A greener protocol for accessing 2,3-dihydro/spiroquinazolin-4(1 H)-ones: Natural acid-sds catalyzed three-component reaction

Article abstract of DOI:10.1055/s-0032-1317014

A novel green and energy-efficient synthesis of 2,3-dihydro/ spiroquinazolin-4(1H)-ones via three-component cyclocondensation reaction involving isatoic anhydride, amines and aldehydes/ketones utilizing recyclable tartaric acid-SDS catalyst system has been achieved. With simple requirements of mechanical stirring or mechanochemical activation at room temperature and one of the shortest reported times as of yet, it is a significant improvement on previously described methods for the synthesis of such compounds. Moreover the catalyst system can also be efficiently applied in large-scale reactions which indicates the potential for applications in industry. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1317014

LETTER
▌2209
lAetteGr reener Protocol for Accessing 2,3-Dihydro/spiroquinazolin-4(1H)-ones:
Natural Acid-SDS Catalyzed Three-Component Reaction
Greener Protocol for 2,3-Dihydro/spiroquinazolin-4(1H)-ones
Rashmi Sharma, Anand Kumar Pandey, Prem M. S. Chauhan*
Division of Medicinal and Process Chemistry, CSIR Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: prem_chauhan_2000@yahoo.com; E-mail: premsc58@hotmail.com
Received: 13.04.2012; Accepted after revision: 09.07.2012
chanical stirring under mild conditions (ambient tempera-
Abstract: A novel green and energy-efficient synthesis of 2,3-di-
ture and pressure) and (B) mechanochemical activation
hydro/spiroquinazolin-4(1H)-ones via three-component cyclo-
(grinding). Mechanochemical conditions can accelerate
various bond-forming reactions compared to solution-
condensation reaction involving isatoic anhydride, amines and
aldehydes/ketones utilizing recyclable tartaric acid–SDS catalyst
system has been achieved. With simple requirements of mechanical based methods and simultaneously minimize the use of
solvents.7 Grinding with a minimal amount of solvent,
known as ‘solvent-drop grinding’, offers higher efficiency
stirring or mechanochemical activation at room temperature and
one of the shortest reported times as of yet, it is a significant im-
provement on previously described methods for the synthesis of
with respect to time, materials and energy usage.
such compounds. Moreover the catalyst system can also be effi-
The significance of our findings lies not only in avoiding
the use of organic solvents as potentially toxic and hazard-
ous materials and use of natural acid–SDS as eco-friendly
and cheap catalytic system but also in the emphasis on en-
ergy efficiency of the reaction. With the increasing prices
of energy and global awareness on energy crises, signifi-
cance of energy efficient chemical transformations can be
expected to increase considerably. Simplicity, energy ef-
ficiency, high throughput and inherent lower cost of the
methodology make it superior compared to the previously
reported ones and well suited for industrial applications.
ciently applied in large-scale reactions which indicates the potential
for applications in industry.
Key words: 2,3-dihydroquinazolin-4(1H)-one, mechanochemical
activation, multicomponent reaction, sodium dodecyl sulfate (SDS),
tartaric acid
To break the negative public image of chemistry and the
chemical industry in particular, the international chemical
community is under continuous pressure to alter current
working practices and to find sustainable and greener al-
ternatives. As a result, development of environmentally
benign chemical transformations, especially syntheses of
biologically relevant heterocycles, has been promoted
worldwide.1,2
At the onset of this research, we investigated the model
one-pot three-component cyclocondensation reaction us-
ing mechanical stirring between isatoic anhydride, benz-
aldehyde and n-butylamine to optimize the reaction
conditions (Table 1). The model reaction performed in
water with tartaric acid as catalyst in stoichiometric
amount was found to be sluggish with an unsatisfactory
yield (entry 2). It was determined by visual inspection that
the reaction mixture was not homogenous in nature and
probably a factor contributing towards low yield of the re-
action. Out of the two available options to obtain a ho-
mogenous mixture providing external energy or using
phase-transfer agents/anionic surfactant, the later was
chosen to keep the methodology energy efficient. Interest-
ingly, phase-transfer agents such as TBAB (entry 3),
TBAHS (entry 4), TMAI (entry 5) were not successful in
terms of reaction time and yield but in case of anionic sur-
factant sodium dodecyl sulfate (SDS) (20 mol%) the reac-
tion was complete in 40 minutes with 73% yield (entry 6).
