Chemoselective one-pot access to benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-diones via copper-catalyzed oxidative [3 + 2] annulation of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols

Article abstract of DOI:10.1016/j.tet.2018.08.026

An operationally simple and efficient one-pot method for the synthesis of 1-aroyl (or alkanoyl)-2-thioalkyl-3-aryl (or alkyl)-3H-benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-diones has been devised by copper-catalyzed cross-coupling of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols in open air for the first time. The key to the success of this transformation is the room temperature oxidation of α-/β-naphthol to 1,2-naphthoquinone as a reactive species, which undergoes formal [3 + 2] annulation with α-oxoketene N,S-acetals/β-ketothioamides via cascade sequence of Michael addition/tautomerization/oxidation/cyclization/aromatization reactions, enabling addition of a pyrrole/thiophene ring onto naphthoquinone moiety. Further, benzo[e]indole-4,5-diones were transformed to pentacyclic fused phenazine derivatives under solvent-free conditions. Based on our experimental outcomes, a tentative mechanistic rationale for this chemoselective protocol is proposed, which is well validated and supported by the control experiments.

Full text of DOI:10.1016/j.tet.2018.08.026

Accepted Manuscript
Chemoselective one-pot access to benzo[e]indole-4,5-diones and
naphtho[2,1-b]thiophene-4,5-diones via copper-catalyzed oxidative [3 + 2] annulation
of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols
Dhananjay Yadav, Gaurav Shukla, Monish A. Ansari, Abhijeet Srivastava, Maya
Shankar Singh
PII:
S0040-4020(18)30990-6
10.1016/j.tet.2018.08.026
TET 29746
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 July 2018
Revised Date: 16 August 2018
Accepted Date: 18 August 2018
Please cite this article as: Yadav D, Shukla G, Ansari MA, Srivastava A, Singh MS, Chemoselective
one-pot access to benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-diones via copper-
catalyzed oxidative [3 + 2] annulation of α-oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.026.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Chemoselective one-pot access to benzo[e]indole-4,5- Leave this area blank for abstract info.
diones and naphtho[2,1-b]thiophene-4,5-diones via
copper-catalyzed oxidative [3 + 2] annulation of α-
oxoketene N,S-acetals/β-ketothioamides with α-/β-
naphthols
Dhananjay Yadav, Gaurav Shukla, Monish A. Ansari, Abhijeet Srivastava and Maya Shankar Singh*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chemoselective one-pot access to benzo[e]indole-4,5-diones and naphtho[2,1-
b]thiophene-4,5-diones via copper-catalyzed oxidative [3 + 2] annulation of α-
oxoketene N,S-acetals/β-ketothioamides with α-/β-naphthols
Dhananjay Yadav, Gaurav Shukla, Monish A. Ansari, Abhijeet Srivastava and Maya Shankar Singh
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An operationally simple and efficient one-pot method for the synthesis of 1-aroyl (or alkanoyl)-
2-thioalkyl-3-aryl (or alkyl)-3H-benzo[e]indole-4,5-diones and naphtho[2,1-b]thiophene-4,5-
diones has been devised by copper-catalyzed cross-coupling of α-oxoketene N,S-acetals/β-
ketothioamides with α-/β-naphthols in open air for the first time. The key to the success of this
transformation is the room temperature oxidation of α-/β-naphthol to 1,2-naphthoquinone as a
reactive species, which undergoes formal [3 + 2] annulation with α-oxoketene N,S-acetals/β-
Available online
ketothioamides
via
cascade
sequence
of
Michael
addition/tautomerization/oxidation/cyclization/aromatization reactions, enabling addition of a
pyrrole/thiophene ring onto naphthoquinone moiety. Further, benzo[e]indole-4,5-diones were
transformed to pentacyclic fused phenazine derivatives under solvent-free conditions. Based on
our experimental outcomes, a tentative mechanistic rationale for this chemoselective protocol is
proposed, which is well validated and supported by the control experiments.
Keywords:
α-oxoketene N,S-acetals
α-/β-naphthols
3H-benzo[e]indole-4,5-diones
naphtho[2,1-b]thiophene-4,5-diones
1H-benzo[a]pyrrolo[3,2-c]phenazines
2018 Elsevier Ltd. All rights reserved
.
1. INTRODUCTION
The development of sustainable chemical processes has
become a key research area providing solutions to important
societal demands by optimizing the use of natural resources, and
minimizing waste and environmental impact. Among the relevant
methods for achieving this goal, catalysis represents a key and
central approach. It is of great significance to effectively
construct privileged molecules from synthetic chemistry and drug
discovery viewpoints. Amongst nitrogen-containing fused
heterocycles, indoles and their analogues are well recognized as
privileged scaffolds prevalent in a vast array of natural products,1
which find applications as pharmaceuticals and in agricultural
chemicals.2 Among benzo-fused indoles, benzo[e]indole and its
analogues have recently drawn significant interest from industry
and academia as a core architecture of many natural products and
fused indole moiety has great potential for the generation of new
biologically active molecules or therapeutic agents.
Given the synthetic and practical significance of these
intriguing scaffolds, over the years, different strategies for the
construction of benzo[e]indoles5,6 and benzo[f]indole-4,9-diones7
have been explored. Recently, a direct synthetic approach to
access benzo[e]indoles by Diels-Alder reaction of 2-
vinylpyrroles and arynes was developed.8 Despite some notable
recent achievements, the reported methods inevitably suffer from
some clear disadvantages such as inaccessible starting
materials,3c,d
complicated
procedures,5
harsh
reaction
conditions,6,7 and generation of undesired by-products, which
limit their application to a certain extent. Considering these
concerns, development of operationally simple and pot-/atom-
/step-economic (PASE) methods utilizing readily available and
inexpensive materials to access benzo-fused indoles and
fundamental extension of their range are very much required,
which would definitely complement the previously known
strategies.
pharmacologically
active
compounds.3
For
example,
benzo[e]indole serves as an important synthetic intermediate to
generate hasubanan alkaloid hasubanonine.3a Also, 5-hydroxy-
CBI-TMI has been utilized as a stable prodrug to construct
cyclopropylindole antitumor agents and antibiotics.3c Further,
benzo[f]indole-4,9-dione
derivatives
exhibit
diversified
In this regard, the α-oxoketene S,S-acetals,9 N,O-acetals10 and
biological activities such as antineoplastic, antibacterial, virus-
static, fungicidic and anticoagulant properties.4 Hence, the benzo-
———
N,S-acetals,11 owing to their easy preparation, high stability and
Corresponding author.
Fax: +91-542-2368127; e-mail: mayashankarbhu@gmail.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and discussion
wonderful reactivity, have proven to be the fascinating and
multipurpose synthons for the construction of diverse
heterocyclic frameworks. However, to the best of our knowledge,
no report is known to date on the synthesis of benzo-fused indole
derivatives utilizing α-oxoketene N,S-acetals. Keeping the
knowledge of benzo-fused indole syntheses5-8 in mind, we
reasonably envisioned that the α-oxoketene N,S-acetals behaving
as enaminones could be utilized as three atoms (C-C-N) reaction
partner. As a consequence, we hypothesized the possibility of
annulation between 1,2-naphthoquinone (generated in situ from
β-naphthol) and α-oxoketene N,S-acetal, in order to open new
intriguing synthetic possibility for the construction of benzo-
fused indole scaffold. Herein, we report a TEMPO mediated,
copper-catalyzed one-pot synthesis of a broad array of 1-aroyl (or
Most of the reactions in organic chemistry are reagent- or
catalyst-controlled reactions, and the regio- and stereoselectivity
of these reactions are determined by the inherent nature of the
reagent or catalyst. In sharp contrast, substrate-directed reactions
determine the selectivity of the reactions by the functional group
on the substrate, and can strictly distinguish sterically and
electronically similar multiple reaction sites in the substrate. In
this perspective, the rich and fascinating chemistry of α-
oxoketene N,S-acetals with general formula I (Figure 1), features
an unusual structure with electron-withdrawing and electron-
donating functionalities (carbonyl, thioalkyl, and amino groups)
attached to the two ends of the olefinic carbon−carbon bond.
They exert amazing reactivity and emerged as novel multi-role-
synthons for the construction of various heterocyclic systems and
related useful frameworks.17,18 On the other hand, cheap, easily
available, and easy to handle β-naphthol has been well
recognized as highly reactive reaction partner in various organic
transformations.19
alkanoyl)-2-thioalkyl-3-aryl
(or
alkyl/cycloalkyl)-3H-
benzo[e]indole-4,5-diones via oxidative formal [3 + 2] annulative
coupling of α-oxoketene N,S-acetals with β-naphthols in a single
operation (Scheme 1). Notably, the consecutive formation of
C−C and C−N bonds enabled a pyrrole ring over naphthoquinone
moiety empowering this strategy an excellent tool towards
molecular diversity. However, the demand for better synthetic
methods leading to bioactive scaffolds and their derivatives is
still high and continuous. Of particular interest is the
chemoselectivity of the reactions consistent with a cascade
process.
Figure 1. Reactivity profile of α-oxoketene N,S-acetals.
However, the synthetic utility of α-oxoketene N,S-acetals
towards β-naphthol has not yet been reported, which could be an
impetus for untold numbers of research projects. Recently, Li and
co-workers20 exploited N,S-ketene acetals for the direct
construction of 2-aryliminochromenes. Inspired by above
findings, and in continuation of our ongoing research toward the
development of powerful synthetic strategies to assemble
different heterocyclic scaffolds utilizing α-oxoketene N,S-
acetals21 as a good reaction partner, we turned our attention to
utilize N,S-acetal and β-naphthol with the aim to generate
hitherto unknown benzo-fused indole via one-pot cascade aza-
annulation. To validate our hypothesis, we commenced our study
employing β-naphthol (1a) and α-oxoketene N,S-acetal (3a) as
model substrates to examine various reaction parameters. The
results are summarized in Table 1.
Scheme 1. One-pot synthesis of 3H-benzo[e]indole-4,5-diones 4.
The metal-catalyzed cross coupling reactions12 (MCCCR)
have proven to be powerful strategies enabling realization of
molecular diversity and synthetic versatility. They have
profoundly changed the protocols for the construction of
simple/complex molecules for organic materials, polymers and
lead compounds in medicinal chemistry. Oxidative cross-
coupling13 (OCC) is a hot research topic that covers aspects of
classical coupling, C−H functionalization, oxidation reactions,
and radical chemistry for chemical, materials and biological
synthesis. Indeed, it is well established that a copper-oxygen
system14 could be viewed as powerful reaction system for
carbon–carbon and carbon–heteroatom bonds formation due to
low toxicity, ease of handling and good functional group
tolerance. Cascade processes15 have received tremendous
developments over the past decades, and remain one of the most
powerful tools to create C−C and C−X (X = heteroatom) bonds in
one-pot due to their ecologic and economic competence. These
strategies are not only limited to the syntheses of simple
molecules, but also have been utilized for the biomimetic
synthesis of several natural products transforming the field
dramatically.16
At the outset of our study, we performed the model reaction of
1a (0.5 mmol) with 3a (0.5 mmol) in 3 mL of AcOH without any
oxidant and catalyst at room temperature in open air.
Disappointingly, we did not observe any trace of the desired
product 4aa, even after 12 h of stirring, and the starting materials
remained completely unreacted (Table 1, entry 1). During the
recent past, TEMPO has emerged as clean and mild oxidant that
could be used to construct C−C/C−N bonds.22 Therefore; we
carried out the model reaction in the presence of 1 equiv of
TEMPO at room temperature and at 100 °C, separately. Reaction
failed under above both conditions (Table 1, entries 2 and 3).
Keeping in mind the use of relatively inexpensive and less toxic
copper salts23 in organic synthesis, we performed the test reaction
in the presence of 10 mol % of CuCl and 1 equiv of TEMPO at
room temperature. Notably, CuCl triggered the reaction
producing the desired product 4aa, albeit in only 18% isolated
yield (Table 1, entry 4). The above observation was encouraging
enough to optimize the reaction conditions. To improve the yield

