Copper-catalyzed synthesis of 2,3-disubstituted quinazolin-4(3H)-ones from benzyl-substituted anthranilamides

Article abstract of DOI:10.1515/hc-2018-0051

An efficient, practical approach to the copper-catalyzed synthesis of 2,3-disubstituted quinazolin-4(3H)-one derivatives is described. The preparation involves treatment of benzyl amines with benzyl anthranilamides in the presence of Cu(OAc)₂ and tetra-n-butylammonium bromide (TBAB).

Full text of DOI:10.1515/hc-2018-0051

Heterocycl. Commun. 2018; aop
Parham Foroumadi, Vahid Lotfi, Mohammad Mahdavi, Setareh Moghimi, Mehdi Soheilizad,
ECborahpimpKeiarn-mceahr,tLaoglhymzaen Fdirosozyponurt, hAlieAssaidsipoourf* a2nd,3Al-irdezaisFourobumsatdii*tuted
quinazolin-4(3H)-ones from benzyl-substituted
anthranilamides
https://doi.org/10.1515/hc-2018-0051
antimicrobial [5], anti-inflammatory [6], anticonvulsant
[7], anti-ulcer [8], anti-bacterial [9] and aldose reductase
inhibitory activity [10] are some of the biological proper-
ties of quinazolin-4(3H)-ones. Considering the remarkable
biological activities of quinazolines [11], it is not surprising
that many synthetic procedures have been reported, giving
access to the libraries of this scaffold [12–20]. Transition-
metal coupling reactions form important approaches to
this class of compounds by utilizing various substrates,
Received March 29, 2018; accepted August 13, 2018
Abstract: An efficient, practical approach to the copper-
catalyzed synthesis of 2,3-disubstituted quinazolin-4(3H)-
one derivatives is described. The preparation involves
treatment of benzyl amines with benzyl anthranilamides
in the presence of Cu(OAc)2 and tetra-n-butylammonium
bromide (TBAB).
Keywords: anthranilamide; copper acetate; quinazolin- including palladium-catalyzed carbonylation of 2-amin-
4(3H)-one; TBAB.
obenzamide [21], palladium-catalyzed isocyanide inser-
tion/cyclization sequence between 2-aminobenzamides
and aryl halides [22], C-H bond carboxamidation of N-aryl-
amidines catalyzed by palladium acetate [23] and coupling
reaction between 2-bromobenzoic acid and amidines cata-
lyzed by CuI [24]. In our previous report, oxidative synthe-
sis of 2-substituted quinazolin-4(3H)-ones starting from
benzyl-substituted anthranilamides was described [25].
Surprisingly, it was found that 2,3-disubstituted quinazo-
lin-4(3H)-ones are formed as the major products from the
same substrates and benzylamines in the reaction con-
ducted under similar conditions. This work is a continua-
tion of our efforts directed toward the development of new
heterocyclic chemistry [26–31].
Introduction
Nitrogen-containingheterocycliccompoundsareprivileged
structures in medicinal chemistry [1–3]. Quinazolin-4(3H)-
one is a significant pharmacophore among nitrogen-
containing heterocyclic compounds, due to the various
biological and pharmacological properties. Anticancer [4],
*Corresponding authors: Ali Asadipour, Pharmaceutics Research
Center, Institute of Neuropharmacology, Kerman University
of Medical Sciences, PO Box 7616913555, Kerman, Iran,
e-mail: aliasadipour@yahoo.com; and Alireza Foroumadi, Drug
Design and Development Research Center, The Institute of
Pharmaceutical Sciences (TIPS), Tehran University of Medical
Sciences, Tehran, Iran; and Neuroscience Research Center, Institute
of Neuropharmacology, Kerman University of Medical Sciences,
PO Box 7616913555, Kerman, Iran, e-mail: aforoumadi@yahoo.com
Parham Foroumadi: Pharmaceutics Research Center, Institute
of Neuropharmacology, Kerman University of Medical Sciences,
PO Box 7616913555, Kerman, Iran
Vahid Lotfi, Mehdi Soheilizad and Ebrahim Kianmehr: School of
Chemistry, College of Science, University of Tehran, PO Box 14155-
6455, Tehran, Iran
Mohammad Mahdavi: Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism Clinical Sciences Institute,
Tehran University of Medical Sciences, PO Box 1411713137, Tehran, Iran
Setareh Moghimi and Loghman Firoozpour: Drug Design and
Development Research Center, The Institute of Pharmaceutical
Sciences (TIPS), Tehran University of Medical Sciences,
PO Box 1417614411, Tehran, Iran
Results and discussion
A new pathway for the preparation of 2,3-disubstituted
quinazolin-4(3H)-ones by the reaction of N-benzylanthra-
nilamides 3a–h with benzylamines is shown in Scheme 1.
