Expeditious Synthesis of 2-Phenylquinazolin-4-amines via a Fe/Cu Relay-Catalyzed Domino Strategy

Article abstract of DOI:10.1021/acs.orglett.5b02020

A highly efficient Fe/Cu relay-catalyzed domino protocol has been developed for the synthesis of 2-phenylquinazolin-4-amines from commercially available ortho-halogenated benzonitriles, aldehydes, and sodium azide. This elegant domino process involved con

Full text of DOI:10.1021/acs.orglett.5b02020

Letter
pubs.acs.org/OrgLett
Expeditious Synthesis of 2‑Phenylquinazolin-4-amines via a Fe/Cu
Relay-Catalyzed Domino Strategy
Feng-Cheng Jia, Zhi-Wen Zhou, Cheng Xu, Qun Cai, Deng-Kui Li, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient Fe/Cu relay-catalyzed domino
protocol has been developed for the synthesis of 2-phenyl-
quinazolin-4-amines from commercially available ortho-halogenated
benzonitriles, aldehydes, and sodium azide. This elegant domino
process involved consecutive iron-mediated [3 + 2] cycloaddition,
copper-catalyzed SNAr, reduction, cyclization, oxidation, and
copper-catalyzed denitrogenation sequences. The formed structure
is the privileged core in drugs and bioactive molecules.
Scheme 1. Synthetic Routes to 2-Substituted 4-
Aminoquinazolines
uinazoline represents an important and abundant class of
1
Q nitrogen-containing heterocycles. In particular, as one of
the diverse quinazoline derivatives, the 4-aminoquinazoline
nucleus is exemplified as a privileged structure that exists in
many pharmaceutical molecules and biologically active com-
pounds,2,3 such as erlotinib (I),2a geftinib (II),2b prazosin (III),2c
and human adenosine A3 receptor antagonist (IV)2d (Figure 1).
In addition, 4-aminoquinazoline derivatives are often used as
synthetic intermediates for the direct synthesis of biologically
active molecules.2d,3
limited by a lack of suitable substrates, poor substitution
diversity, and the requirement for harsh reaction conditions.
Therefore, the development of effective new methods for the
facile construction of 4-aminoquinazolines is highly desirable.
Sodium azide (NaN3), which was used as a convenient
nitrogen source, has been widely applied in organic syn-
thesis.8−15 The common functions of NaN3 mainly includes
two types: (i) a 1,3-dipole to react with electron-deficient
olefins,8 alkynes,9 or nitriles10 and (ii) a coupling partner
participating in copper-catalyzed SNAr reactions.11 Substantial
progress has been made in developing domino reactions based
on these two fundamental reactions involving NaN3.12−14 As part
of our ongoing efforts toward developing novel copper-catalyzed
domino reaction related to sodium azide,15 herein we present a
Figure 1. Selected drugs or biologically active compounds with a 4-
aminoquinazoline moiety.
Because of their great value, the synthesis of 4-aminoquinazo-
lines has gained much attention. The current synthetic methods
of this skeleton are mainly summarized as the following three
types: (i) the nucleophilic addition/cyclization reaction of
anthranilonitrile with benzonitriles;2d,4 (ii) the coupling/
cyclization reaction of 2-bromobenzonitriles with amidines;5
and (iii) the SNAr/cyclization reaction of 2-fluorobenzonitriles
with amidines;6 Alternatively, 2-substituted 4-aminoquinazolines
can be prepared by the decoration of the existing quinazoline
nucleus3b,7 (Scheme 1). Although these reactions provide
efficient access to 4-aminoquinazolines, their applications are
Received: July 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02020
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Organic Letters
Letter
a b
,
novel Fe/Cu relay-catalyzed domino strategy for the direct
synthesis of pharmaceutically significant 2-phenylquinazolin-4-
amine derives from commercially available ortho-halogenated
benzonitriles, aldehydes, and sodium azide (Scheme 1).
Scheme 2. Scope of Aryl Aldehydes
To explore the feasibility of this domino protocol, our study
commenced with o-bromobenzonitrile (1a), benzaldehyde (2a),
and sodium azide as model substrates to optimize the reaction
conditions. Initially, various Lewis acids were screened in view of
their potential catalytic activity toward initial [3 + 2] cyclo-
addition of nitriles with NaN3 according to the existing
literature,10 and FeCl3 showed the highest efficiency in the
presence of CuI/L-proline in DMF at 110 °C in a sealed vessel
under air (Table 1, entries 1−9). Then several solvents were
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
CAN
solvent
DMF
temp (°C)
yield (%)
1
110
110
110
110
110
110
110
110
110
110
110
110
80
62
71
2
FeCl3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
1,4-dioxane
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
a
3
ZnCl2
AlCl3
42
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), NaN3 (2.0
mmol), FeCl3 (0.15 mmol), CuI (0.05 mmol), and L-proline (0.1
mmol) in DMF (3 mL) at 110 °C in a sealed vessel under air for 12 h.
