Pd-catalyzed benzylic C-H amidation with benzyl alcohols in water: A strategy to construct quinazolinones

Article abstract of DOI:10.1021/jo301282n

A novel method for the synthesis of 4-phenylquinazolinones via a palladium-catalyzed domino reaction of o-aminobenzamides with benzyl alcohols is developed. This protocol involves N-benzylation, benzylic C-H amidation, and dehydrogenation in water, which may play an important role in the smooth generation of the (η³-benzyl)palladium species by activation of the hydroxyl group of the benzyl alcohol.

Full text of DOI:10.1021/jo301282n

Article
pubs.acs.org/joc
Pd-Catalyzed Benzylic C−H Amidation with Benzyl Alcohols in Water:
A Strategy To Construct Quinazolinones
Hidemasa Hikawa,* Yukari Ino, Hideharu Suzuki, and Yuusaku Yokoyama*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
S
* Supporting Information
ABSTRACT: A novel method for the synthesis of 4-phenyl-
quinazolinones via a palladium-catalyzed domino reaction of o-
aminobenzamides with benzyl alcohols is developed. This
protocol involves N-benzylation, benzylic C−H amidation, and
dehydrogenation in water, which may play an important role in
the smooth generation of the (η3-benzyl)palladium species by
activation of the hydroxyl group of the benzyl alcohol.
Furthermore, benzylic C−H activation (second step in
Schemes 1 and 2) is usually achieved in organic solvents, and
extrusion of moisture is essential. To the best of our knowledge,
palladium-catalyzed C−H functionalization in water is ex-
tremely rare. For example, Sajiki and co-workers reported that
the Pd/C-catalyzed hydrogen−deuterium (H−D) exchange
reaction proceeded in D2O in the presence of H2 gas.16 Li and
Zhang reported Pd-catalyzed allylic C−H amination of alkenes
in the presence of a catalytic amount of water.2a
INTRODUCTION
■
Palladium-catalyzed activation of carbon−hydrogen bonds for
coupling reactions is a promising strategy in organic synthesis.1
Amidation of C(sp3)−H bonds has been particularly attractive
since N-containing compounds, especially N-heterocycles, are
ubiquitous in natural products and pharmaceuticals.2
We propose that a palladium-catalyzed N-benzylation/
benzylic C−H activation of anilines substituted with directing
groups should afford versatile compounds. In our previous
work,3a N-benzylation of anthranilic acid with benzyl alcohol
and benzylic C−H benzylation occurred simultaneously to give
the dibenzylated product A (Scheme 1). The carboxyl group
may play an important role as a directing group in the benzylic
C−H activation. By replacing anthranilic acid with o-amino-
benzamide as a starting material, we expect the N-benzylated
product to undergo benzylic C−H amidation followed by
dehydrogenation to give 2-phenylquinazolin-4(3H)-one (3;
Scheme 2). Quinazolinones are key units in a wide range of
relevant pharmacophores with a broad spectrum of activ-
ities.4−11 While many methods for the synthesis of 3 have been
developed,4−13 palladium-catalyzed benzylic C−H amidation
has not been described before. Herein, we report a synthesis of
3 via a palladium-catalyzed domino reaction of o-amino-
benzamides with benzyl alcohols in water.
Palladium-catalyzed benzylation with benzylic alcohols is
especially interesting because it is known that the reactivity of
benzylic alcohols toward Pd(0) is poor compared with benzylic
halides, esters, carbonates, or phosphates.14 Only a few papers
describe palladium-catalyzed benzylation with benzylic alcohols.
For example, Sheldon and co-workers reported that the water-
soluble Pd(tppts)3 complex is an active catalyst for the
carbonylation of benzylic alcohols in an aqueous/organic two-
phase system in the presence of an acid cocatalyst.15 Most
recently, we reported the palladium-catalyzed S-benzylation of
anthranilic acid with benzyl alcohols in water.3b Water may play
an important role in the smooth generation of the (η3-benzyl)
palladium species by hydration of the hydroxyl group.