3
of 4aa, we performed the reaction at higher temperature. We
found that maximum conversion occurred at 100 °C, providing
the desired product 4aa in 44% yield (Table 1, entries 5 and 6).
The improvement in the result of the protocol prompted us to
investigate copper(II) salts such as CuBr2, Cu(OAc)2, Cu(OTf)2,
and Cu(acac)2 (Table 1, entries 7-10). Among above screened
copper salts, copper acetate showed better catalytic activity than
other copper species (Table 1, entry 8).
such as tert-butyl hydroperoxide (TBHP), PhI(OAc)2 and
ACCEPTED MANUSCRIPT
Oxone® were also evaluated but were found to be inferior to
TEMPO (Table 1, entries 17-19). To check the generality of the
protocol, we screened some other transition-metal catalysts such
as NiCl2 and FeCl3. They also catalyzed the reaction but could
not provide better result than Cu(OAc)2 (Table 1, entries 20 and
21). Without TEMPO and with 20 mol % of Cu(OAc)2 at 100 °C,
the reaction did not occur (Table 1, entry 22), revealing the
significance of TEMPO to the success of the reaction. Thus, the
optimum condition for the synthesis of 4aa was achieved by
employing 1a (0.5 mmol), 3a (0.5 mmol), TEMPO (2.5 equiv),
20 mol % of Cu(OAc)2, in 3 mL of AcOH at 100 °C in open air
(Table 1, entry 13).
Table 1
Optimization of reaction conditionsa
With the established optimal conditions in hand, we then set
out to explore the generality of the protocol by using structurally
diverse α-oxoketene N,S-acetals and β-naphthols. As shown in
Tables 2 and 3, a myriad of N,S-acetals are successful substrates,
providing the corresponding desired product 4 in good to
excellent yield. To address the factors that determine the reaction
outcome, the electronic and steric properties of the substituents
R1, R2 and R3 at α-oxoketene N,S-acetals were systematically
varied. R1 moiety as various aromatic groups with electron-
donating and electron-withdrawing substituents, regardless of
their positions, participated well in the reaction affording the
corresponding 3H-benzo[e]indole-4,5-diones in high yields,
revealing no obvious electronic impact (Table 2). The variants of
the substituents like Me, OMe, Cl, and Br groups on the phenyl
ring (R1 moiety) were found to be compatible under the standard
conditions (Table 2, 4ab-4ae and 4am-4ar). The introduction of
halogen (e.g., chloro and bromo) substituents into target product
is attractive because of their potential for further synthetic
elaborations. Importantly, N,S-acetals bearing π-electron
excessive groups such as 2-furyl and 2-thienyl as well as π-
electron deficient 3-pyridyl substituent at R1 moiety were also
well tolerated under standard conditions resulting the
corresponding products in high yields (Table 2, 4af-4ah). It is
noteworthy that N,S-acetals bearing not only aromatic and
heteroaromatic groups at R1 moiety, but extended aromatics such
as 1-naphthyl and biphenyl groups were also found to be
compatible well (Table 2, 4ai, 4aj). Notably, when R1 was
switched to alkyl substituent such as cyclopropyl and iso-butyl
groups, the corresponding products 4ak and 4al were obtained in
85% and 80% yield, respectively.
Next, we evaluated the substrate 3 bearing different R3 groups.
Replacing the R3 methyl group with substituents such as ethyl, n-
propyl, n-butyl, benzyl and methallyl were successfully amenable
to this protocol affording the corresponding 3H-benzo[e]indole-
4,5-diones in high yields (Table 2, 4am-4ar), revealing the broad
adaptability of this method. The one-pot cascade strategy
reported herein allows a novel entry to 1,2,3-trisubstituted-3H-
benzo[e]indole-4,5-diones 4 with full regiocontrol on all the three
positions of the newly formed pyrrole ring, which would
otherwise be more difficult to prepare by alternative routes. In
order to extend the substrate scope, we investigated the effect of
R2 on the efficacy of this protocol. For R2 of α-oxoketene N,S-
acetals, substituents such as alkyl and aryl groups could be
tolerated well, resulting the desired products in high yields.
Delightedly, when R2 are alkyl substituents such as methyl and
cyclohexyl groups, the corresponding products were obtained in
good yields (Table 2, 4as-4aw). When R2 moieties are electron-
donating 4-methylphenyl and electron-withdrawing 4-
flurophenyl groups, the corresponding products were obtained in
85% and 89% yield, respectively (Table 2, 4ax and 4ay).
Remarkably, switching R2 as a 1-naphthyl group also worked
well furnishing the desired product 4az in 78% yield.
Entry
Oxidant
(equiv)
Catalyst
(mol %)
Temp Time Yieldb
(oC)
rt
(h)
12
12
12
12
12
12
10
5
(%)
1
none
none
NR
NR
NR
18
36
44
56
72
60
56
82
82
92
92
65
62
32
26
18
76
64
NR
2
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (1)
TEMPO (2.5)
TEMPO (3)
TEMPO (2.5)
TEMPO (2.5)
TBHP (2.5)
none
rt
3
none
100
rt
4
CuCl (10)
5
CuCl (10)
70
6
CuCl (10)
100
100
100
100
100
100
100
100
100
70
7
CuBr2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Cu(acac)2 (10)
Cu(OAc)2 (20)
Cu(OAc)2 (30)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
8
9
7
10
11
12
13
14
15
16
17
18
8
3
3
2
2
4
120
100
100
2
6
PhI(OAc)2 (2.5) Cu(OAc)2 (20)
6
19
20
21
22
Oxone (2.5)
TEMPO (2.5)
TEMPO (2.5)
none
Cu(OAc)2 (20)
NiCl2 (20)
100
100
100
100
6
4
FeCl3 (20)
4
Cu(OAc)2 (20)
12
a Reaction conditions: All the reactions were performed with 1a (0.5
mmol), 3a (0.5 mmol) in 3 mL of AcOH in open air.
b Isolated yields.
NR = No reaction.
Observing the efficacy of Cu(OAc)2, next we optimized its
loading. It was found that 20 mol % of Cu(OAc)2 furnished the
best result providing the desired product 4aa in 82% yield within
3 h (Table 1, entry 11). Further increasing the amount of
Cu(OAc)2 could not improve the result (Table 1, entry 12). Then,
we screened the loading of TEMPO, and it was observed that 2.5
equiv of TEMPO afforded maximum conversion in minimum
time providing the desired product 4aa in 92% yield (Table 1,
entries 13 and 14). Further, decreasing or increasing the
temperature was found to be unfavorable to the reaction (Table 1,
entries 15 and 16). Thus, 100 °C was found to be the optimum
temperature for the appropriate yield of 4aa. Some other oxidants

4
Tetrahedron
naphthoquinone 2 in the first step, which followed the similar
Table 2
Scope of α-oxoketene N,S-acetals
ACCEPTED MANUSCRIPT
sequence of reactions to afford the desired 3H-benzo[e]indole-
4,5-diones 4 in high yields (Table 3). Thus, α-naphthol was also
found to be equally facile towards this novel one-pot cascade
protocol under standard conditions.
one-pot
O
R1
SR3
(i) TEMPO (2.5 equiv)
AcOH, rt, 20 min
OH
O
NHR2
SR3
R1
(ii) Cu(OAc)2 (20 mol %)
100 °C, 2-3 h
N
O
3a-z
1a
R2
O
Table 3
open air
4aa-4az (time, yield)
Use of substituted β-naphthols and α-naphthol toward the
synthesis of compounds 4
Cl
MeO
Me
O
O
O
O
SMe
SMe
N
N
SMe
SMe
O
O
N
N
O
Ph
Ph
O
O
O
Ph
Ph
O
O
4aa (2 h, 92%)
4ab (2 h, 86%)
4ac (2 h, 80%)
4ad (3 h, 83%)
Br
O
O
N
S
O
O
O
SMe
SMe
SMe
SMe
N
O
N
Ph
N
Ph
O
N
Ph
O
O
Ph
O
O
O
O
4ag (2.5 h, 85%)
4af (3 h, 82%)
4ae (2.5 h, 80%)
4ah (3 h, 76%)
O
O
O
O
SMe
SMe
N
Ph
O
SEt
N
O
SMe
N
Ph
O
O
Ph
N
O
O
4aj (3 h, 80%)
O
Ph
O
4ak (3 h, 85%)
4al (3 h, 80%)
4ai (3 h, 80%)
Cl
O
O
OMe
O
O
Br
O
SBun
SPrn
N
SEt
N
O
O
SEt
N
O
Ph
Ph
N
O
O
Ph
O
Ph
4ap (2 h, 87%)
O
4ao (2 h, 87%)
4am (2 h, 85%)
4an (2 h, 82%)
OMe
Me
O
Cl
Br
O
O
O
SEt
S
SBn
N
SEt
N
Me
O
O
N
Ph
N
Ph
O
Me
O
O
O
O
O
4as (2 h, 87%)
4ar (2 h, 87%)
4aq (2 h, 87%)
4at (2 h, 87%)
Me
O
Br
Cl
O
O
O
SMe
N
SEt
N
SMe
N
O
O
O
SEt
N
O
O
Me
O
O
Me
O
4av (2 h, 86%)
4aw (3 h, 85%)
4au (2 h, 80%)
Me
O
4ax (2 h, 85%)
Me
O
To demonstrate the broad synthetic usefulness of our
developed one-pot methodology, next we envisioned to utilize β-
ketothioamide in place of N,S-acetal. Consequently, when β-
ketothioamide 6a was treated with β-naphthol 1a under the
previously described one-pot optimized conditions, entirely
SMe
N
O
SMe
N
O
O
O
F
4ay (2 h, 89%)
4az (2 h, 78%)
different
scaffold
1-aroyl-2-(phenylamino)naphtho[2,1-
b]thiophene-4,5-dione 7aa was obtained in 76% yield (Table 4).
The generality of the above reaction was established by
synthesizing six naphtho[2,1-b]thiophene-4,5-diones (7aa-7af)
utilizing different β-ketothioamides (6a-6f) under standard
reaction conditions (Table 4). R4 moiety of thioamide as various
aromatic groups with electron-donating and electron-withdrawing
substituents as well as heteroaromatic groups such as 2-furyl and
2-thienyl participated well in the reaction affording the
corresponding product 7 in good yield (Table 4). Very recently,
we synthesized 2,3-disubstituted naphtho[2,1-b]thiophene-4,5-
diones by the reaction of α-enolic dithioesters with β-naphthols
via cross-dehydrogenative thienannulation.24 Heterocycle-fused
naphthoquinones are common structural motifs in a large number
of natural and synthetic products, which usually possess
important biological activities such as anti-inflammatory and
anti-cancer properties.25
To further extend the synthetic utility of this one-pot cascade
reaction, we also investigated substituted β-naphthols 1b-1f with
a view to add further diversity to the benzene ring of 3H-
benzo[e]indole-4,5-diones. The results demonstrated that
substituted β-naphthols displayed similar reactivity as β-naphthol
and took part in the reaction effectively to yield the desired
products 4 in good yields (Table 3). Thus, substituted β-
naphthols such as 6-cyano-2-naphthol 1b, 6-bromo-2-naphthol
1c,
6-carbomethoxy-2-naphthol
1d,
and
6-(p-
methoxyphenylethynyl)-2-naphthol 1e upon treatment with N,S-
acetals under the previously described one-pot standard
conditions, afforded 1,2,3,8-tetrasubstituted 3H-benzo[e]indole-
4,5-diones in 76-85% yields (Table 3). This result greatly
expanded the structural diversity of product 4. However, 6-
amino-β-naphthol 1f did not proceed under standard conditions,
thus limiting the scope of the reaction to some extent. To further
demonstrate the general applicability of this coupling reaction,
we used α-naphthol in place of β-naphthol. Treatment of α-
naphthol 1h instead of β-naphthol also generated the same 1,2-

