Cu/Ag-catalyzed reaction of azirines with anthranils: Synthesis of (quinazolin-2-yl)methanone derivatives

Article abstract of DOI:10.1021/acs.orglett.0c02222

A Cu/Ag-catalyzed annulation of 3-aryl-2H-azirines with anthranils has been developed to expedite syntheses of (quinazolin2-yl)methanone derivatives. The transformation represents an unprecedented approach which employs a copper catalysis to cleave both a N-C2 azirine bond and N-O anthranil bond. Subsequently, an unexplored 1,3-hydroxyl migration and β-N elimination are likely the key to access (quinazolin-2-yl)methanone derivatives.

Full text of DOI:10.1021/acs.orglett.0c02222

pubs.acs.org/OrgLett
Letter
Cu/Ag-Catalyzed Reaction of Azirines with Anthranils: Synthesis of
(Quinazolin-2-yl)methanone Derivatives
Yajun Sun, Huimin Sun, Ying Wang, and Fang Xie*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02222
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A Cu/Ag-catalyzed annulation of 3-aryl-2H-azirines
with anthranils has been developed to expedite syntheses of
(quinazolin2-yl)methanone derivatives. The transformation repre-
sents an unprecedented approach which employs a copper catalysis
to cleave both a N−C2 azirine bond and N−O anthranil bond.
Subsequently, an unexplored 1,3-hydroxyl migration and β-N
elimination are likely the key to access (quinazolin-2-yl)methanone
derivatives.
Scheme 1. Transition-Metal-Catalyzed Synthesis of
(Quinazolin-2-yl)methanones
itrogen-containing heterocyclic scaffolds are significant
synthetic targets that widely exist in bioactive products
N
and functional materials.1 With the advent of new transition-
metal-catalyzed reactions and the recognition that versatile
synthetic intermediates can open up new vistas of reactivity,
the development of novel methods to quickly access important
heterocycles will be of long-standing interest of synthetic
chemists. Quinazoline is a well-known strutural motif which
has a broad spectrum of biological activity2 such as sedative,
anticonvulsant, anticancer, antitussive, antidiabetic properties.
Nowadays, the effective molecular targeted drugs for lung
cancer such as gefitunib and erlotinib are all quinazoline-
related scaffolds.3 Over the past decades, numerous protocols
had been established to synthesize these particular heterocyles.
For example, reactions utilizing 2-aminobenzylamine with
either aldehydes, nitriles, amines, alcohols, or acids in the
presence of various oxidants are the classical methods to
achieve 2-substituted quinazolines.4 However, methods for
synthesis of quinazolin-2-yl-methanone derivatives with
potential activities have rarely been investigated. Recently,
the Tang group disclosed a Rh(II)-catalyzed synthesis of (4-
methylquinazolin-2-yl)(phenyl)methanone derivatives through
transannulation of N-sulfonyl-1,2,3-triazoles with 2,1-benzisox-
azoles (Scheme 1a).5 However, this protocol requires
expensive transition metals, and the atom economy of using
N-sulfonyl-1,2,3-triazoles as cycloaddition component is
unsatisfactory. In view of the importance of heterocycles in
drug reseach and our ungoing research interest in developing
new synthetic methods derived from the cheap, earth abundant
metal catalysis, we became interested in exploring novel
approaches to produce (quinazolin-2-yl)methanones.
azirines under conditions such as heating or the attack of
various nucleophiles, carbenes, carbenoids, and transition
metals. In contrast, various transition metals like Cu(II),
Fe(II), Rh(II), Ni(II), or Pd(II) are known to catalyze the ring
opening mainly via a N−C2 bond cleavage to give 4−6-
membered heterocycles.7 Anthranils are also a class of versatile
synthetic intermediates owing to their significant coordinating
property and cleavable N−O bonds. In various metal such as
Rh-, Cu-, Au-, and Pd-catalyzed reactions, anthranils have been
used as nucleophiles or aryl nitrene intermediates, and the
breakage of N−O bonds leads to a skeleton which normally
contains an electrophilic formyl group.8 Although the dual
functionalities of anthranils are extradinarily useful for
constructing organic π-conjugated molecules containing nitro-
gen atoms, to the best of our knowledge, the cleavage of C−N
bonds of 2H-azirines attacked by anthranils as nucleophiles or
Received: July 4, 2020
2H-Azirines have been extensively used as precursors in the
synthesis of 4−7-membered nitrogen-containing heterocycles.6
Although UV irradiation causes the cleavage of the C−C bond
of the three-membered ring, the majority of annulation
reactions occur through the ring-opening of C−N bonds of
https://dx.doi.org/10.1021/acs.orglett.0c02222
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
nitrenes is unprecedented, probably because 2H-azirines can
also act as the nucleophile to cleave the N−O bond of
anthranils. It is rarely seen that either of the coupling
components can coordinate with metal and further have
ring-opening through formation of a nitrene complex. Since
the mechanistically interesting reaction has never been
explored, we report a Cu/Ag-catalyzed annulation of anthranils
with 3-aryl-2H-azirines to construct (quinazolin-2-yl)-
methanones derivatives with specific selectivity and good
functional group tolerance (Scheme 1b).
