Hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of thioethers and ethers from quinazolin-4(3H)-ones

Article abstract of DOI:10.3390/molecules18055580

A hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of quinazoline (thio)ethers from quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, diisopropylethylamine (DIPEA), and thiophenols resulted in formation of the corresponding 4-arylthioquinazoline derivatives in moderate to excellent yields. This method has also been utilized to prepare 4-aryloxyquinazoline and 4-alkoxyquinazoline derivatives using phenols and sodium alkoxides as the nucleophiles.

Full text of DOI:10.3390/molecules18055580

Molecules 2013, 18, 5580-5593; doi:10.3390/molecules18055580
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Hexachlorocyclotriphosphazene (HCCP)-Mediated Direct Formation
of Thioethers and Ethers from Quinazolin-4(3H)-ones
Baoxiang Hu 1, Xiaochu Zhang 1, Lili Sheng 1, Ming Guo 2, Zhenlu Shen 1,*, Xinquan Hu 1,
Nan Sun 1 and Weimin Mo 1,*
1
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
College of Chemical Engineering and Materials Science, Zhejiang University of Technology,
Hangzhou 310014, China
2
Department of Chemistry, Zhejiang Agriculture & Forestry University, Lin’An 311300, China
* Authors to whom correspondence should be addressed; E-Mails: zhenlushen@zjut.edu.cn (Z.S.);
mowm@zjut.edu.cn (W.M.); Tel.: +86-571-8832-0416 (Z.S.); Fax: +86-571-8832-0103 (Z.S.).
Received: 25 March 2013; in revised form: 12 May 2013 / Accepted: 13 May 2013 /
Published: 15 May 2013
Abstract: A hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of
quinazoline (thio)ethers from quinazolin-4(3H)-ones has been developed. Treatment of
quinazolin-4(3H)-ones with HCCP, diisopropylethylamine (DIPEA), and thiophenols
resulted in formation of the corresponding 4-arylthioquinazoline derivatives in moderate to
excellent yields. This method has also been utilized to prepare 4-aryloxyquinazoline and
4-alkoxyquinazoline derivatives using phenols and sodium alkoxides as the nucleophiles.
Keywords: quinazolin-4(3H)-ones; hexachlorocyclotriphosphazene; 4-arylthioquinazolines;
4-aryloxyquinazolines; 4-alkoxyquinazolines
1. Introduction
Quinazoline derivatives are an important class of nitrogen-containing heterocycles. They have
attracted interest in the past because of their varied biological activities, such as anticonvulsant,
antihypertensive, vasodilator, antiinflammatory, antibiosis, fibrinogen receptor antagonistic and
nanomolar Hedgehog-antagonistic properties [1–8]. Among the family of quinazolines, quinazoline
(thio)ethers, including 4-arylthioquinazolines and 4-aryloxyquinazolines, have received considerable
interest because of their potential pharmacological activity [9–16].

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Generally, 4-arylthioquinazolines and 4-aryloxyquinazolines are obtained through SNAr substitution
of electron-deficient 4-chloroquinazolines with the appropriate thiophenols or phenols in the presence
of a base [9–19]. The common method for preparation of 4-chloroquinazolines is the chlorination of
corresponding quinazolin-4(3H)-ones. The chlorination reagents used include SOCl2, POCl3, PCl5 or
their combinations, and the chlorination reactions are usually performed under harsh conditions.
However, these chlorination reagents are not environmentally friendly, and some sensitive functional
groups may be destroyed under the chlorination conditions. In addition, many 4-chloroquinazoline
derivatives are moisture sensitive, thus special treatments are required for their purification and storage.
In order to avoid the use of chlorination reagents and an individual activation step, an in situ
activation of quinazolin-4(3H)-ones is highly desirable. Phosphonium compounds, such as benzotriazol-
1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), have been developed to activate
quinazolin-4(3H)-ones and successfully employed in the synthesis of 4-aminoquinazolines,
4-arylthioquinazolines and 4-aryloxyquinazolines using amine, thiophenol and phenol nucleophiles,
respectively [20,21]. However, BOP and other phosphonium reagents are expensive, moreover,
utilization of BOP generates as an end product HMPA, a highly carcinogenic chemical.
As a part of our research program focused on quinazoline chemistry [22,23], we have recently,
reported that hexachlorocyclotriphosphazene (Cl6N3P3, HCCP) can be used as an inexpensive and
readily available activating reagent in the direct amination of quinazolin-4(3H)-ones (1) [24]. In the
reaction, quinazolin-4(3H)-ones are activated in situ with HCCP to generate the highly reactive
phosphonium intermediate 2, then amines can nucleophilically attack 2 to form 4-aminoquinazolines.
Thus, we speculated that other nucleophiles, such as thiophenol and phenol ones, might attack 2 to
form the corresponding products. Herein, we report a HCCP-mediated, single-pot, facile synthesis of
thioethers and ethers from quinazolin-4(3H)-ones in moderate to excellent yields (Scheme 1).
Scheme 1. One-pot synthesis of quinazoline (thio)ethers from quinazolin-4(3H)-ones
mediated by HCCP.
Ar
S
ArSH
N
R1
Cl
Cl
P
N
P
N
P
N
O
O
N
Cl
Cl
N
O
N
HCCP, DIPEA
NH
Ar
N
R2
N
R1
Cl
O
N
R1
ArOH or R2ONa
R1
R1
or
N
N
1
2
2. Results and Discussion
Initially, the reaction of quinazolin-4(3H)-one (1a) and thiophenol was investigated as the model
reaction to establish the feasibility of the strategy and to optimize the reaction conditions. The effects
of solvent, base, temperature and HCCP loading, etc., were evaluated for this model reaction, and the
results are summarized in Table 1.

