A simple and efficient approach to the synthesis of 2-phenylquinazolines via sp3 C-H functionalization

Article abstract of DOI:10.1021/ol100954x

(Figure presented) A facile and novel approach to the synthesis of 2-phenylquinazolines was developed via a tandem reaction following sp ³ C-H functionalization. Twenty-five examples of 2-phenylquinazolines were obtained from easily available 2-aminobenzophenones and benzylic amines with good to excellent yields.

Full text of DOI:10.1021/ol100954x

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2841-2843
A Simple and Efficient Approach to the
Synthesis of 2-Phenylquinazolines via
sp3 C-H Functionalization
Jintang Zhang, Dapeng Zhu, Chenmin Yu, Changfeng Wan, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry and Department of Chemistry, UniVersity of Science and
Technology of China, Hefei, 230026, P. R. China
zwang3@ustc.edu.cn
Received April 27, 2010
ABSTRACT
A facile and novel approach to the synthesis of 2-phenylquinazolines was developed via a tandem reaction following sp3 C-H functionalization.
Twenty-five examples of 2-phenylquinazolines were obtained from easily available 2-aminobenzophenones and benzylic amines with good to
excellent yields.
Transition-metal-catalyzed C-H functionalization and sub-
sequent formation of C-N bonds have attracted worldwide
interest in recent years.1 Although many excellent results
have been achieved, various transition-metal catalysts are
always essential to the C-H functionalization, such as
catalysts of Ru, Rh, Ir, Pt, Pd, Mg, etc. (Scheme 1).1c There
are only a few examples on C-H functionalization under
transition-metal-free conditions.2 In addition, the application
of C-H functionalization in tandem reactions has been scarce
until now.
depend on the availability of the indispensable 2-aminoben-
zoic acid or 2-nitrobenzoic acid derivatives or 2-aminoben-
zonitrile or 2-nitrobenzonitrile derivatives or 2-halophenyl
precursors. The availability of these special starting materials
restricts the application of these methods.
Scheme 1. Methods for C-H Functionalization
On the other hand, quinazoline derivatives have drawn
much attention for their various biological and medicinal
activities, and they can be used as anticonvulsant, antibacte-
rial, antidiabetic, anticarcinogen, and other biological or
medicinal agents.3 Although there are a number of well-
established methods to prepare quinazolines,3a,4 they mainly
Recently, we reported an efficient nonmetal catalytic
oxidation system by using molecular iodine.5 Herein, based
(1) For selected reviews, see: (a) Lyons, T. W.; Sanford, M. S. Chem.
ReV. 2010, 110, 1147–1169. (b) Godula, K.; Sames, D. Science 2006, 312,
67–72. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463.
(d) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061–5074.
(e) Li, C.-J. Acc. Chem. Res. 2008, 42, 335–344.
(3) For selected reviews, see: (a) Witt, A.; Bergman, J. Curr. Org. Lett.
2003, 7, 659–677. (b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166–187.
(c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223–246.
(2) (a) Tu, W. Y.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed.
2008, 47, 4184–4187. (b) Fan, R. H.; Li, W. X.; Pu, D. M.; Zhang, L. Org.
Lett. 2009, 11, 1425–1428. (c) Bajracharya, G. B.; Daugulis, O. Org. Lett.
2008, 10, 4625–4628. (d) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006,
128, 4242–4243.
(4) For selected examples, see: (a) Connolly, D. J.; Cusack, D.;
O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153–10202. (b)
Liu, X. W.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Angew. Chem., Int. Ed. 2009,
48, 348–351. (c) Li, J. R.; Chen, X.; Shi, D. X.; Ma, S. L.; Li, Q.; Zhang,
Q.; Tang, J. H. Org. Lett. 2009, 11, 1193–1196.
10.1021/ol100954x  2010 American Chemical Society
Published on Web 05/18/2010

