Solvent- and transition metal catalyst-dependent regioselectivity in the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines: Switchable access to 3- and 5-trifluoromethylpyrazoles

Article abstract of DOI:10.1002/adsc.201400853

The regioselectivity of the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines can be readily tuned to preferentially afford either 3- or 5-trifluoromethylpyrazoles through variation of the reaction conditions. Under catalysis with copper(II) acetate (2.0 mol%), cyclocondensation proceeded smoothly to yield 3-trifluoromethylpyrazoles with high regioselectivity. In contrast, when the reaction was conducted in dimethyl sulfoxide under catalyst-free conditions, the formation of 5-trifluoromethylpyrazoles was predominantly observed.

Full text of DOI:10.1002/adsc.201400853

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DOI: 10.1002/adsc.201400853
Solvent- and Transition Metal Catalyst-Dependent Regioselectivi-
ty in the [3+2]Cyclocondensation of Trifluoromethyl-a,b-ynones
with Hydrazines: Switchable Access to 3- and 5-Trifluoromethyl-
pyrazoles
Min-Tsang Hsieh,a,b,* Sheng-Chu Kuo,a and Hui-Chang Lina
a
School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
Chinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung
b
40447, Taiwan, R.O.C.
Fax : (+886)-4-2203-0760; phone: (+886)-4-2205-3366; e-mail: d917410@alumni.nthu.edu.tw
Received: September 1, 2014; Revised: December 19, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400853.
Abstract: The regioselectivity of the [3+2]cyclocon-
densation of trifluoromethyl-a,b-ynones with hydra-
zines can be readily tuned to preferentially afford
either 3- or 5-trifluoromethylpyrazoles through var-
iation of the reaction conditions. Under catalysis
with copper(II) acetate (2.0 mol%), cyclocondensa-
tion proceeded smoothly to yield 3-trifluoromethyl-
pyrazoles with high regioselectivity. In contrast,
when the reaction was conducted in dimethyl sulf-
oxide under catalyst-free conditions, the formation
of 5-trifluoromethylpyrazoles was predominantly
observed.
op synthetic methods to synthesise 3- and 5-trifluoro-
methylpyrazole compounds. The most general meth-
ods for the preparation of these compounds include
condensation[8] of hydrazines with 1,1,1-trifluorometh-
yl-1,3-diketones or their synthetic equivalents, such as
a,b-unsaturated carbonyl and related compounds.[9]
However, achieving appreciable regiochemical control
in these reactions remains a challenge because the
formation of regioisomers is frequently encountered,
Keywords: celecoxib; copper catalysis; [3+2]cyclo-
condensation; fluorinated substituents; regioselec-
tivity; solvent effects; trifluoromethylpyrazoles
The pyrazole ring is a ubiquitous core structure in
many pharmaceuticals, agrochemicals and natural
compounds.[1] Over the past few years, the synthesis
of pyrazole derivatives bearing a trifluoromethyl
group at the 3- or 5-position of the pyrazole ring has
attracted considerable attention because the com-
pounds containing this structural motif exhibit signifi-
cant biological activities. As shown in Figure 1, well-
known examples of these compounds include the
COX-2 inhibitor celecoxib (anti-inflammatory),[2]
measles virus RdRp inhibitor AS-136A (antiviral),[3]
COX-1 inhibitor SC-560 (anticancer),[4] RyRs calcium
release channel modulator DP-23 (insecticidal),[5]
factor Xa inhibitor razaxaban (anticoagulant)[6] and
protox inhibitor fluazolate (herbicidal).[7] Such attrac-
Figure 1. Selected biologically active compounds containing
tive biological properties motivate chemists to devel- either 3- or 5-trifluoromethylpyrazole skeletons.
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Min-Tsang Hsieh et al.
Scheme 1. Synthesis of celecoxib.
