Molybdenum-catalyzed synthesis of nitrogenated polyheterocycles from nitroarenes and glycols with reuse of waste reduction byproduct

Article abstract of DOI:10.1021/acs.orglett.7b02792

A novel domino reduction/imine formation/intramolecular cyclization/oxidation for the efficient synthesis of pyrrolo(indolo)[1,2-a]quinoxalines and pyrrolo(indolo)-[3,2-c]-quinolines from readily available nitrobenzenes and glycols is reported. The process utilizes the carbonyl byproduct of the initial dioxomolybdenum(VI)-catalyzed reduction of nitroaromatics with glycols as a reagent for the imine generation. This method represents the first sustainable domino reaction for the preparation of biologically relevant heterocycles that internally incorporates the waste formed in the first step to the final product.

Full text of DOI:10.1021/acs.orglett.7b02792

Letter
pubs.acs.org/OrgLett
Molybdenum-Catalyzed Synthesis of Nitrogenated Polyheterocycles
from Nitroarenes and Glycols with Reuse of Waste Reduction
Byproduct
́
Ruben Rubio-Presa, Marıa R. Pedrosa, Manuel A. Fernandez-Rodríguez, Francisco J. Arnaiz,
́
́
́
and Roberto Sanz*
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza Misael Banuelos s/n, 09001 Burgos, Spain
̃
S
* Supporting Information
ABSTRACT: A novel domino reduction/imine formation/
intramolecular cyclization/oxidation for the efficient synthesis
of pyrrolo(indolo)[1,2-a]quinoxalines and pyrrolo(indolo)-
[3,2-c]-quinolines from readily available nitrobenzenes and
glycols is reported. The process utilizes the carbonyl byproduct
of the initial dioxomolybdenum(VI)-catalyzed reduction of
nitroaromatics with glycols as a reagent for the imine
generation. This method represents the first sustainable
domino reaction for the preparation of biologically relevant heterocycles that internally incorporates the waste formed in the
first step to the final product.
itroaromatics are readily available, abundant, and
inexpensive nitrogen sources,1 which are typically
variety of glycols could be oxidatively cleaved with DMSO
(Scheme 1).10
At this point, we envisaged a new tandem sequence for the
synthesis of aza-polyheterocycles triggered by our Mo-catalyzed
reduction method of nitrobenzenes using pinacol, and
potentially other glycols, as reducing agents. We also thought
N
reduced to the corresponding anilines as the initial step for
accessing elaborated nitrogenated compounds. Nevertheless,
the direct use of nitroarenes as starting materials, avoiding their
prior reduction, is highly desirable for preparing value added
nitrogen-containing products in one-pot tandem reactions.2 In
this field, the straight production of aza-heterocycles from
nitrobenzene precursors has recently emerged as a powerful
and highly efficient synthetic tool.3
Also in the context of the searching for sustainable synthetic
methods, a highly interesting, although underexplored,
approach consists in the fine-tuning of “one-pot” tandem
reactions. Accordingly, the byproduct generated in the first step
of the sequence could be advantageously employed, as a
reagent or catalyst, for the following one. In the development of
this strategy, pioneered by Shibasaki4 and Zhou,5 most of the
few reported examples are byproduct-catalyzed reactions, i.e.,
processes in which the waste from one reaction catalyzes or
modulates a subsequent step in one-pot reaction sequences.6
Although some examples have been described in which a waste
generated in a first step of a given reaction is recycled and
employed as an essential reagent to facilitate the following
step,7 to the best of our knowledge, no precedent details the
reuse of a byproduct as a reagent, which ultimately is embodied
into the final product.
