One-Pot Cascade Synthesis of Quinazolin-4(3H)-ones via Nickel-Catalyzed Dehydrogenative Coupling of o-Aminobenzamides with Alcohols

Article abstract of DOI:10.1021/acs.joc.7b00643

In this paper, we report a general, efficient, and environmentally benign method for the one-pot cascade synthesis of quinazolin-4(3H)-ones via acceptorless dehydrogenative coupling of o-aminobenzamide with alcohols catalyzed by a simple Ni(II) catalyst, [Ni(MeTAA)], featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)). A wide variety of substituted quinazolin-4(3H)-ones were synthesized in high yields starting from readily available benzyl alcohols and o-aminobenzamides. Several controlled reactions along with deuterium labeling studies were carried out to establish the acceptorless dehydrogenative nature of the reactions.

Full text of DOI:10.1021/acs.joc.7b00643

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Article
One-pot Cascade Synthesis of Quinazolin-4(3H)-ones via Nickel-
Catalyzed Dehydrogenative Coupling of o-Aminobenzamides with Alcohols
Seuli Parua, Siuli Das, Rina Sikari, Suman Sinha, and Nanda D. Paul
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00643 • Publication Date (Web): 27 Jun 2017
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One-pot Cascade Synthesis of Quinazolin-4(3H)-ones via Nickel-
Catalyzed Dehydrogenative Coupling of o-Aminobenzamides with
Alcohols
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Seuli Parua,# Siuli Das,# Rina Sikari, Suman Sinha and Nanda D. Paul*
Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur,
Botanic Garden, Howrah 711103, India
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Abstract. In this article we report a general, efficient and environmentally benign method for the
oneꢀpot cascade synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative coupling
of oꢀaminobenzamide with alcohols catalyzed by a simple Ni(II)ꢀcatalyst, [Ni(MeTAA)]
featuring tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)). A wide
variety of substituted quinazolinꢀ4(3H)ꢀones were synthesized in high yields starting from
readily available benzyl alcohols and oꢀaminobenzamides. Several controlled reactions along
with deuterium labeling studies were carried out to establish the acceptorless dehydrogenative
nature of the reactions.
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Introduction. Quinazolinꢀ4(3H)ꢀones are fundamental building blocks in nature, and part of the
backbone of more than 150 naturally occurring alkaloids and several biologically active
compounds such as 2ꢀmethylꢀ4(3H)ꢀquinazolinone, luotonin A, luotonin F, rutaecarpine,
bouchardatine, tryptanthrin etc. (Scheme 1).1 They are the crucial substructure of a wide variety
of known pharmaceutical agents and drug candidates with antimicrobial,2 antiꢀinflammatory,3
anticonvulsant,4 antihypertensive,5 hypolipidemic,6 sedative,7 antitubercular,8 antiviral,9
antimalarial,10 and anticancer11 activities. Due to the immense importance as a pharmacophore in
drug candidates, the quinazolinꢀ4(3H)ꢀone skeleton is assigned as privileged structure.12
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O
N
O
N
O
N
N
NH
Me
N
NH
N
O
2-methyl-4(3H)-quinazolinone
O
Luotonin F
Luotonin A
O
O
NH
N
N
CHO
N
N
N
O
HN
HN
Rutaecarpine
Tryptanthrin
Bouchardatine
Scheme 1. Selected examples of quinazolinꢀ4(3H)ꢀone skeleton containing natural products.
Consequently, considerable efforts have been made over the years for their synthesis.
Synthetic methods developed so far include fusion of anthranilic acid with amides, amidation of
2ꢀaminobenzoic acids and cascade reaction of aldehydes with oꢀaminobenzamide involving
condensation followed by oxidation of the aminal intermediate.13 All these synthetic routes
involve multistep reaction sequences, and many of them require stoichiometric or excess
amounts of strong oxidants like DDQ,14a CuCl2,14b MnO2,14c KMnO414d, I2,14e tꢀBuOOH14fꢀh and
in most of the cases the reactions are carried out at high temperature.14 Another limitation
associated with these methodologies is the use of relatively unstable aldehydes which are
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synthesized from readily available alcohols via oxidation with different toxic oxidants.
Substituted 2ꢀnitrobenzamides were also used as the starting precursor for cascade synthesis of
quinazolinꢀ4(3H)ꢀones.15 Initial reduction of the nitroꢀgroup followed by condensation with
suitable coupling partners affords the desired quinazolinꢀ4(3H)ꢀones. Other synthetic routes
involves Cuꢀcatalyzed Nꢀarylation of 2ꢀhalobenzoic acid or its derivatives with ammonia,
benzylamines, amidines, amino acids, and amides.16 A few reports are also available on the Pdꢀ
catalyzed carbonylative synthesis of quinazolinꢀ4(3H)ꢀones using gaseous CO.17 Direct synthesis
of carboxylic acids and their derivatives via palladiumꢀcatalyzed carbonylation of aryl halides
and C–H bonds followed by intramolecular or intermolecular carboxamidation indeed represents
a direct and convenient synthetic strategy for quinazolinꢀ4(3H)ꢀones. Other synthetic routes
include condensation of oꢀaminobenzamide with aryl methyl ketones18 and keto alkynes.19
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An environment friendly and comparatively mild approach for the synthesis of
quinazolinꢀ4(3H)ꢀones is via acceptorless dehydrogenative cyclization of oꢀaminobenzamide or
its derivatives with alcohols (Scheme 2).20 Only hydrogen gas and H2O is generated as chemical
waste. Moreover, this method eliminates the use of preformed aldehydes which are relatively
unstable at the reaction conditions and the use of toxic strong oxidants can also be avoided. In
recent years a few groups used this concept to synthesize quinazolinꢀ4(3H)ꢀones; however, in all
cases expensive heavy metals like Ir,20bꢀd Pt,20e and Pd20f were used as catalysts. In 2011 Zhou
and coꢀworkers reported a oneꢀpot oxidative cyclization of primary alcohols with oꢀ
aminobenzamides to quinazolinꢀ4(3H)ꢀones catalyzed by iridium under hydrogen transfer
conditions.20b In 2015 Li and coꢀworkers reported the acceptorless dehydrogenative condensation
of oꢀaminobenzamides with aldehydes to quinazolinꢀ4(3H)ꢀones in water catalyzed by a water
soluble iridium catalyst.20c In 2016, using a different iridium catalyst, Li and coꢀworkers also
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reported the synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative coupling of oꢀ
aminobenzamides with the activation of methanol as a C1 Source.20d Herein we report oneꢀpot
synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative coupling of oꢀ
aminobenzamides with benzyl alcohols catalyzed by a square planner Ni(II)ꢀcomplex
([Ni(MeTAA)]) featuring tetraaza macrocyclic ligand (Figure 1).
