One-pot synthesis of 2-amino-4(3H)-quinazolinones via ring-opening of isatoic anhydride and palladium-catalyzed oxidative isocyanide-insertion

Article abstract of DOI:10.1039/c4ob00484a

An efficient and practical two-step process has been developed for the synthesis of 2-amino-4(3H)-quinazolinones via ring-opening of isatoic anhydride and palladium-catalyzed oxidative isocyanide-insertion in one pot. This regioselective procedure could construct a wide range of 2-amino-4(3H)- quinazolinones in moderate to excellent yields. Furthermore, the methodology also had distinct advantages of easily accessible starting materials and operational simplicity. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00484a

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ARTICLE TYPE
One-pot Synthesis of 2-Amino-4(3H)-Quinazolinones via Ring-opening
of Isatoic anhydride and Palladium-catalyzed Oxidative Isocyanide-
insertion
Fei Ji,a, b Meiꢀfang Lv,a, b Wenꢀbin Yi,a Chun Caia*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient and practical twoꢀstep process has been developed for the synthesis of 2ꢀaminoꢀ4(3H)ꢀ
quinazolinones via ringꢀopening of isatoic anhydride and palladiumꢀcatalyzed oxidative isocyanideꢀ
insertion in oneꢀpot. This regioselective procedure could construct a wide range of 2ꢀaminoꢀ4(3H)ꢀ
10 quinazolinones in moderate to excellent yields. Furthermore, the methodology also had distinct
advantages of easily accessible starting materials and operational simplicity.
substrate scope (variable group at nitrogen) over carbon
Introduction
monoxide.[5] In 2012, R. V. A. Orru and coꢀworkers reported a
palladiumꢀcatalyzed oxidative isocyanideꢀinsertion reaction
involving bisꢀnucleophiles to synthesize 2ꢀaminoꢀ4(3H)ꢀ
50 quinazolinones.[6a] Nevertheless, this protocol was unfortunately
not only highly inefficient for the variation at the 3ꢀN position of
2ꢀaminoꢀ4(3H)ꢀquinazolinones, but also required multiꢀstep
process to synthesize the poor commercial available starting
The quinazolinꢀ4(3H)ꢀone skeleton is an unique unit that exists
widely in the medically important products.[1] For example, 2ꢀ
15 aminoꢀ4(3H)ꢀquinazolinone derivatives have shown high
activities as thymidylate synthase inhibitors,[2a] cognition
enhancement agents,[2b] tumor necrosis factor α inhibitors,[2c]
dopamine agonists,[2d] histamine H4 receptor inverse agonists,[2e]
antiꢀinflammatory agents,[2f] antiꢀhypertentive agents,[2g] antiꢀ
20 convulsant agents,[2h] antiꢀhyperglycemic agents,[2i] and antiꢀ
bacterial agents.[2j]
materials. Based on our previous work on the commercial
8a]
55 available isatoic anhydrides[7,
and isocyanides,[8] we have
developed a novel and efficient oneꢀpot process for the synthesis
of a wide range of 2ꢀaminoꢀ4(3H)ꢀquinazolinones via ringꢀ
opening of isatoic anhydrides and palladiumꢀcatalyzed oxidative
isocyanideꢀinsertion reaction in a more rapid and flexible manner
60 than the above mentioned conventional methods (Scheme 1). To
the best of our knowledge, the previously reported transitionꢀ
metal catalyzed isocyanideꢀinsertion reactions are mainly
confined to inserting isocyanides to CꢀH or Cꢀhalogen bonds, and
this direct insertion of isocyanides into the active NꢀH bonds in
65 this paper are still relatively rare.[6]
A great number of synthetic methods for the generation of 2ꢀ
aminoꢀ4(3H)ꢀquinazolinone derivatives have been developed. In
general, the synthetic methods can be classified into the following
25 categories: 1) amidation of 2ꢀaminobenzoic acid[3a] and its
derivatives: 2ꢀaminobenzonitrile,[3b] 2ꢀaminobenzoate,[3c] isatoic
anhydride[3dꢀ3e] and so on; 2) the tandem azaꢀwittig reaction of
iminophosphorane;[3fꢀ3h] 3) the tandem palladiumꢀcatalyzed
cyclocarbonylation;[3iꢀ3j] 4) reactions of nucleophiles: guanidines,
30 with orthoꢀfluorobenzoyl.[3k] However, these procedures often
suffer from a variety of drawbacks, such as multiꢀstep process,
harsh reaction conditions, low yields, hardly accessible starting
materials, the utilization of toxic CO, and low molecular
diversity, which limit their usages in practical application.
35 Therefore, the development of an efficient and stepꢀeconomic
procedure for the synthesis of 2ꢀaminoꢀ4(3H)ꢀquinazolinones is
highly desired.
