Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis-Hillman adducts

Article abstract of DOI:10.1016/S0040-4039(03)01648-4

Tetrasubstituted pyrazole derivatives 3a-j were synthesized regioselectively in good yields from the reaction of Baylis-Hillman adducts 1a-f and hydrazine hydrochlorides 2a-d in 1,2-dichloroethane.

Full text of DOI:10.1016/S0040-4039(03)01648-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6737–6740
Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from
Baylis–Hillman adducts
Ka Young Lee, Jeong Mi Kim and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, South Korea
Received 7 May 2003; revised 4 June 2003; accepted 27 June 2003
Abstract—Tetrasubstituted pyrazole derivatives 3a–j were synthesized regioselectively in good yields from the reaction of
Baylis–Hillman adducts 1a–f and hydrazine hydrochlorides 2a–d in 1,2-dichloroethane.
© 2003 Elsevier Ltd. All rights reserved.
The pyrazole moiety is present in a wide variety of
biologically active compounds.1–4 Numerous com-
pounds containing pyrazole moiety have been shown to
exhibit antihyperglycemic, analgesic, anti-inflammatory,
antipyretic, antibacterial, hypoglycemic, sedative-hyp-
notic activity.1–4 Thus, continuous efforts have been
devoted to the development of more general and ver-
satile synthetic methodologies to this class of com-
pounds.1–4 Usually they can be prepared from the
reaction of hydrazines and 1,3-dicarbonyls.1 However,
the appealing generality of this method is somewhat
vitiated by the severe reaction conditions or the multi-
step sequence usually required to access the starting
materials.2
these respects, we intended to develop an efficient syn-
thetic method for pyrazole derivatives from Baylis–Hill-
man adducts. The reaction of the Baylis–Hillman
adduct and phenylhydrazine would afford 3,4-dimethyl-
1,5-diphenylpyrazole via the successive hydrazone for-
mation, cyclization, and double bond isomerization
sequence (Scheme 1).
Initially, we examined the reaction of 1a and free
phenylhydrazine in 1,2-dichloroethane or methanol.
However, the reaction was found to be very complex
and we could not obtain any pyrazole derivatives in
appreciable yields. Instead, intractable complex mix-
tures were observed on TLC. After many trials we
finally find out an efficient condition for the synthesis
of 3,4-dimethyl-1,5-diphenylpyrazole (3a) in good yield.
The reaction of the Baylis–Hillman alcohol 1a and
phenylhydrazine hydrochloride (2a) in dichloroethane
afforded the desired compound 3a in 89% yield after
heating the reaction mixture at 50–60°C for 6 h. When
the reaction was carried out with phenylhydrazine
hydrochloride in other solvent such as methanol or
aqueous ethanol showed complex mixtures also. Use of
acetonitrile in the reaction gave somewhat lower yield
(65%) of 3a. Some representative results are summa-
rized in Table 1.7
1,5-Diarylpyrazole derivatives are important in medici-
nal and pesticidal chemistry.3–5 Recently, it was known
that some 1,5-diarylpyrazole derivatives showed nonnu-
cleoside HIV-1 reverse transcriptase inhibitory activi-
ties.3a Extensive studies have been devoted to the
1,5-diarylpyrazole derivatives including Celecoxib, the
famous cyclooxygenase-2 inhibitor.5 For the synthesis
of these compounds, appropriately substituted 1,3-
dicarbonyl compounds were needed. However, the syn-
thesis of these starting materials must suffer from
multi-step synthesis and low yields of products as men-
tioned above.
