Palladium-Catalyzed Intramolecular Fujiwara-Hydroarylation: Synthesis of Benzo[a]phenazines Derivatives

Article abstract of DOI:10.1021/acs.joc.6b02096

An atom-economical Pd-catalyzed approach for the synthesis of benzophenazine derivatives using substituted 2-aryl-3-(aryl/alkylethynyl) quinoxaline in the presence of trifluoroacetic acid at 65 °C has been described. The chemistry involves in situ generation of cationic Pd(II) species, which functionalized the aromatic C-H bonds via electrophilic metalation followed by concomitant intramolecular trans-insertion of C-C triple bond to aryl-Pd complex. The results were supported by various control experiments including with electron-deficient arenes and deuterium labeling studies. The deuterium labeling studies supports electrophilic palladation of aromatic C-H over activation of C-C triple bond of alkyne. The structure of synthesized compounds was further confirmed by X-ray crystallography studies. This catalytic protocol has been efficiently applied for novel synthesis of highly functionalized benzo fused phenazines.

Full text of DOI:10.1021/acs.joc.6b02096

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Palladium-Catalyzed Intramolecular Fujiwara-
Hydroarylation: Synthesis of Benzo[a]phenazines Derivatives
Sonu Kumar, Rakesh K. Saunthwal, Mohammad Mujahid, Trapti Aggarwal, and Akhilesh K. Verma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02096 • Publication Date (Web): 26 Sep 2016
Downloaded from http://pubs.acs.org on September 27, 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 38
The Journal of Organic Chemistry
1
2
3
Palladium-Catalyzed Intramolecular Fujiwara-
Hydroarylation: Synthesis of Benzo[a]phenazines
Derivatives
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
Sonu Kumar, Rakesh K. Saunthwal, Mohammad Mujahid, Trapti Aggarwal and
Akhilesh K. Verma*
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of
Delhi, Delhi, 110007, India
averma@acbr.du.ac.in
ABSTRACT: An atom-economical Pd-catalyzed approach for the synthesis of benzophenazine
derivatives using substituted 2-aryl-3-(aryl/alkylethynyl) quinoxaline in the presence of
trifluoroacetic acid at 65 °C has been described. The chemistry involves in situ generation of
cationic Pd(II) species, which functionalized the aromatic C−H bonds via electrophilic
metalation followed by concomitant intramolecular trans-insertion of C-C triple bond to aryl-Pd
complex. The results were supported by various control experiments including with electron–
deficient arenes and deuterium labeling studies. The deuterium labeling studies supports
electrophilic palladation of aromatic C-H over activation of C-C triple bond of alkyne. The
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 38
1
2
3
4
5
6
7
8
9
structure of synthesized compounds was further confirmed by X-ray crystallography studies.
This catalytic protocol has been efficiently applied for novel synthesis of highly functionalized
benzo fused phenazines.
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
INTRODUCTION
Fused heterocycles and their analogues are pharmaceutically important scaffolds.1
Among various heterocycles phenazines and their derivatives are significant motifs in
pharmaceutical and agricultural chemistry and are used as key building blocks in natural product
synthesis.2 Some of the phenazine derivatives show ant-malarial (Figure i),3 anti-plasmodial
activity,4a antibacterial,4b antifungal,4c antitumor,4d cancer chemopreventive,5 neuroprotective,6a
and anti Chagas6b agent. The nucleus of benzophenazine derivatives (II) act as dual inhibitors of
topoisomerase I and II and in the cell cycles7 topology of DNA affected by key enzymes while
some act as anticancer and antitumor agents (Figure ii and iii).7a,b The application of Fluorescent
phenazine derivatives has been considered as photo-sensitizers in photodynamic therapy (PDT)8
in which the combination of light and photo-sensitizer creates highly reactive oxygen species
near the tumor to selectively destroy the targeted tissue.
Figure 1. Biologically active phenazine derivatives
Metal-catalyzed hydroarylation of aryl ring has emerged as a significant tool for the
construction of heterocycles and carbocycles9. In particular, Pd-catalyzed selective arylation for
2
ACS Paragon Plus Environment

Page 3 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the synthesis of polyheterocycle still remain challenging. Pioneering work on hydroarylation has
been reported by Fujiwara in 200010 using Pd-catalyst under acidic environment via C-H
activation (Scheme 1, i). In 2005, Tunge11 has described the hydroarylation of arylalkynes with
Pd-catalyst via electrophilic aromatic substitution. Later, Soriano12 explained the mechanism of
metal-catalyzed hydroarylation of alkynes and allenes (Scheme 1 i). Further, Au/Pt/Fe were also
employed for electrophilic cylization to synthesized fused heterocycles (Scheme 1 ii).13
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. Previous Synthetic Approaches
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 38
1
2
3
4
5
6
7
8
9
In 2013, Ellman group has reported the Rh-catalyzed domino approach to synthesize
phenazine derivatives via amination followed by cyclization (Scheme 1 iii).14 Other groups15 also
made significant contributions for the synthesis of heterocycles in the presence of strong acids.
However; the chemistry has been explored with limited substrates scope. In continuation of our
interest for the construction of fused heterocyclic scaffolds from alkynes16 herein, we report the
synthesis of medicinally important functionalized benzophenazines and quinoxaline analogues
by intramolecular hydroarylation from easily accessible 2-aryl 3- ethynylquinoxalines and
pyrazines, respectively (Scheme 1 iv).
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
RESULTS AND DISCUSSION
To find the optimal reaction condition, 2-phenyl-3-(phenylethynyl)quinoxaline 1a was
chosen as model substrates with different catalysts in various solvents (Table 1). We commenced
our study with Fujiwara’s conditions10 of Pd(OAc)2 (3 mol%) in TFA/DCM at 25 °C for 5 h, and
the desired product 2a was obtained in 40% yield (entry 1). On further increasing the reaction
o
temperature from 45oC to 65 C for 24 h, the product 2a was formed in 52 and 60% yield,
respectively (entries 2-3). Interestingly, when the reaction was performed in TFA without co-
o
solvent at 65 C for 24 h, 70% yield of the desired product was obtained (entry 4). Lower yield
was obtained at elevated temperature (entries 5-6). However, on decreasing the catalyst loading
from 3 to 2 mol %, (2a) was obtained in best yield (entry 7). While, further decreasing the catalyst
loading, 2a was observed in 64% yield in 36 h (entry 8). No significant results were obtained with
high catalyst loading (entries 9-10). The reaction with Pd(OCOCF3)2 afforded the 68% yield of
desired product 2a (entry11). Inferior results were obtained with other Pd catalyst like PdCl2,
Pd(CH3CN)4(BF4)2 and Pd2(dba)2 (entry 12-14). No product formation was observed, when
CH3COOH, DCE, DMF and DMSO were used as solvent (entries 15–18). When reaction was
4
ACS Paragon Plus Environment

Page 5 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
performed using Komeyama13b condition, i.e. 10 mol % of Fe(OTf)3 in DCE at 80 °C for 24 h,
only 20% yield of the desired product was achieved (entry 19). After screening various
conditions, we next examined other acetate salts of Fe and Cu in TFA at 65 °C for 24 h, however
we failed to obtained the desired product (entries 20-21). In order to understand the role of metal,
we performed the reaction in the absence of catalyst, no reaction was observed (entry 22).
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
Table 1. Optimization of Reaction Conditionsa
temp(°C)/
entry
catalyst/mol %
solvent
yield (%)
time (h)
25/5
1
2
Pd(OAc)2/3
Pd(OAc)2/2
Pd(OAc)2/3
Pd(OAc)2/3
Pd(OAc)2/3
Pd(OAc)2/2
Pd(OAc)2/2
Pd(OAc)2/1
Pd(OAc)2/5
Pd(OAc)2/10
Pd(OCOCF3)2/2
TFA/DCM(4:1)
TFA
40
52
60
70
65
62
70
64
61
56
68
45/24
65/24
65/24
70/24
85/24
65/24
65/36
65/24
65/24
65/24
3
TFA/DCM(4:1)
TFA
4
5
TFA
6
TFA
7
TFA
8
TFA
9
TFA
10
11
TFA
TFA
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 38
1
2
3
4
5
6
7
8
9
12
13
14
15
16
17
18
19
20
21
22
PdCl2/2
TFA
65/24
65/24
65/24
65/24
65/28
65/28
65/48
80/24
65/24
65/24
65/24
30
28
Pd(CH3CN)4(BF4)2/2 TFA
Pd2(dba)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Pd(OAc)2/2
Fe(OTf)3/10
Fe(OAc)3/10
Cu(OAc)2/10
-
TFA
20
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
CH3COOH
DCE
NR
NR
NR
NR
20
DMF
DMSO
DCE
TFA
NR
NR
NR
TFA
TFA
aReactions were performed using 0.5 mmol of o-alkynylaryls 1a, catalyst in 4.0 mL of solvent.
N.R. = no reaction, TFA = Trifluoroacetic acid, DCE = 1,2-Dichloroethane.
We next examined the scope and efficacy of the reaction by employing a wide range of 2-
aryl-3-(aryl/alkylethynyl)quinoxalines 1a−w with different electronic properties at aryl as well as
alkyne substituents (Scheme 2). Reaction of 2-phenyl-3-(phenylethynyl) quinoxaline 1a provided
the fused cyclized product 2a in 70% yield. Substrates 1b bearing p-NMe2 group to the triple
bonded phenyl ring afforded the corresponding desired product 2b in 65% yield. The reaction was
well tolerated with aryl as well heteroaryl alkynes (2c−e). 3,5-Dimethoxy arenes having aromatic
and aliphatic alkynes afforded the product 2f−i in 96−82% yields. Quinoxalines 1j−r with
electron rich and electron deficient alkynes gave the corresponding product 2j−r in good to
excellent yields. The structure of phenazine 2j was further supported by X-ray crystallographic
6
ACS Paragon Plus Environment

