A new CAN-catalyzed domino process related to the Nenitzescu reaction: Very concise access to fused ortho-indolequinones from simple precursors

Article abstract of DOI:10.1016/j.tet.2013.04.101

The CAN-catalyzed three-component reaction between primary amines, β-ketoesters and naphthoquinone in ethanol at room temperature afforded as the main products the corresponding Michael adducts, oxidized to the quinone stage. When these compounds were refluxed in ethanol in the presence of CAN, they afforded tricyclic ortho-quinones derived from the benzo[g]indole-4,5-dione framework via a domino mechanism comprising a sequence of 5-exo-trig cyclization, elimination, Michael addition, oxo-enol tautomerism and hydroquinone oxidation individual steps.

Full text of DOI:10.1016/j.tet.2013.04.101

Accepted Manuscript
A new CAN-catalyzed domino process related to the Nenitzescu reaction: Very
concise access to fused ortho-indolequinones from simple precursors
Padmakar A. Suryavanshi, Vellaisamy Sridharan, J. Carlos Mené ndez
PII:
S0040-4020(13)00661-3
10.1016/j.tet.2013.04.101
TET 24301
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 March 2013
Revised Date: 18 April 2013
Accepted Date: 24 April 2013
Please cite this article as: Suryavanshi PA, Sridharan V, Mené ndez JC, A new CAN-catalyzed domino
process related to the Nenitzescu reaction: Very concise access to fused ortho-indolequinones from
simple precursors, Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.101.
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A new CAN-catalyzed domino process
related to the Nenitzescu reaction: Very
concise access to fused ortho-indolequinones
from simple precursors
Leave this area blank for abstract info.
Padmakar A. Suryavanshi,a Vellaisamy Sridharana,b and J. Carlos Menéndeza*
aDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
bPermanent address: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur–613401, Tamil Nadu, India.
O
O
R1 NH2
1. CAN, rt
2. CAN, reflux
O
O
O
O
OR3
R2
OR3
O
N
R1
R2

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1
Tetrahedron
journal homepage: www.elsevier.com
A new CAN-catalyzed domino process related to the Nenitzescu reaction: Very
concise access to fused ortho-indolequinones from simple precursors
Padmakar A. Suryavanshi,a Vellaisamy Sridharana,b and J. Carlos Menéndeza*
aDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
bPermanent address: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur–613401, Tamil Nadu, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The CAN-catalyzed three-component reaction between primary amines, β-ketoesters and
naphthoquinone in ethanol at room temperature afforded as the main products the corresponding
Michael adducts, oxidized to the quinone stage. When these compounds were refluxed in
ethanol in the presence of CAN, they afforded tricyclic ortho-quinones derived from the
benzo[g]indole-4,5-dione framework via a domino mechanism comprising a sequence of 5-exo-
trig cyclization, elimination, Michael addition, oxo-enol tautomerism and hydroquinone
oxidation individual steps.
Available online
Keywords:
Keyword_1 Quinones
Keyword_2 Fused indoles
2009 Elsevier Ltd. All rights reserved.
Keyword_3 Multicomponent reactions
Keyword_4 Cerium(IV) ammonium nitrate
Keyword_5 Nenitzescu indole synthesis
1. Introduction
originally proposed by Evans and widely employed as a guide to
drug design.6 Indole-4,7-quinones related to the natural product
Quinones are a very important class of compounds owing to
the relevance of the biochemical roles of compounds such as
ubiquinone, plastoquinone and phylloquinone (vitamin K1).
Furthermore, quinone moieties are essential structural fragments
of a large number of pharmacologically active compounds,
specially in the anticancer field.1 Due to the fact that heterocycles
are the most important single class of compounds in the
pharmaceutical and agrochemical industries, comprising around
60% of all drug substances in therapeutic use, heterocyclic
quinones can be considered as particularly relevant.2 Most
compounds in this cathegory are para-quinones, but some ortho-
quinones are also known.
