Continuous flow synthesis of indoles by Pd-catalyzed deoxygenation of 2-nitrostilbenes with carbon monoxide

Article abstract of DOI:10.1039/c7ra01087g

The palladium-catalyzed deoxygenation of o-vinylnitrobenzenes employing carbon monoxide as a terminal reductant produces indoles in a continuous flow environment. The reaction proceeds with catalyst loadings of 1 to 2 mol% Pd(OAc)₂ in the presence of suitable ligands/additives and generates carbon dioxide as the only stoichiometric side-product. The reductive cyclization proceeds in a clean fashion with high initial reaction rates in the pressurized flow reactor, ultimately leading to deposition of catalytically inactive palladium(0) inside the channels of the flow device, allowing for an efficient catalyst recovery. A variety of o-vinylnitrobenzenes (o-nitrostilbenes and -styrenes) were converted to the corresponding indoles within 15 to 30 min at a reaction temperature of 140 °C to furnish products in good to excellent yields (10-20 bar CO pressure). Mechanistic aspects and the scope of the transformation are discussed.

Full text of DOI:10.1039/c7ra01087g

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Continuous flow synthesis of indoles by
Pd-catalyzed deoxygenation of 2-nitrostilbenes
Cite this: RSC Adv., 2017, 7, 10469
with carbon monoxide†
a
ab
*
Gabriel Glotz, Bernhard Gutmann,
Paul Hanselmann,c Anna Kulesza,c
c
ab
*
*
Dominique Roberge and C. Oliver Kappe
The palladium-catalyzed deoxygenation of o-vinylnitrobenzenes employing carbon monoxide as a terminal
reductant produces indoles in a continuous flow environment. The reaction proceeds with catalyst loadings
of 1 to 2 mol% Pd(OAc)2 in the presence of suitable ligands/additives and generates carbon dioxide as the
only stoichiometric side-product. The reductive cyclization proceeds in a clean fashion with high initial
reaction rates in the pressurized flow reactor, ultimately leading to deposition of catalytically inactive
palladium(0) inside the channels of the flow device, allowing for an efficient catalyst recovery. A variety
of o-vinylnitrobenzenes (o-nitrostilbenes and -styrenes) were converted to the corresponding indoles
within 15 to 30 min at a reaction temperature of 140 ꢀC to furnish products in good to excellent yields
(10–20 bar CO pressure). Mechanistic aspects and the scope of the transformation are discussed.
Received 24th January 2017
Accepted 1st February 2017
DOI: 10.1039/c7ra01087g
rsc.li/rsc-advances
nitroaromatic compound is thereby typically heated in boiling
triethyl phosphite to accomplish a deoxygenative cyclization.2
Introduction
This approach is appealing for the construction of highly
functionalized indoles, since the reaction is inherently regio-
selective and the respective starting materials can be assembled
in a convergent manner by highly developed, robust trans-
formations. On the other hand, the extreme reaction conditions
Indoles are among the most abundant heterocycles in nature
and a vastly diverse array of natural and synthetic compounds
contain the indole scaffold. Even though rst methods for the
generation of indoles were discovered well over a century ago,
the ubiquity and structural diversity of biologically active
indoles has continued to drive research towards their synthesis
and functionalization.1 In particular, the development of
regioselective methods for the construction of indoles with
complex substitution patterns has remained an active area of
research.1 In the 1960s, Cadogan and Sundberg reported the
generation of indoles by reductive cyclization of o-nitrostyrenes
(cf. Scheme 1).2 For the Cadogan–Sundberg indole synthesis, the
ꢀ
(reaction temperatures in excess of 150 C) and the generation
of large amounts of phosphorus waste renders this trans-
formation increasingly unacceptable in contemporary organic
synthesis. Transition metal catalyzed alternatives employing
carbon monoxide as stoichiometric reducing agent were devel-
oped in the 1990s (Scheme 1).3 In particular, palladium-based
systems have proven to be effective for this transformation.
Watanabe and co-workers demonstrated a procedure for the
reductive cyclization of 2-ethenyl-1-nitrobenzenes employing
PdCl2(PhCN)2 as catalyst and triphenylphosphine as the
ligand.4 A stoichiometric amount of tin dichloride and a CO
pressure of 20 bar was required to yield the corresponding
ꢀ
4
¨
indoles within a reaction time of 16 h at 100 C. Soderberg and
co-workers accomplished the indolization with mol%
6
Scheme 1 Reductive cyclization of o-vinylnitrobenzenes.
Pd(OAc)2 and 24 mol% triphenylphospine as ligand using
MeCN as solvent.5 Typically, the reaction was completed aer
reaction times of 15 h at 70 ꢀC under a CO pressure of 4 bar to
furnish the indoles in fair to excellent yields (40 to 100%).5 More
recent work has demonstrated the great potential of this
transformation for the construction of functionalized
indoles.6–8 For instance, a thorough study by Davies and co-
workers revealed that the reaction proceeds under compara-
tively mild conditions and with high functional group toler-
ance.8 With catalyst loadings as low as 1 mol%, a variety of o-
aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz,
Austria. E-mail: oliver.kappe@uni-graz.at
bResearch Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz,
Austria
cMicroreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
† Electronic supplementary information (ESI) available: Further experimental
results and optimization data; Wittig synthesis of o-nitrostilbenes and
characterization data; ICPMS analysis of the processed reaction mixture;
1H-NMR and 13C-NMR spectra. See DOI: 10.1039/c7ra01087g
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nitrostyrenes were convertedꢀto the respective indoles within
reaction times of 16 h at 80 C.8 Alternative procedures using
molybdenum hexacarbonyl [Mo(CO)6] as a convenient but
expensive source of CO have been developed.9
Even though the reductive cyclization of o-nitrostyrene
derivatives with CO as stoichiometric reductant provides an
appealing approach for the synthesis of indoles, the necessity to
employ a highly toxic gas under elevated pressure and temper-
ature has severely limited the practicality of this trans-
formation. Continuous ow microreactors represent an
excellent platform for multiphase reactions.10–12 Since mass
transfer between the phases is directly proportional to the
interfacial area per unit volume, increasing interfacial area is
crucial for achieving high reaction rates and to minimize
unwanted side reactions in the homogeneous phase. Using
dedicated continuous ow micromixers, specic interfacial
areas orders of magnitude larger than in conventional stirred
tank reactors can be established.10–12 Importantly, large, well-
dened specic interfacial areas can be maintained up to
high production volumes. In particular, gas–liquid reactions
benet tremendously from the unique characteristics of
microreactors.12,13 Gases can be dosed into the ow system with
precise stoichiometry using mass ow controllers and intense
mixing of the gaseous and liquid phase can be achieved.
