Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromoaldehydes, Benzylamines, and Sodium Azide for the Assembly of Quinazoline Derivatives

Article abstract of DOI:10.1021/acs.joc.5b02843

An efficient three-component domino reaction of 2-bromoaldehydes, benzylamines, and sodium azide has been developed for the synthesis of quinazoline derivatives. This domino process involves copper-catalyzed S_NAr, oxidation/cyclization, and denitrogenation sequences. The mild catalytic system enabled the effective construction of three C-N bonds in one operation.

Full text of DOI:10.1021/acs.joc.5b02843

Subscriber access provided by GAZI UNIV
Note
Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromoaldehydes,
Benzylamines and Sodium Azide for the Assembly of Quinazoline Derivatives
Cheng Xu, Feng-Cheng Jia, Zhi-Wen Zhou, Si-Jie Zheng, Han Li, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02843 • Publication Date (Web): 09 Mar 2016
Downloaded from http://pubs.acs.org on March 11, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Multicomponent Domino Reaction of
2-Bromoaldehydes, Benzylamines and Sodium Azide for the
Assembly of Quinazoline Derivatives
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cheng Xu, FengꢀCheng Jia, ZhiꢀWen Zhou, SiꢀJie Zheng, Han Li and AnꢀXin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China
Eꢀmail: chwuax@mail.ccnu.edu.cn.
TOC Graphic:
Abstract: An efficient threeꢀcomponent domino reaction of 2ꢀbromoaldehydes,
benzylamines and sodium azide has been developed for the synthesis of quinazoline
derivatives. This domino process involves copperꢀcatalyzed SNAr, oxidation/
cyclization and denitrogenation sequences. The mild catalytic system enabled the
effective construction of three C–N bonds in one operation.
In the past years, aryl azides have emerged as powerful synthons and exhibited
enormous potential in metalꢀcatalyzed Nꢀatom transfer reactions for the assembly of
nitrogenꢀcontaining frameworks.1 Since pioneering examples were demonstrated by
Driver to realize the construction of Nꢀheterocycles through intramolecular C–N or
N–N bond formation from orthoꢀsubstituted aryl azides,2 continued attention has been
focused on this fascinating research area. However, in most cases, these elaborative
designs implied a multistep process for the preparation of orthoꢀfunctionalized aryl
azides. To address this gap, copperꢀcatalyzed coupling3 of orthoꢀsubstituted
haloarenes with NaN3 was combined with subsequent intramolecular N–N or C–N
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
bond formation.4ꢀ7 For instance, in 2011, Lee’s group described a copperꢀcatalyzed
oneꢀpot threeꢀcomponent synthesis of 2Hꢀindazole via consecutive condensation,
C–N and N–N bond formations (Scheme 1a).4 Recently, Chen and coꢀworkers
developed a new strategy to form 2Hꢀbenzotriazoles via copperꢀcatalyzed C–N
coupling and intramolecular addition of nitrene to N=N bonds (Scheme 1b).5
Moreover, Ramana introduced a simple procedure for the synthesis of 2ꢀaroylindole
derivatives, which consisted of a oneꢀpot CuIꢀcatalyzed SNAr reaction of
oꢀbromochalcones with sodium azide and subsequent intramolecular cyclization
through nitrene C–H insertion (Scheme 1c).6 Despite these limited examples, the
strategy of using inꢀsitu generated aryl azides as key intermediates can still provide
new valuable transformations for the facile synthesis of other Nꢀcontaining
heterocycles.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthesis of Nꢀheterocycles via copperꢀcatalyzed domino reactions of
orthoꢀfunctionalized aryl halides and sodium azide
Quinazoline represents a fundamental and abundant class of nitrogenꢀcontaining
heterocycles. Many compounds that contain the quinazoline motif possess a wide
range of remarkable biological and medicinal activities including anticancer,8
antiviral,9 antitubercular,10 and antimalarial properties.11 The growing importance of
quinazoline and its derivatives is also highlighted by the huge sales of commercially
available drugs (e.g., Erlotinib,12 Prazosin,13 Iressa14). Because of their great value,
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
the synthesis of quinazolines has always attracted much attention.15ꢀ19 However,
traditional condensation/oxidation sequences generally required the assistance from
stoichiometric or large excess amounts of strong oxidants such as DDQ,16a NaClO16b
or MnO2,16c therefore limiting functional group tolerance of these procedures.
Although some improved methods for the synthesis of quinazolines have been
proposed,17ꢀ19 it is still highly desirable to search for a more convenient and efficient
approach. Sodium azide (NaN3) has been widely applied as a convenient nitrogen
source in various chemical transformations.4ꢀ7,20,21 As part of our ongoing efforts
towards the development of novel copperꢀcatalyzed domino reactions related to
sodium azide,21 herein we present another protocol for efficient synthesis of
quinazoline derivatives from commercially available 2ꢀbromobenzoaldehydes,
benzylamines and sodium azide under mild conditions. Notably, the C–N bond
formation, not the N–N bond formation,4 is followed by the copper catalyzed C–N
coupling (Scheme 1d).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our initial efforts were focused on the optimization of the reaction conditions by
using 2ꢀbromoꢀ5ꢀmethoxybenzaldehyde (1d), benzylamine (2a) and sodium azide as
model substrates. Delightfully, the desired product 6ꢀmethoxyꢀ2ꢀphenylquinazoline
(3d) was obtained in 42 % yield using 10 mol% CuI catalyst at 100 °C in DMSO for
15 h (Table1, entry 1). To further improve the yield, various reaction parameters such
as ligands, copper salts, solvents, and temperatures, were evaluated systematically.
