Use of a Traceless Activating and Directing Group for the Construction of Trifluoromethylpyrazoles: One-Pot Transformation of Nitroolefins and Trifluorodiazoethane

Article abstract of DOI:10.1002/anie.201700955

We disclose an efficient one-pot transformation of trifluorodiazoethane and higher perfluorinated homologues with various nitroolefins. This method takes advantage of the nitro group as a traceless activating and directing group (TADG) that is released in the aromatization step to produce 4-substituted 3-perfluoroalkyl pyrazoles with complete regioselectivity. The potential of this method is further demonstrated by the synthesis of penthiopyrad.

Full text of DOI:10.1002/anie.201700955

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Chemie
International Edition: DOI: 10.1002/anie.201700955
German Edition: DOI: 10.1002/ange.201700955
Synthetic Methods
Use of a Traceless Activating and Directing Group for the Construction
of Trifluoromethylpyrazoles: One-Pot Transformation of Nitroolefins
and Trifluorodiazoethane
Zhen Chen, Yan Zheng, and Jun-An Ma*
Dedicated to Professor Qi-Lin Zhou on the occasion of his 60th birthday
Abstract: We disclose an efficient one-pot transformation of
trifluorodiazoethane and higher perfluorinated homologues
with various nitroolefins. This method takes advantage of the
nitro group as a traceless activating and directing group
(TADG) that is released in the aromatization step to produce 4-
substituted 3-perfluoroalkyl pyrazoles with complete regiose-
lectivity. The potential of this method is further demonstrated
by the synthesis of penthiopyrad.
T
he 3-trifluoromethylpyrazoles are key structural motifs
found in many important pharmaceuticals and agrochemicals,
and related biologically active compounds (Figure 1).[1,2]
Consequently, substantial effort has been devoted to the
development of synthetic methods for the construction of
these highly functionalized architectures.[3] Traditional pro-
cesses involved the cyclocondensation of various 4,4,4-tri-
fluoro-1,3-dicarbonyl compounds with the corresponding
hydrazines. However, these methods are limited by the
accessibility of the required starting materials and regiose-
lectivity issues.[3c]
Intermolecular cycloaddition reactions are powerful
transformations for the construction of carbo- and hetero-
cycle frameworks from simple starting materials.[4] In the past
decade, 2,2,2-trifluorodiazoethane has emerged as an attrac-
tive building block, and a great number of unprecedented
reactions and elegant procedures have been developed for the
facile synthesis of various fluorine-containing compounds.[5,6]
In this context, the research group of Mykhailiuk and our
research group have disclosed cycloaddition reactions of
alkynes and allenes with 2,2,2-trifluorodiazoethane
(CF3CHN2) for the preparation of 5-substituted and 4,5-
disubstituted 3-trifluoromethylpyrazoles (Scheme 1a).[7] On
the basis of this behavior, we surmised that 4-substituted 3-
trifluoromethylpyrazoles, which remain an unsolved case for
preparation with CF3CHN2 owing to unique challenges with
regard to regioselectivity in the formation of the product and
Figure 1. 3-Trifluoromethylpyrazole-based bioactive compounds.
[*] Z. Chen, Dr. Y. Zheng, Prof. Dr. J.-A. Ma
Department of Chemistry, Tianjin Key Laboratory of Molecular
Optoelectronic Sciences, Tianjin University, and Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin)
Tianjin 300072 (P. R. of China)
Scheme 1. Use of CF3CHN2 for the synthesis of 3-trifluoromethylpyr-
azoles. EWG=electron-withdrawing group.
http://www.tjuchemistry.org/usr/maja.htm
E-mail: majun_an68@tju.edu.cn
isomerization, could be constructed through a one-pot multi-
step reaction of 2,2,2-trifluorodiazoethane with nitroolefins
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201700955.
