Mechanochemical Copper-Catalyzed Asymmetric Michael-Type Friedel–Crafts Alkylation of Indoles with Arylidene Malonates

Article abstract of DOI:10.1002/chem.201901826

A mechanochemical version of the asymmetric Michael-type Friedel–Crafts alkylation of indoles with arylidene malonates was developed. The reaction proceeds under ambient atmosphere using a chiral bis(oxazoline)copper catalyst in a mixer mill. Under these

Full text of DOI:10.1002/chem.201901826

A Journal of
Accepted Article
Title: Mechanochemical copper-catalyzed asymmetric Michael-type
Friedel-Crafts alkylations of indoles with arylidene malonates
Authors: Plamena Staleva, Jose Hernandez, and Carsten Bolm
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Mechanochemical copper-catalyzed asymmetric Michael-type
Friedel-Crafts alkylations of indoles with arylidene malonates
Plamena Staleva, José G. Hernández, and Carsten Bolm*
a) Mechanochemical cross-dehydrogenative couplings[10a]
Abstract: A mechanochemical version of the asymmetric Michael-
type Friedel-Crafts alkylation of indoles with arylidene malonates
was developed. The reaction proceeds under ambient atmosphere
DDQ / PyBox
copper balls
ball milling
N
Ar
using a chiral copper bis(oxazoline) catalyst in a mixer mill. Under
these reaction conditions nineteen 3-substituted indole derivatives
were synthesized in good to excellent yields (up to 98%), and with
good enantioselectivities (up to 91:9 e.r.) after short milling times.
+
R
H
N
Ar
R
60-75% yield
10-79% e.e.
b) Mechanochemical Mannich-type couplings of aldehyde-alkyne-amine[10b]
Ar2
Chiral indoles, in particular 3-substituted ones, represent
valuable structural unit in organic chemistry due to their
prevalence in bioactive natural products, pharmaceuticals, and
synthetic chemicals.[1] Enantioenriched derivatives are often
Ar1
CHO
HN
Cu(OTf)2 / PyBox
ball milling
R
H
+
Ar1
Ar2
NH2
R
prepared by asymmetric Friedel-Crafts alkylation of indoles.[2]
A
90-99% yield
88-99% e.e.
typical example is the reaction of indole with arylidene
malonates in the presence of chiral copper(II)-complexes.[3]
Despite the effectiveness of these protocols in terms of yield and
enantioselectivity, many of them still face drawbacks such as a
strong dependence of the catalytic activity of the metal complex
on the nature of the solvent. Additionally, in most cases, an inert
atmosphere and prolonged cooling periods are required, thereby
rendering cumbersome and lengthy synthetic procedures.
c) Mechanochemical fluorinations of β-keto esters[10c]
O
O
F
Cu(OTf)2 /
diphenylamine BOX
O
O
R2
OR1
R2
OR1
NFSI
+
ball milling
R3
R3
85-99% yield
74-99% e.e.
O
Cl
Cl
Cl
In recent years, the number of studies searching for novel
concepts, new chemical reactivity, and more sustainable organic
processes has steadily increased. In this context, mechano-
chemistry has proven to be a powerful alternative for the
implementation of a wide range of chemical transformations,
exhibiting benefits such as solvent-free conditions, higher
reaction rates and the possibility to discover novel reaction
pathways.[4,5] Specifically, in the field of metal catalysis a
plethora of solvent-free reactions has been enabled using ball
milling techniques.[6] Interestingly, metal complexes have shown
remarkable stability under high mechanical stress,[7] a feature
that allowed introducing metal-catalyzed mechanochemical C–H
bond functionalization protocols.[8] Conversely, the mechano-
chemical formation of chiral metal complexes and their
application in asymmetric reactions by mechanochemistry have
remained underexplored. Presumably that is due to the
generally very critical fine-tuning of all reaction conditions such
as reaction media, concentration, inert atmosphere and,
especially, temperature required for achieving high enantio-
selectivities.[9] As a result, to date, only a handful of examples of
metal-catalyzed asymmetric transformations in ball mills have
been reported (Scheme 1a–c).[10] Here, we extend this pallet and
present Cu(I)-BOX-catalyzed asymmetric Michael-type Friedel-
Crafts alkylations of indoles 1 with benzylidene malonates 2
under solventless conditions in a mixer mill (Scheme 1d).
O
S
F
O
S
O
O
N
N
H
Ph
N
Ph
N
N
Cl
O
N
N
O
O
O
PyBox
Ph
Ph
O
NFSI
Bn Bn
DDQ
diphenylamine BOX
CO2R2
CO2R2
d) This work:
Ar
*
CO2R2
Ar
chiral Cu-complex
ball milling
R1
R1
+
N
H
N
H
CO2R2
1
2
3
Scheme 1. Mechanochemical metal-catalyzed asymmetric reactions.
