Regioselective synthesis and biological evaluation of: N -substituted 2-aminoquinazolin-4-ones

Article abstract of DOI:10.1039/c8ob00624e

The reaction of methyl anthranilates with N-arylcyanamides in the presence of p-TsOH in t-BuOH under reflux afforded predominantly 3-arylquinazolin-4-ones. In contrast, the reaction of the same reactants with TMSCl in t-BuOH at 60 °C followed by the Dimro

Full text of DOI:10.1039/c8ob00624e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Regioselective Synthesis and Biological Evaluation of
N-Substituted 2-Aminoquinazolin-4-ones
Received 00th January 20xx,
Accepted 00th January 20xx
Zhen-Yuan Liao,a Wen-Hsiung Yeh,a Pen-Yuan Liao,a Yu-Ting Liu,a Ying-Cheng Chen,a Yi-Hung
Chen,a Tsung-Han Hsieh,a Chia-Chi Lin,a Ming-Hsuan Lu,a Yi-Song Chen,b Ming-Chih Hsu,b Tsai-Kun
Li,*,b and Tun-Cheng Chien*,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The reaction of methyl anthranilates with N-arylcyanamides in the presence of p-TsOH in t-BuOH under reflux afforded
predominantly 3-arylquinazolin-4-ones. In contrast, the reaction of same reactants with TMSCl in t-BuOH at 60 oC followed
by Dimroth rearrangement in aqueous ethanolic sodium hydroxide gave exclusive the regioisomers, 2-(N-
arylamino)quinazolin-4-ones. The regioselective synthesis of N-aryl-substituted 2-aminoquinazolin-4-ones can be further
applied to the synthesis of benzimidazo[2,1-b]quinazolin-12-ones.
group have been extensively studied,15-18 we found that the
regio-structural isomers, 3-substituted 2-aminoquinazolin-4-
ones, have much less been explored, mainly due to the lack of
Introduction
Quinazoline is
a
benzene-fused pyrimidine derivative
20
a
general synthetic method.19,
Naturally occurring
frequently appeared in a wide variety of natural products and
artificial substances.1, 2 Owing to its structural resemblance to
pteridine, purine and pyrimidine, quinazoline has often been
employed as bioisosteric replacement for these biologically
essential heterocycles in molecular design and become an
attractive target for synthetic chemists.3-5 Amino-substituted
quinazolinone derivatives are among the most common
quinazoline derivatives. Their structures feature similar
hydrogen-bond donor/acceptor properties as folic acid,
guanine and cytosine, and could well mimic the interaction of
these biomolecules with their molecular targets (Figure 1).6, 7
As a result, amino-substituted quinazolinones are privileged
scaffolds commonly integrated into the design of biologically
quinazoline alkaloids are primarily biogenetically derived from
22
anthranilates originated from the shikimate pathway.21,
Albeit a number of synthetic strategies started from benzoic
acid or aniline derivatives have been developed, chemical
preparation of aminoquinazoline derivatives also often utilize
23-25
anthranilic acid derivatives as synthetic precursors.2,
Therefore, the reaction of anthranilic acid derivatives with
monosubstituted urea, thiourea, cyanamide and their
equivalent reagents becomes the most straightforward
approach toward N-substituted 2-aminoquinazolin-4-one
derivatives.
O
interested
compounds.8-10
Our
studies
on
O
NH
COOH
aminoquinazolinones emerged out of long-standing interests
in the synthesis and biological activities of pyrimidine
derivatives. Since we have previously reported the synthesis
and biological evaluation of some 4-aminoquinazolin-2-one
derivatives,11 we devoted our continuous efforts to the studies
of N-substituted 2-aminoquinazolin-4-ones.
N
N
HN
H2N
N
H
O
N
N
N
N
O
HOOC
HN
H2N
folic acid
O
N
HO
5
4
3
HN
O
6
7
HN
H2N
1
N
A
perusal of literature reveals that several 2-
2
H2N
HO
OH
8
aminoquinazolin-4-one derivatives have been shown to display
12-14
guanosine 2-aminoquinazolin-4-one 2-aminopyrimidin-4-one
(isocytosine)
a range of diverse biological activities (Figure 2).10,
Figure 1. Structures of 2-aminoquinazolin-4-one, guanosine, folic acid, and isocytosine
Although the synthesis and biological evaluation of 2-
aminoquinazolin-4-ones with substituents on the 2-amino
In the course of our studies on the synthetic application of
N-substituted cyanamides,26 the formation of 2-
aminoquinazolin-4-ones from the reaction of anthranilate
derivatives and cyanamides attracted our attention. Our
retrosynthetic analysis of 3-subtituted and N2-substituted 2-
aminoquinazolin-4-ones both led to anthranilates and N-
substituted cyanamides as common precursors. Thus, we
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speculated that the reaction of anthranilates and N-
In 2008, K. S. Shikhaliev et al. reported that 2-(N-
substituted cyanamides would result in
mixture containing both 3-subtituted and N2-substituted 2- reaction of methyl anthranilates with N-substituted
aminoquinazolin-4-ones Scheme ). However, literature cyanamides in the presence of concentrated hydrochloric
a regioisomeric substituted-amino)quinazolin-4-ones were obtained from the
(
1
survey revealed that the reaction of anthranilates with N- acid.27 Hence, Shikhaliev’s condition was adopted in our initial
substituted cyanamides mostly afforded only 2-(N-substituted- attempts in order to explore the reaction outcome. Our
amino)quinazolin-4-ones and the 3-substituted congener was reaction of methyl anthranilate (1a) with N-(p-tolyl)cyanamide
nearly absent from the reactions.27, 28 In an effort to explore
(2b) in the presence of concentrated hydrochloric acid in
the chemical synthesis and biological profiles of 2- isopropyl alcohol under reflux afforded a mixture of two
aminoquinazolin-4-one derivatives, we embarked on the products, which were identified as 2-amino-3-(p-
investigation to alter the regioselectivity of the above- tolyl)quinazolin-4-one (3ab, 44%) and the regioisomer, 2-(p-
mentioned reaction for the synthesis of 3-substituted 2- tolylamino)quinazolin-4-one (4ab, 14%) (entry 1 in Table 1).
aminoquinazolin-4-ones.
The major byproduct from the reaction is N-(p-tolyl)urea from
acidic hydrolysis of the cyanamide 2b 29
It is notable that the 3-
.
aryl-2-aminoquinazolin-4-one was the major product from our
reaction and the result was contradictive to Shikhaliev’s
observation that they only obtained the 2-(N-substituted-
amino)quinazolin-4-ones from the reaction.30
Table 1. Optimization of the reaction condition
H
N
CN
Me
O
O
O
Me
2b
Me
(1.5 equiv)
N
NH
OMe
+
additive
solventa
temperatureb
4 h
NH2
N
3ab
NH2
N
4ab
N
H
1a
entry
additive
(1.2 equiv)a
aq. conc. HCl
AcCl
solventb
(0.5 M)
i-PrOH
i-PrOH
MeOH
EtOH
yieldc
overall
yield
58%
26%
10%
27%
73%
83%
55%
97%
86%
4%
3ab
4ab
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
44%
24%
10%
24%
67%
65%
13%
14%
2%
0%
3%
AcCl
AcCl
AcCl
AcCl
t-BuOH
t-amyl-OH
t-BuOH
t-BuOH (60 oC) 56%
6%
18%
42%
41%
36%
trace
2%
3%
5%
6%
2%
30%
3%
32%
26%
15%
3%
pyridinium chloride
TMSCl
TMSCl
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-amyl-OH
1,4-dioxane
MeCN
50%
4%
1%
AcOH
TFA
MsOH
TfOH
3%
72%
73%
76%
76%
33%
57%
16%
19%
8%
75%
78%
82%
78%
63%
60%
48%
45%
23%
75%
45%
70%
51%
CSA
TsOH.H2O
TsOH.H2O (0.5 equiv)
TsOH.H2O (2.0 equiv)
PPTS
Figure 2. Biologically active 2-aminoquinazolin-4-one derivatives
CuCl2 (0.4 equiv)
FeCl3 (0.4 equiv)
TsOH.H2O
TsOH.H2O
TsOH.H2O
TsOH.H2O
72%
45% trace
66%
47%
4%
4%
toluene
a
b
additive = 1.2 equiv, unless specified elsewhere ; reaction temperature =
reflux, unless specified elsewhere; c isolated yields
The preliminary result suggested that the direct
condensation reaction of anthranilates with cyanamides would
potentially provide a feasible route for the synthesis of 3-
substituted 2-aminoquinazolin-4-one derivatives. Thus, this
reaction was chosen as a model reaction to investigate
whether the formation of 3-substituted 2-aminoquinazolin-4-
ones can be optimized to reach a synthetically meaningful
Scheme 1. Retrosynthetic analysis of N-substituted 2-aminoquinazolin-4-ones
Results and discussion
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yield. The screening of the reaction conditions started with regardless both regioisomers were obtained in comparable
various Brønsted and Lewis acids in different solvents (part of amounts. Since 2-(N-substituted-amino)quinazolin-4-ones (
4)
the results is summarized in Table 1). The survey of reaction can be readily separated from the product mixture by alkaline
conditions showed that the maximal yield for the formation of extraction, the direct condensations of anthranilates with N-
o
3-(p-tolyl)-2-aminoquinazoline (3ab) was obtained when the substituted cyanamdes at 60 C in the presence of TMSCl in t-
reaction was carried out at reflux temperature in t-butyl BuOH became an handy procedure to produce two separable
alcohol in the presence of stoichiometric p-toluenesulfonic regioisomers in one pot. A set of selected examples was
acid.31 Meanwhile, 2-(p-tolylamino)quinazolin-4-one (4ab) was demonstrated in Scheme 3
obtained nearly in a minimal yield from this reaction (entry 15
in Table 1).
