Ultrasound assisted one-pot synthesis of benzo-fused indole-4,9-dinones from 1,4-naphthoquinone and α-aminoacetals

Article abstract of DOI:10.1016/j.tetlet.2016.04.031

A one-pot synthesis of benzo[f]indole-4,9-diones from 1,4-naphthoquinone with α-aminoacetals has been developed. This method provides a straightforward synthesis of benzo[f]indole-4,9-diones via intramolecular nucleophilic attack of aminoquinones to aldehydes under mild reaction conditions. The detailed mechanism was also investigated.

Full text of DOI:10.1016/j.tetlet.2016.04.031

Tetrahedron Letters 57 (2016) 2253–2256
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ultrasound assisted one-pot synthesis of benzo-fused indole-4,
9-dinones from 1,4-naphthoquinone and a-aminoacetals
Quang H. Luu a, Jorge D. Guerra a, Cecilio M. Castañeda a, Manuel A. Martinez a, Jong Saunders a,
Benjamin A. Garcia b, Brenda V. Gonzales b, Anushritha R. Aidunuthula b, Shizue Mito a,b,
⇑
a Department of Chemistry, The University of Texas at El Paso, El Paso, TX 79968, USA
b Department of Chemistry, The University of Texas Rio Grande Valley, Edinburg, TX 78539, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of benzo[f]indole-4,9-diones from 1,4-naphthoquinone with
a-aminoacetals has
Received 24 March 2016
Revised 9 April 2016
Accepted 11 April 2016
Available online 16 April 2016
been developed. This method provides a straightforward synthesis of benzo[f]indole-4,9-diones via
intramolecular nucleophilic attack of aminoquinones to aldehydes under mild reaction conditions. The
detailed mechanism was also investigated.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
p-Indolequinone
Cyclization
One-pot reaction
Ultrasound-assisted
Heterocycles
Introduction
resulted in low yields.35,17 In addition, it was reported that the syn-
thesis was irreproducible.36 Thus, a general method was sought to
p-Indolequinones are important heterocycles since they display
interesting bioactivities such as anticancer activitiy1–8 as well as the
ability to trigger drug release.9–13 Additionally, they are useful pre-
cursors for the syntheses of bioactive compounds.14–18 Therefore,
over decades, many methodologies have been investigated for the
synthesis of p-indolequinones.19 First, oxidation of indoles has been
developed and used as a conventional method. However, the reac-
tions can be problematic due to the less functional group tolerance.
Thus, as alternate methodologies, the syntheses of p-indole-
quinones from p-quinones have been developed since the 1970s.
In these quinone approaches, transition metals were mostly used
to cyclize aminoquinones.20–25 More recently, one-pot syntheses
via Sonogashira coupling have been reported.26–28 p-Quinones also
successfully underwent reactions with enamines, in which amino-
quinones were proposed to act as electrophiles.29–32 In contrast to
these works, there are three examples in which it seems that
aminoquinones worked as nucleophiles. Although the mechanism
was not mentioned, aminoquinones intramolecularly attack alco-
hol,17 carboxylic,33,34 or carbonyl carbons.35 These reactions
required multi-step procedures,17 proceeded with only one specific
substrate along with laborious syntheses of starting materials,35 or
develop a synthesis of p-indolequinones utilizing the nucleophilic-
ity of aminoquinones. Herein, we report a new synthetic method of
benzo[f]indole-4,9-diones from 1,4-naphthoquinone
1 and a-
aminoacetals 2 in one-pot with a detailed mechanism (Eq. 1).
CeCl3·7H2
(5 mol%)
CH3CN
O
O
O
O
O
R
N
OCH3
OCH3
R
OCH3
OCH3
N
H2SO4 aq
H
N
+
R
ultrasound
rt, 24 h
CH3CN
70 oC, 24 h
O
O
1 (1 equiv.)
2 (10 equiv.)
3
4
ð1Þ
Our initial investigation was carried out in a two-step manner.
The first step is the amination of 1,4-naphthoquinone 1, catalyzed
by CeCl3ꢀ7H2O.37 Using 1.5 equiv of a primary amine 2a (R = H) in
acetonitrile as a solvent, aminoquinone 3a was obtained quantita-
tively (Eq. 2).
