Unexpected Insertion of Nitrogen into a C-C Bond: Access to 2,3-Disubstituted Quinazolinone Scaffolds

Article abstract of DOI:10.1021/acs.orglett.1c01235

A novel, practical, highly efficient, and transition metal free nitrogen insertion reaction for the synthesis of 2,3-disubstituted quinazolinone derivatives was developed. Diverse functionalized 3-indolinone-2-carboxylates and nitrosoarenes with a wide range of substituted nitrosobenzenes, nitrosopyridines, dibenzofuranyl, or dibenzothienyl nitroso compounds worked smoothly to give 2,3-disubstituted quinazolinone derivatives in good to excellent yields (69-98%). A gram-scale reaction was achieved, and an afloqualone analogue was synthesized under the mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.1c01235

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Unexpected Insertion of Nitrogen into a C−C Bond: Access to 2,3-
Disubstituted Quinazolinone Scaffolds
Hui-Li Liu, Xiao-Tong Li, Heng-Zhi Tian, and Xing-Wen Sun*
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ABSTRACT: A novel, practical, highly efficient, and transition metal free
nitrogen insertion reaction for the synthesis of 2,3-disubstituted quinazolinone
derivatives was developed. Diverse functionalized 3-indolinone-2-carboxylates
and nitrosoarenes with a wide range of substituted nitrosobenzenes, nitro-
sopyridines, dibenzofuranyl, or dibenzothienyl nitroso compounds worked
smoothly to give 2,3-disubstituted quinazolinone derivatives in good to excellent yields (69−98%). A gram-scale reaction was
achieved, and an afloqualone analogue was synthesized under the mild reaction conditions.
uinazolinone structural units are widespread in natural
synthesize 2,3-disubstituted quinazolinones were applied
successfully. Alper and Wu described palladium-catalyzed
cyclocarbonylation to give 2,3-disubstituted quinazolinones.17
Deng and Chu developed the hydrogen transfer reaction of N-
substituted o-nitrobenzamides with benzylic alcohols under
iron or ruthenium catalysis.18 Chiba and co-workers described
transition metal free access to 2,3-disubstituted quinazolinones
utilizing 5-aryl-4,5-dihydro-1,2,4-oxadiazoles in the presence of
O2.19 From the viewpoint of the construcaton of 2,3-
disubstituted quinazolinones, transition metal free, concise,
and elegant strategies are still in great demand.
1
Q products and synthetic pharmaceuticals. As shown in
Figure 1, tryptanthrin and sclerotigenin are the natural
The Michael, aza-Michael, and Robinson annulation
reactions of 3-indolinone-2-carboxylates with nitroolefins,20
azodicarboxylates,21 and cyclohexenone22 have been reported
extensively in recent years. However, the nitrogen insertion
reaction of 3-indolinone-2-carboxylates remains unexplored,
although insertion of nitrogen into a carbon−carbon bond as a
key step has been demonstrated as a powerful strategy for the
preparation of heterocyclic or carbocyclic compounds.23
Herein, we disclose an interesting and unexpected nitrogen
insertion reaction to afford 2,3-disubstituted quinazolinones.
Initially, methyl 1-acetyl-3-oxoindoline-2-carboxylate 3a and
nitrosobenzene 4a were examined as the reactants in the
presence of a catalytic amount of DABCO in DCM at room
temperature. To our delight, the reaction proceeded effectively,
affording the desired 2,3-disubstituted quinazolinones 5aa in
82% yield (Table 1, entry 1). With an increase in the amount
of DABCO, a slight enhancement of the yields was detected
(entries 2 and 3 vs entry 1). Subsequently, by screening various
Figure 1. Bioactive quinazolinone scaffolds.
