Acid-Catalyzed Multicomponent Tandem Double Cyclization: A One-pot, Metal-free Route to Synthesize Polyfunctional 4,9-Dihydropyrrolo[2,1-b]quinazolines

Article abstract of DOI:10.1021/acs.joc.6b01660

An acid-catalyzed multicomponent tandem double cyclization protocol has been developed for the synthesis of polyfunctional 4,9-dihydropyrrolo[2,1-b]quinazolines from simple and readily available arylglyoxal monohydrates, 2-aminobenzylamine, and trans-β-nitrostyrenes. This practical and metal-free reaction proceeds through an imine formation/cyclization/Michael addition/Henry cyclization protocol, resulting in the construction of four new bonds and two ring moieties directly in one pot.

Full text of DOI:10.1021/acs.joc.6b01660

Subscriber access provided by United Arab Emirates University | Libraries Deanship
Note
Acid-Catalyzed Multicomponent Tandem Double
Cyclization: A One-pot, Metal-free Route to Synthesize
Polyfunctional 4,9-Dihydropyrrolo[2,1-b]quinazolines
Qun Cai, Deng-Kui Li, Rong-Rong Zhou, Shi-Yi Zhuang, Jin-Tian Ma, Yan-Dong Wu, and An-Xin Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01660 • Publication Date (Web): 09 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 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 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
AcidꢀCatalyzed Multicomponent Tandem Double
Cyclization: A Oneꢀpot, Metalꢀfree Route to Synthesize
Polyfunctional 4,9ꢀDihydropyrrolo[2,1ꢀb]quinazolines
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
Qun Cai, DengꢀKui Li, RongꢀRong Zhou, ShiꢀYi Zhuang, JinꢀTian Ma, YanꢀDong
Wu*, 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: chwuyd@mail.ccnu.edu.cn (Y. ꢀD. Wu); chwuax@mail.ccnu.edu.cn (A. ꢀX. Wu)
TOC Graphic:
Abstract: An acidꢀcatalyzed multicomponent tandem double cyclization protocol
has
been
developed
for
the
synthesis
of
polyfunctional
4
,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines from simple and readily available arylglyoxal
monohydrates, 2ꢀaminobenzylamine, and transꢀβꢀnitrostyrenes. This practical and
metalꢀfree reaction proceeds through an imine formation/cyclization/Michael
addition/Henry cyclization protocol, resulting in the construction of four new bonds
and two ring moieties directly in one pot.
The straightforward construction of fused Nꢀheterocyclic scaffolds is an
important and ongoing research area in organic synthesis due to their presence in
1
drugs and functional materials. Among them, 4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline
is one of the privileged structural motifs in heteropolycyclic systems, and its
derivatives can be found in numerous natural products and biologically active
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
4
molecules such as vasicoline (I), vasicine (II), batracylin (III), and antimicrobial
5
molecule (IV) (Figure 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Selected natural products and biologically active compounds with a
,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline moiety.
4
Due to the importance and utility of 4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline
derivatives, a simplified synthesis of this heteropolycyclic system offers great value.
To the best of our knowledge, however, only a few approaches have been reported
thus far to construct this novel structure. In 2011, Stephens and coꢀworkers exploited
a Pdꢀcatalyzed intramolecular C−N coupling reaction for the synthesis of
4
,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines from prefabricated 2ꢀaminopyrroles having a
6
2ꢀbromobenzyl group at the Nꢀ1 position (Scheme 1a). In addition, the Zhao group
reported a Cuꢀcatalyzed Ullmannꢀtype coupling reaction for the synthesis of
5
,12ꢀdihydroindolo[2,1ꢀb]quinazolines through a sequential C−C and C−N bond
formation from Nꢀ(2ꢀbromobenzyl)ꢀ2ꢀiodoanilines and acetonitriles substituted with
7
electronꢀwithdrawing groups under an argon condition (Scheme 1b). Despite these
limited examples, the development of new and practical synthetic strategies,
especially
,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines is highly desirable.
In recent years, tandem cyclization has emerged as a versatile and economical
strategy for the synthesis of highly functionalized polycyclic ring systems, which has
metalꢀfree
pathways,
to
access
polyfunctional
4
8
ꢀ14
attracted substantial interest from chemists.
In particular, tandem double
cyclization has found wide applications in total synthesis of natural products because
of its advantages in unparalleled efficiencies, reducing the reaction steps and waste
15ꢀ16
production.
In continuation of our efforts to synthesize heterocycles using tandem
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
17
cyclization methods, we herein report a new acidꢀcatalyzed multicomponent
reaction to construct polysubstituted 4,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines from
readily
available
arylglyoxal
monohydrates,
2ꢀaminobenzylamine,
and
transꢀβꢀnitrostyrenes in a single operation (Scheme 1c). Notably, this work represents
a fascinating approach for the direct construction of three C−N bonds and one C−C
bond via tandem double cyclization in a single step without any metal additives.
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. Strategies for the Synthesis of 4,9ꢀDihydropyrrolo[2,1ꢀb]quinazoline
Derivatives
Our initial investigations of the tandem double cyclization reaction focused on
optimizing the reaction conditions of phenylglyoxal monohydrate 1a,
2ꢀaminobenzylamine 2, and transꢀβꢀnitrostyrene 3a in the presence of different
Brønsted acids and solvents. To our delight, the reaction proceeded to give the desired
product 4a in 30% yield when it was conducted in methanol with 30 mol % of
CF
3
SO
3
H (Table 1, entry 1). Thus, we screened a series of solvents, including iꢀPrOH,
CHCl
3
, CH CN, 1,4ꢀdioxane, THF, DMF, and DMSO (Table 1, entries 2–8), and
3
DMSO was shown to be the most effective for this reaction. Based on this
encouraging result, we then evaluated several other acids, but none of these performed
any better than CF
amounts of CF SO
3
SO
3
H (Table 1, entries 9–13). After screening several different
3
3
H, we found that 30 mol % of CF
3
SO H was still the most suitable
3
for the reaction (Table 1, entries 14–18 vs entry 8). Moreover, the yield decreased
slightly when the reaction was performed at a lower or higher temperature (Table 1,
entries 19–22).
a
Table 1. Optimization of the Reaction Conditions
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
entry
solvent
MeOH
iꢀPrOH
acid (mol %)
temp (°C)
65
yield (%)
1
2
3
4
5
6
7
8
9
CF
CF
CF
CF
CF
CF
CF
CF
3
SO
SO
SO
SO
SO
SO
SO
3
3
3
3
3
3
3
H(30)
H(30)
H(30)
H(30)
H(30)
H(30)
H(30)
30
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
80
48
CHCl
3
3
40
10
3
CH CN
3
80
28
1,4ꢀdioxane
THF
3
100
66
16
3
12
DMF
3
100
100
100
100
100
100
100
100
100
100
100
100
r.t.
