An efficient HCCP-mediated direct amination of quinazolin-4(3H)-ones

Article abstract of DOI:10.1016/j.tet.2010.12.067

An efficient direct amination of quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, DIPEA, and N-contained nucleophiles in acetonitrile could be able to form the corresponding 4-aminoquinazoline derivatives. Under the

Full text of DOI:10.1016/j.tet.2010.12.067

Tetrahedron 67 (2011) 1665e1672
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An efficient HCCP-mediated direct amination of quinazolin-4(3H)-ones
,
a
a
a,b,
*
Zhenlu Shen a, Xiaofei He a, Jialiang Dai a, Weimin Mo a , Baoxiang Hu , Nan Sun , Xinquan Hu
*
a College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient direct amination of quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4
(3H)-ones with HCCP, DIPEA, and N-contained nucleophiles in acetonitrile could be able to form the
corresponding 4-aminoquinazoline derivatives. Under the optimal reaction conditions, the amination
products were achieved in good yields.
Received 25 September 2010
Received in revised form 17 December 2010
Accepted 28 December 2010
Available online 8 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Quinazolin-4(3H)-ones
4-Aminoquinazolines
Hexachlorocyclotriphosphazene
1. Introduction
these reagents are not environmentally benign, and the reaction
conditions may cause destruction of some functional groups. In
Nitrogen-containing heterocycles are present in a variety of bi-
ologically active compounds that can be used in a wide range of
therapeutic areas.1 Quinazoline derivatives are an important class
of nitrogen-containing heterocycles, which display a wide variety
of biological activities, such as anticonvulsant, antihypertensive,
vasodilator, antiinflammatory, antibiosis, fibrinogen receptor an-
tagonistic, and nanomolar Hedgehog antagonistic.2 Among the
family of quinazolines, 4-aminoquinazolines have been received
particular interests because of their potential pharmacological ac-
tivity.3 For example, three drugs Gefitnib (Iressa), Erlotinib (Tar-
ceva), and Lapatinib (Tykerb), derived from 4-aminoquinazolines,
have been approved and marketed for non-small-cell lung cancer
treatment (Fig. 1).4
4-Aminoquinazolines are usually synthesized from acid- or
base-mediated amination of electron-deficient 4-chloroquinazo-
lines via SNAr substitution.5 Alternatively, Tasler’s group have
reported a Pd-catalyzed BuchwaldeHartwig amination reaction to
prepare the corresponding 4-aminoquinazolines from 4-chloro-
quinazolines.6a Very recently, we have also described a Pd-cata-
lyzed selective amination of 4-chloroquinazolines with bifunctional
amines.6b Both methods employ the same starting material
4-chloroquinazolines.3e6 The common method for preparation of
4-chloroquinazolines is the chlorination of quinazolin-4(3H)-ones,
which often require harsh and acidic conditions with SOCl2, POCl3,
PCl5 or their combinations as the chlorination reagents. However,
addition, many 4-chloroquinazoline derivatives are moisture sen-
sitive and their purification and storage require special treatment.
In order to avoid the use of chlorination reagents and an in-
dividual activation step of the quinazolin-4(3H)-ones, a direct
amination of quinazolin-4(3H)-ones via in situ activation is highly
desirable for the synthesis of 4-aminoquinazoline derivatives.
Phosphonium compounds, such as benzotriazol-1-yloxytris(di-
methyl-amino)phosphonium hexafluorophosphate (BOP) and its
analogues (i.e., BroP, PyBOP, PyBroP), are efficient coupling reagents
for amide bond formation between a carboxylic acid and an amine
under mild conditions.7 In recent years, they have also been suc-
cessfully employed in the one-step aminations of cyclic amides and
ureas.8e13 Successful results have also been obtained in BOP-me-
diated direct amination of quinazolin-4(3H)-ones.11b,c In fact, when
quinazolin-4(3H)-ones are treated with BOP in the presence of
a base, a phosphonium intermediate 1 possessing an active CeOeP
fragment is readily formed (Fig. 2), which subsequently undergoes
SNAr substitution with a reactive amine nucleophile to give the
desired product.11aec,14 Unfortunately, BOP and its analogues are
expensive, moreover, utilization of BOP generates end product
HMPA, a highly carcinogenic chemical. We hoped that a less ex-
pensive and readily available activating reagent can be used as the
BOP surrogate. The mechanism of the BOP-involved activation in-
dicates that a compound, which can react with quinazolin-4(3H)-
ones to form the active CeOeP fragment, could be considered to
serve as this role. Hexachlorocyclotriphosphazene (Cl6N3P3, HCCP),
a bulky flame-retardant polyphosphazenes,15 could be a good
candidate. We assumed that quinazolin-4(3H)-ones can convert to
* Corresponding authors. E-mail address: xinquan@zjut.edu.cn (X. Hu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.067

1666
Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
F
HN
N
O
HN
N
Cl
O
O
O
O
N
N
O
O
N
Gefitnib (Iressa)
Erlotinib (Tarceva)
O
O
S
F
NH
O
HN
N
Cl
O
N
Lapatinib (Tykerb)
Fig. 1. The structures of commercialized 4-aminoquinazoline derivatives.
