On the Fischer indole synthesis of 7-ethyltryptophol - Mechanistic and process intensification studies under continuous flow conditions

Article abstract of DOI:10.1021/op300363s

7-Ethyltryptophol, a key intermediate in the synthesis of the anti-inflammatory agent etodolac, was produced by Fischer indole synthesis of 2-ethylphenylhydrazine and 2,3-dihydrofuran under continuous flow conditions. The reaction generates several undesired byproducts and therefore product yields could not be improved above 40-50%. The mechanism of this transformation was studied in detail and the structure of the byproducts carefully elucidated. Despite the only moderate product yield, the synthesis of 7-ethyltryptophol by this protocol remains interesting compared to alternative methods and starts from inexpensive reagents. The developed process is executed in an environmentally benign solvent (methanol) and, importantly, the majority of byproducts can be removed from the 7-ethyltryptophol product by a straightforward extraction process.

Full text of DOI:10.1021/op300363s

Article
pubs.acs.org/OPRD
On the Fischer Indole Synthesis of 7‑EthyltryptopholMechanistic
and Process Intensification Studies under Continuous Flow
Conditions
Bernhard Gutmann,† Michael Gottsponer,‡ Petteri Elsner,‡ David Cantillo,† Dominique M. Roberge,*,‡
and C. Oliver Kappe*,†
†Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens University Graz,
Heinrichstrasse 28, A-80010 Graz, Austria, and
‡Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
S
* Supporting Information
ABSTRACT: 7-Ethyltryptophol, a key intermediate in the synthesis of the anti-inflammatory agent etodolac, was produced by
Fischer indole synthesis of 2-ethylphenylhydrazine and 2,3-dihydrofuran under continuous flow conditions. The reaction
generates several undesired byproducts and therefore product yields could not be improved above 40−50%. The mechanism of
this transformation was studied in detail and the structure of the byproducts carefully elucidated. Despite the only moderate
product yield, the synthesis of 7-ethyltryptophol by this protocol remains interesting compared to alternative methods and starts
from inexpensive reagents. The developed process is executed in an environmentally benign solvent (methanol) and,
importantly, the majority of byproducts can be removed from the 7-ethyltryptophol product by a straightforward extraction
process.
indolylglyoxylate was formed from 7-ethylindole and oxalyl
chloride.3 Other methods for the synthesis of tryptophols
include aldol condensation of ketones with isatins and
subsequent reduction of the 3-substituted-dioxyindoles,2a
palladium catalyzed coupling of an iodoaniline species with
protected butynol derivatives,2b or alkylation of the indole or
indolyl-metal salt with ethylene oxide or with ethylene glycol
under pressure.5 The formation of 7-ET by a Fischer indole
synthesis from 2-ethylphenylhydrazine hydrochloride and
dihydrofuran (DHF), as disclosed by Demerson and Humber6
and Stevensen et al.,7 clearly would be a simpler and cheaper
alternative, but unfortunately the reaction produces a lot of side
products and 7-ET is generally isolated from the reaction as a
tarry solid or sticky oil in poor yields (less than 50%) and
INTRODUCTION
■
Tryptophol and tryptophol analogues are common intermedi-
ates in the synthesis of several important pharmaceutically
active molecules including tryptamine-based pharmaceuticals,
such as certain members of antimigraine drugs of the triptan
family (e.g., Sumatriptan, rizatriptanm and zolmitriptan; Figure
1),1,2 the alpha-1 selective adrenoceptor antagonist indoramin,
requires column chromatography for purification.2c,d,4,6,7
A
related strategy for the one-pot synthesis of various tryptophol
and tryptophol homologues by a Fischer indole synthesis was
described in 2004 by Campos and co-workers (Scheme 1).8
Substituted phenylhydrazine hydrochlorides 1 were mixed with
cyclic enol ethers in DMA/H2O as solvent in the presence of
sulfuric acid. The hydrazones 2 were formed in situ from the
hydrazine hydrochloride and the enol ether, and the ensuing
[3,3]-rearrangement of the respective ene-hydrazine at 100 °C
provided 3-substituted indoles 3 in good yields after
chromatography.8 The major side product was the adduct 4,
which evidently is derived from a further reaction of the indole
product with unconsumed enol ether.8 Several subsequent
papers have described modifications of this protocol, such as
the use of Montmorillonite-K10 or mesoporous MCM-41 as
Figure 1. Selected pharmaceutically important indoles derived from
tryptophol analogues.
or compounds based on the pyranoindole structure, such as
etodolac.3,4 Etodolac is a potent anti-inflammatory and
analgesic compound synthesized from 7-ethyltryptophol (7-
ET, cf. 3a in Scheme 2) as the key intermediate.3,4
Different methods for the synthesis of indoles bearing a C-3
hydroxyethyl side chain are described in the patent and
scientific literature. For example, 7-ET was prepared from the
7-ethyl-3-indolylglyoxylate by reduction with LiAlH4, while the
Received: December 20, 2012
Published: January 15, 2013
© 2013 American Chemical Society
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Scheme 1. Synthesis of Tryptophol and Homologs from Arylhydrazines and Cyclic Enol Ethers
Scheme 2. Continuous Flow Synthesis of 7-ET 3a11
Table 1. Yields of 7-ET for Flow Reactions Performed at Different Reaction Temperatures and Residence Times with 1 equiv of
a
DHF and 1.2 equiv of H2SO4 (Scheme 2)
flow feed A
flow feed B
flow feed C
temp.