The substrates 3a–h are easily prepared by treatment of
isatoic anhydride (1) with benzylamines 2a–h in aqueous
media. In order to optimize the reaction condition, the syn-
thesis of 3-benzyl-2-phenylquinazolin-4(3H)-one (4a) was
chosen as a model reaction. First, the effects of tetra-n-bu-
tylammonium bromide (TBAB) and Cu(OAc)2 were evalu-
ated in this reaction in the presence of K2CO3 in p-xylene.
The best yield of the product was obtained in the presence
of 20 mol% of TBAB and 5 mol% of Cu(OAc)2. Different sol-
vents including toluene, N,N-dimethylformamide (DMF)
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2ꢀ ꢀP. Foroumadi et al.: Synthesis of quinazolinones
O
O
O
N
ArCH2NH2
2a–h
Cu(OAc)2
Ar
N
Ar
N
O
H
Ar
NH2
H2O
K2CO3, TBAB
p-xylene, air
∆, 24 h
NH2
Ar
N
O
H
1
3
4a–h
e: Ar = 2-ClC6H4
f: Ar = 4-ClC6H4
g: Ar = 3,4-Cl2C6H4
h: Ar = 2-furyl
a: Ar = Ph
b: Ar = 4-MeOC6H4
c: Ar = 4-MeC6H4
d: Ar = 4-FC6H4
Scheme 1ꢀSynthesis of compounds 4a–h from N-benzylanthranilamides.
O
Ar
NH
O
O
N
H
H
H2N
O2
Ar
Cu(OAc)2
-HOAc
N
3a–h
N
Ar
Ar
NH2
2a–h
Ar
N
CuIIOAc
Ar
NH
H
-NH3
ox.
Ar
N
Ar
5a–h
6a–h
7a–h
4a–h
Scheme 2ꢀSuggested mechanism for the synthesis of quinazolin-4(3H)-ones 4.
and dimethyl sulfoxide (DMSO) were also investigated. procedure, ready availability of the starting materials and
However, these changes did not enhance the yield of the good yields are the main advantages of this method.
desired product as compared with the use of p-xylene. The
important role of air in this reaction was demonstrated by
performing the reaction under inert atmosphere, which
Experimental
led to trace amounts of the desired product only. As shown
in Scheme 1, the reactions of aromatic benzylamines con-
All commercially available chemicals and reagents were pur-
taining electron-donating groups, such as Me and OMe,
or electron-withdrawing groups, such as F and Cl, furnish
the corresponding products 4a–h in 61–77% yields. An
attempted synthesis with aliphatic amines was not suc-
cessful, however. The structures of all synthesized products
were confirmed by analytical and spectral data including
Fourier transform infrared spectroscopy (FT-IR), proton
chased from Merck or Fluka and were used without further puri-
fication. Melting points were measured with a Koffler hot stage
1
apparatus and are uncorrected. H NMR (500 MHz) and 13C NMR
(125 MHz) spectra were recorded on a Bruker FT-500 spectrometer in
DMSO-d6, using tetramethylsilane (TMS) as an internal standard. IR
spectra were recorded on a Shimadzu 470 spectrophotometer in KBr
disks. electron ionization (EI) mass spectra were obtained using an
Agilent Technology (HP) mass spectrometer operating at an ioniza-
tion potential of 70 eV. Elemental analysis was performed using an
Elemental Analysen system.
13
nuclear magnetic resonance (1H NMR), C NMR and mass
spectrometry (MS). For example, in the 1H NMR spectra the
CH2 benzylic group for sterically unhindered molecules
appears as a singlet. By contrast, the restricted rotation in
4e gives rise to the appearance of benzylic protons as an
AB system with two doublets at δ 4.90 and 5.51.