RESULTS AND DISCUSSION
■
First, we heated a mixture of o-aminobenzamide (1a) and
benzyl alcohol (2a; 5 equiv) in the presence of Pd(OAc)2 (5
mol %) and sodium (diphenylphosphino)benzene-3-sulfonate
(TPPMS; 10 mol %) in water at 100 °C for 16 h under air in a
sealed tube. To our surprise, dehydrogenated product 3a was
obtained in 93% yield in spite of the possibility of forming the
aminal 4a (Table 1, entry 1). The reaction did not proceed in
the absence of the palladium catalyst and phosphine ligand or
in the presence of only TPPMS (entry 2). With regard to the
palladium catalyst, the use of PdCl2 also gave the product 3a in
excellent yield (entry 3, 92%). Although the use of zerovalent
palladium, Pd2(dba)3, resulted in no reaction at 100 °C,
improvement of the yield was observed at 120 °C (entry 4,
88%). Heating at 120 °C may be necessary to form the
Pd(tppms)n complex from Pd2(dba)3 with TPPMS. Since the
reaction did not occur when using Pd(PPh3)4 instead of a
water-soluble ligand (entry 5) or when using DMSO, EtOH,
AcOH, 1,4-dioxane, or toluene (entry 6) as a solvent, water
must play an important role in the benzylation with benzyl
alcohol. Indeed, the reaction in 1,4-dioxane/H2O (1:1)
proceeded in 93% yield (entry 7).
Results for the reaction of o-aminobenzamide (1a) with a
number of benzyl alcohols 2 using Pd(OAc)2 and TPPMS are
summarized in Table 2. The benzyl alcohols with electron-
Received: June 21, 2012
Published: August 1, 2012
© 2012 American Chemical Society
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Scheme 1. Our Previous Work
Scheme 2. Our Concept of Pd-Catalyzed Benzylic C−H Amidation
a
a
Table 1. Effect of Catalysts and Solvents
Table 2. Reactions of 1a with Substituted Benzyl Alcohols 2
b
entry
R
product 3
yield (%)
b
entry
1
catalyst
solvent
yield (%)
93
1
2
3
4
5
4-Me (2b)
4-Et (2c)
3b
3c
3d
3e
3f
90
96
65
88
89
Pd(OAc)2/
TPPMS
H2O
H2O
4-OMe (2d)
3-OMe (2e)
2-Me (2f)
2
none or only
TPPMS
0
3
4
PdCl2/TPPMS
H2O
H2O
92
c
a
Pd2(dba)3 /
TPPMS
trace
Reaction conditions: 1a (1 mmol), Pd(OAc)2 (5 mol %), TPPMS
d
(88)
(10 mol %), benzyl alcohols 2 (5 equiv), H2O (4 mL), 120 °C, 16 h in
a sealed tube. Yield of isolated product.
5
6
Pd(PPh3)4
H2O
0
b
Pd(OAc)2/
TPPMS
DMSO, EtOH, AcOH, dioxane, or trace
toluene
7
Pd(OAc)2/
TPPMS
dioxane/H2O (1:1)
93
yields (entry 4, 90%; entry 5, 86%). 2-(Methylamino)-
benzamide (1f) also afforded the desired 3l in good yield
(entry 6, 72%). The sterically demanding N-methyl substituent
did not influence the intramolecular cyclization.
a
Reaction conditions: 1a (0.5 mmol), Pd catalyst (5 mol %), ligand
(10 mol %), benzyl alcohol (2a; 5 equiv), solvent (2 mL), 100 °C, 16
h under air in a sealed tube. Yield of isolated product. Concentration
b
c
Several control experiments were performed to exclude the
possibility of other reaction pathways. First, palladium-catalyzed
reaction of N-benzylated 6a with benzyl alcohol (2a) gave the
desired 3a in quantitative yield (Scheme 3A). 2a plays an
important role in the benzylic C−H amidation step, since the
reaction does not proceed in its absence. Additionally, the
reaction of o-aminobenzamide (1a) with benzaldehyde (7) in
the absence of palladium catalyst in water gave cyclic aminal 4a
in quantitative yield with no 3a detected. Subsequent
palladium-catalyzed reaction of 4a proceeded to give the
desired product 3a in 99% yield (Scheme 3B). Under an Ar
atmosphere, the reaction occurred in 90% yield (Scheme 3C).17
These observations suggested that aerobic oxidation using
d
of 2.5 mol %. The reaction was carried out at 120 °C.
donating methyl, ethyl, and methoxy groups resulted in good
yields (entry 1, 90%; entry 2, 96%; entry 3, 65%, entry 4, 88%).
