Facile and efficient cyclization of anthranilonitrile to 2,4-dichloroquinazoline by bis(trichloromethyl) carbonate and catalytic amount triphenylphosphine oxide

Article abstract of DOI:10.3987/COM-12-12466

2,4-Dichloroquinazolines were synthesized by the cyclization of anthranilonitrile using bis(trichloromethyl) carbonate (BTC) with the aid of catalytic amount of triphenylphosphine oxide (Ph₃PO) at 120 °C. This method was also applied to the syn

Full text of DOI:10.3987/COM-12-12466

HETEROCYCLES, Vol. 85, No. 6, 2012
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HETEROCYCLES, Vol. 85, No. 6, 2012, pp. 1417 - 1426. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 17th March, 2012, Accepted, 24th April, 2012, Published online, 1st May, 2012
DOI: 10.3987/COM-12-12466
FACILE AND EFFICIENT CYCLIZATION OF ANTHRANILONITRILE
TO 2,4-DICHLOROQUINAZOLINE BY BIS(TRICHLOROMETHYL)
CARBONATE AND CATALYTIC AMOUNT TRIPHENYLPHOSPHINE
OXIDE
Zhenhua Li, Danli Wu, and Weihui Zhong*
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment
of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou 310014, P. R. China; Fax:
+86(571)88871087; E-mail: weihuizhong@zjut.edu.cn
Abstract – 2,4-Dichloroquinazolines were synthesized by the cyclization of
anthranilonitrile using bis(trichloromethyl) carbonate (BTC) with the aid of
catalytic amount of triphenylphosphine oxide (Ph3PO) at 120 °C. This method
was also applied to the synthesis of 2,4-dichlorothieno[2,3-d]pyrimidine. The
plausible mechanism is presented.
INTRODUCTION
Quinazoline derivatives have been shown to be promising pharmaceutical agents for the treatment of viral
diseases1 and cancer.2,3 In addition, quinazoline derivatives often served as precursors to
2,4-dichloroquinazolines, which were widely used as intermediates in the synthesis of a variety of
pharmaceutical agents.3,4 Important drugs of the quinazoline family in current use for the treatment of
hypertension are prozocin,5 doxazosin,6 and so on (Figure 1).
O
O
NH2
C
N
O
MeO
MeO
N
MeO
MeO
N
N
N
N
O
N
N
NH2
O
doxazosin
prozocin
Figure 1

