Rh(III)-catalyzed oxidative ortho -C-H alkylation of 2,4-diarylquinazoline with potassium alkyltrifluoroborates

Article abstract of DOI:10.1139/cjc-2017-0258

Alkyltrifluoroborates were used for Rh(III)-catalyzed ortho-alkylation of 2,4-disubstituted quinazoline via C-H bond activation. The reaction proceeded well with a broad substrate scope, providing a direct way to access high functional quinazoline core structure derivatives in yields up to 95%.

Full text of DOI:10.1139/cjc-2017-0258

Page 1 of 28
Rh(III)ꢀcatalyzed oxidative orthoꢀC−H alkylation of
2
,4ꢀdiarylquinazoline with potassium alkyltrifluoroborates
a,b
b
a
a
b
a
Wei Gao , Chun Gong , Qin Yang , Jianjun Yuan , Linchu Xu , Yiyuan Peng*
a
Key Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi
Province’s Key Laboratory of Green Chemistry, and Jiangxi Normal University, Nanchang,
Jiangxi 330022, China.
b
Jiangxi academy of forestry, Nanchang, Jangxi 330013, China.
*Corresponding author. Eꢀmail address: yypeng@jxnu.edu.cn

Page 2 of 28
Abstract
Alkyltrifluoroborates were used for Rh(III)ꢀcatalyzed orthoꢀalkylation of
,4ꢀdisubstituted quinazoline via CꢀH bond activation. The reaction proceeded well
2
with a broad substrate scope, providing a direct way to access high functional
quinazoline core structure derivatives in yields up to 95%.
Keywords：2,4ꢀdiarylquinazoline, alkylation, potassium alkyltrifluoroborates

Page 3 of 28
Introduction
The alkyl group, as one of the most common building blocks in small organic
1
molecules, plays an vital role in a myriad of biological processes. The introduction of
a alkyl group, especially methyl, to a natural skeleton compound is also an essential
process in organic and medicinal chemistry, due to its presence may alter the
2
biological and physical properties of organic compounds. The traditional methylating
reagents, such as methyl iodide, dimethyl sulfate, diazomethane and dimethyl
3
carbonate are still widely used in industry as well as in academic. However, these
hazardous and toxic alkylating reagents require strongly basic reaction conditions and
frequently give both monoꢀ and diꢀalkylated products. In the past decades, for
chemists, much attention has been devoted to the development of new alkylating
4
5
6
7
8
reagents. For example, alkyl halides, alkylzinc halides, alcohols, alkanes, alkenes,
9
10
11
12
13
14
allyl acetates, amides, amino acids, ethers, epoxides, nitroalkanes, organotin
15
16
17
18
reagents, peroxides, αꢀdiazoesters, and organoboron reagents have been
reported as transitionmetalꢀcatalyzed alkylation reagents. Among them, organoboron
reagents owing to the advantage of commercial availability and excellent stability to
air and moisture, have been extensively employed in CꢀH alkylation ever since a
18a
series of reports about alkylation of arenes by Yu group in 2006.
In recent years, Rh(III)ꢀcatalyzed reactions have been widely used in CꢀH
1
9
20
activation of arenes with the coupling partners such as alkenes, alkynes, ketones
2
1
22
23
24
25
26
and aldehydes, imines, azides, isocyanates, azides, and strained rings.
However, there are only limited reports on rhodium catalyzed CꢀH activation of

Page 4 of 28
arenes with organoboron. Li and coꢀworkers revealed that aryl pyridine could be
alkylated with alkyltrifluoroborates under rhodium catalysis in the presence of silver
1
8g
salt in 2015. Recently, Liu reported the Rh(III)ꢀcatalyzed siteꢀselective CꢀH
1
8h
alkylation of pyridones using organoboron reagents. Soon afterward, our group
disclosed rhodium(III)ꢀcatalyzed orthoꢀCꢀH alkylation of 2ꢀarylbenzothiazoles and
18i
2
ꢀarylthiazoles with potassium alkyltrifluoroborates.
Quinazoline or quinazolinone core structures are known as kinds of important
27
potential biological active compounds. In 2012, Durga reported a simple route to
2
7d
2
,4ꢀdisubstituted quinazolines in aqueous medium. In order to obtain methylated
quinazoline, we use the traditional method to synthesize
ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀphenylquinazoline (Scheme 1). However, the desired
2
product was isolated in less than 5% yield due to steric effects. Therefore, more
effective methods for the synthesis of 2ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀphenylquinazoline
are desirable. Recently, we have synthesized selectively alkylation and amidation
quinazoline derivatives by rhodiumꢀcatalyzed regioselective direct CꢀH activation of
2
8
2
,4ꢀdiarylquinazoline. Based on these precedents, we here want to report
Rh(III)ꢀcatalyzed ortho directing oxidative CꢀH alkylation of 2,4ꢀdiarylquinazoline
with potassium alkyltrifluoroborates for synthesis of
2
ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀphenylquinazoline.
Ph
N
O
CHO
Ph
N
AcONH4
+
o
H O, 75 C
NH2
2
yield < 5%
Scheme 1. Synthesis of 2ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀphenylquinazoline with traditional method