Scheme 2. Preparation of trifluoromethyl-a,b-ynones.
which results in unsatisfactory yields of the desired
products.[10]
been recently realised by Zora et al. via CuI-mediated
To date, only a few methods of preparing 3- and 5- cyclisation of a,b-alkynic hydrazones.[19] Therefore,
trifluoromethylpyrazole compounds via regioselective the nature of some transition metal complexes might
transformations have been reported, and most of similarly influence the regioselectivity of the title
these approaches involve microwave irradiation and system. Herein, we report a general and highly regio-
a fluorinated alcohol or an ionic liquid as the sol- selective [3+2]cyclocondensation of trifluoromethyl-
vent.[11,12] Recently, Ma et al. reported the regiocon- a,b-ynones and hydrazines for the preparation of 3-
trolled cycloaddition of terminal alkynes with and 5-trifluoromethylpyrazoles, where the regioselec-
CF3CHN2, which resulted in the exclusive formation tivity is tuned via the selection of appropriate solvents
of 3-trifluoromethylpyrazoles.[13] However, excess and metal catalysts.
Ag2O (2 equivalents) was required to effect the reac-
The trifluoromethyl-a,b-ynones employed in the
tion. Harrity et al. reported that 5-trifluoromethylpyr- current study were prepared by the nucleophilic sub-
azoles could be regioselectively synthesised from 4- stitution of lithium acetylides to ethyl trifluoroacetate
trifluoromethylsydnones via an intricate four-step se- 3.[20] As shown in Scheme 2, the substitution reactions
quence to prepare the sydnone precursors.[14] Recent- were performed in THF with BF3·OEt2 as a catalyst
ly, Togni reagent-mediated trifluoromethylation of for 1 h to afford the desired 4a–c and 1 in 77–91%
a,b-alkynic hydrazones was reported by Wang et al.; yields.
however, only moderate yields of the desired 3-tri-
Table 1 presents the screening conditions under
fluoromethylpyrazoles were obtained.[15] Because lim- which 4a and phenylhydrazine 5a were used as model
ited synthetic protocols exist, the development of substrates to afford the cyclocondensation products.
more general and efficient methods for the prepara- Accordingly, the solvent, temperature, time and metal
tion of 3- and 5-trifluoromethylpyrazoles is needed.
catalyst [i.e., AuCl, AgNO3, Ag2O, AgOTf, CuI,
As shown in Scheme 1, the reaction of trifluorome- CuCl2·2H2O, CuSO4, Cu(OAc)2, Pd(OAc)2, ZnI2 and
thylbutynones 1 with 4-hydrazinobenzenesulfonamide FeCl3] were systematically examined. When 4a was
hydrochloride 2 yields celecoxib with good regioselec- reacted with 5a in EtOH, which is a solvent that is
tivity (9:1 dr).[16] The reaction was conducted in alco- typically employed in the [3+2]cyclocondensation for
holic solvents at elevated temperature without the ad- the synthesis of celecoxib, a ca. 3:1 mixture of
dition of a promoter or catalyst. In addition, excess 2 trifluoroACTHNUTRGNEmNUG ethylpyrazole isomers 6a and 7a was ob-
(up to 1.3 equivalents) was required to drive the reac- tained in 81% yield (entry 1). However, when EtOH
tion to completion. However, the synthetic utility of was replaced with a low-polarity aprotic solvent such
this process appears limited in terms of the scope of as CH2Cl2, THF, 1,4-dioxane or toluene (entries 2–5)
the available substrates. The use of this protocol to se- under reflux conditions, a decreased reaction rate,
lectively yield 3-trifluoromethylpyrazoles, especially poor to moderate regioselectivity (6a:7a=5:4 to 5:1)
with alkyl and heteroaryl functional groups at the 1- and the formation of a significant amount of hydroxy-
or 5-position of the pyrazole ring, and analogous 5-tri- pyrazoline 8a were observed. Compound 8a was iden-
fluoromethylpyrazoles remains unexplored.
tified as a synthetic intermediate and was further
Recently, the solvent-controlled switch of stereose- transformed to 7a via a dehydration process when
lectivity has emerged as an important strategy in or- heated in DMSO (1108C, 4 h, 93% yield). To our sur-
ganic synthesis.[17] To the best of our knowledge, no prise, the regioselectivity was dramatically switched
effort has been made to provide detailed insight into toward 7a when the reactions were carried out in
the solvent-controlled regioselectivity of the title highly polar aprotic solvents such as DMSO and
system. In metal-catalysed electrophilic cyclisation, DMF (entries 6 and 7) at elevated temperatures.
