Electrochemical utilization of methanol and methanol-d4 as a C1 source to access (deuterated) 2,3-dihydroquinazolin-4(1H)-one

Article abstract of DOI:10.1016/j.cclet.2021.09.019

Herein, an electrocatalytic protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-one has been disclosed. Methanol is activated and utilized as the C1 source to cyclize with 2-aminobenzamides. This cyclization reaction proceeds conveniently (room temperature and air atmosphere) without any homogeneous metal catalysts, external oxidants, or bases. A wide variety of N,N-disubstituted 2,3-dihydroquinazolin-4(1H)-ones are obtained via this approach. Moreover, when methanol-d₄ is used, a deuterated methylene motif is incorporated into the N-heterocycles, providing an efficient approach to the deuterated N-heterocycles.

Full text of DOI:10.1016/j.cclet.2021.09.019

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Electrochemical utilization of methanol and methanol-d4 as a C1
source to access (deuterated) 2,3-dihydroquinazolin-4(1H)-one
Mingzhu Liu , Liang X , Yu Wei
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Please cite this article as: Mingzhu Liu , Liang X , Yu Wei , Electrochemical utilization of methanol
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Chinese Chemical Letters
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Communication
Electrochemical utilization of methanol and methanol-d4 as a C1 source to access
(deuterated) 2,3-dihydroquinazolin-4(1H)-one
Mingzhu Liu, 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
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, an electrocatalytic protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-one has been
disclosed. Methanol is activated and utilized as the C1 source to cyclize with 2-aminobenzamides.
This cyclization reaction proceeds conveniently (room temperature and air atmosphere) without any
homogeneous metal catalysts, external oxidants, or bases. A wide variety of N,N-disubstituted 2,3-
dihydroquinazolin-4(1H)-ones are obtained via this approach. Moreover, when methanol-d4 is used,
a deuterated methylene motif is incorporated into the N-heterocycles, providing an efficient
approach to the deuterated N-heterocycles.
Available online
Keywords:
Electrochemistry
Heterocycles
Dihydroquinazolinone
Aminobenzamide
C1 source
of reagents are utilized as the C1-precursors and applied in these
transformations, such as carbon monoxide, formic acid, HCHO
[3]. With an increasing demand for high environmental
friendliness and atom economy [4], methanol (MeOH), one
abundant, biodegradable, and renewable feedstock, which can be
efficiently obtained from fossil fuels and agricultural products [5,
6], has gradually gained accelerating application as the C1 source
in the last decades [7, 8]. An array of transition-metal-catalyzed
MeOH utilization reactions have emerged, forging a variety of C-
C and C-heteroatom bonds [9]. Among these, Ir- and Ru-based
catalysts are most frequently used [10-16]. In this regard, a
metal-free protocol with MeOH as C1 source should be
beneficial to address the cost and metal residue issues [17, 18].
On the other hand, electrochemical synthesis, which directly
employs electrons as the redox agent, has recently gained
renaissance as an environmentally benign protocol and enabled
Graphical Abstract
An environmentally benign protocol is disclosed herein,
which takes advantage of methanol as a methylene source to
access 2,3-dihydroquinazolin-4(1H)-one via an
electrochemical cyclization process.
many
previous
challenging
transformations
[19-27].
Electrochemical utilization of MeOH as the C1 source instead of
methoxy source remains rather unexplored. The only examples
were disclosed in 2020. Pan, Tang, Wang and co-workers
achieved the electrochemical activation of MeOH, realizing α-
methoxymethylation and aminomethylation of propiophenones
under metal- and oxidant-free conditions [28]. Zhao group
disclosed a pathway for direct C–H methylthiolation of electron-
rich aromatics, using KSCN as sulfur source and methanol as the
methylation reagent [29]. This leaves ample space to investigate
the electrochemical toolkit of MeOH as the C1 source.
Incorporation of C1-motif to the organic skeleton, such as
methyl, methylene and methenyl, has always been an important
research topic in organic synthesis. Such transformations have
been demonstrated to be an effective way to modify the chemical
and biochemical properties of organic molecules [1, 2]. A variety
———
 Corresponding authors.
E-mail addresses: xuliang4423@shzu.edu.cn (L. Xu); yuweichem@shzu.edu.cn (Y. Wei)

