Palladium-catalyzed synthesis of novel trifluoromethylated quinazolinone, N-arylquinazoline and N-benzylquinazoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2021.153053

A simple and palladium-catalyzed procedure for synthesis of a novel series of potentially biologically active trifluoromethyl-substituted quinazolinones and N-arylquinazoline derivatives via condensation-cyclization reaction of 2-aminobenzamide, 2-amino-N′-arylbenzimidamides and 2-amino-N′-benzylbenzimidamides with trifluoroacetimidoyl chlorides has been developed. noteworthy, this investigation showed the possible of transition-metal-catalyzed activation of trifluoroacetimidoyl chlorides as a carbon trifluoromethylated source for the synthesis of quinazolines and quinazolinone derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2021.153053

Tetrahedron Letters 71 (2021) 153053
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed synthesis of novel trifluoromethylated
quinazolinone, N-arylquinazoline and N-benzylquinazoline derivatives
⇑
Mahdieh Sadat Sajadi, Elham Kazemi, Ali Darehkordi
Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanja, Rafsanjan 77176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and palladium-catalyzed procedure for synthesis of a novel series of potentially biologically
active trifluoromethyl-substituted quinazolinones and N-arylquinazoline derivatives via condensation-
cyclization reaction of 2-aminobenzamide, 2-amino-N0-arylbenzimidamides and 2-amino-N0-benzylben-
zimidamides with trifluoroacetimidoyl chlorides has been developed. noteworthy, this investigation
showed the possible of transition-metal-catalyzed activation of trifluoroacetimidoyl chlorides as a carbon
trifluoromethylated source for the synthesis of quinazolines and quinazolinone derivatives in good to
excellent yields.
Received 7 February 2021
Revised 25 March 2021
Accepted 27 March 2021
Available online 1 April 2021
Keywords:
Trifluoroacetimidoyl chlorides
2-Aminobenzamide
Ó 2021 Elsevier Ltd. All rights reserved.
2-Amino-N0-arylbenzimidamides
2-Amino-N0-benzylbenzimidamides
Trifluoromethylated quinazolinones
Trifluoromethylated-N-arylquinazolines
Trifluoromethylated-N-benzylquinazolines
Quinazoline and quinazolinones form a main group of pharma-
ceutical heterocyclic derivatives that have a considerable place in
medicinal and pesticide chemistry [1], like analgesic, anti-inflam-
matory, anti-hypertensive, anti-tubercular, anti-bacterial and
anti-viral activities [2]. Also, quinazolines are extensively used as
sedative [3a], anti-bacterial [3b,c], anti-diabetic [3d], anti-inflam-
matory [3e], anti-viral [3f] and anti-tumor agents [3g].
4-Anilinoquinazoline derivatives are a group of potentially high
selective anti-cancer reagents for their powerful ability to prevent
several receptor tyrosine kinases, such as EGFR, NGFR, and VEGFR-
2, which often over-expresses or deregulates in many solid tumors
[4]. For example, compounds A and B, establish a main subgroup of
kinase inhibitor anti-cancer reagents and exhibited dihydrofolate
reductase inhibition respectively. Also, KSP ATPase inhibitor C
shows antimitotic activity and now is in phase II clinical trials as
a potential anti-cancer chemotherapeutic factor, while methaqua-
lone D is a clinically used sedative hypnotic drug (Fig. 1) [5].
According to the above and from our point of view, fluorinated
quinazolinones and quinazoline derivatives are very more impor-
tant relative to the non-fluorinated quinazolinones and quinazoli-
nes due to the fluorine atom effects. Many synthetic efforts have
been made for its construction starting from a variety of substrates
[6], among which 2-aminobenzamide is probably the most typical
one.
One of the general procedure for the synthesis of quinazolinone
derivatives is commonly reaction of 2-aminobenzamide with
either carboxylic acid derivatives under harsh conditions [7], or
aldehydes and followed by oxidation using strong oxidants [8].