Table 1
Cl
P
N
Cl
P
N
HCCP-mediated direct amination of 3a with n-butylaminea
N
P
N
Cl
Cl
N
P
Bu
N
N
PF6
O
HN
N
HCCP, base,
O
N
Cl
O
solvent, rt,
N
NH
N
n-BuNH2
R1
R1
N
R2
N
R2
3a
4
1
2
Entry
Base
Solvent
Yieldb (%)
Fig. 2. Active phosphonium intermediates.
1
2
3
4
5
6
7
8
DBU
DABCO
TEA
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
DMF
DCM
NMP
1,4-Dioxane
MeCN
MeCN
70
74
75
90
82
81
76c
32
41
39
53
10
65d
89e
the above-mentioned active CeOeP fragment with HCCP (2, Fig. 2)
or its analogues, since the CleP bond of HCCP can react with hy-
droxyl group, and thus promote direct amination.
DIPEA
K2CO3
Cs2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
2. Results and discussion
9
10
11
12
13
14
Our initial experiments proved that HCCP can promote the di-
rect amination of quinazolin-4(3H)-one (3a) with n-butylamine.
Thus, 3a and n-butylamine were used as the model system for in-
vestigating the effects and amounts of solvent, base, and HCCP
(Table 1). Although DBU was an efficient base in the BOP-mediated
amination,11b,c it proved not to be the best in our case (entry 1).
Diisopropylethylamine (DIPEA) was found to be most effective in
comparison with others (entry 4). Inorganic bases K2CO3 and
Cs2CO3 could also be employed (entries 5 and 6).
a
Conditions: 3a (0.5 mmol), HCCP (1.0 equiv), base (6.0 equiv), solvent (2 mL), rt,
activation time (1 h), then n-BuNH2 (6.0 equiv), 16 h.
b
Isolated yield after chromatographic purification.
HCCP (0.8 equiv).
n-BuNH2 (4.0 equiv).
DIPEA (5.0 equiv).
c
d
e
Previously, we hypothesized that the phosphonium in-
termediate 2 or its analogues was the crucial intermediate for the
current direct amination. If this intermediate 2 or its analogues
could be confirmed or separated, it would be beneficial to un-
derstand the reaction mechanism and further optimize reaction
conditions. In a designed experiment, a mixture of 3a (1 equiv),
HCCP (1 equiv) and DIPEA (6.0 equiv) in acetonitrile was stirred for
1 h at room temperature. TLC showed that 3a was completely
converted to a new compound, which was relatively stable and
readily isolable by flash chromatographic separation. Structural
analyses confirmed that this compound was the desired phos-
phonium intermediate 2a (R1¼R2¼H).16 Decrease of the amount of
HCCP from 1.0 to 0.8 equiv resulted in a loss of the yield (entry 7).
By TLC monitoring, the experiment with 0.8 equiv of HCCP showed
that 3a could not be completely converted into the active inte-
mediate 2a even after prolonging the activation time to 12 h. These
results indicated that only one CleP bond in all six CleP bonds of an
HCCP molecule could react with one 3a molecule to form 2a at
room temperature. Thus, we proposed the mechanism of HCCP-
mediated direct amination of 3a as follows:(1) tautomerization of
3a to 4-hydroxyquinazoline in the presence of DIPEA; (2) activation
of 4-hydroxyquinazoline with HCCP generating the high reactive
intermediate 2a; (3) nucleophilic attack of n-butylamine to 2a
forming the product 4.
Results inTable 1 showed the solvent can greatlyaffect the HCCP-
mediated amination, and acetonitrile was found to be the most
suitable solvent (entries 4, 8e12). When nucleophile n-butylamine
attacked 2a, two competitive SNAr substitutions are both present
either on CꢀO bond or PꢀCl bond. This could explain that only 65%
yield of 4 was obtained when decreasing the amount of n-BuNH2
from 6.0 equiv (entry 4) to 4.0 equiv (entry 13). On the other hand,

Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
1667
variation of the large excess amount of DIPEA from 6.0 equiv to
5.0 equiv did not significantly change the results (entry 4 versus
entry 14). On the basis of these experimental data, a combination of
1.0 equiv of HCCP, 5.0 equiv of DIPEA, 6.0 equiv of amine, and ace-
tonitrile as the reaction solvent were chosen as the optimal reaction
conditions and were employed for the following studies.
The results of HCCP-mediated direct amination between 3a and
various N-containing nucleophiles are summarized in Table 2. Less
hindered primary and secondary amines smoothly reacted with 3a
at room temperature to afford the desired products in good yields
(entries 1e3 and 5e7), while sterically hindered amines, for ex-
ample, tert-butylamine, are much difficult substrates for this
transformation even at a higher reaction temperature (entry 4).