Isocyanides, a kind of unsaturated molecules similar to carbon
monoxide, have emerged as versatile building blocks in the
40 construction of medicinally important molecules and natural
products.[4] Transitionꢀmetal catalyzed isocyanideꢀinsertion
reactions to assemble biological Nꢀheterocycles have been
previously undervalued and have drawn great attention only in
very recent years.[5] This methodology offers several distinct
45 advantages such as simple handling, mild condition and wide
Scheme 1 Approaches towards 2ꢀaminoꢀ4(3H)ꢀquinazolinone derivatives
Results and Discussion
To explore this approach, we selected isatoic anhydride (1a),
70 benzyl amine (2a) and tertꢀbutyl isocyanide (3a) as the model
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substrates to optimize the reaction conditions including solvents,
Subsequently, other oxidant reagents such as copper (II) salts,
oxidant reagents, and palladium catalysts. Initially, we performed 10 silver (I) salts, TBHP and K2S2O8 were screened to obtain the
this oneꢀpot process according to the optimized reaction
conditions of the pioneering work by R. V. A. Orru.[6a]
Disappointingly, the desired substituted 2ꢀaminoꢀ4(3H)ꢀ
quinazolinone was obtained only in a moderate yield (Table 1,
better yield (Table 1, entries 5ꢀ10). Notably, Ag2CO3 was
examined to be a more effective oxidant reagent and the yield of
4a could be improved to 78% yield. Additionally, some
commercial palladium catalysts were also screened, but no
5
entry 1). To our delight, switching the reaction solvent to toluene 15 obvious improvement in yields was observed (Table 1, entries 11
could improve the yields obviously (Table 1, entries 2ꢀ4).
Table 1 Optimization of the reaction conditionsa
and 12).
Entry
1
Pd catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(amphos)Cl2
Oxidant reagent
Solvent
MeTHF
toluene
DMF
T/°C
75
Yieldc (%)
b
O2
42
68
37
42
23
72
25
78
67
37
70
52
b
2
O2
100
110
81
b
3
O2
b
4
O2
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5
K2S2O8
100
100
100
100
100
100
100
100
.
6
Cu(TFA)2 XH2O
7
TBHP
Ag2CO3
AgOAc
Cu(OAc)2
Ag2CO3
Ag2CO3
8
9
10
11
12
a Reaction conditions: 1) The reaction was carried out using 1a (0.50 mmol) and 2a (0.50 mmol) in solvent (4 ml) at T/°C for 4 h; 2) 3a (0.75 mmol) was
20 added subsequently in the presence of Pd catalyst (2 mol%) and Oxidant reagent (1.00 mmol) at T/°C for 24 h in oneꢀpot. b In O2 atmosphere (1 atm,
balloon). c Isolated yields based on 1a.
Under the optimized reaction conditions, the scope of this
yields, due to relatively lower activity of aryl amines (Table 2,
reaction was extended to a variety of amines, isocyanides and 40 4k-4m). Unfortunately, the complex product was formed when 4ꢀ
isatoic anhydrides. The results were summarised in Table 2.
25 Generally, various amines, including aryl amines and alkyl
amines were well tolerated. Benzyl amines bearing both electronꢀ
rich and electronꢀdeficient aromatic ring furnished the desired
nitroꢀaniline was employed in this transformation. This successful
utilization of a broad range of amines further efficiently increased
the diversification at 3ꢀN position of 2ꢀaminoꢀ4(3H)ꢀ
quinazolinones. Next, different isocyanides were also applied to
products in high yields (Table 2, 4a-4c). Orthoꢀsubstituted benzyl 45 probe the scope of the reaction. When cylcohexyl isocyanide and
amine would not decrease the reaction rate obviously (Table 2,
30 4d). In addition, primary alkyl amines and secondary alkyl
amines also generated the products in moderate to high yields
(Table 2, 4e-4g). It’s worth noticing that the Nꢀbocꢀamino group
1,1,3,3ꢀtetramethylbutyl isocyanide were employed instead of
tertꢀbutyl isocyanide, the reaction worked as expected giving
corresponding products in high yields (Table 2, 4n and 4o).
Finally, we examined the use of different isatoic anhydrides.
of the product 4f could be further modified to explore the 50 Noticeably, isatoic anhydrides containing electronꢀdonating (R2=
diversification of substituted 2ꢀaminoꢀ4(3H)ꢀquinazolinones.
35 With regard to amines bearing heterocycles, we could also isolate
the corresponding products in high yields (Table 2, 4i and 4j).
Meanwhile, the reaction was also tolerant of different substituted
6ꢀMe) and halogen group (R2= 6ꢀF, 6ꢀCl) reacted efficiently,
affording 4 in moderate to high yields (Table 2, 4q, 4s and 4t).
However, the electronꢀwithdrawing group on the aromatic ring of
isatoic anhydrides (R2=6ꢀNO2, 6ꢀCOOMe) had a negative effect
aryl amines giving the corresponding product, albeit in moderate 55 on this reaction, and could not obtain the desired product.
