Step and redox efficient nitroarene to indole synthesis

Article abstract of DOI:10.1039/d0cc03258a

Step and redox efficiencies are a rising priority in synthetic method development, in order to make synthetic processes more sustainable and more affordable. Herein, a step and redox efficient nitroarene to indole synthesis is developed, in sharp contrast to the rich literature on the construction of indoles. Elemental zinc was found to be the best terminal reductant. This journal is

Full text of DOI:10.1039/d0cc03258a

ChemComm
View Article Online
View Journal
COMMUNICATION
Step and redox efficient nitroarene to indole
synthesis†
Cite this:DOI: 10.1039/d0cc03258a
Bunyamin O¨ zkaya,
¨
Christina L. Bub
and Frederic W. Patureau
*
Received 6th May 2020,
Accepted 13th July 2020
DOI: 10.1039/d0cc03258a
rsc.li/chemcomm
Step and redox efficiencies are a rising priority in synthetic method shorter route towards the indole scaffold, through pre-activation
development, in order to make synthetic processes more sustain- of the ortho position of the aniline intermediate with a halide.16–19
able and more affordable. Herein, a step and redox efficient This is then followed by a classical cross-coupling step with
nitroarene to indole synthesis is developed, in sharp contrast to internal alkynes (i.e., dehydrated ketones) under Pd-catalysis
the rich literature on the construction of indoles. Elemental zinc (Scheme 1a).
was found to be the best terminal reductant.
In 2008, Fagnou, inspired by the then recent emergence of
Rh-catalysed C–H bond activation, improved this alkyne
The indole scaffold is one of the most important heterocyclic approach further utilizing the corresponding protected aceta-
motifs in organic chemistry. Its frequent occurrence in pharma- nilide under oxidative conditions.20–22 While the scope of that
ceuticals and natural products and its biological properties reaction is generally broad, making it an important synthetic
make it an essential basic structure.1–5 This has led to ongoing tool, the Fagnou approach represents still three redox opera-
interest in the scientific community on synthesizing indoles tions from the arene starting material: (1) (oxidative) nitration,
using different approaches, leading to many strategies.6–13 One (2) reduction to the aniline or anilide, and (3) oxidative Rh-
of the earliest is of course the Fischer indole synthesis, arguably catalysed coupling with the alkyne. Moreover, getting to the
a remarkably powerful coupling reaction.1,14,15
target indole requires a final deacetylation/deprotection step.
Much of early organic chemistry, however, focused on fine- In terms of the overall step and redox efficiency, at least with
tuning the reacting functional groups, often through multiple respect to the arene substrate, one of the most straightforward
(redox) pre-activation steps, in order to trick the desired cou- approaches remains that of Bartoli with his direct synthesis of
pling reactions into occurring (Fig. 1). The Fischer indole indoles from nitroarenes and vinyl organomagnesium reagents
synthesis is a good example of this problem (Scheme 1a).
Indeed, the starting arene substrate on which one wishes to
build an indole must be oxidized and reduced back and forth a
few times in order to reach the desired hydrazine reactive state.
Only then will the Fischer indole coupling occur in a final
overall redox neutral step through condensation with ketones.
Meanwhile, the development of more sustainable synthetic
methods has become a major concern and priority in order to
reduce the environmental footprint of these desired processes.
In principle, this can be achieved by reducing the number of
superfluous redox operations, and thereby the associated
chemical waste. In 1991, Larock utilized the recent progress
made in Pd-catalysed cross-coupling chemistry to propose a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
52074 Aachen, Germany. E-mail: Frederic.patureau@rwth-aachen.de
Web: https://www.patureau-oc-rwth-aachen.de
Fig. 1 The problem of step and redox efficiency in synthetic methodology:
† Electronic supplementary information (ESI) available: Optimization, methods,
fine-tuning the functional groups for a desired coupling reaction.
characterization and spectra. See DOI: 10.1039/d0cc03258a
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
One of the most step and redox efficient indole syntheses in the
literature is probably that of Nicholas (2002, Scheme 1c).6 This
early and inspiring Ru-catalysed C–H bond activation reaction
requires, however, as much as 50 bars of toxic CO gas as the
reductant, 170 1C reaction temperature, and 48 h reaction time for
only very moderate yields of indole coupling products. Several
other methods exist for the construction of the indole scaffold,
though usually these do not operate directly from the nitroarene
but rather from a derivative of it, and involve therefore at least one
additional redox operation in the retrosynthetic strategy.26–28
For the sake of clarity, not all methods could be graphically
summarized in Scheme 2. Thus, clearly, practical step and
redox efficient strategies to build the indole scaffold are still
in high demand, in particular using non-ortho functionalized
nitroarenes. Herein, we propose to develop such a strategy, by
directly intercepting the reduction of the nitroarene substrate29–46
to achieve a straightforward Rh-catalysed C–H bond activation47–52
event and coupling with the alkyne.
