An expeditious and environmentally benign methodology for the synthesis of substituted indoles from cyclic enol ethers and enol lactones

Article abstract of DOI:10.1016/j.tetlet.2008.02.107

A simple and environmentally friendly method is developed for the synthesis of substituted indoles from commercially available aryl hydrazines and cyclic enol ethers with Montmorillonite-K10 as a heterogeneous catalyst. The catalyst is non-toxic, inexpensive and recyclable and the process is clean, high yielding and operationally simple.

Full text of DOI:10.1016/j.tetlet.2008.02.107

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3335–3340
An expeditious and environmentally benign methodology
for the synthesis of substituted indoles from cyclic enol
ethers and enol lactones
Pankajkumar R. Singh *, Mandar P. Surpur, Sachin B. Patil
Organic Chemistry Research Laboratory, University Institute of Chemical Technology, N. M. Parekh Marg, Matunga, Mumbai 400 019, India
Received 19 September 2007; revised 11 February 2008; accepted 18 February 2008
Available online 10 March 2008
Abstract
A simple and environmentally friendly method is developed for the synthesis of substituted indoles from commercially available
aryl hydrazines and cyclic enol ethers with Montmorillonite-K10 as a heterogeneous catalyst. The catalyst is non-toxic, inexpensive
and recyclable and the process is clean, high yielding and operationally simple.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Aryl hydrazine; Cyclic enol ether; Indole; Montmorillonite K-10
Indoles are an important class of compounds which
have attracted considerable interest in recent years due to
their therapeutic and pharmacological activities.1–3 Substi-
tuted indoles are sometimes referred to as ‘privileged struc-
tures’ due to their high affinity towards many receptors.4
For example, the neurotransmitter serotonin (5-hydroxy-
tryptamine) is involved in various physiological functions
such as appetite, sleep, body temperature and sexual
behaviour.5
Numerous serotonin-like compounds, such as sumatrip-
tan (1), avitriptan (2) and indomethacin (3) are well-known
anti-migraine and anti-infammatory drugs.6–8
NMe2
SO2NHMe
N
H
1
COOH
MeO
SO2NHMe
N
N
N
N
N
O
MeO
N
H
2
Cl
3
*
Corresponding author. Fax: +91 022 24145614.
E-mail address: singhpk20@yahoo.co.in (P. R. Singh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.107

