One-Pot Synthesis of Functionalized Carbazoles via a CAN-Catalyzed Multicomponent Process Comprising a C-H Activation Step

Article abstract of DOI:10.1021/acs.joc.7b01199

The microwave-promoted three-component reaction between o-nitrochalcones, primary amines and β-dicarbonyl compounds in the presence of Ce(IV) ammonium nitrate constitutes the first example of a multicomponent carbazole synthesis. This reaction furnishes highly substituted and functionalized carbazole derivatives via a double annulation process that generates two C-C and two C-N bonds, with water as the only side product. Mechanistically, this transformation has some unusual features that include an intramolecular coupled hydrogenation-dehydrogenation process, the functionalization of a C-H group by direct attack onto a nitrogen function and a CAN-catalyzed reduction via hydride transfer from ethanol. The mechanisms of these reactions were studied with the aid of computational techniques.

Full text of DOI:10.1021/acs.joc.7b01199

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Article
One-Pot Synthesis of Functionalized Carbazoles via a CAN-
catalyzed Multicomponent Process Comprising a C-H Activation Step
Juan Francisco González, Damiano Rocchi, Tomas Tejero, Pedro Merino, and J. Carlos Menéndez
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Jun 2017
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The Journal of Organic Chemistry
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One-Pot Synthesis of Functionalized Carbazoles via a CAN-
catalyzed Multicomponent Process Comprising a C-H Activa-
tion Step
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Juan F. González,a Damiano Rocchi,a Tomás Tejero, b Pedro Merino,c* and J. Carlos Menéndeza*
a Departamento de Química Orgánica y Farmacéutica, Universidad Complutense, Facutad de Farmacia, Plaza de Ramón y
Cajal s.n., 28010 Madrid, Spain.
b
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza, CSIC, 50009 Zaragoza, Spain.
c Instituto de Biocomputación y Fisica de Sistemas Complejos (BIFI), Universidad de Zaragoza, 50009 Zaragoza, Spain.
Keywords: Nitrogen heterocycles; multicomponent reactions, carbazole; Ce(IV) ammonium nitrate; DFT calculations
ABSTRACT: The microwaveꢀpromoted threeꢀcomponent reaction between oꢀnitrochalcones, primary amines and βꢀdicarbonyl
compounds in the presence of Ce(IV) ammonium nitrate constitutes the first example of a multicomponent carbazole synthesis.
This reaction furnishes highly substituted and functionalized carbazole derivatives via a double annulation process that generates
two CꢀC and two CꢀN bonds, with water as the only side product. Mechanistically, this process has some unusual features that
include an intramolecular coupled hydrogenationꢀdehydrogenation process, the functionalization of a CꢀH group by direct attack
onto a nitrogen function and a CANꢀcatalyzed reduction via hydride transfer from ethanol. The mechanisms of these
transformations were studied with the aid of computational techniques.
er transition metalꢀcatalyzed version of this reaction has been
INTRODUCTION
developed using stoichiometric CO as an alternative reducing
agent, but yields are often moderate due to the
Carbazoles are widespread in nature and are very important in
medicinal chemistry and functional materials science. Thus,
carbazole is the central core of a large family of alkaloids,1
with both natural and unnatural carbazoles exhibiting a variety
of interesting biological activities including antibacterial,
antifungal, antitumor, antiꢀinflammatory and neuroprotective
properties.2 In recent years, the carbazole moiety is being
widely investigated as a privileged building block for the
synthesis of polymers of relevance in organic electronics3 and
materials science, in general.4 Some representative carbazole
derivatives are shown in Figure 1.
Because of its importance, synthetic methodology leading to
the carbazole framework has been widely investigated,5,6 with
most known methods creating the carbazole framework from
two preꢀexisting aromatic rings (Scheme 1.a). The traditional
Borsche–Drechsel reaction (disconnection A) relies on the
adaptation of the Fischer indole synthesis and involves an
additional dehydrogenation step. A second approach involves
the construction of carbazole from biphenyls bearing an ortho
nitrogen substituent. Reductive cyclization of nitroaromatic
compounds (disconnection B) is known as the Cadogan synꢀ
thesis and is usually achieved by deoxygenative cyclization of
the starting material at high temperature in the presence of
triethyl phosphite or triphenylphosphine and involves the
exhaustive deoxygenation of the nitro group to a singlet
nitrene, which then undergoes the Nꢀannulation step.7 A mildꢀ
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Figure 1. Some carbazoles with scientific and technical
relevance.
functionalization of C–H fragments in the orthoꢀposition
relative to the nitro group of nitroarenes.26
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3
4
5
6
7
8
9
formation of side products arising from overꢀreduction and CO
insertion.8 In another approach to the same overall transforꢀ
mation, carbazoles have been prepared by treating 2ꢀ
nitrobiphenyls with 3 equivalents of phenylmagnesium broꢀ
mide.9 The cyclization of 2ꢀazidobiphenyls to carbazoles via
insertion of transition metal nitrenoids generated at high temꢀ
peratures from the azido group in the presence of different
metal catalysts10 and the Pd or Rhꢀ catalyzed oxidative
intramolecular aromatic amination reactions starting from 2ꢀ
aminobiphenyls11 or from their amides12 provide alternative
ways to create the carbazole 8aꢀ9 bond. The oxidative
RESULTS AND DISCUSSION
In the context of our work in the synthesis of nitrogen heteroꢀ
cycles by multiple bondꢀforming reactions,27 we became interꢀ
ested in the possibility to synthesize carbazole derivatives by
cyclization of a suitable nitrogen function onto an adjacent
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cyclization
of
arylamineꢀsubstituted
tricarbonyl(η4ꢀ
cyclohexadiene)iron complexes13 corresponds also to this
disconnection. Double CꢀN bond formation strategies are also
known (disconnection C), via Pdꢀcatalyzed double amination
reactions of 2,2’ꢀdihaloꢀ1,1’ꢀbiaryls.14 The dehydrogenative
intramolecular crossꢀcoupling oxidative cyclization of diaꢀ
rylamines (disconnection D) was originally reported using
stoichiometric palladium(II),15 although later several alternaꢀ
tive coꢀoxidants have allowed recycling palladium (0), and
thus the use of catalytic amounts of Pd(II).16 A palladiumꢀ
catalyzed oneꢀpot sequence comprising an intermolecular
Buchwald−Hartwig amination and an intramolecular arylation
via CꢀH activation allows the regioselective syntheses of
carbazoles from anilines and 1,2ꢀdihaloarenes (disconnection
E)17 or anilines and aromatic triflates.18
A
similar
disconnection (F) is achieved by means of oneꢀpot Suzukiꢀ
Cadogan sequences in the presence of palladium acetate and
triphenylphosphine.19 The generation of carbazole by creation
of one of its aromatic rings has also received some attention
and has been achieved by cyclization of indoleꢀtethered
propargyl alcohol precursors20 or by 6π electrocyclic ring
closure of 2,3ꢀdivinylindoles21 or (Z)ꢀ2ꢀ(enynyl)indoles.22 On
the other hand, disconnections involving the generation of two
of the carbazole rings in the same operation have received
very little attention,23 in spite of their potential to create the
target framework with the highest efficiency from simple
starting materials.