4
45
5
InBr3
68
b
Isolated yields.
6
ZnBr2
Cu(OAc)2
Pd(OAc)2
AgNO3
FeCl3
11
7
trace
trace
trace
6
8
9
electron-deficient (3-NO2) groups were well tolerated, giving
the corresponding products in moderate to good yields (42%−
82%, 3aa−ag). To our delight, the optimized conditions were
mild enough to allow halo-substituted substrates (67%−73%,
3ah−aj), which provided the possibility for further functionaliza-
tion. Furthermore, sterically hindered substrates such as 1-
naphthaldehyde and 2-naphthaldehyde were also found to be
suitable for this transformation (3ak−al, 57% and 74%).
Meanwhile, the optimized conditions could be applied to
heteroaryl aldehydes including furan-2-carbaldehyde, thio-
phene-2-carbaldehyde, and thiophene-3-carbaldehyde (3am−
ao, 65%−78%). Furthermore, the structure of 3aa was
unambiguously determined by X-ray crystallographic analysis
(see the Supporting Information).
To further expand the scope of the substrates, a variety of
ortho-halogenated benzonitriles and aryl aldehydes were then
examined. Gratifyingly, electron-neutral (4-Me, 5-Me) groups on
the phenyl rings of 2-bromobenzonitriles were compatible and
provided the corresponding products in moderate to good yields
(Scheme 3, 53−84%, 3ba−cg). Halogen-substituted 2-bromo-
benzonitriles (5-F, 5-Cl) also afforded the desired products in
moderate yields (Scheme 3, 45% and 67%, 3da and 3ea). In
addition, other ortho-halogenated benzonitriles such as 2-
fluorobenzonitrile, 2-chlorobenzonitrile, and 2-iodobenzonitrile
all also exhibit good reactivity under the optimized conditions
(Scheme 3, 74−82%, 3aa−aa).
10
11
12
13
14
15
16
FeCl3
trace
trace
53
FeCl3
FeCl3
FeCl3
100
120
100
110
110
110
64
FeCl3
70
trace
trace
trace
80
c
17
FeCl3
FeCl3
FeCl3
d
18
e
19
a
Reactions conditions: 1a (0.5 mmol), 2a (0.5 mmol), NaN3 (2.0
mmol), CuI (10%), L-proline (20%), and catalyst (10%) were heated
b
in 3 mL of solvent in a sealed vessel under air for 12 h. Isolated yield.
c
d
e
Absence of CuI. Absence of L-proline. 30 mol % of FeCl3 was used.
tested (Table 1, entries 10−12), and DMF proved to be the most
effective solvent (Table 1, compare entries 2 and 10−12).
Increasing or decreasing the temperature of the reaction did not
lead to any further improvements in the yield (Table 1, entries
13−15). A control experiment confirmed that FeCl3, CuI, and L-
proline are indispensable elements in our catalytic system (Table
1, entries 16−18). Slightly improved efficiency was observed
when the loading of FeCl3 was increased from 10 to 30 mol %
(Table 1, entry 19). Overall, the optimized reaction conditions
were identified as 1a (0.5 mmol), 1.0 equiv of 2a, 4.0 equiv of
sodium azide, 30 mol % of FeCl3, 10 mol % of CuI, and 20 mol %
of L-proline in 3 mL of DMF at 110 °C in a sealed vessel under air.
With the optimal reaction conditions in hand, we next
investigated the scope of the domino process. A variety of
aromatic aldehydes bearing different substituents were tested,
and the results are summarized in Scheme 2. It was found that the
transformation was very general; electron-neutral (4-H, 2-Me, 4-
Me), electron-donating (4-OMe, 4-OEt, 3,4-(OMe)2), and
Notably, this method could also be successfully applied in the
convenient synthesis of 1-(2-methoxyphenyl)-3-(2-(pyridin-3-
yl)quinazolin-4-yl)urea (IV), which is a potent and selective
human adenosine A3 receptor antagonist demonstrated by van
Muijlwijk-Koezen.2d As shown in Scheme 4, the reaction of o-
bromobenzonitrile (1a) with sodium azide and nicotinaldehyde
occurred smoothly under the standard conditions to afford the
corresponding products 3ap in 77% yield. The product 3ap was
B
DOI: 10.1021/acs.orglett.5b02020
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Scheme 3. Scope of o-Halogenated Benzonitriles and Aryl
Aldehydes
Scheme 5. Control Experiments
a b
,
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), NaN3 (2.0
mmol), FeCl3 (0.15 mmol), CuI (0.05 mmol), and L-proline (0.1
mmol) in DMF (3 mL) at 110 °C in a sealed vessel under air for 12 h.
