69451 Weinheim, Germany - Wiley- · PDF fileCl NO2 iPr 6b White crystalline ... 394.1893,...

Supporting Information

© Wiley-VCH 2007

69451 Weinheim, Germany

Reaction of “Huisgen Zwitterion” with Chalcones and Dienones: Efficient Strategy

for the Synthesis of Pyrazoline and Pyrazolopyridazine Derivatives

Vijay Nair;*a

Smitha C. Mathew;a A. T. Biju

a and Eringathodi Suresh

b

Dedicated with best regards to Professor C. N. R. Rao

[a] Dr. V. Nair, S. C. Mathew, A. T. Biju

Organic Chemistry Section

Regional Research Laboratory, CSIR

Trivandrum 695019 (India)

Fax: +91 471-2491712

E-mail: [email protected]

[b] Dr. E. Suresh

Analytical Sciences Discipline

Central salt and Marine Chemicals Research Institute,

CSIR, Bhavnagar 364002 (India)

General

All reactions were conducted in oven-dried glassware sealed with rubber septa under a positive

pressure of deoxygenated argon from a manifold. Solvents used for the experiments were distilled or

dried as specified. Diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD) and di-tert-

butyl azodicarboxylate (DTAD) were purchased from Aldrich and used as received. The chalcones and

dienones were prepared by standard procedures. All other reagents were purchased from local suppliers

and used without purification. All reactions were monitored by TLC, visualization was effected with UV

and/or by developing in iodine. Chromatography refers to open column chromatography on silica gel

(100-200 mesh).

Melting points were recorded on a Buchi melting point apparatus and are uncorrected. NMR

spectra were recorded at 300 (1H) and 75 (

13C) MHz respectively on a Brucker Advance DPX-300 MHz.

Chemical shifts are reported in δ (ppm) relative to TMS (1H) or CDCl3 (

13C) as internal standards. IR

spectra were recorded on Bomem MB series FT-IR spectrometer; absorbencies are reported in cm-1

.

High resolution mass spectra were recorded under EI / HRMS (at 5000 resolution) using JOEL JMS 600

H Mass Spectrometer.

General Procedure for the synthesis of functionalized pyrazoline:

To a stirred solution of chalcone 4 (0.33 mmol) in toluene (5 mL) under an atmosphere of Ar, was

added DIAD 2 (0.49 mmol) and the reaction mixture was stirred under reflux. To the refluxing solution

was added triphenylphosphine (128 mg, 0.49 mmol) in 2 mL toluene dropwise. The reaction mixture was

kept stirring under reflux for 3 h. The reaction mixture cooled and the solvent was removed under

reduced pressure on a rotary evaporator. The residue was subjected to column chromatography on silica

gel (100-200 mesh) using 85:15 petroleum ether-ethyl acetate as eluent to afford the corresponding

product (6a-6m).

Functionalized Pyrazoline 6a

N N

CO2iPr

O2C

Br

F6a

iPr

White crystalline solid Mp. 105-107°C

IR (KBr) ννννmax: 2982, 2934, 1716, 1508, 1367, 1294, 1226, 1100, 832, 749 cm-1

.

1H NMR δ: 7.49 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.33-7.29 (m, 2H), 7.02 (t, J = 8.6 Hz, 2H),

5.85 (d, J = 3.1 Hz, 1H), 5.75 (d, J = 3.3 Hz, 1H), 5.12-5.05 (m, 1H), 4.87-4.79 (m, 1H), 1.35-1.31 (m,

6H), 1.13 (d, J = 6.2 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H).

13C NMR δ: 162.7 (d, JCF = 245.3 Hz), 155.7, 143.5, 134.9, 132.2, 131.7, 131.4, 130.6, 129.9, 128.9,

128.5, 123.1, 115.8 (d, JCF = 21.5 Hz), 111.9, 71.0, 70.8, 65.8, 22.3, 22.2, 21.8, 21.6.

LRMS (FAB) for C23H24BrFN2O4: calcd. (M+): 490.09, found: 490.8.

Crystal structure of compound 6a has been deposited at the Cambridge Crystallographic Data Center and

allocated the reference no. CCDC 616377.

Single crystal X-ray structure of 6a

Functionalized Pyrazoline 6b

N N

CO2iPr

O2C

Cl

NO2

iPr

6b

White crystalline solid Mp. 114-116 °C

IR (KBr) ννννmax: 2987, 2939, 1717, 1596, 1523, 1460, 1372, 1343, 1294, 1177, 1095, 847, 749, 696 cm-1

.

