Organocatalyst in Direct C(sp2)-H Arylation of Unactivated Arenes: [1-(2-Hydroxyethyl)-piperazine]-Catalyzed Inter-/Intra-molecular C-H Bond Activation

Article abstract of DOI:10.1021/acs.joc.0c01019

This article describes the identification of 1-(2-hydroxyethyl)-piperazine as a new, cost-effective, highly efficient organocatalyst, which promotes both inter- A nd intra-molecular direct C(sp2)-H arylations of unactivated arenes in the presence of potassium tert-butoxide. While the inter-molecular C-H arylation of unactivated benzenes with aryl halides (Ar-X; X = I, Br, Cl) toward biaryl syntheses underwent smoothly in the presence of only 10 mol percent organocatalyst, the intra-molecular C-H arylation catalytic system composed of 40 mol percent each of the catalyst and the additive (4-dimethylaminopyridine (DMAP)). The novel catalyst was also able to perform both inter- A nd intra-molecular direct arylations simultaneously in a single pot. The mechanistic studies confirmed the involvement of aryl radical anions and proceeded via a single-electron-transfer (SET) mechanism. The large substrate scope, high functional group tolerance, competition experiments, gram-scale synthesis, and kinetic studies further highlight the importance and versatile nature of the methodology as well as the compatibility of the new catalyst. To the best of our knowledge, this is the first report on any organocatalyst that reported detailed investigations of both inter- A nd intra-molecular direct C(sp2)-H arylations of unactivated arenes in a single representation.

Full text of DOI:10.1021/acs.joc.0c01019

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Article
Organocatalyst in Direct C(sp2)–H Arylation of
Unactivated Arenes: [1-(2-Hydroxyethyl)-piperazine]-
catalyzed Inter- /Intra-molecular C–H bond activation
Lalit Yadav, MOHIT KUMAR KUMAR TIWARI, Bharti Rajesh Kumar Shyamlal, and Sandeep Chaudhary
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01019 • Publication Date (Web): 22 May 2020
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The Journal of Organic Chemistry
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Organocatalyst in Direct C(sp )–H Arylation of Unactivated Arenes: [1-(2-
1
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8
Hydroxyethyl)-piperazine]-catalyzed Inter- /Intra-molecular C–H bond activation
Lalit Yadav, Mohit K. Tiwari, Bharti Rajesh Kumar Shyamlal and Sandeep Chaudhary*
aLaboratory of Organic and Medicinal Chemistry, Department of Chemistry, Malaviya National
Institute of Technology, Jawaharlal Nehru Marg, Jaipur-302017, India.
9
Fax: 911412529029; Tel: 911412713319; E-mail: schaudhary.chy@mnit.ac.in
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R3
1-(2-hydroxyethyl)-piperazine as new catalyst
O
Organocatalytic C-H bond activation
Large substrate scope
B
R1
N
H
Ar2
Ar1
I +
A
H
R2
Br
OH
Intra-molecular
Inter-molecular
HN
N
O
O
Organocatalyst E
1-(2-hydroxyethyl)-piperazine
R1
R1
R2
Ar2
Ar1
NH
NH
A
A
+
R2
B
B
R3
One-pot double direct arylation
Gram scale synthesis
Diverse variety of biaryls & phenanthridinones
3a-v
24-42
31 examples
Upto 94% yield
R3
30 examples
Upto 89% yield
ABSTRACT: This article describes the identification of 1-(2-hydroxyethyl)-piperazine as a new, cost-
effective, highly efficient organocatalyst which promotes both inter- as well as intra-molecular direct
2
C(sp )–H arylation of unactivated arenes in the presence of potassium tert-butoxide. While the inter-
molecular C–H arylation of unactivated benzenes with aryl halides (Ar–X; X = I, Br, Cl) towards biaryl
syntheses underwent smoothly in the presence of only 10 mol% organocatalyst; the intra-molecular C-H
arylation catalytic system comprises of 40 mol% each of the catalyst and the additive (DMAP). The
novel catalyst is also able to perform both inter- as well as intra-molecular direct arylation
simultaneously in a single pot. The mechanistic studies confirmed the involvement of aryl radical anion
and proceeded via single electron transfer (SET) mechanism. The large substrate scope, high functional
group tolerance, competition experiments, gram-scale synthesis and kinetic studies further highlights the
importance and versatile nature of the methodology as well as the compatibility of the new catalyst. To
the best of our knowledge, this is the first report by any organocatalyst reported in the literature which
2
gives detailed extensive investigations of both inter- as well as intra-molecular direct C(sp )–H arylation
of unactivated arenes in a single representation.
Introduction
During the last two decades, organocatalyzed C(sp2)–H bond activation of arenes/heteroarenes has been
recognized advantageous over transition-metal catalysis and has been found as a promising area of
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research in the field of C–H bond activation.1 This is due to their inherent non-metal properties,
environmentally benign, broad functional group tolerance, mild reaction conditions with high degree of
selectivity and productivity.1 Biaryls are important pharmaceutically previleged structural moieties
which are present in several natural products, pharmaceuticals, agrochemicals and functional materials.2
Recently, organocatalyzed synthesis of biaryls has been reported by the reaction of aryl halides with
arenes using small organic molecule as an organocatalyst I-XI in the presence of strong base which
generally involves radical chain mechanism (Figure 1).3-5 Several inter-molecular organocatalytic
approach has been reported by Itami,3a Kwong,3b Lei,3b Shirakawa/ Hayashi,3c and Shi3d to synthesize
biaryl moiety via single electron transfer (SET) mechanism (Figure 1).3,4
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Similarly, many intra-molecular C(sp2)-H direct arylation have also been reported via organocatalyzed
base-promoted homolytic aromatic substitution (BHAS) reaction to construct various biaryl-based
heterocyclic compounds.5 However, all these inter- as well as intra-molecular C(sp2)–H direct arylation
are being facilitated by costly organocatalyst such as 1,10-phenanthridinone, 1,2-diamines, 1,2-diols,
amino acids, hydrazine derivative, N-heterocyclic carbenes and a pyridone-fused cavity complex, P5a
etc (Figure 1).3-5 Therefore, the identification of a new cost-effective organocatalyst, which can perform
both inter- as well as intra-molecular C(sp2)–H direct arylation of unactivated arenes, is highly desirable
in higher yields under ambient reaction conditions.
Catalyst.
Base
Ar2
Ar1
Ar2
Ar1
+ H
I
Preceedings Organocatalyst
NH
H
N
H
N
OH
H
N
Et
Et
N
O
H
O
OH
O
C8H17
N
IV
III
I
II
O
H
N
BocHN
O
NC8H17
N
O
H
C8H17
N
O
O
C8H17
N
N
N
H
O
O
N
H
O
HN
O
N
H
O
N
O
H
N
O
N
NC8H17
EtOOC
N
N
C8H17
O
C8H17
V
VII
XI
VI
Ph
tBu
NH
Ph
N
N
N
N
N
N
N
N
Mes
VIII
IX
X
2
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Figure 1. Structures of selected organocatalyst I-XI used in previous organocatalyzed C-H bond activation.3-5
1
The inter-molecular direct arylation of unactivated arenes has been mainly reported to be catalyzed by
N,N-bidentate ligands. Few examples of O,O-bidentate ligand has been reported to execute intra-
molecular direct arylation reactions. Therefore, in our efforts to prepare bioactive heterocycles through
novel synthetic strategies6a-b and to search for new metal-free/organocatalytic system;6c-d we anticipated
that reaction catalyzed by N,O-bidentate ligand could effectively generate coupled product in excellent
yields. Thus, based on above hypothesis, without neglecting N,N- and O,O-bidentate ligands, we plan to
carry out extensive investigation for the search of new organocatalyst [possibly with N,O-bidentate
ligand(s)] which can effectively facilitate both inter-as well as intra-molecular organocatalyzed direct
arylation of unactivated arenes in a cost-effective manner under ambient reaction conditions. Herein, we
uncovered 1-(2-hydroxyethyl)-piperazine as a new, cost-effective, highly efficient organocatalyst which
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promotes both inter- as well as intra-molecular direct C(sp )–H arylation of unactivated arenes in the
presence of potassium tert-butoxide. Both inter-molecular as well as intra-molecular direct arylation
underwent smoothly to furnish biaryls and phenanthridinones (scaffold chosen in the present study),
respectively. To the best of our knowledge, this is the first report by any organocatalyst reported in the
literature which gives detailed extensive investigations (comprehensive optimization studies, substrate
scope, gram-scale synthesis, kinetic isotopic studies, competition experiments, ICP-MS data studies,
2
one-pot double direct arylation etc.) of both inter- as well as intra-molecular direct C(sp )–H arylation of
unactivated arenes in a single representation.
Results and Discussion
Inter-molecular Organocatalyzed C(sp2)-H direct arylation of unactivated arenes
4-iodotoluene 1a and extrapure anhydrous benzene 2 was selected as starting materials for the
optimization of inter-molecular organocatalyzed C(sp2)–H direct arylation of unactivated arenes (Table
1). Initially, the screening of organocatalyst (A-M) was carried out for the optimization study involving
reaction of 1a with 2 to furnish 4-methylbiphenyl 3a (Table 1, entry 1-13, figure 2). The choice of the
organocatalyst were based on previous findings and most of the ligands have either N,N-/O,O- or N,O-
coordinating atoms between two carbon atoms. While the catalyst A, D, J and M were found ineffective
to furnish biaryl product 3a (Table 1, entry 1, 4, 10 and 13); the organocatalyst C, E, H, and L
furnished 3a in >50% yields (Table 1, entry 3, 5, 8 and 12). Rest of the organocatlayst were able to
afford 3a in lower yields (Table 1, entry 2, 6-7, 9 and 11). No conversion of 1a into 3a was observed
when the reaction was carried out in the absence of an organocalalyst (Table 1, entry 14). Therefore,
after screening of several commercially available organocatalysts A-M, [1-(2-hydroxyethyl)-piperazine]
i.e., Catalyst E having N,O–coordinating atoms between two carbon atoms was found to be the best
organocatalyst which afforded 4-methylbiphenyl 3a in 72% yield (Table 1, entry 5). It has been
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observed that 2-(1H-imidazole-1-yl)ethan-1-ol (catalyst F), piperazine (catalyst H), and [2,2'-
(piperazine-1,4-diyl)bis(ethan-1-ol)] (catalyst G) were found less effective than 2-(piperazin-1-
yl)ethan-1-ol (catalyst E) (Table-1, entry 5-8). Once oragnocatalyst is optimized, then, screening of
various aprotic polar solvents such as DMF, DMSO, DMA were carried out in which 4 equiv. of 2 was
taken (Table 1 entry 15-18). These solvents were not found effective in enhancing the yield of the
reaction.
