Efficient aerobic oxidative synthesis of 2-aryl quinazolines via benzyl C-H bond amination catalyzed by 4-hydroxy-TEMPO

Article abstract of DOI:10.1039/c1cc12308d

A novel and efficient aerobic protocol for the oxidative synthesis of 2-aryl quinazolines via benzyl C-H bond amination by a one-pot reaction of arylmethanamines with 2-aminobenzoketones and 2-aminobenzaldehydes has been carried out using the 4-hydroxy-TEMPO radical as the catalyst, without any metals or additives.

Full text of DOI:10.1039/c1cc12308d

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COMMUNICATION
Efficient aerobic oxidative synthesis of 2-aryl quinazolines via benzyl
C–H bond amination catalyzed by 4-hydroxy-TEMPOwz
Bing Han,* Chao Wang, Run-Feng Han, Wei Yu,* Xiao-Yong Duan, Ran Fang and
Xiu-Long Yang
Received 20th April 2011, Accepted 17th May 2011
DOI: 10.1039/c1cc12308d
A novel and efficient aerobic protocol for the oxidative synthesis
of 2-aryl quinazolines via benzyl C-H bond amination by a one-
pot reaction of arylmethanamines with 2-aminobenzoketones
and 2-aminobenzaldehydes has been carried out using the
4-hydroxy-TEMPO radical as the catalyst, without any metals
or additives.
TEMPO.6 As an extension of this chemistry, we attempted to
synthesize 2-aryl quinazolines by a one-pot aerobic reaction of
arylmethanamines with 2-aminobenzoketones and 2-amino-
benzaldehydes using TEMPO as the catalyst.
The study was initiated by treating a mixture of 2-amino-
benzophenone 1a (1 equiv.) and benzylamine 2a (1.5 equiv.) in
o-xylene with a stoichiometric amount of 4-hydroxy-TEMPO
3 as the oxidant7 at 120 1C in an argon atmosphere. As
expected, the desired reaction took place, leading to the
formation of the product 2,4-diphenylquinazoline 4aa in
excellent yield (Scheme ESI-1 and Table ESI-1 in ESIz).8
4-Hydroxy-TEMPO 3 was converted to 4-hydroxy-TEMPOH
during the reaction. As 4-hydroxy-TEMPOH can be oxidized
quantitatively to 3 by oxygen or air, a strategy for the aerobic
catalytic oxidative synthesis of 2-aryl quinazolines using 3 as
the catalyst was developed.
The aminoxyl radical TEMPO (2,2,6,6-tetramethylpiperidine-
1-oxyl radical) has been proven to be a powerful promoter for
the aerobic oxidation of alcohols.1 However, its application in
C–H bond activation/functionalization2 and the synthesis of
heterocycles is rarely reported. Herein, we wish to report a
novel and efficient approach for the aerobic oxidative synthesis
of 2-aryl quinazolines via benzyl C–H bond amination using
the 4-hydroxy-TEMPO radical as the catalyst (Scheme 1), by a
one-pot reaction of arylmethanamines with 2-aminobenzo-
ketones and 2-aminobenzaldehydes.
In order to optimize the reaction conditions, we used
various solvents and discovered that nonpolar aromatic
solvents gave better results than polar solvents under the same
reaction conditions (Table 1, entries 1–6). Such a phenomenon
is in accordance with our previous observations.6 In addition,
the reaction temperature significantly affected the reaction, as
high temperatures accelerated the rate of hydrogen abstraction
between the TEMPO radical and the substrate (Table 1,
entries 3 and 5–7). Moreover, the amount of the solvent also
affected the reaction rate, as a high reaction concentration
could facilitate the oxidative process (Table 1, entry 8). It is
noteworthy that using 15–20 mol% of 3 as the catalyst would
guarantee excellent yields of 4aa (Table 1, entries 6, 7 and 9),
while the reaction could not proceed in the absence of 3 under
the same conditions, indicating that 3 is the key catalyst in the
reaction (Table 1, entry 11). In addition, another aminoxyl
radical precursor NHPI (N-hydroxy-phthalimide) was also
tested in the reaction (Table 1, entries 12–14). Recently, NHPI
has been widely used for the C–H oxidation of hydrocarbons
Six-membered heterocycles, such as quinazolines, are
present in natural products and synthetic pharmaceutical
compounds.3 Substituted quinazolines have been synthesized
by a number of methods involving a variety of substrates.4
Recently, facile approaches for the synthesis of 2-phenyl
quinazolines using 2-aminobenzoketones and benzylamines
as the starting materials and TBHP (tert-butyl hydroperoxide)
as the oxidant promoted by iodine or copper nanoparticles
have been reported.5 Although accessible starting materials
were used and good yields were obtained, a stoichiometric and
non-renewable oxidant is still needed and the reaction scale
and substrate applicability are limited. Therefore, a more
effective and environmentally friendly process is needed.