[°C]
RT module 1
[min]
RT module 2
[min]
total RT
[min]
yield 7-ET (incl. HPLC
b
entry
[g min−1
]
[g min−1
]
[mL min−1
]
assay)
1
2
3
4
5
6
7
8
9
4.3
5.3
7.2
4.3
5.3
7.2
4.3
5.3
7.2
4.3
5.3
7.2
4.3
5.3
7.2
4.3
5.3
7.2
0.5
0.7
0.9
0.5
0.7
0.9
0.5
0.7
0.9
108
108
108
115
115
115
122
122
122
0.6
0.5
0.4
0.6
0.5
0.4
0.6
0.5
0.4
5.1
4.1
3.0
5.1
4.1
3.0
5.0
4.1
3.0
6.2
5.1
3.7
6.2
5.1
3.7
6.1
5.1
3.7
39
37
36
36
38
50
24
39
43
a
Conditions: feed A: 0.8 M 2-ethylphenylhydrazine hydrochloride 1a, 1 equiv NaOH in ethylene glycol/H2O; feed B: 0.8 M DHF, 0.008 equiv HCl
in ethylene glycol/H2O; feed C: 50% H2SO4; RT module 1: Hastelloy C-22 flowplate and PFA coil (2.8 and 2 mL); RT module 2: Corning glass
b
reactor and stainless steel coil (5.6 and 38 mL). Yields are based on quantitative HPLC analysis (%) of samples after extraction and removing of
solvent. RT = residence time.
heterogeneous catalysts.9,10 It was argued that the use of
heterogeneous catalysts reduces dimerization and polymer-
ization of the tryptophol owing to the shape and size selectivity
of these catalysts.10
residence tube and no DHF (or aldehyde) should be present
during indolization in the second tube reactor, and therefore,
no adduct 4a should be formed. Indeed, the reported yields of
7-ET 3a increased from 45% for a one-pot batch process to
75% for the two-stage continuous flow process.11
The synthesis of 7-ET 3a from 2-ethylphenylhydrazine
hydrochloride 1a and DHF on a kilogram scale was reported in
2011 by Su and co-workers (Scheme 2).11,12 The reaction was
performed as a continuous flow process in three consecutive
tube reactors. The hydrazine hydrochloride 1a was neutralized
first with 1 equiv of NaOH in ethylene glycol/water as solvent.
DHF, also dissolved in ethylene glycol/water as solvent, was
stirred for 10 min at room temperature in the presence of
hydrochloric acid to open the enol ether to the 4-
hydroxybutyraldehyde. These two solutions were pumped
into a T-joint and further through a first residence tube heated
to 115 °C where the hydrazone 2a was formed. After the first
residence loop, 50% aqueous sulfuric acid was fed in to catalyze
the Fischer indolization which then occurred in a second
residence loop at 115 °C. The processed reaction mixture was
finally quenched in a third residence coil held at 20 °C. The
authors hypothesized that, by performing this reaction as a two-
stage process, the DHF (or aldehyde) is consumed in the first
This apparently very elegant procedure and the reported high
yields of 7-ET 3a achieved by this method encouraged us to
establish an analogous continuous flow process for the
synthesis of 7-ET in our laboratories. Unfortunately, however,
all of our attempts to synthesize 7-ET following the above-
mentioned protocol provided the desired product in rather
moderate yields only (50% at best). In this publication, we
discuss some of the mechanistic and process chemistry details
of this industrially very relevant transformation, and provide
rationalization on why the yields in this particular Fischer
indole synthesis are difficultif not impossibleto improve.
RESULTS AND DISCUSSION
■
Replication of the Reaction Conditions Reported by
Su and Coworkers. Our initial experiments were aimed to
reproduce the continuous flow protocol described by Su and
co-workers (Scheme 2).11 The two feed solutions (feed A:
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Table 2. Yields of 7-ET for Flow Reactions Performed with Different Stoichiometries of DHF and H2SO4 at 115 °C Reaction
a
Temperature.
flow feed A
flow feed B
flow feed C
equiv of
DHF
equiv of
H2SO4
RT module 1 RT module 2
total RT
[min]
yield 7-ET (incl.
b
entry
[g min−1
]
[g min−1
]
[mL min−1
]
[min]
[min]
HPLC assay)
1
2
3
4
5
6
7.2
7.0
6.7
7.2
7.3
7.2
7.2
7.7
8.1
7.2
7.3
7.2
0.9
0.9
0.8
0.7
0.6
0.9
1.0
1.1
1.2
1.0
1.0
1.0
1.2
1.2
1.2
1.0
0.8
1.2
0.4
0.3
0.3
0.4
0.4
0.4
3.0
3.0
3.0
3.1
3.1
3.0
3.7
3.7
3.6
3.8
3.8
3.7
41
44
35
41
38
41
a
Conditions: feed A: 0.8 M 2-ethylphenylhydrazine hydrochloride 1a, 1 equiv NaOH in ethylene glycol/H2O; feed B: 0.8 M DHF, 0.008 equiv HCl
in ethylene glycol/H2O; feed C: 50% H2SO4; RT module 1: Hastelloy C-22 flowplate and PFA coil (2.8 and 2 mL); RT module 2: Corning glass
b
reactor and stainless steel coil (5.6 and 38 mL). Yields are based on quantitative HPLC analysis (%) of samples after extraction and removing of
solvent. RT = residence time.
