Zinc-Enabled Annulation of Trifluorodiazoethane with 2 H-Azirines to Construct Trifluoromethyl Pyrazolines, Pyrazoles, and Pyridazines

Article abstract of DOI:10.1021/acs.orglett.1c02139

A diethylzinc-promoted unconventional annulation reaction of 2,2,2-trifluorodiazoethane with 2H-azirines is described. This transformation involves two [3 + 2] cycloaddition steps and one dinitrogen extrusion process in one pot, thus giving a broad array

Full text of DOI:10.1021/acs.orglett.1c02139

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Letter
Zinc-Enabled Annulation of Trifluorodiazoethane with 2H‑Azirines
to Construct Trifluoromethyl Pyrazolines, Pyrazoles, and Pyridazines
Yue-Ji Chen, Fa-Guang Zhang,* and Jun-An Ma*
Cite This: Org. Lett. 2021, 23, 6062−6066
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ABSTRACT: A diethylzinc-promoted unconventional annulation
reaction of 2,2,2-trifluorodiazoethane with 2H-azirines is described.
This transformation involves two [3 + 2] cycloaddition steps and
one dinitrogen extrusion process in one pot, thus giving a broad
array of 3-trifluoromethyl pyrazolines in good yields with excellent
diastereoselectivities. Further transformations provide facile access
to 3-trifluoromethyl pyrazoles and 3,5-ditrifluoromethyl pyrida-
zines with good efficiency.
rifluoromethylated N-heterocycles are a kind of ubiq-
Scheme 1. CF CHN -based Annulation Reactions
3 2
T
uitous structural motif found in a vast number of
1
pharmaceuticals, agrochemicals, and functional materials.
Over the past decade, 2,2,2-trifluorodiazoethane (CF CHN )
3
2
2
has emerged as a highly attractive and powerful CF -synthon.
3
Among the established synthetic methods, 1,3-dipolar cyclo-
addition and cyclization reactions are the most frequently
utilized approaches for the construction of five-membered
3
trifluoromethylated N-heterocycles. For example, the [3 + 2]
cycloaddition and cyclization reactions of CF CHN with
3
2
various alkenes, alkynes, allenes, isocynides, imines, and arene-
diazonium salts have allowed straightforward access to a broad
array of trifluoromethylated pyrazolines, pyrazoles, triazoles,
4
and tetrazoles (Scheme 1a). In 2017, Cossy and coworkers
found that the reaction of CF CHN with strained alkenes
3
2
such as difluorocyclopropenes proceeds in a [3 + 2]
cycloaddition/cyclopropane ring-opening process, thus provid-
5
ing a novel entry to 6-CF -pyridazines (Scheme 1b). Recently,
3
our group disclosed a silver-catalyzed [3 + 3] cycloaddition of
glycine imines with CF CHN2 for the synthesis of CF -
3
3
6
(
tetrahydro)triazines (Scheme 1c). On this basis, we
envisioned that 2H-azirines, as highly versatile and strained
imines, may undergo a [3 + 3] annulation reaction with
CF CHN to furnish the dihydrotriazines, which would be
3
2
sequentially oxidized to afford CF -triazines (Scheme 1d,
3
7
top). However, none of the [3 + 3] annulation products were
obtained under the various reaction conditions. Unexpectedly,
an interesting [3 + 2] annulation reaction in the presence of
diethylzinc proceeded well to give 3-trifluoromethyl pyrazo-
lines and could involve the formation of four bonds and the
cleavage of three bonds in a one-pot operation (Scheme 1d,
bottom). Herein we present our findings on this subject.