Catalytic oxidative reactions using oxygen as the terminal
oxidant have received much attention in view of the concepts
of green chemistry and atom economy. Recently, we devel-
oped an efficient aerobic oxidative process for the synthesis of
benzoxazoles, benzimidazoles and benzothiazoles catalyzed by
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of
China. E-mail: hanb@lzu.edu.cn, yuwei@lzu.edu.cn
w Dedicated to Professor Zhong-Li Liu on the occasion of his
70th birthday.
z Electronic supplementary information (ESI) available: General
information, experimental details, characterization data for the
products. See DOI: 10.1039/c1cc12308d
Scheme 1 TEMPO-mediated benzyl C–H bond oxidation and C–N
bond formation.
c
7818 Chem. Commun., 2011, 47, 7818–7820
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Table 1 Optimization of the catalytic aerobic oxidative synthesis of
2-aryl quinazolinea
Table 2 The catalytic aerobic reaction of 2-aminobenzoketones and
2-aminobenzaldehydes with benzylaminea
Entry
Product
R
t/h
Yieldb (%)
1
2
3
4
(1a) H
13
24
15
11
91, 80c (4aa)
63 (4ba)
88 (4ca)
Entry
Catalyst (mol%)
Solvent
T/1C
Yieldb (%)
(1b) 2,5-di-Me
(1c) 4-MeO
(1d) 4-Br
1
2
3
4
5
6
7
8
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (20)
3 (15)
3 (10)
—
NHPI (10)
NHPI (10)
NHPI (10)
MeCN
80
80
80
0c
ethyl acetate
benzene
t-butanol
toluene
o-xylene
o-xylene
o-xylened
o-xylene
o-xylene
o-xylene
MeCN
0c
91 (4da)
tracec
0c
120
100
120
140
140
140
140
140
80
91, 88d (4ea)
43
87
91
35
88
66e
0
5
(1e)
10
6
7
8
9
10e
11e
12e
13e
14e
15e
(1f) Et
7
9
7
10
57 (4fa)
70 (4ga)
60 (4ha)
78 (4ia)
(1g) n-Bu
(1h) i-Pr
(1i) s-Bu
9
10
11
12
13
14
0c
(1j) 6,8-di-Br
(1j) 6,8-di-Br
(1k) 6-NO2
(1l) 6-CO2CH3
(1m) 7-CO2CH3
(1n) H
10
10
4
6
6
0f (4ja)
o-xylene
PhCl
140
140
0c
80, 73d (4ja)
65 (4ka)
65 (4la)
0c
a
A mixture of 2-aminobenzophenone 1a (1 mmol), benzylamine 2a
(3 mmol), catalyst (0.1–0.2 mmol) and solvent (0.3 mL) was stirred for
60 (4ma)
70 (4na)
4
b
13 h under O2 at different temperatures. Isolated yield based on
a
c
substrate 1. TLC analysis. 3 mL solvent was used. After 24 h.
d
e
A
mixture of 2-aminobenzoketone or 2-aminobenzaldehyde 1
(1 mmol), benzylamine 2a (3 mmol), 4-hydroxy-TEMPO 3 (0.2 mmol)
b
and o-xylene (0.3 mL) was stirred under O2 at 140 1C. Isolated yield
based on substrate 1. Gram scale. 0.15 mmol of 3 was used. At
c
d
e
and alcohols by an in situ generated PINO (phthalimido-
N-oxyl) radical under oxygen atmosphere1a–c,9 and we also
reported its application in the aerobic oxidative dehydrogenation
of dihydropyridines and pyrazolines.10 However, NHPI is
inefficient in the reaction because it would be deactivated by
benzylamine.11 Therefore, 15–20 mol% of 3 was used in the
following reaction.
f
120 1C. In the absence of 3.
Table 3 The catalytic aerobic reaction of 2-aminobenzoketones and
2-aminobenzaldehydes with arylmethanaminesa
The 4-hydroxy-TEMPO-catalyzed aerobic oxidative process
was not only suitable for 2-aminobenzoketones but also for
2-aminobenzaldehydes. 2-Aminobenzoaryl and alkyl ketones
(1a–1i) gave excellent yields of 4-aryl and 4-alkyl quinazolines
(Table 2, entries 1–9), respectively, and 2-aminobenzaldehydes
(1j–1n) participated in the reaction to give the corresponding
4-H quinazolines in good yields (Table 2, entries 10–15).
Notably, the aerobic oxidative reaction could also be easily
carried out on a gram scale without difficulty, thereby delivering
4aa in good yield.