Scheme 1 (a) Fischer indole synthesis (4 redox steps) and indole synthesis
by Larock using Pd-catalysis and a pre-functionalized aniline (3 redox steps),
(b) Bartoli synthesis requiring ortho-substituted nitrobenzenes (2 redox steps),
and Dobbs synthesis utilizing 1,2-bromonitroarenes, then removing the halide
with Bu3SnH (3 redox steps), (c) Nicholas Ru-catalysed indole synthesis with
50 bars of CO gas as the reductant, (d) Rh-catalysed indole synthesis starting
from acetanilides (3 redox steps), and (e) this work: reductive nitroarene to
indole synthesis (directly from the nitroarene) with Zn0 powder.
(1989).23,24 Bartoli’s strategy features only two redox operations:
(1) (oxidative) nitration, and (2) reductive coupling with an
organometallic species, which is both nucleophile and reduc-
tant (Scheme 1b).
Unfortunately, Bartoli’s indole synthesis is associated with
two main limitations: (1) the harshness of the organomagne-
sium reagent, thus limiting functional group tolerance and,
more problematically: (2) the requirement for an ortho-
functional group at the nitroarene substrate for the coupling
reaction to occur. In 2001, Dobbs found one way around the latter
problem by utilizing 1,2-bromonitroarenes, thereafter removing
the ortho bromide in a third redox operation with Bu3SnH as a –
not so convenient nor environmentally friendly – final reductant.25
Scheme 2 (a) Optimized reaction conditions, (b) scope, isolated yields,
and (c) scope limits.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
ChemComm
Communication
We thus started with nitrobenzene and diphenylacetylene as late stage C–H ‘‘indolisation’’ of an important anthelmintic drug,
model substrates, in the presence of catalytic amounts of the Niclosamid, with a promising 47% isolated yield (3zf) and excel-
classical [Cp*RhCl2]2 dimer.47–52 The fairly simple idea was that lent regioselectivity (Scheme 2b).
although the nitro group is not reputed to be an efficient C–H
In order to gain some insights into the role and oxidation
bond activation ortho directing group, some of its reduction states of the directing group, some selected control experi-
intermediates (i.e., nitroso or similar)53 – if sufficiently long- ments were conducted (Scheme 3). Of course, as the coupling
lived – might be more susceptible. Of course, the challenge was reaction was optimized for trivial nitroarenes, it is not too
to achieve Rh-catalysed ortho C–H bond activation and functio- surprising to find that they were also the best directing group
nalization before full reduction to the aniline, at which point (DG) precursor under those conditions. It is nevertheless inter-
any directing group and C–H oxidative ability would have been esting that, without altering the reaction conditions, nitroso-
suppressed. Indeed, primary anilines are not reputed as effi- benzene 4 and N-phenylhydroxylamine 5 deliver some small
cient C–H bond activation ortho directing groups either. Large isolable amounts of target indole 3a (14% and 5% respectively).
numbers of additives and especially reductants were therefore However, aniline 6, 1,2-diphenylhydrazine 7 and azobenzene 8
screened, as well as temperature and solvent. The full optimiza- are not competent coupling reagents/directing groups. More-
tion table is given in the ESI.† Eventually, elemental Zn-powder over, interestingly, when we performed the reaction on nitroso-
was found to be the optimal reductant, in the presence of TMSCl, benzene 4 and N-phenylhydroxylamine 5 in the absence of
acetic acid and 3 Å molecular sieves, in acetonitrile. Full conver- the zinc terminal reductant, an undefined and complex mixture
sion to the corresponding product was never observed, due to the of products and perhaps some decomposition were observed
formation of homo-coupled over-reduction by-products (i.e., (Scheme 3). This surprising result – one might have expected a
hydrazines). Moreover, relatively long reactions times were found high yield of indole coupling product, or its oxide – contradicts
to be necessary (very little product formation in the first hours, our original simplified mechanistic scenario, wherein (1)
24 h reaction time recommended), thus highlighting the kinetic reduction of the nitro directing group and (2) C–H activation/
challenge of performing nitro reduction concomitantly to ortho insertion/reductive elimination were thought to be sequential
directed C–H bond activation/functionalization. Importantly, the and unrelated. In contrast, our results suggest that Zn is more
indole coupling product is not observed unless the solvent is a than a simple reductant in this reaction, and might structurally
nitrile. Utilizing a RhCp* source turned out to be crucial, since participate in some of the critical steps of the herein described
other Rh-catalysts did not give any desired product. Organic reaction. Intermediate crystallization attempts unfortunately
reductants or other metal salts turned out to be inefficient in failed so far. Further research efforts are currently ongoing in
the reaction. Moreover, replacing TMSCl with TMSI or a different our laboratory to elucidate and perhaps exploit those effects in
Si-species gave only trace amounts or no product at all. The other future coupling reactions.
