Silver-mediated cycloaddition of alkynes with CF3CHN 2: Highly regioselective synthesis of 3-trifluoromethylpyrazoles

Article abstract of DOI:10.1002/anie.201301870

Silver screen: The title reaction provides a convenient and efficient method for the construction of 5-substituted 3-trifluoromethylpyrazoles under mild reaction conditions. By using this protocol, the marketed drug Celecoxib (antiarthritic) could be easily synthesized (see scheme; DMF=N,N- dimethylformamide). Copyright

Full text of DOI:10.1002/anie.201301870

Angewandte
Chemie
DOI: 10.1002/anie.201301870
Synthetic Methods
Silver-Mediated Cycloaddition of Alkynes with CF3CHN2: Highly
Regioselective Synthesis of 3-Trifluoromethylpyrazoles**
Feng Li, Jing Nie, Long Sun, Yan Zheng, and Jun-An Ma*
3-Trifluoromethylpyrazole is the core unit of many drugs,
agrochemicals, and related candidates.[1] Among them are
Celecoxib and Mavacoxib (antiarthritic), SC-560 (antitumor),
AS-136A (antiviral), Razaxaban (anticoagulant), as well as
DP-23 (insecticidal activity; Figure 1).[2] As a result of the
developed the copper(I)-catalyzed cross-coupling of terminal
alkynes and gaseous CF3CHN2, thus leading to the formation
of C H insertion products[7] (Scheme 1, top). These reactions
À
Scheme 1. Different products from the reactions of alkynes with
CF3CHN2. DMF=N,N-dimethylformamide.
are proposed to follow a similar step that involves metal
carbene formation. In sharp contrast, the use of 2,2,2-
trifluorodiazoethane as a 1,3-dipole for the cycloaddition of
alkynes to construct functionalized 3-trifluoromethylpyra-
zoles has not received much attention. In 1979 Fields and
Tomlinson described a dark reaction of terminal alkynes with
2,2,2-trifluorodiazoethane in a sealed tube.[9] Unfortunately,
the harsh reaction conditions and long reaction times (over
two weeks) render the process impractical and untenable. To
address these limitations, we herein report a silver-mediated
1,3-dipolar cycloaddition of various terminal alkynes with
2,2,2-trifluorodiazoethane (Scheme 1, bottom). The notable
features of this reaction are its high regioselectivity, opera-
tional simplicity, easily accessible starting materials, and mild
reaction conditions. Furthermore, the potential application of
this cycloaddition reaction was demonstrated as a key step in
a new and efficient synthesis of the antiarthritic drug
Celecoxib.
The intermolecular 1,3-dipolar cycloaddition of electron-
deficient diazocarbonyl compounds with alkynes was first
disclosed by Li and co-workers,[10a] and additional methods
have been reported by the groups of Ready,[10b] Liang,[10c] and
Legros.[10d] Considering that CF3CHN2 is also an electron-
deficient diazo compound, we first examined the model
reaction of phenylacetylene (1a) with 2,2,2-trifluorodiazo-
ethane under otherwise identical reaction conditions (as
reported by the groups of Li, Ready, Liang, and Legros).
However, none of the target cycloadduct 2a was obtained. So
the efficient realization of such transformation necessitates
the development of new metal systems. Next, a large number
of metal salts, which included lithium, magnesium, zinc,
Figure 1. 3-Trifluoromethylpyrazole-based bioactive compounds.
