Fischer indole synthesis of 3-benzyl-1H-indole via conductive and dielectric heating

Article abstract of DOI:10.1007/s10593-017-1983-2

As a part of designing one-pot synthesis conditions for a combination of Heck isomerization and Fischer indolization (HIFI sequence), a model reaction was studied using 3-phenylpropanal and phenylhydrazine to furnish 3-benzyl-1H-indole under conductive and dielectric heating. While Amberlyst 15 as an acidic catalyst or T3P (propylphosphonic acid cyclic anhydride) as a condensation agent gave high yields of 3-benzyl-1H-indole under both conductive and dielectric heating, these agents were not compatible with the conditions of the initial Heck isomerization. However, the catalyst-free thermal process for the indolization step proceeded with good yields in conjunction with the preceding Heck isomerization in a one-pot process under dielectric heating in N-methylpyrrolidone as a solvent.

Full text of DOI:10.1007/s10593-017-1983-2

DOI 10.1007/s10593-017-1983-2
Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Fischer indole synthesis of 3-benzyl-1H-indole
via conductive and dielectric heating
Jesco Panther1, Julian Rechmann1, Thomas J. J. Müller1*
1 Institute of Organic and Macromolecular Chemistry, Heinrich Heine University Düsseldorf,
Universitätsstrasse 1, D-40225 Düsseldorf, Germany; e-mail: ThomasJJ.Mueller@hhu.de
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(11), 897–903
Submitted July 27, 2016
Accepted August 22, 2016
As a part of designing one-pot synthesis conditions for a combination of Heck isomerization and Fischer indolization (HIFI sequence),
a model reaction was studied using 3-phenylpropanal and phenylhydrazine to furnish 3-benzyl-1H-indole under conductive and dielectric
heating. While Amberlyst® 15 as an acidic catalyst or T3P® (propylphosphonic acid cyclic anhydride) as a condensation agent gave high
yields of 3-benzyl-1H-indole under both conductive and dielectric heating, these agents were not compatible with the conditions of the
initial Heck isomerization. However, the catalyst-free thermal process for the indolization step proceeded with good yields in conjunction
with the preceding Heck isomerization in a one-pot process under dielectric heating in N-methylpyrrolidone as a solvent.
Keywords: indole, acid catalysis, condensation, Fischer indole synthesis, Heck isomerization, microwave-assisted reactions, one-pot
reactions, thermal reactions.
The indole core is omnipresent in numerous naturally
occurring and synthetic biologically active compounds,
pharmaceutical ingredients,1–6 and also in natural and
synthetic dyes.7 As a consequence, the development of indole
syntheses has always remained an interesting synthetic task.8–13
Undoubtedly, the classical Fischer indole synthesis14–17
offers universal access to indoles by virtue of directly
transforming ethanones as immediate structural precursors.
The advent of transition metal catalysis within the concept
of multicomponent syntheses of heterocycles, enabling
modular, diversity-oriented synthetic strategies, has increa-
singly attracted attention over the past two decades.18–20
Besides the pronounced practicability and efficiency, such
domino, sequential, and consecutive multicomponent
reactions (MCR) represent a reactivity-based concept21
where reactive functionalities are created and transformed
most efficiently in a one-pot fashion.22–26 Eventually, MCR
syntheses of indoles have become particularly interesting.27
In the course of our studies to develop novel MCR
syntheses of heterocycles initiated by transition metal
catalysis, using carbonyl derivatives as reactive interme-
diates,28–31 and driven by our interest to develop diversity-
oriented syntheses of functional chromophores,32–35 we
have discovered a novel consecutive three-component
synthesis of intensively blue emissive 5-(3-indolyl)-
oxazoles based on a one-pot concatenation of Sonogashira
coupling, cycloisomerization, and concluding Fischer
indole synthesis.36 Just recently we reported a novel con-
secutive three-component one-pot synthesis of 3-aryl-
methyl-substituted indoles by a Heck isomerization–
Fischer indolization (HIFI) sequence, starting from aryl
bromides, allyl alcohols, and aryl hydrazines (Scheme 1).37
Scheme 1
0009-3122/16/52(11)-0897©2016 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Scheme 2
The relevant intermediate enabling the terminal Fischer
indolization step was a 3-aryl-1-oxopropyl derivative.