1H NMR δ: 8.19 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.58-7.55 (m, 1H), 7.42-7.38 ( m, 2H),

7.27-7.24 (m, 1H), 6.23 (d, J = 3.2 Hz, 1H), 6.15 (d, J = 3.3 Hz, 1H), 5.14- 5.07 (m, 1H), 5.05-4.94

(m,1H), 1.38-1.31 (m, 6H), 1.21-1.17 (m, 6H).

13C NMR δ: 156.7, 154.9, 147.6, 141.1, 137.5, 136.1, 131.2, 130.6, 129.8, 129.2, 129.1, 128.1, 127.5,

126.9, 123.9, 114.0, 73.0, 71.9, 65.5, 22.0, 21.6, 21.5, 21.2.

LRMS (FAB) for C23H24ClN3O6: calcd. (M+): 473.14, found: 473.1.

Functionalized Pyrazoline 6c

N N

CO2

iPr

O2C

OMe

MeO

iPr

6c

Yellow viscous oil.

IR (film) ννννmax: 2982, 2934, 1716, 1596, 1508, 1377, 1251, 1173, 1105, 1027, 822 cm-1

.

1H NMR δ: 7.46 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 6.88-6.83 ( m, 4H), 5.8 (d, J = 2.9 Hz, 1H)

5.64 (d, J = 3.2 Hz, 1H), 5.1-5.03 (m, 1H), 4.87-4.79 (m, 1H), 3.81(s, 3H), 3.78 (s, 3H), 1.32-1.28 (m,

6H), 1.13 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.2 Hz, 3H).

13C NMR δ: 159.3, 155.7, 143.7, 131.5, 130.6, 130.0, 128.5, 127.8, 124.2, 119.5, 114.3, 113.9, 113.4,

109.9, 70.2, 70.1, 65.7, 55.3, 55.2, 22.1, 21.9, 21.6, 21.5.

LRMS (FAB) for C25H30N2O6: calcd. (M+): 454.21, found: 454.8.

Functionalized Pyrazoline 6d

N N

CO2

iPr

O2C

Cl

iPr

6d

Colorless viscous oil

IR (film) ννννmax: 2981, 2934, 1713, 1484, 1372, 1289, 1100, 1007, 754, 691 cm-1

.

1H NMR δ: 7.53-7.56 (m, 2H), 7.35-7.25 (m, 7H), 5.85 (d, J = 3.0 Hz, 1H), 5.72 (d, J = 3.3 Hz, 1H), 5.09

(m, 1H), 4.83 (m, 1H), 1.34 (t, J = 5.7 Hz, 6H), 1.09 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H.)

13C NMR δ: 155.4, 144.3, 137.8, 133.7, 131.4, 128.9, 128.8, 127.9, 127.4, 127.2, 110.7, 70.5, 70.4, 65.5,

22.1, 22.0, 21.6, 21.5.

HRMS (EI) for C23H25ClN2O4: calcd. (M+): 428.1503, found: 428.1518.

Functionalized Pyrazoline 6e

N N

CO2

iPr

O2C

Br

F3C

iPr

6e


IR (film) ννννmax: 2985, 2933, 1714, 1460, 1377, 1315, 1161, 1104, 1012, 831cm-1

.

1H NMR δ: 7.61 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.7 Hz, 4H), 7.38 (d, J = 8.4 Hz, 2H), 5.95 (d, J = 2.7

Hz, 1H), 5.77 (d, J = 3.6 Hz, 1H), 5.13-5.04 ( m, 1H), 4.89-4.81 (m, 1H), 1.36-1.32 (m, 6H), 1.13 (d, J =

6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H).

13C NMR δ: 155.4, 155.2, 143.5, 132.1, 131.5, 131.2, 130.2, 129.8, 128.8, 128.3, 127.6, 126.6, 125.8,

125.2, 110.9, 71.7, 70.9, 65.8, 64.9, 22.1, 21.9, 21.6, 21.3.

HRMS (EI) for C24H24BrF3N2O4: calcd (M+): 540.0872, found: 540.0898.

Functionalized Pyrazoline 6f

N N

CO2

iPr

O2C

Br

Cl

iPr

6f



.

1H NMR δ: 7.53-7.37 (m, 8H), 5.86 (d, J = 3.2 Hz, 1H), 5.76 (d, J = 3.3 Hz, 1H), 5.12-5.06 (m, 1H),

4.88-4.84 (m, 1H), 1.36-1.32 (m, 6H), 1.15 (d, J = 6.5 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H).

13C NMR δ: 157.5, 155.4, 141.4, 134.3, 132.5, 131.2, 130.2, 129.8, 129.3, 129.4, 128.0, 126.6, 124.6,

111.2, 71.0, 70.7, 65.7, 22.1, 21.7, 21.5, 21.4.

HRMS (EI) for C23H24BrClN2O4: calcd (M+): 506.0608, found: 506.0604.

