Aluminium Chloride-Mediated Synthesis of 1-Chloro-2,2,2-Trifluoroethylidene-Substituted Pyrrolidones

Article abstract of DOI:10.1002/adsc.201800275

An aluminium chloride-mediated cascade reaction between pyrrolidones and trifluoroacetic anhydride is reported. Functionally diverse 1-chloro-2,2,2-trifluoroethylidene-substituted pyrrolidones were obtained in moderate to high yields through electrophilic trifluoroacetylation, nucleophilic chlorination, and elimination. This procedure has a wide scope, good functional-group tolerance and the reaction conditions are amenable to scale up. Additionally the obtained 1-chloro-2,2,2-trifluoroethylidene products can be applied to further functionalization as trifluoromethyl-containing building blocks. Some of the title compounds showed fungicidal activity against cucumber downy mildew (CDM). (Figure presented.).

Full text of DOI:10.1002/adsc.201800275

Title: Aluminium Chloride-Mediated Synthesis of 1-Chloro-2,2,2-
Trifluoroethylidene-Substituted Pyrrolidones
Authors: Zeng Wang, Zihang Yuan, Xiaoyan Han, and Zhiqiang Weng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800275
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10.1002/adsc.201800275
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Aluminium Chloride-Mediated Synthesis of 1-Chloro-2,2,2-
Trifluoroethylidene-Substituted Pyrrolidones
Zeng Wang,a Zihang Yuan,a Xiaoyan Han*,b and Zhiqiang Weng*,a
a State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University,
Fujian 350108, China. b Testing and Analysis Center, Soochow University, Suzhou 215123, China.
Fax: (+86)-591-22866121; e-mail: hanxiaoyan@suda.edu.cn (XH); zweng@fzu.edu.cn (ZW)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An aluminium chloride-mediated cascade reaction Additionally the obtained 1-chloro-2,2,2-trifluoroethylidene
between pyrrolidones and trifluoroacetic anhydride is products can be applied to further functionalization as
reported.
Functionally
diverse
1-chloro-2,2,2- trifluoromethyl-containing building blocks. Some of the
trifluoroethylidene-substituted pyrrolidones were obtained in title compounds showed fungicidal activity against
moderate
trifluoroacetylation,
to
high
yields
nucleophilic
through
electrophilic cucumber downy mildew (CDM).
and
chlorination,
elimination. This procedure has a wide scope, good
functional-group tolerance and the reaction conditions are
amenable to scale up.
Keywords: Trifluoromethylation; Pyrrolidones;
Aluminium chloride-mediated; Trifluoroacetic anhydride;
2,2,2-Trifluoroethylidene
Pyrrolidone structural motifs are frequently found
in many biologically active natural products and
pharmaceuticals. For example, Aniracetam is a drug
with anti-depressive properties used as a mental
performance enhancer.[13] Pyrrolidone derivatives are
also used as 11--hydroxysteroid dehydrogenase
inhibitors,[14] or monoamine oxidase B inhibitors[15]
(Figure 1). This biological and medicinal importance
makes pyrrolidone derivatives desirable compounds
for the screening of new biological activities.
Introduction
Fluorinated groups-containing drugs and pesticides,
frequently synthesized by convenient fluorination and
trifluoromethylation
methods,
have
attracted
increasing attention in modern bioorganic
chemistry.[1] The replacement of hydrogen by
fluorine can drastically affect the physical, chemical,
and biological properties of pharmaceutical
molecules, to enhance their metabolic stability and
selectivities. Given the unique physicochemical
properties engendered by the trifluoromethyl (CF3)
group, considerable efforts have been directed
towards new methodologies for the selective
introduction of CF3 groups into bioactive molecules.[2]
Among a variety of synthetically important
trifluoromethylated
compounds,
molecules
containing the CvinylCF3 moiety are known to play
important roles in a wide field of science, especially
in medicinal chemistry.[3] Therefore, development of
efficient methods for the synthesis of these
compounds is in great demand. Conventional
approaches for the synthesis of CvinylCF3 compounds
mainly rely on the coupling of aryl halides with
highly volatile reagents, such as 1-iodo-3,3,3-
trifluoropropane,[4] (E)-trimethyl-(3,3,3-trifluoroprop-
1-enyl)silane[5] and 2-(trifluoromethyl)acrylic acid,[6]
and the direct trifluoromethylation reaction with
Figure 1. Bioactive 2-pyrrolidone derivatives.
