Deep eutectic solvent mediated synthesis of quinazolinones and dihydroquinazolinones: Synthesis of natural products and drugs

Article abstract of DOI:10.1039/c6ra00855k

A mild and greener protocol was developed to synthesize substituted quinazolinones and dihydroquinazolinones via deep eutectic solvent (DES) mediated cyclization with a series of aliphatic, aromatic, and heteroaromatic aldehydes in good to excellent yields. This greener strategy was further utilised to synthesize various quinazolinone natural products and drugs.

Full text of DOI:10.1039/c6ra00855k

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Deep eutectic solvent mediated synthesis of quinazolinones and
dihydroquinazolinones: synthesis of natural products and drugs
Received 00th January 20xx,
Accepted 00th January 20xx
Suman Kr Ghosh and Rajagopal Nagarajan*
A mild and greener protocol was developed to synthesize substituted quinazolinones and dihydroquinazolinones
via deep eutectic solvent (DES) mediated cyclization with a series of aliphatic, aromatic, heteroaromatic
aldehydes in good to excellent yields. This greener strategy was further utilised to synthesize various
quinazolinone natural products and drugs.
DOI: 10.1039/x0xx00000x
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compounds should be the major aim.
Introduction:
Minimizing the waste and maximizing the sustainability of a
reaction would be the breakthrough in the field of synthetic
chemistry to favour the human race.1 Although the
achievements are still limited but sustainable chemistry and
their applications are the new era in beginning. For chemists
to mimic the nature and design an environment friendly
chemical synthesis with respect to reagents, solvents and
ambient conditions is very challenging. Since, from last decade
more efforts were devoted towards the design of
environmentally benign solvents that could be easily
biodegradable or reusable.2 In recent years there are green
solvents like water,3 Ionic liquids (ILs),4 supercritical liquids,5
Polyethylene glycol (PEG)6 emerged to outplace many organic
solvents, however the use of these solvents are restricted due
to their poor solubility and stability of organic compounds.
Extensive usage of ILs as solvent was well documented for
many organic reactions over a decade but depending on their
counterpart, it can be toxic and non biodegradable. Thus,
nowadays the use of ILs as solvent is reduced by less than a
half.7 Whereas, deep eutectic solvents (DES) has risen as a
green solvent due to their properties like polarity, low toxicity,
non-volatility, biodegradability, low-cost, thermal stability, and
ready availability from bulk renewable resources without any
further modification.8 Use of DES as a replacement of typical
organic solvents in reactions like, Perkin,9 Diels-Alder,10
Heck,11 Suzuki,12 Biginelli13 were well documented in literature.
Hence, improvisation on the uses of DES in synthesis of organic
Figure 1. Examples of biologically and pharmaceutically important
quinazolinones
Among the nitrogen containing natural products,
quinazolinone is one of the most important heterocyclic core
that accessorize many naturally occurring alkaloids as well as
marketed drugs. Substituted and unsubstituted quinazolinones
exhibit broad biological and pharmaceutical properties like
protein tyrosine kinase inhibitory, cholecystokinin inhibitory,
anti-microbial, anticonvulsant, sedative, hypotensive, anti-
depressant, antiinflammatory, and anti-allergy.14 Certain
quinazolionones which is being marketed as drugs, like
methqualone (quaalude), mebroqualone, mecloqulaone
(Casfen) contains sedative, hypnotic and anxiolytic properties
and are used for treatment of insomnia (Fig. 1).15 In 2011,
Wang and Che group isolated two alkaloids, penipanoid C and
2-(4-hydroxybenzyl)quinazolin-4(3H)-one from the marine
sediment-derived fungus penicillium paneum SD-44 that
exhibits cytotoxicity against the human lung carcinoma cell line
A549 and BEL-7402 cell lines with IC50 values of 17.5 and 19.8
μM, respectively.16 Due to this undeniable impression of
quinazolione alkaloids over pharmacological industry, there is
a continuous interest among the researchers to develop new
methods for synthesis of quinazolinone core. Over the years,
plenty of protocols have been reported by various scientific
groups using metal (Cu, Pd, Ir),17 Sp3 carbon oxidation,18 multi
component reaction,19 microwave condition,20 gallium(III)
triflate,21 montmorillonite K-10,22 Zinc(II) perfluorooctanoate,23
KAl(SO4)2·12H2O,24 Al(H2PO4)3,25 Cu-CNTs26 and MNP-PSA (N-
S. K. Ghosh, Prof. R. Nagarajan
School of Chemistry, University of Hyderabad
Hyderabad- 500046, India
(+) 91 40 23012460
rnsc@uohyd.ernet.in
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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propylsulfamic acid supported onto magnetic Fe3O4 we had obtained the corresponding dihydro derivatives within
nanoparticles)27 as catalysts. A keen survey of literature also 2h (3e’, 3h’) of the reaction.
reveals the use of metal free conditions like iodine,28
Scheme 1. Synthesis of 2- substituted quinazolinonea
amberlyst-15,29 Bronsted acid,30 citric acid,31 ionic liquids,32 β-
cyclodextrin,33 water-Sodium dodecayl sulfate (SDS),34
cellulose-SO3H,35 CLAY,36 Propane phosphonic acid anhydride
(T3P)37 for synthesis of quinazoline as well as quinazolinone.
Deep eutectic solvents (DES) being more eco-friendly due to
their inherent properties (vide supra) it is now becoming the
choice of solvent over many organic solvents. In 2012, Zhang
et al. reported a three component synthesis of quinazoline in
DES media.38 Whereas, to the best of our knowledge there was
limited report39 till date for synthesis of quinazolinone using
particularly deep eutectic solvents in spite of their
aforementioned environmental impact. Furthermore, this DES
mediated cyclization can be utilised for synthesis of
O
O
N
O
N
O
N
O
N
NH
NH
NH
NH
NH
N
H
Me
OMe
3c, 24h,
61 %yield
3d, 6h,
79 %yield
3a, 10h,
78 %yield
3c', 24h,
25 %yield
3b, 15h,
73 %yield
quinazolinone alkaloids or drugs as
a key step. In
O
O
O
N
O
environmental perspective, use of deep eutectic solvent
mediated cyclization as a key step for total synthesis of
alkaloids would open new directions for the scientific
community. With this outlook to our ongoing research,40
herein we report a DES mediated cyclization strategy to
synthesize substituted/ unsubstituted quinazolinones that has
been further utilised for synthesis of various natural products
and drugs.
NH
NH
NH
NH
N
N
H
N
N
H
N
Br
3g, 5h,
76 %yield
3h', 2h,
81 %yield
3e', 2h,
83 %yield
3f, 8h,
74 %yield
NO2
O
O
O
O
NH
NH
NH
NH
H
N
MeO
N
N
N
H
N
N
H
HN
OMe
OMe
N
Bn
O
3l, 8h,
72 %yield
3j', 4h,
72 %yield
3k, 13h,
67 %yield
3i', 2h,
92 %yield
Me
Results & Discussion:
a
Reaction was performed in a scale with 1 (1.0 equiv.), 2 (1.2 equiv.), in L-(+)-
Tartaric acid : DMU (3:7) mixture at 90 0C in an open mouth round bottomed
To obtain 2-(o-tolyl)quinazolin-4(3H)-one (3a, scheme 1) we
started our venture with optimizing few of the deep eutectic
solvents mixture like, citric acid–N, N’-Dimethylurea (DMU), D-
(−)-fructose–DMU, L-(+)-tartaric acid–DMU and mannose–
DMU–NH4Cl with model substrates anthranilamide (1a) (1.0
equiv.) and o-tolualdehyde (2a) (1.2 equiv). Among them, L-
flask.
The same outcome was obtained when we used substituted
anthranilamides (1b, 1c) with heterocyclic (pyridine, indole,
pyrrole) aldehydes. This observation showed that with
variation of time, both dihydroquinazolinone product as well
as quinazolinone products can be obtained. All the compounds
were extracted with ethyl acetate and purified using column
chromatography. Once we gained an insight of this DES
mediated cyclization, to synthesize various substituted
dihydroquinazolinone and quinazolinones, we shifted our
focus to apply this protocol for formal synthesis of some
biologically important quinazolinone natural products and
drugs.
