Straightforward access to complex isoindolinones from the ...III- Ugi adducts synthesis N-allyl-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-2-nitrobenzamide (1a)

Straightforward access to complex isoindolinones from the Ugi reaction of o-nitrobenzoic acid derivatives

Mahanandaiah Kurva, Mansour Dolé Kerim, Rocio Gamez-Montano, Laurent El Kaim

Table of contentsI- General Information........................................................................................................................2

II- Generals procedures .......................................................................................................................3

III- Ugi adducts synthesis ..................................................................................................................5

IV- Cyclized Ugi adduct 2a...............................................................................................................47

V- Hydroxyisoindolinones synthesis ..................................................................................................49

VI- O- alkylation of hydroxyisoindolinones .....................................................................................64

VII- RCM of N-allyl-O-allyl isoindolinone..........................................................................................93

VIII- Pd triggered CH activation.......................................................................................................105

IX- SNAr/ deamidification/ oxidation/ Pictet-Spengler sequence .................................................111

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2019

2

I- General Information

All reactions requiring anhydrous conditions were conducted in dried apparatus under an inert

atmosphere of nitrogen. All commercial materials were used without further purification.

Commercially available anhydrous bottle of DMSO were used without degazing the solvent.

Reactions were followed by thin- layer chromatography (TLC) performed using precoated

plates of silica 60 F254 and U.V light as a visualizing agent. Column chromatography was

carried out on silica gel (40-63 μm). 1H-NMR spectra were recorded on a Brucker Avance 400

MHz spectrometer, using CDCl3 as solvent. 13C-NMR spectra were recorded on a 100.6 MHz

spectrometer. Chemical shifts are expressed in ppm relative to internal TMS. Coupling

constants (J) are quoted in hertz (Hz), data are reported as follows: chemical shift, multiplicity

(s = singlet, d = doublet, br = broad, m = multiplet), coupling constant(Hz), integration. IR

spectra were performed on a Perkin-Elmer FT 1600 spectrometer with wavelengths in cm-1

and only peaks of interest are reported. High-Resolution Mass spectra (HRMS) were carried

out with maXis255552.0 spectrometer using an electronic impact ionization source. Melting

points (mp) were determined on a Stuart SMP3 apparatus and were left uncorrected.

3

II- Generals procedures

General procedure I (for the synthesis of UGI products)

To a 2 M solution of aldehyde in methanol were added successively 1.0 equiv of amine, 1.0

equiv of carboxylic acid and 1.0 equiv of isocyanide. The resulting mixture was stirred at room

temperature for 1 day. The solvent was removed under reduced pressure and the crude was

purified by flash column chromatography on silica gel to afford Ugi adduct 1. For most Ugi

adducts obtained using these 2-nitrobenzoic acids, the NMR data analysis were complicated

by the presence of rotamers together with relaxation problems even trying to perform the

NMR at higher temperature. Due to these characterization problems, most Ugi adducts were

just considered as synthetic intermediates for the following steps without full data analysis of

the C13 and H1 spectra. These problems disappear after the following cylization steps.

General procedure II (cyclization of Ugi adducts)

To a 2M solution of Ugi adduct in DMSO under N2 atmosphere was added 3 equiv of t-BuOK

and the mixture stirred at room temperature for 6h. The reaction mixture was neutralized

with a saturated solution of citric acid, extracted with EtOAc (25 mL x3) and the organic layer

dried over MgSO4 before evaporation of the solvents. The obtained residue was purified by

column chromatography to afford isoindolinone 3.

General procedure III (one-pot cyclization/oxidation/alkylation procedure)

To a 2M solution of Ugi adduct 1 in DMSO under N2 atmosphere was added 3 equiv of t-BuOK

and the mixture stirred at room temperature for 6h. (2 equiv) of t-BuOK was further added

followed by the respective alkylating agent (2 equiv). The mixture was stirred at room

temperature till completion. The reaction mixture was neutralized with saturated citric acid

solution and extracted with EtOAc (25 mL x 3). The organic layer was washed with water, dried

over MgSO4 and concentrated in vacuum, before purification by flash chromatography.

General Procedure IV (ring closure metathesis)

To a 2M solution of bisallyl adducts 4 in Toluene under N2 atmosphere, was added (0.07 mol

%) of Hoveyda-Grubbs catalyst (2nd generation) and the mixture was heated at 70 °C till

4

completion (monitored by TLC). Then the solvent was evaporated and the residue was purified

by column chromatography to afford RCM adduct.

General procedure V (Pd triggered CH activation)

To a 1M solution of isoindolinone 6 in dry DMF were consecutively added Pd(OAc)2, (6 mol %),

DPPE (10 mol%) and CS2CO3 (1 equiv). The mixture was irradiated under microwave at 150 °

C for 1 hour. The reaction mixture was cooled to room temperature and poured into water

and extracted with EtOAc (25x3 ml). The organic layer was dried on MgSO4 and concentrated.

The obtained residue was purified by column chromatography to afford isoindolinone 7.

General procedure VI (SNAr/ deamidification/ oxidation/ Pictet-Spengler sequence)

To a 0.25M solution of Ugi adduct 1 (0.5 mmol) in dry DMSO was added 3 equiv of t-BuOK and

the mixture stirred at room temperature for 3h. Then 20 ml of satured aqueous solution of

ammonium chloride and 100 ml of diethyl ether were added to the reaction mixture. The

organic layer was washed with 2*20 ml of water. After evaporation, 9.5 ml of DCM and 0.5 ml

of CF3COOH was added. The reaction mixture was stirred at room temperature until

completion (1 h), 20 ml of satured aqueous solution of K2CO3 followed by 80 ml of water were

then added. The organic layer was extracted using dichloromethane (3*30 ml). Drying on

MgSO4 followed by evaporation afford the crude product which was purified by flash

chromatography on silica gel.

5

III- Ugi adducts synthesis

N-allyl-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-2-nitrobenzamide (1a)

NO

HN

O

NO2Cl

Cl

C22H23Cl2N3O4

MW = 464.3417

The compound was synthesized according to general procedure I, using 4 chlorobenzaldehyde

(282 mg, 2.0 mmol), allylamine (0.151 ml, 2.0 mmol), 4-chloro-2-nitrobenzoic acid (404 mg,

2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol). Purification by flash chromatography

using (Et2O: PE = 50: 50) gave the desired product in 77% isolated yield (715 mg) as white solid.

MP = 118–119 °C.

Rf(Et2O: PE = 5 : 5) = 0.3.

1H NMR (400 MHz, CDCl3, 55°C) δ 8.17 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 10.2 Hz, 1H), 7.49 – 7.37

(m, 5H), 5.86 (brs, 1H), 5.30 (brs, 1H), 4.88– 4.56 (brs, 2H), 3.9 – 3.65 (m, 2H), 1.37 (s, 9H).

6

NO

HN

O

NO2Cl

Cl

13C-NMR (CDCl3, 101 MHz, 55°C): δ (ppm) 167.7, 167.4, 145.8, 136.0, 134.8, 134.1, 133.5,

133.0, 131.1, 129.7, 129.0, 124.8, 117.9, 62.4, 51.8, 50.9, 28.4

HRMS: calculated for [M-CONHTBU]: 363.0298, found 363.0308

I.R. (thin film): ν 3417, 3329, 3084, 2968, 2930, 1682, 1628, 1250, 1154, 1092, 1016 , 835 cm-1.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.04

2.02

2.02

1.00

1.05

5.04

1.03

1.08

7

NO

HN

O

NO2Cl

Cl

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

28.4

50.9

51.8

62.4

117.

912

4.8

129.

012

9.7

131.

113

3.0

133.

513

4.1

134.

813

6.0

145.

8

167.

416

7.7

9

N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-N-(2-methoxyethyl)-2-nitrobenzamide (1b)

NO

HNO

NO2Cl

Cl

O

C22H25Cl2N3O5

MW = 482.3570

The compound was synthesized according to general procedure I, using 4-chloro

benzaldehyde (281 mg 2.0 mmol), methoxy ethanol amine (0.18 ml, 2.0 mmol), 4-chloro-2-

nitrobenzoic acid (404 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol).

Purification by flash chromatography using (Et2O: PE = 50: 50) gave the desired product in 78

% isolated yield (803 mg) as a white fluffy solid.

MP = 134–135 °C.

Rf (Et2O: PE = 6 : 4) = 0.3.

1H NMR (400 MHz, CDCl3, 55 ° C) δ 8.17 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H),

7.43 – 7.33 (m, 4H), 5.78 (s, 1H), 3.40 – 3.31 (m, 2H), 3.26 – 3.18 (m, 2H), 3.06 (s, 3H), 1.40 (s,

9H). 13C NMR (101 MHz, CDCl3, 55 ° C) δ 167.9, 167.5, 145.9, 135.9, 134.6, 134.0, 133.6, 130.9,

130.0, 128.9, 124.8, 70, 63.3, 58.4, 51.9, 48.1, 28.6

HRMS: calculated for [M-CONHTBU]: 381.0403, found 381.0396

I.R. (thin film): ν 3313, 3087, 2968, 2929, 1647, 839

10

NO

HNO

NO2Cl

Cl

O

NO

HNO

NO2Cl

Cl

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.01

3.04

2.04

2.00

1.00

4.00

1.01

1.04

1.00

12

N-(2-(tert-butylamino)-2-oxo-1-(pyridin-2-yl)ethyl)-4-chloro-N-(2-methoxyethyl)-2-

nitrobenzamide (1c)

NO

HNO

NO2Cl

N

O

C21H25ClN4O5

MW = 448.9000

The compound was synthesized according to the general procedure I, using 2-pyridine

carbaldehyde (0.2 ml 2.0 mmol), methoxy ethanol amine (0.18 ml, 2.0 mmol), 4-chloro-2-

nitrobenzoic acid (404 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol).


% isolated yield (803 mg) as pale brown solid.

MP = 136–137 °C.

Rf(Et2O: PE = 9: 1) = 0.25.

1H NMR (400 MHz, CDCl3, 55 ° C) δ 8.56-8.53(m, 1H), 8.15 (d, J = 11.9 Hz, 1H), 7.75 (d, J = 6.8

Hz, 2H), 7.68 – 7.63 (m, 2H), 7.24 – 7.20 (m, 1H), 5.54 (s, 1H), 3.48 – 3.40 (m, 2H), 3.35 – 3.32

(m, 2H), 3.12 (s, 3H), 1.43 (s, 9H).13C NMR (101 MHz, CDCl3, 55 ° C) δ 167.5, 166.4, 156.0, 148.2, 145.9, 136.9, 135.7, 134.1,

131.3, 130.4, 124.6, 124.1, 122.4, 70.2, 66.5, 58.5, 51.5, 50.5, 29.5, 28.6

I.R. (thin film): ν 3317, 3067, 2945, 2922, and 1647, 1560 cm-1.

13

NO

HNO

NO2Cl

N

O

NO

HNO

NO2Cl

N

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

9.00

3.00

2.02

2.01

1.00

1.05

2.09

2.00

1.05

1.08

0102030405060708090100110120130140150160170180f1 (ppm)

28.6

29.5

50.5

51.5

58.5

66.5

70.2

122.

412

4.1

124.

613

0.4

131.

313

4.1

135.

713

6.9

145.

914

8.2

156.

0

166.

416

7.5

14

N-(2-(tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-4-chloro-N-(2,2-dimethoxyethyl)-

2-nitrobenzamide (1d)

N

NHO

OMeO

O2N Cl

MeO

OMe

C24H30ClN3O7

MW = 507.9639

The compound was synthesized according to general procedure I, using 4-

methoxybenzaldehyde (0.25 ml 2.0 mmol), 2,2-dimethoxyethan-1-amine (0.22 ml, 2.0 mmol),

4-chloro-2-nitrobenzoic acid (404 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol).