alkaloids that incorporate quinazolinone motifs with significant
biological activities.2 Afloqualone is a commercial oral muscle
relaxant drug.3 Idelalisib is used as a PI3Kδ inhibitor and has
been approved for the treatment of relapsed chronic
lymphocytic leukemia (CLL).4 Raltiterxed is a clinical
medication for the treatment of colorectal cancer.5 Due to
the prospects for application, continuous effort has been spent
to develop new methodologies for the construction of
quinazolinone derivatives.6 In addition to the traditional
formation of quinazolinones via Niementowski reaction7 and
cyclocondensation and cascade reactions,8 other strategies
such as methods involving a transition matel catalyst or an
oxidant have emerged in recent years.9 For instance, the
copper- or palladium-catalyzed N-arylation reactions of N-
substituted o-bromobenzamides or o-bromobenzoates with
various benzylamines,10 amides,11 or amidines12 were reliable
protocols for obtaining 2,3-disubstituted quinazolinones. The
N-substituted anthranilamides with aldehydes,13 alcohols,14
methylarenes,15 or (o-azaaryl)methanes16 through oxidative
heterocyclizations or amination of the sp3 C−H bond to
Received: April 12, 2021
Published: June 1, 2021
https://doi.org/10.1021/acs.orglett.1c01235
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4579−4583
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a
Table 1. Optimization of Reaction Conditions
Scheme 1. Scope of the Reactions of 3-Indolinone-2-
a
carboxylates
b
entry
base
solvent
yield (%)
c
d
1
DABCO
DABCO
DABCO
DMAP
Et3N
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
82
87
87
76
78
76
91
75
96
94
90
81
44
21
87
96
96
92
2
e
3
f
4
f
5
f
6
DIPEA
DBU
f
7
8
9
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
13
14
15
16
17
18
g
DCE
THF
h
MTBE
toluene
CH3CN
DCM
a
Reaction conditions: 3a−3p (0.40 mmol), 4a (0.48 mmol), and
Cs2CO3 (0.20 mmol) in DCM (2.0 mL) at rt for the determined time.
i
b
X-ray of 5aa.
j
DCM
DCM
k
application of heteroaromatic and polyaromatic fused com-
pounds 3p and 3o to the reaction conditions presented here,
the reaction gave the desired products 5pa and 5oa in 94% and
97% yields, respectively.
To further estimate the efficiency of the methodology, a
wide range of nitroso compounds were applied using this
strategy. As described in Scheme 2, the nitrogen insertion
reactions of nitrosoarenes with diverse substituents at the para
or meta position of the phenyl ring afforded the corresponding
products 5ab−5an in 89−97% yields. It is worth mentioning
that reactants bearing a strong electron-witdrawing substituent
like an ester group or a formyl group on the aromatic ring
demanded longer times to complete the reaction. The reaction
a
Reaction conditions: 3a (0.10 mmol), 4a (0.15 mmol), and base (0.5
equiv) in the indicated solvent (0.5 mL) at rt for 22 h, unless
b
c
otherwise noted. Isolated yield of product 5aa. With 0.2 equiv of
DABCO. DABCO = 1,4-diazabicyclo[2.2.2]octane. With 1.0 equiv
d
e
f
g
of DABCO. With 1.0 equiv of base. DCE = 1,2-dichloroethane.
h
i
j
MTBE = methyl tert-butyl ether. With 1.3 equiv of 4a. With 1.2
k
equiv of 4a. With 1.1 equiv of 4a.
bases such as DMAP, Et3N, DIPEA, DBU, K2CO3, and
Cs2CO3 (entries 4−9, respectively), we found that Cs2CO3
was the best choice, giving product 5aa in 96% yield (entry 9).
Different solvents such as CHCl3, DCE, THF, MTBE, toluene,
and acetonitrile were tested with Cs2CO3 as the base (entries
10−15, respectively). The results revealed that the reaction
yields apparently reduction when MTBE or toluene was used
as the solvent (entry 13 or 14, respectively). To further
improve the reaction efficiency, the ratios of nitrosobenzene 4a
and 3a were investigated (entries 16−18). The yields of
product 5aa could be maintained when the amount of
nitrosobenzene 4a was decreased to 1.2 equiv of 3a (entry
17). Finally, the optimal reaction conditions were found to be
3a (0.1 mmol), 4a (0.12 mmol), and Cs2CO3 (0.5 equiv) as
the base in DCM at room temperature for 22 h, affording
product 5aa in 96% yield.
