Quinazolinones from o-Aminobenzonitriles by One-Pot Sequential Selective Hydration/Condensation/Acceptorless Dehydrogenation Catalyzed by an Iridium Complex

Article abstract of DOI:10.1002/cctc.201501385

A new strategy for the direct synthesis of quinazolinones from o-aminobenzonitriles was proposed and accomplished. In the presence of [Cp?IrCl₂]₂ (Cp?=pentamethylcyclopentadienyl), a variety of desirable products was obtained easily through the one-pot sequential selective hydration/condensation/acceptorless dehydrogenation. This protocol is highly attractive because it uses readily available starting materials, has a high atom efficiency, good to excellent yields, and minimal consumption of chemicals and energy. Notably, this research exhibited new potential for the development of transition-metal-catalyzed one-pot sequential reactions that involve acceptorless dehydrogenation.

Full text of DOI:10.1002/cctc.201501385

DOI: 10.1002/cctc.201501385
Full Papers
Quinazolinones from o-Aminobenzonitriles by One-Pot
Sequential Selective Hydration/Condensation/Acceptorless
Dehydrogenation Catalyzed by an Iridium Complex
Wei Zhao,[a] Pengcheng Liu,[a] and Feng Li*[a, b]
A new strategy for the direct synthesis of quinazolinones from
o-aminobenzonitriles was proposed and accomplished. In the
presence of [Cp*IrCl2]2 (Cp*=pentamethylcyclopentadienyl),
a variety of desirable products was obtained easily through
the one-pot sequential selective hydration/condensation/ac-
ceptorless dehydrogenation. This protocol is highly attractive
because it uses readily available starting materials, has a high
atom efficiency, good to excellent yields, and minimal con-
sumption of chemicals and energy. Notably, this research ex-
hibited new potential for the development of transition-metal-
catalyzed one-pot sequential reactions that involve acceptor-
less dehydrogenation.
Introduction
Quinazolinones are an important class of fused heterocyclic
compounds that occur as key scaffolds in many natural alka-
loids (Figure 1)[1] and exhibit a broad spectrum of biological
properties, such as antibacterial,[2a] antiviral,[2b] and anticancer
activities.[2c] Recently, quinazolinones have been utilized as
potent inhibitors of nicotinamide phosphoribosyltransferase
(Nampt),[3a] microsomal prostaglandin synthase 1 (mPGES 1),[3b]
histone deacetylase-6,[3c] and ADP-Ribosyltransferase ARTD3/
PARP3.[3d] Although a number of synthetic methods has been
developed,[4] most classical and versatile routes to quinazoli-
nones rely on the condensation between o-aminobenzamides
and aldehydes followed by the oxidation of the resulting
aminal intermediates (Scheme 1).[5] However, these procedures
Scheme 1. Classical and versatile routes for the synthesis of quinazolinones.
require the use of stoichiometric amounts or a large excess of
environmentally harmful oxidants, such as KMnO4,[5a] MnO2,[5b]
I2,[5c]
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ),[5d]
PhI(OAc)2,[5e] and tBuOOH.[5f] Moreover, only a limited number
of o-aminobenzamides is available commercially, and most of
them are typically prepared by the hydration of o-aminobenzo-
nitriles in the presence of a strong acid or base under harsh
conditions.[6] From the standpoint of sustainable chemistry, the
development of a new strategy for the synthesis of quinazoli-
nones from easily available starting materials under environ-
mentally benign conditions is highly desirable.
Figure 1. Selected examples of quinazolinones as key scaffolds of natural al-
kaloids.
[a] W. Zhao, P. Liu, Dr. F. Li
School of Chemical Engineering
Nanjing University of Science & Technology
200 Xiaolingwei Street, Nanjing 210094 (P.R. China)
Fax: (+86)25-84431939
Recently, much attention has been paid to the development
of acceptorless dehydrogenation reactions accompanied by
the liberation of hydrogen gas without the use of any oxi-
dants,[7] such as the acceptorless dehydrogenation of alcohols[8]
and N-containing heterocycles.[9] Such methodologies provide
the clearest and most atom-economical processes as alterna-
tives to traditional oxidation reactions.
E-mail: fengli@njust.edu.cn
[b] Dr. F. Li
State Key Laboratory of Fine Chemicals
Dalian University of Technology
2 Lingong Road, Dalian 116024 (P.R. China)
Supporting Information for this article can be found under http://
dx.doi.org/10.1002/cctc.201501385.
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We have reported a series of environmentally friendly reac-
tions based on “hydrogen autotransfer” or “dehydrogenation”
catalyzed by Ir[10] and Rh complexes.[11] As part of our continu-
ing effort in this field, we are interested in the exploration
of the direct synthesis of quinazolinones from commercially
available o-aminobenzonitriles by one-pot sequential selec-
tive hydration/condensation/acceptorless dehydrogenation
(Scheme 2). In the presence of a single catalyst, o-aminobenzo-
Scheme 3. Exploration of the feasibility of the model reaction.