However, in this procedure in general excess amounts of oxidants
should be used and produces a large amount of waste, therefore,
requiring tedious purification processes [9]. To overcome these
drawbacks such as low yields, multistep reactions, or harsh reac-
tion conditions, latter investigations gave improved methods using
Vilsmeier reagent, which are more eco-friendly, without any by-
products [10]. On the other hand heterogeneously-catalyzed pro-
cesses have a notable role in prevent of the harmful process,
declining the waste manufactures, avoiding the calamitous sol-
vents usage, and crude catalysts separation and recycling [9].
For example, N-substituted quinazolinones have been synthe-
sized from anthranilamide derivatives using dicumyl peroxide
(DCP) as the methyl source. This reaction is a tandem N-methyla-
tion-sp3 CAH amination-oxidation process with use of a copper
catalyst [6]. Also, the Ding and Fu groups individually reported that
copper-catalyzed N-arylation of o-bromobenzoic acid derivatives
with amidines and following that intramolecular reaction could
produce 2-substituted and 2,3-disubstituted quinazolinones [11].
Quinazolinones have been synthesized from reaction of 2-
aminobenzamide, aryl bromides, and carbon monoxide in present
⇑
Corresponding author.
E-mail address: darehkordi@vru.ac.ir (A. Darehkordi).
https://doi.org/10.1016/j.tetlet.2021.153053
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Mahdieh Sadat Sajadi, E. Kazemi and A. Darehkordi
Tetrahedron Letters 71 (2021) 153053
Fig. 1. Structures of some biologically important 4-anilinoquinazolines and
quinazolinones.
Scheme 1. Synthesis of 3-aryl-2-(trifluoromethyl)quinazolin-4(3H)-one 3 and N-
aryl-2-(trifluoromethyl)quinazolin-4-amine or N-benzyl-2-(trifluoromethyl)quina-
zolin-4-amine derivatives 5.
of palladium as a catalyst in good yields [12]. Also, palladium-
catalyzed
three-component
carbonylative
reaction
of
N
CF3
trifluoroacetimidoyl chlorides and amines resulted to synthesis of
2-(trifluoromethyl)quinazolin-4(3H)-one derivatives [13].
Reaction 4-halo- or 4-mercaptoquinazolines with aromatic
amines [14], 4(3H)-quinazolone with aromatic amine hydrochlo-
rides in the presence of phosphorus pentoxide and dimethylcyclo-
hexylamine [15], desulfurization of 4-phenylaminoquinazol-2-
thione using Raney nickel [16], and 2-aminobenzonitrile with ani-
line derivatives using AlCl3, and then reaction of the products with
formic acid [17] are some of the approaches reported for synthesis
of substituted 4-aryl amino quinazolines.
Fluorine is an element which has very more important role in
pharmaceutical and organic chemistry, because, it donates special
characteristics to the organic compounds and therefore change
their physicochemical and biological properties [18]. The trifluo-
romethyl substituent (CF3) is one of the most prevalent fluorinated
groups in drug chemistry, agricultural, and material sciences [19].
Because it provides simultaneously high lipophilicity, a high elec-
tron density and a steric demand similar to that of the isopropyl
group [20]. recently, synthesis of new organofluorine compounds
via reactions of trifluoromethylation have been extensively inves-
tigated [21].
Some drugs can results side effects such as gastric irritation,
ulceration, and hemorrhage. In this regard, the functionalized of
molecule with fluorine atoms has emerged as a reliable method
to eliminate the harmful mentioned. The presence of fluorine
atoms changes the physical–chemical properties of the molecules
to which they are attached, thus modify cell permeability and
decrease metabolic degradation, and also result to a longer half-life
[22].
Due to the above mentioned and in follow of our studies inter-
est on synthesis of trifluoromethylated heterocycles via palladium
catalyzed reactions [23], quinazolinone and quinazoline deriva-
tives [24,25], herein, we report palladium-catalyzed synthesis of
trifluoromethylated quinazolinones and quinazoline derivatives
from reaction 2-aminobenzamide and 2-amino-N0-arylbenzimi-
damides or 2-amino-N0-benzylbenzimidamides with trifluoroace-
timidoyl chlorides with use of Pd(PPh3)2Cl2 and Et3N respectively
(Scheme 1).