Entry
Substrate 1
R3
t/h
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
3-MeC6H4 (2d)
2-MeC6H4 (2e)
4-ClC6H4 (2f)
2-ClC6H4 (2g)
4-FC6H4 (2h)
15
10
12
13
13
14
20
13
90, 87c (4ab)
88 (4ac)
80 (4ad)
70 (4ae)
88 (4af)
77 (4ag)
73 (4ah)
82 (4ai)
4-Substituted benzylamines (2a–2h) with a range of electronic
properties also gave the corresponding quinazolines (Table 3).
Weak steric effects were observed when ortho, meta and para-
substituted benzylamines were used in the reaction (Table 3,
entries 2–6). In addition, a heterocyclic methanamine, such
as 3-picolylamine (2i), could also be used in the reaction,
resulting in 2-(3-picolyl)-4-phenyl quinazoline in excellent
yields (Table 3, entry 9).
3-pyridinyl (2i)
9
10
4-MeC6H4 (2c)
4-ClC6H4 (2f)
12
13
70 (4ic)
65, 57c (4if)
11d
12d
4-MeC6H4 (2c)
4-FC6H4 (2h)
8
73, 62c (4jc)
70, 62c (4jh)
15
To gain some insight into the mechanism of the above-
mentioned process, the intermolecular kinetic isotopic effects
(KIE) were measured through a competition process, by
subjecting 1j to a 1 : 1 mixture of 2a and 2a–d7 (Scheme 2).
The relative rate constant of 2a to 2a–d7 was determined to be
20.3,12 indicating that the hydrogen atom abstraction from the
benzyl C–H bond of the imines A by TEMPO is a rate-
determining step during the oxidation process. The measured
high value of KIE also suggests a possible involvement of the
13d
4-MeC6H4 (2c)
10
71, 64c (4lc)
a
A
(1 mmol), arylmethanamine
mixture of 2-aminobenzoketone or 2-aminobenzaldehyde
(3 mmol), 4-hydroxy-TEMPO
1
3
2
(0.2 mmol) and o-xylene (0.3 mL) was stirred under O2 at 140 1C.
b
c
d
Isolated yield based on substrate 1. 0.15 mmol of 3 was used. At
120 1C.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7818–7820 7819

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We thank the National Natural Science Foundation of China
(20902040) and the Fundamental Research Funds for the
Central Universities (lzujbky-2009-74) for financial support.
Notes and references
Scheme 2 The kinetic isotope effect (KIE) experiment.
1 For reviews, see: (a) R. A. Sheldon and I. W. C. E. Arends, Adv.
Synth. Catal., 2004, 346, 1051; (b) R. A. Sheldon, I. W. C. E
Arends, G.-J. Brink and A. Dijksman, Acc. Chem. Res., 2002,
35, 774; (c) C. Galli, P. Gentili and O. Lanzalunga, Angew. Chem.,
Int. Ed., 2008, 47, 4790; (d) T. Vogler and A. Studer, Synthesis,
2008, 1979; (e) J. Piera and Jan-E. Backvall, Angew. Chem., Int.
Ed., 2008, 47, 3506; (f) L. Tebben and A. Studer, Angew. Chem.,
Int. Ed., 2011, 50, 5034. Selected examples, see: (g) R. Liu,
X. Liang, C. Dong and X. Hu, J. Am. Chem. Soc., 2004, 126, 4112;
(h) X. Wang, R. Liu, Y. Jin and X. Liang, Chem.–Eur. J., 2008,
14, 2679.
2 (a) J. E. Babiarz, G. T. Cunkle, A. D. DeBellis, D. Eveland,
S. D. Pastor and S. P. Shum, J. Org. Chem., 2002, 67, 6831;
(b) T. J. Connolly and J. C. Scaiano, Tetrahedron Lett., 1997, 38, 1133.
3 For examples in medicinal chemistry, see: (a) A. Foster,
H. A. Coffrey, M. J. Morin and F. Rastinejad, Science, 1999,
286, 2507; (b) R. Gundla, R. Kazemi, R. Sanam, R. Muttineni,
J. A. R. P. Sarma, R. Dayam and N. Neamati, J. Med. Chem.,
2008, 51, 3367; (c) A. Luth and W. Lowe, Eur. J. Med. Chem.,
2008, 43, 1478.
4 For recent reviews, see: (a) D. J. Connolly, D. Cusack, T. P. O’Sullivan
and P. J. Guiry, Tetrahedron, 2005, 61, 10153; (b) J. P. Michael, Nat.
Prod. Rep., 2008, 25, 166; (c) A. Witt and J. Bergman, Curr. Org.
Chem., 2003, 7, 659. Selected examples: (d) D. S. Yoon, Y. Han,
T. M. Stark, J. C. Haber, B. T. Gregg and S. B. Stankovich, Org. Lett.,
2004, 6, 4775; (e) S. Ferrini, F. Ponticelli and M. Taddei, Org. Lett.,
2007, 9, 69; (f) U. Maheswari, S. Kumar, M. Venkateshwar, R. Arun
Kumar, L. Kantam and R. Reddya, Adv. Synth. Catal., 2010, 352, 341;
(g) Y. Ohta, Y. Tokimizu, S. Oishi, N. Fujii and H. Ohno, Org. Lett.,
2010, 12, 3963.
