Room-temperature direct alkenylation of 5-pyrazolones

Article abstract of DOI:10.1002/ejoc.201300765

A mild and efficient method for the direct alkenylation of 5-pyrazoles by Pd-catalyzed C-H bond activation is described. The reaction smoothly proceeds at room temperature to provide products in up to 92 % yield. Heterocycles containing the 5-pyrazolone moiety are synthesized by an oxidative Heck-type reaction. The direct alkenylation of 5-pyrazolones at room temperature through Pd-catalyzed C-H bond activation is described. Copyright

Full text of DOI:10.1002/ejoc.201300765

Eur. J. Org. Chem. 2013 · © WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2013 · ISSN 1099–0690
SUPPORTING INFORMATION
DOI: 10.1002/ejoc.201300765
Title: Room-Temperature Direct Alkenylation of 5-Pyrazolones
Author(s): Yiwen Yang, Hao Gong, Chunxiang Kuang*

Table of Contents
1. General considerations ……………………………………………….2-2
2. Experimental details and characterization data for 5-pyrazolones 1….2-5
3. Experimental details and characterization data for products 3….……5-10
4. 1H NMR and 13C NMR spectra for all compounds …………………11-35
1

1. General considerations
All commercially available reagents and solvent were obtained from the commercial providers and
used without further purification. Melting points were recorded using a WRS-2A melting point apparatus
and were uncorrected. IR spectra were obtained on a Nexus FT-IR spectrophotometer. 1H NMR and 13C
NMR spectra were recorded using a Bruker Avance 400 MHz spectrometer. Chemical shifts were
reported relative to internal tetramethylsilane (0.00 ppm) for 1H and CDCl3 (77.0 ppm) for 13C. High
resolution mass spectra were determined using a Finnigan-NAT GC/MS/DS 8430 spectrometer. Flash
column chromatography was performed on 300-400 mesh silica gel. 5-Pyrazolones 1 (except 1a) were
prepared according to literature procedures.1 5-Pyrazolone 1a was a commercially available reagent.
2. Experimental details and characterization data for 5-pyrazolones 1(except 1a)
1) Experimental details and characterization data for 1b-1f
O
O
CH3I
O
N
O
Ar NHNH2
O
molecular sieves(4A )
N
CH3CN,120℃ 17 h
toluene, 120℃ 17 h
Ar
1b-1f
A reaction mixture containing aryl hydrazine (2mmol), ethyl acetoacetate (2mmol), molecular sieves(4
Å) and toluene(4mL) was stirred in the dark in a sealed tube maintained at 120℃in an oil bath. After 17
h, the reaction mixture was cooled to room temperature. To this mixture acetonitrile (2mL) and
iodomethane(6mmol) were added successively and stirred in the dark in the sealed tube maintained at
120℃ for additional 17 h, After the reaction was completed (as monitored by TLC), the mixture was
cooled to room temperature. The solvent was then evaporated in vacuo. The resulting residue was
purified by flash column chromatography (ethyl acetate) to yield 1b-1f.
N
O
N
1b
Me
1,2-Dihydro-2,3-dimethyl-1-p-tolylpyrazol-5-one (1b): Yellow solid (182 mg, 45%); mp:147.8-148.6 °C.
1H NMR (400 MHz, CDCl ): δ = 2.23 (s, 3H), 2.38 (s, 3H), 3.06 (s, 3H), 5.38 (s, 1H), 7.25(s, 4H); 13C NMR
3
(100 MHz, CDCl ): δ = 12.9, 21.1, 35.1, 98.4, 124.7 (2C), 129.8 (2C), 132.6, 136.9, 155.7, 166.4; IR (KBr):
3060, 2911, 1630, 1565, 1547, 1513, 1483, 1384 cm ; HR-MS (ESI): m/z calcd for C12H14N2O: 202.1132 [M] ;
3
−1
+
found: 202.1128.
N
O
N
1c
OMe
1,2-Dihydro-1-(4-methoxyphenyl)-2,3-dimethylpyrazol-5-one (1c): Yellow solid (174 mg, 40%); mp:
124.7-125.8°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.24 (s, 3H), 3.07 (s, 3H), 3.85 (s, 3H), 5.40 (s, 1H), 6.99 (d,
J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl
): δ = 12.9, 34.8, 55.6, 97.9, 114.6 (2C),
127.0 (2C), 127.9, 154.9, 158.8, 166.5; IR (KBr): 3002, 2823, 1629, 1565, 1552, 1530, 1483, 1452, 1384, 1275
3
−1
+
cm ; HR-MS (ESI): m/z calcd for C12H14N2O2: 218.1126 [M] ; found: 218.1135.
N
O
N
1d
Cl
2