(+)-tartaric acid–DMU (3:7) mixture melt at 90 °C was found to
be the most effective to give the maximum yield of compound
3a. The reaction was carried out in an open air atmosphere to
aromatize the initially formed dihydroquinazolinone to
quinazolinone product via aerobic oxidation. With this
optimized conditions, we explored the scope and generality of
the reaction using this DES. The initial formation of
dihydroquinazolinone can be identified with thin layer
chromatography (bright blue long UV active) which was further
aromatized to the corresponding quinazolinone via aerobic
oxidation. An array of aldehydes (aromatic, aliphatic,
heterocyclic) (2a- 2l) was exposed to these conditions with
substituted/ unsubstituted anthranilamides (1a- 1c). To our
delight, all reactions underwent smoothly to give the
Bouchardatine41
(
Fig.
1
), is
a
very well known β-
indoloquinazoline alkaloid isolated from B. neurococca
(Rutaecae), shows wide biological properties like anti-cancer,
anti-inflammatory and anti-tuberculosis. Recently it has also
been documented as a novel inhibitor of adipogenesis/
lipogenesis in 3T3-L1 adipocytes. Due to these vital properties,
it immediately draws the attention and we were eager to
apply our DES mediated protocol for synthesizing it. Indole-2-
corresponding
dihydroquinazolinone/
quinazolinone
depending on time of the reaction. The electron donating
aromatic/ aliphatic aldehydes and anthranilamides were
transferred smoothly to the cyclized quinazolinone product
within 6-15 h in good yields (3a, 3b, 3d), whereas, in case of
benzaldehyde we obtained both the quinazolinone (3c) and
dihydroquinazolinone (3c’) product even after 24h also. The
electron withdrawing aromatic aldehydes were not converted
to the corresponding quinazolinone after 24h also, although
carboxaldehyde (
carboxylic acid which on treatment with anthranilamide (1a) in
L-(+)-tartaric acid-DMU (3:7) melt at 90 C for 8h gave the 2-
(1H-indol-2-yl)quinazolin-4(3H)-one 5) in 81% yield.
Formylation of compound with DMF/POCl3 will introduced
4) was obtained in two steps from indole-2-
°
(
5
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Scheme 3: Synthesis of 2, 2’-disubstitued quinazolinonesb
the aldehyde group at indole C3 to give bouchardatine, that
has already been reported from our group (Scheme 2, part
).42
A
Scheme 2. Formal Synthesis of 2-substitued quinazolinone alkaloids
Part A: Formal Synthesis of Bouchardatine
Part B: Formal synthesis of Schizocommunin
In, part
B; a formal synthesis of schizocommunin was
b Reaction was performed in a scale with 1a (1.0 equiv.), ketone (1.0 equiv.), in L-
(+)-Tartaric acid : DMU (3:7) mixture at 90 0C in an open mouth round bottomed
flask.
achieved. Schizocommunin was first reported in 1999 from the
liquid culture medium of Schizophyllum commune by Hosoe et
al. It shows strong cytotoxic activity against murine lymphoma
cells, further biological studies on schizocommunin were
prevented because of its scarcity from natural sources, and
there had been no reports of the total synthesis for
schizocommunin until Nishida et al. in 2013 reported the
revised structure.43 Their synthesis of schizocommunin was
demonstrated from 2-methyl-4(3H)-quinazolinone on refluxing
in acetic acid media with istain. Hence, the scarcity of
schizocommunin in nature, and high cost of the commercially
available 2-methyl-4(3H)-quinazolinone attracted us. 2-
Methyl-4(3H)-quinazolinone could be easily prepared via our
protocol from cheaper starting material anthranilamide (1a).
Hence, anthranilamide (1.0 equiv.) was treated with
After a successful manifestation of our green protocol over 2-
substituted/ 2, 2-disubstituted quinazolinones, we were eager
to explore the scope of the reaction on synthesis of 2, 3-
disubstitued quinazolinones. Significance of this quinazolinone
core was more prominent particularly in respect to their
pharmacological properties (vide supra, Fig. 1).
Scheme 4: Synthesis of 2, 3 substituted quinazolinones (Drugs and Natural
products)
Part A: Preparation of starting materials
acetaldehyde (3.0 equiv) in the green melt at 90 °C for 2 h to
obtain the corresponding dihydroquinazolione (7’) which was
further treated with 2,3-Dichloro-5,6-dicyano-p-benzoquinone
(DDQ) in dry DCM at rt to acquire 2-methyl-4(3H)-
Part B: General method for synthesis of 2, 3 substituted quinazolinone drugs and
quinazolinone
Schizocommunin can be synthesized in one step from
compound following Nishida’s procedure.
(7) in 85% yield (Scheme 2, part B).
alkaloids
7
Though 2,2’-disubstituted quinazolinones were not found
often in naturally occurring alkaloids but their synthetic
versions show wide spectrum of pharmacological activities.
Incorporation of a spirocyclohexane, aliphatic or hetrocyclic
moiety at C2 of the quinazolinone heterocycles gives anti-
inflammatory, analgesic, antileishmanial agents. Some
spiroquinazolinones exhibiting anti-amoebic activity in vitro
was also tested as central nervous system depressants.44 Thus
we were excited to test our protocol for the synthesis of
different 2, 2’-disubstitued quinazolinone. Variety of ketones
reacted smoothly over the melt at 90 °C with anthranilamide
1a) to furnish the corresponding substituted quinazolinones.
(
A wide range of compounds were (aliphatic-aliphatic, aliphatic-
aromatic, aromatic-aromatic, cyclic ketones and isatin) well
tolerated in this reaction condition to give excellent yield of
products (Scheme 3).
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Hence, we selected some of the drugs (methaqualone,
2 for the compound 11b shows, with the increase of
mecloqualone, mebroqualone) and alkaloids as our target temperature the signal spread (∆δ) between signals of a (3H,
molecules to validate our protocol. and start
s) and b (1H, q) decreases. At 50 oC the signals of
To synthesize the exact target molecules, we prepared the to coalesce on NMR time scale. Measurement at 70 C shows,
corresponding starting material 2-amino-N-(substituted) peaks of both and merged as both the conformers lost
a
b
o
a
b
benzamide from 2-nitrobenzoic acid in two steps. In the first their identity and exhibit a rapidly equilibrating species.
step 2-nitrobenzoic acid was stirred with oxalyl chloride in dry Next, dihydroquinazolinones were aromatized with DDQ to
DCM for 3h at rt, followed by removal of excess solvent and furnish respective quinazolinones in good yields (12a-f). We
oxalyl chloride under pressure led to the corresponding acid have tested a variety of substitutes on aniline particularly like
chloride. Next, this acid chloride was added to the mixture of halo, ester, and alkyl to synthesis the exact drugs and alkaloid.
substituted benzamides and triethylamine, and stirred for To our delight, all reaction went with ease to give excellent
another 4-6 h at rt to furnish the respective 2-nitro-N- yields of the compounds including 2-(4-methoxyphenyl)-3-
(substituted)benzamides (9a-e).45 Nitro group reduction of phenylquinazolin-4(3H)-one (12f). Drugs like methaqualone
compound 9a-e in presence of Zn/NH4Cl gave 2-amino-N-
(substituted)benzamides (10a-e) in good yields. Pleasingly, all methyl 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)benzoate
2-amino-N-(substituted)benzamides reacted smoothly with was synthesized with good overall yields Scheme
corresponding aldehydes onto the green melt at 90 C to give Compounds 12a and 12e can be further improvise to two more
(
12a), mecloqualone (12b), mebroqualone (12c) and alkaloid
12e)
).
(
(
4
°
corresponding dihydroquinazoliones
excellent yields.
(
11a-f
)
in good to natural products piriqualone and sclerotigenin in one and two
steps via Welch46 and Zhou’s47 method (Scheme 5).
Figure 2: Temperature effect on conformational isomerism 11b
Scheme 5: Formal syntheses of sclerotigenin and piriqualone
a (3H,s)
b (1H, q) Temperature: 80 °C
Temperature: 70 °C
Conclusions
Temperature: 50 °C
In conclusion, we have developed a greener and cheaper
strategy to synthesis substituted and unsubstituted
dihydroquinazolinones as well as quinazolinones in good to
excellent yields. Numerous aldehydes/ ketones and
substituted anthranilamides were well tolerated in this
optimized condition. This protocol was further utilized for
formal synthesis of many naturally occurring alkaloids and
drugs.
