Palladium-Catalyzed Deaminative Phenanthridinone Synthesis from Aniline via C-H Bond Activation

Article abstract of DOI:10.1021/acs.joc.6b00378

This work reports palladium-catalyzed phenanthridinone synthesis using the coupling of aniline and amide by formation of C-C and C-N bonds in a one-pot fashion via dual C-H bond activation. It involves simultaneous cleavage of four bonds and the formation of two new bonds. The present protocol is ligand-free, takes place under mild reaction conditions, and is environmentally benign as nitrogen gas and water are the only side products. This transformation demonstrates a broad range of aniline and amide substrates with different functional groups and has been scaled up to gram level.

Full text of DOI:10.1021/acs.joc.6b00378

Subscriber access provided by LAURENTIAN UNIV
Article
Palladium-Catalyzed Deaminative Phenanthridinone
Synthesis from Aniline via C-H bond Activation
Subhash Laxman Yedage, and Bhalchandra M. Bhanage
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00378 • Publication Date (Web): 18 Apr 2016
Downloaded from http://pubs.acs.org on April 19, 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 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Palladium-Catalyzed Deaminative Phenanthridinone Synthesis from Aniline
8
9
via C-H bond Activation
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
Subhash L.Yedage and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Mumbai-400 019, India
E-mail: bm.bhanage@ictmumbai.edu.in, bm.bhanage@gmail.com
ABSTRACT: This work reports palladium catalyzed phenanthridinone synthesis using coupling
of aniline and amide by formation of C-C and C-N bonds in one pot fashion via dual C-H bond
activation. It involves simultaneous cleavage of four bonds and the formation of two new bonds.
Present protocol is ligand-free and takes place under mild reaction conditions. The present
protocol is environmentally benign as nitrogen gas and water are the only side products. This
transformation demonstrates a broad range of aniline and amide substrates with different
functional groups and has been scaled up to gram level.
TOC Graphic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 31
1
2
3
4
5
6
7
INTRODUCTION
8
9
Phenanthridinone is an important building block which is found in various biologically active
molecules and natural products.1 Interestingly, these are also important scaffolds in anticancer
drugs and treatment of nerve diseases (Scheme 1).2 Despite several methods for the synthesis of
phenanthridinone derivatives,3 versatile and flexible methodologies to construct
phenanthridinones are still desirable.
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
The methodology involving C-H activation has gained great prominence in organic synthesis.4 It
is very important to use inexpensive and readily available starting materials to enhance
sustainability through non-reactive C-H bond activation.5 Usually, C-H bond activation has been
brought about successfully by transition metal based catalytic systems.6
Scheme 1. Examples of Molecules Containing Phenanthridinones Skeleton.
The most developed strategy is to obtain selective C-H bond activation by the use of a
neighbouring directing group (DG) that pre-complexes with the metal and directs to the desired
position.7 With the help of C-H bond activation, construction of C-C and C-N bonds have been
achieved.8 Analogous to C-H bond activation and coupling reactions, the activation of functional
groups has also been achieved.9 Such a combination of C-H bond activation and functional group
ACS Paragon Plus Environment

Page 3 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
activation has a great advantage in the form of reducing synthetic steps in pharmaceutical and
drug synthesis, thus making the process cost effective. Recently, several groups have employed
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
+
aryldiazonium salts as aryl surrogates for the construction of C-C and C-N bond.10 The C-N2
bond is a weak bond having the dissociation energy (~130 KJ∙mol-1) which allows the oxidative
addition to palladium under mild conditions.11 However, compared to externally prepare
diazonium salts, the in situ prepared diazonium salts avoid wastage and handling of large
quantities of solvents required for the purification of the crystalline form. The important utility of
aromatic amine/arene diazonium salts is that, they have been established in classical methods for
functional group transformations. Furthermore, in situ synthesis of diazonium salts have been
applied widely in various named reactions such as Suzuki coupling, Heck coupling and
Sonogashira coupling reactions having aniline as an aryl source.12 Moreover, Beller’s group and
Wu’s group have reported carbonylative Sonogashira coupling reactions for synthesis of
alkynones from aniline.13
Scheme 2. Synthetic Approach for Phenanthridinones.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 31
1
2
3
4
5
6
7
8
9
This work is to develop a deaminative C-C bond coupling along with ortho C-H bond activation
of aniline. The literature survey shows that in situ generated diazonium salt has been employed
only in deaminative coupling reactions. To the best of our knowledge, there is no report on the
deaminative C-C coupling with ortho C-H bond activation of aniline for the synthesis of
phenanthridinone.
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
Traditionally, preparation of phenanthridinones needs more number of synthetic steps and the
overall yields observed are lower.14 In 2011, the group of Li and other groups reported
palladium-catalyzed coupling of ortho X/H (X= I) benzamides with aromatic halides.15 This
reported protocol has some disadvantages like high temperature and longer reaction time. In the
same year, Chen’s group reported electron rich arenes for the phenanthridinone synthesis.16 The
same group also reported Rh(III) catalyzed boronic acid coupling for phenanthridinone
synthesis.17 Subsequently, phenanthridinones were also synthesized by coupling of benzamides
with aryltriethoxysilanes in the presence of Rh(III) catalyst.18 This work also suffers from the use
of expensive starting materials and Rh(III) catalyst. Recently, Jeganmohan’s group has also
reported an alternate protocol for the synthesis of phenanthridinones by coupling of benzamide
with externally prepared benzyne generating source (Scheme 2).19
Considering the importance of phenanthridinones,1,2 herein we report deaminative C-C and C-N
bond coupling via ortho C-H bond activation of aniline to give phenanthridinones under mild
reaction conditions. This developed methodology has number of advantages: (i) Three steps in
one pot reaction i.e., involves four bond cleavage and two bond formations simultaneously, (ii) it
does not require the isolation of diazonium crystalline salts, (iii) the diazonium salt is generated
in situ during the progress of reaction, (iv) only non-toxic byproducts such as N2, H2O and t-
ACS Paragon Plus Environment

