Synthesis of Quinazoline and Quinazolinone Derivatives via Ligand-Promoted Ruthenium-Catalyzed Dehydrogenative and Deaminative Coupling Reaction of 2-Aminophenyl Ketones and 2-Aminobenzamides with Amines

Article abstract of DOI:10.1021/acs.orglett.9b01082

The in situ formed ruthenium catalytic system ([Ru]/L) was found to be highly selective for the dehydrogenative coupling reaction of 2-aminophenyl ketones with amines to form quinazoline products. The deaminative coupling reaction of 2-aminobenzamides with amines led to the efficient formation of quinazolinone products. The catalytic coupling method provides an efficient synthesis of quinazoline and quinazolinone derivatives without using any reactive reagents or forming any toxic byproducts.

Full text of DOI:10.1021/acs.orglett.9b01082

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Quinazoline and Quinazolinone Derivatives via Ligand-
Promoted Ruthenium-Catalyzed Dehydrogenative and Deaminative
Coupling Reaction of 2‑Aminophenyl Ketones and
2‑Aminobenzamides with Amines
Pandula T. Kirinde Arachchige and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881 United States
S
* Supporting Information
ABSTRACT: The in situ formed ruthenium catalytic system
([Ru]/L) was found to be highly selective for the dehydrogen-
ative coupling reaction of 2-aminophenyl ketones with amines
to form quinazoline products. The deaminative coupling
reaction of 2-aminobenzamides with amines led to the efficient
formation of quinazolinone products. The catalytic coupling
method provides an efficient synthesis of quinazoline and
quinazolinone derivatives without using any reactive reagents
or forming any toxic byproducts.
uinazolines and quinazolinones are a privileged class of
Similar Cu-catalyzed oxidative coupling methods of aniline
derivatives with aldehydes and nitriles have also been
developed for the construction of quinoline core structures.8
Transition-metal-catalyzed oxidative C−H amination and
alkylation methods have also been successfully employed to
synthesize quinazoline and quinazolinone derivatives.9 Cho
and co-workers recently devised a practical synthesis of 2-
arylquinazoline derivatives from the coupling of 2-aminobezyl-
amines with halogenated toluene substrates.10
Q nitrogen heterocyclic scaffolds that have been found to
exhibit a broad spectrum of pharmacological activities,
including anti-inflammatory, antitubercular, and antiviral
activities.1 A number of quinazoline-based drugs such as
prazocin and doxazosine have been approved to treat benign
prostatic hyperplasia and post-traumatic stress disorder,2 while
both erlotinib and gefitinib have been used for the treatment of
lung and pancreatic cancers (Figure 1).3 Lapatinib, as an
Since the advent of the Niementowski condensation of
anthranilic acids with amides,11 a variety of sustainable
synthetic methods have also been devised for the assembly
of quinazolinone core structures.12 Much recent research effort
has been devoted to the development of catalytic coupling
methods to increase efficiency and selectivity in constructing
quinazolinone core structures. A number of transition-metal-
catalyzed direct coupling methods of aminobenzamides with
alcohols and carbonyl compounds have been successfully
exploited to synthesize quinazolinone derivatives.13 Transition-
metal-catalyzed couplings of 2-aminobenzamides with alcohols
and ketones14 and three-component couplings of 2-amino-
benzamides, aryl halides or equivalents, and isocyanides15 are
among the notable examples of catalytic synthesis of
quinazolinones.
We previously reported that a phenol-coordinated cationic
ruthenium−hydride complex is a highly effective catalyst for
mediating the hydrogenolysis of aldehydes and ketones to give
the corresponding aliphatic products.16 We subsequently
devised a catalytic system generated in situ from a tetranuclear
ruthenium−hydride complex and a catechol ligand to promote
Figure 1. Selected examples of quinazoline and quinazolinone-based
drugs.
inhibitor for epidermal growth factor, has been shown to be
effective in combination therapy for breast cancer.4 Several
quinazolinone-based drugs including idelalisib and fenquizone
have been shown to exhibit a broad spectrum of antimicrobial,
antitumor, antifungal, and cytotoxic activities.5
A number of different synthetic strategies for quinazolines
and quinazolinones have been developed over the years, in part
to meet the growing needs for screening such derivatives.6
Several research groups have successfully utilized copper-
catalyzed Ullmann-type coupling methods of aryl bromides
and benzamidines for the synthesis of quinazoline derivatives.7
Received: March 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01082
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a direct deaminative coupling of primary amines.17 We have
been exploring the coupling reactions of amines to further
extend the synthetic utility of ligand-promoted catalysis, and
herein, we disclose an efficient catalytic synthesis of quinazo-
line and quinazolinone derivatives from the dehydrogenative
and deaminative coupling reactions of amino ketones and
aminobenzamides with amines.