Scheme 2. Proposed strategy for the synthesis of quinazolinones from o-
aminobenzonitriles.
1.1 equiv.) was added, and the reaction proceeded at 110 8C for
4 h to give 5aa in 85% yield. If we used [Ru(p-cymene)Cl2]2 as
an alternative catalyst for this one-pot sequential reaction, the
product 5aa was obtained in only 32% yield. Apparently,
[Cp*IrCl2]2 is better than [Ru(p-cymene)Cl2]2 in the acceptorless
dehydrogenation step.
nitriles undergo selective hydration with aldoximes as water
surrogates to form o-aminobenzamides, which undergo con-
densation with aldehydes to afford dihydroquinazolinones.
These were further converted to quinazolinones through ac-
ceptorless dehydrogenation. Transition metal salts or com-
plexes based on Rh,[12a] Pd,[12b] In,[12c] Cu,[12d–e] Ni,[12f] and Ir[10f]
have been utilized as efficient catalysts for the hydration of ni-
triles with aldoximes to amides under neutral reaction condi-
tions. However, these procedures generally required high cata-
lyst loading (5–10 mol%) and/or an excess of aldoximes (2–
5 equiv.). Moreover, only one example was presented for the
hydration of o-aminobenzonitrile, and the desirable o-amino-
benzamide was obtained in only 71% yield with 25% of an un-
identified byproduct.[12d]
With the established catalytic system in hand, we examined
the scope of the reaction with respect to aldehydes, and the
results are outlined in Table 1. Similar to the case of 4a, halo-
genated benzaldehydes (4b–4d) were converted to the de-
sired products 5ab–5ad in 81–85% yield (Table 1, entries 1–3).
The reactions of benzaldehydes that bear a stronger electron-
withdrawing group, such as trifluoromethyl (4e–4 f) and tri-
fluoromethoxy (4g), afforded the corresponding products
5ae–5ag in 78–84% yield (Table 1, entries 4–6). Benzaldehydes
that bear one or two electron-donating groups, such as methyl
(4h–i), isopropyl (4j), methoxy (4k), dimethyl (4l), and dime-
thoxy (4m), were tested, and the desired products 5ah–5am
were obtained in 76–87% yield (Table 1, entries 7–12). The cat-
alytic system was also compatible with 2-thiophenaldehyde
(4n) and 2-naphthaldehyde (4o) to afford the corresponding
products 5an and 5ao in 83 and 87% yield, respectively
(Table 2, entries 13–14). In addition to aromatic aldehydes, ali-
phatic ones, such as butyraldehyde (4p), cyclohexanecarbalde-
hyde (4q), and phenylpropyl aldehyde (4r), were suitable part-
ners, and the desired products 5ap–5ar were obtained in 77–
85% yield (Table 1, entries 15–17).
Results and Discussion
To explore the feasibility of the above proposal, some commer-
cially available transition metal complexes, which include [Ir-
(cod)Cl]2 (cod=1,5-cyclooctadienyl), [Cp*IrCl2]2 (Cp*=penta-
methylcyclopentadienyl), [Rh(cod)Cl]2, [Cp*RhCl2]2, and [Ru(p-
cymene)Cl2]2, were screened initially for their ability to catalyze
the selective hydration of o-aminobenzonitrile with an aldox-
ime. In the presence of a catalyst (1 mol%), the reaction of o-
aminobenzonitrile (1a) with n-butylaldoxime (2a) (1.1 equiv.)
was performed in p-xylene at 708C for 12 h. [Cp*IrCl2]2 and
[Ru(p-cymene)Cl2]2 exhibited high catalytic activities to afford
2-aminobenzamide (3aa) as the sole product in 89 and 86%
yields, respectively (Scheme 3).[13] Furthermore, [Cp*IrCl2]2 was
selected as the catalyst for the one-pot sequential selective hy-
dration/condensation/acceptorless dehydrogenation. After 1a
was converted completely to 3a, benzylaldehyde (4a;
The generality of the reaction with respect to o-aminoben-
zonitriles was then investigated. The transformations of o-ami-
nobenzonitriles that bear one or two electron-withdrawing
groups, such as fluorine (1b–1c) and chlorine (1d–1e), gave
the corresponding products 5ba–5ea in 75–91% yield
(Table 2, entries 1–4). Furthermore, the reactions of o-amino-
benzonitriles that bear a bromine on different positions (1 f–
1i) proceeded smoothly to afford the desired products 5 fa–
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Table 1. Scope of reaction with respect to aldehydes.[a]
Table 1. (Continued)
Entry
Aldehyde
Product
Yield
[%][b]
Entry
Aldehyde
Product
Yield
[%][b]
12
87
83
1
85
81
84
13
2
3
14
15
16
87
78[c]
85
4
5
82
84
17
77
[a] Reaction conditions: 1) 1a (1 mmol), 2a (1.1 mmol), [Cp*IrCl2]2
(1 mol%), p-xylene (2 mL), 708C, 12 h; 2) 4 (1.1 mmol), 110 8C, 4 h. [b] Iso-
lated yield. [c] 4p (2 mmol).