We are recently interested in the synthesis of aromatic
and heteroaromatic compounds from Baylis–Hillman
adducts, which included quinolines or naphthalenes.6 In
* Corresponding author. Fax: 82-62-530-3389; e-mail: kimjn@
chonnam.chonnam.ac.kr
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01648-4

6738
K. Y. Lee et al. / Tetrahedron Letters 44 (2003) 6737–6740
Table 1. Synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives 3
The starting Baylis–Hillman alcohols 1a–f were pre-
pared from the reaction of aldehydes and activated
alkenes as previously reported.6 We used four
hydrazines: phenylhydrazine hydrochloride (2a), tert-
butylhydrazine hydrochloride (2b), 2,4-dinitrophenyl-
hydrazine (2c), and 2,4-difluorophenylhydrazine
hydrochloride (2d). For the reaction with 2,4-dinitro-
phenylhydrazine, we used p-toluenesulfonic acid as
the acid catalyst. The formation of pyrazole 3a could
be explained as shown in Scheme 2: Conversion of
Baylis–Hillman adduct 1a into the corresponding
hydrazone derivative (I), acid-catalyzed cyclization to
(II), and subsequent 1,3-hydrogen transfer gave the
pyrazole 3a.

K. Y. Lee et al. / Tetrahedron Letters 44 (2003) 6737–6740
6739
Scheme 2.
Scheme 3.
As shown in Table 1, we could synthesize the pyrazoles
3h–j fused to cyclopentane or cyclohexane rings. Simi-
lar compounds were prepared previously as the minor
products by adopting the classical cyclocondensation
procedure from 1,3-dicarbonyl compounds as the start-
ing materials.4 The synthesis of 3a could also be carried
out in 75% yield from the reaction of cinnamyl chloride
derivative 4, which was synthesized from 1a by the
reported procedure.8 We could not obtain the benzyl
substituted pyrazole derivative 5 from the reaction
(Scheme 3).
3. (a) Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.;
Swaney, S. M.; Tarpley, W. G.; Yagi, Y.; Romero, D. L.
J. Med. Chem. 2000, 43, 1034; (b) Stauffer, S. R.; Coletta,
C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2000, 43, 4934; (c) Huang, Y. R.; Katzenellenbo-
gen, J. A. Org. Lett. 2000, 2, 2833; (d) Kees, K. L.;
Fitzgerald, J. J.; Steiner, K. E.; Mattes, J. F.; Mihan, B.;
Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem.
1996, 39, 3920; (e) Bauer, V. J.; Dalalian, H. P.; Fanshawe,
W. J.; Safir, S. R.; Tocus, E. C.; Boshart, C. R. J. Med.
Chem. 1968, 11, 981.
In conclusion, we prepared some pyrazole derivatives
regioselectively in good yields from the Baylis–Hillman
adducts. The biological activities of the prepared com-
pounds are currently under investigation including their
herbicidal and fungicidal activities and will be reported
in due course.
4. Lyga, J. W.; Patera, R. M.; Plummer, M. J.; Halling, B.
P.; Yuhas, D. A. Pestic. Sci. 1994, 42, 29.
5. (a) Hashimoto, H.; Imamura, K.; Haruta, J.-i.; Wakitani,
K. J. Med. Chem. 2002, 45, 1511; (b) Palomer, A.; Cabre,
F.; Pascual, J.; Campos, J.; Trujillo, M. A.; Entrena, A.;
Gallo, M. A.; Garcia, L.; Mauleon, D.; Espinosa, A. J.
Med. Chem. 2002, 45, 1402; (c) Desiraju, G. R.; Gopalakr-
ishnan, B.; Jetti, R. K. R.; Nagaraju, A.; Raveendra, D.;
Sarma, J. A. R. P.; Sobhia, M. E.; Thilagavathi, R. J.
Med. Chem. 2002, 45, 4847; (d) Habeeb, A. G.; Rao, P. N.
P.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039; (e) Price,
M. L. P.; Jorgensen, W. L. J. Am. Chem. Soc. 2000, 122,
9455; (f) Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.;
Carter, J. S.; Graneto, M. J.; Kellogg, M. S.; Koboldt, C.
M.; Yuan, J.; Zhang, Y. Y.; Seibert, K. J. Med. Chem.
2000, 43, 1661; (g) Penning, T. D.; Talley, J. J.; Berten-
shaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J.
M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997,
40, 1347.
Acknowledgements
This work was supported by the grant (R05-2003-000-
10042-0) from the Basic Research Program of the
Korea Science & Engineering Foundation.
References
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2002, 43, 6597; (b) Kim, J. N.; Chung, Y. M.; Im, Y. J.