hydrazine hydrochloride and NaOH in ethylene glycol/water;
feed B: DHF and HCl in ethylene glycol/water) were pumped
by two gear pumps into the first reactor module consisting of a
plate microreactor, wherein the two feed solutions were mixed,
and an ensuing residence loop. The reaction mixture leaving
the first module was combined with 50% aqueous sulfuric acid,
fed via a syringe pump into a second reactor module. The
second module again consisted of a plate microreactor and a
consecutive residence loop. The reaction mixture was cooled in
a third residence loop and was collected in a collection vessel
under nitrogen (for more details, see Experimental Section).
The collected mixtures were extracted with MTBE/H2O, the
solvent removed under vacuum, and the content of 7-ET 3a in
the samples were determined by quantitative HPLC analysis
(see Experimental Section for details).
but they precipitated during the reaction and repeatedly
blocked the channels of the microreactor.
Dimerization and Oligo-/Polymerization of 7-ET 3a. It
is well-known that indoles form dimers, trimers, and oligomers
under acidic conditions by electrophilic attack of the 3-
protonated species on the indole nucleus of an unprotonated
species.13 Even though pure 7-ET was rather stable under
various conditions and just slowly decomposed in the presence
of sulfuric acid (Figure 2), it rapidly decomposed when both
Flow experiments with this setup under reaction conditions
adopted from the work of Su and co-workers (i.e., ∼0.8 M
solutions of starting materials, 115 °C reaction temperature in
both reactor modules, 30 s and 4 min residence time in reactor
module 1 and 2, respectively) led to the 7-ET 3a in product
yields of only 35−41% based on quantitative HPLC analysis of
the obtained samples (Table 1, entry 5). Increasing or
decreasing the temperature of module 1 and 2 and/or altering
the total residence time in the reactor by varying the flow rates
of the three feeds did not give any notable improvement. Often,
it was observed that the yields of 7-ET 3a increased when the
residence time was shortened, even though a full consumption
of hydrazone was no longer achieved. This was particularly
obvious for the reactions performed at 122 °C where the yields
decreased from 43% to 24% when the total residence time in
the reactor was increased from 3.7 to 6 min (Table 1, entry 7 to
9). The best result in this set of experiments was a yield of 50%
of 7-ET, obtained at 115 °C with a total residence time of 3.7
min (Table 1, entry 6). Varying the residence times of the
reaction mixture in the individual reactor modules by adding a
second residence tube to module 2 (residence volume of 38 +
38 mL) or by replacing the 2 mL tube of module 1 by a 6 mL
tube did not show any significant effect on the reaction at a
reaction temperature of 115 °C (see Tables S1 and S2 in the
Supporting Information). Also, adjusting the flow rates of the
individual feeds to change the stoichiometry (1.0, 1.1, and 1.2
equiv of DHF) or the concentration of sulfuric acid (0.8, 1.0,
and 1.2 equiv of H2SO4) had very little effect, and the yields of
7-ET 3a were consistently around 40% only (see Table 2).
Formation of black, tarry materials in the second reactor
module after sulfuric acid was fed in was observed in all of these
reactions. The tarry compounds were not detectable by HPLC,
Figure 2. Decomposition of pure 7-ET 3a in MeOH/H2O at 150 °C
(sealed vessel microwave irradiation) based on quantitative HPLC
analysis of the reaction mixtures. Conditions: 1 mmol 7-ET 3a,
additive in 1.5 mL MeOH/H2O 2:1. The main product in the reaction
with H2SO4 was the O-methylated 7-ET.
DHF and strong acids were present. For example, the isolated
and purified 7-ET heated together with 0.5 equiv of DHF and 1
equiv of HCl in MeOH/H2O as solvent decomposed
completely within 15 s at 130 °C. The main compound
detected by HPLC was the adduct 4a (Scheme 3). In addition
to adduct 4a, a significant amount of tarry, polymeric material
was formed which was insoluble in both aqueous and unpolar
organic solvents and precipitated upon extraction of the
Scheme 3. Formation of Adduct 4a
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Table 3. HPLC Purity (Peak Area Integration at 215 nm) and Yields of 7-ET (quant. HPLC) for Batch Reactions Performed
a
with Different Additives
b
entry
solvent
additive [mol %]
t [min]
hydrazone 2a
7-ET 3a
adduct 4a
7-ET yield (HPLC)
1
MeOH/H2O
NaHCO3 [10]
NaHCO3 [10]
NaHCO3 [10]
none
5
15
50
5
16
6
78
84
85
81
76
51
77
79
78
47
78
83
84
72
2
3
37
38
39
39
39
21
36
35
35
17
40
43
45
37
2
3
3
4
4
8
4
5
H2SO4 [20]
H2SO4 [40]
5
1
18
43
2
6
5
0
c
7
i-PrOH/H2O
NaHCO3 [10]
5
12
5
8
none
5
5
9
H2SO4 [20]
H2SO4 [20]
H2SO4 [20]
H2SO4 [20]
H2SO4 [40]
H2SO4 [80]
5
1
10
41
6
c
10
11
12
13
14
MeCN/H2O
5
0
c
THF/H2O
5
7
DMA/H2O
5
10
2
2
5
5
5
0
19
a
Conditions: 1 mmol 2-ethylphenylhydrazine hydrochloride 1a, 1 equiv of DHF in 1.5 mL solvent/H2O 2:1 at a reaction temperature of 130 °C
b
c
(sealed vessel microwave irradiation). Yields are based on quantitative HPLC analysis (%) of the crude reaction mixtures. An organic and an
aqueous liquid phase separate during the reaction.
reaction mixture. The adduct 4a was isolated in 43% product
yield by column chromatography from this experiment.