% isolated yield (910 mg) as a pale-yellow solid.

MP = 100 –101 °C.

Rf(Et2O: PE = 7: 3) = 0.28.

1H NMR (400 MHz, CDCl3, 55°C) (two rotamers A and B) δ 8.15 (d, J = 14.9 Hz, 1H), 7.63 (d, J =

7.9 Hz, 1H), 7.52-7.44 (m, 2H), 7.17-6.84 (m, 3H), 5.95 (brs, 1H, A), 5.80 (brs, 1H, B), 5,10 (brs,

1H, A), 4.90 (brs, 1H, B), 3.93-3.75 (m, 4H), 3.52-3.23 (m, 8H), 3.20-2.84 (m, 6H), 1.40 (s, 9H).13C NMR (101 MHz, CDCl3, 55°C) δ 13C NMR (101 MHz, ) δ 168.6, 168.2, 160.0, 159.8, 145.9,

135.5, 133.8, 131.3, 131.1, 130.9, 130.4, 126.8, 125.1, 124.6, 114.4, 103.4, 102.5, 68.1, 63.4,

55.3, 54.9, 54.8, 51.6, 28.6

HRMS: calculated for [M-CONHtBu]: 407.1004, found 407.1006

15

N

NHO

OMeO

O2N Cl

MeO

OMe

N

NHO

OMeO

O2N Cl

MeO

OMe

I.R. (thin film): ν 3312, 3066, 2961, 2928, 2841, 1676, 1629, 1528, 1036 and 831 cm-1.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.05

6.00

2.02

1.09

4.01

1.05

3.09

2.09

1.04

1.00

0102030405060708090100110120130140150160170180190f1 (ppm)

28.6

51.6

54.8

54.9

55.3

63.4

68.1

102.

510

3.4

114.

412

4.6

125.

112

6.8

130.

413

0.9

131.

113

1.3

133.

813

5.5

145.

9

159.

816

0.0

168.

216

8.6

17

N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(2,2-dimethoxyethyl)-2-nitrobenzamide (1e)

NOMe

O

O2N

Cl

OMe

O NH

C23H28ClN3O6

MW = 477.9379

This compound was synthesized according to the modified general procedure I, using 4-chloro

benzaldehyde (282 mg 2.0 mmol), 2,2-dimethoxyethan-1-amine (0.22 ml, 2.0 mmol), 2-

nitrobenzoic acid (334 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol) in 2 ml of

methanol. Purification by flash chromatography using (Et2O: PE = 70: 30) gave the desired

product in 99 % isolated yield (945 mg) as a mixture of two rotamers (A and B).

Aspect: yellow fluffy solid

Rf = 0.35 (Et2O: PE = 8: 2)

1H NMR (400 MHz, CDCl3) δ 8.24 (t, J = 7.6 Hz, 1H), 7.79-7.24 (m, 7H), 6.5 (brs, 1H, A) 6.12 (brs,

1H, B), 5.87 (brs, 1H, B), 5.19 (s, 1H, A), 5.13 (brs, 1H), 3.56 (s, 3H, B), 3.48 (dd, J = 14.6, 3.9 Hz,

1H, B), 3.44 (s, 3H, A), 3.34 (dd, J = 15.5 Hz, 4.8 Hz, 1H, A), 3.20 (dd, J = 15.5 Hz, 5.3 Hz, 1H, B),

3.15 (s, 3H, B), 3.06 (s, 3H, A), 1.48 (s, 9H, B), 1.44 (s, 9H, A).13C NMR (101 MHz, CDCl3) δ 170.1, 169.2, 145.0, 134.4, 131.1, 130.7, 130.0, 129.2, 128.9,

125.3, 124.7, 103.1 (A), 102.3 (B), 67.4 (A), 63.6 (B), 56.1 (B), 55.0 (A), 53.5 (B), 52.0 (A), 51.7,

47.9 (B), 28.6

HRMS: calculated for [M-CONHtBu]: 377.0899, found 377.0890

I.R. (thin film): 3319, 2967, 2835, 1651, 1529, 1346, 1069, 1016, 733, 699.

18

NOMe

O

O2N

Cl

OMe

O NH

NOMe

O

O2N

Cl

OMe

O NH

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.09.

22

8.25

1.00

1.11

7.08

1.01

3.06

3.15

3.18

3.19

3.22

3.23

3.32

3.33

3.35

3.37

3.44

3.46

3.47

3.49

3.50

3.56

5.13

5.19

5.87

6.12

6.50

7.30

7.34

7.36

7.74

7.76

8.22

8.23

8.25

-100102030405060708090100110120130140150160170180190200

28.6

2

47.9

251

.75

51.9

854

.96

56.0

8

63.6

0

67.3

9

102.

2710

3.11

124.

7212

5.33

128.

9412

9.15

130.

0413

0.71

131.

1413

4.36

144.

96

169.

1517

0.11

20

N-allyl-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-2-nitrobenzamide (1f)

N

O

HN

Cl

NO2O

C22H24ClN3O4

MW = 429.8967


(282 mg, 2.0 mmol), allylamine (0.16 ml, 2.0 mmol), 2-nitrobenzoic acid (335 mg, 2.0 mmol)

and tert-butyl isocyanide (0.23 ml, 2.0 mmol). Purification by flash chromatography using

(Et2O: PE = 50: 50) gave the desired product in 70% isolated yield (602 mg) as yellow fluffy

solid.

MP = 135–136 °C

Rf (Et2O: PE = 5: 5) = 0.33

1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.5 Hz, 1H), 7.74-7.66 (m, 1H), 7.60-7.55 (m, 1H), 7.53-

7.42 (m, 3H), 7.38 (d, J = 8.5 Hz, 2H), 5.91 (brs, 1H), 5.45-4.60 (brm, 3H), 3.84-3.61 (m, 2H),

1.37 (s, 9H).13C NMR (101 MHz, CDCl3) δ 168.8, 167.6, 145.0, 134.6, 134.4, 133.7, 132.9, 132.6, 131.6,

131.2, 130.1, 129.1, 128.6, 124.8, 118.2, 61.9, 51.7, 50.9, 28.3

.I.R. (thin film): 3327, 2968, 1683, 1631, 1530, 856 and 765cm -1.

21

N

O

HN

Cl

NO2O

N

O

HN

Cl

NO2O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.04

2.00

3.06

2.00

2.02

3.01

1.05

1.09

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

28.3

50.9

51.7

61.9

118.

212

4.8

128.

612

9.1

130.

113

1.2

132.

613

4.4

134.

6

145.

0

167.

616

8.8

22

N-allyl-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-2,4-dinitrobenzamide (1g)

N

O

HN

Cl

NO2O

O2N

C22H23ClN4O6

MW = 474.8942


(282 mg, 2.0 mmol), allylamine (0.16 ml, 2.0 mmol), 2,4-dinitrobenzoic acid (425 mg, 2.0

mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol). Purification by flash chromatography

using (Et2O: PE = 50: 50) gave the desired product in 74% isolated yield (705 mg) as a yellow

paste.

Rf(Et2O: PE = 5 : 5) = 0.28.

1H NMR (400 MHz, CDCl3, 55 ° C) δ 9.01-8.97 (m, 1H), 8.54-8.48 (m, 1H), 7.74-7.70 (m, 1H),

7.53-7.48 (m, 2H), 7.45-7.39 (m, 2H), 5.82 (s, 1H), 5.68 (s, 1H), 5.45-5.34 (m, 1H), 4.88-4.78 (m,

1H), 4.73-4.54 (m, 1H), 3.85-3.78 (m, 1H), 3.76-3.68 (m, 1H), 1.40 (s, 9H).13C NMR (101 MHz, CDCl3, 55 ° C) δ 167.2, 166.6, 148.2, 145.6, 137.9, 135.1, 133.1, 132.9,

131.1, 130.2, 129.2, 128.2, 120.1, 62.5, 52.1, 50.9, 28.6

I.R. (thin film): 3410, 3333, 3074, 2958, 2923, 1677, 1623, 12407, 1150, 1088, 1010 and 827

cm-1.

23

N

O

HN

Cl

NO2O

O2N

N

O

HN

Cl

NO2O

O2N

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

9.03

1.00

1.05

1.03

1.10

1.00

1.00

1.01

2.05

2.01

1.03

1.02

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

28.6

50.9

52.1

62.5

120.

112

8.2

129.

213

0.2

131.

113

2.9

133.

113

5.1

137.

914

5.6

148.

2

166.

616

7.2

24

N-(2-(tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-4-chloro-N-(2-methoxyethyl)-2-nitrobenzamide (1h)

N

NHO

O

O

O2N Cl

MeO

C23H28ClN3O6

MW = 477.9379

This compound was synthesized according to the general procedure I, using 4-methoxy

benzaldehyde (0.25 ml, 2.0 mmol), methoxy ethanol amine (0.18 ml, 2.0 mmol), 4-chloro-2-

nitrobenzoic acid (404 mg, 2.0 mmol) and t-butyl isocyanide (0.23 ml, 2.0 mmol). Purification

by flash chromatography using (Et2O: PE = 50: 50) gave the desired product in 84% isolated

yield (803 mg) as a white fluffy solid.

MP = 124–125 °C.

Rf (Et2O: PE = 6 : 4) = 0.3.

1H NMR (400 MHz, CDCl3) δ 8.14-8.11 (m, 1H), 7.62-7.58 (m, 1H), 7.39-7.36 (m, 2H), 6.89-6.85

(m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 3.76 (s, 3H), 3.73 (s, 1H), 3.30-3.20 (m, 2H), 2.95

(s, 2H), 1.33 (s, 9H).13C NMR (101 MHz, CDCl3) δ 168.5, 168.0, 159.8, 145.7, 136.3, 135.7, 134.3, 131.2, 131.1,

130.1, 125.4, 124.9, 114.5, 114.4, 70.1, 69.1, 58.6, 55.4, 51.9, 51.7, 28.7


25

N

NHO

O

O

O2N Cl

MeO

N

NHO

O

O

O2N Cl

MeO

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.07

2.04

2.03

1.06

3.00

1.01

1.02

2.02

2.04

1.02

1.09

0102030405060708090100110120130140150160170180f1 (ppm)

28.7

51.7

51.9

55.4

58.6

69.1

70.1

114.

411

4.5

124.

912

5.4

130.

113

1.1

131.

213

4.3

135.

713

6.3

145.

7

159.

8

168.

016

8.5

26

N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-N-cyclopropyl-2-

nitrobenzamide (1i)

N

NHO

O

O2N Cl

Cl

C22H23Cl2N3O4

MW = 464.3417

The compound was synthesized according to general procedure I, using 4-chloro

benzaldehyde (281 mg 2.0 mmol), cyclopropyl amine (0.14 ml, 2.0 mmol), 4-chloro-2-

nitrobenzoic acid (404 mg, 2.0 mmol) and t-butyl isocyanide (0.23 ml, 2.0 mmol). Purification

by flash chromatography using (Et2O: PE = 50: 50) gave the desired product in 65 % isolated

yield (600 mg) as a pale white solid.

MP = 120–121 °C.