The results are summarized in Table 1. A range of ligands such as DMEDA, TMEDA,
Lꢀproline, 1,10ꢀphenanthroline, transꢀ4ꢀOHꢀLꢀproline, and DLꢀpipecolic acid were
Table 1. Optimization of the reaction conditionsa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
9
entry
1
catalyst
CuI
ligand
ꢀ
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
temp (°C) yieldb (%)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
42
48
58
63
55
56
61
40
42
36
23
26
30
33
45
trace
trace
12
72
35
53
2
CuI
Lꢀ1
Lꢀ2
Lꢀ3
Lꢀ4
Lꢀ5
Lꢀ6
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
Lꢀ3
L-3
Lꢀ3
Lꢀ3
3
CuI
4
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
CuI
6
CuI
7
CuI
8
CuCl
CuBr
Cu2O
CuCl2
CuBr2
Cu(OAc)2
Cu(OTf)2
CuI
9
10
11
12
13
14
15
16
17
18
19
20
21
CuI
1,4ꢀdioxane
toluene
CH3CN
DMSO
DMSO
DMSO
CuI
CuI
CuI
CuI
120
60
CuI
aReactions conditions: 1d (0.5 mmol), 2a (0.5 mmol), NaN3 (1.0 mmol), catalyst (10 %) and ligand
(20 %) were heated in 3 mL solvent in a sealed vessel for 15 h. bIsolated yields.
firstly screened (Table 1, entries 2–7), and Lꢀproline showed the highest efficiency
(Table 1, entry 4). Then, various copper salts were evaluated (Table 1, entries 8–14),
and the results suggested that the use of CuI as a catalyst provided the optimum result.
This transformation was also performed with several other solvents (Table 1, entries
15–18), and DMSO proved to be the most compatible (compare entries 4 and 15–18).
An improvement of the yield was observed for decreasing temperature from 100 °C to
80 °C; subsequent increases or decreases in the temperature did not enhance the
outcome of the reaction any further (Table 1, entries 19–21). The Cu/L ratio for this
transformation was also investigated, reaction with CuI/Lꢀproline (1:2) gave the best
result (Supporting Information, Table S2). Eventually, the optimized reaction
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
conditions were determined as 1d (0.5 mmol), 1.0 equiv of 2a, 2.0 equiv of sodium
azide, 10 mmol% of CuI, and 20 mmol% of Lꢀproline in 3 mL of DMSO at 80 °C in a
sealed vessel under air.
9
Table 2. Scope of 2ꢀbromoaldehydes a,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
R1
NH2
N
O
CuI, L-proline
DMSO, 80 o
NaN3
C
Br
N
2a
1
3
Me
N
N
N
N
3a 62%
N
Me
N
3c 63%
3b 65%
MeO
MeO
MeO
O
O
N
N
N
N
N
N
3d 72%
3e 78%
3f 81%
F
Cl
N
N
N
N
N
Cl
N
3g 42%
3h 48%
3i 36%
S
N
N
N
N
N
N
N
N
N
F
Cl
3l 60%
3m 41%
3j 55%
3k 58%
aReaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), NaN3 (1.0 mmol), CuI (0.05 mmol) and Lꢀproline
(0.1 mmol) in DMSO (3 mL) at 80 °C in a sealed vessel for 15 h; bIsolated yields.
Having identified the optimized reaction conditions, the substrate scope of this
copperꢀcatalyzed process was explored with a range of different 2ꢀbromoaldehydes
(Table 2). To our delight, 2ꢀbromoaldehydes bearing both electronically neutral (4ꢀH,
5ꢀMe, 4ꢀMe) and electronꢀdonating (5ꢀOMe, 4,5ꢀ(OMe)2, 4,5ꢀOCH2O) substituents
proceeded smoothly to afford the corresponding products in moderate to good yields
(Table 2, 62–81%, 3a–3f). Gratifyingly, haloꢀsubstituted aldehydes were also
successfully converted into the corresponding products (Table 2, 36–58%, 3g–3k),
therefore providing the possibility for further derivatization. This method was further
extended
to
several
representative
heteroaryl
aldehydes
such
as
2ꢀbromonicotinaldehyde and 3ꢀbromothiopheneꢀ2ꢀcarbaldehyde. Much to our
satisfaction, the optimized conditions were mild enough for the conversion to these
new medicinally relevant molecules that may possess distinct biological activity
(Table 2, 41–60%, 3l–3m).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
Table 3. Scope of benzylaminesa,b
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), NaN3 (1.0 mmol), CuI (0.05 mmol) and Lꢀproline
(0.1 mmol) in DMSO (3 mL) at 80 °C in a sealed vessel for 15 h; bIsolated yields.
Inspired by these results, we further extended the scope of this reaction to various
benzylamines. It was noticed that the electronic properties of benzylamines had a
significant influence on the reaction efficiency. For example, benzylamines with
electronically neutral (4ꢀMe, 2ꢀMe) and electronꢀdonating (4ꢀOMe, 3ꢀOMe, 4ꢀOH)
groups attached to the aryl ring gave good yields (Table 3, 60–82%, 3n–3r). However,
when electronꢀdeficient substrates were used, the reactivity was largely decreased to
deliver the desired products in lower yields (Table 3, 38–48%, 3s–3v). In addition,
naphthalenꢀ1ꢀylmethanamine and [1,1'ꢀbiphenyl]ꢀ4ꢀylmethanamine only proceeded to
the products in moderate yields, which might be owing to steric effects (Table 3,
42–51%, 3w–3x). Heteroaryl substrate such as pyridinꢀ3ꢀylmethanamine also
proceeded in good yield (Table 3, 75%, 3y). Furthermore, the structure of 3u was
unambiguously determined by Xꢀray crystallographic analysis (see Supporting
Information).