immense usefulness of 3-trifluoromethylpyrazole derivatives,
efficient construction of the 3-trifluoromethylpyrazole frame-
work has become the subject of intensive research in the fields
of synthetic and medicinal chemistry.[3] Generally, 3-trifluoro-
methylpyrazoles can be accessed by cyclocondensations of an
appropriate hydrazine with the corresponding 1,3-dicarbonyl
compounds.[4] However, these methods often suffer from the
formation of regioisomeric mixtures with respect to substitu-
ents incorporated at the 3- and 5-positions of the pyrazole
ring. Recently, 2,2,2-trifluorodiazoethane has emerged as an
attractive synthon in transition-metal-catalyzed/mediated and
organocatalytic reactions for the construction of fluorine-
containing building blocks.[5–8] In this regard, Morandi,
Carreira, and co-workers disclosed a rhodium-catalyzed
cyclopropenation of alkynes with CF3CHN2 generated
in situ from CF3CH2NH2·HCl in aqueous media,[6b] and we
[*] F. Li, J. Nie, L. Sun, Y. Zheng, Prof. J.-A. Ma
Department of Chemistry, Tianjin Key Laboratory
for Modern Drug Delivery & High-Efficiency
Tianjin University, Tianjin 300072 (China)
E-mail: majun_an68@tju.edu.cn
[**] This work was supported financially by the NSFC (No. 21002068,
21172170, and 21225208). We also thank Dr. Dominique Cahard
(CNRS & Universitꢀ et INSA de Rouen, France) for his helpful
discussions and suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301870.
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Table 1: Reaction conditions: Optimization for silver-mediated cyclo-
addition of 1a with CF3CHN2.[a]
NaOAc in DMF at 458C was found to be the best reaction
conditions for this silver-mediated cycloaddition reaction.
Although 2.0 equivalents of Ag2O was employed in the
reaction, the excess Ag2O and the resulting silver species
could be recycled conveniently by filtration and treatment
with nitric acid and NaOH. The regenerated Ag2O could still
promote this cycloaddition in comparable yield without loss
of activity (entry 21).
With the optimized reaction conditions in hand, we next
investigated the substrate scope of this silver-mediated cyclo-
addition of 2,2,2-trifluorodiazoethane with a variety of
terminal alkynes, and the results are summarized in
Scheme 2. In the case of aryl acetylenes, the cycloaddition
Entry
[Ag]/base
solvent
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Ag2O
Ag2CO3
AgNO3
AgOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAC
dioxane
CH3CN
toluene
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
45
60
45
45
45
48
48
48
48
48
12
12
12
12
12
12
12
12
12
12
12
5
63
58
40
61
65
69
71
78
78
45
76
52
53
18
21
25
84
83
54
86
83
Ag2O/Na2CO3
Ag2O/K2CO3
Ag2O/Cs2CO3
Ag2O/NaOAc
Ag2O/KOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
Ag2O/NaOAc
9
10[c]
11
12
13
14
15
16
17
18
19[d]
20[e]
21[f]
CH2Cl2
DMF
DMF
DMF
DMF
DMF
5
5
5
5
[a] General reaction conditions: 1a (0.22 mmol), Ag salt (2.0 equiv),
base (2.0 equiv), solvent (3.0 mL), CF3CH2NH2·HCl (4.0 equiv), NaNO2
(5.0 equiv), toluene (0.8 mL) and H2O (40 mL). [b] Yields of isolated
product averaged over two runs. [c] CF3CH2NH2·HCl (2.0 equiv). [d] 1.0
equivalent of Ag2O. [e] 3.0 equivalents of Ag2O. [f] The use of the
regenerated Ag2O. THF=tetrahydrofuran.