Furthermore, high pressure operation increases the concen-
tration of the gas in the liquid phase (Henry's law). It is not
surprising, therefore, that continuous ow reactions with
gaseous carbon monoxide as reagent have found quite consid-
erable usage.13,14 Indeed, in several cases it was reported that
carbonylation reactions in microreactors performed consider-
ably cleaner compared to batch reactions under otherwise
identical conditions.13
Scheme 2 Experimental setup for continuous flow deoxygenations
with carbon monoxide.
Herein we present an intensied continuous ow protocol
for the reductive cyclization of o-vinylnitrobenzenes of type 1
(Scheme 1). The reactions proceeded with low catalyst loadings
ꢀ
within residence times of only 15 to 30 minutes at 140 C and
CO pressures of 10–20 bar. The protocol was successfully
applied for the generation of various 2-aryl-substituted indoles.
The products were isolated with excellent purities, generally
without the need for chromatography.
Results & discussion
The initial ow reactor setup consisted of an HPLC pump for
introducing the liquid feed (Scheme 2; see also Fig. S1 in the
ESI†). CO gas was fed from a gas cylinder into the system via
a mass ow controller. The liquid and gaseous streams were
combined in a simple stainless steel T-mixer at room temper-
ature. The T-mixer was connected to the residence tube reactor
Fig. 1 Top: 3-D surface image showing for the strongly IR active
asymmetrical stretch band of CO2 in the region from 2300 to 2400
cmꢁ1, and the weaker CO absorption in the region of 2100 to 2200
cmꢁ1. Bottom: evolution of CO2 during a reaction.
via a uoropolymer tubing (PFA, 1/1600 o.d., 0.8 mm i.d.). The directly aer the pump (PS1 and PS2; Scheme 2). The evolution
PFA tubing allowed visual observation of the ow prole. The of carbon dioxide during the reaction could be conveniently
residence time reactor was a 20 mL stainless steel coil heated on monitored by in-line FTIR analysis (Mettler Toledo ReactIR with
an aluminum heating block (Uniqsis FlowSyn). The processed silicon probe).15 The strongly IR active asymmetrical stretch
reaction mixture nally exited the system through a short band of CO2 in the region from 2300 to 2400 cmꢁ1 was the
cooling loop in a water bath (1 mL stainless steel, 1/1600 o.d., dominant feature in the IR-spectrum (see Fig. 1). The weaker
1 mm i.d.) and an adjustable back-pressure regulator (0 to 25 stretch band of CO was detectable in the region of 2100 and
bar). Pressure sensors were integrated into the T-mixer and 2200 cmꢁ1
.
15
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Table 1 Reductive cyclization of methyl 2-nitrocinnamate (1a) in various solvents at 120 ꢀC (Scheme 2)a
Solvent
1ab (%)
2ab (%)
3ab(%)
Othersb,c (%)
1
2
3
4
5
6
MeCN
DMF
Dioxane
EtOAc
Toluene
i-PrOH
14
9
8
20
85
83
64
45
1
7
28
35
1
0
0
0
1a not soluble
1a not soluble
a
Conditions: 0.9 mmol substrate 1a, 2 mol% Pd(OAc)2 and 4 mol% 1,10-phenanthroline in 3 mL solvent. Flow rate gas/liquid: 5.0/0.5 mL minꢁ1
(ꢂ1.4 equiv. of CO); ꢂ20 bar pressure; residence time ꢂ30 min (Scheme 2). HPLC peak area integration at 215 nm. c Unidentied compounds.
b
Initial experiments were performed with methyl 2-nitro- equiv. of CO and thus less than required by stoichiometry (2
cinnamate (1a) as model substrate under conditions close to those equiv.). The palladium(II) acetate was reduced to palladium(0)
reported by Davies and co-workers (Table 1).8 For these reactions, immediately upon contact with CO and the Pd(0) partly deposited
0.9 mmol of the substrate, Pd(OAc)2 (2 mol%) and 1,10-phenan- on the PFA tubing which connected the T-mixer and the stainless
throline ligand (phen) were dissolved in the respective solvent steel residence coil (Scheme 2).16 Furthermore, palladium(0)
(3 mL). The solutions were loaded into the sample loop of the 6- particles were observed in the collected reaction mixtures. Even
port injection valve. When the reaction was started, the injection though considerable amounts of palladium were lost from the
valve was switched and the reaction mixture was carried into the mixture by precipitation on the tubing, reasonable conversions
mixer, where it was combined with carbon monoxide. The liquid and remarkably clean reactions were obtained (Table 1). The only
and the gaseous feed were pumped at ow rates of respectively 0.5 side product detectable in the reaction mixture in appreciable
and 5 mL minꢁ1 for the initial reactions. This corresponded to 1.4 amounts showed an m/z of 191, and is probably N-hydroxyindole
Scheme 3 Putative mechanisms for palladium-catalyzed indolization of o-nitrostyrene (coordination of Pd to the double bond of the o-
nitrostyrene has been omitted for clarity).7b
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3a (Table 1). Conversions of methyl 2-nitrocinnamate (1a) between addition, temperature and reaction time had surprisingly little
80 and 90% were obtained in all tested solvents aer a residence effect on the reaction (see Table 3). In particular, decreasing the
time of ꢂ30 min at 120 ꢀC (Table 1). DMF and MeCN stabilize the residence time did not decrease the conversion as strongly as
palladium(0) better than the other tested solvents and less Pd- expected. Indeed, at a reaction temperature of 140 ꢀC, the
particles were found in the processed reaction mixtures. Only conversion increased with increasing ow rate (entries 1 to 4 in
traces of N-hydroxyindole 3a were formed in MeCN as solvent. In Table 3). We hypothesized that at higher ow rates less of the
contrast, signicant amounts of N-hydroxyindole 3a were palladium precipitates on the initial PFA tubing at room
produced in less polar solvents, such as dioxane and EtOAc. temperature (cf. Scheme 2) and more palladium is therefore
Interestingly, the corresponding reaction with 2-nitrocinnamic available in the stainless steel tube at 140 ꢀC. Therefore, all
acid did not provide the expected indole-2-carboxylic acid as subsequent reactions were performed with a heated static
product. Instead, compounds derived from nitro reduction and mixer, to allow the combination of the gaseous CO feed with the
from decarboxylation with subsequent reductive cyclization were liquid reaction mixture directly at elevated temperatures
formed (Scheme S1 in the ESI†).