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(Scheme 1b). In this scenario, the nitro group would function
as a traceless activating and directing group to facilitate
regioselective alkene incorporation and would ultimately be
removed by elimination in situ. Herein, we report the
successful implementation of this strategy and outline an
efficient regiospecific route to 4-substituted 3-trifluorome-
thylpyrazoles. The potential of this approach is also demon-
strated by the synthesis of the agrochemical fungicide
penthiopyrad.
Scheme 2. Cycloaddition of nitrostyrene 1a with CF3CHN2.
One earlier study focused on a stepwise process involving
the intermolecular cycloaddition of nitroolefins with diazo
compounds and the decomposition of the resulting nitro-
pyrazolines to give a limited range of pyrazoles.[8a,b] More
recently, an interesting report by Xie et al. addressed the
catalyst-free one-pot transformation of nitroolefins and ethyl
diazoacetate into the corresponding pyrazoles.[8c] On the basis
of this important precedent, we examined the reaction of
nitrostyrene 1a with 2,2,2-trifluorodiazoethane in tetrahydro-
furan (THF; Scheme 2). Although the desired product 4-
phenyl-3-trifluoromethylpyrazole (3a) was not obtained at
room temperature after 72 h,
moted this one-pot process to provide 4-phenyl-3-trifluoro-
methylpyrazole (3a) as a single regioisomer in 20% yield; all
other metal additives tested were ineffective (Table 1,
entries 1 and 2). Subsequently, a series of silver salts and
bases were examined (entries 3–12). A combination of Ag2O
and Na3PO4 was found to remarkably increase the reactivity
and efficiency of the system, and the yield of isolated 3a was
further improved to 89% (entry 10). Additional solvent
screening demonstrated that besides THF, toluene and
acetonitrile also promoted this transformation, whereas the
a small amount of the cycloaddition
Table 1: Optimization of the reaction conditions for the one-pot transformation of nitrostyrene 1a and
CF3CHN2 into 4-phenyl-3-trifluoromethylpyrazole (3a).[a]
intermediate 2 was observed by
19F NMR analysis during the
course of the reaction (doublet at
À78.9 ppm, 13% conversion; see
the Supporting Information: SI).
Unfortunately, an attempt to isolate
this intermediate species by column
chromatography was not successful.
ESI mass spectrometry of the reac-
tion mixture allowed the further
identification of this cycloadduct on
the basis of the high-resolution
mass data (m/z [M+Na]+ calcd for
Entry
1
Additives (equiv)
Solvent
THF
t [h]
Yield [%][b]
0
Zn(OAc)2 (1), Mn(OAc)2 (1), Ni(OAc)2 (1),
or Pd(OAc)2 (1)/ NaOAc (1)
AgOAc (1)/ NaOAc (1)
AgOAc (1)/ Cs2CO3 (1)
AgNO3 (1)/ Cs2CO3 (1)
Ag2CO3 (1)/ Cs2CO3 (1)
Ag2O (1)/ Cs2CO3 (1)
12
2
3
4
5
6
THF
THF
THF
THF
12
10
10
10
3
20
35
41
28
70
70
72
78
89
85
35
83
5[c]
3[c]
83
5[c]
60
85
0[c]
12[c]
0[c]
[C10H8F3N3O2Na]+:
282.0461;
THF
7
Ag2O (1)/ K2CO3 (1)
THF
3
found: 282.0460). The addition of
excess CF3CHN2 (8 equiv) to the
reaction system led to the formation
of more of the cycloadduct (27%
conversion). Thus, this cycloaddi-
tion might be a reversible process
that results in an equilibrium mix-
ture of the reactants and the cyclo-
adduct. Further changes in the reac-
tion temperature and the ratio of
reactants did not furnish the target
product 3a, nor did the use of
various acid or basic additives (see
the Supporting Information).