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O
H
N
NH2
NH2
H
H3C
N
N
N
HN
CH3
O
H
N
N
N
N
N1,N2-dimethylethane-1,2-diamine
10H-phenoxazine-2,3-diamine
2,2':6',2''-terpyridine
[2,2':6',2''-terpyridin]-4'(1'H)-one
B, 18%
A, 0%
D, 0%
C, 60%
OH
OH
OH
N
N
NH
N
N
HN
NH
N
HO
OH
HO
N
2-(piperazin-1-yl)ethan-1-ol
2,2'-(piperazine-1,4-diyl)bis(ethan-1-ol)
pyridine-2,3-diol
2-(1H-imidazol-1-yl)ethan-1-ol
piperazine
E, 72%
I, 12%
H, 65%
G, 45%
F, 18%
Cl
N
N
CH3
H3C
N
OH
N
CH3
N
H
H2N
H3C
N1,N1,N2,N2-tetramethyl-
ethane-1,2-diamine
M, 0%
2-(pyridin-2-yl)-1H-benzo[d]imidazole
2-aminoethan-1-ol
N
K, 10%
N
N
L, 55%
4'-(4-chlorophenyl)-2,2':6',2''-terpyridine
J, 0%
Figure 2. Structures of different organocatalyst A-M used in this study.
Subsequently, various bases such as LiOtBu, NaOtBu, KOH, K2CO3, and LiHMDS etc. were screened
(Table 1, entry 19-23). Using 20 mol% of Catalyst E in benzene (4 mL), potassium tert-butoxide was
found to be the best efficient base for the synthesis of 3a (Table 1, entry 18). Other bases such as
LiOtBu, NaOtBu, KOH, K2CO3 were found ineffective (Table 1, entry 19-23). An increase or decrease
in gram equivalents of base do not have beneficial effect on the yield of the reaction (Table 1, entry 24-
25). Then, the study towards variation of mol% of catalyst E {1-(2-hydroxyethyl)-piperazine} along
with increase in temperature (100 °C) and time (24 h) and 3 equivalents of KOtBu was carried out
(Table 1, entry 26-27). It was found that the reaction of 1a with 2 to furnish 3a underwent effectively in
85% isolated yield using 10 mol% of catalyst E as compared to the reaction where 20 mol% of cat. E
was used (Table 1, entry 26-27).5d The formation of thick reddish reaction mixture using 20 mol% of
cat. E might be the probable cause for the low yield of the reaction. However, using 10 mol% of cat. E,
there is comparatively very less formation of thick reddish mixture. Eventually, decrease in the yield of
the reaction was also observed when 5 mol% of cat. E was utilized keeping all the other parameters
same (Table 1, entry 28). Overall, 10 mol % of Catalyst E {1-(2-hydroxyethyl)-piperazine}, 3
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equivalents of KOtBu dissolved in 4 mL of benzene at 100 °C for 24 h was found to be the best optimized
reaction conditions for inter-molecular organocatalyzed direct arylation reaction.
Using optimized reaction conditions, several substituted aryl/heteroaryl halides 1a-v were reacted with
benzene 2 in presence of catalyst E and potassium tert-butoxide at 100 °C for 24 h furnished substituted
biaryls 3a-v upto 89% yields (Scheme 1).
1
2
3
4
5
6
7
8
9
Table 1. Optimization study: Inter-molecular Organocatalyzed C(sp2)-H direct arylation of aryl
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halides unactivated benzene.a
H
Catalyst, Base
H3C
H3C
I
+
Solvent, Temp.
Time
1a
2
3a
Temp
[oC]
80
80
80
80
80
80
80
80
80
80
80
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80
110
120
130
RT
80
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100
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100
Time
[h]
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24
entry
Catalyst
solvent
Base
Yield [%]b
1.
2.
A
B
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
DMFc
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
LiOtBu
NaOtBu
KOH
trace
18
60
trace
72
18
45
65
12
trace
10
55
Trace
0
trace
48
trace
55
0
0
0
0
8
60
65
76
3.
C
4.
5.
D
E
6.
F
7.
8.
9.
G
H
I
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
J
K
L
M
-------
E
E
E
E
E
E
E
E
E
DMSOc
DMAc
DMSOc
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
K2CO3
Li-HMDS
KOtBu(4)
KOtBu(2)
KOtBu
KOtBu
KOtBu
E
E
E
Ed
Ee
85
65
aThe reaction was carried out using 1a (0.5 mmol), and benzene 2a (4 mL) in the presence of catalyst and base (1.5 mmol) in
sealed tubes., bisolated yield, c 4 equiv. of benzene was taken along with 2 mL of the solvent. d10 mol% of cat. E. e5 mol% of
cat. E.
The yields of the reaction showed wide range of values and were found satiffactorily with both electron-
donating group (EDG) and electron-withdrawing group (EWG) on aryl halides (3a-m). The electron-
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donating methyl group at p- as well as m-position of 1a and 1b furnished biaryl coupling product 3a and
3b in 85% and 83% yields, respectively. However, introduction of two CH3 group (3c) diminishes the
yield of the reaction. Similarly, o-/m-/p-OMe group containing iodobenzene also furnished coupled
product (3d-f) in excellent yields. Here, it is to be noted that the sterically hindered biaryl product 3f
was formed in 82% yield from o-OMe iodobenzene 1f. Furthermore, terphenyl 3g or 3n have been
synthesized either from biphenyl iodide 1g or from diiodobenzene in significant yields. Like electron-
donating groups, arylhalide containing electron-withdrawing groups such as CN, F, OCF3 etc. also
furnished the desired product in reasonably sufficient yields (3h-j) except 3k where m-terphenyl is
obtained in 30% yield. In contrast, the reaction of p-fluoroiodobenzene 1i furnished the p-terphenyl in
only trace amount. In addition, p-chloro and m-chloro –iodobenzene 1l and 1m furnished 3l and 3m in
71% and 51% yields, respectively. However, there is a formation of o-/m-/p-terphenyls in significant
yields in the case of haloiodobenzene X–Ar–I (X = Cl, Br, I) which has been explained in Table 2.
Scheme 1. Substrate scope: 1-(2-hydroxyethyl)-piperazine-catalyzed biaryl coupling with aryl
iodides/bromides /chlorides.a
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Cat. E (10 mol%), KOtBu
R
I
R
N
NH
H
+
X
1x
or
100 °C
HO
3a-w
S
N
2
1a-w
2-(piperazin-1-yl)ethan-1-ol
Br
Catalyst E
1y
O
H3C
H3C
H3C
O
F
H3C
3a
, 85% (X= I)
O
3e
, 80% (X= I)
, 60% (X= I)
3b
3g
3d
, 83% (X= I)
, 85% (X= I)
3c
3h
, 61% (X= I)
NC
F3CO
3i
, 89% (X= I)
76% (X=Cl)
, 64% (X= I)
3j
, 65% (X= I)
3f
, 82% (X= I)
F
H3C
O
Cl
Cl
3k b
, 34% (X= I)
3l
, 71% (X= I)
3o
3n
, 71% (X=Br)
N
, 69% (X= I)
3m,
51% (X= I)
N
N
N
N
CH3
N
3r
, 83% (X= I)
3t
3s
, 30% (X= I)
, 77% (X= I)
3p
, 65% (X= Br)
3q
, 68% (X= Br)
S
N
S
S
3x
3v
, 0%
, 50% (X= I)
3w
3u
, 0%
, 31% (X= I
aReaction conditions: The reaction was carried out under a nitrogen atmosphere using an aryl halide (1a-y: 0.5 mmol),
benzene (2: 4 mL), KOtBu (1.5 mmol), and 1-(2-hydroxyethyl)-piperazine (Cat. E: 0.05 mmol) in a sealed tube for 24 h.
bConversion of 1k to Compound 6 in 30% yield.
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Similarly, functionalized bromoarene 1o on direct arylation furnished functionalized biaryls 3o in 71%
yield. Some heteroaryl halides (X = Br, I) such as quinoline, isoquinoline, pyridine, pyrazine, thiophene
etc. furnished heterobiaryls 3p-v in moderate to high yields (up to 83%). It was also noticed that the
reaction behaves differently with unsubstituted halobenzenes (X = Cl, Br). Chlorobenzene on reaction
with 2 do not undergo direct arylation to furnish biaryl under optimal reaction conditions. However,
bromobenzene on reaction with 2 furnished biaryl in only 20% yield. Overall, it can be interpreted that
inspite of having electron-donating (EDG) and electron-withdrawing (EWG) group in the starting
substrate; the reaction facilitates smooothy in relatively significant yields. The aliphatic iodoalkyl 1w
and iodo-thiazole 1x was ineffective to accomplished the desired product 3w and 3x, respectively, under
optimized reaction conditions.
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60
To further explore the substrate scope of our optimized methodology, several dihalobenzenes 4a-i
substituted at ortho-, meta- and para-positions were subjected to direct double arylation under
optimized reaction conditions which furnished mono-arylated 1g/5a-f/3l/3m as well as bis-arylated
products 3n/6/7 in good to moderate yields (Table 2).
Table 2. Substrate scope: 1-(2-hydroxyethyl)-piperazine catalyzed direct double arylation of
dihalobenzenes with unsubstituted benzene.a
20 mol% Cat. E
+
I
H
+
KOtBu, 100 °C
24 h
X
X
4a-i
2
3n / 6 / 7
1g / 5a-f / 3l / 3m
Product (yield %)
entry
substrate
Biaryl
Terphenyl
1.
2.
3.
4a, X = I
4b, X = Br
4c, X = Cl
1g (7)
5a (50)
3l (71)
3n (69)
3n (35)
3n (9)
I
X
I
4.
5.
4d, X = I
4e, X = Br
5b (traces)
5c (25)
6 (71)
6 (50)
6.
7.
8.
9.
4f, X = Cl
4g, X = I
5d (32)
5e (63)
5f (34)
3m (51)
6 (26)
7 (17)
7 (30)
7 (31)
X
I
4h, X = Br
4i, X = Cl
X
I
10.b
4b, X = Br
5a (25)
3n (67)
X
aReaction conditions: The reaction was carried out under a nitrogen atmosphere using an aryl halide (4a-i: 0.5 mmol),
benzene (2: 4 mL), KOtBu (1.5 mmol), and 1-(2-hydroxyethyl)-piperazine (Cat. E: 0.05 mmol) in a sealed tube for 24 h. b5
equivalents of KOtBu was used.
Different para-substituted halo-iodobenzenes 4a-c (X = I, Br, Cl) reacted with 2 under optimized
reaction conditions showed variation in the yield of the mono-arylated and bis-arylated products
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depending upon the bond energies of the C–X bond (Table 2, entry 1-3). 1,4-Diiodobenzene 4a on
reaction with 2 furnished biaryl (mono-arylated) 1g and terphenyl (bis-arylated) 3n in 7% and 69%
yields, respectively (Table 2, entry 1). However, 1-bromo-4-iodobenzene 4b reacted with 2 under
optimized conditions and furnished biaryl 5a and terphenyl 3n in 50% and 35% yields, respectively
(Table 2, entry 2). Contrary to 4a, 1-chloro-4-iodobenzene 4c (having relatively stronger C–Cl bond)
gives biaryl 3l and terphenyl 3n in 71% and 9% yields, respectively (Table 2, entry 3). Similar variation
in the yield of biaryl and terphenyl was observed in the case of meta-substituted halo-iodoarenes 4d-f (X
= I, Br, Cl). While mono-arylated products 5b and 5d were obtained in lower yield in the case of m-
diiodobenzene 4d and higher yield in the case of m-chloro-iodobenzene 4f, respectively; bis-arylated
product 6 was obtained in higher yield in the case of m-diiodobenzene 4d and lower yield in the case of
m-chloro-iodobenzene 4f (Table 2, entry 4 and 6). In addition, 5c and 6 were obtained in average yields
in the case of m-bromo-iodobenzene (Table 2, entry 5).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sterically hindered ortho-Substituted halo-iodobenzenes 4g-i undergoes this reaction in contrast to
para- and meta-substituted halo-iodobenzenes 4a-c and 4d-f. 1,2-Diiodobenzene 4g on reaction with 2
furnished biaryl (mono-arylated) 5e and terphenyl (bis-arylated) 7 in 63% and 17% yields, respectively
(Table 2, entry 7). However, 2-bromo-1-iodobenzene 4h reacted with 2 under optimized conditions and
furnished biaryl 5f and terphenyl 7 in 34% and 30% yields, respectively (Table 2, entry 8). Contrary to
4g, 1-chloro-1-iodobenzene 4i, (having relatively stronger C–Cl bond) gives biaryl 3m and terphenyl 7
in 51% and 31% yields, respectively (Table 2, entry 9). Thus, the newly developed catalyst potentially
activates two C-H bond to effectively facilitate organocatalyzed double direct arylation. The most
important characteristic feature of our reaction was observed with m-fluoro-iodoarenes as illustrated in
Scheme 1 where meta-flouro-iodoarenes 1k, inspite of having strong C–F bond, was subjected to direct
arylation under optimized reaction conditions afforded meta-diarylated product 6 in 12% yield. It was
also observed that increasing the amount of KOtBu from 3 equivalents to 5 equivalents increases the
yield of the bis-arylated product (Table 2, entry 10).
