Base-Promoted Synthesis of 2-Aryl Quinazolines from 2-Aminobenzylamines in Water

Article abstract of DOI:10.1021/acs.joc.8b00327

A transition-metal-free procedure for the synthesis of a highly valuable class of heteroaromatics, quinazolines, was developed by using easily available 2-aminobenzylamines and α,α,α-trihalotoluenes. The transformation proceeded smoothly in the presence of only sodium hydroxide and molecular oxygen in water at 100 °C, furnishing a variety of 2-aryl quinazolines. The crystallization process of the crude reaction mixture for the purification of the solid products circumvents huge solvent-consuming workup and column chromatographic techniques, which make the overall process more sustainable and economical.

Full text of DOI:10.1021/acs.joc.8b00327

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Base-Promoted Synthesis of 2-Aryl Quinazolines
from 2-Aminobenzylamines in Water
Tanmay Chatterjee, Dong In Kim, and Eun Jin Cho
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00327 • Publication Date (Web): 12 Apr 2018
Downloaded from http://pubs.acs.org on April 13, 2018
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The Journal of Organic Chemistry
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BaseꢀPromoted Synthesis of 2ꢀAryl Quinazolines from 2ꢀ
Aminobenzylamines in Water
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Tanmay Chatterjee,a Dong In Kim,b and Eun Jin Cho*,b
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aDepartment of Chemistry
Birla Institute of Technology & Science, Pilani, Hyderabad Campus
Jawahar Nagar, Shameerpet Mandal, Hyderabad, Telangana 500078, India.
bDepartment of Chemistry, ChungꢀAng University
84 Heukseokꢀro, Dongjakꢀgu, Seoul 06974, Republic of Korea.
*Eꢀmail: ejcho@cau.ac.kr
Abstract
A transitionꢀmetal free procedure for the synthesis of a highly valuable class of
heteroaromatics, quinazolines, was developed by using easily available 2ꢀaminobenzylamines
and α,α,αꢀtrihalotoluenes. The transformation proceeded smoothly in the presence of only
sodium hydroxide and molecular oxygen in water at 100 °C, furnishing a variety of 2ꢀaryl
quinazolines. The crystallization process of the crude reaction mixture for the purification of
the solid products circumvents huge solvent consuming workꢀup and column
chromatographic techniques, which make the overall process more sustainable and
economical.
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Introduction
The interest of organic chemists in developing green methodologies for the synthesis of
useful organic molecules has continued to increase.1 A reaction is considered ideal if it
proceeds in a green reaction medium in the presence of benign reagents without the use of
hazardous organic solvents, metal complexes and reagents, and also produces minimum or
benign waste.1 The metalꢀfree approach in organic synthesis is always more economical and
is preferred over metalꢀmediated/catalyzed reactions that suffer from disadvantages such as
the high cost of metal complexes and the possibility of toxic metal contamination in the final
product; the latter restricts the use of such products in biological applications as
pharmaceuticals. Hence, a huge number of metalꢀfree synthetic methodologies has been
developed over the past decades and the number continues to increase.2
Quinazoline is one of the highly valuable classes of fused heteroaromatics that is prevalent in
numerous bioactive natural products, alkaloids, and lifeꢀsaving synthetic pharmaceuticals.
This scaffold is associated with anticancer, antituberculosis, antihypertensive, anticonvulsant,
antibacterial, antiꢀinflammatory, and antimalarial properties (Figure 1).3
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Figure 1. Examples of pharmaceuticals having the quinazoline core structure.
Because of their great importance, a wide variety of synthetic methodologies4−18 have been
developed for the synthesis of quinazolines, including copperꢀcatalyzed Ullmanꢀtype
coupling followed by oxidation of oꢀbromobenzylamines or oꢀbromobenzyl (pseudo)halides
with amides or amidines [Scheme 1(A)]5 and the oxidative cyclization of arylamidines6 with
one carbon synthons,6a aldehyde equivalents,6b,6c,6d or functionalized alkynes6d [Scheme
1(B)]. Quinazolines can also be generated by the reaction of benzimidates with
dioxazolones,7 and the reaction of
oꢀaminoarylꢀ or oꢀhaloaryl carbonyl equivalents such as
aldehydes, ketones, imines, and methanols with amines8 or amide equivalents such as
nitriles,9 or ammonia equivalents in the presence of carbon sources such as aldehydes10 and
DMA11 [Scheme 1(C)]. These species can also be produced by condensation of
oꢀ
aminobenzylamines with carbonyl equivalents such as aldehydes,12 ketones,13 alcohols,14
carboxylic acids,15 nitriles,16 or imine equivalents such as benzylamines17 or CO/ArBr18
[Scheme 1(D)]. Despite the significant advancements, many of these methods suffer from one
or several drawbacks such as harsh reaction conditions and the use of hazardous and/or
expensive transition metal complexes, ligands, additives, base, oxidants, and solvents, which
can lead to the production of hazardous waste and metal contamination of the final
product.4−18 Hence the development of greener synthetic methodologies for the synthesis of
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quinazolines is still desirable. As a part of our continuing interest in the synthesis of valuable
heteroaromatics,19 herein, we develop a sustainable methodology for the synthesis of 2ꢀaryl
quinazolines from easily available oꢀaminobenzylamines and α,α,α
ꢀtrihalotoluenes20 by using
9
only sodium hydroxide and molecular oxygen in water in the absence of any transition metal
complex, ligand, chemical oxidant, or additive [Scheme 1(E)].
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Scheme 1. Strategies for the Synthesis of Quinazolines
Previous work
A
(
)
Cu-cat.
additive, base
Y
X
N
R1
R1
+
R2
O2, solvent
NH2
Br
X = NH2; Y = O
X = Br, OTs; Y = NH
N
R2
B
(
)
R5
one carbon
synthon
NH
R2
R1
Cu-cat. or Lewis acid
ligand, additive
N
N
R1
or
H
+
oxidant, base
solvent
R4CHO
or
N
R2
R3
R2
HN
R1
one carbon
synthon
DMSO, DMF, DMA, NMP, TMEDA
=
N
R4CHO = R4CHO, (HCHO) , RCH OH,
R
TIPS
n
2
C
(
)
Y
X
O
R5
N
R3
Pd, Rh, Co, Cu-cat.
or organocatalyst
ligand, additive
O
R2
O
N
or
R4CH2NH2
R1
N
R1
+
oxidant, base
solvent
R2
or
X = H; Y = NH
X = NH2; Y = O
X = I, Br; Y = O
Nitrogen and
carbon sources
NH
NH2
R4CH2NH2 = R4CH2NH2, RCH2OH, RCN,
R
[Nitrogen sources] = NH3, NH4Cl, NH4OAc, NaN3
[Carbon sources] = ArCHO, ArCH2NH2, DMA
D
(
)
R1
Pd, Ir, Pt, Fe, Cu-cat.
or photocatalyst
and/or oxidant
ligand, additive
R2R3C=O
NH2
or
N
+
R1
R2CH=NH
NH2
N
R2
or
base, solvent
CO + ArBr
= R2CHO, R2COR3, R2CH2OH, R2COOH, R2CN etc.