8
Ag2O (1)/ Na2CO3 (1)
THF
3
9
Ag2O (1)/ Na3PO4 (1)
THF
3
10
11
12
13
14
15
16
17
18
19[d]
20[e]
21[e]
22[e]
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (2)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na2HPO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (1.5)
Ag2O (1.5)/ Na3PO4 (2)
Ag2O (1.5)/ Na3PO4 (2)
Ag2O (1.5)/ Na3PO4 (2)
Ag2O (1.5)/ Na3PO4 (2)
THF
THF
THF
3
3
3
3
24
24
3
24
3
toluene
CH2Cl2
CHCl3
CH3CN
DMF
hexane
THF
H2O
3
12
12
12
H2O/toluene
H2O/THF
Clearly, the rules that govern
the synthesis of nonfluorinated ana-
logues could not be transposed to
fluorinated compounds, and we
explored the use of metal additives
to promote this transformation to
afford 4-substituted 3-trifluorome-
thylpyrazoles. We were pleased to
[a] Reaction conditions (method A): A mixture of 1a (0.5 mmol) and CF3CHN2 (1.0 mmol) was stirred in
the indicated solvent (5.0 mL) at room temperature. [b] Yield of the isolated product. [c] The yield was
determined by 19F NMR spectroscopy with (trifluoromethyl)benzene as an internal standard.
[d] Reaction conditions (method B): A mixture of trifluoroethylamine (1.0 mmol), tert-butyl nitrite
(1.1 mmol), and acetic acid (0.2 mmol) in THF (5 mL) was heated at 558C for 15 min and then cooled to
258C. Then, 1a (0.5 mmol), Ag2O (0.75 mmol), and Na3PO4 (1.0 mmol) were added, and the mixture
was stirred at 258C for 3 h. [e] Reaction conditions (method C): A mixture of trifluoroethylamine
hydrochloride (1.0 mmol) and sodium nitrite (1.1 mmol) were stirred at 08C in water or toluene/water
(10:1) or THF/water (10:1) for 1 h. Then, 1a (0.5 mmol), Ag2O (0.75 mmol), and Na3PO4 (1.0 mmol)
find that AgOAc and NaOAc pro- were added, and the mixture was stirred at 258C for 12 h. DMF=N,N-dimethylformamide.
2
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use of dichloromethane, chloroform, DMF, or hexane led to
conversion (< 15%) into the desired product (Table 1,
entries 20–22).
a significantly lower yield (entries 13–18). Encouraged by the
seminal studies of Morandi and Carreira[6c] and Mykhailiuk[9]
on the in situ preparation and use of diazo compounds, we
also investigated the generation of trifluorodiazoethane
in situ and its subsequent one-pot reaction with nitrostyrene
1a (entries 19–22). In an organic medium, 3-trifluoromethyl-
pyrazole 3a could be obtained in 85% yield (entry 19),
whereas the use of aqueous media resulted in very low
Having optimized the reaction conditions, we proceeded
to expand the scope of the reaction with a broad array of
nitroolefin substrates. In most cases the use of a stock solution
of CF3CHN2 (method A) gave rise to a higher yield than the
generation of CF3CHN2 in situ (method B; Scheme 3). A
series of nitrostyrenes with electron-donating and electron-
withdrawing substituents on the phenyl ring, such as methyl,
Scheme 3. Silver(I)-mediated reaction of nitroolefins with RfCHN2. Method A: A mixture of nitroolefin 1 (0.5 mmol), RfCHN2 (1.0 mmol), Ag2O
(0.75 mmol), and Na3PO4 (0.75 mmol) in THF (5.0 mL) was stirred at room temperature. Method B: A mixture of the perfluoroalkyl amine
(1.0 mmol), tert-butyl nitrite (1.1 mmol), and acetic acid (0.2 mmol) in THF (5 mL) was heated at 558C for 15 min and then cooled to room
temperature. Then, nitroolefin 1 (0.5 mmol), Ag2O (0.75 mmol), and Na3PO4 (1.0 mmol) were added, and the mixture was stirred at the same
temperature. All yields are for the isolated product (the first values are for method A; those in parenthesis are for method B). [a] Cs2CO3 was used
instead of Na3PO4, and the reaction was carried out at 408C for 10 h.