Page 5 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
BuOH were generated, (v) the catalytic system is ligand-free and (vi) the reaction could be
completed at mild reaction temperature. The results of our studies are described herein.
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 DISCUS SION
To optimize the reaction conditions, N-methoxybenzamide 1a and p-toluidine 2b were chosen as
model substrates for the phenanthridinone synthesis. A series of experiments were carried out to
study the effect of various reaction parameters such as Pd-catalyst precursors, oxidants, solvents,
time and temperature. The results are displayed in Table 1. Initially, Pd(OAc)2 (5 mol %), p-
toluidine 2b (0.7 mmol), N-methoxybenzamide 1a (0.50 mmol) and K2S2O8 (1 mmol) were
added to a solution of 5 mL acetic acid under nitrogen atmosphere. The system was degassed
four to five times by vacuum pump. To the resulting suspension, 0.8 mmol of t-BuONO (tert-
butyl nitrite) was added by syringe. The mixture was heated at 40 °C for 12 h to obtain a 58%
yield of product 3ab (Table 1, entry 1). Next, various palladium precursors such as PdCl2,
Pd(Ph3P)4 and PdCl2(CH3CN)2 catalysts were screened. Pd(OAc)2 was found to be the best
catalyst, as it provided a good yield of the desired product 3ab and other Pd catalysts provide
moderate to poor yields (Table 1, entries 2-4). No formation of product 3ab was observed when
the reaction was performed in the absence of Pd-catalyst (Table 1, entry 5). Increasing the
amount of oxidant (K2S2O8) to 2 equiv. did not show any significant effect on the yield of 3ab
(Table 1, entry 6). With our desire to increase the yield of product 3ab, the catalyst loading was
increased up to 10 mol %. Unfortunately, no significant change in the yield of product 3ab was
noted (Table 1, entry 7). In the next set of experiments, other Ag containing oxidants such as
AgOAc, AgOTf, Ag2O Ag2CO3 and AgNO3 were screened and we were delighted to observe
that Ag2O provided a very good yield of 3ab (Table 1, entries 8-12).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 31
1
2
3
4
5
6
7
Table 1. Optimization of Reaction Conditionsa
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
entry catalyst
(mol %)
Oxidant
Solvent
time T (°C) yield (%)b
(h)
1
Pd(OAc)2 (5)
K2S2O8(1)
K2S2O8(1)
K2S2O8(1)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
18
17
18
18
18
18
18
18
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
50
32 (rt)
40
40
40
40
58
23
Trace
Trace
00
61
57
64
27
90
81
Trace
00
00
00
90
89
2
PdCl2 (5)
3
Pd(Ph3P)4 (5)
4
PdCl2(CH3CN)2 (5) K2S2O8(1)
5
-
K2S2O8(1)
K2S2O8(2)
K2S2O8(1)
AgOAc(1)
AgOTf(1)
Ag2O(1)
6
7
8
9
Pd(OAc)2(5)
Pd(OAc)2(10)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(7)
Pd(OAc)2(3)
Pd(OAc)2(5)
Pd(OAc)2(5)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ag2CO3(1) AcOH
AgNO3(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(1)
Ag2O(0.5)
Ag2O(1.5)
AcOH
HCOOH
CF3COOH
MeSO3H
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
76
61
90
71
61
90
AcOH
AcOH
a
Reaction conditions: N-methoxybenzamide (1a, 0.5 mmol), p-toluidine (2b, 0.7 mmol), Pd source,
Oxidant, Solvent (5 mL), time , temp. b G.C. yield, rt = Room temperature.
Moreover, when the reaction was performed in CF3COOH and HCOOH no formation of product
3ab was observed (Table 1, entries 13 and 14). Also, no product was observed when the reaction
was performed in MeSO3H (Table 1, entry 15). Next, the reaction time was studied (Table 1,
entries 16-17).
ACS Paragon Plus Environment

Page 7 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The reaction time can be reduced to 18 h providing 90% yield of 3ab (Table 1, entry 16).
Further, decreasing the reaction duration to 17 h resulted in a considerable decrease in the yield
of the desired product 3ab (Table 1, entry 17). Increasing the reaction temperature above 40 °C
or decreasing the reaction temperature below 40 °C led to a significant decrease in the yield of
3ab (Table 1, entries 18 and 19). The increase in Pd(OAc)2 loading to 7 mol % did not show any
effect on the yield of 3ab (Table 1, entry 20). However, the decrease in the Pd(OAc)2 loading led
to a drastic decrease in the yield of 3ab (Table 1, entry 21). 1.0 equiv. of Ag2O was found to be
effective for this transformation, further decreasing the amount Ag2O to 0.5 equiv. provided
lower yield of 3ab (Table 1, entry 22). On the other hand, no significant change in the yield of
3ab was found when the reaction was performed with 1.5 equiv. of Ag2O (Table 1, entry 23).
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
Hence, we have established the optimized reaction conditions in hand and this developed
methodology was explored for the scope and limitation of the substrates. As shown in table 2, all
the examined substrates provided good to excellent yields. The effect of electron donating and
withdrawing groups on N-methoxybenzamide was studied. It was found that electron donating
groups such as -Me, -OMe and -t-butyl produced corresponding products 3bb-3fb in good to
excellent yields (Table 2, entries 1-5). The para substituted N-methoxybenzamides 1b-1d
provided excellent yields of 3bb-3db, whereas meta substituted N-methoxybenzamide 1e offered
a good yield of 3eb regioselectively. Hindered ortho methyl-N-methoxybenzamide furnished
lower yield of product 3fb. Interestingly, β and α -N-methoxybenzamide could also be
transformed into corresponding products 3gb and 3hb selectively (Table 2, entries 6 and 7).
Next, N-methoxybenzamide bearing weakly electron withdrawing groups such as -F, -Cl and -Br
at the para position were explored and furnished respective products 3ib-3kb in good to
excellent yields (Table 2, entries 8-10).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 31
1
2
3
4
5
6
7
8
9
Table 2. Palladium Catalyzed Phenanthridinone Synthesis from p-toluidine with Various
N-methoxybenzamide.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
Entry
1
amide
Aniline
Product
yield (%)b
91
2b
2
3
87
87
2b
2b
O
OMe
N
4
5
86
71
2b
2b
3eb
6
7
86
89
2b
2b
ACS Paragon Plus Environment

Page 9 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8
87
81
78
2b
2b
2b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
10
11
12
13
83
63
57
2b
2b
2b
14
73
2b
a Reaction conditions: Amide (1a-1o) (0.5 mmol), p-toluidine (2b, 0.7 mmol), t-BuONO (0.8
mmol) Pd(OAc)2 (5.0 mol %), Ag2O (1.0 mmol), AcOH (5 mL) at 40 oC for 18 h, b Yield.
The meta chloro substituted N-methoxybenzamide provided an excellent yield of 3lb and ortho
chloro N-methoxybenzamide provided the low yield of 3mb, this may be due to steric hindrance
(Table 2, entries 11 and 12). The N-methoxy-4-nitrobenzamide was also tolerated to give 3nb in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 31
1
2
3
4
5
6
7
57% yield (Table 2, entry 13). To our delight, the amide containing external double bond could
8
9
also be transformed into the corresponding product 3ob (Table 2, entry 14).
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
Having showed the viability of the mild catalytic system in efficient phenanthridinone synthesis
from amide, we turned our attention to other aniline substrates (Table 3). In general, 2a reacts
with 1a to give 3aa in 89% yield (Table 3, entry 1). It was observed that the reactions of aniline
having electron donating substituents such as -CH3 and -OCH3 offer good yields of 3ac-3ae
(Table 3, entries 2-4). The weak electron withdrawing group such as chloro furnished good yield
of product 3af (Table 3, entry 5). Aniline having -NO2 group such as 2g and 2h were studied.
Only 2g could be converted into the desired product 3ag however, 3h could not be transformed
into the desired product 3ah (Table 3, entries 6 and 7). Unfortunately, heteroatom containing
aniline such as 2i and 2j did not give the corresponding products 3ai and 3aj (Table 3, entries 8
and 9).
Table 3. Palladium Catalyzed Phenanthridinone Synthesis with Various Aniline
Derivatives.a
ACS Paragon Plus Environment