Table 3. Role of radicals/cation in direct arylation reactions.
Cat. E (10 mol%), KOtBu
H3C
H3C
I
+
H
Additive, 100 °C
1a
3a
2
entry
1.
Additive
Yield (%)a
No radical scavenger
TEMPO (10 mol %)
TEMPO (100 mol %)
85
12%
0
2.
3.
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The Journal of Organic Chemistry
4.
aIsolated yield.
18-crown-6 (3 equiv.)
27%
1
2
3
Based on previous investigations,7 we then examined experimentally the plausible mechanism of the 1-
(2-hydroxyethyl)-piperazine catalyzed direct C(sp2)–H arylation reaction and the possible role of free-
radicals involved in it. 1a was reacted with 2 under optimized reaction conditions in the presence of
TEMPO (10 mol%) which furnished 3a in only 12% yield (Table 3, entry 2). However, without radical
scavenger, 3a was obtained in 85% yield (Table 3, entry 1). Similarly, when the same reaction was
carried out in presence of 100 mol% of TEMPO; the reaction was aborted and 3a was not formed at all
(Table 3, entry 3). However, our efforts to isolate any TEMPO adduct with the aryl radical was
not successful. Then, we also figure out the role of K+ cation (coming from the base KOtBu). 1a was
reacted with 2 under optimized reaction conditions using 18-crown-6 in stoichiometric amount in order
to trap the K+ cation during the course of the reaction; it was found that a significantly low conversion of
3a (27%) was observed which underlines the importance of KOtBu. Thus, it can be speculated that the
alkali metal cation is possibly playing a role in this transformation.
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
The reaction profile comparative study was carried out to understand the reactivity of substituted
iodobenzenes with unactivated benzene with the passage of time in order to study its overall effects on
the yield of the reaction. Therefore, 1d was reacted with 2 under optimized conditions which afforded
3d and plot against %yield versus time was generated (Scheme 2, Figure 3A). It was observed that the
yield of the organocatalytic direct arylation reaction was increased with the passage of time (Figure 3A).
Scheme 2. Reaction profile comparative study: reactivity vs time.a
Reaction for Figure 3A
Cat. 10 mol%, KOtBu
H3CO
H3CO
I + H
100 °C
2
1d
Reaction for Figure 3B
3d
Cat. 10 mol%, KOtBu
100 °C
+
I
H
+
I
I
4a
Reaction for Figure 3C
3n
1g
2
Cat. 10 mol%, KOtBu
100 °C
I
I
+
H
+
4a
2
3n
Cat. 10 mol%, KOtBu
100 °C
I
H
1g
2
3g or 3n
aReaction conditions: The reaction was carried out under a nitrogen atmosphere using an aryl halide (1d/4a/1g: 0.5 mmol),
benzene (2: 4 mL), KOtBu (1.5 mmol), and 1-(2-hydroxyethyl)-piperazine (Cat. E: 0.05 mmol) in a sealed tube for 24 h.
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3A
Figure 3B
Figure 3c
Figure 3. (A) Reaction profile of the direct arylation of 1d with benzene to furnish 3d. (B) Distribution of bis-arylated 3n
and monoarylated 1g with the interval of time during the reaction of 4a with benzene. (C) The reaction profiles (amount of
1g or 4a and time of response) of the direct arylations of benzene with 4a and 1g, respectively.
Then, the comparative study of the yield of 1g and 3n was performed by carrying out the reaction of 4a
with 2 under optimized reaction conditions and plot against %conversion versus time was generated. It
was noticed that the yield of bis-arylated product 3n increased with the passage of time (over 12 hours).
However, the yield of the monoarylated product 1g was restricted upto 7% with the passage of time
(Scheme 2, Figure 3B). This indicates that, unless otherwise noted, the diarylated product formation
occurs faster as compared to monoarylated product. In addition, we also further prove the reactivity
order of biphenyl iodide 1g with diiodobenzene 4a to furnish terphenyl 3g or 3n and performed
competitive reactions separately. It was delineated that the reactivity of 1g to furnish 3g is less than that
of 4a (Scheme 2, Figure 3C).Kinetic isotope experiment was performed by reacting 1a with a
equalmolar mixture of benzene and benzene-D6. The kH/D was found to be 1.12 which confirms that
C−H bond cleavage does not constitute a rate-limiting step (for details, see SI).
A plausible mechanism has been depicted in figure 4. The catalytic cycle gets initiated via coordination
of K+ cation of KOtBu with –OH and –NH groups of catalyst E which formed the KOtBu-Catalyst E
complex 7 which transfer the single electron to Ar-I (1) to form the radical anoin 8. This radical anion 8
transformed to aryl radical 9 which, then, added to benzene to afford the cyclohexadienyl radical 10.
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The Journal of Organic Chemistry
Single elecctron oxidation of 10 by radical cation 11 gives cation 13, which is deprotonated by t-BuO- to
1
2
3
4
give desired coupling product 3 and t-BuOH. Complex 12 reacts with KOtBu to regenerate the complex
7.
5
6
7
8
9
Ar-I
1
N
O
K
O
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
t-Bu
Ar-I
8
7
I
K
Ar
9
N
O
K
O
t-Bu
11
Ar
H
10
2
KOtBu
N
O
K
Ar
12
t-BuO
+
Ar
+ t-BuOH
H
13
3
Figure 4: Plausible mechanism for inter-molecular organocatalyzed C(sp2)-H direct arylation reaction.
Scheme 3. Traditional cross couplings with general reaction partners in the reaction mixture
under optimized reaction conditions.
Cat. E (10 mol%)
O
O
O
O
B(OH)2
H3C
I
+
H3C
H3C
O
+
KOtBu (3.0 eq.), PhH, 100°C, 24 h
1a
1a
3a
3a
Not observed
Not observed
Not observed
Not observed
(85%)
Cat. E (10 mol%)
+
+
H3C
O
+
ZnI
KOtBu (3.0 eq.), PhH, 100°C, 24 h
(60%)
Cat. E (10 mol%)
H3C
O
1a
1a
3a
+
+
Si(OEt)3
SnBu3
KOtBu (3.0 eq.), PhH, TBAF (1.0 eq.)
100°C, 24 h
(10%)
Cat. E (10 mol%)
+
H3C
O
3a
KOtBu (3.0 eq.), PhH, 100°C, 24 h
(80%)
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We had also carried out some traditional cross-coupling reactions with Ar-B(OH)2, ArZnI, Ar-Si(OEt)3,
Ar-Sn(Bu)3 under our optimized organo-catalyzed reaction conditions. However, there is no observation
of any cross-coupled product which illustrates that our methodology was working through SET
mechanism rather than any transition metal-mediated cross coupling pathway (Scheme 3).
1
2
3
4
5
6
7
8
9
The ICP-MS analysis of the catalyst E (procured from Sigma aldrich), the base KOtBu (procured from
TCI), and the reaction mixture obtained after the completion of our optimized reaction was further
investigated to check the presence of transition metals such as Fe, Co, Cu, Rh, Ag, Ni, Ru, Zn, Pd etc.
The ICP-MS data revealed that all these transition metals (Fe, Co, Cu, Rh, Ag, Ni, Ru, Zn, Pd) were
detected in <1.4 ppb level except Fe (28.23-30.04 ppb) and Zn (19.56-24.25 ppb) which indicates the
exclusion of the possibility of transition metal-catalyzed C(sp2)-H direct arylation reaction (for details,
see SI).
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
Intra-molecular Organocatalyzed C(sp2)-H direct arylation of unactivated arenes
Phenanthridinone, a well-known tricyclic bioactive heterocycle, was selected as a model substrate to
illustrate the intra-molecular organocatalyzed C(sp2)-H direct arylation with unactivated arenes. This
scaffold is present in several bioactive natural products8 and are blended with a wide range of biological
activities.9 Several phenanthridinones such as 14-22 showed potent bioactivities such as antitumor, anti-
HIV, and antileukemic, inhibition of DNA topoisomerase, PARP inhibitors etc (Figure 5).
O
iPr
O
O
Me
Me
Me
O
O
O
O
O
O
O
O
O
N
N
N
N
NH
O
O
17
)
15
5,6-dihydrobicolorine (
O
N-isopentylcrinasiadine (
O
NMe2
)
16
14)
oxysanguinarine (
HO
)
N-methylcrinasiadine (
O
HN
O
N
O
O
Me
N
N
NH
N
O
O
HO
O
O
N
22
PJ-34 (
)
19
Oxynitidine (
)
20
21
)
18
Assoniane (
)
Phenaglydon (
ARC-111 (
)
Figure 5. Structures of few bioactive phenanthridinone-based natural products and synthetic molecules.
Several methodologies have been reported in the literature for the synthesis of phenanthridinones via
either transition-metal-catalysis (Pd, Rh, Cu) or radical-mediated catalysis9-13 either via C–C/C–N bond
formation (I, III, IV),11,14 or via aminocarbonylation CO insertion (II)12 (Scheme 4).
Scheme 4. Synthetic approaches to phenanthridinone skeleton.
(III)
C-C bond formation
(II)
CO insertion
O
R
N
(I)
C-N bond formation
(IV)
C-C bond formation
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The Journal of Organic Chemistry
In continuation to metal-catalysis, few organocatalytic/metal-free/radical-initiated methodologies have
also been reported in the literature.5c,5h, 14-15 However, the phenanthridinones synthesis via C(sp2)–H
direct activation using cost-effective organocatalyst which can catalyze both inter- as well as intra-
molecular direct arylation of unactivated arenes/heteroarenes is certainly a promising area of
investigation. Herein, we report the cost-effective, transition-metal-free, intra-molecular
organocatalyzed synthesis of phenanthridinones using 2-(piperazin-1-yl)ethan-1-ol as an organocatalyst,
the same catalyst used in inter-molecular organocatalyzed C(sp2)-H direct arylation with unactivated
arenes.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Initially, we started optimization study of intra-molecular organocatalyzed C(sp2)-H direct arylation
taking 2-bromo-N-phenylbenzamide 23a as the starting material to construct phenanthridinones (Table
4). Therefore, using optimized reaction conditions obtained during inter-molecular organocatalyzed
direct arylation, 23a was reacted with 10 mol% of catalyst E in benzene in the presence of KOtBu (3.
