Metal-Free Mild Synthesis of Novel 1′ H -Spiro[Cycloalkyl-1,2′-quinazolin]-4′(3′ H)-ones by an Organocatalytic Cascade Reaction

Article abstract of DOI:10.1055/s-0036-1590917

A concise organocatalytic method for the facile synthesis of some novel 1′ H -spiro[cycloalkyl-1,2′-quinazolin]-4′(3′ H)-ones via a one-pot, three-component condensation of isatoic anhydride, aryl or aliphatic amines and a cyclic ketone is described.

Full text of DOI:10.1055/s-0036-1590917

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© Georg Thieme Verlag Stuttgart · New York
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R. Ramesh et al.
Letter
Synlett
Metal-Free Mild Synthesis of Novel 1′H-Spiro[Cycloalkyl-1,2′-
quinazolin]-4′(3′H)-ones by an Organocatalytic Cascade Reaction
Rathinam Ramesha
O
O
O
Periyathambi Kalisamya
Jan Grzegorz Maleckib
Appaswami Lalitha*a
NH2
R
AcOH (10 mol%)
N
O
+
+
R
MeOH, 65 °C
40–90 min
N
H
N
H
O
26 examples
up to 97% yield
a Department of Chemistry, Periyar University, Periyar
Palkalai Nagar, Salem-636011, Tamil Nadu, India
b Department of Crystallography, University of Silesia,
Szkolna 9, 40-006 Katowice, Poland
R = H, 4-CH(CH3)2, 4-Cl, 4-Br, 4-F, 3-OCH3, 3-Cl, 4-CH3, 4-OCH3, 3-CH3
lalitha253@periyaruniversity.ac.in
Received: 15.08.2017
Accepted after revision: 05.09.2017
Published online: 26.09.2017
condensation of isatoic anhydride, an aryl or aliphatic
amine, and a cyclic ketone in the presence of a catalytic
amount of acetic acid.
DOI: 10.1055/s-0036-1590917; Art ID: st-2017-d0626-l
We started our study by investigating the 4-toluenesul-
fonic acid (PTSA)-catalyzed three-component reaction of
aniline (1a), isatoic anhydride (2), and cyclohexanone (3) as
model substrates in ethanol at reflux temperature. We
found that the desired product 4a was obtained in 51% yield
after heating at reflux for two hours. In attempts to increase
the reaction efficiency, we studied sulfamic acid and acetic
acid as catalysts (Table 1, entries 2–4). From these observa-
tions, it was clear that acetic acid (20 mol%) gave the best
yield (91%) in the shortest reaction time (entry 4). Subse-
quently, we screened a range of polar solvents (ethanol,
methanol, acetonitrile, and propan-2-ol) (entries 4–7) and
we found that methanol was the most efficient solvent for
Abstract A concise organocatalytic method for the facile synthesis of
some novel 1′H-spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-ones via
a
one-pot, three-component condensation of isatoic anhydride, aryl or
aliphatic amines and a cyclic ketone is described.
Key words spiro compounds, quinazolinones, isatoic anhydride,
amines, cycloalkanones, multicomponent reactions
The exploration of synthetic efficiency while minimiz-
ing needless synthetic steps is key to the synthesis of com-
plex organic skeletons.1 One-step synthetic strategies are
increasingly used to access drug-like molecules.2 Specifical-
ly, heterocyclic frameworks bearing spiro centers possess
structural rigidity resulting from conformational restric-
tion, and they have consequently received attention due to
their enhanced activities against a number of pharmacolog-
ical targets.3
Table 1 Optimization of Reaction Conditions for Synthesis of Spiro
Product 4aa
Entry
Catalyst (mol %)
Solvent
Time (min)
Yieldb (%)
Spiroquinazolinones and their derivatives constitute a
privileged class of fused heterocycles, as they possess nota-
ble biological properties, especially antimicrobial activi-
ties.4 Such scaffolds have been explored as core structures
and have been extensively studied in many bioactive natu-
ral and synthetic molecules.5 Quinazolinones present nu-
merous biological actions, such as antitumor,6,7 antifibrilla-
tory,8 antidepressant,9 analgesic,10 diuretic,11 antihista-
mine,12 vasodilatory,13 antihypertensive,14 CNS-stimulant,15
tranquilizing,16 anxiolytic,17 and plant-growth-regulating18
activities. In addition, quinazolin-4(3H)-ones are useful
synthetic precursors.19–23 In continuation of our interest in
the design and synthesis of heterocyclic candidates,24 we
describe an efficient and scalable cascade strategy for the
synthesis of diversely functionalized 1′H-spiro[cycloalkyl-
1,2′-quinazolin]-4′(3′H)-one derivatives through a one-pot
1
2
–
EtOH
180
120
120
75
trace
51
57
91
94
84
79
83
93
94
PTSA (20)
NH2SO3H (20)
AcOH (20)
AcOH (20)
AcOH (20)
AcOH (20)
AcOH (5)
AcOH (10)
AcOH (15)
EtOH
3
EtOH
4
EtOH
5
MeOH
MeCN
i-PrOH
MeOH
MeOH
MeOH
60
6
120
120
90
7
8
9
60
10
60
a Reaction conditions: isatoic anhydride (2; 3 mmol), aniline (1a; 3 mmol),
cyclohexanone (3; 3 mmol), solvent (10 mL), catalyst, reflux.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