Table 1. Synthesis of Quinazolines from the Coupling of 2-
Aminophenyl Ketones with Amines
a
In an effort to extend the scope and utility of deaminative
coupling methods, we initially explored the coupling reaction
of 2-amino ketones with amines by employing the ligand-
promoted catalysis protocol. Among the initially screened Ru
catalysts and ligands, the in situ generated catalytic system
from the cationic ruthenium−hydride complex [(C6H6)-
(PCy3)(CO)RuH]+BF4 (1) with 4-(1,1-dimethylethyl)-1,2-
−
a
Reaction conditions: amino ketone (0.5 mmol), amine (0.7 mmol),
1 (3 mol %), L1 (10 mol %), dioxane (2 mL), 140 °C, 20 h. Ar =
3,4,5-trimethoxyphenyl, Ar′ = 3,5-methylenedioxybenzyl.
benzenediol (L1) was found to give the highest activity and
selectivity for the coupling of 2-(aminophenyl)ethanone with
4-methoxybenzylamine in yielding the quinazoline product 2a
(Table S1). After further ligand screening and optimization
studies, we established the standard conditions for the
quinazoline product 2a as 1 (3 mol %) and 4-(1,1-
dimethylethyl)-1,2-benzenediol (L1) (10 mol %) in 1,4-
dioxane (2 mL) at 140 °C (eq 1).
mmol) with benzylamine (0.7 mmol) in dioxane (2 mL) at
140 °C in the presence of the catalyst system 1 (3 mol %)/L1
(10 mol %) led to the selective formation of the quinazolinone
product 3a, which was analyzed by both GC and NMR
spectroscopic methods (eq 2).
The substrate scope of the coupling reaction was explored
by using the catalyst system 1/L1 under the standard
conditions (Table 2). The coupling of 2-aminobenzamides
with both benzyl- and alkyl-substituted amines led to the
We explored the substrate scope of the coupling reaction by
using the catalyst system 1/L1 under the standard conditions
(Table 1). The coupling of 2-aminophenyl ketones with a
variety of benzylic amines selectively formed the quinazoline
products 2a−o. The coupling of 2-aminophenyl ketones with
phenethylamines and with aliphatic amines also gave the
selective formation of 2q,r and 2s−u, respectively. While the
coupling reaction of 2-aminphenyl ketone substrate with a
branched amine smoothly yielded the coupling products 2v
and 2cc, coupling with sterically demanding secondary amines
and branched amines generally yielded only a trace amount of
the coupling products under the standard reaction conditions.
Analytically pure quinazoline products were readily isolated
after silica gel column chromatographic separation, and their
structures were completely established by spectroscopic
methods. The structure of 2j was also confirmed by X-ray
crystallography. The coupling reaction was easily scalable to a
2−3 mmol scale reaction to yield 0.5−0.7 g of 2b, 2l and 2z.
The catalytic coupling method furnishes a direct synthesis of
quinazoline products without resorting to employing any
reactive reagents.
Table 2. Synthesis of Quinazolinones from the Coupling of
a
2-Aminobenzamides with Amines
Adopting the previously developed deaminative coupling
protocol,17 we next sought the catalytic coupling reaction of
the arylamides with amine substrates to form quinazolinone
products. Thus, the treatment of 2-aminobenzamide (0.5
a
Reaction conditions: benzamide (0.5 mmol), amine (0.7 mmol), 1
(3 mol %), L1 (10 mol %), dioxane (2 mL), 140 °C, 20 h.
B
DOI: 10.1021/acs.orglett.9b01082
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Letter
selective formation of the quinazolinone products 3a−n with
no significant amount of the quinazoline or other side
products. The analogous coupling reaction of N-alkyl-2-
benzamides with both benzylamines and alkyl-substituted
amines afforded the corresponding coupling products 3o−t
in moderate to high yields.
structure and stereochemistry of both 3w (major diaster-
eomer) and 3x have been confirmed by X-ray crystallography.
Single crystals of 3c were obtained by slow evaporation in
hexanes/EtOAc at room temperature, and its structure was
determined by X-ray crystallography. The formation of
quinazolinone product can be rationalized by initial deami-
native coupling of amide and amine substrates followed by the
cyclization dehydrogenation steps. The coupling reaction
efficiently assembles synthetically valuable quinazolinone core
structures by employing readily available amine and benzamide
substrates.