Equiv.) at 100 °C for 24 h which furnished the desired cyclized product phenanthridinone 24 in only
27% yield (Table 4. Entry 1). Since we obtained less yield in entry 1; after extensive literature search,
we plan to execute the same reaction using 40 mol% of catalyst E in benzene in the presence of KOtBu
(3. Equiv.) at 150 °C for 24 h which furnished 24 in 65% yield (Table 4, entry 2).
In order to further increase the yield of 24, as we did for inter-molecular optimization studies, the
catalytic screening (40 mol%) of other organocatalyst A-D and F-M were also carried out. However, all
these catalyst furnished cyclized product 24 only in 10-26% yield range. Thereafter, the screening of
different solvents such as mesitylene, toluene, cyclohexane, 1,4-dioxane, DMF, DMSO etc. were carried
out (Table 4, entry 3-8). While the reaction in mesitylene and toluene using 40 mol% of Cat. E and
KOtBu (3 equiv.) at 150 °C for 24 h furnished 24 in 68% and 59% yields, respectively; other solvents
have detrimental effect on the yield of the reaction (Table 4, entry 3-8). Since, the inter-molecular
organocatalyzed direct arylation involves free-radical pathway; we screened the same reaction in the
presence of K2S2O8 as an additive. The formation of 24 does not takes place at all (Table 4, entry 9).
In our endeavor to develop new catalytic system for the synthesis of bioactive heterocycles in our lab;6i-j
we noticed that the mixture of two bases can be used in C–C bond forming reactions for the
improvement of the yield of the reaction.6j Based on these facts, organic bases (0.4 equiv.) such as TEA,
Triton-B, n-methyl aniline, DMAP, DABCO etc. were utilized as an additive in the same reaction
conditions reported in entry 3 (Table 4, entry 10-14). Intriguingly, it was observed that out of all bases
screened, DMAP furnished the desired product in 89% isolated yield (Table 4, entry 13). Other
additives do not show promising results in improving the yield of the reaction. In addition, other strong
bases such as LiOtBu, Li-HMDS and weak bases (K2CO3) were also screened keeping all the other
reaction conditions same as given in entry 3 (Table 4, entry15-17). It was observed that the use of bases
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other than KOtBu have a negative effect on the yield of the reaction. Furthermore, it was also found that
increasing or decreasing the gram equivalents of KOtBu leads to slight decrease in the yield of the
reaction keeping same all the other reaction conditions (Table 4, entry 18-19). To further check the
importance of catalyst; a reaction without catalyst E was carried out (Table 4, entry 20). It has been
noticed that no conversion of 23a into 24 takes place which further emphasize the importance of newly
discovered organocatalyst. In addition, decreasing the time interval of the reaction or catalyst loading
eventually leads to decrease in overall yield of the reaction (Table 4, entry 21-22). Succinctly, 40 mol %
of catalyst E {1-(2-hydroxyethyl)-piperazine}, 3 equivalents of KOtBu along with DMAP (40 mol%) in 4
mL of mesitylene at 150 °C for 24 h was found to be the best optimized reaction conditions for the intra-
molecular organocatalyzed C(sp2)-H direct arylation reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Optimization study: Intra-molecular organocatalyzed C(sp2)-H direct cyclization of 2-bromo-
N-phenylbenzamide.a
O
O
Catalyst, Additive
Base,Temp. Time
NH
N
H
Br
23a
24
Catalyst (40
mol %)
Additive
(equiv.)
Base
(3 equiv.)
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Temp.
(°C)
100
150
150
150
150
150
150
150
150
150
150
Yield
(%)b
27
65
68
59
21
26
>5
25
00
61
58
Entry
Solvent
Time(h)
1.
2.
3.
4.
5.
6.
7.
8.
9.
Ec
Ed
E
E
E
E
E
E
E
E
E
Benzene
Benzene
Mesitylene
Toluene
cyclohexane
1,4-dioxane
DMF
----
----
----
----
----
----
----
----
24
24
24
24
24
24
24
18
24
24
24
DMSO
Mesitylene
Mesitylene
Mesitylene
K2S2O8
10.
11.
TEA (0.4)
Triton B (0.4)
n-methyl aniline
(0.4)
12.
E
Mesitylene
KOtBu
150
24
63
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
E
E
E
E
E
E
E
----
E
E
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
DMAP (0.4)
DABCO (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
DMAP (0.4)
KOtBu
KOtBu
150
150
150
150
150
150
150
150
150
150
24
24
24
24
24
24
24
24
18
24
89
55
7
10
5
84
64
00
75e,
70f
LiOtBu
Li-HMDS
K2CO3
KOtBu (4.0)
KOtBu (2.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
aReaction conditions: 23a (0.25 mmol), KOtBu (0.75 mmol), Catalyst 40 mol%, and additive 40 mol% (entry 8-21) were
b
dissolved in solvents (as given in table) and heated at 150 °C for 24 h under a N2 atmosphere in a sealed tube. Isolated
c
d
yields. Catalyst E (10 mol%). Other organocatalysts A-D and F-M furnished 24 in 10-26% yield range. eTime 18h.
fCatalyst 20 mol%.
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1
The Journal of Organic Chemistry
Scheme 5. Substrate scope: Organocatlyzed direct C-H activation of 2-halobenzamide to construct
2
3
phenanthridinonea
O
R3
O
4
5
6
7
8
9
R1
O
R1
NH
B
B
Cat. E, KOtBu
R1
R2
NH
A
A
+
N
R2
Mesitylene, DMAP
150 °C, 24 h
A
R2
H
B
Br
R3
R3
23a-v
24-42
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
R1
R2
N
N
N
N
N
H
H
H
H
S
Br
Br
Br
Br
1
2
23a
23b
23c
23d
23u
, R = H, R = H
R3
23f
23g
23e
1
2
, R = CH3, R = H
O
1
2
3
R1
R = OCH3, R = OCH3
N
1
2
O
O
, R = Br, R = H
2
OMe
H
1
2
R2
1
Br
, R = NO2, R = H
N
N
H
H
R1
2
3
23h
, R = H, R = H, R = CH3
Br
Br
1
2
3
23i
23j
23k
, R = H, R = H, R = OCH3
O
23v
23o,
, 23p,
2-OMe
3-OMe
O
1
2
3
, R = H, R = H, R = Cl
N
H
1
2
3
, R = CH3, R = H, R = CH3
1
2
3
23l
H3C
, R = CH3, R = H, R = OCH3
Br
N
H
O
1
2
3
1
23m
, R = CH3, R = H, R = Cl
23r
,R = CH3
1
2
3
1
1
23q
23n
, R = OCH3, R = OCH3, R = CH3
Br
23s,
23t
, R = Cl,
R = OCH3;
O
O
O
O
O
Br
H3C
O
O
NH
NH
NH
NH
NH
c
26
27
, (60%)
25
, (40%)
, (77%)
28
, (79%)
NH
24
, (89%), (94%)
O
O
O
O
NH
2
NH
NH
4
OCH3
S
N
1
3
OCH3
38b
, (70%), (1.0:0.30)
38a
38a
and
38a 32b
38b
(74%), (1.0:0.50:0.35)
, 2-OMe; , 4-OMe
,
and
30
, (55%)
O
29
, (30%)
38b
, 1-OMe,
, 4-OMe
38a
32b
38b
1-OMe;
O
d
O
R1
R2
O
R1
R2
O2N
NH
R3
NH
NH
H3C
NH
R3
OCH3
39b
(82%), (1.0:0.68:1.6)
, R = H, R = H, R3 = CH3 and
=
1
2
1
39a 35b
,
and
35b
31a
31b
, R
O
39a
39b
1-OMe;
, 2-OMe;
, 4-OMe
H, R2 = H, R3 = CH3, (80 %), (1.0:0.46
, R = H, R2 = H, R3 = OCH3 and
1
1
32a
32b
, R
NH
= H, R2 = H, R3 = OCH3, (94%), (1.0:0.85)
O
O
d
1
2
3
1
33a
R2
33b
, R = H,
, R = H, R = H, R = Cl and
NH
R1
H, R3
=
Cl, (53%), (1.0:0.50)
NH
=
, R = CH3, R2 = H, R3 = CH3 and
, R
1
1
44
, (0%)
34a
34b
= CH3, R2 = H, R3 = CH3, (82%), (1.0:0.72)
R1
, R = CH3, R2 = H, R3 = OCH3 and
1
35a
35b
,
R1 = CH3, R2 = H, R3 = OCH3, (80%), (1.0:0.64
1
1
40a
41a
42a
40b
, R = CH3 and
, R = CH3, (87%), (1.0:0.25)
, R1 = CH3, R2 = H, R = Cl and
=
3
1
36a
36b
, R
1
1
41b
, R = OCH3 and
, R = OCH3, (76%), (1.0:0.60
CH3, R2 = H, R3 = Cl, (37%), (1.0:0.51)
1
1
42b
, R = Cl (37%) and
, R = Cl, (20%), (1.0:0.54)
1
2
3
37
, R =OCH3, R = OCH3, R = CH3, (25%)
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aReaction conditions: 23a-v (0.5 mmol), KOtBu (1.5 mmol), Catalyst E (40 mol%), and DMAP (40 mol%) were mixed in
mesitylene and heated at 150 °C for 24 h under N2 atmosphere in a sealed tube. bIsolated yields. c2-Iodo-N-phenylbenzamide
was used.dCombined/individual yields and ratio of diastereomeric mixtures are given in parentheses.
1
2
3
Utilizing the optimized conditions in hand, various substituted amides 23a-g having substitutions at ring
A and without substitution at ring B were subjected to intra-molecular cyclization using catalyst E (40
mol %) in the presence of KOtBu (3 equiv.) and DMAP (40 mol%) in mesitylene (4 mL) 150 °C for 24
h which furnished substituted phenanthridinones 24-30 upto 94% yield (Scheme 5). Similarly, amides
23h-q having substitution at both ring A and B were subjected to intra-molecular cyclization using
catalyst E (40 mol %) in the presence of KOtBu (3 equiv.) and DMAP (40 mol%) in mesitylene (4 mL)
150 °C for 24 h which furnished substituted phenanthridinones 31-42 upto 94% yield (Scheme 5).
Extensive examination of the substrate scope revealed that amides having no substitution at ring B leads
to the formation of single product; whereas amides having o-, m- or p-substitutions at ring B produced
5-exo and 6-exo/endo regioisomers as described earliar.5c The intramolecular cyclization of 23a to 24
occurs in 89% and 94% yield from 2-bromo- and 2-iodo-derivatives of 23a, respectively. The substrates
having electron-donating groups (EDG) such as CH3, OCH3, and dimethoxy (23b-c, 23k-n, 23q-s etc.
on aryl ring A were well tolerated and successfully cyclized into the corresponding phenanthridinones
25-26, 34-37, 38, 40 and 41, respectively in moderate to excellent yields. The substrate having bromo-
group 23d was found to be well-tolerated in benzene solvent to give the compound 27 in 60% yield. The
electron-withdrawing group (EWG) having nitro group i.e., 23u completely aborted the reaction and no
cyclized product was obtained. The naphthalene and thiophene-based 2-bromo arylamide 23e-f were
also cyclized to 28 and 29 in 79% and 30% yield, respectively.