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methoxy, dimethylamino, phenyl, halo, trifluoromethyl, and
cyano groups, underwent the desired transformation in
a regiospecific fashion to deliver the corresponding products
3a–m in good to excellent yields (60–99%). The structure of
4-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole (3j) was
confirmed by means of X-ray crystallographic analysis (see
the Supporting Information). 1-Naphthyl-, 2-naphthyl-, 9-
anthracenyl-, 2-furanyl-, and 2-thienyl-substituted nitroole-
fins were also found to be good substrates, thus generating the
desired products 3n–r in high yields. For 2-pyridinyl- and 3-
pyridinyl-substituted nitroolefins, the use of the stock solution
of CF3CHN2 for the cycloaddition provided products 3s and
3t in 77 and 74% yield, whereas the one-pot protocol with
CF3CHN2 generated in situ in THF furnished the products in
lower yields of 32 and 20%, respectively. Interestingly, several
nitrodienes and nitroenynes also reacted well under the same
reaction conditions to afford the corresponding 4-substituted
3-trifluoromethylpyrazoles 3u–x with perfect chemo- and
regioselectivity. To further define the scope of our protocols,
we tested the reactions of trisubstituted and alkyl-substituted
nitroolefins. These substrates also gave the expected products
3y, 3z, and 3a’–f’ in 50–99% yield. Several perfluorinated
diazo compounds were also prepared and tested, and the
corresponding products 3g’-j’ were obtained in moderate to
good yields with excellent regioselectivity. However, when
difluorodiazoethane was used, no cycloadduct was observed,
and the starting nitrostyrene 1a was fully recovered.[10]
We next turned our attention to the application of the
current protocols to the synthesis of the agricultural fungicide
penthiopyrad. With the stock solution of CF3CHN2 in THF,
the 2-furanyl-substituted nitroolefin 1q was found to undergo
the desired transformation on a gram scale to afford the
corresponding product 3q in 86% yield (Scheme 4, top). The
one-pot reaction of CF3CHN2, generated in situ, with nitro-
olefin 1 f’ on a gram scale also proceeded well to give the
cycloaddition product 3 f’ in good yield (Scheme 4, bottom).
Notably, the excess Ag2O and the resulting silver species
could be recycled by simple filtration and treatment with
nitric acid and NaOH. The regenerated Ag2O could still
promote this cycloaddition without loss of activity. Direct N-
methylation of 3q with iodomethane under basic conditions
and subsequent oxidation with NaIO4 and RuCl3 (catalytic
amount) gave the corresponding 3-trifluoromethylpyrazole-4-
carboxylic acid 4 in 84% yield. This acid intermediate 4 could
be also prepared in 74% yield by successive methylation and
hydrolysis of the cycloaddition product 3 f’. Upon the treat-
ment of 4 with phosphorus pentachloride and 2-(4-methyl-
pentan-2-yl)thiophen-3-amine in a one-pot process, the
desired product penthiopyrad (5) was obtained in 90%
yield. The melting point and spectral data of penthiopyrad
are in full agreement with those reported previously.[2d]
To further probe the progression of this one-pot trans-
formation, we monitored the reaction mixture of nitrostyrene
1a, CF3CHN2, Ag2O, and Na3PO4 in THF by NMR spectros-
copy. 19F NMR analysis of the reaction filtrate revealed the
appearance of two new signals at À48.0 and À58.4 ppm
(Figure 2a). To gain more insight into this interesting
observation, we performed several control experiments (Fig-
ure 2b). When a mixture of CF3CHN2 with Ag2O and Na3PO4
Scheme 4. Scaled-up one-pot reaction and further synthetic transfor-
mation.