Page 7 of 38
The Journal of Organic Chemistry
1
2
3
4
analysis (See, ESI). It is note worthy, that the 3-thienyl substituted quinoxalines were also capable
5
6
to give corresponding thienophenazine 2s−w in 75−88% yields.
7
8
9
Scheme 2. Scope of 2-Aryl-3-(alkynyl)quinoxalinesa
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
aUsing optimized conditions (entry 7, Table 1).
We further extended the scope of the reaction with 6-methyl/chloro substituted alkynyl
quinoxaline 3a−j (Scheme 3). The reaction was compatible with aryl and alkyl substituent on
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 38
1
2
3
4
5
6
7
8
9
quinoxaline and afforded the corresponding single regioisomers 4a–j in 73–88% yield. Both
electron-rich and electron-deficient alkyne substituted quinoxalines afforded the corresponding
product in good yields. The formation of regioselective product was confirmed by the X-ray
crystallographic analysis of 4c (See, ESI). The reaction condition was also successful with benzo
fused quinoxaline 3k and afforded the desired product 4k in 86% 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
Scheme 3. Scope of Substituted Quinoxalinesa
aUsing optimized conditions (entry 7, Table 1).
Next, we explored the scope of the developed protocol for the synthesis of benzo[f]quinoxaline
6a−b from pyrazines 5a−b in 12 h, probably due to the electronic effect of the substrate (Scheme
4). The reaction afforded 85% yield of quinoxaline 6a with trimethoxy substituted
8
ACS Paragon Plus Environment

Page 9 of 38
The Journal of Organic Chemistry
1
2
3
4
ethynylpyrazine 5a. While pyrazine 5b (R = p-Et) gave the desired hydroarylated product 6b in
5
6
82% yield.
7
8
9
Scheme 4. Synthesis of Benzo[f]quinoxaline
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
Encouraged by the above results, we next examine the scope of hydroarylation via
elctrophilic metalation on electron-deficient aryl substrate 1x−z (Scheme 5). Interestingly, an
uncyclized enolic form of quinoxalines 7a−c were obtained in 86−90% yields via hydration of
C-C triple bonds of alkynes to ketones17 which tautomerize to furnished enolic products. The
product has been confirmed by X-ray crystallography (Scheme 5a).
Scheme 5. Unusual Hydroxylation
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 38
1
2
3
4
5
6
7
8
9
The probable reason might be due to the nature of electron-poor arenes which restrain
electrophilic metalation on aromatic C-H bond. Later, we performed a reaction on 3-
chloroquinoxaline 1' and surprisingly we observed a cyclized product 3' rather than 2' which
may be through the electrophilic attack of Pd-TFA complex at C-3 position of quinoxaline 1'
followed by coordination with alkyne to generate cyclized compound 3' (Scheme 5b).
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 6. Deuterium Labeling Experiments
To further validate the reaction mechanism, when quinoxaline 1 was treated with TFA under
optimized reaction condition followed by work up via D2O, no deuterium incorporation was
observed in product 2a (Scheme 6). This suggested that the exchange of proton occur in situ in the
reaction. It is interesting to note that, when deuterated TFA was used as a solvent; products 8a-b
were obtained in 64−65% yields with 84−90% incorporation of deuterium. This is probably due to
electron-rich aromatic rings in compound 1p and 1i which favours deuteration at more than one
position. Even in the products, the may occur due to a highly acidic TFA solvent under the
reaction conditions. As from the past decade deuterated drugs has gained importance due to their
medicinal value and application in the study of reaction mechanism.18
10
ACS Paragon Plus Environment

Page 11 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
On the basis of the above preliminary results and literature information, a plausible
mechanism showing two routes was proposed in Scheme 7. The deuterium isotopic experiments
shown in scheme 6 revealed that vinyl and aromatic H or D in all adducts results from the
protonation of vinyl-Pd complex10a,b S by deuterated TFA or TFA (Scheme 7). The facile
formation of complex Q through electrophilic metalation of the aromatic C–H bond from cationic
Pd(II) species has been well documented.10 This reaction required TFA for the protonation of a
vinyl-Pd intermediate S as reaction failed in other solvents like acetic acid.
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 7. Plausible Mechanism
Thus, the electrophilic attack of the aromatic C–H bond by cationic Pd(II) species to
generate Q followed by coordination of alkyne to give R. Then, trans insertion19 of C–C triple
bonds to the aryl-Pd bond results in species S, and later, 1/6 aryl-Pd adduct (S) releases Pd(II) to
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 38
1
2
3
4
5
6
7
8
9
give 1,6-D-benzo[a]phenazines. Alternatively, the reaction may proceed via coordination of Pd(II)
cationic species with alkyne P’ to generate vinyl palladium species Q’ which forms Wheland
intermediate10 R’ through electrophilic cylization. The intermediate R’ then undergoes
aromatization followed by protodemetallation to give product 8 as shown in path B.
In conclusion, we have described an intramolecular alkyne-hydroarylation reaction in the
presence of Pd-catalyst under strong acidic condition. The reaction was well tolerated with
electron-rich and electron-neutral groups and provided the intriguing benzophenazines and
quinoxalines in good yields, while new enolic compounds were obtained with electron–
withdrawing substitutents. Various preliminary studies involving deuterium-labeling experiments
were performed to support the mechanistic pathway via electrophilic metalation on aromatic C-H
bond over alkyne activation. Further the structure of benzophenazine derivatives were confirmed
by the X-ray crystallographic studies.
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
Experimental Section
General Information and Method. Nuclear magnetic resonance spectra were recorded in
1
CDCl3, H NMR (400 MHz) and 13C NMR (100 MHz), at ambient temperature. Chemical
shifts (δ) for all protons are reported in parts per million (ppm) and were measured relative to
the residual CHCl3 resonance as an internal reference in the deuterated solvent. Chemical shifts
were reported as parts per million (δ in ppm) using tetramethylsilane (TMS) as internal standard
or by reference to proton resonances resulting from incomplete deuteration of the NMR solvent.
The following abbreviations were used to describe the multiplicities: when appropriate s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet. Reactions
were monitored using thin-layer chromatography on commercially prepared silica gel plates and
visualized by either UV irradiation or by staining with I2. Chemical yields are referred to the
12
ACS Paragon Plus Environment

Page 13 of 38
The Journal of Organic Chemistry
1
2
3
4
pure isolated substances. Chromatographic purification of the label compounds was
5
6
accomplished by column chromatography using 100− 200 mesh size silica gels.
7
8
9
General Procedure for the Synthesis of starting substrate
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
General experimental procedure for sequential Sonogashira/Suzuki coupling reaction and
Analytic data of 1a-z, 3a-k and 5a-b
To a solution of substituted 2,3-dichloroquinoxaline/ 2,3-dichloropyrazine (0.5 mmol) in DMF (2
mL), 2 mol% of Pd(PPh3)2Cl2 was added. The reaction vial was then sealed and flushed with
nitrogen. Then, 1.5 equiv of Et3N and 0.51 mmol of alkyne 2 were added to the reaction mixture.
The reaction was then stirred at 70 °C until TLC revealed complete conversion of the starting
material. After the completion of the first coupling reaction (Monitored by TLC) 3 mol% of
Pd(PPh3)2Cl2, 0.5 mmol of boronic acid, 1.5 equiv of Et3N was added under nitrogen
atmosphere. The reaction was then stirred at 80 °C until TLC revealed complete conversion of
the starting material. The reaction mixture was then allowed to cool and diluted with H2O and
extracted with EtOAc (3X10 mL). The combined organic layers were dried over Na2SO4,
concentrated under vacuum, and purified by column chromatography using 100−200 mesh size
silica gels (hexane: ethylacetate) to afford the corresponding product.
2-Phenyl-3-(phenylethynyl)quinoxaline (1a). The product was obtained as a yellow needles (110.2
mg, 72%): mp 108–112 °C; 1H NMR (400 MHz, CDCl3) δ 8.16–8.09 (m, 4H), 7.78–7.74 (m, 2H),
13
7.59–7.54 (m, 3H), 7.50–7.47 (m, 2H), 7.39–7.30 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ
155.1, 141.0, 140.7, 138.1, 137.6, 132.1, 130.6, 130.3, 129.7, 129.3, 128.7, 128.4, 128.1, 121.7,
95.0, 88.3; HRMS (ESI) calcd for [C22H14N2] requires [M+H]+ 307.1235, found 307.1224.
N,N-Dimethyl-4-((3-phenylquinoxalin-2-yl)ethynyl)aniline.(1b).The product was obtained as a
1
yellow needles (132.7 mg, 76%): mp 120–124 °C; H NMR (400 MHz, CDCl3) δ 8.11–8.07 (m,
4H), 7.74–7.67 (m, 2H), 7.57–7.50 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 9.3 Hz, 2H), 2.97
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 38
1
2
3
4
5
6
7
8
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.8, 150.8, 141.0, 140.2, 138.9, 137.8, 133.5, 130.0,
129.8, 129.6, 129.4, 129.1, 128.4, 127.9, 111.5, 107.7, 98.0, 87.6, 39.9; HRMS (ESI) calcd for
[C24H19N3] requires [M+Na]+ 372.1477, found 372.1474.
9
2-(p-Tolyl)-3-(p-tolylethynyl)quinoxaline (1c). The product was obtained as a yellow needles
(128.7 mg, 77%): mp 113–117 °C; 1H NMR (400 MHz, CDCl3) δ 8.20–8.17 (m, 2H), 8.13 (d, J =
7.6 Hz, 2H), 7.81–7.79 (m, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 7.6
Hz, 2H), 2.54 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 140.7, 140.5, 139.8,
139.6, 138.0, 134.6, 131.9, 130.3, 129.9, 129.5, 129.1, 128.7, 128.5, 118.6, 95.1, 88.0, 21.5, 21.4;
HRMS (ESI) calcd for [C24H18N2] requires [M+Na]+ 357.1368, found 357.1354.
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-(Thiophen-3-ylethynyl)-3-(p-tolyl)quinoxaline (1d). The product was obtained as a yellow
needles (120.7 mg, 74%): mp 144–149 °C; 1H NMR (400 MHz, CDCl3) δ 8.11–8.06 (m, 2H), 8.0
(d, J = 7.6 Hz, 2H), 7.74–7.69 (m, 2H), 7.58 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.28–
7.24 (m, 1H), 7.15 (d, J = 3.8 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.7,
140.8, 140.7, 139.8, 137.9, 134.6, 131.2, 130.5, 130.0, 129.65, 129.56, 129.2, 128.8, 128.6, 125.7,
120.9, 90.3, 88.2, 21.4; HRMS (ESI) calcd for [C21H14N2S] requires [M+Na]+ 349.0775, found
349.0768.
2-((4-Tert-butyl)phenyl)ethynyl)-3-(4-ethylphenyl)quinoxaline (1e). The product was obtained as a
1
yellow oil (138.6 mg, 71%); H NMR (400 MHz, CDCl3) δ 8.05–8.03 ( m, 2H), 7.97 (d, J =7.6
Hz, 2H), 7.69–7.65 (m, 2H), 7.38–7.36 (m, 2H), 7.32–7.29 (m, 4H), 2.70 (q, J =7.6 Hz, 2H), 1.26–
1.23(m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.1, 153.1, 146.1, 140.9, 140.7, 138.3, 135.0,
131.9, 130.5, 130.1, 129.7, 128.6, 127.7, 125.5, 118.7, 115.2, 95.4, 88.1, 34.9, 31.1, 28.9, 15.6;
HRMS (ESI) calcd for [C28H26N2] requires [M+H]+ 391.2174, found 391.2168.
2-(3,5-Dimethoxyphenyl)-3-(o-tolylethynyl)quinoxaline (1f). The product was obtained as a yellow
1
needles (155.9 mg, 82%): mp 125–129 °C; H NMR (400 MHz, CDCl3) δ 8.22–8.16 ( m, 2H),
7.85–7.80 (m, 2H), 7.59–7.57 (m, 1H), 7.34–7.30 (m, 1H), 7.25–7.22 (m, 4H), 6.67 (t, J = 2.4 Hz,
1H), 3.89 (s, 6H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 155.0, 141.20, 141.16,
140.4, 139.5, 138.3, 132.8, 130.6, 130.3, 129.6, 129.2, 128.7, 125.6, 121.4, 107.6, 101.9, 94.4,
14
ACS Paragon Plus Environment