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
Then, we analyzed the substrate scopes in aryl ring B in order to understand the occurrence of
regioselective isomer(s) in the organocatalyzed direct arylation. It has been interpreted that due to the p-
substitution in ring B, irrespective of the electron-donating or electron-withdrawing groups; the major
product obtained had 6-exo/endo regioselectivity whereas 5-exo regioisomer was obtained as a minor
product. Thus, 23h, having no substitution on ring A and the p-CH3 substituents (R3 = CH3) on ring B,
undergoes intra-molecular cyclization under optimized conditions afforded an inseparable mixture of
1
31a (major) and 31b (minor) in 1.0:0.46 ratio (as determined by H NMR spectral data of mixture) in
overall 80% combined yields. Similarly, 23i having p-OMe substituents on ring B undergone intra-
molecular direct arylation furnished an inseparable mixture of 32a (major) and 32b (minor) in 1.0:0.85
ratio in 94% combined yields.
Additionally, when the substrate having no substitution on ring A and p-Cl group on ring B i.e., 23j was
used, an inseparable mixture of 33a and 33b were isolated in the ratio of 1.0:0.50, respectively, in
comparatively less yields (53%). Unlike compounds 31 and 32, when the substrate having 5-CH3
substitution on ring A and p-CH3 group on ring B i.e., 23k was used, an inseparable mixture of 34a and
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The Journal of Organic Chemistry
34b were isolated in the ratio of 1.0:0.72, respectively, in 82% yield. In contrast to compounds 31 and
32, when the substrate having 5-CH3 substitution on ring A and p-OCH3 group on ring B i.e., 23l was
used, an inseparable mixture of 35a and 35b were isolated in the ratio of 1.0:0.64, respectively, in 80%
yield. The substrate having 5-CH3 substitution on ring A and p-chloro group on ring B i.e., 23m, was
subjected to intra-molecular cyclization under optimized reaction conditions, it furnished an inseparable
mixture of 36a and 36b in the ratio of 1.0:0.51, respectively, in relatively lower (37%) yield. Similar
was the case with the substrate 23n which undertakes selective conversion to 37 in reasonably lower
(25%) yield. In continuation, the substrates 23p, having no substitution on ring A and m-OMe on ring B
undergoes cyclization and furnished 5-exo regioisomer 38a as the major product and 6-exo/endo
regioisomer 38b along with 32b in 1.0:0.35:0.50:ratios. In the same way, the substrates 23o, having no
substitution on ring A and o-OMe on ring B undergoes cyclization and furnished 5-exo regioisomer 38a
as the major product and 6-exo/endo regioisomer 38b in 1.0:0.30 ratio. Consequently, the substrates
23q, having 5-CH3 substitution on ring A and m-OMe on ring B undergoes cyclization and furnished 5-
exo regioisomer 39a as the major product and 6-exo/endo regioisomer 39b along with 35b in
1.0:0.68:1.6 ratios. The substrate 23r-t which have naphthalene at ring A leads to the formation of 40-42
in 57-87% yields, respectively. Therefore, in brief, it can be understood that 1-(2-hydroxyethyl)-
piperazine-catalyzed intra-molecular C(sp2)-H direct arylation reaction proceeded smoothly and
furnished the combined desired mixtures of regioisomers in significantly excellent yields.
Scheme 6. Intra-molecular organocatalyzed direct arylation of N-(2-bromophenyl)benzamide 23w:
Cyclization attempt by reversing the bromo-substitution (as in the case of 2-bromo-N-
phenylbenzamide).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
Cat. E (40 mol%), DMAP(40 mol%)
KOtBu,
NH
N
OH
H
Mesitylene,150 °C, 24 h
Br
45
23w
The substrate N-(2-bromophenyl)benzamide 23w having Br-group on ring B, the opposite of 23a where
Br-group is on ring A, failed to undergo C-C coupling reaction under optimized reaction conditions
(Scheme 6). Instead, the formation of N-(2-hydroxyphenyl)benzamide 45 takes place which illustrates
that the cyclization is favoured via Br-group on ring A rather than on ring B.5c
As interpreted in the inter-molecular C-C coupling reaction, the SET mechanism might be also involved
in the intra-molecular cyclization. The free-radical scavenging experiment was performed where 23a
was subjected to intra-molecular cyclization under optimized reaction conditions in the presence of 40
mol% TEMPO; 24 was obtained in only 35% yield. However, performing the same reaction in the
presence of 100 mol% TEMPO stopped the reaction completely.
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Scheme 7. Kinetic isotope experiment.
1
2
3
4
5
6
7
8
9
45% D
O
Cat. E (40 mol%),
O
O
O
DMAP(40 mol%)
KOtBu (3.0 eq.)
NH
NH
NH
+
N
+
D/H
H
Mesitylene,150 °C, 24 h
D
Br
23x
H/D
15% D
24
46a
46b
KH/KD =1.22
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
Kinetic isotope experiment was performed by reacting 23x [deuterated at o-position of ring B (aniline
part)], with optimized reaction conditions which furnished expected isotopic phenanthridinone products
24, 46a and 46b (For the synthesis of 23x, see experimental section). Since ortho-H/D is involved in the
cyclization; the kH/kD was found to be 1.22 which confirms that C−H bond cleavage does not constitute
a rate-limiting step (Scheme 7).
Plausible SET mechanism
R
tBuO-
-tBuOH
R
H
K+
6-Exo/end
NK
Br
52
o
NK
O
53
O
KBr
Br
O
K
N
H
N
R
O
23
Br
R
R
Br
O
48
N
O
K
K
K
O
NK
N
5-Exo
tBu
O
SET
R
47
product B
R
KOtBu
N
O
K
OBut
N
O
K
NK
R
O
tBuO-
49
NK
O
product A
R
KBr
R
H
NK
K+
Br
50
O
NK
-tBuOH
tBuO-
51
O
Figure 6. Proposed mechanism for the formation of product A and B.
Basis on the above facts, the plausible mechanism is depicted in figure 6. The Catalyst E–KOtBu
complex might directly donate a single electron to the 2-halo aryl amide 23 to form complex 47, which
further transformed into the radical species 48 with the elimination of bromide anion. The radical 48,
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The Journal of Organic Chemistry
then could attack on the aniline ring in a 6-exo/endo or 5-exo-trig manner to form the 52 or 49,
respectively.
1
2
3
Ring expansion of 5-exo-trig intermediates 49 might be giving more stable hexadienyl radical
intermediate 50. Hexadienyl radical intermediate 50 and 52 further deprotonated via tert-butoxy anion
to form intermediate anion radical 51 and 53, respectively. In the last step, these radical anions would
undergo electron transfer to 23 to give respective products, KBr, and new radical 47, thus continuing the
radical chain with concomitant release of the product A and product B.
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
The ICP-MS analysis of the catalyst E (Procured from Sigma aldrich), KOtBu (Procured from TCI), and
the reaction mixture (after the completion of the reaction) was carried out to investigate the presence of
transition metals such as Fe, Co, Cu, Rh, Ag, Ni, Ru, Zn, Pd etc. The analytical data excludes the
possibility of transition metal-catalyzed C-H bond activation as all these transition metals were detected
at < 1.7 ppb level except Fe (28.23-42.53 ppb) and Zn (18.51-24.25ppb) (for details, see SI).
Scheme 8. One-pot double direct arylation.
O
Cat. E, KOtBu
NH
A
27
23d
+
Benzene, DMAP
130 °C, 24 h
(60%)
B
54
(15%)
Finally, the new catalyst was utilized to carry out both inter- as well as intra-molecular direct arylation
reaction simultaneously in a one-pot. Thus, 23d was reacted with benzene in the presence of Cat. E and
KOtBu at 130 °C for 24 h which furnished double arylated inter- and intra-molecular product 54 in 15%
yield along with the formation of bromo derivative of intra-molecular product 27 (Scheme 8). This
further exemplifies the importance of one-pot dual arylation catalyzed by {1-(2-hydroxyethyl)-
piperazine} as an organocatalyst.
Conclusion
In summary, we disclose the identification of 1-(2-hydroxylethyl) piperazine as a new cost-effective
organocatalyst for the direct inter- as well as intra-molecular C-H bond activation of unactivated arenes
to construct biaryls and phenanthridinones upto 94% yield. The protocol involves cost-effective
organocatalyst (compared with a reported one) and was found well–tolerated under variable reaction
conditions and feasible successfully with various Ar-X (X = I, Br, Cl) substrates. The wide substrate
scope (aryl/heteroaryl), easy handling, gram-scale synthesis for both inter-/intra-molecular direct
arylation using a single organocatalyst, kinetic studies further highlights the importance and versatile
nature of the methodology as well as the efficacy of the newly developed organocatalyst. This finding
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offers a novel organocatalyst for direct C-H activation toward the synthesis of biaryls-/phenthridinones-
based bioactive heterocycles.
1
2
3
4
Experimental Details & Characterization Data
5
6
7
8
General information: All the reactions were carried out in screw cap glass reaction vial under argon
atmosphere with magnetic stirring. Potassium tert-butoxide was purchased from TCI chemicals.
Spectrochem and 1-(2-Hydroxyethyl) piperazine was brought from Sigma Aldrich and used without
prior purification. Benzene was distilled over Na and benzophenone prior to use. All other reagents
were procured from commercial source and used as received, unless otherwise stated. Column
chromatography was performed over Merck silica-gel (particle size: 100-200 Mesh) procured from
Merck (India). Hexane or hexane and ethyl acetate mixture was used as an eluting solvent in the column
purification. Borosil glass column were used for purification. Thin layer chromatography was performed
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
1
13
on Si 60 F254 which supplied from MERCK. H NMR, C NMR spectroscopy, HRMS, FT-IR were
1
used to characterize all the compounds. H NMR spectra were recorded on JEOL ECS-400 instrument
(400 MHz). Chemical shifts were informed in parts per million (ppm) referenced to 0.0 ppm for
Tetramethylsilane, 7.26 ppm for relative to residual CHCl3 and 2.50 ppm for DMSO. 13C NMR spectra
were recorded on JEOL ECS-400 instrument (100 MHz) and were fully decoupled by broad band
proton decoupling. Chemical shifts were reported in ppm referenced to the center line of a triplet at
77.16 ppm of Chloroform-d and 39.2 ppm for DMSO-D6. High-resolution mass spectra (HRMS) were
recorded on a Xevo G2-S Q Tof (Waters, USA) mass spectrometer. IR spectra were recorded on a FT-
IR Spectrum 2 (Perkin-Elmer) spectrophotometer.
General procedure (GP1) for inter-molecular organocatalyzed C(sp2)-H direct arylation (synthesis
of 3a-v): An oven-dried sealed reaction vial was charged with cat. E (7 mg, 0.05 mmol) and KOtBu
(0.168g, 1.5 mmol) under nitrogen gas atmosphere at room temperature. Aryl halide 1a-y (0.5 mmol)
and benzene 2 (4 ml) were added into the reaction vial and stirred at 100 ˚C (heated in oil bath) for 24
hr. The reaction mixture was allowed to cool to room temperature. Then, the reaction mixture was
filtered through a celite bed and washed with ethyl acetate (3 × 10 mL). The combined filtrate was
concentrated under vacuo to get crude compound which was further purified by silica-gel (100-200
mesh) column chromatography using either hexane alone or ethyl acetate/Hexane as an eluent which
afforded the corresponding biaryl product 3a-v.
