Regioselective synthesis of multisubstituted pyrazoles via cyclocondensation of β-thioalkyl-α,β-unsaturated ketones with hydrazines

Article abstract of DOI:10.1016/j.tetlet.2011.08.168

Multisubstituted pyrazoles were efficiently synthesized by cyclocondensation of β-thioalkyl-α,β-unsaturated ketones with hydrazines under relatively mild conditions. A one-pot synthetic protocol through tandem Liebeskind-Srogl cross-coupling/cyclocondensation using a-oxo ketene dithioacetals as the starting materials was also realized for the same purpose.

Full text of DOI:10.1016/j.tetlet.2011.08.168

Tetrahedron Letters 52 (2011) 5884–5887
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Regioselective synthesis of multisubstituted pyrazoles via cyclocondensation
of b-thioalkyl-a,b-unsaturated ketones with hydrazines
Weiwei Jin a, Haifeng Yu a,b, Zhengkun Yu a,
⇑
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, China
b Department of Chemistry, Anshan Normal University, Anshan, Liaoning 114007, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Multisubstituted pyrazoles were efficiently synthesized by cyclocondensation of b-thioalkyl-a,b-unsatu-
rated ketones with hydrazines under relatively mild conditions. A one-pot synthetic protocol through
Received 13 July 2011
Revised 29 August 2011
Accepted 30 August 2011
Available online 2 September 2011
tandem Liebeskind–Srogl cross-coupling/cyclocondensation using
starting materials was also realized for the same purpose.
a-oxo ketene dithioacetals as the
Ó 2011 Elsevier Ltd. All rights reserved.
R1
O
Pyrazoles and their derivatives usually possess vital pharmaceu-
tical and biological activities,1 and are also widely used in coordina-
tion and materials chemistry.2 Versatile synthetic routes have been
developed for the synthesis of pyrazoles, including cyclocondensa-
tion of 1,3-diketones and related derivatives with hydrazines,3
1,3-dipolar cycloaddition of diazo compounds with alkynes and al-
kyne equivalents,4 and other procedures.5 However, it remains a
challenge to reach sufficient regioselectivity for the target pyrazoles
in a synthetic task. Recently, Junjappa and co-workers reported the
synthesis of substituted 1-aryl-5(or 3)-N-(cycloamino) pyrazoles by
condensation of N,S-acetal precursors with unsymmetrical phen-
ylhydrazines in a regiocontrolled fashion.3a Kimpe and co-workers
documented the preparation of fluorinated pyrazoles with rela-
R1
R2
R2
R3NHNH2
+
N
ð1Þ
N
R3
SEt
1
2
3
The reactions of b-thioalkyl-a,b-unsaturated ketones (1) with
hydrazines (2) were carried out in the presence of t-BuOK or HOAc
in refluxing t-BuOH, efficiently affording multisubstituted pyra-
zoles (Table 1). When R1 was methyl, the reactions of 1a–g with
phenylhydrazine (2a) underwent under the basic conditions (con-
dition A), forming 1,3,5-trisubstituted pyrazoles 3a–g in 76–92%
yields (entries 1–7). Methoxy, tert-butyl, chloro, and fluoro groups
on R2 substituents, that is, b-aryls in 1, can be tolerated during the
reaction. Diene 1g reacted with 2a to give rare 3-styryl-pyrazole 3g
(83%, entry 7). Altering R1 to aryls and heteroaryls, the cyclocon-
densation reactions of 1h–l with phenylhydrazine were also effi-
ciently carried out under condition A, forming the desired
products 3h–l in 78–95% yields (entries 8–12). Under slightly
acidic conditions (condition B), the reactions of 1a with benzylhy-
drazine (2b) and 2-hydrazinopyridine (2c) produced the target
N-benzyl and 2-pyridyl trisubstituted pyrazoles 3m and 3n in
96% and 75% yields, respectively, (entries 13–14). In order to obtain
N-unprotected multisubstituted pyrazoles, hydrazine hydrate (2d)
tively poor regioselectivity by means of a similar strategy.3c
A
new access to 3,4-disubstituted pyrazoles from FeCl3-catalyzed
aminolysis of b-carbonyl-1,3-dithianes with hydrazine hydrate
has also been developed.3d Very recently, our group realized an effi-
cient palladium(0)-catalyzed, Cu(I)-mediated regio- and stereose-
lective approach to b-thioalkyl-a,b-unsaturated ketones via oxo
directing Liebeskind–Srogl cross-coupling reactions of
a-oxo ke-
tene dithioacetals with aryl or alkenylboronic acids.6 With their
determined molecular structures in hand, we envisioned that b-thi-
oalkyl-a,b-unsaturated ketones may be viewed as the equivalents
of 1,3-diketones.
As part of our ongoing work on the development of pyrazole-
was used to react with b-thioalkyl-a,b-unsaturated ketones (1).
based NNN ligands7 and transformation of
a-oxo ketene dithio-
Thus, N-unprotected 3,5-disubstituted pyrazoles 3o–r were ob-
tained in 80–95% yields (entries 15–18). Notably, the (E)/(Z)-con-
figurations of 1 did not affect the formation of pyrazoles 3, and
the synthetic methodology was exclusively regioselective to afford
N-protected 1,3,5-trisubstituted or 1H-3,5-disubstituted pyrazoles,
forming no tautomers of the desired products 3, that is, 30. As com-
pared to 1,3-diketones, the different electrophilicity of ethylthio
from that of carbonyl toward hydrazines may facilitate such regio-
selective reactions of 1 with 2. It is proposed that the more acidic
acetals,8 herein we report an efficient synthetic protocol to
regioselectively multisubstituted pyrazoles by cyclocondensation
of b-thioalkyl-a
,b-unsaturated ketones6 with hydrazines
(Eq. (1)).
⇑
Corresponding author. Tel./fax: +86 411 8437 9227.
E-mail address: zkyu@dicp.ac.cn (Z. Yu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.168