To further demonstrate synthetic utility of the catalytic
method, we next performed the couplings of both 2-
aminophenyl ketones and 2-aminobenzamides with a number
of biologically active amine substrates (Table 3). The
We performed the following set of experiments to probe
mechanistic insights on the coupling reaction. First, we
examined the deuterium-labeling pattern from the reaction of
2-aminophenylethanone-d3 (89% D) with 4-methoxybenzyl-
amine (eq 3). The treatment of 2-aminophenylethanone-d3
(0.5 mmol) with 4-methoxybenzylamine (0.7 mmol) in the
presence of 1 (3 mol %)/L1 (10 mol %) in 1,4-dioxane (2
mL) was heated in an oil bath at 140 °C for 20 h. The isolated
1
2
product 2a-d as analyzed by H and H NMR contained only
11% of the deuterium on the methyl group as most of the
deuterium had been washed away (Figure S1). A relatively
small amount of the deuterium on 2a-d suggests an extensive
keto−enol tautomerization under the reaction conditions.
We next monitored the reaction progress by using NMR
spectroscopy to discern intermediate species for the coupling
reaction. In a resealable NMR tube, a reaction mixture of 2-
aminophenylethanone (0.25 mmol), 4-methoxybenzylamine
(0.25 mmol), and in situ generated catalyst 1 (3 mol %)/L1
(10 mol %) in toluene-d8 (0.5 mL) was immersed an oil bath
set at 140 °C. The tube was taken out from the oil bath at 20
Table 3. Coupling Reaction of 2-Aminophenyl Ketones and
a
2-Aminobenzamides with Biologically Active Amines
1
min intervals, and the reaction progress was recorded by H
NMR. The appearance of new set of peaks attributed to the
imine product 4a has been observed initially as both starting
substrates are consumed. After about 100 min of reaction time,
the peaks due to the quinazoline product 2a began to appear as
the imine peaks gradually disappeared. The plot of relative
concentration vs time is shown in Figure 2.
a
Reaction conditions: amino ketone or benzamide (0.5 mmol), amine
(0.7 mmol), 1 (3 mol %), L1 (10 mol %), dioxane (2 mL), 140 °C, 20
b
To establish the imine as a requisite intermediate for the
formation of 2, independently synthesized 4b was treated with
h. Benzamide (0.25 mmol), amine (0.35 mmol).
treatment of 2-aminophenylethanone with tryptamine under
the standard conditions led to the indole-substituted product
2ff. The analogous coupling with (−)-cis-myrtanylamine
formed the quinazoline product 2gg (dr = 10:1) with a
minimal racemization on the benzylic carbon. The coupling of
2-aminophenylethanone with a morpholinyl-substituted amine
predictively formed 2ii. The coupling of a thiophene-
substituted amino ketone with 3,4,5-trimethoxybenzylamine
yielded the product 2jj in 52% yield. The analogous treatment
of 2-aminobenzamide with geranylamine formed the corre-
sponding quinazolinone product 3u, in which the neighboring
olefinic group is selectively hydrogenated, while the treatment
of a thiophene-substituted amide with 4-phenylbenzylamine
formed the corresponding quinazolinone product 3v. The
coupling of 2-aminobenzamide with (−)-cis-myrtanylamine
formed the coupling product 3w with a modest diastereose-
lectivity (dr = 1.9:1). In sharp contrast, the analogous coupling
with (+)-dehydroabietylamine resulted in the formation of the
coupling product 3x without any detectable racemization. The
Figure 2. Plot of relative concentration vs time for the coupling
■
reaction of 2-aminophenylethanone ( ) with 4-methoxybenzylamine
⧫
●
▲
( ), 2a ( ), and 4a ( ).
C
DOI: 10.1021/acs.orglett.9b01082
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Organic Letters
Letter
Accession Codes
1/L1 under the standard conditions, which proceeded
smoothly to afford the quinazoline product 2h in 87% yield
(eq 4). In a control experiment, the analogous treatment of 4b
with p-toluenesulfonic acid (5 mol %) did not form the
product 2h under otherwise similar reaction conditions. The
results showed that the ruthenium catalysis is essential for the
cyclization and dehydrogenation steps of the product
formation.
