Regioselective Decarboxylative Cycloaddition Route to Fully Substituted 3-CF3-Pyrazoles from Nitrilimines and Isoxazolidinediones

Article abstract of DOI:10.1002/adsc.202100091

1,4-Diaryl-5-carboxamido substituted 3-trifluoromethylpyrazoles are obtained with exclusive regioselectivity under transition-metal-free conditions. This decarboxylative [3+2] cycloaddition protocol was enabled by employing trifluoromethyl nitrilimines as 1,3-dipoles, and isoxazolidinediones as CO₂-masked alkynyl dipolarophiles. The applicability of this method is further manifested by its compatibility with difluoromethyl, alkyl, aryl, and heteroaryl nitrilimines, as well as the preparation of 4-carboxylic amido analogue of drug Celebrex. (Figure presented.).

Full text of DOI:10.1002/adsc.202100091

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DOI: 10.1002/adsc.202100091
Very Important Publication
Regioselective Decarboxylative Cycloaddition Route to Fully
Substituted 3-CF3-Pyrazoles from Nitrilimines and
Isoxazolidinediones
Yu-Chen Tian,+a Jun-Kuan Li,+a Fa-Guang Zhang,a, b,* and Jun-An Maa, b,*
a
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic
Biology (Ministry of Education), and Tianjin Collaborative Innovation Centre of Chemical Science & Engineering, Tianjin
University, Tianjin 300072
E-mail: zhangfg1987@tju.edu.cn; majun_an68@tju.edu.cn
Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai
b
New City, Fuzhou 350207, People’s Republic of China
+
Y.-C. T. and J.-K. L. contributed equally to this work
Manuscript received: January 22, 2021; Revised manuscript received: February 19, 2021;
Version of record online: March 3, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100091
direct access to N-functionalized pyrazoles. Therefore,
Abstract: 1,4-Diaryl-5-carboxamido substituted 3-
it is still of high interest and significance to develop
trifluoromethylpyrazoles are obtained with exclu-
alterative CF3-synthons en route to versatile
sive regioselectivity under transition-metal-free con-
trifluoromethyl pyrazoles, especially the challenging
ditions. This decarboxylative [3+2] cycloaddition
protocol was enabled by employing trifluoromethyl
fully substituted ones.[5] In this context, we turned our
attention to nitrilimines, which have been recognized
nitrilimines as 1,3-dipoles, and isoxazolidinediones
as a powerful category of 1,3-dipoles in dipolar
as CO2-masked alkynyl dipolarophiles. The applic-
cycloaddition reactions since Huisgen’s seminal work
ability of this method is further manifested by its
in 1959.[6] However, a literature survey reveals that
compatibility with difluoromethyl, alkyl, aryl, and
explorations on trifluoromethyl-substituted nitrilimines
heteroaryl nitrilimines, as well as the preparation of
remain scarce. The first example of CF3-nitrilimines
4-carboxylic amido analogue of drug Celebrex.
was disclosed by Tanaka and co-workers in 1982,
albeit with poor regioselectivity in cycloaddition
reactions with terminal alkynes.[7] Subsequently, Oh
Keywords: Pyrazoles; Trifluoromethyl groups; Cy-
and Jasiński illustrated the utility of CF3-nitrilimines in
cloaddition reactions; Nitrilimines
producing trisubstituted CF3-pyrazoles by employing
Trifluoromethylated pyrazoles have received tremen-
dous attention owing to their widespread appearance in
numerous active pharmaceutical therapeutic agents.[1]
Among the established methods to access 3-
trifluoromethyl pyrazoles,[2] 1,3-dipolar cycloaddition
conversions of trifluorodiazoethane (CF3CHN2) have
emerged as
a
particularly attractive strategy
(Scheme 1a).[3] While the merit of this methodology
has been extensively practiced by Mykhailiuk, Koe-
nigs, Jamison, Bi, Wang, and our group over the past
decade,[4] furthering its applicability is rather hampered
due to several inherent drawbacks such as difficult
handling with highly reactive CF3CHN2, limited scope
for disubstituted alkynes, and most importantly, no
Scheme 1. Construction of 3-Trifluoromethyl Pyrazoles via
Intermolecular Cycloaddition Reactions.
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Table 1. Evaluation of Reaction Parameters.[a]
enamines or enol ethers as specific dipolarophiles,
independently.[8] More recently, Jasiński and co-work-
ers disclosed the [3+2] cycloaddition of CF3-nitrili-
mines with arynes to access 3-trifluoromethyl-1H-
indazoles.[9] Despite the advances, the coupling of CF3-
nitrilimines with multiple-substituted unsaturated car-
bon-carbon bonds have not been realized until now.