transition metal complexes, such as Au(I), Ag(II), Among these solvents, DMSO appeared to be the sol-
Cu(I), Zn(II), Pd(II) and Fe(III) complexes, activate vent of choice on the basis of the regioselectivity re-
the alkyne moiety toward nucleophilic addition of sults. Further optimisation of the reaction conditions
a heteroatom.[18] Application of this metal-catalysed revealed that a stepwise heating approach (entry 8)
process for the synthesis of pyrazole compounds has provided greater regioselectivity and yield compared
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Solvent- and Transition Metal Catalyst-Dependent Regioselectivity
Table 1. Optimisation of reaction conditions.
Entry
Conditions
HPLC Yield [%][b]
Solvent
Temperature/Time
Catalyst
4a
6a
7a
8a
1
2
3
4
5
6
7
8
EtOH
DCM
THF
reflux, 12 h
reflux, 36 h
reflux, 40 h
reflux, 36 h
0
0
0
0
0
1
0
0
0
11
0
4
1
2
1
0
0
0
0
2
0
1
1
1
69 (60)
75
24
40
40
3
6
4
17 (12)
70
96 (92)
90
83
26 (21)
16
45
34
31
79 (74)
86 (83)
92 (90)
0
6
28
22
21
7
0
0
0
3
3
0
1
5
0
1
0
0
dioxane
toluene
DMF
DMSO
DMSO
DMSO
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
reflux, 14 h
1108C, 26 h
1108C, 14 h
208C, 1 h then 1108C, 14 h
208C, 1 h then 1108C, 14 h
reflux, 1 h
reflux, 1 h
reflux, 2 h
reflux, 4 h
reflux, 1.5 h
reflux, 1 h
9[c]
10
11
12
13
14
15
16
17
18
19
20
21[c,d]
22
23[e]
24
80 (74)
AuCl (10 mol%)
12
1
1
0
6
0
0
0
0
0
0
0
2
0
2
AgOTf (10 mol%)
AgNO3 (10 mol%)
Ag2O (10 mol%)
CuI (10 mol%)
85
CuCl2·2H2O (10mol%)
CuSO4 (10 mol%)
Cu(OAc)2 (10 mol%)
Cu(OAc)2 (5 mol%)
Cu(OAc)2 (2mol%)
Cu(OAc)2 (1 mol%)
Cu(OAc)2 (2 mol%)
Pd(OAc)2 (10 mol%)
ZnI2 (10 mol%)
93 (90)
95 (92)
99 (96)
98 (96)
98 (96)
97 (94)
95 (90)
91 (86)
64 (57)
81 (73)
reflux, 1 h
reflux, 25 min
reflux, 30 min
reflux, 1 h
reflux, 2.5 h
reflux, 2.5 h
reflux, 2 h
0
0
0
2
0
2
DCM
DCM
reflux, 3 h
reflux, 3.5 h
FeCl3 (10 mol%)
[a]
All of the reactions (except entries 9 and 21) were performed under standard reaction conditions: substrate 4a (200 mg,
1.00 mmol), phenylhydrazine 5a (109 mg, 1.00 mmol) and solvent (3 mL).
HPLC assay yield; isolated yields after purification by flash chromatography are provided in parentheses.
Phenylhydrazine hydrochloride was used instead of phenylhydrazine.
Two drops of EtOH were added to the reaction media to dissolve the phenylhydrazine hydrochloride salt.
An unidentified product was detected by HPLC with 28% HPLC purity.
[b]
[c]
[d]
[e]
to direct heating to 1108C. In addition, the replace- 12, 13, 15, 16, 22 and 24, respectively). However, the
ment of phenylhydrazine with its hydrochloride salt metal complexes commonly employed for the electro-
was detrimental to the regioselectivity (entry 9). The philic cyclisation of acetylenic hydrazones, such as
decrease in the regioselectivity appears to be due to AuCl and CuI,[18f,19] exhibited fair to poor catalytic ac-
the hydrazine hydrochloride salt being less nucleo- tivity in terms of reaction yields and regioselectivity
philic, which results in the retardation of the cyclo- (entries 10 and 14, respectively). Disappointingly, the
condensation of 7a and the formation of regioisomer use of ZnI2 afforded 6a in moderate yield, along with
6a. Therefore, entry 8 was tentatively considered to a significant amount of an unidentified compound.
