FeCl3-Mediated Synthesis of 2-(Trifluoromethyl)quinazolin-4(3 H)-ones from Isatins and Trifluoroacetimidoyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.0c01927

An FeCl3-mediated cascade coupling/decarbonylative annulation reaction for the efficient construction of 2-(trifluoromethyl)quinazolin-4(3H)-ones has been developed. This transformation employs readily available isatins and trifluoroacetimidoyl chlorides as the starting materials, providing a facile and practical route to diverse biologically relevant quinazolin-4(3H)-one derivatives. A plausible reaction pathway has been proposed based on the mechanistic observations.

Full text of DOI:10.1021/acs.orglett.0c01927

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Letter
FeCl3‑Mediated Synthesis of 2‑(Trifluoromethyl)quinazolin-
4(3H)‑ones from Isatins and Trifluoroacetimidoyl Chlorides
Le-Cheng Wang, Shiying Du, Zhengkai Chen,* and Xiao-Feng Wu*
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ABSTRACT: An FeCl3-mediated cascade coupling/decarbon-
ylative annulation reaction for the efficient construction of 2-
(trifluoromethyl)quinazolin-4(3H)-ones has been developed. This
transformation employs readily available isatins and trifluoroace-
timidoyl chlorides as the starting materials, providing a facile and
practical route to diverse biologically relevant quinazolin-4(3H)-
one derivatives. A plausible reaction pathway has been proposed
based on the mechanistic observations.
uinazolin-4(3H)-ones are one class of highly privileged
substituted quinazolin-4(3H)-ones are rather limited.5 For
instance, anthranilic amides were applied as versatile substrates
to react with ethyl trifluoroacetate, trifluoroacetic anhydride, or
TFA under different conditions for producing 2-trifluorome-
thylquinazolin-4(3H)-ones (Scheme 1a).5a−d Another synthetic
pathway is the annulation of anthranilic esters with unstable
Q structural motifs that widely exist in natural products and
biologically active pharmaceuticals (Figure 1).1 They possess a
Scheme 1. Synthesis of 2-Trifluoromethylquinazolin-4(3H)-
ones Derivatives
Figure 1. Selected examples of biologically active quinazolin-4(3H)-
ones.
variety of useful biological activities, including anticancer,
antiviral, anticonvulsant, anti-inflammatory, antifungal, and
antimalarial activities.2 Therefore, except for the traditional
synthetic strategies involving 2-aminobenzamide and its
derivatives, tremendous impressive methods have been
developed for the construction of functionalized quinazolin-
4(3H)-ones.3
Because of the unique properties of fluorine atoms, the
substituents involving fluorine or trifluoromethyl could greatly
improve the physicochemical and pharmacological properties of
heterocyclic molecules.4 Nevertheless, among the vast literature
regarding the synthesis of quinazolin-4(3H)-ones, the reported
approaches for the efficient assembly of 2-trifluoromethyl
Received: June 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01927
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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trifluoroacetamidine (Scheme 1b).5e,f The reaction of isatoic
anhydride with trifluoroacetic anhydride and the subsequent
displacement with amines could afford the target molecules,
which was reported by Bergman and co-workers (Scheme 1c).5g
Recently, the Tortoioli group described a one-pot approach for
the synthesis of 2-trifluoromethylquinazolin-4(3H)-ones
through a T3P (n-propanephosphonic anhydride)-promoted
cascade reaction of anthranilic acids and amines by using TFA as
the trifluoromethyl source (Scheme 1d).5h Furthermore, the
cyclization of nitrile derivatives with trifluoroacetic anhydride
also provided another access to 2-trifluoromethylquinazolin-
4(3H)-ones.5i The transformation of isatins into 2-trifluorome-
thylquinazolin-4(3H)-ones was reported, which involved multi-
step conversion.6 Despite an impressive advance made in the
field, most of the existing methods generally require harsh
reaction conditions, not readily accessible reagents, poor yields,
or narrow substrate scope. Consequently, the exploration of
more general and efficient strategies for the preparation of 2-
trifluoromethylquinazolin-4(3H)-ones from readily available
starting materials is still highly desirable.