At the outset, 2,3-diphenyl-2H-azirine 1a was reacted with
Received: June 25, 2021
Published: July 28, 2021
2
,2,2-trifluorodiazoethane (CF CHN ) in the presence of
3 2
diethylzinc at low temperatures. To our surprise, neither the
direct [3 + 3] cycloaddition product 3 nor the 1,2-addition
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c02139
6
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Letter
8
product 4 was observed (Table 1). Instead, a unique 3-
trifluoromethyl pyrazoline 2a was obtained as the major
Scheme 2. Scope of 2H-Azirines in the Annulation Reaction
Table 1. Annulation Reaction of Trifluorodiazoethane with
a
2H-Azirine 1a
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
none
82
73
0
ZnMe instead of Et Zn
2
2
Zn(OTf) instead of Et Zn
2
2
n
BuLi instead of Et Zn
0
2
MeMgBr instead of Et Zn
0
0
2
t
BuOK instead of Et Zn
2
Ag O instead of Et Zn
0
0
60
0
63
28
59
60
85
2
2
DBU instead of Et Zn
1.0 equiv of Et Zn was used
2
2
10
11
12
13
14
15
Et Zn was not added
2
2.0 equiv of CF CHN was used
3
2
toluene instead of MeCN
THF instead of MeCN
0 °C instead of −30 °C
gram-scale experiment
a
N CHCF in a stock solution of acetonitrile (1 mmol, 0.5 mol/L, 5.0
2
3
equiv) was stirred with 2,3-diphenyl-2H-azirine 1a (38.6 mg, 0.2
mmol) in acetonitrile (2 mL) under an argon atmosphere, Et Zn (0.4
2
mL, 0.4 mmol, 1 mol/L in hexane) was added dropwise, and the
reaction mixture reacted at −30 °C for 5 h unless otherwise indicated.
b
Yield of isolated 2a after column chromatography on silica gel.
product (X-ray confirmed), implying that 2 equiv of CF CHN
3
2
was involved in the reaction process. After a series of reaction
parameter optimizations, the yield of 2a could be improved to
8
2% as a single diastereoisomer when the reaction was
performed at −30 °C in acetonitrile for 5 h (entry 1).
Changing diethylzinc to dimethylzinc resulted in a similar
outcome, but the use of other zinc salts such as Zn(OTf)2
completely inhibited the reaction (entries 2 and 3). Moreover,
n
when employing other strong metal bases such as BuLi,
t
MeMgBr, and BuOK, a basic silver salt such as Ag O, and an
2
organic base such as DBU, all turned out with no formation of
the desired product 2a (entries 4−8), demonstrating the
critical role of dialkylzinc in this reaction. Further optimization,
including modifying the amount of starting materials and
changing the solvent and reaction temperature, did not give a
better result, thus establishing the optimal conditions as shown
in entry 1 (entries 9−14). This reaction could also be robustly
conducted on the gram scale, giving 1.7 g of 3-trifluoromethyl
pyrazoline 2a in 85% yield (entry 15).
This zinc-enabled unconventional [3 + 2] annulation
reaction was found to be general for a wide scope of 2H-
azirines. As shown in Scheme 2, changing the aryl groups at the
three-positions of 2H-azirines, including methyl-, methoxyl-,
fluorine-, chlorine-, and bromine-substituted phenyl groups, all
proved to be well compatible with the standard conditions,
giving products 2b−2i in good yields with excellent
diastereoselectivity. 2-Naphthyl- and 2-furyl-derived 2H-
azirines also smoothly participated in the annulation process
and led to the formation of pyrazolines 2j and 2k with good
results. Furthermore, the substituents at the two-positions of
2H-azirines could also be changed with different groups. For
example, the introduction of a methyl group at para, ortho, and
meta positions on the phenyl ring has no significant impact on
the reaction performance (2l−2n). We also tested 2H-azirines
substituted with phenyl groups bearing methoxyl, fluorine,
6
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chlorine, and bromine moieties and obtained the correspond-
ing pyrazoline products in 78−95% yields with excellent dr
ratios in most cases (2o−2v). We have obtained the crystal
structures of both compounds 2e and 2p, which clearly show
the cis stereochemistry of the two different phenyl groups.
Notably, this reaction could also tolerate alkyl groups at the
two-positions of 2H-azirines, thus allowing the liberation of 3-
trifluoromethyl pyrazolines 2w and 2x in good yields with
constant excellent dr values. However, no desired cycloadduct
was observed by using difluorodiazoethane or pentafluorodia-
Scheme 4. Proposed Mechanism
9
zopropane under otherwise identical conditions.