= R2CH2NH2
R2R3C=O
R2CH=NH
This work
E
(
)
R1
CX3 NaOH
N
NH2
R1
R2
+
+ NaX
R2
O2, H2O
N
NH2
X = Br, Cl
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Results and Discussion
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The investigation was commenced by reacting 2ꢀaminobenzylamine (1a) with
α,α,αꢀ
8
9
tribromotoluene (2a) in the presence of 4 equiv of 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) in
0.2 M MeCN at 80 °C under molecular oxygen atmosphere. Gratifyingly, 52% of the desired
2ꢀphenylquinazoline (3aa) was formed, along with 25% of 2ꢀphenylꢀ3,4ꢀdihydroquinazoline
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(3aa′) (Table 1, entry 1). Controlled experiments confirmed that base, molecular oxygen, and
heat were essential for the transformation (Table 1, entries 2−4). The use of various tertiary
amine bases such as quinuclidine, NMM, DMAP, TEA, TMEDA, and DBU did not improve
the yield of 3aa (Table 1, entry 1 vs. entries 5−10). The reactant concentration was also
optimized. When the reactant concentration was increased to 1 M, the yield of 3aa increased
(Table 1, entry 1 vs. entries 11−13), which may be due to higher rate of intermolecular
substitution at higher concentration. The reaction temperature was optimized to 100 °C
(Table 1, entry 12 vs. entries 14−16). Various solvents such as DMF, DMSO, dioxane,
toluene, and H2O were found to be less efficient than MeCN (Table 1, entry 15 vs. entries
18−22), but the use of an inorganic base, K2CO3, instead of DABCO in water was found to
be more effective (Table 1, entry 22 vs. entry 23). Various inorganic bases (Cs2CO3, NaOH,
and KOH) were also employed using water as the solvent, among which NaOH was found to
be most effective (Table 1, entry 23 vs. entries 24−26). The stoichiometry of the base (NaOH)
was optimized to 3 equivalents (Table 1, entry 25 vs. entry 27). The use of 1.5 equiv of 2a did
not improve the result (Table 1, entry 27 vs. entry 28). Similar results were achieved when 2a
was chosen as the limiting reagent in the presence of 1.2 equiv of 1a (Table 1, entry 27 vs.
entry 29). Thus, two different reaction conditions were considered optimal for the
corresponding organic transformation, one using DABCO as the base in MeCN (Table 1,
entry 15; condition A) and the other using NaOH as the base in water (Table 1, entry 27;
condition B). Under both the optimized reaction conditions A and B, α,α,αꢀtrichlorotoluene
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was found to be slightly less reactive compared to α,α,αꢀtribromotoluene (Table 1, entries 15
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vs 30 and 27 vs 31). Being more environmentally benign and economical, condition B was
generally employed to explore the substrate scope by using NaOH as one of the least
expensive bases that also generates a benign salt (NaBr or NaCl) as the side product.
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Table 1. Optimization of Reaction Conditionsa
CX3
base
N
NH2
NH
+
+
solvent, O2
temp., 16 h
N
NH2
1a
N
X = Br, Cl
2a
3aa
3aa'
yieldb
3aa'
temp. (o C)
entry
1
X
base (equiv)
solvent (conc)
MeCN (0.2 M)
variation
3aa
Br
Br
Br
Br
DABCO (4)
DABCO (4)
ꢀ
80
ꢀ
ꢀ
ꢀ
52
25
2
3
4
5
6
7
8
MeCN (0.2 M) 25 (r.t.)
trace
0
63
0
MeCN (0.2 M)
MeCN (0.2 M)
80
80
80
80
80
80
DABCO (4)
argon atmospherec
0
83
22
17
20
0
Br Quinuclidine (4) MeCN (0.2 M)
ꢀ
ꢀ
ꢀ
ꢀ
48
41
31
6
Br
Br
Br
NMM (4)
DMAP (4)
TEA (4)
MeCN (0.2 M)
MeCN (0.2 M)
MeCN (0.2 M)
9
Br
Br
Br
Br
Br
TMEDA (4)
DBU (4)
MeCN (0.2 M)
MeCN (0.2 M)
MeCN (0.5 M)
MeCN (1 M)
MeCN (2 M)
80
80
80
80
80
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
8
trace
60
0
0
10
11
12
13
DABCO (4)
DABCO (4)
DABCO (4)
12
9
70
62
0
14
15
16
17
18
19
Br
Br
Br
Br
Br
Br
DABCO (4)
DABCO (4)
DABCO (4)
DABCO (3)
DABCO (4)
DABCO (4)
MeCN (1 M)
MeCN (1 M)
MeCN (1 M)
MeCN (1 M)
DMF (1 M)
90
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
75
78
74
72
52
50
0
0
100
110
100
100
100
0
0
trace
trace
DMSO (1 M)
20
21
22
23
24
25
26
27
28
Br
Br
Br
Br
Br
Br
Br
Br
Br
DABCO (4)
DABCO (4)
DABCO (4)
K2CO3 (4)
Cs2CO3 (4)
NaOH (4)
Dioxane (1 M)
toluene (1 M)
H2O (1 M)
100
100
100
100
100
100
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
10
trace
45
43
trace
0
0
0
0
H2O (1 M)
65
H2O (1 M)
48
H2O (1 M)
74
H2O (1 M)
H2O (1 M)
H2O (1 M)
H2O (1 M)
MeCN (1 M)
H2O (1 M)
KOH (4)
NaOH (3)
NaOH (3)
NaOH (3)
DABCO (4)
NaOH (3)
100
100
100
100
100
100
70
73
73
72
65
63
0
0
0
0
0
0
ꢀ
1.5 equiv 2a
29d Br
30
31
ꢀ
ꢀ
ꢀ
Cl
Cl
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aReaction conditions: 1a (0.1 mmol) and 2a (0.12 mmol) were used unless and otherwise
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8
9
b
1
stated. Yield was determined by H NMR spectrometry of crude reaction mixture using
bromoform as an internal standard. cMolecular oxygen was removed by repeated vacuumꢀ
freezeꢀthaw cycles. d1a (0.12 mmol) and 2a (0.1 mmol) were used.
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The substrate scope of the reaction was explored under both optimized conditions
A and B
(Table 2). First, the scope of the reaction with respect to 2ꢀaminobenzylamines was explored.