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Table 1. Optimization of reaction conditions a.
O
S
N
HCCP, base,
solvent
NH
N
PhSH
N
1a
3
Entry
Base
Solvent
MeCN
MeCN
MeCN
MeCN
THF
Temperature (°C)
Yield (%) b
1
2
TEA
45
45
45
45
45
45
45
45
25
65
45
45
45
45
48
32
K2CO3
Cs2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
3
69
4
81
5
12
6
DMF
23
7
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
7
8
76 c
68
9
10
11
12
13
55
79 d
71 e
81 f
70 g
14
a
Conditions: 1a (0.5 mmol), HCCP (1.1 equiv.), base (5.0 equiv.), solvent (5 mL), rt, activation time (1 h),
b
c
d
then thiophenol (6.0 equiv.), 45 °C, 23 h; Isolated yield; HCCP (1.0 equiv.); Thiophenol (5.0 equiv.);
e Thiophenol (4.0 equiv.); f DIPEA (6.0 equiv.); g DIPEA (4.0 equiv.).
Compared with triethylamine (TEA), K2CO3 and Cs2CO3 (entries 1–3), diisopropylethylamine
(DIPEA) was found to be the most effective in the model reaction of 1a and thiophenol (entry 4). The
results in Table 1 show that the solvent can greatly affect the reaction, and acetonitrile led to much
better yield of product 3 than tetrahydrofuran, N,N-dimethylformamide or dichloromethane (entries
4–7). According to Scheme 1, 1.0 equiv. HCCP loading was enough, but we found that increasing the
HCCP loading from 1.0 to 1.1 equiv. resulted in 5% yield increases (entry 8 versus entry 4). After in situ
activation of 1a with HCCP at room temperature for 1 h, the SNAr substitution of phosphonium
intermediate 2a (R1 = H) with thiophenol was performed at 45 °C. At both lower and higher
temperature, the yield of 3 decreased (entries 9 and 10). Like the HCCP-mediated direct amination of
quinazolin-4(3H)-ones with amines [24], when the thiophenol nucleophile attacks 2a, two competitive
SNAr substitutions were possible, either on the C–O bond or P–Cl bond. Thus, five to six equiv. of
thiophenol and DIPEA were needed in this reaction. It was found variation of the amount of thiophenol
or DPIEA from 6.0 equiv. to 5.0 equiv. did not significantly change the results (entry 4 versus entries
11 and 13), whereas upon decreasing the amount of thiophenol or DPIEA to 4.0 equiv., the yield of 3
was obviously decreased (entries 12 and 14). On the basis of these experimental data, the optimal
reaction conditions were: 1.1 equiv. of HCCP, 5.0 equiv. of DIPEA, 5.0 equiv. of thiophenol, 45 °C
of reaction temperature and acetonitrile as the reaction solvent, and these were employed in the
following studies.