Rf(Et2O: PE = 5: 5) = 0.35.1H NMR (400 MHz, CDCl3, 55°C) δ 8.14-8.12 (m, 1H), 7.66-7.63 (m, 1H), 7.50-7.44 (m, 3H), 7.39-

7.36 (m, 2H), 5.84-5.75 (m, 2H), 2.35-2.29 (m, 1H), 1.37 (s, 10H), 0.91-0.85 (m, 1H), 0.50-0.31

(m, 3H).13C NMR (101 MHz, CDCl355°C) δ 169.1, 167.9, 146.1, 135.7, 134.4, 133.8, 133.7, 132.4, 131.2,

129.5, 128.8, 124.7, 65.5, 51.8, 28.8, 9.9, 8.1


27

N

NHO

O

O2N Cl

Cl

N

NHO

O

O2N Cl

Cl

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

3.01

1.06

9.02

1.07

2.01

2.00

3.05

1.07

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

8.1

9.9

28.8

51.8

65.5

124.

712

8.8

129.

513

1.2

132.

413

3.7

133.

813

4.4

135.

7

146.

1

167.

916

9.1

28

N-allyl-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-2-nitrobenzamide(1j)

NO

N

HN

O

O2N

C21H24N4O4

MW = 396.4397

This compound was synthesized according to the general procedure I, using pyridine-3-

carbaldehyde (0.19 ml, 2.0 mmol), allyl amine (0.15 ml, 2.0 mmol), 2-nitrobenzoic acid (335

mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol). Purification by flash

chromatography using (Et2O: PE = 90: 10) gave the desired product in 83 % isolated yield (660

mg) as a white fluffy solid.

MP = 128 –129 °C.

Rf(Et2O: PE = 9: 1) = 0.23.

1H NMR (400 MHz, CDCl3, 55 °C ) δ 8.70 (brs, 1H), 8.44 (brs, 1H), 8.11 (d, J = 8.3, Hz, 1H), 7.93

(d, J = 7.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.53-7.46 (m, 1H), 7.34 (dd, J = 7.6, 1.3 Hz, 1H), 7.26 (dd,

J = 7.7, 4.8 Hz, 1H), 6.21 (s, 1H), 5.77 (s, 1H), 5.44-5.32 (m, 1H), 4.80 (dd, J = 10.2, 1.1 Hz, 1H),

4.63 (dd, J = 17.1, 1.1 Hz, 1H), 3.78-3.64 (m, 2H), 1.35 (s, 9H). 13C NMR (101 MHz, CDCl3, 55 °C) δ 168.7, 166.9, 150.3, 149.3, 145.2, 137.5, 134.0, 132.7,

132.4, 131.5, 130.1, 128.4, 124.7, 123.4, 118.6, 61.1, 52.0, 51.5, 28.8

I.R. (thin film): ν 3325, 3069, 2971, 2928, 2832, 1675, 1629, 1539, 1028 cm-1.

29

NO

N

HN

O

O2N

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

9.08

2.03

1.05

1.08

1.06

1.03

1.00

1.01

1.02

1.06

1.09

0.94

1.15

2.00

30

N-(2-(tert-butylamino)-1-(3,4-dimethoxyphenyl)-2-oxoethyl)-4-chloro-N-(2,2-

dimethoxyethyl)-2-nitrobenzamide (1k)

N

NHO

OMeO

O2N Cl

MeOOMe

OMe

C25H32ClN3O8

MW = 537.9899

The compound was synthesized according to general procedure I, using 3,4-

dimethoxybenzaldehyde (333 mg 2.0 mmol), 2,2-dimethoxyethan-1-amine (0.22 ml,

2.0mmol), 4-chloro-2-nitrobenzoic acid (404 mg, 2.0 mmol) and t-butyl isocyanide (0.23 ml,

2.0 mmol). Purification by flash chromatography using (Et2O: PE = 70: 30) gave the desired

product in 79 % isolated yield (850 mg) as a pale-yellow solid.

MP = 90–91 °C.

Rf (Et2O: PE = 7: 3) = 0.25.

1H NMR (400 MHz, CDCl3, 55 °C)(mixture of rotamers) δ 8.14 (d, J = 18.7 Hz, 1H), 7.66-7.58 (m,

1H), 7.47 (d, J = 8.0 Hz, 1H), 7.18-7.09 (m, 1H), 6.92-6.74 (m, 2H), 5.87 (s, 1H), 3.90-3.83 (m,

6H), 3.48-3.38 (m, 2H), 3.35-3.26 (s, 1H), 3.21-2.89 (m, 6H), 1.41 (s, 9H).13C NMR (101 MHz, CDCl3, 55 °C) δ 168.2, 168.1, 149.7, 145.9, 135.6, 133.9, 131.1, 130.4, 125.2,

125.1, 124.6, 122.5, 122.2, 113.7, 113.3, 111.7 103.4, 102.5, 68.1, 56.1, 56.0, 54.8, 51.6, 28.6


31

N

NHO

OMeO

O2N Cl

MeOOMe

OMe

N

NHO

OMeO

O2N Cl

MeOOMe

OMe

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.07

6.01

1.00

2.04

6.01

1.04

2.02

1.01

1.06

1.06

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

28.6

51.6

54.8

56.0

56.1

68.1

102.

510

3.4

111.

711

3.3

113.

712

2.2

122.

512

4.6

125.

112

5.2

130.

413

1.1

133.

913

5.6

145.

9

149.

7

168.

116

8.2

32

N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1l)

N O

Cl

NO2O

O

O

HN

Cl

C29H31Cl2N3O6

MW = 588.4789


benzaldehyde (703 mg, 5.0 mmol), 2-(3,4-dimethoxyphenyl)ethanamine (0.8 ml, 5.0 mmol),

4-chloro-2-nitrobenzoic acid (1 g, 5.0 mmol) and tert-butyl isocyanide (0.57 ml, 5.0 mmol) in

5 ml of methanol. Purification by flash chromatography using (Et2O: PE = 80: 20) gave the

desired product in 95 % isolated yield (2.8 mg) as a mixture of two rotamers (A and B).


Rf = 0.28 (Et2O: PE = 8: 2)

1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.0 Hz, 1H, A), 8.06 (brs, 1H, B), 7.59 (dd, J = 8.2, 2.0

Hz, 1H, A), 7.55 (dd, J = 8.2, 2.0 Hz, 1H, B), 7.46-7.17 (m, 5H), 6.75-4.71 (m, 5H), 3.72 (s, 6H, B),

3.66 (s, 3H, A), 3.59 (s, 3H, A), 3.42-2.69 (m, 2H), 2.60-1.53 (m, 2H), 1.29 (s, 9H, A), 1.22 (s, 9H,

B)13C NMR (101 MHz, CDCl3) δ 167.84 (A), 167.56, 166.69 (B), 148.74 (A), 148.58 (B), 147.56 (A),

147.19 (B), 145.95 (B), 145.30 (A), 135.87 (A), 135.27 (B), 134.70, 134.33 (A), 134.17 (B), 133.47

(A), 132.67 (B), 131.65 (B), 131.49 (B), 131.18 (A), 130.86 (A), 129.96 (A), 129.73 (A), 129.35

(B), 129.21 (B), 129.07 (A), 125.08 (B), 124.91 (A), 120.40 (B), 120.18 (A), 111.70 (B), 111.20

(A), 111.08, 65.94 (B), 62.61 (A), 55.75, 55.51, 52.02 (B), 51.78 (A), 49.95 (A), 47.40 (B), 35.14

(A), 33.40 (B), 28.48

HRMS: calculated for C29H31Cl2N3O6: 587.1590, found 587.1566

I.R. (thin film): 3346, 2967, 2835, 1678, 1642, 1530, 1354, 1029, 1017, 736, 688.

33

N O

Cl

NO2O

O

O

HN

Cl

N O

Cl

NO2O

O

O

HN

Cl

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5

9.23

1.85

1.96

6.19

5.01

6.10

1.00

1.22

1.29

1.74

2.41

2.53

2.86

3.20

3.35

3.59

3.66

3.70

3.72

3.74

4.90

6.58

6.60

7.46

7.54

7.54

7.56

7.57

7.58

7.59

7.60

8.06

8.10

8.11

-100102030405060708090100110120130140150160170180190200210

28.4

833

.40

35.1

4

47.4

049

.95

51.7

852

.02

55.5

155

.75

62.6

165

.94

111.

0811

1.20

111.

7012

0.18

124.

9112

9.07

129.

7313

0.86

131.

1813

4.33

134.

70

145.

3014

5.95

147.

1914

7.56

148.

5814

8.74

166.

6916

7.56

167.

84

35

N-(2-(tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-4-chloro-N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1m)

N O

Cl

NO2O

O

O

HN

O

C30H34ClN3O7

MW = 584.0599

This compound was synthesized according to the modified general procedure I, using para-

anisaldehyde (0.24 ml, 2.0 mmol), 2-(3,4-dimethoxyphenyl)ethanamine (0.34 ml, 2.0 mmol),

4-chloro-2-nitrobenzoic acid (404 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol)

in 2 ml of methanol. Purification by flash chromatography using (Et2O: PE = 90: 10) gave the

desired product in 87 % isolated yield (1.02 g) as a mixture of two rotamers (A and B).


Rf = 0.38 (Et2O: PE = 9: 1)

1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 2.0 Hz, 1H, A), 8.11 (d, J = 1.7 Hz, 1H, B), 7.59 (dd, J =

8.2, 2.0 Hz, 1H, A), 7.55 (br, 1H, B), 7.50-7.17 (m, 3H), 6.91 (d, J = 8.8 Hz, 2H, A), 6.87 (d, J = 8.5

Hz, 2H, B), 6.65-6.20 (m, 2H), 6.12-4.77 (m, 3H), 3.75 (s, 3H, A), 3.74 (s, 3H, B), 3.72 (s, 3H, B),

3.71 (s, 3H, B), 3.68 (s, 3H, A), 3.60 (s, 3H, A), 3.34-2.68 (m, 2H), 2.57-1.59 (m, 2H), 1.31 (s, 9H,

A), 1.22 (s, 9H, B).13C NMR (101 MHz, CDCl3) δ 168.54 (A) , 167.50, 166.65 (B), 160.21 (B), 159.97 (A), 148.76 (A),

148.63 (B), 147.56 (A), 147.21 (B), 146.06 (B), 145.37 (A), 135.83 (B), 135.75 (A), 134.33 (A),

134.20 (B), 131.92 (B), 131.72 (A), 131.41 (A), 131.29 (B), 130.37 (A), 130.01, 129.57 (B), 125.83

(B), 125.12 (A), 124.91, 120.57 (B), 120.24 (A), 114.44 (B), 114.37 (A), 111.92 (B), 111.34 (A),

111.08 (A), 111.03 (B), 66.35 (A), 62.78 (B), 55.84 (A), 55.71 (B), 55.60 (A), 55.38 (B), 55.35,

51.98 (B), 51.77 (A), 49.56 (B), 47.27 (A), 35.28 (B), 33.40 (A), 28.63.

HRMS: calculated for C30H34ClN3O7: 583.2085, found 583.2059

36

N O

Cl

NO2O

O

O

HN

O

N O

Cl

NO2O

O

O

HN

O

I.R. (thin film): 3348, 2964, 2839, 1679, 1642, 1531, 1353, 1029, 1016, 735, 682.

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5

9.52

1.84

1.95

9.45

3.24

4.13

4.08

1.00

1.22

1.31

1.72

2.37

2.44

2.86

3.09

3.11

3.15

3.18

3.60

3.68

3.71

3.72

3.74

3.75

4.90

5.08

5.20

5.87

6.05

6.29

6.32

6.61

6.86

6.88

6.90

6.92

7.20

7.46

7.58

7.59

7.61

8.11

8.11

8.12

8.13

0102030405060708090100110120130140150160170180190

28.6

333

.40

35.2

8

47.2

749

.56

51.7

751

.98

55.3

555

.38

55.6

055

.71

55.8

462

.78

66.3

5

111.