5
Table 4
ACCEPTED MANUSCRIPT
To define the possible intermediates and pathway, several
control experiments were carried out, as shown in Scheme 3.
First, we treated compound 2 with 3a in the presence of 20 mol
Synthesis of naphtho[2,1-b]thiophene-4,5-diones 7
o
% of Cu(OAc)2 at 100 C in open air. Gratifyingly, the desired
3H-benzo[e]indole-4,5-dione 4aa was obtained in 92% yield
within 2 h (Scheme 3, Eq I), validating the intermediacy of 1,2-
naphthoquinone 2 during the course of the reaction. The standard
reaction of 2 with 3a without Cu(OAc)2 was unsuccessful even
after 12 h (Scheme 3, Eq II). Similarly, another standard
experiment of 1a with 3a without TEMPO could not provide the
desired product 4aa even after 12 h (Scheme 3, Eq III),
suggesting the crucial role of TEMPO for the efficient oxidation
of 1a to 2 for successful transformation. To ascertain the role of
the atmospheric oxygen during the transformation, we performed
the standard reaction of 1a with 3a under the argon atmosphere.
The much decreased yield (36%) of the desired product 4aa
under argon atmosphere indicated that the oxygen played an
important accelerating role toward this transformation (Scheme
3, Eq IV). Finally, we treated both ortho-positions blocked β-
naphthol 1g with 3a under optimized conditions. We did not
observe any trace of the desired product 4ga, even after 12 h of
stirring, and the starting materials remained completely unreacted
(Scheme 3, Eq V). The results of these control experiments
revealed that the in situ generation of 1,2-naphthoquinone 2 as
key intermediate is must for the progress of the reaction, and
TEMPO, Cu(OAc)2 as well as atmospheric oxygen are essential
for the success of this protocol.
The structures of all the newly synthesized 3H-
benzo[e]indole-4,5-diones 4 and naphtho[2,1-b]thiophene-4,5-
diones 7 were fully characterized by their satisfactory spectral
(1H, 13C, and HRMS) studies. Structure of one of the
representative 1-cyclopropanecarbonyl-2-thiomethyl-3-phenyl-
3H-benzo[e]indole-4,5-dione 4ak was further unambiguously
established by the single crystal X-ray diffraction analysis
(Figure 2, see Supporting Information for details).
Figure 2. ORTEP diagram of compound 4ak (CCDC No. 1570938).
To demonstrate the practical application and synthetic utility
of the present protocol, we performed a gram-scale experiment
with 1a (10 mmol) and 3a (10 mmol) under the optimal reaction
conditions (Scheme 2). The desired product 1-benzoyl-2-
Scheme 3. Control experiments.
Based on literature reports and our experimental outcomes, a
plausible mechanism for the formation of compounds 4 is
depicted in Scheme 4. Considering the structural characteristics
of this transformation, it could be suggested that the initial in situ
oxidation of β-naphthol followed by a series of cascade reactions
enabled 3H-benzo[e]indole-4,5-dione core 4. The first step is
believed to be a TEMPO mediated rapid oxidation of β-naphthol
(1) to 1,2-naphthoquinone (2) that has been isolated and fully
characterized. Then, Michael-type addition of α-carbon of N,S-
acetal (3) to C4 of Cu2+-complexed naphthoquinone (2) resulted
into Michael adduct intermediate A, which eventually undergoes
enamine and keto-enol two fold tautomerization to the
thermodynamically more stable tautomer B. Subsequent
oxidation of B by Cu(II), enabled the formation of enamine-
thiomethyl-3-phenyl-3H-benzo[e]indole-4,5-dione
4aa
was
obtained in 88% yield (3.73 g), which is comparable to the small
scale experiment shown in Table 2 (92%). This result showed
that the present method could be easily adopted for a large-scale
preparation.
Scheme 2. Gram-scale synthesis of 3H-benzo[e]indole-4,5-
dione 4aa.

6
Tetrahedron
ACCEPTED MANUSCRIPT
enone intermediate C1, which could probably undergo
intramolecular cyclization via its possible two rotamers C1 and
C2 through pathways I and II to furnish compounds 4 and 5,
respectively. The intermediate C1 undergoes chemoselective N-
cyclization via path I followed by oxidation to give the desired
3H-benzo[e]indole-4,5-dione 4 exclusively. The rotamer C2
could lead to compound 5 by alternative O-cyclization via path
II, which was not observed even in trace during our investigation.
Here, Cu(OAc)2 plays dual role as a Lewis acid to stabilize the
structures of transition states via electrostatic interactions, and as
oxidative catalyst. Molecular oxygen that acts as the terminal
oxidant is involved in the oxidation of Cu(I) for the regeneration
of Cu(II) to complete the catalytic cycle.
Scheme 5. Synthetic application of compound 4:
Transformation to pentacyclic phenazine derivatives 9.
3. Conclusion
In summary, a practical and reliable one-pot annulative
coupling strategy has been developed for the direct synthesis of
diverse 1,2,3-trisubstituted and 1,2,3,8-tetrasubstituted 3H-
benzo[e]indole-4,5-diones from cheap and readily available α-/β-
naphthols and α-oxoketene N,S-acetals in open air for the first
time. This operationally simple domino [3 + 2] azaannulation
features good atom and step economy, high yields and broad
substrate scope. The reaction involved in situ generation of 1,2-
naphthoquinone, the actual reactive species by the oxidation of
α-/β-naphthol,
functionalization with α-carbon atom and nitrogen atom of α-
oxoketene N,S-acetal via Michael-type
addition/tautomerization/oxidation/intramolecular
which
undergoes
unique
sequential
cyclization/aromatization cascade sequence. This protocol not
only allows the assembly of a huge range of benzo[e]indole-4,5-
diones, but also expands the application towards the synthesis of
naphtho[2,1-b]thiophene-4,5-diones employing β-ketothioamides
instead of N,S-acetals, which are difficult to obtain otherwise.
Further, the 3H-benzo[e]indole-4,5-dione frameworks undergo L-
Proline-catalyzed cross-dehydrative coupling with ortho-
Scheme 4. Plausible mechanism for the formation of 3H-
benzo[e]indole-4,5-diones 4.
phenylenediamines
enabling
pentacyclic
1H-
This method not only provides a new approach to tri- and
tetra-substituted 3H-benzo[e]indole-4,5-diones, but also expands
the application toward the synthesis of fused phenazine
derivatives. To demonstrate the synthetic utility of the annulated
products, further post functionalization was carried out. Since the
3H-benzo[e]indole-4,5-diones 4 bear two adjacent carbonyl
groups as highly functional handles, we considered evaluating
their scope with 1,2-diaminobenzenes26 with a vision to install
quinoxaline moiety onto benzo[e]indole-4,5-dione core to get
fused phenazine derivatives. Phenazine derivatives have immense
applications in various fields such as dyes, pharmaceuticals and
antibiotics.27
benzo[a]pyrrolo[3,2-c]phenazine derivatives in excellent yields
under solvent-free conditions. Notably, copper acetate plays dual
role as a Lewis acid and oxidative catalyst, and atmospheric
oxygen acts as the terminal green oxidant.
4. Experimental Section
4.1. General information
Unless otherwise noted, all reagents have been purchased
from commercial suppliers and used without further purification.
The α-oxoketene N,S-acetals21a-c and β-ketothioamides21d,e are not
commercially sourced and were synthesized in good yields
following the reported procedures. All the reactions were carried
out in an oven-dried glassware under open air. Chromatograms
were visualized by fluorescence quenching with UV light at 254
nm. 1H and 13C NMR spectra were recorded on NMR
spectrophotometer operating at 500 and 125 MHz, respectively.
Subsequently, we treated compound
4
with 1,2-
diaminobenzenes 8 in the presence of 10 mol % of L-Proline at
100 oC under solvent-free conditions (for details in the
optimization of conditions, refer to Supporting Information,
Table S1). Differently decorated benzo[e]indole-4,5-diones 4ab,
4ac, 4aj and 4am could be successfully employed. The reaction
proceeded smoothly affording the corresponding 1H-
benzo[a]pyrrolo[3,2-c] phenazines in almost quantitative yields
with a 6-6-6-6-5 pentacyclic core bearing aroyl and thioalkyl
groups as functional handles for further modifications (Scheme 5,
9aba, 9acb, 9aja and 9amb).
Chemical shifts for H and 13C NMR spectra are reported as δ in
1
units of parts per million (ppm) downfield from SiMe4 (δ 0.0).
Coupling constants (J) are given in Hz. Mass spectra were
recorded under ESI/HRMS using ion trap mass analyzer. Melting
points have been determined with Büchi B-540 melting point
apparatus and are uncorrected.

