Regioselective cycloaddition of trifluorodiazoethane with electron-deficient allenic esters and ketones: Access to CF3- substituted pyrazolines and pyrazoles

Article abstract of DOI:10.1021/ol501249h

A highly regioselective cycloaddition procedure of electron-deficient allenes with trifluorodiazoethane (CF₃CHN₂) is described. In absence of bases, the reaction proceeded smoothly to give 5-(trifluoromethyl)pyrazolines, whereas the utility of Et₃N led to the formation of 3-(trifluoromethyl)pyrazoles.

Full text of DOI:10.1021/ol501249h

Letter
pubs.acs.org/OrgLett
Regioselective Cycloaddition of Trifluorodiazoethane with Electron-
Deficient Allenic Esters and Ketones: Access to CF3‑Substituted
Pyrazolines and Pyrazoles
Fa-Guang Zhang, Yi Wei, Yu-Ping Yi, Jing Nie, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (the Ministry of Education), Tianjin University and
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: A highly regioselective cycloaddition procedure of
electron-deficient allenes with trifluorodiazoethane (CF3CHN2) is
described. In absence of bases, the reaction proceeded smoothly to
give 5-(trifluoromethyl)pyrazolines, whereas the utility of Et3N led to
the formation of 3-(trifluoromethyl)pyrazoles.
rifluoromethyl-substituted pyrazolines and pyrazoles are
Scheme 1. Cycloaddition Reactions of CF3CHN2 with
T
privileged structural motifs found in many pharmaceut-
Electron-Deficient Alkenes, Alkynes, and Allenes
icals and bioactive compounds (Figure 1),1 and thus, the
dipolarophile scope. To overcome the problems, our group
developed silver-mediated [3 + 2] cycloaddition of alkynes with
the stock solution of CF3CHN2 in organic solvents,4 whereas
Mykhailiuk and co-workers reported the [3 + 2] cycloaddition
of the in situ generated CF3CHN2 with electron-deficient
alkenes and alkynes to give a series of trifluoromethyl-
substituted pyrazolines and pyrazoles.5 In comparison with
the previous methods, these newly protocols employ milder
conditions and afford the desired adducts with improved
functional group tolerance. Despite this promising progress, it
is still highly desirable to develop new cycloaddition reactions
Figure 1. Bioactive molecules based on trifluoromethylated pyrazo-
lines and pyrazoles.
development of new methodologies for constructing these
compounds has been an active research area in organic
synthesis and drug chemistry.2 The cycloaddition of 2,2,2-
trifluorodiazoethane (CF3CHN2) with alkenes and alkynes
represents a convenient access to trifluoromethylated pyrazo-
lines and pyrazoles (Scheme 1a). In this context, the earlier
studies focused on the use of liquid CF3CHN2 purified at
superlow temperature.3 Unfortunately, these methods usually
suffer from relatively harsh reaction conditions and limited
Received: May 1, 2014
© XXXX American Chemical Society
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Letter
with CF3CHN2 and to broaden the diversity of trifluoromethy-
lated pyrazoline and pyrazole species.
Scheme 2. Cycloaddition of CF3CHN2 with Electron-
Deficient Allenes 1 into 5-Trifluoromethylpyrazolines 2
a
In recent years, allenes, in particular electron-deficient
allenes, have emerged as attractive building blocks in organic
synthesis,6 and many cycloaddition reactions of electron-
deficient allenes have been developed for the construction of
carbo- and heterocyclic molecules.7 However, the use of
electron-deficient allenes as the dipolarophiles for the cyclo-
addition reaction of CF3CHN2 still remains elusive. Herein, we
report our efforts in the development of this cycloaddition
process (Scheme 1b). Such studies would be of benefit in
expanding the diversity of pyrazoline and pyrazole derivatives in
synthetic chemistry.
We began our investigations by evaluating the stock solution
of CF3CHN2 in several solvents, and the results are shown in
Table 1. To our surprise, at room temperature and without any
a
Table 1. Screening Optimal Conditions
b
CF3CHN2 in solvent (mol/L,
equiv)
temp (°C)/time
yield
(%)
entry
(h)
1
DMF (0.15, 2.0)
DMF (0.15, 2.0)
DMF (0.15, 2.0)
THF (0.2, 2.0)
25/30
40/30
60/30
40/30
40/30
40/30
40/30
40/30
40/30
40/48
40/60
50
83
82
82
68
45
10
10
0
2
3
4
5
Toluene (0.15, 2.0)
DCE (0.3, 3.0)
6
7
DCM (0.2, 3.0)
DME (0.15, 3.0)
CH3CN (0.2, 3.0)
DMF (0.15, 2.0)
DMF (0.15, 2.0)
8
a
General reaction conditions: allene 1 (0.2 mmol, 1.0 equiv) and
CF3CHN2 (0.4 mmol, 2.0 equiv) in DMF were reacted in a sealed
9
10
11
88
85
b
tube at 40 °C for 48 h. Isolated yield.
a
General reaction conditions: benzyl allenoate 1a (0.2 mmol, 1.0
equiv) and CF3CHN2 in appropriate solvent were reacted in a sealed
tube at constant temperature. Isolated yield.
cycloaddition or cyclopropanation byproducts despite the
presence of olefin moieties in the reactants. Several allenoates
with different ester substituents were also capable in this
approach to give the cycloadducts 2i−l in high yields. The
exocyclic CC double bond was determined to be Z geometry
by a 2D-NOESY analysis of 2i (see the Supporting
Information). Furthermore, this can be rationalized by
assuming that trifluorodiazoethane is approaching from the
less hindered side of the substituted allene to generate (Z)-
product (Figure 2). In addition, enhanced 1,3-allylic strain in
the formed (E)-cycloadduct should favor formation of the (Z)-
product. Subsequently, two allenic ketones could also be used
as the dipolarophile partners, thus providing the cycloadducts
2m and 2n in the yield of 82% and 56%, respectively. Finally,