.
Subsequently, a series of N-substituted cyanamdes (2),
prepared from corresponding nitriles via Tiemann
rearrangement,26 were subjected to the condensation
reactions with various methyl anthranilates (1) under the
3aa : 4aa
3ab : 4ab
3ac : 4ac
3ad : 4ad
3ae : 4ae
3af : 4af
3ah : 4ah
3ba : 4ba
3bb : 4bb
=
=
=
=
=
=
=
=
=
76 : 14
75 : 25
75 : 6
74 : 10
0 : 79
70 : 30
19 : 44
68 : 14
65 : 26
3bc : 4bc
3be : 4be
3ca : 4ca
3cb : 4cb
3cc : 4cc
3cd : 4cd
3ce : 4ce
3cg : 4cg
=
=
=
=
=
=
=
=
57 : 20
35 : 44
65 : 19
56 : 37
55 : 24
44 : 33
20 : 80
28 : 65
optimized p-TsOH condition (entry 15 in Table 1) in order to
establish the scope and generality of the reaction. Our
investigation showed that this reaction protocol is highly
regioselective for the formation of 3-substituted 2-
aminoquinazolin-4-ones
(
3),
except
N-(p-
nitrophenyl)cycnamide (2e) and N-propylcyanamide (2h) gave
moderate yields with poor regioselectivity. Nevertheless, 2-(N-
Scheme 3. Reactions of anthranilates (1) with N-substituted cyanamdes (2) under
TMSCl condition
substituted-amino)quinazolin-4-ones
(
4)
can be easily
separated from the product mixtures by alkaline extraction
attributed to its fairly acidic N-3 proton. Therefore, this
serendipitous discovery provided an effective approach for the
synthesis of 3-substituted 2-aminoquinazolin-4-ones
(3)
(Scheme 2).
H
N
O
O
N
O
N
R2
CN
R2
2
OMe
N
NH
R1
R1
R1
+
R2
TsOH.H2O
t-BuOH
NH2
NH2
N
H
1
3
4
reflux, 4 h
removed by
basic extraction
R
R
R
O
O
N
O
N
Cl
MeO
MeO
N
N
N
NH2
68% (4%)
NH2
55% (10%)
N
NH2
3aa R = H
3ba R = H
3ca R = H
81% (3%)
3ab R = Me 76% (2%)
3ac R = OMe 84% (2%)
3bb R = Me 68% (7%)
3bc R = OMe 66% (10%)
3be R = NO2 22% (32%)
3cb R = Me 96% (4%)
3cc R = OMe 85% (4%)
3ad R = Cl
38% (1%)
3cd R = Cl
72% (5%)
25% (19%)
33% (11%)
3ae R = NO2
3ce R = N
a O
2
O
N
N
O
O
Cl
MeO
MeO
N
N
R
Me
Me
NH2
NH2
N
N
NH2
3cf R = 2-Me 86% (5%)
3cg R = 3-OMe 81% (14%)
3af 71% (25%)
3bf 54% (32%)
R
Scheme 4. Reactions of anthranilates (1) with N-substituted cyanamdes (2) under
O
N
O
N
O
R
R1
R2
Pr
TMSCl condition followed by Dimroth rearrangement
N
Br
NH2
N
N
NH2
NH2
19% (38%)
N
81% (5%)
53% (9%)
3ak R = F 84% (6%)
55% (trace) 3ah R1 = R2 = H
3ai R = H
3aj R = Me
3da R = OMe
3ea R = Br
Through
a
thorough literature review of 2-
50% (trace) 3bh R1 =Cl, R2 = H 9% (27%)
aminoquinazolin-4-ones, we found that R. J. Grout and M. W.
Partridge reported that 3-substituted 2-aminoquinazolin-4-
ones can be converted into the corresponding 2-(N-
substituted-amino)quinazolin-4-ones in 10 N sodium hydroxide
solution under reflux for 8 hours.32 We interpreted that the
alkaline-promoted translocation of the exo- and endo-cyclic
1 = R2 = OMe 37% (59%)
3ch
R
Percent yields in parentheses are the isolated yields for the corresponding
compound from the reactions.
4
Scheme 2. Reactions of anthranilates (1) with N-substituted cyanamdes (2) under p-
TsOH condition
During the survey of conditions, we observed that the guanidino nitrogens (3-N and N2-amino nitrogens) on 2-
model reaction can reach the maximum overall yield when aminoquinazolin-4-ones is an example of Dimroth
trimethylsilyl chloride was used as the acid (entry 8 in Table 1), rearrangement.33-35 We pondered that a combination of the
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high-yielded but poor regioselective condensation reaction TsOH condition (entry 15 in Table 1) to give the corresponding
Scheme 3) followed by Dimroth rearrangement to convert 3- regioisomeric mixtures of 2-aminoquinazolin-4-ones ( and
(
3
4)
substituted 2-aminoquinazolin-4-ones into 2-(N-substituted- in very good yields with inferior regioselectivities (Scheme 6).
amino)quinazolin-4-ones in situ would allow the preparation of For comparison purpose, the same set of examples was
2-(N-substituted-amino)quinazolin-4-ones to
be
more subjected to our TMSCl condition (entry 8 in Table 1) followed
effective. To validate our hypothesis, N-substituted by Dimroth rearrangement. The reactions formed the desired
cyanamides (2) were reacted with anthranilates (1) in the 2-(N-substituted-amino)quinazolin-4-ones (4) but the overall
presence of TMSCl in t-BuOH at 60 oC for 4 hours. The reaction yields are lower than the reactions under p-TsOH (Scheme 7).
mixtures were then subjected to Dimroth rearrangement in 2
N aqueous ethanolic sodium hydroxide solution under reflux
for 6 hours. Our investigation demonstrated that the two-step
sequential reactions in one pot can afford exclusively 2-(N-
substituted-amino)quinazolin-4-ones (
Scheme 4).
4) in very good yields
(
Percent yields in parentheses are the isolated yields for the corresponding
compound from the reactions.
4
Scheme 6. Reactions of anthranilic acids (5) with N-substituted cyanamdes (2) under p-
TsOH condition
Scheme 5. Reactions of anthranilate derivatives 5a, 6 and 7 with N-(p-tolyl)cyanamide
(2b) under p-TsOH condition
The success in the regioselective synthesis of 2-
aminoquinazolin-4-one derivatives from methyl anthranilates
prompted us to examine the reaction of N-substituted
cyanamides (
2) with other anthranilate derivatives. Anthranilic
acid (5a), anthranilamide (
6
) and anthranilonitrile (7) are
abundant and commercially available derivatives in
anthranilate family. These anthranilate derivatives were
subjected to the reactions with N-(p-tolyl)cyanamide (2b) and
p-TsOH in t-BuOH at reflux temperature. Our results showed
that the reaction of anthranilic acid (5a) gave a mixture of both
3-(p-tolyl) and N2-(p-tolyl) 2-aminoquinazolin-4-ones (3ab and
4ab, respectively) in a very good overall yield with poor
regioselectivity. Meanwhile, the reactions of anthranilamide
Scheme 7. Reactions of anthranilic acids (5) with N-substituted cyanamdes (2) under
TMSCl condition followed by Dimroth rearrangement
(6) and anthranilonitrile (7) both resulted in the formation of
3-(p-tolyl)-2-aminoquinazolin-4-one (3ab) as the major product
but only in moderate yields. It is noticeable that either 2-
amino-4-imino-3-(p-tolyl)-3,4-dihydroquinazoline
amino-2-(N-(p-tolyl)amino)quinazoline (8b) was not obtained
from the reaction of anthranilonitrile ( ). We rationalized that
(8a) or 4-
7
the trace amount of water in the reaction participated the
cyclization process and introduced the 4-oxo substituent via
acidic hydrolysis (Scheme 5).