General procedure for the synthesis of
N-benzylanthranilamides 3a–h
As suggested in Scheme 2, the mechanism may involve
coordination of Cu(II) with benzylamine followed by oxi-
dation of the resultant complex 5 to benzylamine 6. A
subsequent addition reaction of 3 with 6 may generate inter-
mediate product 7 which is the final precursor to 4 [32–34].
A mixture of isatoic anhydride 1 (1 mmol) and benzylamine 2a–h
(1 mmol) in H2O (10 mL) was stirred at room temperature. Upon comple-
tion of the reaction, as monitored by thin-layer chromatography (TLC),
the resulting precipitate was filtered, washed with cold water, dried and
crystallized from ethanol to afford the desired compound 3a–h.
General procedure for the synthesis of 2,3-disubstituted
quinazolin-4(3H)-ones 4a–h
Conclusions
A straightforward, copper-catalyzed approach to the syn-
A mixture of N-benzylanthranilamide 3a–h (1 mmol), Cu(OAc)2
(5 mol%), K2CO3 (1 mmol) and TBAB (20 mol%) in p-xylene (10 mL)
thesis of 2,3-disubstituted quinazolin-4(3H)-ones from
benzyl anthranilamides is described. The simplicity of the was stirred for 24 h under reflux. Upon completion of the reaction, as
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P. Foroumadi et al.: Synthesis of quinazolinonesꢂ ꢂ3
indicated by TLC analysis, the mixture was cooled and filtered. The 3-(4-Chlorobenzyl)-2-(4-chlorophenyl)quinazolin-4(3H)-one
filtrate was concentrated and the residue was purified by silica gel (4f)ꢀThis compound was obtained as a white solid; yield 72%; mp
column chromatography eluting with petroleum ether/EtOAc (4:1) to 164–166°C; IR: 3054, 2962, 1666, 1559, 1258 cm−1; 1H NMR (DMSO-d6):
afford pure product 4a–h.
δ 8.22 (d, Jꢁ=ꢁ8.0 Hz, 1H), 7.87 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.71 (d, Jꢁ=ꢁ8.0 Hz, 1H),
7.59 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.50 (d, Jꢁ=ꢁ8.0 Hz, 2H), 7.47 (d, Jꢁ=ꢁ8.0 Hz, 2H),
3-Benzyl-2-phenylquinazolin-4(3H)-one (4a)ꢀThis compound 7.28 (d, Jꢁ=ꢁ8.0 Hz, 2H), 6.90 (d, Jꢁ=ꢁ8.0 Hz, 2H), 5.16 (s, 2H); 13C NMR
was obtained as a white solid; yield 65%; mp 150–152°C (lit mp (DMSO-d6): δ 161.3, 154.9, 146.8, 135.5, 134.7, 134.6, 133.7, 131.8, 129.8,
152–153°C, [19, 35, 36]); IR: 2949, 1682, 1567, 1271 cm−1; 1H NMR (DMSO- 128.3, 128.2, 127.3 (2C), 126.4 (2C), 120.3, 47.6; MS: m/z (%) 383 (M ꢁ+ꢁ2,
+
+
d6): δ 8.22 (d, Jꢁ=ꢁ8.0 Hz, 1H), 7.87 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.72 (d, Jꢁ=ꢁ8.0 Hz, 15), 381 (M , 40), 345 (55), 269 (61), 144 (100), 124 (44), 76 (29). Anal.
1H), 7.59 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.51–7.40 (m, 5H), 7.24–7.18 (m, 3H), 6.92– Calcd for C21H14Cl2N2O: C, 66.16; H, 3.70; N, 7.35. Found: C, 66.38; H,
6.90 (m, 2H), 5.18 (s, 2H); 13C NMR (DMSO-d6): δ 161.9, 156.6, 147.4, 3.89; N, 7.19.
137.2, 135.6, 135.2, 130.2, 128.9, 128.7, 128.4, 127.8, 127.7, 127.5, 126.9,
126.7, 120.8, 48.7. Anal. Calcd for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. 3-(3,4-Dichlorobenzyl)-2-(3,4-dichlorophenyl)quinazolin-4(3H)-
Found: C, 80.56; H, 5.35; N, 9.14.