1-(3-Chlorophenyl)-1,2-dihydro-2,3-dimethylpyrazol-5-one (1d): Gray solid (214 mg, 48%); mp: 104.3-
105.9°C.1H NMR (400 MHz, CDCl
): δ = 2.26 (s, 3H), 3.07 (s, 3H), 5.42 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H),
7.33 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.40 (s, 1H); 13C NMR (100 MHz, CDCl
): δ = 13.1, 35.9,
99.2, 121.9, 123.6, 126.4, 130.1, 134.8, 136.6, 158.1, 166.5; IR (KBr): 3025, 2971, 1630, 1582, 1548, 1513,
3
3
35
−1
+
1483, 1451, 1384, 769 cm ; HR-MS (ESI): m/z calcd for C11H11 ClN2O: 222.0612 [M] ; found: 222.0608.
N
O
N
Cl
1e
Cl
1-(2,4-Dichlorophenyl)-1,2-dihydro-2,3-dimethylpyrazol-5-one(1e): Yellow solid (231 mg, 45%); mp:
139.2-140.1°C.1H NMR (400 MHz, CDCl
3
): δ = 2.20 (s, 3H), 3.02 (s, 3H), 5.28 (s, 1H), 7.26 (d, J = 8.4 Hz,
1H), 7.33 (d, J = 8.0 Hz, 1H) , 7.50 (s, 1H); 13C NMR (100 MHz, CDCl
): δ = 12.9, 34.2, 96.8, 128.1, 130.7,
131.5, 131.6, 134.9, 135.8, 155.1, 166.5; IR (KBr): 3042, 2930, 2839, 1672, 1599, 1552, 1530, 1481, 1468,
3
35
−1
+
1332, 621 cm ; HR-MS (ESI): m/z calcd for C11H10 Cl2N2O: 256.0224 [M] ; found: 256.0215.
N
O
N
1f
NO2
1,2-Dihydro-2,3-dimethyl-1-(4-nitrophenyl)pyrazol-5-one (1f): Tan solid (234 mg, 30%); mp: 164.8-
165.6 °C.1H NMR (400 MHz, CDCl
3
): δ = 2.28 (s, 3H), 3.09 (s, 3H), 5.45 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),
8.30 (d, J = 9.2 Hz, 2H); 13C NMR (100 MHz, CDCl
3
): δ = 13.3, 36.7, 100.0, 122.2 (2C), 124.7 (2C), 141.1,
−1
144.7, 160.7, 166.4; IR (KBr): 3010, 2944, 2893, 1630, 1563, 1530, 1513, 1481, 1352, 1324 cm ; HR-MS
(ESI): m/z calcd for C11H11N3O3: 233.0816 [M] ; found: 233.0822.
+
2) Experimental details and characterization data for 1g-1j
O
O
Ph
CH3I
Ph
O
N
O
Ar NHNH2
O
molecular sieves(4A)
N
CH3CN,120℃ 17 h
toluene, 120℃ 17 h
Ar
1g-1j
A reaction mixture containing aryl hydrazine (2mmol), ethyl 3-oxo-3-phenylpropanoate (2mmol), molecular
sieves(4 Å) and toluene(4mL) was stirred in the dark in a sealed tube maintained at 120℃in an oil bath. After
17 h, the reaction mixture was cooled to room temperature. To this mixture acetonitrile (2mL) and
iodomethane(6mmol) were added successively and stirred in the dark in the sealed tube maintained at 120℃
for additional 17 h, After the reaction was completed (as monitored by TLC), the mixture was cooled to room
temperature. The solvent was then evaporated in vacuo. The resulting residue was purified by flash column
chromatography (petroleum ether/ethyl acetate = 2:1, v/v) to yield 1g-1j.
Ph
N
O
N
1g
Ph
1,2-Dihydro-2-methyl-1,3-diphenylpyrazol-5-one (1g): Yellow solid (175 mg, 35%); mp:157.2-158.5°C.
1H NMR (400 MHz, CDCl ): δ = 3.02 (s, 3H), 5.82 (s, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.45-7.60 (m, 9H); 13C
3
NMR (100 MHz, CDCl ): δ = 39.1, 100.2, 123.7 (2C), 126.5, 128.4 (2C), 129.1 (2C), 129.2 (2C), 129.3, 130.6,
3
−1
135.2, 161.6, 165.6; IR (KBr): 3087, 2943, 2878, 1630, 1565, 1552, 1513, 1484cm ; HR-MS (ESI): m/z calcd
+
for C16H14N2O: 250.1107 [M] ; found: 250.1103.
3