was stirred at room temperature, a new species with
a
19F NMR signal at À48.0 ppm was produced, the structure
of which was determined to be a silver trifluorodiazoethylide
by 1H and 13C NMR spectroscopy. When nitrostyrene 1a was
added to the above-mentioned mixture and the mixture was
then stirred at room temperature for 3 h, a stable species with
a
19F NMR signal at À58.4 ppm was observed, probably
pointing to a pyrazolyl silver intermediate. When this reaction
was quenched with a saturated solution of NaCl in D2O, the
deuterated product 3a was identified by 19F and H NMR
1
spectroscopy as anticipated. Furthermore, we found that the
reaction yield of CF3CHN2 and nitrostyrene decreased
gradually as the amount of water present increased (Fig-
ure 2c). This result showed that excess water was deleterious
to our one-pot transformation.
On the basis of these preliminary results, a stepwise
process could be involved in the reaction (Figure 2d): In the
presence of Ag2O and Na3PO4, CF3CHN2 is initially con-
verted into silver trifluorodiazoethylide (A). The selective
addition of A to nitroolefins 1 gives an active intermediate B,
which is believed to undergo fast elimination under the basic
conditions to afford the pyrazolyl silver intermediate C.
Intermediate C could also be produced from the cycloadduct
intermediate 2. Subsequent hydrolysis of C furnished the final
products 3.
In conclusion, we have developed an expedient one-pot
transformation of trifluorodiazoethane with a wide variety of
nitroolefins. This methodology, based on a traceless activating
and directing group (TADG) strategy, exhibits remarkable
features, such as mild reaction conditions, operational sim-
plicity, readily accessible starting materials, and excellent
regioselectivity, thus providing facile access to highly func-
tionalized 4-substituted 3-trifluoromethyl-1H-pyrazoles. The
4
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Figure 2. Mechanistic studies. a) 19F NMR analysis of the reaction progress. b) Several control experiments. c) Influence of water on the reaction
yield. d) Proposed mechanism. MS=molecular sieves.
synthetic potential of this approach was demonstrated by the
further transformation of two of the products into the
agrochemical fungicide penthiopyrad. Furthermore, per-
fluorinated diazo compounds were also converted into the
corresponding pyrazole derivatives in a regiospecific fashion.
Further mechanistic investigations and studies of the appli-
cation of trifluorodiazoethane and perfluorodiazo com-
pounds in other synthetic reactions are under way in our
laboratory.
Keywords: diazo compounds · nitroolefins · pyrazoles ·
regioselectivity · traceless directing groups
[1] For reviews, see: a) C. Lamberth, Heterocycles 2007, 71, 1467;
b) L. Yet, Comprehensive Heterocyclic Chemistry III, Vol. 4, 1st
ed., Elsevier, Oxford, 2008, p. 1; c) J. Elguero, A. M. S. Silva,
A. C. Tomꢀ in Modern Heterocyclic Chemistry, 1st ed., Wiley-
VCH, Weinheim, 2011, p. 635.
[2] For selected examples, see: a) T. D. Penning, J. J. Talley, S. R.
Bertenshaw, J. S. Carter, P. W. Collins, S. Doctor, M. J. Greveto,
L. F. Lee, J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. J.
Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, S. A. Gregory,
C. M. Icoboldt, W. E. Perkus, K. Seibert, A. W. Veenhuizen,
Y. Y. Zhang, P. C. Isakson, J. Med. Chem. 1997, 40, 1347; b) H.
Katsuta, S. Ishii, K. Tomiya, K. Kodaka, EP 1036793, 2000; c) N.
Masao, K. Ryotaro, M. Masahiro, K. Koichiro, F. Makoto, U.
Ryohei, T. Satoru, WO2002062770, 2002; d) S. M. Sakya, X.
Hou, M. L. Minich, B. Rast, A. Shavnya, K. M. L. DeMello, H.
Cheng, J. Li, B. H. Jaynes, D. W. Mann, C. F. Petras, S. B. Seibel,
M. L. Haven, Bioorg. Med. Chem. Lett. 2007, 17, 1067; e) S. R.
Cox, S. P. Lesman, J. F. Boucher, M. J. Krautmann, B. D.