With the scope of the method established, we then turned our attention to
evaluate the reaction mechanism. It’s noticed that the yield of product
2ꢀphenylquinazoline (3a) decreased significantly when the reaction was performed
under an argon atmosphere, thus suggesting that oxygen is essential for this
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cuꢀcatalyzed multicomponent reaction (Scheme 2a). When treatment of the
presynthesized (E)ꢀNꢀbenzylꢀ1ꢀ(2ꢀbromophenyl)methanimine (4)22 with sodium azide
(2.0 equiv.) under the standard conditions for 15 h, 2ꢀphenylquinazoline (3a) was
obtained in 68 % yield (Scheme 2b). This result showed that 4 may be an intermediate
in this transformation. Considering that the orthoꢀhalogenated substrates may
transform to the corresponding aryl azides through a copperꢀcatalyzed SNAr sequence,
2ꢀazidobenzaldehyde (5) was applied to gain insight into the subsequent
denitrogenation process. In the following experiments, 2ꢀazidobenzaldehyde (5),
benzylamine (2a) together with 2.0 equiv. of sodium azide were reacted under the
optimal conditions, the desired product (3a) was generated in 72 % yield. In contrast,
only a trace amount of 3a was observed in the absence of CuI (Scheme 2c). The
results indirectly indicated that the catalytic amount of CuI may act as dual role in
both the SNAr process and subsequent intramolecular CꢀN bond formation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Mechanistic Studies
Although the mechanistic details are not completely clear at this stage, on the
basis of our experimental observations and previous literature reports,2,3,23 a tentative
mechanism for the copperꢀcatalyzed domino sequence was proposed by using
2ꢀbromobenzaldehyde (1a), benzylamine (2a) and sodium azide as an example
(Scheme 3). Initially, 2ꢀbromobenzaldehyde (1a) condensed with benzylamine (2a) to
generate the resultant Schiff base 4 in situ. Subsequently, copperꢀcatalyzed SNAr of
Schiff base 4 with NaN3 proceeded to give the azido intermediate A. In the presence
of Cu/O2, A could be further oxidated to ion intermediate B,23 which would undergo
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
7
8
9
intramolecular cyclization via nucleophilic attack by the pendant azide to furnish the
C–N bond formation.2d,7c After extrusion of N2 and proton elimination of C, the
desired product 2ꢀphenylquinazoline (3a) was finally obtained. A concerted procedure
is also taken into consideration, whereby the cyclization of complex D directly
converted to C without the formation of azido intermediate A. However, in view of
the earlier works of Driver where the intramolecular CꢀN bonding may involve a
nitreneꢀmediated sp3 CꢀH insertion,2aꢀc an analogous reaction pathway cannot be
overlooked for this Cuꢀcatalyzed quinazoline synthesis (Supporting Information,
Scheme S1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. A possible mechanism
Conclusion
In summary, we have developed an efficient and practical Cuꢀcatalyzed domino
protocol for the synthesis of quinazoline derivatives from simple and readily available
2ꢀbromoaldehydes, benzylamines and sodium azide under mild conditions. CuI was
used as a tandem catalyst to trigger the SNAr and to promote the subsequent
denitrogenation/cyclization sequences. Further studies on the development of new
domino reactions related to NaN3 for the construction of other fascinating
Nꢀheterocycles are underway in our laboratory.
Experimental Section
General Methods.
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Unless otherwise stated, all starting materials and catalysts were obtained from
commercial suppliers and used without further purification. All new compounds were
fully characterized. TLC analysis was performed using precoated glass plates.
Column chromatography was performed using silica gel (200–300 mesh). IR spectra
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
were recorded as KBr pellets with absorption in cm–1. H spectra were recorded in
CDCl3 on 600 MHz spectrometers and resonances (δ) are given in ppm relative to
TMS (internal standard). 13C spectra were recorded in CDCl3 or DMSOꢀd6 on
100/150 MHz NMR spectrometers. HRMS were obtained on a 7.0T FTMS equipped
with ESI. Melting points were determined using an electrothermal capillary melting
point apparatus and not corrected.
General Procedures for the Synthesis of the Products 3 (3a as an example)
A sealed tube was charged with 2ꢀbromobenzaldehyde 1a (92.5 mg, 0.50 mmol),
benzylamine 2a (53.5 mg, 0.50 mmol), NaN3 (65.0 mg, 1.0 mmol), CuI (9.5 mg, 0.05
mmol) and Lꢀproline (11.5 mg, 0.10 mmol) at room temperature, and then solvent
DMSO (3 mL) was added. The resulting mixture was stirred at 80 °C for 15 hours,
after disappearance of the reactant (monitored by TLC), then added 50 mL water to
the mixture, extracted with EtOAc 3 times (3 × 50 mL). The extract was washed with
30% NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel
(PEꢀEtOAc, 5:1) to yield the desired products 3a.
Experimental Procedure for Preparation of 4
(E)ꢀNꢀbenzylꢀ1ꢀ(2ꢀbromophenyl)methanimine (4) was prepared according to the
related literature.22 The mixture of (2ꢀbromophenyl)methanol (412 mg, 2.2 mmol),
benzylamine (214 mg, 2 mmol), CuI (3.8 mg, 0.02 mmol, 1 mol%), 2,2’ꢀBipy (3.1 mg,
0.02 mmol, 1 mol%), TEMPO (6.3 mg, 0.04 mmol, 2 mol%) was stirred in open air at
room temperature (ca. 25ꢀ30 °C) and monitored by TLC. The reaction mixture was
then directly purified (without any workup) by column chromatography on neutral
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
alumina gel (petroleum ether/ethyl acetate/triethylamine 100:10:1) to afford 4 in 90 %
5
6
isolated yield.