be the optimal conditions for 5-trifluoromethylpyra- Therefore, Cu(OAc)2 was considered to be the cata-
zoles. In sharp contrast, we observed that, when the lyst of choice. Additional experiments to decrease the
aforementioned metal complexes were added in cata- Cu(OAc)2 loading from 10 mol% to 5 and 2 mol%
lytic quantities, both the reaction rate and regioselec- were successful and did not result in loss of yield or
tivity were significantly improved, which favoured stereoselectivity (entries 18 and 19). However, a fur-
isomer 6a. Among the metal complexes studied, the ther reduction in the Cu(OAc)2 loading to 1 mol%
use of 10 mol% of Cu(OAc)2 furnished 6a in the led to the need for an extended reaction time and
highest yield and with the greatest regioselectivity slightly diminished yield but with excellent regioselec-
(entry 17),
CuCl2·2H2O, CuSO4, Pd(OAc)2 and FeCl3 provided
lower yields and inferior regioselectivity (entries 11, conditions with phenylhydrazine hydrochloride salt
whereas
AgOTf,
AgNO3,
Ag2O, tive control (entry 20).
In addition, performing the reaction under similar
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Table 2. Substrate scope for the [3+2]cyclocondensation of trifluoromethyl-a,b-ynones with hydrazines.
Entry
Substrate
Conditions A[a]
Product (yield)[d]
Conditions B[b]
Product (yield)[d]
4[c]
5
Time
Time
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
1
5b
5c
5d
5e
5f
5g
5h
5i
45 min
1 h
1 h
1.5 h
1 h
2.5 h
1 h
1 h
1 h
40 min
40 min
40 min
1 h
6b (95%)
6c (91%)
6d (94%)[e]
6e (83%)
6f (87%)
6g (93%)
6h (90%)
6i (92%)
19 h
18 h
13 h
28 h
26 h
7b (93%)
7c (90%)
7d (93%)
7e (78%)+6e (6%)
7f (86%)
13 h
33 h
30 h
11 h
19 h
11 h
15 h
21 h
7h (84%)+6h (4%)
7i (86%)
9 (90%)
7k (82%)+6k (6%)
7l (95%)
7m (86%)+6m (3%)
7n (83%)+6n (5%)
7o (92%)
9
5j
6j (92%)
10
11
12
13
14
15
16
17
18
5a
5b
5d
5e
5f
5a
5d
5f
5g
6k (91%)[f]
6l (89%)
6m (90%)
6n (87%)
6o (86%)
6p (82%)
6q (86%)
11 (87%)
celecoxib (94%)
1 h
50 min
50 min
2 h
19 h
19 h
10 (86%)
7r (88%)
2.5 h
[a]
Substrate 4 (1.51 mmol), substrate 5 (1.51 mmol), DMSO (3 mL).
Substrate 4 (1.51 mmol), substrate 5 (1.51 mmol), 2 mol% Cu(OAc)2, DCM (3 mL).
4a R1 =Ph; 4b R1 =n-Bu; 4c R1 =SiMe3; 1 R1 =Tol (see Scheme 2).
Isolated yields.
In the absence of Cu(OAc)2, the cyclocondensation of 4a with 5d only provided a 2:1 mixture of 6d and 7d in 83% yield.
In the absence of Cu(OAc)2, the cyclocondensation of 4b with 5a only provided a 1.5:1 mixture of 6k and 7k in 73%
[b]
[c]
[d]
[e]
[f]
yield.
instead of phenylhydrazine afforded inferior results tions A (entries 1–9), all of the hydrazines, including
(entry 21), implying that HCl was not beneficial to several different phenylhydrazines 5b–5g, tert-butylhy-
the catalytic system. Therefore, the reaction system drazine 5h, 2-hydrazinobenzothiazole 5i and 2-hydra-
[2.0 mol% Cu(OAc)2, CH2Cl2, reflux] shown in zinopyridine 5j, efficiently reacted with 4a, irrespec-
entry 18 was considered to be optimal and was used tive of the steric or electronic nature of the substitu-
as the general procedure. Notably, these synthetic ents, to provide the corresponding 3-trifluoromethyl-
methods were easy to perform and all of the afore- pyrazoles 6b–6j in good to excellent yields (83–95%)
mentioned screening reactions were conducted under and with excellent regioselectivity. Other structurally
air without exclusion of oxygen or moisture.