Initially, a non-asymmetric version of Friedel-Crafts alkylations
under mechanochemical conditions was examined. Thus, a
mixture of indole (1a) and benzylidene malonate (2a) were
ground in the presence of Cu(OTf)2 (10 mol%) at 25 Hz in a
mixer mill. Pleasingly, after a milling time of only 60 min the
desired product 3a was formed in 94% yield (Table 1, entry 1).
This result evidenced the feasibility of the reaction to be realized
in the ball mill, but at the same time it also highlighted the high
reactivity of the copper salt to facilitate the formation of rac-3a, a
potential challenge to develop an asymmetric version of the
Friedel-Crafts alkylation by ball milling. To overcome this
challenge, Cu(OTf)2 and the chiral ligands (L1–L4) were first
milled for 10 min to favor the formation of the chiral copper
complexes. Then, 1a and 2b were added into the jar, and the
milling was continued for another 60 min of milling at 25 Hz.[11] In
general, the presence of the C2-symmetric bis(oxazoline) ligands
L1-L4 did not significantly affect the reaction rate of the Friedel-
Crafts alkylation, and product 3a was obtained in excellent yield
[a]
P. Staleva, Dr. J. G. Hernández, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany) Fax: (+49)241-8092-391
E-mail: carsten.bolm@oc.rwth-aachen.de
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Screening of the catalytic system for the alkylation of indole (1a) with
benzylidene malonate (2a).[a]
Table 2. Screening of the ball milling conditions and additives in the alkylation
of indole (1) with benzylidene malonate (2a) using indane-BOX L6 as ligand.[a]
CO2Et
Ph
CO2Et
L6 (5 mol%)
Ph
CO2Et
Lewis acid / ligand
Ph
CO2Et
CO2Et
Ph
CO2Et
CO2Et
CuCl/AgNTf2 (5 mol%)
+
CO2Et
+
N
ball milling
60 min, 25 Hz
N
H
N
ball milling
20 Hz, 60 min
H
H
N
1a
2a
3a
H
R2 R2
1a
2a
3a
Me
Me
O
H
H
O
O
L5: R2 = Me
L6: R2 = H
L1: R1 = iPr
L2: R1 = tBu
L3: R1 = Bn
L4: R1 = Ph
Entry
Freq. [Hz]
Additive
–
Yield [%][b]
e.r.[c]
O
N
N
N
N
H
H
1
25
20
15
20
20
20
20
20
20
97
92
41
99
99
99
95
95
37
85:15
87:13
87:13
85:15
87:13
88:12
91:9
R1
R1
2
–
Entry
Lewis acid
Cu(OTf)2
Ligand
̶
Yield [%][b]
e.r.[c]
̶
3
–
1
94
98
95
90
96
97
97
97
97
97
97
4
iPrOH
TFE
HFIP
PFP
PFP
PFP
2
Cu(OTf)2
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
50:50
65:35
52:48
50:50
62:38
78:22
81:19
85:15
85:15
85:15
5
3
Cu(OTf)2
6
4
Cu(OTf)2
7
8[d]
9[e]
90:10
85:15
5
Cu(OTf)2
6
Cu(OTf)2
7
Cu(OTf)2
[a] Reaction conditions: 1a (0.30 mmol), 2b (0.30 mmol), CuCl/AgNTf2/L6
(5 mol%), silica gel [as milling auxiliary (60 mg per 0.30 mmol of 1a)], for
entries 4–9: additive (0.30 mmol). [b] Determined by 1H NMR spectros-
copy with dimethylsulfone as an internal standard. [d] Use of 2.5 mol% of
CuCl/AgNTf2/L6. [e] Use of 1 mol% of CuCl/AgNTf2/L6.
8
CuCl2/AgNTf2
CuCl/AgNTf2
CuCl/AgNTf2
CuCl/AgNTf2
9
10[d]
11[e]
enantioselectivity of the mechanochemical reaction were
maintained (Table 1, entry 11).[12]
Having identified the CuCl/AgNTf2/L6 combination (5 mol%) as
the best catalytic system for the asymmetric alkylation reaction,
the influence of some milling parameters and additives on the
outcome of the reaction was investigated. Reducing the milling
frequency from 25 Hz to 20 Hz led to the formation of product 3a
in slightly lower yield, but pleasingly, an improvement in the
stereoselectivity of the reaction was noticed. Probably, that was
a result of an overall lowering of the temperature of the reaction
mixture due to the reduced energy input, resulting in better
enantioselectivity (Table 2, entry 2). However, performing the
reaction at 15 Hz led to a dramatic drop in the yield without
further improvement of the enantioselectivity (Table 2, entry 3).