On the basis of the above observations and literature
precedent,10−19 a possible reaction mechanism of this trans-
formation was represented in Scheme 6. Initially, the sodium 5-
b
Isolated yields.
Scheme 4. Synthetic Application
Scheme 6. Possible Mechanism
subsequently transformed to pharmaceutically active molecular
IV according to the reported procedure.2d
Having established the scope of our new domino reaction, we
turned our attention to evaluate the reaction mechanism. We
initially investigated the reaction of o-bromobenzonitrile (1a)
with sodium azide (2 equiv) in DMF in the presence of FeCl3 at
110 °C for 12 h, which gave 5-(2-bromophenyl)-1H-tetrazole
(4) in 71% yield (Scheme 5a). When 5-(2-bromophenyl)-1H-
tetrazole (4) was treated with benzaldehyde (2a) and NaN3 (2
equiv) in the presence of CuI in DMF at 110 °C in a sealed vessel
under air for 12 h, the target product 2-phenylquinazolin-4-
amine (3aa) was isolated in 84% yield (Scheme 5b).
Furthermore, the reactions of 2-(1H-tetrazol-5-yl)aniline (5)
and benzaldehyde (2a) were conducted under standard
conditions, and the desired product 3aa was obtained in 83%
yield (Scheme 5c). When 5-(2-bromophenyl)-1H-tetrazole (4)
was treated with benzaldehyde (2a) and NaN3 (2 equiv) in the
presence of CuI and L-proline in DMF at 80 °C for 6 h, 5-
phenyltetrazolo[1,5-c]quinazoline (6) and 2-phenylquinazolin-
4-amine (3aa) were obtained in 51% and 27% yields, respectively
(Scheme 5d). Next, when 5-phenyltetrazolo[1,5-c]quinazoline
(6) was heated at 110 °C for 12 h in DMF in the presence of CuI
and L-proline, the substrate could be converted to the desired
product 3aa in almost quantitative yield (Scheme 5e). Taken
together, these control experiments clearly demonstrated that 5-
(2-bromophenyl)-1H-tetrazole (4), 2-(1H-tetrazol-5-yl)aniline
(5), and 5-phenyltetrazolo[1,5-c]quinazoline (6) may be key
intermediates in this reaction.
(2-bromophenyl)tetrazol-1-ide (A) was generated though an
iron-mediated [3 + 2] cycloaddition of o-bromobenzonitrile (1a)
with NaN3.10 Subsequently, intermediate A would undergo a
copper-catalyzed SNAr with NaN3 to afford intermediate B in the
light of the ortho-substituent effect.10,16 Coordination of azide to
copper, followed by an electrocyclization with the concomitant
release of N2, would give the Cu(III) complex D,17 which would
undergo a reduction with the aid of trace H2O in DMF to give
intermediate 2-(1H-tetrazol-5-yl)aniline (5).11c−e Next, 2-(1H-
1,2,3-triazol-5-yl)aniline (5) could easily condense with
benzaldehyde (2a) to give imine intermediate E. Then
intramolecular nucleophilic attack of nitrogen to imine in E
followed by oxidative dehydrogenation led to F. Eventually, the
target product 3aa was obtained after final cooper-catalyzed
denitrogenation process.18 It is also possible that 5-
phenyltetrazolo[1,5-c]quinazoline (6) and 2-(1H-tetrazol-5-
yl)aniline (5) could be formed via a synergistic oxidation−
C
DOI: 10.1021/acs.orglett.5b02020
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reduction reaction between intermediates B and F.19 Further
mechanistic studies of the detailed process of reduction and
oxidation in this reaction system are in progress.
(7) (a) Ahmad, O. K.; Hill, M. D.; Movassaghi, M. J. Org. Chem. 2009,
74, 8460−8463. (b) Yadav, M. R.; Grande, F.; Chouhan, B. S.; Naik, P.