Since anthranilic acid (5a) is the upstream precursor for
methyl anthranilate (2a), we herein also demonstrated that 2-
aminoquinazolin-4-ones can be prepared directly from the
Figure 3. Benzimidazo[2,1-b]quinazolin-12-ones and tryptanthrin
condensation reactions of anthranilic acids
(5) with N-
substituted cyanamides (2). A series of anthranilic acids (5)
were reacted with N-substituted cyanamides (2) under our p-
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Benzimidazo[2,1-b]quinazolin-12-one
(9ai), a
tetracyclic ligand, potassium carbonate as the base in DMF at 120 oC.38
heterocycle constituted by benzimidazole-fused quinazolin-4- The intramolecular C-N bond formation reactions furnished
one, is a 6-deoxo-6-aza analog of natural occurring quinazoline the corresponding tetracyclic heterocycles in very good
alkaloid, tryptanthrin (Figure 3). Benzimidazo[2,1-b]quinazolin- yields. It is worth to mentioned that the Cu(I) catalyzed
12-one (9ai) inherits most of structural features and similar reaction of 3-(4-substituted-2-bromophenyl)-2-
biological profiles from tryptanthrin derivatives. In particular, a aminoquinazolin-4-ones 3aj and 3ak resulted in the
9
(
)
series of benzimidazo[2,1-b]quinazolin-12-one derivatives formation of 8-substituted benzimidazo[2,1-b]quinazolin-12-
were demonstrated to possess significant immunosuppressive ones (9aj and 9ak, respectively), while 2-(N-(4-substituted-2-
and antiproliferative activities.36, 37 The unique structural motif bromophenyl)amino)quinazolin-4-ones (4aj and 4ak) afforded
with interesting biological activities has stimulated interests 9-substituted adducts
from synthetic chemists to develop practical synthesis toward synthetic approach demonstrated that the same anthranilate
benzimidazo[2,1-b]quinazolin-12-ones. and N-(2-bromophenyl)cyanamides could give two
Our retrosynthetic analysis by disconnection of C10a-N11 or regioisomeric 2-aminoquinazolin-4-ones under two different
N6-C6a bond of benzimidazo[2,1-b]quinazolin-12-one
9ai reaction conditions and, after the C-N bond formation, two
(9bj and 9bk, respectively). Our
(
)
leads to either 3-aryl-2-aminoquinazolin-4-one or 2-(N- different regioisomeric benzimidazo[2,1-b]quinazolin-12-ones
arylamino)quinazolin-4-one derivatives, respectively. We could be obtained if N-(2-bromophenyl)cyanamides possess
anticipated that the tetracyclic heterocycle could be additional substituents.
constructed
from
either
3-(2-bromophenyl)-2-
aminoquinazolin-4-one
or
2-(N-(2-
bromophenyl)amino)quinazolin-4-one derivatives via metal-
catalyzed C-N bond formation (Scheme 8). Thus, the synthesis
of benzimidazo[2,1-b]quinazolin-12-ones was undertaken to
demonstrate the synthetic application of our regioselective
synthesis of N-subtituted 2-aminoquinazolin-4-ones.
O
C10a-N11
O
N
disconnection
OMe
NH2
Br
NH2
10
O
N
O
1
11
N
12
+
7
Br
NC
6
Br
NH
N
N
4
H
5
N6-C6a
N
Scheme 9. Synthesis of benzimidazo[2,1-b]quinazolin-12-ones from methyl anthranilate
(1a) and N-(2-bromophenyl)cyanamides (2i-k)
N
N
H
disconnection
H
Scheme 8. Retrosynthetic analysis of benzimidazo[2,1-b]quinazolin-12-ones
Preliminary anti-cancer activity of synthesized 2-
Acid-catalyzed condensation reaction of methyl aminoquinazolin-4-one derivatives has also been evaluated. All
anthranilate
bromophenyl)cyanamides
regioisomers,
(
1a
)
with
a
series
of
pairs
N-(2- the synthesized compounds were subjected to cytotoxicity
of assay against human leukemia cell line HL-6039 and the results
(
2i
-
k
)
afforded
3-(2-bromophenyl)-2-aminoquinazolin-4-ones are summarized in Table 2. The results indicated that several
and 2-(N-(2-bromophenyl)amino)quinazolin-4-ones compounds showed the IC50 of anti-leukemia activity in the
ak), individually under our regioselective conditions. single-digit micromolar range. Notably, both 4ae and 4cb show
M range as clinically
(
(
3ai
4ai
-
-
ak)
Subsequently, both N-(2-bromophenyl)-substituted 2- the same magnitude order in the sub-
aminoquinazolin-4-ones (3ai ak and 4ai ak) were subjected to used etoposide (VP-16).
the intramolecular C-N bond formation reaction in the
µ
-
-
presence of copper(I) iodide as the catalyst,
L
-proline as the
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Table 2. Cytotoxicity against human leukemia cell line HL-6039
compound
3aa
3ab
3ac
3ad
3ae
3af
3ah
3ai
3aj
3ak
3ba
3bb
3bc
3bd
3be
3bf
3bh
3ca
3cb
3cc
R1
R3
Ph
IC50 (μM)
40
20
35
40
> 200
40
134
> 200
14
16
17
55
80
80
2.26
50
79
40
45
35
15
38
152
50
> 200
> 200
76
84
90
50
68
compound
4aa
4ab
4ac
4ad
4ae
4af
4ah
4ai
4aj
4ak
4ba
4bb
4bc
4bd
4be
4bf
4bh
4ca
4cb
4cc
R1
R2
IC50 (μM)
60
H
H
H
H
H
H
H
H
H
H
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
H
H
H
H
H
H
H
H
H
H
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6-MeO
6-MeO
6-Br
Ph
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
Pr
2-Br-C6H4
2-Br-4-Me-C6H3
2-Br-4-F-C6H3
Ph
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
Pr
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
Pr
2-Br-C6H4
2-Br-4-Me-C6H3
2-Br-4-F-C6H3
Ph
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
Pr
35
100
1.97
0.67
50
30
> 200
1.49
4.79
10
7.38
18
1.01
0.99
30
135
20
0.11
25
6.28
20
16
13
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6,7-di-MeO
6-MeO
6-MeO
6-Br
Ph
Ph
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
3-MeO-C6H4
Pr
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
2-Me-C6H4
3-MeO-C6H4
Pr
3cd
3ce
3cf
4cd
4ce
4cf
3cg
4cg
3ch
3da
3db
3ea
3fa
3fb
3fd
3gb
4ch
4da
4db
4ea
4fa
4fb
4fd
4gb
87
48
Ph
Ph
4-Me-C6H4
Ph
4-Me-C6H4
Ph
7.81
8.8
> 200
5.18
> 200
24
6-Me
6-Me
6-Me
6-HO
Ph
6-Me
6-Me
6-Me
6-HO
Ph
4-Me-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
4-Cl-C6H4
4-Me-C6H4
5.98
compound
9ai
9aj
9ak
9bj
9bk
R8
H
Me
F
H
H
R9
H
H
H
Me
F
IC50 (μM)
11
> 200
> 200
39
compound
Dox
VP-16
IC50 (μM)
0.03
0.12
(doxorubicin)
(etoposide)
76
different reaction pathways to afford two different
regioisomeric products, 3-substituted or N2-substituted 2-
aminoquinazolin-4-one derivatives, which allowed the
Conclusions
preparation of
a
wider variety of N-substituted 2-
In summary, we disclosed the regioselective synthesis of N-
substituted 2-aminoquinazolin-4-ones from methyl
aminoquinazolin-4-ones from readily available precursors.
Further applications of these approaches would be amenable
to the synthesis of more complicated quinazoline-containing
heterocycles.
anthranilates and N-substituted cyanamdes via acid-prompted
condensation reactions. By choosing different reaction
conditions, the same set of reactants can undergo two
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ARTICLE
MgSO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash column
chromatography to give 2-(N-substituted-amino)quinazolin-4-
Experimental section
General information
The chemical shift values are reported in δ values (parts
per million, ppm) relative to the standard chemical shift for the
hydrogen residue peak and carbon-13 peak in the deuterated
solvent, CDCl3, or DMSO-d6.40 The coupling constant (J) values
are expressed in hertz (Hz). The numbers of protons directly
attached to the individual carbons were determined by 13C
NMR DEPT experiments. Thin-layer chromatography (TLC) was
performed on silica gel plates. Compounds on TLC were
visualized by illumination under UV light (254 nm), or dipped
into 10% phosphomolybdic acid in ethanol followed by
charring on a hot plate. Solvent systems are expressed as a
volumetric ratio (v/v) of the less polar component to the more
polar component. Silica gel (230-400 mesh) was used for flash
column chromatography and this technique has been
described by W. C. Still et al.41 Evaporations were carried out
under reduced pressure (water aspirator or vacuum pump)
with the bath temperature below 50 oC unless specified
otherwise. Materials obtained from commercial suppliers were
used without further purification.
one (4).
