Synthesis of quinazolin-4(3H)-ones via electrochemical decarboxylative cyclization of α?keto acids with 2-aminobenzamides

Article abstract of DOI:10.1016/j.mcat.2020.111345

Herein, an environmentally benign electrochemical protocol has been disclosed for the synthesis of quinazolin-4(3H)-one derivatives from readily available α?keto acids and 2-aminobenzamides. This decarboxylative cyclization process proceeds conveniently in the absence of any homogeneous metal catalysts, bases, or external oxidants. This protocol also features CO₂ by-products, mild reaction conditions (room temperature and air atmosphere), and a wide variety of substrate scope, including an array of 2,3-disubstituted quinazolinone products.

Full text of DOI:10.1016/j.mcat.2020.111345

Molecular Catalysis 500 (2021) 111345
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
Synthesis of quinazolin-4(3H)-ones via electrochemical decarboxylative
cyclization of α‑keto acids with 2-aminobenzamides
Qing Tian, Jinli Zhang*, Liang Xu*, Yu Wei*
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University Shihezi, 832003,
China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Herein, an environmentally benign electrochemical protocol has been disclosed for the synthesis of quinazolin-4
Electrochemistry
Quinazolinone
(3H)-one derivatives from readily available α‑keto acids and 2-aminobenzamides. This decarboxylative cycli-
zation process proceeds conveniently in the absence of any homogeneous metal catalysts, bases, or external
oxidants. This protocol also features CO2 by-products, mild reaction conditions (room temperature and air at-
mosphere), and a wide variety of substrate scope, including an array of 2,3-disubstituted quinazolinone products.
α
‑Keto acids
Aminobenzamide
Decarboxylation
Introduction
approaches not only promote the traditional reactions to be greener but
also provide opportunities to achieve previously challenging trans-
The
α-keto acids (
α
-oxocarboxylic acids), which play a crucial role in
formations [19].
the energy-supplying biochemical processes, such as the Krebs cycle,
have been utilized as versatile acylating agents in a plethora of acylation
and cyclization reactions in the last decades. With extruded CO2 as the
byproduct, they are accredited to be greener acyl surrogates, compared
with the traditionally used counterparts that usually employ stoichio-
metric activating reagents and lead to undesirable and toxic wastes.
Therefore, their use in the synthesis of value-added chemicals has
attracted considerable interest from the synthetic community. However,
On the other hand, the quinazolinone skeleton is one privileged
structure in numerous synthetic intermediates, natural alkaloids, and
pharmaceuticals of biological and pharmacological activities, such as
Methaqualone, Luotonin A, Rutaecarpine, Tryptanthrin, etc (Scheme 1).
Consequently, considerable efforts have been made towards their effi-
cient synthesis. Among the established methods, the most commonly
used ones have been the fusion of readily available 2-aminobenzamides
with aldehydes [20–23] or equivalents, such as alcohols [24–27],
methyl arenes [28], amines [29–31], alkynes, CO plus aryl bromides
[32], which can in-situ lead to similar reactive intermediates with al-
dehydes [33–37]. Although fruitful, these approaches still suffer from
some of the following limitations: the use of stoichiometric or excess
amounts of oxidants [38–43], such as TBHP (tert-butyl hydroperoxide),
H2O2, K2S2O8, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), in
the presence of chemically unstable aldehydes (Scheme 1a); require-
ment for (noble) transition metal catalysts that might result in the
contaminant of metal residue in products; high reaction temperature;
excess amounts of bases and/or other additives that may lead to more
wastes. Therefore, the development of other atom-economic strategies
that can employ greener reactants and reagents is still of great signifi-
typically, to facilitate the decarboxylation process of α-keto acids, over
stoichiometric amounts of oxidants are needed, which necessitates
further development of more atom-economic reaction systems [1].
Electrochemical reactions enable the direct interaction between re-
actants and electrons, thereby bypassing the use of extra oxidants or
reductants. This strategy has seen a renaissance in the field of organic
synthesis, in the pursuit of more sustainable and environmentally benign
synthetic protocols [2–5]. Historically, the Kolbe decarboxylative reac-
tion should be one of the earliest examples of organic electrochemical
reactions. However, it is very recently that more other types of elec-
trochemical decarboxylative transformations were investigated, along
with the revival of electrosynthesis [6–13]. More specifically, the elec-
trochemical decarboxylation has been found efficient in activating
cance in the field. As mentioned above, the
α-keto acids have been
α
-keto acids and then transferring acyl groups in the acylation of het-
applied as acyl suppliers in diverse reactions [1], and in some cases
under electrochemical conditions [4]. However, an inspection into the
erocycles or cyclization reactions [14–18]. These electrochemical
* Corresponding authors.
E-mail addresses: zhangjinli@tju.edu.cn (J. Zhang), xuliang4423@shzu.edu.cn (L. Xu), yuweichem@shzu.edu.cn (Y. Wei).
https://doi.org/10.1016/j.mcat.2020.111345
Received 7 August 2020; Received in revised form 6 December 2020; Accepted 9 December 2020
Available online 30 December 2020
2468-8231/© 2020 Elsevier B.V. All rights reserved.