Page 15 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
91.6, 55.5, 20.3; HRMS (ESI) calcd for [C25H20N2O2] requires [M+Na]+ 403.1422, found
403.1415.
7
8
2-((4-(tert-Butyl)phenyl)ethynyl)-3-(3,5-dimethoxyphenyl)quinoxaline (1g). The product was
9
1
obtained as a yellow needles (179.5 mg, 85%): mp 133–137 °C; H NMR (400 MHz, CDCl3) δ
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
8.14–8.10 (m, 2H), 7.78–7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.24–
7.23 (m, 2H), 6.65–6.64 (m, 1H), 3.85 (s, 6H), 1.30 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
160.6, 154.9, 153.1, 146.4, 141.1, 138.3, 132.0, 130.5, 128.7, 128.1, 127.6, 126.9, 125.6, 118.7,
107.8, 102.3, 95.9, 87.9, 55.54, 55.49, 34.9, 31.1; HRMS (ESI) calcd for [C28H26N2O2] requires
[M+H]+ 423.2073, found 423.2066.
2-(Cyclopropylethynyl)-3-(3,5-dimethoxyphenyl)quinoxaline (1h). The product was obtained as a
1
yellow needles (165.1 mg, 81%): mp 115–121 °C; H NMR (400 MHz, CDCl3) δ 8.09–8.03 (m,
2H), 7.73–7.70 (m, 2H), 7.185–7.154 (m, 2H), 6.60 –6.59 (m, 1H), 3.87 (s, 6H), 1.51–1.44 (m,
1H), 0.92–0.84 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 154.0, 140.3, 139.7, 138.8,
137.7, 129.74, 129.67, 128.6, 127.9, 107.1, 101.5, 100.9, 74.5, 55.0, 54.9, 8.4, 0.0; HRMS (ESI)
calcd for [C21H18N2O2] requires [M+Na]+ 353.1266, found 353.1261.
2-(3,5-Dimethoxyphenyl)-3-(hex-1-yn-1-yl)quinoxaline (1i). The product was obtained as a yellow
oil (118.6 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 8.20–8.13 (m, 2H), 7.84–7.79 (m, 2H), 7.24–
7.23 (m, 2H), 6.68 (s, 1H), 3.94 (s, 6H), 2.54 (t, J = 6.7 Hz, 2H), 1.67–1.60 (m, 2H), 1.49–1.40 (m,
2H), 0.96 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, 154.6, 140.9, 140.3,
139.4, 138.3, 130.3, 130.1, 129.1, 128.5, 107.6, 101.8, 98.0, 79.7, 55.4, 29.9, 22.0, 19.5, 13.5;
HRMS (ESI) calcd for [C22H22N2O2] requires [M+H]+ 347.1760, found 347.1741.
2-(Phenylethynyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1j). The product was obtained as a
1
yellow needles (176.4 mg, 89%): mp 189–193 °C; H NMR (400 MHz, CDCl3) δ 7.99 (s, 2H),
13
7.63 (s, 2H), 7.35 (s, 2H), 7.24 (s, 5H), 3.82 (s, 3H), 3.77 (s, 6H); C{1H} NMR (100 MHz,
CDCl3) δ 154.4, 152.8, 140.7, 140.3, 139.2, 137.6, 132.7, 131.9, 130.6, 130.1, 129.5, 129.0, 128.5,
128.4, 121.3, 106.9, 95.1, 88.3, 60.8, 56.0; HRMS (ESI) calcd for [C25H20N2O3] requires [M+Na]+
419.1372, found 419.1368.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 38
1
2
3
4
5
6
2-(p-Tolylethynyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1k). The product was obtained as a
1
yellow needles (184.7 mg, 90%): mp 148–152 °C; H NMR (400 MHz, CDCl3) δ 8.01–7.99 (m,
7
8
9
2H), 7.65–7.63 (m, 2H), 7.27–7.24 (m, 4H), 7.03 (d, J = 7.6 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 6H),
2.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5, 152.9, 140.9, 140.2, 139.3, 138.0, 132.9,
132.0, 130.6, 130.2, 129.3, 129.1, 128.6, 118.4, 106.9, 104.5, 95.8, 87.9, 60.9, 56.2, 21.6; HRMS
(ESI) calcd for [C26H22N2O3] requires [M+Na]+ 433.1528, found 433.1536.
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-(o-Tolylethynyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1l). The product was obtained as a
1
yellow needles (164.1 mg, 80%): mp 152–156 °C; H NMR (400 MHz, CDCl3) δ 8.07–8.04 (m,
2H), 7.71–7.69 (m, 2H), 7.41 (d, J = 6.8 Hz, 1H), 7.21–7.18 (m, 3H), 7.12–7.07 (m, 2H), 3.85 (s,
3H), 3.80 (s, 6H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5, 152.8, 140.8, 140.7,
140.1, 139.1, 137.9, 132.9, 130.4, 130.0, 129.4, 128.9, 128.4, 125.4, 121.0, 106.8, 94.1, 91.6, 60.6,
55.9, 20.1; HRMS (ESI) calcd for [C26H22N2O3] requires [M+Na]+ 433.1528, found 433.1540.
2-((4-Methoxyphenyl)ethynyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1m). The product was
1
obtained as a yellow needles (187.6 mg, 88%): mp 132–136 °C; H NMR (400 MHz, CDCl3) δ
8.00–7.98 (m, 2H), 7.64–7.62 (m, 2H), 7.31 (d, J = 9.1 Hz, 2H), 7.24 (s, 2H), 6.74 (d, J = 8.4 Hz,
2H), 3.83 (s, 3H), 3.79 (s, 6H), 3.69 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 154.4,
152.9, 140.9, 140.3, 139.2, 138.1, 133.7, 132.9, 130.4, 130.1, 129.1, 128.6, 114.2, 113.4, 106.9,
95.9, 87.6, 60.9, 56.1, 55.3; HRMS (ESI) calcd for [C26H22N2O4] requires [M+Na]+ 449.1477,
found 449.1469.
N,N-Dimethyl-4-((3-(3,4,5-trimethoxyphenyl)quinoxalin-2-yl)ethynyl) aniline (1n). The product
was obtained as a yellow needles (184.5 mg, 84%): mp 183–187 °C; 1H NMR (400 MHz, CDCl3)
δ 8.07–8.05 (m, 2H), 7.70–7.69 (m, 2H), 7.33–7.31 (m, 4H), 6.58 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H),
3.89 (s, 6H), 2.96 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.6, 153.0, 151.0, 141.2, 140.2,
139.3, 138.8, 133.7, 133.3, 130.2, 130.1, 129.2, 128.6, 111.7, 107.7, 107.1, 98.5, 87.8, 61.1, 56.3,
40.1; HRMS (ESI) calcd for [C27H25N3O3] requires [M+Na]+ 462.1794, found 462.1785.
2-((4-(Trifluoromethyl)phenyl)ethynyl)-3-(3,4,5-trimethoxyphenyl) quinoxaline (1o). The product
was obtained as a yellow needles (176.4 mg, 76%): mp 182–186 °C; 1H NMR (400 MHz, CDCl3)
δ 8.04 (s, 2H), 7.69 (s, 2H), 7.51 (s, 4H), 7.25 (s, 2H), 3.86 (s, 3H), 3.82 (s, 6H); 13C{1H} NMR
16
ACS Paragon Plus Environment