The use of readily available, convenient, and
inexpensive trifluoroacetic acid (TFA) and its
anhydride (TFAA) as a trifluoromethyl source for
trifluoromethylation reactions, would be an attractive
approach to the synthesis of trifluoromethylated
compounds.[16] In this context, Zhang and co-workers
reported
a
silver-catalyzed
radical
C−H
trifluoromethylation of arenes employing TFA as the
unsaturated alkenes,[7] vinyl sulfonates,[8] vinylboron
trifluoromethylating reagent.[17] Stephenson and co-
derivatives,[9] vinyl halides,[3b,
,-unsaturated
10]
workers
reported
an
elegant
radical
carboxylic acids,[11] and other methods.[12]
trifluoromethylation of arenes and heteroarenes using
1
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10.1002/adsc.201800275
Advanced Synthesis & Catalysis
TFAA as the trifluoromethylating reagent and
pyridine N-oxide and photoredox catalysis.[18] Later,
Schꢀfer and co-workers also reported the synthesis of
trifluoromethylated imidazo-fused N-heterocyles
using TFAA as trifluoromethylating reagent.[19]
Despite these advancements, to the best of our
knowledge, there is no literature precedence on the
To validate the feasibility of our postulation,
readily available 1-methyl-2-pyrrolidinone 2a was
chosen as a model substrate to react with TFAA 1
under Lewis acid-catalytic system (Table 1). After
screening various reaction parameters, we were
pleased to observe 78% NMR yield of the desired
pyrrolidone product 3a, using 1.0 equiv of AlCl3 in
DMF at 60 C for 24 h (entry 1). The structure of 3a
was unequivocally confirmed by single crystal X-ray
analysis (Figure 2).[22]
one-pot
synthesis
of
1-chloro-2,2,2-
pyrrolidone
trifluoroethylidene-substituted
compounds using TFAA as 2,2,2-trifluoroethylidene
source. Continuing our study on copper-mediated
synthesis of trifluoromethylated compounds utilizing
TFA or TFAA as trifluoromethylating reagent,[20] we
envisioned the feasibility of AlCl3-mediated
trifluoroacetylation of 2-pyrrolidone derivatives[21]
with TFAA followed by hydroxyl chlorination
leading
to
1-chloro-2,2,2-trifluoroethylidene-
substituted pyrrolidones (Scheme 1). Herein we
disclose the first report of 1-chloro-2,2,2-
trifluoroethylidene-substituted pyrrolidones synthesis
from pyrrolidone derivatives via AlCl3-mediated
trifluoroacetylation and hydroxyl chlorination with
TFAA.
Figure 2. ORTEP diagrams of (Z)-3a (top), (Z)-3r
(bottom-left), and (E)-3r (bottom-right).
It is noteworthy that other Lewis acid-catalytic
systems such as CuCl2, ZnCl2, InCl3, and FeCl3 were
found to be totally ineffective under identical reaction
conditions (entries 2-5). Similarly, the reaction did
not proceed in the absence of AlCl3 catalyst (entry 6).
The utilization of other solvents, such as DMSO,
DCE, CH3CN, or THF, was also inefficient (entries 7-
10). Fortunately, increasing the catalyst loading to 1.5
equiv improved the chemical yield dramatically, and
the desired product 3a was obtained in high chemical
yield with a high stereoselectivity of the CC
configuration (96%, Z/E= 93:7; entry 11). When the
reaction was conducted at 30 C, lower yield of 3a
was obtained (62%; entry 12). Moreover, shorter
reaction time to 12 h led to a lower yield of product
3a (81%; entry 13).
Scheme 1. Proposed One-Pot Synthesis of 1-Chloro-2,2,2-
Trifluoroethylidene-Substituted Pyrrolidones.