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O
NH2
O
O
N
NH2
R2
NH
R1
NH
R1
R1
OH
R1
H2
H2O
O
N
H
R2
R2
Scheme 2. Cascade synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative
coupling of alcohols and oꢀaminobenzamides.
N
N
N
N
Ni
[Ni(MeTAA)]
Figure 1. Catalyst used in this study.
Results and Discussion. The Ni(II)ꢀmacrocyclic complex [Ni(MeTAA)] is the nickel(II)
complex of the (tetramethyltetraaza[14]annulene (MeTAA)) ligand. It was synthesized following
a known literature method.21 The reaction of 2.0 equivalent of 1,2ꢀphenylenediamine, 2.0
equivalent of 2,4ꢀpentanedione, and excess of nickel(II) acetate tetrahydrate in methanol under
refluxing condition for 48 h resulted in the formation of green colored nickel(II) macrocyclic
complex [Ni(MeTAA)] in almost quantitative yield. Characterization data of the Ni(II)ꢀcomplex
thus obtained matched exactly with that reported previously.
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The cascade synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative
cyclization of oꢀaminobenzamide or its derivatives with alcohols is believed to proceed through
the initial dehydrogenative formation of aldehyde followed by condensation with oꢀ
aminobenzamide to form the cyclic aminal intermediate which upon further dehydrogenation
affords the desired quinazolinꢀ4(3H)ꢀones (Scheme 2).20 Therefore, our initial studies were
focused on to find out the optimal conditions for the acceptorless dehydrogenation of alcohols22ꢀ
24 using [Ni(MeTAA)] as catalyst.
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Optimization of the reaction conditions using benzyl alcohol as the model substrate
revealed that the reaction proceeded most efficiently in nonpolar solvents like toluene, xylene
whereas reactions in solvents of high polarities such as MeCN, dioxane, methanol, and DMF
afforded poor yields (Table 1, entries 1ꢀ7). Among the series of bases examined such as K3PO4,
K2CO3, Na2CO3, NaHCO3, NaH, NaOtBu, KOtBu, NaOMe, and NaOH, the best results were
obtained with NaOtBu (Table 1, entries 1ꢀ13). Highest conversion of benzyl alcohol to
benzaldehyde was achieved when the reaction was carried out at 85oC in xylene for 7 h in
presence of NaOtBu using 3.0 mol% of the catalyst (Table 1, entry 2). Lowering the temperature
or catalyst loading below 3.0 mol% leads to poor conversion of the alcohols to the corresponding
aldehydes or ketones.
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Table 1. Optimization of Reaction Conditions for the Dehydrogenation of Benzyl Alcohol (1a)
5
6
Catalyzed by [Ni(MeTAA)].a,b
7
8
9
Ni(II)-catalyst
H2
OH
O
Solvent, Base,
85 oC, 7h
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1a
1aa
Entry
1
Ni(II)ꢀcatalyst (mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol%)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
ꢀ
Solvent
Base
KOtBu
Yield (%)b
85
xylene
xylene
toluene
acetonitrile
methanol
ethanol
THF
2
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
K2CO3
K3PO4
NaH
93
3
89
4
trace
NR
NR
74
5
6
7
8
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
45
9
52
10
11
12
13
14
15
16
17
18
58
NaOH
82
Na2CO3
NaHCO3
NaOtBu
ꢀ
NaOtBu
NaOtBu
NaOtBu
30
trace
NR
NR
87
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (2 mol %)
NiCl2 (10mol%)
NR
trace
Ni(OAc)2 (10mol%)
aStoichiometry: benzyl alcohol (1.0 mmol); catalyst (0.03 mmol); base (1.5 mmol, 1.5 equiv).
bIsolated yields after column chromatography.
The stability of the catalytic system was checked in aerial conditions. The catalyst
[Ni(MeTAA)], itself is air stable and excellent conversion of alcohol to aldehyde was achieved
when the reaction was carried out in presence of air. However, the yield of the corresponding
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aldehyde or ketones decreases significantly when the reaction was carried out in a closed schlenk
tube (Table 2). This experimental observation is in agreement with the other reported
dehydrogenation reactions where the removal of H2 from the reaction mixture is essential for the
progress of the reaction.23
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Table 2. Dehydrogenation of Benzyl alcohol (1a) in Open/Closed Systems.a,b
[Ni(MeTAA)]
(3.0 mol%)
H2
OH
O
xylene, NatOBu,
85 oC, 7h
1a
1aa
Entry
Open/Closed
open
Atmosphere
Yield (%)a
1
2
3
Ar
air
air/Ar
93
80
45
open
closed
aStoichiometry: benzyl alcohol (1.0 mmol); catalyst (0.03 mmol); base (1.5 mmol, 1.5 equiv).
bIsolated yields after column chromatography.
Controlled experiments showed that no product was obtained in presence of only
macrocyclic ligand and base. While other Nickel(II) sources like NiCl2 and Ni(OAc)2 (Table 1,
entries 17 and 18) only afforded the corresponding aldehydes in trace amounts (<10%).
Various substituted alcohols with different electronic properties and functional groups
were tested under the optimized reaction conditions. As shown in Table 3, excellent yields were
obtained with alcohols containing electron donating groups. Benzyl alcohols having ꢀMe or ꢀ
OMe groups either at the orthoꢀ, paraꢀ or metaꢀ positions afforded the corresponding aldehydes
in high yield (Table 3, entry 2ꢀ7). Reactions also proceeded with electronꢀwithdrawing groups at
the orthoꢀ, paraꢀ or metaꢀ positions of benzyl alcohols, albeit leading to lower yields (Table 3,
entry 8ꢀ15). For example, 4ꢀnitrobenzyl alcohol (1o) produces the corresponding aldehyde (1oo)
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in a moderate yield (55%) (Table 3, entry 15). 1ꢀPyrenecarboxaldehyde (1pp) or 9ꢀ
anthracenecarboxaldehyde (1qq) were also isolated in high yields 87 and 82% respectively from
their corresponding alcohols (Table 3, entry 16, 17). Heterocyclic alcohols were also found to
produce the corresponding aldehydes (Table 3, entry 18ꢀ19). For example, 2ꢀ
pyridinecarboxaldehyde (1rr) was obtained in 65% yield from 2ꢀpyridinemethanol under the
optimized reaction conditions. Secondary alcohols also undergo dehydrogenation to produce the
corresponding ketones under the same optimized reaction conditions. 1ꢀPhenylethanol or
diphenylmethanol afforded acetophenone (1tt) and benzophenone (1uu) in high yields 83 and
85% respectively (Table 3, entry 20, 21).
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Table 3. Dehydrogenation of Various Alcohols Catalyzed by [Ni(MeTAA)].aꢀb
3
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8
9
R'
R'
[NiII(MeTAA)]
xylene, NatOBu
80 oC, 7h
H2
OH
O
R
R
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1aa-uu
1a-u
1
2
3
O
O
O
1aa
93%
1bb
1cc
86%
5
89%
4
6
O
O
O
MeO
OMe
1ee
75%
8
1ff
83%
1dd
92%
7
MeO
10
9
O
O
O
OMe
F
Cl
Cl
1gg
85%
1hh
78%
1ii
69%
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12
O
O
O
Cl
Cl
1jj
Cl
75%
1kk
73%
1ll
72%
13
16
14
15
O
O
O
O
O
Br
O2N
1nn
78%
Br
1oo
55%
1mm
76%
17
18
O
N
1pp
87%
1qq
82%
1rr
65%
O
O
19
20
21
O
S
1ss
69%
1tt
83%
1uu
85%
aStoichiometry: alcohol (1.0 mmol), catalyst (0.03 mmol); base (1.5
mmol, 1.5 equiv). Isolated yields after column chromatography.
b
Once we have the results of alcohol dehydrogenation reactions in hand, we set out to
study the acceptorless dehydrogenative coupling of oꢀaminobenzamide or its derivatives with
alcohols to construct the quinazolinꢀ4(3H)ꢀone moiety using our nickel catalyst, [Ni(MeTAA)].
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As expected, the reaction of benzyl alcohol (1a) with oꢀaminobenzamide (2a) under the preꢀ
optimized reaction conditions (optimal conditions for alcohol dehydrogenation) produces 2ꢀ
phenylquinazolinꢀ4(3H)ꢀone (3aa) in 40% isolated yield (Table 4, entry 1). Further optimization
of the reaction conditions using benzyl alcohol (1a) and oꢀaminobenzamide (2a) as model
substrates revealed that the reaction proceeded most efficiently in xylene in presence of NaOtBu
as base at 100oC. Longer reaction time is required for higher conversion and increasing the
catalyst loading from 3.0 to 5.0 mol% further increases the yield (Table 4, entry 11). Similar to
the dehydrogenation of alcohols, high yield of quinazolinꢀ4(3H)ꢀone was obtained when the
reaction was carried out in presence of argon under open conditions and the yield decreases
significantly when the reaction was carried out in a closed schlenk tube (Table 5). Controlled
reactions using other Nickel(II) sources like NiCl2 and Ni(OAc)2, however, failed to produce
quinazolinꢀ4(3H)ꢀone under the optimized conditions (Table 4, entry 14, 15). In all further
catalytic synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative coupling of oꢀ
aminobenzamide or its derivatives with alcohols, we therefore focused on reactions with
[Ni(MeTAA)] (5 mol%) in xylene at 100 °C (Table 4, entry11).
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Table 4. Optimization of Reaction Conditions for the Dehydrogenative Coupling of Benzyl
Alcohol (1a) and oꢀAminobenzamide (2a) Catalyzed by [Ni(MeTAA)].a,b
7
8
9
O
O
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OH
NH2
NH
Ni-catalyst
+
+
H2
solvent,
temperature (oC),
time (h)
NH2
N
2a
3aa
1
Entry Ni(II)ꢀcatalyst (mol %)
Solvent Temperature(oC) Time(h)
Base
NaOtBu
NaOtBu
NaOtBu
KOtBu
K2CO3
K3PO4
NaOH
Na2CO3
NaHCO3
NaH
NaOtBu
NaOtBu
ꢀ
NaOtBu
NaOtBu
Yield (%)aꢀd
1
2
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (3 mol %)
[Ni(MeTAA)] (5 mol %)
ꢀ
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
85
7
40
45
100
100
100
100
100
100
100
100
100
100
100
100
100
100
7
3
36
36
36
36
36
36
36
36
36
36
36
36
36
74
4
68
5
36
6
40
7
65
8
20
9
trace
56
10
11
12
13
14
86
NR
NR
NR
trace
[Ni(MeTAA)] (5mol %)
NiCl2 (10mol%)
15
Ni(OAc)2 (10mol%)
aStoichiometry: benzyl alcohol (1a) (1.1 mmol); oꢀaminobenzamide (2a) (1.0 mmol); base
(1.5 mmol, 1.5 equiv). bIsolated yields after column chromatography.
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Table 5. Dehydrogenative Coupling of Benzyl Alcohol (1a) and oꢀAminobenzamide (2a) in
5
6
Open/Closed Systems.a,b
7
8
9
O
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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43
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
NH2
NH
[Ni(MeTAA)]
xylene, 100 oC,
36 h
+
+
H2
NH2
2a
3aa
1a
Entry
Open/Closed
open
Atmosphere
Yield (%)a
1
2
3
Ar
air
air/Ar
86
74
50
open
closed
aStoichiometry: benzyl alcohol (1a) (1.1 mmol); oꢀaminobenzamide (2a) (1.0 mmol); base (1.5
mmol, 1.5 equiv). bIsolated yields after column chromatography.
With the optimal conditions in hand (Table 4, entry 11), we explored the substrate scope
and versatility of the developed [Ni(MeTAA)]ꢀcatalyzed cascade reaction. Coupling of oꢀ
aminobenzamide (2a) with various substituted benzyl alcohols were investigated under the
optimal reaction conditions and the results are summarized in Table 6. Excellent yields of
quinazolinꢀ4(3H)ꢀones were obtained with alcohols containing electron donating groups. Benzyl
alcohols having methyl substituents either at orthoꢀ, metaꢀ or paraꢀpositions (Table 6, entry 2ꢀ4)
produced the corresponding quinazolinꢀ4(3H)ꢀones in 84, 87 and 90% isolated yield
respectively. Presence of electron donating ꢀOMe group in the benzyl alcohols further increases
the yield (Table 6, entry 5). Reaction of 3ꢀmethoxybenzyl alcohol with oꢀaminobenzamide was
found to produce the corresponding quinazolinꢀ4(3H)ꢀone in 89% isolated yield (Table 6, entry
5). However, starting from 4ꢀmethoxybenzyl alcohol only 65% of 2ꢀ(4ꢀ
methoxyphenyl)quinazolinꢀ4(3H)ꢀone (3ff) was isolated. Addition of styrene as a sacrificial
hydrogen acceptor,20b however, improves the yield of 2ꢀ(4ꢀmethoxyphenyl)quinazolinꢀ4(3H)ꢀone
to 88%.
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Table 6. Dehydrogenative Coupling of oꢀAminobenzamide with Various Benzyl Alcohols
5
6
Catalyzed by [Ni(MeTAA)].aꢀc
7
8
9
O
O
N
[Ni(MeTAA)]
NH2 (5.0 mol%)
OH
NH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
+
H2
NH2 NatOBu, xylene,
100 oC,36h
R
2a
3aa-oo
1a-o
O
O
2
O
1
3
Me
NH
NH
NH
Me
N
N
N
3aa
3bb
3cc
86%
84%
87%
O
O
5
O
4
6
NH
NH
NH
OMe
N
N
N
3dd
3ee
89%
3ff
65%;
c88%, 24h
O
Me
OMe
Cl
90%
O
O
7
8
9
OMe
Cl
NH
NH
NH
N
N
N
3gg
3hh
3ii
OMe
Br
45%
c57%
64%
73%
O
O
O
11
14
17
12
10
13
16
NH
NH
N
NH
N
N
3kk
3ll
3jj
Cl
F
71%
75%
66%
O
O
O
15
NH
N
NH
NH Cl
N
N
3mm
67%
3nn
3oo
Br
NO2
Cl
50%
67%
O
O
O
18
NH
N
NH
NH
N
S
N
N
3pp
3rr
3qq
56%
c69%
55%
c67%
c69%
O
19
NH
N
3ss
24%, 60h
aStoichiometry: benzyl alcohol (1.1 mmol); oꢀaminobenzamide (1.0 mmol); base (1.5 mmol, 1.5 equiv).
bIsolated yields after column chromatography. cStyrene was added as additive
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Reactions also proceeded with electronꢀwithdrawing groups at the orthoꢀ, metaꢀor paraꢀ
positions of benzyl alcohols, albeit leading to lower yields and required longer reaction time
(Table 6, entry 7ꢀ12). For example, the coupling of oꢀaminobenzamide (2a) with 4ꢀnitrobenzyl
alcohol (1o) afforded the corresponding quinazolinꢀ4(3H)ꢀone in a moderate yield (Table 6,
entry 14). This may be attributed to the lower reactivity of benzyl alcohols with electronꢀ
withdrawing groups to form the corresponding aldehydes via [Ni(MeTAA)] catalyzed
acceptorless dehydrogenation as observed earlier (Table 3, entry 15). 9ꢀAnthracenemethanol was
also found to be suitable coupling partners; desired quinazolinꢀ4(3H)ꢀone (3pp) was isolated in
69% yield in presence of styrene as the sacrificial hydrogen abstractor (Table 6, entry 16).
Starting from heterocyclic alcohols, like 2ꢀthiophenemethanol or 2ꢀpyridinemethanol the
corresponding quinazolinꢀ4(3H)ꢀone were obtained in 67 and 69% isolated yield in presence of
styrene as the sacrificial hydrogen abstractor (Table 6, entry 17, 18). Aliphatic alcohols were also
found to be a suitable coupling partner, albeit leading to lower yields and required longer
reaction time. Reaction of 1ꢀpentanol with oꢀaminobenzamide (2a) afforded the corresponding
quinazolinꢀ4(3H)ꢀone (3ss) in 24% isolated yield (Table 6, entry 19) in 60h.
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59
60
To further expand the substrate scope various substituted oꢀaminobenzamides were
employed as substrates to test the catalytic formation of quinazolinꢀ4(3H)ꢀones using benzyl
alcohol (1a) as the reaction partner. As shown in Table 7, oꢀaminobenzamides either with
electronꢀdonating or withdrawing groups were all effective, affording the corresponding
quinazolinꢀ4(3H)ꢀones in good yields (Table 7, entries 1ꢀ3). oꢀAminobenzamide bearing multiple
electronꢀdonating groups, such as trimethoxy, produced the corresponding quinazolinꢀ4(3H)ꢀ
ones (3ww) in 67% yield (Table 7, entry 4). Reactions also proceeded with oꢀaminobenzamide
bearing both electronꢀdonating and withdrawing groups, the corresponding quinazolinꢀ4(3H)ꢀone
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(3xx) was isolated in 92% yield (Table 7, entry 5). 3ꢀAminonaphthaleneꢀ2ꢀcarboxamide was also
found to a suitable coupling partner, affording the 2ꢀphenylbenzo[g]quinazolinꢀ4(3H)ꢀone (3yy)
in 85% yield.
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Table 7. Dehydrogenative Coupling of Various oꢀAminobenzamide with Benzyl Alcohol
Catalyzed by [Ni(MeTAA)].aꢀc
O
O
[Ni(MeTAA)]
NH2 (5.0 mol%)
OH
NH
+
+
H2
NH2 NatOBu, xylene,
100 oC,36h
N
R
R
2b-g
3pp-uu
3
1a
O
N
O
N
O
1
2
Me
NH
NH
NH
N
Me
Br
3tt
3uu
3vv
85%
81%
72%
O
O
5
O
4
6
Me
MeO
NH
NH
NH
N
N
MeO
N
Br
OMe
3xx
92%
3ww
3yy
85%
c67%
7
O
Me
NH
N
Br
Cl
3zz
70%
aStoichiometry: benzyl alcohol (1.1 mmol); oꢀaminobenzamide (1.0 mmol); base (1.5 mmol, 1.5 equiv).
bIsolated yields after column chromatography. cStyrene was added as additive.
To explore the reaction mechanism and to check the dehydrogenative nature of the
catalytic reactions and to confirm H2 evolution during the cascade synthesis of quinazolinꢀ4(3H)ꢀ
ones several controlled reactions were carried out. Initial experiments were focused on the
[Ni(MeTAA)]ꢀcatalyzed dehydrogenation of alcohols.
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Intermolecular hydrogen transfer experiments were carried out to make use of the H2,
liberated during dehydrogenation of alcohols, to reduce easily reducible substrates (Scheme 3).
The dehydrogenation of diphenylmethanol (1u) when carried out separately in presence of 2,4ꢀ
dimethoxybenzaldehyde (1gg) in a closed system, benzophenone (1uu) was obtained in 40%
yield, and 2,4ꢀdimethoxybenzyl alcohol (1g) was obtained as the hydrogenated product of 2,4ꢀ
dimethoxybenzaldehyde. However, when the reaction was carried out in an open condition under
argon atmosphere the hydrogen transfer reactions were found to be retarded by some extent. 65%
of H2 was found to be transferred to the corresponding aldehyde when the reaction was carried
out in closed condition whereas only 40% H2 transfer occurs when the reaction was carried out in
an open condition under argon atmosphere.
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60
Scheme 3. Controlled Experiments During Dehydrogenation of Alcohols .
a) Intermolecular hydrogen transfer during dehydrogenation of alcohols:
H
O
O
H
H
H
O
[Ni(MeTAA)]
O
+
+
xylene, NatOBu
MeO
OMe
MeO
OMe
85oC, 7h
1u
1gg
1uu
1g
(1.0 equiv)
40% (closed condition)
35% (open condition)
26% (closed condition)
14% (open condition)
closed or open
H
O
O
[Ni(MeTAA)]
H2
xylene, NatOBu
Pd/C, THF
85oC, 7h
1u
1gg
4
b) Deuterium labeling study during intermolecular hydrogen transfer
D
O
O
D
D
D
O
[Ni(MeTAA)]
O
+
+
xylene, NatOBu
85oC, 7h
MeO
OMe
1.0 equiv
MeO
OMe
1u-D2
1gg
1g-D2
closed
1uu
To further confirm the H2 evolution, hydrogenation of styrene was carried out using Pd/C
catalyst using the H2 liberated during dehydrogenation of diphenylmethanol (1u) catalyzed by
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[Ni(MeTAA)]. In a typical experiment, the dehydrogenation reactions were carried out in a flask
connected through a rubber tube with a second flask containing styrene and catalytic amount of
Pd/C in THF. The H2 gas liberated in the first flask during the dehydrogenation of
diphenylmethanol (1u) was found to reduce styrene present in the second flask (S69). These
experimental results along with the available literature data indeed conclusively support the
acceptorless dehydrogenation of alcohols catalyzed by [Ni(MeTAA)].22ꢀ24
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60
To further confirm the H2 evolution, intermolecular transfer hydrogenation reactions
were carried out with deuterium labeled compound 1u-D2 (Scheme 3). The dehydrogenation of
deuterated diphenylmethanol (1u-D2) when carried out in presence of 2,4ꢀ
dimethoxybenzaldehyde (1gg) in a closed system, benzophenone was obtained, and deuterium
exchange was observed in 2,4ꢀdimethoxybenzyl alcohol (1g-D2), the deuterated product of 2,4ꢀ
dimethoxybenzaldehyde (1g).
Once the acceptorless dehydrogenative nature of alcohol oxidation is confirmed, we
synthesized the cyclic aminal, 2,3ꢀdihydroꢀ2ꢀphenylquinazolinꢀ4(1H)ꢀone (4) via direct
condensation of oꢀaminobenzamide and benzaldehyde (Scheme 4). Interestingly, 2,3ꢀdihydroꢀ2ꢀ
phenylquinazolinꢀ4(1H)ꢀone (4), when heated in presence of NatBuO and [Ni(MeTAA)] under
the optimized catalytic conditions afforded the desired 2ꢀphenylquinazolinꢀ4(3H)ꢀone (3aa) in
90% isolated yield.
Scheme 4. [Ni(MeTAA)]ꢀCatalyzed Dehydrogenation of Aminal.
O
O
O
NH2
toluene
NH
+
reflux, argon
NH2
N
H
4
O
O
[Ni(MeTAA)]
NH
NH
xylene, NatOBu
reflux, 24 h,N2 atm
N
N
H
90%
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To confirm the H2 evolution during the [Ni(MeTAA)]ꢀcatalyzed dehydrogenative
transformation of the cyclic aminal, 2,3ꢀdihydroꢀ2ꢀphenylquinazolinꢀ4(1H)ꢀone (4) to 2ꢀ
phenylquinazolinꢀ4(3H)ꢀone (3aa), this catalytic transformation was carried out in presence of a
sacrificial hydrogen abstractor like 2,4ꢀdimethoxybenzaldehyde (1gg). To our desire, as observer
earlier during dehydrogenation of alcohols, 2,4ꢀdimethoxybenzyl alcohol (1g) was isolated as the
hydrogenated product of 2,4ꢀdimethoxybenzaldehyde (1gg) (Scheme 5). Deuterium labeling
experiments were also carried out starting from the deuterium labeled cyclic aminal (4-D),
synthesized from the direct coupling of benzaldehydeꢀαꢀd1 with oꢀaminobenzamide. Deuterium
exchange was observed when the cyclic aminal (4ꢀD) was heated in presence of the catalyst
[Ni(MeTAA)] and 2, 4ꢀdimethoxybenzaldehyde, under the optimized reaction (Scheme 5).
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58
59
60
Attempts were also made to quantify the liberated hydrogen during both dehydrogenation
of alcohol and dehydrogenative coupling of oꢀaminobenzamide and alcohols using a gas buret.
After repeated experiments nearly 67% of theoretical yield of hydrogen has been measured in
our experimental conditions during dehydrogenation of diphenylmethanol (1u) and 70%
theoretical yield of hydrogen has been measured during dehydrogenative coupling of oꢀ
aminobenzamide (2a) and benzyl alcohol (1a) (see experimental section for details).
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Scheme 5. Controlled Experiments During Dehydrogenation of Aminal.
5
6
7
a) Intermolecular hydrogen transfer during dehydrogenation of aminal:
O
O
H
H
8
9
[Ni(MeTAA)]
NH
NH
O
O
+
+
xylene, NatOBu
reflux, 36 h
MeO
OMe
MeO
OMe
N
H
4
N
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11
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55
56
57
58
59
60
1g
3aa
1gg
(1.0 equiv)
20% (closed condition)
11% (open condition)
36% (closed condition)
31% (open condition)
b) Deuterium labeling study during intermolecular hydrogen transferfrom aminal:
O
O
D
D
O
[Ni(MeTAA)]
NH
NH
O
+
+
D
xylene, NatOBu
reflux, 36 h, closed
MeO
OMe
MeO
OMe
1g-D2
N
H
N
3aa
1gg
4-D
Based on the above experimental results along with the available literature20 a plausible
mechanism for the present [Ni(MeTAA)]ꢀcatalyzed acceptorless dehydrogenative coupling of oꢀ
aminobenzamide or its derivatives with alcohols for the construction of quinazolinꢀ4(3H)ꢀones is
depicted in Scheme 6. The reaction is believed to proceed via the formation of a alkoxy nickel
species (A), which underwent βꢀH elimination to afford a nickelꢀhydride species (B) and
aldehyde. The nickelꢀhydride species (B) releases gaseous hydrogen upon reaction with a second
molecule of alcohol with the regeneration of the nickelꢀalkoxide (A). The aldehyde, generated
inꢀsitu, then undergoes condensation with oꢀaminobenzamide to produce the cyclic aminal (C).
In cycle II, the cyclic aminal (C) thus generated afforded amino nickel species (D), which upon
βꢀH elimination produces quinazolinꢀ4(3H)ꢀones with the liberation of H2.20
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O
N
NH
R1
[Ni(MeTAA)]
H
7
(B)
O
8
9
NH
R1
R1
OH
H2
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R1
OH
CYCLE-II
O
N
H
C
base
[Ni(MeTAA)]
H2
NH
R1
O
[Ni(MeTAA)]
[Ni(MeTAA)]
H
(B)
R1
O
N
CYCLE-I
(A)
NH2
[Ni(MeTAA)]
(D)
NH2
R1
O
Scheme 6. Proposed reaction mechanism.
Conclusion. In summary, we have reported a general and efficient method for the oneꢀpot
cascade synthesis of quinazolinꢀ4(3H)ꢀones via acceptorless dehydrogenative coupling of oꢀ
aminobenzamides with alcohols catalyzed by a cheap and earth abundant simple Ni(II)ꢀcatalyst,
[Ni(MeTAA)]. This straightforward methodology is economical, practical, and has a broad
substrate scope. A wide variety of desired quinazolinꢀ4(3H)ꢀones were obtained in high yields
starting from readily available starting materials. These results indeed opens up an opportunity
for the construction of diverse and useful organic molecules of bioꢀmedicinal importance using
similar cheap and earth abundant nickel catalysts.
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Experimental section
5
6
A. General information
7
8
9
All reactions were carried out using standard Schlenk techniques under argon
atmosphere. Tetrahydrofuran (THF), toluene, xylene, 1,4ꢀdioxane were refluxed over
sodium/benzophenone, distilled under argon atmosphere, and stored over 4 Å molecular sieves.
All other chemicals were purchased from commercial suppliers and used as received without
further purification. Analytical TLC was performed on a Merck 60 F254 silica gel plate (0.25mm
thickness) and column chromatography was performed on Merck 60 silica gel (60ꢀ120 mesh).
During purification of the reaction mixture of some of the controlled experiments preparative
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1
TLC was used. H NMR spectra were recorded on a Bruker DPXꢀ300(300 MHz), Bruker DPXꢀ
400(400 MHz) and Bruker DPXꢀ500(500 MHz) spectrometers. TMS (tetramethylsilane) was
used as a the internal standard. ESI mass spectra were recorded on a micromass QꢀTOF mass
spectrometer (serial no. YA 263). A PerkinElmer 240C elemental analyzer was used to collect
microanalytical data (C, H, N). GC analysis was performed on 7980A GC system from Agilent
Technologies equipped with an FID detector and J & W HP−5 column.
Synthesis of Ni(II)-Catalyst [Ni(MeTAA)]. [Ni(MeTAA)] was synthesized following a known
literature method.21 Reaction of 2.0 equiv. of 1,2ꢀphenylenediamine, 2.0 equiv. of 2,4ꢀ
pentanedione, and excess of nickel(II) acetate tetrahydrate in methanol under refluxing
condition for 48h resulted in the formation of green color [Ni(MeTAA)] in nearly quantitative
yield.
General Procedure for Dehydrogenation of Alcohols. Under argon atmosphere a mixture of
[Ni(MeTAA)](0.03 mmol) and NaOtBu(1.5mmol) were added in a flameꢀdried Schlenk tube.
The tube was capped with a Teflon screw cap, evacuated, and backfilled with argon. The screw
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cap was replaced with a rubber septum and a balloon filled with argon was inserted using a long
5
6
neck needle. Alcohol (1.0 mmol) dissolved in 5 mL of xylene was added to the Schlenk via a
7
8
9
°
syringe. The Schlenk tube was then placed in an oil bath and heated at 85 C for a set period.
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Once the reaction is finished, the resulting mixture was concentrated, volatiles were removed in
vacuum and the residue was purified by column chromatography using silica.
General Procedure for Dehydrogenative Coupling of Alcohols and o-Aminobenzamides.
Under argon atmosphere a mixture of [Ni(MeTAA)] (0.05mmol), NaOtBu (1.5 mmol) and oꢀ
aminobenzamide (1.0 mmol) were added in a flameꢀdried Schlenk tube. Alcohol (1.10 mmol)
dissolved in 10 mL of xylene was added to the Schlenk once via a syringe. A balloon filled with
argon was inserted into the Schlenk tube using a long neck needle. The Schlenk tube was then
placed in an oil bath and heated at 100oC for a set period. After the reaction finished, the
resulting mixture was concentrated and the residue was purified by flash chromatography (silica
gel).
Hydrogenation of Styrene by Evolved Hydrogen During Alcohol Oxidation. Under argon
atmosphere a mixture of [Ni(MeTAA)](0.03 mmol) and NaOtBu (1.5 mmol) were added in a
flameꢀdried Schlenk tube connected through a rubber tube to another schlenk tube in which
styrene (1.0 mmol) and Pd/C ( 0.5 g) were placed in THF with a magnetic stirrer. The tube was
capped with a Teflon screw cap, evacuated, and backfilled with argon. The screw cap was
replaced with a rubber septum. Alcohol (1.0 mmol) dissolved in 5 mL of xylene was added to the
first Schlenk via a syringe. The Schlenk tube was then placed in an oil bath and heated at 100°C
for 36h. GC analysis of the reaction mixture present in the second Schlenk containing styrene
revealed the conversion of styrene to ethylbenzene.
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Volumetric Estimation of Evolved Hydrogen:
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(I) During [Ni(MeTAA)]-Catalyzed Dehydrogenation of Alcohol. Diphenyl methanol
(1u)(1.0 mmol), [Ni(MeTAA)](0.03 mmol), and NaOtBu(1.5 mmol) in 5 mL of xylene were
placed in an ovenꢀdried 25 ml Schlenk tube connected to a gas buret. The Schlenk tube was then
placed in an oil bath preꢀheated at 85 °C. The reaction was continued until evolution of gas
ceased. The experiment was repeated multiple times to get consistent readings. Volume of water
displaced was found to be 17.5mL. The number of moles of hydrogen evolved was calculated by
taking into account the vapor pressure of water at 304 K = 33.7Torr, volume of water displaced
17.5 mL, atmospheric pressure 761.3126 Torr, R = 62.3635 LTorr K−1mol−1, n(H2) = [(Patm−
Pwater)V]/RT = 0.000672mol, expected value 0.001 mol .24
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(II) During [Ni(MeTAA)]-Catalyzed Dehydrogenative Coupling of Alcohols and o-
Aminobenzamide. Benzyl alcohol (1a) (1.10 mmol), oꢀaminobenzamide (2a) (1.0 mmol),
[Ni(MeTAA)] (0.05 mmol), and NaOtBu (1.5 mmol) in 5 mL of xylene were placed in an ovenꢀ
dried 25 ml Schlenk tube connected to a gas buret. Then it was placed in an oil bath preꢀheated
at 100 °C. The reaction was continued for 36h. The experiment was repeated multiple times to
get consistent readings. Volume of water displaced was found to be 38mL. The number of moles
of hydrogen evolved was calculated by taking into account the vapor pressure of water at 304 K
= 33.7 Torr, volume of water displaced 38 mL, atmospheric pressure 761.3126 Torr, R =
62.3635 LTorr K−1mol−1, n(H2) = [(Patm−Pwater)V]/RT = 0.001475mol, expected value
0.0021mol.24
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Characterization Data of the Isolated Compounds.
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I. Characterization Data for the Carbonyl Compounds.
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Benzaldehyde (1aa).25 Eluent: petroleum ether/dichloromethane (4:1). Colorless liquid (98 mg,
93%), 1H NMR (400 MHz, CDCl3): δ (ppm) = 10.06 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.67 (t, J
= 8.0 Hz, 1H), 7.57(t, J = 8.0 Hz, 2H).
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2-Methylbenzaldehyde (1bb) 25e,f
Eluent: petroleum ether/dichloromethane (4:1). Colorless
.
liquid (103 mg, 86%), 1H NMR (400MHz, CDCl3): δ (ppm) = 10.28 (s, 1H), 7.80 (d , J = 12 Hz,
1H), 7.47 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 2.68 (s, 3H).
3-Methylbenzaldehyde (1cc).25c,e Eluent: petroleum ether/dichloromethane (4:1). Colorless
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liquid (107 mg, 89%), H NMR (400MHz, CDCl3): δ (ppm) = 9.97 (s, 1H), 7.66 (d, J = 4.0 Hz,
2H), 7.38 (t, J = 8.0 Hz, 2H), 2.41 (s, 3H).
4-Methylbenzaldehyde (1dd).25c,e,f Eluent: petroleum ether/dichloromethane (4:1). Colorless
liquid (111 mg, 92%), H NMR (400 MHz, CDCl3): δ (ppm) = 9.89 (s, 1H), 7.75 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H).
3-methoxybenzaldehyde (1ee).25a,c,e Eluent: petroleum ether/dichloromethane (4:1).Yellow
liquid (92 mg, 75%), 1H NMR (300 MHz, CDCl3): δ (ppm) = 9.86 (t, J =5.0 Hz, 1H), 7.26 ꢀ7.35
(m, 3H), 7.06 – 7.07(m, 1H), 3.74(t, J = 5.5 Hz, 3H).
4-methoxybenzaldehyde (1ff).25aꢀc Eluent: petroleum ether/dichloromethane (4:1).Yellow liquid
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(113 mg, 83%), H NMR (300 MHz, CDCl3): δ (ppm) = 9.84 (s, 1H), 7.80(d, J = 8.7 Hz, 2H),
6.97(d, J = 8.6 Hz, 2H), 3.85(s, 3H).
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2,4-dimethoxybenzaldehyde (1gg).25bꢀd Eluent: petroleum ether/dichloromethane (4:1).White
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solid (141 mg, 85%), H NMR (300 MHz , CDCl3): δ (ppm) = 10.28 (s, 1H), 7.80 (d, J = 8.7
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Hz, 1H), 6.52(t, J = 8.7Hz, 2H), 3.88 (d, J = 7.71Hz, 6H).
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4-Fluorobenzaldehyde (1hh).25a Eluent: petroleum ether/dichloromethane (4:1).Yellow liquid
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(96 mg, 78%), H NMR (500 MHz, CDCl3): δ (ppm) = 9.96(s, 1H), 7.89ꢀ7.93(m, 2H),7.19ꢀ
7.24(m, 2H).
2,4-Dichlorobenzaldehyde(1ii).25h Eluent: petroleum ether/dichloromethane (4:1). Light yellow
crystalline powder (121 mg, 69%), 1H NMR (300 MHz, CDCl3): δ (ppm) =10.41(s, 1H), 7.87(d,
J = 8.37 Hz, 1H), 7.48 (d, J = 8.20 Hz ,1H), 7.38 (d, J = 8.37 Hz, 1H).
3-Chlorobenzaldehyde (1jj).25g Eluent: petroleum ether/dichloromethane (4:1). Light yellow
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liquid (105 mg, 75%), H NMR (500 MHz, CDCl3): δ (ppm) = 9.97(s, 1H), 7.83(t, J = 1.7 Hz,
1H), 7.75ꢀ7.79 (m, 1H), 7.56ꢀ7.60 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H).
4-Chlorobenzaldehyde (1kk).25cꢀe Eluent: petroleum ether/dichloromethane (4:1). White solid
(103 mg, 73%), 1H NMR (400 MHz, CDCl3): δ (ppm) = 9.98 (s, 1H), 7.81ꢀ7.84 (m ,2H), 7.52
(d, J = 8.4 Hz, 2H).
2-Chlorobenzaldehyde (1ll).25d Eluent: petroleum ether/dichloromethane (4:1). Brown liquid
(101 mg, 72%), 1H NMR (4 00MHz, CDCl3): δ (ppm) = 10.50 (s, 1H), 7.53(d, J = 8.19 Hz, 1H),
7.26 (s, 2H), 7.08 (d, J = 8.0 Hz, 1H).
3-Bromobenzaldehyde (1mm).25f Eluent: petroleum ether/dichloromethane (4:1). Yellow liquid
(141 mg, 76%)1H NMR (400MHz, CDCl3): δ (ppm) = 9.95 (s, 1H), 7.98 (d, J = 0.4 Hz, 1H),
7.82ꢀ7.72 (m, 2H), 7.44ꢀ7.40 (m, 1H).
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4-Bromobenzaldehyde (1nn).25a Eluent: petroleum ether/dichloromethane (4:1). White
crystalline solid (144 mg, 78%),1H NMR (400MHz, CDCl3): δ (ppm) = 9.95(s, 1H), 7.51ꢀ7.94
(m, 4H).
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4-Nitrobenzaldehyde (1oo).25 Eluent: petroleum ether/dichloromethane (4:1). Slightly yellowish
crystalline powder (83 mg, 55%),1H NMR (300MHz, CDCl3): δ (ppm) = 10.10 (s, 1H), 8.34(d, J
= 8.1Hz, 2H), 8.02 (d, J = 9.3 Hz, 2H).
Pyrene 1-aldehyde (1pp).22e Eluent: petroleum ether/dichloromethane (4:1). Dark yellow solid
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(200 mg, 87%), H NMR (400 MHz, CDCl3): δ (ppm) = 10.80 (s, 1H), 9.45(d, J = 8.0 Hz, 1H),
8.47(d, J = 8.0Hz, 1H), 8.24ꢀ8.35 (m, 5H), 8.12(d, J = 10.0, 2H).
Anthracene 9-carbaldehyde (1qq).25c Eluent: petroleum ether/dichloromethane (4:1).Yellow
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solid (169 mg, 82%), H NMR (400 MHz, CDCl3): δ (ppm) = 11.43 (s, 1H), 8.91(d, J = 7.2Hz,
2H), 8.56 (s, 1H), 7.97 (d, J = 6.4 Hz ,2H), 7.60ꢀ7.63 (m, 2H), 7.49 (t, J = 6.0, 1H).
Pyridine 2-aldehyde (1rr).25a,b Eluent: petroleum ether/dichloromethane (4:1). Yellow liquid
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(70 mg, 65%), H NMR (300 MHz, CDCl3): δ (ppm) = 10.05 (s, 1H), 8.77 (d, J = 3.6 Hz, 1H,),
7.83ꢀ7.95 (m, 2H), 7.51(t, J = 5.0 Hz,1H).
Thiophene 2-carbaldehyde (1ss).25aꢀc Eluent: petroleum ether/dichloromethane (4:1). Light
brown liquid (77 mg, 69%), 1H NMR (300 MHz, CDCl3): δ (ppm) = 9.93(s, 1H), 7.77ꢀ7.80 (m,
2H), 7.19 (d, J = 2.7 Hz, 1H).
Acetophenone (1tt).23a Eluent: petroleum ether/dichloromethane (4:1). Colorless liquid (100 mg,
83%),1H NMR (400 MHz, CDCl3): δ (ppm) = 7.85 (t, J = 7.6Hz, 2H), 7.43ꢀ7.47 (m, 1H), 7.35 (t,
J = 7.6 Hz, 2H), 2.48 (d, J = 1.2 Hz, 3H).
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Benzophenone (1uu).23a,25f Eluent: petroleum ether/dichloromethane (4:1).White solid (155 mg,
85%)1H NMR (400 MHz, CDCl3): δ (ppm) = 7.80 (t, J = 7.2 Hz, 4H), 7.58 (t, J = 6.4 Hz, 2H),
7.48 (t, J = 6.0 Hz, 4H).
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II. Characterization Data for the Quinazolin-4-(3H)-ones:
2-phenylquinazolin-4(3H)-one (3aa).16a,20b Eluent: petroleum ether/ethyl acetate (3:1). White
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solid (191 mg, 86%) , M.p: 239ꢀ241 C ; 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 12.53 ( s,
1H), 8.15ꢀ8.20 (m, 3H ), 7.81ꢀ7.85 (m, 1H ), 7.74 ( d, J = 7.89 Hz, 1H ), 7.50ꢀ7.61( m, 4H ).
13C NMR (100MHz, DMSOꢀd6): δ (ppm) = 162.1, 152.2, 148.6, 134.5, 132.6, 131.3, 128.5,
127.7, 125.8, 127.4, 126.5, 125.8, 120.9.
2-(o-tolyl)quinazolin-4(3H)-one (3bb).19 Eluent: petroleum ether/ethyl acetate (3:1). White
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solid (198 mg, 84%), M.p: 223 – 224 C. H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 12.43 (s,
1H), 8.18 ( dd, J = 7.9, 1.03 Hz, 1H), 7.81ꢀ7.85 (m, 1H), 7.69 ( d, J = 8.07 Hz, 1H), 7.50ꢀ
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7.56(m, 2H ), 7.43 ( td, J = 7.68, 1.1 Hz,1H), 7.31ꢀ7.36 (m, 2H), 2.39(s, 3H). C NMR (100
MHz, DMSOꢀd6): δ (ppm) =161.7, 154.3, 148.6, 136.0, 134.3, 134.1, 130.4, 129.8, 129.0, 127.3,
126.5, 125.7, 125.6, 120.9, 19.5.
2-m-tolylquinazolin-4(3H)-one(3cc).14g,20b Eluent: petroleum ether/ethyl acetate (3:1). White
solid (206 mg, 87%), M.p: 210ꢀ212 °C. 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 12.46 ( s, 1H
), 8.15 ( dd, J = 7.83, 1.06 Hz, 1H), 8.03( s, 1H ), 7.97 ( d, J = 8.0 Hz, 1H ), 7.85ꢀ7.81 ( m, 1H),
7.74 ( d, J = 8.0Hz, 1H ), 7.49ꢀ7.53 ( m, 1H), 7.39ꢀ7.45 (m, 2H), 2.40 ( s, 3H ). 13C NMR (100
MHz, DMSOꢀd6): δ (ppm) = 162.1, 152.3, 148.7, 137.8, 134.5, 132.5, 131.9, 128.4, 128.2,
127.4,126.4, 125.7, 124.8, 120.9, 20.9.
2-(p-tolyl)quinazolin-4(3H)-one (3dd).19,20b Eluent: petroleum ether/ethyl acetate (3:1). White
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solid (213 mg, 90%), M.p: 245 – 246 C. H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 12.45 (s,
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1H), 8.16 (dd, J = 7.84, 1.1 Hz, 1H), 8.1 (d, J = 8.2 Hz, 2H), 7.80ꢀ7.84 (m, 1H), 7.72 (d, J =
7.84 Hz, 1H), 7.48ꢀ7.52 ( m,1H), 7.34 ( d, J = 8.17 Hz, 2H), 2.38 ( s, 3H). 13C NMR (100 MHz,
DMSOꢀd6): δ (ppm) = 162.2, 152.2, 148.7, 141.4, 134.4, 129.8, 129.1, 127.6, 127.2, 126.3,
125.8, 120.8, 20.9.
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2-(3-methoxyphenyl)quinazolin-4(3H)-one(3ee).14g,20b Eluent: petroleum ether/ethyl acetate
(3:1). White solid (225 mg, 89%), M.p: 210ꢀ211OC. 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) =
12.51(s, 1H), 8.16(dd, J = 7.92, 1.09 Hz, 1H), 7.78ꢀ7.86 (m, 2H), 7.75ꢀ7.74 (m, 2H), 7.43ꢀ7.54
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(m, 2H), 7.15 ( dd, J = 8.03, 2.13 Hz, 1H), 3.87 (s, 3H). C NMR (100 MHz, DMSOꢀd6): δ
(ppm) = 162.9, 159.8, 152.2, 149.1, 147.6, 135.1, 134.5, 130.2, 127.1, 126.3, 121.5, 120.6,
118.1, 113.0, 55.9.
2-(4-methoxyphenyl)quinazolin-4(3H)-one (3ff).14g,20b,19 Eluent: petroleum ether/ethyl acetate
(3:1). White solid (222 mg, 88%), M.p: 240 – 241oC. 1H NMR (400 MHz, DMSOꢀd6): δ (ppm)
= 12.39 (s. 1H), 8.21ꢀ8.17 (m, 2H), 8.13(dd, J = 7.9, 1.6 Hz, 1H), 7.79ꢀ7.83 (m, 1H), 7.69ꢀ7.71
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(m, 1H), 7.46ꢀ7.50 (m, 1H), 7.07ꢀ7.11(m, 2H), 3.85 (s, 3H). C NMR (100 MHz, DMSOꢀd6): δ
(ppm) = 162.2, 161.8, 151.8, 148.7, 134.4, 129.4, 127.2, 126.0, 125.7, 124.7, 120.6, 113.9, 55.4.
2-(2,4-dimethoxyphenyl)quinazolin-4(3H)-one(3gg).19b Eluent: petroleum ether/ethyl acetate
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(3:1). White solid (161 mg, 57%), M.p: 205ꢀ206oC. H NMR (400 MHz, DMSOꢀd6): δ (ppm) =
8.16(d, J = 9.0 Hz, 1H), 7.81(d, J = 8.9 Hz, 1H), 7.64(d, J = 10.4 Hz, 1H), 7.55 (d, J = 9.5 Hz,
1H), 7.36 (d, J =10.9 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H).
2-(2-chlorophenyl)quinazolin-4(3H)-one(3hh).14g,20b Eluent: petroleum ether/ethyl acetate
(3:1). White solid (164 mg, 64%), M.p: 195ꢀ196OC. 1H NMR (300 MHz, DMSOꢀd6): δ (ppm) =
12.53 (s, 1H), 8.16 (t, J = 6.81 Hz, 3H), 7.83 (t, J = 7.2Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.49ꢀ
7.38 (m, 3H).
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