Complementary Reactivity in Selective Radical Processes: Electrochemistry of Oxadiazolines to Quinazolinones

Article abstract of DOI:10.1021/acs.orglett.1c01676

Electrochemistry has recently emerged as a sustainable approach for efficiently generating radical intermediates utilizing eco-friendly electric energy. An electrochemical process was developed to transform 1,2,4-oxadiazolines under mild conditions. The electrochemical N-O bond cleavage at a controlled oxidation potential led to the selective synthesis of quinazolinone derivatives that could not be obtained by photocatalytic radical processes, indicating complementary reactivities in radical processes. The electrochemical reaction pathways were fully revealed by density functional theory-based investigations.

Full text of DOI:10.1021/acs.orglett.1c01676

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Letter
Complementary Reactivity in Selective Radical Processes:
Electrochemistry of Oxadiazolines to Quinazolinones
Ho Seong Hwang and Eun Jin Cho*
Cite This: Org. Lett. 2021, 23, 5148−5152
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ABSTRACT: Electrochemistry has recently emerged as a sustainable approach for efficiently generating radical intermediates
utilizing eco-friendly electric energy. An electrochemical process was developed to transform 1,2,4-oxadiazolines under mild
conditions. The electrochemical N−O bond cleavage at a controlled oxidation potential led to the selective synthesis of
quinazolinone derivatives that could not be obtained by photocatalytic radical processes, indicating complementary reactivities in
radical processes. The electrochemical reaction pathways were fully revealed by density functional theory-based investigations.
−2.16 V vs SCE; Eox = +1.24 V vs SCE in DMSO),4 A is a
ecently, the synthetic chemistry of radical ion intermedi-
1
Rates has attracted more attention. Photo- and electro- challenging substrate for use in either reductive or oxidative
electron transfer pathways with commonly used photocatalysts
chemistry have both proven to be marvelous and sustainable
approaches that efficiently generate radical intermediates by
utilizing eco-friendly photons and electric energy, respec-
tively.2,3 In particular, photochemistry has resulted in a
significant resurgence in radical chemistry that uses visible-
light-absorbing catalysts.2 However, reactions involving photo-
chemistry often have a limited substrate scope and limited
selectivity because of the restricted redox potentials of the
photocatalyst and competition between the modes of electron
transfer (photoredox) and energy transfer. Redox reactions
using electrochemistry can be conducted at controlled potentials
under neutral conditions.3 They can be used to complement
photochemistry and even stimulate orthogonal reactivity to
afford different products, because of the high flexibility of
electrochemical synthesis.
IV/III*
*III/II
[E1/2
= −1.73 V and E1/2
= 0.31 V vs SCE for fac-
Ir(ppy)3; E1/2III/II* = −0.81 V and E1/2*II/I = 0.77 V vs SCE for
Ru(bpy)32+] (Scheme 1).5
Previously, the radical reaction of A (ET = 55 kcal/mol) has
been achieved by selective energy transfer with fac-Ir(ppy)3 (ET
= 61 kcal/mol). The N−O homolysis of A generated a nitrene
intermediate that was converted into benzimidazole by an
intramolecular aromatic substitution process or to sulfoximine
by coupling with sulfoxide.6 Remarkably, in the presence of O2,
singlet oxygen generated by dual energy transfer participated in
Received: May 18, 2021
Published: June 18, 2021
Oxadiazoline is a useful class of reactive substrates that can be
converted into multiple valuable products through N−O bond
activation, depending on the reaction conditions (Scheme 1).
According to the redox potentials of 1,2,4-oxadiazoline A (Ered
=
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 5148−5152
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Scheme 1. Radical Processes of 1,2,4-Oxadiazolines
Scheme 2. Control Experiments
a
b
On a 0.4 mmol scale. Yields were determined by GC-MS using n-
c
a
dodecane as the internal standard. The reaction was conducted using
an H-type divided cell, and the yields were determined by H NMR
Table 1. Optimization Process
1
using bromoform as an internal standard.
and the 1,2-migration of the carbonyl group to afford
quinazolinone.