Information. Overall, the yields of 7-ET 3a were around 40%
with surprising indifference regarding the reaction conditions.
Even though the reaction without any acid catalyst required
several minutes (e.g., around 8 min at 150 °C) to obtain an
essentially full consumption of the hydrazone (HPLC at 280
nm), the yields of 7-ET 3a did not increase any further after the
first few minutes of reaction (Figure 3 and Figure S1 in the
To get further insight into the Fischer indole synthesis of 7-
ET 3a, a set of experiments was performed with a variety of
acidic or basic additives in different organic solvent/water
mixtures as solvents. The reactions were performed as one feed
continuous flow reactions with premixed reagents in a
Hastelloy tube reactor (9.8 mL, 1/8 in. o.d.; see Experimental
Section for details) heated in an oil bath or as one-pot batch
reactions in glass vials heated on a hot plate or in a microwave
reactor (see Experimental Section for details). Water is required
as a cosolvent to dissolve the 2-ethylphenylhydrazine hydro-
chloride 1a and to keep the solution homogeneous during the
reaction, i.e., prevent precipitation of NH4Cl during the
reaction. The main side product of the reaction of hydrazine
hydrochloride 1a with DHF detectable by HPLC was the
adduct 4a. Further side products detected in minor amounts
were 2-ethylphenol and a compound which appeared to be a
positional isomer of 7-ET (it had the same mass and
fragmentation pattern). Significant amounts of the adduct 4a
were formed in the presence of sulfuric acid or other acidic
catalysts in all solvents tested (Table 3) and the yields of 7-ET
in the processed reaction mixtures were below 50% in all of
these reactions (yields were determined from the crude
reaction mixture by quantitative HPLC). Without any acid
catalyst, formation of the adduct was reduced and its formation
was almost completely suppressed when the reaction was
performed in the presence of a mild base such as NaHCO3,
triethylamine or pyridine. Unfortunately, consumption of the
hydrazone became rather slow in the presence of a base and the
overall yield of 7-ET did not increase. Adduct formation also
depended strongly on the solvent and it was considerably less
in protophilic solvents such as DMA/H2O, NMP/H2O, or
DMF/H2O. The pKa of protonated amides (∼ −0.5) is higher
than the pKa of protonated MeOH (−2.2) or water (−1.7) and,
presumably, amide-based solvents buffer the reaction mixture
somewhat and thus suppress dimerization of 7-ET. Indolization
of the hydrazone, however, was significantly slower in these
solvents and, again, the overall yield did not increase (Table 3).
For more data of reactions under flow and batch conditions, see
Figures S1−S9 and Tables S4−S6 in the Supporting
Figure 3. Yields of 7-ET (quantitative HPLC analysis of the crude
reaction mixtures) for flow reactions performed without any catalyst in
a Hastelloy tube reactor (9.8 mL; 1/8 in. o.d.). Conditions: 1 feed: 0.4
M 2-ethylphenylhydrazine hydrochloride 1a, 1 equiv DHF in MeOH/
H2O 2:1; 40 bar back pressure.
Supporting Information). Apparently, the rate of decomposi-
tion of 7-ET becomes comparable to the rate of its formation
after a few minutes and then even exceeds it. Interestingly, the
yields of 7-ET consistently increased with increasing reaction
temperature in the investigated temperature range (Figure 3).
Analogous behavior, but with shorter reaction times to attain
the optimum yield at a particular reaction temperature, was also
observed with acids being present in the solution (Figure 4).
An important factor may be the efficiency with which the
hydrazone is formed. As described above, dimerization and
oligo/polymerization requires the presence of DHF and, thus,
ought to be diminished when DHF is consumed by hydrazone
formation in the preceding step. In MeOH/H2O as solvent, the
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was formed even when the reaction was performed with the
isolated hydrazone 2a in non-solvolytic (non-nucleophilic)
solvents such as MTBE (Table 4, entries 2−5). Equilibrium
concentrations of DHF in the reaction mixture thus seem to be
unavoidable and an advantage of a flow process with three feeds
and two consecutive residence tubes (cf. Scheme 2)11 over flow
reactions with premixed reagents, and one residence tube is not
expected.
Selectivity of the [3,3]-Rearrangement. As indicated
above (and in more detail in the Supporting Information), even
though dimerization of 7-ET 3a could be mostly prevented by
adjusting the pH of the reaction mixture, the 7-ET yields were
invariably below 50% regardless of the catalyst, solvent, reaction
temperature, or reaction time. In large part, this seemed to be
owed to oligo/polymerization of 7-ET in the presence of DHF.