a
Scheme 2. Scope of the Reactions of Nitrosoarenes
With the optimal conditions in hand, the substrate scope of
the nitrogen insertion reaction was examined. As shown in
Scheme 1, a series of 2,3-disubstituted quinazolinones could be
obtained in good to excellent yields. We found that ethyl (3b)
or tert-butyl (3c) ester proceeds with an efficiency similar to
that of 3a, giving products 5ba and 5ca in 92% and 93% yields,
respectively. Regardless of whether electron-donating or
electron-withdrawing groups were at position 5 or 6 of 3-
oxoindolines, the corresponding 2,3-disubstituted quinazoli-
nones (5da−5ka) were efficiently obtained in excellent yields
(93−98%). In the case of 4-fluorine and 7-methyl derivatives
(3m and 3n, respectively) as the reactants, because of the
effect of steric hindrance, the nitrogen insertion reaction
required longer times and afforded products 5ma and 5na in
relatively low yields (69% and 85%, respectively). Upon
a
Standard reaction conditions: 3a (0.40 mmol), 4a−4z (0.48 mmol),
and Cs2CO3 (0.20 mmol) in DCM (2.0 mL) at rt for the determined
time.
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yields and times were sensitive to the steric hindrance of the
substituents on the nitrosoarenes. The introduction of methyl,
chlorine, bromine, and cyano at the ortho position of the
nitrosoarene aromatic rings led to decreases in the yields of the
corresponding products 5ao−5ar and 5az. To expand the
reactant scope of the nitrogen insertion reaction, we paid
attention to nitrosoheteroaryl compounds. A series of
monosubstituted or disubstituted nitrosopyridines could also
perform well in the reaction system, giving products 5as−5aw
in 87−98% yields. In addition, in the case of dibenzofuranyl
and dibenzothienyl nitroso compounds were applied under the
standard reaction conditions, and the reaction proceeded
smoothly giving products 5ax and 5ay in 96% and 82% yields,
respectively.
Scheme 4. Proposed Reaction Mechanism
To illustrate the reaction mechanism, control experiments
were conducted. As mentioned above, substrate 3a bearing an
acyl group on the nitrogen worked well with nitrosobenzene 4a
under the standard reaction conditions, giving product 5aa in
96% yield. However, unprotected 3-oxoindoline 3q afforded
only a trace of 5aa, and N-methyl-protected 3-oxoindoline 3r
did not afford product 5aa (as shown in Scheme 3). The
Scheme 3. Control Experiments
selectively attacked nitrosoarene. Meanwhile, the O-addition
product perhaps existed. In particular, when o-bromonitroso-
benzene was involved in the reaction, compound 7ar could be
detected, separated and verified by X-ray diffraction, because of
the stetric hindrance. Because compound 7ar did not convert
into a stable product and the addition reaction was reversible,
7ar could revert to the original materials, and the substrate
underwent the N-selective addition reaction again. Intermedi-
ate II could transform into VI through O-nucleophilic
addition, and cleavage of the C2−C3 and N−O bonds.
Complex VI underwent an addition−elimination reaction that
led to the formation of amidine compound VIII. Afterward,
the intramolecular substitution reaction of anhydride and
amidine in VIII afforded the desired compound 5ar.