R. Ramesh et al.
Letter
Synlett
this condensation, affording the desired spiro product 4a in
94% yield (entry 5). Screening the quantity of the catalyst
showed that a yield of 93% was obtained by using 10 mol%
of acetic acid (entry 9). We also attempted to reduce the re-
action temperature from reflux to ambient temperature,
but the reaction was sluggish and the yield decreased (not
shown). Hence, the optimal conditions were determined to
be refluxing methanol containing 10 mol% of acetic acid as
the catalyst.
Table 2 Synthesis of 1′H-Spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-
one Derivativesa
Entry Amine
Product
Time
(min)
Yieldb
(%)
O
NH2
N
1
2
60
75
93
91
N
H
1a
After the optimization studies, the synthesis of a variety
of functionalized 1′H-spiro[cyclohexane-1,2′-quinazolin]-
4′(3′H)-ones25,26 was performed to explore the efficiency
and versatility of this method (Scheme 1), and the results
are presented in Table 2. Various aromatic amines bearing
either electron-withdrawing or electron-donating substitu-
ents successfully afforded the corresponding products 4b–j
in good to excellent yields (Table 2, entries 2–10). In con-
trast, aliphatic amines 1k and 1l (Table 2, entries 11 and 12)
provided only moderate yields, presumably due to their
higher nucleophilicity compared with aryl amines. The
4a
NH2
O
N
N
H
1b
4b
NH2
Cl
O
N
3
4
5
40
45
40
96
95
96
1
products were characterized by means of H and 13C NMR
N
H
Cl
spectroscopy and by X-ray single-crystal analysis.
1c
4c
NH2
Br
O
O
O
O
NH2
R
AcOH (10 mol%)
N
N
O
+
+
R
MeOH, 65 °C
40–80 min
N
H
N
H
4d
N
H
O
Br
1d
1a–j
4a–j
3
2
NH2
F
Scheme 1 Acetic acid-assisted three-component synthesis of 3′-aryl-
1′H-spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-ones
O
N
N
H
4e
F
In the 1H NMR spectrum of compound 4b, as a represen-
tative example, the aliphatic protons (–CH2–) of the cyclo-
hexane moiety appeared as multiplets at δ = 0.91, 1.25,
1.55, and 2.04 ppm; the secondary amine (–NH–) proton
appeared as a singlet at δ = 7.01 ppm; and the aromatic
protons were observed as multiplets at δ = 6.68–7.65 ppm.
In the 13C NMR spectrum, the carbons in the cyclohexane
ring appeared as resonances at δ = 21.1, 24.0 and 34.5 ppm,
and the amide carbon (–CONX) exhibited as a peak at
δ = 162.8 ppm. Furthermore, the structures of compounds
4a (Figure 1) and 4e (Figure 2) were confirmed by single-
crystal X-ray analysis.27
To extend the scope of the reaction, we applied the opti-
mized protocol to the synthesis of 1′H-spiro[cyclopentane-
1,2′-quinazolin]-4′(3′H)-ones by reaction with cyclopenta-
none (5; Scheme 2). Aromatic amines 1a–j bearing various
functional groups at various positions reacted with isatoic
anhydride (2) smoothly in the presence of cyclopentanone
(5), and the corresponding targets (6a–j) were obtained.
The results are summarized in Table 3.