mitomycin (Figure 1) are well known as anticancer agents acting
by alkylation of the DNA minor groove.7 The mitosenes, such as
WV15 (1) and the aziridinylindolequinones, such as EO9 (2),
constitute typical examples. On the other hand, ortho-quinones
derived from indole frameworks are not well represented in the
O
O
O
O
OCOCH3
OCOCH3
OH
OH
H3CO
H3C
N
N
N
CH3
2
1
Indole is a widespread structural motif found in a large
number of natural products and its derivatives can be considered
as one of the most important single class of heterocyclic
O
O
N
CO2H
systems.3 They possess
a wide range of therapeutically
N
H
interesting biological activities,4 and indeed indole derivatives
have been included in the “privileged scaffolds” cathegory5
because they constitute “a molecular framework able to provide
ligands for diverse receptors”, thus satisfying the definition
HO2C
CO2H
3
Figure 1 Examples of bioactive indole-4,7-quinones and indole-4,5-quinones
———
*
Corresponding author. Tel.: +0034-913941840; fax: +0034-913941822; e-mail: josecm@farm.ucm.es

ACCEPTED MANUSCRIPT
2
Tetrahedron
literature. Probably the most important one is pyrroloquinoline-
Against this background, we became intrigued by the
possibility of using this chemistry for the preparation of ortho-
quinone derivatives. More specifically, we wished to ascertain
whether compounds 6 might be suitable precursors to iminium
derivatives 9, the putative intermediates of the conventional
redox mechanism. We reasoned that, in the absence of reductive
species, these intermediates should behave as excellent Michael
acceptors able to trap hydroxide, acting as a nucleophile, thereby
afording compounds dioxygenated at the 4 and 5 positions of the
indole ring, which should be easy to transform into the target
ortho-quinones 8 (Scheme 2). It is relevant to mention at this
point that this transformation was rendered particularly
significant by the observation that we were unable to obtain
compounds 8 from 4 by oxidation with Fremy’s salt under a
variety of conditions.14 We were also encouraged to attempt this
transformation by the fact that the benzo[g]indole-4,5-dione
framework present in 8 is almost unknown in the literature, and
its preparation normally requires multistep sequences.15,16 There
is a report of the synthesis of three benzo[g]indole-4,5-diones in
a two-step sequence from 2,3-dichloronaphthoquinone and N-
substituted β-aminocrotonic esters, but it has very clear
disadvantages, including the need to prepare the starting
enaminones in a separate step, its very narrow scope, its poor
atom economy owing to the release of two molecules of HCl and
the very harsh reaction conditions required for the cyclization
step, which led to “strong resinification of the reaction
medium”.17
quinone (PQQ, 3), which plays crucial roles as a cofactor and is
involved in a range of biochemical reactions including oxidative
deaminations and free-radical redox reactions.8
In this context, we became interested in developing a fast
route for the synthesis of indole derivatives containing an ortho-
quinone moiety. We were stimulated to undertake this work by
our recent development9 of a three-component version of the
Nenitzescu indole synthesis catalyzed by cerium(IV) ammonium
nitrate10,11 in refluxing ethanol and affording benzo[g]indoles 4.
We found that this reaction did not seem to follow the
conventional Nenitzescu mechanism, in which the initial Michael
addition of the enaminone to the quinone gives
5 (a
hydroquinone tautomer). Air oxidation of the latter intermediate
gives quinone 6 whose formation, even in trace amounts, may
trigger a redox cycle involving cyclization of 6 to an iminium
derivative, which is then reduced by 5 to give another molecule
of 6 and the observed product 4.12 However, treatment of one of
the quinones 6 (isolated in minor amounts from one of the
reactions, see below) with one equivalent of externally added
hydroquinone under our standard reaction conditions (5 mol% of
CAN in refluxing ethanol) did not afford the corresponding
compound 4. For this reason, we proposed
a non-redox
alternative mechanism in which the presence of the Lewis acid
catalyst promoted the cyclization of 5 to 7, which was finally
dehydrated to the final products 4,13 with traces of 6 being
sometimes isolated from a side reaction involving the air
oxidation of the hydroquinone tautomer of 5 (Scheme 1, first
column).
2. Results and discussion
As a first step towards our goal, we needed to establish
reliable conditions for the preparation of compounds 6, bearing in
mind the competition with the formation of the Nenitzescu-like
product 4. After extensive manipulation of the reaction
conditions, we established that the best option to shift the
processes summarized in Scheme 1 towards the formation of 6
Ce(IV)
O
R1
R1 NH2
NH
O
CAN
-H2O
+
R2
OR3
O
O
O
R2
OR3
O
R1 NH2
R1
CAN (5 mol%)
CH3CN, EtOH, rt
O
OH
Objective of the
present work
NH O
O
O
O
O
R2
OR3
R2
OR3
OR3
OR3
O
Michael
O
O
R2
HN
R1
R2
HN
R1
Ce(IV)
5
5
Ox.
Nenitzescu
6
Reflux
6
4
[ref 9]
-Ce(IV)
Scheme 2 Synthesis of quinones 6
OH
O
O
H
O
Table 1 Results obtained in the preparation of compounds 6
OR3
HO
R1
OR3
Entry Cmpd. R1
R2
R3
Time, h 6/4 ratioa Yield of 6, %b
N
OH
R1
N
R2
R2
7
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
n-Bu
n-Bu
Me
Me
Et
1.5
1
85:15
80:20
75:25
75:25
78:22
70:30
65:35
65:35
65
68
62
60
65
58
62
60
tBu
Et
-H2O
Allyl Me
1
OH
O
O
n-Bu
n-Bu
n-Pr
Bn
Me
Me
Me
Me
n-Pr
Me
1.5
O
O
Allyl 1.5
OR3
OR3
N
N
Et
Et
Et
1
R1
R2
R1
R2
8
6g
6h
1.5
1
4 (Nenitzescu
product)
n-Bu
Scheme 1 A summary of our previous work on the CAN-catalyzed reaction
between primary amines, β-ketoesters and naphthoquinoneError!
defined. and our plan for the synthesis of benzo[g]indole-4,5-diones
aDetermined on the crude 1H-NMR spectra. bIsolated yields after
chromatography.