Here we report in detail on the optimization of the
Fischer indolization step with 3-benzyl-1H-indole as the
model target compound. Our primary focus within this
study is the comparative use of conductive and dielectric
heating.
For the conception of the consecutive HIFI synthesis, we
had to identify compatible conditions for all individual
steps intended for the final one-pot procedure. Therefore,
we reasoned that the terminal Fischer indole formation step
could be studied by using the model reaction of 3-phenyl-
propanal (1) and phenylhydrazine (2) furnishing 3-benzyl-
1H-indole (3) (Scheme 2).
First we set out to screen the conditions for acid
catalysis. Brønsted and Lewis acids were previously identi-
fied to efficiently catalyze the Fischer indole synthesis,
giving high yields of the desired indoles.15 Brønsted acids
that were successful in Fischer indolizations have ranged
from strong acids (p-toluenesulfonic acid (PTSA),38 poly-
phosphoric acid (PPA),39 HCl,40 H2SO441), weak acids
(acetic acid,42 pyridinium chloride43), and acids on solid
support (alumosilicates, such as bentonite clay K-10,44
zeolite Y,45 ion exchange resins, such as Amberlyst
resins46). The Lewis acids previously used in these reac-
tions include PCl3,47 POCl3,48 trimethylsilyl polyphosphate
(PPSE),49 ZnCl2,50 Sc(OTf)3,51 Al(OTf)3,51 Y(OTf)3,51
Mg(OTf)2,51 NaOTf,51 Me3OBF4.51 The reactions were
monitored by TLC and the yields of 3-benzyl-1H-indole (3)
were determined by gas chromatography with n-dodecane
as a standard (Table 1). The screening was performed in
closed vessels both for conductive heating in a preheated
oil bath (Fig. 1, Table 2), as well as for dielectric heating in
a microwave reactor (Fig. 2, Table 3), using THF and
1,4-dioxane as solvents. While the temperature range was
screened between room temperature and 115°C for
reactions in THF, higher temperatures could be used for
1,4-dioxane solutions under conductive heating. Under
dielectric heating it was possible to perform superheating
for both solvents uneventfully.
Table 1. Details of the calibration line for 3-benzyl-1H-indole (3)
Integral for indole 3 Integral for n-dodecane Integral for indole 3 /
(the average value)
(the average value) integral for n-dodecane
0
502877
503211
0.00
226674
0.4504
465647
674866
938588
1107699
478737
471305
488278
467122
0.9725
1.4322
1.9224
2.3713
Table 4) and dielectric heating (Fig. 4, Table 5)
experiments performed in THF and 1,4-dioxane.
For conductive heating experiments, the reaction tempe-
rature of 150°C and reaction time of 180 min in
1,4-dioxane turned out to give the highest yield of 3-benzyl-
1H-indole (3). The presence of Cy2NMe·HBr as a cocata-
lyst obviously slowed down the indole formation. Under
dielectric heating conditions in both THF and 1,4-dioxane,
the reaction temperature of 150°C and reaction times of 30
and 20 min were found to give almost identical high yields
of 3-benzyl-1H-indole (3). Interestingly, neither a decrease
nor increase of T3P® concentration could improve the yield
of the indole under dielectric heating conditions. Also,
increasing the concentration of aldehyde 1 and hydrazine 2
could not raise the yield of the indole 3.
When probing the optimal conditions of indolization
(150°C, microwave heating, 180 min) in the one-pot
sequence,37 only an 8% yield of 3-benzyl-1H-indole (3)
was obtained. The general mechanism of the Fischer
indolization suggested a [3,3]-sigmatropic rearrangement
of an ene-hydrazinyl intermediate forming the carbon–
carbon bond between the ortho-phenyl position and
position 3 of the prospective indole in the sense of a diaza-
Cope rearrangement (Scheme 3).53 The purely thermal
rearrangement of hydrazones to indoles54,55 and aza-
indoles56 was shown to proceed at elevated temperatures
(>170°C). Therefore, we rather preferred to switch to the
uncatalyzed thermal process than to battle with the
incompatibility of acidic catalysts with the ingredients of
the preceding Heck reaction.