Page 5 of 28
Experimental
General information
All solvents were dried and distilled according to standard procedures. All reactions
were formed in reaction tubes. The Flash column chromatography was performed
using silica gel (60 Åpore size, 32ꢀ63 mm, standard grade). Analytical thinꢀlayer
chromatography was performed using glass plates preꢀcoated with 0.25mm 230ꢀ400
mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer
chromatography plates were visualized by exposure to ultraviolet light. Organic
solutions were concentrated on rotary evaporators at 0ꢀ20 Torr (house vacuum) at
0
2
5ꢀ35 C. Nuclear magnetic resonance (NMR) spectra are recorded in parts per
million from internal tetramethylsilane (TMS) on the δ scale. HRMS was measured
on TOF mass spectrometer equippedwith an ESI source.
General procedure
*
2
,4ꢀdiphenylquinazoline 1a (0.2 mmol), MeBF K 2a (0.8 mmol), [RhCp Cl ]
3
2 2
(
4.0 mol %), AgSbF
6
(16 mol %) and Ag
2
CO
3
(0.36 mmol) in DCE (3 mL). After
sealed, the tube was heated to 85℃. After completion of the reaction as indicated by
TLC, the reaction mixture was extracted with EtOAc (3 mL*3). The combined
2 4
organic layers were dried over Na SO , filtered and concentrated in vacum. The crude
residue was purified by flash column chromatograph (EtOAc/Petroleum ether = 1:20)
to give the desired product 3a, as a light yellow solid.
2
-(2,6-dimethylphenyl)-4-p-tolylquinazoline(4a). Yellow solid, 91% yield, mp =
1
1
66ꢀ168 ℃. H NMR (400 MHz, CDCl ) δ 8.11 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4
3

Page 6 of 28
Hz, 1H), 7.80 (t, J = 7.6Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.7 Hz, 1H),
.26 (d, J = 7.8Hz, 2H), 7.15ꢀ.07 (m, 1H), 7.02 (d, J = 7.6Hz, 2H), 2.35 (s, 3H), 2.10
7
13
(
s, 6H). C NMR (100 MHz, CDCl
3
) δ 168.6, 163.9, 151.6, 140.2, 139.7, 135.8,
1
34.5, 133.7, 130.2, 129.3, 129.0, 128.3, 127.8, 127.5, 127.2, 121.2, 21.5, 20.2.
+
+
HRMS (ESI): m/z [M + H] calcd for C23
-mesityl-4-p-tolylquinazoline(4b). Yellow solid, 90% yield, mp = 123ꢀ124 ℃. H
NMR (400 MHz, CDCl ) δ 8.21 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H),
.91ꢀ7.88 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.64ꢀ7.57 (m, 1H), 7.36 (d, J = 7.6 Hz,
21 2
H N : 325.1705; found: 325.1701.
1
2
3
7
2
1
3
H), 6.95 (s, 2H), 2.46 (s, 3H), 2.32 (s, 3H), 2.18 (s, 6H). C NMR (100 MHz, CDCl )
3
δ 168.4, 164.1, 151.6, 140.1, 137.8, 136.9, 135.7, 134.5, 133.5, 130.2, 129.3, 129.0,
+
1
28.6, 127.3, 127.3, 121.1, 21.5, 21.2, 20.1. HRMS (ESI): m/z [M + H] calcd for
+
2
C
24
H
23
N
: 339.1861; found: 339.1865.
2
-(4-methoxy-2,6-dimethylphenyl)-4-p-tolylquinazoline(4c). Yellow solid, 95% yield,
1
mp = 185ꢀ186 ℃. H NMR (400 MHz, CDCl
3
) δ 8.21 (d, J = 8.4 Hz, 1H), 8.14 (d, J
=
8.4 Hz, 1H), 7.91ꢀ7.89 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.63ꢀ7.59 (m, 1H), 7.37 (d,
13
J = 7.6 Hz, 2H), 6.69 (s, 2H), 3.82 (s, 3H), 2.47 (s, 3H), 2.21 (s, 6H). C NMR (100
MHz, CDCl
3
) δ 168.3, 163.8, 159.2, 151.5, 140.1, 137.6, 134.4, 133.5, 132.7, 130.1,
+
1
29.2, 128.9, 127.2, 127.1, 120.9, 113.2, 55.2, 21.4, 20.5. HRMS (ESI): m/z [M + H]
+
calcd for C H N O : 355.1810; found: 355.1814.
24
23
2
N,N,3,5-tetramethyl-4-(4-p-tolylquinazolin-2-yl)aniline(4d). Yellow solid, 92% yield,
1
mp = 153ꢀ154 ℃. H NMR (400 MHz, CDCl
3
) δ 8.19 (d, J = 8.4 Hz, 1H), 8.13 (d, J
=
8.4 Hz, 1H), 7.91ꢀ7.85 (m, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H),