0311

1.08

111.

3411

1.92

114.

3711

4.44

120.

2412

4.91

130.

0113

0.37

131.

2913

1.41

131.

7213

4.33

135.

75

145.

3714

6.06

147.

2114

7.56

148.

6314

8.76

159.

9716

0.21

166.

6516

7.50

168.

54

38

N-(2-(tert-butylamino)-2-oxo-1-(pyridin-2-yl)ethyl)-N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1n)

N O

NO2O

O

O

HN

N

C28H32N4O6

MW = 520.5769

This compound was synthesized according to the modified general procedure I, using pyridine-

2-carboxaldehyde (0.19 ml, 2.0 mmol), 2-(3,4-dimethoxyphenyl)ethanamine (0.34 ml, 2.0

mmol), 2-nitrobenzoic acid (334 mg, 2.0 mmol) and tert-butyl isocyanide (0.23 ml, 2.0 mmol)

in 2 ml of methanol. Purification by flash chromatography using (AcOEt: PE = 80: 20) gave the

desired product in 97 % isolated yield (1.01 g) as a mixture of two rotamers (A and B).


Rf = 0.21 (AcOEt: PE = 7: 3)

1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.24-7.27 (m, 7H),

6.68 (d, J = 8.2 Hz, 1H) 6.92-6.17 (m, 2H), 6.01-5.01 (m, 1H), 3.90 (s, 3H, B), 3.88 (s, 3H, B),

3.83 (s, 3H, A), 3.76 (s, 3H, A), 4.01-2.28 (m, 4H), 1.50 (s, 9H, A), 1.44 (s, 9H, B).13C NMR (101 MHz, CDCl3) δ 168.59, 168.50 (A), 166.54 (B), 148.91, 148.60, 147.72, 145.88,

144.84, 134.65, 134.41, 130.40, 130.00, 124.69, 122.92, 120.75, 120.45, 112.17, 111.64,

111.25, 111.20, 65.92, 55.97 (A), 55.94, 55.91 (B), 55.81, 52.58 (B), 51.69 (A), 34.78 (A), 33.24

(B), 28.72.

HRMS: calculated for C30H34ClN3O7: 520.2322, found 520.2298

I.R. (thin film): 3419, 3350, 3056, 2967, 2836, 1675, 1640, 1528, 1514, 1346, 1261, 1234, 731,

699.

39

N O

NO2O

O

O

HN

N

N O

NO2O

O

O

HN

N

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5

9.13

10.2

1

0.94

3.15

8.09

1.00

1.44

1.50

2.40

3.76

3.83

3.88

3.90

3.95

3.96

5.25

5.83

5.86

6.32

6.67

6.69

6.79

6.81

7.31

7.33

8.23

8.26

8.28

8.66

8.67

0102030405060708090100110120130140150160170180190200

28.7

233

.24

34.7

8

51.6

952

.58

55.8

155

.91

55.9

455

.97

65.9

2

111.

2011

1.25

111.

6411

2.17

120.

4512

0.75

122.

9212

4.69

130.

0013

0.40

134.

4113

4.65

144.

8414

5.88

147.

7214

8.60

148.

91

166.

5416

8.50

168.

59

41

N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1o)

N O

NO2O

O

O

HN

N

C28H32N4O6

MW = 520.5769

This compound was synthesized according to the modified general procedure I, using pyridine-

3-carboxaldehyde (0.19 ml, 2.0 mmol), 2-(3,4-dimethoxyphenyl)ethanamine (0.34 ml, 2.0

mmol), 2-nitrobenzoic acid (334 mg, 2.0 mmol) and t-butyl isocyanide (0.23 ml, 2.0 mmol) in

2 ml of methanol. Purification by flash chromatography using (AcOEt 100%) gave the desired

product in 95 % isolated yield (0.99 g) as a mixture of two rotamers (A and B).


Rf = 0.23 (AcOEt: PE = 9: 1)

1H NMR (400 MHz, CDCl3) δ 8.88-8.35 (m, 2H), 8.29 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H),

8.25 -7.31 (m, 4H), 6.64 (d, J = 8.2 Hz, 1H), 6.92-4.87 (m, 4H), 3.80 (s, 3H), 3.71 (s, 3H) 4.14-

2.12 (m, 4H), 1.47 (s, 9H, A), 1.36 (s, 9H, B).13C NMR (101 MHz, CDCl3) δ 168.76, 167.46, 149.75, 148.91, 147.78, 144.88, 134.60, 132.39,

131.51, 131.41, 130.28, 129.85, 128.59, 124.95, 123.71, 120.32, 111.41, 111.23, 64.82 (B),

64.68 (A), 55.90, 55.76, 52.09, 47.54, 35.15 (A), 33.54 (B), 28.61 (A), 28.43 (B)

HRMS: calculated for C30H34ClN3O7: 520.2322, not found

I.R. (thin film): 3228, 3056, 2834, 1682, 1642, 1526, 1514, 1345, 1260, 1235, 760, 699.

42

N O

NO2O

O

O

HN

N

N O

NO2O

O

O

HN

N

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5

9.17

10.0

1

5.02

6.03

2.00

1.36

1.47

2.19

3.71

3.80

3.99

4.02

5.07

6.63

6.65

6.80

6.82

7.31

7.35

7.64

7.66

7.68

8.25

8.28

8.30

8.41

8.45

8.80

0102030405060708090100110120130140150160170180190

28.4

828

.61

33.5

435

.15

47.5

452

.09

55.7

655

.90

64.6

864

.82

111.

2311

1.41

120.

3212

3.71

124.

9512

8.59

129.

8513

0.28

131.

4113

1.51

132.

3913

4.60

144.

8814

7.78

148.

9114

9.75

167.

4616

8.76

43

N-(2-(tert-butylamino)-2-oxo-1-(quinolin-3-yl)ethyl)-4-chloro-N-(3,4-dimethoxyphenethyl)-2-nitrobenzamide (1p)

N O

NO2O

O

O

HN

N

Cl

C32H33ClN4O6

MW = 605.0806

This compound was synthesized according to the modified general procedure I, using

quinoline-3-carboxaldehyde (314 mg, 2.0 mmol), 2-(3,4-dimethoxyphenyl)ethanamine (0.34

ml, 2.0 mmol), 4-chloro-2-nitrobenzoic acid (404 mg, 2.0 mmol) and tert-butyl isocyanide (0.23

ml, 2.0 mmol) in 2 ml of methanol. Purification by flash chromatography using (AcOEt: PE =

60: 40) gave the desired product in 93 % isolated yield (1.13 g) as a mixture of two rotamers

(A and B).

Aspect: yellow solid

MP = 128–130 °C.

Rf = 0.40 (EtOAc: PE = 3: 7)

1H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 2.1 Hz, 1H) 9.16-8.07 (m, 2H), 8.27 (d, 1.9 Hz, 1 H), 7.94

(d, J = 8.0 Hz, 1H), 7.81 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.72 (dd, J = 8.2, 2.0 Hz, 1H), 7.65 (ddd, J

= 8.1, 7.0, 1.1 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.30-5.01 (m, 4H), 3.79

(s, 6H, A), 3.58 (s, 6H, B), 3.99-2.24 (m, 4H), 1.48 (s, 9H, A), 1.40 (s, 9H, B)

13C NMR (101 MHz, CDCl3) δ 168.0, 151.3, 148.9, 147.8, 147.8, 145.5, 137.1, 136.3, 134.5,

130.7, 130.4, 129.8, 129.7, 129.3, 128.4, 128.0, 127.7, 127.4, 125.1, 120.3, 111.2, 111.2, 64.8,

55.9, 55.5, 52.2, 50.5, 35.3, 28.7

HRMS: calculated for C32H33ClN4O6: 604.2089, not found

I.R. (thin film): 3346, 3055, 2967, 2836, 1684, 1642, 1533, 1514, 1348, 1263, 1236, 731, 701

44

N O

NO2O

O

O

HN

N

Cl

N O

NO2O

O

O

HN

N

Cl

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.012.5

9.00

10.0

0

5.06

4.99

4.08

1.40

1.48

2.31

3.58

3.79

3.85

5.25

6.27

6.29

6.59

6.61

7.39

7.41

7.65

7.67

7.71

7.71

7.73

7.73

7.81

7.81

8.27

8.27

8.87

9.03

9.04

0102030405060708090100110120130140150160170180190200

28.6

6

35.2

5

50.5

052

.20

55.5

355

.88

64.7

6

111.

1611

1.24

120.

2812

7.44

127.

6512

8.04

129.

2712

9.68

129.

7813

0.44

130.

6913

4.54

136.

25

145.

5014

7.77

147.

8314

8.90

151.

32

168.

00

45

N-(2-(1H-indol-3-yl)ethyl)-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-2-nitrobenzamide (1q)

NH

N

ONO2

Cl OHN

Cl

C29H28Cl2N4O4

MW = 567.4630


benzaldehyde (703 mg, 5.0 mmol), tryptamine (801 mg, 5.0 mmol), 4-chloro-2-nitrobenzoic

acid (1 g, 5.0 mmol) and t-butyl isocyanide (0.57 ml, 5.0 mmol) in 5 ml of methanol. Purification

by flash chromatography using (Et2O: PE = 80: 20) gave the desired product in 95 % isolated

yield (2.6 g).

Aspect: yellow solid

MP = over 200°C with decomposition

Rf: 0.3 (40: 60 petroleum ether/ diethyl ether)

1H NMR (400 MHz, CDCl3) δ 8.12 (br, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.58-7.44 (m, 2H), 7.35 (d, J

= 8.5 Hz, 2H), 7.25 (dd, J = 8.2, 2.0 Hz, 1H), 7.19-7.13 (m, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.95 (d, J

= 8.2 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 6.76-6.47 (m, 2H), 6.13-4.58 (m, 2H), 3.80-2.84 (m, 2H),

2.83-2.33 (m, 2H), 1.32 (s, 9H).13C NMR (101 MHz, CDCl3) δ 168.0, 145.2, 136.1, 135.9, 134.9, 134.4, 133.7, 131.1, 130.6,

129.7, 129.3, 126.8, 124.9, 122.6, 122.2, 119.5, 117.7, 111.4, 111.4, 66.5 (B), 63.6 (A), 52.0,

49.1, 28.7, 25.0

HRMS: calculated for C29H28Cl2N4O4: 566.1488, not found

I.R. (thin film): 3411, 3917, 2840, 1698, 1611, 1045, 1010

46

NH

N

ONO2

Cl OHN

Cl

NH

N

ONO2

Cl OHN

Cl

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

9.17

1.83

2.04

2.00

11.3

7

2.00

1.32

2.48

2.50

2.52

2.53

2.77

2.98

3.60

3.63

4.95

5.04

6.02

6.59

6.81

6.94

6.96

7.01

7.15

7.17

7.17

7.23

7.24

7.25

7.26

7.34

7.36

7.48

8.02

8.03

8.12

-100102030405060708090100110120130140150160170180190200210

25.0

2

28.6

8

49.0

952

.02

63.5

966

.47

111.

3811

1.44

117.

7111

9.45

122.

1912

2.56

124.

8512

9.31

129.

6813

1.14

134.

4013

6.14

145.

23

168.