To investigate the efficiency and practical utility of this
method, a gram-scale reaction of 3a and o-bromonitrosoben-
zene 4r was carried out under the standard conditions,
providing desired product 5ar in 72% yield. Furthermore, the
transformation of 5ar is depicted in Scheme 5. The ester group
of 5ar could be selectively reduced by treatment with LiBH4,
giving reduction product 8ar in 53% yield.25 Subsequently, 8ar
was treated with the DAST reagent, affording afloqualone
analogue 9ar in 60% yield.26
results of the reaction indicated that no protection group and
the methyl protection group were not compatible for the
nitrogen insertion reaction. To further explore the mechanism
of the reaction, we synthesized compounds 3s and 3t.24
Substrate 3s provided nitrogen insertion product 5sa in 79%
yield, and reactant 3t gave ring-opening compound 6ta in 88%
yield under the standard reaction conditions. These results
hinted that the conjugated structure was vital in the process of
ring closure. Furthermore, when substrate 3a reacted with o-
bromonitrosobenzene 4r under the optimized reaction
condition for 1.5 h, compound 7ar and product 5ar were
detected. It is worth mentioning that if compound 7ar is left
for a long time, it could convert into ring expansion product
5ar but with a dramatic decrease in the yield. The
configurations of 5sa, 6ta, and 7ar were confirmed by X-ray
diffraction analysis.
In conclusion, we have demonstrated a highly efficient and
convenient nitrogen insertion reaction for the preparation of
Scheme 5. Gram-Scale Synthesis of 5ar Followed by
Transformation
A possible reaction mechanism was proposed on the basis of
the results of control experiments, as depicted in Scheme 4.
Initially, enolization of substrate 3a was achieved in the
presence of Cs2CO3. Subsequently, the enolate anion of 3a N-
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(3) Ochiai, T.; Ishida, R. Pharmacological studies on 6-amino-2-
fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinones (afloqualone), a new
centrally acting muscle relaxant. (II). Effects on the spinal reflex
potential and rigidity. Jpn. J. Pharmacol. 1982, 32, 427−438.
(4) Kost, S. E. F.; Saleh, A.; Mejia, E. M.; Mostafizar, M.; Bouchard,
E. D. J.; Banerji, V.; Marshall, A. J.; Gibson, S. B.; Johnston, J. B.;
Katyal, S. Transcriptional Modulation by Idelalisib Synergizes with
Bendamustine in Chronic Lymphocytic Leukemia. Cancers 2019, 11,
1519−1537.
(5) Chaudhary, A. P.; Shukla, A. K.; Pandey, J.; Kant, P. Study of
developments of biologically active Quinazolinones derivatives: A
review. Chem. Biol. Interface 2018, 8, 62−83.
2,3-disubstituted quinazolinones from 3-indolinone-2-carbox-
ylates and nitrosoarenes with Cs2CO3 as the base. The reaction
proceeded smoothly under mild reaction conditions and was
free of transition metals, oxidants, and peroxide. 3-Indolinone-
2-carboxylates containing diverse functional groups worked
well with nitrosobenzene, giving products 5aa−5pa in
moderate to excellent yields (69−98%). A wide range of
nitroso compounds were compatible with the reaction,
affording desired products 5ab−5az in good to excellent yields
(77−98%). Further development of this methodology is
ongoing in our laboratory.
(6) (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Synthesis of quinazolinones and quinazolines. Tetrahedron 2005, 61,
10153−10202. (b) He, L.; Li, H.; Chen, J.; Wu, X.-F. Recent advances
in 4(3H)-quinazolinone syntheses. RSC Adv. 2014, 4, 12065−12077.
(7) (a) Pereira, M.-F.; Picot, L.; Guillon, J.; Léger, J.-M.; Jarry, C.;
Thiéry, V.; Besson, T. Efficient synthesis of novel pentacyclic 6,7-
dihydro-5a,7a,13,14-tetraaza-pentaphene-5,8-diones. Tetrahedron Lett.
2005, 46, 3445−3447. (b) de Fatima Pereira, M.; Thiéry, V.; Besson,
T. Synthesis of novel 2,3-substituted quinazolin-4-ones by con-
densation of alkyl or aromatic diamines with 5-(N-arylimino)-4-
chloro-5H-1,2,3-dithiazoles. Tetrahedron 2007, 63, 847−854.
(c) Kabri, Y.; Gellis, A.; Vanelle, P. Microwave-assisted synthesis in
aqueous medium of new quinazoline derivatives as anticancer agent
precursors. Green Chem. 2009, 11, 201−208.