3336
P. R. Singh et al. / Tetrahedron Letters 49 (2008) 3335–3340
OH
X
n
Mont.-K10
50% aq. DMAc
O
n
R2
R1
X
R1
R2
+
NH2.HCl
N
R
80 ºC
N
R
3a-3m
R1 = H, CH3, F, Cl,
Br, COOH, OCH3
n = 1,2 ; X= CH2, C=O
R2 = H, CH3
(R = PhCH2 when R2 = CH3 and X = CO, otherwise R = H)
Scheme 1.
Among the various approaches towards the synthesis of
indoles,9,10 the Fischer indole synthesis has maintained its
prominent role. Further, the Fischer indole reaction with
aldehydes or ketones often involves a two-step process,
that is, hydrazone formation followed by cyclization and
can result in low yields of products.11–13 The reaction con-
ditions range from warming with acetic acid to fusing with
ZnCl2, and refluxing with HCl/CH3COOH, and PPA.14–18
However, these catalysts are environmentally unfriendly,
hazardous or difficult to handle and are also required in
very large amounts (e.g., PPA in 8- to 9-fold excess by
weight, ZnCl2 in 3-fold excess).
geneous Brønsted acidic catalysts—silica, Amberlyst-15,
Amberlite-120, Indion-130, Montmorillonite K10 and
zeolites-HY at 80 °C in 50% N,N-dimethylacetamide
DMAc–H2O for 3 h (Table 1).
It was found that Montmorillonite K10 was superior to
all the other catalysts examined and gave a good yield of
product. When we tried the same reaction in water as
solvent, the product was obtained in only 50% yield. A
significant amount of by-product 4 was formed.19
OH
OH
OH
Campos has recently reported19 the synthesis of substi-
tuted indoles from cyclic enol ethers, used as aldehydes
equivalents, and enol lactones using 4% H2SO4 and
dimethylacetamide (DMAc) as a co-solvent.
N
H
N
H
4
Thus, the discovery of a new, inexpensive and environ-
mentally benign approach towards the synthesis of indoles
continues. The use of clays as catalysts has gained signifi-
cant interest in different areas of organic synthesis due to
their environmental compatibility combined with good
yields, reusability, non-corrosiveness, low cost, operational
simplicity and the selectivities that can be achieved.20–22
Thus, herein we report a convenient and practical one-
pot synthesis of 3-substituted indoles from commercially
available cyclic enol ethers or enol lactones and aryl hydr-
azines using Montmorillonite K10 clay as catalyst (Scheme
1).
In a purely aqueous system, the product and dihydro-
pyran were insoluble creating a highly concentrated
‘organic layer’ that resulted in increased formation of the
triol by-product 4. It was found that the addition of a
co-solvent to the reaction decreased the formation of by-
product to less than 5%. Encouraged by this result, we
investigated the scope of this reaction in other polar
solvents such as 50% aqueous acetonitrile, THF, DMF
and DMAc (Table 2).
It was found that the reaction proceeded smoothly and
gave an excellent 88% yield in 50% aq DMAc. To extend
the scope of the reaction and to generalize the procedure,
we investigated the reactions of a series of aryl hydrazine
hydrochlorides with enol ethers such as DHP and DHF
in the presence of Montmorillonite K10 at 80 °C in 50%
aqueous DMAc (Table 3).
In our preliminary study, the reaction of phenylhydr-
azine hydrochloride with dihydropyran (DHP) was selected
as a model reaction to test the activity of different hetero-
Table 1
Reaction of phenylhydrazine hydrochloride with dihydropyran in the
presence of various solid acidsa
Table 2
Effect of solvent on the reaction of phenylhydrazine hydrochloride with
dihydropyran in the presence of Mont. K10 at 80 °Ca
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
a
Silica
25
75
73
70
88
52
Entry
Solvent
Yieldb (%)
Amberlyst-15
Amberlite-120
Indion-130
Montmorillonite K10
Zeolite-HY
1
2
3
4
5
a
H2O
50
66
88
75
60
H2O–CH3CN (1:1)
H2O–N,N-DMAc (1:1)
H2O–DMF (1:1)
H2O–THF (1:1)
Phenylhydrazine hydrochloride: 5 mmol, dihydropyran: 5 mmol,
catalyst: 800 mg, solvent: H2O: N,N-DMAc (1:1 v/v) 15 mL, reaction
temperature 80 °C, 3 h.
Phenylhydrazine hydrochloride: 5 mmol, dihydropyran: 5 mmol,
Mont. K-10: 800 mg, 3 h, solvent: 15 mL.
b
b
Isolated yield.
Isolated yield.

P. R. Singh et al. / Tetrahedron Letters 49 (2008) 3335–3340
3337
Table 3
Synthesis of 3-substituted indoles from cyclic enol ethers or enol lactones using Mont. K10a
Entry
Aryl hydrazine
Enol ether/enol lactone
Time (h)
Product
Yieldb (%)
OH
O
1
3
88
N
H
NH2.HCl
NH
3a
OH
O
2
1.5
90
N
NH2.HCl
H
NH
3b
R1
OH
O
3
2
70 3c:3d (55:45)c
NH2.HCl
N
R2
NH
H
3c: R1= H, R2= Me
3d: R1= Me, R2= H
OH
F
F
O
O
4
5
1.5
2.5
83
68
N
H
NH2.HCl
NH
3e
OH
Cl
Cl
N
H
NH2.HCl
NH
3f
OH
Br
Br
O
O
O
6
7
8
9
2.5
1.5
3
70
80
65
N
H
NH2.HCl
NH
3g
OH
MeO
MeO
N
NH2.HCl
H
NH
3h
OH
HO2C
HO2C
N
NH2.HCl
H
NH
3i
OH
O
2
75
N
H
NH2.HCl
NH
3j
(continued on next page)