6
7
8
78
84
85
5ia in 77–87% yield (Table 2, entries 5–8). In the case of o-ami-
nobenzonitriles that bear one or two electron-donating
groups, such as methyl (1j–1k) and dimethoxy (1l), the corre-
sponding products 5ja–5la could be obtained in 83–88%
yield (Table 2, entries 9–11).
A possible mechanism is proposed to account for the pres-
ent one-pot sequential reaction (Scheme 4). In cycle I, the ini-
tial step involved the generation of iridium nitrile species B,
which was subsequently attacked by aldoximes to give the
five-membered cyclic species C. Accompanied by the decom-
position of C, o-aminobenzamide was released and the catalyt-
ically active Ir species A was regenerated.[14] Furthermore, the
condensation between o-aminobenzamides and aldehydes oc-
curred to give dihydroquinazolinones. In cycle II, the b-hydro-
gen elimination of amido iridium species D and/or E, which
were formed by the oxidative addition of the NÀH bond of di-
hydroquinazolinones to coordinatively unsaturated Ir species,
afforded quinazolinones as the desired products and iridium
dihydride species F. Finally, catalytically active species A was re-
generated with the liberation of hydrogen gas from iridium di-
hydride species F.
9
76
10
11
80
83
A series of mechanistic experiments was undertaken to sup-
port the proposed mechanism (Scheme 5). Initially, n-butyroni-
1
trile (6) was observed as a byproduct (85% yield) from H NMR
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4a proceeded for 1 h to give 2-phenyl-2,3-dihydroquinazolin-
4(1H)-one (7) in 95% yield. In the presence of [Cp*IrCl2]2
(1 mol%), the reaction of 7 afforded product 5aa in 96% yield
with an almost quantitative amount of hydrogen gas collected
by water displacement. These experimental results support the
proposed mechanism shown in Scheme 4.
Table 2. Scope of reaction with respect to o-aminobenzonitriles.[a]
Entry
o-Aminobenzonitrile
Product
Yield
[%][b]
Conclusions
We have established a new, efficient, and versatile strategy for
the direct synthesis of quinazolinones from o-aminobenzoni-
triles. In the presence of [Cp*IrCl2]2 (Cp*=pentamethylcyclo-
pentadienyl), a variety of desirable products was obtained
easily through one-pot sequential selective hydration/conden-
sation/acceptorless dehydrogenation. This protocol is highly at-
tractive because of the readily available starting materials, high
atom efficiency, good to excellent yields, and minimal con-
sumption of chemicals and energy. Notably, this research ex-
hibited new potential for the development of transition-metal-
catalyzed one-pot sequential reactions that involve acceptor-
less dehydrogenation.
1
80
75
2
3
4
5
6
91
83
81
87
Experimental Section
General details
HRMS was measured by using a HPLC-Q-Tof MS(Micro) spectrome-
ter and are reported as m/z (relative intensity). Accurate masses
1
are reported for the molecular ion [MÀH]À. H NMR spectra were
recorded at 500 MHz by using a Bruker Avance 500 spectrometer.
Chemical shifts (d) are reported in parts per million (ppm) down-
field from tetramethylsilane or relative to the center of the singlet
at d=7.26 ppm for CDCl3 or d=2.50 ppm for [D6]DMSO. Coupling
constants (J) are reported in Hertz (Hz), and the splitting patterns
were designated as follows: s, singlet; d, doublet; t, triplet; m, mul-
tiplet; b, broad. 13C NMR spectra were recorded at 125 MHz by
using a Bruker Avance 500 spectrometer. Chemical shifts (d) are re-
ported relative to the center of the triplet at d=77.0 ppm for
CDCl3 or d=39.5 ppm for [D6]DMSO. 13C NMR spectra were per-
formed routinely with broadband decoupling.
7
86
77
83
86
88
8
General procedure for the direct synthesis of quinazolinones
from o-aminobenzonitriles by one-pot sequential selective
hydration/condensation/acceptorless dehydrogenation
9
To an oven-dried, N2-purged 25 mL Schlenk tube were added
[Cp*IrCl2]2 (0.01 mmol, 1 mol%), o-aminobenzonitrile (1 mmol), n-
butylaldoxime (1.1 mmol, 1.1 equiv.) and p-xylene (2 mL), and the
mixture was heated at 708C for 12 h. The reaction mixture was al-
lowed to cool to RT, and aldehyde (1.1 mmol, 1.1 equiv.) was
added. The Schlenk tube was flushed with nitrogen, and the mix-
ture was heated at 110 8C for 4 h. The reaction mixture was cooled
to RT, concentrated in vacuo, and purified by flash column chroma-
tography with hexanes/ethyl acetate to afford the product.
10
11
[a] Reaction conditions: 1 (1 mmol), 2a (1.1 mmol), [Cp*IrCl2]2 (1 mol%),
p-xylene (2 mL), 708C, 12 h; 2) 4a (1.1 mmol), 1108C, 4 h. [b] Isolated
yield.
