Cyanuric chloride catalyzed mild protocol for synthesis of biologically active dihydro/spiro quinazolinones and quinazolinone-glycoconjugates

Article abstract of DOI:10.1021/jo2020856

We have developed an efficient cyanuric chloride (2,4,6-trichloro-1,3,5- triazine, TCT) catalyzed approach for the synthesis of 2,3-dihydroquinazolin- 4(1H)-one (3a-3x), 2-spiroquinazolinone (5, 7), and glycoconjugates of 2,3-dihydroquinazolin-4(1H)-one (10a, 10b) derivatives. The reaction allows rapid cyclization (8-20 min) with 10 mol % cyanuric chloride to give skeletal complexity in good to excellent yield. We believe that this novel procedure may open the door for the easy generation of new and bioactive quinazolinones.

Full text of DOI:10.1021/jo2020856

Article
pubs.acs.org/joc
Cyanuric Chloride Catalyzed Mild Protocol for Synthesis of
Biologically Active Dihydro/Spiro Quinazolinones and
Quinazolinone-glycoconjugates
Moni Sharma,† Shashi Pandey,† Kuldeep Chauhan,† Deepty Sharma,‡ Brijesh Kumar,‡
and Prem M. S. Chauhan*,†
‡
†Division of Medicinal and Process Chemistry and Sophisticated Analytical Instrumentation Facility,
CSIR-Central Drug Research Institute, Lucknow 226001, India
S
* Supporting Information
ABSTRACT: We have developed an efficient cyanuric chloride
(2,4,6-trichloro-1,3,5-triazine, TCT) catalyzed approach for
the synthesis of 2,3-dihydroquinazolin-4(1H)-one (3a−3x),
2-spiroquinazolinone (5, 7), and glycoconjugates of 2,3-dihydro-
quinazolin-4(1H)-one (10a, 10b) derivatives. The reaction
allows rapid cyclization (8−20 min) with 10 mol % cyanuric
chloride to give skeletal complexity in good to excellent yield. We
believe that this novel procedure may open the door for the easy
generation of new and bioactive quinazolinones.
markers in certain cancer, and as ligands for proteins.22−24
Furthermore, cancer cells display an array of tumor-associated
antigens, many of which are based on a carbohydrate
skeleton.25 In recent years a composite picture of the biological
role of O-aryl glycosides has emerged, with antitumor, anti-
HIV, antibiotic, and antidiabetic activities.26,27 Moreover,
carbohydrate linked heterocyclic moieties are often proved to
be an expedient entry for biological activity and can thus greatly
influence the pharmacokinetics, drug targeting, and mechanism
of action. In this context, several carbohydrate coupled
heterocycles are also reported with excellent biological
properties.28−30 Thus, aiming to modulate the glycoside residue
diversity preserving the potency of parent molecule, synthesis
of the glycoconjugate of quinazolinone is obvious.
INTRODUCTION
■
In the community of fused heterocycles, 2,3-dihydroquinazolin-
4(1H)-one and 2-spiroquinazolinone are omnipresent and have
been referred to as “core structures” in drug discovery. These
quinazolinones displayed wide range of biological activities as
antitumor,1,2 antidefibrillatory,3 antidepressant,4 analgesic,5 diu-
retic,6 antihistamine,7 vasodilating agent,8 antihypertensive,9 CNS
stimulant,10 tranquilizer11 and antianxietic (Figure 1).12 Moreover
Most of the synthetic protocols for quinazolinone31−39 and
spiroquinazolinone40−42 reported so far suffer from harsh reaction
conditions,33 prolonged time period,34 use of hazardous acid
catalysts,40 high catalyst loading,36 and expensive methods,38 and
therefore yields are oftentimes low due to poor selectivity in such
conditions. Several nonacidic transition metal catalyzed,36,39 nano-
particle catalyzed,43 and ionic liquid mediated44 syntheses of these
molecules have also been reported. Despite the advances in syn-
thetic methodologies, the synthesis of quinazolinone-glycoconjugate
still has not been achieved. Therefore development of a new
catalytic route toward this direction is an active area of research.
Inexpensive and readily available catalysts that bring about
organic transformations in operationally simple ways are always
an attractive approach for an organic as well as for a medicinal
chemist, and such methodology for the selective and mild
Figure 1. Biologically active quinazolinone and quinazolinone based
natural product.
these quinazolinones also have plant growth regulator13 abilities.
On the other hand corresponding quinazolin-4(3H)-one are also
important building blocks in natural products (Rutaecarpine,
Figure 1) and compounds of pharmacological interest.14−20
Among the major classes of biomolecules carbohydrates
exhibit unlimited structural variability and thus offer potential
as a major probe in drug discovery.21 Carbohydrates are involve
in various physiological processes including cell-biomolecule
interactions, masking of receptors by cell surface glycans,
Received: October 12, 2011
Published: December 19, 2011
© 2011 American Chemical Society
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synthesis of 2,3-dihydroquinazolin-4(1H)-one, spiroquinazolinone,
and corresponding quinazolinone glycoconjugates is still not
explored. Careful tuning of catalysts in a synchronized manner
can lead to new synthetic transformations possessing significant
chemoselectivity in functionally complex systems. To exemplify this
concept, we first dwell on the use of cyanuric chloride as a catalyst in
organic transformations following our interest of its use in medicinal
chemistry.45−50 Moreover, the significance of cyanuric chloride as
catalyst revealed that its treatment with alcohols and acids furnishes
the corresponding alkyl halides51 and activated cyanurate esters.
These cyanurate esters undergo nucleophilic substitution and
produce acyl chlorides,52 amide,53 peptide,54 acyl azide,55 sulphonyl
chloride,56 thiiranes,57 diazoketones,58 homoallylic alcohols,59 and
alcohols.60 Cyanuric chloride and DMF adduct is used in the
Beckman rearrangement61 and formyl protection of the primary
hydroxyl group,62 and the cyanuric chloride/DMSO adduct is used
in classical Swern oxidation.63 Syntheses of some important
heterocycles as xanthen derivatives64 and polysubstituted quino-
lines65 are also reported to be catalyzed by cyanuric chloride. Very
recently, a mild and general method for preparation of glycosyl
chloride using cyanuric chloride was also reported.66 Here, we
describe an innovative one-pot highly selective synthesis of
quinazolinones catalyzed by cyanuric chloride. The reaction takes
place through a cascade comprising (a) a novel and mild cyanuric
chloride mediated activation of the carbonyl group of an aldehyde or
ketone, which is further attacked by the amine functionality of
anthralinamide to generate the imine and,(b) intramolecular
cyclocondensation of imine to furnish the final quinazolinones.
The assertion of the activation of carbonyl group is based on the
electron deficiency of the cyanuric chloride, as in the case of cyanuric
chloride/DMSO and cyanuric chloride/DMF adduct where a
reactive intermediate formed, to furnish the final product.61−63
loading leads to the formation of side products (observed on
TLC), which eventually reduces the yield of the desired product.
Further to validate our assumption, we catalyzed the same
reaction with 10 mol % of cyanuric acid instead of cyanuric
chloride, and it was observed that the reaction proceeded quite
slowly (5 h) compared to the reaction using cyanuric chloride
(10 min).
To determine the effect of solvents, next we examined our
reaction in different solvent systems as depicted in Table 2.