optimized conditions and the substrate scope are depicted in
In conclusion, we have herein developed a direct nitroarene
Scheme 2. Overall, the isolated yields were found promising. to indole synthesis, relying on elemental Zn as the terminal
Ethers (3b and 3c), methylthioether (3d) and halides (3e and 3f) reductant. This therefore represents another milestone in the
in the para-position with respect to the nitro-group gave moderate
yields. Alkyl and aryl groups (3g–k, 3u–v, 3x–y) as well as different
kinds of amines/amides (3l–q) led smoothly to the corresponding
coupling products.
Moreover, meta functionalization of the nitroarene sub-
strates led to outstanding C–H bond functionalization regio-
selectivity (3r–za), a phenomenon that was already observed by
Fagnou and co-authors under oxidative reaction conditions.20
Indeed, the other regioisomers (C–H bond functionalization on
the more sterically congested ortho position) could not be
detected. This outstanding selectivity can be interpreted as
the result of a sterically controlled highly regioselective alkyne
insertion into the C–Rh bond subsequent to the C–H bond
activation event. This high sensitivity to steric effects may also
explain the more moderate performance of ortho functionalized
nitroarenes (3zg–zh), therefore highlighting a useful methodo-
logical orthogonality with the Bartoli reaction. It is unclear
however why unsymmetrically substituted alkynes should fail
(Scheme 2) in this reaction. Nevertheless, surprisingly, the
anilide functional group (3p–q, 3z) is particularly well tolerated.
This is interesting because anilides are privileged directing
groups in the field of C–H bond activation,20 thus offering further
Scheme 3 Selected control experiments with different oxidation states of
the nitrogen atom under optimized conditions.
functionalization possibilities. In addition, this has allowed the
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
25 A. Dobbs, J. Org. Chem., 2001, 66, 638.
quest for more redox efficient routes towards valuable indole
scaffolds. More generally, the relatively underexplored concept
of reductive or oxidative process interception might lead to new
strategies for the design of innovative coupling reactions.
ERC project 716136:2O2ACTIVATION is acknowledged for
generous support.
26 S. Murru, A. A. Gallo and R. S. Srivastava, ACS Catal., 2011, 1, 29.
27 S. Murru, A. A. Gallo and R. S. Srivastava, Eur. J. Org. Chem., 2011,
2035.
28 G. Zhang, H. Yu, G. Qin and H. Huang, Chem. Commun., 2014,
50, 4331.
29 For inspiring prior work with Palladium catalysis and CO gas as the
reductant, see for example: F. Ragaini, A. Rapetti, E. Visentin,
M. Monzani, A. Caselli and S. Cenini, J. Org. Chem., 2006, 71, 3748.
30 J. Liu, C. Zhang, Z. Zhang, X. Wen, X. Dou, J. Wei, X. Qiu, S. Song
and N. Jiao, Science, 2020, 367, 281.
31 H. Song, Z. Yang, C.-H. Tung and W. Wang, ACS Catal., 2020, 10, 276.
32 M. Rauser, R. Eckert, M. Gerbershagen and M. Niggemann, Angew.
Chem., Int. Ed., 2019, 58, 6713.
Conflicts of interest
There are no conflicts to declare.
33 S. Zhao and N. P. Mankad, Org. Lett., 2019, 21, 10106.
34 N. Shen, C. W. Cheung and J.-A. Ma, Chem. Commun., 2019,
55, 13709.
35 L. Ling, C. Chen, M. Luo and X. Zeng, Org. Lett., 2019, 21, 1912.
36 C. Lu, Z. Su, D. Jing, S. Jin, L. Xie, L. Li and K. Zheng, Org. Lett., 2019,
21, 1438.
Notes and references
1 E. Fischer and O. Hess, Chem. Ber., 1884, 17, 559.
2 A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010,
110, 4489.
3 M. Ishikura, T. Abe, T. Choshi and S. Hibino, Nat. Prod. Rep., 2013,
30, 694.
4 N. K. Kaushik, N. Kaushik, P. Attri, N. Kumar, C. H. Kim, A. K. Verma
and E. H. Choi, Molecules, 2013, 18, 6620.