Additionally, however, it must be stressed that the [3,3]-
sigmatropic rearrangement of the ene-hydrazine intermediate
6a may produce two isomeric nonaromatic species, 7a and 8a
(Scheme 5). Importantly, only 7a can rearomatize to form 7-
ET 3a after cyclization and expulsion of ammonia from the
cyclic aminal. The intermediate 8a, on the other hand, will form
a nonaromatic dienylimine (9a) after cyclization of the
transitional diimine intermediate 8a.14,15 Dienylimines of this
kind have been isolated and characterized on a few occasions,
providing good evidence for the accepted reaction mechanism
of the Fischer indolization.15
Figure 4. Yields of 7-ET (quantitative HPLC analysis of the crude
reaction mixtures) for flow reactions performed with TFA as catalyst
in a Hastelloy tube reactor (9.8 mL; 1/8 in. o.d.). Conditions: 1 feed:
0.4 M 2-ethylphenylhydrazine hydrochloride 1a, TFA, 1 equiv DHF in
MeOH/H2O 2:1; 40 bar back pressure.
DHF reacts very rapidly in the presence of the hydrazine
hydrochloride even at room temperature. 1H NMR monitoring
in deuterated MeOH/H2O showed that the 1H NMR signals of
DHF disappear within 10 to 15 min (see Figure S10 in the
Supporting Information). Three distinct compounds were
detected in this reaction, but the main product was apparently
not the hydrazone 2a, but a compound tentatively assigned to
the tetrahydrofuran 5a (Scheme 4). In contrast, hydrazone
A nonaromatic compound, which appears to have the
structure of the dienylimine 9a, along with small amounts of 2-
ethylaniline could be isolated from the crude reaction mixture
by extraction with MTBE/H2O, neutralization of the water
phase with NaHCO3, and subsequent re-extraction of the water
phase with EtOAc. Notably, dienylimine 9a does not absorb
UV light strongly and is therefore not easily detectable with
HPLC-UV/vis and, further, elutes together with remaining
Scheme 4. Equilibration of Hydrazone and Hydrazine/DHF
in Non-Solvolytic Solvents
1
hydrazine and the 2-ethylaniline. However, GC-FID and H
NMR analysis of the reaction mixtures after extraction with sat.
NaHCO3/EtOAc indicated that the 7-ET/dienylimine ratio is
around 3:1 for reactions in the presence of 20% of H2SO4 as
the catalyst (see Figure 5 and Figure S12 in the Supporting
Information). 2-Ethylaniline, isolated together with the
dienylimine 9a, is probably formed by thermal decomposition
of the 2-ethylphenylhydrazine 1a.16 Attempts to purify the
dienylimine 9a from the aniline by crystallization or by
chromatography were unsuccessful because of its susceptibility
to decomposition.
For model compound 2b (cf. Scheme 6), full MP2
calculations17 with the 6-311+G(d,p) basis set using the
Gaussian 09 package18 indicate that the energy barrier for the
uncatalyzed [3,3]-rearrangement to the position occupied by
the o-ethyl group is not even 0.5 kcal mol−1 higher than the
formation proceeded cleaner in THF/H2O as solvent (see
Figure S11 in the Supporting Information) and the crude
hydrazone could be isolated from this mixture in 75% product
yield. However, the yields of 7-ET were virtually identical for
reactions in THF/H2O compared to MeOH/H2O as solvent.
Furthermore, comparable product compositions as observed
for reactions with hydrazine hydrochloride 1a and DHF
forming various amounts of adduct 4a as side-productwere
also obtained when the hydrazone 2a was isolated and
subsequently used for the indolization, indicating a fast
equilibration of hydrazone and hydrazine/DHF under the
employed reaction conditions (Table 4). In fact, the adduct 4a
Table 4. HPLC Purity (Peak Area Integration at 215 nm) and Yields of 7-ET (quant HPLC) for Batch Reactions Performed
a
with the Isolated Hydrazone 2a
b
entry
solvent
additive
t [min]
hydrazone 2a
7-ET 3a
adduct 4a
7-ET yield (HPLC)
1
2
3
4
5
MeOH/H2O
MTBE
1 equiv HCl
0.5 equiv H2SO4
1 equiv TFA
1 equiv TFA
2 equiv TFA
1
1
1
6
1
0
56
31
8
50
25
44
61
58
37
2
20
7
MTBE
0
13
22
30
MTBE
5
MTBE
0
26
a
b
Conditions: 1 mmol hydrazone 2a, additive in 1.5 mL solvent at a reaction temperature of 150 °C (sealed vessel microwave irradiation). Yields are
based on quantitative HPLC analysis (%) of the crude reaction mixtures.
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Scheme 5. [3,3]-Rearrangement of Ene-Hydrazine 6a
Figure 5. 1H NMR analysis of a sample containing dienylimine 9a after extraction of the reaction mixture with sat. NaHCO3/EtOAc. Conditions: 1
mmol 2-ethylphenylhydrazine hydrochloride 1a, 1 equiv DHF, 1.5 mL MeOH/H2O 2:1; 20% H2SO4; 5 min reaction temperature at 130 °C.
