LETTER
A Mild Procedure for the Preparation of 3-Aryl-4-formylpyrazoles
2301
covered in pure form from the reaction mixture.16 This
method is characterized by mild reaction conditions, non-
toxic by-products, and easy reaction work-up, making it
ideal for use on both laboratory and large scale.
(16) All solvents and reagents were used as obtained from
1
13
commercial source. Standard H NMR and C NMR were
recorded at 300 and 75.4 MHz from CDCl solutions. All
3
runs were conducted at least in duplicate.
General Preparation of 4-Formylpyrazoles. The
procedure for 1,3-diphenyl-4-formylpyrazole (Table 1, run
1
) is representative for all cases. 2,4,6-Trichloro-[1,3,5]-
Acknowledgment
triazine (1.83 g, 10.0 mmol) was added to DMF (2 mL),
maintained at 25 °C. After the formation of a white solid, the
reaction was monitored (TLC) until complete disappearance
of TCT, then the phenylhydrazone of acetophenone (1.00 g,
The University of Sassari (Fondi ex-60%) has financially supported
this work.
5
.0 mmol) in DMF (15 mL) was added. After the addition,
References
the mixture was stirred at r.t., monitored (TLC) until
completion (16 h). A 15% solution of Na CO (20 mL) was
2
3
(
1) Elguero, J. In Comprehensive Heterocyclic Chemistry, Vol.
added then the organic phase extracted twice with 15 mL of
Et O. The organic layer was dried (Na SO ) and the solvent
5; Katritzky, A., Ed.; Pergamon Press: Oxford, 1984, 277–
2
2
4
282.
evaporated to yield 1,3-diphenyl-4-formylpyrazole that was
(
(
2) Elguero, J. In Comprehensive Heterocyclic Chemistry II,
Vol. 5; Shintai, I., Ed.; Elsevier: Oxford, 1986, 3–75.
recovered without other purifications (1.12 g, 90%): mp
1
1
(
1
1
45 °C. H NMR: d = 10.12 (s, 1 H), 8.55 (s, 1 H), 7.86–7.74
3) Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem. 1966,
1
3
m, 5 H), 7.54–7.44 (m, 5 H) ppm. C NMR: d = 185.5,
58.1, 139.7, 136.5, 129.7, 129.1, 128.5, 127.3, 127.0,
26.5, 118.8, 106.3 ppm.
6, 347.
(
(
4) Wiley, R. H.; Hexner, P. E. Org. Synth. 1951, 31, 43.
5) (a) Falorni, M.; Giacomelli, G.; Spanedda, A. M.
Tetrahedron: Asymmetry 1998, 9, 3039. (b) De Luca, L.;
Falorni, M.; Giacomelli, G.; Porcheddu, A. Tetrahedron
Lett. 1999, 40, 8701. (c) Bishop, B. C.; Brands, K. M. J.;
Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43.
All new compounds were identified through their elemental
analyses and spectroscopic data.
Preparation of 4-(Dimethoxymethyl)-1,3-diphenyl-1H-
pyrazole. To a solution of 1,3-diphenyl-4-formylpyrazole
(
0.50 g, 2.01 mmol) in dry MeOH (20 mL) was added of
(
6) Elguero, J. In Comprehensive Heterocyclic Chemistry, Vol.
NH Cl (0.01 g) and of 0.50 g of molecular sieves (4 Å). The
4
3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
mixture was refluxed under argon atmosphere for 10 h, and
then concentrated in vacuo. The organic residue washed with
H O (20 mL), aq Na CO (20 mL), dried on Na SO , and
Pergamon Press: Oxford, 1996, 1–75.
(7) (a) Almirante, N.; Cerri, A.; Fedrizzi, G.; Marazzi, G.;
Santagostino, M. Tetrahedron Lett. 1998, 39, 3287.
2
2
3
2
4
filtered on Celite. After evaporation of the solvent 4-(di-
(
(
b) Cacchi, S.; Fabrizi, G.; Carangio, A. Synlett 1997, 959.
c) Nunn, A. J.; Rowell, F. J. J. Chem. Soc., Perkin Trans. 1
methoxymethyl)-1,3-diphenyl-1H-pyrazole was recovered
1
(
7
(
1
0.59 g, 100%): H NMR: d = 8.15 (s, 1 H), 7.90 (d, 2 H),
1975, 2435. (d) Kizer, D. E.; Miller, R. B.; Kurth, M. J.
.80 (d, 2 H), 7.47 (t, 4 H), 7.39 (t, 1 H), 7.25 (t, 1 H), 5.61
s, 1 H), 3.38 (s, 6 H) ppm. C NMR: d = 150.7, 139.8,
32.9, 129.3, 129.1, 128.7, 128.4, 128.0, 127.9, 127.6,
27.3, 126.3, 120.2, 118.8, 112.3, 98.3, 52.1 ppm. Anal.
