Mechanochemical Rhodium(III)- and Gold(I)-Catalyzed C?H Bond Alkynylations of Indoles under Solventless Conditions in Mixer Mills

Article abstract of DOI:10.1002/anie.201805778

Mechanochemical activations in Rh^III- and Au^I-catalyzed C?H alkynylations lead selectively to C₂- and C₃-alkynylated indoles. The processes show excellent functional group tolerance, do not require additional heating and proceed under solventless conditions. Compared to solvent-based standard protocols, the reaction times are shorter and the catalyst quantities lower resulting in high product yields under ambient atmosphere in mixer mills.

Full text of DOI:10.1002/anie.201805778

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Accepted Article
Title: Mechanochemical Rhodium(III)-and Mechanochemical
Rhodium(III)- and Gold(I)-Catalyzed C-H Bond Alkynylations of
Indoles under Solventless Conditions in Mixer Mills
Authors: Gary Hermann, Marvin Unruh, Se-Hyeong Jung Se-Hyeong
Jung, Maik Krings Maik Krings, and Carsten Bolm
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805778
Angew. Chem. 10.1002/ange.201805778
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10.1002/anie.201805778
Angewandte Chemie International Edition
COMMUNICATION
Mechanochemical Rhodium(III)- and Gold(I)-Catalyzed C–H Bond
Alkynylations of Indoles under Solventless Conditions in Mixer
Mills
Gary N. Hermann, Marvin T. Unruh, Se-Hyeong Jung, Maik Krings, and Carsten Bolm*
Abstract: Mechanochemical activations in RhIII- and AuI-catalyzed
C–H alkynylations lead selectively to C2- and C3-alkynylated indoles.
R3
The processes show excellent functional group tolerance, do not
RhIII catalyst
R1
R4
require additional heating and proceed under solventless conditions.
Compared to solvent-based standard protocols, the reaction times
are shorter and the catalyst quantities lower resulting in high product
yields under ambient atmosphere in mixer mills.
ball milling
N
R2
H
R4
R4
R3
H
I
O
R1
+
O
N
R2
R3
As indoles are prevalent in a vast variety of natural products,
agrochemicals and advanced materials they represent an
important heterocyclic core structure. Consequently, the
construction[1] and selective functionalization[2] of this motif
remains an important goal for organic chemists. In the last
decades, direct transition metal-catalyzed C–H bond
functionalization[3] has been established as a straightforward and
elegant way for diversifying indoles.[2] In this context, Waser, Li,
and Shi introduced highly C2- and C3-selective transition metal-
catalyzed C–H alkynylation reactions of indoles using
ethynylbenziodoxolone (EBX) reagents.[4-6] Despite the
effectiveness of these procedures, the use of significant
amounts of organic and often harmful solvents, long reaction
times and relatively high catalyst loadings are still limiting the
overall sustainability of these transformations.
R1
N
R2
AuI catalyst
or
Me
ball milling
TIPS
N
H
Scheme 1. Mechanochemical C–H bond alkynylations of indoles (TIPS =
triisopropylsilyl).
arylation processes, among others.[16,17] Although most of these
reactions proceed within a shorter reaction time than in solvent,
a reduction of the catalyst loading has remained a major
challenge.
Herein, we report two mechanochemical C–H alkynylation
processes of indoles that both employ EBX reagents as alkynyl
sources under solvent-free conditions in mixer mills (Scheme 1).
Gratifyingly, both the C2-selective, directing group assisted RhIII-
catalysis as well as the C3- (or C2)-selective AuI-catalyzed
alkynylation process are not only operating in shorter reaction
times than their solvent-based counterparts but more importantly
also require significantly less catalyst. In addition, the two
reactions represent, to the best of our knowledge, the first
examples of mechanochemical transition metal-catalyzed sp2 C–
In recent years, ball milling[7,8] has been developed into a
valuable technique to conduct a wide range of organic trans-
formations under mechanochemical conditions, including metal-
catalyzed Sonogashira,[9] Glaser,[10] and cross-dehydrogenative
coupling reactions.[11] Besides the most striking advantage that
nearly all of these processes can be performed in the absence
of organic solvents, often lower quantities of the catalyst and
shorter reaction times are needed to provide higher yields
compared to solvent-based standard protocols.[12]
H
alkynylation reactions that obviate the necessity of
The first mechanochemical C–H functionalization was
reported by our group in 2015.[13,14] Although this discovery was
important, it is fair to state that the solventless process was
limited in terms of catalyst efficiency, as the reaction in t-
AmylOH at 120 °C required only a fraction of the rhodium
catalyst to generate an even higher product yield.[15] Since then,
we and others have expanded the scope of mechanochemical
C–H functionalizations to amidations, halogenations, and
halogenated starting materials.