The sterically demanding ortho-substituted methyl group was
also tolerated in the reaction (entry 5, 89%).
Results for the reactions of several o-aminobenzamides 1
using Pd(OAc)2 and TPPMS in water are summarized in Table
3. The 2-aminobenzamides with 4-methyl, 5-fluoro, and 6-
fluoro groups resulted in good yields (entry 1, 74%; entry 2,
75%; entry 3, 77%). The reaction of 2-amino-N-methylbenza-
mide (1e) proceeded to give the desired products 3j−k in good
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a
ation steps. Furthermore, N-benzylated 6a and aminal 4a must
be intermediates in our catalytic system.
Table 3. Scope of Amide 1
Next we utilized 1H NMR experiments to monitor the
reaction using benzyl-α,α-d2 alcohol (2a′). In oxidative
cyclization of 6a and subsequent dehydrogenation steps, 2
equiv of toluene should be formed from the (η3-benzyl)-
palladium complex in our catalytic system. We were delighted
to observe that indeed toluene was obtained in the reaction
mixture (see the Supporting Information). Dehydrogenation of
aminal 4a with 2a′ in D2O gave 3a along with deuterated
toluene (8a:8b = 4:1) (Table 4, entry 1), suggesting that both
Table 4. Pd-Catalyzed Reaction with Benzyl-α,α-d2 Alcohol
a
(2a′)
entry
1a or 4a
solvent
8a:8b
1
2
4a
1a
D2O
H2O
4:1
1:9
a
Reaction conditions: 1a or 4a (0.25 mmol), Pd(OAc)2 (5 mol %),
TPPMS (10 mol %), benzyl alcohol 2a′ (3 equiv), solvent (1 mL), 120
°C, 16 h in a sealed tube. After cooling, the reaction mixture was
1
extracted with CDCl3. The organic layer was analyzed by H NMR.
C−H and N−H palladation of aminal 4b occurred to form
benzylic C−H activated 10a and palladium amide 11a (Scheme
4). In contrast, the monohydrogenated toluene 8b was mainly
a
Reaction conditions: 1 (1 mmol), Pd(OAc)2 (5 mol %), TPPMS (10
Scheme 4. Dehydrogenation of 4b in D2O (Table 4, Entry 1)
mol %), benzyl alcohols 2 (5 equiv), H2O (4 mL), 120 °C, 16 h in a
sealed tube. The yields in column 5 are those of isolated product.
b
Time of 48 h.
Scheme 3. (A) N-Benzylation with Benzyl Chloride and Pd-
Catalyzed Reaction of N-Benzylated 6a, (B) Intramolecular
Nucleophilic Addition of the Amide to the Imine and Pd-
Catalyzed Dehydrogenation of Aminal 4a, and (C) Pd-
Catalyzed Reaction under Ar
formed (8a:8b = 1:9) from the reaction of o-aminobenzamide
(1a) in H2O (Table 4, entry 2). This result suggested that N-
palladated intermediate 13 should not form and only amide-
directed benzylic C−H activation would occur to form
intermediate 12 because, as shown in Scheme 5, selective
formation of 12 might only produce the dideuterated toluene
8b with the formation of 4c and then a 1:4 molar ratio of 8a
and 8b might be produced by the reaction of intermediate 4c
with (η3-benzyl)palladium complex 9b as shown in Scheme 4.
Exclusive formation of 12, but not 13, from N-benzylated 6b
with palladium complex 9b suggested that the amide group
plays an important role as a directing group in the selective
benzylic C−H activation.18 Additionally, palladation of aminal
4c, which has no directing group, afforded both benzylic C−H
activated 10b and palladium amide 11b, which underwent
dehydrogenation to give the desired 3a along with deuterated
toluene (8a:8b = 1:4) according to the result of entry 1 in
Table 4. This observation clearly explained the formation of
oxygen did not occur in our catalytic system and a palladium
intermediate must play an important role in the dehydrogen-
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transfer and C−H activation. Furthermore, subsequent reaction
steps for C−H activation require an oxidant capable of
converting palladium to a higher oxidation state, and benzyl
alcohols 2 work for regeneration of PdII species to toluene in
our catalytic system. Thus, our method provides a unique
strategy for the benzylation and activation of a benzylic C−H
bond by palladium catalyst and benzyl alcohols in water.