O
O
R
N
OCH3
R
OCH3
OCH3
CeCl3·7H2O (5 mol%)
OCH3
HN
+
CH3CN
rt, 24 h
O
O
1
2a: R = H (1.5 equiv)
2b:R = Bn (1.5 equiv)
3a: R = H (quant.)
3b: R = Bn
⇑
ð2Þ
Corresponding author. Tel.: +1 956 665 8740.
E-mail address: shizue.mito@utrgv.edu (S. Mito).
http://dx.doi.org/10.1016/j.tetlet.2016.04.031
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2254
Q. H. Luu et al. / Tetrahedron Letters 57 (2016) 2253–2256
Table 2
On the other hand, in the case of a secondary amine 2b (R = Bn),
The formation of 4d in various solvents
the reaction did not complete, and 58% of 1 was recovered. 100%
conversion of naphthoquinone was accomplished when the reac-
tion was carried out in dry acetonitrile using 10 equiv of amine
2b with the use of ultrasound. The formation of aminoquinone
3b was confirmed by crude 1H NMR. However, the product 3b
could not be isolated by column chromatography on silica gel or
alumina since an N-debenzylation happened as reported.38 The
synthesis of indolequinones was further investigated in one-pot
synthesis, as shown in Eq. 1. Ten equivalents of 2b were added
to a 1 mL of 1 M solution of 1 in dry acetonitrile in the presence
of 5 mol % of CeCl3ꢀ7H2O at room temperature, and the mixture
was placed in a sonicator for 24 h. The resulted solution was then
diluted with additional 1 mL of acetonitrile and treated with 1 mL
of 1 M H2SO4 aq and was kept at 70 °C for 24 h. The corresponding
benzo-fused p-indolequinone 4b was obtained in 77% yield (Eq. 3).
Solvent
Yield of 4d (%)
CH3CN
THF
EtOH
81
50
47
—
CH3NO2
Table 3
Reaction concentration and acid scope
Entry Addition of CH3CN
Acid
Yield
(%)
(x mL)
1
2
3
4
5
6
7
0a
0
1
2
3
1
1
H2SO4 Trace
H2SO4 38
H2SO4 88
H2SO4 66
H2SO4 66
CeCl3·7H2
O
O
O
O
Bn
N
OCH3
OCH3
Bn
(5 mol%)
Bn
HN
OCH3
OCH3
1 M H2SO4 aq
(1 mL)
N
CH3CN (1 mL)
TsOH
HCl
63
16
+
ultrasound
rt, 24 h
CH3CN (1 mL)
70 oC, 24 h
O
O
O
a
Reaction was run under neat conditions. No solvent
3b
4b (77%)
1 (0.1 mmol)
2b (1.0 mmol)
was used in both steps.
ð3Þ
We examined the amount of amines under the same condition in
Eq. 3, and it was determined that 10 equiv of the amines are
required to achieve a good yield of indolequinone (Eq. 4, Table 1).
equivalents of acids were used to assure the excess amount of
amine was neutralized and was found not to hinder the cyclization.
Sulfuric acid showed the better activity than TsOH or HCl (entries
2, 6, 7).
1. CeCl3·7H2O (5 mol%)
OMe
MeO
dry CH3CN (1 mL)
ultrasound
O
O
1. CeCl3·7H2O (5 mol%)
Cl
N
Cl
rt, 24 h
dry solvent (1 mL)
ultrasound
O
O
OCH3
OCH3
+
HN
N
rt, 24 h
2. 1 M H2SO4 aq (1 mL)
CH3CN (1 mL)
OCH3
OCH3
+
O
O
HN
70 oC, 24 h
2. 1 M H2SO4 aq (1 mL)
solvent (1 mL)
1
2c
4c
O
O
70 oC, 24 h
1
2d (10 equiv.)
4d
ð4Þ
ð5Þ
For an effective one-pot reaction, the amination step and deprotec-
tion–cyclization steps should work in the same solvent system.