We started our investigation using 3,4,5-triphenyl-1,2,4-
oxadiazoline 1a (=A in Scheme 1) as a model substrate. The
reaction was performed under constant current electrolysis in an
undivided cell using tetra-n-butylammonium salt (TBAPF6) as
the electrolyte, CH3CN as the solvent, and graphite [C(+)/
C(−)] as the working and counter electrodes. Electrolysis at
ambient temperature for 6 h (2 mA, 2.3 F/mol) afforded the
desired product 2a in 60% yield (Table 1, entry 1). The use of
DMSO and DMF solvents, which were themselves oxidized
instead of 1a, did not promote the electrochemical reaction
(entries 2 and 3, respectively). Of all of the solvents typically
used for oxidative electrochemical processes, THF demon-
strated superior reactivity in the oxidative N−O bond cleavage
of 1a to afford 88% of 2a (entries 4−6). The use of other
working electrode materials, such as Ni, stainless steel (SS), or
Pt, resulted in lower reaction yields, while changing the counter
electrode from C to Pt did not change the efficiency much
(entries 7−10). Using 10 mM 1a in THF afforded a similar
product yield (entry 11). However, the yield decreased when
higher concentrations were used, which may be attributed to the
lower solvent conductivity (entry 12). Increasing the current to
10 mA did not significantly change the reactivity; however, the
yield decreased considerably at currents of >10 mA, which may
be attributed to the higher cell resistance in the reaction medium
(entries 13−15). The use of 2 equiv of CF3CO2H (TFA) as the
proton additive decreased the electrochemical cell resistance,
resulting in a slightly better yield (entry 16).
b
entry
solvent
variation
yield (%)
1
2
3
4
5
6
7
8
CH3CN
DMF
DMSO
MeOH
DCM
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
60
trace
trace
33
57
88
42
23
38
82
85
52
89
90
43
95
(+)Ni instead of (+)C
(+)SS instead of (+)C
c
9
(+)Pt instead of (+)C
(−)Pt instead of (−)C
10 mM substrate
80 mM substrate
0.5 mA, 2.3 F/mol
10 mA, 2.3 F/mol
15 mA, 2.3 F/mol
2 equiv of TFA
10
11
12
13
14
15
16
a
b
On a 0.2 mmol scale. Yields were determined by GC-MS using n-
c
dodecane as an internal standard. SS, stainless steel.
N−O bond homolysis to afford the iminyl radical intermediate,
eventually leading to the synthesis of spiro-azalactam com-
pounds.4
Herein, we report a selective electrochemical N−O bond
cleavage at a controlled oxidation potential, which could not be
achieved by photocatalytic electron transfer; the result was the
same iminyl radical intermediate as with energy transfer
photocatalysis, though with a different final product, quinazo-
linone (Scheme 1).7 Notably, quinazolinone was previously
generated under thermal conditions with O2 by the Chiba
group.8 Several control experiments and density functional
theory (DFT) studies supported the electrochemical pathway of
A, involving iminyl radical generation by oxidative N−O bond
cleavage, the ipso attack of the radical on the tethered aryl ring,
When carried out under an oxygen atmosphere, the reaction
clearly demonstrated that the reactivity of the electrochemical
process is different from that of photocatalysis (Scheme 2a).
Irrespective of the presence of O2, the electrochemical process of
1a provided quinazolinone 2a as the major product. Under an
oxygen atmosphere, only a trace amount of 3a, which was the
product of the Ir-catalyzed energy transfer process, was
detected.4 The reaction of 1a was also tested using divided
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a
Scheme 3. Proposed Mechanism Obtained Using DFT Studies
a
b
All energies are in kilocalories per mole. The free energy of III+, which has one fewer electron than III, was reset to 0.
cell electrolysis (Scheme 2b). 1a underwent the process to afford
2a on the anode, while 1a remained unreacted on the cathode.
These results clearly indicate that the oxidation pathway of 1a is
operative for the transformation.
was also found to be compatible with the conditions presented
here (2h). Variations at position 4 (R2) of 1 were also possible.
The reactions of both electron-rich (-4-Me, -2,4-diMe, -4-n-Bu,
and -4-OCOEt) and electron-poor (-4-COMe, -4-F, -3-Cl-4-F,
and -2-Br) substrates proceeded smoothly to afford the
corresponding quinazolinones (2i−2p). The applicability of
the current method was further demonstrated by the installation
of aliphatic groups (2q and 2r). The scale-up of 2a from 1a on a
2 mmol scale was found to be straightforward, although it
afforded a slightly lower yield. Notably, the reaction is highly
practical and does not require inert conditions, as the process
provides quinazolinone derivative 2 regardless of the presence of
O2. The main side products are benzoic acid, benzimidine, or the
amide derivatives produced by the fragmentation of inter-
mediate I (Scheme S1).
The reactions of substrates with variations at position 5
afforded diverse product distributions (Scheme 5). Substrates
with ortho-substituted phenyl rings underwent site-selective
transformation to afford single products regardless of the
electron density of the substituents (2s−2u). The results
indicate that the quinazolinone products were formed through a
proposed kinetic pathway comprising the ipso attack of the
iminyl intermediate at the tethered ring in II followed by
carbonyl migration (III−III+−V in Scheme 3). However, the
activation barrier is not much higher for ortho attack than for ipso
attack in II, and thus, 1 may follow the ortho attack pathway
depending on the substituent pattern of 1. The reaction of a 1-
naphthyl variant (1v) afforded 2v as the major product through
the selective ortho attack of the II-type intermediate, although
the reaction produced a low yield and resulted in the formation
of several fragmented side products. The reactions of meta-
substituted variants (1w and 1x) yielded mixtures of isomers.