In spite of the plethora of known methods for carbazole synꢀ
thesis, there is still much room for improvement since most of
them lack generality regarding the positions to which substituꢀ
ents can be attached, and few of the available methodologies
lead to polysubstituted and functionalized carbazoles. One
area that is key in terms of synthetic efficiency but has been
neglected so far is the use of multicomponent reactions for the
construction of the carbazole framework, in spite of the fact
that they are widely accepted to constitute a step towards
achieving the ideal synthesis.24 In this context, we describe in
this article a synthetic method that affords densely substituted
and functionalized carbazole derivatives (compounds 4) conꢀ
taining a synthetically and biologically relevant βꢀaminoester
unit.25 These carbazoles were obtained in a fully regioselective
fashion via a threeꢀcomponent reaction that generates four new
bonds and two rings from 2ꢀnitrochalcones 1, primary amines
2 and βꢀdicarbonyl compounds 3 (Scheme 1.b). Besides being,
to our knowledge, the first multicomponent synthesis of carꢀ
bazole derivatives, the method includes the functionalization
of a CꢀH group by direct attack onto a nitrogen function, a
transformation that is very rare in contrast to the direct
Scheme 1. Main disconnections of the carbazole system,
compared with the one reported here
aromatic CH bond. Some years back, we reported a CANꢀ
catalyzed threeꢀcomponent reaction starting from alkylamines,
β ketoesters and chalcones that affords cisꢀ4,6ꢀdisubstituted
2ꢀalkylaminocyclohexeneꢀ1ꢀcarboxylic esters,28 which we
subsequently found to spontaneously dehydrate to the correꢀ
sponding cyclohexadiene derivatives when the reaction is
performed under microwave irradiation. 29 We envisioned the
possibility to generate a carbazole ring by coupling the aromaꢀ
tization of the cyclohexadiene ring with the generation of the
carbazole 8aꢀ9 bond. To this end, the experiments summarized
in Scheme 2 and Table 1 were performed. The starting cycloꢀ
hexadiene derivative 5a was synthesized by our previously
reported
MCR
strategy,
from
(2ꢀ
nitrobenzylidene)acetophenone, ethyl acetoacetate and butylꢀ
amine in the presence of CAN. An experiment involving exꢀ
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posure of 5a to microwave irradiation at 100 °C in ethanol as solution, at 100 °C for 2.5 hours, followed by an increase of
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3
4
5
6
7
8
solvent and in the presence of 30% CAN was promising in
that it led directly to a carbazole derivative 4a albeit in only 7
% yield, along with recovered starting material (table 1, entry
1). An increase in temperature to 140 °C considerably imꢀ
proved the yield of the target compound 4a, accompanied by
6a, the product from the aromatization of the starting material;
a 30% catalyst load was still considered necessary at this stage
(entries 2ꢀ4). The presence of the catalyst was proved to be
essential, since only recovered starting material was isolated in
its absence (entry 5), and replacement of CAN by InCl3, even
in equimolecular amounts, was not satisfactory (entry 6).
Finally, in an effort to decrease the amount of aromatized
starting material, we resorted to the use of 10% of the CAN
catalyst, at 140 °C, but with longer reaction times (entries 7
and 8). Indeed, carrying out the reaction for 2.5 hours under
these conditions provided 4a in 85% yield, with only 5% of
the aromatic product 6a being recovered (entry 8).
the temperature to 140 °C for additional 2.5 hours afforded 4a
in 85% yield (entry 1, table 2).
To further probe the scope of the oneꢀpot protocol, a variety of
chalcones 1, primary amines 2 and β ketoesters 3 were next
subjected to the optimal conditions, with the results shown in
Scheme 3 and Table 2. The reaction worked well for all kinds
of substitution in the C5ꢀC8 part of the carbazole framework,
allowing the preparation of allꢀhydrogen derivatives (entries 1,
2, 4, 8 and 12ꢀ15), as well as compounds bearing electronꢀ
releasing substituents (entries 9ꢀ11) and electron acceptors, in
particular halogens (entries 3 and 5ꢀ7). The latter are interestꢀ
ing for their potential to generate further structural complexity
via crossꢀcoupling reactions. The phenyl substituent at Cꢀ1 is
also amenable to varied types of substitution, including allꢀ
hydrogen (entries 1, 3, 9, 13 and 15), electronꢀreleasing groups
(entries 2, 7, 8 and 11) and electronꢀwithdrawing substituents
(entries 4ꢀ6, 10, 12 and 14). Steric hindrance caused by ortho
substituents was also well tolerated (entries 4, 6, 10 and 14).
Aromatic substituents different from phenyl were also readily
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introduced, as shown by the preparation of
a 1ꢀ(2ꢀ
furyl)carbazole (entry 8). The substituent at Cꢀ3 was normally
an alkylamino, but arylamino groups could also be introduced,
albeit in slightly lower yields (entry 15). Some variations in
the ester group at Cꢀ4 were also examined (entries 13 and 14).
The presence of amino and ester functional groups at Cꢀ3 and
Cꢀ4, respectively, is potentially useful for conjugation reacꢀ
tions in both biologyꢀ and materialsꢀoriented synthetic proꢀ
jects. It is noteworthy that the reactions starting from doubly
Scheme 2. Initial optimization of the synthesis of carba-
zoles from cyclohexadiene derivatives.
Table 1. Optimization of the synthesis of carbazole 4aa
Entry
Time
(min)
Catalyst t (ºC)b 6a (%)c
(eq)
4a (%)c
1
2
3
4
5
6
7
8
60
30
60
60
60
60
90
150
0.3
0.1
0.1
0.3
0
1 eqd
0.1
0.1
100
140
140
140
140
140
140
140
ꢀ
7
35
32
32
ꢀ
35
42
61
ꢀ
Scheme 3. One-pot, three component carbazole synthesis.
Table 2. Scope and yields of the carbazole synthesis
Entry
R
R1
R2
Ar
Product Yield,
30
13
5
42
72
85
a
%
1
2
3
4
5
Et
Et
Et
Et
Et
H
Bu
Bu
Bu
Bu
Bu
Ph
85
82
78
83
72
4a
4b
4c
4d
4e
H
4ꢀMeC6H4
Ph
6ꢀCl
H
a Conditions: 5a (1 equiv) was dissolved in EtOH and the
catalyst (normally CAN) was added, Microwave
irradiation heating to the indicated temperature, c Yield of
isolated products. d The reaction was carried out in the
presence of InCl3.
b
2ꢀNO2C6H4
4ꢀBrC6H4
6ꢀBr
4ꢀBrꢀ2ꢀ
NO2C6H3
6
Et
6ꢀBr
Bu
76
4f
The fact that both the initial multicomponent reaction leading
to the cyclohexadiene derivative and the transformation of the
latter into a carbazole could be performed with the same cataꢀ
lyst encouraged us to investigate whether the synthesis of
carbazole derivatives would proceed in a oneꢀpot process from
acyclic precursors. Optimization studies revealed that heating
an equimolecular mixture of nitrochalcone 1a, ethyl acetoaceꢀ
tate, butylamine and catalytic CAN (10 %) in a 0.2 M ethanol
7
Et
Et
Et
Et
Et
6ꢀBr
Bu
Bu
Bu
Bu
Bu
4ꢀMeC6H4
2ꢀfuryl
87
82
81
78
74
4g
4h
4i
8
H
9
6,7ꢀ(MeO)2
6,7ꢀ(OCH2O)
6,7ꢀ(MeO)2
Ph
10
11
2ꢀNO2C6H4
4ꢀMeC6H4
4j
4k
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ble with the experimental observation that the reaction does
not take place when the orthoꢀnitro substituent is at the aroꢀ
12
13
14
15
Et
H
H
H
H
Bu
Bu
Bu
Ph
4ꢀClC6H4
Ph
71
90
88
65
4l
1
2
3
4
5
6
7
8
tBu
tBu
Et
4m
4n
4o
matic ring adjacent to the chalcone carbonyl, as in the case of
compound 1x (Scheme 5.b). The possibility of a cyclization of
ban aromatic nitro derivative was also discarded, since the
chalcone 6a failed to afford the corresponding carbazole 4a
under our reaction conditions (Scheme 5.c).
2ꢀNO2C6H4
Ph
a
b
Yield of isolated products. In this case, the starting
mixture was heated in a microwave reactor at 100 ºC, for 4
hours, then the temperature was increased to 140 ºC for
additional 2.5 hours
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orthoꢀnitrated chalcones proceeded in full regioselectivity,
giving only cyclizations para with respect to the alkylamino
substituent (entries 4, 6, 10 and 14). This observation has
mechanistic relevance, as will be discussed below.
The structure of the carbazole derivatives was derived from
spectral data (see the Supporting Information for a summary
of the 2DꢀNMR study of compound 4l) and confirmed by
single cristal XꢀRay diffraction of 4f (see the corresponding
ORTEP diagram in the Supporting Information).
The carbazole synthesis described above raises some points of
mechanistic interest. The overall process can be viewed as the
combination of the initial threeꢀcomponent reaction that genꢀ
erates a cyclohexadiene derivative with a second domino
transformation involving a Lewis acidꢀcatalyzed heterocyꢀ
clization. The MCR can be assumed to take place by the
mechanism summarized in Scheme 4, involving the formation
of a βꢀenaminone from the primary amine and βꢀdicarbonyl
components followed by a Michael addition to the chalcone,
imineꢀenamine tautomerism and a final cyclocondensation
step. The intermediacy of a βꢀenaminone in this mechanism
has been proved previously.27
Scheme 5. (a) Initial mechanistic proposal, based on refer-
ence 23 and initiated by the enolization of the ester group
in intermediate 5. This proposal was subsequently discard-
ed on the basis of experimental evidence (b and c).
The commonly accepted mechanism for the reductive cyclizaꢀ
tion of nitroaromatics involves the formation of nitrenes.