2-Phenylquinazolin-4(3H)-one (5aa):[4i] White solid; 85% yield
1
(189 mg); m.p. 237–2388C; H NMR (500 MHz, CDCl3): d=11.56 (br
s, 1H), 8.34 (d, J=7.8 Hz, 1H), 8.26 (dd, J=3.1 Hz and 6.7 Hz, 2H),
7.80–7.86 (m, 2H), 7.59–7.60 (m, 3H), 7.51 ppm (t, J=7.3 Hz, 1H);
13C {1H} NMR (125 MHz, CDCl3): d=163.9, 151.8, 149.5, 134.9, 132.8,
131.6, 129.0, 128.0, 127.4, 126.7, 126.4, 120.9 ppm.
spectroscopy of the crude reaction mixture of the hydration of
1a with 2a. Furthermore, the condensation between 3aa and
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Scheme 4. Proposed reaction mechanism.
J=7.5 Hz, 1H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=162.1, 151.5,
148.6, 134.7, 131.9, 131.6, 129.8, 127.5, 126.7, 125.9, 125.2,
121.0 ppm.
2-[4-(Trifluoromethyl)phenyl]quinazolin-4(3H)-one (5ae):[4i] White
solid; 82% yield (238 mg); m.p. 309–3108C; 1H NMR (500 MHz,
[D6]DMSO): d=12.75 (br s, 1H), 8.38 (d, J=8.2 Hz, 2H), 8.18 (dd,
J=1.2 Hz, J=8.0 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.87 (t, J=7.7 Hz,
1H), 7.79 (d, J=7.7 Hz, 1H), 7.57 ppm (t, J=7.5 Hz, 1H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=162.0, 151.1, 148.4, 136.6, 134.7,
131.1 (q, JCÀF =32.1 Hz), 128.7, 127.6, 127.1, 125.8, 125.4 (q, JCÀF
3.0 Hz), 123.9 (q, JCÀF =272.3 Hz), 121.2 ppm.
=
2-[2-Fluoro-5-(trifluoromethyl)phenyl]quinazolin-4(3H)-one
(5af): White solid; 84% yield (259 mg); m.p. 235–2378C; 1H NMR
(500 MHz, [D6]DMSO): d=12.73 (br s, 1H), 8.17–8.19 (m, 2H), 8.03
(s, br,1H), 7.87 (t, J=7.3 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.66 (t, J=
9.1 Hz, 1H), 7.59 ppm (t, J=7.4 Hz, 1H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=161.4, 161.1 (d, JCÀF =256.7 Hz), 148.5, 148.4, 134.6,
130.0 (d, JCÀF =6.2 Hz), 128.6, 127.6, 127.3, 125.8, 125.5 (q, JCÀF
=
33.5 Hz), 123.5 (q, JCÀF =273.0 Hz), 123.2 (d, JCÀF =15.0 Hz), 121.3,
117.7 ppm (d, JCÀF =23.1 Hz); HRMS (EI, 70 eV) m/z: calcd for
C15H7F4N2O: 307.0495 [MÀH]À; found 307.0489.
Scheme 5. Mechanistic experiments.
2-[4-(Trifluoromethoxy)phenyl]quinazolin-4(3H)-one
(5ag):[5f]
2-(2-Fluorophenyl)quinazolin-4(3H)-one (5ab):[15] White solid;
85% yield (204 mg); m.p. 162–1638C; 1H NMR (500 MHz,
[D6]DMSO): d=12.58 (br s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.86 (t, J=
7.6 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.60–
7.65 (m, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.36–7.41 ppm (m, 2H); 13C
{1H} NMR (125 MHz, [D6]DMSO): d=161.4, 159.5 (d, JCÀF =250.3 Hz),
149.9, 148.7, 134.6, 132.8 (JCÀF =8.2 Hz), 131.0, 127.5, 127.0, 125.8,
124.6, 122.3 (d, JCÀF =13.1 Hz), 121.1, 116.1 ppm (d, JCÀF =21.3 Hz).
White solid; 78% yield (239 mg); m.p. 268–2708C; 1H NMR
(500 MHz, [D6]DMSO): d=12.65 (br s, 1H), 8.30 (d, J=8.7 Hz, 2H),
8.16 (d, J=7.8 Hz, 1H), 7.84 (t, J=7.4 Hz, 1H), 7.74 (d, J=8.1 Hz,
1H), 7.52–7.56 ppm (m, 3H); 13C {1H} NMR (125 MHz, [D6]DMSO):
d=162.1, 151.1, 150.4, 148.5, 134.6, 131.8, 130.1, 127.5, 126.8,
125.8, 121.0, 120.8, 120.0 ppm (d, JCÀF =193.0 Hz).