on this result, we developed a simple and efficient approach
to the synthesis of 2-phenylquinazolines with this catalytic
oxidation system. Various 2-phenylquinazolines were pre-
pared from 2-aminobenzophenones and benzylic amines via
a tandem reaction following sp3 C-H functionalization under
metal-free conditions.
were optimized, the reaction yield was finally improved to
94% (Table 1, entries 11-17). Therefore, the optimal
reaction conditions were obtained; that is, the mixture of
2-aminobenzophenone (1a) and 2 equiv of benzylic amine
(2a) was heated at 90 °C for 12 h with 10 mol % of iodine
as catalyst and 2 equiv of TBHP as oxidant (Table 1, entry
16).
Subsequently, we investigated the scope of the reaction
substrates under the optimized conditions, as shown in Table
2. Compound 3aa without any substitution on the phenyl
rings was obtained with an isolated yield of 91% (Table 2,
entry 1). The introduction of electron-withdrawing group to
the para position of the free phenyl ring of 2-aminoben-
zoketone affected the reaction slightly. For instance, 3ba and
3ca could give similar yields to 3aa (Table 2, entries 2 and
3). When this phenyl ring bore an electron-donating group
at the para position, such as a methyl group, there was a
negative effect on the reaction and the corresponding reaction
yield was decreased to 78% (Table 2, entry 4). When the
ortho position of the phenyl ring was occupied with a methyl
group, the reaction yield was decreased further to 73% (Table
2, entry 5). This implied steric effect had an adverse influence
on the reaction, as was verified with the failure when 2,4,6-
trimethyl substitution on the phenyl ring was employed as a
Initially, when 2-aminobenzophenone (1a) was treated
with 2 equiv of benzylic amine (2a), 5 mol % of iodine and
Table 1. Optimization of the Reaction Conditions for the
Construction of Quinazolinea
I2
BnNH2
(equiv)
TBHP
(equiv)
temp
(°C)
yieldb
(%)
entry
(mol %)
1c
2
3
5
5
2
2
2
2
2
2
2
2
2
2
2
d
2
2
2
2
2
2
2
2
2
1.5
2.5
2
80
80
80
80
80
80
80
80
90
100
90
90
90
90
90
90
90
42
49
0
5
42
0
4
5
5
5
5
5
5
5
5
5
5
5
5
10
20
5e
6f
7g
8h
9
0
0
Table 2. Reaction of Different 2-Aminobenzoketones with
2
2
83
84
72
87
86
78
89
94
87
Benzylic Aminea
10
11
12
13
14
15
16
17
1.5
2.5
3
2.5
2.5
2.5
2.5
2
a Reaction conditions: 1a (0.2 mmol) and 2a were heated with I2 and
TBHP for 12 h. b Yield was determined by GC-MS based on peak areas.
c 5 mol % of pyridine was added. e 30% of aqueous H2O2 was used as
oxidant. 0.2 mL of solvent was added. d Solvent: MeCN. f Solvent: water.
g Solvent: t-BuOH. h Solvent: dioxane.
pyridine, and 2 equiv of aqueous tert-butyl hydroperoxide
(TBHP) at 80 °C for 12 h, 42% of 3aa was obtained (Table
1, entry 1). In the absence of pyridine, the reaction can give
a higher yield (Table 1, entry 2). Without iodine, no product
was observed (Table 1, entry 3). Then other environmental
benign oxidants, such as t-BuOOt-Bu, aqueous H2O2, and
oxygen, were also examined, but only aqueous H2O2 can
generate a trace amount of the product (Table 1, entry 4).
No better result was observed when various solvents were
introduced to the reaction (Table 1, entries 5-8). Raising
the reaction temperature to 90 °C can increase the reaction
yield to 83%. Further raising the reaction temperature cannot
enhance the reaction yield obviously (Table 1, entries 9 and
10). After the ratios of iodine, benzylic amine, and TBHP
a Reaction conditions: 1 (0.2 mmol), 2a (0.5 mmol), I2 (10 mol %), and
TBHP (0.4 mmol) were heated at 90 °C for 12 h. b Isolated yields. c The
starting material was recovered. d The starting material was converted to a
complex mixture.
(5) (a) Zhang, J. T.; Wang, Z. T.; Wang, Y.; Wan, C. F.; Zheng, X. Q.;
Wang, Z. Y. Green Chem. 2009, 11, 1973–1978. (b) Wan, C. F.; Wan,
C. F.; Zhang, J. T.; Wang, S. J.; Fan, J. M.; Wang, Z. Y. Org. Lett.
2010,DOI: 10.1021/ol100688c.
2842
Org. Lett., Vol. 12, No. 12, 2010