Scheme 3 A plausible mechanism for the 4-hydroxy-TEMPO-catalyzed
aerobic oxidative synthesis of 2-aryl quinazolines.
quantum tunneling effect. Similar KIE was observed for the
reaction of ethyl benzene with PINO radical.13
5 (a) J. Zhang, C. Yu, S. Wang, C. Wan and Z. Wang, Chem.
Commun., 2010, 46, 5244; (b) J. Zhang, D. Zhu, C. Yu, C. Wan and
Z. Wang, Org. Lett., 2010, 12, 2841.
Based on the above observations, we propose a plausible
mechanistic pathway for the present oxidation. We believe
that 4-hydroxy-TEMPO 3 initially abstracts a hydrogen atom
from the benzyl C–H bond of compound A to produce the
a-amino benzyl radical B and 4-hydroxy-TEMPOH, which
can be reoxidized to 3 by oxygen. The a-amino benzyl radical
B is further oxidized by 3 via single-electron transfer (SET) to
produce carbocation intermediate C,14 which is attacked by
the amino group via intramolecular cyclization and sub-
sequent deprotonation to form the corresponding compound
1,2-dihydroquinazoline 5.15 The 4-hydroxy-TEMPO anion
traps a proton to form 4-hydroxy-TEMPOH, which can be
reoxidized to 3 by oxygen. Next, 5 can be easily aromatized
to the target compound quinazolines 4 by 3 or oxygen.
A proposed oxidative cycle is shown in Scheme 3.
6 Y.-X. Chen, L.-F. Qian, W. Zhang and B. Han, Angew. Chem.,
Int. Ed., 2008, 47, 9330.
7 For TEMPO or 4-substituted TEMPO used as an oxidant, see:
(a) M. S. Maji, T. Pfeifer and A. Studer, Angew. Chem., Int. Ed.,
2008, 47, 9547; (b) J. Guin, S. D. Sarkar, S. Grimme and A. Studer,
Angew. Chem., Int. Ed., 2008, 47, 8727; (c) M. S. Maji, S. Murarka
and A. Studer, Org. Lett., 2010, 12, 3878.
8 The same results were obtained when TEMPO or 4-methoxy-
TEMPO were used as the oxidant instead of 4-hydroxy-TEMPO
in the reaction (see electronic supplementary informationw),
however, the separation of the product quinazoline from TEMPO
or 4-methoxy-TEMPO is not easy due to their similar polarity.
Therefore, 4-hydroxy-TEMPO is more suitable for the reaction
due to its high polarity.
9 For reviews, see: (a) Y. Ishii, S. Sakaguchi and T. Iwahama,
Adv. Synth. Catal., 2001, 343, 393; (b) F. Recupero and
C. Punta, Chem. Rev., 2007, 107, 3800.
10 (a) B. Han, Q. Liu, Z.-G. Liu, R.-Z. Mu, W. Zhang, Z.-L. Liu and
W. Yu, Synlett, 2005, 2333; (b) B. Han, Z.-G. Liu, Q. Liu, L. Yang,
Z.-L. Liu and W. Yu, Tetrahedron, 2006, 62, 2492.
In conclusion,
a novel, efficient and environmentally
friendly one-pot approach for the aerobic oxidative synthesis
of 2-aryl quinazolines via benzyl C–H bond amination, using
2-aminobenzoketones or 2-aminobenzaldehydes and aryl-
methanamines as the accessible starting materials and
catalyzed by 4-hydroxy-TEMPO, was successfully developed.
In addition, a mechanistic proposal is made on the basis of the
kinetic isotope effects and isolation of the reaction inter-
mediate 1,2-dihydroquinazoline. The extension of this catalytic
system for the preparation of other useful heterocycles is under
way in our laboratory.
11 For the deactivation of NHPI by primary amines, see:
A. Cecchetto, F. Minisci, F. Recupero, F. Fontana and G. F.
Pedulli, Tetrahedron Lett., 2002, 43, 3605.
12 See supplementary information for detailsw.
13 J. M. Lee, E. J. Park, S. H. Cho and S. Chang, J. Am. Chem. Soc.,
2008, 130, 7824.
14 For the oxidation of the a-amino carboradical to the carbocation
by TEMPO via SET, see ref. 1b.
15 1,2-Dihydroquinazoline 5 was obtained as the reaction inter-
mediate and could be oxidized easily to quinazoline 4 using
TEMPO or oxygen as the oxidant. For details, see electronic
supplementary informationw.
c
7820 Chem. Commun., 2011, 47, 7818–7820
This journal is The Royal Society of Chemistry 2011