Characterization data of biaryl coupling compounds 3a-v.
4-methyl-1,1'-biphenyl3b (3a): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.72 (eluent:
hexane); White solid; Yield: 85% (0.072 g) ; 1H NMR (400 MHz, Chloroform-d) δ: 7.63–7.60 (m, 2H),
13
7.55–7.52 (m, 2H), 7.48–7.44 (m, 2H), 7.38–7.34 (m, 1H), 7.30–7.26 (m, 2H), 2.42 (s, 3H); C{1H}
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NMR (100 MHz, Chloroform-d) δ: 141.3, 138.5, 137.1, 129.6, 128.8, 127.1, 127.1, 21.2.
1
3-methyl-1,1'-biphenyl3b (3b): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.69 (eluent:
hexane); White solid; Yield: 83% (0.070 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.63–7.61 (m, 2H),
7.48–7.43 (m, 4H), 7.40–7.35 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 2.46 (s, 3H); 13C{1H} (100 MHz,
Chloroform-d) δ: 141.5, 141.3, 138.4, 128.8, 128.8, 128.1, 127.3, 124.4, 21.7.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3,5-dimethyl-1,1'-biphenyl3d (3c): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.56 (eluent:
hexane); White solid; Yield: 61% (0.056 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.59 (d, J = 7.2 Hz,
13
2H), 7.45–7.41 (m, 2H), 7.35–7.32 (m, 1H), 7.23 (s, 2H), 7.01 (s, 1H), 2.40 (s, 6H); C{1H} NMR
(100 MHz, Chloroform-d) δ: 141.5, 141.4, 138.3, 128.9, 128.7, 127.3, 127.2, 125.2, 21.5.
4-methoxy-1,1'-biphenyl3b (3d): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.53 (eluent:
hexane); White Solid; Yield: 85% (0.078 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.58–7.53 (m, 4H),
7.43 (t, J = 7.6 Hz, 2H), 7.34–7.30 (m, 1H), 7.00–6.98 (m, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 159.2, 140.9, 133.9, 128.8, 128.2, 126.8, 126.8, 114.3, 55.4.
3-methoxy-1,1'-biphenyl3b (3e): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.28 (eluent:
1
hexane); Colorless liquid; Yield: 80% (0.074 g); H NMR (400 MHz, Chloroform-d) δ: 7.62–7.60 (m,
2H), 7.47–7.43 (m, 2H), 7.39–7.35 (m, 2H), 7.21–7.18 (m, 1H), 7.15–7.14 (m, 1H), 6.93–6.90 (m, 1H),
13
3.88 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ: 160.0, 142.9, 141.2, 129.8, 128.8, 127.5,
127.3, 119.8, 112.9, 112.8, 55.4.
2-methoxy-1,1'-biphenyl3b (3f): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.17 (eluent:
1
hexane); Colorless liquid; Yield: 82% (0.076 g); H NMR (400 MHz, Chloroform-d) δ: 7.56–7.54 (m,
2H), 7.46–7.41 (m, 2H), 7.36–7.32 (m, 3H), 7.06–7.00 (m, 2H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 156.5, 138.6, 131.0, 129.6, 128.7, 128.1, 127.0, 120.9, 111.3, 55.6.
1,1':4',1''-terphenyl3b (3g or 3n): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.47 (eluent:
1
hexane); White Solid Yield: 65% (0.075 g); H NMR (400 MHz, Chloroform-d) δ: 7.70–7.66 (m, 8H),
7.50–7.46 (m, 4H), 7.40–7.36 (m, 2H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 140.8, 140.2, 128.9,
127.6, 127.4, 127.1.
[1,1'-biphenyl]-4-carbonitrile3b (3h): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.12 (eluent:
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hexane); White Solid; Yield: 89% (0.080 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.74–7.68 (m, 4H),
7.61–7.58 (m, 2H), 7.51–7.41 (m, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 145.7, 139.3, 132.7,
129.22, 128.8, 127.8, 127.3, 119.1, 110.9.
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4-fluoro-1,1'-biphenyl3b (3i): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.61 (eluent: hexane); White
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solid; Yield: 64% (0.055 g); H NMR (400 MHz, Chloroform-d) δ: 7.58–7.53(m, 4H), 7.47–7.42 (m,
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2H), 7.37–7.33 (m, 1H), 7.16–7.11 (m, 2H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 163.8 (d, JC-F
=
244.8 Hz), 140.3, 137.4 (d, JC-F = 2.3Hz), 128.9, 128.8 (d, JC-F = 8.1 Hz) , 127.3 (d, JC-F = 8.6 Hz), 127.1,
115.8 (d, JC-F = 21.2 Hz).
4-(trifluoromethoxy)-1,1'-biphenyl3d (3j): The compound was synthesized according to the GP1 and
purified through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.81(eluent:
hexane); White solid; Yield: 60% (0.071 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.63–7.55 (m, 4H),
7.48–7.44 (m, 2H), 7.40–7.35 (m, 1H), 7.30 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, Chloroform-
d) δ: 148.7, 140.1, 139.9, 128.9, 128.5, 127.7, 127.2, 121.3, 120.6 (q, J = 255.9 Hz).
3-fluoro-1,1'-biphenyl16b (3k): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.60 (eluent:
hexane); White solid; Yield: 34% (0.029 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.62–7.60 (m, 2H),
7.50–7.45 (m, 2H), 7.43–7.39 (m, 3H), 7.35–7.32 (m, 1H), 7.10–7.05 (m, 1H); 13C{1H} NMR (100
MHz, Chloroform-d) δ: 164.6 (d, JC-F = 244.2 Hz), 143.7 (d, JC-F = 7.6 Hz), 140.1 (d, JC-F = 1.5 Hz),
130.4 (d, JC-F = 8.5 Hz), 129.0, 127.9, 127.2, 122.9 (d, JC-F = 2.5 Hz), 114.3, 114.0 (d, JC-F = 1.4 Hz).
4-chloro-1,1'-biphenyl3d (3l): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.13 (eluent: hexane); White
solid; Yield: 71% (0.067 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.75 (d, J = 8.8 Hz, 2H), 7.56–7.52
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(m, 2H), 7.45–7.41 (m, 3H), 7.34–7.31 (m, 2H); C{1H} NMR (100 MHz, Chloroform-d) δ: 140.8,
140.1, 137.9, 129.1, 128.9, 128.5, 127.8, 126.9.
2-chloro-1,1'-biphenyl6c (3m): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the hexane as an eluent. Rf value: 0.14 (eluent:
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hexane); Colorless liquid; Yield: 51% (0.048 g); H NMR (400 MHz, Chloroform-d) δ: 7.61–7.59 (m,
2H), 7.47–7.30 (m, 7H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 144.3, 141.3, 139.6, 130.2, 129.4,
128.8, 128.2, 128.0, 127.3, 127.3.
1-([1,1'-biphenyl]-4-yl)ethan-1-one16a (3o): The compound was synthesized according to the GP1 and
purified through silica-gel column chromatography using the 3% ethyl acetate/hexane as an eluent. Rf
value: 0.486 (eluent: 5% ethyl acetate/hexane); White solid; Yield: 71% (0.070 g); 1H NMR (400 MHz,
Chloroform-d) δ: 8.05–8.03 (m, 2H), 7.70–7.68 (m, 2H), 7.65–7.62 (m, 2H), 7.49–7.46 (m, 2H), 7.43-
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7.41 (m, 1H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 197.9, 145.9, 139.9, 135.9,
129.05, 129.0, 128.3, 127.4, 127.1, 26.8.
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2-methyl-6-phenylquinoline3d (3p): The compound was synthesized according to the GP1 and purified
through silica-gel column chromatography using the 8% ethyl acetate/hexane as an eluent. Rf value:
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0.16 (eluent: 10% ethyl acetate/hexane); White solid; Yield: 65% (0.071 g); H NMR (400 MHz,
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Chloroform-d) δ: 8.08 (d, J = 8.8, 2H), 7.96–7.94 (m, 2H), 7.72–7.70 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H),
7.39 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 2.77 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-
d) δ: 159.1, 147.3, 140.5, 138.5, 136.4, 129.2, 129.1, 129.0, 127.6, 127.5, 126.7, 125.3, 122.5, 25.5.
4-phenylisoquinoline3d (3q): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the 10% ethyl acetate/hexane as an eluent. Rf value: 0.16
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(eluent: 10% ethyl acetate/hexane); Colorless liquid; Yield: 68% (0.07 g); H NMR (400 MHz,
Chloroform-d) δ: 9.26 (s, 1H), 8.50 (s, 1H), 8.05–8.03 (m, 1H), 7.93–7.91 (m, 1H), 7.69–7.60 (m, 2H),
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7.54–7.47 (m, 5H); C{1H} NMR (100 MHz, Chloroform-d) δ: 152.1, 142.9, 137.1, 134.3, 133.3,
130.6, 130.2, 128.7, 128.5, 128.0, 127.9, 127.2, 124.8.
2-phenylpyridine3c (3r): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the 10% ethyl acetate/hexane as an eluent. Rf value: 0.47
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(eluent: 10% ethyl acetate/hexane); Colorless liquid; Yield: 83% (0.064 g); H NMR (400 MHz,
Chloroform-d) δ: 8.72–8.69 (m, 1H), 8.01–7.98 (m, 2H), 7.78–7.72 (m, 2H), 7.50–7.40 (m, 3H), 7.25–
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7.22 (m, 1H); C{1H} NMR (100 MHz, Chloroform-d) δ: 157.5, 149.7, 139.4, 136.9, 129.1, 128.8,
127.0, 122.2, 120.7.
3-phenylpyridine3c (3s): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the 10% ethyl acetate/hexane as an eluent. Rf value: 0.13
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(eluent: 10% ethyl acetate/hexane); Brown liquid; Yield: 77% (0.060 g); H NMR (400 MHz,
Chloroform-d) δ: 8.85 (dd, J = 2.4, 0.8 Hz, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 7.89–7.86 (m, 1H),
7.60–7.57 (m, 2H), 7.50–7.46 (m, 2H), 7.43–7.35 (m, 2H); 13C{1H} NMR (100 MHz, Chloroform-d) δ:
148.5, 148.4, 137.9, 136.7, 134.5, 129.2, 128.2, 127.2, 123.6.
2-phenylpyrazine3c (3t): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the 7% ethyl acetate/hexane as an eluent. Rf value: 0.40
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(eluent: 10% ethyl acetate/hexane); White solid; Yield: 30% (0.023 g); H NMR (400 MHz,
Chloroform-d) δ: 9.04 (d, J = 1.6 Hz, 1H), 8.65–8.64 (m, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.03–8.01 (m,
2H), 7.54–7.48 (m, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 152.9, 144.3, 143.0, 142.4, 136.4,
130.0, 129.2, 127.0
2-phenylthiophene16d (3u): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.65 (eluent: hexane); White
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solid; Yield: 31% (0.025 g); H NMR (400 MHz, Chloroform-d) δ: 7.64–7.62 (m, 2H), 7.41–7.37 (m,
2H), 7.33–7.27 (m, 3H), 7.10–7.08 (m, 1H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 144.5, 134.5,
128.9, 128.1, 127.6, 126.1, 124.9, 123.2.
