Synthesis of quinazolines from (2-aminoaryl)methanols and arylmethanamines catalyzed by rhodium complex

Article abstract of DOI:10.1134/S1070363217040235

Efficient synthesis of quinazoline derivatives via rhodium-catalyzed dehydrogenation and ring-closing method was developed with moderate to high yields.

Full text of DOI:10.1134/S1070363217040235

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 4, pp. 812–815. © Pleiades Publishing, Ltd., 2017.
Synthesis of Quinazolines from (2-Aminoaryl)methanols
and Arylmethanamines Catalyzed by Rhodium Complex1
L. Wang*, J. Cao, and Z. Li
Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education,
School of Chemical and Environmental Engineering, Jianghan University,
8 Sanjiaohu Road, Wuhan, Hubei, 430056 China
*e-mail: wangliang@jhun.edu.cn
Received December 7, 2015
Abstract—Efficient synthesis of quinazoline derivatives via rhodium-catalyzed dehydrogenation and ring-
closing method was developed with moderate to high yields.
Keywords: dehydrogenation, rhodium, arylmethanamines, alcohols, quinazoline
DOI: 10.1134/S1070363217040235
INTRODUCTION
RESULTS AND DISCUSSION
Quinazoline and its derivatives are commonly
occurring structural blocks of numerous natural
compounds and pharmaceuticals [1–3]. Over the recent
years nitrogen containing analogues of quinazoline
derivatives attracted close attention due to their high
biological activity [4–10]. Zhang et al. [11] developed
a facile and efficient synthesis of 2-phenylquina-
zolines via a tandem reaction with moderate to high
yields and a metal-free intramolecular oxidative
decarboxylative coupling of α-amino acids, that led to
a wide range of 2-substituted quinazolines [12]. Han
et al. [13] reported an one-pot approach to the aerobic
oxidative synthesis of 2-aryl quinazolines via benzyl
C–H bond amination, using 2-aminobenz-aldehydes or
2-aminobenzoketones with arylmethanamines as starting
materials. Chen et al. [14] described the first example
of a copper-catalyzed cascade reaction of aldehydes
and (2-aminophenyl)methanols in the presence of
cerium nitrate hexahydrate and ammonium chloride
leading to synthesis of 2-substituted quinazolines.
Synthesis of quinazolines from 1,2-dihydroquinazoline-
3-oxides was carried out under visible light mediation
[15]. In most studies the starting materials scope
mainly focused on aldehydes, ketones, with amine or
nitriles [16–20]. Herein, we present an efficient syn-
thesis of quinazoline derivatives via rhodium-catalyzed
dehydrogenation ring-closing method (Scheme 1).
Primarily we examined Rh-catalyzed dehydrogenation
ring-closing reaction using (2-aminophenyl)methanol
(2a) and benzylamine (3a) as a model substrate
catalyzed by a highly active rhodium complex, [(P,P-
dppe)(P,N-Ph2PAr)Rh], [21]. The anticipated quina-
zoline 4a was obtained in low yield (28%) (Table 1,
entry 1). Following screening of reaction conditions
including solvents and bases was carried out (Table 1,
entries 2–8). The tests of solvents demonstrated that
1,3,5-trimethylbenzene (TMB) was the best. Screening
of bases revealed that Cs2CO3 was superior to the
others tested (Table 1, entry 13). Attempts to decrease
the reaction temperature did not improve the yields.
The worked out optimal conditions made it possible
to evaluate the scope and limitations of the reaction
(Table 2). According to the accumulated data, various
benzylamines containing electron-donating and
electron-withdrawing groups could be converted to the
quinazoline derivatives smoothly (Table 2, compounds
4b–4e) with moderate to high yields. However,
substrates with strong electron- withdrawing groups
gave slightly lower yields (Table 2, compounds 4b and
4e). Additionally, thiophenemethylamine was also
found to be a good reaction partner (Table 2, com-
pound 4f ).
To get some insights into the reaction procedure, a
test experiment was carried out. Under optimal
conditions 2-aminobenzaldehyde gave the desired
product with almost the same yield. Supposedly, the
1 The text was submitted by the authors in English.
812