Table 2. Screening of Solvent and Mixture of Solvent
entry
solvent
dry DCM
time (min)
yield (%)
1
10
10
15
40
10
10
10
15
10
40
20
45
35
20
91
80
87
72
96
90
96
80
85
70
87
70
85
90
2
dry THF
dry methanol
dry toluene
dry acetonitrile
DCM
3
4
5
6
7
acetonitrile
methanol
THF
8
9
10
11
12
13
14
toluene
DMSO
water
THF/water
acetonitrile/water
Among all the solvents screened, it was found that acetonitrile
was the most suitable solvent for this reaction (Table 2, entry 7).
Interestingly, in water the reaction proceeds very smoothly but
requires a long reaction time, which might be attributed to the
poor solubility of the starting substrates in water.
In order to study the scope of reaction, we condensed
anthralinamide (1) with commercially available aromatic
aldehydes (2a−2m) having electron-donating and electron-
withdrawing substituents to form a series of dihydroquinazo-
linones (3a−3m) (Table 3). The electronic effects have no
significant impact on reaction rate; nevertheless in ortho-
substituted aldehydes the reaction time was long, which directly
reflects its steric property. Heteroaromatic aldehyde (2n) was
also readily introduced into the quinazolinone skeleton at the
2-position, and desired product (3n) was formed in good yield.
Moreover to access the feasibility of the process, 2,3-
disubstituted quinazolinones (3o−3r) were also synthesized
with aliphatic and aromatic amines, and no any significant
alteration was observed in reaction rate in either case. The
reaction of deactivated anilines67 with isatoic anhydride led to
the synthesis of highly deactivated N-substituted benzamides,
which have poor nucleophilicity toward the cyclocondensation
reaction in the synthesis of 3-substituted quinazolinones. To
countermand this lack of reactivity, we screened cyanuric
chloride as catalyst in such cyclocondensation reactions, and
the results obtained are good (3s−3u, Table 3). These 3-
substituted quinazolinones are also important molecules in
pharmacological aspects. As only few methods are available for
the synthesis of these 3-substituted quinazolinones,36 our
methodology can serve as a useful tool in synthesis of these
pharmacologically active scaffolds.
RESULTS AND DISCUSSION
Initially, we examined the model cyclocondensation reaction
between anthranilamide (1) and benzaldehyde (2a) (Scheme 1)
■
Scheme 1. Model Cyclocondensation Reaction
at room temperature with altered catalyst loading, and the results
are summarized in Table 1. It was found that 10 mol % of
Table 1. Catalyst Loading
entry
catalyst (mol %)
time (min)
yield (%)
1
2
3
4
5
2
5
45
20
10
10
10
90
92
96
85
75
10
20
30
cyanuric chloride efficiently catalyzed the reaction, which was
complete in 10 min. On decreasing the catalyst loading the
reaction time was increased (Table 1, entries 1 and 2), and
increasing the catalyst loading did not significantly alter the
course of reaction and time (Table 1, entry 5). Also high catalyst
The structure of 3a−3x was confirmed by IR, NMR, Mass,
and HRMS and also with the literature where both were in
good agreement. The HRMS analysis of 3a shows a (M + H)+
peak at m/z = 225.1017 as C14H12N2O, which matches the
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Table 3. Scope of the Reaction with Different Aromatic and Heteroaromatic Aldehydes
entry
Ar/HetAr aldehyde
benzaldehyde (2a)
R
time (min)
yield (%)
3a
3b
3c
3d
3e
3f
H
10
10
10
10
10
8
96
93
85
90
90
95
87
86
79
92
84
81
76
84
77
73
87
65
75
67
70
84
60
74
4-methyl benzaldehyde (2b)
4-ethyl benzaldehyde (2c)
4-isopropyl benzaldehyde (2d)
4-chloro benzaldehyde (2e)
4-methoxy benzaldehyde (2f)
4-thiomethyl benzaldehyde (2g)
3-bromo benzaldehyde (2h)
2-fluoro benzaldehyde (2i)
4-tert-butyl benzaldehyde (2j)
3-nitro benzaldehyde (2k)
4-formylbenzonitrile (2l)
2-naphthaldehyde (2m)
pyridine 3-aldehyde (2n)
benzaldehyde (2a)
H
H
H
H
H
3g
3h
3i
H
8
H
10
15
10
15
10
10
15
10
10
8
H
3j
H
3k
3l
H
H
3m
3n
3o
3p
3q
3r
H
H
aniline
benzaldehyde (2a)
benzyl amine
benzaldehyde (2a)
2-phenylethyl amine
tetrahydrofurfuryl amine
2,4-difluoroaniline
2-chloro, 4-fluoro aniline
3-trifluoromethylaniline
p-phenylenediamine
H
benzaldehyde (2a)
8
3s
3t
benzaldehyde (2a)
10
10
10
120
15
10
benzaldehyde (2a)
3u
3v
3w
3x
benzaldehyde (2a)
benzaldehyde (2a)
terephthalaldehyde (2o)
ferrocenecarboxaldehyde (2p)
H
expected 2-phenyl-2,3-dihydro-1H-quinazolinone. In the 1H
and 13C NMR spectrum of the molecule all of the signals are in
good accord with the structure.
scope of our cyanuric chloride mediated cyclocondensation
methodology in such electron-rich systems.
To explore the utility of cyanuric chloride-catalyzed imine
formation and subsequent cyclization reaction, the method-
ology was extended toward alicyclic ketone, heteroalicyclic
ketone, and aryl O-glycosidic aldehydes. The alicyclic
ketone (cyclohexanone) (Scheme 2) and heteroalicyclic ketone
After the successful exploitation of our methodology with
several aromatic and heteroaromatic aldehydes and several
anilines (deactivated), next we explored our methodology in
functional molecules where chemoselectivity is an important
issue. When we applied our methodology to such functional
molecules as in case of 2-amino-N-(4-aminophenyl)benzamide,
reaction was sluggish and furnished a mixture of products with
the formation of 3v in 35% isolated yield. To further achieve
chemoselectivity in such a system, the reaction was again
catalyzed with cyanuric chloride at low temperature (0 °C).
Exceptionally significant chemoselectivity was observed at low
temperature in the process, and product (3v) was formed in
84% yield with longer reaction time (2 h). In a bifunctional
system where both functional groups are same and have the
same reactivity pattern, it is very difficult to create diversity at
only one functional group. For example several groups have
reported the synthesis of the bisquinazolinone system starting
with terepthalaldehyde, but the monomer derivative is not
reported.68,69 However, when we applied our cyclocondensa-
tion methodology to such a bifunctional system, monomer
(3w) was obtained as major product with 60% yield, and this
monomer can be used to generate library of biologically active
compounds.
Scheme 2. Synthesis of Spirocyclized Product
(N-carbethoxy protected piperidone) (Scheme 3) were successfully
entered in spirocyclized products. As relatively fewer methods
Scheme 3. Synthesis of Spirocyclized Product
are available for such spirocyclization, our method can serve as
a feasible approach for this transformation. This spirocycliza-
tion between anthranilamide and cycloalkanones was confirmed
Because of the increasing demand for ferrocene-containing
heterocycles in organic and organometallic synthesis70 and in
medicinal chemistry,71−73 we have attempted to expand the
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by the disappearance of the signal of quaternary carbonyl
carbon of cycloalkanones, which is shifted from δ 207.1 to
70.57 ppm in the 13C spectrum.