(8) (a) Lecoutey, C.; Fossey, C.; Rault, S.; Fabis, F. Efficient Room-
Temperature One-Pot Synthesis of 2-Amino-3-alkyl(3-aryl)-quinazo-
lin-4(3H)-ones. Eur. J. Org. Chem. 2011, 2011, 2785−2788. (b) Liu,
T.; Zhu, C.; Yang, H.; Fu, H. Copper-Catalyzed Domino Synthesis of
Isoquinolino[2,3-a]quinazolinones. Adv. Synth. Catal. 2012, 354,
1579−1584. (c) Upadhyaya, K.; Thakur, R. K.; Shukla, S. K.; Tripathi,
R. P. One-Pot Copper(I)-Catalyzed Ligand/Base-Free Tandem
Cyclooxidative Synthesis of Quinazolinones. J. Org. Chem. 2016, 81,
5046−5055. (d) Heravi, M. M.; Sadjadi, S.; Mokhtari Haj, N.;
Oskooie, H. A.; Hekmat Shoar, R.; Bamoharram, F. F. A novel multi-
component synthesis of 4-arylaminoquinazolines. Tetrahedron Lett.
2009, 50, 943−945. (e) Wang, B.; Li, Z.; Wang, X. N.; Tan, J. H.; Gu,
L. Q.; Huang, Z. S. A new approach to the facile synthesis of 2-
substituted-quinazolin-4(3H)-ones. Chin. Chem. Lett. 2011, 22, 951−
953. (f) Lygin, A. V.; de Meijere, A. ortho-Lithiophenyl Isocyanide: A
Versatile Precursor for 3H-Quinazolin-4-ones and 3H-Quinazolin-4-
thiones. Org. Lett. 2009, 11, 389−392.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01235.
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Experimental details, characterization data, spectral data,
and a description of the crystallographic data (PDF)
Accession Codes
CCDC 2075789−2075792 and 2084083 contain the supple-
mentary 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
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AUTHOR INFORMATION
Corresponding Author
■
Xing-Wen Sun − Department of Chemistry, Fudan University,
Shanghai 200433, China; orcid.org/0000-0003-0432-
7935; Email: sunxingwen@fudan.edu.cn
Authors
Hui-Li Liu − Department of Chemistry, Fudan University,
Shanghai 200433, China
Xiao-Tong Li − Department of Chemistry, Fudan University,
Shanghai 200433, China
(9) (a) He, L.; Li, H.; Neumann, H.; Beller, M.; Wu, X.-F. Highly
Efficient Four-Component Synthesis of 4(3H)-Quinazolinones:
Palladium-Catalyzed Carbonylative Coupling Reactions. Angew.
Chem., Int. Ed. 2014, 53, 1420−1424; Angew. Chem. 2014, 126,
1444−1448. (b) Wang, L.; Wang, Y.; Chen, M.; Ding, M.-W.
Reversible P(III)/P(V) Redox: Catalytic Aza-Wittig Reaction for the
Synthesis of 4(3H)-Quinazolinones and the Natural Product
Vasicinone. Adv. Synth. Catal. 2014, 356, 1098−1104. (c) Hakim
Siddiki, S. M. A.; Kon, K.; Touchy, A. S.; Shimizu, K.-i. Direct
synthesis of quinazolinones by acceptorless dehydrogenative coupling
of o-aminobenzamide and alcohols by heterogeneous Pt catalysts.
Catal. Sci. Technol. 2014, 4, 1716−1719. (d) Cao, L.; Huo, H.; Zeng,
H.; Yu, Y.; Lu, D.; Gong, Y. One-Pot Synthesis of Quinazolin-4(3H)-
ones through Anodic Oxidation and the Related Mechanistic Studies.
Adv. Synth. Catal. 2018, 360, 4764−4773. (e) Liu, X.; Fu, H.; Jiang,
Y.; Zhao, Y. A Simple and Efficient Approach to Quinazolinones
under Mild Copper-Catalyzed Conditions. Angew. Chem., Int. Ed.
2009, 48, 348−351. For selected examples of 2-substituted
quinazolinones, see: (f) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H.
