Aerobic C-H olefination of indoles via a cross-dehydrogenative coupling in continuous flow

Article abstract of DOI:10.1021/ol502910e

Herein, we report the first site-selective, Pd(II)-catalyzed, cross-dehydrogenative Heck reaction of indoles in micro flow. By use of a capillary microreactor, we were able to boost the intrinsic kinetics to accelerate former hour-scale reaction condition

Full text of DOI:10.1021/ol502910e

Letter
pubs.acs.org/OrgLett
Aerobic C−H Olefination of Indoles via a Cross-Dehydrogenative
Coupling in Continuous Flow
Hannes P. L. Gemoets, Volker Hessel, and Timothy Noel*
̈
Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of
Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands
*
S Supporting Information
ABSTRACT: Herein, we report the first site-selective, Pd(II)-catalyzed, cross-dehydrogenative Heck reaction of indoles in
micro flow. By use of a capillary microreactor, we were able to boost the intrinsic kinetics to accelerate former hour-scale reaction
conditions in batch to the minute range in flow. The synergistic use of microreactor technology and oxygen, as both terminal
oxidant and mixing motif, highlights the sustainable aspect of this process.
1
7
3
-Vinylindole motifs play a prominent role in active
oxidant. Inspired by the work of Fujiwara, several other
research groups continued developing selective C-3 cross-
pharmaceutical ingredients (API) as they impart interesting
biological properties, such as anticarcinogenic, antiviral,
antibacterial, and antidepressant activities (Figure 1).
dehydrogenative Heck reactions for (NH)-indoles, utilizing a
variety of oxidants.
1
−8
18−22
In 2012, Wang reported the use of
Consequently, reliable methods to prepare such compounds
are of great importance. One appealing approach to prepare
vinylindoles is via a cross-dehydrogenative Heck coupling.
gaseous oxygen as a sole terminal oxidant for this trans-
20
formation. Despite being the cleanest and cheapest oxidant, the
use of oxygen in combination with flammable solvents raises
significant safety concerns, especially on a larger scale. In
addition, direct oxidation of Pd(0) by molecular oxygen is
kinetically unfavored, allowing for the reduced palladium to
9
,10
Cross-dehydrogenative coupling (CDC) reactions allow the
connection of two different C−H bonds under oxidative
11
conditions. In contrast to traditional cross-coupling, CDC
bypasses the need for prefunctionalized coupling partners and
produces, in theory, only water as a byproduct. Despite these
apparent advantages, challenges still remain with regard to
23−30
agglomerate into inactive bulk metal.
With this in mind, the
development of a safe and reliable CDC procedure to prepare 3-
vinylindoles would be an attractive goal.
Due to its small dimensions, continuous-flow microreactors
12−15
reactivity, selectivity, practicality, and scope.
have received an increasing amount of attention to carry out such
31−46
hazardous and challenging reactions.
Moreover, high gas−
liquid mass-transfer coefficients are typically obtained in such
devices which provides uniform oxygen concentration in the
liquid phase. Gas−liquid flow regimes lead to a segmented flow
which enables an intense contact between the liquid phase and
gaseous reactants and induces small vortices inside each segment,
47−53
allowing for fast mixing.
We anticipated that these features
could prevent possible palladium agglomeration, ensure
reoxidation of Pd(0) to Pd(II), and thus, efficiently avoid
catalyst deactivation. The excellent gas−liquid mass transfer in
combination with high reaction temperatures can further boost
the reactivity of the catalytic system in flow. Herein, we report a
minute-range protocol for the formation of 3-vinylindoles via
cross-dehydrogenative Heck reaction in continuous flow using
oxygen both as green oxidant and mixing motif.
Figure 1. Examples of 3-vinylindole compounds displaying interesting
biological activities.
