Mechanochemical indole synthesis by rhodium-catalysed oxidative coupling of acetanilides and alkynes under solventless conditions in a ball mill

Article abstract of DOI:10.1039/c7gc00499k

A mechanochemical indole synthesis by rhodium(iii)-catalysed C-H bond functionalisation in a planetary mill has been developed. It occurs in the absence of any solvent, does not require additional heating and only needs catalytic quantities of Cu(OAc)₂ in combination with dioxygen as a terminal oxidant. Accordingly, the process represents a powerful and environmentally benign alternative to the common solution-based standard protocols.

Full text of DOI:10.1039/c7gc00499k

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DOI: 10.1039/C7GC00499K
Journal Name
COMMUNICATION
Mechanochemical Indole Synthesis by Rhodium-Catalysed
Oxidative Coupling of Acetanilides and Alkynes under
Solventless Conditions in a Ball Mill
Received 00th January 20xx,
Accepted 00th January 20xx
Gary N. Hermanna, Celine L. Junga,b and C. Bolm*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mechanochemical indole synthesis by rhodium(III)-catalysed C– compared to analogous transformations in solution, higher
H bond functionalisation in a planetary mill has been developed. It yields could often be achieved after shorter reaction times
occurs in the absence of any solvent, does not require additional compared to analogous transformations using a solvent-based
heating and only needs catalytic quantities of Cu(OAc)2 in system. Positive effects of mechanochemical conditions have
combination with dioxygen as terminal oxidant. Accordingly, the also been noted in metal catalysis,10 and altered reactivity has
process represents
a
powerful and environmentally benign led to variations in the product portfolio.11 In 2014, Stolle and
alternative to the common solution-based standard protocols.
co-workers reported a mechanochemically induced indole
synthesis by intramolecular hydroamination reaction [Scheme
1, Eq. (1)].12 In the absence of any solvent zinc bromide (100
mol%) activated 2-alkynylanilines providing the corresponding
products in good to high yields. Considering literature reports6
and results from previous work on catalytic C–H bond
functionalisations under mechanochemical conditions,13 we
started wondering about an alternative approach towards
indoles. It involved the use of a rhodium catalyst, its site-
specific activation of acetanilides and subsequent oxidative
couplings with alkynes [Scheme 1, Eq. (2)]. The realisation of
this concept is reported here.
The indole framework represents one of the most abundant
and relevant heterocyclic core structures in bioactive
compounds and natural products, and consequently, its
construction has attracted the attention of organic chemists
since more than 100 years.1 Supplementing traditional
preparative methods such as the Fischer indole synthesis,2
transition metal catalysis has greatly advanced the field. A
milestone in this context is the palladium-catalysed approach
towards indoles introduced by Larock.3 Newly developed
strategies involving catalytic C–H bond activations appear
particularly attractive because they allow utilising
unfunctionalised substrates.4 Along these lines, several
methods for accessing indoles have been described including
intramolecular cross-couplings,5 annulations of anilides,6 and
others.1f An interesting ruthenium(II)-catalysed oxidative C–H
bond functionalisation providing indoles from N-2-pyrimidyl-
substituted anilines and internal alkynes was reported by
Ackermann and Lygin in 2012.7 Although the yields were
generally high it was noted that for the success of the reaction
an over-stoichiometric amount of Cu(OAc)2 and a reaction
temperature of 100 °C was critically needed. Furthermore,
water had to be used as reaction medium. Neat conditions led
to poor yields of indoles.8
Previous work:
R
ZnBr2
ball milling
R
(1)
N
H
NH2
This work:
R2
H
R3
R1
R3
R1
Rh catalyst
ball milling
(2)
+
NH
N
R2
Me
O
Me
O
Scheme 1 Mechanochemical indole synthesis in ball mills.
In the past decade, organic synthesis has greatly benefited
from mechanochemistry.9 Applying this technique allowed
performing reactions under solventless conditions and
We initiated our study using reaction conditions similar to
those reported by Fagnou, Stuart, and co-workers6a,6d for the
oxidative coupling of acetanilide (1a) and diphenylacetylene
(2a) in t-amylOH at 60 °C with [Cp*Rh(MeCN)3][SbF6]2 (5 mol%)
as catalyst and Cu(OAc)2 (2.1 equiv.) as oxidant. To our delight
the switch to solventless mechanochemical conditions proved
a. Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany. E-mail: carsten.bolm@oc.rwth-aachen.de;
Fax: +49 241 80 92 391; Tel: +49 24 80 94 675.
