Bimetallic Cu–Mn-Catalyzed Synthesis of 2-Arylquinazolin-4(3H)-ones: Aqueous Ammonia as Source of a Ring Nitrogen Atom

Article abstract of DOI:10.1002/ejoc.201601024

A new method for the synthesis of 2-arylquinazolin-4(3H)-ones that involves a three-component coupling reaction of 2-bromobenzamide, aryl aldehydes, and aqueous ammonia has been developed. This protocol employs Cu–Mn spinel oxide as a heterogeneous catalyst and does not require the presence of a ligand or external oxidant. Key features of the reaction include a recyclable catalyst, ligand-free conditions, and a wide scope of possible substrates. The mechanism begins with the replacement of the bromine atom with NH₂from aqueous ammonia followed by imine formation, intramolecular ring cyclization (C–N bond formation), and aromatization.

Full text of DOI:10.1002/ejoc.201601024

A Journal of
Accepted Article
Title: Bimetallic Cu-Mn catalyzed synthesis of 2-arylquinazolin-4(3H)-ones: Aqueous
ammonia as a source of ring nitrogen
Authors: Sandip Bibishan Bharate; Rohit Sharma; Ram A Vishwakarma
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601024
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COMMUNICATION
Bimetallic Cu-Mn catalyzed synthesis of 2-arylquinazolin-4(3H)-ones:
Aqueous ammonia as a source of ring nitrogen
Rohit Sharma,[a], Ram A. Vishwakarma,*[a] Sandip B. Bharate*[a]
Abstract: A new method for synthesis of 2-arylquinazolin-4(3H)-
ones comprising a 3-component coupling of 2-bromobenzamide, aryl
aldehydes and aqueous ammonia has been reported. The protocol
involves Cu-Mn spinel oxide as a heterogeneous catalyst and does
not require any ligand or external oxidant. Key features of the
reaction include recyclable catalyst, ligand-free conditions and wide
substrate scope. Reaction involves replacement of bromine with NH2
from aqueous ammonia, which is then followed by imine formation,
intramolecular ring cyclization (C-N bond formation) and
aromatization.
There are numerous reports on the synthesis of quinazolin-4-
16f, 17]
(3H)-ones.[15b,
Amongst these reports, most common
approach is the condensation of 2-aminobenzamide or O-
nitrobenzamides with aldehydes,[18],[15b] aryl acid chlorides,[19]
22]
benzyl bromides,[20] benzylamines,[21] and alcohols.[15b,
Another common approach is the Ullmann-type coupling of 2-
bromobenzamide with benzyl amine.[23] Many of these Ullmann
coupling protocols requires copper catalyst, ligand and high
heating.[1c, 24] Guo et al reported synthesis of this scaffold by 3-
component coupling of 2-bromobenzamide, aryl aldehydes and
aqueous ammonia using CuBr catalyst and L-proline ligand.[25]
Herein, we report ligand-free synthesis of 2-arylquinazolin-
4(3H)-ones via condensation of 2-bromobenzamides, aryl
aldehydes and ammonia[25] using heterogeneous bimetallic Cu-
Mn catalyst. The “aqueous ammonia” acts as a source for ring
“nitrogen”, for construction of 2-arylquinazolin-4(3H)-ones
(Figure 2).
Introduction
The cross-coupling reaction between aryl halide and amines has
gained a lot of attention for construction of aromatic C-N bond.[1]
Furthermore, the use of heterogeneous catalysts[2] in organic
synthesis has proved to be highly beneficial from economical
point of view. Amongst various heterogeneous catalysts, several
bimetallic catalysts have displayed promising catalytic efficiency
for wide range of chemical transformations - e.g. Ru-Ce for
dihydroxylation of glycals,[3] Ni-Pd for cross-coupling of two
different aryl electrophiles,[4] bimetallic Pd and Cu-Mn for
Huisgen [3+2]-cycloaddition,[5] for synthesis of imidazo[1,2-
a]pyridines,[6] regioselective halogenations of phenols,[7] and for
coupling of aryl boronic acids with amines.[8]
Quinazolin-4(3H)-one scaffold has gained tremendous
importance in synthetic organic chemistry in past few decades
because of their diverse range of pharmacological activities such
as
anticancer,[9]
antifungal,[10]
anti-diabetic,[11]
anti-
inflammatory,[12] antimicrobial,[13] hypolipidemic,[14] and many
other properties.[2c,
Furthermore, it has wide occurrence
15]
among natural products.[2c, 15b, 16] Examples of quinazolin-4(3H)-
Figure 2. Approaches for synthesis of 2-aryl quinazolin-4(3H)-
ones
one natural products are shown in Figure 1.