copper, silver, gold, and some of their complexes, were
screened for this model reaction. It was found that silver salts
were the most promising promoters for the test reaction
(Table 1, entries 1–4), whereas all the other metal complexes
tested resulted in poor yields (not listed in Table 1; see the
À
Supporting Information). Additionally, cyclopropenation, C
H insertion, or homocoupling of the alkyne was not a detect-
able side reaction for these silver-mediated processes. These
preliminary results encouraged us to further optimize the
reaction conditions. The introduction of bases as additives
was found to significantly increase the reaction efficiency and
yield (Table 1, entries 5–9). After screening several bases, the
yield of 2a was increased to 78% when the reaction was
carried out using NaOAc or KOAc (entries 8 and 9). The use
of an excess of the CF3CH2NH2·HCl reagent was essential for
the high efficiency of this cycloaddition. Reducing the loading
of CF3CH2NH2·HCl to 2.0 equivalents resulted in much lower
yield of 2a (entry 10). Exploration of solvents revealed that
besides DMF, its analogue N,N-dimethylacetamide (DMAC)
also promoted this transformation, whereas the use of
toluene, THF, or CH2Cl2 led to a significantly lower yield
(entries 11–16). Notably, a faster conversion was achieved by
increasing the reaction temperature (entries 17 and 18). A
lesser amount of Ag2O reduced the reaction yield (entry 19),
but 3.0 equivalents of Ag2O did not improve the yield when
compared to that obtained with 2.0 equivalents of Ag2O
(entries 17 and 20). Therefore, the combination of Ag2O and
Scheme 2. Scope of the silver-promoted cycloaddition of terminal
alkynes with CF3CHN2. [a] Yields of isolated products. [b] The reactions
were carried out at room temperature for 1 h.
reaction tolerates various substitution patterns and a range of
different substituents on the aryl ring. Alkyl-, alkoxy-, halo-,
nitro-, cyano-, and alkoxycarbonyl-substituted phenyl acety-
lenes all undergo the desired reaction to give the cycloadducts
2a–q in good to high yields. The structure of compound 2b
was further confirmed to be 3-trifluoromethyl-5-p-tolyl-1H-
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pyrazole by means of X-ray crystallographic analysis (see the
Supporting Information).[11] 2-Naphthyl-, 2-thiophenyl- and 3-
pyridyl-substituted aryl acetylenes were also found to be good
substrates, thus delivering the products 2r–t in good yields.
Furthermore, several enynes also worked well under the same
reaction conditions to afford the corresponding products 2u–
x. It is remarkable that electron-deficient alkynes were found
to undergo the desired transformation efficiently, even at
room temperature for one hour, thus furnishing the cyclo-
addition products in excellent yields (2y, 2z, and 2a’). In all
cases, the reaction can be conducted under mild reaction
conditions without the need for anhydrous solvents. Finally,
we found that alkyl-substituted terminal alkynes cannot be
converted using the present protocol, even when the reaction
temperature is decreased to 08C. We also attempted to
optimize the reactions with alkyl-substituted alkynes by
increasing the amounts of 2,2,2-trifluorodiazoethane and
Ag2O but still could not obtain any of the desired products.
Subsequently, we want to comment on the synthetic utility
of this cycloaddition reaction (Scheme 3). As expected,
almost the same results were obtained when the cycloaddition
trifluoromethyl-pyrazole-5-carboxylic acid (3) in 85% yield.
The acid 3 is a known intermediate in the synthesis of the
measles virus inhibitor AS-136A (Scheme 3, bottom).[2d]
It is noteworthy that the amount of water can significantly
interfere with this cycloaddition. We found that, in the
presence of freshly activated molecular sieve powder (4 ꢀ),
the reaction between 4-methylphenylacetylene (1b) and
2,2,2-trifluorodiazoethane proceeded very slowly (48 h) to
give the cycloadduct 2b in 15% yield. In contrast, the
cycloaddition performed with varying stoichiometric amounts
of water led to respectable yields, while excess water was
found to inhibit the reaction (Scheme 4a). To gain some
Scheme 4. a) Effect of water on the cycloaddition. b) Isotopic-labeling
experiments. 3) reaction of silver phenylacetylide with CF3CHN2.