Scheme 5. Plausible Reaction Mechanism for the Formation
of Dihydroquinazolinone
Preparation of O-aryl glycosides is a challenging task in
synthetic organic chemistry as these O-glycosidic linkages are
chemically sensitive.74 Therefore more importantly, to further
explore the potential of this protocol for synthesis of O-aryl
glycosides in carbohydrate chemistry, we applied our cyanuric
chloride catalyzed cyclocondensation methodology in carbo-
hydrates (Scheme 4), and the results obtained are promising.
Scheme 4. Synthesis of Glycoconjugates
amount of HCl. The so produced HCl might further catalyze
the reaction to form the Schiff base after the elimination of the
bulky cynauryloxy group, and finally intramolecular cyclization
affords the desired product in quantitative yield. The isolation
of the intermediates in the given course of reaction is not
possible as the cyanuric chloride-aldehyde/ketone adduct may
be unstable or short-lived, and in next step the elimination of
cyanuryloxy group might be very fast.
The synthesized glycoconjugate and intermediate sugar
aldehyde were well characterized by the spectroscopic
techniques. The molecular formula of 10a was suggested to
be C28H30N2O11 by the HRMS peak (M + H)+ at 571.1926.
The different cross correlations as shown in Figure 2 were very
CONCLUSION
■
In summary, herein we have demonstrated a most concise,
efficient, mild, and facile protocol for the synthesis of
dihydroquinazolinones, spiroquinazolinone, and the hybrid
of quinazolinone with sugar molecules in a selective manner.
This new chemistry would provide a simple, compatible, and
potentially powerful method for the modular construction of
quinazolinones with flexible control over the sensitive
functionalities. Furthermore the moderate reaction conditions,
absence of any cocatalyst, and production of nonvolatile and
essentially nontoxic cyanuric acid make this an environment-
friendly methodology amenable for scale-up.
Figure 2. Important (a) COSY (dark lines) and (b) HMBC cross
correlation (curved arrows) in synthesized glycoconjugates.
well characterized with the help of 2D COSY, HSQC, and
HMBC experiments. The attachment of the bridged phenyl
ring between sugar moiety and quinazolinone was assigned
by the key HMBC cross correlations between the anomeric
proton 1″H at δ 5.46 and the carbon of the phenyl ring 4′C at
δ 161.7 ppm. Furthermore these assignments were confirmed
by HMBC cross correlations between 2H-1′C and 2H-2′C.
Beside these, other important cross correlations between 4′C-
2′H/6′H and 1′C-3′H/5′H were also observed in the HMBC
spectrum. The position of 6″Ha and Hb was confirmed by
HSQC and HMBC spectrum as both protons having chemical
shift value between δ 4.08−4.13 and 4.44−4.40 were attached
at the same carbon at δ 66.2 ppm. The anomeric proton 1″H
was identified at δ 5.46 ppm as a doublet with a J value of
7.5 Hz, and further its position was confirmed by the 2D
1H−1H correlation and HSQC cross correlation between 1″H
5.46 and 1″C 102.9. Other sugar protons appear as a multiplet
between 5.17 and 5.37. A singlet for 2H appeared at δ 5.72
EXPERIMENTAL SECTION
■
General Procedure 1: Synthesis of 2,3-Dihydroquinazolin-
4(1H)-ones (3a−3x). Cyanuric chloride (0.135 mmol, 10 mol %) was
added to a solution of anthranilamide (1) (0.73 mmol) and desired
aldehydes (1 equiv) in acetonitrile (2 mL). The mixture was stirred at
room temperature for the specified period of time as indicated in
Table 3. The progress of the reaction was monitored by TLC. After
completion, solvent was evaporated at reduced pressure, and solid was
washed with water. The corresponding solid products were obtained in
quantitative yield (Table 3) through column chromatography by using
100−200 mesh silica gels or by crystallization from ethanol.
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (3a). The title
compound was prepared according to general procedure 1 using
anthranilamide (1) (0.1 g, 0.73 mmol), benzaldehyde (2a) (0.074 mL,
0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol %) in
acetonitrile (2 mL). Purification by crystallization in ethanol afforded
3a as a white solid. Yield: 158 mg (96%). Mp: 218−220 °C (lit.39
1
ppm. The 2D H−1H correlations between 2H δ 5.72 and 3H
218−219 °C). H NMR (CDCl3, 200 MHz): δ 7.96 (d, J = 8.1 Hz,
1
1H) 7.58−7.26 (m, 6H), 6.94 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.0 Hz,
1H), 5.90 (s, 1H), 5.82 (s, 1H, NH), 4.41 (s, 1H, NH). 13C NMR
(CDCl3, 75 MHz): 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 (KBr): 3296, 3190, 3070, 1656,
1606 cm−1. Mass: 224.00. HRMS (ESI): calcd for [C14H12N2O + H+]
225.1022, found 225.1017.
2-p-Tolyl-2,3-dihydroquinazolin-4(1H)-one (3b). The title
compound was prepared according to general procedure 1 using
anthranilamide (1) (0.1 g, 0.73 mmol), 4-methylbenzaldehyde (2b)
(0.086 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol %)
(NH) at δ 8.21 confirmed the formation of quinazolinone. On
the basis of all of these assignments the name of the molecule is
suggested as 2-[4′(6″,4″,3″,2″-tetra-O-acetyl-β-D-galactopyr-
anosyloxy)-1′-phenyl]-2,3-dihydroquinazoline-4(1H)-one.
A plausible mechanism for the formation of these
quinazolinones is proposed in Scheme 5. Being an electron-
deficient system, cyanuric chloride might activate the carbonyl
group of aldehyde or ketone, which is simultaneously attacked
by anthranilamide to form the intermediate with an equivalent
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in acetonitrile (2 mL). Purification by crystallization in ethanol
(0.135 mmol, 10 mol %) in acetonitrile (2 mL). Purification by
afforded 3b as a white solid. Yield: 163 mg (93%). Mp: 232−234 °C
crystallization in ethanol afforded 3g as a white solid. Yield: 173 mg
(lit.39 233−234 °C). H NMR (DMSO-d6, 300 MHz): δ 8.18 (s, 1H,
(87%). Mp: 178−180 °C. H NMR (CDCl3+DMSOd6, 300 MHz): δ
1
1
NH), 7.62 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.26−7.17 (m,
3H), 7.02 (bs, 1H, NH), 6.75 (d, J = 8.0 Hz, 1H), 6.69 (t, J = 7.4 Hz,
1H), 5.71 (s, 1H), 2.29 (s, 3H). 13C NMR (DMSO-d6, 50 MHz): δ
164.4, 148.2, 138.9, 138.2, 133.8, 129.2, 127.7, 127.0, 117.6, 115.2,
114.8, 66.7, 21.0. IR (KBr): 3313, 3196, 3061, 1662, 1610 cm−1. Mass:
238.00. HRMS (ESI): calcd for [C15H14N2O + H+] 239.1179, found
239.1177.