Page 11 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
yield
(%)b
entry
1
amide
aniline
product
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
89
85
2
3
1a
1a
90
4
5
6
73
76
53
1a
1a
1a
O
OMe
N
3ag
NO2
7
8
9
00
00
00
1a
1a
1a
a Reaction conditions: N-methoxybenzamide (1a) (0.5 mmol), aniline derivatives (2a-2j) (0.7
o
mmol), t-BuONO (0.8 mmol), Pd(OAc)2 (5.0 mol %), Ag2O (1.0 mmol), AcOH (5 mL) at 40 C
for 18 h, b Yield.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 31
1
2
3
4
5
6
7
Scheme 3. Reaction of N-substituted Benzamide Derivatives
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
After the substrate study of various N-methoxy amides and aromatic amines, we moved towards
screening of N-substituted amides (Scheme 3). Benzamide, N-hydroxybenzamide and N-alkyl/N-
arylbenzamide were inactive for synthesis of phenanthridinone products 3pa, 3qa, 3ra, 3sa.
Further, the reactivity of N-methoxy-N-methyl benzamide 1t was tested and no conversion of 3ta
was observed at standard reaction conditions. However, in the presence of MeSO3H solvent and
AgOTf oxidant, the formation of product 3ta was observed with a 21% yield
In order to understand the chemoselectivity and mechanism of this transformation, some control
experiments were conducted. Notably, no formation of product 3ab was observed when N-
methyltoluidine 2b’ and N,N-dimethyltoludine 2b’’ were employed (Scheme 4). This is possible
because there is no generation of azo salts with 2b’ and 2b’’ under the given reaction conditions.
The excellent yield of product 3aa was observed in the presence of externally prepared
diazonium salt.
ACS Paragon Plus Environment

Page 13 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Scheme 4. Controlled experiments
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
To demonstrate the synthetic utility of this developed protocol, gram scale phenanthridinone
synthesis was carried out by employing p-toluidine 2b (9.4 mmol, 1.40 mg), 1.06 g (7 mmol) of
N-methoxybenzamide 1a under the standard reaction condition (Scheme 5). This transformation
proceeded smoothly to afford 1.19 g (71%) of product 3ab.
Scheme 5. Gram Scale Phenanthridinone Synthesis
On the basis of known Pd(II)/Ag(I) catalyzed directing-group assisted C-H bond activation
reactions20 and obtained results, a plausible mechanism for the reaction of 1a with 2a to give 3aa
has been proposed in Scheme 6. The arylation of N-methoxybenzamide using aniline most likely
proceeds through a pathway similar to the para-selective arylation of amides with aryl halide.21
The initial step involves the coordination of 1a to a PdII species, and is followed by an ortho C-H
bond activation to form a five membered palladacycle A,15,16,19,20c,22 and the release of protons.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 31
1
2
3
4
5
6
7
8
9
Parallel in-situ diazotization of the aniline 2a takes place in the presence of t-BuONO and acid to
form a diazonium salt 2a’’ with the release of water and t-BuOH. The oxidative addition of
diazonium salt10-13,23 in palladacycle A with simultaneous expulsion of nitrogen forms
intermediate B with PdIV.
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. Plausible Reaction Mechanism
Then, reductive elimination of B gives ortho-arylated amide intermediate C.16 The reaction goes
through intermediate C was observed by stopping the reaction after 6 h and B’ was isolated and
characterized by IR and NMR. In the IR spectrum, the band at 3221 cm-1 corresponds to the N-H
stretch of 1a, whereas the band at 3195 cm-1 corresponds to the N-H stretch of the isolated
1
intermediate B’. This was also confirmed by H NMR, in which a broad singlet of N-H is
observed at δ 8.17 ppm. Hence, it can be concluded that, the reaction proceeds through the ortho-
arylated intermediate B’ which is subsequently followed by C-N coupling and not through C-N
coupling intermediate B’’ followed by ortho-arylation. Subsequently, the release of proton gives
the seven membered palladacycle D.15,16 The C-N bond forming reductive elimination from D
ACS Paragon Plus Environment

Page 15 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
affords 3ab and Pd0, which is oxidized by Ag2O regenerates PdII catalyst for the next catalytic
8
9
cycle.
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 conclusion, we have shown for the first time, the synthesis of phenanthridinone from N-
methoxybenzamide and aniline as novel surrogates using Pd(OAc)2 as an efficient catalyst. The
developed methodology is ligand free and proceeds via ortho C-H bond activation of N-
methoxybenzamide under mild reaction conditions. The elimination of the purification step of
the in situ generated diazonium salt and formation of only non-toxic byproducts such as N2, H2O
and t-BuOH makes this protocol greener. Interestingly, it involves simultaneous four bond
cleavage and two bond formation, i.e., three steps in one pot. A series of phenanthridinones were
synthesized containing electron withdrawing and donating groups in good to excellent yields.
The use of inexpensive and easily available aniline has made this protocol potentially viable for
commercial and academic applications. This reaction can also be scaled up to gram level.
EXPERIMENTAL SECTION
All reactions were carried out in oven-dried glassware. All derivatives of aniline, palladium and
silver precursor were purchased from commercial sources. Analytical TLC was performed with
silica gel plates (0.25 mm thickness). Column chromatography was performed with silica gel
13
(40-200 mesh). NMR spectra were recorded with an (1H NMR at 500 MHz, C NMR at 125
MHz) spectrometer. The chemical shifts are reported in ppm relative to tetramethylsilane as an
internal standard and the coupling constant J in Hz. The reaction was monitored by GC and the
products were analyzed by GC-MS and IR. HRMS were recorded on a micro-mass ESI TOF
(time of flight) mass spectrometer.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 31
1
2
3
4
5
6
7
General Procedure for the Synthesis of N-methoxybenzamides
8
9
Following a modified procedure by Glorious et al.24 in a 50 mL single neck round-bottom flask,
O-methylhydroxylamine (301.0 mg, 3.6 mmol, 1.2 equiv.) and K2CO3 (829.0 mg, 6.0 mmol, 2.0
equiv.) were combined in a 2:1 mixture of EtOAc (24 mL) and H2O (12 mL). The flask was
capped with rubber cap and the mixture was cooled in an ice bath. The acid chloride (1.0 mmol,
1.0 equiv.) was added drop wise and the mixture was stirred at room temperature over 16 h to 18
h. The reaction mixture was then diluted with EtOAc and washed twice with water and brine.
Consequently, the ethyl acetate layer was washed with 5% aqueous solution of 25 to 30 mL
sodium bicarbonate. The organic layers were dried over Na2SO4, filtered and concentrated. The
pure products were obtained without any further purification and it was confirmed by GC-MS.
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 Procedure for Phenanthridionone Synthesis from p-toluidine
In 15 mL Schlenktube, a solution of 5 mL acetic acid, Pd(OAc)2, (5 mol %, 11.2 mg), p-toluidine
2b (0.7 mmol, 0.74 mg), N-methoxybenzamide 1a (0.50 mmol, 76 mg) and Ag2O (1 mmol, 223
mg) were added under nitrogen atmosphere. The system was degassed four to five times by
vacuum pump. To the resulting suspension a tert-butyl nitrite (0.8 mmol, 85 mg) was added by
syringe. The reaction mixture was stirred at 40 °C, the total time indicated in table 1. After
completion of the reaction, the reaction mixture was cooled to room temperature. All volatiles
were removed under vacuum. The product was extracted with 20 mL of ethyl acetate and the
organic layer was dried over Na2SO4 and the solvent was removed under vacuum. The colorless
solid phenanthridionone product 3ab was purified by column chromatography (silica gel, 40-200
mesh).
ACS Paragon Plus Environment