Page 7 of 28
1
3
7
.35 (d, J = 8.4 Hz, 2H), 6.53 (s, 2H), 2.95 (s, 6H), 2.46 (s, 3H), 2.23 (s, 6H). C
NMR (100 MHz, CDCl ) δ 167.9, 164.4, 151.6, 150.7, 139.9, 136.9, 134.7, 133.3,
30.2, 129.2, 128.9, 127.0, 126.9, 120.8, 112.5, 40.81 , 21.5, 20.9. HRMS (ESI): m/z
3
1
+
+
[
M + H] calcd for C H N : 368.2127; found: 368.2124.
24 26 3
2
-(4-chloro-2,6-dimethylphenyl)-4-p-tolylquinazoline(4e). Yellow solid, 65% yield,
1
mp = 112ꢀ114 ℃. H NMR (400 MHz, CDCl
3
) δ 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d, J
=
8.4 Hz, 1H), 7.95ꢀ7.91 (m, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.66ꢀ7.62 (m, 1H), 7.37 (d,
1
3
J = 7.6 Hz, 2H), 7.14 (s, 2H), 2.47 (s, 3H), 2.18 (s, 6H). C NMR (100 MHz, CDCl
3
)
δ 168.7, 162.9, 151.5, 140.3, 138.1, 137.9, 134.2, 133.7, 133.6, 130.1, 129.3, 128.9,
+
+
1
3
2
1
3
27.6, 127.2, 121.2, 21.44, 20.06. HRMS (ESI): m/z [M + H] calcd for C23
H
20ClN
2
:
59.1315; found: 359.1314.
-(2,5-dimethylphenyl)-4-phenylquinazoline(4f). Yellow solid, 70% yield, mp =
1
63ꢀ164 ℃. H NMR (400 MHz, CDCl
3
) δ 8.15 (t, J = 7.6 Hz, 2H), 7.90 ꢀ7.84 (m,
H), 7.79 (s, 1H), 7.58ꢀ7.55 (m, 4H), 7.25ꢀ7.13 (m, 2H), 2.61 (s, 3H), 2.39 (s, 3H);
1
3
C NMR (100 MHz, CDCl
3
) δ 167.9, 163.5, 151.6, 138.5, 137.4, 135.3, 134.2, 133.5,
1
31.2, 131.1, 130.0, 129.9, 129.8, 129.0, 128.5, 127.1, 126.9, 120.9, 20.9, 20.7.HRMS
+
+
(
19 2
ESI): m/z [M + H] calcd for C22H N : 311.1548; found: 311.1543.
2
1
8
1
-(2,6-dimethylphenyl)-4-phenylquinazoline(4g). Yellow solid, 93% yield, mp =
1
64ꢀ165 ℃. H NMR (400 MHz, CDCl
3
) δ 8.18 (t, J = 9.2 Hz, 2H), 7.93 (ddd, J =
.4, 6.8, 1.2 Hz, 1H), 7.82 (dd, J = 6.8, 2.0 Hz, 2H), 7.63 (ddd, J = 8.4, 7.6, 1.2 Hz,
13
H), 7.60ꢀ7.54 (m, 3H), 7.25ꢀ7.19 (m, 1H), 7.13 (d, J = 7.6 Hz, 2H), 2.20 (s, 6H). C
) δ 168.6, 163.9, 151.5, 137.2, 135.8, 133.7, 130.1, 129.9,
NMR (100 MHz, CDCl
3

Page 8 of 28
+
1
28.9, 128.5, 128.2, 127.8, 127.5, 127.0, 121.1, 20.1. HRMS (ESI): m/z [M + H]
+
calcd for C22
H
19
N
2
: 311.1548; found: 311.1543.
2
-(2,6-dimethylphenyl)-4-(4-fluorophenyl)quinazoline(4h). Yellow solid, 90% yield,
1
mp = 153ꢀ155 ℃. H NMR (400 MHz, CDCl
3
) δ 8.17 (dd, J = 8.8, 4.0 Hz, 2H),
7
.97ꢀ7.93 (m, 1H), 7.87ꢀ7.82 (m, 2H), 7.68ꢀ7.64 (m, 1H), 7.29ꢀ7.21 (m, 3H), 7.14 (d,
13
1
J = 7.2 Hz, 2H), 2.19 (s, 6H). C NMR (100 MHz, CDCl
3
) δ 167.4, 163.9 (d, J =
3
3
2
1
49 Hz ), 163.8, 151.6, 139.4, 135.8, 133.8, 133.3 (d, J = 3Hz), 132.1 (d, J = 9 Hz),
2
29.1, 128.4, 127.8, 127.7, 126.7, 120.9, 115.7 (d, J = 22 Hz ), 20.1. HRMS (ESI):
+
+
2
m/z [M + H] calcd for C H FN : 329.1454; found: 329.1449.
2
2
18
2
-(2,6-dimethylphenyl)-4-m-tolylquinazoline(4i). Yellow solid, 85% yield, mp =
1
1
53ꢀ154 ℃. H NMR (400 MHz, CDCl
3
) δ 8.18 (dd, J = 14.4, 8.0 Hz, 2H), 7.93 (ddd,
J = 8.4, 6.8, 1.2 Hz, 1H), 7.65ꢀ7.60 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6
13
Hz, 1H), 7.23ꢀ7.12 (m, 3H), 2.47 (s, 3H), 2.20 (s, 6H). C NMR (100 MHz, CDCl
3
) δ
1
1
68.8, 163.9, 151.5, 139.6, 138.4, 137.1, 135.7, 133.7, 130.7, 130.6, 128.9, 128.3,
+
28.2, 127.7, 127.4, 127.3, 127.1, 121.2, 21.5, 20.1. HRMS (ESI): m/z [M + H] calcd
+
for C23
H
21
N
2
: 325.1705; found: 325.1701.
2
-(2,6-dimethylphenyl)-4-(4-methoxyphenyl)quinazoline(4j). Yellow solid, 70%
1
yield. mp = 165ꢀ167 ℃. H NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 7.91 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.85ꢀ7.82 (m, 2H), 7.63 (ddd,
J = 8.2, 7.2, 0.8 Hz, 1H), 7.23ꢀ7.19 (m, 1H), 7.14ꢀ7.07 (m, 4H), 3.90 (s, 3H), 2.20 (s,
3
) δ 8.24 (d, J = 8.4 Hz, 1H), 8.14
(
1
3
6
H). C NMR (100 MHz, CDCl
3
) δ 167.9, 163.9, 161.2, 151.6, 139.6, 135.8, 133.5,
1
31.8, 129.7, 128.9, 128.2, 127.7, 127.3, 127.1, 121.0, 114.0, 55.4, 20.1. HRMS (ESI):