Results and Discussion
In order to establish
quinazolin-4(3H)-ones,
a
protocol for synthesis 2-aryl
a
model reaction between 2-
bromobenzamide (2a), benzaldehyde (3a) and aqueous
ammonia in presence of various copper catalysts and a base
(Table 1) was investigated. Initially, CuI and CuBr catalysts were
used in the presence of potassium carbonate base and DMSO
as a solvent. The desired product 1a was obtained, however
only in 30-40% yield. Further, we investigated the catalytic
activity of heterogeneous Cu-Mn bimetallic catalysts available in
our laboratory. Three types of Cu-Mn catalysts, varying in
copper and manganese content[6] i.e. Cu-Mn A (2: 0.25), Cu-Mn
B (1: 0.25) and Cu-Mn C (3: 0.25) were studied. Initially, we
used catalyst loading of 10% w/w for these catalysts (entries 5-
7). Amongst these three catalysts, Cu-Mn B gave desired
product 1a in 85% yield (entry 4). However, in case of catalysts
Cu-Mn A and Cu-Mn C, the higher product yield was obtained
Figure 1. Examples of biologically active quinazolin-4(3H)-ones.
[a]
Rohit Sharma, Ram A. Vishwakarma, Sandip B. Bharate
Medicinal Chemistry Division
Academy of Scientific & Innovative Research (AcSIR),
CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu - 180001, India
E-mail: sbharate@iiim.ac.in; sandipbharate@gmail.com
www.iiim.res.in
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Catalyst and solvent optimization studies[a]
Entry
1.
Catalyst (loading)
Base
Temp. (ºC)
100
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMF
Time (h)
% Yield[b]
40
CuI (5 mol%)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
6
6
6
6
6
6
6
2
6
6
6
6
6
6
2.
CuBr (5 mol%)
100
30
3.
Cu (OAc)2 (5 mol%)
Cu (CF3SO3)2 (5 mol%)
Cu-Mn A (10% w/w)
Cu-Mn B (10% w/w)
Cu-Mn C (10% w/w)
Cu-Mn B (5% w/w)
Cu-Mn A (20% w/w)
Cu-Mn C (20% w/w)
Cu-Mn B (10% w/w)
Cu-Mn B (10% w/w)
Cu-Mn B (10% w/w)
Cu-Mn B (10% w/w)
Cu-Mn B (10% w/w)
100
35
4.
100
60
5.
100
50
6. [c]
7.
100
100
85
55
8.
100
70
9.
100
65
10.
11.
12.
13.
14.
15.
100
50
100
75
100
70
110
60
120
65
100
1,4-dioxane
6
60
[a] Reagents and conditions: 2-bromobenzamide (1.0 equiv), aldehyde (1.8 equiv), ammonia (2.5 mL);
reaction conditions.
isolated yield;
optimized
[b]
[c]
when catalyst loading was increased from 10 to 20% w/w
(entries 9 and 10). The Cu-Mn B catalyst even showed good
yield at 5% w/w loading of the catalyst (entry 8). Due to distinct
phases of Cu and Mn present in Cu-Mn B as predicted from
PXRD studies, it gave best results.[6] Amongst various bases
investigated (K2CO3, K3PO4, and Cs2CO3), K2CO3 gave better
results (entries 6, 11 and 12). Amongst various solvents studied
(entries 6, 13-15), DMSO was found to be the best solvent for
this reaction. In nutshell, the best condition identified is entry 6.
In order to check whether reaction works with other amines,
reaction was also carried out with methyl amine, aniline and
benzylamine; however corresponding product was not formed
with any of these amine substrates.
formed. Next, we also attempted the reaction with N-substituted
2-bromobenzamide but desired product was not formed.