Q. Tian et al.
Molecular Catalysis 500 (2021) 111345
Scheme 1. Biologically active molecules containing the quinazoline-4(3H)-one skeleton; Methods for the construction of the quinazolin-4(3H)-one skeleton.
under transition metal-, oxidant- and bases-free conditions (Scheme 1c)
Table 1
[49,50]. Such a strategy should be well consistent with the principles of
green chemistry, in terms of atom economy, energy efficiency, catalysis,
and safer chemicals and chemistry.
Optimization of the reaction conditions a)
.
Results and discussion
Entry
Variations from the standard conditions
Yield b)
The investigation was initiated by exploring the reactions between 2-
aminobenzamides 1a and 2-oxo-2-phenylacetic acid 2a (Table 1). The
apparatus for electrochemical reaction consists of an undivided cell with
a platinum (Pt) anode and a platinum (Pt) cathode. After extensive
screening, the desired product 3aa could be obtained in 90 % isolated
yield, under the following conditions: constant current (I =5 mA), 2,2,2-
trifluoroethanol (TFE) as solvent, Bu4NPF6 as electrolyte [Bu4NPF6/TFE
(0.1 M, 2.0 mL)], room temperature for 4 h (Entry 1). Variations from
these standard conditions would result in inferior outcomes. When the
time was extended to 6 h, the yield would be reduced to 56 % (Entry 2),
probably due to the electrolytic consumption of the product over time.
Using different solvents, such as acetonitrile, methanol, or hexa-
fluoroisopropanol (HFIP), could also lead to the formation of 3aa, but
the yields decreased significantly (around 35 %, Entries 3–5). When
DMF or DMSO was used, the formation of 3aa was fully suppressed
(Entries 6, 7). When other quaternary ammonium salts were exploited as
electrolytes, it was found that their counter anions played a critical role
in this transformation. While the use of Bu4NBF4 and Bu4NClO4 led to
decreased yields by 5 % and 17 %, respectively (Entries 8, 9), the
presence of Bu4NAc inhibited the reaction, affording only trace of the
product (Entry 10). Using the graphite electrode instead of one platinum
electrode, the yield of 3aa fell to 40 % (Entry 11). Also, other electrode
combinations, such as C/C, Pt/GCE (glassy carbon electrode), resulted in
decreased yields or no reactivity. When the current was regulated to
3 mA or 8 mA, also, a substantial decrease in the yield was obtained
1
None
90 %
56 %
33 %
32 %
38 %
N.R.
2
reaction time: 6 h
CH3CN
3
4
CH3OH
5
HFIP
6
DMF
7
DMSO
N.R.
8
Bu4NBF4 as electrolyte
Bu4NClO4 as electrolyte
Bu4NAc as electrolyte
C/Pt instead of Pt/Pt
C/C instead of Pt/Pt
Pt/GCE instead of Pt/Pt
GCE/C instead of Pt/Pt
GCE/GCE instead of Pt/Pt
I =3 mA
85 %
73 %
trace
40 %
29 %
84 %
trace
N.R.
9
10
11
12
13
14
15
16
17
34 %
35 %
I =8 mA
a)
Standard conditions: undivided cell, constant current =5 mA, 1a
(0.20 mmol) and 2a (0.3 mmol, 1.5 equiv) in Bu4NPF6/TFE solution (0.1 M,
2.0 mL), room temperature for 4 h.
b)
Isolated yields.
literature data indicated that they have not been utilized in the synthesis
of quinazolinone, except for one case where their potassium salts were
used in the presence of K2S2O8 (Scheme 1b) [44]. This situation inspired
our following efforts [45–48], to activate the α-keto acids using elec-
trochemical technology, and to realize the construction of quinazolinone
2