Page 17 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(100 MHz, CDCl3) δ 154.6, 153.0, 140.8, 140.6, 139.5, 137.0, 132.6, 132.2, 131.1, 130.4, 129.1,
1
128.7, 125.41 (q, JC-F = 15.2 Hz, 1C), 125.2, 124.9, 122.1, 106.9, 93.0, 90.1, 60.9, 56.2; HRMS
(ESI) calcd for [C26H19F3N2O3] requires [M+Na]+ 487.1245, found 487.1243.
9
2-((2-Fluorophenyl)ethynyl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1p). The product was
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
obtained as a yellow needles (155.4 mg, 75%): mp 162–166 °C; H NMR (400 MHz, CDCl3) δ
8.16–8.13 ( m, 2H), 7.81–7.78 (m, 2H), 7.54–7.50 (m, 1H), 7.34–7.33 (m, 1H), 7.26–7.25 (m, 1H),
7.16–7.08 (m, 2H), 6.71(s, 1H), 3.94–3.92 (m, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3 (d,
1JC-F =253.9 Hz, 113C), 154.6, 153.0, 140.9, 140.6, 137.4, 133.9, 133.8, 132.6, 131.6–131.4 (m,
113C), 130.9, 129.1, 128.8, 124.2–124.0 (m, 113C), 115.9–115.5 (m, 113C), 110.3 (d, 2JC-F =15.3 Hz,
113C), 107.0, 106.9, 104.6, 92.7, 88.3, 60.8, 56.2; HRMS (ESI) calcd for [C25H19FN2O3] requires
[M+H]+ 415.1458, found 415.1487.
2-(3-Phenoxyprop-1-yn-1-yl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1q). The product was
1
obtained as a yellow needles (153.5 mg, 72%): mp 100–104 °C; H NMR (400 MHz, CDCl3) δ
8.12–8.08 (m, 2H), 7.80–7.74 (m, 2H), 7.27–7.24 (m, 4H), 6.99–6.91 (m, 3H), 4.93 (s, 2H), 3.90
(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.5, 154.2, 153.0, 140.76, 140.67, 139.5, 136.6,
132.3, 131.1, 130.3, 129.5, 129.1, 128.7, 121.7, 114.6, 106.8, 89.8, 85.5, 60.9, 56.4, 56.1; HRMS
(ESI) calcd for [C26H22N2O4] requires [M+Na]+ 449.1477, found 449.1479.
2-(4-Phenylbut-1-yn-1-yl)-3-(3,4,5-trimethoxyphenyl)quinoxaline (1r). The product was obtained
as a yellow needles (144.3 mg, 68%): mp 94–98 °C; 1H NMR (400 MHz, CDCl3) δ 8.10–8.07 (m,
2H), 7.75–7.73 (m, 2H), 7.27–7.22 (m, 4H), 7.19–7.13 (m, 3H), 3.91 (s, 6H), 3.89 (s, 3H), 2.90 (t,
J = 6.8 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.2, 152.9, 140.7,
140.4, 139.8, 139.3, 137.8, 132.8, 130.5, 130.1, 129.0, 128.5, 128.4, 128.2, 126.4, 106.9, 96.4,
80.4, 60.9, 56.1, 34.3, 22.0; HRMS (ESI) calcd for [C27H24N2O3] requires [M+Na]+ 447.1685,
found 447.1702.
((4-Ethylphenyl)ethynyl)-3-(thiophen-3-yl)quinoxaline (1s). The product was obtained as a yellow
needles (129.3 mg, 76%): mp 86–91 °C; 1H NMR (400 MHz, CDCl3) δ 8.39–8.37 (m, 1H), 8.03–
7.99 (m, 2H), 7.95–7.94 (m, 1H), 7.68–7.63 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.39–7.37 (m, 1H),
7.18–7.15 (m, 2H), 2.61 (q, J = 7.8 Hz, 2H), 1.18 (t, J = 7.8 Hz, 3H); 13C{1H} NMR (100 MHz,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 38
1
2
3
4
5
6
7
8
CDCl3) δ 149.5, 146.4, 140.6, 139.0, 137.4, 132.2, 130.6, 130.0, 129.1, 128.9, 128.6, 128.2, 128.0,
125.3, 118.8, 95.4, 88.2, 29.0, 15.2; HRMS (ESI) calcd for [C22H16N2S] requires [M+H]+
341.1112, found 341.1109.
9
2-((4-(tert-Butyl)phenyl)ethynyl)-3-(thiophen-3-yl)quinoxaline (1t). The product was obtained as a
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
yellow needles (130.8 mg, 71%): mp 88–93 °C; H NMR (400 MHz, CDCl3) δ 8.44–8.42 (m,
1H), 8.08–8.03 (m, 2H), 8.00–7.98 (m, 1H), 7.74–7.69 (m, 2H), 7.56–7.53 (m, 2H), 7.45–7.42 (m,
1H), 7.41–7.39 (m, 2H), 1.39 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.3, 149.6, 140.73,
140.68, 137.5, 132.0, 130.6, 130.0, 129.1, 128.9, 128.7, 128.0, 125.6, 125.3, 118.6, 95.4, 88.3,
35.0, 31.1; HRMS (ESI) calcd for [C24H20N2S] requires [M+H]+ 369.1425, found 369.1428.
2-((2-Fluorophenyl)ethynyl)-3-(thiophen-3-yl)quinoxaline (1u). The product was obtained as a
yellow needles (120.5 mg, 73%): mp 122–126 °C; 1H NMR (400 MHz, CDCl3) δ 8.60–8.59 ( m,
1H), 8.09–8.04 (m, 3H), 7.76–7.69 (m, 2H), 7.66–7.62 (m, 1H), 7.45–7.41 (m, 1H), 7.40–7.36 (m,
1H), 7.18–7.11 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3 (d, 1JC-F =253.9 Hz, 1C), 149.2,
140.8, 140.5, 138.5, 136.6, 134.0, 131.5 (d, J = 7.6, 1C), 130.8, 130.0, 129.0, 128.8, 128.7, 128.37,
128.35, 125.3, 124.2 (d, 4JC-F = 3.8 Hz, 113C), 115.7 (d, 2JC-F = 20.1 Hz, 1C), 110.3 (d, 3JC-F = 14.3
Hz, 1C), 93.1, 88.2; HRMS (ESI) calcd for [C20H11FN2S] requires [M+H]+ 331.0705, found
331.0728.
2-(Cyclohexylethynyl)-3-(thiophen-3-yl)quinoxaline (1v). The product was obtained as a yellow oil
(106.6 mg, 67%); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.98–7.96 (s, 2H), 7.89 (d, J = 4.56
Hz, 1H), 7.64 –7.62 (m, 2H), 7.35–7.33 (m, 1H), 2.69–2.62 (m, 1H), 1.91–1.89 (m, 2H), 1.72–1.65
(m, 2H), 1.58–1.48 (m, 2H), 1.33–1.17 (m, 4H); C{1H} NMR (100 MHz, CDCl3) δ 149.4,
13
140.50, 140.47, 139.03, 137.6, 130.3, 129.8, 129.0, 128.9, 128.5, 127.9, 125.0, 101.1, 80.2, 31.8,
30.0, 25.7, 24.9; HRMS (ESI) calcd for [C20H18N2S] requires [M+Na]+ 341.1088, found 341.1095.
2-(Cyclopropylethynyl)-3-(thiophen-3-yl)quinoxaline (1w). The product was obtained as a yellow
1
needles (88.4 mg, 64%): mp 78–82°C; H NMR (400 MHz, CDCl3) δ 8.29–8.28 (m, 1H), 7.94–
7.90 (m, 2H), 7.85 (d, J = 5.3 Hz, 1H), 7.60 –7.56 (m, 2H), 7.32–7.30 (m, 1H), 1.52–1.46 (m, 1H),
0.88–0.86 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 140.4, 140.3, 138.9, 137.4, 130.1,
18
ACS Paragon Plus Environment

