.335 0.100

range, ° 1.875 – 31.728 2.311 – 35.133 2.479 - 30.613

Reflection collected 9 568 25 778 192 577

Reflections unique 3 862 7 430 4 636

Rint 0.0321 0.0315 0.0890

GOF 1.039 1.038 1.027

Refl. obs. (I>2(I)) 3 003 6 257 3 853

Parameters / restraints 208 / 0 245 / 0 209 / 0

wR2 (all data) 0.1247 0.0952 0.0702

R value (I>2(I)) 0.0457 0.0338 0.1892

Largest diff. peak and hole (e-

.Å-3) -0.344 ; 0.457 -0.395; 0.592 -0.467 ; 1.143

Compound 4e

SI-63

Compound 10

Compound 11a

[1] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi,

A. G. G. Moliterni, G. Polidori and R. Spagna, J. Appl. Crystallogr., 1999, 32, 115-119.

[2] G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008, 64, 112-122.

[3] L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837-838.

[4] C. F. Macrae, P. R. Edgington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, Towler

and van der Streek, J. Appl. Crystallogr., 2006, 39, 453-457.