Temperature: RT
Experimental Section
General Information:
Although in NMR spectrum, we observed a firm existence of
two isomers for compounds 11a, 11b, 11c and 11e (see
supporting) with different ratios. We presumed that due to the
presence of R1 group in compound 11 restrict the C-C bond
rotation and generate conformational isomerism. To prove the
existence of rotamers, we carried out temperature variant
NMR experiment where spectral changes were measured in
DMSO-d6 solvent over a temperature range of RT-80 0C. As fig.
1H and 13C-NMR spectra were recorded at 400 and 100 MHz,
respectively, or at 500 and 125 MHz, respectively. Chemical
shifts were calculated in ppm downfield from TMS (δ = 0) for
1H NMR, and relative to the central CDCl3 resonance (δ =77.0)
and DMSO-d6 (δ = 39.51) for 13C NMR. Data presented in the
experimental section are as follows: chemical shift,
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integration, multiplicity (s=singlet, d=doublet, t=triplet, 2-Phenylquinazolin-4(3H)-one (3c):
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q=quartet, m=multiplet, dd=doublet doublet), coupling This compound was obtained as yellow solid; yield = (0.099 g/
constant in Hertz (Hz). TOF and quadrupole mass analyzer 0.100 g of 1a; 61%); m.p. = 236 oC; Rf = 0.40 (EtOAc: hexanes=
1
types are used for the HRMS measurements. Mass spectral 3:7); IR (KBr) 2918, 1666, 1601, 1291, 1265, 768 cm-1; H NMR
data was obtained from HRMS (ESI). IR spectra were recorded (400 MHz, CDCl3+ DMSO-d6) δ 11.94 (1H, s), 8.05 (1H, d, J = 7.2
on a FT-IR spectrometer using KBr pellets or neat. Melting Hz), 7.99- 7.98 (2H, m), 7.57- 7.55 (2H, m), 7.32- 7.29 (3H, m),
points were measured in open capillary tubes and are 7.27- 7.21 (1H, m); 13C NMR (100 MHz, CDCl3+ DMSO-d6) δ
uncorrected. All the obtained products were purified by 163.2, 152.3, 149.2, 134.3, 132.9, 131.2, 129.5, 128.6, 128.1,
column chromatography using silica gel (100-200 mesh). All 127.6, 126.3, 126.0, 121.1; m/z=223 (M+H), positive mode;
reaction solvents used were dried from GR grade solvents. All Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60%. Found:
other commercial reagents were used as received.
C, 75.81; H, 4.51; N, 12.53%.
General
experimental
procedure
to
synthesis 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (3c’):
This compound was obtained as white solid; yield = (0.040 g/
dihydroquinazolinone/ quinazolinone:
For 0.100 g starting amide, a total 2g mixture of L-(+)-Tartaric 0.100 g of 1a; 25%); m.p. = 216 oC; Rf = 0.41 (EtOAc: hexanes=
acid and N, N‘-Dimethylurea (DMU) in a ratio of 3:7 was taken 3:7); IR (KBr) 3299, 2925, 1651, 1608, 1264 cm-1; H NMR (400
1
in an oven dried open mouth round bottomed flask and MHz, DMSO-d6) δ 8.29 (1H, s), 7.63 (1H, d, J = 7.6 Hz), 7.51 (2H,
heated to its eutectic point 70 0C, where the mixture melted to d, J = 7.6 Hz), 7.42- 7.34 (3H, m), 7.26 (1H, t, J = 7.2 Hz), 7.12
give a clear solution. Next, aldehyde (1.2/ 1.5 equiv.) and (1H, s), 6.77 (1H, d, J = 8.4 Hz), 6.69 (1H, t, J = 7.2 Hz), 5.77 (1H,
substituted anthraniliamide (1.0 equiv.) was added to this melt s); 13C NMR (100 MHz, DMSO-d6) δ 164.1, 148.3, 142.1, 133.8,
and heated at 90 0C for 2-24h, depending on the desired 128.9, 128.8, 127.8, 127.3, 117.6, 115.4, 114.9, 67.0; m/z=225
product. On Completion of the reaction water was (checked by (M+H), positive mode; Anal. Calcd for C14H12N2O: C, 74.98; H,
thin layer chromatography technique) added to it. The mixture 5.39; N, 12.49%. Found: C, 74.82; H, 5.45; N, 12.56%.
was extracted with EtOAc, dried over Na2SO4 and evaporated
in vacuum. The residue was purified by column 2-Butylquinazolin-4(3H)-one (3d):
chromatography on silica gel using ethyl acetate/ hexane This compound was obtained as white solid; yield = (0.117 g/
mixture to afford the desired dihydroquinazolinone/ 0.100 g of 1a; 79%); m.p. = 110 oC; Rf = 0.36 (EtOAc: hexanes=
quinazolinone.
3:7); IR (KBr) 2919, 1682, 1616, 1467, 1261, 1130 cm-1; 1H NMR
(400 MHz, DMSO-d6 ) δ 12.02 (1H, s), 8.29 (1H, d, J = 8.0 Hz),
7.77 (1H, t, J = 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.47 (1H, t, J =
8.0 Hz), 2.81 (2H, t, J = 8.0 Hz), 1.92- 1.82 (2H, m), 1.51 (2H, q, J
2-(o-Tolyl)quinazolin-4(3H)-one (3a):
This compound was obtained as white solid; yield = (0.135 g/ = 7.4 Hz), 1.00 (3H, t, J = 8.0 Hz); 13C NMR (100 MHz, DMSO-d6)
0.100 g of 1a; 78%); m.p. = 232-234 oC; Rf = 0.45 (EtOAc: δ 164.4, 157.0, 149.5, 134.8, 127.2, 126.3, 126.2, 120.5, 35.7,
hexanes= 3:7); IR (KBr) 3057, 1670, 1601, 1469, 1286, 1264, 29.7, 22.4, 13.8; HRMS (ESI-MS) cald. for C12H14N2O (M+H)
1
765 cm-1; H NMR (400 MHz, CDCl3) δ 11.49 (1H, s, br), 8.34 203.1184, found 203.1187.
(1H, d, J = 7.6 Hz), 8.15 (2H, d, J = 8.0 Hz), 7.82 (2H, t, J = 8.0
Hz), 7.50 (1H, t, J = 8.0 Hz), 7.38 (2H, d, J = 2.0 Hz), 2.47 (3H, s); 2-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e’):
13C NMR (100 MHz, CDCl3) δ 164.1, 151.9, 149.6, 142.1, 134.8,
130.0, 129.7, 127.9, 127.4, 127.3, 126.5, 126.3, 120.8, 21.5; This compound was obtained as brown solid; yield = (0.082 g/
m/z=237 (M+H), positive mode; Anal. Calcd for C15H12N2O: C, 0.050 g of 1a; 83%); m.p. = 216 oC; Rf = 0.16 (EtOAc: hexanes=
76.25; H, 5.12; N, 11.86%. Found: C, 76.12; H, 5.18; N, 11.96%.
3:7); IR (KBr) 2920, 1731, 1682, 1616, 1468, 1200, 1145 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, s), 8.35 (1H, s), 8.19
(1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 7.2 Hz), 7.68 (1H, t, J = 8.0
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (3b):
This compound was obtained as white solid; yield = (0.135 g/ Hz), 7.61 (1H, d, J = 7.2 Hz), 7.34 (1H, s), 7.26 (1H, t, J = 7.2 Hz),
o
0.100 g of 1a; 73%); m.p. = 216 C; Rf = 0.24 (EtOAc: hexanes= 6.78 (1H, d, J = 8.0 Hz), 6.68 (1H, t, J = 7.2 Hz), 5.94 (1H, s); 13
C
3:7); IR (KBr) 1678, 1602, 1484, 1264, 834 cm-1;1H NMR (500 NMR (100 MHz, DMSO-d6) δ 163.8, 148.2, 147.8, 144.7, 134.1,
MHz, DMSO-d6) δ 12.39 (1H, s, br), 8.19 (2H, d, J = 8.5 Hz), 8.13 133.8, 130.5, 127.9, 123.7, 122.0, 118.0, 115.4, 115.1, 65.6;
(1H, d, J = 7.0 Hz), 7.81 (1H, t, J = 6.5 Hz), 7.70 (1H, d, J = 8.0 HRMS (ESI-MS) cald. for C14H11N3O3 (M+H) 270.0878, found
Hz), 7.48 (1H, t, J = 7.0 Hz), 7.09 (2H, d, J = 9.0 Hz), 3.85 (3H, s); 270.0874.