2
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Table 2 Synthesis of 2ꢀaminoꢀ4(3H)ꢀquinazolinone derivativesa, b
O
O
2) Pd(OAc)2/Ag2CO3
O
R1
isocyanide 3
1) Toluene, 100°C
N
R1
O
+
R2
R2
N
H2N R1
R2
One-pot
H
N
4
NH
R3
N
H
1
O
2
NH2
O
N
O
O
F
O
N
O
O
NHBoc
N
Me
N
N
N
N
F
N
NH
N
NH
N
NH
NH
N
NH
N
NH
4b
4c
72%
4a
4d
4e
4f
78%
81%
74%
65%
72%
Cl
Me
O
N
O
O
O
O
O
O
O
Me
N
N
N
N
N
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
4l
62%
4g
56%
4j
4k
4i
4h
65%
O
78%
75%
45%
O
O
O
N
N
O
O
Cl
Cl
Cl
N
N
N
N
N
N
NH
N
NH
NH
N
NH
N
NH
N
NH
4p
72%
4m
4n
4o
4q
4r
72%
75%
76%
70%
49%
O
O
N
F
Me
N
N
N
NH
NH
4t
4s
51%
75%
a Reaction conditions: 1) The reaction was carried out using 1 (0.50 mmol) and 2 (0.50 mmol) in toluene (4 mL) at 100 °C, and the reaction time was
determined by TLC (3ꢀ8 h); 2) 3 (0.75 mmol) was added subsequently in the presence of Pd catalyst (2 mol%) and Ag2CO3 (1.00 mmol) at 100 °C for 24
h in oneꢀpot. b Isolated yields on 1.
5
To further expand the scope of 2ꢀaminoꢀ4(3H)ꢀquinazolinone, we
also tried to access the unsubstituted 2ꢀaminoꢀ4(3H)ꢀ
quinazolinone by the acidꢀpromoted dealkylation sequence
(Scheme 2). Addition of TFA to 2ꢀ(tertꢀbutylamino)ꢀquinazolinꢀ
4(3H)ꢀone and subsequent heating under reflux finally furnished
10 unsubstituted 2ꢀaminoꢀ4(3H)ꢀquinazolinone in a moderate yield.
This process provided a valuable alternative to the use of highly
toxic cyanogens bromide,[6a] especially since tertꢀbutyl isocyanide
was an easily accessible and convertible isocyanide.
Figure 1 singleꢀcrystal Xꢀray analysis of 4j
15
Scheme 2 Synthesis of unsubstituted 2ꢀaminoꢀ4(3H)ꢀquinazolinone
25 generates the bisꢀnucleophile II. Catalysis I reacts with the bisꢀ
nucleophile II to form the intermediate III. Then, isocaynideꢀ
insertion reaction occurs, resulting in the species IV. Species IV
subsequently undergoes reductive elimination to afford the
product 4. Pd(0) species VI is stabilized by coordination of
30 multiple isocyanides and then oxidized by silver carbonate to
regenerate the catalyst. The occurrence of silver and carbon
dioxide in the experiment also further confirmed this mechanism.
The structures of 2ꢀaminoꢀ4(3H)ꢀquinazolinones 4a-4u were fully
characterized by Mass spectrometry, 1H NMR, 13C NMR
spectroscopy and elemental analysis. Moreover, the structure of
4j was also confirmed by singleꢀcrystal Xꢀray analysis (Figure 1).
20 Based on the wellꢀestablished chemistry of isocyanide,[6] the
proposed mechanism was depicted in Scheme 3. Initially, the
ringꢀopening reaction of isatoic anhydride 1 with amine 2
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30 advantages of easily accessible starting materials, operational
simplicity and molecular diversity compared to previous reported
methods. It’s believable that this method may be instrumental to
the rapid and flexible construction of important 2ꢀaminoꢀ
quinazolinꢀ4(3H)ꢀone derivatives with promising biological and
35 pharmaceutical activities.
Experimental section
Unless otherwise stated, all commercial reagents were used as
received. All melting points were uncorrected. Mass spectra were
recorded on Shimadzu LCMSꢀ2020. 1H and 13C NMR spectra
40 were recorded at 500 MHz and 125 MHz in CDCl3, and chemical
shifts were reported in ppm from internal TMS (δ). Elemental
analyses were performed on a Yanagimoto MT3CHN recorder.
General procedure for the synthesis of 2-substituted-amino-
45 4(3H)-quinazolinones 4a-4t: To a solution of isatoic anhydride 1
(0.50 mmol) in toluene (4 mL) was added amine 2 (0.50 mmol).
The mixture was stirred at 100 °C in a sealed tube for 3ꢀ8 h
(according to the determination of TLC). Upon the completion of
the reaction, isocyanide 3 (0.75 mmol), Pd(OAc)2 (2 mol%) and
50 Ag2CO3 (1.00 mmol) was successively added. The mixture was
then kept stirring at 100 °C for another 24 h. After that, the
product was then concentrated under vacuum and the resulting
residue was purified by column chromatography.
Scheme 3 Possible mechanism of this twoꢀstep reaction
Considering the fact that the discovery of new molecular
scaffolds is essential to meet the temporary demands for
improved materials and pharmaceuticals, we used this method to
synthesize 2ꢀaminoꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀones (Scheme 4).
Its analogous bicyclicꢀpyrimidinones have been proved to be
effective HCV NS5B active site inhibitors.[9] The ringꢀopening
5
3-benzyl-2-(tert-butylamino)quinazolin-4(3H)-one 4a: white
1
55 solid, 138ꢀ140 °C; H NMR (500 MHz, CDCl3) δ: 1.35 (s, 9H),
10 reaction of isatoic anhydride with Oꢀbenzyl hydroxylamine and
subsequent palladiumꢀcatalyzed oxdative isocyanideꢀinsertion
reaction in oneꢀpot proceeded smoothly in the presence of
Pd(OAc)2 and Ag2CO3 to afford 3ꢀ(benzyloxy)ꢀ2ꢀaminoꢀ
quinazolinꢀ4(3H)ꢀone 4v in 65% yield. The following
15 hydrogenating debenzylation is wellꢀknown to furnish 2ꢀaminoꢀ3ꢀ
hydroxyquinazolinꢀ4(3H)ꢀones 4w in a high yield to further
increase the variation at the 3ꢀN position of 2ꢀaminoꢀ4(3H)ꢀ
quinazolinones.