Et3N/PPh3/CCl4
reflux
NH2
CF3COOH
+
Cl
R1
R1
1
82-92 %
R1= 4-Me, 4-OMe, 4-Cl, 3,4-di Me, 3,4-di Me, 2,3-di Me, 2,4,6- tri Me
Scheme 2. Preparation of 2,2,2-trifluoroacetimidoyl chloride derivatives 1.
acetimidoyl chloride 1a and 2-aminobenzamide 2a was selected
as the model reaction. Different base, catalysts and solvents were
used at room temperature and reflux conditions. The results have
been showed in Table 1.
Without use of any catalyst, with both room temperature and
reflux conditions in presence of various solvents and base, no
desired 3-(p-tolyl)-2-(trifluoromethyl)quinazolin-4(3H)-one 3a
was observed after 24 h, based on the TLC (n-Hexane: EtOAc 3:1)
(Table 1, entries 1–3 and 5–6). To evaluate the catalytic activity
of TiO2 for the synthesis of quinazolinone, catalytic amounts of
TiO2 were added to the reaction mixture and only a trace amount
of 3a was obtained in presence of NaH or Et3N in CH3CN under
reflux conditions (Table 1, entry 7–8). But, the yield of the desired
product 3a was significantly improved in shorter reaction time
when catalytic amounts (5 mol%) of Pd(PPh3)2Cl2 were added to
the reaction mixture in presence of Et3N in CH3CN under reflux
conditions (Table 1, entry 4). Therefore, the optimal reaction con-
ditions are 1 equiv of 1a and 1 equiv 2a in the presence of 5 mol
% Pd(PPh3)2Cl2, 2 mmol Et3N in CH3CN at the reflux conditions
for 3 h (Table 1, entry 4). With determining of optimized reaction
conditions, the scope and generality of reaction were investigated
and the representative results are shown in table 2. The reactions
carried out smoothly under optimized conditions. After the end
of reaction (monitored by TLC), the catalyst was easily removed
by filtration. Therefore, a simple work-up produced the target
products 3a-f in good to excellent yields.
Also, in order to expanding the scope of reaction, in addition of
2-aminobenzamide 2a, 2-amino-N-phenylbenzamide 2b, 2-amino-
N-methylbenzamide 2c and 2-amino-N-ethylbenzamide 2d, exam-
ined under the optimized conditions. In these cases also we did not
see significant difference in reaction time, yield and elimination of
amine group, resulted to formation of 3-aryl-2-(trifluoromethyl)
quinazolin-4(3H)-one derivatives 3a-f (Scheme 3).
In order to the investigation of electronic effects on the reaction
time and yield, various imidoyl chlorides contains electron with-
drawing and electron donating groups, were used (Table 2). The
reaction proceeds without significant difference in reaction time
or yield. Therefore, with suitable reaction conditions, synthesis of
2,2,2-Trifluoro-N-arylacetimidoyl chlorides 1 have been synthe-
sized by reaction of trifluoroacetic acid, primary aryl amines, and
triphenylphosphine in CCl4 and triethylamine. Work-up and distil-
lation of the mixture reaction gave the target trifluoroacetimidoyl
chlorides in good to excellent yields (Scheme 2) [21].
Then in other to the synthesis of quinazolinone derivatives, we
carried out condensation-cyclization reaction between 2-
aminobenzamide 2a and trifluoroacetimidoyl chlorides 1. To gain
the optimized conditions, reaction of 2,2,2-trifluoro-N-(p-tolyl)
2

Mahdieh Sadat Sajadi, E. Kazemi and A. Darehkordi
Tetrahedron Letters 71 (2021) 153053
Table 1
Optimization of conditions reaction for synthesis the 3-(p-tolyl)-2-(trifluoromethyl)quinazolin-4(3H)-one 3a.