13C NMR (125 MHz, DMSO-d6) δ 162.7, 162.4, 152.3, 149.4,
134.9, 129.9, 127.7, 126.5, 126.3, 125.3, 121.2, 114.5, 55.9; 2-(Pyridin-2-yl)quinazolin-4(3H)-one (3f):
m/z=253 (M+H), positive mode; Anal. Calcd for C15H12N2O2: C,
71.42; H, 4.79; N, 11.10%. Found: C, 71.57; H, 4.71; N, 11.26%.
This compound was obtained as white crystalline solid; yield =
o
(0.061 g/ 0.050 g of 1a; 74%); m.p. = 166 C; Rf = 0.35 (EtOAc:
hexanes= 3:7); IR (KBr) 1684, 1607, 1472, 1331, 769 cm-1;1H
NMR (400 MHz, DMSO-d6) δ 11.82 (1H, s, br), 8.74 (1H, d, J =
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4.4 Hz), 8.43 (1H, d, J = 8.0 Hz), 8.17 (1H, d, J = 8.0 Hz), 8.06 (1H, d, J = 2.0 Hz), 5.70 (1H, s, br), 5.66 (1H, d, J = 11.2 Hz), 5.55
(1H, t, J = 8.0 Hz), 7.86 (1H, t, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 (1H, d, J = 11.6 Hz), 3.79 (3H, s), 3.31 (3H, s); 13C NMR (100
Hz), 7.65-7.62 (1H, m), 7.56 (1H, t, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 169.5, 151.2, 143.3, 142.7, 141.8,
MHz, DMSO-d6) δ 161.3, 150.3, 149.5, 149.0, 148.8, 138.5, 131.7, 127.8, 125.9, 125.4, 124.2, 122.8, 120.2, 118.3, 114.2,
135.2, 128.1, 127.8, 127.0, 126.5, 122.6, 122.4 ; m/z=224 108.9, 78.9, 66.3, 60.8, 60.4; m/z=338(M+H), positive mode;
(M+H), positive mode; Anal. Calcd for C13H9N3O: C, 69.95; H, Anal. Calcd for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46%.
4.06; N, 18.82%. Found: C, 69.86; H, 4.15; N, 18.75%.
Found: C, 67.49; H, 5.73; N, 12.38%.
2-(Pyridin-4-yl)quinazolin-4(3H)-one (3g):
2-(1H-Indol-2-yl)-7-methoxyquinazolin-4(3H)-one (3k):
This compound was obtained as white solid; yield = (0. 125g/ This compound was obtained as brown solid; yield = (0.065 g/
o
0.100 g of 1a; 76%); m.p. = >240 C; Rf = 0.2 (EtOAc: hexanes= 0.056 g of 1c; 67%); m.p. = 244-246 oC; Rf = 0.37 (EtOAc:
1:1); IR (KBr) 3358, 2964, 1682, 1561, 1468, 1260, 1030 cm-1; hexanes= 3:7); IR (KBr) 3484, 2898, 1654, 1600, 1315, 1145 cm-
1
1H NMR (500 MHz, DMSO-d6) δ 12.77 (1H, s), 8.79 (2H, d, J = 1; H NMR (400 MHz, DMSO-d6) δ 12.48 (1H, s), 11.77 (1H, s),
4.0 Hz), 8.18 (1H, d, J = 7.6 Hz), 8.12 (2H, d, J = 4.5 Hz), 7.88 8.06 (1H, t, J = 9.2 Hz), 7.63 (2H, d, J = 11.2 Hz), 7.51 (1H, d, J =
(1H, t, J = 7.5 Hz), 7.79 (1H, d, J = 7.9 Hz), 7.58 (1H, t, J = 7.2 8.4 Hz), 7.21 (1H, t, J = 8.4 Hz), 7.12 (1H, s), 7.09- 7.03 (2H, m),
Hz); 13C NMR (125 MHz, DMSO-d6) δ 162.5, 151.0, 150.7, 3.91 (3H, s); 13C NMR (100 MHz, DMSO-d6) δ 164.6, 161.8,
140.4, 135.3, 128.2, 127.9, 126.4, 122.0, 121.9; HRMS (ESI-MS) 151.4, 147.6, 138.1, 130.5, 128.2, 127.9, 124.5, 122.0, 120.4,
cald. for C13H9N3O (M+H) 224.0824, found 224.0820.
116.1, 115.0, 112.9, 108.6, 105.4, 56.1; HRMS (ESI-MS) cald.
for C17H13N3O2 (M+H) 292.1086, found 292.1086.
2-(2-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3h’):
2-(1H-Pyrrol-2-yl)quinazolin-4(3H)-one (3l):
This compound was obtained as light yellow solid; yield=
o
(0.180 g/ 0.100 g of 1a; 81%); m.p. = 188 C; Rf = 0.32 (EtOAc: This compound was obtained as brown powder; yield = (0.112
hexanes= 3:7); IR (KBr) 3220, 1656, 1612, 1486, 1249 cm-1;1H g/ 0.100 g of 1a; 72%); m.p. = > 240oC; Rf = 0.45 (EtOAc:
NMR (400 MHz, DMSO-d6) δ 8.21 (1H, s), 7.69- 7.65 (3H, m), hexanes= 3:7); IR (KBr) 2919, 1672, 1596, 1496, 1261, 765 cm-
7.44 (1H, t, J = 7.2 Hz), 7.32 (1H, t, J = 7.6 Hz), 7.27 (1H, t, J = 1;1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 11.70 (1H, s),
7.6 Hz), 7.00 (1H, s), 6.78 (1H, d, J = 8.4 Hz), 6.74 (1H, t, J = 7.6 8.08 (1H, d, J = 7.6 Hz), 7.77 (1H, t, J = 7.6 Hz), 7.62 (1H, d, J =
Hz), 6.11 (1H, s); 13C NMR (100 MHz, DMSO-d6) δ 164.2, 148.1, 8.0 Hz), 7.41 (1H, t, J = 7.2 Hz), 7.29 (1H, s), 7.05 (1H, s), 6.21
139.6, 133.9, 133.3, 131.2, 129.5, 128.5, 127.9, 122.6, 118.0, (1H, s) ; 13C NMR (100 MHz, DMSO-d6) δ 162.4, 149.7, 146.8,
115.1, 115.0, 66.8; HRMS (ESI-MS) cald. for C14H11BrN2O 135.0, 126.9, 126.4, 125.7, 124.7, 124.3, 120.9, 112.9, 110.2;
(M+Na) 324.9952, found 324.9959.
m/z=212 (M+H), positive mode; Anal. Calcd for C12H9N3O: C,
68.24; H, 4.29; N, 19.89%. Found: C, 68.15; H, 4.36; N, 19.78%.
2-(1-Benzyl-1H-indol-2-yl)-8-methoxy-2,3-dihydroquinazolin-
4(1H)-one (3i’):
2-(1H-Indol-2-yl)quinazolin-4(3H)-one (5):
This compound was obtained as yellowish brown solid; yield = This compound was obtained as yellow solid; yield = (0.154 g/
(0.230 g/ 0.108 g of 1b; 92%); m.p. = 198- 200 oC; Rf = 0.18 0.100 g of 1a; 81%); m.p. = 268 oC; Rf = 0.24 (EtOAc: hexanes=
1
(EtOAc: hexanes= 3:7); IR (KBr) 2920, 1671, 1610, 1457, 1249 1:1); IR (KBr) 3413, 1665, 1589, 1468, 1260, 772 cm-1; H NMR
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (1H, s), 7.52 (1H, d, J (400 MHz, DMSO-d6) δ 12.62 (1H, s), 11.81 (1H, s), 8.17 (1H, d,
= 7.6 Hz), 7.33- 7.28 (5H, m), 7.09- 6.94 (5H, m), 6.69 (1H, t, J = J = 8.0 Hz); 7.88- 7.85 (1H, m), 7.75 (1H, d, J = 8.0 Hz), 7.68 (1H,
7.6 Hz), 6.43 (1H, s, br), 6.39 (1H, s), 6.05 (1H, s), 5.65 (2H, s), s), 7.65 (1H, d, J = 8.0 Hz), 7.54 (2H, t, J = 7.2 Hz), 7.24 (1H, t, J
3.72 (3H, s); 13C NMR (100 MHz, DMSO-d6) δ 164.0, 146.9, = 8.4 Hz), 7.07 (1H, t, J = 7.2 Hz); 13C NMR (125 MHz, DMSO-d6)
140.5, 138.6, 137.8, 136.5, 129.0, 127.6, 127.0, 126.8, 122.2, δ 162.3, 149.2, 147.0, 138.1, 135.2, 130.5, 127.9, 127.4, 126.7,
120.9, 120.0, 119.3, 117.4, 116.0, 114.0, 110.8, 101.9, 60.1, 126.5, 124.5, 122.0, 121.6, 120.4, 112.9, 105.5; HRMS (ESI-MS)
56.0, 46.7:; HRMS (ESI-MS) cald. for C24H21N3O2 (M+H) cald. for C16H11N3O (M+H) 262.0980, found 262.0980.