Scheme 1. Our Previous Work on Dioxomolybenum(VI)-
Catalyzed Reactions and Proposed Sequence for the
Synthesis of Polyheterocycles (This Work)
Following our interest in the development of clean and
efficient synthetic methodologies involving redox processes by
using nontoxic and easily available dioxomolybdenum(VI)
complexes as catalysts,8 we had previously reported that
nitrobenzenes could be efficiently reduced using pinacol as an
oxygen acceptor that releases acetone and water as the only
byproducts.9 In addition, we had also demonstrated that a
Received: September 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02792
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Organic Letters
Letter
that the synthetic efficiency could be significantly improved by
recycling the carbonyl byproduct of the upstream reduction
step, a carbonyl compound, as a reagent for the imine
formation step, thus incorporating it in the tandem reaction
(Scheme 1). Herein, we report our results exploiting this
concept, which allows the preparation of a wide variety of
interesting N-heterocycles from nitroaromatics.
as starting materials, and the fact that these aniline derivatives
are typically prepared by reduction of their nitroaromatic
precursors, the development of methods for using nitroarenes
as starting materials in one-pot processes represents a challenge
in the field.16
The next goal was to evaluate the scope of the new method
(Table 2). In a first set of experiments, the structure of the
With these goals in mind, we selected commercially or
readily available 1-(2-nitrophenyl) pyrrole 1a and 1,2-
diphenylethanediol 2a as model substrates for testing our
initial hypothesis (Table 1). After some experimentation,11 and
Table 2. Reactions of 1-(2-Nitrophenyl)pyrroles 1 with 1,2-
Diols 2. Synthesis of 3 and 4
a
a
Table 1. Preliminary Results
b
entry temp (° C) time (min)
additive
3aa/4aa ratio
1
2
3
4
5
180
180
180
180
170
30
60
1.3/1
4/1
6/1
1/0
1/0
30
cat. (20 mol %)
20
PTSA (50 mol %)
PTSA (50 mol %)
c
180
a
Reactions were conducted with 1a (0.25 mmol) and 2a (0.55 mmol)
in DMA (0.5 mL) under microwave irradiation unless otherwise
b
stated. Determined by 1H NMR. Complete conversion was observed
c
in all the cases. Reaction performed under conventional heating, with
an additional load of catalyst (5 mol %).
based on the conditions we had previously developed for the
Mo-catalyzed reduction of nitroarenes with pinacol,9 we found
that the treatment of 1a with 2a (2.2 equiv) in the presence of a
catalytic amount of a dioxomolybdenum(VI) complex, in DMA
as solvent and under microwave irradiation at 180 °C, led to a
mixture of the desired pyrroloquinoxaline 3aa and its dihydro
derivative 4aa, proving our proposed concept (entry 1).
Although the increase of reaction time or catalyst loading
gave rise to higher 3aa/4aa ratios (entries 2 and 3), gratifyingly,
we found that the addition of a substoichiometric amount of a
simple Brønsted acid like PTSA favored the oxidation of 4aa to
3aa leading to the selective formation of pyrrolo[1,2-
a]quinoxaline 3aa, which was isolated in 78% yield (entry 4).
Although the cooperative effect between the dioxomolybenum-
(VI) catalyst and PTSA provides enhanced rates in the tandem
process reduction/imine formation/cyclization/oxidation, the
role of the added Brønsted acid is not crucial for the overall
transformation. As previously well-established for several
Pictet−Spengler reactions,12 its function could be either to
favor the cyclization or the oxidation step. In addition, the
reaction could also be performed under conventional heating
with only slightly lower yields, although an extra catalyst
loading and longer reaction times were required (entry 5).
It should be noted that pyrrolo- and indoloquinoxalines are
quite interesting heterocyclic compounds possessing a wide
range of biological activities.13 For their construction from
pyrrole or indole derivatives, the Pictet−Spengler and
Bischler−Napieralski reactions are the most extensively used
approaches, starting from 1-(2-aminophenyl) pyrroles or
indoles.14 Recent efforts in this area have been devoted to
the replacement of the carbonyl counterpart by other
reagents.15 Taking into account that most of the reported
methods for the synthesis of these N-heterocycles use anilines
a
All reactions were conducted with 0.5 mmol of nitroarene derivative
1 and 1.1 mmol of glycol 2 in DMA (1 mL) under microwave
irradiation (maximum wattage 150 W; see the Supporting Information
b
for details). Isolated yield based on the starting nitroaromatic 1.
c
Carried out under conventional heating at 170−180 °C for 3 h (an
additional 5 mol % of the catalyst was added after 1 h).