Nitrogen heterocycles, such as pyrrolidine, piperidine, morpholine,
and imidazole were also tested as nucleophiles in the HCCP-me-
diated amination of 3a to afford the desired products in high yields
(entries 8e11). It is noteworthy that imidazole, which was regarded
as a weak and less reactive nucleophile in the previous reported
direct amination,11b can conveniently complete the transformation
in this HCCP-mediated direct amination (entry 11). When a bi-
functional heteroaromatic amine, 5-methyl-1H-pyrazol-3-amine,
was used as the nucleophile, 3a was selectively aminated with the
primary amino group of 5-methyl-1H-pyrazol-3-amine to form
product 15 in moderate yield (entry 12). Anilines were much
weaker nucleophiles compared to the alkylamines. Not surpris-
ingly, no desired amination products were formed at room tem-
perature. However, moderate yields were observed under reflux
conditions (entries 13e17). An electron-deficient aniline proved to
be less efficient (entry 15).
Table 3 listed the results of HCCP-mediated direct aminations
between n-butylamine and a variety of substituted quinazolin-4
(3H)-ones. An array of substituted quinazolin-4(3H)-ones were
suitable for this HCCP-mediated amination reaction and gave the
desired product in good yields at room temperature (entries 1e6).
Table 2
HCCP-mediated amination of 3a with various N-containing Nucleophilesa
R4
R3
N
O
N
N
HCCP, DIPEA,
MeCN
NH
R3R4NH
N
3a
4-20
Entry
1
R3R4NH
Product
Time (h)
16
Yieldb (%)
89
Bu
N
HN
4
5
H2N
N
HN
2
3
16
16
88
82
H2N
N
N
HN
6
H2N
N
N
HN
N
4
5
6
7
7
24
16
16
16
53c
H2N
N
HN
H2N
8
90
N
N
HN
9
87
H2N
N
N
N
N
N
H
10
83
(continued on next page)
N

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Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
Table 2 (continued )
Entry
R3R4NH
Product
Time (h)
Yieldb (%)
N
N
N
8
9
11
12
1
80
N
H
N
N
N
16
79
N
H
O
O
N
N
10
11
12
13
14
15
13
14
15
16
17
18
3
1.5
16
5
92
89
N
H
N
N
N
N
N
H
N
N
NH
N
HN
N
64
NH
N
H2N
N
HN
N
72d
68d
41d
N
H2N
HN
6
N
H2N
N
Cl
Cl
HN
9
N
H2N
N
O
O
HN
16
19
20
6
7
63d
H2N
N
N
N
N
17
61d
N
H
N
a
Conditions: 3a (0.5 mmol), HCCP (1.0 equiv), DIPEA (5.0 equiv), MeCN (2 mL), rt, activation time (1 h), then N-containing nucleophile (6.0 equiv).
Isolated yield after chromatographic purification.
b
c
After addition of t-BuNH2, the mixture was stirred at 45 ꢁC.
d
MeCN (5 mL), after addition of nucleophile, the mixture was stirred under reflux.

Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
1669
When 8-methylquinazolin-4(3H)-one (3c) or 8-methylquinazolin-
4(3H)-one (3g) was used as the substrate, a longer activation time
was essential for a full conversion to phosphonium intermediate 2
(entries 2 and 6). When 6,7-dimethoxyquinazolin-4(3H)-one (3h)
containing two methoxy groups was used as the substrate,
activation should be performed under reflux condition (entry 7). In
addition, a more complex substrate benzo[g]quinazolin-4(3H)-one
(3i) was also converted to 28 in 73% yield (entry 8). Pyrido[2,3-d]
pyrimidin-4(3H)-one (3j), with a nitrogen incorporated in the distal
aromatic ring, was transformed to 29 in 85% yield (entry 9).
Table 3
a
HCCP-mediated amination of Quinazolin-4(3H)-ones with n-BuNH2
Bu
O
HN
HCCP, DIPEA,
MeCN, rt,
NH
R2
N
R1
R1
n-BuNH2
N
N
R2
3
21-29
Entry
1
Quinazolin-4(3H)-one
Product
Time (h)
16
Yieldb (%)
63
Bu
O
HN
N
3b
3c
21
NH
N
N
Bu
O
HN
NH
N
2
N
22
16
80c
N
Bu
N
O
HN
Cl
Cl
3
4
5
6
7
8
3d
3e
3f
23
24
25
26
27
28
3
3
80
69
NH
N
N
Bu
N
O
HN
NH
N
Cl
F
Cl
F
N
Bu
N
O
HN
2
86
NH
N
N
Bu
O
HN
3g
3h
3i
6
74c
65d
73e
NH
N
N
N
Bu
N
O
HN
O
O
O
2
NH
N
O
N
Bu
N
O
HN
16
NH
N
N
Bu
O
HN
N
9
3j
29
2
85
NH
N
N
N
N
a
Conditions: 3 (0.5 mmol), HCCP (1.0 equiv), DIPEA (5.0 equiv), MeCN (2 mL), rt, activation time (1 h), then n-BuNH2 (6.0 equiv).