(Uniqsis glass static mixer; 1.8 mL mixing volume). With the
Formation of N-hydroxyindoles has previously been reported static mixer heated to 140 ꢀC, the conversion increased to >90%
for reductive cyclizations involving CO and has been taken as (entry 6 in Table 3). The stainless steel residence coil was then
evidence for a reaction mechanism involving partial deoxygen- removed, still providing >90% conversion aer a residence time
ation of nitrostyrene to a nitrosostyrene intermediate (mecha- of ꢂ3 min at 160 ꢀC (entry 8 in Table 3). The reaction was
nism
A
in Scheme 3).8 Spontaneous intramolecular remarkably clean with methyl indole-2-carboxylate (3b) as the
electrocyclization of the nitrosostyrene, followed by [1,5]- virtually only product. Even with a catalyst loading of only 1
hydrogen shi and isomerization yields the N-hydroxyindole 3.17 mol%, palladium(0) immediately formed upon contact with CO
A subsequent palladium-catalyzed reduction of the N-hydrox- and precipitated on the channels of the static mixer. Indeed,
yindole 3 with CO as terminal reductant forms indole 2 as the aer only a few experiments, a palladium lm covered the
nal product (Scheme 3).8 In contrast, earlier mechanistic inves- channel of the static mixer over most of its length (Fig. S4 in the
¨
tigations by Watanabe, Cenini, and Soderberg have suggested the ESI†). Notably, the palladium(0) on the mixer showed no cata-
formation of a metal nitrene as intermediate (IV) by exhaustive lytic activity for reductive cyclization (entry 10 in Table 3).
deoxygenation of the nitrostyrene 1 (mechanism B in Scheme Decreasing the amount of Pd(OAc)2 below 1 mol% decreased
3).3,4,7 Cyclization followed by reductive elimination directly the conversions signicantly (entry 9 in Table 3).
generates the indole 2 without a N-hydroxyindole intermediate.7
Davies and co-workers obtained efficient cyclization at low
¨
As suggested by Soderberg, both mechanisms may operate catalyst loading with 3,4,7,8-tetramethyl-1,10-phenanthroline
depending on the specic reaction conditions.7b This is supported (tm-phen) as ligand in DMF as solvent.8 Under our conditions,
by kinetic data from our laboratory, acquired in various solvents reactions with phenanthroline provided slightly better results
and at various temperatures. The latter cycle (B) predominates in than reactions with tm-phen (entry 1 and 2 in Table 4).
MeCN as solvent, while hydroxyindole 3a slowly accumulates in Furthermore, despite the similar structure of phen and bipyr-
EtOAc or toluene (for additional experiments, see the ESI†).
idyl, the conversion decreased to <5% using the latter ligand
For subsequent experiments the catalyst loading was further (entry 3 and 4 in Table 4). Likewise, essentially no reaction was
reduced to 1 mol%. At this catalyst loading, the conversion observed using 4,5-diazauoren-9-one (daf) as ligand (entry 5 in
increased signicantly with increasing 1,10-phenanthroline Table 4). The palladium-catalyzed reductive cyclization is oen
loading. Probably, the phenanthroline ligand stabilizes the performed using phosphines as ligands.5,6 Surprisingly, methyl
Pd(0) and prevents deposition of Pd black on the tubing wall 2-nitrocinnamate (1a) exhibited only low reactivity in the pres-
(Table 2).
ence of various phosphine ligands under the present reaction
As expected, better conversions were obtained with increased conditions (conversion <10%; entry 7 in Tables 4 and S3 in the
stoichiometry of CO. However, more than 2 equiv. of CO did not ESI†). Better results were obtained with mixtures of phenan-
increase the conversion further (Table S2 in the ESI†). In throline and phosphines (entry 8 to 11 in Table 4). Palladium(0)
in combination with mixtures of phen and bidentate phosphine
ligands was identied as an efficient catalyst system by
7
Table 2 Influence of 1,10-phenanthroline ligand loadinga
¨
Soderberg. However, in our hands, signicant amounts of the
N-hydroxyindole 3a were formed using these conditions.