Tetrahedron Lett. 2002, 43, 6209; (c) Im, Y. J.; Lee, K. Y.;
Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2002, 43, 4675;
(d) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H. Synlett
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6740
K. Y. Lee et al. / Tetrahedron Letters 44 (2003) 6737–6740
2001, 42, 9023; (g) Kim, J. N.; Kim, H. S.; Gong, J. H.;
CDCl3) l 1.26 (t, J=7.5 Hz, 3H), 1.40 (s, 9H), 1.68 (s,
3H), 2.63 (q, J=7.5 Hz, 2H), 7.24–7.28 (m, 2H), 7.38–7.40
(m, 3H); 13C NMR (75 MHz, CDCl3) l 8.06, 13.76, 20.31,
31.13, 60.16, 113.86, 127.95, 127.99, 130.87, 134.65, 140.74,
149.29; Anal. calcd for C16H22N2: C, 79.29; H, 9.15; N,
11.56. Found: C, 79.46; H, 9.10; N, 11.53. 3f: oil; 1H
NMR (300 MHz, CDCl3) l 2.02 (s, 3H), 2.32 (s, 3H),
7.07–7.32 (m, 9H); 13C NMR (75 MHz, CDCl3) l 8.54,
11.92, 114.83, 124.54, 126.58, 128.68, 128.74, 129.41,
130.95, 133.91, 138.94, 139.93, 148.79; Anal. calcd for
C17H15ClN2: C, 72.21; H, 5.35; N, 9.91. Found: C, 72.31;
Chung, Y. M. Tetrahedron Lett. 2001, 42, 8341; (h) Kim,
J. N.; Im, Y. J.; Gong, J. H.; Lee, K. Y. Tetrahedron Lett.
2001, 42, 4195; (i) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim,
H. S. Tetrahedron Lett. 2001, 42, 3737; (j) Kim, H. S.;
Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J.
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further references cited therein.
7. Synthesis of 3,4-dimethyl-1,5-diphenylpyrazole (3a) is typi-
cal. A stirred mixture of 1a (100 mg, 0.57 mmol) and
phenylhydrazine hydrochloride (2a, 83 mg, 0.57 mmol) in
1,2-dichloroethane (4 mL) was heated to 50–60°C for 6 h.
The reaction mixture was diluted with methylene chloride
and washed with water. After removal of solvent and flash
chromatography (hexane/ether, 10:1), desired 3a was
obtained, 126 mg (89%). Some selected spectroscopic data
of prepared pyrazoles is as follows. 3a:3a oil; 1H NMR
(300 MHz, CDCl3) l 2.03 (s, 3H), 2.33 (s, 3H), 7.12–7.35
(m, 10H); 13C NMR (75 MHz, CDCl3) l 8.51, 11.93,
114.56, 124.41, 126.25, 127.77, 128.29, 128.53, 129.65,
130.91, 140.09, 140.12, 148.61; Mass (70 eV) m/z (rel.