Isolated yield after chromatographic purification.
Activation time (20 h).
Activation and amination were performed under reflux conditions.
Activation time (3 h).
b
c
d
e

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Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
In summary, we have successfully developed an HCCP-mediated
149.3, 132.2, 128.7, 125.8, 120.3, 115.4, 52.8, 28.9. MS (ESI), m/z,
202.1 (MHþ).
amination of quinazolin-4(3H)-ones with various amines. This di-
rect amination is mild, economical, and suitable for a wide range of
less expensive amine nucleophiles including primary and second-
ary amines, heteroarylamines, and substituted anilines. This
methodology would facilitate the syntheses of 4-aminoquinazo-
lines derivatives in medicinal chemistry.
3.2.5. 4-(Benzylamino)quinazoline (8). The reaction time was 16 h.
The product was obtained as a white solid in 90% yield, mp:
168e170 ꢁC. 1H NMR (CDCl3) 8.71 (s, 1H), 7.86 (d, J¼8 Hz, 1H),
7.71e7.76 (m, 2H), 7.31e7.47 (m, 6H), 6.07 (br s, 1H), 4.88 (d,
J¼5.5 Hz, 2H). 13C NMR 159.4, 155.5, 149.5, 138.1, 132.8, 129.0, 128.7,
128.1, 127.9, 126.2, 120.6, 114.9, 45.4. MS (ESI), m/z, 235.6 (MHþ).
3. Experimental section
3.1. General
3.2.6. 4-((a-Methyl)benzylamino)quinazoline (9). The reaction
time was 16 h. The product was obtained as a white solid in 87%
yield, mp: 106e108 ꢁC. 1H NMR (CDCl3) 8.66 (s, 1H), 7.84 (d,
J¼8 Hz, 1H), 7.71e7.75 (m, 2H), 7.44e7.46 (m, 3H), 7.30e7.38 (m,
2H), 7.27e7.29 (m, 1H), 6.01 (br s, 1H), 5.62e5.68 (m, 1H), 1.69 (d,
J¼6.5 Hz, 3H). 13C NMR 158.6, 155.4, 149.4, 143.2, 132.6, 128.8,
128.6, 127.6, 126.4, 126.0, 120.5, 114.9, 50.2, 21.8. MS (ESI), m/z,
250.1 (MHþ).
1H NMR (500 MHz),13C NMR (125 MHz), and 31P NMR (202 MHz)
spectra were obtained on a Bruker Avance III spectrometer. CDCl3
andDMSO-d6 were used asthe solvent with tetramethylsilane (TMS)
as the internal standard or 85% H3PO4 as external standard. Low and
high resolution mass spectra were recorded in the ESI mode on an
Agilent 6210 LC/TOF mass spectrometer. Melting points were mea-
sured using XRL-1 melting point instrument and are uncorrected.
Quinazolin-4(3H)-ones were synthesized from anthranilic acids and
amidineseacetate, and their structures were confirmed by MS, 1H
NMR, and 13C NMR. Other reagents were purchased from supplier
and used without any further treatment.
3.2.7. 4-(N-Benzyl-N-methylamino)quinazoline (10). The reaction
time was 16 h. The product was obtained as a yellow liquid in 83%
yield. 1H NMR (CDCl3) 8.71(s, 1H), 7.88e7.93 (m, 2H), 7.68e7.72 (m,
1H), 7.32e7.43 (m, 6H), 4.98 (s, 2H), 3.29 (s, 3H). 13C NMR 163.9,
154.0, 151.8, 137.1, 132.3, 128.9, 128.4, 127.6, 127.2, 125.03, 124.98,
116.1, 57.1, 39.5. MS (ESI), m/z, 250.1 (MHþ).
3.2. General procedure for HCCP-mediated amination of
quinazolin-4(3H)-ones
3.2.8. 4-(Pyrrolidin-1-yl)quinazoline (11). The reactiontimewas1 h.
Theproduct wasobtainedasawhitesolidin 80% yield, mp:39e42ꢁC.
1H NMR (CDCl3) 8.59 (s, 1H), 8.14 (t, J¼0.5 Hz,1H), 7.80e7.82 (m,1H),
7.66e7.69 (m, 1H), 7.35e7.38 (m, 1H), 3.92 (t, J¼6.5 Hz, 4H),
2.03e2.06 (m, 4H). 13C NMR 159.7, 154.5, 151.5, 131.9, 128.1, 125.3,
124.3, 116.5, 51.0, 25.7. MS (ESI), m/z, 200.1 (MHþ).