reaction substrate (Table 2, entry 6). This phenyl ring of
2-aminobenzoketone was then replaced with different ali-
phatic alkyl groups. Although 3ga was not obtained, other
alkyl substitutions, including straight chains with different
lengths, branched chains, and cycloalkyl, provided the desired
products with good yield (Table 2, entries 7-13). It was
noteworthy that an unsaturated carbon-carbon bond can also
survive the reaction (Table 2, entry 14). Different substituents
on the anilino ring of 2-aminobenzoketone were also
examined. The chloro or bromo group had little influence
on the result (Table 2, entries 15 and 16), while the electron-
donating group disfavored the reaction obviously (Table 2,
entry 17). Finally, when 2-amino-5-chlorobenzaldehyde was
employed as a substrate, the reaction also provided the
desired product with a yield of 43% (Table 2, entry 18).
The generality of benzylic amines was also examined, as
shown in Table 3. Generally, different benzylic amines could
give the corresponding products with good to excellent
yields. When a methyl group was moved from the para
position to the ortho position of benzylic amine, the yield
was reduced from 90% to 81% (Table 3, entries 1-3), which
indicated that steric hindrance disfavored this reaction. When
electron-donating groups were introduced to the phenyl ring
of benzylic amine, the yield decreased further (Table 3,
entries 4 and 5). However, when electron-withdrawing
groups, such as bromo-, fluoro-, and trifluoromethyl-, were
introduced to the phenyl ring of benzylic amine, good results
were obtained (Table 3, entries 6-8). Moreover, naphthalen-
1-ylmethanamine was also a suitable substrate for this
reaction, providing the desired product with a yield of 63%
(Table 3, entry 9).
A tentative mechanism was proposed in Scheme 2. First,
intermediate I can be generated from 2-aminobenzophenone
(1a) and benzylic amine (2a). Subsequently, I is oxidized
to intermediate III via sp3 C-H functionalization under the
reaction conditions.6 Then intermediate III is converted to
the quinazoline product after intramolecular cyclization and
further oxidization in tandem process (Scheme 2).7
Scheme 2. Tentative Reaction Mechanism
In conclusion, a facile and efficient approach to the
synthesis of 2-phenylquinazolines was developed via a
tandem reaction following sp3 C-H functionalization. Vari-
ous 2-phenylquinazolines were obtained from easily available
2-aminobenzophenones and benzylic amines. This new
method can avoid the use of hazard reagents or any kind of
metal. A detailed investigation of the mechanism and the
application of this reaction are currently in progress in our
laboratory.
Table 3. Reaction of 2-Aminobenzophenone with Different
Benzylic Aminesa
Acknowledgment. We are grateful to the Natural Science
Foundation of China (20932002, 20972144, 20628202,
20772188 and 90813008), the Chinese Academy of Sciences,
and the Graduate Innovation Fund of USTC for support.
entry
R
product
yieldb (%)
1
2
3
4
5
6
7
8
9
p-tolyl
m-tolyl
o-tolyl
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
90
88
81
78
71
88
82
91
63
Supporting Information Available: Experimental details
and compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org
4-methoxyphenyl
benzo[d][1,3]dioxol-5-yl
4-chlorophenyl
4-fluorophenyl
4-(trifluoromethyl)phenyl
naphthalen-1-yl
OL100954X
(6) This may undergo a similar procedure to that proposed by C. J. Li.:
(a) Li, Z. P.; Li, C. J. J. Am. Chem. Soc. 2004, 126, 11810–11811. (b) Li,
Z. P.; Li, C. J. J. Am. Chem. Soc. 2005, 127, 3672–3673.
(7) Intermediate I was prepared according to the literature and could
be converted to the desired product completely under the reaction
conditions.
3aj
a Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), I2 (10 mol %), and
TBHP (0.4 mmol) were heated at 90 °C for 12 h. b Isolated yields.
Org. Lett., Vol. 12, No. 12, 2010
2843