Importantly, the reaction of o-aminobenzamide 1 afforded
only desired quinazolinone 3 via benzylic C−H amidation in
spite of the possibility of forming dibenzylated product 14
(Scheme 8, this work). Since Pd-catalyzed reaction proceeds by
intramolecular oxidative coupling of an amide NH with a
C(sp3)−H bond,18b amidation of intermediate 12 also might
proceed smoothly. In contrast, the reaction of anthranilic acid
afforded only dibenzylated product A, with no internal cyclized
product 15 (Scheme 8, our previous work), since the oxygen
nucleophilicity of the carboxyl group might be weak in neutral
aqueous conditions.
Scheme 5. C−H Amidation and Dehydrogenation Steps in
H2O (Table 4, Entry 2)
CONCLUSION
■
In summary, we have developed a methodology for achieving a
palladium-catalyzed domino reaction for the construction of 2-
phenylquinazolin-4(3H)-one (3). The domino reactions
achieved N-benzylation, benzylic C−H amidation, and
dehydrogenation in water, which played an important role in
the activation of the benzylic alcohols to form the
corresponding palladium complexes. Water is still not
commonly used as a solvent in organic synthesis despite its
distinctive properties. Furthermore, the (η3-benzyl)palladium
system could be used for not only benzylation, but also C−H
activation and dehydrogenation. We are currently investigating
the scope of various nucleophiles on the benzylation and are
developing new reactions using (η3-benzyl)palladium from
benzyl alcohols in aqueous media.
deuterated toluenes 8a and 8b in 10% and 90% yield (50%
from 12 and 40% from 10b), respectively.
As a proof of the concept, our strategy of amide-directed
benzylic C−H amidation was used to construct quinazolinones
with our catalytic system. Although Zhou and co-workers
recently reported the same reaction, i.e., the one-pot synthesis
of 2-phenylquinazolin-4(3H)-one (3) from o-aminobenzamide
(1a) with benzyl alcohols 2 via iridium-catalyzed hydrogen
transfers (Scheme 6),19 our (η3-benzyl)palladium system works
Scheme 6. One-Pot Synthesis of Quinazolinones Starting
with Benzyl Alcohols
EXPERIMENTAL SECTION
■
General Procedure. A mixture of 2-aminobenzamide 1 (0.5−1
mmol), palladium(II) acetate (5 mol %), sodium
(diphenylphosphino)benzene-3-sulfonate (TPPMS; 10 mol %), and
benzyl alcohol 2 (5 equiv) in H2O (2−4 mL) was heated at 100−120
°C for 16−48 h in a sealed tube. After cooling, the reaction mixture
was poured into water and extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica gel,
hexanes/EtOAc) to give desired product 3.
2-Phenylquinazolin-4(3H)-one (3a; Table 1, Entry 1).19 Following
the general procedure, 3a was obtained as a white solid: 103 mg
(93%); mp 232−235 °C; IR (KBr) (cm−1) 3078, 1667, 1606; H
1
NMR (400 MHz, DMSO-d6) δ 7.50−7.65 (m, 4H), 7.76 (d, J = 8.0
Hz, 1H), 7.85 (dd, J = 7.2, 7.2 Hz, 1H), 8.15−8.25 (m, 3H) 12.5 (br s,
1H); 13C NMR (400 MHz, DMSO-d6) δ 120.9, 125.8, 126.5, 127.4,
127.7, 128.6, 131.3, 132.7, 134.5, 148.6, 152.3, 162.3; MS (EI) m/z
(rel intens, %) 222 (M+, 82.5), 119 (100).