W. Jin et al. / Tetrahedron Letters 52 (2011) 5884–5887
5885
Table 1
Synthesis of pyrazoles (3)a,b
1
1
O
R
R
3
1
2
t-BuOK or AcOH
R
R
2
2
3
R
R
+
R NHNH
2
N
N
t-BuOH/reflux
N
R
N
R
SEt
3
1
2
3
3', not detected
Entry
1
1
R4NHNH2
Conditions
Product
Yieldb (%)
O
Me
Me
Ph
Ph
N
N
PhNHNH2 (2a)
A
A
87
87
SEt
Ph
1a
OMe
3a
Me
N
OMe
O
O
O
N
Ph
2
3
4
2a
2a
2a
Me
Me
Me
Me
3b
SEt
SEt
SEt
1b
tBu
Me
N
tBu
N
Ph
A
A
92
85
3c
1c
Cl
Me
N
Cl
N
Ph
3d
1d
F
F
Me
N
F
O
F
5
6
2a
2a
A
A
82
76
N
Ph
3e
SEt
1e
Me
N
O
O
Me
Me
N
Ph
3f
SEt
SEt
1f
Ph
Me
N
Ph
7
8
2a
2a
A
A
83
92
N
Ph
1g
3g
O
Ph
N
Ph
Ph
Ph
N
SEt
1h
Ph
3h
Cl
MeO
O
9
2a
2a
A
A
79
95
MeO
Cl
Cl
N
N
SEt
Cl
Ph
1i
3i
Cl
O
10
Cl
N
N
Ph
SEt
1j
3j
(continued on next page)