02

47

IV- Cyclized Ugi adduct 2a

2-allyl-N-(tert-butyl)-6-chloro-1-(4-chlorophenyl)-3-oxoisoindoline-1-carboxamide (2a)

N

O

Cl

Cl

O

HN

C22H22Cl2N2O2

MW = 417.3283

The synthesis of 2a with the highest yield was best performed in acetonitrile: To a solution

of Ugi product (1a, 232 mg, 0.5 mmol) in acetonitrile (2 ml, 0.25 M) was added 1 equiv of

cesium carbonate (1.2 equiv, 195 mg, 0.6 mmol). The mixture was refuxed for 3 hours.

Purification by flash chromatography using (Et2O: PE = 40: 60) gave the desired product in

90% isolated yield (188 mg) as white solid.

Rf(Et2O: PE = 4 : 6) = 0.3.

1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 8.1,

1.8 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.10 (br.s, 1H), 5.84 – 5.68 (m, 1H),

5.18 – 5.06 (m, 2H), 4.07 – 3.96 (m, 1H), 3.60 (dd, J = 15.5, 7.5 Hz, 1H), 1.30 (s, 9H).

13C NMR (101 MHz, CDCl3) δ 168.9, 167.1, 148.3, 139.5, 135.7, 134.9, 132.5, 130.2, 130.1,

129.1, 128.8, 124.9, 124.6, 119.5, 75.6, 52.6, 44.9, 28.6.

48

N

O

Cl

Cl

O

HN

N

O

Cl

Cl

O

HN

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

9.06

1.06

1.08

2.09

1.05

1.00

2.08

2.03

1.03

1.00

1.05

1.30

3.57

3.59

3.61

3.63

3.99

4.03

4.04

4.04

4.05

5.11

5.15

5.16

5.72

5.81

5.82

6.10

6.97

6.99

7.27

7.29

7.50

7.50

7.52

7.52

7.58

7.59

7.79

7.81

-100102030405060708090100110120130140150160170180190200210

28.6

2

44.9

2

52.5

6

75.5

8

119.

4712

4.55

124.

8712

8.79

129.

0913

0.11

130.

2413

2.47

134.

9313

5.73

139.

53

148.

28

167.

0516

8.92

49

V- Hydroxyisoindolinones synthesis

2-allyl-5-chloro-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (3a)

NCl

O

HO

Cl

C17H13Cl2NO2

MW = 334.1966

Following of general procedure II, the synthesis was carried out with 1a (232 mg, 0.5 mmol)

and t-BuOK (168 mg, 1.5 mmol) for 6h. The crude product was purified by flash

chromatography over silica gel (EtOAc: PE = 15: 85) to afford the title compound 3a as a yellow

solid (101 mg, 60 %).

MP = 187–189 °C.

Rf = 0.25 (EtOAc: PE = 3: 7)

1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.42-7.33 (m, 5H), 7.28 (d, J = 1.63 Hz, 1H),

5.69-5.58 (m, 1H), 5.07-4.98 (m, 2H), 4.50 (s, 1H), 4.01 (ddt, J = 15.5, 6.33, 1.2 Hz, 1H), 3.66

(ddt, J = 15.5, 6.3, 1.2 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 166.7, 150.3, 139.2, 136.4, 134.9, 132.9, 130.1, 128.9, 128.5,

127.9, 124.5, 123.4, 117.9, 90.5, 42.1

HRMS: calculated for C17H13Cl2NO2: 333.0323, found 333.0318

I.R. (thin film): 3265, 2976, 2921, 1686, 1606, 1492, 1433, 1418, 1389, 1092, 1078

50

NCl

O

HO

Cl

NCl

O

HO

Cl

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.05

1.06

1.00

2.03

1.07

1.01

5.05

1.00

0102030405060708090100110120130140150160170180190f1 (ppm)

42.1

90.5

117.

912

3.4

124.

512

7.9

128.

512

8.9

130.

113

2.9

134.

913

6.4

139.

2

150.

3

166.

7

52

5-chloro-3-(4-chlorophenyl)-3-hydroxy-2-(2-methoxyethyl)isoindolin-1-one (3b)

N

O

HOCl

O

Cl

C17H15Cl2NO3

MW = 352.2119

Following of general procedure II, the synthesis was carried out with 1b (241 mg, 0.5 mmol)


chromatography over silica gel (EP/Et2O, 100:0 to 30:70) to afford the title compound 3b as a

yellow solid (98 mg, 56%).

MP: 137°C


1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.1, 1.8 Hz, 1H), 7.35-7.28 (m,

4H), 7.20 (d, J = 1.8 Hz, 1H), 6.11 (s, 1H), 4.03 (dt, J = 15.2, 2.6 Hz, 1H), 3.70-3.57 (m, 1H), 3.48

(dt, J = 9.8, 2.6 Hz, 1H), 3.38 (s, 3H), 2.99-2.85 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.2, 150.6, 139.3, 137.8, 134.9, 129.9, 129.2, 128.1, 127.8,

124.9, 123.2, 89.6, 71.0, 59.1, 39.6

HRMS: calculated for C17H15Cl2NO3: 351.0429, found 351.0440

I.R. (thin film): 3288, 2975, 2928, 1681, 1609, 1489, 1468, 1417, 1393, 1356, 1309, 1090, 1049,

951, 865, 698

53

N

O

HOCl

O

Cl

N

O

HOCl

O

Cl

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1.05

3.09

1.09

1.10

1.04

1.00

0.99

4.14

1.12

1.00

2.89

2.96

2.96

3.38

3.47

3.49

3.50

3.62

4.01

4.02

4.02

4.05

4.05

4.06

6.11

7.20

7.21

7.29

7.34

7.35

7.40

7.41

7.42

7.43

7.72

7.74

0102030405060708090100110120130140150160170180190200

39.6

1

59.0

7

70.9

5

89.5

8

123.

2212

4.86

127.

8412

8.07

129.

1812

9.93

134.

8513

7.83

139.

30

150.

56

167.

16

55

5-chloro-2-(2-methoxyethyl)-3-(pyridin-2-yl)isoindolin-1-one (3c)

NCl

O

HO

O

N

C16H15ClN2O3

MW = 318.7549

Following of general procedure II, the synthesis was carried out with 1c (283 mg, 0.63 mmol)


chromatography over silica gel (EtOAc: PE = 50: 50) to afford the title compound 3c as a yellow

solid (140 mg, 70 %).

MP = 141–143 °C.

Rf = 0.2 (EtOAc: PE = 5: 5)

1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.7 Hz, 1H), 7.74 – 7.61 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H),

7.28 – 7.23 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.78 (s, 1H), 3.77 – 3.73 (m, 1H), 3.42

– 3.30 (m, 2H), 3.16 (s, 3H), 3.10 – 3.0 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.3, 156.6, 149.5, 148.3, 138.8, 137.8, 130.1, 129.4, 124.7,

124.1, 123.1, 121.1, 89.5, 70.1, 58.5, 38.9

I.R. (thin film): ν 3063, 2932, 2825, 1707, and 1569, cm-1.

HRMS Spectrum of [C16H15ClN2O3]+[M -OH]+; 302.0822; Found :301.0748

56

NCl

O

HO

O

N

NCl

O

HO

O

N

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.04

3.08

2.10

1.04

1.00

1.00

1.06

1.00

1.03

2.04

1.00

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

38.9

58.5

70.1

89.5

121.

112

3.1

124.

112

4.7

129.

413

0.1

137.

813

8.8

148.

314

9.5

156.

6

167.

3

58

5-chloro-2-(2,2-dimethoxyethyl)-3-hydroxy-3-(4-methoxyphenyl)isoindolin-1-one (3d)

N

O

HOCl

OO

O

C19H20ClNO5

MW = 377.8188

Following of general procedure II, the synthesis was carried out with 1d (254 mg, 0.5 mmol)


chromatography over silica gel (EP/Et2O, 100:0 to 10:90) to afford the title compound 3d as a

white solid (126 mg, 66%).

MP: 132°C


1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.33 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 – 7.03

(m, 3H), 6.80 (d, J = 9.0 Hz, 2H), 5.32 (s, 1H), 4.54 (dd, J = 7.0, 3.4 Hz, 1H), 3.90 (dd, J = 14.8,

3.4 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 2.82 (dd, J = 14.8, 7.0 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 167.4, 160.0, 151.2, 139.3, 130.5, 129.7, 127.9, 127.6, 124.8,

123.3, 114.3, 102.2, 90.5, 55.4, 54.6, 41.6

HRMS: calculated for C19H20ClNO5: 377.1030, found 377.1039

I.R. (thin film): 3330, 2935, 2836, 1682, 1609, 1510, 1464, 1418, 1384, 1302, 1250, 1170, 1046,

950, 832, 734

59

N

O

HOCl

OO

O

N

O

HOCl

OO

O

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

1.04

6.26

3.36

1.08

1.05

1.00

2.25

3.14

1.08

1.06

2.79

2.81

2.83

2.85

3.32

3.33

3.73

3.88

3.89

3.92

3.93

4.53

4.54

4.55

4.56

5.32

6.79

6.81

7.16

7.19

7.20

7.34

7.35

7.65

7.67

0102030405060708090100110120130140150160170180190

41.5

5

54.5

555

.39

90.5

4

102.

20

114.

27

123.

2812

4.78

127.

6312

7.93

129.

7413

0.46

139.

26

151.

15

159.

98

167.

42

61

3-(4-chlorophenyl)-2-(2,2-dimethoxyethyl)-3-hydroxyisoindolin-1-one (3e)

N

O

HO

O

Cl

O

C18H18ClNO4

MW = 347.7928

Following of general procedure II, the synthesis was carried out with 1e (239 mg, 0.5 mmol)


chromatography over silica gel (EP/Et2O, 100:0 to 20:80) to afford the title compound 3e as a

white solid (54 mg, 31%).

MP: 132°C


1H NMR (400 MHz, CDCl3) δ 7.81-7.75 (m, 1H), 7.51-7.39 (m, 2H), 7.29 (s, 4H), 7.24-7.19 (m,

1H), 5.41 (s, 1H), 4.60 (dd, J = 6.8, 3.7 Hz, 1H), 3.93 (dd, J = 14.8, 3.7 Hz, 1H), 3.37 (s, 3H), 3.35

(s, 3H), 2.85 (dd, J = 14.8, 6.8 Hz, 1H)13C NMR (101 MHz, CDCl3) δ 168.3, 149.1, 138.0, 134.6, 133.1, 129.5, 129.5, 129.0, 127.8,

123.6, 122.6, 102.0, 90.6, 55.3, 54.3, 41.4

HRMS: calculated for C18H18ClNO4: 347.0924, found 347.0919

I.R. (thin film): 3245, 2946, 2918, 2830, 1679, 1467, 1410, 1194, 1064, 921, 817, 764

62

N

O

HO

O

Cl

O

N

O

HO

O

Cl

O

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1.05

6.03

1.00

1.00

1.00

1.01

4.06

2.10

1.02

2.82

2.84

2.86

2.88

3.35

3.37

3.91

3.92

3.95

3.96

4.59

4.60

4.61

4.62

5.41

7.20

7.22

7.22

7.29

7.42

7.50

7.50

7.77

7.79

7.79

0102030405060708090100110120130140150160170180190200

41.4

3

54.2

755

.25

90.5

7

101.

96

122.

5912

3.58

127.

8312

8.97

129.

4612

9.50

133.

0813

4.57

138.

04

149.

06

168.

