Convenient and scalable process for the preparation of indole via raney nickel-catalyzed hydrogenation and ring closure

Article abstract of DOI:10.1080/00397911.2010.495828

An efficient and practical method for the synthesis of indole as a key starting material for many useful chemicals is described. Using 2-nitrotoluene as starting material, hydroxymethylation with formaldehyde under alkaline conditions gave 2-(2-nitrophenyl) ethanol on a large scale. Raney Ni catalyst was used for both reduction of the nitro group as well as for the indole formation. The overall yield was 78% from 2-nitrotoluene. Copyright

Full text of DOI:10.1080/00397911.2010.495828

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Convenient and Scalable Process for
the Preparation of Indole via Raney
Nickel–Catalyzed Hydrogenation and Ring
Closure
a
b
b
b
Xianghai Guo , Zhiliang Peng , Shende Jiang & Jiaxiang Shen
a
Key Laboratory of Systems Bioengineering, Ministry of Education
and Department of Pharmaceutical Engineering, School of Chemical
Engineering and Technology, Tianjin University, Tianjin, China
b
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin, China
Available online: 20 May 2011
To cite this article: Xianghai Guo, Zhiliang Peng, Shende Jiang & Jiaxiang Shen (2011): Convenient
and Scalable Process for the Preparation of Indole via Raney Nickel–Catalyzed Hydrogenation and Ring
Closure, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 41:14, 2044-2052
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1
Synthetic Communications , 41: 2044–2052, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.495828
CONVENIENT AND SCALABLE PROCESS FOR THE
PREPARATION OF INDOLE VIA RANEY NICKEL–
CATALYZED HYDROGENATION AND RING CLOSURE
1
Xianghai Guo, Zhiliang Peng, Shende Jiang, and
2
2
2
Jiaxiang Shen
1
Key Laboratory of Systems Bioengineering, Ministry of Education and
Department of Pharmaceutical Engineering, School of Chemical Engineering
and Technology, Tianjin University, Tianjin, China
2
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin, China
GRAPHICAL ABSTRACT
Abstract An efficient and practical method for the synthesis of indole as a key starting
material for many useful chemicals is described. Using 2-nitrotoluene as starting material,
hydroxymethylation with formaldehyde under alkaline conditions gave 2-(2-nitrophenyl)
ethanol on a large scale. Raney Ni catalyst was used for both reduction of the nitro group
as well as for the indole formation. The overall yield was 78% from 2-nitrotoluene.
Keywords Indole synthesis; 2-nitrotoluene; Raney Ni
INTRODUCTION
Indole (4) is widely used for the syntheses of pharmaceuticals, agrochemicals,
[
1–3]
perfumes, dyes, and additives to foods and feed stocks.
obtained by distillation from tar, the method suffered from low indole content
usually 0.2%) and increasing energy cost. Therefore, facile and economical syntheses
of indole are intensively pursued. There have been papers dealing with indole ring
Although indole could be
(
[
4–10]
syntheses, but only a few are of industrial significance. According to our knowl-
[
edge, three methods are currently being used to produce indole: from aniline,
and 2-ethylaniline.
Unfortunately, there are some problems with present indole syntheses. Prep-
aration of indole from 2-ethylaniline involves high temperatures (usually 600 C)
11–13]
[14–16]
[17–23]
2
-methylaniline,
ꢀ
Received April 20, 2010.
Address correspondence to Xianghai Guo, Key Laboratory of Systems Bioengineering, Ministry of
Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and
Technology, Tianjin University, Tianjin 300072, China. E-mail: Guoxh@tju.edu.cn
2
044