7
4.2. General procedure for the synthesis of compounds 4.
A red solid (201.6 mg, 80% yield), Rf = 0.40 (hexane/ethyl
ACCEPTED MANUSCRIPT
1
acetate = 7:3). Mp: 185-187 °C. H NMR (500 MHz, CDCl3): δ
8.04 (d, J = 7.45 Hz, 1H), 7.75 (d, J = 6.50 Hz, 1H), 7.71 (d, J =
7.65 Hz, 1H), 7.67 (d, J = 7.90 Hz, 1H), 7.52-7.51 (m, 3H), 7.45-
7.37 (m, 3H), 7.31-7.30 (m, 3 H), 1.86 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 193.6, 181.2, 168.5, 140.0, 139.4, 136.5, 135.5,
134.6, 133.3, 132.2, 131.9, 130.71, 129.9, 129.6, 129.2, 128.7,
127.7, 127.6, 126.2, 121.8, 29.7, 19.4; HRMS (EI-TOF): calcd
for C26H17BrNO3S [M+H]+: 502.0107, found: 502.0114.
To the stirred solution of β-naphthol (0.5 mmol) in acetic acid
(3 mL), TEMPO (2.5 equiv) was added at room temperature.
With a stay of 20 minutes, 20 mol % of Cu(OAc)2 was added
followed by addition of N,S-acetal (0.5 mmol). The reaction
mixture was heated at 100 °C till the completion of reaction
(monitored by TLC). The reaction mixture was allowed to cool at
room temperature followed by work up using ethyl acetate. The
organic layer was dried over anhydrous Na2SO4, and solvent was
evaporated under reduced pressure. The crude residue thus
obtained was purified by column chromatography over silica gel
(100-200 mesh) using hexane/ethyl acetate (17:3) as eluent to
afford the pure desired products 4 (Rf = 0.40; hexane/ethyl
acetate = 70/30).
4.2.6. 1-(Furan-2-carbonyl)-2-(methylthio)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4af)
A red solid (180.1 mg, 82% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 196-198 °C. H NMR (500 MHz, CDCl3): δ
1
8.13 (d, J = 8.15 Hz, 1H), 8.03 (d, J = 7.55 Hz, 1H), 7.76 (d, J =
8.30 Hz, 2H), 7.65 (d, J = 7.25 Hz, 2H), 7.55-7.53 (m, 1H), 7.49-
7.46 (m, 1H), 7.42 (d, J = 7.40 Hz, 1H), 7.39-7.37 (m, 1H), 7.33
(d, J = 7.75 Hz, 1H), 7.28-7.26 (m, 1H), 2.03 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 193.7, 181.4, 168.0, 147.2, 139.5, 138.2,
136.5, 136.1, 135.4, 132.0, 130.7, 130.6, 130.0, 129.90, 129.6,
129.2, 129.1, 128.6, 128.5, 127.7, 127.4, 126.6, 125.8, 19.6;
HRMS (EI-TOF): calcd for C24H16NO4S [M+H]+: 414.0795,
found: 414.0829.
4.2.1. 1-Benzoyl-2-(methylthio)-3-phenyl-3H-
benzo[e]indole-4,5-dione (4aa)
A red solid (190.1 mg, 92% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 199-201 °C. H NMR (500 MHz, CDCl3): δ
8.06-8.04 (m, 2H), 8.02 (d, J = 7.65 Hz, 1H), 7.67-7.64 (m, 1H),
7.55-7.52 (m, 5H), 7.37-7.35 (m, 2H), 7.33-7.30 (m, 1H), 7.26-
7.21 (m, 2H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
194.2, 181.3, 168.0, 138.2, 137.4, 136.5, 135.4, 134.5, 131.9,
130.7, 130.0, 129.8, 129.6, 129.3, 129.2, 129.1, 128.4, 127.7,
126.5, 125.8, 19.5; HRMS (EI-TOF): calcd for C26H17NNaO3S
[M+Na]+: 446.0821, found: 446.0833.
4.2.7. 2-(Methylthio)-3-phenyl-1-(thiophene-2-
carbonyl)-3H-benzo[e]indole-4,5-dione (4ag)
A red solid (181.2 mg, 85% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 195-197 °C. H NMR (500 MHz, CDCl3): δ
1
4.2.2. 1-(4-Methylbenzoyl)-2-(methylthio)-3-phenyl-
3H-benzo[e] indole-4,5-dione (4ab)
8.03 (d, J = 7.95 Hz, 1H), 7.82 (d, J = 4.70 Hz, 1H), 7.71 (d, J =
3.70 Hz, 1H), 7.54-7.53 (m, 3H), 7.38-7.34 (m, 4H), 7.29-7.27
(m, 1H), 7.18-7.17 (m, 1H), 2.07 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 185.7, 181.3, 167.9, 146.8, 144.8, 138.5, 136.4, 135.7,
135.4, 131.7, 130.6, 129.8, 129.6, 129.6, 129.1, 129.0, 128.8,
128.4, 127.6, 126.2, 125.7, 19.6; HRMS (EI-TOF): calcd for
C24H16NO3S2 [M+H]+: 430.0566, found: 430.0573.
A red solid (190.3 mg, 86% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 198-200 °C. H NMR (500 MHz, CDCl3): δ
8.02 (d, J = 7.40 Hz, 1H), 7.95 (d, J = 8.15 Hz, 2H), 7.54-7.52
(m, 3H), 7.37-7.36 (m, 2H), 7.33-7.30 (m, 3H), 7.24-7.22 (m,
2H), 2.45 (s, 3H), 2.00 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
193.7, 181.4, 167.9, 145.7, 138.1, 136.5, 135.3, 134.9, 131.9,
130.6, 130.1, 129.9, 129.9, 129.8, 129.5, 129.1, 129.1, 128.3,
127.6, 126.7, 125.7, 21.9, 19.4; HRMS (EI-TOF): calcd for
C27H20NO3S [M+H]+: 438.1158, found: 438.1166.
4.2.8. 2-(Methylthio)-1-nicotinoyl-3-phenyl-3H-
benzo[e]indole-4,5-dione (4ah)
A red solid (160.6 mg, 76% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 105-107 °C. H NMR (500 MHz, CDCl3): δ
1
4.2.3. 1-(2-Methoxybenzoyl)-2-(methylthio)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4ac)
9.19 (s, 1H), 8.86 (d, J = 3.80 Hz, 1H), 8.36 (d, J = 7.70 Hz, 1H),
8.05 (d, J = 7.55 Hz, 1H), 7.55-7.51 (m, 4H), 7.36-7.34 (m, 3H),
7.29 (d, J = 7.50 Hz, 1H), 7.23 (d, J = 7.80 HZ, 1H), 1.99 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 192.9, 181.0, 168.1, 154.5,
151.5, 136.8, 136.3, 135.4, 132.9, 131.6, 130.9, 129.7, 129.3,
128.7, 127.6, 125.6, 124.0, 19.6; HRMS (EI-TOF): calcd for
C25H16N2NaO3S [M+Na]+: 447.0774, found: 447.0774.
A red solid (170.2 mg, 80% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 174-176 °C. H NMR (500 MHz, CDCl3): δ
8.02 (d, J = 7.45 Hz, 1H), 7.88 (d, J = 7.10 Hz, 1H), 7.58-7.55
(m, 1H), 7.52-7.51 (m, 3H), 7.48 (d, J = 7.95 Hz, 1H), 7.38-7.35
(m, 1H), 7.32-7.30 (m, 2H), 7.27-7.24 (m, 1H), 7.09-7.06 (m,
1H), 7.01 (d, J = 8.40 Hz, 1H), 3.80 (s, 3H), 1.93 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 192.9, 181.6, 168.0, 159.7, 137.8,
136.6, 135.2, 135.2, 132.2, 132.2, 130.4, 129.8, 129.7, 129.6,
129.4, 129.0, 128.2, 127.9, 127.7, 125.8, 120.7, 112.2, 56.0, 19.2;
HRMS (EI-TOF): calcd for C27H19NNaO4S [M+Na]+: 476.0927,
found: 476.0933.
4.2.9. 1-(1-Naphthoyl)-2-(methylthio)-3-phenyl-3H-
benzo[e]indole-4,5-dione (4ai)
A red solid (193.1 mg, 80% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 102-104 °C. H NMR (500 MHz, CDCl3): δ
1
9.20 (d, J = 8.60 Hz, 1H), 8.11 (d, J = 8.15 Hz, 1H), 8.04-7.97
(m, 3H), 7.79-7.76 (m, 1H), 7.66-7.64 (m, 1H), 7.53-7.45 (m,
5H), 7.37-7.35 (m, 2H), 7.29-7.26 (m, 1H), 7.25-7.22 (m, 1H),
1.87 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 195.8, 181.4,
168.2, 138.8, 136.5, 135.5, 135.1, 134.7, 134.2, 133.1, 132.0,
131.0, 130.7, 130.1, 129.8, 129.6, 129.4, 129.2, 129.2, 128.8,
128.8, 128.5, 127.7, 127.1, 126.0, 125.8, 124.5, 19.4; HRMS
(EI-TOF): calcd for C30H20NO3S [M+H]+: 474.1158, found:
474.1152.
4.2.4. 1-(2-Chlorobenzoyl)-2-(methylthio)-3-phenyl-
3H-benzo[e] indole-4,5-dione (4ad)
A red solid (191.3 mg, 83% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 201-203 °C. H NMR (500 MHz, CDCl3): δ
8.05 (d, J = 7.60 Hz, 1H), 7.79 (d, J = 7.70 Hz, 1H), 7.63 (d, J =
7.85 Hz, 1H), 7.52-7.50 (m, 5H), 7.46-7.43 (m, 1H), 7.40-7.38
(m, 1H), 7.32-7.30 (m, 3H), 1.87 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 192.9, 181.2, 168.4, 138.1, 135.4, 133.5, 133.3, 131.9,
131.8, 131.2, 130.6, 129.5, 129.1, 128.6, 127.7, 127.0, 126.0,
19.3; HRMS (EI-TOF): calcd for C26H17ClNO3S [M+H]+:
458.0612, found: 458.0613.
4.2.10. 1-([1,1'-Biphenyl] -4-carbonyl)-2-
(methylthio)-3-phenyl-3H-benzo[e]indole-4,5-dione
(4aj)
A red solid (201.9 mg, 80% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 202-204 °C. H NMR (500 MHz, CDCl3): δ
1
4.2.5. 1-(2-Bromobenzoyl)-2-(methylthio)-3-phenyl-
3H-benzo[e] indole-4,5-dione (4ae)
8.13 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 7.35 Hz, 1H), 7.75 (d, J =

8
Tetrahedron
8.4 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.55-7.54 (m, 3H), 7.49-
130.8, 129.8, 129.6, 129.4, 129.1, 128.5, 127.8, 125.6, 38.6, 22.8,
ACCEPTED MANUSCRIPT
7.46 (m, 2H), 7.57 (d, J = 6.9 Hz, 1H), 7.39-7.37 (m, 1H), 7.35-
7.32 (m, 1H), 7.27-7.26 (m, 3H), 2.02 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 193.7, 181.4, 168.0, 147.2, 139.5, 138.2, 136.5,
136.0, 135.4, 131.9, 130.7, 130.6, 130.0, 129.8, 129.6, 129.2,
129.1, 128.6, 128.5, 127.7, 127.4, 126.6, 125.8, 19.6; HRMS
(EI-TOF): calcd for C32H22NO3S [M+H]+: 500.1315, found:
500.1322.
12.8; HRMS (EI-TOF): calcd for C28H20ClNNaO3S [M+Na]+:
508.0745, found: 508.0897.
4.2.16. 1-Benzoyl-2-(butylthio)-3-phenyl-3H-
benzo[e]indole-4,5-dione (4ap)
A red solid (200.5 mg, 87% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 141-143 °C. H NMR (500 MHz, CDCl3): δ
1
8.05-8.02 (m, 3H), 7.67-7.64 (m, 1H), 7.54-7.52 (m, 5H), 7.35-
7.30 (m, 3H), 7.24-7.22 (m, 2H), 2.35 (t, J = 7.30 Hz, 2H), 1.25-
1.18 (m, 2H), 1.08-1.01 (m 2H), 0.69 (t, J = 7.25 HZ, 3H); 13C
NMR (125 MHz, CDCl3): δ 194.1, 181.4, 167.9, 137.4, 137.3,
136.4, 135.3, 134.3, 131.9, 130.6, 129.9, 129.4, 129.0, 129.0,
128.3, 127.8, 127.1, 125.7, 36.2, 31.4, 21.3, 13.3; HRMS (EI-
TOF): calcd for C29H23NNaO3S [M+Na]+: 488.1291, found:
488.1309.
4.2.11. 1-(Cyclopropanecarbonyl)-2-(methylthio)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4ak)
A red solid (160.2 mg, 85% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 195-197 °C. H NMR (500 MHz, CDCl3): δ
8.05 (d, J = 7.60 Hz, 1H), 7.65 (d, J = 7.80 Hz, 1H), 7.53-7.52
(m, 4H), 7.35-7.29 (m, 3H), 2.57-2.52 (m, 1H), 2.17 (s, 3H),
1.47-1.45 (m, 2H), 1.22-1.20 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ 203.3, 181.5, 168.2, 138.4, 136.7, 135.4, 132.2, 130.8,
130.0, 129.6, 129.2, 128.6, 127.7, 125.9, 24.5, 20.0, 13.9; HRMS
(ESI/Q-TOF): calcd for C23H17NNaO3S [M+Na]+: 410.0821,
found: 410.0876.
4.2.17. 2-(Benzylthio)-1-(4-bromobenzoyl)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4aq)
A red solid (250.9 mg, 87% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 206-208 °C. H NMR (500 MHz, CDCl3): δ
4.2.12. 2-(Ethylthio)-1-(3-methylbutanoyl)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4al)
8.03 (d, J = 7.55 Hz, 1H), 7.85 (d, J = 8.50 Hz, 2H), 7.64 (d, J =
8.45 Hz, 2H), 7.50-7.47(m, 1H), 7.42-7.39 (m, 2H), 7.35-7.32
(m, 1H), 7.27 (d, J = 7.60 Hz, 1H), 7.20-7.13 (m, 4H), 6.93 (d, J
= 7.75 Hz, 2H), 6.88 (d, J = 7.10 Hz, 2H), 3.65 (s, 2H); 13C
NMR (125 MHz, CDCl3): δ 193.1, 181.2, 168.0, 136.2, 136.1,
136.0, 135.4, 132.4, 131.8, 131.3, 130.8, 129.9, 129.8, 129.8,
129.4, 129.2, 128.9, 128.9, 128.7, 128.5, 127.8, 127.1, 125.8,
41.48; HRMS (EI-TOF): calcd for C32H20BrNNaO3S [M+Na]+:
600.0239, found: 600.0210.
A red solid (170.6 mg, 80% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 75-77 °C. H NMR (500 MHz, CDCl3): δ
8.05 (d, J = 7.70 Hz, 1H), 7.53-7.48 (m, 5H), 7.34-7.31 (m, 1H),
7.28-7.26 (m, 2H), 2.97 (d, J = 6.65 Hz, 2H), 2.50 (q, J = 7.38
Hz, 2H), 2.42-2.34 (m, 1H), 1.08-1.04 (m, 9H); 13C NMR (125
MHz, CDCl3): δ 203.7, 181.3, 168.0, 136.5, 135.6, 135.3, 132.1,
130.7, 130.2, 129.8, 129.4, 129.0, 128.5, 127.8, 125.3, 54.5, 31.3,
24.4, 22.7, 14.7; HRMS (EI-TOF): calcd for C25H23NNaO3S
[M+Na]+: 440.1291, found: 440.1291.
4.2.18. 1-(4-Chlorobenzoyl)-2-((2-
methylallyl)thio)-3-phenyl-3H-benzo[e] indole-4,5-
dione (4ar)
4.2.13. 2-(Ethylthio)-1-(4-methoxybenzoyl)-3-
phenyl-3H-benzo[e]indole-4,5-dione (4am)
A red solid (200.5 mg, 80% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 159-161 °C. H NMR R (500 MHz, CDCl3):
1
A red solid (202.1 mg, 85% yield), Rf = 0.40 (hexane/ethyl
1
δ 8.03 (d, J = 7.60 Hz, 1H), 7.99 (d, J = 8.50 Hz, 2H), 7.52-7.48
(m, 5H), 7.34-7.31 (m, 3H), 7.27-7.24 (m, 1H), 7.17 (d, J = 7.60
Hz, 1H), 4.63 (d, J = 10.55 Hz, 2H), 2.98 (s, 2H), 1.30 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 192.7, 181.3, 168.1, 141.0,
140.0, 136.4, 136.1, 135.8, 135.4, 131.8, 131.4, 130.7, 129.8,
129.8, 129.5, 129.4, 129.2, 129.0, 128.5, 128.1, 127.3, 125.8,
115.4, 44.4, 20.4; HRMS (EI-TOF): calcd for C29H21ClNO3S
[M+H]+: 498.0925, found: 498.0931.
acetate = 7:3). Mp: 185-187 °C. H NMR (500 MHz, CDCl3): δ
8.02 (d, J = 8.20 Hz, 2H), 7.53-7.51 (m, 3H), 7.35-7.31 (m, 3H),
7.26-7.22 (m, 3H), 6.99 (d, J = 8.70 Hz, 2H), 3.89 (s, 3H), 2.41
(q, J = 7.31 Hz, 2H), 0.96 (t, J = 7.55 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 192.5, 181.5, 167.9, 164.7, 136.8, 136.6, 135.4,
132.5, 132.1, 130.6, 130.5, 129.8, 129.4, 129.2, 129.1, 128.3,
127.8, 127.6, 125.8, 114.3, 55.7, 30.8, 14.8; HRMS (ESI/Q-
TOF): calcd for C28H21NNaO4S [M+Na]+: 490.1083, found:
490.1085.
4.2.19. 3-Methyl-1-(4-methylbenzoyl)-2-
(methylthio)-3H-benzo[e]indole-4,5-dione (4as)
4.2.14. 1-(4-Bromobenzoyl)-2-(ethylthio)-3-phenyl-
3H-benzo[e] indole-4,5-dione (4an)
A red solid (170.2 mg, 87% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 186-188 °C. H NMR (500 MHz, CDCl3): δ
1
A red solid (210.5 mg, 82% yield), Rf = 0.40 (hexane/ethyl
1
8.02 (d, J = 7.55 Hz, 1H), 7.85 (d, J = 8.20 Hz, 2H), 7.28-7.27
(m, 3H), 7.22-7.19 (m, 1H), 7.13 (d, J = 7.90 Hz, 1H), 4.11 (s,
3H), 2.72 (q, J = 7.46 Hz, 2H), 2.42 (s, 3H), 1.16 (t, J = 7.40 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 193.9, 181.6, 169.1, 145.5,
136.4, 135.4, 134.9, 132.2, 130.6, 130.1, 129.7, 129.6, 129.3,
128.8, 128.1, 127.4, 125.7, 34.0, 31.5, 21.9, 15.0; HRMS (EI-
TOF): calcd for C23H19NNaO3S [M+Na]+: 412.0978, found:
412.0991.
acetate = 7:3). Mp: 208-210 °C. H NMR (500 MHz, CDCl3): δ
8.03 (d, J = 7.50 Hz, 1H), 7.90 (d, J = 8.30 Hz, 2H), 7.66 (d, J =
8.40 Hz, 2H), 7.53-7.51 (m, 3H), 7.35-7.32 (m, 3H), 7.27 (d, J =
7.35 Hz, 1H), 7.19 (d, J = 7.80 Hz, 1H), 2.38 (q, J = 7.43 Hz,
2H), 0.95 (t, J = 7.52 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
193.2, 181.2, 168.0, 136.9, 136.4, 136.2, 135.4, 132.5, 131.8,
131.4, 130.8, 129.9, 129.9, 129.8, 129.6, 129.4, 129.1, 128.6,
127.8, 126.8, 125.6, 30.9, 29.7, 14.7; HRMS (ESI/Q-TOF): calcd
for C27H18BrNNaO3S [M+Na]+: 538.0083, found: 538.0083.
4.2.20. 2-(Ethylthio)-1-(3-methoxybenzoyl)-3-
methyl-3H-benzo[e]indole-4,5-dione (4at)
4.2.15. 1-(4-Chlorobenzoyl)-3-phenyl-2-
(propylthio)-3H-benzo[e]indole-4,5-dione (4ao)
A red solid (170.6 mg, 87% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 147-149 °C. H NMR (500 MHz, CDCl3): δ
1
A red solid (217.2 mg, 87% yield), Rf = 0.40 (hexane/ethyl
1
8.03 (d, J = 7.50 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J = 7.50 Hz, 1H),
7.37-7.33 (m, 1H), 7.30-7.27 (m, 1H), 7.24-7.21 (m, 1H), 7.17 (d,
J = 6.50 Hz, 1H), 7.12 (d, J = 7.65 Hz, 1H), 4.12 (s, 3H), 3.87 (s,
3H), 2.73 (q, J = 7.31 Hz, 2H), 1.17 (t, J = 7.40 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 194.1, 181.5, 169.1, 160.1, 138.7,
136.5, 135.4, 132.1, 130.6, 130.0, 129.7, 129.4, 128.8, 128.2,
acetate = 7:3). Mp: 212-214 °C. H NMR (500 MHz, CDCl3): δ
8.03 (d, J = 7.55 Hz, 1H), 7.98 (d, J = 8.45 Hz, 2H), 7.53-7.49
(m, 5H), 7.35-7.32 (m, 3H), 7.27 (d, J = 7.55 Hz, 1H), 7.20 (d, J
= 7.55 Hz, 1H), 2.33 (t, J = 7.17 Hz, 2H), 1.29-1.26 (m, 2H),
0.66 (t, J = 7.20 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 193.0,
181.3, 168.0, 141.1, 137.3, 136.4, 135.8, 135.4, 131.8, 131.3,