2-(4′-Ethylphenyl)-2,3-dihydroquinazolin-4(1H)-one (3c).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 4-ethylbenzaldehyde
(2c) (0.10 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol,
10 mol %) in acetonitrile (2 mL). Purification by crystallization in
ethanol afforded 3c as a white solid. Yield: 157 (85%). Mp: 178−
180 °C. 1H NMR (CDCl3, 300 MHz): δ 7.99 (d, J = 7.8 Hz, 1H), 7.54
(d, J = 7.8 Hz, 2H), 7.39−7.29 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H), 6.70
(d, J = 8.1 Hz, 1H), 5.90 (s, 1H), 5.81 (s, 1H, NH), 4.40 (s, 1H, NH),
2.76 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H). 13C NMR (CDCl3 +
DMSO-d6, 75 MHz): δ 170.0, 153.3, 150.5, 142.8, 138.7, 133.2, 133.0,
132.5, 123.2, 120.3, 119.9, 73.3, 33.7, 20.9. IR (KBr): 3343, 3198,
3056, 1657, 1612 cm−1. Mass: 252.00. HRMS (ESI): calcd for
[C16H16N2O + H+] 253.1335, found 253.1330.
2-(4′-Isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one
(3d). The title compound was prepared according to general
procedure 1 using anthranilamide (1) (0.1 g, 0.73 mmol),
isopropylbenzaldehyde (2d) (0.11 mL, 0.73 mmol) and cyanuric
chloride (0.135 mmol, 10 mol %) in acetonitrile (2 mL). Purification
by crystallization in ethanol afforded 3d as a white solid. Yield: 176 mg
(90%). Mp: 162−164 °C. 1H NMR (DMSO-d6, 300 MHz): δ 8.21 (s,
1H), 7.64 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H),
7.29−7.25 (m, 3H), 7.05 (s, 1H), 6.76−6.68 (m, 2H), 5.73 (s, 1H),
2.95 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H). 13C NMR (DMSO-d6, 50
MHz): δ 164.1, 149.3, 148.4, 139.5, 133.7, 127.8, 127.4, 126.7, 117.5,
115.4, 114.8, 67.0, 33.7, 24.3. IR (KBr): 3292, 3191, 3021, 1658, 1610
cm−1. Mass: 266.00. HRMS (ESI): calcd for [C17H18N2O + H+]
267.1492, found 267.1489.
7.84 (d, J = 7.7 Hz, 1H), 7.57−7.50 (m, 2H), 7.29−7.27 (m, 3H), 7.01
(s, 1H, NH), 6.82−6.75 (m, 2H), 6.01 (s, 1H, NH), 5.83 (s, 1H), 2.51
(s, 3H). 13C NMR (CDCl3+ DMSOd6, 50 MHz): δ 163.7, 147.5,
138.5, 137.4, 132.8, 127.7, 127.0, 125.3, 116.9, 114.5, 114.1, 66.3, 14.6.
IR (KBr): 3298, 3189, 3063, 1657, 1610 cm−1. Mass: 270.00. HRMS
(ESI): calcd for [C15H14N2OS + H+] 271.0900, found 271.0893.
2-(3′-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3h).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 3-bromobenzaldehyde
(2h) (0.086 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3h as a white solid. Yield: 191 mg (86%). Mp: 229−231 °C
(lit.75 231−233 °C). 1H NMR (CDCl3, 200 MHz): δ 7.94 (d, J = 7.8
Hz, 1H), 7.77 (dd, J1 = 7.8, J2= 1.2 Hz, 1H),7.62 (dd, J1 = 7.8 Hz, J2 =
1.2 Hz, 1H), 7.41−7.20 (m, 3H), 6.91−6.83 (m, 1H), 6.69 (d, J = 8.0
Hz, 1H), 6.30 (s, 1H), 6.09 (s, 1H, NH), 4.67 (s, 1H, NH). 13C NMR
(CDCl3, CD3OD, 50 MHz): δ 170.0, 152.0, 146.4, 138.6, 136.7, 134.6,
132.2, 130.1, 123.0, 119.0, 71.8. IR (KBr): 3276, 3181, 3057, 1655,
1628 cm−1. Mass: 302.00. HRMS (ESI): calcd for [C14H11BrN2O +
H+] 303.0128, found 303.0121.
2-(2′-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3i).
The title compound was prepared acording to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 2-fluorobenzaldehyde
(2i) (0.077 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3i as a white solid. Yield: 140 mg (79%). Mp: 185−187 °C
(lit.77 189−193 °C). 1H NMR (CDCl3, 300 MHz): δ 7.73 (dd, J1 = 7.8
Hz, J2 = 1.2 Hz, 1H), 7.57 (dt, J1 = 7.5 Hz, J2 = 1.4 Hz, 1H), 7.30−7.18
(m, 2H), 7.10−6.97 (m, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 8.1
Hz, 1H), 6.13 (s, 1H). 13C NMR (CDCl3 + DMSO-d6, 50 MHz): δ
172.9, 155.2, 141.7, 138.4, 138.2, 135.9, 135.6, 134.9, 132.0, 126.1,
123.4, 123.0, 122.4, 69.0. IR (KBr): 3371, 3184, 3067, 1656, 1613
cm−1. Mass: 242.00. HRMS (ESI): calcd for [C14H11FN2O + H+]
243.0928, found 243.0922.
2-(4′-tert-Butylphenyl)-2,3-dihydroquinazolin-4(1H)-one
(3j). The title compound was prepared according to general procedure
1 using anthranilamide (1) (0.1 g, 0.73 mmol), 4-t-butylbenzaldehyde
(2j) (0.122 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3j as a white solid. Yield: 189 mg (92%). Mp: 219−221 °C
(lit.75 219−220 °C).1H NMR (CDCl3, 200 MHz): δ 7.88 (dd, J = 7.8
Hz, 1H), 7.47−7.18 (m, 5H), 6.85 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.1
Hz, 1H), 5.80 (s, 1H), 5.74 (bs, 1H), 4.33 (bs, 1H, NH), 1.26 (s, 9H).
13C NMR (CDCl3 + DMSO-d6, 50 MHz): δ 175.7, 169.3, 156.6,
153.1, 142.9, 138.2, 133.8, 132.5, 131.9, 130.1, 122.3, 119.9, 119.4,
72.4, 39.4, 36.2. IR (KBr): 3278, 3184, 3055, 1653, 1623 cm−1. Mass:
280.00. HRMS (ESI): calcd for [C18H20N2O + H+] 281.1648, found
281.1643.
2-(4′-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 4-chlorobenzaldehyde
(2e) (0.10 g, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3e as a white solid. Yield: 170 mg (90%). Mp: 204−206 °C
(lit.75 205−206 °C). H NMR (CDCl3, 300 MHz): δ 7.97 (d, J = 7.8
1
Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H),7.39 (t, J =
7.2 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.91 (s,
1H), 5.81 (s, 1H, NH), 4.38 (s, 1H, NH). 13C NMR (CDCl3
+
DMSO-d6, 50 MHz): δ 169.4, 152.5, 144.1, 139.3, 138.4, 133.6, 133.4,
132.6, 123.0, 119.9, 119.5, 72.1. IR (KBr): 3318, 3190, 3075, 1659,
1609 cm−1. Mass: 258.00. HRMS (ESI): calcd for [C14H11ClN2O +
H+] 259.0633, found 259.0625
2-(3′-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3k).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 3-nitrobenzaldehyde
(2k) (0.110 g, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol %)
in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3k as a yellow solid. Yield: 166 mg (84%). Mp: 210−212 °C
(lit.39 216−217 °C). 1H NMR (CDCl3 + DMSO-d6, 300 MHz): δ 8.42
(s, 1H), 8.24 (s, 1H, NH), 8.17 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 7.5,
1H), 7.73 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.2
Hz, 1H), 6.90 (s, 1H, NH), 6.79−6.69 (m, 2H), 5.91 (s, 1H). 13C
NMR (CDCl3+DMSO-d6, 50 MHz): δ 169.1, 152.9, 152.0, 148.6,
138.5, 138.0, 134.4, 132.6, 128.2, 126.9, 122.9, 120.0, 119.6, 71.1. IR
(KBr): 3280, 3188, 3068, 1658, 1617 cm−1. Mass: 269.00. HRMS
(ESI): calcd for [C14H11N3O3 + H+] 270.0873, found 270.0875.