2ꢀAminoarylamines substituted with both electronꢀdonating groups (Me and OMe) and
electronꢀwithdrawing groups (Br, Cl, F, OCF3, CN, and NO2) were successfully reacted with
α
,
α
,
α
ꢀtribromotoluene or
quinazoline derivatives in moderate to high yields (Table 2, 3aa
reaction was then evaluated with respect to ꢀtrihalotoluenes.
substituted with electronꢀdonating and ꢀwithdrawing groups reacted smoothly with 1a (Table
2, 3ab 3af). The scaleꢀup experiment (gramꢀscale reaction of 1a with 2a under condition B
was found to be straightforward, producing 50% of 3aa (Table 2, 3aa). The attempted
reaction of 2ꢀaminobenzyl alcohol (4a) with 2a under condition B to furnish 2ꢀphenylꢀ4
benzo[ ][1,3]oxazine (5aa) did not proceed, possibly due to the lower nucleophilicity of
α
,
α
,
α
ꢀtrichlorotoluene to furnish the corresponding 2ꢀaryl
3ma). The scope of the
ꢀTrihalotoluenes
–
α,
α,
α
α,α,α
–
)
Hꢀ
d
alcohols compared to amines [Scheme S1(A), see Supporting Information]. The aliphatic
trichloride, 1,1,1ꢀtrichloroꢀ2ꢀmethylpropanꢀ2ꢀol also did not participate in the reaction with
1a [Scheme S1(B), SI].
Notably, under condition B the process generated NaX (X = Br, Cl) as the only side product
that remained in the aqueous phase and could be easily removed from the crude reaction
mixture through washing. In addition, all the products were solid, except for 3ae. Therefore,
crystallization could be attempted in order to isolate and purify the solid products to make the
overall process more sustainable by avoiding a huge solvent consuming workꢀup and column
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chromatographic steps. To our delight, the yields of 3ba, 3fa, 3ga, 3ja, and 3ab (Table 2)
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8
obtained through crystallization of the crude reaction mixture were similar to that obtained
through workꢀup followed by silica gel column chromatography.
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Table 2. Substrate Scopea,b
DABCO (4 equiv), MeCN (1 M)
Condition A
(
)
CX3
or
NH2
N
R1
R2
R1
+
NaOH (3 equiv), H2O (1 M)
NH2
(Condition B)
N
R2
1
2
3
O2, 100 oC, 16 - 24 h
X = Br and Cl
Me
N
N
N
N
Me
N
N
3aa: 75% (X = Br, A)
70% (X = Br, B)
61% (X = Cl, B)
50%c (X = Cl, B)
3ba: 64% (X = Br, A)
58% (X = Br, B)
3ca: 62% (X = Br, A)
60% (X = Br, B)
55%d (X = Br, B)
43% (X = Cl, B)
MeO
Br
Cl
N
N
N
N
N
N
3da: 65% (X = Br, B)
3ea: 60% (X = Br, A)
3fa: 67% (X = Br, A)
62% (X = Br, B)
60%d (X = Br, B)
B
)
61% (X = Br,
45% (X = Cl, B)
F
Cl
N
N
N
Cl
N
N
N
Cl
3ga: 70% (X = Br, A)
64% (X = Br, B)
3ha: 69% (X = Br, A)
3ia: 75% (X = Br, B)
B
79% (X = Br,
)
52% (X = Cl, B)
59%d (X = Br, B)
F3CO
O2N
N
N
N
N
N
N
CN
3ja: 78% (X = Br, A)
81% (X = Br, B)
77%d (X = Br, B)
60% (X = Cl, B)
3ka: 55% (X = Br, B)
3la: 61% (X = Br, B)
O2N
N
N
N
N
N
N
Br
Me
Br
3ac: 65% (X = Br, A)
3ma: 61% (X = Br, A)
3ab: 76% (X = Br, A)
B
B
)
64% (X = Br,
)
66% (X = Br,
71% (X = Br, B)
70%d (X = Br, B)
N
N
N
N
N
Cl
N
Cl
3ad: 68% (X = Cl, B)
F
3ae: 58% (X = Br, B)
3af: 71% (X = Br, A)
B
)
61% (X = Cl,
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b
aReaction conditions:
1
(0.3 mmol),
2
(0.36 mmol). Yield of isolated products is reported.
4
5
6
d
cGramꢀscale synthesis: 1a (7 mmol), 2a (8.4 mmol); Yield of products obtained through
7
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crystallization of crude mixture.
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To shed light on the reaction mechanism, we performed a series of controlled experiments
including a kinetic isotopic effect (KIE) experiment. When the reaction of 1a with 2a was
performed in the presence of DABCO in MeCN (condition A) at room temperature under
argon atmosphere, only 2ꢀphenylꢀ3,4ꢀdihydroquinazoline (3aa′) was formed in 60% yield
[Scheme 2(A)]. 3aa′ was isolated and subjected to several reaction conditions. When 3aa′
was heated in MeCN or H2O at 100 °C under molecular oxygen atmosphere, it was fully
1
converted to 3aa (based on the remaining 3aa′ detected by H NMR analysis of the crude
reaction mixture), which revealed that 3aa′ was the intermediate of the reaction [Scheme
2(B)]. However, under argon atmosphere, 3aa′ was not converted to 3aa, which confirms the
role of molecular oxygen as an oxidant for the oxidation of 3aa′ to 3aa [Scheme 2(C)].
Interestingly, when 3aa′ was heated in MeCN or H2O at 70 °C under molecular oxygen
atmosphere, a trace amount of 3aa was formed, which revealed that high temperature (over
70 °C) is required for the oxidation of 3aa′ to 3aa [Scheme 2(D)].
Scheme 2. Controlled Experiments for Mechanistic Studies
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To check the involvement of radical intermediates in the reaction, the model reaction of 1a
with 2a was performed under condition B in the presence of radical quenchers such as
TEMPO and 1,4ꢀdinitrobenzene and was found to be unaffected, indicating the nonꢀ
involvement of radicals during the full course of the reaction (Scheme S2, SI).
Further, a kinetic isotopic effect (KIE) experiment was carried out by subjecting 2a to
a 1:1 mixture of 1a and 1aꢀD2 under condition B and molecular oxygen atmosphere at 100
°C for 4 h (Scheme 3). The relative rate constant (kH/kD) of 3aa versus 3aaꢀD, determined by
1HꢀNMR analysis of the isolated products, was 6.67, which revealed that the oxidation of 2ꢀ
phenylꢀ3,4ꢀdihydroquinazoline (3aa′) to 2ꢀphenyl quinazoline (3aa) is the rateꢀdetermining
step of the reaction.21
Scheme 3. Kinetic Isotopic Effect (KIE) Experiment
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Based on the results of the above experiments, we proposed a reaction mechanism as outlined
below (Scheme 4). The baseꢀpromoted intermolecular substitution of 2a by 1a produced
A,
which upon baseꢀmediated intramolecular substitution followed by elimination furnished the
key intermediate 2ꢀphenylꢀ3,4ꢀdihydroquinazoline (3aa′). Finally, 3aa′ was oxidized to 3aa
by molecular oxygen as the rateꢀdetermining step.