9
4.2.26. 1-(4-Methylbenzoyl)-2-(methylthio)-3-
(naphthalen-1-yl)-3H-benzo[e]indole-4,5-dione
(4az)
127.2, 125.7, 123.2, 120.9, 113.3, 55.6, 34.0, 31.5, 15.0; HRMS
(EI-TOF): calcd for C23H19NNaO4S [M+Na]+: 428.0927, found:
428.0928.
ACCEPTED MANUSCRIPT
A red solid (190.2 mg, 78% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 108-110 °C. H NMR (500 MHz, CDCl3): δ
4.2.21. 1-(3-Bromobenzoyl)-2-(ethylthio)-3-methyl-
3H-benzo[e] indole-4,5-dione (4au)
1
8.05 (d, J = 8.25 Hz, 1H), 8.03-8.00 (m, 2H), 7.97 (d, J = 8.10
Hz, 1H), 7.63-7.60 (m, 1H), 7.55-7.47 (m, 4H), 7.36-7.33 (m,
3H), 7.30-7.27 (m, 3H), 2.46 (s, 3H), 1.92 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 193.7, 181.1, 167.5, 145.7, 135.3, 134.9,
134.1, 133.5, 132.6, 131.9, 131.8, 130.6, 130.5, 130.2, 130.1,
130.0, 129.9, 129.8, 129.3, 128.9, 128.6, 128.4, 127.8, 126.7,
126.6, 125.7, 125.7, 125.1, 121.5, 21.92, 20.21; HRMS (EI-
TOF): calcd for C31H21NNaO3S [M+Na]+: 510.1134, found:
510.1146.
A red solid (183.0 mg, 80% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 163-165 °C. H NMR (500 MHz, CDCl3): δ
1
8.13 (s, 1H), 8.05 (d, J = 7.50 Hz, 1H), 7.83 (d, J = 7.65 Hz, 1H),
7.75 (d, J = 7.70 Hz, 1H), 7.37-7.30 (m, 2H), 7.24 (d, J = 7.85
Hz, 1H), 7.11 (d, J = 7.71 Hz, 1H), 4.12 (s, 3H), 2.73 (q, J = 7.05
Hz, 2H), 1.17 (t, J = 7.17 Hz, 3H); 13C NMR (125 MHz, CDCl3):
δ 193.0, 181.3, 169.2, 139.2, 137.1, 136.5, 135.4, 132.4, 131.9,
130.7, 130.5, 129.7, 129.4, 129.0, 128.7, 128.4, 126.3, 125.5,
123.4, 34.1, 31.6, 14.9; HRMS (EI-TOF): calcd for
C22H17BrNO3S [M+H]+: 454.0107, found: 454.0113.
4.2.27. 1-(4-Bromobenzoyl)-2-(ethylthio)-4,5-dioxo-
3-phenyl-4,5-dihydro-3H-benzo[e]indole-8-
carbonitrile (4bn)
4.2.22. 1-Benzoyl-3-methyl-2-(methylthio)-3H-
benzo[e]indole-4,5-dione (4av)
A red solid (220.4 mg, 80% yield), Rf = 0.40 (hexane/ethyl
1
A red solid (160.2 mg, 86% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 279-281 °C. H NMR (500 MHz, CDCl3): δ
1
acetate = 7:3). Mp: 167-169 °C. H NMR (500 MHz, CDCl3): δ
8.08 (d, J = 8.15 Hz, 1H), 7.90 (d, J = 8.45 Hz, 2H), 7.68-7.67
(m, 3H), 7.63 (s, 1H), 7.55-7.53 (m, 3H), 7.35-7.33 (m, 2H), 2.41
(q, J = 7.33 Hz, 2H), 0.96 (t, J = 7.22 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 192.9, 180.7, 167.4, 167.2, 139.2, 138.0, 136.2,
132.6, 132.2, 131.8, 131.3, 131.0, 130.1, 129.7, 129.2, 127.7,
127.3, 126.7, 124.6, 30.9, 14.7; HRMS (EI-TOF): calcd for
C28H17BrN2NaO3S [M+Na]+: 563.0035, found: 563.0035
8.03-7.96 (m, 3H), 7.65-7.62 (m, 1H), 7.51-7.42 (m, 2H), 7.29-
7.20 (m, 2H), 7.12 (d, J = 7.60 Hz, 1H), 4.12 (s, 3H), 2.26 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 194.2, 181.4, 169.1, 137.7,
137.3, 135.3, 134.3, 132.0, 130.5, 129.8, 128.9, 128.1, 126.3,
125.6, 33.8, 19.5; HRMS (EI-TOF): calcd for C21H16NO3S
[M+H]+: 362.0845, found: 362.0854.
4.2.23. 3-Cyclohexyl-1-(4-methylbenzoyl)-2-
(methylthio)-3H-benzo[e]indole-4,5-dione (4aw)
4.2.28. 1-(2-Methoxybenzoyl)-2-(methylthio)-4,5-
dioxo-3-phenyl-4,5-dihydro-3H-benzo[e]indole-8-
carbonitrile (4bc)
A red solid (190.5 mg, 85% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 116-118 °C. H NMR (500 MHz, CDCl3): δ
A red solid (200.9 mg, 85% yield), Rf = 0.40 (hexane/ethyl
1
8.01 (d, J = 7.50 Hz, 1H), 7.86 (d, J = 7.80 Hz, 2H), 7.29-7.28
(m, 3H), 7.21-7.18 (m, 1H), 7.13 (d, J = 7.60 Hz, 1H), 2.64-2.62
(m, 2H), 2.43 (s, 3H), 2.27 (s, 3H), 1.95-1.93 (m, 2H), 1.71 (br,
3H), 1.45-1.42 (m, 3H), 0.89-0.84 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 194.3, 181.5, 166.0, 145.5, 135.3, 130.3, 130.0, 130.0,
129.7, 129.5, 128.0, 125.6, 58.9, 26.2, 21.8; HRMS (EI-TOF):
calcd for C27H26NO3S [M+H]+: 444.1628, found: 444.1637.
acetate = 7:3). Mp: 187-189 °C. H NMR (500 MHz, CDCl3): δ
8.09 (d, J = 7.80 Hz, 1H), 7.79 (dd, J1 = 1.55 Hz, J2 = 7.70 Hz,
1H), 7.77 (s, 1H), 7.61-7.57 (m, 1H), 7.56-7.51 (m, 4H), 7.32-
7.30 (m, 2H), 7.10-7.07 (m, 1H), 7.04 (d, J = 8.40 Hz, 1H), 3.86
(s, 3H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 192.2,
180.7, 166.9, 159.5, 139.5, 136.3, 135.5, 133.2, 131.9, 131.4,
130.5, 129.8, 129.3, 129.3, 128.0, 127.6, 120.9, 118.4, 117.5,
112.2, 56.1, 19.4; HRMS (EI-TOF): calcd for C28H19N2O4S
[M+H]+: 479.1060, found: 479.1060.
4.2.24. 1-(4-Chlorobenzoyl)-2-(ethylthio)-3-(p-
tolyl)-3H-benzo[e]indole-4,5-dione (4ax)
A red solid (210.2 mg, 89% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 223-225 °C. H NMR (500 MHz, CDCl3): δ
4.2.29. 8-Bromo-1-(4-chlorobenzoyl)-3-phenyl-2-
(propylthio)-3H-benzo[e]indole-4,5-dione (4co)
1
8.03 (d, J = 7.60 Hz, 1H), 7.98 (d, J = 8.55 Hz, 2H), 7.49 (d, J =
8.45 Hz, 2H), 7.33-7.31 (m, 3H), 7.27-7.24 (m, 1H), 7.21 (d, J =
8.05 Hz, 2H), 7.18 (d, J = 8.10 Hz, 1H), 2.46 (s, 3H), 2.40 (q, J =
7.50 Hz, 2H), 0.96 (t, J = 7.20 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 193.0, 181.3, 168.0, 141.0, 139.7, 136.9, 135.8, 135.4,
133.8, 131.8, 131.3, 130.7, 129.8, 129.4, 128.5, 127.4, 126.7,
125.6, 30.9, 21.4, 14.7; HRMS (ESI/Q-TOF): calcd for
C28H20ClNNaO3S [M+Na]+: 508.0745, found: 508.0741.
A red solid (221.5 mg, 78% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 261-263 °C. H NMR (500 MHz, CDCl3): δ
1
7.97 (d, J = 8.25 Hz, 2H), 7.87 (d, J = 8.10 Hz, 1H), 7.54-7.51
(m, 5H), 7.41 (d, J = 8.35 Hz, 1H), 7.36-7.33 (m, 3H), 2.34 (t, J =
7.12 Hz, 2H), 1.30-1.25 (m, 2H), 0.67 (t, J = 7.30 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 192.5, 180.4, 167.6, 141.2, 137.9,
136.2, 135.8, 133.3, 131.9, 131.6, 131.2, 131.0, 129.7, 129.5,
129.2, 128.8, 128.4, 127.7, 126.7, 38.6, 22.8, 12.8; HRMS (EI-
TOF): calcd for C28H20BrClNO3S [M+H]+: 564.0030, found:
564.0036
4.2.25. 1-Benzoyl-3-(4-fluorophenyl)-2-
(methylthio)-3H-benzo[e]indole-4,5-dione (4ay)
A red solid (201.7 mg, 89% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 162-164 °C. H NMR (500 MHz, CDCl3): δ
4.2.30. 1-(4-Chlorobenzoyl)-8-((4-
methoxyphenyl)ethynyl)-3-phenyl-2-(propylthio)-
3H-benzo[e] indole-4,5-dione (4eo)
1
8.05-8.02 (m, 3H), 7.68-7.65 (m, 1H), 7.55-7.52 (m, 2H), 7.37-
7.30 (m, 3H), 7.27-7.20 (m, 4H), 2.01 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 194.0, 181.2, 168.1, 162.9 (d, JC-F = 248.65 Hz,
Cipso), 138.3, 137.3, 135.4, 134.6, 132.3, 131.7, 130.7, 130.1,
130.0, 129.8, 129. 6 (d, JC-CCF = 8.96 Hz), 129.3, 129.1, 128.6,
126.7, 125.8, 116.3 (d, JC-CF = 22.97 Hz), 19.5; HRMS (EI-
TOF): calcd for C26H17FNO3S [M+H]+: 442.0908, found:
442.0913.
A red solid (250.0 mg, 80% yield), Rf = 0.40 (hexane/ethyl
1
acetate = 7:3). Mp: 201-203 °C. H NMR (500 MHz, CDCl3): δ
8.00 (d, J = 7.90 Hz, 3H), 7.53-7.50 (m, 5H), 7.40 (d, J = 8.40
Hz, 2H), 7.37-7.34 (m, 3H), 7.28 (s, 1H), 6.89 (d, J = 8.40 Hz,
2H), 3.84 (s, 3H), 2.34 (t , J = 7.12 Hz, 2H), 1.30-1.26 (m, 2H),
0.67 (t, J = 7.20 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 192.7,
180.5, 168.0, 160.4, 141.0, 137.5, 136.4, 136.0, 133.5, 131.8,
131.3, 131.1, 131.1, 130.7, 129.6, 129.4, 129.2, 129.1, 128.4,
128.3, 127.8, 126.7, 114.2, 95.2, 87.4, 55.4, 38.6, 22.8, 12.8;