4-(4′-Oxo-1′,2′,3′,4′-tetrahydroquinazolin-2′-yl)benzonitrile
(3l). The title compound was prepared acording to general procedure
1 using anthranilamide (1) (0.1 g, 0.73 mmol), 4-formylbenzonitrile
(2 L) (0.096 g, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol %)
in acetonitrile (2 mL). Purification by crystallization in ethanol
2-(4′-Methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3f).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 4-methoxybenzaldehyde
(2f) (0.089 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3f as a white solid. Yield: 177 mg (95%). Mp: 187−190 °C
(lit.76 192−193 °C). H NMR (CDCl3, 300 MHz): δ 7.86 (d, J = 7.8
1
Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.26 (t, J = 7.8 Hz, 1H), 6.87−6.77
(m, 3H), 6.57 (d, J = 8.1 Hz, 1H), 5.75 (s, 1H), 5.63 (bs, 1H, NH),
4.24 (bs, 1H, NH), 3.74 (s, 3H). 13C NMR (CDCl3 + CD3OD, 50
MHz): δ 170.4, 152.4, 138.5, 135.5, 132.9, 132.4, 123.1, 119.1, 118.9,
118.4, 72.7, 59.5. IR (KBr): 3299, 3109, 3021, 1659, 1610 cm−1. Mass:
254.00. HRMS (ESI): calcd for [C15H14N2O2 + H+] 255.1128, found
255.1125.
2-(4′-(Methylthio)phenyl)-2,3-dihydroquinazolin-4(1H)-one
(3g). The title compound was prepared according to general procedure
1 using anthranilamide (1) (0.1 g, 0.73 mmol), 4-thiomethyl-
benzaldehyde (2g) (0.097 mL, 0.73 mmol) and cyanuric chloride
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afforded 3l as a light yellow solid. Yield: 148 mg (81%). Mp: >250 °C
(CDCl3, 200 MHz): δ 8.04 (d, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.39−
7.12 (m, 11H), 6.94 (t, J = 6.7 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.59
(s, 1H), 4.44 (bs, 1H, NH), 4.16−4.06 (m, 1H), 3.13−2.75 (m, 3H).
13C NMR (CDCl3, 50 MHz): δ 163.3, 145.3, 139.6, 139.2, 133.5,
(lit.78 350−351 °C). H NMR (DMSO-d6, 300 MHz): δ 8.43 (s, 1H,
1
NH), 7.87 (d, J = 8.1 Hz, 2H), 7.67−7.59 (m, 3H), 7.28 (t, J = 7.4 Hz,
1H), 6.77 (d, J = 8.0 Hz, 2H), 6.71 (t, J = 7.4 Hz, 1H), 5.84 (s, 1H).
13C NMR (DMSO-d6, 75 MHz): δ 168.9, 152.2, 151.9, 138.4, 137.1,
137.0, 133.6, 132.7, 132.5, 123.3, 122.6, 119.9, 119.6, 116.6, 71.1. IR
(KBr): 3286, 3178, 3056, 1651, 1613 cm−1. Mass: 249.00. HRMS
(ESI): calcd for [C15H11N3O + H+] 250.0975, found 250.0973.
2-(Naphthalen-2′-yl)-2,3-dihydroquinazolin-4(1H)-one (3m).
The title compound was prepared according to general procedure 1
using anthranilamide (1) (0.1 g, 0.73 mmol), 2-naphthylbenzaldehyde
(2 m) (0.11 g, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol
%) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3m as a white solid. Yield: 153 mg (76%). Mp: 172−174 °C.
1H NMR (CDCl3, 300 MHz): δ 8.58 (s, 1H), 8.05−7.76 (m, 5H),
7.55−7.51 (m, 3H), 7.29 (t, J = 6.9 Hz 1H), 6.81−6.68 (m, 3H), 6.51
(s, 1H). 13C NMR (CDCl3 + CD3OD, 75 MHz): δ 169.9, 153.4,
139.4, 139.3, 138.8, 135.6, 134.6, 133.6, 132.8, 132.1, 131.4, 130.0,
129.2, 122.8, 120.0, 71.6. IR (KBr): 3381, 3126, 3017, 1653, 1616
cm−1. Mass: 274.00. HRMS (ESI): calcd for [C18H14N2O + H+]
275.1179, found 275.1183.
2-(Pyridin-3′-yl)-2,3-dihydroquinazolin-4(1H)-one (3n). The
title compound was prepared according to general procedure 1 using
anthranilamide (1) (0.1 g, 0.73 mmol), pyridine-3-carboxaldehyde
(2n) (0.069 mL, 0.73 mmol) and cyanuric chloride (0.135 mmol, 10
mol %) in acetonitrile (2 mL). Purification by column chromatography
(chloroform/methanol, 9.9:0.1) afforded 3n as a white solid. Yield:
140 mg (84%). Mp: 190−192 °C (lit.39 187−188 °C). 1H NMR
(CDCl3, 200 MHz): δ 8.62 (s, 1H), 8.54−8.51 (m, 1H), 7.99−7.93
(m, 1H), 7.80 (dd, J1 = 7.8 Hz, J2 = 1.4 Hz, 1H), 7.38−7.22 (m, 2H),
6.84 (t, J = 7.8 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H). 13C
NMR (CDCl3 + CD3OD, 75 MHz): δ 169.6, 153.6, 151.9, 151.5,
143.0, 140.3, 139.6, 138.2, 131.8, 128.0, 122.8, 118.5, 117.7, 69.7. IR
(KBr): 3326, 3264, 3068, 1659, 1613 cm−1. Mass: 225.00. HRMS
(ESI): calcd for [C13H11N3O + H+] 226.0975, found 226.0972.
2,3-Diphenyl-2,3-dihydroquinazolin-4(1H)-one (3o). The title
compound was prepared according to general procedure 1 using 2-
amino-N-phenylbenzamide (0.1 g, 0.47 mmol), benzaldehyde (2a)
(0.045 mL, 0.44 mmol) and cyanuric chloride (0.048 mmol, 10 mol %)
in acetonitrile (2 mL). Purification by column chromatography
(chloroform/methanol, 9.9:0.1) afforded 3o as a white solid. Yield:
109 mg (77%). Mp: 212−214 °C (lit.39 214−215 °C). 1H NMR
(CDCl3, 300 MHz): δ 8.04 (d, J = 7.8 Hz, 1H), 7.38−7.19 (m, 11H),
6.92 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.11 (s, 1H), 4.88
(bs, 1H, NH). 13C NMR (CDCl3 + CD3OD, 75 MHz): 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, 3261, 3063, 1649, 1610 cm−1. Mass:
300.00. HRMS (ESI): calcd for [C20H16N2O + H+] 301.1335, found
301.1333.