Using the optimized reaction conditions, the substrate scope of
the reaction was then investigated for various substituted
aldehydes (Figure 3). Reaction proceeded well with various
heteroaryl and aryl aldehydes substituted with electron-
withdrawing (examples 1b, 1c, 1e, 1h, 1i, 1o, 1p, 1q, 1r and 1s)
as well as electron donating groups (examples 1d, 1f, 1j, 1m
and 1n). Biphenyl aldehyde and fused aryl aldehyde also
produced good yields (examples 1g and 1l). No specific
electronic effect was seen; however the higher yields were
obtained with aldehydes comprising electron-donating group in
comparison to aldehydes with electron-withdrawing groups. It is
noteworthy to mention that reaction worked well with ortho-
substituted aryl aldehydes (examples 1d, 1e, 1h, 1i) as well as
with phenolic OH group containing aryl aldehydes (example 1f).
Reaction also worked well with heteroaryl aldehydes such as 4-
pyridine carboxyaldehyde (example 1t) and 3-pyridine
carboxaldehyde (example 1u). Next, we explored the substrate
scope of this reaction for aliphatic aldehydes (phenyl
acetaldehyde, hexanal), however desired product was not
Figure 3. Substrate scope of the reaction. Reagents and
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European Journal of Organic Chemistry
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COMMUNICATION
conditions: 2-bromobenzamide 2 (1.0 equiv), aldehyde 3 (1.8
equiv), aq. ammonia (2.5 ml), Cu-Mn B (10% w/w), K2CO3 (2.5
equiv) in DMSO (5 mL), 6 h, 50-85%.
Experimental Section
General. All chemicals were obtained from Sigma-Aldrich
Company and used as received. 1H, 13C and DEPT NMR
spectra were recorded on Brucker-Avance DPX FT-NMR 500
and 400 MHz instruments. Chemical data for protons are
reported in parts per million (ppm) downfield from
tetramethylsilane and are referenced to the residual proton in
the NMR solvent (CDCl3, 7.26 ppm; CD3OD, 3.31 ppm; DMSO-
d6, 2.55, 3.33ppm). The carbon nuclear magnetic resonance
spectra (13C NMR) were recorded at 125 MHz or 100 MHz:
chemical data for carbons are reported in parts per million (ppm,
δ scale) downfield from tetramethylsilane and are referenced to
the carbon resonance of the solvent (CDCl3, 77.16 ppm; CD3OD,
49.0; DMSO-d6, 39.52 ppm). ESI-MS and HRMS spectra were
recorded on Agilent 1100 LC-Q-TOF and HRMS-6540-UHD
machines. IR spectra were recorded on Perkin-Elmer IR
spectrophotometer. Melting points were recorded on digital
melting point apparatus.
Next, in order to understand the catalytic efficiency of Cu-Mn B
catalyst on its repeated use, we performed recyclability studies.
Under optimized reaction conditions, the product 1a was
obtained in 85, 80, 73 and 67% yields over four cycles,
indicating excellent catalytic activity on repeated use. The metal
content of the catalyst before and after use was also analyzed
using ICP-MS studies. The catalyst recycled after 4 cycles
showed similar metal (Cu and Mn) content. This clearly indicated
that even after recycling catalyst for 4 times, there was no
leaching of metals from the bimetallic spinel catalyst.
Towards elucidating the reaction mechanism, a control reaction
of 2-bromobenzamide (2a) with aqueous ammonia under
optimized reaction conditions was carried out, which led to the
formation of anthranilamide 4a (Figure 4) in 80% yield.
General procedure for synthesis of 2-phenylquinazolin-
4(3H)-ones 1a-u. To the solution of 2-bromobenzamide (2a, 1
equiv.) in 4 mL of DMSO was added aqueous ammonia (2.5 mL),
aryl aldehyde (3, 1.8 equiv.), Cu-Mn B (10% w/w) and K2CO3
(2.5 equiv). Reaction mixture was then heated at 100 °C for 6 h.
Completion of the reaction was monitored by TLC. Reaction
mixture was cooled and filtered to recover catalyst and further
extracted with ethyl acetate (50 ml × 3). Combined organic layer
was dried over anhydrous sodium sulphate and evaporated on
vacuo rotavapor to get crude product. Crude products were
purified by silica gel (#100-200) column chromatography to get
1a-s formed in 85-45% yield. The products were characterized
by comparison of their spectral data with literature values.