76
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
SO
SO
CO
CO
3
H(30)
88
CH
3
3
H(30)
70
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
CH
3
2
H(30)
82
CF
3
2
H(30)
68
TsOH(30)
HCl(30)
ꢀ
74
62
trace
35
CF
CF
CF
CF
CF
CF
CF
CF
3
SO
SO
SO
SO
SO
SO
SO
SO
3
3
3
3
3
3
3
3
H(10)
H(60)
H(120)
H(150)
H(30)
H(30)
H(30)
H(30)
3
75
3
trace
trace
50
3
3
3
60
56
21
22
3
80
70
3
120
73
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.24 mmol, 1.2 equiv), 3a (0.2 mmol, 1.0 equiv), and acid (x
b
mol %) were heated in 2 mL of solvent in a sealed tube for 3 h. Isolated yields.
With the optimized conditions in hand, the substrate scope of arylglyoxal
monohydrate (1) was explored. It is noteworthy that the reaction demonstrated a wide
tolerance for diverse substituents of arylglyoxal monohydrates. As shown in Scheme 2,
arylglyoxals bearing electronꢀneutral (4ꢀH, 4ꢀMe), electronꢀrich (4ꢀOMe, 3ꢀOMe),
2
and electronꢀdeficient (3ꢀNO ) substituents were smoothly converted to the
corresponding products in moderate to excellent yields (76–90%; 4a–4e). Gratifyingly,
haloꢀsubstituted (4ꢀCl, 4ꢀBr, 3ꢀBr) arylglyoxals were also found to furnish the
corresponding products in excellent yields (82–87%; 4f–4h), which provided the
possibility for further functionalization. Additionally, heterocyclic (2ꢀthiophenyl and
3ꢀthiophenyl) and sterically hindered (1ꢀnaphthyl and 2ꢀnaphthyl) arylglyoxals were
found to be suitable for this transformation (70–80%; 4i–4l). Furthermore, the
structure of 4b was unambiguously confirmed by Xꢀray diffraction analysis (see the
Supporting Information).
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
a,b
Scheme 2. Scope of Arylglyoxal Monohydrates
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
a
3 3
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), 3a (0.3 mmol), and CF SO H (0.09 mmol) were heated in 3
b
mL of DMSO in a sealed tube for 3 h. Isolated yields.
Encouraged by the results described above, the scope of arylꢀsubstituted
nitroolefins (3) was subsequently examined (Scheme 3). Much to our satisfaction, the
electronic properties of the arylꢀsubstituents on the nitroolefins were shown to have
little influence on the efficiency of this reaction. In general, electronꢀneutral (4ꢀMe),
electronꢀrich (4ꢀOMe, 4ꢀOH), and halogenated (4ꢀF, 2ꢀCl, 2,4ꢀCl
all found compatible under the optimal reaction conditions with excellent yields
72–85%; 4m–4s). Sterically hindered (1ꢀnaphthyl) nitroolefin was also tolerated in
2
, 2ꢀBr) groups were
(
this reaction to afford the desired product 4t in 74% yield. Furthermore, methylꢀ,
bromoꢀ, 3ꢀthiophenylꢀ, and 2ꢀnaphthylꢀsubstituted arylglyoxal monohydrates reacted
smoothly with 2ꢀaminobenzylamine and methylꢀ or methoxylꢀsubstituted nitrostyrene
to obtain the corresponding products in moderate yields (68–86%; 4u–4x).
a,b
Scheme 3. Scope of Nitroolefins and Arylglyoxal Monohydrates
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ar2
Ar1
O
Ar2
CF3SO3H
N
Ar1
OH
OH
+
NH2
NH2
+
NO2
NO2
DMSO, 100 °C
N
H
1
2
3
4
Me
OMe
OH
F
N
N
N
N
NO2
NO2
NO2
NO2
N
N
N
N
H
H
H
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
m 85%
4n 72%
4o 73%
4p 84%
Cl
Cl
Cl
Br
N
N
N
N
NO2
NO2
NO2
NO2
N
H
N
H
N
N
H
H
4
q 78%
4r 80%
4s 76%
4t 74%
Me
Me
OMe
OMe
N
N
N
N
NO2
NO2
NO2
NO2
N
H
N
H
N
N
H
H
S
Me
Br
4u 86%
4v 87%
4w 70%
4x 68%
a
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), 3 (0.3 mmol), and CF SO H (0.09 mmol) were heated in 3 mL
3
3
b
of DMSO in a sealed tube for 3 h. Isolated yields.
To gain some insight into the mechanism of this reaction, a series of control
experiments were performed as shown in Scheme 4. When phenylglyoxal
monohydrate 1a reacted with 2ꢀaminobenzylamine 2 under the standard conditions for
0
.5 h, 1,2,3,4ꢀtetrahydroquinazoline B was obtained in 15% yield together with large
amounts of quinazoline 5 (Scheme 4a). Then, the treatment of B and
transꢀβꢀnitrostyrene 3a under the standard conditions directly generated the target
product 4a in 85% yield (Scheme 4b). These results implied that B was the key
intermediate for this reaction. To further demonstrate the reaction order of three
substrates, 2 and 3a were first subjected to the reaction under the standard conditions
for 2 h, then 1a was added into the mixture; however, the target product 4a was not
obtained, which excluded the reaction order of (2 + 3a) + 1a (Scheme 4c).
Furthermore, when this reaction was conducted under an argon condition, the desired
product 4a was isolated in 13% yield along with a possible unstable intermediate D
detected by MS (Scheme 4d). In contrast, when this reaction was conducted under an
oxygen condition, 4a was still isolated in a low yield accompanying the byproduct 5
in 41% yield (Scheme 4e), which indicated that a large amount of oxygen is
unfavorable to the smooth transformation of the reaction.
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 4. Control Experiments
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
7ꢀ19
Based on the above results and previous reports,
a possible mechanism for
the formation of polyfunctional 4,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines 4 was
presented in Scheme 5 (4a as an example). Initially, phenylglyoxal monohydrate 1a
transformed to the corresponding dehydrated species 1a′, which was protonated to
form 1a′′ in acid condition. Subsequently, 1a′′ reacted with 2ꢀaminobenzylamine 2 to
afford imine intermediate A. Then, intramolecular cyclization of intermediate A led to
the formation of intermediate B. Afterward, Michael addition of intermediate B to
transꢀβꢀnitrostyrene 3a furnished intermediate C, which straightly underwent
intramolecular Henry cyclization to form intermediate D. Finally, D went through
oxidative aromatization to give the desired product 4a.
Scheme 5. Possible Mechanism
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
To further make this reaction more attractive in terms of synthetic practicality, a
gramꢀscale synthesis of 4,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines (4a) was carried out.