Page 9 of 28
+
+
m/z [M + H] calcd for C23
21 2
H N O : 341.1654; found: 341.1649.
2
-(2,6-dimethylphenyl)-4-(naphthalen-1-yl)quinazoline(4k). Yellow solid, 71%
1
yield. mp = 176ꢀ177 ℃. H NMR (400 MHz, CDCl
3
) δ 8.22 (d, J = 8.4 Hz, 1H), 8.02
dd, J = 6.8, 2.8 Hz, 1H), 7.96ꢀ7.91 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.64 ꢀ7.60 (m,
H), 7.52ꢀ7.48 (m, 3H), 7.41ꢀ7.37 (m, 1H), 7.23ꢀ7.18 (m, 1H), 7.12 (d, J = 7.6 Hz,
(
2
2
1
1
1
3
3
H), 2.24 (s, 6H). C NMR (100 MHz, CDCl ) δ 169.4, 164.1, 151.1, 139.5, 135.6,
34.5, 134.1, 133.6, 131.6, 129.7, 128.9, 128.4, 128.3, 127.7, 127.6, 127.3, 126.7,
+
26.2, 126.1, 125.4, 125.0, 122.8, 20.1. HRMS (ESI): m/z [M + H] calcd for
+
2
C H N : 361.1705; found: 361.1707.
26
21
2
-(2,6-dimethylphenyl)-6-methoxy-4-o-tolylquinazoline(4l). Yellow solid, 78% yield,
1
mp = 154ꢀ155 ℃. H NMR (400 MHz, CDCl
3
) δ 8.08 (d, J = 9.2 Hz, 1H), 7.58 (dd, J
=
9.2, 2.8 Hz, 1H), 7.39ꢀ7.36 (m, 4H), 7.19 (dd, J = 8.4, 6.8 Hz, 1H), 7.11 (d, J = 7.6
1
3
Hz, 2H), 6.92 (d, J = 2.8 Hz, 1H), 3.78 (s, 3H), 2.19 (s, 3H), 2.16 (s, 6H). C NMR
(
100 MHz, CDCl ) δ 168.4, 162.0, 158.4, 147.3, 139.6, 136.8, 135.9, 135.7, 130.6,
3
1
30.4, 129.1, 129.9, 128.1, 127.6, 126.8, 125.7, 122.9, 104.0, 55.7, 19.9, 19.8. HRMS
+
+
(
23 2
ESI): m/z [M + H] calcd for C24H N O : 355.1810; found: 325.1816.
2
-(2,6-dimethylphenyl)-6-methoxy-4-p-tolylquinazoline(4m). Yellow solid, 83%
1
yield, mp = 156ꢀ157 ℃. H NMR (400 MHz, CDCl
3
) δ 8.06 (d, J = 9.2 Hz, 1H), 7.74
(dd, J = 8.0, 1.6 Hz, 2H), 7.58 (dd, J = 9.2, 2.8 Hz, 1H), 7.47 (d, J = 2.8 Hz, 1H), 7.37
(d, J = 7.8 Hz, 2H), 7.22ꢀ7.11 (m, 1H), 7.12 (d, J = 7.6 Hz, 2H), 3.88 (s, 3H), 2.47 (s,
1
3
3
H), 2.18 (s, 6H). C NMR (100 MHz, CDCl
3
) δ 166.8, 162.0, 158.3, 147.8, 139.9,
1
39.6, 135.9, 134.7, 130.4, 129.7, 129.3, 128.1, 127.7, 126.3, 121.9, 104.4, 55.7, 21.4,

Page 10 of 28
+
+
2
23 2
0.1. HRMS (ESI): m/z [M + H] calcd for C24H N O : 355.1810; found: 325.1816.
2
-(2,6-dimethylphenyl)-6-methoxy-4-m-tolylquinazoline(4n) Yellow solid, 80%
1
yield, mp = 156ꢀ157 ℃. H NMR (400 MHz, CDCl
3
) δ 8.07 (d, J = 9.2 Hz, 1H), 7.64
ꢀ7.57 (m, 3H), 7.46ꢀ7.43 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.4, 6.8 Hz,
1
3
1
H), 7.12 (d, J = 7.6 Hz, 2H), 3.87 (s, 3H), 2.46 (s, 3H), 2.18 (s, 6H). C NMR (100
) δ 1671, 162.0, 158.30, 147.7, 139.6, 138.5, 137.5, 135.8, 130.5, 130.4,
30.3, 128.3, 128.2, 127.7, 126.8, 126.3, 121.9, 104.4, 55.7, 21.5, 20.1. HRMS (ESI):
MHz, CDCl
3
1
+
+
23 2
m/z [M + H] calcd for C24H N O : 355.1810; found: 325.1816.
2
9
7
-(2,6-dimethylphenyl)-4-(4-fluorophenyl)-6-methoxyquinazoline(4o). Yellow solid,
1
5% yield, mp = 143ꢀ144 ℃. H NMR (400 MHz, CDCl
3
) δ 8.08 (d, J = 9.2 Hz, 1H),
.86ꢀ 7.82 (m, 2H), 7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.28ꢀ7.19
1
3
(
m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.18 (s, 6H). C NMR (100 MHz,
1
CDCl
3
) δ 165.6, 163.7 (d, J = 249 Hz ), 161.9, 158.5, 147.8, 139.4, 135.8, 133.6 (d,
2
3
J = 33 Hz ), 131.7 (d, J = 9 Hz ), 130.6, 128.2, 127.8, 126.5, 121.8, 115.9, 115.7 (d,
2
+
+
2
J = 22 Hz ), 103.9, 55.7, 20.1. HRMS (ESI): m/z [M + H] calcd for C23H20FN O :
3
59.1560; found: 359.1566.
6
-chloro-2-(2,6-dimethylphenyl)-4-o-tolylquinazoline(4p). Yellow solid, 65% yield,
1
mp = 155ꢀ156℃. H NMR (400 MHz, CDCl
3
) δ 8.12 (d, J = 8.8 Hz, 1H), 7.86 (dd, J
=
8.8, 2.0 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.46ꢀ7.41 (m, 1H), 7.38ꢀ7.34 (m, 3H),
1
3
7
.21 (dd, J = 8.4, 7.2 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 2.19 (s, 3H), 2.16 (s, 6H). C
NMR (100 MHz, CDCl ) δ 169.5, 164.3, 149.5, 139.2, 135.9, 135.8, 135.5, 135.0,
33.4, 130.8, 130.6, 129.5, 129.2, 128.4, 127.7, 125.8, 125.8, 122.7, 19.9, 19.8.
3
1