CCDC 1906356−1906359 contain the supplementary crys-
tallographic 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 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Although much kinetic and spectroscopic information is still
needed to ascertain a detailed reaction mechanism, we offer a
plausible mechanistic sequence for the formation of quinazo-
line products 2 on the basis of these preliminary results
(Scheme 1). The reaction profile study clearly implicates that
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chae.yi@marquette.edu
ORCID
Chae S. Yi: 0000-0002-4504-1151
Notes
Scheme 1. Possible Mechanistic Sequence for the
Formation of Quinazoline Products
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation
(CHE-1664652) and the National Institute of Health General
Medical Sciences (R15 GM109273) is gratefully acknowl-
edged.
REFERENCES
■
(1) Recent reviews: (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) Gupta, T.; Rohilla, A.; Pathak,
A.; Akhtar, M. J.; Haider, M. R.; Yar, M. S. Current perspectives on
quinazolines with potent biological activities: A review. Synth.
Commun. 2018, 48, 1099−1127.
the imine intermediate 4 is generated from initial dehydrative
coupling of amino ketone and amine substrates. We propose
that the Ru catalyst facilitates the imine isomerization to form
the imine-coordinated species 5. The subsequent cyclization
and dehydrogenation steps would yield the quinazoline
product 2. In support of this, we previously found that the
ruthenium−hydride complexes are efficient catalysts for olefin
isomerization reaction18 and dehydrogenation of saturated
amines and carbonyl compounds.19 While the exact role of
catechol ligand has yet to be established, we believe that a
redox-active catechol ligand may be facilitating the dehydro-
genation step on the catalysis.20
In summary, we have been able to devise a catalytic protocol
for the synthesis of quinazoline and quinazolinone derivatives
from the dehydrogenative and deaminative couplings of 2-
aminophenyl ketones and 2-aminobenzamides with amines.
The in situ formed ruthenium−hydride complex with a
catechol ligand (1/L1) was found to exhibit uniquely high
catalytic activity and selectivity in forming these products. The
salient features of the catalytic method are that it employs
readily available substrates, exhibits a broad substrate scope
while tolerating common organic functional groups, and does
not require any reactive reagents or forms any wasteful
byproducts. We are currently exploring synthetic utility of the
deaminative coupling protocol in constructing other nitrogen
heterocyclic core structures.
(2) (a) Akduman, B.; Crawford, E. D. Terazosin, doxazosin, and
prazosin: current clinical experience. Urology 2001, 58, 49−54.
(b) McConnell, J. D.; et al. The long-term effect of doxazosin,
finasteride, and combination therapy on the clinical progression of
benign prostatic hyperplasia. N. Engl. J. Med. 2003, 349, 2387−2398.
(3) (a) Pao, W.; Miller, V. A. Epidermal growth factor receptor
mutations, small-molecule kinase inhibitors, and non-small-cell lung
cancer: current knowledge and future directions. J. Clin. Oncol. 2005,
23, 2556−2568. (b) Miller, V. A.; et al. Bronchioloalveolar pathologic
subtype and smoking history predict sensitivity to gefitinib in
advanced non-small-cell lung cancer. J. Clin. Oncol. 2004, 22,
1103−1109.
(4) (a) Geyer, C. E.; Forster, J.; Lindquist, D.; Chan, S.; Romieu, C.
G.; Pienkowski, T.; Jagiello-Gruszfeld, A.; Crown, J.; Chan, A.;
Kaufman, B.; Skarlos, D.; Campone, M.; Davidson, N.; Berger, M.;
Oliva, C.; Rubin, S. D.; Stein, S.; Cameron, D. Lapatinib plus
capecitabine for HER2-positive advanced breast cancer. N. Engl. J.
Med. 2006, 355, 2733−2743. (b) Johnston, S.; Pippen, Jr. J.; Pivot, X.;
Lichinitser, M.; Sadeghi, S.; Dieras, V.; Gomez, H. L.; Romieu, G.;
Manikhas, A.; Kennedy, M. J.; Press, M. F.; Maltzman, J.; Florance,
A.; O’Rourke, L.; Oliva, C.; Stein, S.; Pegram, M. Lapatinib combined
with letrozole versus letrozole and placebo as first-line therapy for
postmenopausal hormone receptor-positive metastatic breast cancer.
J. Clin. Oncol. 2009, 27, 5538−5546.
(5) (a) Amin, K. M.; Kamel, M. M.; Anwar, M. M.; Khedr, M.;
Syam, Y. M. Synthesis biological evaluation and molecular docking of
novel series of spiro[(2H, 3H)quinazoline-2, 1′-cyclohexan]-4(1H)-
one derivatives as anti-inflammatory and analgesic agents. Eur. J. Med.