Tetrahedron Lett. 1999, 40, 3535. (e) Jungheim, L. N.
Tetrahedron Lett. 1989, 30, 1889. (f) Grosche, P.; Holtzel,
A.; Walk, T. B.; Trautwein, A. W.; Jung, G. Synthesis 1999,
1
3
1
1
961. (g) Wang, X.-j.; Tan, J.; Grozinger, K.; Betageri, R.;
Kirrane, T.; Proudfoot, J. R. Tetrahedron Lett. 2000, 41,
321.
8) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett.
999, 40, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu,
Calcd for C H N O (294.35): C, 73.45; H, 6.16; N, 9.52.
1
8
18
2
2
Found: C, 73.45; H, 6.12; N, 9.50.
Preparation of 1,3-Diphenyl-1H-pyrazole-4-carboxylic
acid. The reported procedure is representative for all
5
(
1
experiments. An aq 15% solution of NaHCO (15 mL) was
3
A.; Taddei, M. J. Org. Chem. 1999, 64, 8962. (c) Falchi,
A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000,
added to a solution of 1-phenyl-3-p-tolyl-1H-pyrazole-4-
carbaldehyde (0.34 g, 1.3 mmol) in acetone (20 mL), stirred
and maintained at 0 °C, followed by solid NaBr (0.05 g, 0.5
mmol) and TEMPO (0.015 g, 0.1 mmol).
275. (d) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org.
Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.;
Porcheddu, A. Org. Lett. 2001, 3, 1519. (f) De Luca, L.;
Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553.
Trichloroisocyanuric acid (0.58 g, 2.5 mmol) was then
slowly added within 10 min, at 0 °C. After the addition, the
mixture was warmed to r.t., stirred for the required time until
completion, then i-PrOH (1 mL) was added. The mixture
was filtered on Celite, concentrated under vacuum and
treated with 15 mL of a sat. solution of Na CO . The aqueous
(
g) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org.
Chem. 2002, 67, 5152. (h) De Luca, L.; Giacomelli, G.;
Porcheddu, A. J. Org. Chem. 2002, 67, 6272.
(
9) (a) Gold, H. Angew. Chem. 1960, 72, 956. (b) Gupton, J. T.;
Colon, C.; Harrison, C. R.; Lizzi, M. J.; Polk, D. E. J. Org.
Chem. 1980, 45, 4522.
2
3
phase was washed with portions of EtOAc, treated with 1 N
HCl and extracted twice with EtOAc. The organic layer were
dried (Na SO ), and the solvent evaporated to yield 1-
(
(
(
10) Kira, M. A.; Abdel-Rahman, M. O.; Gadalla, K. Z.
2
4
Tetrahedron Lett. 1969, 109.
phenyl-3-p-tolyl-1H-pyrazole-4-carboxylic acid that was
11) Bernard, M.; Hulley, E.; Molenda, H.; Stochla, K.;
Wrzeclono, U. Pharmazie 1986, 41, 56.
12) (a) Rainer, G.; Karüger, U.; Klemm, K. Arzneim.-Forsch.
1
recovered without other purifications (0.35 g, 97%): H
NMR: d = 10.95 (s, 1 H), 8.00 (s, 1 H), 7.62 (d, 2 H) 7.42 (m,
1
3
5
1
H), 7.25 (d, 2 H), 2.40 (s, 3 H) ppm. C NMR: d = 172.0,
1981, 31, 649. (b) Riedel, R. Arzneim.-Forsch. 1981, 31,
47.4, 140.3, 129.8, 129.6, 129.2, 114.1, 21.4 ppm. Anal.
655.
Calcd for C H N O (278.31): C, 73.37; H, 5.07; N, 10.07.
1
7
14
2
2
(
(
(
13) Some of these structures are reported in the commercial page
from Aldrich. See: Aldrichimica Acta 2004, 37, 27.
14) Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J.
Bioorg. Med. Chem. Lett. 2002, 12, 2105.
15) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J.
Org. Chem. 2003, 68, 4999.
Found: C, 73.35; H, 5.12; N, 10.04.
-Phenyl-3-(4-chlorophenyl)-1H-pyrazole-4-carboxylic
1
1
acid: H NMR: d = 11.00 (s, 1 H), 8.10 (s, 1 H), 7.52 (d, 2
1
3
H) 7.43 (d, 2 H), 7.30–7.22 (m, 5 H) ppm. C NMR: d =
70.0, 149.4, 139.7, 134.4, 131.2, 129.6, 129.2, 126.3,
1
Synlett 2004, No. 13, 2299–2302 © Thieme Stuttgart · New York