Zinc-catalyzed synthesis of pyrazolines and pyrazoles via hydrohydrazination

Article abstract of DOI:10.1021/ol800592s

(Chemical Equation Presented) A novel regioselective synthesis of aryl-substituted pyrazolines and pyrazoles has been developed. Substituted phenylhydrazines react with 3-butynol in the presence of a catalytic amount of zinc triflate to give pyrazoline derivatives. The resulting products are easily oxidized in a one-pot procedure to the corresponding pyrazoles.

Full text of DOI:10.1021/ol800592s

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2377-2379
Zinc-Catalyzed Synthesis of Pyrazolines
and Pyrazoles via Hydrohydrazination
Karolin Alex, Annegret Tillack, Nicolle Schwarz, and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V., UniVersita¨t Rostock, Albert-Einstein-Str. 29a,
18059 Rostock, Germany
matthias.beller@catalysis.de
Received March 14, 2008
ABSTRACT
A novel regioselective synthesis of aryl-substituted pyrazolines and pyrazoles has been developed. Substituted phenylhydrazines react with
3-butynol in the presence of a catalytic amount of zinc triflate to give pyrazoline derivatives. The resulting products are easily oxidized in a
one-pot procedure to the corresponding pyrazoles.
Pyrazoline and pyrazole derivatives play an important role in
the pharmaceutical and agrochemical industries. For example,
pyrazolines have been reported to show a wide range of
biological activity, including antidepressant, anticancer, and
antibacterial activity.1 On the other hand, the pyrazole motif is
found in blockbuster drugs such as celecobix (Celebrex),2
sildenafil (Viagra),3 and rimonabant (Acomplia).4
reaction often results in a mixture of regioisomers. Notably,
the use of R,ꢀ-unsaturated ketones with hydrazines presents
a modification of the common method, wherein pyrazole and
pyrazoline derivatives can be synthesized with high regio-
selectivity.6 In addition, several other methods have also been
reported for the preparation of pyrazoles.7
In recent years, catalytic processes have also become of
interest. In this regard, Buchwald et al. demonstrated an
elegant copper-catalyzed domino coupling/hydroamidation
reaction,8 and Mori et al. developed an efficient palladium-
catalyzed four-component coupling9 for the synthesis of
pyrazoles.
In general, pyrazoles are obtained by condensation of 1,3-
diketones with hydrazine derivatives.5 Unfortunately, this
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10.1021/ol800592s CCC: $40.75
Published on Web 05/27/2008
2008 American Chemical Society

Over the past years, we investigated catalytic reactions of
arylhydrazines with alkynes in more detail.10 Most recently,
we succeeded in an intermolecular zinc-mediated and
-catalyzed hydrohydrazination reaction of alkynes, which
allows a general synthesis of substituted indoles.11 Following
these investigations, we discovered that the reaction of
phenylhydrazine 1a with 3-butynol 2 in the presence of a
stochiometric amount of zinc chloride did not result in the
expected indole motif. Instead, the formation of the pyra-
zoline 3a occurred via hydrohydrazination of the alkyne and
condensation reaction (Scheme 1).
Table 1. Reaction of Phenylhydrazine 1a with 3-Butynol 2
under Different Conditionsa
entry catalyst solvent T (°C) time (h) convb (%) yieldb (%)
1
2
3
4
5
6
7
8
9
ZnCl2
Zn(OAc)2 THF
Zn(OTf)2 THF
Zn(OTf)2 dioxane 100
Zn(OTf)2 toluene 100
THF
100
100
100
24
24
24
24
24
24
24
9
67 (100c) 36 (93c)
26
12
98
57
96
62
93
76
94
85
100
63
100
64
Zn(OTf)2 THF
Zn(OTf)2 THF
Zn(OTf)2 THF
Zn(OTf)2 THF
80
120
100
100
100
100
85
16
24
94
91
10d Zn(OTf)2 THF
Scheme 1. Synthesis of Pyrazoline 3a
a Reaction conditions: 3-butynol (1.0 mmol), phenylhydrazine (1.3
mmol), 5 mol % of catalyst, solvent (2 mL). b Yield is determined by GC
analysis with dodecane as internal standard. c 100 mol % of catalyst.
d Phenylhydrazine (1.0 mmol).
sion and yield (Table 1, entry 2). To our delight applying 5
mol % Zn(OTf)2 an excellent product yield (98%) was
observed (Table 1, entry 3). Dioxane gave a somewhat lower
yield compared to tetrahydrofuran and toluene as solvent
(Table 1, entries 4 and 5). Also in the presence of a
stoichiometric amount of phenylhydrazine a high product
yield was obtained (Table 1, entry 10).
Next, we studied reactions of 3-butynol 2 with various
substituted arylhydrazines 1a-k under optimized conditions
in the presence of 5 mol % Zn(OTf)2. In general, hydrohy-
drazination and condensation reactions proceeded smoothly,
and it was possible to isolate the pyrazoline derivatives 3a-k
in good to excellent yields (Table 2).
For example, reaction of p-tolylhydrazine (1b) proceeded
in 96% yield, while the more sterical hindered o-tolylhy-
drazine (1c) gave a lower yield of 88% (Table 2, entry 3).
A similar effect was observed for the reaction of the
p-chlorophenylhydrazine, which led to pyrazoline 3d in 98%
yield compared to the o-chlorophenyl-substituted pyrazoline
3e (52% yield) (Table 2, entries 4 and 5).
In addition, bromo-, cyano-, methylsulfonyl-, and isopro-
pylphenyl-substituted pyrazolines were synthesized in up to
99% yield (Table 2, entries 6-9). Dichloro-substituted
phenylhydrazines in para and meta positions gave the
corresponding pyrazolines 3j and 3k in 98% and 97% yields,
respectively.
In agreement with previous studies the aryl-substituted
pyrazolines were easily oxidized to the corresponding
pyrazoles. Due to the ease of reaction conditions and
environmental advantages we applied air as oxidant.12,13 As
shown in Scheme 2 after successful formation of the
pyrazolines, we added acetic acid to the reaction mixture
and heated the reaction mixture for additional 24-72 h in
air. The reaction time depended largely on the substituent
on the aryl group. While p-methyl- and p-isopropylphenyl-
substituted pyrazolines were easily oxidized (Table 3, entries
Apparently, in the first step the hydrohydrazination of
3-butynol gave the corresponding arylhydrazone. In general,
the arylhydrazone undergoes Fischer indole cyclization in
the presence of a stochiometric amount of Lewis acid, such
as ZnCl2.11 However, in the case of 3-butynol, the pyrazoline
was formed by an unusual nucleophilic substitution of the
hydroxy group.
To study this novel pyrazoline formation in more detail,
we investigated the influence of different catalysts, solvents,
and temperatures on the reaction of phenylhydrazine 1a with
3-butynol 2. Selected results are presented in Table 1. The
model reaction proceeded in excellent yield (93%) in the
presence of a stochiometric amount of ZnCl2 (Table 1, entry
1). Unfortunately, when 5 mol % of ZnCl2 was used, only
36% yield was observed. Similarly, in the presence of a
catalytic amount of Zn(OAc)2 we obtained only low conver-
(10) (a) Alex, K.; Schwarz, N.; Khedkar, V.; Sayyed, I. A.; Tillack, A.;
Michalik, D.; Holenz, J.; Diaz, J. L.; Beller, M. Org. Biomol. Chem. 2008,
. in press. (b) Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.; Spannenberg,
A.; Michalik, D.; Beller, M. Tetrahedron 2008, 64, 4590–4595. (c) Schwarz,
N.; Alex, K.; Sayyed, I. A.; Khedkar, V.; Tillack, A.; Beller, M. Synlett
2007, 1091–1095. (d) Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.;
Michalik, D.; Beller, M. Eur. J. Org. Chem. 2007, 4525–4528. (e) Khedkar,
V.; Tillack, A.; Michalik, D.; Beller, M. Tetrahedron 2005, 61, 7622–7631.
(f) Tillack, A.; Jiao, H.; Garcia Castro, I.; Hartung, C. G.; Beller, M. Chem.
Eur. J. 2004, 10, 2409–2420. (g) Khedkar, V.; Tillack, A.; Michalik, M.;
Beller, M. Tetrahedron Lett. 2004, 45, 3123–3126. For the first example
of Ti-catalyzed hydrohydrazination of alkynes, see: (h) Cao, O.; Shi, Y.;
Odom, A. L. Org. Lett. 2002, 4, 2853–2856.
(12) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 1015–
(11) (a) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem.
2008, 120, 2337-2340; Angew. Chem., Int. Ed. 2008, 47, 2304-2307.
1020.
(13) Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505–3508
.
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Org. Lett., Vol. 10, No. 12, 2008