Ph
N
O
N
1h
Me
1,2-Dihydro-2-methyl-3-phenyl-1-p-tolylpyrazol-5-one (1h): Tan solid (201 mg, 38%); mp: 131.8-
132.7°C.1H NMR (400 MHz, CDCl
): δ = 2.41 (s, 3H), 3.02 (s, 3H), 5.82 (s, 1H), 7.30 (d, J =8.0 Hz, 2H), 7.43
(d, J = 8.4 Hz, 2H), 7.48-7.60 (m, 5H); 13C NMR (100 MHz, CDCl
): δ = 21.1, 38.9, 100.2, 124.0 (2C), 128.4
(2C), 129.1 (2C), 129.4, 129.8 (2C), 130.5, 132.6, 136.7, 161.0, 165.6; IR (KBr): 3031, 2936, 2804, 1638,
3
3
−1
+
1617, 1564, 1554, 1513, 1480, 1381 cm ; HR-MS (ESI): m/z calcd for C17H16N2O: 264.1320 [M] ; found:
264.1325.
Ph
N
O
N
1i
Cl
1-(3-Chlorophenyl)-1,2-dihydro-2-methyl-3-phenylpyrazol-5-one (1i): Tan solid (205 mg, 36%); mp:
140.3-141.6 °C. 1H NMR (400 MHz, CDCl
3
): δ = 3.03 (s, 3H), 5.82 (s, 1H), 7.27 (s, 1H), 7.41-7.51 (m, 2H),
7.52-7.60 (m, 6H); 13C NMR (100 MHz, CDCl
): δ = 39.5, 100.5, 121.4, 123.1, 126.4, 128.4(2C), 129.0, 129.2
(2C), 130.2, 130.9, 134.9, 136.4, 162.7, 165.7; IR (KBr): 3091, 2933, 1641, 1582, 1553, 1513, 1483, 1384, 848
3
35
−1
+
cm ; HR-MS (ESI): m/z calcd for C16H13 ClN2O: 284.0712 [M] ; found: 284.0708.
Ph
N
O
N
Cl
1j
Cl
1-(2,4-Dichlorophenyl)-1,2-dihydro-2-methyl-3-phenylpyrazol-5-one (1j): Brown solid (262 mg, 41%);
mp: 119.6-120.5°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.98 (s, 3H), 5.73 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.41
(d, J = 8.4 Hz, 1H), 7.46-7.54 (m, 5H), 7.55 (s, 1H); 13C NMR (100 MHz, CDCl
): δ = 37.6, 98.5, 128.1, 128.4
(2C), 129.0, 129.1 (2C), 130.6, 130.7, 131.2, 131.5, 134.4, 135.7, 160.8, 165.8; IR (KBr): 3081, 2969, 1666,
3
35
−1
+
1582, 1550, 1530, 1469, 1384, 841,735 cm ; HR-MS (ESI): m/z calcd for C16H12 Cl2N2O: 318.0321 [M] ;
found: 318.0316.
2) Experimental details and characterization data for 1k
RX
N
R N
O
O
N
N
CH3CN,120℃ 17 h
Ph
Ph
1k
1l
BrCH COOEt
RX =
RX =
2
PhCH Br
2
A mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one(2mmol), 2-bromoacetate (6mmol) [or 1-(bromomethyl)
benzene (6mmol)]and acetonitrile (4mL) was stirred in the dark in a sealed tube maintained at 120℃in an oil
bath. After 17 h, the mixture was cooled to room temperature. The solvent was then evaporated in vacuo. The
resulting residue was purified by flash column chromatography (ethyl acetate) to yield 1k and 1l.
EtOOCH2C N
O
N
1k
Ph
Ethyl 2-(3-methyl-5-oxo-1-phenyl-1H-pyrazol-2(5H)-yl)acetate (1k): Tan oil (250 mg, 48%).
1H NMR (400 MHz, CDCl
3
): δ = 1.21 (t, J = 7.2 Hz, 3H), 2.25 (s, 3H), 4.13 (q, J = 7.2, 7.2 Hz, 2H), 4.21 (s,
2H), 5.48 (s, 1H), 7.29-7.37 (m, 3H), 7.45 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl
3
): δ = 12.8, 14.1,
48.2, 61.8, 99.6, 124.8 (2C), 127.2, 129.4 (2C), 134.9, 156.3, 166.6, 166.9; IR (KBr): 3016, 2917, 2850, 1727,
4

−1
1690, 1629, 1564, 1552, 1513, 1483, 1384, 1154, 1010, 748, 700 cm ; HR-MS (ESI): m/z calcd for
+
C14H16N2O3: 260.1208 [M] ; found: 260.1212.
PhH2C N
O
N
1l
Ph
2-Benzyl-1,2-dihydro-3-methyl-1-phenylpyrazol-5-one (1l): Light reddish brown solid (238 mg, 45%); mp:
112.7-113.6°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.28 (s, 3H), 4.70 (s, 2H), 5.43 (s, 1H), 6.91 (t, J = 3.4 Hz,
2H), 7.25 (t, J = 3.0 Hz, 3H), 7.31 (t, J = 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H); 13C
NMR (100 MHz, CDCl ): δ = 13.2, 50.4, 99.4, 125.1(2C), 127.0 (2C), 127.1, 128.2, 128.7 (2C), 129.2 (2C),
134.4, 134.9, 154.8, 166.6; IR (KBr): 3037, 2945, 2688, 1734, 1683, 1616, 1558, 1540, 1507, 1458, 1395, 796,
3
−1
+
771,713 cm ; HR-MS (ESI): m/z calcd for C17H16N2O: 264.1322 [M] ; found: 264.1316.
3. Experimental details and characterization data for products 3
R
R1
R2
R1
R2
H
Pd(OAc)2
CH2Cl2
K2S2O8
r.t.16h
,
,
H
+
N
N
O
O
N
Ar
3
N
Ar
1
R
2
A mixture of 5-pyrazolone 1 (0.2mmol), methyl acrylate (or butyl acrylate, or styrene) (0.4mmol),
Pd(OAc)2(0.02mmol), K2S2O8(0.4mmol)and dichloromethane (2mL) was stirred under air in a sealed tube at
room temperature for 16 h in an oil bath. After the reaction was completed (as monitored by TLC), the solvent
was evaporated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate) to
yield 3.
CO2Me
N
O
N
3a
Ph
(2E)-methyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylate(3a): Tan solid (44 mg,
80%); mp: 152.5-153.3°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.40 (s, 3H), 3.25 (s, 3H), 3.77 (s, 3H), 7.05 (d, J
= 15.6Hz, 1H), 7.32-7.40 (m, 3H), 7.47 (d, J = 16.0 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz,
CDCl ): δ = 10.8, 34.9, 51.4, 104.5, 115.6, 125.2 (2C), 127.6, 129.4 (2C), 133.0, 134.3, 153.1, 163.5, 169.1; IR
3
−1
(KBr): 3018, 2926, 1726, 1678, 1641, 1586, 1548, 1513, 1483, 1383, 1284, 1009, 979 cm ; HR-MS (ESI): m/z
+
calcd for C15H16N2O3: 272.1230 [M] ; found: 272.1236.
CO2Et
N
O
N
3b
Ph
(2E)-ethyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylate (3b): Yellow solid (47
mg, 83%); mp: 144.5-145.3°C. 1H NMR (400 MHz, CDCl
3
): δ = 1.28 (t, J = 7.0 Hz, 3H), 2.36 (s, 3H), 3.21 (s,
3H), 4.20 (q, J = 7.0, 7.2 Hz, 2H), 6.99 (d, J = 15.2Hz, 1H), 7.32-7.38 (m, 3H), 7.43 (d, J = 15.2 Hz, 1H), 7.47
(t, J = 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl
): δ = 10.8, 14.4, 34.9, 60.0, 104.4, 115.9, 125.2 (2C), 127.6,
129.3 (2C), 132.8, 134.3, 153.1, 163.5, 169.6; IR (KBr): 3041, 2927, 1734, 1684, 1653, 1616,1558, 1540, 1507,
3
−1
+
1457, 1092 cm ; HR-MS (ESI): m/z calcd for C16H18N2O3: 286.1305 [M] ; found: 286.1307.
CO2Et
Me
N
O
N
3c
Ph
(2E)-ethyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)-2-methylacrylate (3c): Yellow
solid (38 mg, 64%); mp: 104.7-105.5°C. 1H NMR (400 MHz, CDCl
): δ = 1.34 (t, J = 7.0 Hz, 3H), 2.08 (s,
3
3H), 2.27 (s, 3H), 3.19 (s, 3H), 4.25 (q, J = 7.2, 7.2 Hz, 2H), 7.29 (s, 1H), 7.33 (t, J = 7.2Hz, 1H), 7.39 (d, J =
5