2-(o-Tolyl)quinazolin-4(3H)-one (5ah):[4i] White solid; 84% yield
1
(198 mg); m.p. 222–2238C; H NMR (500 MHz, [D6]DMSO): d=12.45
2-(4-Chlorophenyl)quinazolin-4(3H)-one (5ac):[4i] White solid;
81% yield (208 mg); m.p. 300–3018C; 1H NMR (500 MHz,
[D6]DMSO): d=12.62 (br s, 1H), 8.20 (d, J=8.6 Hz, 2H), 8.15 (d, J=
7.6 Hz, 1H), 7.85 (t, J=7.6 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.63 (d,
J=8.6 Hz, 2H), 7.54 ppm (t, J=7.4 Hz, 1H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=162.1, 151.3, 148.5, 136.3, 134.6, 131.5, 129.6, 128.6,
127.5, 126.7, 125.8, 121.0 ppm.
(br s, 1H), 8.17 (d, J=7.7 Hz, 1H), 7.84 (t, J=7.4 Hz, 1H), 7.69 (d,
J=8.0 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H),7.43
(t, J=7.3 Hz, 1H), 7.31–7.36 (m, 2H), 2.38 ppm (s, 3H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=161.7, 154.3, 148.7, 136.1, 134.4,
134.2, 130.5, 129.8, 129.1, 127.3, 126.6, 125.7, 125.6, 121.0,
19.5 ppm.
2-(p-Tolyl)quinazolin-4(3H)-one (5ai):[4i] white solid; 85% yield
2-(4-Bromophenyl)quinazolin-4(3H)-one (5ad):[16] White solid;
84% yield (253 mg); m.p. 296–2978C; 1H NMR (500 MHz,
[D6]DMSO): d=12.61 (br s, 1H), 8.15 (d, J=8.0 Hz,1H), 8.13 (d, J=
8.6 Hz,2H), 7.84 (t, J=7.6 Hz, 1H), 7.74–7.78 (m, 3H), 7.55 ppm (t,
(200 mg); m.p. 242–2438C; H NMR (500 MHz, CDCl3): d=12.45 (br
1
s, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.1 Hz, 2H), 7.82 (t, J=
7.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.34 (d,
J=8.0 Hz, 2H), 2.38 ppm (s, 3H); 13C {1H} NMR (125 MHz, CDCl3):
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d=162.2, 152.2, 148.8, 141.4, 134.5, 130.0, 129.1, 127.6, 127.4,
126.3, 125.8, 120.9, 20.9 ppm.
J=3.2 Hz, 1H, CH), 1.89 (d, J=12.4 Hz, 2H), 1.78(d, J=12.8 Hz, 1H),
1.67(d, J=11.9 Hz, 1H), 1.54–1.61 (m, 2H), 1.20–1.33 ppm (m, 3H);
13C {1H} NMR (125 MHz, [D6]DMSO): d=161.9, 160.7, 148.9, 134.1,
126.9, 125.8, 125.6, 120.9, 42.8, 30.2, 25.5, 25.3 ppm.
2-(4-Isopropylphenyl)quinazolin-4(3H)-one (5aj):[4i] White solid;
76% yield (200 mg); m.p. 210–2128C; 1H NMR (500 MHz,
[D6]DMSO): d=12.48 (br s, 1H), 8.12–8.16 (m, 3H), 7.84 (t, J=
7.4 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.52 (t, J=7.4 Hz, 1H), 7.42 (d,
J=8.1 Hz, 2H), 2.94–3.03 (m, 1H), 1.25 ppm (d, J=6.7 Hz, 6H); 13C
{1H} NMR (125 MHz, [D6]DMSO): d=162.2, 152.2, 152.1, 148.8,
134.5, 130.3, 127.8, 127.4, 126.5, 126.4, 125.8, 120.9, 33.3, 23.6 ppm.
2-Phenethylquinazolin-4(3H)-one (5ar):[18] White solid; 77% yield
1
(193 mg); m.p. 209–2108C; H NMR (500 MHz, [D6]DMSO): d=12.26
(br s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.62 (d,
J=8.0 Hz, 1H), 7.46 (t, J=7.3 Hz, 1H), 7.27–7.30 (m, 3H), 7.17–7.21
(m, 1H), 3.05 (t, J=8.0 Hz, 2H), 2.89 ppm (t, J=8.0 Hz, 2H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=161.7, 156.5, 148.8, 140.7, 134.3,
128.3, 126.8, 126.0, 126.0, 125.7, 120.8,36.3,32.4 ppm.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (5ak):[4d] White solid;
80% yield (202 mg); m.p. 246–2478C; 1H NMR (500 MHz,
[D6]DMSO): d=12.39 (br s, 1H), 8.19 (d, J=8.7 Hz, 2H), 8.13 (d, J=
7.8 Hz, 1H), 7.80 (t, J=7.5 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.47 (t,
J=7.5 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 3.84 ppm (s, 3H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=162.3, 161.8, 151.8, 148.9, 134.5,
129.4, 127.2, 126.1, 125.8, 124.8, 120.7, 114.0, 55.4 ppm.