30

64

VI- O- alkylation of hydroxyisoindolinones

2,3-diallyl-5-chloro-3-(4-chlorophenyl) isoindolin-1-one (4a)

N

O

OCl

Cl

C20H17Cl2NO2

MW = 374.2605

This compound was synthesized according to the general procedure III with N-allyl-N-(2-(tert-

butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-2-nitrobenzamide 1a (186 mg, 0.4

mmol). After addition of t-BuOK (135 mg, 1.20 mmol) the mixture was stirred at room

temperature for 6 h followed by further addition of t-BuOK (90 mg, 0.80 mmol) and allyl

bromide (0.07 ml, 0.8 mmol). The final product was obtained after 4 h stirring at room

temperature. Purification by column chromatography using (EtOAc: PE = 30 :70) gave the

desired product in 79% isolated yield (113 mg) as white semi solid.

Rf (EtOAc: PE = 3 :7) = 0.35.

1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.40 (dd, J = 8.1, 1.8 Hz, 1H), 7.24 (s, 4H),

7.07 (d, J = 1.8 Hz, 1H), 5.80-5.70 (m, 1H), 5.70-5.60 (m, 1H), 5.24-5.18 (m, 1H), 5.13-5.09 (m,

1H), 5.05-5.00 (m, 1H), 4.95 (d, J = 10.1, 1H), 3.96-3.89 (m, 1H), 3.68-3.62 (m, 1H), 3.58-3.52

(m, 1H), 3.43-3.36 (m, 1H).13C NMR (101 MHz, CDCl3) δ 166.8, 146.9, 139.2, 136.6, 134.8, 133.2, 132.3, 130.5, 130.1,

128.8, 127.9, 124.9, 123.5, 118.5, 117.1, 94.2, 63.9, 42.3

I.R. (thin film): ν 3420, 3081, 2919, 1710, 1645, and 830 cm-1.

HRMS Spectrum of [C20H17Cl2NO2]+[M+H]+; 373.0730, Found: 374.0730.

65

N

O

OCl

Cl

N

O

OCl

Cl

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.02

1.05

1.02

1.08

1.03

1.04

1.07

1.07

1.02

1.08

1.00

4.01

1.04

1.00

0102030405060708090100110120130140150160170180190200f1 (ppm)

42.3

63.9

94.2

117.

111

8.5

123.

512

4.9

127.

912

8.8

130.

113

0.5

132.

313

3.2

134.

813

6.6

139.

214

6.9

166.

8

67

3-(allyloxy)-5-chloro-3-(4-chlorophenyl)-2-(2-methoxyethyl)isoindolin-1-one (4b)

N

OO

Cl

ClO

C20H19Cl2NO3

MW = 392.2758

This compound was synthesized according to the general procedure III with N-(2-(tert-

butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-N-(2-methoxyethyl)-2-nitrobenzamide 1b (190

mg, 0.394 mmol). After addition of t-BuOK (133 mg 1.184 mmol) the mixture was stirred at room




desired product in 72% isolated yield (107 mg) as a white semi solid.

Rf (EtOAc: PE = 3 :7) = 0.4.

1H NMR (400 MHz, CDCl3 ) δ 7.74 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.25 (s, 4H), 7.05

(s, 1H), 5.89-5.73 (m, 1H), 5.28-5.21 (m, 1H), 5.15-5.08(m, 1H), 3.78-3.70 (m, 1H), 3.60-3.51

(m, 1H), 3.45-3.47 (m, 1H), 3.36-3.27 (m, 2H), 3.19-3.09 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 167.5, 147.0, 139.2, 136.7, 134.9, 133.4, 130.5, 130.0, 128.9,

127.8, 124.9, 123.5, 116.9, 94.3, 69.5, 63.8, 58.4, 39.0

I.R. (thin film): ν 3072, 2973, 2929, 2873, 1703, 1439 and 1070 cm-1

HRMS (ESI+) m/z calculated for [C20H19Cl2NO3]+[M+H+]+ : 392.0820 found 392.0816.

68

N

OO

Cl

ClO

N

OO

Cl

ClO

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

4.07

2.05

1.07

1.07

1.04

1.05

1.09

1.08

1.00

4.00

1.05

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

39.0

58.4

63.8

69.5

94.3

116.

912

3.5

124.

912

7.8

128.

913

0.0

130.

513

3.4

134.

913

9.2

147.

0

167.

5

70

3-(allyloxy)-3-(4-chlorophenyl)-2-(2,2-dimethoxyethyl)isoindolin-1-one (4e)

N

OO

O

Cl

O

C21H22ClNO4

MW = 387.8567

This compound was synthesized according to the general procedure III with 1e (239 mg, 0.5

mmol). After addition of t-BuOK (168 mg, 1.5 mmol) the mixture was stirred at room



temperature. Purification by column chromatography using (Et2O: PE = 30:70) gave the desired

product in 52 % isolated yield (101 mg) as a yellow oil.

Rf (Et2O: PE = 3 :7) = 0.22

1H NMR (400 MHz, CDCl3) δ 7.83-7.78 (m, 1H), 7.46-7.40 (m, 2H), 7.28-7.17 (m, 4H), 7.09-7.05

(m, 1H), 5.87-5.75 (m, 1H), 5.28-5.05 (m, 2H), 4.52-4.45 (m, 1H), 3.81-3.74 (m, 1H), 3.56 (dd, J

= 14.5, 6.3 Hz, 1H), 3.42-3.30 (m, 1H), 3.22 (s, 3H), 3.20 (s, 3H), 2.98 (dd, J = 14.5, 5.3 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 168.5, 145.3, 137.3, 134.6, 133.8, 132.9, 131.4, 130.0, 128.8,

128.0, 123.8, 123.2, 116.6, 100.5, 94.8, 63.9, 53.6, 52.4, 41.0

I.R. (thin film): 2933, 2834, 1705, 1488, 1467, 1424, 1371, 1301, 1123, 1091, 1061, 993, 820,

765, 709

HRMS: calculated for [M-MeO]: 356.1048, found 356.1057

71

N

OO

O

Cl

O

N

OO

O

Cl

O

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1.01

6.02

1.10

1.02

1.00

1.07

1.06

1.02

1.03

1.00

4.04

2.05

1.02

2.95

2.96

2.99

3.00

3.20

3.22

3.34

3.39

3.39

3.54

3.55

3.57

3.59

3.75

3.75

3.79

3.79

3.80

4.47

4.48

4.50

5.08

5.10

5.11

5.21

5.26

5.26

5.77

5.78

5.84

5.85

5.86

7.06

7.06

7.09

7.20

7.21

7.26

7.42

7.43

7.44

7.44

7.46

7.79

7.80

7.82

7.82

7.82

0102030405060708090100110120130140150160170180190

41.0

4

52.4

153

.61

63.8

5

94.7

9

100.

47

116.

6212

3.18

123.

7812

8.01

128.

8013

0.00

131.

4013

2.86

133.

8213

4.59

137.

34

145.

25

168.

51

73

2-allyl-3-(allyloxy)-3-(4-chlorophenyl)isoindolin-1-one (4f)

N

O

O

Cl

C20H20ClNO3

MW = 357.8707

This compound was synthesized according to the general procedure III using N-allyl-N-(2-(tert-

butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-2-nitrobenzamide 1f (300 mg, 0.7 mmol). After

addition of t-BuOK (235 mg, 2.09 mmol) the mixture was stirred at room temperature for 6 h

followed by further addition of t-BuOK (157 mg, 1.4 mmol ) and allyl bromide (0.13 ml, 1.4

mmol). The final product was obtained after 4 h stirring at room temperature. Purification by

column chromatography using (EtOAc:PE = 30:70) gave the desired product in 68 % isolated

yield (153 mg) as a white semi solid.

Rf (EtOAc: PE = 3 :7) = 0.38.

1H NMR (400 MHz, CDCl3) δ 7.83 -7.79 (m, 1H), 7.45-7.41 (m, 2H), 7.28-7.25 (m, 2H), 7.22-7.19

(m, 2H), 7.11-7.07 (m, 1H), 5.81-5.63 (m, 2H), 5.23-5.17 (m, 1H), 5.10-5.00 (m, 2H), 4.93 (dd, J

= 10.1, 1.3 Hz, 1H), 3.94 (m, 1H), 3.65-3.55 (m, 2H), 3.40-3.34 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.9, 145.1, 137.4, 134.5, 133.5, 132.6, 131.8, 130.0, 128.7,

128.0, 123.6, 123.1, 118.2, 116.8, 94.6, 64.0, 42.0

I.R. (thin film): ν 3425, 3076, 2912, 1718, 1639, and 834 cm-1

HRMS (ESI+) m/z calculated for [C20H18ClN2O2]+M+H+]+ : 340.1104 found 340.1099.

74

N

O

O

Cl

N

O

O

Cl

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.08

2.08

1.09

1.06

2.06

1.09

2.07

1.05

2.08

2.05

2.06

1.00

0102030405060708090100110120130140150160170180190f1 (ppm)

42.0

64.0

94.6

116.

811

8.2

123.

112

3.6

128.

012

8.7

130.

013

1.8

132.

613

3.5

134.

513

7.4

145.

1

167.

9

76

2-allyl-3-(allyloxy)-3-(4-chlorophenyl)-5-nitroisoindolin-1-one (4g)

N

O

N+O

-O

Cl

O

C20H17ClN2O3

MW = 384.8180

This compound was synthesized according to the general procedure III using N-allyl-N-(2-(tert-

butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-2-nitrobenzamide 1g (750 mg, 1.58 mmol). After

addition of t-BuOK (532 mg, 4.74 mmol), the mixture was stirred at room temperature for 6 h

followed by further addition of t-BuOK (355 mg, 3.16 mmol) and allyl bromide (0.274 ml, 3.16

mmol). The final product was obtained after 5 h stirring at room temperature. Purification by

column chromatography using (EtOAc:PE = 30:70) gave the desired product in 67 % isolated

yield (381 mg) as an orange semi solid.

Rf (EtOAc: PE = 3 :7) = 0.38.

1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 8.2, 1.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J =

1.8 Hz, 1H), 7.33 (s, 4H), 5.87-5.70 (m, 2H), 5.27 (d, J = 17.2 Hz, 1H), 5.22-5.12 (m, 2H), 5.10-

5.05 (m, 1H), 4.04 (dd, J = 14.9, 6.5 Hz, 1H), 3.78-3.64 (m, 2H), 3.48-3.42 (m, 1H).13C NMR (101 MHz, CDCl3) δ 165.5, 151.0, 146.6, 136.7, 135.7, 135.3, 132.8, 131.7, 129.1,

127.9, 125.7, 124.8, 119.2, 118.7, 117.5, 94.3, 64.4, 42.6

I.R. (thin film): ν 3080, 2963, 2923, 2868, 1709, 1456 and 1090 cm-1

HRMS (ESI+) m/z calculated for [C20H17ClN2O4]+M+H+]+ : 385.0955 found 385.0951.

77

N

O

N+O

-O

Cl

O

N

O

N+O

-O

Cl

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.06

2.08

1.08

1.07

2.01

1.05

2.09

4.01

1.01

1.03

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

42.6

64.4

94.3

117.

511

8.7

119.

212

4.8

125.

712

7.9

129.

113

1.7

132.

813

5.3

135.

713

6.7

146.

6

151.

0

165.

5

79

3-(allyloxy)-5-chloro-2-(2-methoxyethyl)-3-(4-methoxyphenyl)isoindolin-1-one (4h)

N

OO

ClO

MeO

C21H22ClNO4

MW = 387.8567

This compound was synthesized according to the general procedure III using 1h (205 mg, 0.43

mmol). After addition of t-BuOK (145 mg, 1.28 mmol), the mixture was stirred at room



temperature. Purification by column chromatography using (EtOAc:PE = 30:70) gave the

desired product in 76 % isolated yield (121 mg) as a white semi solid.

Rf (EtOAc: PE = 3 :7) = 0.38.