P.; Giridhar, R.; Garofalo, A.; Neamati, N. Eur. J. Med. Chem. 2012, 48,
231−243. (c) Itoh, T.; Mase, T. Tetrahedron Lett. 2005, 46, 3573−3577.
(8) (a) Quiclet-Sire, B.; Zard, S. Z. Synthesis 2005, 19, 3319−3326.
(b) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng, X.; Zhao, M.; Chen, B. Org.
Lett. 2012, 14, 26−29. (c) Quan, X. J.; Ren, Z. H.; Wang, Y. Y.; Guan, Z.
H. Org. Lett. 2014, 16, 5728−5731.
In conclusion, we have developed a highly efficient Fe/Cu
relay-catalyzed domino reaction for the facile synthesis of
pharmaceutically significant 2-phenylquinazolin-4-amines from
commercially available ortho-halogenated benzonitriles, alde-
hydes, and sodium azide. This elegant domino process involved
consecutive iron-mediated [3 + 2] cycloaddition, copper-
catalyzed SNAr, reduction, cyclization, oxidation, and copper-
catalyzed denitrogenation sequences. Notably, sodium azide
acted as dual nitrogen source in the construction of these fused
N-heterocycles. Moreover, the free NH2 generated from this
reaction can be utilized for further manipulation. Application of
this self-sequence strategy utilizing NaN3 as a simple nitrogen
donor for the synthesis of other fascinating N-heterocycles are
underway in our laboratory.
(9) Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009, 11,
3024−3027.
(10) For selected papers, see: (a) Gawande, S. D.; Raihan, M. J.;
Zanwar, M. R.; Kavala, V.; Janreddy, D.; Kuo, C. W.; Chen, M. L.; Kuo,
T. S.; Yao, C. F. Tetrahedron 2013, 69, 1841−1848. (b) Kumar, S.;
Dubey, S.; Saxena, N.; Awasthi, S. K. Tetrahedron Lett. 2014, 55, 6034−
6038. (c) Mani, P.; Singh, A. K.; Awasthi, S. K. Tetrahedron Lett. 2014,
55, 1879−1882.
(11) (a) Zhu, W.; Ma, D. Chem. Commun. 2004, 888−889.
(b) Andersen, J.; Madsen, U.; Bjorkling, F.; Liang, X. Synlett 2005,
̈
2209−2213. (c) Markiewicz, J. T.; Wiest, O.; Helquist, P. J. Org. Chem.
2010, 75, 4887−4890. (d) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010,
75, 3311−3316. (e) Goriya, Y.; Ramana, C. V. Tetrahedron 2010, 66,
7642−7650.
ASSOCIATED CONTENT
* Supporting Information
■
S
(12) For representive papers of domino reactions initiated by [3 + 2]
cycloaddition involving NaN3, see: (a) Arigela, R. K.; Samala, S.; Mahar,
R.; Shukla, S. K.; Kundu, B. J. Org. Chem. 2013, 78, 10476−10484.
(b) Chen, Z. Y.; Wu, M. J. Org. Lett. 2005, 7, 475−477. (c) Gulevskaya,
A. V.; Tyaglivy, A. S.; Pozharskii, A. F.; Nelina-Nemtseva, J. I.; Steglenko,
D. V. Org. Lett. 2014, 16, 1582−1585. (d) Yan, J.; Zhou, F.; Qin, D.; Cai,
T.; Ding, K.; Cai, Q. Org. Lett. 2012, 14, 1262−1265.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02020.
Crystallographic data of 3aa (CIF)
Experimental procedures, product characterizations, and
copies of the 1H and 13C NMR spectra(PDF)
(13) For representive papers related to the formation of organic azide
and sequential relay of click reaction with alkynes, see: (a) Pericherla, K.;
Jha, A.; Khungar, B.; Kumar, A. Org. Lett. 2013, 15, 4304−4307.
(b) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org.
Lett. 2008, 10, 3081−3084. (c) Liu, Z.; Zhu, D.; Luo, B.; Zhang, N.; Liu,
Q.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Org. Lett. 2014, 16, 5600−5603.
(d) Qian, W.; Winternheimer, D.; Allen, J. Org. Lett. 2011, 13, 1682−
1685.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
(14) For representive papers related to the formation of organic azide
and sequential relay of intramolecular N-atom transfer reaction, see:
(a) Shang, X.; Zhao, S.; Chen, W.; Chen, C.; Qiu, H. Chem. - Eur. J. 2014,
20, 1825−1828. (b) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett.