2-Amino-3-phenylquinazolin-4-one19, 42 (3aa)
Compound 3aa was prepared by general procedure 1. The
product (3aa, solid, 0.6201 g, 2.614 mmol, 64%, Rf = 0.20
(CHCl3 / MeOH = 98 : 2)) was purified by flash column
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 245–250 oC
(CHCl3 / MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 7.89 (d, 1H, J =
8.0 Hz), 7.62–7.50 (m, 4H), 7.35 (d, 2H, J = 7.5 Hz), 7.25 (d, 1H,
J = 8.0 Hz), 7.12 (t, 1H, J = 7.5 Hz), 6.27 (br, 2H, NH2); 13C NMR
(DMSO-d6, 125 MHz) δ 162.3, 152.1, 150.6, 135.9, 134.9 (CH),
130.4 (CH), 129.6 (CH), 129.3 (CH), 127.0 (CH), 124.4 (CH),
122.0 (CH), 117.3; MS (EI, 70 eV) m/z 77 (22), 237 (100) (M+);
HRMS (APCI, TOF) calcd for C14H12N3O: 238.0980 (M+H).
Found: 238.0986.
2-Amino-3-(4-tolyl)quinazolin-4-one38 (3ab)
Compound 3ab was prepared by general procedure 1 or
general procedure 3. The product (3ab, solid, 0.1471 g, 0.586
mmol, 76%, Rf = 0.35 (CHCl3 / MeOH = 98 : 2)) was purified by
flash column chromatography (CHCl3 / MeOH = 99 : 1). m.p.
General procedure for cytotoxicity assay (Table 2)
o
1
266 C (CHCl3 / MeOH); H NMR (DMSO-d6, 400 MHz) δ 7.88
(dd, 1H, J = 8.0, 1.2 Hz), 7.60 (dt, 1H, J = 7.2, 1.6 Hz), 7.36 (d,
2H, J = 8.0 Hz), 7.25–7.21 (m, 3H), 7.10 (dt, 1H, J = 8.0, 0.8 Hz),
6.23 (br, 2H, NH2), 2.40 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ
161.9, 151.8, 150.1, 138.5, 134.3 (CH), 132.8, 130.5 (CH), 128.5
(CH), 126.5 (CH), 123.9 (CH), 121.4 (CH), 116.8, 20.8 (CH3); MS
(EI, 70 eV) m/z 90 (19), 251 (100) (M+); HRMS (APCI, TOF) calcd
for C15H14N3O: 252.1137 (M+H). Found: 252.1132.
Leukemia cell line HL-60 was obtained from ATCC. HL-60
was cultivated in RPMI 1640 media (Mediatech, Inc. Manassas,
VA, USA) containing 10% fetal calf serum, 100 unit/mL
penicillin, 100 mg/mL streptomycin, and 2 mM glutamine in a
5% CO2 incubator at 37 oC. Cytotoxicity was measured by MTT
assay after continuous treatment with the tested compounds
for 4 days as described. The quantitative results of IC50 were
estimated with the 3 replicates data.39
2-Amino-3-propylquinazolin-4-one42 (3ah)
[General procedure 1] Preparation of 3-substituted 2-
aminoquinazolin-4-one (3) under the optimized p-TsOH condition
(Scheme 2)
Compound 3ah was prepared by general procedure 1. The
product (3ah, solid, 0.2586 g, 1.273 mmol, 19%, Rf = 0.15
(CHCl3 / MeOH = 98 : 2)) was purified by flash column
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 182–184 oC; 1H
NMR (DMSO-d6, 500 MHz) δ 7.87 (d, 1H, J = 8.0 Hz), 7.53 (dt,
1H, J = 7.5, 1.5 Hz), 7.16 (d, 1H, J = 8.0 Hz), 7.06 (t, 1H, J = 7.0
Hz), 6.97 (br, 2H, NH2), 3.92 (t, 2H, J = 7.5 Hz, CH2), 1.62-1.55
(m, 2H, CH2), 0.87 (t, 3H, J = 7.5 Hz, CH3); 13C NMR (DMSO-d6,
125 MHz) δ 162.3, 152.2, 149.8, 134.5 (CH), 126.8 (CH), 123.9
(CH), 121.9 (CH), 116.4, 42.9 (CH2), 20.7 (CH2), 11.2 (CH3); MS
(ESI+) m/z 204 (100) (M+H); HRMS (ESI+, TOF) calcd for
C11H14N3O: 204.1137 (M+H). Found: 204.1115.
To a mixture of N-substituted cyanamide26
and methyl anthranilate ( , 1.0 equiv) in tert-butanol (0.5 M)
(2, 1.5 equiv)
1
was added p-toluenesulfonic acid monohydrate (1.2 equiv).
The mixture was heated at reflux temperature for 4 hours.
After cooling to room temperature, the solvent was removed
under reduced pressure, and the residue was partitioned
between CHCl3 and 2 N NaOH aqueous solution. The organic
layer was washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography to give 3-substituted 2-aminoquinazolin-4-
2-Amino-3-(2-bromophenyl)quinazolin-4-one (3ai)
one
aminoquinazolin-4-one (
from CHCl3 / MeOH or CHCl3 / EtOH (approximately 1 : 5 (v/v)).
The regioisomer, 2-(N-substituted-amino)quinazolin-4-one ( ),
(3
). An analytical sample of 3-substituted 2-
Compound 3ai was prepared by general procedure 1. The
product (3ai, solid, 0.9679 g, 3.06 mmol, 87%, Rf = 0.30 (CH2Cl2
3) was obtained by recrystallization
/
MeOH = 98 : 2)) was purified by flash column
4
chromatography (CH2Cl2 / MeOH = 99 : 1). m.p. 237–238 oC; 1H
NMR (DMSO-d6, 400 MHz) δ 7.89 (dd, 1H, J = 7.9, 1.4 Hz), 7.85
(dd, 1H, J = 8.0, 1.2 Hz), 7.62 (dt, 1H, J = 7.8, 1.6 Hz), 7.60–7.51
(m, 2H), 7.46 (dt, 1H, J = 7.8, 2.0 Hz), 7.25 (d, 1H, J = 8.0 Hz),
7.12 (t, 1H, J = 8.0 Hz), 6.44 (br, 2H, NH2); 13C NMR (DMSO-d6,
100 MHz) δ 161.6, 151.4, 150.8, 135.08 (CH), 135.06, 134.1
was retrieved by acidifying the aqueous layer with 2 N
aqueous acetic acid solution (0.8 equiv to the 2 N NaOH
aqueous solution) followed by CHCl3 extraction. The CHCl3
layer was washed with saturated aqueous Na2CO3 solution,
saturated aqueous NaCl solution, dried over anhydrous
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Journal Name
(CH), 131.7 (CH), 131.6 (CH), 130.0 (CH), 127.0 (CH), 124.4 solution (4 N NaOH aqueous solution / EtOH = 1 : 1 (v/v), 4
(CH), 123.2, 122.0 (CH), 116.9; MS (EI, 20 eV) m/z 236 (100), times of volume of t-BuOH to bring the final reaction
315 (22) (M+), 317 (20) (M+2); HRMS (EI, sector) calcd for concentration to 0.1 M) and the reaction mixture was heated
C14H10BrN3O: 315.0007. Found: 315.0000.
at reflux temperature for 6 hours. The volatile solvents were
removed under reduced pressure, and the resulting solution
was partitioned between CHCl3 and water. The aqueous layer
2-Amino-3-(2-bromo-4-methylphenyl)quinazolin-4-one (3aj)
Compound 3aj was prepared by general procedure 1. The was acidified with 2 N aqueous acetic acid solution (0.8 equiv
product (3aj, solid, 0.3509 g, 1.06 mmol, 53%, Rf = 0.25 (CH2Cl2 to the 4 N NaOH aqueous solution), and then extracted with
/
MeOH = 98 : 2)) was purified by flash column CHCl3. The CHCl3 layer was washed with saturated aqueous
chromatography (CH2Cl2 / MeOH = 99 : 1). m.p. 293–294 oC; 1H Na2CO3 solution, saturated aqueous NaCl solution, dried over
NMR (DMSO-d6, 400 MHz) δ 7.88 (dd, 1H, J = 8.0, 1.2 Hz), 7.68 anhydrous MgSO4, and the solvent was evaporated under
(s, 1H), 7.61 (t, 1H, J = 8.4 Hz), 7.38 (s, 2H), 7.24 (d, 1H, J = 8.0 reduced pressure. The residue was purified by flash column
Hz), 7.11 (t, 1H, J = 7.6 Hz), 6.42 (br, 2H, NH2), 2.40 (s, 3H, Me); chromatography to give 2-(N-substituted-amino)quinazolin-4-
13C NMR (DMSO-d6, 100 MHz) δ 161.7, 151.6, 150.8, 141.7, one
135.0 (CH), 134.3 (CH), 132.4, 131.0 (CH), 130.6 (CH), 127.0 amino)quinazolin-4-one (
(
4
). An analytical sample of 2-(N-substituted-
4) was obtained by recrystallization
(CH), 124.4 (CH), 122.8, 121.9 (CH), 116.9, 20.9 (CH3); MS (EI, from CHCl3 / MeOH or CHCl3 / EtOH (approximately 1 : 5 (v/v)).