At the reaction temperature of 115°C in THF solution,
Amberlyst® 15 as an acid catalyst on solid support gave the
highest yields of 75% (conductive heating for 240 min) and
74% (dielectric heating for 30 min). Alumosilicates, such
as bentonite clay K10 and zeolite Y, were not effective
catalysts and, surprisingly, Lewis acidic catalysts also did
not provide comparable yields neither in conductive nor
dielectric heating experiments. Although Amberlyst® 15
turned out to be a superior catalyst system for Fischer indo-
lization, the acidic conditions were not quite compatible
with the preceding basic Heck reaction and only provided
a 35–39% overall yield of 3-benzyl-1H-indole (3) in the
one-pot sequence.37
Among higher-boiling solvents suitable for this reaction
we quickly identified ethylene glycol and N-methyl-
2-pyrrolidone (NMP). While the former only furnished
Scheme 3
Recently, T3P® (propylphosphonic acid cyclic anhy-
dride) was identified as a multifunctional agent in Fischer
indolization, i.e., as a water scavenger in the hydrazone
formation and then forming an acid to catalyze the [3,3]-
sigmatropic diaza-Cope rearrangement.52 Therefore, we
screened T3P® as a condensation agent in conductive (Fig. 3,
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Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Table 2. Acid catalyst screening for conductive heating
Table 2 (continued)
Yield*
of indole 3,
%
Temperature, Time,
Yield*
Temperature, Time,
Acid catalyst
Solvent
Acid catalyst
Solvent
°C
100
100
70
min of indole 3, %
°C
min
Concd H3PO4 (1.50 ml)
PPA (870 mg)
1,4-Dioxane
1,4-Dioxane
100
130
150
130
150
150
115
210
120
60
16
68
32
36
64
42
29
Glacial acetic acid (1.00 ml) THF
465
960
1
46
34
–
0.5 M HCl (1.00 ml)
THF
THF
THF
THF
PTSA (285 mg, 1.25 mmol) 1,4-Dioxane
ZnCl2 (200 mg, 1.47 mmol) 1,4-Dioxane
1.0 M H2SO4 (0.76 mmol)
180
90
Cy2NMe·HBr
(553 mg, 2.00 mmol)
Pyridinium chloride
(115.6 mg, 1.00 mmol)
100
70
65
Amberlyst® 15 (300 mg)
Amberlyst® 16 wet (300 mg) 1,4-Dioxane
Amberlyst® 15 (300 mg)
DMF
1,4-Dioxane
180
180
240
1200
1020
60
2
POCl3 (277 mg, 1.81 mmol) THF
rt
20
18
14
12
6
* The yield of product 3 was determined by GC analysis.
PCl3 (275 mg, 2.00 mmol)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
rt
Sc(OTf)3
(50.7 mg, 0.10 mmol)
Al(OTf)3
(48.4 mg, 0.10 mmol)
Y(OTf)3
(63.9 mg, 0.10 mmol)
Mg(OTf)2
(32.9 mg, 0.10 mmol)
85
1320
1320
1320
1320
1320
1440
210
85
85
85
2
NaOTf
85
–
(17.6 mg, 0.10 mmol)
Bentonite clay K-10
(200 mg)
70
2
Amberlyst® 15 (300 mg)
Amberlyst® 15 (300 mg)
Amberlyst® 36 (300 mg)
115
115
115
115
115
85
56
75
70
66
70
51
34
240
270
Amberlyst® 16 wet (300 mg) THF
Amberlyst® 16 wet (300 mg) THF
240
1260
20
PPSE (565 mg)
THF
THF
Figure 1. Acid catalyst screening in the synthesis of 3-benzyl-1H-
indole (3) by conductive heating in THF (blue), 1,4-dioxane (red),
or DMF (green) (c0(1) = c0(2) = 0.5 M).
