Direct Regioselective [3 + 2] Cycloaddition Reactions of Masked Difluorodiazoethane with Electron-Deficient Alkynes and Alkenes: Synthesis of Difluoromethyl-Substituted Pyrazoles

Article abstract of DOI:10.1021/acs.orglett.8b01854

Phenylsulfone difluorodiazoethane (PhSO₂CF₂CHN₂), an easy-to-prepare and bench-stable masked CF₂-building block, has been developed. The synthetic utility of this reagent is demonstrated by a direct regioselecti

Full text of DOI:10.1021/acs.orglett.8b01854

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct Regioselective [3 + 2] Cycloaddition Reactions of Masked
Difluorodiazoethane with Electron-Deficient Alkynes and Alkenes:
Synthesis of Difluoromethyl-Substituted Pyrazoles
Jun-Liang Zeng, Zhen Chen, Fa-Guang Zhang,* and Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation
Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P. R. China
*
S Supporting Information
ABSTRACT: Phenylsulfone difluorodiazoethane (PhSO CF CHN ), an easy-to-prepare and bench-stable masked CF -
2
2
2
2
building block, has been developed. The synthetic utility of this reagent is demonstrated by a direct regioselective [3 + 2]
cycloaddition with electron-deficient alkynes and alkenes. This protocol enables facile construction of an array of
difluoromethyl-substituted pyrazoles in good to high yields under mild reaction conditions.
ver the past decade, remarkably increasing efforts have
Scheme 1. Strategies for Synthesis of CF H-Containing
2
O
been devoted to the construction of difluoromethyl
CF H)-containing molecules in synthetic chemistry. It has
Pyrazoles with Diazo Compounds
1
(
2
been demonstrated that introducing a CF H moiety into
2
biologically active compounds could bring dramatic effects,
such as improvement of lipophilicity, metabolic stability, o2r
bioavailability relative to their nonfluorinated counterparts.
Besides, the difluoromethyl group can also act as a bioisostere
3
for carbinols, thiols, hydroxamic acids, and amides. Among
plenty of CF H-functionalized entities, the difluoromethylated
2
pyrazoles represent an important class of core-structure in
4
agrochemicals. As a consequence, the efficient and divergent
synthesis of difluoromethyl-substituted pyrazoles are in high
5
demand. In this context, conventional synthetic methods to
access CF H-pyrazolic skeletons mainly employ condensation of
2
difluoromethyl-substituted ketones with hydrazines under acidic
6
conditions. Despite considerable effort, these protocols often
thiophenol within five steps in 62% yield, is found to be a stable
liquid compound. More importantly, the [3 + 2] cycloaddition
with electron-deficient alkynes and alkenes proceed smoothly,
thus providing facile access to difluoromethyl-substituted
pyrazoles in good to high yield (Scheme 1b). Moreover, it has
been disclosed that DBU can be employed as an efficient
encounter formation of regioisomeric mixtures with respect to
substituents incorporated at the 3- and 5-positions of the
pyrazole ring. To overcome these limitations, Mykhailiuk
reported the in situ generation of difluorodiazoethane
(
CF HCHN ) and its [3 + 2] cycloaddition with alkynes to
2 2
7
10
provide 3-CF H pyrazoles (Scheme 1a). Subsequently, both
desulfonation reagent to produce pyrazoles from pyrazolines.
2
the groups of Koenigs and Jamison have developed elegant
methods to prepare CF H-pyrazoles with CF HCHN by the
utilization of continuous-flow technology (Scheme 1a).
Herein, we would like to report our investigations on the
development and utility of this masked difluorodiazoethane.