b New address: Institute of Technical and Macromolecular Chemistry, RWTH Aachen
University
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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possible providing indole 3a in 37% yield (Table 1, entry 1). Next, the scope of the mechanochemically induced indole
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DOI: 10.1039/C7GC00499K
Shorter milling times and reduced catalyst loadings resulted in synthesis was investigated, and each product was isolated
lower yields (see ESI for details). Increasing the number of (Scheme 2). First, the acetanilide was varied in reactions with
milling balls from 16 to 30 (with a diameter of 5 mm) and 2a as coupling partner. Using acetanilide (1a) led to the
employing an excess of acetanilide 1a had positive effects on formation of 3a in 70% yield.15 The presence of a fluoro or a
the coupling, and the yield of 3a was raised to 42% and 48%, methoxy substituent in para-position of the anilinic amide
respectively (Table 1, entries 2 and 3). Changing Cu(OAc)2 to group reduced the yield of the corresponding products, and 3b
Fe(OAc)2 or NaOAc proved detrimental, and the product was and 3c were formed in only 45% and 58% yield, respectively.
formed in only 5% and 9% yield, respectively (Table 1, entries 4 Meta-methyl-substituted acetanilide 1d reacted with 2a
and 5). Stuart and co-workers observed a positive effect when affording 70% of 3d as single regioisomer. Presumably, the
the reaction was performed under an atmosphere of dioxygen intrinsic high site-selectivity of the C–H-bond functionalisation
instead of air.6d This behaviour was also found here, rendering had steric reasons. Ortho-substituted anilides reacted
the transformation even catalytic in Cu(OAc)2. Thus, under smoothly as well, and 3e and 3f were obtained in 48% and 62%
mechanochemical conditions in an atmosphere of dioxygen yield, respectively.16
with only 2.5 mol% of Cu(OAc)2, 3a was obtained in 59% yield
Subsequently, the influence of the alkyne was investigated
(Table 1, entry 6). In addition, the amount of 1a could be using anilide 1a as representative coupling partner. Various
reduced from 3.0 equiv. to 2.0 equiv. without affecting the aryl/alkyl-disubstituted alkynes performed well affording the
product yield (Table 1, entry 7). Finally, changing the limiting corresponding products (3g-3i) in yields up to 77% and with
agent from 2a to 1a and increasing the milling speed from 800 exclusive regioselectivity. In each case the aromatic
rpm to 900 rpm increased the yield of 3a further allowing to substituent was located at C2 of the indole core (Scheme 2).17
isolate the product in 76% (NMR) yield (Table 1, entries 8 and A significant drop in yield was observed when dialkyl-
9).
substituted alkyne 2j was applied. For this substrate, the yield
of the resulting indole 3j was only 9%.14
Table 1 Optimisation of the mechanochemical indole synthesisa
Ph
R2
[Cp*Rh(MeCN)3][SbF6]2 (5 mol%)
[Cp*Rh(MeCN)3][SbF6]2 (5 mol%)
redox modulator
H
R2
O
R1
Cu(OAc)2 (2.5 mol%), O2 (1 atm)
Ph
Ph
R1
+
R3
+
NHAc
R3
N
ball milling, 900 rpm
N
H
Me
ball milling, 800 rpm
Ph
N
15 x (60 min. + 15 min. break)
15 x (60 min. + 15 min. break)
O
Ac
Me
1
2
3
1a
2a
3a
Yield (%)b
Ph
Ph
Ph
Entry
1
1a (equiv.)
1.0
2a (equiv.)
Redox modulator
(equiv.)
F
MeO
Ph
Ph
N
Ph
3.0
Cu(OAc)2 (2.1)
37
42
48
5
N
N
Ac
Ac
Ac
2c
1.0
3.0
Cu(OAc)2 (2.1)
Cu(OAc)2 (2.1)
Fe(OAc)2 (2.1)
NaOAc (2.1)
3a: 70%
3b: 45%
3c: 58%
Ph
Ph
Ph
3c
3.0
1.0
Ph
Ph
N
Ph
4c
3.0
1.0
N
N
Me
Ac
Ac
Ac
Me
MeO
5c
3.0
1.0
9
3d: 70%
3e: 48%
3f: 62%
R2
6c,d
7c,d
8c,d
9c,d,e
3.0
1.0
Cu(OAc)2 (0.025)
Cu(OAc)2 (0.025)
Cu(OAc)2 (0.025)
Cu(OAc)2 (0.025)
59
60
68
76
3g: R2 = Me, R3 = Ph 77%
3h: R2 = Et, R3 = Ph 72%
3i: R2 = nPr, R3 = Ph 70%
3j: R2 = nPr, R3 = nPr 9%
R3
N
2.0
1.0
Ac
1.0
2.0
1.0
2.0
Scheme 2 Scope of the mechanochemical rhodium-catalysed
indole synthesis. The yields refer to isolated product
quantities. For 3j: when 1.1 equiv. of the alkyne was used the
a Reaction conditions: Pulverisette 7 premium line; vessels (20 mL) and balls (16 balls, 5
mm diameter) made of ZrO2; 800 rpm. b Determined by 1H NMR spectroscopy with
1,3,5-trimethoxybenzene as internal standard. c Use of 30 milling balls (with 5 mm yield was 10%.
diameter). d Performed under an atmosphere of O2. e 900 rpm. Cp* = pentamethyl-
cyclopentadienyl.