Out of the various phase-transfer agents and surfactants
screened, since only SDS forms micellar aggregates, it is
believed that localization which creates a favorable
microenvironment for the catalyzed reaction rather than
phase transfer has contributed to the acceleration of reac-
tion rate.8 Screening of the solvent and/or solvent systems
suggested that water–ethanol mixture (3:1) is the best one
and afforded the highest yield among several solvent ra-
tios optimized (entries 7–9). Further the reaction was per-
formed with tartaric acid as catalyst in water–ethanol (3:1)
2,3-Dihydroquinazolin-4(1H)-one, a well-documented
heterocyclic scaffold, widely occurs in natural products
and shows a wide range of biological activities.3 In addi-
tion, these molecules can be further oxidized to their re-
spective quinazolin-4(3H)-one analogues,4 another
important class of biologically active heterocyclic com-
pounds.5 The unique biological significance of the 2,3-di-
hydroquinazolin-4(1H)-one skeleton prompted several
research groups to develop new protocols for its synthesis.
However, most of the reported methods6 are either not en-
vironmentally benign, suffer from harsh reaction condi-
tions,
have
prolonged
reaction
time,
use
hazardous/expensive catalysts and/or use specialized
equipment. Therefore, development of a simple and con-
venient approach for the preparation of 2,3-dihydroquin-
azolinone class of compounds is still required.
Accordingly, comprising the twelve principles of green
chemistry formulated by Anastas and Warner,2a herein we
report two parallel novel approaches for the synthesis of
2,3-dihydroquinazolin-4(1H)-one derivatives, (A) me-
SYNLETT 2012, 23, 2209–2214
Advanced online publication: 14.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317014; Art ID: ST-2012-D0322-L
© Georg Thieme Verlag Stuttgart · New York

2210
R. Sharma et al.
LETTER
solvent system which afforded the product in 135 minutes Further to explore the scope of both green protocols
with 81% yield (compare entries 10 and 2) while SDS (methods A and B), the reaction was investigated with an
alone was sufficient to provide 74% yield in 315 minutes array of aromatic aldehydes appended with various sub-
(entry 11). To explore the efficiency of other natural stituents (Table 2)10 under the optimized conditions
acids,6c,9 the reaction was performed successfully with cit- (entries 7 and 16, Table 1). Reactions with electron-re-
ric acid (entry 12), succinic acid (entry 13), oxalic acid leasing substituents were in general better as compared to
(entry 14) and ascorbic acid (entry 15) in stoichiometric those with electron-withdrawing substituents in terms of
amount but tartaric acid (entry 7) was found to be the best reaction time (entries 4c, 4d and 4j). Reactions in case of
choice in terms of yield and reaction time.
aryl aldehydes with electron-withdrawing substituents at
para position took longer time as compared to electron-
withdrawing substituents at meta position (entries 4j and
4k) but in case of electron-withdrawing substituents at or-
tho position, the reaction failed to provide the expected
product even after 24 hours (entries 4i and 4l), which sug-
gests that steric effect has a significant impact on the reac-
tion rate. The products were isolated and purified by
simple filtration/water washing. Further, the efficiency of
this methodology was explored with heteroaryl aldehydes
including 2-thiophene aldehyde and 5-nitrofurfural (en-
tries 4o and 4p). Considering medicinal value of ferrocene-
Encouraged with our green findings, we further looked for
greener alternatives in terms of time, yield and energy in-
put and found mechanochemical activation (grinding) as
a very promising technique. The above protocol proceed-
ed successfully in a porcelain mortar and pestle using
minimal amount of water–ethanol (3:1) mixture as sol-
vent. Reaction with the grinding in slurry form provided
the product 4a in two minutes with 94% yield (entry 16).
As conversion was quantitative, only washing with water
to remove tartaric acid and SDS was deemed sufficient for
spectroscopic analysis without any further purification.