one (4g)ꢀThis compound was obtained as a white solid; yield 63%;
mp 160–162°C; IR: 3064, 2968, 1677, 1564, 1256 cm−1; 1H NMR (DMSO-
d6): δ 8.23 (d, Jꢁ=ꢁ8.0 Hz, 1H), 7.88 (t, Jꢁ=ꢁ7.0 Hz, 1H), 7.73–7.70 (m, 2H),
7.66 (d, Jꢁ=ꢁ2.0 Hz, 1H), 7.62 (t, Jꢁ=ꢁ7.5 Hz, 1H), 7.48 (d, Jꢁ=ꢁ8.0 Hz, 1H),
7.44 (dd, Jꢁ=ꢁ8.0, 1.5 Hz, 1H), 7.24 (s, 1H), 6.99 (d, Jꢁ=ꢁ8.0 Hz, 1H), 5.12
(s, 2H); 13C NMR (DMSO-d6): δ 161.30, 153.49, 146.67, 137.61, 135.14,
134.69, 132.68, 131.13, 131.01, 130.52, 130.45, 130.17, 129.78, 128.88,
128.08, 127.40, 127.30, 126.76, 126.34, 120.47, 47.33; MS: m/z (%) 454
3-(4-Methoxybenzyl)-2-(4-methoxyphenyl)quinazolin-4(3H)-
one (4b)ꢀThis compound was obtained as a white solid; yield 77%;
mp 158–160°C; IR: 3061, 2952, 1677, 1577, 1266 cm−1; H NMR (CDCl3):
1
δ 8.36 (d, Jꢁ=ꢁ7.3 Hz, 1H), 7.81–7.76 (m, 2H), 7.54–7.51 (m, 1H), 7.35 (d,
Jꢁ=ꢁ8.7 Hz, 2H), 6.95 (d, Jꢁ=ꢁ8.7 Hz, 2H), 6.90 (d, Jꢁ=ꢁ8.7 Hz, 2H), 6.75
(d, Jꢁ=ꢁ8.7 Hz, 2H), 5.26 (s, 2H), 3.87 (s, OCH3), 3.77 (s, OCH3); 13C NMR
(CDCl3): δ 162.4, 161.0, 158.9, 156.5, 134.6, 132.3, 130.6, 129.8, 129.6,
129.2, 128.6, 128.3, 127.7, 127.1, 120.6, 117.4, 55.4, 55.2, 48.4; MS: m/z (%)
+
+
+
(M ꢁ+4, 11), 452 (M ꢁ+2, 16), 450 (M , 43), 303 (41), 159 (51), 144 (100),
77 (34). Anal. Calcd for C21H12Cl4N2O: C, 56.03; H, 2.69; N, 6.22. Found:
C, 55.86; H, 2.85; N, 6.44.
+
372 (M , 31), 341 (19), 265 (43), 145 (100), 121 (59), 77 (25). Anal. Calcd
for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 73.89; H, 5.67; N, 7.76.
2-(Furan-2-yl)-3-(furan-2-ylmethyl)quinazolin-4(3H)-one
(4h)ꢀThis compound was obtained as a white solid; yield 65%;
mp 173–175°C; IR: 3057, 2946, 1664, 1571, 1263 cm−1; 1H NMR (CDCl3):
δ 8.33 (d, Jꢁ=ꢁ8.1 Hz, 1H), 7.78–7.74 (m, 1H), 7.66 (d, Jꢁ=ꢁ1.3 Hz, 1H),
7.51 (dd, Jꢁ=ꢁ5.4, 2.8 Hz, 1H), 7.49 (dd, Jꢁ=ꢁ5.6, 2.6 Hz, 1H), 7.29
(d, Jꢁ=ꢁ1.3 Hz, 1H), 7.14 (d, Jꢁ=ꢁ3.4 Hz, 1H), 6.60 (dd, Jꢁ=ꢁ3.6, 1.8 Hz, 1H),
6.25 (dd, Jꢁ=ꢁ3.2, 1.8 Hz, 1H), 6.16 (d, Jꢁ=ꢁ3.2 Hz, 1H), 5.26 (s, 2H); 13C
NMR (CDCl3): δ 162.04, 149.60, 147.32, 147.20, 145.83, 144.43, 142.26,
134.55, 127.57, 127.25, 127.12, 120.65, 115.63, 111.99, 110.44, 108.44,
3-(4-Methylbenzyl)-2-(p-tolyl)quinazolin-4(3H)-one (4c)ꢀThis
compound was obtained as a white solid; yield 72%; mp 144–146°C;
1
IR: 3053, 2948, 1566, 1273 cm−1; H NMR (CDCl3): δ 8.36 (d, Jꢁ=ꢁ7.9 Hz,
1H), 7.78–7.77 (m, 2H), 7.53–7.50 (m, 1H), 7.29 (d, Jꢁ=ꢁ7.9 Hz, 2H), 7.23 (d,
Jꢁ=ꢁ7.9 Hz, 2H), 7.01 (d, Jꢁ=ꢁ7.9 Hz, 2H), 6.87 (d, Jꢁ=ꢁ7.9 Hz, 2H), 5.25 (s,
CH2), 2.42 (s, CH3), 2.29 (s, CH3); 13C NMR (CDCl3): δ 162.5, 156.7, 147.2,
140.1, 137.1, 134.5, 133.6, 132.4, 129.2, 129.2, 128.0, 127.4, 127.1, 127.0,
+
126.9, 120.8, 48.7, 21.4, 21.0; MS: m/z (%) 340 (M , 22), 325 (31), 311 (12),
+
235 (71), 145 (100), 91 (19), 77 (34). Anal. Calcd for C23H20N2O: C, 81.15;
H, 5.92; N, 8.23. Found: C, 81.00; H, 5.74; N, 8.41.