7.6 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl
): δ = 12.1, 14.3, 15.5, 35.6, 60.6, 106.6,
3
124.7 (2C), 127.1, 127.7, 129.2 (2C), 129.5, 134.9, 153.5, 163.3, 168.5; IR (KBr): 3035, 2908, 2830,1734,
−1
1684, 1653, 1558, 1540, 1507, 1457, 1396, 1273, 1095, 775 cm ; HR-MS (ESI): m/z calcd for C17H20N2O3:
+
300.1485 [M] ; found: 300.1482.
CO2nBu
N
O
N
3d
Ph
(2E)-butyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylate (3d): Tan solid (51 mg,
81%); mp: 152.5-153.3°C. 1H NMR (400 MHz, CDCl
3
): δ = 0.95 (t, J = 7.2 Hz, 3H), 1.40-1.46 (m, 2H), 1.64-
1.69 (m, 2H), 2.40 (s, 3H), 3.24 (s, 3H), 4.17 (t, J = 6.8 Hz, 3H), 7.04 (d, J = 15.6Hz, 1H), 7.32-7.40 (m, 3H),
7.46 (d, J = 15.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl
): δ = 10.8, 13.7, 19.2, 30.8,
3
35.0, 64.0, 104.5, 116.1, 125.2 (2C), 127.6, 129.3 (2C), 132.7, 134.3, 153.1, 163.5, 168.8; IR (KBr): 3049,
2925, 2854, 1709, 1679, 1629, 1563, 1547, 1513, 1468, 1263, 1030, 957 cm−1; HR-MS (ESI): m/z calcd for
+
C18H22N2O3: 314.1612 [M] ; found: 314.1618.
CO2tBu
N
O
N
3e
Ph
(2E)-tert-butyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylate (3e): Yellow solid
(50 mg, 79%); mp: 175.6-176.8°C. 1H NMR (400 MHz, CDCl
3
): δ = 1.49 (s, 9H), 2.34 (s, 3H), 3.20 (s, 3H),
6.93 (d, J = 15.6Hz, 1H), 7.30-7.40 (m, 4H), 7.46 (d, J = 15.6 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H); 13C NMR (100
MHz, CDCl ): δ = 10.8, 28.2 (3C), 35.0, 79.7, 104.5, 118.0, 125.1 (2C), 127.5, 129.3 (2C), 131.7, 134.4, 153.1,
163.5, 168.0; IR (KBr): 3033, 2966, 2867, 1734, 1684, 1653, 1558, 1540, 1507, 1457, 1396,1374,1196, 706
3
−1
+
cm ; HR-MS (ESI): m/z calcd for C18H22N2O3: 314.1624 [M] ; found: 314.1620.
CN
N
O
N
3f
Ph
(2E)-3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylonitrile (3f): Yellow solid (25 mg,
52%); mp: 171.2-172.3°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.37 (s, 3H), 3.29 (s, 3H), 6.63 (d, J = 15.6Hz,
1H), 7.10 (d, J = 16.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H) , 7.52 (t, J = 7.8 Hz, 2H); 13C
NMR (100 MHz, CDCl ): δ = 10.6, 34.7, 93.5, 103.5, 125.6 (2C), 128.2, 129.6 (2C), 132.6, 133.7, 138.5, 151.5,
3
−1
163.1; IR (KBr): 3061, 2952, 2199,1734, 1684, 1636, 1558, 1540, 1507, 1457, 1374, 700 cm ; HR-MS (ESI):
+
m/z calcd for C14H13N3O: 239.1086 [M] ; found: 239.1092.
Ph
N
O
N
3g
Ph
1,2-Dihydro-2,3-dimethyl-1-phenyl-4-styrylpyrazol-5-one (3g): Yellow solid (32 mg, 55%); mp: 165.6-
166.6°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.39 (s, 3H), 3.15 (s, 3H), 6.82 (d, J = 16.0Hz, 1H), 7.22 (t, J = 7.2
Hz, 1H), 7.30-7.37 (m, 3H), 7.40-7.53 (m, 6H) , 7.80 (d, J = 16.0Hz, 1H); 13C NMR (100 MHz, CDCl
3
): δ =
11.0, 35.9, 107.7, 116.8, 124.2 (2C), 126.1 (2C), 126.7, 126.9, 128.5 (3C), 129.1 (2C), 135.0, 138.5, 151.7,
−1
164.2; IR (KBr): 3085, 2916, 2889, 1678, 1641, 1599, 1552, 1513, 1482, 1468, 1383, 989 cm ; HR-MS (ESI):
+
m/z calcd for C19H18N2O: 290.1423 [M] ; found: 290.1417.
SO2Ph
N
O
N
3h
Ph
1,2-Dihydro-2,3-dimethyl-1-phenyl-4-((E)-2-(phenylsulfonyl)vinyl)pyrazol-5-one (3h): Earth yellow solid
(29 mg, 41%); mp: 215.0-216.2°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.42 (s, 3H), 3.28 (s, 3H), 7.29 (d, J =
6