SYNTHESIS OF QUINAZOLINES FROM (2-AMINOARYL)METHANOLS
813
Scheme 1. Synthesis of quinazoline derivatives from alcohols with arylmethanamines.
1, base
OH
NH2
N
NH2
+
solvent, temperature
N
Ph
N
PPh2
PPh2
(Rh complex, 1).
Rh
Ph2P
first step of the reaction was dehydrogenation of (2-amino-
phenyl)methanol leading to 2-aminobenzaldehyde.
115.4 d (J = 22.8 Hz), 117.4 d (J = 21.8 Hz), 123.7,
124.1 d (J = 3.2 Hz), 127.1, 127.6, 128.7, 130.0 d (J =
8.2 Hz), 134.2, 140.4 d (J = 8.0 Hz), 150.6, 159.8,
160.5, 163.3 d (J = 242.8 Hz).
EXPERIMENTAL
2-(4-(Methylthio)phenyl)quinazoline (4c). Yellow
solid, mp 106–107°C. 1H NMR spectrum, δ, ppm: 2.48
s (3H), 7.31 d (J = 7.8 Hz, 2H), 7.51 t (J = 7.8 Hz,
1H), 7.79–7.75 m (2H), 7.97 d (J = 7.8 Hz, 1H), 8.48 d
Chemicals used were commercially available and
applied without further purification. Reactions
progress was monitored by TLC (100–400 mesh silica
gel plates, GF254). The products were isolated by
column chromatography on silica gel (200–300 mesh
or 100–200 mesh) using petroleum ether (60–90°C)
Table 1. Screening of reaction conditionsa
1
with ethyl acetate as the eluent. H NMR spectra were
OH
measured on a Bruker Advance 400 in CDCl3 using
TMS as the internal reference.
NH2
N
1, base
+
TEMPO,
solvent
NH2
N
Ph
General procedyre of synthesis of 4a. To the
mixture of (2-aminophenyl)methanol 2a (0.5 mmol)
with TMB (5 mL) were added phenylmethanamine 3a
(0.6 mmol) and TEMPO (0.1 mmol) at room
temperature. Upon following addition of Cs2CO3
(2.0 mmol) the mixture was stirred for 5 min and then
refluxed upon stirring for 16 h. Upon the reaction
completion, the mixture was cooled down and purified
by column chromatography with petroleum ether/ethyl
acetate (10 : 1) eluent leading to the product 4a.
2a
3a
4a
Entry
1
Base
NEt3
Solvent
Toluene
DMF
Yieldb, %
28
2
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
–
<5
3
Dioxane
DCM
<5
4
<5
5
CH3CN
Xylene
TMB
<5
6
38
2-Phenylquinazoline (4a). Yellowish solid, mp 97–
1
98°C. H NMR spectrum, δ, ppm: 7.46 m (3H), 7.55 t
7
47
(J = 7.8 Hz, 1H), 7.85 t (J = 8.2 Hz, 2H), 8.03 d (J =
9
TMB
<5
13
8.2 Hz, 1H), 8.56 d (J = 7.8 Hz, 2H), 9.41 s (1H). C
10
11
12
13
KOH
K2CO3
Na2CO3
Cs2CO3
TMB
16
NMR spectrum, δ, ppm: 123.6, 127.1, 127.2, 128.6,
128.65, 128.67, 130.6, 134.0, 138.0, 150.8, 160.5, 161.6.
TMB
56
2-(3-Fluorophenyl)quinazoline (4b). Yellowish solid,
TMB
52
1
mp 95–96°C. H NMR spectrum, δ, ppm: 7.23 t (J =
TMB
76
7.8 Hz, 1H), 7.53 d.d (J = 14.3, 7.2 Hz, 1H), 7.66 t (J =
8.2 Hz, 1H), 7.95 t (J = 8.2 Hz, 2H), 8.11 d (J =
8.2 Hz, 1H), 8.37 d (J = 11.8 Hz, 1H), 8.46 d (J =
a
Reaction conditions: 2a (0.5 mmol), 3a (0.6 mmol), Rh 1 (5 mol %),
TEMPO (0.1 mmol), base(2.0 mmol), solvent (5 mL), 150°C or
reflux, 16 h, TMB = 1,3,5-trimethylbenzene, N2.
Isolated yield.
13
b
7.8 Hz, 1H), 9.49 s (1H). C NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017