5-Fluoro-2-phenylquinazolin-4(3H)-one (5ba):[19] White solid;
80% yield (192 mg); m.p. 281–2848C; 1H NMR (500 MHz,
[D6]DMSO): d=12.55 (br s, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.82–7.78
(m, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.57–7.54 (m, 3H), 7.28–7.24 ppm
(m, 1H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=161.6, 159.5 (d,
J
CÀF =11.8 Hz), 153.3, 150.9, 135.1 (d, JCÀF =10.4 Hz), 132.3, 131.7,
2-(3,4-Dimethylphenyl)quinazolin-4(3H)-one (5al):[4b] White solid;
83% yield (208 mg); m.p. 240–2418C; 1H NMR (500 MHz,
[D6]DMSO): d=12.41 (br s, 1H), 8.14 (d, J=7.7 Hz, 1H), 8.01 (s, 1H),
7.92 (d, J=7.7 Hz, 1H), 7.82 (t, J=7.4 Hz, 1H), 7.72 (d, J=8.0 Hz,
1H), 7.50 (t, J=7.4 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 2.31 (s, 3H),
2.29 ppm (s, 3H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=162.2,
152.3, 148.8, 140.2, 136.6, 134.5, 130.1, 129.7, 128.6, 127.4, 126.3,
125.8, 125.1, 120.9, 19.4, 19.3 ppm.
128.6, 127.9, 123.5, 112.9 (d, JCÀF =20.5 Hz), 110.4 ppm (d, JCÀF
6.0 Hz).
=
8-Fluoro-2-phenylquinazolin-4(3H)-one (5ca):[20] White solid; 75%
yield (180 mg); m.p. 272–2748C; H NMR (500 MHz, [D6]DMSO): d=
12.73 (br s, 1H), 8.21 (d, J=7.4 Hz, 2H), 7.98 (d, J=7.9 Hz, 1H),
7.72 (t, J=9.2 Hz, 1H), 7.56–7.64 (m, 3H), 7.49–7.53 ppm (m, 1H);
13C {1H} NMR (125 MHz, [D6]DMSO): d=161.4, 156.7 (d, JCÀF
1
=
253.8 Hz), 152.9, 153.9, 138.0 (d, JCÀF =11.3 Hz), 132.5, 131.6, 128.6,
127.9, 126.7 (d, CÀF =7.5 Hz), 123.0, 121.6 (d, CÀF =3.3 Hz),
119.9 ppm (d, JCÀF =18.8 Hz).
2-(3,4-Dimethoxyphenyl)quinazolin-4(3H)-one (5am):[17] White
solid; 87% yield (245 mg); m.p. 242–2438C; 1H NMR (500 MHz,
[D6]DMSO): d=12.43 (br s, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.87 (d, J=
8.4 Hz, 1H), 7.80–7.83 (m, 2H), 7.71 (d, J=8.1 Hz, 1H), 7.49 (t, J=
7.2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 3.85 ppm (s, 3H);
13C {1H} NMR (125 MHz, [D6]DMSO): d=162.3, 151.8, 151.6, 148.9,
148.5, 134.5, 127.3, 126.1, 125.8, 124.7, 121.1, 120.7, 111.43, 110.7,
55.7 ppm (2C, overlap).
J
J
7-Chloro-2-phenylquinazolin-4(3H)-one (5da):[4i] White solid; 91%
1
yield (233 mg); m.p. 276–2788C; H NMR (500 MHz, [D6]DMSO): d=
12.68 (br s, 1H), 8.17 (d, J=7.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 1H),
7.79 (d, J=2.0 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54–7.57 ppm (m,
3H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=161.6, 153.7, 149.8,
139.1, 132.4, 131.6, 130.7, 128.6, 127.9, 127.9, 126.7, 126.5,
119.8 ppm.
2-(Thiophen-2-yl)quinazolin-4(3H)-one (5an):[4d] White solid; 83%
1
yield (189 mg); m.p. 276–2778C; H NMR (500 MHz, [D6]DMSO): d=
12.66 (br s, 1H), 8.23 (d, J=3.2 Hz, 1H), 8.12 (d, J=7.4 Hz, 1H),
7.87 (d, J=4.7 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=8.0 Hz,
1H), 7.48 (t, J=7.3 Hz, 1H), 7.23 ppm (t, J=4.3 Hz 1H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=161.8, 148.6, 147.8, 137.3, 134.6,
132.1, 129.4, 128.5, 126.9, 126.3, 126.0, 120.9 ppm.
8-Chloro-2-phenylquinazolin-4(3H)-one (5ea):[4l] White solid; 83%
1
yield (214 mg); m.p. 286–2888C; H NMR (500 MHz, [D6]DMSO): d=
12.77 (br s, 1H), 8.24 (d, J=7.1 Hz, 2H), 8.11 (dd, J=8.0 Hz and
1.3 Hz, 1H), 7.99 (dd, J=7.8 Hz and 1.3 Hz, 1H), 7.64–7.56 (m, 3H),
7.49 ppm (t, J=7.8 Hz, 1H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=
161.8, 152.9, 145.2, 134.6, 132.4, 131.8, 131.0, 128.7, 128.0, 126.8,
125.0, 122.8 ppm.