3-Benzyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (3p).
The title compound was prepared according to general procedure 1
using 2-amino-N-benzylbenzamide (0.1 g, 0.44 mmol), benzaldehyde
(2a) (0.045 mL, 0.44 mmol) and cyanuric chloride (0.044 mmol, 10
mol %) in acetonitrile (2 mL). Purification by crystallization in ethanol
afforded 3p as a white solid. Yield: 101 mg (73%). Mp: 125−127 °C.
1H NMR (CDCl3, 300 MHz): δ 7.96 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz,
1H), 7.25−7.13 (m, 11H), 6.80 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 8.1 Hz,
1H), 5.54−5.49 (m, 2H), 4.41 (bs, 1H, NH), 3.62 (d, J = 15.3 Hz,
1H). 13C NMR (CDCl3, 75 MHz): δ 163.3, 145.2, 139.4, 136.7, 133.6,
129.2, 128.9, 128.7, 128.6, 127.9, 127.4, 126.5, 119.0, 115.5, 114.3,
71.0, 46.9. IR (KBr): 3322, 3263, 3067, 1658, 1613 cm−1. Mass:
314.00. HRMS (ESI): calcd for [C21H18N2O + H+] 315.1492, found
315.1481.
3-Phenethyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one
(3q). The title compound was prepared according to general
procedure 1 using 2-amino-N-phenethylbenzamide (0.1 g, 0.41
mmol), benzaldehyde (2a) (0.045 mL, 0.44 mmol) and cyanuric
chloride (0.041 mmol, 10 mol %) in acetonitrile (2 mL). Purification
by column chromatography (chloroform/methanol, 9.9:0.1) afforded
3q as a white solid. Yield: 119 mg (87%). Mp: 145−147 °C. 1H NMR
129.5, 129.3, 129.0, 128.9, 128.5, 126.9, 126.4, 119.3, 114.4, 73.0, 47.0,
34.2. IR (KBr): 3473, 3299, 3019, 1628, cm−1. Mass: 328.00. HRMS
(ESI): calcd for [C22H20N2O + H+] 329.1648, found 329.1652.
2-Phenyl-3-((tetrahydrofuran-2-yl)methyl)-2,3-dihydroqui-
nazolin-4(1H)-one (3r). The title compound was prepared according
to general procedure 1 using of 2-amino-N-(tetrahydrofuran-2-
ylmethyl)benzamide (0.1 g, 0.46 mmol), benzaldehyde (2a) (0.045
mL, 0.44 mmol) and cyanuric chloride (0.046 mmol, 10 mol %) in
acetonitrile (2 mL). Purification by column chromatography (chloro-
form/methanol, 9.9:0.1) afforded 3r as a white solid. Yield: 91 mg
(65%). Mp: >250 °C. 1H NMR (CDCl3, 300 MHz): δ 7.97 (d, J = 6.8
Hz, 1H), 7.32−7.20 (m, 6H), 6.85 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 7.8
Hz, 1H), 6.06 (s, 1H), 4.69 (bs, 1H, NH), 4.35−4.26 (m, 1H), 4.11−
4.10 (m, 1H), 3.98−3.91 (m, 1H), 3.83−3.71 (m, 1H), 3.06 (dd, J1 =
3.6 Hz, J2 = 3.6 Hz, 1H), 2.03−1.79 (m, 4H). 13C NMR (CDCl3, 75
MHz): δ 163.8, 145.1, 140.0, 133.4, 128.9, 128.8, 128.5, 126.5, 126.3,
119.1, 116.2, 114.5, 72.3, 68.3, 46.3, 28.3, 26.1. IR (KBr): 3475, 3297,
3019, 1628, 1037 cm−1. Mass: 308.00. HRMS (ESI): calcd for
[C19H20N2O2 + H+] 309.1598, found 309.1584.
3-(2,4-Difluorophenyl)-2-phenyl-2,3-dihydroquinazolin-
4(1H)-one (3s). The title compound was prepared according to
general procedure 1 using of 2-amino-N-(3,4-difluorophenyl)-
benzamide (0.1 g, 0.40 mmol), benzaldehyde (2a) (0.045 mL, 0.44
mmol) and cyanuric chloride (0.040 mmol, 10 mol %) in acetonitrile
(2 mL). Purification by column chromatography (chloroform/
methanol, 9.9:0.1) afforded 3s as a white solid. Yield: 100 mg
(75%). Mp: 210−212 °C. 1H NMR (CDCl3, 300 MHz): δ 8.04 (d, J =
7.5 Hz, 1H), 7.44−7.28 (m, 6H), 7.04−6.92 (m, 2H), 6.79−6.69 (m,
3H), 6.18 (s, 1H), 4.65 (bs, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ
163.6, 146.5, 137.8, 134.1, 129.7, 129.3, 128.6, 127.7, 119.7, 115.8,
114.5, 111.4, 104.5, 104.1, 74.78. IR (KBr): 3414, 3311, 3074, 1635,
1098 cm−1. Mass: 336.00. HRMS (ESI): calcd for [C20H14F2N2O +
H+] 337.1147, found 337.1146.
3-(2-Chloro-4-fluorophenyl)-2-phenyl-2,3-dihydroquinazo-
lin-4(1H)-one (3t). The title compound was prepared according to
general procedure 1 using 2-amino-N-(2-chloro-4-fluorophenyl)-
benzamide (0.1 g, 0.37 mmol), benzaldehyde (2a) (0.045 mL, 0.44
mmol) and cyanuric chloride (0.037 mmol, 10 mol %) in acetonitrile
(2 mL). Purification by column chromatography (chloroform/
methanol, 9.9:0.1) afforded 3t as a white solid. Yield: 89 mg (67%).
Mp: 220−222 °C. 1H NMR (CDCl3, 300 MHz): δ 8.02 (d, J = 7.8 Hz,
1H), 7.37−7.24 (m, 7H), 7.02−7.00 (m, 2H), 6.94 (t, J = 7.5 Hz, 1H),
6.67 (d, J = 7.8, 1H), 6.07 (s, 1H), 4.78 (bs, 1H, NH). 13C NMR
(CDCl3, 75 MHz): δ 163.5, 158.2, 145.6, 138.8, 136.7, 134.3, 129.8,
129.5, 129.0, 128.9, 127.4, 127.2, 126.9, 119.6, 116.7, 116.4, 116.0, 114.8,
74.9. IR (KBr): 3410, 3309, 3064, 1629, 1087 cm−1. Mass: 352.00. HRMS
(ESI): calcd for [C20H14ClFN2O + H+] 353.0851, found 353.0850.
2-Phenyl-3-(3-(trifluoromethyl)phenyl)-2,3-dihydroquinazo-
lin-4(1H)-one (3u). The title compound was prepared according to
general procedure 1 using 2-amino-N-(3-(trifluoromethyl)phenyl)-
benzamide (0.1 g, 0.35 mmol), benzaldehyde (2a) (0.045 mL, 0.44
mmol) and cyanuric chloride (0.035 mmol, 10 mol %) in acetonitrile
(2 mL). Purification by column chromatography (chloroform/
methanol, 9.9:0.1) afforded 3u as a white solid. Yield: 92 mg (70%).