1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.22 (d, J = 8.7 Hz, 2H),

7.07 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 9.1 Hz, 2H), 5.87-5.77 (m, 1H), 5.29-5.22 (m, 1H), 5.13-5.18

(m, 1H), 3.76-3.71 (m, 4H), 3.60-3.53 (m, 1H), 3.43-3.26 (m, 3H), 3.18 (s, 3H), 3.16-3.09 (m,

1H).13C NMR (101 MHz, CDCl3) δ 167.5, 159.9, 147.6, 139.0, 133.7, 130.2, 130.0, 129.9, 127.6,

124.8, 123.5, 116.5, 114.0, 94.5, 69.4, 63.7, 58.5, 55.4, 39.0

I.R. (thin film): ν 2925, 2834, 1710, 1609, 1013 and 829 cm-1

HR-MS (ESI+) m/z calculated for [C21H22ClNO4]+[M+H+]+ : 388.1316 found 388.1310.

80

N

OO

ClO

MeO

N

OO

ClO

MeO

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)

1.02

3.03

3.08

1.03

4.08

1.01

1.02

1.01

2.01

1.00

2.04

1.02

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

39.0

55.4

58.5

63.7

69.4

94.5

114.

011

6.5

123.

512

4.8

127.

612

9.9

130.

013

0.2

133.

713

9.0

147.

6

159.

9

167.

5

82

3-(allyloxy)-5-chloro-3-(4-chlorophenyl)-2-cyclopropylisoindolin-1-one (4i)

N

O

Cl

Cl

O

C20H17Cl2NO2

MW = 374.2605

This compound was synthesized according to the general procedure III using 1i (700 mg, 1.51

mmol). After addition of t-BuOK (510 mg, 4.53 mmol), the mixture was stirred at room




desired product in 60 % isolated yield (322 mg) as a white gummy paste.

Rf (EtOAc: PE = 3 :7) = 0.4.

1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.0, 1.8 Hz, 1H), 7.30-7.23 (m,

4H), 7.04 (s, 1H), 5.89-5.70 (m, 1H), 5.24 (d, J = 17.2 Hz, 1H), 5.12 (dd, J = 1,03, 10.5 Hz, 1H),

3.60-3.50 (m, 1H), 3.43-3.35 (m, 1H), 2.39-2.06 (m, 1H), 1.00-0.91 (m, 1H), 0.71-0.56 (m, 2H),

0.47-0.37 (m, 1H).13C NMR (101 MHz, CDCl3) δ 168.3, 146.8, 139.3, 137.2, 134.5, 133.2, 130.5, 129.8, 128.8,

127.7, 124.8, 123.3, 117.0, 94.8, 63.7, 23.1, 4.6, 3.0

I.R. (thin film): ν 3307, 3056, 2972, 2929, 2827,2328, 1910, 1709, 1628, and 828 cm-1.

HRMS (ESI+) m/z calculated for [C20H17Cl2NO2]+[M+H+]+ : 374.0715 found 374.0711

83

N

O

Cl

Cl

O

N

O

Cl

Cl

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.08

2.09

1.09

1.05

1.04

1.06

1.09

1.07

1.06

1.00

4.01

1.03

1.00

0102030405060708090100110120130140150160170180190f1 (ppm)

3.0

4.6

23.1

63.7

94.8

117.

012

3.3

124.

812

7.7

128.

813

0.5

133.

213

7.2

139.

3

146.

8

168.

3

85

2-allyl-3-(allyloxy)-3-(pyridin-3-yl)isoindolin-1-one (4j)

N

O

N

O

C19H18N2O2

MW = 306.3584

This compound was synthesized according to the general procedure III using using N-allyl-N-

(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl) ethyl)-2-nitrobenzamide 1j (660 mg, 1.66 mmol).

After addition of t-BuOK (561 mg, 5.0 mmol), the mixture was stirred at room temperature for

6 h followed by further addition of t-BuOK (373 mg, 3.32 mmol) and allyl bromide (0.28 ml,

3.185 mmol). The final product was obtained after 4 h stirring at room temperature.

Purification by column chromatography using (EtOAc: PE = 5: 5) gave the desired product in

60 % isolated yield (271 mg) as an orange gummy paste.

Rf (EtOAc: PE = 5 :5) = 0.4.

1H NMR (400 MHz, CDCl3 ) δ 8.64 (s, 1H), 8.53-8.41 (m, 1H), 7.87-7.77 (m, 1H), 7.62-7.52 (m,

1H), 7.50-7.39 (m, 2H), 7.22-7.09 (m, 2H), 5.85-5.55 (m, 2H), 5.22 (dd, J = 17.2, 1.5 Hz, 1H),

5.09 (dd, J = 10.5, 1.3 Hz, 1H), 4.95 (dd, J = 27.4, 13.6 Hz, 2H), 4.0-3.86 (m, 1H), 3.72-3.58 (m,

2H), 3.47-3.30 (m, 1H).

13C NMR (101 MHz, CDCl3) δ 167.7, 149.8, 148.3, 144.6, 134.7, 134.4, 133.3, 132.9, 132.5,

131.7, 130.2, 123.8, 123.2, 118.4, 116.9, 93.8, 63.8, 42.2

HRMS (ESI+) m/z calculated for [C19H18N2O2]+[M+H+]+ : 307.1447 found 307.1440.

86

N

O

N

O

N

O

N

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

1.05

2.04

1.00

2.02

1.05

1.07

2.04

2.09

2.04

1.01

1.01

1.01

1.00

0102030405060708090100110120130140150160170180f1 (ppm)

42.2

63.8

93.8

116.

911

8.4

123.

212

3.8

131.

713

2.5

132.

913

3.3

134.

413

4.7

144.

614

8.3

149.

8

167.

7

88

5-chloro-2-(2,2-dimethoxyethyl)-3-((2-iodobenzyl)oxy)-3-(4-methoxyphenyl)isoindolin-1-

one (6a)

N

OO

Cl

MeO

OI

O

C26H25ClINO5

MW = 593.8379

This compound was synthesized according to the general procedure III using N-(2-(tert-

butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-4-chloro-N-(2,2-dimethoxyethyl)-2-nitro-

benzamide 1d (660 mg, 1.3 mmol). After addition of t-BuOK (438 mg, 3.90 mmol), the mixture

was stirred at room temperature for 6 h followed by further addition of t-BuOK ( 292 mg, 2.6

mmol) and 1-(bromomethyl)-2-iodobenzene (772 mg, 2.59 mmol). The final product was

obtained after 4 h stirring at room temperature. Purification by column chromatography using

(EtOAc: PE = 40 :60) gave the desired product in 64.5 % isolated yield (485 mg) as pale white

semi solid.

Rf (EtOAc: PE = 4 :6) = 0.38

MP : 141-142. °C.

1H NMR (400 MHz, CDCl3) δ δ 7.79-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.30-7.26 (m, 3H), 7.11 (s,

1H), 6.93 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 4.52 (t, J = 5.7 Hz, 1H), 4.36 (d, J = 11.8 Hz,

1H), 3.92 (d, J = 11.8 Hz, 1H), 3.73 (s, 3H), 3.61 (dd, J =6.0, 14.5 Hz, 1H), 3.20 (d, J = 18.9 Hz,

6H), 3.01 (dd, J = 14.4, 5.6 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 167.6, 159.7, 147.0, 139.8, 139.3, 138.9, 130.4, 129.6, 129.5,

129.3, 128.3, 127.7, 124.9, 124.0, 114.1, 100.3, 98.2, 95.0, 68.9, 55.4, 53.7, 52.0, 41.3

89

N

OO

Cl

MeO

OI

O

N

OO

Cl

MeO

OI

O

I.R. (thin film): ν 3402, 3059, 2933, 2834, 1704, 1633, 1514, 1026 and 809 cm-1

HRMS (ESI+) m/z calculated for [C26H25ClNO5]+[M+H+]+ : 594.0544 found 594.0539.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.03

6.02

1.02

3.00

1.00

1.08

1.03

2.00

1.04

1.09

3.00

2.07

2.08

0102030405060708090100110120130140150160170180190f1 (ppm)

41.3

52.0

53.7

55.4

68.9

95.0

98.2

100.

3

114.

112

4.0

127.

712

8.3

129.

312

9.5

130.

4

138.

913

9.3

139.

8

147.

0

159.

7

167.

6

91

5-chloro-2-(2,2-dimethoxyethyl)-3-(3,4-dimethoxyphenyl)-3-(2-iodobenzyl)isoindolin-1-one (6b)

NO

Cl

MeO

OMeMeO

MeO IO

C27H27ClINO6

MW = 623.8639

This compound was synthesized according to the general procedure III using N-(2-(tert-

butylamino)-1-(3,4-dimethoxyphenyl)-2-oxoethyl)-4-chloro-N-(2,2-dimethoxyethyl)-2-nitro-

benzamide 1k (570 mg, 1.06 mmol). After addition of t-BuOK (357 mg, 3.18 mmol), the mixture

was stirred at room temperature for 6 h followed by further addition of t-BuOK (238 mg, 2.12

mmol) and 1-(bromomethyl)-2-iodobenzene (629.5 mg, 2.12 mmol). The final product was

obtained after 4 h stirring at room temperature. Purification by column chromatography using

(EtOAc: PE = 40 :60) gave the desired product in 71 % isolated yield (469 mg) as a white solid.

Rf (EtOAc: PE = 4 :6) = 0.38

MP = 141-142. °C.

1H NMR (400 MHz, CDCl3) δ 7.78-7.73 (m, 2H), 7.41-7.34 (m, 2H), 7.29-7.22 (m, 1H), 7.14 (d, J

= 1.40 Hz, 1H), 6.97-6.84 (m, 3H), 6.76 (d, J = 8.6 Hz, 1H), 4.58 -4.51 (m, 1H), 4.35 (d, J = 11.6

Hz, 1H), 3.95 (d, J = 11.6, 4.4 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.67-3.60 (m, 1H), 3.20 (s, 3H),

3.18 (s, 3H), 3.09-3.02 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.7, 149.4, 149.1, 147.2, 139.9, 139.4, 139.0, 130.4, 130.0,

129.6, 129.5, 129.4, 128.3, 124.9, 124.0, 118.9, 111.1, 109.5, 100.1, 98.5, 95.0, 69.0, 56.0, 53.6,

52.0, 41.3

92

NO

Cl

MeO

OMeMeO

MeO IO

NO

Cl

MeO

OMeMeO

MeO IO

I.R. (thin film): ν 3402, 3062, 2933, 2834, 2022, 1703, 1603, 1514, 1024 and 811cm-1.

HRMS Spectrum of [C27H28ClINO6]+[M+H]+624.0650; Found:624.0624

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.06

6.05

1.04

6.01

1.02

1.01

1.05

1.05

3.01

1.00

1.06

2.09

2.00

0102030405060708090100110120130140150160170180f1 (ppm)

41.3

52.0

53.6

56.0

69.0

95.0

98.5

100.

1

109.

511

1.1

118.

912

4.0

124.

912

8.3

129.

512

9.6

130.

4

139.

013

9.4

139.

914

7.2

149.

114

9.4

167.

7

93

VII- RCM of N-allyl-O-allyl isoindolinone

9-chloro-10b-(4-chlorophenyl)-1,10b-dihydropyrido[2,1-a]isoindol-6(4H)-one (5a)

N

O

Cl

Cl

O

94

C18H13Cl2NO2

MW = 346.2073

This compound was synthesized according to the general procedure IV using 2,3-diallyl-5-

chloro-3-(4-chlorophenyl)isoindolin-1-one 4a (140 mg, 0.39 mmol) and Hoveyda Grubbs

catalyst (2nd generation) (17.2 mg, 0.0274 mmol). Purification by column chromatography

using (EtOAc: PE = 20: 80) gave the desired product in 78 % isolated yield (100.5 mg) as white

gummy paste.