10
Tetrahedron
HRMS (EI-TOF): calcd for C37H26ClNNaO4S [M+Na]+:
115.8, 21.8; HRMS (EI-TOF): calcd for C26H17NNaO3S
ACCEPTED MANUSCRIPT
638.1163, found: 638.1163.
[M+Na]+: 446.0821, found: 446.0767.
4.2.31. 1-Benzoyl-8-bromo-2-(butylthio)-3-phenyl-
3H-benzo[e] indole-4,5-dione (4cp)
4.3.3. 1-(4-Methoxybenzoyl)-2-
(phenylamino)naphtho[2,1-b]thiophene-4,5-dione
(7ac)
A red solid (201.0 mg, 75% yield), Rf = 0.40 (hexane/ethyl
1
A
brown solid (180.9 mg, 84% yield), Rf = 0.40
acetate = 7:3). Mp: 186-188 °C. H NMR (500 MHz, CDCl3): δ
(hexane/ethyl acetate = 7:3). Mp: 109-111°C. 1H NMR (500
MHz, CDCl3): δ 10.08 (br, 1H), 8.01 (d, J = 7.50 Hz, 1H), 7.28
(s, 1H), 7.46-7.43 (m, 5H), 7.25-7.21 (m, 2H), 7.08 (t, J = 7.52
Hz, 1H), 6.94 (d, J = 7.75 Hz, 1H), 6.80 (d, J = 7.10 Hz, 2H),
3.80 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 191.6, 181.5,
171.3, 165.6, 164.1, 146.5, 138.7, 133.6, 130.1, 130.0, 129.8,
129.4, 126.2, 121.0, 116.1, 114.1, 55.6; HRMS (EI-TOF): calcd
for C26H18NO4S [M+H]+: 440.0951, found: 440.0894.
8.03 (d, J = 7.15 Hz, 2H), 7.85 (d, J = 8.50 Hz, 1H), 7.69-7.66
(m, 1H), 7.55-7.52 (m, 5H), 7.39-7.33 (m, 4H), 2.37 (t, J = 7.50
Hz, 2H), 1.25-1.19 (m, 2H), 1.09-1.02 (m, 2H), 0.70 (t, J = 7.22
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 193.6, 180.5, 167.5,
138.0, 137.3, 136.3, 134.4, 133.3, 131.7, 131.4, 130.9, 129.8,
129.5, 129.1, 128.9, 128.3, 127.7, 127.2, 36.3, 31.3, 21.3, 13.3;
HRMS (EI-TOF): calcd for C29H22BrNNaO3S [M+Na]+:
566.0396, found: 566.0396.
4.3.4. 2-(Phenylamino)-1-(4-
(trifluoromethylbenzoyl)naphtho[2,1-b]thiophene-
4,5-dione (7ad)
4.2.32. Methyl
phenyl-2-(propylthio)-4,5-dihydro-3H-
benzo[e]indole-8-carboxylate (4do)
1-(4-chlorobenzoyl)-4,5-dioxo-3-
A
brown solid (170.4 mg, 72% yield), Rf = 0.40
A red solid (212.6 mg, 76% yield), Rf = 0.40 (hexane/ethyl
acetate = 7:3). Mp: 227-229 °C. H NMR (500 MHz, CDCl3): δ
1
1
(hexane/ethyl acetate = 7:3). Mp: 155-157 °C. H NMR (500
MHz, CDCl3): δ 10.65 (br, 1H), 8.00 (d, J = 7.55 Hz, 1H), 7.87
(d, J = 7.65 Hz, 2H), 7.57 (d, J = 7.90 Hz, 2H), 7.50-7.47 (m,
2H), 7.44-7.43 (m, 2H), 7.31 (t, J = 7.22 Hz, 1H), 7.22 (t, J =
7.50 Hz, 1H), 7.00 (t, J = 7.57 Hz, 1H), 6.57 (d, J = 7.75 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 191.4, 181.1, 171.5, 167.4,
146.7, 142.0, 138.4, 133.2, 130.3, 130.2, 130.1, 129.9, 129.7,
126.9, 121.5, 114.5; HRMS (EI-TOF): calcd for
C26H14F3NNaO3S [M+Na]+: 500.0539, found: 500.0473.
8.08 (d, J = 7.80 Hz, 1H), 8.01 (d, J = 8.45 Hz, 2H), 7.90-7.88
(m, 1H), 7.82 (s, 1H), 7.55-7.53 (m, 3H), 7.50 (d, J = 8.55 Hz,
2H), 7.36-7.34 (m, 2H), 3.82 (s, 3H), 2.39 (t, J = 7.22 Hz, 2H),
1.33-1.29 (m, 2H), 0.68 (t, J = 7.50 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 192.2, 180.9, 167.3, 165.1, 141.0, 138.1, 136.2,
135.7, 135.6, 132.3, 131.8, 131.2, 130.5, 129.6, 129.4, 129.1,
127.7, 126.8, 52.5, 38.6, 22.8, 12.8; HRMS (EI-TOF): calcd for
C30H22ClNNaO5S [M+Na]+: 566.0799, found: 566.0799.
4.3.5. 1-(Furan-2-carbonyl)-2-
(phenylamino)naphtho[2,1-b]thiophene-4,5-dione
(7ae)
4.3. General procedure for the synthesis of compounds 7.
Following the same procedure for the synthesis of 4, β-
ketothioamide 6 (0.5 mmol) was added instead of N,S-acetal. The
reaction mixture was heated at 100 °C till the completion of
reaction (monitored by TLC). The reaction mixture was allowed
to cool at room temperature followed by work up using ethyl
acetate. The organic layer was dried over anhydrous Na2SO4, and
solvent was evaporated under reduced pressure. The crude
residue thus obtained was purified by column chromatography
over silica gel (100-200 mesh) using hexane/ethyl acetate (17:3)
as eluent to afford the pure desired products 7 (Rf = 0.50;
hexane/ethyl acetate = 70/30).
A
brown solid (140.2 mg, 71% yield), Rf = 0.40
1
(hexane/ethyl acetate = 7:3). Mp: 223-225 °C. H NMR (500
MHz, CDCl3): δ 10.25 (br, 1H), 7.99 (d, J = 7.55 Hz, 1H), 7.39
(t, J = 7.57 Hz, 2H), 7.33 (d, J = 7.80 Hz, 2H), 7.26-7.19 (m, 4H)
7.14 (t, J = 7.65 Hz, 1H), 6.95 (d, J = 7.75 Hz, 1H), 6.42 (s, 1H);
13C NMR (125 MHz, CDCl3): δ 181.55, 179.15, 171.49, 166.38,
146.89, 138.62, 134.01, 131.14, 130.17, 129.34, 126.56, 121.27,
113.24; HRMS (EI-TOF): calcd for C23H14NO4S [M+H]+:
400.0638, found: 400.0635.
4.3.6. 2-(Phenylamino)-1-(thiophene-2-
carbonyl)naphtho[2,1-b] thiophene-4,5-dione (7af)
4.3.1. 1-Benzoyl-2-(phenylamino)naphtho[2,1-
b]thiophene-4,5-dione (7aa)
A
brown solid (151.5 mg, 74% yield), Rf = 0.40
1
A
brown solid (161.3 mg, 76% yield), Rf = 0.40
(hexane/ethyl acetate = 7:3). Mp: 135-137 °C. H NMR (500
MHz, CDCl3): δ 9.82 (br, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.58 (d, J
= 4.85 Hz, 1H), 7.39-7.30 (m, 5H), 7.22-7.17 (m, 2H) 7.11 (t, J =
7.57 Hz, 1H), 7.30 (d, J = 7.90 Hz, 1H), 6.84 (t, J = 4.32 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 184.41, 181.40, 171.28,
165.42, 145.99, 144.32, 138.63, 135.78, 135.40, 133.67, 132.21,
131.27, 130.15, 130.12, 129.62, 129.57, 129.34, 128.48, 126.43,
121.31, 121.08, 116.02; HRMS (EI-TOF): calcd for
C23H14NO3S2 [M+H]+: 416.0410, found: 416.0410.
1
(hexane/ethyl acetate = 7:3). Mp: 116-118 °C. H NMR (500
MHz, CDCl3): δ 10.47 (br, 1H), 7.98 (d, J = 7.30 Hz, 1H), 7.76
(d, J = 6.60 Hz, 2H), 7.46-7.41 (m, 5H), 7.33-7.27 (m, 3H), 7.19
(t, J = 7.20 Hz, 1H), 6.99 (t, J = 7.22 Hz, 1H), 6.83 (d, J = 7.55
Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 192.9, 181.3, 171.4,
166.4, 146.9, 133.4, 133.2, 130.1, 129.9, 129.8, 129.3, 128.7,
126.4, 121.2, 120.8, 115.4; HRMS (EI-TOF): calcd for
C25H15NNaO3S [M+Na]+: 432.0665, found: 432.0611.
4.3.2. 1-(4-Methylbenzoyl)-2-
(phenylamino)naphtho[2,1-b]thiophene-4,5-dione
(7ab)
4.4. General procedure for the synthesis of compounds 9.
In an oven dried 25 mL round bottom flask, 0.5 mmol of
compound 4, 0.5 mmol of 1,2-diaminobenzene 8 and 10 mol %
of L-Proline were taken. The reaction mixture was heated at 100
oC under solvent-free conditions till the completion of the
reaction (monitored by TLC). The residue thus obtained was
recrystallized with dichloromethane (DCM) to give the pure
desired product 9.
A
brown solid (171.0 mg, 80% yield), Rf = 0.40
1
(hexane/ethyl acetate = 7:3). Mp: 131-133 °C. H NMR (500
MHz, CDCl3): δ 10.26 (br, 1H), 7.99 (d, J = 7.55 Hz, 1H), 7.68
(d, J = 6.90 Hz, 2H), 7.47-7.39 (m, 4H), 7.27-7.19 (m, 2H), 7.12
(d, J = 7.75 Hz, 2H), 7.05-7.02 (m, 1H), 6.72 (d, J = 7.80 Hz,
1H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 192.7, 181.5,
171.4, 166.0, 146.7, 144.7, 138.7, 136.1, 133.4, 132.0, 131.1,
130.1, 130.0, 129.9, 129.5, 129.4, 126.3, 121.1, 121.0, 120.8,
4.4.1. (2-(Methylthio)-1-phenyl-1H-
benzo[a]pyrrolo[3,2-c]phenazin-3-yl)(p-
tolyl)methanone (9aba)