4.35 (s, 1H), 5.33 (s, 2H), 7.22 (t, J=7.0 Hz, 1H), 7.28ꢀ7.30 (m,
2H), 7.34ꢀ7.36 (m, 1H), 7.37ꢀ7.41 (m, 3H), 7.59ꢀ7.61 (m, 1H),
8.21 (d, J=1.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 27.83,
43.89, 51.59, 115.97, 121.44, 124.28, 125.71, 126.27, 127.25,
60 128.33, 133.19, 134.49, 147.45, 148.07, 162.29; Ms (ESI) m/z:
308 [M+H]; Anal. Calcd for C19H21N3O: C,74.24; H, 6.89; N,
13.67; found C, 74.39; H, 6.98; N, 13.61.
2-(tert-butylamino)-3-(4-methylbenzyl)quinazolin-4(3H)-one
65 4b: white solid, 141ꢀ143 °C; 1H NMR (500 MHz, CDCl3) δ: 1.36
(s, 9H), 2.37 (s, 3H), 4.41 (s, 1H), 5.28 (s, 2H), 7.17ꢀ7.19 (m,
5H), 7.40 (d, J=8.0 Hz, 1H), 7.59ꢀ7.60 (m, 1H), 8.20ꢀ8.22 (m,
1H); 13C NMR (125 MHz, CDCl3) δ: 20.16, 27.85, 43.76, 51.56,
115.99, 121.39, 124.25, 125.70, 126.25, 128.98, 131.34, 133.16,
70 137.05, 147.57, 148.07, 162.34; Ms (ESI) m/z: 322 [M+H]; Anal.
Calcd for C20H23N3O: C,74.74; H, 7.21; N, 13.07; found C,
74.62; H, 7.12; N, 13.12.
2-(tert-butylamino)-3-(4-fluorobenzyl)quinazolin-4(3H)-one
1
75 4c: white solid, 158ꢀ160 °C; H NMR (500 MHz, CDCl3) δ: 1.36
(s, 9H), 4.26 (s, 1H), 5.28 (s, 2H), 7.08 (t, J=8.5 Hz, 2H), 7.20 (t,
J=7.0 Hz, 1H), 7.25ꢀ7.28 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.59ꢀ
7.60 (m, 1H), 8.18ꢀ8.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ:
27.87, 43.25, 51.66, 115.23, 115.40, 115.91, 121.57, 124. 32,
80 126.23, 127.43, 127.49, 130.26, 133.31, 147.22, 147.99, 160.55,
162.25, 162.52; Ms (ESI) m/z: 326 [M+H]; Anal. Calcd for
C19H20FN3O: C,70.13; H, 6.20; N, 12.91; found C, 70.27; H,
6.27; N, 12.82.
20
Scheme 4 Synthesis of 2ꢀaminoꢀ3ꢀhydroxyquinazolinꢀ4(3H)ꢀones
Conclusions
In counclusion, we have developed an efficient and practical oneꢀ
pot process for the synthesis of 2ꢀaminoꢀ4(3H)ꢀquinazolinones
25 via ringꢀopening of isatoic anhydride and palladiumꢀcatalyzed
oxidative isocyanideꢀinsertion. This regioselective methodology
was successful with a range of amines, isatoic anhydrides and
isocyanides, and could afford the desired heterocycles in
moderate and high yields. This process also had distinct
85 2-(tert-butylamino)-3-(2-fluorobenzyl)quinazolin-4(3H)-one
4d: white solid, 148ꢀ150 °C; 1H NMR (500 MHz, CDCl3) δ: 1.43
(s, 9H), 4.61 (s, 1H), 5.34 (s, 2H), 7.11ꢀ7.20 (m, 3H), 7.29ꢀ7.31
(m, 1H), 7.37ꢀ7.39 (m, 2H), 7.58ꢀ7.59 (m, 1H), 8.17ꢀ8.19 (m,
1H); 13C NMR (125 MHz, CDCl3) δ: 27.86, 36.33, 51.72, 114.23,
4
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114.40, 115.87, 121.40, 121.55, 124.23, 126.19, 128.95, 133.26, 65 Calcd for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49; found C,
146.77, 148.02, 158.28, 160.22, 162.41; Ms (ESI) m/z: 326
[M+H]; Anal. Calcd for C19H20FN3O: C,70.13; H, 6.20; N, 12.91;
found C, 70.02; H, 6.14; N, 12.99.
69.34; H, 6.72; N, 13.56.