on a mechanism quite different from the hydrogen transfer
methodology. Although benzyl alcohols 2 form benzaldehyde
(7) via iridium-catalyzed hydrogen transfers, oxidative additions
of benzyl alcohols 2 to Pd0 afford the (η3-benzyl)palladium
complex 9 in aqueous media (Scheme 7). Notably, the (η3-
benzyl)palladium system plays an important role in the benzyl
2-p-Tolylquinazolin-4(3H)-one (3b; Table 2, Entry 1).19 Following
the general procedure, 3b was obtained as a white solid: 213 mg
1
(90%); mp 231−234 °C; IR (KBr) (cm−1) 3075, 1662, 1605; H
NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.36 (d, J = 8.0 Hz, 2H),
7.51 (dd, J = 8.0, 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.83 (dd, J =
8.0, 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.0 Hz, 1H),
12.5 (br s, 1H); 13C NMR (400 MHz, DMSO-d6) δ ; 21.0, 120.9,
125.8, 126.4, 127.4, 127.7, 129.2, 129.9, 134.5, 141.4, 148.8, 152.2,
162.2; MS (EI) m/z (rel intens, %) 236 (M+, 73.1), 119 (100).
2-(4-Ethylphenyl)quinazolin-4(3H)-one (3c; Table 2, Entry 2).20
Following the general procedure, 3c was obtained as a white solid: 240
Scheme 7. Role of (η3-Benzyl)palladium Species 9
1
mg (96%); mp 201−204 °C; IR (KBr) (cm−1) 3178, 1666, 1606; H
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Scheme 8. Comparison between Our Previous Work and This Work
NMR (400 MHz, DMSO-d6) δ 1.23 (t, J = 7.6 Hz, 3H), 2.70 (q, J =
7.6 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H),
7.74 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 7.6, 7.6 Hz, 1H), 8.13 (d, J = 8.0
Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 12.5 (br s, 1H); 13C NMR (400
MHz, DMSO-d6) δ 15.2, 28.0, 120.9, 125.8, 126.4, 127.4, 127.8, 128.0,
130.1, 134.5, 147.5, 148.8, 152.2, 162.2; MS (EI) m/z (rel intens, %)
250 (M+, 100).
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3d; Table 2, Entry
3).19 Following the general procedure, 3d was obtained as a white
solid: 163 mg (65%); mp 231−234 °C; IR (KBr) (cm−1) 3091, 1680,
1608; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 2H), 7.09 (d, J = 8.8
Hz, 2H), 7.49 (dd, J = 7.6, 7.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.82
(dd, J = 7.6, 7.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.8 Hz,
2H), 12.4 (br s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 55.4, 113.9,
120.7, 124.8, 125.8, 126.1, 127.2, 129.4, 134.5, 148.9, 151.8, 161.8,
162.2; MS (EI) m/z (rel intens, %) 252 (M+, 100).
151.8, 158.7, 161.4 (J = 188 Hz); MS (EI) m/z (rel intens, %) 240
(M+, 77.7), 137 (100).
5-Fluoro-2-phenylquinazolin-4(3H)-one (3i; Table 3, Entry 3).22
Following the general procedure, 3i was obtained as a white solid: 185
1
mg (77%); mp 235−238 °C; IR (KBr) (cm−1) 3059, 1687, 1616; H
NMR (400 MHz, DMSO-d6) δ 7.26 (dd, J = 11.2, 8.4 Hz, 1H), 7.50−
7.65 (m, 4H), 7.75−7.85 (m, 1H), 8.18 (d, J = 8.0 Hz, 2H), 12.6 (br s,
1H); 13C NMR (400 MHz, DMSO-d6) δ 110.4, 112.9 (J = 82 Hz),
123.6, 127.9, 128.6, 131.7, 132.2, 135.1 (J = 40 Hz), 150.9, 153.3,
159.4 (J = 128 Hz), 161.8; MS (EI) m/z (rel intens, %) 240 (M+,
82.8), 137 (100).
3-Methyl-2-phenylquinazolin-4(3H)-one (3j; Table 3, Entry 4).
Following the general procedure, 3j was obtained as a white solid: 213
mg (90%); mp 130−132 °C (lit.23 mp 131−132 °C); IR (KBr)
1
(cm−1) 1678, 1560; H NMR (400 MHz, DMSO-d6) δ 3.37 (s, 3H),
7.50−7.60 (m, 4H), 7.65−7.70 (m, 3H), 7.84 (dd, J = 8.0, 8.0 Hz,
1H), 8.19 (d, J = 8.0 Hz, 1H); 13C NMR (400 MHz, DMSO-d6) δ
33.8, 120.1, 126.1, 126.8, 127.1, 128.2, 128.4, 129.8, 134.3, 135.4,
147.0, 156.1, 161.6; MS (EI) m/z (rel intens, %) 236 (M+, 68.7), 235
(100).
