Month 2013
A Simple and Efficient Synthesis of Ethyl 1-Aryl-4-formyl-1H-pyrazole-3-carboxylates
Ethyl 2-[2-(4-bromophenyl)hydrazinylidene]propanoate (3h).
Yield: 2.22 g (78%); mp 154°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.37 (t, J = 7.1 Hz, 3H, CH3CH2), 2.09 (s, 3H, CH3), 4.31
(q, J = 7.1 Hz, 2H, CH2), 7.08 (d, J = 9.0 Hz, 2H, Ar-H), 7.38
(d, J = 9.0 Hz, 2H, Ar-H), 7.76 (br s, 1H, NH); 13C-NMR
(CDCl3, 50 MHz) δ: 10.4, 14.3, 61.3, 115.6 (2C), 126.2, 132.1
(2C), 133.3, 142.3, 165.0. Anal. Calcd. for C11H13BrN2O2: C,
46.33; H, 4.60; N, 9.82. Found: C, 46.54; H, 4.51; N, 9.96.
Ethyl 2-[2-(2-nitrophenyl)hydrazinylidene]propanoate (3i).
Yield: 1.68 g (67%); mp 110°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.39 (t, J = 7.1 Hz, 3H, CH3CH2), 2.25 (s, 3H, CH3), 2.39
(q, J = 7.1 Hz, 2H, CH2), 6.94–7.01 (m, 1H, Ar-H), 7.54–7.62
(m, 1H, Ar-H), 7.98–8.04 (m, 1H, Ar-H), 8.17 (d, J = 8.4 Hz,
1H, Ar-H), 10.95 (br s, 1H, NH); 13C-NMR (CDCl3, 50 MHz)
δ: 11.7, 14.3, 61.7, 116.8, 120.3, 125.8, 132.7, 136.3, 139.2,
140.6, 162.5. Anal. Calcd. for C11H13N3O4: C, 52.59; H, 5.22;
N, 16.72. Found: C, 52.27; H, 5.29; N, 16.58.
Ethyl 2-[2-(3-nitrophenyl)hydrazinylidene]propanoate (3j).
Yield: 1.63 g (65%); mp 143°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.40 (t, J = 7.2 Hz, 3H, CH3CH2), 2.17 (s, 3H, CH3), 4.34
(q, J = 7.2 Hz, 2H, CH2), 7.43 (t, J = 8.0 Hz, 1H, Ar-H), 7.58
(ddd, J = 8.0 Hz, 2.0 Hz, 1.0 Hz, 1H, Ar-H), 7.77 (ddd, J = 8.0
Hz, 2.0 Hz, 1.0 Hz, 1H, Ar-H), 8.01 (t, J = 2.0 Hz, 1H, Ar-H),
8.13 (br s, 1H, NH); 13C-NMR (CDCl3, 50 MHz) δ: 10.7, 14.3,
61.6, 108.7, 116.2, 119.7, 130.1, 135.2, 144.5, 149.0, 164.8.
Anal. Calcd. for C11H13N3O4: C, 52.59; H, 5.22; N, 16.72.
Found: C, 52.70; H, 5.31; N, 16.83.
Ethyl 2-[2-(4-nitrophenyl)hydrazinylidene]propanoate (3k).
Yield: 1.81 g (72%); mp 171°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.40 (t, J = 7.0 Hz, 3H, CH3CH2), 2.18 (s, 3H, CH3), 4.35
(q, J = 7.0 Hz, 2H, CH2), 7.27 (d, J = 9.2 Hz, 2H, Ar-H), 8.06
(br s, 1H, NH), 8.21 (d, J = 9.2 Hz, 2H, Ar-H); 13C-NMR
(CDCl3, 50 MHz) δ: 10.8, 14.3, 61.7, 112.7, 113.4 (2C), 125.9
(2C), 136.9, 148.3, 164.5. Anal. Calcd. for C11H13N3O4: C,
52.59; H, 5.22; N, 16.72. Found: C, 52.74; H, 5.34; N, 16.55.