2-Phenylquinazolin-4(3H)-one (1a[26]). White solid; yield 95
mg; mp 232-235 oC; 1H NMR (400 MHz, CDCl3) δ 10.94 (bs, 1H),
8.34-8.32 (m, 1H), 8.20-8.18 (m, 2H), 7.86-7.79 (m, 2H), 7.61-
7.49 (m, 4H). ); 13C NMR (125 MHz, DMSO-d6) δ 162.2, 152.3,
148.7, 134.6, 132.7, 131.4, 128.6, 127.7, 127.5, 126.6, 125.8,
120.9; ESI-MS: m/z 223.20 [M+H]+; HRMS: m/z 223.0867 calcd
for C14H10N2O+H+ (223.0866); IR (CHCl3): νmax 2918, 2850, 2344,
1664, 1601, 1572, 1555, 1480, 1469, 1451, 1286, 1143, 1020
cm-1.
Figure 4. Reaction of 2-bromobenzamide (2a) with aqueous
ammonia under optimized reaction conditions
On the basis of control experiment, a plausible mechanism for
synthesis of 1a has been depicted in Figure 5. First, the Cu-Mn
B catalyzed amination of 2a with aqueous ammonia through
intermediates I and II leads to formation of anthranilamide 4a.
Condensation of 4a with aryl aldehyde produces imine
intermediate III, which on intramolecular cyclization followed by
aromatization leads to the formation of quinazolinone 1a.
2-(4-Fluorophenyl)quinazolin-4(3H)-one (1b[26]). White
o
1
solid; yield 90 mg; mp 240-242 C; H NMR (400 MHz, CDCl3 +
CD3OD) δ 8.29 (d, J = 7.6 Hz, 1H), 8.13-8.09 (m, 2H), 7.82 (d,
3.6Hz, 2H), 7.53-7.50 (m,1H), 7.27-7.23 (m, 1H); ); 13C NMR
1
Figure 5. Proposed mechanism for synthesis of 1a.
(125 MHz, DMSO-d6): δ 165 (d, JCF = 249 Hz), 163, 162.3,
151.5, 134.6, 130.4, 130.3, 129.2, 127.4, 126.6, 125.8, 120.8,
115.7 (d, JCF = 21.9 Hz); ESI-MS: m/z 241.20 [M+H]+; HRMS:
2
m/z 241.0802 calcd for C14H10FN2O+H+ (241.0772); IR (CHCl3):
νmax 3584, 3392, 2920, 2851, 1680, 1609, 1484, 1447, 1346,
1288, 1236, 1148, 1020 cm-1.
Conclusions
In summary, we have developed an efficient, Cu-Mn B catalysed
2-(4-Chlorophenyl)quinazolin-4(3H)-one (1c[27]). White
solid; yield 95 mg; mp 239-240 oC; 1HNMR (400 MHz, DMSO-d6)
δ 12.64 (bs, 1H)8.22-8.16 (m, 3H), 7.88 (t, J = 6.4, 12 Hz, 1H),
7.77 (d, J = 6.4 Hz, 1H), 7.65 (d, J = 6.4 Hz, 2H), 7.56 (t, J = 6,
12 Hz, 1H); ); ESI-MS: m/z 257.20 [M+H]+; HRMS: m/z 257.0492
calcd for C14H10ClN2O+H+ (257.0476); IR (CHCl3): νmax 3584,
synthesis of 2-arylquinazolin-4(3H)-ones using aqueous
ammonia as
a nitrogen source. Cu-Mn B is recyclable
heterogeneous catalyst and can be used up to 4 cycles without
significant loss of catalytic activity. The reaction has broad
substrate scope and tolerates wide range of functional groups.
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European Journal of Organic Chemistry
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COMMUNICATION
3397, 2919, 2850, 2091, 1672, 1600, 1555, 1468, 1442, 1344,
1279, 1148, 1119, 1094, 1011 cm-1.
MHz, DMSO-d6) δ 163, 161, 152, 149, 135, 135, 128, 127, 126,
121, 106, 104, 57; ESI-MS: m/z 283.08 [M+H]+; HRMS: m/z
283.1084 calcd for C16H15N2O3+H+ (283.1077); IR (CHCl3): νmax
3685, 3367, 2821, 1730, 1680, 1649, 1613, 1585, 1460, 1419,
1335, 1261, 1185, 1062, 1019 cm-1.