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (3e; Table 2, Entry
4).19 Following the general procedure, 3e was obtained as a white
solid: 223 mg (88%); mp 204−205 °C; IR (KBr) (cm−1) 3040, 1672,
1607; 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.15 (d, J = 8.0
Hz, 1H), 7.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.50−7.58 (m, 1H), 7.75−7.90
(m, 4H), 8.17 (d, J = 7.6 Hz, 1H), 12.5 (br s, 1H); 13C NMR (400
MHz, DMSO-d6) δ 55.4, 112.5, 117.6, 120.1, 121.0, 125.8, 126.6,
127.6, 129.7, 134.0, 134.6, 148.6, 152.0, 159.3, 162.2; MS (EI) m/z
(rel intens, %) 252 (M+, 100).
3-Methyl-2-p-tolylquinazolin-4(3H)-one (3k; Table 3, Entry 5).
Following the general procedure, 3k was obtained as a white solid: 215
mg (86%); mp 139−140 °C (lit.24 mp 128 °C); IR (KBr) (cm−1)
1
3023, 1672, 1596; H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H),
3.31 (s, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.55−7.57 (m, 1H), 7.57 (d, J =
8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.83 (ddd, J = 6.8, 6.8, 1.2 Hz,
1H), 8.18 (dd, J = 8.0, 1.2 Hz, 1H); 13C NMR (400 MHz, DMSO-d6)
δ 20.9, 33.9, 120.0, 126.0, 126.7, 127.1, 128.2, 128.8, 132.6, 134.3,
139.5, 147.1, 156.2, 161.7; MS (EI) m/z (rel intens, %) 250 (M+,
80.9), 249 (100).
2-o-Tolylquinazolin-4(3H)-one (3f; Table 2, Entry 5).12d Following
the general procedure, 3f was obtained as a white solid: 211 mg
1
(89%); mp 212−215 °C; IR (KBr) (cm−1) 3054, 1684, 1605; H
NMR (400 MHz, DMSO-d6) δ 2.39 (s, 3H), 7.30−7.40 (m, 2H), 7.44
(dd, J = 7.6, 7.6 Hz, 1H), 7.50−7.60 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H),
7.84 (t, J = 7.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 12.4 (br s, 1H); 13C
NMR (400 MHz, DMSO-d6) δ 19.5, 120.9, 125.6, 125.7, 126.6, 127.3,
129.1, 129.8, 130.5, 134.2, 134.4, 136.1, 148.7, 154.3, 161.7; MS (EI)
m/z (rel intens, %) 236 (M+, 89.5), 235 (100).
1-Methyl-2-phenylquinazolin-4(1H)-one (3l; Table 3, Entry 6).25
Following the general procedure, 3l was obtained as an off-white solid:
1
170 mg (72%); mp 158−161 °C; IR (KBr) (cm−1) 1641, 1600; H
NMR (400 MHz, DMSO-d6) δ 3.64 (s, 3H), 7.53−7.64 (m, 4H),
7.65−7.72 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 7.6, 7.6 Hz,
1H), 8.15 (d, J = 7.6 Hz, 1H); 13C NMR (400 MHz, DMSO-d6) δ
37.8, 116.8, 119.7, 125.9, 127.0, 128.3, 128.6, 130.2, 133.9, 135.2,
141.7, 162.0, 167.6; MS (EI) m/z (rel intens, %) 236 (M+, 70.0), 105
(100).
7-Methyl-2-phenylquinazolin-4(3H)-one (3g; Table 3, Entry 1).19
Following the general procedure, 3g was obtained as a white solid: 175
1
mg (74%); mp 227−230 °C; IR (KBr) (cm−1) 3040, 1672, 1611; H
NMR (400 MHz, DMSO-d6) δ 2.49 (s, 3H), 7.36 (d, J = 8.0 Hz, 1H),
7.50−7.65 (m, 4H), 8.05 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 6.8 Hz, 2H),
12.5 (br s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 21.3, 118.6, 125.7,
127.1, 127.7, 128.0, 128.6, 131.3, 132.8, 145.0, 148.8, 152.3, 162.1; MS
(EI) m/z (rel intens, %) 236 (M+, 75.0), 133 (100).