Scheme 3. Scaled-up cycloaddition reaction and further synthetic trans-
formation of the cycloadducts.
insight into the reaction mechanism and to further identify the
role of water in this transformation, we conducted the
following experiments under the standard reaction condi-
tions. Reaction 1b with 2,2,2-trifluorodiazoethane in the
presence of D2O delivered the cycloadduct 2b in 58% yield
upon isolation (Scheme 4b). The deuterated product was
detected by 1H NMR spectroscopy as anticipated. In the
control experiment, however, we did not observe any
incorporation of the deuterium into the pyrazole ring when
D2O was used as an additive. Therefore, the intermolecular
proton exchange between cycloadduct and water is impos-
sible. In addition, we synthesized the silver acetylide,[12] and
investigated its reaction with 2,2,2-trifluorodiazoethane
(Scheme 4c). Without the additional Ag2O, the cycloadduct
2a was obtained in 28% yield. In the presence of additional
silver oxide, silver phenylacetylide could react with 2,2,2-
reaction of the terminal alkynes 1b, 1h, and 1y with 2,2,2-
trifluorodiazoethane was run on a gram scale. These cyclo-
adducts (2b, 2h, and 2y) are versatile synthetic intermediates,
and can be further used in the preparation of relative drugs
including Celecoxib, Mavacoxib, AS-136 A, and Razaxaban.
For example, copper-catalyzed N arylation of 2b with N,N-
dibenzyl-4-iodobenzenesulfonamide,
and
subsequent
removal of the benzyl group afforded the antiarthritic drug
Celecoxib in the yield of 51%. The melting point and spectral
data of Celecoxib are in full agreement with those described
in the literature (Scheme 3, top).[2a] Methylation of ethyl 3-
trifluoromethyl pyrazole-5-carboxylate (2y) with iodome-
thane in DMF, and subsequent hydrolysis afforded the 3-
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trifluorodiazoethane and afford the product 2a in good yield.
The internal 1,2-diphenylethyne was also tested in the
reaction, instead of terminal alkynes, however, no desired
product was observed. These results indicate that silver
acetylide might be the active species in the reaction, and that
the additional silver oxide must be needed to achieve this
cycloaddition.
On the basis of these experimental results, we proposed
the reaction mechanism as outlined in Scheme 5. Initially, the
silver acetylide complex A is formed by the reaction of the
[3] a) L. Yet, Comprehensive heterocyclic chemistry III, 1st ed.,
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Scheme 5. Proposed mechanism.
terminal alkyne 1 with silver(I). Then, through the silver-
promoted 1,3-dipolar cycloaddition of A with CF3CHN2, the
crucial intermediate B is obtained. The subsequent step is the
1,3-hydrogen shift and hydrolysis of B, thus giving rise to the
1H-pyrazole product. Further analysis will be necessary to
elucidate the nature of this cycloaddition more accurately.
In summary, we have developed a novel silver-mediated
cycloaddition reaction of terminal alkynes with CF3CHN2
generated from readily available CF3CH2NH2·HCl. This
protocol represents a direct and efficient way to construct 5-
substituted 3-trifluoromethylpyrazoles under mild reaction
conditions. The reaction is exceptionally regioselective and
the products are of high value for multiple synthetic
applications. Meanwhile, the recovery experiment of silver
species could dramatically reduce the cost and waste which
would allow a large range of applications in the organic
synthesis. Efforts are currently underway to elucidate the
mechanistic details, and the scope and limitations of this
reaction, the results of which will be reported in due course.
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Received: March 5, 2013
Published online: && &&, &&&&
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Keywords: alkynes · cycloaddition · fluorine · regioselectivity ·
silver
.
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4
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Chemie
Communications
Synthetic Methods
F. Li, J. Nie, L. Sun, Y. Zheng,
J.-A. Ma*
&&&& — &&&&
Silver-Mediated Cycloaddition of Alkynes
with CF3CHN2: Highly Regioselective
Synthesis of 3-Trifluoromethylpyrazoles
Silver screen: The title reaction provides
a convenient and efficient method for the
construction of 5-substituted 3-trifluoro-
methylpyrazoles under mild reaction
conditions. By using this protocol, the
marketed drug Celecoxib (antiarthritic)
could be easily synthesized (see scheme;
DMF=N,N-dimethylformamide).
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