Functionalized Pyrazoline 6g

N N

CO2

iPr

O2C

6g

iPr

Colorless viscous oil.


.

1H NMR δ: 7.54- 7.51 (m, 2H), 7.37-7.26 (m, 8H), 5.88 (d, J = 3.2 Hz, 1H), 5.76 (d, J = 3.3 Hz, 1H),

5.12-5.03 (m, 1H), 4.87-4.81 (m, 1H), 1.38-1.31 (m, 6H), 1.1 (d, J = 6.2 Hz, 3H), 0.99 (d, J = 6.2 Hz,

3H).

13C NMR δ: 155.4, 143.8, 139.1, 131.6, 128.6, 127.8, 127.7, 127.1, 126.3, 125.9, 111.3, 70.1, 70.0, 66.2,

22.1, 21.6, 21.4, 21.0.

HRMS (EI) for C23H26N2O4: calcd. (M+): 394.1893, found: 394.1843.

Functionalized Pyrazoline 6h

N N

CO2

iPr

O2C

Cl

6h

iPr

White crystalline solid Mp. 147-149 °C

IR (KBr) ννννmax: 2985, 2938, 1714, 1593, 1490, 1377, 1299, 1176, 1103, 769 cm-1

.

1H NMR δ: 8.25 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 7.1

Hz, 1H), 7.59-7.51 (m, 2H), 7.42 (d, J = 8.4 Hz, 3H), 7.31-7.24 (m, 2H), 6.63 (d, J = 2.6 Hz, 1H), 5.93 (d,

J = 3.2 Hz ,1H), 5.15-5.09 (m, 1H), 4.93-4.88 (m, 1H), 1.36-1.31 (m, 6H), 1.14 (d, J = 6.2 Hz, 3H), 1.06

(d, J = 6.2 Hz, 3H).

13C NMR δ: 155.4, 142.5, 134.6, 134.2, 134.1, 130.2, 128.9, 128.5, 128.2, 126.4, 125.8, 125.7, 123.3,

123.2, 112.4, 70.7, 64.4, 22.2, 22.1, 21.7, 21.6.


Functionalized Pyrazoline 6i

N N

CO2

iPrO2C

Cl

iPr

6i


IR (film) ννννmax: 2980, 2933.73, 1714.1, 1588.7, 1377.7, 1295.2, 1094.3, 836.7, 754.4cm-1

.

1H NMR δ: 8.44 (s,1H), 8.32 (d, J = 9.5 Hz, 2H), 7.99-7.96 ( m, 2H), 7.49-7.44 (m, 8H), 7.33 (d, J = 8.5

Hz, 2H), 5.69 (d, J = 3.2 Hz,1H), 5.01-4.94 (m, 2H), 1.3-1.18 (m, 9H), 0.99 (d, J = 6.2 Hz, 3H).

13C NMR δ: 162.3, 155.5, 141.8, 134.6, 133.9, 131.7, 130.8, 130.3, 129.5, 129.4, 128.9, 128.8, 128.2,

127.4, 127.2, 126.1, 124.7, 123.9, 120.9, 113.3, 71.1, 69.9, 63.2, 22.1, 21.9, 21.7, 21.6.


Functionalized Pyrazoline 6j

N N

CO2EtEtO2C

6jCl


IR (film) ννννmax: 2981, 1734, 1689, 1595, 1521, 1489, 1413, 1377, 1319, 1238, 1093, 1062, 1012, 829,

759, 692 cm-1

.

1H NMR δ: 7.54-7.51 (m, 2H), 7.36-7.31 (m, 7H), 5.87 (d, J = 3.3 Hz, 1H), 5.73 (d, J = 3.3 Hz, 1H),

4.36-4.27 (m, 2H), 4.11-4.02 (m, 2H), 1.35 (t, J = 7.1Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H).

13C NMR δ: 157.4, 155.8, 144.2, 137.6, 134.2, 131.2, 128.9, 127.9, 127.8, 127.2, 126.7, 110.8, 65.7,

63.7, 14.6, 13.9.


Functionalized Pyrazoline 6k

N N

CO2EtEtO2C

Cl

NO2

6k


IR (film) ννννmax: 3053, 2983, 1724, 1598, 1524, 1469, 1375, 1309, 1265, 1174, 1109, 902, 771cm-1

.

1H NMR δ: 8.21 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.57-7.54 (m, 1H), 7.43-7.40 (m, 1H),

7.29-7.24 (m, 2H), 5.24 (d, J = 3.3 Hz, 1H), 5.15 (d, J = 3.4 Hz, 1H), 4.39-4.16 (m, 4H), 1.38-1.33 (m,

3H), 1.17-1.12 (m, 3H).