2-(2,3-Dimethoxyphenyl)quinazolin-4(3H)-one
(1d[28]).
o
1
White solid; yield 100 mg; mp 270-272 C; HNMR (400 MHz,
DMSO-d6) δ 12.23 (bs, 1H), 8.17-8.16 (m, 1H), 7.85-7.83 (m,
1H), 7.72 (d, J = 6.4 Hz, 1H), 7.57-7.55 (m, 1H), 7.27-7.21(m,
3H) 3.89 (s, 3H), 3.77 (s, 3H) ; 13C NMR (125 MHz, DMSO-d6) δ
161, 153, 152, 149, 147, 135, 128, 127, 126, 125, 122, 121, 116,
61, 56; ESI-MS: m/z 283.08 [M+H]+; HRMS: m/z 283.1074 calcd
for C16H15N2O3+H+ (283.1077) ; IR (CHCl3): νmax 3291, 3018,
2922, 2848, 1747, 1679, 1604, 1563, 1573, 1474, 1434, 1310,
1297, 1166, 1134, 1112, 1085, 1057 cm-1.
2-(4-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (1k[34]).
o
1
White solid; yield 103 mg; mp 240-242 C; HNMR (400 MHz,
DMSO-d6) δ 12.8 (s, 1H), 8.39 (d, J = 8 Hz, 2H), 8.20 (d, J = 7.6
Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.88-7.86(m, 1H), 7.80 (d, J =
8 Hz, 1H), 7.59 (t, J = 7.6, 14.8 Hz, 1H); 13C NMR (125 MHz,
1
DMSO-d6): δ 162.1, 151.2, 148.4, 136.6, 134.7, 131.2 (d, JCF
=
31 Hz), 128.7, 127.6, 127.1, 125.9, 125.5 (dd, 2JCF = 3.3, 7.1 Hz),
125, 124.9, 122.9, 121.2; ESI-MS: m/z 291.08 [M+H]+; HRMS:
m/z 291.0738 calcd for C15H10F3N2O+H+ (291.0740); IR (CHCl3):
νmax 3334, 2919, 2850, 1739, 1667, 1602, 1489, 1449, 1471,
1341, 1328, 1290, 1114, 1084, 1067, 1019 cm-1.
2-(2-Chlorophenyl)quinazolin-4(3H)-one (1e[27]). White
solid; yield 88 mg; mp 239-240 oC; 1HNMR (400 MHz, CDCl3 +
CD3OD) δ 8.31 (d, J = 7.6 Hz, 1H), 7.84-7.82 (m, 2H), 7.72-7.69
(m, 1H), 7.57-7.45 (m, 4H); 13C NMR (125 MHz, CDCl3
+
CD3OD ) δ 162, 151, 149, 135, 133, 132, 131, 130, 128, 127,
127, 121); ESI-MS: m/z 257.20 [M+H]+; HRMS: m/z 257.0474
calcd for C14H10ClN2O+H+ (257.0476); IR (CHCl3): νmax 3584,
3388, 2918, 2346, 1671, 1604, 1565, 1471, 1447, 1303, 1145,
1052 cm-1
2-(Naphthalen-2-yl)quinazolin-4(3H)-one (1l[35]). White
o
1
solid; yield 106 mg; mp 239-240 C; HNMR (400 MHz, DMSO-
d6) δ 12.70 (s,1H), 8.83 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 8.20 (d,
J = 6.4 Hz, 1H), 8.09-8.02 (m, 3H), 7.89-7.80 (m, 2H), 7.68-7.62
(m, 2H), 7.57 (t, J = 6, 12 Hz, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 163, 153, 149, 135, 134, 132, 130, 129, 128, 128, 128, 128,
128, 127, 127, 126, 125, 122; ESI-MS: m/z 273.13 [M+H]+;
HRMS: m/z 273.1025 calcd for C18H13N2O+H+ (273.1022); IR
(CHCl3): νmax 3744, 3335, 2921, 1672, 1610, 1570, 1510, 1470,
2-(4-Hydroxy-3-methoxyphenyl)quinazolin-4(3H)-one
o
1
(1f[29]). White solid; yield 92 mg; mp 286-288 C; HNMR (400
MHz, DMSO-d6) δ 12.56 (bs, 1H), 8.24-8.16 (m, 2H), 7.87 (t, J =
6.8, 14 Hz, 1H), 7.79 (t, 6.8, 14 Hz, 1H), 7.61-7.47 (m, 3H), 3.43
(s, 3H); ESI-MS: m/z 269.10 [M+H]+; IR (CHCl3): νmax 3386, 3009, 1449, 1348, 1306, 1248, 1151 cm-1.