Page 19 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
129.7, 128.9, 128.7, 128.3, 127.7, 125.0, 100.6, 75.6, 8.8, 0.5; HRMS (ESI) calcd for [C17H12N2S]
requires [M+Na]+ 299.0619, found 299.0622.
7
8
9
2-((4-(tert-Butyl)phenyl)ethynyl)-3-(4-nitrophenyl)quinoxaline (1x). The product was obtained as a
yellow needles (107.9 mg, 53%): mp 111–116 °C; 1H NMR (400 MHz, CDCl3) δ 8.42–8.39 (m,
2H), 8.32–8.30 (m, 2H), 8.15–8.11 (m, 2H), 7.84–7.79 (m, 2H), 7.42–7.37 (m, 4H), 1.31 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 152.4, 148.4, 143.8, 141.4, 140.5, 137.7, 131.9, 131.2,
131.0, 130.8, 129.4, 128.8, 125.7, 123.3, 118.0, 96.4, 87.1, 35.0, 31.0; HRMS (ESI) calcd for
[C26H21N3O2] requires [M+H]+ 408.1712, found 408.1700.
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
Methyl 4-(3-((4-methoxyphenyl)ethynyl)quinoxalin-2-yl)benzoate (1y). The product was obtained
as a yellow needles (116.3 mg, 59%): mp 150–155 °C; 1H NMR (400 MHz, CDCl3) δ 8.17–8.15
(m, 4H), 8.07–8.05 (m, 2H), 7.73–7.69 (m, 2H), 7.36–7.33 (m, 2H), 6.81–6.79 (m, 2H), 3.91 (s,
13
3H), 3.75 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 166.8, 160.8, 153.7, 142.0, 141.2, 140.5,
138.1, 133.8, 130.9, 130.7, 130.6, 129.8, 129.3, 128.7, 114.3, 113.4, 96.1, 87.2, 55.3, 52.3; HRMS
(ESI) calcd for [C25H18N2O3] requires [M+H]+ 395.1396, found 395.1384.
3-((3-Methoxyphenyl)ethynyl)-6-methyl-2-(4-(trifluoromethyl)phenyl)quinoxaline
(1z).
The
product was obtained as a yellow needles (115.2 mg, 57%): mp 109–112 °C; 1H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 7.6 Hz, 2H), 8.09–8.03 (m, 2H), 7.76–7.71 (m, 4H), 7.20–7.16 (m, 1H), 6.97
13
(d, J =7.6 Hz, 1H), 6.88–6.86 (m, 2H), 3.70 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 159.3,
153.5, 141.3, 140.6, 137.6, 131.0, 130.9, 130.2, 130.1, 129.6, 129.4, 129.3, 125.04 (q, 1JC-F = 15.2
Hz, 1C), 124.6, 122.2, 117.0, 116.5, 116.2, 95.6, 87.5, 55.3; HRMS (ESI) calcd for [C24H15F3N2O]
requires [M+H]+ 405.1215, found 405.1209.
2-((4-(tert-Butyl)phenyl)ethynyl)-3-chloroquinoxaline (1’). The product was obtained as a yellow
1
needles (137.9 mg, 86%): mp 111–116 °C; H NMR (400 MHz, CDCl3) δ 8.10–8.07 (m, 1H),
8.00–7.96 (m, 1H), 7.78–7.74 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.43 (d, J =8.4 Hz, 2H), 1.33 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 148.1, 140.2, 138.8, 132.3, 131.2, 130.6, 128.9,
128.7, 125.5, 118.1, 97.8, 85.1, 35.0, 31.0; HRMS (ESI) calcd for [C20H17ClN2] requires [M+H]+
321.1159, found 321.1163.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 38
1
2
3
4
5
6
7
8
9
6-Methyl-2-phenyl-3-(p-tolylethynyl)quinoxaline (3a). The product was obtained as a yellow
needles (135.4 mg, 81%): mp 130–134 °C; 1H NMR (400 MHz, CDCl3) δ 8.01–8.00 (m, 2H), 7.92
(d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.51–7.44 (m, 4H), 7.29 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz,
2H), 2.51 (s, 3H), 2.27 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.1, 141.2, 141.0, 140.7,
139.8, 139.1, 138.0, 137.7, 132.8, 131.9, 129.6, 129.1, 128.7, 128.0, 127.4, 118.6, 95.2, 88.0, 21.8,
21.5; HRMS (ESI) calcd for [C24H18N2] requires [M+H]+ 335.1548, found 335.1572
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
3-(Cyclopropylethynyl)-6-methyl-2-phenylquinoxaline (3b). The product was obtained as a yellow
needles (96.6 mg, 68%): mp 111–116 °C; 1H NMR (400 MHz, CDCl3) δ 8.00–7.93 (m, 3H), 7.86–
7.82 (m, 1H), 7.58–7.49 (m, 4H), 2.58 (s, 3H), 1.50–1.42 (m, 1H), 0.89–0.82 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3) δ 153.5, 140.4, 140.2, 138.4, 137.3, 132.1, 129.0, 128.8, 128.2, 127.5,
127.4, 126.8, 100.2, 74.8, 21.4, 8.3, 0.00; HRMS (ESI) calcd for [C20H16N2] requires [M+H]+
285.1392, found 285.1391.
6-Methyl-3-(p-tolylethynyl)-2-(3,4,5-trimethoxyphenyl)quinoxaline (3c). The product was obtained
as a yellow needles (186.7 mg, 88%): mp 124–128 °C; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J =
8.4 Hz, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.39–7.34 (m, 3H), 7.26 (s, 2H), 7.17–7.15 (m,
1H), 3.94 (s, 3H), 3.91 (s, 6H), 2.61 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
153.3, 152.9, 141.0, 140.9, 140.1, 139.2, 139.0, 133.1, 133.0, 132.0, 129.3, 128.6, 127.4, 118.5,
107.0, 104.6, 95.5, 88.1, 60.9, 56.3, 56.2, 21.9, 21.6; HRMS (ESI) calcd for [C27H24N2O3] requires
[M+H]+ 425.1865, found 425.1882.
3-(Hex-1-yn-1-yl)-6-methyl-2-(3,4,5-trimethoxyphenyl)quinoxaline (3d). The product was obtained
as a yellow oil (160.0 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 7.91–7.88 ( m, 1H), 7.96–7.76 m,
1H), 7.50 (d, J = 8.5 Hz, 1H), 7.20–7.19 (m, 2H), 3.88 (s, 6H), 3.85 (s, 3H), 2.50 (s, 3H), 2.39 (t, J
= 7.6 Hz, 2H), 1.53–1.45 (m, 2H), 1.34–1.25 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 153.6, 152.9, 140.9, 140.7, 139.2, 138.8, 133.2, 132.8, 128.6, 128.1, 127.3, 106.9,
97.4, 80.0, 60.9, 56.2, 30.1, 22.0, 21.9, 19.5, 13.5; HRMS (ESI) calcd for [C24H26N2O3] requires
[M+H]+ 391.2022, found 391.2021.
3-((4-Tert-butyl)phenyl)ethynyl)-2-(3,5-dimethoxyphenyl)-6-methylquinoxaline (3e). The product
was obtained as a yellow semi-solid (200.8 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=
20
ACS Paragon Plus Environment

Page 21 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8.4 Hz, 1H), 7.90–7.89 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.46–7.44 (m, 2H), 7.38–7.36 (m, 2H),
7.24–7.23 (m, 2H), 6.65–6.64 (m, 1H), 3.86(s, 6H), 2.61(s, 3H), 1.31 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 160.5, 154.0, 153.0, 141.2, 140.9, 139.6, 139.0, 132.9, 131.9, 128.8, 128.1, 127.5,
125.5, 118.7, 107.7, 102.2, 95.6, 88.0, 55.54, 55.50, 34.9, 31.1, 21.9; HRMS (ESI) calcd for
[C29H28N2O2] requires [M+H]+ 437.2229, found 437.2229.
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
6-Methyl-2-(thiophen-3-yl)-3-(p-tolylethynyl)quinoxaline (3f). The product was obtained as a
1
yellow needles (129.3 mg, 76%): mp 129–134 °C; H NMR (400 MHz, CDCl3) δ 8.48–844 (m,
1H), 8.05–8.03 (m, 1H), 8.00–7.97 (m, 1H), 7.87 (s, 1H), 7.60–7.53 (m, 3H), 7.49–7.47 (m, 1H),
7.23 (d, J = 7.6 Hz, 2H), 2.61(s, 3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.7,
141.3, 140.7, 140.5, 140.0, 139.1, 137.1, 132.9, 132.0, 129.3, 128.8, 128.5, 127.6, 127.4, 125.1,
118.6, 95.0, 88.3, 21.8, 21.6; HRMS (ESI) calcd for [C22H16N2S] requires [M+H]+ 341.1112,
found 341.1121.
6-Chloro-3-(phenylethynyl)-2-(3,4,5-trimethoxyphenyl)quinoxaline (3g). The product was obtained
as a yellow needles (172.3 mg, 80%): mp 155–159 °C; 1H NMR (400 MHz, CDCl3) δ 8.106–8.103
(m, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 2.3 and 9.1 Hz, 1H), 7.50–7.48 (m, 2H), 7.40–7.34
(m, 5H), 3.94 (s, 3H), 3.89 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.7, 153.0, 141.1, 139.6,
139.0, 138.7, 136.1, 132.4, 132.1, 131.7, 130.3, 129.9, 128.6, 127.5, 121.3, 106.9, 96.1, 88.2, 61.0,
56.2; HRMS (ESI) calcd for [C25H19ClN2O3] requires [M+H]+ 431.1162, found 431.1183.
6-Chloro-3-(thiophen-3-ylethynyl)-2-(3,4,5-trimethoxyphenyl) quinoxaline (3h). The product was
1
obtained as a yellow needles (181.3 mg, 83%): mp 157–161 °C; H NMR (400 MHz, CDCl3) δ
8.06–7.97(m, 2H), 7.67–7.63 (m, 1H), 7.58–7.57 (m, 1H), 7.34–7.27 (m, 3H), 7.12 (d, J = 5.0 Hz,
1H), 3.92 (s, 3H), 3.88 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.0, 141.1, 139.6, 139.0,
138.7, 136.1, 132.4, 131.7, 131.6, 130.6, 129.6, 127.5, 126.1, 120.5, 107.0, 99.2, 91.6, 88.0, 61.0,
56.3, 56.2; HRMS (ESI) calcd for [C23H17ClN2O3S] requires [M+H]+ 437.0727, found 437.0743.
6-Chloro-2-(3,5-dimethoxyphenyl)-3-(phenylethynyl)quinoxaline (3i). The product was obtained as
a yellow needles (170.3 mg, 85%): mp 176–181 °C; 1H NMR (400 MHz, CDCl3) δ 7.96–7.95 (m,
1H), 7.64–7.62 (m, 3H), 7.52–7.50 (m, 1H), 7.38–7.31 (m, 3H), 6.42–6.41 (m, 2H), 6.35– 6.34 (m,
13
1H), 3.74 (s, 6H); C{1H} NMR (100 MHz, CDCl3) δ 160.5, 154.9, 141.2, 139.0, 138.9, 136.2,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 38
1
2
3
4
5
6
132.2, 131.6, 130.5, 129.8, 128.5, 127.5, 121.4, 107.6, 102.4, 96.2, 88.0, 55.5; HRMS (ESI) calcd
for [C24H17ClN2O2] requires [M+H]+ 401.1057, found 401.1038.
7
8
9
3-((4-(Tert-butyl)phenyl)ethynyl)-6-chloro-2-(3,5-dimethoxyphenyl) quinoxaline (3j). The product
was obtained as a yellow needles (187.3 mg, 82%): mp 171–175 °C; 1H NMR (400 MHz, CDCl3)
δ 8.11 (d, J = 2.3 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 2.2 and 9.1 Hz, 1H), 7.46 (d, J =
9.1 Hz, 2H), 7.38 (m, J = 8.4 Hz, 2H), 7.23 (d, J = 1.5 Hz, 2H), 6.66 (t, J = 2.2 Hz, 1H), 3.87 (s,
6H), 1.32 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 154.9, 153.4, 141.3, 139.1, 139.0,
138.9, 136.1, 132.1, 131.4, 130.5, 127.4, 125.5, 118.3, 107.7, 102.4, 96.8, 87.7, 55.6, 35.0, 31.1;
HRMS (ESI) calcd for [C28H25ClN2O2] requires [M+H]+ 457.1683, found 457.1701.
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-Tolylethynyl)-3-(3,4,5-trimethoxyphenyl)benzo[g]quinoxaline (3k). The product was obtained
1
as a yellow needles (177.3 mg, 77%): mp 185–200 °C; H NMR (400 MHz, CDCl3) δ 8.74–8.73
(m, 2H), 8.19–8.14 (m, 2H), 7.65–7.61 (m, 2H), 7.47–7.46 (m, 3H), 7.23 (d, J = 7.6 Hz, 2H), 6.77–
6.76 (m, 1H), 4.02–3.99 (m, 9H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5, 153.3,
152.9, 140.4, 139.4, 137.6, 136.9, 134.3, 134.0, 133.0, 132.1, 129.4, 128.7, 128.4, 127.4, 127.1,
126.9, 118.3, 107.0, 104.5, 96.6, 88.5, 61.0, 56.2, 21.7; HRMS (ESI) calcd for [C30H24N2O3]
requires [M+H]+ 461.1865, found 461.1876.
2-(p-Tolylethynyl)-3-(3,4,5-trimethoxyphenyl)pyrazine (5a). The product was obtained as a yellow
needles (147.7 mg, 82%): mp 99–105 °C; 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.2 Hz, 1H),
8.59 (d, J = 2.2 Hz, 1H), 7.46 (s, 1H), 7.44 (s, 3H), 7.22 (d, J = 8.4 Hz, 2H), 4.01 (s, 3H), 3.96 (s,
6H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 152.9, 142.2, 142.0, 140.0, 139.4,
137.2, 132.3, 131.8, 129.3, 118.6, 106.7, 95.3, 87.1, 60.9, 56.2, 56.1, 21.6; HRMS (ESI) calcd for
[C22H20N2O3] requires [M+H]+ 361.1552, found 361.1559.
2-(4-Ethylphenyl)-3-(p-tolylethynyl)pyrazine (5b). The product was obtained as a yellow needles
(113.3 mg, 76%): mp 89–94 °C; 1H NMR (400 MHz, CDCl3) δ 8.54–8.48 (m, 2H), 8.02 (d, J = 8.2
Hz, 2H), 7.39–7.33 (m, 4H), 7.15 (d, J = 8.2 Hz, 2H), 2.74 (q, J = 7.8 Hz, 2H), 2.35 (s, 3H), 1.29
(t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.3, 146.1, 142.1, 142.0, 139.7, 137.3,
134.4, 131.8, 139.3, 129.2, 127.6, 118.8, 94.8, 87.1, 28.7, 21.6, 15.4; HRMS (ESI) calcd for
[C21H18N2] requires [M+H]+ 299.1548, found 299.1545.
22
ACS Paragon Plus Environment