7.2Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 14.8Hz, 1H), 7.45-7.56 (m, 5H), 7.58 (d, J = 14.4Hz, 1H),
7.91 (d, J = 7.6Hz, 2H); 13C NMR (100 MHz, CDCl
): δ = 10.8, 34.7, 102.1, 124.0, 125.6 (2C), 127.3 (2C),
3
128.1, 129.1 (2C), 129.5 (2C), 130.7, 132.8, 133.7, 141.7, 152.8, 163.0; IR (KBr): 3069, 2966, 2870,
−1
1734,1684, 1653, 1636,1558, 1540, 1507, 1457, 1395, 1374, 1143, 1129, 1005, 751, 694 cm ; HR-MS (ESI):
+
m/z calcd for C19H18N2O3S: 354.1015 [M] ; found: 354.1018.
CONMe2
N
O
N
3i
Ph
(2E)-3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)-N,N-dimethylacrylamide (3i): Light
yellow solid (22 mg, 38%); mp: 199.1-200.4°C. 1H NMR (400 MHz, CDCl
3
): δ =2.40 (s, 3H), 3.06 (s, 3H),
3.15 (s, 3H), 3.24 (s, 3H), 7.30-7.40 (m, 3H), 7.46 (d, J = 15.2Hz, 1H), 7.48-7.58 (m, 2H), 7.69 (d, J = 14.8 Hz,
1H); 13C NMR (100 MHz, CDCl
): δ = 10.7, 35.1, 35.8, 37.3, 105.3, 115.5, 124.9 (2C), 127.4, 129.3 (2C),
130.3, 134.4, 153.2, 164.0, 168.0; IR (KBr): 3039, 2948, 2870,1734, 1684, 1653, 1617,1585, 1558, 1507, 1457,
3
−1
+
1392, 1375, 1067, 769, 708 cm ; HR-MS (ESI): m/z calcd for C16H19N3O2: 285.1487 [M] ; found: 285.1493.
CO2Me
N
O
N
3j
Me
(2E)-methyl 3-(2,5-dihydro-2,3-dimethyl-5-oxo-1-p-tolyl-1H-pyrazol-4-yl)acrylate(3j): Yellow solid (51
mg, 90%); mp: 203.5-204.2°C. 1H NMR (400 MHz, CDCl
3
): δ =2.38 (s, 3H), 2.41 (s, 3H), 3.23 (s, 3H), 3.77
(s, 3H), 7.03 (d, J = 15.6Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 15.6 Hz, 1H);
13C NMR (100 MHz, CDCl
): δ = 10.7, 21.1, 34.6, 51.3, 104.1, 115.2, 125.6 (2C), 130.0 (2C), 131.6, 133.2,
138.0, 152.1, 163.4, 169.2; IR (KBr): 3001, 2915, 1726, 1679, 1629, 1581, 1551, 1513, 1480, 1451, 1384,
3
−1
+
1300, 1014, 964 cm ; HR-MS (ESI): m/z calcd for C16H18N2O3: 286.1302 [M] ; found: 286.1308.
CO2Me
N
O
N
3k
OMe
(2E)-methyl 3-(2,5-dihydro-1-(4-methoxyphenyl)-2,3-dimethyl-5-oxo-1H-pyrazol-4-yl)acrylate (3k):
Yellow solid (56 mg, 92%); mp:146.6-147.3°C. 1H NMR (400 MHz, CDCl
3
): δ =2.36 (s, 3H), 3.21 (s, 3H),
3.75 (s, 3H), 3.84 (s, 3H), 6.99 (d, J = 8.8Hz, 2H), 7.01 (d, J = 15.6 Hz, 1H), 7.23 (d, J = 9.2 Hz, 2H), 7.46 (d,
J = 15.2 Hz, 1H); 13C NMR (100 MHz, CDCl
): δ = 10.7, 34.2, 51.3, 55.6, 103.5, 114.6, 114.8 (2C), 126.7,
3
128.0 (2C), 133.4, 151.1, 159.5, 163.4, 169.2; IR (KBr): 3045, 2917, 2841, 1727, 1679, 1630, 1554, 1529,
+
1469, 1443, 1384, 1161, 959, 849 cm−1; HR-MS (ESI): m/z calcd for C16H18N2O4: 302.1322 [M] ; found:
302.1318.
CO2Me
N
O
N
3l
Cl
(2E)-methyl 3-(1-(3-chlorophenyl)-2,5-dihydro-2,3-dimethyl-5-oxo-1H-pyrazol-4-yl)acrylate (3l): Yellow
solid (47 mg, 76%); mp: 159.2-160.1°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.40 (s, 3H), 3.25 (s, 3H), 3.78 (s,
3H), 7.04 (d, J = 15.6 Hz, 1H), 7.29-7.36 (m, 2H), 7.38 (s, 1H), 7.40-7.46 (m, 1H), 7.45 (d, J = 15.6 Hz, 1H);
13C NMR (100 MHz, CDCl
3
): δ = 11.0, 35.4, 51.4, 105.0, 116.2, 122.7, 124.5, 127.4, 130.3, 132.6, 135.0,
7