384.1712, found 384.1706.
2-Methyl-2,3-dihydroquinazolin-4(1H)-one (7’):
8-Methoxy-2-(1-(methoxymethyl)-1H-indol-2-yl)-2,3-
dihydroquinazolin-4(1H)-one (3j’):
This compound was obtained as yellow solid; yield = (0.094g/
0.100 g of 1a; 79%); m.p. = 136 oC; Rf = 0.14 (EtOAc: hexanes=
This compound was obtained as brown solid; yield = (0.290 g/ 1:1); IR (KBr) 3266, 1668, 1615, 1257, 753 cm-1;1H NMR (400
0.200 g of 1b; 72%); m.p. = > 184oC; Rf = 0.37 (EtOAc: hexanes= MHz, DMSO-d6 ) δ 7.90 (1H, s), 7.59 (1H, d, J = 8.0 Hz), 7.23
3:7); IR (KBr) 3419, 1687, 1605, 1468, 1276, 761cm-1; H NMR (1H, t, J = 8.0 Hz), 6.68 (2H, d, J = 8.0 Hz), 6.60 (1H, s), 4.82 (1H,
1
(400 MHz, CDCl3 + DMSO-d6) δ 7.57 (1H, s, br), 7.52- 7.43(3H, q, J = 5.6 Hz), 1.31 (3H, d, J = 5.6 Hz); 13C NMR (100 MHz,
m), 7.22 (1H, t, J = 8.0 Hz), 7.09 (1H, t, J = 8.0 Hz), 6.85 (1H, dd, DMSO-d6) δ 164.6, 149.2, 133.6, 127.9, 117.6, 115.6, 114.8,
J = 1.2 Hz, J = 8.0 Hz), 6,74 (1H, t, J = 8.0 Hz), 6.63 (1H, s), 6.16
6 | J. Name., 2012, 00, 1-3
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61.3, 21.7; HRMS (ESI-MS) cald. for C9H10N2O (M+H) 163.0871, 1; H NMR (500 MHz, CDCl3+ DMSO-d6) δ 7.64 (1H, d, J = 8.0
found 163.0870.
Hz), 7.60 (1H, s, br), 7.43 (2H, d, J = 8.0 Hz), 7.17 (2H, t, J = 8.0
Hz), 7.14- 7.08 (2H, m), 6.64 (1H, d, J = 8.0 Hz), 6.59 (1H, t, J =
8.0 Hz), 5.98 (1H, s, br), 1.72 (3H, s) ; 13C NMR (100 MHz,
CDCl3+ DMSO-d6) δ 164.8,146.4, 146.0, 133.7, 128.2, 128.0,
2-Methylquinazolin-4(3H)-one (7):
Compound 7’ (0.050g, 0.308 mmol) was taken in to an oven 127.6, 125.2, 118.1, 115.2, 114.7, 70.7, 30.3; HRMS (ESI-MS)
dried round bottom flask, dry DCM (5mL), DDQ (0.350g, 1.54 cald. for C15H14N2O (M+Na) 261.1004, found 261.1003.
mmol) was added and stirred at rt for 30 mins. After
completion of the (checked by TLC) reaction, reaction mixture 1'H-Spiro[cyclohexane-1,2'-quinazolin]-4'(3'H)-one (8d):
was extracted with DCM, dried over Na2SO4 and evaporated in
vacuum. The residue was purified by column chromatography This compound was obtained as yellow crystalline solid; yield =
on silica gel (EtOAc: hexane) to afford a desired product (
This compound was obtained as yellowish brown crystalline; (EtOAc: hexanes= 3:7); IR (KBr) 3169, 2922, 2852, 1642, 1606,
7
). (0.131g/ 0.100g of 1a; 83%); m.p. = 212-214 oC; Rf = 0.13
o
1
yield = (0.042 g/ 0.050 g of 7’; 85%); m.p. = 228 C; Rf = 0.21 1479, 1267 cm-1; H NMR (400 MHz, CDCl3+ DMSO-d6) δ 7.62-
(EtOAc: hexanes= 1:1); IR (KBr) 2915, 1693, 1665, 1610, 1468, 7.58 (1H, m), 7.06 (1H, d, J = 6.8 Hz), 6.89 (1H, s), 6.55- 6.52
1254 cm-1;1H NMR (400 MHz, CDCl3) δ 11.81 (1H, s, br), 8.29 (2H, m), 5.21 (1H, s, br), 1.63 (4H, s), 1.41 (4H, s), 1.26 (2H, s);
(1H, d, J = 8.0 Hz), 7.78 (1H, t, J = 8.0 Hz), 7.69 (1H, d, J = 8.0 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 164.3, 146.2, 133.5,
Hz), 7.48 (1H, t, J = 8.0 Hz), 2.60 (3H, s); 13C NMR (100 MHz, 127.8, 117.7, 114.7, 68.2, 37.4, 24.6, 21.6; m/z=217 (M+H),
CDCl3) δ 164.2, 153.2, 149.4, 134.9, 127.0, 126.4, 126.2, 120.3, positive mode. Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N,
22.1; HRMS (ESI-MS) cald. for C9H8N2O (M+H) 161.0715, found 12.95%.Found: C, 72.25; H, 7.41; N, 13.07%.
161.0710;We followed the same procedure for compound
12a- 12f
.
1'H-Spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione (8e):
This compound was obtained as yellow solid; yield = (0.121g/
o
0.100g of 1a; 62%); m.p. = 214 C; Rf = 0.15 (EtOAc: hexanes=
1:1); IR (KBr) 1726, 1659, 1609, 1585, 1264 cm-1;1H NMR (400
2,2-Dimethyl-2,3-dihydroquinazolin-4(1H)-one (8a):
This compound was obtained as white solid; yield = (0.123g/ MHz, DMSO-d6) δ 10.31 (1H, s), 8.36 (1H, s), 7.61 (1H, d, J = 7.2
0.100 g of 1a; 95%); m.p. = 176-178 oC; Rf = 0.25 (EtOAc: Hz), 7.48 (1H, d, J = 7.2 Hz), 7.34 (1H, t, J = 7.6 Hz), 7.28 (1H, s),
hexanes= 1:1); IR (KBr) 3255, 1632, 1485, 1270, 1175, 750 cm- 7.24 (1H, t, J = 8.0 Hz), 7.07 (1H, t , J = 7.6 Hz), 6.87 (1H, d, J =
1;1H NMR (400 MHz, CDCl3) δ 7.89 (1H, d, J = 7.2 Hz), 7.31 (1H, 7.6 Hz), 6.69 (1H, t, J = 7.6 Hz), 6.62 (1H, d, J = 7.6 Hz); 13C NMR
t, J = 8.0 Hz), 7.05 (1H, s, br), 6.83 (1H, t, J = 7.2 Hz), 6.64 (1H, (100 MHz, DMSO-d6) δ 176.5, 164.5, 147.3, 142.5, 133.8,
d, J = 7.6 Hz), 4.25 (1H, s, br), 1.58 (6H, s) ; 13C NMR (100 MHz, 131.3, 129.8, 127.3, 125.8, 122.8, 117.7, 114.7, 114.3, 110.6,
CDCl3) δ 164.7, 146.0, 133.9, 128.3, 118.7, 114.7, 114.6, 67.6, 71.4; m/z=266(M+H), positive mode; Anal. Calcd for
29.6; m/z=177(M+H), positive mode. Anal. Calcd for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84%.Found: C, 67.85; H,
C10H12N2O: C, 68.16; H, 6.86; N, 15.90%. Found: C, 68.26; H, 4.12; N, 15.76%.