Given the appealing promise that this reaction might
provide facile access to valuable fully substituted CF3-
pyrazoles, we embarked on this project by searching
for appropriate diploarophiles. Therefore, herein we
describe our investigations on a base-mediated [3+2]
cycloaddition reaction between a CO2-masked alkyne
surrogate (isoxazolidinediones) and CF3-nitrilimines
in situ generated from hydrazonoyl chlorides under
simple conditions (Scheme 1b). Notably, this transi-
tion-metal-free decarboxylative transformation features
excellent regioselectivity, and is broadly extended to
difluoromethyl, alkyl, aryl, and heteroaryl-derived
nitrilimine coupling partners.
Inspired by recent remarkable achievements in
decarboxylative cycloaddition reactions with various
CO2-masked coupling reagents,[10] we chose isoxazoli-
dinedione 2a as a candidate for performing as reactive
alkyne surrogate, which was easily prepared from N-
phenylhydroxylamine and 4-methyl benzaldehyde.[11]
Trifluoromethyl phenylhydrazonoyl chloride 1a was
employed as the starting precursor for in situ generat-
ing corresponding trifluoromethyl nitrilimine inter-
mediate under basic conditions (Table 1). Encourag-
ingly, the desired 3-CF3-5-amido pyrazole 3a was
indeed observed by heating model substrates 1a and
2a in the presence of DBU, albeit with low isolated
yield (entry 4). To our delight, simple alkali metal salts
outperformed organic bases in most cases (entries 5–
12), among which 3a was obtained in 93% yield as a
single detectable regio-isomer when potassium
carbonate was engaged (entry 9). In comparison, al-
most no cycloaddition occurred by just changing
potassium carbonate to sodium carbonate or potassium
bicarbonate under otherwise identical conditions,
underscoring the crucial impact of the salt’s basicity
(entry 8 or 11 vs entry 9). Further evaluating various
solvents (entries 13–18) showed that this reaction
could also proceed well in 1,4-dioxane or acetonitrile
(entries 15 and 16). Decreasing the amount of K2CO3
or operating the reaction at lower temperatures led to a
significant drop in the yield of 3a (entries 19–21).
°
Entry
Base
Solvent
Temp. ( C)
Yield
(%)[b]
1
2
3
4
5
6
7
8
Et3N
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
1,4-dioxane
CH3CN
DMF
EtOH
DCE
DCE
DCE
DCE
DCE
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
60
rt
trace
16
nd
34
nd
25
45
trace
93
48
nd
42
14
47
77
79
17
12
58
42
17
87
75
nd
DIPEA[g]
DABCO
DBU
NaOAc
KOAc
K3PO4
Na2CO3
K2CO3
Cs2CO3
KHCO3
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14
15
16
17
18
19[c]
20
21
22[d]
23[e]
24[f]
90
90
90
DCE
[a] All reactions were conducted with trifluoromethyl phenylhy-
drazonoyl chloride 1a (0.2 mmol), isoxazolidinedione 2a
(0.3 mmol), and base (0.4 mmol) in 2 mL of solvent at
respective temperature for 12 h unless otherwise notified.
[b] Yield of pyrazole 3a after column chromatography.
[c] 0.2 mmol of K2CO3 was employed.
[d] 0.2 mmol of 2a was employed.
[e] 1a (5 mmol), 2a (7.5 mmol), and K2CO3 (10 mmol) in
°
20 mL of DCE at 90 C for 12 h.
[f] N-phenyl-3-(p-tolyl)propiolamide (0.3 mmol) was employed
instead of 2a.
[g] DIPEA=N,N-Diisopropylethylamine (EtNiPr2).
Comparable result was obtained when subjecting equal lighting the superior reactivity of isoxazolidinediones
amounts of both starting materials (entry 22). Gram- in such cycloaddition transformations.
scale experiment was conducted under standard con-
The scope of 3-CF3-5-carboxylic amido pyrazoles 3
ditions and gave 1.6 g of 3a in practical yield was first evaluated by varying isoxazolidinediones 2
(entry 23). X-ray diffraction analysis unambiguously (Scheme 2). Alkyl and alkoxyl groups substituted at
confirmed the structure of fully substituted pyrazole the benzene ring of 2 were well compatible, giving rise
3a.[12] Finally, N-phenyl-3-(p-tolyl)propiolamide (al- to the corresponding pyrazoles 3a–3h in good to high
kyne surrogate of 2a) was reacted with 1a, and turned yields. Diverse functional groups were tolerated,
out with no conversion at all (entry 24), clearly high- including halogens, trifluoromethyl, and cyano groups
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Scheme 3. Scope of Trifluoromethyl Nitrilimine Precursors 1 in
the Cycloaddition Reactions with Isoxazolidinedione 2a.