2918, 2147, 1617, 1509, 1471, 1435, 1405, 1316, 1141, 1020
cm-1.
2-(p-Tolyl)quinazolin-4(3H)-one (1m[26]). White solid; yield
o
1
95 mg; mp 232-233 C; HNMR (400 MHz, DMSO-d6) δ 12.42
(bs, 1H), 8.16-8.10 (m, 3H), 7.86-7.73 (m, 2H), 7.54 (t, J = 7.6,
15.2Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 2.40 (s, 3H); ); 13C NMR
(125 MHz, DMSO-d6) δ 162.3, 152.2, 148.8, 141.4, 134.5, 129.9,
129.8, 129.2, 127.7, 126.4, 125.8, 120.8; ESI-MS: m/z 237.30
2-([1,1'-Biphenyl]-4-yl)quinazolin-4(3H)-one (1g[30]). White
o
1
solid; yield 118 mg; mp 247-249 C; HNMR (400 MHz, CDCl3)
δ 9.80 (bs,1H), 8.34 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8 Hz, 1H),
7.91-7.79 (m, 4H), 7.68-7.61 (m, 3H), 7.52-7.41 (m, 4H); ESI-
MS: m/z 299.50 [M+H]+; IR (CHCl3): νmax 3389, 2959, 2921, 2853, [M+H]+; HRMS: m/z 237.1015 calcd for C15H13N2O+H+
2226, 2147, 1970, 1672, 1667, 1614, 1563, 1517, 1487, 1471,
1435, 1405, 1315, 1290, 1141, 1119, 1023 cm-1.
(237.1022); IR (CHCl3): νmax 3585, 3385, 3134, 3061, 2917, 2850,
1672, 1601, 1557, 1526, 1486, 1469, 1444, 1344, 1241, 1193,
1076, 1020 cm-1;
2-(2-Fluorophenyl)quinazolin-4(3H)-one (1h[31]). White
solid; yield 67 mg; mp 239-240 oC; 1HNMR (400 MHz, DMSO-d6)
δ 12.58 (s, 1H), 8.19-8.17 (m, 1H), 7.89-7.86 (m, 1H), 7.82-7.80
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (1n[26]). White
o
1
solid; yield 102 mg; mp 241-243 C; HNMR (400 MHz, DMSO-
d6) δ 12.56 (s,1H), 8.18 (d, J = 8 Hz, 1H), 7.87-7.76(m, 4H), 7.56
(t, 7.2, 14.8 Hz, 1H), 7.47 (t, J = 8, 16 Hz, 1H), 7.17 (d, J = 8.4
Hz, 1H), 3.87 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160,
157, 150, 146, 133, 132, 127, 125, 124, 123, 119, 118, 115, 110,
53; ); ESI-MS: m/z 253.20 [M+H]+ ; HRMS: m/z 253.0977 calcd
for C15H13N2O2+H+ (253.0972);IR (CHCl3): νmax 3585, 33922,
3122, 3035, 2917, 1672, 1610, 1587, 1505, 1471, 1444, 1309,
1284, 1266, 1221, 1147, 1094, 1045 cm-1); ESI-MS: m/z 253.20
[M+H]+
(m, 1H), 7.78-7.73 (m, 1H), 7.65-7.56 (m, 2H), 7.43-7.36 (m,
1
2H); 13C NMR (100 MHz, DMSO-d6): δ 161.9, 161.3 (d, JCF
=
248 Hz), 150.4, 135.1, 133.3, 131.5, 127.9, 127.5, 126.3, 125.1
2
(d, 2JCF = 3.4 Hz), 122.8, 116.7 (d, JCF = 21.3 Hz); ESI-MS: m/z
240.70 [M+H]+; HRMS: m/z 241.0776 calcd for C14H10FN2O+H+
(241.0772); IR (CHCl3): νmax 3194, 3065, 1692, 1602, 1578,
1469, 1308, 1255, 1218, 1148, 1120, 1020 cm-1.