Bookmark not

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3
Table 2 Results obtained in the synthesis of compounds 8
involved the reaction in ethanol between primary amines, β-
Entry Cmpd. R1
R2
R3
Time, h 8/4 ratioa Yield of 8, %b
ketoesters and naphthoquinone in the presence of 5% CAN, at
room temperature in a flask open to the air and using as solvent a
5:1 mixture of acetonitrile and ethanol. Under these conditions,
the 6/4 ratios ranged betwen 85:15 and 65:35 (Scheme 2 and
Table 1). The intermediacy of an enaminone was verified by
carrying out the reaction from an isolated example, prepared by a
literature method.18
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
n-Bu Me
n-Bu Me
Allyl Me
n-Bu Me
n-Bu Me
Et
2
75:25
75:25
85:15
65:35
73:27
75:25
80:20
85:15
61
55
56
58
55
59
57
60
tBu
1
Et
2
Me
Allyl
Et
0.5
1
With compounds 6 in hand, we could study the final step of
our route. After some experimentation, we discovered that a
simple reflux in ethanol containing CAN allowed their one-pot
transformation into the target ortho-quinones 8, again with small
amounts of compounds 4 as side products (Scheme 3 and Table
2). The spectral data, specially the very close chemical shifts for
the carbonyl 13C-NMR signals,14,19 fitted the expected structure
for the final products, but in view of the possibility of a
cyclization pathway leading to a linear para-quinone system 9
via an aza-Michael addition of the enamine nitrogen onto the
quinone moiety in 6, we considered it desirable to have
independent chemical evidence for the presence of an ortho-
quinone unit in 8. To achieve this goal, we treated 8a with o-
phenylenediamine in refluxing ethanol, and this reaction afforded
the fused quinazoline derivative 10 in 90% yield, a result that
confirmed the ortho-quinone structure.
n-Pr
Me
Me
2
8g
8h
Bn
Et
2
n-Bu n-Pr
Et
1
aDetermined on the crude 1H-NMR spectra. bIsolated yields after
chromatography.
increase the 8/4 ratio by carrying out the reaction in an oxygen
atmosphere and in the presence of hydroxide anion in order to
facilitate the oxidation of intermediates 12 without the
intervention of 11 and was also employed for the same purpose,
but only complex mixtures were obtained.
O
O
CAN
O
Regarding the mechanism of this transformation, we propose
the sequence of reactions summarized in Scheme 4, where
compound 6 undergoes a 5-exo-trig cyclization followed by
extrusion of hydroxyde anion to give iminium salt 11. Conjugate
addition of the hydroxide anion to the position 4 of compound
11, conjugated with the iminium group, followed by
tautomerization would afford intermediate catechol 12, whose
oxidation by air would afford the final product 8. On the other
hand, according to the conventional Nenitzescu mechanism, the
oxidation of 12 could be coupled to the reduction of 11,
explaining the isolation of small amounts of 4 from the reaction.
On the basis of this rationalization, an effort was made to
6
O
OR3
OR3
HO
O
N
HN
R1
R2
R1
R2
Ce(IV)
O
O
H
Major
pathway
OH
OH
R2
O
O
OR3
OR3
N
N
R1
R1
R2
11
R1
O
Minor
11
N
OH
N
pathway
R2
4
OH
O
O2
OR3
8
O
O
O
O
9
OR3
CAN (5 mol%)
EtOH, reflux
O
R1
R2
12
OR3
O
Scheme 4 Mechanistic rationalization of the reaction leading to compounds 8
HN
R1
6
R2
O
+
4
O
OR3
Finally, in view of the similarity in the reaction conditions for
both steps of our route, we examined the possibility of carrying
out the whole sequence in one pot, avoiding the isolation of
intermediates 6. Thus, treatment of an ethanol solution of
butylamine with ethyl acetoacetate followed by naphthoquinone
in the presence of 5% CAN for 1.5 h was followed by reflux in
the same solvent, leading to a yield of 8a virtually identical to the
one obtained in the two-step method. Unfortunately, the one-pot
protocol seems to lack generality and failed for other cases (8c
and 8g), giving complex mixtures.
N
R1
R2
8
H2N
H2N
EtOH, reflux,
1 h [from 8a]
N
N
O
3. Conclusions
OEt
N
In conclusion, we have developed a two-step method for the
synthesis of pharmacologically relevant ortho-quinones derived
from the benzo[g]indole-4,5-dione system, which combines two
multibond-forming processes. The first step of the route consists
nBu
CH3
10 (90%)
Scheme 3 Preparation of compounds 8 and confirmation of their angular
ortho-quinone structure
of
a three-component room temperature reaction between

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4
Tetrahedron
primary amines, β-ketoesters and naphthoquinone comprising
13C NMR (CDCl3, 63 MHz): δ 14.2, 17.4, 20.5, 28.6, 32.5, 43.8,
79.8, 91.6, 126.1, 127.0, 132.7, 133.5, 133.6, 133.7, 136.2, 150.3,
161.4, 169.0, 186.0. 186.3. Anal. Calcd for C22H27NO4: C, 71.52;
H, 7.37; N, 3.79; Found: C, 71.27; H, 7.09; N, 3.53.
β-enaminone formation and dehydrogenative coupling (i.e.,
Michael addition followed by hydroquinone oxidation) individual
steps. In the second step, which is achieved by simply heating the
product of the first reaction in ethanol containing CAN, 5-exo-
trig cyclization, elimination, Michael addition, oxo-enol
tautomerism and hydroquinone oxidation steps are achieved in a
single operation. Taken in the aggregate, the two-step sequence
involves up to nine individual reactions and achieves the
generation of two C-N and one C-C bonds from very simple
starting materials and catalysts with a very high atom economy,
since the only by-product is a molecule of water.
4.1.3. (E)-Ethyl 3-(allylamino)-2-(1,4-dioxo-1,4-dihydronaphth-
2-yl)but-2-enoate (6c).