However, Houk and Davies have presented computational
evidence for the existence of oxygenated intermediates conꢀ
sidering a nitroso derivative as starting point.30 Consequently,
an alternative process initiated by reduction of the nitro group
to nitroso and concomitant aromatization of the cyclohexadiꢀ
ene ring was considered with the help of computational DFT
methods (for details, see the SI). For convenience, this mechaꢀ
nism has been divided into three stages (Scheme 6): i) transꢀ
formation of 5 into intermediate I; ii) transformation of interꢀ
mediate I into Nꢀhydroxycarbazole II and iii) reductive loss of
the hydroxy group, leading to the final product 4.
Scheme 4. Literature-based mechanistic proposal for the
initial three-component reaction
A mechanism for the transformation of compounds 5 into the
observed carbazoles 4 based on an initial enolization (Scheme
5.a) may be feasible in principle, and indeed this pathway is
similar to the one proposed in the closest literature precedent
to our reaction, involving the synthesis of 3ꢀ
hydroxycarbazoles from oꢀnitrochalcones and βꢀdicarbonyl
compounds in the presence of Cs2CO3.23 However, this mechꢀ
anism can be discarded in our case because it is not compatiꢀ
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located. Since it is well known that proton transfers usually are
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5
6
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8
bimolecular processes and the reaction is carried out in EtOH,
we added a discrete molecule of MeOH to calculations. The
first step is the formation of intermediate nitrone VII from I
through transition state TS1. A further 1,3ꢀH shift promoted
by a molecule of solvent would afford hydroxylamine II
through TS2. The rateꢀlimiting step of the process is the forꢀ
mation of VII from I, with a barrier of 27.4 kcal/mol. The
whole transformation from I to II is exergonic by 17.9
kcal/mol (Figures S2 and S3, Supporting Information). The
geometries of TS1 and TS2 are given in Figure 3.
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Scheme 6. The three stages proposed for the transfor-
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mation of intermediate 5 into carbazole 4.
Stage 1
Our hypothesis is based on the initial nitro to nitroso transforꢀ
mation driven by CAN, with the requirement of an accessible
proton. The whole catalytic process involves a coupled hydroꢀ
genationꢀdehydrogenation within the same molecule. Coupled
dehydrogenation/hydrogenation processes are known in the
literature and include the traditional Skraup quinoline syntheꢀ
sis, in which nitrobenzene acts as a hydrogen acceptor with
concomitant dehydrogenation of another molecule. These
transformations have been performed in the presence of a
number of catalysts,31 but intramolecular examples are rare.32
Scheme 7 illustrates the catalytic cycle proposed for stage 1,
and the optimized geometries for all intermediates can be
found in the Supporting Information (Figure S1). The catalytic
species III, generated initially from CAN, coordinates the
nitro group in 5 to give intermediate IV. Hydride transfer of
Ha to the nitro group to give V is promoted by cerium by
transferring the positive charge from the nitro nitrogen toꢀ
wards the amine nitrogen even though it will be delocalized by
the whole conjugated system. The charge of the amine nitroꢀ
gen is essentially the same throughout the process. In fact, the
displaced charge is delocalized by the whole conjugated sysꢀ
tem, the representation V in Scheme 7 being a resonant form.
Scheme 7. Catalytic cycle proposed to explain stage 1 of
our mechanism
The Hꢀtransfer elongates the corresponding NꢀO bond faciliꢀ
tating its cleavage in the next step. Further aromatization by
loss of one Hb proton to form water gives rise to VI in which
the nitroso group is formed. The subsequent release of nitroso
intermediate I and water regenerates III, which continues the
cycle. Minima I, III, IV and V have been located and the
geometrical parameters are in agreement with the formation of
V and VI, the nitroso group being already formed in the latter
(Figure 2). After the first hydride transfer both NꢀO bonds are
different (1.35 Å for that coordinated to cerium and 1.52 Å for
that to which hydride has been transferred). The N=O distance
in VI is reduced to 1.24 Å, in agreement with a N=O double
bond that is further away from cerium than in V. The thermoꢀ
dynamics of the transformation of IV into VI is highly favoraꢀ
ble (ca. ꢀ90 kcal/mol) as well as the transformation of 5 into I
+ H2O (ꢁG = ꢀ11.8 kcal/mol).
Figure 2. Geometrical parameters in angstroms (black)
and selected NBO charges (red for negative and blue for
positive) for intermediates V and VI.
In some instances, it has been reported that 1,3ꢀH shifts take
place through two consecutive 1,2ꢀH shifts. Although such a
process is not possible for VII, we have studied an alternative
transformation of VII into II through an initial 1,2ꢀH shift
followed by a MeOHꢀassisted 1,4ꢀH shift (Figure S4, Supportꢀ
ing Information). However, the rateꢀlimiting step for this route
is higher (37.9 kcal/mol) than the direct 1,3ꢀH shift shown in
Scheme 8 and Figure 3.
Stage 2
Once the nitroso intermediate I is formed, the reaction proꢀ
ceeds following the mechanism suggested by Davies and
Houk (Scheme 8).30 We have carried out a complete DFT
analysis of the process and all stationary points have been
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oxidized and reduced species come from the system, CAN
does not act as a typical oxidizing agent but as an electron
transporter,33 and can be employed in catalytic amounts.34
1
2
3
4
5
6
7
8
9
O
OMe
Me
N
+1
O
N
H
H
N
O
O
O
O
Ph
O
Ce
O
N
O
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N
+1
O
O
N
O
O
O
H
O
IX
Cycle II
Ce
O
N
H
O
N
O
O
O
O
II
XII
CeIV(NO3)6(NH4)2
O
O
N
O
O
OMe
N
+1
O
Ce
H2O
O
H3C-OH
4
N
N
N
O
O
O
Me
O
III
Ph
XI
O
+1
N
H
H
+1
H
H
N
O
Ph
O
C
O
O
N
Ce IV
H
Cycle I
O
O
O
N
O
MeO2C
NMe
O
N
O
O
H
Ce
Scheme 8. Formation of hydroxycarbazole II from the
nitroso intermediate I (relative free-energies are given in
kcal/mol)
O
N
O
O
VIII
N
O
O
O
O
H
O
XIII
+1
HCHO
H
O
N
O
O
H
O
H
Ce IV
O
O
N
N
O
O
O
X
Scheme 9. Catalytic cycles for stage 3.
Catalytic transfer hydrogenation from alcohols is known in the
literature, and it has been performed in the presence of cataꢀ
lysts such as magnesium oxide, zirconium oxide, MgOꢀB2O3,
Al2O3ꢀAlPO4 and several ruthenium species.35 In order to
obtain experimental support for the reduction of quinoid sysꢀ
tems by primary alcohols in the presence of CAN, we exposed
benzoquinone to our usual reaction conditions, and found that
it was transformed into hydroquinone in quantitative yield
(Scheme 10a). Thus, computational support for catalytic cyꢀ
cles I and II given in Scheme 9 has been obtained by studying
the quinone/hydroquinone model system, as illustrated in
Scheme 10b. We have located all the minima and demonstratꢀ
ed the ability of CAN to promote electron transfer from methꢀ
anol to quinone QU to form formaldehyde and hydroquinone
HQ. The catalytic species in all cases is III which forms VIII
leading to a concomitant Hꢀtransfer and βꢀelimination yielding
X. A typical hydride C=O insertion releasing formaldehyde
forms intermediate XIIIq which upon a second Hꢀtransfer
regenerates the catalytic species III and produces hydroquiꢀ
none HQ. The overall process was thermodynamically favoraꢀ
ble (ꢀG = ꢀ14.7 kcal/mol). The optimized geometries for the
intermediates of this catalytic cycle can be found in the Supꢀ
porting Information (Figure S5).
Figure 3. Transition states for the transformation of I into
II (distances are in angstroms).