To our great pleasure, the reaction proceeded well and the desired product 4a was
isolated in 80% yield (Scheme 6).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Gramꢀscale Experiment of Product 4a
In conclusion, we have developed a highly efficient multicomponent tandem
double
cyclization
protocol
for
the
synthesis
of
polyfunctional
4
,9ꢀdihydropyrrolo[2,1ꢀb]quinazolines from simple and readily available starting
materials in one pot. This method features in the consecutive construction of four new
bonds and two rings under metalꢀfree conditions. This reaction represents a highly
efficient and convenient methodology for the synthesis of diversely substituted
heteropolycyclic scaffolds under mild conditions.
Experimental Section
General Methods.
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
–1 1
were recorded as KBr pellets with absorption in cm . H spectra were recorded with
6
00/400 MHz spectrometers and resonances (δ) are given in ppm relative to TMS
13
(
internal standard). C spectra were recorded with 150/100 MHz NMR spectrometers.
HRMS were obtained on a 7.0T FTMS equipped with ESI or APCI. Melting points
were determined using an electrothermal capillary melting point apparatus and not
corrected.
General Procedures for the Synthesis of the Products 4 (4a as an example)
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A
mixture of phenylglyoxal monohydrate 1a (46 mg, 0.3 mmol),
2
ꢀaminobenzylamine 2 (44 mg, 0.36 mmol), transꢀβꢀnitrostyrene 3a (45 mg, 0.3
mmol), and CF SO H (14 mg, 0.09 mmol) was heated at 100 °C in 3 mL of DMSO in
3
3
a sealed tube for 3 h till almost completed conversion of the substrates by TLC
analysis, then extracted with EtOAc three times (3 × 50 mL). The extract was dried
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 4
over anhydrous Na SO and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (eluent: petroleum ether/EtOAc = 5/1) to afford
the product 4a.
Experimental Procedure for Preparation of B and 5
A
mixture of phenylglyoxal monohydrate 1a (76 mg, 0.5 mmol),
2ꢀaminobenzylamine 2 (73 mg, 0.6 mmol), and CF SO H (23 mg, 0.15 mmol) was
3
3
heated at 100 °C in 3 mL of DMSO in a sealed tube for 0.5 h till almost completed
conversion of the substrates by TLC analysis, then extracted with EtOAc three times
2 4
(3 × 50 mL). The extract was dried over anhydrous Na SO and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel (eluent:
petroleum ether/EtOAc = 10/1) to afford B and 5.
Gram Scale Reaction for product 4a
A
mixture of phenylglyoxal monohydrate 1a (760 mg,
ꢀaminobenzylamine 2 (732 mg, 6 mmol), transꢀβꢀnitrostyrene 3a (745 mg, 5 mmol),
and CF SO H (225 mg, 1.5 mmol) was heated at 100 °C in 50 mL of DMSO in a
5
mmol),
2
3
3
sealed tube for 5 h till almost completed conversion of the substrates by TLC analysis,
then extracted with EtOAc three times (3 × 100 mL). The extract was dried over
2 4
anhydrous Na SO and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (eluent: petroleum ether/EtOAc = 5/1) to afford
the product 4a.
Analytical Data for Products 4, B and 5
2ꢀnitroꢀ1,3ꢀdiphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4a). Yield: 88% (97 mg);
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
Yellow solid; m.p. 98–100 C; H NMR (DMSOꢀd , 600 MHz):
δ 8.93 (s, 1H), 7.58 (d, J =
6
6.0 Hz, 2H), 7.52 (d, J = 6.6 Hz, 3H), 7.44 (t, J = 7.2 Hz, 2H), 7.40–7.28 (m, 3H), 7.19–6.99
13
(
m, 3H), 6.79 (t, J = 7.2 Hz, 1H), 4.89 (s, 2H); C NMR (DMSOꢀd , 150 MHz):
δ
136.6,
6
131.7, 131.4, 130.9, 130.2, 129.5, 129.0, 128.8, 128.32, 128.28, 128.1, 127.4, 126.9, 126.4,
1
19.9, 114.8, 114.2, 96.3, 44.1; IR (KBr):, 3410, 3056, 2924, 2858, 1621, 1587, 1547, 1492,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
+
18 3 2
1345, 1250, 844, 763, 700 cm ; HRMS (APCI): m/z [M + H] calcd for C23H N O :
368.1394; found: 368.1398.
2
ꢀnitroꢀ1ꢀphenylꢀ3ꢀ(pꢀtolyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4b). Yield: 86% (98
o
1
mg); Yellow solid; m.p. 203–205 C; H NMR (CDCl
3
, 600 MHz):
δ 7.54–7.46 (m, 5H),
7
6
δ
1
1
.34–7.26 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.87 (t, J = 7.8 Hz, 1H),
1
3
3
.68 (d, J = 7.8 Hz, 1H), 6.36 (s, 1H), 4.84 (s, 2H), 2.42 (s, 3H); C NMR (CDCl , 150 MHz):
136.7, 136.3, 131.8, 130.7, 129.6, 129.1, 129.0, 128.9, 128.7, 128.6, 128.4, 127.3, 126.9,
20.9, 114.6, 114.3, 110.0, 97.4, 44.6, 21.3; IR (KBr): 3415, 3020, 2919, 2853, 1620, 1588,
–1
+
548, 1492, 1344, 1255, 848, 755, 696 cm ; HRMS (ESI): m/z [M + H] calcd for
: 382.1550; found: 382.1556.
24 20 3 2
C H N O
3
9
1
2
1
1
1
ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4c). Yield:
o
1
0% (107 mg); Yellow solid; m.p. 152–154 C; H NMR (DMSOꢀd
6
, 600 MHz): δ 8.85 (s,
H), 7.60–7.45 (m, 5H), 7.28 (d, J = 8.4 Hz, 2H), 7.13–7.05 (m, 3H), 7.00 (d, J = 7.8 Hz,
13
6
H), 6.77 (t, J = 6.6 Hz, 1H), 4.88 (s, 2H), 3.81 (s, 3H); C NMR (DMSOꢀd , 100 MHz): δ
58.0, 136.7, 131.6, 131.5, 130.8, 129.4, 129.0, 128.9, 128.3, 128.1, 127.0, 126.9, 123.7,
19.8, 114.7, 114.2, 113.8, 96.1, 55.1, 44.1; IR (KBr): 3405, 3057, 2836, 1624, 1590, 1492,
–1
+
468, 1341, 1248, 1178, 1030, 836, 750, 699 cm ; HRMS (ESI): m/z [M + H] calcd for
24 20 3 3
C H N O
: 398.1499; found: 398.1497.