Page 11 of 28
+
+
HRMS (ESI): m/z [M + H] calcd for C23
2
H20ClN : 359.1315; found: 359.1319.
6
-chloro-2-(2,6-dimethylphenyl)-4-p-tolylquinazoline(4q). Yellow solid, 62% yield,
1
mp = 156ꢀ158 ℃. H NMR (400 MHz, CDCl
3
) δ 8.11 (d, J = 2.4 Hz, 1H), 8.01 (d, J
=
8.8 Hz, 1H), 7.76 (dd, J = 9.2, 24 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0
1
3
Hz, 2H), 7.17ꢀ7.12 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 2.39 (s, 3H), 2.10 (s, 6H).
NMR (100 MHz, CDCl ) δ 167.8, 164.2, 150.1, 140.6, 139.3, 135.8, 134.6, 133.9,
33.2, 130.7, 130.1, 129.5, 128.5, 127.9, 125.9, 121.7, 21.5, 20.2. HRMS (ESI): m/z
C
3
1
+
+
[
2
M + H] calcd for C23H20ClN : 359.1315; found: 359.1319.
6
-chloro-2-(2,6-dimethylphenyl)-4-m-tolylquinazoline(4r). Yellow solid, 70% yield,
1
mp = 157ꢀ158 ℃. H NMR (400 MHz, CDCl
3
) δ 8.16 (d, J = 2.4 Hz, 1H), 8.10 (d, J
=
9.2 Hz, 1H), 7.86 (dd, J = 9.2, 2.4 Hz, 1H), 7.61ꢀ7.57 (m, 2H), 7.47 (dd, J = 9.6, 4.0
Hz, 1H), 7.40 ꢀ7.33 (m, 1H), 7.22 (dd, J = 8.4, 6.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H),
1
3
2
1
1
3
6
6
8
7
.47 (s, 3H), 2.18 (s, 6H). C NMR (100 MHz, CDCl
3
) δ 1681, 164.2, 150.0, 139.2,
38.7, 136.6, 135.7, 134.7, 133.2, 131.0, 130.7, 130.4, 128.5, 128.4, 127.8, 127.1,
+
+
25.9, 121.7, 21.5, 20.1. HRMS (ESI): m/z [M + H] calcd for C23
H
20ClN
2
:
59.1315; found: 359.1319.
-chloro-2-(2,6-dimethylphenyl)-4-(naphthalen-1-yl)quinazoline(4s). Yellow solid,
1
8% yield, mp = 183ꢀ184 ℃. H NMR (400 MHz, CDCl
3
) δ 8.16 (d, J = 9.2 Hz, 1H),
.04 (dd, J = 7.6, 1.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 9.2, 2.4 Hz, 1H),
.68ꢀ 7.60 (m, 3H), 7.54ꢀ7.48 (m, 2H), 7.43ꢀ 7.39 (m, 1H), 7.25ꢀ 7.19 (m, 1H), 7.12 (d,
13
J = 7.6 Hz, 2H), 2.23 (s, 6H). C NMR (100 MHz, CDCl
3
) δ 168.6, 164.4, 149.7,
1
39.1, 135.6, 135.2, 133.8, 133.7, 133.3, 131.4, 130.6, 130.1, 128.5, 128.4, 127.8,