Dark red viscous liquid; IR (neat): 2981, 1649, 1593, 1300, 1252,
1220 cm-1; 1H NMR (CDCl3, 250 MHz): 1.12 (t, J = 7.1 Hz, 3H),
1.96 (s, 3H), 3.93-3.98 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 5.23-
5.36 m, 2H), 5.86-5.99 (m, 1H), 6.77 (s, 1H), 7.74-7.77 (m, 2H),
8.10-8.14 (m, 2H), 9.86 (s, 1H); 13C NMR (CDCl3, 63 MHz):
14.6, 17.2, 46.1, 59.7, 90.5, 117.1, 126.2, 127.2, 132.8, 133.2,
133.7, 133.9, 134.2, 137.8, 149.2, 161.9, 169.1, 185.7, 186.0.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31; Found: C,
69.85; H, 6.04; N, 3.88.
4. Experimental section
All reagents (Aldrich, Fluka, SDS, Probus) and solvents
(SDS) were of commercial quality and were used as received.
Reactions were monitored by thin layer chromatography, on
aluminium plates coated with silica gel with fluorescent indicator
(SDS CCM221254). Separations by flash chromatography were
performed on silica gel (SDS 60 ACC 40-63 µm) or neutral
alumina (Merck S22). Melting points were measured on a
Reichert 723 hot stage microscope, and are uncorrected. Infrared
spectra were recorded on a Perkin Elmer Paragon 1000 FT-IR
spectrophotometer, with all compounds examined as KBr pellets
or as thin films on NaCl disks. NMR spectra were obtained on a
4.1.4.
(E)-Methyl
3-(butylamino)-2-(1,4-dioxo-1,4-dihydro-
naphth-2-yl)but-2-enoate (6d).
Dark red viscous liquid; IR (neat): 2954, 1650, 1592, 1439, 1323,
1299, 1259, 1220, 1143, 1069, 1015 cm-1; H NMR (CDCl3, 250
1
MHz): δ 0.99 (t, J = 7.2 Hz, 3H), 1.40-1.55 (m, 2H), 1.61-1.72
(m, 2H), 1.96 (s, 3H), 3.32 (q, J = 6.8 Hz, 2H), 3.58 (s, 3H), 6.78
(s, 1H), 7.72-7.79 (m, 2H), 8.10-8.15 (m, 2H), 9.78 (s, 1H); 13C
NMR (CDCl3, 63 MHz): δ 14.2, 17.5, 20.5, 32.3, 43.7, 51.1,
89.1, 126.2, 127.3, 132.8, 133.1, 133.8, 133.9, 138.0, 149.0,
162.2, 169.6, 185.7, 186.0. Anal. Calcd for C19H21NO4: C, 69.71;
H, 6.47; N, 4.28; Found: C, 69.58; H, 6.41; N, 4.19.
1
Bruker Avance 250 spectrometer operating at 250 MHz for H
and 63 MHz for 13C (CAI de Resonancia Magnética Nuclear,
Universidad Complutense). Elemental analyses were determined
by the CAI de Microanálisis Elemental, Universidad
4.1.5. (E)-Allyl 3-(butylamino)-2-(1,4-dioxo-1,4-dihydronaphth-
2-yl)but-2-enoate (6e).
Complutense, using
microanalyzer.
a
Leco 932 CHNS combustion
Dark red viscous liquid; IR (neat): 2926, 2339, 1650, 1592, 1455,
1324, 1298, 1252, 1142, 1055, 1015, 992 cm-1; 1H NMR (CDCl3,
250 MHz): δ 0.99 (t, J = 7.2 Hz, 3H), 1.40-1.54 (m, 2H), 1.60-
1.71 (m, 2H), 1.97 (s, 3H), 3.32 (q, J = 6.8 Hz, 2H), 4.51-4.54
(m, 2H), 5.06-5.18 (m, 2H), 5.74-5.89 (m, 1H), 6.79 (s, 1H),
7.73-7.77 (m, 2H), 8.10-8.14 (m, 2H), 9.77 (s, 1H); 13C NMR
(CDCl3, 63 MHz): δ 14.2, 17.6, 20.5, 32.3, 43.8, 64.2, 89.2,
117.0, 126.2, 127.3, 132.7, 133.2, 133.3, 133.8, 133.9, 137.9,
149.1, 162.4, 168.7, 185.8, 186.0. Anal. Calcd for C21H23NO4: C,
71.37; H, 6.56; N, 3.96; Found: C, 71.06; H, 6.31; N, 3.87.
4.1. Synthesis of quinones 6: General procedure
A solution of the suitable β-ketoester (1 mmol), the suitable
primary amine (1 mmol) and CAN (5 mol %) in acetonitrile (0.5
mL) was stirred at room temperature for 30 min. A solution of
1,4-naphthoquinone (158 mg, 1 mmol) in EtOH (110 µL) was
added, and stirring at room temperature was continued for 30
min. Thereafter, the reaction was diluted with water (3 mL) and
extracted with dichloromethane (4 x 5 mL). The combined
organic phases were evaporated to dryness, and then the crude
product was purified by flash column chromatography eluting
with petroleum ether-ethyl acetate. Characterization data for the
major products 6 are given below; the side products 4 were
known compounds.9
4.1.6. (E)-Ethyl 2-(1,4-dioxo-1,4-dihydronaphth-2-yl)-3-propyl-
aminobut-2-enoate (6f).