conditions in an undivided cell. The desired aminal-type product
3a could be obtained fortunately. After an extensive screening of
an array of variables, the electrolysis could result in a 97%
isolated yield of the target product 3a in a mixed solvent of
MeOH/HFIP (1:1) at room temperature (Table 1, entry 1), when
the reaction was conducted under a constant current of 5 mA in
an undivided cell equipped with a glassy carbon electrode (GCE)
anode and a platinum cathode. Et4NPF6 was explored as the
supporting electrolyte. Replacing Et4NPF6 with other electrolytes,
n
such as Me4NPF6, Bu4NBF4 and Et4NBF4, was found to be
detrimental to this cyclization process (entries 2-4). Thereafter,
other solvents/C1 sources were investigated. DMF and MeCN
were found ineffective for the formation of 3a (entries 5 and 6).
The Pt(+)/Pt(−) and GCE(+)/GCE(−) electrode combinations led
to slightly decreased yields (entries 7 and 8). Reducing the
current slightly affect the result (entry 9), while increasing the
current to 8 mA resulted in a 22% decrease in isolated yield
(entry 10). When the reaction time was shortened or prolonged,
the isolated yield both lowered. Finally, the transformation was
totally prohibited when the electric current was cut off, indicating
its essential role in this cyclization (Table 1, entry 13).
Scheme 1. (a) Biologically active molecules containing the 2,3-
dihydroquinazolin-4(1H)-one skeleton; (b) Ir-catalyzed activation of
methanol as a C1 source for the construction of quinazolin-4(3H)-
ones; (c) Electrochemical synthesis of 2,3-dihydroquinazolin-4(1H)-
ones.
As our continued efforts to discover new methods to construct
N-heterocycles [30-33], we envisioned that electrochemical
activation of MeOH with 2-aminobenzamides would provide an
alternative paradigm to access 2,3-dihydroquinazolin-4(1H)-one
skeleton, which exist in many naturally occurring alkaloids and
drug molecules (Scheme 1a) [34-38]. To the best of our
knowledge, there are no precedents achieving this transformation,
no matter under thermochemical, photochemical, or
electrochemical conditions [39, 40], although one protocol for the
construction of quinazolinones has been disclosed via Ir-
catalyzed activation of MeOH as the C1 source (Scheme 1b) [41].
Herein, the success of this hypothesis was reported (Scheme
1c). A range of N,N'-disubstituted dihydroquinazolinones, which
could only be obtained from aldehyde/ketone previously [42], are
accessed via this approach under metal-, oxidant, and additive-
free conditions.
With the optimal conditions in hand, the substrate scope for
the synthesis of 2,3-dihydroquinazolin-4(1H)-one was then
investigated via this electrochemical cyclization approach
(Scheme 2).
Table 1
Optimization of the reaction conditions. a
Entry
1
Variations from the standard conditions
none
Yield (%)b
97
2
3
4
5
6
7
8
9
10
11
12
13
Me4NPF6 as electrolyte
nBu4NBF4 as electrolyte
Et4NBF4 as electrolyte
DMF as solvent
90
85
63
N.R.
N.R.
84
92
91
75
82
86
N.R.
CH3CN as solvent
Pt/Pt instead of GCE/Pt
GCE/GCE instead of GCE/Pt
3 mA instead of 5 mA
8 mA instead of 5 mA
12 h instead of 16 h
20 h instead of 16 h
no electricity
CCE: constant current electrolysis, GCE: glassy carbon electrode.
a
Standard conditions: undivided cell, 1a (0.3 mmol), solvent (2.0
mL), nEt4NPF6 (0.1 mol/L), 5 mA, room temperature for 16 h.
b Isolated yields.
Initially, N,N'-disubstituted 2-aminobenzamide 1a and MeOH
were chosen as the model substrate to explore the reaction