Page 12 of 28
+
1
27.7, 126.9, 126.3, 125.9, 125.2, 125.0, 123.4, 20.1. HRMS (ESI): m/z [M + H]
+
2
calcd for C26
H
20ClN
: 395.1315; found: 395.1315.
6
6
7
-chloro-2-(2,6-dimethylphenyl)-4-(4-fluorophenyl)quinazoline(4t). Yellow solid,
1
8% yield, mp = 138ꢀ139 ℃. H NMR (400 MHz, CDCl
3
) δ 8.12 (d, J = 8.4 Hz, 2H),
.87 (dd, J = 9.2, 2.4 Hz, 1H), 7.85ꢀ7.81 (m, 2H), 7.30ꢀ 7.21 (m, 3H), 7.14 (d, J = 7.6
1
3
1
3
Hz, 2H), 2.18 (s, 6H). C NMR (100 MHz, CDCl ) δ 166.6, 164.2, 164.1 (d, J = 249
3
3
Hz ), 162.9, 150.1, 139.0, 135.7, 134.8, 133.5, 132.7 (d, J = 3.3 Hz ), 132.1 (d, J = 9
2
Hz), 130.8, 128.5, 127.9, 125.5, 121.5, 115.8 (d, J = 22 Hz), 20.1. HRMS (ESI): m/z
+
+
[
M + H] calcd for C H ClFN : 363.1064; found: 363.1069.
22 17 2
2
6
8
7
2
1
1
3
4
2
5
8
-(2-benzyl-6-methylphenyl)-4-(naphthalen-1-yl)quinazoline(3u). Yellow solid,
1
0% yield, mp = 183ꢀ185 ℃. H NMR (400 MHz, CDCl
3
) δ 8.18 (d, J = 8.4 Hz, 1H),
.00 (d, J = 8.0 Hz, 1H), 7.94ꢀ7.90 (m, 2H), 7.62ꢀ7.57 (m, 2H), 7.51ꢀ7.45 (m, 3H),
.34ꢀ7.29 (m, 2H), 7.20 (dd, J = 23.2, 7.6 Hz, 2H), 7.10ꢀ7.06 (m, 4H), 6.98ꢀ6.96 (m,
13
H), 4.02 (s, 2H), 2.25 (s, 3H). C NMR (100 MHz, CDCl ) δ 169.2, 163.8, 150.9,
3
40.8, 139.4, 138.9, 136.2, 134.5, 1341, 133.6, 131.6, 129.7, 129.0, 128.8, 128.5,
28.4, 128.3, 128.1, 127.8, 127.7, 127.5, 127.3, 126.7, 126.2, 125.7, 125.0, 122.76,
+
+
2
9.66, 20.30. HRMS (ESI): m/z [M + H] calcd for C32
H
25
N
: 437.2018; found:
37.2017.
-(2-cyclopropyl-6-methylphenyl)-4-(naphthalen-1-yl)quinazoline(3v). Yellow solid,
1
7% yield, mp = 180ꢀ181 ℃. H NMR (400 MHz, CDCl
3
) δ 8.23 (d, J = 8.4 Hz, 1H),
.06ꢀ8.00 (m, 1H), 7.99ꢀ7.90 (m, 2H), 7.73ꢀ7.67 (m, 1H), 7.66 ꢀ7.61 (m, 2H), 7.51 (dd,
J = 8.0, 7.6 Hz, 3H), 7.40ꢀ7.34 (m, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.11 (d, J = 7.4 Hz,

Page 13 of 28
1
H), 6.93 (d, J = 7.8 Hz, 1H), 2.23 (s, 3H), 1.82 (dt, J = 13.6, 6.8 Hz, 1H), 0.75ꢀ0.51
13
(
m, 4H). C NMR (100 MHz, CDCl
3
) δ 169.2, 164.3, 151.1, 140.9, 140.5, 135.4,
1
1
34.6, 134.1, 133.7, 131.7, 129.7, 128.9, 128.5, 127.7, 127.6, 127.5, 127.3, 126.6,
+
26.2, 125.5, 125.1, 123.1, 122.8, 20.1, 14.0, 7.9. HRMS (ESI): m/z [M + H] calcd
+
for C28
H
23
N
2
: 387.1861; found: 387. 1866.
1
2
-(o-tolyl)quinazoline (3w). yellow solid, 15% yield, mp = 36ꢀ39 °C. H NMR (400
MHz, CDCl ) δ 9.49 (s, 1H), 8.01ꢀ7.96 (m, 1H), 7.84ꢀ7.82 (m, 1H), 7.60ꢀ7.54 (m, 1H),
.50 (dd, J = 8.2, 1.2 Hz, 1H), 7.43ꢀ7.34 (m, 4H), 2.65 (s, 3H). C NMR (100 MHz,
CDCl ) δ 162.3, 159.9, 151.7, 140.4, 138.6, 137.4, 131.5, 130.9, 129.6, 128.6, 126.1,
3
13
7
3
+
+
1
13 2
22.9, 117.1, 114.5, 21.5. HRMS (ESI): m/z [M + H] calcd for C15H N : 221.1079;
found: 221.1076.
Results and discussions
The methylation reaction of 2,4ꢀdiarylquinazoline is possible on the 2ꢀaryl group or
4
ꢀaryl group. Therefore, initially, we selected 2ꢀphenylꢀ4ꢀ(pꢀtolyl)quinazoline 1a and
potassium methyltrifluoroborate 2a as the model substrate to optimize the reaction
*
conditions. To our delight, a coupling occurred with [RhCp Cl
2
]
2
(4.0 mol %) and
AgSbF
6
(16 mol %), using AgF (2.8 equiv) as a oxidant in DCM (Table 1, entry 1) at
8
5℃, and the product 3a was isolated in 15% yield. Interestingly, the methylation
occured only on the 2ꢀaryl group rather than the 4ꢀaryl group by analyzing the
1
HꢀNMR, which was consistent with the results of our previous direct CꢀH amidation
28
of 2,4ꢀdiarylquinazoline with sulfonyl azides . The isolation of diꢀalkylated products
4
a caught our attention. In order to investigate the selectivity of the reaction, different