2-(2,4-Dichlorophenyl)quinazolin-4(3H)-one (1i[32]). White
solid; yield 70 mg; mp 280-283 oC; 1HNMR (400 MHz, DMSO-d6)
δ 12.68 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.74
(d, J = 8.4 Hz, 2H), 7.62-7.57 (m, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 161, 151, 148, 135, 134, 132, 132, 132, 129, 127,
127, 126, 121; ESI-MS: m/z 291.01 [M+H]+; HRMS: m/z
291.0095 calcd for C14H9Cl2N2O+H+ (291.0086); IR (CHCl3): νmax
3585, 3362, 2920, 1678, 1304, 1552, 1472, 1374, 1300, 1255,
1219, 1114, 1019 cm-1.
2-(3-Fluorophenyl)quinazolin-4(3H)-one (1o[36]). White
solid; yield 70 mg; mp 232-234 oC; 1HNMR (400 MHz, DMSO-d6)
δ 12.64 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 8.08-8.07 (m, 2H), 7.89
(t, J = 7.2, 14.8 Hz, 1H), 7.79 (d, J = 8 Hz, 1H), 7.65-7.44 (m,
1
3H); 13C NMR (125 MHz, DMSO-d6): δ 163.3, 162.2 (d, JCF
=
131 Hz), 151.1, 148.4, 135, 134.7, 130.8, 127, 126.9, 125.9,
2
2
123.9, 123.8, 121.1, 118.3 (d, JCF = 21 Hz), 114.6 (d, JCF = 24
Hz); ESI-MS: m/z 240.70 [M+H]+; HRMS: m/z 241.0790 calcd for
C14H10FN2O+H+ (241.0772); IR (CHCl3): νmax 3585, 2920, 2066,
1678, 1605, 1576, 1471, 1454, 1343, 1317, 1343, 1298, 1275,
1143, 1021 cm-1.
2-(3,5-Dimethoxyphenyl)quinazolin-4(3H)-one
(1j[33]).
o
1
White solid; yield 100 mg; mp 280-282 C; HNMR (400 MHz,
DMSO-d6) δ 12.5 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.87 (t, J =
1.2, 8 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.55 (t, J = 7.2, 14.4 Hz,
1H), 7.40-7.39 (m, 2H), 6,71 (s, 1H), 3.5 (s, 6H); 13C NMR (125
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European Journal of Organic Chemistry
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COMMUNICATION
2-(3-Chlorophenyl)quinazolin-4(3H)-one (1p[37]). White
solid; yield 90 mg; mp 232-234 oC; 1HNMR (400 MHz, DMSO-d6)
δ 12.64 (bs, 1H), 8.25-8.16 (m, 3H), 7.86-7.84(m, 2H), 7.68-7.55
(m, 3H); ESI-MS: m/z 257.10 [M+H]+; HRMS: m/z 257.0474
calcd for C14H10ClN2O+H+ (257.0476); IR (CHCl3): νmax 3123,
3027, 2915, 1739, 1680, 1610, 1566, 1505, 1472, 1450, 1410,
1346, 1272, 1153, 1091 cm-1.
recycled 4 times and the amount of catalyst recovered and
percentage yield of the 1a was determined.
Acknowledgements
RS is thankful to DST for the award of research fellowship. SBB
thanks DST-SERB for financial support under Fast-Track
Scheme (grant no. SR/FT/CS-168/2011). Authors are thankful to
Ms. Parveen Sharma for technical support.