We began our studies by screening the reaction conditions
for the RhIII-catalyzed coupling between N-pyrimidyl indole (1a)
and
1-[(triisopropylsilyl)-ethynyl]-1,2-benziodoxol-3(1H)-one
(TIPS-EBX, 2a) under solvent-free conditions in a mixer mill.
Using [{Cp*RhCl2}2] (5 mol %) in combination with AgBF4 (20
mol %) as the catalyst and AgOAc (20 mol %) as an additive,
94% of the C2-alkynylated product 3a was isolated after just 99
minutes of milling at 30 Hz (Table 1, entry 1). Pleasingly,
lowering the amount of catalyst to 0.5 mol % as well as the
amount of AgBF4 and AgOAc to 2 mol % had almost no effect,
and 3a was obtained in 97% yield (Table 1, entries 2–4). Control
experiments revealed that [{Cp*RhCl2}2] and AgBF4 were
essential for the outcome of this transformation, whereas AgOAc
was not (Table 1, entries 5–7). A short screening of different
silver salts revealed that AgNTf2 worked the best for this
coupling (Table 1, entry 8, 99%). Furthermore, decreasing the
[*]
G. N. Hermann, M. T. Unruh, S.-H. Jung, M. Krings, Prof. Dr. C.
Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
Homepage: http://bolm.oc.rwth-aachen.de/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under: https://....
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10.1002/anie.201805778
Angewandte Chemie International Edition
COMMUNICATION
Table 1: Optimization of the RhIII-catalyzed C–H alkynylation under
[{Cp*RhCl2}2]
(0.5 mol %)
AgNTF2 (2.0 mol %)
R2
R1
R2
R1
I
O
H
mechanochemical conditions.[a]
N
N
+
O
N
N
catalyst
30 Hz, 60 min
ball milling
N
N
additive 1
additive 2
TIPS
I
O
H
TIPS
N
N
+
1
2
3
O
30 Hz
ball milling
N
N
N
N
1a
2a
3a
TIPS
TBDMS
TBDPS
N
N
N
N
N
N
N
N
N
Additive 1
(mol %)
Additive 2
(mol %)
Entry
Catalyst (mol %)
[{Cp*RhCl2}2] (5)
Yield [%]b
3a: 98%
(2 mmol scale: 98%)
3b: 73%
3c: 77%
1
2
3
4
5
AgBF4 (20)
AgBF4 (10)
AgBF4 (4)
AgBF4 (2)
AgBF4 (10)
AgOAc (20)
AgOAc (10)
AgOAc (4)
AgOAc (2)
AgOAc (10)
94
98
97
97
-
Me
MeO
[{Cp*RhCl2}2] (2.5)
[{Cp*RhCl2}2] (1.0)
[{Cp*RhCl2}2] (0.5)
-
tBu
TIPS
TIPS
N
N
N
N
N
N
N
N
N
3d: 93%
3e: 91%
3f: 99%
MeO2C
F
Br
6
7
[{Cp*RhCl2}2] (0.5)
-
AgOAc (2)
-
TIPS
TIPS
TIPS
N
N
N
N
[{Cp*RhCl2}2] (0.5)
[{Cp*RhCl2}2] (0.5)
AgBF4 (10)
AgNTf2 (2)
-
-
95
99
98
75
N
N
N
N
N
8
9[c]
[{Cp*RhCl2}2] (0.5)
AgNTf2 (2)
-
3g: 44%
3h: 83%
3i: 65%
Me
10[d]
[{Cp*RhCl2}2] (0.5)
AgNTf2 (2)
-
Cl
I
[a]
TIPS
TIPS
Reaction conditions: 1a (0.6 mmol, 1.0 equiv.), 2a (0.66 mmol, 1.1
equiv.), 30 Hz, 99 min., RETSCH mixer mill (MM 400), vessel (10 mL), and
ball (diameter:
pentamethylcyclopendadienyl, Tf
chromatography; [c] milling time: 60 min; [d] milling time: 30 min.