2-(tert-butylamino)-3-p-tolylquinazolin-4(3H)-one 4k: white
1
5
solid, 148ꢀ150 °C; H NMR (500 MHz, CDCl3) δ: 1.40 (s, 9H),
3-butyl-2-(tert-butylamino)quinazolin-4(3H)-one 4e: white 70 2.44 (s, 3H), 3.99 (s, 1H), 7.12ꢀ7.16 (m, 3H), 7.37 (d, J=8.0 Hz,
1
solid, 145ꢀ147 °C; H NMR (500 MHz, CDCl3) δ: 1.00 (t, J=7.4
Hz, 3H), 1.44ꢀ1.48 (m, 2H), 1.55 (s, 9H), 1.66ꢀ1.72 (m, 2H), 4.00
(t, J=7.8 Hz, 2H), 4.37 (s, 1H), 7.13 (t, J= 8.0 Hz, 1H), 7.36 (d,
2H), 7.42 (d, J=8.0 Hz, 1H), 7.57ꢀ7.59 (m, 1H), 8.10ꢀ8.12 (m,
1H); 13C NMR (125 MHz, CDCl3) δ: 20.35, 28.04, 51.48, 116.58,
121.33, 124.15, 126.13, 127.51, 130.21, 131.41, 133.34, 138.84,
147.30, 148.22, 161.87; Ms (ESI) m/z: 308 [M+H]; Anal. Calcd
10 J=8.2 Hz, 1H), 7.53ꢀ7.57 (m, 1H), 8.09ꢀ8.11 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ: 12.75, 19.28, 28.21, 28.77, 39.94, 51.57, 75 for C19H21N3O: C, 74.24; H, 6.89; N, 13.67; found C, 74.12; H,
116.11, 121.28, 124.11, 125.93, 132.94, 146.93, 147.80, 161.85;
Ms (ESI) m/z: 274 [M+H]; Anal. Calcd for C16H23N3O: C,70.30;
H, 8.48; N, 15.37; found C, 70.17; H, 8.41; N, 15.45.
6.80; N, 13.76.
2-(tert-butylamino)-3-(4-chlorophenyl)quinazolin-4(3H)-one
4l: white solid, 170ꢀ172 °C; H NMR (500 MHz, CDCl3) δ: 1.41
1
15
80 (s, 9H), 3.84 (s, 1H), 7.16 (t, J=1.0 Hz, 1H), 7.23ꢀ7.25 (m, 2H),
7.33 (d, J=8.0 Hz, 1H), 7.55ꢀ7.56 (m, 2H), 7.56ꢀ 7.60 (m, 1H),
8.09ꢀ8.11 (m, 1H); 13C NMR (125 MHz, CDCl3) δ: 28.03, 51.71,
116.38, 121.60, 124.30, 126.10, 129.36, 129.85, 132.69, 133.61,
134.85, 146.61, 148.17, 161.72; Ms (ESI) m/z: 328 [M+H]; Anal.
tert-butyl-2-(2-(tert-butylamino)-4-oxoquinazolin-3(4H)-yl)
ethylcarbamate 4f: white solid, 204 ꢀ206 °C; 1H NMR (500
MHz, CDCl3) δ: 1.46 (s, 9H), 1.59 (s, 9H), 3.28ꢀ3.32 (m, 2H),
4.07ꢀ4.10 (m, 2H), 5.23 (s, 1H), 6.28 (s, 1H), 7.10 (t, J=7.5 Hz,
20 1H), 7.37ꢀ7.38 (m, 1H), 7.52ꢀ7.55 (m, 1H), 8.04ꢀ8.06 (m, 1H);
13C NMR (125 MHz, CDCl3) δ: 27.34, 28.09, 37.54, 39.27, 85 Calcd for C18H18ClN3O: C, 65.95; H, 5.53; N, 12.82; found C,
52.02, 79.40, 115.50, 121.00, 124.09, 125.67, 133.12, 147.51,
148.18, 156.01, 162.22; Ms (ESI) m/z: 361 [M+H]; Anal. Calcd
for C19H28N4O3: C, 63.31; H, 7.83; N, 15.54; found C, 63.23; H,
25 7.75; N, 15.61.
65.82; H, 5.59; N, 12.75.
2-(tert-butylamino)-3-phenylquinazolin-4(3H)-one 4m: white
1
solid, 120ꢀ122 °C; H NMR (500 MHz, CDCl3) δ: 1.39 (s, 9H),
90 3.91 (s, 1H), 7.15 (t, J=1.0 Hz, 1H), 7.28ꢀ7.30 (m, 2H), 7.44 (d,
J=8.0 Hz, 1H), 7.53ꢀ7.54 (m, 1H), 7.57ꢀ7.60 (m, 3H), 8.10ꢀ8.11
(m, 1H); 13C NMR (125 MHz, CDCl3) δ: 28.00, 51.51, 116.56,
121.41, 124.22, 126.12, 127.87, 128.75, 129.56, 133.44, 134.22,
147.08, 148.27, 161.81; Ms (ESI) m/z: 294 [M+H]; Anal. Calcd
2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one 4g: white
solid, 118ꢀ120°C; H NMR (500 MHz, CDCl3) δ: 1.52 (s, 3H),
1.53 (s, 3H), 1.54 (s, 9H), 4.47 (s, 1H), 5.59 (s, 1H), 7.08ꢀ7.12
1
30 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.50ꢀ7.54 (m, 1H), 8.06ꢀ8.08 (m,
1H); 13C NMR (125 MHz, CDCl3) δ: 19.40, 28.32, 42.47, 51.68, 95 for C18H19N3O: C, 73.69; H, 6.53; N, 14.32; found C, 73.76; H,
116.50, 121.18, 123.80, 126.07, 132.91, 147.11, 147.68, 162.35;
Ms (ESI) m/z: 260 [M+H]; Anal. Calcd for C15H21N3O: C, 69.47;
H, 8.16; N, 16.20; found C, 69.34; H, 8.21; N, 16.27.