20 eV) m/z 250 (100), 329 (17) (M+), 331 (16) (M+2); HRMS (EI,
sector) calcd for C15H12BrN3O: 329.0164. Found: 329.0165.
2-(N-Phenylamino)quinazolin-4-one16, 43-45 (4aa)
Compound 4aa was prepared by general procedure 2. The
product (4aa, solid, 0.6351 g, 2.677 mmol, 74%, Rf = 0.16 (Hex
2-Amino-6-chloro-3-(4-tolyl)quinazolin-4-one (3bb)
Compound 3bb was prepared by general procedure 1 or / EtOAc = 7 : 3)) was purified by flash column chromatography
o
1
general procedure 3. The product (3bb, solid, 0.6341 g, 2.219 (CHCl3 / MeOH = 99 : 1). m.p. 264–265 C; H NMR (DMSO-d6,
mmol, 68%, Rf = 0.33 (CHCl3 / MeOH = 98 : 2)) was purified by 500 MHz) δ 10.81 (br, 1H, NH), 8.66 (br, 1H, NH), 7.97 (d, 1H, J
flash column chromatography (CHCl3 / MeOH = 99 : 1). m.p. = 7.0 Hz), 7.74 (d, 2H, J = 8.0 Hz), 7.65 (t, 1H, J = 7.0 Hz), 7.40
315 oC (CHCl3 / MeOH); 1H NMR (DMSO-d6, 400 MHz) δ 7.80 (d, (d, 1H, J = 8.5 Hz), 7.35 (t, 1H, J = 8.0 Hz), 7.23 (t, 1H, J = 7.5
1H, J = 2.5 Hz), 7.61 (dd, 1H, J = 8.8, 2.5 Hz), 7.37 (d, 2H, J = 8.1 Hz), 7.04 (t, 1H, J = 7.5 Hz); 13C NMR (DMSO-d6, 125 MHz) δ
Hz), 7.25 (d, 1H, J = 8.8 Hz), 7.23 (d, 2H, J = 8.1 Hz), 6.42 (br, 161.6, 150.0, 147.4, 139.0, 134.4 (CH), 128.8 (CH), 125.9 (CH),
2H, NH2), 2.40 (s, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ 125.3 (CH), 123.0 (CH), 122.5 (CH), 119.3 (CH), 118.4; MS (ESI-)
161.5, 152.7, 149.5, 139.2, 134.8 (CH), 133.0, 131.0 (CH), 128.9 m/z 236 (100) (M-H); HRMS (ESI-, TOF) calcd for C14H11N3O:
(CH), 126.6 (CH), 125.7 (CH), 125.6, 118.2, 21.3 (CH3); MS (EI, 236.0829 (M-H). Found: 236.0831.
70 eV) m/z 123 (18), 285 (100) (M+), 287 (23) (M+2); HRMS
(APCI, TOF) calcd for C15H13ClN3O: 286.0747 (M+H). Found: 2-(N-(4-Tolyl)amino)quinazolin-4-one16, 43, 44 (4ab)
286.0742.
Compound 4ab was prepared by general procedure 2. The
product (4ab, solid, 0.500 g, 1.989 mmol, 81%, Rf = 0.28 (CHCl3
2-Amino-6,7-dimethoxy-3-phenylqinazolin-4-one (3ca)
/ MeOH = 98 : 2)) was purified by flash column
o
Compound 3ca was prepared by general procedure 1. The chromatography (CHCl3 / MeOH = 99 : 1). m.p. 275 C (CHCl3 /
product (3ca, solid, 1.3160 g, 4.426 mmol, 81%, Rf = 0.23 MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 10.8 (br, 1H, NH), 8.54
(CHCl3 / MeOH = 98 : 2)) was purified by flash column (br, 1H, NH), 7.96 (dd, 1H, J = 7.5, 1.0 Hz), 7.63 (t, 1H, J = 7.5
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 253–256 oC Hz), 7.61 (d, 2H, J = 8.5 Hz), 7.37 (d, 1H, J = 8.5 Hz), 7.21 (t, 1H,
(CHCl3 / MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 7.57 (t, 2H, J = J = 7.5 Hz), 7.15 (d, 2H, J = 8.5 Hz), 2.27 (s, 3H, CH3); 13C NMR
7.0 Hz), 7.51 (t, 1H, J = 7.5 Hz), 7.32 (d, 2H, J = 7.5 Hz), 7.23 (s, (DMSO-d6, 125 MHz) δ 161.6, 150.1, 147.5, 136.4, 134.4 (CH),
1H), 6.71 (s, 1H), 5.98 (br, 2H, NH2), 3.85 (s, 3H, Me), 3.77 (s, 131.5, 129.2 (CH), 125.9 (CH), 125.3 (CH), 122.8 (CH), 119.5
3H, Me); 13C NMR (DMSO-d6, 125 MHz) δ 161.6, 155.6, 151.3, (CH), 118.3, 20.4 (CH3); MS (EI, 70 eV) m/z 251 (100) (M+);
146.8, 145.7, 136.2, 130.4 (CH), 129.5 (CH), 129.3 (CH), 109.5, HRMS (ESI+, TOF) calcd for C15H14N3O: 252.1137 (M+H). Found:
106.7 (CH), 105.7 (CH), 56.14 (CH3), 56.09 (CH3); MS (EI, 70 eV) 252.1134.
m/z 280 (28), 282 (57), 297 (100) (M+); HRMS (ESI+, TOF) calcd
for C16H16N3O3: 298.1192 (M+H). Found: 298.1198.
2-(N-Propylamino)quinazolin-4-one (4ah)
Compound 4ah was prepared by general procedure 2. The
product (4ah, solid, 0.2489 g, 1.22 mmol, 61%, Rf = 0.12 (CHCl3
[General procedure 2] Preparation of 2-(N-substituted-
amino)quinazolin-4-one (4) under the optimized TMSCl condition
followed by Dimroth rearrangement (Scheme 4)
/
MeOH = 98 : 2)) was purified by flash column
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 189–190 oC; 1H
NMR (DMSO-d6, 500 MHz) δ 10.79 (br, 1H, NH), 7.87 (dd, 1H, J
= 8.0, 1.5 Hz), 7.55 (dt, 1H, J = 7.8, 2.0 Hz), 7.24 (d, 1H, J = 8.0
Hz), 7.09 (t, 1H, J = 7.5 Hz), 6.29 (br, 1H, NH), 3.28 (m, 2H,
propyl), 1.59-1.52 (m, 2H, propyl), 0.92 (t, 3H, J = 7.5 Hz,
propyl); 13C NMR (DMSO-d6, 125 MHz) δ 162.7, 151.3, 134.5
(CH), 126.4 (CH), 124.8, 122.0 (CH), 117.8, 42.4 (CH2), 22.6
To a mixture of N-substituted cyanamide26
and methyl anthranilate ( , 1.0 equiv) in tert-butanol (0.5 M)
was added trimethylsilyl chloride (1.2 equiv). The mixture was
heated at 60 oC for
hours. After cooling to room
(2, 1.5 equiv)
1
4
temperature, the mixture was added aqueous ethanolic NaOH
8 | J. Name., 2012, 00, 1-3
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(CH2), 11.8 (CH3); 13C NMR (added a drop of TFA, DMSO-d6, 125 NH), 7.73 (d, 2H, J = 7.5 Hz), 7.35 (dd, 2H, J = 7.5, 1.0 Hz), 7.32
MHz) δ 160.4, 150.8, 139.6, 136.7 (CH), 127.8 (CH), 125.9 (CH), (s, 1H), 7.02 (t, 1H, J = 7.5 Hz), 6.90 (s, 1H), 3.88 (s, 3H, Me),
118.1 (CH), 116.4, 44.1 (CH2), 22.3 (CH2), 11.5 (CH3); MS (ESI+) 3.81 (s, 3H, Me); 13C NMR (DMSO-d6, 125 MHz) δ 161.4, 155.4,
m/z 204 (100) (M+H); HRMS (ESI+, TOF) calcd for C11H14N3O: 147.2, 146.6, 146.5, 139.7, 129.3 (CH), 122.6 (CH), 119.5 (CH),
204.1137 (M+H). Found: 204.1138.