Zeolite Y (300 mg)
115
1200
Table 3. Acid catalyst screening for dielectric heating method
Yield*
Temperature, Time,
Acid catalyst
Solvent
of indole 3,
°C
min
%
1.0 M H2SO4 (0.76 mmol)
POCl3 (277 mg, 1.81 mmol)
PCl3 (280 mg, 2.00 mmol)
THF
THF
THF
THF
THF
THF
100
100
100
150
115
150
100
150
15
41
30
42
35
74
28
11
46
20
10
Me3O·BF4
(152.5 mg, 1.00 mmol)
Amberlyst® 15 (300 mg)
30
30
Amberlyst® 15 (300 mg)
57
Bentonite clay K-10 (200 mg) THF
120
30
1,4-
PTSA (285 mg, 1.25 mmol)
Dioxane
Figure 2. Acid catalyst screening in the synthesis of 3-benzyl-1H-
indole (3) by dielectric heating in THF (blue) or 1,4-dioxane (red)
(c0(1) = c0(2) = 0.5 M).
* The yield of product 3 was determined by GC analysis.
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Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Table 4. Solvent screening for synthesis under conductive heating
conditions, using T3P® as a condensation agent
Solvent
Temperature, °C Time, min Yield* of indole 3, %
THF**
THF**
100
150
150
150
150
30
35
30
24
74
43
180
180
180
180
DMF***
1,4-Dioxane***
1,4-Dioxane***,*4
Figure 3. The temperature and solvent screening results in the
synthesis of 3-benzyl-1H-indole (3) with T3P® as the condensa-
tion agent, using conductive heating in THF, 1,4-dioxane, and
DMF after the reaction time of 30 min (red) and 180 min (blue)
(c0(1) = c0(2) = 0.5 M).
* The yield of compound 3 was determined by GC analysis.
** T3P® was employed as 50 wt% solution in THF.
*** T3P® was employed as 50 wt% solution in toluene.
*4 Cy2NMe·HBr (276 mg, 1.00 mmol) was added.
Table 5. Screening the reaction conditions using dielectric
heating with T3P® as a condensation agent
T3P®,
mg (mmol)
Temperature, Time,
Yield*
of indole 3, %
Solvent
°C
min
795 (1.25)**
THF
THF
THF
THF
THF
THF***
THF
THF
THF
THF
150
150
150
150
150
150
150
150
150
150
150
150
150
150
165
180
180
180
30
60
30
30
30
30
30
10
20
30
60
10
20
30
10
10
20
30
80
28
59
75
57
14
55
46
53
56
57
73
75
44
62
79
82
50
795 (1.25l)**
636 (1.00)**
955 (1.50)**
1590 (2.50)**
795 (1.25)**
795 (1.25)**,*4
795 (1.25)**,*5
795 (1.25)**,*5
795 (1.25)**,*5
795 (1.25)**,*5
795 (1.25)**,*6
795 (1.25)**,*6
795 (1.25)**,*6
795 (1.25)**
795 (1.25)*7
THF
THF
THF
THF
THF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
795 (1.25)*7
795 (1.25)*7
* The yield of product 3 was determined by GC analysis.
** T3P® was employed as 50 wt% solution in THF.
*** Ethanol (1 ml) was added.
*4 The amount of phenylhydrazine (2) was 135 mg (1.25 mmol).
*5 The amount of phenylhydrazine (2) was 216 mg (2.00 mmol).
*6 The amount of 3-phenylpropanal (1) was 268 mg (2.00 mmol) and the
amount of phenylhydrazine (2) was 216 mg (2.00 mmol).
*7 T3P® was employed as 50 wt% solution in PhMe.
Figure 4. Screening the conditions for the synthesis of 3-benzyl-
1H-indole (3) with T3P® as a condensation agent using dielectric
heating at 150°C in THF (blue), 165°C in THF (red), and at 180°C in
1,4-dioxane (green) (c0(1) = c0(2) = 0.5 M).