TIPS
N
N
N
N
N
N
N
1
cm) are made of stainless steel (Cp*
=
after
N
[b]
N
=
trifluoromethanesulfonyl);[18]
3j: 94%
3k: 68%
3l: 97%
Br
milling time to only 60 minutes had almost no influence on the
product yield (Table 1 entry 9, 98%). The efficiency of this
mechanochemical process is worth highlighting, since a similar
reaction in DCE required 16 hours and a fourfold amount of the
rhodium catalyst to achieve a slightly lower yield.[5c,19] With the
optimized reaction conditions in hand, the scope of the RhIII-
catalyzed alkynylation process was investigated (Scheme 2).
The use of unsubstituted N-pyrimidyl indole (1a) in the coupling
with TIPS-EBX (2a) led to 98% of the alkynylated indole 3a on a
0.6 mmol scale. The process was highly reproducible [(three
individual reactions between 1a and 2a gave 3a each time in a
similar yield (98–99%)] and the robustness of the reaction was
further highlighted by the excellent scalability, as demonstrated
by a 2.0 mmol scale reaction in which 3a was again isolated in
98% yield (730 mg). Next, the influence of the functional group
on the alkyne was investigated. Replacing the TIPS group by a
TBDMS- (tert-butyldimethylsilyl), TBDPS- (tert-butyl-diphenyl-
silyl) or tBu-group was unproblematic and the corresponding
products 3b–d were obtained in good to excellent yields (73–
93%). Both, electron-donating and -withdrawing groups at the 5-
position of the indole, such as methyl (1e), methoxy (1f), fluoro
(1h), bromo (1i), chloro (1j) or iodo (1k) were well tolerated in
the mechanochemical coupling and the corresponding products
were obtained in high yields (65–99%). Using a carboxyl
functionality (1g) led to only 44% of the desired product 3g.
Furthermore, N-pyrimidyl indoles containing substituents at
various positions could be used in the mechanochemical
process, and products 3l–p were isolated in good to essentially
quantitative yields (71–97%).
TIPS
TIPS
TIPS
N
N
N
Me
N
N
N
Me
N
N
N
3m: 71%
3n: 92%
3o: 72%
TIPS
N
N
F
N
3p: 97%
.
Scheme 2. Substrate scope of the mechanochemical RhIII-catalyzed C–H
alkynylation.
Cl
H
[{Cp*RhCl2}2] (1.0 equiv.)
NaOAc (3.0 equiv.)
Rh
N
Cp*
N
N
(1)
18 Hz, 60 min
ball milling
N
N
N
(20%)
1a
4
4 (1.0 mol %)
AgNTf2 (2.0 mol %)
2a (1.1 equiv.)
H
TIPS
N
N
(2)
30 Hz, 60 min
ball milling
N
N
N
N
1a
(96%)
3a
Scheme 3. Preliminary mechanistic studies of the mechanochemical RhIII-
catalyzed C–H alkynylation.
To confirm the hypothesized intermediacy of a 5-membered
rhodacycle in the mechanochemical process, rhodacycle 4 was
prepared after milling a mixture of N-pyrimidyl indole (1a, 2.5
To gain
a
closer insight into the RhIII-catalyzed
mechanochemical alkynylation process, preliminary mechanistic
studies were conducted (Scheme 3).
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10.1002/anie.201805778
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equiv.), [{Cp*RhCl2}2] (1.0 equiv.) and NaOAc (3.0 equiv.) under
solvent-free conditions for 60 min at 30 Hz in a mixer mill
[Scheme 3, eq. (1)].[20] Then, rhodacycle 4 was utilized as a
catalyst (1.0 mol %) together with AgNTf2 (2.0 mol %) in the
coupling of 1a and 2a [Scheme 3, eq. (2)]. After 60 min of milling,
3a was obtained in 96% yield, confirming that rhodacycle 4 was
most likely an intermediate (in its cationic form) in the
mechanochemical alkynylation reaction.
and 6c was isolated in 82% yield. Subsequently, the influence of
substituents at the C2- and C3-position of the indole core was
R4
H
Me
AuCl (2.0 mol %)
2 (1.2 equiv.)