As shown in Table 4, best results were obtained with 1,10-
phenanthroline as ligand (entry 1 in Table 4). With 1 mol%
Pd(OAc)2 and 4 mol% ligand, conversions of ꢂ70% were ach-
ieved aer a residence time of ꢂ3 min at 140 ꢀC. Increasing the
residence time above ꢂ3 min did not increase the conversion
appreciably (Fig. 2a). Furthermore, increasing the temperature
phen (%)
1ab (%)
2ab (%)
Othersb,c (%)
1
2
3
4
1%
2%
4%
8%
82
54
32
27
18
42
65
67
0
4
3
4
a
Conditions: 0.9 mmol substrate 1a,
1 mol% Pd(OAc)2, 1,10-
phenanthroline in 3 mL MeCN. Flow rate gas/liquid: 5.0/0.5 mL did not drive the reaction to completion (Fig. 2b). Gratifyingly,
minꢁ1 (ꢂ1.4 equiv. CO); ꢂ20 bar pressure; 120 ꢀC; residence time
the addition of tributylamine further stabilized palladium. The
reaction proceeded to >90% conversion within a residence time
of 15 min at 140 ꢀC even with reduced amounts of
b
ꢂ30 min (Scheme 2). HPLC peak area integration at 215 nm.
c
Unidentied compounds.
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Table 3 Continuous flow reductive cyclization of 1a with and without a static mixera
Pd(OAc)2/phen
(mol%)
Flow rate liquid
Flow rate CO
Temp RT1b
(ꢀC)
Temp RT2b
(ꢀC)
rtc
(min)
1ad
(%)
2ad
(%)
Othersd,e
(%)
(mL minꢁ1
)
(mL minꢁ1
)
1
2
3
4
5
6
7
8
9
1/4
1/4
1/4
1/4
1/4
1/4
1/4
1/4
0.5/2
0/4
0.5
1
2
8
—
—
—
—
110
140
140
160
160
160
140
140
140
140
140
140
—
—
—
—
22
11
5
39
28
24
21
19
7
34
7
56
100
61
72
76
79
80
92
65
92
44
0
0
0
0
0
1
1
1
1
0
0
16
32
48
8
8
8
8
8
8
3
3
0.5
0.5
0.5
0.5
0.5
0.5
20
23
3
3
3
10
3
a
Conditions: 0.9 mmol substrate 1a, Pd(OAc)2 and 1,10-phenanthroline in 3 mL MeCN; ꢂ2.2 equiv. of CO; ꢂ20 bar pressure. b Temp RT1/RT2 ¼
temperature of static mixer/stainless steel residence tube. c rt ¼ residence time (see Experimental section for details). d HPLC peak area integration
e
at 215 nm. Unidentied compounds.
Table 4 Continuous flow reductive cyclization of 3b in the presence of various nitrogen ligandsa
Ligand (mol%)
1ab (%)
2ab (%)
3ab (%)
Othersb,c (%)
1
2
3
4
5
7
8
9
phen (4)
tm-phen (4)
bipy (4)
dm-bipy (4)
daf (4)
dppp (4)
phen/dppp (3 : 1)
phen/dppp (1 : 1)
phen/dppp (2 : 2)
phen/dppp (1 : 3)
31
39
99
96
99
92
27
40
15
49
69
60
1
4
1
0
0
0
0
0
0
19
16
26
28
0
1
0
0
0
2
2
2
3
4
6
52
42
56
19
10
11
a
Conditions: 0.9 mmol substrate 1a, 1 mol% Pd(OAc)2 and 4 mol% ligand in 3 mL MeCN. Flow rate gas/liquid: 8/0.5 mL minꢁ1 (ꢂ2.2 equiv. CO);
b
c
ꢂ20 bar pressure; 140 ꢀC; ꢂ3 min residence time (RT1). HPLC peak area integration at 215 nm. Unidentied compounds.
phenanthroline (Fig. 2). The reaction remained very clean and about 50% of its original volume, the pure indole 2a precipi-
only the expected indole 2a was detected by HPLC-UV/Vis tated from the solution and was isolated by ltration in 81%
analysis. Upon concentration of the processed mixture to yield.
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substituted o-nitrostilbenes. The corresponding o-nitrostilbenes
were easily prepared employing sealed vessel microwave heating
using an aqueous/CHCl3-biphasic Wittig reaction (40 min at
100 ꢀC, see the ESI†).19 The nitrostilbenes were isolated as E/Z
mixtures aer column chromatography in good to excellent
yields. The E/Z mixture of 1j was further separated by column
chromatography to give pure E-1j and Z-1j in 23 and 51% yield,
respectively (see the ESI†). The reductive cyclization of stilbenes 1
was performed in the ow system shown in Table 3 using the glass
static mixer and a subsequent 20 mL stainless steel tube reactor
(Table 5). The amount of catalyst was increased to 2 mol% for
these reactions. No further optimization was attempted as it has
previously been reported that the reaction is largely independent
of the substitution pattern and the electronic properties of the
substituents on the aromatic rings.5,6e,7 In contrast to these
previous reports, the conversion obtained for the continuous ow
reactions using our experimental conditions depended strongly
on the electron density of the stilbene. For instance, while reac-
tions proceeded to high conversions with stilbenes bearing an
electron withdrawing CF3-moity (1b to 1e), conversions <16% were
obtained for stilbenes 1k to 1m with the strongly electron
donating NMe2 group on the aromatic ring containing the nitro
group (Table 5). Reprocessing of the mixture did not increase the
conversion appreciably. Furthermore, increasing reaction
temperature did not have a noticeable effect. With the cyano-
derivative, (Z)-4-(2-nitrostyryl)benzonitrile Z-1j, the conversion
increased to 57%. Aer a second pass through the reactor,
a conversion of 95% was obtained and the product was isolated in
74% yield (Table 5). A clear trend is not easily discernible from the
experiments shown in Table 5, and both inherent reaction rate
and stabilization of palladium(0) by the stilbene are likely to play
a decisive role. The intermediate homogeneous Pd(0) species have
the tendency to aggregate to clusters, which ultimately irreversibly
precipitate from the mixture in the form of catalytically inactive Pd
black. Since p-complexation and stabilization of low-valent
palladium by electron-poor alkenes is generally stronger, the
active species is available for more catalytic cycles and the reaction
proceeds to higher conversions in these cases. Reactions with
substrates 1f to 1i proceeded to conversions ranging from 95% for
the cyano substituted stilbene 1f to 14% for the uoro derivative 1i
(Table 5). Again, a second pass through the reactor did not drive
the reaction to higher conversions. ICPMS analysis revealed that
more than 90% of the palladium was already lost from the
mixture aer stilbene 1f and 1g were processed through the static
mixer (no residence tube; ꢂ3 min residence time; see Table S6 in
the ESI†). These results suggest that the palladium-catalyzed
indolization is inherently fast, but the catalyst is quickly lost
from the solution. In contrast, almost 50% of palladium was still
present in the processed reaction mixture containing methyl 2-
nitrocinnamate (1a) as substrate. With no stabilizing alkene in the
reaction mixture, 97% of the palladium was lost according to
ICPMS analysis. Importantly, the palladium could be essentially
quantitatively recovered from the static mixer by washing the
reactor with aqua regia (Table S6 in the ESI†).