Scheme 4. Proposed Reaction Mechanism
In conclusion, we developed a sustainable synthetic procedure for the synthesis of valuable 2ꢀ
aryl quinazolines by using easily available 2ꢀaminobenzylamines and α,α,αꢀtrihalotoluene in
aqueous sodium hydroxide solution at 100 °C. This methodology possesses several
advantages, such as a transitionꢀmetalꢀfree protocol, the use of cheap sodium hydroxide as a
base, use of water and molecular oxygen as a green and renewable solvent and oxidant,
respectively, and isolation/purification of the solid products through crystallization of the
crude reaction mixture, which circumvents huge solvent consuming workꢀup and column
chromatographic techniques. These features make the overall process more sustainable and
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economical. A wide variety of 2ꢀaryl quinazolines was synthesized by the procedure and
scaleꢀup of the experiment to the gramꢀscale was also found to be straightforward. Based on
the controlled experiments and kinetic isotopic effect experiments, baseꢀpromoted
intermolecular substitution followed by intramolecular substitution (cyclization), elimination,
and oxidation by molecular oxygen is proposed for the synthesis of quinazolines through the
intermediacy of 3,4ꢀdihydroquinazolines, where the oxidation step was found to be the rateꢀ
determining step. We believe that this simple synthetic methodology will find useful
application for the synthesis of valuable quinazolines in an economical and sustainable
manner.
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EXPERIMENTAL SECTION
General Reagent Information
All reagents and solvents including DABCO and NaOH were purchased from SigmaꢀAldrich,
Alfa Aesar, TCI chemical companies. Flash column chromatography was performed using
Merck silica gel 60 (70ꢀ230 mesh).
General Analytical Information
The 2ꢀaminobenzylamine derivatives and quinazoline products were characterized by 1H, 13C
NMR, and FTꢀIR spectroscopy. NMR spectra were recorded on a Bruker 600 MHz
instrument (600 MHz for 1H NMR and 151 MHz for 13C NMR). Copies of 1H and 13C NMR
1
spectra can be found at the end of the Supporting Information. H NMR experiments are
reported in units, parts per million (ppm), and were measured relative to residual chloroform
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(7.26 ppm) in the deuterated solvent. 13C NMR spectra are reported in ppm relative to
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deuterochloroform (77.23 ppm) and all were obtained with H decoupling. Coupling
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constants were reported in Hz. FTꢀIR spectra were recorded on a Nicolet iS 10 ThermoFisher
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FTꢀIR spectrometer. Reactions were monitored by HꢀNMR of the crude reaction mixture
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using bromoform as the internal standard and products were detected by GCꢀMS using the
Agilent GC 7890B/5977A inert MSD with TripleꢀAxis Detector. Mass spectral data of all
unknown compounds were obtained from the Korea Basic Science Institute (Daegu) on a Jeol
JMS 700 high resolution mass spectrometer. A quadrupole mass analyzer was used for
HRMS measurements. Melting points of unknown compounds were recorded on a Stuart
SMP30 apparatus.
Representative experimental procedure; Synthesis of 2ꢀaminoꢀ5ꢀmethylbenzylamine
(1b): An ovenꢀdried 100 mL round bottom flask equipped with a magnetic stir bar was
charged with 2ꢀaminoꢀ5ꢀmethylbenzonitrile (5 mmol, 0.66 g) in dry tetrahydrofuran (10 mL)
under argon atmosphere. To the solution of benzonitrile at 0
℃ and under an argon
atmosphere was slowly added borane (1.0 M in THF) in drops. The solution was stirred for
10 min at 0 and further 24 h at room temperature. The reaction progress was monitored by
TLC and gas chromatography. The reaction mixture was quenched by addition of ethanol.
HCl (2.0 M in diethyl ether) was added to resulting solution for salt formation. Precipitated
salts were filtered with diethyl ether and then treated with excess of aqueous solution of
ammonia. The resulting suspension was extracted with ethyl acetate. The combined organic
layers were dried over anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography (MC/methanol = 10/1) to give 2ꢀaminoꢀ5ꢀ
methylbenzylamine (2.95 mmol, 0.40 g) in 59 % yield.
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Representative experimental procedure; Synthesis of α,α,αꢀtribromotoluene (2a): To an
ovenꢀdried two neck 100 mL round bottom flask equipped with a magnetic stir bar and a
reflux condenser were flame dried and charged with aluminum bromide (2 mmol, 0.53 g),
trimethylsilyl bromide (28 mmol, 4.29 g), α,α,αꢀtrifluorotoluene (10 mmol, 1.46 g) under
argon atmosphere. The reaction mixture was placed in the oil bath and heated at 80 °C. The
reaction progress was monitored by TLC and gas chromatography. After completion of the
reaction (about 20 h), the flask was cooled to room temperature and the reaction mixture was
diluted with dichloromethane and water. The aqueous phase was further extracted with
dichloromethane. The combined organic layers were dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by silica gel flash column chromatography
(hexane/EtOAc = 30/1) to give α,α,αꢀtribromotoluene (9.6 mmol, 3.12g) in 96% yield.
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Representative experimental procedure; Synthesis of 2ꢀphenylquinazolines (3aa):
A
resealable tube equipped with a magnetic stir bar was charged with 2ꢀamino benzylamine, 1a
(37 mg, 0.3 mmol, 1.0 equiv.) and α,α,αꢀtribromotoluene, 2a (118 mg, 0.36 mmol, 1.2
equiv.). Then, for Condition A, DABCO (118 mg, 1.2 mmol, 4 equiv.) and MeCN (0.3 mL,
1M) and for Condition B, NaOH (40 mg, 0.93 mmol, 3.1 equiv; considering 93% purity of
the reagent) and H2O (0.3 mL, 1 M) was added to the reaction mixture. Next, molecular
oxygen was bubbled through the reaction mixture for 10 min and the reaction tube was
o
completely sealed. The sealed tube was then heated in an oil bath at 100 C for the required
period of time. The reaction progress was monitored by TLC. After completion of reaction,
the mixture was allowed to come to room temperature and diluted with ethyl acetate (EA)
followed by washing with water. Under Condition B, the sludge was washed several times
with ethyl acetate before its disposal to the environment. The combined organic layers were
dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (SiO2) with hexane/EA to furnish the pure 2ꢀphenylquinazolines,
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3aa (46 mg, 75%; Condition A and 43mg, 70%; Condition B), and the remaining 2a was
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recovered. The same procedure was followed for all the reactions mentioned in Table 2.
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For crystallization technique, after the completion of reaction, the solid product was
filtered and washed several times with water and dried by using blotting paper. Then the
crude solid compound was crystallized from either hot hexane or hexane/ethyl acetate
mixture.
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Analytic Data of 2ꢀAminobenzylamines (1bꢀ1m)
2ꢀAminoꢀ5ꢀmethylbenzylamine (1b):22 white solid (401 mg, 59%); 1H NMR (600 MHz,
CDCl3) δ 6.90 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 3.86 (s, 2H) 2.24 (s,
3H); 13C NMR (151 MHz, CDCl3) δ 143.8, 129.9, 128.8, 127.4, 126.6, 116.2, 45.1, 20.6; IR
(neat): νmax = 3347, 3012, 2917, 1508, 816 cmꢀ1; Rf 0.38 (DCM/Methanol, 9/1).
2ꢀAminoꢀ4ꢀmethylbenzylamine (1c):22 white solid (421 mg, 62%); 1H NMR (600 MHz,
CDCl3) δ 6.93 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.51 (s, 1H), 3.86 (s, 2H), 2.26 (s,
3H); 13C NMR (151 MHz, CDCl3) δ 146.4, 139.3, 129.2, 123.6, 118.9, 116.8, 44.9, 21.3; IR
(neat): νmax = 3357, 3233, 2860, 1625, 726 cmꢀ1; Rf 0.38 (DCM/Methanol, 9/1).