Stage 3
The final stage consists of a deoxygenation from II to yield
the final product 4. This transformation is proposed to be also
catalyzed by CAN via the catalytic cycle outlined in Scheme
9, formed by two internal cycles and taking place at the exꢀ
pense of the oxidation of methanol into formaldehyde. Firstly,
CAN forms the catalytic species III which takes the MeOH
molecule from II to form VIII and IX. VIII is converted into
X were the methanol has been oxidized to acetaldehyde (cycle
I). Loss of the NH proton in IX (cycle II) furnishes quinoid
intermediate XI together with XII which, upon release of a
water molecule, regenerates the catalytic species III. Intermeꢀ
diate XI then enters cycle I and forms XIII by reaction with
X, with release of formaldehyde (the oxidized species). Proton
transfer in XIII regenerates III and releases the final reduced
species, the final product 4. The global balance for this stage 3
is the transformation of II + MeOH into 4 + HCHO mediated
by CAN, with an overall ꢀG = ꢀ14.3 kcal/mol. Since both
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Finally, in order to underscore the synthetic applicability of
1
the carbazole derivatives obtained by our method, we underꢀ
took a brief study of the synthesis of indolocarbazoles. This
ring system represents an important class of nitrogen heteroꢀ
cycles, with a broad array of applications, especially in the
fields of cancer chemotherapy and the chemistry of new mateꢀ
rials.36 Among the possible indolocarbazole regioisomers, the
indolo[3,2ꢀa]carbazole framework has received the least attenꢀ
tion because of the absence of efficient and selective methods
for its synthesis. With these ideas in mind, we briefly examꢀ
ined the preparation of indolo[3,2ꢀa]carbazoles based on the
chemistry described in this article. While, in agreement with
our initial data discussed above (Table 2), oneꢀpot double
cyclizations from chalcones bearing two ortho substituents
were not feasible (Scheme 11.a), the second carbazole was
readily generated using a microwaveꢀpromoted Cadogan reacꢀ
tion in the presence of triethyl phosphite in toluene, as shown
by the preparation of three representative derivatives of
framework 7 from the corresponding carbazoles 4 (Scheme
11.b and Table 3).
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Results obtained in the synthesis of indolo[3,2-
a]carbazoles
Entry
R1
R2
R3
Product
Yield,
%
1
2
3
H
H
H
Br
H
67
58
62
7a
7b
7c
Br
H
Scheme 10. Experimental support for the reduction of a
simple quinone system under our reaction conditions and
its mechanistic explanation
ꢀOꢀCH2ꢀOꢀ
CONCLUSIONS
Both targetꢀoriented and propertyꢀoriented synthesis require
tools that allow the rapid generation of molecular diversity and
complexity from simple building blocks. In this context, we
disclose in this article a method for the synthesis of highly
substituted and functionalized carbazole derivatives via a
threeꢀcomponent reaction between oꢀnitrochalcones, primary
amines and βꢀdicarbonyl compounds. This reaction involves
the generation of two rings and four new bonds (two CꢀC and
two CꢀN) and proceeds in high atom economy, with water as
the only side product. Mechanistically, it involves an
intramolecular hydrogenationꢀdehydrogenation process driven
by CAN, the functionalization of a CꢀH group by direct attack
onto a nitrogen function and a CANꢀcatalyzed reduction via
hydride transfer from ethanol. The proposed mechanism was
based on experimental observations and computational
studies.
EXPERIMENTAL SECTION
General experimental details. All reagents and solvents were of
commercial quality and were used as received. Reactions were moniꢀ
tored by thin layer chromatography on aluminium plates coated with
silica gel and fluorescent indicator. Separations by flash chromatogꢀ
raphy were performed on silica gel (40–63
 m particle size). Melting
points were determined in capillary tubes using an immersion appaꢀ
ratus and are uncorrected. Separations by flash chromatography were
performed on silica gel columns, either manually or using an
automated flash chromatograph. A CEMꢀDiscover focused microꢀ
wave synthesizer with microwave power maximum level of 300 W
and microwave frequency of 2455 MHz was employed for the miꢀ
crowaveꢀassisted reactions, which were performed in sealed vessels
Scheme 11. Synthesis of some indolo[3,2-a]carbazoles by
application of the Cadogan reaction to compounds 4
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controlling the reaction temperature with an internal temperature
Hz, 1H), 1.68 – 1.51 (m, 4H), 1.51 – 1.34 (m, 3H), 1.07 – 0.89 (m,
probe. Infrared spectra were recorded with a FTIR spectrophotometer
working by attenuated total reflection (ATR), with a diamond accesoꢀ
ry for solid and liquid samples. NMR spectroscopic data were recordꢀ
7H). 13C NMR (63 MHz, CDCl3) 169.9, 154.5, 149.4, 148.0, 144.1,
140.4, 136.5, 133.0, 132.4, 130.3, 129.9, 129.0, 127.1, 124.5, 124.0,
118.8, 88.8, 59.1, 42.9, 35.5, 32.8, 32.1, 30.4, 20.2, 14.0.
1
2
3
4
5
6
7
8
1
ed using a spectrometer operating at 250 MHz for H NMR and 63
MHz for 13C NMR; chemical shifts are given in ppm and coupling
constants in Hertz. Elemental analyses were determined using a
microanalyzer based on the flash combustion technique.
General procedure for the preparation of carbazoles 4. A tube
containing a mixture of the suitable primary amine (1 eq), the suitable
βꢀketoester (1 eq), the suitable nitrochalcone (1 eq), CAN (0.1 eq) in
absolute EtOH (2 mL) was sealed and placed in the cavity of a CEM
Discover microwave reactor. The tube was subjected to microwave
irradiation, programmed at 100 °C and 200 W. After a period of 2ꢀ3
min, the temperature was kept constant at 100 °C for 2.5 hours. Then
the reaction mixture was irradiated for an additional period of 2.5
hours at 140 °C. The tube was cooled to room temperature, the solꢀ
vent was removed in vacuo to dryness and the residue was purified by
flash column chromatography on silica gel eluting with petroleum
ether/ ethyl acetate (95/5), to give compounds 4.
General procedure for the preparation of chalcones 1. To a soꢀ
lution of the suitable acetophenone (30 mmol) and oꢀ
nitrobenzaldehyde (30 mmol) in ethanol (30 mL) was added 6M
aqueous sodium hydroxide solution. The reaction was stirred at room
temperature and monitored by TLC for completion. The precipitated
solid was filtered and purified by recrystallization from ethanol,
affording chalcones 1. For characterization data of these compounds,
see the Supporting Information.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 3-(butylamino)-1-phenyl-9H-carbazole-4-carboxylate (4a).
Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀphenylꢀ2ꢀpropenꢀ1ꢀone 1a
(507 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol) and
butylamine (0.20 mL, 2.0 mmol). Yield: 657 mg (85 %), as a pale
brown oil. Elemental analysis (%) calcd for C25H26N2O2 (M= 386.49):
General
procedure
for
the
preparation
of
5,6-
dihydroanthranilates 5. A tube containing a mixture of butylamine
(1.3 eq), ethyl acetoacetate (1 eq), the suitable oꢀnitrochalcone 1 (1.1
eq) and CAN (0.1 eq) in EtOH (2 mL) was sealed and placed in a
CEM Discover microwave oven. The tube was subjected to microꢀ
wave irradiation, programmed at 100 °C and 200 W. After a period of
2ꢀ3 min, the temperature remained constant at 100 °C. After compleꢀ
tion of the reaction (2.5 hours), the tube was cooled to room temperaꢀ
ture and the solvent was removed in vacuum to dryness and the resiꢀ
due was purified by column chromatography on silica gel, eluting
with petroleum ether/EtOAc (9/1) to give compounds 5.
C, 77.69; H, 6.78; N, 7.25; found: C, 77.73; H, 6.82; N, 7.21. IR
1
(neat)
νmax 3379, 1674, 1524, 1236 cmꢀ1. H NMR (250 MHz,
CDCl3) δ 8.25 (d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 7.68 (dd, J = 8.2, 1.4
Hz, 2H), 7.61 – 7.53 (m, 2H), 7.52 – 7.47 (m, 1H), 7.38 – 7.32 (m,
2H), 7.19 – 7.09 (m, 1H), 6.90 (s, 1H), 4.60 (q, J = 7.2 Hz, 2H), 3.27
(t, J = 7.0 Hz, 2H), 1.71 (q, J = 7.4, 7.0 Hz, 2H), 1.61 – 1.54 (m, 2H),
1.49 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz,
CDCl3) δ 169.5, 140.6, 138.7, 130.9, 129.6, 129.4, 128.6, 128.4,
126.0, 124.7, 122.8, 122.2, 118.7, 111.9, 110.9, 60.9, 44.4, 31.8, 20.6,
14.5, 14.1.
Ethyl-6-butylamino-2-(4-nitrophenyl)-4-phenyl-2,3-
dihydrobenzoate (5a). Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀphenylꢀ
2ꢀpropenꢀ1ꢀone 1a (0.55 g, 2.2 mmol) according to the general proceꢀ
dure, and obtained as a pale brown oil (665 mg, 72%). Elemental
analysis (%) calcd for C25H28N2O4 (M= 420.50): C, 71.41; H, 6.71; N,
6.66; found: C, 71.37; H, 6.73; N, 6.62. IR (film) νmax: 3266, 2957,
Ethyl 3-(butylamino)-1-(p-tolyl)-9H-carbazole-4-carboxylate (4b).
Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀ(pꢀtolyl)ꢀ2ꢀpropenꢀ1ꢀone 1b
(535 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol) and
butylamine (0.20 mL, 2.0 mmol). Yield: 657 mg (82 %), as a pale
yellow oil. Elemental analysis (%) calcd for C26H28N2O2 (M=
400.51): C, 77.97; H, 7.05; N, 6.99; found: C, 77.92; H, 7.08; N, 7.02.
1646 cmꢀ1; H NMR (250 MHz, CDCl3) 9.11 (s, 1H), 8.09 (d, J =
1
8.8 Hz, 2H), 7.49 – 7.30 (m, 8H), 6.69 (d, J = 2.8 Hz, 1H), 4.37 (d, J
= 7.3 Hz, 1H), 4.18 – 3.97 (m, 2H), 3.51 – 3.35 (m, 2H), 3.24 (ddd, J
= 16.9, 8.6, 2.9 Hz, 1H), 2.91 (dd, J = 16.9, 1.7 Hz, 1H), 1.78 – 1.63
(m, 2H), 1.59 – 1.44 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.2
Hz, 3H); 13C NMR (63 MHz, CDCl3) 169.9, 155.2, 154.0, 146.3,
145.9, 139.7, 128.9, 128.7, 128.0, 125.7, 123.3, 116.2, 87.8, 58.8,
42.7, 37.0, 34.6, 32.6, 20.1, 14.5, 13.8.
1
IR (neat) νmax 3385, 2958, 1667, 1524, 1237 cmꢀ1. H NMR (250
MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz, 1H), 8.11 (s, 1H), 7.57 (d, J = 8.1
Hz, 2H), 7.42 – 7.32 (m, 5H), 7.19 – 7.08 (m, 1H), 6.92 (s, 1H), 4.60
(q, J = 7.2 Hz, 2H), 3.27 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 1.81 – 1.62
(m, 2H), 1.64 – 1.53 (m, 2H), 1.49 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.3
Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.5, 140.6, 138.3, 135.7,
131.0, 130.2, 130.1, 128.4, 125.9, 124.7, 122.8, 122.1, 118.7, 110.9,
60.9, 31.7, 21.5, 20.5, 14.5, 14.1.
Ethyl-6-butylamino-2-phenyl-4-(4-nitrophenyl)-2,3-
dihydrobenzoate (5b). Prepared from (E)ꢀ1ꢀ(2ꢀnitrophenyl)ꢀ3ꢀphenylꢀ
2ꢀpropenꢀ1ꢀone 1m (1000 mg, 3.95 mmol), ethyl acetoacetate (0.45
mL, 3.59 mmol) and butylamine (0.46 mL, 4.67 mmol). Yield: 1253
mg (83 %), as a pale brown oil. Elemental analysis (%) calcd for
C25H28N2O4 (M= 420.50): C, 71.41; H, 6.71; N, 6.66; found: C, 71.37;
H, 6.73; N, 6.62. IR max (film): 2957, 2925, 2868, 1675, 1586, 1524
Ethyl
3-(butylamino)-6-chloro-1-phenyl-9H-carbazole-4-
carboxylate (4c). Prepared from (E)ꢀ3ꢀ(5ꢀchloroꢀ2ꢀnitrophenyl)ꢀ1ꢀ
phenylꢀ2ꢀpropenꢀ1ꢀone 1c (575 mg, 2.0 mmol), ethyl acetoacetate
(0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0 mmol). Yield:
657 mg (78 %), as a brown oil. Elemental analysis (%) calcd for
C25H25ClN2O2 (M= 420.93): C, 71.33; H, 5.99; N, 6.66; found: C,
71.32; H, 6.03; N, 6.62. IR (neat) νmax 3372, 2957, 1668, 1236
cmꢀ1. 1H NMR (250 MHz, CDCl3) δ 8.31 (d, J = 1.9 Hz, 1H), 8.12 (s,
1H), 7.69 – 7.62 (m, 2H), 7.61 – 7.55 (m, 2H), 7.54 – 7.47 (m, 1H),
7.30 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.94 (s, 1H), 4.61
(q, J = 7.2 Hz, 2H), 3.27 (t, J = 7.0 Hz, 2H), 1.80 – 1.66 (m, 2H),
1.54 (t, J = 7.2 Hz, 3H), 1.52 – 1.39 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).
13C NMR (63 MHz, CDCl3) δ 169.1, 138.7, 138.3, 131.4, 129.5,
128.6, 128.5, 126.0, 124.7, 124.0, 123.9, 121.3, 111.8, 61.2, 44.5,
31.6, 20.5, 14.4, 14.1.
1
cmꢀ1. H NMR (250 MHz, CDCl3) 9.05 (s, J = 5.2 Hz, 1H), 7.88
(dd, J = 7.8, 1.6 Hz, 1H), 7.54 – 7.35 (m, 3H), 7.34 – 7.30 (m, 2H),
7.27 – 7.18 (m, 2H), 6.83 (dd, J = 7.4, 1.7 Hz, 1H), 6.35 (d, J = 3.0
Hz, 1H), 4.29 (dd, J = 8.2, 1.5 Hz, 1H), 4.22 – 3.98 (m, 2H), 3.44 –
3.23 (m, 3H), 2.56 (dd, J = 16.6, 1.7 Hz, 1H), 1.77 – 1.58 (m, 2H),
1.58 – 1.40 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H).
13C NMR (63 MHz, CDCl3)
170.4, 154.5, 148.0, 145.2, 143.7,
137.0, 132.9, 129.9, 128.6, 128.1, 127.5, 126.1, 124.1, 119.3, 89.6,
58.9, 43.0, 37.2, 36.8, 32.9, 20.2, 14.6, 14.0.
Ethyl-6-butylamino-2,4-bis(2-nitrophenyl)-2,3-dihydrobenzoate
(5c). Prepared from (E)ꢀ1,3ꢀbis(2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ1ꢀone 1d
(1000 mg, 3.35 mmol), ethyl acetoacetate (0.39 mL, 3.05 mmol) and
butylamine (0.39 mL, 3.96 mmol). Yield: 880 mg (62 %), as a pale
brown solid. Mp: 139ꢀ140 ºC. Elemental analysis (%) calcd for
C25H27N3O6 (M= 465.50): C, 64.50; H, 5.85; N, 9.03; found: C, 64.47;
H, 5.85; N, 9.06. IR max (film): 2957, 2930, 2868, 1653, 1577, 1519
Ethyl
3-(butylamino)-1-(2-nitrophenyl)-9H-carbazole-4-
carboxylate (4d). Prepared from (E)ꢀ1,3ꢀbis(2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ
1ꢀone 1d (597 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol)
and butylamine (0.20 mL, 2.0 mmol). Yield: 716 mg (83 %), as a red
oil. Elemental analysis (%) calcd for C25H25N3O4 (M= 431.48): C,
69.59; H, 5.84; N, 9.74; found: C, 69.63; H, 5.86; N, 9.77. IR (neat)
νmax 3377, 2959, 1668, 1526 1236 cmꢀ1. 1H NMR (250 MHz,
CDCl3) δ 8.25 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.78 –
7.67 (m, 2H), 7.65 – 7.54 (m, 2H), 7.36 (ddd, J = 7.8, 6.6, 1.1 Hz,
1
cmꢀ1. H NMR (250 MHz, CDCl3) 9.00 (s, 1H), 8.10 (dd, J = 8.2,
1.0 Hz, 1H), 7.84 (dd, J = 8.0, 1.3 Hz, 1H), 7.79 – 7.68 (m, 2H), 7.65
– 7.56 (m, 1H), 7.55 – 7.37 (m, 5H), 7.35 – 7.27 (m, 1H), 7.04 (dd, J
= 7.6, 1.5 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 4.68 (dd, J = 9.9, 1.3 Hz,
1H), 4.01 – 3.75 (m, 2H), 3.43 – 3.21 (m, 3H), 2.66 (dd, J = 17.8, 1.5
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The Journal of Organic Chemistry
1H), 7.32 – 7.27 (m, 1H), 7.15 (ddd, J = 8.2, 6.6, 1.6 Hz, 1H), 6.72 (s,
(0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0 mmol). Yield:
723 mg (81 %), as a brown oil. Elemental analysis (%) calcd for
C27H30N2O4 (M= 446.54): C, 72.62; H, 6.77; N, 6.27; found: C, 72.65;
1H), 4.60 (q, J = 7.2 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H), 1.75 – 1.61
(m, 2H), 1.50 (t, J = 7.2 Hz, 3H), 1.48 – 1.36 (m, 2H), 0.97 (t, J = 7.3
Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.3, 149.7, 140.8, 133.1,
132.6, 132.3, 130.5, 129.5, 126.3, 126.1, 124.8, 124.7, 122.8, 122.6,
119.0, 111.5, 111.1, 61.0, 44.3, 31.6, 20.5, 14.5, 14.1.