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The results of HCCP-mediated direct formation of thioethers (4-arylthioquinazolines) from 1 and
thiophenols are summarized in Table 2. Different substituted thiophenols smoothly reacted with 1a to
afford the desired 4-arylthioquinazolines in moderate to excellent yields (entries 1–9). When o, m, and
p-methoxythiophenols were used as the nucleophiles, o-methoxythiophenol gave the highest product
yield, while m-methoxythiophenol showed the lowest reactivity (entries 4–6). It is noteworthy that
chlorothiophenols, which usually exhibit lower nucleophilicity than methoxythiophenols, could
conveniently undergo the transformation and gave excellent product yields in this HCCP-mediated
direct formation of 4-arylthioquinazolines (entries 7 and 9). The reactions between thiophenol and a
variety of substituted quinazolin-4(3H)-ones were also investigated. An array of substituted
quinazolin-4(3H)-ones were suitable for this HCCP-mediated formation of thioethers and gave
the desired 4-arylthioquinazolines in moderate to good yields (entries 1, 10–15). When
5-methylquinazolin-4(3H)-one (1b) and 5-chloroquinazolin-4(3H)-one (1e) were used as the substrates,
activation time should be prolonged (entries 10 and 13).
Table 2. HCCP-mediated formation of quinazoline thioethers from quinazolin-4(3H)-ones a.
Ar
O
S
HCCP, DIPEA,
MeCN
NH
N
R1
R1
ArSH
N
N
1
3-17
Entry
Quinazolin-4(3H)-one
ArSH
Product
Yield (%) b
O
SH
S
N
N
NH
1
1a
3
4
5
6
79
N
SH
S
2
3
4
1a
64 c
N
N
N
N
S
SH
1a
1a
69
N
S
SH
OCH3
59
OCH3
N

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Table 2. Cont.
Entry
Quinazolin-4(3H)-one
ArSH
SH
Product
Yield (%) b
S
OCH3
5
1a
1a
7
8
50
N
N
OCH3
N
S
OCH3
SH
6
86
CH3O
N
SH
Cl
S
7
8
1a
1a
9
94
66
Cl
N
N
SH
S
Cl
Cl
10
N
Cl
N
S
SH
9
1a
11
91
Cl
N
N
O
SH
SH
S
10
11
1b
1c
12
13
54 d
NH
N
N
N
O
S
NH
60
N
N
N
O
S
SH
NH
12
1d
14
64
N
N
N

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Table 2. Cont.
Entry
Quinazolin-4(3H)-one
ArSH
Product
Yield (%) b
Cl
O
SH
SH
SH
Cl
S
N
N
13
1e
1f
15
16
17
51 d
NH
N
O
S
N
N
Cl
NH
14
15
79
72
Cl
N
O
S
N
N
NH
1g
Cl
N
Cl
a
Reagents and Conditions: 1 (0.5 mmol), HCCP (1.1 equiv.), DIPEA (5.0 equiv.), MeCN (5 mL), rt,
activation time (1 h), then thiophenols (5.0 equiv.), 45 °C, 23 h; b Isolated yield; c m-CH3PhSH (6.0 equiv.);
reaction time (48 h); d Activation time (20 h).
The method was further extended to the synthesis of 4-aryloxyquinazolines through the reaction of 1
and phenols under the same reaction conditions (Table 3). Different phenols (phenol, m-methylphenol,
o-chlorophenol and p-chlorophenol) could react with 1a and afforded the corresponding products
18–21 in moderate to good yields (entry 1–5). There is no significant electronic effect of substituents
for products. Substituted quinazolin-4(3H)-ones were also used as the substrates to react with phenol.
6-Chloroquinazolin-4(3H)-one (1f) and 7-chloroquinazolin-4(3H)-one (1g) gave products 14 and 15 in
70% yield (entries 6 and 7), whereas in the case of 5-methylquinazolin-4(3H)-one (1b), the product 12
was obtained in 54% yield (entry 5). Alcohols were also used as the nucleophiles in this reaction.
Unfortunately, no desired 4-alkoxyquinazolines were formed. It might be due to that the nucleophilicity
of alcohols was too weak to undego SNAr substitution. Thus, sodium alkoxides were further utilized as
the nucleophiles in this reaction to give the corresponding 4-alkoxyquinazolines (Table 3). When 1a,
8-methylquinazolin-4(3H)-one (1d) and 1g reacted with sodium ethoxide for 3 h, the yields of products
4-ethoxyquinazolines were 54%, 64% and 67%, respectively (entries 8,10 and 11), while 1b gave only
33% product yield (entry 9). 4-Propoxyquinazoline (29) could be obtained in 48% yield in the reaction
between 1a and sodium propoxide (entry 12).
Table 3. HCCP-mediated formation of quinazoline ethers from quinazolin-4(3H)-ones a.
Ar
R2
O
O
O
N
HCCP, DIPEA,
MeCN
N
N
R1
R1
NH
or
R1
ArOH or R2ONa
N
N
1
18-24
25-39