2ꢀAminoꢀ5ꢀmethoxylbenzylamine (1d):22 white liquid (532 mg, 70%); 1H NMR (300 MHz,
CDCl3) δ 6.69 (s, 1H), 6.68 (dd,
J = 7.2, 2.4 Hz, 1H), 6.64 (dd, J = 7.2, 2.4 Hz, 1H), 3.86 (s,
2H), 3.75 (s, 3H), 2.01 (bs, 2H); IR (neat): νmax = 3352, 3225, 2832, 1504, 816 cmꢀ1; Rf 0.30
(DCM/Methanol, 9/1).
2ꢀAminoꢀ4ꢀchlorobenzylamine (1e):22 white solid (624 mg, 80%); 1H NMR (600 MHz,
CDCl3) δ 6.93 (d,
J
= 7.8 Hz, 1H), 6.65 ꢀ 6.62 (m, 2H), 3.85 (s, 2H), 4.69 (bs, 2H), 3.86 (s,
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2H), 1.30 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 147.7, 133.5, 130.1, 124.3, 117.5, 115.4,
44.6; IR (neat): νmax = 3354, 3220, 2866, 1494, 729 cmꢀ1; Rf 0.50 (DCM/Methanol, 9/1).
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2ꢀAminoꢀ5ꢀchlorobenzylamine (1f):22 white solid (390 mg, 50%); 1H NMR (600 MHz,
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CDCl3) δ 7.03 (d,
J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.56 (bs, 2H), 3.85
(s, 1H), 1.39 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 145.2, 129.0, 128.0, 127.8, 122.5
117.1, 45.0; IR (neat): νmax = 3354, 3222, 2860, 1490, 728 cmꢀ1; Rf 0.50 (DCM/Methanol,
9/1).
2ꢀAminoꢀ3,5ꢀdichlorobenzylamine (1g): white solid (665 mg, 70%); 1H NMR (600 MHz,
CDCl3) δ 7.18 (d,
J = 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 5.10 (bs, 2H), 3.86 (s, 2H), 1.30
(bs, 2H); 13C NMR (151 MHz, CDCl3) δ 142.0, 128.1, 127.6, 127.5, 121.5, 120.1, 45.3; IR
(neat): νmax = 3438, 3306, 2864, 1468, 860 cmꢀ1; HRMS m/z (EI) calc. for C7H8Cl2N2 [M+]
190.0065, found 190.0065; Rf 0.55 (DCM/Methanol, 9/1).
2ꢀAminoꢀ5ꢀbromobenzylamine (1h):22 white solid (630 mg, 63%); 1H NMR (600 MHz,
CDCl3) δ 7.17 ꢀ 7.15 (m, 2H), 6.55 (d,
J = 7.8 Hz, 1H), 4.58 (bs, 2H), 3.85 (s, 2H), 1.40 (bs,
2H); 13C NMR (151 MHz, CDCl3) δ 145.7, 131.8, 131.0, 128.2, 117.5, 109.6, 45.0; IR
(neat): νmax = 3355, 3222, 2857, 1489, 815 mꢀ1; Rf 0.50 (DCM/Methanol, 9/1).
2ꢀAminoꢀ5ꢀfluorobenzylamine (1i):22 white solid (329 mg, 47%); 1H NMR (600 MHz,
CDCl3) δ 6.81 ꢀ 6.77 (m, 2H), 6.59 (dd, 3J
=8.4,
J
= 4.8, 1H), 4.34 (bs, 2H), 3.85 (s, 2H),
1.31 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 156.1 (d, 1J CꢀF = 157.5 Hz), 142.3 (d, 4J CꢀF
1.4 Hz), 127.8 (d, 3J = 4.2 Hz), 116.6 (d, 3J = 5.1 Hz), 115.6 (d, 2J
HꢀF
=
= 14.9 Hz),
CꢀF
CꢀF
CꢀF
114.4 (d, 2J CꢀF = 14.7 Hz), 49.9 (d, 4J CꢀF = 0.9 Hz); IR (neat): νmax = 3347, 3231, 2863, 1501,
724 mꢀ1; Rf 0.50 (DCM/Methanol, 9/1).
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2ꢀAminoꢀ5ꢀ(trifluoromethoxy)benzylamine (1j): black liquid (535 mg, 52%); 1H NMR (600
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MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.9 (bs, 2H),
4.22 (s, 1H), 1.75 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 145.5, 140.9, 126.7, 122.3, 121.3,
120.9 (q, 1J CꢀF = 170.9 Hz), 116.2, 45.1; IR (neat): νmax = 3349, 3235, 1504, 1154, 723 cmꢀ1;
HRMS m/z (EI) calc. for C8H9F3N2O [M+] 206.0667, found 206.0665; Rf 0.50
(DCM/Methanol, 9/1).
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2ꢀAminoꢀ5ꢀnitrobenzylamine (1k):22 yellow solid (484 mg, 58%); 1H NMR (600 MHz,
CDCl3) δ 8.01 (dd,
J = 8.4, 2.4 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H),
5.60 (bs, 2H), 3.98 (s, 1H), 1.42 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 153.7, 125.7,
125.4, 124.3, 114.3, 45.5 (overlapped peaks present); IR (neat): νmax = 3416, 3059, 2936, 903,
724 cmꢀ1; Rf 0.55 (DCM/Methanol, 9/1).
2ꢀAminoꢀ3ꢀ(aminomethyl)benzonitrile (1l): yellow liquid (485 mg, 66%); 1H NMR (600
MHz, CDCl3) δ 7.32 (dd, J = 7.8, 1.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.64 (dd, J = 7.8, 7.8
Hz, 1H), 5.63 (bs, 2H), 3.94 (s, 2H), 1.38 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 150.6,
133.6, 131.5, 126.1, 118.2, 117.2, 96.8, 45.6; IR (neat): νmax = 3370, 3212, 2850, 2214, 1638
mꢀ1; HRMS m/z (EI) calc. for C8H9N3 [M+] 147.0796, found 147.0795; Rf 0.63
(DCM/Methanol, 9/1).
o
2ꢀAminoꢀ3ꢀbromoꢀ5ꢀnitrobenzylamine (1m): yellow solid (857 mg, 70%), m.p. 170ꢀ172 C;
1H NMR (600 MHz, CDCl3) δ 8.33 (d,
J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 6.26 (bs,
2H), 4.02 (s, 2H), 1.52 (bs, 2H); 13C NMR (151 MHz, CDCl3) δ 151.1, 128.2, 124.6, 124.5,
108.2, 46.1 (overlapped peaks present); IR (neat): νmax = 3430, 3180, 2850, 903, 723 mꢀ1;
HRMS m/z (EI) calc. for C7H8BrN3O2 [M+] 244.9800, found 244.9798; Rf 0.63
(DCM/Methanol, 9/1).