Since the deprotection of acetals requires water for the formation
of aldehydes, water-miscible solvents were examined, which
included acetonitrile, ethanol, THF, and nitromethane (Eq. 5,
Table 2). The reaction in acetonitrile gave the highest yield, whereas
THF and ethanol both resulted in a low yield of 4d. We believe that
the low yield in ethanol is due to the effect of the solvent on the
equilibrium forming the aldehyde. In addition, the higher yield in
acetonitrile compared to THF can be attributed to the miscibility
with water. Furthermore, nitromethane was found to suppress the
reaction process because of its amine sensitizing activity.39
The solvent miscibility with water has effects on the reaction,
and the addition of more acetonitrile in the cyclization step was
then investigated (Eq. 6, Table 3, entries 1–5). The addition of
1 mL of CH3CN in the second step, which resulted in a total amount
of 2 mL of CH3CN, gave the highest yield (entry 3). Without the
addition of CH3CN, a significant drop in the yield was observed
(entry 2). When the reaction was run under neat conditions, only
trace amounts of the product formed (entry 1). The dilution of
the reaction mixture with more than 1 mL of CH3CN resulted in
lower yields (entries 4, 5). In the cyclization step, acid is essential
for the formation of an aldehyde as an electrophile. Therefore, the
aqueous solutions of different acids were also examined. Ten
MeO
1. CeCl3·7H2O (5 mol%)
dry CH3CN (1 mL)
ultrasound
OMe
O
O
O
N
rt, 24 h
OCH3
HN
+
OCH3
2. 1 M Acid aq (1 mL)
CH3CN (x mL)
70 oC, 24 h
O
1
2e (10 equiv.)
4e
ð6Þ
Table 4
Synthesis of benzo[f]indole-4,9-diones 4 from 1,4-naphthoquinone 1 and
a
-aminoac-
etals 2a
Entry
Amines
R
Products
Yield (%)b
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
C6H5CH2
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
77
87
81 (61)
88
80 (49)
80
83
45
70
74 (67)
82
4-CH3OC6H4CH2
4-ClC6H4CH2
3-CH3OC6H4CH2
4-CH3C6H4CH2
2-CH3C6H4CH2
2-HOC6H4CH2
C6H5CBCCH2
1-Naph-CH2
4-BrC6H4CH2
4-FC6H4CH2
(CH3)2CH
9
10
11
12
13
14
15
16
–
CH2@CHCH2
4-CH3OC6H5
4-CH3C6H5
25c
—
Table 1
—
–
Screening of amine equivalents
C6H5
a
Equivalents of amine 2c
Yield of 4c (%)
All reactions were carried out with 1 (0.1 mmol), 2 (1 mmol), and CeCl3ꢀ7H2O
(5 mol %) in CH3CN (1 mL), then CH3CN (1 mL) and 1 M H2SO4 aq (1 mL) were
added.
2
5
10
19
43
87
b
Yields without ultrasound in the amination step are given in parentheses.
42% of 1 was recovered.
c

Q. H. Luu et al. / Tetrahedron Letters 57 (2016) 2253–2256
2255
More examples of benzo[f]indole-4,9-diones prepared using
this optimized one-pot process are summarized in Table 4 (Eq.
7). Amines 2 were synthesized by reductive amination or substitu-
tion reaction of 2-chloroacetaldehyde dimethyl acetal. The pres-
ence of electron donating groups on the benzene ring resulted in
better yields of the products 4 compared to other groups (entries
2, 4–7). Furthermore, halogen substituents had a positive effect
the reaction yields (entries 3, 10, 11). In this one-pot condition,
the use of ultrasound in the amination step was necessary to give
higher yields (entries 3, 5, 10). The amine with an allyl substituent
was found to be unstable under heating conditions. Consequently,
the indolequinone 4n was afforded in a low yield (entry 13). In the
case of an alkyl amine, the amination step did not proceed well,
and no cyclization product formed (entry 12). When aromatic ami-
nes were used, the amination was completed, but the cyclization
step did not occur even in the presence of an electron-donating
group on the benzene ring (entries 15–17). It is suggested that
the nitrogen atom was deactivated due to the conjugation of the
aromatic system.
addition of aqueous acid. The result indicates that the aldehyde 5 is
the intermediate, and AcOH provided the proton that is required in
the deprotection process.
1. CeCl3·7H2O
OH
(5 mol%)
dry CH3CN
(1 mL)
OH
O
O
O
O
OH
N
N
rt, 24 h
O
+
HN
OH
2. DMP (4 equiv.)
CH3CN (1 mL)
O
O
1
(1.5 equiv.)