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Table 3. Cont.
Entry Quinazolin-4(3H)-one
ArOH or RONa
Product
Yield (%) b
OH
OH
O
N
N
1
2
3
1a
1a
1a
18
19
20
75
52
73
O
N
N
OH
Cl
O
Cl
N
N
Cl
OH
O
N
4
1a
21
51
Cl
N
OH
OH
OH
O
N
5
6
1b
1f
22
23
53 c
N
O
70
Cl
N
N
O
7
8
1g
1a
24
25
70
54
N
Cl
N
O
N
CH3CH2ONa
N

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Table 3. Cont.
Entry Quinazolin-4(3H)-one
ArOH or RONa
Product
Yield (%) b
O
N
N
9
1b
1d
CH3CH2ONa
CH3CH2ONa
26
27
33 c
O
N
N
10
11
67
O
N
1g
1a
CH3CH2ONa
28
29
64
48
Cl
N
O
N
N
12
CH3CH2CH2ONa
a
Reagents and Conditions: 1 (0.5 mmol), HCCP (1.1 equiv.), DIPEA (5.0 equiv.), MeCN (5 mL), rt, activation
time (1 h), then phenols (5.0 equiv.), 45 °C, 23 h; or R2ONa (5.0 equiv.), 45 °C, 3 h; Isolated yield;
b
c Activation time (20 h).
3. Experimental
3.1. General
1H-NMR (500 MHz) and 13C-NMR (125 MHz) spectra were obtained on a Bruker Avance III
spectrometer. CDCl3 and DMSO-d6 were used as the solvent with tetramethylsilane (TMS) as the
internal standard. Low and high resolution mass spectra were recorded in the ESI mode on an Agilent
6210 LC/TOF mass spectrometer. Melting points were measured using XRL-1 melting point
instrument and are uncorrected. Quinazolin-4(3H)-ones were synthesized from anthranilic acids and
1
formamidine acetate, and their structures were confirmed by MS, H-NMR, and 13C-NMR. Other
reagents were purchased from supplier and used without any further treatment.
3.2. General Procedure for HCCP-Mediated Formation of Thioethers and Ethers from
Quinazolin-4(3H)-ones
Quinazolin-4(3H)-ones (1, 0.5 mmol), HCCP (171.2 mg, 0.55 mmol, 1.1 equiv.), DIPEA (323.8 mg,
2.5 mmol, 5 equiv.), and CH3CN (5 mL) were added to a nitrogen purged vial. The reaction mixture
was stirred at room temperature for 1 h as activation time. Then nucleophile (2.5 mmol, 5 equiv. was
added, and the reaction mixture was stirred at 45 °C for 23 h. The reaction mixture was partially
concentrated under reduced pressure. The crude product was separated on a silica gel plate with ethyl
acetate–hexane (1:10 or 1:5) as eluent. Then the area corresponding to the product was scraped off the