2-(3-Bromophenyl)quinazolin-4(3H)-one (1q[22d]). White
solid; yield 90 mg; m.p 220-230; 1HNMR (400 MHz, DMSO-d6) δ
12.61 (bs, 1H), 8.39 - 8.38 (m, 1H), 8.21 – 8.16 (m, 2H), 7.87 –
7.77 (m, 3H), 7.57 – 7.51 (m, 2H); ); 13C NMR (125 MHz,
DMSO-d6) δ 162, 150.9, 145, 134.9, 134.6, 133.9, 130.7, 130.3,
126.8, 126.7, 125.8, 121.8, 121; IR (CHCl3): νmax 3583, 3387,
3060, 2917, 2343, 1739, 1680, 1606, 1559, 1504, 1470, 1309,
1269, 1152, 1069, 1021 cm-1. ESI-MS: m/z 303.50 [M+H]+
2-(3,5-Difluorophenyl)quinazolin-4(3H)-one (1r[38]). White
solid; yield 75 mg; m.p 255-260; 1HNMR (400 MHz, DMSO-d6) δ
12.63 (bs, 1H), 8.17 - 8.16 (m, 1H), 7.94 – 7.85 (m, 3H), 7.78 –
7.76 (m, 1H), 7.58 – 7.53 (m, 2H); ); 13C NMR (125 MHz,
Keywords: 2-aryl quinazolin-4(3H)-ones • Cu-Mn catalyst •
aqueous ammonia • heterogeneous catalyst • Ligand-free
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1
DMSO-d6): δ 163.7, 162.5 (d, JCF = 250 Hz), 161.7 (d, JCF
=
2
248 Hz), 148.6, 135.2, 128.2, 127.7, 126.4, 121.7, 111.6 (d, JCF
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2-(4-Nitrophenyl)quinazolin-4(3H)-one (1s[15c]). White solid;
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(bs, 1H), 8.45 – 8.39 (m, 4H), 8.21 – 8.18 (m, 1H), 7.91 – 7.80
(m, 2H), 7.61 – 7.57 (m, 1H); IR (CHCl3): νmax 3585, 3300, 3178,
3025, 2921, 2852, 1751, 1681, 1589, 1468, 1450, 1349, 1304,
1291, 1150, 1107, 1014 cm-1. ESI-MS: m/z 268.40 [M+H]+
2-(pyridin-4-yl)quinazolin-4(3H)-one (1t[39]). White solid;
m.p 280-283; 1HNMR (400 MHz, DMSO-d6) δ 12.76 (bs, 1H),
8.80 (d, J = 6Hz, 2H), 8.20 (d, J = 8Hz, 1H), 8.12 (d, J = 6Hz,
2H), 7.91 – 7.87 (m, 1H), 7.81 (d, J = 7.6Hz, 1H), 7.61 – 7.57 (m,
1H); 13C NMR (100 MHz, DMSO-d6): δ 162, 150.6, 150.2,
139.9, 134.7, 127.7, 127.4, 125.9, 121.6, 121.4; IR (CHCl3): νmax
3401, 2921, 2256, 2129, 1679, 1607, 1552, 1505, 1487, 1469,
1449, 1410, 1303, 1225, 1151, 1048 cm-1. ESI-MS: m/z 224.01
[M+H]+; HRMS: m/z 224.0796 calcd for C13H9N3O+H+
(224.0818).
2-(Pyridin-3-yl)quinazolin-4(3H)-one (1u[2c]). White
solid; m.p. 272-275 °C; 1H NMR (400 MHz, CD3OD): δ 9.26 (d, J
= 1.9 Hz, 1H), 8.74 (d, J = 3.7 Hz, 1H), 8.51 – 8.47 (m, 1H), 8.30
(d, J = 8.1 Hz, 1H), 7.86-7.83 (m, 2H), 7.60-7.54 (m, 2H); IR
(CHCl3): νmax 3585, 2921, 1673, 1467, 1169 cm-1; ESI-MS: m/z
224.07 [M+H]+; HRMS: m/z 224.0790 calcd for C13H9N3O+H+
(224.0824).
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Entry for the Table of Contents
COMMUNICATION
C-N Bond formation*
Rohit Sharma, Ram A. Vishwakarma,*
Sandip B. Bharate*
Page No. – Page No.
Bimetallic Cu-Mn catalyzed synthesis
of 2-arylquinazolin-4(3H)-ones:
Aqueous ammonia as a source of
ring nitrogen
A Cu-Mn catalyzed synthesis of 2-arylquinazolin-4(3H)-ones comprising a 3-
component coupling of 2-bromobenzamide, aryl aldehydes and aqueous ammonia
has been reported.
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