Table 2. Reaction of Arylhydrazines 1 with 3-Butynol 2 to
Scheme 2. One-Pot Formation of the Pyrazoles
Various Substituted Pyrazolinesa
is used, indole derivatives are obtained via a domino
amination-cyclization sequence. Apparently, in the case of
3-butynol, the formation of the five-membered ring is
preferred compared to the Fischer indole cyclization.
Table 3. Synthesis of Different Pyrazole Derivatives Starting
from Phenylhydrazines 1 and 3-Butynol 2a
a Reaction conditions: (step 1) 3-butynol (1.5 mmol), phenylhydrazine
derivative (1.95 mmol), 5 mol % of Zn(OTf)2, THF (3 mL), 24 h, 100 °C;
(step 2) CH3COOH, air, 24-72 h, 50 °C. b Isolated yield. c Yield only for
the last step using the purified pyrazoline as educt.
In summary, we have developed a novel method for the
synthesis of aryl-substituted pyrazolines and pyrazoles.
Various substituted arylhydrazines react with 3-butynol in
the presence of a catalytic amount of Zn(OTf)2 to give
pyrazoline derivatives in excellent yields. Subsequent one-
pot oxidation with air led to the corresponding pyrazoles.
This methodology is complementary to the classical pyra-
zoline synthesis from hydroxy ketones.
a Reaction conditions: 3-butynol (1.5 mmol), phenylhydrazine derivative
(1.95 mmol), 5 mol % of Zn(OTf)2, THF (3 mL), 24 h, 100 °C. b Isolated
yield.
Acknowledgment. This work has been funded by the State
of Mecklenburg-Western Pomerania, the BMBF (Bundesmini-
sterium fu¨r Bildung and Forschung), the Deutsche Forschungs-
gemeinschaft (Graduiertenkolleg 1213, and Leibniz-price), and
the Fonds der Chemischen Industrie (FCI). We thank Dr. W.
Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, and K.
Mevius for their excellent technical and analytical support.
1, 3), the more deactivated o-methyl- and p-bromophenyl-
substituted pyrazolines needed a longer reaction time for full
conversion (Table 3, entries 2, 4).
Interestingly, there was no significant difference in yield
between the synthesis of the pyrazoles by one-pot or
sequential reactions. For example, 4a was obtained in 56%
yield by adding acetic acid directly to the reaction mixture
compared to 61% yield observed with the pure pyrazoline
3b (Table 3, entry 1). Advantageously, a purification of the
reaction mixture is not necessary for the direct synthesis of
pyrazoles 4. Notably, when 4-pentynol instead of 3-butynol
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data of all com-
pounds mentioned in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800592S
Org. Lett., Vol. 10, No. 12, 2008
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