Molecules 2013, 18
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TLC plate, and extracted with dichloromethane. The extract was concentrated to afford the
corresponding products (3–29).
4-(Phenylthio)quinazoline (3). White solid (79% yield); mp 109–110 °C; 1H-NMR (DMSO-d6) δ 8.84
(s, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.07–8.04 (m, 1H), 8.00–7.99 (m, 1H), 7.83–7.79 (m, 1H), 7.68–7.66
13
(m, 2H), 7.56–7.54 (m, 3H); C-NMR (DMSO-d6) δ 170.3, 153.5, 147.8, 135.8, 134.6, 129.9, 129.6,
128.5, 128.4, 126.5, 123.6, 122.3; HRMS (ESI), m/z, 239.0644 [MH+], calcd for C14H11N2S, 239.0643.
4-(m-Tolylthio)quinazoline (4). White solid (64% yield); mp 58–61 °C; 1H-NMR (DMSO-d6) δ 8.83 (s,
1H), 8.25 (d, J = 8.0 Hz, 1H), 8.05–8.02 (m, 1H), 7.99–7.97 (m, 1H), 7.81–7.77 (m, 1H), 7.48–7.41 (m,
3H), 7.36–7.35 (m, 1H), 2.37 (s, 3H); 13C-NMR (DMSO-d6) δ 170.5, 153.5, 147.8, 139.0, 136.0, 134.6,
132.9, 130.6, 129.4, 128.5, 128.3, 126.2, 123.6, 122.4, 20.7; HRMS (ESI), m/z, 253.0795 [MH+], calcd
for C15H13N2S, 253.0799.
1
4-(p-Tolylthio)quinazoline (5) White solid (69% yield); mp 104–105 °C; H-NMR (DMSO-d6) δ 8.81
(s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.02–7.98 (m, 1H), 7.96–7.95 (m, 1H), 7.77–7.73 (m, 1H), 7.50–7.48
13
(m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H); C-NMR (DMSO-d6) δ 170.6, 153.4, 147.7, 139.7,
135.7, 134.4, 130.1, 128.4, 128.2, 123.4, 122.9, 122.3, 20.8; HRMS (ESI), m/z, 253.0798 [MH+], calcd
for C15H13N2S, 253.0799.
4-(2-Methoxyphenylthio)quinazoline (6). White solid (59% yield); mp 111–113 °C; 1H-NMR (DMSO-d6)
δ 8.80 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.04–8.01 (m, 1H), 7.98–7.96 (m, 1H), 7.80–7.76 (m, 1H),
7.60–7.54 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.10–7.07 (m, 1H), 3.74 (s, 3H); 13C-NMR (DMSO-d6) δ
170.0, 160.0, 153.5, 147.8, 137.5, 134.4, 132.2, 128.4, 128.2, 123.7, 122.5, 121.2, 114.2, 112.3, 55.9;
HRMS (ESI), m/z, 269.0747 [MH+], calcd for C15H13N2OS, 269.0749.
4-(3-Methoxyphenylthio)quinazoline (7). White solid (50% yield); mp 80–82 °C; 1H-NMR (DMSO-d6)
δ 8.86 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.06–8.03 (m, 1H), 8.00–7.98 (m, 1H), 7.81–7.78 (m, 1H),
7.47–7.44 (m, 1H), 7.24–7.22 (m, 2H), 7.14–7.11 (m, 1H), 3.80 (s, 3H); 13C-NMR (DMSO-d6) δ 170.3,
159.7, 153.5, 147.8, 134.6, 130.3, 128.5, 128.3, 127.8, 127.5, 123.5, 122.4, 120.9, 115.7, 55.3; HRMS
(ESI), m/z, 269.0746 [MH+], calcd for C15H13N2OS, 269.0749.
4-(4-Methoxyphenylthio)quinazoline (8). White solid (86% yield); mp 125–128 °C; 1H-NMR (DMSO-d6)
δ 8.82 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.04–8.01 (m, 1H), 7.98–7.96 (m, 1H), 7.80–7.77 (m, 1H),
7.57–7.54 (m, 2H), 7.10–7.09 (m, 2H), 3.84 (s, 3H); 13C-NMR (DMSO-d6) δ 171.1, 160.7, 153.5,
147.7, 137.6, 134.6, 128.4, 128.3, 123.6, 122.3, 116.6, 115.3, 55.4; HRMS (ESI), m/z, 269.0739 [MH+],
calcd for C15H13N2OS, 269.0749.
4-(2-Chlorophenylthio)quinazoline (9). White solid (94% yield); mp 124–126 °C; 1H-NMR (DMSO-d6)
δ 8.85 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.08–8.05 (m, 1H), 8.02–8.00 (m, 1H), 7.84–7.80 (m, 2H),
7.74–7.72 (m, 1H), 7.62–7.59 (m, 1H), 7.52–7.49 (m, 1H); 13C-NMR (DMSO-d6) δ 168.9, 153.4,
147.9, 138.8, 138.4, 134.7, 132.2, 130.3, 128.51, 128.47, 128.2, 125.9, 123.6, 122.3; HRMS (ESI), m/z,
273.0244 [MH+], calcd for C14H10ClN2S, 273.0253.