Mp: 140−142 °C. 1H NMR (CDCl3, 300 MHz): δ 7.85 (d, J = 7.3 Hz,
1H), 7.64 (s, 1H), 7.35−7.33 (m, 2H), 7.24−7.20 (m, 3H), 6.90 (d,
J = 8.5 Hz, 2H), 6.75−6.68 (m, 2H), 6.55 (d, J = 8.5 Hz, 2H), 6.00 (s,
1H), 4.20 (bs, 1H, NH). 13C NMR (CDCl3, 75 MHz): δ 163.2, 145.5,
140.8, 138.9, 134.2, 130.5, 129.3, 129.1, 128.8, 126.9, 124.1, 123.4,
119.8, 114.9, 74.7. IR (KBr): 3300, 3029, 3019, 1616, 1127 cm−1.
Mass: 368.00. HRMS (ESI): calcd for [C21H15F3N2O + H+] 369.1209,
found 369.1196.
3-(4-Aminophenyl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-
one (3v). The title compound was prepared according to general
procedure 1 using 2-amino-N-(4-aminophenyl)benzamide (0.1 g, 0.44
mmol), benzaldehyde (2a) (0.045 mL, 0.44 mmol) and cyanuric
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chloride (0.044 mmol, 10 mol %) in acetonitrile (2 mL). Purification
by column chromatography (hexane/ethyl acetate, 7.5:2.5) afforded 3v
as a white solid. Yield: 116 mg (84%). Mp: >250 °C. 1H NMR
(DMSO-d6, 300 MHz): δ 7.70 (d, J = 7.3 Hz, 1H), 7.43 (bs, 1H, NH),
7.35−7.21 (m, 6H), 6.86 (d, J = 8.5 Hz, 1H), 6.72 (m, 2H), 6.47 (d,
J = 8.5 Hz, 2H), 6.06 (s, 1H), 5.05 (bs, 2H, NH). 13C NMR (DMSO-
d6, 75 MHz): δ 162.6, 147.5, 147.0, 141.5, 133.8, 129.7, 128.7, 128.6,
128.3, 127.0, 117.7, 115.9, 114.9, 114.0, 73.8. IR (KBr): 3384, 3286,
3047, 1620, 1159. Mass: 315.00. HRMS (ESI): calcd for [C20H17N3O +
H+] 316.1444, found 316.1455.
4-(4-Oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzaldehyde
(3w). The title compound was prepared according to general
procedure 1 using anthranilamide (1) (0.1 g, 0.73 mmol),
terephthalaldehyde (2o) (0.098 g, 0.73 mmol) and cyanuric chloride
(0.135 mmol, 10 mol %) in acetonitrile (2 mL). Purification by
column chromatography (chloroform/methanol, 9.85: 0.15) afforded
3w as a white solid. Yield: 115 mg (60%). Mp: 185−187 °C. 1H NMR
(CDCl3 + DMSO-d6 300 MHz): δ 9.95 (s, 1H), 7.85−7.67 (m, 5H),
7.38 (s, 1H), 7.24−7.19 (m, 2H), 6.75−6.67 (m, 2H), 5.87 (s, 1H).
13C NMR (CDCl3, 75 MHz): δ 193.2, 163.8, 148.7, 147.9, 136.6,
2.03−1.82 (m, 4H), 1.28 (t, J = 6.9 Hz, 3H). 13C NMR (CDCl3 +
CD3OD, 50 MHz): δ 155.5, 145.5, 134.2, 128.1, 119.0, 115.2, 66.7,
61.7, 39.5, 36.8, 29.6, 14.5. IR (KBr): 3359, 3202, 3064, 1657, 1618
cm−1. Mass: 289.00. HRMS (ESI): calcd for [C15H19N3O3 + H+]
290.1499, found 290.1482.
2′,3′,4′,6′-Tetra O-acetyl 4-formylphenyl-O-β-D-galactopyr-
anoside (9b). 1H NMR (CDCl3, 300 MHz): δ 9.93 (s, 1H), 7.87 (d,
J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 5.52−5.47 (m, 2H), 5.18−
5.16 (m, 2H), 4.23−4.12 (m, 3H), 2.19 (s, 3H), 2.15 (s, 6H), 2.02 (s,
3H). 13C NMR (CDCl3, 50 MHz): δ 190.6, 170.2, 170.1, 170.0, 169.2,
161.2, 131.8, 116.7, 98.5, 71.3, 70.6, 68.4, 66.7, 61.3, 20.6, 20.5, 20.
Mass: 452.00.
General Procedure 3: Synthesis of Glycoconjugates of
Quinazolinone (10a, 10b). Cyanuric chloride (0.004 g, 0.022 mmol,
10 mol %) was added to a solution of desired aryl O-glycosidic aldehydes81
(0.1 g, 0.22 mmol) and anthranilamide (1) (0.03 g, 0.22 mmol) in
acetonitrile (2 mL). The mixture was stirred at room temperature for the
specified period of time as indicated in Scheme 4. The progress of the
reaction was monitored by TLC. After completion, solvent was
evaporated at reduced pressure, and solid products were purified through
column chromatography by using 100−200 mesh silica gel and
recrystallized from ethanol. Synthesized glycoconjugates were well
characterized using 2D NMR experiments as HMBC, COSY, and HSQC.
2-[4′(2″,3″,4″,6″-Tetra-O-acetyl-β-D-glucopyranosyloxy)-1′-
phenyl]-2,3 dihydroquinazoline-4(1H)-one (10a). The title
compound was prepared according to general procedure 3 using
2′,3′,4′,6′-tetra-O-acetyl-4-formylphenyl-O-β-D-glucopyranoside (0.1 g,
0.22 mmol), anthralinamide (1) (0.03 g, 0.22 mmol) and cyanuric
chloride (0.004 g, 0.022 mmol, 10 mol %) in acetonitrile. Purification
by column chromatography (chloroform/methanol, 9.9: 0.1) afforded
10a as a white solid. Yield: 85 mg (68%). Mp: 118−120 °C. 1H NMR
(DMSO-d6, 300 MHz): δ 8.23 (s, 1H, NH), 7.61 (d, J = 7.0 Hz, 1H),
7.45 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.04−6.98 (m, 2H,
1NH), 6.74−6.64 (m, 2H), 5.71 (s, 1H), 5.54 (d, J = 7.9 Hz, 1H), 5.42
(t, J = 9.6 Hz, 1H), 5.07−4.96 (m, 2H), 4.24−4.17 (m, 2H), 4.07−
4.04 (m, 1H), 2.00−1.96 (m, 12H). 13C NMR (DMSO-d6, 75 MHz):
δ 170.4, 170.0, 169.7, 169.5, 164.1, 159.6, 148.3, 136.5, 133.7, 128.7,
127.8, 117.6, 116.6, 115.4, 114.8, 97.5, 72.4, 71.2, 71.1, 68.5, 66.4, 62.0,
20.9, 20.8, 20.7. IR (KBr): 3374, 2928, 1756, 1654, 1227, 1047 cm−1;
Mass: 570.00. HRMS (ESI): calcd for [C28H30N2O11 + H+] 571.1923,
found 571.1926.
133.9, 130.0, 127.9, 117.8, 115.3, 114.9, 66.3. IR (KBr): 3296, 3190,
3070, 1656, 1606 cm−1. Mass: 252.08. HRMS (ESI): calcd for
[C15H12N2O2 + H+] 253.0972, found 253.0965.