Fig. 2 HPLC conversions after reactions with various residence times
(140 ꢀC; (a)) and temperature (ꢂ3 min residence time; (b)) using
Pd(OAc)2/phen (1 mol%/4 mol%) or Pd(OAc)2/phen/Bu3N (1 mol%/2
mol%/20 mol%) as catalyst system.
Scheme 4 Unsuccessful attempts for the reduction of nitro arenes.
Palladium phenanthroline complexes have been demon-
strated to be among the most active catalysts for the reductive
carbonylation of nitrobenzenes to isocyanates.18 However,
nitroaromatic compounds did not react under the reaction
conditions employed for the reductive cyclization (see Table S4
in the ESI†). Neither nitrobenzenes with electron-withdrawing
nor with electron-donating substituents exhibited any reac-
tivity. Notably, ethyl 4-nitrocinnamate was recovered
unchanged aer subjecting it to the reaction conditions
¨
(Scheme 4). As already observed by Soderberg, a close proximity
of the double bond to the nitro group seems to be crucial for the
reduction to occur.5 Indeed, the presence of nitrobenzene
apparently interferes with the reductive cyclization and nitro-
stilbene 1b did not cyclize in the presence of 9% nitrobenzene
(see Table S5 in the ESI†). A similar observation was reported by
6b
¨
Soderberg and co-workers.
The stereochemistry of the alkene had little effect on the
reaction and the indolization of both E-1j and Z-1j proceeded with
essentially identical reaction rates (Table S7 in the ESI†). Slightly
With optimized conditions for the reductive cyclization in
hand, the scope was briey investigated using a variety of
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Table 5 Continuous flow reductive cyclization of o-nitrostilbenes 1 with CO as terminal reductanta
R1
H
R2
R3
First passb (rt ¼ 15 min)
Second passb (rt ¼ 30 min)
Yieldc (%)
1b
1c
1d
1e
1f
1g
1h
1i
Z-1j
1k
1l
CF3
CN
H
tBu
F
CN
H
tBu
F
CN
H
tBu
F
CN
H
F
57
98
57
90
95
81
37
14
57
16
13
6
89
—
95
—
—
81
39
16
95
25
14
14
—
58
—
80
90
85
83
90
70
n.d.
n.d.
74
n.d.
n.d.
n.d.
40
H
H
Cl
H
NMe2
H
1m
1n
1o
1p
41
51
87
45
80
a
Conditions: see Experimental section. b HPLC peak area integration. c Isolated yields of pure compounds. Purity of compounds was determined by
1H NMR, HPLC and GC-MS analysis. n.d. ¼ not determined.
faster reactions were usually observed for the E isomer when as substrate and 1 mol% catalyst loading (Scheme 5). For this
mixtures of the E/Z-stilbenes were processed (Table S7 in the reaction the injection loop was removed and the HPLC pump was
ESI†). Even though full conversion was not obtained for all stil- replaced by a high-pressure syringe pump. At a reaction time of
benes under the present reaction conditions, the reactions were 140 ꢀC and a residence time of 15 min, conversions of 95% were
very clean and only the expected indole was observed by HPLC- afforded with 2-nitrocinnamate (1a) as substrate. The product
UV/Vis analysis of the crude reaction mixtures. Indole 1n imme- crystalized from the mixture upon standing to furnish the pure
diately crystallized from the mixture aer the continuous ow indole 2a in 84% product yield. ICPMS analysis revealed that the
reaction and was isolated by simple ltration. Indole 1b was iso- isolated indole 2a contained 45 ppm of palladium. Recrystalliza-
lated by column chromatography. For the other indoles, the tion of the indole reduced the amount to 16 ppm without
solvent was evaporated and the products were nally recrystal- reducing product yield appreciably.20
lized from petroleum ether (see Experimental section for details).
The reaction was nally scaled up to 60 mL (12 mmol
substrate) in the same reactor using methyl 2-nitrocinnamate (1a)
Conclusion
We have presented a continuous ow reductive cyclization of
various o-vinylnitrobenzenes with carbon monoxide as terminal
reductant. The reaction was performed with catalyst loadings of
1 to 2 mol% Pd(OAc)2 using 1,10-phenanthroline/tributylamine
as ligand system. The carbon monoxide reduced palladium(II) to
palladium(0) nearly instantly and palladium quickly deposited
on the channels of the ow system. Thus, for less reactive o-
nitrostilbenes the reaction came to a halt before reasonable
conversions were obtained. Nevertheless, in the pressurized
ow reactor, reactions proceeded to high conversions for
Scheme 5 Palladium-catalyzed reductive cyclization of methyl 2-
nitrocinnamate (1a).