A classic tactic to develop fluoroalkylation reagents is the
combination of sulfur and fluorine, as exemplified by a long list
of fluorinated sulfones, sulfoxides, sulfides, and sulfoximines in
2
2
2
8
Nevertheless, as an unstable and hazardous gas, the wide
applicability of CF HCHN still suffers from difficult handling
2
2
11
organic synthesis. With this concept in mind and inspired by
along with its generation, storage, and reaction operation. In this
regard, we speculated that a suitable masked difluorodiazo-
ethane might serve as promising difluoromethyl building block
12
the elegant work from Hu’s group, we set out to investigate the
9
to provide target fluorinated entities. To our delight, phenyl-
Received: June 14, 2018
sulfone difluorodiazoethane (PhSO CF CHN ), prepared from
2
2
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01854
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
feasibility of employing a sulfone moiety for the development of
masked difluorodiazoethane. Pleasingly, phenylsulfone difluor-
odiazoethane 1 (PhSO CF CHN or Ps-DFA) has been
Scheme 3. Synthesis of Phenylsulfone Difluoromethyl-
pyrazoles from Alkynes
2
2
2
synthesized smoothly within five steps in 62% yield (Scheme
). The synthetic route starts with ethyl bromodifluoroacetate,
2
Scheme 2. Synthesis of PhSO CF CHN
2
2
2
through sulfidation, reduction of ester, oxidation of sulfide,
amination, and diazotization, and finally provides target reagent
1
as a liquid compound. It should be noted that previous studies
from Mykhailiuk reveal that the in situ generation of fluorinated
diazoalkanes only worked for difluoro compounds,
RCF CH NH , where R was a fluorine atom or a fluoroalkyl
2
2
2
1
3
Scheme 4. Synthesis of 3-CF H Pyrazoles
2
substituent. In this context, our result provides solid proof for
the feasibility of generating masked difluorinated diazoalkanes.
Typical features of this procedure include inexpensive reagents,
simple operations, and easiness to scale-up (see the Supporting
Information (SI)). More importantly, owing to the strong
electron-withdrawing property of the sulfone group, Ps-DFA 1 is
a bench-stable diazo compound, thus rendering the easy
handling as a great merit. Furthermore, as the sulfone group
has the ability to be readily removed or transformed, this newly
developed masked difluorodiazoethane offers great opportuni-
ties for the generation of difluoromethyl-functionalized
molecules.
With masked difluorodiazoethane Ps-DFA in hand, we first
engaged our efforts in the [3 + 2] cycloaddition with alkynes to
highlight the synthetic utility of this reagent. Pleasingly, a
screening of several reaction parameters (solvents, temperature,
and reaction time) revealed that phenylsulfone difluoromethyl-
pyrazole 3a was obtained in 95% yield when the reaction with
methyl propiolate was performed in toluene at 40 °C for 18 h.
Having the optimal reaction conditions in hand, we then
proceeded to investigate the scope of this cycloaddition reaction
CF H-substituted pyrazoles 4d and 4e in good yields (80%,
94%), while the ketone functional group was also reduced to
alcohol in the meantime.
2
These results demonstrate that the phenylsulfone moiety can
act as a traceless group for the preparation of CF H-contaning
2
(Scheme 3). Alkynes substituted with an electron-withdrawing
pyrazoles. However, a two-step procedure is inevitable for the
group including ester, amide, and ketone, are all found to be
good substrates, thereby generating the corresponding phenyl-
sulfone difluoromethylpyrazoles 3a−f in excellent yields (90−
transformations with electron-deficient alkynes. To address this
issue, we envisioned that a one-pot manner to synthesize CF H-
2
contaning pyrazoles might be achieved by the transformations of
Ps-DFA with electron-deficient alkenes. Moreover, the use of
alkenes as cyclization partners is more appealing attributed to
their abundance, lost cost, as well as wide synthetic accessibility.
It has been reported that [3 + 2] cycloaddition of difluorodiazo
9
5%). Disubstituted alkynes are also compatible with this [3 + 2]
cycloaddition reaction, leading to the formation of 3-
difluoroalkyl)pyrazoles 3g−h in nearly quantitative yield.
(
Moreover, it is worth mentioning that only one equivalent of
Ps-DFA was employed in these cycloaddition reactions. This is a
distinct advantage compared with previously reported
CF HCHN chemistry in which the diazo compound was
7
b,8a,b
compounds with alkenes would produce pyrazolines.