Page 23 of 38
The Journal of Organic Chemistry
1
2
3
4
General Procedure for the Synthesis of benzophenazine 2a-w
5
6
7
8
9
In a oven-dried RBF, a solution of o-alkynylaryls derivatives (1) (0.5 mmol) in 4 mL of
CF3COOH as a solvent and Pd(OAc)2 (2 mol %), were added. The resulting reaction mixture
was heated at 65 °C for 24 h. Progression of the reaction was monitored by TLC, while noticing
complete consumption of o-alkynylaryls, reaction was brought to room temperature. The
reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL) and then filtered
through a plug of celite. The layers were separated, and the organic layer was washed with
aqueous saturated brine solution, dried over Na2SO4. Organic layer was concentrated under
reduced pressure. The crude material so obtained was purified by column chromatography on
silica gel (hexane: ethylacetate) and DCM:Hexane have used for crystallization. The structure
and purity of known starting materials were confirmed by comparison of their physical and
spectral data (1H NMR, 13C NMR and HRMS ).
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-Phenylbenzo[a]phenazine (2a). The product was obtained as a yellow needles (107.2 mg,
70%): mp 138–142 °C; 1H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 7.8 Hz, 1H), 8.31–8.27 (m,
1H), 8.21–8.16 (m, 1H), 7.84 –7.82 (m, 2H), 7.78–7.75 (m, 2H), 7.74–7.70 (m, 1H), 7.63–7.59
13
(m, 1H), 7.54–7.52 (m, 2H), 7.49–7.42 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 145.2,
143.1, 143.0, 142.3, 142.0, 139.3, 132.7, 131.4, 130.0, 129.7, 129.64, 129.59, 129.1, 128.5,
128.1, 127.8, 127.2, 127.0, 125.7; HRMS (ESI) calcd for [C22H14N2] requires [M+H]+
307.1235, found 307.1247.
4-(Benzo[a]phenazin-5-yl)-N,N-dimethylaniline (2b). The product was obtained as a brown
1
needles (113.5 mg, 65%): mp 175–179 °C; H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 7.6 Hz,
1H), 8.29–8.27 (m, 1H), 8.19–8.16 (m, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.77–7.70
(m, 3H), 7.63 (t, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 2.99 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.3, 145.6, 143.5, 143.1, 142.3, 141.7, 133.1, 131.5,
130.6, 129.9, 129.7, 129.45, 129.36, 129.0, 127.6, 127.2, 126.9, 126.4, 125.6, 112.1, 40.5;
HRMS (ESI) calcd for [C24H19N3] requires [M+H]+ 350.1657, found 350.1674.
3-Methyl-5-(p-tolyl)benzo[a]phenazine (2c). The product was obtained as a yellow needles
1
(120.3 mg, 72%): mp 184–189 °C; H NMR (400 MHz, CDCl3) δ 9.29 (d, J = 7.6 Hz, 1H),
8.29–8.24 (m, 1H), 8.18–8.13 (m, 1H), 7.78 (s, 1H), 7.76– 7.73 (m, 2H), 7.62 (s, 1H), 7.52 (d, J
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 38
1
2
3
4
5
6
7
8
9
= 8.4 Hz, 1H), 7.43–7.41 (m, 2H), 7.29–7.27 (m, 2H), 2.41 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 145.2, 143.1, 142.9, 142.4, 141.9, 139.9, 137.9, 136.5, 132.9, 129.7, 129.6, 129.5,
129.2, 129.0, 127.2, 126.9, 125.6, 22.0, 21.3; HRMS (ESI) calcd for [C24H18N2]requires
[M+H]+ 335.1548, found 335.1535.
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
3-Methyl-5-(thiophen-3-yl)benzo[a]phenazine (2d). The product was obtained as a yellow
1
needles (122.4 mg, 75%): mp 192–196 °C; H NMR (400 MHz, CF3COOD) δ 9.63–9.57 (m,
1H), 8.91–8.86 (m, 1H), 8.53–8.37 (m, 4H), 8.19 (s, 1H), 8.11 (t, J = 7.6 Hz, 1H), 8.04–7.99 (m,
1H), 7.84–7.81 (m, 1H), 7.67–7.66 (m, 1H), 2.82 (s, 3H); 13C{1H} NMR (100 MHz, CF3COOD)
δ 153.7, 145.5, 143.1, 138.3, 137.1, 133.5, 133.4, 133.1, 132.9, 131.0, 129.7, 129.4, 128.6,
128.2, 127.8, 127.6, 126.5, 119.8, 115.5, 21.1; HRMS (ESI) calcd for [C21H14N2S]requires
[M+H]+ 327.0956, found 327.0950.
5-(4-(tert-Butyl)phenyl)-3-ethylbenzo[a]phenazine (2e). The product was obtained as a yellow
1
needles (138.6 mg, 71%): mp 173–177 °C; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz,
1H), 7.75 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.55–7.50 (m, 2H), 7.45–7.42 (m, 2H),
7.40–7.37 (m, 2H), 7.26 (s, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.33 (s, 9H), 1.20 (t, J = 6.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 157.1, 154.4, 147.3, 146.2, 137.0, 134.7, 131.7, 130.5,
129.2, 128.8, 128.2, 126.5, 125.6, 125.4, 119.1, 34.9, 31.2, 28.8, 15.5; HRMS (ESI) calcd for
[C28H26N2] requires [M+H]+ 391.2174, found 391.2163.
2,4-Dimethoxy-5-(o-tolyl)benzo[a]phenazine (2f). The product was obtained as a yellow
1
needles (182.6 mg, 96%): mp 179–183 °C; H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 2.4 Hz,
1H), 8.30–8.27 (m, 1H), 8.17–8.15 (m, 1H), 7.76–7.73 (m, 2H), 7.49 (s, 1H), 7.19–7.14 (m,
4H), 6.44 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 3.36 (s, 3H), 1.98 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.1, 158.5, 144.1, 143.6, 143.5, 143.4, 141.7, 141.6, 135.3, 134.5, 130.1, 129.7,
129.4, 129.0, 128.5, 127.6, 126.5, 125.4, 124.8, 118.1, 102.0, 99.1, 55.8, 20.0; HRMS (ESI)
calcd for [C25H20N2O2] requires [M+H]+ 381.1603, found 381.1600.
5-(4-(tert-Butyl)phenyl)-2,4-dimethoxybenzo[a]phenazine (2g). The product was obtained as a
brown needles (194.3 mg, 92%): mp 186–190 °C; 1H NMR (400 MHz, CDCl3) δ 8.64–8.63 (m,
1H), 8.35–8.33 (m, 1H), 8.23–8.21 (m, 1H), 7.82–7.80 (m, 2H), 7.65 (s, 1H), 7.43–7.41 (m,
2H), 7.37–7.35 (m, 2H), 6.73–6.72 (m, 1H), 4.11 (s, 3H), 3.46 (s, 3H), 1.41 (s, 9H); 13C{1H}
24
ACS Paragon Plus Environment