Molecules 2013, 18
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4-(3-Chlorophenylthio)quinazoline (10). White solid (66% yield); mp 125–126 °C; 1H-NMR (DMSO-d6)
δ 8.86 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.04–8.03 (m, 1H), 8.00–7.98 (m, 1H), 7.81–7.76 (m, 2H),
7.65–7.61 (m, 2H), 7.58–7.55 (m, 1H); 13C-NMR (DMSO-d6) δ 169.7, 153.4, 147.9, 135.0, 134.7,
134.4, 133.6, 131.1, 129.9, 128.8, 128.5, 128.4, 123.5, 122.3; HRMS (ESI), m/z, 273.0243 [MH+],
calcd for C14H10ClN2S, 273.0253.
4-(4-Chlorophenylthio)quinazoline (11). White solid (91% yield); mp 133–134 °C; 1H-NMR (DMSO-d6)
δ 8.85 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.07–8.03 (m, 1H), 8.00–7.99 (m, 1H), 7.82–7.79 (m, 1H),
7.70–7.67 (m, 2H), 7.62–7.60 (m, 2H); 13C-NMR (DMSO-d6) δ 169.9, 153.4, 147.8, 137.5, 135.0,
134.7, 129.6, 128.5, 128.4, 125.5, 123.5, 122.3; HRMS (ESI), m/z, 273.0240 [MH+], calcd for
C14H10ClN2S, 273.0253.
5-Methyl-4-(phenylthio)quinazoline (12). White solid (54% yield); mp 131–133 °C; 1H-NMR (DMSO-d6)
δ 8.66 (s, 1H), 7.85–7.82 (m, 1H), 7.80–7.78 (m, 1H), 7.62–7.57 (m, 3H), 7.55–7.52 (m, 3H), 3.07
13
(s, 3H); C-NMR (DMSO-d6) δ 171.3, 152.2, 150.2, 135.9, 135.4, 133.4, 130.8, 129.7, 129.5, 128.2,
127.0, 123.4, 24.7; HRMS (ESI), m/z, 253.0790 [MH+], calcd for C15H13N2S, 253.0799.
6-Methyl-4-(phenylthio)quinazoline (13). White solid (60% yield); mp 100–102 °C; 1H-NMR (DMSO-d6)
δ 8.83 (s, 1H), 8.00 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.67–7.65 (m, 2H),
7.52–7.51 (m, 3H), 2.62 (s, 3H); 13C-NMR (DMSO-d6) δ 170.4, 153.3, 146.9, 137.9, 136.0, 135.8,
129.7, 129.4, 128.6, 127.4, 123.3, 122.7, 21.8; HRMS (ESI), m/z, 253.0796 [MH+], calcd for
C15H13N2S, 253.0799.
8-Methyl-4-(phenylthio)quinazoline (14). White solid (64% yield); mp 98–100 °C; 1H-NMR (DMSO-d6)
δ 8.84 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.65–7.62 (m, 3H), 7.54–7.53 (m,
3H), 2.66 (s, 3H); 13C-NMR (DMSO-d6) δ 170.3, 152.6, 146.8, 136.7, 135.7, 134.2, 129.7, 129.5,
127.7, 126.8, 122.2, 121.1, 17.0; HRMS (ESI), m/z, 253.0789 [MH+], calcd for C15H13N2S, 253.0799.
5-Chloro-4-(phenylthio)quinazoline (15). White solid (51% yield); mp 133–134 °C; 1H-NMR (CDCl3)
δ 8.73 (s, 1H), 7.91–7.89 (m, 1H), 7.74–7.68 (m, 2H), 7.60–7.58 (m, 2H), 7.51–7.50 (m, 3H);
13C-NMR (CDCl3) δ 172.5, 153.2, 151.3, 135.9, 132.7, 130.6, 129.9, 129.7, 129.4, 129.3, 128.5, 122.6;
HRMS (ESI), m/z, 273.0244 [MH+], calcd for C14H10ClN2S, 273.0253.
6-Chloro-4-(phenylthio)quinazoline (16). White solid (79% yield); mp 103–105 °C; 1H-NMR (CDCl3)
δ 8.86 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.83–7.81 (m, 1H), 7.66–7.64 (m,
13
2H), 7.53–7.51 (m, 3H); C-NMR (CDCl3) δ 170.7, 154.0, 146.9, 135.8, 134.8, 133.3, 130.5, 130.0,
129.5, 126.7, 123.8, 122.9; HRMS (ESI), m/z, 273.0241 [MH+], calcd for C14H10ClN2S, 273.0253.
7-Chloro-4-(phenylthio)quinazoline (17). White solid (72% yield); mp 142–143 °C; 1H-NMR (DMSO-d6)
δ 8.85 (s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.83–7.81 (m, 1H), 7.67–7.66 (m, 2H),
7.57–7.55 (m, 3H); 13C-NMR (DMSO-d6) δ 170.7, 154.5, 148.6, 139.2, 135.7, 130.0, 129.6, 128.9,
127.3, 126.1, 125.7, 121.0; HRMS (ESI), m/z, 273.0255 [MH+], calcd for C14H10ClN2S, 273.0253.