Page 17 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
5-methoxy-3-methylphenanthridin-6(5H)-one (3ab)16
8
9
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76 mg), p-toluidine
2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl acetate = 4/1)
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
of the product 3ab afforded as a colorless solid (106 mg, 89% yield). H NMR (500 MHz,
CDCl3): δH/ppm 8.55 (d, J = 8.1 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.82
– 7.73 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.15 (s, 3H), 2.54
(s, 3H). 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.5, 140.6, 135.7, 133.1, 132.6, 128.5,
127.6, 125.9, 124.4, 123.1, 121.7, 116.2, 112.7, 62.7, 21.9; GCMS (EI, 70 eV): m/z (%): 239.00
(0.06), 209.05 (40), 165.05 (44.18), 111.60 (5.73); IR (ATR) ṽ (cm-1): 2920, 1644 and 1607.
5-methoxy-3,9-dimethylphenanthridin-6(5H)-one (3bb)16
The typical procedure was applied to N-methoxy-4-methylbenzamide 1b (0.50 mmol, 83 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
1
acetate = 4/1) of the product 3bb afforded as a colorless solid (115 mg, 91% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.42 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.47
(s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.13 (s, 3H), 2.56 (s, 3H), 2.53 (s, 3H).
13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.5, 143.1, 140.4, 135.8, 133.1, 129.0, 128.4,
124.3, 123.5, 123.1, 121.7, 116.1, 112.7, 62.7, 22.1, 21.9; GCMS (EI, 70 eV): m/z (%): 253.10
(53.94), 194.10 (55.29), 165.10 (14.91), 96.60 (13.21); IR (ATR) ṽ (cm-1): 2920, 1651 and
1614.
5,9-dimethoxy-3-methylphenanthridin-6(5H)-one (3cb)16
The typical procedure was applied to N,4-dimethoxybenzamide 1c (0.50 mmol, 91 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
1
acetate = 4/1) of the product 3cb afforded as a colorless solid (117 mg, 87% yield). H NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 31
1
2
3
4
5
6
7
8
9
(500 MHz, CDCl3): δH/ppm 8.46 (d, J = 8.9 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.58 (s, 1H), 7.46
(s, 1H), 7.13 (t, J = 9.1 Hz, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.53 (s, 3H); 13C{1H}NMR (125
MHz, CDCl3): δC/ppm 163.1, 157.3, 140.7, 136.1, 135.0, 130.6, 124.6, 123.1, 119.4, 115.5,
112.7, 104.6, 62.7, 55.6, 21.9; GCMS (EI, 70 eV): m/z (%): 269.05 (42.93), 239.05 (40), 201.05
(34.93), 167.05 (20.00), 103.60 (6.88); IR (ATR) ṽ (cm-1): 2939, 1657 and 1612.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-(tert-butyl)-5-methoxy-3-methylphenanthridin-6(5H)-one (3db)16
The typical procedure was applied to 4-(tert-butyl)-N-methoxybenzamide 1d (0.50 mmol, 104
mg), p-toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum
ether/ethyl acetate = 4/1) of the product 3db afforded as a colorless solid (128 mg, 87% yield).
1H NMR (500 MHz, CDCl3): δH/ppm 8.52 – 8.40 (m, 1H), 8.24 – 8.17 (m, 2H), 7.67 – 7.60 (m,
1H), 7.48 (s, 1H), 7.17 (dd, J = 8.1, 0.5 Hz, 1H), 4.13 (s, 3H), 2.53 (s, 3H), 1.45 (s, 9H);
13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.4, 156.1, 140.3, 135.8, 132.8, 128.3, 125.6,
124.3, 123.5, 123.0, 117.8, 116.5, 112.7, 62.5, 35.5, 31.2, 21.9; GCMS (EI, 70 eV): m/z (%):
295.10 (54.21), 265.10 (50.50), 250.05 (40), 221.10 (24.44), 111.10 (24.67), 96.60 (18.62); IR
(ATR) ṽ (cm-1): 2956, 1662 and 1613.
5-methoxy-3,8-dimethylphenanthridin-6(5H)-one (3eb)16
The typical procedure was applied to N-methoxy-3-methylbenzamide 1e (0.50 mmol, 83 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
1
acetate = 4/1) of the product 3eb afforded as a colorless solid (108 mg, 86% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.34 (s, 1H), 8.12 (t, J = 8.0 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.48
(s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 4.14 (d, J = 1.0 Hz, 3H), 2.53 (s, 3H), 2.52 (s. 3H);
13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.5, 140.0, 137.8, 135.4, 133.9, 130.7, 128.2,
ACS Paragon Plus Environment