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a variety of stilbenes within reaction times of 15 to 30 min. In a calibrated mass ow controller (Bronkhorst). The liquid and
general, only the indole was detected in the crude reaction gaseous streams were combined in a glass static mixer at 140 ꢀC
mixtures and the products were isolated in high purity without (GSM 2 mL, Uniqsis). The mixer was connected to the residence
the need for column chromatography.
tube reactor via a uoropolymer tubing (PFA, 1/1600 o.d., 0.8 mm
The reductive cyclization of o-nitrostyrenes provides i.d.). The residence coil reactor (stainless steel, 1/600 o.d., 1.0 mm
ꢀ
a general and inherently regioselective approach to indoles. The i.d., 20 mL) was heated on a heating block to 140 C (Uniqsis
reaction proceeds under neutral conditions and tolerates FlowSyn). The reaction mixture exited the system through
a broad range of functionality. The respective starting materials a short cooling loop and an adjustable back-pressure regulator
can be assembled in a convergent manner by well-developed, (Swagelok KCB1H0A2A5P60000, 0–26 bar). The reaction
robust transformations. Furthermore, using CO as the stoi- mixtures consisted of 0.9 mmol of stilbene, 2 mol% Pd(OAc)2, 4
chiometric reductant and palladium as catalyst, CO2 is the only mol% of phenanthroline and 40 mol% of tributylamine in 3 mL
stoichiometric by-product. The continuous ow indolization of MeCN (HPLC grade) as solvent. The mixtures were loaded
reported herein proceeded with reaction speeds 1 to 2 orders of into a 5 mL injection loop and injected from the loop into the
magnitude faster than those reported for batch processes.
reactor at ow rates of the liquid stream of 0.5 mL minꢁ1 and
a ow rate of the CO stream of 8.0 mL minꢁ1. The total resi-
dence time was 15 min (determined by a stopwatch). Some
starting materials were reprocessed under the same reaction
conditions (see Table 5). Indole 1n immediately crystallized
from the mixture aer the continuous ow reaction and was
isolated by simple ltration. Indole 1b was isolated by column
chromatography on silica gel using ethyl acetate and petroleum
ether as eluent. For the other indoles, the solvent was evapo-
rated. The remaining material dissolved in hot boiling petro-
leum ether and palladium was removed by ltration. Aer
cooling to ꢁ10 ꢀC, the obtained crystals were ltered off,
washed with cold chloroform and dried in a drying oven at
Experimental section
General experimental conditions
1H-NMR spectra were recorded on a Bruker 300 MHz instru-
ment. 13C-NMR spectra were recorded on the same instrument
at 75 MHz. Chemical shis (d) are expressed in ppm downeld
from TMS as internal standard. The letters s, d, t, q, and m are
used to indicate singlet, doublet, triplet, quadruplet, and
multiplet. High-resolution mass spectra were recorded on a FT-
ICR-MS instrument using electrospray ionization (ESI) in posi-
tive mode. Low resolution mass spectra were obtained on a LC-
MS instrument using electrospray ionization (ESI) in positive or
negative mode (Shimadzu LCMS-2020). GC-MS spectra were
recorded using a Thermo Focus GC coupled with a Thermo DSQ
II (EI, 70 eV). A HP5-MS column (30 m ꢃ 0.250 mm ꢃ 0.025 mm)
was used with helium as carrier gas (1 mL minꢁ1 constant ow).
The injector temperature was set to 280 ꢀC.ꢁA1er 1 min at 50 ꢀC
the temperature was increased in 25 ꢀC min steps up to 300 ꢀC
ꢀ
50 C.
Methyl 1H-indole-2-carboxylate (2a). Colorless crystals, mp
150–151 ꢀC (lit.21 mp 151–152 ꢀC), 81% yield (127 mg, 0.73
mmol); 1H NMR (300 MHz, DMSO-d6) d 11.94 (brs, 1H), 7.66 (dd,
J ¼ 8.0, 0.7 Hz, 1H), 7.46 (dd, J ¼ 8.3, 0.9 Hz, 1H), 7.29–7.24 (m,
1H), 7.17–7.16 (m, 1H), 7.11–7.05 (m, 1H), 3.88 (s, 3H). 13C NMR
(75 MHz, DMSO-d6) d 162.2, 137.8, 127.5, 127.2, 125.1, 122.5,
120.6, 113.0, 108.2, 52.3. MS (EI): m/z: 175 [M]+.
ꢀ
and kept at 300 C for 4 minutes. Analytical HPLC (Shimadzu
4-(6-(Triuoromethyl)-1H-indol-2-yl)benzonitrile (2b). White
crystals, mp 201–202 ꢀC, 80% yield (205 mg, 0.71 mmol); 1H
NMR (300 MHz, acetone-d6) d 11.18 (brs, 1H), 8.00–7.92 (m, 2H),
7.79–7.72 (m, 2H), 7.68 (d, J ¼ 8.4 Hz, 1H), 7.65 (d, J ¼ 0.7 Hz,
1H), 7.22 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.13–7.07 (m, 1H). 13C NMR
(75 MHz, acetone-d6) d 139.0, 136.7, 136.0, 132.9, 131.4, 126.0,
125.4 (q, J ¼ 270.6 Hz), 124.0 (q, J ¼ 31.8 Hz), 121.5, 118.3, 116.6
(q, J ¼ 3.5 Hz), 111.1, 108.9 (q, J ¼ 5.1 Hz), 101.7; 19F NMR (282
MHz, acetone-d6) d ꢁ61.20 (s), MS (EI): m/z: 286 [M]+, HRMS
(ESI): calc. for C16H10F3N2+ 285.0645 [M + H]+, found 285.0643.
2-Phenyl-6-(triuoromethyl)-1H-indole (2c). White crystals,
LC20) analysis was carried out on a C18 reversed-phase (RP)
ꢀ
analytical column (150 ꢃ 4.6 mm, particle size 5 mm) at 25 C
using a mobile phase A (water/acetonitrile 90 : 10 (v/v) + 0.1%
TFA) and B (MeCN + 0.1% TFA) at a ow rate of 1.0 mL minꢁ1
.
The following gradient was applied: linear increase from solu-
tion 30% B to 100% B in 8 min, hold at 100% solution B for
2 min. Melting points were determined on a Stuart™ SMP3
melting point apparatus. Reagents and solvents were purchased
from commercial sources and were used without further
purication.