6.81; N, 15.82%.
2, 2-Diphenyl-2,3-dihydroquinazolin-4(1H)-one (8f):
2-Ethyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one (8b):
This compound was obtained as yellowish white solid; yield =
o
This compound was obtained as yellowish brown solid; yield = (0.165g/ 0.100g of 1a; 75%); m.p. = 140 C; Rf = 0.26 (EtOAc:
(0.137g/ 0.100 g of 1a; 98%); m.p. = 164-166 oC; Rf = 0.18 hexanes= 3:7); IR (KBr) 3375, 3243, 1649, 1610, 1484, 1375,
(EtOAc: hexanes= 1:1); IR (KBr) 3270, 1638, 1612, 1266, 754 1210, 750 cm-1;1H NMR (500 MHz, CDCl3) δ 7.81 (1H, d, J = 7.6
cm-1;1H NMR (500 MHz, CDCl3) δ 7.88 (1H, d, J = 7.5 Hz), 7.31 Hz), 7.43- 7.40 (4H, m), 7.34- 7.27 (7H, m), 6.78 (1H, t, J = 7.6
(1H, d, J = 8.5 Hz), 6.82 (1H, t, J = 7.0 Hz), 6.62 (1H, d, J = 8.0 Hz), 6.73 (2H, d, J = 8.0 Hz), 5.36 (1H, s, br); 13C NMR (125 MHz,
Hz), 6.17 (1H, s, br), 4.13 (1H, s, br), 1.82 (2H, q, J = 7.4 Hz), CDCl3) δ 164.3, 145.6, 143.7, 134.2, 128.6, 128.5, 127.3, 119.2,
1.51 (3H, s), 1.01 (3H, t, J = 7.4 Hz) ; 13C NMR (100 MHz, CDCl3) 115.4, 114.9, 76.0; HRMS (ESI-MS) cald. for C20H16N2O (M+Na)
δ 165.1, 146.1, 134.1, 128.3, 118.4, 114.5, 114.2, 70.1, 34.8, 323.1160, found 323.1163.
27.5, 8.2; m/z=191(M+H), positive mode. Anal. Calcd for
C11H14N2O: C, 69.45; H, 7.42; N, 14.73%. Found: C, 69.56; H, Compound 9a- 9e:
7.35; N, 14.62%.
These compounds were prepared via adopting method from
reference 44.
2-Methyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (8c):
This compound was obtained as light yellow solid; yield =
o
(0.141g/ 0.100g of 1a; 81%); m.p. = 220 C; Rf = 0.13 (EtOAc:
hexanes= 3:7); IR (KBr) 3402, 1665, 1610, 1501, 1380, 1265 cm- 2-Amino-N-(o-tolyl)benzamide (10a):
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Compound 9a (0.500, 2.2 mmol) was dissolved in THF-H2O This compound was obtained as yellowish white solid; yield =
o
solution (5:1, 20 mL).To this solution NH4Cl (0.353 g, 6.6 mmol) (0.212g/ 0.500g of 9e; 47%); m.p. = 112 C; Rf = 0.65 (EtOAc:
1
and Zn dust (1.15 g, 17.6 mmol) was added. The reaction was hexanes= 3:7); H NMR (400 MHz, CDCl3) δ 11.84 (1H, s, br),
stirred at rt for 5-6 h. After the completion of the reaction, 8.85 (1H, dd, J = 0.8 Hz, J = 8.8 Hz), 8.10 (1H, dd, J = 1.6 Hz, J =
reaction mixture was filtered and extracted with ethyl acetate 8.0 Hz), 7.76 (1H, dd, J = 1.2 Hz, J = 8.0 Hz), 7.61 (1H, t, J = 7.2
and evaporated to dryness. The residue was purified by Hz), 7.29 (1H, t, J = 8.4 Hz), 7.13 (1H, t, J = 8.0 Hz), 6.80 (1H, t, J
column chromatography on silica gel to give compound 10a
We followed the same procedure for preparation of 4.00 (3H, s) ; 13C NMR (100 MHz, CDCl3) δ 169.0, 168.2, 149.8,
compound 10b- 10e This compound was obtained as 141.9, 134.6, 132.9, 131.0, 127.7, 122.3, 120.5, 117.5, 116.9,
yellowish white solid; yield = (0.380g/ 0.500g of 10a; 86%); 115.7, 115.3, 52.5; HRMS (ESI-MS) cald. for C15H14N2O3 (M+Na)
.
= 8.0 Hz), 6.74 (1H, dd, J = 0.8 Hz, J = 8.4 Hz), 5.80 (2H, s, br),
.
o
1
m.p. = 104 C; Rf = 0.55 (EtOAc: hexanes= 3:7); H NMR (400 293.0902, found 293.0907.
MHz, CDCl3) δ 7.84 (1H, d, J = 8.0 Hz), 7.66 (1H, s, br), 7.53 (1H,
d, J = 8.0 Hz), 7.31- 7.26 (3H, m), 7.15 (1H, t, J = 7.2 Hz), 6.76 2-Methyl-3-(o-tolyl)-2,3-dihydroquinazolin-4(1H)-one (11a):
(2H, d, J = 8.0 Hz), 5.56 (2H, s, br), 2.35 (3H, s); 13C NMR (100
MHz, CDCl3) δ 167.6, 149.2, 135.7, 132.8, 130.6, 130.0, 127.2, It is probably the steric reason for that these compounds exists
126.8, 125.5, 123.7, 117.6, 116.8, 116.1, 17.9; HRMS (ESI-MS) as rotamers, the ratio of both isomer is variable depending on
cald. for C14H14N2O (M+Na) 249.1004, found 249.1008.
the substitution (11a, 11b, 11c, 11e). This compound (11a) was
obtained as white crystalline solid; yield = (0.097g/ 0.100g of
10a; 87%); m.p. = 176-178 oC; Rf = 0.42 (EtOAc: hexanes= 3:7);
IR (KBr) 3296, 1632, 1612, 1506, 1326, 1263, 758 cm-1; 1H NMR
2-Amino-N-(2-chlorophenyl)benzamide (10b):
This compound was obtained as yellowish white solid; yield = (400 MHz, DMSO-d6) δ 7.68 (2H, t, J = 6.4 Hz), 7.33 (4H, t, J =
o
(0.345g/ 0.500g of 9b; 77%); m.p. = 108 C; Rf = 0.65 (EtOAc: 6.8 Hz), 7.28- 7.24 (5H, m), 7.19 (1H, d, J = 6.8 Hz), 6.93 (2H, d,
1
hexanes= 3:7); H NMR (400 MHz, CDCl3) δ 8.48 (1H, d, J = 8.4 J = 8.8 Hz), 6.80 (2H, d, J = 8.0 Hz), 6.75 (2H, t, J = 7.6 Hz), 5.33
Hz), 8.37 (1H, s, br), 7.57 (1H, d, J = 7.6 Hz), 7.44 (1H, d, J = 8.0 (1H, q, J = 5.6 Hz), 4.97 (1H, q, J = 5.6 Hz), 2.22 (3H, s), 2.17
Hz), 7.37- 7.29 (2H, m), 7.10 (1H, t, J = 8.0 Hz), 6.77 (2H, t, J = (3H, s), 1.28 (3H, d, J = 5.6 Hz), 1.13 (3H, d, J = 5.6 Hz); 13C NMR
7.6 Hz), 5.63 (2H, s, br) ; 13C NMR (100 MHz, CDCl3) δ 167.3, (100 MHz, DMSO-d6) δ 162.5, 162.2, 148.5, 147.9, 139.43,
149.4, 134.8, 133.1, 129.1, 127.7, 127.2, 124.6, 123.4, 121.7, 139.38, 137.3, 136.0, 133.91, 133.86, 131.3, 130.8, 130.6,
117.7, 116.9, 115.6; HRMS (ESI-MS) cald. for C13H11ClN2O 128.5, 128.4, 128.3, 128.2, 127.9, 127.3, 126.8, 118.0, 117.9,
(M+H) 247.0638, found 247.0636.
115.9, 115.5, 115.3, 114.9, 67.9, 67.1, 20.5, 18.6, 17.9;
m/z=253(M+H), positive mode. Anal. Calcd for C16H16N2O: C,
76.16; H, 6.39; N, 11.10%.Found: C, 76.31; H, 6.31; N, 11.18%.