Scheme 6. Relative Free Energies for the Intermediates and Transition Structures Involved in the Uncatalyzed and Proton
a
Promoted Transformation of Hydrazone 2b to Diimine 7b and 8b Calculated at the MP2/6-311+G(d,p) Level
a
Relative free energies (ΔG in kcal mol−1) for the uncatalyzed and proton-catalyzed reaction are given relative to the free energy of the free
hydrazone or the Nβ-protonated hydrazone, respectively.
barrier for the rearrangement to the free position (energy
barriers of, respectively, 28.1 and 27.7 kcal mol−1 were
calculated with respect to the hydrazone).19,20 Solvation effects
using MeOH as solvent were included for geometry
optimizations, and frequency analyses using the SMD solvation
model (a more detailed description of these calculations with
comparison of all calculated energies on MP2 and M06−2X
levels are given in the Supporting Information).21 Protonation
on either of the nitrogen atoms decreases the energy barrier for
the rearrangement substantially (ΔΔG‡ is around 9−10 kcal
mol−1; Scheme 6). The Nβ protonated pathway is thereby
slightly favored by 1.3 and 0.5 kcal mol−1 for the attack on the
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Scheme 7. Elimination and Migration of the Ethyl Group of Dienylimine 9a
free and occupied position, respectively. Protonation of the Nβ
nitrogen stabilizes the transition structure for the rearrange-
ment to the free position more than the alternative transition
structure, and thus, protonation should increase the selectivity
towards the desired product. However, the difference in the
energy barriers with 0.9 kcal mol−1 is still rather low and good
regioselectivities for this reaction therefore cannot be expected.
Both elimination14a,15c and migration (1,2-14c,d and 1,4-
migrations14c) of the alkyl-group of the dienylimine inter-
mediate with accompanied rearomatization to the dealkylated
or isomeric indole derivative were reported. A 1,2-migration of
the ethyl group of the protonated dienylimine 9a to the
adjacent carbon would form 4-ET after rearomatization and
would explain the origin of the regioisomer of 7-ET detected in
the reaction mixtures. However, heating the isolated, crude
dienylimine 9a for 10 min to 150 °C in the presence of an acid
in MeOH/H2O as solvent gave three main products in a
roughly 1:3:1 mixture after column chromatography (Scheme 7
and Figure 6). The first product was identified as tryptophol by
its mass and by comparison with an authentic sample prepared
form phenylhydrazine hydrochloride and DHF. The two other
products had the mass of ethyltryptophol and were assigned to
4-ET and 7-ET, respectively, by comparing the HPLC trace of
dienylimine 9a after heating with the HPLCs obtained from the
reaction mixture of a 7-ET synthesis and a mixture of a reaction
with the 3-ethylphenylhydrazine hydrochloride and DHF (see
Figure 6 and Figure S13 in the Supporting Information). 7-ET
may be formed from the dienylimine by a sigmatropic [1,5]-
shift of the ethyl group or by two consecutive [1,2]-shifts.22
Interestingly, the dienylimine 9a was not detected in the
1
reaction mixture by H NMR analysis in the absence of acids
even though the same side products (tryptophol and 4-ET)
were observed by HPLC (Figure 6).
CONCLUSIONS
■
Efforts to synthesize the industrially important building block 7-
ET 3a by a direct reaction of ethylphenylhydrazine hydro-
chloride 1a with DHF provided 7-ET in yields of 40−50%
(quantitative HPLC). Polymeric material, apparently formed by
a follow-up reaction of 7-ET with DHF, was generated in all
transformations performed in this study. In addition, two
molecules of 7-ET reacted with DHF to form a dimer type
structure 4a under acidic conditions and the [3,3]-rearrange-
ment of the ene-hydrazine to the position occupied by the
ethyl-group led to dienylimine 9a as an isolable side product
(this is one of very rare examples where this dienylimine
actually could be isolated). Migration of the ethyl-group of the
dienylimine 9a forms 4-ET as a minor side product. Even
though no or only small amounts of adduct 4a were observed
when the reaction was performed in the presence of a mild base
or without any acidic catalyst, the yields of 7-ET did not
increase.
Despite the moderate product yield, it must be emphasized
that both the 2-ethylphenylhydrazine 1a and DHF are
inexpensive and readily available starting materials. Further-
more, the developed process is operationally simple, can be
executed in the absence of strong acids or bases using an
environmentally benign solvent, and importantly, the majority
of side products can be removed from the product simply by
extraction. Residence times of only a few minutes are required
at temperatures of 150−170 °C, thus allowing a high
throughput even with rather compact reactors with residence
loops of small volume. The final experimental setup used in the
present study comprising a single syringe pump, a Hastelloy
loop immersed into an oil bath, a short stainless steel loop to
cool the processed reaction mixture, and a back-pressure
regulator (Scheme 8). The crude product was isolated by
Scheme 8. Continuous Flow Synthesis of 7-ET
Figure 6. Comparison of HPLC traces of reaction mixtures (215 nm)
of (a) 7-ET synthesis: Conditions: 1 mmol 2-ethylphenylhydrazine
hydrochloride 1a, 1 equiv DHF, 1.5 mL MeOH/H2O 2:1; 20 s
reaction time at 170 °C (sealed vessel microwave heating) and (b)
dienylimine 9a after heating for 10 min at 150 °C in MeOH/H2O in
the presence of 1 equiv of HCl (after column chromatography).