Page 14 of 28
amounts of MeBF
the tested cases, monoꢀmethylation product and diꢀmethylation were generated
depending on the amount of MeBF K. Further studied showed that 4.0 equiv of
MeBF K provided a comparable yield of product 4a with 84%. Next, other oxidants
3
K were studied (Table 1, entry 2ꢀ4). It was noteworthy that in all
3
3
such as Ag
indicated that Ag
Ag O and AgOAc also accelerate this reaction with respectively less yields 81% and
0% (Table 1, entries 6 and 7), whereas AgBF and AgNO were totally ineffective
Table 1, entries 8 and 9). Screening of the solvent revealed that ClCH CH Cl (DCE)
2
CO
3
, Ag
2
4 3
O, AgOAc, AgBF , AgNO were screened, and the results
2
CO
3
was the best choice, affording 89% yield (Table 1, entry 5).
2
4
4
3
(
2
2
seemed to be the crucial one with relatively higher yields 91% (Table 1, entries 15),
and the coupling in other solvents afforded inferior results (Table 1, entries 10ꢀ14). To
2 3
our delight, reducing the amount of oxidant Ag CO to 1.8 equiv, the reaction was not
affected (Table 1, entry 16). The reaction proceeded with poor efficiency when
lowering the reaction temperature to 60℃, while elevating the reaction temperature to
9
5℃ or 100℃ could not make the reaction better than ever before (Table 1, entries
1
7ꢀ19). Moreover, product 4a was isolated in 70 % yield using a lower loading of the
*
catalyst ([RhCp Cl
2
]
2
(1.0 mol %) and AgSbF
6
(4 mol %)) (Table 1, entry 20). In
*
contrast, the reaction gave no conversion when [RhCp Cl
2
]
2
was omitted (Table 1,
entry 21).
a
Table 1. Optimization Studies

Page 15 of 28
b
b
Entry 2a (equiv)
Oxidant (equiv)
Solvent
T (℃) Yield 3a (%) Yield 4a (%)
1
2
3
4
5
6
7
8
9
1.0
1.5
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
AgF (2.8)
AgF (2.8)
AgF (2.8)
AgF (2.8)
DCM
DCM
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
60
15
6
2
20
DCM
30
30
84
89
81
40
trace
10
10
15
20
24
26
91
91
85
DCM
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
2 3
Ag CO (2.8)
DCM
2
Ag O (2.8)
DCM
AgOAc (2.8)
DCM
AgBF (2.8)
DCM
4
AgNO
3
(2.8)
(2.8)
(2.8)
(2.8)
DCM
10
Ag
Ag
Ag
2
2
2
CO
3
3
3
MeCN
THF
11
CO
CO
12
13
14
15
16
17
Toluene
1,4ꢀdioxane
DMSO
DCE
Ag CO (2.8)
2
3
Ag
2
CO
3
(2.8)
Ag CO (2.8)
2
3
3
3
Ag
2
CO
(1.8)
DCE
Ag
2
CO
(1.8)
DCE

Page 16 of 28
1
8
9
4.0
4.0
4.0
4.0
Ag CO (1.8)
DCE
DCE
DCE
DCE
95
100
85
trace
trace
trace
NR
90
2
2
2
2
3
3
3
3
1
Ag
Ag
Ag
CO
CO
CO
(1.8)
(1.8)
(1.8)
90
c
20
70
d
21
85
NR
a
Reactions were carried out using 2ꢀoꢀtolylꢀ4ꢀpꢀtolylquinazoline 1a (0.2 mmol), MeBF
3
K 2a (0.8
*
mmol), [RhCp Cl
2
]
2
(4.0 mol %), AgSbF
6
(16 mol %) and oxidant in a solvent (3 mL) at 85°C.
b
Isolated yield.
c
*
Reaction was performed in the presence of [RhCp Cl ] (1.0 mol %) and AgSbF (4 mol %).
2
2
6
d
No catalyst was added.
With the optimized conditions [1a (0.2 mmol), MeBF
3
K 2a (0.8 mmol),
*
[
RhCp Cl ] (4.0 mol %), AgSbF (16 mol %), and Ag CO (0.36 mmol) in DCE (3
2
2
6
2
3
mL) at 85°C] in hand, the reaction scope was further explored, and the results were
summarized in Table 2. The results indicated that a broad range of quinazolinones
could be well tolerated in this catalytic system. Firstly, the effect of a substituent on
the phenyl ring at the 2ꢀposition was examined. Evidently, the substrates bearing
electronꢀdonor substitutions provided higher yields (4b, 90%; 4c, 95%; 4d, 92%) than
the electronꢀwithdrawing one (4e, 65%). It was noteworthy that methylation reacted at
the less sterically hindered site to furnish the monoꢀproduct in good yield, when the
substituted group at the meta-position of 2ꢀphenyl ring (4f, 70%). No detectable
diꢀmethylation was noticed by TLC analysis during this reaction process. Thus, we
can conclude herein that monoꢀmethylation product can be obtained by steric
hindrance regulated in these reactions. Fortunately, the reaction didn’t occur when

Page 17 of 28
2
ꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀ(naphthalenꢀ1ꢀyl)quinazoline was selected as the substrate
under the standered reaction conditions(not list in Table 2), and this also indicated the
methylation occurred on the phenyl ring at the 2ꢀposition.
Then, the electronic effect of phenyl ring at the 4ꢀposition was also investigated.
When R
desired product in excellent yield (4g, 93%; 4h, 90%). In contrast, the electron
donating substituents such as methyl and CH Oꢀ on 4ꢀaromatic ring made great
impact on the yield (4i, 85%; 4j, 70%). Substrate with naphthalene substituted at
2
was phenyl or 4ꢀfluorophenyl, the reaction provided the corresponding
3
4
ꢀposition was also tolerant with moderat yield (4k, 71%).
Next, we checked the mother aromatic ring of the quinazolinone. A group of
quinazolinones were assessed. From the overall evaluation, the substrates with
methoxyl group on the mother ring was favorable for the reaction, providing the
desired product in higher yield (4lꢀ4o, with 78%ꢀ95% yields) than those bearing
electronꢀdonor groups such as halogen respectively (4pꢀ4t, with 62%ꢀ70% yields).
a
Table 2. Substrate exploration
Product
1
2
3
Entry
Substrate
R
R
R
a
(
% yield)
4a (91)
4b (90)
1
2
1a
1b
H
H
4ꢀmethylphenyl
4ꢀmethylphenyl
H
4ꢀmethyl