11
A
yellow solid (241.0 mg, 96% yield), Rf
=
0.40
Supplementary Material
ACCEPTED MANUSCRIPT
1
(hexane/ethyl acetate = 7:3). Mp: 228-230 °C. H NMR (500
MHz, CDCl3): δ 9.36 (d, J = 7.95 Hz, 1H), 8.22 (d, J = 9.80 Hz,
1H), 8.02 (d, J = 7.75 Hz, 2H), 7.83 (d, J = 7.90 Hz, 1H), 7.73-
7.70 (m, 1H), 7.65-746 (m, 9H), 7.29 (d, J = 7.95 Hz, 2H), 2.42
(s, 3H), 2.09 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 195.5,
144.8, 142.3, 140.8, 140.3, 139.5, 136.2, 135.9, 132.4, 130.3,
130.1, 129.5, 129.4, 129.3, 129.3, 129.1, 129.0, 128.9, 128.6,
126.4, 125.7, 125.6, 124.4, 122.6, 21.84, 20.8; HRMS (EI-TOF):
calcd for C34H24N3OS [M+H]+: 510.1635, found: 510.1635.
Supplementary data (1H and 13C NMR spectra of compounds
and X-ray crystallography data for compound 4ak) associated
with this article can be found in the online version, at
http://dx.doi.
References and notes
1. (a) Sundberg, R. J. Indoles, Academic Press, San Diego, London,
1996;
4.4.2. (11-Chloro-2-(methylthio)-1-phenyl-1H-
benzo[a]pyrrolo[3,2-c]phenazin-3-yl)(2-
methoxyphenyl)methanone (9acb)
(b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications, 2nd ed., Wiley-
VCH, Weinheim, 2003;
(c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278;
(d) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73;
(e) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761;
(f) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489;
A
yellow solid (261.3 mg, 92% yield), Rf = 0.40
1
(hexane/ethyl acetate = 7:3). Mp: 204-206 °C. H NMR (500
MHz, CDCl3): δ 9.32 (d, J = 8.35 Hz, 1H), 8.22-8.12 (m, 2H),
7.85 (d, J = 7.50 Hz, 1H), 7.66-7.58 (m, 6H), 7.54-7.50 (m, 1H),
7.45-7.38 (m, 3H), 7.02-7.00 (m, 2H), 3.77 (s, 3H), 2.00 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 194.7, 159.6, 140.9, 140.4,
139.5, 138.7, 134.3, 132.4, 130.6, 130.4, 130.4, 130.3, 130.2,
129.9, 129.2, 129.2, 128.7, 128.6, 128.6, 128.3, 128.0, 127.5,
126.4, 126.2, 125.9, 124.8, 120.4, 112.2, 55.9, 20.4; HRMS (EI-
TOF): calcd for C33H23ClN3O2S [M+H]+: 560.1194, found:
560.1200.
(g) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29.
2. (a) Sundberg, R. J. The Chemistry of Indoles, Academic Press,
New York, 1970;
(b) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R.; Rees, C. W. Eds., Pergamon Press, Oxford, U.K.,
1984, Vol. 4;
(c) Joule, J. A. In Science of Synthesis, Houben-Weyl Methods of
Molecular Transformations, Thomas, E. J. Ed., George Thieme
Verlag, Stuttgart, Germany, 2000, Vol. 10, Chapter 10.13;
(d) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II,
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Bird, C. W. Eds.,
Pergamon Press, Oxford, 1996; Vol. 2, p 207;
4.4.3. [1,1'-Biphenyl] -4-yl(2-(methylthio)-1-phenyl-
1H-benzo[a]pyrrolo[3,2-c]phenazin-3-yl)methanone
(9aja)
(e) Gribble, G. W. In Top. Heterocycl. Chem. "Heterocyclic
Scaffolds II: Reactions and Applications of Indoles" Springer-
Verlag, Berlin, Heidelberg, 2010, Vol. 26.
A
yellow solid (260.1 mg, 90% yield), Rf = 0.40
1
(hexane/ethyl acetate = 7:3). Mp: 241-243 °C. H NMR (500
MHz, CDCl3): δ 9.38 (d, J = 8.90 Hz, 1H), 8.25 (d, J = 8.55 Hz,
1H), 8.19 (d, J = 8.40 Hz, 2H), 7.87 (d, J = 7.50 Hz, 1H), 7.73-
7.72 (m, 3H), 7.68-7.67 (m, 6H), 7.58 (d, J = 8.85 Hz, 1H), 7.54
(d, J = 7.35 Hz, 3H), 7.50-7.45 (m, 3H), 7.41-7.38 (m, 1H), 2.18
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 195.4, 146.4, 142.3,
140.9, 140.4, 139.8, 139.5, 137.1, 136.2, 132.6, 130.7, 130.2,
129.6, 129.4, 129.3, 129.3, 129.1, 128.9, 128.6, 128.3, 127.4,
127.3, 126.4, 125.8, 124.5, 20.9; HRMS ( EI-TOF): calcd for
C38H26N3OS [M+H]+: 572.1791, found: 572.1803.
3. (a) Evans, D.; Bryan, C.; Wahl, G. J. Org. Chem. 1970, 35, 4122;
(b) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A.
Chem. Rev. 1997, 97, 787;
(c) Yang, S.; Denny, W. A. J. Org. Chem. 2002, 67, 8958;
(d) Kumar, R.; Lown, J. W. Org. Biomol. Chem. 2003, 1, 2630;
(e) Boger, D. L.; Desharnais, J.; Capps, K. Angew. Chem., Int. Ed.
2003, 42, 4138;
(f) Tietze, L. F.; Schuster, H. J.; Schmuck, K.; Schuberth, I.;
Alves, F. Bioorg. Med. Chem. 2008, 16, 6312.
4. (a) Lee, H.-J.; Suh, M.-E.; Lee, C.-O. Bioorg. Med. Chem. 2003,
11, 1511;
(b) Lee, E.-J.; Lee, H.-J.; Park, H.-J.; Min, H.-Y.; Suh, M.-E.;
Chung, H.-J.; Lee, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 5175;
(c) Park, H. J.; Lee, H.-J.; Min, H.-Y.; Chung, H.-J.; Suh, M. E.;
Park-Choo, H.-Y.; Kim, C.; Kim, H. J.; Seo, E.-K.; Lee, S. K. Eur.
J. Pharmacol. 2005, 527, 31;
(d) Ryu, C.-K.; Lee, J. Y.; Jeong, S. H.; Nho, J.-H. Bioorg. Med.
Chem. Lett. 2009, 19, 146;
(e) Efdi, M.; Fujita, S.; Inuzuka, T.; Koketsu, M. Nat. Prod. Res.
2010, 24, 657;
(f) Bauer, J. D.; King, R. W.; Brady, S. F. J. Nat. Prod. 2010, 73,
976;
(g) Moharam, B. A.; Jantan, I.; Jalil, J.; Ahmad, F. Phytother. Res.
2012, 26, 687.
4.4.4. (11-Chloro-2-(ethylthio)-1-phenyl-1H-
benzo[a]pyrrolo[3,2-c]phenazin-3-yl)(4-
methoxyphenyl)methanone (9amb)
A
yellow solid (270.1 mg, 94% yield), Rf = 0.40
1
(hexane/ethyl acetate = 7:3). Mp: 229-231 °C. H NMR (500
MHz, CDCl3): δ 9.31 (d, J = 7.50 Hz, 1H), 8.23-8.15 (m, 1H),
8.02 (d, J = 8.40 Hz, 2H), 7.85 (d, J = 7.85 Hz, 1H), 7.65-7.52
(m, 6H), 7.48 (d, J = 7.45 Hz, 2H), 7.44-7.38 (m, 1H), 6.96 (d, J
= 8.50 Hz, 2H), 3.87 (s, 3H), 2.51 (q, J = 7.31 Hz, 2H), 1.00 (t, J
= 7.47, 3H); 13C NMR (125 MHz, CDCl3): δ 194.2, 164.2, 161.6,
142.4, 140.9, 139.43, 138.7, 136.7, 135.1, 134.6, 132.5, 131.5,
130.6, 130.4, 130.2, 130.0, 129.4, 129.3, 128.7, 128.6, 128.0,
127.5, 126.5, 126.4, 125.9, 124.6, 114.0, 55.5, 31.4, 14.6; HRMS
(EI-TOF): calcd for C34H25ClN3O2S [M+H]+: 574.1351, found:
574.1358.
5. (a) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761;
(b) Shiri, M. Chem. Rev. 2012, 112, 3508;
(c) Martins, G. M.; Zeni, G.; Back, D. F.; Kaufman, T. S.;
Silveira, C. C. Adv. Synth. Catal. 2015, 357, 3255.
6. (a) Pears, D. A.; Pitts, M. R.; Treacher, K. E. e-EROS
Encyclopedia of Reagents for Organic Synthesis, 2008;
(b) Farney, E. P.; Yoon, T. P. Angew. Chem., Int. Ed. 2014, 53,
793;
Acknowledgments
(c) Zhang, F.; Li, C.; Wang, C.; Qi, C. Org. Biomol. Chem. 2015,
13, 5022.
7. (a) Germeraad, P.; Moore, H. W. J. Org. Chem. 1974, 39, 774;
(b) Mithani, S.; Weeratunga, G.; Taylor, N. J.; Dmitrienko, G. I. J.
Am. Chem. Soc. 1994, 116, 2209;
We acknowledge the financial support from the Science and
Engineering
Research
Board
(Grant
No.
SERB/EMR/2015/002482), New Delhi and the Council of
Scientific and Industrial Research (Grant No. 02(0263)/16/EMR-
II), New Delhi, India. The authors (D.Y., G.S., M.A.A., and
A.S.) are thankful to UGC and CSIR, New Delhi for research
fellowships.
(c) Jiang, M.-C.; Chuang, C.-P. J. Org. Chem. 2000, 65, 5409;
(d) Tseng, C.-M.; Wu, Y.-L.; Chuang, C.-P. Tetrahedron 2004,
60, 12249;
(e) Suryavanshi, P. A.; Sridharan, V.; Menéndez, J. C. Org.
Biomol. Chem. 2010, 8, 3426;
(f) Inman, M.; Moody, C. J. J. Org. Chem. 2010, 75, 6023;