Ethyl 6-bromo-1-(4-bromophenyl)-3-(butylamino)-9H-carbazole-4-
carboxylate (4e). Prepared from (E)ꢀ3ꢀ(5ꢀbromoꢀ2ꢀnitrophenyl)ꢀ1ꢀ(4ꢀ
bromophenyl)ꢀ2ꢀpropenꢀ1ꢀone 1e (822 mg, 2.0 mmol), ethyl acetoꢀ
acetate (0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0 mmol).
Yield: 784 mg (72 %), as a brown oil. Elemental analysis (%) calcd
for C25H24Br2N2O2 (M= 544.28): C, 55.17; H, 4.44; N, 5.15; found: C,
1
2
3
4
5
6
7
8
H, 6.74; N, 6.29. IR (neat)
νmax 3364, 2853, 1673 cmꢀ1. 1H RMN
(250 MHz, CDCl3) δ 8.03 (s, 1H), 7.80 (s, 1H), 7.70 (dd, J = 8.2, 1.4
Hz, 2H), 7.62 – 7.52 (m, 2H), 7.52 – 7.44 (m, 1H), 6.85 (s, 1H), 6.83
(s, 1H), 4.64 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.94 (s, J = 2.0 Hz,
3H), 3.29 (t, J = 7.0 Hz, 2H), 1.75 (dt, J = 14.4, 7.0 Hz, 2H), 1.64 –
1.40 (m, 5H), 1.01 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ
169.4, 149.8, 145.9, 143.4, 138.8, 136.2, 130.8, 130.4, 129.3, 128.6,
128.5, 122.7, 115.1, 110.2, 107.2, 104.2, 93.6, 60.7, 56.6, 56.0, 44.4,
31.8, 20.5, 14.7, 14.1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
55.23; H, 4.47; N, 5.21. IR (neat)
νmax 3439, 3377, 2930, 1668,
Ethyl
8-(butylamino)-6-(2-nitrophenyl)-5H-[1,3]dioxolo[4,5-
(4j). Prepared from (E)ꢀ3ꢀ(6ꢀ
1525, 1236 cmꢀ1. H NMR (250 MHz, CDCl3) δ 8.46 (d, J = 1.9 Hz,
1H), 8.01 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),
7.42 (dd, J = 8.6, 1.9 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H),
6.84 (s, 1H), 4.59 (q, J = 7.2 Hz, 2H), 3.24 (t, J = 6.9 Hz, 2H), 1.83 –
1.63 (m, 2H), 1.55 (t, J = 7.2 Hz, 3H), 1.56 – 1.33 (m, 2H), 0.98 (t, J
= 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.1, 146.5, 139.1,
137.2, 132.6, 130.3, 130.1, 130.1, 128.6, 127.7, 124.5, 122.7, 121.5,
112.3, 111.6, 104.4, 61.2, 44.1, 31.7, 20.5, 14.3, 14.1.
b]carbazole-9-carboxylate
1
nitrobenzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ1ꢀ(2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ1ꢀone 1j
(685 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol) and
butylamine (0.20 mL, 2.0 mmol). Yield: 742 mg (78 %), as a brown
oil. Elemental analysis (%) calcd for C26H25N3O6 (M= 475.49): C,
65.67; H, 5.30; N, 8.84; found: C, 65.64; H, 5.33; N, 8.85. IR
(neat) νmax 3376, 2925, 1673 cmꢀ1. H RMN (250 MHz, CDCl3) δ
1
8.08 – 7.99 (m, 1H), 7.78 – 7.56 (m, 5H), 6.68 (d, J = 32.0 Hz, 2H),
6.00 (s, 2H), 4.60 (q, J = 7.1 Hz, 2H), 3.23 – 3.14 (m, J = 7.0 Hz,
2H), 1.77 – 1.62 (m, 2H), 1.52 (t, J = 7.2 Hz, 3H), 1.48 – 1.38 (m,
2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.2,
149.7, 147.6, 145.6, 142.2, 136.9, 133.0, 132.6, 132.3, 130.5, 129.4,
126.0, 124.7, 122.9, 116.0, 109.8, 104.9, 103.5, 101.2, 91.7, 60.9,
44.2, 31.7, 20.5, 14.5, 14.1
Ethyl
6-bromo-1-(4-bromo-2-nitrophenyl)-3-(butylamino)-9H-
carbazole-4-carboxylate (4f). Prepared from (E)ꢀ1ꢀ(4ꢀbromoꢀ2ꢀ
nitrophenyl)ꢀ3ꢀ(5ꢀbromoꢀ2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ1ꢀone 1f (912 mg,
2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol) and butylamine
(0.20 mL, 2.0 mmol). Yield: 448 mg (76 %), as a dark brown oil.
Elemental analysis (%) calcd for C25H23Br2N3O4 (M= 589.28): C,
50.96; H, 3.93; N, 7.13; found: C, 50.91; H, 3.89; N, 7.16. IR
(neat) νmax 3348, 2931, 1673, 1526, 1234 cmꢀ1. 1H NMR (250
MHz, CDCl3) δ 8.46 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H),
7.78 (d, J = 2.1 Hz, 1H), 7.76 – 7.70 (m, 2H), 7.43 (dd, J = 8.6, 1.9
Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 6.70 (s, 1H), 4.60 (q, J = 7.2 Hz,
2H), 3.17 (t, J = 7.0 Hz, 2H), 1.75 – 1.61 (m, 2H), 1.55 (t, J = 7.2 Hz,
3H), 1.52 – 1.37 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (63
MHz, CDCl3) δ 168.9, 148.2, 139.3, 135.2, 134.3, 132.8, 129.0,
127.8, 126.3, 124.4, 121.8, 112.4, 111.9, 61.3, 44.2, 31.6, 29.8, 20.5,
14.3, 14.1.
Ethyl
carboxylate
3-(butylamino)-6,7-dimethoxy-1-(p-tolyl)-9H-carbazole-4-
(4k). Prepared from (E)ꢀ3ꢀ(4,5ꢀdimethoxyꢀ2ꢀ
nitrophenyl)ꢀ1ꢀ(pꢀtolyl)ꢀ2ꢀpropenꢀ1ꢀone 1k (655 mg, 2.0 mmol), ethyl
acetoacetate (0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0
mmol). Yield: 682 mg (74 %), as a brown oil. Elemental analysis (%)
calcd for C28H32N2O4 (M= 460.56): C, 73.02; H, 7.00; N, 6.08; found:
C, 73.07; H, 7.04; N, 6.05. IR (neat) νmax 3363, 2925, 1673 cmꢀ1. 1H
RMN (250 MHz, CDCl3) δ 8.06 (s, 1H), 7.79 (s, 1H), 7.58 (d, J = 8.1
Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 7.9 Hz, 1H), 6.86 (s,
1H), 4.64 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.95 (s, 3H), 3.30 (t, J =
7.0 Hz, 2H), 2.48 (s, 3H), 1.84 – 1.68 (m, 2H), 1.60 – 1.39 (m, 5H),
1.00 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.3, 149.9,
143.5, 138.3, 136.2, 130.9, 130.0, 128.4, 122.6, 115.1, 107.2, 93.6,
60.9, 56.7, 56.1, 45.2, 31.5, 21.4, 20.5, 14.7, 14.0.