5886
W. Jin et al. / Tetrahedron Letters 52 (2011) 5884–5887
Table 1 (continued)
Entry
11
1
R4NHNH2
Conditions
Product
Yieldb (%)
Cl
Cl
O
O
O
Cl
2a
A
78
N
N
O
S
Ph
3k
3l
SEt
SEt
1k
1l
S
Cl
12
13
14
2a
A
B
B
88
96
75
N
N
Ph
Me
Ph
N
N
1a
1a
PhCH2NHNH2 (2b)
2-C5H4NNHNH2 (2c)
Ph
3m
Me
Ph
N
N
N
N
3n
F
F
Me
Ph
O
F
15
NH2NH2H2O (2d)
B
80
Me
N
H
F
3o
SEt
1m
Ph
16
17
1h
2d
2d
B
B
91
83
N
N
H
3p
O
O
Ph
O
S
O
Ph
SEt
N
1n
1o
N
H
3q
3r
Ph
S
18
2d
B
95
Ph
N
SEt
N
H
a
Condition (A): 1 (0.5 mmol), 2 (0.6 mmol), t-BuOK (1.0 mmol), t-BuOH (5 mL), reflux, 7–16 h. Condition (B): 1 (0.3 mmol), 2 (0.45 mmol), AcOH (18
reflux, 5–9 h.
l
L), t-BuOH (3 mL),
b
Isolated yields.
N–H in 2 undergoes nucleophilic substitution with 1 to form an
2
1
R B(OH)
PhNHNH
(1.2 equiv)
2
intermediate hydrazino-a,b-unsaturated ketone which is then
R
2
O
dehydrated to give the pyrazole product.3a
1
1
(1.5 equiv)
2
R
SEt
SEt
R
N
N
Finally, a one-pot, two-step three-component tandem reactions
via Liebeskind–Srogl cross-coupling9/cyclocondensation sequence
starting from 411 was developed to prepare highly functionalized
pyrazoles (Scheme 1). After the first step Liebeskind–Srogl cross-
coupling reaction was completed by TLC monitoring, all the vola-
tiles were pumped off under reduced pressure, and then t-BuOK
base and a new solvent t-BuOH were added to initiate the next step
transformation. Thus, trisubstituted pyrazoles 3b, 3h, and 3j–l
were efficiently generated in 77–89% yields. Although a one-step
condensation of symmetrical 1,3-diketones with hydrazines has
been extensively applied for the synthesis of 3,5-disubstituted pyr-
azoles, unsymmetrical and functionalized 1,3-diketones are not
readily available that no ready access has been developed for the
preparation of multisubstituted pyrazoles. To the best of our
knowledge, the present protocol has demonstrated an efficient reg-
ioselective route to highly functionalized pyrazoles.
condition (a)
condition (b)
Ph
2
R
=: Me (4a)
Ph (4b)
R
=: 4-MeOC H (5a)
3b, 80%
3h, 85%
3j, 89%
3k, 78%
3l, 77%
6
4
Ph (5b)
4-ClC H (5c)
4-ClC H (4c)
6
4
6 4
2-furyl (4d)
2-thienyl (4e)
4-ClC H (5c)
6 4
4-ClC H (5c)
6 4
Scheme 1. One-pot synthesis of pyrazoles via Liebeskind–Srogl cross-coupling/
cyclocondensation reactions. Reagents and conditions: (a) (0.50 mmol),
(0.75 mmol), Pd(PPh3)4 (7.5 mol %), copper(I) thiophene-2-carboxylate (CuTC10
1.0 mmol), Cs2CO3 (1.0 mmol), THF (5 mL), 50 °C, 2 h; (b) t-BuOK (1.0 mmol),
t-BuOH (5 mL), reflux, 9–16 h.
4
5
,
In summary, an efficient regioselective synthetic route to multi-
substituted pyrazoles has been developed by cyclocondensation of

