Synthesis of 3-trifluoromethylpyrazoles via trifluoromethylation/ cyclization of α,β-alkynic hydrazones using a hypervalent iodine reagent

Article abstract of DOI:10.1039/c4cc01280a

A mild and efficient method for the synthesis of 3-trifluoromethylpyrazoles has been established via trifluoromethylation/cyclization of α,β-alkynic hydrazones using a hypervalent iodine reagent under transition-metal-free conditions.

Full text of DOI:10.1039/c4cc01280a

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Synthesis of 3-trifluoromethylpyrazoles via
trifluoromethylation/cyclization of a,b-alkynic
hydrazones using a hypervalent iodine reagent†
Cite this: Chem. Commun., 2014,
50, 4361
Received 18th February 2014,
Accepted 4th March 2014
Guojing Ji,ab Xi Wang,*a Songnan Zhang,a Yan Xu,a Yuxuan Ye,a Ming Li,b
Yan Zhanga and Jianbo Wang*a
DOI: 10.1039/c4cc01280a
www.rsc.org/chemcomm
A mild and efficient method for the synthesis of 3-trifluoro-
methylpyrazoles has been established via trifluoromethylation/
cyclization of a,b-alkynic hydrazones using a hypervalent iodine
reagent under transition-metal-free conditions.
The trifluoromethylated arenes and heteroarenes play an
increasingly important role in the fields of pharmaceuticals,
agrochemicals, and materials science, because of their unique
properties, including high electronegativity, lipophilicity, meta-
bolic stability, and bioavailability.1,2 However, the compounds
bearing CF3 group are absent in nature. Accordingly, the
scientific community exerts a great effort to develop efficient
methods for introducing the trifluoromethyl group onto aro-
matic and heteroaromatic rings.3
Scheme 1 Bioactive compounds bearing a 3-trifluoromethyl-pyrazole
moiety.
The pyrazole ring is an important moiety found in many
natural products and compounds with biological activities,
which draw considerable attention in pharmaceutical and
agrochemical research.4 3-Trifluoromethylpyrazole is a feature
structure of many drugs, agrochemicals, and related candi-
dates. For example, as shown in Scheme 1, Celecoxib is a
nonsteroidal anti-inflammatory drug,5a and Mavacoxib is a
veterinary drug.5b SC-560 shows antitumor activity.5c
Scheme 2 Strategies for the synthesis of 3-trifluoromethyl-pyrazoles.
In general, functionalized 3-trifluoromethylpyrazoles are
prepared via cyclocondensations of 1,3-dicarbonyl compounds
with substituted hydrazines. (Scheme 2a).6 An alternative suffer from some limitations, which include: (1) for method a,
strategy is the use of 1,3-dipole cycloaddition of alkyne with the cyclocondensation of unsymmetrical 1,3-diketone with
2,2,2-trifluorodiazoethane, generated in situ from 2,2,2-trifluoro- hydrazines leads to the formation of a mixture of two regio-
ethylamine hydrochloride (Scheme 2b).7
isomers, which are often difficult to separate; (2) for method b, an
Although remarkable progress has been made in the syn- excess amount of CF3CH2NH2ÁHCl and transition metal promoters
thesis of substituted 3-trifluoromethylpyrazoles, these methods are essential for the high efficiency of 1,3-dipole cycloaddition.
Consequently, it is still highly desirable to develop new methods
a Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China.
E-mail: wangjb@pku.edu.cn
for the synthesis of 3-trifluoromethylpyrazoles.
To this end, we have conceived that deprotonation of
a,b-alkynic hydrazones 1,8 followed by a nucleophilic attack to the
+
electrophilic trifluoromethylation reagent ‘‘CF3 ’’ 2 and subsequent
b College of Chemistry and Molecular Engineering, Qingdao University of Science
cyclization may lead to the formation of 3-trifluoromethylpyrazoles.9
With this in mind, we first studied the reaction of
a,b-alkynic hydrazones 1a and Togni reagent 2a in acetonitrile
and Technology, Qingdao 266042, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc01280a
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Table 1 Optimization of the conditionsa
2 ‘‘CF3+’’
Entry Base (equiv.) (equiv.) Solvent
T (1C) Yieldb (%)
1
2
3
4
LiOt-Bu (2.0) 2a (1.0) MeCN
KOt-Bu (2.0) 2a (1.0) MeCN
25
25
25
25
25
25
25
50
25
25
25
25
25
16
14
14
16
39
0
28
23
0
35
26
22
14
46
68 (70)
Et3N (2.0)
2a (1.0) MeCN
K2CO3 (2.0) 2a (1.0) MeCN
Cs2CO3 (2.0) 2a (1.0) MeCN
5
6
None
2a (1.0) MeCN
7c
8
Cs2CO3 (2.0) 2a (1.0) MeCN
Cs2CO3 (2.0) 2a (1.0) MeCN
Cs2CO3 (2.0) 2b (1.0) MeCN
Cs2CO3 (2.0) 2c (1.0) MeCN
Cs2CO3 (2.0) 2d (1.0) MeCN
Cs2CO3 (2.0) 2a (1.0) DCE
Cs2CO3 (2.0) 2a (1.0) MeOH
9
10
11
12
13
14
15d
Cs2CO3 (2.0) 2a (1.0) MeCN : H2O (20 : 1) 25
Cs2CO3 (2.0) 2a (1.3) MeCN : H2O (20 : 1) 25
a
Reaction conditions: 1a (0.20 mmol), 2, solvent (1 mL), 24 h, under a
N2 atmosphere. Unless otherwise noted, the yields are based on 19F
NMR with p-CF3OC6H4OCH3 as an internal standard. CuCl (20 mol%)
was used. Values in parentheses refer to isolated yield.
b
c
d
at 25 1C with a series of bases. Preliminary screening showed
that Cs2CO3 was the suitable base for the expected conversion,