glycol 2 was varied. Functionalized secondary glycols 2b−d
were reacted with model pyrrole derivative 1a leading to the
corresponding pyrroloquinoxalines 3ab−ad in good to high
yields (entries 2−4). Moreover, tertiary glycols 2e−g also
participate in this tandem reaction and react with 1a under the
same optimized conditions. In these cases, dihydropyrrolo[1,2-
a]quinoxalines 4 were obtained due to the generation of a
ketone as byproduct in the initial reduction of 1a with the
tertiary glycol (entries 5−7).17 Then the functional group
tolerance in nitroaromatic 1 was evaluated using pyrrole
derivatives 1b−d,11 bearing chlorine or methoxy groups at
different positions, by their treatment with any of the glycols
2a−e (entries 8−13). Remarkably, this tandem process works
nicely in most of the examined examples providing the final
(dihydro)pyrrolo[1,2-a]quinoxalines 3 and 4 in good to high
yields.
Due to the interest of functionalized ullazines (indolizino-
[6,5,4,3-aij]quinolines) in optoelectronics applications, a few
approaches have been developed for their syntheses.18 In this
B
DOI: 10.1021/acs.orglett.7b02792
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Letter
context, Langer and co-workers have reported the first
preparation, as well as the physical properties of aza-ullazines,19
whereas the only synthesis of related triazacyclopenta[c,d]-
phenalenes (diaza-ullazines) was reported by Balli in 1992.20
We therefore proposed to apply our methodology to access this
type of interesting heterocycles. Thus, treatment of 1-(2,6-
dinitrophenyl)pyrrole 1e with glycol 2a gave rise to the 3,9-
diphenyl-substituted diazaullazine 5 in 50% yield (Scheme 2).
Remarkably, the previous preparation of this compound
reported by Balli from the same 1e was performed in three
independent steps with an overall 14% yield.20
described for the synthesis of quinoxalines 3 and 7, afforded
high yields of the intended pyrrolo- and indoloquinolines 10
(Scheme 4). In addition, dihydroquinoline derivatives 11 could
Scheme 4. Synthesis of Pyrrolo- and Indolo[3,2-c]quinoline
Derivatives 10 and 11 from 2-(2-Nitrophenyl)pyrroles and
Indoles 9a−c
Scheme 2. Synthesis of Diazaullazine 5
In an analogous way, the reaction of 1-(2-nitrophenyl)-
indoles 6 with a selection of secondary glycols 2a,c enabled
facile access to related indolo[1,2-a]quinoxalines 7, whereas
reaction employing a tertiary glycol like 2f afforded the
corresponding dihydroindolo[1,2-a]quinoxaline 8 (Scheme 3).
Scheme 3. Preparation of Indolo[1,2-a]quinoxalines 7 and
Dihydroindolo[1,2-a]quinoxaline 8af
also be obtained via use of tertiary glycols 2e,f.23 The reported
examples also show the usefulness of glycols possessing
substituents at the ortho-position (2h) as well as that there is
no need to protect the nitrogen atom of the starting nitroarene,
thus allowing the synthesis of N-H heterocycles (Scheme 4). In
addition, indoloquinoline 10ca was also synthesized under
conventional heating and isolated in 78% yield. Interestingly,
the reactions of starting pyrrole derivatives 9a,b took place
without the addition of the Brønsted acid, further proving that
this cascade sequence could be catalyzed exclusively by the
molybdenum complex with highly reactive substrates.
In summary, we have shown that dioxomolybdenum(VI)
complexes are able to catalyze the formation of a wide variety of
pyrrolo- and indolo-fused quinoxalines and quinolines using
easily available nitroarenes as the nitrogen source and glycols as
the carbonyl source and reducing agents. The nitro reduction,
imine generation, annulation with heterocycle formation, and
final oxidation occurred in a new domino process that involves
the incorporation of the carbonyl reduction byproduct into the
final aza-heterocycle. Remarkably, this is the first report in
which the waste byproduct of a reaction has been used as a
reactant for the next step and included into the final product,
thus enhancing the overall atom economy of the process. This
strategy offers an economic and clean method for the one-pot
synthesis of these N-heterocycles, frequently found in biological
active compounds, from nitroaromatics.
Interestingly, a trifluoromethyl group does not interfere in the
outcome of the reaction as shown with the preparation of 7ba.