13C NMR δ: 157.1, 155.6, 147.8, 141.1, 137.4, 135.9, 131.3, 129.9, 129.3, 128.1, 127.7, 126.9, 123.3,

114.2, 65.7, 63.3, 14.2, 14.0.


Functionalized Pyrazoline 6l

N N

CO2EtEtO2C

Cl

6lO


IR (film) ννννmax: 3053, 2985, 1722, 1591, 1469, 1404, 1377, 1328, 1261, 1178, 1097, 1060, 1012, 1012,

916, 792 cm-1

.

1H NMR δ: 8.11 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 3.2Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.05 (s. 1H), 6.72

(s, 1H), 6.29 (d, J = 4.9 Hz, 1H), 5.90 (s, 1H), 5.71 (bs, 1H), 4.35-4.16 (m, 4H), 1.41-1.22 (m, 6H).

13C NMR δ: 160.2, 140.8, 136.5, 132.5, 130.9, 129.3, 64.2, 63.7, 50.7, 14.5, 14.3.


Functionalized Pyrazoline 6m

N N

CO2

tBu

O2C

F

Br

6m

tBu


IR (film) ννννmax: 3053, 2985, 1720, 1604, 1546, 1510, 1421, 1269, 1155, 894, 762cm-1

.

1H NMR δ: 7.53 (d, J = 6Hz, 2H), 7.40-7.31 (m, 4H), 7.05-6.99 (m, 2H), 5.74 (s, 1H), 5.65 (m, 1H),

1.24-1.18 (m, 18H).

13C NMR δ: 162.3 , (d, JCF = 244.6 Hz), 160.7, 154.5, 143.9, 135.2, 131.8, 128.2, 127.9, 127.1, 126.4,

124.7, 122.5, 115.4 , (d, JCF = 21.3 Hz) 110.7, 82.1, 81.9, 65.2, 28.1, 27.5.

LRMS (FAB) for C25H28BrFN2O4: calcd. (M+): 518.12, found: 518.6.

Polycyclic pyrazoline derivative 11

NN

O2CCO2

iPr

Ph

iPr

11


IR (film) ννννmax: 3065, 2982, 2939, 1728, 1707, 1459, 1377, 1304, 1187, 1104, 1022, 939, 759, 696 cm-1

.

1H NMR δ: 7.45 (d, J = 7.4 Hz, 1H), 7.37-7.29 (m, 5H), 7.25-7.1 (m, 3H), 5.5 (s, 1H), 5.08-4.93 (m,

2H), 3.06-2.93 (m, 1H), 2.82-2.75 (m, 1H), 2.5-2.36 (m, 1H), 2.25-2.17 (m, 1H), 1.33-1.27 (m, 6H), 1.23

(d, J = 6.3 Hz, 3H), 1.1 (d, J = 6.2 Hz, 3H).

13C NMR δ: 156.8, 139.1, 137.2, 134.8, 129.6, 128.9, 128.5, 128.4, 128.1, 127.8, 127.4, 126.4, 125.4,

120.4, 71.2, 70.6, 68.2, 66.2, 29.4, 28.8, 22.3, 21.9, 21.6, 20.9.

LRMS (EI) for C25H28N2O4, calcd (M+): 420.20, found 420.2.

Procedure for the synthesis of pyrazolopyridazine:

To a stirred solution of dienone 12 (0.42 mmol) in toluene (5 mL) under an atmosphere of Ar, was

added DIAD (1.0 mmol) and the reaction mixture was stirred under reflux. To the refluxing solution was

added triphenylphosphine (0.58 mmol) in 2 mL toluene dropwise. The reaction mixture was kept stirring

under reflux for 12 h. The reaction mixture cooled and the solvent was removed under reduced pressure

on a rotary evaporator. The residue was subjected to column chromatography on silica gel (100-200

mesh) using 70:30 petroleum ether-ethyl acetate as eluent to afford the corresponding product (13a-13m).

Pyrazolopyridazine derivative 13a

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

iPr

iPr

S

13a

White crystalline solid Mp.105-107 °C

IR (KBr) ννννmax: 2987, 2939, 1733, 1716, 1705, 1650, 1542, 1455, 1377, 1294, 1231, 1177, 1105, 1036,

924, 827, 754, 696 cm-1

.

1H NMR δ: 7.56 (s, 1H), 7.38-7.23 (m, 6H), 6.95-6.93 (m, 1H), 6.39 (s, 1H), 6.19 (d, J = 11.4 Hz, 2H),

5.06-4.99 (m, 4H), 4.73 (s, 1H), 4.44 (s, 1H), 1.33-1.27 (m, 20 H), 1.12 (s, 4H).

13C NMR δ: 156.6, 154.6, 154.1, 152.9, 141.8, 138.5, 134.7, 128.3, 127.9, 127.3, 126.6, 126.4, 125.7,

125.3, 125.1, 71.0, 70.9, 70.6, 69.8, 65.9, 59.4, 55.8, 22.1, 22.0, 21.9, 21.4.