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3-phenylthiophene3c (3v): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.69 (eluent: hexane); White
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solid; Yield: 50% (0.040 g); H NMR (400 MHz, Chloroform-d) δ: 7.62–7.60 (m, 2H), 7.47–7.46 (m,
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1H), 7.43–7.39 (m, 4H), 7.30 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 142.4,
135.9, 128.9, 127.2, 126.5, 126.4, 126.3, 120.4.
1,1':3',1''-terphenyl3b (6): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.50 (eluent: hexane); White
Solid; Yield: 69% (0.079 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.83 (d, J = 1.3 Hz, 1H), 7.68–7.66
(m, 4H), 7.61–7.60 (m, 2H), 7.55–7.47 (m, 5H), 7.41–7.37 (m, 2H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 141.9, 141.3, 129.3, 128.9, 127.5, 127.4, 126.3, 126.2.
1,1':2',1''-terphenyl3b (7): The compound was synthesized according to the GP1 and purified through
silica-gel column chromatography using the hexane as an eluent. Rf value: 0.60 (eluent: hexane);
Colorless liquid; Yield: 50% (0.058 g); 1H NMR (400 MHz, Chloroform-d) δ: 7.44–7.43 (m, 4H), 7.25–
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7.19 (m, 6H), 7.16–7.14 (m, 4H); C{1H} NMR (100 MHz, Chloroform-d) δ: 141.6, 140.7, 130.7,
130.0, 127.9, 127.6, 126.5.
General procedure for the gram-scale synthesis of compound 3d: An oven-dried sealed reaction
tube was charged with cat. E (0.111 g, 0.85 mmol) and KOtBu (2.87 g, 25.64 mmol) under nitrogen gas
atmosphere at room temperature. 4-Iodoanisole 1d (2.0 g, 8.55 mmol) and benzene 2 (70 mL) were
added into the reaction mixture and was allowed to stirr at 100 °C (heated in oil bath) for 24 h. After the
completion of the reaction, the reaction mixture was allowed to cool to r.t; then, it was filtered through a
celite pad and washed with ethyl acetate (3 × 20 mL). The combined filtrate was concentrated under
vacuo to get crude compound which was further purified by silica-gel (100-200 mesh) column
chromatography using hexane as an eluent which afforded 3d (1.4 g, 7.60 mmol) as a white solid in
89% yield.
General procedure for the reaction for the examination of the role of KOtBu: An oven-dried sealed
reaction vial was charged with Cat. E (7 mg, 0.05 mmol), KOtBu (0.168 g, 1.5 mmol) and 18-crown-6-
ether (0.396 g, 1.5 mmol) under nitrogen gas atmosphere at room temperature. 4-Iodotoluene 1a (0.109
g, 0.5 mmol) and benzene 2 (4 ml) was added into reaction vial and stirred at 100 ˚C (heated in oil bath)
for 24 hr. After the completion of the reaction, the reaction mixture was allowed to cool to r.t; then, it
was filtered through a celite pad and washed with ethyl acetate (3 × 10 mL). The combined filtrate was
concentrated under vacuo to get crude compound which was further purified by silica-gel (100-200
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mesh) column chromatography using either hexane as an eluent which afforded 3a as a white solid in
23% (0.019g) yield.
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General procedure for the free-radical reaction pathway: An oven-dried sealed reaction vial was
charged with Cat. E (7 mg, 0.05 mmol), KOtBu (0.168 g, 1.5 mmol) and TEMPO (0.078 g, 0.5 mmol)
under nitrogen gas atmosphere at room temperature. 4-Iodotoluene 1a (0.5 mmol) and benzene 2 (4 ml)
were added into the reaction vial and stirred at 100 ˚C (heated in oil bath) for 24 hr. After the
completion of the reaction, the reaction mixture was cooled to room temperature. TLC observation of
the TEMPO-assisted reaction indicates the non-formation of the desired product.
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General procedure for the competition reaction between 1a and 1d: A mixture of cat. E (7.0 mg,
0.05 mmol), Potassium t-butoxide (168 mg, 1.5 mmol), 4-iodotoluene 1a (109 mg, 0.5 mmol) 4-
iodoanisole 1d (117 mg, 0.5 mmol) and benzene 2 (4 mL) in a 10 mL oven-dried pressure-resistant tube
was stirred at 100 °C (heated in oil bath) for 24 h. After the completion of the reaction, the reaction
mixture was allowed to cool to r.t; then, it was filtered through a celite pad and washed with ethyl
acetate (3 × 20 mL). The combined filtrate was concentrated under vacuo to get crude compound which
was further purified by silica-gel (100-200 mesh) column chromatography using either hexane as an
eluent which afforded 3a and 3d in 63% (0.053g) and 76% (0.070g) yields, respectively.
General procedure for the competition reaction between 1a and 1j: A mixture of cat. E (7.0 mg,
0.05 mmol), Potassium t-butoxide (168 mg, 1.5 mmol), 4-iodotoluene 1a (109 mg, 0.5 mmol), 1-iodo-4-
(trifluoromethoxy) benzene 1j (144 mg, 0.5 mmol), and benzene 2 (4 mL) in a 10 mL oven-dried
pressure-resistant tube was stirred at 100 °C (heated in oil bath) for 24 h. The reaction mixture was
allowed to cool to r.t; then, it was filtered through a celite pad and washed with ethyl acetate (3 × 20
mL). The combined filtrate was concentrated under vacuo to get crude compound which was further
purified by silica-gel (100-200 mesh) column chromatography using either hexane as an eluent which
afforded 3a and 3j n 74% (0.062g) and 13% (0.016g) yields, respectively.
General procedure for the kinetic-isotope effect in the inter-molecular biaryl coupling: An oven
dried reaction vial was charged with cat. E (7 mg, 0.05 mmol) and KOtBu (0.168 g, 1.5 mmol) under
nitrogen gas atmosphere at room temperature. 1-iodotoluene 1a (0.109 g, 0.5 mmol), benzene 2 (2 mL)
and benzene-D6 (2 mL) were added into the reaction vial. The reaction mixture was allowd to stirr at
100 °C (heated in oil bath) for 24 hr. After the completion of the reaction, the reaction mixture was
allowed to cool to r.t; then, it was filtered through a celite pad and washed with ethyl acetate (3 × 20
mL). The combined filtrate was concentrated under vacuo to get crude compound which was further
purified by silica-gel (100-200 mesh) column chromatography using either hexane alone or ethyl
acetate/hexane as an eluent which afforded the desired product. The product distribution (KH/KD = 1.12)
was analyzed by 1H NMR.
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General procedure5c (GP2) for the synthesis of substituted amides 23a-w
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Compounds were prepared from the corresponding carboxylic acids and respective substituted amine.
Substituted 2-bromo-benzoyl chlorides/benzoyl chlorides were prepared from respective benzoic acids
(2.0 mmol) by refluxing with an excess of thionyl chloride (10.0 mmol) for 2-3 h. The excess amount of
thionyl chloride was removed under vacuum. Then, additional dry THF was added to the reaction
residue and again evaporated under reduced pressure to remove the traces amount of thionyl chloride.
The resulted residue was used for the amide preparation without further purification. The substituted 2-
bromo-benzoyl chlorides/benzoyl chloride (2.0 mmol) in DCM (10 mL) was added dropwise to a
stirring solution of respective aniline (2.2 mmol,), Et3N (4 mmol) and DMAP (0.2 mmol, 10 mol %) in
DCM (15 mL) at 0-5 °C under nitrogen atmosphere. After the addition, the resulting mixture was
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allowed to room temperature and stirred for 6 h. The reaction was quenched with water at 0 C and
diluted with DCM (20 mL). The resulting solution was sequentially washed by aqueous HCl (15 mL,
1.0 M), saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried over
anhydrous Na2SO4 and then evaporated under vacuum. The residue was purified by column
chromatography to afford the corresponding substituted amide 23a-v for phenanthridinones synthesis.
Compounds 2-bromo-N-phenylbenzamide17a 23a, 2-bromo-4,5-dimethoxy-N-phenylbenzamide17b 23c,
N-((2-bromothiophen-3-yl)methyl)aniline5c 23f, 2-bromo-N-(pyridin-2-yl)benzamide17c 23g, 2-bromo-
N-(p-tolyl)benzamide17a 23h, 2-bromo-N-(4-methoxyphenyl)benzamide17a 23i, 2-bromo-N-(4-
chlorophenyl)benzamide17a 23j, 2-bromo-4,5-dimethoxy-N-(p-tolyl)benzamide17b 23n, 2-bromo-N-(2-
methoxyphenyl)benzamide17a 23o, 2-bromo-N-(3-methoxyphenyl)benzamide17d 23p, 2-bromo-5-nitro-
N-phenylbenzamide17f 23u and 2-bromo-N-cyclohexylbenzamide17e 23v are known compounds.
Characterization data of substrates amides (23b, 23d-e, 23k-m and 23q-s)
2-bromo-5-methyl-N-phenylbenzamide (23b): The compound was synthesized according to the GP2
and purified through silica-gel column chromatography using the ethyl acetate/hexane (05:95) as an
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eluent. Rf value: 0.71 (eluent: 30% ethyl acetate/hexane); White solid; Yield: 81% (0.470 g); H NMR
(400 MHz, Chloroform-d) δ: 7.68 – 7.63 (m, 3H), 7.51 – 7.48 (m, 2H), 7.40 – 7.36 (m, 2H), 7.19 – 7.13
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(m, 2H), 2.34 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ: 165.7, 138.1, 137.6, 137.4, 133.4,
132.7, 130.7, 129.2, 124.9, 120.1, 115.8, 20.9; HRMS (ESI/QTOF) m/z: [M + H]+ calcd for
C14H13BrNO 290.0175; found 289.0176.
2,5-dibromo-N-phenylbenzamide (23d): The compound was synthesized according to the GP2 and
purified through silica-gel column chromatography using the ethyl acetate/hexane (08:92) as an eluent.
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Rf value: 0.78 (eluent: 30% ethyl acetate/hexane); White Solid; Yield: 65% (0.462 g); H NMR (400
MHz, Chloroform-d) δ: 7.79 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 3H), 7.52 – 7.44 (m, 2H), 7.39 (t, J
= 8.0 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 164.0, 155.9,
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139.4, 137.2, 135.0, 134.7, 132.8, 129.3, 129.3, 125.3, 121.9, 120.2, 117.9; HRMS (ESI/QTOF) m/z:
[M + H]+ calcd for C13H10Br2NO 353.9124; found 353.9128.
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3-bromo-N-phenyl-2-naphthamide (23e): The compound was synthesized according to the GP2 and
purified through silica-gel column chromatography using the ethyl acetate/hexane (15:75) as an eluent.
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Rf value: 0.75 (eluent: 30% ethyl acetate/hexane); Light brown solid; Yield: 70% (0.457 g); H NMR
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(400 MHz, Chloroform-d ) δ: 8.15 (d, J = 7.2 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H),
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7.69 (d, J = 7.6 Hz, 2H), 7.61 – 7.55 (m, 2H), 7.43–7.39 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H); C{1H}
NMR (100 MHz, Chloroform-d) δ: 165.6, 137.7, 135.0, 134.8, 132.5, 131.6, 129.8, 129.3, 128.5, 127.4,
126.9, 124.9, 120.2, 115.8; HRMS (ESI/QTOF) m/z: [M + H]+ calcd for C17H12Br2NO 326.0175; found
326.0172.