3,5,7
In 1967, Moritani and Fujiwara were the first to report a cross-
16
dehydrogenative Heck reaction. Their pioneering studies
involved the coupling between olefins and benzene in the
presence of stoichiometric amounts of PdCl . In 1999, Fujiwara
2
described a highly efficient dehydrogenative Heck reaction of
heterocycles, including (NH)-indole substrates, with olefins
Received: October 2, 2014
using catalytic amounts of Pd(OAc) and tBuOOH as a terminal
2
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502910e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a54
Table 1. Optimization of Reaction Conditions in Batch
b
entry additive (equiv) temp (°C) reaction time (h) conversion (%)
Figure 2. Schematic representation of micro flow setup. MFC = mass
flow controller.
1
2
3
4
5
6
7
8
9
1
1
1
1
70
70
70
70
70
60
60
60
60
60
60
60
60
1
1
trace
43
TFA (8)
PivOH (8)
p-TsOH (8)
PhCOOH (8)
1
30
Table 2. Optimization of Reaction Conditions in Continuous
1
14
a
Flow
1
trace
11
14
14
14
14
14
14
14
14
TFA (1)
TFA (2)
TFA (4)
TFA (8)
TFA (8)
TFA (8)
TFA (8)
>95
>95
78
0
1
2
3
69
c
NR
trace
21
d
e
b
entry
olefin
cyclohexene
temp (°C)
conversion (%)
a
1
2
3
4
5
6
7
70
90
18
41
57
Reaction conditions: 1a (0.5 mmol), 2j (1.0 mmol, 2 equiv),
Pd(OAc) (0.05 mmol, 10 mol %), internal standard (0.05 mmol), and
additive in DMSO (2.5 mL), O balloon, specified temperature. A
mixture of 3k and 3l was obtained. Conversion of indole was
determined with GC−FID and decafluorobiphenyl as the internal
standard. No Pd(OAc) . Pd(OAc)2 (0.005 mmol, 1 mol %).
Pd(OAc) (0.025 mmol, 5 mol %). NR = no reaction.
cyclohexene
2
cyclohexene
100
110
120
130
150
110
110
110
110
110
2
b
g
cyclohexene
67, 43
cyclohexene
67
c
d
2
cyclohexene
59
e
2
cyclohexene
clogging
clogging
73
c
8
d
tert-butyl acrylate
tert-butyl acrylate
tert-butyl acrylate
2,2,2-trifluoroethyl acrylate
2,2,2-trifluoroethyl acrylate
We commenced our investigations by performing an initial
screening of some reaction parameters in batch (Table 1). (NH)-
indole (1a) was reacted with cyclohexene (2j) in the presence of
9
d
d
d
,
,
e
f
1
1
0
1
90
79
g
h
1
0 mol % of Pd(OAc) as a catalyst and O as sole oxidant in
2
2
12
100, 82, 82
DMSO. From the literature, DMSO was found to be strongly
a
Reaction conditions: 1a (4.0 mmol), Pd(OAc) (0.4 mmol, 10 mol
), internal standard (0.4 mmol), and TFA (32.0 mmol, 8 equiv) in
2
coordinating, overriding any effect that acids may have on
%
1
8,20
selectivity (e.g., migration to the C-2 carbon).
As a result, the
DMSO (10 mL) loaded in a 10 mL syringe. 2 (8.0 mmol, 2 equiv) in
reaction is characterized by excellent C-3 regioselectivity and E
stereoselectivity. In addition, the use of such polar solvents is
advantageous since they allow effective dissolution of organic
products, efficiently avoiding microreactor clogging. At first,
different organic acids, such as trifluoroacetic acid (TFA), pivalic
acid (PivOH), benzoic acid (PhCOOH), and p-toluenesulfonic
acid (p-TsOH), were tested as possible ligands to activate the
Pd(II) complex (Table 1, entries 1−5). TFA was found to be the
most suitable ligand (Table 1, entry 2). Next, the amount of TFA
was investigated (Table 1, entries 6−10), demonstrating that 1
equiv of TFA was optimal (Table 1, entry 7). It was found that
lowering the catalyst loading resulted in sluggish reaction
conditions and incomplete conversion (Table 1, entries 11−13).