3
8
1
6
1
1
2
ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4d). Yield:
o
1
4% (100 mg); Yellow solid; m.p. 183–185 C; H NMR (DMSOꢀd , 600 MHz):
δ
8.94 (s,
6
H), 7.60–7.49 (m, 5H), 7.34 (t, J = 7.8 Hz, 1H), 7.14–7.09 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H),
13
.94–6.87 (m, 3H), 6.78 (t, J = 7.8 Hz, 1H), 4.88 (s, 2H), 3.80 (s, 3H); C NMR (DMSOꢀd ,
6
50 MHz):
δ 159.1, 136.6, 132.9, 131.5, 130.8, 129.5, 129.2, 129.0, 128.8, 128.3, 128.1,
27.2, 126.9, 122.6, 119.9, 115.6, 114.8, 114.2, 112.2, 96.2, 54.9, 44.1; IR (KBr): 3362, 3040,
–
1
+
830, 1618, 1590, 1544, 1485, 1464, 1334, 1256, 757, 702 cm ; HRMS (ESI): m/z [M + H]
calcd for C H N O : 398.1499; found: 398.1497.
2
4
20
3
3
2
ꢀnitroꢀ3ꢀ(3ꢀnitrophenyl)ꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4e). Yield: 76%
o
1
6
(94 mg); Yellow solid; m.p. 150–152 C; H NMR (DMSOꢀd , 600 MHz): δ 9.14 (s, 1H),
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
.23–8.14 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.62–7.51 (m, 5H),
13
7.17–7.09 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 4.91 (s, 2H); C NMR
(
DMSOꢀd , 150 MHz): 147.8, 137.4, 136.2, 133.6, 130.9, 130.8, 130.3, 129.6, 129.2, 128.6,
δ
6
128.40, 128.35, 128.2, 127.1, 125.0, 121.3, 120.3, 114.6, 114.2, 94.1, 44.2; IR (KBr): 3379,
–1
2842, 1625, 1589, 1530, 1495, 1345, 1259, 1036, 832, 753, 700 cm ; HRMS (ESI): m/z [M +
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
+
H] calcd for C23
H
17
N
4
O
4
: 413.1244; found: 413.1244.
3
ꢀ(4ꢀchlorophenyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4f). Yield:
o
1
8
6
2% (99 mg); Yellow solid; m.p. 133–135 C; H NMR (DMSOꢀd , 600 MHz): δ 8.99 (s,
1H), 7.57 (d, J = 6.6 Hz, 2H), 7.52 (d, J = 6.0 Hz, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
7
.8 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.09–7.00 (m, 2H), 6.79 (t, J = 7.2 Hz, 1H), 4.88 (s, 2H);
13
C NMR (DMSOꢀd
6
, 150 MHz): δ 136.4, 132.2, 131.1, 130.8, 130.7, 129.8, 129.0, 128.7,
1
28.3, 128.2, 128.1, 127.7, 127.0, 120.0, 114.7, 114.2, 95.0, 44.1; IR (KBr): 3415, 2922, 1624,
–
1
+
1588, 1547, 1491, 1341, 1257, 1194, 1091, 838, 749, 700 cm ; HRMS (ESI): m/z [M + Na]
calcd for C23 NaO : 424.0823; found: 424.0823.
H16ClN
3
2
3
8
1
ꢀ(4ꢀbromophenyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4g). Yield:
o
1
7% (116 mg); Yellow solid; m.p. 134–136 C; H NMR (DMSOꢀd
6
, 600 MHz): δ 8.99 (s,
H), 7.61 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 6.6 Hz, 2H), 7.54–7.45 (m, 3H), 7.31 (d, J = 7.8
Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.79 (t, J
13
=
6
7.8 Hz, 1H), 4.88 (s, 2H); C NMR (DMSOꢀd , 100 MHz): δ 136.4, 132.4, 131.1, 131.00,
1
9
6
30.97, 130.7, 129.6, 128.9, 128.6, 128.2, 128.0, 127.6, 126.8, 119.9, 119.6, 114.6, 114.1,
5.0, 44.0; IR (KBr): 3404, 3059, 2925, 2856, 1680, 1623, 1587, 1490, 1258, 1195, 833, 749,
–1
+
3 2
98 cm ; HRMS (ESI): m/z [M + K] calcd for C23H16BrN KO : 484.0058; found: 484.0050.
3ꢀ(3ꢀbromophenyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4h). Yield:
o
1
8
1
7
5% (114 mg); Yellow solid; m.p. 157–159 C; H NMR (DMSOꢀd
6
, 600 MHz): δ 9.07 (s,
H), 7.57 (d, J = 6.0 Hz, 2H), 7.55–7.49 (m, 5H), 7.41–7.35 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H),
1
3
.08 (d, J = 7.8 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 4.89 (s, 2H); C NMR (DMSOꢀd
136.4, 134.3, 132.9, 131.1, 130.8, 130.2, 129.9, 129.5, 129.3, 129.1, 128.7, 128.3,
28.1, 127.8, 127.0, 121.5, 120.1, 114.7, 114.2, 94.9, 44.2; IR (KBr): 3377, 2921, 1622, 1589,
6
, 150
MHz):
δ
1
1
–1
+
546, 1494, 1471, 1334, 1260, 854, 753, 703 cm ; HRMS (ESI): m/z [M + H] calcd for
23 3 2
C H17BrN O
: 446.0499; found: 446.0499.
2ꢀnitroꢀ1ꢀphenylꢀ3ꢀ(thiophenꢀ2ꢀyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4i). Yield: 80%
o
1
(
89 mg); Yellow solid; m.p. 220–222 C; H NMR (DMSOꢀd , 600 MHz): δ 9.03 (s, 1H),
6
7.62–7.56 (m, 3H), 7.55–7.49 (m, 3H), 7.20–7.11 (m, 4H), 7.04 (d, J = 7.2 Hz, 1H), 6.79 (t, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
=
6.6 Hz, 1H), 4.88 (s, 2H); C NMR (DMSOꢀd , 150 MHz):
δ
136.3, 132.1, 131.6, 131.0,
6
130.8, 129.1, 128.7, 128.5, 128.4, 128.2, 127.6, 127.2, 126.9, 126.5, 120.2, 114.9, 114.1, 88.5,
–1
4
4.2; IR (KBr): 3408, 3101, 1622, 1588, 1549, 1494, 1471, 1357, 1250, 1178, 851, 759 cm ;
+
HRMS (ESI): m/z [M + Na] calcd for C21
H
15
N
3
2
NaO S: 396.0777; found: 396.0778.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2ꢀnitroꢀ1ꢀphenylꢀ3ꢀ(thiophenꢀ3ꢀyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4j). Yield: 78%
o
1
(
87 mg); Yellow solid; m.p. 264–266 C; H NMR (DMSOꢀd , 600 MHz):
δ
8.86 (s, 1H),
6
7.60–7.47 (m, 7H), 7.12 (d, J = 3.6 Hz, 3H), 7.07 (d, J = 7.8 Hz, 1H), 6.82–6.75 (m,, 1H),
13
4
.87 (s, 2H); C NMR (DMSOꢀd , 150 MHz):
δ
136.5, 131.4, 130.9, 130.8, 129.84, 129.82,
6
1
29.0, 128.9, 128.3, 128.1, 127.2, 126.9, 124.9, 123.7, 120.0, 114.8, 114.2, 91.5, 44.1.; IR
–
1
(
(
KBr): 3411, 3103, 1623, 1590, 1546, 1493, 1471, 1355, 1333, 1250, 757, 699 cm ; HRMS
+
ESI): m/z [M + H] calcd for C21
H
16
N
3
O
2
S: 374.0958; found: 374.0957.
3ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4k). Yield:
o
1
7
0% (87mg); Yellow solid; m.p. 163–165 C; H NMR (DMSOꢀd
6
, 600 MHz): δ 8.81 (s, 1H),
8.03–7.93 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.71–7.65 (m, 2H), 7.64–7.45 (m, 7H),
1
3
7
.12–7.04 (m, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.81–6.73 (m, 1H), 4.98 (s, 2H); C NMR
(
DMSOꢀd , 150 MHz): 136.6, 133.5, 133.2, 132.3, 131.0, 130.1, 129.8, 129.1, 129.04,
6
δ
1
1
6
29.00, 128.3, 128.1, 127.6, 127.5, 127.0, 126.1, 125.9, 125.7, 125.5, 119.8, 114.4, 114.0,
09.6, 93.7, 44.3; IR (KBr): 3404, 3052, 1624, 1588, 1546, 1493, 1254, 1208, 792, 864, 750,
–
1
+
20 3 2
98 cm ; HRMS (ESI): m/z [M + H] calcd for C27H N O : 418.1550; found: 418.1552.
3
7
4
1
ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀnitroꢀ1ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4l). Yield:
o
1
3
4% (93 mg); Yellow solid; m.p. 137–139 C; H NMR (CDCl , 600 MHz): δ 7.88–7.80 (m,
H), 7.51–7.43 (m, 8H), 7.09 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 7.8 Hz,
13
H), 6.59 (d, J = 7.8 Hz, 1H), 6.49 (s, 1H), 4.80 (s, 2H); C NMR (CDCl
3
, 150 MHz):
δ
136.1, 133.5, 132.2, 131.7, 130.7, 129.5, 129.4, 129.2, 128.8, 128.6, 128.44, 128.37, 128.2,
27.7, 127.6, 127.5, 126.8, 126.1, 125.9, 120.9, 114.5, 114.3, 97.4, 44.6; IR (KBr): 3412,
1
–
1
3053, 1623, 1588, 1493, 1469, 1343, 1250, 1203, 823, 751, 699 cm ; HRMS (ESI): m/z [M +
+
H] calcd for C27
H
20
N
3
O
2
: 418.1550; found: 418.1551.
2
ꢀnitroꢀ3ꢀphenylꢀ1ꢀ(pꢀtolyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4m). Yield: 85% (97
o
1
mg); Yellow solid; m.p. 201–203 C; H NMR (CDCl
3
, 600 MHz):
d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.33–7.28 (m, 3H), 7.12 (t, J = 7.2 Hz, 1H), 6.96
d, J = 7.2 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.82 (s,
δ 7.46–7.42 (m, 2H), 7.39
(
(
1
3
2
3
H), 2.43 (s, 3H); C NMR (CDCl , 150 MHz): δ 139.2, 136.2, 131.7, 131.6, 130.5, 129.7,
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
29.1, 129.0, 128.7, 128.6, 127.7, 126.82, 126.79, 125.7, 120.8, 114.5, 114.3, 97.4, 44.6, 21.4;
–
1
IR (KBr): 3416, 3018, 1620, 1591, 1553, 1502, 1473, 1344, 1256, 1198, 849, 753, 703 cm ;
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 382.1550; found: 382.1559.
2
4
20
3
2
1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4n). Yield:
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
o
1
72% (86 mg); Yellow solid; m.p. 129–131 C; H NMR (DMSOꢀd
H), 7.50 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.32 (t, J =
7.2 Hz, 1H), 7.15–7.09 (m, 2H), 7.07 (d, J = 8.4 Hz, 3H), 6.82–6.74 (m, 1H), 4.88 (s, 2H),
6
, 600 MHz): δ 8.90 (s,
1
13
3
.84 (s, 3H); C NMR (DMSOꢀd , 150 MHz):
δ
159.7, 136.7, 132.4, 131.8, 131.4, 130.2,
6
1
29.3, 128.3, 128.1, 127.6, 126.9, 126.3, 120.6, 119.9, 114.8, 114.3, 113.7, 96.3, 55.2, 44.1;
IR (KBr): 3354, 3052, 2838, 1620, 1588, 1550, 1498, 1468, 1339, 1251, 1030, 848, 760, 701
–
1
+
20 3 3
cm ; HRMS (ESI): m/z [M + H] calcd for C24H N O : 398.1499; found: 398.1507.
4ꢀ(2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazolinꢀ1ꢀyl)phenol (4o). Yield: 73% (84
o
1
mg); Yellow solid; m.p. 252–254 C; H NMR (DMSOꢀd
6
, 600 MHz):
δ 9.87 (s, 1H), 8.85 (s,
1
6
H), 7.42 (t, J = 7.8 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.35–7.23 (m, 3H), 7.16–7.03 (m, 3H),
1
3
.89 (d, J = 8.4 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H), 4.87 (s, 2H); C NMR (DMSOꢀd , 100
6
MHz):
δ
158.1, 136.7, 132.2, 131.8, 131.3, 130.0, 129.1, 128.1, 128.0, 127.9, 126.8, 126.2,
1
1
19.8, 118.8, 115.1, 114.7, 114.4, 96.2, 44.0; IR (KBr): 3409, 2843, 1620, 1589, 1551, 1497,
–1
+
467, 1342, 1275, 1251, 852, 756, 702 cm ; HRMS (ESI): m/z [M + H] calcd for
: 384.1343; found: 384.1348.
23 18 3 3
C H N O
1
8
1
ꢀ(4ꢀfluorophenyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4p). Yield:
o
1
4% (97 mg); Yellow solid; m.p. 190–192 C; H NMR (DMSOꢀd
6
, 600 MHz): δ 8.92 (s,
H), 7.68–7.62 (m, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.40–7.31 (m, 5H), 7.16–7.05 (m, 3H), 6.79
13
(t, J = 7.2 Hz, 1H), 4.89 (s, 2H); C NMR (DMSOꢀd
6
, 150 MHz): δ 162.5 (d, 1JCꢀF = 244.5
Hz), 136.6, 133.31, 133.25, 131.6, 131.5, 130.2, 129.5, 128.3, 128.1, 126.9, 126.4, 126.3,
1
25.2, 119.9, 115.4, 115.2, 114.8, 114.2, 96.4, 44.1; IR (KBr): 3408, 1622, 1589, 1551, 1499,
–1
+
1
3 2
472, 1345, 1235, 853, 759, 702 cm ; HRMS (ESI): m/z [M + H] calcd for C23H17FN O :
386.1299; found: 386.1305.