Next, the effect of additives on the reaction was studied (Table 2,
entries 4–7). The addition of iPrOH and trifluoroethanol (TFE)
accelerated the formation of 3a, but did not improve the
enantioselectivity (Table 2, entries 4 and 5). Using the more
acidic hexafluoroisopropanol (HFIP) led to full conversion of the
starting materials, and product 3a was isolated with an
enantiomeric ratio of 88:12 (Table 2, entry 6). The
enantioselectivity of the reaction was further improved by using
pentafluorophenol (PFP) as an additive. After this modification,
3a was obtained in 95% yield with an e.r. of 91:9 (Table 2, entry
7). Decreasing the catalyst loading to 2.5 mol% was possible
without significantly affecting the yield and enantioselectivity
(Table 2, entries 8). Applying only 1 mol% of the catalyst led to a
drastic erosion in the yield of 3a (Table 2, entry 9).
[a] Reaction conditions: 1a (0.30 mmol), 2b (0.30 mmol), Lewis acid / ligand (10
mol%), silica gel [as milling auxiliary (60 mg per 0.30 mmol of 1a)], for entries 8–
11: use of AgNTf2 (10 mol%). [b] Yield after purification by column
chromatography; for entries 8–11: determined by 1H NMR spectroscopy with
dimethylsulfone as an internal standard. [c] Determined by CSP-HPLC analysis.
[d] The chiral copper complex was prepared in solution. [e] Use of 5 mol% of
Lewis acid / ligand.
after only 60 min of milling (Table 1, entries 2-5). More
importantly, the use of tBu-BOX ligand L2 provided the desired
product 3a with an enantiomeric ratio of 65:35 in favor of the (S)-
3a enantiomer (Table 1, entry 3).[3d] Encouraged by this result,
the screening was extended by applying additional ligands, e. g.
L5 and L6 (for a full ligand list, see the Supporting Information).
Also indane-BOX L5 gave an active catalyst under the milling
conditions, and the results were similar to the ones obtained with
BOX-ligand L2 (Table 1, entries 3 and 6). On the other hand, the
presence of unsubstituted indane-BOX L6 had a positive effect
on the enantioinduction of the reaction, and product 3a was
obtained with an e.r. of 78:22 (Table 1, entry 7). A further fine
tuning of the reaction conditions revealed that the cationic
complex generated in situ from AgNTf2 and CuCl2 gave 3a in
97% yield and 81:19 e.r (Table 1, entry 8). An additional
improvement in the enantioselectivity of the reaction was
achieved when CuCl was used instead of CuCl2 (Table 1, entry
9). A control experiment in the ball mill using the chiral Cu-
complex prepared in solution resulted in product 3a being
formed in identical yield and with the same enantioselectivity
(Table 1, entries 9 and 10), indicating that both the anion
exchange and the complex formation were completed under ball
milling conditions. Moreover, reducing the catalyst loading from
10 mol% to 5 mol% proved possible while the yield and the
With the optimized conditions established (Table 2, entry 7),
the substrate scope of the reaction was investigated. Various
structurally diverse indoles 1 and arylidene malonates 2 were
applied (Scheme 2). A number of substituents on the aryl ring of
the arylidene malonates 2a–h were tolerated, regardless of the
steric hindrance and electronic properties, affording products
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CO2R5
L6 (5 mol%)
R4
N
L6 (2.5 mol%)
CO2Et
CO2Et
CuCl/AgNTf2 (5 mol%)
PFP (1.0 equiv)
CO2R5
R1
Ph
R4
CO2R5
CO2R5
CuCl/AgNTf2 (2.5 mol%)
PFP (1.0 equiv)
R1
R2
Ph
CO2Et
CO2Et
+
R2
N
R3
+
ball milling
20 Hz, 60 min
N
H
ball milling
20 Hz, 90 min
R3
N
1
2
3
H
3a 92%, 91:9 e.r.
1a
1.2 mmol scale
2a
3a R = H; 95%, 91:9 e.r.
>99.9% e.e.
R
after single recrystallization
3b R = p-Cl; 91%, 89:11 e.r.
3c R = p-Me; 91%, 86:14 e.r.
3d R = p-SMe; 60%,a 84:16 e.r.
3e R = p-NO2; 96%, 86:14 e.r.
3f R = o-Cl; 83%, 87:13 e.r.
93%, 86:14 e.r.b
CO2Et
CO2Et
CO2Et
CO2Et
Scheme 3. Up-scaled mechanochemical Cu-catalyzed asymmetric
Friedel−Crafts alkylation of indole (1) with benzylidene malonate (2a).
N
N
H
H
While the results depicted in Scheme 2 were obtained with a
catalyst loading of 5 mol%, a reduction to 2.5 mol% was
possible in many cases without significantly affecting the
reaction outcome (for details, see the Supporting Information).