2-Ferrocenyl-2,3-dihydroquinazolin-4(1H)-one (3x). The title
compound was prepared according to general procedure 1 using
anthranilamide (1) (0.1 g, 0.73 mmol), ferrocenecarboxaldehyde (2p)
(0.16 g, 0.74 mmol) and cyanuric chloride (0.135 mmol, 10 mol %) in
acetonitrile (2 mL). Purification by crystallization in ethanol afforded
3x as a white solid. Yield: 180 mg (74%). Mp: 240−242 °C. 1H NMR
(CDCl3, 200 MHz): δ 7.89 (d, J = 7.7 Hz, 1H), 7.29−7.18 (m, 2H),
6.85 (t, J = 7.7 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.01 (bs, 1H, NH),
5.53 (s, 1H),, 4.38−4.20 (m, 10H). 13C NMR (DMSO-d6, 75 MHz): δ
163.7, 147.8, 133.6, 127.6, 117.3, 115.6, 114.8, 90.9, 69.1, 67.9, 66.6,
66.4, 63.4. IR (KBr): 3489, 3399, 3251, 1640, 1024 cm−1. Mass:
332.00. HRMS (ESI): calcd for [C18H16FeN2O + H+] 333.0685, found
333.0705.
General Procedure 2: General Method for the Synthesis of
Spiroquinazolinones (5, 7). Cyanuric chloride (0.135 mmol, 10
mol %) was added to a solution of anthranilamide (1) (0.73 mmol)
and appropriate cyclic ketone (1 equiv) in acetonitrile (2 mL). The
mixture was stirred at room temperature for the specified period of
time as indicated in Schemes 2 and 3. The progress of the reaction was
monitored by TLC. After completion, solvent was evaporated at
reduced pressure and solid was washed with water. The corresponding
solid products were obtained through column chromatography by
using 100−200 mesh silica gels.
1′H-Spiro [cyclohexane-1,2′-quinazolin]-4′(3′H)-one (5). The
title compound was prepared according to general procedure 2 using
anthranilamide (1) (0.1 g, 0.73 mmol), cyclohexanone (4) (0.076 mL,
0.73 mmol) and cyanuric chloride (0.135 mmol, 10 mol %) in
acetonitrile (2 mL). Purification by column chromatography (chloro-
form/methanol, 9.5:0.05) afforded 5 as a white solid. Yield: 143 mg
(90%). Mp: 217−219 °C (lit.79 217−219 °C). 1H NMR (CDCl3, 200
MHz): δ 7.89 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.33−7.28 (m, 1H),
6.84 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H, NH),
4.40 (s, 1H, NH), 1.84 (bs, 4H), 1.68−1.47 (m, 6H). 13C NMR
(CDCl3+CD3OD, 75 MHz): δ 167.0, 148.0, 136.2, 130.3, 120.7, 117.0,
70.5, 39.7, 26.8, 24.0. IR (KBr): 3362, 3179, 3016, 1647, 1618 cm−1.
Mass: 216.00. HRMS (ESI): calcd for [C13H16N2O + H+] 217.1335,
found 217.1326.
2-[4′(6″,4″,3″,2″-Tetra-O-acetyl-β-D-galactopyranosyloxy)-1′
phenyl]-2,3 dihydroquinazoline-4(1H)-one (10b). The title
compound was prepared according to general procedure 3 using
2′,3′,4′,6′-tetra-O-acetyl 4-formylphenyl-O-β-D-galactopyranoside (0.1
g, 0.22 mmol), anthralinamide (1) (0.03 g, 0.22 mmol) and cyanuric
chloride (0.004 g, 0.022 mmol, 10 mol %) in acetonitrile. Purification
by column chromatography (chloroform/methanol, 9.9:0.1) afforded
1
10b as white solid. Yield: 90 mg (72%). Mp: 158−160 °C. H NMR
(DMSO-d6, 300 MHz): δ 8.19 (bs, 1H, NH), 7.62 (dd, J1 = 7.6 Hz,
J2 = 1.2 Hz,1H), 7.46 (d, J = 8.6 Hz, 2H), 7.26 (t, J = 8.2 Hz, 1H), 7.01
(d, J = 8.6 Hz, 2H), 6.74−6.65 (m, 2H), 5.72 (s, 1H), 5.46 (d, J = 7.5
Hz, 1H), 5.37−5.17 (m, 3H,1NH), 4.44 (t, J = 6.0 Hz, 1H), 4.13−4.08
(m, 2H), 2.16−1.94 (m, 12H). 13C NMR (DMSO-d6,75 MHz): δ
175.1, 175.0, 174.7, 174.4, 168.8, 161.7, 153.1, 141.1,138.4, 134.8,
133.5, 132.5, 122.3, 121.3, 120.2, 119.6, 102.9, 75.5, 75.3, 73.5, 72.4,
71.2, 66.2, 25.7, 25.6, 25.6, 25.5. IR (KBr): 3372, 2926, 1753, 1659,
1231, 1043 cm−1. Mass: 570.00. HRMS (ESI): calcd for [C28H30N2O11
+ H+] 571.1923, found 571.1928.
Ethyl 4′-Oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quina-
zoline]-1-carboxylate (7). The title compound was prepared
according to general procedure 2 using anthranilamide (1) (0.1 g,
0.73 mmol), ethyl 4-oxopiperidine-1-carboxylate (6) and cyanuric
chloride (0.135 mmol, 10 mol %) in acetonitrile (2 mL). Purification
by column chromatography (chloroform/methanol, 9.85:0.15)
afforded 7 as a white solid. Yield: 150 mg (70%). Mp: 188−190 °C
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of selected compounds.
(lit.80 224−225 °C). H NMR (CDCl3, 300 MHz): δ 7.88 (d, J = 7.5
1
This material is available free of charge via the Internet at
http://pubs.acs.org.
Hz, 1H), 7.34−7.26 (m, 2H), 6.88 (t, J = 7.2 Hz 1H), 6.69 (d, J = 8.1
Hz, 1H), 4.33 (s, 1H, NH), 4.20 (q, J = 6.6 Hz, 1H), 3.62 (bs, 4H),
935
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The Journal of Organic Chemistry
Article
(30) Wilkinson, B. L.; Bornaghi, L. F.; Houston, T. A.; Innocenti, A.;
Vullo, D.; Supuran, C. T.; Poulsen, S. A. J. Med. Chem. 2007, 50,
1651−1657.
(31) Baghbanzadeh, M.; Salehi, P.; Dabiri, M.; Kozehgarya, G.
Synthesis 2006, 2, 344−348.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +91 522 2612411. Fax: +91 522 2623405. E-mail: prem_
chauhan_2000@yahoo.com; premsc58@hotmail.com.
(32) Su, W. K.; Yang, B. B. Aust. J. Chem. 2002, 55, 695.
(33) Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Zolfigol, M. A.; Agheb,
M.; Heydari, S. Catal. Commun. 2008, 9, 785−788.
(34) Dabiri, M.; Salehi, P.; Otokesh, S.; Baghbanzadeh, M.;
Kozehgarya, G.; Mohammadi, A. A. Tetrahedron Lett. 2005, 46,
6123−6126.
ACKNOWLEDGMENTS
■
M.S. and S.P. thank ICMR and UGC for providing financial
support for the work. We also thank SAIF division of the CDRI
for providing all analytical data. CDRI communication no. is
8179.
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