Quinazolin-4(3H)-ones (3, 0.5 mmol), HCCP (173.9 mg, 0.5 mmol,
1 equiv), DIPEA (323.8 mg, 2.5 mmol, 5 equiv), and MeCN (2 mL)
were added to a nitrogen purged vial. The reaction mixture was
stirred at room temperature for 1 h as activation time. The reactions
were monitored by TLC. Then N-containing nucleophile (3.0 mmol,
6 equiv) was added, and the reaction mixture was stirred at room
temperature for an appropriate time. After the mixture was con-
centrated under reduced pressure, the residue was purified by
chromatography on silica gel to afford the corresponding products 4-
aminoquinazolines (4e29).
3.2.9. 4-(Piperidin-1-yl)quinazoline (12). The reaction time was
16 h. The product was obtained as a yellow liquid in 79% yield. 1H
NMR (CDCl3) 8.71 (s, 1H), 7.87 (d, J¼8.5 Hz, 2H), 7.70e7.73 (m, 1H),
7.42e7.45 (m, 1H), 3.71e3.73 (m, 4H), 1.77e1.81 (m, 6H). 13C NMR
164.9, 154.1, 151.7, 132.3, 128.5, 125.2, 125.1, 116.8, 51.0, 26.0, 24.8.
MS (ESI), m/z, 214.1 (MHþ).
3.2.1. 4-(n-Butylamino)quinazoline (4). The reaction time was 16 h.
The product was obtained as a yellow solid in 89% yield, mp:
107e110 ꢁC. 1H NMR (CDCl3) 8.67 (s, 1H), 7.84 (d, J¼8.5 Hz, 1H),
7.68e7.76 (m, 2H), 7.46e7.49 (m, 1H), 5.67 (br s, 1H), 3.65e3.69 (m,
2H), 1.72e1.75 (m, 2H), 1.47e1.51 (m, 2H), 1.00 (t, J¼7.5 Hz, 3H). 13C
NMR 159.5, 155.5, 149.4, 132.5, 128.6, 125.9, 120.5, 115.0, 41.2, 31.5,
20.3, 13.9. MS (ESI), m/z, 202.1 (MHþ).
3.2.10. 4-(Morpholino)quinazoline (13). The reaction time was 3 h.
The product was obtained as a yellow solid in 92% yield, mp:
87e90 ꢁC. 1H NMR (CDCl3) 8.77 (s,1H), 7.88e7.94 (m, 2H), 7.74e7.77
(m, 1H), 7.46e7.49 (m, 1H), 3.90e3.92 (m, 4H), 3.79 (t, J¼4.5 Hz,
4H). 13C NMR 164.7, 154.0, 151.7, 132.6, 128.8, 125.6, 124.7, 116.6,
66.8, 50.3. MS (ESI), m/z, 216.2 (MHþ).
3.2.2. 4-(Isopropylamino)quinazoline (5). The reaction time was
16 h. The product was obtained as a white solid in 88% yield, mp:
167e170 ꢁC. 1H NMR (CDCl3) 8.67 (s, 1H), 7.84 (d, J¼8 Hz, 1H),
7.70e7.74 (m, 2H), 7.44e7.47 (m, 1H), 5.60 (br s, 1H), 4.54e4.61 (m,
1H), 1.36 (d, J¼6.5 Hz, 6H). 13C NMR 158.7, 155.4, 149.3, 132.4, 128.5,
125.8，120.4, 114.9, 42.9, 22.7. MS (ESI), m/z, 188.1 (MHþ).
3.2.11. 4-(1H-Imidazol-1-yl)quinazoline (14). The reaction time was
1.5 h. The product was obtained as a yellow solid in 89% yield, mp:
112e114 ꢁC. 1H NMR (DMSO-d6) 9.26 (s, 1H), 8.46 (s, 1H), 8.13e8.46
(m, 3H), 7.97 (t, J¼1.0 Hz, 1H), 7.86e7.89 (m, 1H), 7.29 (t, J¼1.0 Hz,
1H). 13C NMR 155.1, 154.1, 152.1, 138.1, 135.2, 130.1, 129.4, 128.4,
124.7, 120.4, 117.5. MS (ESI), m/z, 197.1 (MHþ).
3.2.3. 4-(Cyclohexylamino)quinazoline (6). The reaction time was
16 h. The product was obtained as a white solid in 82% yield, mp:
138e140 ꢁC. 1H NMR (CDCl3) 8.65 (s, 1H), 7.83 (d, J¼8.5 Hz, 1H),
7.68e7.74 (m, 2H), 7.44e7.47 (m, 1H), 5.61 (br s, 1H), 4.24e4.30 (m,
1H), 2.14e2.17(m, 2H),1.79e1.83(m, 2H),1.69e1.73(m,1H),1.46e1.55
(m, 2H), 1.25e1.35 (m, 3H). 13C NMR 158.7, 155.5, 149.4, 132.4, 128.5,
125.8, 120.4, 114.9, 49.7, 33.1, 25.7, 24.9. MS (ESI), m/z, 227.6 (MHþ).