LRMS (FAB) for C31H40N4O8S: calcd. (M+1): 629.26, found: 629.4.

Crystal structure of compound 13a has been deposited at the Cambridge Crystallographic Data Center

and allocated the reference no. CCDC 616376.

Single-crystal X-ray structure of 13a

Pyrazolopyridazine derivative 13b

NN

N N

CO2

iPr

O2C CO2

iPr

H

F3CF3CO2C

iPr

iPr

13b

White crystalline solid Mp. 134-136°C

IR (KBr) ννννmax: 3070, 2987, 2939, 1732, 1716, 1606, 1455, 1372, 1319, 1231, 1104, 1041, 924, 832, 769,

735 cm-1

.

1H NMR δ: 7.92 (s, 1H), 7.71-7.34 (m, 9H), 5.86 (s, 1H), 5.57 (s, 1H), 5.13-5.07 (m, 4H), 4.86 (s, 1H),

3.94 (s, 1H), 1.35-1.20 (m, 24H).

13C NMR δ: 156.6, 154.9, 151.1, 140.4, 139.8, 137.2, 132.9, 131.9, 128.9, 128.2, 127.7, 127.4, 126.4,

122.7, 122.5, 107.9, 71.4, 70.9, 70.5, 69.9, 59.8, 55.7, 22.1, 21.8.

LRMS (FAB) for C35H40F6N4O8: calcd. (M+Na): 781.28, found: 781.1.

Pyrazolopyridazine derivative 13c

NN

N N

O2CCO2

iPr

O2C CO2iPr

H

FF

iPr

iPr

13c Colorless viscous oil

IR (film) ννννmax: 2982, 2944, 1747, 1733, 1716, 1704, 1537, 1484, 1372, 1309, 1231, 1182, 1095, 1031,

929, 759 cm-1

.

1H NMR δ: 7.56-7.45 (m,2H), 7.28 (bs, 2H), 7.16-6.99 (m, 4H), 4.79 (bs, 1H), 4.58 (s, 1H), 1.31-1.08

(m, 24H).

13C NMR δ: 162.4, 158.9, 156.4, 154.4, 135.2, 131.6, 130.9, 129.5, 129.4, 129.4, 129.3, 127.7, 125.7,

123.7, 115.5, 115.3, 70.7, 69.5, 59.9, 50.5, 21.8, 21.7, 21.6, 21.4.

LRMS (FAB) for C33H40F2N4O8: calcd. (M+): 658.28, found: 658.9.

Pyrazolopyridazine derivative 13d

NN

N N

O2C

CO2

iPr

O2C CO2

iPr

H

iPr

iPr

13d

F

Yellow viscous oil

IR (film) ννννmax: 2979, 1749, 1734, 1717, 1697, 1557, 1540, 1455, 1304, 1226, 1178, 1100, 1027, 920,

832, 749 cm-1

.

1H NMR δ: 7.59-7.57 (m, 2H), 7.4-7.25 ( m, 5H), 7.05-6.98 (m, 2H), 5.96 (d, J = 12 Hz, 2H), 5.08-4.94

(m, 4H), 4.7 (bs, 1H), 4.38-4.33 (m, 1H), 1.34-1.25 (m, 24H).

13C NMR δ: 162.1 (d, JCF = 244.1 Hz), 156.8, 154.4, 153.9, 141.3, 138.4, 135.3, 134.6, 129.7, 128.8,

128.2, 127.8, 127.2, 126.8, 126.2, 115.0 (d, JCF = 25.2 Hz), 71.9, 71.7, 70.9, 69.7, 66.3, 61.3, 55.59, 21.9,

21.8, 21.7, 21.6, 21.5, 21.2, 20.8.

LRMS (FAB) for C33H41FN4O8: calcd. (M+1): 641.29, found: 641.5.

Pyrazolopyridazine derivative 13e

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

iPr

iPr

F

13e

F

Colourless viscous oil

IR (film) ννννmax: 2987, 2944, 1732, 1716, 1606, 1508, 1459, 1372, 1304, 1231, 1177, 1100, 1012, 905,

832, 749 cm-1

.

1H NMR δ: 7.57 (bs, 2H), 7.36 (bs, 2H), 7.07-6.99 (m, 4H), 6.32 (bs, 1H), 5.95 (s, 1H), 5.10-4.97 (m,

4H), 4.7 (bs, 1H), 4.31 (bs, 1H), 1.35-1.25 (m, 24 H).