31% yield of aldehyde 1 in the separate Heck reaction at
70°C in the microwave reactor, the latter turned out to be
an excellent solvent giving 92% yield of aldehyde 1 with a
minimum amount of NMP, so that the reaction could be
performed at substrate concentrations of 2.0 M. Upon
optimization of all parameters of the Heck step in NMP,
96% yield of the aldehyde 1 was obtained after 10 min
microwave irradiation at 70°C, setting the stage for conca-
tenating the indolization under thermal conditions with
dielectric heating.
Therefore, as a model reaction for optimizing the
terminal Fischer indolization step in the HIFI sequence,37
bromobenzene (4) and allyl alcohol (5) were reacted in the
presence of a palladium catalyst and Cy2NMe in NMP in
the microwave reactor at 70°C for 10 min, furnishing
3-phenylpropanal (1) that was subsequently treated with
phenylhydrazine (2) in the microwave reactor for various
duration at various temperatures to furnish 3-benzyl-1H-
indole (3) (Scheme 4, Fig. 5, Table 6).
While a reaction temperature of 180°C did not prove to
be sufficient for the indolization and only the hydrazone
could be detected, maintaining the reaction mixture at
temperatures between 200 and 240°C caused the formation
of indole 3. Performing the reaction at the maximum power
of the microwave reactor (300 W), however, caused an
automatic shutdown after 24 s due to rapid pressure
increase in the vial. The optimal reaction temperature was
identified to be 220°C for the duration of 15 min. With
these parameters, the HIFI sequence was ultimately
methodologically developed.
The optimization of Fischer indolization conditions for
efficient concatenation into a one-pot sequence was started
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Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Scheme 4
Table 6. Optimization of dielectric heating temperature
and duration in the indolization step
Temperature, °C
Time, min
Yield* of indole 3, %
180
200
200
220
220
220
220
220
240
Pmax
15
15
30
5
10
10
15
30
15
(5)
0**
37
28
50
49
50***
53
43
46
35*4
* The yield of product 3 was determined by GC analysis.
** Only the hydrazone was formed.
*** Phenylhydrazine hydrochloride (2·HCl) was employed (145 mg,
1.00 mmol).
*4 The reaction was performed at the maximum power of the microwave
reactor (300 W), however, the experiment was automatically shut down
after 24 s due to a rapid increase of pressure in the vial.
Figure 5. Optimization of the microwave-assisted Fischer in-
dolization step in the one-pot HIFI synthesis of 3-benzyl-1H-
indole (3) (c0(4) = c0(5) = c0(2) = 0.5 M).
by testing acid-catalyzed (Amberlyst® 15) and conden-
sation agent-mediated (T3P®) procedures, using THF and
1,4-dioxane as solvents, both under conductive and
dielectric heating. The immediate advantages of dielectric
heating are considerably shorter reaction times at compa-
rable temperatures, presumably due to the more efficient
gradientless energy transfer into the reaction vessel.
However these conditions failed in the context of the rather
basic conditions of the preceding Heck isomerization step.
Nevertheless, switching to NMP as a high-boiling solvent
enabled higher reaction temperatures under microwave heating
and thereby circumvented the problems caused by acid
catalysts used for triggering the [3,3]-sigmatropic diaza-
Cope rearrangement. Again, the advantage of dielectric
heating was in the rapid energy input, thereby overcoming
high activation barriers.
hydrazine (2) and phenylhydrazine hydrochloride (2·HCl)
were purchased from Sigma-Aldrich and used without
further purification.
1
3-Phenylpropanal (1). H NMR spectrum, δ, ppm (J, Hz):
2.66–2.74 (2H, m, 2-CH2); 2.88 (2H, t, J = 7.3, 3-CH2);
7.09–7.25 (5H, m, H Ph); 9.74 (1H, t, J = 1.4, CHO).