Hummel, M. Savides, S. Marsh, A. Fielder, M. R. Stegemann,
Acknowledgements
This research was supported financially by the National
Natural Science Foundation of China (No. 21225208,
21472137 and 21532008) and the National Basic Research
Program of China (973 Program: 2014CB745100).
Conflict of interest
The authors declare no conflict of interest.
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J. Vet. Pharmacol. Ther. 2010, 33, 461; f) J. E. Harms, M.
Benveniste, J. K. F. Maclean, K. M. Partin, C. Jamieson, Neuro-
pharmacology 2013, 64, 45.
chev, P. K. Mykhailiuk, Eur. J. Org. Chem. 2014, 3592; l) T.-R. Li,
S.-W. Duan, W. Ding, Y.-Y. Liu, J.-R. Chen, L.-Q. Lu, W.-J. Xiao,
J. Org. Chem. 2014, 79, 2296; m) H.-Y. Xiong, Z.-Y. Yang, Z.
Chen, J.-L. Zeng, J. Nie, J.-A. Ma, Chem. Eur. J. 2014, 20, 8325;
n) H. Mao, A. Lin, Z. Tang, H. Hu, C. Zhu, Y. Cheng, Chem. Eur.
J. 2014, 20, 2454; o) G. A. Molander, D. Ryu, Angew. Chem. Int.
Ed. 2014, 53, 14181; Angew. Chem. 2014, 126, 14405; p) G. Wu,
Y. Deng, C. Wu, X. Wang, Y. Zhang, J. Wang, Eur. J. Org. Chem.
2014, 4477; q) H. Luo, G. Wu, Y. Zhang, J. Wang, Angew. Chem.
Int. Ed. 2015, 54, 14503; Angew. Chem. 2015, 127, 14711; r) S.
Hyde, J. Veliks, B. Liꢀgault, D. Grassi, M. Taillefer, V.
Gouverneur, Angew. Chem. Int. Ed. 2016, 55, 3785; Angew.
Chem. 2016, 128, 3849; s) B. Pieber, C. O. Kappe, Org. Lett. 2016,
18, 1076; t) L. Mertens, K. J. Hock, R. M. Koenigs, Chem. Eur. J.
2016, 22, 9542.
[3] a) S. Fustero, M. Sꢁnchez-Rosellꢂ, P. Barrio, A. Simꢂn-Fuentes,
Chem. Rev. 2011, 111, 6984; b) F. Giornal, S. Pazenok, L.
Rodefeld, N. Lui, J.-P. Vors, F. R. Leroux, J. Fluorine Chem.
2013, 152, 2; c) J. C. Sloop, C. Holder, M. Henary, Eur. J. Org.
Chem. 2015, 3405.
[4] a) W. C. Herndon, Chem. Rev. 1972, 72, 157; b) W. Carruthers,
Cycloaddition Reactions in Organic Synthesis, Elsevier, Amster-
dam, 1990, pp. 1 – 382 (Tetrahedron Organic Chemistry Series
Vol. 8); c) N. Nishiwaki, Methods and Applications of Cyclo-
addition Reactions in Organic Syntheses, Wiley-VCH, Hoboken,
2014, pp. 1 – 655.
[5] a) O. O. Grygorenko, O. S. Artamonov, I. V. Komarov, P. K.
Mykhailiuk, Tetrahedron 2011, 67, 803; b) D. Qiu, M. Qiu, R.
Ma, Y. Zhang, J. Wang, Acta Chim. Sin. 2016, 74, 472.
[7] a) F. Li, J. Nie, L. Sun, Y. Zheng, J.-A. Ma, Angew. Chem. Int. Ed.
2013, 52, 6255; Angew. Chem. 2013, 125, 6375; b) E. Y. Slobo-
dyanyuk, O. S. Artamonov, O. V. Shishkin, P. K. Mykhailiuk,
Eur. J. Org. Chem. 2014, 2487; c) F.-G. Zhang, Y. Wei, Y.-P. Yi, J.