111.1, 107.2 (CH), 106.0 (CH), 56.3 (CH3), 56.1 (CH3); MS (ESI-)
m/z 296 (100) (M-H); HRMS (ESI-, TOF) calcd for C16H14N3O3:
296.1041 (M-H). Found: 296.1055.
2-(N-(2-Bromophenyl)amino)quinazolin-4-one (4ai)
Compound 4ai was prepared by general procedure 2. The
product (4ai, light red solid, 0.9385 g, 2.99 mmol, 95%, Rf = [General procedure 3] Preparation of 3-substituted 2-
0.21 (CHCl3 / MeOH = 98 : 2)) was purified by flash column aminoquinazolin-4-one (3) and 2-(N-substituted-amino)quinazolin-
o
1
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 275–276 C; H 4-one (4) from corresponding anthranilic acids (5) under the
NMR (DMSO-d6, 500 MHz) δ 11.46 (br, 1H, NH), 8.33 (br, 1H), optimized p-TsOH condition (Scheme 6)
8.17 (br, 1H, NH), 7.96 (dd, 1H, J = 8.0, 1.0 Hz), 7.67–7.62 (m,
To a mixture of N-substituted cyanamide26
(
2
, 1.5 equiv)
2H), 7.41 (t, 1H, J = 8.5 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.24 (t, 1H,
J = 7.8 Hz), 7.06 (t, 1H, J = 8.3 Hz); 13C NMR (DMSO-d6, 125
MHz) δ 163.0, 148.6, 137.1, 135.2 (CH), 133.3 (CH), 128.8 (CH),
126.6 (CH), 125.8 (CH), 125.6, 124.9 (CH), 124.0 (CH), 119.1,
115.7; MS (EI, 20 eV) m/z 236 (100), 315 (13) (M+), 317 (12)
(M+2); HRMS (EI, sector) calcd for C14H10BrN3O: 315.0007.
Found: 315.0003.
and anthranilic acid (
5, 1.0 equiv) in tert-butanol (0.5 M) was
added p-toluenesulfonic acid monohydrate (1.2 equiv). The
mixture was heated at reflux temperature for 4 hours. After
cooling to room temperature, the solvent was removed under
reduced pressure, and the residue was partitioned between
CHCl3 and 2 N NaOH aqueous solution. The organic layer was
washed with saturated aqueous NaCl solution, dried over
anhydrous MgSO4, and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography to give 3-substituted 2-aminoquinazolin-4-
2-(N-(2-Bromo-4-methylphenyl)amino)quinazolin-4-one (4aj)
Compound 4aj was prepared by general procedure 2. The
product (4aj, white solid, 0.5613 g, 1.70 mmol, 85%, Rf = 0.13
(CHCl3 / MeOH = 98 : 2)) was purified by flash column
one
aminoquinazolin-4-one (
from CHCl3 / MeOH or CHCl3 / EtOH (approximately 1 : 5 (v/v)).
The regioisomer, 2-(N-substituted-amino)quinazolin-4-one ( ),
(
3). An analytical sample of 3-substituted 2-
3) was obtained by recrystallization
o
1
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 260–261 C; H
NMR (DMSO-d6, 400 MHz) δ 11.52 (br, 1H, NH), 8.17 (br, 1H),
8.06 (br, 1H, NH), 7.96 (d, 1H, J = 6.8 Hz), 7.62 (t, 1H, J = 8.2
Hz), 7.49 (d, 1H, J = 1.2 Hz), 7.32 (d, 1H, J = 8.4 Hz), 7.22 (t, 2H,
J = 7.4 Hz), 2.29 (s, 3H, Me); 13C NMR (DMSO-d6, 100 MHz) δ
162.3, 150.3, 148.3, 135.3, 134.8 (CH), 134.3, 133.1 (CH), 129.2
(CH), 126.4 (CH), 125.7 (CH), 124.8 (CH), 123.6 (CH), 118.9,
115.5, 20.4 (CH3); MS (EI, 20 eV) m/z 250 (100), 329 (13) (M+),
331 (13) (M+2); HRMS (EI, sector) calcd for C15H12BrN3O:
329.0164. Found: 329.0168.
4
was retrieved by acidifying the aqueous layer with 2 N
aqueous acetic acid solution (0.8 equiv to the 2 N NaOH
aqueous solution) followed by CHCl3 extraction. The CHCl3
layer was washed with saturated aqueous Na2CO3 solution,
saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash column
chromatography to give 2-(N-substituted-amino)quinazolin-4-
one (4).
6-Chloro-2-(N-(4-tolyl)amino)quinazolin-4-one (4bb)
Compound 4bb was prepared by general procedure 2. The
product (4bb, solid, 0.4920 g, 1.721 mmol, 52%, Rf = 0.30
(CHCl3 / MeOH = 98 : 2)) was purified by flash column
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 300 oC
(decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 10.94 (br, 1H, NH),
8.60 (br, 1H, NH), 7.86 (d, 1H, J = 2.5 Hz), 7.63 (dd, 1H, J = 9.0,
2.5 Hz),7.58 (d, 2H, J = 8.0 Hz), 7.37 (d, 1H, J = 9.0 Hz), 7.14 (d,
2H, J = 8.0 Hz), 2.27 (s, 3H, CH3); 13C NMR (DMSO-d6, 125 MHz)
δ 160.7, 149.0, 147.9, 136.1, 134.3 (CH), 131.8, 129.2 (CH),
127.4 (CH), 126.7, 124.8 (CH), 119.7 (CH), 119.4, 20.4 (CH3); MS
(EI, 70 eV) m/z 124 (26), 285 (100) (M+), 287 (32) (M+2); HRMS
(ESI+, TOF) calcd for C15H13ClN3O: 286.0747 (M+H). Found:
286.0748.
2-Amino-6-chloro-3-(4-chlorophenyl)quinazolin-4-one (3bd)
Compound 3bd was prepared by general procedure 3. The
product (3bd, solid, 0.6227 g, 2.034 mmol, 47%, Rf = 0.30
(CHCl3 / MeOH = 98 : 2) was purified by flash column
chromatography (CH2Cl2 / MeOH = 99 : 1). m.p. 315–317 oC
(CHCl3 / MeOH); 1H NMR (DMSO-d6, 500 MHz) δ 7.79 (d, 1H, J =
2.5 Hz), 7.62 (d, 2H, J = 8.5 Hz), 7.61 (dd, 1H, J = 8.5, 3.0 Hz),
7.41 (d, 2H, J = 8.0 Hz), 7.24 (d, 2H, J = 8.5 Hz), 6.59 (br, 2H,
NH2); 13C NMR (DMSO-d6, 125 MHz) δ 161.4, 152.4, 149.5,
134.9 (CH), 134.6, 134.4, 131.3 (CH), 130.5 (CH), 126.6 (CH),
125.7 (CH), 125.6, 118.1; MS (EI, 70 eV) m/z 305 (100) (M+),
307 (62) (M+2), 309 (17) (M+4); HRMS (ESI+, TOF) calcd for
C14H10Cl2N3O: 306.0201 (M+H). Found: 306.0193.
6,7-Dimethoxy-2-(N-phenylamino)quinazolin-4-one46 (4ca)
Compound 4ca was prepared by general procedure 2. The
product (4ca, solid, 0.6957 g, 2.34 mmol, 78%, Rf = 0.10 (CHCl3
2-Amino-6-methoxy-3-(4-tolyl)quinazolin-4-one (3db)
Compound 3db was prepared by general procedure 3. The
product (3db, solid, 0.2457 g, 0.873 mmol, 44%, Rf = 0.3
(CH2Cl2 / MeOH = 99 : 1) was purified by flash column
chromatography (CH2Cl2 / MeOH = 99 : 1). m.p. 259-260 oC; 1H
/
MeOH = 98 : 2)) was purified by flash column
o
chromatography (CHCl3 / MeOH = 99 : 1). m.p. 256–257 C; H
1
NMR (DMSO-d6, 500 MHz) δ 10.64 (br, 1H, NH), 8.54 (br, 1H,
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NMR (DMSO-d6, 400 MHz) δ 7.37 (d, 2H, J = 8.0 Hz), 7.30 (d, 7.67 (dd, 1H, J = 8.5, 2.5 Hz), 7.42 (d, 1H, J = 8.5 Hz), 7.39 (d,
1H, J = 2.8 Hz), 7.26 (dd, 1H, J = 8.8, 2.8 Hz), 7.21 (d+d, 2H+1H, 2H, J = 9.0 Hz); 13C NMR (DMSO-d6, 125 MHz) δ 161.1, 149.1,
J = 8.4 Hz), 6.06 (br, 2H, NH2), 3.78 (s, 3H, Me), 2.40 (s, 3H, 148.1, 138.2, 134.9 (CH), 129.1 (CH), 128.0 (CH), 127.6, 126.8,
Me); 13C NMR (DMSO-d6, 100 MHz) δ 161.6, 154.2, 150.4, 125.3 (CH), 121.6 (CH), 120.1; MS (ESI+) m/z 306 (100) (M+H),
144.5, 138.5, 133.0, 130.4 (CH), 128.5 (CH), 125.6 (CH), 124.2 308 (55) (M+H+2), 310 (9) (M+H+4); HRMS (ESI+, TOF) calcd for
(CH), 116.9, 106.4 (CH), 55.4 (CH3), 20.8 (CH3); MS (ESI+) m/z C14H10Cl2N3O: 306.0201 (M+H). Found: 306.0200.