Results and Discussion
Table 1. Optimization of the Reaction Conditions a)
Entr Lewis acid Solvent
T
(C)
Time Yield Z/E c
y
(equiv)
(h)
(%) b
1
2
3
4
5
6
7
8
AlCl3 (1)
CuCl2 (1)
ZnCl2 (1)
InCl3 (1)
FeCl3 (1)
-
AlCl3 (1)
AlCl3 (1)
AlCl3 (1)
AlCl3 (1)
DMF
DMF
DMF
DMF
DMF
DMF
DMSO 60
DCE 60
CH3CN 60
60
60
60
60
60
60
24
24
24
24
24
24
24
24
24
24
24
24
12
78
0
0
0
0
0
0
0
0
<1
96
62
81
92:8








Using the optimized reaction conditions, the
substrate scope of the reaction was explored using a
range of electronically and sterically differentiated 2-
pyrrolidone derivatives (Scheme 2). Various alkyl
groups such as methyl (3a), ethyl (3b), n-butyl (3c),
cyclohexyl (3d), and benzyl (3e) tethered on the
pyrrolidone nitrogen were all well compatible,
providing good yields of the corresponding products.
The N-phenyl 2-pyrrolidone furnished corresponding
product 3f in high chemical yield (92%). N-Aryl 2-
pyrrolidone substrates bearing electron-donating (3g–
3l) substituents on the aryl ring were smoothly
converted to the corresponding products in 91–94%
yields irrespective of the substituent position.
However, reactions of N-aryl 2-pyrrolidones
9
10
11
12
13
THF
60
60
30
60

AlCl3 (1.5) DMF
AlCl3 (1.5) DMF
AlCl3 (1.5) DMF
93:7
94:6
93:7
a)
Reaction conditions: 1 (0.30 mmol), 2a (0.10 mmol),
solvent (1.2 mL), N2; The yield was determined by 19F
b)
containing
electron-withdrawing
(3m–3r)
b
NMR spectroscopy with PhOCF3 as internal standard;
substituents on the aryl ring furnished the desired
products in modest to good yields. Substrates bearing
a halide substitution on the para- or meta-position of
the aryl group gave the desired products (3s–3y) in
Z/E ratios were determined by 19F NMR.
2
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10.1002/adsc.201800275
Advanced Synthesis & Catalysis
63–87% yields. The tolerance of halide groups under
these conditions demonstrated the additional
synthetic utility of the present method.
The reaction was found to be stereospecific as the
Z-isomer was obtained as the major product. The
stereochemistry, easily assignable by the 19F NMR (Z
isomers: -64.6 ± 0.2 ppm; E isomers: -57.5 ± 0.5
ppm), is in accordance with the results obtained in
closely related molecules.[23] The two E- and Z-
isomers of 3r could be isolated by flash column
chromatography, and the structures of the two
isomers were unambiguously confirmed by the
single-crystal X-ray analysis (Figure 2).[22]
To further examine the potential of our
methodology in late-stage functionalization, we next
investigated drug molecules of higher complexity.
The reactions of aniracetam (4) and 1 proceeded
smoothly under similar reaction conditions to afford
the corresponding product 5 in 51% yield (Scheme 3).
Thus, pharmaceutically relevant molecules can
readily be synthesized with this new method.
In addition, this strategy was further extended to
N-biphenyl and 1-naphthyl 2-pyrrolidones to obtain
the corresponding products 3z and 3aa in 65% and
94% yields, respectively. It was worth noting that
heterocyclic derivatives such as N-3-pyridyl (3ab)
and 3-thienyl 2-pyrrolidones (3ac) were also found
to be compatible. Further, when 4-phenyl-1-(o-
tolyl)pyrrolidin-2-one was used, the corresponding
product 3ad was isolated in 90% yield.
Scheme
3.
Synthesis
of
1-Chloro-2,2,2-
Trifluoroethylidene-Substituted Aniracetam Derivative.