3.2.12. 4-((5-Methyl-1H-pyrazol-3-yl)amino)quinazoline (15)6b. The
reaction time was 16 h. The product was obtained as a white solid
in 64% yield, mp: 279e280 ꢁC. 1H NMR (DMSO-d6) 12.18 (br s, 1H),
10.31 (br s, 1H), 8.58e8.61 (m, 2H), 7.74e7.83 (m, 2H), 7.54e7.57 (m,
1H), 6.58 (br s, 1H), 2.27 (m, 3H).
3.2.13. 4-(Phenylamino)quinazoline (16). MeCN (5 mL) was used as
the solvent. After addition of aniline, the mixture was stirred under
reflux for 5 h. The product was obtained as a white solid in 72%
yield, mp: 222e224 ꢁC. 1H NMR (DMSO-d6) 9.81 (s, 1H), 8.57e8.62
(m, 2H), 7.86e7.90 (m, 3H), 7.80e7.81(m, 1H), 7.64e7.67 (m, 1H),
7.39e7.43 (m, 2H), 7.13e7.17 (m, 1H). 13C NMR 157.8, 154.5, 149.7,
3.2.4. 4-(tert-Butylamino)quinazoline (7). After addition of t-BuNH2,
the mixture was stirred at 45 ꢁC for 24 h. The product was obtained
as a white solid in 53% yield, mp: 129e131 ꢁC. 1H NMR (CDCl3) 8.65
(s, 1H), 7.82 (d, J¼8 Hz, 1H), 7.68e7.72 (m, 1H), 7.63 (d, J¼8 Hz, 1H),
7.42e7.45 (m, 1H), 5.59 (br s, 1H), 1.61 (s, 9H). 13C NMR 159.0, 155.0,

Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
1671
139.2, 133.0, 128.5, 127.8, 126.2, 123.8, 123.0, 122.5, 115.2. MS (ESI),
yield, mp: 164e167 ꢁC. 1H NMR (DMSO-d6) 8.47 (s, 1H), 8.40 (d,
J¼5.5 Hz, 1H), 8.29 (d, J¼9.0 Hz, 1H), 7.70 (d, J¼2.0 Hz, 1H), 7.56 (dd,
J¼9.0, 2.0 Hz, 1H), 3.51e3.55 (m, 2H), 1.60e1.65 (m, 2H), 1.34e1.41
(m, 2H), 0.93 (t, J¼7.5 Hz, 3H). 13C NMR 159.2, 156.3, 150.1, 137.0,
126.2, 125.8, 125.0, 113.6, 40.2, 30.5, 20.0, 13.7. HRMS (ESI), m/z,
236.0961 [MHþ], calcd for C12H15ClN3, 236.0955.
m/z, 222.2 (MHþ).
3.2.14. 4-(p-Tolylamino)quinazoline (17). MeCN (5 mL) was used as
the solvent. After addition of p-toluidine, the mixture was stirred
under reflux for 6 h. The product was obtained as a white solid in
68% yield, mp: 190e192 ꢁC. 1H NMR (CDCl3) 8.75 (s, 1H), 7.91e7.92
(m, 2H), 7.78e7.81 (m, 1H), 7.53e7.59 (m, 4H), 7.21e7.23 (m, 2H),
2.36 (s, 3H). 13C NMR 157.8, 155.0, 149.8, 135.4, 134.7, 132.9, 129.7,
128.8, 126.6, 122.4, 120.4, 115.1, 20.9. MS (ESI), m/z, 236.3 (MHþ).
3.2.22. 4-(n-Butylamino)-7-fluoroquinazoline (25). The reaction
time was 2 h. The product was obtained as a white solid in 86%
yield, mp: 120e124 ꢁC. 1H NMR (CDCl3) 8.64 (s, 1H), 7.73e7.76 (m,
1H), 7.45e7.47 (m, 1H), 7.18e7.22 (m, 1H), 5.83 (br s, 1H), 3.65e3.69
(m, 2H), 1.69e1.75 (m, 2H), 1.44e1.51 (m, 2H), 0.99 (t, J¼7.5 Hz, 3H).
13C NMR 165.0 (d, J¼251.3 Hz), 159.4, 156.5, 151.4 (d, J¼12.5 Hz),
123.1 (d, J¼10.0 Hz), 115.6 (d, J¼25.0 Hz), 112.7 (d, J¼21.3 Hz), 111.9,
41.3, 31.5, 20.3, 13.9. HRMS (ESI), m/z, 220.1261 [MHþ], calcd for
C12H15FN3, 220.1250.
3.2.15. 4-(4-Chlorophenylamino)quinazoline (18). MeCN (5 mL) was
used as the solvent. After addition of 4-chlorobenzenamine, the
mixture was stirred under reflux for 9 h. The product was obtained
as a white solid in 41% yield, mp: 194e196 ꢁC. 1H NMR (CDCl3) 8.77
(s, 1H), 7.93e7.96 (m, 2H), 7.82 (t, J¼7.5 Hz, 1H), 7.72 (d, J¼9 Hz, 2H),
7.67 (br s, 1H), 7.58 (t, J¼7.5 Hz, 1H), 7.38 (d, J¼9 Hz, 2H). 13C NMR
157.5, 154.7, 149.8, 136.8, 133.2, 129.7, 129.1, 128.9, 126.9, 123.2,
120.4, 115.1. MS (ESI), m/z, 256.3 (MHþ).