Copper-Catalyzed Domino Synthesis of Quinazolinones via Ullmann-
Type Coupling and Aerobic Oxidative C-H Amidation. Org. Lett.
2011, 13, 1274−1277. (g) Wu, X.-F.; He, L.; Neumann, H.; Beller, M.
Palladium-Catalyzed Carbonylative Synthesis of Quinazolinones from
2-Aminobenzamide and Aryl Bromides. Chem. - Eur. J. 2013, 19,
12635−12638. (h) Zhang, Z.; Wang, M.; Zhang, C.; Zhang, Z.; Lu, J.;
Wang, F. The cascade synthesis of quinazolinones and quinazolines
Heng-Zhi Tian − Department of Chemistry, Fudan University,
Shanghai 200433, China
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the Natural Science Foundation of Shanghai (20ZR1405500).
REFERENCES
■
(1) (a) Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Synthetic
approaches, functionalization and therapeutic potential of quinazoline
and quinazolinone skeletons: The advances continue. Eur. J. Med.
Chem. 2015, 90, 124−169. (b) Kshirsagar, U. A. Recent developments
in the chemistry of quinazolinone alkaloids. Org. Biomol. Chem. 2015,
13, 9336−9352.
(2) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Recent advances in the
structural library of functionalized quinazoline and quinazolinone
scaffolds: Synthetic approaches and multifarious applications. Eur. J.
Med. Chem. 2014, 76, 193−244.
4582
https://doi.org/10.1021/acs.orglett.1c01235
Org. Lett. 2021, 23, 4579−4583

Organic Letters
pubs.acs.org/OrgLett
Letter
using an α-MnO2 catalyst and tert-butyl hydroperoxide (TBHP) as an
oxidant. Chem. Commun. 2015, 51, 9205−9207. (i) Liu, W.; Wu, G.;
Gao, W.; Ding, J.; Huang, X.; Liu, M.; Wu, H. Palladium-catalyzed
oxidative CC bond cleavage with molecular oxygen: one-pot
synthesis of quinazolinones from 2-amino benzamides and alkenes.
Org. Chem. Front. 2018, 5, 2734−2738. (j) Ma, Z.; Song, T.; Yuan, Y.;
Yang, Y. Synergistic catalysis on Fe−Nx sites and Fe nanoparticles for
efficient synthesis of quinolines and quinazolinones via oxidative
coupling of amines and aldehydes. Chem. Sci. 2019, 10, 10283−
10289. (k) Hu, Y.; Li, S.; Li, H.; Li, Y.; Li, J.; Duanmu, C.; Li, B.
Copper-catalyzed tandem oxidative synthesis of quinazolinones from
2-aminobenzonitriles and benzyl alcohols. Org. Chem. Front. 2019, 6,
2744−2748. (l) Li, F.; Lu, L.; Ma, J. Acceptorless dehydrogenative
condensation of o-aminobenzamides with aldehydes to quinazoli-
nones in water catalyzed by a water-soluble iridium complex
[Cp*Ir(H2O)3][OTf]2. Org. Chem. Front. 2015, 2, 1589−1597.
(m) Zhang, F.-L.; Wang, Y.-F.; Chiba, S. Orthogonal aerobic
conversion of N-benzyl amidoximes to 1,2,4-oxadiazoles or
quinazolinones. Org. Biomol. Chem. 2013, 11, 6003−6007.
(n) Zhao, P.; Yu, X.-X.; Zhou, Y.; Geng, X.; Wang, C.; Huang, C.;
Wu, Y.-D.; Zhu, Y.-P.; Wu, A.-X. Splitting Methyl Ketones into Two
Parts: Synthesis of 4(3H)-Quinazolinones via Consecutive Cycliza-
tion/Ring-Opening Reaction. Org. Lett. 2020, 22, 7103−7107.
(10) Kotipalli, T.; Kavala, V.; Janreddy, D.; Bandi, V.; Kuo, C.-W.;
Yao, C.-F. Synthesis of 2,3-Disubstituted Quinazolinone Derivatives
through Copper Catalyzed C−H Amidation Reactions. Eur. J. Org.