Caution: Carbon monoxide is a highly poisonous, colourless,
odourless and tasteless gas. Reactions have to be performed in
an efficient fume hood. Excess carbon monoxide should be
directly vented into the exhaust duct of the fume hood. Carbon
monoxide detectors must be used inside and outside the fume
hood at all times!
mp 181–182 C (lit.22 mp 181–182 C), 90% yield (211 mg, 0.81
ꢀ
ꢀ
1
mmol); H NMR (300 MHz, CDCl3) d 8.56 (brs, 1H), 7.77–7.68
(m, 4H), 7.54–7.47 (m, 2H), 7.44–7.36 (m, 2H), 6.90–6.89 (m,
1H). 13C NMR (75 MHz, CDCl3) d 140.6, 135.6, 131.6, 129.2,
128.5, 125.4, 125.2 (q, J ¼ 271.5 Hz), 124.2 (q, J ¼ 31.9 Hz), 120.9,
117.0 (q, J ¼ 3.5 Hz), 108.4 (q, J ¼ 4.1 Hz), 100.0. MS (EI): m/z:
260 [M]+. 19F NMR (282 MHz, CDCl3) d ꢁ60.93.
General procedure for indole synthesis (Table 5)
2-(4-(tert-Butyl)phenyl)-6-(triuoromethyl)-1H-indole (2d).
The indole synthesis was performed in the ow setup shown in White crystals, mp 107–108 ꢀC, 85% yield (242 mg, 0.76 mmol);
Table 3. The reactor consisted of an HPLC pump for introducing 1H NMR (300 MHz, CDCl3) d 8.68 (brs, 1H), 7.73–7.68 (m, 2H),
the liquid feed (Uniqsis FlowSyn). Carbon monoxide gas from 7.65 (d, J ¼ 8.5 Hz, 2H), 7.52 (d, J ¼ 8.5 Hz, 2H), 7.37 (d, J ¼
a gas cylinder (N18, 98% CO) was fed into the system via 9.2 Hz, 1H), 6.86 (m, 1H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3)
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d 151.7, 140.7, 135.5, 131.7, 128.8, 126.1, 125.2, 125.2 (q, J ¼ NMR (75 MHz, acetone-d6) d 162.4 (d, J ¼ 245.7 Hz), 138.8,
271.4 Hz), 123.9 (q, J ¼ 31.8 Hz), 120.7, 116.8, 108.3, 99.5, 34.7, 135.9, 130.4, 128.7, 127.3 (d, J ¼ 8.2 Hz), 124.8, 121.8, 119.3,
31.2. 19F NMR (282 MHz, CDCl3) d ꢁ60.87. MS (EI): m/z: 317 115.8 (d, J ¼ 21.9 Hz), 112.5 (d, J ¼ 3.8 Hz), 98.7. 19F NMR (282
[M]+, HRMS (ESI): calc. for C19H19F3N+ 316.1319 [M + H]+, found MHz, acetone-d6) d ꢁ115.57. MS (EI): m/z: 244 [M]+.
316.1316.
2-(4-Fluorophenyl)-6-(triuoromethyl)-1H-indole (2e). White
crystals, mp 121–122 ꢀC, 83% yield (208 mg, 0.75 mmol); 1H
NMR (300 MHz, acetone-d6) d 10.97 (brs, 1H), 7.83–7.76 (m, 2H),
7.63–7.59 (m, 2H), 7.21–7.09 (m, 3H), 6.85 (d, J ¼ 1.3 Hz, 1H).
13C NMR (75 MHz, CDCl3) d 162.8 (d, J ¼ 248.8 Hz), 140.0, 135.6,
131.5, 127.9 (d, J ¼ 3.3 Hz), 127.2 (d, J ¼ 8.2 Hz), 125.1 (q, J ¼
271.5 Hz), 124.2 (q, J ¼ 32.0 Hz), 120.9, 117.1 (q, J ¼ 3.4 Hz),
116.24 (d, J ¼ 21.9 Hz), 108.4 (q, J ¼ 4.0 Hz), 100.0. 19F NMR (282
MHz, acetone-d6) d ꢁ60.94 (3H), ꢁ114.91 (1H). MS (EI): m/z: 279
[M]+.
Acknowledgements
Funding from NAWI Graz and Research Center Pharmaceutical
Engineering (RCPE) for the ReactIR system is gratefully
acknowledged. We thank Prof. W. Goessler (Graz University) for
performing ICPMS analysis.
Notes and references
4-(1H-Indol-2-yl)benzonitrile (2f). White crystals, mp 190–
192 ꢀC (lit.23 mp 190–191 ꢀC), 90% yield (176 mg, 0.81 mmol); 1H
NMR (300 MHz, DMSO-d6) d 11.76 (brs, 1H), 8.07–8.05 (m, 2H),
7.93–7.90 (m, 2H), 7.58 (d, J ¼ 7.9 Hz, 1H), 7.44 (dd, J ¼ 8.1,
0.8 Hz, 1H), 7.19–7.14 (m, 2H), 7.06–7.01 (m, 1H). 13C NMR (75
MHz, DMSO-d6) d 138.1, 137.0, 136.0, 133.3, 128.8, 125.8, 123.2,
121.1, 120.3, 119.5, 112.1, 109.6, 102.0. MS (EI): m/z: 218 [M]+.
2-Phenyl-1H-indole (2g). White crystals, mp 190–191 ꢀC (lit.22
mp 186–187 ꢀC), 70% yield (121 mg, 0.63 mmol), 1H NMR (300
MHz, acetone-d6) d 10.5 (brs, 1H), 7.75–7.69 (m, 2H), 7.43 (d, J ¼
7.9 Hz, 1H), 7.34–7.25 (m, 3H), 7.20–7.13 (m, 1H), 7.00–6.93 (m,
1H), 6.88 (td, J ¼ 7.5, 1.1 Hz, 1H), 6.77–6.75 (m, 1H). 13C NMR
(75 MHz, acetone-d6) d 137.9, 137.5, 132.7, 129.3, 128.9, 127.4,
125.0, 121.8, 120.2, 119.6, 111.1, 99.1. MS (EI): m/z: 193 [M]+.