diverse ynones, such as 1,1,1-trifluorooct-3-yn-2-one
With the optimised reaction conditions having been 4b, 1,1,1-trifluoro-4-(trimethylsilyl)but-3-yn-2-one 4c
established, the substrate scope and generality of the and substrate 1, were subjected to the Cu(OAc)2-cata-
newly developed synthetic method were examined. lysed cyclocondensation reaction (conditions A) to
First, the scope of the hydrazines[21] was evaluated afford the corresponding pyrazoles 6k–6q in 82–91%
with regard to 4a. As listed in Table 2, under condi- yield and celecoxib in 94% yield, except that the desi-
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Solvent- and Transition Metal Catalyst-Dependent Regioselectivity
lylated pyrazole compound 11[22] was formed
(entry 17; conditions A). Notably, the yield and regio-
selectivity of the celecoxib produced from our proto-
col are comparable or slightly superior to that ob-
tained using other synthetic methods.[15,23] However,
in most cases under conditions B, the [3+2] cyclocon-
densation reactions predominantly afforded the de-
sired 5-trifluoromethylpyrazoles (5-/3-regioisomer se-
lectivityꢀ13:1). The exceptions were entry 9, where
hydroxypyrazolone intermediate 9 (90%) was pro-
duced,[24] and entry 16, where desilylated pyrazole
compound 11 (87%) was formed instead.[22] In addi-
tion, the presence of electron-withdrawing functional-
ities on the aromatic ring of the hydrazine substrates
(5b, 5c, 5e, 5f, 5g and 5i) adversely affected the reac-
tion rate. All of the synthetic 3- and 5-trifluorome-
thylpyrazoles were carefully characterised on the
Scheme 3. Synthesis of 3-difluoromethylpyrazole derivatives.
1
basis of their H NMR, 13C NMR, 19F NMR, IR and
HR-mass spectra. The 19F NMR spectra are important
for distinguishing the 3- and 5-trifluoromethylpyra-
zoles, where the trifluoromethyl signal of the 3-tri-
fluoromethylpyazoles was farther upfield compared to
that of the 5-trifluoromethylpyazoles. Compound 9
was subjected to standard acid-mediated dehydration
conditions (HCl, EtOH, reflux);[25] however, the sub-
strate was recovered intact, even when the reaction
time was extended to 30 h. These results may be due
to the formation of a hydrogen chloride salt via proto-
nation of the nitrogen atom in the pyridine ring, ren-
dering the hydroxyl group resistant to dehydration. In
Scheme 4. Proposed reaction mechanism.
addition, the strong electron-withdrawing trifluoro- dig cyclisation via nucleophilic attack of the hydra-
methyl group may also play an important role in sta- zone nitrogen atom. Finally, protonation of the result-
À
bilising the hydroxypyrazolone intermediate and re- ing Cu(II) C bond yields 3-trifluoromethylpyrazole
tarding the dehydration process.[26]
6a and restarts the catalytic cycle. In DMSO (pathway
To further broaden the synthetic scope of the B), the more nucleophilic nitrogen atom at the phe-
Cu(OAc)2-catalysed [3+2]cyclocondensation reaction, nylhydrazine is prone to attacking the b-carbon of 5
we examined the reaction with bromodifluoromethyl- in a 1,4-addition manner to afford b-keto hydrazone
a,b-ynone 12 and phenyldifluoromethyl-a,b-ynone 13. intermediate 17, which can quickly cyclise to form hy-
The related synthetic procedures are described in the droxypyrazolone 8a followed by dehydration to yield
Supporting Information. As shown in Scheme 3, the the final product (i.e., 5-trifluoromethylpyrazole 7a).