Table 1 Optimization of Reaction Conditions with Isatoic Anhydride (1), n-Butyl Amine (2a) and Benzaldehyde (3a)
O
O
H
O
N
O
+
+
NH2
N
H
N
H
O
4a
1
2a
3a
Entry
Catalyst
Additivea
Solvent
Time (min)
Yield (%)b
1
2
–
–
H2O
–
no reactionc
tartaric acid
tartaric acid
tartaric acid
tartaric acid
tartaric acid
tartaric acid
tartaric acid
tartaric acid
tartaric acid
–
–
H2O
960
110
420
480
40
59
48
23
trace
73
87
78
56
81
74
62
72
70
58
94
3
TBABd
TBAHSd
TMAId
SDS
SDS
SDS
SDS
–
H2O
4
H2O
5
H2O
6
H2O
7
H2O–EtOH (3:1)
H2O–EtOH (1:1)
H2O–EtOH (1:3)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
H2O–EtOH (3:1)
20
8
15
9
120
135
315
15
10
11
12
13
14
15
16e
SDS
SDS
SDS
SDS
SDS
SDS
citric acid
succinic acid
oxalic acid
ascorbic acid
tartaric acid
45
40
45
2
a Amount: 20 mol%.
b Isolated yield.
c No product was observed after 24 h.
d TBAB: tetrabutylammonium bromide; TBAHS: tetrabutylammonium hydrogen sulfate; TMAI: tetramethylammonium iodide.
e Reaction was performed with grinding: method B.
Synlett 2012, 23, 2209–2214
© Georg Thieme Verlag Stuttgart · New York

LETTER
Greener Protocol for 2,3-Dihydro/spiroquinazolin-4(1H)-ones
2211
containing heterocycles,11 our methodology was success- worked well with aqueous ammonia as well (entry 4u),
fully applied to obtain 3-butyl-2-ferrocenyl-2,3-di- however the product 2-phenyl-2,3-dihydroquinazolin-
hydroquinazolin-4(1H)-one in very good yield from 4(1H)-one could not be obtained with ammonium
ferrocenecarboxaldehyde (entry 4q). As expected from acetate.6c,e
preliminary results, the average time span of reaction with
different aryl/heteroaryl aldehydes in case of method A (8
min to 9 h) decreased to one to eight minutes with appre-
ciable increase in yield via method B.
The methodology was further extended to cyclic ketones
such as cyclohexanone, 3,4-dihydronaphthalen-2(1H)-
one and 1-ethyl-1H-indole-2,3-dione to provide respec-
tive spirocyclized products 4v, 4w and 4x (Table 4). Al-
Subsequently, the substrate scope regarding amines was though a few methods of synthesis of such class of
also examined. Aliphatic amines, aromatic amines, cyclic spirocyclized compounds are known in literature,12 to the
amines and hydroxyl amines were found to be effective best of our knowledge, no such synthesis using isatoic an-
substrates and afforded the corresponding 2,3-dihydro- hydride has been reported yet. Further exploration of this
quinazolin-4(1H)-one derivatives in excellent yields. methodology with other ketones is underway in our labo-
Method B again proved to be better than method A in ratory.