3.2.23. 4-(n-Butylamino)-2-methyl-quinazoline (26). The activation
time was 20 h, and the reaction time was 6 h. The product was
obtained as a white solid in 74% yield, mp: 114e116 ꢁC. 1H NMR
(CDCl3) 7.75e7.77 (m, 1H), 7.66e7.69 (m, 2H), 7.36e7.39 (m, 1H),
5.72 (br s, 1H), 3.65e3.69 (m, 2H), 2.64 (s, 3H), 1.67e1.73 (m, 2H),
1.43e1.51 (m, 2H), 0.99 (t, J¼7.5 Hz, 3H). 13C NMR 164.4, 159.4,
149.9, 132.3, 127.7, 124.9, 120.3, 112.9, 40.8, 31.5, 26.7, 20.2, 13.8. MS
(ESI), m/z, 216.2 (MHþ).
3.2.16. 4-(4-Methoxyphenylamino)quinazoline (19). MeCN (5 mL)
was used as the solvent. After addition of 4-methoxybenzenamine,
the mixture was stirred under reflux for 6 h. The product was
obtained as a yellow solid in 63% yield, mp: 169e171 ꢁC. 1H NMR
(DMSO-d6) 8.72 (s, 1H), 7.90 (t, J¼8 Hz, 2H), 7.78e7.81 (m, 1H),
7.54e7.58 (m, 3H), 7.47 (br s, 1H), 6.96 (d, J¼7.5 Hz, 2H), 3.83 (s, 3H).
13C NMR 158.0, 157.1, 155.0, 149.5, 133.0, 130.8, 128.6, 126.6, 124.5,
120.5, 114.9, 114.4, 55.5. MS (ESI), m/z, 252.3 (MHþ).
3.2.24. 4-(n-Butylamino)-6,7-dimethoxy-quinazoline (27). The acti-
vation time was 1 h, and the reaction time was 2 h. Activation and
amination were performed under reflux conditions. The product
was obtained as a white solid in 65% yield, mp: 130e132 ꢁC. 1H NMR
(CDCl3) 8.56 (s,1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.13 (t, J¼5 Hz, 1H), 3.93
(s, 3H), 3.87 (s, 3H), 3.61e3.65 (m, 2H), 1.64e1.71 (m, 2H), 1.40e1.45
(m, 2H), 0.93 (t, J¼7.5 Hz, 3H). 13C NMR 158.5, 154.2, 154.0, 148.9,
146.2, 108.7, 107.5, 99.9, 56.09, 56.06, 41.2, 31.6, 20.2, 13.8. HRMS
(ESI), m/z, 262.1551 [MHþ], calcd for C14H20N3O2, 262.1556.
3.2.17. 4-(N-Methyl-N-phenylamino)quinazoline (20). MeCN (5 mL)
was used as the solvent. After addition of N-methylbenzenamine, the
mixture was stirred under reflux for 7 h. The product was obtained as
a yellow solid in 61% yield, mp: 68e70 ꢁC. 1H NMR (CDCl3) 8.85 (s,
1H), 7.84 (d, J¼8.0 Hz, 1H), 7.57e7.60 (m, 1H), 7.39 (t, J¼8.0 Hz, 1H),
7.27e7.30 (m, 2H), 7.18e7.19 (m, 2H), 7.03e7.05 (m, 2H), 3.65 (s, 3H).
13C NMR 161.8, 154.3, 151.4, 148.5, 131.9, 130.0, 128.4, 126.5, 126.3,
125.8, 125.0, 116.8, 42.5. MS (ESI), m/z, 256.3 (MHþ).
3.2.25. 4-(n-Butylamino)benzo[g]quinazoline (28). The activation
time was 3 h, and the reaction time was 16 h. The product was
obtained as a yellow solid in 73% yield, mp: 220e223 ꢁC. 1H NMR
(CDCl3) 8.67 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 7.96e8.00 (m, 2H),
7.54e7.56 (m, 1H), 7.49e7.51 (m, 1H), 6.21 (br s, 1H), 3.73e3.77 (m,
2H), 1.76e1.82 (m, 2H), 1.50e1.55 (m, 2H), 1.02 (t, J¼7.5 Hz, 3H). 13C
NMR 159.9, 154.9, 144.5, 135.7, 131.1, 128.5, 128.0, 127.6, 126.0, 125.7,
120.5, 114.9, 41.4, 31.4, 20.3, 13.8. HRMS (ESI), m/z, 252.1503 [MHþ],
calcd for C16H19N3, 252.1501.