optimal reaction conditions (Table 1, entry 19) were Our proposed mechanism is supported by the isola-
successfully applied to these two substrates to afford tion of hydroxypyrazolone intermediates[27] as well as
the corresponding pyrazole products 14 (94%) and 15 by experimental evidence, including the influence of
(92%) with excellent regioselectivity. Compound 14 the solvent polarity on the reaction rate and regiose-
was regarded as a useful intermediate that could be lectivity.
functionalised into the corresponding 3-difluorome-
In summary, we have developed a highly efficient
thylpyrazole compounds by further manipulation of approach for the regioselective synthesis of 3- and 5-
the bromo group. Currently, the investigation of suita- trifluoromethylpyrazoles via the [3+2]cyclocondensa-
ble reaction conditions for the structural transforma- tion of trifluoromethyl-a,b-ynones with hydrazine de-
tion is underway in our laboratory.
rivatives. The salient features of this newly developed
A reasonable mechanism for the selective synthesis method include very high reaction yields, easy opera-
of 3- and 5-trifluoromethylpyrazole is shown in tions, low catalyst loading (2 mol%) and excellent
Scheme 4 using substrate 4a and 5a as a specific ex- control of regioselectivity, which makes this approach
ample. In CH2Cl2 (pathway A), Cu(II) first coordi- practical for preparing a highly structurally diverse li-
nates to the alkyne moiety of the in situ generated brary for new drug screening.
a,b-alkynic hydrazone 16, which is followed by activa-
tion of the carbon-carbon triple bond toward 5-endo-
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[4] E. Lee, M. K. Choi, H. J. Youk, C. H. Kim, I. C. Han,
B. C. Yoo, M. K. Lee, S. J. Lim, J. Cancer Res. Clin.
Oncol. 2006, 132, 223–233.
[5] G. P. Lahm, T. P. Selby, J. H. Freudenberger, T. M. Ste-
venson, B. J. Myers, G. Seburyamo, B. K. Smith, L.
Flexner, C. E. Clark, D. Cordova, Bioorg. Med. Chem.
Lett. 2005, 15, 4898–4906.
[6] M. L. Quan, P. Y. S. Lam, Q. Han, D. J. P. Pinto, M. Y.
He, R. Li, C. D. Ellis, C. G. Clark, C. A. Teleha, J.-H.
Sun, R. S. Alexander, S. Bai, J. M. Luettgen, R. M.
Knabb, P. C. Wong, R. R. Wexler, J. Med. Chem. 2005,
48, 1729–1744.
Experimental Section
General Procedure for the Synthesis of 3-Trifluoro-
methylpyrazoles
The general procedure is described below, with compound
6a used as a specific example. To a stirred solution of com-
pounds 4a (0.200 g, 1.00 mmol) and 5a (0.109 g, 1.00 mmol)
in CH2Cl2 (3 mL), Cu(OAc)2 (3.6 mg, 0.02 mmol) was
added. The resulting mixture was stirred under reflux for
1 h. Then, a saturated NH4Cl solution (1 mL) was added to
quench the reaction. The aqueous layer was separated and
extracted with CH2Cl2 (2ꢁ3 mL). The combined organic ex-
tracts were washed with brine, dried over MgSO4, filtered
and concentrated to yield the crude residue, which was puri-
fied by flash chromatography on silica gel with EtOAc/n-
hexane (1:9) to afford compound 6a; yield: 0.280 g (96%).
[7] B. D. Maxwell, J. Labelled. Cpd. Radiopharm. 2000, 43,
645–654.
[8] a) K. Makino, H. S. Kim, Y. Kurasawa, J. Heterocycl.
Chem. 1998, 35, 489–497; b) Z. Wang, H. Qin, Green
Chem. 2004, 6, 90–92; c) Y. L. Janin, Chem. Rev. 2012,
112, 3924–3958; d) S. Fustero, M. Sꢃnchez-Rosellꢄ, P.
Barrio, A. Simꢄn-Fuentes, Chem. Rev. 2011, 111, 6984–
7034, and references cited therein.