Q. Tian et al.
Molecular Catalysis 500 (2021) 111345
Table 2
Table 3
Substrate scope of
α
-keto acids a)
.
Substrate scope of 2-aminobenzamides a)
.
a) Standard conditions in Table 1 were applied with extended reaction time (6 h);
b) Et4NPF6 as the electrolyte.
a) Standard conditions in Table 1 were applied with extended reaction time (6 h).
and naphthalen-2-yl cycles were also competent to undergo this decar-
boxylative cyclization process, affording 3ao and 3ap in 66 % and 41 %
yields, respectively.
(Entries 16, 17).
After obtaining the optimal reaction conditions, we began to explore
the substrate scope of this transformation.
The variations of 2-aminobenzamides were then explored (Table 3).
In the beginning, the starting materials with different substitution on the
phenyl rings were treated with 2a. When methyl was at the 4- or 5-po-
sition of 2-aminobenzamides, the corresponding cyclization products
3ba or 3bb could be obtained in similar yields (82 %, 74 %). As antic-
ipated, the halide atoms on 2-aminobenzamides were also compatible,
leading to good to excellent yields of products. The reaction yield greatly
decreased when 2-amino-5-methoxybenzamide was applied (3be, 36
%).
First, 2-aminobenzamide 1a was treated with a series of 2-(hetero)
aryl α-keto acids. The results were illustrated in Table 2. As indicated,
when the phenyl rings of α-keto acids were substituted by the electron-
donating methoxy group, the transformations proceeded efficiently,
regardless of the substitution pattern (para-, meta- or ortho-) of the
starting materials. Correspondingly, 3ab, 3ac and 3ad could be isolated
in 83 %, 94 % and 75 % yields, respectively. The situation remained
unchanged when a typical withdrawing substitution, the fluorine atom,
was used. However, in this case, the divergence of isolated yields was
much more obvious. While 2-(4-fluorophenyl)-2-oxoacetic acid led to
the decarboxylative cyclization product 3ae in 99 % yield. Its meta-
substituted counterpart only afforded the corresponding product 3af in
48 % yield. Disubstituted substrates, which also contained electron-
donating or withdrawing groups, were also attempted to obtain 3ai
and 3aj in moderate yields. It should be noted the bromine and chlorine
atoms on the phenyl rings were well compatible with the reaction
conditions. The obtained halide-substituted quinazolinones (3ak-3an)
should be ready for further decoration, due to the diverse reactivity of
Then, 2-amino-N-substituted benzamides were used. In general,
moderate to excellent yields could be obtained, no matter the substitu-
tion was aromatic or aliphatic groups. Therefore, an array of 2,3-disub-
stituted quinazolin-4(3H)-one products (3bf-3bl) were synthesized via
this protocol. This should be the first time such compounds were
accessed with α-keto acids as acyl surrogates, to the best of our knowl-
edge. Specifically, while 2-amino-N-methylbenzamide was almost fully
converted into the decarboxylative cyclization product 3bf (99 %), its N-
phenyl analogue showed much lower reactivity, affording the corre-
sponding product 3bg in only 43 % yield. When 2-amino-N-(o-tolyl)
benzamide applied, 66 % of the product could be obtained. As for the
aryl halides. Fortunately, the α-keto acids with hanging thiophen-3-yl
Scheme 2. Further exploration of the substrate scope.
3