6.59; N, 14.21.
3-benzyl-2-(2,4,4-trimethylpentan-2-ylamino)-quinazolin-
4(3H)-one 4n: white solid, 124ꢀ126 °C; 1H NMR (500 MHz,
100 CDCl3) δ: 0.67 (s, 9H), 1.28 (s, 6H), 1.73 (s, 2H), 4.26 (s, 1H),
5.20 (s, 2H), 7.08 (t, J=7.0 Hz, 1H), 7.16ꢀ7.18 (m, 2H), 7.22 (d,
J=7.0 Hz, 1H), 7.25ꢀ7.31 (m, 3H), 7.47ꢀ7.49 (m, 1H), 8.08ꢀ8.10
(m, 1H); 13C NMR (125 MHz, CDCl3) δ: 28.62, 30.29, 30.43,
44.05, 49.61, 55.43, 115.84, 121.39, 124.24, 125.88, 126.24,
35
2-(cyclohexylamino)-3-isopropylquinazolin-4(3H)-one
4h:
white solid, 129ꢀ131°C; 1H NMR (500 MHz, CDCl3) δ: 1.26ꢀ1.32
(m, 3H), 1.45ꢀ1.51 (m, 2H), 1.54 (s, 3H), 1.56 (s, 3H), 1.65ꢀ1.68
(m, 1H), 1.73ꢀ1.75 (m, 2H), 2.12ꢀ2.13 (m, 2H), 4.17 (s, 1H), 4.53
40 (s, 1H), 5.54 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.38 (s, 1H), 7.54 (t,
J=7.5 Hz, 1H), 8.07 (d, J= 8.0 Hz, 1H); 13C NMR (125 MHz, 105 127.36, 128.37, 133.23, 134.39, 147.26, 147.93, 162.33; Ms
CDCl3) δ: 19.32, 23.70, 24.74, 32.11, 42.93, 49.28, 116.36,
121.40, 123.24, 126.17, 133.18, 147.90, 162.03; Ms (ESI) m/z:
286 [M+H]; Anal. Calcd for C17H23N3O: C, 71.55; H, 8.12; N,
45 14.72; found C, 71.42; H, 8.17; N, 14.81.
(ESI) m/z: 364 [M+H]; Anal. Calcd for C23H29N3O: C, 76.00; H,
8.04; N, 11.56; found C, 76.19; H, 8.11; N, 11.49.
3-benzyl-2-(cyclohexylamino)quinazolin-4(3H)-one 4o: white
1
110 solid, 144ꢀ146 °C; H NMR (500 MHz, CDCl3) δ: 1.00ꢀ1.06 (m,
2H), 1.13ꢀ1.18 (m, 1H), 1.32ꢀ1.39 (m, 2H), 1.48ꢀ1.54 (m, 3H),
1.83ꢀ1.86 (m, 2H), 3.96ꢀ3.98 (m, 1H), 4.35 (s, 1H), 5.34 (s, 2H),
7.20 (m, 1H), 7.27ꢀ7.39 (m, 6H), 7.58ꢀ7.60 (m, 1H), 8.19ꢀ8.20
(m, 1H); 13C NMR (125 MHz, CDCl3) δ: 23.20, 24.58, 31.52,
2-(tert-butylamino)-3-(furan-2-ylmethyl)quinazolin-4(3H)-one
4i: white solid, 148ꢀ150 °C; H NMR (500 MHz, CDCl3) δ: 1.42
(s, 9H), 5.01 (s, 1H), 5.14 (s, 2H), 6.27ꢀ6.28 (m, 1H), 6.37 (d,
1
50 J=3.2 Hz, 1H), 7.02ꢀ7.05 (m, 1H), 7.27ꢀ7.28 (m, 2H), 7.44ꢀ7.45
(m, 1H), 8.00ꢀ8.02 (m, 1H); 13C NMR (125 MHz, CDCl3) δ: 115 43.61, 48.74, 115.92, 121.43, 123.97, 125.62, 126.36, 127.26,
28.05, 36.89, 51.77, 108.78, 110.18, 116.00, 121.48, 124.19,
126.04, 133.21, 141.41, 147.35, 147.73, 148.41, 161.70; Ms
(ESI) m/z: 298 [M+H]; Anal. Calcd for C17H19N3O2: C, 68.67; H,
55 6.44; N, 14.13; found C, 68.55; H, 6.51; N, 14.18.
128.38, 133.35, 134.34, 148.45, 162.17; Ms (ESI) m/z: 334
[M+H]; Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60;
found C, 75.52; H, 6.87; N, 12.69.