2-Amino-N-(2-bromophenyl)benzamide (10c):
This compound was obtained as yellowish white solid; yield = 3-(2-Chlorophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-
o
(0.375g/ 0.500g of 9c; 82%); m.p. = 102 C; Rf = 0.65 (EtOAc: one (11b):
hexanes= 3:7); 1H NMR (400 MHz, CDCl3) δ 8.47 (1H, dd, J = 1.6
Hz, J = 8.4 Hz), 8.37 (1H, s, br), 7.60 (2H, t, J = 7.6 Hz), 7.39 (1H, This compound was obtained as brown solid; yield = (0.100g/
t, J = 7.6 Hz), 7.33- 7.29 (1H, m), 7.03 (1H, dt, J = 1.2 Hz, J = 7.6 0.100g of 10b; 91%); m.p. = 162 oC; Rf = 0.27 (EtOAc: hexanes=
Hz), 6.77 (2H, t, J = 8.0 Hz), 5.65 (2H, s, br); 13C NMR (100 MHz, 3:7); IR (KBr) 3057, 2915, 1687, 1605, 1468, 1342, 1282, 1068
CDCl3) δ 169.3, 149.5, 135.9, 133.1, 132.3, 128.4, 127.2, 125.1, cm-1; 1H NMR (400 MHz, CDCl3) δ 8.00 (1H, d, J = 8.0 Hz), 7.54-
122.0, 117.7, 117.0, 115.5, 114.1; HRMS (ESI-MS) cald. for 7.51 (1H, m), 7.41- 7.31 (4H, m), 6.92 (1H, t, J = 7.6 Hz), 6.74
C13H11BrN2O (M+H) 291.0133, found 291.0139.
(1H, d, J = 8.0 Hz), 5.31 (1H, q, J = 5.2 Hz), 4.59- 4.54 (1H, m),
1.38- 1.34 (3H, m); 13C NMR (100 MHz, CDCl3) δ 163.2, 162.7,
146.6, 146.5, 136.8, 134.5, 133.7, 132.9, 132.3, 130.4, 130.3,
129.9, 129.3, 129.2, 127.9, 127.5, 119.6, 116.6, 115.3, 115.1,
68.4, 66.6, 20.5; m/z=272 (M+), positive mode. Anal. Calcd for
2-Amino-N-phenylbenzamide (10d):
This compound was obtained as yellowish white solid; yield = C15H13ClN2O: C, 66.06; H, 4.80; N, 10.27%.Found: C, 66.15; H,
o
(0.370g/ 0.500g of 9d; 84%); m.p. = 118 C; Rf = 0.55 (EtOAc: 4.73; N, 10.36%.
hexanes= 3:7); 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, s, br),
7.59 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.39 (2H, t, J = 3-(2-Bromophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-
7.6 Hz), 7.28 (1H, t, J = 7.6 Hz), 7.17 (1H, t, J = 7.2 Hz), 6.74 (2H, one (11c):
d, J = 7.6 Hz), 5.51 (2H, s, br); 13C NMR (100 MHz, CDCl3) δ
167.6, 148.9, 137.8, 132.7, 129.1, 127.2, 124.5, 120.6, 117.6, This compound was obtained as brown solid; yield = (0.087g/
116.8, 116.3; HRMS (ESI-MS) cald. for C13H12N2O (M+H) 0.086g of 10c; 93%); m.p. = 120 oC; Rf = 0.31 (EtOAc: hexanes=
213.1028, found 213.1026.
3:7); IR (KBr) 3088, 2349, 1679, 1601, 1567, 1469, 1275, 757
cm-1;1H NMR (400 MHz, CDCl3) δ 8.00 (1.2H, dd, J = 0.8 Hz, J =
7.6 Hz), 7.73- 7.69 (1.2H, m), 7.43- 7.31 (3.6H, m), 7.27- 7.22
Methyl 2-(2-aminobenzamido)benzoate (10e):
8 | J. Name., 2012, 00, 1-3
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(1.2H, m), 6.94- 6.90 (1.33H, m), 6.75- 6.72 (1.29H, m), 5.32 This compound was obtained as yellow solid; yield = (0.044g/
(1.4H, q, J = 6.0 Hz),4.62- 4.57 (1.36H, m), 1.37- 1.35 (3.6H, m); 0.050g of 11a; 89%); m.p. = 112 oC; Rf = 0.12 (EtOAc: hexanes=
13C NMR (100 MHz, CDCl3) δ 163.0, 162.9, 146.8, 146.5, 139.1, 3:7); IR (KBr) 2920, 1678, 1608, 1270, 771 cm-1;1H NMR (400
138.5, 133.75, 133.69, 133.6, 132.4, 129.9, 129.5, 129.3, MHz, CDCl3) δ 8.18 (1H, d, J = 8.0 Hz), 7.66 (1H, t, J = 8.0 Hz),
129.27, 129.2, 128.6, 128.2, 125.1, 123.2, 119.6, 116.9, 116.6, 7.59 (1H, d, J = 8.0 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.30- 7.23 (3H,
115.4, 115.1, 68.2, 66.7, 20.45, 20.42 ; HRMS (ESI-MS) cald. for m), 7.05 (1H, d, J = 7.2 Hz), 2.08 (3H, s), 2.02 (3H, s); 13C NMR
C15H1379BrN2O
C15H1381BrN2O (M+Na) 341.0088, found 341.0099.
(M+Na)
339.0109,
found
339.0114; (100 MHz, CDCl3) δ 161.0, 153.7, 147.0, 136.2, 134.7, 134.0,
130.9, 128.9, 127.3, 127.0, 126.5, 126.2, 126.0, 120.1, 23.3,
16.8; HRMS (ESI-MS) cald. for C16H14N2O (M+H) 251.1184,
2-Methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (11d):
found 251.1181.
This compound was obtained as yellow solid; yield = (0.108g/ Mecloqualone (12b):
0.100g of 10d; 96%); m.p. = 168 oC; Rf = 0.26 (EtOAc: hexanes=
3:7); IR (KBr) 3299, 1634, 1612, 1495, 1263 cm-1;1H NMR (400 This compound was obtained as yellow solid; yield = (0.058g/
MHz, CDCl3) δ 8.00 (1H, d, J = 8.0 Hz), 7.44 (2H, t, J = 8.0 Hz), 0.075g of 11b; 78%); m.p. = 98-100 oC; Rf = 0.30 (EtOAc:
7.36- 7.29 (4H, m), 6,90 (1H, t, J = 7.6 Hz), 6.70 (1H, d, J = 8.0 hexanes= 3:7); IR (KBr) 2917, 1686, 1607, 1472, 1280 cm-1;1H
Hz), 5.23 (1H, q, J = 6.0 Hz), 4.61 (1H, s, br), 1.42 (3H, d, J = 6.0 NMR (400 MHz, CDCl3) δ 8.31 (1H, dd, J = 1.2 Hz, J = 8.0 Hz),
Hz); 13C NMR (100 MHz, CDCl3 + DMSO- d6) δ 162.9, 145.9, 7.83- 7.79 (1H, m), 7.72 (1H, d, J = 8.0 Hz), 7.66- 7.62 (1H, m),
140.2, 133.7, 129.3, 129.1, 127.8, 127.3, 119.4, 116.7, 115.1, 7.52- 7.47 (3H, m), 7.38- 7.35 (1H, m), 2.25 (3H, s); 13C NMR
68.5, 20.9; m/z=239 (M+H), positive mode. Anal. Calcd for (100 MHz, CDCl3) δ 161.5, 153.7, 147.5, 135.5, 134.8, 132.6,
C15H14N2O: C, 75.61; H, 5.92; N, 11.76%.Found: C, 75.52; H, 130.85, 130.81, 129.9, 128.4, 127.2, 126.9, 126.8, 120.6, 23.6;
6.07; N, 11.65%.
m/z=271 (M+H), positive mode. Anal. Calcd for C15H11ClN2O: C,
66.45; H, 4.10; N, 10.35%.Found: C, 66.42; H, 4.18; N, 10.26%.