7
8
9
Analytical Data for Products 3 and 4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Phenylquinazoline (3a).17a Yellow solid; 63.9 mg (yield 62%); IR (KBr): 3060,
2924, 1613, 1583, 1548, 1480, 1397, 1206, 1020 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ
9.48 (s, 1H), 8.62 (d, J = 7.2 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.94ꢀ7.89 (m, 2H),
7.62 (t, J = 7.8 Hz, 1H), 7.56ꢀ7.50 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0,
160.5, 150.7, 137.9, 134.1, 130.6, 128.59, 128.56, 128.52, 127.2, 127.1, 123.5;
HRMS (ESI): m/z [M + H]+ calcd for C14H11N2: 207.0917; found: 207.0918.
6-Methyl-2-phenylquinazoline (3b).17c Yellow solid; 71.6 mg (yield 65%); IR
1
(KBr): 3060, 2918, 1555, 1490, 1422, 1371, 1163, 1015 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 9.36 (s, 1H), 8.59 (d, J = 7.2 Hz, 2H), 7.97(d, J = 8.4 Hz, 1H), 7.71(d, J =
8.4 Hz, 1H), 7.65 (s, 1H), 7.55ꢀ7.49 (m, 3H) , 2.54 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 160.3, 159.7, 149.3, 138.1, 137.4, 136.4, 130.4, 128.6, 128.4, 128.2, 125.8,
123.5, 21.6; HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found:
221.1074.
7-Methyl-2-phenylquinazoline (3c).19a White solid; 69.4 mg (yield 63%); IR (KBr):
2922, 1622, 1547, 1489, 1453, 1379, 1243, 1052 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ
9.38 (s, 1H), 8.60 (d, J = 7.2 Hz, 2H), 7.86 (s, 1H), 7.79(d, J = 8.4 Hz, 1H), 7.55ꢀ7.48
(m, 3H), 7.42 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0,
159.8, 151.0, 145.2, 138.1, 130.5, 129.5, 128.6, 128.5, 127.5, 126.7, 121.8, 22.3;
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found: 221.1074.
6-Methoxy-2-phenylquinazoline (3d).18b Yellow solid; 85.1 mg (yield 72%); IR
1
(KBr): 2921, 1691, 1556, 1490, 1349, 1221, 1163, 1024 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 9.34 (s, 1H), 8.57 (d, J = 7.2 Hz, 2H), 7.98 (d, J = 9.0 Hz, 1H), 7.52 (t, J =
7.8 Hz, 3H), 7.48 (t, J = 7.2 Hz, 1H), 7.12 (s, 1H) , 3.94 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 159.3, 158.7, 158.1, 146.9, 138.1, 130.1, 130.0, 128.6, 128.1, 127.1, 124.4,
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
103.8, 55.7; HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O: 237.1022; found:
237.1024.
3
4
5
6
7
8
9
6,7-Dimethoxy-2-phenylquinazoline (3e).18a White solid; 103.9 mg (yield 78%); IR
1
(KBr): 2921, 1619, 1581, 1498, 1452, 1407, 1343, 1229, 1155, 1004 cmꢀ1; H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(600 MHz, CDCl3) δ 9.22 (s, 1H), 8.54 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 7.2 Hz, 2H),
7.48 (t, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.10 (s, 1H) , 4.08 (s, 3H), 4.03 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 159.8, 157.0, 156.1, 150.3, 148.5, 138.2, 130.1, 128.5,
128.1, 119.3, 106.8, 103.9, 56.4, 56.2; HRMS (ESI): m/z [M + H]+ calcd for
C16H15N2O2: 267.1128; found: 267.1130.
6-Phenyl-[1,3]dioxolo[4,5-g]quinazoline (3f).18b White solid; 101.4 mg (yield 81%);
IR (KBr): 3048, 2920, 1612, 1565, 1455, 1337, 1219, 1042 cmꢀ1; 1H NMR (600 MHz,
CDCl3) δ 9.14 (s, 1H), 8.53 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.47 (t, J =
7.2 Hz, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.11 (s, 2H); 13C NMR (150 MHz, CDCl3) δ
159.9, 157.3, 154.1, 150.2, 148.2, 138.0, 130.2, 128.5, 128.1, 120.6, 104.9, 102.1,
101.8; HRMS (ESI): m/z [M + H]+ calcd for C15H11N2O2: 251.0815; found: 251.0817.
6-Fluoro-2-phenylquinazoline (3g).18b Yellow solid; 47.1 mg (yield 42%); IR (KBr):
1
3068, 1626, 1591, 1555, 1488, 1434, 1378, 1349, 1209, 1143, 1019 cmꢀ1; H NMR
(600 MHz, CDCl3) δ 9.42 (s, 1H), 8.59 (d, J = 7.2 Hz, 2H), 8.11ꢀ8.08 (m, 1H), 7.66 (t,
J = 9.0 Hz, 1H), 7.55ꢀ7.51 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 161.2, 160.6,
159.8, 159.5, 147.9, 137.6, 131.4, 130.7, 128.7, 128.4, 124.6, 124.4, 123.8, 110.2,
110.1; HRMS (ESI): m/z [M + H]+ calcd for C14H10FN2: 225.0823; found: 225.0824.