120 3-benzyl-6-chloro-2-(2,4,4-trimethylpentan-2-ylamino)
quinazolin-4(3H)-one 4p: white solid, 130ꢀ132 °C; 1H NMR
(500 MHz, CDCl3) δ: 0.75 (s, 9H), 1.37 (s, 6H), 1.80 (s, 2H),
4.40 (s, 1H), 5.27 (s, 2H), 7.25ꢀ7.26 (m, 2H), 7.32ꢀ7.38 (m, 4H),
7.48ꢀ7.50 (m, 1H), 8.13ꢀ8.14 (m, 1H); 13C NMR (125 MHz,
2-(tert-butylamino)-3-((5-methylfuran-2-yl)methyl)quinazolin
-4(3H)-one 4j: white solid, 130ꢀ132 °C; 1H NMR (500 MHz,
CDCl3) δ: 1.55 (s, 9H), 2.29 (s, 3H), 5.18 (s, 2H), 5.30 (s, 1H),
60 5.96 (t, J=2.2 Hz, 1H), 6.35 (d, J=3.1 Hz, 1H), 7.16 (t, J=7.1 Hz,
1H), 7.38ꢀ7.40 (m, 1H), 7.54ꢀ7.58 (m, 1H), 8.11ꢀ8.13 (m, 1H); 125 CDCl3) δ: 28.58, 30.26, 30.41, 44.20, 49.59, 55.56, 116.68,
13C NMR (125 MHz, CDCl3) δ: 12.49, 28.09, 36.92, 51.78,
105.98, 109.75, 116.08, 121.39, 124.13, 126.04, 133.11, 146.57,
147.56, 147.72, 151.18, 161.65; Ms (ESI) m/z: 312 [M+H]; Anal.
125.40, 125.86, 126.55, 127.49, 128.43, 133.53, 134.04, 146.51,
147.41, 161.36; Ms (ESI) m/z: 398 [M+H]; Anal. Calcd for
C23H28ClN3O: C, 69.42; H, 7.09; N, 10.56; found C, 69.30; H,
7.18; N, 10.51.
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65 reaction, tertꢀbutylisocyanide (0.75 mmol), Pd(OAc)2 (2 mol%)
and Ag2CO3 (1.00 mmol) was successively added and the mixture
was stirred at 100 °C for another 24 h. The product was then
concentrated under vacuum and the resulting residue was purified
by column chromatography to give 3ꢀ(benzyloxy)ꢀ2ꢀ(tertꢀ
70 butylamino)quinazolinꢀ4(3H)ꢀone 4v. Secondly, Pd/C 10% was
added to the solution of 4v in ethanol (4 mL) and the mixture was
hydrogenated at the room temperature at 40 psi for 6 h. After that,
the reaction mixture was passed through Celite, followed by
evaporation to afford the crude product, which was purified by
75 column chromatography to yield 2ꢀ(tertꢀbutylamino)ꢀ3ꢀ
hydroxyquinazolinꢀ4(3H)ꢀone 4w.
3-benzyl-2-(tert-butylamino)-6-chloroquinazolin-4(3H)-one
4q: white solid, 152ꢀ154 °C; 1H NMR (500 MHz, CDCl3) δ: 1.30
(s, 9H), 4.38 (s. 1H), 5.28 (s, 2H), 7.24ꢀ7.25 (m, 2H), 7.30ꢀ7.38
(m, 4H), 7.48ꢀ7.50 (m, 1H), 8.13 (d, J=2.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ: 27.78, 44.04, 51.75, 116.76, 125.41,
125.68, 125.94, 126.59, 127.41, 128.42, 133.52, 134.10, 146.64,
147.57, 161.34; Ms (ESI) m/z: 342 [M+H]; Anal. Calcd for
C19H20ClN3O: C, 66.76; H, 5.90; N, 12.29; found C, 66.88; H,
5
10 5.81; N, 12.23.
3-benzyl-6-chloro-2-(cyclohexylamino)quinazolin-4(3H)-one
4r: white solid, 174ꢀ176 °C; 1H NMR (500 MHz, CDCl3) δ: 1.00ꢀ
1.06 (m, 2H), 1.14ꢀ1.18 (m, 1H), 1.31ꢀ1.38 (m, 2H), 1.47ꢀ1.55
15 (m, 3H), 1.81ꢀ1.84 (m, 2H), 3.93ꢀ3.94 (m, 1H), 4.39 (s, 1H), 5.31
(s, 2H), 7.26ꢀ7.27 (m, 2H), 7.30ꢀ7.39 (m, 4H), 7.50ꢀ7.52 (m, 1H),
8.14 (d, J=2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 23.17,
24.52, 31.48, 43.78, 48.89, 116.72, 125.59, 126.63, 127.42,
128.46, 133.67, 133.96, 147.02, 148.25, 161.17; Ms (ESI) m/z:
20 368 [M+H]; Anal. Calcd for C21H22ClN3O: C, 68.56; H, 6.03; N,
11.42; found C, 68.68; H, 6.09; N, 11.31.
3-(benzyloxy)-2-(tert-butylamino)quinazolin-4(3H)-one
4v:
1
white solid, 120ꢀ122 °C; H NMR (500 MHz, CDCl3) δ: 1.32 (s,
80 9H), 5.19 (s, 1H), 5.26 (s, 2H), 7.16 (t, J=7.0 Hz, 1H), 7.36 (d,
J=8.0 Hz, 1H), 7.41ꢀ7.44 (m, 5H), 7.55 (t, J=7.0 Hz, 1H), 8.12ꢀ
8.13 (m, 1H); 13C NMR (125 MHz, CDCl3) δ: 27.65, 50.82,
77.45, 117.63, 121.18, 124.33, 125.63, 128.12, 128.79, 129.29,
132.81, 133.16, 145.50, 147.04, 157.58; Ms (ESI) m/z: 324
85 [M+H]; Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99;
found C, 70.63; H, 6.67; N, 12.91.