2-bromo-5-methyl-N-(p-tolyl) benzamide (23k): The compound was synthesized according to the GP2
and purified through silica-gel column chromatography using the ethyl acetate/hexane (10:90) as an
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eluent. Rf value: 0.71 (eluent: 30% ethyl acetate/hexane); White solid; Yield: 82% (0.50 g); H NMR
(400 MHz, Chloroform-d ) δ: 7.60 (s, 1H), 7.53 – 7.47 (m, 4H), 7.18 (d, J = 8.4 Hz, 2H), 7.174 – 7.11
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(m, 1H), 2.35 (s, 6H); C{1H} NMR (100 MHz, Chloroform-d) δ: 165.6, 138.0, 137. 6, 135.0, 134.6,
133.3, 132.6, 130.7, 129.7, 120.2, 115.8, 21.0, 20.9; HRMS (ESI/QTOF) m/z: [M + H]+ calcd for
C15H14BrNO 304.0332; found 304.0337.
2-bromo-N-(4-methoxyphenyl)-5-methylbenzamide (23l): The compound was synthesized according to
the GP2 and purified through silica-gel column chromatography using the ethyl acetate/hexane (20:80)
1
as an eluent. Rf value: 0.52 (eluent: 30% ethyl acetate/hexane); White solid; Yield: 59% (0.378 g); H
NMR (400 MHz, Chloroform-d) δ: 7.62 (s, 1H), 7.56 – 7.52 (m, 2H), 7.49 – 7.46 (m, 2H), 7.11 (dd, J =
8.4, 2.0 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H), 3.81 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 165.6, 156.9, 138.1, 137.6, 133.4, 133.3, 132.6, 130.8, 130.7, 122.0, 115.9, 114.4,
55.6, 20.9; HRMS (ESI/QTOF) m/z: [M + H] + calcd for C15H14BrNO2 320.0281; found 320.0285.
2-bromo-N-(4-chlorophenyl)-5-methylbenzamide (23m): The compound was synthesized according to
the GP2 and purified through silica-gel column chromatography using the ethyl acetate/hexane (15:75)
1
as an eluent. Rf value: 0.72 (eluent: 30% ethyl acetate/hexane); White solid; Yield: 67% (0.435 g); H
NMR (400 MHz, Chloroform-d ) δ: 7.74 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.50 – 7.45 (m, 2H), 7.33 (d,
J = 8.8 Hz, 2H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d)
δ: 165.7, 138.2, 137.1, 136.2, 133.5, 132.9, 130.7, 129.9, 129.3, 121.4, 115.8, 20.9; HRMS (ESI/QTOF)
m/z: [M + H]+ calcd for C14H12BrClNO 323.9786; found 323.9791.
2-bromo-N-(3-methoxyphenyl)-5-methylbenzamide (23q): The compound was synthesized according to
the GP2 and purified through silica-gel column chromatography using the ethyl acetate/hexane (20:80)
1
as an eluent. Rf value: 0.60 (eluent: 30% ethyl acetate/hexane);White solid; Yield: 60% (0.384 g); H
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NMR (400 MHz, Chloroform-d ) δ: 7.70 (s, 1H), 7.50 – 7.41 (m, 3H), 7.28 – 7.24 (m, 1H), 7.14 – 7.08
(m, 2H), 6.74 (dd, J = 8.4, 2.0 Hz, 1H), 3.83 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 165.7, 160.4, 138.9, 138.1, 137.5, 133.4, 132.7, 130.7, 129.9, 115.9, 112.2, 110.9,
1
2
3
4
5
6
+
105.8, 55.5, 20.9; HRMS (ESI/QTOF) m/z: [M + H] calcd for C15H14BrNO2 320.0281; found
7
8
320.0283.
9
3-bromo-N-(p-tolyl)-2-naphthamide (23r): The compound was synthesized according to the GP2 and
purified through silica-gel column chromatography using the ethyl acetate/hexane (15:75) as an eluent.
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
Rf value: 0.72 (eluent: 30% ethyl acetate/hexane); Light brown solid; Yield: 72% (0.490 g); H NMR
(400 MHz, Chloroform-d ) δ: 8.11 (s, 2H), 7.85 – 7.75 (m, 3H), 7.56 – 7.55 (m, 4H), 7.19 (d, J = 7.6 Hz,
2H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ: 165.6, 135.2, 134.8, 134.7, 132.5, 131.6,
129.78, 129.7, 128.5, 128.5, 127.4, 126.9, 120.3, 115.9, 21.1; HRMS (ESI/QTOF) m/z: [M + H]+ calcd
for C18H15BrNO 340.0332; found 340.0335.
3-bromo-N-(4-methoxyphenyl)-2-naphthamide (23s): The compound was synthesized according to the
GP2 and purified through silica-gel column chromatography using the ethyl acetate/hexane (20:80) as
an eluent. Rf value: 0.54 (eluent: 30% ethyl acetate/hexane); Light brown solid; Yield: 67% (0.477 g);
1H NMR (400 MHz, Chloroform-d) δ: 8.11 (d, J = 6.0 Hz, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 5.2
Hz, 2H), 7.59 – 7.53(m, 4H), 6.92 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ: 165.5, 156.9, 135.1, 134.7, 132.4, 131.6, 130.8, 129.7, 128.5, 128.4, 127.3, 126.9,
122.0, 115.9, 114.3, 55.6; HRMS (ESI/QTOF) m/z: [M + H]+ calcd for C18H15BrNO2 356.0281; found
356.0285.
3-bromo-N-(4-chlorophenyl)-2-naphthamide (23t): The compound was synthesized according to the
GP2 and purified through silica-gel column chromatography using the ethyl acetate/hexane (10:90) as
an eluent. Rf value: 0.81 (eluent: 30% ethyl acetate/hexane); Light brown solid; Yield: 64% (0.462 g);
1H NMR (400 MHz, Chloroform-d ) δ: 8.13 (d, J = 7.2 Hz, 2H), 7.88 – 7.77 (m, 3H), 7.65 – 7.56 (m,
13
4H), 7.35 (d, J = 8.8 Hz, 2H); C{1H} NMR (100 MHz, Chloroform-d) δ: 165.6, 136.2, 134.9, 134.6,
132.6, 131.5, 129.9, 129.9, 129.3, 128.6, 128.5, 127.5, 126.9, 121.4, 115.6; HRMS (ESI/QTOF) m/z:
[M + H] + calcd for C13H11BrClNO 359.9786; found 359.9790.
General procedure (GP3) for intra-molecular organocatalyzed C(sp2)-H direct arylation
(Synthesis of phenanthridines 24-42): 2-bromo-N-phenylbenzamide/ substituted 2-bromo-N-
phenylbenzamide (0.5 mmol), potassium tert-butoxide (168 mg, 1.5 mmol), 1-(2-hydroxyl ethyl)
piperazine (0.2 mmol) and additive DMAP (0.2 mmol) were added in mesitylene (4 mL) in a sealed
tube. Then, the reaction mixture was degassed with N2 gas and heated at 150 °C (heated in oil bath) for
24 h. After the completion of the reaction, the reaction mixture was allowed to cool to r.t and dissolved
in 5% methanol: chloroform (10 ml) and then, filtered through a celite pad and washed with 5% MeOH:
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The Journal of Organic Chemistry
chloroform (3 × 10 mL). The combined filtrate was concentrated under vacuo to get crude compound
which was further purified by silica-gel (100-200 mesh) column chromatography using MeOH: CHCl3
or EtOAc: Hexane as an eluent which afforded the desired product.
1
2
3
4
5
6
Characterization data of phenanthridinones compounds (24-42).
Phenanthridin-6(5H)-one5c (24): The compound was synthesized according to the GP3 and purified
through silica-gel column chromatography using the ethyl acetate/hexane (1:3) as an eluent. Rf value:
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
1
0.46 (eluent: 5% MeOH/CHCl3); White solid; Yield: 89% (0.089 g); H NMR (400 MHz, DMSO-d6)
δ:11.68 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.87–7.83
(m, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.50–7.47 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ: 161.3, 137.1, 134.7, 133.3, 130.1, 128.5, 128.00, 126.2, 123.8,
123.16, 122.8, 118.1, 116.6; HRMS (ESI/QTOF) m/z: [M + H] + calcd for C13H10NO 196.0757; found
196.0759; FT-IR (KBr); 3021, 1604, 1363, 1226, 725, 622 cm-1.
8-methylphenanthridin-6(5H)-one12b (25): The compound was synthesized according to the GP3 and
purified through silica-gel column chromatography using the ethyl acetate/hexane (1:3) as an eluent. Rf
1
value: 0.43 (eluent: 5% MeOH/CHCl3); White Solid; Yield: 77% (0.081 g); H NMR (400 MHz,
DMSO-d6) δ:11.59 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 7.64 (dd, J =
8.0, 1.6 Hz, 1H), 7.44–7.40 (m, 1H), 7.32–7.30 (m, 1H), 7.23–7.19 (m, 1H), 2.45 (s, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ: 161.3, 138.1, 136.7, 134.5, 132.3, 129.6, 127.7, 126.1, 123.5, 123.2,
122.7, 118.2, 116.5, 21.5; HRMS (ESI/QTOF) m/z: [M + H]+ calcd for C14H12NO, 210.0913; found
210.0914; FT-IR (KBr); 2854, 1667, 1358, 1208, 886, 744, 658, 445 cm-1.
8,9-dimethoxyphenanthridin-6(5H)-one5c (26): The compound was synthesized according to the GP3
and purified through silica-gel column chromatography using the MeOH/CHCl3 (1:99) as an eluent. Rf
1
value: 0.76 (eluent: 5% MeOH/CHCl3); White Solid; Yield: 40% (0.051 g); H NMR (400 MHz,
DMSO-d6) δ: 11.56 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.40–7.37 (m, 1H), 7.29
(d, J = 8.4 Hz, 1H), 7.22–7.18 (m, 1H), 3.98 (s, 3H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6
) δ: 160.9, 153.7, 149.9, 136.5, 129.5, 129.0, 123.7, 122.4, 119.8, 118.1, 116.4, 108.3, 104.6, 56.6, 56.0;
HRMS (ESI/QTOF) m/z: [M + H]+ calcd for C15H14NO3 256.0968; found 256.0970; IR (KBr); 2921,
1646, 1602, 1514, 1373, 1207, 1099, 840, 754, 585 cm-1.
8-bromophenanthridin-6(5H)-one16d (27): The compound was synthesized according to the GP3 and
purified through silica-gel column chromatography using the MeOH/CHCl3 (1:99) as an eluent. Rf
1
value: 0.76 (eluent: 10% MeOH/CHCl3); White Solid; Yield: 60% (0.082 g); H NMR (400 MHz,
DMSO-d6); δ 11.65 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.28 (dd, J = 8.0, 1.2 Hz,
1H), 7.84–7.79 (m, 1H), 7.63–7.58 (m, 1H), 7.48–7.43 (m, 1H), 7.34–7.31(m, 1H), 7.25–7.20 (m, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ: 161.3, 137.0, 134.8, 133.4, 130.1, 128.5, 127.9, 126.16, 123.8,
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