Chem. 2010, 45, 2117−2131. (b) Furman, R. R.; et al. Idelalisib and
rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med.
2014, 370, 997−1007. (c) Kshirsagar, U. A. Recent developments in
the chemistry of quinazolinone alkaloids. Org. Biomol. Chem. 2015,
13, 9336−9352.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01082.
Experimental procedures, spectroscopic data, and NMR
spectra (PDF)
(6) (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Synthesis of quinazolinones and quinazolines. Tetrahedron 2005, 61,
D
DOI: 10.1021/acs.orglett.9b01082
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
10153−10202. (b) 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.
Bromide. Synthesis 2013, 45, 3349−3354. (c) Li, F.; Lu, L.; Liu, P.
Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with
the Activation of Methanol as a C1 Source for the Construction of
Quinazolinones. Org. Lett. 2016, 18, 2580−2583. (d) 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.
(14) (a) Siddiki, S. M. A.; Kon, K.; Touchy, A. S. A. T.; Shimizu, K.
Direct synthesis of quinazolinones by acceptorlessdehydrogenative
coupling of o-aminobenzamide and alcohols by heterogeneous Pt
catalysts. Catal. Sci. Technol. 2014, 4, 1716−1719. (b) Zhang, W.;
Meng, C.; Liu, Y.; Tang, Y.; Li, F. Auto-Tandem Catalysis with
Ruthenium: From o-Aminobenzamides and Allylic Alcohols to
Quinazolinones via Redox Isomerization/Acceptorless Dehydrogen-
ation. Adv. Synth. Catal. 2018, 360, 3751−3759.
(15) (a) Jiang, X.; Tang, T.; Wang, J.-M.; Chen, Z.; Zhu, Y.-M.; Ji,
S.-J. Palladium-Catalyzed One-Pot Synthesis of Quinazolinones via
tert-Butyl Isocyanide Insertion. J. Org. Chem. 2014, 79, 5082−5087.
(b) Qian, C.; Liu, K.; Tao, S.-W.; Zhang, F.-L.; Zhu, Y.-M.; Yang, S.-
L. Palladium-Catalyzed Oxidative Three-Component Coupling of
Anthranilamides with Isocyanides and Arylboronic Acids: Access to
2,3-Disubstituted Quinazolinones. J. Org. Chem. 2018, 83, 9201−
9209.
(16) Kalutharage, N.; Yi, C. S. Scope and Mechanistic Analysis for
Chemoselective Hydrogenolysis of Carbonyl Compounds Catalyzed
by a Cationic Ruthenium-Hydride Complex with Tunable Phenol
Ligand. J. Am. Chem. Soc. 2015, 137, 11105−11114.
(17) Arachchige, P. T. K.; Lee, H.; Yi, C. S. Synthesis of Symmetric
and Unsymmetric Secondary Amines from the Ligand Promoted
Ruthenium Catalyzed Deaminative Coupling Reaction of Primary
Amines. J. Org. Chem. 2018, 83, 4932−4947.
(18) Yi, C. S.; Lee, D. W. Regioselective Intermolecular Coupling
Reaction of Arylketones and Alkenes Involving C−H Bond Activation
Catalyzed by an in-Situ Formed Cationic Ruthenium-Hydride
Complex. Organometallics 2009, 28, 4266−4268.
(19) Yi, C. S.; Lee, D. W. Efficient Dehydrogenation of Amines and
Carbonyl Compounds Catalyzed by a Tetranuclear Ruthenium-μ-oxo-
μ-hydroxo-hydride Complex. Organometallics 2009, 28, 947−949.
(20) Broere, D. L. J.; Plessius, R.; Van der Vlugt, J. I. New avenues
for ligand-mediated processes-expanding metal reactivity by the use of
redox-active catechol, o-aminophenol and o-phenylenediamine
ligands. Chem. Soc. Rev. 2015, 44, 6886−6915.
(7) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. A Simple and Efficient
Approach to Quinazolinones under Mild Copper-Catalyzed Con-
ditions. Angew. Chem., Int. Ed. 2009, 48, 348−351. (b) Wang, C.; Li,
S.; Liu, H.; Jiang, Y.; Fu, H. J. Copper-Catalyzed Synthesis of
Quinazoline Derivatives via Ullmann-Type Coupling and Aerobic
Oxidation. J. Org. Chem. 2010, 75, 7936−7938. (c) 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. (d) Malakar, C. C.;
Baskakova, A.; Conrad, J.; Beifuss, U. Copper-Catalyzed Synthesis of
Quinazolines in Water Starting from o-Bromobenzylbromides and
Benzamidines. Chem. - Eur. J. 2012, 18, 8882−8885. (e) Omar, M. A.;
Conrad, J.; Beifuss, U. Copper-catalyzed domino reaction between 1-
(2-halophenyl)methanamines and amidines or imidates for the
synthesis of 2-substituted quinazolines. Tetrahedron 2014, 70,
3061−3072.