First, we conducted a reaction of anthranil 1a (0.2 mmol), 3-
phenyl-2H-azirine 2a (0.4 mmol), copper(I) acetate (20 mol
%), and HOAc (1 equiv) in DCE. After stirring at 80 °C for 12
h under a nitrogen atmosphere, no product was detected.
Different copper catalysts such as CuCl, CuBr, and CuI were
also tried, none of them were effective to induce the reaction.
Fortunately, when AgSbF6 (20 mol %) was employed, the
reaction proceeded smoothly to produce phenyl(quinazolin-2-
yl)methanone 3a,4a,9 albeit in moderate isolated yield (Table 1,
PIDA, and oxygen were added in order to improve the
reaction efficacy (Table 1, entries 13−15). To our delight, the
presence of oxygen accelerated the reaction rate and 3a was
obtained in 59% yield (Table 1, entry 15). Several solvents
have also been tested for the model reaction and found that
DMF, THF, toluene, and acetonitrile all led to poor results
(Table 1, entries 16−19). Finally, up to 71% yield of 3a was
gained by reducing the quantity of Cu(OAc)2 from 20 to 12
mol % (Table 1, entry 20).
With the optimized conditions in hand, we sought to study
the reaction scope with respect to the azirine substrates
(Scheme 2). Gratifyingly, a variety of azirines with electroni-
Scheme 2. Substrate Scope of 2H-Azirines of Synthesis of
a b
,
(Quinazolin-2-yl)methanones
a
Table 1. Optimization of Reaction Conditions
b
entry
1
Cu
Ag
solvent
temp (°C) yield (%)
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgOTf
AgOAc
AgBF4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
THF
toluene
DMF
DCE
DCE
80
80
80
80
80
40
ND
10
c
2
3
d
4
5
6
7
8
9
38
trace
trace
trace
42
48
45
40
40
48
32
80
80
100
100
100
100
100
100
100
100
100
100
100
100
100
100
Cu(OAc)2
CuCl
CuBr
10
11
12
13
14
15
16
17
18
CuI
e
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
None
f
g
59
g
ND
ND
31
42
71
g
a
g
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu (12 mol %),
g
Ag (20 mol %), and HOAc (1.0 equiv) were stirred in DCE (2.0 mL)
19
20
21
b
gh
,
under O2 for 12 h. Isolated yield after chromatography.
h
ND
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu (20 mol %),
Ag (20 mol %) and HOAc (1.0 equiv) were stirred in a solvent (2.0
cally and sterically variable functional groups at different
positions were accommodated well. As depicted in Scheme 2,
the steric hindrance did not influence the reaction efficiency
significantly where a Cl and methyl at the ortho-positions gave
good yields (3e and 3h). Monohalogen (F, Cl, Br) or
pentafluoro substituents and electron-donating groups (OMe
or Me) at the meta- or para-positions were well tolerated, and
the (quinazolin-2-yl)methanones products were isolated in
54−72% yield (3a−3k). Notably, azirines bearing electron-
withdrawing groups such as CF3, OAc, and COOMe at the
para-position also reacted smoothly. Moreover, the reaction
condition was compatible with the substrate bearing other
aromatic rings (3m). However, when 3-(thiophene-2-yl)-2H-
azirine was subjected to the current conditions, no desired
product (3q) was obtained.
b
c
mL) under N2 for 12 h. Isolated yield after chromatography. HOAc
was not used. 1a (0.4 mmol), 2a (0.2 mmol) were used. TBHP (0.2
mmol) was used. PIDA (0.2 mmol) was added. under O2. Cu (12
mol %) was used.
d
e
f
g
h
entry 1). Then, the effects of silver additives such as AgNTf2,
AgOTf, AgOAc, and AgBF4 were studied, but only AgNTf2
gave the desired product in 38% yield (Table 1, entries 4−7).