1e
OCH3
NH2
O
6
80
89
N
OCH3
N
H
1f
4f
Cl
NH2
O
7
8
45
75
93
90
N
Cl
N
H
4g
1g
NH2
CH3
O
N
N
H
CH3
1h
4h
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
R. Ramesh et al.
Letter
Synlett
Entry Amine
Product
Time
(min)
Yieldb
(%)
Entry Amine
Product
Time
(min)
Yieldb
(%)
OCH3
Cl
Br
F
NH2
NH2
O
O
N
N
N
N
9
80
80
88
86
3
45
45
45
97
94
95
N
H
N
H
OCH3
1i
Cl
1c
6c
4i
NH2
CH3
O
NH2
O
4
10
N
N
H
Br
CH3
N
H
1d
6d
1j
4j
NH2
O
H2N
5
6
O
N
H
F
11
12
90
90
84
81
N
1e
6e
N
H
1k
OCH3
4k
NH2
O
O
N
85
90
NH2
OCH3
N
N
H
1f
N
H
6f
1l
4l
Cl
a Reaction conditions: isatoic anhydride (2; 3 mmol), amine 1 (3 mmol),
cyclohexanone (3; 3 mmol), AcOH (10 mol%), MeOH (10 mL), reflux.
b Isolated yield.
NH2
O
7
50
92
N
N
N
Cl
N
H
1g
Table 3 Synthesis of 1′H-Spiro[cyclopentane-1,2′-quinazolin]-4′(3′H)-
6g
one Derivativesa
CH3
NH2
O
Entry Amine
Product
Time
(min)
Yieldb
(%)
8
9
80
90
89
86
N
H
CH3
1h
O
NH2
6h
N
NH2
OCH3
1
2
60
80
91
94
O
N
H
1a
6a
N
H
OCH3
NH2
1i
6i
O
CH3
N
NH2
O
N
H
1b
6b
N
10
90
85
CH3
N
H
1j
6j
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
R. Ramesh et al.
Letter
Synlett
Entry Amine
Product
Time
(min)
Yieldb
(%)
H2N
O
N
11
95
86
N
H
1k
6k
O
N
NH2
12
110
81
Figure 2 ORTEP of compound 4e (CCDC 1543282)28
N
H
1l
6l
a Reaction conditions: isatoic anhydride (2; 3 mmol), amine (1; 3 mmol),
cyclopentanone (5; 3 mmol) AcOH (10 mol%), MeOH (10 mL), reflux.
b Isolated yields.
1
The H NMR spectrum of compound 6b showed multi-
plets at δ = 1.43, 1.71, and 1.89 ppm corresponding to the
aliphatic protons of the cyclopentane group. The secondary
amine (–NH–) proton appeared as a singlet at δ = 6.93 ppm,
and the aromatic protons appeared as multiplets at
δ = 6.69–7.67 ppm. In the 13C NMR spectrum, the amide
carbon (–CONX) was evident as a resonance at δ = 163.0
ppm.29 Moreover, the structure of 6e was confirmed by sin-
gle-crystal X-ray analysis (Figure 3).
Figure 3 ORTEP of compound 6e (CCDC 1543283)28
Finally, we examined the reaction with benzene-1,4-di-
amine (7) instead of an aromatic monoamine (Scheme 3),
and this pseudo-five-component reaction led to the novel
bis{1′H-spiro[cycloalkane-1,2′-quinazolin]-4′(3′H)-ones}
8
and 9 in good yields. Their structures were confirmed by 1H
and 13C NMR spectroscopic analyses.
In conclusion, we have disclosed an efficient and con-
cise approach for the one-pot synthesis of various 1′H-
spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-one
derivatives
O
O
NH2
O
R
AcOH (10 mol%)
N
O
+
+
R
MeOH, 65 °C
45–90 min
N
H
N
H
O
1a–j
6a–j
2
5
Scheme 2 Three-component synthesis of 3′-aryl-1′H-spiro[cyclopen-
tane-1,2′-quinazolin]-4′(3′H)-ones
Figure 1 ORTEP of compound 4a (CCDC 1543174)28
H
N
NH2
O
N
O
O
O
O
AcOH (10 mol%)
+
N
+
N
H
O
MeOH, 65 °C
45 min
N
H
NH2
3 or 5
2
7
8 or 9
Scheme 3 Pseudo-five-component synthesis of bis{1′H-spiro[1,2′-quinazolin]-4′(3′H)-ones}
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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R. Ramesh et al.
Letter
Synlett
through a three-component reaction in the presence of a
catalytic amount of acetic acid. The method tolerates an ar-
ray of functional groups and has the advantages of mild re-
action conditions, short reaction times, experimental sim-
plicity, and excellent yields.
(14) Beau de Loménie, G.; Armengaud, A.; Houssard, G. FR 1893(M),
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(15) Schipper, E. S. US 3265697, 1966.
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Acknowledgment
(19) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
R.R. thanks DST, New Delhi, India (No: DST/INSPIRE Fellow-
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590917.