Entry
Catalyst
Base
Solvents
T(°C)
Yield (%)
1
2
3
4
5
6
7
8
-
-
-
Et3N
Et3N
Et3N
Et3N
K2CO3
K2CO3
Et3N
NaH
Toluene
Toluene
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
reflux
rt
reflux
rt
reflux
reflux
reflux
-
-
-
85
-
-
a
Pd(PPh3)2Cl2
-
-
TiO2
TiO2
b
Trace
Trace
c
a
b
c
Conditions: 1a (1 mmol), 2a (1 mmol) Et3N (2 mmol) and Pd(PPh3)2Cl2 (5 mol %) in CH3CN at reflux.
Conditions: 1a (1 mmol), 2a (1mmmol) Et3N (2 mmol) and TiO2 (5 mol %) in CH3CN at reflux.
Conditions: 1a (1 mmol), 2a (1mmmol) NaH (2 mmol) and TiO2 (5 mol %) in CH3CN at reflux.
Table 2
Synthesis of 3-phenyl-2-(trifluoromethyl)quinazolin-4(3H)-one derivatives 3a-f
under optimized conditions.a
Scheme 3. Synthesis of 3-phenyl-2-(trifluoromethyl)quinazolin-4(3H)-one deriva-
tives 3a-f using 2-aminobenzamides 2.
trifluoromethyl-substituted quinazolinone could be accessed by
this transformation in good to excellent yields.
A possible mechanism for this reaction is proposed in Scheme 4.
According to the obtained results, the above mechanism can be
proposed for the synthesis of trifluoromethyl-substituted quina-
zolinone derivatives from reaction of the 2-aminobenzamide 2a
and trifluoroacetimidoyl chlorides 1 in the presence of Pd(PPh3)2-
Cl2, as a heterogeneous catalyst (Scheme 4). According to the liter-
ature [26–29], firstly, Pd(II) becomes to Pd(0) which activates the
trifluoroacetimidoyl chlorides 1a-f to produce palladium imidoyl
complex A. Then this activated complex reacts with 2-aminoben-
zamide 2a and produce organopalladium compound B. In continue,
organopalladium compound B under a reduction-elimination reac-
Compound
R1
Product
Yield (%)
87
3a
4-Me
3b
3c
3d
4-OMe
2-Cl
87
80
72
3,4-di Me
PdII(PPh3)2Cl2
O
H2N
H2N
O
N
CF3
N
CF3
Pd0(PPh3)2
NH2
NH
(Ph3P)2Pd II
CF3
2a
R1
R1
Cl
PdIIPPh3)2
Cl
Et3N
1a-f
N
3e
3f
2,4,6-tri Me
2,5-di Me
80
80
R1
Reduction
Elimination
Pd0(PPh3)2
O
N
O
O
R1
Et3N
-NH3
NH2
NH2
N
N
NH
N
CF3
N
CF3
R1
H
R1
CF3
3a-f
A
a
Conditions: 1 (1 mmol), 2a (1 mmol) Et3N (2 mmol) and Pd(PPh3)2Cl2 (5 mol%)
in CH3CN at reflux.
Scheme 4. A possible mechanism for the synthesis of 3-aryl-2-(trifluoromethyl)
quinazolin-4(3H)-one derivatives (3a-f).
3

Mahdieh Sadat Sajadi, E. Kazemi and A. Darehkordi
Tetrahedron Letters 71 (2021) 153053
Table 3
Synthesis of N-aryl-2-(trifluoromethyl)quinazolin-4-amine and N-benzyl-2-(trifluo-
romethyl)quinazolin-4-amine derivatives under optimized conditions.a
Scheme 5. Synthesis of 2-amino-N0-phenylbenzimidamide and 2-amino-N0-ben-
zylbenzimidamides derivatives 4.
Compound
R3
Product
Yield (%)
87
5a
4-Me-Ph
Scheme 6. Synthesis of N-(p-tolyl)-2-(trifluoromethyl)quinazolin-4-amine 5a.
5b
5c
4-OMe-Ph
87
80
tion results to 2-(2,2,2-trifluoro-N0-arylacetimidamido)benzamide
C which tautomerizes to compound D. Finally, intermolecular
nucleophilic attack of NH- group and elimination of NH3 molecule,
to afford the desired 3-aryl-2-(trifluoromethyl)quinazolin-4(3H)-
one derivatives 3a-f.