Dark red viscous liquid; IR (neat): 2966, 2362, 1646, 1593, 1458,
1323, 1298, 1259, 1221, 1142, 1064, 1018 cm-1; 1H NMR
(CDCl3, 250 MHz): δ 1.02-1.15 (m, 6H), 1.63-1.75 (m, 2H), 1.98
(s, 3H), 3.30 (q, J = 6.9 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 6.76
(s, 1H), 7.73-7.77 (m, 2H), 8.09-8.14 (m, 2H), 9.81 (s, 1H); 13C
NMR (CDCl3, 63 MHz): δ 11.9, 14.7, 17.5, 23.6, 45.7, 59.6,
89.7, 126.2, 127.2, 132.8, 133.3, 133.7, 133.8, 137.5, 149.4,
162.0, 169.2, 185.9, 186.0. Anal. Calcd for C19H21NO4: C, 69.71;
H, 6.47; N, 4.28; Found: C, 69.92; H, 6.29; N, 4.07.
4.1.1.
(E)-Ethyl
3-(butylamino)-2-(1,4-dioxo-1,4-dihydro-
naphthalen-2-yl)but-2-enoate (6a).
Dark red viscous liquid; IR (neat): 2960, 2931, 1706, 1652, 1594
1
cm-1; H NMR (CDCl3, 250 MHz): δ 0.99 (t, J = 7.1 Hz, 3H),
1.11 (t, J = 7.1 Hz, 3H), 1.40-1.54 (m, 2H), 1.60-1.71 (m, 2H),
1.97 (s, 3H), 3.30 (q, J = 6.8 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H),
6.76 (s, 1H), 7.71-7.78 (m, 2H), 8.07-8.15 (m, 2H), 9.77 (s, 1H);
13C NMR (CDCl3, 63 MHz): δ 14.2, 14.7, 17.5, 20.5, 32.3, 43.7,
59.6, 89.7, 126.2, 127.2, 132.8, 133.3, 133.7, 133.8, 137.5, 149.4,
162.0, 169.2, 185.9, 186.0. Anal. Calcd for C20H23NO4: C, 70.36;
H, 6.79; N, 4.10; Found: C, 70.04; H, 6.79; N, 4.00.
4.1.7.
(E)-Ethyl
3-(benzylamino)-2-(1,4-dioxo-1,4-dihydro-
naphth-2-yl)but-2-enoate (6g).
Dark red viscous liquid; IR (neat): 3272, 1645, 1594, 1448, 1414,
1299, 1258, 1220, 1098, 1068 cm-1; 1H NMR (CDCl3, 250 MHz):
δ 1.12 (t, J = 7.1 Hz, 3H), 1.98 (s, 3H), 4.07 (q, J = 7.1 Hz, 2H),
4.55 (d, J = 5.8 Hz, 2H), 6.78 (s, 1H), 7.29-7.44 (m, 5H), 7.74-
7.78 (m, 2H), 8.10-8.15 (m, 2H), 10.11 (s, 1H); 13C NMR
(CDCl3, 63 MHz): δ 14.6, 17.6, 47.8, 59.8, 90.9, 126.3, 127.2,
127.3, 128.0, 129.3, 132.7, 133.2, 133.8, 133.9, 137.8, 138.1,
149.1, 161.8, 169.1, 185.7, 186.0. Anal. Calcd for C23H21NO4: C,
73.58; H, 5.64; N, 3.73; Found: C, 73.26; H, 5.36; N, 3.42.
4.1.2.
(E)-tert-Butyl
3-(butylamino)-2-(1,4-dioxo-1,4-
dihydronaphth-2-yl)but-2-enoate (6b).
Dark red viscous liquid; IR (neat): 2973, 2932, 1691, 1665, 1596,
1
1547, 1529, 1501, 1460, 1390, 1066 cm-1; H NMR (CDCl3, 250
MHz): δ 0.99 (t, J = 7.1 Hz, 3H), 1.35 (s, 9H), 1.48-1.52 (m,
2H), 1.60-1.69 (m, 2H), 1.99 (s, 3H), 3.29 (q, J = 6.8 Hz, 2H),
6.68 (s, 1H), 7.72-7.76 (m, 2H), 8.08-8.14 (m, 2H), 9.73 (s, 1H);

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4.1.8. (E)-Ethyl 3-(butylamino)-2-(1,4-dioxo-1,4-dihydronaphth-
Red solid; mp 125-126 ºC; IR (neat): 2958, 2873, 1710, 1666,
2-yl)hex-2-enoate (6h).
1650, 1594, 1548, 1536, 1502, 1468, 1442, 1402, 1312, 1223,
1
1126 cm-1; H NMR (CDCl3, 250 MHz): δ 1.08 (t, J = 7.2 Hz,
Dark red viscous liquid; IR (neat): 2961, 2932, 2873, 1667, 1649,
1595, 1665, 1363, 1324, 1253, 1142, 1028
3H), 1.50-1.59 (m, 2H), 1.83-1.95 (m, 2H), 2.49 (s, 3H), 3.92 (s,
3H), 4.21 (t, J = 7.7 Hz, 2H), 7.34-7.38 (m, 1H), 7.40-7.62 (m,
2H), 8.12 (d, J = 8.2 Hz, 1H); 13C NMR (CDCl3, 63 MHz): δ
11.3, 14.0. 20.3, 32.2, 46.5, 52.4, 114.7, 120.6, 122.7, 128.7,
130.4, 130.7, 131.8, 135.5, 136.7, 139.9, 165.7, 174.7, 182.7.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31; Found: C,
69.96; H, 5.90; N, 4.44.