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References and Notes
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(25) 1′H-Spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-ones 4a–l and
6a–l; General Procedure
A 50 mL round-bottomed flask was charged with MeOH (5 mL),
isatoic anhydride (2; 3 mmol), the appropriate amine 1 (3
mmol), and AcOH (10 mol%), and the mixture was stirred at r.t.
for about 5 min. Cyclohexanone or cyclopentanone (3 mmol) in
MeOH (5 mL) was added, and the resulting mixture was stirred
at the reflux temperature until the reaction was complete [TLC;
EtOAc–hexane (3:7); see Tables 2 and 3]. The mixture was
allowed to cool to r.t., and the resulting solid was collected by
filtration. The crude product was purified by crystallization
from EtOH.
(26) 3′-(4-Isopropylphenyl)-1′H-spiro[cyclohexane-1,2′-
quinazolin]-4′(3′H)-one (4b)
Colorless crystals; yield: 914 mg (91%); mp 208–210 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 0.91 (d, J = 12.0 Hz, 1 H, CH2), 1.23 (d,
J = 6.8 Hz, 6 H, CH2), 1.29 (d, J = 12.4 Hz, 2 H, CH2), 1.55 (m, 5 H,
CH2), 2.01 (d, J = 12.0 Hz, 2 H, CH), 2.91 (m, 1 H, CH), 6.68 (s, 1 H,
ArH), 6.70 (s, 1 H, NH), 7.03 (m, 3 H, ArH), 7.27 (d, J = 6.8 Hz, 3 H,
ArH), 7.63 (t, J = 7.2 Hz, 1 H, ArH). 13C NMR (100 MHz, DMSO-
d6): δ = 21.1, 23.7, 24.0, 32.9, 34.5, 72.9, 115.1, 115.6, 117.1,
126.4, 127.5, 130.0, 132.9, 135.7, 145.5, 147.3, 162.8. Anal.
Calcd for C22H26N2O (334.45): C 79.0, H 7.84, N 8.38; Found: C
79.44, H 8.15, N 8.76.
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Sharpe, A.; Taylor, A. J.; Whitworth, J. M.; Williams, S. C. Bioorg.
Med. Chem. Lett. 2005, 15, 5335.
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(27) Crystals of compounds 4a, 4e, and 6e were mounted on a
Gemini A Ultra Oxford Diffraction automatic diffractometer
equipped with a CCD detector. Data were collected with graph-
ite-monochromated MoKα radiation (λ = 0.71073 Å) at 295(2) K
with an ω scan mode. Lorentz, polarization, and empirical
absorption corrections using spherical harmonics implemented
in the SCALE3 ABSPACK scaling algorithm were applied.30 The
structure was solved by direct methods and subsequently com-
pleted by difference Fourier recycling. Nonhydrogen atoms
were refined anisotropically by using the full-matrix least-
squares technique. Hydrogen atoms were found by difference
Fourier synthesis after four cycles of anisotropic refinement,
and refined as riding on the adjacent carbon atom with an indi-
vidual isotropic temperature factor equal to 1.2 times the value
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
R. Ramesh et al.
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of equivalent temperature factor of the parent atom. Olex231
and SHELXS, SHELXL32 programs were used for all the calcula-
tions.
CH), 6.71 (t, J = 7.2 Hz, 1 H, ArH), 6.86 (d, J = 8.0 Hz, 1 H, ArH),
6.93 (s, 1 H, NH), 7.10 (d, J = 8.0 Hz, 2 H, ArH), 7.28 (d, J = 7.6 Hz,
3 H, ArH), 7.67 (d, J = 7.2 Hz, 1 H, ArH). 13C NMR (100 MHz,
DMSO-d6): δ = 21.2, 23.7, 32.9, 36.2, 81.6, 114.9, 115.6, 117.1,
126.5, 127.8, 129.7, 132.9, 136.1, 146.4, 147.4, 163.0. Anal.
Calcd for C21H24N2O (320.43): C 78.71, H 7.55, N 8.74; Found: C
79.26, H 7.89, N 9.03.
(28) CCDC 1543174, 1543282, and 1543283 contains the supple-
mentary crystallographic data for compounds 4a, 4e, and 6e,
respectively. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(30) CrysAlis RED, ; Version 1.171.37.35g; Oxford Diffraction Ltd:
London,.
(31) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
(29) 3′-(4-Isopropylphenyl)-1′H-spiro[cyclopentane-1,2′-
quinazolin]-4′(3′H)-one (6b)
Colorless crystals; yield: 907 mg (94%); mp 244–246 °C. 1H NMR
(400 MHz, DMSO-d6): δ = 1.22 (d, J = 6.8, 6 H, CH3), 1.43 (s, 2 H,
CH2), 1.71 (d, J = 7.6 Hz, 4 H), 1.89 (s, 2 H, CH2), 2.91 (m, 1 H,
(32) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F