Notably, 1,2,4-oxidazoline with an aliphatic substituent at
position 3 (1y) demonstrated exceptional reactivity in the
A plausible mechanistic pathway for the current trans-
formation using 1a is proposed, as depicted in Scheme 3. This
mechanism is supported by DFT calculations. The oxidation of
1a was observed at +1.42 V versus SCE using cyclic voltammetry
(CV) (Figure S1). On the anode, the single-electron oxidation
of 1a generates the corresponding radical cation 1a•+, in which
the high acidity of α-H causes sequential H abstraction9 and
deprotonation to provide radical intermediate I. According to
DFT calculations, the homolytic N−O bond cleavage in
intermediate I proceeds smoothly to generate key iminyl radical
II through TS1 (ΔG⧧ = 10.49 kcal/mol). Then, II can proceed
via two possible pathways, either the ipso or ortho attack of the
iminyl radical on the tethered phenyl ring. The ipso attack is
kinetically more feasible, affording a spiro intermediate III
through a transition state TS2ipso with a 13.41 kcal/mol barrier
that is slightly lower than that for the ortho attack to afford IV
(TS2ortho; ΔG⧧ = 15.33 kcal/mol).4,10 Then, the single-electron
oxidation of III on the anode affords cationic intermediate III+.
Notably, carbonyl migration in III+ is much more favorable
kinetically through TS3C (ΔG⧧ = 3.01 kcal/mol) than iminyl
migration (TS3N; ΔG⧧ = 13.22 kcal/mol) even though the
energy of intermediate V is higher than that of IV+.11 Finally, the
deprotonation of V affords quinazolinone 2a.
The generality of the transformation was investigated by
exposing other 1,2,4-oxadiazoline derivatives to the optimized
conditions (Scheme 4). The scope of the R1 substituents at
position 3 of 1 was examined first. Substrates with both electron-
rich (-Me, -iPr, and -OMe) and electron-poor (-Cl and -Br)
aromatic substituents underwent electrochemical quinazolinone
synthesis successfully (2a−2g). A heteroaryl furyl substituent
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Scheme 4. Substrate Scope of 1,2,4-Oxadiazolines with
Scheme 5. Substrate Scope of 1,2,4-Oxadiazolines with
a,b
a,
b
Variations at Positions 3 (R1) and 4 (R2)
Variations at Position 5
a
b
On a 0.5 mmol scale. Isolated yields and ratios were determined by
1H NMR spectroscopy using a crude mixture of the products.
Scheme 6. Reaction of 1y with an Aliphatic Substituent at
a,b
Position 3 of the Oxadiazoline
a
b
c
On a 0.5 mmol scale. Isolated yields. Two millimole (0.6 g)
semigram scale reaction using 0.1 M TBAPF6, 15 mL of THF, and a
constant current of 5 mA.
presence of O2 (Scheme 6). The reaction of 1y under an argon
atmosphere afforded the corresponding quinazolinone 2y and
generated spiro-azalatam 3y selectively in the presence of O2.
In conclusion, an electrochemical reaction of 1,2,4-oxadiazo-
lines was developed to provide quinazolinone derivatives under
mild reaction conditions. The electrochemical N−O bond
cleavage at a controlled oxidation potential made the electron
transfer process selective, resulting in a product pattern different
from those of photochemistry. The electrochemical reaction
pathways were fully revealed by DFT-based investigations. We
believe these findings regarding the complementary reactivities
of oxadiazolines will serve to guide the development of various
radical processes in the future.
a
b
On a 0.5 mmol scale. Isolated yields.
AUTHOR INFORMATION
■
Corresponding Author
Eun Jin Cho − Department of Chemistry, Chung-Ang
University, Seoul 06974, Republic of Korea; orcid.org/
0000-0002-6607-1851; Email: ejcho@cau.ac.kr
Author
Ho Seong Hwang − Department of Chemistry, Chung-Ang
University, Seoul 06974, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01676
ASSOCIATED CONTENT
■
sı
* Supporting Information
Notes
The authors declare no competing financial interest.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01676.
ACKNOWLEDGMENTS
■
Experimental procedures, additional experimental results,
analytical data of the synthesized compounds, NMR
spectra, and DFT calculation details (PDF)
The authors gratefully acknowledge the National Research
Foundation of Korea (NRF-2012M3A7B4049657, NRF-
2020R1A2C2009636, and NRF-2021R1A5A6002803).
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