3.2.18. 4-(n-Butylamino)-6-methyl-quinazoline (21). The reaction
time was 16 h. The product was obtained as a yellow solid in 63%
yield, mp: 104e107 ꢁC. 1H NMR (CDCl3) 8.63 (s, 1H), 7.73 (d,
J¼8.5 Hz, 1H), 7.54e7.56 (m, 1H), 7.49 (s, 1H), 5.80 (br s, 1H),
3.64e3.68 (m, 2H), 2.50 (s, 3H), 1.69e1.75 (m, 2H), 1.44e1.52 (m,
2H), 0.99 (t, J¼7.5 Hz, 3H). 13C NMR 159.1, 154.6, 147.5, 135.9, 134.3,
128.2, 119.6, 114.7, 41.1, 31.43, 21.7, 20.2, 13.8. HRMS (ESI), m/z,
216.1508 [MHþ], calcd for C13H18N3, 216.1501.
3.2.26. 4-(n-Butylamino)pyrido[2,3-d]pyrimidine (29). The reaction
time was 2 h. The product was obtained as a white solid in 85% yield,
mp: 164e167 ꢁC. 1H NMR (CDCl3) 9.04e9.05 (m, 1H), 8.85 (s, 1H),
8.26e8.28 (m, 1H), 7.39e7.41 (m, 1H), 6.36 (br s, 1H), 3.68e3.72 (m,
2H), 1.70e1.76 (m, 2H), 1.43e1.51 (m, 2H), 0.99 (d, J¼7.5 Hz, 3H). 13C
NMR 160.8,158.8,158.3,155.7,131.0,121.2,109.8, 41.5, 31.2, 20.2,13.8.
HRMS (ESI), m/z, 203.1303 [MHþ], calcd for C11H15N4, 203.1297.
3.2.19. 4-(n-Butylamino)-8-methyl-quinazoline (22). The activation
time was 20 h, and the reaction time was 16 h. The product was
obtained as a white solid in 80% yield, mp: 94e96 ꢁC. 1H NMR
(CDCl3) 8.73 (s, 1H), 7.54e7.59 (m, 2H), 7.33e7.36 (m, 1H), 5.76 (br s,
1H), 3.63e3.67 (m, 2H), 2.69 (s, 3H), 1.68e1.74 (m, 2H), 1.45e1.50
(m, 2H), 0.99 (t, J¼7.5 Hz, 3H). 13C NMR 159.7, 154.4, 148.2, 136.6,
132.7, 125.3, 118.0, 114.6, 41.2, 31.4, 20.2, 17.9, 13.8. HRMS (ESI), m/z,
216.1498 [MHþ], calcd for C13H18N3, 216.1501.
3.2.27. Phosphonium intermediate 2a. White solid. 1H NMR (CDCl3),
d
8.91 (s,1H), 8.17 (d, J¼8.0 Hz,1H), 8.08 (d, J¼8.5 Hz,1H), 7.97e8.00
3.2.20. 4-(n-Butylamino)-6-chloroquinazoline (23). The reaction
time was 3 h. The product was obtained as a white solid in 80% yield,
mp: 148e150 ꢁC. 1H NMR (DMSO-d6) 8.47 (s, 1H), 8.43 (d, J¼2.0 Hz,
1H), 8.33 (t, J¼5.0 Hz, 1H), 7.77 (dd, J¼9.0 Hz; J¼2.0 Hz, 1H), 7.69 (d,
J¼9.0 Hz, 1H), 3.51e3.55 (m, 2H), 1.60e1.66 (m, 2H), 1.34e1.42 (m,
2H), 0.93 (t, J¼7.5 Hz, 3H). 13C NMR 158.6, 155.5, 147.8, 132.7, 129.6,
129.5, 122.0, 115.8, 40.3, 30.5, 19.7, 13.7. MS (ESI), m/z, 236.2 (MHþ).
(m, 1H), 7.71e7.75 (m, 1H). 13C NMR 162.0 (d, J¼8.8 Hz), 152.7, 152.6,
135.2, 128.8, 128.3, 123.1, 115.6 (d, J¼8.8 Hz). 31P NMR (202 MHz,
CDCl3),
d
24.01 (d, J¼60.6 Hz), 15.01 (t, J¼60.6 Hz). MS (ESI), m/z,
455.8233 [MHþ], calcd for C8H5ClN5OP3, 455.8228.
Acknowledgements
The authors gratefully acknowledge the financial support of the
Natural Science Foundation of China (NSFC, 20876149, 20772111),
the Zhejiang Provincial Natural Science Foundation of China
3.2.21. 4-(n-Butylamino)-7-chloroquinazoline (24). The reaction
time was 3 h. The product was obtained as a white solid in 69%

1672
Z. Shen et al. / Tetrahedron 67 (2011) 1665e1672
4. Liu, L. T.; Yuan, T.-T.; Liu, H.-H.; Chen, S.-F.; Wu, Y.-T. Bioorg. Med. Chem. Lett.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.12.067.
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16. NMR spectra: see Supplementary data.