R3
R1
H
TIPS
or
30 Hz, 99 min
ball milling
R3
R1
N
H
N
R2
N
R2
6a-d, f-k
Aiming at expanding the scope of the mechanochemical
C–H alkynylations, a screening of conditions for a C3-selective
C–H alkynylation process was initiated. As a starting point,
similar reaction conditions to those reported by Waser[5a] for the
gold-catalyzed C–H coupling of indole (5a) with TIPS-EBX 2a
were applied under mechanochemical conditions in a mixer mill.
To our delight, after mixing the reactants together with AuCl (5.0
mol %) as the catalyst for only 99 min at 30 Hz, 72% of 6a was
obtained (Table 2, entry 1). Furthermore, it was possible to
decrease the catalyst loading to only 2.0 mol % without
impairing the product yield of 6a (Table 2, entry 2).[21] Shortening
to reaction time had a negative effect on the coupling (Table 2,
entries 3 and 4).
5
6e
TIPS
TIPS
TBDMS
N
N
N
H
H
Me
6a: 75%
6b: 31%[a]
6c: 82%
TIPS
TIPS
Me
Me
TIPS
N
H
Me
N
N
H
H
6d: 80%[b]
6e: 71%[a,b]
6f: 64%[b]
Again, the high effectiveness of the presented mechano-
chemical gold-catalyzed coupling is worth mentioning as 6a was
obtained in almost the same yield compared to the solvent-
based standard protocol (in diethyl ether) but with less than 50%
of the catalyst and after a fraction of the reaction time.[5a,19]
TIPS
TIPS
TIPS
MeO
I
Br
N
H
N
H
N
H
Table 2: Optimization of the AuI-catalyzed C–H alkynylation under
6h: 70%[a,b]
6i: 60%[b]
6g: 59%
mechanochemical conditions.[a]
TIPS
TIPS
TIPS
H
TIPS
I
O
AuCl
+
O
30 Hz
N
H
N
ball milling
N
H
N
Cl
H
H
Me
5a
2a
6a
6k: 71%[a,b]
6j: 58%
Scheme 4. Substrate scope of the mechanochemical AuI-catalyzed C–H
alkynylation; [a] 2 x 99 min.; [b] AuCl (3.0 mol %).
Entry
AuCl (mol %)
Time (min)
Yield [%]b
1
2
3
4
5.0
2.0
2.0
2.0
99
99
60
30
72
75
68
47
evaluated. Using 2-methyl (5d) or 3-methyl indole (5e) in the
coupling with 2a led smoothly to products 6d (80%) and 6e
(71%) in high yields, albeit under slightly modified conditions (for
details, see footnotes in Scheme 4). Subsequently, the influence
of substituents at the 5-position of the indole scaffold was
investigated. Both electron-donating (5f: Me, 5g: OMe)[23] and -
withdrawing groups (5h: I, 5i: Br) were well tolerated, and the
corresponding products were obtained in moderate to good
yields (59–70%). In addition, applying 6-Cl (5j) or 7-Me indole
(5k) in the mechanochemical coupling yielded 6j[23] and 6k in 58
and 71%, respectively.
In summary, we developed two metal-catalyzed C–H
alkynylation reactions in mixer mills. Both processes proceed
under solventless conditions and do not require additional
heating to produce the products in high yields. They are highly
efficient as in both cases significantly smaller quantities of
catalysts and shorter reaction times than in solvent were
required.
[a]
Reaction conditions: 5a (0.6 mmol, 1.0 equiv.), 2a (0.72 mmol, 1.2
equiv.), 30 Hz, RETSCH mixer mill (MM 400), vessel (10 mL), and ball
(diameter: 1 cm) are made of stainless steel; [b] After chromatography.