282 (100) (M+H); HRMS (ESI+, TOF) calcd for C16H15N3O2:
282.1243 (M+H). Found: 282.1245.
6-Methoxy-2-(N-(4-tolyl)amino)quinazolinone (4db)
Compound 4db was prepared by general procedure 4. The
product (4db, solid, 0.2134 g, 0.759 mmol, 76%, Rf = 0.1
2-Amino-6-hydroxy-3-(4-tolyl)quinazolin-4-one (3gb)
Compound 3gb was prepared by general procedure 3. The (CH2Cl2 / MeOH = 99 : 1) was purified by flash column
product (3gb, soild, 0.1523 g, 0.296 mmol, 57%, Rf = 0.11 chromatography (CH2Cl2 / MeOH = 98 : 2). m.p. 277–278oC; 1H
(CH2Cl2 / MeOH = 98 : 2) was purified by flash column NMR (DMSO-d6, 400 MHz) δ 10.81 (br, 1H, NH), 8.46 (br, 1H,
chromatography (CH2Cl2 / MeOH = 98 : 2); m.p. 287 oC; 1H NH), 7.59 (d, 2H, J = 8.0 Hz), 7.37 (d, 1H, J = 2.8 Hz), 7.35 (d, 1H,
NMR (DMSO-d6, 400 MHz) δ 9.51 (br, 1H, OH), 7.36 (d, 2H, J = J = 8.8 Hz), 7.27 (dd, 1H, J = 8.8, 2.8 Hz), 7.14 (d, 2H, J = 8.4 Hz),
8.1 Hz), 7.23 (d, 1H, J = 2.1 Hz), 7.18 (d, 2H, J = 8.2 Hz), 7.14– 3.81 (s, 3H, Me), 2.27 (s, 3H, Me); 13C NMR (DMSO-d6, 100
7.08 (m, 2H, Ar), 5.85 (br, 2H, NH2), 2.39 (s, 3H, Me); 13C NMR MHz) δ 161.5, 155.2, 146.2, 144.4, 136.6, 131.1 129.2 (CH),
(DMSO-d6, 100 MHz) δ 161.8, 152.4, 149.9, 143.1, 138.7, 126.8 (CH), 123.8 (CH), 119.1 (CH), 118.5, 106.2 (CH), 55.4
133.1, 130.6 (CH), 128.6 (CH), 125.5 (CH), 124.4 (CH), 117.4, (CH3), 20.4 (CH3); MS (ESI+) m/z 282 (100) (M+H); HRMS (ESI+,
109.5 (CH), 21.0 (CH3); MS (EI, 70 eV) m/z 266 (90), 267 (100) TOF) calcd for C16H15N3O2: 282.1243 (M+H). Found: 282.1242.
(M+); HRMS (EI, sector) calcd for C15H13N3O2: 267.1008. Found:
267.1010.
6-Hydroxy-2-(N-(4-tolyl)amino)quinazolin-4-one (4gb)
Compound 4gb was prepared by general procedure 4. The
product (4gb, soild, 0.3255 g, 1.21 mmol, 70%, Rf = 0.05
(CH2Cl2 / MeOH = 98 : 2) was purified by flash column
chromatography (CH2Cl2 / MeOH = 96 : 4); m.p. 180 oC; 1H
NMR (DMSO-d6, 400 MHz) δ 11.02 (br, 1H, NH), 9.48 (br, 1H,
OH), 7.83 (d, 2H, J = 8.0 Hz), 7.33 (d, 1H, J = 2.6 Hz), 7.21 (d,
1H, J = 8.7 Hz), 7.08 (d, 2H, J = 8.7 Hz), 7.06 (dd, 1H, J = 8.2, 2.9
Hz), 2.26 (s, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz) δ 161.7,
153.4, 145.6, 143.1, 136.9, 131.0 (CH), 129.3 (CH), 126.7 (CH),
123.9 (CH), 119.0, 118.9, 109.2 (CH), 20.4 (CH3); MS (EI, 70 eV)
m/z 266 (95), 267 (100) (M+); HRMS (EI, sector) calcd for
C15H13N3O2: 267.1008. Found: 267.1007.
[General procedure 4] Preparation of 2-(N-substituted-
amino)quinazolin-4-one (4) from corresponding anthranilic acids
(5) under the optimized TMSCl condition followed by Dimroth
rearrangement (Scheme 7)
To a mixture of N-substituted cyanamide26
and anthranilic acid ( , 1.0 equiv) in tert-butanol (0.5 M) was
added trimethylsilyl chloride (1.2 equiv). The mixture was
heated at 60 oC for
hours. After cooling to room
(2, 1.5 equiv)
1
4
temperature, the mixture was added aqueous ethanolic NaOH
solution (4 N NaOH aqueous solution / EtOH = 1 : 1 (v/v), 4
times of volume of t-BuOH to bring the final reaction
concentration to 0.1 M) and the reaction mixture was heated
at reflux temperature for 6 hours. The volatile solvents were
removed under reduced pressure, and the resulting solution
was partitioned between CHCl3 and water. The aqueous layer
was acidified with 2 N aqueous acetic acid solution (0.8 equiv
to the 4 N NaOH aqueous solution), and then extracted with
[General procedure 5] Preparation of benzimidazo[2,1-
b]quinazolin-12-one derivatives (9) from 3-(2-bromophenyl)-2-
aminoquinazolin-4-ones (3ai-3ak) or 2-(N-(2-
bromophenyl)amino)quinazolin-4-ones (4ai-4ak) (Scheme 9)
To
a
mixture of N-(2-bromophenyl)-substituted 2-
ak or 4ai ak) (1.0 equiv), -proline
CHCl3. The CHCl3 layer was washed with saturated aqueous aminoquinazolin-4-one (3ai
-
-
L
Na2CO3 solution, saturated aqueous NaCl solution, dried over (0.2 equiv), and potassium carbonate (4.0 equiv) in DMF (0.2
anhydrous MgSO4, and the solvent was evaporated under M) was added copper(I) iodide (0.1 equiv) at room
reduced pressure. The residue was purified by flash column temperature. The flask was capped with septum, and then
chromatography to give 2-(N-substituted-amino)quinazolin-4- evacuated and backfilled with argon gas for three times. The
o
). An analytical sample of 2-(N-substituted- reaction mixture was stirred at 120 C for 8 hours (for 3ai
one
(
4
-
ak)
amino)quinazolin-4-one (
4) was obtained by recrystallization or 24 hours (for 4ai-ak). The solvent was removed by reduced
from CHCl3 / MeOH or CHCl3 / EtOH (approximately 1 : 5 (v/v)). pressure, and the residue was partitioned between CHCl3 and
saturated aqueous NH4OAc solution. The organic layer was
6-Chloro-2-(N-(4-chlorophenyl)amino)quinazolinone (4bd)
concentrated under reduced pressure. The residue was
Compound 4bd was prepared by general procedure 4. The dissolved in a mixture of CHCl3 and conc. aqueous NH4OH
product (4bd, solid, 0.8437 g, 2.755 mmol, 68%, Rf = 0.25 solution (1 : 1 (v/v), 0.1 M) and the mixture was stirred at
(CHCl3 / MeOH = 98 : 2) was purified by flash column room temperature for 1.5 hours (The purpose was to separate
o
chromatography (CHCl3 / MeOH = 99 : 1). m.p. >320 C (IPA / the trace amount of copper residue from the product.). The
DMF); 1H NMR (DMSO-d6, 500 MHz) δ 11.04 (br, 1H, NH), 8.85 resulting undissolved solid was collected. The organic layer
(br, 1H, NH), 7.89 (d, 1H, J = 2.5 Hz), 7.75 (d, 2H, J = 8.5 Hz), was dried over anhydrous MgSO4 and concentrated under
10 | J. Name., 2012, 00, 1-3
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reduced pressure. The residue was combined with the chromatography (CH2Cl2 / MeOH = 98 : 2) then recrystallized
undissolved solid and purified with flash column from CHCl3 / EtOH (about 1 : 1 (v/v)) (brown solid, 0.0746 g,
chromatography to give benzimidazo[2,1-b]quinazolin-12-one 0.30 mmol, 75%). m.p. 285–286 oC; 1H NMR (DMSO-d6, 500
(
9
). An analytical sample of benzimidazo[2,1-b]quinazolin-12- MHz) δ 12.44 (br, 1H), 8.26 (d, 1H, J = 8.0 Hz), 8.21 (d, 1H, J =
one ( ) was obtained by recrystallization from CHCl3 / MeOH 8.0 Hz), 7.76 (td, 1H, J = 7.8, 1.3 Hz), 7.51 (d, 1H, J = 8.0 Hz),
or CHCl3 / EtOH (approximately 1 : 1 (v/v)).