Rf (EtOAc: PE = 2:8) = 0.35.

1H NMR (400 MHz, CDCl3 ) δ 7.70 (d, J = 8.1 Hz, 1H), 7.41 (dd, J =8.1, 1.8 Hz, 1H), 7.37-7.33 (m,

2H), 7.29-7.25 (m, 2H), 7.16 (d, J = 1.5 Hz, 1H), 5.71-5.65 (m, 1H), 5.60-5.53 (m, 1H), 4.48 (dd,

J = 17.7, 5.3 Hz, 1H), 4.05-3.98 (m 1H), 3.76-3.68 (m, 1H), 3.47-3.40 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.0, 147.1, 139.4, 136.5, 135.0, 130.7, 129.7, 129.0, 128.4,

127.8, 127.4, 124.7, 123.6, 94.8, 61.7, 38.7

I.R. (thin film): ν 3393, 3033, 2953, 2907, 2856, 1911, 1709, 1608, 1533, and 830 cm-1

HRMS Spectrum of [C18H14Cl2NO2]+[M+H]+;346,0402, Found: 346.0390.

95

N

O

Cl

Cl

O

N

O

Cl

Cl

O

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.07

1.08

1.08

1.08

1.09

1.09

1.00

2.06

2.07

1.08

1.00

96

10b-(4-chlorophenyl)-1,10b-dihydropyrido[2,1-a]isoindol-6(4H)-one (5b)

N

O

Cl

O

C18H14ClNO2

MW = 311.7623

This compound was synthesized according to the general procedure IV using 2,3-diallyl-3-(4-

chlorophenyl)isoindolin-1-one 4f (255 mg, 0.79 mmol) and Hoveyda-Grubbs catalyst (2nd

generation) (34.5 mg, 0.0551 mmol). Purification by column chromatography using (EtOAc:

PE = 20: 80) gave the desired product in 75 % isolated yield (174.3 mg) as a white semi solid.

97

N

O

Cl

O

Rf (EtOAc: PE = 2 :8) = 0.34.

1H NMR (400 MHz, CDCl3) δ 7.79 – 7.75 (m, 1H), 7.48 – 7.42 (m, 2H), 7.39 – 7.34 (m, 2H), 7.26

– 7.23 (m, 2H), 7.20 – 7.18 (m, 1H), 5.71 – 5.64 (m, 1H), 5.59 – 5.51 (m, 1H), 4.50 (dd, J = 17.6,

5.3 Hz, 1H), 3.98 (dd, J = 16.4, 5.7 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.48 – 3.40 (m, 1H).13C NMR (101 MHz, CDCl3) δ 167.9, 145.2, 137.3, 134.6, 133.1, 131.3, 130.1, 128.8, 128.5,

127.9, 127.5, 123.4, 123.0, 95.3, 61.4, 38.8

I.R. (thin film): ν 3407, 3033, 2921, 2854, 1708, 1656, 1595, and 830 cm-1.

HRMS Spectrum of [C18H15ClNO2]+ [M+H]+; 312.0791: Found: 312.0781.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.09

1.07

1.08

1.08

1.09

1.08

1.01

2.01

2.08

2.05

1.00

98

N

O

Cl

O

0102030405060708090100110120130140150160170180f1 (ppm)

38.8

61.4

95.3

123.

012

3.4

127.

512

7.9

128.

512

8.8

130.

113

1.3

133.

113

4.6

137.

314

5.2

167.

9

99

10b-(4-chlorophenyl)-9-nitro-1,10b-dihydropyrido[2,1-a]isoindol-6(4H)-one (5c)

N

O

Cl

O NO2

C18H13ClN2O4

MW = 356.7598

This compound was synthesized according to the general procedure IV using 2,3-diallyl-3-(4-

chlorophenyl)-5-nitroisoindolin-1-one 4g (135 mg, 0.366 mmol) and Hoveyda Grubbs catalyst

(2nd generation) (16.8 mg, 0.0256 mmol). Purification by column chromatography using

100

N

O

Cl

O NO2

(EtOAc: PE = 20: 80) gave the desired product in 70 % isolated yield (100 mg) as an orange

gummy paste.

Rf (EtOAc: PE = 2 :8) = 0.32.

1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 8.2, 2.0 Hz, 1H), 8.12-8.07 (m, 1H), 8.01 (d, J = 8.2 Hz,

1H), 7.46-7.43 (m, 2H), 7.38-7.35 (m, 2H), 5.80-5.73 (m, 1H), 5.67-5.61 (m, 1H), 4.60 (dd, J =

17.62, 5.3 Hz, 1H), 4.14 (dd, J = 16.6, 5.9 Hz, 1H), 3.80-3.72 (m, 1H), 3.61-3.52 (m, 1H).13C NMR (101 MHz, CDCl3) δ 165.7, 151.2, 146.8, 136.2, 135.5, 131.4, 129.2, 128.9, 128.3,

127.4, 125.8, 124.6, 118.7, 95.1, 61.9, 39.3

I.R. (thin film): ν 3036, 2957, 2923, 2856, 1713, and 884 cm-1.

HRMS Spectrum of [C18H14ClN2O4]+[M+H]+; 357.0642, Found: 357.0645

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.05

1.04

1.06

1.07

1.05

1.00

2.02

2.03

1.08

1.05

1.00

101

N

O

Cl

O NO2

0102030405060708090100110120130140150160170180f1 (ppm)

39.3

61.9

95.1

118.

712

4.6

125.

812

7.4

128.

312

8.9

129.

213

1.4

135.

513

6.2

146.

8

151.

2

165.

7

102

10b-(pyridin-3-yl)-1,10b-dihydropyrido[2,1-a]isoindol-6(4H)-one (5d)

N

N

O

O

C17H14N2O2

MW = 278.3053

This compound was synthesized according to the general procedure IV using 2,3-diallyl-3-

(pyridin-3-yl)isoindolin-1-one 4j (200 mg, 0.689 mmol) and Hoveyda Grubbs catalyst (2nd

generation) (30 mg, 0.048 mmol). Purification by column chromatography using (EtOAc: PE =

40: 60) gave the desired product in 45 % isolated yield (81 mg) as a brown paste.

103

N

N

O

O

Rf (EtOAc: PE = 2 :8) = 0.24.

1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.70

(d, J = 8.0 Hz, 1H), 7.50-7.44 (m, 2H), 7.24-7.20 (m, 2H), 5.62 (d, J = 45.5 Hz, 2H), 4.56-4.50 (m,

1H), 4.02 (dd, J = 16.4, 5.6 Hz, 1H), 3.74 (d, J = 16.6 Hz, 1H), 3.45 (d, J = 18.1 Hz, 1H).

13C NMR (101 MHz, CDCl3) δ 168.0, 149.9, 147.8, 144.8, 134.6, 133.9, 133.2, 131.3, 130.3,

128.5, 127.8, 123.5, 123.4, 123.1, 94.8, 61.6, 39.0

HRMS Spectrum of [C17H15N2O2]+[M+H]+; 279.1134, Found: 279.1136.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.09

1.08

1.08

1.05

2.00

2.01

2.09

1.08

1.07

1.09

1.07

104

N

N

O

O

0102030405060708090100110120130140150160170180f1 (ppm)

39.0

61.6

94.8

123.

112

3.4

123.

512

7.8

128.

513

0.3

131.

313

3.2

133.

913

4.6

144.

814

7.8

149.

9

168.

0

105

VIII- Pd triggered CH activation

1-chloro-5-(2,2-dimethoxyethyl)-5a-(4-methoxyphenyl)-5a,7dihydrobenzo[5,6]oxepino

[2,3,4-cd]isoindol-4(5H)-one (7a)

N

O

OO

OO

Cl

C26H24ClNO5

MW = 465.9255

This compound was synthesized according to general procedure V using 5-chloro-2-(2,2-

dimethoxyethyl)-3-(2-iodobenzyl)-3-(4-methoxyphenyl)isoindolin-1-one (160 mg, 0.277

106

N

O

OO

OO

Cl

mmol), Pd(OAc)2 (6 mol%, 0.0194 mmol), DPPE (10 mol%, 0.0387 mmol) and Cs2CO3 (1 equiv,

91mg, 0.296 mmol). Purification by column chromatography using (EtOAc: PE = 40: 60) gave

the desired product in 54 % isolated yield (67.2 mg) as a brown paste.

Rf (EtOAc:PE = 2 :8) = 0.22.

1H NMR(400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz,

1H), 7.39 (d, J = 7.3 Hz, 1H), 7.28-7.34 (m, 1H), 7.21-7.18(m, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.40

(d, J = 8.0 Hz, 2H), 4.73 (d, J = 12.3 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.48-4.44 (m, 1H), 3.66-

3.60 (m, 1H), 3.57 (s, 3H), 3.23 (s, 3H), 3.22 (s, 3H), 2.82 (dd, J = 14.6, 4.2 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 166.1, 159.2, 145.4, 137.0, 135.7, 133.9, 132.5, 132.3, 130.0,

129.9, 129.8, 129.8, 129.1, 128.3, 127.6, 123.9, 113.1, 101.0, 94.9, 70.0, 54.8, 53.7, 52.6, 40.7

I.R. (thin film): 3407, 2933, 2835, 1707, 1509, and 758 cm-1.

HRMS Spectrum of [C26H25ClNO5]+[M+H]+; 466.1421; Found: 466.1439.

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

1.02

6.05

3.08

1.06

1.05

1.06

1.09

2.07

2.09

1.03

1.04

1.09

1.06

1.07

1.08

107

N

O

OO

OO

Cl

102030405060708090100110120130140150160170180f1 (ppm)

40.7

52.6

53.7

54.8

70.0

95.0

101.

0

113.

112

3.9

127.

612

8.3

129.

112

9.8

129.

812

9.9

130.

013

2.5

137.

0

145.

4

159.

2

166.

1

108

1-chloro-5-(2,2-dimethoxyethyl)-5a-(3,4-dimethoxyphenyl)-5a,6-

dihydrodibenzo[cd,f]indol-4(5H)-one (7b)

N

O

O

O

O

O

Cl

O

C27H26ClNO6

MW = 495.9514

This compound was synthesized according to general procedure V using 6b (180 mg, 0.296

mmol), Pd(OAc)2 (6 mol%, 0.0178 mmol), DPPE (10 mol%, 0.030 mmol)and Cs2CO3 (1 equiv,

97 mg, 0.296 mmol). Purification by column chromatography using (EtOAc: PE = 40: 60) gave

the desired product in 58 % isolated yield (81 mg) as a brown paste.

Rf (EtOAc: PE = 2 :8) = 0.22.

109

N

O

O

O

O

O

Cl

O

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.7,

1.1 Hz, 1H), 7.43 (dd, J = 7.4, 1.1 Hz, 1H), 7.36-7.26 (m, 1H), 7.25-7.20 (m, 1H), 6.41 (d, J = 8.5

Hz, 1H), 6.32-6.13 (m, 2H), 4.75 (d, J = 12.3 Hz, 1H), 4.62-4.46 (m, 2H), 3.71-3.60 (m, 1H), 3.65

(s, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 3.23 (s, 3H), 2.85 (dd, J

Documents

Straightforward access to complex isoindolinones from the ...III- Ugi adducts synthesis N-allyl-N-(2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-4-chloro-2-nitrobenzamide (1a)