41.13; MS: m/z (%) 292 (M , 29), 225 (50), 145 (100), 82 (47), 67 (33).
Anal. Calcd for C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C, 69.98;
H, 4.09; N, 9.66.
3-(4-Fluorobenzyl)-2-(4-fluorophenyl)quinazolin-4(3H)-one
(4d)ꢀThis compound was obtained as a white solid; yield 61%; mp
171–173°C; IR: 3064, 2966, 1667, 1572, 1256 cm−1; 1H NMR (CDCl3): δ 8.33
(d, Jꢁ=ꢁ8.5 Hz, 1H), 7.73–7.71 (m, 1H), 7.68 (d, Jꢁ=ꢁ8.6 Hz, 1H), 7.35–7.32 (m,
3H), 7.14–7.11 (m, 3H), 6.89–6.80 (m, 3H), 5.31 (s, 2H); 13C NMR (CDCl3): Supplementary information
δ 164.6, 162.6 (d, JC-Fꢁ=ꢁ175 Hz), 161.2 (d, JC-Fꢁ=ꢁ124 Hz), 155.4, 145.5, 135.1,
(online only)
133.2, 131.9, 131.1, 130.2 (d, JC-Fꢁ=ꢁ7.8 Hz), 129.3, 128.8 (d, JC-Fꢁ=ꢁ7.8 Hz),
126.5, 121.8, 115.8 (d, JC-Fꢁ=ꢁ21.4 Hz), 115.5 (d, JC-Fꢁ=ꢁ21.7 Hz), 48.2; MS:
+
m/z (%) 348 (M , 44), 239 (73), 144 (100), 109 (62), 95 (41). Anal. Calcd
Characterization of compounds 3a–h.
for C21H14F2N2O: C, 72.41; H, 4.05; N, 8.04. Found: C, 72.60; H, 4.23;
N, 7.86.
Acknowledgments: This study was supported by the
research council of Kerman University of Medical Sciences,
Grant no: 95000218.
3-(2-Chlorobenzyl)-2-(2-chlorophenyl)quinazolin-4(3H)-one
(4e)ꢀThis compound was obtained as a white solid; yield 70%; mp
176–178°C; IR: 3063, 2962, 1673, 1572, 1277 cm−1; 1H NMR (DMSO-d6): δ
8.30 (d, Jꢁ=ꢁ8.0 Hz, 1H), 7.92 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.79 (d, Jꢁ=ꢁ8.0 Hz, 1H),
7.66 (t, Jꢁ=ꢁ8.0 Hz, 1H), 7.57 (d, Jꢁ=ꢁ8.0 Hz, 1H), 7.51 (t, Jꢁ=ꢁ8.5 Hz, 1H),
7.36–7.30 (m, 3H), 7.24–7.20 (m, 2H), 7.02 (d, Jꢁ=ꢁ7.5 Hz, 1H), 5.51 (d,
Jꢁ=ꢁ16.5 Hz, 1H), 4.90 (d, Jꢁ=ꢁ16.5 Hz, 1H); 13C NMR (DMSO-d6): δ 161.0,
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Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/hc-2018-0051).
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