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HETEROCYCLES, Vol. 85, No. 6, 2012
The combination of pharmacological application and synthetic utility has generated interest in the
development of methodology for the synthesis of quinazoline derivatives. 2,4-Dichloroquinazolines have
been prepared in a conventional manner from the corresponding 2,4-dihydroxyquinazolines, which was
prepared by antranylic acid,7 2-aminobenzoate8,9 or anthranilonitrile,10 etc, followed by chlorination using
excess phosphoryl chloride.7-11 However, according to our knowledge, there have been few reports of the
direct synthesis of 2,4-dichloroquinazolines from aniline analogues until now. The first example reported
by Chi et al. described one-step cyclization of anthranilonitrile to 2,4-dichloroquinazoline using
diphosgene and acetonitrile system.12 However, this method suffered from several drawbacks such as use
of toxic diphosgene, harsh reaction conditions and relatively low yields.
Based on the postulated mechanism of this protocol and our previous studies on dichlorotriphenyl
phosphine (PPh3Cl2),13,14 which can be generated in situ by bis(trichloromethyl) carbonate (BTC,
triphosgene) and triphenylphosphine oxide (Ph3PO), we examined their reactivity the novel system
combined by BTC and Ph3PO toward this reaction. As a result, we achieved facile and efficient one-pot
synthesis of 2,4-dichloroquinazolines by the cyclization of anthranilonitrile using BTC with the aid of
catalytic amount of Ph3PO. Herein, we wish to report our preliminary results in this area.
RESULTS AND DISCUSSION
Initially, we started our investigation using anthranilonitrile 1a as the model substrate to examine its
behavior under different conditions. Upon treatment of 1a with 2.0 equiv BTC and 1.0 equiv Ph3PO at
o
100 C for 3.0 h, the reaction proceeded smoothly as indicated by TLC and furnished one product with
85 % yield after workup and purification by column chromatography. From the spectral and analytical
data, the product was characterized as 2,4-dichloroquinazoline 2a (Scheme 1).
Subsequently, the reaction conditions, including reaction temperature, solvent and the ration of 1a to BTC
and Ph3PO, were then investigated. It was found that the reaction temperature at around 120 °C was
effective for the reaction of 1a to form product 2a with the yield of 95%. Besides chlorobenzene, other
solvents such as toulene, o-xylene and 1,1,2,2-tetrachloroethane were compared, but the conversion was
relatively low. Moreover, experimental result revealed that the yield was not affected with a higher molar
ratio of Ph3PO to 1a (Table 1, entry 2) or BTC to 1a (Table 1, entry 3).
Stimulated by our previous finding that dichlorotriphenylphosphine (PPh3Cl2) can be formed from Ph3PO
and BTC,14 we reasoned that a reaction cycle could be established between Ph3PO and PPh3Cl2 in the
above reaction. To our delight, when the protocol was applied, 2a were successfully obtained with 2.1
equiv BTC and a catalytic amount of Ph3PO (0.2 equiv) to give excellent yield of 2,4-dichloroquinazoline
by prolonging the reaction time to 6 h (Table 1, entry 7), indicating that the reaction cycle could proceed
smoothly. However, the yield was reduced significantly with 0.1 equiv. Ph3PO (Table 1, entry 8).

HETEROCYCLES, Vol. 85, No. 6, 2012
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Table 1. Synthesis of 2a from 1a with different amount of Ph3PO and BTCa
Temp. (oC)
Entry
Ratio：Ph3PO /BTC /1a (equiv)
Time (h)
Yield of 2ab (%)
1
2
3
4
5
6
7
8
1 : 2 : 1
100
120
120
120
120
120
120
120
3
1
1
1
4
6
6
6
85.0
95.0
95.5
94.0
93.0
92.0
95.0
78.0
1 : 2 : 1
1.5 : 2 : 1
1 : 3 : 1
0.5 : 2 : 1
0.2 : 2 : 1
0.2 : 2.1 : 1
0.1 : 2 : 1
aReaction conditions: BTC was dropped into Ph3PO at -5~0 °C , followed by stirring at room
temperature for 30 min, then 1a was added and the temperature was rise to 120 °C.
b Isolated yields based on 1a
Having established the optimal conditions for the cyclization, We next turned our attention to exploring
the scope and generality of this method for the synthesis of other 2,4-dichloroquinazolines. A wide range
of substituted and structurally diverse anthranilonitriles 1 prepared by the reaction of appropriate
substituted isatin15 were subjected to this reaction under similar conditions. The results were summarized
in Table 2. Gratifyingly, under the optimized conditions, all the substrates listed in Table 2 afforded the
desired products 2 in good to excellent yields. Table 2 indicated the following trends that compounds 1
with electron-donating groups produced the 2,4-dichloroquinazolines 2 in excellent yields (Table 2,
entries 2–5), while with electron-withdrawing groups afforded the products in relatively lower yields
(Table 3, entries 6–12). At this stage, it could be concluded that our protocol tolerates a wide variety of
anthranilonitriles.