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4-Phenoxyquinazoline (18). White solid (75% yield); mp 123–125 °C; 1H-NMR (CDCl3) δ 8.80 (s, 1H),
8.42–8.40 (m, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.96–7.94 (m, 1H), 7.69 (t, J =1.0 Hz, 1H), 7.54–7.50
(m, 2H), 7.37–7.35 (m, 1H), 7.30–7.28 (m, 2H); 13C-NMR (CDCl3) δ 167.0, 154.4, 152.4, 151.7, 134.2,
129.8, 128.0, 127.6, 126.1, 123.7, 121.9, 116.5; HRMS (ESI), m/z, 223.0868 [MH+], calcd for
C14H11N2O, 223.0871.
1
4-(m-Tolyloxy)quinazoline (19). White solid (52% yield); mp 100–101 °C; H-NMR (CDCl3) δ 8.81
(s, 1H), 8.41–8.39 (m, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.95–7.92 (m, 1H), 7.70–7.67 (m, 1H), 7.41–7.38
(d, J = 7.5 Hz, 1H), 7.17–7.08 (m, 3H), 2.44 (s, 3H); 13C-NMR (CDCl3) δ 167.1, 154.4, 152.3, 151.6,
140.1, 134.1, 129.5, 127.9, 127.6, 126.9, 123.7, 122.4, 118.8, 116.5, 21.4; HRMS (ESI), m/z, 237.1025
[MH+], calcd for C15H13N2O, 237.1028.
1
4-(2-Chlorophenoxy)quinazoline (20). White solid (73% yield); mp 118–119 °C; H-NMR (CDCl3) δ
8.78 (s, 1H), 8.46–8.45 (m, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.98–7.96 (m, 1H), 7.74–7.72 (m, 1H),
13
7.57–7.56 (m, 1H), 7.43–7.41 (m, 1H), 7.38–7.36 (m, 1H), 7.34–7.32 (m, 1H); C-NMR (CDCl3) δ
166.2, 154.1, 151.9, 148.6, 134.3, 130.7, 128.1, 128.0, 127.8, 127.31, 127.26, 124.1, 123.7, 116.1;
HRMS (ESI), m/z, 257.0479 [MH+], calcd for C14H10ClN2O, 257.0482.
1
4-(4-Chlorophenoxy)quinazoline (21). White solid (51% yield); mp 105–108 °C; H-NMR (CDCl3) δ
8.79 (s, H), 8.39 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.97–7.94 (m, 1H), 7.72–7.69 (m, 1H),
13
7.49–7.46 (m, 2H), 7.28–7.23 (m, 2H); C-NMR (CDCl3) δ 116.8, 154.1, 151.8, 150.9, 134.3, 131.5,
129.9, 128.0, 127.8, 123.5, 123.3, 116.3; HRMS (ESI), m/z, 257.0469 [MH+], calcd for C14H10ClN2O,
257.0482.
5-Methyl-4-phenoxyquinazoline (22). White solid (53% yield); mp 73–75 °C; 1H-NMR (CDCl3) δ 8.70
(s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.53–7.50 (m, 2H), 7.45 (d, J = 7.5 Hz, 1H),
13
7.36–7.33 (m, 1H), 7.28–7.25 (m, 2H), 3.00 (s, 3H); C-NMR (CDCl3) δ 168.0, 153.7, 153.4, 152.3,
136.7, 133.4, 129.9, 129.8, 126.1, 125.9, 122.0, 116.3, 24.1; HRMS (ESI), m/z, 237.1021 [MH+], calcd
for C15H13N2O, 237.1028.
6-Chloro-4-phenoxyquinazoline (23). White solid (70% yield); mp 94–97 °C; 1H-NMR (CDCl3) δ 8.77
(s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.86–7.83 (m, 1H), 7.52–7.49 (m, 2H),
13
7.36–7.33 (m, 1H), 7.29–7.27 (m, 2H); C-NMR (CDCl3) δ 166.1, 154.4, 152.1, 150.1, 134.9, 133.2,
129.8, 129.6, 126.2, 122.7, 121.7, 117.1; HRMS (ESI), m/z, 257.0471 [MH+], calcd for C14H10ClN2O,
257.0482.
1
7-Chloro-4-phenoxyquinazoline (24). White solid (70% yield); mp 190–192 °C; H-NMR (CDCl3) δ
8.78 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.65–7.63 (m, 1H), 7.53–7.50 (m, 2H),
7.36 (t, J = 7.5 Hz, 1H), 7.29–7.27 ppm (m, 2H); 13C-NMR (CDCl3) δ 166.9, 155.5, 152.4, 152.2,
140.5, 129.8, 128.7, 127.2, 126.2, 125.2, 121.8, 114.9; HRMS (ESI), m/z, 257.0471 [MH+], calcd for
C14H10ClN2O, 257.0482.
1
4-Ethoxyquinazoline (25). White solid (54% yield); mp 31–33 °C; H-NMR (CDCl3) δ 8.80 (s, 1H),
8.19–8.18 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.84–7.81 (m, 1H), 7.58–7.54 (m, 1H), 4.64 (q, J = 7.0 Hz,