Ethyl
6-bromo-3-(butylamino)-1-(p-tolyl)-9H-carbazole-4-
carboxylate (4g). Prepared from (E)ꢀ3ꢀ(5ꢀbromoꢀ2ꢀnitrophenyl)ꢀ1ꢀ(pꢀ
tolyl)ꢀ2ꢀpropenꢀ1ꢀone 1g (692 mg, 2.0 mmol), ethyl acetoacetate
(0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0 mmol). Yield:
834 mg (87 %), as an orange oil. Elemental analysis (%) calcd for
C26H27BrN2O2 (M= 479.41): C, 65.14; H, 5.68; N, 5.84; found: C,
65.26; H, 5.61; N, 5.87. IR (neat) νmax 3383, 2927, 1668, 1525,
Ethyl
3-(butylamino)-1-(4-chlorophenyl)-9H-carbazole-4-
carboxylate (4l). Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀ(4ꢀ
chlorophenyl)ꢀ2ꢀpropenꢀ1ꢀone 1l (575 mg, 2.0 mmol), ethyl acetoaceꢀ
tate (0.25 mL, 2.0 mmol) and butylamine (0.20 mL, 2.0 mmol). Yield:
598 mg (71%), as a yellow solid. Mp: 108ꢀ109 ºC. Elemental analysis
(%) calcd for C25H25ClN2O2 (M= 420.93): C, 71.33; H, 5.99; N, 6.66;
found: C, 71.32; H, 5.97; N, 6.64. IR (neat) νmax 2955, 2918, 2850,
1
1463, 1236 cmꢀ1. H NMR (250 MHz, CDCl3) δ 8.48 (d, J = 1.9 Hz,
1H), 8.10 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.42 (dd, J = 8.6, 2.0 Hz,
1H), 7.37 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.89 (s, 1H),
4.59 (q, J = 7.2 Hz, 2H), 3.26 (t, J = 7.0 Hz, 2H), 2.47 (s, 3H), 1.79 –
1.64 (m, 2H), 1.55 (t, J = 7.2 Hz, 3H), 1.53 – 1.39 (m, 2H), 0.98 (t, J
= 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.2, 146.7, 139.0,
138.5, 135.4, 131.5, 130.7, 130.2, 128.4, 127.7, 124.6, 121.1, 112.5,
112.2, 111.4, 61.1, 44.2, 31.8, 29.8, 21.5, 20.5, 14.4, 14.1.
Ethyl 3-(butylamino)-1-(furan-2-yl)-9H-carbazole-4-carboxylate
(4h). Prepared from (E)ꢀ1ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ1ꢀ
one 1h (486 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol)
and butylamine (0.20 mL, 2.0 mmol). Yield: 617 mg (82 %), as a red
oil. Elemental analysis (%) calcd for C23H24N2O3 (M= 376.45): C,
73.38; H, 6.43; N, 7.44; found: C, 73.41; H, 6.47; N, 7.46. IR
(neat) νmax 3380, 2926, 1713, 1682, 1524 cmꢀ1. 1H NMR (500
MHz, CDCl3) δ 9.15 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.73 (s, 1H),
7.49 (d, J = 8.0 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.21 – 7.12 (m, 2H),
6.94 (d, J = 3.4 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H), 4.61 (q, J =
7.2 Hz, 2H), 3.31 (t, J = 7.0 Hz, 2H), 1.80 – 1.72 (m, 2H), 1.57 – 1.53
(m, 2H), 1.51 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 169.3, 142.7, 141.9, 140.8, 137.9, 127.7, 126.3,
124.6, 123.4, 122.1, 118.7, 118.7, 117.3, 114.8, 112.1, 111.0, 107.6,
61.0, 31.7, 29.9, 20.6, 14.5, 14.1.
1677, 1600 cmꢀ1. H RMN (250 MHz, CDCl3) δ 8.31 – 8.24 (m, 1H),
1
8.05 (bs, 1H), 7.67 – 7.60 (m, 2H), 7.59 – 7.52 (m, 2H), 7.42 – 7.36
(m, 2H), 7.23 – 7.13 (m, 1H), 6.87 (s, 1H), 4.63 (q, J = 7.2 Hz, 2H),
3.28 (t, J = 7.0 Hz, 2H), 1.83 – 1.68 (m, 2H), 1.61 – 1.46 (m, 5H),
1.02 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.4, 145.8,
140.7, 137.1, 134.3, 130.1, 129.9, 129.6, 129.5, 126.1, 124.7, 122.7,
122.4, 118.8, 111.6, 110.9, 105.3, 61.0, 44.2, 31.7, 20.5, 14.5, 14.1.
tert-Butyl
3-(butylamino)-1-phenyl-9H-carbazole-4-carboxylate
(4m). Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀphenylꢀ2ꢀpropenꢀ1ꢀone
1m (507 mg, 2.0 mmol), tertꢀbutyl acetoacetate (0.33 mL, 2.0 mmol)
and butylamine (0.20 mL, 2.0 mmol). Yield: 746 mg (90 %), as a
brown oil. Elemental analysis (%) calcd for C27H30N2O2 (M= 414.54):
C, 78.23; H, 7.29; N, 6.76; found: C, 78.27; H, 7.34; N, 6.73. IR νmax
(film) 3382, 2852, 1674 cmꢀ1. H RMN (250 MHz, CDCl3) δ 8.42
1
(d, J = 8.1 Hz, 1H), 8.14 (s, 1H), 7.72 (d, J = 6.8 Hz, 2H), 7.60 (t, J =
7.3 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.20 (ddd,
J = 8.2, 6.0, 2.2 Hz, 1H), 6.97 (s, 1H), 3.31 (t, J = 6.9 Hz, 2H), 1.81
(s, 9H), 1.79 – 1.65 (m, 2H), 1.63 – 1.43 (m, 2H), 1.03 (t, J = 7.3 Hz,
3H). 13C NMR (63 MHz, CDCl3) δ 168.6, 144.0, 140.6, 138.8, 130.7,
129.7, 129.4, 128.6, 128.2, 126.0, 124.7, 122.7, 122.0, 118.5, 112.3,
110.8, 108.5, 82.2, 44.8, 31.8, 28.7, 20.5, 14.1.
Ethyl
3-(butylamino)-6,7-dimethoxy-1-phenyl-9H-carbazole-4-
carboxylate (4i). Prepared from (E)ꢀ3ꢀ(4,5ꢀdimethoxyꢀ2ꢀnitrophenyl)ꢀ
1ꢀphenylꢀ2ꢀpropenꢀ1ꢀone 1i (627 mg, 2.0 mmol), ethyl acetoacetate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 12
tert-Butyl
3-(butylamino)-1-(2-nitrophenyl)-9H-carbazole-4-
53.88; H, 4.16; N, 7.54; found: C, 53.91; H, 4.18; N, 7.57. IR νmax
carboxylate (4n). Prepared from (E)ꢀ1,3ꢀbis(2ꢀnitrophenyl)ꢀ2ꢀpropenꢀ
1ꢀone 1d (597 mg, 2.0 mmol), tertꢀbutyl acetoacetate (0.33 mL, 2.0
mmol) and butylamine (0.20 mL, 2.0 mmol). Yield: 809 mg (88 %),
as a brown oil. Elemental analysis (%) calcd for C27H29N3O4 (M=
459.54): C, 70.57; H, 6.36; N, 9.14; found: C, 70.54; H, 6.32; N, 9.18.
(film): 2924, 2853, 1679 cmꢀ1. 1H NMR (250 MHz, CDCl3) δ 8.51 (d,
J = 3.1 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.43 – 7.33 (m, 1H), 7.29 – 7.20 (m, 1H), 7.17 (s, 1H), 6.94 (s, 1H),
4.54 (q, J = 7.2 Hz, 2H), 3.19 (q, J = 6.7, 6.1 Hz, 2H), 1.49 – 1.36
(m, 5H), 1.27 – 1.23 (m, 2H), 1.02 (d, J = 7.1 Hz, 3H). 13C NMR (63
MHz, CDCl3) δ 169.1, 146.5, 142.9, 139.2, 133.2, 132.5, 130.5,
128.8, 127.6, 126.9, 125.1, 124.3, 121.4, 117.6, 113.2, 112.4, 111.6,
110.6, 104.9, 61.3, 44.1, 31.7, 20.5, 14.4, 14.1.
1
2
3
4
5
6
7
8
IR νmax (film): 3374, 2854, 1707 cmꢀ1. H RMN (250 MHz, CDCl3) δ
1
8.38 (d, J = 8.1 Hz, 1H), 8.06 (dd, J = 7.9, 1.1 Hz, 1H), 7.80 – 7.71
(m, 2H), 7.69 – 7.58 (m, 2H), 7.43 – 7.30 (m, 2H), 7.23 – 7.13 (m,
1H), 6.84 (bs, 1H), 3.20 (t, J = 7.0 Hz, 2H), 1.78 (s, 9H), 1.76 – 1.65
(m, 3H), 1.59 – 1.41 (m, 3H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (63
MHz, CDCl3) δ 168.4, 167.0, 149.8, 140.8, 133.3, 132.7, 132.4,
130.9, 129.4, 126.3, 124.8, 124.7, 124.7, 122.7, 122.4, 118.9, 111.8,
110.9, 82.4, 44.7, 31.7, 28.7, 20.5, 14.1.