Isatins have been widely applied as versatile building blocks
for the construction of a variety of N-heterocycles.7 Among
various isatin-based reactions, ring-expansions and decarbox-
ylative couplings of isatins offer facile and direct routes to build
structurally diverse heterocyclic compounds. For instance, Wu
and co-workers developed a series of tert-butyl hydroperoxide
(TBHP)-promoted oxidative cyclization reactions of isatins for
the synthesis of quinazolin-4(3H)-ones and tryptanthrins,8
12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones,9 and 3-car-
boxylate-4-quinolone derivatives,10 respectively. Huang and Yin
described a copper-catalyzed domino reaction of isatins and 2-
bromopyridines to enable the formation of 11H-pyrido[2,1-b]-
quinazolin-11-ones.11 Encouraged by the seminal works
involving isatins and our ongoing research on the heterocyclic
synthesis,12 we herein report a FeCl3-mediated cascade
coupling/decarbonylative annulation of readily available isatins
with trifluoroacetimidoyl chlorides to lead to 2-
(trifluoromethyl)quinazolin-4(3H)-ones (Scheme 1e). Nota-
bly, the trifluoroacetimidoyl chlorides are easily prepared and
have been extensively employed as a kind of important
trifluoromethyl-containing synthon.13
Initially, the isatin 1a and N-(4-(tert-butyl)phenyl)-2,2,2-
trifluoroacetimidoyl chloride 2f were chosen as model substrates
to optimize the reaction conditions. The reaction of 1a and 2f
was carried out in the presence of 1.2 equiv of NaH and 4 Å MS
in DMF at 40 °C for 10 h, then at an elevated temperature of 120
°C for another 20 h. Gratifyingly, the cascade decarboxylative
cyclization reaction proceeded smoothly to give the desired
product 3f in 19% yield in the absence of any metal catalysts
(Table 1, entry 1). Considering the important promotive effect
of metals, CuCl (20 mol %) was used as a catalyst to be added
into the reaction and the yield was greatly increased to 64%
(Table 1, entry 2). Stimulated by the positive result, different
copper salts and other transition metals (nickel and iron) were
surveyed in the transformation. The observations revealed that
FeCl3 was the best catalyst to improve the reaction’s efficiency
and the product 3f could be delivered in up to 92% isolated yield
(Table 1, entries 3−10). The screening of other bases was next
performed, including NaHCO3, Na2CO3, Cs2CO3, and NEt3,
which showed inferior reactivity compared with NaH (Table 1,
entries 11−14). Further investigation of the solvent effect using
different solvents indicated that DMF was the optimal candidate
(Table 1, entries 15−19). Lowering the temperature had a
a
Table 1. Optimization of Reaction Conditions
b
entry
[M] (mol %)
base (equiv)
solvent (mL)
yield (%)
1
2
3
4
5
6
7
8
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
CH3CN
toluene
Dioxane
DMSO
DMF
DMF
DMF
19
64
52
64
32
59
55
88
78
CuCl
CuBr
CuI
Cu(OAc)2
CuCl2
Ni(OTf)2
FeCl2
Fe(OTf)3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
9
NaH
c
10
11
12
13
14
15
16
17
18
19
20
21
22
NaH
NaHCO3
Na2CO3
Cs2CO3
NEt3
NaH
NaH
NaH
NaH
NaH
98 (92)
39
32
24
67
42
22
23
38
73
d
NaH
NaH
NaH
65
91
43
e
f
a
Reaction conditions: 1a (0.20 mmol), 2f (0.24 mmol), [M] (20 mol
%), base (1.2 equiv), and 4 Å MS (50 mg) in solvent (2.0 mL) at 40
b
°C for 10 h, then at 120 °C for another 20 h. Yields determined by
c
GC analysis using dodecane as an internal standard. Isolated yield.
d
e
f
90 °C. 130 °C. The reaction was performed under N2 atmosphere.
detrimental influence on the reaction and elevating the reaction
temperature to 130 °C resulted in a slight decrease of the yield
(Table 1, entries 20−21). Performing the reaction under inert
atmosphere could give the product 3f in 43% yield (Table 1,
entry 22). It is reasonable that the reaction at 40 °C for 10 h
could be beneficial for the initial coupling of isatin and
trifluoroacetimidoyl chloride, and the subsequent reaction at
elevated temperature could facilitate the decarbonylative
cyclization process.
With the establishment of the optimized reaction conditions,
the generality and limitation of the present transformation was
studied with respect to a series of fluorinated imidoyl chlorides
(Scheme 2). The reaction exhibited broad substrate scope, as
verified that numerous N-aryl-trifluoroacetimidoyl chlorides
bearing electron-donating or -withdrawing groups reacted
smoothly with isatins to give the corresponding 2-
(trifluoromethyl)quinazolin-4(3H)-one products in good to
excellent yields (3a−3r). The electronic effect (3a−3r) and
steric hindrance (3b−3d, 3o−3q) of the aryl ring exerted a
negligible influence on the reaction due to the observed
comparable yields of these substrates. The good tolerance of
the halogen atom (F, Cl, Br, and I) at different positions on the
aryl ring demonstrated good compatibility of the protocol (3j−
3m, 3o−3q). The transformation could be easily scaled up to 1
mmol scale in 71% yield for the product 3f. The
trifluoroacetimidoyl chlorides bearing a naphthalene ring were
also applicable to the current reaction to lead to the desired
products 3s and 3t in 79−84% yields. Noteworthy was that
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a
a
Scheme 2. Scope of Fluorinated Imidoyl Chlorides
Scheme 3. Scope of Isatins.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol) FeCl3 (20 mol
%), NaH (1.2 equiv), and 4 Å MS (50 mg) in DMF (2.0 mL) at 40
°C for 10 h, then at 120 °C for another 20 h, isolated yields.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), FeCl3 (20 mol
%), NaH (1.2 equiv), and 4 Å MS (50 mg) in DMF (2.0 mL) at 40
°C for 10 h, then at 120 °C for another 20 h, isolated yields. The
reaction was performed on 1 mmol scale.