With optimized batch conditions in hand, a continuous-flow
microreactor setup was assembled as described in Figure 2 (see
the Supporting Information for a detailed description).
DMSO (10 mL) loaded in a 10 mL syringe. 2 mL microreactor, FEP
tubing 750 μm inner diameter, t (residence time) = 10 min, 5:1 gas/
r
b
liquid flow ratio provided a Taylor flow regime. Conversion of indole
was determined with GC−FID and decafluorobiphenyl as the internal
c
d
e
standard. TFA (4.0 mmol, 1 equiv). TFA (8.0 mmol, 2 equiv). t =
r
f
2
1
0 min. 4 mL microreactor, FEP tubing 750 μm inner diameter, t =
r
g h
19
0 min, Taylor flow regime. Isolated yield.
F NMR yield with
decafluorobiphenyl as the internal standard.
presumably due to catalyst decomposition (Table 2, entries 5−
7). Indeed, we observed microreactor clogging at 150 °C due to
excessive Pd(0) precipitation inside the microchannels (Table 2,
57
entry 7). Next, we investigated two more activated olefins (tert-
butyl acrylate and 2,2,2-trifluoroethyl acrylate) (Table 2, entries
9 and 11). To avoid catalyst degradation and thus microreactor
clogging, we found that 2 equiv of TFA was mandatory (Table 2,
entries 8−9). To achieve complete conversion, the residence
time was doubled and the reactor was made twice as long (Table
2, entry 10 and 12). The latter ensured that higher flow rates
could be obtained, leading to a higher degree of mixing in the
segmented flow regime. This has a pronounced effect on the
gas−liquid mass transfer, ensuring efficient palladium reoxida-
tion. To our delight, this provided the conditions necessary to
obtain full conversion (Table 2, entry 12).
Initially, we investigated the temperature dependence in flow
while keeping the residence/reaction time constant at 10 min
(
Table 2, entries 1−7). Microreactor technology offers the
opportunity to accelerate reactions substantially at elevated
temperatures without compromising safety aspects.
3
2,55,56
More-
over, by keeping the exposure time of the reaction mixture in the
heated zone limited to what is kinetically required, extensive
product degradation can be avoided. We found that increasing
the temperature had a positive impact on the conversion, with
With optimized flow conditions in hand, we explored the
substrate scope for our system by varying the olefin coupling
partner (Table 3) and the indole moiety (Table 4). A reaction
1
10 °C being the optimal temperature (Table 2, entry 4). A
further increase of the temperature gave lower conversion,
B
dx.doi.org/10.1021/ol502910e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Olefin Substrate Scope for the Pd(II)-Catalyzed
Cross-Dehydrogenative Heck Reaction in Flow
Table 4. Indole Substrate Scope for the Pd(II)-Catalyzed
a
a
Cross-Dehydrogenative Heck Reaction in Flow
a
Reaction conditions: 1c−g (4.0 mmol), Pd(OAc) (0.4 mmol, 10
2
mol %), internal standard (0.4 mmol), and TFA (8.0 mmol, 2 equiv)
in DMSO (10 mL) loaded in a 10 mL syringe. 2d (8.0 mmol, 2 equiv)
in DMSO (10 mL) loaded in a 10 mL syringe. 4 mL microreactor,
FEP tubing 750 μm inner diameter, 5:1 gas/liquid flow ratio provided
a Taylor flow regime. Conversion monitored with TLC and/or GC−
b
c
MS. Isolated yield. No full conversion was observed.
(
72−92%). The reaction of 6-fluoroindole (1b) with methyl
acrylate (2f) produced methyl (E)-3-(6-fluoro-1H-indol-3-
yl)acrylate (3f), a potential anticancer agent, with a good yield
3
a
of 67%. 1-Octen-3-one (2h) showed a lower reactivity (49%)
toward C-3 olefination of indole, as compared to acrylates.