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HETEROCYCLES, Vol. 85, No. 6, 2012
Table 2. Synthesis of 2 form 1 by Ph3PO and BTC system
Entry
1
Product
2a
R (2a-2l)
H
Time (h)
Yielda (%)
95.0
6
2
2b
2c
6-OMe
6-Me
6
96.0
3
6
95.1
4
2d
2e
6,7-diOMe
5,7-diMe
6-Cl
8
94.8
5
8
93.5
6
2f
8
90.3
7
2g
8-Cl
8
89.6
8
2h
2i
7-F
6
88.0
9
6-F
10
10
10
10
88.8
10
11
12
2j
6-Br
93.2
2k
2l
6-NO2
5,7-diCl
80.0
75.4
aReaction conditions: BTC (2.1 mmol) was dropped into Ph3PO (0.6 mmol) at -5~0 °C,
followed by stirring at room temperature for 30 min, then 1 (3 mmol) was added and the
temperature was rise to 120 °C.
b Isolated yields based on 1.
To further extend the scope and generality of this reaction, another example was attempted to show that
this reaction is generally applicable to the synthesis of other pyrimidine-containing heterocyclic
compounds. Substitued aminothiophene nitriles 3, which were prepared by the reaction of appropriate
ketones, propanedinitriles, and elemental sulfur in the presence of Et2NH at 120 °C,16 reacted with BTC
and Ph3PO under the similar conditions to afford 2,4-dichlorothieno[2,3-d]pyrimidines 4. The results
showed that this reaction is a very reliable method for the synthesis of thienopyrimidines 4 with moderate
to good yields.

HETEROCYCLES, Vol. 85, No. 6, 2012
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Table 3. Synthesis of 4 from 3 by Ph3PO and BTC system
Entry
1
Reactants
Products
Time (h)
Yield (%)
77.0
Cl
CN
NH2
N
Cl
7
N
S
S
3a
4a
Cl
N
Cl
2
3
6
7
90.1
83.5
N
S
4b
Cl
CN
NH2
N
Cl
N
S
S
3c
4c
aReaction conditions: BTC (2.1 mmol) was dropped into Ph3PO (0.6 mmol) at
-5~0 °C, followed by sirring at room temperature for 30 min, then 3 (3 mmol)
was added and the temperature was rise to 120 °C.
bIsolated yields based on 3.
On the basis of the above results and previous literatures,12,13 a reaction mechanism for the formation of
2,4-dichloroquinazolines from athranilonitrile is presented in Scheme 1. Athranilonitrile 1a first reacts
with BTC to afford compound 5. Further reaction of 5 with Ph3PCl2 generated in situ from BTC and
Ph3PO, forms the O-P bond and gets the intermediate 6. Finally primary chlorination of the C4 position,
secondary chlorination of the C2 position is performed by the replacement of Ph3PO leaving group with
chloride, to yield the corresponding 2,4-dichloroquinazoline 2a.

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HETEROCYCLES, Vol. 85, No. 6, 2012
Scheme 1
In summary, we have successfully developed a new method for the synthesis of 2,4-dichloroquinazolines
by using BTC and Ph3PO. The mild cycle reaction condition, convenient operational procedure, and good
yield were the notable advantages. Moreover, 2,4-dichlorothieno[2,3-d]pyrimidine can be synthesized
from aminothiophene nitrile. It could therefore be concluded that our synthetic method has significant
generality for the synthesis of many pyrimidine-containing heterocyclic compounds. We believe this
strategy will bring a more practical alternative to the existing methods in the future.
EXPERIMENTAL
All reagents were purchased from commercial sources and used without treatment, unless otherwise
indicated. Melting points (mp) were obtained on digital melting point apparatus WRS-1B and are
1
uncorrected. H NMR, 13C NMR were recorded at VARAIN-400 on a 400 MHz and 100 MHz,
respectively, and TMS as internal standard. IR spectra (KBr) were recorded on AVATAR-370. All
reactions were monitored by TLC with GF254 silica gel coated plates. Column chromatography was
carried out on silica gel.
General procedure for the synthesis of 2,4-dichloroquinazolines (2a~2l)
To an ice-cold magnetically stirred solution of PhCl (5 mL) and Ph3PO (0.17 g, 0.6 mmol), added four
drops of Et3N, bis(trichlormethyl)carbonate (0.63 g, 2.1 mmol/6 mL PhCl) was added dropwise. The
reaction mixture was placed to room temperature for 30 min. Then athranilonitriles 1a~1l (3 mmol) was