terms of reaction time and yields (Table 3). The reaction
Table 2 Synthesis10 of Quinazolinone Derivatives 4a–q Using Isatoic Anhydride (1), n-Butyl Amine (2a) and Different Aromatic and
Heteroaromatic Aldehydes (3a–q) via Methods Aa and Bb
O
O
method A
method B
O
N
Ar/HetAr
aldehyde
+
+
NH2
N
H
O
N
H
4a–q
Ar/HetAr
aldehyde
1
2a
3a–q
Product
Ar/HetAr aldehyde
Method A
Method B
Time (min)
Yield (%)c
Time (min)
Yield (%)c
4ad
4b
4c
4d
4e
4f
benzaldehyde (3a)
20
8
87
84
89
78
81
83
80
79
2
1
1
5
3
1
3
3
–
6
3
–
4
8
2
1
3
94
93
96
86
89
93
91
90
4-isopropylbenzaldehyde (3b)
4-methoxybenzaldehyde (3c)
4-cyanobenzaldehyde (3d)
4-hydroxybenzaldehyde (3e)
4-fluorobenzaldehyde (3f)
4-cholorobenzaldehyde (3g)
4-bromobenzaldehyde (3h)
2-nromobenzaldehyde (3i)
4-nitrobenzaldehyde (3j)
3-nitrobenzaldehyde (3k)
2-nitrobenzaldehyde (3l)
terephthalaldehyde (3m)
9-anthraldehyde (3n)
12
150
90
10
45
55
–
4g
4h
4i
e
e
–
–
4j
335
60
–
73
79
84
87
4k
4l
e
e
–
–
4m
4n
4o
4p
4qd
70
540
28
10
33
62
80
81
86
72
78
83
88
95
81
2-thiophenecarboxaldehyde (3o)
5-nitrofurfural (3p)
ferrocenecarboxaldehyde (3q)
a Method A: magnetic stirring, reaction conditions: 1 (0.61 mmol), 2a (0.61 mmol), 3a–q (0.61 mmol), tartaric acid (0.61 mmol), SDS
(20 mol%), H2O–EtOH (3:1, 4 mL) as solvent.
b Method B: grinding using mortar and pestle, reaction conditions: 1 (0.61 mmol), 2a (0.61 mmol), 3a–q (0.61 mmol), tartaric acid (0.61 mmol),
SDS (20 mol%), few drops of H2O–EtOH (3:1) as solvent.
c Isolated yield.
d Analytical data provided.10
e No product was observed after 24 h.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2209–2214

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R. Sharma et al.
LETTER
Table 3 Synthesis of Quinazolinone Derivatives 4r–u Using Isatoic Anhydride (1), Benzaldehyde (3a) and Different Amines 2b–e via
Methods Aa and Bb
O
O
O
H
R
N
method A
method B
O
H2N
R
+
+
N
H
N
H
O
1
2b–e
3a
4r–u
Product
R
Method A
Method B
Time (min)
Yield (%)c
Time (min)
Yield (%)c
4r
2b (cyclohexyl)
23
8
73
81
74
89
2
1
6
1
84
92
86
96
4s
2c (3-hydroxypropyl)
2d (Ph)
4td
4ud
130
15
2e (H)
a Method A: magnetic stirring, reaction conditions: 1 (0.61 mmol), 2b–e (0.61 mmol), 3a (0.61 mmol), tartaric acid (0.61 mmol), SDS
(20 mol%), H2O–EtOH (3:1; 4 mL) as solvent.
b Method B: grinding using mortar and pestle, reaction conditions: 1 (0.61 mmol), 2b–e (0.61 mmol), 3a (0.61 mmol), tartaric acid (0.61 mmol),
SDS (20 mol%), few drops of H2O–EtOH (3:1) as solvent.
c Isolated yield.
d Analytical data provided.10
Table 4 Synthesis of Spiroquinazolinone Derivatives 4v–x Using Isatoic Anhydride (1), Aqueous Ammonia (2f) and Cyclic Ketones 5a–c via
Methods Aa and Bb
O
O
O
NH
O
method A
method B
+
NH3
+
N
H
N
H
O
1
2f
5a–c
4v–x
Product
Ketone 5
Method A
Method B
Time (min)
Yield (%)c
Time (min)
Yield (%)c
4vd
4w
4xd
cyclohexanone (5a)
25
120
135
71
68
76
3
6
9
86
83
85
3,4-dihydronaphthalen-2(1H)-one (5b)
1-ethyl-1H-indole-2,3-dione (5c)
a Method A: magnetic stirring, reaction conditions: 1 (0.61 mmol), 2f (0.61 mmol), 5a–c (0.61 mmol), tartaric acid (0.61 mmol), SDS (20
mol%), H2O–EtOH (3:1; 4 mL) as solvent.
b Method B: grinding using mortar and pestle, reaction conditions: 1 (0.61 mmol), 2f (0.61 mmol), 5a–c (0.61 mmol), tartaric acid (0.61 mmol),
SDS (20 mol%), few drops of H2O–EtOH (3:1) as solvent.
c Isolated yield after recrystallization.
d Analytical data provided.10
Finally, the recyclability of the tartaric acid–SDS catalyst
system in method A was investigated. As shown in
Figure 1, the reaction medium was reused for four runs in
the preparation of 4a without any significant loss of activ-
ity (with the yield of the product 4a being 86%, 84%,
82%, and 83%, respectively).