Interestingly, within 20 min residence time, nonactivated olefins,
such as styrene (2i) and cyclohexene (2j), gave the desired
compounds (3i and 3j), albeit in more moderate yield (27−
43%).
Variation of the indole substrate was performed with ethyl
acrylate as a benchmark coupling partner. The reaction
proceeded smoothly with either electron-withdrawing (NO2
and F) or electron-donating (MeO) substituents, producing,
respectively, the 3-vinylindoles 3f, 4c, and 4d in good yields (66−
78%). Methyl substituents on the C-2 position were well
tolerated (52−62%) (Table 4, entries 2 and 5). The use of N-
methylindole (1c) as substrate only resulted in a small drop in
yield (84%).
In summary, we have developed a fast and straightforward
continuous-flow protocol for the dehydrogenative C-3 olefina-
tion of indoles using molecular oxygen as the sole oxidant.
Because of the enhanced mass- and heat-transfer characteristics
and the high degree of control provided by microflow processing,
we were able to accelerate the intrinsic kinetics of the cross-
dehydrogenative Heck coupling. Furthermore, the high surface-
to-volume ratio of the oxygen phase with the liquid phase
prevents catalyst degradation. Our protocol is effective to prepare
a wide variety of 3-vinylindoles in good to excellent yields (27−
92%) within residence times of 10−20 min. Notably, we were
Reaction conditions: 1a (4.0 mmol), Pd(OAc) (0.4 mmol, 10 mol
), internal standard (0.4 mmol), and TFA (8.0 mmol, 2 equiv) in
2
%
DMSO (10 mL) loaded in a 10 mL syringe. 2 (8.0 mmol, 2 equiv) in
DMSO (10 mL) loaded in a 10 mL syringe. 4 mL microreactor, FEP
tubing 750 μm inner diameter, 5:1 gas/liquid flow ratio provided a
Taylor flow regime. Conversion monitored with TLC and/or GC−
MS. Isolated yield. Yield after 4 h batch reaction in similar
conditions. 6-fluoroindole (1b) as substrate. Isolated yield after
b
c
d
e
hydrogenation.
between (NH)-indole and 2,2,2-trifluoroethyl acrylate (2a)
resulted in a good isolated yield (82%) in only 10 min reaction
time (Table 3, entry 1). Remarkably, a control experiment in
batch showed that a 4 h reaction time was required to achieve full
conversion. In addition, a drop in selectivity was observed due to
prolonged exposure in the heated zone leading to a lower isolated
yield of 58% (Table 3, entry 1). It is generally known that free
(NH)-indoles are prone to decomposition when exposed to
20
higher temperatures (>60 °C). Next, a variety of electron-
deficient olefins (acrylates, fluorinated acrylates, N,N-dimethy-
lacrylamide, and 1-octen-3-one) and nonactivated olefins
(
styrene and cyclohexene) could be successfully coupled with
free (NH)-indole in moderate to excellent yields (27−92%)
within a 10−20 min residence time (Table 3, entries 2−10). C-3
olefination occurs smoothly for activated acrylates: (NH)-indole
(1a) reacted with 2a−e to form 3a−e products in high yield
C
dx.doi.org/10.1021/ol502910e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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* Supporting Information
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AUTHOR INFORMATION
̈
kvall, J.-E. Org. Lett. 2014, 16, 1664−1667.
■
(
3
̈
Corresponding Author
*E-mail: t.noel@tue.nl.
(
Notes
The authors declare no competing financial interest.
(
̈
, T.; Wang, Q.
ACKNOWLEDGMENTS
■
(
̈
̈
Financial support is provided by the Dutch Science Foundation
(NWO) via an ECHO grant (Grant No. 713.013.001) and a
(
VENI grant for T.N. (Grant No. 12464). We also acknowledge
the European Union for a Marie Curie CIG grant for T.N. (Grant
No. 333659) and an ERC Advanced Grant for V.H. (Grant No.
(
267443).
̈
(
4
(
2
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dx.doi.org/10.1021/ol502910e | Org. Lett. XXXX, XXX, XXX−XXX