Increasing the reaction temperature from 80 to 100 °C
furnished a slightly higher yield of 3a (entry 8). Further
improvement was achieved by screening different copper salts
at 100 °C (entries 9−12). Although the reaction can undergo
dehydrogenation spontaneously, oxidants such as TBHP,
B
https://dx.doi.org/10.1021/acs.orglett.0c02222
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
We next explored the scope of the anthranil coupling
reagents (Scheme 3). The reactions of 3-phenyl-2H-azirine
Scheme 5. Control Reactions
Scheme 3. Substrate Scope of Anthranils of Synthesis of
a b
,
(Quinazolin-2-yl)methanones
anthranils can also form aryl nitrene intermediate, azirines
engage in the reaction through an imine annulation could not
be completely excluded.
A proposed mechanism to account for the formation of
quinazolin-2-yl-(phenyl)methanones is depicted in Scheme 6.
Scheme 6. Plausible Catalytic Cycle
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Cu (12 mol %),
Ag (20 mol %), and HOAc (1.0 equiv) were stirred in DCE (2.0 mL)
b
under O2 for 12 h. Isolated yield after chromatography.
with anthranils bearing halogen (F, Cl, Br) at different
positions all furnished products in good yields (55−71%)
(3r−3v). Both electron-donating groups such as OMe or
alkoxy (3w and 3x) and weak electron-withdrawing group OAc
(3y) performed well in the reaction leading to the desired
products in 50−62% yields. The annulation reaction was also
extended to anthranils with an alkyl or phenyl group at the C-3
position and gave slightly lower yields of the corresponding 4-
substituted-quinazolin-2-yl)(phenyl)methanones, as shown by
the cases of 3z and 3z′.
To illustrate the utility of this protocol in organic synthesis, a
scale-up reaction of 1a with 2a under the standard reaction
conditions was conducted. The reaction proceeded well to
deliver the product 3a in 70% yield, which is comparable to
those in the smaller scale reaction (Scheme 4).
Scheme 4. Scale-up Reaction
Azirine A coordinates with the copper catalyst producing
azirine complex Ia, which is further transformed into the
nitrene copper complex IIa through a reversible N−C2 bond
cleavage.7a,b IIa is then attacked by anthranil to form
intermediate IIIa. In IIIa Cu gets insertion into the adjacent
N−O bond to generate intermediate IVa, which quickly
isomerizes to produce the complex IVb (path A). Alternatively,
Cu salt can insert into the cleavable N−O bond of anthranil B
and lead to formation of the copper nitrenoid species IIb,
which further coordinates with 2H-azirine A to provide
intermediate IIIb. Subsequent migratory insertion of nitrenoid
into the N−C2 bond in IIIb affords the complex IVb (path B).
Protonation of IVb by HOAc delivers the intermediate V and
copper(II) acetate is regenerated to finish the whole catalytic
cycle. AgSbF6 promoted cyclization of V generates the
intermediate VI.11 1,3 migration of hydroxy group and β-N
elimination are followed to produce α-aminocarbonyl inter-
To gain more mechanistic insights of this new methodology,
we also conducted the control experiments. First, 1 equiv of a
known radical quencher TEMPO (2,2,6,6-tetramethylpiper-
idine-1-oxyl) was subjected to the standard reaction to identify
if there was any free-radical intermediate involved (Scheme
5a). The reaction works albeit in a slightly lower yield of
(quinazolin-2-yl)methanones 3a, which indicates that a radical
mechanism is unlikely. It is well-known that both azirines and
vinyl azides can convert into vinyl nitrenes upon heating.10
Treatment of anthranil 1a with (1-azidovinyl)benzene under
optimized reaction condition gave 53% yield of product 3a
(Scheme 5b), revealing that the reaction probably occurs
through vinyl nitrene metal complex formation. Notably, while
C
https://dx.doi.org/10.1021/acs.orglett.0c02222
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
J.; Zhang, Y.; Dong, L.; Wang, Z.; Chen, L.; Liang, D.; Shi, D.; Shan,
X.; Liang, G. Chem. Biol. Drug Des. 2015, 85, 672−684. (f) Ple, P. A.;
Green, T. P.; Hennequin, L. F.; Curwen, J.; Fennell, M.; Allen, J.;
Lambert-van der Brempt, C.; Costello, G. J. Med. Chem. 2004, 47,
871−887.
(3) (a) Gundla, R.; Kazemi, R.; Sanam, R.; Muttineni, R.; Sarma, J.