To evaluate the efficiency of this new synthetic
strategy, a gram-scale reaction of 1-methylpyrrolidin-
2-one (2a) with 1 was carried out, and the
corresponding product 3a was given in 82% isolated
yield (Scheme 4). This result indicates that the
process could potentially be amenable towards scale-
up.
Scheme 4. Gram Scale Experiment.
To test the synthetic utility of the present synthetic
protocol, the transformation of the 1-chloro-2,2,2-
trifluoroethylidene-substituted pyrrolidone products
was performed. As shown in Scheme 5, the reaction
of 3i with p-tolylboronic acid under Suzuki cross
coupling conditions or with NaBH4 under reductive
dechlorination conditions provided the corresponding
product 6 and 7 in 40% and 45% isolated yields,
respectively. These results demonstrate that the
obtained 1-chloro-2,2,2-trifluoroethylidene products
can serve as CF3-containing building blocks.
Scheme 2. Scope of the Reaction. a) Reaction conditions: 1
(1.50 mmol, 3.0 equiv), 2 (0.50 mmol), AlCl3 (0.75 mmol,
1.5 equiv), DMF (4.0 mL), 60 C, 24 h, N2; Isolated yields.
b) Performed at 80 C.
3
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10.1002/adsc.201800275
Advanced Synthesis & Catalysis
Experimental Section
General Information
1H NMR, 19F NMR and 13C NMR spectra were recorded
1
using Bruker AVIII 400 spectrometer. H NMR and 13C
NMR chemical shifts were reported in parts per million
(ppm) downfield from tetramethylsilane and 19F NMR
chemical shifts were determined relative to CFCl3 as the
external standard and low field is positive. Coupling
constants (J) are reported in Hertz (Hz). The residual
Scheme 5. Synthetic Utility of 3i.
1
solvent peak was used as an internal reference: H NMR
(chloroform δ 7.26) and 13C NMR (chloroform δ 77.0).
The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. HRMS were obtained
on Waters GCT-TOF at the Shanghai Institute of Organic
Chemistry and State Key Discipline Testing Center for
Physical Chemistry of Fuzhou University. Reagents were
received from commercial sources. Solvents were freshly
dried and degassed according to the published procedures
prior to use.
To evaluate biological activity of the title
compounds, a general screening on their bactericidal
activity was performed (See Supporting Information).
The biological assays revealed that some of the
pyrrolidone products showed potent fungicidal
activities against cucumber downy mildew (CDM).
A plausible reaction mechanism is illustrated in
Scheme 6. First, AlCl3-promoted electrophilic
addition of trifluoroacetyl cation to 2-pyrrolidones
gave intermediate I, which smoothly underwent
deprotonation to afford trifluoroacetylated 2-
pyrrolidone derivatives II. Subsequently, AlCl3
activated II by coordinating with the carbonyl oxygen
forming complex III. Finally, nucleophilic attack of
the chloride anion to the carbon of III following with
elimination led to the desired product 3.
General Procedure for AlCl3-mediated synthesis of 1-
chloro-2,2,2-trifluoroethylidene-substituted
pyrrolidones.
The pyrrolidones derivatives (2) (0.50 mmol),
trifluoroacetic anhydride (1) (1.50 mmol, 3.0 equiv), AlCl3
(100.0 mg, 0.75 mmol, 1.5 equiv), and DMF (4.0 mL)
were added to a reaction tube equipped with a stir bar. The
mixture was stirred at 60 °C for 24 h. The reaction mixture
was diluted with ethyl acetate (30 mL), washed with
saturated brine (30 mL), and water (20 mL), dried over
MgSO4. The solvent was removed by rotary evaporation
and the resulting product 3 was purified by column
chromatography over silica gel (n-pentanes/ethyl acetate =
1:1).
Acknowledgements
This work was supported by National Natural Science
Foundation of China (21772022).
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5
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Advanced Synthesis & Catalysis
FULL PAPER
Aluminium Chloride-Mediated Synthesis of 1-
Chloro-2,2,2-Trifluoroethylidene-Substituted
Pyrrolidones
Adv. Synth. Catal. Year, Volume, Page – Page
Zeng Wang, Zihang Yuan, Xiaoyan Han* and
Zhiqiang Weng*
6
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