General Procedure for the Synthesis of 5-Trifluoro-
methylpyrazoles
[9] For recent examples, see: a) J. P. Waldo, S. Mehta,
R. C. Larock, J. Org. Chem. 2008, 73, 6666–6670;
b) F. A. Rosa, P. Machado, P. S. Vargas, H. G. Bonacor-
so, N. Zanatta, M. A. P. Martins, Synlett 2008, 11, 1673–
1678; c) C. P. Frizzo, M. R. B. Marzari, L. Buriol, D. N.
Moreira, F. A. Rosa, P. S. Vargas, N. Zanatta, H. G. Bo-
nacorso, M. A. P. Martins, Catal. Commun. 2009, 10,
1967–1970; d) W. Jin, H. Yu, Z. Yu, Tetrahedron Lett.
2011, 52, 5884–5887; e) M. Zora, A. Kivrak, C. Yazici,
J. Org. Chem. 2011, 76, 6726–6742; f) J. D. Kirkham,
S. J. Edeson, S. Stokes, J. P. A. Harrity, Org. Lett. 2012,
14, 5354–5357; g) D. X. Xiang, X. H. Bi, P. Q. Liao,
G. C. Fang, Z. K. Wang, X. Q. Xin, D. W. Dong, RSC
Adv. 2013, 3, 386–389.
The general procedure is described below, with compound
7a used as a specific example. A mixture of compounds 4a
(0.200 g, 1.00 mmol) and 5a (0.109 g, 1.00 mmol) in DMSO
(3 mL) was stirred at room temperature (208C) for 1 h. The
resulting mixture was heated to 1108C and stirred for an ad-
ditional 14 h. Water (6 mL) was added to quench the reac-
tion. The aqueous layer was separated and extracted with
EA (3ꢁ3 mL). The combined organic extracts were washed
with brine, dried over MgSO4, filtered and concentrated to
yield the crude residue, which was purified by flash chroma-
tography on silica gel with EtOAc/n-hexane (1:9) to afford
compound 7a; yield: 0.262 g (90%).
[10] The lack of regioselectivity has been reported by sever-
al authors. For reviews, see refs.[8c,8d]
Acknowledgements
[11] a) P. S. Humphries, J. M. Finefield, Tetrahedron Lett.
2006, 47, 2443–2446; b) L. Buriol, C. P. Frizzo, L. D. T.
Prola, D. N. Moreira, M. R. B. Marzari, E. Scapin, N.
Zanatta, H. G. Bonacorso, M. A. P. Martins, Catal. Lett.
2011, 141, 1130–1135.
[12] a) M. A. P. Martins, M. R. B. Marzari, C. P. Frizzo, M.
Zanatta, L. Buriol, V. P. Andrade, N. Zanatta, H. G.
Bonacorso, Eur. J. Org. Chem. 2012, 36, 7112–7119;
b) S. Fustero, R. Romꢃn, J. F. Sanz-Cervera, A. Simꢄn-
Fuentes, A. C. CuÇat, S. Villanova, M. Murguꢅa, J. Org.
Chem. 2008, 73, 3523–3529.
We are grateful to the Taiwan Ministry of Science and Tech-
nology (MOST 103-2113M-039-002-MY2) and Chinese Med-
icine Research Center, China Medical University (the Minis-
try of Education, the Aim for the Top University Plan) for fi-
nancial support.
References
[13] F. Li, J. Nie, L. Sun, Y. Zheng, J.-A. Ma, Angew. Chem.
[1] a) A. Schmidt, A. Dreger, Curr. Org. Chem. 2011, 15,
1423–1463; b) J. Elguero, A. M. S. Silva, A. C. Tomꢂ,
in: Modern Heterocyclic Chemistry, 1st edn., (Eds.: J.
Alvarez-Builla, J. J. Vaquero, J. Barluenga, Wiley-VCH,
Weinheim, 2011, pp 635–725.
[2] T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter,
P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W.
Malecha, J. M. Miyashiro, R. S. Rogers, D. J. Rogier,
S. S. Yu, G. D. Anderson, E. G. Burton, J. N. Cogburn,
S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert,
A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med.
Chem. 1997, 40, 1347–1365.
Int. Ed. 2013, 52, 6255–6258.
[14] R. S. Foster, H. Jakobi, J. P. A. Harrity, Org. Lett. 2012,
14, 4858–4861.