CONVENIENT, SCALABLE PROCESS FOR INDOLES
2045
and expensive platinum catalyst, and the yield and selectivity are poor. Synthesis of
ꢀ
indole from 2-methylaniline employs temperatures as high as 350 C, and lots of
thick polymer are produced in the process, which is difficult to handle and exerts
a huge burden on environment. Indole synthesis from aniline and glycol developed
[11]
by Mitsui Toatsu Chemicals in 1980s is a good method and deserves further devel-
opment, but the efforts are compromised by severe reaction conditions, nonstoichio-
metric molar ratio of aniline to glycol (usually 7–10:1), poor selectivity, and short
catalyst life. We have now developed a new process that was successfully implemen-
ted to produce kilogram quantities of indole and is efficient and cost-effective. The
details of our development work are described herein.
RESULTS AND DISCUSSION
At the beginning of our work, we wanted to take advantage of the superfluous
supply of 2-nitroethylbenzene (1), a by-product from the production of chloram-
[
23,24]
phenicol.
We presumed that functionalization of the ethyl side chain on the
benzene ring might help to moderate the cyclization temperature and consequently
increase the selectivity of indole. Upon this assumption, a route to indole
(Scheme 1) was designed. Starting from 2-nitroethylbenzene, a conventional sequence
of oxidation and reduction was expected to give a good yield of 2-(1-hydroxyethyl)-
aniline (3), which was then subjected to indole synthesis. However, experimental
results from every step fell short of our expectations, and the last step to indole 4 gave
a yield of only 19%.
We then changed our starting material to 2-nitrotoluene (5), and hydroxy-
methylation with paraformaldehyde under alkaline conditions gave 2-(2-nitrophenyl)
[25,26]
ethanol (6) (Scheme 2).
In this study, we used Raney Ni catalyst both for
reduction of the nitro group as well as for the indole production in the last step.
The overall yield for the three consecutive steps came as 78% based on 2-nitrotoluene.
Preparation of 2-(2-Nitrophenyl)ethanol 6
Step 1 involved base-catalyzed condensation of 2-nitrotoluene and paraformal-
dehyde. The main by-product is the diol 8 (Scheme 3). Different catalysts were used
[25,27–31]
in this reaction,
and some catalysts are strongly basic anion exchange resins
Scheme 1. Synthesis of indole from 2-nitroethylbenzene.

2046
X. GUO ET AL.
Scheme 2. Synthesis of indole from 2-nitrotoluene.
(
(
Amberlite IRA-401, IRA-900 and IRA-900C), but no exceptional result came out
Table 1). It was decided that a 20% aqueous NaOH solution, which exhibited better
balance among yield, selectivity, and economy, was the most preferable catalyst for
this study.
The effect that the reaction temperature had on the hydroxymethylation is
shown in Table 2, where a maximum yield of 6 was acheived at the temperature
ꢀ
ꢀ
of 50 C. The relatively narrow temperature range (40–60 C) was used, because
beyond this temperature range the rate of hydroxymethylation was too low or
decreased selectivity was observed.
The effect of molar ratio of formaldehyde to 5 was studied over the range of
.2–0.6 under the standard reaction conditions. The results are shown in Table 3.
0
As seen from these data, a molar ratio of 0.4–0.5 gave the best results. Further
increase of molar ratio of formaldehyde to 2-nitrotoluene resulted in a rapid increase
of by-product 8 without substantially improving the yield.
We were frustrated that the yield of 2-(2-nitrophenyl)ethanol 6 could not be
improved under the aforementioned conditions. Most of our results gave yields of
6
around 30%. In the process of optimization, we noticed a gradual reduction of
alkalinity during the hydroxymethylation reaction, which could be explained by for-
maldehyde undergoing a Cannizzaro reaction to form formic acid, which neutralized
the catalyst NaOH. It suggested to us that gradual disappearance of the catalyst
might be the reason that we cannot achieve a better result. An experiment was set
to explain this question. After 1.5 h of reaction under standard conditions, when
pH changed from 9.4 to 7.4, a second batch of catalyst was added to the reaction
mixture, and the reaction was continued for another 1.5 h. High-Performance Liquid
Chromatographic (HPLC) analysis showed that contents of 6 and 8 in the reaction
mixture were 35.8% and 8.5% respectively. Although the yield of 6 was increased from
3
1.6% to 35.8%, the content of 8 was increased more quickly from 1.8% to 8.5%.
Although the yield of 2-(2-nitrophenyl)ethanol 6 was hard to improve, the sel-
ectivity and recycling of starting materials by distillation in vacuo endow this method
with practical value. In fact, we had scaled up this preparation to produce 38.4 kg of
6 in a yield of 87% (based on reacted 5). The decomposition temperature of 6 was
ꢀ
about 190 C under reduced pressure (<1 mmHg).
Scheme 3. Hydroxymethylation of 2-nitrotoluene.