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Analytic Data of α,α,αꢀTribromotoluenes (2aꢀ2c, 2e, 2f)
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(Tribromomethyl)benzene (2a):23 white solid (3120 mg, 96%); 1H NMR (600 MHz, CDCl3)
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δ 8.01 (d, J = 7.2, 2H), 7.40 (dd,
J = 7.2, 7.2 Hz, 2H), 7.34 (t, J
= 7.2, 1H); 13C NMR (151
MHz, CDCl3) δ 147.2, 130.3, 128.3, 126.7, 36.5; IR (neat): νmax = 3061, 1489, 1443, 722,
652 cmꢀ1; Rf 0.49 (hexane).
1ꢀMethylꢀ4ꢀ(tribromomethyl)benzene (2b):23 white solid (1223 mg, 36%); 1H NMR (600
MHz, CDCl3) δ 7.89 (d,
J = 8.4 Hz, 2H), 7.19 (d, J
= 8.4 Hz, 2H), 2.41 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 144.7, 140.7, 128.8, 126.6, 36.3, 21.2; IR (neat): νmax = 3029, 2920,
1607, 717, 649 cmꢀ1; Rf 0.47 (hexane).
1ꢀBromoꢀ4ꢀ(tribromomethyl)benzene (2c):23 white solid (3256 mg, 80%); 1H NMR (600
MHz, CDCl3) δ 7.88 (d, J = 9 Hz, 2H), 7.53 (d, J
= 9 Hz, 2H); 13C NMR (151 MHz, CDCl3)
δ 146.3, 131.3, 128.4, 124.8, 34.5; IR (neat): νmax = 3086, 1581, 903, 728, 649 cmꢀ1; Rf 0.53
(hexane).
1ꢀChloroꢀ2ꢀ(tribromomethyl)benzene (2e):23 white liquid (2952 mg, 82%); 1H NMR (600
MHz, CDCl3) δ 8.27 ꢀ 8.24 (m, 1H), 7.51 ꢀ 7.48 (m, 1H), 7.33 ꢀ 7.30 (m, 2H); 13C NMR
(151 MHz, CDCl3) δ 140.4, 133.7, 133.2, 131.7, 129.6, 126.6, 30.8; IR (neat): νmax = 3053,
1687, 1592, 744, 647 cmꢀ1; Rf 0.45 (hexane).
1ꢀFluoroꢀ4ꢀ(tribromomethyl)benzene (2f):23 pale yellow liquid (2470 mg, 72%); 1H NMR
(600 MHz, CDCl3) δ 8.02 (dd, J J
= 9.0, 4J HꢀF = 4.8 Hz, 2H), 7.07 (dd, = 9.0, 3J HꢀF = 8.7 Hz,
2H); 13C NMR (151 MHz, CDCl3) δ 163.3 (d, 1J CꢀF = 169.0 Hz), 143.4 (d, 4J CꢀF = 2.2 Hz),
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129.0 (d, 3J
= 5.9 Hz), 115.0 (d, 2J
= 14.8 Hz), 34.4; IR (neat): νmax = 3076, 1602,
CꢀF
CꢀF
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Analytic Data of 2ꢀArylquinazolines (3aa – 3af)
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2ꢀPhenylquinazoline (3aa):6c white solid (46 mg, 75%, condition A); 1H NMR (600 MHz,
CDCl3) δ 9.45 (s, 1H), 8.63 (d,
J = 7.0 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.93 – 7.87 (m,
2H), 7.59 (dd,
J
= 7.8, 6.6 Hz, 1H), 7.56 – 7.50 (m, 3H); 13C NMR (151 MHz, CDCl3)
δ
161.3, 160.7, 151.0, 138.3, 134.3, 130.8, 128.84, 128.82, 128.78, 127.4, 127.3, 123.8; IR
(neat): νmax = 3062, 2924, 1617, 1585, 1550, 1485, 1402, 704 cmꢀ1; Rf 0.35 (hexane/EtOAc,
9/1).
6ꢀMethylꢀ2ꢀphenylquinazoline (3ba):6c offꢀwhite solid (42 mg, 64%, condition A); 1H NMR
(600 MHz, CDCl3) δ 9.35 (s, 1H), 8.60 (d,
J = 6.9 Hz, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.70
(dd,
J
= 8.6, 1.9 Hz, 1H), 7.63 (s, 1H), 7.56 – 7.48 (m, 3H), 2.53 (s, 3H); 13C NMR (151
MHz, CDCl3) δ 160.6, 159.9, 149.5, 138.6, 137.6, 136.5, 130.5, 128.8, 128.6, 128.4, 125.9,
123.8, 21.8; IR (neat): νmax = 3056, 2919, 1588, 1556, 1425, 1371, 707 cmꢀ1; Rf 0.35
(hexane/EtOAc, 9/1).
7ꢀMethylꢀ2ꢀphenylquinazoline (3ca):12b offꢀwhite solid (40 mg, 60%, condition B); 1H NMR
(600 MHz, CDCl3) δ 9.37 (s, 1H), 8.61 (d,
J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.79 (d, J = 8.3 Hz,
1H), 7.57 – 7.47 (m, 3H), 7.41 (d,
J
= 8.3 Hz, 1H), 2.59 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 161.3, 160.0, 151.2, 145.3, 138.4, 130.7, 129.7, 128.8, 128.7, 127.8, 126.9, 122.1,
22.5; IR (neat): νmax = 3058, 2922, 1622, 1589, 1548, 1401, 705 cmꢀ1; Rf 0.32
(hexane/EtOAc, 9/1).
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6ꢀMethoxyꢀ2ꢀphenylquinazoline (3da):6c yellow solid (46 mg, 65%, condition B); 1H NMR
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5
6
7
8
(600 MHz, CDCl3) δ 9.32 (s, 1H), 8.58 (d,
J
= 7.5 Hz, 2H), 7.97 (d,
J = 9.2 Hz, 1H), 7.54 –
7.50 (m, 3H), 7.48 (dd,
J
= 7.5, 6.9 Hz, 1H), 7.09 (d, J
= 2.8 Hz, 1H), 3.91 (s, 3H); 13C NMR
9
(151 MHz, CDCl3) δ 159.5, 158.9, 158.4, 147.1, 138.4, 130.3, 130.3, 128.7, 128.4, 127.3,
124.6, 104.0, 55.8; IR (neat): νmax = 3061, 2999, 1620, 1572, 1489, 1164, 1026, 762, 707 cmꢀ
1; Rf 0.34 (hexane/EtOAc, 4/1).
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6ꢀBromoꢀ2ꢀphenylquinazoline (3ea):6c white solid (52 mg, 61%, condition B); 1H NMR (600
MHz, CDCl3) δ 9.39 (s, 1H), 8.60 (dd,
J = 6.7, 1.5 Hz, 2H), 8.09 (d, J = 1.5 Hz, 1H), 7.96 (d,
J
= 1.4 Hz, 2H), 7.56 – 7.50 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 161.6, 159.6, 149.7,
137.8, 131.1, 130.7, 129.5, 128.9, 128.8, 128.8, 124.7, 120.9; IR (neat): νmax = 2923, 1572,
1543, 1476, 1276, 837, 704 cmꢀ1; Rf 0.51 (hexane/EtOAc, 9/1).