while LiOt-Bu, KOt-Bu, and Et3N seemed to be incompatible with
+
the strong electrophilic ‘‘CF3 ’’ reagent (Table 1, entries 1–5). The
reaction was completely shut down without the base (Table 1
entry 6). The copper chloride catalyst, which was used for single
electron reduction of Togni reagent 2a to generate the trifluoro-
methyl radical,10 was less efficient for this transformation
(Table 1, entry 7). Diminished yield of 3a was observed when
the reaction was conducted at an elevated temperature (Table 1,
Scheme 3 Trifluoromethylation/cyclization of a,b-alkynic hydrazones
using a hypervalent iodine reagent 2a. Reaction conditions: 1a (0.20 mmol,
1.0 equiv.), 2a (0.26 mmol, 1.3 equiv.), Cs2CO3 (0.40 mmol, 2.0 equiv.),
CH3CN/H2O (20 : 1, v/v, 1 mL), 25 1C, 24 h, under a N2 atmosphere.
a
Isolated yield.
+
entry 8). Then we turned to other electrophilic ‘‘CF3 ’’ reagents.
The study revealed that Togni reagent 2b had essentially no
effect (Table 1, entry 9), while Umemoto reagents 2c and 2d electron-donating substituents on the aromatic ring provides
afforded the expected product 3a in 35% and 26% yields, the corresponding 3-trifluoromethylpyrazoles in moderate to
respectively (Table 1, entries 10 and 11). Further screening of good yields (3b–e). Chloro- and iodo-substituted aryl alkynic
different solvents showed that DCE and MeOH were inferior to hydrazones 1f and 1g, which are valuable for further function-
MeCN (Table 1, entries 12 and 13). We have speculated that a alization, undergo smooth conversion. The strong electron-
small amount of water may facilitate the proton transfer in the withdrawing groups –CF3 and –NO2 are also compatible with
transformation. Indeed, a mixed solvent of MeCN/H2O (20 :1, v/v) the reaction conditions, giving 3h and 3i in 55% and 72%
led to further improvement of the yield (Table 1, entry 14). Finally, isolated yields, respectively. To our delight, for the substrates
the optimal conditions were obtained when the ratio 1a/2a bearing thiophene and pyridine moieties, the transformation
was maintained at 1 : 1.3, giving 3a in 70% isolated yield affords moderate yields of 3j and 3k. Besides, the alkyl-
(Table 1, entry 15).
substituted a,b-alkynic hydrazone 1l is successfully converted
The scope of a,b-alkynic hydrazones for this trifluoro- into 3-trifluoromethylpyrazole 3l in 47% yield. The N-Boc
methylation/cyclization transformation is summarised in protected pyrazole 3m, which can be used as a starting material
Scheme 3. The reaction exhibits good functional group toler- for further transformations, can also be obtained by this
ance in general. The transformation of electron-neutral phenyl method. Finally, this novel method has been successfully
a,b-alkynic hydrazones 1a and aryl a,b-alkynic hydrazones with applied for the synthesis of the antiarthritic drug Celecoxib 3n.
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In conclusion,
a
novel strategy for the synthesis of
3-trifluoromethylpyrazole derivatives through transition-metal-
free trifluoromethylation/cyclization of a,b-alkynic hydrazones
has been developed. Further work will be focused on in-depth
mechanistic studies of this reaction and the exploration of
other functionalization of pyrazoles through a coupling/cyclization
sequence.
The project was supported by the 973 Program
(No. 2012CB821600) and NSFC (Grant 21172005, 21272010
and 21332002).
Notes and references
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Scheme 5 Proposed mechanism.
Several experiments have been carried out in order to gain
insights into the reaction mechanism. First, 1.3 equiv. of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was introduced
as the free radical trapping agent in the standard reaction.
The yield of 3a was dropped to 28%, while TEMPO–CF3 adduct
4 was produced in 26% (Scheme 4a). These observations do not
support a pure trifluoromethyl radical pathway. Next, direct
C–H trifluoromethylation of pyrazole 5 with 2a under the
standard conditions does not give 3a (Scheme 4b). Finally,
condensation of alkynyl trifluoromethyl ketone 6 with phenyl-
hydrazine 7 in the absence of base affords 3a directly, instead of
a,b-alkynic hydrazone 8 (Scheme 4c).
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is proposed as shown in Scheme 5. The reaction is initialized
with deprotonation of a,b-alkynic hydrazones 1 with a base to
form the anionic intermediate A, which reacts with a highly
electrophilic Togni reagent to form the C–CF3 bond, affording
azo intermediate B or a,b-alkynic hydrazone C. Species B or C
undergoes a deprotonation/cyclization/protonation sequence to
give products 3. However, since the trifluoromethyl radical has
been trapped by TEMPO in this reaction, a radical mechanism
cannot be strictly removed. Further studies are needed to firmly
establish the reaction mechanism.
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Chem. Commun., 2014, 50, 4361--4363 | 4363