1
ꢀ(2ꢀchlorophenyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4q). Yield:
o
1
78% (94 mg); Yellow solid; m.p. 115–117 C; H NMR (CDCl , 600 MHz):
δ 7.55 (d, J = 7.8
3
Hz, 1H), 7.52–7.36 (m, 7H), 7.34 (t, J = 6.6 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8
Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.39 (s, 1H), 4.87–4.68 (m, 2H);
13
C NMR (CDCl
3
, 150 MHz): δ 135.9, 135.3, 132.6, 132.0, 131.5, 130.9, 129.9, 129.7, 129.3,
128.7, 128.64, 128.61, 127.0, 126.9, 126.8, 124.3, 120.9, 114.3, 114.0, 97.3, 44.2; IR (KBr):
–
1
3
405, 3057, 1621, 1587, 1547, 1489, 1344, 1255, 1198, 846, 757, 701 cm ; HRMS (ESI):
+
m/z [M + Na] calcd for C23
H16ClN
3
NaO
2
: 424.0823; found: 424.0832.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1ꢀ(2,4ꢀdichlorophenyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4r). Yield:
o
1
8
1
1
4
1
4
3
0% (105 mg); Yellow solid; m.p. 144–146 C; H NMR (CDCl , 600 MHz): δ 7.61–7.57 (m,
H), 7.47 (t, J = 7.8 Hz, 2H), 7.45–7.38 (m, 4H), 7.36 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 7.8 Hz,
H), 7.01 (d, J = 7.2 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.38 (s, 1H),
13
.89–4.71 (m, 2H); C NMR (CDCl
3
, 150 MHz): δ 136.4, 136.2, 135.9, 133.5, 132.2, 131.3,
30.0, 129.7, 129.6, 128.8, 128.3, 127.4, 127.3, 127.2, 126.9, 122.8, 121.1, 114.4, 113.9, 97.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
1
4.3; IR (KBr): 3416, 3052, 2849, 1668, 1622, 1585, 1493, 1338, 1273, 842, 749, 696 cm ;
+
HRMS (ESI): m/z [M + Na] calcd for C23
H15Cl
2
3 2
N NaO : 458.0434; found: 458.0435.
1
ꢀ(2ꢀbromophenyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4s). Yield:
o
1
76% (102 mg); Yellow solid; m.p. 142–144 C; H NMR (CDCl
3
, 600 MHz):
δ
7.72 (d, J =
7.8 Hz, 1H), 7.55–7.38 (m, 6H), 7.38–7.30 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 7.2
Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.38 (s, 1H), 4.86–4.66 (m, 2H);
13
3
C NMR (CDCl , 150 MHz): δ 135.9, 132.7, 132.6, 131.7, 131.5, 131.0, 130.8, 129.9, 129.1,
1
28.7, 128.6, 127.5, 127.0, 126.9, 126.0, 125.4, 120.9, 114.3, 113.9, 97.2, 44.2; IR (KBr):
–
1
3424, 1624, 1586, 1548, 1486, 1343, 1255, 1198, 1029, 846, 752, 701 cm ; HRMS (ESI):
+
m/z [M + H] calcd for C H BrN O : 446.0499; found: 446.0502.
23
17
3
2
1
ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀnitroꢀ3ꢀphenylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4t). Yield:
o
1
74% (93 mg); Yellow solid; m.p. 161–163 C; H NMR (CDCl
H), 7.63 (d, J = 7.8 Hz, 1H), 7.60–7.53 (m 2H), 7.53–7.35 (m, 6H), 7.35–7.28 (m, 1H), 7.05
t, J = 6.6 Hz, 1H), 6.84–6.64 (m, 2H), 6.58 (d, J = 7.8 Hz, 1H), 6.46 (s, 1H), 4.74–4.45 (m,
3
, 600 MHz): δ 8.04–7.84 (m,
2
(
13
2H); C NMR (CDCl , 150 MHz): δ 135.9, 133.4, 132.7, 131.7, 129.9, 129.8, 129.30,
3
129.25, 128.7, 128.6, 128.5, 127.1, 126.9, 126.8, 126.7, 126.3, 125.7, 125.2, 124.8, 120.8,
1
7
4
14.2, 114.1, 97.2, 44.1; IR (KBr): 3402, 3053, 1621, 1587, 1541, 1479, 1340, 1256, 860, 787,
–1
+
50, 700 cm ; HRMS (ESI): m/z [M + H] calcd for C27
18.1551.
20 3 2
H N O : 418.1550; found:
2
ꢀnitroꢀ1,3ꢀdiꢀpꢀtolylꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4u). Yield: 86% (102 mg);
o
1
Yellow solid; m.p. 146–148 C; H NMR (CDCl
3
, 600 MHz): δ 7.37 (d, J = 7.8 Hz, 2H),
7.32–7.28 (m, 4H), 7.27 (d, J = 7.8 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H),
6.85 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 7.8 Hz, 1H), 6.36 (s, 1H), 4.83 (s, 2H), 2.44 (s, 3H), 2.40
13
(
s, 3H); C NMR (CDCl , 150 MHz):
δ
139.2, 136.6, 136.3, 131.7, 130.6, 129.5, 129.1,
3
1
28.9, 128.7, 128.6, 127.5, 126.9, 125.8, 120.8, 114.6, 114.2, 109.9, 97.3, 44.6, 21.5, 21.3; IR
–
1
(
KBr): 3425, 2918, 1623, 1591, 1549, 1498, 1463, 1337, 1255, 916, 814, 751, 730 cm ;
+
HRMS (ESI): m/z [M + Na] calcd for C25
H
21
N
3
2
NaO : 418.1526; found: 418.1534.
3
ꢀ(4ꢀbromophenyl)ꢀ2ꢀnitroꢀ1ꢀ(pꢀtolyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline (4v). Yield:
o
1
87% (120 mg); Yellow solid; m.p. 280–282 C; H NMR (DMSOꢀd
6
, 600 MHz):
δ
8.94 (s,
1H), 7.59 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.37–7.21 (m, 4H), 7.17–6.98 (m,
13
3
H), 6.78 (t, J = 7.2 Hz, 1H), 4.86 (s, 2H), 2.40 (s, 3H); C NMR (DMSOꢀd
6
, 150 MHz):
δ
138.5, 136.4, 132.5, 131.1, 131.0, 130.6, 129.6, 128.9, 128.0, 127.8, 126.9, 125.7, 119.9,
119.6, 114.6, 114.1, 95.0, 44.1, 21.0; IR (KBr): 3417, 2918, 1621, 1589, 1551, 1499, 1471,
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
–
1
+
1339, 1257, 843, 819, 752 cm ; HRMS (ESI): m/z [M + H] calcd for C24
3 2
H19BrN O :
460.0655; found: 460.0655.