2-(Naphthalen-2-yl)quinazolin-4(3H)-one (5ao):[4i] White solid;
87% yield (236 mg); m.p. 276–2778C; 1H NMR (500 MHz,
[D6]DMSO): d=12.67 (br s, 1H), 8.82 (s, 1H), 8.31 (d, J=8.4 Hz, 1H),
8.19 (d, J=7.6 Hz, 1H), 8.07 (t, J=7.1 Hz, 1H), 8.01 (d, J=7.4 Hz,
1H), 7.86 (t, J=7.3 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.61–7.66 (m,
2H), 7.54 ppm (t, J=7.3 Hz, 1H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=162.2, 152.2, 148.8, 134.6, 134.1, 132.3, 129.9, 128.9,
128.1, 128.1, 127.9, 127.6, 127.5, 126.9, 126.6, 125.9, 124.5,
121.0 ppm.
5-Bromo-2-phenylquinazolin-4(3H)-one (5 fa):[10j] White Solid;
81% yield (244 mg); m.p. 283–2848C; 1H NMR (500 MHz,
[D6]DMSO): d=12.56 (br s, 1H), 8.18 (d, J=7.2 Hz, 2H), 7.71–7.74
(m, 2H), 7.67–7.63 (m, 1H), 7.61(t, J=7.2 Hz, 1H), 7.56 ppm (t, J=
7.5 Hz, 2H); 13C {1H} NMR (125 MHz, [D6]DMSO): d=160.5, 152.7,
151.1, 134.6, 132.6, 132.1, 131.6, 128.6, 127.8, 127.7, 120.1,
118.8 ppm.
2-Propylquinazolin-4(3H)-one (5ap):[4a] White solid; 78% yield
(147 mg); m.p. 198–1998C; H NMR (500 MHz, [D6]DMSO): d=12.15
(br s, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H), 7.59 (d,
J=8.1 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H), 2.57 (t, J=7.5 Hz, 2H), 1.70–
1.78 (m, 2H), 0.93 ppm (t, J=7.4 Hz, 3H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=161.8, 157.3, 148.9, 134.2, 126.8, 125.9, 125.6, 120.8,
36.3, 20.2, 13.4 ppm.
6-Bromo-2-phenylquinazolin-4(3H)-one (5ga):[21] White solid;
87% yield (262 mg); m.p. 285–2868C; 1H NMR (500 MHz,
[D6]DMSO): d=12.71 (br s, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=
7.5 Hz, 2H), 7.98 (dd, J=8.7 Hz and 2.0 Hz, 1H), 7.69 (d, J=8.7 Hz,
1H), 7.60 (t, J=7.1 Hz, 1H), 7.55 ppm (t, J=7.4 Hz, 2H); 13C {1H}
NMR (125 MHz, [D6]DMSO): d=161.2, 153.0, 147.7, 137.4, 132.5,
131.6, 129.8, 128.6, 128.0, 127.9, 122.6, 118.9 ppm.
1
2-Cyclohexylquinazolin-4(3H)-one (5aq):[4b] White solid; 85%
yield (194 mg), m.p. 229–2308C; H NMR (500 MHz, [D6]DMSO): d=
7-Bromo-2-phenylquinazolin-4(3H)-one (5ha): White solid; 86%
yield (259 mg); m.p. 269–2718C; H NMR (500 MHz, [D6]DMSO): d=
1
1
12.06 (br s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.58
(d, J=8.2 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 2.57 (tt, J=11.8 Hz and
12.67 (br s, 1H), 8.16 (d, J=7.3 Hz, 2H), 8.06 (d, J=8.6 Hz, 1H),
7.94 (d, J=1.8 Hz, 1H), 7.68 (dd, J=8.4 Hz and 1.8 Hz, 1H), 7.61 (t,
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Full Papers
J=7.2 Hz, 1H), 7.56 ppm (t, J=7.4 Hz, 2H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=161.8, 153.7, 149.9, 132.4, 131.7, 129.6, 129.5, 128.6,
128.1, 127.9 (2C, overlap), 120.1 ppm; HRMS (EI, 70 eV) m/z: calcd
for C14H8BrN2O: 298.9820 [MÀH]À; found 298.9829.
GC analysis was performed by using a gas chromatograph with
a thermal conductivity detector (TCD). Injector temperature=
1008C, column temperature=708C, detector temperature (TCD)=
1008C, carrier gas=N2, t=0.965 min.
8-Bromo-2-phenylquinazolin-4(3H)-one (5ia): White solid; 77%
yield (232 mg); m.p. 281–2838C; H NMR (500 MHz, [D6]DMSO): d=
The volume of 1.0 mol of H2 at 296.15 K, 99920 Pa was calculated
according to the van der Waals equation [Eq. (1)]:
1
12.78 (br s, 1H), 8.28 (d, J=7.2 Hz, 2H), 8.16 (d, J=7.8 Hz, 2H),
7.65–7.58 (m, 3H), 7.42 ppm (t, J=7.8 Hz, 1H); 13C {1H} NMR
(125 MHz, [D6]DMSO): d=161.9, 152.9, 146.1, 137.9, 132.4, 131.8,
128.6, 127.9, 127.3, 125.7, 122.6, 122.2 ppm; HRMS (EI, 70 eV) m/z:
calcd for C14H8BrN2O: 298.9820 [MÀH]À; found 298.9827.
n2a
ðpþ
ÞðVÀnbÞ ¼ nRT
V2
in which R=8.3145 m3 PamolÀ1 KÀ1; T=296.15 K; p=99920 Pa; a=
0.02476 m6 PamolÀ1; and b=0.02661”10À3 m3 molÀ1; thus, V (H2,
296.15 K, 99920 Pa)=24.7 LmolÀ1
.