A. R. P.; Dayam, R.; Neamati, N. J. Med. Chem. 2008, 51, 3367−3377.
(b) Zhang, Y.; Tortorella, M. D.; Liao, J.; Qin, X.; Chen, T.; Luo, J.;
Guan, J.; Talley, J. J.; Tu, Z. ACS Med. Chem. Lett. 2015, 6, 1086−
1090.
(4) (a) Saha, M.; Mukherjee, P.; Das, A. R. Tetrahedron Lett. 2017,
58, 2044−2049. (b) Tiwari, A. R.; Bhanage, B. M. Asian J. Org. Chem.
2017, 6, 831−836. (c) Maheswari, C. U.; Kumar, G. S.;
Venkateshwar, M.; Kumar, R. A.; Kantam, M. L.; Reddy, K. R. Adv.
Synth. Catal. 2010, 352, 341−346.
(5) Lei, X.; Gao, M.; Tang, Y. Org. Lett. 2016, 18, 4990−4993.
(6) For recent reviews on azirine chemistry, see: (a) Khlebnikov, A.
F.; Novikov, M. S.; Rostovskii, N. V. Tetrahedron 2019, 75, 2555−
2624. (b) Zhou, H.; Shen, M.-H.; Xu, H.-D. Synlett 2016, 27, 2171−
2177. (c) Khlebnikov, A. F.; Novikov, M. S. Top. Heterocycl. Chem.
2015, 41, 143−232. (d) Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014,
114, 8153−8198. (e) Khlebnikov, A. F.; Novikov, M. S. Tetrahedron
2013, 69, 3363−3401.
mediate VIII, which can be coordinated with copper(II) and
oxidized to form intermediate IX.12 It further evolves into the
1,2-dihydroquinazoline product X via 6π electrocyclization.
Finally, autoxidation of X affords the quinazoline derivative C.
In summary, a novel, short, and atom-economical synthesis
of quinazoline derivatives through Cu/Ag-catalyzed annual-
ation of 3-aryl-2H-azirines with anthranils was developed. This
synthetic strategy has first utilized two building blocks, either
of which can coordinate with copper and further have ring
opening through formation of a nitrene complex. A possible
mechanism involving the formation of copper nitrenoid, 1,3-
hydroxy migration, and β-N elimination is postulated to clarify
the generation of (quinazolin-2-yl)methanones. Further
investigations of the reaction mechanism and the synthetic
utility involving 2H-azirines or anthranils are ongoing in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02222.
(7) (a) Sakharov, P. A.; Rostovskii, N. V.; Khlebnikov, A. F.;
Novikov, M. S. Tetrahedron 2017, 73, 4663−4670. (b) Rostovskii, N.
V.; Novikov, M. S.; Khlebnikov, A. F.; Korneev, S. M.; Yufit, D. S.
Org. Biomol. Chem. 2013, 11, 5535−5545. (c) Baek, Y.; Maeng, C.;
Kim, H.; Lee, P. H. J. Org. Chem. 2018, 83, 2349−2360. (d) Zhao,
M.-N.; Ren, Z.-H.; Yang, D.-S.; Guan, Z.-H. Org. Lett. 2018, 20,
1287−1290. (e) Sujatha, C.; Bhatt, C. S.; Ravva, M. K.; Suresh, A. K.;
Namitharan, K. Org. Lett. 2018, 20, 3241−3244. (f) Peng, Q.; Zhang,
B.; Xie, Y.; Wang, J. Org. Lett. 2018, 20, 7641−7644. (g) Agafonova,
A. V.; Smetanin, I. A.; Rostovskii, N. V.; Khlebnikov, A. F.; Novikov,
M. S. Org. Chem. Front. 2018, 5, 3396−3401. (h) Candito, D. A.;
Lautens, M. Org. Lett. 2010, 12, 3312−3315. (i) Wang, L.; Li, H.;
Wang, L. Org. Lett. 2018, 20, 1663−1666. (j) Wagh, S. B.; Liu, R.-S.
Chem. Commun. 2015, 51, 15462−15464. (k) Funt, L. D.;
Krivolapova, Y. V.; Khoroshilova, O. V.; Novikov, M. S.;
Khlebnikov, A. F. J. Org. Chem. 2020, 85, 4182−4194.
(8) (a) Yu, S.; Tang, G.; Li, Y.; Zhou, X.; Lan, Y.; Li, X. Angew.
Chem., Int. Ed. 2016, 55, 8696−8700. (b) Jin, H.; Huang, L.; Xie, J.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed.