CONVENIENT, SCALABLE PROCESS FOR INDOLES
2047
a
Table 1. Catalysts for hydroxymethylation of 2-nitrotoluene
b
Entry
Catalysts
Catalyst=5 (mol=mol) Area (%) 6 [8]
1
2
3
4
5
6
Triton B, 40% w=w in methanol
PhONa
0.011
0.017
0.029
0.013
0.025
0.025
0.027
0.025
0.025
31.2 [2.1]
25.3 [3.5]
29.8 [3.1]
29.6 [2.8]
36.4 [3.3]
30.8 [2.2]
4.2
3 2
CH CH ONa
w(NaOH) ¼ 10% (in methanol)
NaOH
w(NaOH) ¼ 20% (in water)
Amberlite IRA-401
Amberlite IRA-900
Amberlite IRA-900C
c
d
d
d
7
c
8
c
7.4
3.9
9
a
Reaction conditions: 13.7 g (0.1 mol) 5, 20 mL DMSO, 1.5 g (0.05 mol)
ꢀ
paraformaldehyde, reaction temperature 60 C.
b
Area percentage by HPLC.
Reaction temperatures were 40 C.
c
ꢀ
d
Estimated by 70% total exchange capacity.
Preparation of 2-(2-Aminophenyl)ethanol 7
Two methods were reported for the reduction of 2-(2-nitrophenyl)ethanol 6 to
-(2-aminophenyl)ethanol 7, including the Zn=CaCl =H O system and hydrogen-
2
ation under Rh=C or Pd=C.
2
2
[10a]
The former method was not desirable because of
environmental and economic factors. The latter method was reasonable if an effec-
tive and economical catalyst was found with adequate reuse. The Rh=C catalyst was
excluded because of the high cost of catalyst, so only commonly used Pd=C (5%,
1
0%) and Pt=C (3%) catalysts were tested under atmospheric hydrogen. It turned
out that Pd=C was not an effective catalyst in this reaction, possibly because of
strong hydroxyl (or amino) absoption and poisoning on palladium surface. Pt=C
exhibited only low activity in this condition. After 7 h of reaction under Pt=C,
by-product 7 was formed in a yield of 15%. Studies on catalytic hydrogenation with
Raney Ni turned out to be successful. Simple optimized experiments showed the
ꢀ
reaction could best be carried out under conditions of 110 C and 2 MPa hydrogen
pressure, and it could be carried out in liquid paraffin or even without a solvent as
long as reaction heat was removed from system continuously. The activity of Raney
nickle was rather stable (Table 4) under these conditions. It was clear from this stab-
ility data that reaction time was prolonged with each run, which could be explained
a
Table 2. Temperature screen for hydroxymethylation
ꢀ
b
Entry
Temperature ( C)
Reaction time (h)
Area (%) 6 [8]
1
2
3
40
50
60
3.0
2.0
2.0
29.6 [1.6]
31.6 [1.8]
30.8 [2.2]
a
Reaction conditions: 13.7 g (0.1 mol) 5, 20 mL DMSO, 1.5 g
0.05 mol) paraformaldehyde, 0.5 g 20 w% NaOH aqueous solution.
(
b
Area percentage by HPLC.

2048
X. GUO ET AL.
a
Table 3. Molar ratio for hydroxymethylation
Molar ratios
(formaldehyde to 5)
Reaction
time (h)
b
Entry
Area (%) 6 [8]
1
2
3
4
0.2
0.4
0.5
0.6
1.5
1.5
2.0
1.6
17.0 [1.9]
28.5 [2.9]
31.6 [1.8]
34.1 [6.1]
a
Reaction conditions: 13.7 g (0.1 mol) 5, 20 mL DMSO, reaction
ꢀ
temperature 50 C, 0.5 g 20 w% NaOH aqueous solution.
b
Area percentage by HPLC.
by catalyst granules’ fragmentation under strong mechanical stirring and loss in
separation. In general, Raney Ni worked well in this reaction.
Preparation of Indole 4 (Scheme 2, Step 3)
It is known that 2-(2-aminophenyl)ethanol can be converted into indole by
hydrogenation in the presence of a catalyst such as homogeneous ruthenium
[
25]
[26]
[32]
catalyst, Raney nickel, and Cu=Al O . These reactions proceed readily with-
2
3
out the aid of a hydrogen acceptor, and indole is afforded in excellent yields with
spontaneous hydrogen evolution. Addition of transitional metals (with the exception
of ruthenium) could enhance the Raney nickel activity, and palladium showed the
greatest effect. Further addition of triphenyl phosphine enhanced the effect even
more. Addition of triphenyl phosphine to the Raney Ni-Rh system showed the opti-
mal results. However, it had no effect at all on single Raney nickel system (Table 5). It
occurred to us that in using Raney nickel as catalyst for indole formation, the reaction
might have proceeded first by dehydrogenation of the side chain ethanol group to
form an aldehyde and then by joining with the amino group to form the ring.
It was observed that when Raney nickel was used as catalyst for this reaction,
an unexpected by-product was produced (Scheme 4). We isolated this by-product,
and further purification by chromatography gave this by-product as yellow solid
0
in a yield of 15%, whose structure was assigned unambiguously as 2,3 -biindolyl 9
a
Table 4. Stability experiment (recycle) of Raney Ni catalyst
Run
Reaction time (h)
Weight of product 7 (g)
Yield (%)
1
2
3
4
5
6
7
12.2
14.5
14.2
15.7
16.3
16.9
18.5
977
991
97.0
98.4
99.2
99.6
99.5
99.3
99.0
999
1003
1002
1000
997
a
Reaction conditions: 1228 g (1.0 L) 2-(2-nitrophenyl)ethanol 6, reaction
ꢀ
temperature 110 C, hydrogen pressure 2 MPa, 62.0 g Raney Ni (recycled),
no solvent. Reaction time was calculated at the end of reaction.