Page 19 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
125.7, 124.4, 122.9, 121.7, 116.3, 112.6, 62.6, 21.9, 21.3; GCMS (EI, 70 eV): m/z (%): 253.05
(66.89), 223.00 (40), 194.05 (88.16), 96.60 (17.12); IR (ATR) ṽ (cm-1): 2918, 1646 and 1613.
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-methoxy-3,7-dimethylphenanthridin-6(5H)-one (3fb)16
The typical procedure was applied to N-methoxy-2-methylbenzamide 1f (0.50 mmol, 83 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
acetate = 4/1) of the product 3fb afforded as a colorless solid (89 mg, 71% yield). 1H NMR (500
MHz, CDCl3): δH/ppm 7.86 (s, 1H), 7.33 (d, J = 7.4 Hz, 2H), 7.20 – 7.16 (m, 3H), 3.47 (s, 3H),
2.42 (s, 3H), 2.37 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.5, 140.0, 137.8, 135.4,
133.9, 130.6, 128.1, 125.7, 124.3, 122.9, 121.7, 116.3, 112.6, 62.6, 21.9, 21.3; GCMS (EI, 70
eV): m/z (%): 25.00 (0.12), 223.05 (40), 194.05 (37.06), 165.05 (27.02), 96.60 (22.35); IR
(ATR) ṽ (cm-1): 2918, 1646 and 1613.
5-methoxy-3-methylbenzo[j]phenanthridin-6(5H)-one (3gb)
The typical procedure was applied to N-methoxy-2-naphthamide 1g (0.50 mmol, 40 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
1
acetate = 4/1) of the product 3gb afforded as a colorless solid (124 mg, 86% yield). H NMR
(500 MHz, CDCl3): δH/ppm 9.11 (s, 1H), 8.66 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.08-8.01 (m,
2H), 7.65-7.55 (m, 2H), 7.47 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.17 (s, 3H), 2.54 (s, 3H);
13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.9, 140.3, 135.6, 135.1, 131.9, 129.8, 129.3,
129.1, 128.5, 120.0, 126.6, 124.5, 124.0, 123.3, 120.6, 116.5, 113.0, 62.7, 21.9; GCMS (EI, 70
eV): m/z (%): 289.10 (3.55), 281.00 (30.29), 207 (64.35), 73.05 (71.51), 43.95 (40); HRMS (H+)
calcd for C19H16NO2 290.1176, found 290.1169; IR (ATR) ṽ (cm-1): 2922, 1660 and 1614.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 31
1
2
3
4
5
6
7
6-methoxy-8-methylbenzo[i]phenanthridin-5(6H)-one (3hb)
8
9
The typical procedure was applied to N-methoxy-1-naphthamide 1h (0.50 mmol, 40 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
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
acetate = 4/1) of the product 3hb afforded as a colorless solid (128 mg, 89% yield). H NMR
(500 MHz, CDCl3): δH/ppm 10.22 (d, J = 8.8 Hz, 1H), 8.25 - 8.17 (m, 2H), 8.09 – 8.07 (m, 1H),
7.87 (d, J = 7.5 Hz, 1H), 7.73 (dd, J = 8.5, 7.1 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (s, 1H),
7.14 (d, J = 8.1 Hz, 1H), 4.17 (s, 3H), 2.03 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm
171.1, 158.2, 141.0, 135.9, 134.1, 133.9, 132.7, 132.3, 128.6, 128.2, 127.7, 126.7, 124.2, 123.8,
119.5, 119.3, 115.6, 112.1, 60.4, 21.0; GCMS (EI, 70 eV): m/z (%): 289.00 (0.3), 259.05 (100),
230.05 (19.75), 202.05 (8.57), 161.10 (8.34), 128.60 (17.16), 43.00 (9.84); HRMS (Na+) calcd
for C19H15NNaO2 312.1000, found 312.0995; IR (ATR) ṽ (cm-1): 2913, 1645 and 1614.
9-fluoro-5-methoxy-3-methylphenanthridin-6(5H)-one (3ib)16
The typical procedure was applied to 4-fluoro-N-methoxybenzamide 1i (0.50 mmol, 85 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
1
acetate = 4/1) of the product 3ib afforded as a colorless solid (112 mg, 87% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.60 – 8.50 (m, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.83 (dd, J = 10.2, 1.9
Hz, 1H), 7.47 (s, 1H), 7.28 – 7.24 (m, 1H), 7.19 – 7.15 (m, 1H), 4.17 – 4.12 (m, 3H), 2.54 (s,
3H); C{1H}NMR (125 MHz, CDCl3): δC/ppm 165.7 (d, J = 252.6 Hz), 156.8, 141.5, 136.1,
13
135.7 (d, J = 9.6 Hz), 131.6 (d, J = 10.0 Hz), 124.6, 123.4, 122.3 (d, J = 2.0 Hz), 116.0 (d, J =
115.87 Hz), 115.4 (J = 115.37 Hz), 107.7 (d, J = 23.4 Hz), 62.8, 21.9; GCMS (EI, 70 eV): m/z
(%): 257.05 (52.42), 227.00 (40), 198.00 (54.40), 170.05 (12.03), 112.60 (9.15); IR (ATR) ṽ
(cm-1): 2923, 1658 and 1613.
ACS Paragon Plus Environment