Page 18 of 28
3
4
5
6
7
8
9
1c
1d
1e
1f
H
H
4ꢀmethylphenyl
4ꢀmethylphenyl
4ꢀmethylphenyl
phenyl
4ꢀmethoxy
4c (95)
4d (92)
4e (65)
4f (70)
4g (93)
4h (90)
4i (85)
4j (70)
4k (71)
4l (78)
4m (83)
4n (80)
4o (95)
4p (65)
4q (62)
4r (70)
4s (68)
4t (68)
4ꢀN,Nꢀdimethyl
H
4ꢀchloro
H
3ꢀmethyl
1g
1h
1i
H
phenyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4ꢀfluorophenyl
3ꢀmethylphenyl
4ꢀmethoxyphenyl
naphthalenꢀ1ꢀyl
2ꢀmethylphenyl
4ꢀmethylphenyl
3ꢀmethylphenyl
4ꢀfluorophenyl
2ꢀmethylphenyl
4ꢀmethylphenyl
3ꢀmethylphenyl
naphthalenꢀ1ꢀyl
4ꢀfluorophenyl
H
10
1j
H
11
1k
1l
H
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
0
methoxy
methoxy
methoxy
methoxy
chloro
chloro
chloro
chloro
chloro
1m
1n
1o
1p
1q
1r
1s
1t
2
a
*
Reactions were carried out using 1 (0.2 mmol), MeBF
3
K 2a (0.8 mmol), [RhCp Cl
2
]
2
(4.0 mol
%
), AgSbF (16 mol %) and Ag CO (0.36 mmol) in DCE (3 mL) at 85°C.
6 2 3
After finishing the above examined, we moved on to explore the other alkylation
reagents. As a consequence potassium benzyltrifluoroborate (2b) and potassium

Page 19 of 28
cyclopropyltrifluoroborate (2c) were selected to probe the substrates scope of
quinazoline (Scheme 2). To our delight, these two kinds of alkylation reagents can
also be carried out in this reaction system. However, due to their steric effects, boron
reagents containing a benzyl 2b or cyclopropyl group 2c only gave the corresponding
benzylation product (3u, 60% yields) and the cycloalkylation product in moderate
yields (3v, 57% yields). We concluded that steric hindrance effect was the main factor
affecting 4ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀoꢀtolylquinazoline alkylation on 2 aromatic ring.
These results also revealed that the coupling partners in this catalytic system are not
limited only to methyl boron reagent MeBF K (2a).
3
[
RhCp*Cl ] 4%
2 2
AgSbF 16%
N
R
+
6
N
RBF K
3
N
Ag CO (1.8 eq)
(
2.0 equiv)
2
3
N
o
DCE, 85 ( C)
1u
2b: R=benzyl
c: R=cyclopropyl
3u 60%,R=benzyl
v 57%,R=cyclopropyl
2
3
Scheme 2. Reactions of different methylation reagents with
4
ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀoꢀtolylquinazoline
In order to gain an insight into the mechanism, other azine substrate such as
ꢀphenylquinoxalin (not list) was investigated under the standard conditions.
2
However, the results indicated that this substrate did not tolerant the reaction
conditions very well giving the monoꢀalkyation product 2ꢀ(oꢀtolyl)quinazoline
3w, with only in 15% yields). Also, it was quite interesting that 4ꢀarylquinazoline
，
(
did not undergo the standard reaction. It seems that the phenyl substitution
would have resonance effect to favor the catalytic cycle.
On the base of recent Rhꢀcatalyzed direct orthoꢀCꢀH bond functionalization of

Page 20 of 28
18g,18h,18i
arenes
, a plausible mechanistic pathway has been illustrated in Scheme 3.
Initially, intermediate I, generated by Rh(III)ꢀpromoted orthoꢀCꢀH bond activation,
yield fiveꢀmembered Rh intermediate II via transmetalation with boron reagent. Then
the desired methylation product 3 along with Rh(I) species were formed via reductive
elimination. Subsequently, Rh(I) species undergoes reoxidation by oxidant Ag
2 3
CO to
regenerate the active cationic Rh(III) species for the following catalytic cycle.
Scheme 3. Proposed catalytic pathway
Conclusion
In conclusion, we have developed an effective Rh(III)ꢀcatalyzed oxidative CꢀH
methylation of 2,4ꢀdiarylquinazoline, which exerted several advantages: ligand free,
practical reaction conditions, moderate to good yields. When both ortho-CꢀH sites on
2
aromatic ring are accessible, monoꢀ and diꢀmethyllation products will be generated,
and this selectivity is controllable by the amount of methylation reagents. This
methodology gave a rapid and straight forward synthesis of functionalized
quinazolines which were potential biological compounds. Boron reagents containing a

Page 21 of 28
benzyl or cyclopropyl group were also applied. However, the main factor affecting
,4ꢀdiarylquinazoline methylation on 2 aromatic ring is steric hindrance effect.
2
Acknowledgments
Financial support from National Natural Science Foundation of China (No. 21162012
and 21362014), key laboratory of Functional Small Organic Molecule, Ministry of
Education, Jiangxi Normal University (NO.KLFSꢀKFꢀ201407) is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found in the online version.
References and notes
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