13C NMR δ: 162.5 , (d, JCF = 245.8 Hz), 162.2(d, JCF = 244.7 Hz) , 156.8, 154.4, 154.0, 152.5, 136.6,

135.2, 134.5, 134.4, 132.5, 131.9, 130.2, 129.8, 128.9, 127.8, 115.9, 115.3, 72.1, 71.8, 71.0, 70.8, 66.5,

55.1, 54.0, 22.1, 22.0, 21.8, 21.6, 21.5, 21.3.


Pyrazolopyridazine derivative 13f

NN

N N

O2C

CO2

iPr

O2C CO2iPr

H

iPr

iPr

S

13f

S

Yellow viscous oil

IR (film) ννννmax: 2982, 2939, 1748, 1732, 1716, 1705, 1698, 1649, 1542, 1513, 1455, 1377, 1309, 1231,

1182, 1109, 1041, 934, 832, 769, 705 cm-1

.

1H NMR δ7.23 (bs, 3H), 7.03-6.93 (m, 2H), 6.01 (bs, 2H), 5.03-4.99 (m, 4H), 4.78 (bs, 1H), 4.44 (s, 1H),

1.33-1.26 (m, 24H).

13C NMR δ: 156.6, 154.0, 152.6, 144.3, 141.4, 135.5, 134.9, 126.5, 126.3, 125.8, 125.6, 125.1, 112.4,

71.3, 71.0, 70.9, 69.9, 65.9, 59.2, 51.8, 50.7, 22.1, 22.0, 21.9, 21.4.


Pyrazolopyridazine derivative 13g

NN

N N

O2C

CO2

iPr

O2C CO2

iPr

H

iPr

iPr

13g

Cl

Yellow viscous oil

IR (film) ννννmax: 2982, 2939, 1746, 1732, 1716, 1705, 1635, 1558, 1472, 1373, 1311, 1233, 1180, 1105,

920, 754, 691 cm-1

.

1H NMR δ: 7.59 (d, J = 7.2 Hz, 2H), 7.5-7.3 (m, 7H), 5.96 (bs, 2H), 5.06-4.97 (m, 4H), 4.76 (bs, 1H),

4.36 (bs, 1H), 1.32-1.3 (m, 24 H).

13C NMR δ: 156.9, 154.5, 154.0, 152.3, 140.9, 135.5, 134.3, 129.5, 129.1, 128.6, 128.2, 127.9, 127.3,

126.9, 126.3, 126.1, 125.6, 111.3, 71.9, 71.0, 70.8, 69.9, 66.8, 60.9, 54.6, 22.0, 21.9, 21.8, 21.6, 21.3.


Pyrazolopyridazine derivative 13h

NN

N N

O2CCO2

iPr

O2C CO2iPr

H

iPr

iPr

BrBr

13h

Yellow viscous oil

IR (film) ννννmax: 2987, 2939, 1733, 1716, 1508, 1464, 1382, 1309, 1265, 1236, 1182, 1032, 910, 832, 759

cm-1

.

1H NMR δ: 7.65-7.55 (m, 3H), 7.33- 7.13 (m, 5H), 5.99 (s, 1H), 5.74 (s, 1H), 5.12-4.96 (m, 4H), 4.94 (s,

1H), 4.29 (s, 1H), 1.45- 1.25 (m, 24H).

13C NMR δ: 156.5, 154.7, 151.7, 151.5, 138.9, 136.3, 133.3, 133.1, 132.4, 130.1, 129.2, 128.9, 128.4,

127.7, 127.4, 122.5, 72.3, 72.0, 70.9, 70.5, 70.1, 63.5, 57.6, 22.0, 21.9, 21.7, 20.1.

LRMS (FAB) for C33H40Br2N4O8: calcd. (M+2): 780.12, found (M+2): 780.6.

Pyrazolopyridazine derivative 13i

N N

NN

CO2CO2

iPr

H

F

F

CO2

iPr

O2CF

F

iPr

iPr

13i

Yellow viscous oil.

IR (film) ννννmax: 3070, 2987, 2944, 1732, 1716, 1620, 1591, 1469, 1377, 1304, 1221, 1177, 1100, 1002,

919, 788, 735 cm-1

.

1H NMR δ: 7.29-7.22 (m, 2H), 6.92-6.83 (m, 4H), 6.03 (s, 1H), 5.84 (d, J = 5.8 Hz, 1H), 5.08-4.88 (m,

4H), 4.79-4.76 (m, 2H), 1.35-1.19 (m, 24H).

13C NMR δ: 163.0, 160.2, 159.9, 156.3, 130.2, 130.0, 129.3, 115.3, 111.8, 111.6, 111.5, 111.3, 71.1,

70.6, 69.7, 60.3, 54.9, 21.9, 21.7, 21.6, 21.4.

LRMS (FAB) for C33H38F4N4O8: calcd. (M+1): 695.26, found: 695.1.