6-Chloro-2-phenylquinazoline (3h).17c White solid; 57.8 mg (yield 48%); IR (KBr):
1
2922, 1573, 1547, 1475, 1428, 1383, 1342, 1275, 1179, 1076 cmꢀ1; H NMR (600
MHz, CDCl3) δ 9.36 (s, 1H), 8.58 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.86
(s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.54ꢀ7.50 (m, 3H); 13C NMR (150 MHz, CDCl3) δ
161.2, 159.4, 149.1, 137.5, 135.0, 132.7, 130.8, 130.3, 128.7, 128.5, 125.8, 123.9;
HRMS (ESI): m/z [M + H]+ calcd for C14H10ClN2: 241.0527; found: 241.0529.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
7
8
9
7-Chloro-2-phenylquinazoline (3i). White solid; 43.3 mg (yield 36%); mp
142ꢀ144 °C; IR (KBr): 3451, 2923, 1660, 1610, 1541, 1474, 1450, 1397, 1328, 1276,
1236, 1186, 1069, 1020 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 9.38 (s, 1H), 8.58 (d, J =
6.6 Hz, 2H), 8.05 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.53ꢀ7.50 (m, 4H); 13C NMR (150
MHz, CDCl3) δ 161.7, 160.1, 151.2, 140.3, 137.5, 130.9, 128.6, 128.3, 127.7, 121.8;
HRMS (ESI): m/z [M + H]+ calcd for C14H10ClN2: 241.0527; found: 241.0529.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8-Fluoro-2-phenylquinazoline (3j). White solid; 61.7 mg (yield 55%); mp
137ꢀ139 °C; IR (KBr): 3066, 1626, 1560, 1442, 1407, 1379, 1302, 1245, 1081, 1022
cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 8.64 (d, J = 6.0 Hz, 2H), 7.66 (d, J
= 8.4 Hz, 1H), 7.56ꢀ7.46 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 161.0, 160.1, 158.0,
156.3, 141.1, 141.0, 137.4, 130.9, 128.7, 128.6, 126.92, 126.87, 124.7, 122.70, 122.67,
118.1, 118.0; HRMS (ESI): m/z [M + H]+ calcd for C14H10FN2: 225.0823; found:
225.0825.
8-Chloro-2-phenylquinazoline (3k). Yellow solid; 69.8 mg (yield 58%); mp
111ꢀ113 °C; IR (KBr): 3022, 1609, 1573, 1544, 1464, 1402, 1321, 1205, 1166, 1067,
1020 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 9.42 (s, 1H), 8.68 (d, J = 6.6 Hz, 2H), 7.95
(d, J = 7.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.56ꢀ7.50 (m, 3H), 7.47 (t, J = 7.8 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 161.4, 160.7, 147.2, 137.5, 133.8, 133.1, 131.0,
128.8, 128.6, 127.0, 125.9, 124.5; HRMS (ESI): m/z [M + H]+ calcd for C14H10ClN2:
241.0527; found: 241.0534.
2-Phenylpyrido[2,3-d]pyrimidine (3l). Yellow solid; 62.2 mg (yield 60%); mp
201ꢀ203 °C; IR (KBr): 3080, 1603, 1593, 1582, 1545, 1460, 1366, 1358, 1312, 1155,
1
1020 cmꢀ1; H NMR (600 MHz, CDCl3) δ 9.50 (s, 1H), 9.25 (s, 1H), 8.74ꢀ8.72 (m,
2H), 8.28 (d, J = 8.4 Hz, 1H), 7.55ꢀ7.52 (m, 4H); 13C NMR (150 MHz, CDCl3) δ
164.3, 161.8, 158.6, 158.1, 136.9, 136.2, 131.4, 129.1, 128.5, 122.7, 118.0; HRMS
(ESI): m/z [M + Na]+ calcd for C13H9N3Na: 230.0689; found: 230.0690.
2-Phenylthieno[3,2-d]pyrimidine (3m). Yellow solid; 43.5 mg (yield 41%); mp
118ꢀ120 °C; IR (KBr): 3090, 1561, 1543, 1521, 1511, 1387, 1298, 1275, 1240, 1105,
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
1046 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 9.33 (s, 1H), 8.54ꢀ8.52 (m, 2H), 8.00 (d, J
= 5.4 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.54ꢀ7.47 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 161.5, 160.9, 151.7, 137.9, 136.5, 130.3, 129.0, 128.6, 128.2, 124.6; HRMS
(ESI): m/z [M + H]+ calcd for C12H9N2S: 213.0481; found: 213.0483.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(p-Tolyl)quinazoline (3n).17a Yellow solid; 79.3 mg (yield 72%); IR (KBr): 2919,
1
1613, 1584, 1549, 1484, 1401, 1169, 1013 cmꢀ1; H NMR (600 MHz, CDCl3) δ 9.41
(s, 1H), 8.51 (d, J = 7.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.8 Hz, 2H),
7.54 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.0, 160.4, 150.7, 140.8, 135.3, 133.9, 129.3, 128.48, 128.47, 127.0,
126.9, 123.4, 21.5; HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found:
221.1074.
2-(o-Tolyl)quinazoline (3o).18a Yellow solid; 66.1 mg (yield 60%); IR (KBr): 3065,
1
2922, 1619, 1551, 1483, 1446, 1378, 1289, 1140, 1035 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 9.48 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.93ꢀ7.89 (m, 3H), 7.64ꢀ7.61 (m, 1H),
7.38ꢀ7.32 (m, 3H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 159.9, 150.2,
138.4, 137.2, 133.9, 131.1, 130.5, 129.1, 128.3, 127.3, 126.9, 125.8, 122.7, 21.0;
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found: 221.1073.
2-(4-Methoxyphenyl)quinazoline (3p).17a White solid; 92.2 mg (yield 78%); IR
1
(KBr): 2914, 2834, 1609, 1586, 1548, 1399, 1248, 1163, 1026 cmꢀ1; H NMR (600
MHz, CDCl3) δ 9.40 (s, 1H), 8.58 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 8.4 Hz, 1H), 7.86
(t, J = 8.4 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.7, 160.7, 160.2, 150.7, 133.9, 130.6, 130.1, 128.2,
127.0, 126.6, 123.2, 113.8, 55.2; HRMS (ESI): m/z [M + H]+ calcd for C15H13N2O:
237.1022; found: 237.1023.