5
6 (49%)
ð9Þ
1. CeCl3·7H2O
OMe
OMe
(5 mol%)
O
O
O
O
O
O
dry CH3CN (1 mL)
ultrasound, rt, 24 h
N
N
+
+
2e
2. 1 M H2SO4 aq (1 mL)
CH3CN (1 mL)
O
70 °C, 5 h
1
4e
ð10Þ
1. CeCl3·7H2O (5 mol%)
Furthermore, the reaction was stopped after 5 hours of addition of
1 M H2SO4 aq, and the reaction mixture was extracted using ice-
cold deuterated chloroform (Eq. 10). 1H NMR spectrum of the mix-
ture showed a characteristic aldehyde signal at 9.97 ppm indicating
the aldehyde was the intermediate.
dry CH3CN (1 mL)
ultrasound
O
O
R
N
rt, 24 h
R
OCH3
OCH3
+
HN
2. 1 M H2SO4 aq (1 mL)
CH3CN (1 mL)
70 °C, 24 h
O
O
1
2b–q (10 equiv.)
4b–q
ð7Þ
When the primary amine 2a was used, product 4a was not
obtained under the optimized conditions. The result can be attrib-
uted to an acid–base reaction between the aminoquinone 3a and
sulfuric acid, which resulted in a salt. The salt made the substrate
less reactive and led to the failure of the reaction. As a solution,
when the cyclization step was performed under reflux conditions
in dichloroethane in the presence of triethylamine and trifluo-
roacetic anhydride,40 product 4a was obtained in 35% yield without
isolation of 3a (Eq. 8).
ð11Þ
In addition, the effect of alcohol group for the cyclization was
investigated (Eq. 11). After protonation, intermediate 9 will be
formed, and the cyclization may occur. When the diethanolamine
and N-benzylethahanolamine were used, product
8 was not
TEA
obtained using either sulfuric acid or TFA. There is one report of
the use of b-hydroxylamine as a benzylalcohol in their course of
the total synthesis.17 In this case, the cyclization happens with
TFA. Our results can be clarified that the oxonium ion does not
a-carbon electrophilic enough for the cyclization. This
result supports that our acetal strategy is a good solution for that
(1.5 equiv.)
CeCl3·7H2O
O
O
OCH3
OCH3
(CF3CO)2O
(1.2 quiv.)
DCE
O
(5 mol%)
CH3CN
H
N
OCH3
OCH3
H
N
H2N
+
ultrasound
rt, 24 h
reflux, 24 h
O
O
O
make the
1
2a (1.5 equiv.)
3a
4a (35%)
ð8Þ
remaining problem
O
O
R
N
The proposed mechanism includes the formation of an aldehyde
intermediate with a nucleophilic attack by the aminoquinone
(Scheme 1). Subsequent dehydration furnishes p-indolequinones.
To confirm the aldehyde intermediate, an experiment using
diethanolamine with Dess–Martin periodinane (DMP) was per-
formed (Eq. 9). The amination followed by oxidation with DMP
should generate the corresponding aldehyde and AcOH as a
byproduct. The reaction resulted in 49% yield of product 6 without
OH2
9
.
O
O
Bn
N
OCH3
OCH3
CeCl3·7H2O
(5 mol%)
Bn
HN
OCH3
OCH3
H2SO4 aq
complex
mixture
+
CH3CN
rt, 24 h
CH3CN
70 oC, 24 h
O
O
O
O
R
N
OCH3
OCH3
O
O
R
N
O
O
Ce2+
OCH3
OCH3
Ce3+
H3O+
H
N
2b: (10 equiv)
10
+
R
11
OH
ð12Þ
O
O
O
H2O
H
O
O
R
N
R
N
We also employed p-benzoquinone 10 as a starting material. It was
confirmed by 1H NMR that the amination step proceeded, but the
cyclization did not occur under the optimized acidic condition
and resulted in a complex mixture (Eq. 12). It is concluded that
the aromatic ring of 1,4-naphthoquinone assists the nucleophilic
attack of quinone on the aldehyde intermediate.
R
N
H3O+
H
H
O
OH
H
O
H3O+
H
H2O
Scheme 1. Plausible mechanism.

2256
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This work was supported by the College of Science Dean’s
Research Enhancement Fund at UTEP and the start-up fund from
the University of Texas Rio Grande Valley. JDG would like to thank
the Campus Office of Undergraduate Research Initiatives (COURI)
for their financial support. BVG was supported by the RISE program
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