6-Methyl-2-phenylquinazolin-4(3H)-one (5ja):[4b] White solid; 83%
1
yield (196 mg), m.p. 238–2408C; H NMR (500 MHz, [D6]DMSO): d=
12.46 (br s, 1H), 8.17 (d, J=6.9 Hz, 2H), 7.95 (s, 1H), 7.68–7.64 (m,
2H), 7.60–7.52 (m, 3H), 2.46 ppm (s, 3H); 13C {1H} NMR (125 MHz,
[D6]DMSO): d=162.1, 152.5, 146.7, 136.3, 135.9, 132.8, 131.2, 128.6,
127.6, 127.4, 125.2, 120.7, 20.8 ppm.
The collected volume of gas in this experiment above was 23.0 mL,
which corresponds to 0.93 mmol of H2.
7-Methyl-2-phenylquinazolin-4(3H)-one (5ka):[19] White solid;
86% yield (203 mg), m.p. 239–2408C; 1H NMR (500 MHz,
[D6]DMSO): d=12.45 (br s, 1H), 8.17 (d, J=5.5 Hz, 2H), 8.03 (d, J=
7.0 Hz, 1H), 7.55 (s, 4H), 7.33 (d, J=6.8 Hz, 1H), 2.47 ppm (s, 3H);
13C {1H} NMR (125 MHz, [D6]DMSO): d=162.1, 152.3, 148.8, 145.0,
132.8, 131.3, 128.5, 128.0, 127.7, 127.1, 125.7, 118.6, 21.3 ppm.
Acknowledgements
Financial support by the National Natural Science Foundation of
China (No.21272115) and the State Key Laboratory of Fine Chemi-
cals (KF1401) is greatly appreciated.
6,7-Dimethoxy-2-phenylquinazolin-4(3H)-one (5la):[19] White
solid; 88% yield (248 mg); m.p. 281–2848C; 1H NMR (500 MHz,
[D6]DMSO): d=12.40 (br s, 1H), 8.16 (d, J=7.0 Hz, 2H), 7.57–7.52
(m, 3H), 7.49 (s, 1H), 7.22 (s, 1H), 3.93 (s, 3H), 3.89 ppm (s, 3H); 13C
{1H} NMR (125 MHz, [D6]DMSO): d=161.6, 154.8, 150.8, 148.6,
144.8, 132.9, 131.0, 128.6, 127.4, 114.0, 108.3, 105.0, 56.0, 55.7 ppm.
Keywords: dehydrogenation · heterocycles · homogeneous
catalysis · iridium · synthesis design
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trile and benzaldehyde
To an oven-dried, N2-purged 25 mL Schlenk tube were added 3aa
(1 mmol), 4a (1 mmol), and p-xylene (2 mL), and the mixture was
heated at 110 8C for 1 h, at which point the reaction mixture was
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2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (7):[22] White solid;
95% yield (213 mg); m.p. 216–2188C; 1H NMR (500 MHz, CDCl3):
d=7.95 (d, J=7.7 Hz, 1H), 7.61–7.59 (m, 2H), 7.46–7.45 (m, 3H),
7.34 (t, J=7.7 Hz, 1H), 6.91 (t, J=7.5 Hz, 1H), 6.67 (d, J=8.1 Hz,
1H), 5.91 (s, 1H), 5.76 (br s, 1H), 4.39 ppm (br s, 1H); 13C {1H} NMR
(125 MHz, CDCl3): d=164.7, 147.2, 138.6, 134.0, 130.2, 129.1,
1328.7, 127.4, 119.7, 115.7, 114.6, 69.1 ppm.
Procedure for the hydrogen evolution experiment[9e]
Compound 7 (1 mmol), [Cp*IrCl2]2 (1 mol%), and p-xylene (2 mL)
were added to a 10 mL thick-walled glass vessel fitted with a side
arm and a rubber septum. The vessel was previously degassed
three times and placed under a N2 atmosphere. The vessel was
connected to the gas collection apparatus (standard water dis-
placement apparatus with a graduated cylinder to determine
volume), and the entire system was flushed with N2 for 5 min and
allowed to equilibrate for 5 min. The reaction was stirred vigorous-
ly at 110 8C until gas evolution ceased (4 h). The presence of hydro-
gen in the collected gas was confirmed by GC analysis.
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Received: December 19, 2015
Published online on March 16, 2016
ChemCatChem 2016, 8, 1523 – 1530
www.chemcatchem.org
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