As demonstrated from 3a, mechanochemical conditions
also allowed removing the N-acetyl groups from the products
(Scheme 3). Noteworthy, a significantly lower amount of KOH
was needed than in MeOH/H2O solution (2.0 equiv. versus 5.0
equiv.)6a for achieving a comparable yield of 4a (90%).
Several points are noteworthy at this stage: first, applying
ball milling to this process led to a high product yield without
the need of any solvent or additional heating. Then, dioxygen
could be used as terminal oxidant allowing an 8-fold reduction
of the amount of Cu(OAc)2 compared to the standard solvent
based protocol.6d
2 | J. Name., 2012, 00, 1-3
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Ph
Ph
M. Miura, Chem. Commun., 2012, 48, 10704; (s) N. Kuhl, M.
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Ph
Ph
ball milling, 600 rpm
60 min.
N
N
H
Me
O
3a
4a (90%)
Scheme 3 Mechanochemical cleavage of the directing group.
5
6
In summary, we have developed a mechanochemically induced
indole synthesis by rhodium-catalysed C–H bond
functionalisation in a ball mill. The reaction takes place in the
absence of any solvent and forms the corresponding products
in moderate to good yields. No additional heating is required
and only catalytic amounts of Cu(OAc)2 are needed by
employing dioxygen as the terminal oxidant.
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Acknowledgements
This research was supported by the Distinguished Professorship
Program at RWTH Aachen University funded by the Excellence
Initiative of the German federal and state governments. We are
grateful to Dr. José Gregorio Hernández (RWTH Aachen University)
for proofreading the manuscript.
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9
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characteristics of the substrates have to be taken into
DOI: 10.1039/C7GC00499K
account in reactions under mechanochemical conditions, as
in many cases a homogenous dispersion of the reactants is
essential for achieving high conversions and product yields.
The reaction parameters utilized here [900 rpm, 15 x (60
min. + 15 min. break)] led to a temperature increase of the
reaction mixture to ca. 70 °C (± 2 °C) as measured using an
infrared thermometer after opening the milling beaker.
Thus, substrate 2a (mp: 59 – 61 °C) must have melted and
the reaction mixture been blended well. As alkynes 2g-j were
liquids, the same should be true for the reaction with those
substrates (see ESI for all mp). (a) For a discussion of mass-
transport limitations under ball-milling conditions, see: F.
Schneider, T. Szuppa, A. Stolle, B. Ondruschka, H. Hopf,
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R3
R1
RhIII-catalyst
R1
R2
H
+
N
N
ball milling
R2
Me
Me
O
11 (a) J. G. Hernández and C. Bolm, J. Org. Chem., DOI:
10.1021/acs.joc.6b02887; (b) J.-L. Do and T. Frisčić, ACS Cent.
Sci., 2017, 3, 13.
12 M. Zille, A. Stolle, A. Wild and U. S. Schubert, RSC Adv., 2014,
4, 13126.
O
Indoles are prepared by rhodium(III)-catalysed C–H bond functionalisation under
mechanochemical conditions in a planetary mill.
13 (a) G. N. Hermann, P. Becker and C. Bolm, Angew. Chem. Int.
Ed., 2015, 54, 7414; (b) J. G. Hernández and C. Bolm, Chem.
Commun., 2015, 51, 12582; (c) G. N. Hermann, P. Becker and
C. Bolm, Angew. Chem. Int. Ed., 2016, 55, 3781; (d) S.-J. Lou,
Y.-J. Mao, D.-Q. Xu, J.-Q. He, Q. Chen and Z.-Y. Xu, ACS Catal.,
2016, 6, 3890; (e) K.-Y. Jia, J.-B. Yu, Z.-J. Jiang and W.-K. Su, J.
Org. Chem., 2016, 81, 6049.
14 This observation was in accordance with results reported by
Stuart and co-workers (ref. 6d), who found a negative effect,
when the reaction was carried out with a high amount of an
alkyl/alkyl-disubstituted alkyne. Reducing the quantity of 2j
from the standard 2.0 equiv. to 1.1 equiv. had essentially no
influence here (9% versus 10% yield of 3j). Ref. 6a also
contains
a detailed comparison of the reactivity of
alkyl/alkyl-disubstituted alkynes with the one of aryl/aryl-
bearing substrates. In general, the former proved less
suitable for the reported catalysis.
15 Attempts to recover the catalyst remained unsuccessful.
Scaling up the reaction to 3 mmol (using the same-size ball
milling equipment) led to a lower yield of 3a (37%)
presumably due to the altered reaction environment.
4 | J. Name., 2012, 00, 1-3
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