1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀnitroꢀ3ꢀ(thiophenꢀ3ꢀyl)ꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline
o
1
(
4w). Yield: 70% (85 mg); Yellow solid; m.p. 147–149 C; H NMR (CDCl
3
, 600 MHz):
δ
7
.39 (d, J = 8.4 Hz, 3H), 7.29 (s, 1H), 7.20–7.12 (m, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.98 (d, J
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
=
7.8 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H), 4.83 (s, 2H),
1
3
3.87 (s, 3H); C NMR (CDCl , 150 MHz):
δ
160.2, 136.3, 132.0, 131.6, 129.5, 129.3, 128.7,
3
127.5, 126.9, 125.7, 122.4, 120.9, 120.7, 115.1, 114.6, 114.3, 113.9, 92.5, 55.3, 44.6; IR
–1
(
(
KBr): 3377, 1620, 1591, 1546, 1502, 1473, 1331, 1251, 1108, 867, 803, 765 cm ; HRMS
+
ESI): m/z [M + H] calcd for C22
H
18
N
3
O
3
S: 404.1063; found: 404.1067.
1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ(naphthalenꢀ2ꢀyl)ꢀ2ꢀnitroꢀ4,9ꢀdihydropyrrolo[2,1ꢀb]quinazoline
o
1
(
4x). Yield: 68% (91 mg); Yellow solid; m.p. 142–144 C; H NMR (CDCl
.88–7.80 (m, 4H), 7.46 (d, J = 6.6 Hz, 3H), 7.39 (d, J = 7.8 Hz, 2H), 7.09 (t, J = 7.8 Hz, 1H),
7.01 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.8 Hz,
3
, 600 MHz): δ
7
13
1
1
1
3
H), 6.48 (s, 1H), 4.81 (s, 2H), 3.84 (s, 3H); C NMR (CDCl , 150 MHz): δ 160.2, 136.3,
33.5, 132.2, 132.1, 131.7, 129.6, 129.2, 128.6, 128.4, 128.2, 127.8, 127.67, 127.65, 127.5,
26.8, 126.1, 125.9, 120.9, 120.6, 114.6, 114.3, 113.9, 97.4, 55.3, 44.6; IR (KBr): 3402, 3050,
–
1
2931, 2836, 1622, 1589, 1550, 1467, 1334, 1250, 1177, 821, 747 cm ; HRMS (ESI): m/z [M
+
+
H] calcd for C28
H
22
N
3
O
3
: 448.1656; found: 448.1661.
phenyl(1,2,3,4ꢀtetrahydroquinazolinꢀ2ꢀyl)methanone (B). Yield: 15% (18 mg); White solid;
o
1
m.p. 161–163 C; H NMR (CD
3
OD, 600 MHz): δ 7.94 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 7.8
Hz, 2H), 7.48–7.28 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 8.4
13
Hz, 2H), 5.45 (s, 1H), 4.73 (s, 2H); C NMR (CD
3
OD, 150 MHz): δ 164.4, 131.3, 130.2,
130.0, 129.9, 129.8, 128.7, 128.0, 127.5, 127.4, 119.1, 73.0, 43.8; IR (KBr): 3513, 3370, 3052,
–
1
2939, 2844, 1733, 1599, 1482, 1447, 1255, 1137, 1089, 943, 909, 807, 750, 705 cm ; HRMS
+
(
ESI): m/z [M + H] calcd for C15
H
15
N
2
O: 239.1179; found: 239.1178.
o
phenyl(quinazolinꢀ2ꢀyl)methanone (5). Yield: 62% (73 mg); Yellow solid; m.p. 106–108 C;
1
H NMR (CDCl
3
, 400 MHz): δ 9.55 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.14–8.07 (m, 2H),
8
.04–7.96 (m, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H);
1
3
C NMR (CDCl
3
, 100 MHz): δ 191.7, 160.8, 158.7, 149.5, 135.4, 134.9, 133.4, 131.0, 129.4,
129.2, 128.3, 127.2, 124.7; IR (KBr): 3060, 2350, 1743, 1700, 1644, 1519, 1397, 1317, 807,
–
1
+
770, 734, 697 cm ; HRMS (ESI): m/z [M + H] calcd for C15
35.0869.
11 2
H N O: 235.0866; found:
2
ASSOCIATED CONTENT
Supporting Information
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
13
Crystallographic data and copies of the H and C NMR spectra are involved. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
*Eꢀmail: chwuyd@mail.ccnu.edu.cn (Y. ꢀD. Wu); chwuax@mail.ccnu.edu.cn (A. ꢀX. Wu)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (Grant
21272085 and 21472056) and the Fundamental Research Funds for the Central
Universities (CCNU15ZX002 and CCNU16A05002) for financial support.
REFERENCES
(1) For selected reviews, see: (a) Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, P. A.
Chem. Rev. 2008, 108, 238ꢀ263. (b) Scott, J. D.; Williams, R. M. Chem. Rev. 2002,
1
02, 1669ꢀ1730. (c) Coughlin, J. E.; Henson, Z. B.; Welch, G. C.; Bazan, G. C. Acc.
Chem. Res. 2014, 47, 257ꢀ270. (d) Fried, L. E.; Manaa, M. R.; Pagoria, P. F.;
Simpson, R. L. Annu. Rev. Mater. Res. 2001, 31, 291ꢀ321. (e) Chen, D.; Su, S.ꢀJ.; Cao,
Y. J. Mater. Chem. C 2014, 2, 9565ꢀ9578.
(
2) Joshi, B. S.; Bai, Y.; Puar, M. S.; Dubose, K. K.; Pelletier, S. W. J. Nat. Prod.
1994, 57, 953ꢀ962.
(
3) Shevyakov, S. V.; Davydova, O. I.; Pershin, D. G.; Krasavin, M.; Kravchenko, D.
V.; Kiselyov, A.; Tkachenko, S. E.; Ivachtchenko, A. V. Nat. Prod. Res. 2006, 20,
35ꢀ741.
7
(
4) Dzierzbicka, K.; Trzonkowski, P.; Sewerynek, P.; Myśliwski, A. J. Med. Chem.
2
003, 46, 978ꢀ986.
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
5) Grandolini, G.; Ambrogi, V.; Perioli, L.; Giannangeli, M.; Jovicevic, L.; Rossi, V.
Farmaco. 1997, 52, 679ꢀ683.
(6) Suthiwangcharoen, N.; Pochini, S. M.; Sweat, D. P.; Stephens, C. E. J. Heterocycl.