12
Tetrahedron
ACCEPTED MANUSCRIPT
(g) Sun, J.-W.; Wang, X.-S.; Liu, Y. J. Org. Chem. 2013, 78,
10560.
16. (a) Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am.
Chem. Soc. 1971, 93, 4332;
8. Yuan, J.; Wu, X.-Y.; Sha, F. Eur. J. Org. Chem. 2016, 2929.
9. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423;
(b) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J.
Am. Chem. Soc. 1982, 104, 5555;
(c) Nicolaou, K. C.; Petasis N. A.; Zipkin, R. E. J. Am. Chem. Soc.
1982, 104, 5560;
(b) Verma, R. K.; Ila, H.; Singh, M. S. Tetrahedron 2010, 66,
7389;
(d) Piettre, S.; Heathcock, C. H. Science 1990, 248, 1532.
17. (a) Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H.
Org. Lett. 2005, 7, 2169;
(c) Verma, G. K.; Verma, R. K.; Shukla, G.; Nagaraju, A.;
Srivastava, A.; Singh, M. S Tetrahedron 2013, 69, 6612;
(d) Pan, L.; Bi, X. H.; Liu, Q. Chem. Soc. Rev. 2013, 42, 1251;
(e) Wang, L. D.; He, W.; Yu, Z. K. Chem. Soc. Rev. 2013, 42,
599;
(b) Zhao, Y.; Zhang, W.; Wang, S.; Liu, Q. J. Org. Chem. 2007,
72, 4985;
(c) Kumar, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2009, 74, 7046;
(d) Xu, C.; Liu, J.; Ming, W.; Liu, Y.; Liu, J.; Wang, M.; Liu, Q.
Chem. Eur. J. 2013, 19, 9104;
(f) Yang, X.; Wu, K.; Wu, P.; Chen, J.; Sun, C.; Yu, Z. Chem.
Eur. J. 2015, 21, 9323;
(g) Guo, T.; Jiang, Q.; Yu, Z. Adv. Synth. Catal. 2016, 358, 3450;
(h) Wang, L.; Liu, X.; Wang, M.; Liu, J. Org. Lett. 2016, 18,
2162;
(i) Yuan, H.; Zheng, Y.; Zhang, J. J. Org. Chem. 2016, 81, 1989;
(j) Zhang, L.; Dong, J.-H.; Xu, X.-X.; Liu, Q. Chem. Rev. 2016,
116, 287;
(e) Guo, W.-S.; Wen, L.-R.; Li, M. Org. Biomol. Chem. 2015, 13,
1942;
(f) Janni, M.; Arora, S.; Peruncheralathan, S. Org. Biomol. Chem.
2016, 14, 8781.
18. (a) Huang, F.; Wu, P.; Wang, L.; Chen, J.; Sun, C.; Yu, Z. Chem.
Commun. 2014, 50, 12479;
(k) Wang, Q.; Lou, J.; Wu, P.; Wu, K.; Zhengkun Yu, Z. Adv.
Synth. Catal. 2017, 359, 2981.
(b) Huang, F.; Wu, P.; Wang, L.; Chen, J.; Sun, C.; Yu, Z. J. Org.
Chem. 2014, 79, 10553;
10. (a) Bai, Y.-X.; Ping, D.-W.; Little, R. D.; Tian, H.-Y.; Hua, L.-M.;
Zeng, C.-C. Tetrahedron 2011, 67, 9334;
(c) Nandi, G. C.; Soumini, K. J. Org. Chem. 2016, 81, 11909;
(d) Sharma, N.; Chundawat, T. S.; Mohapatra, S. C.; Bhagat, S.
Synthesis 2016, 48, 4495;
(e) Kumari, P.; Sharma, N.; Kumar, A.; Mohapatra, S. C.; Bhagat,
S. Synlett 2017, 28, 2008;
(b) Singh, O. M.; Devi, L. R.; Singh, T. P.; Ila, H. Arkivoc 2011,
ii, 297;
(c) Basu, S.; Gupta, V.; Nickel, J.; Schneider, C. Org. Lett. 2014,
16, 274.
(f) Huang, F.; Liu, Z.; Wang, Q.; Lou, J.; Yu, Z. Org. Lett. 2017,
19, 3660.
11. (a) Ila, H.; Junjappa, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry: A Critical Review of the 2000 Literature
Preceded by Two Chapters on Current Heterocyclic Topics,
Gribble, G. W.; Thomas, L. G. Eds., Pergamon Press, Oxford,
2001, Vol. 13, Chapter 1;
19. (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron
2009, 65, 7129;
(b) Kumar, R.; Nandi, G. C.; Verma, R. K.; Singh, M. S.
Tetrahedron Lett. 2010, 51, 442;
(b) Mathew, P.; Asokan, C. V. Tetrahedron Lett. 2005, 46, 475;
(c) Ila, H.; Junjappa, H. Chimia 2013, 67, 17;
(c) Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron 2012, 68,
1247;
(d) Yugandar, S.; Konda, S.; Parameshwarappa, G.; Ila, H. J. Org.
Chem. 2016, 81, 5606;
(d) Singh, M. S.; Nagaraju, A.; Anand, N.; Chowdhury, S. RSC
Adv. 2014, 4, 55924;
(e) Jadhav, A. M.; Krishnammagari, S. K.; Kim, J. T.; Jeong, Y. T.
Tetrahedron 2017, 73, 5163;
(f) Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H. Synthesis 1980,
748.
(e) Narute, S.; Pappo, D. Org. Lett. 2017, 19, 2917;
(f) Shao, L.; Wang, Y.-H.; Zhang, D.-Y.; Xu, J.; Hu, X.-P. Angew.
Chem., Int. Ed. 2016, 55, 5014.
20. Wen, L.-R.; Man, N.-N.; Yuan, W.-K.; Li, M. Org. Chem. 2016,
81, 5942.
21. (a) Singh, M. S.; Nandi, G. C.; Samai, S. Green Chem. 2012, 14,
447;
12. (a) Meijere, A. D.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd Edn., Wiley-VCH: Weinheim, Germany, 2008;
(b) Meijere, A. D.; Bräse, S.; Oestreich, M. Metal-Catalyzed
Cross-Coupling Reactions and More, Wiley-VCH: Weinheim,
Germany, 2013;
(c) Zhao, K.; Shen, L.; Shen, Z.-L.; Loh, T.-P. Chem. Soc. Rev.
2017, 46, 586.
13. (a) Lei, A.; Shi, W.; Liu, C.; Liu, W.; Zhang, H.; He, C. Oxidative
Cross-Coupling Reactions, Wiley-VCH: Weinheim, Germany,
2016, pp. 229;
(b) Verma, G. K.; Shukla, G.; Nagaraju, A.; Srivastava, A.;
Raghuvanshi, K.; Singh, M. S. RSC Adv. 2014, 4, 11640;
(c) Srivastava, A.; Shukla, G.; Nagaraju, A.; Verma, G. K.;
Raghuvanshi, K.; Jones, R. C. F.; Singh, M. S. Org. Biomol.
Chem. 2014, 12, 5484;
(d) Nagl, M.; Panuschka, C.; Barta, A.; Schmid, W. S. Synthesis
2008, 4012;
(b) Zhu, Z.-Q.; Bai, P.; Huang, Z.-Z. Org. Lett. 2014, 16, 4881;
(c) Lei, S.; Mai, Y.; Yan, C.; Mao, J.; Cao, H. Org. Lett. 2016, 18,
3582;
(d) Wang, F.-F.; Luo, C.-P.; Deng, G.; Yang, L. Green Chem.
2014, 16, 2428;
(e) Ge, L.-S.; Wang, Z.-L.; An, X.-L.; Luo, X.; Deng, W.-P. Org.
Biomol. Chem. 2014, 12, 8473.
22. (a) Dornan, L. M.; Cao, Q.; Flanagan, J. C. A.; Crawford, J. J.;
Cook, M. J.; Muldoon, M. J. Chem. Commun. 2013, 49, 6030;
(b) Tao, C.; Liu, F.; Zhu, Y.; Liu, W.; Cao, Z. Org. Biomol. Chem.
2013, 11, 3349;
(e) Jiang, B.; Ning, Y.; Fan, W.; Tu, S.-J.; Li, G. J. Org. Chem.
2014, 79, 4018;
(c) Kim, J.; Stahl, S. S. ACS Catal. 2013, 3, 1652;
(d) Yin, W.; Wang, C.; Huang, Y. Org. Lett. 2013, 15, 1850;
(e) Hu, W.; Lin, J.-P.; Song, L.-R.; Long, Y.-Q. Org. Lett. 2015,
17, 1268;
(f) Noh, J.-H.; Kim, J. J. Org. Chem. 2015, 80, 11624;
(g) Zhao, X.; Liu, T.-X.; Ma, N.; Zhang, G. J. Org. Chem. 2017,
82, 6125.
(f) Wang, N.-N.; Hao, W.-J.; Zhang, T.-S.; Li, G.; Wu, Y.-N.; Tu,
S.-J.; Jiang, B. Chem. Commun. 2016, 52, 5144;
(g) Qiu, J.-K.; Hao, W.-J.; Wang, D.-C.; Wei, P.; Sun, J.; Jiang,
B.; Tu, S.-J. Chem. Commun. 2014, 50, 14782;
(h) Sun, J.; Qiu, J.-K.; Wu, Y.-N.; Hao, W.-J.; Guo, C.; Li, G.; Tu,
S.-J.; Jiang, B. Org. Lett. 2017, 19, 754.
14. (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2011, 50, 11062;
23. Guo, X. X.; Gu, W.; Wu, D. Z. X.; Zhang, W. B. Chem. Rev.
2015, 115, 1622.
(b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464;
(c) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R. P.;
Kozlowski, M. C. Chem. Rev. 2013, 113, 6234;
(d) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res. 2014, 47, 3459;
(e) McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756;
(f) Dai, C.; Deng, S.; Zhu, Q.; Tang, X. RSC Adv. 2017, 7, 44132.
15. (a) L. F. Tietze, G. Brasche K. M. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH: Weinheim, Germany, 2006;
(b) H. Pellissier, Chem. Rev. 2013, 113, 442-524;
(c) Tietze, L. F. Domino Reactions: Concepts for Efficient
Organic Synthesis, Wiley-VCH: Weinheim, Germany, 2014;
(d) Hayashi, Y. Chem. Sci. 2016, 7, 866.
24. Shukla, G.; Srivastava, A.; Yadav, D.; Singh, M. S. J. Org. Chem.
2018, 83, 2173.
25. (a) Rao, M. M.; Kingston, D. G. I. J. Nat. Prod. 1982, 45, 600;
(b) Wu, C. M.; Randall, K. J.; Michael, R. M.; Jackson, C. W.;
Kingston, D. G. I. J. Nat. Prod. 1999, 62, 963;
(c) Kenneth, O. E.; Ponminor, S. K.; Victor, K.; Gabriel, N. F.;
Ephriam, A. N.; Sundarababu, B. Bioorg. Med. Chem. Lett. 2008,
18, 5387;
(d) Kevin, W. W. RSC Adv. 2015, 5, 20309.
26. (a) Cheng, C.; Jiang, B.; Tu, S.-J.; Li, G. Green Chem. 2011, 13,
2107;
(b) Jiang, B.; Zhang, G.; Ma, N.; Shi, F.; Tu, S.-J.; Kaur, P.; Li, G.
Org. Biomol. Chem. 2011, 9, 3834;

13
(c) Wang, S.-L.; Zhang, G.; Jie, D.; Jiang, B.; Wang, X.-H.; Tu,
ACCEPTED MANUSCRIPT
S.-J. Comb. Chem. High Throughput Screening 2012, 15, 400.
27. (a) Gamage, S.; Spicer, J.; Rewcastle, G.; Milton, J.; Sohal, S.;
Dangerfield, W.; Mistry, P.; Vicker, N.; Charlton, P.; Denny, W.
J. Med. Chem. 2002, 45, 740;
(b) Gao, X.; Lua, Y.; Xing, Y.; Ma, Y.; Lu, J.; Bao, W.; Wang, Y.;
Xi, T. Microbiol. Res. 2012, 167, 616;
(c) Pierson, L. S.; Pierson, E. A. Appl. Microbiol. Biotechnol.
2010, 86, 1659;
(d) Borrero, N. V.; Bai, F.; Perez, C.; Duong, B. Q.; Rocca, J. R.;
Jin, S.; Huigens, R. W. Org. Biomol. Chem. 2014, 12, 881.