cm-1; 1H NMR
(CDCl3, 250 MHz): δ 0.86-1.01 (m, 6H), 1.09 (t, J = 7.1 Hz,
3H), 1.40-1.55 (m, 4H), 1.60-1.72 (m, 2H), 2.19-2.25 (m, 2H),
3.30 (q, J = 6.8 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 6.80 (s, 1H),
7.73-7.77 (m, 2H), 8.10-8.14 (m, 2H), 9.69 (s, 1H); 13C NMR
(CDCl3, 63 MHz): δ 14.2, 14.6, 14.7, 20.5, 22.2, 32.2, 32.6, 43.3,
59.6, 89.2, 126.2, 127.2, 132.7, 133.2, 133.7, 133.9, 137.3, 149.5,
165.4, 169.4, 186.0, 186.1. Anal. Calcd for C22H27NO4: C, 71.52;
H, 7.37; N, 3.79; Found: C, 71.44; H, 7.24; N, 3.59.
4.2.5.
Allyl
1-butyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8e).
4.2. Synthesis of compounds 8: General procedure
Red solid; mp 145-146 ºC; IR (neat): 2959, 1701, 1666, 1593,
1
1499, 1466, 1267, 1126 cm-1; H NMR (CDCl3, 250 MHz): δ
To a suspension of the suitable quinone 6 (0.5 mmole) in EtOH
(1.5 mL) and CAN (5 mol %) was refluxed for the time indicated
in table 2. After the disappearance of starting material, as
indicated by tlc, the reaction mixture was diluted with water (5
mL) and extracted with dichloromethane (3 x 15 mL). The
combined organic layers were evaporated under reduced pressure
and crude residue thus obtained was purified by silica gel column
chromatography, eluting with 20% petroleum ether/ethyl acetate.
Characterization data for compounds 8 are given below.
1.07 (t, J = 7.3 Hz, 3H), 1.50-1.63 (m, 2H), 1.82-1.94 (m, 2H),
2.48 (s, 3H), 4.20 (t, J = 7.8 Hz, 2H), 4.83-4.86 (m, 2H), 5.29
(dd, J = 1.4, 10.3 Hz, 1H), 5.44 (dd, J = 1.4, 17.2, 1H), 6.03-6.19
(m, 1H), 7.30-7.40 (m, 1H), 7.55-7.61 (m, 2H), 8.12 (d, J = 7.7
Hz, 1H); 13C NMR (CDCl3, 63 MHz): δ 11.3, 14.0, 20.3, 32.2,
46.5, 66.2, 114.7, 119.0, 120.5, 122.7, 128.6, 130.3, 130.6, 131.7,
132.6, 135.5, 136.7, 140.1, 165.0, 174.4, 182.5. Anal. Calcd for
C21H21NO4: C, 71.78; H, 6.02; N, 3.99; Found: C, 71.63; H, 6.26;
N, 4.19.
4.2.1.
Ethyl
1-butyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
4.2.6.
Ethyl
2-methyl-4,5-dioxo-1-propyl-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8a).
benzo[g]indole-3-carboxylate (8f).
Purple solid ; mp 112 ºC; IR (neat) 2961, 2931, 2873, 1693,
1666, 1650.3, 1594, 1548, 1503, 1469, 1302, 1223, 1127, 1021
Purple solid; mp. 79-80 ºC; IR (neat) 3014, 2925, 2853, 1697,
1
1666, 1595, 1536, 1501, 1465, 1366, 1271, 1128, 1020 cm-1; H
1
cm-1; H NMR (CDCl3, 250 MHz): δ 1.04 (t, J = 7.1 Hz, 3H),
NMR (CDCl3, 250 MHz): δ 1.13 (t, J = 7.4 Hz, 3H), 1.42 (t, J =
7.1 Hz, 3H), 1.89-1.99 (m, 2H), 2.49 (s, 3H), 4.17 (dd, J = 6.3,
8.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 7.34-7.40 (m, 1H), 7.53-
7.61 (m, 2H), 8.13 (dd, J = 1.4, 7.7 Hz, 1H); 13C NMR (CDCl3,
63 MHz): δ 11.3, 11.4, 14.5, 23.6, 48.0, 61.4, 115.2, 120.5,
122.6, 128.6, 130.3, 130.7, 131.8, 135.5, 136.6, 139.6, 165.3,
174.4, 182.6. Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N,
4.31; Found: C, 70.30; H, 5.52; N, 4.08.
1.42 (t, J = 7.1 Hz, 3H), 1.47-1.61 (m, 2H), 1.81-1.61 (m, 2H),
2.47 (s, 3H), 4.19 (t, J = 8.0 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H),
7.32-7.39 (m, 1H), 7.54-7.60 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H);
13C NMR (CDCl3, 63 MHz): δ 11.3, 14.0, 14.5, 20.3, 32.2, 46.5,
61.4, 115.2, 120.5, 122.7, 128.6, 130.3, 130.7, 131.8, 135.5,
136.6, 139.6, 165.4, 174.4, 182.6. Anal. Calcd for C20H21NO4: C,
70.78; H, 6.24; N, 4.13; Found: C, 70.93; H, 6.28 ; N, 4.18.