Finally, to further demonstrate the synthetic potential of the
mechanochemical approach, a four-fold scale up experiment
was conducted. After 90 min of milling at 20 Hz, the reaction
provided product 3a with an e.r. of 91:9 in 90% yield (Scheme 3).
3i 98%,a 91:9 e.r.
3g R = o-Me; 83%, 83:17 e.r
3h R = m-Br; 91%, 91:9 e.r.
CO2Et
Ph
CO2Et
R4
CO2Et
CO2Et
S
CO2Et
R1
CO2Et
N
H
N
R3
N
H
3m R1 = Me; 91%, 74:26 e.r.
3n R1 = Ph; 52%,a 57:43 e.r.
3j 90%, 83:17 e.r.
3k R3 = H, R4 = Me;
88%, 71:29 e.r.
Notably, recrystallization of 3a from
a
mixture of
3l R3 = Me, R4 = Ph;
87%, 86:14 e.r.
heptane/chloroform afforded a solid sample of 3a with >99.9%
e.e.
CO2R5
Ph
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Ph
CO2R5
In summary, we developed a mechanochemical copper-
catalyzed asymmetric alkylation of indoles in a mixer mill. The
transformation features short reaction times, solvent-free
conditions, ambient atmosphere and low catalyst loading. The
products are formed in high to excellent yields and good
enantioselectivities. The reaction times are shorter compared to
those required for analogous couplings in solution. Additionally,
an up-scaling of the mechanochemical catalysis proved
successful providing the enantioenriched product in excellent
yield, without any loss of enantioselectivity.
Br
N
N
N
Cl
H
H
H
3o 95%, 86:14 e.r
3p 95%,c 87:13 e.r.
3q R5 = Me; 92%, 85:15 e.r.
3r R5 = iPr; 97%, 85:15 e.r.
3s R5 = Bn; 95%, 91:9 e.r.
a reaction time: 180 min
b reaction time: 90 min
c with 1.5 equiv of indole
Scheme 2. Mechanochemical Cu-catalyzed asymmetric Friedel−Crafts
alkylations of indoles 1 with various arylidene malonates 2.
3a–h in excellent yields and good enantioselectivities (Scheme
2). 1-Naphthyl and 2-thiophenyl substituted arylidene malonates
also reacted well under the standard reaction conditions giving
the corresponding products 3j and 3i in yield of 98% and 90%
having 91:9 and 83:17 e.r., respectively. The reaction with
ethylidene malonate (2k) provided product 3k in high yield, but
the enantioselectivity (71:29 e.r.) was significantly lower than the
ones with aryl-containing substrates. Meanwhile, the effect of
the substituents on the indole reaction partner was investigated.
N-Methyl indole and 2a reacted in the ball mill to give product 3l
in good yield and enantioselectivity. Introducing a substituent on
the 2-position of the indole negatively affected the yield and the
enantioselectivity of the alkylation reaction. Although 2-methyl
indole gave the corresponding product 3m in excellent yield, the
e.r. of 3m was only 74:26. Even more pronounced was this
effect for 2-phenyl indole product 3n, which was formed in only
52% yield after 180 min of milling with an enantiomeric ratio of
57:43. Pleasingly, 5- or 6-halogen substituted indoles reacted
well affording the respective products 3o and 3p in high yields
and good asymmetric induction (Scheme 2). The use of
substituted indoles bearing electron donating groups such as 4-
and 5-methyl indole derivatives proved more challenging, and
only 5-methyl indole provided the alkylated product, albeit in low
yield (22% yield after 60 min of milling). Next, the nature of the
ester group in the benzylidene malonates 2 was varied. Thus,
methyl, isopropyl and benzyl esters were tested giving the
corresponding products 3q–s in excellent yields and with
enantioselectivities close to the values obtained using the model
substrate benzylidene malonate (2a).
Acknowledgements
The authors are grateful to RWTH Aachen University for
financial support through the Distinguished Professorship
Program funded by the Excellence Initiative of the German
Federal and State Governments. We also thank Keanu
Birkelbach for practical assistance.
Keywords: asymmetric alkylation • ball milling • indole • Friedel-
Crafts • mechanochemistry
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10.1002/chem.201901826
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Plamena Staleva, José G. Hernández
and Carsten Bolm*
Page No. – Page No.
Mechanochemical copper-catalyzed
asymmetric Michael-type Friedel-
Crafts alkylations of indoles with
arylidene malonates
In mixer mills, Cu(I)-BOX complexes catalyze asymmetric Michael-type Friedel-
Crafts alkylations of indoles with benzylidene malonates under solvent-free
conditions. With low catalyst loadings, the transformations proceed under ambient
atmosphere and lead to products with good enantioselectivities in high to excellent
yields after short reaction times.
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