intensity) 77 (23), 144 (12), 206 (17), 232 (8), 247 (84), 248
1
H, 5.43; N, 9.92. 3g: oil; H NMR (300 MHz, CDCl3) l
0.81 (t, J=6.9 Hz, 3H), 1.17–1.23 (m, 4H), 1.39–1.44 (m,
2H), 1.99 (s, 3H), 2.24 (s, 3H), 2.59 (t, J=7.8 Hz, 2H),
7.31–7.46 (m, 5H); 13C NMR (75 MHz, CDCl3) l 8.21,
11.84, 13.83, 22.13, 24.51, 28.54, 31.33, 112.59, 125.40,
127.30, 128.92, 140.38, 140.86, 147.92; Anal. calcd for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.24;
1
H, 9.31; N, 11.52. 3h:2c oil; H NMR (300 MHz, CDCl3)
l 1.74–1.94 (m, 4H), 2.60 (t, J=6.3 Hz, 2H), 2.82 (t,
J=6.3 Hz, 2H), 7.16–7.31 (m, 10H); 13C NMR (75 MHz,
CDCl3) l 21.44, 23.30, 23.49, 23.50, 116.80, 124.74,
126.53, 127.68, 128.34, 128.68, 129.18, 130.80, 138.39,
140.36, 150.29; Mass (70 eV) m/z (rel intensity) 77 (25),
246 (44), 273 (42), 274 (M+, 100). 3i: oil; 1H NMR (300
MHz, CDCl3) l 1.76–1.94 (m, 4H), 2.62 (t, J=6.3 Hz,
2H), 2.80 (t, J=6.3 Hz, 2H), 6.75–6.92 (m, 2H), 7.13–7.16
(m, 2H), 7.24–7.44 (m, 4H); 13C NMR (75 MHz, CDCl3)
l 21.45, 23.15, 23.42, 23.50, 104.49, 104.81, 105.15, 111.45,
111.50, 111.75, 111.80, 115.94, 127.88, 128.37, 129.77,
129.89, 130.12, 140.33, 151.13, 154.99, 155.16, 158.37,
158.53, 160.22, 160.37, 163.54, 163.69; Anal. calcd for
C19H16F2N2: C, 73.53; H, 5.20; N, 9.03. Found: C, 73.70;
H, 5.17; N, 9.26. 3j: oil; 1H NMR (300 MHz, CDCl3) l
2.45–2.54 (m, 2H), 2.77–2.87 (m, 4H), 7.18–7.40 (m, 10H);
13C NMR (125 MHz, CDCl3) l 23.78, 24.79, 29.93,
125.10, 126.76, 126.80, 127.62, 128.41, 128.53, 128.82,
130.97, 136.24, 140.91, 162.28; Mass (70 eV) m/z (rel.
intensity) 77 (26), 259 (72), 260 (M+, 100); Anal. calcd for
C18H16N2: C, 83.04; H, 6.19; N, 10.76. Found: C, 83.19;
H, 6.07; N, 10.92.
1
(M+, 100). 3b: white solid, mp 102–103°C; H NMR (300
MHz, CDCl3) l 1.40 (s, 9H), 1.66 (s, 3H), 2.23 (s, 3H),
7.24–7.27 (m, 2H), 7.38–7.40 (m, 3H); 13C NMR (75 MHz,
CDCl3) l 8.08, 11.94, 31.15, 60.16, 114.76, 127.99, 128.06,
130.79, 134.55, 140.77, 143.97; Mass (70 eV) m/z (rel.
intensity) 130 (19), 171 (70), 172 (100), 213 (23), 228 (M+,
29); Anal. calcd for C15H20N2: C, 78.90; H, 8.83; N, 12.27.
Found: C, 78.82; H, 8.94; N, 12.22. 3c:9 yellow solid, mp
184–185°C; 1H NMR (300 MHz, CDCl3) l 2.06 (s, 3H),
2.30 (s, 3H), 7.15–7.19 (m, 2H), 7.29 (d, J=8.7 Hz, 1H),
7.35–7.40 (m, 3H), 8.26 (dd, J=8.7 and 2.7 Hz, 1H), 8.62
(d, J=2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) l 8.53,
12.13, 117.03, 120.80, 126.86, 128.92, 128.96, 129.03,
129.07, 129.58, 138.33, 141.31, 144.75, 145.17, 152.52. 3d:
oil; 1H NMR (300 MHz, CDCl3) l 1.33 (t, J=7.5 Hz, 3H),
2.05 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 7.13–7.34 (m, 10H);
13C NMR (75 MHz, CDCl3) l 8.49, 13.47, 20.22, 113.90,
124.54, 126.26, 127.80, 128.32, 128.58, 129.80, 131.04,
140.25, 140.26, 153.92; Anal. calcd for C17H14N4O4: C,
60.35; H, 4.17; N, 16.56. Found: C, 60.50; H, 4.26; N,
8. Basavaiah, D.; Hyma, R. S.; Padmaja, K.; Krishna-
macharyulu, M. Tetrahedron 1999, 55, 6971.
9. Elguero, J.; Jacquier, R. Bull. Soc. Chim. Fr. 1966, 2832.
1
16.48. 3e: white solid, mp 53–54°C; H NMR (300 MHz,