CONVENIENT, SCALABLE PROCESS FOR INDOLES
Table 5. Effects of addition of transition metals and PPh
2049
3
Transition metal
PPh
3
Time of cyclization (h)
N=A
N=A
PPh
N=A
PPh
N=A
PPh
N=A
PPh
5.0
5.0
3
RuCl
3
3
ꢁ nH
ꢁ 3H
2
O
O
>5.0
1.75
2.75
0.5
3
RhCl
2
3
Pd(CH COO)
3
2
1.75
1.25
3
0
Scheme 4. Formation of 2,3 -diindolyl 9.
1 13
through its H NMR, C NMR, and Infrared (IR) spectra.
[33]
We now know the
formation of 9 could be prevented by removing oxygen from the reaction system.
0
This transformation can be a useful way to synthesize 2,3 -biindolyl and deserves
further investigation (Scheme 4). Furthermore, it was observed that Raney nickel
maintained a stable activity after more than 20 runs in this reaction.
EXPERIMENTAL
IR spectra (KBr pellets) were recorded on a Bio-Rad FTS 135 spectrophot-
1
ometer. H and C NMR spectra were recorded on a Bruker AV400, AV500, or
13
Mercury 300-MHz instrument. Chemical shifts (d) are reported in parts per million
(ppm) relative to tetramethylsilane (TMS) used as internal standard. Organic
solvents were purified by standard methods when necessary. Thin-layer chromato-
graphy (TLC) was performed on glass sheets coated with silica gel (type GF254,
Qingdao Haiyang). Flash-column chromatography was carried out using silica gel
(200–300) mesh. Pd on carbon (5% Pd, 10% Pd) and Pt on carbon (3% Pt) were
purchased. Raney nickel was prepared according to literature methods.
[
34]
Preparation of 2-(2-Nitrophenyl)ethanol 6
A 500-L reactor with internal cooling was charged with 120.0 kg 2-nitrotolu-
ene, 200.0 kg dimethyl sulfoxide, 13.1 kg paraformaldehyde, and 4.4 kg 20% aqueous
ꢀ
sodium hydroxide. The contents were stirred for 1 h at 50 C (reaction is exothermic),
affording a dark brown solution. The reaction was quenched with concentrated HCl
solution, and then 38.4 kg 2-(2-nitrophenyl)ethanol 6 (yellow thick oil, >99.5%
purity by area % HPLC) was obtained by distillation in vacuo. In the meantime,
8
3.5 kg 2-nitrotoluene were recovered. The yield of 2-(2-nitrophenyl)ethanol was