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (4a; Scheme 3B).19
A
mixture of 2-aminobenzamide (1a; 136 mg, 1 mmol) and
benzaldehyde (7; 101 μL, 1 mmol) in H2O (4 mL) was heated at
120 °C for 16 h in a sealed tube. After cooling, the reaction mixture
was poured into water and extracted with EtOAc. The organic layer
was washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (silica gel,
hexanes/EtOAc) to give desired product 4a (224 mg, quant) as an off-
white solid: mp 222−225 °C; IR (KBr) (cm−1) 3302, 1660; 1H NMR
(400 MHz, DMSO-d6) δ 5.75 (s, 1H), 6.60−6.70 (m, 1H), 6.74 (d, J =
6-Fluoro-2-phenylquinazolin-4(3H)-one (3h; Table 3, Entry 2).21
Following the general procedure, 3h was obtained as a white solid: 180
1
mg (75%); mp 229−231 °C; IR (KBr) (cm−1) 3036, 1680, 1616; H
NMR (400 MHz, DMSO-d6) δ 7.50−7.65 (m, 3H), 7.30 (dt, J = 8.4,
2,4 Hz, 1H), 7.75−7.90 (m, 2H), 8.17 (d, J = 8.0 Hz, 2H), 12.7 (br s,
1H); 13C NMR (400 MHz, DMSO-d6) δ 110.5 (J = 92 Hz), 122.2,
123.0 (J = 92 Hz), 127.7, 128.6, 130.2, 130.3, 131.4, 132.5, 145.6,
7050
dx.doi.org/10.1021/jo301282n | J. Org. Chem. 2012, 77, 7046−7051

The Journal of Organic Chemistry
Article
8.0 Hz, 1H), 7.09 (s, 1H), 7.20−7.30 (m, 1H), 7.30−7.45 (m, 3H),
7.45−7.55 (m, 2H), 7.60 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H); 13C NMR
(400 MHz, DMSO-d6) δ 66.5, 114.4, 114.9, 117.1, 126.8, 127.3, 128.3,
128.4, 133.3, 141.6, 147.8, 163.5; MS (EI) m/z (rel intens, %) 224
(M+, 31.9), 147 (100).
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2-(Benzylamino)benzamide (6a; Scheme 3A).12a A mixture of 2-
aminobenzamide (1a; 1.0 g, 7.4 mmol), K2CO3 (1.0 g, 7.4 mmol), NaI
(1.1 g, 7.4 mmol), and benzyl chloride (5; 1.2 mL, 10 mmol) in DMF
(10 mL) was stirred at rt for 1 d. The reaction mixture was poured into
water and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, hexanes/EtOAc)
to give desired product 6a (1.6 g, 93%) as a pale yellow solid: mp
1
166−169 °C; IR (KBr) (cm−1) 3441, 3205, 1620, 1575; H NMR
(400 MHz, DMSO-d6) δ 4.38 (s, 2H), 6.53 (dd, J = 7.6, 7.6 Hz, 1H),
6.61 (d, J = 8.0 Hz, 1H), 7.10−7.45 (m, 7H), 7.62 (dd, J = 8.0, 1.2 Hz,
1H), 7.85 (br s, 1H), 8.59 (br s, 1H); 13C NMR (400 MHz, DMSO-
d6) δ 46.0, 111.5, 114.2, 126.8, 127.0, 127.1, 128.4, 129.0, 132.4, 139.6,
149.5, 171.6; MS (EI) m/z (rel intens, %) 226 (M+, 99.9), 180 (100).
ASSOCIATED CONTENT
■
S
* Supporting Information
General procedure and 1H NMR spectra (Table 4) and 1H and
13C NMR spectra of compounds 3a−l, 4a, and 6a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hidemasa.hikawa@phar.toho-u.ac.jp (H.H.);
yokoyama@phar.toho-u.ac.jp (Y.Y.).
Notes
The authors declare no competing financial interest.
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