814
WANG et al.
Table 2. Substrate scope of the reactiona,b
R
OH
1, Cs2CO3
TEMPO, solvent
N
+
Ar
NH2
NH2
N
Ar
2a
3a
4a
Comp. no.
Ar
Product
Yieldb, %
76
4a
C6H5
N
N
4b
4c
3-F-C6H4
72
87
N
N
F
N
N
4-SMe-C6H4
SMe
4d
4e
4f
4-NMe2-C6H4
4-CF3-C6H4
2-Thiophene
85
63
78
N
N
N
N
N
NMe2
CF3
N
S
a
Reaction conditions: 2 (0.5 mmol), 3 (0.6 mmol), Rh 1 (5 mol %), TEMPO (0.1 mmol), Cs2CO3 (2.0 mmol), TMB (5 mL), reflux, 16 h,
TMB = 1,3,5-trimethylbenzene, N2. b Isolated yield.
13
(J = 8.2 Hz, 2H), 9.35 s (1H). C NMR spectrum, δ,
ppm: 15.2, 123.5, 125.8, 127.10, 127.14, 128.52, 128.9,
134.1, 134.6, 142.0, 150.8, 160.4, 160.6.
6-Methyl-2-(4-(trifluoromethyl)phenyl)quina-
zoline (4e). Yellow solid, mp 155–156°C. H NMR
1
spectrum, δ, ppm: 2.51 s (3H), 7.62 s (1H), 7.69 d (J =
8.2 Hz, 3H), 7.92 d (J = 7.8 Hz, 1H), 8.64 d (J =
N,N-Dimethyl-4-(quinazolin-2-yl)aniline (4d).
13
8.0 Hz, 2H), 9.31 s (1H). C NMR spectrum, δ, ppm:
1
Yellowish solid, mp 126–127°C. H NMR spectrum, δ,
21.6, 123.8, 125.4, 125.8, 128.4, 128.6, 131.7, 132.0,
136.6, 138.1, 141.4, 149.2, 158.9, 159.8.
ppm: 2.95 s (6H), 6.72 d (J = 7.8 Hz, 2H), 7.41 t (J =
7.8 Hz, 1H), 7.72 t (J = 7.8 Hz, 2H), 7.91 d (J =
7.8 Hz, 1H), 8.41 d (J = 7.8 Hz, 2H), 9.25 s (1H). C
13
2-(Thiophen-2-yl)quinazoline (4f). Yellow solid,
1
NMR spectrum, δ, ppm: 40.2, 111.7, 123.0, 125.7, 126.1,
mp 131–132°C. H NMR spectrum, δ, ppm: 7.09 m
127.1, 128.1,129.9, 133.8, 151.0, 152.2, 160.2, 161.5.
(1H), 7.50–7.35 m (2H), 7.75 d (J = 7.8 Hz, 2H), 7.89
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017

SYNTHESIS OF QUINAZOLINES FROM (2-AMINOARYL)METHANOLS
815
d (J = 8.2 Hz, 1H), 8.05(m, 1H), 9.23 s (1H). 13C NMR
spectrum, δ, ppm: 123.3, 127.0, 127.2, 128.19, 128.4,
129.2, 129.9, 134.3, 143.8, 150.6, 157.8, 160.5.
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A rhodium-catalyzed synthesis of quinazoline
derivatives via dehydrogenation and ring-closing
reaction is developed. This method provides an easy
and efficient approach to quinazoline derivatives with
moderate to high yields.
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We gratefully acknowledge financial support of this
work by the Natural Science Foundation (20130124).
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