In conclusion, an energy efficient and green synthetic
methodology has been developed for the facile synthesis
of 2,3-dihydroquinazolin-4(1H)-ones at room tempera-
ture via mechanical stirring and mechanochemical activa-
tion. The protocol was shown to be successfully
applicable to a wide range of aryl/heteroaryl aldehydes
Figure 1 Recyclability of tartaric acid–SDS catalyst system
Synlett 2012, 23, 2209–2214
© Georg Thieme Verlag Stuttgart · New York

LETTER
Greener Protocol for 2,3-Dihydro/spiroquinazolin-4(1H)-ones
2213
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and amines with the shortest reaction time reported so far
at ambient temperature besides obtaining high yields. Fur-
ther, it was extended to the synthesis of spiro compounds
as well. Thus the developed methodology provides oppor-
tunity for the construction of diverse bioactive molecules
with numerous other advantages such as: (1) theoretically,
this combination of MCR (multicomponent reaction)
spans a chemical space of greater than 1000 × 1000 × 100
= 108 molecules,12 (2) high bond-forming efficiency13 as
three C–N bonds are formed, (3) economic methodology
which offers a great possibility for applications in indus-
try,14 (4) use of water–ethanol mixture as green solvent
and (5) simple purification process/clean synthesis.
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Acknowledgment
The authors thank the Council of Scientific and Industrial Research,
India for financial support, for the award of senior research fellow-
ship and the S.A.I.F. division, CDRI, Lucknow, for providing
spectroscopic data. CDRI communication number is 8280.
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(10) Representative Procedure:
Method A: In a round-bottom flask, isatoic anhydride
(0.1 g, 0.61 mmol) and amine (0.61 mmol) were dissolved in
micellar solution of H2O–EtOH (3:1; 4 mL) sensitized with
SDS (20 mol%). Tartaric acid (0.92 g, 0.61 mmol) and
aldehyde/ketone (0.61 mmol) were then successively added
and the reaction was allowed to stir at r.t. for an appropriate
time indicated in Tables 2–4. The solid precipitate was
filtered, washed with H2O, dried and could be used without
further purification, however in case of 4r, 4s and 4t
recrystallization with EtOH–ice was required.
Method B: isatoic anhydride (0.1 g, 0.61 mmol) and amine
(0.61 mmol) were mixed with a few drops of the solvent
system (H2O–EtOH, 3:1) in a mortar. Tartaric acid (0.92 g,
0.61 mmol), SDS (20 mol%) and aldehyde/ketone (0.61
mmol) were then successively added and ground together
with a pestle until completion of the reaction (Tables 2–4).
In most of the cases the product was washed with H2O,
however in case of 4r–t recrystallization with EtOH–ice was
required.
3-Butyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (4a):
colorless solid; yield: 0.15 g (87%); mp 132–135 °C. 1H
(300 MHz, CDCl3): δ = 7.88 (d, 1 H, J = 6.9 Hz), 7.21 (br s,
4 H), 7.13–7.19 (m, 2 H), 6.76 (t, 1 H, J = 7.3 Hz), 6.44 (d,
1 H, J = 8.0 Hz), 5.76 (s, 1 H), 3.85–3.94 (m, 1 H), 2.64–2.74
(m, 1 H), 1.45–1.49 (m, 2 H), 1.20–1.27 (m, 2 H), 0.80 (t, 3
H, J = 7.3 Hz).13C (50 MHz, CDCl3): δ = 163.2, 145.2, 140.0,
133.4, 129.2, 128.9, 128.4, 126.5, 119.1, 116.2, 114.4,
72.1, 44.6, 29.8, 20.2, 13.8. IR (KBr): 3360, 1634 cm–1.