Page 25 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
NMR (100 MHz, CDCl3) δ 160.2, 158.5, 149.4, 144.0, 143.5, 143.4, 141.7, 141.2, 134.9, 130.1,
129.8, 129.4, 129.1, 127.8, 126.1, 124.0, 117.8, 102.4, 99.2, 55.9, 55.7, 34.7, 31.6; HRMS (ESI)
calcd for [C28H26N2O2] requires [M+H]+ 423.2073, found 423.2065.
9
5-Cyclopropyl-2,4-dimethoxybenzo[a]phenazine (2h). The product was obtained as a yellow
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
needles (158.5 mg, 96%): mp 178–182 °C; H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.7 Hz,
1H), 8.21–8.18 (m, 1H), 8.13–8.10 (m, 1H), 7.71–7.67 (m, 2H), 7.44 (s, 1H), 6.73 (d, J = 2.2
Hz, 1H), 4.0 (s, 3H), 3.87 (s, 3H), 2.85–2.78 (m, 1H), 0.98–0.93 (m, 2H), 0.85–0.81(m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 159.6, 146.2, 143.9, 143.3, 141.7, 141.5, 134.8,
130.1, 129.8, 129.0, 128.8, 121.3, 119.3, 102.2, 99.1, 56.0, 55.8, 18.8, 8.3; HRMS (ESI) calcd
for [C21H18N2O2] requires [M+H]+ 331.1447, found 331.1434.
5-Butyl-2,4-dimethoxybenzo[a]phenazine (2i). The product was obtained as a yellow needles
(122.3mg, 82%): mp 177–181 °C; 1H NMR (400 MHz, CDCl3) δ 8.53–8.52 (m, 1H), 8.22–8.20
(m, 1H), 8.12 (d, J =7.6 Hz, 1H), 7.76–7.73 (m, 2H), 7.46 (s, 1H), 6.71–6.70 (m, 1H), 4.0 (s,
3H), 3.87 (s, 3H), 3.20 (t, J = 8.0 Hz, 2H), 1.66–1.58 (m, 2H), 1.45–1.35(m, 2H), 0.89 (t, J = 7.6
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 158.8, 145.8, 143.6, 143.2, 141.5, 141.3,
135.0, 129.9, 129.7, 128.8, 128.7, 124.2, 118.2, 101.8, 99.2, 55.7, 55.5, 38.3, 33.7, 22.9, 14.1;
HRMS (ESI) calcd for [C22H22N2O2] requires [M+H]+ 347.1760, found 347.1765.
2,3,4-Trimethoxy-5-phenylbenzo[a]phenazine (2j). The product was obtained as a brown
1
needles (168.4 mg, 85%): mp 188–192 °C; H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.31–
8.27 (m, 1H), 8.18–8.15 (m, 1H), 7.79–7.74 (m, 2H), 7.59 (s, 1H), 7.42–7.40 (m, 2H), 7.38–
7.31 (m, 3H), 4.15 (s, 3H), 3.89 (s, 3H), 3.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.8,
151.0, 144.9, 143.4, 143.2, 143.0, 142.5, 141.7, 141.4, 129.8, 129.5, 129.0, 128.7, 128.2, 127.4,
127.1, 126.6, 121.6, 102.9, 61.0, 60.9, 56.2; HRMS (ESI) calcd for [C25H20N2O3] requires
[M+Na]+ 419.1372, found 419.1384.
2,3,4-Trimethoxy-5-(p-tolyl)benzo[a]phenazine (2k). The product was obtained as a brown
1
needles (176.4 mg, 86%): mp 168–172 °C; H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.34–
8.30 (m, 1H), 8.22–8.18 (m, 1H), 7.81–7.78 (m, 2H), 7.64 (s, 1H), 7.38 (d, J = 7.6 Hz, 2H), 7.23
(d, J = 7.6 Hz, 2H), 4.19 (s, 3H), 3.96 (s, 3H), 3.30 (s, 3H), 2.44 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 153.8, 151.1, 145.0, 143.5, 143.1, 142.6, 141.7, 141.5, 140.3, 136.1, 129.7,
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 38
1
2
3
4
5
6
129.5, 129.4, 129.0, 128.7, 128.1, 127.8, 127.4, 121.8, 103.0, 61.1, 61.0, 56.2, 21.3; HRMS
(ESI) calcd for [C26H22N2O3] requires [M+Na]+ 433.1528, found 433.1523.
7
8
9
2,3,4-Trimethoxy-5-(o-tolyl)benzo[a]phenazine (2l). The product was obtained as a brown
1
needles (172.3 mg, 84%): mp 160–164 °C; H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 8.27–
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
8.25 (m, 1H), 8.15–8.13 (m, 1H), 7.73 –7.71 (m, 2H), 7.52 (s, 1H), 7.25–7.22 (m, 2H), 7.20–
7.14 (m, 2H), 4.11 (s, 3H), 3.58 (s, 3H), 3.17 (s, 3H), 2.0 (s, 3H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 153.8, 150.9, 144.8, 143.2, 143.0, 142.7, 141.8, 141.4, 135.9, 129.8, 129.5, 129.0,
128.7, 128.4, 127.7, 126.8, 126.6, 124.7, 122.1, 102.9, 61.0, 60.8, 56.2, 20.2; HRMS (ESI)
calcd for [C26H22N2O3] requires [M+Na]+ 433.1528, found 433.1546.
2,3,4-Trimethoxy-5-(4-methoxyphenyl)benzo[a]phenazine (2m). The product was obtained as a
1
brown needles (187.6 mg, 88%): mp 181–185 °C; H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H),
8.30–8.28 (m, 1H), 8.18–8.16 (m, 1H), 7.78 –7.75 (m, 2H), 7.59 (s, 1H), 7.36 (d, J = 8.4 Hz,
2H), 6.90 (d, J = 8.4 Hz, 2H), 4.15 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 3.25 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 158.5, 153.8, 151.2, 145.0, 143.2, 143.1, 142.7, 141.7, 141.4, 139.2,
135.6, 129.9, 129.5, 129.0, 128.8, 127.5, 121.8, 114.0, 112.5, 103.1, 61.2, 61.1, 56.2, 55.3;
HRMS (ESI) calcd for [C26H22N2O4] requires [M+Na]+ 449.1477, found 449.1470.
N,N-Dimethyl-4-(2,3,4-trimethoxybenzo[a]phenazin-5-yl)aniline (2n). The product was
obtained as a yellow needles (188.9 mg, 86%): mp 195–199 °C; 1H NMR (400 MHz, CDCl3) δ
8.83 (s, 1H), 8.29–8.26 (m, 1H), 8.17–8.15 (m, 1H), 7.76–7.73 (m, 2H), 7.61 (s, 1H), 7.35–7.33
(m, 2H), 6.73 (d, J = 9.2 Hz, 2H), 4.14 (s, 3H), 3.92 (s, 3H), 3.26 (s, 3H), 2.96 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 153.6, 151.3, 149.5, 145.0, 143.9, 143.1, 142.9, 141.6, 131.1, 129.7,
129.5, 129.4, 129.2, 129.0, 127.2, 121.9, 111.2, 103.1, 61.3, 61.2, 56.2, 40.7; HRMS (ESI)
calcd for [C27H25N3O3] requires [M+Na]+ 462.1794, found 462.1785.
2,3,4-Trimethoxy-5-(4-(trifluoromethyl)phenyl) benzo[a]phenazine (2o). The product was
obtained as a brown needles (174.1 mg, 75%): mp 198–202 °C; 1H NMR (400 MHz, CDCl3) δ
8.80 (s, 1H), 8.26–8.24 (m, 1H), 8.14–8.12 (m, 1H), 7.76 –7.71 (m, 2H), 7.61 (d, J = 7.8 Hz,
2H), 7.51 (t, J = 5.0 Hz, 3H), 4.12 (s, 3H), 3.88 (s, 3H), 3.20 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 154.1, 150.6, 147.0, 144.9, 143.1, 142.3, 141.9, 141.7, 141.4, 130.0, 129.8, 129.6,
26
ACS Paragon Plus Environment