Next, the substrate scope of the gold-catalyzed
mechanochemical C–H alkynylation was examined (Scheme
4).[22] The use of unsubstituted indole (5a) in the coupling with 2a
led to 75% of 6a, along with ca. 6% of an undefined side-product.
Again, the mechanochemical coupling exhibited high
reproducibly, as demonstrated by three individual reactions
between 5a and 2a in which 6a was isolated each time in a
similar yield (73–77%). Unfortunately, scaling up the reaction to
2.0 mmol led only to 42% of 6a after 2 x 99 min of shaking.
Changing the protecting group on the alkyne from a TIPS- to a
TBDMS-group diminished the yield, and 6b was obtained in only
31%.[23] In contrast, using N-methyl indole (5c) as the reaction
partner in the mechanochemical coupling proved unproblematic,
Experimental Section
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10.1002/anie.201805778
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COMMUNICATION
[5]
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Angew. Chem. Int. Ed. 2014, 53, 2722–2726; (b) K. D. Collins, F. Lied,
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Representative procedures: All reactants and catalysts were transferred
to a ball-milling vessel (stainless steel, 10 mL) containing one grinding
ball (stainless steel, diameter: 1.0 cm). The ball-milling vessel was then
transferred to a mixer mill (RETSCH MM400), and the reaction mixture
was milled at 30 Hz for the specified duration. In the case of the rhodium-
catalyzed coupling, the crude reaction mixture was extracted by washing
the vessel and the ball with DCM or EtOAc (5 x 10 mL), and the resulting
mixture was filtered through a thin layer of SiO2 and concentrated in
vacuo. The product was then isolated by flash column chromatography
on silica gel (n-pentane/EtOAc). To decrease the amount of solvent used
for the extraction of the reaction mixture from the vessel, the crude
product can alternatively be taken up by adding silica (2 x 1 g) to the ball-
milling vessel and milling the resulting mixture for 5 min (x 2). In the case
of the gold-catalyzed alkynylation, the crude was recovered by washing
the vessel and the ball with Et2O (5 x 10 mL). The organic layer was
washed with 0.1 M NaOH (2 x 50 mL) and the combined aqueous layers
were extracted with Et2O (50 mL). The organic layers were combined,
washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over
MgSO4, concentrated in vacuo and purified by flash chromatography
(SiO2, n-pentane/Et2O).
[7]
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Acknowledgements
The financial support by RWTH Aachen University through the
Distinguished Professorship Program funded by the Excellence
Initiative of the German Federal and State Governments is
highly appreciated. We are also grateful to Dr. José G.
Hernández (RWTH Aachen University) for proofreading the
manuscript and helpful discussions.
Keywords: ball milling • mechanochemistry • solventless
reactions • C–H alkynylation • rhodium catalysis • gold catalysis
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COMMUNICATION
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[18] For more details regarding the used stainless steel jars and balls, see
the Supporting Information.
[19] For
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[21] A slightly lower yield (67%) was observed when the reaction was
performed in a RETSCH mixer mill (cryo mill) using a vessel (25 mL)
and ball (diameter: 1.5 cm) made of ZrO2.
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[23] Performing the reaction with higher amounts of catalyst and/or longer
reaction times did not lead to a higher yield.
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COMMUNICATION
R3
Under
solventless
RhIII catalyst
G. N. Hermann, M. T. Unruh, S.-
H. Jung, M. Krings, C. Bolm*
R1
R4
mechanochemical conditions,
C2- and C3-alkynylated indoles
have selectively been prepared
in mixer mills by RhIII- and AuI-
catalyzed C–H alkynylations,
respectively. Additional heating
is not required, and both
catalyses show an excellent
H
N
R2
R3
R4
I
O
O
R1
+
H
R4
N
R2
Me
Page No. – Page No.
AuI catalyst
R3
R1
or
TIPS
N
N
H
Mechanochemical Rhodium(III)-
R2
and
Gold(I)-Catalyzed
C–H
Bond Alkynylations of Indoles
under Solventless Conditions
in Mixer Mills
functional
group
tolerance.
Compared to their solvent-
based counterparts, shorter
reaction times and lower
catalysts loadings are needed
to provide high product yields.
This article is protected by copyright. All rights reserved.