we investigated the cycloaddition reaction of trifluorodiazo-
ethane with γ-aryl-substituted allenoate esters, such as benzyl γ-
phenylbuta-2,3-dienoate, benzyl γ-(2-thiophenyl)buta-2,3-dien-
oate, and ethyl γ-phenylbuta-2,3-dienoate. These substrates
were found to be unsuitable for this transformation, and no
desired cycloadducts were obtained even when the reaction
temperature was increased to 80 °C.
b
additive, the cycloaddition of benzylbuta-2,3-dienoate 1a with
CF3CHN2 in N,N-dimethylformamide (DMF) proceeded to
give 5-trifluoromethylpyrazoline 2a as a single regioisomer in
50% yield (entry 1). Increasing the reaction temperature
provided 2a in higher yields (entries 2 and 3). Good yield of
the cycloadduct 2a was also obtained in tetrahydrofuran (THF)
(entry 4). The utility of other solvents, such as toluene,
dichloroethane (DCE), dichloromethane (DCM), and 1,2-
dimethoxyethane (DME), led to a corresponding decrease in
the yield for 2a (entries 5−8). The cycloaddition reaction of 1a
with CF3CHN2 did not occur in acetonitrile (entry 9). Finally,
the yield of the cycloadduct 2a could be further improved to
88% in DMF with prolonged reaction time (entries 10 and 11).
With these optimized conditions in hand, we set out to
investigate the scope of this cycloaddition reaction (Scheme 2).
A broad range of γ-alkyl-substituted allenoate esters have been
successfully employed in our approach, and a series of 5-
(trifluoromethyl)pyrazolines 2b−f were obtained in 78−86%
yields. Two γ-alkenyl-substituted allenoate esters were sub-
jected to this cycloaddition reaction under the same conditions,
and the corresponding products 2g and 2h were obtained in
good yields without any detectable quantities of other
It is noteworthy that, under the catalysis of triethylamine, 5-
(trifluoromethyl)pyrazoline 2a could be readily isomerized into
the 3-(trifluoromethyl)pyrazole 3a in essentially quantitative
yield (Scheme 3). Furthermore, the structure of 3a was
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Scheme 4. Et3N-Triggered Cycloaddition of CF3CHN2 with
a
Electron-Deficient Allenes 1
Figure 2. Steric interactions favoring formation of (Z)-cycloadducts.
Scheme 3. Isomerization of 2a into 3a
confirmed by means of X-ray crystallographic analysis (see the
Supporting Information). These interesting findings prompted
us to investigate further Et3N-triggered one-pot cycloaddition
of CF3CHN2 with electron-deficient allenic esters and ketones.
Careful reaction optimization revealed that the cycloaddition is
best conducted with 20 mol % of Et3N in toluene at 40 °C (see
the Supporting Information). Results of the cycloaddition of
various electron-deficient allenes with CF3CHN2 are summar-
ized in Scheme 4.
a
We found that the allene scope of the Et3N-triggered
cycloaddition with trifluorodiazoethane is fairly broad. A series
of γ-alkyl-substituted allenoate esters delivered the cycloadducts
3a−f in good to high yields. Moreover, γ-alkyl linkers carrying
chloro, ester, and thioether substituents, as well as olefin
moieties are compatible with this cycloaddition reaction,
furnishing 5-(trifluoromethyl)pyrazoles 3g−k in 51−78%
yields. γ-Aryl- and heteroaryl-substituted allenoate esters also
participated in this transformation, giving rise to the cyclo-
adducts 3l and 3m in the yield of 76% and 71%, respectively. In
addition, other electron-deficient allenic esters and ketones
were employed as dipolarophile substrates, and the correspond-
ing cycloadducts 3n−p were obtained in good yields. It is well
known that 3-alkynoates can be readily isomerized to allenoates
upon treatment with organic bases.8 Thus, the present protocol
was further extended to a one-pot sequential isomerization/
cycloaddition of 3-alkynoate 4 with trifluorodiazoethane in the
presence of triethylamine, and the desired cycloadduct 3n was
produced in 84% yield (Scheme 5). In sharp contrast, in the
absence of Et3N the cycloaddition reaction of 3-alkynoate 4
with CF3CHN2 did not proceed smoothly, and only a trace of
product 3n was detected by 19F NMR spectrometry.
General reaction conditions: allene 1 (0.2 mmol, 1.0 equiv),
CF3CHN2 (0.4 mmol, 2.0 equiv), and Et3N (0.04 mmol, 0.2 equiv)
b
in toluene reacted in sealed tube at 40 °C for 30 h. Isolated yield.
Scheme 5. Et3N-Catalyzed One-Pot Sequential
Isomerization/Cycloaddition of 3-Alkynoate 4
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data of all the new compounds,
and X-ray data for 3a (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, we have successfully developed a novel and
efficient procedure for highly regioselective cycloaddition of
electron-deficient allenic esters and ketones with trifluorodiazo-
ethane. A variety of 5-(trifluoromethyl)pyrazolines and 3-
(trifluoromethyl)pyrazoles can be accessed in good to high
yields under the mild reaction conditions. Further application
of this cycloaddition reaction and detailed mechanistic studies
are underway in our laboratory.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: majun_an68@tju.edu.cn.
Notes
The authors declare no competing financial interest.
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Letter
(h) Inokuma, T.; Furukawa, M.; Suzuki, Y.; Kimachi, T.; Kobayashi,
Y.; Takemoto, Y. ChemCatChem 2012, 4, 983.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21172170 and 21225208) and the
National Basic Research Program of China (973 Program,
2014CB745100).
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