Methyl
2-(2-methyl-4-oxo-1,2-dihydroquinazolin-3(4H)-
yl)benzoate (11e):
Mebroqualone (12c):
This compound was obtained as white solid and is unstable in This compound was obtained as white solid; yield = (0.040g/
NMR solvent media (CDCl3/ DMSO-d6), thus after several 0.050g of 11c; 81%); m.p. = 144 oC; Rf = 0.36 (EtOAc: hexanes=
efforts also we were unable to get a very clear 13C spectra. 3:7); IR (KBr) 1685, 1605, 1341, 1282, 774 cm-1;1H NMR (400
o
yield = (0.033g/ 0.050g of 10e; 61%); m.p. = 158 C; Rf = 0.18 MHz, CDCl3) δ 8.31 (2H, d, J = 7.6 Hz), 7.81 (1H, t, J = 8.0 Hz),
(EtOAc: hexanes= 3:7); IR (KBr) 3304, 2958, 2920, 1726, 1649, 7.72 (1H, d, J = 7.6 Hz), 7.57- 7.49 (2H, m), 7.42 (1H, t, J = 8.0
1523, 1260, 958 cm-1;1H NMR (400 MHz, CDCl3) δ 8.04 (1H, s, Hz), 7.38 (1H, d, J = 8.0 Hz), 2.25 (3H, s); 13C NMR (100 MHz,
br), 7.98 (1H, d, J = 7.6 Hz), 7.61 (1H, t, J = 7.6 Hz), 7.45 (1H, t, J CDCl3) δ 161.4, 153.6, 147.6, 137.2, 134.8, 134.0, 130.9, 129.9,
= 6.8 Hz), 7.36 (2H, d, J = 6.8 Hz), 6.93 (1H, t, J = 7.6 Hz), 6.76 129.1, 127.2, 126.9, 126.7, 122.9, 120.6, 23.7; HRMS (ESI-MS)
(1H, d, J = 8.0 Hz), 5.41 (1H, d, J = 5.2 Hz), 4.51 (1H, s, br), 3.83 cald. for C15H1179BrN2O (M+H) 315.0133, found 315.0128;
(3H, s), 1.3 (3H, s); 13C NMR (125 MHz, CDCl3) δ 166.0, 163.8, C15H1181BrN2O (M+H) 317.0113, found 317.0109.
146.5, 139.2, 134.6, 133.5, 132.9, 132.3, 132.1, 131.5, 131.0,
129.1, 128.0, 127.7, 122.4, 120.5, 119.8, 117.5, 115.7, 67.7,
52.3, 20.6; HRMS (ESI-MS) cald. for C17H16N2O3 (M+Na)
319.1059, found 319.1065.
2-Methyl-3-phenylquinazolin-4(3H)-one (12d):
2-(4-Methoxyphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-
This compound was obtained as brown solid; yield = (0.042g/
0.050g of 11d; 85%); m.p. = 130-132 oC; Rf = 0.29 (EtOAc:
hexanes= 3:7); IR (KBr) 1682,1607, 1342, 1274, 769 cm-1; 1H
one (11f):
This compound was obtained as white solid; yield = (0.130g/ NMR (500 MHz, CDCl3) δ 8.28 (1H, dd, J = 1.0 Hz, J = 7.5 Hz),
0.100g of 10d; 84%); m.p. = 194-196 oC; Rf = 0.35 (EtOAc: 7.79- 7.76 (1H, m), 7.70 (1H, d, J = 8.0 Hz), 7.59-7.51 (3H, m),
hexanes= 3:7); IR (KBr) 3294, 1631, 1610, 1507, 1249, 1160, 7.49- 7.46 (1H, m), 7.29- 7.27 (2H, m), 2.26 (3H, s); 13C NMR
747 cm-1;1H NMR (400 MHz, CDCl3) δ 8.05 (1H, t, J = 7.2 Hz), (125 MHz, CDCl3) δ 162.3, 154.3, 147.4, 137.8, 134.6, 130.0,
7.33- 7.29 (5H, m), 7.22- 7.19 (3H, m), 6.91 (1H, t, J = 7.2 Hz), 129.3, 128.0, 127.1, 126.75, 126.7, 120.8, 24.4; HRMS (ESI-MS)
6,79 (2H, d, J = 7.6 Hz), 6.65 (1H, d, J = 8.0 Hz), 6.09 (1H, s), cald. for C15H12N2O (M+Na) 259.0848, found 259.0846.
4.77 (1H, s), 3.77 (3H, s); 13C NMR (100 MHz, CDCl3) δ 163.2,
159.9, 145.5, 140.6, 133.8, 131.9, 129.1, 128.9, 128.2, 127.1, Methyl 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)benzoate (12e):
126.8, 119.5, 116.9, 114.8, 113.9, 74.3, 55.2; m/z=331 (M+H),
positive mode. Anal. Calcd for C21H18N2O2: C, 76.34; H, 5.49; N, This compound was obtained as yellow solid; yield = (0.041g/
8.48%.Found: C, 76.25; H, 5.41; N, 8.56%.
0.050g of 11e; 84%); m.p. = 136 oC; Rf = 0.14 (EtOAc: hexanes=
3:7); IR (KBr) 3052, 2964, 1600, 1419, 1260, 1095 cm-1;1H NMR
(400 MHz, DMSO-d6) δ 8.20 (1H, d, J = 8.0 Hz), 8.12 (1H, d, J =
Methaqualone (12a):
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Org. Synth., 2012,
9
,
17-30. e) T. Kitanosonoa and S.
7.6 Hz), 7.91 (2H, t, J = 8.0 Hz), 7.78- 7.73 (2H, m), 7.68 (1H, d, J
= 7.6 Hz), 7.57 (1H, t, J = 8.0 Hz), 3.70 (3H, s), 2.15 (3H, s); 13C
NMR (100 MHz, DMSO-d6) δ 164.4, 161.3, 154.1, 147.3, 137.7,
134.6, 134.3, 131.3, 130.4, 129.7, 127.3, 126.6, 126.3, 126.2,
120.2, 52.3, 23.6; HRMS (ESI-MS) cald. for C17H14N2O3 (M+Na)
317.0902, found 317.0899.
Kobayashi, Adv. Synth. Catal., 2013, 355, 3095–3118.
a) F. V. Rantwijk and R. A. Sheldon, Chem. Rev., 2007, 107
2757-2785. b) R. Giernoth, Angew. Chem. Int. Ed., 2010, 49
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Plaquevent, Y. G. Nisson, J. Rodriguez and T. Constantieux,
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Génissona and C. R. D. Correia, Curr. Org. Chem., 2013, 17
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238-256. e) M. Smiglak, J. M. Pringle, X. Lu, L. Han, S. Zhang,
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2-(4-Methoxyphenyl)-3-phenylquinazolin-4(3H)-one (12f):
This compound was obtained as white solid; yield = (0.069g/
0.050g of 11d; 87%); m.p. = 146 oC; Rf = 0.33 (EtOAc: hexanes=
1
3:7); IR (KBr) 1682, 1606, 1512, 1252, 774 cm-1; H NMR (400
5
6
a) R. Noyori, Chem. Commun., 2005, 1807-1811. b) R. Skouta,
Green Chem. Lett. Rev., 2009, 2, 121-156. c) R. Sui and P.
MHz, CDCl3) δ 8.37 (1H, d, J = 7.6 Hz), 7.84 (2H, s), 7.56- 7.54
(1H, m), 7.39- 7.29 (5H, m), 7.19 (2H, d, J = 7.2 Hz), 6.74 (2H, d,
J = 8.4 Hz), 3.78 (3H, s); 13C NMR (100 MHz, CDCl3) δ 162.5,
160.3, 154.9, 147.6, 137.9, 134.7, 130.8, 129.1, 129.0, 128.3,
127.8, 127.6, 127.2, 127.0, 120.8, 113.4, 55.2; m/z=329 (M+H),
positive mode; Anal. Calcd for C21H16N2O2: C, 76.81; H, 4.91; N,
8.53%.Found: C, 76.95; H, 5.07; N, 8.45%.
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Journal Name
Graphical Abstract:
O
O
O
N
O
R
R
Synthesis of
R
N
N
H/R2 R1
N
quinazolinone based
natural products &
drugs
H
NH2
N
H
R1
DES
R1
open air
R1= aromatic, aliphatic, heterocyles
R2= aromatic, aliphatic; R= aromatic
> Environment benign protocol
> H igh substrate scope, 31 example
> 3 total & 4 f ormal synthesis
12 | J. Name., 2012, 00, 1-3
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