4.2.2. tert-Butyl 1-butyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8b).
4.2.7.
Ethyl
1-benzyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8g).
Red solid; mp 145 ºC; IR (neat) 2996, 1691, 1660, 1593, 1502,
1462, 1366, 1321, 1278, 1153, 1132, 1066 cm-1; 1H NMR
(CDCl3, 250 MHz): δ 1.07 (t, J = 7.2 Hz, 3H), 1.47-1.59 (m, 2H),
1.64 (s, 9H), 1.80-1.93 (m, 2H), 2.45 (s, 3H), 4.17 (t, J = 8.1 Hz,
2H), 7.32-7.38 (m, 1H), 7.53-7.63 (m, 2H), 8.11 (d, J = 8.5 Hz,
1H); 13C NMR (CDCl3, 63 MHz): δ 11.1, 14.0, 20.3, 28.4, 31.3,
32.2, 46.4, 82.2, 117.0, 122.6, 128.5, 130.3, 130.8, 131.8, 135.5,
136.2, 138.8, 164.8, 174.0, 182.5; Anal. Calcd for C22H25NO4: C,
71.91; H, 6.86; N, 3.81; Found: C, 71.69; H, 6.68; N, 3.98.
Red solid; mp. 200-201 ºC; IR (neat): 2981, 2928, 1710, 1666,
1
1594, 1494, 1462, 1302, 1203, 1028 cm-1; H NMR (CDCl3, 250
MHz): δ 1.45 (t, J = 7.1 Hz, 3H), 2.41 (s, 3H), 4.43 (q, J = 7.1
Hz, 2H), 5.51 (s, 2H), 7.17 (d, J = 6.6 Hz, 2H), 7.27-7.45 (m,
6H), 8.08-8.11 (m, 1H); 13C NMR (CDCl3, 63 MHz): δ 11.1,
14.5, 50.1, 61.5, 115.3, 120.4, 123.2, 125.7, 128.7, 128.8, 130.0,
130.1, 130.2, 131.6, 134.7, 135.5, 138.0, 140.6, 165.1, 174.4,
182.5. Anal. Calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75;
Found: C, 73.78; H, 5.35; N, 3.41.
4.2.3.
Ethyl
1-allyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
4.2.8.
Ethyl
1-butyl-4,5-dioxo-2-propyl-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8c).
benzo[g]indole-3-carboxylate (8h).
Red solid; mp 114-115 ºC; IR (neat) 2918, 2850, 1709, 1666,
1594, 1548, 1492.9, 1462, 1407, 1302, 1273, 1228, 1139, 1069
Red solid; mp. 114-115 ºC; IR (Neat): 2962, 2933, 2873, 1711,
1
1667, 1594, 1502, 1466, 1308, 1218, 1126, 1024 cm-1; H NMR
1
cm-1; H NMR (CDCl3, 250 MHz): δ 1.43 (t, J = 7.1 Hz, 3H),
(CDCl3, 250 MHz): δ 1.02-1.10 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H),
1.50-1.59 (m, 2H), 1.62-1.71 (m, 2H), 1.81-1.94 (m, 2H), 2.82 (t,
J = 7.7 Hz, 2H), 4.20 (t, J = 8.0 Hz, 2H), 4.39 (q, J = 7.1 Hz,
2H), 7.33-7.40 (m, 1H), 7.59-7.61 (m, 2H), 8.13 (d, J = 8.4 Hz,
1H); 13C NMR (CDCl3, 63 MHz): δ 14.0, 14.3, 14.5, 20.3, 23.7,
27.0, 32.8, 46.2, 61.4, 115.2, 120.8, 122.7, 128.6, 130.4, 130.9,
131.8, 135.5, 136.4, 143.6, 165.3, 174.5, 182.6. Anal. Calcd for
C22H25NO4: C, 71.91; H, 6.86; N, 3.81; Found: C, 71.69; H, 6.72;
N, 3.90.
2.45 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 4.87 (br s, 2H), 5.11 (d, J
= 17.1 Hz, 1H), 5.46 (d, J = 10.4 Hz, 1H), 6.10-6.23 (m, 1H),
7.28-7.41 (m, 1H), 7.54-7.56 (m, 2H), 8.11 (d, J = 7.6 Hz, 1H);
13C NMR (CDCl3, 63 MHz): δ 10.8, 14.5, 48.7, 61.5, 115.2,
118.8, 120.2, 123.3, 128.8, 130.2, 130.3, 131.0, 131.6, 135.4,
137.9, 140.4, 165.2, 174.6, 182.8; Anal. Calcd for C19H17NO4: C,
70.58; H, 5.30; N, 4.33; Found: C, 70.36; H, 5.48; N, 4.11.
4.2.4.
Methyl
1-butyl-2-methyl-4,5-dioxo-4,5-dihydro-1H-
benzo[g]indole-3-carboxylate (8d).
4.3.
Ethyl
3-butyl-2-methyl-3H-benzo[a]pyrrolo[2,3-
c]phenazine-1-carboxylate (10).

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6
Tetrahedron
Chem. 2006, 13, 65. (d) Shelat, A. A.; Guy, R. K. Nature Chem.
Biol. 2007, 3, 442. (e) Welsch, M. E.; Snyder, S. A.; Stockwell, B.