HETEROCYCLES, Vol. 85, No. 6, 2012
1423
added, rise the temperature to 120 °C for 6 h. When the reaction was completed, poured the mixture into
water and extracted with EtOAc. After dryness and condensation, the crude reaction product was
separated by column chromatography using 10% EtOAc in petroleum ether as eluent to afford pure 2a~2l.
2,4-Dichloroquinazolines (2a).
White solid, mp 119.3–121.0 oC (lit.,3 118 oC). 1H NMR (400MHz, CDCl3) δH: 8.26 (d, J = 8.4 Hz, 1H),
13
8.01–7.97 (m, 2H), 7.76 – 7.70 (m, 1H). C NMR (100 MHz, CDCl3) δC: 163.7, 154.9, 152.1, 135.9,
129.0, 127.8, 125.8, 122.2.
2,4-Dichloro-6-methoxyquinazoline (2b).
o
1
White solid, mp 170–171 °C (lit.,17 171 C). H NMR (400 MHz, CDCl3) δH: 7.89 (d, J = 9.2 Hz, 1H),
7.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H). 13C NMR (100 MHz, CDCl3) δC:
161.5, 159.4, 152.5, 148.4, 129.3, 129.0, 123.3, 102.9, 56.0.
2,4-Dichloro-6-methylquinazoline (2c).
White solid, mp 140–141 °C (lit.,18 140–141 °C). 1H NMR (400 MHz, CDCl3) δH: 8.00 (s, 1H), 7.88 (d, J
= 8.6 Hz, 1H), 7.80 (dd, J = 8.6, 1.8 Hz, 1H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δC: 162.9, 154.0,
150.8, 139.8, 138.2, 127.5, 124.5, 122.2, 22.0.
2,4-Dichloro-6,7-dimethoxyquinazoline (2d).
White soli, mp 160.8–161.7 °C (lit.,8 157–159°C). 1H NMR (400 MHz, CDCl3) δH: 7.33 (s, 1H), 7.25 (s,
1H), 4.07 (s, 3H), 4.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δC: 159.9, 157.6, 153.4, 151.4, 150.4, 117.7,
106.21, 102.7, 56.8, 56.5. IR (KBr): νmax = 1611, 1546, 1505, 1401, 1238, 1205, 1142, 848 cm-1. MS
(ESI): =259.1 ([M+H]+).
2,4-Dichloro-5,7-dimethylquinazoline (2e).
White solid, mp 140.2–143.1 °C. 1H NMR (400 MHz, CDCl3) δH: 7.59 (s, 1H), 7.30 (s, 1H), 2.96 (s, 3H),
2.52 (s, 3H). 13C NMR (100 MHz, CDCl3) δC: 162.2, 154.6, 154.0, 146.5, 136.2, 134.2, 125.7, 120.0, 24.8,
21.9. HRMS(ESI) C10H9Cl2N2 ([M+H]+): calcd. 227.0143, found 227.0148.
2,4,6-Trichloroquinazoline (2f).
White solid, mp 132.5–135.8 °C (lit., 22 129.1–130.8 °C). 1H NMR (400 MHz, CDCl3) δH: 8.22 (d, J =
2.0 Hz, 1H), 7.98–7.88 (m, 2H). 13C NMR (100 MHz, CDCl3) δC: 162.6, 155.2, 150.6, 136.9, 135.07,
129.5, 124.7, 122.8.
2,4,8-Trichloroquinazoline (2g).
1
White solid. mp 150.8–152.9 °C (lit.,19 no data). H NMR (400 MHz, CDCl3) δH: 8.19 (dd, J = 8.8, 1.2
Hz, 1H), 8.07 (dd, J = 7.6, 1.2 Hz, 1H), 7.65 (dd, J = 8.2, 7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC:
164.2, 155.8, 148.9, 135.7, 132.6, 128.8, 124.7, 123.4.
2,4-Dichloro-7-fluoroquinazoline (2h).
White solid, mp 142.3–145.1°C (lit.,20 no data). 1H NMR (400 MHz, CDCl3) δH: 8.34–8.24 (m, 1H), 7.62