Chem. 2016, 2016, 1182−1193.
Nitrobenzamides and Alcohols. Org. Lett. 2013, 15, 4900−4903.
(b) Qiao, J.; Jiang, H.; Liu, X.; Xu, C.; Sun, Z.; Chu, W. Ruthenium-
Catalyzed Synthesis of Quinazolinones through Hydrogen Transfer
and Cyclization. Eur. J. Org. Chem. 2019, 2019, 2428−2434.
(19) Wang, Y.-F.; Zhang, F.-L.; Chiba, S. Oxidative Radical Skeletal
Rearrangement Induced by Molecular Oxygen: Synthesis of
Quinazolinones. Org. Lett. 2013, 15, 2842−2845.
(20) Jin, C.-Y.; Wang, Y.; Liu, Y.-Z.; Shen, C.; Xu, P.-F.
Organocatalytic Asymmetric Michael Addition of Oxindoles to
Nitroolefins for the Synthesis of 2,2-Disubstituted Oxindoles Bearing
Adjacent Quaternary and Tertiary Stereocenters. J. Org. Chem. 2012,
77, 11307−11312.
(21) Yarlagadda, S.; Ramesh, B.; Ravikumar Reddy, C.; Srinivas, L.;
Sridhar, B.; Subba Reddy, B. V. Organocatalytic Enantioselective
Amination of 2-Substituted Indolin-3-ones: A Strategy for the
Synthesis of Chiral α-Hydrazino Esters. Org. Lett. 2017, 19, 170−173.
(22) Yarlagadda, S.; Sankaram, G. S.; Balasubramanian, S.; Subba
Reddy, B. V. Asymmetric Robinson Annulation of 3-Indolinone-2-
carboxylates with Cyclohexenone: Access to Chiral Bridged Tricyclic
Hydrocarbazoles. Org. Lett. 2018, 20, 4195−4199.
(23) (a) Jeffs, P. W.; Molina, G.; Cortese, N. A.; Hauck, P. R.;
Wolfram, J. Aza-Ring Expansion of cis -Bicyclo[4.2.0]octanones and
Related Compounds. A Regiospecific Synthesis of cis -Octahydroin-
dolones. J. Org. Chem. 1982, 47, 3876−3881. (b) Sahasrabudhe, K.;
Gracias, V.; Furness, K.; Smith, B. T.; Katz, C. E.; Srinivasa Reddy, D.;
Aubé, J. Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with
Ketones. J. Am. Chem. Soc. 2003, 125, 7914−7922. (c) Banerjee, R.;
King, S. B. Synthesis of Cyclic Hydroxamic Acids through -NOH
Insertion of Ketones. Org. Lett. 2009, 11, 4580−4583. (d) Lachia, M.;
Richard, F.; Bigler, R.; Kolleth-Krieger, A.; Dieckmann, M.;
Lumbroso, A.; Karadeniz, U.; Catak, S.; De Mesmaeker, A. An
improved procedure for the Beckmann rearrangement of cyclo-
butanones. Tetrahedron Lett. 2018, 59, 1896−1901. (e) Sietmann, J.;
(11) Xu, L.; Jiang, Y.; Ma, D. Synthesis of 3-Substituted and 2,3-
Disubstituted Quinazolinones via Cu-Catalyzed Aryl Amidation. Org.
Lett. 2012, 14, 1150−1153.
(12) Li, B.; Samp, L.; Sagal, J.; Hayward, C. M.; Yang, C.; Zhang, Z.
Synthesis of Quinazolin-4(3H)-ones via Amidine N-Arylation. J. Org.
Chem. 2013, 78, 1273−1277.
(13) Tian, X.; Song, L.; Li, E.; Wang, Q.; Yu, W.; Chang, J. Metal-
free one-pot synthesis of 1,3-diazaheterocyclic compounds via I2-
mediated oxidative C−N bond formation. RSC Adv. 2015, 5, 62194−
62201.