Again, we demonstrated that the process could be also
performed under conventional heating (170−180 °C, 3 h),
and in this way, 7aa was isolated in 83% yield.
At this point, we tried to extend the scope of this strategy for
the direct synthesis of aza-heterocycles from nitroarenes to the
preparation of pyrrolo- and indolo[3,2-c]quinolines. These
heterocycles are present in natural alkaloids and several
analogues with a wide spectrum of relevant biological or
pharmacological properties.21 Although there have been
reported different syntheses for these heterocyclic derivatives,22
most of them required expensive or multistep preparation of
starting materials, and displayed limited substrate scope or lack
of functional group tolerance. Based on our previous results, we
proposed easily prepared 2-(2-nitrophenyl)pyrroles and indoles
9 as starting materials.11 Thus, their treatment with a variety of
secondary glycols 2, under similar reaction conditions as
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02792.
Full experimental procedures, characterization data, and
NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b02792
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) García, N.; García-García, P.; Fernan
Rubio, R.; Pedrosa, M. R.; Arnai
2012, 354, 321−327. More recently, we have updated this
methodology to the deoxygenation of N-oxides and N-hydroxybenzo-
́
dez-Rodríguez, M. A.;
z, F. J.; Sanz, R. Adv. Synth. Catal.
AUTHOR INFORMATION
■
́
Corresponding Author
*E-mail: rsd@ubu.es.
ORCID
triazoles: (b) Rubio-Presa, R.; Fernan
M. R.; Arnaiz, F. J.; Sanz, R. Adv. Synth. Catal. 2017, 359, 1752−1757.
(10) García, N.; Rubio-Presa, R.; García-García, P.; Fernandez-
Rodríguez, M. A.; Pedrosa, M. R.; Arnaiz, F. J.; Sanz, R. Green Chem.
2016, 18, 2335−2340.
(11) See the Supporting Information for further details.
́
dez-Rodríguez, M. A.; Pedrosa,
́
́
Manuel A. Fernandez-Rodríguez: 0000-0002-0120-5599
́
́
Roberto Sanz: 0000-0003-2830-0892
Notes
(12) Kamal, A.; Babu, K. S.; Kovvuri, J.; Manasa, V.; Ravikumar, A.;
Alarifi, A. Tetrahedron Lett. 2015, 56, 7012−7015.
The authors declare no competing financial interest.
(13) See, for instance: Lv, W.; Budke, B.; Pawlowski, M.; Connell, P.
P.; Kozikowski, A. P. J. Med. Chem. 2016, 59, 4511−4525.
(14) See, for instance: (a) Preetam, A.; Nath, M. RSC Adv. 2015, 5,
21843−21853. (b) Wang, C.; Li, Y.; Zhao, J.; Cheng, B.; Wang, H.;
Zhai, H. Tetrahedron Lett. 2016, 57, 3908−3911. For pioneering work,
see: (c) Cheeseman, G. W. H.; Tuck, B. J. Chem. Soc. C 1966, 852−
855.
(15) Benzylamines: (a) Ramamohan, M.; Sridhar, R.;
Raghavendrarao, K.; Paradesi, N.; Chandrasekhar, K. B.; Jayaprakash,
S. Synlett 2015, 26, 1096−1100. 1,3-Dicarbonyls: (b) Xie, C.; Feng,
L.; Li, W.; Ma, X.; Ma, X.; Liu, Y.; Ma, C. Org. Biomol. Chem. 2016, 14,
8529−8535. Alcohols: (c) Li, J.; Zhang, J.; Yang, H.; Gao, Z.; Jiang, G.
J. Org. Chem. 2017, 82, 765−769. DMSO: (d) Xie, C.; Zhang, Z.; Li,
D.; Gong, J.; Han, X.; Liu, X.; Ma, C. J. Org. Chem. 2017, 82, 3491−
3499.
ACKNOWLEDGMENTS
■
We are grateful to the Junta de Castilla y Leon
́
and FEDER
́
(BU076U16) and Ministerio de Economia y Competitividad
(MINECO) (CTQ2015-70371-REDT and CTQ2016-75023-
C2-1-P) for financial support. R.R.-P. thanks Universidad de
Burgos for a predoctoral contract.
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