Pyrazolopyridazine derivative 13j

NN

N N

O2CCO2

iPr

O2C CO2iPr

H

F3C

iPr

iPr

13j



.

1H NMR δ: 7.75 (d, J = 7.9 Hz, 1H), 7.58-7.57 (m, 4H), 7.38-7.26 (m, 4H), 5.99 (bs, 2H), 5.09-4.96 (m,

4H), 4.71 (bs, 1H), 4.39 (s, 1H), 1.35- 1.08 (m, 24 H).

13C NMR δ: 157.1, 154.7, 154.2, 152.5, 150.2, 143.1, 140.9, 138.7, 136.0, 131.1, 130.7, 130.3, 129.6,

128.5, 128.1, 127.8, 126.5, 125.9, 122.4, 72.2, 71.1, 70.1, 67.1, 61.6, 55.6, 22.2, 22.1, 22.0, 21.9.


Pyrazolopyridazine derivative 13k

NN

N N

CO2Et

EtO2C CO2Et

H

FFEtO2C

13k

Yellow viscous oil

IR (Film) ννννmax: 3012, 2935, 1724, 1616, 1589, 1490, 1415, 1377, 1315, 1222, 1099, 1045, 927, 765 cm-1

.

1H NMR δ: 7.47 (bs, 2H), 7.36-7.23 (m, 2H), 7.14-7.01 (m, 4H), 6.19 (s, 1H), 6.00 (s, 1H), 4.35-4.15 (m,

8H), 3.90 (bs, 2H), 1.30-1.21 (m, 12H).

13C NMR δ: 162.4, 159.1, 156.7, 154.9, 135.0, 129.7, 129.6, 129.5, 127.7, 125.6, 123.9, 115.8, 115.5,

114.9, 63.9, 62.9, 62.2, 14.4, 14.3, 14.2.


Pyrazolopyridazine derivative 13l

NN

N N

CO2Et

EtO2C CO2Et

H

F3CF3CEtO2C

13l

Yellow viscous oil

IR (Film) ννννmax: 2983, 2937, 1734, 1712, 1608, 1583, 1452, 1398, 1373, 1313, 1228, 1163, 1126, 1058,

1039, 866, 842, 769, 711, 657, 603 cm-1

.

1H NMR δ: 7.72-7.35 (m, 8H), 6.78 (bs, 1H), 5.91 (bs, 1H), 5.62 (bs, 1H), 4.38-4.23 (m, 8H), 4.01 (bs,

1H), 1.36-1.27 (m, 12H).

13C NMR δ: 156.9, 155.6, 151.5, 150.8, 139.9, 136.9, 132.9, 132.2, 128.6, 128.3, 127.8, 127.4, 126.8,

126.4, 122.7, 108.9, 64.3, 64.1, 62.9, 62.6, 55.8, 14.6, 14.5, 14.3.


Pyrazolopyridazine derivative 13m

NN

N N

CO2

tBu

O2C CO2

tBu

H

F3CF3CO2C

13m

tBu

tBu

White crystalline solid, Mp. 212-214°C

IR (Film) ννννmax: 2980, 1737, 1716, 1454, 1392, 1369, 1313, 1251, 1157, 1128, 1035, 854, 767 cm-1

.

1H NMR δ: 7.77-7.33 (m, 4H), 6.86 (s, 1H), 5.81 (s, 1H), 5.49 (s, 1H), 3.90 (s, 1H), 1.53-1.49 (m, 27H),

1.33 (s, 9H).

13C NMR δ:155.2, 150.0, 140.9, 140.3, 137.1, 132.7, 131.6, 128.6, 127.7, 127.3, 126.2, 122.6, 107.5,

82.9, 82.3, 81.5, 69.6, 59.4, 55.2, 53.3, 28.2, 28.0.

Vinyl pyrazoline derivative 15

NN

O2C CO2

iPri

Pr

S

15

Yellow viscous oil

IR (Film) ννννmax: 2982, 2934, 1713, 1601, 1460, 1367, 1299, 1177, 1100, 905, 759, 696.cm-1

.

1H NMR δ: 7.45 (d, J = 6.9 Hz, 1H), 7.34-7.19 (m, 4H), 7.02-6.93 (m, 3H), 6.04 (bs, 1H), 5.74 (bs, 1H),

5.07-4.91 (m, 2H), 1.34-1.13 (m, 12H).

13C NMR δ: 155.5, 143.2, 142.6, 136.3, 133.1, 128.9, 128.6, 126.9, 125.5, 124.9, 119.2, 109.9, 70.6,

70.4, 61.2, 22.7, 21.8, 21.7, 21.6.