Nie, J.-A. Ma, Org. Lett. 2014, 16, 3122; d) P. K. Mykhailiuk, Org.
Biomol. Chem. 2015, 13, 3438.
[8] a) W. E. Parham, J. L. Bleasdale, J. Am. Chem. Soc. 1950, 72,
3843; b) W. E. Parham, J. L. Bleasdale, J. Am. Chem. Soc. 1951,
73, 4664; c) J.-W. Xie, Z. Wang, W.-J. Yang, L.-C. Kong, D.-C. Xu,
Org. Biomol. Chem. 2009, 7, 4352.
[6] For selected examples, see: a) P. K. Mykhailiuk, S. Afonin, G. V.
Palamarchuk, O. V. Shishkin, A. S. Ulrich, I. V. Komarov,
Angew. Chem. Int. Ed. 2008, 47, 5765; Angew. Chem. 2008,
120, 5849; b) B. Morandi, E. M. Carreira, Angew. Chem. Int. Ed.
2010, 49, 938; Angew. Chem. 2010, 122, 950; c) B. Morandi, E. M.
Carreira, Angew. Chem. Int. Ed. 2010, 49, 4294; Angew. Chem.
2010, 122, 4390; d) B. Morandi, B. Mariampillai, E. M. Carreira,
Angew. Chem. Int. Ed. 2011, 50, 1101; Angew. Chem. 2011, 123,
1133; e) B. Morandi, E. M. Carreira, Angew. Chem. Int. Ed.
2011, 50, 9085; Angew. Chem. 2011, 123, 9251; f) C.-B. Liu, W.
Meng, F. Li, S. Wang, J. Nie, J.-A. Ma, Angew. Chem. Int. Ed.
2012, 51, 6227; Angew. Chem. 2012, 124, 6331; g) Z. Chai, J.-P.
Bouillon, D. Cahard, Chem. Commun. 2012, 48, 9471; h) O. S.
Artamonov, E. Y. Slobodyanyuk, O. V. Shishkin, I. V. Komarov,
P. K. Mykhailiuk, Synthesis 2013, 225; i) G. A. Molander, L. N.
Cavalcanti, Org. Lett. 2013, 15, 3166; j) O. A. Argintaru, D. Ryu,
I. Aron, G. A. Molander, Angew. Chem. Int. Ed. 2013, 52, 13656;
Angew. Chem. 2013, 125, 13901; k) O. S. Artamonov, E. Y.
Slobodyanyuk, D. M. Volochnyuk, I. V. Komarov, A. A. Tolma-
[9] a) P. K. Mykhailiuk, Chem. Eur. J. 2014, 20, 4942; b) P. K.
Mykhailiuk, Angew. Chem. Int. Ed. 2015, 54, 6558; Angew.
Chem. 2015, 127, 6658.
[10] 19F NMR analysis of the reaction mixture showed that difluor-
odiazoethane underwent rapid decomposition under the current
conditions.
Manuscript received: January 26, 2017
Final Article published: && &&, &&&&
6
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
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Angewandte
Communications
Chemie
Communications
Synthetic Methods
Z. Chen, Y. Zheng,
J.-A. Ma*
&&&& — &&&&
Use of a Traceless Activating and
Directing Group for the Construction of
Trifluoromethylpyrazoles: One-Pot
Transformation of Nitroolefins and
Trifluorodiazoethane
Leaves discreetly when the job is done: A
one-pot reaction of trifluorodiazoethane
and higher perfluorinated homologues
with various nitroolefins takes advantage
of the nitro group as a traceless activating
and directing group that is released in the
aromatization step to produce 4-substi-
tuted 3-perfluoroalkyl pyrazoles with
complete regioselectivity (see scheme).
The method was applied to the synthesis
of the fungicide penthiopyrad.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!