135.7, 154.8, 163.6, 168.9; IR (KBr): 3041, 2916, 2852, 1725, 1678, 1630, 1582, 1548, 1513, 1480, 1383,
35
−1
+
1277, 1010, 977, 848 cm ; HR-MS (ESI): m/z calcd for C15H15 ClN2O3: 306.0833 [M] ; found: 306.0829.
CO2nBu
N
O
N
3m
Cl
(2E)-butyl 3-(1-(3-chlorophenyl)-2,5-dihydro-2,3-dimethyl-5-oxo-1H-pyrazol-4-yl)acrylate (3m): Yellow
solid (52 mg, 75%); mp: 211.2-212.0°C. 1H NMR (400 MHz, CDCl
3
): δ = 0.93 (t, J = 6.0 Hz, 3H), 1.38-1.44
(m, 2H), 1.63-1.67 (m, 2H), 2.38 (s, 3H), 3.22 (s, 3H), 4.16 (t, J = 5.2 Hz, 2H), 7.01 (d, J = 12.4Hz, 1H), 7.26-
7.33 (m, 2H), 7.37 (s, 1H), 7.38-7.44 (m, 1H), 7.41 (d, J = 12.4 Hz, 1H); 13C NMR (100 MHz, CDCl
): δ =
3
10.9, 13.7, 19.1, 30.8, 35.4, 64.0, 105.0, 116.8, 122.6, 124.4, 127.3, 130.2, 132.2, 135.0, 135.7, 154.8, 163.6,
−1
168.5; IR (KBr): 3033, 2923, 1630, 1565, 1548, 1513, 1468, 1384, 1009, 959, 847 cm ; HR-MS (ESI): m/z
35
+
calcd for C18H21 ClN2O3: 348.1241 [M] ; found: 348.1237.
CO2Me
N
O
N
Cl
3n
Cl
(2E)-methyl 3-(1-(2,4-dichlorophenyl)-2,5-dihydro-2,3-dimethyl-5-oxo-1H-pyrazol-4-yl)acrylate (3n):
Tan solid (48 mg, 70%); mp: 147.7-149.1°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.39 (s, 3H), 3.20 (s, 3H), 3.77
(s, 3H), 6.99 (d, J = 15.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 15.2 Hz, 1H),
7.59 (s, 1H); 13C NMR (100 MHz, CDCl
): δ = 10.6, 33.6, 51.3, 103.0, 115.2, 128.4, 130.5, 130.8, 132.0, 133.0,
135.1, 136.6, 151.3, 163.2, 169.1; IR (KBr): 3069, 2944, 1726, 1679, 1629, 1565, 1547, 1513, 1483, 1384,
3
35
−1
+
1279, 1152, 847 cm ; HR-MS (ESI): m/z calcd for C15H14 Cl2N2O3: 340.0415 [M] ; found: 340.0420.
CO2nBu
N
O
N
Cl
3o
Cl
(2E)-butyl 3-(1-(2,4-dichlorophenyl)-2,5-dihydro-2,3-dimethyl-5-oxo-1H-pyrazol-4-yl)acrylate (3o):
Yellow solid (55 mg, 72%); mp: 179.9-180.8°C. 1H NMR (400 MHz, CDCl
): δ = 0.93 (t, J = 6.0 Hz, 3H),
3
1.36-1.44 (m, 2H), 1.62-1.65 (m, 2H), 2.37 (s, 3H), 3.18 (s, 3H), 4.15 (t, J = 5.2 Hz, 2H), 6.97 (d, J = 12.4 Hz,
1H), 7.30 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.43 (d, J = 12.4 Hz, 1H), 7.57 (s, 1H); 13C NMR (100
MHz, CDCl
3): δ = 10.6, 13,7, 19.2, 30.8, 33.7, 63.9, 103.1, 115.8, 128.3, 130.6, 130.8, 131.9, 132.6, 135.1,
136.6, 151.4, 163.2, 168.8; IR (KBr): 3096, 2925, 1726, 1650, 1629, 1565, 1547, 1513, 1479, 1451, 1384,
35
−1
+
1283, 1007, 964, 848 cm ; HR-MS (ESI): m/z calcd for C18H20 Cl2N2O3: 382.0906 [M] ; found: 382.0910.
CO2Me
N
O
N
3p
NO2
(2E)-methyl 3-(2,5-dihydro-2,3-dimethyl-1-(4-nitrophenyl)-5-oxo-1H-pyrazol-4-yl)acrylate (3p): Yellow
solid (14 mg, 22%); mp: 194.8-195.7°C. 1H NMR (400 MHz, CDCl
3
): δ =2.42 (s, 3H), 3.25 (s, 3H), 3.77 (s,
3H), 7.03 (d, J = 12.4Hz, 1H), 7.41 (d, J = 12.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 8.35 (d, J = 7.2 Hz, 2H); 13C
NMR (100 MHz, CDCl
3
): δ = 11.2, 36.4, 51.5, 106.1, 117.3, 122.9 (2C), 124.8 (2C), 131.9, 140.2, 145.4, 157.6,
8