6ꢀChloroꢀ2ꢀphenylquinazoline (3fa):6c white solid (48 mg, 67%, condition A); 1H NMR (600
MHz, CDCl3) δ 9.36 (s, 1H), 8.59 (dd,
J = 7.9, 1.9 Hz, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.87 (d,
J
= 2.4 Hz, 1H), 7.80 (dd, J
= 9.0, 2.4 Hz, 1H), 7.57 – 7.50 (m, 3H).; 13C NMR (151 MHz,
CDCl3) δ 161.5, 159.7, 149.4, 137.8, 135.2, 133.0, 131.0, 130.6, 128.9, 128.8, 126.0, 124.2;
IR (neat): νmax = 3057, 2923, 2853, 1573, 1547, 1478, 1430, 1277, 833, 703 cmꢀ1; Rf 0.46
(hexane/EtOAc, 9/1).
7ꢀChloroꢀ2ꢀphenylquinazoline (3ga):12a white solid (50 mg, 70%, condition A); 1H NMR
(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.61 (dd,
J = 7.3, 1.9 Hz, 2H), 8.09 (d, J = 1.3 Hz, 1H),
7.86 (d,
J
= 8.6 Hz, 1H), 7.61 – 7.47 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 162.1, 160.4,
151.6, 140.6, 137.8, 131.2, 128.9, 128.9, 128.7, 128.6, 128.0, 122.2; IR (neat): νmax = 2970,
1613, 1543, 1452, 1377, 873, 701 cmꢀ1; Rf 0.40 (hexane/EtOAc, 9/1).
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6,8ꢀDichloroꢀ2ꢀphenylquinazoline (3ha): pale yellow solid (65 mg, 79%, condition B), m.p.
4
5
6
7
132ꢀ134 oC; 1H NMR (600 MHz, CDCl3) δ 9.39 (s, 1H), 8.68 (dd,
= 2.2 Hz, 1H), 7.57 – 7.52 (m, 3H); 13C NMR (151 MHz,
J = 8.6, 1.2 Hz, 2H), 7.96
(d,
J = 2.2 Hz, 1H), 7.83 (d, J
8
9
CDCl3) δ 161.9, 160.1, 146.3, 137.4, 134.8, 134.7, 132.4, 131.5, 129.1, 129.0, 125.0, 124.8;
IR (neat): νmax = 3067, 1573, 1540, 1461, 1436, 1329, 769, 707 cmꢀ1; HRMS m/z (EI) calc.
for C14H8Cl2N2 [M+] 274.0065, found 274.0067; Rf 0.53 (hexane/EtOAc, 9/1).
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6ꢀFluoroꢀ2ꢀphenylquinazoline (3ia):10c white solid (50 mg, 75%, condition B); 1H NMR (600
MHz, CDCl3) δ 9.42 (s, 1H), 8.60 (dd,
J = 8.1, 1.6 Hz, 2H), 8.09 (dd, J = 9.2, 5.0 Hz, 1H),
7.67 (ddd,
J
= 9.2, 8.4, 2.8 Hz, 1H), 7.56 – 7.50 (m, 4H); 13C NMR (151 MHz, CDCl3)
δ
1
4
3
160.6 (d, JCꢀF = 251.3 Hz), 160.9, 160.6 (d, JCꢀF = 5.4 Hz), 148.1, 137.9, 131.6 (d, JCꢀF
=
2
3
8.6 Hz), 130.9, 128.9, 128.7, 124.7 (d, JCꢀF = 25.8 Hz), 124.1 (d, JCꢀF = 9.4 Hz), 110.3 (d,
2JCꢀF = 21.9 Hz); IR (neat): νmax = 3065, 1630, 1590, 1552, 1493, 1353, 1212, 837, 701 cmꢀ1 ;
Rf 0.30 (hexane/EtOAc, 9/1).
2ꢀPhenylꢀ6ꢀ(trifluoromethoxy)quinazoline (3ja):6c offꢀwhite solid (70 mg, 81%, condition B);
1H NMR (600 MHz, CDCl3) δ 9.45 (s, 1H), 8.61 (dd,
1.9 Hz, 1H), 7.78 – 7.69 (m, 2H), 7.59 – 7.49 (m, 3H); 13C NMR (151 MHz, CDCl3)
J = 7.8, 1.9 Hz, 2H), 8.12 (dd, J = 7.8,
δ
161.8, 160.4, 149.3, 147.3 (q, 3JCꢀF = 2.0 Hz), 137.7, 131.4, 131.1, 128.9, 128.8, 128.4, 123.7,
1
120.7 (q, JCꢀF = 259.0 Hz), 117.1; IR (neat): νmax = 3070, 2914, 1590, 1557, 1487, 1351,
1256, 904, 725 cmꢀ1; Rf 0.60 (hexane/EtOAc, 9/1).
2ꢀPhenylquinazolineꢀ8ꢀcarbonitrile (3ka): pale yellow solid (38 mg, 55%, condition B), m.p.
o
155ꢀ157 C; 1H NMR (600 MHz, CDCl3) δ 9.54 (s, 1H), 8.78 – 8.71 (m, 2H), 8.28 (dd,
J =
7.2, 1.4 Hz, 1H), 8.16 (dd, J = 8.2, 1.4 Hz, 1H), 7.67 (dd, J = 8.2, 7.2 Hz, 1H), 7.56 ꢀ7.54 (m,
3H); 13C NMR (151 MHz, CDCl3) δ 162.9, 161.1, 150.7, 139.9, 136.9, 132.1, 131.9, 129.4,
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129.0, 126.6, 123.5, 116.2, 112.9; IR (neat): νmax = 3065, 1607, 1583, 1569, 1470, 1401,
1320, 768, 713 cmꢀ1; HRMS m/z (EI) calc. for C15H9N3 [M+] 231.0796, found 231.0797; Rf
0.34 (hexane/EtOAc, 2/1).
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6ꢀNitroꢀ2ꢀphenylquinazoline (3la):8b white solid (46 mg, 61%, condition B); 1H NMR (600
MHz, CDCl3) δ 9.61 (s, 1H), 8.85 (s, 1H), 8.70 – 8.61 (m, 3H), 8.19 (dd,
J = 9.4, 2.3 Hz,
1H), 7.56ꢀ7.55 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 164.2, 162.4, 153.3, 146.0, 137.2,
132.1, 130.9, 129.5, 129.0, 127.6, 124.1, 122.5; IR (neat): νmax = 2922, 2851, 1624, 1555,
1525,1436, 1345, 853, 701 cmꢀ1; Rf 0.54 (hexane/EtOAc, 4/1).