Scheme 4. Control Experiments
b
trifluoroacetimidoyl chloride derived from aliphatic amine was
not suitable for the transformation and only a trace of product
3u was detected. Furthermore, several other fluorinated imidoyl
chlorides were applied as viable substrates to furnish the various
fluoroalkyl-substituted quinazolin-4(3H)-ones with high effi-
ciency (3v−3y). The exact structure of the obtained product 3p
was further confirmed by single X-ray diffraction analysis
(CCDC: 2010044).14
The scope of the protocol was further extended by the
employment of a library of isatins (Scheme 3). Diverse isatins
bearing different substituents smoothly participated in the
decarboxylative annulation reactions to deliver the correspond-
ing products in moderate to excellent yields (4a−4g, 4i−4k).
The substitutions located at 4-, 5-, 6-, and 7- positions of isatins
could be all tolerant, displaying the good generality of the
reaction. It was worth mentioning that steric hindrance of the
substituents located at the 7-position of isatins had a great effect
on the transformation due to the observed inferior yield of
product 4i and no reactivity of 7-methylindoline-2,3-dione.
Notably, the halogen atom at different positions survived the
reaction, offering the synthetic handle for further modification.
The reaction mechanism was investigated by performing
several control experiments, as outlined in Scheme 4. Initially,
the radical trapping experiments were implemented by the
addition of 2.0 equiv of TEMPO (2,2,6,6-tetramethylpiperidine
1-oxyl) and BHT (2,4-di-tert-butyl-4-methylphenol) under the
standard conditions, and almost no influence upon the reaction
yield was observed, which indicated that the reaction possibly
did not undergo a radical pathway (Scheme 4a). The reaction of
2-amino-5-methylbenzoic acid 5 with trifluoroacetimidoyl
chloride 2f under the optimal conditions failed to furnish the
desired product, suggesting the irreplaceability of isatin in the
reaction (Scheme 4b). Furthermore, the 1H-benzo[d][1,3]-
oxazine-2,4-dione 6 was employed as substrate to react with 2f,
and only trace of the target 2-(trifluoromethyl)quinazolin-
4(3H)-one product 3f was detected. Therefore, the isatoic
anhydride 6 did not act as the intermediate of this reaction,
which was usually identified as the key intermediate in oxidant-
promoted reactions of isatin (Scheme 4c).8−10 Finally, the
coupling product 7 of isatin 1a with 2f was submitted into the
standard conditions and the desired product 3f was obtained in
76% yield. When the reaction was performed without NaH or
without FeCl3 and NaH, the product 3f was delivered in 97% or
48% yield, respectively (Scheme 4d). The above observations
demonstrated the intermediacy of compound 7. In addition, the
decarbonylative cyclization step could be enabled by only
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heating and greatly facilitated by FeCl3, whereas the additional
NaH inhibited this process (Scheme 4d).
On the basis of the mechanistic observations and precedent
literatures,11,15 we proposed a plausible mechanism for the
reaction as depicted in Scheme 5. At first, the coupling of isatin
AUTHOR INFORMATION
Corresponding Authors
■
Zhengkai Chen − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
orcid.org/0000-0002-5556-6461; Email: zkchen@
zstu.edu.cn
Xiao-Feng Wu − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
Scheme 5. Plausible Reaction Mechanism
Leibniz-Institut fur Katalyse e. V. an der Universitat Rostock,
̈
̈
Rostock 18059, Germany; orcid.org/0000-0001-6622-
3328; Email: xiao-feng.wu@catalysis.de
Authors
Le-Cheng Wang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Shiying Du − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01927
Notes
1a with trifluoroacetimidoyl chloride 2f in the presence of NaH
gave the compound 7. Subsequently, the intramolecular
nucleophilic attack of amidine nitrogen atom to ketone could
lead to a tricyclic zwitterionic intermediate A. Finally, the
decarbonylative process of intermediate A in the presence or
absence of FeCl3 occurred to enable the formation of 2-
(trifluoromethyl)quinazolin-4(3H)-one 3f with the extrusion of
carbon monoxide,11,15 which was successfully trapped by CO
detector. The reaction proceeded smoothly in the absence of
water or strong oxidant, so the decarbonylative process with the
release of carbon dioxide was presumably not involved in the
reaction,8−11 which was further verified by the result of the
control experiment as shown in Scheme 4c.
In conclusion, an FeCl3-mediated cascade coupling/decar-
bonylative annulation reaction of isatin with fluorinated imidoyl
chlorides has been disclosed, providing a straightforward and
efficient approach for the assembly of pharmaceutically valuable
quinazolin-4(3H)-one derivatives. The transformation has
several notable features, including readily available reagents,
nonexpensive iron catalyst, broad substrate scope, high
efficiency, and easy scalability. A reasonable reaction mechanism
has been proposed according to the preliminary mechanistic
studies.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (21772177), the Natural Science
Foundation of Zhejiang Province (LY19B020016), and the
Fundamental Research Funds of Zhejiang Sci-Tech University
(2019Q065).
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01927.
General comments, general procedure, optimization
details, analytic data, and NMR spectra PDF)
Accession Codes
CCDC 2010044 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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