MS (ES+): m/z = 281.1 [M+ + 1]. HRMS (DART): m/z calcd
for [C18H20N2O + H+]: 281.1654; found: 281.1647.
3-Butyl-2-ferrocenyl-2,3-dihydroquinazolin-4(1H)-one
(4q): yellow solid; yield: 0.17 g (72%); mp 137–140 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.83 (d, 1 H, J = 7.4 Hz), 7.19–
7.27 (m, 1 H), 6.79 (t, 1 H, J = 7.4 Hz), 6.64 (d, 1 H, J = 6.9
Hz), 5.40 (s, 1 H), 4.08–4.21 (m, 10 H), 3.75–3.79 (m, 1 H),
2.88–2.92 (m, 1 H), 1.42–1.50 (m, 2 H), 1.19–1.28 (m, 2 H),
0.82 (t, 3 H, J = 7.5 Hz). 13C NMR (50 MHz, CDCl3): δ =
162.7, 146.4, 133.3, 128.7, 119.3, 116.5, 113.9, 88.6, 73.3,
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H. J. Nat. Prod. 2004, 67, 1131.
(6) (a) Gao, L.; Ji, H.; Rong, L.; Tang, D.; Zha, Y.; Shi, Y.; Tu,
S. J. Heterocycl. Chem. 2011, 48, 957. (b) Niknam, K.;
Jafarpour, N.; Niknam, E. Chin. Chem. Lett. 2011, 22, 69.
(c) Ghorbani-Choghamarani, A.; Taghipour, T. Lett. Org.
Chem. 2011, 8, 470. (d) Zeng, L. Y.; Cai, C. J. Heterocycl.
Chem. 2010, 47, 1035. (e) Zhang, Z. H.; Lu, H. Y.; Yang, S.
H.; Gao, J. W. J. Comb. Chem. 2010, 12, 643.
(f) Rostamizadeh, S.; Amani, A. M.; Mahdavinia, G. H.;
Sepehrian, H.; Ebrahimi, S. Synthesis 2010, 1356.
(g) Shaterian, H. R.; Oveisi, A. R.; Honarmand, M. Synth.
Commun. 2010, 40, 1231. (h) Dabiri, M.; Salehi, P.;
Baghbanzadeh, M.; Zolfigol, M. A.; Agheb, M.; Heydari, S.
Catal. Commun. 2008, 9, 785. (i) Chen, J.; Wu, D.; He, F.;
Liu, M.; Wu, H.; Ding, J.; Su, W. Tetrahedron Lett. 2008,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2209–2214

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R. Sharma et al.
LETTER
69.1, 68.81, 68.76, 68.6, 68.2, 66.3, 44.0, 30.1, 20.3, 14.0. IR
(KBr): 3285, 1631 cm–1. MS (ES+) m/z = 389.0 [M+ + 1].
HRMS (DART): m/z calcd for [C22H24FeN2O + H+]:
389.1316; found: 389.1318.
117.0, 70.5, 39.7, 26.8, 24.0. IR (KBr): 3362, 3179, 1647
cm–1. MS (ES+): m/z = 217.0 [M+ + 1]. HRMS (DART): m/z
calcd for [C13H16N2O + H+]: 217.1335; found: 217.1326.
1-Ethyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-
dione (4x): tan solid; yield: 0.15 g (85%); mp 227–230 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.29 (s, 1 H, NH), 7.62
(d, 1 H, J = 7.1 Hz), 7.52 (d, 1 H, J = 7.2 Hz), 7.42 (t, 1 H, J
= 7.6 Hz), 7.18–7.25 (m, 2 H), 7.00–7.16 (m, 2 H), 6.69 (t, 1
H, J = 7.3 Hz), 6.61 (d, 1 H, J = 4.0 Hz), 3.57–3.68 (m, 2 H),
1.16 (t, 3 H, J = 6.9 Hz). 13C NMR (75 MHz, DMSO-d6):
δ = 173.8, 163.9, 146.7, 142.6, 133.3, 130.9, 129.0, 126.8,
125.1, 122.7, 117.2, 114.2, 113.9, 109.0, 70.7, 34.0, 12.3.