Scheme 2. Substrate scope of 2,3-dihydroquinazolin-4(1H)-one from
MeOH. Reaction conditions: undivided cell, 1 (0.3 mmol), solvent
n
a
(2.0 mL), Et4NPF6 (0.1 mol/L), 5 mA, r.t., 16 h. 1a (3.0 mmol),
solvent (10.0 mL), nEt4NPF6 (0.1 mol/L), 5 mA, r.t., 36 h.
At first, variants on the phenyl of anthranilamide were
explored. 5-Methyl (1b), 5-Cl (1c) and 5-Br (1e) substituted
anthranilamides
afforded
the
corresponding
dihydroquinazolinone compounds in good yields, indicating the
compatibility of the conditions with electron-withdrawing and
donating groups. Halogen (Cl and Br) substituted anthranilamide
reacted smoothly with methanol, affording 3c-3e in isolated
yields of 78%-88%. When the methyl on the aniline motif of 1a
was replaced by a phenyl, N3-benzyl-N1-phenyl-substituted 3f
was obtained in 74% yield. Also, the electron-donating and
electron-withdrawing groups on the N1-aryl group were well
tolerated to access the corresponding products 3g-3j in 61%-70%
yields. Similarly, 3n-3t could be obtained in moderate to good
yields, affording diverse N3-aryl-N1-methyl substituted substrates.
Methoxy, trifluoromethoxy, methyl, and halogens were all
compatible herein. When two methyls were present on the aniline
and benzamide motifs, 3l was obtained in 80% yields. In the
same while, probably due to the steric effect, a bulky cyclohexyl
resulted in a dramatically decreased yield to 36% (3m). N1,N3-
Diphenyl substrate 3u could be accessed in 70% yield. The
presence of the aminal motif, with methylene between two
nitrogen atoms, was confirmed unambiguously by X-ray single-
crystal diffraction.
Scheme 4. Substrate scope of 2,3-dihydroquinazolin-4(1H)-one-2,2-
d2 from methanol-d4. Reaction conditions: undivided cell,
anthranilamide (0.3 mmol), methanol-d4 (1.0 mL), HFIP (1.0 mL),
a
nEt4NPF6 (0.1 mol/L), 5 mA, r.t., 16 h. The ratio of deuterium-
incorporation.
Deuterium is a stable isotope of hydrogen. Deuterated
ingredients can be utilized in mechanistic, spectroscopic, and
tracer studies during the discovery and development of
pharmaceuticals [43-45]. Therefore, the incorporation of
deuterium into potential drug substances has seen a great
progress in recent years. It was envisioned that methanol-d4, a
readily available and relatively cheap deuterated solvent, might
introduce a deuterated methylene motif in this electrosynthesis
process [46]. As illustrated in Table 4, methanol-d4 was found to
engage in the cyclization process smoothly, leading to 2,2-
deuterated dihydroquinazolin-4(1H)-ones. Generally, compared
with its methanol counterpart, deuterated methanol resulted in the
products in decreased yields. For example, 5a could be isolated
in 77% yield (Scheme 4), which was 20% lower than the value of
undeuterated 3a (97%, Scheme 2). Also, an array of variants
from the starting anthranilamides were explored, demonstrating
this protocol to be compatible with different N,N’-disubstituted
substrates.
Scheme 3. Substrate scope of 2,3-dihydroquinazolin-4(1H)-one from
other alcohols. Reaction conditions: undivided cell, anthranilamide
(0.3 mmol), alcohol (1.0 mL), HFIP (1.0 mL), nEt4NPF6 (0.1 mol/L),
5 mA, r.t., 16 h. a 7 mA.
Then, different alcohols were treated under such
electrochemical cyclization conditions (Scheme 3). Generally,
lower isolated yields were obtained probably due to steric
hindrance, in comparison with the MeOH case. Without
modifying the conditions in Scheme 2, ethanol reacted with
anthranilamide derivatives to access corresponding products 4a-
4c with methyl on the aminal carbon in 45%-60% yields. When
secondary alcohols were used, increasing the current to 7 mA
resulted in the products in moderate yields (4d, 48%).
Scheme 5. Control experiments.
The mechanism of the reaction was explored by several
control
reactions.
When
5.0
equiv.
of
2,2,6,6-
tetramethylpiperidine N-oxyl (TEMPO), a radical scavenger, was
added into the standard reaction conditions, the yield of the
desired product is only 16% (Scheme 5a), which implied the
involvement of radical species during the reaction. Oxygen has
also been determined to be not critical to this transformation

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formaldehyde could proceed efficiently in the absence of
current (Scheme 5c).
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