To showcase the synthetic utility of the obtained 3-
trifluoromethyl pyrazolines, we have attempted fragmentation
and ring-expansion transformations (Scheme 3). Treating 2a
Scheme 3. Transforming Pyrazolines 2 to Pyrazoles 5 and
Pyridazines 6
pyrazoline product 2. On the basis of this observation and
4
−6
previous studies,
a tentative mechanism is outlined in
Scheme 4b. Diethylzinc deprotonated CF CHN and the in-
3
2
situ-formed zinc trifluorodiazoethylide underwent a [3 + 2]
cycloaddition reaction with 2H-azirine 2 to give the
triazabicyclo[3.1.0]hex-3-ene intermediate Int-1. Ring opening
of the strained three-membered ring in Int-1 gave the dihydro-
1,2,3-triazine Int-2; then, dinitrogen extrusion proceeded to
form an α,β-unsaturated trifluoromethyl imine Int-3. It is
noteworthy that the observed side product 7 in Scheme 4a is
probably the hydrolyzed product of Int-3, thus supporting the
proposed mechanistic process. Finally, a second round of the
[
3 + 2] cycloaddition process of zinc trifluorodiazoethylide
occurred with Int-3 and provided the final 3-trifluoromethyl
pyrazoline product 2 after hydrolysis.
In summary, an unconventional annulation reaction of zinc
trifluorodiazoethylide with 2H-azirines consisting of two
rounds of [3 + 2] cycloaddition steps, one ring-opening step,
and one dinitrogen elimination step, is developed. Not only
does this one-pot transformation provide efficient access to a
broad range of 3-trifluoromethyl pyrazolines but also further
transformations offer novel synthetic routes to 3-trifluor-
omethyl pyrazoles and 3,5-ditrifluoromethyl pyridazines. The
detailed mechanism and extension of zinc diazo species in
synthetic chemistry are currently under investigation in our
laboratory.
with iodosobenzene diacetate (PhI(OAc) ) under mild
2
conditions could trigger the elimination of the trifluoromethyl
imino motif, thereby generating 3-trifluoromethyl pyrazole 5a
10
in 96% yield (X-ray confirmed). The extension of this
protocol to other substrates proved to be well applicable (5b−
ASSOCIATED CONTENT
sı Supporting Information
■
*
5
g). More interestingly, treating 2a with carbonyldiimidazole
(
CDMI) under basic conditions in refluxing acetonitrile could
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02139.
afford the 3,5-ditrifluoromethyl pyridazine 6a in 75% yield (X-
ray confirmed), which is otherwise difficult to prepare via
Experimental procedures and characterization data of all
11,12
previous synthetic methods.
We are pleased to find that a
1
19
13
new compounds including H, F, and C NMR
spectra (PDF)
series of tetra-substituted 3,5-ditrifluoromethyl pyridazines
6
b−6g could also be smoothly provided in practical yields.
Accession Codes
To investigate the mechanism of this unusual annulation
reaction, we have reduced the amount of CF CHN and Et Zn
CCDC 2086388−2086389 and 2086392−2086394 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
3
2
2
in the model reaction (Scheme 4a). In this case, an α,β-
unsaturated trifluoromethyl ketone 7 was observed in
considerable amount, indicating that a similar ring-opening
species might be the key intermediate leading to the final
6
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Letter
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002-0251-0456; Email: zhangfg1987@tju.edu.cn
Jun-An Ma − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Center of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
P. R. China; Joint School of National University of Singapore
and Tianjin University, International Campus of Tianjin
University, Fuzhou 350207, P. R. China; orcid.org/0000-
(
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002-3902-6799; Email: majun_an68@tju.edu.cn
Author
Yue-Ji Chen − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Center of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
P. R. China; Joint School of National University of Singapore
and Tianjin University, International Campus of Tianjin
University, Fuzhou 350207, P. R. China
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural
Science Foundation of China (nos. 21772142, 21901181, and
■
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