(14) Hu, Y.; Chen, L.; Li, B. Iron nitrate/TEMPO-catalyzed aerobic
oxidative synthesis of quinazolinones from alcohols and 2-amino-
benzamides with air as the oxidant. RSC Adv. 2016, 6, 65196−65204.
(15) Zhao, D.; Wang, T.; Li, J.-X. Metal-free oxidative synthesis of
quinazolinones via dual amination of sp3 C−H bonds. Chem.
Commun. 2014, 50, 6471−6474.
(16) Liu, H.; Zhai, T.; Ding, S.; Hou, Y.; Zhang, X.; Feng, L.; Ma, C.
Direct and metal-free oxidative amination of sp3 C−H bonds for the
construction of 2-hetarylquinazolin-4(3H)-ones. Org. Chem. Front.
2016, 3, 1096−1099.
Ong, M.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Wiest, J. M.
̈
Desymmetrization of Prochiral Cyclobutanones via Nitrogen
Insertion: A Concise Route to Chiral γ-Lactams. Angew. Chem., Int.
Ed. 2021, 60, 9719−9723.
(24) Zvilichovsky, G.; Gurvich, V. Ozonolysis of 2-(1,4-
Cyclohexadienyl)glycine. Tetrahedron 1995, 51, 5479−5490.
(25) Vacher, B.; Funes, P.; Chopin, P.; Cussac, D.; Heusler, P.;
Tourette, A.; Marien, M. Rigid Analogues of the α2-Adrenergic
Blocker Atipamezole: Small Changes, Big Consequences. J. Med.
Chem. 2010, 53, 6986−6995.
(26) Hamaguchi, W.; Masuda, N.; Samizu, K.; Mihara, T.; Takama,
K.; Watanabe, T. Synthesis and in Vivo Evaluation of Novel Quinoline
Derivatives as Phosphodiesterase 10A Inhibitors. Chem. Pharm. Bull.
2014, 62, 1200−1213.
(17) (a) Zheng, Z.; Alper, H. Palladium-Catalyzed Cyclocarbony-
lation of o-Iodoanilines with Imidoyl Chlorides to Produce
Quinazolin-4(3H)-ones. Org. Lett. 2008, 10, 829−832. (b) Zeng,
F.; Alper, H. Tandem Palladium-Catalyzed Addition/Cyclocarbony-
lation: An Efficient Synthesis of 2-Heteroquinazolin-4(3H)-ones. Org.
Lett. 2010, 12, 1188−1191. (c) Zeng, F.; Alper, H. One-Step
Synthesis of Quinazolino[3,2-a]quinazolinones via Palladium-Cata-
lyzed Domino Addition/Carboxamidation Reactions. Org. Lett. 2010,
12, 3642−3644. (d) Chen, J.; Natte, K.; Spannenberg, A.; Neumann,
H.; Langer, P.; Beller, M.; Wu, X.-F. Base-Controlled Selectivity in the
Synthesis of Linear and Angular Fused Quinazolinones by a
Palladium-Catalyzed Carbonylation/Nucleophilic Aromatic Substitu-
tion Sequence. Angew. Chem., Int. Ed. 2014, 53, 7579−7583.
(e) Chen, J.; Feng, J.-B.; Natte, K.; Wu, X.-F. Palladium-Catalyzed
Carbonylative Cyclization of Arenes by C-H Bond Activation with
DMF as the Carbonyl Source. Chem. - Eur. J. 2015, 21, 16370−16373.
(f) Li, H.; Li, W.; Spannenberg, A.; Baumann, W.; Neumann, H.;
Beller, M.; Wu, X.-F. A Novel Domino Synthesis of Quinazoline-
diones by Palladium-Catalyzed Double Carbonylation. Chem. - Eur. J.
2014, 20, 8541−8544.
(18) (a) Wang, H.; Cao, X.; Xiao, F.; Liu, S.; Deng, G.-J. Iron-
Catalyzed One-Pot 2,3-Diarylquinazolinone Formation from 2-
4583
https://doi.org/10.1021/acs.orglett.1c01235
Org. Lett. 2021, 23, 4579−4583