Page 21 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
9-chloro-5-methoxy-3-methylphenanthridin-6(5H)-one (3jb)16
8
9
The typical procedure was applied to 4-chloro-N-methoxybenzamide 1j (0.50 mmol, 93 mg), p-
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
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
1
acetate = 4/1) of the product 3jb afforded as a colorless solid (110 mg, 81% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.40 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.50
13
– 7.37 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 4.11 (s, 3H), 2.49 (s, 3H). C{1H}NMR (125 MHz,
CDCl3): δC/ppm 156.7, 141.4, 139.3, 136.0, 134.4, 130.1, 127.9, 124.6, 124.1, 123.1, 121.6,
114.9, 112.7, 62.7, 21.9; GCMS (EI, 70 eV): m/z (%):273.05 (51.63), 243 (40), 214.05 (44.01),
165.10 (20.01), 151.10 (14.51), 120.60 (10.38), 82.15 (10.75); IR (ATR) ṽ (cm-1): 2923, 1661
and 1598.
9-bromo-5-methoxy-3-methylphenanthridin-6(5H)-one (3kb)16
The typical procedure was applied to 4-bromo-N-methoxybenzamide 1k (0.50 mmol, 76 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
1
acetate = 4/1) of the product 3kb afforded as a colorless solid (123 mg, 78% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.41 – 8.34 (m, 2H), 8.06 (d, J = 8.2 Hz, 1H), 7.67 (dd, J = 8.5, 1.3
13
Hz, 1H), 7.48 (s, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.14 (s, 3H), 2.54 (s, 3H); C{1H}NMR (125
MHz, CDCl3): δC/ppm 156.9, 141.5, 136.1, 134.7, 130.8, 130.3, 128.0, 124.8, 124.7, 124.6,
123.3, 114.9, 112.8, 62.8, 21.9; GCMS (EI, 70 eV): m/z (%): 318.95 (44.38), 316.95 (44.22),
286.95 (40), 257.95 (34.68), 179.05 (46.79), 151.10 (23.41), 82.55 (17.83); IR (ATR) ṽ (cm-1):
2920, 1662 and 1594.
8-chloro-5-methoxy-3-methylphenanthridin-6(5H)-one (3lb)
The typical procedure was applied to 3-chloro-N-methoxybenzamide 1l (0.50 mmol, 93 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 31
1
2
3
4
5
6
1
acetate = 4/1) of the product 3lb afforded as a colorless solid (113 mg, 83% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.52 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.2
Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 7.18 (d, J = 7.2 Hz, 1H), 4.14 (s, 3H), 2.54 (s,
3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 156.4, 141.0, 135.7, 133.8, 133.2, 132.9, 131.6,
128.0, 124.7, 123.4, 123.1, 115.5, 112.8, 77.2, 76.9, 76.7, 62.7, 21.9; GCMS (EI, 70 eV): m/z
(%): 273.05 (53.26), 214.05 (43.16), 179.10 (20.06), 165.10 (20.65), 82.15 (10.48); HRMS
(Na+) calcd 296.0449 for C15H12ClNNaO2 found 296.0441; IR (ATR) ṽ (cm-1): 2918, 1656 and
1619.
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
7-chloro-5-methoxy-3-methylphenanthridin-6(5H)-one (3mb)16
The typical procedure was applied to 2-chloro-N-methoxybenzamide 1m (0.50 mmol, 93 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
1
acetate = 4/1) of the product 3mb afforded as a colorless solid (86 mg, 63% yield). H NMR
(500 MHz, CDCl3): δH/ppm 7.99 (s, 1H), 7.39 (d, J = 4.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.31
13
– 7.27 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 3.60 (s, 3H), 2.38 (s, 3H); C{1H}NMR (125 MHz,
CDCl3): δC/ppm 164.4, 142.3, 138.2, 135.6, 132.5, 131.8, 130.8, 129.2, 128.5, 128.3, 128.3,
126.6, 125.7, 64.1, 21.2; GCMS (EI, 70 eV): m/z (%): 273.05 (46.39), 243.05 (40), 214.05
(42.76), 179.10 (19.69), 120.60 (8.39), 82.15 (9.00); IR (ATR) ṽ (cm-1): 2922 and 1658.
5-methoxy-3-methyl-9-nitrophenanthridin-6(5H)-one (3nb)
The typical procedure was applied to N-methoxy-4-nitrobenzamide 1n (0.50 mmol, 98 mg), p-
toluidine 2b, (0.70 mmol, 74 mg). Silica gel chromatography (eluent:petroleum ether/ethyl
acetate = 4/1) of the product 3nb afforded as a colorless solid (81 mg, 57% yield). 1H NMR (500
MHz, CDCl3): δH/ppm 9.09 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.21 (d, J
13
= 8.2 Hz, 1H), 7.53 (s, 1H), 7.27 (d, J = 5.6 Hz, 1H), 4.17 (s, 3H), 2.57 (s, 3H); C{1H}NMR
ACS Paragon Plus Environment

Page 23 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(125 MHz, CDCl3): δC/ppm 156.0, 150.5, 142.5, 136.4, 134.3, 130.6, 129.8, 125.2, 123.6, 121.2,
117.5, 115.0, 113.1, 62.9, 22.0; GCMS (EI, 70 eV): m/z (%): 284.00 (47.87), 254.00 (40),
208.00 (59.98), 103.05 (64.82), 57.05 (66.86); HRMS (H+) calcd 285.0870 for C15H13N2O4,
found 285.0876; IR (ATR) ṽ (cm-1): 2916, 1666 and 1602.
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-methoxy-7-methyl-4-phenylquinolin-2(1H)-one (3ob)
The typical procedure was applied to N-methoxycinnamamide 1o (0.50 mmol, 89 mg), p-
toluidine 2b (0.70 mmol, 74 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
acetate = 4/1) of the product 3ob afforded as a colorless oil (97 mg, 73% yield). 1H NMR (500
MHz, CDCl3): δH/ppm 7.69 (d, J = 8.3 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.50 – 7.34 (m, 2H), 7.19
(t, J = 7.6 Hz, 2H), 6.97 (s, 1H), 6.67 (s, 1H), 4.14 (s, 3H), 2.43 (s, 3H); 13C{1H}NMR (125
MHz, CDCl3): δC/ppm 157.4, 150.8, 138.9, 138.0, 133.7, 131.1, 129.3, 128.7, 127.7, 125.4,
122.6, 121.7, 119.8, 112.0, 112.0, 62.9, 21.3; GCMS (EI, 70 eV): m/z (%):265.15 (42.68),
235.10 (40), 206.10 (25.28), 178.10 (14.57), 102.20 (17.96); HRMS (H+) calcd 266.1176 for
C17H16NO2, found 266.1173; IR (ATR) ṽ (cm-1): 2934, 1648 and 1588.
5-methoxyphenanthridin-6(5H)-one (3aa)15a
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76mg), aniline 2a
(0.70 mmol, 65 mg). Silica gel chromatography (eluent: petroleum ether/ethyl acetate = 4/1) of
the product 3aa afforded as a colorless solid (40 mg, 89% yield). 1H NMR (500 MHz, CDCl3):
δH/ppm 8.57 (dd, J = 8.0, 0.9 Hz, 1H), 8.28 (dd, J = 8.0, 3.8 Hz, 2H), 7.82 – 7.76 (m, 1H), 7.69
(d, J = 8.3 Hz, 1H), 7.60 (td, J = 8.1, 1.0 Hz, 2H), 7.40 – 7.32 (m, 1H), 4.15 (s, 3H);
13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.3, 135.8, 132.9, 132.6, 129.9, 128.5, 128.1,
126.4, 123.2, 123.2, 121.9, 118.6, 112.6, 62.7; GCMS (EI, 70 eV): m/z (%): 225.00 (57.20), 195
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 31
1
2
3
4
5
6
7
(40), 180.00 (34.45), 166.05 (55.58), 140.10 (23.07), 82.60 (12.43); IR (ATR) ṽ (cm-1): 2922,
8
9
1651 and 1660.
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
3,5-dimethoxyphenanthridin-6(5H)-one (3ac)16
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76 mg), 4-
methoxyaniline 2c (0.70 mmol, 85 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
1
acetate = 4/1) of the product 3ac afforded as a colorless solid (108 mg, 85% yield). H NMR
(500 MHz, CDCl3): δH/ppm 8.52 – 8.42 (m, 1H), 8.08 (t, J = 8.2 Hz, 2H), 7.74 – 7.64 (m, 1H),
7.47 (dd, J = 7.9, 7.2 Hz, 1H), 7.15 – 7.05 (m, 1H), 6.86 (dd, J = 9.0, 2.0 Hz, 1H), 4.11 (s, 3H),
3.91 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 161.3, 157.6, 137.2, 133.1, 132.6,
128.4, 126.9, 124.9, 124.7, 121.3, 111.9, 110.6, 96.7, 62.6, 55.6.; GCMS (EI, 70 eV): m/z (%):
255.00 (40), 225.00 (82.00), 196.00 (81.99), 153.05 (40.65), 127.10 (12.48); IR (ATR) ṽ (cm-1):
2937, 1659 and 1605.
5-methoxy-2,3-dimethylphenanthridin-6(5H)-one (3ad)16
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76 mg), 3,4-
dimethylaniline 2d (0.70 mmol, 85 mg). Silica gel chromatography (eluent: petroleum
ether/ethyl acetate = 4/1) of the product 3ad afforded as a colorless solid (114 mg, 90% yield).
1H NMR (500 MHz, CDCl3): δH/ppm 8.52 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.97 (s,
1H), 7.77 – 7.70 (m, 1H), 7.54 (dd, J = 8.0, 7.2 Hz, 1H), 7.42 (s, 1H), 4.13 (s, 3H), 2.42 (s, 3H),
2.39 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.2, 139.5, 133.9, 133.0, 132.4,
131.8, 128.4, 127.4, 126.0, 123.7, 121.6, 116.3, 113.2, 62.6, 20.4, 19.6; GCMS (EI, 70 eV): m/z
(%): 253.10 (79.72), 223.05 (86.21), 194.05 (40), 165.10 (17.67), 126.65 (10.86), 89.10 (12.16);
IR (ATR) ṽ (cm-1): 2914, 1641 and 1607.
ACS Paragon Plus Environment