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13
2H), 1.53 (t, J = 7.0 Hz, 3H); C-NMR (CDCl3) δ 166.7, 154.5, 150.9, 133.4, 127.7, 126.9, 123.6,
116.8, 63.1, 14.4; HRMS (ESI), m/z, 175.0873 [MH+], calcd for C10H11N2O, 175.0871.
1
4-Ethoxy-5-methylquinazoline (26). White solid (33% yield); mp 66–69 °C; H-NMR (CDCl3) δ 8.72
(s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 4.61 (q, J = 7.0 Hz,
13
2H), 2.86 (s, 3H), 1.54 (t, J = 7.0 Hz, 3H); C-NMR (CDCl3) δ 167.8, 153.8, 152.6, 136.9, 132.7,
129.3, 125.8, 116.4, 63.1, 24.0, 14.4; HRMS (ESI), m/z, 189.1034 [MH+], calcd for C11H13N2O,
189.1028.
1
4-Ethoxy-8-methylquinazoline (27). White solid (67% yield); mp 31–32 °C; H-NMR (CDCl3) δ 8.84
(s, 1H), 8.04–8.02 (m, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 4.63 (q, J = 7.0 Hz, 2H),
13
2.73 (s, 3H), 1.52 (t, J = 7.0 Hz, 3H); C-NMR (CDCl3) δ 166.9, 153.4, 150.0, 135.9, 133.5, 126.4,
121.2, 116.6, 62.9, 17.6, 14.3; HRMS (ESI), m/z, 189.1023 [MH+], calcd for C11H13N2O, 189.1028.
1
7-Chloro-4-ethoxyquinazoline (28). White solid (64% yield); mp 87–88 °C; H-NMR (CDCl3) δ 8.76
(s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.49–7.47 (m, 1H), 4.62 (q, J = 7.0 Hz, 2H),
13
1.51 (t, J = 7.0 Hz, 3H); C-NMR (CDCl3) δ 166.6, 155.5, 151.6, 139.6, 127.8, 126.9, 125.0, 115.0,
63.3, 14.3; HRMS (ESI), m/z, 209.0479 [MH+], calcd for C10H10ClN2O, 209.0482.
4-Propoxyquinazoline (29). White solid (48% yield); mp 190–192 °C; 1H-NMR (CDCl3) δ 8.79 (s, 1H),
8.19-8.17 (m, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.83–7.80 (m, 1H), 7.57–7.53 (m, 1H), 4.52 (t, J = 6.5 Hz,
2H), 1.95–1.91 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H); 13C-NMR (CDCl3) δ 166.8, 154.4, 150.9, 133.4,
127.6, 126.9, 123.5, 116.7, 68.7, 22.1, 10.5; HRMS (ESI), m/z, 189.1023 [MH+], calcd for C11H13N2O,
189.1028.
4. Conclusions
In summary, we have successfully developed an HCCP-mediated direct formation of thioethers
(4-arylthioquinazolines) from quinazolin-4(3H)-ones and thiophenols in moderate to excellent yields.
This method has also been utilized to prepare quinazoline ethers, including 4-aryloxyquinazolines and
4-alkoxyquinazolines, using phenols and sodium alkoxides as the nucleophiles. This direct formation
of quinazoline (thio)ethers is mild, convenient, and suitable for a wide range of less expensive
nucleophiles. This methodology would facilitate the syntheses of 4-arylthioquinazoline and
4-aryloxyquinazoline derivatives in medicinal chemistry.
Acknowledgments
The authors gratefully acknowledge the financial support of the National Natural Science
Foundations of China (NSFC 21146001), and the Key Science and Technology Innovation Team of
Zhejiang Province (2009R09002-04).
Conflict of Interest
The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 3–17 are available from the authors.
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