Ethyl 6-(butylamino)-7,13-dihydro-[1,3]dioxolo[4,5-b]indolo[2,3-
g]carbazole-5-carboxylate (7c). Prepared from ethyl 8ꢀ(butylamino)ꢀ
6ꢀ(2ꢀnitrophenyl)ꢀ5Hꢀ[1,3]dioxolo[4,5ꢀb]carbazoleꢀ9ꢀcarboxylate 4j
(444 mg, 1.0 mmol). Yield: 275 mg, (62 %), as a pale brown oil.
Elemental analysis (%) calcd for C26H25N3O4 (M= 443.49): C, 70.41;
H, 5.68; N, 9.47; found: C, 70.45; H, 5.62; N, 9.44; IR νmax (film)
3357, 2928,1703 cmꢀ1. 1H NMR (250 MHz, CDCl3) δ 8.51 (d, J = 3.1
Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43 –
7.33 (m, 1H), 7.29 – 7.20 (m, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 4.54 (q,
J = 7.2 Hz, 2H), 3.19 (q, J = 6.7, 6.1 Hz, 2H), 1.49 – 1.36 (m, 5H),
1.27 – 1.23 (m, 2H), 1.02 (d, J = 7.1 Hz, 3H). 13C NMR (63 MHz,
CDCl3) δ 170.6, 146.3, 143.1, 138.9, 137.8, 135.0, 132.3, 125.9,
125.4, 124.1, 122.5, 121.2, 120.1, 116.3, 111.4, 108.4, 101.4, 100.1,
92.8, 62.1, 55.5, 50.0, 31.9, 21.0, 15.0, 14.7.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 1-phenyl-3-(phenylamino)-9H-carbazol-4-carboxylate (4o).
Prepared from (E)ꢀ3ꢀ(2ꢀnitrophenyl)ꢀ1ꢀphenylꢀ2ꢀpropenꢀ1ꢀone 1a
(507 mg, 2.0 mmol), ethyl acetoacetate (0.25 mL, 2.0 mmol) and
aniline (0.18 mL, 2.0 mmol). Yield: 529 mg (65 %), as a pale brown
oil. Elemental analysis (%) calcd for C27H22N2O2 (M= 406.48): C,
79.78; H, 5.46; N, 6.89; found: C, 79.82; H, 5.48; N, 6.91. IR νmax
(film): 3385, 2925, 1711 cmꢀ1. H RMN (250 MHz, CDCl3) δ 8.28 (s,
1
1H), 8.17 (d, J = 8.1 Hz, 1H), 7.82 (s, 1H), 7.67 – 7.61 (m, 2H), 7.59
– 7.50 (m, 4H), 7.44 – 7.37 (m, 4H), 7.23 (s, 1H), 7.17 – 7.11 (m,
3H), 6.91 (t, J = 7.2 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2
Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 168.2, 143.4, 139.8, 137.4,
136.9, 132.2, 128.9, 128.8, 128.6, 127.9, 127.8, 127.7, 125.7, 123.1,
121.7, 120.2, 118.7, 117.6, 117.4, 110.4, 60.9, 13.7.
ASSOCIATED CONTENT
Supporting Information
Ethyl-6-butylamino-2-(2-nitrophenyl)-4-phenyl benzoate (6). Isoꢀ
lated during the optimization studies leading to 4a as a pale brown oil.
Elemental analysis (%) calcd for C25H26N2O4 (M= 418.48): C, 71.75;
H, 6.26; N, 6.69; found: C, 71.79; H, 6.24; N, 6.65. IR νmax (film):
Additional synthetic protocols, additional details of DFT calculaꢀ
tions and copies of spectra (pdf).
2925, 2854, 1656, 1595, 1522 cmꢀ1. H NMR (250 MHz, CDCl3) δ
1
The Supporting Information is available free of charge on the
ACS Publications website.
8.06 (dd, J = 8.1, 1.2 Hz, 1H), 7.76 – 7.55 (m, 3H), 7.54 – 7.31 (m,
6H), 6.94 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 1.7 Hz, 1H), 3.91 (q, J =
7.2 Hz, 2H), 3.31 (q, J = 6.8 Hz, 2H), 1.84 – 1.67 (m, 2H), 1.66 –
1.35 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7.2 Hz, 3H). 13C
NMR (63 MHz, CDCl3) δ 168.1, 151.1, 147.4, 144.9, 141.3, 140.0,
139.7, 131.8, 130.7, 128.3, 127.8, 126.9, 123.4, 115.6, 109.1, 108.0,
59.6, 42.7, 30.9, 20.1, 13.6, 12.8.
AUTHOR INFORMATION
Corresponding Author
General procedure for the microwave-assisted Cadogan reac-
tion for the synthesis of indolocarbazoles 7a-7c. A microwave tube
containing a solution of suitable starting carbazole (1 eq) and triethyl
phosphite (3 eq) in dry toluene (0.1 M), was closed and placed in the
cavity of a CEM Discover focused microwave oven. The reaction
mixture was irradiated with microwaves for 2 h, at 180 °C. The reacꢀ
tion mixture was allowed to cool to room temperature and was diluted
with AcOEt (20 mL). The organic phase was washed with water (10
mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and
evaporated under reduced pressure to give a residue that was purified
by column chromatography on silica gel, eluting with petroleum
ether/EtOAc.
* Pedro Merino, Instituto de Biocomputación y Fisica de Sistemas
Complejos (BIFI), Universidad de Zaragoza, 50009 Zaragoza,
Spain, eꢀmail: pmerino@unizar.es.
J. Carlos Menéndez,. Departamento de Química Orgánica y Farꢀ
macéutica, Universidad Complutense, Facutad de Farmacia, Plaza
de Ramón y Cajal s.n., 28010 Madrid, Spain, eꢀmail: joꢀ
secm@ucm.es.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
Ethyl
6-(butylamino)-5,12-dihydroindolo[3,2-a]carbazole-7-
carboxylate (7a). Prepared from ethyl 3ꢀ(butylamino)ꢀ1ꢀ(2ꢀ
nitrophenyl)ꢀ9Hꢀcarbazoleꢀ4ꢀcarboxylate 4d (432 mg, 1.0 mmol).
Yield: 268 mg (67 %), as a pale brown oil. Elemental analysis (%)
calcd for C25H25N3O2 (M= 399.48): C, 75.16; H, 6.31; N, 10.52;
ACKNOWLEDGMENT
found: C, 75.21; H, 6.34; N, 10.53. IR
(film) 3361, 2927,
max
Financial support from MINECO (grants CTQ2015ꢀ68630ꢀR, to
JCM, and CTQ2016ꢀ76155ꢀR, to PM) is gratefully acknowledged.
The authors also acknowledge with thanks the use of resources
from the supercomputers "Memento" and “Cierzo” and technical
expertise and assistance provided by BIFIꢀZCAM (Universidad de
Zaragoza, Spain) and the XꢀRay study of compound 4f, performed
by Dr. Francisca Sanz (Universidad de Salamanca).
1674, 1614, 1524, 1235 cmꢀ1. H NMR (250 MHz, CDCl3) δ 8.25 (d,
J = 8.2 Hz, 1H), 8.12 (s, 1H), 7.37 – 7.33 (m, 2H), 7.32 – 7.27 (m,
2H), 7.18 – 7.09 (m, 1H), 6.97 (s, 1H), 6.93 (dd, 2H), 6.88 (dd, J =
7.4, 1.2 Hz, 1H), 4.61 (q, J = 7.2 Hz, 2H), 3.25 (t, J = 7.0 Hz, 2H),
1.81 – 1.62 (m, 2H), 1.50 (t, J = 7.1 Hz, 3H), 1.47 – 1.42 (m, 2H),
0.97 (t, J = 7.3 Hz, 3H). 13C NMR (63 MHz, CDCl3) δ 169.4, 143.8,
140.8, 131.0, 129.7, 128.0, 126.2, 124.7, 123.5, 122.7, 122.1, 119.1,
118.8, 116.1, 111.1, 61.1, 31.6, 29.8, 20.5, 14.5, 14.1.
1
Ethyl-2,9-dibromo-6-(butylamino)-5,12-dihydroindolo[3,2-
a]carbazole-7-carboxylate (7b). Prepared from ethyl 6ꢀbromoꢀ1ꢀ(4ꢀ
bromoꢀ2ꢀnitrophenyl)ꢀ3ꢀ(butylamino)ꢀ9Hꢀcarbazoleꢀ4ꢀcarboxylate 4f
(589 mg, 1.0 mmol). Yield: 323 mg, (58 %), as a brown oil.
Elemental analysis (%) calcd for C25H23Br2N3O2 (M= 557.28): C,
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