163.6, 168.5; IR (KBr): 3062, 2926, 2869, 1726, 1679, 1641, 1599, 1552, 1530, 1513, 1483, 1384, 1344, 1187,
−1
+
1009, 979 cm ; HR-MS (ESI): m/z calcd for C15H15N3O5: 317.1025 [M] ; found: 317.1021.
CO2Me
Ph
N
O
N
3q
Ph
(2E)-methyl 3-(2,5-dihydro-2-methyl-5-oxo-1,3-diphenyl-1H-pyrazol-4-yl)acrylate (3q): Yellow solid (41
mg, 62%); mp:133.6-134.7°C. 1H NMR (400 MHz, CDCl
3
): δ = 3.09 (s, 3H), 3.74 (s, 3H), 7.19 (d, J = 15.6Hz,
1H), 7.34-7.42 (m, 1H), 7.39 (d, J = 15.2 Hz, 1H), 7.48-7.56 (m, 6H), 7.57-7.64 (m, 3H); 13C NMR (100 MHz,
CDCl ): δ = 38.0, 51.4, 106.3, 117.6, 124.6 (2C), 127.3, 127.8, 129.4 (2C), 129.4 (2C), 129.7 (2C), 131.0,
133.5, 134.4, 157.8, 163.1, 168.8; IR (KBr): 3039, 2925, 2854, 1726, 1678, 1630, 1564, 1552, 1513, 1480,
3
−1
+
1277, 1157 cm ; HR-MS (ESI): m/z calcd for C20H18N2O3: 334.1342 [M] ; found: 334.1338.
CO2Me
Ph
N
O
N
3r
Me
(2E)-methyl 3-(2,5-dihydro-2-methyl-5-oxo-3-phenyl-1-p-tolyl-1H-pyrazol-4-yl)acrylate (3r): Yellow
solid (39 mg, 56%); mp: 174.5-176.3°C. 1H NMR (400 MHz, CDCl
3
): δ =2.43 (s, 3H), 3.08 (s, 3H), 3.74 (s,
3H), 7.17 (d, J = 15.6Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 15.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H),
7.48-7.53 (m, 2H), 7.56-7.63 (m, 3H); 13C NMR (100 MHz, CDCl
): δ = 21.1, 37.6, 51.3, 106.0, 117.3, 125.0
3
(2C), 127.8, 129.4(2C), 129.7(2C), 130.0 (2C), 130.9, 131.7, 133.7, 137.7, 157.0, 163.0, 168.9; IR (KBr): 3029,
−1
2915, 2872, 1726, 1630, 1563, 1553, 1530, 1483, 1384, 952 cm ; HR-MS (ESI): m/z calcd for C21H20N2O3:
+
348.1516 [M] ; found: 348.1522.
CO2Me
Ph
N
O
N
3s
Cl
(2E)-methyl 3-(1-(3-chlorophenyl)-2,5-dihydro-2-methyl-5-oxo-3-phenyl-1H-pyrazol-4-yl)acrylate (3s):
Yellow solid (39 mg, 53%); mp: 144.2-145.1°C. 1H NMR (400 MHz, CDCl
3
): δ = 3.08 (s, 3H), 3.75 (s, 3H),
7.18 (d, J = 15.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.38 (d, J = 15.6 Hz, 1H), 7.44-7.50 (m, 2H), 7.50-7.56 (m, 3H),
7.58-7.64 (m, 3H); 13C NMR (100 MHz, CDCl
): δ = 38.5, 51.4, 106.6, 118.2, 122.1, 123.9, 127.2, 127.6,
3
129.5(2C), 129.7(2C), 130.3, 131.2, 133.1, 135.1, 135.7, 159.2, 163.2, 168.6; IR (KBr): 3087, 2999, 1726,
−1
1678, 1630, 1563, 1554, 1513, 1483, 1452, 1329, 1009, 957, 848 cm ; HR-MS (ESI): m/z calcd for
35
+
C20H17 ClN2O3: 368.0935 [M] ; found: 368.0939.
CO2Me
Ph
N
O
N
Cl
3t
Cl
(2E)-methyl 3-(1-(2,4-dichlorophenyl)-2,5-dihydro-2-methyl-5-oxo-3-phenyl-1H-pyrazol-4-yl) acrylate
(3t): Tan solid (18 mg, 22%); mp: 151.0-152.0°C. 1H NMR (400 MHz, CDCl
3
): δ = 3.06 (s, 3H), 3.73 (s, 3H),
7.11 (d, J = 16.0 Hz, 1H), 7.34 (d, J = 15.6 Hz, 1H), 7.42-7.52 (m, 3H), 7.45 (s, 1H), 7.56-7.66 (m, 4H); 13C
NMR (100 MHz, CDCl ): δ = 36.3, 51.3, 104.7, 117.0, 127.3, 128.3, 129.4(2C), 129.7(2C), 130.7, 130.9, 131.0,
3
131.6, 133.5, 134.7, 136.4, 156.3, 163.0, 168.8; IR (KBr): 3045, 2935, 2874, 1726, 1638, 1618, 1581, 1552,
9