2016, 55, 794−797. (c) Li, L.; Wang, H.; Yu, S.; Yang, X.; Li, X. Org.
Lett. 2016, 18, 3662−3665. (d) Biswas, A.; Karmakar, U.; Nandi, S.;
Samanta, R. J. Org. Chem. 2017, 82, 8933−8942. (e) Wang, Z.; Yin,
Z.; Wu, X.-F. Chem. - Eur. J. 2017, 23, 15026−15029. (f) Mishra, N.
K.; Jeon, M.; Oh, Y.; Jo, H.; Park, J.; Han, S.; Sharma, S.; Han, S. H.;
Jung, Y. H.; Kim, I. S. Org. Chem. Front. 2017, 4, 241−249. (g) Li, P.-
G.; Zhu, H.; Fan, M.; Yan, C.; Shi, K.; Chi, X.-W.; Zou, L.-H. Org.
Biomol. Chem. 2019, 17, 5902−5907. (h) Xie, F.; Shen, B.; Li, X. Org.
Lett. 2018, 20, 7154−7157.
Experimental details and chemical compound informa-
tion (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Fang Xie − School of Chemistry and Chemical Engineering, Qufu
Normal University, Qufu 273165, China; orcid.org/0000-
0001-7621-2665; Email: hollyxfang@hotmail.com
Authors
Yajun Sun − School of Chemistry and Chemical Engineering,
Qufu Normal University, Qufu 273165, China
Huimin Sun − School of Chemistry and Chemical Engineering,
Qufu Normal University, Qufu 273165, China
Ying Wang − School of Chemistry and Chemical Engineering,
Qufu Normal University, Qufu 273165, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02222
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Start-up funding from Qufu
Normal University.
■
(9) Cai, Q.; Li, D.-K.; Zhou, R.-R.; Zhuang, S.-Y.; Ma, J.-T.; Wu, Y.-
D.; Wu, A.-X. J. Org. Chem. 2016, 81, 8104−8111.
(10) (a) Curiel Tejeda, J. E.; Irwin, L. C.; Kerr, M. A. Org. Lett.
2016, 18, 4738−4741. (b) Taber, D. F.; Tian, W. J. Am. Chem. Soc.
2006, 128, 1058−1059. (c) Man, L.; Copley, R. C. B.; Handlon, A. L.
Org. Biomol. Chem. 2019, 17, 6566−6569. (d) Padwa, A.; Carlsen, P.
J. Tetrahedron Lett. 1978, 19, 433−436.
(11) Wang, F.; Xu, P.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2018, 20,
2204−2207.
(12) Chen, C.; Zhu, M.; Jiang, L.; Zeng, Z.; Yi, N.; Xiang, J. Org.
Biomol. Chem. 2017, 15, 8134−8139.
REFERENCES
■
(1) For selected reviews, see: (a) Baraldi, P. G.; Tabrizi, M. A.;
Gessi, S.; Borea, P. A. Chem. Rev. 2008, 108, 238−263. (b) Scott, J.
D.; Williams, R. M. Chem. Rev. 2002, 102, 1669−1730. (c) Coughlin,
J. E.; Henson, Z. B.; Welch, G. C.; Bazan, G. C. Acc. Chem. Res. 2014,
47, 257−270. (d) Fried, L. E.; Manaa, M. R.; Pagoria, P. F.; Simpson,
R. L. Annu. Rev. Mater. Res. 2001, 31, 291−321. (e) Chen, D.; Su, S.-
J.; Cao, Y. J. Mater. Chem. C 2014, 2, 9565−9578.
(2) (a) Madapa, S.; Tusi, Z.; Mishra, A.; Srivastava, K.; Pandey, S.
K.; Tripathi, R.; Puri, S. K.; Batra, S. Bioorg. Med. Chem. 2009, 17,
222−234. (b) Juvale, K.; Gallus, J.; Wiese, M. Bioorg. Med. Chem.
2013, 21, 7858−7873. (c) Foster, B. A.; Coffey, H. A.; Morin, M. J.;
Rastinejad, F. Science 1999, 286, 2507−2510. (d) Parhi, A. K.; Zhang,
Y.; Saionz, K. W.; Pradhan, P.; Kaul, M.; Trivedi, K.; Pilch, D. S.;
LaVoie, E. J. Bioorg. Med. Chem. Lett. 2013, 23, 4968−4974. (e) Hu,
D
https://dx.doi.org/10.1021/acs.orglett.0c02222
Org. Lett. XXXX, XXX, XXX−XXX