(8) (a) Han, B.; Yang, X.-L.; Wang, C.; Bai, Y.-W.; Pan, T.-C.; Chen,
X.; Yu, W. CuCl/DABCO/4-HO-TEMPO-Catalyzed Aerobic
Oxidative Synthesis of 2-Substituted Quinazolines and 4H-3,1-
Benzoxazines. J. Org. Chem. 2012, 77, 1136−1142. (b) Chen, Z.;
Chen, J.; Liu, M.; Ding, J.; Gao, W.; Huang, X.; Wu, H. Unexpected
Copper-Catalyzed Cascade Synthesis of Quinazoline Derivatives. J.
Org. Chem. 2013, 78, 11342−11348. (c) Liu, Q.; Zhao, Y.; Fu, H.;
Cheng, C. Copper-Catalyzed Sequential N-Arylation and Aerobic
Oxidation: Synthesis of Quinazoline Derivatives. Synlett 2013, 24,
2089−2094. (d) Wang, X.; He, D.; Huang, Y.; Fan, Q.; Wu, W.; Jiang,
H. Copper-Catalyzed Synthesis of Substituted Quinazolines from
Benzonitriles and 2-Ethynylanilines via Carbon-Carbon Bond
Cleavage Using Molecular Oxygen. J. Org. Chem. 2018, 83, 5458−
5446.
(9) (a) Wiedemann, S. H.; Ellman, J. A.; Bergman, R. G. Rhodium-
Catalyzed Direct C-H Addition of 3,4-Dihydroquinazolines to
Alkenes and Their Use in the Total Synthesis of Vasicoline. J. Org.
Chem. 2006, 71, 1969−1976. (b) Mohammed, S.; Vishwakarma, R.
A.; Bharate, S. B. Iodine Catalyzed Oxidative Synthesis of Quinazolin-
4(3H)-ones and Pyrazolo[4,3-d]pyrimidin-7(6H)-ones via Amination
of sp3 C-H Bond. J. Org. Chem. 2015, 80, 6915−6921. (c) Wang, X.;
Jiao, N. Rh- and Cu-Cocatalyzed Aerobic Oxidative Approach to
Quinazolines via [4 + 2] C-H Annulation with Alkyl Azides. Org. Lett.
́
́
2016, 18, 2150−2153. (d) Gutierrez-Bonet, A; Remeur, C.; Matsui, J.
K.; Molander, G. A. Late-Stage C-H Alkylation of Heterocycles and
1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines. J. Am.
Chem. Soc. 2017, 139, 12251−12258.
(10) Chatterjee, T.; Kim, D. I.; Cho, E. J. Base-Promoted Synthesis
of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water. J. Org.
Chem. 2018, 83, 7423−7430.
(11) (a) Williamson, T. A. The chemistry of quinazoline. In
Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons:
New York, 1957; Vol. 6, pp 324−376. (b) Ferrini, S.; Ponticelli, F.;
Taddei, M. Convenient Synthetic Approach to 2,4-Disubstituted
Quinazolines. Org. Lett. 2007, 9, 69−72. (c) Hensbergen, A. W.;
Mills, V. R.; Collins, I.; Jones, A. M. An expedient synthesis of
oxazepino and oxazocino quinazolines. Tetrahedron Lett. 2015, 56,
6478−6483.
(12) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Solvent-Free Heterocyclic Synthesis. Chem. Rev. 2009,
109, 4140−4182. (b) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.;
Afonso, C. A. M.; Trindade, A. F. More Sustainable Approaches for
the Synthesis of N-Based Heterocycles. Chem. Rev. 2009, 109, 2703−
2802.
(13) (a) 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. (b) Wei, H.; Li, T.; Zhou, Y.; Zhou, L.;
Zeng, Q. Copper-Catalyzed Domino Synthesis of Quinazolin-4(3H)-
ones from (Hetero)arylmethyl Halides, Bromoacetate, and Cinnamyl
E
DOI: 10.1021/acs.orglett.9b01082
Org. Lett. XXXX, XXX, XXX−XXX