2050
X. GUO ET AL.
8
1
1
6.7% based on recovered starting material. IR (KBr): 3360, 2945, 2882, 1524, 1348,
ꢂ1 13
043, 742 cm
;
C NMR (100 MHz, CDCl ) d: 149.90, 133.83, 133.02, 132.84,
3
1
27.65, 124.88, 62.78, 36.17; H NMR (400 MHz, CDCl ) d: 7.92–7.90 (dd,
3
J ¼ 1.2, 8 Hz, 1H, ArH), 7.56–7.52 (dt, J ¼ 1.2, 7.6 Hz, 1H, ArH), 7.43–7.34 (m,
2
1
H, ArH), 3.95–3.91 (t, J ¼ 6.4 Hz, 2H, CH ), 3.17–3.14 (t, J ¼ 6.4 Hz, 2H, CH ),
2
2
.86 (br s, 1H, OH).
Preparation of 2-(2-Aminophenyl)ethanol 7
To a 5-L reactor, 446 g 2-(2-nitrophenyl)ethanol, 2000 mL liquid paraffin, and
ꢀ
2
8 g Raney Ni were added. The solution was stirred over a period of 1.5 h at 110 C
ꢀ
under 2 MPa hydrogen pressure. The mixture was cooled to 20 C, and catalyst was
filtered off. The filtrate was separated by liquid separation and then dried over anhy-
drous MgSO to afford burgundy 2-(2-aminophenyl)ethanol 7 354 g (yield 97%). IR
4
ꢂ1 13
C NMR (100 MHz,
(
KBr): 3361, 3252, 2943, 2879, 1625, 1498, 1043, 753 cm
CDCl ) d: 144.87, 130.49, 127.54, 124.38, 119.17, 116.23, 63.05, 34.66; H NMR
;
1
3
(
400 MHz, CDCl ) d: 7.07–7.06 (dd, J ¼ 1.2, 3.2 Hz, 2H, ArH), 6.79–6.75 (dt,
3
J ¼ 1.2, 7.6 Hz, 1H, ArH), 6.79–6.75 (d, J ¼ 7.6 Hz, 1H, ArH), 3.90–3.87 (t, J ¼ 6 Hz,
H, CH ), 3.17 (br s, 3H, NH and OH), 2.80–2.77 (t, J ¼ 6 Hz, 2H, CH ).
2
2
2
2
Preparation of Indole 4
To a 250-mL, four-necked flask equipped with thermometer, Dean–Stark trap,
condenser, and mechanic stirrer, 80 g 2-(2-aminophenyl)ethanol, 80 mL liquid paraf-
ꢀ
fin, and 10 g Raney Ni were charged. The mixture was stirred for 5 h at 220 C under
nitrogen protection. Water (16 g) was collected from the Dean–Stark trap. The mix-
ꢀ
ture was cooled to 80 C, and Raney nickel was filtered off. The filtrate was distilled
in vacuo to afford 60.3 g indole as a white crystalline solid (yield 88.3%, 99.8% purity
ꢂ1
by area % HPLC). IR (KBr): 3402, 1456, 1415, 1337, 1247, 1090, 1059, 747, 725 cm
1
;
3
C NMR (75 MHz, CDCl ) d: 136.04, 128.10, 124.47, 122.24, 121.02, 120.10, 111.34,
02.83; H NMR (300 MHz, CDCl ) d: 7.98 (br s, 1H, NH), 7.66–7.63 (dd, J ¼ 1.2,
3
1
1
1
3
0 Hz, 1H), 7.35–7.33 (d, J ¼ 10.8 Hz, 1H), 7.22–7.09 (m, 3H), 6.55–6.53 (m, 1H).
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9: IR (KBr): 3399, 1618, 1594, 1456, 1429, 1308, 1104, 775, 745 cm
;
C NMR
(
1
125 MHz, DMSO) d: 136.65, 135.99, 134.13, 129.21, 124.64, 123.15, 121.72, 120.29,
1
19.75, 119.62, 119.06, 118.80, 111.93, 110.41, 108.44, 96.79; H NMR (500 MHz, DMSO)
d: 11.38 (s, 1 H, NH), 11.18 (s, 1 H, NH), 8.00–7.99 (d, J ¼ 7.5 Hz, 1 H), 7.86–7.85

2052
X. GUO ET AL.
(
(
(
d, J ¼ 2.5 Hz, 1H), 7.50–7.46 (q, J ¼ 7.5 Hz, 2H), 7.36–7.34 (d, J ¼ 2.5 Hz, 1H), 7.19–7.13
m, 2 H), 7.04–7.01 (t, J ¼ 7.5 Hz, 1H), 6.97–6.94 (t, J ¼ 7.5 Hz, 1H), 6.75–6.75
d, J ¼ 2.0 Hz, 1H).
3
4. Dominguez, X.; Lopez, I.; Franco, R. Simple preparation of a very active Raney nickel
catalyst. J. Org. Chem. 1961, 26, 1625.