Thus, the key of this proposal relies on the subsequent
desulfonylation process to give target CF H-pyrazoles. To test
2
2
2
7
,8
often requisite for more than two equivalents.
this hypothesis, Ps-DFA 1 was first treated with ethyl acrylate 5b
in THF at 40 °C for 36 h (Table 1, entry 1). Reaction detection
indicated that Ps-DFA was consumed completely, then DBU
was added to facilitate the desulfonylation step. To our delight,
Next, the desulfonylation process of compounds 3a−h was
conducted to provide the corresponding CF H-substituted
2
pyrazoles. As depicted in Scheme 4, the phenylsulfone moiety
was smoothly cleaved in the presence of magnesium at room
temperature. This protocol enables the rapid preparation of
the CF H-pyrazole 4b was obtained in 58% yield in one-pot
2
operation. The yield of 4b was further increased to 78% when
ethyl acrylate was employed as the limiting reagent, while Ps-
DFA was still only used in 1.1 equiv (entry 2). Next, various
solvents and organic bases were evaluated for this one-pot
CF H-substituted pyrazoles 4a−h in high yields under mild
2
conditions. It should be noted that ketone-containing
compounds 3d and 3e underwent this transformation to give
B
DOI: 10.1021/acs.orglett.8b01854
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Studies
compounds also worked well under the identical reaction
conditions to give the products 4g and 4n in high yield. Ethyl
(
E)-4,4,4-trifluorobut-2-enoate also proved to be a viable
substrate, thus delivering the cycloadduct 4o equipped with
both of CF H and CF groups. When vinyl sulfones were
2
3
employed under the current reaction conditions, very
interestingly, monosubstituted pyrazole 4p was obtained in
good yield. To highlight the synthetic value of our approach, this
cycloaddition was scaled up to the gram-scale, and further
transformation of the cycloadduct 4p proceeded efficiently
through methylation, desulfonylation, and bromination
b
entry
1/5b (equiv)
solvent
THF
THF
toluene
MeCN
CHCl3
DCM
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
base
DBU
yield (%)
1
2
3
4
5
6
7
8
9
1.0:1.2
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
1.1:1.0
58
78
83
52
37
20
DBU
DBU
DBU
DBU
DBU
DBU
DMAP
(
Scheme 6). 4-Bromo-3-difluoromethyl-1-methylpyrazole 6c,
14
an important intermediate of agrochemicals, was obtained in
good yield.
c
89 (86)
3
5
0
Et N
3
Scheme 6. Gram-Scale Cycloaddition Reaction and Further
Synthetic Transformation of the Cycloadducts
i
1
0
( Pr) NEt
2
a
Reaction conditions: Ps-DFA 1 (0.22 mmol), 5b (0.2 mmol),
solvent (3 mL), 40 °C, 36 h; then base (0.4 mmol), 40 °C, 48 h.
b
19
c
Yields were determined by F NMR. Isolated yield.
reaction (entries 3−10), and the desired product 4b was
afforded in 86% yield when 1,4-dioxane was chosen as the
reaction media (entry 7). It is worth noting that other bases such
as DMAP, Et N, or DIPEA, could not lead to the generation of
3
target pyrazole in practical amount (entries 7−10), highlighting
the crucial role of DBU in the desulfonylation step.