W. Jin et al. / Tetrahedron Letters 52 (2011) 5884–5887
5887
b-thioalkyl-a
,b-unsaturated ketones with hydrazines.12–14 The
present methodology has exhibited exclusive regioselectivity for
the target products, generating no pyrazole tautomers. The
one-pot synthetic procedure via tandem Liebeskind–Srogl cross-
J.; Deng, H. X.; Dong, J. H.; Chen, J. Z.; Wang, H. M.; Pei, C. X. J. Organomet. Chem.
2007, 692, 2306; (e) Zeng, F. L.; Yu, Z. K. Organometallics 2008, 27, 2898; (f)
Zeng, F. L.; Yu, Z. K. Organometallics 2008, 27, 6025; (g) Tan, W. Q.; Yu, Z. K.; He,
W.; Wang, L. D.; Sun, J.; Chen, J. Z. Organometallics 2008, 27, 4833; (h) Zeng, F.
L.; Yu, Z. K. Organometallics 2009, 28, 1855.
8. (a) Yu, H. F.; Jin, W. W.; Sun, C. L.; Chen, J. P.; Du, W. M.; He, S. B.; Yu, Z. K.
Angew. Chem., Int. Ed. 2010, 49, 5792; (b) Yu, H. F.; Yu, Z. K. Angew. Chem., Int. Ed.
2009, 48, 2929.
coupling/cyclocondensation sequence using
a-oxo ketene dithio-
acetals as the starting materials has also shown promising
9. Liebeskind, L. S.; Yang, H.; Li, H. Angew. Chem., Int. Ed. 2009, 48, 1417.
10. Zhang, S. J.; Zhang, D. W.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312.
11. Fu, Z. Q.; Wang, M.; Ma, Y. H.; Liu, Q.; Liu, J. J. Org. Chem. 2008, 73, 7625.
12. A general synthetic procedure—synthesis of 5-(4-tert-butylphenyl)-3-methyl-
1-phenyl-1H-pyrazole (3c): A mixture of 1c (131 mg, 0.5 mmol), PhNHNH2
(2a) (65 mg, 0.6 mmol), t-BuOK (112 mg, 1.0 mmol) in 5 mL t-BuOH was
refluxed for 9 h. After cooled to ambient temperature, the resulting mixture
was filtered through a short pad of celite and rinsed with 10 mL CH2Cl2. The
combined filtrate was evaporated all the volatiles under reduced pressure. The
resultant residue was purified by silica gel column chromatography (eluent:
potentials in the preparation of highly functionalized pyrazoles.
Acknowledgments
We are grateful to the National Basic Research Program of China
(2009CB825300), Natural Science Foundation of Liaoning Province
(20102225) and the Innovation Program of Chinese Academy of
Sciences (DICP K2009D04) for support of this research.
petroleum ether (60–90 °C)/EtOAc = 20:1, v/v), affording 3c as
a yellow
crystalline solid (134 mg, 92% yield). Mp: 54–56 °C. 1H NMR (CDCl3, 23 °C,
400 MHz): d 7.30 (m) and 7.14 (d, J = 8.0 Hz) (7:2 H, aromatic CH), 6.29 (s, 1 H,
pyrazolyl CH), 2.38 (s, 3 H, CH3C@N), 1.30 (s, 9 H, tBu); 13C{1H} NMR (CDCl3,
23 °C, 100 MHz): d 151.3 (Cq, C@N), 149.5 (Cq, C–N), 143.9, 140.5 and 127.9 (Cq
each), 128.9, 128.3, 127.1, 125.4 and 125.3 (aromatic CH), 107.7 (pyrazolyl CH),
34.8 (Cq, C(CH3)3), 31.4 (C(CH3)3), 13.7 (CH3C@N). HRMS cacld for C20H22N2:
290.1783; Found: 290.1783.
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.168.
13. A general synthetic procedure—synthesis of 5-(3,5-difluorophenyl)-3-methyl-
1H-pyrazole (3o): A mixture of 1m (58 mg, 0.3 mmol), 80% NH2NH2ꢀH2O (2d)
References and notes
(28 mg, 0.45 mmol), AcOH (18 lL) in 3 mL t-BuOH was refluxed for 5 h. After
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cooled to ambient temperature, the resulting mixture was evaporated all the
volatiles under reduced pressure. The resultant residue was purified by silica
gel column chromatography (eluent: petroleum ether (60–90 °C)/EtOAc = 20:1,
v/v), affording 3o as a yellow crystalline solid (46 mg, 80% yield). Mp: 123–
125 °C. 1H NMR (CDCl3, 23 °C, 400 MHz): d 7.61 and 7.27 (d each, J = 1.7 and
1.6 Hz, 2:1 H, aromatic CH), 6.33 (s, 1 H, pyrazolyl CH), 2.32 (s, 3 H, CH3);
13C{1H} NMR (CDCl3, 23 °C, 100 MHz): d 149.2 (Cq, C@N), 141.9 (Cq, C–N),
136.2 (Cq, i-C of C6H3F2), 135.4 (Cq, C–F), 127.6 and 124.2 (aromatic CH), 102.6
(pyrazolyl CH), 11.3 (CH3). HRMS cacld for C10H8N2F2 [Mꢁ1]: 193.0577; Found:
193.0358.
14. A general procedure for one-pot synthesis of pyrazoles—synthesis of 5-(4-
methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole (3b): Under nitrogen
atmosphere a mixture of
a-oxo ketene dithioacetal (4a) (95 mg, 0.50 mmol),
arylboronic acid 5a (114 mg, 0.75 mmol), Pd(PPh3)4 (43 mg, 0.0375 mmol),
CuTC (191 mg, 1.0 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in 5 mL THF was
stirred at 50 °C for 2 h. All the volatiles were pumped off under reduced
pressure, and then hydrazine PhNHNH2 (2a) (65 mg, 0.6 mmol), t-BuOK
(112 mg, 1.0 mmol) and t-BuOH (5 mL) were added and the mixture was
further stirred under refluxing conditions for 12 h. After cooled to ambient
temperature, the resulting mixture was filtered through a short pad of celite
and rinsed with 10 mL CH2Cl2. The combined filtrate was evaporated all the
volatiles under reduced pressure. The resultant residue was purified by silica
gel column chromatography (eluent: petroleum ether (60–90 °C)/EtOAc = 20:1,
v/v), affording 3b as a yellow crystalline solid (106 mg, 80% yield). All the new
products were characyerized by NMR and HRMS determinations. The known
compounds 3a, 3b, and 3h,15a 3d,15b 3i and 3j,15c 3l,15d 3m,15e 3n,15f 3p–r3h
were identified by comparison of their NMR features with those of the
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