Page 27 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
1
129.1, 128.7, 128.5, 127.5, 125.8, 124.10 (q, JC-F = 15.2 Hz, 113C), 123.1, 121.1, 103.1, 61.0,
60.7, 56.2; HRMS (ESI) calcd for [C26H19F3N2O3] requires [M+H]+ 465.1426, found 465.1426.
7
8
9
5-(2-Fluorophenyl)-2,3,4-trimethoxybenzo[a]phenazine (2p). The product was obtained as a
yellow needles (161.6 mg, 78%): mp 187–191 °C; 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H),
8.32–8.29 (m, 1H), 8.20–8.17 (m, 1H), 7.79–7.77 (m, 2H), 7.646–7.643 (m, 1H), 7.44–7.40 (m,
1H), 7.36–7.30 (m, 1H), 7.22–7.15 (m, 1H), 7.07 (t, J = 9.1 Hz, 1H), 4.15 (s, 3H), 3.91 (s, 3H),
3.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 152.9 (d, 1JC-F = 208.0 Hz, 113C), 150.9,
144.7, 143.1, 142.6, 142.0, 141.7, 139.3, 137.3, 130.0, 129.8, 129.7, 129.6, 129.1, 128.8, 128.7,
128.0, 123.5, 123.3 (d, 4JC-F = 3.8 Hz, 113C), 121.7, 115.9, 114.4 (d, 2JC-F = 21.1 Hz, 1H), 114.1,
102.9, 61.1, 61.0, 56.3; HRMS (ESI) calcd for [C25H19FN2O3] requires [M+H]+ 415.1458,
found 415.1460.
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
2,3,4-Trimethoxy-5-(phenoxymethyl)benzo[a]phenazine (2q). The product was obtained as a
1
brown needles (179.1 mg, 84%): mp 159–162 °C; H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H),
8.23–8.21 (m, 1H), 8.14–8.10 (m, 2H), 7.73–7.71 (m, 2H), 7.27–7.23 (m, 2H), 7.02 (d, J = 7.9
Hz, 2H), 6.90 (t, J = 7.3 Hz, 1H), 5.66 (s, 2H), 4.11 (s, 3H), 4.0 (s, 3H), 3.96 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 158.7, 153.5, 150.9, 144.6, 142.9, 142.8, 141.7, 141.3, 138.4, 129.8,
129.5, 129.4, 129.0, 128.6, 122.7, 120.9, 120.2, 114.8, 103.2, 69.3, 61.6, 61.0, 56.2; HRMS
(ESI) calcd for [C26H22N2O4] requires [M+Na]+ 449.1477, found 449.1483.
2,3,4-Ttrimethoxy-5-phenethylbenzo[a]phenazine (2r). The product was obtained as a brown
1
needles (169.7 mg, 80%): mp 123–127 °C; H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.25–
8.21 (m, 1H), 8.15–8.10 (m, 1H), 7.74–7.69 (m, 2H), 7.57 (s, 1H), 7.24 (d, J = 4.6 Hz, 4H),
7.16–7.11 (m, 1H), 4.12 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.49–3.45 (m, 2H), 3.02–2.98 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.4, 151.4, 145.0, 143.7, 143.0, 142.9, 142.3, 141.6,
141.5, 129.8, 129.5, 129.2, 128.9, 128.5, 128.4, 125.9, 125.7, 121.6, 103.4, 61.6, 61.0, 56.2,
39.7, 37.8; HRMS (ESI) calcd for [C27H24N2O3] requires [M+Na]+ 447.1685, found 447.1684.
4-(4-Ethylphenyl)thieno[3,2-a]phenazine (2s). The product was obtained as a yellow needles
1
(149.7 mg, 88%): mp 162–166 °C; H NMR (400 MHz, CDCl3) δ 8.59 (d, J =5.3 Hz, 1H),
8.36–8.33 (m, 1H), 8.29–8.26 (m, 1H), 8.06 (s, 1H), 7.88–7.81 (m, 3H), 7.75(d, J= 5.3 Hz, 1H),
7.41 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 2.79 (q, J = 7.6 Hz, 2H), 1.35 (t, J =7.6 Hz, 3H); 13C{1H}
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 38
1
2
3
4
5
6
7
8
NMR (100 MHz, CDCl3) δ 145.5, 143.0, 142.5, 142.3, 141.3, 140.9, 140.1, 139.3, 137.4, 136.5,
130.0, 129.5, 129.0, 128.6, 128.3, 127.7, 124.8, 123.6, 28.7, 15.4; HRMS (ESI) calcd for
[C22H16N2S] requires [M+H]+ 341.1112, found 341.1141.
9
4-(4-(tert-Butyl)phenyl)thieno[3,2-a]phenazine (2t). The product was obtained as a brown
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
needles (158.4 mg, 86%): mp 166–170 °C; H NMR (400 MHz, CDCl3) δ 8.60–8.58 (m, 1H),
8.36–8.32 (m, 1H), 8.29–8.26 (m, 1H), 8.07 (s, 1H), 7.87–7.83 (m, 4H), 7.76–7.74 (m, 1H),
7.61–7.59 (m, 2H), 1.43 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.2, 143.4, 142.9, 142.2,
141.1, 140.4, 139.9, 137.4, 136.2, 129.9, 129.8, 129.5, 129.4, 128.0, 127.5, 126.0, 124.7, 124.0,
34.8, 31.3; HRMS (ESI) calcd for [C24H20N2S] requires [M+H]+ 369.1425, found 369.1430.
4-(2-Fluorophenyl)thieno[3,2-a]phenazine (2u). The product was obtained as a brown needles
1
(125.5 mg, 76%): mp 169–173 °C; H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.3 Hz, 1H),
8.28–8.26 (m, 1H), 8.21–8.19 (m, 1H), 8.0 (s, 1H), 7.81–7.77 (m, 2H), 7.66–7.63 (m, 2H),
7.47–7.41 (m, 1H), 7.28–7.20 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 159.7(d, JC-F
249.2 Hz, 113C), 142.84, 142.82, 142.6, 142.4, 141.6, 140.1, 137.2, 134.3, 130.9, 130.8, 130.3,
129.9, 129.5 (d, JC-F = 3.8 Hz, 113C), 129.4, 127.6, 126.2, 124.6, 124.5, 116.6 (d, JC-F = 22.4
13
1
=
4
2
Hz, 113C); HRMS (ESI) calcd for [C20H11FN2S] requires [M+H]+ 331.0705, found 331.0708.
4-Cyclohexylthieno[3,2-a]phenazine (2v). The product was obtained as a brown needles (119.4
mg, 75%): mp 139–143 °C; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 5.3 Hz, 1H), 8.25–8.23
(m, 1H), 8.19–8.16 (m, 1H), 7.81 (s, 1H), 7.78–7.74 (m, 2H), 7.62 (d, J = 5.3 Hz, 1H), 2.95–
2.87 (m, 1H), 2.25–2.15 (m, 2H), 1.98–1.77 (m, 4H), 1.69–1.59 (m, 2H), 1.54–1.43 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 146.4, 143.6, 142.5, 142.2, 142.0, 139.8, 136.6, 129.6,
129.4, 129.2, 126.2, 124.9, 120.6, 44.0, 33.2, 29.7, 26.8; HRMS (ESI) calcd for [C20H18N2S]
requires [M+H]+ 319.1269, found 319.1282.
4-Cyclopropylthieno[3,2-a]phenazine (2w). The product was obtained as a brown needles
1
(113.3 mg, 82%): mp 131–135 °C; H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 5.3 Hz, 1H),
8.22–8.20 (m, 1H), 8.14–8.11 (m, 1H), 7.75–7.72 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.51 (s,
1H), 2.23–2.16 (m, 1H), 1.15–1.11 (m, 2H), 1.00–0.96 (m, 2H); C{1H} NMR (100 MHz,
13
CDCl3) δ 143.5, 143.3, 142.4, 141.8, 139.8, 136.2, 129.62, 129.57, 129.4, 129.2, 126.6, 124.7,
28
ACS Paragon Plus Environment

Page 29 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
119.2, 15.0, 8.4; HRMS (ESI) calcd for [C17H12N2S] requires [M+H]+ 277.0799, found
277.0810.
7
8
9
General Procedure for the Synthesis of Substituted benzophenazine 4a-k and
Benzoquinoxaline (6a-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
In a oven-dried RBF, a solution of o-alkynylaryls derivatives (3 and 5) (0.5 mmol) in 4 mL of
CF3COOH as a solvent and Pd(OAc)2 (2 mol %), were added. The resulting reaction mixture
was heated at 65 °C for 24 h. Progression of the reaction was monitored by TLC, while noticing
complete consumption of o-alkynylaryls, reaction was brought to room temperature. The
reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL) and then filtered
through a plug of celite. The layers were separated, and the organic layer was washed with
aqueous saturated brine solution, dried over Na2SO4. Organic layer was concentrated under
reduced pressure. The crude material so obtained was purified by column chromatography on
silica gel (hexane: ethylacetate) and DCM:Hexane have used for crystallization. The structure
and purity of known starting materials were confirmed by comparison of their physical and
spectral data (1H NMR, 13C NMR and HRMS ).
9-Methyl-5-(p-tolyl)benzo[a]phenazine (4a). The product was obtained as a yellow needles
(125.4 mg, 75%): mp 161–165 °C; 1H NMR (400 MHz, CDCl3) δ 9.36–9.33 (m, 1H), 8.10 (d, J
= 8.7 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.66–7.62 (m, 1H), 7.56–7.51
(m, 2H), 7.40–7.38 (m, 2H), 7.25–7.23 (m, 2H), 2.51 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.9, 143.1, 142.5, 141.5, 140.5, 140.2, 137.8, 136.5, 132.6, 132.5, 132.3,
131.5, 129.6, 129.1, 128.5, 127.53, 127.45, 127.1, 126.9, 125.4, 22.1, 21.3;HRMS (ESI) calcd
for [C24H18N2]requires [M+H]+ 335.1548, found 335.1568.
5-Cyclopropyl-9-methylbenzo[a]phenazine (4b). The product was obtained as a yellow needles
(122.2 mg, 86%): mp 142–146 °C; 1H NMR (400 MHz, CDCl3) δ 9.39–9.29 (m, 1H), 8.35–8.33
(m, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.73–7.67 (m, 2H), 7.59 (s, 1H), 7.56–7.52 (m,
13
1H), 2.54 (s, 3H), 2.32–2.27 (m, 1H), 1.10–1.05 (m, 2H), 0.88–0.84 (m, 2H); C{1H} NMR
(100 MHz, CDCl3) δ 144.7, 143.5, 142.9, 141.6, 140.4, 133.8, 132.1, 131.0, 129.4, 129.1,
128.4, 127.5, 127.4, 125.3, 124.7, 123.6, 22.1, 13.9, 6.9, 1.0; HRMS (ESI) calcd for [C20H16N2]
requires [M+H]+ 285.1392, found 285.1391.
29
ACS Paragon Plus Environment