2-(3-Methoxyphenyl)quinazoline (3q).18a White solid; 86.2 mg (yield 73%); IR
1
(KBr): 3001, 2953, 2829, 1615, 1548, 1487, 1395, 1339, 1227, 1037 cmꢀ1; H NMR
(600 MHz, CDCl3) δ 9.43 (s, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.19 (s, 1H), 8.07 (d, J =
8.4 Hz, 1H), 7.87 (t, J = 7.8 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
7.06 (d, J = 7.8 Hz, 1H), 3.94 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.7, 160.3,
159.9, 150.6, 139.4, 134.0, 129.6, 128.5, 127.2, 127.0, 123.5, 121.1, 117.2, 112.9,
55.4; HRMS (ESI): m/z [M + Na]+ calcd for C15H12N2NaO: 259.0842; found:
259.0859.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(Quinazolin-2-yl)phenol (3r).16c Yellow solid; 91.1 mg (yield 82%); IR (KBr):
1
3066, 2800, 2676, 1608, 1577, 1407, 1340, 1237, 1166, 1054 cmꢀ1; H NMR (600
MHz, CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.36 (d, J = 7.8
Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 6.24 (t, J = 7.8 Hz, 1H), 5.92 (t, J = 7.8 Hz, 1H),
5.32 (d, J = 9.0 Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 160.9, 160.2, 160.0,
150.0, 134.4, 130.1, 128.5, 127.62, 127.60, 126.8, 122.9, 115.5; HRMS (ESI): m/z [M
+ H]+ calcd for C14H11N2O: 223.0866; found: 223.0867.
2-(4-Fluorophenyl)quinazoline (3s).17a Yellow solid; 52.7 mg (yield 47%); IR
1
(KBr): 3052, 1600, 1508, 1405, 1340, 1220, 1145, 1007 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 9.38 (s, 1H), 8.60 (t, J = 6.6 Hz, 2H), 8.02 (d, J = 9.0 Hz, 1H), 7.86 (t, J =
13
7.2 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 2H); C NMR (100 MHz,
CDCl3) δ 165.8, 163.4, 160.4, 160.0, 150.6, 134.1, 130.7, 130.6, 128.4, 127.2, 127.0,
123.4, 115.5, 115.3; HRMS (ESI): m/z [M + H]+ calcd for C14H10FN2: 225.0823;
found: 225.0823.
2-(4-Chlorophenyl)quinazoline (3t).17a White solid; 45.7 mg (yield 38%); IR (KBr):
1
3053, 1618, 1582, 1548, 1487, 1404, 1289, 1082, 1007 cmꢀ1; H NMR (600 MHz,
CDCl3) δ 9.41 (s, 1H), 8.55 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 9.0 Hz, 1H), 7.89 (t, J =
7.2 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.3, 159.7, 150.4, 136.6, 136.3, 134.0, 129.7, 128.6, 128.4, 127.2, 126.9,
123.4; HRMS (ESI): m/z [M + H]+ calcd for C14H10ClN2: 241.0527; found: 241.0529.
2-(4-Bromophenyl)quinazoline (3u).17c White solid; 64.1 mg (yield 45%); IR (KBr):
1
3054, 2924, 1616, 1579, 1546, 1485, 1402, 1288, 1062, 1003 cmꢀ1; H NMR (600
MHz, CDCl3) δ 9.41 (s, 1H), 8.48 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz, 1H),
7.90ꢀ7.87 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H); 13C NMR (100
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 160.3, 159.8, 150.4, 136.8, 134.0, 131.6, 130.0, 128.4, 127.3, 127.0,
125.2, 123.4; HRMS (ESI): m/z [M + H]+ calcd for C14H10BrN2: 285.0022; found:
285.0024.
9
2-(3-Chlorophenyl)quinazoline (3v).17a White solid; 57.8 mg (yield 48%); IR (KBr):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2923, 1617, 1584, 1549, 1455, 1402, 1339, 1241, 1143, 1057 cmꢀ1; H NMR (600
MHz, CDCl3) δ 9.46 (s, 1H), 8.63 (s, 1H), 8.51 (d, J = 6.6 Hz, 1H), 8.09 (d, J = 8.4
Hz, 1H), 7.95ꢀ7.91 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.2 Hz, 2H); 13C
NMR (150 MHz, CDCl3) δ 160.6, 160.5, 159.6, 150.6, 139.7, 134.7, 134.4, 130.6,
129.8, 128.6, 127.7, 127.2, 126.6, 123.7; HRMS (ESI): m/z [M + H]+ calcd for
C14H10ClN2: 241.0527; found: 241.0529.
2-(Naphthalen-1-yl)quinazoline (3w).16b White solid; 53.8 mg (yield 42%); IR
1
(KBr): 3047, 1618, 1550, 1480, 1379, 1287, 1242, 1186, 1016 cmꢀ1; H NMR (600
MHz, CDCl3) δ 9.54 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.15
(d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.93ꢀ7.88 (m, 3H), 7.63ꢀ7.59 (m, 2H),
13
7.56ꢀ7.49 (m, 2H); C NMR (100 MHz, CDCl3) δ 163.3, 160.3, 150.4, 136.2, 134.2,
134.1, 131.1, 130.3, 129.6, 128.5, 128.4, 127.6, 127.0, 126.7, 125.9, 125.8, 125.2,
123.0; HRMS (ESI): m/z [M + H]+ calcd for C18H13N2: 257.1073; found: 257.1074.