3-benzyl-2-(tert-butylamino)-6-fluoroquinazolin-4(3H)-one 4s:
1
white solid, 130ꢀ132°C; H NMR (500 MHz, CDCl3) δ: 1.32 (s,
25 9H), 4.32 (s, 1H), 5.30 (s, 2H), 7.26 ꢀ7.27(m, 1H), 7.32ꢀ7.39 (m,
6H), 7.81ꢀ7.83 (m, 1H); 13C NMR (125 MHz, CDCl3) δ: 27.79,
44.06, 51.61, 110.56, 110.75, 116.41, 121.66, 121.85, 125.69,
126.21, 126.27, 127.35, 128.38, 134.22, 144.70, 146.97, 156.36,
158.29, 161.65; Ms (ESI) m/z: 326 [M+H]; Anal. Calcd for
30 C19H20FN3O: C, 70.13; H, 6.20; N, 12.91; found C, 70.23; H,
6.15; N, 12.84.
2-(tert-butylamino)-3-hydroxyquinazolin-4(3H)-one 4w: white
solid, 174ꢀ176 °C; H NMR (500 MHz, CDCl3) δ: 1.51 (s, 9H),
1
90 5.80 (s, 1H), 7.11ꢀ7.14 (m, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.55ꢀ7.58
(m, 1H), 8.03ꢀ8.05 (m, 1H), 11.37 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ: 28.12, 50.96, 115.61, 121.27, 123.68, 125.15, 133.68,
148.21, 164.44; Ms (ESI) m/z: 234 [M+H]; Anal. Calcd for
C12H15N3O2: C, 61.79; H, 6.48; N, 18.01; found C, 61.86; H,
95 6.39; N, 18.07.
3-benzyl-2-(tert-butylamino)-6-methylquinazolin-4(3H)-one
1
4t: white solid, 152ꢀ154°C; H NMR (500 MHz, CDCl3) δ: 1.31
Crystallographic data for the product 4j has been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 966928. These data can be obtained free of
100 charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk /data_request/cif.
35 (s, 9H), 2.42 (s, 3H), 4.26 (s, 1H), 5.30 (s, 2H), 7.25ꢀ7.27 (m,
2H), 7.29ꢀ7.43 (m, 5H), 7.98 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ: 20.95, 28.79, 44.83, 52.46, 116.55, 125.08, 126.50,
126.65, 128.16, 129.25, 132.07, 135.53, 135.69, 146.88, 147.93,
163.25; Ms (ESI) m/z: 322 [M+H]; Anal. Calcd for C20H23N3O:
40 C, 74.74; H, 7.21; N, 13.07; found C, 74.63; H, 7.15; N, 13.14.
Acknowledgements
General procedure for the synthesis of 2-unsubstituted-
amino-4(3H)-quinazolinones 4u: The solution of 2ꢀ(tertꢀ
butylamino)ꢀ3ꢀ(4ꢀmethylbenzyl)quinazolinꢀ4(3H)ꢀone 4b (0.30
45 mmol) in TFA (4 mL) was stirred under reflux in a sealed tube
overnight. Subsequently, the mixture was basified with aq. NaOH
(3 M). The product was extracted with EtOAc and dried
(Na2SO4), which was then purified by column chromatography to
We thank financial support from Jiangsu Creative Research
Funding for Graduate Students (CXZZ13_02) and Jiangsu
105 Natural Science Foundation (BK20131346)
Notes and references
a
give 2ꢀunsubstitutedꢀaminoꢀ4(3H)ꢀquinazolinones 4u.
Chemical Engineering College, Nanjing University of Science and
50
Technology, Nanjing, China. Fax: (+86)ꢀ25ꢀ8431ꢀ5030; Eꢀmail:
c.cai@mail.njust.edu.cn.
2-amino-3-(4-methylbenzyl)quinazolin-4(3H)-one 4u: white
solid, 167ꢀ169 °C; H NMR (500 MHz, CDCl3) δ: 2.34 (s, 3H),
110 b Fei Ji and Meiꢀfang Lv contributed equally to this paper.
† Electronic Supplementary Information (ESI) available: Copies of 1H
and 13C NMR spectra (4a-4u). Crystallographic data for 4j: CCDC
966928. See DOI: 10.1039/b000000x/
1
5.33 (s, 2H), 7.16ꢀ7.20 (m, 4H), 7.26ꢀ7.29 (m, 1H), 7.34 (d, J=8.0
Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H); 13C
55 NMR (125 MHz, CDCl3) δ: 20.08, 44.26, 116.32, 122.42, 123.11,
125.64, 126.56, 129.12, 130.79, 133.71, 137.27, 147.30, 150.45,
161.61; Ms (ESI) m/z: 266 [M+H]; Anal. Calcd for C16H15N3O:
C, 72.43; H, 5.70; N, 15.84; found C, 72.56; H, 5.62; N, 15.71.
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60 General procedure for the synthesis of 2-amino-3-
hydroxyquinazolin-4(3H)-ones 4w: To a solution of isatoic
anhydride (0.50 mmol) in toluene (4 mL) was added Oꢀ
phenylhydroxylamine (0.50 mmol). The mixture was stirred at
100 °C in a sealed tube for 4 h. Upon the completion of the
6
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