IR (KBr): 3368, 3227, 1638, 1613 cm–1. MS (ES+): m/z =
294.0 [M+ + 1]. HRMS (DART): m/z calcd for [C17H15N3O2
+ H+]: 294.1164; found: 294.1156.
2,3-Diphenyl-2,3-dihydroquinazolin-4(1H)-one (4t):
colorless solid; yield: 0.14 g (74%); mp 212–214 ºC. 1H
NMR (300 MHz, CDCl3): δ = 8.04 (d, 1 H, J = 7.8 Hz), 7.19–
7.38 (m, 11 H), 6.92 (t, 1 H, J = 7.5 Hz), 6.65 (d, 1 H, J = 7.8
Hz), 6.11 (s, 1 H). 13C NMR (75 MHz, CDCl3 + CD3OD):
δ = 165.6, 147.8, 142.1, 141.6, 135.8, 130.6, 130.5, 130.2,
128.7, 128.4, 120.5, 117.5, 116.5, 76.2. IR (KBr): 3327,
1649 cm–1. MS (ES+): m/z = 301.1 [M+ + 1]. HRMS
(DART): m/z calcd for [C20H16N2O + H+]: 301.1335; found:
301.1333.
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (4u):
colorless solid; yield: 0.12 g (89%); mp 218–220 ºC. 1H
NMR (200 MHz, CDCl3): δ = 7.96 (d, 1 H, J = 8.1 Hz), 7.26–
7.58 (m, 6 H), 6.94 (t, 1 H, J = 7.2 Hz), 6.69 (d, 1 H, J = 8.0
(11) Bellot, F.; Cosledan, F.; Vendier, L.; Brocard, J.; Meunier,
B.; Robert, A. J. Med. Chem. 2010, 53, 4103.
(12) (a) Subba Reddy, B. V.; Venkateswarlu, A.; Madan, C.;
Vinu, A. Tetrahedron Lett. 2011, 52, 1891. (b) Miklós, F.;
Fülöp, F. Eur. J. Org. Chem. 2010, 959. (c) Wang, X.; Yang,
K.; Zhou, J.; Tu, S. J. Comb. Chem. 2010, 12, 417. (d) Shi,
D.; Rong, L.; Wang, J.; Zhuang, Q.; Wangb, X.; Hu, H.
Tetrahedron Lett. 2003, 44, 3199.
(13) The corresponding starting materials for this reaction are
broadly commercially available, mostly in numbers
exceeding 1000 (RNH2, RCHO, RCOR). However, less than
1000 substituted isatoic anhydrides are available.
Hz), 5.90 (s, 1 H), 5.82 (s, 1 H, NH), 4.41 (s, 1 H, NH). 13
NMR (75 MHz, CDCl3): δ = 169.5, 152.9, 145.8, 138.4,
133.8, 133.3, 132.6, 132.0, 122.6, 119.8, 119.5, 72.5. IR
C
(KBr): 3296, 3190, 1656 cm–1. MS (ES+): m/z = 225.0 [M+ +
1]. HRMS (DART): m/z calcd for [C14H12N2O + H+]:
225.1022; found: 225.1017.
1′H-Spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-one
(4v): colorless solid; yield: 0.09 g (71%); mp 217–219 °C.1H
NMR (200 MHz, CDCl3): δ = 7.89 (dd, 1 H, J1 = 7.8 Hz, J2
= 1.2 Hz), 7.28–7.33 (m, 1 H), 6.84 (t, 1 H, J = 7.5 Hz), 6.67
(d, 1 H, J = 7.8 Hz), 6.43 (s, 1 H, NH), 4.40 (s, 1 H, NH),
1.84 (br s, 4 H), 1.47–1.68 (m, 6 H). 13C NMR (75 MHz,
CDCl3 + CD3OD): δ = 167.0, 148.0, 136.2, 130.3, 120.7,
(14) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(15) For large-scale reaction, reaction with 20 g of isatoic
anhydride successfully afforded 4a with 84% yield (29.5 g)
via method A.
Synlett 2012, 23, 2209–2214
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