2-([1,1'-Biphenyl]-4-yl)quinazoline (3x).19b White solid; 72.0 mg (yield 51%); IR
(KBr): 3030, 1615, 1581, 1545, 1484, 1407, 1342, 1287, 1177, 1064 cmꢀ1; H NMR
1
(600 MHz, CDCl3) δ 9.46 (s, 1H), 8.71ꢀ8.68 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.89 (t,
J = 7.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 7.8 Hz, 2H), 7.62ꢀ7.57 (m, 1H),
7.48 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
160.6, 160.3, 150.7, 143.1, 140.5, 136.9, 134.0, 128.97, 128.95, 128.7, 128.5, 127.6,
127.2, 127.1, 127.0, 123.5; HRMS (ESI): m/z [M + H]+ calcd for C20H15N2:
283.1230; found: 283.1232.
2-(Pyridin-3-yl)quinazoline (3y).17a Yellow solid; 77.7 mg (yield 75%); IR (KBr):
3050, 1618, 1583, 1550, 1487, 1400, 1380, 1291, 1242, 1068, 1022 cmꢀ1; H NMR
1
(600 MHz, CDCl3) δ 9.81 (s, 1H), 9.45 (s, 1H), 8.85 (d, J = 7.8 Hz, 1H), 8.74 (s, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
7
8
9
8.08 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.8 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.46ꢀ7.43
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 160.5, 159.0, 151.1, 150.5, 150.2, 135.7,
134.3, 133.4, 128.5, 127.7, 127.1, 123.7, 123.3; HRMS (ESI): m/z [M + Na]+ calcd
for C13H9N3Na: 230.0689; found: 230.0698.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-N-benzyl-1-(2-bromophenyl)methanimine (4). Yellow liquid; 493 mg (yield
90%); IR (KBr): 3457, 3062, 3028, 2887, 1696, 1635, 1587, 1564, 1494, 1435, 1374,
1341, 1270, 1213, 1158, 1116, 1025 cmꢀ1; 1H NMR (600 MHz, CDCl3) δ 8.75 (s, 1H),
8.06 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.34ꢀ7.31 (m, 4H), 7.29 (t, J = 7.8
Hz, 1H), 7.27ꢀ7.24 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 4.84 (s, 2H); 13C NMR (150
MHz, CDCl3) δ 160.8, 138.9, 134.3, 132.9, 131.8, 128.8, 128.4, 127.9, 127.5, 127.0,
125.0, 65.0; HRMS (ESI): m/z [M + H]+ calcd for C14H13BrN: 274.0226; found:
274.0229.
ASSOCIATED CONTENT
Supporting Information
1
Crystallographic data and copies of the H and 13C NMR spectra are involved. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: chwuax@mail.ccnu.edu.cn.
Author Contributions
§C.X. and F.ꢀC.J. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
We are grateful to the National Natural Science Foundation of China (Grant
21272085 and 21472056) and excellent doctorial dissertation cultivation grant from
Central China Normal University (2015YBYB094 and 2015YBZD015) for financial
support.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) For selected reviews, see: (a) Driver, T. G. Org. Biomol. Chem. 2010, 8,
3831–3846. (b) Katsuki, T. Chem. Lett. 2005, 34, 1304ꢀ1309. (c) Collet, F.; Dodd, R.
H.; Dauban, P. Chem. Commun. 2009, 5061–5074. (d) Cenini, S.; Gallo, E.; Caselli,
A.; Ragaini, F.; Fantauzzi, S.; Piangiolino, C. Coord. Chem. Rev. 2006, 250,
1234–1253.
(2) For selected pioneering work of Driver, see: (a) Nguyen, Q.; Sun, K.; Driver T. G.
J. Am. Chem. Soc. 2012, 134, 7262ꢀ7265. (b) Nguyen, Q.; Nguyen, T.; Driver T. G. J.
Am. Chem. Soc. 2013, 135, 620ꢀ623. (c) Sun, K.; Sachwani, R.; Richert, K. J.; Driver,
T. G. Org. Lett. 2009, 11, 3598ꢀ3601. (d) Shen, M.; Driver, T. G. Org. Lett. 2008, 10,
3367ꢀ3370. (e) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133,
4702ꢀ4705. (f) Pumphrey, A. L.; Dong, H.; Driver, T. G. Angew. Chem., Int. Ed.
2012, 51, 5920ꢀ5923.
(3) (a) Zhu, W.; Ma, D. Chem. Commun. 2004, 888ꢀ889. (b) Andersen, J.; Madsen,
U.; Björkling, F.; Liang, X. Synlett. 2005, 14, 2209ꢀ2213.
(4) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett. 2011, 13, 3542–3545.
(5) Shang, X.; Zhao, S.; Chen, W.; Chen, C.; Qiu, H. Chem.–Eur. J. 2014, 20,
1825–1828.
(6) Goriya, Y.; Ramana, C. V. Chem. Commun. 2014, 50, 7790–7792.
(7) For other selected papers on synthesis of Nꢀheterocycles from
orthoꢀfunctionalized aryl halides and sodium azide, see: (a) Ou, Y.; Jiao, N. Chem.
Commun. 2013, 49, 3473–3475. (b) Goriya, Y.; Ramana, C. V. Chem. Commun.
2013, 49, 6376–6378. (c) Kim, Y.; Kumar, M. R.; Park, N.; Heo, Y.; Lee, S. J. Org.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
6
Chem. 2011, 76, 9577–9583. (d) Khatun, N.; Gogoi, A.; Basu, P.; Das, P.; Patel, B. K.
RSC Adv. 2014, 4, 4080–4084.