Indazole derivative 17

NN

N

H

OO

O2CCO2

iPr

F3CF3C

iPr

17

Yellow viscous oil

IR (Film) ννννmax: 3231, 3080, 2987, 2939, 1748, 1732, 1716, 1698, 1649, 1537, 1533, 1372, 1304, 1158,

1105, 1036, 764 cm-1

.

1H NMR δ: 8.56 (s, 1H), 7.74-7.26 (m, 8H), 6.54 (s, 1H), 6.03 (s, 1H), 5.17-5.09 (m, 1H), 5.01-4.99 (m,

1H), 3.89 (bs, 1H), 3.62 (bs, 1H), 3.32 (m, 1H), 2.84 (bs, 1H), 1.37-1.25 (m, 12H).

13C NMR δ: 176.6, 175.8, 156.2, 153.7, 139.5, 137.6, 132.5, 131.6, 129.4, 128.8, 127.5, 126.3, 126.2,

125.9, 114.1, 106.9, 71.3, 71.2, 63.1, 59.3, 47.1, 41.9, 36.1, 22.2, 21.8, 21.7.

LRMS (FAB) for C31H29F6N3O6: calcd. (M+Na): 676.20, found: 676.2.

Spectra of Compounds

1H NMR Spectrum of Functionalized pyrazoline 6a

N N

CO2iPr

O2C

Br

F6a

iPr

13C NMR Spectrum of Functionalized pyrazoline 6a

N N

CO2iPr

O2C

Br

F6a

iPr

1H NMR Spectrum of Functionalized pyrazoline 6b

N N

CO2iPr

O2C

Cl

NO2

iPr

6b

13C NMR Spectrum of Functionalized pyrazoline 6b

N N

CO2iPr

O2C

Cl

NO2

iPr

6b

1H NMR Spectrum of Functionalized pyrazoline 6c

N N

CO2

iPr

O2C

OMe

MeO

iPr

6c

13C NMR Spectrum of Functionalized pyrazoline 6c

N N

CO2

iPr

O2C

OMe

MeO

iPr

6c

1H NMR Spectrum of Functionalized pyrazoline 6d

N N

CO2

iPr

O2C

Cl

iPr

6d

13C NMR Spectrum of Functionalized pyrazoline 6d

N N

CO2

iPr

O2C

Cl

iPr

6d

1H NMR Spectrum of Functionalized pyrazoline 6j

N N

CO2EtEtO2C

Cl

6j

13C NMR Spectrum of Functionalized pyrazoline 6j

N N

CO2EtEtO2C

Cl

6j

1H NMR Spectrum of polycyclic pyrazoline 11

NN

O2CCO2

iPr

Ph

iPr

11

13C NMR Spectrum of polycyclic pyrazoline 11

NN

O2CCO2

iPr

Ph

iPr

11

1H NMR Spectrum Pyrazolopyridazine derivative 13a

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

iPr

iPr

S

13a

13C NMR Spectrum of Pyrazolopyridazine derivative 13a

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

iPr

iPr

S

13a

1H NMR Spectrum Pyrazolopyridazine derivative 13b

NN

N N

O2CCO2

iPr

O2C CO2iPr

H

iPr

iPr

13b

F3C

F3C

13C NMR Spectrum of Pyrazolopyridazine derivative 13b

NN

N N

O2CCO2

iPr

O2C CO2iPr

H

iPr

iPr

13b

F3C

F3C

1H NMR Spectrum of Pyrazolopyridazine derivative 13c

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

FF

iPr

iPr

13c

13C NMR Spectrum of Pyrazolopyridazine derivative 13c

NN

N N

O2CCO2

iPr

O2C CO2

iPr

H

FF

iPr

iPr

13c

1H NMR Spectrum of Pyrazolopyridazine derivative 13d

NN

N N

O2C

CO2

iPr

O2C CO2iPr

H

iPr

iPr

13d

F

13C NMR Spectrum of Pyrazolopyridazine derivative 13d

NN

N N

O2C

CO2

iPr

O2C CO2

iPr

H

iPr

iPr

13d

F

1H NMR Spectrum Vinyl pyrazoline derivative 15

NN

O2C CO2iPri

Pr

S

15

13C NMR Spectrum Vinyl pyrazoline derivative 15

NN

O2C CO2iPri

Pr

S

15

1H NMR Spectrum of Indazole derivative 17

NN

N

H

OO

O2CCO2

iPr

F3CF3C

iPr

17

13C NMR Spectrum of Indazole derivative 17

NN

N

H

OO

O2CCO2

iPr

F3CF3C

iPr

17

69451 Weinheim, Germany - Wiley- · PDF fileCl NO2 iPr 6b White crystalline ... 394.1893,...

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Transcript of 69451 Weinheim, Germany - Wiley- · PDF fileCl NO2 iPr 6b White crystalline ... 394.1893,...