8ꢀBromoꢀ6ꢀnitroꢀ2ꢀphenylquinazoline (3ma): offꢀwhite solid (63 mg, 64%, condition B),
o
m.p. 255ꢀ257 C; 1H NMR (600 MHz, DMSOꢀD6) δ 9.95 (s, 1H), 9.17 (d,
J
= 2.4 Hz, 1H),
8.93 (d,
J
= 2.4 Hz, 1H), 8.65 (dd,
J
= 7.8, 1.9 Hz, 2H), 7.64 – 7.60 (m, 3H); 13C NMR (151
MHz, DMSOꢀD6) δ 164.6, 163.8, 150.3, 145.7, 136.9, 132.5, 130.9, 129.4, 129.4, 124.9,
124.7, 123.4; IR (neat): νmax = 2922, 2851, 1660, 1530, 1432, 1349, 821, 702 cmꢀ1; HRMS
m/z (EI) calc. for C14H8BrN3O2 [M+] 328.9800, found 328.9798; Rf 0.54 (hexane/EtOAc,
4/1).
2ꢀ(
MHz, CDCl3) δ 9.44 (s, 1H), 8.52 (d,
(m, 2H), 7.58 (dd,
p
ꢀTolyl)quinazoline (3ab):6c offꢀwhite solid (50 mg, 76%, condition A); 1H NMR (600
J
= 8.2 Hz, 2H), 8.07 (d,
J = 8.5 Hz, 1H), 7.92 – 7.86
J
= 8.0, 6.9 Hz, 1H), 7.35 (d, J
= 8.2 Hz, 2H), 2.45 (s, 3H); 13C NMR (151
MHz, CDCl3) δ 161.4, 160.6, 151.0, 141.1, 135.6, 134.2, 129.6, 128.8, 128.7, 127.3, 127.2,
123.7, 21.7; IR (neat): νmax = 3016, 2919, 1611, 1586, 1550, 1486, 1399, 1377, 1174, 1056,
796, 726 cmꢀ1; Rf 0.43 (hexane/EtOAc, 9/1).
2ꢀ(4ꢀBromophenyl)quinazoline (3ac):6c white solid (56 mg, 66%, condition B); 1H NMR
(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.49 (d,
J = 8.6 Hz, 2H), 8.06 (dd, J = 7.8, 1.1 Hz, 1H),
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7.90 (dd,
J = 7.8, 7.2 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.61 (td, J
= 7.2, 1.1 Hz, 1H); 13C
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5
6
7
8
NMR (151 MHz, CDCl3) δ 160.7, 160.3, 150.9, 137.2, 134.5, 132.0, 130.4, 128.8, 127.7,
127.3, 125.6, 123.8; IR (neat): νmax = 3056, 1618, 1581, 1546, 1487, 1404, 906, 725 cmꢀ1; Rf
0.43 (hexane/EtOAc, 9/1).
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2ꢀ(4ꢀChlorophenyl)quinazoline (3ad):6c white solid (49 mg, 68%, condition B); 1H NMR
(600 MHz, CDCl3) δ 9.44 (s, 1H), 8.57 (d,
J
= 8.6 Hz, 2H), 8.06 (d,
J = 8.3 Hz, 1H), 7.92ꢀ
7.89 (m, 2H), 7.62 (dd,
J
= 8.2, 7.0 Hz, 1H), 7.49 (d, J
= 8.6 Hz, 2H); 13C NMR (151 MHz,
CDCl3) δ 160.7, 160.3, 150.9, 137.0, 136.7, 134.4, 130.1, 129.0, 128.8, 127.7, 127.4, 123.8;
IR (neat): νmax = 3056, 1620, 1585, 1550, 1490, 1408, 1291, 1085, 846, 796, 726 cmꢀ1; Rf
0.43 (hexane/EtOAc, 9/1).
2ꢀ(2ꢀChlorophenyl)quinazoline (3ae):6c pale yellow liquid (42 mg, 58%, condition B); 1H
NMR (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.13 (d,
J
= 8.4 Hz, 1H), 7.98 (dd,
J
J
= 7.8, 6.3 Hz,
= 8.1, 7.2 Hz,
1H), 7.96 (dd,
1H), 7.54 (dd,
J = 8.4, 7.8 Hz, 1H), 7.83 (dd, J = 6.6, 6.0 Hz, 1H), 7.70 (dd,
J
= 7.2, 6.3 Hz, 1H), 7.42 ꢀ 7.39 (m, 2H); 13C NMR (151 MHz, CDCl3)
δ
162.2, 160.4, 150.5, 138.5, 134.6, 133.1, 132.0, 130.7, 130.5, 128.8, 128.2, 127.3, 127.1,
123.5; IR (neat): νmax = 3059, 2924, 1619, 1553, 1486, 1399, 1033, 765, 731 cmꢀ1; Rf 0.31
(hexane/EtOAc, 4/1).
2ꢀ(4ꢀFluorophenyl)quinazoline (3af):12b white solid (48 mg, 71%, condition A); 1H NMR
(600 MHz, CDCl3) δ 9.41 (s, 1H), 8.63 ꢀ 8.60 (m, 2H), 8.05 (d,
J = 8.2 Hz, 1H), 7.88 (dd, J =
8.4, 7.2 Hz, 2H), 7.58 (dd,
J = 8.4, 7.2 Hz, 1H), 7.20 (dd, J
= 8.4, 7.2 Hz, 2H); 13C NMR
(151 MHz, CDCl3) δ 164.9 (d, 1JCꢀF = 250.7 Hz), 160.7, 160.3, 150.9, 134.40 (d, 4JCꢀF = 3.0
Hz), 134.35, 130.85 (d, 3JCꢀF = 8.6 Hz), 128.7, 127.43, 127.30, 123.7, 115.71 (d, 2JCꢀF = 21.7
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Hz); IR (neat): νmax = 3059, 2924, 1600, 1582, 1508, 1402, 1221, 1147, 800, 731 cmꢀ1; Rf
4
5
6
0.40 (hexane/EtOAc, 9/1).
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Analytic Data of 2ꢀphenylꢀ3,4ꢀdihydroquinazoline (3aa′)
2ꢀPhenylꢀ3,4ꢀdihydroquinazoline (3aa′):24 offꢀwhite solid (125 mg, 60%, 1 mmol scale); 1H
NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.43 (dd, J = 8.3, 6.8 Hz, 1H), 7.38 (dd,
J
= 8.3, 7.2 Hz, 2H), 7.18 (dd,
J = 7.9, 6.8 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.4
Hz, 1H), 6.92 (d,
J
= 7.4 Hz, 1H), 5.83 (s, 1H), 4.71 (s, 2H); 13C NMR (151 MHz, CDCl3)
δ
155.1, 141.7, 135.7, 130.6 128.7, 128.2, 126.6, 125.6, 124.5, 121.8, 120.4, 44.9.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: Additional experimental results (unsuccessful reactions and radical quenching
experiments) and copies of NMR spectra (1H NMR spectrum of KIE experiment, 1H and 13C
NMR spectra for all synthesized compounds).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ejcho@cau.ac.kr
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
This research was supported by the ChungꢀAng University Graduate Research Scholarship in
2017 for Dong In Kim. We gratefully acknowledge the National Research Foundation of
Korea [NRFꢀ2012M3A7B4049657, NRFꢀ2014ꢀ011165, NRFꢀ2016K1A3A1A19945930, and
NRFꢀ2017R1A2B2004082].
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