Page 25 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
5-methoxy-1,3-dimethylphenanthridin-6(5H)-one (3ae)
8
9
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76 mg), 2,4 dimethyl
aniline 2e (0.70 mmol, 85 mg). Silica gel chromatography (eluent: petroleum ether/ethyl acetate
= 4/1) of the product 3ae afforded as a colorless solid (92 mg, 73% yield). 1H NMR (500 MHz,
CDCl3): δH/ppm 8.55– 8.51 (m, 1H), 8.28 – 8.24 (m, 1H), 8.01 (s, 1H), 7.78 – 7.74 (m, 1H), 7.58
– 7.56 (m, 1H), 7.46 (s, 1H), 4.14 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H); 13C{1H}NMR (125 MHz,
CDCl3): δC/ppm 157.3, 139.5, 135.7, 132.5, 132.4, 131.8, 128.5, 128.4, 127.4, 123.8, 122.2,
121.6, 113.3, 62.6, 20.4, 19.6; GCMS (EI, 70 eV): m/z (%):253.05 (68.01), 223.00 (40), 194.05
(91.30), 165.05 (18.76), 76.00 (9.72); HRMS (Na+) calcd 276.0995 for C16H15NNaO2 found
276.1000; IR (ATR) ṽ (cm-1): 2916, 1666 and 1554.
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-chloro-5-methoxyphenanthridin-6(5H)-one (3af)16
The typical procedure was applied to N-methoxybenzamide 1a (0.50 mmol, 76 mg), 4-chloro
aniline 2f, (0.70 mmol, 89 mg). Silica gel chromatography (eluent: petroleum ether/ethyl acetate
= 4/1) of the product 3af afforded as a colorless solid (98 mg, 76% yield). 1H NMR (500 MHz,
CDCl3) δH/ppm 8.56 (d, J = 8.0 Hz, 1H), 8.23 – 8.18 (m, 2H), 7.80 (t, J = 7.2 Hz, 1H), 7.71 –
7.59 (m, 2H), 7.36 – 7.30 (m, 1H), 4.16 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3) δC/ppm
157.3, 139.3, 136.2, 132.9, 132.3, 131.14, 128.7, 128.4, 124.5, 123.5, 121.9, 114.0, 112.6, 62.9;
GCMS (EI, 70 eV): m/z (%): 258.95 (22.02), 229.95 (69.43), 103.05 (40), 57.05 (88.14); IR
(ATR) ṽ (cm-1): 2916, 1663 and 1602.
5-methoxy-3-nitrophenanthridin-6(5H)-one (3ag)15a
The typical procedure was applied to N-methoxy-N-methylbenzamide 1a (0.50 mmol, 76 mg), 4-
nitro aniline 2g (0.70 mmol, 97 mg). Silica gel chromatography (eluent: petroleum ether/ethyl
acetate = 4/1) of the product 3ag afforded as a colorless solid (71 mg, 53% yield). 1H NMR (500
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 31
1
2
3
4
5
6
7
8
9
MHz, CDCl3): δH/ppm 8.62 (d, J = 8.0 Hz, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.42 (d, J = 8.8 Hz,
1H), 8.33 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.8, 2.3 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.75 (t, J = 7.6
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
13
Hz, 1H), 4.22 (s, 3H); C{1H}NMR (125 MHz, CDCl3): δC/ppm 157.0, 148.5, 136.4, 133.3,
131.2, 130.1, 129.0, 127.3, 124.4, 123.5, 123.0, 117.63, 108.4, 63.3; GCMS (EI, 70 eV): m/z
(%): 270.00 (31.36), 240.00 (40), 182.00 (57.54), 103.05 (88.18), 43.95 (70.54); IR (ATR) ṽ
(cm-1): 2917, 1661 and 1515.
N-methoxy-N-methyl-[1,1'-biphenyl]-2-carboxamide (3ta)25
In 15 mL Schlenktube, a solution of 5 mL methane sulphonic acid, Pd(OAc)2, (5 mol %, 11.2
mg), aniline 2a (0.7 mmol, 0.65 mg), N-methoxy-N-methylbenzamide 1t (0.50 mmol, 83 mg)
and AgOTf (1 mmol, 257 mg) were added under nitrogen atmosphere. The system was degassed
four to five times by vacuum pump. To the resulting suspension a tert-butyl nitrite (0.8 mmol, 85
mg) was added by syringe. The reaction mixture was stirred at 40 °C for 18 h. After completion
of the reaction, the reaction mixture was cooled to room temperature. All volatiles were removed
under vacuum. The product was extracted with 20 mL of ethyl acetate and the organic layer was
dried over Na2SO4 and the solvent was removed under vacuum. The colorless solid
phenanthridionone product 3ta was purified by column chromatography (silica gel, 40-200
1
mesh, eluent: petroleum ether/ethyl acetate = 4/1, 25 mg, 21% yield). H NMR (500 MHz,
CDCl3): δH/ppm 7.69 – 7.07 (m, 9H), 3.48 (br s, 1H), 3.24 (br s, 2H), 3.08 (br s, 2H), 2.65 (br s,
1H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 172.0, 167.1, 140.5, 139.5, 139.5, 134.9, 134.8,
129.6, 129.4, 128.4, 128.3, 127.7, 127.6, 127.4, 126.8, 61.1, 59.8, 35.8, 32.4, 29.7; GCMS (EI,
70 eV): m/z (%): 241.05 (1.73), 181.10 (40), 152.15 (40.35), 76.05 (7.34); IR (ATR) ṽ (cm-1):
2932, 1645 and 1375.
ACS Paragon Plus Environment