[15] G. Ji, X. Wang, S. Zhang, Y. Xu, Y. Ye, M. Li, Y.
Zhang, J. Wang, Chem. Commun. 2014, 50, 4361–4363.
[16] R. Reddy, V. Ramma, S. C. Bell, WO Patent WO
2003024958A3, 2003.
[17] a) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J.
Gaunt, Angew. Chem. 2005, 117, 3185–3189; b) L. Hin-
termann, R. Masuo, K. Suzuki, Org. Lett. 2008, 10,
4859–4862; c) A. W. Garner, C. F. Harris, D. A. K.
Vezzu, R. D. Pike, S. Huo, Chem. Commun. 2011, 47,
1902–1904; d) C.-D. Wang, Y.-F. Hsieh, R.-S. Liu, Adv.
Synth. Catal. 2014, 356, 144–152.
[3] A. Sun, J. J. Yoon, Y. Yin, A. Prussia, Y. Yang, J. Min,
R. K. Plemper, J. P. Snyder, J. Med. Chem. 2008, 51,
3731–3741.
6
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COMMUNICATIONS
Solvent- and Transition Metal Catalyst-Dependent Regioselectivity
[18] a) P. Aschwanden, D. E. Frantz, E. M. Carreira, Org.
Lett. 2000, 2, 2331–2333; b) P. A. Wender, D. Strand, J.
Am. Chem. Soc. 2009, 131, 7528–7529; c) H. Gao, J.
Zhang, Adv. Synth. Catal. 2009, 351, 85–88; d) L. Hin-
termann, Top. Organomet. Chem. 2010, 31, 123–155;
e) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011,
111, 2981–3019; f) J. Qian, Y. Liu, J. Zhu, B. Jiang, Z.
Xu, Org. Lett. 2011, 13, 4220–4223; g) B. Godoi, R. F.
Schumacher, G. Zeni, Chem. Rev. 2011, 111, 2937–
2980; h) T. Ishida, S. Kikuchi, T. Tsubo, T. Yamada,
Org. Lett. 2013, 15, 848–851; i) M. T. Herrero, J. D. de
Sarralde, R. SanMartin, L. Bravo, E. Domꢅnguez, Adv.
Synth. Catal. 2012, 354, 3054–3064.
The precise reasons for the unexpected desilylation
await further investigation.
[23] a) L. M. Oh, Tetrahedron Lett. 2006, 47, 7943–7946;
b) A. R. Reddy, A. Sampath, G. Goverdhan, B. Yakam-
baram, K. Mukkanti, P. P. Reddy, Org. Process Res.
Dev. 2009, 13, 98–101; c) S. M. Gaulier, R. Mckay,
N. A. Swain, Tetrahedron Lett. 2011, 52, 6000–6002.
[24] The structure of compound 9 was supported by X-ray
analysis. See the Supporting Information for the crys-
tallographic structure of compound 9. CCDC 1000495
contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[25] T. Norris, R. Colon-Cruz, D. H. B. Ripin, Org. Biomol.
Chem. 2005, 3, 1844–1849.
[26] L.-P. Song, S.-Z. Zhu, J. Fluorine Chem. 2001, 107, 201–
205.
[27] Three hydroxypyrazolone intermediates, including
compounds 8a, 9 and 18, were isolated. For the struc-
ture of 18, see Supporting Information.
[19] M. Zora, A. Kivrak, J. Org. Chem. 2011, 76, 9379–9390.
[20] R. J. Linderman, M. S. Lonikar, J. Org. Chem. 1988, 53,
6013–6022.
[21] All hydrazine derivatives employed in Table 2 were
commercially available in free base form.
[22] At the current stage, whether the desilylation precedes
the cyclocondensation or vice versa remains unclear.
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8 Solvent- and Transition Metal Catalyst-Dependent
Regioselectivity in the [3+2]Cyclocondensation of
Trifluoromethyl-a,b-ynones with Hydrazines: Switchable
Access to 3- and 5-Trifluoromethylpyrazoles
Adv. Synth. Catal. 2015, 357, 1 – 8
Min-Tsang Hsieh,* Sheng-Chu Kuo, Hui-Chang Lin
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