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HETEROCYCLES, Vol. 85, No. 6, 2012
(d, J = 8.8 Hz, 1H), 7.54–7.44 (m, 1H). 13C NMR (100 MHz, CDCl3) δC: 161.5 (d, J1 = 295 Hz), 158.1 (s),
150.9 (s), 148.7 (d, J3 = 14 Hz), 123.8(d, J3= 11 Hz), 114.5 (s), 114.2 (d, J3=16 Hz), 106.9 (d, J2 = 28
Hz).
2,4-Dichloro-6-fluoroquinazoline (2i).
1
White solid, mp 135.7–137.2 °C (lit.,22 no data). H NMR (400 MHz, CDCl3) δH: 8.03 (dd, J = 9.2, 4.8
Hz, 1H), 7.87 (dd, J = 8.0, 2.8 Hz, 1H), 7.79–7.70 (m, 1H). 13C NMR (100 MHz, CDCl3) δC: 163.0 (d, J4
= 6 Hz), 161.1 (d, J1 = 252 Hz), 154.5 (d, J4 = 3 Hz), 149.2 (s), 130.7 (d, J4 = 9 Hz), 126.4 (d, J2 = 26 Hz),
123.1 (d, J3 = 10 Hz), 109.7 (d, J2 = 24 Hz).
6-Bromo-2,4-dichloroquinazoline (2j).
White solid, mp 131.0–136.1 °C (lit.,23 no data). 1H NMR (400MHz, CDCl3) δH: 8.40 (d, J = 2.0Hz, 1H),
8.04 (dd, J = 8.8, 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δC: 162.5, 155.2,
150.8, 139.5, 129.5, 128.4, 123.2, 123.1.
2,4-Dichloro-6-nitroquinazoline (2k).
White solid, mp 121.1–123.4 °C (lit.,7 122–124 oC). 1H NMR (400 MHz, CDCl3) δH: 9.16 (d, J =2.4, Hz,
1H), 8.73 (dd, J = 9.2, 2.4Hz, 1H), 8.16 (dd, J = 9.2, 0.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC: 162.3,
155.1, 150.6, 139.3, 129.3, 127.9, 123.0, 122.9.
2,4,5,7-Tetrachloroquinazoline (2l).
White solid. mp 100.3–101.2 °C (lit.,4b no data). 1H NMR (400MHz, CDCl3) δH: 7.90 (d, J = 2.0 Hz, 1H),
7.73 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC: 162.0, 156.0, 154.5, 141.3, 132.5, 126.8, 118.8.
2,4-Dichloro-5,6-dimethylthieno[2,3-d]pyrimidine (4a).
White solid. mp 150.6–153.7 °C (lit.,21 no data). 1H NMR (400 MHz, CDCl3) δH: 2.51 (s, 6H).13C NMR
(100 MHz, CDCl3) δC: 169.4, 153.7, 152.4, 136.5, 127.7, 124.7, 14.2, 14.1.
2,4-Dichloro-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine (4b).
Pale yellow solid, mp 169.8–174.6 °C (lit.,21 178–180 °C). 1H NMR (400 MHz, CDCl3) δH: 3.07 (t, J =
4.2 Hz, 1H), 2.86 (t, J = 4.2 Hz, 1H), 1.92 (dt, J = 6.1, 2.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δC:
170.2, 153.6, 152.6, 139.9, 127.3, 126.9, 26.2, 26.1, 22.4, 22.2.
2,4-Dichloro-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidine (4c).
Pale yellow solid. mp 129.8–133.5 °C (lit.,21 134–135 oC). 1H NMR (400 MHz, CDCl3) δH: 3.21–3.10 (m,
2H), 3.06 (dd, J = 10.4, 4.2 Hz, 2H), 2.62 – 2.46 (m, 2H).13C NMR (101 MHz, CDCl3) δ: 174.7, 153.3,
152.3, 145.0, 135.8, 124.6, 30.3, 29.3, 27.4.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China [21076194] for financial support.

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