3,4-di Me-Ph
Possessing accepted
a
new method for synthesis of
trifluoromethylated arylquinazolinones 3a-f from the reaction of
2-aminobenzamide 2a with imidoyl chlorides 1, we were then
investigated in whether this procedure could be used in the
synthesis of N-aryl-2-(trifluoromethyl)quinazolins or N-benzyl-2-
(trifluoromethyl)quinazolines by replacing 2-aminobenzamide 2a
with 2-amino-N0-arylbenzimidamides or 2-amino-N0-benzylbenz-
imidamides 4a-l. For this purpose, in the first, 2-amino-N0-arylben-
zimidamides or 2-amino-N0-benzylbenzimidamides 4a-l. are
obtained via reaction of o-aminobenzonitrile and aniline or benzyl
amine derivatives in the presence of AlCl3 at 150–180 °C according
to the literature reported (Scheme 5) [30].
5d
3-Et-Ph
85
5e
5f
4-F-Ph
75
78
To examine our idea, firstly, we reacted 2-amino-N0-(p-tolyl)
benzimidamide 4a and N-(3,4-dimethylphenyl)-2,2,2-trifluoroace-
timidoyl chloride 1d in presence of Pd(PPh3)2Cl2 as catalyst and
Et3N base in CH3CN under reflux conditions (Same conditions for
synthesis of quinazolinones). After elimination of arylamine mole-
cule related to N-(3,4-dimethylphenyl)-2,2,2-trifluoroacetimidoyl
chloride 1d, N-(p-tolyl)-2-(trifluoromethyl)quinazolin-4-amine 5a
was produced (Scheme 6).
4-Cl-Ph
As mentioned in Scheme 4 quinazolinone derivatives 3a-f
were obtained from reaction of 2-aminobenzamide with
2,2,2-trifluoroacetimidoyl chlorides after elimination of NH3
molecule. In this reaction NH3 molecule eliminates from
2-aminobenzamide due to the electron-withdrawing effect of
carbonyl group. But when used 2-amino-N0-arylbenzimidamides
or 2-amino-N0-benzylbenzimidamides 4 instead of 2-aminoben-
zamide 2a, 3,4-dimethylaniline group related to N-(3,4-dimethyl-
phenyl)-2,2,2-trifluoroacetimidoyl chloride 1d was eliminated
and therefore arylaminequinazolines or benzylaminequinazolines
were produced. In order to generalize the optimum conditions
and method, various 2-amino-N0-arylbenzimidamide or 2-
amino-N0-benzylbenzimidamides 4 were used as substrates.
The results summarized in table 3, indicate the effect of the
substituent attached on the N-aryl or N-benzyl rings (R3) in this
reaction. As shown in Table 3, 2-amino-N0-arylbenzimidamide or
5g
4-Br-Ph
80
5h
5i
3-Br-Ph
80
80
2-Me-Ph
2-amino-N0-benzylbenzimidamide derivatives
4 bearing Me,
OMe, Et, 3,4-di Me, 2,4,6-tri Me and 2-Me on the phenyl and 4-
Me on the benzyl moiety reacted at shorter time and higher yield.
A possible mechanism for this reaction is proposed in Scheme 7.
4

Mahdieh Sadat Sajadi, E. Kazemi and A. Darehkordi
Tetrahedron Letters 71 (2021) 153053
Table 3 (continued)
Declaration of Competing Interest
Compound
R3
Product
Yield (%)
85
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
5j
2,4,6-tri Me-Ph
Acknowledgment
5k
CH2-Ph
85
We gratefully acknowledge financial support of a research grant
from the Rafsanjan Faculty of Vail-e-Asr University.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153053.
5l
4-Me-Ph-CH2
87
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Scheme 7. A possible mechanism for the synthesis of N-aryl-2-(trifluoromethyl)
quinazolin-4-amine derivatives 5.
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reacts with 2-amino-N0-arylbenzimidamide or 2-amino-N0-benzyl-
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