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extraction, and further purification could readily be accom-
plished by precipitation of polymeric material, remaining in the
product after extraction, with unpolar solvents, such as a
mixture of MTBE/petroleum ether (PE). Thus, heating a
solution of the hydrazine hydrochloride 1a (0.4 M) and 1 equiv
of DHF in MeOH/H2O 2:1 for 3 min at 150 °C produced 39%
of 7-ET 3a (corrected for purity based on quantitative HPLC)
after extraction and treatment of the extracted product with
MTBE/PE in a HPLC purity (215 nm) of 92%. Analytically
pure and crystalline 7-ET was obtained by extraction and
subsequent column chromatography in 41% product yield.
HCl (0.74 g 32% aqueous HCl; 6.52 mmol) in ethylene glycol/
water as solvent (723.2 g/288.8 g). The two solutions were
introduced into a plate microreactor (Flowplate A6 reactor with
SZ mixers, 2.8 mL) by two gear pumps (Reglo-Z; Ismatec) and
the combined solution passed through a first residence coil (2
mL PFA tube, 1/8 in. o.d.). 50% H2SO4 was fed in by a syringe
pump (MDP1f; MMT GmbH) and was combined with the
effluent reaction mixture of the first residence coil in a second
plate microreactor (Corning glass reactor NIM 06-017-C, 5.6
mL). The mixture passed through a second residence coil (1/8
in. o.d., 38 mL). The two plate reactors and the two residence
coils were heated to the temperature indicated in the Tables 1
and 2. The reaction mixture was finally cooled to room
temperature in a PFA tube (1/8 in. o.d., 2 mL) and collected in
a flask under nitrogen. The processed reaction mixtures were
neutralized with NaOH to pH7 and the crude 7-ET was
isolated by extraction with H2O/MTBE. The isolated product
was analyzed by quantitative HPLC.
One Feed Continuous Flow Reactions (Scheme 8). 2-
Ethylphenylhydrazine hydrochloride 1a was dissolved in the
respective solvent. Additives and DHF were added under
stirring. The reaction mixture was pumped through a Hastelloy
tube reactor (9.8 mL, 1/8 in. o.d.), which was heated in an oil-
bath, by a syringe pump (ISCO; Teledyne). The reaction
mixture passed a stainless steel coil (2.2 mL, 1/8 in. o.d.) which
was cooled in a water bath to room temperature and the
reaction mixture left the reactor through a back-pressure
regulator (30 to 50 bar). The processed reaction mixture was
analyzed by quantitative HPLC. The crude 7-ET was isolated
by extraction with MTBE/H2O or toluene/H2O and the
isolated product was again analyzed by HPLC. Additional
purification can be accomplished by precipitation of polymeric
material remaining in the product after extraction with unpolar
solvents, such as MTBE/PE.
EXPERIMENTAL SECTION
General. H NMR spectra were recorded on a Bruker 300
■
1
MHz instrument. 13C NMR spectra were recorded on the same
instrument at 75 MHz. Chemical shifts (δ) are expressed in
ppm downfield from TMS as internal standard. The letters s, d,
t, q, and m are used to indicate singlet, doublet, triplet,
quadruplet, and multiplet. GC-FID analysis was performed on a
Trace-GC (ThermoFisher) with a flame ionization detector
using a HP5 column (30 m × 0.250 mm × 0.025 μm). After 1
min at 50 °C, the temperature was increased in 25 °C min−1
steps up to 300 °C and kept at 300 °C for 4 min. The detector
gas for the flame ionization is H2 and compressed air (5.0
quality). 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 × 0.250 mm × 0.025 μm) was used with Helium
as carrier gas (1 mL min−1 constant flow). The injector
temperature was set to 280 °C. After 1 min at 50 °C, the
temperature was increased in 25 °C min−1 steps up to 300 °C
and kept at 300 °C for 4 min. Low-resolution mass spectra were
obtained on a Shimadzu LCMS-QP2020 instrument using
electrospray ionization (ESI) in positive or negative mode.
Analytical HPLC (Shimadzu LC20) analysis was carried out on
a C18 reversed-phase (RP) analytical column (150 × 4.6 mm,
particle size 5 μm) at 37 °C using a mobile phase A (water/
acetonitrile 90:10 (v/v) + 0.1% TFA) and B (MeCN + 0.1%
TFA) at a flow rate of 1.0 mL min−1 (the following gradient
was applied: linear increase from solution 30% B to 100% B in
8 min, hold at 100% solution B for 2 min), or on a Agilent 1100
with a C18 reversed-phase (RP) analytical column (150 × 4.6
mm, particle size 5 μm) using a mobile phase A (water/
methanol/THF 700:160:60 (v/v/v)) and B (water/acetonitrile
300:700 (v/v)) at a flow rate of 1.3 mL min−1 (isocratic 62%
mobile phase A and 38% mobile phase B). For quantitative
HPLC, calibration curves were established with analytically
pure 7-ET as calibration standard. These calibration curves
were used to translate the integrated peak areas from the HPLC
analysis into absolute quantities. TLC analyses were performed
on precoated (silica gel 60 HF254) plates. All chemicals were
purchased from commercial sources and were used without
further purification. 2-Ethylphenylhydrazine hydrochloride and
DHF were purchased from Shandong Xinhua Pharmaceutical
Company Limited and Zhejiang Realsun Chemical Industry
Co. Ltd., respectively. Chromatographic purification was done
on an automated flash-chromatography system (SP1, Biotage)
using cartridges packed with KP-SIL, 60 Å (40−63 μm particle
size), and ethyl acetate/petroleum ether mixtures as eluents.