7
8
9
(8) (a) Juvale, K.; Gallus, J.; Wiese, M. Bioorg. Med. Chem. 2013, 21, 7858ꢀ7873. (b)
Foster, B. A.; Coffey, H. A.; Mornin, M. J.; Rastinejad, F. Science 1999, 286,
2507ꢀ2510.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Chien, T. C.; Chen, C. S.; Yu, F. H.; Chern, J. W. Chem. Pharm. Bull. 2004,
52, 1422ꢀ1426. (b) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.; Stamminger,
T.; Marschall, M. Antimicrob. Agents Chemother. 2004, 48, 4154ꢀ4162.
(10) (a) Kunes, J.; Bazant, J.; Pour, M.; Waisser, K.; Slosarek, M.; Janota, J. Farmaco
2000, 55, 725ꢀ729. (b) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.;
Klimesova, V.; Kaustova, J. Farmaco 2001, 56, 803ꢀ807.
(11) (a) Madapa, S.; Tusi, Z.; Mishra, A.; Srivastava, K.; Pandey, S. K.; Tripathi, R.;
Puri, S. K.; Batra, S. Bioorg. Med. Chem. 2009, 17, 222ꢀ234. (b) Ashton, W. T.; Hynes,
J. B. J. Med. Chem. 1973, 16, 1233ꢀ1237.
(12) Gundla, R.; Kazemi, R.; Sanam, R.; Muttineni, R.; Sarma, J. A. R. P.; Dayam, R.;
Neamati, N. J. Med. Chem. 2008, 51, 3367–3377.
(13) Mendes da Silva, J. F.; Walters, M.; AlꢀDamluji, S.; Ganellin, C. R. Bioorg. Med.
Chem. 2008, 16, 7254–7263.
(14) Luth, A.; Lowe, W. Eur. J. Med. Chem. 2008, 43, 1478–1488.
(15) For selected reviews on quinazoline syntheses, see: (a) Witt, A.; Bergman, J. Curr.
Org. Chem. 2003, 7, 659ꢀ677. (b) Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry,
P. J. Tetrahedron 2005, 61, 10153ꢀ10202.
(16) (a) Vanden Eynde, J. J.; Godin, J.; Mayence, A.; Maquestiau, A.; Anders, E.
Synthesis 1993, 867ꢀ869. (b) Maheswari, C. U.; Kumar, G. S.; Venkateshwar, M.;
Kumar, R. A.; Kantam, M. L.; Reddy, K. R. Adv. Synth. Catal. 2010, 352, 341ꢀ346. (c)
Peng, Y.; Zeng, Y.; Qiu, G.; Cai, L.; Pike, V. W. J. Heterocycl. Chem. 2010, 47,
1240ꢀ1245.
ACS Paragon Plus Environment

Page 19 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(17) (a) Han, B.; Yang, X. L.; Wang, C.; Bai, Y. W.; Pan, T. C.; Chen, X.; Yu, W. J.
Org. Chem. 2012, 77, 1136ꢀ1142. (b) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z.
Angew. Chem., Int. Ed. 2012, 51, 8077ꢀ8081. (c) Chen, M.; Zhang, M.; Xiong, B.; Tan,
Z.; Lv, W.; Jiang, H. Org. Lett. 2014, 16, 6028ꢀ6031.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) (a) Truong, V. L.; Morrow, M. Tetrahedron Lett. 2010, 51, 758−760. (b) Malakar,
C. C.; Baskakova, A.; Conrad, J.; Beifuss, U. Chem.– Eur. J. 2012, 18, 8882ꢀ8885.
(19) (a) Omar, M. A.; Conrad, J.; Beifuss, U. Tetrahedron 2014, 70, 3061ꢀ3072. (b)
Yamaguchi, K.; Noda, T.; Higuchi, Y.; Aoki, N.; Yamaguchi, R.; Kubo, M.; Harada,
K., Fukuyama, Y.; Hioki, H. Tetrahedron Lett. 2014, 55, 5793−5797.
(20) For other representive papers related to sodium azide, see: (a) Quan, X. J.; Ren, Z.
H.; Wang, Y. Y.; Guan, Z. H. Org. Lett. 2014, 16, 5728−5731. (b) Li, J.; Wang, D.;
Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009, 11, 3024−3027. (c) Cantillo, D.; Gutmann,
B.; Kappe, C. O. J. Am. Chem. Soc. 2011, 133, 4465ꢀ4475. (d) Arigela, R. K.; Samala,
S.; Mahar, R.; Shukla, S. K.; Kundu, B. J. Org. Chem. 2013, 78, 10476−10484. (e)
Yan, J.; Zhou, F.; Qin, D.; Cai, T.; Ding, K.; Cai, Q. Org. Lett. 2012, 14, 1262−1265.
(f) Percherla, K.; Jha, A.; Khungar, B.; Kumar, A. Org. Lett. 2013, 15, 4304−4307. (g)
Liu, Z.; Zhu, D.; Luo, B.; Zhang, N.; Liu, Q.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Org.
Lett. 2014, 16, 5600−5603.
(21) (a) Jia, F. C.; Xu, C.; Zhou, Z. W.; Cai, Q.; Li, D. K.; Wu, A. X. Org. Lett. 2015,
17, 2820−2823. (b) Jia, F. C.; Zhou, Z. W.; Xu, C.; Cai, Q.; Li, D. K.; Wu, A. X. Org.
Lett. 2015, 17, 4236−4239.
(22) Tian, H.; Yu, X.; Li, Q.; Wang, J.; Xu, Q. Adv. Synth. Catal. 2012, 354,
2671ꢀ2677.
(23) Cai, Z. J.; Wang, S. Y.; Ji, S. J. Org. Lett. 2012, 14, 6068−6071.
ACS Paragon Plus Environment