4-(6-(Dimethylamino)-1H-indol-2-yl)benzonitrile (2j). Yellow
needles, mp 220–221 ꢀC, 74% yield (174 mg, 0.67 mmol); 1H
NMR (300 MHz, acetone-d6) d 10.29 (brs, 1H), 7.82–7.77 (m, 2H),
7.64–7.59 (m, 2H), 7.29 (d, J ¼ 8.7 Hz, 1H), 6.86–6.82 (m, 1H),
6.64–6.58 (m, 1H), 6.56–6.55 (m, 1H), 2.81 (s, 6H). 13C NMR (75
MHz, acetone-d6) d 148.8, 140.0, 137.3, 133.4, 132.6, 124.4,
121.2, 121.2, 118.8, 109.9, 108.8, 102.1, 93.8, 40.6. MS (pos-ESI):
m/z: 260 [M + H]+, HRMS (ESI): calc. for C17H16N3+ 260.1193 [M +
H]+, found 260.1191.
1 For reviews on recent advances in the eld of indole
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¨
5 B. C. Soderberg and J. A. Shriver, J. Org. Chem., 1997, 62,
4-(5-Chloro-1H-indol-2-yl)benzonitrile (2n). White crystals,
5838–5845.
1
ꢀ
mp 198–200 C, 40% yield (90 mg, 0.36 mmol); H NMR (300
MHz, acetone-d6) d 10.93 (brs, 1H), 7.94–7.89 (m, 2H), 7.75–7.70
(m, 2H), 7.50 (d, J ¼ 2.0 Hz, 1H), 7.32 (d, J ¼ 8.7 Hz, 1H), 7.02
(dd, J ¼ 8.7, 2.0 Hz, 1H), 6.97 (s, 1H). 13C NMR (75 MHz, acetone-
d6) d 137.5, 136.4, 136.3, 132.8, 130.1, 125.7, 125.2, 123.0, 119.9,
118.4, 112.9, 110.7, 101.3. MS (EI): m/z: 252 [M]+.
6 For further examples using Pd(OAc)2/ligand as catalyst, see:
(a) B. C. Soderberg, A. C. Chisnell, S. N. O'Neil and
J. A. Shriver, J. Org. Chem., 1999, 64, 9731–9734; (b)
¨
¨
B. C. G. Soderberg, S. R. Banini, M. R. Turner, A. R. Minter
and A. K. Arrington, Synthesis, 2008, 6, 903–912; (c)
B. C. G. Soderberg, J. W. Hubbard, S. R. Rector and
¨
5-Chloro-2-phenyl-1H-indole (2o). White crystals, mp 196–
197 ꢀC (lit.24 mp 195–196 ꢀC), 45% yield (91 mg, 0.40 mmol); 1H
NMR (300 MHz, acetone-d6) d 10.73 (brs, 1H), 7.76–7.70 (m, 2H),
7.44 (d, J ¼ 2.0 Hz, 1H), 7.37–7.18 (m, 4H), 6.96 (dd, J ¼ 8.6,
2.1 Hz, 1H), 6.76 (d, J ¼ 2.2 Hz, 1H). 13C NMR (75 MHz, acetone-
d6) d 139.7, 135.9, 132.1, 130.4, 129.0, 127.8, 125.2, 124.8, 121.7,
119.4, 112.5, 98.7. MS (EI): m/z: 227[M]+.
S. N. O'Neil, Tetrahedron, 2005, 61, 3637–3649; (d)
¨
B. C. Soderberg, S. R. Rector and S. N. O'Neil, Tetrahedron
Lett., 1999, 40, 3657–3660; (e) T. L. Scott and
¨
B. C. G. Soderberg, Tetrahedron, 2003, 59, 6323–6332; (f)
N. H. Ansari, C. A. Dacko, N. G. Akhmedov and
¨
B. C. G. Soderberg, J. Org. Chem., 2016, 81, 9337–9349.
¨
7 (a) T. L. Scott and B. C. G. Soderberg, Tetrahedron Lett., 2002,
5-Chloro-2-(4-uorophenyl)-1H-indole (2p). White crystals,
43, 1621–1624; (b) R. W. Clawson Jr, R. E. Deavers,
mp 165–166 C (lit.25 mp 167–168 C), 80% yield (176 mg, 0.72
mmol); 1H NMR (300 MHz, acetone-d6) d 10.72 (brs, 1H), 7.80–
7.73 (m, 2H), 7.44 (d, J ¼ 2.0 Hz, 1H), 7.28 (d, J ¼ 8.6 Hz, 1H),
N. G. Akhmedov and B. C. G. Soderberg, Tetrahedron, 2006,
ꢀ
ꢀ
¨
62, 10829–10834.
8 I. W. Davies, J. H. Smitrovich, R. Sidler, C. Qu, V. Gresham
and C. Bazaral, Tetrahedron, 2005, 61, 6425–6437.
7.16–7.07 (m, 2H), 6.96 (dd, J ¼ 8.6, 2.1 Hz, 1H), 6.73 (s, 1H). 13
C
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in Preparative Chemistry, ed. W. Reschetilowski, Wiley-VCH,
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¨
N. Kockmann, T. Noel and Q. Wang, ChemSusChem, 2013,
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12 For recent reviews on continuous ow gas–liquid reactions, 19 E. Sinkovec and M. Krajnc, Org. Process Res. Dev., 2011, 15,
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2016, 20, 327–360; (b) H. P. Gemoets, Y. Su, M. Shang, 20 The limit for the total amount of platinoid-group metals is
5 mg kgꢁ1 (for dosages of up to 10 g per day). Guideline on
the specication limits for residues of metal catalysts from
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¨
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