Three Feed Continuous Flow Reactions (Scheme 2). 2-
Ethylphenylhydrazine hydrochloride 1a (144.5 g; 0.829 mol)
was dissolved in ethylene glycol/water (656.2 g/161.4 g) and
25% aqueous NaOH was added (134.7 g; 0.842 mol NaOH).
DHF (56.7 g; 0.805 mol) was stirred at room temperature with
Batch Reactions. 2-Ethylphenylhydrazine hydrochloride 1a
was dissolved in the respective solvent. Additives and DHF
were added under stirring. The reaction mixture was heated to
the desired temperature either in a Biotage Initiator 8 EXP
microwave reactor or on a hot plate. The processed reaction
mixture was analyzed by HPLC. The crude 7-ET was isolated
by extraction with MTBE/H2O or toluene/H2O and the
isolated product was again analyzed by HPLC.
1
7-Ethyltryptophol 3a. H NMR (300 MHz, CDCl3): δ =
8.27 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.17−7.04 (m, 3H), 3.93
(t, J = 6.4 Hz, 2H), 3.06 (t, J = 6.4, 2H), 2.88 (q, J = 7.6 Hz,
2H), 1.39 (t, J = 7.6 Hz, 2H); MS (pos. ESI): m/z = 190 (M
+H+).
1
Adduct 4a. H NMR (300 MHz, CDCl3) δ = 9.35 (s, 2H),
7.35 (d, J = 7.6 Hz, 2H), 7.05 (t, J = 7.5 Hz, 2H), 6.97 (d, J =
7.0 Hz, 2H), 4.68 (t, J = 7.7 Hz, 1H), 3.98 (t, J = 5.2 Hz, 4H),
3.61 (t, J = 5.3 Hz, 2H), 3.20−3.05 (m, 4H), 2.76 (q, J = 7.4
Hz, 4H), 2.48 (br s, 3H), 2.44−2.35 (m, 2H), 1.67−1.51 (m,
2H), 1.30 (t, J = 7.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ =
137.19, 134.66, 128.00, 126.38, 120.05, 119.33, 115.71, 108.36,
62.81, 62.41, 36.62, 30.70, 29.98, 27.60, 23.82, 13.75;MS (pos.
ESI): m/z = 449 (M+H+).
1
Dienylimine 9a. H NMR (300 MHz, CDCl3) δ = 6.48
(ddd, J = 9.7, 5.2, 0.8 Hz, 1H), 6.39 (d, J = 9.7 Hz, 1H),6.23 (d,
J = 9.4 Hz, 1H), 6.17 (ddd, J = 9.5, 5.2, 1.0 Hz, 1H),5.91 (d, J =
4.8 Hz, 1H), 3.88−3.79 (m, 1H), 3.57 (dd, J = 16.0, 7.6 Hz,
1H), 2.78 (dt, J = 10.3, 5.2 Hz, 1H), 1.91 (ddt, J = 12.7, 10.1,
7.6 Hz, 1H), 1.71−159 (m, 1H), 1.59−1.47 (m, 1H), 1.33 (dt, J
= 10.6, 5.9 Hz, 1H), 0.87 (t, J = 7.5 Hz, 3H); 13C NMR (75
301
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in 20 mL THF/H2O 1:1. One equivalent of DHF was added
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crude hydrazone 2a as a orange oil in 76% product yield. The
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6.82 (m, 1H), 3.74 (t, J = 6.2 Hz, 2H), 2.60−2.34 (m, 4H),
1.92−1.81 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ = 142.46, 141.62, 128.12, 127.10, 126.01,
119.64, 112.97, 62.25, 29.53, 28.89, 23.60, 13.31; MS (pos.
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ASSOCIATED CONTENT
* Supporting Information
■
(13) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(14) (a) Maddirala, S. J.; Gokak, V. S.; Rajur, S. B.; Basanagoudar, L.
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(16) Phenylhydrazine decomposes according to: 2 C6H5NHNH2 →
C6H6 + C6H5NH2 + NH3 + N2. However, even though ethylbenzene
and 2-ethylaniline were detected upon heating of 2-ethylphenylhy-
drazine, ethylbenzene was not observed in the reaction mixtures of the
7-ET synthesis. See also: Moldoveanu, S. Pyrolysis of Organic Molecules:
Applications to Health and Environmental Issues; Elsevier Science:
Dordrecht, 2010; Chapter 14.5.
S
Additional experimental information. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dominique.roberge@lonza.com, oliver.kappe@uni-
graz.at.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the Christian
Doppler Research Society (CDG). D.C. thanks the Research,
Technological Innovation, and Supercomputing Center of
́
Extremadura (CenitS) for their support in the use of
(17) Head-Gordon, M.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett.
1988, 153, 503−506.
LUSITANIA computer resources.
(18) Frisch, M. J. et al. Gaussian 09, rev A.1; Gaussian, Inc.;
Wallingford, CT, 2009.
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