Chem. 2011, 48, 706ꢀ709.
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
(
7) Jiang, M.; Li, J.; Wang, F.; Zhao, Y.; Zhao, F.; Dong, X.; Zhao, W. Org. Lett. 2012,
1
4, 1420ꢀ1423.
(8) For selected reviews, see: (a) Guo, L.ꢀN.; Duan, X.ꢀH.; Liang, Y.ꢀM. Acc. Chem.
Res. 2011, 44, 111ꢀ122. (b) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Chem. Rev.
2
1
1
014, 114, 2390ꢀ2431. (c) Wang, Y.; Lu, H.; Xu, P.ꢀF. Acc. Chem. Res. 2015, 48,
832ꢀ1844. (d) Guo, X.ꢀX.; Gu, D.ꢀW.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115,
622ꢀ1651. (e) Sears, J. E.; Boger, D. L. Acc. Chem. Res. 2016, 49, 241ꢀ251.
(9) (a) Xia, X.ꢀF.; Wang, N.; Zhang, L. L.; Song, X.ꢀR.; Liu, X.ꢀY.; Liang, Y.ꢀM. J.
Org. Chem. 2012, 77, 9163ꢀ9170. (b) Zhou, Z.ꢀZ.; Jin, D.ꢀP.; Li, L.ꢀH.; He, Y.ꢀT.;
Zhou, P.ꢀX.; Yan, X.ꢀB.; Liu, X.ꢀY.; Liang, Y.ꢀM. Org. Lett. 2014, 16, 5616ꢀ5619. (c)
Qiu, Y.ꢀF.; Zhu, X.ꢀY.; Li, Y.ꢀX.; He, Y.ꢀT.; Yang, F.; Wang, J.; Hua, H.ꢀL.; Zheng, L.;
Wang, L.ꢀC.; Liu, X.ꢀY.; Liang, Y.ꢀM. Org. Lett. 2015, 17, 3694ꢀ3697.
(10) (a) Liu, H.ꢀC.; Tao, H.ꢀY.; Cong, H.; Wang, C.ꢀJ. J. Org. Chem. 2016, 81,
3
752ꢀ3760. (b) Li, J.; Huang, R.; Xing, Y.ꢀK.; Qiu, G.; Tao, H.ꢀY.; Wang, C.ꢀJ. J. Am.
Chem. Soc. 2015, 137, 10124ꢀ10127. (c) Tong, M.ꢀC.; Chen, X.; Li, J.; Huang, R.;
Tao, H.; Wang, C.ꢀJ. Angew. Chem. Int. Ed. 2014, 53, 4680ꢀ4684.
(11) (a) Pan, X.; Luo, Y.; Wu, J. J. Org. Chem. 2013, 78, 5756ꢀ5760. (b) Xiao, Q.; Ye,
S.; Wu, J. Org. Lett. 2012, 14, 3430ꢀ3433. (c) Zheng, D.; Li, S.; Luo, Y.; Wu, J. Org.
Lett. 2011, 13, 6402ꢀ6405.
(12) (a) Yi, X.; Xi, C. Org. Lett. 2015, 17, 5836ꢀ5839. (b) Zhao, P.; Liu, Y.; Xi, C.
Org. Lett. 2015, 17, 4388ꢀ4391. (c) Liao, Q.; Yang, X.; Xi, C. J. Org. Chem. 2014, 79,
8
2
507ꢀ8515. (d) Yan, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50,
775ꢀ2777.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
13) (a) Wang, B.; Liu, Y.; Lin, C.; Xu, Y.; Liu, Z.; Zhang, Y. Org. Lett. 2014, 16,
4
574ꢀ4577. (b) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Org. Lett. 2012, 14, 3894ꢀ3897. (c)
Sang, P.; Xie, Y.; Zou, J.; Zhang, Y. Adv. Synth. Catal. 2012, 354, 1873ꢀ1878.
(14) (a) Mühmel, S.; Alpers, D.; Hoffmann, F.; Brasholz, M. Chem. ꢀ Eur. J. 2015, 21,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2308ꢀ12312. (b) Rettenmeier, E.; Hansmann, M. M.; Ahrens, A.; Rübenacker, K.;
Saboo, T.; Massholder, J.; Meier, C.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K.
Chem. ꢀ Eur. J. 2015, 21, 14401ꢀ14409. (c) Chen, D.; Xu, W.ꢀD.; Liu, H.ꢀM.; Li,
M.ꢀM.; Yan, Y.ꢀM.; Li, X.ꢀN.; Li, Y.; Cheng, Y.ꢀX.; Qin, H.ꢀB. Chem. Commun. 2016,
5
2, 8561ꢀ8564. (d) Chen, Z.ꢀZ.; Liu, S.; Hao, W.ꢀJ.; Xu, G.; Wu, S.; Miao, J.ꢀN.; Jiang,
B.; Wang, S.ꢀL.; Tu, S.ꢀJ.; Li, G. Chem. Sci. 2015, 6, 6654ꢀ6658.
(15) Kärkäs, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev. 2016.
DOI: 10.1021/acs.chemrev.5b00760.
(16) (a) Kanoh, N.; Sakanishi, K.; Iimori, E.; Nishimura, K. i.; Iwabuchi, Y. Org. Lett.
2
011, 13, 2864ꢀ2867. (b) Chiou, W.ꢀH.; Lin, Y.ꢀH.; Chen, G.ꢀT.; Gao, Y.ꢀK.; Tseng,
Y.ꢀC.; Kao, C.ꢀL.; Tsai, J.ꢀC. Chem. Commun. 2011, 47, 3562ꢀ3564. (c) Jiang, S.ꢀZ.;
Zeng, X.ꢀY.; Liang, X.; Lei, T.; Wei, K.; Yang, Y.ꢀR. Angew. Chem. Int. Ed. 2016, 55,
4
044ꢀ4048.
(17) Cai, Q.; Li, D.ꢀK.; Zhou, R.ꢀR.; Shu, W.ꢀM.; Wu, Y.ꢀD.; Wu, A.ꢀX. Org. Lett.
2
016, 18, 1342ꢀ1345.
(18) (a) Sinkkonen, J.; Zelenin, K. N.; Potapov, A.ꢀK. A.; Lagoda, I. V.; Alekseyev, V.
V.; Pihlaja, K. Tetrahedron 2003, 59, 1939ꢀ1950. (b) Correa, W. H.; Papadopoulos, S.;
Radnidge, P.; Roberts, B. A.; Scott, J. L. Green Chem. 2002, 4, 245ꢀ251.
(
19) (a) Urushima, T.; Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12,
588ꢀ4591. (b) Albertshofer, K.; Tan, B.; Barbas, C. F. Org. Lett. 2012, 14,
1834ꢀ1837.
4
ACS Paragon Plus Environment