2011, 13, 3542−3545. (c) Kim, Y.; Kumar, M. R.; Park, N.; Heo, Y.; Lee,
S. J. Org. Chem. 2011, 76, 9577−9583. (d) Goriya, Y.; Ramana, C. V.
Chem. Commun. 2013, 49, 6376−6378. (e) Li, K.; Chen, J.; Li, J.; Chen,
Y.; Qu, J.; Guo, X.; Chen, C.; Chen, B. Eur. J. Org. Chem. 2013, 2013,
6246−6248. (f) Ou, Y.; Jiao, N. Chem. Commun. 2013, 49, 3473−3475.
(g) Goriya, Y.; Ramana, C. V. Chem. Commun. 2014, 50, 7790−7792.
(15) Jia, F. C.; Xu, C.; Zhou, Z. W.; Cai, Q.; Li, D. K.; Wu, A. X. Org.
Lett. 2015, 17, 2820−2823.
(16) For papers involving the ortho-substituent effect, see: (a) Yang,
D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv. Synth. Catal. 2012, 354,
477−482. (b) Jia, F. C.; Xu, C.; Cai, Q.; Wu, A. X. Chem. Commun. 2014,
50, 9914−9916.
(17) For papers related to the Cu(III) complex, see: (a) Zhang, H.;
Zhao, L.; Wang, D. X.; Wang, M. X. Org. Lett. 2013, 15, 3836−3839.
(b) Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.; Jiang, H. Org. Lett.
2013, 15, 6254−6257. (c) Yu, D. G.; Suri, M.; Glorius, F. J. Am. Chem.
Soc. 2013, 135, 8802−8805. (d) Dhar, D.; Tolman, W. B. J. Am. Chem.
Soc. 2015, 137, 1322−1329.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21272085 and 21472056) for financial
support.
REFERENCES
■
(1) For selected papers, see: (a) 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. (b) Ugale, V. G.; Bari, S. B. Eur. J.
Med. Chem. 2014, 80, 447−501. (c) Juvale, K.; Gallus, J.; Wiese, M.
Bioorg. Med. Chem. 2013, 21, 7858−7873.
(2) (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) Omar, M. A.; Conrad, J.; Beifuss, U. Tetrahedron 2014, 70, 3061−
3072. (c) Wilson, L. J. Org. Lett. 2001, 3, 585−588. (d) van Muijlwijk-
Koezen, J. E.; Timmerman, H.; van der Goot, H.; Menge, W. M. P. B.;
Frijtag von Drabbe Kunzel, J.; de Groote, M.; IJzerman, A. P. J. Med.
̈
Chem. 2000, 43, 2227−2238.
(3) (a) El-Azab, A. S.; Al-Omar, M. A.; Abdel-Aziz, A. A. M.; Abdel-
Aziz, N. I.; El-Sayed, M. A. A.; Aleisa, A. M.; Sayed-Ahmed, M. M.;
Abdel-Hamide, S. G. Eur. J. Med. Chem. 2010, 45, 4188−4198.
(b) Marvania, B.; Lee, P. C.; Chaniyara, R.; Dong, H.; Suman, S.;
Kakadiya, R.; Chou, T. C.; Lee, T. C.; Shah, A.; Su, T. L. Bioorg. Med.
Chem. 2011, 19, 1987−1998.
(18) Shi, L. L.; Yang, H. J.; Jiang, Y. Y.; Fu, H. Adv. Synth. Catal. 2013,
355, 1177−1184.
(19) (a) Cenini, S.; Gallo, E.; Penoni, A.; Ragaini, F.; Tollari, S. Chem.
Commun. 2000, 2265−2266. (b) Ragaini, F.; Penoni, A.; Gallo, E.;
Tollari, S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem. -
Eur. J. 2003, 9, 249−259. (c) Nguyen, Q.; Nguyen, T.; Driver, T. G. J.
Am. Chem. Soc. 2013, 135, 620−623.
́
(4) Seijas, J. A.; Vazquez-Tato, M. P.; Montserrat Martínez, M.
Tetrahedron Lett. 2000, 41, 2215−2217.
(5) Yang, X.; Liu, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synlett 2010,
2010, 101−106.
(6) (a) Cargill, M. R.; Linton, K. E.; Sandford, G.; Yufit, D. S.; Howard,
J. A. K. Tetrahedron 2010, 66, 2356−2362. (b) Yan, S.; Dong, Y.; Peng,
Q.; Fan, Y.; Zhang, J.; Lin, J. RSC Adv. 2013, 3, 5563−5569.
D
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