Page 27 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
N-methoxy-[1,1'-biphenyl]-2-carboxamide (B’)18
8
9
1H NMR (500 MHz, CDCl3) δH/ppm 8.17 (s, 1H), 7.57 (s, 1H), 7.48 (td, J = 7.6, 1.4 Hz, 1H),
7.39 - 7.35 (m 7H), 3.47 (s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δC/ppm 167.3, 140.1, 140.0,
139.7, 132.3, 130.6, 130.0, 129.0, 128.7, 127.9, 127.6, 63.7; GCMS (EI, 70 eV): m/z (%):
227.10 (1.10), 197.10 (39.43), 180.05 (100.00), 152.15 (55.01), 76.05 (23.17); IR (ATR) ṽ (cm-
1): 3221, 1639, 1508, 1310.
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
Typical procedure for the synthesis of 3ab on the gram scale
In 40 mL double neck round bottom flask, a solution of 20 mL acetic acid, Pd(OAc)2, (5 mol %),
p-toluidine 2a (9.7 mmol, 1.40 g), N-methoxybenzamide 1a (7 mmol, 1.06 g) and Ag2O (14
mmol, 3.12 g) were added under nitrogen atmosphere. The system was degassed four to five
times by vacuum pump. To the resulting suspension a tert-butyl nitrite (11.2 mmol, 1.5 mL) was
added by syringe at room temperature. The reaction mixture was at 40 °C up to 18 h. After
completion of the reaction, the reaction mixture was cooled to room temperature. All volatiles
were removed under vacuum. All volatiles were removed under vacuum. The product was
extracted with 20 mL of ethyl acetate and the organic layer was dried over Na2SO4 and the
solvent was removed under vacuum. The phenanthridionone product was purified by column
chromatography (silica gel, 40-200 mesh).
ACKNOWLEDGMENT
Author SLY is thankful to Council of Scientific and Industrial Research (CSIR), New Delhi,
India for providing a Senior Research Fellowship (SRF). We are also thankful to Department of
chemistry, IIT Mumbai for providing HR-MS analysis of products.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 31
1
2
3
4
5
6
7
8
9
SUPPORTING INFORMATION
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
The copies of H and 13C NMR spectra are available free of charge via the internet at
http://pubs.acs.org
REFERENCES
(1) (a) Holl, V.; Coelho, D.; Weltin, D.; Dufour P.; Bischoff, P. Anticancer Res., 2000, 20,
3233. (b) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.; Abe,
H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans., 2001, 1, 523.
(2) (a) Singh, K. N. Tetrahedron Lett. 1998, 39, 4391. (b) Geen, G. R.; Mann, I. S.; Mullane,
M. V.; Mckillop, A. Tetrahedron 1998, 54, 9875. (c) Nakanishi, T.; Suzuki, M. Org. Lett.
1999, 1, 985. (d) Orito, K.; Satoh, Y.; Nishizawa, H.; Harada, R.; Tokuda, M. Org. Lett.
2000, 2, 2535. (e) Treus, M.; Estevez, J. C.; Castedo, L.; Estevez, R. J. Tetrahedron Lett.
2002, 43, 5323. (f) Liu, L. Synthesis 2003, 11, 1705. (g) Patil, S.; Kamath, S.; Sanchez,
T.; Neamati, N.; Schinazi, R. F.; Buolamwini, J. K. Bioorg. Med. Chem., 2007, 15, 1212.
(3) (a) Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 5479. (b) Le, T. N.; Gang, S. G.;
Cho, W. J. J. Org. Chem. 2004, 69, 2768. (c) Ashburn, B. O.; Carter, R. G.; Zakharov, L.
N. J. Org. Chem. 2008, 73, 7305.
(4) (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev., 2012, 41, 3651. (b) Chen, Z.; Wang, B.;
Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107. (c) Li, H.; Wei,
W.; Xu, Y.; Zhang, C.; Wan, X. Chem. Comm., 2010, 47, 1497. (d) Arockiam, P. B.;
Bruneau, C.; Dixneuf, P. H. Chem. Rev., 2012, 112, 5879. (e) Yamaguchi, J.; Yamaguchi,
ACS Paragon Plus Environment

Page 29 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A. D.; Itami, K. Angew. Chem., Int. Ed., 2012, 51, 8960. (f) Li, J.; Ackermann, L. Org.
Chem. Front., 2015, 2, 1035.
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) (a) Beng, T.; Langevin, S.; Braunstein, H.; Khim, M. Org. Biomol. Chem., 2016, 14, 830.
(b) Hu, F.; Szostak, M. ChemCatChem, 2015, 7, 1061. (c) Guo, H.; Xing, F.; Du, G.;
Huang, K.; Dai, B.; He, L. 2015, J. Org. Chem., 2015, 80, 12606. (d) Patra, T.; Watile,
R.; Agasti, S.; Naveena, T.; Maiti, D. Chem. Comm. 2015, 52, 2027.
(6) (a) Yang, L.; Huang, H. Catal. Sci. Technol., 2012, 2, 1099. (b) Flegeau, E.; Bruneau, C.;
Dixneuf, P.; Jutand, A. J. Am. Chem. Soc., 2011, 133, 10161. (c) Siegbahn, P.; Blomberg,
M. Dalton Trans., 2009, 5820 (d) Giri, R.; Shi, B.; Engle, K. M.; Maugelc, N.; Yu, J.
Chem. Soc. Rev., 2009, 38, 3242. (e) McNally, A.; Haffemayer, B.; Collins, B.; Gaunt,
M. Nature, 2014, 510, 129.
(7) (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed., 2013, 52, 11726. (b) Ye, X.; Shi, X.
Org. Lett. 2014, 16, 4448. (c) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (d) Tlili, A.; Schranck, J.; Pospech, J.; Neumann, H.; Beller,
M. ChemCatChem, 2014, 6, 1562. (e) Yedage, S. L.; Bhanage, B. M. Synlett, 2015, 26,
2161.
(8) (a) Khemnar, A. B.; Bhanage, B. M. Org. Biomol. Chem. 2014, 12, 9631. (b) Khemnar,
A. B.; Bhanage, B. M. Rsc. Adv., 2014, 4, 8939. (c) Yedage, S. L.; Bhanage, B. M.
Synthesis, 2015, 47, 526. (d) Yedage, S. L.; D'silva D. S.; Bhanage, B. M. RSC Adv.,
2015, 5, 80441. (e) Tiwari, A. R.; Bhanage, B. M. Green Chem., 2016, 18, 144. (f)
Gautam, P.; Bhanage, B. M. J. Org. Chem., 2015, 80, 7810. (g) Mane, R. S.; Sasaki, T.;
Bhanage, B. M. RSC Adv., 2015, 5, 94776.
ACS Paragon Plus Environment