9
7.31 (t, 1H, J = 7.5 Hz), 7.26 (s, 1H), 7.09 (d, 1H, J = 8.0 Hz), 2.44
During structural characterization of benzimidazo[2,1- (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 159.3, 147.7, 135.9,
1
b]quinazolin-12-ones (
9
) with NMR spectroscopy, we observed 134.9, 127.1, 125.3, 122.6, 122.4, 115.3, 115.0, 113.3, 21.8; H
obscure 13C NMR spectra with indistinct and broad peaks as NMR (added a drop of TFA, DMSO-d6, 500 MHz) δ 8.27 (dd, 2H,
well as obvious missing peaks, particularly for the quaternary J = 9.8, 3.8 Hz), 7.87 (t, 1H, J = 8.5 Hz), 7.65 (d, 1H, J = 8.0 Hz),
carbons. We rationalized that the nitrogen-bonded protons of 7.46 (t, 1H, J = 7.8 Hz), 7.40 (s, 1H), 7.22 (d, 1H, J = 8.5 Hz), 2.44
benzimidazo[2,1-b]quinazolin-12-ones (9
) can rapidly hopping (s, 3H); 13C NMR (added a drop of TFA, DMSO-d6, 125 MHz) δ
among the basic nitrogens inter- and intra-molecularly in 158.5, 146.2, 141.4, 137.6, 136.4, 132.5, 128.0, 125.1, 125.02,
solution. The dynamic process involves at least the equilibrium 124.99, 120.0, 115.8, 115.7, 113.5, 21.9; MS (EI, 20 eV) m/z
between two non-equivalent structures and the transient 249 (100) (M+); HRMS (EI, sector) calcd for C15H11N3O:
states in between, which caused significant peak broadening 249.0902. Found: 249.0900.
due to non-equivalent environments for the carbons nearby
the basic nitrogens. Therefore, for NMR spectroscopic 9-Methylbenzimidazo[2,1-b]quinazolin-12-one (9bj)
characterization purpose, an additional set of 1H & 13C NMR Compound 9bj was prepared by the general procedure 5 from
spectra for benzimidazo[2,1-b]quinazolin-12-ones (9) were 4aj. The product (9bj, soild, 0.0968 g, 0.39 mmol, 97%, Rf =
acquired with the addition of one drop of TFA, which was 0.12 (CHCl3 / MeOH = 98 : 2)) was purified by flash column
intended to saturate the basic nitrogen sites with additional chromatography (CH2Cl2 / MeOH = 98 : 2) then recrystallized
proton source to prevent the proton transfer. As a result, the from CHCl3 / EtOH (about 1 : 1 (v/v)) (white solid, 0.0283 g,
carbon skeletons of benzimidazo[2,1-b]quinazolin-12-ones (
9)
0.11 mmol, 28%). m.p. 316–317 oC; 1H NMR (DMSO-d6, 500
were confirmed unambiguously by both unprotonated and MHz) δ 12.45 (br, 1H), 8.23 (s, 1H), 8.20 (d, 1H, J = 8.0 Hz), 7.75
protonated 13C NMR spectra.
(td, 1H, J = 7.8, 1.0 Hz), 7.49 (d, 1H, J = 8.0 Hz), 7.34 (d, 1H, J =
8.0 Hz), 7.30 (t, 1H, J = 7.5 Hz), 7.23 (d, 1, J = 8.0 Hz), 2.46 (s,
3H); 13C NMR (DMSO-d6, 125 MHz) δ 159.5, 147.5, 146.2,
Benzimidazo[2,1-b]quinazolin-12-one15, 38, 47-49 (9ai)
Compound 9ai was prepared by the general procedure 5 from 135.0, 133.8, 130.8, 127.7, 127.2, 127.0, 122.5, 122.1, 115.6,
1
3ai or 4ai. The product (9ai from 3ai, soild, 0.1042 g, 0.44 115.1, 112.9, 21.7; H NMR (added a drop of TFA, DMSO-d6,
mmol, 89%, Rf = 0.21 (CHCl3 / MeOH = 98 : 2)) was purified by 500 MHz) δ 8.26 (dd, 2H, J = 6.3, 1.3 Hz), 7.86 (t, 1H, J = 8.3
flash column chromatography (CH2Cl2 / MeOH = 98 : 2) then Hz), 7.61 (d, 1H, J = 8.0 Hz), 7.48–7.42 (m, 2H), 7.31 (d, 1H, J =
recrystallized from CHCl3 / EtOH (about 1 : 1 (v/v)) (white solid, 8.0 Hz), 2.47 (s, 3H); 13C NMR (added a drop of TFA, DMSO-d6,
0.0760 g, 0.32 mmol, 65%). Alternatively, the product (9ai 125 MHz) δ 158.8, 146.3, 142.2, 136.1, 133.1, 130.9, 128.0,
from 4ai, solid, 0.2214 g, 0.94 mmol, 94%, Rf = 0.21 (CHCl3 / 127.8, 127.3, 124.4, 120.2, 116.0, 115.4, 113.0, 21.7; MS (EI, 20
MeOH = 98 : 2)) was purified by flash column chromatography eV) m/z 249 (100) (M+); HRMS (EI, sector) calcd for C15H11N3O:
(CH2Cl2 / MeOH = 98 : 2) then recrystallized from CHCl3 / EtOH 249.0902. Found: 249.0903.
(about 1 : 1 (v/v)) (white solid, 0.0918 g, 0.39 mmol, 39%). m.p.
342–343 oC; 1H NMR (DMSO-d6, 600 MHz) δ 8.41 (d, 1H, J = 7.8
Conflicts of interest
Hz), 8.23 (dd, 1H, J = 8.4, 1.8 Hz), 7.78 (td 1H, J = 7.8, 1.2 Hz),
7.52 (d, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.43 (td, 1H, J =
7.5, 0.8 Hz), 7.33 (td, 1H, J = 8.1, 0.8 Hz), 7.29 (t, 1H, J = 7.8 Hz);
13C NMR (DMSO-d6, 150 MHz) δ 159.5, 147.5, 146.0, 135.1,
127.7, 127.2, 126.2, 122.6, 122.1, 121.5, 115.4, 115.1, 112.5;
1H NMR (added a drop of TFA, DMSO-d6, 600 MHz) δ 8.46 (d,
1H, J = 7.8 Hz), 8.29 (dd, 1H, J = 8.1, 1.5 Hz), 7.89–7.86 (m, 1H),
7.63 (dd, 2H, J = 8.4, 5.2 Hz), 7.53 (t, 1H, J = 8.4 Hz), 7.47–7.40
(m, 2H); 13C NMR (added a drop of TFA, DMSO-d6, 150 MHz) δ
158.9, 146.5, 142.1, 136.2, 133.3, 127.9, 127.3, 127.2, 124.6,
123.6, 120.2, 116.0, 115.6, 113.6; MS (EI, 20 eV) m/z 235 (100)
(M+); HRMS (EI, sector) calcd for C14H9N3O: 235.0746. Found:
235.0747.
There are no conflicts to declare.
Acknowledgements
This work was supported by Research Grants MOST 106-2113-
M-003-006- and MOST 105-2113-M-003-003- from Ministry of
Science and Technology, Taiwan. We also thank Mr. Ting-Shen
Kuo (National Taiwan Normal University) for his assistance
with X-ray crystallogrphic analysis.
References
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3aj. The product (9aj, soild, 0.0979 g, 0.39 mmol, 98%, Rf =
0.12 (CHCl3 / MeOH = 98 / 2)) was purified by flash column
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