pyrazole 3ao was obtained in 98% yield. Lastly, and
perhaps more excitingly, difluoromethyl-substituted
nitrilimine performed as feasible 1,3-dipole, producing
unprecedented fully substituted 2-CF2H-pyrazole 3ap
Scheme 2. Scope of Isoxazolidinediones 2 in the Cycloaddition
Reactions with Trifluoromethyl Nitrilimine Precursor 1a.
(3i–3n). In addition to phenyl substituents, 2-naphthyl, in high yield as a single regio-isomer.[13]
1-naphthyl, 2-furyl, and 2-thienyl-derived isoxazolidi-
To further illustrate the broad applicability of this
nediones also cyclized with CF3-nitrilimine smoothly, transition-metal-free cycloaddition protocol, an array
thus furnishing highly functionalized CF3-pyrazoles of aryl nitrilimine precursors were evaluated
3o–3s in up to 96% yield with constant complete (Scheme 4). Pleasingly, the corresponding N1-phenyl-
regio-control. The carboxylic amide moiety in 3 could 3,4-diaryl-5-carboxylic amido pyrazoles 3aq–3aw
also be easily tuned as exemplified by the generation were readily formed under identical conditions. Fur-
of compound 3t in high yield.
thermore, alkyl- and cycloalkyl-substituted 1,3-dipoles
We then proceeded to investigate the generality of were also tolerated in this reaction and generated
trifluoromethyl nitrilimines in the cycloaddition trans- products 3ax and 3ay, albeit with isolated regio-
formation with model dipolarophile 2a (Scheme 3). isomer 3ax’ in the former case (the major product 3ax
Again, phenyl substrates bearing methyl, tert-butyl, and the minor product 3ax’ were both confirmed by X-
methoxyl, and halogens at varied positions on the ray).[12]
benzene ring were all equally amenable and afforded
The utility of this regio-selective cycloaddition
various N-functionalized CF3-pyrazoles 3ab–3ak in approach was further showcased via the preparation of
uniformly good yields (80–96%) and exclusive regio- several drug-like 3-trifluoromethyl pyrazoles. For
selectivity.
Electron-deficient
group-appended example, two specific densely functionalized pyrazoles
trifluoromethyl nitrilimines also underwent cycloaddi- 4a and 4b were routinely synthesized using the
tion process with practical to good results (3al–3an). standard procedure which possess some structural
In addition, we were pleased to find that N-2-naphthyl similarity compared with the anti-obesity drug Rimo-
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Scheme 4. Scope of Various Nitrilimine Precursors 1 in the
Cycloaddition Reactions with Isoxazolidinedione 2a.
nabant (Scheme 5a and 5c)[14] While employing hydra-
zonoyl chloride didn’t produce 5-carboxylic amido
analogue of anti-inflammatory drug Celecoxib, entail-
ing hydrazonoyl benzenesulfonate 1z as alternative
nitrilimine precursor successfully obviated the limita-
tion and afforded the target molecular 5 in practical
yield with excellent regio-selectivity (Scheme 5b and
5c).[15]
In summary, a broad group of fully substituted 3-
CF3-pyrazoles have been constructed with excellent
regio-control by means of an alkali base-promoted [3
+2] cycloaddition reaction of trifluoromethyl nitrili-
mines with isoxazolidinediones. This protocol is
generally applicable to difluoromethyl, alkyl, aryl, and
heteroaryl nitrilimine partners, thus providing rapid
access to versatile densely functionalized pyrazole
frameworks. Further applying trifluoromethyl nitrili-
mines in other heterocycle synthesis and mechanistic
studies are in progress.
Scheme 5. Synthesis of Drug-like Fully Substituted 3-
Trifluoromethyl Pyrazoles.
on silica gel (eluting with petroleum ether/ethyl acetate) to give
the desired product 3.
Acknowledgements
We thank the National Key Research and Development Program
of China (2019YFA0905100), National Natural Science Foun-
dation of China (Nos. 21772142, 21901181, and
[21961142015]), and Tianjin Municipal Science & Technology
Commission (19JCQNJC04700) for financial support.
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