Ethyl 2-[2-(3,4-dichlorophenyl)hydrazinylidene]propanoate
(3l). Yield: 1.68 g (61%); mp 125°C. 1H-NMR (CDCl3, 200
MHz) δ: 1.38 (t, J = 7.1 Hz, 3H, CH3CH2), 2.10 (s, 3H, CH3),
4.32 (q, J = 7.1 Hz, 2H, CH2), 7.01 (dd, J = 8.8 Hz, 2.5 Hz,
1H, Ar-H), 7.32 (d, J = 8.8 Hz, 1H, Ar-H), 7.34 (d, J = 2.5 Hz,
1H, Ar-H), 7.75 (br s, 1H, NH); 13C-NMR (CDCl3, 50 MHz)
δ: 10.5, 14.3, 61.5, 113.4, 115.6, 124.7, 130.8, 133.2, 134.3,
142.8, 164.8. Anal. Calcd. for C11H12Cl2N2O2: C, 48.02; H,
4.40; N, 10.18. Found: C, 47.87; H, 4.29; N, 10.08.
Ethyl 2-[2-(3,5-dichlorophenyl)hydrazinylidene]propanoate
(3m). Yield: 1.84 g (67%); mp 115°C. 1H-NMR (CDCl3, 200
MHz) δ: 1.39 (t, J = 7.1 Hz, 3H, CH3CH2), 2.10 (s, 3H, CH3),
4.33 (q, J = 7.1 Hz, 2H, CH2), 6.93 (s, 1H, Ar-H), 7.10(s, 2H,
Ar-H), 7.73 (br s, 1H, NH); 13C-NMR (CDCl3, 50 MHz)
δ: 10.6, 14.3, 61.6, 111.8, 112.5 (2C), 121.7 (2C), 135.7, 145.0,
164.7. Anal. Calcd. for C11H12Cl2N2O2: C, 48.02; H, 4.40; N,
10.18. Found: C, 48.23; H, 4.27; N, 10.30.
under constant manual stirring. After neutralization with
K2CO3 solution, ethyl acetate (30 mL) was added. The
organic phase was separated and the aqueous phase extracted
with AcOEt (2 Â 30 mL). The combined organic solutions
were washed with water (30 mL) and brine (30 mL), dried, and
concentrated. The product was isolated by recrystallization
from ethanol.
Ethyl 4-formyl-1-(2-methylphenyl)-1H-pyrazole-3-carboxylate
(4a). Yield: 0.94 g (73%); mp 99°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.45 (t, J = 7.1 Hz, 3H, CH3CH2), 2.24 (s, 3H, CH3), 4.51
(q, J = 7.1 Hz, 2H, CH2), 7.30–7.42 (m, 4H, Ar-H), 8.18 (s, 1H,
CHpyr), 10.50 (s, 1H, CHO); 13C-NMR (CDCl3, 50 MHz) δ: 14.3,
17.7, 61.8, 124.9, 126.1, 126.8, 129.9, 131.4, 133.6, 133.9, 138.4,
143.9, 161.4, 186.6. Anal. Calcd. for C14H14N2O3: C, 65.11; H,
5.46; N, 10.85. Found: C, 64.93; H, 5.54; N, 10.67.
Ethyl 4-formyl-1-(4-methylphenyl)-1H-pyrazole-3-carboxylate
(4b). Yield: 1.05 g (81%); mp 112°C. 1H-NMR (CDCl3, 200
MHz) δ: 1.47 (t, J = 7.1 Hz, 3H, CH3CH2), 2.41 (s, 3H, CH3),
4.52 (q, J = 7.1 Hz, 2H, CH2), 7.30 (d, J = 8.4 Hz, 2H, Ar-H),
7.64 (d, J = 8.4 Hz, 2H, Ar-H), 8.46 (s, 1H, CHpyr), 10.46 (s, 1H,
CHO); 13C-NMR (CDCl3, 50 MHz) δ: 14.3, 21.0, 61.8, 120.2
(2C), 125.5, 129.9, 130.1 (2C), 136.3, 138.8, 144.1, 161.3, 186.5.
Anal. Calcd. for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85.
Found: C, 65.01; H, 5.32; N, 10.70.
Ethyl 4-formyl-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate
(4c). Yield: 0.88 g (64%); mp 94°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.47 (t, J = 7.1 Hz, 3H, CH3CH2), 3.86 (s, 3H, CH3), 4.52
(q, J = 7.1 Hz, 2H, CH2), 7.00 (d, J = 9.0 Hz, 2H, Ar-H), 7.65
(d, J = 9.0 Hz, 2H, Ar-H), 8.40 (s, 1H, CHpyr), 10.46 (s, 1H,
CHO); 13C-NMR (CDCl3, 50 MHz) δ: 14.3, 55.6, 61.8, 114.7
(2C), 121.9 (2C), 125.4, 129.9, 132.1, 144.0, 159.8, 161.4, 186.5.