3338
P. R. Singh et al. / Tetrahedron Letters 49 (2008) 3335–3340
Table 3 (continued)
Entry
Aryl hydrazine
Enol ether/enol lactone
Time (h)
Product
Yieldb (%)
F
OH
F
O
10
2
68
N
NH2.HCl
H
NH
3k
N
Me
N
O
O
11
3
88
NH2.HCl
NH
O
3l
CO2H
Me
O
O
12
3
65
NH2
Ph
N
N
CH2Ph
3m
a
All reactions were run in 50% aq DMAc at 80 °C.
Isolated and unoptimised yields.
Determined by 1H NMR spectroscopy.
b
c
The reaction with m-tolylhydrazine hydrochloride led to
can be hydrated easily in the presence of the acid catalyst
in water to give 1a25,26 which then undergoes facile ring
opening in water to produce 1b. The condensation reaction
between phenylhydrazine and 1b generates hydrazone 1c,
which subsequently undergoes a 3,3-sigmatropic shift
followed by a further rearrangement to give product 3a.
The catalyst was recovered by filtration, washed with
ethyl acetate, dried and recycled for use in subsequent reac-
tions without significant loss in activity. For example, the
reaction of phenylhydrazine hydrochloride and DHP under
the present reaction conditions afforded, 86%, 88% and
83% yields of the corresponding indole over three cycles.
In summary, we have developed a simple and general
method for the synthesis of substituted indoles, which
offers several advantages including good to excellent yields,
the formation of a 55:45 mixture of regioisomeric indoles
(entry 3). When the same procedure was employed on
angelica lactone, the cyclic acyl hydrazone (3l) was the only
observed product.23 Formation of a cyclic acyl hydrazone
could be possibly due to cyclization of acid hydrazone 5
rather than the expected 3,3-sigmatropic rearrangement
to afford 2-methylindole 3-acetic acid (6) (Scheme 2). This
could be successfully avoided by protecting the 1-NH of
phenyl hydrazine with benzyl bromide24 and subjecting
N-benzyl phenylhydrazine to the same conditions, which
afforded N-benzyl-2-methylindole acetic acid (3m) in 65%
yield.
A tentative mechanism to rationalize the formation of
the products is shown in Scheme 3. The cyclic enol ether
O
N
O
Mont. K10
N
N
+
N
H
50% aq. DMAc
80 ºC
NHNH2.HCl
O
HOOC
3l
5
COOH
N
H
6
Scheme 2.

P. R. Singh et al. / Tetrahedron Letters 49 (2008) 3335–3340
3339
CHO
1b
OH
O
HO
O
+
1a
NHNH2
OH
H
OH
H
(3,3-shift)
NH
NH
OH
NH
N
N
N
H
H
1c
OH
OH
OH
H
NH2
..
NH2
NH
N
H
-NH3
N
H
3a
Scheme 3.
use of an inexpensive and recyclable catalyst and cleaner
reaction profiles.
References and notes
1. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York,
1970.
Typical experimental procedure: To a mixture of phenyl-
hydrazine hydrochloride (5 mmol) and Montmorillonite K-
10 (800 mg) in 50% aqueous DMAc (15 mL) at 80 °C was
added dihydropyran (5 mmol) dropwise over 1 min. The
resultant reaction mixture was stirred at 80 °C or 3 h.
The catalyst was then filtered off and the filtrate was
extracted with ethyl acetate (5 Â 2 mL). The combined
organic layer was washed with water and concentrated.
The crude product was purified by flash column
chromatography (silica gel: 60–120 mesh and eluted with
20% ethyl acetate–petroleum-ether). All the products were
fully characterized by comparison with authentic samples19
and by elemental analysis and spectroscopic methods.
Representative data for compound 3a, 3-(1H-indol-3-yl)
propan-1-ol; IR (neat) 3544, 3412, 2937, 1458, 1339, 1229,
1054, 743 cmÀ1; 1H NMR (300 MHz, CDCl3): d = 8.05 (br
s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.26 (d, 1H, J = 7.8 Hz),
7.15 (t, 1H, J = 7.5 Hz), 7.08 (t, 1H, J = 7.2 Hz), 6.8 (s,
1H), 3.65 (t, 2H, J = 6.4 Hz), 2.8 (t, 2H, J = 7.5 Hz), 2.01
(m, 2H); MS (EI, 70 eV) m/z, 175 (M+), 130 (100), 77
(15). Anal. Calcd for C11H13NO: Calcd: C, 75.43; H,
7.43; N, 8.00. Found, C, 75.40; H, 7.45; N, 8.03.
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Acknowledgement
17. Brodfuehrer, P. R.; Chen, B.; Sattelberg, T. R., Sr.; Smith, P. R.;
Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G. J. Org. Chem.
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P.R.S. thanks the CSIR, New Delhi, for the award of a
fellowship.

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P. R. Singh et al. / Tetrahedron Letters 49 (2008) 3335–3340
18. Nenajdenko, V. G.; Zakurdaev, E. P.; Prusov, E. V.; Balenkova, E. S.
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