Q. Tian et al.
Molecular Catalysis 500 (2021) 111345
The mechanism of the reaction was explored by several control re-
actions. To study the function of current during this transformation,
based on the optimal conditions, a series of control experiments were
carried out (Table 4). The results showed the transformation from 1 and
2 to 3 was not feasible in the absence of the passing current, indicating
its critical role in initiating this reaction.
Table 4
The function of electrosynthesis.
Entry
Variation from standard conditions
Yield a)
1
2
3
4
5
6
7
8
5 mA, 1 h
14 %
15 %
33 %
35 %
50 %
51 %
90 %
90 %
5 mA, 1 h +0 mA, 2 h
5 mA, 2 h
5 mA, 2 h +0 mA, 2 h
5 mA, 3 h
When 5.0 equiv of 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO), a
radical scavenger, was added into the standard reaction conditions, the
formation of the desired product was almost halted (Scheme 3a), which
implied the involvement of radical species during the reaction. When
this experiment was completed under the protection of nitrogen, the
yield of product was 67 % (Scheme 3b), which showed the oxidative
process was feasible in the absence of air. The electricity was also
identified to be critical to this transformation (Scheme 3c). The reaction
between 1a and benzaldehyde under standard conditions led to the
formation of 3aa in 61 % isolated yield (Scheme 3d). In addition, 9 could
be oxidized to 3aa in 29 % yield (Scheme 3e). These results indicated
these two reactions might share similar reaction mechanisms/in-
5 mA, 3 h +0 mA, 2 h
5 mA, 4 h
5 mA, 4 h +0 mA, 2 h
a)
Isolated yields.
termediates with the reaction using α-keto acids. Based on the above
observations and previous reports, [14–18,49,50] two plausible mech-
anisms of this electrochemical cyclization were proposed, which were
shown in Scheme 4. In Pathway A, the reaction was thought to be
initiated by the condensation between 2-aminobenzamides and α-keto
acids and the following deprotonation, which would generate carbox-
ylate anion intermediate A. The carboxylate moiety then bound to the
electrode surface and went through the anodic oxidation process to loss
one electron and afford aroyloxy radical intermediate B, whose
following decarboxylation would give C. Then, cyclization of this in-
termediate constructed the six-membered ring D. Finally, the anodic
oxidation and deprotonation would occur once again to release the
desired product. During this process, H2 was released on the cathode via
the consumption of the proton.
Conclusions
Scheme 3. Control experiments.
In summary, an efficient electrochemical protocol for the construc-
tion of quinazolin-4(3H)-one skeleton has been developed herein. Using
aliphatic substitutions, n-butyl, 3-isopentyl, benzyl, 2-phenylethyl were
all competent for this transformation, affording products in moderate to
good yields.
α
-keto acids as the acyl surrogate, an array of quinazolin-4(3H)-one
derivatives could be accessed under metal catalyst, base, and external
oxidant-free conditions at room temperature. This electrochemical
methodology is expected to complement the existing methods in the
construction of the privilege quinazolinone skeleton.
As shown in Scheme 2, 3,3-dimethyl-2-oxobutanoic acid 4 was also
treated with 1a, and 2-tert-butyl-substituted 5 could be obtained 49 %
yield, initially confirming the effectiveness of this protocol in handling
alkyl α-keto acids. After exploring the substrate scope of 2-aminobenza-
CRediT authorship contribution statement
mide, we turned attention to its sulfonamide analogue. Under slightly-
modified conditions, the electrocatalytic reaction between 6 and 2a
led to the decarboxylative cyclization product 7 in 67 % yield.
Qing Tian: Investigation, Methodology. Jinli Zhang: Resources,
Supervision. Liang Xu: Conceptualization, Writing - original draft. Yu
Scheme 4. Plausible reaction mechanism.
4

Q. Tian et al.
Molecular Catalysis 500 (2021) 111345
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