Anal. Calcd. for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21.
Found: C, 61.08; H, 5.31; N, 10.36.
Ethyl 1-(3,4-dimethylphenyl)-4-formyl-1H-pyrazole-3-carboxylate
(4d). Yield: 1.20 g (88%); mp 97°C. 1H-NMR (CDCl3, 200 MHz)
δ: 1.47 (t, J = 7.1 Hz, 3H, CH3CH2), 2.31 (s, 3H, CH3), 2.33
(s, 3H, CH3), 4.52 (q, J = 7.1 Hz, 2H, CH2), 7.23 (d, J = 8.0 Hz,
1H, Ar-H), 7.43 (dd, J = 8.0 Hz, 2.4 Hz, 1H, Ar-H), 7.55 (d,
J = 2.4 Hz, 1H, Ar-H), 8.44 (s, 1H, CHpyr), 10.45 (s, 1H, CHO);
13C-NMR (CDCl3, 50 MHz) δ: 14.3, 19.4, 19.8, 61.8, 117.5,
121.4, 125.4, 129.9, 130.5, 136.5, 137.5, 138.3, 144.0, 161.4,
186.5. Anal. Calcd. for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29.
Found: C, 66.38; H, 5.75; N, 10.36.
Ethyl 1-(4-fluorophenyl)-4-formyl-1H-pyrazole-3-carboxylate
1
(4e). Yield: 0.90 g (69%); mp 84°C. H-NMR (DMSO-d6, 400
MHz) δ: 1.43 (t, J = 7.2 Hz, 3H, CH3), 4.43 (q, J = 7.2 Hz, 2H,
CH2), 7.21 (t, J = 8.8 Hz, 2H, Ar-H), 8.04 (dd, JHH = 8.8 Hz, JHF
= 4.8 Hz, 2H, Ar-H), 9.19 (s, 1H, CHpyr), 10.31 (s, 1H, CHO);
13C-NMR (CDCl3, 50 MHz) δ: 14.3, 62.0, 116.6 (d, JC-F = 23.0
Hz, 2C), 122.4 (d, JC-F = 8.7 Hz, 2C), 125.7, 130.2, 136.7, 144.4,
161.2, 162.3 (d, JC-F = 248.4 Hz, 1C) 186.4. Anal. Calcd. for
C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.79; H,
4.41; N, 10.47.
General procedure for the synthesis of ethyl 1-aryl-4-
formyl-1H-pyrazole-3-carboxylates (4a–m). The Vilsmeier–
Haack reagent was prepared by adding of 1.4 mL (15 mmol)
POCl3 to 1.5 mL DMF at 0°C in a round-bottomed flask in
an ice-cold condition (0–5°C) under constant stirring.
Appropriate ethyl 2-(2-arylhydrazinylidene)propanoates 3a–m
(5 mmol) in 5 mL DMF were added to the Vilsmeier–Haack
reagent and stirred for further an hour, and the reaction
mixture was kept on a water bath at 70°C for 4 h. After the
reaction, the mixture was poured into 20 g of crushed ice
Ethyl 1-(3-chlorophenyl)-4-formyl-1H-pyrazole-3-carboxylate
1
(4g). Yield: 0.82 g (59%); mp 94°C. H-NMR (DMSO-d6, 400
MHz) δ: 1.43 (t, J = 7.2, 3H, CH3), 4.44 (q, J = 7.2, 2H, CH2),
7.44 (d, J = 8.4, 1H, Ar-H), 7.55 (t, J = 8.4, 1H, Ar-H), 8.00
(d, J = 8.4, 1H, Ar-H), 8.10 (s, 1H, Ar-H), 9.30 (s, 1H, CHpyr),
10.31 (s, 1H, CHO); 13C-NMR (CDCl3, 50 MHz) δ: 14.3, 62.1,
118.1, 120.8, 125.8, 128.8, 130.1, 130.7, 135.7, 139.4, 144.6,
161.2, 186.3. Anal. Calcd. for C13H11ClN2O3: C, 56.03; H, 3.98;
N, 10.05. Found: C, 55.87; H, 4.09; N, 10.23.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet