Accessing Polysubstituted Quinazolines via Nickel Catalyzed Acceptorless Dehydrogenative Coupling

Article abstract of DOI:10.1021/acs.joc.8b01479

Two environmentally benign methods for the synthesis of quinazolines via acceptorless dehydrogenative coupling of 2-aminobenzylamine with benzyl alcohol (Path A) and 2-aminobenzylalcohol with benzonitrile (Path B), catalyzed by cheap, earth abundant and easy to prepare nickel catalysts, containing tetraaza macrocyclic ligands (tetramethyltetraaza[14]annulene (MeTAA) or 6,15-dimethyl-8,17-diphenyltetraaza[14]annulene (MePhTAA)) are reported. A wide variety of substituted quinazolines were synthesized in moderate to high yields starting from cheap and easily available starting precursors. A few control reactions were performed to understand the mechanism and to establish the acceptorless dehydrogenative nature of the catalytic reactions.

Full text of DOI:10.1021/acs.joc.8b01479

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Article
Accessing Polysubstituted Quinazolines via Nickel
Catalyzed Acceptorless Dehydrogenative Coupling
Seuli Parua, Rina Sikari, Suman Sinha, Gargi Chakraborty, Rakesh Mondal, and Nanda D. Paul
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01479 • Publication Date (Web): 09 Aug 2018
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Accessing Polysubstituted Quinazolines via Nickel Catalyzed
Acceptorless Dehydrogenative Coupling
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Seuli Parua, Rina Sikari, Suman Sinha, Gargi Chakraborty, Rakesh Mondal 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. Two environmentally benign methods for the synthesis of quinazolines via
acceptorless dehydrogenative coupling of 2-aminobenzylamine with benzyl alcohol (Path A) and
2-aminobenzylalcohol with benzonitrile (Path B), catalyzed by cheap, earth abundant and easy to
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prepare
nickel
catalysts,
containing
tetraaza
macrocyclic
ligands
(tetramethyltetraaza[14]annulene (MeTAA) or 6,15-dimethyl-8,17-diphenyltetraaza[14]annulene
(MePhTAA)) are reported. A wide variety of substituted quinazolines were synthesized in
moderate to high yields starting from cheap and easily available starting precursors. A few
control reactions were performed to understand the mechanism and to establish the acceptorless
dehydrogenative nature of the catalytic reactions.
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Introduction. Organo-heterocyclic compounds are one of the major building blocks/structural
motif in the pharmaceutical and agrochemical industries, and almost comprise more than 50% of
all drug substances in therapeutic use (Figure 1).1 Among them the quinazoline scaffolds, in
particular, are very common structural motifs and are found in a large number of bioactive
natural products and pharmacologically relevant compounds having antimicrobial,2 anti-
convulsant,3 anti-inflammatory,4 anti-hypertensive,5 antitubercular,6 antimalarial,7 antiviral,8 and
anticancer9 activities. Due to the prevalence of these scaffolds in drug discovery and medicinal
chemistry, the development of new synthetic approaches for the synthesis of quinazoline
derivatives continues to be a active field of research.
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NH2
O
HN
N
N
O
O
O
N
O
N
N
O
N
O
Parazosin
O
Icotinib
N
O
N
S
O
HN
HN
N
O
F
MeO
MeO
N
HN
N
Cl
O
N
Erlotinib
Lapatinib
Figure 1. Selected examples of compounds containing quinazoline moiety.
Over the years, significant advances have been made in developing efficient
strategies for the synthesis of quinazoline derivatives. Majority of the synthetic
procedures reported till date involves either oxidative condensation or oxidative coupling
of two suitable coupling partners.10-12 Among them, the classic approach involves
oxidative condensation of 2-aminobenzophenones with aldehydes, acyl chloride and
ammonium acetate, or benzylamines.10 Condensation of oxime derivatives with aldehydes
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under oxidative conditions has also been reported for the synthesis of quinazolines.11
Similarly, the oxidative coupling reactions, involving o-carbonyl halobenzenes, ammonia
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and aldehydes were reported.12 A few Ullmann or Buchwald
−Hartwig type coupling
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followed by intramolecular cyclization reactions were also developed successfully for the
synthesis of quinazolines.13,14 These methods mainly involve copper13 or palladium14 catalyzed
cyclization of amidines with o-carbonyl halobenzenes, 2-halobenzyl halides/tosylates and
2-halobenzyl amines respectively. Some reports are also available involving the oxidative
coupling of amidines with benzyl alcohols, benzaldehydes and hypervalent iodine-
substituted alkynes respectively.15
In spite of significant advances on quinazoline synthesis, the synthetic methods
developed so far involve multistep reaction sequences; require pre-functionalized starting
precursors and many of them require stoichiometric or excess amounts of strong oxidants.
Therefore, development of new, efficient and environmentally benign alternatives for
accessing quinazolines from stable and easily available substrates are still a major challenge
in catalysis research.
In this regard, the acceptorless dehydrogenative coupling of alcohols with suitable
coupling partners has emerged as an attractive atom-economic and environment friendly
approach for the synthesis of quinazolines and similar heterocycles.16, 17 Only H2O and hydrogen
gas are produced as chemical waste. The gradual in situ generation of the relatively unstable
aldehydes curtails the possibility of decomposition as well as retards the other side reactions
which are one of the major drawback during the synthesis of organo-heterocycles via direct
coupling of aldehydes with other coupling partners. It can also circumvent the use of toxic
oxidants during oxidative cyclization. However, the majority of currently available acceptorless
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dehydrogenative coupling reactions rely on expensive and relatively scarce heavier transition
metal ions.17
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Recently, we reported the acceptorless dehydrogenative synthesis of quinazolin-4(3H)-
ones and quinolines, catalyzed by a simple nickel catalyst [Ni(MeTAA)], featuring a tetraaza
macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)).18 To further expand the scope
of the [Ni(MeTAA)]-catalyzed synthesis of other organo-heterocycles via acceptorless
dehydrogenative coupling, we hypothesized that [Ni(MeTAA)] catalyzed acceptorless
dehydrogenative coupling of 2-aminobenzylamine with alcohols would form the cyclic 1,2,3,4-
tetrahydro-2-phenylquinazoline (A) intermediate which might undergo further dehydrogenation
to afford quinazolines (Scheme 1, path A). On the other hand, the acceptorless dehydrogenative
coupling of 2-aminobenzyl alcohols with benzonitriles can also afford quinazolines. As reported
by Zhang and co-workers,17d this reaction may proceed via the initial nucleophilic addition of the
amino group of aminobenzyl alcohol to the benzonitrile to form an amidine intermediate (A')
which upon [Ni(MeTAA)]-catalyzed dehydrogenation (alcohol group of (A')) will produce an o-
carbonyl amidine intermediate (B') which upon intramolecular condensation could afford
quinazolines (Scheme 1, path B). Base mediated conversion of benzonitrile to benzamide
followed by cyclocondensation with 2-aminobenzaldehyde, formed via [Ni(MeTAA)] catalyzed
acceptorless dehydrogenation, can also produce quinazolines (Scheme 1).19
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Herein we report two alternative approaches for the one-pot synthesis of quinazolines via
acceptorless dehydrogenative coupling of (i) 2-aminobenzylamine with alcohols and (ii) 2-
aminobenzyl alcohols with benzonitriles, catalyzed by square planar Ni(II) complexes featuring
tetraaza macrocyclic ligands (Figure 1). Two different Ni(II)-catalysts differing in the ligand
functionality were tested: [NiII(MeTAA)] (1a), [NiII(MePhTAA)] (1b) (Figure 2). The catalyst,
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[NiII(MeTAA)] (1a), has been found to be more effective affording a wide variety of substituted
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quinazolines in moderate to good yield.
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NH2
9
NH
NH2
AD
-H2
AAD
-H2
R
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O
N
R
Path A ( X = CH2OH )
H
(A)
N
OH
NH
R
X
( X = CH2OH, CN )
N
R
OH
NH2
O
N
N
H
R
NH2
AAD
-H2
OH
-H2O
R
NH2
(B')
Base
N
R
(A')
Path B ( X = CN )
OH
O
H2N
O
O
NH2
R
R
NH2
AAD
-H2
NH2
Path B ( X = CN )
Scheme 1. Synthetic hypothesis for the synthesis of quinazolines via acceptorless
dehydrogenative coupling. (AAD: acceptorless alcohol dehydrogenation; AD: acceptorless
dehydrogenation).
Ph
N
N
N
N
N
N
N
N
Ni
Ni
Ph
[Ni(MePhTAA)] (1b)
[Ni(MeTAA)] (1a)
Figure 2. Structures of the Ni(II) catalysts used in this study.
Results and Discussion. The nickel(II) tetraaza[14]annulene catalysts, [Ni(MeTAA)] (Ni(II)
tetramethyltetraaza[14]annulene) (1a), and [Ni(MePhTAA)] (Ni(II) 6,15-dimethyl-8,17-
diphenyltetraaza[14]annulene) (1b), were synthesized via the straightforward template
condensation between 1,2-phenylenediamine and a 2,4-substituted diketone.18 The reaction of
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2.0 equiv of 1,2-phenylenediamine, 2.0 equiv of 2,4-substituted diketone, and excess nickel(II)
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acetate tetrahydrate in methanol under refluxing conditions for 48 h afforded complexes 1a and
1b.
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Our initial studies were focused on the synthesis of quinazolines via acceptorless
dehydrogenative coupling of 2-aminobenzylamines with alcohols, catalyzed by nickel(II)
tetraaza[14]annulenes (1a, 1b) (Scheme 1, path A). At first, 2-aminobenzylamine (2a) and
benzylalcohol (3a) were used as the model substrates to optimize reaction conditions including
solvents, bases and reaction temperatures using [Ni(MeTAA)] (1a) as the catalyst. The reaction
was found to proceed most efficiently in non-polar solvents like toluene, xylene etc. However, in
polar solvents like ethanol, acetonitrile, DMF, the yield of the desired quinazoline decreases
significantly. Effect of bases were also investigated (Table 1, entries 1-6), and KOtBu provided
the best result (Table 1, entry 1). The reaction did not proceed in absence of base. Highest yield
°
of the 2-phenylquinazoline (4a) was obtained when the reaction was performed at 140 C in
xylene in presence of 1.0 equiv of KOtBu and 4.0 mol% catalyst 1a (Table 1, entry 1). Upon
lowering base loading and the temperature the yield of quinazoline (4a) decreases significantly
however, no notable improvement of yield was observed with higher base loading at high
temperature (>150°C). Under identical conditions, using 1b as the catalyst, almost comparable
yield of 4a was obtained (Table 1, entry 12).
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Table 1. Screening for Optimal Reaction Conditions.a-e
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NH2
OH
X
(2a)
(2a')
NH2
NH2
N
N
Ni-catalyst
Ni-catalyst
Base, solvent,
temperature (°C)
N
N
Base, solvent,
temperature (°C)
X = CH2OH (3a)
X = CN (3a')
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Path A (X = CH2OH)
Path B (X = CN)
Entry
Ni-catalyst
(mol%)
Solvent
Base
Temperature Yield (%)
Yield (%)
Path B
(°C)
(Path A)
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18
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MePhTAA)] (4 mol%)
[Ni(MeTAA)] (4 mol%)
[Ni(MeTAA)] (2.5 mol%)
-
xylene
xylene
xylene
xylene
xylene
xylene
toluene
KOtBu
NaOtBu
KOH
140
140
135
140
140
140
140
140
140
140
140
140
100
100
140
140
140
140
66
57
56
85
70
60
NaOH
K3PO4
NEt3
52
59
trace
NR
60
trace
trace
59
trace
62
55
trace
NR
75
trace
trace
65
trace
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85
KOtBu
acetonitrile KOtBu
ethanol
THF
DMF
xylene
xylene
xylene
xylene
xylene
xylene
xylene
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
-
53
85
NR
NR
NR
NR
NR
NR
trace
trace
[Ni(MeTAA)] (4 mol%)
NiCl2 (10 mol%)
Ni(OAc)2 (10 mol%)
KOtBu
KOtBu
aStoichiometry (Path A): 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol); (Path
B): 2-aminobenzylalcohol (2a') (1.0 mmol), benzonitrile (3a') (1.0 mmol); base (1.0 mmol, 1.0 equiv.);
bsolvent : 5.0 mL; cunder argon atmosphere; dIsolated yields after column chromatography; eTime: 24h.
Next, we studied the possibility of quinazoline synthesis via acceptorless
dehydrogenative coupling of 2-aminobenzylalcohols with benzonitriles, catalyzed by nickel(II)
tetraaza[14]annulenes (1a, 1b). Under the pre-optimized reaction conditions (optimal conditions
for the dehydrogenative coupling of 2-aminobenzylamine (2a) and benzylalcohol (3a)), the
dehydrogenative coupling of 2-aminobenzylalcohol (2a') and benzonitrile (3a'), catalyzed by
[Ni(MeTAA)] (1a) afforded 85% of desired 2-phenylquinazoline (4a). The reaction even
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proceeded efficiently at 100°C, and catalyst loading of 2.5 mol% is sufficient enough to afford
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the highest yield of (4a) (Table 1, entry 14) in 24h.
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Table 2. Acceptorless Dehydrogenative Coupling of 2-Aminobenzylamine (2a) and 2-
Aminobenzylalcohol (2a') with Benzylalcohol (3a) and Benzonitrile (3a') in open/ closed
conditions.a-c
Entry Open/Closed
Atmosphere
Yield (%)
(path A)
66
Yield (%)
(path B)
85
1
2
3
open
open
closed
Ar
air
air/Ar
64
45
83
56
aPath A: stoichiometry: 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol);
temperature: 140 °C; [Ni(MeTAA)] loading: 4.0 mol%; KOtBu (1.0 mmol, 1.0 equiv.). Path B:
b
2-aminobenzylalcohol (2a') (1.0 mmol), benzonitrile (3a') (1.0 mmol); temperature: 100 °C;
c
[Ni(MeTAA)] loading: 2.5 mol%; KOtBu (1.0 mmol, 1.0 equiv.). Isolated yields after column
chromatography.
Since the complex [Ni(MeTAA)] (1a) is air stable, we studied the catalytic reactions
under aerial conditions. 2-phenylquinazoline (4a) was isolated in almost identical yield when the
reaction was carried out in the presence of air (Table 2, entry 2). However, the removal of H2
from the reaction mixture is essential for the progress of these dehydrogenative coupling
reactions as observed previously during the acceptorless dehydrogenative synthesis of quinolines
and quinazolin-4(3H)-ones.18 The yield of the 2-phenylquinazoline (4a) decreased significantly
when the reaction was carried out in a closed Schlenk tube (Table 2, entry 3).
Control experiments showed that no product was obtained in the absence of the catalyst,
[Ni(MeTAA)] (Table 1, entry 15). While in presence of other nickel(II) sources like NiCl2 and
Ni(OAc)2 only a trace amount of quinazoline formation was observed (Table 1, entries 17, 18).
Once we had the optimized conditions in hand, we set out to investigate the substrate
scope and versatility of the above two alternative pathways (Path A & Path B) for the synthesis
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of quinazolines via acceptorless dehydrogenative coupling reactions, catalyzed by [Ni(MeTAA)]
(1a) (Table 3). Initially, 2-aminobenzylamine (2a) and 2-aminobenzylalcohol (2a') were reacted
separately with various substituted benzylalcohols (3a-3t) and benzonitriles (3a'-3t')
respectively, under the optimized reaction conditions. Both benzylalcohols and benzonitriles
bearing electron donating and electron withdrawing groups were found to be compatible as
coupling partners with 2-aminobenzylamine (2a) and 2-aminobenzylalcohol (2a') respectively,
affording the corresponding quinazolines in good to excellent yields. For example,
benzylalcohols having -Me substituents either at ortho-, meta-, or para-positions produced the
corresponding 2-o-tolylquinazoline (4b), 2-m-tolylquinazoline (4c) and 2-p-tolylquinazoline (4d)
in 60, 61 and 64% yields respectively. On the other hand, benzonitriles bearing -Me substituents
either at ortho-, meta-, or para-positions produced the corresponding quinazolines in 65, 69 and
70% yields respectively. It is noteworthy to mention here that, in path A, during acceptorless
dehydrogenative coupling of benzylalcohols bearing electron donating groups, addition of
styrene as the sacrificial hydrogen acceptor increases the yields of the desired quinazolines
significantly whereas, the acceptorless dehydrogenative coupling of 2-aminobenzylalcohol with
benzonitriles did not require any sacrificial hydrogen acceptor.
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Reactions also proceeded with benzylalcohols bearing electron withdrawing substituents;
the desired quinazolines were obtained in slightly higher yields than that of their counterparts
containing electron donating groups. On the other hand, benzonitriles bearing electron
withdrawing groups were found to be equally effective, affording the corresponding quinazolines
in good yields. Benzylalcohols bearing electron withdrawing -Cl group at the ortho-, meta-, or
para-positions afforded the corresponding quinazolines in 69, 67 and 65% yields respectively
(Table 3, entries 9-11). The corresponding benzonitriles having -Cl group at the ortho-, meta-, or
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para-positions afforded the corresponding quinazolines in 70, 75 and 71% yields respectively
(Table 3, entries 9-11). Similarly benzylalcohols/benzonitriles bearing electron withdrawing -F
group at the para- position or -Br group at the para-, or meta- positions afforded the
corresponding quinazolines in 63, 65, 63% (with benzylalcohols) and 72, 70 and 74% (with
benzonitriles) yields respectively (Table 3, entries 12-14). Reaction also proceeded with
substrates (benzylalcohols/benzonitriles) bearing multiple electron withdrawing groups; 3, 5-
difluorobenzylalcohol and the corresponding 3, 5-difluorobenzonitrile afforded the
corresponding 2-(3,5-difluorophenyl)quinazoline (4o) in 57% and 75% isolated yields
respectively (Table 3, entry 15). Reactions also proceeded with heterocyclic alcohols and nitriles,
the corresponding quinazolines were isolated in moderate to good yields. For example, 2-
thiophenemethanol, 2-pyridinemethanol, 4-pyridinemethanol or the corresponding nitriles when
reacted with 2-aminobenylamine (2a) and 2-aminobenzylalcohol (2a') separately under the
optimized reaction conditions afforded the corresponding quinazolines in 59, 45, 50% (via Path
A), and 62, 50, 56% (via Path B) isolated yields respectively (Table 3, entries 17-19). Reactions
also proceed with aliphatic alcohols or nitriles as the coupling partner, albeit the yield of the
desired quinazoline decreases significantly and require a longer reaction time (Table 3, entry 20).
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Table 3. Dehydrogenative Coupling of 2-Aminobenzylamine and 2-Aminobenzylalcohol with
Various Benzylalcohols and Benzonitriles, Catalyzed by [Ni(MeTAA)] (1a).a-d
7
8
9
NH2
NH2
OH
NH2
X
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11
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13
14
15
16
17
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19
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22
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N
N
[Ni(MeTAA)] (4.0 mol%)
KOtBu, xylene,
140° C, 24h
Path A (X = CH2OH)
[Ni(Me(TAA)] (2.5 mol%)
KOtBu, xylene,
N
N
R
4a
100° C, 24h
Path B (X = CN)
4a
1
2
3
4
N
N
N
N
Me
Me
N
N
N
N
Me
4a
4b
4c
4d
*60%,#65%
*66%,#85%
*64%,#70%
*61%,#69%
5
6
7
8
N
N
N
OMe
N
OMe
10
N
N
N
N
4h
OMe
OMe
tBu
4g
4f
4e
*62%,#68%
*66%,#74%
*64%,#67%
*60%,#69%
11
12
9
N
N
N
Cl
N
N
N
Cl
N
N
4j
Cl
F
F
4i
*69%,#70%
4l
4k
*65%,#71%
15
*67%,#75%
14
*63%,#72%
13
16
N
N
N
N
Br
N
N
N
N
Br
4o
4n
*65%,#70%
4m
*63%,#74%
CF3
4p
F
*57%,#75%
*59%,#49%
17
18
19
20
N
N
N
N
N
N
S
N
N
N
4t
N
4q
*59%,#62%
4r
*45%,#50%
4s
*50%,#56%
*25%,#30%
aStoichiometry (Path A): 2-aminobenzylamine (2a) (1.0 mmol), benzylalcohol (3a) (1.0 mmol); (Path B): 2-
aminobenzylalcohol (2a') (1.0 mmol), benzonitrile (3a') (1.0 mmol); KOtBu (1.0 mmol, 1.0 equiv.); bxylene : 5.0 mL; cunder
argon atmosphere; dIsolated yields after column chromatography.*represents the yield of quinazolines obtained via
dehydrogenative coupling of 2-aminobenzylamine (2a) with benzylalcohols (3a-t). #represents the yield of quinazoline
obtained via dehydrogenative coupling of 2-aminobenzylalcohol (2a') with benzonitriles (3a'-3t')
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To further expand the substrate scope various substituted 2-aminobenzylamines and 2-
aminobenzylalcohols were employed as substrates to test the catalytic formation of quinazolines
using benzylalcohol (3a) and benzonitrile (3a') as the coupling partners respectively. 2-
aminobenzylamines and 2-aminobenzylalcohols bearing either electron donating or electron
withdrawing groups were all effective, affording the corresponding quinazolines in good yields
(Table 4, entries 1-9). 2-aminobenzylamines and 2-aminobenzylalcohols bearing both electron
donating and withdrawing groups were also found to produce the corresponding quinazoline (4v)
in 70% and 80% isolated yields respectively (Table 4, entry 2). Reactions also proceeded with 2-
aminobenzylalcohols with the substitution at the benzyl position (Table 4, entries 5, 6).
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Table 4. Dehydrogenative Coupling of Various Substituted 2-Aminobenzylamines and 2-
Aminobenzylalcohols with Benzylalcohols and Benzonitriles, Catalyzed by [Ni(MeTAA)] (1a).a-
d
7
8
9
R'
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11
12
13
14
15
16
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18
19
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22
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26
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NH2
NH2
OH
R'
N
R'= H, Me
X
NH2
N
N
R
R
[Ni(MeTAA)] (4.0 mol%)
[Ni(MeTAA)] (2.5 mol%)
N
KOtBu, xylene,
KOtBu, xylene,
R
R
140° C, 24h
Path A (X = CH2OH)
100° C, 24h
Path B (X = CN)
1
2
3
4
MeO
MeO
Me
Me
N
N
N
N
N
N
N
Cl
N
OMe
Br
4v
*70%,#80%
4x
4u
4w
*60%,#81%
*74%,#86%
Me
*69%,#84%
7
Me
8
N
N
6
5
N
N
N
N
Cl
Cl
Me
N
4z''
N
4z'
Br
Me
4z
4y
#55%
*68%,#83%
*67%,#80%
#50%
9
Me
N
N
*70%,#83%
4z'''
Cl
aStoichiometry (Path A): 2-aminobenzylamine (1.0 mmol), benzylalcohol (1.0 mmol); (Path B): 2-aminobenzylalcohols (1.0
mmol), benzonitrile (1.0 mmol); KOtBu (1.0 mmol, 1.0 equiv.); bxylene : 5.0 mL; cunder argon atmosphere; dIsolated yields
after column chromatography.*represents the yield of quinazolines obtained via dehydrogenative coupling of 2-
aminobenzylamines (2b-j) with benzylalcohol (3a). #represents the yield of quinazoline obtained via dehydrogenative
coupling of 2-aminobenzylalcohols (2a'-h') with benzonitrile (3a')
To gain mechanistic insights on the quinazoline forming process via path A, the cyclic
1,2,3,4-tetrahydro-2-phenylquinazoline (4) derivative was synthesized via direct condensation of
2-aminobenzylamine and benzaldehyde (Scheme 2, eq 1 ) and subjected to dehydrogenation
under the optimized catalytic conditions. The desired 1-phenylquinazoline (4a) was formed in
82% yield (Scheme 2, eq 2 ).
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NH2
NH
O
EtOH
RT, 24 h
(1)
(2)
+
NH2
2a
N
H
4 (80%)
N
NH
[Ni(MeTAA)]
xylene, KtOBu
N
N
H
140oC, 24 h
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4a (82%)
4
Scheme 2. Control reactions during [Ni(MeTAA)] catalyzed dehydrogenative coupling of 2-
aminobenzylamine and benzylalcohol (Path A).
A few control reactions were also carried out to understand the possible intermediates
involved in the [Ni(MeTAA)] catalyzed dehydrogenative coupling of 2-aminobenzylalcohol and
benzonitrile (Path B). KOtBu, other than acting as a deprotonating agent, can convert nitriles to
the corresponding amides even in anhydrous reaction medium under nitrogen atmosphere.19
Therefore, the [Ni(MeTAA)]-catalyzed dehydrogenative coupling of 2-aminobenzylalcohol and
benzonitrile can proceed via (i) initial nucleophilic addition of the amino group of 2-
aminobenzyl alcohol/aldehyde to the benzonitrile to form an amidine intermediate followed by
stepwise dehydrogenation and intramolecular condensation as proposed earlier by Zhang and co-
workers17d or (ii) dehydrogenation of 2-aminobenzylalcohol to the corresponding aldehyde
followed by the condensation with amides generated in-situ from benzonitrile via KOtBu
mediated transformation.
To eliminate the possibility of KOtBu mediated conversion of nitriles to amide and to
check the possibility of amidine formation,17d when benzonitrile was reacted with the sodium salt
of the 2-aminobenzylalcohol under the optimized catalytic reaction conditions (in absence of
KOtBu) only 4% of 4a was obtained along with 8% of 2-aminobenzaldehyde, 26% of unreacted
benzonitrile and some unidentified products were also isolated (Scheme 3, eq 1). Interestingly,
when the same reaction of benzonitrile and the sodium salt of the 2-aminobenzylalcohol was
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carried out in presence of one equivalent of KOtBu and [Ni(MeTAA)] (2.5 mol%), the yield of
4a drastically increases to 80% (Scheme 3, eq 2). And on lowering the amount of KOtBu to 0.5
equivalent, the yield of quinazoline decreases to 50% indicating the possibility of active
involvement of KOtBu, other than as a deprotonating agent. However, these reactions did not
produce any quinazoline 4a in absence of the catalyst [Ni(MeTAA)] (1a). The reaction of
benzonitrile with the preformed 2-aminobenzaldehyde or 1-(2-aminophenyl)ethanone in absence
of KOtBu also failed to produce the desired quinazoline 4a (Scheme 3, eq 4), further indicating
the active involvement of KOtBu during quinazoline formation.
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To check the possibility of KOtBu mediated benzamide formation, when benzonitrile was
reacted alone with KOtBu (1.0 equiv.) under argon atmosphere in anhydrous xylene 50% of
benzamide was isolated from the reaction medium (Scheme 3, eq 6).19 Further reaction of
benzamide with 2-aminobenzylalcohol under the optimized catalytic conditions afforded 56% of
the desired quinazoline (Scheme 3, eq 7). Moreover, the reaction of benzamide with the
preformed 2-aminobenzaldehyde in absence of [Ni(MeTAA)] afforded the desired quinazoline in
16% yield. The lower yield obtained in this case may be attributed to the instability of 2-
aminobenzaldehyde (Scheme 3, eq 8).
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CN
CN
CN
CN
CN
+
ONa
N
O
[Ni(MeTAA)] (2.5 mol%)
other products
+
+
+
xylene, 100oC, 24 h
NH2
N
NH2
(1)
argon atmosphere
4a
3a'
3a'
3a'
3a'
R = H, Me
R = H, Me
R = H, Me
4%
26%
8%
N
ONa
[Ni(MeTAA)] (2.5 mol%)
+
+
+
KOtBu, xylene, 100oC, 24 h
argon atmosphere
(2)
(3)
N
NH2
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4a
80%
xylene, 100oC, 24 h
argon atmosphere
ONa
N
N
NH2
R
N
R
4a
0%
xylene, 100oC, 24 h
argon atmosphere
O
(4)
(5)
NH2
N
R = H (4a) (0%)
R = Me (4y) (0%)
R
N
N
R
CN
KtOBu (1.0 equiv.)
xylene, 100oC, 24 h
argon atmosphere
O
+
NH2
3a'
R = H, Me
R = H (4a) (20%)
R = Me (4y) (17%)
O
CN
KtOBu (1.0 equiv.)
xylene, 100oC, 24 h
NH2
(6)
(7)
argon atmosphere
50%
3a'
O
O
[Ni(MeTAA)] (2.5 mol%)
KtOBu (1.0 equiv.)
N
NH2
OH
NH2
+
+
xylene, 100oC, 24 h
argon atmosphere
N
4a (56%),
N
KtOBu (1.0 equiv.)
xylene, 100oC, 24 h
argon atmosphere
NH2
O
(8)
N
NH2
4a (16%)
Scheme 3. Control reactions during [Ni(MeTAA)] catalyzed dehydrogenative coupling of 2-
aminobenzylalcohol and benzonitrile.
Finally to confirm the hydrogen evolution during the dehydrogenative synthesis of
quinazolines via either Path A or Path B, dehydrogenation reactions were performed in presence
of a sacrificial hydrogen acceptor like, 4-methoxybenzaldehyde under argon atmosphere. When
the cyclic 1,2,3,4-tetrahydro-2-phenylquinazoline (4') intermediate was subjected to
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dehydrogenation in presence of 4-methoxybenzaldehyde, 4-methoxybenzylalcohol was isolated
in 37% (Scheme 4, eq 2). Moreover, Pd/C catalyzed hydrogenation of styrene using the evolved
H2 during these dehydrogenation reactions clearly shows the formation ethyl benzene (see
experimental section for details) (Scheme 4, eq 3 and 4).
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H
H
H
MeO
+
NH
O
O
NH2
EtOH
RT, 24 h
(1)
(2)
OMe
N
NH2
2a
H
3g'
4' (65%)
H
H
H
H
H
[Ni(MeTAA)]
(4.0 mol%)
NH
N
OH
+
+
xylene, KtOBu
N
H
N
MeO
MeO
130oC, 24 h
H
3f (37%)
3f'
4e (29%)
4'
OMe
OMe
[Ni(MeTAA)]
(4.0 mol%)
xylene, KtOBu
130oC, 24 h
NH2
NH2
N
N
OH
(3)
(4)
+
+
+
H2
Pd/C, THF
Pd/C, THF
N
N
3a
2a
4a
4a
5'
5'
CN
[Ni(MeTAA)]
(2.5 mol%)
OH
NH2
+
H2
xylene, KtOBu
100oC, 24 h
3a'
2a'
Scheme 4. Transfer hydrogenation reactions.
Quantification of the liberated hydrogen was done using gas burette. A 53% of theoretical
yield of hydrogen was measured experimentally during the dehydrogenative coupling of 2-
aminobenzylamine and 3-methoxybenzylalcohol and 75% of theoretical yield of hydrogen was
determined experimentally during direct dehydrogenation of 1,2,3,4-tetrahydro-2-
phenylquinazoline (4'). On the other hand, 83% hydrogen was quantified for the dehydrogenative
coupling of 2-aminobenzyalcohol (1a) with benzonitrile (3a').
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H
4
5
6
N
N
Ni
N
N
NH
(D)
7
8
9
H2
N
R
(F)
-H2
CYCLE-2
N
N
NH
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R
O
N
R
NH2
R
NiII-Catalyst
KOtBu
NH2
NH
N
N
R
OH
Ni
N
N
N
N
Ni
N
N
H
R
N
H2
(C)
(A)
(E)
Path A
CYCLE-1
H
R
O
R
OH
N
N
Ni
N
N
R =
O
NH2
(D)
-H2O
N
NH2
R
N
R
KOtBu
Path B
R
CN
Scheme 5. Plausible mechanism of quinazoline synthesis via Path A and Path B.
Based on the above experimental results and available literature, a plausible mechanism
for the dehydrogenative synthesis of quinazoline either via Path A or Path B is shown in Scheme
5. The first step in both Path A and Path B is the dehydrogenation of the alcohols to the
corresponding aldehydes. It is believed to proceed via the initial deprotonation of the alcohols
(benzyl alcohol in Path A and 2-aminobenzyl alcohol in Path B) followed by formation of the
nickel-alkoxy intermediate (C) which then undergoes dehydrogenation to produce the
corresponding aldehydes. Benzaldehydes, thus formed (Path A) undergoes cyclocondensation
with 2-aminobenzylamine to form the intermediate (A) which upon further [Ni(MeTAA)]
catalyzed dehydrogenation afforded (4a). On the other hand, in Path B, base promoted
cyclocondensation of 2-aminobenzyldehyde (formed via [Ni(MeTAA)]-catalyzed acceptorless
dehydrogenation of 2-aminobenzyl alcohol) with benzamide (formed in-situ from benzonitrile)
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produce the desired quinazoline (4a). The other possible pathway via amidine intermediate
seems less likely as no quinazoline (4a) formation was observed even when the preformed 2-
aminobenzaldehyde or 1-(2-aminophenyl)ethanone was reacted separately with benzonitrile in
absence of KOtBu, however, cannot be ruled out completely.
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Conclusion. In summary we have developed two simple but efficient alternative methods for the
synthesis of quinazolines via acceptorless dehydrogenative coupling reactions, catalyzed by a
cheap, earth abundant and easy to prepare Ni(II)-catalyst [Ni(MeTAA)]. A wide variety of
substituted quinazolines were obtained in moderate to good isolated yields starting from cheap
and easily available starting precursors. Overall, these synthetic approaches are operationally
simple, straightforward, and proceeds with high atom efficiency and does not require expensive
heavier transition metals like ruthenium or iridium.
Experimental Section.
General Information. Unless otherwise stated all the reactions were carried out under argon
atmosphere using standard Schlenk techniques. Tetrahydrofuran (THF), toluene, xylene, 1,4-
dioxane, were refluxed over sodium/benzophenone and distilled under argon atmosphere, and
then stored over molecular sieves of 4 Å. All other chemicals used in this work were purchased
from commercial suppliers and used as received without any further purification. Analytical TLC
was performed by using Merck 60 F254 silica gel plate of 0.25mm thickness and column
chromatography was performed by using Merck 60 silica gel of 60-120 mesh. Bruker DPX-
1
300(300 MHz), and Bruker DPX-400(400 MHz) spectrometers was used for H NMR spectra
measurement. TMS (tetramethylsilane) was used as the internal standard. ESI mass were
recorded on a mass spectrometer of micromass Q-TOF (serial no. YA 263). Perkin Elmer
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CLARUS 680 instrument was used for GC-MS. 'Caution! reactions should be handled with
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care with appropriate safety precautions where hydrogen evolution occurs at high temperature.'
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Synthesis of Ni(II)-catalysts. [Ni(MeTAA)] and [Ni(MePhTAA)] were synthesized following
the known literature methods.18
General Procedure for Acceptorless Dehydrogenative Coupling of 2-Aminobenzylamine
with Benzylalcohol. Under argon atmosphere a 10 mL process vial fitted with a magnetic stir
bar was charged with 2-aminobenzylamine (1.0 mmol), benzylalcohol (1.0 mmol),
[Ni(MeTAA)] (4.0 mol%), KOtBu (1.0 mmol) and 5.0 ml xylene. The vial was then closed and
placed in an oil bath preheated at 140°C for a given time. After the reaction was complete, the
reaction mixture was concentrated under vacuum and the products were purified by flash column
chromatography (silica gel) using EtOAc/petroleum ether (1:24) as the eluent.
General Procedure for Acceptorless Dehydrogenative Coupling of o-Aminobenzylalcohol
with Benzonitrile. A oven-dried Schlenk tube fitted with a magnetic stir bar was charged with 2-
aminobenzyl alcohol (1.0 mmol), [Ni(MeTAA)] (2.5 mol%) and KOtBu (1.0 mmol). The
Schlenk tube was then capped with a rubber septum, evacuated and backfilled with argon three
times. A long neck needle connected with a balloon filled with argon was then inserted to the
Schlenk tube. To it 1.0 mmol of the corresponding benzonitriles dissolved in 5.0 mL of degassed
xylene was added through a syringe. The Schlenk tube was then placed in an oil bath preheated
at 100°C for a given time. After the reaction was complete, the reaction mixture was
concentrated under vacuum and the products were purified by flash column chromatography
(silica gel) using EtOAc/petroleum ether (1:24) as the eluent.
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General Procedure for the Synthesis of 1,2,3,4-tetrahydro-2-phenylquinazoline. A oven-
dried Schlenk tube fitted with a magnetic stir bar was charged with 2-aminobenzyl amine (1.0
mmol). The Schlenk tube was then capped with a rubber septum, evacuated and backfilled with
argon three times. A long neck needle connected with a balloon filled with argon was then
inserted to the Schlenk tube. To it 1.0 mmol of benzaldehyde dissolved in 5.0 mL of EtOH was
added through a syringe. The Schlenk tube was the stirred for 24 h. After the reaction was
complete, the reaction mixture was concentrated under vacuum and the products were purified
by flash column chromatography (silica gel) using EtOAc/petroleum ether (1:2) as the eluent.
Hydrogenation of Styrene by Evolved Hydrogen.
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(i) During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-
Aminobenzyamine (2a) with Benzylalcohol (3a). In a typical experimental setup two Schlenk
tubes were connected using a rubber tube. Under argon atmosphere, the first Schlenk tube was
charged with [Ni(MeTAA)] (4.0 mol%) and KOtBu (1.0 mmol). In the second Schlenk tube
styrene and Pd/C ( 0.5 g) were placed in THF with a magnetic stir bar. Then this tube was
capped by using a Teflon screw cap, evacuated, and backfilled with argon. Rubber septum was
used in place of screw cap. In the first Schlenk 2-aminobenzylamine (2a) (1.0 mmol) and
benzylalcohol (3a) (1.0 mmol) dissolved in 5.0 mL of xylene was added via a syringe. Then this
Schlenk tube was placed in an oil bath preheated at 130 oC for 24 h. The conversion of styrene to
ethylbenzene was confirmed by GC-Ms analysis of the reaction mixture present in the second
Schlenk containing styrene.
(ii) During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-
Aminobenzyalcohol (2a') with Benzonitrile (3a'). Under argon atmosphere, a mixture of
[Ni(MeTAA)] (2.5 mol%) and KOtBu (1.0 mmol) were added to a Schlenk tube connected with
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another Schlenk tube by a rubber tube in which styrene and Pd/C ( 0.5 g) were placed in THF
with a magnetic stir bar. Then this tube was capped by using a Teflon screw cap, evacuated, and
backfilled with argon. Rubber septum was used in place of screw cap. In the first Schlenk 2-
aminobenzyl alcohol (2a') (1.0 mmol) and benzonitrile (3a') (1.0 mmol) dissolved in 5.0 mL of
xylene was added via a syringe. Then this Schlenk tube was placed into an oil bath and then
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heated at 100 C for 24 h. The conversion of styrene to ethylbenzene was confirmed by GC-Ms
analysis of the reaction mixture present in the second Schlenk containing styrene.
Estimation of Evolved Hydrogen by Volumetric Measurement.
(i) During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-
Aminobenzyamine (2a) with 3-Methoxybenzylalcohol (3e). A mixture of 2-aminobenzylamine
(2a) (1.0 mmol), 3-methoxybenzylalcohol (3e) (1.0 mmol), [Ni(MeTAA)] (4.0 mol%), and
KOtBu (1.0 mmol) in 5 mL of xylene were placed in an oven-dried 25 mL Schlenk tube linked
to a gas buret. Then the Schlenk tube was placed in an oil bath pre-heated at 140 °C and the
reaction was continued for 24h. To get consistent reading this experiment was repeated several
times. Volume of water level displaced was found to be 42.0 mL. The number of moles of
hydrogen evolved was calculated by taking into account the vapor pressure of water at 306 K =
37.7 Torr, the atmospheric pressure 761.3126 Torr, R = 62.3635 LTorr K−1mol−1, n(H2) =
[(Patm− Pwater)V]/RT = 0.0 01593 mol, expected value 0.003 mol.18
(ii) During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenation of 1,2,3,4-tetrahydro-2-
(3-methoxyphenyl)quinazoline.
1,2,3,4-tetrahydro-2-(3-methoxyphenyl)quinazoline
(1.0
mmol), [Ni(MeTAA)] (4.0 mol%), and KOtBu (1.0 mmol) in 5 mL of xylene were placed in an
oven-dried 25 mL Schlenk tube linked to a gas buret. The Schlenk tube was then placed in an oil
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bath pre-heated at 140 °C. The reaction was continued for 24h. To get consistent reading this
experiment was repeated several times. Volume of water level displaced was found to be 40.0
mL. The number of moles of hydrogen evolved was calculated by taking into account the vapor
pressure of water at 307 K = 39.9 Torr, volume of water displaced (52.0 mL), the atmospheric
pressure 761.3126 Torr, R = 62.3635 L Torr K−1mol−1, n(H2) = [(Patm−Pwater)V]/RT =
0.001507 mol, expected value 0.0020 mol.18
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(iii) During [Ni(MeTAA)] Catalyzed Acceptorless Dehydrogenative Coupling of 2-
Aminobenzyalcohol (2a') with Benzonitrile (3a'). A mixture of 2-aminobenzylalcohol (1.0
mmol), benzonitrile (1.0 mmol), [Ni(MeTAA)] (2.5 mol%), and KOtBu (1.0 mmol) in 5 mL of
xylene were placed in an oven-dried 25 mL Schlenk tube linked to a gas buret. The Schlenk tube
was then placed in an oil bath pre-heated at 100 °C. The reaction was continued for 24h. To get
consistent reading this experiment was repeated several times. Volume of water level displaced
was found to be 22.0 mL. The number of moles of hydrogen evolved was calculated by taking
into account the vapor pressure of water at 306 K = 37.7 Torr, the atmospheric pressure
761.3126 Torr, R = 62.3635 LTorr K−1mol−1, n(H2) = [(Patm− Pwater)V]/RT = 0.00083 mol,
expected value 0.001 mol.18
#
Characterization Data of the Isolated Compounds. (* represents the yield of Path A and
represents the yield of Path B).
2-Phenylquinazoline (4a).10f, 13h, 17d Eluent: petroleum ether/ethyl acetate (24:1). White solid
#
#
1
(*66% and 85% ,*136 and 175 mg). M.p: 97−98 °C; H NMR (400 MHz, CDCl3): (ppm) =
9.47 (s, 1H), 8.67-8.65 (m, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.92-7.88 (m, 2H), 7.61-7.53 (m, 4H).
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13C NMR (100 MHz, CDCl3): (ppm) = 160.9, 160.4, 150.6, 138.0, 134.0, 130.5, 128.5 ( 2C),
5
6
128.5, 127.1, 127.0, 123.5.
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2-o-Tolylquinazoline (4b).10f Eluent: petroleum ether/ethyl acetate (24:1). colorless oil (*60%
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#
*
#
1
and 65%, 132 and 143 mg). M.p: 44–45 °C; H NMR (300 MHz, CDCl3): (ppm) = 9.52 (s,
1H), 8.12 (d, J = 9 Hz, 1H), 7.99-7.90 (m, 3H), 7.70-7.65 (m, 1H), 7.39-7.34 (m, 3H), 2.62 (s,
3H) .13C (75 MHz, CDCl3): (ppm) = 164.2, 160.2, 150.5, 138.7, 137.5, 134.2, 131.4, 130.7,
129.4, 128.7, 127.6, 127.1, 126.0, 122.9, 20.9 .
2-m-Tolylquinazoline (4c).17f Eluent: petroleum ether/ethyl acetate (24:1). White solid (*61%
and #69%, 134 and 152 mg). M.p: 101–102 °C; H NMR (400 MHz, CDCl3): (ppm) = 9.49
(s, 1H), 8.46-8.43 (m, 2H), 8.12 (d, J = 8.5 Hz, 1H), 7.96-7.91 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H),
7.46 (t, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 2.52 (s, 3H); 13C (100 MHz, CDCl3): (ppm) =
161.1, 160.3, 150.7, 138.2, 137.9, 134.0, 131.3, 129.0, 128.5, 128.5, 127.1, 127.0, 125.7, 123.5,
21.4.
*
#
1
2-p-Tolylquinazoline (4d).13g-h Eluent: petroleum ether/ethyl acetate (24:1). White solid (*64%
and #70%, *141 and #154 mg). M.p: 107−109 °C; 1H NMR (400 MHz, CDCl3): (ppm) = 9.45 (s,
1H), 8.54 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H), 7.95-7.92 (m, 2H), 7.64-760 (m, 1H),
7.36 (d, J = 7.9 Hz, 2H), 2.47 (s, 3H). 13C (100 MHz, CDCl3):  161.1, 160.3, 150.7, 140.7,
135.2, 133.9, 129.3, 128.5, 128.4, 127.0, 126.9, 123.4, 21.4.
2-(3-Methoxyphenyl)quinazoline (4e).17f Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*66% and #74%, 156 and 175 mg). M.p: 93-95oC; 1H NMR (300 MHz, CDCl3): δ(ppm)
= 9.47 (s, 1 H), 8.21 (t, J = 7.74 Hz, 2 H), 8.10 (d, J = 8.25 Hz, 1 H), 7.93 (d, J = 6.06 Hz, 2 H),
7.62 (t, J = 6.84 Hz, 1 H), 7.45 (t, J = 7.80 Hz, 1 H), 7.07 (d, J = 5.73 Hz, 1 H), 3.96 (s, 3 H).
*
#
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13C (100 MHz, CDCl3): (ppm) = 160.8, 160.5, 160.0, 150.7, 139.5, 134.1, 129.7, 128.7, 127.3,
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127.1, 123.7, 121.2, 117.3, 113.0, 55.5.
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2-(4-Methoxyphenyl)quinazoline (4f).13g-h Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*64% and #67%, *151 and #158 mg). M.p: 87−89 °C; 1H NMR (400 MHz, CDCl3): (ppm)
= 9.43 (s, 1H), 8.60 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.91-7.87 (m, 2H), 7.58 (t, J =
7.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3): (ppm) =
161.7, 160.7, 160.3, 150.7, 133.9, 130.6, 130.1, 128.3, 127.0, 126.7, 123.2, 113.9, 55.3.
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2-(2,4-dimethoxyphenyl)quinazoline (4g). Eluent: petroleum ether/ethyl acetate (5:1). White
solid (*60% and #69%, *160 and #184 mg). M.p: 90–91 °C; 1H NMR (400 MHz, CDCl3): (ppm)
= 9.39 (s, 1H, (H1)), 8.01 (d, J = 8.4 Hz, (1H, H5)), 7.85-7.75 (m, 3H, (H2, H3, H4)), 7.54 (d, J
= 7.6 Hz, (1H, H6)), 6.58-6.54 (m, 2H, (H7, H8)), 3.80 (br s, 6H, (H9A-C), (H10A-C)). 13C
NMR (100 MHz, CDCl3): (ppm)= 162.2, 162.1, 160.0, 159.2, 150.7, 134.0, 133.2, 128.4, 127.2,
127.1, 122.9, 121.8, 105.0, 99.4, 56.0, 55.5. HRMS (ESI-TOF): m/z [M + H]+ calcd for
+
C16H15N2O2 267.1133, found 267.1100.
2-(4-tert-butylphenyl)quinazoline (4h).10d Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*62% and #68%, *162 and #178 mg). M.p: 82–84 °C; 1H NMR (400 MHz, CDCl3): (ppm)
= 9.45 (s, 1H), 8.56 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.95-7.89 (m, 2H), 7.64-7.58
(m, 3H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3): (ppm) = 161.0, 160.3, 153.8, 150.7, 135.2,
133.9, 128.5, 128.2, 127.0, 126.9, 125.5, 123.4, 34.8, 31.2.
2-(2-chlorophenyl)quinazoline (4i).12b Eluent: petroleum ether/ethyl acetate (24:1). yellow solid
#
(*69% and #70%, *166 and 168 mg). M.p: 69−70 °C; 1H NMR (400 MHz, CDCl3) δ(ppm) =
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9.50 (s, 1H), 8.11 (t, J = 8.8 Hz, 1H), 7.97−7.90 (m, 2H), 7.45(d, J = 8.0 Hz, 2H), 7.39-7.32 (m,
5
6
2H).
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2-(3-chlorophenyl)quinazoline (4j).12b, 17f Eluent: petroleum ether/ethyl acetate (24:1). White
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solid (*67% and 75%, 161 and #181 mg). M.p: 148−150 °C; H NMR (300 MHz, CDCl3):
(ppm) = 9.46 (s, 1H), 8.64 (s, 1H), 8.53-8.51 (m, 1H), 8.09 (d, J = 9Hz, 1H), 7.95-7.90 (m, 2H),
7.64 (t, J = 9Hz, 1H), 7.50-7.44 (m, 2H) . 13C (75 MHz, CDCl3): (ppm) = 160.7, 159.8, 150.7,
139.9, 134.8, 134.4, 130.6, 129.9, 128.7, 128.7, 127.7, 127.2, 126.7, 123.8 .
2-(4-chlorophenyl)quinazoline (4k).12b, 17d Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*65% and 71%, 156 and 171 mg). M.p: 133−135 °C; 1H (400 MHz, CDCl3): (ppm) =
9.47 (s, 1H), 8.60 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.3, 1H), 7.96-7.92 (m, 2H), 7.65 (t, J = 7.8
Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H). 13C (100 MHz, CDCl3): (ppm) = 160.4, 159.9, 150.6, 136.7,
136.4, 134.1, 129.8, 128.7, 128.5, 127.3, 127.0, 123.5.
#
*
#
2-(4-fluorophenyl)quinazoline (4l).12b, 13h,17f Eluent: petroleum ether/ethyl acetate (24:1). White
#
*
#
1
solid (*63% and 72%, 141 and 161mg). M.p: 122−123 °C; H NMR (300 MHz, CDCl3):
(ppm) = 9.43(s, 1H), 8.64-8.59(m, 2H), 8.06(d, J = 8.2 Hz, 1H), 7.91(d, J = 7.6 Hz, 2H),
7.60(t, J = 6.8 Hz, 1H), 7.32-7.17(m, 2H). 13C NMR (100 MHz, CDCl3): (ppm) = 165.9, 163.4,
160.5, 160.1, 150.7, 134.2, 130.7, 130.6, 128.5, 127.3, 127.2, 123.5, 115.7, 115.5.
2-(3-bromophenyl)quinazoline (4m).12b, 17f Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*63% and 74% and 180 and 211 mg). M.p: 153−155 °C; 1H NMR (300 MHz, CDCl3):
(ppm) = 9.47(d, J = 4.98 Hz, 1H), 8.79(s, 1H), 8.55(d, J = 6.45 Hz, 1H), 8.09(d, J = 6.12 Hz,
1H), 7.94(d, J = 6.4 Hz, 2H), 7.65(d, J = 5.79 Hz, 2H), 7.40(t, J = 5.94 Hz, 1H). 13C (100 MHz,
#
*
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CDCl3): (ppm) = 160.5, 159.5, 150.6, 140.1, 134.3, 133.5, 131.6, 130.1, 128.7, 127.7, 127.2,
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127.1, 123.7, 122.9.
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2-(4-bromophenyl)quinazoline (4n).17f Eluent: petroleum ether/ethyl acetate (24:1). White solid
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(*65% and #70%, *185 and 200 mg). M.p: 120−121 °C; H NMR (400 MHz, CDCl3): (ppm) =
9.45 (s, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.6 Hz, 1H), 7.94-7.90 (m, 2H), 7.68-7.61 (m,
13
3H); C NMR (100 MHz, CDCl3): (ppm) = 160.4, 160.0, 150.6, 136.9, 134.1, 131.7, 130.0,
128.5, 127.4, 127.0, 125.3, 123.5.
2-(3,5-difluorophenyl)quinazoline (4o). Eluent: petroleum ether/ethyl acetate (24:1). White
solid (*57% and 75%, 138 and 182 mg). M.p: 137−138 °C; H NMR (400 MHz, CDCl3):
(ppm) = 9.46 (s, 1H, (H1)), 8.20-8.14 (m, 2H, (H4, H5)), 8.09 (d, J = 8.0 Hz, 1H, (H2)), 7.94 (t,
J = 7.6 Hz, 2H, (H6, H8)), 7.66 (t, J = 7.6 Hz, 1H, (H3)), 6.97-6.91(m, 1H, (H7)). 13C NMR (100
MHz, CDCl3): (ppm) = 164.5 (d, J = 10.0 Hz), 162.5 (d, J = 10.0 Hz), 160.7 (d, J = 23.0 Hz),
159.0, 150.7, 141.8 (t, J = 7.0 Hz), 134.6 (d, J = 20.0 Hz), 128.9 (d, J = 19.0 Hz), 128.1 (d, J =
18.0 Hz), 127.3 (d, J = 20.0 Hz), 124.1, 111.7-111.3(m), 106.1-105.6 (m). HRMS (ESI-TOF):
#
*
#
1
m/z [M + H]+ calcd for C14H9F2N2 243.0734, found 243.0754.
+
2-(4-(trifluoromethyl)phenyl)quinazoline (4p).10h Eluent: petroleum ether/ethyl acetate(24:1)
white solid (*59% and 49%, 162 and 134 mg). M.p: 146-147oC; 1H NMR (CDCl3, 400 MHz)
δ(ppm) = 9.37 (s, 1H), 8.64 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.83 (t, J = 8.0 Hz, 2H),
7.68 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ(ppm) = 160.6,
159.6, 150.6, 141.3, 134.4, 132.3, 131.9, 128.8, 128.8, 127.9, 127.2, 125.5 (q, JC-F = 4.0 Hz),
123.8.
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2-(Thiophen-2-yl)quinazoline (4q).13h Eluent: petroleum ether/ethyl acetate (5:1). White solid
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*
#
(*59% and #62%, 125 and 132 mg). M.p: 137−138 °C; 1H NMR (CDCl3, 400 MHz) δ(ppm) =
9.32 (s, 1H), 8.14(d, J = 3.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.85 (t, J = 6.8 Hz, 2H),
7.55−7.50 (m, 2H), 7.18 (t, J = 4.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ(ppm) = 160.6,
157.8, 150.6, 143.9, 134.4, 130.0, 129.3, 128.4, 128.2, 127.3, 127.0, 123.4.
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2-(pyridin-2-yl)quinazoline (4r).15d Eluent: petroleum ether/ethyl acetate (5:1). White solid
*
#
1
(*45% and #50%, 93 and 104 mg). M.p: 90-92oC; H NMR (CDCl3, 400 MHz) δ(ppm) = 9.98
(s, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.74 (dd, J = 4.0 Hz, 0.8 Hz, 1H), 8.23 (dd, J = 8.0, 0.8 Hz,
1H), 7.89-7.82 (m, 3H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.45-7.42 (m, 1H).
2-(pyridin-4-yl)quinazoline(4s).15d Eluent: petroleum ether/ethyl acetate (5:1). Grey solid (*50%
and 56%, 104 and 116 mg). M.p: 134-138oC; 1H NMR (CDCl3, 400 MHz) δ(ppm) = 9.52(s,
1H), 8.82 (d, J = 5.6 Hz, 2H), 8.47 (t, J = 4.4 Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H), 8.00-7.96 (m,
2H), 7.71 (t, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ(ppm) = 161.0, 159.0, 150.6, 150.6,
145.6, 134.8, 128.6, 128.4, 127.4, 124.4, 122.6.
#
*
#
2-butylquinazoline (4t).10e Eluent: petroleum ether/ethyl acetate (24:1). yellow oil (*25% and
#30%, 47 and 56 mg). 1H NMR (CDCl3, 400 MHz) δ(ppm) = 9.37 (s, 1H), 7.97-7.91 (m, 1H),
7.84-7.81 (m, 2H), 7.52-7.50 (m, 1H), 3.58 (t, J = 5.6 Hz, 2H), 1.97 (t, J = 7.2 Hz, 2H), 1.63-
1.51 (m, 2H) 0.81 (t, J = 6.4 Hz, 3H).
*
#
6-methyl-2-phenyl quinazoline (4u).11a, 17d Eluent: petroleum ether/ethyl acetate (24:1). White
#
*
#
1
solid (*74% and 86%, 163 and 189 mg). M.p: 130−132°C ; H NMR (CDCl3, 300 MHz)
δ(ppm) = 9.38 (d, J = 3.72 Hz, 1H), 8.60 (s, 2H), 7.98 (d, J = 7.92 Hz, 1H), 7.71 (t, J = 9.09 Hz,
2H), 7.53 (s, 3H), 2.57 (d, J = 3.69 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ(ppm) = 160.4,
159.8, 149.4, 138.2, 137.5, 136.4, 130.4, 128.6, 128.4, 128.3, 125.8, 123.6, 21.7.
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