3-Benzyl-1H-indole (3). Colorless solid, mp 102°C (mp
101–102°C59). IR spectrum (film), ν, cm–1: 692, 748, 808,
853, 907, 935, 974, 1036, 1088, 1109, 1148, 1179, 1192,
1227, 1265, 1314, 1368, 1391, 1454, 1497, 1603, 1653,
1717, 2858, 2905, 2934, 2980, 3026. 1H NMR spectrum, δ,
ppm (J, Hz): 4.04 (2H, s, CH2); 6.81 (1H, m, CH); 6.97–
7.29 (9H, m, H Ph, H Ar); 7.83 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 31.7 (CH2); 111.2 (CH); 115.9
(Cquat); 119.3 (CH); 119.5 (CH); 122.3 (CH); 122.5 (CH);
126.0 (CH); 127.6 (Cquat); 128.4 (CH); 128.5 (CH); 128.8
(CH); 129.1 (CH); 136.6 (Cquat); 141.3 (Cquat). Mass spectrum
(EI), m/z (Irel, %): 207 [M]+ (100), 206 [M–H]+ (78), 130
[M–C6H5]+ (90), 91 [C7H7]+ (24), 77 [C6H5]+ (13). Found, %:
C 86.66; H 6.43; N 6.99. C15H13N. Calculated, %: C 86.92;
H 6.32; N 7.76.
Experimental
IR spectrum was recorded on a Shimadzu IRAffinity-1
1
FT-IR spectrometer. H and 13C NMR spectra (300 and
75 MHz, respectively) were acquired on a Bruker Avance
III-300 instrument in CDCl3. Mass spectra were recorded
on a Finnigan MAT 8200 spectrometer. Elemental analysis
was performed on a Perkin Elmer Series II Analyzer 2400.
The melting point of indole 3 was determined on a Reichert
Thermovar apparatus.
Gas chromatographic calibration of the yields of
3-benzyl-1H-indole (3). Gas chromatography was per-
formed on a Shimadzu GC-2012 instrument, using a DB-5
column. 3-Benzyl-1H-indole (3) was identified by its
retention time (RT) and its content was quantified by a
calibration line determined from the integrals of various
defined amounts of 3-benzyl-1H-indole (3) relative to
n-dodecane as a standard (Table 1, Fig. 6).
3-Phenylpropanal (1) was obtained by a modified Heck
reaction37 of bromobenzene (4) and allyl alcohol (5) as
1
yellowish oil, with H NMR spectra in full agreement with
the literature.57 3-Benzyl-1H-indole (3) was isolated from
the reaction mixtures by chromatography and purified by
sublimation to give a colorless solid with spectroscopic
data in full agreement with the literature.58 Phenyl-
The conditions were as follows:
Complete measurement time: 25 min, initial tem-
perature: 50°C (0 min), end temperature 250°C (25 min,
linear slope);
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Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
Temperature and solvent screening for the synthesis
of 3-benzyl-1H-indole (3) with T3P® as a condensation
agent under conductive heating conditions.
In a flame-dried Schlenk tube, solution of T3P®
(795 mg, 1.25 mmol) in the appropriate solvent and a
portion of pure solvent (2 ml) were placed under nitrogen
atmosphere (Table 4). Then 3-phenylpropanal (1) (134 mg,
1.00 mmol) and phenylhydrazine (2) (108 mg, 1.00 mmol)
were added. The reaction vessel was placed in a preheated
oil bath at various temperatures for the time indicated, until
the hydrazone formed from starting materials 1 and 2 was
completely consumed or no further reaction could be detected
(monitored by TLC, hexane–ethyl acetate, 5:1). For deter-
mining the yield after the end of the reaction, n-dodecane
(100 μl) was added as a standard. A 20-μl aliquot of the
reaction mixture was filtered with THF (1.5 ml) through a
short plug of silica gel (ca. 4×15 mm) into a GC vial and
subjected to gas chromatography to determine the yield of
3-benzyl-1H-indole (3).
Figure 6. Calibration line for determining the yield of 3-benzyl-
1H-indole (3).
RT (1) = 9.08 min, RT (2) = 9.40 min, RT (n-dodecane) =
= 9.57 min, RT (3) = 20.43 min, RT (hydrazone) =
= 20.59 min.
Acid catalyst screening for the synthesis of 3-benzyl-
1H-indole (3) under conductive heating conditions.