With the optimized conditions in hand, the generality of this
one-pot reaction was probed with a series of electron-deficient
alkenes. As shown in Scheme 5, an array of CF H-pyrazoles were
On the basis of our experimental results and previous
2
15
studies, a possible mechanism for the one-pot transformation
of Ps-DFA 1 with electron-deficient alkene 5 is illustrated in
Scheme 7a. First, [3 + 2] cycloaddition of alkene with a diazo
a
Scheme 5. Synthesis of 3-CF H Pyrazoles from Alkenes
2
Scheme 7. Plausible Mechanism of One-Pot Transformation
compound would proceed to give pyrazoline I-1. This step is
confirmed by the isolation and characterization of a pyrazoline
intermediate I-1a in control experiment without DBU (Scheme
7b). Subsequently, DBU would abstract a proton from
intermediate I-1 to form the anionic intermediate I-2, followed
by an isomerization process to generate intermediate I-3. Then
a
Reaction conditions: Ps-DFA 1 (0.22 mmol), 5 (0.2 mmol), solvent
b
(3 mL), 40 °C, 36 h; then DBU (0.4 mmol), 40 °C, 48 h. Methyl
c
vinyl sulfone as starting material. Phenyl vinyl sulfone as starting
material.
−
+
the PhSO2 would eliminate as a combination with DBUH to
smoothly obtained in good to high yield under mild conditions.
For instance, various acrylates with an ester or amide group
underwent the [3 + 2] cycloaddition and subsequent
desulfonylation to give the desired products 4a−k in 56−88%
yields. The ketone-containing alkenes are also compatible with
this transformation to furnish the corresponding products 4l and
give the desired CF H-substituted pyrazoles 4. Specifically, a salt
complex 7, which is predicted to be generated from the reaction,
2
was successfully isolated and subjected to X-ray analysis to
16
support the proposed mechanism (see the SI).
In summary, a bench-stable difluorodiazoethane reagent with
a masked phenylsulfonyl group has been designed and
successfully synthesized in good yield within five steps from
4
m in 69% and 50% yields, respectively. Two fumarate
C
DOI: 10.1021/acs.orglett.8b01854
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thiophenol and ethyl bromodifluoroacetate. The potential
application of this complementary and viable compound is
demonstrated by direct regioselective [3 + 2] cycloaddition
reactions with electron-deficient alkynes and alkenes. This
protocol provides facile access to a variety of difluoromethyl-
containing pyrazoles under mild reaction conditions. DBU is
found to be an efficient desulfonation reagent to produce
pyrazoles from pyrazolines. Further exploration of this masked
difluorodiazoethane in other synthetic reactions is currently
underway in our laboratory, the results of which will be reported
in due course.
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ASSOCIATED CONTENT
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*
S
Supporting Information
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01854.
Ostrovskyi, D.; Mkrtchyan, S.; Villinger, A.; Langer, P. Tetrahedron
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Experimental details and spectral data of all the new
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Accession Codes
Wollner, T. WO 2009106230, 2009. (i) Pazenok, S.; Muller, M.; Lui,
CCDC 1837133 contains 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 Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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*
E-mail: majun_an68@tju.edu.cn.
*E-mail: zhangfg1987@tju.edu.cn.
ORCID
Matsuo, T.; Tokitoh, N. Angew. Chem., Int. Ed. 2016, 55, 12877.
f) Saadi, J.; Wennemers, H. Nat. Chem. 2016, 8, 276. (g) Nayak, S.;
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O.; Roldan-Gomez, S.; Martin-Diaconescu, V.; Parella, T.; Luis, J. M.;
(
Fa-Guang Zhang: 0000-0002-0251-0456
Jun-An Ma: 0000-0002-3902-6799
Notes
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Company, A.; Ribas, X. J. Am. Chem. Soc. 2017, 139, 14649. (i) Harry,
N. A.; Saranya, S.; Krishnan, K. K.; Anilkumar, G. Asian J. Org. Chem.
The authors declare no competing financial interest.
2017, 6, 945. (j) Olaizola, I.; Campano, T. E.; Iriarte, I.; Vera, S.;
Mielgo, A.; Garica, J. M.; Odriozola, J. M.; Oiarbide, M.; Palomo, C.
Chem. - Eur. J. 2018, 24, 3893.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (No. 21472137, 21532008, and
1772142), the National Basic Research Program of China
973 Program, 2014CB745100).
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DOI: 10.1021/acs.orglett.8b01854
Org. Lett. XXXX, XXX, XXX−XXX