´
´
37 S. Suarez-Pantiga, R. Hernandez-Ruiz, C. Virumbrales, M. R. Pedrosa
and R. Sanz, Angew. Chem., Int. Ed., 2019, 58, 2129.
38 C. W. Cheung, J.-A. Ma and X. Hu, J. Am. Chem. Soc., 2018, 140, 6789.
39 M. Rauser, C. Ascheberg and M. Niggemann, Chem. – Eur. J., 2018,
24, 3970.
5 J.-H. Lee and J. Lee, FEMS Microbiol. Rev., 2010, 34, 426.
6 A. Penoni and K. M. Nicholas, Chem. Commun., 2002, 484.
7 G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875.
40 M. Rauser, C. Ascheberg and M. Niggemann, Angew. Chem., Int. Ed.,
2017, 56, 11570.
¨
8 S. Wu¨rtz, S. Rakshit, J. J. Neumann, T. Droge and F. Glorius, Angew.
41 C. W. Cheung and X. Hu, Nat. Commun., 2016, 7, 12494.
42 J. Gui, C.-M. Pan, Y. Jin, T. Qin, J. C. Lo, B. J. Lee, S. H. Spergel,
M. E. Mertzman, W. J. Pitts, T. E. La Cruz, M. A. Schmidt, N. Darvatkar,
S. R. Natarajan and P. S. Baran, Science, 2015, 348, 886.
43 H. Yan, H. Wang, X. Li, X. Xin, C. Wang and B. Wan, Angew. Chem.,
Int. Ed., 2015, 54, 10613.
44 Z. Zhou, G. Liu, Y. Chen and X. Lu, Adv. Synth. Catal., 2015, 357, 2944.
45 C. Wang, D. Wang, H. Yan, H. Wang, B. Pan, X. Xin, X. Li, F. Wu and
B. Wan, Angew. Chem., Int. Ed., 2014, 53, 11940.
46 L. L. Anderson, M. A. Kroc, T. W. Reidl and J. Son, J. Org. Chem.,
2016, 81, 9521.
47 F. W. Patureau, J. Wencel-Delord and F. Glorius, Aldrichimica Acta,
2012, 45, 31.
48 D. L. Davies, S. A. Macgregor and C. L. McMullin, Chem. Rev., 2017,
117, 8649.
49 J. Park and S. Chang, Chem. – Asian J., 2018, 13, 1089.
50 S. Rej and N. Chatani, Angew. Chem., Int. Ed., 2019, 58, 8304.
51 Y. Shang, K. Jonnada, S. L. Yedage, H. Tu, X. Zhang, X. Lou,
S. Huang and W. Su, Chem. Commun., 2019, 55, 9547.
52 C. Wang, H. Sun, Y. Fang and Y. Huang, Angew. Chem., Int. Ed., 2013,
52, 5795.
Chem., Int. Ed., 2008, 47, 7230.
9 D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67, 7195.
10 N. Yoshikai and Y. Wei, Asian J. Org. Chem., 2013, 2, 466.
11 M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29.
12 T. Guo, F. Huang, L. Yu and Z. Yu, Tetrahedron Lett., 2015, 56, 296.
13 S. Agasti, A. Dey and D. Maiti, Chem. Commun., 2017, 53, 6544.
14 B. Robinson, Chem. Rev., 1963, 63, 373.
15 M. M. Heravi, S. Rohani, V. Zadsirjan and N. Zahedi, RSC Adv., 2017,
7, 52852.
16 R. C. Larock and E. K. Yum, J. Am. Chem. Soc., 1991, 113, 6689.
17 R. C. Larock, E. K. Yum and M. D. Refvik, J. Org. Chem., 1998, 63, 7652.
18 L. Ackermann, Organometallics, 2003, 22, 4367.
19 M. Shen, G. Li, B. Z. Lu, A. Hossain, F. Roschangar, V. Farina and
C. H. Senanayake, Org. Lett., 2004, 6, 4129.
20 D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess and K. Fagnou,
J. Am. Chem. Soc., 2008, 130, 16474.
21 Y. Hoshino, Y. Shibata and K. Tanaka, Adv. Synth. Catal., 2014,
356, 1577.
22 G. N. Hermann, C. L. Jung and C. Bolm, Green Chem., 2017, 19, 2520.
23 G. Bartoli, G. Palmieri, M. Bosco and R. Dalpozzo, Tetrahedron Lett.,
1989, 30, 2129.
24 G. Bartoli, R. Dalpozzo and M. Nardi, Chem. Soc. Rev., 2014, 43, 4728. 53 A. Penoni, J. Volkmann and K. M. Nicholas, Org. Lett., 2002, 4, 699.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020