In a flame-dried Schlenk tube, the acid catalyst was
placed in the solvent (2 ml) under nitrogen (Table 2). Then
3-phenylpropanal (1) (134 mg, 1.00 mmol) and phenyl-
hydrazine (2) (108 mg, 1.00 mmol) were added. The reaction
vessel was placed in a preheated oil bath at various tempe-
ratures for the time indicated, until the hydrazone formed
from starting materials 1 and 2 was completely consumed
or no further reaction could be detected (monitored by
TLC, hexane–ethyl acetate, 5:1). For determining the yield
after the end of reaction, n-dodecane (100 μl) was added as
a standard. A 20 μl aliquot of the reaction mixture was
filtered with THF (1.5 ml) through a short plug of silica gel
(ca. 4×15 mm) into a GC vial and subjected to gas
chromatography to determine the yield of 3-benzyl-1H-
indole (3).
Screening the conditions of 3-benzyl-1H-indole (3)
synthesis with T3P® as a condensation agent under
dielectric heating conditions.
In a microwave vial (10 ml), a solution of T3P® in the
appropriate solvent and a portion of pure solvent (2 ml)
were placed under nitrogen atmosphere (for experimental
details see Table 5). Then, 3-phenylpropanal (1) (134 mg,
1.00 mmol) and phenylhydrazine (2) (108 mg, 1.00 mmol)
were added. The microwave vial was placed in the
microwave reactor at various temperatures for the times
indicated until the hydrazone formed from starting
materials 1 and 2 was completely consumed or no further
reaction could be detected (monitored by TLC, hexane–
ethyl acetate, 5:1). For determining the yield after end of
reaction, n-dodecane (100 μl) was added as a standard. A
20-μl aliquot of the reaction mixture was filtered with THF
(1.5 ml) through a short plug of silica gel (ca. 4×15 mm)
into a GC vial and analyzed by gas chromatography to
determine the yield of 3-benzyl-1H-indole (3).
Acid catalyst screening for the synthesis of 3-benzyl-
1H-indole (3) under dielectric heating conditions.
In a microwave vial (10 ml), the acid catalyst was placed
in the solvent (2 ml) under nitrogen atmosphere (Table 3).
Then 3-phenylpropanal (1) (134 mg, 1.00 mmol) and
phenylhydrazine (2) (108 mg, 1.00 mmol) were added. The
microwave vial was placed in the microwave reactor at
various temperatures for the times indicated until the
hydrazone formed from starting materials 1 and 2 was
completely consumed or no further reaction could be detected
(monitored by TLC, hexane–ethyl acetate, 5:1). For deter-
mining the yield after the end of reaction, n-dodecane (100 μl)
was added as a standard. A 20 μl aliquot of the reaction
mixture was filtered with THF (1.5 ml) through a short
plug of silica gel (ca. 4×15 mm) into a GC vial and
subjected to gas chromatography to determine the yield of
3-benzyl-1H-indole (3).
The optimization of dielectric heating temperature
and duration in the indolization step.
A microwave vial (10 ml) was charged with Pd2(dba)3
(4.58 mg, 0.05 mmol), CataCXium®PtB (5.80 mg,
0.02 mmol), bromobenzene (4) (158 mg, 1.00 mmol), allyl
alcohol (5) (65 mg, 1.1 mmol), Cy2NMe (215 mg,
1.10 mmol), and NMP (0.5 ml) and filled with nitrogen.
902

Chemistry of Heterocyclic Compounds 2016, 52(11), 897–903
24. Tietze, L. F. Chem. Rev. 1996, 96, 115.
The microwave vial was placed in the microwave reactor
and the vial was irradiated at 70°C temperature for 10 min.
After cooling to room temperature, phenylhydrazine (2)
(216 mg, 1.00 mmol) was added, the microwave vial was
placed again in the microwave reactor at various
temperatures for the times indicated (Table 6). For deter-
mining the yield after cooling to room temperature,
n-dodecane (100 μl) was added as a GC standard. A 20 μl
of the reaction mixture was filtered with THF (1.5 ml)
through a short plug of silica gel (ca. 4 × 15 mm) into a GC
vial and analyzed by gas chromatography to determine the
yield of 3-benzyl-1H-indole (3).
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