R. Curr. Opin. Chem. Biol. 2010, 14, 347.
To a solution of compound 8a (339 mg, 1 mmol) in ethanol (5
mL) was added o-phenylenediamine (108 mg, 1 mmol). The
resulting solution was refluxed for 1 h, cooled and a mixture of
water (10 mL) and ethyl acetate (15 mL) was added. The aqueous
phase was extracted with additional ethyl acetate (3 x 15 mL).
The combined extracts were dried over Na2SO4 and evaporated to
yield 370 mg (90%) of compound 10, as a yellow solid; mp 167
ºC; IR (neat): 2957, 2921, 2855, 1712, 1577, 1544, 1508, 1463,
6. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Verber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. H.; Chen,
T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J.
Med. Chem. 1988, 31, 2235.
7. Avendaño, C.; Menéndez, J. C. Medicinal Chemistry of
Anticancer Drugs, chapter 6. Elsevier, Oxford, 2008.
8. For a review, see: Stites, T. E.; Mitchell, A. E.; Rucker, R. B. J.
Nutrition 2000, 130, 719.
1412, 1343, 1277, 1232, 1172, 1121, 1071, 1020 cm-1; H NMR
1
(CDCl3, 250 MHz): δ 1.09 (t, J = 7.2 Hz, 3H), 1.49 (t, J = 7.1
Hz, 3H), 1.56-1.65 (m, 2H), 1.95-2.07 (m, 2H), 2.65 (s, 3H), 4.53
(t, J = 7.5 Hz, 2H), 4.66 (q, J = 7.1 Hz, 2H), 7.66-7.83 (m, 4H),
8.17-8.24 (m, 2H), 8.31-8.35 (m, 1H), 9.60 (dd, J = 1.4, 8.0 Hz,
1H); 13C NMR (CDCl3, 63 MHz): δ 11.8, 14.2, 14.5, 14.9, 20.5,
23.1, 29.7, 30.0, 30.1, 32.3, 32.6, 46.6, 61.5, 121.0, 125.7, 126.6,
127.8, 128.7, 129.9, 130.1, 130.2, 140.9, 168.5. Anal. Calcd for
C26H25N3O2: C, 75.89; H, 6.12; N, 10.21; Found: C, 75.63; H,
6.03; N, 10.05.
9. Suryavanshi, P. A.; Sridharan, V.; Menéndez, J. C. Org. Biomol.
Chem. 2010, 8, 3345.
10. For a review of the synthetic applications of CAN, with emphasis
on those that employ stoichiometric amounts of the reagent, see:
Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
11. For a review of the use of CAN as a catalyst in organic synthesis,
see, Sridharan, V.; Menéndez, J. C. Chem. Rev. 2010, 110, 3805.
12. For a review of the Nenitzescu reaction, see: Patil, S. A.; Ratil, R.;
Miller, D. D. Curr. Org. Chem. 2008, 12, 691.
13. For mechanistic discussions of the Nenitzescu reaction involving
redox processes, see: (a) Kuckländer, U. Tetrahedron 1972, 28,
5251; (b) Patrick, J. B.; Saunders, E. K. Tetrahedron Lett. 1979,
20, 4009; (c) Bernier, J.-L.; Hénichart, J.-P. J. Org. Chem. 1981,
46, 4197.
Acknowledgments
Financial support from MICINN and MINECO (grant
CTQ2012-33272-BQU) is gratefully acknowledged. We also
thank Agencia Española de Cooperación Internacional
Desarrollo (AECID) for a predoctoral fellowship to Padmakar
Suryavanshi.
14. López-Alvarado, P.; Avendaño, C.; Menéndez, J. C. J. Chem. Soc.
Perkin Trans. 1 1997, 229.
y
15. (a) Nesterova, I. N.; Grinev, A. N.; Rubtsov, N. M. Khim.
Geterosikl. Soed. 1989, 66-68 and references therein. (b) Itoh, S.;
Fukui, Y.; Ogino, M.; Haranou, S.; Komatsu, M.; Ohshiro, Y. J.
Org. Chem. 1992, 57, 2788. (c) Suginome, H.; Sakurai, H.; Sasaki,
A.; Takeuchi, H.; Kobayashi, K. Tetrahedron 1994, 50, 8293.
16. A synthesis of a cyclohexane-fused derivative of 8 has been
recently described, although it was a side product isolated in low
yield. See: Otero, J. M.; Barcia, J. C.; Salas, C. O.; Thomas, P.;
Estévez, J. C.; Estévez, R. J. Tetrahedron 2012, 68, 1612.
17. Nesterova, I. N.; Grinev, A. N.; Rubtsov, N. M. Khim. Geterotsikl.
Soedin. 1989, 66.
References and notes
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and 1330.
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Supporting Information
A CAN-catalyzed domino process allowing two-step access to
fused ortho-indolequinones from simple precursors
Padmakar A. Suryavanshi, Vellaisamy Sridharan and J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain
Contents
Spectra of compound 6a
Spectra of compound 6b
Spectra of compound 6c
Spectra of compound 6d
Spectra of compound 6e
Spectra of compound 6f
Spectra of compound 6g
Spectra of compound 6h
Spectra of compound 8a
Spectra of compound 8b
Spectra of compound 8c
Spectra of compound 8d
Spectra of compound 8e
Spectra of compound 8f
Spectra of compound 8g
Spectra of compound 8h
Spectra of compound 10
S2
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