35
−1
+
1513, 1483, 1443, 1382, 1152, 980, 745 cm ; HR-MS (ESI): m/z calcd for C20H16 Cl2N2O3: 402.0524 [M] ;
found: 402.0530.
CO2Me
EtOOCH2C N
O
N
3u
Ph
(2E)-methyl 3-( 2-ethoxylcarbonylmethyl-2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)
acrylate (3u): Yellow solid (40 mg, 58%); mp: 128.8-129.4°C. 1H NMR (400 MHz, CDCl
): δ = 1.21 (t, J =
3
7.2 Hz, 3H), 2.38 (s, 3H), 3.78 (s, 3H), 4.15 (q, J = 7.2, 7.2 Hz, 2H), 4.33 (s, 2H), 7.07 (d, J = 15.6 Hz, 1H),
7.32 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.49(d, J = 15.6 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl
3
): δ = 10.8, 14.1, 48.2, 51.4, 62.2, 105.9, 116.5, 125.3(2C), 127.9, 129.5(2C), 132.8, 134.1,
154.1, 164.0, 166.1, 168.9; IR (KBr): 3029, 2970, 1745, 1726, 1630, 1564, 1548, 1513, 1483, 1451, 1326,
−1
+
1010, 957 cm ; HR-MS (ESI): m/z calcd for C18H20N2O5: 344.1428 [M] ; found: 344.1432.
CO2Me
PhH2C N
O
N
3v
Ph
(2E)-methyl 3-(2-benzyl-2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)acrylate (3v): Yellow
solid (51 mg, 73%); mp: 152.0-153.0°C. 1H NMR (400 MHz, CDCl
3
): δ = 2.40 (s, 3H), 3.75 (s, 3H), 4.83 (s,
2H), 6.81-6.91 (m, 2H), 7.04 (d, J = 15.6Hz, 1H), 7.19-7.31 (m, 5H), 7.35 (d, J = 7.4 Hz, 1H), 7.40-7.50 (m,
2H),7.46 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl
): δ = 11.0, 50.3, 51.4, 105.1, 115.5, 125.8 (2C),
3
126.7(2C), 127.9, 128.4, 128.9(2C), 129.4 (2C), 133.1, 134.0, 134.0, 152.3, 163.8, 169.0; IR (KBr): 3015,
−1
2903, 2800,1734, 1684, 1653, 1558, 1540, 1507, 1457, 1362, 1155, 1001, 692 cm ; HR-MS (ESI): m/z calcd
+
for C21H20N2O3: 348.1502 [M] ; found: 348.1505.
References:
(1) Balestra, M.; Bunting, H.; Chen, D.; Egle, I.; Forst, J.; Frey, J.; Isaac, M.; Ma, F.; Nugiel, D.; Slassi, A.;
Steelman, G.; Sun, G.; Sundar, B.; Ukkiramapandian, R.; Urbanek, R.; Walsh, S. PCT Int. Appl. WO
2006071730, 2006.
10

4.1H NMR and 13C NMR spectra for all compounds
N
O
N
Me
1b
N
N
O
Me
1b
11

N
O
N
OMe
1c
N
O
N
OMe
1c
12

N
O
N
Cl
1d
N
O
N
Cl
1d
13

N
O
N
Cl
Cl
1e
N
O
N
Cl
Cl
1e
14

N
O
N
NO2
1f
N
O
N
NO2
1f
15

Ph
N
O
N
Ph
1g
Ph
N
O
N
Ph
1g
16

Ph
N
O
N
Me
1h
Ph
N
O
N
Me
1h
17

Ph
N
O
N
Cl
1i
Ph
N
O
N
Cl
1i
18

Ph
N
O
N
Cl
Cl
1j
Ph
N
O
N
Cl
Cl
1j
19

EtOOCH2C
N
O
N
Ph
1k
EtOOCH2C
N
O
N
Ph
1k
20

PhH2C N
O
N
Ph
1l
PhH2C N
O
N
Ph
1l
21

CO2Me
N
O
N
Ph
3a
CO2Me
N
O
N
Ph
3a
22

CO2Et
N
O
N
Ph
3b
CO2Et
N
O
N
Ph
3b
23

CO2Et
Me
N
O
N
Ph
3c
CO2Et
Me
N
O
N
Ph
3c
24

CO2nBu
N
O
N
Ph
3d
CO2nBu
N
O
N
Ph
3d
25

CO2tBu
N
O
N
Ph
3e
CO2tBu
N
O
N
Ph
3e
26

CN
N
O
N
Ph
3f
CN
N
O
N
Ph
3f
27

Ph
N
O
N
Ph
3g
Ph
N
O
N
Ph
3g
28

SO2Ph
N
O
N
Ph
3h
SO2Ph
N
O
N
Ph
3h
29